NZ192949A

NZ192949A - Compounds with penicillin ring structure and pharmaceutical compositions

Info

Publication number: NZ192949A
Application number: NZ192949A
Authority: NZ
Inventors: M Foglio; H Franceschi; C Scarafile; F Arcamone; A Sanfilippo
Original assignee: Erba Farmitalia
Priority date: 1979-02-24
Filing date: 1980-02-22
Publication date: 1984-03-16
Also published as: CA1154010A; YU42964B; IT1193922B; CH651570A5; ES8200685A1; IT8020021A0; GB2043639B; AT368506B; AU535080B2; UA6041A1; FI75163B; CA1212665B; GB2043639A; SE449489B; IE800338L; NL8001012A; NO161000C; ES495977A0; DK159448C; HK74487A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 1 92949 t 92949 ; 1,-yjoarHY Dstsw •• ^ g, S Complsto Specification Filed: i , Afel£ •uta~ MH&J84-. ' 1555 ?ub!icat!on Date: - O, J&urnai ftis: I^PATBfTQflai^ 2 2F£B 1980 * fieCQVEo NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION g-LACTAM CONTAINING ANTIBACTERIAL AGENTS AND (5-LACTAMASE INHIBITORS AND PREPARATION THEREOF XK/We, FARMITALIA CARLO ERBA S.p.A., Via Carlo Imbonati, 24 - Milan, Italy, an Italian Company hereby declare the invention for whichXK/ we pray that a patent may be granted to hjk/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - _ 1 _ (followed by page la) \9l9t-9 This invention relates to 3-lactam-containing compounds, to processes for their preparation, and to compositions containing them. More particularly, the present invention relates to penem-carboxylic acids of the formula: (0), / 6 5 ' 1 2 7 4 o si J (1) COOR ov wherein R is a hydrogen atom, lower alkyl, 2,2,2-trichloroethyl, acetonyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p-nitrophenyl, benzyhydryl, or a residue known to undergo metabolic activation "in vivo" and having favorable pharmacokinetic properties, including acetoxymethyl, pivaloyloxymethyl or 2 phthalidyl or a group of the formula -CH-OCOOC^H^ or -CH^NHCOR CH, 2 in which R is alkyl having from 1 to 5 carbon atoms, cycloalkyl or aryl; either R"*" is a hydrogen atom, and Z represents hydrogen or halogen atom, hydroxy, amino, carbamoyloxy, mercapto, pyridinium, or a group of the formula 3 3 3 4 -3 4. OR , OCOR , NHCOR , or 1 SR wherein each of R and R is lower alkyl, aryl or a heterocyclic ring, each of which may be substituted or unsubstituted, or R"*" is lower alkyl, lower alkoxy, cycloalkyl or hydroxy- alkyl (preferably lower hydroxyalkyl), the alcoholic function of the hydroxy alkyl being free or protected, the protecting group being preferably p-nitrobenzyloxycarbonyl or dimethyl-t- butyl-silyl, and Z represents a pyrazinylthio, carbamoyloxy or pyridinium group; and n is 0 or 1. The substitution of the 6 position has the a-configuration as well as the ^-configuration. The a-configuration is preferred. The terms "lower alkyl" and "lower alkoxy" mean alkyl and alkoxy each having from 1 to 4 carbon atoms. - la - I92949 Examples of residues included within the definition of R that are known to undergo metabolic activation "in vivo" and have favorable pharmacokinetic properties, include acetoxymethyl, pivaloyloxymethyl, and phthalidyl and groups of the formulae -CH.OCOOC„H and -CH„NHCOR2. I 25 2 CH3 Representative values of R^" include methyl, ethyl, methoxy, 1-hydroxyethyl, and 1-(p-nitrobenzyloxycarbonyloxy)- ethyl, and 1-(dimethyl-t-butyl-silyloxy)-ethyl. 3 4 R and R , when heterocyclic, are preferably a 5- or 6-membered heterocyclic ring residue, for example 5-methyl-l,3,4-thiadiazol-2-yl, l-methyl-tetrazol-5-yl, 1,2,3-triazol-5-yl or pyrazinyl. These compounds possess a wide spectrum of antibacterial activity and also have g-lactamase-inhibiting activity. It should be pointed out that the stereochemistry at of the novel £3-lactam-containing compounds, including the intermediates for their preparation, is identical to the naturally-occurring penicillins and cephalosporins. Pharmaceutically acceptable salts of penem^carboxylic acids of formula (1) including sodium, potassium, benzathine, procaine, and like salts usually formed with penicillins and cephalosporins, are also within the scope of the invention. The invention also includes processes of preparing the compounds of formula (1), intermediates therefor, and pharmaceutically acceptable compositions containing the compounds of formula (1) in admixture with the usual carriers for oral and parenteral administration. The following diagram illustrates the preparation of the compounds of formula (1) according to the invention. 1 92949 - 3 - COOR5 ^ O' N X^OH^-Y COOR (7) (14) 30 JAN 1931 (o) I I X *>// •N. fY N (n=l^ (8) v-0(^f O) II CI ^ COOR O' o OH COOR (O) II n (15) \ Y PPh„ ay N COOR t—PPh (9) | 3 <r ~NV O CI COOR t£ COOR I (16)* ✓ S. ^X Y x "N . r rPPh3 COOR o^ \COOR <— • N X (£ot -PPh. OOR (1: n=0) (17.) •i o -? q ■; o I / y When R"*" is hydrogen, compounds of formula (2) are prepared starting from (5R) 6-aminopenicillanic acid (6-APA), following the widely-known general procedure (see CIGNARELLA et al., Journal of Organic Chemistry, 27, 2668 and EVRARD et al., Nature, 201, 1124) . When R"1" is lower alkyl, cycloalkyl, or hydroxyalkyl, the R"*" group can be introduced according to the procedure of Di Ninno et al., Journal of Organic Chemistry, 42, 2960 (1977). When R1 is lower alkoxy, the R^" group can be introduced in the 6-position starting from 6-APA in accordance with the procedure of Hauser et al., Helv. Chem. Acta, 5£; 1327 (1967) and Giddings et al., Tetrahedron'Letters, 11, 995 (1978). " I Alternatively compounds of general formula (2) in which R"*" is H can be converted to compounds of the general formula (2) in 1 ^ which R as lower alkyl, cycloalkyl or hydroxyl introducing the substituent into the 6 position using a strong base as illustrated in the following examples. Compounds of formula (2) in which 'is lower alkyl, cycloalkyl or hydroxyalkyl can be prepared also starting from a suitable ester 0f the penicillanic acid S-oxide, as illustrated in the following examples. The substitution of the 6 position is stereo-specifically directed to the 6a derivatives. The ester of penicillanic acid S-oxide (2) wherein R5 is a lower alkyl group and R^" is as above defined, may be heated in an inert solvent, such as benzene or toluene, usually at a temperature of from 70°C to 14 0°C, with a suitable acetylenic derivative of the general formula X'CsCY wherein X' is a group of the formula CH,Z' wherein Z' is a hydrogen or halogen atom, 3 3 hydroxy, amino, carbamoyloxy or a group of formula OR , OCOR , 3 3 or NHCOR where R is lower alkyl, aryl or a heterocyclic ring, any of R being optionally substituted, and Y is a hydrogen atom, lower alkyl, cyano or a group of the formula COOR5 or CHjZ' wherein R5 and Z' have the meanings given above. In the compounds of formula (3), X', when different from X, can be con verted to a group X, wherein X is a group of the formula CI^Z wherein Z has the meaning given to it supra by means of the widely-known substitution reactions, one example of which i;s given in the following examples. The compound of formula (3) may be isomerized by using a base into the compound of _ 4 _ 192949 i fetfT ^Ac- formula (4) which can be converted to the final compound of formula (1) in two different ways. In the first way, the compound of formula (4) may be ozonized selectively on the isopropenyl double bond to give a compound of formula (5) where n = 1, which may be reduced to a compound of formula (5) where n = 0 with suitable 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 formula (9) where n = O. Moreover, 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 withdrawing group. In the case involving the compound of formula (9) where n = 0, the compound may be selectively ozonized as a phosphonium salt in acidic conditions to give the compound of formula (11), which is cyclised to the compounds of formula (1), simply by heating in an inert solvent, such as toluene, at a temperature of from 50°C. to 140°C. ^ Q In case compound of formula (9) where n = 1, the compound must be reduced to the compound of formula (10) and V^CE^S i-. subsequently selectively ozonized to the compound of formula (11) , which gives in turn the compound of formula (1). In the second way, the compound of formula (4) may be reduced in the usual conditions to give the compound of formula (12), which is ozonized on both double bonds to giv6 the compoun> - 5 - 1 92949 of formula (13) and, after hydrolysis, the compound of formula (14). Following the same procedure as in the previous way, glyoxylation of the compound of formula (14) gives the compound of fonuula.._(15) , which may be. transformed to the chloroderivati.%' of formula (16) and then to the phosphorane of formula (11), which is a common intermediate for both ways. When R^- is hydroxyalkyl, the 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 compounds. Compounds -of formula 41) in which rr = 1 are easily prepared starting from compounds of formula (1) in which n = 0, following tne widely known oxidation processes. Peracids can be advantageously used; m-chlorperbenzoic acid"and -peracetic acid are preferred. The processes illustrated hereinabove are within the scope of the invention. A series of tests was carried out in vitro to compare the activities of (5R) acetoxymethyl-2.-acetoxymethyl-2=.penem-3-carboxylate (Laboratory code FCE/20077/S40/341), (5R) acetoxy-methyl-2- [ (l'-methyl-l'H-tetrazol-5-yl) -thiomethyl] -2-penem-3-carboxylate (compound A) and two reference compounds (ampicillin and cefoxitin). Table 1 below, reports the results of the above assays as MIC (minimal inhibitory concentration). 1 92949 TABLE 1 MIC yig/ml Strains FCE/2Q077/B40/34I Compound A flmpicillin Cefoxitin Staphylococcus aureus 209P 0 . 39 0 . 39 _< 0.19 0.78 Staphylococcus aureus 153 1.56 0.78 1.56 0.78 Staphylococcus aureus FV2 .. 0.39 0.78 <_ 0.19 0.78 Staphylococcus aureus Smith ATCC 13709 £ 0.19 0.39 f 0.19 0.78 Streptococcus pyogenes ATCC 12384 3.12 0.78 3.12 1.56 Escherichia coli B 1.56 0.78 0.39 1.56 Escherichia coli V14 1.56 0.78 1.56 3.12 Escherichia coli V23 3.12 0.78 3.12 12.5 Enterubacter sp. V19 . 