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药物详细合成路线

Name Valsartan;VAL-489;CGP-48933;Nisis;Kalpress;Vals;Miten;Varexan;Provas;Valpression;Tareg;Diovan
Chemical Name N-Pentanoyl-N-[2-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-L-valine
CAS 137862-53-4
Related CAS
Formula C24H29N5O3
Structure
Formula Weight 435.53043
Stage 上市-1996
Company Novartis (Originator), Esteve (Licensee), Ipsen (Licensee), Lacer (Licensee), Menarini (Licensee), Schwarz (Licensee)
Activity/Mechanism Acute Myocardial Infarction, Treatment of, Cardiovascular Diseases (Not Specified), CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Angiotensin AT1 Antagonists
Syn. Route 3
Route 1
this compound has been obtained by two related ways:1) the hydrolysis of 4-(bromomethyl)biphenyl-2-carbonitrile (i) with naoac in refluxing acetic acid gives the corresponding carbinol (ii), which is oxidized with oxalyl chloride in dmso/dichloromethane yielding the aldehyde (iii). the reductocondensation of (iii) with l-valine methyl ester (iv) by means of nabh4cn in thf affords the n-alkylated valine (v), which is acylated with pentanoyl chloride (vi) and tea in dichloromethane providing the pentanamide (vii). the reaction of the cn group of (vii) with tributyltin azide in refluxing xylene gives the tetrazol derivative (viii). finally, the ester group of (viii) is hydrolyzed with naoh to furnish the target compound.2) l-valine methyl ester (iv) can be condensed directly with the bromo-methyl derivative (i) by means of diea in dichloromethane giving the n-alkylated valine (v) already reported.
List of intermediates No.
2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-ethanone (vi)
tert-butyl (3s)-2,6-dioxopiperidinylcarbamate (i)
1-(tert-butyl) 4-[6-(7-chloro[1,8]naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5h-[1,4]dithiino[2,3-c]pyrrol-5-yl] 1,4-piperazinedicarboxylate (iv)
(2r)-3-(2-aminoanilino)-2-[(tert-butoxycarbonyl)amino]propionic acid (ii)
tert-butyl (3r)-2-oxo-2,3,4,5-tetrahydro-1h-1,5-benzodiazepin-3-ylcarbamate (iii)
tert-butyl (3r)-1-(2-cyclohexen-1-yl)-4-oxo-2,3,4,5-tetrahydro-1h-1,5-benzodiazepin-3-ylcarbamate (v)
tert-butyl (3r)-1-cyclohexyl-4-oxo-2,3,4,5-tetrahydro-1h-1,5-benzodiazepin-3-ylcarbamate (vii)
(3r)-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2h-1,5-benzodiazepin-2-one (viii)
Reference 1:
    buhlmayer, p.; ostermayer, f.; schmidlin, t. (novartis ag); acyl cpds.. ep 0443983; jp 1992235149; us 5399578; us 5965592 .
Reference 2:
    buhlmayer, p.; et al.; valsartan, a potent, orally active angiotensin ii antagonist developed from the structurally new amino acid series. bioorg med chem lett 1994, 4, 1, 29.

Route 2
the reaction of 2-bromo-4-methylbiphenyl (i) with 14c labeled cuprous cyanide in refluxing dmf gives 4-methylbiphenyl-2-carbonitrile (ii), which is brominated with nbs and aibn in refluxing ccl4 to yield the bromomethyl derivative (iii). the condensation of (iii) with l-valine benzyl ester (iv) by means of diea in hot dmf affords the n-substituted valine (v), which is acylated with pentanoyl chloride (vi) and diea to provide the n-acylated valine (vii). the cyclization of the cyano group of (vii) with tributyltin azide at 140 c furnishes the tetrazol derivative (viii) which is finally debenzylated by hydrogenation with h2 over pd/c in dioxane.
List of intermediates No.
(2s,4r)-2-[(tert-butoxycarbonyl)amino]-4-methyloctanoic acid (ii)
2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-ethanone (vi)
tert-butyl (3s)-2,6-dioxopiperidinylcarbamate (iii)
dimethyl {[(4,7-dichloro-1-benzothiophen-2-yl)sulfonyl]amino}methylphosphonate (i)
{[(4,7-dichloro-1-benzothiophen-2-yl)sulfonyl]amino}methylphosphonic acid (iv)
2-amino-4,5-dimethoxybenzoic acid methyl ester; methyl 2-amino-4,5-dimethoxybenzoate; methyl 4,5-dimethoxyanthranilate (v)
4-amino-3-chlorophenol (vii)
2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline; 2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenylamine (viii)
2-[2-(4-ethyl-6-quinazolinyl)ethynyl]-4-methoxyphenyl methyl ether; 6-[2-(2,5-dimethoxyphenyl)ethynyl]-4-ethylquinazoline (ii)
allyl (5r,6s)-6-((1r)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(hydroxymethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (iii)
allyl (5r,6s)-6-((1r)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-{[(methylsulfonyl)oxy]methyl}-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (v)
allyl (5r,6s)-3-{[(2-amino-2-oxoethyl)(methyl)amino]methyl}-6-((1r)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (vii)
allyl (5r,6s)-3-{[(2-amino-2-oxoethyl)(methyl)amino]methyl}-6-[(1r)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (viii)
Reference 1:
    moenius, t.; et al.; carbon-14 labelling of diovan(tm) in its valine-moiety. j label compd radiopharm 2000, 43, 13, 1245.

