• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【分子编号】51100

【品名】ethyl (Z)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)-2-propenoate

【CA登记号】

【 分 子 式 】C16H15F3N2O5

【 分 子 量 】372.3007896

【元素组成】C 51.62% H 4.06% F 15.31% N 7.52% O 21.49%

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:(IX)

Nitration of 2,4,5-trifluoro-3-methylbenzoic acid (I) with H2SO4 and HNO3 provides nitrobenzoic acid derivative (II), which is then converted into the nitrobenzoyl chloride derivative (III) by reaction with oxalyl chloride in CH2Cl2 in the presence of DMF. Condensation of (III) with diethyl malonate (IV) by means of Mg in EtOH in the presence of CCl4 yields diethyl (2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)malonate (V), which is then treated with p-toluene sulfonic acid in refluxing H2O to furnish ethyl acetate derivative (VI). Reaction of (VI) with ethyl orthoformate and acetic anhydride at reflux affords ethyl acrylate derivative (VII), which is then treated with cyclopropylamine (VIII) in EtOH to give compound (IX). Cyclization of (IX) is then induced either by treatment with NaH in 1,4-dioxane or with 18-crown-6-ether and K2CO3 in THF to provide quinolone derivative (X), whose nitro group is reduced by hydrogenation over Ni Raney in HOAc to give amino derivative (XI). Hydrolysis of the ethyl ester moiety of (XI) is performed by refluxing with HCl/HOAc to furnish carboxylic acid (XII), which is then treated with boron trifluoride etherate to give boron chelate (XIII). Finally, condensation of (XIII) with (S)-7-trifluoroacetylamino-5-azaspiro[2.4]heptane hydrochloride (XIV) by means of Et3N in DMSO, followed by deprotection with KOH in H2O and treatment with MeSO3H affords the desired compound. Alternatively, the target product can also be synthesized from the Boc protected derivative (XVI) obtained either by coupling of boron chelate (XIII) with (S)-7-Boc-amino-5-azaspiro[2.4]heptane hydrochloride (XIV) by means of DIEA in DMSO (or Et3N in MeOH) or by reaction between carboxylic acid (XII) and compound (XV) by heating in DMSO. Finally, the Boc protecting group of (XVI) is removed with HCl and the corresponding methanesulfonate salt formed by treatment with MeSO3H.

1 Yoshida, T.; et al.; Studies on quinolone antibacterials.V. Synthesis and antibacterial activity of chiral 5-amino-7-(4-substituted-3-amino-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acids and derivatives. Chem Pharm Bull 1996, 44, 7, 1376.
2 Ito, Y.; Kato, H.; Yasuda, S.; Kado, N.; Yoshida, T.; Yamamoto, Y. (Hokuriku Seiyaku Co., Ltd.); 5-Amino-8-methyl-7-pyrrolidinylquinoline-3-carboxylic acid deriv.. CA 2126118; EP 0641793; JP 1995309864; US 5547962 .
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) 51094 2,4,5-trifluoro-3-methylbenzoic acid C8H5F3O2 详情 详情
(II) 51095 2,4,5-trifluoro-3-methyl-6-nitrobenzoic acid C8H4F3NO4 详情 详情
(III) 51096 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride C8H3ClF3NO3 详情 详情
(IV) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(V) 51097 diethyl 2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)malonate C15H14F3NO7 详情 详情
(VI) 51098 ethyl 3-oxo-3-(2,4,5-trifluoro-3-methyl-6-nitrophenyl)propanoate C12H10F3NO5 详情 详情
(VII) 51099 ethyl (Z)-3-ethoxy-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)-2-propenoate C15H14F3NO6 详情 详情
(VIII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(IX) 51100 ethyl (Z)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)-2-propenoate C16H15F3N2O5 详情 详情
(X) 51101 ethyl 1-cyclopropyl-6,7-difluoro-8-methyl-5-nitro-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H14F2N2O5 详情 详情
(XI) 51102 ethyl 5-amino-1-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H16F2N2O3 详情 详情
(XII) 51103 5-amino-1-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C14H12F2N2O3 详情 详情
(XIII) 51104   C14H11BF4N2O3 详情 详情
(XIV) 51105 N-[(7S)-5-azaspiro[2.4]hept-7-yl]-2,2,2-trifluoroacetamide C8H11F3N2O 详情 详情
(XV) 15193 tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate C11H20N2O2 详情 详情
(XVI) 51106 5-amino-7-[(7S)-7-[(tert-butoxycarbonyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C25H31FN4O5 详情 详情
Extended Information