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药物详细合成路线

Name Candesartan cilexetil;Candesartan hexetil;H212/91;TCV-116;Kenzen;Blopress 16 mg Plus;Parapres;Ratacand;Blopress;Amias;Atacand
Chemical Name (±)-2-Ethoxy-1-[2-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-benzimidazole-7-carboxylic acid 1-(cyclohexyloxycarbonyloxy)ethyl ester
CAS 145040-37-5
Related CAS
Formula C33H34N6O6
Structure
Formula Weight 610.67553
Stage 上市-1997
Company Takeda (Originator), Abbott (Licensee), Almirall Prodesfarma (Licensee), AstraZeneca (Licensee)
Activity/Mechanism CARDIOVASCULAR DRUGS, Diabetic Nephropathy, Agents for, Diabetic Retinopathy, Agents for, ENDOCRINE DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Nephritis, Agents for, RENAL-UROLOGIC DRUGS, Restenosis Treatment of, Treatment of Diabetic Complications, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Treatment of Renal Diseases, Angiotensin AT1 Antagonists
Syn. Route 1
Route 1
this compound can be obtained by two related ways:1) the partial esterification of 3-nitrophthalic acid (i) with ethanol and h2so4 gives 3-nitrophthalic acid 1-monoethyl ester (ii), which is treated with socl2 in refluxing benzene to yield the corresponding acyl chloride (iii). the reaction of (iii) first with sodium azide in dmf and then with refluxing tert-butanol affords 2-(tert-butoxycarbonylamino)-3-nitrobenzoic acid ethyl ester (iv), which is condensed with 4-(2-cyanophenyl)benzyl bromide (v) by means of nah in thf giving 2-(2-cyanobiphenyl-4-ylmethylamino)-3-nitrobenzoic acid ethyl ester (vi). the reduction of (vi) with sncl2.2h2o in ethanol yields the corresponding 3-amino derivative (vii), which is cyclocondensed with ethyl orthocarbonate and acetic acid affording 1-(2-cyanobiphenyl-4-ylmethyl)-2-ethoxybenzimidazole-7-carboxylic acid ethyl ester (viii). the reaction of (viii) with trimethyltin azide in refluxing toluene gives the 2-(1h-tetrazol-5-yl) derivative (ix), which is saponified with naoh in ethanol to the corresponding free acid (x). protection of (x) with trityl chloride and triethylamine in dichloromethane gives the protected compound (xi), which is finally esterified with cyclohexyl 1-iodoethyl carbonate (xii) by means of k2co3 in dmf.2) compound (viii) can also be obtained by reaction of 2-chloro-1-(2-cyanobiphenyl-4-ylmethyl)benzimidazole-7-carboxylic acid ethyl ester (xiii) with sodium ethoxide in refluxing ethanol.
List of intermediates No.
benzyl (2s)-2-([(2s)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl]amino)-5-methylhexanoate (i)
benzyl (2s)-2-amino-3-phenylpropanoate (ii)
benzyl (6s,9s,12s)-12-benzyl-9-isopentyl-6-isopropyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oate (iii)
(2s)-6-amino-2-[(tert-butoxycarbonyl)amino]-6-oxohexanoic acid (iv)
tert-butyl (3s)-2,6-dioxopiperidinylcarbamate (v)
tert-butyl (3s)-2-hydroxy-6-oxopiperidinylcarbamate (vi)
methyl 2-(diethoxyphosphoryl)acetate (vii)
methyl (e,4s)-8-amino-4-[(tert-butoxycarbonyl)amino]-8-oxo-2-octenoate (viii)
methyl (e,4s)-4,8-diamino-8-oxo-2-octenoate (ix)
chloro(methylsulfanyl)methane (x)
methyl 2-bromo-4-nitrobenzoate (xi)
1-naphthylboronic acid (xii)
methyl 2-(1-naphthyl)-4-nitrobenzoate (xiii)
Reference 1:
    naka, t.; nishikawa, k.; kato, t. (takeda chemical industries, ltd.); benzimidazole derivs., their production and use. ep 0459136; ep 0720982; jp 1992364171; jp 1996099960; us 5196444; us 5328919; us 5401764; us 5703110; us 5705517; us 5962491; us 6004989 .
Reference 2:
    prous, j.; mealy, n.; castaner, j.; tcv-116. drugs fut 1993, 18, 7, 609.
Reference 3:
    obara, y.; kubo, k.; imamiya, e.; sugiura, y.; inada, y.; shibaida, y.; ishikawa, k.; yoshimura, y.; naka, t.; synthesis of tcv-116, a new non-peptide angiontensin ii (aii) receptor antagonist and its aii antagonist action. 113th annu meet pharmaceut soc jpn (march 29-31, osaka) 1993, abst 29cc 13-5.

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坎地沙坦西来替昔酯;英文名Candesartan cilexetil;Candesartan hexetil;H212/91;TCV-116;Kenzen;Blopress 16 mg Plus;Parapres;Ratacand;Blopress;Amias;Atacand;CAS[145040-37-5]

 
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