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药物详细合成路线

Name Olmesartan medoxomil;CS-866DM;CS-866;Olmetec;Benicar;Benevas
Chemical Name 4-(1-Hydroxy-1-methylethyl)-2-propyl-1-[2-(1H-5-tetrazolyl)biphenyl-4-ylmethyl]imidazole-5-carboxylic acid 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl ester
CAS 144689-63-4
Related CAS
Formula C29H30N6O6
Structure
Formula Weight 558.59905
Stage 上市-2002
Company Sankyo (Originator), Forest (Marketer), Pfizer (Marketer), Menarini (Comarketer), Nikken Chemicals (Comarketer), Sanwa (Comarketer), Kowa (Codevelopment)
Activity/Mechanism CARDIOVASCULAR DRUGS, Diabetic Nephropathy, Agents for, ENDOCRINE DRUGS, Hypertension, Treatment of, Treatment of Diabetic Complications, Angiotensin AT1 Antagonists
Syn. Route 3
Route 1
the cyclization of trimethyl orthobutyrate (i) with (z)-2,3-diaminobutenedinitrile (ii) gives 2-propylimidazole-4,5-dicarbonitrile (iii), which is hydrolyzed with 6n hcl to the corresponding dicarboxylic acid (iv). the esterification of (iv) with ethanol/dry hcl yields the diethyl ester (v), which is treated with methylmagnesium iodide in ethyl ether/dichloromethane affording 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester (vi). the condensation of (vi) with 5-[4-(bromomethyl)biphenyl-2-yl]-1-(triphenylmethyl)tetrazole (vii) by means of potassium tert-butoxide in dimethylacetamide (dma) (1) or sodium hydride in dmf (2) gives 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2-[1-(triphenylmethyl)-5-tetrazolyl]biphenyl-4-ylmethyl]imidazole-5-carboxylic acid ethyl ester (viii), which is hydrolyzed with lioh in dioxane/water to the corresponding free acid (ix). the esterification of (ix) with the chloromethyldioxole (x) by means of k2co3 in dma gives the desired ester (xi), which is finally deprotected with aqueous acetic acid.
List of intermediates No.
n-isopropyl-n-phenylamine (vii)
(e)-3-(3-pyridinyl)-2-propenoic acid (i)
(e)-3-(3-pyridinyl)-2-propenoyl chloride (ii)
1-(trimethylsilyl)-2-pyrrolidinone (iii)
(4r)-3-[(2s,3s)-3-amino-2-hydroxy-4-phenylbutanoyl]-n-(tert-butyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxamide (iv)
3,3-dimethyldihydro-2,5-furandione (v)
4-[((1s,2s)-1-benzyl-3-[(4r)-4-[(tert-butylamino)carbonyl]-5,5-dimethyl-1,3-thiazolidin-3-yl]-2-hydroxy-3-oxopropyl)amino]-2,2-dimethyl-4-oxobutyric acid (vi)
4-([(2s,3s,5r)-3-azido-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2h)-pyrimidinyl]tetrahydro-2-furanyl]methoxy)-2,3-dimethyl-4-oxobutyric acid (viii)
4-amino-5-chloro-2-methoxybenzoic acid methoxycarbonyl anhydride (ix)
butyl 2-bromoacetate (x)
2-hydroxy-5-methoxybenzaldehyde (xi)
Reference 1:
    graul, a.; leeson, p.; casta?er, j.; cs-866. drugs fut 1997, 22, 11, 1205.
Reference 2:
    yanagisawa, h.; shimoji, y.; fujimoto, k.; kanazaki, t.; anemiya, y.; koike, h.; sada, t. (sankyo co., ltd.); angiotensin ii antagonist 1-biphenylmethylimidazole cpds. and their therapeutic use. ep 0503785; ep 0545912; jp 1993078328; us 5616599 .

