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药物详细合成路线

Name Rivastatin;Cerivastatin sodium;Bay-w-6228;Certa;Baycol;Lipobay(free acid)
Chemical Name (+)-(3R,5S,6E)-7-[4-(4-Fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)pyridin-3-yl]-3,5-dihydroxy-6-heptenoic acid monosodium salt
CAS 143201-11-0
Related CAS 145599-86-6 (free acid)
Formula C26H33FNNaO5
Structure
Formula Weight 481.54481
Stage 撤市-2001
Company Bayer (Originator), Fournier (Licensee), GlaxoSmithKline (Licensee), Takeda (Licensee)
Activity/Mechanism Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, HMG-CoA Reductase Inhibitors
Syn. Route 3
Route 1
the compound can be obtained in a multistep synthesis as outlined in scheme 18923701a. the cyclization of ethyl 3-amino-4-methylpent-2-enoate and 4-(ethoxycarbonyl)-5-(4-fluorophenyl)-2-methylpent-4-en-3-one (ii) in a conventional dihydropyridine synthesis gives the dihydropyridine (iii), which is oxidized to the symmetric penta-substituted pyridine (iv).after selective monoreduction with red-al the pyridine alcohol (v) is methylated to (vi). the second ester group is converted to the aldehyde (vii) in a two-step reduction/oxidation procedure. trans-selective wittig-horner reaction with diethyl 2-(cyclohexylamino)vinylphosphonate affords the alpha,beta-unsaturated aldehyde (viii). the condensation of (viii) with methyl acetoacetate and subsequent erythro-selective reduction with triethylborane and nabh4 results in the racemic dihydroxyester (ix).the reaction of (ix) with (s)-(+)-phenylglycinol yields the two diastereomeric (s)-(+)-phenylglycinolamides which can be separated on a silical gel column. after hydrolysis of the phenylglycinolamide (x) the sodium salt of the (+)-enantiomer is obtained.
List of intermediates No.
n-benzyl-n-isopropyl-3-oxo-2-[(e)-2-phenylhydrazono]butanamide (i)
isobutyl 3-oxo-2-[(e)-2-phenylhydrazono]butanoate (ii)
(2r,3s)-2-[(tert-butoxycarbonyl)amino]-3-(1h-indol-3-yl)butyric acid (iii)
tert-butyl (2s)-6-[[(benzyloxy)carbonyl]amino]-2-[[(2r,3s)-2-[(tert-butoxycarbonyl)amino]-3-(1h-indol-3-yl)butanoyl]amino]hexanoate (iv)
tert-butyl (2s)-2-[[(2r,3s)-2-amino-3-(1h-indol-3-yl)butanoyl]amino]-6-[[(benzyloxy)carbonyl]amino]hexanoate (v)
tert-butyl (2s)-6-[[(benzyloxy)carbonyl]amino]-2-[[(2r,3s)-3-(1h-indol-3-yl)-2-([[4-(2-oxo-2,3-dihydro-1h-benzimidazol-1-yl)-1-piperidinyl]carbonyl]amino)butanoyl]amino]hexanoate (vi)
1-phenethyl-2-pyrrolidinone (vii)
tert-butyl 2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)acetate (viii)
tert-butyl 2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)-4-pentenoate (ix)
1-[[([[(benzyloxy)carbonyl]amino]carbonyl)oxy]methyl]benzene (x)
methyl (2s)-2-[(tert-butoxycarbonyl)amino]-3-methyl-3-phenylbutanoate
Reference 1:
    angerbauer, r.; fey, p.; hubsch, w.; philipps, t.; bischoff, h.; petzinna, d.; schmidt, d.; thomas, g. (bayer ag); substituted pyridines. au 8928617; ep 0325130; jp 1989216974; us 5006530; us 5169857 .
Reference 2:
    angerbauer, r.; fey, p.; hubsch, w.; philipps, t.; bischoff, h.; petzinna, d.; schmidt, d.; thomas, g. (bayer ag); substituted pyridyl-dihydroxy-heptenoic acid and its salts. de 4040026; ep 0491226; jp 1992308573; us 5177080 .
Reference 3:
    bischoff, h.; ritter, w.; steinke, w.; angerbauer, r.; bay w 6228. drugs fut 1994, 19, 6, 537.

Route 2
in an alternative approach, the racemic dihydroxymethyl ester (ix) is converted to the racemic lactone (xi), which can be separated into the pure enantiomers on a large-scale chromatography using the newly developed chiral phase baychiral pm. finally, the (+)-lactone (xii) is hydrolyzed to bay w 6228.
List of intermediates No.
tert-butyl 2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)-4-pentenoate (ix)
tert-butyl 4-[bis[(benzyloxy)carbonyl]amino]-2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)butanoate (xii)
3,4-difluorobenzoyl chloride (xiii)
Reference 1:
    angerbauer, r.; bischoff, h.; b?mer, b.; fey, p.; grosser, r.; hübsch, w.; lange, w.; lautz, j.; philipps, t.; schmidt, d.; stereoselective biological activity of the synthetic hmg-coa reductase inhibitor bay w 6228. 2nd eur med chem conf (march 31-april 4, bad nauheim) 1993, 1993.
Reference 2:
    bischoff, h.; ritter, w.; steinke, w.; angerbauer, r.; bay w 6228. drugs fut 1994, 19, 6, 537.

