.beta.-Lactam antibiotics, a process for their prepaeration and their use in pharmaceutical compositions

The present invention provides the antibacterial agents of the formula (II): ##STR1## wherein R.sub.1 is a group such that CO.sub.2 R.sub.1 is a carboxylic acid group or a salt thereof or is a group of the formula CO.sub.2 R.sub.1.sup.1 wherein R.sub.1.sup.1 is a group such that CO.sub.2 R.sub.1.sup.1 is an ester group, R.sub.2 is a hydrogen atom or a lower alkyl group; R.sub.3 is a hydrogen atom or a lower alkyl group; and R.sub.4 is a NH. CO.sub.n R.sub.6 group where R.sub.6 is a lower alkyl group, a phenyl group or a phenyl group substituted by one or two halogen atoms, lower alkyl or lower alkoxyl groups; and n is 1 or 2. A process for their preparation and their use in pharmaceutical compositions is also described.

British Pat. No. 1,483,142 discloses that the compound of the formula (I): 
##STR2## 
wherein Z is HO.sub.3 S and its salts may be obtained by fermentation of 
strains of Streptomyces olivaceus. Danish Patent Application No. 984/78 
discloses that the compound of the formula (I) wherein Z is H and its 
salts could also be obtained by fermentation of strains of that organism. 
We have found that a distinct class of synthetic antibacterial agents 
which contain a .beta.-lactam ring fused to a pyrroline ring may be 
prepared. 
Accordingly the present invention provides the compounds of the formula 
(II): 
##STR3## 
wherein R.sub.1 is a group such that CO.sub.2 R.sub.1 is a carboxylic acid 
group or a salt thereof or is a group of the formula CO.sub.2 
R.sub.1.sup.1 wherein R.sub.1.sup.1 is a group such that CO.sub.2 
R.sub.1.sup.1 is an ester group, R.sub.2 is a hydrogen atom or a lower 
alkyl group; R.sub.3 is a hydrogen atom or a lower alkyl group; and 
R.sub.4 is a phenyl group or a phenyl group substituted by one or two 
groups selected from a fluorine, chlorine, OR.sub.5, NH.CO.R.sub.5, 
NH.CO.sub.2 R.sub.5 or CO.sub.2 R.sub.5 where R.sub.5 is a lower alkyl or 
benzyl group or R.sub.4 is a hydrogen atom or lower alkyl group or R.sub.4 
is a CO.sub.2 R.sub.5 group where R.sub.5 is a lower alkyl group or benzyl 
group or R.sub.4 is a NH.CO.sub.n R.sub.6 group where R.sub.6 is a lower 
alkyl group, a phenyl group or a phenyl group substituted by one or two 
halogen atoms, lower alkyl or lower alkoxyl groups; and n is 1 or 2. 
When used herein the term "lower" means the group contains up to 4 carbon 
atoms. 
Aptly CO.sub.2 R.sub.1 in the compounds of the formula (II) represents a 
carboxylic acid group or a salt thereof. 
Aptly CO.sub.2 R.sub.1 in the compounds of the formula (II) represents an 
ester group CO.sub.2 R.sub.1.sup.1. 
Particularly suitable lower alkyl groups include the methyl and ethyl 
groups. A preferred lower alkyl group is the methyl group. 
A favoured value for R.sub.2 is a hydrogen atom. 
Favoured values for R.sub.3 include the hydrogen atom and the methyl group. 
A preferred value for R.sub.3 is the hydrogen atom. 
Suitably R.sub.4 is a phenyl group or a phenyl group substituted by one or 
two groups selected from fluorine, chlorine, OR.sub.5, NH.CO.R.sub.5, 
NH.CO.sub.2 R.sub.5 or CO.sub.2 R.sub.5 where R.sub.5 is a lower alkyl or 
benzyl group or R.sub.4 is a hydrogen atom or lower alkyl group or R.sub.4 
is a CO.sub.2 R.sub.5 group where R.sub.5 is a lower alkyl or benzyl 
group. 
Suitably R.sub.4 is a NH.CO.sub.n R.sub.6 group where R.sub.6 is a lower 
alkyl group, a phenyl group or a phenyl group substituted by one or two 
halogen atoms, lower alkyl or lower alkoxyl groups; and n is 1 or 2. 
From the foregoing it will be realised that certain favoured compounds of 
this invention include those of the formula (III) and (IV): 
##STR4## 
wherein R.sub.1, n and R.sub.6 are as defined in relation to formula (II). 
