CA1212665B - PREPARATION OF .beta.-LACTAM-CONTAINING ANTIBACTERIAL AGENTS AND .beta.-LACTAMASE INHIBITORS - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
There is disclosed a process for the preparation of .beta.-lactam-containing compounds of the formula

Description

~Z:ILZ6~S

This invention relates to the preparation of ~-lactam-containing compounds.
More particularly, the present invention r~lat~s to the preparation penem-carboxylia aaids of the formula:

Rl ( )~ CH z (1) 0~' ~ COOR
wherein R iS a hydrogen atom, lower alkyl, Z,2,2-trichloroethyl, acetonyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p-nitrophenyl, or benzyhydryl, a residue known to undergo metabolic aetivation "in vivo" and having favorable pharmacokinetic pro-perties, including acetoxymethyl, pivaloyloxymethyl or phthalidyl or a sroup of the formula -CH-OCOOC2H5 or -CH2NHCOR2 in which R2 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 oR3, oCOR3~ NHCoR3, 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 hydrogen atom, lower alkyl, lower alkoxy, cycloalkyl or hydro~ya~kyl (prererably lower hydroxyalkyl), the alcoholic function of the hydroxy alkyl being free or protected, ths pro-tecting group being preferably p-nitxobenzyloxycarbonyl or dimethyl-t-butyl-silyl, and n is O or 1. The substitution of the 6 position has the a-configuration as well as the ~-configuration.
The ~-configuration is preferred.

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

LZ1~6S

1 have faborable pharmacokinetic properties, include acetoxymethyl, pivaloyloxymethyl, and phthalidyl and groups of the formulae ~CH.OCOOC2H5 and -CH2~HCOR2.

Rep~esentative values of Rl include methyl, ethyl, methoxy, l-hydroxyethyl, and l-(p-nitrobenzyloxycarbonyloxy)-ethyl.
R3 and R4, when heterocyclic, are preferably a 5- or .j . .
6- membered heterocyclic ring residue, for example 5-methyl-1,3, 4-thiadiazol-2-yl, 1-methyl-tetrazol-5-yl, 1,~,3-triazol-5-yl or pyrazinyl.
These compounds possess a wiae spectrum of antibacter-ial activity and also have B-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 pharmaceutically acceptable salts of penem-carboxylic acids o formula ~l) including sodium, potassium, benzathin, procaine, and like salts usually formed with penicill-ins and cephalosporins, are also within the scope o the inven-tion.
The ollowing diagram illustrates the preparation of the compounds o~ formula ~l) according to the invention.

,....................................... .

~2~Z66S

~Xl ~N ~ S o~N ~ y ~N 1~ Y
O ~" COOR H COORS / oO

11 ~\ 11 ~X ~ X~S ~¢ X

H . COOR ~ COOR j CooR5 (12) R~X R ;C~ ~X

~6) COO~ (13) R r~5~X ~- N~ O (14) ~7) ~ COOR ¦ ...
R1 1 1I n ~ G rf ~

1 ~8) COOR ¦ OOR (15) ~ ~¢ < (n-lt ~ ~
~10) ~?Ph3 o N~p Y ~ ~r Cl 116) COOR ~ (9) COOR COOR
,............ (n=o~/ , Rl S ~X R~ R S
N F~PPh 0~/--N COOR o COOR ( 11) COOR ~1: n=O) ~Z~ 6~5 1 ~len Rl is hydrogen, compownds of Eormula (2~ ars prepared starting from (5R) 6- aminopenicillanic acid ~6~A~A), following the widely--known general procedure (see CIGNAREI,LA et al., ~ournal o Oryanic Che~istry, 27, 266~ and EVRAr~D et al., Wature, 201, 1124). When Rl is lower alkyl, cycloalkyl, or hydroxyalkyl, the Rl 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 ~auser et al., ~elv. Chem. Acta, 50; 1327 (1967) and Giddings et al., Tetrahedran ~etters, 11, 995 ~1978).
Alternatively compounds of general formula ~2¦ in which R"' is }I 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 . 20 in the following examples. The substitution of the 6 position is stereospecifically directed to the 6a derivatives.
The ester of penicillanic acid S-oxide ~2) wherein R5 is an alkyl group of ~1 is as above defined, may be heated in an inert solvent, such as ben~ene or toluene, usually at a temp-erature of from 70C to 140C, with a suitable acetylenia der-ivative of the general formula XC_CY wherein X is a g~oup of the .
formula CH2Z' wherein Z' is a hydrogen or halogen atom, hydroxy, amino, carbamoyloxy or a group of formula OR , OCOR ~ or NHCoR3 where R3 is lower alkyl, aryl or a heterocyclic ring, any of R3 being optionally substituted, and Y is a hydrogen atom, lower 12~266S

, .

1 alkyl, cyano or a group of the formula CoOR5 or CH2Z' wherein RS and Z' have the meaninys ~iven above. In the compounds of formula (~),thc v gro~lp, if desired,may be convert~l into a differ~nt X ~coup wherein X is a group of the formula Cll2Z wherein Z has the meaning given to it supra hy means of -the widely-known sub-; stitution reactions, one e~ample of which is given in the following examples. The trapped compound of the formula ~3) may be isomeri~ed 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 ~41 may be ozonized selectively on the iso~ropenyl double bondto give a compound of formula (5~ where n = 1, which may be reduced to a compound of formula ~51 where n = 0 with suitable 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 transformed into the chloroderivative of formula (8~ where n = 0 by means of a chlorinating agent such as thionyl chloride and pyridine, and then into the phosphorane of ormula (91 vhere n = 0. More-over, the same group of reactions are also performed starting from the unexpected compounds of formula ~6) where n = 1 which is stable when Y is not a strong witharawing group. In the case involving the compound of formula ~9~ where n = 0, the compound may be selectively ozoni~ed as a phosphonium salt in acidic conditions -to give the compound of formula (ll), which is cyclised to the compounas of formula tll, simply by heating in an inert solvent, such as toluene, at a temperature of from 50C to 140C.
In case of the compouna of formula ~9) where n = 1, the compound must bs reduced to the compound of formula (lOl, and ~Z~LZ665 1 subsequently selectively ozonized to the compound o form~
which gives in turn the compound of ormula ~1).
In the s~cond way, the compound of Eormula (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, after hydrolysis, the compound of formula (141. Following the sa~e procedure as in the previous way, glyoxylation o~ the compound o formula ~14~ gives the compound of formula ~15), w~ich may be transformed to the chloroderlva-tive of formula (16) and then to the phosphorane o formula , which is a CQmmOn intermediate for both ways.
When R is hydroxyalkyl, tha reaction sequence is preferably 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 compoùnds. Compounds of formula ~1) in which n = 1 are easily prepared starting from compounds of formula (1l 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 o the invention.
A series o tests was carried out in vitro to compare the activities of (5RI acetoxymethyl-2-acetoxymethyl-2-penem-3 carboxylate (Laboratory code FCE/20077/B40/34~, (SRl acetoxy-methyl-2- ~ methyl-1'~-tetrazol-5'-yll-thiomethyl] -2-penem-3-carboxylate ~compound Al and two reference compounds (ampicillin , ..
and cefoxitin). Table 1 below reports the results of the above assays as MIC ~minimal inhibitory concentration).

3~

~2~6~5 M I C ~g~ml Compound Strains FcE/2oo77/B4o/3~l A Ampicillin Cefo~itin Staphyloeocaus aureus 209P 0.390.39 ~ 0.19 0.78 Staphylococcus aureus 153 1.560.78 1.56 0.78 Staphylococcus aureus PV2 0.390.78 ~ 0.19 0.78 9taphylococcus - i aureus Smith ; ATCC 13709 ~ 0.190.39 ~ 0.19 0.78 Streptococcus pyogenes ATCC
1238~ 3.120.78 3.12 1.56 .

Escherichia coli B 1.56 0.78 0.39 1.56 Escherichia coli V14 1.55 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 Klebsiella pneumoniae ATCC 10031 - 3.12 50 0.78 Klebsiella sp. R225 - 50 12.5 Proteus vulgaris V15 3.12 6.25 1.56 0.78 Proteus mirabilis V150.39 0.78 ~ 0.19 0.78 Proteus mirabilis 5253.12 0.78 0.39 L.56 - Shigella flexneri0.390.39~ 0.19 0.78 Pseudomonas aeruginosa3.120.39 25 6.25 Salmonella typhimuriu~1.560.78 0.78 3.12 Salmonella panamae FlS1.560.78 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 e~amples are illustrative but should not be regarded as limiting the invention.

~L~lZEi65 ~X/~U~LE 1 48-VinylthiO - C1,2-diacetoxymethy~ ethoxycarbonyl-2~methyl-2-propen ~ tidin-2-one-S-oxide, Reaction ~2)-~3) c ~ S ~ ~ CH3 C ~ ~ ~ OCOCH3 N ~ ~ ~ " N ~" ~ ¢ ococr~3 COOCN3 ~ // H 'COOCH3 IO 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 refluxing temperature for 24 hrs. The title compound can be purified by column chromatography on silica gel eluting with 96:4 dichloro-methane-ethyl acetate. There ~as obtained 1.4 g of 4B-vinYlthio-~,2-diacetoxymethy~ -1- [1-methoxycarbonyl~2-methyl-2-propenyl3 -azetid~n-2-one-S-oxide.
PMR ~CDC13~ : 2.03~ ~s~crl3-c-)~ 2.15 and 2.20 ~(two s, 2CH3CO), 2.88~ (dd, Jgem = 14 Hz, Jvic cis = 4 Hz, C-3-H~), 3.88~ (dd, Jgem = 14 Hz, Jvic trans - 2 Hz, C-3-H8), ' 3,83~ (s, CH30), 4.88~ (d, Jvic = 6 Hz, CH2-c=J
~H) 4.92~ (broad s, CH2-C=~
-N~ ~C
4.93-5.33~ ~m, = CH2 and CH

COO

5.32~ (dd, Jvic = 4 and 2 Hz, C-4-H), 6.47~ (t, Jvic = 6 Hz, =C-C(H2~ ) H

4R-Vinylthio- ~,2-diacetoxymethy~ -methoxycarbonyl-2-methyl-l-propeny~ -azetidin-2-one-S-oxide. Reaction (3)-(4) ~Z~Z66S

~ S~ ~ OCOCH3 ~ ~ OCOCH3 L 11 ~ OCOC~3 ~ ~ ~ I ~ ~ OCOCH3 H COOCf~3 COOC113 ~' 1.7 g of 4B~vinylthio- E,2-diacctoxymethyl] -1- ~-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 temerature.
After evaporating the solvent, the title compound was o~tained pure in quantitative yields.
PMR (CDC13) : 2.13 (9H) and 2.32 ~3H) ~ ~two s, 2 CH3CO and 2 CH3 C ~
2.92~ (dd, Jgem = 15 Hz, Jvic cis = 5 Hz, C-3-H~), 3.38~ (dd, Jgem = 15 Hz, Jvic trans = 2.5 Hz, C-3-HB), 3.82~ ~s, CH30), 4.88~ (d, Jvic - 6.5 Hz, CH2-C=) (H) .
XO 4.923 ts, CH2-C=) 5.15~ (dd, Jvic = 5 and 2.5 Hz, C-4-H), 6.50~ (t, Jvic 605 Hz, = C-(H2) ) H

4B-Vinylthio-~l~2-diacetoxymethy~ -l-methoxyoxaloyl-azetidin-2-one-S-oxide. Reaction (4~-(5¦

S ~OCOC~I S OCOC}13 ~N ~ ~ OCOCH3 O, ~N ~ O ~ OCOCH3 _g _ ~21Z6~;S

1 2.0 g o 48-vinylthio- ~,2-diacetoxymethy~ -1~ El-methoxYcarhon~l-2-methyl-1-propenyl] -azetidin-2-one-S-oxide, were dissolved in 150 ml of dichloromethane and, after cooling at -78C, a flo~r 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 o~ Na2S2O5, and dried over Na2SO4. The resulting organin phase gave, after evaporating the solvent "in vacuo", 1.4 g of the title compound.
PMR (CDC13) : 2.05 and 2.08~ ~two s, 2 CH3CO), 3.03C (dd, Jgem = 17 Hz, Jvic cis = 5.5 Hz, C-3-Ha~, 3.50~ tdd, Jgem = 17 Hz, Jvic trans = 3 Hz, C-3-H~), 3,90~ (s, CH30~, 4.82~ Id, Jvic = 6.5 Hz, CH2-C=) 4.90~ (s, CH2-C=), 5.32~ (dd, Jvic = 5.5 and 3 Hz, C-4-H), 6.47~ (t, Jvic = 6.5 Hz, =C-C(H2).

