(1S,3aR,6aS)-Octahydrocyclopenta[c]pyrrole-1-carboxylic acid tert-butyl ester -Drug Synthesis Database

【结构式】

【分子编号】65428

【品名】(1S,3aR,6aS)-Octahydrocyclopenta[c]pyrrole-1-carboxylic acid tert-butyl ester

【CA登记号】714194-68-0

【分子式】C₁₂H₂₁NO₂

【分子量】211.30428

【元素组成】C 68.21% H 10.02% N 6.63% O 15.14%

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：(XIV)

An alternative route to the precursor N-acyl tripeptide (VIII) consists of coupling of N-Cbz-L-tert-leucine (XIII) with the bicyclic amino ester (XIV) to afford the protected dipeptide (XV), from which the N-Cbz group is removed by catalytic hydrogenolysis over Pearlman’s catalyst, yielding (XVI). The dipeptide ester (XVI) is then coupled with N-Cbz-L-cyclohexylglycine (XVII) to give (XVIII), which is further deprotected by catalytic hydrogenolysis to afford the tripeptide ester (XIX). After acylation of (XIX) with pyrazinecarboxylic acid (III) employing CDI, the resulting N-acyl tripeptide tert-butyl ester (XX) is treated with HCl in formic acid to provide the target intermediate (VIII) (3). Scheme 2.

参考文献中间体

合成目标

【3】 Tanoury, G.J., Chen, M., Cochran, J.E. (Vertex Pharmaceuticals, Inc.). Processes and intermediates. WO 2007022459.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	37256	2-pyrazinecarboxylic acid; Pyrazinoic acid	98-97-5	C₅H₄N₂O₂	详情	详情
(VIII)	65423	(1S,3aR,6aS)-(2S)-2-Cyclohexyl-N-(pyrazinylcarbonyl)glycyl-3-methyl-L-valyloctahydrocyclopenta[c]pyrrole-1-carboxylic acid	402958-98-9	C₂₇H₃₉N₅O₅	详情	详情
(XIII)	65427	Cbz-L-tert-Leucine; (S)-N-Cbz-2-amino-3,3-dimethyl-butyric acid	62965-10-0	C₁₄H₁₉NO₄	详情	详情
(XIV)	65428	(1S,3aR,6aS)-Octahydrocyclopenta[c]pyrrole-1-carboxylic acid tert-butyl ester	714194-68-0	C₁₂H₂₁NO₂	详情	详情
(XV)	65429	(1S,3aR,6aS)-2-[(2S)-3,3-Dimethyl-1-oxo-2-[[(phenylmethoxy)carbonyl]amino]butyl]octahydrocyclopenta[c]pyrrole-1-carboxylic acid tert-butyl ester	926276-15-5	C₂₆H₃₈N₂O₅	详情	详情
(XVI)	65430	(1S,3aR,6aS)-2-[(2S)-2-Amino-3,3-dimethyl-1-oxobutyl]octahydrocyclopenta[c]pyrrole-1-carboxylic acid tert-butyl ester	926276-16-6	C₁₈H₃₂N₂O₃	详情	详情
(XVII)	65431	Cbz-Cyclohexyl-L-glycine; (S)-Cbz-Cyclohexylglycine; (S)-N-Cbz-Aminocyclohexylacetic acid	69901-75-3	C₁₆H₂₁NO₄	详情	详情
(XVIII)	65432	(1S,3aR,6aS)-2-[(2S)-2-[[(2S)-2-Cyclohexyl-2-[[(phenylmethoxy)carbonyl]amino]acetyl]amino]-3,3-dimethyl-1-oxobutyl]octahydrocyclopenta[c]pyrrole-1-carboxylic acid tert-butyl ester	926276-17-7	C₃₄H₅₁N₃O₆	详情	详情
(XIX)	65433	(1S,3aR,6aS)-2-[(2S)-2-[[(2S)-2-Amino-2-cyclohexylacetyl]amino]-3,3-dimethyl-1-oxobutyl]octahydrocyclopenta[c]pyrrole-1-carboxylic acid tert-butyl ester	926276-18-8	C₂₆H₄₅N₃O₄	详情	详情
(XX)	65434	(1S,3aR,6aS)-2-[(2S)-2-[[(2S)-2-Cyclohexyl-2-[(2-pyrazinylcarbonyl)amino]acetyl]amino]-3,3-dimethyl-1-oxobutyl]octahydrocyclopenta[c]pyrrole-1-carboxylic acid tert-butyl ester	926276-19-9	C₃₁H₄₇N₅O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIV)

