Unsaturated amino acids

The invention relates to unsaturated amino acids of the formula I ##STR1## in which R.sup.1 represents hydroxy or etherified hydroxy, R.sup.2 represents hydrogen, alkyl, hydroxy or etherified hydroxy, R.sup.3 represents hydrogen, alkyl, haloalkyl, hydroxyalkyl, lower alkoxyalkyl, arylalkyl, lower alkenyl, halogen or aryl, R.sup.4 represents hydrogen, alkyl or aryl, R.sup.5 represents hydrogen or alkyl, R.sup.6 represents carboxy or esterified or amidated carboxy, R.sup.7 represents amino or amino substituted by alkyl or acyl, A represents unsubstituted or alkyl-substituted .alpha.,.omega.-alkylene having from 1 to 3 carbon atoms or represents a bond, and B represents methylene or a bond, with the proviso that A is other than a bond when B represents a bond, and salts thereof. They can be manufactured, for example, in accordance with the Michaelis-Arbuzov reaction and can be used as pharmacologically active substances.

The invention relates to novel unsaturated amino acids, salts thereof, 
processes for the manufacture of these novel substances, pharmaceutical 
preparations containing these substances and the use of these substances 
and of preparations containing them. 
The compounds according to the invention are compounds of the formula I 
##STR2## 
in which R.sup.1 represents hydroxy or etherified hydroxy, R.sup.2 
represents hydrogen, alkyl, hydroxy or etherified hydroxy, R.sup.3 
represents hydrogen, alkyl, haloalkyl, hydroxyalkyl, lower alkoxyalkyl, 
arylalkyl, lower alkenyl, halogen or aryl, R.sup.4 represents hydrogen, 
alkyl or aryl, R.sup.5 represents hydrogen or alkyl, R.sup.6 represents 
carboxy or esterified or amidated carboxy, R.sup.7 represents amino or 
amino substituted by alkyl, aralkyl or acyl, A represents unsubstituted or 
alkyl-substituted .alpha.,.omega.-alkylene having from 1 to 3 carbon atoms 
or represents a bond, and B represents methylene or a bond, with the 
proviso that A is other than a bond when B represents a bond, and salts 
thereof. 
The compounds of the formula I contain at least one chiral centre and may 
be in the form of enantiomers or enantiomeric mixtures, such as racemates, 
and if they contain more than one chiral centre, they may also be in the 
form of diastereoisomers or diastereoisomeric mixtures. 
The carbon-carbon double bond of the compounds according to the invention 
is in the trans-configuration in relation to R.sup.3 and R.sup.4, or in 
relation to A and B, that is to say the compounds of the formula I are 
compounds of the E-series. 
Compounds of the formula I in which R.sup.2 represents hydrogen are 
phosphonous acids, those in which R.sup.2 represents alkyl are phosphinic 
acids, and those in which R.sup.2 represents hydroxy are phosphonic acids. 
In the names of the compounds of the formula I that are to be regarded as 
substituted carboxylic acids the prefixes "phosphino" (R.sup.2 represents 
hydrogen), "phosphonyl" (R.sup.2 represents alkyl) and "phosphono" 
(R.sup.2 represents hydroxy) are used. Within the scope of this invention, 
alkyl is a saturated aliphatic hydrocarbon radical having, for example, up 
to 12 carbon atoms, but especially having up to 8 carbon atoms, the latter 
range also being represented by the term lower alkyl. 
.alpha.,.omega.-Alkylene having from 1 to 3 carbon atoms is methylene, 
1,2-ethylene or 1,3-propylene .alpha.,.omega.-Alkylene substituted by 
alkyl is substituted at any position. Thus, methylene substituted by alkyl 
is, for example, 1,1-ethylene, 1,1-butylene or 1,1-octylene, 1,2-ethylene 
substituted by alkyl is, for example, 1,2-propylene, 1,2-butylene, 
2,3-butylene, 1,2-pentylene or 1,2-nonylene, and 1,3-propylene substituted 
by alkyl is, for example, 1,3-butylene, 1,3-pentylene or 1,3-decylene. 
Amino R.sup.7 substituted by acyl may be acylamino or diacylamino. Amino 
R.sup.7 substituted by alkyl is mono- or di-lower alkylamino. 
In a corresponding acylamino group acyl is, for example, the acyl radical 
of an organic acid having, for example, up to 18 carbon atoms, especially 
an alkanecarboxylic acid optionally substituted, for example, by halogen, 
amino or phenyl, or benzoic acid optionally substituted, for example, by 
halogen, lower alkoxy or nitro, or of a carbonic acid semiester. Such acyl 
groups are, for example, lower alkanoyl, such as formyl, acetyl or 
propionyl, halo-lower alkanoyl, such as 2-haloacetyl, especially 
2-fluoro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloro-acetyl, 
aroyl, such as optionally substituted benzoyl, for example benzoyl, 
halobenzoyl, such as 4-chlorobenzoyl, lower alkoxybenzoyl, such as 
4-methoxybenzoyl, or nitrobenzoyl, such as 4-nitrobenzoyl. Also suitable 
is especially lower alkenyloxycarbonyl, for example allyloxycarbonyl, or 
lower alkoxycarbonyl optionally substituted in the 1- or 2-position, such 
as lower alkoxycarbonyl, for example methoxy- or ethoxy-carbonyl, 
optionally substituted benzyloxycarbonyl, for example benzyloxycarbonyl or 
4-nitrobenzyloxycarbonyl, or aroylmethoxycarbonyl in which the aroyl group 
is benzoyl optionally substituted, for example, by halogen, such as 
bromine, for example phenacyloxycarbonyl or bromophenacyloxycarbonyl. 
In a corresponding acylamino group acyl may represent especially 
alkanoylamino substituted by amino and/or by phenyl, carbamoyl, carboxy, 
imidazolyl, lower alkylthio, tetrahydropyrrolyl, hydroxy, indolyl or 
hydroxyphenyl, so that the term includes, for example, the acyl radicals 
of amino acids, for example naturally occurring amino acids, such as 
alanyl, asparaginyl, aspartyl, glycyl, histidyl, isoleucyl, leucyl, lysyl, 
methionyl, phenylalanyl, prolyl, seryl, threonyl, tryptophyl, tyrosyl or 
valyl; also included thereby are the acyl radicals of oligopeptides, for 
example di- or tri-peptides, such as oligopeptides of alanine, asparagine 
or aspartic acid. 
In a diacylamino group diacyl is, for example, two acyl radicals as defined 
hereinbefore, or is, for example, the acyl radical of an organic 
dicarboxylic acid having, for example, up to 12 carbon atoms, especially a 
corresponding aromatic dicarboxylic acid, such as phthalic acid. Such a 
group is especially phthalimido. Esterified carboxy is, for example, 
carboxy esterified by an aliphatic or araliphatic alcohol, such as an 
unsubstituted or substituted lower alkanol or phenyl-lower alkanol, such 
as corresponding lower alkoxy- or phenyl-lower alkoxycarbonyl. Esterified 
carboxy is preferably pharmaceutically acceptable esterified carboxy, such 
as, for example, esterified carboxy that can be converted into carboxy 
under physiological conditions. These esters of formula I may also be 
called prodrug esters. 
Carboxy esterified in a pharmaceutically acceptable manner is, for example, 
lower alkoxycarbonyl; lower alkoxycarbonyl substituted in a position 
higher than the .alpha.-position by amino, by mono- or di-lower alkylamino 
or by hydroxy; lower alkoxycarbonyl substituted by carboxy, for example 
.alpha.-carboxy-substituted lower alkoxycarbonyl; lower alkoxycarbonyl 
substituted by lower alkoxycarbonyl, for example .alpha.-lower 
alkoxycarbonyl-substituted lower alkoxycarbonyl, aryl-lower 
alkoxycarbonyl, for example unsubstituted or substituted 
benzyloxycarbonyl, or pyridylmethoxycarbonyl; lower 
alkanoyloxy-substituted methoxycarbonyl, for example 
pivaloyloxymethoxycarbonyl; lower alkoxymethoxycarbonyl substituted by 
lower alkanoyloxy or by lower alkoxy; bicyclo[2.2.1]heptyloxycarbonyl 
substituted methoxycarbonyl, such as bornyloxycarbonylmethoxycarbonyl; 
3-phthalidoxycarbonyl; 3-phthalidoxycarbonyl substituted by lower alkyl, 
lower alkoxy or by halogen; or lower alkoxycarbonyloxy-lower 
alkoxycarbonyl, for example 1-(methoxy- or 
ethoxy-carbonyloxy)-ethoxycarbonyl. 
Especially preferred prodrug esters are, for example, lower alkyl esters 
having up to four carbon atoms, such as, for example, butyl or ethyl 
esters, lower alkanoyloxymethyl esters, such as, for example, 
pivaloyloxymethyl ester, lower alkyl esters that have from two to four 
carbon atoms in each lower alkyl group and are substituted in a position 
higher than the .alpha.-position by di-lower alkylamino, such as, for 
example, 2-diethylaminoethyl ester, and also pyridylmethyl esters, such as 
3-pyridylmethyl ester. 
In amidated carboxy the amino group is, for example, amino that is 
unsubstituted, monosubstituted by hydroxy, or mono-or di-substituted by 
aliphatic radicals, such as amino, hydroxyamino, mono- or di-lower 
alkylamino or lower alkyleneamino having from 5 to 7 ring members. 
Preferably, amidated carboxy is pharmaceutically acceptable amidated 
carboxy, such as, for example, amidated carboxy that can be converted into 
carboxy under physiological conditions. Preferred pharmaceutically 
acceptable amides are compounds of formula I in which R.sup.6 is 
carbamoyl, lower alkylcarbamoyl, for example ethylcarbamoyl, di-lower 
alkylcarbamoyl, for example diethylcarbamoyl, or in the form of 
N-(di-lower alkylamino)-lower alkylcarbamoyl, for example 
N-(2-diethylaminoethyl)carbamoyl or (3-diethylaminopropyl)carbamoyl. 
Etherified hydroxy is, for example, hydroxy etherified by an aliphatic 
alcohol, such as hydroxy etherified by a lower alkanol, lower alkenol or 
lower alkynol each optionally substituted by halogen or, in a position 
higher than the .alpha.-position, by hydroxy, oxo, lower alkoxy, lower 
alkanoyloxy and/or mono- or di-lower alkylamino, and is, for example, 
lower alkoxy, halo-lower alkoxy, or corresponding hydroxy- oxo-, lower 
alkoxy-, lower alkanoyloxy- or mono- or di-lower alkylamino-lower alkoxy. 
Compounds in which R.sup.1 and/or R.sup.2 represent etherified hydroxy are 
esters of the phosphorus-containing acid group and, depending on the 
meaning of R.sup.2, phosphonous acid esters, phosphinic acid esters or 
phosphonic acid esters. Preferred esters are the respective lower alkyl 
esters and hydroxy-lower alkyl esters. 
Salts of compounds according to the invention are especially 
pharmaceutically acceptable non-toxic salts of compounds of formula I. 
Such salts are formed, for example, from the carboxy group present in 
compounds of formula I, and are especially metal or ammonium salts, such 
as alkali metal and alkaline earth metal salts, for example sodium, 
potassium, magnesium or calcium salts, and also ammonium salts with 
ammonia or suitable organic amines, such as lower alkylamines, for example 
methylamine, diethylamine or triethylamine, hydroxy-lower alkylamines, for 
example 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine, 
tris-(hydroxymethyl)-methylamine or tris-(2-hydroxyethyl)-amine, basic 
aliphatic esters of carboxylic acids, for example 4-aminobenzoic acid 
2-diethylaminoethyl ester, lower alkylene-amines, for example 
1-ethylpiperidine, lower alkylenediamines, for example ethylenediamine, 
cycloalkylamines, for example dicyclohexylamine, or benzylamines, for 
example N,N'-dibenzylethylenediamine, benzyltrimethylammonium hydroxide, 
dibenzylamine or N-benzyl-.beta.-phenylethylamine. Compounds of formula I 
having a primary or secondary amino group may also form acid addition 
salts, for example with preferably pharmaceutically acceptable inorganic 
acids, such as hydrohalic acids, for example hydrochloric acid or 
hydrobromic acid, sulphuric acid, nitric acid or phosphoric acid, or with 
suitable organic carboxylic or sulphonic acids, for example acetic acid, 
propionic acid, succinic acid, glycolic acid, lactic acid, fumaric acid, 
maleic acid, tartaric acid, oxalic acid, citric acid, pyruvic acid, 
benzoic acid, mandelic acid, malic acid, ascorbic acid, pamoa acid, 
nicotinic acid, methanesulphonic acid, ethanesulphonic acid, 
hydroxyethanesulphonic acid, benzenesulphonic acid, 4-toluenesulphonic 
acid or naphthalenesulphonic acid. 
It is also possible to use pharmaceutically unsuitable salts for isolation 
or purification. Only the pharmaceutically acceptable non-toxic salts are 
used therapeutically, and these are therefore preferred. 
Aryl, also in definitions such as aroyl or aryl-lower alkoxycarbonyl, 
represents aromatic hydrocarbon radicals that are unsubstituted or 
substituted by lower alkyl, hydroxy, protected hydroxy, lower alkoxy, 
halogen, amino, halo-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl 
or by nitro, and is, for example, unsubstituted or correspondingly 
substituted 1- or 2-naphthyl, but preferably unsubstituted or 
correspondingly substituted phenyl, such as phenyl, lower alkylphenyl, for 
example methylphenyl, hydroxyphenyl, halophenyl, for example 4-halophenyl, 
such as 4-chlorophenyl, benzyloxyphenyl, lower alkoxyphenyl, for example 
methoxyphenyl, hydroxymethylphenyl, aminomethylphenyl or nitrophenyl. 
The general terms used hereinbefore and hereinafter, unless defined 
otherwise, have the following meanings: 
The term "lower" indicates that groups or compounds so defined contain up 
to and including 8, preferably up to and including 4, carbon atoms. 
Alkyl represents, for example, lower alkyl, such as methyl, ethyl, 
n-propyl, isopropyl, n-butyl, isobutyl or tert.-butyl, and also n-pentyl, 
n-hexyl, n-heptyl or n-octyl, preferably methyl, but may also represent, 
for example, nonyl, decyl, undecyl or dodecyl. 
Arylalkyl represents, for example, aryl-lower alkyl in which aryl has the 
meanings given hereinbefore, and is especially, for example, unsubstituted 
phenyl-lower alkyl, such as benzyl or 1- or 2-phenylethyl. 
Lower alkenyl contains preferably up to 6 carbon atoms and is bonded by way 
of an sp.sup.3 -hybridised carbon atom, and may be, for example, 
2-propenyl, 2- or 3-butenyl or 3-pentenyl, but may also be vinyl. 
Lower alkoxy represents especially methoxy, ethoxy, n-propoxy, isopropoxy, 
n-butoxy, isobutoxy or tert.-butoxy. 
Halogen preferably has an atomic number of up to 35 and is especially 
chlorine, also fluorine or bromine, but may also be iodine. 
Protected hydroxy is esterified hydroxy, for example hydroxy esterified as 
an acyl group, such as lower alkanoyloxy, benzyloxycarbohyloxy or lower 
alkoxycarbonyloxy, or etherified hydroxy, for example 
2-tetrahydropyranyloxy or benzyloxy, and also lower alkoxy. 
Halo-lower alkyl is, for example, halomethyl, such as fluoromethyl, 
trifluoromethyl or 1- or 2-chloroethyl. 
Hydroxy-lower alkyl is, for example, mono- or di-hydroxy-lower alkyl, 
carries the hydroxy group(s), for example, especially in a position higher 
than the .alpha.-position and represents, for example, hydroxymethyl, 
2-hydroxyethyl, 3-hydroxy- or 2,3-dihydroxy-propyl, 4-hydroxy- or 
2,4-dihydroxy-butyl, or 5-hydroxy-, 2,5-dihydroxy- or 
3,5-dihydroxy-pentyl. 
Lower alkoxy-lower alkyl is, for example, mono- or di-lower alkoxy-lower 
alkyl, carries the lower alkoxy group(s), for example, especially in a 
position higher than the .alpha.-position and is, for example, 2-methoxy-, 
2-ethoxy-, 2-propoxy- or 2-isopropoxy-ethyl, 3-methoxy- or 3-ethoxy-propyl 
or 3,3-dimethoxy-, 3,3-diethoxy, 2,3-dimethoxy- or 2,3-diethoxy-propyl or 
4,4-dimethoxybutyl, and also methoxy-, ethoxy-, dimethoxy-, or propoxy- or 
isopropoxy-methyl. 
Amino-lower alkyl is, for example, aminomethyl or 1- or 2-aminoethyl. 
Lower alkanoyloxy is, for example, acetoxy, propionyloxy or butyryloxy, or 
also formyloxy or pivaloyloxy. 
Lower alkoxycarbonyl is, for example, methoxycarbonyl or ethoxycarbonyl. 
Aryl-lower alkoxycarbonyl is preferably phenyl-lower alkoxycarbonyl, for 
example, benzyloxycarbonyl or 1- or 2-phenylethoxycarbonyl. 
Mono- or di-lower alkylamino is, for example methylamino, dimethylamino, 
ethylamino, diethylamino, propylamino, isopropylamino or butylamino. 
The compounds prepared in accordance with the invention have valuable 
pharmacological properties. They are, for example, active and selective 
antagonists of N-methyl-D-aspartic acid (NMDA)-sensitive excitatory amino 
acid receptors in mammals. They are therefore suitable for the treatment 
of diseases that respond to a blocking of NMDA-sensitive receptors, such 
as, for example, cerebral ischaemia, muscular spasms (spasticity), 
convulsions (epilepsy), conditions of anxiety or manic conditions. 
These advantageous effects may be demonstrated in in vitro or in in vivo 
test arrangements. For these, preferably mammals are used, for example 
mice, rats or monkeys, or tissue or enzyme preparations from such mammals. 
The compounds may be administered enterally or parentally, preferably 
orally; or subcutaneously, intravenously or intraperitoneally, for example 
in gelatin capsules or in the form of aqueous suspensions or solutions. 
The dosage to be used in vivo may range from 0.1 to 600 mg/kg, preferably 
from 1 to 300 mg/kg. In vitro, the compounds may be used in the form of 
aqueous solutions, the concentrations ranging from 10.sup.-4 to 10.sup.-9 
molar solutions. 
The inhibiting action on the NMDA-sensitive excitatory amino acid receptors 
may be determined in vitro by measuring, in accordance with G. Fagg and A. 
Matus, Proc. Nat. Acad. Sci., U.S.A., 81, 6876-80 (1984), to what extent 
the binding of L-.sup.3 H-glutamic acid to NMDA-sensitive receptors is 
inhibited. In vivo, the inhibiting action on NMDA-sensitive excitatory 
amino acid receptors may be demonstrated by the inhibition of NMDA-induced 
convulsions in mice. 
The anti-convulsive properties of the compounds according to the invention 
may furthermore be shown by their effectiveness in preventing 
audiogenically induced attacks in DBA/2 mice (Chapman et al., 
Arzneimittel-Forsch. 34, 1261, 1984). 
The anti-convulsive properties may furthermore be shown by the 
effectiveness of the compounds according to the invention as electric 
shock antagonists in mice or in rats. 
An indication of the anxiolytic activity of the compounds of the present 
invention is given by their pronounced effectiveness in the conflict model 
according to Cook/Davidson (Psychopharmacologia 15, 159-168 (1968)). 
The pronounced effectiveness of the compounds of formula I depends to a 
surprisingly high extent on the configuration at the double bond. For 
example, the racemate of D-2-amino-5-phosphono-3-cis-pentenoic acid known 
from Agric. Biol. Chem. 41, 573-579 (1979), B. K. Park et al., proves, for 
example in its ability to bond to the NMDA-sensitive receptor, to be far 
inferior to the racemate of the 2-amino-5-phosphono-3-trans-pentenoic acid 
according to the invention (in the Examples these compounds are referred 
to as compounds of the "E-series"). Compounds of the formula I, wherein 
the carbon atom carrying the group R.sub.6 has R-configuration, have been 
found to be especially active. 
Preferred are compounds of the formula I in which R.sup.3 represents 
hydrogen, alkyl or aryl. 
Also preferred are the compounds of the formula I in which R.sup.1 
represents hydroxy, lower alkoxy or hydroxy-lower alkoxy, R.sup.2 
represents hydrogen, alkyl, hydroxy, lower alkoxy or hydroxy-lower alkoxy, 
R.sup.3 represents hydrogen, lower alkyl, halo-lower alkyl, hydroxy-lower 
alkyl, lower alkoxy-lower alkyl, phenyl-lower alkyl that is unsubstituted 
or substituted in the phenyl moiety, lower alkenyl, halogen, or 
unsubstituted or substituted phenyl, R.sup.4 represents hydrogen, lower 
alkyl or unsubstituted or substituted phenyl, R.sup.5 represents hydrogen 
or lower alkyl, R.sup.6 represents carboxy or pharmaceutically acceptable 
esterified or amidated carboxy, R.sup.7 represents amino, mono- or 
di-lower alkylamino, alkanoylamino or alkanoylamino substituted by 
halogen, by amino and/or by phenyl, carbamoyl, carboxy, imidazolyl, lower 
alkylthio, tetrahydropyrrolyl, hydroxy, indolyl or by hydroxyphenyl, 
benzoylamino or benzoylamino substituted by halogen, lower alkoxy or by 
nitro, or phthalimino, A represents unsubstituted or lower 
alkyl-substituted .alpha.,.omega.-alkylene having from 1 to 3 carbon 
atoms, or represents a bond, and B represents methylene or a bond, with 
the proviso that A is other than a bond when B represents a bond, wherein 
the substituents of phenyl are selected from the group consisting of lower 
alkyl, hydroxy, lower alkoxy, halogen, amino, halo-lower alkyl, 
hydroxy-lower alkyl, amino-lower alkyl and nitro, and pharmaceutically 
acceptable salts thereof. 
Also preferred are compounds of the formula I in which R.sup.1 to R.sup.5 
are as defined above, R.sup.6 represents carboxy, alkoxycarbonyl, or 
alkoxycarbonyl substituted by amino, mono- or di-lower alkylamino, hydroxy 
or by lower alkanoyloxy, R.sup.7 represents amino, mono-lower alkylamino, 
lower alkanoylamino or benzoylamino, and A and B are as defined above, and 
pharmaceutically acceptable salts thereof. 
Likewise preferred are compounds of the formula I in which R.sup.1, 
R.sup.2, R.sup.5 to R.sup.7 and A and B are as defined immediately above 
and in which R.sup.3 and R.sup.4, independently of one another, each 
represents hydrogen, lower alkyl, phenyl, or phenyl substituted by lower 
alkyl, hydroxy, lower alkoxy, halogen, amino, halo-lower alkyl, 
hydroxy-lower alkyl, amino-lower alkyl or by nitro, and pharmaceutically 
acceptable salts thereof. 