H
IR (CH2C12): 1830 cm 1 ~-lactam C=o 1750 cm 1 esters C=O
1715 cm 1 amide C=O

4~-Vinylthio- ~,2-diacetoxymethyl~]-1-methoxyoxaloyl-azetidin-2-one. Reaction (5) 1l c_~S ~ OCOCH3 ~C1' ~DCOCH3 N ~ o ~ OCOCH3 ~ N ~ o ~ OCOCH3 ~Z~Z66S

1 A solution of 1.4 g of 4B-vinYlthio- ~,2-diacetox~methy~
methoxyoxaloyl-azetidin-2-one-S-oxide in 10 ml of anhydrous di-methy:Lfoxmamide was cooled at 25~C and 0.9 tnl o phosphorous tribromide were added tllereto. After lO minutes, the mixture was diluted with ethyl aceta-te and washed twice ~ith a saturated solution of NaMC03. After drying over Na2S04 and evaporating the solvent, 0.9 g of the title compound were o~tained.
PMR (CDC13) : 2.07~ (s, 2 CH3C0), 3.17~ ~dd, Jgem = 19 Hz, Jvic Trans=3.5 Hz, C-3-H~), 1Q 3.65~ (dd, Jgem = 19 Hz, Jvic cis = S 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 = S and 3.5 Hz, C-4-H
6.25~ (t, Jvic = 6.5 Hz~ =f-C(H2) IR (cHcl3) : 1815 cm 1 ~-lactam C=0 1745 cm 1 esters C=0 1710 cm 1 amide C-0 4~-Vinylthio- ~,2-diacetoxymethy~ -aæetidin-2-one. Reaction (5)-(6).

S ~ ococll ~ S ~ OCOC~3 ~L N~o ~ 3 1.5 g of 4~-vinylthio- ~,2-diacetoxymethyl~ -l-methoxyoxaloyl-azetidin-2-one were dissolved in 100 ml of methanol and a few grams of silica gel were added under stirring. After one hour, --11-- .

~2~Z6~S

1 the silica gel was filtered off and the methanolic solution evaporated, to give 0.8 g o 4~-vinylthio- ~,2-diacetoxymethyD -azetidin 2-one.

PMR (CDC13) : 2.25~ tS, 2 CH3CO), 2.98~ ~dd, Jgem - lS Hz, Jvic trans = 2 Hz, C-3-H~), 3.48~ (dd, Jgem=lSHz, Jvic cis=4.5 ~Iz, C-3-H), 4.78~ (d, ~vic = 7 Hz, CH2-f=), ~H) 4.87~ ~s, CH2-C), to5.03~ (dd, Jvic = 4.5 and 2 Hz, C-4-H]~

6.02~ ~t, Jvic = 7 H~, - C-C~H2) H

7.13~ (broad s, N-H).

IR ~CHC13) : 1770 cm l ~-lactam C=0 1740 cm 1 esters C=o - EXA~IPLE 6 4~-Vinylthio- ~,2-aiacetoxymethy~ -a~etidin-2-one-S-oxide.

Reaction (5)-(6~

Il ' l 20// C N ~ ~ OCOCH3 ~ C N~ ~ OCOCH3 0.8 g of 4~-vinylthio- ~,2-diacetoxymethy~ -l-methoxyo~aloyl-a~etidin-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-diacetoxymethyi] -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), ~2~Z~i6S

1 4.70~ (m, 2 C-4-H~
4.88~ (d, Jvic - 6 Hz, CHz~

4.93~ (s, CH2-C-¦
6.53~ ~t, Jvia = 6 Hz, =CI-Ct~l2~ ), 7.23~ (s, N}l~. Ir IR ~CHC13) : 1190 cm 1 ~-lactam C=O
1745 cm 1 esters C=O
. EX~PLE 7 -4~-Acetylglycolylthio-l-acetoxymethyloxyoxaloyl-azetidin-2-one.

Reaction ~12)-(13) S ~ OCOCH3 r I s~ OCOCH3 OCOCH3 ~ ~ O

0.8 g of 4~-vinylthio- ~,2-diacetoxymethyy -l-El-acetoxymethyloxy-; carbonyl-2-methyl-1-propeny~ -azetidin-2-one were dissolved in 80 ml of dichloromethane, cooled at -78C and a flow of ozone in oxygen was bubbled into the cooled solution until a ~lue color appeared. The solution, after it shaking with an aqueous sol-ution of Na2S2O5, was dried over Na2SO~ to give 0.45 g of the title compound.
PMR (CDC13) : 2.10 and 2~13~ ~two s, 2 CH3CO) 3.20~ tdd, Jqem = 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), 5.87~ (s, COO-CH2-OCO~.

.~ . .

~212665 XX~ll'LX li 4B-Ace~tylslycol~thio-azetidin-2-one. Rea~tion ~13~- U41 r ~ OCOCH3 ~ OCOCH3 ` COOC~3 0.6 g of 4~-acetylglycolylthio-l-methoxyoxaloyl-azetidin-2-one were dissolved in 1~0 ml of methanol and a few grams of silica 1 1:1 gel were added as the solution was stirred. After one hour, the silica gel was ~iltered off and the resulting solution gave, after evaporation of the solvent, O. 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, NH~.

4 ~-Vinyl thio- Cl,2-diacetoxymethy~ -l- Cl-acetoxymethyloxycarbonyl-l-hydroxymethyl~-azetidin-2-one. Reaction (6)-(7) OCOCH3 ~ ~ O ~ OCOCH3 i N ~ ~ OCOCH3 o ~ ~ - OCOC13 o/ H COOCH2OCOCH3 0.7 g of aeetoxymethyl-glyoxylate ~freshly prepared by the ozono-lysis of diacetoxymethyl fumarate) were dissolved in 30 ml of benzene and the resulting solution was reEluxed for 20 minutes through a Dean-Stark apparatus.

-14~

~2iZ~

1 ~fter cooling the solution at 50 to 60C, 0.1 g o~
4~-~inylthio- ~,2-diacetoxymethyl~-azetidin-2-one dissolved in 10 ml of benzene were added and the resulting solution was re1uxed for 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 = 13 Hz, Jvic cis=4 Hz, C-3-H~, 4.70~ ~d, Jvic = 6 Hz, CH2-f=), lHl 4.77~ ls, CH2-$=), 5 ~ O~S n 4 ~ (m, C-4-H and -N-CH-COO-~
O(H~
5.77~ (s, - COO-CHz-OCO)~

6.12~ (t, Jvic = 6 Hz, =C-C~H2) ) H

4R-VinYlthio- ~,2-diacetoxymethy~ -l-Cl-acetoxymethyloxycarbonyl-l-chloromethy~ -azetidin-2-one. Reaction (7)-~8~

C r ~ oCOCH3 ~ C ~ ~ OCOCH3 N ~ OH OCOCH3 N ~ Cl ~ OCOCH3 OOCH20COCH3 COOC~120COCH3 0.6 g of 4R-~inYlthio- ~,2-diacetoxymethyl]-1-[acetoxymethyloxy-carbonyl-l-hydroxymethyl~-azetidin-2-one dissolved in 15 ml o~
tetrahydrofuran wcre cooled at 0C; O.llS 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 ~12!66~i 1 off and the solution was evaporated "in vacuo" at room tempera-ture to give the title compound in high yiold. A samplc was puri~ied on preparative l'LC for analyt.iaal purposes, but the crude mixture can be used without purif~aation for the nex~ step.
PMR (CDC13) : 2.14~ ~s, 3 CEI3CO), 3.10~ (dd, Jgem = lS.S 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) 1a 4.83~ ~s, CH2-C=~, 5.4-5.9~ (m, C-4-~ and -N-CHCl-COO), 5.88~ ~s,`-COO-C~2-OC~
6.13~ (t, Jvic = 6.5 Hæ, =C-CIH2).

EX~IPLE 11 4~-Vinylthio- rl,2-diacetoxymethY~ -acetoxymethyloxycarbonyl-l-triphenylphosphoranylidenemethyl3-azetidin-2-one. Reaction (8)-(9l .
~ S ~ OCOCH3 ~ OCOCH
20O/~ ~ ~ Cl ~ 3 0 / N PPh ~OCOCH3 OOcH20COCH3 r COOCE~20COCH3 A solution of 0.430 g of 4~-vinylthio- Cl,2-diacetoxymethyl]-1-~l-acetoxymethyloxycarbonyl-l chloromethy~ -azetidin-2-cne, in 5 ml of tetrahydrouran and 5 ml o dioxane containing 0.520 g of triphenylphosphine and 0.08 ml o pyridine, was stirred over-night at 50C. The resulting phosphorane was puriied 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 CH3CO), 4.10C (d Jvic = 6.5 ~z, CH2-C=) Il 26~S

1 4.13~ ~s, CH2-CI=) 5 . 7 7 ~ (s, ~COO-CH2-OCO-) 5.90~ (t, JV.iG - 6.5 }~Z, = C~-C(tl2) ) 7.1-8.0~ ~m, 3C611$).

lycolylthio-l-rl-acetoxymethyloxycar~onyl-l-triphenyl-~ phosphoranylidenemethyl]-azetidin-2-one. Reaction U0)-(11) ~ S ~ OCOCH3 ~ S ~ OCOCH3 L I ~ OCOCH3 ~-~~ ~ N ~
COOCH20COCH3 CoocH2ococH3 0.7 g of 4B-vinylthio- rl,2-diacetoxymethyl]-1- ~-acetoxymethyloxy-cax~onyl-l-triphenylphosphoranylidenemethyl] -azetidin-2-one were dissolved in 40 ml of dichloromethane and, after cooling at -20C, 50 ml of a 10~ solution of trifluoroacetic acid in dichlorome~hane were added. After few minutes, a flow of ozone in oxygen was bubbled into the solution at -20C until a slightly blue color appeared. ~t 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 of the title compound.
PMR (CDC131 : 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-car~oxylate Reaction ~11l-~1) ~2~Zl~i65 O/~ PPh o~ r N ~ OCOCH3 COOCH2OCOCH~

0.7 g oE 4~-acetylglycolylthio-1- ~-acetoxymethyloxycarbonyl-l-triphenylphosphoranylidenemethyl]-azetidin-2-one were dissolved ; in 30 ml of dry toluene and heated at refluxing temperature ~or 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-acetoxyme~hyl-2-penem-3-carboxylate.
P~R ~CDC13~ : 2.11 and 2.13~ (two s, 2 CH3CO), 3.49C ~dd, Jgem=16.5 Hz, Jvic trans=2 Hz, C-6-H~), 3.86C ~dd, Jgem=15.5 Hz, Jvic cis=3.8 Hz, C-6-H~), 5.12 and 5.45C (two d, Jgem = 15.5 Hæ, =C-CH2), 5.68C tdd, Jvic = 3.8 and 2 Hz, C-5-Hl, 5.87~ ~s, -COO-C~2-OCO-).
IR tCHC132 : 1800 cm l ~-lactam C=O
1750-1725 cm 1 esters C=O
U.V. (EtOH2: ~ max 325 nm.
MS : m/e 315.04108 ~] calculated for C}2H13N O7S
315.04127.

