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【结 构 式】

【药物名称】Brinzolamide, AL-4862, Azopt

【化学名称】4(R)-(Ethylamino)-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide

【CA登记号】138890-62-7

【 分 子 式 】C12H21N3O5S3

【 分 子 量 】383.51027

【开发单位】Alcon (Originator)

【药理作用】Antiglaucoma Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Carbonic Anhydrase Type II Inhibitors

合成路线1

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

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
Extended Information