3(1-hydoxyethyl)azetidinone compounds and their production

An amino acid compound of the formula: ##STR1## wherein R is a lower alkyl group, R.sub.1 is a hydrogen atom or a protecting group for carboxyl, R.sub.2 is a hydrogen atom, a protecting group for amino, an optionally substituted allyl group of the formula: ##STR2## (wherein R.sub.3 and R.sub.4 are each a hydrogen atom, a lower alkyl group or an aryl group), a beta-hydroxyethyl group in which the hydroxyl group is optionally protected, a formylmethyl group in which the formyl group is optionally protected, a carboxymethyl group in which the carboxyl group is protected or a 2-furylmethyl group and X is an optionally protected carboxyl group, a hydroxymethyl group in which the hydroxyl group is optionally protected or a substituted mercaptomethyl group of the formula: EQU --CH.sub.2 SR.sub.5 (wherein R.sub.5 is an aryl group or an ar(lower)alkyl group), which is a useful intermediate in the synthesis of 1-alkylcarbapenem compounds.

The present invention relates to amino acid compounds and their production 
particularly, it relates to novel amino acid compounds useful as 
intermediates in the synthesis of 1-alkylcarbapenem compounds and their 
production. 
The amino acid compounds of this invention are representable by the 
formula: 
##STR3## 
wherein R is a lower alkyl group, R.sub.1 is a hydrogeh atom or a 
protecting group for carboxyl, R.sub.2 is a hydrogen atom, a protecting 
group for amino, an optionally substituted allyl group of the formula: 
##STR4## 
(wherein R.sub.3 and R.sub.4 are, the same or different, each a hydrogen 
atom, a lower alkyl group or an aryl group), a beta-hydroxyethyl group in 
which the hydroxyl group is optionally protected, a formylmethyl group in 
which the formyl group is optionally protected, a carboxymethyl group in 
which the carboxyl group is protected or a 2-furylmethyl group and X is an 
optionally protected carboxyl group, a hydroxymethyl group in which the 
hydroxyl group is optionally protected or a substituted mercaptomethyl 
group of the formula: 
EQU --CH.sub.2 SR.sub.5 
(wherein R.sub.5 is an aryl group or an ar(lower)alkyl group). 
Since the successful isolation of an antimicrobial substance "thienamycin" 
from the nature [U.S. Pat. No. 3,950,357; J.Am.Chem.Soc., 100, 313 
(1978)], various carbapenem compounds have been synthesized. Among them, 
there are known some carbapenem compounds substituted at the 1-position, 
and 1-alkylcarbapenem compounds are particularly notable in exerting 
strong antimicrobial activity against various microorganisms with 
excellent stability in living bodies [Heterocycles, 21, 29 (1984)]. 
As a result of the extensive study, it has now been found that the amino 
acid compounds (I), which are novel, are valuable intermediates for the 
production of 1-alkylcarbapenem compounds. 
Throughout this specification, particularly in the above formula (I), the 
term "lower" is generally intended to mean any group having not more than 
8 carbon atoms, especially not more than 6 carbon atoms, more especially 
not more than 4 carbon atoms. Accordingly, for instance, the term "lower 
alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, 
t-butyl, etc. The term "lower alkoxy" includes methoxy, ethoxy, n-propoxy, 
isopropoxy, n-butoxy, sec-butoxy, t-butoxy, etc. The term "lower alkanoyl" 
covers acetyl, propionyl, butyryl, etc. Further, the term "halogen" is 
usually intended to mean chlorine, bromine, iodine and fluorine. 
Furthermore, the term "aryl" means normally an aromatic hydrocarbon group 
having not more than 20 carbon atoms such as phenyl, naphthyl or 
anthranyl. When the aryl group is substitued, the substituent(s) may be 
chosen from lower alkyl, lower alkoxy, nitro, amino, halogen, etc. 
General protection of the functional groups such as carboxyl, amino, 
hydroxyl and formyl are disclosed in various textbooks such as "Protective 
Groups in Organic Synthesis" (1981) published by John Wiley & Sons, New 
York, U.S.A. and "New Experimental Chemistry" ("Shin-Jikken Kagaku Koza" 
in Japanese), Vol. 14 (1978) published by Maruzen, Tokyo, Japan as well as 
many literatures as cited in those textbooks. Conventional protecting 
groups as disclosed therein are ordinarily usable in this invention. 
