2-[3,5-bis(trifluoromethyl)phenyl]-N-(4-oxo-1-phenylcyclohexyl)propanamide -Drug Synthesis Database

【结构式】

【分子编号】57089

【品名】2-[3,5-bis(trifluoromethyl)phenyl]-N-(4-oxo-1-phenylcyclohexyl)propanamide

【CA登记号】

【分子式】C₂₃H₂₁F₆NO₂

【分子量】457.4156992

【元素组成】C 60.39% H 4.63% F 24.92% N 3.06% O 7%

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：(XIII)

Michael addition of methyl acrylate (VIII) to methyl phenylacetate (VII) in the presence of NaH produces the intermediate triester (IX) which, under the reaction conditions, undergoes Dieckmann cyclization to the cyclohexanone diester (X). Hydrolysis and decarboxylation of keto diester (X) leads to keto acid (XI). This is then subjected to Curtius rearrangement in the presence of diphenylphosphoryl azide (DPPA) to yield, after acidic hydrolysis of the intermediate isocyanate, the amino cyclohexanone (XII). Acylation of amine (XII) by acid chloride (VI) then gives amide (XIII).

参考文献中间体

合成目标

【1】 Elliott, J.M.; Castro Pineiro, J.L.; Swain, C.J.; Hollingworth, G.J.; Dinnell, K.; Shaw, D.E. (Merck Sharp & Dohme Ltd.); Cyclohexane derivs. and their use as therapeutic agents. WO 0187838 .

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)	57084	2-[3,5-bis(trifluoromethyl)phenyl]propanoyl chloride		C₁₁H₇ClF₆O	详情	详情
(VII)	32831	methyl 2-phenylacetate	101-41-7	C₉H₁₀O₂	详情	详情
(VIII)	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(IX)	57085	trimethyl 3-phenyl-1,3,5-pentanetricarboxylate		C₁₇H₂₂O₆	详情	详情
(X)	57086	dimethyl 4-oxo-1-phenyl-1,3-cyclohexanedicarboxylate		C₁₆H₁₈O₅	详情	详情
(XI)	57087	4-oxo-1-phenylcyclohexanecarboxylic acid		C₁₃H₁₄O₃	详情	详情
(XII)	57088	4-amino-4-phenylcyclohexanone		C₁₂H₁₅NO	详情	详情
(XIII)	57089	2-[3,5-bis(trifluoromethyl)phenyl]-N-(4-oxo-1-phenylcyclohexyl)propanamide		C₂₃H₂₁F₆NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIII)

Alkylation of the enolate derived from N-Boc ethyl isonipecotate (XIV) with allyl bromide (XV) gives the alpha-allyl ester (XVI). Double bond ozonolysis in (XIV) with reductive work-up in the presence of NaBH4 leads to lactone (XVII). Reductive ring-opening of lactone (XVII) by means of DIBAL affords diol (XVIII). This is then cyclized under Mitsunobu conditions to the spirocyclic amine (XIX). Acidic Boc group cleavage in (XIX) provides 2-oxa-8-azaspiro[4.5]decane (XX). Finally, reductive amination of cyclohexanone (XIII) with the bicyclic amine (XX) gives rise to a cis/trans mixture of diamino cyclohexanes, from which the desired trans isomer is isolated by chromatography.

参考文献中间体

合成目标

【1】 Cooper, L.C.; et al.; 4,4-Disubstituted cyclohexylamine NK1 receptor antagonists II. Bioorg Med Chem Lett 2002, 12, 13, 1759.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIII)	57089	2-[3,5-bis(trifluoromethyl)phenyl]-N-(4-oxo-1-phenylcyclohexyl)propanamide		C₂₃H₂₁F₆NO₂	详情	详情
(XIV)	49847	1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine	142851-03-4	C₁₃H₂₃NO₄	详情	详情
(XV)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(XVI)	57090	1-(tert-butyl) 4-ethyl 4-allyl-1,4-piperidinedicarboxylate		C₁₆H₂₇NO₄	详情	详情
(XVII)	57091	tert-butyl 1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate		C₁₃H₂₁NO₄	详情	详情
(XVIII)	57092	tert-butyl 4-(2-hydroxyethyl)-4-(hydroxymethyl)-1-piperidinecarboxylate		C₁₃H₂₅NO₄	详情	详情
(XIX)	57093	tert-butyl 2-oxa-8-azaspiro[4.5]decane-8-carboxylate		C₁₃H₂₃NO₃	详情	详情
(XX)	57094	2-oxa-8-azaspiro[4.5]decane		C₈H₁₅NO	详情	详情

Extended Information