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药物详细合成路线

Name Dofetilide;UK-68798;Tikosyn;Xelide
Chemical Name N-[4-[2-[N-[2-[4-(Methanesulfonamido)phenyl]ethyl]-N-methylamino]ethoxy]phenyl]methanesulfonamide
CAS 115256-11-6
Related CAS
Formula C19H27N3O5S2
Structure
Formula Weight 441.57214
Stage 上市-2000
Company Pfizer (Originator)
Activity/Mechanism Antiarrhythmic Drugs, CARDIOVASCULAR DRUGS, Potassium Channel Blockers
Syn. Route 1
Route 1
this compound can be prepared by several related ways:1) the condensation of n-methyl-2-(4-nitrophenyl)ethylamine (i) with 4-(2-chloroethoxy)nitrobenzene (ii) by means of nai and k2co3 in refluxing acetonitrile gives 1-(4-nitrophenoxy)-5-(4-nitrophenyl)-3-methyl-3-azapentane (iii), which is reduced with h2 over pd/c in ethanol, yielding the corresponding diamino derivative (iv). finally, this compound is acylated with methanesulfonyl anhydride in dichloromethane.2) the condensation of (i) with n-[4-(2-chloroethoxy)phenyl]methanesulfonamide (v) with nai and k2co3 as before gives 1-[4-(methanesulfonamide)phenoxy]-3-methyl-5-(4-nitrophenyl)-3-azapentane (vi), which is reduced with h2 over pd/c as before, yielding the corresponding amino derivative (vii). finally, this compound is acylated with methanesulfonyl anhydride as usual.3) the condensation of (ii) with n-[4-[2-(methylamino)ethyl]phenyl]methanesulfonamide (viii) with nai and k2co3 as usual gives 1-[4-(methanesulfonamido)phenyl]-3-methyl-5-(4-nitrophenoxy)-3-azapentane (ix), which is reduced with h2 and rani to the corresponding amino derivative (x). finally, this compound is acylated with methanesulfonyl chloride and pyridine.4) by condensation of n-[4-[2-(methanesulfonyloxy)ethyl]phenyl]methanesulfonamide (xi) with n-[4-[2-(methylamino)ethoxy]phenyl]methanesulfonamide (xii) in refluxing ethanol.5) by condensation of (v) with (viii) by means of nahco3.
List of intermediates No.
(e)-n-[(1r,2r)-2-hydroxy-1-methyl-2-phenylethyl]-n,6-dimethyl-4-heptenamide (i)
1-(bromomethyl)-4-fluorobenzene (ii)
(2s,4e)-2-(4-fluorobenzyl)-n-[(1r,2r)-2-hydroxy-1-methyl-2-phenylethyl]-n,6-dimethyl-4-heptenamide (iii)
(3r,5s)-5-[(1r)-1-bromo-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3h)-furanone (iv)
(3r,5s)-5-[(1s)-1-azido-2-methylpropyl]-3-(4-fluorobenzyl)dihydro-2(3h)-furanone (v)
tert-butyl (1s)-1-[(2s,4r)-4-(4-fluorobenzyl)-5-oxotetrahydro-2-furanyl]-2-methylpropylcarbamate (vi)
(2r,4s,5s)-5-[(tert-butoxycarbonyl)amino]-2-(4-fluorobenzyl)-4-hydroxy-6-methylheptanoic acid (vii)
(2r,5s)-5-[(tert-butoxycarbonyl)amino]-2-(4-fluorobenzyl)-6-methyl-4-oxoheptanoic acid (viii)
ethyl (e,4s)-4-amino-7-oxo-7-(tritylamino)-2-heptenoate (ix)
ethyl (e,4s)-4-[[(2r,5s)-5-[(tert-butoxycarbonyl)amino]-2-(4-fluorobenzyl)-6-methyl-4-oxoheptanoyl]amino]-7-oxo-7-(tritylamino)-2-heptenoate (x)
ethyl (e,4s)-4-[[(2r,5s)-5-amino-2-(4-fluorobenzyl)-6-methyl-4-oxoheptanoyl]amino]-7-oxo-7-(tritylamino)-2-heptenoate (xi)
1-[(chlorocarbonyl)sulfanyl]cyclopentane (xii)
Reference 1:
    arrowsmith, j.e.; cross, p.e.; thomas, g.n. (pfizer inc.); n-substituted p-aminoethylsulphonanilides as antiarrhythmic agents, and intermediates therefor. ep 0245997; jp 1987267250; us 4959366; us 5079248 .
Reference 2:
    cross, p.e.; thomas, g.n.; gwilt, m.; arrowsmith, j.e.; burges, r.a.; selective class iii antiarrhythmic agents. 1. bis(arylalkyl)amines. j med chem 1990, 33, 4, 1151-5.
Reference 3:
    castaner, j.; prous, j.; uk-68,798. drugs fut 1991, 16, 6, 521.

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多非利特;英文名Dofetilide;UK-68798;Tikosyn;Xelide;CAS[115256-11-6]

 
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