Specific examples of the protecting group for carboxyl are a lower alkyl 
grcup such as C.sub.1 -C.sub.4 alkyl (e.g. methyl, ethyl, n-propyl, 
isopropyl, n-butyl, sec-butyl, t-butyl), a halogenated lower alkyl group 
such as C.sub.1 -C.sub.4 alkyl substituted with one to three halogen atoms 
(e.g. 2-iodoethyl, 2,2,2-trichloroethyl), a lower alkoxymethyl group such 
as C.sub.1 -C.sub.4 alkoxymethyl (e.g. methoxymethyl, ethoxymethyl, 
isobutoxymethyl), a lower alkoxycarbonyloxyethyl group such as C.sub.1 
-C.sub.4 alkoxycarbonyloxyethyl (e.g. 1-methoxycarbonyloxyethyl, 
1-ethoxycarbonyloxyethyl), a lower alkanoyloxymethyl group such as C.sub.2 
-C.sub.7 alkanoyloxymethyl (e.g. acetoxymethyl, propionyloxymethyl, 
butyryloxymethyl, pivaloyloxymethyl), an optionally substituted lower 
alkenyl group such as optionally substituted C.sub.3 -C.sub.6 allyl (e.g. 
allyl, 2-methylallyl, 3-methylally, cinnamyl), an optionally substituted 
arylmethyl group such as optionally substituted phenylmethyl (e.g. benzyl, 
p-methoxybenzyl, 2,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, 
p-chlorobenzyl), an optionally substituted diarylmethyl group such as 
optionally substituted diphenylmethyl (e.g. diphenylmethyl, 
di-p-anisylmethyl), an optionally substituted aryl group such as 
optionally substituted phenyl (e.g. phenyl, p-nitrophenyl, p-chlorophenyl, 
2,6-dimethylphenyl), etc. 
Specific examples of the protecting group for amino are a lower 
alkoxycarbonyl group such as C.sub.1 -C.sub.5 alkoxycarbonyl (e.g. 
t-butoxycarbonyl), a halogenated lower alkoxycarbonyl group such as 
C.sub.1 -C.sub.3 alkoxycarbonyl substituted with one to three halogen 
atoms (e.g. 2-iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl), an 
optionally substituted arylmethoxycarbonyl group such as optionally 
substituted phenylmethoxycarbonyl (e.g. benzyloxycarbonyl, 
o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 
p-methoxybenzyloxycarbonyl), an optionally substituted arylmethyl group 
such as optionally substituted phenylmethyl group (e.g. benzyl, 
p-methoxybenzyl, 2,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl), an 
optionally substituted diarylmethyl group such as optionally substituted 
diphenylmethyl (e.g. diphenylmethyl, di-p-anisylmethyl), an alpha-lower 
alkyl-benzyl group such as alpha-C.sub.1 -C.sub.4 alkylbenzyl(e.g. 
alpha-methylbenzyl, alpha-ethylbenzyl), a trityl group, a substituted aryl 
group such as substituted phenyl (e.g. p-methoxyphenyl, 
2,4-dimethoxyphenyl, o-nitrophenyl, p-nitrophenyl, 2,4-dinitrophenyl), a 
tri(lower)alkylsilyl group such as tri(C.sub.1 -C.sub.4)alkylsilyl (e.g. 
trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylmethylsilyl), a 
substituted methyl group (e.g. methoxymethyl, 2-methoxyethoxymethyl, 
benzyloxymethyl, methylthiomethyl), a tetrahydropyranyl group, etc. 
Specific examples of the protecting group for hydroxyl are a lower alkyl 
group such as C.sub.1 -C.sub.4 alkyl (e.g. t-butyl), a substituted methyl 
group (e.g. methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 
t-butoxymethyl, methylthiomethyl, 2,2,2-trichloroethoxymethyl), a 
tetrahydropyranyl group, a substituted ethyl group (e.g. 1-ethoxyethyl, 
1-methyl-1-methoxyethyl, trichloroethyl), an optionally substituted 
monophenylmethyl, diphenylmethyl or triphenylmethyl group (e.g. benzyl, 
p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-chlorobenzyl, 
diphenylmethyl, triphenylmethyl), a substituted silyl group (e.g. 
trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, 
t-butyldiphenylsilyl), a formyl group, a lower alkanoyl group such as 
C.sub.2 -C.sub.5 alkanoyl (e.g. acetyl, isobutyroyl, pivaloyl), a 
halogenated lower alkanoyl group (e.g. dichloroacetyl, trichloroacetyl, 
trifluoroacetyl), an arylcarbonyl group (e.g. benzoyl, toluoyl, 
naphthoyl), a lower alkoxycarbonyl group such as C.sub.1 -C.sub.5 
alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl), 
a halogenated lower alkoxycarbonyl group such as C.sub.1 -C.sub.5 
alkoxycarbonyl substituted with one to three halogen atoms (e.g. 
