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【结 构 式】 
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【分子编号】12280 【品名】Flurbiprofen; 2-(2-Fluoro[1,1'-biphenyl]-4-yl)propionic acid 【CA登记号】5104-49-4 |
【 分 子 式 】C15H13FO2 【 分 子 量 】244.2654232 【元素组成】C 73.76% H 5.36% F 7.78% O 13.1% |
合成路线1
该中间体在本合成路线中的序号：(I)By esterification of 2-(2-fluoro-4-biphenylyl)propionic acid (I) with 1-(acetoxy)ethyl chloride (II) or 1-(acetoxy)ethyl bromide (III) by means of anhydrous K2CO3 in DMF or by transesterification of the acid (I) and ethylidene diacetate (IV) in benzene.
| 【1】 Mimura, M.; Uchida, K.; Ieda, T.; et al.; Method for the preparation of 1-acetoxyethyl 2-(2-fluoro-4-biphenylyl)propionate. JP 89211550 . |
| 【2】 Uchida, K.; Masumoto, S.; Tohno, M.; Mimura, M.; Okumura, M.; Ichikawa, K.; Matsumura, M. (Kaken Pharmaceutical Co., Ltd.); Biphenylpropionic acid deriv., process for preparing the same and pharmaceutical compsn. containing the same. EP 0103265; US 5196567 . |
| 【3】 Mizushima, Y.; Uchida, K.; Masumoto, S.; Tohno, M.; Hashimoto, Y.; Yokoyama, K.; Okamoto, H.; Nabeta, K.; Suyama, T. (Welfide Corporation); Ester of flurbiprofen and emulsion containing the same. EP 0129435; JP 1985001122; US 4613505 . |
| 【4】 Prous, J.; Castaner, J.; Liposomal Flurbiprofen Axetil. Drugs Fut 1992, 17, 9, 788. |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of 2-(2-fluorobiphenyl-4-yl)propionic acid (I) with thionyl chloride followed by treatment with tris (trimethylsilyloxy)ethylene gives 3-(2-fluorobiphenyl-4-yl)-1-hydroxy-2-butanone (II), which upon treatment with carbon tetrachloride and triphenylphosphine affords 1-chloro-3-(2-fluorobiphenyl-4-yl)-2-butanone (III). Finally, compound (III) is heated with N-methylthiourea in water.
| 【1】 Ozato, Y.; Tamura, N.; Masumori, H.; Yamamoto, M.; Kojima, A.; Nishikakau, F.; Kimura, Y. (Sumitomo Pharmaceuticals Co., Ltd.); Aminazole derivatives and their production and use. EP 0248399; JP 1988152368; JP 1993247014; US 4914112; US 5066666; US 5180731 . |
| 【2】 Prous, J.; Castaner, J.; Graul, A.; SM-8849. Drugs Fut 1994, 19, 4, 347. |
合成路线3
该中间体在本合成路线中的序号：(A)The adopted procedure for the preparation of HCT-1026 consisted in the reaction of flurbiprofen sodium salt (I) and 1,4-dibromobutane (II) in acetonitrile at reflux temperature to obtain HCT-1031 (III), the 4-bromobutyl ester of flurbiprofen. HCT-1031 was then converted into HCT-1026 by reaction with silver nitrate in acetonitrile at reflux temperature. The crude HCT-1026 thus obtained showed 85% HPLC purity with the presence of one major impurity (15%) that was identified as the bis-compound HCT-1028. The crude product was then purified by silica gel column chromatography using toluene as eluent to give a product with >99% HPLC purity in 57% overall yield. After cooling, pure HCT-1026 was obtained as a thick oil.
| 【1】 Benedini, F.; Burgaud, J.L.; Del Soldato, P.; Robinson, E.M.; HCT-1026. Drugs Fut 1999, 24, 8, 858. |
| 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) | 12280 | Flurbiprofen; 2-(2-Fluoro[1,1'-biphenyl]-4-yl)propionic acid | 5104-49-4 | C15H13FO2 | 详情 | 详情 |
| (I) | 26005 | sodium 2-(2-fluoro[1,1'-biphenyl]-4-yl)propanoate | C15H12FNaO2 | 详情 | 详情 | |
| (II) | 11883 | 1,4-Dibromobutane; 1,4-Butylene bromide | 110-52-1 | C4H8Br2 | 详情 | 详情 |
| (III) | 26006 | 4-bromobutyl 2-(2-fluoro[1,1'-biphenyl]-4-yl)propanoate | C19H20BrFO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Formation of the diastereoisomeric salts with (R)-alpha-methylbenzylamine (II), followed by crystallization from methanol/toluene, provided the desired (R)-phenylpropionic acid salt (III) in good enantiomeric purity, which was further enriched in the desired enantiomer by recrystallization from the same solvent. The chiral carboxylic acid was then liberated from the recrystallized methylbenzylamine salt (III) by acidification with HCl in a water/heptane two-phase system.
| 【1】 Coe, P.F.; Hardy, R.; Hirst, A.; O'Donnell, H.O. (The Boots Company plc); Process for preparing substantially pure enantiomers of phenylpropionic acids. WO 9412460 . |