Pharmaceutical Substances Syntheses, Patents, Applications - Part 38 pdf

Cefaloglycin C 371 Pivacef (Firma) Zetacef (Menarini) J: Cephalomax (Daisan) Cephazal (Hokuriku) Cepol (Torii) CEX (Glaxo) Ciponium (Nippon Kay aku) Derantel (Nippon Chemiphar) Garasin (Wakamoto) Iwalexin (Iwaki) Keflex (Shionogi) Larixin (Toyama) Madlexin (Meiji) Mamalexin (Showa) Mepilacin-DS (Kanto Ishi) Ohlexin (Ohta) Oracocin (Tobishi) Oroxin (Otsuka) USA: Rinesal (Kissei) Salitex (Banyu) Segoramin (Takata) Sencephalin (Takeda) Suciralin (Mohan) Sync1 (Toyo Jozo) Taicelexin (Taiyo) Tokiolexin (Isei) Xakl (SS Seiyaku) Keflex (Dista; 1971) Cefaloglycin (Cephaloglycin) ATC: JOlDA Use: antibiotic RN: 3577-01-3 MF: C,,HI,N306S MW: 405.43 EINECS: 222-696-7 LD,,: >10 gikg (M, p.0.); >10 gikg (R, p.0.) CN: [6R-(6a,7~(R*))]-3-[(acetyloxy)methyl]-7-[(amin~phenylacetyl)amino]-8-oxo-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid dihydrate RN: 22202-75-1 MF: C,,H,,N306S . 2H20 MW: 441.46 &COOH HGbo N-Cbo-D-phenyl- glycine Hp. Pd-C I Reference (s): b 1. isobutyl chloroformate 2. 7-aminocephalosporanic acid COOH 0 N-Cbo-cefaloglycin (I) COOH 0 NH, Cefologlycin 0 Cbo: -'?o b GB 985 747 (Eli Lilly; appl. 22.8.1962; USA-prior. 11.9.1961). US 3 497 505 (Eli Lilly; 24.2.1970; appl. 24.10.1966). GB 1 017 624 (Merck & Co.; appl. 10.1.1963; USA-prior. 16.1.1962). acylation via silyl-derivatives: DOS 1 942 454 (Lilly; appl. 20.8.1969; USA-prior. 23.8.1968). microbiological acylation: US 4 073 687 (Shionogi; 14.2.1978; J-prior. 14.5.1975). Formulation(s): cps. 250 mg, 500 mg 372 C Cefaloridine Trade Name(s): J: Kefglycin (Shionogi) USA: Kafocin (Lilly); wfm Cefaloridine (Cephaloridine) ATC: JOlDA02 Use: antibiotic RN: 50-59-9 MF: Cl,H,,N3O4S2 MW: 415.49 EINECS: 200-052-6 LD,,,: 2200 mgkg (M, i.v.); >20 glkg (M, p.0.); 1065 mgkg (R, i.v.); 2500 mgkg (R, p.0.) CN: (6R-trans)-l-[[2-carboxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-l-azabicyclo[4.2.0]oct-2-en-3- yl]methyl]pyridinium hydroxide inner salt COOH o COO- pH 6.5 H cefolotin pyridine Cefoloridine Reference(s): GB 1 030 630 (Glaxo; appl. 14.12.1962). DE 1 445 828 (Glaxo; appl. 14.12.1963; GB-prior. 14.12.1962, 2.12.1963). FR 1 384 197 (Glaxo; appl. 13.12.1963; GB-prior. 14.12.1962, 2.12.1963). . DAS 1 670 599 (Lilly; appl. 17.1.1966; USA-prior. 5.3.1965). DAS 1 795 581 (Glaxo; appl. 4.1 1.1964; GB-prior. 13.7.1964, 29.9.1964). DE 1 795 61 0 (Glaxo; appl. 4.11.1964; GB-prior. 4.1 1.1963, 13.7.1964. 