Route 3
the reaction of 14c labeled chiral bromoacetyl sultam (i) with benzophenoneimine (ii) in hot acetonitrile gives the substituted benzophenoneimine (iii), which is estereoselectively alkylated with isopropyl iodide (iv) and n-buli in thf yielding the labeled l-valine derivative (v). the hydrolysis of (v) with hcl in thf affords the valine derivative (vi) with a free amino group that is protected with boc2o in thf providing the carbamate (vii). the basic hydrolysis of (vii) with lioh in thf gives the labeled n-(tert-butoxycarbonyl)-l-valine (viii), which is esterified with bn-oh, edc and dmap in dichloromethane yielding the protected benzyl ester (ix). treatment of (ix) with tfa in dichloromethane affords l-valine benzyl ester (x), which is condensed with the bromomethylbiphenyl (xi) by means of diea in hot dmf to give the n-alkylated valine ester (xii). the acylation of (xii) with pentanoyl chloride (xiii) by means of diea in toluene yields the n-disubstituted valine ester (xiv), which is finally deprotected by hydrogenation with h2 over pd/c in etoh.
List of intermediates No.
2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-ethanone (xiii)
n-isopropyl-n-phenylamine (xi)
(1s,2s)-2-amino-1-phenyl-1,3-propanediol (iv)
3-sulfothiophene-2-carboxylic acid; 3-sulfo-2-thiophenecarboxylic acid (viii)
isopropyl (3s,6r,7s,8s,12z,15s,16e)-15-(acetoxy)-7-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate (ii)
{[(4,7-dichloro-1-benzothiophen-2-yl)sulfonyl]amino}methylphosphonic acid (x)
3-[(tert-butoxycarbonyl)(methyl)amino]propyl methanesulfonate (v)
tert-butyl 3-(1h-imidazo[4,5-b]pyridin-1-yl)propyl(methyl)carbamate (vi)
tert-butyl 3-(3h-imidazo[4,5-b]pyridin-3-yl)propyl(methyl)carbamate (ix)
2,3-diaminopyridine (xii)
tert-butyl methyl(3-oxopropyl)carbamate (xiv)
tert-butyl 3-[(2-amino-3-pyridinyl)amino]propyl(methyl)carbamate (i)
3-amino-2-pyridinylformamide (iii)
4-methoxybenzyl (7r)-7-{[2-{5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl}-2-(ethoxyimino)acetyl]amino}-3-(iodomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (vii)
2-chloroethanethioic s-acid (i)
s-[(2r,3s)-3-((1r)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidinyl] 2-chloroethanethioate (iii)
allyl 2-{(2r,3s)-3-((1r)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-[(2-chloroacetyl)sulfanyl]-4-oxoazetidinyl}-2-oxoacetate (v)
allyl (5r,6s)-6-((1r)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(chloromethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (vi)
[8-cyclopentyl-3-(3-hydroxypropyl)-2,6-dioxo-1-propyl-1,2,3,6-tetrahydro-7h-purin-7-yl]methyl pivalate (vii)
[8-cyclopentyl-3-(3-{[(4-methylphenyl)sulfonyl]oxy}propyl)-2,6-dioxo-1-propyl-1,2,3,6-tetrahydro-7h-purin-7-yl]methyl pivalate (viii)
Reference 1:
    moenius, t.; et al.; carbon-14 labelling of diovan(tm) in its valine-moiety. j label compd radiopharm 2000, 43, 13, 1245.

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缬沙坦;英文名Valsartan;VAL-489;CGP-48933;Nisis;Kalpress;Vals;Miten;Varexan;Provas;Valpression;Tareg;Diovan;CAS[137862-53-4]

 
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