CA1154010A

CA1154010A - PREPARATION OF .beta.-LACTAM-CONTAINING ANTIBACTERIAL AGENTS AND .beta.-LACTAMASE INHIBITORS

Info

Publication number: CA1154010A
Application number: CA000346011A
Authority: CA
Inventors: Aurora Sanfilippo; Federico Arcamone; Cosimo Scarafile; Maurizio Foglio; Giovanni Franceschi
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1979-02-24
Filing date: 1980-02-20
Publication date: 1983-09-20
Also published as: YU46180A; FI800493A; FI75163B; ES8107224A1; AU535080B2; NO161000C; LU82192A1; AT368506B; ES8200685A1; NO800501L; ES495977A0; YU42964B; NL192265C; NO161000B; HK74487A; PT70849A; IE800338L; AU5567080A; GB2043639B; DK159448B

Abstract

ABSTRACT OF THE DISCLOSURE

There is disclosed a process for the preparation of .beta.-lactam-containing compounds of the formula where R is hydrogen, lower alkyl, trichloroethyl, acetonyl, benzyl, substituted benzyl, phenyl, substituted phenyl, benzyl-dryl or a residue that will undergo metabolic activation "in vivo" and have favorable pharmacokinetic properties: R1 is a hydrogen atom, lower alkyl, lower alkoxy, cycloalkyl, or hydro-alkyl, with the alcoholic function of the hydroxy alkyl being free or protected; Z is hydrogen, halogen, hydroxy, amino, carbam oyloxy, mercapto, pyridinium, OR2, OCOR2, NHCOR2, or SR3 wherein each of R2 and R3 is lower alkyl, aryl, or a heterocylic ring, each of which may be substituted or unsubstituted, and n is O
or 1. The compounds have wide spectrum antibacterial activity and .beta.-lactamase inhibiting activity.

Description

~S4010 GENER~L DESCR~:PTION OF T~ INVENTION
This invention relates to the preparation of ~-lactam-containing compounds.
More particularly, the present invention relates to the preparation penem-carboxylic acids of the formula:

~ ~ ( ( 1~

wherein R is a hydrogen atom, lower alkyl, 2,2,2-trichloroethyl, acetonyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p-nitrophenyl, or benzyhydryl, a residue known to undergo metabolic activation "in vivo" and having favorable pharmacokinetic pro-perties, including acetoxymethyl, pivaloyloxymethyl or phthalidyl or a group of the formula -CH-OCOOC2H5 or -CH2NHCOR in which R is alkyl having from 1 to 5 carbon atoms or aryl; Z is a hydrogen or halogen atom, hydroxy, amino, carbamoyloxy, mercapto, or pyridinium, or a group of the formula OR , OCOR , NHCOR , and SR4, wherein each of R3 and R4 is lower alkyl, aryl or a hetero-cyclic ring, each of which may be substituted or unsubstituted;
and Rl is a hydroyen atom, lower alkyl, lower alkoxy, cycloalkyL
or hydroxyalkyl (preferably lower hydroxyalkyl), the alcoholic function of the hydroxy a].kyl being frec or protected, the pro-tecting group being preferably p-nitrobenzyloxycarbonyl or dimethyl-t-butyl-silyl, and n is O or 1. The substitution of the 6 position has the ~-con iguration as well as the ~-configuration.
The a-configuration is preferred.

Examples of residues included within the definition of R that are known to undergo metabolic activation "in vivo" and 1154~

1 have faborable pharmacokinetic properties, include acetoxymethyl, pivaloyloxymethyl, and phthalidyl and groups of the formulae -C~.OCOOC2H5 and -CH2NHCOR .

C~3 Representative values of R include methyl, ethyl, methoxy, l-hydroxyethyl, and l-~p-nitrobenzyloxycarbonyloxy)-ethyl.
R3 and R4, when heterocyclic, are preferably a 5- or 6- membered heterocyclic ring residue, for example 5-methyl-1,3, 4-thiadiazol-2-yl, 1-methyl-tetrazol-5-yl, 1,2,3-triazol-5-yl or pyrazinyl.
These compounds possess a wide spectrum of antibacter-ial activity and also have ~-lactamase-inhibiting activity. It should be pointed out that the stereochemistry at C5 of the novel ~-lactam-containing compounds, including the intermediates for their preparation, is identical to the naturally-occurring penicillins and cephalosporins.
Preparation of pharmaceutica]ly acceptable salts of penem-carboxylic acids of formula (1) including sodium, potassium, O ben2athin, procaine, and like salts usually formed with penicill-ins and cephalosporins, are also within the scope of the inven-tion.
The followLng diagram illu~tra~s the preparation of the compounds of formula (11 according to the invention.

llS4V10 ~X' R r~rS \~ y R,~rS--¦ ~ S~ X

o ~ 71 "" cooR5 0 ~ l Y 0~ ~,U~ y / (2) ~\ H cooR5 / cooR5 Rl ~ r,X ~' R~ rS b~ X

O H HCOOR COOR CooR5 (12) CoOR5 ~1, (o) 1 ~ l Rl n X R ~ r ~

xo~-s?~(14) ¦ ()n w R ~ ~ , X Rl~ ~X

~ 8 ) COOR ¦ COOR ~15 ) `1/
R~ S~¢x Rl ~S R ~ S ~ X

O (]0) ~3?Ph3 ~,r-- N~p Y ~r Cl (16) . COOR / (9 ~ COOR COOR
n~ \ /
ROl ~ r~ ~ COOR o~ N O
COOR (1: n=O) COOR (11) ~ ~ .

11~4010 1 When Rl is hydrogen, compounds of formula (2) are prepared starting from (5R) 6- aminopenicillanic acid (6-APA), following the widely-known general procedure (see CIGNARELLA et al., Journal of Organic Chemistry, 27, 266~ and EVRARD et al., Nature, 201, 1124). When Rl is lower alkyl, cycloalkyl, or hydroxyalkyl, the R group can be introduced according to the procedure of Di Nimmo et al., Journal of Organic Chemistry, 42, 2960 ~1977).
When Rl is lower alkoxy, the Rl group can be introduced in the 6-position starting from 6-APA in accordance with the procedure of Hauser et al., Helv. Chem. Acta, 50; 1327 (1967) and Giddings et al., Tetrahedran Letters, 11, 995 (1978).
Alternatively compounds of general formula (2~ in which R"' is H can be converted to compounds of the general formula (2) in which R"' is lower alkyl, cycloalkyl or hydroxyl introducing the substituent into the 6 postion using a strong base as illustrated in the following examples.
Compounds of formula (2) in which R"' is lower alkyl, cycloalkyl or hydroxyalkyl can be prepared also starting from a suitable ester of the penicillanic acid S-oxide, as illustrated in the following examples. The substitution of the 6 position is stereospecifically directed to the 6~ derivatives.
The ester of penicillanic acid S-oxic1e ~2) wherein R5 is an alkyl group of Rl is a~ above defined, may be heated in an inert solvent, such as benzene or toluene, usually at a temp-erature of from 70C to 140C, with a suitable acetylenic der-ivative of the general formula XC-CY wherein X is a ~rou~ of the formula CH2Z' wherein Z' is a hydrogen or halogen atom, hydroxy, amino, carbamoyloxy or a group of formula oR3, OCOR , or NHCoR3 where R is lower alkyl, aryl or a heterocyclic ring, any of R3 being optionally substituted, and Y is a hydrogen atom, lower 1 alkyl, cyano or a group of the formula CoOR5 or CH2Z' wherein R5 and Z' have the meanings given above. In the compounds of formula (4),the Y,gro~p, if desire1,may ke converted into a different X group wherein X is a group of the formula CH2Z wherein Z has the meaning given to it supra by means of the widely-known sub-stitution reactions, one,example of which is given in the following examples. The trapped compound of the formula (3) may be isomerized by using a base into the compound of formula (4) which can be converted to the final compound of formula (1) in two different ways. In the first way, the compound of formula (4) may be ozonized ~electively on the isopropenyl double bond to give a compound of formula ~5) where n = 1, which. may be ~ reduced to a compound of formula ~5) where n = 0 with suitable 'l reducing agents such as phosphorous tribromide or sodium iodide in acetyl chloride and subsequently hydrolized to a compound of formula (.6~ where n - 0 in mild basic conditions or on silica . .
gel. Condensation with a suitable ester of glyoxylic acid gives ~ a compound of formula (.7) where n = 0, which may be transEormed ', into the chloroderivative of formula (.8) where._ = O.by means of a chlorinating agent such as thionyl chloride and pyridine, ' and then into the phosphorane of formula (9) where n = 0. More-over, the same gxoup of reactions are also per~ormed starting rom the unexpected compounds o~ formula ~6) where n = 1 which is stable when Y is not a strong withdrawing group. In the case involving the compound of formula (9j where n = 0,'the compound may be selectively ozonized as a phosphonium salt in acidic conditions to give the compound of formula ~11), which is cyclised to th.e compounds of formula (1), simply by heating in an inert solvent, such as toluene, at a temperature of from 50C to 140C.
In case of the compound of formula (9) where _ = 1, the compound must be reduced to the compound of formula (10), and ~ -5- ' 1 subse~uently selectively ozonized to the compound of formula (11), which gives in turn the compound of formula (1).
In the second way, the compound of formula (4) may be reduced in the usual conditions to give the compound of formula (12), which is ozonized on both double bonds to give the compound of formula (13) and, a~ter hydrolysis, the compound of formula (14). Following the same procedure as in the previous way, glyoxylation of the compound of formula (14~ gives the compound of formula C15), which may be transformed to the chloroderiva-tive of formula (16) and then to the phosphorane of formula ¢111, which is a common intermediate for both ways.
When R is hydroxyalkyl, the reaction sequence ispreferably carried out with the alcoholic function protected.
Compounds of formula (1) in which R is a hydrogen atom can be obtained by hydrolysis or hydrogenolylis of the corresponding esterified compounds. Compounds of formula (1) in which n = 1 are easily prepared starting from compounds of formula (1) in which n = 0, following the widely known oxidation processes.
Peracids can be advantageously used; m-chlorperbenzoic acid and ~ peracetic acid are preferred. The processes illustrated herein-above are within the scope of the invention.
A series of t~sts was car~ied out in vitro to compare the activities o~ (SR) acetoxymethyl-2-acetoxymethyl-2-penem-3-carboxylate (Laboratory code FCE/20077/B40/34~, (5Rl acetoxy-methyl-2- ~(1'-methyl-l'H-tetraæol-5'~yl)-thiomethyl]-2-penem-3-car~oxylate (compound A) and two reference compounds Campicillin and cefoxitin). Table 1 below reports the results o~ the above assays as MIC (minimal inhibitory concentration).

3~

1~59~

1 T A B L B _ 1 M I C ~g/ml Compound StrainsFCE/20077/B40/341 AAmpicillin Cefoxitin _ _ Staphylococcus aureus 209P 0.39 0.39< 0.19 0.78 Staphylococcus aureus 153 1.56 0.78 1.56 0.78 Staphylococcus aureus PV2 0.39 0.78< 0.19 0.78 Staphylococcus aureus Smith ATCC 13109 < 0.19 0.39< 0.19 0.78 Streptococcus lOpyogenes ATCC
12384 3.12 0.7~ 3.12 1.56 Escherichia coli B 1.560.78 0.39 1.56 Escherichia coli V14 1.56 0.78 1.56 3.12 Escherichia coli V23 3.12 0.78 3.12 12.5 Enterobacter sp. Vl9 12.5 > 100 >100 12.5 Rlebsiella pneumoniae ATCC 10031 - 3.12 50 0.78 Klebsiella sp. R2 25 - 50 12.5 Proteus vulgaris V15 3.12 6.25 1.56 0.78 Proteus mirabilis V15 0.39 0.78 ~ 0.19 0.78 Proteus mirabilis 525 3.12 0.78 0.39 1.56 ~0 Shi~ella flexneri 0.390.39 < 0.19 0.78 Pseudomonas aeruginosa 3.12 0.39 25 6.25 Salmonella typhimurium 1.56 0.78 0.78 3.12 Salmonella panamae F15 1.56 0.78 0.78 1.56 Salmonella Saint paul F20 1.56 0.78 0.78 3.12 Salmonella derby F14 3.12 0.78 0.78 3.12 Salmonella montevideo F16 3.12 0.78 0.78 3.12 The following examples are illustrative but should not be regarded as limiting the invention.

~1540~

4~-VinylthiO - [1,2-diacetoxymethy~ methoxycar~onyl-2-methyl-

2-propeny~ -azetidin-2-one-5-oxide. Reaction (2)-~3) N ~ > ~N ~ ¢ OCOCH3 COOCH3 ~ COOCH3 A solution of 2.0 g of methylpenicillinate S-oxide and 2.8 g of butyndiol diacetate in 40 ml of toluene was heated at re~luxing temperature for 24 hrs. ~he title compound can be purified by column chromatography on silica gel eluting with 96:4 dichloro-methane-ethyl acetate. There was obtained 1.4 g of 4~-vinylthio-~,2-diacetoxymethy~ -1- C1-methoxycarbonyl-2-methyl-2-propeny~ -azetidin-2-one-S-oxide.
PMR (CDC13) : 2.03~ (srcrI3-c-)~ 2.15 and 2.20 ~(two s, 2CH3CO), 2.88~ (dd, Jgem = 14 E~z, Jvic cis = 4 EIz, C-3-H~),

3.88~ (dd, Jgem = 14 Hz, Jvic trans ~ 2 Hz, C-3-H~), 3,83~ (s, CH30),

4.88~ (d, Jvic = 6 Hz, CH2-C=
(H) 4.92~ (broad s, CE~2-C~
I -N C
4.93-5.33~ (m, = CH2 and ~fH

COO

5.32~ (dd, Jvic = 4 and 2 E-Iæ, C-4-H),

6.47~ (t, Jvic = 6 Hz, =IC-C(H2~ ) 4~-Vinylthlo- ~,2-diacetoxymethy~ -methoxycarbonyl-2-methyl-l~propeny~ -azetidin-2-one-S-oxide. Reaction (3)-(4) .. .. . _ _ . .. ..

_~_ ~lS411 iO

o ~ 1I C CH3 3 ~ ~, C CH3 1.7 g of 4~-vinylthio- rl,2-diacetoxymethyl~ rl-methoxycarbonyl-2-methyl-2-propeny~ -azetidin-2-one-S-oxide were dissolved in 80 ml of dichloromethane; 0.5 ml of triethylamine were added and the solution was left for a few hours at room tem~erature.
After evaporating the solvent, the title cornpound was obtained pure in quantitative yields.
P~R (CDC13) : 2.13 (9H) and 2.32 t3H) ~ (two s, 2 CH3CO and 2 CH3-C=l 2.92~ (dd, Jgem = 15 HZ, Jvic CiS = S Hz, C-3-H~), 3.38~ (dd, Jgem = 15 Hz, Jvic trans - 2.5 Hz, C-3-H~), 3.82~ (s, CH30), 4.88~ (d, Jvic - 6. 5 HZ, CH2-C=) (H) 4.92~ (s, CH2-C=) 5.15~ (dd, Jvic = 5 and 2.5 Hz, C-4-H), 6.50~ (t, Jvic 6.5 HZ, - C~(I12) ) 4~-Vinylthio-~1,2-diacetox~meth~ methoxyoxa]oyl-azetidin-2-one-S-oxide. Reaction ~4)-(51 .

1l 1 ~ ~ 3 _ ~ ~ ~ OCOCH3 30/ ~ -OCOCH3- o ~ ~ o ~ OCOCH3 _g_ l~S401() 1 2.0 g of 4~-vinylthio- C1,2-diacetoxymethy~ -1- Cl-methoxycarbonyl-2-methyl-1-propenyl~ -azetidin-2-one-S-oxide, were dissolved in 150 ml of dichloromethane and, after cooling at -78C, a flow of ozone in oxygen was bubbled into the cooled solution until a slightly blue color appeared. The solution was warmed to room temperature, shaken with an aqueous solution of ~a2S2O5, and dried over Na2SO4. The resulting organin phase gave, a~ter evaporating the solvent "in vacuo", 1.4 g of the title compound.

