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药物详细合成路线

Name Quinapril hydrochloride;PD-109522;CI-906;Accuretic;Lidaltrin;Ectren;Conan;Accupril;Korec;Quinazil;Acequin;Accupro;Accuprin
Chemical Name [3S-[2[R*(R*),3R*]]-2-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid monohydrochloride;(S)-2-[(S)-N-[(S)-1-Carboxy-3-phenylpropyl]alanyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid 1-ethyl ester monohydrochloride;2-[N-[1(S)-(Ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylic acid monohydrochloride
CAS 82586-55-8
Related CAS 85441-61-8 (free base), 90243-99-5 (monohydrate), 82768-84-1 (undefined stereoch.)
Formula C25H31ClN2O5
Structure
Formula Weight 474.98922
Stage 上市-1989
Company Pfizer (Originator), Japan Tobacco (Licensee), Lacer (Licensee), Malesci (Licensee), Menarini (Licensee), Mitsubishi Pharma (Licensee), Recordati (Licensee), Sankyo (Licensee)
Activity/Mechanism CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Angiotensin-I Converting Enzyme (ACE) Inhibitors
Syn. Route 2
Route 1
the condensation of alanine tert-butyl ester (i) with ethyl 2-bromo-4-phenylbutanoate (ii) by means of triethylamine in hot dmf gives ethyl 2-[[1-(tert-butoxycarbonyl)ethyl]amino]-4-phenylbutanoate (iii), which is partially hydrolyzed with trifluoroacetic acid yielding ethyl 2-[[1-carboxyethyl]amino]-4-phenylbutanoate (iv). the condensation of (iv) with benzyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (v) [prepared from the corresponding acid (vi) and benzyl alcohol (a) by means of polyphosphoric acid] by means of triethylamine and 1-hydroxybenzotriazole affords benzyl 2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (vii), which is finally debenzylated by hydrogenolysis with h2 over pd/c in thf.
List of intermediates No.
tert-butyl (2s)-4-methyl-2-(methylamino)pentanoate (vi)
4,5-dimethyl-1,3-dioxol-2-one (a)
(6r,7r)-7-[[5-carboxy-5-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)pentanoyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (ii)
tert-butyl (4r)-4-benzyl-4-[3-(1h-imidazol-1-yl)-3-oxopropyl]-5-oxo-1,3-oxazolidine-3-carboxylate (i)
[(2r,3s)-3-isopropyloxiranyl]methanol (iii)
(4r,5s)-3-benzyl-4-(hydroxymethyl)-5-isopropyl-1,3-oxazolidin-2-one (v)
(4s,5s)-3-benzyl-5-isopropyl-2-oxo-1,3-oxazolidine-4-carboxylic acid (vii)
methyl (4s,5s)-3-benzyl-5-isopropyl-2-oxo-1,3-oxazolidine-4-carboxylate (iv)
Reference 1:
    hoefle, m.l.; klutchko, s. (pfizer inc.); substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids. dd 201787; ep 0049605; ep 0096157; us 4344949 .
Reference 2:
    castaner, j.; serradell, m.n.; blancafort, p.; ci-906. drugs fut 1983, 8, 12, 1014.

Route 2
the condensation of alanine tert-butyl ester (i) with ethyl 2-bromo-4-phenylbutanoate (ii) by means of triethylamine in hot dmf gives ethyl 2-[[1-(tert-butoxycarbonyl)ethyl]amino]-4-phenylbutanoate (iii), which is partially hydrolyzed with trifluoroacetic acid yielding ethyl 2-[[1-carboxyethyl]amino]-4-phenylbutanoate (iv). the condensation of (iv) with tert-butyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (viii) [prepared from the corresponding acid (vi) and isobutylene (b) by means of h2so4] as before gives tert-butyl-2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (ix), which is finally hydrolyzed partially by treatment with trifluoroacetic acid.
List of intermediates No.
tert-butyl (2s)-4-methyl-2-(methylamino)pentanoate (vi)
[5-chloro-2-nitro-4-(trifluoromethyl)anilino]methylphosphonic acid (b)
(6r,7r)-7-[[5-carboxy-5-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)pentanoyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (ii)
tert-butyl (4r)-4-benzyl-4-[3-(1h-imidazol-1-yl)-3-oxopropyl]-5-oxo-1,3-oxazolidine-3-carboxylate (i)
[(2r,3s)-3-isopropyloxiranyl]methanol (iii)
methyl (4s,5s)-3-benzyl-5-isopropyl-2-oxo-1,3-oxazolidine-4-carboxylate (iv)
(4r,5s)-3-benzyl-5-isopropyl-2-oxo-1,3-oxazolidine-4-carboxylic acid (viii)
(2r,3s)-2-amino-3-hydroxy-4-methylpentanoic acid (ix)
Reference 1:
    hoefle, m.l.; klutchko, s. (pfizer inc.); substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids. dd 201787; ep 0049605; ep 0096157; us 4344949 .
Reference 2:
    castaner, j.; serradell, m.n.; blancafort, p.; ci-906. drugs fut 1983, 8, 12, 1014.

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盐酸喹那普利;英文名Quinapril hydrochloride;PD-109522;CI-906;Accuretic;Lidaltrin;Ectren;Conan;Accupril;Korec;Quinazil;Acequin;Accupro;Accuprin;CAS[82586-55-8]

 
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