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【结 构 式】 
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【分子编号】63958 【品名】cis-rac(1S,2S)-2-fluorocyclopropanecarboxylic acid 【CA登记号】 |
【 分 子 式 】C4H5FO2 【 分 子 量 】104.0809032 【元素组成】C 46.16% H 4.84% F 18.25% O 30.74% |
合成路线1
该中间体在本合成路线中的序号：(XII)The chiral intermediate (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) is obtained as follows: 1) The cyclization of butadiene (IX) with dibromofluoromethane by means of BuONa, followed by oxidation with KMnO4, esterification with ethanol - sulfuric acid and reduction with tributyltin hydride gives 2-fluorocyclopropanecarboxylic acid ethyl ester as a cis/trans mixture (X), which is separated by crystallization. The cis-racemic-isomer (XI) is hydrolyzed with NaOH to the corresponding acid (XII), which is condensed with (R)-alpha-methylbenzylamine (XIII) by means of diphenyl chlorophosphate to give the mixture of diastereomers (XIV). This mixture is separated by crystallization, yielding pure (1S,2S)-2-fluoro-N-[alpha(R)-methylbenzyl]cyclopropanecarboxamide (XV), which is hydrolyzed with HCl to the corresponding free acid (XVI). Finally, this compound is converted into (III) by treatment with diphenylphosphoryl azide in refluxing tert-butanol.
| 【1】 Hayakawa, I.; Kimura, Y. (Daiichi Pharmaceutical Co., Ltd.); Optically active pyridone carboxylic acid derivs. AU 8933702; EP 0341493; JP 1990231475; JP 1995300416; JP 1999124367; JP 1999124380; US 5587386; US 5767127 . |
| 【2】 Castaner, J.; Graul, A.; Prous, J.; DU-6859. Drugs Fut 1994, 19, 9, 827. |
| 【3】 Sato, K.; Saito, T.; Hayakawa, I.; Sato, M.; Yafune, T.; Atarashi, S.; Une, T.; Kimura, Y.; Kawakami, K.; Design and structure-activity relationship of new N1-cis-2-fluorocyclopropyl quinolones. 31st. 31st Intersci Conf Antimicrob Agents Chemother (Sept 29-Oct 2, Chicago) 1991, Abst 1504. |
| 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) | 15139 | (1S,2S)-2-fluoro-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C12H14FNO | 详情 | 详情 | |
| (XIVb) | 63959 | (1S,2R)-2-fluoro-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C12H14FNO | 详情 | 详情 | |
| (III) | 15127 | tert-butyl N-[(1R,2S)-2-fluorocyclopropyl]carbamate | 127199-16-0 | C8H14FNO2 | 详情 | 详情 |
| (IX) | 11579 | 1,3-Butadiene; Butadiene | 106-99-0 | C4H6 | 详情 | 详情 |
| (X) | 15134 | ethyl 2-fluorocyclopropanecarboxylate | C6H9FO2 | 详情 | 详情 | |
| (XI) | 63960 | cis-rac[ethyl (1S,2S)-2-fluorocyclopropanecarboxylate] | C6H9FO2 | 详情 | 详情 | |
| (XII) | 63958 | cis-rac(1S,2S)-2-fluorocyclopropanecarboxylic acid | C4H5FO2 | 详情 | 详情 | |
| (XIII) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (XV) | 15139 | (1S,2S)-2-fluoro-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide | C12H14FNO | 详情 | 详情 | |
| (XVI) | 15140 | (1S,2S)-2-fluorocyclopropanecarboxylic acid | C4H5FO2 | 详情 | 详情 |