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【结 构 式】

【分子编号】14337

【品名】4-[1-(acetamido)cyclopropyl]-2,3,5-trifluorobenzoyl chloride

【CA登记号】

【 分 子 式 】C12H9ClF3NO2

【 分 子 量 】291.6569096

【元素组成】C 49.42% H 3.11% Cl 12.16% F 19.54% N 4.8% O 10.97%

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:(X)

A new synthesis of T-3761 has been described: The esterification of 2,3,4,5-tetrafluorobenzoic acid (I) with ethyl bromide and K2CO3 in DMSO gives the corresponding ethyl ester (II), which is condensed with tert-butyl cyanoacetate (III) by means of K2CO3, yielding 4-(cyanomethyl)-2,3,5-trifluorobenzoic acid ethyl ester (V) through the intermediate (IV). The cyclopropanation of (V) with 1,2-dibromoethane and benzyltriethylammonium chloride and NaOH in water/dichloromethane affords 4-(1-cyanocyclopropyl)-2,3,5-trifluorobenzoic acid, which by treatment with H2O2 and NaOH is converted to 4-(1-carbamoylcyclopropyl)-2,3,5-trifluorobenzoic acid (VII). Degradation of amide (VII) with Cl2 and NaOH gives the corresponding 4-aminocyclopropyl derivative (VIII), which is acetylated with acetic anhydride to the acetamide (IX). The reaction of (IX) with SOCl2 yields the acid chloride (X), which is condensed with malonic acid monoethyl ester potassium salt (XI) by means of triethylamine to afford 2-[4-(1-acetamidocyclopropyl)-2,3,5-trifluorobenzoyl]acetic acid ethyl ester (XII). The consecutive reaction of (XII) first with dimethylformamide dimethylacetal (XIII) in acetic acid and then with 2(S)-aminopropanol (XIV) gives the benzoylacrylic intermediate (XV), which, without isolation, is treated with K2CO3 in DMSO at 100 C to afford the ethyl ester of the acetylated T-3761 (XVI). Finally, this compound is deprotected by successive treatment first with ethanolic NaOH and then with hot 6N HCl.

1 Iino, F.; Momonoi, K.; Hayashi, K.; Todo, Y.; Kuroda, H.; Takagi, H.; Narita, H.; Takata, M.; Practical synthesis of T-3761, (S)-10-(1-aminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid. Chem Pharm Bull 1994, 42, 12, 2629.
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) 14328 2,3,4,5-tetrafluorobenzoic acid 1201-31-6 C7H2F4O2 详情 详情
(II) 14313 diethyl (2S)-2-[(4-[2-[(6R)-2-(acetamido)-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl)amino]pentanedioate C27H35N5O7 详情 详情
(III) 14330 tert-Butyl cyanoacetate; tert-butyl 2-cyanoacetate 1116-98-9 C7H11NO2 详情 详情
(IV) 14331 ethyl 4-[2-(tert-butoxy)-1-cyano-2-oxoethyl]-2,3,5-trifluorobenzoate C16H16F3NO4 详情 详情
(V) 14332 ethyl 4-(cyanomethyl)-2,3,5-trifluorobenzoate C11H8F3NO2 详情 详情
(VI) 14333 ethyl 4-(1-cyanocyclopropyl)-2,3,5-trifluorobenzoate C13H10F3NO2 详情 详情
(VII) 14334 4-[1-(aminocarbonyl)cyclopropyl]-2,3,5-trifluorobenzoic acid C11H8F3NO3 详情 详情
(VIII) 14335 4-(1-aminocyclopropyl)-2,3,5-trifluorobenzoic acid C10H8F3NO2 详情 详情
(IX) 14336 4-[1-(acetamido)cyclopropyl]-2,3,5-trifluorobenzoic acid C12H10F3NO3 详情 详情
(X) 14337 4-[1-(acetamido)cyclopropyl]-2,3,5-trifluorobenzoyl chloride C12H9ClF3NO2 详情 详情
(XI) 14338 potassium 3-ethoxy-3-oxopropanoate 6148-64-7 C5H7KO4 详情 详情
(XII) 14339 ethyl 3-[4-[1-(acetamido)cyclopropyl]-2,3,5-trifluorophenyl]-3-oxopropanoate C16H16F3NO4 详情 详情
(XIII) 11984 N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine; Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal 4637-24-5 C5H13NO2 详情 详情
(XIV) 14341 L-Alaninol; (2S)-2-Amino-1-propanol; L-(+)-Alaninol 2749-11-3 C3H9NO 详情 详情
(XV) 14342 ethyl (E)-2-[4-[1-(acetamido)cyclopropyl]-2,3,5-trifluorobenzoyl]-3-[[(1S)-2-hydroxy-1-methylethyl]amino]-2-propenoate C20H23F3N2O5 详情 详情
(XVI) 14343 ethyl (3S)-10-[1-(acetamido)cyclopropyl]-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate C20H21FN2O5 详情 详情
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