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藥物詳細合成路線

Name Adenosine;SUN-Y4001;MEDR-640;SR-96225;Adenocor;Pallacor;Adenoscan;Adenocard
Chemical Name 9-beta-D-Ribofuranosyladenine;6-Amino-9-beta-D-ribofuranosyl-9H-purine
CAS 58-61-7
Related CAS
Formula C10H13N5O4
Structure
Formula Weight 267.24621
Stage 上市-1989
Company King Pharmaceuticals (Originator), Medco (Originator), Daiichi Suntory Pharma (Licensee), Fujisawa (Licensee), Sanofi-synthélabo (Licensee)
Activity/Mechanism Acute Myocardial Infarction, Treatment of, Antiarrhythmic Drugs, CARDIOVASCULAR DRUGS, DIAGNOSTIC AGENTS, Hypertension, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Vasodilators
Syn. Route 3
Route 1
this compound has been obtained by two similar ways:1) the condensation of 1-o-acetyl-2,3,5-o-tribenzoyl-beta-d-ribofuranose (i) with n6-benzoyl-9-(trimethylsilyl)adenine (ii) by means of trimethylsilyl perchlorate or trimethylsilyl trifluoromethanesulfonate in dichloroethane gives the tetrabenzoyladenosine (iii), which is finally debenzoylated with ammonia in methanol.2) the reaction of tetraacetyl-d-ribofuranose (iv) with dry hcl in ethyl ether gives the 1-chloro derivative (v), which is condensed with the silver salt of 2,8-dichloroadenine (vi) in refluxing xylene yielding the acetylated dichloroadenosine (vii). the hydrolysis of (vii) with ammonia in methanol affords 2,8-dichloroadenosine (viii), which is finally dechlorinated by hydrogenation with h2 over pd/baso4 in aqueous naoh.
List of intermediates No.
(3r)-3-[(4-methoxybenzyl)oxy]-2-butanone (i)
tert-butyl (2s)-2-[(r)-1,3-benzothiazol-2-yl(hydroxy)methyl]-1-pyrrolidinecarboxylate (iv)
allyl 3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenyl([(2s,3s)-3-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1-[(4-methylphenyl)sulfonyl]aziridinyl]methyl)carbamate (ii)
allyl 3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-hydroxyethyl)phenyl([(2s,3s)-3-(hydroxymethyl)-1-[(4-methylphenyl)sulfonyl]aziridinyl]methyl)carbamate (iii)
allyl 3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-oxoethyl)phenyl([(2s,3s)-3-formyl-1-[(4-methylphenyl)sulfonyl]aziridinyl]methyl)carbamate (v)
allyl (1as,8s,9s,9as)-7-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-9-hydroxy-8-(hydroxymethyl)-1-[(4-methylphenyl)sulfonyl]-1,1a,2,8,9,9a-hexahydro-3h-azireno[2,3-c][1]benzazocine-3-carboxylate (vi)
allyl (1as,8s,9s,9as)-7-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-8-([[tert-butyl(diphenyl)silyl]oxy]methyl)-9-hydroxy-1-[(4-methylphenyl)sulfonyl]-1,1a,2,8,9,9a-hexahydro-3h-azireno[2,3-c][1]benzazocine-3-carboxylate (vii)
allyl (1as,8s,9as)-7-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-8-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1-[(4-methylphenyl)sulfonyl]-9-oxo-1,1a,2,8,9,9a-hexahydro-3h-azireno[2,3-c][1]benzazocine-3-carboxylate (viii)
Reference 1:
    davoll, j.; et al.; experiments on the synthesis of purine nucleosides. part xix. a synthesis of adenosine. j chem soc 1948, 967.
Reference 2:
    krolikiewicz, k.; vorbrueggen, h.; new catalysts for the synthesis of nucleosides. angew chem. int ed engl 1975, 14, 6, 421.

