有机化学人才网 | 最新人才 | 最新职位 | 技术交易 | 药物合成 |
   
全站搜索: |
  您当前位置:网站首页 >> 药物合成路线图解
 

药物详细合成路线

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]

 
推荐VIP企业
无锡景耀生物科技有限公司
杭州卢普生物科技有限公司
宁波赛伦化工有限公司
苏州昊赛生物科技有限公司
北京嘉盛扬医药科技有限公司
上海泽涵生物医药科技有限公司
河北固安三利化工公司
郑州凯普瑞生物技术有限公司
上海药谷药业有限公司
兰州康寓信生物科技有限公司
湖北朗昕生化药业有限公司
武汉福鑫化工有限公司
嘉兴市英南化工有限公司
苏州迪飞医药科技有限公司
唐山盛源泽兴化工有限公司
上海盛中医药化工有限公司
连云港天和化学有限公司
南京晨瑞医药科技有限公司
南京苏如化工有限公司
常州瑞盛化工有限公司
热门文章
未来已至,只是分布不均
中农立华原药价格指数20200
中化助力新疆“大国棉仓”升级!
农业农村部种植业管理司:这10
红太阳全球首家拥有敌草快二氯盐
先正达在意大利推出杀虫剂Min
国内创制的植物免疫激活抗病毒新
近期我国农药制造业十大规模项目
解读:新化学物质环境管理登记办
拉美非法农药贸易有增无减,各国
“禾本绿色农药研究院”被认定为
坚决禁止不必要环保执法! 违规
先正达以行动助力可持续农业!“
国际农药分析协作委员会的农药与
先正达将在阿根廷分销Rizob
非法倾倒生产溴虫腈产生的废酸液
拜耳作物科学事业部2020一季
Amoeba与拜耳签署关于生物
透过颖泰生物2019年报看行业
主打植物生长调节剂和水溶性肥的
 友情链接
有机化学人才网  
首页 | 广告服务 | 建站服务 | 关于我们 | 联系我们 | 版权声明