29.9.1964). Formulation(s): amp. 250 mgl2 ml, 500 mgl3 ml, 1 g14 ml Trade Name(s): D: Cepaloridin-Glaxo (Glaxo); KCflodin (Lilly); wfm Keflodin (Shionogi) wfm I: Ceporin (Glaxo) USA: Loridine (Lilly); wfm generics J: Ceporan (Torii) F: CCporine (Glaxo); wfm CER (Glaxo) Cefalotin (Cephalotin) ATC: JOlDA03 Use: antibiotic RN: 153-61-7 MF: C,6H,,N20,S2 MW: 396.44 EINECS: 205-815-7 LD,,,: 4990 mgkg (M, i.v.); >5 glkg (R, i.v.) CN: (6R-trans)-3-[(acetyloxy)methyl]-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-l-azabicyclo[4.2.O]oct-2-ene- 2-carboxylic acid monosodium salt RN: 58-71-9 MF: C16H,,N2Na06S, MW: 418.43 EINECS: 200-394-6 LD,,,: 4800 mglkg (M, i.v.); 5600 mgkg (R, i.v.); >10 glkg (R, p.0.) Cefamandole C 373 2-(2-thieny1)- 7-aminocepholo- ocetyl chloride sporanic acid Cefalotin Reference(s): DE 1 445 684 (Eli Lilly; appl. 4.6.1962; USA-prior. 8.6.1961). BE618 663 (Eli Lilly; appl. 7.6.1962; USA-prior. 8.6.1961). DAS 1 670 641 (Lilly; appl. 23.1 1.1967; USA-prior. 23.1 1.1966). DOS 2 730 579 (Pierre1 S.p.A.; appl. 6.7.1977; GB-prior. 10.7.1976). acylation via silyl-derivatives of 7-aminocephalosporanic acid: DOS 1 942 454 (Lilly; appl. 20.8.1969; USA-prior. 23.8.1968). acylation via 1,3,2-dioxaboranyl-derivatives: DOS 2 755 902 (Dobfar; appl. 15.12.1977; I-prior. 16.12.1976). total synthesis: Ratcliffe, R.W.; Christensen, G.B.: Tetrahedron Lett. (TELEAY) 1973, 4649. "easily soluble form" for parenteral application by freeze-drying: US 4029 655 (Lilly; 14.6.1977; appl. 11.4.1975). US 4 132 848 (Lilly; 2.1.1979; prior. 3.1 1.1977). DOS 2752 442 (Lilly; appl. 24.1 1.1977). crystalline sterile preparation for parenteral application: US 4 029 655 (Lilly; 14.6.1977; appl. 11.4.1975). Formulation(s): amp. 500 mg, 1 g, 2 g, 4 g (as sodium salt) Trade Name(s): D: Cepovenin (Hoechst; J: Cephation (Meiji) Sucira N (Mohan) 1973); wfm CET (Glaxo) Synclotin (Toyo Jozo) F: CCfalotine (Panpharma) Coaxin (Tobishi) Toricelocin (Torii) KCflin (Lilly; 1966) Keflin (Shionogi Lilly) USA: Keflin (Lilly; 1975); wfm generics Resting (Ono) Seffin Neutral (Glaxo; I: Cefalo (Formulario Naz.) Sodium Cephalotin (Green 1984); wfm Keflin (Lilly) Cross) Cefamandole ATC: JOlDA07 Use: antibiotic RN: 34444-01-4 MF: C,,Hl,N,05S, MW: 462.51 EINECS: 252-030-0 CN: [6R-[6a,7~(R*)]]-7-[(hydroxyphenylacetyl)amino]-3-[[(l-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5- thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid formate monosodium salt (nafate) RN: 42540-40-9 MF: C,,H17N,Na0,S, MW: 512.50 EINECS: 255-877-4 LDSo: 3915 mglkg (M, i.v.); 2562 mgkg (R, i.v.) 374 C Cefamandole fol.mic 7-orninocepholosporonic 7-formomidocepholo- ocid ocid sporonic ocid (I) 1. pH 6.9 HA, HA 2. conc. HCI COOH N-'?. + + NOS 1 -methyl- 1H-tetrozole- 5-thiol sodium solt 7-amino-3-(1 -methyl- tetrazol-5-ylthiomethyl) 3-cephem-4-corboxylic ocid (I!) D-onhydro-0- carboxymondelic acid (from D(-)- rnondelic ocid ond phosgene) Cefamondole I Referencefs): US 3 641 021 (Lilly; 8.2.1972; appl. 18.4.1969). DE 2 01 8 600 (Lilly; appl. 17.4.1970; USA-prior. 