PMR ~CDC13) : 2.05 and 2.08~ ~two s, 2 CH3CO), 3.03~ (dd, Jgem = 17 HZ, Jvic cis = 5.5 Hz, C-3-H~), 3.50~ (dd, Jgem = 17 HZ, JVic trans = 3 HZ, C-3-H~), 3 90~ (5, CH30), 4.82~ (d, JViC = 6.5 HZ, CH2-C=) 4.90~ (8, CH2-C=)~

5.32~ (dd, Jvic = 5.5 and 3 HZ, C-4-H), 6.47~ (t, Jvic = 6.5 Hz, =IC-C(H2).

IR (CH2C12): 1830 cm 1 ~-lactam C=O

1750 cm~l esters C=O
1715 cm amide C=O

4~-Vin,vlthio- r',2-diacetoxym ~ ~meth~yoxaloyl-azetidin-2-one. Reaction (5) S ~ OCOCH3 _ ~ ~ S ~ COCH3 N ~ ~ OCOCH3 ~ ~ N ~ o - OCOCH3 11~4010 1 A solution of 1.4 g of 4~-vinylthio- El,2-diacetoxymethy~
methoxyoxaloyl-azetidin-2-one-S-oxide in 10 ml of anhydrous di-methylformamide was cooled at -25C and 0.9 ml of phosphorous tribromide were added thereto. After 10 minutes, the mixture was diluted with ethyl acetate and washed twice with a saturated solution of NaHCO3. After drying over Na2SO4 and evaporating the solvent, 0.9 g of the title compound were o~tained.
PMR (CDCl3) : 2.07~ (s, 2 CH3CO), 3.17~ (dd, Jgem = 19 Hz, Jvic Trans=3.5 Hz, C-3-H~), 3.65~ (dd, Jgem = 19 Hz, Jvic cis = 5 Hz, C-3-Ha), 3.90~ (s, CH30), 4.73~ (d, Jvic = 6.5 Hz, CH2-C=) (H) 4.88~ (broad s, CH2-C=), 5.52~ (dd, Jvic = 5 and 3.5 Hz, C-4-H) 6.25~ (t, Jvic = 6.5 Hz, =C-C(H2) I
H

IR (CHC13~ : 1815 cm ~-lactam C=O

1745 cm 1 esters C=O

1710 cm 1 amide C=O

4~-Vinylthio- ~,2-diacetoxymeth~~ -azeti.din~2-one. Reaction (5)-(.6). .

~ ~ OCOCII3 ~ C1' S~¢OCOCH3 ,L N ~ ~ / 3 O~y ~ H 3 1.5 g of 4~-vinylthio- ~,2-diacetoxymethyy -1-methoxyoxaloyl-azetidin-2-one were dissolved in lO0 ml of methanol and a few grams of silica gel were added under stirring. After one hour, ~154010 1 the silica gel was filtered off and the methanolic solution evaporated, to give 0.8 g of 4~-vinylthio- [1,2-diacetoxymethy~ -azetidin-2-one.

PMR (CDC13): 2.25~ (s, 2 CH3CO), 2~98~ (dd, Jgem = 15 Hz, Jvic trans = 2 Hz, C-3-H~), 3.48~ (dd, Jgem=15Hz, Jvic cis=4.5 Hz, C-3-Ha), 4.78~ (d, Jvic = 7 Hz, CH2-f=), (H) 4.87~ (s, CH2-C), 5.03~ (dd, Jvic = 4.5 and 2 Hz, C-4-H), 6.02~ ~t, Jvic = 7 Hz, = C-C(H2) H

7.13~ (broad s, N-H).

IR (CHC13) : 1770 cm ~-lactam C=O

1740 cm 1 esters C-o EXA~IPLE 6 4~-Vinylthio- ~,2- iacetoxymethy~ -azetidin-2-one-S-oxide.

Reaction (5)-(6~

Il . l 20~ ~ OCOCH3 > ~ ~ OCOCH3 0// N ~ O ~ N \E OCOCH3 0.8 g of 4~~vinylthio- El,2-diacetoxymethyl~-1-methoxyoxaloyl-azetidin-2-one-S-oxide were dissolved in 80 ml of methanol and a few grams of silica were added under stirring. After one hour the silica gel was filtered off and 0.5 g of 4~-vinylthio- ~,2-diacetoxymethyl] -azetidin-2-one-S-oxide were obtained after evaportion of the solvent.

30PMR (CDC13) : 2.13~ (s, 2 CH2CO), 3.0-3.3~ ~m, 2 protons at C-3~, 11541)1~) 14.70~ (m, 2 C-4-H~

4.88~ (d, Jvic = 6 Hz, CH2-f=) (H~
4.93~ (s, CH2--C=~

6.53~ (t, Jvic = 6 Hz, -C-C(H2) ~, 7.23~ (s, NH~.

IR ~CHC13) : 1790 cm ~-lactam C=O

1745 cm esters C=O

EX~PLE 7 . . .
1~ 4~-Acetylglycolylthio-l-acetoxymethyloxyoxaloyl-azetidin-2-one.
... . _ .
Reaction ~12)-(13~

~ S ~OCOCH3 ~ ~ OCOCH3 ,~, N~ OCOCH3 ~ N~o 0.8 g of 4~-vinylthio- ~,2-diacetoxymethyl~ Cl-acetoxymethyloxy-carbonyl-2-methyl-1-propeny~ -azetidin-2-one were dissolved in 80 ml of dichloromethane, cooled at -78C and a -Elow of ozone in oxygen was hubbled into the cooled solution until a ~lue color appeared. The solution, af~er it shaking with an aqueous sol-ution of Na2S2O5, was dried over Na2SO4 to give 0.45 g of the title compound.
PMR (CDC13) : 2.]0 and 2.13~ (two 5, 2 CH3CO) 3.20~ (dd, Jgem , 17 Hz, Jvic trans = 3.5 Hz, C-3-H~), 3.77~ (dd, Jgem = 17 Hz, Jvic cis = 5.5 Hz, C-3-Ha), 4.73~ ~s, -CO-CH2-OCO-), 5.73~ (dd, Jvic 5.5 and 3.5 Hz, C-4-H), 305.87~ (s, COO-CH2-OCO).

1~5~ViO
1 EX~MPLE B
4~-Acetylglycolythio-azetidin-2~one. Reaction (131-(14) r ~ 3 ) ~ ~ ~ 3 0.6 g of 4~-acetylglycolylthio-l-me thoxyoxaloyl-azetidin-2-one were dissolved in l00 ml of methano l and a few grams of silica gel were added as the solution was stirred. After one hour, the silica geL was filtered off and the resulting solution gave, after evaporation of the solvent, 0 . 35 g of the title compound.
PMR (CDC13~ : 2.20~ (s, CH3CO), 3.03~ (dd, Jgem = 16 Hz, Jvic trans=2.5 Hz, C-3-H~), 3.50~ (dd, Jgem = 16 Hz, Jvic cis=4.5 Hz, C-3-H~), 4.77~ (s, -CO-CH2-OCO
-~
5.32~ (dd, Jvic = 4.5 e 2.5 Hz, C-4-H), 6.40~ (broad s, NHI.

4~-Vinylthio- Cl,2-diacetoxymethyl~
-l- Cl-acetoxymethyloxycarb-onyl--l-hydroxymethyl~-azetidin-2-one, Re action (6)-t7) S ~ OCOCH3 > ~ ~ OCOCEI

N ~ OCOCH3 o N ~~ OCOCII3 0.7 g of acetoxymethyl-glyoxylate ~
freshly prepared by the ozono-lysis of diacetoxymethyl fumarate) were dissolved in 30 ml of benzene and the resulting solution was refluxed for 20 minutes through a Dean-Stark apparatus.

1 After cooling the solution at 50 to 60 C, 0.7 g of 4~-vinylthio-rl,2-diacetoxymethyl~-azetidin-2-one dissolved in 10 ml of benzene were added and ~he resulting solution was refluxed .or 2 hours. The title compound was obtained in almost quantitative yields and can be used as a crude mixture for the next step. A pure sample was obtained by preparative TLC, for analytical purposes.
PMR ~CDC13~ : 2.07~ (s, 3 CH3CO), 2.97~ (dd, Jgem=18 Hz, Jvic trans=2 Hz, C-3-H~), 3.40~ (dd, Jgem = 18 Hz, Jvic cis=4 Hz, C-3-H~), 4.70~ (d, JVic = 6 HZ, CH2-C=), ~H

4.77~ (s, CH2-C=), I
5.0-5.4~ (m, C-4-H and -N-CH-COO-) O(H) 5.77~ (s, - COO-CH2-OCO), 6.12~ (t, JVic = 6 Hz, =C-C~H2~ ) H
- EX~MPLE 10 .
4~-Vinylthio- ~,2-diacetoxymet~y -l-rl-acetoxymethyloxycarbonyl-1-cbloromethy~ -azetidin-2-one. Reaction (7)-(8) S ~ OCOC~3 ~ 5 ` - OCOC~13 N ~ OH OCOCH3 N~ ~ Cl ~ OCOCH3 0.6 g of 4~-~inylthio- ~,2-diacetoxymethyl~-1-[acetoxymethylox,v,-carbonyl-l-hydroxymethyl~-azetidin-2-one dissolved in 15 ml of tetrahydrofuran were cooled at 0C; 0.115 ml of pyridine and 0.104 ml of thionyl chloride were added and the resulting mixture was stirred for 10 minutes. The insoluble material was filtered llS40i~
1 off and the solution was evaporated "in vacuo" at room tempera-ture to give the title compound in high yield. A sample was purified on preparative TLC for analytical purposes, but the crude mixture can be used without purification for the next step.
RMR (CDC13) : 2.14~ (s, 3 CH3CO), 3.10~ (dd, Jgem = 15.5 HZ, JViC trans=2 Hz,C-3-H~), 3.55~ (dd, Jgem = 15.5 HZ, JViC CiS = 5 Hz,C-3-Ha), 4.77~ (d, Jvic = 6.5 Hz, CH2-C=), (H) 4.83~ (s, CH -C=~, 5.4-5.9~ (m, C-4-H and N-CHCl-COO), 5.88~ ~s, -COO-CH2-OCO-), 6.13cS ~t, Jvic = 6.5 Hz, =C-C(X2).
H

4 ~-Vinylthio- rl,2-diacetoxymethyl]-1- ~-acetoxYmethylox~_arbonyl-l-triphenylphosphoranylidenemethyl]-azetidin-2-one. Reaction

(8)-(92 ~ ~ ~ COCH3 ~ S ~ OCOCH3 O~ ~ Cl OCOCH3 ~ 0 ~ - PPh ~ OCOCH3 OOCH20COcH3 r 3 A solution of 0.430 g of ~-vinylthio- ~,2-diacetoxymethyl]-1-[l-acetoxymethyloxycarbonyl-l-chloromethy~ -azetidin-2-one, in 5 ml of tetrahydrofuran and S ml of dioxane containing 0.520 g of triphenylphosphine and 0.08 ml of pyridine, was stirred over-night at 50C. The resulting phosphorane was purified by column chromatography on silica gel eluting with 70:30 dichloromethane-ethylacetate; 0.400 g of the title compound were obtained.

PMR ~CDC13) : 2.05~ ~s, 3 CH3C0), 4.70cS (d Jvic - 6.5 ~z, CH2-C=) 1~5401(~

t 4.73~ ~s, CH2-CI=) 5.77~ (s, -CoO-CH2-OCO-l 5.90~ (t, Jvic = 6.5 Hz, = C-C(H2) ) 7.1-8.0~ (m, 3C6H5).

4~-Acetylglycolylthio-l-cl-acetoxymethyloxycarbony~ t-riphen _ _ phosphoranylidenemethyl]-azetidin-2-one. Reaction ~10)-(11) rN ~ ~OCOCH3 0 / ~`F PPh3 I= PPh3 COOCE~20COCH3 COOCH20COCH3 ., Q.7 g Of 4B-vinylthio- rl,2-diacetoxymethyl~ acetoxymethyloxy-car~onyl-l-triphenylphosphoranylidenemethyl] -azetidin-2-one were dissolved in 40 ml of dichloromethane and, after cooling at -20C, 50 ml of a lO~ solution of trifluoroacetic acid in dichloromethane were added. After few minutes, a flow of ozone in oxygen was bubbled into the solution at 20C until a slightly blue color ~O appeared. At this point, the reaction was stopped and a few drops of trimethylphosphite were added. The organic solution was washed with a saturated solution o~ NaHCO3 and dried over Na2SO4 to give 0.550 o~ the titlc compound.
PMR (CDC13~ : 2.10 and 2.15~ (two d/ 2 CH3CO), 4.72~ (s, -CO-CH2-OCO-), 5.64~ ~s. -COO-CH2-OCO), 7.1-8.0~ (m, 3 C6H5).

~5R)-Acetoxymethyl-2-acetoxymethyl-2-penem-3-carbox~late.
Reaction Cll~-(l) S ~\ OCOCH3 ~5 ~f OCOCH3 ~F . .. _ , L ~1~

0.7 g of 4~-acetylglycolylthio-1- rl-acetoxymethyloxycarbonyl-l-triphenylphosphoranylidenemethyl]-azetidin-2-one were dissolved in 30 ml of dry toluene and heated at refluxing temperature for 2 hours. The reaction mixture, consisting of the title compound and triphenylphosphine oxide, was purified by a short column chromatography on silica gel, eluting with 97:3 dichloromethane-ethylacetate, to give 0.250 g of acetoxymethyl-2-acetoxymethyl-2-acetoxymethyl-2-penem-3-car~oxylate.
PMR ~CDC13) : 2.11 and 2.13~ (two s, 2 CH3CO), 3.49~ (dd, Jgem=16.5 Hz, ~vic ~rans=2 Hz, C-6-H~), 3.86~ (dd, Jgem=16.5 Hz, Jvic cis=3.8 Hz, C-6-H~), 5.12 and 5.45~ (two d, Jgem = 15.5 Hz, =C-CH2), 5.68~ (dd, Jvic = 3.8 and 2 Hz, C-5-H), 5.87~ (s, -COO-CH2-OCO-).

IR (CHC131 : 1800 cm 1 ~-lactam C=O
1750-1725 cm 1 esters C=O
U.V. ~EtOH): ~ max 325 nm.
MS : m/e 315~04108 (M 1 calculated for C12H13N O7S
315.04127.

4~-Vinylthio-(1,2-diac~ ym-ethy~ p nitrobenzyloxycarbonyl-l-hydroxymethyl)~azetidin-2-one. Reaction (6~-(7) llS~OlV

C~ ~ OAC L --IC

0// ~H OAc ~ _ N~,~ OH OAc COOCH2 ~ N2 The title compound was obtained following the same procedure of Example 9, using p-nitro~enzylglyoxylate which had been freshly prepared by the ozonolysis of p-nitrobenzylfumarate.

Quantitative yield.
PMR CCDCl3) ~ : 2.1 (s, 6HI; 2.8-2.7 (m, 2H); 4.7-4.9 (m, 5H);
5.1-5.6 (m, 2H); 5.2 ~m, lH~; 6.1 (m, lH);
7.5-8.3 ~m, 4H~.

4~-Vinylth.io-(1,2-diacetoxymethyl~-(1-p-nitrobenzyloxycarbonyl-l-chloromethyl)-azetidin-2-one. Reaction (7),-(8) _ . . _ _ . _ _ _ _ . _ _ _ _ _ _ _ _ _ _ . _ OAc ~ L N ~ ~ O~c ~~~--~~--~~-~ 0// ~ Cl COoC ~ No2 COOCH2 ~ No2 The title compound was obtained following the procedure shown in Example 10.
PMR (C~C132 ~: 2.1 (s, 6H); 2.8-3.7 (m~ 21I); 4.7-4.9 (m, 4H);
5.2-5.4 (m, lH); 5.4 Cm, 2H); 6.1-6.3 Cm, 2H);
7.5-8.4 (m, 4H~.

