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【结 构 式】 
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【药物名称】Tonabersat, SB-220453 【化学名称】(-)-(3S,4S)-cis-N-(6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)-3-chloro-4-fluorobenzamide 【CA登记号】175013-84-0 【 分 子 式 】C20H19ClFNO4 【 分 子 量 】391.83013 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Antimigraine Drugs |
合成路线1
The cyclization of 4-hydroxyacetophenone (I) with 3-chloro-3-methyl-1-butyne (II) gives 6-acetyl-2,2-dimethyl-2H-1-benzopyran (III), which is enantioselectively epoxidized by means of Mn+3 salen catalysts, yielding the chiral epoxide (IV). The cleavage of the epoxide ring of (IV) with ammonia in ethanol affords the (3R,4S)-trans-aminoalcohol (V). The acylation of (V) with 3-chloro-4-fluorobenzoyl chloride (VI) and triethylamine yields the (3R,4S)-trans-amide (VII). The cyclization of (VII) by means of diethylaminosulfur trifluoride (DAST) in dichloromethane affords the (3aS-cis)-oxazoline (VIII), which is finally treated with 5N H2SO4.
| 【1】 Chan, W.N.; et al.; Synthesis of novel trans-4-(substituted-benzamido)-3, 4-dihydro-2H-benzo[b]-pyran-3-ol derivatives as potential anticonvulsant agents with a distinctive binding profile. J Med Chem 1996, 39, 23, 4537. |
| 【2】 Castañer, J.; Leeson, P.; Rabasseda, X.; Tonabersat. Drugs Fut 1999, 24, 10, 1078. |
| 【3】 Chan, W.N.; Morgan, H.K.A.; Thompson, M.; Evans, J.M. (SmithKline Beecham plc); Benzopyrans and their use as therapeutic agents. EP 0764157; JP 1998501251; US 5760074; WO 9534545 . |
| 【4】 Thompson, M.; Evans, J.M.; Upton, N.; Chan, W.N.; Vong, K.K.; Willette, R.N. (SmithKline Beecham plc); Bicyclic cpds. with pharmaceutical activity. EP 0673373; JP 1996505132; US 5908860; WO 9413656 . |
| 【5】 Attrill, R.P.; Bell, D.; Miller, D. (SmithKline Beecham plc); Chiral catalysts and epoxidation reactions catalyzed thereby. WO 9403271 . |
| 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) | 18123 | 1-(4-hydroxyphenyl)-1-ethanone; 4'-Hydroxyacetophenone | 99-93-4 | C8H8O2 | 详情 | 详情 |
| (II) | 22416 | 3-chloro-3-methyl-1-butyne | 1111-97-3 | C5H7Cl | 详情 | 详情 |
| (III) | 28706 | 1-(2,2-dimethyl-2H-chromen-6-yl)-1-ethanone | C13H14O2 | 详情 | 详情 | |
| (IV) | 28707 | 1-[(1aR,7bR)-2,2-dimethyl-1a,7b-dihydro-2H-oxireno[2,3-c]chromen-6-yl]-1-ethanone | C13H14O3 | 详情 | 详情 | |
| (V) | 28708 | 1-[(3R,4S)-4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl]-1-ethanone | C13H17NO3 | 详情 | 详情 | |
| (VI) | 24370 | 3-chloro-4-fluorobenzoyl chloride | 65055-17-6 | C7H3Cl2FO | 详情 | 详情 |
| (VII) | 28709 | N-[(3R,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-chloro-4-fluorobenzamide | C20H19ClFNO4 | 详情 | 详情 | |
| (VIII) | 28713 | 1-[(3aS,9bS)-2-(3-chloro-4-fluorophenyl)-4,4-dimethyl-3a,9b-dihydro-4H-chromeno[4,3-d][1,3]oxazol-8-yl]-1-ethanone | C20H17ClFNO3 | 详情 | 详情 |