12.5 > 100 > 100 12.5 Klebsiella pneumoniae ATCC 10031 - 3.12 50 0.78 Klebsiella sp. R2 25 - 50 12.5 Proteus vulgaris V15 3.12 6.25 1.56 0.78 Proteus mirabilis V15 0.39 0.78 <_ 0.19 0.78 Proteus mirabilis 525 3.12 0.78 0.39 1.56 Shigella flexneri 0.39 0.39 <_ 0.19 0.78 Pseudortcnas aeruginosa 3.12 0.39 25 6.25 Salmonella typhimurium 1.56 0.78 0.78 3.12 Salmonella panamae F15 1.56 0.78 0.78 1.56 Salmonella Saint paul F20 1.56 0.78 0.78 3.12 Salmonella derby F14 3.12 0.78 0.78 3.12 Salmonella irontevideo F16 3.12 0.78 0.78 3.12 The following examples are illustrative but should not be regarded as limiting the invention. -7" H 92949 EXAMPLE 1 4 g-Vinylthio-[1,2-diacetoxymethyl]-1-[methoxycarbonyl-2-methy1- / 2-prope'nyl] -azetidin-2-one-S-oxide. Reaction (2)-(3) r N- z;—s. ^ OCOCH, 3 i—f °coch3 «/ in , a*1— N>AS/ococ,i3 0 H tOQCH. A ^ H COOCH3 A solution of 2.0 g of methylpenicillinate S-oxide and 2.8 g of butyndiol diacetate in 40 ml of toluene was heated at 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 was" obtain-ed 1.4 g of 4£-vinylthio-[1,2-diacetoxymethyl]-1-[l-methoxycarbonyl-2-methyl-2-propenyl]-azetidin-2-one-S-oxide. II PMR (CDC13) : 2.036 (s,CH -C-), 2.15 and 2.20 6(two s, 2CH3CO), 2.885 (dd, Jgem = 14 Hz, Jvic cis = 4 Hz, C-3-Hct) , 3.386 (dd, Jgem = 14 -Hz, Jvic trans - 2 Hz, C-3-Hg) , 3. 836 (s, CH30) , 4.886 (d, Jvic = 6 Hz, Cfl„-C=) 2 ! (H) 4 .926 (broad s, CH9-C=) , || 1 -N C \ / 4.9 3-5.3 36 (m, = CH and CH ) & I COO 5.326 (dd, Jvic = 4 and 2 Hz, C-4-H), 6.476 (t, Jvic = 6 Hz, =C-C(H_) ) i 2 -8- CI 929 4 9 EXAMPLE 2 4i3-Vinylthio- [1, 2-diacetoxyraethyl] -1- [l-methoxycarbonyl-2-methyl-1-propenyl]-azetidin-2-one-S-oxide. Reaction (3)-(4) p.S—OCOCH I ' II V / OCOCH COOCH. fjC N'* COOCH, OCOCH. OCOCH. 1.7 g of 4g-vinylthio-[1,2-diacetoxymethyl]-1-[1-methoxycarbonyl-2-methyl-2-propenyl]-azetidin-2-one-S-oxide were dissolved in 8 0 ml of dichloromethane; 0.5 ml of triethylamine were added and the solution was left for a few hours at room temperature. After evaporating the solvent, the title compound was obtained pure in quantitative yields. PMR (CDC13) 2.13 (9H) and 2.32 (3H)6 (two s, 2 CH3CO and I 2 CH3-C=) 2.92<5 (dd, Jgem = 15 Hz, Jvic cis = 5 Hz, C-3-Ha) , 3.386 (dd, Jgem = 15 Hz, Jvic trans-- 2.5 Hz, C-3-HB) , 3. 826 (s, CH30) , 4.886 (d, Jvic - 4.926 (s, CH2-C=) 6.5 Hz, CH -C=) 2 I (H) 5.156 (dd, Jvic = 5 and 2.5 Hz, C-4-H), 6. 506 (t, Jvic.6.5 Hz, = C-(H-) ) I z H -9- 1 92949 EXAMPLE 3 4 8-Vinylthio-[1,2-diacetoxymethyl]-1-methoxyoxaloyl-azetidin-2-one-s/-oxide. Reaction (4)-(5) 0' /S COOCH. OCOCH OCOCH OCOCH. OCOCH. 2.0 g of 40-vinylthio-[1,2-diacetoxymethyl]-1-[1-methoxycarbonyl-2-methyl-l-propenyl]-azetidin-2-one-S-oxitte-; wer-e dissolved in 150 ml of dichloromethane.-and, after cooling at -78°C, a flow of ozone in oxygen was bubbled into the cooled solution until a slightly blue color appeared. The solution was warmed to room temperature, shaken with an-aqueous.solution of Na2S20,-, and dried over Na^SO^. The.~resulting organic phase gave, after evaporating the solvent "in__vacuo" , 1.4: g of the title compound. PMR (CDC1. (two s-,- 2 CH3CO) , 2.0 5 and 2.0! 3.035 (dd, Jgera = 17 Hz, Jvic cis = 5.5 Hz, C-3-ffa) , 3.506 (dd, Jgem = 17"Hz", Jvic trans = 3 Hz, C-3-H&) , 3.906 ts,"CH30), 4.826 (d, Jvic = 6.5 Hz, CH0-C=) 2 i 4.906 (s, CH2-C=) , 5.326 (dd, Jvic = 5.5 and 3 Hz, C-4-H), 6.476 (t, Jvic = 6.5 Hz, =C-C(H_). i 2 IR (CH2C12) 18 30 cm 1750 cm -1 -1 -1 B-lactam C=0 esters C=0 1715 cm amide C=0 -10- II 92949 EXAMPLE 4 4g-Vinylthio-[1,2-diacetoxymethyl]-l-methoxvoxaloyl-azetidin-2-one Reaction (5) OCOCH. OCOCH, HVO I COOCH, >° doc OCOCH, OCOCH. OOCH. A solution of 1.4 g of 43-vinylthio-[1,2-diacetoxymethyl]-1-methoxy oxaloyl-azetidin-2-one-S-oxide in 10 ml of anhydrous dimethylforra-amide was cooled at -25°C and 0.9 ml of phosphorous"tribromide were added thereto. After 10 minutes, the mixture was diluted with ethyl acetate and washed twice with a saturated solution of NaHCO.j. After drying over Na^SO^ and evaporating the solvent, 0.9 g of the title compound were obtained. PMR (CDC13) 2.076 (s, 2 CH3CO), 3.175 (dd, Jgem = 19 Hz, Jvic trans=3.5 Hz, C-3-H3) , 3.656 (dd, Jgem = 19 Hz, J-vic cis = 5 Hz, C-3-Ha) , 3.906 (s, CH30), 4.736 (d, Jvic =-6.5 Hz, CH -C=) ^ I (H) 4.886 (broad s, CH„-C=), 2 l 5.525 (dd, J vie = 5 and 3.5 Hz, C-4-H) 6.256 (t, Jvic = 6.5 Hz, =C-C(H.) H IR (CHC13) 1815 cm 174 5 cm -1 3-lactam C=0 esters C=0 1710 cm amide C=0 -11- 1 929 4 9 EXAMPLE 5 4g-Vinylthio-[1,2-diacetoxymethyl]-azetidin-2-one. Reaction (5)-(6) . azetidin-2-one were dissolved in 100 ml of methanol and a few grams of silica gel were added under stirring. After one hour, [ the silica gel- was filtered _off and the methanolic soLution evaporated, to give 0.8 g of 4g-vinylthio-[1,2-diacetoxymethyl]-azetidin-2-one. PMR (CDC13) : 2.256 (s, 2.CH3CO), 2.985 (dd, Jgem = 15 Hz, Jvic trans=2 Hz, C-3-H£), 3.486 (dd, Jgem = 15 Hz, Jvic cis = 4.5 Hz, C-3-Ha), j 4.785 (d, Jvic = 7 Hz, CH-,-C=) , 1 i (H) 4.876 (s, CH2-C) , 5.036 (dd, Jvic = 4.5 and 2 Hz, C-4-H), 6.026 (t, Jvic = 7 Hz, = C-C(H-) ) I 2 H 7.136 (broads, N~H). IR (CHC13) : 1770 cm"1 g-lactam C=0 1740 cm ^ esters C=o .1 929 4 9 EXAMPLE 6 4S-Vinylthio-[1,2-diacetoxymethyl]-azetidin-2-one-S-oxide. / Reactiqn (5)-(6) 0 0 II OCOCH OCOCH 3 3 OCOCH OCOCH 3 3 0 >° COOCH 3 0.8 g of 43-vinylthio-[1,2-diacetoxymethyl]-1-methoxyoxaloyl-azetidin-2-one-S-oxide were dissolved in 80 ml of methanol and a few grams of silica were added under- -stirring. After one hour the silica gel was filtered off and 0.5 g of 43-vinylthio-[1,2-diacetoxymethyl]-azetidin-2-one-S-oxide were obtained after evaportion of the solvent. PMR (CDC13) : 2.136 (s, 2 CH3CO) , 3.0-3.36 (m, 2 protons at C-3) , 4.706 (m, C-4-H) 4.886 (d, Jvic = 6 Hz, CH^-C=) 2 f (H) 4.936 (s, CH2-C=) 6.536 (t, Jvic = 6 Hz, =C-C(H ) ) I ^ 1745 cm ^ esters C=0 f J Li 929 4 9 EXAMPLE 7 4B-Acetylglycolylthio-l-acetoxymethyloxyoxaloyl-azetidin-2-one. Reaction (12)-(13) . carbonyl-2-methyl-l-propenyl]-azetidin-2-one were dissolved in 80 ml of dichloromethane, cooled at -78°C and a flow of ozone in oxygen was bubbled into the cooled solution until a blue color appeared. The solution, after it shaking with an aqueous solution of Na„S„Oc, was dried over Na_SO. to give 0.45 g of £ 1 D £. 4 the title compound. PMR (CDC13) : 2.10 and 2.136 (too s, 2 CH3CO). cooch2ococh3 cooch2ococh3 0.8 g of 46-vinylthio-[1,2-diacetoxymethyl]-1-[1-acetoxymethyloxy- 3.206 (dd, Jgem = 17 Hz, Jvic trans = 3.5 Hz, C-3-HB) 3.776 (dd, Jgem = 17 Hz, Jvic cis = 5.5 Hz, C-3-Ha), 4.736 (s, -co-ch2~oco-), 5.736 (dd, Jvic 5.5 and 3.5 Hz, C-4-H) 5.876 (s, coo-ch2-oco). -14- 392949 example 8 * 4g-Acetylglycolylthio-azetidin-2-one. Reaction j !!$-_( 14) ococh3 r—t^v^ OCOCH j »--0n > n* N' 0 " T= o cooch3 H 0.6 g of 4 3-acetylglycolylthio-l-methoxyoxaloyl-azetidin-2.-one were dissolved in 100 ml of methanol and a few grams of silica -gel were added as the solution was stirred. After one hour, .the silica gel was filtered off and the resulting solution gave, after evaporation of the solvent, 0.35 g of the title compound.— PMR (CDC13) : 2.206 (s, CH3C0), 3.035 (dd, Jgem = 16 Hz, Jvic trans=2.5 Hz, C-3-Hf3) , 3.506 (dd, Jgem = 16 Hz, Jvic cis=4.5 Hz, C-3-Hcc) , . A.IIS (s, -CO-CH2-OCO-), 5.32 6 (dd, Jvic = 4.5 e'_2.-5 Hz, C-4-H) , - -6 . 406 (broad s, NH) . EXAMPLE 9 4g-Vinylthio- [ 1,2-diacetoxymethyl] -1- [ 1-acetoxvmethyloxycarbonyl-r 1-hydroxyraethyl] -azetidin-2-one. Reaction (6)-(7) & 3\ t tl ■ ococh3 °c0ch3 L_ I 1 ^ q ^ n x ococh 3 - o^ ^ 0c0ch3 h cooch2ococh3 -15- 1929 4 9 0.7 g of acetoxymethyl-glyoxylate (freshly prepared by the ozonolys:. of diacetoxymethyl fumarate) were dissolved in 30 ml of benzene and the resulting,, solution was refluxed for 20 minutes-through a JDaan-StarX .-appaxat&Fu After - cooling the solution at 50° to 60°C, 0.7 g of 4B-vinylthio-[1,2-diacetoxymethyl]-azetidin-2-one dissolved in 10 ml of benzene were added and the resulting solution was refluxed for 2 hours. The title compound was obtained in almost quantitative yields and can be used as a crude mixture for the i next step. A pure sample was obtained by preparative TLC,- for analytical purposes. - PMR (CDC13) : 2 .076 (s, 3 CH^O) , 2.976 (dd, Jgem-18 Hz, Jvic trans=2 Hz, C-3-HfS) h... 3.406 (dd, Jgem = 18 Hz, Jvic cis=4 Hz, c-3-Ha), 4.70 6 (d, Jvic = 6 Hz, CH -C=), ^ I (H) 4. 776 (s, CH2-C=) , : 5.0-5.4 5 (m, C-4-H and -N-CH-COO-) ' ! I I 0(H) 5.776 (s, - C00-CH2-0C0), €.126 (t, Jvic = 6 Hz, =C-C(H-) ) I l H EXAMPLE 10 4g-Vinylthio-[1,2-diacetoxymethyl]-1-[1-acetoxymethyloxycarbonyl-1-chloromethyl]-azetidin-2-one. Reaction (7)-(3) c00ch2cc0ch3 c00ch20c0ch3 -16- 1 92949 '! 0 . 6 g of 4 6-vinylthio- [ 1,2-diacetoxymethyl]-1- [acetoxymethyloxy- carbonyl-l-hvdroxymethyl]-azetidin-2-one dissolved in 15 ml of / tetrahyarofuran were cooled at 0°C; 0.115 ml of pyridine and ! -0,1(14 ml of thionyl chloride were added and the .resulting mixture i J was stirred for 10 minutes. The insoluble material was filtered off and -the solution was evaporated "in vacuo" at room temperature to give the title compound in high yield. A sample was purified on preparative TLC for analytical purposes, but the crude mixture can be used without purification for the next step... PMR (CDC1 ) : 2.146 (s, 3 CH3C0), 3.106 (dd, Jgem = 15.5 Hz, Jvic txans=2 Hz, C-3-H3), 3.556 (dd, J gem = 15.5 Hz, Jvic cis = 5 Hz, C-3-Ha) 4.776 (d, Jvic = 6.5 Hz, CH_-C=), ^ I (H) 4.836 (s, CH2-C=), 5.4-5.96 (m, C-4-H and -N-CHC1-COO-), 5.886 (s, -COO-CH2-OCO-), - - ■ 6.136 (t, Jvic = 6.5 Hz, =C-C(H„). i 2 EXAMPLE 11 4&-Vinylthio-[1,2-diacetoxymethyl]-1-[1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl]-azetidin-2-one. Reaction (8)-(9) -17- 1 9294 A solution of 0.4 30 g of 43-vinylthio-[1,2-diacetoxymethyl]-1-[1-acetoxymethyloxycarbonvl-l-chloromethyl]-azetidin-2-one, in 5 ml of tetrahydrofuran and 5 ml of dioxane containing 0.520 g of triphenylrphosphi-ne and 0.08 ml of pyridine, was stirred overnight at 50°C. The resulting phosphorane was purified by column chromatography on silica gel eluting with 70:30 dichloromethane-ethyiacetate; 0.400 g of the title compound were obtained. ... PMR (CDC13): 2.056 (s, 3 CH3C0), 4 . 