18.4.1969). DAS 2 065 621 (Lilly; appl. 17.4.1970; USA-prior. 18.4.1969). US 3 840 531 (Lilly; 8.10.1974; appl. 21.3.1972). US 3 903 278 (Smith Kline Corp.; 2.9.1975; prior. 4.1 1.1971). DOS 2 730 579 (Pierrel S.p.A.; appl. 6.7.1977; GB-prior. 10.7.1976). preparation andor purification via the trimethylsilyl-derivatives: DOS 2 71 1 095 (Lilly; appl. 14.3.1977; USA-prior. 17.3.1976). pur$cation: US 4 11 5 644 (Lilly; 19.9.1978; appl. 19.9.1978). DOS 2 839 670 (Lilly; appl. 12.9.1978; USA-prior. 19.9.1977). crystalline sodium salt: US 4 054 738 (Lilly; 18.10.1977; appl. 22.12.1975). US 4 168 376 (Lilly; 18.9.1979; appl. 5.6.1978). lithium salt: GB 1 546 757 (Lilly; appl. 10.4.1975; valid from 7.4.1976). 0,formyl-derivative: US 3 928 592 (Lilly; 23.12.1975; appl. 21.2.1974). GB 1 493 676 (Lilly; appl. 20.2.1975; USA-prior. 22.2.1974). GB 1 546 898 (Lilly; appl. 7.4:1976; USA-prior. 11.4.1975). DOS 2 506 622 (Lilly; appl. 17.2.1975; USA-prior. 22.2.1974). crystalline sodium .salt of 0-formylcefamandole: US 4 006 138 (Lilly; 1.2.1977; appl. 11.4.1975). Cefapirin C 375 complex of cefamandole sodium with 1,4-dioxane and water: US 3 947 414 (Lilly; 30.3.1976; appl. 23.12.1974). complex of cefamandole sodium with ethyl L-(-)-lactate: US 3 947 415 (Lilly; 30.3.1976; appl. 23.12.1974). Formulation(s): vial 0.5 g, I g, 2 g (as nafate) Trade Name(s): D: Mandokef (Lilly ; 1977) Cefaseptolo (Miba) Mandolsan (San Carlo) F: Kefandol (Lilly) Cefiran (Pierrel) Neocefal (Metapharma) GB: Kefadol (Dista; 1978) Cemado (Francia Farm.) Septomandolo (IPA) 1: Bergacef (Bergamon) Fado (Caber) J: Kefadole (Shionogi) Cedol (Eurofarmaco) Lampomandol (AGIPS) USA: Mandol (Lilly; 1978) Cefarn (Magis) Mancef (Lafare) Cefarnen (Menarini) Mandokef (Lilly) Cefapirin ATC: JOIDA~O (Cephapirin; Cefaprin) Use: P-lactam antibiotic RN: 21593-23-7 MF: C17H,7N,0,S, MW: 423.47 EINECS: 244-466-5 LD,,: >760 mglkg (M, i.v.); 26.1 g/kg (M, p.0.); 6048 mglkg (R, i.v.); 16.356 g/kg (R, p.0.) ' CN: (6R-trans)-3-[(acetyloxy)methyl]-8-oxo-7-[[(4-pyridinylthio)acetyl]amino]-5-thia-l-azabicyclo[4.2.0]oct- 2-ene-2-carboxylic acid monosodium salt RN: LD,,: @ 24356-60-3 MF: C,,H,,N,NaO,S, MW: 445.45 EINECS: 246-194-2 4600 mglkg (M, i.v.); 26.1 glkg (M, p.0.); 4580 mglkg (R, i.v.); 16.4 glkg (R, p.0.); 2500 mglkg (dog, i.v.) 4-chloro- thioglycolic 4-pyridylthio- (1) pyridine acid acetic acid brornoocetyl bromide 7-arninocepholo- Cefopirin sporonic acid (11) - 7 376 C Cefatrizine Reference(s): Crast, L.B. et al.: J. Med. Chem. (JMCMAR) 16, 1413 (1973). US 3 422 I00 (Bristol-Myers; 14.1.1969; appl. 2.5.1967; prior. 