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【结 构 式】

【分子编号】21308

【品名】ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate

【CA登记号】

【 分 子 式 】C15H12ClF2NO3

【 分 子 量 】327.7147264

【元素组成】C 54.98% H 3.69% Cl 10.82% F 11.59% N 4.27% O 14.65%

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:(XV)

The reduction of 2,3,4-trichloro-5-fluoronitrobenzene (I) with Fe - HCl in hot water gives 2,3,4-trichloro-5-fluoroaniline (II), which by diazotation with NaNO2 - HCl and reaction with sodium tetrafluoroborate and cuprous cyanide is converted to 2,3,4-trichloro-5-fluorobenzonitrile (III). The reaction of (III) with KF in DMSO at 140 C affords 3-chloro-2,4,5-trifluorobenzonitrile (IV), which by hydrolysis with 30% HBr in refluxing acetic acid gives 3-chloro-2,4,5-trifluorobenzamide (V). The hydrolysis of (V) with 18N H2SO4 at 135 C yields the corresponding benzoic acid (VI), which is treated with refluxing SOCl2 to afford the acyl chloride (VII). The condensation of (VII) with diethyl malonate (VIII) by means of Mg - ethanol in hot toluene gives diethyl 3-chloro-2,4,5-trifluorobenzoylmalonate (IX), which is partially decarboxylated with p-toluenesulfonic acid in refluxing water to give ethyl 3-chloro-2,4,5-trifluorobenzoylacetate (X). The condensation of (X) with triethyl orthoformate (XI) in refluxing acetic anhydride yields ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylate (XII), which is treated with cyclopropylamine (XIII) in ethanol to afford ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(cyclopropylamino)acrylate (XIV). The cyclization of (XIV) by means of NaF in DMF at 150 C gives ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (XV), which is hydrolyzed with H2SO4 in refluxing water - acetic acid to the corresponding carboxylic acid (XVI). The condensation of (XVI) with 3-(tert-butoxycarbonylamino)pyrrolidine (XVII) by means of 1,8-diazabicyclo [5.4.0]undecane (DBU) in refluxing acetonitrile yields 7-[3-(tert-butoxycarbonylamino)-1-pyrrolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XVIII), which is finally deprotected by a treatment with concentrated HCl in methanol.

1 Irikura, T.; Suzue, S.; Murayama, S.; Hirai, K.; Ishizaki, T. (Kyorin Pharmaceutical Co., Ltd.); 7-(1-Pyrrolidinyl)-3-quinolinecarboxylic acid derivs.. AU 8542829; AU 8654272; EP 0195316; EP 0195841; ES 8606330; ES 8704932; JP 1986205235; JP 1986205237; JP 1986205238; JP 1986205239; JP 1986205258; JP 1986205259 .
2 Serradell, M.N.; Castaner, J.; Castaner, R.M.; Saito, H.; Tomioka, H.; Sato, K.; Hirai, K.; Suzue, S.; AM-1091. Drugs Fut 1989, 14, 10, 931.
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) 21294 2,3,4-trichloro-1-fluoro-5-nitrobenzene C6HCl3FNO2 详情 详情
(II) 21295 2,3,4-trichloro-5-fluorophenylamine; 2,3,4-trichloro-5-fluoroaniline C6H3Cl3FN 详情 详情
(III) 21296 2,3,4-trichloro-5-fluorobenzonitrile C7HCl3FN 详情 详情
(IV) 21297 3-chloro-2,4,5-trifluorobenzonitrile C7HClF3N 详情 详情
(V) 21298 3-chloro-2,4,5-trifluorobenzamide C7H3ClF3NO 详情 详情
(VI) 11678 3-Chloro-2,4,5-trifluorobenzoic acid C7H2ClF3O2 详情 详情
(VII) 11679 3-Chloro-2,4,5-trifluorobenzoyl chloride C7HCl2F3O 详情 详情
(VIII) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(IX) 21302 diethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)malonate C14H12ClF3O5 详情 详情
(X) 11681 ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate 101987-86-4 C11H8ClF3O3 详情 详情
(XI) 21304 Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether 122-51-0 C7H16O3 详情 详情
(XII) 11682 ethyl (Z)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxy-2-propenoate C14H12ClF3O4 详情 详情
(XIII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(XIV) 11683 ethyl (E)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(cyclopropylamino)-2-propenoate C15H13ClF3NO3 详情 详情
(XV) 21308 ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate C15H12ClF2NO3 详情 详情
(XVI) 11684 8-Chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 101987-89-7 C13H8ClF2NO3 详情 详情
(XVII) 21310 tert-butyl 3-pyrrolidinylcarbamate 99724-19-3 C9H18N2O2 详情 详情
(XVIII) 21311 7-[3-[(tert-butoxycarbonyl)amino]-1-pyrrolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C22H25ClFN3O5 详情 详情
Extended Information