705 (d Jvic = 6.5 Hz, CH2-(J=) H example 12 ~4 8-Acetylglycolylthio-l-[1-acetoxymethyloxycarbonyl-l-triphenyl-phosphoranylidenemethyl]-azetidin-2-one■ Reaction' (10)-(11) 0.7 of 4g-vinylthio-[1,2-diacetoxymethyl]-1-[1-acetoxymethyloxy-carbonyl-.l-triphenylphosphoranylidenemethyl]-azetidin-2-one were ■ dissolved in 40 ml of dichloromethane and, after cooling at -20°C 50 ml of a 10% solution of trifluoroacetic acid in dichloromethan were added. After few minutes, a flow of ozone in oxygen was 4.736 (s, CH -C=) ^ I 5.776 (s, -COO-CH2-OCO-) 5.906 (t, Jvic = 6.5 Hz, = C-C(H2) ) H 7.1-8.06 (m, 3C-H ). 6 5 cooch2ococh3 COOCH-OCOCHt C, -J -18- II 929 4 bubbled into the solution at -20°C until a slightly blue color appeared. At this point, the reaction was stopped and a few drops of trimethylphosphite were added. The organic soltuion was washed with a .saturated solution of NaHCO^ and dried over .Na^SO^ to give 0.550 of the title compound. PMR (CDC13): 2.10 and 2.156 (two d, 2 CH3CO), 4.725 (s, -CO-CH2-OCO~), 5.645 (s, -COO-CH2~OCO), 7.1-8.06 (m,.3 C^Hc). 6 5 EXAMPLE 13 (5R)-Acetoxymethyl-2-acetoxymethyl-2-penem-3-carboxylate, Reaction (11)-(1) f ■Ns ococh . 0 ■fcrPPh^ N" "ococh. \ 'C00CHo0C0CH3 COOCH2OCOCH3 0.7 g of 46-acetylglycolylthio-l-[1-acetoxymethyloxycarbonyl-l-triphenylphosphoranylidenemethyl]-azetidin-2-one were dissolved in..30..ml of dry toluene .and heated at re fluxing temperature for 2 hours. The reaction mixture, consisting of the title compound and triphenylphosphine oxide, was purified by a short column chromatography on silica gel, eluting with 97:3 dichloromethane-' ethylacetate, to give 0.250 g of. acetoxymethyl-2-acetoxymethyl-2-acetoxymethyl-2-penem-3-carboxylate. -19- 1929 4 9 PMR (CDC13) : 2.11 and 2.135 (two s, 2 CH^CO), / / 3.496 (dd, Jgem=16.5 Hz, Jvic trans=2 Hz, C-6-H8) , / 3.866 (dd, Jgem = 16.5 Hz, Jvic cis=3.8 Hz, C-6-Hct) , 15 -1Z? 3-^ 43<5 J[i3SE> J3.,- -T- 1 ~i .3 r _ 5.686 (dd, Jvic = 3.8 and 2 Hz, C-5-H), 5.876 (s, -COO-CH2~OCO-). IR (CHC13) : 1800 cm"1 ^-lactam C=0 1750-1725 cm 1 esters C=0 U.V. (EtOH): X max 325 nm. MS : m/e 315. 04108 (M+) calculated for C]_2Hi3N Q-js 315.04127. EXAMPLE 14 4 g-Vinylthio-(1,2-diacetoxymethyl)-1-(1-p.nitrobenzvloxycarbonyl-1-hydroxymethyl)-azetidin-2-one.. Reaction (6)-(7) The title compound was obtained following the same procedure of Example 9, using p-nitrobenzylglyoxylate which had been freshly prepared by the ozonoLysis of p-nitrobenzylfumarate. Quantitative yield. PMR (CDC13) .5: 2.1 ^s, 6H) ; 2.8-2.7 (m, 2H) ; 4.7-4.9 (m, 5H) ; 5.1-5.6 (m, 2H); 5.2 (m, 1H); 6.1 (m, 1 H); 7.5-8.3 (m, 4H). -20- 0 9294 9 EXAMPLE 15 / 4 g-Vinvlthio-(1,2-diacetoxyraethyl)-(1-p-nitrobenzyloxycarbonyl-1-chloi/omethyl)-azetidin-2-one. Reaction (7)-(8) wH°2 °ac s 0A0 COOCH2 VQ\ \H/ N02 The title compound was obtained following the procedure shown in Example 10. PMR (CDC13) <5: 2.1 (s, 6H) ; 2.8-3.7 (m, 2H) ; 4.7-4.9 m, 4H) ; 5.2-5.4 (m, 1H) ; 5.-4 (m, 2H) ; 6.1-6.3 (m, 2H) ; 7.5-8.4 (m, 4Ii) . . - EXAMPLE 16 4 3-Vinylthio-(1,2-diacetoxymethyl)-1-(l-fr-nitrobenzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)-azetidin-2-one. Reaction (8)--(9) ys N- OAc OAc 0 s> N > . , , NO COOCH2 \^-y 2 r PPh OAc OAc COOCH, NO, The title compound was obtained following the procedure of Example 11. -21- 1 929 4 9 EXAMPLE 17 4 $-AcetylglycolyTthio-l- (1-p-nitrobenzyloxycarbonyl-l-tripheny 1-phosphoranylidenemeth'yl)-azetidin-2-one. Reaction (9) -(11) > n l'o Y pph3 OAc cooch2 \or no2 The title compound was obtained following the procdure of Example 12. EXAMPLE 18 (5R)-p-nitrobenzyl-2-acetoxymethyl-2-penem-3-carboxylate. Reaction (11)-(1) I 0 OAc N N=- PPh. r OAc cooch, no. cooch^-/ q v-no, PMR (CDC13) 6 2~w /2 The title- compound was obtained following the procedure of Example 13. •J 3.75 (1H, dd, J = 2.3 Hz, 16.8 Hz, H-6a) 3.87 (1H, dd, -J = 3.6 Hz, 16.8 Hz, H-68) ; 5.14 (1H, d, J = 15.8, -C-CH20-); 5.50 (1H, d, J = 15.8 Hz, =C-CH20), 5.71 (1H, dd, J - 2.3 Hz, 3.6 Hz, H-5). [a] + 87° (C 1.2 CHC13). IR (CHC13) : 1800 (g-lactam, 1750 and 1720 cm"1. UV (EtOH) : 265 (e 11000) and 322 (e 7000) ran. M.S. : m/e 37 8 (M+) : M.p. : ' 122 °-123°C -22- a 92949 EXAMPLE 19 (5R)-2-Acetoxymethyl-2-penem-3-carboxylic acid. Reaction (1) OAc COOH 200 mg of (5R)-p-nitrobenzyl-2-acetoxymethyl-2-penem-3-carboxylate, prepared as described in Example 18, were dissolved in 12 ml of ethyl acetate. Then 8 ml of a 0.2 M NaHCO^ solution and 400 mg of 10% Pd/C were added and the resulting biphasic ►minutes mixture was shaken under hydrogen for 60 beesss. After, filtering-the catalyst, the aqueous phase was acidified with 20 ml of 5% -aqueous citric acid and extracted three times with methylene chloride. The organic layers were .dried over Na2S04 and evaporated to give 60 mg of the title compound. -1790 (8 lactam), 1735 and 1700 cm U.V. (EtOH) : 300 nm. . . I.R. (CHC13) -1 EXAMPLE 2 0 4 (1-Hydroxyrnethyl) -vinylthio-1- [ l-methoxycarbonyl-2-me-thyl--2-propenyl] -azetidin-2-one-S-oxide. Reaction (2)-{3)" — 0 II COOCH. OH H COOCH. 4 g of penicillanic acid methyl ester S-oxide were dissolved in 15 ml of toluene and refluxed with 15 ml of propargyl alcohol -23- 192949 for 8 hours. After evaporating in vacuo, the residue was / purified by short column chromatography on silica gel, eluting I with di'chloromethane-ethy±—acetate 1:1. 2.8 -g -taie "fci'tle 'COTCpOiind 'wesre -^irtaiTied PMR (CDC13) 6: 1.96 (bs, 3 H, 'c-OJ-) ; 2.91 and-3.35 (dd, 2H," J = 2 Hz, 5 Hz,- -15-Hz, eO-CH2-CH-S); 3.78 (s, 3H, COOCH3); 4.36 (bs, 2H, O^OH) ; 4.90-5.25 (m, 3H, CH-COOCH3 C-C=CH2); 5.35 (m, 1H, CH2~CH~S); I 5.88 (s, 2H, CH2=C-S). EXAMPLE 21 4|3- (1-hydroxymethyl) -vinylthio-1- [ l-methoxycarbonyl-2-Tnethyl-1-propenyl'}-azetidin-2-one-S-oxide . Reaction (3)-(4) 3.0 g of 4j3~ (1-hydroxymethyl)-vinylthio-1- [l-methoxycarbonyl-2-methyl-2-propenyl]-azetidin-2-one-S-oxide were dissolved in 100 ml o.f dichloromethane and left at room temperature for a few hours. -. After eva-porating the solvent, the residue consisted of pure title compound "in a quantitative yield. PMR (CDC13) <5: 2.08 (s, 3H, =]-gj •) ; 2.18 (s, 3H, =LCH3) ; 2.7-3.6 (m, J = 2 Hz, 5 Hz, 16 Hz, CO-CH2-CH-S); 3.78 (s, 3H, COOCH3) ; 4.35 <s, 2H, CH2OH) ; 5.32 (m, 1H, CH-S); 5.90 (bs, 2H, = CH2). -24- 1 929 4 9 EXAMPLE 22 4g- (1-Bromornethyl) -vinylthio-1- [l-methoxycarbonyl-2-methyl-l-propenyl]-azetidin-2-one. Reaction (4)-(12). /T COOCH. 1.8 g of 4 0-(l-hydroxvmethyl) vinvlthio-l-[l-methoxycarbonyl-2-methyl-l-propenyl]-azetidin-2-one-S-oxide were dissolved in 40 ml of-dimethylformamide and cooled at -20°C. Thereafter, 0.7 ml..of pyridine and 3.0 ml of.PBr^ were added and the mixture left far 15 minutes while stirring. Ethyl acetate was added and the organic layer was shaken with a NaHCO^ saturated solution, washed with water, and then dried over Na,,S04 giving, after evaporation of the solvent, 1.6 g of the title compound. „CH. PMR (CDC1'3) <5: 2.04 (s, 3H, =' ; 2.24 (s, 3H, =- -CH. 3.24 (dd, J = 2.8, 5, 16'Hz,.2H, C-CH2~CH) ; 3.75 (s, 3H, 0CH3); 4.02 (s, 2H, CH2BR); 5.24 (bs, 1H, =CH); 5.37 (dd, J = 2.8 Hz, 5 Hz, 1H, CH2-OJ-S); 5.60 (bs, 1H, = CH). EXAMPLE 2 3 4S~ 11— (l-methyl-l-H-tetrazol-5-y])-thiomethyl] -viRylth.io-1-[l-raethoxycarbonyl-2-methyl-l-propenyl j -azetidin~2-one. Reaction (12) / V^Br" ® ^ > >s e OOCH. O ' N--' CH. COOCH. -25- J 929 4 9 1.4 of 40-(1-bromoraathyl)-vinylthio-1-[l-methoxycarbonyl-2-methyl-l-propenyl]-azetidin-2-one were dissolved in 25 ml of tetrahydrofuran and cooled at 0°C. 0.8( g of 1-methy1-5-thio1-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 Na^SO^ and evaporated The residue consisted of 2.-0 g-of pure title compound. PMR (CDC13) 6: 2.00 (s, 3H, =C-CH3; 2.22 (s, 3H, =C-CH3); 2.70-3.80 (m, 2H, J=2 Hz, 5 Hz, CQ-CH2~CH-S); 3.72 (.s, 3H, COOCH J ; 3.95 (s, 3H, N-CH3) ; 4.10 (s, 2H, CH2-S); 5.18 (bs, 1H, S-C=CH); 5.36 (m, 1H, CH2-CH-S) ; 5.57 (bs, 1H, S-C=C-H) . EXAMPLE 24 4*0- (1-methyl-l-H-tetrazol-Sryl). thioigsES&E^Lacetylthio-l-methoxy-oxaloyl-azetidin-2-one. Reaction (12)—(13) S s N N „ N sipy r^SV"N SJOj, f /—L° T T CH ^ r 0 CH- 0 COOCH-, 3 0 COOCH 1.8 of 40-[1-(l-methyl-l-H-tetrazol-5-yl)-thiomethyl}- vinylthio-1-[l-methoxycarbonyl-2-methyl-l-propenyl]-azetidin-2-one were dissolved in 200 ml of dichloromethane and cooled at -78°C. A flow .of ozonized oxygen was bubbled .through the solution until a blue color appeared. A few drops of P(OCH-)» were added and J J the mixture was raised to room temperature and evaporated to ; give 1.3 g of the title compound. -26- 0 9294 P.M.R. (CDC13) S:2 i 9-3.7 (m, 2 H, CDCH^CH S); 3.85 (s, 3 H, COOCH_3) ; 3.98 (s, 3 H, N-CH3) ; 4.35 (s, 2 H, CH2S) ; 5.75 (m, 1 H, CH2CH S). EXAMPLE 25 : 4 (3-(l-methyl-l-H-tetrazol-5-yl)-thio-acetyl-thio-azetidin-2-one. 1.2 g of 4f3-(l-methyl-l-H-tetrazol-5-yl)-thioacetylthio-1- ' methoxyoxaloyl-azetidin-2-one were dissolved in a 1:1 ethylace-tate/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. EXAMPLE 26 : 4&-(l-Methyl-l-H-tetrazol-5-yl)-thioacetylthio-1-(1-acetoxymethyloxycarbonyl-l-hydroxymethyl)-azetidin-2-one. N N cooch3 C H ch 3 cooch2ococh3 - 27 - 1 9294 9 1. 5 g of 4 6- (l-methyl-l-H-tetrazol-5-yl) -thionn8£fr*gart- acetylthio-azetidin-2-one were refluxed in 50 ml of benzene with 1.2 g of acetoxymethyigl-yoxgtlate (freshly prepared by the "ozonolysis of diacetoxymethylfumarate). The reaction was completed after 3. hours.. The crude oi.i_"abtained. after ...evaporating -the solvent can be used for the next step witout further-^purification. A sample was- purified on TLC -for spectroscopic data. PMR (CDC13) 6: 2.05 (s, 3H); 2.7-3.8 (m, 2H); 3.95 (s, 3H); 4.30 (s, 2H) ; 5.40 (s, 1H) ; 5.50 (m, 1H) ; 5.80 s, 2H). EXAMPLE 2 7 -4B- (l-Methyl-l-H-tetrazol-5-yl) -thiotegfefry4acetylthio-l- (1- acetoxymethyloxycarbonyl-l-chloromethyl)-azetidin-2-one. Reaction (15)-(16)J 0 •N COOCH„OCOCH_, COOCH2OCOCH3 The oi-1 ■'obtained from Example~26 consisting of crude 4g- (1-methyl-l-H-tetrazol-5-yl) -thioRsss^s^iacetylthio-1- (l-acetoxymethyloxy-carbonyl-l-hydroxymethyl)-azetidin-2-one, was dissolved in j-an*rydrous_.tetrahydrofuran-- (20 ml), and. treated at 0°C with equi-molar amounts of pyridine and thionyl chloride until all starting material disappeared. - After filtering the insoluble material, the filtrate was used immediate for the next step. -2 2- 11 929 4 9 EXAMPLE 2 8 4g- (l-Methyl-l-H-tetrazol-5-yl) -thioMate^i.acetylthio-1- (1- I acetoxymethvloxycarbonyl-l-triphenyl-phosphoranylidenemet-hyl)-azetidin-2-one. Reaction (16)-11) To a solution containing crude 43-(l-methyl-l-H-tetrazol-5-yl)-thioHsssfstegsiacetyl thio-1- (1-acetoxymethyloxycarbonyl-l-chloro-methyl)-azetidin-2-one, 80 0 mg o-f triphenylphosphine and 0.4 ml of pyridine were added and the resulting mixture was heated at 60° to 70°C for a few hours. The phosphorane was purified on silica gel eluting with dichloromethane-ethyl acetate (1:1). EXAMPLE 29 (5R)-Acetoxymethyl-2-[(l-methyl-l-H-tetrazol-5-yl)-thiomethyl] -2-penem- 3-carboxylate . Reaction .