【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% |
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 |