(1S,3aR,6aS)-Octahydrocyclopenta[c]pyrrole-1-carboxylic acid ethyl ester; ethyl cis-perhydrocyclopenta[c]pyrrole-1-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】65421

【品名】(1S,3aR,6aS)-Octahydrocyclopenta[c]pyrrole-1-carboxylic acid ethyl ester; ethyl cis-perhydrocyclopenta[c]pyrrole-1-carboxylate

【CA登记号】402958-25-2

【分子式】C₁₀H₁₇NO₂

【分子量】183.25052

【元素组成】C 65.54% H 9.35% N 7.64% O 17.46%

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：(VI)

Hydrogenolysis of the benzyloxycarbonyl protecting group in N-Cbz-L-cyclohexylglycyl-L-tert-leucine methyl ester (I) in the presence of Pearlman’s catalyst in MeOH gives the free dipeptide ester (II), which is acylated with pyrazinecarboxylic acid (III) by means of DCC in dichloromethane/THF to yield the N-acyl dipeptide (IV) (1). Alkaline hydrolysis of the methyl ester (IV) followed by coupling of the resulting carboxylic acid (V) with ethyl cis-perhydrocyclopenta[c]pyrrole-1-carboxylate (VI) by means of DCC provides the acyl tripeptide ester (VII), which is then hydrolyzed to the corresponding carboxylic acid (VIII) upon treatment with NaOH in EtOH (1, 2). Coupling of L-norvaline (IX) with cyclopropylamine (X) in the presence of EDC and N-hydroxysuccinimide followed by catalytic hydrogenolysis of the N-Cbz group provides N-cyclopropyl-norvalinamide (XI) (3). Subsequent condensation of aminoamide (XI) with the N-acyl tripeptide (VIII) using either PyBOP or EDC/HOBt gives the tetrapeptide derivative (XII). Finally, oxidation of the secondary alcohol (XII) by means of Dess-Martin periodinane or NaOCl and a catalytic amount of TEMPO furnishes the title α-ketoamide (1-3). Scheme 1.

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.
【2】 Chen, S.-H., Lamar, J., Yip, Y. et al. P1 and P1’ optimization of [3,4]-bicycloproline P2 incorporated tetrapeptidyl α-ketoamide based HCV protease inhibitors. Lett Drug Des Discov 2005, 2(2): 118-23.
【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
(I)	65417	N-Cbz-L-cyclohexylglycyl-L-tert-leucine methyl ester		C₂₃H₃₄N₂O₅	详情	详情
(II)	65418	L-cyclohexylglycyl-L-tert-leucine methyl ester		C₁₅H₂₈N₂O₃	详情	详情
(III)	37256	2-pyrazinecarboxylic acid; Pyrazinoic acid	98-97-5	C₅H₄N₂O₂	详情	详情
(IV)	65419	(2S)-2-Cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valine methyl ester	402958-95-6	C₂₀H₃₀N₄O₄	详情	详情
(V)	65420	(2S)-2-Cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valine	402958-96-7	C₁₉H₂₈N₄O₄	详情	详情
(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
(VII)	65422	(1S,3aR,6aS)-(2S)-2-Cyclohexyl-N-(pyrazinylcarbonyl)glycyl-3-methyl-L-valyloctahydrocyclopenta[c]pyrrole-1-carboxylic acid ethyl ester	402958-97-8	C₂₉H₄₃N₅O₅	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
(IX)	65424			C₁₄H₁₉NO₅	详情	详情
(X)	12263	Cyclopropylamine; Cyclopropanamine	765-30-0	C₃H₇N	详情	详情
(XI)	65425	(3S)-3-Amino-N-cyclopropyl-2-hydroxyhexanamide	402960-19-4	C₉H₁₈N₂O₂	详情	详情
(XII)	65426	(1S,3aR,6aS)-(2S)-2-Cyclohexyl-N-(2-pyrazinylcarbonyl)glycyl-3-methyl-L-valyl-N-[(1S)-1-[2-(cyclopropylamino)-1-hydroxy-2-oxoethyl]butyl]octahydrocyclopenta[c]pyrrole-1-carboxamide	402959-36-8	C₃₆H₅₅N₇O₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

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