methyl (3R,6S,9R,9aR)-6-[(methoxycarbonyl)amino]-9-methyl-5-oxooctahydro[1,3]thiazolo[3,2-a]azepine-3-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】38530

【品名】methyl (3R,6S,9R,9aR)-6-[(methoxycarbonyl)amino]-9-methyl-5-oxooctahydro[1,3]thiazolo[3,2-a]azepine-3-carboxylate

【CA登记号】

【分子式】C₁₃H₂₀N₂O₅S

【分子量】316.37828

【元素组成】C 49.35% H 6.37% N 8.85% O 25.29% S 10.14%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XXXII)

In a related method, L-pipecolic acid (XXVI) was protected as the methyl carbamate, followed by esterification with isobutylene to give (XXVII). Oxidation of (XXVII) with NaIO4 in the presence of RuO2 generated the 6-oxopipecolic acid derivative (XXVIII), which was subsequently methylated to yield (XXIX) as the major diastereoisomer. Reduction of (XXIX) with DIBAL afforded the cyclic aminal (XXX). Condensation of (XXX) with methyl L-cysteinate (VIII) gave thiazolidine (XXXIa-b). After tert-butyl ester cleavage in (XXXIa-b) with trifluoroacetic acid, cyclization by means of EEDQ produced the bicyclic system (XXXII). Deprotection of the methyl carbamate group of (XXXII) was carried out using methanesulfonic acid in the presence of dimethyl sulfide to afford amine (XXXIII). Coupling of (XXXIII) with (2S,3S)-2-acetylthio-3-methylpentanoic acid (XII) gave the corresponding mixture of amides, from which the desired isomer (XIII) was isolated by column chromatography. Finally, hydrolysis of methyl ester and tioacetate ester groups of (XIII) using LiOH gave rise to the title compound.

参考文献中间体

合成目标

【1】 Oinuma, H.; Kotake, M.; Suda, S.; et al.; Discovery of a novel and orally active dual inhibitor of NEP and ACE: Synthesis and pharmacology. 217th ACS Natl Meet (March 21 1999, Anaheim) 2000, Abst MEDI 111.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXXIa)	38528	methyl (2R,4R)-2-[(1R,4S)-5-(tert-butoxy)-4-[(methoxycarbonyl)amino]-1-methyl-5-oxopentyl]-1,3-thiazolidine-4-carboxylate		C₁₇H₃₀N₂O₆S	详情	详情
(XXXIb)	38529	methyl (2S,4R)-2-[(1R,4S)-5-(tert-butoxy)-4-[(methoxycarbonyl)amino]-1-methyl-5-oxopentyl]-1,3-thiazolidine-4-carboxylate		C₁₇H₃₀N₂O₆S	详情	详情
(VIII)	27413	methyl (2R)-2-amino-3-sulfanylpropanoate		C₄H₉NO₂S	详情	详情
(XII)	35122	(2S,3S)-2-(acetylsulfanyl)-3-methylpentanoic acid		C₈H₁₄O₃S	详情	详情
(XIII)	38523	methyl (3R,6S,9R,9aR)-6-[[(2S,3S)-2-(acetylsulfanyl)-3-methylpentanoyl]amino]-9-methyl-5-oxooctahydro[1,3]thiazolo[3,2-a]azepine-3-carboxylate		C₁₉H₃₀N₂O₅S₂	详情	详情
(XXVI)	17380	(2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid	3105-95-1	C₆H₁₁NO₂	详情	详情
(XXVII)	38524	2-(tert-butyl) 1-methyl (2S)-1,2-piperidinedicarboxylate		C₁₂H₂₁NO₄	详情	详情
(XXVIII)	38525	2-(tert-butyl) 1-methyl (2S)-6-oxo-1,2-piperidinedicarboxylate		C₁₂H₁₉NO₅	详情	详情
(XXIX)	38526	2-(tert-butyl) 1-methyl (2S,5R)-5-methyl-6-oxo-1,2-piperidinedicarboxylate		C₁₃H₂₁NO₅	详情	详情
(XXX)	38527	2-(tert-butyl) 1-methyl (2S,5R)-6-hydroxy-5-methyl-1,2-piperidinedicarboxylate		C₁₃H₂₃NO₅	详情	详情
(XXXII)	38530	methyl (3R,6S,9R,9aR)-6-[(methoxycarbonyl)amino]-9-methyl-5-oxooctahydro[1,3]thiazolo[3,2-a]azepine-3-carboxylate		C₁₃H₂₀N₂O₅S	详情	详情
(XXXIII)	38521	methyl (3R,6S,9R,9aR)-6-amino-9-methyl-5-oxooctahydro[1,3]thiazolo[3,2-a]azepine-3-carboxylate		C₁₁H₁₈N₂O₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XX)