2-iodoethoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl), a 
lower alkenyloxycarbonyl group such as C.sub.2 -C.sub.6 alkenyloxycarbonyl 
(e.g. vinyloxycarbonyl, allyloxycarbonyl), an optionally substituted 
arylmethyloxycarbonyl group such as optionally substituted 
phenylmethyloxycarbonyl (e.g. benzyloxycarbonyl, 
p-methoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 
o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl), etc. 
Examples of the protected formyl group are a di(lower)alkoxymethyl group 
such as di(C.sub.1 -C.sub.4)alkoxymethyl (e.g. dimethoxymethyl, 
diethoxymethyl, di-n-propyloxymethyl), a di(halogenated lower 
alkoxy)methyl group (e.g. di(trichloroethoxy)methyl), a di(aryloxy)methyl 
group (e.g. di(phenyloxy)methyl), a di(aryl(lower)alkoxy)methyl group 
(e.g. dibenzyloxymethyl), a cyclic group of the formula: 
##STR5## 
(wherein Y is an oxygen atom or a sulfur atom and n is an integer of 2 or 
3), etc. 
Among the amino acid compounds of the formula (I), preferred are those 
wherein R represents a methyl group. More preferred are those wherein R 
represents a methyl group, R.sub.2 represents a benzyl group, a 2-propenyl 
group, a 2-furylmethyl group or a 2,2-dimethoxyethyl group. 
The amino acid compound (I) can be produced from the corresponding 
acetylenamine compound of the formula: 
##STR6## 
wherein R, R.sub.1, R.sub.2 and X are each as defined above by reduction. 
The reduction may be performed by a per se conventional reduction procedure 
such as catalytic hydrogenation using a catalyst (e.g. platinum, 
palladium, nickel), reduction with an alkali metal (e.g. lithium, sodium) 
in liquid ammonia or a lower alkylamine, reduction with a metal hydride 
such as aluminium hydride, an organic tin hydride (e.g. triethyltin 
hydride, tri-n-butyltin hydride, triphenyltin hydride) or a hydrosilane 
(e.g. trimethylsilane, triethylsilane, diethylsilane), reduction with an 
optionally substituted borane (e.g. diborane, 9-borabicyclo[3.3.1]nonane, 
dibenzoyloxyborane, monochloroborane, dichloroborane, catecholborane, 
dicyclohexylborane), reduction with a metal complex hydride (e.g. lithium 
aluminium hydride, sodium borohydride, sodium cyanoborohydride, lithium 
cyanoborohydride, sodium acetoxyborohydride), etc. The reduction may be 
accomplished in a single stage or two stages; in the at different stages. 
Among various reduction procedures as above, the most preferred are the 
following two: 
Procedure A: 
The acetylenamine compound (II) is treated with a reducing agent (e.g. 
sodium cyanoborohydride, sodium borohydride, sodium acetoxyborohydride) in 
an inert solvent (e.g. acetic acid, propionic acid, ethanol, methanol) in 
the presence of an acid such as a mineral acid (e.g. hydrochloric acid, 
sulfuric acid) or a carboxylic acid (e.g. acetic acid, propionic acid, 
tartaric acid, oxalic acid) to give the amino acid compound (I). The 
reducing agent is usually employed in an amount of 2 to 5 equivalents to 
the acetylenamine compound (II). The treatment is normally effected at a 
temperature of about -40.degree. C. to 80.degree. C., although a lower 
temperature or a higher temperature may be adopted for suppressing or 
promoting the progress of the reduction. It is particularly preferred that 
the treatment is effected with sodium cyanoborohydride (NaBH.sub.3 CN) or 
sodium borohydride (NaBH.sub.4) in the presence of acetic acid or 
propionic acid. 
Procedure B: 
The acetylenamine compound (II) is treated first with an optionally 
substituted borane and then with a reducing agent, followed by solvolysis 
to give the amino acid compound (I). 
As the optionally substituted borane, there may be used diborane, 
9-borabicyclo[3.3.1]nonane, dibenzoyloxyborane, monochloroborane, 
dichloroborane, catecholborane or the like, preferably catecholborane or 
the like. The amount of the optionally substituted borane may be usually 
from 1 to 2.5 equivalents to the acetylenamine compound (II). Treatment 
with the optionally substituted borane is usually effected in an inert 
solvent such as an ether (e.g. tetrahydrofuran, diethyl ether, dioxane, 
diglyme), a halogenated hydrocarbon (e.g. chloroform, dichloromethane) or 
an aromatic hydrocarbon (e.g. benzene, toluene) at an temperature of 
-100.degree. C. to room temperature. 