Especially preferred are compounds of the formula I in which R.sup.1 
represents hydroxy or lower alkoxy, R.sup.2 represents hydrogen, alkyl, 
hydroxy or lower alkoxy, R.sup.3 represents hydrogen, lower alkyl, phenyl, 
halophenyl, or phenyl-lower alkyl, R.sup.4 and R.sup.5 represent hydrogen 
or lower alkyl, R.sup.6 represents carboxy, alkoxycarbonyl or 
hydroxy-lower alkoxycarbonyl, R.sup.7 represents amino, mono-lower 
alkylamino, lower alkanoylamino or benzoylamino, A represents 
unsubstituted or lower alkyl-substituted .alpha.,.omega.-alkylene having 
from 1 to 3 carbon atoms or represents a bond and B represents methylene 
or a bond, with the proviso that A is other than a bond when B represents 
a bond, and pharmaceutically acceptable salts thereof. 
Especially preferred are compounds of the formula I in which R.sup.1 is 
hydroxy, R.sup.2 represents hydrogen, alkyl or hydroxy, R.sup.3 represents 
hydrogen, lower alkyl or halophenyl, R.sup.4 represents hydrogen or 
halophenyl and R.sup.5 represents hydrogen, R.sup.6 represents carboxy, 
lower alkoxycarbonyl or hydroxy-lower alkoxycarbonyl, R.sup.7 represents 
amino, mono-lower alkylamino, lower alkanoylamino or benzoylamino, A 
represents .alpha.,.omega.-alkylene having from 1 to 3 carbon atoms or 
represents a bond and B represents methylene or a bond, with the proviso 
that A is other than a bond when B represents a bond, and pharmaceutically 
acceptable salts thereof. 
Most especially preferred are compounds of the formula I in which R.sup.1 
is hydroxy, R.sup.2 represents hydrogen, lower alkyl or hydroxy, R.sup.3 
represents hydrogen or lower alkyl, R.sup.4 and R.sup.5 represent 
hydrogen, R.sup.6 represents carboxy or lower alkoxycarbonyl, R.sup.7 
represents amino or mono-lower alkylamino, A represents 
.alpha.,.omega.-alkylene having from 1 to 3 carbon atoms, and B represents 
a bond, and pharmaceutically acceptable salts thereof. 
Outstanding are the compounds of the formula I in which R.sup.1 and R.sup.2 
represent hydroxy, R.sup.3 represents hydrogen or lower alkyl, R.sup.4 and 
R.sup.5 represent hydrogen, R.sup.6 represents carboxy, R.sup.7 represents 
amino, A represents methylene and B represents a bond, and the carboxylic 
acid lower alkyl esters and pharmaceutically acceptable salts thereof, 
especially the R-enantiomers thereof with reference to the atom carrying 
the amino group. 
The compounds of the present invention may be manufactured in a manner 
known per se, for example as follows: 
a) in a compound of the formula II 
##STR3## 
in which Z.sup.1 has the meaning of R.sup.1 or represents protected 
hydroxy, Z.sup.2 has the meaning of R.sup.2 or represents protected 
hydrogen or protected hydroxy, R.sup.3, R.sup.4, R.sup.5, A and B are as 
defined for formula I, Z.sup.6 has the meaning of R.sup.6 or represents 
protected carboxy, Z.sup.7 represents a protected group R.sup.7 and 
R.sup.1, R.sup.3, R.sup.4, R.sup.5, A and B are as defined for formula I, 
the protected group Z.sup.7 and when applicable, Z.sup.1, Z.sup.2 and/or 
Z.sup.6 are freed, 
b) in order to obtain a compound of the formula I in which R.sup.5 
represents hydrogen, in a compound of the formula IV 
##STR4## 
in which R.sup.3, R.sup.4, A and B are as defined for formula I, Z.sup.1 
has the meaning of R.sup.1 or represents protected hydroxy, Z.sup.2 has 
the meaning of R.sup.2 or represents protected hydroxy or protected 
hydrogen, Z.sup.6 has the meaning of R.sup.6 or represents protected 
carboxy, Z.sup.7 has the meaning of R.sup.7 or represents protected amino, 
and Y represents an optionally esterified carboxy group that can be 
replaced by hydrogen, the group Y is replaced by hydrogen, or 
c) in order to obtain a compound of the formula I in which A represents 
unsubstituted or alkyl-substituted .alpha.,.omega.-alkylene having 2 or 3 
carbon atoms and B represents methylene, a compound of the formula V 
##STR5## 
in which R.sup.3, R.sup.4, R.sup.5 and B are as defined for formula I, 
Z.sup.6 has the meaning of R.sup.6 or represents protected carboxy, 
Z.sup.7 has the meaning of R.sup.7 or represents protected amino, X 
represents reactive esterified hydroxy and A' represents unsubstituted or 
alkylsubstituted .alpha.,.omega.-alkylene having 1 or 2 carbon atoms, is 
reacted with a compound of the formula VI 
##STR6## 
in which Z.sup.1 has the meaning of R.sup.1 or represents protected 
hydroxy, Z.sup.2 has the meaning of R.sup.2 or represents protected 
hydrogen or protected hydroxy and A" represents unsubstituted or 
alkyl-substituted methylene, which is present in metallated form, and any 
protected functional groups that may be present in a compound resulting 
from one of the preceding processes is freed and, if desired, a resulting 
compound of the formula I is converted into a different compound of the 
formula I and/or, if desired, a resulting compound of the formula I is 
converted into a salt or a resulting salt is converted into a different 
salt or into a free compound of the formula I and/or, if desired, an 
optical isomer is isolated from a mixture of stereoisomeric forms of a 
resulting compound of the formula I or of a salt thereof. 
Protected hydroxy Z.sup.1 and/or Z.sup.2 in intermediates of formula II is, 
for example, hydroxy etherified by an aliphatic alcohol, such as hydroxy 
etherified by a lower alkanol, lower alkenol or lower alkynol each of 
which is unsubstituted or substituted by halogen or, in a position higher 
than the .alpha.-position, by hydroxy, oxo, lower alkoxy, lower 
alkanoyloxy and/or by mono- or di-lower alkylamino, and is, for example, 
lower alkoxy, halo-lower alkoxy, or corresponding hydroxy-, oxo-, lower 
alkoxy-, lower alkanoyloxy- or mono- or di-lower alkylamino-lower alkoxy. 
Compounds of formula II in which Z.sup.1 and/or Z.sup.2 are etherified 
hydroxy are esters of the phosphorus-containing acid group and, depending 
on the meaning of R.sup.2, are phosphonous acid esters, phosphinic acid 
esters or phosphonic acid esters. Preferred esters are the respective 
lower alkyl esters and hydroxy-lower alkyl esters. 
Protected hydrogen Z.sup.1 is protected in a manner known per se, such as 
is described, for example, in EP-A-0 009 348. Corresponding protecting 
groups are preferably groups of the formula --C(C.sub.1-4 
-alkyl)(OR.sup.a)OR.sup.b, preferably groups of the formula 
--CH(OR.sup.a)OR.sup.b in which R.sup.1 a and R.sup.b each represents 
C.sub.1-4 -alkyl. Especially suitable is the group --CH(OC.sub.2 
H.sub.5).sub.2. 
Groups Z.sup.7 in intermediates of formula II are, for example, R.sup.7 
groups substituted by acyl, that is to say acylamino that is unsubstituted 
or N-substituted by lower alkyl or by aryl-lower alkyl in which acyl is 
the acyl radical of an organic acid having, for example, up to 18 carbon 
atoms, especially an alkanecarboxylic acid that is unsubstituted or 
substituted, for example, by halo9en, amino or by phenyl, or benzoic acid 
that is unsubstituted or substituted, for example, by halogen, lower 
alkoxy or by nitro, or of a carbonic acid semiester. Such acyl groups are, 
for example, lower alkanoyl, such as formyl, acetyl or propionyl, 
halo-lower alkanoyl, such as 2-haloacetyl, especially 2-fluoro-, 2-bromo-, 
2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloro-acetyl, aroyl, such as 
unsubstituted or substituted benzoyl, for example benzoyl, halobenzoyl, 
such as 4-chlorobenzoyl, lower alkoxybenzoyl, such as 4-methoxybenzoyl, or 
nitrobenzoyl, such as 4-nitrobenzoyl. The following are also especially 
suitable: lower alkenyloxycarbonyl, for example allyloxycarbonyl, or 
especially lower alkoxycarbonyl that is unsubstituted or substituted in 
the 1- or 2-position, such as, especially, lower alkoxycarbonyl, for 
example tertiary butoxycarbonyl and also methoxy- or ethoxy-carbonyl, and 
also unsubstituted or substituted benzyloxycarbonyl, for example 
benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, or aroylmethoxycarbonyl in 
which the aroyl group is benzoyl that is unsubstituted or substituted, for 
example, by halo9en, such as bromine, for example phenacyloxycarbonyl or 
bromophenacyloxycarbonyl. 
Furthermore, in a corresponding acylamino group Z.sup.7, acyl may be 
alkanoylamino substituted by amino and/or by phenyl, carbamoyl, carboxy, 
imidazolyl, lower alkylthio, tetrahydropyrrolyl, hydroxy, indolyl or by 
hydroxyphenyl, and thus includes, for example, the acyl radicals of amino 
acids, for example naturally occurring amino acids, such as alanyl, 
asparaginyl, aspartyl, glycyl, histidyl, isoleucyl, leucyl, lysyl, 
methionyl, phenylalanyl, prolyl, seryl, threonyl, tryptophyl, tyrosyl or 
valyl; also included are the acyl radicals of oligopeptides, for example 
di- or tri-peptides, such as oligopeptides of alanine, asparagine or 
aspartic acid. 
Furthermore, protected amino Z.sup.7 may be a diacylamino group. In this 
group diacyl is, for example, two acyl radicals of the definitions given 
hereinbefore, or diacyl is, for example, the acyl radical of an organic 
dicarboxylic acid having, for example, up to 12 carbon atoms, especially a 
corresponding aromatic dicarboxylic acid, such as phthalic acid. Such a 
group is especially phthalimido. 
In addition, protected amino Z.sup.7 may also be amino substituted by 
substituted lower alkoxycarbonyl, such as amino substituted by 
2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 
2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 
by 2-(tris-substituted silyl)-ethoxycarbonyl, such as 2-tri-lower 
alkylsilylethoxycarbonyl, for example 2-trimethylsilylethoxycarbonyl or 
2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or by 
2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl, or 
etherified mercaptoamino or silylamino, or may be in the form of an 
enamino, nitro or azido group. 
An etherified mercaptoamino group is especially a phenylthioamino group 
that is unsubstituted or substituted by lower alkyl, such as methyl or 
tert.-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine or 
bromine, and/or by nitro, or a pyridylthioamino group. Corresponding 
groups are, for example, 2- or 4-nitrophenylthioamino or 
2-pyridylthioamino. 
A silylamino group is especially an organic silylamino group. In such 
groups the silicon atom contains as substituent(s) preferably lower alkyl, 
for example methyl, ethyl, n-butyl or tert.-butyl, also aryl, for example 
phenyl. Suitable silyl groups are especially tri-lower alkylsilyl, 
especially trimethylsilyl or dimethyl-tert.-butylsilyl. 
Enamino groups contain at the double bond in the 2-position an 
electron-attracting substituent, for example a carbonyl group. Protecting 
groups of this kind are, for example, 1-acyl-lower alk-1-en-2-yl radicals 
in which acyl is, for example, the corresponding radical of a lower 
alkane-carboxylic acid, for example acetic acid, of a benzoic acid that is 
unsubstituted or substituted, for example, by lower alkyl, such as methyl 
or tert.-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, 
and/or by nitro, or especially of a carbonic acid semiester, such as a 
carbonic acid lower alkyl semiester, for example methyl semiester or ethyl 
semiester, and lower alk-1-ene is especially 1-propene. Corresponding 
protecting groups are especially 1-lower alkanoyl-prop-1-en-2-yl, for 
example 1-acetylprop-1-en-2-yl, or 1-lower alkoxycarbonyl-prop-1-en-2-yl, 
for example 1-ethoxycarbonyl-prop-1-en-2-yl. 
In the above-defined processes, protected hydroxy and protected amino have, 
for example, the meanings for protected hydroxy and for acyl-substituted 
amino given hereinbefore. Protected hydroxy represents especially lower 
alkoxy such as methoxy, ethoxy or isopropoxy, protected carboxy is 
especially tri-lower alkylsilylcxycarbonyl, such as 
trimethylsilyloxycarbonyl, and protected amino unsubstituted or 
substituted by lower alkyl or by aryl-lower alkyl is especially lower 
alkanoylamino, especially acetylamino or formylamino, N-lower 
alkanoyl-N-lower alkylamino, especially N-acetyl- or N-formyl-N-lower 
alkylamino, for example N-acetyl- or N-formyl-N-methylamino, or lower 
alkoxycarbonylamino, preferably tertiary butoxycarbonylamino. Another 
preferred exampled of protected hydroxy is trisubstituted silyl, such as 
tri-lower alkylsilyl, for example trimethylsilyl or 
tert.-butyldimethylsilyl. 
Freeing the protected groups, that is to say setting free hydroxy Z.sup.1 
and/or Z.sup.2, hydrogen R.sup.1 from protected hydrogen Z.sup.1, carboxy 
R.sup.6 from protected carboxy Z.sup.6 and/or optionally N-lower alylated 
or N-phenyl-lower alkylated amino R.sup.7 from protected groups Z.sup.7 
can generally be effected either under hydrolytic conditions, such those 
of an acidic hydrolysis, for example in the presence of a hydrohalic acid, 
such as hydrochloric acid, preferably with heating, or by treatment with a 
tri-lower alkylhalosilane in an inert solvent, such as halogenated, 
preferably aliphatic hydrocarbon, for example dichloromethane or, less 
preferably, tri- or tetra-chloromethane, trichloroethane or 
tetrachloroethane, in a temperature range of approximately from 
-25.degree. to +50.degree. C., preferably from approximately 0.degree. C. 
to approximately 30.degree. C., for example at temperatures in the region 
of room temperature, that is to say at from approximately 15.degree. C. to 
approximately 25.degree. C., advantageously under substantially anhydrous 
conditions and under an inert gas, for example under argon or nitrogen. 
In process a), if several of the groups Z.sup.1, Z.sup.2, Z.sup.6 and 
Z.sup.7 represent protected groups, the reaction conditions can be so 
selected that they can be freed in single step, or that, for example, 
esterified carboxy Z.sup.6 is retained. 
Thus, if compounds of the formula I in which R.sup.6 denotes carboxy, are 
desired as end products, compounds of formula II, wherein Z.sup.6 is 
esterified or amidated carboxy, for example lower alkoxycarbonyl, can be 
used as starting materials. When hydrolytic conditions are applied or on 
treatment with a tri-lower alkyljodosilane, the carboxy group R.sup.6 is 
set free under the condition of the cleavage of the protected groups 
Z.sup.1, Z.sup.2 and Z.sup.7. 
Alternatively, if compounds of formula I in which R.sup.6 is esterified or 
amidated carboxy, such as lower alkoxycarbonyl or carbamoyl, are desired 
as end products, the starting materials of formula II and the process 
conditions can be so selected that although in the last step Z.sup.1, 
Z.sup.2 and Z.sup.7 are freed, Z.sup.6, which represents the desired 
R.sup.6 group, remains uneffected. 
An especially preferred process variant is accordingly directed to the 
manufacture of compounds of formula I in which R.sup.6 is lower 
alkoxycarbonyl and R.sup.7 is amino. In this process variant the starting 
materials used are preferably compounds of formula II in which Z.sup.1 and 
Z.sup.2 are lower alkoxy or lower alkoxy substituted in a position higher 
than the .alpha.-position by halogen, such as chlorine, Z.sup.6 is lower 
alkoxycarbonyl and Z.sup.7 is lower alkanoylamino, such as formylamino, or 
lower alkoxycarbonylamino, such as tert.-butoxycarbonylamino. Starting 
from such compounds of formula II the freeing of the protected groups can 
be so controlled by treatment in an inert solvent, such as a halogenated 
hydrocarbon, for example dichloromethane, at temperatures in the region of 
room temperature, with a reagent such as trimethylbromosilane, and by 
subsequent treatment with a lower alkanol, such as ethanol, and a 
substance absorbing hydrogen halide, such as an aliphatic epoxide, 
especially an epoxy-lower alkane, for example propylene oxide, that 
compounds of formula I in which R.sup.2 is hydroxy, R.sup.6 is C.sub.1 
-C.sub.4 alkoxycarbonyl, R.sup.7 is amino and the variables R.sup.3, 
R.sup.4 and R.sup.5 are as defined for formula I, are obtained directly. 
This process is especially preferred for the manufacture of compounds of 
formula I in which A is methylene or 1,3-propylene and B is a bond, 
R.sup.4 and R.sup.5 are hydrogen and R.sup.3 is alkyl having up to 4 
carbon atoms, such as methyl. 
Another especially preferred process variant is the manufacture of 
compounds of formula I in which R.sup.6 is carboxy. In this case the 
starting materials used are preferably compounds of formula II in which 
Z.sup.1 and Z.sup.2 are lower alkoxy or lower alkoxy substituted in a 
position higher than the .alpha.-position by halogen, such as chlorine, 
Z.sup.6 is optionally protected carboxy and Z.sup.7 is lower 
alkoxycarbonylamino, especially .alpha.-branched lower 
alkoxycarbonylamino, such as tert.-butoxycarbonylamino. In this case, the 
carboxy group is preferably, but not necessarily, intermediately 
protected, for example by treatment with a silylation agent, such as an 
N,O-silyl-lower alkanoic acid amide, for example with 
N,O-trimethylsilylacetamide. 
Working up is carried out in a manner known per se, two purifying methods 
especially having proved advantageous. Either the crude product can be 
converted into a readily volatile derivative, for example by silylation, 
and recovered as such by distillation and then desilylated, or the crude 
product can be treated with an agent that reacts with excess acid, such as 
hydrohalic acid, thereby removing it. Suitable agents are, for example, 
compounds to which a corresponding acid can be added, for example lower 
alkylene oxides (epoxides), such as propylene oxide. 
Intermediates of formula II are preferably manufactured by reacting a 
compound of formula 
##STR7## 
in which R.sup.3, R.sup.4, R.sup.5, A and B are as defined for formula I, 
Z.sup.6 has the meaning of R.sup.6 or is protected carboxy, Z.sup.7 is a 
protected R.sup.7 group and X is reactive esterified hydroxy, with a 
compound of formula 
##STR8## 
in which Z.sup.1 is free or protected hydroxy, Z.sub.2 has the meaning of 
R.sub.1 or is protected hydroxy and R is an etherifying group, and can be 
used without being isolated or specially purified. According to another 
preferred process variant, a compound of formula 
##STR9## 
is subjected to selective halogenation, for example by means of thionyl 
chloride, to form the corresponding intermediate III, and this is reacted 
in situ, that is to say without being isolated, with component IV. 
The etherifying group R is, for example, phenyl-lower alkyl, trisubstituted 
silyl, such as tri-lower alkylsilyl or, preferably, alkyl. The reaction is 
carried out in a manner known per se, especially under the known 
conditions of the Michaelis-Arbuzov reaction. 
According to one variant of this process the reaction, for example, of a 
trialkyl phosphite of the formula IV, such as triethyl phosphite, 
especially with compounds of the formula III in which A represents a bond, 
can be catalysed in a suitable manner, such as by a halide of a metal of 
sub-group VIII, preferably a nickel, palladium or platinum halide, 
especially nickel chloride. 
It is preferable to carry out this process with compounds of the formulae 
III and IV in which R.sup.3, R.sup.4, R.sup.5, A and B are as defined for 
formula I, Z.sup.1 represents protected hydroxy, Z.sup.2 represents lower 
alkyl, protected hydrogen or protected hydroxy, R represents lower alkyl, 
Z.sup.6 represents free protected or esterified carboxy, Z.sup.7 
represents a protected group R.sup.7 and X represents reactive esterified 
hydroxy and, following the reaction in which the compound RX becomes free, 
to free the protected groups Z.sup.1, Z.sup.2, Z.sup.7 and, if applicable 
and/or desired Z.sup.6. In this case preferably Z.sup.1 represents lower 
alkoxy, Z.sup.2 represents lower alkyl, di-lower alkoxy-lower alkyl or 
lower alkoxy, R represents lower alkyl, Z.sup.6 represents carboxy or 
lower alkoxycarbonyl, Z.sup.7 represents optionally N-lower alkylated or 
N-phenyl-lower alkylated formylamino or tert.butoxycarbonyl and X 
represents halogen. 
Compounds of formula III can be manufactured, for example, by reacting an 
N-protected aminomalonic acid ester of formula V 
##STR10## 
in which Z.sup.6 and Z.sub.6 ' are identical or different esterified 
carboxy groups, for example lower alkoxycarbonyl groups, in a manner known 
per se with a compound of formula 
##STR11## 
in which X and X', independently of one another, each represents reactive 
esterified hydroxy, such as halogen. The resulting compounds of formula 
##STR12## 
can be converted into compounds of formula III in which R.sup.5 is 
hydrogen by hydrolysis, for example under hydrolytic conditions, such as 
the conditions of an acidic hydrolysis, for example with hydrohalic acids, 
such as hydrochloric acid, preferably with heating, and by 
decarboxylation, or by dealkoxycarbonylation, without previous hydrolysis, 
by heating in an aqueous aprotic solvent, such as dimethyl sulphoxide, in 
the presence of an alkali metal halide, such as sodium chloride. 
This variant is accordingly especially suitable for producing compounds III 
in which R.sup.5 is hydrogen, Z.sup.6 is free or esterified carboxy and 
Z.sup.7 is protected amino, such as lower alkanoylamino. 
Intermediates III in which A is methylene that is unsubstituted or 
substituted by alkyl, B is a bond, X is halogen and Z.sup.7 is formylamino 
can furthermore be produced by reacting a compound of formula 
##STR13## 
wherein D denotes optionally alkylated methylidene, such as a 
corresponding .alpha.,.beta.-unsaturated aldehyde, for example acrolein in 
or methacrolein, with an .alpha.-isocyanoacetic acid derivative, such as 
an .alpha.-isocyanoacetic acid lower alkyl ester. With suitable catalysis, 
such as with low valency metal salts, that is to say metal salts derived 
from metals of groups I and II of the Periodic Table of Elements, for 
example corresponding metal oxides or metal halides, such as zinc 
chloride, cadmium chloride, silver oxide or, preferably, copper oxide or 
complexes of gold-I-tetrafluoroborate with aliphatic or cycloaliphatic 
isocyanides, for example 
bis(cyclohexylisocyanide)gold-I-tetrafluoroborate, there are thus obtained 
in a manner known per se 5-vinyl-2-oxazoline-4-carboxylic acid 
derivatives, for example esters of formula 
##STR14## 
which can be converted into the open-chained compounds of formula 
##STR15## 
in which D is unsubstituted or alkyl-substituted methylidene. These 
compounds can in turn be converted by selective halogenation, such as 
bromination or chlorination, preferably with cooling and with displacement 
of the double bond in the manner of an allyl rearrangement, into compounds 
of formula III. 