Route 2
the esterification of 1h-imidazole-4,5-dicarboxylic acid (i) with etoh and sulfuric acid gives the diethyl ester (ii), which is brominated with nbs in acetonitrile, yielding the 2-bromo derivative (iii). the hydrolysis of (iii) by means of hot aqueous na2co3 affords the 2-bromo-1h-imidazole-4,5-dicarboxylic acid (iv), which is diazocoupled with the labeled diazonium ion (v) to provide the monolabeled azo acid (vi). the reaction of acid (vi) with 15nh4cl and dec in acetonitrile gives the doubly labeled azoamide (vii), which is reduced with h2 over pd/c in methanol to yield the doubly labeled 5-amino-1h-imidazole-4-carboxamide (viii). the cyclization of (viii) with sodium 13c-ethylxanthate (ix) in dmf affords the mercaptoxanthine (x), which is reduced to the hypoxanthine (xi) with raney ni and formic acid. the reaction of (xi) with pocl3 in hot n,n-dimethylaniline provides the triply labeled chloropurine (xii), which is submitted to enzymatic trans-glycosylation with 7-methylguanosine or thymidine and purine nucleoside phosphorylase (pnp) and thymidine phosphorylase (tp) to give the glycosylated chloropurine (xiii). finally, this compound is treated with 15nh4cl and khco3 in hot anhydrous dmso to afford the target tetralabeled adenine nucleoside.
List of intermediates No.
benzhydryl (e)-2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-3-hydroxy-2-butenoate (viii)
1,2,4-butanetriol (xii)
(6e)-9-iodo-2,6-dimethyl-2,6-nonadiene (xiii)
3,4-dimethylpyridine (ii)
1-(3-iodo-4-methoxyphenyl)-5-(trifluoromethyl)-1h-1,2,3,4-tetraazole; 2-iodo-4-[5-(trifluoromethyl)-1h-1,2,3,4-tetraazol-1-yl]phenyl methyl ether (i)
2,6-dichlorobenzenesulfonamide (iii)
2,6-dichloro-3-nitrobenzenesulfonamide (iv)
2-(aminosulfonyl)-3-chloro-6-nitrophenyl acetate (v)
6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (vi)
3-amino-6-chloro-2-hydroxybenzenesulfonamide (vii)
6-methyl-10h-indolo[3,2-b]quinoline-4-carboxylic acid (viii)
methyl 6,10-dimethyl-10h-indolo[3,2-b]quinoline-4-carboxylate (ix)
(4r)-3-((2s,4r)-4-benzyl-2-{[tert-butyl(dimethyl)silyl]oxy}-5-{[(3s,4s)-3-hydroxy-3,4-dihydro-2h-chromen-4-yl]amino}-5-oxopentanoyl)-n-[(3,5-dimethyl-4-isothiazolyl)methyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide (x)
4-[4-(2-chloro-2,3-dihydro-1h-benzimidazol-1-yl)-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone (xi)
2-benzyl 4-(tert-butyl) 3,5-dimethyl-1h-pyrrole-2,4-dicarboxylate (xii)
4-(tert-butoxycarbonyl)-3,5-dimethyl-1h-pyrrole-2-carboxylic acid (xiii)
4-(tert-butyl) 2-propyl 3,5-dimethyl-1h-pyrrole-2,4-dicarboxylate (v)
2,4-dimethyl-5-(propoxycarbonyl)-1h-pyrrole-3-carboxylic acid (vi)
3,3-dimethyl-2-butanol (vii)
5-(tert-butoxycarbonyl)-2,4-dimethyl-1h-pyrrole-3-carboxylic acid (ix)
Reference 1:
    abad, j.-l.; gaffney b.l.; jones r.a.; 15n-multilabeled adenine and guanine nucleosides syntheses of [1,3,nh2-15n3]- and [2-13c-1,3nh2-15n3]-labeled adenosine, guanosine , 2-deoxyadenosine, and 2-deoxyguanosine. j org chem 1999, 64, 18, 6575.