The subsequent treatment with a reducing agent (e.g. sodium 
cyanoborohydride, sodium borohydride) is usually performed in an inert 
solvent (e.g. acetic acid, propionic acid, ether, tetrahydrofuran, 
chloroform) in the presence of an acid (e.g. acetic acid, propionic acid, 
oxalic acid, hydrochloric acid, sulfuric acid) at a temperature of about 
-40.degree. to 80.degree. C. The amount of the reducing agent may be 
normally about 1 to 3 equivalents to the acetylenamine compound (II). 
The solvolysis of the reaction product may be accomplished in a solvent 
such as water or methanol in the presence of a base (e.g. sodium hydrogen 
carbonate, sodium carbonate, sodium hydroxide) at a temperature of about 0 
to 40.degree. C. 
The amino acid compound (I) comprises four asymmetric carbon atoms and have 
many optical isomers and stereo isomers based thereon. All of those 
isomers and their mixtures are included in this invention. 
According to Procedure A or B as illustrated above, there are predominantly 
produced four kinds of isomers, i.e. the isomers of the following 
formulas: 
##STR7## 
wherein R, R.sub.1, R.sub.2 and X are each as defined above and their 
respective enantiomers. Depedning upon the reaction conditions, the 
proportion of these isomers in the reaction mixture is varied. When 
appropriate reaction conditions are chosen, there is obtainable a reaction 
mixture comprising as the major products the isomer (Ia) and its 
enantiomer, said isomer (Ia) being derivable to the corresponding 
18-alkylcarbapenem compound of the formula: 
##STR8## 
wherein R and R.sub.1 are each as defined above, R.sub.6 is a hydrogen 
atom or a protecting group for hydroxyl and Z is an organic group. 
Separation of each enantiomer may be accomplished by a procedure as 
hereinafter illustrated. 
The amino acid compounds of the formula (I) are valuable intermediates for 
production of 1-alkylcarbapenem compounds and can be converted into the 
latter by various procedures, of which a typical one is illustratively 
shown in the following scheme: 
##STR9## 
wherein R, R.sub.1, R.sub.2, R.sub.6, X and Z are each as defined above. 
Step (i): 
The amino acid compound (I) is converted into the corresponding free acid 
(IV) by application of a per se conventional carboxyl-protecting 
group-elimination procedure thereto. 
When the amino acid compound (I) wherein X is a protected carboxyl group is 
used as the starting material, it may be treated acccrding to the method 
as disclosed in Tetrahedron Letters, 21, 2783-2786 (1980) and 22, 913-916 
(1981) to give the corresponding free acid as shown below: 
##STR10## 
wherein R, R.sub.1 and R.sub.2 are each as defined above and R.sub.1 and 
R.sub.1.sup." are each a protecting group for carboxyl. 
The step (1) is concerned with lactonization of the compound (Ic) to the 
lactone (V). The lactonization may be accomplished by treatment of the 
compound (Ic) with a hydrogen halide (e.g. hydrogen chloride, hydrogen 
bromide) in an inert solvent such as a halogenated hydrocarbon (e.g. 
methylene chloride, chloroform, dichloroethane) or an ether (e.g. 
tetrahydrofuran, dioxane). 
When the compound (Ic) is a mixture of the (Ia) type isomer and the (Ib) 
type isomer, the (Ia) type isomer is selectively converted into the 
compound (Va) as shown below, which can be derived to 1.beta.-methyl or 
alkyl carbapenem compounds: 
##STR11## 
wherein R, R.sub.1, R.sub.2 and R.sub.1.sup.' are each as defined above. 
In the step (2), the lactone (V) is converted into the free acid (IV'). 
This conversion may be accomplished in the manner as disclosed in the 
aforementioned literatures and will be hereinafter explained in detail. 
The lactone (V) involves a variety of stereo isomers, and the method as 
hereinafter explained is equally applicable to all of them, although the 
subsequent description will be made on the compound (Va) for the sake of 
convenience. 
Method (a): 
##STR12## 
wherein R, R.sub.1, R.sub.2 and R.sub.1.sup." are each as defined above. 
The compound (Va) is subjected to seletive hydrolysis of the lactone ring 
with alkali to give the compound (Id), which is then subjected to 
protection of the free carboxyl group with a protecting group 
(R.sub.1.sup.") which is not influenced during the removal of the 
carboxyl-protecting group R.sub.1, followed by removal of the latter 
(R.sub.1) to give the compound (IV'a). 