In a related method, L-pipecolic acid (XIV) was protected as the methyl carbamate, followed by esterification with isobutylene to give (XV). Oxidation of (XV) with NaIO4 in the presence of RuO2 generated the 6-oxopipecolic acid derivative (XVI), which was subsequently methylated to yield (XVII) as the major diastereoisomer. Reduction of (XVII) with DIBAL afforded the cyclic aminal (XVIII). Condensation of (XVIII) with methyl L-cysteinate (VIII) gave thiazolidine (XIXa-b). After tert-butyl ester cleavage in (XIXa-b) with trifluoroacetic acid, cyclization by means of EEDQ produced the bicyclic system (XX). Deprotection of the methyl carbamate group of (XX) was carried out using methanesulfonic acid in the presence of dimethyl sulfide to afford amine (XXI). Coupling of (XXI) with (2S,3S)-2-acetylthio-3-methylpentanoic acid (XII) gave the corresponding mixture of amides, from which the desired isomer (XIII) was isolated by column chromatography. Hydrolysis of methyl ester and thioacetate ester groups of (XIII) using LiOH, followed by S-acetylation with Ac2O in the presence of CoCl2 gave rise to the title compound.

参考文献中间体

合成目标

【1】 Oinuma, H.; Kotake, M.; Suda, S.; et al.; Discovery of a novel and orally active dual inhibitor of NEP and ACE: Synthesis and pharmacology. 217th ACS Natl Meet (March 21 1999, Anaheim) 2000, Abst MEDI 111.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIXa)	38528	methyl (2R,4R)-2-[(1R,4S)-5-(tert-butoxy)-4-[(methoxycarbonyl)amino]-1-methyl-5-oxopentyl]-1,3-thiazolidine-4-carboxylate		C₁₇H₃₀N₂O₆S	详情	详情
(XIXb)	38529	methyl (2S,4R)-2-[(1R,4S)-5-(tert-butoxy)-4-[(methoxycarbonyl)amino]-1-methyl-5-oxopentyl]-1,3-thiazolidine-4-carboxylate		C₁₇H₃₀N₂O₆S	详情	详情
(VIII)	27413	methyl (2R)-2-amino-3-sulfanylpropanoate		C₄H₉NO₂S	详情	详情
(XII)	35122	(2S,3S)-2-(acetylsulfanyl)-3-methylpentanoic acid		C₈H₁₄O₃S	详情	详情
(XIII)	38523	methyl (3R,6S,9R,9aR)-6-[[(2S,3S)-2-(acetylsulfanyl)-3-methylpentanoyl]amino]-9-methyl-5-oxooctahydro[1,3]thiazolo[3,2-a]azepine-3-carboxylate		C₁₉H₃₀N₂O₅S₂	详情	详情
(XIV)	17380	(2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid	3105-95-1	C₆H₁₁NO₂	详情	详情
(XV)	38524	2-(tert-butyl) 1-methyl (2S)-1,2-piperidinedicarboxylate		C₁₂H₂₁NO₄	详情	详情
(XVI)	38525	2-(tert-butyl) 1-methyl (2S)-6-oxo-1,2-piperidinedicarboxylate		C₁₂H₁₉NO₅	详情	详情
(XVII)	38526	2-(tert-butyl) 1-methyl (2S,5R)-5-methyl-6-oxo-1,2-piperidinedicarboxylate		C₁₃H₂₁NO₅	详情	详情
(XVIII)	38527	2-(tert-butyl) 1-methyl (2S,5R)-6-hydroxy-5-methyl-1,2-piperidinedicarboxylate		C₁₃H₂₃NO₅	详情	详情
(XX)	38530	methyl (3R,6S,9R,9aR)-6-[(methoxycarbonyl)amino]-9-methyl-5-oxooctahydro[1,3]thiazolo[3,2-a]azepine-3-carboxylate		C₁₃H₂₀N₂O₅S	详情	详情
(XXI)	38521	methyl (3R,6S,9R,9aR)-6-amino-9-methyl-5-oxooctahydro[1,3]thiazolo[3,2-a]azepine-3-carboxylate		C₁₁H₁₈N₂O₃S	详情	详情

Extended Information