4~-Vinylthio-(1,2-diacetoxymethyl)-1-tl-p-nitro~enzyloxycar~onyl-l-hydroxymethyl)-azetidin-2-one. ~eaction (62-~7]

~;~lZ66S

~ S ~ OAa ~ ~
0~ c 0/ ~ N~ r OH ~ OAc COOCH2-~ N2 ; The title compound was obtained following the ~ame procedure o~
Example 9, using p-nitrobenzylglyoxylate which had heen freshly prepared by the ozonolysis of p-nitrobenzylfumarate.
Quantitative yield, tO
PMR ~CDC13) 8 : 2.1 ~s, 6H~; 2.8-2.7 (m, 2H~; 4.7-4.9 ~m, 5H);
5.1-S.6 (m, 2H); 5.2 (m, lH); 6.1 (m, 1~); -7.S-8.3 ~m, 4H).

4~-Vinylthio-(1,2-diacetoxymethyl~-(1-p-nitrobenzyloxycarbonyl-l-chloromethyl)-azetidin-2-one. Reaction ~7~-(81 ~ N ~ ~ ) ~ ~ OAc 20COOC ~ ~2 ~OOC~ ~ No2 The title compound was obtained follo~-ing the procedure shown in Example 10.
PMR (CDC131 ~: 2.1 ~s, 611); 2.8-3.7 ~m, 2H); 4.7-4.9 ~m, 4H);
5.2-5.4 (m, lHl; 5.4 ~m, 2H); 6.1-6.3 ~m, 2H);
7.5-8.4 ~m, 4H).

..
4~-Vinylthio-(1,2-diacetoxymethyll-1-~1-p-nitrobenzyloxycarbonyl-l-triphenylphosphoranylidenemethyl)-azetidin-2-one. Reaction ~8~-(9) ~ZlZ6~5 ,,,~S ~ Oi~C ~ ~ ~
/LN C1 ~
rCOOCH~ NO COOCIr2 ~ N2 " The titla compound was obtained ollowing the procedure of Example 11.

4~ etylglycolyithio-l- U p-nitrobenzyloxycarbonyl-l-triphenyl-phosphoranylidenemethyl)-azetidin-2-one. Reaction (9~-~11) O~c : ~ S ~ OAc ~ i ~ NO
C OCH2 ~ N2 COOCH2 \__f 2 The title compound was obtained following the procedure of ~Example 12.

(SR)-p-nitrobenzyl-2-acetoxymethyl-2-penem-3-carboxylate.
Rsaction ~11)-(1~

S ~ OAc ~ OAc P 3 OOCH2 ~ 2 . COOCH2 ~ 2 The title compound was obtained following the procedure o Example 13.
PMR ~CDC13) ~: 3.75 (lH, dd, J = 2.3 Hz, 16.8 HZ, H-6N~
3.87 ~lH, dd, J = 3.6 Hz, 16.8 Hz, H-6B);
5~14 (lH, d, J = 15-8, -C-CH2O-);

-20~

.

:
~Z12665 1 5.50 (lH, d, J = 15.8 Hz, =C-CH2O), 5.71 ~lH, dd, J - 2.3 llz, 3.6 Hz, H-51.

a D ~ 37 (C 1.2 CHC13~.

IR (CIIC13) : 1800 (~-lactam, 1750 and 1720 cm 1.
UV (EtOH) : 265 (F 11000~ and 322 ~ 7000~ nm.

M.S. : m/e 378 (M ~;

M.p. : 122-123C

, EXAMPLE 19 .
(5R)-2-Acetoxymethyl-2-penem-2-carboxylic acid. Reaction (1) ! s ~_,~" OAc S ~ OAc ~N ~ ~ ~N ~
O ~ ~ COOCH2 ~ - No2 COOH

200 mg of (5RI-p-nitrobenzyl-2-acetoxymethyl-2-penem-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 resultin~ ~iphasic mixture was shaken under hydrogen or 60 minutes. After iltering the catalyst, the aqueous phase was acidified with 20 ml of 5~
aqueous citric acid and extracted three times with methylene chloride. The organia layers were dried over Na2SO4 and evap-orated to give 60 mg of the title compound.
I.R. ~CHC13) : 1790 (~ lactam2, 1735 and 1700 C.~l 1, U.V. ~EtO~ 300 nm.
EXA~PLE 20 4~-(1-Hydroxymethyl)-vinylthio-l-~l-methoxycarbonyl-2~methyl-2-propenyl]-acetidin-2-one-S-oxide. Reaction (2)-(3) .

~2~Z66S

o ~ C~OCE~3 ~ ~ ~ ~ OH

;, ' H COOCE13 4 g of penicillanic acid methyl ester S-oxide were dissolved in ~, 15 ml of toluene and refluxed with 15 ml of propargyl alcohol r for 8 hours. After evaporating in vacuo, the residue ~/as pur-ified ~y short column chromatography on silica gell eluting 2.6 g of the title ~ompound were obtained.
PMR ~CDC13) ~: 1.96 ~bs, 3 H, C-CH31; 2.91 and 3.35 (dd, 2H, J = 2 Hz, 5 Ez, lS Hz, CO-CH2-CH-S~; 3.78 ~s, 3H, COOCH3); 4.36 ~bs, 2H, CH20H~; 4.90-5.25 tm, 3H, CH-COOCH3 C-C-CH2~; 5.35 (m, lH, CH2-CH-S);
5.88 ~s, 2H, CH2=C-S~.

4~-(1-hydroxymethyl)-vinylthio-1- ~-methoxycarbonyl-2-methyl-l-propenyl]-a~etidin-2-one-S-oxide. Reaction ~31-(4) o r~ r~
H ~COOCH3 COOCH3 3.0 g of 4~- U-hYdroxYmethyll-vinylthio-l-~l-methoxycar~onyl-2-methyl-2-propenyl]-a~etidin-2-one-S-oxide were dissolved in 100 ml of dichloromethane and left at room temperature for a few hours. After evaporating the solvent, the resiaue consisted of pure title compound in a quantitative yield.

6~

PMR ~CDC13) ~: 2.08(s, 3H, =-CH3¦; 2.18 ~s, 3H, =lCH3);
2.7-3.6 ~m, J = 2 Hz, 5 Hz, 16 Hz, CO-CH2-C}I-S);
3.78 ~s, 3H, COOCH3~; 4.35 ts, 2EI, CH2OH);
5.32 ~m, lH, CH-S~; 5.90 (bs, 2H,~CH2).

4R-(1-8romomethyl)-vinylthio-1- ~-methoxycarbonyl-2-methyl-1-propeny~ -azetidin-2-one. Reaction ~4)-(12).

S ~ OH ~ S ~ ~ Br ~COOCH3 ~COOCH3 1.8 g of 4~-(1-hydroxymethyll-vinylthio-1- [1-methoxycarbonyl-2-methyl-l-propenyl]-azetidin-2-one-S-oxide were dissolved in 40 ml o~ 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 ~hile 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 ~0 evaporation o the solvent, 1.6 g of the title compound.

PMR ~CDC13) ~: 2.04 ~s, 3H, = ); 2.24 (s, 3H, = ~ );
3.24 (dd, J = 2.8, 5, 16 Hz, 2H, C-CH2-CH);
3.75 (s, 3H, OCH3~; 4.02 ~s, 2H, CH2BRI;
5.24 (bs, lH, =CHl; 5.37 ~dd, J = 2.8 Hz, 5 Hz, lH, CH2-CH-S¦; 5.60 (bs, lH, = CH).

EX~MPLE 23 4R- ~-(l-methyl-l-H-tetrazol-5-yll-thiomethyl]-vinylthio-1-~-methoxycarbonyl-2-methyl-1-propeny~ -azetidin-2-one.
Reaction (12) , . . .

66~

, ~ ~ Br ~ S ~ ~ S ~J
~ r 0'~ _ N ~ ~L__ N ~ ~ CH3 1.4gof4~ romomethyll-vinylthio-l-Ll-methoxycarbonyl-2-; me~hyl-l-propenylJ-azetidin-2-one were dissolved in 25 ml o tetrahydrofuran and cooled at 0C.
0.8 g o 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-S);
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).

methyl-l-H-tetrazol-5-yl~ thio acetylthio-l-metho~y-oxaloyl-azetidin-2-one. Reaction (121-~13) N - N

C~ ~S ~~ S ~,~0 1 ~ ~ 1H o~ ~ CH3 1.8 g o~ 4~- [1~ methyl-1-H-tetrazol-5-yl)-thio]-vinylthio-30 1-[1-methoxycarbonyl-2-methyl-1-propenyl]-azetidin-2-one were .... . .

~LZ~2:61~i~

I dissolvsd in 200 ml of dichloromethane and cooled at -75C. A
flow of ozor.ized oxygen was bubbled through the solution until a blue color appeared. A ew drops o~ P~OCH3~3 were added and the mixture was raised to room tempera-ture and evaporated to give 1.3 g o~ the title compound.
i' PMR ~CDC13) ~: 2.9~3.7 ~m, 2 H, COCH2CH S~; 3.8S (s, 3 H, COOCI[3); 3.98 ~5, 3 H, ~-CH3~; 4-35 (s, 2 ~, CH2S~; 5.75 ~m, 1 H, CH2CH S~.
EX~IPLE 25 ~ 4~ methyl-1-H~tetrazol-5-yl)-thio-acetyl-thio-azetidin-2-one.
N ~ N - N

S ~ S _ l I I ~ S ~ S l ~ N
3 H ~ IH3 1.2 g of 4~ -methyl-l-H-tetrazol-s-yl~-thio-acetylthio-L-methoxyoxaloyl-azetidin-2-one were dissolved in a 1:1 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 ether : obtained 0.6 g.

4~-(1-methyl-1-H-tetrazol-5-yl)-thio-acetylthio-1-(1-acetoxy-methyloxycarbonyl-l-hyaroxymethyl)-azetidin-2-one.

' ~ \ CN ~ ~ CN3 ~L266~S

1 l.5 g of 4~ methyl-l-H-tetrazol-5-yl~-thio-aaetylthio-azetidin-2-one were re1uxed in 50 ml of benzene with l.2 g of acetoxymethylglyoxyla~e ~freshly prepared by the ozonolysls o~
diacetoxymethylfumarate~. The reaction was completed aEter 3 hours. The crude oil obtained after evaporating the so]vent can be used or the next step without further purification. A
sample was purified on TLC for spectroscopic data.
PMR ~CDCl3) ~: 2.05 ~s, 311); 2.7-3.8 (m, 2H); 3.95 ~s, 3H2, 4.30 ~s, 2H); 5.40 (s, lH~, 5.50 ~m, lH~;
5.80 ~s, 2Hl.

~ -~l-Methyl l-H-tetrazol-5-yl2-thio-acetylthio-l- U-acetoxy-methyloxycarbonyl-l-chloromethyll-azetidin-2-one.

Reaction llS)-tl62 N - N

C~13 0 ~ ~ ~

COOCI~ OCOCK

.

The oil obtained from Example 26 consisting of crude 4~-tl-methyl-l-H-tetrazol-5-yll-thio-acetylthio-l-(l-acetoxymethyloxy-carbonyl-l-hydroxymethyl)-azetidin-2-one, was dissolved in anhydrous tetrahydrofuran ~20 mll and treated at 0C with equi-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.
EXP~IPLE 2~
4~ 1ethyl-l-H-tetrazol-5-yl)-thio-acet~Jlthio-l-(l-acetoxy-methyloxycarbonyl~ triphenyl-phosphoranylidenemethyl)-azetidin-2-one. Reaction (16)-(ll) i~2~;6S

N--N N ~ N
C~ S~S 1NNI ~S~I~S ~l O~ N ~ Cl CH3 ~ 3 C}~3 To a solution containing arude 4~ methyl-1-H-tetrazol-5-yl)-thio-acetyl thio-l~Cl-acetoxymethyloxycarSonyl-1-chloromethyl)-azetidin-2-one, 800 mg of triphenylphosphine and 0.4 ml of pyridine were added and the resulting mixture was heated at 60G
to 70C for a few hours. The phosphorane was purified on silica gel eluting with dichloromethane-ethyl acetate ~1:1).