(II)-(1) 0 -1$-- N_ -n= PPh. N I-CH .n I ,N cooch2ococh3 cooch2ococh3 .1 9294 9 0. 500 g of 4(3-(l-methyl-l-H-tetrazol-5-yl)-thionwiffegtfacetylthio-1-(1-acetoxymethyloxycarbonyl-l-triphen ylphosphoranylidenemethyl) azetidin-2-one were- dissolved in 30 ml of toluene and heated at -100°C for two hours, The title compound was purified from PPh^O by short column chromatography on silica gel eluting with dichloromethane-ethyl acetate. (8:2) EMR ,.(GDC1"3) 2.15 (s, 3H, COOI3); 3.30-4.03 (m, J = 4 Hz, 2 Hz, -CH2-(6); 3.9 7 (s, 3H, -NCH ) ; 4.56 (d, J = 14 Hz, 1H, HCH-S); 4,84 (d, J=14 Hz, 1H, HCH-S), 5.65 (dd, J = 4 Hz, 2 Hz, 1H, H-5a); 5.88 (s, 2 H, COOCH 0). EXAMPLE 30 (5R)-2-(l-Methyl-l-h-tetrazol-5-yl)-thiomethyl-2-penem-3-carboxylic acid. Reaction (1) COOH \ / J2 The title compound was obtained following the procedure set out in Example 19. The (5R) p-nitrobenzoyl-2- (l-Methyl-l-*H"-te-trazol-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 (6 lactam), 1750 and 1720. -1?- J 9294 9 EXAMPLE 31 Methyl-6a-(1'-hydroxyethyl)-penicillinate-S-oxide. .Reaction (17)- (2) 0 0 H COOCH. CH fH ? 0 ^7 N '"'COOCH. A solution of methylpenicillinate S-oxide (2.3 g) in 50 ml of anhydrous tetrahydrofuran was cooled at -78°C. Lithium diiso-propylamide (freshly prepared--f rom 5 ml of diisopropylaraine and 20 ml of a 1.6 M BuLi hexane solution) dissolved in anhydrous ... tetrahydrofuran was added and the mixture left at -78°C for 10 minutes. 5 ml of acetaldehyde were successively added and tire solution was stirred for 15. minutes. The reaction was then .quenched with a NH^Cl saturated aqueous solution, extracted with ethyl acetate, washed twice with water, and dried over Na2SO^.. After evaporation of the solvent, the residue was shortly purified by column chromatography on silica gel eluting with dichloromethane-ethyl acetate (1:1)~. Obtained-1.5 g. The title compound consisted of a 2:3 mixture of epimers at the hydroxyl bearing carbon based on the PMR, being the new C^-Cg bond-only in the a-position because of the stereospecificity of ■ the reaction in the used conditions. PMR (CDC13) 5: 1.27 (s, 3 H, a-CH3') ; 1.40 (d, 3H, J = 5.7 Hz, CH3~CHOH) major isomer; 1.4 8 (d, 3H, J = 5.7 Hjz, CH3-CHOH) minor isomer; 1.70 (s, 3H, -ch 3' 31 -30- ft 929 4 9 3.4-3.8 (ra, LH, H-6); 3.80 (s, 3H, COOCH 3 ' / 4.1-4.7 (ra, 1H, CHOH); 4.50 (s, 1H, H-3); 4.S8 (d, J-= 1.3 -Hz,- IH,-H=5) -miner isomer; 5.05 (d, J = 1.9 Hz, 1H, H-5) major isomer. EXAMPLE 32 Methyl-6-[1-hydroxyethyl]-3-penicillanate. Reaction (17)-(2) H COOCH COOCH, To a solution of"2.2 g of methylpenicillanate in 30 ml of anhydrous tetrahydrofuran, a slight excess of lithium diiso-propylamide was added at -7 8°C under nitrogen. An excess of acetaldehyde was added, the mixture stirred for 5 bsaaass, quenched with trace acetic acid, poured into water, and extracted with methylene chloride. The organic layers dried over Na2S04 and evaporated "in vacuo" gave 0.8 g of the title compound. EXAMPLE 3 3 ... . Methyl-6-[l-p-nitrobenzyloxycarbonyloxyethyl]-3-penicillanate. Reaction (2) OH ?C02PNB ■N 7 ■TV H COOCH- 0 "N 7'» ... H COOCH. ~3lr J 9294 9 1.2 g of methyl-6-[1-hydroxyethyl]-3-penicillanate were dissolved in 40 ml of tetrahydrofuran, cooled at -78°C and treated with one equivalent of butyl lithium. 1.2 equivalents of p-nitrobenzyl-oxycarbonylchloride were added.to the previous mixture; after 30 -ksaaeffi at -78 °C, the reaction was left at room temperature for minutes 60 tesrasse, poured into water, and extracted with methylene chloride: 1.4 g of the title compound were obtained after drying-over Na2SO^ and evaporating. EXAMPLE 34 Methyl-6-[1-p-nitrobenzyloxycarbonyloxyethyl]-3-peniciIlanate- S-oxide. Reaction (17)-(2) 0C02PNB OCO PNB X 2 0 rY - COOCH3 ° H COOCH3 1.8 g of methyl-6-[1-p-nitrobenzyloxycarbonyloxyethyl]-3-penicillanate were dissolved in 50 ml of methylene chloride-and .treated at 0°C with 1.5 equivalents of m-chloroperbenzoic aci'd. The-organic phase was shaken -with a- NaHCC>3 saturated solution, extracted, dried. over\Na2SO^, and evaporated giving l-».4 g of .. r, the expected sulphoxide. EXAMPLE 35 - - 4 6-Vinylthio-[1,2-diacetoxymethyl]-3-[l-p-nitrobenzyloxycarbonyl- oxyethyl]-1-[l-methoxycarbonyl-2-methyl-2-propenyl]-azetidin-2- one-S-oxide. Reaction (2)-(3) -33- 19294 9 0c02pnb 0 X " ■n —i\ h cooch3 oco2pnb '}- - N 0 J 'y ococh. ococh. h cooch. .A.solution of 2.0 g of methyl-6-[1-p-nitrobenzyloxycarbonyloxy-ethyl]-3-penicillanate-S-oxide and 2.4 g of butyndiol diacetate in 50 ml of toluene was refluxed for 24 hours. The trapped compound was then purified by silica gel column chromatography .eluting with 9:1 dichloromethane-ethyl acetate. 1.1 g of the title, compound were obtained. example 36 4g-Vinylthio-[1,2-diacetoxymethyl]-3-[l-p-nitrobenzvloxycarbonyl-oxyethyl]-1-[methoxycarbonyL-2-methyl-l-propenyl]-azetidin-2- one-S-oxide. Reaction (3)-(4) oco-pnb \ 0 ^ 0c02pnb coch, ococh, ? h cooch. cooch. ococh. ococh. 1.3 g of 4B-vinylthio-[1,2-diacetoxymethyl]-3-[1-p-nitrobenzyloxy-carbonyloxyethyl] -1-r [methoxycarbonyl-2-methyl-2-propenyl] - -azetidin-2-one-s-oxide were dissolved in 80 ml of dichloromethane; 0.3;-ml of triethylamine were added and the mixture was left at room temperature for 2 hours. The pure title compound was quantatively obtained on evaporation of the solvent. : *1 929 4 9 EXAMPLE 37 48-Vinylthio-[1,2-diacetoxymethyl]-3-[1-p-nitrobenzyloxycarbonyl-oxyethyl]-l-methoxyoxaloyl-azetidin-2-one-S-oxide. Reaction (4)- 0c02pnb 0c0_ pnb ococh. OCOCH. OCOCH. OCOCH. COOCH A solution of 1.1 g of 48-vinylthio-[1,2-diacetoxymethyl]-3- [1-p-nitrobenz.yloxycarbonyloxyethyl] -1- [methoxycarbonyl-2-methyl- 1-propenyl]-azetidin-2-one-S-oxide in 100 ml of dichloromethane was cooled at -78°C. Ozone in oxygen was bubbled into the -solution until a blue color appeared. The solution was shaken with an aqueous solution of Na_S _0_ and dried over Na-SO.. 0.5 g of z 2. o ^4 the title compound were obtained after- evaporation. EXAMPLE 38 4g-Vinylthio-[1,2-diacetoxymethyl]-3-[1-p-nitrobenzyloxycarbonyl-oxyethyl]-l-methoxyoxaloyl-azetidin-2-one. Reaction--(5) oco„pnb oco2pnb ococh ; ococh. OCOCH. OCOCH. COOCH3 A solution of 0.8 g of 43-vinylthio-[1,-2-diacetoxymethyl]-3-[1-p-nitrobenzyloxycarbonyloxyethyl]-1-methoxyoxaloyl-azetidin-2-one in 15 ml of anhydrous dimethylformamide was cooled at -420 °C and 0.6 ml of phosphorous tribromide were added. The reaction 3 9294 9 hninutis was diluted with ethylacetate after 10 hcaasE and washed twice with a solution of NaHCO^. The organic phase, dried over Na^SO^ and evaporated, gave 0.4 g of the reduced compound. EXAMPLE 39 4g-Vinylthio-[1,2-diacetoxymethyl]- 3-[1-p-nitrobenzyloxycarbonyl-oxyethyl]-azetidin-2-one. Reaction (5)-(6) oco2pnb oco2pnb n ococh, T cooch, ococh, "n> ococh. ococh. H 1.2 g of 43-vinylthio-[1,2-diacetoxymethyl]-3-[1-p-nitrobenzyl-oxycarbonyloxyethyl]-l-methoxyoxaloyl-azetidin-2-one were dissolved in methanol and 2 g of silica gel were added to the solution. After 60 jaggm the insoluble material was filtered and the organic phase evaporated. Short column chromatography resulted in 0.4 g of the title compound. EXAMPLE 40 4g-Vinylthio-[1,2-diacetoxymethyl]-3-[1-p-nitrobenzvloxycarbonyl-oxyethyl]-1-[l-acetoxymethyloxycarbonyl-I-hydroxymethyl]-azetidin-2-one. Reaction (6)-(7) oco2pnb oco2pnb ococh. ococh, rV -Nvpr^o: hdiK/ ococh, ococh, cooch ococh r -36- 992941 0.6 g of 4f3-vinylthio- [1,2-diacetoxymethyl]-3- [1-p-nitro; nzyloxy-carbonyloxyethyl]-azetidin-2-one, dissolved in 30 ml of benzene, and 0 .6/g of acetoxymethyl glyc>xv/l<jte (freshly prepared from t-he-o.zo&olvsis of diacetoxymethyl fumarate) were refluxed. The reaction was completed after two hours. The condensation product can be used for the next step without further purification. EXAMPLE 41 4f3-Vinylthio- [1, 2-diacetoxymethyl] -3- [1-p-nitrobenzyloxycarbonyl-oxyethyl]-1-[1-acetoxymethyloxycarbonyl-l-chloromethyl]-azetidin- 2-one. Reaction (7)-(8) oco2pnb oco2pnb ococh. ococh. cooch2ococh3 ococh. ococh. cooch2ococh3 0.5. g of 4g-vinylthio-[1,2-diacetoxymethyl]-3-[1-p-nitrobenzyloxy-carbonyloxyethyl] -1- [1-acetoxyme thy loxycarbonyl-1-hydroxymethyl].- ... azetidin-2-one were dissolved in 12 ml of anhydrous tetrahydrofuran and cooled at 0°C; thereafter 1.1 equivalents of pyridine and 1.1 equivalents of thionyl chloride .wexe~added to the solution The mixture was stirred for 10 minutes. The insoluble material was filtered off and the solution evaporated at room temperature to give the title compound in nearly quantitative yields. The product can be used without further purification for the next step. ->?- 1 92949 EXAMPLE 42 4g-Vinylthio-[1,2-diacetoxymgthyl]-3-[1-p-nitrobenzyloxycarbonyl-oxyethyl]-1-[acetoxymethyloxycarbonyl-l-triphenylphosphoranylidene methylj -azetidin-2-one. Reaction ( 8}.-(9-) A solution of 0.760 g of 4f3-vinylthio-[1,2-diacetoxymethyl]-3-Il-p-nitrobenzoyloxycarbonyloxyethyl]-1-[1-acetoxymethyloxy-carbonyl-1-hydroxymethyl]-azetidin-2-one in 10 ml of tetrahydrofuran and 10 ml of dioxane, with 2 equivalents of triphenyl-phosphine and 1.1 equivalents of pyridine, was stirred overnight at +50°C. The phosphorane. was purified by silica gel column chroma-tography, eluting with 70 : 30 dichloromethane-ethyl acetate. 