As the reagent in the selective hydrolysis, there may be used an aqueous 
solution of barium hydroxide, sodium hydroxide, potassium hydroxide, 
calcium hydroxide, tetrahydrobutylammonium hydroxide or the like, 
preferably an aqueous solution of barium hydroxide. The reaction medium is 
not limitative, and any one as conventionally used in alkali hydrolysis 
may be employed; preferred are tetrahydrofuran, acetone, methanol, 
pyridine, etc. and their mixtures with water. The reaction is favorably 
carried out at a temperature of 0.degree. to 70.degree. C., but a lower 
temperature or a higher perature may be adopted for suppression or 
promotion of the reaction. The carboxyl group-protection and the carboxyl 
group-elimination may be accomplished by per se conventional procedures, 
respectively. 
Method (b): 
##STR13## 
wherein R, R.sub.1, R.sub.1.sup." are each as defined above and 
R.sub.2.sup.' is a protecting group for amino. 
The amino acid having a free amino group (IV'b) can be produced from the 
compound (Vb) by hydrolysis of the ester, elimination of the 
amino-protecting group and cleavage of the lactone ring. When, for 
instance, the carboxyl-protecting group is a lower alkyl group and the 
amino-protecting group is an arylmethyl group such as benzyl, the compound 
(Vb) is first treated with a mineral acid (e.g. hydrochloric acid), 
whereby selective hydrolysis takes place to give the compound (Vc). The 
compound (Vc) is then subjected to hydrogenolysis in the presence of a 
catalyst such as palladium hydroxide-carbon, whereby the amino-protecting 
group is removed to give the compound (Vd). Then, the compound (Vd) is 
subjected to alcoholysis by the use of an alcohol (e.g. benzyl alcohol), 
whereby the lactone ring is cleaved to give the compound (Iv'b). 
Method (c): 
##STR14## 
wherein R, R.sub.1, R.sub.2 and R.sub.1.sup." are each as defined above. 
The compound (IV'c) wherein the steric configuration of the hydroxyl group 
is inversed to that in the compound (IV'a) can be obtained from the amino 
acid compound (Id) by lactonization of the latter with diethyl 
azodicarboxylate and triphenylphosphine and conversion of the resultant 
compound (Ve) to the compound (IV'c) by application of Methods (a) and (b) 
as above. 
In the lactonization, any auxiliary agent such as an organic base (e.g. 
triethylamine) may be used to accelerate production of the compound (Ve). 
Alternatively, the compound (Ic) wherein X is a protected carboxyl group 
may be converted into the compound (Id) by selective hydrolysis with an 
alkali as set forth below: 
##STR15## 
wherein R, R.sub.1, R.sub.2 and R.sub.1.sup.' are each as defined above. 
As the reagent in the selective hydrolysis, there may be used an aqueous 
solution of barium hydroxide, sodium hydroxide, potassium hydroxide, 
calcium hydroxide, tetrahydrobutylammonium hydroxide or the like, among 
which an aqueous solution of barium hydroxide is the most preferred. The 
reaction medium may be any one as conventionally employed in conventional 
alkali hydrolysis, and there may be used, for instance, tetrahydrofuran, 
acetone, methanol, pyridine, etc. or their mixtures with water. The 
reaction is favorably carried out at a temperature of 0.degree. to 
70.degree. C., but a lower temperature or a higher temperature may be 
adopted for suppression or acceleration of the reaction. 
Step (ii): 
The amino acid compound (IV) is subjected to dehydrative cyclization to 
give the azetidinone compound (VI). The dehydrative cyclization may be 
accomplished, for instance, by treatment of the amino acid compound (IV) 
with a dehydrating agent such as 2,2-dipyridyl disulfidetriphenylphospine 
or dicyclohexylcarbodiimide in the presence or absence of a base in an 
inert solvent [J.Am. Chem.Soc., 103, 2405-2406 (1981); Tetrahedron 
Letters, 21, 2783-2786 (1980); ibid., 22, 913-916 (1981)]. 
Step (iii) 
With or without any previous protection of the hydroxyl group on the side 
chain at the 3-position by a per se conventional procedure, the 
azetidinone compound (VI) is converted into the corresponding carboxylic 
acid (VII). For this conversion, there may be adopted any appropriate 
procedure depending upon the kind of the group X. In case of X being a 
protected carboxyl group, the azetidinone compound (VI) may be subjected 
to hydrolysis, hydrogention, treatment with an acid or the like. In case 
of X being a protected hydroxymethyl group, the azetidinone compound (VI) 
may be subjected to removal of the hydroxyl-protecting group by a per se 
conventional procedure, and the thus recovered hydroxymethyl group is then 
oxidized, for instance, with chromic acid to give the compound (VII) 
[J.Am.Chem.Soc., 105, 1659-1660 (1983)]. In case of X being --CH.sub.2 
SR.sub.5, the azetidinone compound (VI) may be treated with an alkyl 
halide (e.g. methyl iodide) to convert --CH.sub.2 SR.sub.5 into a 
halomethyl group, which is then changed to a hydroxymethyl group by a per 
se conventional procedure. The resultant hydroxymethyl group is then 
oxidized in the same manner as above to give the compound (VII) 
[Tetrahedron Letters, 5787 -5788 (1968)]. 
