Ceftobiprole medocaril, BAL-5788, Ro-65-5788/001, Ro-65-5788, Zeftera, -Drug Synthesis Database

【结构式】

【药物名称】Ceftobiprole medocaril, BAL-5788, Ro-65-5788/001, Ro-65-5788, Zeftera

【化学名称】(6R,7R)-7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2(Z)-(hydroxyimino)acetamido]-3-[(E)-1-[1-(5-methyl-2-oxo-1,3-dioxol-4-ylmethoxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-3-cephem-4-carboxylic acid

【CA登记号】376653-43-9

【分子式】C₂₆H₂₆N₈O₁₁S₂

【分子量】690.67212

【开发单位】Basilea Pharmaceutica (Proprietary), Roche (Originator)

【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, Cephalosporins

合成路线1 合成路线2 合成路线3

合成路线1

The cyclization of 3(R)-aminopyrrolidine-1-carboxylic acid allyl ester (I) with 2-bromo-4-chlorobutyryl chloride (II) by means of aqueous NaOH in dichloromethane gives the bipyrrolidine (III), which is treated with triphenylphosphine in dichloromethane yielding the phosphonium salt (IV). The condensation of (IV) with (R,R,R)-7-(tert-butoxycarbonylamino)-3-formyl-2-cephem-4-carboxylic acid diphenylmethyl ester (V) in refluxing THF affords the expected condensation product (VI), which is oxidized at the sulfur atom with triphenylphosphine oxide and meta-chloroperbenzoic acid (MCPBA) in dichloromethane to provide the sulfoxide (VII). Rearrangement of (VII) with simultaneous deoxygenation of the sulfur atom by means of PBr3 in dichloromethane/DMF provides the 3-cephem isomer (VIII).

参考文献中间体

【1】 Hebeisen, P.; Weiss, U.; Angehrn, P.; Runtz, V.; Kansy, M.; Heinze-Krauss, I.; Page, M.; Synthesis and SAR of pyrrolidinone-3-ylidenmethyl cephems against methicillin-resistant Staphylococcus aureus. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-21.
【2】 Page, M.; Hebeisen, P.; Angehrn, P.; Heinze-Krauss, I.; Runtz, V. (F. Hoffmann-La Roche AG); Vinyl pyrrolidine cephalosporins with basic substitutents . EP 0849269; US 5981519 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	25489	allyl (3R)-3-amino-1-pyrrolidinecarboxylate	C₈H₁₄N₂O₂	详情	详情
(II)	25490	2-bromo-4-chlorobutanoyl chloride	C₄H₅BrCl₂O	详情	详情
(III)	25491	3(R)-(3-Bromo-2-oxopyrrolidin-1-yl)pyrrolidine-1-carboxylic acid allyl ester	C₁₂H₁₇BrN₂O₃	详情	详情
(IV)	25492	1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-yl]triphenylphosphonium bromide	C₃₀H₃₃N₂O₃P	详情	详情
(V)	25493	benzhydryl (2R,6R,7R)-7-[(tert-butoxycarbonyl)amino]-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate	C₂₆H₂₆N₂O₆S	详情	详情
(VI)	25494	(6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-(tert-butoxycarbonylmino)-2-cephem-4(R)-carboxylic acid dibenzyl ester	C₃₈H₄₂N₄O₈S	详情	详情
(VII)	25495	(6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-(tert-butoxycarbonylmino)-2-cephem-4(R)-carboxylic acid dibenzyl ester S-oxide	C₃₈H₄₂N₄O₉S	详情	详情
(VIII)	25496	(6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-(tert-butoxycarbonylmino)-3-cephem-4-carboxylic acid dibenzyl ester	C₃₈H₄₂N₄O₈S	详情	详情

合成路线2

Intermediate (VIII) is treated with TFA and anisole in dichloromethane to deprotect the 7-amino group giving (IX). The condensation of (IX) with 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-(trityloxyimino)thioacetic acid S-(benzothiazol-2-yl)ester (XII) in DMF gives the expected 4-acetamido derivative (XIII), which is deprotected first with bis(trimethylsilyl)acetamide (BSA) and bis(triphenylphosphine)palladium dichloride in dichloromethane to eliminate the allyloxycarbonyl group, and then with TFA and triethylsilane to eliminate the trityl group affording Ro-63-9141 (XIV).

参考文献中间体

【1】 Hebeisen, P.; Weiss, U.; Angehrn, P.; Runtz, V.; Kansy, M.; Heinze-Krauss, I.; Page, M.; Synthesis and SAR of pyrrolidinone-3-ylidenmethyl cephems against methicillin-resistant Staphylococcus aureus. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-21.
【2】 Page, M.; Hebeisen, P.; Angehrn, P.; Heinze-Krauss, I.; Runtz, V. (F. Hoffmann-La Roche AG); Vinyl pyrrolidine cephalosporins with basic substitutents . EP 0849269; US 5981519 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VIII)	25496	(6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-(tert-butoxycarbonylmino)-3-cephem-4-carboxylic acid dibenzyl ester	C₃₈H₄₂N₄O₈S	详情	详情
(IX)	25497	(6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-amino-3-cephem-4-carboxylic acid	C₂₀H₂₄N₄O₆S	详情	详情
(X)	25498	S-(1,3-benzothiazol-2-yl) 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(trityloxy)imino]ethanethioate	C₃₀H₂₁N₅O₂S₃	详情	详情
(XI)	25499	1-allyl-1-methylpyrrolidinium 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(trityloxy)imino]acetate	C₃₁H₃₃N₅O₃S	详情	详情
(XII)	25500	1,3-benzothiazol-2-ylsulfide	C₇H₄NS₂	详情	详情
(XIII)	25501	(6R,7R)-3-[1-[1-(Allyloxycarbonyl)pyrrolidin-3(R)-yl]-2-oxopyrrolidin-3-ylidenemethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-(triphenylmethoxyimino)acetamido]-3-cephem-4-carboxylic acid	C₄₃H₄₀N₈O₈S₂	详情	详情
(XIV)	25502	(6R,7R)-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-(hydroxyimino)acetamido]-3-[2-oxo-1-(3(R)-pyrrolidinyl)pyrrolidin-3-ylidenemethyl]-3-cephem-4-carboxylic acid	C₂₀H₂₂N₈O₆S₂	详情	详情

合成路线3

Finally, compound (XIV) is condensed with the mixed carbonate (XV) by literature prodedures.

参考文献中间体

【1】 Hebeisen, P.; et al.; Synthesis, physicochemical and pharmacokinetic properties of water soluble prodrugs of Ro 63-9141/000. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-26.
【2】 Hubschwerlen, C.; Hebeisen, P.; Specklin, J.-L. (F. Hoffmann-La Roche AG); Derivs. of 3-(2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl)-cephems. WO 9965920 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIV)	25502	(6R,7R)-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-(hydroxyimino)acetamido]-3-[2-oxo-1-(3(R)-pyrrolidinyl)pyrrolidin-3-ylidenemethyl]-3-cephem-4-carboxylic acid		C₂₀H₂₂N₈O₆S₂	详情	详情
(XV)	25503	(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-nitrophenyl carbonate		C₁₂H₉NO₈	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)