Route 3
the esterification of 1h-imidazole-4,5-dicarboxylic acid (i) with etoh and sulfuric acid gives the diethyl ester (ii), which is brominated with nbs in acetonitrile, yielding the 2-bromo derivative (iii). the hydrolysis of (iii) by means of hot aqueous na2co3 affords the 2-bromo-1h-imidazole-4,5-dicarboxylic acid (iv), which is diazocoupled with the labeled diazonium ion (v) to provide the monolabeled azo acid (vi). the reaction of acid (vi) with 15nh4cl and dec in acetonitrile gives the doubly labeled azoamide (vii), which is reduced with h2 over pd/c in methanol to yield the doubly labeled 5-amino-1h-imidazole-4-carboxamide (viii). the cyclization of (viii) with sodium ethylxanthate (ix) in dmf affords the mercaptoxanthine (x), which is reduced to the hypoxanthine (xi) with raney ni and formic acid. the reaction of (xi) with pocl3 in hot n,n-dimethylaniline provides the doubly labeled chloropurine (xii), which is submitted to enzymatic trans-glycosylation with 7-methylguanosine or thymidine and purine nucleoside phosphorylase (pnp) and thymidine phosphorylase (tp) to give the glycosylated chloropurine (xiii). finally, this compound is treated with 15nh4cl and khco3 in hot anhydrous dmso to afford the target triply labeled adenine nucleoside.alternatively, the intermediate hypoxanthine (xi) can also be obtained directly by cyclization of the doubly labeled 5-amino-1h-imidazole-4-carboxamide (viii) with formic acid and diethoxymethyl acetate (dema) in dmf.
List of intermediates No.
benzhydryl (e)-2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3.2.0]hept-2-en-6-yl)-3-hydroxy-2-butenoate (viii)
1,2,4-butanetriol (xii)
(6e)-9-iodo-2,6-dimethyl-2,6-nonadiene (xiii)
3,4-dimethylpyridine (ii)
1-(3-iodo-4-methoxyphenyl)-5-(trifluoromethyl)-1h-1,2,3,4-tetraazole; 2-iodo-4-[5-(trifluoromethyl)-1h-1,2,3,4-tetraazol-1-yl]phenyl methyl ether (i)
2,6-dichlorobenzenesulfonamide (iii)
2,6-dichloro-3-nitrobenzenesulfonamide (iv)
2-(aminosulfonyl)-3-chloro-6-nitrophenyl acetate (v)
6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (vi)
3-amino-6-chloro-2-hydroxybenzenesulfonamide (vii)
6-methyl-10h-indolo[3,2-b]quinoline-4-carboxylic acid (viii)
4-(tert-butyl) 2-propyl 3,5-dimethyl-1h-pyrrole-2,4-dicarboxylate (v)
2,4-dimethyl-5-(propoxycarbonyl)-1h-pyrrole-3-carboxylic acid (vi)
3,3-dimethyl-2-butanol (vii)
5-(tert-butoxycarbonyl)-2,4-dimethyl-1h-pyrrole-3-carboxylic acid (ix)
4-benzyl 2-(tert-butyl) 3,5-dimethyl-1h-pyrrole-2,4-dicarboxylate (x)
benzyl 3-oxobutanoate (xi)
2-amino-6-[2-(trimethylsilyl)ethynyl]-4-quinazolinylamine; 6-[2-(trimethylsilyl)ethynyl]-2,4-quinazolinediamine (x)
2-amino-6-ethynyl-4-quinazolinylamine; 6-ethynyl-2,4-quinazolinediamine (xi)
2-amino-6-iodo-4-quinazolinylamine; 6-iodo-2,4-quinazolinediamine (xii)
Reference 1:
    abad, j.-l.; gaffney b.l.; jones r.a.; 15n-multilabeled adenine and guanine nucleosides syntheses of [1,3,nh2-15n3]- and [2-13c-1,3nh2-15n3]-labeled adenosine, guanosine , 2-deoxyadenosine, and 2-deoxyguanosine. j org chem 1999, 64, 18, 6575.

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腺苷;英文名Adenosine;SUN-Y4001;MEDR-640;SR-96225;Adenocor;Pallacor;Adenoscan;Adenocard;CAS[58-61-7]

 
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