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Name Ramatroban;Bay-u-3405;Baynas
Chemical Name (+)-3-[3(R)-(4-Fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]propionic acid
CAS 116649-85-5
Related CAS
Formula C21H21FN2O4S
Structure
Formula Weight 416.47492
Stage 上市-2000
Company Bayer (Originator), Kyorin (Licensee)
Activity/Mechanism Atopic Dermatitis, Agents for, DERMATOLOGIC DRUGS, Drugs for Allergic Rhinitis, RESPIRATORY DRUGS, Treatment of Upper Respiratory Tract Disorders, MCP-1 Expression Inhibitors, Prostanoid TP (Thromboxane A2) Antagonists
Syn. Route 2
Route 1
the synthesis of bay u 3405 was carried out as follows:reductive amination of 3-oxo-1,2,3,4-tetrahydrocarbazole (i) with s-phenethylamine (ii) afforded a mixture of diastereomeric amines, of which the desired isomer (iii) crystallized in high diastereomeric purity as the hydrogensulfate. cleavage of the phenethyl group by transfer hydrogenolysis with amminium formate and palladium on charcoal yielded the enantiomerically pure (3r)-3-amino-1,2,3,4-tetrahydrocarbazole (iv). sulfonylation of (iv) with 4-fluorobenzenesulfonyl chloride (v) to the sulfonamide (vi) followed by addition of acrylonitrile and subsequent hydrolysis gave bay u 3405.
List of intermediates No.
10-chloro-9-fluoro-1,7-dioxo-2,3-dihydro-1h,7h-1lambda(4)-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxylic acid (i)
methyl (3ar,4r,5s)-4-(acetoxy)-3a-ethyl-9-[(13s)-17-ethyl-13-(methoxycarbonyl)-1,11-diazatetracyclo[13.3.1.0(4,12).0(5,10)]nonadeca-4(12),5,7,9,16-pentaen-13-yl]-5-hydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1h-indolizino[8,1-cd]car (iii)
(13s)-13-[(3ar,4r,5s)-4-(acetoxy)-3a-ethyl-5-hydroxy-8-methoxy-5-(methoxycarbonyl)-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1h-indolizino[8,1-cd]carbazol-9-yl]-17-ethyl-13-(methoxycarbonyl)-11-aza-1-azoniatetracyclo[13.3.1.0(4,12).0(5,10)]nonadeca (iv)
(13s)-13-[(3ar,4r,5s)-4-(acetoxy)-3a-ethyl-5-hydroxy-8-methoxy-5-(methoxycarbonyl)-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1h-indolizino[8,1-cd]carbazol-9-yl]-17-ethyl-13-(methoxycarbonyl)-1-[(2,2,2-trifluoroacetyl)oxy]-11-aza-1-azoniatetracyclo[ (v)
3-[(2s)-2-[(3ar,4r,5s)-4-(acetoxy)-3a-ethyl-5-hydroxy-8-methoxy-5-(methoxycarbonyl)-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1h-indolizino[8,1-cd]carbazol-9-yl]-3-methoxy-2-(3-methylene-3h-indol-2-yl)-3-oxopropyl]-5-ethyl-1-methylene-1,2,3,6-tetra (vi)
[(3r,4s,5s,6s)-1,4-dimethyl-3-[(e)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]non-6-yl]methanol (ii)
Reference 1:
    raz, a.; needleman, p.; minkes, m.; thromboxanes: selective biosynthesis and distinct biological properties. science 1976, 193, 163-5.
Reference 2:
    svensson, j.; hamberg, m.; samuelsson, b.; thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. proc natl acad sci usa 1975, 72, 8, 2994-8.
Reference 3:
    gardiner, p.j.; boberg, m.; fiedler, v.b.; perzborn, e.; boshagen, h.; buhner, k.; muller, u.; rosentreter, u.; seuter, f.; weber, h.; norman, p.; ritter, w.; bay u 3405. drugs fut 1991, 16, 8, 701.

