Pharmaceutical Substances Syntheses, Patents, Applications - Part 39 doc

Cefditoren pivoxil C 381 Fotmulation(sJ: vial 500 mg, 1 g Trade Name(s): 1: Keiperazon (Kaken; 1985) Tomiporan (Toy ama: 1985) Cefditoren pivoxil (ME- 1207) ATC: SOlAA Use: cephalosporin RN: 117467-28-4 MF: C25H28N607S3 MW: 620.73 CN: [6R-[3(Z),6u,7~(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[2-(4-methy1-5- thiazoly1)ethenyll-8-0x0-5-thia- l -azabicyclo[4.2.O]oct-2-ene-2-carboxylic acid (2,2-dimethyl- l- oxopropoxy)methyl ester [6R-[3(Z),6a,7P(E)]]-form RN: 104145-87-1 MF: C,SH28N607S3 MW: 620.73 1. P(C,H,),. Nol, ocetone 1. triphenylphosphine. sodium iodide 2. 4-methylthiazole- 5-carboxoldehyde -30 "C ___3 phosphorus pentachloride in pyridine (11) 2-(methoxyimino)-2- (2-tritylomina-thiazol- 4-yl)ocetic acid 1. NaHC03. H20 2. Dioion HP20 382 C Cefixime iodornethyl pivolote I Cefditoren pivoxil Reference(s): synthesis: EP 175 610 (Meiji Seika Kaisha; appl. 26.3.1986; J-prior. 7.9.1984, 18.7.1985). Sakagami, K. et al.: J. Antibiot. (JANTAJ) 43(8), 1047 (1990). Sakagarni, K. et al.: Chem. Pharm. Bull. (CPBTAL) 39(9), 2433 (1992). pharmaceutical compositions: EP 339 465 (Meiji Seika Kaisha; appl. 2.11.1989; J-prior. 19.4.1988). EP 629 404 (Meiji Seika Kaisha; appl. 21.12.1994; J-prior. 16.6.1993). Formulation(s): gran. 100 rng; tabl. 100 mg Trade Name(s): J: Meiact (Meiji Seika) Cefixime (CL-284635; FK-027; FR-17027) ATC: J01DA23 Use: semisynthetic third generation cephem antibiotic (for oral administration), high P-lactamase stability RN: 79350-37-1 MF: C,,H,,N,07S2 MW: 453.46 LDso: 4420 mgkg (M, i.v.); >10 glkg (M, p.0.); 6990 mglkg (R, i.v.); >lO glkg (R, p.0.); >3200 mgkg (dog, i.v.); >600 mgkg (dog, p.0.) CN: [6R-[6a,7~(Z)]]-7-[[(2-amino-4-thiazolyl)[(carboxymethoxy)imino]acetyl]amino]-3-ethenyl-8-oxo-5- thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid trihydrate RN: 1251 10-14-7 MF: C1,Hl,N,07S2~ 3H20 MW: 507.50 Cefixime C 383 Synihesis of intermediates: (2-formamido- tert-butyl thiazol-4.~1)- ominooxyocetote oxoacetic ocid (Z)-2-(tert-butoxycorbonyl- methoxyimino)-2-(2-form- amidothiozal-4-yl)- acetic acid (1) tert-butyl 2-hydroxy- imino-3-oxobutyrote (11) 1. acetyl acetote, OMF, K2C03 2. CI/~~'~~~ . 7.5 h o o H3C CH, I1 b 2. methyl chloroacetote H~c~o~~H~ 0 (Z)-4-chloro-2-(rnethoxy- corbonylrnethoxyimino)- 3-oxobuiyric acid (IV) deacetykephalosporin C benzoyl sodium salt chloride 384 C Cefixime PCI, pyridine 0,o CH2CIZ, -30 OC diphenylmethyl 7-[5-benzamido- 5-(diphenylmethoxycorbonyl)- pentonomido]-3-hydr~xymeth~l- 3-cephern-4-carbaxylate (V) 1. Nal. P(C,H,),, DMF 2. HCHO, CHZCIZ b VII 1. triphenylphosphine H 1 PCI,. pyridine. CH,Cl, 2. CHJOH. -40 'C 3 1O0C. 1 h 0 0 2 05FcH2 N~+ OHCI H 1. PCI,, pyridine, CHZCIZ, -10 'C 2. CH30H, -40 OC diphenylmethyl 7-omino- 