Another process for the manufacture of compounds II in which R.sup.5 is 
hydrogen, A is methylene or 1,3-propylene and R.sup.6 is carboxy, is based 
on the principle that a compound of formula 
##STR16## 
in which R.sub.A and R.sub.B are hydrogen or preferably lower alkyl, such 
as methyl, and R.sub.C is an amino-protecting group, is condensed with a 
2-R.sup.3 -acetic acid ester or condensed first with a 1-R.sup.3 
-ethene-metal compound, for example with isopropenylmagnesium bromide, and 
subsequently with an acetic acid ester, in the resulting compound of 
formula 
##STR17## 
in which Z.sub.6 ' is esterified carboxy, for example lower 
alkoxycarbonyl, this group is reduced to hydroxymethyl, for example by 
means of diisobutylaluminium hydride, the hydroxymethyl group is 
halogenated, for example brominated by means of 
tetrabromomethane/triphenylphosphine, the resulting compound of formula 
##STR18## 
in which A denotes methylene or 1,3-propylene and X is halogen, for 
example bromine, is further reacted with a compound of formula IV, the 
oxazolidine ring is cleaved, for example, by means of an ion exchanger, 
such as Amberlyst 15.RTM., and, in the resulting compound of formula 
##STR19## 
in which Z.sup.7 is a protected amino group of formula RC--NH--(II'), the 
hydroxymethyl group is oxidised to carboxy in customary manner. 
When carrying out the above-described processes for the manufacture of 
intermediates III and the further reaction of the same to form 
intermediates II it is not necessary to isolate all of the intermediate 
stages. For example, especially the conversion of compounds X into 
compounds III and the further reaction thereof with compounds IV to form 
intermediates II can advantageously be carried out in situ. 
Attention is drawn in this connection to the surprising finding that the 
manufacture of the intermediates II and their further reaction according 
to the invention to form the end products I can be carried out 
stereoselectively. That is, neither in the reaction sequence 
III+IV.fwdarw.II or IIa.fwdarw.I, nor in the reaction sequences 
X.fwdarw.III and XI.fwdarw.XII.fwdarw.XIII.fwdarw.XIV.fwdarw.II is there 
reversal of configuration or significant racemisation. The process of the 
invention is therefore excellently suitable for the direct manufacture of 
compounds of formula I with the preferred R-configuration at the carbon 
atom carrying the amino group R.sup.7. The invention also relates to the 
manufacture of sterically homogeneous compounds of formula I and 
sterically homogeneous intermediates of formulae II, III, X, XI, XII, XIII 
and/or XIV. 
According to another preferred process variant, a compound of formula 
##STR20## 
is subjected to selective halogenation, for example by means of thionyl 
chloride, to form the corresponding intermediate III, and this is reacted 
in situ, that is to say without being isolated, with component IV. 
In process b), the group Y represents carboxy or esterified carboxy as 
defined hereinbefore, especially lower alkoxycarbonyl. Replacement of the 
group Y by hydrogen can be carried out, for example, under conditions 
under which first esterified carboxy is hydrolysed and then carboxy is 
replaced by hydrogen (decarboxylation), such as under hydrolytic 
conditions, such as those of an acidic hydrolysis, for example with 
hydrohalic acid, such as with hydrochloric acid, preferably while heating. 
In this process, if several of the groups Z.sup.1, Z.sup.2, Z.sup.6 and 
Z.sup.7 represent protected groups, these may advantageously be so 
selected that they can be freed together in the step in which the 
hydrolysis and the decarboxylation is effected. 
The replacement of the group Y by hydrogen can also be carried out without 
previous hydrolysis, as a dealkoxycarbonylation, for example according to 
A. P. Krapcho, Tetrahedron Letters 957 (1973), such as by heating in an 
aqueous aprotic solvent, such as dimethyl sulphoxide, in the presence of 
an alkali halide, such as sodium chloride. 
It is preferable to carry out this process with compounds of the formula IV 
in which R.sup.3, R.sup.4, A and B are as defined for formula I, Z.sup.1 
represents protected hydroxy, Z.sup.2 represents lower alkyl, protected 
hydrogen or protected hydroxy, Z.sup.6 represents protected carboxy, 
Z.sup.7 represents protected amino and Y represents an optionally 
esterified carboxy group that can be replaced by hydrogen, and for the 
protected groups to be freed together in the step in which the group Y is 
replaced by hydrogen. In this case preferably Z.sup.1 represents lower 
alkoxy, Z.sup.2 represents lower alkyl, di-lower alkoxy-lower alkyl or 
lower alkoxy, Z.sup.6 and Y represent lower alkoxycarbonyl and Z.sup.7 
represents lower alkanoylamino. 
The compounds of the formula IV may be manufactured, for example, 
analogously to process a) by reacting a compound of the formula II' 
##STR21## 
with a compound of the formula III 
##STR22## 
in which all radicals have the meanings given hereinbefore. The compounds 
of the formula II' may in turn be manufactured from a compound of the 
formula VII and an N-protected aminomalonic acid ester, as described in 
process a). 
In process c), the group --A"--H is an alkyl group which may be metallated 
in the .alpha.-position to phosphorus by a suitable base, such as an 
organoalkali metal compound, for example butyllithium. A correspondingly 
metallated compound of the formula VI is then alkylated with a compound of 
the formula V in a manner known per se. 
The manufacture of compounds of the formula V can be carried out 
analogously to the manufacture of compounds of the formula II. The 
compounds of the formula VI are alkylphosphonic acid dialkyl esters 
(Z.sup.1 and Z.sup.2 =alkoxy) or phosphinic acid esters (Z.sup.1 =alkoxy, 
Z.sup.2 =alkyl). These compounds are known or may be manufactured in a 
manner known per se. 
To convert a resulting compound of the formula I into a different compound 
of the formula I conversions such as the following may be carried out: 
As mentioned, compounds obtainable in accordance with the invention can be 
converted into different compounds of formula I. In particular, a free 
amino group R.sup.7 may be substituted, for example converted into an 
unsubstituted or phenylated alkylamino group, free carboxy R.sup.6 may be 
esterified, or esterified or amidated carboxy R.sup.6 may be converted 
into free carboxy, and/or free or esterified carboxy R.sup.6 may be 
converted into amidated carboxy. 
To convert an amino group into an unsubstituted or phenylated alkylamino 
group the amino group may be alkylated by substitution, for example with a 
reactive esterified optionally phenylated alkanol, such as an alkyl 
halide, or by reduction, such as with an aldehyde or ketone, and also with 
catalytically activated hydrogen or, in the case of formaldehyde, 
advantageously with formic acid as reducing agent. 
Compounds of the formula I in which R.sup.7 represents amino may be 
converted into compounds in which R.sup.7 represents acylamino, for 
example using a corresponding acid anhydride or halide, or vice versa, by 
processes belonging to the State of the Art and described herein in 
connection with protecting groups. 
Free carboxylic acids of formula I or salts thereof may be converted 
according to known processes by suitable alcohols or corresponding 
derivatives thereof into the corresponding esters, that is to say into 
compounds of formula I that are, for example, in the form of lower alkyl 
esters, aryl-lower alkyl esters, lower alkanoyloxymethyl esters or lower 
alkoxycarbonyl-lower alkyl esters. 
For the esterification, a carboxylic acid may be reacted directly with a 
diazoalkane, especially diazomethane, or with a corresponding alcohol in 
the presence of a strongly acidic catalyst (for example a hydrohalic acid, 
sulphuric acid or an organic sulphonic acid) and/or of a dehydrating agent 
(for example dicyclohexylcarbodiimide). Alternatively, the carboxylic acid 
may be converted into a reactive derivative, such as into a reactive 
ester, or into a mixed anhydride, for example with an acid halide (for 
example, especially an acid chloride), and this activated intermediate is 
reacted with the desired alcohol. 
Compounds of formula I in which R.sup.6 is esterified carboxy, such as, 
especially, lower alkoxycarbonyl, for example ethoxycarbonyl, can be 
converted into compounds of formula I in which R.sup.6 is carboxy, for 
example by hydrolysis especially in the presence of inorganic acids, such 
as hydrohalic acids or sulphuric acid or, less preferably, aqueous 
alkalis, such as alkali metal hydroxides, for example lithium or sodium 
hydroxide. In this connection attention is drawn to the fact that also 
carboxy can be freed from esterified carboxy in such a manner that no 
significant racemisation occurs. This can be achieved especially by 
treatment with from approximately 0.2N to approximately 4N, for example 
approximately 1N, that is to say from approximately 0.5N to approximately 
2N, aqueous mineral acid, if necessary while heating, for example at from 
approximately 60.degree. C. to approximately boiling temperature, that is 
to say approximately 100.degree. C. Surprisingly, the hydrolysis, for 
example, of phosphonic acid carboxylic acid lower alkyl esters of formula 
I, proceeds with a high yield even without the addition of acidic or basic 
reagents. A preferred process for the manufacture of carboxylic acids of 
formula I from the corresponding lower alkyl esters, such as the 
respective ethyl esters, therefore consists in acidic hydrolysis by 
treatment with from approximately 0.2N to approximately 4N aqueous mineral 
acid, for example hydrochloric acid, sulphuric acid, phosphoric acid or 
the like, and also in the--possibly autocatalytic--hydrolysis in water, 
preferably at elevated temperatures, such as with heating under reflux. 
The above reactions are carried out according to standard methods in the 
absence or presence of diluents, preferably those that are inert towards 
the reagents and are solvents therefor, in the presence of catalysts, 
condensation agents or the other agents and/or in an inert atmosphere, at 
low temperature, room temperature or elevated temperature, preferably at 
the boiling point of the solvents used, at atmospheric or superatmospheric 
pressure. 
The invention includes furthermore any variant of the present processes in 
which an intermediate obtainable at any stage of that process is used as 
starting material and the remaining steps are carried out, or the process 
is discontinued at any stage, or in which the starting materials are 
formed under the reaction conditions or in which the reactants are used in 
the form of their salts or optically pure antipodes. There should 
especially be used in these reactions those starting materials that result 
in the formation of the compounds mentioned hereinbefore as being 
especially valuable. 
The invention relates also to novel starting materials and processes for 
their manufacture. 
Depending on the choice of starting materials and methods, the novel 
compounds may be in the form of one of the possible optical isomers or in 
the form of mixtures thereof, for example depending on the number of 
asymmetric carbon atoms they may be in the form of pure optical isomers, 
such as antipodes, or mixtures of optical isomers, such as racemates, or 
mixtures of diastereoisomers from which one antipode, if desired, may be 
isolated. 
Resulting mixtures of diastereolsomers and mixtures of racemates may be 
separated in known manner on the basis of the physico-chemical differences 
between the constituents into the pure isomers, diastereoisomers or 
racemates, for example by chromatography and/or fractional 
crystallisation. 
The resulting racemates (racemic diastereoisomers) may furthermore be 
separated into the optical antipodes according to methods known per se, 
for example by recrystallisation from an optically active solvent, with 
the aid of microorganisms or enzyme-catalyst in free or in an immobilised 
form or by reaction of an acidic end product with an optically active base 
that forms salts with the racemic acid, and separation of the salts 
obtained in this manner, for example on the basis of their different 
solubilities, into the diastereoisomers, from which the antipodes can be 
freed by the action of suitable agents. Basic racemic products can also be 
separated into the antipodes, for example by separation of the 
diastereoisomeric salts thereof, for example by fractional crystallisation 
of the d- or 1-tartrates thereof. Any racemic intermediate or starting 
material can be separated in a similar manner. 
Finally, the compounds according to the invention are obtained either in 
free form or in the form of their salts. Any resulting base can be 
converted into a corresponding acid addition salt, preferably using a 
pharmaceutically acceptable acid or an anion-exchange preparation, or 
resulting salts can be converted into the corresponding free bases, for 
example using a stronger base, such as a metal or ammonium hydroxide or a 
basic salt, for example an alkali metal hydroxide or carbonate, or a 
cation-exchange preparation. A compound of formula I can also be converted 
into the corresponding metal or ammonium salts. These or other salts, for 
example the picrates, can also be used for the purification of resulting 
bases. The bases are converted into salts, the salts are separated and the 
bases are freed from the salts. In view of the close relationship between 
the free compounds and the compounds in the form of their salts, whenever 
a compound is mentioned in this Application, a corresponding salt of that 
compound is also included, provided that this is possible or appropriate 
under the given circumstances. 
The compounds, including their salts, can also be obtained in the form of 
their hydrates or contain other solvents used for the crystallisation. 
The pharmaceutical preparations according to the invention are those that 
are suitable for enteral, such as oral or rectal, and parenteral 
administration to mammals, including man, for the treatment or prevention 
of diseases that respond to the blocking of NMDA-receptors, such as, for 
example, cerebral ischaemia, muscular spasms (spasticity), convulsions 
(epilepsy), conditions of anxiety or manic conditions. They comprise an 
effective amount of a pharmacologically active compound of formula I or a 
pharmaceutically acceptable salt thereof, on its own or in combination 
with one or more pharmaceutically acceptable carriers. 
The pharmacologically active compounds of the invention can be used in the 
manufacture of pharmaceutical compositions that comprise an effective 
amount of the active compound on its own or in conjunction or admixture 
with excipients or carriers that are suitable for enteral or parenteral 
administration. Preferred are tablets and gelatin capsules that comprise 
the active constituent together with a) diluents, for example lactose, 
dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, b) 
glidants, for example silicon dioxide, talc, stearic acid, the magnesium 
or calcium salt thereof and/or polyethylene glycol, for tablets also c) 
binders, for example magnesium aluminium silicate, starch paste, gelatin, 
tragacanth, methylcellulose, sodium carboxymethylcellulose and/or 
polyvinylpyrrolidone, if desired d) dispersing agents or disintegrators, 
for example starches, agar, alginic acid or the sodium salt thereof, or 
foaming mixtures and/or e) absorbents, colouring agents, flavourings and 
sweeteners. Injectable preparations are preferably aqueous isotonic 
solutions or suspensions, and suppositories are advantageously produced 
from fatty emulsions or suspensions. These compositions may be sterilised 
and/or contain adjuvants, such as preservatives, stabilisers, wetting 
agents or emulsifiers, solubilisers, salts for regulating the osmotic 
pressure and/or buffers. In addition they may also contain other 
therapeutically valuable substances. These preparations are manufactured 
according to conventional mixing, granulating or coating methods and 
contain approximately from 0.1 to 100%, preferably approximately from 1 to 
50%, active constituent. A unit dose for a mammal weighing approximately 
from 50 to 70 kg may contain approximately from 1 to 500 mg, preferably 
approximately from 10 to 500 mg, of active constituent. 
The following Examples are intended to illustrate the invention and do not 
represent limitations. The temperatures are in degrees Celsius and all 
parts are quoted in the form of parts by weight. Unless stated otherwise, 
all evaporation is carried out under reduced pressure, preferably 
approximately from 2 to 13 Kilopascal (kPa).

EXAMPLE 1 
8.22 g of E-2-formylamino-5-diethylphosphono-3-pentenoic acid ethyl ester 
are dissolved in 170 ml of 6N hydrochloric acid and the whole is heated 
under reflux for 22 hours. After concentration in vacuo, the oily residue 
is taken up in a small amount of ethanol and the mixture is again 
concentrated by evaporation in vacuo. This procedure is repeated a further 
twice. The resulting residue is dissolved in 15 ml of ethanol and 20 ml of 
ethanol/propylene oxide (1:1) are added dropwise. The resulting 
brownish-coloured precipitate is filtered off and purified by ion exchange 
chromatography (Dowex 50W.times.8/H.sub.2 O). After concentration and 
lyophilisation, E-2-amino-5-phosphono-3-pentenoic acid is obtained in the 
form of a white amorphous powder, .sup.1 H-NMR (D.sub.2 O): 2.39 (dd, 2H, 
C(5)--H); 4.27 (d, 1H, C(2)--H); 5.53 (m, 1H, C(3)--H); 5.87 (m, 1H, 
C(4)--H), m.p. after recrystallisation from ethanol/water 
191.degree.-192.degree.. 
The starting material is manufactured as follows: 
1.6 g of red copper(I) oxide are added to 200 ml of benzene. With intensive 
stirring, a solution of 140 g of isocyanoacetic acid ethyl ester and 84 g 
of freshly distilled acrolein in 200 ml of benzene are added dropwise to 
this suspension within a period of 10 minutes. During the course of this 
addition the reaction temperature is maintained between 30.degree. and 
32.degree. by cooling with ice. When the addition is complete the mixture 
is maintained at 30.degree.-32.degree. until the exothermic reaction has 
subsided, and then the whole is stirred for 1 hour at room temperature. 
After excess copper(I) oxide has been removed by filtration, the filtrate 
is concentrated by evaporation in vacuo at 30.degree.. 600 ml of ether are 
added to the residue, and the whole is filtered over celite and 
concentrated to dryness by evaporation in vacuo. In this manner 
5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester is obtained in the form 
of a pale yellow oil, b.p. 100.degree.-110.degree. (5.3 Pa). 
128 g of the 5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester are 
dissolved in 70 ml of tetrahydrofuran, and 27.4 g of water and 3.5 g of 
triethylamine are added. The reaction mixture is stirred for 62 hours at 
65.degree.-70.degree. and, having been cooled, is taken up in 200 ml of 
dichloromethane. The solution is dried over 200 g of magnesium sulphate, 
filtered and concentrated by evaporation in vacuo. Purification by column 
chromatography (silica gel;hexane/ethyl acetate 3:2) of the viscous oil 
that remains yields 2-formylamino-3-hydroxy-4-pentenoic acid ethyl ester 
in the form of a diastereoisomeric mixture, m.p. 50.degree.-51.degree.. 
2.0 g of 2-formylamino-3-hydroxy-4-pentenoic acid ethyl ester in 80 ml of 
dry tetrahydrofuran are cooled to -78.degree.. 2.5 ml of thionyl bromide 
are slowly added dropwise thereto in such a manner that the reaction 
temperature does not exceed -75.degree.. When the addition is complete, 
the reaction solution is warmed within a period of approximately 3 hours 
to 0.degree. and is stirred at that temperature for 2.5 hours. The 
orange-yellow solution is then poured onto 300 ml of a cold 
(5.degree.-10.degree.) saturated aqueous sodium hydrogen carbonate 
solution and extracted with dichloromethane. The organic extracts are 
dried over magnesium sulphate and concentrated by evaporation in vacuo at 
room temperature. The oil that remains is dissolved in 20 ml of triethyl 
phosphite and heated for 2 hours in vacuo (10 kPa) under reflux 
(55.degree.). Excess triethyl phosphite is then distilled off under a high 
vacuum. Purification by column chromatography (silica gel, ethyl 
acetate/hexane (2:1), then ethyl acetate) yields 
E-2-formylamino-5-diethylphosphono-3-pentenoic acid ethyl ester in the 
form of a pale yellow oil; .sup.1 H-NMR(CDCl.sub.3): 2.62 (m, 2H, 
C(5)--H); 5.19 (m, 1H, C(2)--H); 5.75 (m, 2H,C(3)--H and C(4)--H). 
EXAMPLE 2 
E-2-amino-4-methyl-5-phosphono-3-pentenoic acid is obtained by hydrolysis 
of E-2-formylamino-4-methyl-5-diethylphosphono-3-pentenoic acid ethyl 
ester in a manner analogous to that described in Example 1, .sup.1 H-NMR 
(D.sub.2 O): 1.73 (s, 3H, CH.sub.3); 4.55 (s, 1H,C(2)--H). 
The starting material is manufactured as follows: 
By reaction of isocyanoacetic acid ethyl ester with methacrolein in a 
manner analogous to that described in Example 1, and after subsequent 
fractional distillation, 5-(2-propenyl)-2-oxazoline-4-carboxylic acid 
ethyl ester is obtained in the form of a colourless oil, b.p. 
110.degree.-130.degree. (5.3 Pa). 
2-Formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester, m.p. 
67.degree., is obtained by hydrolysis of 
5-(2-propenyl)-2-oxazoline-4-carboxylic acid ethyl ester in a manner 
analogous to that described in Example 1. 
By reaction of 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl 
ester with thionyl bromide and subsequent treatment with triethyl 
phosphite in a manner analogous to that described in Example 1, 
E-2-formylamino-4-methyl-5-diethylphosphono-3-pentenoic acid ethyl ester 
is obtained in the form of a pale yellow oil. 
EXAMPLE 3 
By hydrolysis of E-2-formylamino-5-(O-ethylmethylphosphonyl)-3-pentenoic 
acid ethyl ester in a manner analogous to that described in Example 1, 
after precipitation with propylene oxide 
E-2-amino-5-methylphosphonyl-3-pentenoic acid is obtained in the form of 
an amorphous white powder, .sup.1 H-NMR (D.sub.2 O): 2.55 (dd, 2H, 
C(5)--H); 4.38 (d, 1H, C(2)--H); 5.64 (m, 1H, C(3)--H); 5.91 (m, 1H, 
C(4)--H). 
The starting material is manufactured as follows: 
By reaction of E-2-formylamino-3-hydroxy-4-pentenoic acid ethyl ester with 
thionyl bromide and subsequent treatment with methylphosphonous acid 
diethyl ester instead of triethyl phosphite in a manner analogous to that 
described in Example 1, 
E-2-formylamino-5-(O-ethyl-methylphosphonyl)-3-pentenoic acid ethyl ester 
is obtained in the form of a colourless oil, .sup.1 H-NMR (CDCl.sub.3): 
2.63 (dd, 2H, C(5)--H); 5.1 (m, 1H, C(2)--H); 5.75 (m, 2H, C(3)--H) and 
C(4)--H). 
EXAMPLE 4 
25 g of E-2-formylamino-5-O-ethyl-diethoxymethylphosphonyl-3-pentenoic acid 
ethyl ester are stirred under reflux for 16 hours with 500 ml of 6N 
hydrochloric acid and the whole is then concentrated in vacuo at 
70.degree.. The residue is suspended in 100 ml of 95% ethanol/water, 20 ml 
of propylene oxide are added and the product is filtered off. 
Recrystallisation from water yields E-2-amino-5-phosphino-3-pentenoic 
acid, m.p. 139.degree.-140.degree.. 
The starting material is manufactured as follows: 
10 g of 2-formylamino-3-hydroxy-4-pentenoic acid ethyl ester in 50 ml of 
dry tetrahydrofuran are cooled to -78.degree.. 12.7 g of thionyl chloride 
are added dropwise in such a manner that the reaction temperature does not 
exceed -75.degree.. Subsequently, the reaction solution is warmed to 
-20.degree. within a period of 3 hours and stirred at that temperature for 
3 hours. The yellow solution is then poured onto 300 ml of a cold 
(5.degree.) saturated aqueous sodium hydrogen carbonate solution and 
extracted with dichloromethane. The organic extracts are dried over sodium 
sulphate and concentrated by evaporation in vacuo at 30.degree.. The 
residue is pre-purified by column chromatography (silica gel, ethyl 
acetate), and the light-yellow oil that remains is dissolved in 10 ml of 
tetrahydrofuran. After the addition of 17.0 g of diethoxymethylphosphonous 
acid ethyl trimethylsilyl ester, the whole is stirred for 24 hours at 
35.degree.. The dark-yellow solution is then poured onto 100 ml of a cold 
(5.degree.) saturated sodium hydrogen carbonate solution and extracted 
with dichloromethane. The organic extracts are dried over sodium sulphate 
and concentrated by evaporation in vacuo at 30.degree.. After purification 
of the residue by column chromatography (silica gel, ethyl 
acetate/methanol), 
E-2-formylamino-5-O-ethyl-diethoxymethylphosphonyl-3-pentenoic acid ethyl 
ester is obtained in the form of a light-yellow oil, .sup.1 H-NMR 
(CDCl.sub.3): 2.70 (m, 2H, C(5)--H); 4.68 (q, 1H, C(2)--H); 5.20 (m, 1H, 
(C--P)--H); 5.80 (m, 2H, C(3)--H and C(4)--H). 
