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【结 构 式】 
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【分子编号】17318 【品名】(4S)-6-chloro-4-hydroxy-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-1,1(2H)-dione 【CA登记号】160982-16-1 |
【 分 子 式 】C6H6ClNO3S2 【 分 子 量 】239.70328 【元素组成】C 30.06% H 2.52% Cl 14.79% N 5.84% O 20.02% S 26.75% |
合成路线1
该中间体在本合成路线中的序号：(XIX)2) The reaction of 3-acetyl-2,5-dichlorothiophene (XIV) with benzyl chloride and thiourea in ethanol/water gives 3-acetyl-2-(benzylsulfanyl)-5-chlorothiophene (XV), which is treated with Cl2 gas in ethyl acetate yielding the expected sulfenyl chloride (XVI). The oxidation of (XVI) with H2O2/sodium tungstate and treatment with ammonia affords 3-acetyl-5-chlorothiophene-2-sulfonamide (XVII), which is brominated with pyridinium bromide perbromide (IV) giving the corresponding bromoacetyl derivative (XVIII). The reductive cyclization of (XVIII) with (+)-CDPB in THF affords the bicyclic 4(S)-hydroxy derivative (XIX), which is condensed with 3-methoxypropyl bromide (XX) by means of K2CO3 in DMSO giving 6-chloro-4(S)-hydroxy-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e] [1,2]thiazine (XXI). The sulfonation of (XXI) with BuLi, SO2 and hydroxylamine-O-sulfonic acid as before yields the sulfonamide (XIII), already obtained, which is finally treated with trimethyl ortoacetate and ethylamine in refluxing acetonitrile.
| 【1】 Graul, A.; Wroblewski, T.; Castañer, J.; Brinzolamide. Drugs Fut 1998, 23, 4, 365. |
| 【2】 Dean, W.D.; Deason, M.E.; Sproull, S.J.; Conrow, R.E.; DuPriest, M.T.; Zinke, P.W.; Dantanarayama, A.P.; Enantioselective synthesis of brinzolamide (AL-4862), a new topical carbonic anhydrase inhibitor. The "DCAT route" to thiophenesulfonamides. Org Process Res Dev 1999, 3, 2, 114. |
| 【3】 Dean, W.D.; Zinke, P.W.; Sproull, S.J.; Deason, M.E.; Conrow, R.E.; Dantanarayana, A.P. (Alcon Laboratories, Inc.); Preparation of carbonic anhydrase inhibitors. CA 2114877 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 17303 | pyridinium | C5H6N | 详情 | 详情 | |
| (XIII) | 17312 | (4S)-4-hydroxy-2-(3-methoxypropyl)-1,1-dioxo-1,2,3,4-tetrahydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide | 154127-42-1 | C10H16N2O6S3 | 详情 | 详情 |
| (XIV) | 17313 | 3-Acetyl-2,5-dichlorothiophene; 1-(2,5-dichloro-3-thienyl)-1-ethanone | 36157-40-1 | C6H4Cl2OS | 详情 | 详情 |
| (XV) | 17314 | 1-[5-chloro-2-[(4-methylphenyl)sulfanyl]-3-thienyl]-1-ethanone | 160982-09-2 | C13H11ClOS2 | 详情 | 详情 |
| (XVI) | 17315 | 3-acetyl-5-chloro-2-thiophenesulfenyl chloride | C6H4Cl2OS2 | 详情 | 详情 | |
| (XVII) | 17316 | 3-acetyl-5-chloro-2-thiophenesulfonamide | C6H6ClNO3S2 | 详情 | 详情 | |
| (XVIII) | 17317 | 3-(2-bromoacetyl)-5-chloro-2-thiophenesulfonamide | 160982-11-6 | C6H5BrClNO3S2 | 详情 | 详情 |
| (XIX) | 17318 | (4S)-6-chloro-4-hydroxy-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-1,1(2H)-dione | 160982-16-1 | C6H6ClNO3S2 | 详情 | 详情 |
| (XX) | 17319 | 1-bromo-3-methoxypropane; 3-bromopropyl methyl ether | C4H9BrO | 详情 | 详情 | |
| (XXI) | 17320 | (4S)-6-chloro-4-hydroxy-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-1,1(2H)-dione | C10H14ClNO4S2 | 详情 | 详情 |