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 Fenoldopam mesilate;SK&F-82526J;Corlopam
Chemical Name 6-Chloro-7,8-dihydroxy-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine methanesulfonate;6-Chloro-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol methanesulfonate
CAS 67227-57-0
Related CAS 67287-54-1 (HBr salt), 67227-56-9 (racemic; free base)
Formula C17H20ClNO6S
Structure
Formula Weight 401.86905
Stage 上市-1998
Company GlaxoSmithKline (Originator), Abbott (Not Determined), Elan (Licensee), Neurex (Licensee)
Activity/Mechanism CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Dopamine D1 Agonists
Syn. Route 5
Route 1
the condensation of 2-chloro-3,4-dimethoxyphenylethylamine (i) with 4-methoxystyrene oxide (ii) in refluxing thf gives the hydroxy phenylethylamine (iii). the yield of this reaction is only 19%. in a better sequence (i) is heated with methyl 4-methoxymandelate (iv) to give the mandelamide (v), which is then reduced without purification by b2h6 in thf to give (iii). the latter is cyclized by treatment with trifluoroacetic acid - sulfuric acid yielding 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-(1h)-3-benzazepine (vi). finally, this compound is demethylated by treatment with bbr3 in methylene chloride and treated with methanesulfonic acid.
List of intermediates No.
1,8-dibenzyl 2-methyl (2r,3as,8as)-2-methyl-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate (iv)
benzyl 3-((2r)-2-[[(benzyloxy)carbonyl]amino]-3-methoxy-2-methyl-3-oxopropyl)-1h-indole-1-carboxylate (v)
methyl (2r)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1h-indol-3-yl)-2-methylpropanoate (iii)
(2r)-2-[[(benzyloxy)carbonyl]amino]-3-(1h-indol-3-yl)propionic acid (ii)
n-methyl-n-phenylurea (vi)
methyl 2-indanecarboxylate (i)
Reference 1:
    hieble, j.p.; wilson iii, j.w.; weinstock, j.; the chemistry and pharmacology of 3-benzazepines derivatives. drugs fut 1985, 10, 8, 645.
Reference 2:
    weinstock, j.; method for 6-bromination of 1-phenyl-2,3,4,5-tetrahydro-1h-3-benzazepine compounds. be 0860774; dd 2751258; de 133563; fr 2371430; jp 53063335; nl 7712567; us 4160765; za 7705910 .
Reference 3:
    kuo, g.y.; holden, k.g.; tobia, a.j.; hahn, r.a.; sarau, h.m.; ladd, d.l.; ridley, p.t.; wilson, j.w.; setler, p.e.; bush, c.k.; yim, n.c.f.; pfieffer, f.r.; wardell, j.r.; weinstock, j.; separation of potent central and renal dopamine agonist activity in substituted 6-chloro-2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1h-3-benzazepines. j med chem 1980, 23, 9, 973-975.
Reference 4:
    weinstock, j. (smithkline beecham plc); benz-tetrasubstituted 1-phenyl-2,3,4,5-tetrahydro-1h-3-benzazepines. ep 0004794; jp 54135787; jp 63065663b; us 4171359 .
Reference 5:
    castaner, j.; serradell, m.n.; blancafort, p.; skf-82,526-j. drugs fut 1982, 7, 1, 32.

Route 2
the bromination of 4-methoxystyrene (i) with br2 gives the alpha,beta-dibromo derivative (ii), which by selective debromination with potassium tert-butoxide yields the tert-butyl ether (iii). the condensation of (iii) with 2-(2-chloro-3,4-dimethoxyphenyl)ethylamine (iv) affords the secondary amine (v), which is deprotected with h2so4 to provide the substituted ethanolamine (vi). the cyclization of (vi) by means of ms-oh and trifluoroacetic acid gives the 3-benzazepine (vii), which is finally demethylated with bbr3 and treated with methanesulfonic acid to afford the target mesylate.
List of intermediates No.
methyl (2r)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1h-indol-3-yl)-2-methylpropanoate (vi)
n-methyl-n-phenylurea (vii)
methyl 2-indanecarboxylate (iv)
3-fluoro-2-naphthoyl azide (i)
3-fluoro-2-naphthalenamine; 3-fluoro-2-naphthylamine (ii)
1-(3-fluoro-2-naphthyl)hydrazine (iii)
ethyl 1-(3-fluoro-2-naphthyl)-3-methyl-1h-pyrazole-5-carboxylate (v)
Reference 1:
    hieble, j.p.; wilson iii, j.w.; weinstock, j.; the chemistry and pharmacology of 3-benzazepines derivatives. drugs fut 1985, 10, 8, 645.
Reference 2:
    us 4321195 .