EXAMPLE 5 
a) 1.0 g of E-2-amino-5-phosphino-3-pentenoic acid is suspended in 20 ml of 
ethanol and the suspension is saturated with hydrogen chloride gas for 2 
hours at 65.degree.. After concentration, the residue is dissolved in 10 
ml of ethanol, 10 ml of propylene oxide are added and the precipitate is 
filtered off. Recrystallisation from water/acetone 1:1 yields 
E-2-amino-5-phosphino-3-pentenoic acid ethyl ester, m.p. 
172.degree.-173.degree.. 
b) 1.0 g of E-2-amino-5-phosphino-3-pentenoic acid is suspended in 20 ml of 
n-butanol and the suspension is saturated with hydrogen chloride gas for 3 
hours at 60.degree.. After concentration, the residue is dissolved in 15 
ml of n-butanol, 10 ml of propylene oxide are added and the precipitate is 
filtered off. Recrystallisation from water/acetone 1:1 yields 
E-2-amino-5-phosphino-3-pentenoic acid butyl ester, m.p. 
160.degree.-161.degree.. 
EXAMPLE 6 
a) 2.0 g of E-2-amino-5-phosphono-3-pentenoic acid are placed in 50 ml of 
ethanol and the whole is saturated with hydrogen chloride gas for 21/2 
hours at 50.degree.. After concentration, the residue is dissolved in 18 
ml of ethanol, 18 ml of propylene oxide are added and the precipitate is 
filtered off. Recrystallisation from water/ethanol 1:3 yields 
2-amino-5-phosphono-3-pentenoic acid ethyl ester, m.p. 
167.degree.-168.degree.. 
b) 2.0 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 40 ml 
of n-butanol and the suspension is saturated with hydrogen chloride gas 
for 3 hours at 40.degree.. After concentration, the residue is dissolved 
in 30 ml of n-butanol, 15 ml of propylene oxide are added and the 
precipitate is filtered off. Recrystallisation from water/acetone 1:1 
yields E-2-amino-5-phosphono-3-pentenoic acid butyl ester, m.p. 
160.degree.-161.degree.. 
c) 2.0 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml 
of n-octanol and the suspension is saturated with hydrogen chloride gas 
for 4 hours at 70.degree.. The mixture is concentrated in vacuo at 
70.degree. to half its volume, 50 ml of diethyl ether and 15 ml of 
propylene oxide are added and the whole is filtered. Recrystallisation 
from water/acetone 1:1 yields E-2-amino-5-phosphono-3-pentenoic acid octyl 
ester, m.p. 161.degree.-162.degree.. 
d) 2.0 g of 2-amino-5-phosphono-3-pentenoic acid are suspended in 15 ml of 
1-dodecanol and 25 ml of tetrahydrofuran and the suspension is saturated 
with hydrogen chloride gas for 4 hours at 50.degree.. The mixture is freed 
of tetrahydrofuran in vacuo at 50.degree., 40 ml of acetone and 20 ml of 
propylene oxide are added and the whole is filtered. There is obtained 
from water/acetone 1:1, after stirring, E-2-amino-5-phosphono-3-pentenoic 
acid dodecyl ester, m.p. 158.degree.-159.degree.. 
e) 1.5 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml 
of n-propanol and the suspension is saturated with hydrogen chloride gas 
for 21/2 hours at 50.degree.. After concentration, the residue is 
dissolved in 15 ml of n-propanol, 15 ml of propylene oxide are added and 
the precipitate is filtered off. Recrystallisation from water/acetone 1:3 
yields E-2-amino-5-phosphono-3-pentenoic acid propyl ester, m.p. 
161.degree.-162.degree.. 
f) 1.5 g of 2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml of 
n-pentanol and the suspension is saturated with hydrogen chloride gas for 
3 hours at 50.degree.. After concentration, the residue is dissolved in 15 
ml of n-pentanol, 15 ml of propylene oxide are added and the precipitate is 
filtered off. Recrystallisation from water/acetone 1:1 yields 
E-2-amino-5-phosphono-3-pentenoic acid pentyl ester, m.p. 
160.degree.-161.degree.. 
g) 1.5 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml 
of isobutanol and the suspension is saturated with hydrogen chloride gas 
for 31/2 hours at 70.degree.. After concentration, the residue is 
dissolved in 10 ml of isobutanol, 10 ml of propylene oxide are added and 
the precipitate is filtered off. Recrystallisation from water/acetone 1:1 
yields E-2-amino-5-phosphono-3-pentenoic acid isobutyl ester, m.p. 
163.degree.-164.degree.. 
h) 1.5 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml 
of sec.-butanol and the suspension is saturated with hydrogen chloride gas 
for 4 hours at 75.degree.. After concentration, the residue is dissolved in 
10 ml of 2-butanol, 10 ml of propylene oxide are added and the precipitate 
is filtered off. Recrystallisation from water/acetone 1:1 yields 
E-2-amino-5-phosphono-3-pentenoic acid sec.-butyl ester, m.p. 
169.degree.-170.degree.. 
EXAMPLE 7 
E-2-amino-4-methyl-5-phosphono-3-pentenoic acid is obtained by hydrolysis 
of E-2-formylamino-4-methyl-5-dimethyl-phosphono-3-pentenoic acid ethyl 
ester in a manner analogous to that described in Example 1. For .sup.1 
H-NMR see Example 18. E-2-amino-4-methyl-5-methylphosphono-3-pentenoic 
acid, m.p. 149.degree.-150.degree., is obtained as a byproduct in 
preliminary fractions. 
The starting material is manufactured as follows: 
By reaction of 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl 
ester with thionyl bromide and subsequent treatment with trimethyl 
phosphite in a manner analogous to that described in Example 1, 
E-2-formylamino-4-methyl-5-dimethylphosphono-3-pentenoic acid ethyl ester 
is obtained in the form of a pale yellow oil. 
EXAMPLE 8 
a) 2.0 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid are placed in 
50 ml of ethanol and the whole is saturated with hydrogen chloride gas for 
21/2 hours at 50.degree.. After concentration, the residue is dissolved in 
20 ml of ethanol, 20 ml of propylene oxide are added and the precipitate 
is filtered off. Recrystallisation from water/ethanol (1:3) yields 
E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, m.p. 
193.degree.-194.degree.. 
The following esters are obtained in an analogous manner: 
b) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid methyl ester, m.p. 
193.degree.-194.degree. [water/acetone (9:1)]; 
c) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-propyl ester, m.p. 
184.degree.-185.degree., (water); 
d) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-butyl ester, m.p. 
186.degree.-187.degree., [water/acetone (2:1)]; 
e) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid isobutyl ester, m.p. 
181.degree.-182.degree., [water/acetone (9:1)]; 
f) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-pentyl ester, m.p 
207.degree.-208.degree.; 
g) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid n-hexyl ester, m.p. 
207.degree.-208.degree.. 
EXAMPLE 9 
21 g of 
E-2-formylamino-4-methyl-5-O-ethyldiethoxymethylphosphonyl-3-pentenoic 
acid ethyl ester are stirred for 16 hours at 80.degree. with 400 ml of 
4.35N hydrochloric acid and the whole is subsequently concentrated in 
vacuo at 45.degree.. The residue is dissolved in 100 ml of ethanol and 30 
ml of propylene oxide are added, and the product is filtered off. 
Recrystallisation from water yields 
E-2-amino-4-methyl-5-phosphino-3-pentenoic acid, m.p. 
176.degree.-177.degree.. 
The starting material is manufactured as follows: 
50 g of 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester in 
500 ml of dry tetrahydrofuran are cooled to -78.degree.. 89 g of thionyl 
chloride are added dropwise thereto in such a manner that the reaction 
temperature does not exceed -70.degree.. Subsequently, the reaction 
solution is warmed to -10.degree. within a period of 3 hours and is 
stirred for 3 hours at that temperature and then concentrated under a high 
vacuum at 20.degree.. 
The residue is taken up in 400 ml of dichloromethane and neutralised with 
saturated aqueous sodium hydrogen carbonate solution. The organic extracts 
are dried over sodium sulphate and concentrated by evaporation in vacuo at 
30.degree.. The residue is prepurified by column chromatography (silica 
gel, ethyl acetate) and the light-yellow oil that remains is dissolved in 
30 ml of toluene. After the addition of 94 g of diethoxymethylphosphonous 
acid ethyl trimethylsilyl ester, the whole is stirred for 16 hours at 
90.degree.. The dark-yellow solution is poured onto ice/water, neutralised 
with sodium hydrogen carbonate and extracted with dichloromethane. The 
organic extracts are dried over sodium sulphate and concentrated by 
evaporation in vacuo at 30.degree.. Purification of the residue by column 
chromatography (silica gel, ethyl acetate, then ethyl acetate/methanol 
9:1) yields 
E-2-formylamino-4-methyl-5-O-ethyl-diethoxymethylphosphonyl-3-pentenoic 
acid ethyl ester in the form of a light-yellow oil, .sup.1 H-NMR 
(CDCl.sub.3): 2.64 (dd, 2H, C(5)--H); 4.60 (d, 1H, P--CH); 5.26 (m, 2H, 
C(2)--H and c(3)--H). 
EXAMPLE 10 
Racemate separation of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid. 
A solution of 1.5 ml of phenylacetyl chloride in 25 ml of 1,4-dioxan is 
added at 20.degree., within a period of 20 minutes, to 209 mg of 
E-2-amino-4-methyl-5-phosphono-3-pentenoic acid in 21 ml of 2N sodium 
hydroxide solution while stirring vigorously, and the whole is stirred for 
4 hours at room temperature. The reaction solution is poured onto 250 ml of 
water and repeatedly extracted with dichloromethane. The aqueous phase is 
concentrated to 20 ml in vacuo at 40.degree., pre-purified by ion exchange 
chromatography (DOWEX 50 W.times.8/water/1,4-dioxan 3:1) and concentrated 
in vacuo at 40.degree.. The resulting 
E-2-phenylacetylamino-4-methyl-5-phosphono-3-pentenoic acid is adjusted to 
pH 7.5 in 150 ml of water with 2N sodium hydroxide solution and stirred for 
16 hours at 37.degree. with 250 mg of EUPERGIT-ACYLASE. After filtering in 
vacuo at 40.degree. , the mixture is concentrated to 10 ml and separated 
by ion exchange chromatography (DOWEX 50 W.times.8/water) into 
(D)-E-2-phenylacetylamino-4-methyl-5-phosphono-3-pentenoic acid and into 
(L)-E-2-amino-4-methyl-5-phosphono-3-pentenoic acid. 
a) The aqueous phases of (L)-E-2-amino-4-methyl-5-phosphono-3-pentenoic 
acid are concentrated in vacuo and the residue is purified by 
recrystallisation from water, m.p. 196.degree., [.alpha.].sub.D.sup.20 
=+97.1+1.9.degree. (c=0.5; water). 
b) The aqueous phases of 
(D)-E-2-phenylacetylamino-4-methyl-5-phosphono-3-pentenoic acid are 
concentrated in vacuo and the residue is stirred for 3.5 hours at 
85.degree. with 25 ml of 4.35N hydrochloric acid and then repeatedly 
extracted with dichloromethane. Concentration of the aqueous phases in 
vacuo and purification of the residue by ion exchange chromatography yield 
(D)-E-2-amino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 194.degree., 
[.alpha.].sub.D.sup.20 =-96.7+1.2.degree. (c=0.8; water). 
EXAMPLE 11 
2..5 g of E-2-formylamino-5-O-ethyl-methylphosphonyl-4-methyl-3-pentenoic 
acid ethyl ester are heated for 26 hours under nitrogen at 80.degree. in 
200 ml of 4.35N hydrochloric acid. The whole is concentrated by 
evaporation in vacuo and the residue is dissolved, in each case twice, in 
200 ml each of water, tetrahydrofuran and ethanol, the solutions each time 
being concentrated by evaporation in vacuo. Dissolving in 150 ml of 
ethanol, the addition of 5 ml of propylene oxide in 100 ml of 
tetrahydrofuran/ethanol (1:1) at 0.degree. within a period of 20 minutes, 
filtration of the precipitate and drying for 12 hours at 50.degree. in 
vacuo yield crude E-2-amino-4-methyl-5-methylphosphonyl-3-pentenoic acid, 
which is purified by chromatography on 20 g of Dowex 50 W.times.8 (H.sub.2 
O) (amorphous white powder), .sup.1 H-NMR (D.sub.2 O): 1.20 (d, 3H, 
CH.sub.3 --P); 1.75 (d, 3H, CH.sub.3); 2.45 (d, 2H, C(5)--H); 4.50 (d, 1H, 
C(2)--H); 5.15 (m, 1H, C(3)--H). 
The starting material is manufactured by reaction of 
2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester with thionyl 
bromide in the manner described in Example 2 and subsequent treatment with 
methylphosphonous acid diethyl ester instead of triethyl phosphite. 
EXAMPLE 12 
14.5 g of E-2-formylamino-2-methyl-5-diethylphosphono-3-pentenoic acid 
methyl ester are heated for 32 hours under nitrogen at 
100.degree.-105.degree. in 500 ml of 4.35N hydrochloric acid. Working up 
as in Example 11 yields E-2-amino-2-methyl-5-phosphono-3-pentenoic acid, 
m.p. 225.degree.-226.degree. (from water). 
The starting material is manufactured as follows: 
A solution of 14.1 g of 2-isocyanopropionic acid methyl ester and 8.5 g of 
freshly distilled acrolein in 50 ml of tetrahydrofuran is added within a 
period of 20 minutes at 0.degree.-5.degree. under nitrogen to a solution 
of 17 g of anhydrous zinc chloride in 75 ml of tetrahydrofuran, and the 
whole is stirred for 45 hours at 0.degree.-5.degree.. The whole is poured 
onto 500 ml of 10% sodium hydrogen carbonate solution and extracted with 
200 ml of dichloromethane. The organic phase is dried over sodium sulphate 
and concentrated by evaporation. Filtration of the residue over silica gel 
(ethyl acetate as eluant) yields 4-methyl-5-vinyl-2-oxazoline-4-carboxylic 
acid methyl ester. By hydrolysis of the 
4-methyl-5-vinyl-2-oxazoline-4-carboxylic acid methyl ester in a manner 
analogous to that described in Example 1, 
2-formylamino-2-methyl-3-hydroxy-4-pentenoic acid methyl ester is 
obtained. By reaction of the 2-formylamino-3-hydroxy-2-methyl-4-pentenoic 
acid methyl ester with thionyl bromide and subsequent treatment with 
triethyl phosphite in the manner described in Example 1, 
E-2-formylamino-2-methyl-5-diethylphosphono-3-pentenoic acid methyl ester 
is obtained in the form of a yellow oil: 
Calculated C: 46.91%; H: 7.22%; N: 4.56%; P: 10.08%; 
Found C: 46.1%; H: 7.3%; N: 4.1%; P: 10.6%. 
EXAMPLE 13 
6.3 g of E-2-formylamino-3-methyl-5-diethylphosphono-3-pentenoic acid ethyl 
ester are heated for 30 hours at 100.degree.-100.degree. under nitrogen in 
400 ml of 4.35N hydrochloric acid. Working up as in Example 11 yields 
E-2-amino-3-methyl-5-phosphono-3-pentenoic acid in the form of a white 
powder, m.p. 168.degree., .sup.1 H-NMR (D.sub.2 O): 1.50 (d, 3H, 
CH.sub.3); 2.4 (m, 2H, CH.sub.2); 4.30 (s, 1H, C(2)--H); 5.60 (m, 1H, 
C(4)--H). 
The starting material is manufactured as follows: 
5-Methyl-5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester, b.p. 
65.degree.-75.degree. (13 Pa) is obtained by reaction of isocyanoacetic 
acid ethyl ester with methyl vinyl ketone in a manner analogous to that 
described in Example 30. By hydrolysis of the 
5-methyl-5-vinyl-2-oxazoline-4-carboxylic acid ethyl ester in a manner 
analogous to that described in Example 1, 
2-formylamino-3-hydroxy-3-methyl-4-pentenoic acid ethyl ester is obtained. 
Reaction of the 2-formylamino-3-hydroxy-3-methyl-4-pentenoic acid ethyl 
ester with thionyl bromide and subsequent treatment with triethyl 
phosphite in a manner analogous to that described in Example 1 yields 
E-2-formylamino-3-methyl-5-diethylphosphono-3-pentenoic acid ethyl ester 
in the form of a colourless liquid. 
EXAMPLE 14 
E-2-formylamino-5-diethylphosphono-5-methyl-3-pentenoic acid ethyl ester is 
hydrolysed with 4.35N hydrochloric acid in the manner described in Example 
11. E-2-amino-5-methyl-5-phosphono-3-pentenoic acid is isolated in the 
form of an amorphous white solid mass. .sup.1 H-NMR (D.sub.2 O): 1.05 (dd, 
3H, CH.sub.3); 2.45 (m, 1H, C(5)--H); 4.33 (d, 2H, C(2)--H); 5.5 and 5.9 
(2m, 2H, C(3)--H and C(4)--H). 
The starting material is manufactured as follows: Reaction of 
crotonaldehyde with isocyanoacetic acid ethyl ester in a manner analogous 
to that described in Example 1 yields 
5-(propen-1-yl)-2-oxazoline-4-carboxylic acid ethyl ester. By hydrolysis 
of the 5-(propen-1-yl)-2-oxazoline-4-carboxylic acid ethyl ester 
analogously to Example 1, 2-formylamino-3-hydroxy-4-hexenoic acid ethyl 
ester is obtained. Reaction of the 2-formylamino-3-hydroxy-4-hexenoic acid 
ethyl ester with thionyl bromide and subsequent treatment with triethyl 
phosphite in a manner analogous to that described in Example 1 (12 hours) 
yields E-2-formylamino-5-diethylphosphono-5-methyl-3-pentenoic acid ethyl 
ester. 
EXAMPLE 15 
Hydrolysis of E-2-formylamino-4-ethyl-5-dimethylphosphono-3-pentenoic acid 
ethyl ester in a manner analogous to that described in Example 11 yields 
E-2-amino-4-ethyl-5-phosphono-3-pentenoic acid, m.p,. 17620 (H.sub.2 O). 
The starting material is manufactured as follows: Reaction of 
2-methylene-butyraldehyde with isocyanoacetic acid ethyl ester in a manner 
analogous to that described in Example 1 yields 
5-(buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester. A solution of 16 
g of 5-(buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester in 100 ml of 
ethanol/water (1:1) is heated at the boil, under reflux, for 15 hours. The 
whole is concentrated by evaporation in vacuo, the residue is taken up in 
200 ml of dichloromethane, dried over sodium sulphate and filtered, and 
the filtrate is concentrated by evaporation to yield 
2-formylamino-3-hydroxy-4-ethyl-4-pentenoic acid ethyl ester. 
Reaction of the 2-formylamino-3-hydroxy-4-ethyl-4-pentenoic acid ethyl 
ester with thionyl bromide and subsequent treatment with trimethyl 
phosphite in a manner analogous to that described in Example 1 yields 
E-2-formylamino-4-ethyl-5-dimethylphosphono-3-pentenoic acid ethyl ester. 
EXAMPLE 16 
Hydrolysis of E-2-formylamino-4-propyl-5-dimethylphosphono-3-pentenoic acid 
ethyl ester in a manner analogous to that described in Example 11 yields 
E-2-amino-4-propyl-5-phosphono-3-pentenoic acid, m.p. 193.degree. (H.sub.2 
O). 
The starting material is manufactured as follows: Reaction of 
2-methylene-pentanal with isocyanoacetic acid ethyl ester analogously to 
Example 1 yields 5-(penten-2-yl)-2-oxazoline-4-carboxylic acid ethyl 
ester. By hydrolysis of the 5-(penten-2-yl)-2-oxazoline-4-carboxylic acid 
ethyl ester in a manner analogous to that described in Example 15, 
2-formylamino-3-hydroxy-4-propyl-4-pentenoic acid ethyl ester is obtained. 
Reaction of the 2-formylamino-3-hydroxy-4-propyl-4-pentenoic acid ethyl 
ester with thionyl bromide and subsequent treatment with trimethyl 
phosphite in a manner analogous to that described in Example 1 yields 
E-2-formylamino-4-propyl-5-dimethylphosphono-3-pentenoic acid ethyl ester. 
EXAMPLE 17 
Hydrolysis of E-2-formylamino-4-butyl-5-dimethylphosphono-3-pentenoic acid 
ethyl ester in a manner analogous to that described in Example 11 yields 
E-2-amino-4-butyl-5-phosphono-3-pentenoic acid, m.p. 
186.degree.-187.degree.. (H.sub.2 O). 
The starting material is manufactured as follows: Reaction of 
2-methylene-hexanal with isocyanoacetic acid ethyl ester analogously to 
Example 1 yields 5-(hexen-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, 
which is hydrolysed in a manner analogous to that described in Example 15 
to 2-formylamino-3-hydroxy-4-butyl-4-pentenoic acid ethyl ester. Reaction 
of the 2-formylamino-3-hydroxy-4-butyl-4-pentenoic acid ethyl ester with 
thionyl bromide and subsequent treatment with trimethyl phosphite 
analogously to Example 1 yields 
E-2-formylamino-4-butyl-5-dimethylphosphono-3-pentenoic acid ethyl ester. 
EXAMPLE 18 
Hydrolysis of E-2-formylamino-4-isopropyl-5-dimethylphosphono-3-pentenoic 
acid ethyl ester analogously to Example 11 yields 
E-2-amino-4-isopropyl-5-phosphono-3-pentenoic acid, m.p. 201.degree. 
(H.sub.2 O). 
The starting material is manufactured as follows: Reaction of 
3-methyl-2-methylene-tutanal with isocyanoacetic acid ethyl ester 
analogously to Example 1 yields 
5-(3-methyl-buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, which 
is hydrolysed analogously to Example 15 to 
2-formylamino-3-hydroxy-4-isopropyl-4-pentenoic acid ethyl ester. 
Subsequent treatment with thionyl bromide followed by reaction with 
trimethyl phosphite analogously to Example 1 yields 
E-2-formylamino-4-isopropyl-5-dimethylphosphono-3-pentenoic acid ethyl 
ester. 
EXAMPLE 19 
3.9 g of E-2-formylamino-4-tert.-butyl-5-dimethylphosphono-3-pentenoic acid 
ethyl ester are hydrolysed analogously to Example 12. Separation by ion 
exchange chromatography (Dowex W 50, H.sub.2 O) yields 1.8 g of 
E-2-amino-4-tert.-butyl-5-phosphono-3-pentenoic acid and 0.075 g of 
Z-2-amino-4-tert.-butyl-5-phosphono-3-pentenoic acid. 