3-vinyl-3-cephern-4- carboxylate hydrochloride (WI) diphenymethyl 7-amino-3-chloro- methyl-3-cephem- 4-carboxylate hydrochloride (M) synthesis of Cefixime: 1. POCIJ. DMF, ethyl acetote 2. IX . H3C-CO-NH-Si(CH3)3, ethyl acetate 3. H, 1~ b x 2. N-trirnethylsilylacetornide Cefixime C 385 1. Nal, acetone , ethyl acetate 1. HCI, CH,OH 2. CF3COOH, anisole XI1 - HCHO CH2C12 A I Cefixime 1. POC13, OMF, THF 2. WI . H3C-CO-NH-Si(CH3)3, ethyl acetate IV b XlII 2. N-trimethylsilylacetamide thiourea (m) COOH F3C-COOH NaHCO,, H20, 40-45 OC. 7 h . 0 386 C Ccfmenoxime Reference(s): alternative synthesis routes for Vfff starting porn 7-aminocephalosporanic acid are also described in the cited literature: Yamanaka, H. et al.: 1. Antibiot. (JANTAJ) 38, 1738 (1985). Yamanaka, H. et a].: J. Antibiot. (JANTAJ) 39, 101 (1986). Kawabata, K. ct al.: J. Antibiot. (JANTAJ) 39,405 (1986). US 4 409 214 (Fujisawa; 11.10.1983; UK-prior. 19.1 1.1979, 8.2.1980,21.4.1980, 14.7.1980). US 4 423 213 (Fujisawa; 27.12.1983; UK-prior. 19.11.1979, 8.2.1980, 21.4.1980, 14.7.1980). US 4 487 927 (Fujisawa; 11.12.1984; UK-prior. l9.ll.l979, 8.2.1980, 21.4.1980, 14.7.1980). US 4 585 860 (Fujisawa; 29.4.1984; UK-prior. 19.11.1979, 8.2.1980,21.4.1980, 14.7.1980). EP 30 630 (Fujisawa; appl. l5.ll.1980; UK-prior. 19.1 1.1979, 8.2.1980,21 A.1980, 14.7.1980). Formularion(s): cps. 100 mg, 200 mg; fine gran. 50 mglg; f. c. tabl. 200 mg, 400 mg; oral susp. 100 mg/5 ml; syrup 100 mgl5 ml; supplied as trihydrate in all formulations Trade Name(s): D: Ccphoral (Merck; 1991) F: Oroken (Bellon) Unixime (Firma) Suprax (Klinge) I: Cefixoral (Menarini) J: Cefspan (Fujisawa; 1987) Uro-Cephoral (Merck) Suprax (Cyanamid) USA: Suprax (Lederle Labs.) Cefmenoxime ATC: JOlDA16 Use: p-lactam antibiotic (cefalosporin derivative) RN: 65085-01-0 MF: C,,H,,N,OSS3 MW: 51 1.57 CN: , [6R-[6a,7~(Z)l]-7-[[(2-amino-4-thiazolyl)(methoxyiminv)cetyl]amino]-3-[[(l-methyl-1H-tetrazol-5- yl)thiolmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid . hydrochloride (2:l) RN: 75738-58-8 MF: C,,H,,N,0SS3 . 112HCl MW. 1059.60 EINECS: 278-299-4 LD,,: 7830 mglkg (M, i.v.); 17.54 glkg (M, p.0.); 2680 mglkg (R, i.v.); >20 glkg (R, p.0.) COOH N-Fd a CH3 HN H3C N' O\GpsYN" s% o + cH3 I VCI H,N+' CH3 dimethyl- ' ocetornide 2-(2-chloroocetornido- 7(R)-amino-3-(1-methyl- 4-thiozolyl)-2-meth- 1 H-tetrazol-5-ylthio- oxyirninoocetyl methyl)-3-cephern-4- chloride corboxylic ocid (cf. ceflrioxone (cf. cefarnondole synthesis) synthesis) 3 . C,H,OH. THF H2N NH, CH3 thioureo k Cefoperazone C 387 COOH 0 H20, NaHCOJ, (C2H5),N+CH2CsH5Br- -b HS benzyltriethyl- CH3 ammonium bromide cefotoxime (4. v.1 1 -methyl-1H- tetrazole-5- thiol Reference(s): Ochiai, M. et al.: Chem. Pharm. Bull. (CPBTAL) 25,3115 (1977). DOS 2 556 736 (Takeda; appl. 17.12.1975; J-prior. 19.12.1974; GB-prior. 