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【结 构 式】

【分子编号】38525

【品名】2-(tert-butyl) 1-methyl (2S)-6-oxo-1,2-piperidinedicarboxylate

【CA登记号】

【 分 子 式 】C12H19NO5

【 分 子 量 】257.2866

【元素组成】C 56.02% H 7.44% N 5.44% O 31.09%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XXVIII)

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.

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:(XVI)

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.

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