Most suitably n is 1. 
Similarly it will be realised that other favoured compounds of this 
invention include those of the formula (V): 
##STR5## 
where R.sub.1 is as defined in relation to formula (II) and R.sub.4.sup.1 
is a group R.sub.4 as defined in relation to formula (II) excluding the 
NH.CO.sub.n R.sub.6 group. 
Suitably R.sub.4.sup.1 is a phenyl group optionally monosubstituted. 
Suitable groups R.sub.4 include the phenyl, p-chlorophenyl, m-chlorophenyl, 
p-nitrophenyl, m-nitrophenyl, p-ethoxycarbonylphenyl, p-fluorophenyl, 
p-methylphenyl, p-methoxyphenyl and like groups. 
Other suitable groups R.sub.4 include the hydrogen atom and the methyl and 
ethyl groups. 
Yet other suitable groups R.sub.4 include those of the formula CO.sub.2 
R.sub.7 where R.sub.7 is methyl, ethyl, phenyl or benzyl. 
It will be realised that the compounds of the formula (II) may be in either 
of two geometrical forms about the exocyclic double bond as shown in the 
sub-formulae (a) and (b) thus: 
##STR6## 
Both separated geometrical isomers and mixtures of said isomers are within 
the scope of this invention. 
In the compounds of the formulae (II)-(V) CO.sub.2 R.sub.1 is favourably a 
carboxylic acid group or a salt thereof. Most favourably CO.sub.2 R.sub.1 
represents a salted carboxylic acid group wherein the cation is 
pharmaceutically acceptable. Preferred pharmaceutically acceptable salts 
include the sodium, potassium, calcium and magnesium salts of which the 
sodium salt is particularly preferred. 
Suitable groups R.sub.1.sup.1 include alkyl groups of up to 12 carbon 
atoms, alkenyl groups of up to 12 carbon atoms, alkynyl groups of up to 12 
carbon atoms, phenyl or benzyl groups or any aforesaid inertly substituted 
by lower alkoxyl, lower acyloxyl, halogen, nitro or the like group. Used 
herein `inertly substituted` means that the resulting group is stable and 
will not undergo rapid decomposition. 
Particularly suitable groups R.sub.1.sup.1 include lower alkyl groups 
optionally substituted by lower alkoxyl group; the benzyl group optionally 
substituted by lower alkoxyl, nitro, chloro or the like; and those groups 
which are known to give rise to rapid in-vivo hydrolysis in penicillin 
esters. 
Certain preferred groups R.sub.1.sup.1 include the methyl, ethyl, 
methoxymethyl, 2-methoxyethyl, benzyl, methoxybenzyl and the like. Other 
preferred groups R.sub.1.sup.1 include those which give rise to in-vivo 
hydrolysable esters such as the acetoxymethyl, pivaloyloxymethyl, 
.alpha.-ethoxycarbonyloxyethyl, phthalidyl and the like. 
An especially preferred group R.sub.1.sup.1 is the phthalidyl group. 
A further especially preferred group R.sub.1.sup.1 is the p-nitrobenzyl 
group. 
The compounds of the formula (II) most suitably have the configuration 
shown in formula (VI): 
##STR7## 
wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined in relation 
to formula (II). 
Thus the compounds of the invention are preferably those having the S- 
configuration at C-5. However, mixtures of the compounds of the formula 
(VI) with their enantiomers, for example the 5RS compounds, are also 
included within this invention. 
A reaction sequence leading to the compounds of this invention is as 
follows: 
##STR8## 
The process provided by this invention for the preparation of the compounds 
of the formula (II) comprises the ring closing elimination of the elements 
of triphenylphosphineoxide from a compound of the formula (VII): 
##STR9## 
wherein R.sub.1.sup.1, R.sub.2, R.sub.3 and R.sub.4 are as defined in 
relation to formula (II); and thereafter cleaving the ester to yield the 
carboxylic acid or its salt. 
The ring closure is normally brought about by heating the compound of the 
formula (VII) in an inert solvent; for example temperatures of 
90.degree.-120.degree. and more suitably 100.degree.-110.degree. C. may be 
employed in a solvent such as toluene or the like. The reaction is best 
carried out under dry conditions under an inert gas. 
The ester of the compound (II) produced may be isolated by any standard 
method such as fractional crystallisation or chromatography. We have found 
that it is most convenient to separate the desired product by column 
chromatography. 