0.480 g of the title compound were obtained. . EXAMPLE 4 3 4 3-Acetylglycolylthio-3-[l-p-nitrobenzyloxycarbonyloxyethyl]-1-[l-acetoxymethy.loxycarbonyl-l^triphenylphosph<3ranylidenemethyl] -azetidin-2-one. Reaction (9)-(11) OCOCH oco2pnb oco2pnb 0 —j^ OCOCH, -N \^PPh\^ 3 | | Q OCOCH3 ^PPh3 COCCH2OCCCH3 CCOO^CCCCH, -38- r1 929 4 9 1 0.45 g of 4g-vinylthio-[1,2-diacetoxymethyl]-3-[1-p-nitrobenzyloxv carbonyloxyethyl]-1-[acetoxymethyloxycarbonyl-l-triphenylphos-phoranylidenemethyi]-razetidin-2-one were dissolved in 50 ml of dichloromethane and cooled at -20°C; then 30 ml-of trifluoroaeetic 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 trimethylphosphite.. were-added-,-. The organic phase was washed with a saturated solution of NaHCO^ and dried over Na2SC>4 to give 0.2 6 g of the title compound. EXAMPLE 44 4g-Vinylthio-[1,2-diacetoxymethyl]-3-[1-p-nitrobenzyloxycarbonyl-oxyethvl]-1-[methoxycarbonyl-2-methvl-l-propenyl]-azetidin-2-one. Reaction (4)-(12) 1.5 g of vinylthio-[1,2-diacetoxymethyl]-3-[1-p-nitrcbenzyloxy- carbonyloxyethyl] -1- [methoxycarbonyl-2-methvl-l---propenyl] -l-S- oxida ) azetidin-2-oneVwere dissolved in 10 ml of anhydrous dimethylformamide and cooled at -20~°C; 0.8 ml of phosphorous - tribromide were . added. The mixture-was stirred for 10 hours, diluted with ethyl acetate, and washed twice with a NaHCO^ saturated solution.. The organic layer dried over Na2S04 and evaporated gave 1.1 g of'the title compound. -3k r1 92949 EXAMPLE 4 5 4 3~Acetylglycolylthio-3-[1-p-nitrobenzyloxycarbonyloxyethyl]-1-methoxyoxalyl-azetidin-2-one. Reaction (12)—(13) GCG-PNB GCO^PNB ococh. ococh. -M^O ococh. cooch. cooch. 1.4 g of 43-vinylthio-[1,2-diacetoxymethyl]-3-[1-p-nitrobenzyl-oxycarbonyloxyethyl]-1-[methoxycarbonyl-2-methyl-l-propenyl]-azetidin-2-one in 120 ml of dichloromethane were cooled to -78°C. Then ozone oxygen was bubbled through the solution until a blue color appeared. The solution was shaken with an aqueous solution of Na2S20,. and dried of Na2S04> Evaporation of the solution gave 0.8 g of the title compound. EXAMPLE 46 4g-Acetylglycolylthio-3-[1-ft-nitrobenzyloxycarbonyloxvethyl]-azetidin-2-one. Reaction (13)-(14) oco2pnb oco2pnb 0 ococh. ,0 T cooch. ■S 0 ococh. 0.800 g of 43-acetylglycolylthio-3-[l-p-nitrobenzyloxycarbonyl-oxyethyl]-l-methoxyoxalyl-azetidin-2-one were diss^ ved in 50" ml of methanol and a few grams of silica gel added. 'I mixture was minutes left at room temperature for 60 -feesass. The insoluble material filtered off and the filtrate, after evaporation, gave 0.30 g of the title compound. 4-0 -yr- 1 92949 EXAMPLE 4 7 4B-Acetylglycolylthio-3-[1-p-nitrobenzyloxycarbonyloxyethyl]-1- / [1-acetoxymethyloxycarbonyl-l-hydroxvmethyl]-azetidin-2-one Reaction (14)-(15). oco2pnb oco2pnb ococh3. 0 <5 "NpN'OH ococh. cooch2ococh3 0.5 g of 46-acetylglycolylthio-3-[1-p-nitrobenzyloxycarbonyloxy-ethyl]-1-[1-acetoxymethyloxycarbonyl-1-hydroxymethyl[-azetidrin-2 one and 0.5 g of acetoxymethyl olyoxyJate in 30 ml of benzene were refluxed until the reaction was completed (two hours). The obtained title compound, can be used for the next step without further purification. EXAMPLE 4 8 .4 6-Acetylglycolythio-3-[1-fr-nitrobenzyloxycarbonyloxyethyl] -1-[1-acetoxymethyloxycarbonyl-l-chloromethyl]-azetidin-2-one. Reaction (15)—(16) oco2pnb oco2pnb OCOCH, OH ococh. %^C1 cooch2ococh3 cooch2ococh3 0.35 g of 43-acetylglycolylthio-3-[l-p-nitrobenzyloxycarbonyloxy ethyl]-l-[ 1-acetoxymethyloxycarbonyl-1-hydroxymethyl]-azetidin-2 one were dissolved in 10 ml of anhydrous tetrahydrofuran at 6°C. Then 1.1 equivalents of pyridine and 1.1 equivalents of thionyl 192949 ►n i nutt^S chloride were added and the mixture was stirred for 10 -houg-a1. The precipitate was filtered and the filtrate, after evaporation, gave thL title compound in quantitative yield. The crude product was used as such for the next step. ... EXAMPLE 4 9 4S~Acetylglycolylthio-3-[1-p-nitrobenzyloxycarbonyloxyethyl]-1-[1-acetoxymethyloxycarbonyl-l-triphenylphosphoranylidenemethyl]-azetidin-2-one. Reaction (16) -(Ll) oco2pnb 0 / V- I o ococh. •n\ ci cooch2ococh3 0c02pnb J- N 0 pph3 ococh, cooch2ococh3 0.400 g of 4B-acetylglycolylthio-3-[1-p-nitrobenzyloxygarbonyloxy-ethyl]-1-[1-acetoxymethyloxycarbonyl-1-chloromethy1]-azetidin-2-one were dissolved in 20 ml of a 1:1 mixture of tetrahydrofuran and dioxane. Thereafter 2 equivalents of triphenylphosphine and 1.1 equivalents of pyridine were added and the mixture stirred overnight at 50°c. The title compound was purified by silica gel column chromatography, eluting with 70-30 dichloromethane-ethyl-acetate. 0.280 g of the phosphorane were obtained. ■EXAMPLE 50 (5R)-Acetoxymethyl-6-[1-p-nitrobenzyloxycarbonyloxyethyl]-2-acetoxymethyl-2-penem-3-carboxylate. Reaction (11)-(1) oco2pnb oco2pnb ococh. 0 PPh. c00ch20c0ch3 ococh. cooch2ococh3 -41- \ q -yq-/ g I s u- S i / 0.210 g of 4f3-acetylglycolylthio-3-/l-p-nitrobenzyloxycarbonyl-oxyethylZ-l-Zl-acetoxymethyloxycarbonyl-l-triphenylphosphoianylidene-methyl7"-azetidin-2-one were dissolved in 7 ml of toluene and the solution was refluxed for two hours. Purification by short column chromatography eluting with 95:5 dichloromethane-ethyl acetate, gave 0.05 g of the title compound. EXAMPLE 51 (5R) -Acetoxymethyl-6-/l-hydroxyethyl7"-2-acetoxymethyl-2-penem-3- carboxylate. Reaction (1) oco2pnb oh ococh- -> O^ ooch2ococh3 ndcoch- cooch2ococh3 ethanol-K2HPO^ mixture and 1-ydrogenolysed with 10% Pd/C. 0.060 g of 5R-acetoxymethyl-6-/l-p -nitrobenzyloxycarbonyloxyethyl/ 2-acetoxymethyl-2-penem-3-carboxylate were poured in a water- a quick purification by silica gel column chromatography gave 0.015 g of the title compound. Operating as described in the previous working examples but employing 5-methyl-2-thiol-l,3,4-thiadiazole, 5-thiol-l,2,3-triazole, or thiolpyrazine instead of l-methyl-5-thiol-tetrazole, (5R)-2-/5 1-methyl-11 , 3", 4 1 -thiadiazol-2 1 -yl) -thiomethyl7r-2-penem-3-carboxylic acid, (5R)-2-/711,2',31-triazol -5yl)-thio-methyl7-2-penem-3-carboxylic acid, (5)-2-(pyrazinyl)-thiomethyl 2-penem-3-carboxylic acid, (5R)-6-/11-hydroxyethyl/-2- (pyrazinyl) thiomethyl-2-penem-3-carboxylic acid respectively were prepared. Operating as previously described, but reducing the methyl-6-/l'-hydroxyethyl/-3-penicillinate following the widely-known procedure, the corresponding 6-ethy3 obtained. - 43 - \ 5 MAR 1983 DECEIVED ^ i '92949 EXAMPLE 5 2 4ft-(1-Uyd roxymethyl)-vinylthio-3a-(1-p-n i trobcnzvloxycarbony) - oxvethyl)-!-(1-methoxycarbonyl -2 -me thyl-2-propenyl)-a7,etidin-2-one-S-oxlde. Reac t i on (T") (3 ) . ,oco2pnb 0 O n . H COOCH. ?co2pnb /'Ndh cooch. A solution of 2.6 g of methy1-S-(1-p-nitrobenzy1oxycarbony 1 -oxyethy1)-3-penici11inate-S-oxide and 8 ml of propargyl alcohol in 20 ml of toluene were refluxed under nitrogen for 40 hrs. After evaporation of the solvent, the trapped compound was purified by silica gel column chromatography, eluting with (9:1) dich1 oromethane-ethyl acetate, to give 2.0 g of the title compound. - 44 - 15 MAR 1983 1 9 ') Q /; O I ✓ i_ ./ '-7 J EXAMPLE 5 3. 4 B-(1-Hvdr oxymethyl)-vinylthio-3a-(l-p-nitrobenzyloxycarbonyl-oxyet hy1)-1-(1-me thoxvcarbonyl-2-methyl-l-propenyl)-azctidin-2-one-S-oxide. Reaction (3) - (4). 0c02pnb 0C02PNB OH 3 ' COOCH3 2.0 g of 46-(1-hydroxyme thy1)-vinylthio-3a-(1-p-nitrobenzy1oxy-carbony1oxyethy 1)-1-(1-methoxycarbony1-2-methy 1-2-propeny1)-azetidin-2-one-S-oxide, dissolved in 50 ml of dichloromethane, were left at room temperature in the presence of a few drops of triethylamine for 12 hrs. After evaporating the solvent, the pure title compound was recovered in quantitative yield. ■33 \ 5 MAR EXAMPLE 54 4 g-(1-Bromomethyl)-vinylthio-3a-(1-p-nitrobenzyloxycarbonyl-oxyethvl)-I-(l-me thoxycarbonyl-2-me thy1-l-propcnyl)-azetidin-2-one. Reaction (4) - (12). OCO-PNB 9 X OH li 0C02PNB COOCH3 2.0 g of the compound prepared in Example 53 were dissolved in 50 ml of dimethylformamide. After cooling at -20°C, 0.7 ml of pyridine and 3.2 ml of PBr-j were added and the reaction mixture was maintained under stirring for 15 minutes. Ethyl acetate was added to the mixture and the organic phase was shaked with a NaHCOj saturated solution, washed with water and finally dried over Na2SO^. After evaporating the solvent, 1.7 g of pure title compound were obtained. 192949 EXAMPLE 5 5 4B — [1 — (5-Me thyl-l-3,4-thiadiazol-2-yi)-thi omet hy11 -v i ny1t h i o-3n (l-p-nitrobenzyloxycarbonyloxyethyl)-l-(l -me thoxycarbonyl-2-methyl-l-propenyl)-azetidin-2-one. 0C02PNB 0C02PNB Br cooch. .1: N II II S-^CH. COOCH- 1.8 g of the compound prepared in Example 54 were dissolved in 30 ml of tetrahydrofuran. The resulting solution was cooled at 0°C; 1.1 g of 5-methy1-1,3,4-thiadiazol-2-thiol sodium salt were added and the mixture was maintained under stirring for 4 hrs. After filtration of the insolubles, the remaining solution was diluted with ethyl acetate, washed with water, dried over Na2SO^, and evaporated: 2 g of the title compound were obtained. EXAMPLE 56 4 g- [ 1- (1, 2 , 3-Tr iazol-5-yl)-thi omethy H - vinylthio-3ct-(l-p-nitro-benzyloxycarbonyloxyethyl)-l-(l-methoxycarbonyl-2-me thy 1- 1 -propenyl)-azetidin-2-one. oco2pnb A 0c02pnb 0 1 .n Br If cooch- s_Vn ■N h 3 3 Starting from 2.5 g of the compound prepared in Example 54 and operating as in Example 55, but using 1,2,3-1riazo1-5-thio1 sodium salt, 2.2 g of the title compound were obtained. _ 47 _ 1 > 2 9 < 9 EXAMPLE 57 4 B-[ 1 - ( 5-Me thyl-I,3,4-thiadiazol-2-yl)1 -thioacetylthio-3«-(1-p-ni trobenzyloxycarbonyloxvethyl)-1-methoxy-oxaloyl-azet idin-2-onc. oco2pnb X /y N cooch. i —N ll S "^CH. -> 0C02PNB cooch. .17 chj 2 g of the compound prepared in Example 55 were dissolved in 250 ml of dichloromethane and cooled at -78°C. A flow of ozonized oxygen was bubbled through the solution until a blue color results. A few drops of PtOCH^g 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 58 4B-[l-(l>2,3-Triazol-5-yl)1-thioacetylthio-3a-(l-p-nitrobenzyl-oxycarbony1oxyethy 1)-1-methoxy-oxa1oyl-azetidin-2-one. Reaction (12) - (13). oco2pnb rR X ._N T H cooch. 0c02pnb I 0 s n o • n . cooch. rs Starting from 1.6 g of the- compound prepared in Example 56, and operating as in Example 57, 1.1 g of the title compound were obtained. ^ - 48 - 1 S29i9 r .V EXAMPLE 59 4 B~[1 -(5-Me thy1-1,3,4-thiadiazol-2-yl)]-thioacetylthio-3g-(l-p-ni trobenzyloxycarbonyloxye thy 1)-azetidin-2-one. Reac t ion (13) - (14). 0C02PNB -r II 0 ,N— N. 