9.6.1975). US 4 098 888 (Takeda; 4.7.1978; J-prior. 1974; GB-prior. 9.6.1975). DOS 2715 385 (Takeda; appl. 6.4.1977; J-prior. 14.4.1976; 8.9.1976). Formulation(s): vial 500 mg, 1 g, 2 g (as hydrochloride) Trade Name(s): D: Tacef (Takeda; 1983) F: Cemix (Takeda); yrfm J: Bestcall (Takeda; 1983) Cefoperazone ATC: J01DA32 Use: antibiotic RN: 62893-19-0 MF: C2sH27N90xS2 MW: 645.68 EINECS: 263-749-4 CN: [6R-[6a,7~(R*)]]-7-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino](4- hydroxyphenyl)acetyl]amino]-3-[[(I-methyl- 1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia- 1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt RN: 62893-20-3 MF: C2,H2,N,NaOxS2 MW: 667.66 COOH 0 H3C, pH 6.5 COOH Y 7-ominocepholo- 1 -methyl-1 H- 7-amino-3-(1 -methyl- sporanic acid tetrazole-5-thiol tetrozol-5-ylthiomethy1)- 3-cephem-4-corboxylic ocid (I) (cf. cefomondole synthesis) DMF. CH2CIZ. CI-COOC2H5. -1 5 to -1O0C. H,CqSi(CH3)3 N-Si(CH3)> I + b ethyl chloroformote. N.0-bis(tri- OH methylsilyl)ocelomide D(-)-4-hydroxy-N-(2- methoxycorbonyl- 1 - methylethanyl)phanyl- qlycine sodium salt 7-[D(-)-o-omina-(4- hydroxyphenyl)ocetomida]- 3-(I-methyltetrozol-5-yl- Lhiomethy1)-3-cepham- 4-corboxylic ocid (11) 388 C Cefoperazone 2.3-dioxo-4- ethyl-l-pipera- zinecarbonyl chloride (Ill) (cf. piperacillin synthesis) D(-)-4-hydroxy- phenylglycine sodium salt Cefoperazone 0(-)-a-(2.3-dioxo- 4-ethyl-1 -piperazino- carbonylamino)-4- hydroxyphenylacetic acid (IV) 1. CH2CIZ, DMF, N,N-dimethylaniline, -15OC. CI-COOCZH5 N 1. ethyl chloroformate 2. 7-amino-3-[5-(1 -methyltetrazolyl)thiamethyl]-3- cephem-4-carbaxylic acid, N.0-bis(trimethylsilyl)acetamide Reference(s): DE 2 600 880 (Toyama; D-prior. 12.1.1976). US 4 410 522 (Toyama; 18.10.1983; J-prior. 9.5.1974). US 4 110 327 (Toyama; 29.8.1978; ~-~rior. 9.5.1974, 13.5.1974, 31.5.1974, 13.8.1974, 26.9.1974, 13.12.1974, 27.3.1975). DOS 2 519 400 (Toyama; appl. 30.4.1975; J-prior. 9.5.1974, 13.5.1974, 31.5.1974, 13.8.1974,26.9.1974, 13.12.1974, 27.3.1975). GB 1 508 062 (Toyama; appl. 28.4.1975; J-prior. 9.5.1974, 13.5.1974,31.5.1974,24.7.1974,7.8.1974, 13.8.1974, 26.9.1974, 12.10.1974, 28.10.1974, 6.12.1974, 13.12.1974, 17.2.1975, 26.3.1975, 27.3.1975). GB 1 508 071 (Toyama; appl. 19.1 .l976). N,N-dimethylacetamide adducts: DOS 2 841 706 (Toyama; appl. 25.9.1978; J-prior. 27.9.1977). Formulation(s): vial 250 mg, 500 mg, 1 g, 2 g (as sodium salt) Trade Name(s): D: Cefobis (Pfizer; 1981) Cefoneg (Tosi-Novara) F: CCfobis (Pfizer); wfm Cefoper (Menarini) I: Bioperazone (Leben's) Cefosint (Crosara) Cefazone (Locatelli) Dardum (Lisapharma) Cefobid (Pfizer) Farecef (Lafare) Cefogram (Metapharma) Ipazone (IPA) Kefazon (Esseti) Mediper (Medici) Novobiocy 1 (Francia Farm.) Perocef (Pulitzer) Prontokef (Master Pharma) Tomabef (Salus