Any convenient ester may be used in the process of this invention. Since it 
is frequently desirable to form a salt of compounds (II), the ester 
employed is preferably one which is readily converted to the parent acid 
or its salt by mild methods of hydrogenolysis. In a further aspect 
therefore the invention includes a process for preparing a salt or free 
acid of a compound (II) which process comprises de-esterifying an ester of 
a compound of formula (II). Particularly suitable esters for use in this 
process include benzyl esters, optionally substituted in the para position 
by a lower alkoxy, or nitro group or a halogen atom. 
A preferred ester for use in this process is the p-nitrobenzyl ester. 
Esters of compounds (II) may be de-esterified by conventional methods of 
hydrogenolysis. 
Suitable methods include hydrogenation in the presence of a transition 
metal catalyst. The pressure of hydrogen used in the reaction may be low, 
medium or high but in general an approximately atmospheric or slightly 
super-atmospheric pressure of hydrogen is preferred. The transition metal 
catalyst employed is preferably palladium on charcoal or on calcium 
carbonate. The hydrogenation may be effected in a suitable solvent in 
which the ester is soluble such as aqueous dioxan or the like. If this 
hydrogenation is carried out in the presence of a base then a salt of 
compounds (II) is produced. Suitable bases for inclusion include 
NaHCO.sub.3, KHCO.sub.3, Na.sub.2 CO.sub.3, K.sub.2 CO.sub.3, CaCO.sub.3, 
MgCO.sub.3, LiHCO.sub.3, NH.sub.4 OCOCH.sub.3 and the like. If no base is 
present then hydrogenation leads to the preparation of an acid within 
formula (II) which may then be neutralised if desired to yield a salt. 
Suitable bases which may be used to neutralise acids within formula (II) 
include LiOH, NaOH, NaHCO.sub.3, KOH, Ca(OH).sub.2 and Ba(OH).sub.2. 
The salts of acids (II) may be converted to esters in conventional manner, 
for example by reaction with a reactive halide such as bromophthalide in 
solution in dimethylformamide or like solvent. 
The compound of the formula (VII) may be prepared by the reaction of a 
corresponding compound of the formula (VIII): 
##STR10## 
wherein R.sub.1.sup.1 is as defined in relation to formula (VII) with a 
diloweralkylphosphorochloridate and a triloweralkylamine followed by 
reaction with a thallium, silver, sodium or lithium salt of the compound 
of the formula (IX): 
EQU H--S--CR.sub.2 .dbd.CR.sub.3 R.sub.4 (IX) 
where R.sub.2, R.sub.3 and R.sub.4 are as defined in relation to formula 
(II). 
Aptly a sodium, silver or thalliumsalt of the compound of the formula (IX) 
is employed. 
A particularly suitable diloweralkylphosphorochloridate is 
diethylphosphorochloridate. 
A particularly suitable triloweralkylamine is triethylamine. 
The compound of the formula (VIII) may alternatively be converted to the 
acid chloride or anhydride by conventional means and reacted with the salt 
of the compound of the formula (IX) to yield the compound of the formula 
(VII). 
The preceeding reactions are generally carried out in an inert organic 
solvent such as tetrahydrofuran at a non-extreme temperature such as 
0.degree. to 40.degree. C., for example 15.degree.-25.degree. C. 
The compound of the formula (VIII) may be prepared by the reaction of the 
compound of the formula (X): 
##STR11## 
wherein R.sub.1.sup.1 is as defined in relation to formula (VIII) with 
ozone in the presence of trifluoroacetic acid followed by 
m-chloroperbenzoic acid. 
The ozonolysis is generally performed at a depressed temperature such as 
-40.degree. to -80.degree. C., for example about -70.degree. C. and in 
solution in an inert solvent such as methylene chloride. Excess ozone is 
removed by flushing with an inert gas and thereafter a solution of the 
peracid is added to the reaction mixture. 
The compound of the formula (X) may be prepared from the corresponding 
compound of the formula (XI): 
##STR12## 
wherein R.sub.1.sup.1 is as defined in relation to formula (X) by reaction 
with triphenylphosphine. 
This reaction is normally effected in the presence of at least one 
equivalent of a base of relatively low nucleophilicity such as 
2,6-lutidine at an ambient temperature in a dry solvent such as dioxan, 
tetrahydrofuran or the like. 
The compound of the formula (XI) may be prepared from the corresponding 
carbinol of the formula (XII) 
##STR13## 
by reaction with thionyl chloride. 
This reaction is also normally effected in the presence of at least one 
equivalent of a base of relatively low nucleophilicity in a dry solvent 
such as dioxane or tetrahydrofuran but in this instance the reaction is 
performed at a depressed temperature, for example -30.degree. to 
-10.degree. C. 