Route 2
the synthesis of [14c]-labeled bay-u-3405 by two closely related ways has been described:1) [14c]-labeled aniline (i) is diazotized and reduced with sodium sulfite, yielding the labeled hydrazine (ii), which is condensed with the monoketal of cyclohexane-1,4-dione (iii) under fishers indole synthesis (zncl2) to afford the tetrahydrocarbazole (iv). the hydrolysis of (iv) with hcl in thf/water yields 1,2,3,4-tetrahydrocarbazol-3-one (v), which is submitted to a reductive condensation with (s)-1-phenylethylamine (vi) by means of tetrabutylammonium borohydride, yielding preferentially the secondary amine (vii), which, after purification, is dealkylated with ammonium formate and pd/c to afford 1,2,3,4-tetrahydrocarbazole-3(r)-amine (viii). the acylation of (viii) with 4-fluorophenylsulfonyl chloride (ix) gives the corresponding sulfonamide (x), which is condensed with acrylonitrile by means of nah, yielding 3-[3(r)-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]pro pionitrile (xi). finally, this compound is hydrolyzed in the usual way.2) the condensation of the sulfonamide (x) with methyl acrylate by means of nah as before gives 3-[3(r)-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]propionic acid methyl ester (xii), which is finally hydrolyzed in the usual way.
List of intermediates No.
3,4-diphenyl-1h-pyrazole (iii)
5-[4-hydroxy-2,3,5-trimethyl-6-(3-oxopentyl)phenoxy]-2,2-dimethylpentanoic acid (ii)
10-chloro-9-fluoro-1,7-dioxo-2,3-dihydro-1h,7h-1lambda(4)-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxylic acid (v)
methyl (3ar,4r,5s)-4-(acetoxy)-3a-ethyl-9-[(13s)-17-ethyl-13-(methoxycarbonyl)-1,11-diazatetracyclo[13.3.1.0(4,12).0(5,10)]nonadeca-4(12),5,7,9,16-pentaen-13-yl]-5-hydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1h-indolizino[8,1-cd]car (vii)
(13s)-13-[(3ar,4r,5s)-4-(acetoxy)-3a-ethyl-5-hydroxy-8-methoxy-5-(methoxycarbonyl)-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1h-indolizino[8,1-cd]carbazol-9-yl]-17-ethyl-13-(methoxycarbonyl)-11-aza-1-azoniatetracyclo[13.3.1.0(4,12).0(5,10)]nonadeca (viii)
(13s)-13-[(3ar,4r,5s)-4-(acetoxy)-3a-ethyl-5-hydroxy-8-methoxy-5-(methoxycarbonyl)-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1h-indolizino[8,1-cd]carbazol-9-yl]-17-ethyl-13-(methoxycarbonyl)-1-[(2,2,2-trifluoroacetyl)oxy]-11-aza-1-azoniatetracyclo[ (ix)
3-[(2s)-2-[(3ar,4r,5s)-4-(acetoxy)-3a-ethyl-5-hydroxy-8-methoxy-5-(methoxycarbonyl)-6-methyl-3a,4,5,5a,6,11,12,13a-octahydro-1h-indolizino[8,1-cd]carbazol-9-yl]-3-methoxy-2-(3-methylene-3h-indol-2-yl)-3-oxopropyl]-5-ethyl-1-methylene-1,2,3,6-tetra (x)
1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (i)
1-(2-chloroethyl)-2-oxo-1-hydrazinecarbonyl azide (iv)
[(4ar,5as,10bs,10cs)-3-methyl-1,4a,5,5a,10b,10c-hexahydro[1,3]dioxino[5,4:3,4]cyclopenta[1,2-b][1]benzofuran-7-yl]methanol (xi)
(4ar,5as,10bs,10cs)-7-(chloromethyl)-3-methyl-1,4a,5,5a,10b,10c-hexahydro[1,3]dioxino[5,4:3,4]cyclopenta[1,2-b][1]benzofuran (xii)
[(3r,4s,5s,6s)-1,4-dimethyl-3-[(e)-2-(tributylstannyl)ethenyl]-2,9-dioxabicyclo[3.3.1]non-6-yl]methanol (vi)
1-propylpiperazine (i)
(r)-2-hydroxy-4-phenylbutyric acid ethyl ester; ethyl (r)-2-hydroxy-4-phenylbutyrate (ii)
sodium (1e,4e)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-oxo-1,4-pentadien-1-olate (iv)
(e)-5,5-dimethoxy-1-(4-methoxy-2,3,6-trimethylphenyl)-1-penten-3-one (v)
2-[(1e)-3-(2,2-dimethoxyethyl)-1,3-butadienyl]-5-methoxy-1,3,4-trimethylbenzene; 4-[(1e)-3-(2,2-dimethoxyethyl)-1,3-butadienyl]-2,3,5-trimethylphenyl methyl ether (vii)
(e)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methylene-4-pentenal (viii)
(2e,4e)-5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-2,4-pentadienal (x)
(2e,4e,6e,8e)-2-(methoxycarbonyl)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid (xi)
Reference 1:
    pleiss, u.; radtke, m.; rosentreter, u.; boberg, m.; synthesis of (+)-(3r)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-[5,6,7,8,12,13-u-c-14]carbazolepropanoic acid, [c-14]bay u 3405. j label compd radiopharm 1994, 34, 12, 1207.

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雷马曲班;英文名Ramatroban;Bay-u-3405;Baynas;CAS[116649-85-5]

 
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