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药物详细合成路线

Name Atenolol;ICI-66082;Blokium;Tenormin
Chemical Name 2-[4-[2-Hydroxy-3-(isopropylamino)propoxy]phenyl]acetamide
CAS 29122-68-7
Related CAS
Formula C14H22N2O3
Structure
Formula Weight 266.34304
Stage 上市-1975
Company Pfizer (Proprietary), AstraZeneca (Originator), Almirall Prodesfarma (Licensee)
Activity/Mechanism Acute Myocardial Infarction, Treatment of, Angina pectoris, Treatment of, Antiarrhythmic Drugs, CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, beta1-Adrenoceptor Antagonists
Syn. Route 2
Route 1
this compound has been obtained by two related ways:1) the reaction of phenol (i) with formaldehyde gives 4-(hydroxymethyl)phenol (ii), which is treated with nacn in hot dmf to yield 2-(4-hydroxyphenyl)acetonitrile (iii). the hydrolysis of (iii) in refluxing ethanol/water, catalyzed by a pt catalyst affords the corresponding acetamide (iv), which is condensed with an excess of hot epichlorohydrin (v) by means of piperidine gives 2-[4-(2-oxiranylmethoxy)phenyl]acetamide (vi). finally, the oxirane ring of (vi) is opened with isopropylamine in methanol.2)the condensation of acetonitrile (iii) with epichlorohydrin (v) as before gives the 2-[4-(2-oxiranylmethoxy)phenyl]acetonitrile (viii), which is treated with isopropylamine (vii) in methanol yielding 2-[4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]acetonitrile (ix). finally, this compound is hydrolyzed with refluxing ethanol/water catalyzed by a pt catalyst as before to afford the target acetamide.
List of intermediates No.
(6r,7r)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (v)
2,4,5,7,12b,12c-hexahydro-1h-[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridin-2-ol (i)
[1-(4-bromobenzyl)-2-butyl-4-chloro-1h-imidazol-5-yl]methanol (vii)
benzyl (1s,3r)-3-[(2r)-3-((1r)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-2-oxocyclohexyl(methyl)carbamate (ii)
methyl (8s,9s,10r,13s,14s,17s)-17-[(tert-butylamino)carbonyl]-10,13-dimethyl-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthrene-3-carboxylate (iii)
methyl trifluoromethanesulfonate (iv)
benzoic acid (vi)
phenylmethanol (viii)
(z)-2-isobutyryl-n,3-diphenyl-2-propenamide (ix)
Reference 1:
    akisanya, j.; et al.; a synthesis of atenolol using a nitrile hydration catalyst. org process res dev 1998, 2, 4, 274.

Route 2
prepared in two steps by condensation of p-hydroxyphenylacetamide (i) and epichlorhydrine (ii) with piperidine as catalyst, giving 1-(p-carbamoylmethylphenoxy)-2,3-epoxypropane (iii), m.p. 158-60 c, followed by reaction of the epoxy ring with isopropylamine (iv).
List of intermediates No.
(6r,7r)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (ii)
[1-(4-bromobenzyl)-2-butyl-4-chloro-1h-imidazol-5-yl]methanol (iv)
methyl trifluoromethanesulfonate (i)
benzoic acid (iii)
Reference 1:
    barret, a.; et al.; alkanolaminderivate. ch 547257; ch 553747; de 2007751; es 376788; fr 2034561 .
Reference 2:
    castaner, j.; atenolol. drugs fut 1976, 1, 1, 7.

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阿替洛尔;英文名Atenolol;ICI-66082;Blokium;Tenormin;CAS[29122-68-7]

 
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