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【结 构 式】 
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【分子编号】17312 【品名】(4S)-4-hydroxy-2-(3-methoxypropyl)-1,1-dioxo-1,2,3,4-tetrahydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide 【CA登记号】154127-42-1 |
【 分 子 式 】C10H16N2O6S3 【 分 子 量 】356.44492 【元素组成】C 33.7% H 4.52% N 7.86% O 26.93% S 26.99% |
合成路线1
该中间体在本合成路线中的序号：(XIII)1) The reaction of 3-(2,5,5-trimethyl-1,3-dioxan-2-yl)thiophene (I) with butyllithium, SO2 and hydroxylamine-O-sulfonic acid in hexane/THF gives the corresponding sulfonamide (II), which is hydrolyzed with HCl yielding 3-acetylthiophene-2-sulfonamide (III). The cyclization of (III) with pyridinium bromide perbromide (IV) and NaBH4 affords 4-hydroxy-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine 1,1-dioxide (V), which is treated with 1,3-dibromopropane (VI) and NaH in DMF giving the corresponding 3-bromopropyl derivative (VII). The protection of the hydroxy group of (VII) with ethyl vinyl ether (VIII) in p-toluenesulfonic acid yields the ethoxyethyl ether (IX), which by reaction with sodium methoxide in refluxing methanol affords the 3-methoxypropyl derivative (X). The sulfonation of (X) with butyllithium, SO2 and hydroxylamine-O-sulfonic acid in hexane/THF gives the sulfonamide (XI), which is oxidized with CrO3/H2SO4 to yield 2-(3-methoxypropyl)-4-oxo-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide 1,1-dioxide (XII). The stereocontrolled reduction of (XII) with (+)-beta-chlorodiisopinocamphenylborane [(+)-CDPB] in THF affords the 4(S)-hydroxy derivative (XIII), which is finally treated first with p-toluenesulfonyl chloride/triethylamine and then with ethylamine in THF.
| 【1】 Graul, A.; Wroblewski, T.; Castañer, J.; Brinzolamide. Drugs Fut 1998, 23, 4, 365. |
| 【2】 Dean, T.R.; Chen, H.-H.; May, J.A. (Alcon Laboratories, Inc.); Thiophene sulfonamides useful as carbonic anhydrase inhibitors. EP 0527801; JP 1993508832; US 5153192; US 5240923; WO 9115486 . |
| 【3】 Dean, T.R.; Chen, H.-H.; May, J.A. (Alcon Laboratories, Inc.); Sulfonamides useful as carbonic anhydrase inhibitors. US 5378703 . |
| 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) | 17300 | 2,5,5-trimethyl-2-(3-thienyl)-1,3-dioxane | C11H16O2S | 详情 | 详情 | |
| (II) | 17301 | 3-(2,5,5-trimethyl-1,3-dioxan-2-yl)-2-thiophenesulfonamide | 138890-87-6 | C11H17NO4S2 | 详情 | 详情 |
| (III) | 17302 | 3-acetyl-2-thiophenesulfonamide | C6H7NO3S2 | 详情 | 详情 | |
| (IV) | 17303 | pyridinium | C5H6N | 详情 | 详情 | |
| (V) | 17304 | 4-hydroxy-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-1,1(2H)-dione | 138890-97-8 | C6H7NO3S2 | 详情 | 详情 |
| (VI) | 12581 | 1,3-Dibromopropane | 109-64-8 | C3H6Br2 | 详情 | 详情 |
| (VII) | 17306 | 2-(3-bromopropyl)-4-hydroxy-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-1,1(2H)-dione; (±)-2-(3-bromopropyl)-3,4-dihydro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide | 154127-37-4 | C9H12BrNO3S2 | 详情 | 详情 |
| (VIII) | 18762 | 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene | 109-92-2 | C4H8O | 详情 | 详情 |
| (IX) | 17308 | 2-(3-bromopropyl)-4-(1-ethoxyethoxy)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-1,1(2H)-dione | C13H20BrNO4S2 | 详情 | 详情 | |
| (X) | 17309 | 4-(1-ethoxyethoxy)-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-1,1(2H)-dione | 165116-92-7 | C14H23NO5S2 | 详情 | 详情 |
| (XI) | 17310 | 4-hydroxy-2-(3-methoxypropyl)-1,1-dioxo-1,2,3,4-tetrahydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide | 154127-41-0 | C10H16N2O6S3 | 详情 | 详情 |
| (XII) | 17311 | 2-(3-methoxypropyl)-1,1,4-trioxo-1,2,3,4-tetrahydro-2H-thieno[3,2-e][1,2]thiazine-6-sulfonamide | C10H14N2O6S3 | 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 |
合成路线2
该中间体在本合成路线中的序号：(XIII)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 |