'S CH. .LN IN aj. 0C02PNB ^ JCJL S S ^ S" CH- 0 o COOCH. / \T 1.5 g of the compound prepared in Example 57 were dissolved in 1 1:1 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 dich1oromethane:ethy 1 acetate (8:2), giving 0.9 g of pure title compound. EXAMPLE 60 46-[l-(l,2,3-Triazol-5-yl)1-thioacetylthio-3a-(l-p-nitrobenzyl-oxycarbony1oxyethy1)-azetidin-2-one. Reaction (13) - (14). I /- 0C02PNB o N o 1=° COOCH, if -N OCO PNB X. 'T O n J .N N I H O -N \ H Starting from 1.1 g of the compound prepared in Example 58 and operating as in Example 59, 0.6 g of the title compound were obtained. - 49 - 192949 EXAMPLE 61 4 B-[1 -(5-Me thy1-1,3,4-thiadiazoI-2-yl)l-thioacetylthio-3a-(I-p-nitrobenzyloxycarbonyloxyethyl)-l-(l-acetonyloxycarbonyl -1 -hydroxymethy1)-azetidin-2-one. Reaction (14) - (15). A 0 OC.C^PNB jn r c02pnb I' 0 'r—r"s N N, 1 JL \ 0 ■ n H s^OH cooch2coch3 0.9 g of the compound prepared in Example 59 were dissolved in 40 ml of benzene; 0.6 g of acetonyl glyoxylate were added and the resulting solution was refluxed for 3 hrs. After evaporation of the solvent, the crude oil was used for the next step without further purification. EXAMPLE 62 4B-[l-(l,2,3 -Tr iazol-5-yl)1-thioacetylthio-3a-(l-p-nitrobenzyl-oxvca rbony1oxye thy1)-l-(l-acetonyloxycarbonyl-1-hydroxymethyl) ■ azet'i d i n-2-one . Reaction (14) - (15). 0c02pnb J, o ! o /r .N "N ■ I H N 'I N -> H j)c02pnb n S-^-N 11 H 0 H -N cooch2coch3 Starting from 0.6 g of the compound prepared in Example 60 and operating as shown in Example 61, 0.7 g of the title compound were obtained. 50 1929 EXAMPLE 6 3 4 B- [ 1 - ( 5-Me thy l-l,3,4-thiadinzol-2-yl)1-thioacetylthio-3«-(l-p-nitrobenzyloxycarbonyloxyethyl)-l.-(l-acetonyloxycarbonyl-l-ch1 oromethyl)-azetidin-2-one. Reaction (15) - (16). 0C02PNB N — A \ s -^s OCO-.PNB CH- •N \ ^ OH ,N" S ' CH. O COOCH2COCH3 ^ CI COOCH2COCH3 The crude oil obtained in Example 61 was dissolved in anhydrous tetrahydrofuran (30 ml) and cooled at 0°C. Equimolar amounts of pyridine and thionyl chloride were added to the solution until there was a disappearance of the starting material. After filtration of the insoluble material, the filtrate was used immediately for the next step. EXAMPLE 6 4 —3%- [l-(l,2,3-Triazol-5-yl)1-thioacetylthio-3r»-(l-p-nitrobenzyl-® Lft»ycarbony1oxyethyl)-l-(l-acetonyloxycarbonyl-1-chlorome thy 1)-azetidin-2-one . Reaction (15) - (16). 0C02PNB il 0C02PNB I H N "N If Jl -N \X1 COOCH2COCH3 COOCH2COCH3 Starting from 0.7 g of the compound prepared in Example 62 and operating as described in Example 63, the crude chloroderivative was obtained. The product was used for the next step without further purification. - 51 - 192949 EXAMPLE 65 4 B-[1 -(5-Me thy 1-1,3,4-thiadiazol-2-yl)1-thioacetylthio-3a-(l-p-nitrobenzyloxycarbonyloxyethyl)-l-(l-acetonyloxycarbony1 -1 -triphenylphosphoranyli deneme thyl)-azetidin-2-one. Reac t ion (16) t- (11). X 0C02PNB ni CH. a 0C02PNB 0 _N o \^C1 Y; ,o CH. i -N V^PPh. COOCH2COCH3 COOCH2COCH3 Crude product obtained in Example 63 was dissolved in 20 ml of tetrahydrofuran; 700 mg of tripheny1phosphine and 0.35 ml of pyridine were added and the resulting solution was warmed under nitrogen at 70°C for a few hours. The title phosphorane was purified on silica gel by eluting with dich1oromethane:ethy1 acetate (1:1). There was obtained 0.6 g of the title compound. ^PATENT \ 5 MAR \%i EXAMPLE 66 48-[l-(l,2,3-Tr iazol-5-yl)1-thioacetylthio-3q-(l-p-nitrobenzyl-oxycarbony 1oxye thyl)-l-(l-acetonyloxvcarbony 1oxye thy 1-1-triphenylphosphoranyli deneme thyl)-azetidin-2-one. Reac t ion (18) - (11). 0C02PNB A O n 1 JS .N ■N ' I H \ ,-Cl COOCH2COCH3 0C02PNB X .^■s ~s r " 1 o r 1 J* _N Y PPh. COOCH2COCH3 Starting from the crude chloroderivative obtained in Example 64 and operating as illustrated in Example 65, 0.55 g of the title compound were obtained. - 52 - EXAMPLE 6 7 (5R)-Acetonyl-2-[(5-methyl-l,3,4-thiadiazoI-2-yl)-thiomethyll-6«-(1-p-nitrobenzyloxycarbonyloxyethyl)-2-penem-3-ear boxy late. React i on (11) - (1). J. 0c02pnb n n JLSJL 5 s ch. oco2pnb N N 0 - -N O PPh. cooch2coch3 -> /> m j ch. cooch2coch3 0.6 g of the compound prepared in Example 65 were dissolved in 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 0.25 g of the title compftfrrn&TSNTOFFICE I -R* : 1795, 1750, 1720. t5MAR1983 j EXAMPLE 6 8 — (5R)-Ace tonyl-2-[(1,2,3-triazol-5-yl)-thi omethyH -6a-(l-p-nitrobenzyloxycarbonyloxyethyl)-2-penem-3-carboxylate. Reac t ion (11) - (1). X .0C02PNB .n 1) o ■ N 31 J: C02PNB PPh. cooch2coch3 cooch2coch3 Starting from 0.45 g of the compound prepared in Example 66 and operating as shown in Example 67, 0.180 g of the title compound were obtained. _ 53 _ 1 OO QAQ I / y "t S EXAMPLE 69 (5R)-Aeetonyl-2-[(5-met hy1-1,3,4-thiadiazol-2-yl)-thiomct hy11 -Gap-hydro xy ethyl) -2 - peri em-3 -ca rboxylate. Reaction (1). oco2pnb X $- \ N ch- "\ -> cooch2coch3 oh ^ s ~I -n_ n n si si ch. \ cooch2coch3 0.450 g of the compound prepared in Example 67 were dissolved in 25 ml of acetonitrile containing a few drops of ethanol and hydrogenated over 1096 Pd on carbon (400 mg). The catalyst was removed by filtration and the filtrate was chromatographed on silica gel eluting with dichloromethane:ethyl acetate (7:3), giving 0.18 g of the title compound. 1.E. : 3605 , 1795, 1745 , 1720. W. PATENT 0^' 15 MAR 1983 EXAMPLE 70 (5R) - Ace t ony 1 - 2- [ (1 ,2,3-triazol-5-yl)'-*hi ome t hy 11 -6 a - (1-hydroxy-ethy 1)-2-penem-3-carboxy late. Reaction (1). PC02PNB X N O r h cooch2coch3' OH O/- n 'fl cooch2coch3 Starting from 0.380 g of the compound prepared in Example 68 and operating as in Example 69, 0.12 g of the title compound were ob ta i ned. - 54 - 192949 EXAMPLE 71 (5R)-2[(5-Me t hy1 -1,3,4-thiadiazol-2-yl)-thi omethyI]-6 a-(1 hydroxyethyl) -2-penem-3-carboxylie acid. Reaction (1). oh n if oh w ^ \ A. A, 1 ^ n \ v o cooch2coch3 o cooh n. ch3 A solution of 0.200 g of the compound prepared in Example 69 in acetonitrile (30 ml) containing a few drops of water was cooled at 0°C; 5 ml of a 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 dried over Na2SO^ and evaporated giving 0.110 g of the title comoound. l.R. : 3500 , 1795 , 1665 . |* 15MARV5S3 Ik Rk'. - 55 - : EXAMPLE 72 ' (5R)-2-[(l,2,3-Triazol-5-yl)-thiome t hy 11-6ct-(i-hydroxyethyl)-2-penem-3-carboxyl i c acid. Reaction (1). oh , n oh n oh [" n A A_Ij r" ^ >, N [! x X—N A ft a^ cooh o cooch2coch3 o Starting from 0.25 g of the compound prepared in Example 70 and operating as shown in Example 71, 0.135 g of the title compound were obtained. , , yLPr-r-; I.E. : 3490, 1795 , 1660 . t A5MAR 1983 EXAMPLE 7 3 """ ' 4 &-(1-Carbamov1oxvmethy1)-vinylthio-3a-(l-p-ni trobenzy1oxy-carbony1oxyethy1)-!-(!-me thoxycarbony1-2-methy1-1-propenyl)-azetidin-2-one-S-oxide. Reaction (4) - (5). A oco-.pnb 2 o 1^S 0C02PNB oh r-oconh2 I 11 .N 0 cooch. cooch. 2.2 g of the compound prepared in Example 55 were dissolved in 30 ml of acetonitrile and cooled at 0°C. Then 0.8 ml of chlorosulphonyl isocyanate were added under nitrogen and the mixture was stirred for 2 hours. The reaction mixture was poured into a saturated NaHC03 solution, stirred for a few minutes, and then extraced with ethyl acetate. After drying over Na2S04, evaporation of the solvent gave 1.5 g of the title compound. - 56 - ( ) example 74 ) 4 S-(1-Ca rbamov1oxyme thy1)-v i ny1th io-3a-(1-p-ni trobenzyloxy-carbonyloxvethyI)-l-(l-me thoxycarbonyl-2-methyl-I-propenyl)-azetidin-2-one. Reaction (4) - (12). 0c02pnb J. If s. -oconh. \ COOCH. oco2pnb oconh. -N \ COOCH. Starting from 1.7 g of the compound prepared in Example 73 and obtained. 15 MAR 1983 EXAMPLE 75 F£* 4 6- (1 -Carbamoyl oxy. )-acetylthio-3q-(l-p-nitrobenzyloxy- carbonyloxvethyp-l -me t hoxy oxa 1 oyl-azetidin-2-one. React ion (12) - (13). X 0C02PNB "OCONH, , k \ 0C02PNB X -N oconh, COOCH. V° COOCH. Starting from 2.2 g of the compound prepared in Example 74 and operating as illustrated in Example 57, 1.4 g of the title compound were obtained. q? QziQ ✓ u- X 1 / EXAMPLE 76 4 B- (1 -Carbamoyl oxy. . )-acetylthio-3ct-(l-p-nitrobenzyl oxy- carbonyloxyethyl)-azetidin-2-one. Reaction (13) - (14). gco-pnb oco„pnb. z 1 2 A ^ _ X^OCONH„ » s ^oconh2 - ^ -qconh2 1.. 0 > 0' n= o 0 h ccoch3 •N, ° Starting from 1.4 g of the compound prepared in Example 75 and operating as shown in Example 59 0.9 g of the title compound were obtained. FliZ. PATENT OFfldlj example 77 p 15 mar 1983 '• 4 g-( 1-Carbamoyloxyi.T-r - )-acetylthio-3a-(l-p-nitrobenzylcxy-carbony1oxye t hyl)-l-(l-acetonyloxycarbonyl-1-hyd roxyme thy 1)-azet i d i n-2-one . Reaction (14) - (15). 0c02pnb oc02pnb ' oconh. I J ^ -^/^OCONH2 \ T n _ I 0 —n\h / cooch2coch3 Starting from 0.9 g of the compound prepared in Example 76 and 0.6 g of acetonyl glyoxylate and operating as in Example 61, the crude carbino 1 amide was obtained. - 58 - i c 9 0 / Q i y ^ 7 A EXAMPLE 78 4B-(1-Carbamoyloxyi .)-ace tyl th io-3ct-( 1-p-n i t robenzy 1 oxv- carbony]oxyethyl)-!-(1-acetonyloxycarbonyl-l-chIoromethy 1)-azetidin-2-one. Reaction (15) - (16). 0c02pnb 0c02pnb oconh, A N. f A oconh >OH O _n cooch2coch3 ^ CI cooch2coch3 Starting from the crude product obtained in Example 77 and operating as in Example 63, the crude chloroderi va-l.i~v-e—v?g5 obtained. — EXAMPLE 79 ;^\5 4 B~ C1 -Car bamov 1 oxvi.- ' v )-acetylthio-3q-(l-p-nitrobenzyloxy-carbonyloxyethyl)-l-(l-acetonyloxycarbonyl-l-triphenyl-.phosphoranylidenemethy1-1)-azetidin-2-one. Reaction (16) - (11). oco2pnb A oconh, oco-.pnb I 2 .N A> ,^ci .N cooch2coch3 oconh II O "PPh_, c00ch2c0ch3 Starting from the crude product obtained in Example 78 and operating as in Example 65, 0.40 g of the phosphorane were obtained. - 59 - rnci f o x <_ > "t / EXAMPLE 80 (5R)-Acetony1-2-carbamoy1oxyme thy 1 -6p(-(l-p-nitrobenzyloxy-carbonyloxyethyl)-2-penem-3-car boxy late. Reaction (11) - (1). 0C02PNB A )C02PNB OCONH, >>s. OCONH, .N X \ 0 X V PPh, // -N COOO^COO^ COOCH2COCH3 Starting from 0.4 g of the compound prepared in Example 79 and operating as in Example 67, 0.11 g of the title compound were obtained. EXAMPLE 81 if^t 5 MAR 1983 BECEiVBO (5R)-Ace tony1-2-carbamoy1oxyme thyl-6o(-(l-hydroxyethyl)-2-penem-3- carboxylate. Reaction (1). OCONH, OH A , V _N COOCH2COCH3 OCONH- COOCH2COC H Starting from 0.35 g of the compound prepared in Example 80 and operating as in Example 69, 0.11 g of the title compound were obtained. - 60 - </div>