4~-Vinylthio-(1,2-diacetoxymethyl~ p-nitrobenzyloxycarbon l-triphenylphosphoranylidenemethyl)-azetidin-2-one. Reaction C8)-~9) ~19--~54010 ~S ~\OAC ~ S ~f\ OAC
L I ~OAC --~ L I ~/ O~c COOCH2~ N2 COOCH 2 -~ N2 The title compound was obtained following the procedure of Example 11.

4~-Acetylglycolylthio-l Cl-p-nitrobenzyloxycarbonyl-l-triphenyl-. _ . . . .. . _ . . .. . _ phosphoranylidenemethyl?-azetidin-2-one. Reaction ~9~-(ll) S~ OAc 1~ S~ O~C
~ N ~ OAc ~ ¦ O
o ~ ~=PPh3 N2 o~ N ~PPh3 _~

The title compound was obtained following the procedure of - ~xample 12.
EXAMP.LE 18 (5R)-R-nitrobenzyl-2-acetoxymethyl-2-penem-3-carboxyl.ate.
Reaction ~ll)-(l~

OA~:

\~ OOCH2~ N 2 COOCH2~ 2 The title compound was obtained following the procedure of Example 13.
PMR ~CDC13) ~: 3.75 (lH, dd, J = 2.3 Hz, 16.8 Hz, H-6~) 3.87 (lH, dd, J = 3.6 Hz, 16.8 Hz, H-6B);
5.14 (lH, d, J = 15-8, -C-CH20-~;

llS4010 1 5.50 (lH, d, J = 15.8 Hz, =C-CH2O), 5.71 (lH, dd, J - 2.3 Hz, 3.6 H~, H~5).

D + 87 (C 1. 2 CHC13~ .

IR (C~C13) : 1800 (~-lactam, 1750 ~nd 1720 cm 1.
UV (EtOH) : 265 (s 11000~ and 322 (s 7000) nm.
M.S. : m/e 378 (M ~;
M.p. : 122-123C

~5R)-2-Acetoxymethyl-2-penem-2-carboxylic acid. Reaction (1) r OAc ~ OAc ~ \ COOCH2~ 2 COOH

200 mg of (5Rl-p-nitrobenzyl-2-acetoxymethyl-2-penern-3-carboxy-late, prepared as described in Example 18, were dissolved in 12 ml of ethyl acetate. Then 8 ml of a 0.2 M NaHCO 3 solution and 400 mg of 10% Pd/C were added and the resulting biphasic mixture was shaken under hydrogen for 60 minutes. After filtering the catalyst, the aqueous phase was acidi~ied ~ith 20 ml of 5%
aqueous citri.c acid and extracted three times with methylene chloride. The organic layers wer~ dried over Na2SO~ and evap orated to give 60 mg o~ the title compound.
I.R. ~CHC13): 1790 (~ lactam), 1735 and 1700 crn 1.
U.V. (EtOH) : 300 nm.

4~-(1-Hydroxymethyl~-vinylthio-l-[l-methoxycarbonyl-2-methyl-2-propenyl~-acetidin-2-one-S-oxide. Reaction (2)-(3) .. . . _ _ o o ll ll t ooc~3 ~

4 g of penicillanic acid methyl ester S-oxide were dissolved in 15 ml of toluene and refluxed with 15 ml of propargyl alcohol for 8 hours. After evaporating in vacuo, the residue was pur-ified by short column chromatography on silica gel, eluting 2.6 g of the title compound were obtained.

PMR ~CDC13) ~: 1.96 (bs, 3 H, C-CH3~; 2.91 and 3.35 (dd, 2H, J = 2 Hz, 5 Hz, 15 Hz, CO-CH2-CH-S~; 3.78 (s, 3H, COOCH3); 4.36 ~bs, 2H, CH20H~; 4.90-5.25 (m, 3H, CH-COOCH3 C-C-CH2); 5.35 (m, lH, CH2-CH-S);
5.88 ~s, 2H, CH2=C-S).

4~ -hydroxymethyl)-vi~ylthio~ -methox~carbonyl-2-methy :
l-propenyl]-azetidin-2-one-S-oxide. Reaction (3)-(4) ~ ~~~ OH ~ ~ ~ ~ OH
11 11 __~ _ 0~ - N ~ ~ 0// N ~ L_ 3.0 g of 4~-(1-hydroxymethyl~-vinylthio-1-[1-methoxycarbonyl-2-methyl-2-propenyy -azetidin-2-one-S-oxide ~ere dissolved in 100 ml of dichloromethane and left at room temperature for a few hours. After evaporating the solvent, the residue consisted of pure title compound in a quantitative yield.

11~4010 1 PMR (CDC13) ~: 2.08~s, 3H, =-CH3l; 2.18 (s, 3H, =lCI~3~;
2.7-3.6 (m, J = 2 Hz, 5 Hz, 16 Hz, CO-CH2-CH-S);
3.78 (s, 3H, COOCH3~; 4.35 (s, 2H, CH2OH);
5.32 ~m, lH, CH-S); 5.90 (bs, 2H,=CH2).

4~-(1-Bromomethyl)~vinylthic-l- [l-methoxycarbonyl-2-methyl-1-propenyl~ -azetidin-2-one. Reaction (4)-(12~.

~ S ~ OH ~ S ~ ~ Br L N ~ O ~ ~

1.8 g of 4~-(1-hydroxymethy])-vinylthio-1- [1-methoxycarbonyl-2--methyl-l-propenyy -azetidin-2-one-S-oxide were dissolved in 40 ml of dimethylformamide and cooled at -20C. Thereafter, 0.7 ml of pyridine and 3 . 0 ml of PBr3 were added and the mixture left for 15 minutes while stirring. Ethyl acetate was added and the organic layer was shaken with a NaHCO3 saturated solution, washed with water, and then dried over Na2SO4 giving, after evaporation of the solvent, 1.6 g of the title compound.

PMR (CDC13) ~: 2.04 (s, 3H, -- ); 2.24 (~, 3H, - ~ );

3.24 (dd, J ~ 2.8, 5, 16 Hz, 2H, C-CH2-CH);
3.75 (s, 3H, OCH3~; 4.02 (s, 2H, CH2BR);
5.24 (bs, lH, =CH~; 5.37 (dd, J = 2.8 Hz, 5 Hz, lH, CH2-CH-S~; 5.60 (bs, lII, = CH).

4~- E-( l-methyl-l-H-tetrazol-5-yl)-thiomethyl]-vinylthio-1-~-methoxycarbonyl-2-me ~ eny~ -azetid_n-2-Reaction (12) ~S4010 N N

~N ~ ~ ~ ~ 5 ~ C

1.4gof4~-~l-bromomethyl2-vinylthio~ methoxycarbonyl-2-methyl-l-propenyl~-azetidîn-2-one were dissolved in 25 ml of tetrahydrofuran and cooled at 0C.
O.8 g of 1-methyl-5-thiol-tetrazole sodium salt were added and the mixture was stirred for three hours at room temperature.
After filtering the insolubles, the mixtures was diluted with ethyl acetate, washed with water, dried over Na2SO4 and evap-orated. The residue consisted of 2.0 g of pure title compound.

PMR (CDC13) ~: 2.00 (s, 3H, =C-CH3; 2.22 (s, 3H, =C-CH3);
2.70-3.80 ~m, 2H, J=2 Hz, 5 Hz, CO-CH2-CH-S3;
3.72 ~s, 3H, COOCH3); 3.95 ~s, 3H, N-CH3);

4.10 ~s, 2H, CH2-S); 5.18 (bs, lH, S-C=CH);

5.36 ~m, lH, CH2-CH-S); 5.57 (bs, lH, S-C=C-H).
EXAMPLE 2~
4~ ~ zol-5-yl) thio acetylthio-l-methoxy-oxaloyl-azetidin-2-one. Reaction (12)-(13) .
N - N
~ Ir s ~ r' S ~ ,~0 ~ ~OOCH3 CH3 ~ - N ~ O CH3 1.8 g of 4~ rl-(1-methyl-1-H-tetrazol-5-yl)-thio~-vinylthio-1-~1-methoxycarbonyl-2-methyl-1-propenyl3-azetidin-2 one were ~401() I dissolved in 200 ml of dichloromethane and cooled at -78C. A
flow of ozor.ized oxygen was bubbled through the solution until a blue color appeared. A few drops of P~OCH313 were added and the mixture was raised to room temperature and evaporated to give l.3 g of the title compound.
PMR (CDCl3) ~: 2.9-3.7 (m, 2 H, COCH2CH S~; 3.85 (s, 3 H, COOCH3); 3.98 ~s, 3 H, N-CH3); 4.35 (s, 2 H, CH2S); 5.75 (m, l H, CH2CH S~.
EXP~IPLE 25 10 4~methyl-l-H-tetraæol-5-yl)-t _o-acetyl-thio-azetidin-2-one.

N N N - N
~ ~ S l J ~ s ~ o I
CH3 -- N \ ~ 1H3 l.2 g of 4~-~l-methyl-l-H-tetrazol-S-yl~-thio-acetylthio-l-methoxyoxaloyl-azetidin-2-one were dissolved in a l:l ethyl-acetate/methanol mixture and a few grams of silica gel were added under vigorous stirring. After one hour, the insoluble stuff was filtered off and the solution evaporated in vacuo. The title compound crystallized from methanol-ethyl ekher : obtained 0.6 g.
EX~MPLE 26 4~-(l-methyl-l-H-tetrazol- ~ )-~thio-acetylthio-l-(~',-acetoxy-methyloxycarbony~ hydroxym-thyl)-azetidin-2-olle ~ . .

~ H ~ O~l- ~ CH3 ~154010 1 1.5 g of 4~-(1-methyl-1-H-tetrazol-5-yl)-thio-acetylthio-azetidin-2-one were refluxed in 50 ml of benzene with 1.2 g of acetoxymethylglyoxylate (freshly prepared by the ozonolysis of diacetoxymethylfumarate~. The reaction was completed after 3 hours. ~he crude oil obtained after evaporating the solvent can be used for the next step without further purification. A
sample was purified on TLC for spectroscopic data.
PMR ~CDC13) ~: 2.05 (s, 3H~; 2.7-3.8 (m, 2H); 3.95 (s, 3H~, 4.30 (s, 2H); 5.40 (s, lH), 5.50 (m, lHl;
5.80 ~s, 2H~.
EX~MPLE 27 4~ Methyl-l-~-tetrazol-5-yl)-thio-acetylthio-1-Cl-acetoxy-, methyloxycarbonyl-l-chloromethyl)-azetidin-2-one.

Reaction ~15)-(16~

~ N~ ~ r~ ~ I

The oil obtained from Example 26 consisting of crude 4~ meth~yl-l-H-tetrazol-5-yl~-thio-acetylthio-1-(1-acetoxymethylox~-carbonyl-l-hydroxymethyl)-azetidin-2-one, was dissol~ed in anhydrous tetrahydrofuran (20 mll and treated at 0C with e~ui-molar amounts of pyridine and thionyl chloride until all starting material disappeared. After filtering the insoluable material, the filtrate was used immediate for the next step.
EXAMPLE_ 2'8 4~(1-Methyl-l-H-te-trazol-5-yl)-thio-acetylthio-1-11-a etoxy-methyloxycarbonyl-l-triphenyl-pllosphoranylideIlemethyl)-azetid-in 2-one. Reaction (16)-(11) o-~

N--NI N --N
[~ ~ S 1N N ~S ~ ~ ¦ O

O~ ~ Cl CH3 ~ 3 CE~3 To a solution containing crude 4~-~1-methyl-1-H-tetrazol-5-yl)-thio-acetyl thio-l-~l-acetoxymethyloxycarbonyl-l-chloromethyl)-azetidin-2-one, 800 mg of triphenylphosphine and 0.4 ml of pyridine were added and the resulting mixture was heated at 60C
~ to 70C for a few hours. The phosphorane was purified on silica ; gel eluting with dichloromethane-ethyl acetate ~l:l)c (5R¦-Acetoxymethyl-2-~ methyl-1-H-tetrazol-5-yl)-thiomethyl~
_p em-3-carboxylat.e. Reaction (11)-(1l ; N - N N

O ~ h3 3 r N ~ ON~ ~3N
COOCH20COCH'3 0.500 g of 4~ methyl-1-H-tetrazol-5-yl)-thio-acetylthio-1-~l-acetoxymethyloxycarbonyl-l~triph~nylphosphoranyliden~3methyl)-azetidin-2-one were dissolved in 30 ml of toluene and heated at 100C for two hours. The title compound was purified from PPh30 by short column chromatography on silica gel eluting wlth di-chloromethane-ethyl acetate. (8:2) PMR (CDC13) ~: 2.15 (s, 3H, COCH3); 3.30-~4.03 (m, J = 4 Hz, 2 Hz, -CH2-~6); 3.97 ~s, 3H, -NCEI3);
4.56 (d, J = 14 Hz, lH, _CH-S); 4.84 (d, J=14 Hz, ~5~0iO

1H HCH--S) 5 . 65 (dd J = 4 HZ 2 HZ 1H
H-5~); 5.88 ~s, 2 H COOCH20) .

(5R) -2-~1-Methyl-l-H-tetrazol-5-yl~-thiomethyl-2-penem-3-carboxylic acid. Reaction (1) N -N N--N

J~ ~ C113 ~ ~ 3 COOCH3 ~ No2 COOH

The title compound was obtained following the procedure set out in Example 19. The (5RI p-nitrobenzoyl-2-(1-Methyl-l-H-tetrazol-5-yl)-thiomethyl-2-penem-3-carboxylate was obtained by a process similar to the process described in the previous examples.
I.R. (CHC13) : 1800 (~ lactam), 1750 and 1720.

Methyl-6a-(1'-hydroxyethyl)-penicillinate-S-oxide. Reaction (17)-(2~

OH O
Ol1~8~",H H ¦¦
~ S ~ CH3 ~"" ~ ~ S
L N ~ L_ N ~ I 3 ---COOCH3/~ 7 4 ~ ~ COOCE~

A solution of methylpenicillinate S-oxide (2.3 g) in 50 ml of anhydrous tetrahydrofuran was cooled at -78C. Lithium diiso-propylamide (freshly prepared from 5 ml of diisopropylamine and 20 ml of a 1.6 M BuLi hexane solution) dissolved in anhydrous tetrahydrofuran was added and the mixture left at ~78C for 10 minutes. 5 ml of acetaldehyde were successively added and the solution was stirred for 15 minutes. The reaction was then 115401(~

1 quenched with a NH4Cl saturated aqueous solution, extracted with ethyl acetate, washed twice with water, and dried over Na2S04.
After evaporation of the solvent, the residue was shortly purified by column chromatography on silica gel eluting with dichloromethane-ethyl acetate ~ . O~tained 1.5 g. The title compound consisted of a 2:3 mixture of epimers at the hydroxyl bearing carbon based on the PMR, being the new C6-C8 bond only in the a-position because of the stereospecificity of the reaction in the used conditions.
PMR ICDC13~ ~: 1.27 (s, 3 H, ~-CH3); 1.40 (d, 3H, J = 5.7 Hz, CH3-CHOH) major isomerj 1.48 (d, 3H, J = 5.7 Hz, CH3-CHOH) minor isomer; 1.70 (s, 3H , ~~CH3;
3.4~3.8 ~m, LH, H-6) 3.80 ts, 3H, COOCH3);
4.1-4.7 (m, lH, CHOH); 4.50 (s, lH, H-3);
4.98 (d, J = 1.9 Hz, lH, H-5~ minor isomer;
5.05 (d, J = 1.9 Hz, lH, H-5) major isomer.