The bicyclic amino acid building blocks (VI) and (XIV) can be obtained as follows. Reduction of N-Cbz-4-oxoperhydrocyclopenta[c]pyrrole-1-carboxylate (XXI) with NaBH4 in EtOH affords the hydroxy derivative (XXII), which is converted to xanthate (XXIII) by treatment with carbon disulfide, iodomethane and NaH in THF. Desulfurization of (XXIII) by means of tributyltin hydride and AIBN in hot toluene affords the N-protected bicyclic amino ester (XXIV), which is finally submitted to hydrogenolysis over Pearlman’s catalyst to furnish the intermediate (VI) (1). Alternatively, protection of 3-azabicyclo[3.3.0]nonane (XXV) as the N-Boc derivative (XXVI) followed by carboxylation with sec-butyllithium and CO2 gas in the presence of 3,7-dipropyl-3,7-diazabicyclo[3.3.1]nonane leads to the N-protected amino acid (XXVII). After resolution of (XXVII) with either 1,2,3,4-tetrahydro-1(S)-naphthylamine or with (R)-α-methylbenzylamine, the desired 1(S)-amino acid is esterified to (XXVIII) utilizing Boc2O and DMAP in t-BuOH/MTBE. Then, selective Boc group cleavage by means of methanesulfonic acid in THF provides the target intermediate (XIV) (3). Scheme 3.

参考文献中间体

合成目标

【1】 Babine, R.E., Glass, J.I., Lamar, J.E. et al. (Eli Lilly and Company). Peptidomimetic protease inhibitors. JP 2004517047, US 2005197299, WO 2002018369.
【3】 Tanoury, G.J., Chen, M., Cochran, J.E. (Vertex Pharmaceuticals, Inc.). Processes and intermediates. WO 2007022459.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	65421	(1S,3aR,6aS)-Octahydrocyclopenta[c]pyrrole-1-carboxylic acid ethyl ester; ethyl cis-perhydrocyclopenta[c]pyrrole-1-carboxylate	402958-25-2	C₁₀H₁₇NO₂	详情	详情
(XIV)	65428	(1S,3aR,6aS)-Octahydrocyclopenta[c]pyrrole-1-carboxylic acid tert-butyl ester	714194-68-0	C₁₂H₂₁NO₂	详情	详情
(XXI)	65435	2-Benzyl 1-ethyl (1S,3aR,6aS)-4-oxohexahydrocyclopenta[c]pyrrole-1,2(1H)-dicarboxylate	402958-21-8	C₁₈H₂₁NO₅	详情	详情
(XXII)	65436	2-Benzyl 1-ethyl (1S,3aR,6aS)-4-hydroxyhexahydrocyclopenta[c]pyrrole-1,2(1H)-dicarboxylate		C₁₈H₂₃NO₅	详情	详情
(XXIII)	65437			C₂₀H₂₅NO₅S₂	详情	详情
(XXIV)	65438			C₁₈H₂₃NO₄	详情	详情
(XXV)	65439	cis-7-Azabicyclo[3.3.0]octane; (3aR,6aS)-rel-Octahydrocyclopenta[c]pyrrole	1468-87-7	C₇H₁₃N	详情	详情
(XXVI)	65440	(3aR,6aS)-rel-Hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester	926276-08-6	C₁₂H₂₁NO₂	详情	详情
(XXVII)	65441	(1S,3aR,6aS)-Hexahydrocyclopenta[c]pyrrole-1,2(1H)-dicarboxylic acid 2-(tert-butyl) ester	597569-42-1	C₁₃H₂₁NO₄	详情	详情
(XXVIII)	65442	(1S,3aR,6aS)-Hexahydrocyclopenta[c]pyrrole-1,2(1H)-dicarboxylic acid 1,2-di(tert-butyl) ester		C₁₇H₂₉NO₄	详情	详情

Extended Information