(SR~-Acetox~methyl-2-t~1-methyl-1-H-tetrazol-S-yl)-thiomethy ~ -'2-penem-3-carboxylate. Reaction ~Il)-~l) N - N N N

S I ~N ~ ~ ~ ~ Ch3 2! 0 COOCH20COCH3 0.500 g of 4~-(,1-methyl-1-H-tetrazol-S-yl)-thio-acetylthio-l-~l-acetoxymethyloxycarbonyl-l-triphenylphosphoranylidenemethyl)-azetidin-2-one were dissolved in 30 ml of toluene and heated at 100C for two hours. The titlP compound was purified from PPh30 by short column chromatography on silica gel eluting with 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, -NCH3);
3~ 4.56 (d, J = 14 Hz, lH, HCEI-S~; 4.84 (d, J=14 E~z, ~;~1266S

1 lH, HCH-S~, 5.65 Cdd, J = 4 ~Iz, 2 Hz, 1~, -H-5); 5.88 ~s, 2 H, COOCH2O~.

(5R~-2~ Methyl~ tetrazol-S-yl~-tlliomethyl-2-perlem-3-carboxylic acid. Reaction ~1~
: F~ 5 1 3 J

COOCH3 ~ No2 COOH

The title compound was obtained following the procedure set out in Example 19. The (5R) p-nitrohenzoyl-2-Ll-Methyl-l-H-tetra 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.

~ethyl-6~-~1'-hydroxyethyl)-penicillinate-S-oxide. Reaction ~17)-(2 OH O

O l/ ~COOCI ~ '8 ~ ~ COOCH3 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 an~
20 ml of a 1.6 M BuLi hexane solution) dissolved in anhydrous tetrahydrofuran was added and the mixture left at -78C for 10 rr,lnutes. 5 ml of acetaldehyde were successively added and the 3~
solution was stirred for lS minutes. The reaction was then ~Z~LZ6~;5 1 quenched with a NH4Cl saturated aqueous solution, extr~cted ~Jlth ethyl acetate, washed twice with water, and dried over Na2SO~.
~fter evaporation of the solvent, the re~idue was shortly purified by column ch~omatoyraphy on silica ycl eluting wi~h dichloromethane-ethyl acetate (1:1~. Obtained l.S g. The title compound consisted of a 2:3 mixture of epimers at the hydroxyl bearing carbon based on the PMR, ~eing the new C~-C8 bond only in the ~-position ~ecause of the stereospecificity of the reaction in the used conditions.
PMR ~CDC13~ ~: 1.27 (s, 3 H, ~-CH3); 1.40 (d, 3H, J = 5.7 Hz, CH3-CHOH) major isomer; 1.48 (d, 3H, J = 5.7 irz, CH3-CHOH) minor isomer; 1.70 ~s, 3H , e-CH3;
3.4-3.8 ~m, LH, H-6); 3.80 (s, 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-hydroxyethy~ -3-penicillanate. Reaction ~17~-(2) OH

~ fcooCN3 ~ COOCU3 To a solution of 2.2 g of methylpenicillanate in 30 ml of an-hydrous tetrahydrofuran, a slight excess of lithium 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 Na2SO4 and evaporated "in vacuo" gave 0.8 g of the title compound.

~1266S

Met~ rl-p-nitrobenzyloxyaarSony ~ eni~ n~te.
Reaction ~21 ~S~ ~ S~

~ W - J,,6 ~ ~ COOC~3 1.2 g of methyl-6-~1-hydroxyethy~ -3-penicillanate were dis solved in 40 ml of tetrahydrofuran; 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 Na2S04 and evaporating.

Methyl=6- Cl-p-nitrobenzYloxycarbonYloxyethYl] -3-penicillanate-S-oxide. Reaction (17)-(2) oCo2pNB O
~S~ >>~F~S~
N ~ ~J ¦ -Hl COOCH " ~ "~COOCH

1.8 g of methyl-6- rl-p-nitrobenzyloxycarbonyloxyethyl~-3-penicillanate were dissolved in 50 ml of methylene chloride and treated at 0C with 1.5 equivalents o_ m-chloroperbenzoic acid.

The organic phase was sha~en with a NaElC03 saturated solution, :

~266S

1 extracted, dried over Na2S04, and evaporated giving 1.4 y of the expected sulphoxide.
XAMP~E 3S
4~-Vinylthio- ~,2-diacetoxymethyl~-3=~-p-nitrobenzyloxycarbonyl-oxyethy~ -l-rL-methoxycar~onyl-2-m~thyl-2-propeny~ -azetidin~2-one-S-oxide. Reaction ~2)-~31 OC02PNp ~JC02PNB

L ~ ~ ~ r ! 3 A solution of 2.0 g of methyl-6- [l-p-nitrobenzyloxyc~rbonyloxy-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.

4~- Vinylthio-[1,2-diacetoxymethy~ -3- rl-p-nitrobenzyloxy-carbonyloxyethyl~ -l-rmethoxycarbonyl-2-methyl-1-propenyll --azetidin-2-one-S-oxide. Reaction (3)-(4) OCO2P~ OC0 PNB 0 S \ OCOCH3 ~ ~ S ~ OCOCH3 0~ ~ ~ ~ OCOCH3 ~L__ N ~ ~ OCOCH3 H ~ COOCH
COOC~3 3 1.3 g of 4~-vinylthio- ~,2-diacetoxymethyl]-3- ~l-p-nitrobenzyl-oxycarbonyloxyethyl~ methoxycarbonyl-2-methyl-2-propeny~-~Z1266~i 1 azetidin-2 one-S-oxide were dissolved in 80 ml o dichloromethanes 0.3 ml o~ triethylamine were added and the mi~sture was let at room temperature for 2 hours. The pure title compound was quantatively obtained on evaporation of the solvent.

, 4~-vinylt}lio- E, 2-diacetoxymethy~ -3- ~-p-nitrobenzyloxycarbonyl-_~y~ -l-methoxyoxaloyl-azetidin-2-one-S-oxide. Reaction , ~4l-~51.
OCO PNB O
\oco2pNB ol \ 2 11 10 ~ S ~ OCOCH3 ~ S ~ OCOCH3 ~L N ~ ~ OCOCH3~ N~O ~ OCOCH3 OOC~3 COOCH3 solution of 1.1 g of 4B-vinylthio- ~,2-diacetoxymethyl~-3-l-p-nitrobenzyloxycarbonyloxyethyl]-l-[methoxycarbonyl-2-methyl-l-propenyl~-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 Na2S04. 0.5 g of the title compound were obtained ater evaporation.

4~-Vinylthio- ~,2-diacetoxymethyll-3- ~-p-nitrobenzyloxycarbonyl-oxyethyl]-l-methoxyoxaloyl-azetidin-2-one. Reaction (5) ~OC02PNB
,~C02PNB o ~

S ~ OCOCE~3~ ~ OCOCH3 o~LN~) ~/ OCOCH3 ~ N ~"o ~OCOCE~3 ~Z66i5 1 A solution of 0.8 g of 4~-vinylthio- ~1,2--diacetoxymethyl~~3-~-p-nitrobenzyloxycarbonyloxyethyl]-l-methoxyoxaloyl-azetidln-2-one in 15 ml oP anhyc1rous dimethylformamide was cooled at -20C
and 0.6 ml o phosphorous tribromide were added. The reaction was diluted with ethylacetate after 10 minutes and washed twice with a solution of NaHC03. The organic phase, dried over Na2S04 and evaporated, gave 0.4 g of the reduced compound.
EXAMæLE 39 4~-Vinylthio- C1,2-diacetoxymethy~ -3-[1-p-nitrobenzyloxycarbon oxyethy~ -azetidin-2-one. Reaction (5~-~6) OC02PNB ~C02PNB

/ ~ S - ~ oCOCH3 ~ ~ OCOCH3 o/~ N~o COCH3 0,~ N ~ ~_~'oCOCH3 1.2 g of 4~-vinylthio-rl,2-diacetoxymethyl]-3- Cl-p-nitrobenzyl-oxycarbonyloxyethyl]-l-methoxyoxaloyl-azetidin-2-one were dis-solved in methanol and 2 g of silica gel were added to the solution. After 60 minutes the insoluble material was filtered and the organic phase evaporated. Short column chromatography resulted in 0.4 g of the title compound.
EXAMPL~ 40 4R-Vinylthio- rl,2-diacetoxymethyl~-3- rl-p-nitrobenzyloxycarbonyl-__ oxyethyl~ rl-acetoxymethyloxycarbonyl-l-hydroxymethy~ -azetidin-2-one. Reaction (6~-~7) 3~

i5 S` OCOCU --~ ~S ~oCOC~3 L N `¢ OCOC113 ~ C~ NrO~ ~/OCOCH3 O H COOC1120COC~13 , 0.6 g of 4~-vinylthio-~1,2-diacetoxymethyl~-3- ~-p-nitrobenyl-oxycarbonyloxyethyl]-azetidin-2-one, dissolved in 30 ml of ~en-zene, and 0.6 g of acetoxymethyl glyoxylate ~freshly prepared from the ozonolysis of diacetoxymethyl fumaratel were refluxed.
The'reaction was completed after two hours. The condensation product can be used for the next step without further purifi-cation.

4~-Vinylthio- rl,2-diacetoxymethyl~-3- ~-p-nitrobenzyloxycarbonyl-oxyethyl]-l-rl-acetoxymethyloxycarbonyl-l-chloromethyl]-azetidin-2-one. Reaction (7)-(8) .i , .
\C02PNB C2 N
20 ,,- ~ S C OCOCH3 ~ ~ 5 ~ OCOCH3 ~ N ~ O COCH3 o4~ N ~ Cl COCH3 0.5 g of 4~ vinylthio- ~1,2-diacetoxymethyl]-3- ~-p-nitrobenzyloxy-carbonyloxyethyl]-l- ~-acetoxymethyloxycarbonyl-l-hydroxymethy~ -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 insoluble material was filtered off and the solution evaporated at room --3~--, ~

~21;~665 temperature to give the title compound in nearly quantitativo yields. The product can be used without further purification for the next step.
EX~M~LE 42 4~-Vinylthio-ri,2-diacetoxymethy~ -3 - rl-P- nitro~enzyloxycarbonyl-oxyethyl]-l-racetoxymethyloxycarbonyl-l-triphenylphosphorany-lidene-methyU -azetidin-2-one. Reaction (8~-(9) ~02P~B ~02PNB
S OCOCH3~ S ~ OCOCH3 ~ C ~ OCOCH3 N PPh3~ OCOCH3 COOCH OCOCH

A solution of 0.760 g of 43-vinylthio ~1,2-diacetoxymethyl]-3-rl-p-nitrobenzyloxycarbonyloxyethyl,l-1-Cl-acetoxymethyloxy-carbonyl-l-hydroxymethyl]-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 ~S0C. The phosphorane was purified by silica gel colunu~
chromatography, eluting with 70:30 dichloromethane-ethyl acetate.

0.480 g o the title compound were obtained.
EXP~P~E 43 4e-Acetylglycolylthio-3-rl-p-nitrobenzyloxycarbonyloxyethyl~
~-acetoxymethyloxycarbonyl-l-triphenylphosphoranylidenemethyl~-azetidin-2-one. Reaction (9)~

F~ ~ococ~ L~~, COOCH2OCOC1~3 COOCH2OC0C13 s 1 0.45 g o 4B-vinylthio-C1,2-diacetoxymethyl~-3- ~l-p-nitrobenzyl-oxycarbonyloxyethyl~ Cacetoxymethyloxycarbonyl-l-triphenyl phosphoranylideIlemethyl~-azetidin-2-one were dissolved in 50 ml o~ dialoromethane and cooled at -20C: then 30 ml o~ 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.