Methyl-6- rl-hydroxyeth~ -3-penicillanate. Reaction ~17)-(2) OH

~H COOCH3 0 H ~ COOCH3 To a solution of 2.2 g of methylpenicillanate in 30 ml of an-hydrous tetrahydrofuran, a slight excess of ]ithium diisopropyl-amide was added at -78C under nitrogen. An excess of acet-aldehyde was added, the mixture stirred for 5 minutes, quenched with trace acetic acid, poured into water, and extracted with methylene chloride. The organic layers dried over Na2S04 and evaporated "in vacuo" gave 0.8 g of the title compound.

lV10 Methyl-6- rl-p-nitroben~y30xycarbonyloxyethy-1]-3-penicillanat_.
Reaction ~2J

oD ~ COOCH3~ ~ COOCH3 1.2 g of methyl-6-Cl-hydroxyéthy~ -3-penicillanate were dis-solved in 40 ml of tetrahydrofuranj cooled at -78C and treated with one equivalent of butyl lithium. 1.2 equivalents of p-nitrobenzyloxycarbonylchloride were added to the previous mixture; after 30 minutes at -78C, the reaction was left at room temperature for 60 minutes, poured into water, and extracted with methylene chloride: 1.4 g of the title compound were obtained after drying over Na2SO4 and evaporating.

Methyl-6- ~-p-nitrobenzyloxycarbonyloxyethyl~ -3-penicillanate-S-oxide. Reaction (17)-(2) C02 ?NB o COOCH; O / ~COOCH3 1.8 g of methyl-6-Cl-p-nitrobenzyloxycarbonyloxyethyl~-3-penicillanate were d;ssolved in 50 ml of methylene chloride and treated at 0C with 1.5 equivalents of m-chloroperbenzoic acid.

The organic phase was shaken with a NaHCO3 saturated solution, .

llS~OlQ

1 extracted, dried over Na2SO4, and evaporated giving 1.4 g of the expected sulphoxide.

4~-Vinylthio- r],2-diacetoxymethyl~-3- rl-p-nitrobenzyloxycarbonyl-oxyethy~ -l-rl-methoxycarbonyl-2-methyl-2-propeny~ ~azetidin-2-one-S-oxide. Reaction (2)-(3J
C2 NB p 2 J~ 1~

~ COOCH~ ~ CCH3 A solution of 2.0 g of methyl-6- [l-p-nitrobenzyloxycarbonyloxy-ethyl~-3-penicillanate-S-oxide and 2.4 g of butyndiol diacetate in 50 ml of toluene was refluxed for 24 hours. The trapped compound was then purified by silica gel column chromatography eluting with 9:1 dichloromethane-ethyl acetate.
1.1 g of the title compound were obtained.
EXAMPLE_ 36 4~- Vinylthio-[l/2-diacetoxymethy~ -3- ~l-p-nitrobenzyloxy-. . ~
carbony]oxyethyl~ methoxycarbonyl-2-m ~ ~E~5 azetidin-2-one-S-oxide. R~action (3)-(4~

S \ ,' \ OCOC~3 ~ ~ - - ~ 5` ~ ~ OCOC~3 O~ -N y ~ ~ OCOCH3 1 ~ ~ OCOCH3 H '-" COOCH

1.3 g of 4~-vinylthio- ~,2-diacetoxymethyl~-3- [l-p-nitrobenzyl-oxycarbonyloxyethyl~-l-rmethoxycarbonyl-2-methyl-2-propeny~-11540-lO

1 azetidin-2-one-S-oxide were dissolved in 80 ml of dichloromethane;
0.3 ml of triethylamine were added and the mixture was left at room temperature for 2 hours. The pure title compound was quantatively obtaîned on evaporation of the solvent.

4~-Vinylthio- ~,2-diacetoxymeth ~ -3- El~p-nitrobenzyloxycarbonyl-oxyethy~ -l-methoxyoxaloyl-azetidin-2-one-S-oxide. Reaction (4~-(5).
OCO PNB O
~Co2pNB o \ 2 11 10 ~ S ~ OCOCH3 ~ ~ OCOCH3 L N ~ ~ OCOCH3 ~ N ~

A solution of 1.] g of 4B-vinylthio-~1,2-diacetoxYmethYLJ-3-l-p-nitrobenzyloxycarbonyloxyethyl~ [methoxycarbonyl-2-methyl-l-propenyy -azetidin-2-one-S-oxide in 100 ml of dichloromethane was cooled at -78C. Ozone in oxygen was bubbled into the solution until a blue color appeared. The solution was shaken with an aqueous solution of Na2S2o5 and dried over Na~S04. 0.5 g of the title compound were obtained a~ter evaporat.ion.
EXAMPLr. 33 4~-Vinylthio- ~2-diacetoxymethyl~-3- ~-p-nitrobenzyloxycarbonyl-oxyethyl~-l-methoxyoxaloy]-azetidin-2~one. Reaction (5) ~,C02PNB o ~1 ~` oCocH L r -¢~COCII3 ~ l 3 _ ~

O ~ ~ ~ ~ ~ ~- OCOCH3 o~ N ~o ~ "OCOCH3 1 A solution o~ 0.8 g of 4~-vinylthio-~1,2-diacetox~methylJ-3-Cl-p-nitrobenzy]oxycarbonyloxyethyl]-l-methoxyoxaloyl-azetidin-2-one in 15 ml of anhydrous dimethylformamide was cooled at -20C
and 0.6 ml of phosphorous tri~romide were added. The reaction was diluted with ethylacetate after 10 minutes and washed twice with a solution of NaHCO3. The organic phase, dried over Na2SO4 and evaporated, gave 0.4 g of the reduced compound.
XAMPLE_ 39 4~-Vinylthio- C1,2-diacet-oxymethy~ -3-rl-p-nit~ob~q~ ycarbonyl-oxyethyll-azetidin-2-one. Reaction (5)-(6) oCo2pNB ~ 2 / , S ~ COC~3 ~ ~ ~ S ~ OCOCH3 o// N ~ O OCOCH3 ~ N \ ` -'OCOCH3 1.2 g of 4~-vinylthio- rl, 2-diacetoxymethyl~-3-[1-p-nitrobenzyl-oxycarbonyloxyethyl~-l-methoxyoxaloyl-azetidin-2-one were dis-~ solved in methanol and 2 g of silica gel were added to thesolution. After 60 minutes the insoluble material. was filtered and the organic phase evaporate~. Short column chromatography resulted in 0.4 y o~ the title compound.

4~-Vinylthio- ~,2-diacetoxyme~hyl~-3- rl-p-nitrobenzyloxycarbonyl-oxyethyl~-l- rl-acetoxymethyloxycarbonyl-l-hydroxymethyl~-a7,etidin-2-one. Reaction (6)-~7) 11540~V

~ ~ S ~ OCOCH3 ~ OCOCH3 0.6 g of 4~-vinylthio-C1,2-diacetoxymethyl]-3- rl-p-nitro~enyl-oxycarbonyloxyethyl~-azetidin-2-one, dissolved in 30 ml of ben-zene, and 0.6 g of acetoxymethyl glyoxylate ~freshly prepared from the ozonolysis of diacetoxymethyl fumarate~ were refluxed.

The reaction was completed after two hours. The condensationproduct can be used for the next step without further purifi-cation.

4~-Vinylthio- rl,2-diacetoxymethyll-3-[1-p-nitrobenzyloxycarbonyl-oxyethyl~ l-acetoxymethyloxycarbonyl-l-chloromethyl~-azetidin-2-one. Reaction (7)-~8) 2 ~ 2 \ ~ ~ S ~ OCOCH3 ~ _ ~ S ~ \OCocH3 ~ OCOCH3 O~ N ~ ,~OCOC}I3 0.5 g of 4~-vinylthio- El,2-diacetoxymethYl] 3-[1-p-nitrobenzyloxy-carbonyloxyethyl~ -acetoxymethyloxycarbonyl-l-hydroxymethyl~-azetidin-2-one were dissolved in 12 ml of anhydrous tetrahydro-furan and cooled at 0C; thereafter 1.1 equivalents of pyridine and 1.1 equivalents of thionyl chloride were added to the sol-ution. The mixture was stirred for 10 minutes. The insolublematerial was filtered off and the solution evaporated at room 1 temperature to give the title compound in nearly quantitative yields. The product can be used without further purification for the next step.

4~-Vinylthio-rl,2-diacetoxymethy~ ! -3- rl-P- nitro~enzyloxycarbonyl-oxyethyl~-l-racetoxymethyloxycarbonyl-l-triphenylphosphorany-lidene-methyl~-azetidin-2-one. Reaction (8~-~9) ~C2 B ~ 2 ' 11' ~OCOCH3 ' 1 ~ --~ OCOCH3 .C ~ 3 ~ N ~ Ph OCOCH3 ~ COOCH20COCH3 A solution of 0.760 g of 4~-vinylthio~1,2-diacetoxymethyl~-3-rl-p-nitrobenzyloxycarbonyloxyethyl~¦-l-rl-acetoxymethyloxy-carbonyl-l-hydroxymethyl~l-azetidin-2-one in 10 ml of tetrahydro-furan and 10 ml of dioxane, with 2 equivalents of triphenyl-phosphine and 1.1 equivalents of pyridine, was stirred overnight at +50C. The phosphorane was purified by silica gel column chromatography, eluting with 70:30 dichloromethane-ethyl acetate.

0.480 g o the title compound were obtained.
F.XAMP~E 43 4~-Acetylglycolylthio-3- rl-~-nit~o ~ arbonyloxyethy~
rl~acetoxymethyloxycarbonyl-l-triphen~lphosphorany~idenemethyll-azetidin-2-one. Reaction (9)- (11) ~, ~ ococ~ ¦ r s ~,~ OCOCH3 O " N y PPh3 OCOCH3 ~ N ~ PPh3 llS4010 1 0.45 g of 4~-vinylthio-C1,2-diacetoxymethyl~-3- ~l-p-nitrobenzyl-oxycarbonyloxyethyl]~ acetoxymethyloxycarbonyl-l-triphenyl-phosphoranylidenemethyl~-azetidin-2-one were dissolved in 50 ml of dicloromethane and cooled at -20C; then 30 ml of trifluoro-acetic acid solution in dichloromethane were added. After a few minutes ozone in oxygen was bubbled into the solution until a slightly blue color appeared. The reaction was stopped and a few drops of trimethylphos~hite were added. The organic phase was washed with a saturated solution of NaHC03 and dried over Na2S04 to give 0.26 g of the title compound.

EX2~IPLE 44 4~-Vinyl_h o- ~1,2-diacetoxymethyl]-3- ~-p-nitro~enzyloxycarbonyl-oxyethy~ methoxycarbonyl-2-methyl-1-propenyl]-aæetidin-2-one. Reaction (4)-(121 OCO PNB o ~' " OCOCH3 ~ S ~ OCOCH3 N ~ ~ OCOCH3 ~ ~ N ~ OCOCH3 1.5 g of vinylthio- ~1,2-diacetoxymethyl]-3- El-p-nitrobenzyloxy-carbonyloxyethyl~-l-[methoxycarbonyl-2-methyl-1-propenyl]-azetidin-2-one-S-oxide were dissolved in 10 ml o~ anhydrous di-methylformamide and cooled at -20C; 0.8 ml o~ phosphorous tribromide were added. The mixture was stirred ~or 10 hours, diluted with ethyl acetate, and washed twice with NaHC03 sat-urated solution. The organic layer dried over Na~S04 and evaporated gave 1.1 g of the title compound.

_ 4~-Acetylglycolythio-3-~rl-p-nitrobenzyloxycarbonyloxyethyl~-1-. _ . . . _ , .
methoxyoxalyl=azetidin-2-one. Reaction (12~-(13) ~540~0 ~OC02PNB
~OCo2pNB
~ S - ~COCH3 ~f s ~`` OCOCH3 ,~ - N ~fl~ COCH3 N ~ O

1.4 g of 4~-vinylthio-[1,2-diacetoxymethyl~-3~ p-nitrobenzyl-oxycarbonyloxyethyl]-l-rmethoxycar~onyl-2-methyl-1-propenylJ-azetidin-2-one in 120 ml of dichloromethane were cooled to -78C.
Then ozone oxygen was bubbled through the solution until a blue color appeared. The solution was shaken with an aqueous solution of Na2S2O5 and dried of Na2SO4. Evaporation of the solution gave 0.8 g of the title compound.
EXAMPLE_ 46 4~-~cetylglycolylthio-3-rl-p-nitrobenzyloxycarbonyloxyethyl]-azetldin-2-one. Reaction 113~-(14 \OCO2PNB ~ PNB

S ~ OCOCH3 ~ S ~ OCOCH3 ~_ _ N ~ o O N \ H

0.800 g of 4~-acetylglycolylthio-3- [l-p-nitrobenzyloxycarbonyl-oxyethyl~-l-methoxyoxalyl-azetidin-2-one were dissolved in 50 ml of methanol and a few grams oE silica gel added. The mixture was left at room temperature for 60 minutes. The insoluble material filtered off and the filtrate, after evaporation, gave 0.30 g of the t;,tle compound.

~15~ 0 . _ 4~-Acetylglycolylthio-3~ p-nitrobenzyloxycarbonyloxyethyl~-1-[l-acetoxymethyloxycarbonyl-l-hydroxymethy~ azetldin-2-one , Reaction ~141-(15).
2 NB \ 2 N

S ~ OCOCH3 ~ S ~ ~ OCOCH3 N ~ ~ N ~ OH

0.5 g of 4~-acetylglycolylthio-3-~1-p-nitrobenzyloxycarbonyloxy-; ethyl~-l- rl-acetoxymethyl~xycarbonyl-l-hydroxymethyl~-azetidin-2-one and 0.5 g o~ acetoxymethyl glyoxylate in 30 ml of benzene were refluxed until the reaction was completed (two hours~. The obtained title compound can be used for the next step without further purification.
. EXAMPLE 48 4~-Acetylglyco]ylthio-3-~1-p-nitrobenzyloxycarbo~loxyethyl~-1-~-acetoxymethyloxycarbonyl-l-chloromethyl]-azetidin-2-one.

Reaction (15~-~16) OCO PNB
OC02PN~ \ 2 S ~ ~OCOCH3 ~ ~ S ~ ~ OCOCH3 O ~ L ' N O
N ~ OH '~ ~ "Cl 0.35 g of 4~-acetylglycolylthio-3- ~-p-nitrobenzyloxycarbonyloxy-ethyl]-l-[l-acetoxymethyloxycarbonyl-l-hydroxymethylJ-azetidin-2-one were dissolved in 10 ml of anhydrous teterahydrofuran at 0C. Then 1.1 equivalents of pyridine and 1.1 equivalents of - 1~540iO

1 thionyl chloride were added and the mixture was stirred for lO minutes. The precipita;:e was filtered and the filtrate, after evaporation, gave the title compound in quantitative yield. The crude product was used as such for the next step.

4~-Acetylglycolylthio-3-[1-p-nitrobenzyloxycarbonyloxyethyl~ 1-rl-acetoxymethyloxycarbonyl-l-triphenxlphosphoranylidenemethyl~-azetidin-2-one. Reaction U6~-(ll).