Route 3
a synthesis of [14c]-labeled cerivastatin has been developed: the decarboxylative bromination of 4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)pyridine-3-carboxylic acid (i) gave the bromopyridine (ii), which is treated with buli and [14c]-labeled co2 affording the labeled carboxylic acid (iii). the methylation of (iii) with diazomethane gave the corresponding methyl ester (iv), which was reduced with lialh4 in ether to the alcohol (v). the reaction of (v) with socl2 afforded the chloromethyl derivative (vi), which was condensed with triethyl phosphite at 180 c to give the phosphonate (vii). the condensation of (vii) with the tetrahydropyran-2-carbaldehyde (viii) by means of lda in thf yielded the olefine (ix), which was treated with hcl in aqueous thf eliminating the protecting groups and thus, providing the epimeric mixture of hemiacetals (x). the oxidation of (x) with silver carbonate in refluxing toluene gave the lactone (xi), which was finally treated with naoh in water/acetonitrile.
List of intermediates No.
tert-butyl 4-[bis[(benzyloxy)carbonyl]amino]-2-(3-isobutyl-2-oxo-1-phenethyl-3-pyrrolidinyl)butanoate (xi)
(3ar,4s,5r,6as)-4-(dimethoxymethyl)-5-methylhexahydro-2h-cyclopenta[b]furan-2-one (i)
(3ar,4s,5r,6as)-5-methyl-2-oxohexahydro-2h-cyclopenta[b]furan-4-carbaldehyde (iii)
(3ar,4r,5r,6as)-4-[(e)-4,4-dimethyl-3-oxo-1-octenyl]-5-methylhexahydro-2h-cyclopenta[b]furan-2-one (ii)
(3ar,4r,5r,6as)-4-[(e,3r)-3-hydroxy-4,4-dimethyl-1-octenyl]-5-methylhexahydro-2h-cyclopenta[b]furan-2-one (iv)
(3ar,4r,5r,6as)-4-[(e,3r)-4,4-dimethyl-3-[(tetrahydro-2h-pyran-2-yloxy)methyl]-1-octenyl]-5-methylhexahydro-2h-cyclopenta[b]furan-2-one (v)
(3ar,4r,5r,6as)-4-[(e,3r)-4,4-dimethyl-3-[(tetrahydro-2h-pyran-2-yloxy)methyl]-1-octenyl]-5-methylhexahydro-2h-cyclopenta[b]furan-2-ol (vi)
(3-carboxypropyl)(triphenyl)phosphonium bromide (vii)
(z)-7-((1r,2r,3r,5s)-2-[(e,3r)-4,4-dimethyl-3-[(tetrahydro-2h-pyran-2-yloxy)methyl]-1-octenyl]-5-hydroxy-3-methylcyclopentyl)-5-heptenoic acid (viii)
(z)-7-((1r,2r,3r)-2-[(e,3r)-4,4-dimethyl-3-[(tetrahydro-2h-pyran-2-yloxy)methyl]-1-octenyl]-3-methyl-5-oxocyclopentyl)-5-heptenoic acid (ix)
ethyl 1-[3-(10,11-dihydro-5h-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-3-piperidinecarboxylate (x)
1-[3-(10,11-dihydro-5h-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid (iii)
1-[3-(10,11-dihydro-5h-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-3-piperidinecarboxylic acid (iv)
(rac)-methyl (e,4r,5s)-5-(acetyloxy)-4-(benzyloxy)-2-hexenoate (v)
methyl (e,4r,5s)-5-(acetyloxy)-4-(benzyloxy)-2-hexenoate (vi)
methyl (e,4s,5r)-4-(benzyloxy)-5-hydroxy-2-hexenoate (vii)
methyl (e,4r,5s)-4-(benzyloxy)-5-[((3s)-3-{[tert-butyl(dimethyl)silyl]oxy}butanoyl)oxy]-2-hexenoate (ix)
methyl (e,4r,5s)-4-(benzyloxy)-5-{[(3s)-3-hydroxybutanoyl]oxy}-2-hexenoate (x)
Reference 1:
    angerbauer, r.; radtke, m.; synthesis of [c14]cerivastatin. j label compd radiopharm 1999, 42, 2, 101.

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西立伐他汀钠;英文名Rivastatin;Cerivastatin sodium;Bay-w-6228;Certa;Baycol;Lipobay(free acid);CAS[143201-11-0]

 
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