Route 3
the bromination of labeled 4-methoxyacetophenone (i) with cubr2 gives 4-methoxyphenacyl bromide (ii), which is reduced with nabh4, yielding the carbinol (iii). the protection of (iii) with dhp affords the tetrahydropyranyl ether (iv), which is condensed with 2-(2-chloro-3,4-dimethoxyphenyl)ethylamine (v) and acidified to provide the aminoalcohol (vi). the cyclization of (vi) with msoh and trifluoroacetic acid furnishes labeled 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1h-3-benzazepine (vii), which is finally demethylated with bbr3 and msoh.
List of intermediates No.
3,5-dimethoxybenzoic acid (i)
[6-[(2s)-2-hydroxypropyl]-1,3-benzodioxol-5-yl](4-nitrophenyl)methanone n-(2-pyridinyl)hydrazone (ii)
methyl (2r)-2-[[(1-benzofuran-2-ylmethoxy)carbonyl]amino]-3-(1h-indol-3-yl)-2-methylpropanoate (vi)
n-methyl-n-phenylurea (vii)
methyl 2-indanecarboxylate (v)
n-{2-[(tert-butylamino)sulfonyl][1,1-biphenyl]-4-yl}-1-(3-fluoro-2-naphthyl)-3-methyl-1h-pyrazole-5-carboxamide (iii)
methyl 7-hydroxy-2,2-dimethyl-2h-chromene-5-carboxylate (iv)
2-bromo-3-methyl-1-pyridiniumolate (i)
6-bromo-5-methyl-2-pyridinecarbonitrile (ii)
6-bromo-5-(bromomethyl)-2-pyridinecarbonitrile (iii)
1-methyl-5-(triethylsilyl)-1h-imidazole (iv)
4-[hydroxy(1-methyl-1h-imidazol-5-yl)methyl]benzonitrile (vi)
6-bromo-5-{[(4-cyanophenyl)(1-methyl-1h-imidazol-5-yl)methoxy]methyl}-2-pyridinecarbonitrile (vii)
Reference 1:
    hieble, j.p.; wilson iii, j.w.; weinstock, j.; the chemistry and pharmacology of 3-benzazepines derivatives. drugs fut 1985, 10, 8, 645.

Route 4
the optical resolution of the racemic 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine (i) (+)- or (-)-dibenzoyltartaric acid gives the corresponding (r)-isomer (ii), which is n-demethylated by means of brcn to yield 6-chloro-7,8-dimethoxy-1(r)-(4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine (iii). finally, this compound is fully demethylated by treatment with bbr3. the optical resolution can also be performed by treatment of racemic (iii) with (+)- or (-)-dibenzoyltartaric acid.
List of intermediates No.
methyl 5-hydroxy-2,2-dimethyl-2h-chromene-7-carboxylate (i)
sodium 2-iodobenzoate (ii)
5-(hydroxymethyl)-2,2-dimethyl-2h-chromen-7-ol (iii)
Reference 1:
    hieble, j.p.; wilson iii, j.w.; weinstock, j.; the chemistry and pharmacology of 3-benzazepines derivatives. drugs fut 1985, 10, 8, 645.
Reference 2:
    webb, r.l.; horodniak, j.w.; dandridge, p.a.; sarau, h.m.; setler, p.e.; weinstock, j.; ackerman, d.m.; kaiser, c.; matz, e.d.; stereoselectivity of some new dopamine receptor agonists. acta pharm suec 1983, 2, 132-150.

Route 5
the optical resolution of the racemic 6-chloro-7,8-dimethoxy-1-(4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine (i) (+)- or (-)-dibenzoyltartaric acid gives the corresponding (s)-isomer (ii), which is n-demethylated by means of brcn to yield 6-chloro-7,8-dimethoxy-1(s)-(4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine (iii). finally, this compound is fully demethylated by treatment with bbr3. the optical resolution can also be performed by treatment of racemic (iii) with (+)- or (-)-dibenzoyltartaric acid.
List of intermediates No.
methyl 5-hydroxy-2,2-dimethyl-2h-chromene-7-carboxylate (i)
2-{[5-(hydroxymethyl)-2,2-dimethyl-2h-chromen-7-yl]oxy}benzoic acid (ii)
(2,2-dimethyl-6-oxo-2h,6h-pyrano[3,2-b]xanthen-5-yl)methyl 2,2,2-trifluoroacetate (iii)
Reference 1:
    webb, r.l.; horodniak, j.w.; dandridge, p.a.; sarau, h.m.; setler, p.e.; weinstock, j.; ackerman, d.m.; kaiser, c.; matz, e.d.; stereoselectivity of some new dopamine receptor agonists. acta pharm suec 1983, 2, 132-150.
Reference 2:
    hieble, j.p.; wilson iii, j.w.; weinstock, j.; the chemistry and pharmacology of 3-benzazepines derivatives. drugs fut 1985, 10, 8, 645.

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甲磺酸非诺多泮;英文名Fenoldopam mesilate;SK&F-82526J;Corlopam;CAS[67227-57-0]

 
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
北京富安凯科技有限公司
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
山东地区顺酐市场行情整理
华南地区顺酐市场行情整理
华北地区邻苯市场行情暂稳
华北地区顺酐市场行情整理
华东地区BDO市场弱势整理
华东地区邻苯市场行情暂稳
东北地区邻苯市场行情暂稳
江苏地区顺酐市场行情整理
山东地区辛醇市场保持稳定
山东地区木薯乙醇市场变动不大
华东地区丁二烯市场价格盘整
华北地区丁二烯市场价格盘整
华北及山东地区环己酮市场稳定
江西地区二氯甲烷价格暂稳
丙烯酸丁酯价格急涨
河南地区醋酸价格
河北地区醋酸价格
华北地区醋酸价格
山东地区醋酸价格
华南地区苯酚市场稳定
 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