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Name Pravastatin sodium;Eptastatin sodium;SQ-31000;CS-514;Pravaselect;Liplat;Pravachol;Lipostat;Vasten;Selectin;Elisor;Mevalotin
Chemical Name [1S-[1alpha(betaS*,deltaS*),2alpha,6alpha,8beta(R*),8aalpha]]-1,2,6,7,8,8a-Hexahydro-beta,delta,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthaleneheptanoic acid monosodium salt
      (+)-(betaR,deltaR,1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-Hexahydro-beta,delta,6,8-tetrahydroxy-2-methyl-1-naphthaleneheptanoic acid sodium salt 8-[(2S)-2-methylbutyrate]
CAS 81131-70-6
Related CAS 81093-37-0 (free acid)
Formula C23H35NaO7
Structure
Formula Weight 446.521
Stage 上市-1989
Company Sankyo (Originator), Bristol-Myers Squibb (Licensee), Esteve (Licensee), Menarini (Licensee)
Activity/Mechanism Cardioprotective Agents, CARDIOVASCULAR DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, HMG-CoA Reductase Inhibitors
Syn. Route 1
Route 1
the synthesis of [14c]-labeled pravastatin has been reported: the reaction of propylmagnesium bromide (i) with (14)co2 gives [14c]-butyric acid sodium salt (ii), which is converted to the corresponding acyl chloride (iii) by reaction with oxalyl chloride. the condensation of (iii) with 4(s)-benzyloxazolidin-2-one (iv) in thf yields the corresponding acylation product (v), which is methylated with sodium hexamethyldisilazide and methyliodide to afford a mixture of tautomeric n-[4(s)-benzyl-3-[2(r and s)-methylbutyryl]oxazolidin-2-ones, which are separated by preparative hplc to obtain the optically pure diastereomer (vi). the oxidative cleavage of (vi) with h2o2 and lioh, followed by acidification and treatment with naoh, yields sodium 2(s)-methylbutyrate (vii), which is treated with oxalyl chloride to afford the corresponding acyl chloride (viii). the condensation of (viii) with 4(r)-(tert-butyldimethylsilyloxy)-6(r)-[2-[8(s)-hydroxy-2(s)-methyl-1,2,6,7,8,8a(r)-hexahydronaphth-1(s)-yl]ethyl]tetrahydropyran-2-one (ix) by means of 4-(dimethylamino)pyridine in ch2cl2 gives the esterified compound (x), which is deprotected with tetrabutylammonium fluoride and acetic acid, yielding the hydroxylated pyrone (xi). finally, this compound is submitted to an asymmetric hydroxylation with a culture broth of mucor hiemalis mf-5021. the final product is extracted from the culture broth and purified by preparative hplc to give a final radiochemical purity of 95%.
List of intermediates No.
ethyl (2s,3s,4r,5r)-5-(6-amino-2-iodo-9h-purin-9-yl)-3,4-dihydroxytetrahydro-2-furancarboxylate (i)
(2s,3s,4r,5r)-5-(6-amino-2-iodo-9h-purin-9-yl)-n-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide (ii)
1-phenyl-2-propyn-1-ol (iii)
5,7-dihydroxy-4-propyl-2h-chromen-2-one (iv)
5,7-dihydroxy-8-propionyl-4-propyl-2h-chromen-2-one (v)
4,4-dimethoxy-2-methyl-2-butanol (vi)
5-hydroxy-2,2-dimethyl-6-propionyl-10-propyl-2h,8h-pyrano[2,3-f]chromen-8-one (vii)
(10r,11r)-6,6,10,11-tetramethyl-4-propyl-10,11-dihydro-2h,6h,12h-dipyrano[2,3-f:2,3-h]chromene-2,12-dione (viii)
(10r,11s)-6,6,10,11-tetramethyl-4-propyl-10,11-dihydro-2h,6h,12h-dipyrano[2,3-f:2,3-h]chromene-2,12-dione (ix)
(10r,11s,12s)-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2h,6h,10h-dipyrano[2,3-f:2,3-h]chromen-2-one (x)
(10r,11s,12r)-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2h,6h,10h-dipyrano[2,3-f:2,3-h]chromen-2-one (xi)
tert-butyl (1s)-1-{[((3s,4s)-3-hydroxy-1-{2-[3-(2-pyridinyl)phenyl]acetyl}azepanyl)amino]carbonyl}-3-methylbutylcarbamate (ii)
(2s)-2-amino-n-((3s,4s)-3-hydroxy-1-{2-[3-(2-pyridinyl)phenyl]acetyl}azepanyl)-4-methylpentanamide (iii)
n-((1s)-1-{[((3s,4s)-3-hydroxy-1-{2-[3-(2-pyridinyl)phenyl]acetyl}azepanyl)amino]carbonyl}-3-methylbutyl)-5-[2-(4-morpholinyl)ethoxy]-1-benzofuran-2-carboxamide (v)
4-dimethylaminobutylamine (vi)
4-iodobenzene chloride; 4-iodobenzoyl chloride; p-iodobenzene chloride; p-iodobenzoyl chloride (vii)
(7r)-7-[(3as,7s,7ar)-7-hydroxy-3a-methyl-3a,4,5,6,7,7a-hexahydro-1h-inden-3-yl]-2,2-dimethyl-3-octanone (viii)
(3ar,7as)-7a-methyl-1-[(1r)-1,6,6-trimethyl-5-oxoheptyl]-3,3a,5,6,7,7a-hexahydro-4h-inden-4-one (x)
(7r)-7-{(3as,7as)-7-[(e)-2-((3s,5r)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-3a-methyl-3a,4,5,6,7,7a-hexahydro-1h-inden-3-yl}-2,2-dimethyl-3-octanone (xi)
Reference 1:
    wallace, m.a.; dean, d.c.; white, r.f.; ellsworth, r.l.; melillo, d.g.; marks, t.; the synthesis of carbon-14 labeled pravastatin. j label compd radiopharm 1993, 33, 8, 697.

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普伐他汀钠;英文名Pravastatin sodium;Eptastatin sodium;SQ-31000;CS-514;Pravaselect;Liplat;Pravachol;Lipostat;Vasten;Selectin;Elisor;Mevalotin;CAS[81131-70-6]

 
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