5.1.1 967) US 3 503 967 (Bristol-Myers; 31.3.1970; appl. 26.8.1968). US 3 578 661 (Bristol-Myers; 11.5.1971; appl. 2.6.1969). DE 1 670 301 (Bristol-Myers; appl. 5.1.1968; USA-prior. 5.1.1967). ac)ilation via 1,3,2-dioxaboranyl-derivatives: DOS 2 755 902 (Dobfar; appl. 15.12.1977; I-prior. 16.12.1976). salts with amino acids: FR-appl. 2 479 228 (Dobfar; appl. 25.3.1981; I-prior. 1.4.1980). Formulation(s): vial 0.5 g, 1 g, 2 g, 4 g (as sodium salt) Trade Name(s): D: Bristocef (Bristol; 1974); Brisporin (Bristol It. Sud); Cefatrexyl (Nihon Bristol) wfm wfm Cepotril (Tobishi-Kaken) F: Cefalojcct (Bristol-Myers Piricef (CT); wfm Ceropirin (Nichiiko) Squibb; 1974) J: Antibalin (Nippon Taicelepirin (Taiyo) I: Ambrocef (Lusofarmaco); Chemiphar) Vacian (Kantoishi) wfm Cefarin (Fuji) USA: Cefadyl (Bristol; 1974) Cefatrizine ATC: JDlDA21 Use: p-lactam antibiotic RN: 5 1627- 14-6 MF: C,uH,uN60,S2 MW: 462.5 1 EINECS: 257-324-2 CN: [6R-[6a,7~(R*)]]-7-[[amino(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(1H-1,2,3-triazol-4- ylthio)methyl]-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 7-orninocepholo- 4-mercopto- sporonic acid 1,Z.J-triozole 7(R)-omino-3-[(I ,2,3- triozol-4-ylthio)methyl]- 3-cephern-4-corboxylic ocid (I) triethylomine. N.N-dimethyloniline. hexomethyldisilozone NHz 0(-)-2-(4-hydroxypheny1)- glycyl chloride hydrochloride I Cefotrizine Reference(s): US 3 899 394 (Bristol-Myers; 12.8.1975; prior. 26.12.1972). US 3 867 380 (SmithKline Corp.; 18.2.1975; prior. 17.12.1970, 18.2.1971, 14.6.1972). DOS 2 364 192 (Bristol-Myers; appl. 21.12.1973; USA-prior. 26.12.1972). DAS 2 622 985 (Bristol-Myers; appl. 21 S.1976; USA-prior. 23.5.1975). US 3 970 65 1 (Bristol-Myers: 20.7.1976; prior. 7.1.1974, 18.12.1974). US 3 985 747 (Bristol-Myers; 12.10.1976; appl. 24.5.1974). Cefazedone C 377 acylation via 1,3,2-dioxabomnyl derivatives: DOS 2 755 902 (Dobfar; appl. 15.12.1977; I-prior. 16.12.1976). Formulation(s): cps. 125 mg, 250 mg, 500 mg; susp. 5 %; syrup 125 mg, 250 mg Trade Name(s): F: CCfaperos (Bristol-Myers Squibb; 1987) 1: Cefatrix (tekfarma bko Cefotrizin (Firma) Cetrazil (Herdel) Faretrizin (Lafare) Ipatrizina (IPA) Kefoxina (CT) Ketrizin (Esseti) Lampotrix (Leben's) Trixilan (Pulitzer) Latocef (Delsaz & Trizina (Francia Farm.) Filippini) Zanitrin (Bristol It. Sud) Miracef (Tosi-Novara) Zinaf (Crosara) Novacef (Locatelli) Zitrix (Metapharma) Orotrix (San Carlo) J: Bricef (Bristol) Tamyl (Fisons Italchimici) Cepticol (Banyu; 1980) Tricef (Eurofarmaco) Trixidine (ASTA Medica) Cefazedone ATC: JOlDA15 Use: antibiotic RN: 56187-47-4 MF: C18H,5CI,N505S, MW: 548.45 CN: (6R-trans)-7-[[(3,5-dichloro-4-oxo-l(4H)-pyridinyl)acetyI]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2- yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[42.O]oct-2-ene-2-carboxylic acid 3.5-dichloro- ethyl bromo- 4-pyridone acetate 3.5-dichloro-4- oxopyridin-1 -yl- acetic acid (I) 1. DMF, SOCIZ, - 40 oc 2. , N(C,H5),. CH,CI,. -20 OC COOH 0 I 2. 7-aminocepholosporonic acid CI "fi \ 'ANp ()"?pH3 H lhiodiazole Z-mercapto- Cefazedone 5-methyl-1,3.4- 378 C Cefazolin Reference(s): Gericke, R.; Rogalski, W.: Arzneh-Forsch. (ARZNAD) 29 (I), 362 (1979). DOS 2 427 224 (E. Merck; appl. 6.6.1974). DOS 2 345 402 (E. Merck; appl. 8.9.1973). DOS 2 621 01 1 (E. Merck; appl. 12.5.1976). GB 1 436 989 (E. Merck; appl. 5.9.1974; D-prior. 8.9.1973,6.6.1974). US 4 153 693 (E. Merck; 8.5.1979; D-prior. 8.9.1973,6.6.1974). GB 1 539 158 (E. Merck; appl. 11.5.1977; D-prior. 12.5.1976). Formulution(s): vial 1 g, 2 g Trade Narne(s): D: Refosporin (E. Merck); wfrn Cefazolin (Cephazolin) ATC: JOlDA04 Use: antibiotic RN: 25953-19-9 MF: Cj4HI4NRO4S3 MW: 454.52 EINECS: 247-362-8 LDS,,: 3 gkg (M, i.v.) CN: (6R-trans)-3-[[(5-rnethyl-l,3,4-thiadiazol-2-yl)thio]rnethyl]-8-ox0-7-[(lH-tetrazol-l-yla~etyl)amino]-5- thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium saIt RN: 271 64-46-1 MF: CI4HI,N,NaO,S3 MW: 476.50 EINECS: 248-278-4 LDSI; 3900 rnglkg (M, i.v.); >l 1 glkg (M, p.0.); 2760 rnglkg (R, i.v.); >ll glkg (R, p.0.); 2200 rnglkg (dog, i.v.) 2-mercopto- 5-methyl- 1 J.4- thiodiozole Cefozolin US 3 5 16 997 (Fujisawa; 23.6.1970; appl. 12.4.1968; J-prior. 15.4.1967, 24.lO.l967,28.10.1967). DE 1 170 168 (Fujisawa; appl. 10.4.1968; J-prior. 14.4.1967). Cefbuperazone C 379 corresponding: GB 1 206 305 (Fujisawa; appl. 1 1.4.1968; J-prior. 15.4.1967). NL 6 805 179 (Fujisawa; appl. 1 1.4.1968; J-prior. 1 5.4.1967). DOS 1953 861 (Fujisawa; appl. 25.10.1969). alternative syntheses: DOS 2 055 796 (Fujisawa; appl. 13.1 1.1970; J-prior. 17. I 1.1969). DOS 2 540 374 (Lilly; appl. 10.9.1975; USA-prior. 12.9.1974). acylation via 1,3,2-dioxaboranyl-derivatives: DOS 2 755 902 (Dobfar; appl. 15.12.1977; I-prior. 16.12.1976). pur#cation: US 4 115 645 (Lilly; 19.9.1978; appl. 10.5.1977). sodium salt: DOS 2752 443 (Lilly; appl. 24.1 1.1977; USA-prior. 24.11.1976). sodium salt monohydrate: US 4 104 470 (Lilly; 1.8.1978; appl. 3.6.1977). mpidly soluble spray dried sociimn salt: US4 146 971 (Lilly; 3.4.1979; prior. 24.1 1.1976, 14.12.1977). suspension for parenteral application: GB 1 546 479 (Lilly; appl. 23.4.1976; USA-prior. 