EXA~IPLE 44 4~-Vinylthio- rl~2-diacetoxymethyl~-3- ~-p-nitrobenzyloxycarbonyl-oxyethy~ [methoxycarbonyl-2-methyl-1-propeny~ -azetidin-2-one. Reaction (4~-(122 OCOzPNB o S ~ CoCH3 ~ S ~ OCOCH3 O ~ N ~ ~ OCOCH3 > ~ N ~ ~ ~ OCOCH3 COOCH
COOC~3 3 1.5 g of vinylthio- C1,2-diacetoxymethyl]-3- ~-p-nitrobenzyloxy-carbonyloxyethyl~ methoxycarbonyl-2-methyl-1-propenyl~-azetidin-2-one-S-oxide were dissolved in 10 ml of anhydrous di-methylformamide and cooled at -20C; 0.8 ml of phosphorous tribromide were added. The mixture was stirred for 10 hours, diluted with ethyl acetate, and washed twice with NaHC03 sat-urated solution. The organic layer dried over Na2S04 and evaporated gave 1.1 g o f the title compound.

E~AMPLE 45 ~-Acetylglycolythio-3-rl-p-nitrobenzyloxycarbonyloxyethyl!-?-methoxyoxalyl-azetidin-2-one. Reaction (12~-(13 .
~ILZ~ 665 \ CO2 f co2PN~
~S ~ OCOCH3 ~ _ ~ S ~ `~OCOCH3 l l I . ~ O
0 _ N ~ ~ / OCOCH3 o--N ~O

1.4 g of 4~~vinylthio-Cl,2-diacetoxymethylJ-3~ p-nitrobenzyl-oxycarSonyloxyethyl]-l-,rmethoxycarbonyl-2-methyl-1-propenyi~- ' azetidin-2~one in 120 ml of dichloromethane were cooled to -78C.
Then ozone oxygen was bubbled through the solution ~ntil a blue color appeared. The solution was shaken with an aqueous solution of Na2S2O5 and dried of Na2SO4. Evaporation of the solution gave 0,3 g of the title compound.

4B-Acetylglycolylthio-3-rl-p-nitrobenzyloY.ycarbonyloxyethyl~-azetidin-2-one. Reaction (13)-(14) \oco2PN~ C02PNB
~ S ,~ ~ ~ S`~ OCOC1~3 ~ ~ OCOCH3 >
_ N ~ O O / \ H
COOC~13 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 of 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 q of the title compound.

~Z~LZ665 4R-Acetylglycolylthio-3-[1-p-nitrobenz~loxycarbonyloxyethyl~

~-acetox methyloxycarbonyl-l-hydroxymethy~ -azet'id~''n'-2-one.
Y

Reaction ~14l-(15).

\OC02PNB \OC02PN
- ~ S ~ OCOCH3 ~ S ~ OCOCH3 N ~ ~ N ~ ~ OH

0.5 g of 4~-acetylglycolylthio-3-rl-p-nitrobenzyloxycarbonyloxy-' ethylj-l- rl-acetoxymethyloxycarbonyl-l-hydroxymethyl]-azetidin-2-one and 0.5 g of 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.

4~-Acetylglycol~Lthio-3-~1-P-nitrobenzyloxycarbonyloxyethyl~-l-.
, ~l-acetoxymethyloxycarbonyl-l-chloromethyl~-azetidin-2-one.

Reaction ~15)-(16) ~ S ~ OCOCH3 ~ _ f s ~OCOCH3 O ~ I ' o 0~ _ N ~ ~OH ~ N ~

0.35 g of 4~-acetylglycolylthio-3- ~-p-nitrobenzyloxycarbonyloxy-ethyl~~-l-[l-acetoxymethyloxycarbonyl-l-hydroxymethy~ -azetidin-2-one were dissolved in 10 ml of anhydrous teterahydrofuran at 0C, Then 1.1 equivalents of pyridine and 1.1 equivalents of . ~ ~

~Z~266S

1 thionyl chloride were added and the mix~u~e was stirred ~or 10 minutes. The precipitate was filtered and the filtrate, after evaporation, gave the title compound in quantiiative yield. The arude product ~las ueed as such Eor the next step~

_e-Acetylglycolylthio-3- ~-p-nitrobenzyloxycarbonyloxyethyl~
rl-acetoxymethyloxycarbonyl-l-triphenylphosphoranylidenemethyl]-1~
asetidin~2-one. Reaction ~16~-(11).

OC02PNB OC02PN~3 S ~ OCOCH3 ~ r ~ ~ OCOCH3 O~ N ~ 'Cl ~ ~ N ~ PPh3 COOCE2 3 COOCH20COCE~3 0.400 g of 4~-acetylglycolylthio-3-rl-p-nitroben~yloxycarbonyl-oxyethyl]-l- E-acetoxymethyloxycarbonyl-l-chloromethYl]-azetidin-2-one were dissolved in 20 ml o a 1:1 mixture of tetrahydrofuran and dioxane. Thereafter 2 equivalents of triphenylphosphine and 1.1 equivalents of pyridine were added and the mixture stirred overnight at 50C. The title compound was purified by silica gel column chromatography, eluting with 70-30 dichloro-methane-ethyl-acetate. 0.280 g of the phosphorane wère obtained.

(5R)-Acetoxymethyl-6- E -p-nitrobenzyloxycarbonyloxyethy~ -2-acetaxymethyl-2-penem-3-carboxylate. Reaction ~11)-(1) ~OC02PNB

S ~ OCOCE13 / \ ~ ~ ~OCbCH3 _ N ~ PPh3 COOCH2 COC 3 COOCE120COCE~3 ~Z~Z66S

1 0.210 g of 4~-acetylglycolylthio-3-[1-p-nitrobenzyloxycarbonyl~
oxyethy~ -acetoxymethyloxycarbonyl-l- triphenylphosphorany-lidenemcthyl~-azetidin-2-one were dissolved in 7 ml o to~ueno and the solution was ref luxed Eor two hours. Puri~iaation by short column chromatoyraphy eluting with 9S:S dichloromethane-ethyl acetate, gave 0.05 g of the title aompound.
EXAMæLE 51 15R)-Acetoxymethyl-6-rl-hydroxyethyl~-2-acetoxymethyl-2-penem-3-carboxylate. Reaction U~

~ ~ ~ ~ ~ OCOCH3 ; \l ~ OCOC~3 o OoCE~2ococH3 0 COOCH20COCH3 0.060 g of 5R-acetoxymethyl-6-[l-p-nitrobenzyloxycarbonyloxy-ethyl~-2-acetoxymethyl-2-penem-3-carboxylate were poured in a water-ethanol-K2HPO4 mixture and hydrogenolysed with 10g Pd/C.
A quick purification by silica gel column chromatography gave 0.015 g of the title campound.
Operating as de~cribed in the previous working examples, but employing 5-methyl-2--thiol-1,3,4-thiadiazole, S-thiol-1,2,3-triazole, or thiolphyrazine instead o~ l-methyl-5-thiol-tetrazole, (5R)-2-5'-methyl-1',3',4'-thiadiazol-2'-yl~-thiomethyl~-2-penem-3-carboxylic acid, (SR)-2- r(l',2',3'-triazol-5yl)-thio-methyl]-2-penem-3-carboxylic acid, (5R)-2-~pyrazinyl)-thiomethyl-2-penem-3-carboxylic acid, (5R?-6- U'~hydroxyethyl]-2- C5"-methyl-1",3"-4"-thiadiazol-2"-yl)thiomethyl]-2-penem-3- carboxylic acid, (5R)-6-[i'-hydroxyethyl]-2- [~1",2",3''-triazol-S"-yl)thiomethyl~ -2---~0--~2~Z6~5 I (pyrazinyl)thiomethyl-2-penem-3-carbox~lic acid respectively were p~epared.
Operating as previously described, but reducincl the methyl-6-[1'-hydroxyethyy -3-peniaillinate follo~ing thc widely-known procedu~e, the corresponding 6-ethyl-derivatives were obtained.

, . . .
: ' ' ~ ~O

.

.

~21266S

1 - SUPPL~IENT~R~ DISCLOSUR~
EXA~?P1E S2: 6a-methoxypenicillanic acid~trichlorocthyl~ter-S-oxide. Ol CH ~ y C~l~f ~

_ N C H2CC13 N- _ OOCH2CC13 800 mg oE 6cl-methoxypenicillanic-acid--trichloroethylester (prepared according to Giddings et al, Tetrahedron Letters~
11, 995 (1978) were dissolved in 20 ml o~ aichloromethane and treated portionwise with 570 mg of m-chloroperbenzoic acid at room temperature. The organic phase was washed with a ~allCO3 saturated solution and evaporated. The title compound crystallized from ethyl ether. Obtained 650 mg.
M.p. 120-121C.
PMP~(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 }Iz~ CH2CC~3);
4.87 (d, lH, J51. 5 Hz, H-5); 5.07 (d, l}i, J=
1.5 Hz, H-6~.
EX~PLE 53: 3~~~1ethoxy-4~~vinylthio-~1,2-diacetoxymethyl]-_ _ _ .. . . . . ................ . _ l-[trichloro-ethoxycarbonyl-2-methyl-2-propenyl]-azetidin-2-one~S--oxide.
O O
~, ~",1 ~ a ~CH30~ ~ ~ OCOCH3 ~ OCOCH3 / ~ N ~ COOCH2CC13~
30 ~I El Cooc}~2ccl3 ~ 42 -~ Z~i6S
1 550 mg of 6~-methoxypenicillanic acid-trichloroethylester-S-oxide were dissolved in 25 ml of toluene; 1.2 g of butyn diol diacetate were added and the resultiny solution was refluxed for 10 hrs.
The reaction mixture was purified by silica gcl , column cromatography eluting with 10% ethyl acetate-dich--loromethane. 450 mg of the title compound were obtained.
PMR (CDC13)~ -: 2.01 (bs, 3}1, ~ ~ CH3); 2.08-2.10 ttwo s, 6H, OCOCH3) 3.45 ts, 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,~

EX~.PLE 54 3~ ethoxy-4~-vinylthio-[1,2-diacetoxymethyl]-l-[l-tri~hloroethoxycarbonyl-2-methyl-1-propenyl]-azetidi -. .
2-one-S-oxide.
'~ O

O"~C",H"3O S ~ OCOCH3 3 s ~
, f ~ 1¦ ~ ~ OCOCH

1 1 ~ L ~ OCOCE13 ~ ~ ~ ~_" OCOCH3 H CoocH2ccl3 COOCH2CC13 400 mg of 3~-methoxy-4~-vinylthio-11,2-diacetoxymethyl]-l-[trichloroethoxycarbonyl-2-methyl-2-propenyll-azetidin -2-one-S-oxlde were dissolved in 10 ml of dichloromethane and stirred at ~oom temperature with a few drops of triethylamine for 2 hrs. Evaporating the solvent afforded the pure title compound.
PMR tCDC13)~: 2.10 (s, 6E,=~-CH3, OCOCH3); 2.14 ts, 3H, OCOCH3); 2.40 (s, 3H,=1 - 3), 3 49 ts, 3H, OCH3); 4.82-4.88 ttwo s, 4H, ~ 2 ~OCOCH3, ~Zl;:665 , I CH CCl ) 4.91 (d, 2H~ J=6.0 Hz~ ); 4.95 - 2 3 ' C~I
td, lEI, J22.0 Hz, H-4); 5.23 ~d~ lH, J~2.0 ~Iz, ~ H
}I 3): 6.60 ~t, l~I, J=6.0 IIz,~

EXAMPLE 55: 3~-Methoxy-4~-vinylthio-[l~2-aiacetoxymeth~
l-tricloroethoxyoxaloyl-azetidin-2-one-S-oxide~

~ ~ OCOCHi ) -N ~ OCOCH3 O ~ F

2 g of 3~-methoxy-4~~vinylthio-[1,2-diacetoxymethyl~
trichloroethoxy-carbonyl-2-methyl-1-propenyl]-azetidin-2-one-S-oxide were dissolved in 200 ml of dichloromethane and cooled to -70C. Ozone in oxyyen was passed throuyh the solution until a blue co'our 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 (m, 611, CH2CC13, ~ 2\);

5.07 (d, lH, J= 3.0 Hz, H-4); 5.22 (d, lH, J= 3.0 Hz, H-3); 6.61 (t, lH, J=6.0 Hz, : . .
~ E~IPLE 56: ,3~-Methoxy-4~-vinylthio-[1,2-diacetoxy~ethylt-1=
~

trichloroethoxYoxalovl-azetidin-2-one.
oc~3 1t O,C~3 ~ S OCOCI~
OCOCH3 ; ~ ~

OOC112CC13 OoCH2ccl3 - ~4 -.