Step (iv): 
The azetidinone compound (vII) wherein R.sub.2 is a hydrogen atom is 
already known and used as the starting material for production of the 
1-methyl or alkylcarbapenem compounds [Heterocycles, 21, 29-40 (1984); 
Tetrahedron Letters, 26, 587-590 (1985)]. When R.sub.2 comprises any 
protecting group, an appropriate procedure for elimination of the 
protecting group such as hydrogenation, oxidative removal or treatment 
with an acid may be first applied to the azetidinone compound (VII), 
whereby the protecting group is eliminated. 
When R.sup.2 is a group of the formula: 
##STR16## 
the azetidinone compound (VIII) may be converted into the azetidinone 
compound (X) as shown below [Japanese Patent Application No. 123117/1985]: 
##STR17## 
wherein R, R.sub.1, R.sub.3, R.sub.4 and R.sub.6 are each as defined 
above. 
Namely, the compound (VIII) is first subjected to oxidation to give the 
compound (IX). The oxidation may be accomplished by a per se conventional 
procedure; for instance, the compound (VIII) is oxidized with ozone and 
then treated with an oxidizing agent (e.g. m-chloroperbenzoic acid), or 
treated with potassium permanganate in the presence or absence of a phase 
transfer catalyst such as a crown ether or a quaternary ammonium compound. 
The thus produced compound (IX) is then subjected to protection of the 
carboxyl group, removal of the protecting group and acylation with 
thiophenol as set forth below, whereby the compound (X) is obtained: 
##STR18## 
wherein R, R.sub.1 and R.sub.6 are each as defined above. 
When R.sub.2 is a 2-furylmethyl group, the compound (VIII') may be 
converted into the compound (X) through the compound (IX) in entirely the 
same manner as above. 
When R.sub.2 is a protected beta-hydroxyethyl group, the 
hydroxyl-protecting group is eliminated by a per se conventional 
procedure. The resulting beta-hydroxyethyl group is oxidized, for 
instance, with chromic acid to a carboxyl group. The thus produced 
compound, for instance, the compound (IX) may be then converted into the 
compound (X) in the same manner as above. 
When R.sub.2 is a protected formylmethyl group, the formyl-protecting group 
is eliminated by a per se conventional procedure. The resulting 
formylmethyl group is oxidized, for instance, with chromic acid to a 
carboxyl group. The thus produced compound, for instance, the compound 
(IX) may be then converted into the compound (X) in the same manner as 
above. 
When R.sub.2 is a protected carboxymethyl group, the carboxy-protecting 
group is eliminated by a per se conventional procedure. The resulting 
compound (IX) is then converted into the compound (X) in the same manner 
as above. 
The compound (X) as above produced may be converted into the 1-methyl or 
alkylcarbapenem compound for instance, by the method as disclosed in 
Japanese Patent Application No. 290/480/85 as shown below: 
##STR19## 
wherein R.sub.1 is as defined above R.sub.6.sup.' is a protecting group 
for hydroxyl and Ph is a phenyl group. 
In the above route, the conversion in the step (c) may be accomplished by 
treating the compound (Xa) with a base (e.g. sodium diisopropylamide, 
sodium hydride) in an inert solvent such as an ether (e.g. 
tetrahydrofuran), an aromatic hydrocarbon (e.g. toluene) and their 
mixtures. The subsequent conversion of the compound (XI) to the compound 
(XII) in the step (d) may be carried out by reacting the former with 
diphenylphosphoryl chloride in an inert solvent (e.g. acetonitrile) in the 
presence of a base (e.g. diisopropylethylamine). 
The compound (XII) can be derived into various 1-methylcarbapenem compounds 
by known methods as already disclosed in many literatures. 
As stated above, the amino acid compounds (I) have optical isomers due to 
the asymmetric carbon atoms present therein. All of these isomers as well 
as their racemic mixtures are included within the scope of this invention. 
Among them, preferred are the isomers (Ia), which are advantageous 
intermediates in the synthesis of the optically active 
1.beta.-methylcarbapenem compounds of the formula: 
##STR20## 
wherein Z is as defined above. 
