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【结 构 式】 
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【分子编号】21310 【品名】tert-butyl 3-pyrrolidinylcarbamate 【CA登记号】99724-19-3 |
【 分 子 式 】C9H18N2O2 【 分 子 量 】186.2542 【元素组成】C 58.04% H 9.74% N 15.04% O 17.18% |
合成路线1
该中间体在本合成路线中的序号：(XVII)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 |
合成路线2
该中间体在本合成路线中的序号：(B)Treatment of ethyl 2,6-dichloro-5-fluoronicotinylacetate (I) with ethyl orthoformate in refluxing acetic anhydride and then with 2,4-difluoroaniline in methylene chloride at room temperature gives the enaminoketo ester derivative (II). Cyclization of (II) with sodium hydride in THF gives ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (III). Hydrolysis of (III) with hydrochloric acid yields 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (IV). Condensation of (IV) with 3-tert-butoxycarbonylaminopyrrolidine in pyridine in the presence of triethylamine yields 7-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (V). Sodium borohydride reduction of (V) in methanol followed by decarboxylation in the presence of toluenesulfonic acid yields the 7-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,2,3,4-tetrahydro-4-oxo-1,8-naphthyridine (VI). Acylation of (VI) with ethyl formate in THF in the presence of NaH and a catalytic amount of ethanol yields the 7-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-3-formyl-4-hydroxy-1,2-dihydro-1,8-naphthyridine (VII). Oxidation of (VII) with manganese dioxide in methanol gives 7-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-3-formyl-1,4-dihydro-4-oxo-1,8-naphthyridine (VIII). Hydrolysis of (VIII) in hydrochloric acid and dioxane gives A-71497.
| 【1】 Swanson, R.N.; Pernet, A.G.; Marsh, K.C.; Chu, D.T.W.; Lico, I.M.; Plattner, J.J.; Synthesis and biological properties of A-71497: A prodrug of tosufloxacin. 9th Int Symp Fut Trends Chemother 1990, 21. |
| 【2】 Chu, D.T.W.; A-71497. Drugs Fut 1990, 15, 12, 1171. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 19462 | 2,4-difluoroaniline; 2,4-difluorophenylamine；2,4-Difluoro-benzenamine;1-Amino-2,4-difluorobenzene | 367-25-9 | C6H5F2N | 详情 | 详情 |
| (B) | 21310 | tert-butyl 3-pyrrolidinylcarbamate | 99724-19-3 | C9H18N2O2 | 详情 | 详情 |
| (I) | 15228 | ethyl 3-(2,6-dichloro-5-fluoro-3-pyridinyl)-3-oxopropanoate | C10H8Cl2FNO3 | 详情 | 详情 | |
| (II) | 15229 | ethyl (Z)-2-[(2,6-dichloro-5-fluoro-3-pyridinyl)carbonyl]-3-(2,4-difluoroanilino)-2-propenoate | C17H11Cl2F3N2O3 | 详情 | 详情 | |
| (III) | 31219 | ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,2,3,4-tetrahydro[1,8]naphthyridine-3-carboxylate | C17H12ClF3N2O3 | 详情 | 详情 | |
| (IV) | 31220 | 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,2,3,4-tetrahydro[1,8]naphthyridine-3-carboxylic acid | C15H8ClF3N2O3 | 详情 | 详情 | |
| (V) | 31221 | 7-[3-[(tert-butoxycarbonyl)amino]-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,2,3,4-tetrahydro[1,8]naphthyridine-3-carboxylic acid | C24H25F3N4O5 | 详情 | 详情 | |
| (VI) | 31222 | tert-butyl 1-[8-(2,4-difluorophenyl)-3-fluoro-5-oxo-5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl]-3-pyrrolidinylcarbamate | C23H25F3N4O3 | 详情 | 详情 | |
| (VII) | 31223 | tert-butyl 1-[8-(2,4-difluorophenyl)-3-fluoro-6-formyl-5-hydroxy-7,8-dihydro[1,8]naphthyridin-2-yl]-3-pyrrolidinylcarbamate | C24H25F3N4O4 | 详情 | 详情 | |
| (VIII) | 31224 | tert-butyl 1-[8-(2,4-difluorophenyl)-3-fluoro-6-formyl-5-oxo-5,8-dihydro[1,8]naphthyridin-2-yl]-3-pyrrolidinylcarbamate | C24H23F3N4O4 | 详情 | 详情 |