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药物详细合成路线

Name Irbesartan;BMS-186295;SR-47436;Avapro;Karvea;Aprovel
Chemical Name 2-Butyl-1-[2-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]spiro[2-imidazoline-4,1-cyclopentane]-5-one
CAS 138402-11-6
Related CAS
Formula C25H28N6O
Structure
Formula Weight 428.54151
Stage 上市-1997
Company Sanofi-synthélabo (Originator), Bristol-Myers Squibb (Licensee), Shionogi (Licensee)
Activity/Mechanism CARDIOVASCULAR DRUGS, Diabetic Nephropathy, Agents for, ENDOCRINE DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Treatment of Diabetic Complications, Angiotensin AT1 Antagonists
Syn. Route 1
Route 1
the reaction of cyclopentanone (i) with sodium cyanide, nh3 and nh4cl in hot methanol/water gives 1-aminocyclopentanecarbonitrile (ii), which is partially hydrolyzed with concentrated h2so4 to the corresponding amide (iii). the acylation of (iii) with pentanoyl chloride (iv) by means of triethylamine in thf yields 1-(pentanamido)cyclopentane-1-carboxamide (v), which, without isolation, is cyclized by means of koh in refluxing methanol/water to afford 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (vi). this compound (vi) can also be obtained by cyclization of 1-aminocyclopentanecarboxylic acid ethyl ester (vii) with pentanimidic ethyl ester (viii) by means of acetic acid in refluxing xylene. the condensation of (vi) with 4-(bromomethyl)biphenyl-2-carbonitrile (ix) by means of nah in dmf gives 4-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl)biphenyl-2-carbonitrile (x). cyclization of (x) with tributyltin azide in refluxing xylene, followed by reaction with trityl chloride in dmf, affords 2-butyl-3-[2-[1-(triphenylmethyl)tetrazol-5-yl]biphenyl-4-ylmethyl]-1,3-diazaspiro[4.4]non-1-en-4-one (xi). finally, this compound is hydrolyzed to irbesartan with hcl in methanol/thf. the final cyclization of (x) with tributyltin azide or sodium azide also directly gives irbesartan.
List of intermediates No.
tert-butyl 4-[3-[(3r)-3-([[(1s)-3-methoxy-3-oxo-1-(3-pyridinyl)propyl]amino]carbonyl)piperidinyl]-3-oxopropyl]-1-piperidinecarboxylate (i)
1-(3,4-dichlorophenyl)cyclobutanecarbonitrile (ii)
1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-ethanone (iii)
2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-ethanone (iv)
1-[[amino(imino)methyl]sulfanyl]-3-(dimethylamino)propane (v)
n,n-dimethyl-n-(3-sulfanylpropyl)amine sodium salt (vi)
bis[(1r,2s,5r)-2-isopropyl-5-methylcyclohexyl] (1s,2s)-1,2-cyclopropanedicarboxylate (vii)
(1s,2s)-2-([[(1r,2s,5r)-2-isopropyl-5-methylcyclohexyl]oxy]carbonyl)cyclopropanecarboxylic acid (viii)
(1r,2s,5r)-2-isopropyl-5-methylcyclohexyl (1s,2s)-2-(chlorocarbonyl)cyclopropanecarboxylate (xi)
9-(iodomethyl)-9h-xanthene (x)
tert-butyl (3s)-2,6-dioxopiperidinylcarbamate (ix)
Reference 1:
    casas, a.; merlos, m.; castaner, j.; irbesartan. drugs fut 1997, 22, 5, 481.
Reference 2:
    bernhart, c.; breliere, j.-c.; clement, j.; nisato, d.; perreaut, p. (sanofi-synthélabo ); heterocyclic n-substd. derivs., their preparation and the pharmaceutical compsns. containing them. ep 0454511; fr 2659967; fr 2665702; jp 1992506222; jp 1998279566; us 5270317; wo 9114679 .
Reference 3:
    caron, a.; chantreux, d.; bouloumie, c. (sanofi-synthelabo ); method for the preparation of a tetrazole deriv. under two crystalline forms and novel crystalline form of this deriv. ep 0708103 .
Reference 4:
    bernhart, c.a.; perreaut, p.m.; ferrari, b.p.; et al.; a new series of imidazolones: highly specific and potent nonpeptide at1 angiotensin ii receptor antagonists. j med chem 1993, 36, 22, 3371-80.
Reference 5:
    bernhart, c.; clement, j.; ferrari, b.; et al.; spiro-dihydro-imidazolones, a new class of non-peptide angiotensin ii receptor antagonists. 12th int symp med chem (sept 13-17, basel) 1992, abst p-084.a..

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厄贝沙坦;英文名Irbesartan;BMS-186295;SR-47436;Avapro;Karvea;Aprovel;CAS[138402-11-6]

 
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