The preceding carbinol may be prepared by the reaction of a compound of the 
formula (XIII): 
##STR14## 
with a glyoxylic acid ester of the formula (XIV): wherein R.sub.1.sup.1 
is as defined in relation to formula (II) or alternatively by reaction 
with glyoxylic acid followed by esterification in conventional manner. 
Normally this reaction is carried out in an inert solvent at an elevated 
temperature, for example in dry benzene under reflux. 
The compound of the formula (XIII) may be prepared as described in 
Description 1 hereinafter. 
The present invention also provides a pharmaceutical composition which 
comprises a compound of the formula (II) as hereinbefore defined and a 
pharmaceutically acceptable carrier. 
Most suitably the composition will be in unit dosage form and will comprise 
25-1000 mg and more usually 50-500 mg of a compound of the formula (II). 
The compositions may be adapted for oral or parenteral administration. 
Preferably the compound of the formula (II) present in such compositions 
will be in-vivo hydrolysable to the parent acid or its salt. 
The composition of this invention may beneficially also comprise a 
penicillin or cephalosporin. Certain particularly suitable penicillins for 
use in these compositions include amoxycillin trihydrate and sodium 
amoxycillin. 
Sterile salts in water for injection B.P. may be used, for example a sodium 
salt of an antibacterial agent or agents, for example at a concentration 
of 50-100 mg per mil of the sodium salt of a compound of the formula II 
and 100-250 mg per mil of the sodium salt of amoxycillin. 
The salts of the compounds of the formula (IX) wherein R.sub.2 and R.sub.3 
are hydrogen and R.sub.4 is a NH.CO.sub.n R.sub.6 as defined in relation 
to formula (II) are novel and as such form an aspect of this invention. 
Preferred compounds of the formula (IX) are these wherein n is 1 and 
R.sub.6 is methyl. Suitable salts of these compounds include the sodium, 
thallium, silver and lithium salts. 
Intermediates useful for the preparation of this invention may be prepared 
by the general methods set forth in German OLS No. P2811514.2, U.S. Ser. 
No. 930225 or European Patent Application No. 78300231.4. 
The following Examples illustrate this invention. The following 
Descriptions relate to the preparation of useful intermediates. 
DESCRIPTION 1 
4-Allyl-1-(1-tert-butyloxycarbonyl-1-triphenylphosphoranylidenemethyl) 
azetidin-2-one 
(i) Preparation of 4-allyl azetidin-2-one 
##STR15## 
1,4-Pentadiene (d1) (30 g) and chlorosulphonyl isocyanate (d2) (35.4 ml) 
were mixed and allowed to stand at room temperature for 3 days, in a 
pressure bottle. The thick, dark syrup obtained was diluted with methylene 
chloride (500 ml) and added dropwise to a stirred solution of sodium 
sulphite (66 g) in water (240 ml). The pH was maintained between 6.5 and 
7.5 by the addition of 10% aqueous potassium hydroxide (600 ml in total). 
The lower organic phase was separated and the aqueous phase extracted 
(.times.2) with ethyl acetate. The combined organic extracts were dried 
over magnesium sulphate, filtered, and evaporated to give the crude 
azetidinone (d3) as a red oil (16.05 g). This was sufficiently pure for 
use in subsequent reactions e.g. Description 1 (ii), but could be further 
purified by distillation b.p. 76.degree.-80.degree./0.2 mm. .nu..sub.max 
(CHCl.sub.3) 3490, 1770 (strong), 1650 (weak) cm.sup.-1. .delta. ppm 
(CDCl.sub.3) 2.39 (2H, t, J 6 Hz, CH.sub.2), 2.61 (1H, ddd, J 14 Hz, 2 Hz, 
1.5 Hz, collapsing with D.sub.2 O to dd, J 14 Hz, 2 Hz, C3-H), 3.10 (1H, 
ddd, J 14 Hz, 5 Hz, 2 Hz, collapsing with D.sub.2 O to dd, J 14 Hz, 5 Hz, 
C3-H), 3.55-3.91 (1H, m, C4-H), 4.98-6.21 (3H, complex pattern, 
CH.dbd.CH.sub.2), 6.67 (1H, broad s, exch. D.sub.2 O) (Found: M, 111.0683. 
C.sub.6 H.sub.9 NO requires M, 111.0684). 