Research) Cefotaxime C 389 Zoncef (AGIPS) J: Cefobid (ToyamdPfizer; Cefoperazin (Toyama) 1981) USA: Cefobid (Pfizer; 1982) Cefotaxime ATC: JOlDAlO Use: antibiotic RN: 63527-52-6 MF: Cl,H17N507S, MW: 455.47 EINECS: 264-299-1 CN: [6R-[6a,7~(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5- thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt RN: 64485-93-4 MF: C,,H,6N5Na07S, MW: 477.45 LD,,: 6845 mglkg (M, i.v.); >20 glkg (M, p.0.); 7 gkg (R, i.v.); >20 glkg (R, p.0.); >1.5 glkg (dog, i.v.) /OH H3Cm0,CH3 NoNOz, N H,C~,CH~ + I 0 0 dimethyl sulfate 0 0 ethyl ocetoocetate ethyl 2-(hydroxy- imino)ocetoacetote ethyl 2-(rnethoxy- irnino)ocetoocetote (I) ethyl 2-(2-amino- trityl 4-thiazolyl)-2-(rneth- chloride oxyimino)acetate (11) ethyl 4-bramo-2- (methoxyimino)- acetoacetate ethyl 2-(methoxy- imino)-2-[2-(trityl- amino)-4-thiozolyl] acetote (Ill) 111 + , m 7-aminocephalosporonic acid 390 C Cefotetan oq. HCOOH, 55°C . N H COOH 0 H N\ CH3 0' Cefotoxime DOS 2 702 501 (Roussel-Uclaf; appl. 21.1.1977; F-prior. 23.1.1976, 11.6.1976, 18.8.1976). US 4 152 432 (Roussel-Uclaf; 1.5.1979; F-prior. 23.1.1976). sodium salt: DAS 2 708 439 (Hoechst; appl. 26.2.1977). Formulation(s): vial 250 mg, 500 mg, 1 g, 2 g (as sodium salt) Trade Natne(s): D: Claforan (Hoechst; 1980) Zariviz (Hoechst Italia Sud) LISA: Claforan (Hoechst Marion F: Claforan (Hoechst) J: Cefotax (Roussel-Chugai; Roussel) GB: Claforan (Roussel; 1981) 1981) I: Claforan (Roussel) Claforan (Hoechst; 1981) Cefotetan ATC: JOlDA14 Use: P-lactam antibiotic (cefalosporin derivative) RN: 69712-56-7 MF: C,,H,,N,ORS4 MW: 575.63 EINECS: 274-093-3 LD,,,: 4990 mgkg (M, i.v.); >10 g/kg (M, p.0.); 5 glkg (R, i.v.); >I0 glkg (R, p.0.); >6 glkg (dog, i.v.) CN: [6R-(6a,7a)]-7-[[[4-(2-amino-l-carboxy-2-oxoethylidene)-l,3-dithietan-2-yl]carbonyl]amino]-7- methoxy-3-[[(1 -methyl- lH-tetrazol-5-yl)thio]rnethyl]-8-oxo-5-thia-l -azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid disodium salt RN: 74356-00-6 MF: C,,H,,N7Na,08S4 MW: 619.59 EINECS: 277-834-9 LD,,,: 4990 mgkg (M, i.v.); >10 g/kg (M, p.0.); 6790 mgkg (R, i.v.); >10 g/kg (R, p.0.); >6 glkg (dog, i.v.) methyl molonomote 4-corboxy-3-hydroxy- 5-mercaptoisothiozole trisodiurn salt (I) . [6R-(6a,7a) ]-7 -[ [[ 4-( 2-amino-l-carboxy-2-oxoethylidene)-l,3-dithietan-2-yl]carbonyl]amino ]-7 - methoxy- 3-[ [(1 -methyl- lH-tetrazol-5-yl)thio]rnethyl ]-8 -oxo-5-thia-l -azabicyclo[4.2.0]oct-2-ene- 2- carboxylic. 51 1.57 CN: , [6R-[6a,7~(Z)l ]-7 -[ [(2-amino-4-thiazolyl)(methoxyiminv)cetyl]amino ]-3 -[ [(l-methyl-1H-tetrazol- 5- yl)thiolmethyl ]-8 -oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt 7-[ D (-) -o-omina-( 4- hydroxyphenyl)ocetomida ]- 3-( I-methyltetrozol-5-yl- Lhiomethy1 )-3 -cepham- 4-corboxylic ocid (11) 388 C Cefoperazone 2.3-dioxo- 4- ethyl-l-pipera- zinecarbonyl