-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】1-[[3(R)-Amino-2(S)-sulfanyl-3-(2-sulfoethyl)propionyl]-L-isoleucyl]pyrrolidine-2(S),3(R)-dicarboxylic acid inner salt

【CA登记号】

【分子式】C₁₇H₂₉N₃O₉S₂

【分子量】483.56338

【开发单位】INSERM (Originator)

【药理作用】PHARMACOLOGICAL TOOLS

合成路线1 合成路线2

合成路线1

Esterification of N-(benzyloxycarbonyl)-L-aspartic acid beta-tert-butyl ester (I) by means of diazomethane provided the alpha-methyl ester (II), which was subsequently sulfenylated using (2,4-dinitrophenyl)-(4-methoxybenzyl)disulfide (III) in the presence of n-BuLi to furnish the (2R,3R)-sulfide (IV) as the major isomer. Reduction of the methyl ester group of (IV) with DIBAL, followed by Wittig-Horner reaction of a postulated aldehyde aluminoxyacetal intermediate with neopentyl diethoxyphosphoryl methanesulfonate produced the alpha,beta-unsaturated sulfonate ester (V). Reduction of the double bond of (V) employing [(PPh3)CuH]6 in neutral medium afforded the saturated ester (VI) with only a small epimerization at the C2 position. The tert-butyl ester of (VI) was then deprotected with trifluoroacetic acid yielding the free acid (VII).

参考文献中间体

【1】 Davis, C.; Bischoff, L.; Meudal, H.; et al.; Investigation of subsite preferences in aminopeptidase A (EC 3.4.11.7) led to the design of the first highly potent and selective inhibitors of this enzyme. J Med Chem 1999, 42, 25, 5197.
【2】 Fournie-Zaluski, M.-C.; Roques, B.; David, C.; Bischoff, L.; Llorens-Cortes, C. (CNRS (Centre National de la Recherche Scientifique); INSERM (Institut National de la Sante et de la Recherche Medicale)); Tripeptide cpds. useful as selective inhibitors of aminopeptidase A and corresponding pharmaceutical compsns.. FR 2788526; WO 0043414 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
	40723	neopentyl (diethoxyphosphoryl)methanesulfonate	C₁₀H₂₃O₆PS	详情	详情
(I)	36564	(2S)-2-[[(benzyloxy)carbonyl]amino]-4-(tert-butoxy)-4-oxobutyric acid	C₁₆H₂₁NO₆	详情	详情
(II)	36565	4-(tert-butyl) 1-methyl (2S)-2-[[(benzyloxy)carbonyl]amino]butanedioate	C₁₇H₂₃NO₆	详情	详情
(III)	36566	1-[(4-methoxybenzyl)disulfanyl]-2,4-dinitrobenzene; 2,4-dinitrophenyl 4-methoxybenzyl disulfide	C₁₄H₁₂N₂O₅S₂	详情	详情
(IV)	36567	4-(tert-butyl) 1-methyl (2R,3S)-2-[[(benzyloxy)carbonyl]amino]-3-[(4-methoxybenzyl)sulfanyl]butanedioate	C₂₅H₃₁NO₇S	详情	详情
(V)	36568	tert-butyl (2S,3R,4E)-3-[[(benzyloxy)carbonyl]amino]-2-[(4-methoxybenzyl)sulfanyl]-5-[(neopentyloxy)sulfonyl]-4-pentenoate	C₃₀H₄₁NO₈S₂	详情	详情
(VI)	36569	tert-butyl (2S,3R)-3-[[(benzyloxy)carbonyl]amino]-2-[(4-methoxybenzyl)sulfanyl]-5-[(neopentyloxy)sulfonyl]pentanoate	C₃₀H₄₃NO₈S₂	详情	详情
(VII)	36570	(2S,3R)-3-[[(benzyloxy)carbonyl]amino]-2-[(4-methoxybenzyl)sulfanyl]-5-[(neopentyloxy)sulfonyl]pentanoic acid	C₂₆H₃₅NO₈S₂	详情	详情

合成路线2

The resulting free acid (VII) was coupled with the protected dipeptide (VIII) to give tripeptide (IX). Finally, acidic removal of all protecting groups of (IX) provided the title compound.

参考文献中间体

【1】 Davis, C.; Bischoff, L.; Meudal, H.; et al.; Investigation of subsite preferences in aminopeptidase A (EC 3.4.11.7) led to the design of the first highly potent and selective inhibitors of this enzyme. J Med Chem 1999, 42, 25, 5197.
【2】 Fournie-Zaluski, M.-C.; Roques, B.; David, C.; Bischoff, L.; Llorens-Cortes, C. (CNRS (Centre National de la Recherche Scientifique); INSERM (Institut National de la Sante et de la Recherche Medicale)); Tripeptide cpds. useful as selective inhibitors of aminopeptidase A and corresponding pharmaceutical compsns.. FR 2788526; WO 0043414 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VII)	36570	(2S,3R)-3-[[(benzyloxy)carbonyl]amino]-2-[(4-methoxybenzyl)sulfanyl]-5-[(neopentyloxy)sulfonyl]pentanoic acid	C₂₆H₃₅NO₈S₂	详情	详情
(VIII)	36571	dibenzyl (2S,3R)-1-[(2S,3S)-2-amino-3-methylpentanoyl]-2,3-pyrrolidinedicarboxylate	C₂₆H₃₂N₂O₅	详情	详情
(IX)	36572	dibenzyl (2S,3R)-1-[(2S,3S)-2-([(2S,3R)-3-[[(benzyloxy)carbonyl]amino]-2-[(4-methoxybenzyl)sulfanyl]-5-[(neopentyloxy)sulfonyl]pentanoyl]amino)-3-methylpentanoyl]-2,3-pyrrolidinedicarboxylate	C₅₂H₆₅N₃O₁₂S₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)