(ii) Preparation of 4-allyl-1-(1-hydroxy-1-tert-butyloxycarbonylmethyl) 
azetidin-2-one 
##STR16## 
tert-Butyl glyoxylate hydrate (6.22 g) in benzene (120 ml) was refluxed for 
1 hour in a Dean-Stark apparatus to remove the water. The azetidinone (d3) 
(2.31 g) was then added and the reaction mixture refluxed for 4 hours. 
Chromatography of the crude product as in description 3(i) gave the 
alcohol (d4) as a pale yellow oil (4.48 g). .nu..sub.max (CHCH.sub.3) 
3490, 1755, 1735, 1640 (weak) cm.sup.-1 .delta. ppm (CDCl.sub.3) 1.50 (9H, 
s, Bu.sup.t), 2.20-3.25 [4H, 2.66 (1H, dd, J 3 Hz, 14 Hz, C3-H), and 3.09 
(1H, dd, J 14 Hz, 5 Hz, C3-H) obscurring 2H, CH.sub.2 [; 3.68-4.10 (1H, m, 
C4-H), 4.47 (1H, broad s, exch. D.sub.2 O, OH); 4.98-5.37 (3H, m, 
sharpening with D.sub.2 O), 5.52-6.23 (1H, m. CH.dbd.CH.sub.2) . M.sup.+ 
at m/e 241 and (m/e +1). 
(iii) Preparation of 
4-allyl-1-(1-tert-butyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azet 
idine-2-one 
##STR17## 
A stirred solution of the alcohol (d4) (4.2 g) in dry tetrahydrofuran (120 
ml) under argon, was cooled to -20.degree., and treated with lutidine 
(4.03 ml) in tetrahydrofuran (15 ml). Thionyl chloride (2.54 ml) in 
tetrahydrofuran (15 ml) was added dropwise. After allowing to reach 
0.degree. over 30 minutes, the solution was filtered, the lutidine 
hydrochloride being washed with toluene. 
The combined filtrate and washings were evaporated to dryness. The residue 
was taken up in dry dioxan (100 ml) and treated with lutidine (4.03 ml) 
and triphenylphosphine (9.1 g). After stirring at room temperature 
overnight, the phosphorane (d5) was isolated as in description 3 (ii) and 
obtained as white crystals (4.62 g) from ether m.p. 188.degree.-9.degree., 
.nu..sub.max (CHCl.sub.3) 1730, 1638, 1610 cm.sup.-1 (Found: C, 74.1; H, 
6.8; N, 3.0; P, 6.2% C.sub.30 H.sub.32 NO.sub.3 P requires C, 74.2; H, 
6.6; N, 2.9; P, 6.4%). 
DESCRIPTION 2 
4-Allyl-1-(1-methoxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidin-2- 
one 
(i) Preparation of 
4-allyl-1-(1-hydroxy-1-methoxycarbonylmethyl)azetidin-2-one 
##STR18## 
Methyl glyoxylate hydrate (9.75 g) in benzene (500 ml) was refluxed for 1 
hour in a Dean-Start apparatus to remove the water. The azetidinone (d3) 
(2.68 g) was then added and the reaction mixture refluxed for 2 hours. A 
further portion of the azetidinone (1.34 g) (d3) was then introduced, and 
refluxing continued for 3 hours. Chromatography of the crude product as in 
description 3(i) gave the alcohol (d6) as a pale yellow oil (5.33 g). 
.nu..sub.max (CHCl.sub.3) 3500, 3350 (broad), 1760-1740 (strong), 1640 
(weak) cm.sup.-1. .delta. ppm (CDCl.sub.3) 2.24-2.90 (3H, m, including 
[1H, dd, J 3 Hz, 14.5 Hz at .delta. 2.68]), 3.11 (1H, dd, J 4.5 Hz, 14.5 
Hz), 3.72-4.42 (5H, including [3H, s, at .delta. 3.90], 1H, exch. D.sub.2 
O), 5.00-6.29 (4H, m including [1H, s, at .delta. 5.48]). 
(ii) Preparation of 
4-allyl-1-(1-methoxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidin-2 
-one 
##STR19## 
A stirred solution of the alcohol (d6) (5.23 g) in dry tetrahydrofuran (150 
ml) under argon, was cooled to -20.degree., and treated with lutidine 
(6.06 ml) in tetrahydrofuran (20 ml). Thionyl chloride (3.83 ml) in 
tetrahydrofuran (20 ml) was added dropwise. After allowing to reach 
0.degree. over 20 minutes, the solution was filtered, the lutidine 
hydrochloride being washed with toluene. 