E-isomer: M.p. 252.degree.-253.degree. (H.sub.2 O); .sup.1 H-NMR (D.sub.2 
O): 0.95 (s, 9H, (CH.sub.3).sub.3 C); 2.65 (m, 2H, CH.sub.2); 
approximately 4.7 (d, 1 H, C(2)--H); 5.33 (m, 1 H, C(3)--H). 
Z-isomer: .sup.1 H-NMR (D.sub.2 O): 1.08 (s, 9H, (CH.sub.3).sub.3 C); 2.45 
(m, 2H, CH.sub.2); 4.95 (d, 1 H, C(2)--H); 5.20 (m, 1 H, C(3)--H). 
The starting material is manufactured as follows: Reaction of 
3,3-dimethyl-2-methylene-butanal with isocyanoacetic acid ethyl ester in a 
manner analogous to that described in Example 1 yields 
5-(3,3-dimethylbuten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, 
which is hydrolysed analogously to Example 17 to 
2-formylamino-3-hydroxy-4-tert.-butyl-4-pentenoic acid ethyl ester. 
Subsequent reaction with thionyl bromide followed by treatment with 
trimethyl phosphite analogously to Example 1 yields 
E-2-formylamino-4-tert.-butyl-5-dimethylphosphono-3-pentenoic acid ethyl 
ester. 
EXAMPLE 20 
0.44 g of E-2-formylamino-4-benzyl-5-diethylphosphono-3-pentenoic acid 
ethyl ester are dissolved in 8 ml of 4.5N hydrochloric acid and heated at 
85.degree. for 48 hours. After concentration in vacuo, the residue is 
dissolved in a small amount of ethanol and 1 ml of ethanol/propylene oxide 
(1:1) is added dropwise thereto. The resulting white precipitate is 
filtered off and, after recrystallisation from water, 
E-2-amino-4-benzyl-5-phosphono-3-pentenoic acid is obtained in the form of 
colourless needles, m.p. 196.degree.-198.degree.. 
The starting material is manufactured as follows: By reaction of 
isocyanoacetic acid ethyl ester with 2-benzyl-propenal in a manner 
analogous to that described in Example 1 and after purification by column 
chromatography (silica gel; dichloromethane/ethyl acetate 98:2), 
5-(3-phenyl-propen-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester is 
obtained in the form of a colourless oil, .sup.1 H-NMR (CDCl.sub.3): 3.33 
(s, 2H, CH.sub.2); 4.37 (dd, 1H, C(4)--H); 4.87 (s, 1H); 5.07 (dd, 1H, 
C(5)--H); 5.16 (s, 1H). 
By hydrolysis of the 5-(3-phenyl-propen-2-yl)-2-oxazoline-4-carboxylic acid 
ethyl ester in a manner analogous to that described in Example 1, 
2-formylamino-3-hydroxy-4-benzyl-4-pentenoic acid ethyl ester is obtained, 
m.p. 87.degree.-89.degree.. 
By reaction of 2-formylamino-3-hydroxy-4-benzyl-3-pentenoic acid ethyl 
ester with thionyl bromide and subsequent treatment with triethyl 
phosphite at 100.degree. in a manner analogous to that described in 
Example 1, and after chromatography (silica gel; ethyl acetate), 
E-2-formylamino-4-benzyl-5-diethylphosphono-3-pentenoic acid ethyl ester 
is obtained in the form of a colourless oil, .sup.1 H-NMR (CDCl.sub.3): 
2.45 (d, 2H, C(5)--H); 3.80 (s, 1H, CH.sub.2); 5.51 (m, 1H, C(3)--H). 
EXAMPLE 21 
0.15 g of E-2-formylamino-4-phenyl-5-diethylphosphono-3-pentenoic acid 
methyl ester are dissolved in 10 ml of 4.5N hydrochloric acid and heated 
at 75.degree. for 192 hours. After concentration in vacuo, the foamy 
residue is dissolved in a small amount of ethanol and 1 ml of 
ethanol/propylene oxide (1:1) is added dropwise thereto. The resulting 
white precipitate is filtered off and recrystallised from water/acetone 
(1:2). E-2-amino-4-phenyl-5-phosphono-3-pentenoic acid is thus obtained in 
the form of colourless needles, m.p. 230.degree.-233.degree.. 
The starting material is manufactured as follows: 
By reaction of isocyanoacetic acid methyl ester with 2-phenylacrolein in a 
manner analogous to that described in Example 1, and after purification by 
column chromatography (silica gel; dichloromethane/methanol 97.5:2.5), 
5-(1-phenyl-vinyl)-2-oxazoline-4-carboxylic acid methyl ester is obtained 
in the form of a pale yellow oil. .sup.1 H-NMR (CDCl.sub.3) 3.80 (s, 3H, 
CH.sub.3); 4.45 (dd, 1H, C(4)--H); 5.76 (d, 1H, C(5)--H). 
By hydrolysis of the 5-(1-phenyl-vinyl)-2-oxazoline-4-carboxylic acid 
methyl ester in a manner analogous to that described in Example 1, 
2-formylamino-3-hydroxy-4-phenyl-4-pentenoic acid methyl ester is 
obtained, m.p. 173.degree.-174.degree.. 
By reaction of the 2-formylamino-3-hydroxy-4-phenyl-4-pentenoic acid methyl 
ester with thionyl bromide and subsequent treatment with triethyl phosphite 
in a manner analogous to that described in Example 1, and after 
chromatography (silica gel; ethyl acetate/hexane 4:1), 
E-2-formylamino-4-phenyl-5-diethylphosphono-3-pentenoic acid methyl ester 
is obtained in the form of a colourless oil. .sup.1 H-NMR (CDCl.sub.3) 
2.98 (d, 2H, C(5)--H); 5.03 (dd, 1H, C(2)--H); 5.77 (dd, 1H, C(3)--H). 
EXAMPLE 22 
At 0.degree., 170 mg of sodium hydrogen carbonate and, within a period of 5 
minutes, 50 microliters of acetic anhydride are added to a solution of 100 
mg of E-2-amino-5-phosphono-3-pentenoic acid in 6 ml of dioxan/water 
(1:1). The whole is stirred for 30 minutes at 0.degree., approximately 2 
ml of Dowex 50 H.sup.+ are added and filtration is carried out. The 
filtrate is concentrated by evaporation and purified by ion exchange 
chromatography (Dowex 50 H.sup.+). Lyophilisation of the pure fractions 
yields 110 mg of E-2-acetamino-5-phosphono-3-pentenoic acid, m.p. 
155.degree.. 
EXAMPLE 23 
E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester 
a) 5-(2-propenyl)-oxazoline-4-carboxylic acid ethyl ester (1) 
1.6 g of red copper(I) oxide are introduced into 200 ml of benzene. A 
solution of 140 g of isocyanoacetic acid ethyl ester and 105 g of freshly 
distilled methacrolein in 200 ml of benzene is added dropwise to this 
suspension within a period of 10 minutes with vigorous stirring, during 
which time the reaction temperature is kept at between 30.degree. and 
32.degree. by cooling with ice. When the addition is complete, the mixture 
is kept at 30.degree.-32.degree. until the exothermic reaction subsides, 
and is then stirred at room temperature for one hour. After excess 
copper(I) oxide has been filtered off, the filtrate is concentrated by 
evaporation in vacuo at 30.degree.. 600 ml of ether are added to the 
residue, which is then filtered over Celite and concentrated to dryness by 
evaporation in vacuo. In this manner, 
5-(2-propenyl)-2-oxazoline-4-carboxylic acid ethyl ester is obtained in 
the form of a colourless oil having a boiling point of 
110.degree.-130.degree. (5.3 Pa). 
b) E-2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester (2) 
139 g of 5-(2-propenyl)-2-oxazoline-4-carboxylic acid ethyl ester are 
dissolved in 70 ml of tetrahydrofuran, and 27.4 g of water and 3.5 g of 
triethylamine are added thereto. The reaction mixture is stirred at 
65.degree.-70.degree. for 62 hours and, after cooling, is taken up in 200 
ml of dichloromethane. The solution is dried over 200 g of magnesium 
sulphate, filtered and concentrated by evaporation in vacuo. Purification 
of the viscous oil which remains by column chromatography (silica gel; 
hexane/ ethyl acetate 3:2) yields 
2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester in the form 
of a diastereoisomeric mixture having a melting point of 67.degree.. 
c) E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoic acid ethyl 
ester (3) 
Under an argon atmosphere, 18.6 ml of thionyl bromide are added dropwise at 
20.degree., within a period of 5 minutes, to a solution of 40.20 g of crude 
2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester in 600 ml of 
1,2-dichloroethane (slight cooling). After stirring for two hours at room 
temperature, 400 ml of water are added, the first 50 ml being slowly added 
dropwise. The mixture is stirred thoroughly for a further 15 minutes to 
complete the reaction. The organic phase is separated off and washed three 
times with ice-water and once with ice/saturated potassium bicarbonate 
solution (pH approximately 7.5). Drying over sodium sulphate and removal 
of the 1,2-dichloroethane by distillation in vacuo at 35.degree. yields 
the crude bromide as intermediate, to which 160 ml of triisopropyl 
phosphite are added at room temperature, and the mixture is then stirred 
at 75.degree. (bath temperature) under a partial vacuum (approximately 13 
kPa) for 17 hours. The excess triisopropyl phosphite and other volatile 
by-products are then distilled off under a high vacuum (bath temperature 
90.degree.). Chromatography of the residue on ten times the amount by 
weight of silica gel (particle size 0.04-0.06 mm) using ethyl acetate as 
eluant yields E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoic 
acid ethyl ester in the form of a light-yellow honey, 
IR (CH.sub.2 Cl.sub.2): 3410 (NH); 1740 (CO ester); 1690 (CO amide); 1235 
(P.dbd.O); 980-1015 (P--O--C). 
d) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester (4) 
56.7 ml of trimethylbromosilane are added dropwise within a period of 15 
minutes at 20.degree. to a solution of 25.42 g of 
E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoic acid ethyl 
ester in 102 ml of dry dichloromethane. After stirring at room temperature 
for 20 hours, 102 ml of ethanol are added dropwise within a period of 15 
minutes, and the whole is stirred for a further 20 hours. The clear 
reaction solution is then completely concentrated by evaporation in vacuo. 
The residue is concentrated by evaporation a further three times in each 
case after the addition of 100 ml of toluene. The oily residue is 
dissolved in 102 ml of ethanol, and a solution of 102 ml of propylene 
oxide in 102 ml of ethanol is added dropwise thereto. The product, 
obtained in crystalline form, is filtered off after 2 hours (room 
temperature) and washed with ethanol and ether. After drying (80.degree., 
4 hours) under a high vacuum, E-2-amino-4-methyl-5 -phosphono-3-pentenoic 
acid ethyl ester is obtained in analytically pure form, m.p. 212.degree. 
(decomp.). 
EXAMPLE 24 
E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester 
a) E-2-formylamino-4-methyl-5-dimethylphosphono-3-pentenoic acid ethyl 
ester (1) 
100.5 g of 2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester 
are dissolved in 1.5 liters of dichloroethane, and then 47 ml of thionyl 
bromide are added dropwise at 20.degree.-25.degree. and the mixture is 
stirred at room temperature for one hour. 750 ml of water are added to the 
reaction mixture, which is then stirred vigorously for 10 minutes. The 
organic phase is separated off, extracted with 1 liter of ice-water, 1 
liter of 1N potassium hydrogen carbonate solution and a further 1 liter of 
ice-water, dried over magnesium sulphate and concentrated by evaporation. 
50 ml of trimethyl phosphite are added directly to the resulting 
E-5-bromo-2-formylamino-4-methyl-3-pentenoic acid ethyl ester, a yellow 
oil, and the mixture is stirred at a bath temperature of 70.degree. and 
approximately 15 kPa for 15 hours. The reaction mixture is degassed for 30 
minutes under a water-jet vacuum and for one hour under a high vacuum at 
40.degree. -50.degree.. The resulting product is taken up in 600 ml of 
water and extracted three times with 500 ml of ethyl acetate each time. 
The combined organic phases are washed twice with 300 ml of water each 
time. All the aqueous phases are combined, saturated with sodium chloride 
and extracted three times with 500 ml of dichloromethane each time. The 
combined organic phases are dried over magnesium sulphate and concentrated 
by evaporation. The product is chromatographed over silica gel (ethyl 
acetate/isopropanol 7:2). In this manner, 
E-2-formylamino-4-methyl-5-dimethylphosphono-3-pentenoic acid ethyl ester 
is obtained in the form of a yellow oil, .sup.1 H-NMR (DMSO): 1.82 (d, 3H, 
4--CH.sub.3); 2.69 (d, 2H); 5.03 (m, 1 H); 5.32 (m, 1 H). 
b) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester (2) 
16.9 g of E-2-formylamino-4-methyl-5-dimethylphosphono-3-pentenoic acid 
ethyl ester are dissolved in 80 ml of dichloromethane under a nitrogen 
atmosphere, and 30 ml of trimethylbromosilane are added dropwise at 
approximately 25.degree. within a period of 30 minutes. The mixture is 
stirred at room temperature for 20 hours, and then 80 ml of ethanol are 
added dropwise at approximately 25.degree. within a period of 30 minutes. 
The mixture is then again stirred at room temperature for 22 hours and is 
then concentrated by evaporation. The residue is dissolved in 80 ml of 
ethanol, and 80 ml of propylene oxide in 80 ml of ethanol are added 
dropwise with slight cooling. The mixture is stirred at room temperature 
for one hour to complete the reaction, filtered and washed with ethanol 
and ether. In this manner there is obtained 
E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, m.p. 
215.degree.-217.degree. (decomp.). 
EXAMPLE 25 
E-2-amino-4 -methyl-5-phosphono-3-pentenoic acid ethyl ester 
a) E-2-formylamino-4-methyl-5-di(2-chloroethyl)phosphono-3-pentenoic acid 
ethyl ester (1) 
8.2 g of E-5-bromo-2-formylamino-4-methyl-3-pentenoic acid ethyl ester and 
19 ml of tris-(2-chloroethyl)-phosphite are stirred at a bath temperature 
of 70.degree. for 20 hours. The resulting mixture is chromatographed on 
silica gel using ethyl acetate and ethyl acetate/isopropanol (7:1) as 
eluant, and the product is crystallised from ethyl acetate/diethyl ether. 
In this manner there is obtained 
E-2-formylamino-4-methyl-5-di(2-chloroethyl)phosphono-3-pentenoic acid 
ethyl ester, m.p. 47.degree.-49.degree.. 
b) E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester (2) 
In a manner analogous to that described in Example 24, using 3 g of 
E-2-formylamino-4-methyl-5-di(chloroethyl)phosphono-3-pentenoic acid ethyl 
ester, there is also obtained E-2-amino-4-methyl-5-phosphono-3-pentenoic 
acid ethyl ester, m.p. 215.degree. (decomp.). 
EXAMPLE 26 
E-2-amino-4-phosphonomethyl-3,6-heptadienoic acid 
a) 2-methylene-4-pentenealdehyde (1) 24.5 g of a 37% aqueous formaldehyde 
solution are added to a mixture of 14.7 g of piperazine, 20.5 g of glacial 
acetic acid and 21.28 g of water, and the whole is stirred at room 
temperature for 10 minutes. While continuing stirring, 25.35 g of 
4-pentenealdehyde are added, and the reaction mixture is heated at 
75.degree. for 3 hours. After cooling to room temperature, the organic 
phase is separated off and the aqueous phase is extracted three times with 
50 ml of diethyl ether each time. The combined organic phases are washed 
three times with 50 ml of a saturated sodium bicarbonate solution each 
time, dried over magnesium sulphate and concentrated by evaporation in 
vacuo. Fractional distillation of the residue yields 
2-methylene-4-pentenealdehyde in the form of a colourless oil, b.p. 
65.degree./6.6 kPa. 
b) 5-[2-(1,4-pentadienyl)]-2-oxazoline-4-carboxylic acid methyl ester (2) 
By reaction of isocyanoacetic acid methyl ester with 
2-methylene-4-pentenealdehyde in toluene in a manner analogous to that 
described in Example 23, and after subsequent purification by column 
chromatography (silica gel, ethyl acetate/hexane 1:4), 
5-(2-(1,4-pentadienyl))-2-oxazoline-4-carboxylic acid methyl ester is 
obtained in the form of a colourless oil, .sup.1 H-NMR (CDCl.sub.3): 2.80 
(d, 2H, CH.sub.2); 4.45 (dd, 1 H, C(4)--H); 5.82 (m, 1 H, C.dbd.CH--); 
7.00 (d, 1 H, C(2)--H). 
8.1 g of 5-(2-(1,4-pentadienyl))-2-oxazoline-4-carboxylic acid methyl ester 
are dissolved in 20 ml of tetrahydrofuran, and 10 ml of water are added 
thereto. The reaction mixture is stirred at 75.degree. for 1.5 hours and, 
after cooling, is concentrated by evaporation in vacuo. Crystallisation of 
the resulting residue from isopropanol/hexane yields 
2-formylamino-3-hydroxy-4-methylene-6-heptenoic acid methyl ester in the 
form of a diastereoisomeric mixture, m.p. 75.degree.-77.degree.. 
c) E-2-formylamino-4-bromomethyl-3,6-heptadienoic acid methyl ester (3) 
5.0 g of 2-formylamino-3-hydroxy-4-methylene-6-heptenoic acid methyl ester 
in 200 ml of dry tetrahydrofuran are cooled to -78.degree., and 20 ml of 
1,5-hexadiene are added thereto. 9 ml of thionyl bromide are added slowly 
dropwise in such a manner that the reaction temperature does not exceed 
-50.degree.. When the addition is complete, the reaction solution is 
heated to 0.degree. within a period of approximately 3 hours and is 
stirred at that temperature for 3 hours. The solution is then poured onto 
300 ml of a cold (5.degree.-10.degree.) saturated sodium bicarbonate 
solution and extracted with diethyl ether. The organic extracts are washed 
with saturated sodium chloride solution, dried over magnesium sulphate and 
concentrated by evaporation in vacuo. Purification by column 
chromatography (silica gel, ethyl acetate/hexane 1:1) yields 
E-2-formylamino-4-bromomethyl-3,6-heptadienoic acid methyl ester in the 
form of a colourless oil, .sup.1 H-NMR (CDCl.sub.3): 3.20 (d, 2H, C(5 
)--H); 4.00 (s, 2H, CH.sub.2 Br). 
d) E-2-formylamino-4-diethylphosphonomethyl-3,6-heptadienoic acid methyl 
ester (4) 
3.7 g of E-2-formylamino-4-bromomethyl-3,6-heptadienoic acid methyl ester 
are dissolved in 37 ml of triethyl phosphite, and the mixture is heated at 
75.degree. for 8 hours. Excess triethyl phosphite is then distilled off 
under a high vacuum. Purification by column chromatography (silica gel, 
methanol/ethyl acetate 1:10) yields 
E-2-formylamino-4-diethylphosphonomethyl-3,6-heptadienoic acid methyl 
ester in the form of a colourless oil, .sup.1 H-NMR (CDCl.sub.3): 2.54 (d, 
2H, P--CH.sub.2); 3.10 (m, 2H, C(5)--H); 5.10 (m, 2H, C(7)--H); 5.37 (d, 1 
H, C(2)--H); 5.74 (m, 1 H, C(6)--H). 
e) E-2-amino-4-phosphonomethyl-3,6-heptadienoic acid (5) 
0.74 g of E-2-formylamino-4-diethylphosphonomethyl-3,6-heptadienoic acid 
methyl ester is dissolved in 12 ml of dichloromethane, and 0.7 ml of 
trimethyliodosilane is added dropwise thereto. After stirring at room 
temperature for 4 hours, 1N sodium thiosulphate solution is added until 
the colour of the reaction solution becomes lighter. 10 ml of a 4.5N 
hydrochloric acid solution are then added to the reaction mixture, which 
is then stirred at room temperature for 30 minutes. The aqueous phase is 
separated off, washed twice with 20 ml of dichloromethane each time, and 
concentrated by evaporation in vacuo. The residue is dissolved in 10 ml of 
4.5N hydrochloric acid, stirred at room temperature for 16 hours, and then 
concentrated by evaporation in vacuo. The residue so obtained is taken up 
in 40 ml of ethanol and filtered until clear, and then 10 ml of propylene 
oxide/ethanol (1:1) are added dropwise. The resulting white precipitate is 
filtered off and purified by column chromatography (Dowex 
50.times.8/H.sub.2 O). Concentration yields 
E-2-amino-4-phosphonomethyl-3,6-heptadienoic acid in the form of a white 
crystallisate, m.p. 154.degree.-157.degree., .sup.1 H-NMR (D.sub.2 O): 
2.64 (d, 2H, P--CH.sub.2); 3.15 (m, 2H, C(5)--H); 5.20 (m, 2H, C(7)--H); 
5.50 (dd, 1 H, C(3)--H); 5.90 (m, 1 H, C(6)--H). 
