合成路线: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.
参考文献标题:Sulfonamides useful as carbonic anhydrase inhibitors
文献作者:Dean,T.R.; Chen,H.-H.; May,J.A.(Alcon Laboratories,Inc.)
参考来源:US 5378703
合成路线: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.
参考文献标题:Preparation of carbonic anhydrase inhibitors
文献作者:Dean,W.D.; Zinke,P.W.; Sproull,S.J.; Deason,M.E.; Conrow,R.E.; Dantanarayana,A.P.(Alcon Laboratories,Inc.)
参考来源:CA 2114877
合成路线: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.
合成路线: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.
参考文献标题:Brinzolamide
文献作者:Graul,A.; Wroblewski,T.; Castar,J.
参考来源:Drugs Fut 1998,23(4),365
合成路线: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.
参考文献标题:Enantioselective synthesis of brinzolamide (AL-4862),a new topical carbonic anhydrase inhibitor.The "DCAT route" to thiophenesulfonamides
文献作者:Dean,W.D.; Deason,M.E.; Sproull,S.J.; Conrow,R.E.; DuPriest,M.T.; Zinke,P.W.; Dantanarayama,A.P.
参考来源:Org Process Res Dev 1999,3(2),114
产品链接: CAS No. 138890-62-7››