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Name Dorzolamide hydrochloride;MK-507;L-671152;Trusopt
Chemical Name 4(S)-(Ethylamino)-6(S)-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide hydrochloride
CAS 130693-82-2
Related CAS
Formula C10H17ClN2O4S3
Structure
Formula Weight 360.90299
Stage 上市-1995
Company Banyu (Originator), Merck & Co. (Originator)
Activity/Mechanism Antiglaucoma Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Carbonic Anhydrase Inhibitors
Syn. Route 2
Route 1
reaction of (i) with acetic anhydride-sulfuric acid in methylene chloride provided the sulfonic acid in 98% yield. conversion to the sulfonyl chloride with phosphorous pentachloride in methylene chloride followed by treatment with aqueous ammonia gave the sulfonamide (ii). reduction of the carbonyl function with sodium borohydride and oxidation of the thiopyran sulfur with oxone(r) yielded (iv). the 4-hydroxy substituent was converted to the acetylamino functionality under ritter conditions. reduction of (v) with borane-dimethylsulfide complex yielded (vi) as a mixture of diasteriomers. chromatography on silica gel gave the trans-racemate, which was resolved into its individual enantiomers through the di-p-toluoyl-l-tartaric acid salt. the absolute configuration of the s,s-enantiomer, mk-507, was established by single crystal x-ray analysis.
List of intermediates No.
1-[2-hydroxy-5-(1h-1,2,3,4-tetraazol-5-yl)phenyl]-1-ethanone (i)
2-(3-methoxyphenyl)-2-methyl-1-propanamine; 2-(3-methoxyphenyl)-2-methylpropylamine (ii)
n-[2-(3-methoxyphenyl)-2-methylpropyl]-n,n-dimethylamine; 2-(3-methoxyphenyl)-n,n,2-trimethyl-1-propanamine (iii)
3-[2-(dimethylamino)-1,1-dimethylethyl]phenol (iv)
4-(4-morpholinyl)butyl isocyanate; 4-(4-isocyanatobutyl)morpholine (v)
4-(4-morpholinyl)-1-butanamine; 4-(4-morpholinyl)butylamine (vi)
Reference 1:
    baldwin, j.j.; ponticello, g.s.; christy, m.e. (merck & co., inc.); thienothiopyran sulfonamide derivs., pharmaceutical compsns. and use. au 8818387; ep 0296879; jp 1989100174; us 4797413; us 4863922 .
Reference 2:
    baldwing, j.j.; ponticello, g.s.; sugrue, m.f.; mk-507. drugs fut 1990, 15, 4, 350.
Reference 3:
    ponticello, g.s.; freedman, m.b.; habecker, c.n.; et al.; utilization of alpha,beta-unsaturated acids as michael acceptors for the synthesis of thieno[2,3-b]thiopyrans. j org chem 1988, 53, 1, 9-13.

Route 2
a new synthesis of mk-0507 has been described:the condensation of 3(r)-(tosyloxy)butyric acid methyl ester (i) with lithium 2-thienylmercaptide (ii) in formamide-thf gives 3(s)-(2-thienylthio)butyric acid methyl ester (iii), which is hydrolyzed with aqueous hcl to the corresponding free acid (iv). the intramolecular friedel-craftscyclization of (iv) with trifluoroacetic anhydride yields 6(s)-methyl-5,6-dihydro-4h-thieno[2,3-b]thiopyran-4-one (v), which is reduced with lialh4 in toluene to afford 4(r)-hydroxy-6(s)-methyl-5,6-dihydro-4h-thieno[2,3-b]thiopyran (vi). epimerization of (vi) with sulfuric acid gives the alcohol (vii) in a cis:trans ratio of 24:76%. oxidation of (vii) with h2o2 and sodium tungstate yields the 7,7-dioxide (viii; cis-trans mixture), which is acetylated with acetic anhydride to the acetate (ix). the reaction of (ix) with acetonitrile and sulfuric acid affords n-[6(s)-methyl-5,6-dihydro-4h-thieno[2,3-b]thiopyran-4-yl]acetamide 7,7-dioxide (x; cis-trans mixture), which is sulfonated with chlorosulfonic acid and then treated with socl2 to give 4-acetamide-6(s)-methyl-5,6-dihydro-4h-thieno[2,3-b]thiopyran-2-sulfonyl chloride 7,7-dioxide (xi; cis-trans mixture). the reaction of (xi) with concentrated aqueous nh4oh in thf yields the corresponding sulfonamide (xii), which by reduction with bh3-dimethylsulfide in thf affords 4-(ethylamino)-6(s)-methyl-5,6-dihydro-4h-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide (xiii; cis-trans mixture). finally, this mixture is treated with maleic acid in acetone and the resulting maleates are submitted to fractionated crystallization, giving the maleate of the (4s,6s)-isomer, which is treated first with nahco3 and then with hcl to give mk-0507; [alpha](25)589 -17.1 c (c 1, h2o).
List of intermediates No.
2-phenylacetyl chloride (i)
(2r)-3-(2-naphthyl)-2-[(2-phenylacetyl)amino]propionic acid (ii)
(2r)-2-[methyl(2-phenylacetyl)amino]-3-(2-naphthyl)propionic acid (iii)
(2r)-2-[methyl(2-phenylacetyl)amino]-3-(2-naphthyl)propanamide (iv)
n-[(1r)-1-amino-2-(2-naphthyl)ethyl]-n-methyl-2-phenylacetamide (v)
(1r,2s)-2-[(1h-indol-3-ylcarbonyl)amino]cyclohexanecarboxylic acid (vi)
propanal n-phenylhydrazone (vii)
benzenediazonium chloride (viii)
1-[(e)-2-phenyldiazenyl]-1-propanone n-phenylhydrazone (ix)
3-ethyl-1,2,4-benzotriazine (x)
(2r,3s,4s,5r)-2-[(1r)-4-amino-6-oxo-2,4-cyclohexadien-1-yl]-4-hydroxy-5-(hydroxymethyl)tetrahydro-3-furancarbonitrile (xi)
(9r)-2,2-dimethyl-6,12-dioxo-9-(palmitoyloxy)-5,7,11-trioxa-2-azonia-6lambda(5)-phosphaheptacosan-6-olate (xii)
1h-indol-5-yl methyl ether; 5-methoxy-1h-indole; 5-methoxyindole (xiii)
Reference 1:
    sohar, p.; grabowski, e.j.j.; lamanec, t.; blacklock, t.j.; butcher, j.w.; an enantioselective synthesis of the topically-active carbonic anhydrase inhibitor mk-0507 - 5,6-dihydro-(s)-4-(ethylamino)-(s)-6-methyl-4h-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride. j org chem 1993, 58, 7, 1672.

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名鹽酸多佐胺;英文名Dorzolamide hydrochloride;MK-507;L-671152;Trusopt;CAS[130693-82-2]

 
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