EXAMPLE 27 
(2R)-2-amino-4-methyl-5-phosphono-3-pentenoic acid 
a) (L)-N-tert.butoxycarbonyl-serine-N-methoxy-N-methyl-amide (1) 541.6 ml 
of N-methylmorpholine are added within 27 minutes at -20.degree. to 
-25.degree. to a solution of 1 kg of (L)-N-tert.butoxycarbonyl-serine in 1 
liter of tetrahydrofurane. The reaction mixture is stirred for 15 minutes 
at this temperature. Then 699.6 ml of chloroformic acid isobutyl ester and 
subsequently 445,8 ml of N-methoxy-N-methylamine are added within 42 and 
40, resp. minutes. The reaction mixture is allowed to warm to room 
temperature and evaporated to dryness. The residue is dissolved in 3 
liters of ethyl acetate. The solution is extracted with 3.5 liters of 
2n-hydrochloric acid and subsequently with 3 l of saturated aqueous sodium 
hydrogencarbonate solution. The water-layers are extracted with 3 liters of 
ethyl acetate. All organic extracts are combined, washed with 2 liters of 
saturated sodium dichloride solution, dried over magnesium sulfate and 
evaporated at 50.degree. to dryness. The residue is triturated with 3.5 
liters of hexane with ice-cooling. The resulting white precipitate is 
filtrated off, washed with 1 l of hexane and dried under reduced pressure 
to yield 781 g -1, m.p. 116.degree.-117.degree.; calculated for C.sub.11 
H.sub.20 N.sub.2 O.sub.5 C 48.38%, H 8.12% N 11.28%; found C 48.28%, H 
8.02%, N 11.32%. 
b) (L)-3-tert.butoxycarbonyl-2,2-dimethyl-oxazolidine-4-carboxylic 
acid-N-methoxy-N-methyl-amide (2) 
A mixture of 781 g of 1, 3.3 liters of acetone dimethylacetal and 42 g of 
pyridinium(toluol-4-sulfonate) are warmed to 72.degree. and refluxed for 
17 hours. After addition of additional 20 g of 
pyridinium(toluol-4-sulfonate) heating to boil is continued for additional 
9 hours while gradually distilling of approximately 750 ml of solvent and 
adding 700 ml of acetone dimethylacetal. All volatile constituents we 
distilled off. The residue is dessolved in 2 liters of diethyl ether and 
extracted twice with 1 liter and 0.5 liter of n-hydrochloric acid, once 
with 0.3 liter of saturated sodium hydrogencarbonate solution and once 
with 0.3 liter of saturated sodium chloride solution. The aqueous extracts 
we re-extracted twice with 0.5 liter either time of diethyl ether. All 
organic extracts are combined, dried over magnesium sulfate and evaporated 
to dryness. The residue is dissolved hot in a 9:1-mixture of hexane and 
diethyl ether. After addition of additional 600 ml of hexane and 50 ml of 
diethyl ether, the reaction mixture is cooled down while during 
crystallisation with 1.1 liter of hexane. The precipitate formed is 
filtered off, washed with hexane and dried under reduced pressure at 
40.degree. yielding 640 g of 2; m.p. 67.degree.-68.degree.; calculated for 
C.sub.13 H.sub.24 N.sub.2 O.sub.5 C 54.15%, H 8.39%, N 9.72%; found C 
53.96%, H 8.37%, N 9.91%. 
c) (4S)-2,2-dimethyl-4-formyl-3-oxazolidine-carboxylic acid tert.butyl 
ester (3) 
2.53 g of lithium aluminium hydride are added with cooling to maintain a 
temperature of 5.degree. to 15.degree. to 28.8 g of 2, dissolved in 350 ml 
of diethyl ether. After stirring at 5.degree. for 1.5 hours a solution of 
5.77 g of sodium hydrogen sulfate is added slowly to keep the reaction 
temperature at 15.degree. (40 minutes). The suspensions formed is filtered 
clear and the solid portion is washed with ether. The filtrate is washed, 
with cooling, twice with 200 ml each of n-hydrochloric acid, twice with 
150 ml each of 5% sodium hydrogencarbonate solution and with 100 ml of 
saturated sodium chloride solution. The aqueous extracts are re-extracted 
with ether and all organic extracts are combined, dried over sodium 
sulfate and evaporated. The residue is distilled at 0.4 mb yielding 17.78 
g of 3; b.p. 85.degree.-90.degree., [.alpha.].sub.D =-93.degree.(c=1, 
CHCl.sub.3); calculated for C.sub.11 H.sub.19 NO.sub.4 C 57.63%, H 8.35% N 
6.11%, O 27.91%; found C 57.59%, H 8.54%, N 6.17%, O 27.74%. 
d) 
3-((4'R)-N-tert.-butoxycarbonyl-2',2'-dimethyl-4'-oxazolidinyl)-2-methylpr 
openoic acid ethyl ester (4) 
A solution of 39.5 g of (4S)-2,2-dimethyl-4-formyl-3-oxazolidinecarboxylic 
acid tert.-butyl ester 3 in 200 ml of dichloromethane is added dropwise 
within a period of 2 hours to a solution of 68.7 g of 
1-ethoxycarbonylethylidenetriphenylphosphorane in 900 ml of 
dichloromethane. After stirring at room temperature for 6 hours, the 
mixture is cooled to 10.degree. and there are then added dropwise within a 
period of 15 minutes 530 ml of a 10% aqueous sodium hydrogen phosphate 
solution. After stirring at 15.degree. for 30 minutes, the organic phase 
is separated off and the aqueous phase is extracted with 250 ml of 
dichloromethane. The organic phases are dried over magnesium sulphate and 
concentrated by evaporation. The residue is stirred with 70 ml of ether. 
The suspension is filtered and the filtration residue is washed with 
ether. The filtrate is concentrated by evaporation and the residue is 
separated by chromatography on silica gel. Elution with hexane/ethyl 
acetate 9:1 yields, in addition to 2.32 g of cis-isomer and 2.21 g of 
mixed fraction (cis/trans =38:62), 45.4 g of 4. .sup.1 H-NMR (60 MHz, 
CDCl.sub.3, trans-isomer): inter alia 4.7 ppm (m, H--C(4')); 6.7 ppm (d, 
J=9, H--C(3)). .sup.1 H-NMR (60 MHz, CDCl.sub.3, cis-isomer): inter alia 
5.2 ppm (m H--C(4')); 6.08 ppm (d, J=7, H--C(3)). 
e) 
(4R)-2,2-dimethyl-4-(3'-hydroxy-2'-methylprop-1'-enyl)oxazolidine-3-carbox 
ylic acid tert.-butyl ester (5) 
389 ml of a 1 molar solution of diisobutylaluminium hydride in hexane are 
added within a period of 15 minutes to a solution, cooled to 3.degree., of 
48.7 g of 4 in 1 liter of dry diethyl ether. The temperature of the mixture 
is allowed to rise to 11.degree., and there are then added thereto, while 
cooling with ice, 100 ml of ethyl acetate followed by 50 ml of 2N sodium 
hydroxide solution. The temperature of the mixture is allowed to rise to 
approximately 28.degree., without cooling, and then a further 7 ml of 2N 
sodium hydroxide solution are added. The mixture is stirred at room 
temperature for 15 hours, and then sodium sulphate is added and the whole 
is filtered. Concentration of the filtrate by evaporation yields 42.1 g of 
crude 2. A sample (0.97 g) is purified by chromatography on 40 g of silica 
gel. Elution with hexane/ethyl acetate 3:1 yields 0.74 g of 5. .sup.1 
H-NMR (300 MHz, DMSO-d.sub.6): inter alia 3.52 (d.times.d, J=9 and 3) and 
4.02 (d.times.d, J=9 and 6) (2H--C(5)); 3.78 (m, 2H--C(3')); 4.54 (m, 
H--C(4)); 4.81 (t, J=6, OH); 5.33 (d, J=9, H--C(1')). 
f) 
(4R)-2,2-dimethyl-4-(3'-bromo-2'-methylprop-1'-enyl)oxazolidine-3-carboxyl 
ic acid tert.-butyl ester (6) 
47.6 g of triphenylphosphine are added at 0.degree. to a solution of 41.0 g 
of 5 and 60.2 g of tetrabromomethane in 1 liter of dry diethyl ether. After 
30 minutes, the cooling bath is removed and the mixture is stirred at room 
temperature for 17 hours. 20 g of tetrabromomethane and 15.9 g of 
triphenylphosphine are added, and the mixture is stirred at room 
temperature for 2 hours. The white suspension is filtered and the 
filtration residue is washed with ether. The residue remaining after the 
filtrate has been concentrated by evaporation is chromatographed on 0.9 kg 
of silica gel. Elution with hexane/ethyl acetate 9:1 yields 30.59 g of 6, 
m.p. 62.degree.-65.degree. C. .sup.1 H-NMR (300 MHz, DMSO-d.sub.6): inter 
alia 3.55 (d.times.d, J=9 and 2) and 4.04 (d.times.d, J=9 and 6) 
(2H--C(5)); 4.15 (m, 2H--C(3')); 4.49 (m, H--C(4)); 5.65 (d, J=9, 
H--C(1')). 
g) (4R)-2,2-dimethyl 
4-(3'-dimethylphosphono-2'-methylprop-1'-enyl)-oxazolidine-3-carboxylic 
acid tert.-butyl ester (7) 
A solution of 13.4 g of 6 in 70 ml of trimethyl phosphite is stirred at 
80.degree. for 15 hours. The excess phosphite is evaporated off at 24 
mbar. Drying of the residue under a high vacuum yields 14.3 g of crude 7. 
.sup.1 H-NMR (300 MHz, DMSO-d.sub.6): inter alia 2.63 (d, J=23, 
2H--C(3')); 3.59 (d, J=11, (CH.sub.3 O).sub.2 PO). 
h) N-((2R)-5-dimethylphosphono-1-hydroxy-4-methyl-3-penten-2-yl)-carbamic 
acid tert.-butyl ester (8) 
7 g of Amberlyst.RTM. 15 (H.sup.+ form, 20-50 mesh) are added to a solution 
of 14.0 g of 7 in 250 ml of methanol. The mixture is stirred at room 
temperature for 17 hours and filtered, and the filtrate is concentrated by 
evaporation. Chromatography of the residue on 0.33 kg of silica gel using 
ethyl acetate/methanol 10:1 as eluant yields 10.6 g of 8. .sup.1 H-NMR 
(300 MHz, DMSO-d.sub.6): inter alia 4.60 (t, J=6, OH); 6.67 (d, J=7, NH). 
i) 
(2R)-2-tert.-butoxycarbonylamino-5-dimethylphosphono-4-methyl-3-pentenoic 
acid (9) 
i,a) Oxidation with chromosulphuric acid 
To a solution of 0.323 g of 8 in 10 ml of acetone there is added 0.77 ml of 
a solution that is 3.25 molar in chromium trioxide and 5.29 molar in 
sulphuric acid. The mixture is stirred at room temperature for 40 minutes 
and then there are added 2 ml of isopropanol followed by 50 ml of ethyl 
acetate. 0.1 g of activated carbon is then added to the mixture. After 10 
minutes, the mixture is filtered and washed with 50 ml of ethyl acetate. 
The filtrate is extracted three times with 50 ml of 10% sodium hydrogen 
carbonate solution each time. The aqueous phase is extracted twice with 40 
ml of ethyl acetate each time, acidified to pH 1 using 2N hydrochloric 
acid, and then extracted three times with 70 ml of ethyl acetate each 
time. The organic extracts are washed with saturated sodium chloride 
solution, dried over magnesium sulphate and concentrated by evaporation. 
Chromatography on 8 g of silica gel using chloroform/methanol/acetic acid 
18:1:1 as eluant yields 65 mg of 9. .sup.1 H-NMR (300 MHz, DMSO-d.sub.6): 
1.37 (s, (CH.sub.3).sub.3 CO); 1.82 (d, J=2, CH.sub.3 --C(4)); 2.63 (d, 
J=22, 2H--C(5)); 3.61 (d, J=11, (CH.sub.3 O).sub.2 PO); 4.62 (t, J=8, 
H--C(2)); 5.25 (m, H--C(3)); 7.18 (d, J=8, NH); 11.7-12.5 (CO.sub.2 H). 
i,b) Oxidation with oxygen/platinum 
To a solution of 0.66 g of 8 and 0.2 g of sodium hydrogen carbonate in 20 
ml of water and 2 ml of dioxane there is added a suspension of platinum 
prepared by hydrogenation of 313 mg of platinum oxide in 50 ml of water. 
In a cylindrical apparatus, oxygen is passed through the mixture from 
bottom to top at 55.degree. by means of a glass frit, with vigorous 
stirring. The mixture is filtered and washed with water, and the filtrate 
is extracted five times with 100-150 ml of ethyl acetate each time. 
Concentration of the extracts by evaporation yields 220 mg of educt 5. 1 g 
of Amberlyst.RTM. 15 (strongly acidic) is added to the aqueous phase, which 
is then filtered and concentrated by evaporation in vacuo at 40.degree.. 
Purification as in f,a) yields 156 mg of 9. .sup.1 H-NMR (300 MHz, 
CDCl.sub.3): 1.43 (s, (CH.sub.3).sub.3 C); 1.96 (d, J=3 Hz, CH.sub.3 
--C(4)); 2.55 and 2.71 (2 d.times.d, J=22 and 15, 2H--C(5)); 3.75 and 3.76 
(2 d, J=11, 2 OCH.sub.3); 4.97 (m, H--C(2)); 5.25-5.45 (m, NH and H--C(3)). 
j) (2R)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (10) 
0.71 ml of trimethylsilyl bromide is added at 0.degree. to a solution of 
123 mg of 9 in 3 ml of dichloromethane. After stirring at 0.degree. for 4 
hours, 20 ml of water are added. After 30 minutes, the dichloromethane 
phase is separated off and washed three times with 15 ml of water each 
time. The aqueous phases are extracted three times with 20 ml of 
dichloromethane each time and concentrated by evaporation in vacuo. The 
residue is dissolved in 10 ml of 5N hydrochloric acid and is then stirred 
for 48 hours, diluted with 20 ml of water and extracted three times with 
20 ml of dichloromethane each time. The aqueous phase is concentrated by 
evaporation in vacuo, and the residue is dried under a high vacuum and 
dissolved in 3 ml of etharol, and then approximately 1 ml of propylene 
oxide is added dropwise thereto. The suspension is filtered. Washing of 
the filtration residue with ethanol and drying under a high vacuum at room 
temperature yields 62 mg of 10, m.p. 165.degree. C. (decomposition). 
In order to analyse the purity of the enantiomer, a sample is derivatised 
to the amide with (R)-(+)-methoxytrifluoromethylphenylacetic acid 
chloride. .sup.1 H-NMR analysis (300 MHZ) by integration of the OCH.sub.3 
signals gives .gtoreq.95% (2R)-isomer (3.44 ppm) and .ltoreq.5% 
(2S)-isomer (3.37 ppm). 
EXAMPLE 28 
(2R)-2-E-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester 
a) 
(4R)-2,2-dimethyl-4-(3'-diisopropylphosphono-2'-methylprop-1'-enyl)-oxazol 
idine-3-carboxylic acid tert.-butyl ester (1) 
A solution of 6.68 g of bromide according to Example 27f in 14.8 ml of dry 
triisopropyl phosphite is heated at 70.degree. C. for 17 hours under a 
pressure of 100 mbar. The mixture is concentrated by evaporation at 0.4 
mbar/70.degree.. Chromatography on 350 g of silica gel (eluant 
hexane/ethyl acetate 1:1) yields 8.28 g of 1, R.sub.f value=0.077. 
b) 
N-((2R)-5-diisopropylphosphono-1-hydroxy-4-methyl-3-penten-2-yl)-carbamic 
acid tert.-butyl ester (2) 
2.25 g of Amberlyst.RTM. 15 (H.sup.+ form, 20-50 mesh) are added to a 
solution of 4.49 g of phosphonic acid ester 1 according to a) in 100 ml of 
methanol. The mixture is stirred at room temperature for 2 days and is 
filtered, and the filtrate is concentrated by evaporation. Chromatography 
of the residue on 125 g of silica gel (eluant ethyl acetate/methanol 20:1) 
yields 2.44 g of 2. 
c) 
(2R)-2-tert.-butoxycarbonylamino-5-diisopropylphosphono-4-methyl-3-penteno 
ic acid (3) 
To a solution of 1.6 g of alcohol 2 according to b) in 60 ml of acetone 
there are added at 0.degree.-5.degree. 3.3 ml of a solution that is 3.25 
molar in chromium(VI) oxide and 5.29 molar in sulphuric acid. The mixture 
is stirred at 0.degree. for 6 hours and at room temperature for 12 hours. 
After the addition of 5 ml of isopropanol and 40 ml of 20% sodium chloride 
solution, the mixture is stirred for 10 minutes and is then extracted 
continuously with methyl acetate for 15 hours in a Kutscher-Steudel 
apparatus. The organic phase is dried over sodium sulphate and 
concentrated by evaporation, and the residue is chromatographed on 75 g of 
silica gel with hexane/ethyl acetate/acetic acid 16:10:1. This yields 0.92 
g of 3, [.alpha.].sub.D =-94.5.degree. (c=1.2, CHCl.sub.3). .sup.1 H-NMR 
(300 MHz, CDCl.sub.3): 1.2-1.3 (4d, (2-propo).sub.2); 1.4 (s, 
(CH.sub.3).sub.3 CO); 1.95 (d, J=3, CH.sub.3 --C(4)); 3.5 and 3.62 (2 
d.times.d, J=23 and 15, 2H--C(5)); 4.66 (m, (2-propo).sub.2); 4.92 (m, 
H--C(2)); 5.30 (m, H--C(3)); 5.42 (d, J=7, NH); 9.0-10.0 (broad, CO.sub.2 
H). 
d) 
(2R)-2-tert.-butoxycarbonylamino-5-diisopropylphosphono-4-methyl-3-penteno 
ic acid ethyl ester (4) 
0.09 g of 1-amino-1-chloro-N,N,2-trimethylpropene is added at 
0.degree.-5.degree. to a solution of 0.2 g of acid 3 according to c) in 15 
ml of dry dichloromethane. After stirring for 30 minutes at 0.degree., 0.4 
g of pyridine in 5 ml of ethanol is added. The mixture is stirred further 
at 0.degree. for 90 minutes and at room temperature for 15 hours, and is 
then diluted with 20 ml of dichloromethane and washed twice with 20 ml of 
water each time. The organic phase is dried using sodium sulphate, 
concentrated by evaporation and chromatographed on 25 g of silica gel. 
Elution with ethyl acetate/ methanol 10:1 yields 0.12 g of 4. .sup.1 H-NMR 
(300 MHz, CDCl.sub.3): 1.2-1.4 (m, 2 (CH.sub.3).sub.2 CHO, CH.sub.3 
CH.sub.2 O); 1.45 (s, (CH.sub.3).sub.3 CO); 1.98 (d, J=3, CH.sub.3 
--C(4)); 2.55 (d, J=23, 2H--C(5)); 4.2 (m, CH.sub.3 CH.sub.2 O); 4.69 (m, 
2 (CH.sub.3).sub.2 CHO); 5.0 (m, H--C(2)); 5.16 (m, H--C(3), NH). 
e) (2R)-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester (5) 
0.11 ml of trimethtlsilyl bromide is added at 0.degree. to a solution of 
0.1 g of ester 4 according to d) in 10 ml of dichloromethane. The mixture 
is stirred at 0.degree. for 4 hours and at room temperature for 15 hours. 
20 ml of water are added, the mixture is stirred for 15 minutes, and then 
the aqueous phase is separated off and the water is evaporated off under a 
high vacuum. The residue is dissolved twice in 5 ml of ethanol each time, 
concentrated by evaporation and again dissolved in 5 ml of ethanol. 0.5 ml 
of propylene oxide is added. The precipitate is filtered off, washed with 
ethanol and dried under a high vacuum for 15 hours; 48 mg of 5, 
[.alpha.].sub.D =-75.degree. (c=0.5, H.sub.2 O). 
In order to analyse the purity of the enantiomer, a sample is derivatised 
to the amide dimethyl ester with 
(R)-(+)-methoxytrifluoromethylphenylacetic acid chloride followed by 
diazomethane. .sup.1 H-NMR analysis (300 MHz) by integration of the 
OCH.sub.3 signals gives .gtoreq.97% (2R)-isomer (3.5 ppm) and .ltoreq.3% 
(2S)-isomer (3.37 ppm). 
EXAMPLE 29 
(2R)-2-amino-4-methyl-7-phosphono-3-heptenoic acid (10) 
a) 
(4R)-2,2-dimethyl-4-(1'-hydroxy-2'-methylprop-2'-enyl)oxazolidine-3-carbox 
ylic acid tert.-butyl ester (1) 
45 ml of a 1.1 molar solution of isopropenylmagnesium bromide are added 
dropwise at 0.degree.-5.degree. within a period of 25 minutes to a 
solution of 6.9 g of (4S)-2,2-dimethyl-4-formyloxazolidine-3-carboxylic 
acid tert.-butyl ester (according to Example 27c)) in 60 ml of dry 
tetrahydrofuran. The mixture is stirred at 0.degree. for 45 minutes, 
allowed to warm up to room temperature and cooled again to 10.degree., and 
then 90 ml of buffer solution (1 molar, phosphate, pH 7) are added. The 
mixture is filtered and the filtrate is extracted twice with 100 ml of 
ethyl acetate each time. The organic phase is washed twice with 50 ml of 
water each time and with saturated sodium chloride solution, and is dried 
with sodium sulphate. Removal of the solvent by evaporation yields 8 g of 
1, a diastereoisomeric mixture. Separation may be effected by 
chromatography on silica gel using hexane/ethyl acetate 4:1 and yields 
crystalline (1'S)-threo-epimer (R.sub.f value 0.2) and 
(1'R)-erythro-epimer (R.sub.f value: 0.16) in a ratio of approximately 
1:2. 
b) 
(4R)-4-(1'-acetoxy-2'-methylprop-2'-enyl)-2,2-dimethyloxazolidine-3-carbox 
ylic acid tert.-butyl ester (2) 
60 ml of acetic anhydride are added dropwise at 0.degree.-5.degree. within 
a period of 10 minutes to a solution of 15.6 g of the epimer mixture 
according to a) in 60 ml of pyridine. The mixture is stirred at room 
temperature for 15 hours and diluted with 0.5 liter of diethyl ether, and 
then 200 ml of 2N hydrochloric acid are added while cooling with ice. The 
organic phase is washed with 250 ml of 2N hydrochloric acid and twice with 
200 ml of 10% sodium carbonate solution each time. Drying over sodium 
sulphate and removal of the solvent by evaporation yields 15.4 g of 2. 
c) 
(4R)-4-(4'-carboxy-2'-methylbutenyl)-2,2-dimethyl-oxazolidine-3-carboxylic 
acid tert.-butyl ester (3) 
34.5 ml of a 1.6 molar solution of butyllithium in hexane are added at 
0.degree. to a solution of 5.25 g of diisopropylamine in 200 ml of dry 
tetrahydrofuran. The mixture is cooled to -75.degree. C. and a solution of 
15 g of acetate 2 according to b) in 100 ml of tetrahydrofuran is added 
dropwise within a period of 10 minutes, and after 5 minutes a solution of 
8 g of tert.-butyldimethylsilyl chloride in 30 ml of 
1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone is added. The mixture 
is allowed to warm up to room temperature and is then heated under reflux 
for 2 hours and cooled to room temperature. 230 ml of 45% ammonium 
fluoride solution are added, and the whole is stirred at room temperature 
for 20 hours and is then concentrated by evaporation. 150 ml of 1N sodium 
hydroxide solution are added, while cooling with ice, to the oily residue 
which is obtained after concentration of the organic phase by evaporation, 
and the mixture is extracted twice with 200 ml of dichloromethane each 
time. The aqueous phase is acidified with 300 ml of 20% citric acid 
solution and is extracted three times with 300 ml of dichloromethane each 
time. The organic phases are washed with 20% sodium chloride solution, 
dried over sodium sulphate and concentrated by evaporation. Chromatography 
of the residue on 50 g of silica gel using hexane/ethyl acetate 1:1 as 
eluant yields 11 g of solid 3. 
d) 
(4R)-4-(4'-carbaethoxy-2'-methylbutenyl)-2,2-dimethyloxazolidine-3-carboxy 
lic acid tert.-butyl ester (4) 
d,a) Starting from the acid 3 
3.9 ml of 1-amino-1-chloro-N,N,2-trimethylpropene are added dropwise within 
a period of 10 minutes to an ice-cooled solution of 7.8 g of carboxylic 
acid 3 according to c) in 100 ml of dry dichloromethane. After 30 minutes 
at 0.degree., a solution of 2.2 g of pyridine in 80 ml of ethanol is added 
within a period of 20 minutes. After stirring at room temperature for 12 
hours, the mixture is diluted with 100 ml of dichloromethane and washed 
twice with 100 ml of water each time. The organic phase is dried over 
sodium sulphate and concentrated by evaporation. Chromatography of the 
residue on silica gel using hexane/ethyl acetate 10:1 yields 6.5 g of 
ester 4, [.alpha.].sub.D =+6.17.degree. (c=1, CHCl.sub.3). C.sub.18 
H.sub.31 NO.sub.5, calculated: C 63.32%, H 9.15%, N 4.10%; found: C 63.4%, 
H 9.2%, N 4.5%. 
d,b) Starting from the epimer mixture 1 
A solution of 8 g of alcohol 1 according to a) and 0.05 ml of propionic 
acid in 10.5 ml of orthoacetic acid triethyl ester is heated at 
135.degree.-140.degree. for 14 hours, with ethanol slowly being distilled 
off. The whole is concentrated by evaporation at 40.degree. under a high 
vacuum. Chromatography of the residue on silica gel using hexane/ethyl 
acetate 10:1 yields 8 g of 4. 
e) 
(4R)-2,2-dimethyl-4-(5'-hydroxy-2'-methylpent-1'-enyl)oxazolidine-3-carbox 
ylic acid tert.-butyl ester (5) 
1.61 g of lithium aluminium hydride are added in portions at 0.degree. to a 
solution of 14.5 g of 4 according to d) in 250 ml of absolute diethyl 
ether. The mixture is stirred at 0.degree.-2.degree. for 18 hours, and a 
solution of 5 g of potassium hydrogen sulphate in 60 ml of water is added 
while cooling with acetone/dry ice. The mixture is filtered and washed 
four times with 200 ml of diethyl ether each time. The organic phase is 
washed three times with 80 ml of 1N hydrochloric acid each time, three 
times with 80 ml of saturated sodium bicarbonate solution each time, and 
twice with 200 ml of saturated sodium chloride solution each time, and is 
then dried over sodium sulphate and concentrated by evaporation. 
