Brinzolamide, AL-4862, Azopt, -Drug Synthesis Database

【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 合成路线2

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.

参考文献中间体

【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.

参考文献中间体

【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

Drug NewChemical Entity Original Patent(1)