The combined filtrate and washings were evaporated to dryness. The residue 
was taken up in dry dioxan (13.7 g). After stirring at room temperature, 
overnight, the phosphorane (d7) was isolated as in Description 3(ii) and 
obtained as white crystals (7.3 g) from ether m.p. 
208.degree.-212.degree.. .nu..sub.max (CHCl.sub.3) 1738, 1640, 1620 
cm.sup.-1 (Found: C, 72.6; H, 5.9; N, 3.0%. C.sub.27 H.sub.26 NO.sub.3 P 
requires C, 73.1; H, 5.9; N, 3.2%). 
DESCRIPTION 3 
4-Allyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidin- 
2-one 
(i) Preparation of 
4-allyl-1-(1-hydroxy-1-benzyloxycarbonylmethyl)azetidin-2-one 
##STR20## 
Benzyl glyoxylate hydrate (6 g) in benzene (120 ml) was refluxed for 0.5 
hours in a Dean-Stark apparatus to remove the water. The azetidinone (d3) 
(2.13 g) was added and the reaction mixture refluxed for 4 hours. The 
solution was cooled, evaporated, and chromatographed on silica gel, 
eluting with ethyl acetate-petroleum ether mixtures to give a colourless 
oil (5.6 g) consisting mainly of the isomers of (d8) and sufficiently pure 
for use in subsequent reactions. Rechromatography of a small portion of 
this oil, eluting with chloroform gave (d8) as an oil. .nu..sub.max 
(CHCl.sub.3) 3420, 1750 (strong), 1640 (weak) cm.sup.-1. .delta. ppm 
(CDCl.sub.3) 1.90-3.50 [4H, m, including .delta. 2.53 (1H, dd, J 15 Hz, 2 
Hz, C3-H), 2.92 (1H, dd, J 15 Hz, 5 Hz, C3-H), obscuring 2H, CH.sub.2 ], 
4.52 (1H, broad, s, exch. D.sub.2 O, -OH), 4.85-5.90 [6H, m, including 
.delta. 5.40 (1H, broad, collapsing with D.sub.2 O to singlet, 
H-C-OH)+complex pattern for CH.sub.2 Ph and CH.dbd.CH.sub.2 ], 7.29 (5H, 
s). 
(ii) Preparation of 
4-allyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidin 
-2-one 
##STR21## 
A stirred solution of the alcohol (d8) (6.6 g) in dry tetrahydrofuran (200 
ml), under argon, was cooled to -20.degree., and treated with lutidine 
(5.13 g) in tetrahydrofuran (10 ml). Thionyl chloride (5.70 g) in 
tetrahydrofuran (20 ml) was added dropwise. After allowing to reach 
0.degree. over 20 minutes the precipitated solid was filtered off, washing 
with dry toluene. 
The combined filtrate and washings were evaporated to dryness and the 
residue taken up in dry toluene, filtered and evaporated. The gum obtained 
was taken up in dioxan (200 ml) and treated with triphenylphosphine (12.6 
g) and lutidine (5.53 ml). After stirring under argon at room temperature 
for 3 hours and standing overnight, the precipitated solid was filtered 
off. The filtrate was evaporated to dryness. Chromatography on silica gel 
eluting with ethyl acetate-petroleum ether mixtures, gave the required 
phosphorane, initially as a foam, which crystallised from ether (5.70 g) 
m.p. 150.degree.-156.degree.. .nu..sub.max (CHCl.sub.3) 1730, 1638, 1610 
cm.sup.-1. 
DESCRIPTION 4 
Preparation of 
1-(1-t-butoxycarbonyl-1-triphenylphosphoranylidenemethyl)-4-carboxymethyla 
zetidin-2-one 
##STR22## 
The phosphorane (d5) (prepared as in Description 1) (2 g) was dissolved in 
dry methylene chloride (100 ml) and treated with trifluoroacetic acid (3.2 
ml). The solution was cooled to -70.degree. and ozonised until the 
solution turned blue. Excess ozone was removed by passing through argon 
and m-chloroperbenzoic acid (720 mg) in methylene chloride (20 ml) was 
added. The mixture was allowed to reach RT and stirred overnight. The 
solvent was evaporated and the residue chromatographed on Merck Kieselgel 
60 (&lt;230 mesh). Elution with 50% ethanol/ethyl acetate gave the 
phosphorane-acid (d10,a) as a colourless foam which crystallised from 
ethyl acetate/ether (1.6 g) as a mixture of zwitterion and trifluoroacetic 
acid salt, .nu..sub.max 1770, 1750, 1670, 1590 cm.sup.-1. 