Route 2
2) the hydrolysis of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester (vi) with lioh in water gives the corresponding free acid (xii), which is esterified with the chloromethyldioxole (x) by means of diisopropylethylamine (diea) yielding the expected ester (xiii). finally, this compound is condensed with 5-[4-(bromomethyl)biphenyl-2-yl]-1-(triphenylmethyl)tetrazole (vii) by means of potassium carbonate in dma to afford the protected cs-866 (xi) already obtained.
List of intermediates No.
n-isopropyl-n-phenylamine (vii)
4-[((1s,2s)-1-benzyl-3-[(4r)-4-[(tert-butylamino)carbonyl]-5,5-dimethyl-1,3-thiazolidin-3-yl]-2-hydroxy-3-oxopropyl)amino]-2,2-dimethyl-4-oxobutyric acid (vi)
butyl 2-bromoacetate (x)
2-hydroxy-5-methoxybenzaldehyde (xi)
3-bromo-2-hydroxy-5-methoxybenzaldehyde (xii)
4-(7-bromo-5-methoxy-1-benzofuran-2-yl)pyridine (xiii)
Reference 1:
    graul, a.; leeson, p.; casta?er, j.; cs-866. drugs fut 1997, 22, 11, 1205.
Reference 2:
    yanagisawa, h.; shimoji, y.; fujimoto, k.; kanazaki, t.; anemiya, y.; koike, h.; sada, t. (sankyo co., ltd.); angiotensin ii antagonist 1-biphenylmethylimidazole cpds. and their therapeutic use. ep 0503785; ep 0545912; jp 1993078328; us 5616599 .

Route 3
3) the amidation of 4-methylbiphenyl-2-carboxylic acid (xiv) with tert-butylamine by means of oxalyl chloride in dichloromethane gives the corresponding tert-butylamide (xv), which is brominated with n-bromosuccinimide (nbs) and benzoyl peroxide in ccl4 yielding 4-(bromomethyl)-n-(tert-butyl)biphenyl-2-carboxamide (xvi). the condensation of (xvi) with 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester (vi) by means of potassium tert-butoxide in dma affords 1-[2-(n-tert-butylcarbamoyl)biphenyl-4-ylmethyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester (xvii), which by reaction with oxalyl chloride in dichloromethane is converted into 1-(2-cyanobiphenyl-4-ylmethyl)-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester (xviii). the cyclization of (xviii) with tributyltin azide in toluene gives 4-(1-hydroxy-1-methylethyl)-2-propyl 1-[2-(5-tetrazolyl)biphenyl-4-ylmethyl]imidazole-5-carboxylic acid ethyl ester (xix), which is finally tritiated with trityl chloride in pyridine to afford 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2-[1-(triphenylmethyl)-5-tetrazolyl]biphenyl-4-ylmethyl]imidazole-5-carboxylic acid ethyl ester (viii), already obtained.
List of intermediates No.
4-[((1s,2s)-1-benzyl-3-[(4r)-4-[(tert-butylamino)carbonyl]-5,5-dimethyl-1,3-thiazolidin-3-yl]-2-hydroxy-3-oxopropyl)amino]-2,2-dimethyl-4-oxobutyric acid (vi)
4-([(2s,3s,5r)-3-azido-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2h)-pyrimidinyl]tetrahydro-2-furanyl]methoxy)-2,3-dimethyl-4-oxobutyric acid (viii)
4-(7-bromo-5-methoxy-1-benzofuran-2-yl)-1-methylpyridinium (sulfonatooxy)methane (xiv)
4-(7-bromo-5-methoxy-1-benzofuran-2-yl)-1-methyl-1,2,3,6-tetrahydropyridine (xv)
4-(7-bromo-5-methoxy-1-benzofuran-2-yl)-1-methylpiperidine (xvi)
ethyl 4-(7-bromo-5-methoxy-1-benzofuran-2-yl)-1-piperidinecarboxylate (xvii)
1-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1h-pyrazol-3-amine (xviii)
1-[3-(trifluoromethyl)phenyl]-4,5-dihydro-1h-pyrazol-3-ylformamide (xix)
Reference 1:
    mizuno, m.; sada, t.; ikeda, m.; fukuda, n.; miyamoto, m.; yanagisawa, h.; koike, h.; pharmacology of cs-866, a novel nonpeptide angiotensin ii receptor antagonist. eur j pharmacol 1992, 285, 181-188.
Reference 2:
    graul, a.; leeson, p.; casta?er, j.; cs-866. drugs fut 1997, 22, 11, 1205.

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奥美沙坦酯;英文名Olmesartan medoxomil;CS-866DM;CS-866;Olmetec;Benicar;Benevas;CAS[144689-63-4]

 
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