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Name Brinzolamide;AL-4862;Azopt
Chemical Name 4(R)-(Ethylamino)-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide
CAS 138890-62-7
Related CAS
Formula C12H21N3O5S3
Structure
Formula Weight 383.51027
Stage 上市-1998
Company Alcon (Originator)
Activity/Mechanism Antiglaucoma Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Carbonic Anhydrase Type II Inhibitors
Syn. Route 2
Route 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.
List of intermediates No.
ethyl 2-[6-(4-chlorophenoxy)hexyl]acrylate (vi)
trimethylsulfoxonium iodide (i)
3-oxo-6alpha,7alpha,15alpha,16alpha-tetrahydro-17alpha-dicyclopropa-[6,7:15,16]pregn-4-ene-21,17-carbolactone (ii)
(4ar,4bs,6as,7as,8as,8bs,8cr)-2,9-dihydroxy-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7a,8,8a,8b,8c,9-tetradecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1h)-one (iii)
(4ar,4bs,6as,7as,8as,8bs,8cr)-9-hydroxy-4a,6a-dimethyl-7-oxo-1,2,3,4,4a,4b,5,6,6a,7,7a,8,8a,8b,8c,9-hexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-yl pivalate (iv)
(5ar,5bs,7as,8as,9as,9bs,9cr,10ar)-10-hydroxy-5a,7a-dimethyl-8-oxohexadecahydro-2h-cyclopropa[4,5]cyclopenta[1,2:1,2]phenanthro[8a,9-b]oxiren-3-yl pivalate (v)
(1ar,5ar,5bs,7as,8as,9as,9br,9cr,9dr)-1b,3-dihydroxy-5a,7a-dimethyloctadecahydro-8h-cyclopropa[4,5]cyclopenta[1,2-a]cyclopropa[l]phenanthren-8-one (vii)
(1ar,5ar,5bs,7as,8s,8as,9as,9br,9cr,9dr)-8-hydroxy-8-(3-hydroxypropyl)-5a,7a-dimethyl-1,1a,4,5,5a,5b,6,7,7a,8,8a,9,9a,9b,9c,9d-hexadecahydro-3h-cyclopropa[4,5]cyclopenta[1,2-a]cyclopropa[l]phenanthren-3-one (ix)
(7s,8r,9s,10r,13s,14s,15s)-3,7,15-trihydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17h-cyclopenta[a]phenanthren-17-one (x)
(2as,5as,10ar,10bs,12as,12bs,12cr)-8-hydroxy-4,4,10a,12a-tetramethyl-2,2a,5a,7,8,9,10,10a,10b,11,12,12a,12b,12c-tetradecahydro-1h-benzo[h]indeno[1,7,6-def][1,3]benzodioxepin-1-one (xi)
(8r,9s,10r,13s,14s,15s)-15-[(2,2-dimethylpropanoyl)oxy]-7-hydroxy-10,13-dimethyl-17-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl pivalate (xii)
(8r,9s,10r,13s,14s)-3-hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17h-cyclopenta[a]phenanthren-17-one (xiii)
1-[(2r,4s,5r)-4-(benzyloxy)-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-iodo-2,4(1h,3h)-pyrimidinedione (viii)
Reference 1:
    graul, a.; wroblewski, t.; casta?er, j.; brinzolamide. drugs fut 1998, 23, 4, 365.
Reference 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 .
Reference 3:
    dean, t.r.; chen, h.-h.; may, j.a. (alcon laboratories, inc.); sulfonamides useful as carbonic anhydrase inhibitors. us 5378703 .

Route 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.
List of intermediates No.
(4ar,4bs,6as,7as,8as,8bs,8cr)-9-hydroxy-4a,6a-dimethyl-7-oxo-1,2,3,4,4a,4b,5,6,6a,7,7a,8,8a,8b,8c,9-hexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-yl pivalate (iv)
(8r,9s,10r,13s,14s)-3-hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17h-cyclopenta[a]phenanthren-17-one (xiii)
(8r,9s,10r,13s,14s,15s)-3,7,15-trihydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17h-cyclopenta[a]phenanthren-17-one (xiv)
bis(4-chlorophenyl) disulfide; 1-chloro-4-[(4-chlorophenyl)disulfanyl]benzene (xv)
2-tetrahydro-1h-pyrrolizin-7(5h)-ylacetic acid (xvi)
4-(aminomethyl)cyclohexanecarbonyl chloride (xvii)
methyl 3-(4-[[4-(aminomethyl)cyclohexyl]carbonyl]phenyl)propanoate (xviii)
3-(4-[[4-(aminomethyl)cyclohexyl]carbonyl]phenyl)propionic acid (xix)
(3r,4s,5s,6r,8r,9r,10e,12e,15r)-5-[3,6-dideoxy-4-o-(2,6-dideoxy-3-c-methyl-3-o-propionyl-alpha-l-allopyranosyl)-3-(dimethylamino)-beta-d-glucopyranosyloxy]-6-(formylmethyl)-3,9-dihydroxy-4-methoxy-8-methylhexadeca-10,12-dieno-15-lctone (xx)
(3r,4s,5s,6r,8r,9r,10e,12e,15r)-5-[2-o-acetyl-3,6-dideoxy-4-o-(2,6-dideoxy-3-c-methyl-3-o-propionyl-alpha-l-allopyranosyl)-3-(dimethylamino)-beta-d-glucopyranosyloxy]-6-(formylmethyl)-3,9-dihydroxy-4-methoxy-8-methylhexadeca-10,12-dieno-15-lctone (xxi)
Reference 1:
    graul, a.; wroblewski, t.; casta?er, j.; brinzolamide. drugs fut 1998, 23, 4, 365.
Reference 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.
Reference 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 .

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名布林佐胺;英文名Brinzolamide;AL-4862;Azopt;CAS[138890-62-7]

 
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