OCOCH3 r ~ OCOCH3 0 ~ ~ ~Cl N ~ PPh3 0.400 g of 4~-acetylglycolylthio-3-rl-p-nitrobenzyloxycarbonyl-oxyethyl~ -acetoxymethyloxycaxbonyl-l-chloromethyl~-azetidin-2-one were dissolved in 20 ml of a 1:1 mixture of tetrahydrofuran and dioxane. Thereafter 2 equivalents of triphenylphosphine and 1.1 equivalents o F pyridine were added and the mixture stirred overnight at 50C. The title compound was puri-fied by silica gel column chromatography, eluting with 70-30 dichloro-methane-ethyl-Acetate. 0.280 ~ oE th~ phosphorane were obtained~

(5R?-Acetoxymethyl-6- r,l-p-nitrobenzyloxycarbonyloxyethyl~ -2-acetoxymethyl- ~ enem-3-carboxylate. ~eaction (11)-(1) ~OCo2pNB
_ ~ S ~ ~ OCOC ~ \ OCOCH3 - N ~ PPh3 0/ ~ COOCH20COCH3 1 0.210 g of 4~-acetylg]ycolylthio-3-[1-p-nitrobenzyloxycarbonyl-oxyethyl~-l-rl-acetoxymethyloxycarbonyl-l- triphenylphosphorany-lidenemethyl]-azetidin-2-one were dissolved in 7 ml of toluene and the solution was refluxed for two hours. Purification by short column chromatography eluting with 95:5 dichloromethane-ethyl acetate, gave 0.05 g of the title compound.

(SR)-Acetoxymethyl-6-[1-hydroxyethyl~-2-acetoxymethyl-2-penem-3-carboxylate. Reaction (13 .. .

S ~ ~ OCOCH3 - ~ ~ S ~ ~OCOCH3 ~ N ~ ~ N ~ ~
O `~OOCH20COCH3 o/~ 2 CH3 0.060 g o.f 5R-acetoxymethyl-6-[1-p-nitrobenzyloxycarbonyloxy-ethyl~-2-acetoxymethyl-2-penem-3-carboxylate were poured in a water-ethanol-K2HPO4 mixture and hydrogenolysed with 10% Pd/C.
A quick purification by silica gel column chromatography gave 0.015 g of the title compound.
Operating as described in the pr~vious working examples, but employing 5-methyl-2-thiol-1,3,4-thiadiazole, 5-thiol--1,2,3-triazo~e, or thiolphyrazine instead o~ l-methyl-5-thiol-tetrazole, (5R3-2-5'-methyl-1',3',4'-thiadiazol-2'-yl~-thiomethy~ -2-penem-3-carboxylic acid, (5R~-2- [(1',2l,3'-triazol-5yl)-thio-methyl~-2-penem-3-carboxylic acid, (5R~-2-(pyrazinyl)-thiomethyl-2-penem-3-carboxylic acid, (5R?-6- ~'-hydroxyethyl~-2-~5"-methyl-1",3"-4"-thiadiazol-2"-yl)thiomethyl]-2-penem-3-carboxylic acid, (SR)-6- rl'-hydroxyethyl]-2- [(1",2",3"-triazol-5"-yl)thiomethyl¦-2---~o---~540iO

1 (pyrazinyl)thiomethyl-2-penem-3~carboxylic acid r~spectively were prepared.
Operating as previously described, but reducing the methyl-6-rl'-hydroxyethyl]-3-penicillinate following the widely-known procedure, the corresponding 6-ethyl-derivatîves were obtained.

11~40~i0 1 SUPPLEMF.NTARY DISCLOSURE

EXAMPLE 52: 6~-methoxypenicillanic acid-trichloroethylester-S-oxide. q J ~ ~ ~N
O r 2CC 1 3 o 2CC 1 3 800 mg of 6~-methoxypenicillanic-acid-trichloroethylester (prepared according to Giddings et al, Tetrahedron Letters, 11, 995 (1978) were dissolved in 20 ml of dichloromethane and treated portionwise with 570 mg of m-chloroperbenzoic acid at room temperature. The organic phase was washed with a NaIICO3 s~turated solution and evaporated. The title compound crystalliæed from ethyl ether. Obtained 650 mg.

r~.p. 120-121C.
PMR(CDC13)~: 1.35(s, 3H, ~-CH3); 1.75 (s, 3H, ~-CH3); 3.58 ~s,3H,OCH3);

4.52 (s, lH, 3-H); 4.70-5.00 (two d, 2H, J= 9 EIz, CH2CC13);

4.87 (d, lH, J=1.5 Hz, H-5); 5.07 (d, lE, J=

1.5 Hz, H-6~.

EX~PLE 53: 3~-~1ethoxy-4~-vinylthio-tl,2-dlacetoxymethyl]-~ _____ l-[trlchloro-ethoxycarbonyl 2-methyl-2-propenyl]-azetidin-2-one-S-oxide.
, f ~ 3 ~ ~OCOcH3 l ~ ~OCOCH3 / ~ N ¦ COOCH2CCl3 /~~--~--H COOCH2CCl3 11540~

1 550 mg of 6~-methoxypenicillanic acid-trichloroethylester-S-oxide were dissolved in 25 ~1 of toluene; 1.2 g of butyn diol diacetate were added and the resulting solution was refluxed for 10 hrs.
The reaction mixture was purified by silica gel column cromatography eluting with 10% ethyl acetate-dich-loromethane. 450 mg of the title compound were obtained.
PMR (CDC13)~ : 2.01 (bs, 3H, / ~ C~3); 2.08-2.10 (two s, 6H, OCOCH3~
3.45 (s, 3H, OCH3); 4.75-5.00 (multiplet, 8H); 5.18 ~bs, 2H, =CH2); 5.27 (d, lH, J=
1.5 Hz, H-3); 6.57 (t, lH, J=6.0 Hz,~ ~.

EXP`~lPLE 54 __3~-r5ethoxy-4~-vinylthio-[1,2-diacetoxymethyl]-~ trichlor ~ carbonyl-2-methyl-1-pro~enyl]-azetidin-___ 2-one-S-oxide.
--. ....... O

O,CH30 S ~ OCOCH3 CEI3O, ~ S \ OCOCH
J ~L OCOCH3 ~ ~ ~ OCOCEI3 ~I ~COOCH2CC13 2 3 400 m~ of 3cb-m~thoxy-4~-vinylthio-[1,2-d.iacetoxymethyl]-l-[trichloroethoxycarboo~ 2-rn~thyl-2-propenyl.~-azetidin !~
-2-one-S-oxide were dissolved in 10 ml of dichloromethane and stirred at room temperature with a few drops of triethylamine for 2 hrs. Evaporating the solvent afforded the pure title compound.
PMR (CDC13)~: 2.10 (s, 6H,~ 3, OCOCH3); 2.14 (s, 3H, OCOCH3); 2.40 (s, 3H,~ --3), 3~49 (s, 3H, OCH3); 4.82-4.88 (two s, 4H, ~ 2 ~OCOCH3, ., ~ ~

1~4010 1 ~ H
CH2CC13); 4.91 (d, 2H, J=6.0 Hz,~ ); 4.95 (d, lH, J=2.0 Hz, H-4); 5.23 (d, lH, J=2.0 Hz, , H
H-3); 6.60 (t, lH, J=6.0 E~z,- S

EXAMPLE 55 3~-Methoxy-4~-vinylthio-[1,2-diacetoxymet yl]-l-tricloroethoxyoxaloyl-azetidin-2-one-S-oxide ~ S ~ OCOCI-Ii OC ~ ~ OCOCH3 ) - N~ 3 ) r OCOCH3 2 g of 3~-methoxy-4~-vinylthio-~1,2-diacetoxymeth~l]-1-11-trichloroethoxy-carbonyl-2-methyl-1-propenyl]-azetidin-2-one-S-oxide were dissolved in 200 ml of dichloromethane and cooled to -70C. Ozonc in oxygen was passed through the solution until a hlue colour appeared. A few drops of trimethylphosphite were added. Evaporating the solvent afforded the pure title compound.
PMR (CDC13)~: 2.10-2.12 (two s, 6H, OCOCH3); 3.58 (s, 3H, OCH3); 4.75-5.05 (mr 6EI, CH2CC13, ~ 2\);

5.07 (d, lH, J= 3.0 Hæ, EI-4); 5.22 td, lH, J= 3.0 Elæ, 11-3); 6.61 (t, :Ltl, J=6.0 IIz, ~' ) ~X~iPLE 56: l3~-~IethoxY-4~-vin~ylthio-[1,2-diacetoxymethyl]-l-_.~
trichloroe-thoxYoxaloYl-azetidin-Z-~ Q~_ O~CH3 ~ ~", ~ S OCOCH

r ¢ ~ 3 ~ ~ OCOCH

OOCI 2CC13 OOCH2CCl3 lV

1 800 mg oE 3~mcthoxy-4~-vinylthio-[1,2-diacetoxymethyl]-1-trichloroethoxy-ozaloyl-azetidin-2-one-S-oxide were dissolved in 30 ml of anhydrous dimethylformamide and cooled to -20C.
0.5 ml of PBr3 were added and the mixture was stirred for 10 minutes. The re~ction mixture was poured into ethyl acetate and u~shcd s~veral ti~;es with w~ter: the residue, after drying over Na2SO4 , consisted essentially of the title compound and was used for the next step without further purification a P~R (CDC13)~ : 2.08-2.11 (two s, 6H, GCOCH3); 3.61 (s, 3H, OCH3); 4.5-5.0 ~m, ?H) ;5.38 (d, lH, J=3.0 Hz, H~3); 6.28 ~t, lH, J=6.5 Hz, HJ ~

EX.~PL~ 57: 3~-IIethoxy-4e _ nYlthio-~1,2-diacetoxymethyl~-azetidin- -one.

3 ~" ~ S ~ COCH3 ~he crude residue obtained from the previous example was dissolved in 100 ml of methanol and 3 g of silica gel were added uncler sti.rring. The mixture was stirred ~or two hours;
after filtering 5:iO2, the r~sidue was purific~d by silica gel column chro~ato~raphy eluting with 20~ ethyl acetate-dichloromethane; obtained 400 mg of the title compound.
PMR (CDC13~: 2.08-2.11 (two s, 6H, OCOCH3); 3.55 (s, 3H, OCH ); 4.68 (d, J=6.5 Hz, 2H, / ~ / );

4.81 (bs, 3H, S ~ ~ C_2~ ; H-4); 4.86 (d, J=
2.0 Hz, lM, H-3 ; 6.04 (t, J=6.5 Hz, 1~, H ~ ~ CH ) 6.50 (bs, lH, NH).

11~40:L(~

t EXP~lPLE 58. 3~ ethoxy-4~-vinylthio-[1,2-diacetoxymethyl]-1-[l-acetoxy-methyloxycarbonyl-l-hydroxymethyl]-azetidin-2-one.
~ `~ ~ OCOCH3 t~ ~ocCoccH3 o N~ H OCOCH3 ~ N ~ H 3 OOCH20COC~3 250 mg of 3~-methox~r-4~-vinylthio-[1,2~diacetoxymethyl]-aze-tidin-2-one were dissolved in 20 ml of benzene and refluxed for 3 hrs. with 300 mg of acetoxymethylglyoxylate (freshly prepared by ozonolysis of diacetoxymethylfumarate). The crude mixture was purified by silica gel column chromato-graphy eluting with 40% ethyl acetate-dichloromethane to gi,ve 150 mg of pure title compound as a mixture of diastereo-lsomers .

EXAMPI,E 59: ~ -l-[l-ac toxymethyloxycarbonyl-l-chlorornethylJ-azetidin-2-one.

S OCOCH3 3Q ~ S ~ ~ OCOCH3 ~OCOCH3 '~~ ' I l l ) ~ ~ ~OH ~/ ~ 1 ~ OCOCH3 OOCH OCOCH
CoocH2ococH3 2 '3 150 mg of 3~-methoxy-4~-vinylthio-[1,2-diacetoxymethyl]-1-[l-acetoxy-methyloxycarhonyl-l-hydroxymcthylJ-azetidin-2-orle were cl:issolvcd in 10 ml oE anhydrous tetrahydrofuran and cool-ed to -20C; stoichiometric amounts of pyridine and thionyl chloride were added and the mixture stirred for 10 minutes.
The mixture was filtered from the insolu~le stuff on celite and evaporated at room temperature to give a residue which was used for the next step without further purification.

,. !

~lS4~iO

1 EXAMPLE 60: 3~-Methoxy-4~-vinylthio-~1,2-diacetoxymethyl~-l_[l-acetoxymethyloxycarbonyl-l-triphenylphosphoranylldene-methyl]-azetidin-2-one.
OCH

"""r--~ S~1~0C0CH3 " ~
)~ -N ~ Cl ~ 3 OOC~20COCH3 COOCH20COCH3 The crude residue obtained from the previous example, consist-ing of nearly pure 3~-methoxy-4~-vinylthio-[1,2-diacetoxy-methyl]-l-[l-ace-toxymethyloxycarbonyl-l-chloromethyl]-azetidin-2-one was dissolved in 10 ml of toluene. 200 mg of triph-enylphosphine were added and the resulting solution was refluxed under nitrogen for 2 hrs. The phosphorane was purified by short silica gel column chromatography eluting with 40~ ethyl acetate-dichloromethane to give 180 mg of the title compound.

EXAMPLE 61. 3~-Methoxy-4~-acetylglycoly-thio-1-[1-acetoxy-methyloxycarbonyl-l-triphenylphosphoranylidenemethyl]~_ azetidin-2-one.
- ~

3- ~ S ~ OCOCH3 ococ~

Coocl-I2ococH3 CoocH2ococH3 230 mg of 3a-me-thoxy -4~-vinylthio-[1,2-diacetoxymethyl]-l-[l-acetoxy-methyloxycarbonyl-l-triphenylphosphoranylidene-methyl]-azetidin-2-one were clissolved in 50 ml of dichloro-methane and, after cooling to -20C, 0.5 ml of trifluoro-acetic acid were added.

.

115~iO

1 Ozone in oxygen was bubbled through the solution until blue colour. A few drops of trimethylphosphite were added, the reaction mixture diluted with dichloromethane and washed several times with a NaHC03 saturated solution.
After drying over Na2S04 and evaporating the solvent, the residue ~180 mg) consisted of pure title compound.

EXAMPLE 62: (5R)-Acetoxymethyl-6~-methoxy-2-acetoxymethyl-~ 3-carboxylate.

CH3~0 ~ S OCOCH 0,CH30 S
r I ~of ~ ~ ~OCOCH3 ~ PPh3 COOCH20COCH
CoocH2o~ocH3 3 180 mg of 3a-methoxy-4~-acetylglycolylthio-1-[1-acetoxy-methyloxycarbonyl-l-triphenylphosphoranylidenemethyl~-aze-tidin-2-one were dissolved in 20 ml of toluene and refluxed under ni-trogen for 2 hrs. The title compound was purified by silica gel column chroma-to~raphy by eluting with 5~ ethyl acetate-dichloromethane. Obtained 50 mg.

PMR (CDC13)~: 2.11 (s, 6H, OCOCH3), 3.56 (SJ 3H, OCH3);
4.94 (d, J=1.7 Hz, lH, H-4); 5.26 (center of ',CE12\
dd, 2H, ~ ); 5.55 ~d, J=1.7 EIz, lM, H-3);
5.86 (s, 2H, COOCH20COCEI3);

IR (CHC13) 17~5 (~lactam), 1745-1720 (esters).

EXAMPLE 63l l(5E~)-Acetonyl-6~-methoxy-2-acetoxymethyl-2-penem-3-carboxylate.
- _ i ~ OCOCH3 N
\ COOCH2COCH3 ~ 48 --,_ ~lS~O10 1 Operating as shown in examples 58, 59, 60, 61 and 62 but using acetonyl glyoxylate in place of acetoxymethyl gly-oxylate in example 58, the title compound was obtained.
IR 1800, 1745, 1710.(CHC13) EXAMPLE 64 _ t5R)-6~-inethoxy-2-acetoxymethyl-2-penem-3-carboxylic acid.