Claims

<div class="application article clearfix printTableText" id="claims"> EXAMPLE 82 (5R) -2(Carbamoy1oxyme thyl)-6a-(l-hydroxyethyl)-2-pen cm- 3 - enrboxy1ic acid. Reaction (1). OH X oconh, O ^ 'I n . i -> \ cooch2coch3 oconh.i cooh Starting from 0.11 g of the compound prepared in Example and operating as in Example 71 0.060 g of the title compound were obta i ned. WHAT WE CLAIM IS:

1. A compound of the formula

R

1

(0) U n rY

CH2Z

.N

(1)

0

wherein R is a hydrogen atom, lower alkyl, 2,2,2-trichloro-ethyl, acetonyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p-nitrophenyl, benzyhydryl, or a residue known to undergo metabolic activation "in vivo" and having favorable pharmacokinetic properties;

either R"'" is a hydrogen atom,

and Z represents hydrogen or halogen atom, hydroxy,

amino, carbamoyloxy, mercapto, pyridinium, or a group of

^ 4 3 4

the formula OR , OCOR , NHCOR , or SR wherein each of R and R

represents lower alkyl, aryl or a heterocyclic ring, each of which may be substituted or unsubstituted,

or R1 is lower alkyl, lower alkoxy, cycloalkyl or hydroxyalkyl, the alcoholic function of the hydroxyalkyl being free or protected,

and Z represents a pyrazinylthio, carbamoyloxy or pyridinium group; and n is 0 or 1.