28.4.1975). Fonulation(s): vial 250 mg, 500 mg, 1 g, 2 g (as sodium salt) Trade Namefs): D: Elzogram (Lilly; 1974) Gramaxin (Roche; 1974) F: Cefacidal (Bristol-Myers Squibb; 1976) Kefzol (Lilly; 1976) GB: Kefzol (Lilly; 1974) I: Acef (Eurofarmaco) Biazolina (1st. Italiano Ferm.) Cefabiozim (IPA) Zolisint (Locatelli) Cefamezin (Carlo Erba) J: Cefamezin (Fujisawa; Cefazil (Delsaz & 1971) Filippini) USA: Anccf (SmithKline Cromezin (Crosara) Bcccham; 1973) Firmacef (Firma) Kefzol (Lilly; 1973) Recef (Farma Uno) Totacef (Bristol It. Sud) Zolin (San Carlo) Cefbuperazone ATC: JOlDA Use: p-lactam antibiotic RN: 76610-84-9 MF: C,,H,,N,O,S, MW: 627.66 CN: [6R-[6a,7a,7(2R*,3S*)l]-7-[[2-[[(4-ethyl-2,3-dioxo- 1-piperazinyl)carbonyl]amino]-3-hydroxy- 1 - oxobutyl]amino]-7-methnxy-3-[[(I-methyl- IN-tetrazol-5-yl)thio]methyl]-8-0x0-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid A H3C OH 1. trimethylchlorosilane A OH$ OH 2. 2,3-dioxo-4-ethyl- 1 -piperazine- D-threonine corbonyl chloride 7(R)-(2.3-dioxo-4-ethyl- (cf, piperocillin synthesis) 1 -piperozinecorboxornido)- 3(S)-hydroxybutyric 380 C Cefbupcrazone 1. TosOH, dioxane t 2. diphenyldiozo- methane 7-ominocepholo- diphenylmethyl sporonic acid 7-aminocephalo- sparonate (11) 1-methyl-1 H- diphenylrnethyl tetrozole-5- 7(R)-amino-3-(1 -methyl- thiol 1 H-tetrazol-5-ylthiomethy1)- 3-cephem-4-carboxylote (Ul) n 1. H3C-FC/O . CH2C12, CI-COOC2H5. -15 "C 2. I11 I 1. 4-methylmorpholine, 0 ethyl chloroformote 1. CH2C12, THF, -70 OC 2. H3C-4- Lit. CH30H 3 (CH3)3C-OCI 4. AcOH 5. NoHCOJ. pH 6.5 IV 3. tert-butyl hypochlorit/ onisole. CF3COOH v b trifluoroacetic acid Cefbuperozone Referenceis): DOS 2 939 747 (Toyama; appl. 1.10.1979; J-prior. 23.4.1979,7.8.1979). FR 2 455 051 (Toyama; appl. 4.10.1979; J-prior. 23.4.1979,7.8.1979). US 4 263 292 (Toyama; 21.4.1981; J-prior. 13.6.1978, 23.4.1979,7.8.1979). GB 2 048 241 (Toyama; appl. 26.9.1979; J-prior. 23.4.1979, 7.8.1979). . ylthio)methyl ]-5 -thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 7-orninocepholo- 4-mercopto- sporonic acid 1,Z.J-triozole 7(R)-omino- 3-[ (I ,2, 3- triozol-4-ylthio)methyl ]- 3-cephern-4-corboxylic. RN: 5618 7-4 7-4 MF: C18H,5CI,N505S, MW: 548.45 CN: (6R-trans )-7 -[ [(3,5-dichloro-4-oxo-l(4H)-pyridinyl)acetyI]amino ]-3 -[ [(5-methyl-1,3,4-thiadiazol- 2- yl)thio]methyl ]-8 -oxo-5-thia-l-azabicyclo[42.O]oct-2-ene-2-carboxylic. 3444 4-0 1-4 MF: C,,Hl,N,05S, MW: 462.51 EINECS: 25 2-0 3 0-0 CN: [6R-[6a,7~(R*)] ]-7 -[ (hydroxyphenylacetyl)amino ]-3 -[ [(l-methyl-1H-tetrazol-5-yl)thio]methyl ]-8 -oxo- 5- thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic