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藥物詳細合成路線

Name alpha-Tocopherol;alpha-Tocoferol;Vitamin E
Chemical Name 2(R),5,7,8-Tetramethyl-2-[4(R),8(R),12-trimethyltridecyl]-3,4-dihydro-2H-1-benzopyran-6-ol
CAS 59-02-9
Related CAS
Formula C29H50O2
Structure
Formula Weight 430.72065
Stage 未確定
Company
Activity/Mechanism  
Syn. Route 3
Route 1
the intermediate triphenylphosphonium salt (xxi) has been obtained as follows: the reformatsky condensation of 4-methoxybenzaldehyde (i) with methyl 2-bromopropionate (ii) gives a mixture of the syn and anti hydroxyesters (iii) and (iv). the syn isomer (iii) was dehydrated by means of msoh yielding the unsaturated ester (v), which is reduced with lialh4 to the unsaturated alcohol (vi). the hydroboration of (vi) affords the diol (rac)-anti-(vii), which is also obtained by direct reduction of the anti-hydroxyester (iv) with lialh4. the optical resolution of (rac)-(vii) with lipase amano p and vinyl acetate affords the chiral monoacetate (2r,3r)-(viii), which is fully acetylated with ac2o giving the diacetate (ix). selective catalytic hydrogenolysis of (ix) with h2 over pd/c in methanol yields the primary monoacetate (x), which is hydrolyzed with k2co3 in methanol to affords the primary alcohol (xi). the reaction of (xi) with cbr4 and pph3 in thf provides the bromide (xii), which by treatment with sodium phenylsulfinate (a) affords the phenylsulfone (xiii). ozonolysis of (xiii) with o3, followed by oxidation with h2o2 gives the carboxylic acid (xiv), which is methylated with diazomethane to the ester (xv). the reduction of (xv) with libh4 in thf yields the alcohol (xvi), which is protected with dhp and ppts yielding the tetrahydropyranyl ether (xvii). the condensation of sulfone (xvii) with the iodoalkane (xviii) by means of lda, followed by treatment with hcl in ethanol affords the intermediate addition compound (xix), which by elimination of the thp group provides the alcohol (xx). finally, the reaction of (xx) with cbr4 and pph3 affords the target intermediate phosphonium salt (xxi).
List of intermediates No.
methyl 2-phenoxyacetate (i)
1,3-dihydroxybenzo[b]acridin-12(5h)-one (ii)
1,4-dioxaspiro[4.5]decan-8-ol (iii)
4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-5-iodo-7h-pyrrolo[2,3-d]pyrimidine (iv)
tert-butyl 4-[4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7h-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenylcarbamate (v)
5-(4-amino-3-fluorophenyl)-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7h-pyrrolo[2,3-d]pyrimidin-4-amine; 4-[4-amino-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7h-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenylamine (vi)
4-[4-amino-5-(4-amino-3-fluorophenyl)-7h-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone (rac-vii)
5-(4-amino-3-fluorophenyl)-7-[4-(4-methyl-1-piperazinyl)cyclohexyl]-7h-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(4-amino-3-fluorophenyl)-7-[4-(4-methyl-1-piperazinyl)cyclohexyl]-7h-pyrrolo[2,3-d]pyrimidin-4-ylamine (2r)
2,3-dichlorobenzenesulfonyl chloride (3r-viii)
benzyl (1s)-1-{[((1s)-4-[(aminocarbonyl)amino]-1-{[4-(hydroxymethyl)anilino]carbonyl}butyl)amino]carbonyl}-2-methylpropylcarbamate (ix)
6-(3-methyl-1,4-dioxo-1,4-dihydro-2-naphthalenyl)hexanoic acid (x)
2-amino-4-[(3s)-3-(dimethylamino)pyrrolidinyl]phenylamine; 4-[(3s)-3-(dimethylamino)pyrrolidinyl]-1,2-benzenediamine (xi)
ethyl 2-{5-[(3s)-3-(dimethylamino)pyrrolidinyl]-1h-benzimidazol-2-yl}acetate (xii)
(2r,3s,4r,5r)-2-(hydroxymethyl)-5-{6-[(3r)tetrahydro-3-furanylamino]-9h-purin-9-yl}tetrahydro-3,4-furandiol (a)
((3ar,4r,6r,6as)-2,2-dimethyl-6-{6-[(3r)tetrahydro-3-furanylamino]-9h-purin-9-yl}tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (xiii)
((3ar,4r,6r,6as)-2,2-dimethyl-6-{6-[(3r)tetrahydro-3-furanylamino]-9h-purin-9-yl}tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl methylcarbamate (xiv)
(3r)tetrahydro-3-furanamine; (3r)tetrahydro-3-furanylamine (xv)
2-hydroxy-2-(3-pyridinyl)acetonitrile (xvi)
tetraethylene glycol; tetraglycol (xvii)
3-[4-(2-{2-[2-(2-{[4-(3-pyridinyl)-1,2,5-thiadiazol-3-yl]oxy}ethoxy)ethoxy]ethoxy}ethoxy)-1,2,5-thiadiazol-3-yl]pyridine; 4-(3-pyridinyl)-1,2,5-thiadiazol-3-yl 2-{2-[2-(2-{[4-(3-pyridinyl)-1,2,5-thiadiazol-3-yl]oxy}ethoxy)ethoxy]ethoxy}ethyl ether (xviii)
Reference 1:
    nozawa, m.; et al.; enantioselective synthesis of (2r,4r,8r)-alpha-tocopherol (vitamin e) based on enzymatic function. chem pharm bull 2000, 48, 2, 272.

Route 2
the esterification of (rac)-6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2h-1-benzopyran-2-carboxylic acid (xxii) with diazomethane gives the methyl ester (xxiii), which is treated with bn-br and k2co3 yielding the benzyl ether (xxiv). the reduction of the ester group of (xxiv) with lialh4 provides the carbinol (xxv), which is debenzylated with h2 over pd/c to afford the racemic phenol (rac)-(xxvi). optical resolution of (xxvi) by means of lipase pl-266 and vinyl acetate gives the chiral acetate (s)-(xxvii), which is rebenzylated with bnbr yielding the benzyl ether (xxviii). the deacetylation of (xxviii) with lialh4 in ethyl ether affords the carbinol (xxix), which is oxidized with oxalyl chloride to the aldehyde (xxx). the condensation of (xxx) with the intermediate phosphonium salt (xxi) by means of n-buli in thf gives the olefin (xxxi), which is finally hydrogenated and debenzylated with h2 over pd/c in ethyl acetate.
List of intermediates No.
3-(5-oxo-2-pyrrolidinyl)propionic acid (xxv)
(2-benzyl-1-benzofuran-3-yl)(4-methoxyphenyl)methanone (xxii)
4-naphtho[2,3-b][1]benzofuran-11-ylphenol (xxvi)
n-(2-chloroethyl)-n-(4-pyridinyl)urea (xxi)
1-(4-pyridinyl)-2-imidazolidinone (xxiii)
4-[(5-bromopentyl)oxy]-1,1-biphenyl; [1,1-biphenyl]-4-yl 5-bromopentyl ether (xxiv)
5-{2-[(4as,4br,5s,6as,9ar,10as,10bs)-4b-fluoro-5-hydroxy-4a,6a,8,8-tetramethyl-2-oxo-2,4a,4b,5,6,6a,9a,10,10a,10b,11,12-dodecahydro-6bh-naphtho[2,1:4,5]indeno[1,2-d][1,3]dioxol-6-yl]-2-oxoethoxy}-5-oxopentanoic acid (xxvii)
[(1as,8s,8ar,8bs)-6-amino-8a-methoxy-5-methyl-4,7-dioxo-1,1a,2,4,7,8,8a,8b-octahydroazireno[2,3:3,4]pyrrolo[1,2-a]indol-8-yl]methyl carbamate (xxviii)
2-nitro-p-phenetidine; 4-amino-3-nitrophenetole; 4-ethoxy-2-nitroaniline; 4-ethoxy-2-nitrobenzeneamine (xxix)
1-hydroxyhydrindene; 1-hydroxyindan; 1-indanol (xxx)
1-bromoindane (xxxi)
Reference 1:
    nozawa, m.; et al.; enantioselective synthesis of (2r,4r,8r)-alpha-tocopherol (vitamin e) based on enzymatic function. chem pharm bull 2000, 48, 2, 272.

Route 3
the chlorination of myrcene (i) with cl2 in refluxing pentane gives the choromyrcene (ii), and the hydrochlorination of (i) catalyzed by cucl yields a mixture of geranyl/neryl chloride (iii). the reductive coupling of (ii) and (iii) by means of mg and cucl affords beta-springene (iv), which is condensed with 2,3,6-trimethylhydroquinone (v) by means of cyclooctadienyl rhodium chloride dimer [rhcl(cod)]2 and k2co3 in refluxing toluene to provide the adduct (vi). the cyclization of (vi) by means of mealcl2 of ts-oh in refluxing hexane furnishes the tocotrienol (vii), which is finally hydrogenated with h2 over pd/c in ethanol to give the target (rac)-vitamin e.
List of intermediates No.
benzyl (1r)-2-(benzylamino)-1-(methoxymethyl)-2-oxoethylcarbamate (v)
3-chloro-2-hydroxy-3-[4-(3-methyl-2-thienyl)phenyl]butanenitrile (i)
(z)-1-cyano-2-[4-(3-methyl-2-thienyl)phenyl]-1-propenyl acetate (ii)
(z)-2-ethoxy-3-[4-(3-methyl-2-thienyl)phenyl]-2-butenenitrile (iii)
3-[4-(3-methyl-2-thienyl)phenyl]-2-oxobutanenitrile (iv)
methyl (e)-2-cyano-3-[4-(3-methyl-2-thienyl)phenyl]-2-butenoate (vi)
methyl 2-(aminocarbonyl)-3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-2-oxiranecarboxylate (vii)
Reference 1:
    bienayme, h.; et al.; rhodium(i)-catalyzed addition of phenols to dienes. a new convergent synthesis of vitamin e. tetrahedron lett 2000, 41, 18, 3339.

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名天然維生素 E;英文名alpha-Tocopherol;alpha-Tocoferol;Vitamin E;CAS[59-02-9]

 
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