Chromatography on silica gel using hexane/ethyl acetate 1:1 yields 11.3 g 
of 5, C.sub.16 H.sub.29 NO.sub.4, calculated: C 64.19%, H 9.77%, N 4.68%; 
found: C 63.6%, H 9.8%, N 4.7%. 
f) 
(4R)-4-(5'-bromo-2'-methylpent-1'-enyl)-2,2-dimethyloxazolidine-3-carboxyl 
ic acid tert.-butyl ester (6) 
4.87 g of tetrabromomethane, 3.85 g of triphenylphosphine and 0.6 ml of 
pyridine are added at 0.degree.-2.degree. to a solution of 4.4 g of 
alcohol 5 according to e) in 200 ml of dichloromethane. After 12 hours at 
0.degree.-2.degree., a further 1 g of tetrabromomethane and 1 g of 
triphenylphosphine are added and the mixture is stirred at 0.degree. for 6 
hours. The mixture is concentrated by evaporation, taken up in ethyl 
acetate, filtered and concentrated. Chromatography on silica gel using 
hexane/ethyl acetate 10:1 yields 4.5 g of 6, C.sub.16 H.sub.28 NO.sub.3 
Br; calculated: C 53.04%, H 7.79%, N 3.87%, Br 22.06%; found: C 53.1%, H 
7.7%, N 3.9%, Br 21.6%. 
g) 
(4R)-2,2-dimethyl-4-(2'-methyl-5'-diisopropylphosphonopent-1'-enyl)-oxazol 
idine-3-carboxylic acid tert.-butyl ester (7) 
A solution of 10.9 g of bromide 6 in 22 ml of triisopropyl phosphite is 
heated at 135.degree.-140.degree. for 24 hours at 100 mbar. The excess 
reagent is evaporated off at 0.1 mbar/60.degree.. Chromatography of the 
residue on silica gel using hexane/ethyl acetate 1:1 yields 10.7 g of 7. 
h) 
N-((2R)-1-hydroxy-4-methyl-7-diisopropylphosphonohept-3-en-2-yl)-carbamic 
acid tert.-butyl ester (8) 
3 g of Amberlyst.RTM. 15 (H.sup.+ form) are added to a solution of 3 g of 7 
according to g) in 100 ml of ethanol. The mixture is stirred at room 
temperature for 20 hours, filtered, concentrated by evaporation and 
chromatographed on 50 g of silica gel. Elution with ethyl acetate/ 
methanol 10:1 yields 2.3 g of 8, [.alpha.].sub.D =-5.9.degree. (c=1, 
CHCl.sub.3). C.sub.19 H.sub.38 NO.sub.6 P; calculated: C 56.0%, H 9.4%, N 
3.44%, P 7.6%; found: C 55.4%, H 9.3%, N 3.4%, P 7.3%. 
i) 
(2R)-2-tert.-butoxycarbonylamino-4-methyl-7-diisopropylphosphono-3-hepteno 
ic acid (9) 
i,a) Oxidation with chromic acid 
0.84 ml of a solution which is 3.25 molar in chromium trioxide and 5.29 
molar in sulphuric acid is added dropwise at 0.degree.-5.degree. to a 
solution of 0.5 g of alcohol 8 according to h) in 15 ml of acetone. The 
mixture is stirred at 0.degree. for 30 minutes and at room temperature for 
35 minutes, and then 4 ml of isopropanol, 80 ml of ethyl acetate and 30 ml 
of 20% sodium chloride solution are added thereto, and the mixture is 
filtered. The aqueous phase is extracted three times with 20 ml of ethyl 
acetate each time. The organic phase is dried over sodium sulphate and 
concentrated by evaporation. Chromatography on 20 g of silica gel using 
hexane/ethyl acetate/acetic acid 16:10:1 yields 0.34 g of 9, 
[.alpha.].sub.D =-35.25.degree. (c=1.39, CHCl.sub.3), .sup.-- C-NMR (75 
MHz, CDCl.sub.3): 173.8 (CO.sub.2 H); 155.0 (OCON); 140.4 (C(4)); 121.1 
(C(3)); 79.5 (OC(CH3)3); 70.3 (OCH); 52.1 (C(2)); 39.7 (d, J=18, C(5)); 
28.3 ((CH.sub.3).sub.3 C); 25.7 (d, J=142, C(7)); 24.0 ((CH.sub.3).sub.2 
CH); 20.2 (d, J=5, C(6)). 
i,b) Oxidation with platinum/oxygen 
To a solution of 3 g of alcohol 8 according to h) in 105 ml of dioxan there 
is added at 55.degree. a suspension of platinum in 45 ml of water prepared 
by hydrogenation and degassing of 1 g of platinum oxide in 45 ml of water. 
Oxygen is passed through the mixture at 55.degree.-60.degree. with vigorous 
stirring (approximately 1900 rpm). The mixture is filtered through 
Celite.RTM. and washed twice with 80 ml of water each time, and the 
filtrate is concentrated by evaporation at 40.degree. under a high vacuum. 
The resulting product is dissolved in 200 ml of water, and 1 g of sodium 
bicarbonate and 50 ml of 20% sodium chloride solution are added and the 
mixture is extracted three times with 100 ml of ethyl acetate each time. 
The organic phases are dried over sodium sulphate. Filtration and 
concentration by evaporation yield 1.8 g of educt 8. The aqueous phase is 
acidified with approximately 20 ml of 1N sulphuric acid and extracted five 
times with 120 ml of ethyl acetate each time. Drying over sodium sulphate, 
concentration by evaporation and chromatography of the residue according 
to i,a) yield 0.8 g of acid 9. 
j) (2R)-2-amino-4-methyl-7-phosphono-3-heptenoic acid (10) 
A solution of 3.3 g of acid 9 according to i) and 2.6 g of 
N,O-bis-trimethylsilylacetamide is stirred at room temperature for one 
hour under argon. After the addition of 4.4 g of trimethylbromosilane, the 
mixture is stirred for 24 hours. The reaction mixture is added dropwise at 
0.degree. to 400 ml of water, and the whole is stirred for 30 minutes. The 
organic phase is separated off and washed three times with 50 ml of water 
each time. The aqueous phases are extracted three times with 30 ml of 
dichloromethane each time and concentrated to 10 ml at 40.degree. under a 
high vacuum. Chromatography on 20 ml of Dowex.RTM. 50 W.times.8 using 
water as eluant, and lyophilisation of the eluate yield 0.4 g of 10 in 
the form of an amorphous white powder having a melting point of 
252.degree. (decomposition); [.alpha.].sub.D =-86.5.degree. (c=1, H.sub.2 
O); C.sub.8 H.sub.16 NO.sub.5 P.1 H.sub.2 O; calculated: C 37.05%, H 6.9%, 
N 5.5%; found: C 36.3%, H 6.5%, N 5.6%. 
In order to analyse the purity of the enantiomer, a sample is derivatised 
to the amide with (R)-(+)-methoxytrifluoromethylphenylacetic acid 
chloride. .sup.1 H-NMR analysis (300 MHz) by integration of the OCH.sub.3 
signals gives .gtoreq.94% (2R)-isomer (3.24 ppm) and .ltoreq.6% 
(2S)-isomer (3.17 ppm). 
EXAMPLE 30 
(2R)-2-amino-7-phosphono-3-heptenoic acid 
a) (4R)-2,2-dimethyl-4-(1'-hydroxyprop-2'-enyl)-oxazolidine-3-carboxylic 
acid tert.-butyl ester (1) 
60 ml of a 2.4M solution of vinylmagnesium bromide in tetrahydrofuran are 
added at 0.degree.-5.degree. within a period of 30 minutes to a solution 
of 25 g of (4S)-2,2-dimethyl-4-formyloxazolidine-3-carboxylic acid 
tert.-butyl ester (according to Example 43c) in 300 ml of dry 
tetrahydrofuran. The mixture is stirred at 0.degree. for one hour, allowed 
to warm up to room temperature and then stirred at room temperature for a 
further one hour. 300 ml of buffer solution (1 molar, phosphate, pH 7) are 
added while cooling to 10.degree.. After 10 minutes, the mixture is 
filtered, extracted twice with 150 ml of ethyl acetate each time and 
washed twice with 100 ml of water each time. The aqueous phase is 
extracted twice with 100 ml of ethyl acetate each time. The organic 
extracts are dried over sodium sulphate and concentrated by evaporation. 
Chromatography of the residue on silica gel using hexane/ ethyl acetate 
4:1 yields 24.2 g of epimer mixture 1; C.sub.13 H.sub.23 NO.sub.4 ; 
calculated: C 60.68%, H 9.01%, N 5.44%; found: C 60.7%, H 9.1%, N 5.6%. 
b) (4R)-4-(4'-ethoxycarbonylbutenyl)-2,2-dimethyloxazolidine-3-carboxylic 
acid tert.-butyl ester (2) 
A solution of 22.5 g of alcohol 1 according to a) and 0.3 ml of propionic 
acid in 38.5 ml of orthoformic acid triethyl ester is heated at 
135.degree.-140.degree. C. for 4 hours, with ethanol slowly being 
distilled off. The mixture is concentrated by evaporation at 50.degree. 
under a high vacuum and chromatographed on 300 g of silica gel. Elution 
with hexane/ethyl acetate 4:1 yields 23.9 g of 2, [.alpha.].sub.D 
=-10.0.degree. (c=1.5, CHCl.sub.3); C.sub.17 H.sub.29 NO.sub.5 ; 
calculated: C 62.36%, H 8.93%, N 4.28%; found: C 62.2%, H 8.9%, N 4.4%. 
c) (4R)-2,2-dimethyl-4-(5'-hydroxypentenyl)-oxazolidine-3-carboxylic acid 
tert.-butyl ester (3) 
2.7 g of lithium aluminium hydride are added in portions at 
0.degree.-2.degree. to a solution of 23.5 g of 2 according to b) in 550 ml 
of absolute diethyl ether. After stirring at 0.degree.-2.degree. for 3 
hours, a solution of 25 g of potassium hydrogen sulphate in 250 ml of 
water is added dropwise with cooling. The mixture is filtered through 
Celite.RTM. and washed thoroughly with diethyl ether. The organic phase is 
washed twice with 200 ml of 1N hydrochloric acid each time and twice with 
250 ml of 10% sodium bicarbonate solution each time. The aqueous phases 
are extracted twice with 100 ml of ether each time. The organic phases are 
washed with 20% sodium chloride solution, dried over sodium sulphate and 
concentrated by evaporation. Chromatography on silica gel using 
hexane/ethyl acetate as eluant yields 18.6 g of 3, [.alpha.].sub.D 
=-10.1.degree. (c=1.4, CHCl.sub.3); C.sub.15 H.sub.27 NO.sub.4 ; 
calculated: 63.13%, H 9.54%, N 4.91%; found: C 63.0%, H 9.5%, N 5.0%. 
d) (4R)-4-(5'-bromopentenyl)-2,2-dimethyloxazolidine-3-carboxylic acid 
tert.-butyl ester (4) 
7 ml of pyridine are added dropwise at 0.degree. to a solution of 18.5 g of 
alcohol 3 according to c), 28.2 g of tetrabromomethane and 22.3 g of 
triphenylphosphine in 600 ml of dichloromethane. The mixture is stirred at 
0.degree.-2.degree. for 12 hours, concentrated by evaporation, taken up in 
150 ml of ethyl acetate, filtered, concentrated to 50 ml and 
chromatographed on 200 g of silica gel. Elution with hexane/ethyl acetate 
10:1 yields 19.9 g of bromide 4, [.alpha.].sub.D =-18.9.degree. (c=1, 
CHCl.sub.3); C.sub.15 H.sub.26 NO.sub.3 Br; calculated: C 51.73%, H 7.53%, 
N 4.02%, Br 22.94%; found: C 51.7%, H 7.7%, N 4.2%, Br 23.0%. 
e) 
(4R)-2,2-dimethyl-4-(5'-di-2-propylphosphonopentenyl)oxazolidine-3-carboxy 
lic acid tert.-butyl ester (5) 
A solution of 19.9 g of bromide 4 according to d) in 60 ml of triisopropyl 
phosphite is heated at 130.degree.-135.degree. for 20 hours at 100 mbar. 
The excess reagent is distilled off at 60.degree./0.1 mbar, and the 
residue is chromatographed on 250 g of silica gel. Elution with 
hexane/ethyl acetate 1:1 yields 20.6 g of phosphonic acid ester 5, 
[.alpha.].sub.D =-8.6.degree. (c=0.8, CHCl.sub.3); C.sub.21 H.sub.40 
NO.sub.6 P; calculated: C 58.18%, H 9.30%, N 3.23%, P 7.15%; found: C 
57.4%, H 9.3%, N 3.2%, P 7.5%. 
f) N-((2R)-1-hydroxy-7-(diisopropylphosphonohept-3-en-2-yl)carbamic acid 
tert.-butyl ester (6) 
A solution of 20.6 g of 5 according to e) in 800 ml of methanol is stirred 
at room temperature for 20 hours with 30 g of Amberlyst.RTM. 15 (H.sup.+ 
form). The mixture is filtered, washed with methanol, concentrated by 
evaporation and chromatographed on 100 g of silica gel. Elution with ethyl 
acetate yields 14.8 g of 6, [.alpha.].sub.D =-3.6.degree. (c=1.5, 
CHCl.sub.3); C.sub.18 H.sub.36 NO.sub.6 P; calculated: C 54.95%, H 9.22%, 
N 3.56%, P 7.87%; found: C 53.6%, H 9.0%, N 3.4%, P 9.0%. 
g) (2R)-2-tert.-butoxycarbonylamino-7-diisopropylphosphono-3-heptenoic acid 
(7) 
To a solution of 7.4 g of alcohol 6 according to f) in 300 ml of acetone 
there are added dropwise at 0.degree.-2.degree. C., within a period of 20 
minutes, 15 ml of a solution which is 3.25 molar in chromium trioxide and 
5.29 molar in sulphuric acid. The mixture is stirred at 
0.degree.-2.degree. for 2 hours and at room temperature for 4 hours, and 
then 30 ml of isopropanol, 300 ml of ethyl acetate and 200 ml of 20% 
sodium chloride solution are added. The aqueous phase is extracted three 
times with 250 ml of ethyl acetate each time, and the organic phases are 
dried over sodium sulphate and concentrated by evaporation. Chromatography 
on 200 g of silica gel using hexane/ethyl acetate/acetic acid 16:10:1 
yields 4.55 g of acid 7, [.alpha.].sub.D =-24.9.degree. (c=0.8, 
CHCl.sub.3). 
h) (2R)-2-amino-7-phosphono-3-heptenoic acid (8) 
A solution of 3.1 g of acid 7 and 3 ml of N,O-bis-trimethylsilylacetamide 
in 200 ml of dry dichloromethane is stirred at room temperature for one 
hour. 3.5 ml of trimethylbromosilane are added, and the mixture is stirred 
at room temperature for 30 hours. The volatile portions are evaporated off, 
the residue is taken up in 50 ml of dichloromethane, and 250 ml of water 
are added at 0.degree.-2.degree.. The aqueous phase is separated off and 
concentrated to 10 ml under a high vacuum. Chromatography on 20 ml of 
Dowex.RTM. 50 W.times.8 using water as eluant, and lyophilisation of the 
eluate yield 1.04 g of 8 in the form of an amorphous powder, 
[.alpha.].sub.D =-65.2.degree. (c=1, H.sub.2 O); .sup.13 C-NMR (75 MHz, 
D.sub.2 O): 172.8 (CO.sub.2 H); 140.3 (C(4)); 122.2 (C(3)); 56.4 (C(2)); 
33.3 (d, J=17, C(5)); 27.3 (d, J=134, C(7)); 22.6 (d, J=4, C(6)). In order 
to analyse the purity of the enantiomer, a sample is derivatised to the 
amide trimethyl ester with (R)-(+)-methoxytrifluoromethylphenylacetic acid 
chloride followed by diazomethane. .sup.1 H-NMR analysis (300 MHz) by 
integration of the OCH.sub.3 signals gives .gtoreq.95% (2R)-isomer (3.54 
ppm) and .ltoreq.5% (2S)-isomer (3.37 ppm). 
EXAMPLE 31 
(2R)-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester 
a) (2R,3S)-2-formylamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester 
(1) 
aa) Starting from 1,1,3,3-tetramethyl-1,3-disila-2-azolidine-N-acetic acid 
ethyl ester 
7.6 ml of a 1.6 molar solution of butyllithium in hexane are added at 
-20.degree. to a solution of 2.26 ml of N-cyclohexyl-N-isopropylamine in 
60 ml of absolute tetrahydrofuran. After 20 minutes, the mixture is cooled 
to -78.degree. and there is added dropwise a solution of 3 g of 
1,1,3,3-tetramethyl-1,3-disila-2-azolidine-N-acetic acid ethyl ester in 60 
ml of tetrahydrofuran. The mixture is stirred at -78.degree. for one hour, 
and then 142 ml of an approximately 0.035 molar solution of 
cyclopentadienyl-bis-1,2:5,6-di-O-isopropylidene-D-glucofuranosyltitanium( 
IV) chloride in ether are added and the mixture is stirred at -78.degree. 
for 17 hours. The reaction solution is transferred via a small steel tube, 
by argon pressure, into a vessel containing a solution, cooled to 
-78.degree., of 1.1 ml of methacrolein in 15 ml of tetrahydrofuran. The 
whole is allowed to warm up slowly to room temperature, and is then 
stirred for 2 hours. 1.5 ml of water are added, and the mixture is 
filtered. The filtrate is diluted with 250 ml of diethyl ether, and is 
then washed three times with 250 ml of approximately 10% sodium chloride 
solution each time and with 250 ml of saturated sodium chloride solution. 
The aqueous phases are extracted twice with 250 ml of diethyl ether each 
time. The organic phases are dried over sodium sulphate, concentrated by 
evaporation, and dissolved hot in 150 ml of cyclohexane. On cooling, 
1,2:5,6-di-O-isopropylidene-D-glucofuranose crystallises. The mother 
liquor is concentrated by evaporation, the residue is taken up in 120 ml 
of tetrahydrofuran, 24 ml of water and 4.5 ml of acetic acid, and the 
mixture is stirred at room temperature for 2 hours. Concentration by 
evaporation at room temperature under a high vacuum yields 10.6 g of 
residue, contamining (2R,3S)-2-amino-3-hydroxy-4-methyl-4-pentenoic acid 
ethyl ester. A sample (5 mg) is derivatised for 2 hours with 0.2 ml of 
trifluoroacetic acid anhydride in 0.3 ml of dichloromethane. Capillary gas 
chromatography (Chirasil.RTM.-L-Val, 90.degree.-180.degree./2.degree. per 
minute) yields 99.25% (2R,3S)-enantiomer (retention time T.sub.ret =10.28 
minutes) and 0.75% (2S,3R)-enantiomer (retention time T.sub.ret =11.48 
minutes). The main mixture is then heated under reflux for 51/2 hours in 
80 ml of formic acid ethyl ester. Concentration by evaporation and 
chromatography on silica gel using hexane/ethyl acetate 1:1 yield 1.64 g 
of formamide 1. Analysis of a sample (5 mg) in the form of the acetate by 
gas chromatography (Chirasil.RTM.-L-Val, 160.degree.-180.degree., 
1.degree. per minute): 99.2% (2R,3S)-enantiomer (T.sub.ret =13.64 
minutes), 0.8% (2S,3R)-enantiomer (T.sub.ret =13.94 minutes). 
a,b) Starting from isocyanoacetic acid ethyl ester 1.65 g of 
(S)-N-methyl-N-[2-(dimethylamino)-ethyl]-1-[(R)1',2-bis-(diphenylphosphino 
)-ferrocenyl]-ethylamine and 1.105 g of bis(cyclohexylisocyanide)gold(I) 
tetrafluoroborate are added at 50.degree. to a solution of 24.88 g of 
isocyanoacetic acid ethyl ester and 18.51 g of methacrolein in 220 ml of 
1,2-dichloromethane. The mixture is stirred at 50.degree. for 5 hours 
under argon, concentrated by evaporation, taken up in 400 ml of diethyl 
ether and filtered, and the filtrate is concentrated by evaporation. 
Distillation of the residue under a high vacuum (0.04 mbar) yields 33.62 g 
of a stereoisomeric mixture of 5-(2-propenyl)-oxazoline-4-carboxylic acid 
ethyl ester having a boiling point of 42.degree.-52.degree.; MS.: m/e =183 
(2%, M.sup.+), 110 (80%), 85 (100%). A solution of 33 g of this mixture in 
74 ml of water and 33 ml of tetrahydrofuran is heated under reflux for 3 
hours. Concentration by evaporation in vacuo yields 36.1 g of a mixture of 
stereo-isomeric 2-formamino-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester 
2. A sample (35 mg) is derivatised in 2 ml of dichloromethane with 0.05 ml 
of N,O-bis-trimethylsilylacetamide and analysed by means of capillary gas 
chromatography (Chirasil.RTM.-L-Val, 150.degree.): 89.1% (2R,3S)-isomer 
(T.sub.ret =22.1 minutes), 5.8% (2S,3R)-isomer (T.sub.ret =23.1 minutes), 
2.8% (2R,3R)-isomer (T.sub.ret =24.3 minutes), 2.3% (2S,3S)-isomer 
(T.sub.ret =25.4 minutes). 