ZÇ~6~
. ( 1 800 mg oE 3~methoxy-4~ vlnylthio-~1,2-diacetoxymethyl~
trichloroethoxy-ozaloyl-azetidin-2-one-S oxide were dissolved in 30 ml o anhydrous dimethylforzoamide and cooled to ~20C.
0.5 ml of PBr3 were added and the mixture was stirred for l0 minutes. The reac~ion mix~ure was poured ir.to ethyl acetate ; and washcd 3everal ti~es with water: the residue, after drying over Na2SO~ , consisted essentially of the title ; compound and was used for the next step without further purification.
tO PMR (CDC13~ : 2.08-2.11 (two s, 6H, OCOCH3); 3.61 ~s, 3H, OCH3); 4.5-5.0 ~m, 7E~);5.38 (d, lH, J=3.0 Hz, H-3); 6.28 lt, lH, J=6.5 Hz, ~J ~ ).

EX.~qPLE 57: 3a-l~ethoxy-4e-vinylthio-ll~2---diacetoxymethyl]
azetidin-2-one.

~ ~ \ ¢ OCoCH3 ~ ~ COCH3 The crude residue obtained from the previous example was dissolved in 100 ml of methanol and 3 g of silica gel were added under stirrin~. The mixture was stirred for two hours;
after filtering SiO2, the residue was purified by silica gel column chrcmato~raphy eluting with 20% ethyl acetate-dichloromethane; obtained 400 mg of the title compound.
P~fR ~CDC13~: 2.08-2.11 (two s, 6H, OCOCH3); 3.55 (s, 3H, - OCH3); 4.68 (d, J=6.5 Elz, 2H, ~ ~ / );

4.81 (bs, 3H, S ~ ~ _ 2~ ; H-4); 4.86 (d, J=
2.0 Hz, lH, H-3 ; 6.04 (t, J=6.5 Hz, lX, H CH2 ): 6-50 (bs, lH, NH).

.

~ Z~l26~5 1 EXP~PI,E 58: 3~-~lethoxy-4B~vinylthio-[l~2-diacetoxymethy~
l-acetoxy-methyloxycarhonyl-l-hydroxymethYll-azetidin-2-one, v ~ ~ 3 _ _~ ~ ~ OCOC~3 - N~ ~OCOCEl3 // - N ~ H

~, 250 mg of 3a-methoxy-4~-vinylthio-[1,2-diacetoxYmethyl)-azra~
tidin-2-one were dissolved in 20 ml oP benzene and refluxed for 3 hrs. with 300 mg of acetoxyrnethylglyoxylate ~freshly prepared by oæonolysis o~ diacetoxymethylfumarate). q'he l crude mixture was purified by silica gel column chromato-graphy eluting with g0~ ethyl acetate dichloromethane to give 150 mg of pure title compound as a mixture of diastereo-isomers.

EX~MPLE 5g: 3a-Methoxv-4~-vinylthio-~1~2-diacetoxYmethvl~-l-ll-acetoxymethYloxvcarbonYl-l--chloromethyll-azetidin-2-one.
OCP. ~ S OCOCH3 3Q ~ S ~ ~ OCOCH3 I OCOCH3 ~~ ) 1 ~ OCOCH3 ~ OOCH OCOCH

150 mg of 3c-methoxy-4~-vinylthio-[1,2-diacetoxymethyl]-1~
[l-acetoxy-methyloxycar~onyl-l-hydroxymethyl]-azetidin-2-one were dissolved in 10 ml of 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.

.
, .~ .