The optically active 1.beta.-methylcarbapenem compounds of the formula 
(IIIa) can be also produced by optical resolution of the compounds (VII) 
or of the carboxyl or amino group-containing compounds as the 
intermediates in the route from the amino acid compounds (I) to the 
compounds (VII). For instance, the optical resolution may be accomplished 
in the manner as set forth below. 
A mixture of the (3S,4S) isomer and the (3R,4R) isomer of the compound 
(VII) is admixed with an optically active amine in an inert solvent to 
form a salt between the compound (VII) and the optically active amine, 
which is as such fractionally crystallized. Alternatively, said salt is 
once crystallized, and the collected crystals are subjected to fractional 
crystallization, whereby the optically active amine salt of the (3S,4S) 
isomer and the optically active amine salt of the (3R,4R) isomer are 
obtained. 
Decomposition of the optically active amine salt of the (3S,4S) isomer or 
of the (3R,4R) isomer gives the (3S,4S) isomer or the (3R,4R) isomer. 
As the optically active amine, there may be used alpha-phenethylamine, 
alpha-naphthylamine, norephedrine, cinchonine, cinchonidine, quinine, 
quinidine, 1-(2-naphthyl)ethylamine (NEA), brucine, 
1,1-diphenyl-2-aminopropanol, 1-phenyl-2-(p-tolyl)ethylamine, etc. Among 
them, particularly preferred are cinchonine, cinchonidine, quinine, 
quinidine, etc. 
As the inert solvent usable on production and/or decomposition of the 
optically active amine salt, there are exemplified hydrocarbons (e.g. 
pentane, hexane, cyclohexane), aromatic hydrocarbons (e.g. benzene, 
toluene, xylene), halogenated hydrocarbons (e.g. dichloromethane, 
chloroform, 1,2-dichloroethane), ethers (e.g. diethyl ether 
tetrahydrofuran, dioxane), alcohols (e.g. methanol, ethanol, isopropanol), 
nitriles (e.g. acetonitrile), ketones (e.g. acetone, methylethylketone), 
water, etc. Their mixtures are also usable. Among them, preferred are 
isopropanol, ethyl acetate, acetone and their mixtures. 
Production of the salt is usually effected by dissolving a mixture of the 
isomers of the compound (VII) and the optically active amine in an inert 
solvent while heating up to the refluxing temperature of the solvent. The 
resultant solution is allowed to cool, if possible, gradually, whereby 
fractional crystallization takes place. Alternatively, said solution is 
cooled, and the precipitated crystals are collected by filtration; the 
collected crystals are subjected to fractional crystallization to 
precipitate one of the diastereomer salts. The precipitated diastereomer 
salt is collected, optionally followed by recrystallization to give the 
diastereomer salt of high purity. 
Crystallization is usually performed within a range of 0.degree. C. to room 
temperature, but a lower temperature range from -20.degree. C. to room 
temperature or a higher temperature range up to 40.degree. C. may be 
adopted. 
The amount of the optically active amine may be appropriately controlled 
depending upon the mixing proportion of the isomers of the compound (VII). 
When, for instance, the proportion of the (3S,4S) isomer and the (3R,4R) 
isomer is 1 : 1, the optically active amine may be used in an amount of 
0.5 to 1.2 mole, preferably of 1 to 1.1 mole, to 1 mole of the compound 
(VII). 
The amount of an inert solvent usable for fractional crystallization is 
varied with the kind of the solvent. When, for instance, ethyl acetate is 
used as the solvent, its weight may be from 10 to 100 times, preferably 
from 20 to 40 times, that of the compound (VII). 
The thus produced optically active amine salt of the desired isomer of the 
compound (VII) shows good filtrability. Further, it is of optically high 
purity. Therefore, the above explained process is advantageous from the 
industrial viewpoint. 
Decomposition of the optically active amine salt as above obtained may be 
accomplished by treating said salt with an acid or an alkali in an inert 
solvent (e.g. water, methylisobutylketone, ethyl acetate, dichloroethane, 
1,2dichloroethane). Application of conventional chemical and physical 
separation procedures to the reaction mixture gives the desired isomer of 
the compound (VII). As the acid usable for the decomposition, there may be 
favorably employed a mineral acid such as hydrochloric acid or sulfuric 
acid. Examples of the alkali usable are aqueous solutions of sodium 
hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, 
etc. 