2. A compound of claim 1 wherein R is a hydrogen atom, lower alkyl, 2,2,2-trichloroethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p-nitrophenyl, benz-hydryl, or a residue known to undergo metabolic activation "in vivo" and having favourable pharmacokinetic properties; R^ is a hydrogen atom and n is 0.

\92sm

3. A compound of claim 1 wherein R is a hydrogen atom, lower alkyl, 2,2,2-trichloroethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p-nitrophenyl, benzhydryl, or a residue known to undergo metabolic activation "in vivo and having favourable pharmacokinetic properties; R1 is lower alkyl, cycloalkyl or hydroxyalkyl, the alcoholic function of the hydroxyalkyl being free or protected, and n is 0.

]

4. A compound of claiir. 1 wherein said residue known to undergo metabolic activation "in vivo" and having favour able pharmacokinetic properties is selected from the group consisting of acetoxymethyl, pivaloyloxymethyl, phthalidyl,

-p - OCOOC2H5, and -CH2NHCOR2 CH3

2

wherein R is alkyl having from 1 to 5 carbon atoms, cycloalkyl, or aryl.

5. A compound of any one of claims 1,2 and 4 in which said heterocyclic ring is selected from the group consisting of 5-methyl-l,3,4-thiadiazol-2-yl; 1-methyl-tetrazol-5-yl; l,2,3-triazol-5-yl and pyrazinyl.

6. A compound of any one of claims 1, 3 and 4 in which R"*" is selected from the group consisting of methyl, ethyl, methoxy, 1-hydroxyethyl, 1-(p-nitrobenzyloxycarbonyl oxy)ethyl and 1-(dimethyl-t-butyl-silyloxy)-ethyl.

7. A compound of claim 6 wherein R"*" is 1-hydroxyethyl .

8. The compound of claim 1 which is (5R)-2-acetoxy-methyl-2-penem-3-carboxylic acid.

o

9. The compound of claim 1 which is (5R)-2-[(l'~ methyl-11-H-tetrazol-5'-yl)-thiomethyl]-2-penem-3-carboxylic acid.

10. The compound of claim 1 which is (5R)-2-[(5'-methyl-1',3',4'-thiadiazol-2'-yl)-thiomethyl]-2-penem-3-carboxylic acid.

11. The compound of claim 1 which is (5R)—2—[ (l',2',3'-triazol-5'-yl)-thiomethyl]-2-penem-3-carboxylic acid.

12. The compound of claim 1 which is (5R)-6-[l'~ hydroxyethyl]-2-[(pyrazinyl)-thiomethyl]-2-penem-3-carboxylic acid.

13. The compound of claim 1 which is (5R)-2-[(pyrazinyl) -thiomethyl]-2-penem-3-carboxylic acid.

14. The compound of claim 1 which is (5R)-2-[(pyrazinyl) -thiomethyl] -6-ethyl-2-penem-3-carboxylic acid.

15. The compound of claim 1 which is (5R)-2-carbamoyl-oxymethyl-6a[1(R)hydroxyethyl]-2-penem-3-carboxylic acid.

16. A_pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier,

17. A process for preparing a compound of claim 1, said process comprising

(a) reacting a compound of formula

} 6 4 -

(2)

0^1

''■COOR5

i^k0!

~ r ■ o

5 1 -

wherein R represents a lower alkyl group and R is as ^defined in claim 1, with an acetylenic derivative of the formula X'C=CY,

wherein X' is a group of formula CH2Zwherein Z' is a halogen or hydrogen atom, hydroxy, amino, carbamoyloxy, or a group of

3 3 3 3

the formula OR , OCOR , NHCOR , where R 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 CI^Z1, wherein is lower alkyl and Z' is as described above, to give a compound of the formula:

/

(3)

wherein R5, R1, X', and Y are as defined above, which is isomerized in basic conditions to give a compound of the formula:

i 0

R .X-

m cr .

(4)

T:,

COOR5

5 1

wherein R , R , X1 , and Y are as defined above, and converting

X', when different from

X-

by a substitution reaction into X, which represents a group of the formula CH2Z in which Z is as defined in claim 1,

(b) reducing, ozonizing, and hydrolyzing the compound of formula (4) to give a compound of the formula:

„1

(14)

_N.

wherein R and X are as defined above;

(c) reacting the compound of formula (14) with a suitable ester of glyoxylic acid of formula CHOCOOR, wherein R

is selected from the group consisting of a hydrogen atom, lower alkyl, 2,2,2-trichloroethyl, acetonyl, benzyl, p-nitrobenzyl,

p-methoxybenzi rr office

- 65 -

i 999:?

phenyl, £-nitrophenyl, benzhydryl, or a residue known to undergo metabolic activation "in vivo" and having favorable pharmacokinetic properties, to give a compound of the formula:

R'

X

p(X

1 pnOR*

wherein X, R and R are as defined above;

(d) converting the compound of formula (15) to the chloroderivative of the formula: pA ^ x

(15)

(16)

wherein X, R , and R are as defined above;

(e) transforming the compound of formula (16) into the phosphorane of the formula:

\

X

-N.

0

Ph.

(11)

COOR

wherein X, R , and R are as defined above, and Ph is phenyl; and (f) cyclising the compound of formula (11) to give the compound of the formula (1).

18.i A process for preparing a compound of claim 1, said process comprising

(a) reacting a compound of formula:

R1 3

(2)

0 E^'COOR °

wherein R^ represents a lower alkyl group and is as defined in Claim 1, with an acetylenic derivative of the formula X1C=CY, wherein X1 is a group of formula C^Z1, wherein Z' is a halogen or hydrogen atom, hydroxy, amino, carbamoyloxy or a grouD of the formula OR3, OCOR3, NHCOR3 where R3 is lower alkyl, arylf or a

66

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, to give a compound of the formula:

XX

O ' 'v r. Y

H COOR

(3)

wherein R^f r\ x', and Y are as defined above, which is isomerized in basic conditions to give a compound of the formula:

'xk ■

0 COOR5

wherein R^, R^", X', and Y are as defined above, and convertinq

X', when different from X , by a substitution reaction into X, which represents a group of the formula CH2Z in which Z

is as defined in claim 1;

(b) selectively ozonizing the compound of the formula

(4) to give a compound of the formula: (0)

R1 11 n v

(5)

' 0^>0"Y

5 1 COOR5

wherein n = 1 and X, Y, R , and R are as defined above;

(c) reducing the compound of formula (5) to a compound of the formula (5) in which n = 0;

(d) hydrolyzing the compound of formula (5) in which n = 0 to a compound of the formula:

1

[6)

wherein X, Y, and R1 are as defined above;

(e) reacting the compound of formula (6) with a suitable ester of glyoxylic acid of formula CHOCOOR, wherein R is

192949

selected from the group consisting of a hydrogen atom, lower alkyl, 2,2,2-trichloroethyl, acetonyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, £-nitrophenyl, benzhydryl, or a residue known to undergo metabolic activation "in vivo" and having favorable pharmacokinetic properties, to give a compound of the formula:

r1n x

. COOK „

wherein X, Y, r\ and R are as defined above;

(f) converting the compound of formula (7) to the chloroderivative of the formula: r^-.

(7)

(8)

wherein X, Y, R , and R are as defined above;

(g) transforming the compound of formula (8) into the phosphorane of the formula:

R. >S\/X

(9)

i

COOR

wherein R^", R, X, and Y are as defined above, and Ph is phenyl;

(h) ozonizing the compound of formula (9),

to give a compound of the formula^

_N

(11)

PPh-

00R

wherein R"*", R, X and Ph are as defined above,

and

(i) cyclizing the compound of formula (11) to give a compound of the formula (1).

19 .' A process for preparing a compound of claim 1, said process comprising

- 68 -

(a) reacting a compound of formula: -i

R7

wherein R^ represents a lower alkyl group and R"*" is as defined in claim 1, with an acetylenic derivative of the formula X'CgCY, wherein X' is a group of formula C^Zwherein Z1 is a halogen or hydrogen atom, hydroxy, amino, carbamoyloxy or a group of the

3 3 3 3

formula OR , OCOR , NHCOR , where R is lower alkyl, aryl, or a heterocyclic ring,and Y represents a hydrogen atom, lower alkyl,

cyano or a group of the formula COOR5or CI^Zwherein R^ is lower alkyl and Z' is as-described above, to give a compound of

1 0

the formula: R ,xf cf

T Y

H «\Y (3) -

'coor5

wherein R5, R1, X1, and Y are as defined above, which is isomerized in basic conditions to give a compound of the formula:

K1. JL Jt'

:oor5

(4)

5 1

wherein R , R , X', and Y are as defined above, and converting X',. when different from X,, by a (substitution reaction into X, which represents a group of the formula CH^Z in which Z is as defined in claim 1;

(b) selectively ozonizing the compound of the formula (4) to give a compound of the formula:

(5)

0 \Y

coor5

wherein X, Y, R~", and R"*" are as defined above;

i <m M

(c) hydrolyzing the compound of formula (5) to a

0

compound of the formula: R1 g X

ca

<€)

° H *

wherein X, Y, and R are as defined above;

(d) reacting the compound of formula (6) with a suitable ester of glyoxylic lacid of the formula CHOCOOR, wherein R is selected from the group consisting_of a hydrogen atom,

lower alkyl, 2,2,2-trichloroethyl, acetonyl, benzyl, p-nitrobenzyl, ■ £-methoxybenzyl, phenyl, £-nitrophenyl, benzhydryl, or a residue known to undergo metabolic activation "in vivo" and having favorable pharmacokinetic properties, to give a compound of

0

the 'formula: • s - -X •

(7)

i I

wherein X, Y, R"*", and R are as defined above; j

(e) converting the compound of formula (7) to the !

o I",

1 II I

chloroderivative of the formula: R \ j i

COOR "

wherein X, Y, R"5", and R are as defined above;

(f) transforming the compound of formula (8) into a

1 0

phosphorane of the formula: R ,x

(8)

i'

i i i i

(9)

I . COOR

wherein R , R , x, and Y are as defined above, and Ph is pheny.

(g) reducing the compound of formula (9) to give a

(10)

compound of the formula: x wherein r\ R, X, Y and Ph are as defined above;

(h) ozonizing the compound of formula (-J0) to give a compound of the formula: 1

. ^PPh3

J COOR

wherein R1, R, X and Ph are as defined above,

and

(i) cyclizing the compound of formula (11) to give a compound of formula (1).

20. A process for preparing a compound of claim 1, ly as hereinbei to the foregoing Examples.

substantially as hereinbefore described with particular reference ^

II

BATES THJS 74A DAY OF 1^83

A. J. PARK & SpN

AGENTS FOR THE APPLICANTS

N.Z. PATENT OFFICE

-7 JUL 1983

. RECEIVED

- 71 -

</div>