~ZlZ6~;5 1 EXAMP~E 60: 3a-Methoxy-4R-vinylthio-tl,2-diace~oxymethyl)-l-ll-acetoxymethyloxycarbonyl-l-triphenylphosphoranylidenè-. . . _ . . _ . .
methyll-az~tidin-2-one.
~~~~ OCH
0~;¢ ~ 3 ~

The crude residue obtained from the previous example, consist--ing o~ nearly pure 3a-methoxy-4~~vinylthio-tl,2-diacetoxy-methyl]-l-[l-ace-toxymethyloxycarbonyl-l-chloromethyll-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-dicnloromethane to give 180 mg of the title compound.
.
EXAMP~E 61: 3a-Methoxy-4~-acetylglycolythio~ l-acetoxy-. . ...... . _ .
methyloxycarbonyl-l-triphenylphosphoranylidenemethyl]- ~ ' .. ... . . . .
azetidin-2-one.
~ O ---- _ _ ~ ~ COC3 ~ r ;~ Coocll2ococH3 COOCH20COCH3 230 mg oE 3a-methoxy -4~-vinylthio-[1,2-diacetoxymethyl]-1 [l-acetoxy-methyloxycarbonyl-l-triphenylphosphoranylidene-methyl]-azetidin-2-one were dissolved in 50 ml of dichloro-methane and, after cooling to -20C, 0.5 ml of trifluoro-30 acetic acid were added.

~12665 1 Ozone in oxycJen was bubbled throuyh the solution antil blue colour. A few drops of trimcthylphosphite Were added, the reaction mixture diluted with diahloromethano and washed several times with a NaHCO3 saturated solution.
~fter drying over Na2SO4 and evaporating the solvent~ the residue ~180 mg) consisted of pure title compound.

EXAMPLE 6? _ (SR)-Acetoxymethyl-6a-methoXy-2-acetoxymethyl-2_ penem-3-carboxylate.
J ~5 -- 3 ~ OCOCH3 o~ ~ PPh3 COOCH OCOCH
COOC}I2OCOCH3 2 3 180 mg of 3~~methoxy-4R-acetylglycolylthio-l-[l-acetoxy-methyloxycarbonyl-l-triphenylphosphoranylidenemethyl~-aze-tidin-2-one were dissolved in 20 ml of toluene and refluxed under nitrogen for 2 hrs. The title compound was purified by silica gel column chromatography by eluting with 5~ ethyl acetate-dichloromethane. Obtained 50 mg.
P~IR ~CDC13~: 2.11 (s, 6H, OCOCH3), 3.56 (s, 3H, OCH3);
4.94 ~d, J=1.7 Hz, lH, H-4); 5.26 (center of dd~ 2H, ~ 2 ); 5.55 (d, J=1-7 Hz, lH, H-3);
5.86 (s, 2H, COOCH2OCOCH3);
IR (CHC13) 1795 tRlactam), 1745-1720 (esters).

:. .
` EXAMP~E 63' i(5R)-Acetonyl-6~-methoxy-2-acetoxymethyl-2-penem-3-carboxylate . . . _ .

~LZ~2665 .
1 Operating as shown in examples 58, S9, 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~CIIC13) EX~MP1E 64: (5R~-6~-inethoxy-2-acetoxymethyl-2-penem-3-... ..
- ' carboxyl1c acid.

C ~ ~ OCOC~I3 J ~ OC~3 260 mg of (SR)-acetonyl-6~-methoxy-2-acetoxymethyl-2-penem-3-carboxylate were dissolved in 25 ml of tetrahydrofuran;
the resulting solution was diluted with S 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 OC 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 organic phases dried over Na2SO4 and evaporated to give 80 mg of the title compound.
IR 1795, 1740, 1700.(CHC13) EXAMPLE 65: 4~-I1-H~droxymethyl)-vinylthio-3~ p-nitro-- ~ - . - -- - _.__~ ._ _ benzyloxycarbony o~yethyl)-1-(1-methoxycarbonyl-2-methyl-, 2-propenyl~-azetidin-2-one-S-~xide. Reaction (2) - (3).

/ ~

~ZlZ665 1 A solution of 2.6 g of methyl-6~ p-nitroben~yloxycarbonyl-oxyethyl)-3-penicillinate~S-oxide and 8 ml of propargyl alcohol in 20 ml of toluen~ were reEluxed under nitrogen for 40 hrs. After evaporation of the solvent, the trapped compound was purified by silica gel column chromatography, eluting with t9:1) dicl1loromethane-ethyl acetate, to give 2.0 g of the title compound.

EXAMPLE 66: 4~ Hydroxymethyl)-vinylthio-3~-~1-p-nitro-benzvloxycarbonyl-oxYethYl)-l-(l-methoxycarbonyl-2-methyl-1-1~ _ prop_nyl)-azetidin-2-one-S-oxide. Reaction (3) - (4).

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

EXAMPLE 67: 4~-(1-BromomethYl)-vinylthio-3-(1-p-nitro-benzyloxycarbonyl-oxyethyl)-l-(l-methoxycarbonyl-2-methyl-..__ ~ l-propenyl)-azetidin-2-one. Reaction (4~ - (12).
OC02PNE3 1l qC02PNB
S ~ OH 1 ~ ~ ~ Br ~0 ~L21266S

1 2.0 g oE the compound prepared in Example 66 were dissolvRd in 50 ml of dimethylformamide. After cooling at -20C, 0.7 ml oE pyridine and 3.2 ml of PBr3 were added and the reaation mixture was maintained u~lder :tirring for 15 minutes. Ethyl acetate was added to the mixture and the organic phase was shaken with a NaHC03 saturated solution, washed with water and finally dried over Na2S04. After evaporating the solvent, 1.7 g of pure title compound were obtained.

EXAMPLE 68: 4~-11-(5-Methyl-1-3,4-thiadiazol-2-yl)-thio-methyl]-vinyl~hio-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-l-(l-methoxycarbonyl-2-methyl-1-propenyl)-azetidin-2-one.

OCo PNB
r 1~5 ~CN3 COOC~3 1.8 g of the compound prepared in Example 67 were dissolved in 30 ml of tetrahydrofuran. The resulting solution was cooled at 0C; 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. A~ter filtration of the insolubles, the remaining solution was dilutea with ethyl acetate, washed with water, dEied over Na2S04, and evaporated: 2 g of the title compou~dlwere obtained.

EXAMPLE 69: 4~-[1-(1,2,3-Triazol-5-yl)-thiomethyl]-vinyl-thio-3~-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-(1-methoxy-carbonyl-2-methyl-1-propenyl)azetidin-2-one.

. ~

~2~LZ6~

~OC02PNB
~S /~ OCO PNB
Br J ~ S

COOCI13 N ~

Starting Erom 2.5 g of the compound prapared in Exarnple 67 and operati~g as in Example 68, but using 1,2,3-triazol-5-thiol sodium salt, 2.2 g of the title compound were obtained.

EXAMP~E 70: 4~-¦1-(5-Methyl-1,3,4-thiadiazol-2-yl)]-thio-acetylthio-3a-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-methoxy-oxaloyl-azetidin-2-one.
OCO PNB N~N OC02PN N ~ N

~ ~ ~ S ~ CH ` ~ S ~ S

O ~ ~N ~ O
OOCH3 OOCHi 2 g of the compound prepared in Example 68 were dissolved in 250 ml of dichloromethane and cooled at -78C. A flow of 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 1.5 g of the title compound.

EXAMPLE 71: 4~-[1-(1,2,3-Triazol-S-yl)~-thioacetylthio-3-tl-p-nitrobenzyl-oxycarbonyloxyethyl)-l- methoxaloyal-azet;~in-2 -one. Reaction (12) - (13) .

2126~i5 ~,oCo~51~W _~c 2~

cooC~I3 ' ~

Starting from i.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: 48-tl-(5-Uethyl-1-,3,4-thiadiazol-2-Yl)I-thio-acetylthio-3a-(1-p-nitrobenzyloxycarbonyloxyethyl)-a~etidin-2-one. Reaction (13) - (14).
OC02PN ~S ~ ~ OC02PNB N-- ~

O ~ ~ O O H CH3 1.5 g of the compound prepared in Example 70 were dissolved in 1 l:l mixture of methanol and ethyl acetate. A few grams of silica gel were added and the mixture maintained at room temperature under vigorous stirring. After filtering the silica gel, the filtrate was evaporated to give an oil which was chromatographed on silica gel with dichloro~ethane:ethyl acetate (8:2), giving 0.9 g of pure title compound.

EXP~IPLE 73: 4~-11-(1,2,3-Triazol-S yl)]-thioacetylthio-3a-(l-p-nitrobenzyl-oxycarbonyloxyethyl)-azetidin-2-one. Reaction (13) - (14).

_ 53 -~Z~2665 ~ ~ N ~ Nl 0~1 Starting 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-acetylthio-3u-(1-p-nitrobenzyloxycarbonyloxYethYl)-l-(l-acetonyloxycarbonvl-l-hydroxymethyl)-azetidin-2-one.

Reaction (1~) - (15). oC0 PNB IN -OC02P~ S N- N 2 ~ ~ ~ S ~ ~ CH3 ~ ~ ~ S ~ S ''\CH

)/ _ N - 3~/ N ~ OH
O . C00~2COC113 0.9 g of the compound prepared in Example 72 were dissolved in 40 ml 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 Qtep without further puri~ication.
EXAMPLE 75: 4~ 1,2,3-Triazol-5-yl)]-thioacetylthio-3a-(l-p-nitrobenzyl-oxycarbonyloxyethyl)-l-~l-acetonyloxycarbonyl -l-hydroxymethyl)-azetidin-2-one. Reaction ~14) - (15).
C2PNB S~ ~N I C2PNB S rl I

0 ~ H ~ ~JOH

~L~126~S

1 Starting from 0.6 g of the compound prepared in Example 73 and operatiny as shown in Example 74, 0.7 g of the ~itle compound were obtained.
EXAMPLE 76: 4~-[1-~5-Methyl-l,3,4-thiadiazoi-2-yl?¦-thio-acetylthio-3-(1-p-ni ~ ethyl~-l-tl-acetonyloxycarbonyl-l-chlorom_thyl)-azetiain-2-one.
Reaction ~15) - tl6). ~ l pC02PNB ~ OC02PNB ~ S~ ~ S ~ S ~` 3 5~s~s~C~

: CoocEl2cocEl3 COOCH2C0CH3 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 solùtion until there was a disappearance of the startin~ material. After filtration of the însoluble ; material, the filtrate was used immediately for the next step.
EXAMPLE 77: 4B-[l-t:1,2,-3-Triazol-5-yl)l-thioacetYlthio-3~-(1-p-nitrobenzyl- xycarbonyloxyethyl)-l-(l-acetonyl-oxycarbonyl-l-chloromethyl~-azetidin-2-one. Reaction (15) - (16~. ~ N .
C0 PNB ~ ~ ~ ~ 2 ~0 ~ 5 ~ N ~ ~ ~ S

COOCH2COCH3 ~--~ 55 -~2~6 . ..

1 Starting from 0.7 g o~ the compound prepared in Example 75 and operating as described in E~ample 74, the crude chloro-derivative was obtained. ~he product was used for the next step without ~urther purification.

EXAMPLE 78: 4B-_l-CS-Methyl-1~3~4-thiadiazol-2-yl)?-thio-,, acetylthio-3a'-(l-p-nitrob'enzyl~ rbonyloxyethyl)-1-(1-;, aceto'nyloXycarbonyl-l tri~henylphosphoranylidenemethyl)-, azetidin-2-one. Reaction (16) - ~1}). N - N

OCO PNB N~--N
~ 2 S ~ sJ S ~CH3 ~C ~ S ~ f~ S ~iCH3 ~ ~ Cl ~ PPh3 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 was purified on silica gel by eluting with dichloromethane:ethyl acetate ~1:1). There was obtained 0.6 g of the title compound.

' EX~PLE 79: 4~ Cl,2',3-Tria2ol-5-yl~]-thioacetylthio-3a-tl-p-nitrohenzyl-oxycarbonyloxyethyl2-1-(1-acetonyl-' oxycar~onyloxyethyl-l-triphenylphosphoranylidenemethyl~-~zetidin-2-one. Reaction (162 - (11~.

_ 56 -~ . .

~Zl?6~SS

N
~C2 N ) S~ ~ S ~ ~ OCO2PNB ~ N

Cl > ~ ~o ~ ll 00}12COCH3 0 :~ COOCE12COCH3 :. .
Starting from the crude chloroderivative obtained in Example 77 and operating as illustrated in Example 78, 0.55 IO g of ~he tLtle compound were obtained.

EXAMPLE 80: (5R)-Acetonyl-2-[(,5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl]-6-(L-p-nitrobenzyloxycarbonyloxyethyl)-2-penem-3-carboxylate. Reaction (ll) - (1). -N
OCO2PNB N _ N
S ~ S S cr~3 OC ~ ~ S ~ S ~CH3 PPh3 ) N ~
COOCH2coC~f3 o /-- cOOCH2COCE13 ~ O
0.6 g of the compound prepared in Example 78 were dissolved ln 50 ml of toluene and refluxed under nitrogen for three hours. The title compound was purified by short column chromatography on silica gel eluting with dichloromethane:

ethyl acetate (8:2). There was obtained O.Z5 g of the title compound. I.R. : 1795, 1750, 1720.

EXP~PLE 81: (5R)-AcetonYl-2-l(1,2,3-triazol-5-yl)-thiomethyl]-6~ p-nitrobenzyloxycarbonyloxyethyl)-2-penem-3-carboxylate~
Reaction (11) - (l)o ~Z~ 6S

( .

.
N

OCO2PNB ; ~ S ~N ~
li 2 ~ 4 ~ 5 N

cooc~l2cocH3 '--> ~

IO Starting from 0.45 g o the compound prepared in Example 79 and operating as shown in Example 80, 0.180 g of the title eompound were obtained. I.R.: 179S, 1750, 1720.

EXAMPLE 82: t5R)-Acetonyl-2-t(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyll-6cY-(l-hydroxyethyl)-2-penem-3-carboxylate.

Reaction ~1).
N - Nl N - N

OCO PNB ~ Otl S S ~: I ] ~IS_~ S ~ S J~CH

~ N

0.450 g of the compound prepared in Example 80 were dissolved in 25 ml of acetonitrile containing a ew drops of ethanol and hydrogenated over 10% Pd on carbon (400 mg).
The eatalyst was removed by filtration and the filtrate was chromat~graphed on siliea gel eluting with dichloro-methane:ethyl acetate (7:3), giving 0.18 g of the title eompound.
I.R. : 3605, 1795, 1745, 1720.

EX~MPLE 83: (5R)-Acetonyl-2-ttl~2~3-triazol-5-Yl)-thiOmethyll -6c~-(1-hydroxyethyl)-2-penem-3-earboxylate. Reaction ~1).

, .

--: lZ~

9) ~ S~

COOCH2COCH3 o COOCH2COCH3 Starting from 0.380 g of the compound prepared in Example lO 81 and operating as in Example 82, 0.12 g of the title compound were obtain~d.
I.R. : 3610, 1795, 1750, 1720.

EXA~PLE 84: ~SR)-2[(5-Methyl-1,3,4-thiadiazol-2-yl)-thio-methyl]-6-(1-hydroxymethyl)-2-penem-3-carboxylic acid.
Reaction (1). N _ N N - N

~ 9 ~f 9J~ 9 ~ CU3 1,~9~9 J~ 9 1193 A solution of 0.200 g of the compound prepared in Example 82 in acetonitrile (30 ml) containing a few drops of water was cooled at 0C; 5 ml of 0.1 N NaOH 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 driea over 30 Na2SO~ and evaporated giving 0.110 g of the title compoundO
I.R. : 3500, 1795, 1665~

lZ121~S

1EXA~PLE 85: (5R)-2-[(l,2,3-Tria~ol-5-yl)-thiomethyll-6 (l-hydroxyethyl)-2-penem-3~carboxy~ic acid. Reaction ~1).

N ~~l 5 ~NN

' - COOCH2COCH3 N COO}I

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

EXAMPLE 86~ 4~ Carbamoyloxymethyl)-vinylthio-3~-(1-p-nitrobenzyloxy-carbonylox~thyl)-l-(l-methoxycarbonyl-2-methyl-l-propenyl)-azetidin-2-one-S-oxide. Reaction (4) -OC02PNB ¦¦ O