The optical resolution as above explained may be applied to any of the 
compounds (VII) wherein R, R.sub.2 and R.sub.6 have various meanings as 
above defined, but preferred are those of the formula (VII) wherein R is 
methyl, R.sub.2 is a furylmethyl group, an optionally substituted 
monoarylmethyl group (e.g. benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, 
o-nitrobenzyl, p-nitrobenzyl) or an optionally substituted diarylmethyl 
group (e.g. diphenylmethyl, di-p-anisylmethyl), especially furylmethyl, 
and R.sub.6 is a hydrogen atom. 
The compound (IIIa) has a 1-hydroxyethyl group at the 6-position, and the 
hydroxyl group in said 1-hydroxyethyl group attaches to the carbon atom at 
the 8-position. The compound (IIIa) wherein said hydroxyl group takes an 
S-configuration can be produced by using the compound (Ia) as such. The 
compound (IIIa) wherein said hydroxyl group takes an R-configuration can 
be obtained by inversion of the steric configuration of the hydroxyl group 
in any intermediate in the route from the compound (Ia) to the compound 
(VII). For inversion of the hydroxyl group, there may be adopted any 
conventional procedure such as the one using diethyl azodicarboxylate and 
triphenylphosphine [Tetrahedron Letters, 21, 2783-2786 (1980) and 22, 
913-916 (1981)]or the one wherein the hydroxyl group is oxidized to an oxo 
group and the oxo group is stereospecifically reduced with a reducing 
agent such as potassium selectride [J.Am.Chem.Joc., 102, 6161-6163 
(1980)]. 
The acetylenamine compound (II) as the starting material for production of 
the amino acid compound (I) can be manufactured by various processes, of 
which some typical examples are as follows: 
Process [A]: 
##STR21## 
wherein R.sub.1, R.sub.2, X and R are each as defined above. 
The acetylenamine compound (II) can be produced by reacting the 
acetylenamine compound (XIII) with an alkylating agent in the presence of 
a base in an inert solvent. Examples of the alkylating agent are lower 
alkyl halides (e.g. methyl iodide, ethyl iodide, n-butyl bromide), lower 
alkyl sulfonates (e.g. methyl tosylate, ethyl tosylate, methyl 
methanesulfonate, ethyl methanesulfonate, methyl 
trifluoromethanesulfonate). Examples of the base is alkali metal hydrides 
(e.g. sodium hydride, potassium hydride), alkali metal amides (e.g. sodium 
amide, lithium diisopropylamide, lithium bis(trimethylsilyl)amide), alkali 
metal alkoxides (e.g. sodium methoxide, sodium ethoxide, potassium 
methoxide, potassium t-butoxide), alkali metals (e.g. metallic sodium, 
metallic lithium), alkali metal carbonates (e.g. potassium carbonate, 
sodium carbonate), n-butyl lithium, sodium methylsulfinylmethide, etc. 
Examples of the inert solvent are aromatic hydrocarbons (e.g. benzene, 
toluene), ethers (e.g. diethyl ether, tetrahydrofuran, dioxane), ketones 
(e.g. acetone, methylisobutylketone), alcohols (e.g. methanol, ethanol, 
t-butanol), dimethylformamide, dimethylsulfoxide, hexamethylphosphoric 
amide (HMPT , etc. 
The alkylating agent and the base are desired to be used respectively in 
sufficient amounts so that the reaction will proceed smoothly. The 
reaction may be effected at room temperature, but when desired, cooling or 
heating may be applied so as to suppress or accelerate the progress of the 
reaction. Post-treatment of the reaction mixture may be effected by a per 
se conventional procedure. 
##STR22## 
wherein R, R.sub.1, R.sub.2 and X are each as defined above. 
The acetylenamine compound (II) can be produced by reacting the enamine 
compound (XIV) with an acetylating agent at the alpha-position to the 
ester group in an inert solvent. Examples of the acetylating agent are 
ketene, acetic anhydride, acetyl halides (e.g. acetyl chloride), etc. When 
acetic anhydride or an acetyl halide is used as the acetylating agent, the 
reaction is normally effected in the presence of a base (e.g. 
triethylamine, pyridine). Examples of the inert solvent are aromatic 
hydrocarbons (e.g. benzene, toluene), halogenated hydrocarbons (e.g. 
chloroform, dichloromethane, 1,2-dichloroethane), ethers (e.g. diethyl 
ether, tetrahydrofuran, dioxane), ketones (e.g. acetone, 
methylisobutylketcne), etc. 
The acetylating agent and, when employed, the base are desired to be used 
respectively in sufficient amounts so that the reaction will proceed 
smoothly. The reaction may be effected normally at a temperature of 
-10.degree. to 95.degree. C., but a lower temperature or a higher 
temperature may be adopted for suppressing or accelerating the reaction. 
Post-treatment of the reaction mixture may be effected by a per se 
conventional procedure.