~ ~ OCOCU3 ~ ~ COCE3 O OOCH2cOcH3 o~/ ~
COOH

260 mg of (5R)-acetonyl-6a-methoxy-2-acetoxymethyl-2-penem-3-carboxylate were dissolved in 25 ml of tetrahydrofuran;
the resulting solution was diluted with 5 ml of water and cooled to 0C. 7.9 ml of a NaOH 0.1 N aqueous solution were added and the mixture left at 0C for 10 minutes. The solution was washed twice with methylene chloride; the aqueous phase was poured under stirring with methylene chloride and 4 ml of a 20% citric acid aqueous solution were added. The aqueous phase was extracted twice with methylene chloride, the combined organ.ic phases dried over Na2SO~ and evaporated to give 80 mg of the title compound.
IR 1795, 1740, 1700.(CHC13) EX~MPLE 65: 4~ Hyd ~
enz loxycarbonyl-oxyethyl~ l-methoxycarbonyl-2-methyl-2-propenyl)-azetidln-2-one-S-~xide Reaction (2) - (3).

- 4c -1~540~V

1 A solution of 2.6 g of methyl-6-(1-p-nitrobenzyloxycarbonyl-oxyethyl)-3-penicillinate-S-oxide and 8 ml of propargyl alcohol in 20 ml of toluene were refluxed under nitrogen for 40 hrs. After evaporation of the solvent, the trapped compound was purified by silica gel column chromatography, eluting witll ~9:1) dichloromethane-ethyl acetate, to give 2.0 g of the title compound.

EXAMPLF. 66: 4~-(1-Hydroxymethyl)-vinylthio-3~ p-nitro-benzyloxycarbonyl-oxyeth~l)-l-(l-me_hoxycarbonyl-2-methyl-1-propenyl)-azetidin-2-one-S-oxide. Reaction (3) - (4).

,~f ~ 0~ ~ 0~

~ COOCH3 ~OCH3 2.0 g of 4~-(1-hydroxymethyl)-vinylthio-3~-(1-p-nitro-benzyloxy-carbonyloxyethyl)-l-(l-methoxycarbonyl-2-methyl-2-propenyl)-azetidin-2-one-S-oxide, dissolved in 50 ml of dichloromethane, were left at room temperature in the presence of a ~ew drops of triethylamine for 12 hrs. After evaporating the solvent, the pure title compound was recoverecl in quantitative yield.

EXAMPLE 67: ~-(1-Bromomethyl)-vinylthio-3~ -nitro-benæylo~ycarbonyl-oxyethyl)-l-(l-methoxycarbonyl-2-methyl-l-propenyl)-azetidin-2-one. Reaction (4) - (12).

OC2PMB O ~ 2 N
5 ~ OM 1 ~ ~ ~ B
~ \~

~0 .~
... .

:
~5~010 1 2.0 g of the compound prepared in Example 66 were dissolved in 50 ml of dimethylformamide. After cooling at -20C, 0.7 ml of pyridine and 3.2 ml of PBr3 were added and the reaction mixture was maintained under stirring for 15 minutes. Ethyl acetate was added to the mixture and the organic phase was shaken with a NaHCO3 saturated solution, washed with water and finally dried over Na2SO4. After evaporating the solvent, 1.7 g of pure title compound were obtained.

EXAMPLE 68: 4~-11-(5-Methyl-1-3,4-thiadiazol-2-ylj-thio-methyl]-vinylthio-3a-(1-p-nitrobenzyloxycarbonylox~ethyl)-l-(l-methoxycarbonyl-2-methyl-1-propenyl)-azetidin-2-one.
.

Br OCO2PNB

J ~ ~ ) ~ 5 S H3 1.8 g of the compound prepared in Example 67 were dissolved in 30 ml of tetrahydrofuran. The resulting solution was cooled at 0JC; 1.1 g of 5-methyl-1,3,4-thiadiazol-2-thiol sodium salt were added and the mixture was maintained under stirring for 4 hrs. After filtration of the insolubles, the remaining solution was diluted with ethyl acetate, washed with water, dried over Na2SO4, and evaporated: 2 g of the title compoundlwere obtained.

EXAMPLE 69:_ 4~ (1 ! 2,3-Triazo].-5-yl)-thiomethyl]-vinyl-thio-3~ -p-nitrobenzyloxycarbonyloxyethy~ -(l-meth carbonyl-2-methyl-l-propenyl)azetidin-2-one~

1~ 1 " ~ i S ~ OCO PNB
Br J ~ ~ S

COOCH3 -N ~

Starting from 2.5 g of the compound prepared in Example 67 and operating as in Example 68, but using 1,2,3-triazol-5-thiol sodium salt, 2.2 g of the title compound were obtained.

EXAMPI.E 70: 4~-[1-(5-Methyl-1,3,4-thiadiazol-2-yl)]-thio-acetylthio-3~ p-nitrobenzyloxycarbonyloxvethyl)-l-methoxy oxaloyl-azetidin-2-one.
Ç02PNB N~N OC02PNB N ~ N
` ~ ~ ~ S~~s ~ S ~ CH3 0)/ '~ ', ~ 0)/`~~ ~

2 g of the compound prepared in Example 68 were dissolved in 250 ml of dlchloromethane and cooled at -78C. A flow o ozonized oxygen was bubbled through the solution until a blue color results. A few drops of P(OCH3)3 were added to the solution and the temperature of the mixture was raised to room temperature. The mixture was evaporated to give l.S g of the title compound.

EXAMPLE 71- 4~-[1-(1,2,3-Triazol-5-yl)]-thioacetylthio-. . .
3~-(1-p-nitrobe~yl-oxycarbon~loxyethYl)-l- methoxaloya]~ n-~

-one. Reaction (12) - (13) ;.1' y' 1~5~0~ 0 2 S 5 1 N N ~C0 PNB 5 U ~ ~ 5 N~

3 ~ ~ - 0 Starting from 1.6 g of the compound prepared in Example 69, and operating as in Example 70, 1.1 g of the title compound were obtained.

EXAMPLE 72: _4~-[1-(5-Methyl-1-,3,4-thiadiazol-~yl)]-thio-acetylthio-3~-(1-p-nitrobenzylox~carbonyloxyethyl)-azetidin-2-one. Reaction ~13) - (14).
JC02PNB~S 9~ OC02PNB
CH3 ~ ~ ~ 5 CH3 1.5 g of the compound prepared in Example 70~were dissolved in 1 l:l mixture of methanol and ethyl aceta-te. A few grams of silica gel were added and the mixture maintained at room temperature under vigorous stirring. After filtering the silica gel, the iltrate was evaporated to give an oil which was chromatographed on silica gel with dichloromethane:ethyl acetate (3:2), giving 0~9 g oE pure titl~ compound.

EXAMPLE 73: ~-[1-(1,2,3-Triazol-5-yl)]-thioacetylthio-3a-., . .. . . _ . _ ... . _ . . _ (l-p-nit:robenzyl-oxycarbonyloxyethyl)-azetidin-2-one. Reaction (13) - (14).

llS~O ~0 J~ H OCO PNH S ~ ll ~ O ,~ ~\ S N Y

Start.ing from 1.1 g of the compound prepared in Example 71 and operating as in Example 72, 0.6 g of the title compound were obtained.

EXAMPLE 74: 4~-[.l-(5-Methyl-1,3,4-thiadiazol-2-yl)]-thio-~1-ace_onyloxycarbonyl-1-hydroxymethyl)-azetidin-2-one.
Ro cti~ ~lQ) - ~15). ~ ~ 5 ~ 5 ~CH3 \ H N ~ OH

0.9 g of the compound prepared in Example 72 were dissolved in 40 m]. of benzene; 0.6 g of acetonyl glyoxylate were add-ed a~nd the resulting solution was refluxed for 3 hrs. Afterevaporation of the solvent, the crude oil was used for the next step without further purification.

EXAMPLE 75: 4~ (1,2~3-Tria7.ol-5-yl)_]-thioace-tylthio~3~--p-nitrobenzyl-oxycarbonyloxyethyl)-l-(].-acetonyloxycarbon din-2-one. Reaction (14) - (15).

OC02PNB I ~ N OC02PNB r ¦l ~ ~ S ~ 5 ~ N ,N ~ ~ S ~ S ~ N~ N

5~ _ ~ C ~ . r.

llS~ V
1 Starting from 0.6 g of the compound prepared in Example 73 and operating as shown in Example 74, 0.7 g of the title compound were obtained.

EXAMPLE 76: 4~-[1-~5-Methyl-1,3,4-thiadiazol-2-y~l)]-thio~
acetylthio-3~ p-nitrobenzyloxycarbonyloxyethyl)-1-~1-acetonylo-xycarbonyl-l-chloromethyl)-azetidin-2-one~
Reaction (lS) - (16). S
~`1 i SlfS~5 ~ t i ~

OH ~ Cl The crude oil obtained in Example 74 was dissolved in anhydrous tetrahydrofuran ~30 ml) and cooled at 0C.
Equimolar amounts of pyridine and thionyl chloride were added to the solution until there was a disappearance of the startin~ material. After filtration of the insoluble material, the filtrate was used immediately for the next step.

EXAMPLE 77:' 4'~-[1-(:1,'2,3-Triazol-5-yl).]-thioacetylthio-. . .
3a-(l~p-n.itrobenæyl-oxycarbonyloxyethyl?-1-(1-acetonyl-. .
oxyc r'b'o'n~l-'l-'chloromethyl)-azetidin-2-one. ~eaction (15~ - (16), N

2 S ~ ~ ~
0CO~N ~ ,N

COOCH2COCH3 ~--- .'5~ -~ , .
-.

llS4(3~0 1 ~tarting from 0.7 g of the compound prepared in Example 75 and operating as described in Example 74, the crude chloro-derivative was obtained. The product was used for the next step without further purification.

EXAMPLE 78_ 4~-'.[1 ~5-Methyl-1,3,4-thiadiazol-2~yl)~-thio-acetylthio-3a-(l-p-nitrobenz ethyl)-l-(l-acetonyloxycarbonyl~ tri~henylphosphoranyl-idenemethyl)-. aze-tidin-2-one. Reaction tl6) - (11). N - N

10 ~ S--~S)~S ~:H3 ~ 5~5 J~ S ~CU

Cl 1~, Crude product obtained in Example 76 was dissolved in 20 ml of tetrahydrofuran; 700 mg of triphenylphosphine and 0.35 ml of pyridine were added and the resulting solution was warmed under nitrogen at 70C for a few hours. The title phosphorane w~s purified on silica gel by eluting with dichloromethane:ethyl acetate (~ . There was obtained 0.6 g of the title compound.

EXAMPLE 7g: 4'~ ~ 2~3-~Triazol-5-yl~J-thioacetylthio~3a _ . . .. ..
l-p-ni'tro~enz'y'l-'oxy ~ -acetonyl-....
oxycarbonylo~yethyl~l~triphenyl~hosphoranylidenemethyl)-.. ....
azetidin-2-one. Reaction (.16 ~ .

11~401~

S ~5J N~l ,INI
OOH2COCH3 o Starting from the crude chloroderivative obtained in Example 77 and operating as illustrated in Example 78, 0.55 g of the title compound were obtained.

EXAMPLE 80: (5R)-Acetonyl-2-[(5-methy~ 3~4-thiadiazol-2 yl)-thiom thyl]-6a--(1-p-nitrobenzyloxycarbonyloxyethyl)-2-penem-3-carboxylate. Reaction (11) - (1).

S ~ 5~ S ~ C1~3 S ~ 5 ~C~
N~PPh3 _~C2~

COOCH2COC~I3 0 H2COCH3 0.6 g of the compound prepared in Example 78 were dissolved in 50 m:l of toluene and refluxed under nitrogen for three hour~. The title compound was purified by short column chromatography on silica gel eluting with dichloromethane:
ethyl acetate (8:2). There was obtained 0.25 g of the title compound. I.R. : 1795, 1750, 1720.

E ~PLE 81: (5~)-Acetonyl-2-~(1,2,3-triazol-5-yl)-thiomethyl]-6~ p-nitrobenzyloxycarbonyloxyethyl)-2-penem-3-carboxylate.
Reaction (111 - (1).

~,~ 54q)1V
N

OCO2PNs ~ S 1 N -COOCH2COCH3 ''' ~ - ~

Starting from 0.45 g of the compound prepared in Example 79 and operating as shown in Example 80, 0.180 g of the title compound were obtained. I.R.: 1795, 1750, 1720.

EXAMP1E 82: (5R)-Acetonyl-2-[(5-methyl-1!3,4-thiadiazol-2-yl)-thiomethyl]-6~ h~drox~eth~1)-2-penem-3-carbox~late.
Reaction (1).
OCO PNB ~ ~ T¦ ¦~
J ~ 5 ~ 5 5 l~ OH ~ 1 0.450 g of the compound prepared in Example 80 were dissolved in 25 ml o e acetonitrile containinCJ a few clrops of ethanol and hydrogenated over 10~ Pd on earbon (400 mg).
The eatalyst was removed by filtration and the filtrate was chromatc~graphed on silica gel eluting with dichloro-me-~ane:e~hyl acetate (7:3), cJiving 0.18 g of the title compound.
I.R. : 3605, 1795, 1745, 1720.

EX~MPLE 83: (5R)-Acetonyl-2-[(1,2l3-triazol-5-yl)-thiometh Reaction (1).

l~S~()iV

Starting from 0.380 g of the compound prepared in Example 81 and operatiny as in Example 82, 0.12 g of the title compound were obtained.
~.R. : 3610, 1795, 1750, 1720.

EXAMPLE 84: (5R)-2[(5-Meth~1,3,4-thiadiazol-2-yl)-thio-_ .
methyl]-6~ -hydroxymethyl)-2-penem-3-carboxylic acid.
Rèaction (]). N N N -~ 5 ~ H3 l~rN~ 5 )~ 5 133 A solution of 0.200 g of the compound prepared in Example 82 in acetonitrile (30 ml) conta~ning a ew drops of water was cooled at 0C; 5 ml of 0.1 N NaOM solution were added under nitrogen and the solution was stirred for 10 minutes. The alkaline mixture was extracted twice with methylene chloride, acidified with a 10% citric acid aqueous solution, and extracted again twice with methylene chloride. The combined organic phases were dried over 3~ Na2SO4 and evaporated giving 0.110 g of the title compound.
I.R. : 3500, 1795, 1665.

.

~.A

1 EXAMPLE 85: (5R)-2-[(1,2,3-Triaz ~ -thiomethyl]-6~-(l-hydroxyethyl)-2-penem-3-c-arboxylic acid. Reaction (1).

OH S ~ ~N'N - ~OH 6 A S ~
f ~ H
1 2 CH3 ~ N COOH

Starting from 0.25 g of the compound prepared in Example 83 and operating as shown in Example 84, 0.135 g of the title compound were obtained.
I.R. : 3490, 1795, 1660.

EXAMPLE 86: 4~-(1-Carbamoyloxymethyl) vinylthio-3~-(1-p-nitrobenzyloxy-carbonyloxyethyl)-l-(l-methoxycarbonyl-2-methyl-l-plop-enyl)-azetidin-Z-one-S-oxide. Reaction (4) -, Oc02PNB ¦¦
~ ~;-\ /`\ OH OC02PNB ll O ~ OCONH2 COOC~13 o ~ ~r COOCEl3 2.2 g of the compound prepared in Example 66 were dissolved in 30 ml of acctonitrile and cooled at 0C. Then 0.8 ml of chlorosulphonyl isocyanate were added under nitrogen and the mixture was stirred for 2 hours~ The reaction mixture was poured into a saturated NaHC03 solution, stirred for a few minutes, and then extraced with ethyl acetate. After drying over Na2S04, evaporation of the solvent gave 1.5 g of the title compound.

~ 60 -.

OiO

1 EX~MPLE 87: 4~ Carbamoyloxymethyl)-vinylthio-3~ p-nitrobenzyloxy-carbon~oxyethyl-l-(l-methoxycarbonyl-2-methyl-l-propenyl)-azetidin-2-one. Reaction (4) - (12).
2 N iI

COO~ OCONB2 Starting from 1.7 g of the compound prepared in Example 86 and operating as in Example 67, 1.4 g of the title compound were obtained.

