BAL-5788, Ro-65-5788/001, Ro-65-5788

Chemical Name: (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
项目整合开发状态: Phase II
项目研究机构: Basilea Pharmaceutica (Proprietary), Roche (Originator)
合成路线: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).

合成路线: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 finally 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.

合成路线: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).

合成路线: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).