A solution of 11.42 ml of acetic anhydride in 50 ml of dichloromethane is 
added dropwise at 0.degree.-3.degree. within a period of 25 minutes to a 
solution of 20.2 g of 2, 16.83 ml of triethylamine and 0.62 g of 
4-(dimethylamino)-pyridine in 300 ml of dichloromethane. After 30 minutes, 
the mixture is washed twice with ice-cold 2N hydrochloric acid and twice 
with 10% sodium chloride solution. The aqueous phases are extracted with 
100 ml of dichloromethane. The organic phases are dried over sodium 
sulphate and concentrated by evaporation, and the residue is dissolved hot 
in hexane/ ethyl acetate 4:1. On cooling slowly to approximately 30.degree. 
there crystallise 1.82 g of racemic 
(2R*,2S*)-2-formamino-3-acetoxy-4-methyl-4-pentenoic acid ethyl ester 
having a melting point of 98.degree.-106.degree.. The mother liquor is 
slowly cooled to -12.degree. C. and kept at that temperature for one hour. 
Filtration yields 15.04 g of acetate 3, m.p. 73.degree.-75.degree., 
[.alpha.].sub.D =-75.6.degree. (c=1, CHCl.sub.3), analysis by gas 
chromatography (Chirasil.RTM.-L-Val, 160.degree.-180.degree., 1.degree. 
per minute): (2R,3S)-isomer 93.5% (T.sub.ret =14.5 minutes), 
(2S,3R)-isomer 2.2% (T.sub.ret =14.8 minutes), (2R,3R)-isomer 2.2% 
(T.sub.ret =16.8 minutes), (2S,3S)-isomer 2.1% (T.sub.ret =17.1 minutes). 
20.64 g of anhydrous potassium carbonate are added at -16.degree. to a 
solution of (2R,3S)-2-formylamino-3-acetoxy-4-methyl-4-pentenoic acid 
ethyl ester (3) in 400 ml of absolute ethanol. After stirring at 
-18.degree. to -11.degree. C. for 4 hours, 500 ml of buffer solution (1 
molar, phosphate, pH=7) are added dropwise. The mixture is stirred at room 
temperature for 30 minutes and extracted three times with 350 ml of 
dichloromethane each time. The organic phases are dried over sodium 
sulphate and concentrated by evaporation, and the residue is 
chromatographed on 1 kg of silica gel using hexane/ethyl acetate 1:2 as 
eluant, yielding 9.8 g of alcohol 1. 
b) (2R)-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoic acid 
ethyl ester (4) 
To a solution of 14.19 g of 1 according to a) in 210 ml of 
1,2-dichloroethane there are added at 18.degree.-20.degree. 6.57 ml of 
thionyl bromide and, after stirring for 2 hours, 135 ml of water. After 15 
minutes, the organic phase is separated off and washed three times with 150 
ml of ice-water each time and once with 100 ml of ice-cooled saturated 
sodium hydrogen carbonate solution. The organic phase is dried over sodium 
sulphate and concentrated by evaporation, and the residue is dissolved in 
60 ml of triisopropyl phosphite and stirred at 75.degree./100 mbar for 17 
hours. The excess reagent is distilled off at 90.degree. under a high 
vacuum. Chromatography of the residue on 650 g of silica gel using ethyl 
acetate/methanol 20:1 yields 10.88 g of phosphonic acid ester 4, 
[.alpha.].sub.D =-123.5.degree. (c=1, CHCl.sub.3). .sup.1 H-NMR analysis 
(300 MHz) with the addition of 
(1R)-1-(9'-anthracenyl)-2,2,2-trifluoroethanol shows an enantiomeric 
purity of .gtoreq.90%. 
c) (2R)-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester (5) 
23 ml of trimethylbromosilane are added dropwise at room temperature within 
a period of 15 minutes to a solution of 10.3 g of 4 according to b) in 42 
ml of dichloromethane. After 211/2 hours, 42 ml of ethanol are added while 
cooling with ice, and the mixture is stirred for 20 hours. The whole is 
then concentrated by evaporation and the residue is dissolved three times 
in 70 ml of toluene each time and in each case is concentrated by 
evaporation again. The residue is dissolved in 42 ml of ethanol, and 42 ml 
of propylene oxide are added. After 11/2 hours, the mixture is filtered. 
Drying the filtration residue in a vacuum desiccator over P.sub.2 O.sub.5 
/KOH (3 hours/80.degree.) yields 6.17 g of 5; [.alpha.].sub.D =-78.degree. 
(c=0.6, H.sub.2 O); m.p. 194.degree.-197.degree. (decomp.), C.sub.8 
H.sub.16 NO.sub.5 P; calculated: C 40.51%, H 6.80%, N 5.91%, P 13.06%; 
found: C 39.4%, H 7.09%, N 5.73%, P 12.98%. 
In order to analyse the purity of the enantiomer, a sample is derivatised 
to the amide dimethyl phosphonate with 
(R)-(+)-methoxytrifluoromethylphenylacetic acid chloride and diazomethane 
and analysed by .sup.1 H-NMR (300 MHz) using the integration of the 
OCH.sub.3 signals: (2R)-isomer .gtoreq.93% (3.51 ppm), (2S)-isomer 
.ltoreq.7% (3.37 ppm). 
EXAMPLE 32 
(2R)-2-E-amino-4methyl-5-phosohono-3-pentenoic acid 
A solution of 100 mg of (2R)-2-amino-4-methyl-5-phosphono-3-pentenoic acid 
ethyl ester according to Example 28 in 3 ml of 1N hydrochloric acid is 
heated in a bath at 100.degree. C. for 41/2 hours. The solution is 
concentrated by evaporation and the residue is dried at 60.degree. under a 
high vacuum for 30 minutes. The residue is dissolved in 15 ml of ethanol, 
and 4 ml of propylene oxide are added thereto. Filtration and drying of 
the filtration residue in a vacuum desiccator over P.sub.2 O.sub.5 /KOH 
yield 62 mg of acid. 
In order to determine the purity of the enantiomer, a sample is derivatised 
to the amide with (R)-(+)-methoxytrifluoromethylphenyl acetic acid chloride 
and is analysed by 1H-NMR (300 MHz), integration of the OCH.sub.3 signals: 
.gtoreq.95% (2R)-enantiomer (3.25 ppm) and .ltoreq.5% (2S)-enantiomer 
(3.18 ppm). 
EXAMPLE 33 
E-2-amino-4-methyl-5-phosphono-3-pentenoic acid 
12 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester are 
stirred under reflux in 70 ml of water for 19 hours. The reaction mixture 
is slowly cooled to room temperature, stirred in an ice bath for one hour, 
filtered and washed with cold water. In this manner there is obtained 
E-2-amino-4-methyl-5-phosphono-3-pentenoic acid in the form of the 
monohydrate, m.p. 163.degree. (decomp.). 
EXAMPLE 34 
E-2-dimethylamino-4-methyl-5-phosphono-3-pentenoic acid 
A mixture of 3.56 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid 
ethyl ester, 45 ml of 98% formic acid and 30 ml of 37% aqueous 
formaldehyde solution is stirred at a bath temperature of 105.degree. for 
30 minutes. The mixture is then concentrated to dryness by evaporation in 
vacuo. The residue is taken up in a little water and the whole is again 
concentrated by evaporation in vacuo. This procedure is repeated twice 
more. The solid residue is stirred with 80 ml of water. After one hour, 
the undissolved material is separated off over a hard filter and washed 
with water. The filtrate and the washing water are concentrated to dryness 
by evaporation in vacuo. The residue is suspended in 100 ml of water and, 
after the addition of 30 ml of 1N sodium hydroxide solution, is left to 
stand at room temperature for 2 days. The reaction mixture is concentrated 
to a residual volume of approximately 25 ml by evaporation in vacuo and 
purified by ion exchanger chromatography (Dowex 50 W.times.8 H.sub.2 O). 
The fractions which contain the desired product are combined, concentrated 
by evaporation in vacuo and recrystallised from water/ethanol. In this 
manner there is obtained 
E-2-dimethylamino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 239.degree. 
(decomp.). 
EXAMPLE 35 
E-2-dimethylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester 
30 ml of 8N ethanolic hydrogen chloride solution are added to 1.19 g of 
E-2-dimethylamino-4-methyl-5-phosphono-3-pentenoic acid, and the mixture 
is stirred at 40.degree. for 24 hours. The reaction mixture is 
concentrated to dryness by evaporation in vacuo. After the addition of 30 
ml of pure ethanol, the mixture is again concentrated by evaporation, 
giving 1.90 g of reddish oil, which is dissolved in hot isopropanol. After 
cooling there is obtained crystalline 
E-2-dimethylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester 
hydrochloride, m.p. 203.degree. (decomp.). 
EXAMPLE 36 
E-2-benzylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester 
16 ml of glacial acetic acid, 5.90 g of sodium acetate (anhydrous) and 12.2 
ml of benzaldehyde are added to a solution of 5.69 g of 
E-2-amino-4-methyl-5-phosphono-3- pentenoic acid ethyl ester in 48 ml of 
water and 48 ml of ethanol. 15.70 g of sodium borohydride are added in 
approximately 70 portions within a period of one hour with intensive 
cooling with ice/sodium chloride, 4 ml of benzaldehyde being added after 
half the addition has taken place, after approximately 30 minutes. The 
temperature of the reaction mixture is kept at from 0.degree. to 
10.degree.. When the addition is complete, the mixture is stirred at 
0.degree. for one hour to complete the reaction, and then 1N hydrochloric 
acid is added dropwise until an acidic reaction to Congo red takes place. 
The undissolved salts are filtered off and washed with water. The filtrate 
is concentrated to dryness by evaporation in vacuo, and the residue is 
concentrated by evaporation twice more after the addition of ethanol. The 
residue is then stirred with 150 ml of ethanol, and the undissolved 
material is filtered off with suction and washed with ethanol. 25 ml of 
propylene oxide are added to the filtrate, and the mixture is then stirred 
for 2 hours. The material which crystallises out (mainly educt) is filtered 
off. The mother liquor is concentrated to dryness by evaporation and 
stirred with 350 ml of ethyl acetate. The crystalline crude product 
obtained after filtration with suction is recrystallised from ethanol. In 
this manner there is obtained 
E-2-benzylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester, m.p. 
192 .degree. (decomp.). 
EXAMPLE 37 
E-2-benzylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester 
A solution of 1.00 g of E-2-benzylamino-4-methyl-5-phosphono-3-pentenoic 
acid ethyl ester in 6 ml of water is stirred under reflux for 20 hours. 
The reaction mixture is concentrated to dryness by evaporation in vacuo. 
Ethanol is added to the residue, and the mixture is again concentrated by 
evaporation. This process is repeated twice more. The residue is dissolved 
in boiling methanol. After cooling there is obtained crystalline 
E-2-benzylamino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 150.degree. 
(decomp.). 
EXAMPLE 38 
E-2-isopropylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester 
6.64 g of sodium acetate (anhydrous) and 18 ml of acetone are added to a 
solution of 6.40 g of E-2-amino-4-methyl-5-phosphono-3-pentenoic acid 
ethyl ester in 54 ml of water and 18 ml of glacial acetic acid. 17.67 g of 
sodium borohydride are added in approximately 70 portions within a period 
of 90 minutes with intensive cooling with ice/sodium chloride, 18 ml of 
acetone being added after 20 minutes and after 50 minutes. When the 
addition is complete, the thick white suspension is stirred at 0.degree. 
for 30 minutes to complete the reaction, and then 1N hydrochloric acid is 
added dropwise until an acidic reaction to Congo red takes place. The 
resulting clear solution is concentrated by evaporation in vacuo, and the 
residue is concentrated by evaporation twice more after the addition of 
ethanol. The residue is then stirred with 200 ml of ethanol at room 
temperature, and the undissolved material is filtered off and washed with 
ethanol. The filtrate is concentrated by evaporation in vacuo, and the 
residue is recrystallised from isopropanol. 
In this manner there is obtained 
E-2-isopropylamino-4-methyl-5-phosphono-3-pentenoic acid ethyl ester 
hydrochloride, m.p. 203.degree.-205.degree. (decomp.). 
EXAMPLE 39 
E-2-isopropylamino-4-methyl-5-phosphono-3-pentenoic acid 
A solution of 1.20 g of E-2-isopropylamino-4-methyl-5-phosphono-3-pentenoic 
acid ethyl ester hydrochloride in 7 ml of water is stirred under reflux for 
20 hours. The reaction mixture is concentrated to dryness by evaporation in 
vacuo. Ethanol is added to the residue, and the mixture is again 
concentrated by evaporation. This process is repeated twice more. The 
residue is dissolved in 25 ml of ethanol, a total of 5 ml of propylene 
oxide is added dropwise thereto with stirring, and the whole is 
concentrated to dryness by evaporation. The residue is dissolved in a 
little water, and ethanol is added until the solution becomes cloudy. The 
solution is stirred at room temperature for 4 hours to complete the 
reaction, during which time crystallisation slowly takes place. The 
product is filtered off, washed with ethanol and diethyl ether and dried 
at 100.degree. under a high vacuum. In this manner there is obtained 
E-2-isopropylamino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 
225.degree.-227.degree. (decomp.). 
EXAMPLE 40 
E-2-methylamino-4-methyl-5-phosphono-3-pentenoic acid 
a) 2-(N-methyl-N-formylamino)-3-hydroxy-4-methyl-4-pentenoic acid ethyl 
ester (1) 
20.60 g of 5-(2-propenyl)-2-oxazoline-4-carboxylic acid ethyl ester, 
prepared according to Example 55, are dissolved in 200 ml of dry 
dichloromethane under argon. A suspension of 16.60 g of trimethyloxonium 
tetrafluoroborate in 200 ml of dry dichloromethane is then added dropwise 
at 15.degree.. The reaction mixture is stirred at room temperature for 17 
hours, and then 150 ml of water and 45 ml of saturated potassium 
bicarbonate solution are added slowly, so that a pH of 7 is produced. The 
organic phase is separated off and washed twice with water and once with 
saturated sodium chloride solution, and is then dried over sodium 
sulphate. After the dichloromethane has been distilled off, the oily 
residue is distilled in a bulb tube, b.p. 120.degree.-130.degree./13 Pa. 
In this manner there is obtained 
2-(N-methylformylamino)-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester in 
the form of a light-yellow honey, IR (CH.sub.2 Cl.sub.2): 3550 (HO); 1740 
(CO ester); 1675 (CO amide). 
b) E-2-(N-methyl-N-formylamino)-4-methyl-5-diisopropylphosphono-3-pentenoic 
acid ethyl ester (2) 
7.70 ml of thionyl bromide are added dropwise at 20.degree. under argon to 
a solution of 17.80 g of 
2-(N-methylformylamino)-3-hydroxy-4-methyl-4-pentenoic acid ethyl ester in 
248 ml of 1,2-dichloroethane. The mixture is stirred at room temperature 
for 2 hours. 150 ml of water are then added dropwise with slight cooling 
(20.degree.). The two-phase mixture is stirred thoroughly for a further 20 
minutes to complete the reaction. The organic phase is separated off and 
washed three times with water/ice, once with ice/saturated potassium 
bicarbonate solution and once with saturated sodium chloride solution. To 
the intermediate obtained after drying over sodium sulphate and removal of 
the 1,2-dichloroethane by distillation at 35.degree. in vacuo there are 
added at room temperature 66 ml of triisopropyl phosphite, and the mixture 
is then stirred at 75.degree. under reduced pressure (approximately 13 kPa) 
for 17 hours. The excess triisopropyl phosphite and other volatile 
by-products are then distilled off under a high vacuum. Purification by 
column chromatography (silica gel, ethyl acetate) yields 
E-2-(N-methylformylamino)-4-methyl-5-diisopropylphosphono-3-pentenoic acid 
ethyl ester in the form of a yellowish honey; IR (CH.sub.2 Cl.sub.2): 1740 
(CO ester); 1670 (CO amide); 1235 (P.dbd.O); 980-1010 (P--O--C). According 
to the .sup.1 H-NMR spectrum, the compound is in the form of a mixture of 
two rotamers. 
c) E-2-methylamino-4-methyl-5-phosphono-3-pentenoic acid (3) 20 ml of 
trimethylbromosilane are added dropwise at 20.degree. within a period of 
10 minutes under argon to a solution of 9.50 g of 
E-2-(N-methylformylamino)-4-methyl-5-diisopropylphosphono-3-pentenoic acid 
ethyl ester in 40 ml of dry dichloromethane. After stirring at room 
temperature for 20 hours, 37 ml of ethanol are added dropwise within a 
period of 15 minutes, and the whole is stirred for a further 20 hours. The 
clear reaction solution is then concentrated to dryness by evaporation in 
vacuo. The residue is concentrated by evaporation twice more in each case 
after the addition of 30 ml of toluene. 128 ml of 2N hydrochloric acid are 
added to the resulting oil, and the mixture is stirred at a bath 
temperature of 85.degree. for 16 hours. The reaction mixture is 
concentrated by evaporation in vacuo. Concentration by evaporation twice 
after the addition of ethanol/toluene 1:1 yields an oily residue, which is 
dissolved in 51 ml of ethanol and to which there is added dropwise a 
solution of 51 ml of propylene oxide in 51 ml of ethanol. The product 
obtained in crystalline form is filtered off after 2 hours and 
recrystallised from water/ethanol. In this manner there is obtained 
E-2-methylamino-4-methyl-5-phosphono-3-pentenoic acid, m.p. 239.degree. 
(decomp.). 
EXAMPLE 41 
23 ml (178 mmols) of trimethylsilyl bromide are added dropwise at room 
temperature to a solution of 18.3 g (44.5 mmols) of benzyl 
E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoate in 73 ml of 
dichloromethane. After 20 hours at room temperature 46 ml of benzyl 
alcohol are added dropwise, and the reaction mixture is allowed to stand 
for additional 20 hours at room temperature. The dichloromethane is 
distilled off, first 40 ml of ethanol and then dropwise 40 ml of propylene 
oxide in 40 ml of ethanol are added. The crystalline precipitate formed is 
filtered off, triturated with 200 ml of water and filtrated off again. 
Benzyl E-2-amino-4-methyl-5-phosphono-pentenoate of m.p. 
196.degree.-197.degree. (decomp.) is thus obtained. 
The starting material can be prepared as follows: 
32.8 ml (65.6 mmols) of a 2N aqueous sodium hydroxide solution are added to 
a solution of ethyl 
E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoate in 230 ml of 
ethanol. After stirring for 1 hour at room temperature 32,8 ml (65,6 
mmols) of 2N hydrochloric acid are added and the reaction mixture is 
evaporated to dryness. This procedure is repeated twice. Then the residue 
is dissolved in dichloromethane, filtrated over Hyflo.RTM. and 
concentrated until crystallization begins. 200 ml of diethyl ether are 
added to complete crystallization. The resulting 
E-2-formylamino-4-methyl-5-diisopropylphosphono-pentenoic acid is 
filtrated off; m.p. 101.degree.-106.degree.. 
11.5 g (56.4 mmols) of dicyclohexylcarbodiimid are added to a solution of 
18.1 g (56.4 mmols) of 
E-2-formylamino-4-methyl-5-diisopropylphosphono-pentenoic acid, 6.1 g 
(56.4 mmols) of benzyl alcohol and 0.7 g of 4-(N,N-dimethylamino)pyridine 
in 140 ml of dichloromethane. The reaction mixture is stirred 2 hours in 
an ice bath and 10 hours at room temperature. The reaction solution is 
filtrated clear, washed with diluted hydrochloric acid and twice with 
water, dried over magnesium sulfate and chromatographed over silica gel 
with first ethyl acetate and then ethyl acetate/isopropanol as eluent. 
Benzyl E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoate is 
obtained as an orange-colored oil which can be crystallized from diethyl 
ether/hexane; m.p. 50.degree.-58.degree.. 
EXAMPLE 42 
A mixture of 2.37 g (10 mmols) of ethyl 
E-2-amino-4-methyl-5-phosphono-pentenoate, 14.3 g (100 mmols) of 
p-chlorobenzyl alcohol, 10 ml of dichloromethane and 20 ml of 4N 
hydrochloric acid is allowed to stand at room temperature for 1 week. The 
reaction mixture is evaporated to dryness, the residue is dissolved in 25 
ml of ethanol and a solution of 15 ml of propylene oxide in 15 ml of 
ethanol is added dropwise. The crystalline precipitate formed is 
collected, washed twice with water, filtrated and dried. p-chlorobenzyl 
E-2-amino-4-methyl-5-phosphono-pentenoate of m.p. 207.degree.-208.degree. 
is thus obtained. 
EXAMPLE 43 
In an analogous manner as described in Examples 41 or 42, the following 
compounds can be prepared: 
o-chlorobenzyl E-2-amino-4-methyl-5-phosphono-pentenoate, m.p. 
216.degree.-219.degree. (decomp.); 
p-fluorobenzyl E-2-amino-4-methyl-5-phosphono-pentenoate, m.p. 
190.degree.-191.degree. (decomp.), and 
m-chlorobenzyl E-2-amino-4-methyl-5-phosphono-pentenoate, m.p. 193.degree. 
(decomp.). 
EXAMPLE 44 
In an analogous manner as described in anyone of Examples 1 to 40 also 
2-E-amino-4-(p-chlorophenyl)-5-phosphono-3-pentenoic acid, m.p. 216.degree. 
(decomp.), and 
(2R)-2-E-amino-4-fluoro-5-phosphono-3-pentenoic acid, m.p. 209.degree. 
(decomp.) 
can be manufactured. 
EXAMPLE 45 
Preparation of 1000 capsules each containing 10 mg of the active ingredient 
of Example 6 and having the following composition: 
______________________________________ 
E-2-amino-4-methyl-5-phosphono-3-hexenoic acid 
10.0 g 
lactose 207.0 g 
modified starch 80.0 g 
magnesium stearate 3.0 g 
______________________________________ 
Method: All the pulverulent constituents are sieved through a sieve having 
a mesh width of 0.6 mm. The active ingredient is then placed in a suitable 
mixer and mixed first with the magnesium stearate and then with the lactose 
and starch, until a homogeneous mixture is obtained. No. 2 gelatin capsules 
are each filled with 300 mg of this mixture, a capsule-filling machine 
being used. 
Capsules that contain from 10 to 200 mg of one of the other disclosed 
compounds mentioned in Examples 1-59 are prepared in analogous manner. 
EXAMPLE 46 
Preparation of 10,000 tablets each containing 10 mg of the active 
ingredient of Example 6 and having the following composition: 
______________________________________ 
E-2-amino-4-methyl-5-phosphono-3-hexenoic acid 
100.00 g 
lactose 2535.00 g 
corn starch 125.00 g 
polyethylene glycol 6000 150.00 g 
magnesium stearate 40.00 g 
purified water q.s. 
______________________________________ 
Method: All the pulverulent constituents are sieved through a sieve having 
a mesh width of 0.6 mm. The active ingredient is then mixed in a suitable 
mixer with the lactose, the magnesium stearate and half of the starch. The 
other half of the starch is suspended in 65 ml of water, and the suspension 
is added to a boiling solution of the polyethylene glycol in 260 ml of 
water. The resulting paste is added to the powders and the mixture is 
granulated, if necessary with the addition of more water. The granulate is 
dried overnight at 35.degree., forced through a sieve having a mesh width 
of 1.2 mm, and compressed to form tablets which have a breaking groove. 
Tablets that contain from 10 to 200 mg of one of the other disclosed 
compounds mentioned in Examples 1-44 are prepared in analogous manner.