EXAMPLE 88: ~-(l-Carb- oyloxy)acetylthio-3~-(l-p-nitrobenzyloxy-carbonylox~thyl)-l-methoxyoxaloyl-azetidin-2-one. Reaction tl2) - (13).

jloco2pNB

/\OCONH2 0C02PNB
---~L ` - ~

Starting Erom 2.2 g oE the compound pr~pared in Example 87 and operatin~ as illustrated in Example 70, 1.4 ~ oE
the title compound were obtained.

EXAMPLE 89: 4~-(l-Carbamoyloxy)-acetylthio-3~-(1-p-nitroben~loxy-ca~rbonyloxye~yl)-azetidin-2-one.
Reaction (13) - (14).

~1~4010 1~ S~\ OCONH2 I OCo PNs J v--N ~ ~1 2 ~ S ~ OCONH2 OOCH3 f ~ \ H

Starting from 1.4 g of the compound prepared in Example 88 and operating as shown in Example 72, 0.9 g of the title compound were obtained.

EXA~5P~E 90: a~ Carbamoyloxy)-acetylthio-3~ p-nitrobenzyloxy-car ~ ~y~ (l-acetonyloxycarbonyl-' l-hydroxymethyl)-azetidin-2-one. Reaction (14) - ~15).

S ~ OCONH2 1~ ~ S ~ OCONH2 _ N \ O) ~ ~

Starting from 0.9 g of the compound prepared in Example 89 and 0.6 g o~ acetonyl glyoxylate and operating as in Example 74, the crude carbinolamide was obtained.

EXP~5PI,E 91: 4~-(1-Carbamoyloxy)-acetylthio-3(~ p-nit'robenzylo'xy'-carbonyloxyethyl)-~ acetonyloxycarbonyl- -l-chloromethyl)-azetidin-2-one. Reaction (15) - (16).

_ f S ~ ~ \ OCONH2OCO~ ~ ~ S ~ ~ ~ OCONH2 - ~ ~ Cl OoCH2cocH3 ~.................. j ,. .

.

-11~4010 1 Starting from the crude product obtained in Example 90 and operating as in Example 76, the crude chloroderivative was obtained.

EX~1PLE 92: 4~ -carbamoyloxy)-acetylthio-3~-(l-p-nitrob~ loxy-carbonyloxye~hyl)-l-(l-acetonyloxy-carbonyl-l-triphenyl-phosphor-nylidenemethyl-l)-azetidin one. Reaction (16) - (ll).

~C0 PNB 5 OC0 PNB
~~ ~ ~ OCONH2 J 2 5 ~ CONH2 ~ N PPh Starting from the crude product obtained in Example 91 and operating as in Example 78, 0.40 g of the phosphorane were obtained.

EXAMPLE 93: _ (5R)-Aceton~1-2-carbamoyloxymethyl-6~( nitrobenzyloxy~-carbonyloxyethyl)-2-penem-3-carboxylate.
Reaction (ll)-(l).

~ S~OCONH2 J~ ~ OCONH2 PPh3 0~/ N

Coacll2cocH3 C12COCH3 Starting from 0.4 g of the compound prepared in Example 92 and operating as in Example 80, 0.11 g of the title compound were obtained.

,~ , .

- llS4V10 EXAMPLE 94: t5R)-A tonyl-?-carbamoyloxymeth~1-6~-~1-hydroxy-ethyl)-2-penem-3-carboxylate. Reaction (1).

~ ~ 2 ~ ~ OCONEI2 O COOCH2COCH3 ~

Starting from 0.35 g of the compound prepared in Example 93 and operating as in Example 82, 0.11 g of the title compound were obtained.

EXAMPLE 95: (5R)-2(Carbamoylox~Ymethyl)-6~ -hydroxyethyl) 2-penem-3-carboxylic acid. Reaction (1).

\ OCONE12 ~ r~ ~ COEIE12 O CoocH2cocH3 COOH
' Starting from 0.11 g of the compound prepared in Example 94 and operating as in Example 84, 0.060 g of the title compound were obtained.

I. R. : 3400-3500, 1795, 1700-1650.

_a) 4~-Acet~y]qlyc-ol-ylth-lo--3~-[l-p-nitrobenzyloxycarbon~y~-oxymeth~]-l-[l-acetonyloxycarbonyl-l-hydroxymethyl]-aze-tidin-2-one. Reaction ~14) - (15).

-. ':.'' ' '' ~ ' ' 1~S4V~O

OCO ~ OCOC~3 A solution of 1.04 g of 4~-acetylglycolylthio-3~-[1-p-nitro-benzyloxycarbonyloxyethyl]-azetidin-2-one, prepared according to Example 46, and 1.8 g of acetonyl glyox~late in 20 ml of benzene was refluxed for 4 hours. Evaporation of the solvent gave the crude title compound which was used for the next step without further purification.
(b) 4~Acetyl~lycolylthio-3~-[1-p-nitrobenzyloxycarbonyl-oxyethyl -l-[l-acetonyloxycarbonyl-l-chloromethyl]-azetidin-_one. Reaction (15) - (16).

OCOCH3 ~ ~ tl COOC~I2COCH3 COOCH COCH
The crude carbinolamide obtained from the ste2p (a)3was dissolved in 20 ml of anhydrous tetrahydrofuran and cooled at 0C. Equimolar amoun~s of pyridine and thionyl chloride were added until all starting material disappeared. The precipitate was filtered, evaporation of the filtrate gave the crude title compound which was used for the next step without further purification.

~ :~7..P'~

1~54010 (C) 413-AcetylqJy(~n~,,lth~ p-nitrobenzyloxycarbonY
oxyethyl]-l-[acetonyloxycarbonyl-l-triphenylphosphorany-lidene-methyl]-azetidin-2-one. Reaction (16) - (11).

~ S C2PNB
J 1 ~1` ococ~l ~ ,, ocoCH3 r--N~
COOCHzCOCH3 ~/ ~ PPh3 The crude chloroderivative was dissolved in 100 ml oE

methylene chloride; 1.5 g of triphenylphosphine and 10 g of silica gel were added and the solvent evaporated under vacuum. The solid material was left overnight at room temperature, poured into a column chromatograph and eluted with 1:1 methylene ethyl acetate, giving 1.5 g o~ the title compound.

(d) (5~)-Acetonyl-6~-[1-p ace~ methyl-2-penem-3-carboxylate. Reaction (11) - (1).

\ 2 ) - ~ ~ ~ COC~3 ~ ~ ~ OCOC~3 - ~ -PPhO ~ N ~

1.5 g oE 4~-acetylglycolylth1o-3-[l-p-nitrobenzyloxycarbon-yloxyethyl]-l-[acetonyloxycarbonyl-l-triphenylphosphorany-lidenemethyl]-azetidin-2-one were dissolved in 50 ml of , I
toluene and refluxed for three hours. Evaporation oE the solvent gave an oil which was purified by short column chromatography on silica gel eluting with (9:1) dichloro-methane-ethyl acetate. There was obtained 0.51 g of the title compound, , ..,~ :,~..

1~54010 1 Erithro PMR (CDC13): 1.46 (d, J = 6.5 Hz, 3H, CH3CH) 2.07 (s, 3H, OCOCH3) 2.16 (s, 3H, COCH3) 4.02 (dd, J = 2.0, 4.0 Hz, lH, H-6) 4.73 (s, 2H, CH2CO) 5.0 - 5.3 (m, lH, _O) 5.12, 5.38 (dd, J = 15.5 Hz, 2H, CH2OCO) 5.22 (s, 2H, COCH2Ph) 7.4 - 8.5 (m, 4H, PhNO2) IR (CHC13) 1725 cm 1 C=O unsaturated esters, ketones 1750 cm 1 C=O esters 1800 cm 1 C=O ~-lactam Threo ___ PMR (CDC13): 1.45 (d, J = 6.0 Hz, 3H, CH3CH) 2.08 (s, 3H, OCOCH3) 2.19 (s, 3H, COCH3) 3.96 (dd, J = 2.0, 7.0 Hz, lH, H-6) 4.i7 (s, 2H, CH2CO) 5.0 - 5.4 ~m, lH, CHO) 5.13, 5.42 (d, J -- 16.0 Hz, CH2OCO) 5.25 ~s, 2H, CH2Ph) 5.66 (d, J = 2.0 Hz, lH, H-5) 7.4 - 8.5 (m, 4H, PhNO2) IR (CHC13~
1725 cm 1 C=O unsaturated esters, ketones 1750 cm 1 C=O esters 1800 cm 1 C=O ~-lactam 1 EXAMPLE 97: (5R)-Aceto~yl-6N-[l~hydroxyethyl]-2-acetoxymethyl -2-penem-3-carboxylate. Reaction (1).
S ~OH S
I l ~ r~ ~

/,- - N~ N _~
r COOCH2COCH3 //

0.51 g of (SR)-acetonyl-6~-[1-p-nitrobenzyloxycarbonyloxy-ethyl]-2-acetoxymethyl-2-penem-3-carboxylate prepared accord-ing to Example 96 were dissolved in 60 ml of a (1:1) acetonitrile: (95%) ethanol mixture. 0.46g of 10% Pd/C
were added and the mixture was stirred under a hydrogen atmosphere ~or one hour. After filtering the catalyst, the filtrate was evaporated and the title compound purified by silica gel column chromatography eluting with (8:2) dichloromethane-ethyl acetate, giving 0.20 g of pure product.
Erithro . _ PMR (CDC13): 1.38 (d, J=6.5 Hz, 3H, CH3CM) 2.09 (5, 3H,OCOCH~) 2.20 (s, 3H,COCH3) 3.86 (dd, J=2.0, 4.0 Hz, lH, H-6) 4.22 (~d~, J=6.5, ~.0 IIz, lH, CEIOI~) 4~72 ~5, 2H, CH2CO) 5.12, 5.42 (d, J=15.5 Hz, 2H, CH20CO) 5.58 (d, J=2.0 Hz, lH, H-5) Threo __ PMR (CDC13): 1.32 (d, J=6.5 Hz, 3H, CH3CH) 2.10 (s, 3H, OCOCH3) 2.20 ~s, 3H, COCH3) ~/

1 '3.06 ~bs, lH, OH) 3.74 (dd, J=2.0, 7.0 Hz, lH, H-6) 4.23 (m, lH, CHOH) 4.77 (s, 2H, CH2CO~
5.12, 5~38 (d, J-16.0 Hz~ 2H, 'CH OCO) 5.63 (d, J=2.0 Hz, lH, H-5) EXAMPLE 98 '(5R)'-2-Acetoxymethyl-6-'(1-hydroxyethyl~-2-penem-3 carb'oxylate sodium salt. Reaction (1) OH OH
/ ~ S ~ ~ OCOCH3 ~ ~ COCH3 Ir ~ ~ ¦ N
O ~ CoocH2cocH3 ~ COONa 0.21 g of C5R)-acetonyl-6-ll-hydroxyethyl]-2-acetoxymethyl-2-penem-3-carboxylate prepared according to Example 97 were dissolved in 20 ml of acetonitrile and 3 ml of water.
The reaction mixture was cooled at 0C under nitrogen and 7.4 ml of a 0.lN NaOEI aqueous solution were added slowly within 30 minutes. ~fter evaporating acetonitrile under vacuum, the residue was extracted twice with cold ethyl acetate. A C18 reverse ph~se chromatography (elutiny Wlth water) of the concentrated aqueous phase gave O . 054 g of pure title compound.
''Eri't'hro PMR (D20) 80mKz: 1.34 ~d, J=6.3 Hz, 3H, CH3CH) 2.14 (s, 3H, OCOCH3) 4.01 (m, lH, H-6) 115~010 1 - 4.22 ~m, lH, CHOIIl 5.10, 5.44 (d, J=14.0 Hz, 21-1, CH20CO) 5~63 ~d, J=1.0 Hz, lH, H-5) U.V. (ethanol 95%): ~ max 262 nm(s 2000), 308 nm ( 2520) ~]D--128 (C=0.92, H20) Threo PMR (D2O): 1.31(d, J=6.5 Hz, 3H, CH3. CH) 2.19 (s, 3H, OCOCH3) 3.92 (dd, J=1.5, 7.0 Hz, lH, H-6) 4.21 (m, lH, CHOH) 5.10, 5.44 (d, J=14.0 Hz, 2H, CH2OCO) 5.67 (d, J=1.5 Hz, lH, H-5) U.V. (ethanol 95%); ~ max 262 nm( 3410), 308 nm(~ 4340) EX~lPLE 99 - 5R-pivaloyloxymethyl-6(S~¦_l(R)hydroxyethyl ]
-2-carbamoyloxy-methyl-2-penem-3-carboxylate.

.. . .... . ... . . ... . .... ... ... .
OH OH
/~ ~\OCONH2 ~ S

M ~ COOH ~N ~ OCO~lH2 COOC~20CO+

775 mg of 5~-6(S~ )hydroxyethyl ~ -2-carbamoyloxymethyl-2-penem-3-carboxylic ac.id (as preparecl in example 95), di.ssolvecl in 15 ml of di.methylformamide were treated wi-th an equimolar amount of Na~, 50 mg of dimethylaminopyridine and 1.15 ml of pivaloyloxymethylchloride at 40C for 4 hours. The reaction mixture was diluted with ethyl acetate, washed with ~ater, dxied over Wa2SO4 and the solvent evaporated. The residue consisted of 480 mg of pure title compound, ~154~

U.V. (EtOH 95%~: max 325 (~: 7000) I.P~. (CIIC13~: 3540, 3420, 1795, 1750 P.M.~. ~200 ME~z, CDC13):
1.21 (s, 9H, (CH3~3) 1.33 (d, J=6, 3Hz, 3H, CHCH3) 3.75(dd, J=1.5, 6.4Hz, lH, H-6) 4.23(m, lH, CHOH) 4.76 (bs, 2H, CONH2) 5.08, 5.42 (two d, J~15.8Hz, CH2OCONH
5.62~d,J=1.5E~z, lH, H-5) 5.81, 5.91(two d, J=5.5Hz, OCH2OCOC(CH3~3) , I

