合成路线1

The cyclization of 2,2'-di(benzyloxycarbonylamino)pimelic acid (I) with PCl5 in methylene chloride gives the bis-N-carboxy anhydride (II), which by reaction with tert-butyl carbazate (A) is converted into the bis(tert-butyloxycarbonylhydrazide) compound (III). The enzymatic hydrolysis of (III) with an aminopeptidase from Streptomyces sapporonensis affords the mono-tert-butoxycarbonylhydrazide (IV), which by selective protection of the amino group with benzyloxycarbonyl chloride (B) under copper chelate conditions yields the selectively protected hydrazide (V). Full protection of (V) with tert-butoxycarbonyl anhydride (C) affords the fully protected monohydrazide (VI), which is condensed with benzyl glycinate (VII) to give the protected dipeptide (VIII). Hydrogenolysis of (VIII) with H2 over Pd/C in methanol-acetic acid yields the di-tert-butoxycarbonyldipeptide (IX), which is condensed with 2-acetoxypropanoylalanylglutamic acid monobenzyl ester (X) by means of isobutoxycarbonyl chloride (D) yielding the protected FK-156 (XI).

合成路线2

A new method for the synthesis of the docetaxel side-chain has been reported: The esterification of (S)-phenylglycine (I) with SOCl2 and methanol gives the corresponding methyl ester (II), which is acylated with tert-butoxycarbonyl anhydride to the tert-butoxycarbonyl derivative (III). The reduction of (III) with dibutylaluminum hydride (DIBAL) in toluene yields the corresponding aldehyde (IV), which is condensed with 2-(trimethylsilyl)thiazole (V) by means of tetrabutylammonium fluoride (TBAF) to afford the (1R,2S)-N-[2-hydroxy-1-phenyl-2-(2-thiazolyl)ethyl]carbamic acid tert-butyl ester (VI) with 88% enantiomeric purity. The cyclization of (VI) with 2,2-dimethoxypropane (VII) catalyzed by camphosulfonic acid (CSA) gives (4S,5R)-3-(tert-butoxycarbonyl)-2,3-dimethyl-4-phenyl-5-(2-thiazolyl)ox azolidine (VIII), which is treated with methyl trifluoromethanesulfonate to afford (4S,5R)-3-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyloxazolidine-5-carb aldehyde (IX). Finally, this compound is oxidized with KMnO4 in tert-butanol/aqueous potassium phosphate buffer to yield the corresponding carboxylic acid, the (4S,5R)-3-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyloxazolidine-5-carb oxylic acid (X), the side-chain of taxotere suitably protected.

合成路线3

2) The acylation of hydrazine (I) with di-tert-butyl dicarbonate (II) gives 1,2-di(tert-butyloxycarbonyl)hydrazine (III), which is cyclized with 1,3-dibromo-2-(tert-butyldimethylsilyloxy)propane (IV) by means of NaH in DMF yielding the pyrazolidine (V). The desilylation of (V) with tetrabutylammonium fluoride in THF affords 1,2-di(tert-butoxycarbonyl)-4-hydroxypyrazolidine (VI). Acylation of (VI) with methanesulfonyl chloride in dichloromethane gives the corresponding mesylate (VII), which is condensed with 4-methoxybenzyl mercaptane (VIII) by means of butyllithium in hexane to yield the benzyl ether (IX). The cyclization of (IX) with methyl formimidate hydrochloride in methanol-water affords 6-(4-methoxybenzylthio)-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium chloride (X), which is deprotected with trifluoroacetic acid giving 6-mercapto-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium chloride (XI). Finally, this compound is condensed with (1R,5R,6S)-2-(diphenylphosphonooxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester (XII) by means of diisopropylethylamine in DMF followed by hydrogenolysis with H2 over Pd/C in butanol-EtOAc-potassium phosphate buffer.

合成路线4

2) Racemic MDL-100907 (VII) can also be obtained by reaction of piperidine-4-carboxylic acid (X) with di-tert-butyl dicarbonate (XI) by means of NaOH in tert-butanol/ water, giving piperidine-1,4-dicarboxylic acid 1-mono-tert-butyl ester (XII), which is treated with N,O-dimethylhydroxylamine (XIII) and carbonyldiimidazole (CDI) in dichloromethane to afford the methoxy(methyl)amide (XIV). The condensation of (XIV) with veratrole (VI) by means of BuLi in THF gives 4-(2,3-dimethoxybenzoyl)-piperidine-1-carboxylic acid tert-butyl ester (XV), which is decarboxylated by means of trifluoroacetic acid, yielding ketone (XVI). The condensation of (XVI) with 2-(4-fluorophenyl)ethyl bromide (II) by means of K2CO3 in DMF affords 1-(2,3-dimethoxyphenyl)-1-[1-[2-(4-fluorophenyl)-ethyl]piperidin-4-yl]methanone (XVII). Finally, this compound is reduced with NaBH4 in methanol

合成路线5

The reaction of m-xylenediamine (I) with triethylamine and di-tert-butyldicarbonate (II) gives the corresponding tert-butyl N-[3-(aminomethyl)benzyl] carbamate hydrochloride (III), which is converted into the tert-butyl N-[3-((acetimidoyl)aminomethyl]benzyl) carbamate hydrochloride (VII) by reaction with S-benzylthioacetimidate hydrochloride (VI). This intermediate (VI) could be obtained by reaction of thioacetamide (IV) with benzyl chloride (V). Finally, compound (VII) is deprotected with HCl to afford the corresponding N-[3-(aminomethyl)benzyl] acetamidine hydrochloride.

合成路线6

1) The reaction of 1-(4-nitrophenyl)piperazine (I) with tert-butyl dicarbonate (II) and triethylamine in dichloromethane gives 4-(4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (III), which is reduced with H2 over Pd/C, yielding the corresponding 4-amino compound (IV). The reaction of (IV) with phenyl chloroformate (V) and triethylamine in dichloromethane affords the carbamate (VI), which by reaction with hydrazine is converted into the semicarbazide (VII). The cyclization of (VII) with formamidine (VIII) and triethylamine in hot 2-methoxyethanol affords the triazolone (IX), which is condensed with 4-(trifluoromethoxy)benzyl bromide (X) by means of Cs2CO3 in DMF, giving the disubstituted triazolone (XI). The deprotection, elimination of the tert-butoxycarbonyl group, of (XI) with HCl yields the monosubstituted piperazine (XII), which is finally condensed with (2R,3S)-oxirane (XIII) by means of LiClO4 in refluxing acetonitrile.

合成路线7