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【结 构 式】 
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【分子编号】36298 【品名】tert-butyl (3S,4S)-4-(fluoromethyl)pyrrolidinylcarbamate 【CA登记号】 |
【 分 子 式 】C10H19FN2O2 【 分 子 量 】218.2715432 【元素组成】C 55.03% H 8.77% F 8.7% N 12.83% O 14.66% |
合成路线1
该中间体在本合成路线中的序号：(XII)The condensation of itaconic acid (I) with (R)-1-phenylethylamine (II) produced a mixture of diastereomeric pyrrolidinones (III). The desired isomer (IV) was then isolated after conversion to the corresponding methyl ester. Introduction of the fluorine atom to give (VI) was achieved by either treatment with diethylaminosulfur trifluoride (DAST) or via conversion to the corresponding mesylate and further displacement by tetrabutylammonium fluoride. Hydroxylation of the lithium enolate of (VI) by means of O2 and (EtO)3P afforded the trans-3-hydroxy-4-(fluoromethyl)pyrrolidinone (VII). This was converted to mesylate (VIII) and subsequently displaced by NaN3 to provide the cis azide (IX). Hydrogenation of the azido group of (IX) over Pd/C in the presence of di-tert-butyl dicarbonate produced the Boc-protected amine (X). The pyrrolidinone ring was then reduced to pyrrolidine (XI) with borane in THF, and further hydrogenation over Pd/C at 50 C removed the alpha-methylbenzyl group, yielding (XII). Optionally, acid deprotection of the Boc group of (XII) provided intermediate (XIII).
| 【1】 Takahaski, H.; et al.; DC-756: A new methoxyquinolone: Synthesis and in vitro activity of 7-(3-amino-4-substituted-pyrrolidin-1-yl) derivatives. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-73. |
| 【2】 Takeda, T.; Kimura, K.; Ohki, H.; Takahashi, H.; Miyauchi, R.; Takemura, M. (Daiichi Pharmaceutical Co., Ltd.); Cis-substd. fluoromethylpyrrolidine derivs.. EP 0995744; WO 9858923 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 36288 | (3R)-5-oxo-1-[(1R)-1-phenylethyl]-3-pyrrolidinecarboxylic acid | C13H15NO3 | 详情 | 详情 | |
| (IIIb) | 36289 | (3S)-5-oxo-1-[(1R)-1-phenylethyl]-3-pyrrolidinecarboxylic acid | C13H15NO3 | 详情 | 详情 | |
| (I) | 27493 | 2-methylenesuccinic acid | 97-65-4 | C5H6O4 | 详情 | 详情 |
| (II) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (IV) | 36290 | methyl (3R)-5-oxo-1-[(1R)-1-phenylethyl]-3-pyrrolidinecarboxylate | C14H17NO3 | 详情 | 详情 | |
| (V) | 36291 | (4R)-4-(hydroxymethyl)-1-[(1R)-1-phenylethyl]-2-pyrrolidinone | C13H17NO2 | 详情 | 详情 | |
| (VI) | 36292 | (4R)-4-(fluoromethyl)-1-[(1R)-1-phenylethyl]-2-pyrrolidinone | C13H16FNO | 详情 | 详情 | |
| (VII) | 36293 | (3R,4S)-4-(fluoromethyl)-3-hydroxy-1-[(1R)-1-phenylethyl]-2-pyrrolidinone | C13H16FNO2 | 详情 | 详情 | |
| (VIII) | 36294 | (3R,4S)-4-(fluoromethyl)-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidinyl methanesulfonate | C14H18FNO4S | 详情 | 详情 | |
| (IX) | 36295 | (3S,4S)-3-azido-4-(fluoromethyl)-1-[(1R)-1-phenylethyl]-2-pyrrolidinone | C13H15FN4O | 详情 | 详情 | |
| (X) | 36296 | tert-butyl (3S,4S)-4-(fluoromethyl)-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidinylcarbamate | C18H25FN2O3 | 详情 | 详情 | |
| (XI) | 36297 | tert-butyl (3S,4S)-4-(fluoromethyl)-1-[(1R)-1-phenylethyl]pyrrolidinylcarbamate | C18H27FN2O2 | 详情 | 详情 | |
| (XII) | 36298 | tert-butyl (3S,4S)-4-(fluoromethyl)pyrrolidinylcarbamate | C10H19FN2O2 | 详情 | 详情 | |
| (XIII) | 36299 | (3S,4S)-4-(fluoromethyl)-3-pyrrolidinamine; (3S,4S)-4-(fluoromethyl)pyrrolidinylamine | C5H11FN2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)Condensation of the protected pyrrolidine (XII) with either the BF2-chelate (XVIa) or the B(OAc)2-chelate (XIVb) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid provided the 7-(pyrrolidinyl)quinoline (XV). The boron chelate of (XV) was then removed upon refluxing with Et3N in aqueous EtOH to give the quinolinecarboxylic acid (XVI). Finally, treatment of (XVI) with concentrated HCl cleaved the Boc protecting group.
| 【1】 Takahaski, H.; et al.; DC-756: A new methoxyquinolone: Synthesis and in vitro activity of 7-(3-amino-4-substituted-pyrrolidin-1-yl) derivatives. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-73. |
| 【2】 Takeda, T.; Kimura, K.; Ohki, H.; Takahashi, H.; Miyauchi, R.; Takemura, M. (Daiichi Pharmaceutical Co., Ltd.); Cis-substd. fluoromethylpyrrolidine derivs.. EP 0995744; WO 9858923 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIVa) | 36300 | 1-cyclopropyl-3-[[(difluoroboryl)oxy]carbonyl]-6,7-difluoro-8-methoxy-4(1H)-quinolinone | C14H10BF4NO4 | 详情 | 详情 | |
| (XIVb) | 36301 | diacetyl (1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinyl)carbonyl borate | C18H16BF2NO8 | 详情 | 详情 | |
| (XVa) | 36302 | tert-butyl (3S,4S)-1-(1-cyclopropyl-3-[[(difluoroboryl)oxy]carbonyl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-7-quinolinyl)-4-(fluoromethyl)pyrrolidinylcarbamate | C24H28BF4N3O6 | 详情 | 详情 | |
| (XVb) | 36303 | tert-butyl (3S,4S)-1-[3-([[bis(acetoxy)boryl]oxy]carbonyl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-7-quinolinyl]-4-(fluoromethyl)pyrrolidinylcarbamate | C28H34BF2N3O10 | 详情 | 详情 | |
| (XII) | 36298 | tert-butyl (3S,4S)-4-(fluoromethyl)pyrrolidinylcarbamate | C10H19FN2O2 | 详情 | 详情 | |
| (XVI) | 36304 | 7-[(3S,4S)-3-[(tert-butoxycarbonyl)amino]-4-(fluoromethyl)pyrrolidinyl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C24H29F2N3O6 | 详情 | 详情 |