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound of the general formula (I) (I) wherein R is a hydrogen atom, lower alkyl, 2,2,2-trichloro-ethyl, acetonyl, benzyl, p, nitrobenzyl, p-methoxybenzyl, phenyl, p-nitrophenyl, benzhydryl, acetoxymethyl, pivaloy-loxymethyl, phtalidyl, and -CH2-NHCOR4 , wherein R4 is alkyl having from 1 to 5 carbon atoms, cycloalkyl or aryl, R1 is a hydrogen atom, lower alkyl, lower alkoxy, cycloalkyl or hydroxyalkyl, the alcoholic function of the hydroxyalkyl being free or protected;
Z represents hydrogen or halogen atom, hydroxy, amino, carbamoyloxy, mercapto, pyridinium, or a group of the formula OR2, OCOR2, NHCOR2, and SR3 wherein each of R2 and R3 represents lower alkyl, aryl or a heterocyclic ring, each of which may be substitued or unsubstituted; n is O
or 1; said process comprising (a) reacting a compound of the formula (II) (II) Claim 1 continued wherein R5 represents an alkyl group and R1 is as defined above, with an acetylenic derivative of the formula X C?CY
wherein X is a group of formula CH2Z' wherein Z' is a halogen or hydrogen atom, a hydroxy, amino, carbamoyloxy or a group of the formula OR2, OCOR2, NHCOR2 where R2 is lower alkyl, aryl, or a heterocyclic ring and Y represents a hydrogen atom, lower alkyl, cyano or a group of the formula COOR5 or CH2Z' wherein R is lower alkyl and Z' is as described above, at a temperature from about 50°C to about 120°C in an inert solvent selected from the group consist-ing of benzene, toluene;
(b) isomerizing the resultant compound of the formula (III) (III) wherein R1 , R5, X and Y are as defined above in dichlo-romethane, in the presence of triethylamine at room temperature, (c)(i) reducing the resultant compound of the formula (IV) (IV) wherein R1, X , Y and R are as above defined with PBr3 in dimethylformamide at a temperature of from about -40°C to about 0°C, or Claim 1 continued (c) (ii)if Z'is OH, reacting the resultant bromoderivative with R3-S-Na wherein R3 is as above defined in tetrahydro-furan or acetonitrile at a temperature of 0°C, or treating said compound of the formula (IV) as defined above and Z' is OH, with chlorosulphonyl isocyanate in acetonitrile or with trichloroacetyl isocyanate in acetone at a temper-ature of 0°C and then reducing with PBr3 in dimethylformam-ide, the resultant carbamoyl derivative, to give a compound of formula (IVa) (IVa) wherein R1, R5 and Y are as above defined, and X is a group of formula CH2Z wherein Z has the meanings above defined, (d) ozonizing at a temperature of from about -20°C to about -78°C in a solvent selected from the group consisting of dichloromethane, ethylacetate and tetrahydrofuran, said compound of formula (IVa) (e) solvolysing the resultant compound in the presence of silica gel in methanol, ethyl acetate or a mixture thereof, at room temperature, (f) condensing the resultant compound of formula (XIV) (XIV) wherein X and R1 are as defined above, with a compound of formula CHOCOOR, wherein R is as above defined, at a temperature of from about 40°C to about 100°C in benzene or toluene, Claim 1 continued (g) chlorinating the resultant compound of formula (XV) (XV) wherein R, R1 and X are as above defined with thionyl chloride in presence of pyridine at a temperature of from about -20°C to about 20°C, (h) condensing the resultant compound of formula (XVI) (XVI) wherein X, R and R1 are as defined above, with triphenyl-phosphine at a temperature of from about 40°C to about 80°C in the presence of pyridine or 2,6 lutidine to give a compound of formula (XI) (XI) wherein R, R1 and X are as defined above, (i) cyclising the compound of the formula (XI) by heating at a temperature of from about 30°C to about 140°C in toluene or benzene, and, (j) if desired, oxidizing the resultant compound of formula (1) with an organic peracid in dichloromethane at room temperature, to give a compound of general formula (1)

Claim 1 continued as defined above, wherein n is 1, deprotecting when neces-sary the resultant compound of formula (1) by an appropriate method selected from the group consisting of hydrolysis with NaOH and hydrogenolysis in the presence of Pd/C 10% to give a compound of formula (I) wherein R is a hydrogen atom and R1 is a hydroxyalkyl group.

2. A process for preparing a compound of general formula (I) as defined in claim 1, said process comprising (a) reacting a compound of the formula (II) (II) wherein R5 represents an alkyl group and R1 is as defined above, with an acetylenic derivative of the formula XC?CY
wherein X is a group of formula CH2Z' wherein Z' is a hal-ogen or hydrogen atom, a hydroxy, amino, carbamoyloxy or a group of the formula OR2, OCOR2, NHCOR2 where R2 is lower alkyl, aryl, or a heterocyclic ring and Y represents a hydrogen atom, lower alkyl, cyano or a group of the formula COOR5 or CH2Z' wherein R5is lower alkyl and Z' is as described above at a temperature from about 50°C to about 120°C in an inert solvent selected from the group consisting of benzene, toluene (b) isomerizing the resultant compound of the formula (III) (III) Claim 2 continued wherein R1, R5, X and Y are as defined above in dichloro-methane, in the presence of triethylamine at room temperat-ure, (c) selectively ozonizing the resultant compound of formula (IV) (IV) wherein R1, X', Y and R5 are as defined at a temperature of from about -20°C to about -72°C in a solvent selected from the group consisting of dichloromethane, ethylacetate and tetrahydrofuran, to give a compound of formula (V) (V) whexein n is 1 and X, Y, R1 and R5 are as above defined (d) reducing said resultant compound to a compound of formula (V) wherein n?0 by means of PBr3 in dimethylform-amide at a temperature of from about -40°C to about 0°C
(e) solvolyzing the resultant compound in the presence of silica gel in methanol, ethylacetate or a mixture there-of at room temperature, (f) condensinq the resulant compound of the formula (VI) (VI)
Claim 2 continued wherein n=O, X, Y, R1 are as defined above, with a compound of formula CHOCOOR, wherein R is as above defined, at a temperature of from about 40°C to about 100°C in benzene or toluene, (g) chlorinating the resultant compound of formula (VII) (VII) wherein n=O, R, R1 Y, X are as above defined, with thionyl chloride in presence of pyridine at a temperature of from -20°C to 20°C
(h) condensing the resultant compound of the formula (VIII) (VIII) wherein n is O, X, Y, R and R1 are as defined above, with triphenylphosphine at a temperature of from about 40°C to about 80°C in presence of pyridine or 2,6 lutidine, (i) ozonizing the resulting compound of the formula (IX) (IX) whexein n=O, R, R1, Y and X are as defined above, at a temperature of from about -20°C to about -78°C in a solvent selected from the group consisting of dichloro-methane, ethylacetate or tetrahydrofuran, (j) cyclising the resultant compound of formula (XI) (XI) wherein R, R1 and X are as defined above, by heating at a temperature of from about 30°C to about 140°C in toluene or benzene, and, (k) if desired, oxidizing the resultant com-pound of general formula (I) with an organic peracid in dichloromethane at room temperature to give a compound of the formula (1) as defined above, wherein n is 1; deprotect-ing, when necessary, the resultant compound of formula (I) by an appropriate method selected from the group consisting of hydrolysis with NaOH and hydrogenolysis in presence of Pd/C 10%, to give a compound of the formula (I) wherein R
is hydrogen and R1 is hydroxyalkyl group.

3. A process for prepariny a compound of formula (I) as defined in claim 1, said process comprising (a) reacting a compound of the formula:

(II) Claim 3 continued wherein R represents an alkyl group and R is as defined in claim 1, with an acetylenic derivative of the formula XC ?CY wherein X is a group of formula CH2Z' wherein Z' is a halogen or hydrogen atom, hydroxy, amino, carbamoyloxy or a group of the formula OR2, OCOR2, NHCOR2, where R2 is lower alkyl, aryl, or a heterocyclic ring and Y represents a hydrogen atom, lower alkyl, cyano, or a group of the formula COOR or CH2Z' wherein R is lower alkyl and Z' is as described above at a temperature from 50 to 120°C in an inert solvent selected from the group consisting of benzene, toluene;
(b) isomerizing the resultant compound of formula (III) (III) wherein R1, R5, X and Y are as defined above in dichloro-methane, in the presence of triethylamine at room temperature, (c) selectively ozonizing the resultant compound of general formula (IV) (IV) wherein R1 , X , Y and R5 are as above defined at a temperature of from about -20°C to about -78°C in a solvent selected from the group consisting of dichloromethane, ethylacetate and tetrahydrofuran;

Claim 3 continued (d) solvolyzing the resultant compound of formula (V) (V) wherein n is 1 and X, Y, R1 and R5 are as above defined, in the presence of silica gel in methanol, ethylacetate or a mixture thereof at room temperature, (e) condensing the resultant compound of formula (VI) (VI) wherein n=1, X, Y, R1 are as defined above, with a compound of formula CHOCOOR, wherein R is as above defined at a temperature of from about 40°C to about 100°C in benzene or toluene, (f) chlorinating the resultant compound of formula (VII) (VII) wherein n=1, R, R1, Y, X are as above defined, with thionyl chloride in presence of pyridine at a temperature of from -20°C to 20°C, (g) condensing the resultant compound of formula (VIII) (VIII) wherein n is 1, X, Y, R and R1 are as defined above, with triphenylphosphine at a temperature of from about 40°C to about 80° in the presence of pyridine or 2,6 lutidine (h) reducing the resultant compound of formula (IX) (IX) wherein n=1, R, R1, Y and X are as defined above, with PBr3 in dimethylformamide at a temperature of from about -40°C to about 0°C
(i) ozonizing the resultant compound of formula (IX) wherein n=O at a temperature of from about -20°C to about -78°C in a solvent selected from the group consisting of dichloromethane, ethylacetate or a mixture thereof, (j) cyclizing the resultant compound of formula (XI) (XI)
Claim 3 continued wherein R, R1 and X are as defined above, by heating at a temperature of from 30°C to 140° in toluene or benzene, and, (h) if desired, oxidizing the resultant compound of formula (I) with an organic peracid in dichloromethane at room temperature to give compound of formula (I) as defined above, wherein n is 1, deprotecting, when necessary, the resultant compound of formula (I) by an appropriate method selected from the group consisting of hydrolysis with NaOH
and hydrogenolysis in presence of Pd/C 10%, to give compound of formula (I) wherein R is hydrogen atom and R1 is hydroxyalkyl group.
4. A process as claimed in claim 1, 2 or 3 in which said heterocyclic ring is selected from the group consist-ing of 5-methyl-1, 3,4-thiadiazol-2-yl; l-methyl-tetrazol-5-yl; 1,2,3-triazol-5-yl and pyrazinyl.
5. A process as claimed in claim 1, 2 or 3 in which R1 is selected from the group consisting of methyl, ethyl, methoxy, l-hydroxy-ethyl, l-(p-nitrobenzyloxycarbonyloxy) -ethyl and l-(dimethyl-t-butyl-silyloxy)-ethyl.
6. A compound of the general formula (I) as defined in claim 1 whenever prepared by a process as claimed in claim 1 or an obvious chemical equivalent thereof.
7. A compound of the general formula (I) as defined in claim 1 whenever prepared by a process as claimed in claim 2 or an obvious chemical equivalent thereof.
8. A compound of the general formula (I) as defined in claim 1 whenever prepared by a process as claimed in claim 3 or an obvious chemical equivalent thereof.

CLAIMS SUPPORTED BY SUPPLEMENTARY DISCLOSURE
9. A process as claimed in claim 1 for preparing (5R)-2[(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyll-6.alpha.
(1-hydroxyethyl)-2-penem-3-carboxylic acid which comprises (a) reacting methyl-6-(1-p-nitro benzyloxycarbonyl-oxy-ethyl)-3-penicillinate-S-oxide with propargyl alcohol in toluene;
(b) isomerizing the resultant compound;
(c) reducing the resultant compound;
(d) reacting the resultant compound with 5-methyl-1,3,4-thiadiazol-2-thiolsodium salt;
(e) ozonizing the resultant compound in dichloromethane;
(f) solvolyzing the resultant compound in presence of silica gel;
(g) condensing the resultant compound with acetonyl glyoxylate in benzene;
(h) chlorinating the resultant compound;
(i) condensIng the resultant compound with triphenyl-phosphine;
(j) cyclizing the resultant compound in the presence of toluene;
(k) hydrogenating the resultant compound; and (l) hydrolyzing the resultant compound.
10. (5R)-2[(5-Methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-6.alpha.-(1-hydroxyethyl)-2-penem-3-carboxylic acid whenever prepared hy a process as claimed in claim 9 or an obvious chemical equivalent thereof.
11. A process as claimed in claim 1 for preparing (5R)-2[(1,2,3-triazol-5-yl)-thiomethyl-6.alpha.-(hydroxyethyl)-2-penem-3 carboxylic acid which comprises (a) reacting methyl-6-(1-p-nitrobenzyloxycarbonyl-oxyethyl)-3-penicillinate-S-oxide with propargyl alcohol in toluene;
(b) isomerizing the resultant compound;
(c) reducing the resultant compound;
(d) reacting the resultant compound with 1,2,3-triazol-5-thiol sodium salt;
(e) ozonizing the resultant compound in dichloromethane;
(f) solvolyzing the resultant compound in the presence of silica gel (g) condensing the resultant compound with acetonyl gly-oxylate in benzene;
(h) chlorinating the resultant compound;
(i) condensing the resultant compound with triphenyl-phosphine (j) cyclizing the resultant compound in the presence of toluene;
(k) hydrogenating the resultant compound; and (l) hydrolyzing the resultant compound.
12. 5(R)-2[(1,2,3-Triazol-5-yl)-thiomethyl-6.alpha.-(1-hydroxyethyl)-2-penem-3-carboxylic acid whenever prepared by a process as claimed in claim 11 or an obvious chemical equivalent thereof.
13. A process as claimed in claim l for preparing (5R)-2-(carbamoyloxyethyl)-6.alpha.-(hydroxyethyl)-2-penem-3-carboxylic acid which comprises:
(a) reacting methyl-6-(1-p-nitrobenzyloxycarbamoyl-oxyethyl) -3-penicillinate-S-oxide with propargyl alcohol in toluene;
(b) isomerizing the resultant compound;
(c) reacting the resultant compound with chlorosulphnyl isocyanate in acetonitrile;
(d) reducing the resultant compound; .
(e) ozonizing the resultant compound with dichloromethane;
(f) solvolyzing the resultant compound in the presence of silica gel;
(g) condensing the resultant compound with acetonyl glyoxylate in benzene;
(h) chlorinating the resultant compound;
(i) condensing the resultant compound with triphenyl-phosphine;
(j) cyclising the resultant compound in the presence of toluene;
(k) hydrogenating the resultant compound; and (l) hydrolysing the resultant compound.
14. (5R)-2(Carbamoyloxyethyl)-6.alpha.-(1-hydroxymethyl)-2-penem-3-carboxylic acid whenever prepared by a process as claimed in claim 13 or an obvious chemical equivalent thereof.

15. A pxocess as claimed in claim 1 for preparing (5R)-2-acetoxymethyl-6a-(hydroxyethyl-2-penem-3-carboxylate sodium salt which comprises:
Claim 15 continued (a) reacting methyl-6-[1-p-nitrobenzyloxycarbonyloxyethyl]-3-penicillinate-S-oxide with butyndiol diacetate in toluene;
(b) isomerizing the resultant compound;
(c) reducing the resultant compound;
(d) ozonizing the resultant compound in dichloromethane;
(e) solvolyzing the resultant compound in presence of silica gel;
(f) condensing the resultant compound with acetonyl glyoxylate in benzene;
(g)chlorinating the resultant compound with thionyl chloride;
(h) condensing the resultant compound with triphenyl phos-phine;
(i) cyclising the resultant compound in toluene;
(j) hydrogenolysising the resultant compound; and (k) hydrolysing the resultant compound.
16. (5R)-2-Acetoxymethyl-6.alpha.-(1-hydroxyethyl-2-penem-3-carboxylate sodium salt whenever prepared by a process as claimed in claim 15 or an obvious chemical equivalent thereof.

17. A proeess as claimed in claim 1 for preparing 5R-pivaloyloxymethyl-6(S)[1(R)hydroxyethyl]-2-carbamoyloxy-methyl-2-pernem-3-carboxylate which comprises (a) reacting methyl-6-(1-p-nitrobenzyloxycarbamoyl-oxy-ethyl)-3-penicillinate-S-oxide with propargyl alcohol in toluene;
(b) isomerizing the resultant compound;

(c) reacting the resultant compound with chlorosulphnyl isocyanate in acetonitrile;
Claim 17 continued (d) reducing the resultant compound;
(e) oxonizing the resultant compound with dichloromethane;
(f) solvolyzing the resultant compound in the presence of silica gel;
(g) condensing the resultant compound with acetonyl gly-oxylate in benzene;
(h) chlorinating the resultant compound;
(i) condensing the resultant compound with triphenyl-phosphine;
(j) cyclising the resultant compound in the presence of toluene;
(k) hydrogenating the resultant compound;
(l) hydrolysing the resultant compound; and (m) reacting the resultant compound with pivaloyloxymethyl-chloride.
18. 5-R-Pivaloyloxymethyl-6(S)[1(R)hydroxyethyl]-2-carbamoyloxymethyl-2-penem-3-carboxylate whenever prepared by a process as claimed in claim 17 or an obvious chemical equivalent thereof.