The product (1.6 g) was taken up in CHCl.sub.3 (50 ml) and stirred with 
basic alumina (4 g) overnight. The solution was filtered, the solvent 
evaporated and the residue triturated with ether to yield the 
phosphorane-acid (d10,a) as a white solid (0.9 g) m.p. 
141.degree.-143.degree.. .nu..sub.max (CHCl.sub.3) 1750, 1595, 1590 
cm.sup.-1. 
The acid (d10,a) was further characterised by treatment with benzyl bromide 
and potassium carbonate in dimethylformamide to give the benzyl ester 
(d10,b) obtained as white crystals (ex ether) m.p. 
176.5.degree.-178.degree.. .nu..sub.max (CHCl.sub.3) 1735, 1640, 1610 
cm.sup.-1 (Found: C, 72.20; H, 6.59; N, 2.28. C.sub.36 H.sub.36 NO.sub.5 P 
requires C, 72.83; H, 6.11; N, 2.36%). 
DESCRIPTION 5 
Preparation of 
1-(1-methoxycarbonyl-1-triphenylphosphoranylidenemethyl)-4-carboxymethylaz 
etidine-2-one 
##STR23## 
The phosphorane (d7) (Prepared as in Description 2). (4.47 g) in dry 
methylene chloride (250 ml), was treated with trifluoroacetic acid (7.7 
ml). The solution, cooled to -70.degree., was ozinised until it became 
blue. After passing argon through to remove excess ozone, 
m-chloroperbenzoic acid (1.74 g) in methylene chloride (50 ml) was added. 
The stirred mixture was allowed to reach room temperature, and after 
stirring overnight, was evaporated to dryness. After re-evaporation from 
dry toluene the residue was chromatographed on Merck Kieselgel 60. Elution 
with ethyl acetate gave m-chlorobenzoic acid. Further elution with 10% 
ethanol in ethyl acetate gave the phosporane-acid (d11 a), partially as 
the trifluoroacetic acid salt, as a yellow foam (3.7 g), .nu..sub.max 
(CH.sub.2 Cl.sub.2) 1770, 1755, 1738, 1705-1675 (several weak peaks), 1585 
cm.sup.-1. 
This foam was taken up in dry methylene chloride (70 ml), and stirred with 
basic alumina (8 g), for 2 hours. Evaporation of the filtered solution 
gave a foam (3 g). Trituration with ether gave the zwitterionic form of 
the acid-phosphorane (d11 a), as a pale yellow solid, which was collected 
and dried in vacuo (2.35 g) .nu..sub.max (CH.sub.2 Cl.sub.2) 1750, 1740, 
1590 cm.sup.-1. 
The acid (d11 a) was characterised by treatment with benzyl bromide and 
potassium carbonate in dimethylformamide to give the benzyl ester (d11 b), 
as white crystals (ex ethyl acetate/petroleum ether), m.p. 
146.degree.-148.degree., .nu..sub.max (CHCl.sub.3) 1740, 1620 cm.sup.-1 
(Found: C, 71.71; H, 5.67; N, 2.44. C.sub.33 H.sub.30 NO.sub.5 P requires 
C, 71.87; H, 5.44; N, 2.54%). 
DESCRIPTION 6 
Preparation of 
1-(1-Benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)-4-carboxymethyl 
azetidin-2-one 
##STR24## 
The phosphorane (d9, prepared as in Description 3). (2.076 g) in dry 
methylene chloride (120 ml) was treated with trifluoroacetic acid (3.08 
ml). The solution, cooled to -70.degree., was ozonized until it became 
blue. After passing argon through to remove excess ozone, 
m-chloroperbenzoic (0.69 g) in methylene chloride (25 ml) was added. The 
stirred mixture was allowed to reach room temperature. After stirring for 
3 days work up and chromatography as in description 4 gave the phosphorane 
acid (d12) partially as the trifluoroacetic acid salt, as a yellow foam 
(1.215 g), .nu..sub.max (CHCl.sub.3) 1770 (shoulder) 1750, 1730, 1700, 
1665, 1590, 1575 cm.sup.-1. 
This foam was taken up in chloroform (20 ml) and stirred with basic alumina 
(4 g) for 4 hours. Evaporation of the filtered solution gave the 
zwitterionic form of the acid-phosphorane (d12) as a foam (0.855 g) 
.nu..sub.max (CHCl.sub.3) 1735, 1590, 1585, 1575 cm.sup.-1. 