OH OCo2PNB ll 0 ~ OOC~3 ~ ~ 5 ~ OCO~U

2.2 g of the compound prepared in Example 66 were dissolvedin 30 ml of acetonitrile and cooled at 0C. Then 0.8 ml of chlorosulphonyl isocyanate were added under nitroyen 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 yave 1.5 g of the ti-tle compound.

~LZ~ 5 1 EXAMPLE 87. 4~ Carbamoyloxymethyl)-vinyltllio-3-(1-~

nitr.ob~enzyloxy-car~;onl~loxy-~thyl-l-(l-methoxycarbonvl-?-methyl-l-propenyl)-azetidin-?-one. Reaation (4) - ~12).

OC02PNB ~1 , ~ ~ S ~ OCONH OC02PNB
" ~ ~ ~ S~/~ OCONH2 ' COOCI13 N ~
'' COOCH

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: ~-(1-Carhamoyloxy)acetylthio-3~-(1-p-nitrobenzyloxy-carbonyloxyethyl)-l-methoxyoxaloyl-azetidin-2-one. Reaction (12) - (13).

jOC02PNB
S OCO~PNB

h~ ~jl/\OCONH2 ~ CONH2 L -~ )~NI
COOCH3 ~

Starting from 2.2 g of the compound prepared in Example 87 and operating as illustrated in Example 70, 1.4 g of the title compound were obtained.

EXAMPLE 89: 4~-(1-Carbamoyloxy?-acetylthio-3~-(1-p-" nitrobenzyloxy-carbonyloxyethyl)-azetidin-2-one.

Reaction (13) - ~14).

3~

~ ~ S~ OCONH2 OCO PNB
_ N ~ ~ ~ OCONfl~

, ' OOCH3 ~ ~ \ H
, Starting from 1.4 g of the compound prepared in Example 88 and ope,rating as shown in Example 72, O.g g of the title compound were obtained.
EXAMPLE 90: 4~ Carbamoylox,y)-acetylthio-3~ p-nitrobenzyloxy-carbonyloxyethyl)-l-ll-acetonyloxycarbonyl-1-hydroxyme-thyl)-azetidin-2-one. Reaction (14) - S15).
2 NB OC02PNB 5 ~
s " COOCH2COCH3 Starting from 0.9 g of the compound prepared in Example 89 and 0.6 g of ace-tonyl glyoxylate and operating as in Example 79, the crude carbi lamide was obtained.
EXP~IPLE 91: 4~-tl-Carbamoyloxy)-acetylthio-3~-ll-p-..... . . _ . _ _ .. _ , n'itrobenzyloxy-carbonyloxyethyl)-l-(l-acetonyloxycarbonyl- ---l-chloromethyl)-azetidin-2-one. Reaction (15) - (16).
'~ OC02PNB
' ~ ~ 2 OlCO ~ S ~ OCONH2 08 ''''~~~~ ~ Cl OOC~2COCH3 ~r - 6~ -- .

121Z6~
~.

i Starting from the crude product obtained in Example 90 and operating as in Example 76, the crude chloroderivative was obtained.
E~U~PI.E 92: 4~ Carbamoyloxy)-acetylthio-3~-~l-p-nitrobenzyloxy-carbonyloxyetllyl)-1~ clcetonYlo-xy-carbonyl-l-triphenyl-~hosphoranylidenemethyl-l)-azetidin-2-one. Reaction (16) - (11).
OCO2PN~ S OCO PNB

~ ~ OCONH2 ~ 2 S ~ CONH2 ~ O N ~ PPh3 3 . COOCH2COCH3 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: (SR)-Acetonyl-2-carbamoyloxYmethY.l-6~ p-nitrobenæyloxy-carbonyloxyethyl)-2-penem-3-carboxylate~
Reaction (11)-(1).

~\ocoNH2 .~(\OCONH2 CoocH2cocH3 2COCH3 Star-~ing 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.

.

EXAMPLE 94: (5R)-Acetonyl-2-carbamoyloxymethyl-6-tl-hydroXy-ethyl)-2-penem-3-carboxylate. Reaction '~C02PNB OH
S~ ~ OCON~ 1 ~ OCONH
~; ~ ~ , 2 ~ 2 COOCH2COCH ~

Starting from 0.35 g o~ the compound prepared in Example 93 and operating as in Example 82, 0.11 g of the title compound were obtained.
EXAMPLE 9S: ~5R~-2~Carbamoyloxymethyl)-6a-tl-hydroxyethyl)-2-penem-3-carboxylic acid. Reaction tl).

~ 2 ~ ~ ~ \ ~ CONH2 o CoocH2cocH3 COOH

Starting from 0.11 g of the compound prepared in Example 94 20 and operating as in Ex~mple 84, 0.060 g of the title compound were obtained.

I. R. : 3400-3500, 1795, 1700-1650.
EXAMPLE ~6 ~a) 4~-AcetYlqlycolylthio-3a-[1-p-nitrobenzyloxycarbonyl-oxymethyl]-1-rl-acetonyloxycarbonyl-1-hydroxymethyl]-aze-tidin-2-one. Reaction ~14) - (15).

- ~4 -.

~ LZ665 lOC02I'NB
~f S~ocor~ 0:0_~ ' ,s OoCH2cocH3 A solution of 1.04 g of 4~-acetylglycolylthio-3u~[1-p-nitro- f benzyloxycarbonyloxyethyl]-azetidin-2-one, prepared according to Example 46, and 1.8 g of acetonyl glyoxylate in 20 ml of benzene was reEluxed for ~ hours. Evaporation of the solvent gave the crude title compound which was used for the next step without further purification.
(b) 4~Acetylglycolylthio-3~-[1-p-nitrobenzyloxycarbonyl-oxyethyl]-l-[l-acetonyloxycarbonyl-l-chloromethyl]-azetidin-2-one. Reaction (15) - (16).

0~C02PNB S OCO PNB
~J~OCOCS3 ~J ~ ~ \ ~ OCOC~l3 COOC~I2COCH3 0 ~COOCH COCH
The crude carbinolamide obtained from the ste2p (a)3was -dissolved in 20 ml of anhydrous tetrahydrofuran and cooled at 0C. Equimolar amounts 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.

~2~LZ6~S

1 ~c) 4~-Acetyl~lycoly~ th; ~ ~- tl-p-nitrohenzyloxycarbonYl-ox~ethyl~ [ac~tonyloxycarbonyl-l-t~iphenYlphosphoran~

lid~ne-methyl]-azetidin-2~one. Reaation ~16) - ~11).

~ . S OC02PNB
0COCil3 ~ ~ S

CoocH2coc~l3 ~ ~ PPh3 The crude chloroderivative was dissolved in 100 ml of 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 of the title compound .

(d? (5R)-AcetonYl-5cL-[l_p_nitrobenzyloxycarbonyloxyethyl-?-acetoxymethyl-2-penem-3-carboxylate. Reaction (11) - (1).

~ ~ S \ ~ OCOC~3 ) ~ COCII3 ~ ~ COOCH2COCH3 1.5 g of 4~-acetylglycolylthio-3-[1-p-nitrobenzyloxycarbon-yloxyethyl]-l-tacetonyloxycarbonyl-l-triphenylphosphorany-lidenemethyl]-azetidin-2-one were dissolved in 50 ml of toluene and refluxed for three hours. Evaporation of the solvent gave an oil which was purified by short column chromatograplly on silica gel eluting with (9:1) dichloro-methane-ethyl acetate. There was obtained 0.51 g of the title compound.

. . .

~Z~26~5 1 Erithro PMR ~CDC13): 1.46 td, J = 6.S }Iz, 3ll, CH3CH) 2.07 (s, 3H, OCOCH3) 2.16 ~s, 3N, COCH31 4.02 ~dd, J = 2.0, 4.0 }lz, lEI, H-6) 4.73 ~s, 211, C}12CO) 5.0 - 5.3 (m, lH, CHO) 5.12, 5.38 (dd, J = 15.5 Hz, 2H, CH20CO) ~ 5.22 (s, 2H, COCH2Ph) 7.4 - 8.5 (m, 4H, PhNO2) IR lCHC13j 1725 cm 1 C=O unsaturated esters, ketones 1750 cm 1 C=O esters 1800 cm 1 C=O ~-lactam hreo 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) 4.77 ~s, 2H, CH2CO) 5.0 - 5.4 (m, lH, CHO) 5.13, 5.42 (d, J = 16.0 Hz, CH2OCO) '? , 1 5.25 ~s, 2H, CH2Ph) 5.66 ~d, J = 2.0 Hz, lH, H 5) 7.4 - 8.5 (m, 4H, PhNO2) IR lCHC13) 1725 cm 1 C=O unsaturated esters, ketones 1750 cm 1 C=O esters 1800 cm 1 C=O ~-lactam '' , ~2~26~5 1 EXAM_ E 97: (5R)-Acetonyl-6a-[1-hydroXyethyl]-2-acetoXymethyl -2-penem-3-carboxylate. Reaction ~1).
OCO PNP
1~ ~s ,~ s ' 1 ~ CC~'3 ---~ r~ ocoC~3 N _ N _____~
I COOCH COCH I

O. 51 q of (SR)-acetonyl-6a-11-p-nitrobenzyloxycarbonyloxy-e~hyl]-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 for 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, qiving 0.20 q of pure product.
Srithro P~R (CDC13): 1.38 ~d, J=6.5 Hæ, 3H, CH3CH) 2.09 (s, 3H,OCOCH3) 2.20 (5, 3~l,CO~ ) 3.86 (dd, J=2.o,34.o Hz, lH, H-6) 4.22 ~dq, J=6.5, 4.0 Hz, lH, CHOD) 4.72 ~s, 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, OCOCE13) 3~ 2.20 ~s, 3H, COCH3) :
~%~z~

1 '3.06 ~bs~ lH~ OH) 3.74 (dd, ~2.0, l.0 MZ, lH, H-6) 4.23 (m, lU,' CHOH) 4.77 ~s, 2H, CH2CO) 5.12, 5.38 ~d, J=16.0 Hz, 2~1, CH2OCO) 5.63 ~d, J=2.0 }Iz, lH, H-5) ` EX~MPL~ 98: '(5R)'-2-Aee'to'xymethyl-6-(l-hydroxyethy].)-2-' penem-3-earboxylate s'odium salt. Reaetion (l~
OH OH
OCOCH3 ~ ~ COCH3 ' ' l COOC 2 3 COONa O.21 g of ~5R)-acetonyl-6-[1-hydroxyethylJ-2-acetoxymethyl-2-penem-3-earboxylate prepared according to Example 97 were dissolved in 20 ml of aeetonitrile and 3 ml of water.
The reaction mixture was eooled at 0C under nitrogen and 7.4 ml of a 0.lN NaOH aqueous solution were added slowly within 30 minutes. After evaporating acetonitrile under vaeuum, the residue was extracted twice with eold ethyl acetate. A C18 reverse phase ehromatography ~eluting with water~ of the concentrated aqueous phase ' gave 0~054 g of pure title eompound.
. .
' Erithro PMR (Dz0~'80mKz: 1.34 ~d, J=6.3 Hz~ 3H~
C~3CH) 2.14 ~s, 3H, OCOCH3) 4.01 (m, lH, H-6) , Z6~5 4, 22 ~m, 1H, C~IOIII
5.10~ 5.4q td~ J=14.0 HZ~ 2~, Cll20CO) 5.63 ~d, J~1.0 Hz, lH, Il-5) U.V. (ethanol 95%): ~ max 262 nm~c 2000)~ 308 nM ~ 2520 ¦~D--128 (C=0.92, l120) Threo PMR (D2O): 1.31(d, J=6.5 H~ 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, C~12OCO) 5.67 (d, J=1.5 Hz, lH~ H-5) U.V. ~ethanol 95~ max 262 nm( 3410), 308 nm( 43q0) EXP.~IPLE 99 - 5R-pivaloyloxymethyl-6(S)¦_l(R)hydroxyethyl -2-carbamoyloxy-methyl-2-penem-3-carboxylate.
.. ..

OH OH
~f ~ OCO~ 2 ~ ~ , OJ ~l ~ COOH ~ X OCONH2 29 COOCH2OCO +

775 mg of 5R-6(S)/ l(R)11ydroxyethyl ~ -2-carbamoyloxymethyl-2-penem-3-carboxylic acid (as prepared in example 95), dissolved in 15 ml of dimethylformamide were treated with an equimolar amount of NaH, 50 mg of dimethylaminopyridine and 1.15 ml of pivaloyloxymethylchloride at A0C for 4 hours. The reaction mixture was diluted with ethyl acetate, ~7ashed with ~:ater, dri~d over l~la2SO4 and the solvent evaporated. The residue consisted of 480 mg of pure title compound, , ~0 .

:121Zf~5 .

I U.V. (EtOH 95~) max 325 (~ 7000) I.R. ~CIIC13~: 3540, 3420, 1795~ 1750 P.~.R. ~200 MHz, CDC13):
1.21 (s, 9EI~ ~cEl3'3' 1.33 ~d, J~6, 3EIz, 3EI, CHCH3) 3.75(dd, J~l.S, 6.4Hz, lH, 11-6) 4.23 ~m, lEI, CEIOH) 4.76 ~bs, 21{, CONH2) S .08, 5.42 (two d, J~15.8Hz, CH2OCO~H2) IO 5.62~d,J=l.SEIz, lH, H-S~
5.81, 5.91 (two d, J=5.5Hz, OCH2OCOC (CH3~ 3) ~: ' ' ' ' .

.

.

Claims (18)

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 0 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 R5 are as above defined with PBr3 in dimethylformamide at a temperature of from about -40°C to about 0°C, or Claim l 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, (b) 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) wherein 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) condensing the resultant compound of the formula (VI) (VI) Claim 2 continued wherein n=0, 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-0, 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) wherein 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 cornpound 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 preparing 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 R5 represents an alkyl group and R1 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=0 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; 1-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, 1-hydroxy-ethyl, 1-(p-nitrobenzyloxycarbonyloxy) -ethyl and 1-(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)-thiomethyl-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 S-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 by 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.-(1-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 1 for preparing (5R)-2-(carbamoyloxymethyl)-6.alpha.-(1-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) reacting the resultant compound with chlorosulphonyl isocyanate in acetonitrile;
(d) reducing the resultant compound;
(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 glyoxylate in benzene;
(h) chlorinating the resultant compound;
(i) condensing the resultant compound with triphenyl-phosphine;
(j) cyclising the resultant compound in toluene;
(k) hydrogenating the resultant compound; and (l) hydrolysing the resultant compound.

14. (5R)-2(Carbamoyloxymethyl)-6.alpha.-(1-hydroxyethyl)-2-penem-3-carboxylic acid whenever prepared by a process as claimed in claim 13 or an obvious chemical equivalent thereof.

15. A process as claimed in claim 1 for preparing (5R)-2-acetoxymethyl-6.alpha.-(1-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 phosphine;
(i) cyclising the resultant compound in toluene;
(j) hydrogenolysing 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 process as claimed in claim 1 for preparing 5R-pivaloyloxymethyl-6(S) [1(R)hydroxyethyl]-2-carbamoyloxy-methyl-2-penem-3-carboxylate which comprises (a) reacting methyl-6-(1-p-nitrobenzyloxycarbonyl-oxy-ethyl)-3-penicillinate-S-oxide with propargyl alcohol in toluene;

Claim 17 continued ...

(b) isomerizing the resultant compound;
(c) reacting the resultant compound with chlorosulphonyl isocyanate in acetonitrile;
(d) reducing the resultant compound;
(e) oxonizing the resultant compound in dichloromethane;
(f) solvolyzing the resultant compound in the presence of silica gel;
(g) condensing the xesultant 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 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 pre-pared by a process as claimed in claim 17 or an obvious chemical equivalent thereof.