(1R,2S,3S)-3-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-2-(4-fluorophenyl)cyclopentyl isocyanate; 1-((1R)-1-[[(1S,2S,3R)-2-(4-fluorophenyl)-3-isocyanatocyclopentyl]oxy]ethyl)-3,5-bis(trifluoromethyl)benzene -Drug Synthesis Database

【结构式】

【分子编号】40786

【品名】(1R,2S,3S)-3-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-2-(4-fluorophenyl)cyclopentyl isocyanate; 1-((1R)-1-[[(1S,2S,3R)-2-(4-fluorophenyl)-3-isocyanatocyclopentyl]oxy]ethyl)-3,5-bis(trifluoromethyl)benzene

【CA登记号】

【分子式】C₂₂H₁₈F₇NO₂

【分子量】461.3792824

【元素组成】C 57.27% H 3.93% F 28.82% N 3.04% O 6.94%

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：(XVIII)

Reduction of 3',5'-bis(trifluoromethyl)acetophenone (XI) with NaBH4 gave alcohol (XII). This was either converted to imidate (XIII) by addition of trichloroacetonitrile, or to bromide (XIV) upon treatment with triphenylphosphine dibromide. Condensation of the chiral hydroxy ester (-)-(X) with imidate (XIII) in the presence of triflic acid provided ether (XVa-b) as a diastereomeric mixture. Alternatively, (XV) was obtained by alkylation of alcohol (-)-(X) with bromide (XIV). Cromatographic separation of the diastereomeric mixture (XVa-b), followed by basic hydrolysis of the desired isomer yielded carboxylic acid (XVI). Activation of the carboxyl group of (XVI) as the corresponding acid chloride by means of oxalyl chloride, and subsequent treatment with NaN3 generated the acyl azide (XVII). Curtius rearrangement ot the acyl azide (XVII) in hot toluene provided isocyanate.

参考文献中间体

合成目标

【1】 MacCoss, M.; Meurer, L.C.; Finke, P.E.; et al.; Discovery of potent human NK1 antagonists having a cyclopentane-based core structure. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 98.
【2】 Caldwell, C.G.; Chen, P.; Durette, P.L.; Finke, P.; Hale, J.; Holson, E.; Kopka, I.; Maccoss, M.; Meurer, L.; Mills, S.G.; Robichaud, A. (Merck & Co., Inc.); Cycloalkyl tachykinin receptor antagonists. US 5750549 .
【3】 Finke, P.E.; Maccoss, M.; Meurer, L.C.; Mills, S.G.; Caldwell, C.G.; Chen, P.; Durette, P.L.; Hale, J.; Holson, E.; Kopka, I.; Robichaud, A. (Merck & Co., Inc.); Cyclopentyl tachykinin receptor antagonists. EP 0858444; WO 9714671 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(-)-(X)	40777	(-)-methyl (1R,2R,3S)-2-(4-fluorophenyl)-3-hydroxycyclopentanecarboxylate		C₁₃H₁₅FO₃	详情	详情
(XVa)	40782	methyl (1R,2R,3S)-3-([(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-2-(4-fluorophenyl)cyclopentanecarboxylate		C₂₃H₂₁F₇O₃	详情	详情
(XVb)	40783	methyl (1R,2R,3S)-3-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-2-(4-fluorophenyl)cyclopentanecarboxylate		C₂₃H₂₁F₇O₃	详情	详情
(XI)	40778	1-[3,5-bis(trifluoromethyl)phenyl]-1-ethanone	30071-93-3	C₁₀H₆F₆O	详情	详情
(XII)	40779	1-[3,5-bis(trifluoromethyl)phenyl]-1-ethanol	368-63-8	C₁₀H₈F₆O	详情	详情
(XIII)	40780	1-[3,5-bis(trifluoromethyl)phenyl]ethyl 2,2,2-trichloroethanimidoate		C₁₂H₈Cl₃F₆NO	详情	详情
(XIV)	40781	1-(1-bromoethyl)-3,5-bis(trifluoromethyl)benzene		C₁₀H₇BrF₆	详情	详情
(XVI)	40784	(1R,2R,3S)-3-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-2-(4-fluorophenyl)cyclopentanecarboxylic acid		C₂₂H₁₉F₇O₃	详情	详情
(XVII)	40785	(1R,2R,3S)-3-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-2-(4-fluorophenyl)cyclopentanecarbonyl azide		C₂₂H₁₈F₇N₃O₂	详情	详情
(XVIII)	40786	(1R,2S,3S)-3-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-2-(4-fluorophenyl)cyclopentyl isocyanate; 1-((1R)-1-[[(1S,2S,3R)-2-(4-fluorophenyl)-3-isocyanatocyclopentyl]oxy]ethyl)-3,5-bis(trifluoromethyl)benzene		C₂₂H₁₈F₇NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVIII)

Addition of benzyl alcohol (C) to isocyanate (XVIII) gave rise to carbamate (XIX), which was further N-alkylated with iodomethane and NaH. Hydrogenolysis of carbamate (XX) over Pd/C produced methyl amine (XXI). This was then converted to the target triazolylmethyl derivative by alkylation with N-formyl-2-chloroacetamidrazone (XXII), followed by thermal cyclization in refluxing xylene.

参考文献中间体

合成目标

【1】 MacCoss, M.; Meurer, L.C.; Finke, P.E.; et al.; Discovery of potent human NK1 antagonists having a cyclopentane-based core structure. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 98.
【2】 Finke, P.E.; Maccoss, M.; Meurer, L.C.; Mills, S.G.; Caldwell, C.G.; Chen, P.; Durette, P.L.; Hale, J.; Holson, E.; Kopka, I.; Robichaud, A. (Merck & Co., Inc.); Cyclopentyl tachykinin receptor antagonists. EP 0858444; WO 9714671 .
【3】 Caldwell, C.G.; Chen, P.; Durette, P.L.; Finke, P.; Hale, J.; Holson, E.; Kopka, I.; Maccoss, M.; Meurer, L.; Mills, S.G.; Robichaud, A. (Merck & Co., Inc.); Cycloalkyl tachykinin receptor antagonists. US 5750549 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVIII)	40786	(1R,2S,3S)-3-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-2-(4-fluorophenyl)cyclopentyl isocyanate; 1-((1R)-1-[[(1S,2S,3R)-2-(4-fluorophenyl)-3-isocyanatocyclopentyl]oxy]ethyl)-3,5-bis(trifluoromethyl)benzene		C₂₂H₁₈F₇NO₂	详情	详情
(XIX)	40787	benzyl (1R,2S,3S)-3-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-2-(4-fluorophenyl)cyclopentylcarbamate		C₂₉H₂₆F₇NO₃	详情	详情
(XX)	40788	benzyl (1R,2S,3S)-3-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-2-(4-fluorophenyl)cyclopentyl(methyl)carbamate		C₃₀H₂₈F₇NO₃	详情	详情
(XXI)	40789	N-[(1R,2S,3S)-3-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-2-(4-fluorophenyl)cyclopentyl]-N-methylamine; (1R,2S,3S)-3-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-2-(4-fluorophenyl)-N-methylcyclopentanamine		C₂₂H₂₂F₇NO	详情	详情
(XXII)	40790	2-chloro-N'-formylethanehydrazonamide		C₃H₆ClN₃O	详情	详情
(C)	18710	Benzyl alcohol; Phenylmethanol	100-51-6	C₇H₈O	详情	详情

Extended Information