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【结 构 式】

【分子编号】65573

【品名】 

【CA登记号】 

【 分 子 式 】C10H8F2O

【 分 子 量 】182.1697264

【元素组成】C 65.93% H 4.43% F 20.86% O 8.78%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XXVIII)

In an alternative route to intermediate (III), ortho-metalation of 1,2-difluorobenzene (XXIV) with n-hexyllithium in THF followed by sequential addition of ZnCl2, CuCl and then chloroacetyl chloride (XXV) gives 2-chloro-2’,3’-difluoroacetophenone (XXVI). Subsequent condensation of chloroketone (XXVI) with vinylmagnesium bromide followed by cyclization of the resulting chlorohydrin (XXVII) under alkaline conditions yields epoxide (XXVIII). This is then coupled with diethyl acetamidomalonate (XXIX) in the presence of Pd(OAc)2 and 1,2-bis(diphenylphosphino)ethane (dppe) to generate the allyl alcohol adduct (XXX), which after conversion to the corresponding mesylate (XXXI) is reacted with 2,2,2-trifluoroethylamine (XXXII) in dimethylacetamide to furnish the allylic amine (XXXIII). Decarbethoxylation of malonate (XXXIII) by heating with LiCl in moist dimethylacetamide provides the N-acetyl aminoester (XXXIV). Then, cyclization of (XXXIV) by means of trifluoroacetic acid in hot toluene gives the azepinone derivative (XXXV). After acidic hydrolysis of acetamide (XXXV), the resulting racemic amine is resolved utilizing (-)-O,O’-di-p-toluoyl-L-tartaric acid (DTTA) in the presence of a trace amount of 5-nitrosalicylaldehyde to provide the (S)-amine ditoluoyltartrate salt (XXXVI). Finally, liberation of the tartrate salt (XXXVI) with HCl in isopropanol and simultaneous hydrogenation of the azepine double bond in the presence of Pd/BaSO4 provides the trans-perhydroazepinone (III) (2-5). Scheme 3.

2 Palucki, M., Davies, I., Steinhuebel, D., Rosen, J. (Merck & Co., Inc.). Process for the preparation of caprolactam CGRP antagonist intermediate. WO 2007120589.
3 McLaughlin, M., Palucki, M., Marcantonio, K. (Merck & Co., Inc.). Process for the preparation of pyridine heterocycle CGRP antagonist intermediate. WO 2007120590.
4 Belyk, K., Rivera, N. (Merck & Co., Inc.). Process for the preparation of CGRP antagonist. WO 2007120591.
5 Belyk, K. (Merck & Co., Inc.). CGRP antagonist salt. WO 2007120592.
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) 65556 (3R,6S)-3-Amino-6-(2,3-difluorophenyl)hexahydro-2-oxo-1-(2,2,2-trifluoroethyl)-1H-azepine   C14H15F5N2O 详情 详情
(XXIV) 65570 1,2-Difluorobenzene 367-11-3 C6H4F2 详情 详情
(XXV) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(XXVI) 65571 2-Chloro-2',3'-difluoroacetophenone   C8H5ClF2O 详情 详情
(XXVII) 65572     C10H9ClF2O 详情 详情
(XXVIII) 65573     C10H8F2O 详情 详情
(XXIX) 16710 Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate 1068-90-2 C9H15NO5 详情 详情
(XXX) 65574     C19H23F2NO6 详情 详情
(XXXI) 65575     C20H25F2NO8S 详情 详情
(XXXII) 42542 2,2,2-trifluoroethylamine; 2,2,2-trifluoro-1-ethanamine 753-90-2 C2H4F3N 详情 详情
(XXXIII) 65576     C21H25F5N2O5 详情 详情
(XXXIV) 65577     C18H21F5N2O3 详情 详情
(XXXV) 65578     C16H15F5N2O2 详情 详情
(XXXVI) 65579     C14H13F5N2O.C20H18O8 详情 详情
Extended Information