DESCRIPTION 7 
4-Allyl-1-(1-p-nitrobenzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)az 
etidin-2-one 
(i) Preparation of 
allyl-1-(1-hydroxy-1-p-nitrobenzyloxycarbonylmethyl)azetidin-2-one 
##STR25## 
p-Nitrobenzylglyoxylate hydrate (6.8 g) in benzene (120 ml) was refluxed 
for one hour with removal of water (Dean-Stark). The azetidinone (d3) (3 
g) was added and the mixture refluxed for two hours. The solution was 
cooled, the solvent evaporated and the residue chromatographed. Elution 
with 80% ethyl acetate/petroleum ether (60.degree.-80.degree.) gave the 
product (d13). The product was rechromatographed to complete purification 
and collected as an oil (3.2 g) (37%). .nu..sub.max (CHCl.sub.3) 3.500 
(OH), 1755 (br), 1530, 1355 cm.sup.-1. .delta. ppm (CDCl.sub.3) 2.39 (2H, 
m, CH.sub.2 CH.dbd.CH.sub.2) 2.61 (1H, dd, J 16 Hz, 4 Hz, C3-H) 3.05 (1H, 
dd, J 16 Hz, 6 Hz, C3-H) 3.92 (1H, m, C4-H) 4.63 (1H, m, collapsing to a 
singlet on D.sub.2 O exchange, CH-OH) 4.80 to 5.80 (6H, complex pattern 
including CH.sub.2 PhNO.sub.2 at 5.35, OH [exchangeable] and 
CH.dbd.CH.sub.2) 7.56 and 8.23 (4H, ABq, J 8 Hz, aromatics). 
(ii) Preparation of 
4-allyl-1-(1-p-nitrobenzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)a 
zetidin-2-one 
##STR26## 
A stirred solution of the alcohol (d13) (1.6 g) in dry THF (100 ml) was 
treated with 2,6-lutidene (1.07 g) and thionyl chloride (1.19 g) in THF 
(20 ml) at -20.degree. and stirring continued for 20 minutes. The mixture 
was filtered the solvent evaporated and the residue azeotroped twice with 
toluene. It was dissolved in dioxan (100 ml), and 2,6-lutidene (1.07 g) 
and triphenylphosphine (2.62 g) were added. The reaction was stirred 
overnight at R.T. and filtered. The solvent was evaporated and the residue 
chromatographed to yield the product (d14), after decolourising with 
charcoal (ethanol/ethyl acetate) and trituration of the evaporated 
solution with ether, as a light yellow solid (1.5 g; 53%) m.p. 
182.degree.-183.degree.. .nu..sub.max (CHCl.sub.3) 1740, 1620, 1525, 1355 
cm.sup.-1. (Found: C, 70.26; H, 5.33; N, 4.80. C.sub.33 H.sub.29 N.sub.2 
O.sub.5 P requires C, 70.21; H, 5.14; N, 4.96%). 
DESCRIPTION 8 
Preparation of 
1-(1-p-Nitrobenzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)-4-carbox 
ymethylazetidin-2-one 
##STR27## 
The phosphorane (d14, prepared as in Description 7) (2.82 g) in dry 
methylene chloride (125 ml) was treated with trifluoroacetic acid (4 ml) 
at 0.degree.. The solution was cooled to -70.degree. and treated with 
ozone until blue. Argon was passed through to remove excess ozone and 
m-chloroperbenzoic acid (0.9 g) in methylene chloride (20 ml) was added 
and the mixture stirred at R.T. overnight. The solvent was evaporated and 
the resulting white solid dissolved in ethyl acetate and chromatographed 
on silica gel. Elution with 10% ethanol/ethyl acetate gave the product as 
the trifluoroacetic acid salt. The product was stirred in ethyl acetate 
with basic alumina (6 g) for two hours. Evaporation of the solvent and 
trituration of the residue with ether gave the acid (d15) as a light 
yellow hygroscopic solid (2 g; 69%). 
A small portion crystallised from ether gave a microcrystalline solid m.p. 
127.degree.-133.degree.. .nu..sub.max (CHCl.sub.3) 1745, 1600, 1355, 1115 
cm.sup.-1. (Found: C, 64.59; H, 4.82; N, 4.66; C.sub.32 H.sub.27 N.sub.2 
O.sub.7 P. 1/2H.sub.2 O requires C, 64.97; H, 4.73; N, 4.73).