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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]

 
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