有机化学人才网 | 最新人才 | 最新职位 | 技术交易 | 药物合成 |
   
全站搜索: |
  您当前位置:网站首页 >> 药物合成路线图解
 

药物详细合成路线

Name Dideoxyadenosine;NSC-98700;ddA
Chemical Name 2,3-Dideoxyadenosine
CAS 4097-22-7
Related CAS
Formula C10H13N5O2
Structure
Formula Weight 235.24741
Stage I 期临床
Company Ajinomoto (Originator), Bristol-Myers Squibb (Originator), National Cancer Institute (Originator)
Activity/Mechanism AIDS Medicines, ANTIINFECTIVE THERAPY, Antiviral Drugs, Reverse Transcriptase Inhibitors
Syn. Route 10
Route 1
this compound is prepared by two related ways:1) the partial silylation of adenosine (i) with tert-butyldimethylsilyl chloride and imidazole gives 5-o-(tert-butyldimethylsilyl)adenosine (ii), which by reaction with 1,1-thiocarbonyldiimidazole (iii) in hot dmf is converted into 5-o-(tert-butyldimethylsilyl)-2,3-o-thionocarbonyladenosine (iv). the desulfurization of (iv) with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine (v) or triethyl phosphite in thf yields 5-o-(tert-butyldimethylsilyl)-2,3-didehydro-2,3-dideoxyadenosine (vi), which is deprotected with tetrabutylammonium fluoride in thf affording 2,3-didehydro-2,3-dideoxyadenosine (vii). finally, this compound is hydrogenated with h2 over pd/c in methanol.2) the reaction of silylated adenosine (ii) with cs2 and naoh in dmso, followed by methylation with methyl iodide gives 5-o-(tert-butyldimethylsilyl)-2,3-bis-o-[(methylthio)thiocarbonyl]ad enosine (viii), which is desulfurized with tributyltin hydride and aibn in refluxing toluene to yield the dideoxy-didehydroadenosine (vi), already obtained.
List of intermediates No.
n-butyl-2-(3,4-dimethoxyphenyl)-n-propylacetamide (i)
n-(3,4-dimethoxyphenethyl)-n-propyl-1-butanamine (ii)
2-(4-hydroxy-3-nitrophenyl)propanenitrile (iii)
2-(4-hydroxy-3-nitrophenyl)propionic acid (iv)
2-(3-amino-4-hydroxyphenyl)propionic acid (v)
2-[3-[(4-fluorobenzoyl)amino]-4-hydroxyphenyl]propionic acid (vi)
2-[2-(4-fluorophenyl)-1,3-benzoxazol-5-yl]propionic acid (vii)
2-(3-methoxyphenyl)tetradecanenitrile (viii)
Reference 1:
    chu, c.k.; bhadti, v.s.; doboszewski, b.; gu, z.p.; kosugi, y.; pullaiah, k.c.; van roey, p.; general syntheses of 2,3-dideoxynucleosides and 2,3-didehydro-2,3-dideoxynucleosides. j org chem 1989, 54, 2217-25.

Route 2
a new synthesis of 2,3-dideoxyadenosine has been described:the reaction of uridine (i) with methyl orthoformate and p-toluenesulfonic acid gives the cyclic orthoester (ii), which is acetylated with acetic anhydride at 100 c to the acetate (iii). the reaction of (iii) with acetic anhydride at temperatures over 120 c yields 5-o-acetyl-2,3-dideoxy-2,3-didehydrouridine (iv), which is hydrogenated to 5-o-acetyl-2,3-dideoxyuridine (v).
List of intermediates No.
1-iodo-4-nitrobenzene (vii)
3-chloro-n-(3-methoxyphenethyl)-n-methyl-1-propanamine (i)
3-methoxyphenylacetonitrile; 2-(3-methoxyphenyl)acetonitrile (ii)
1-bromododecane (iii)
2-(3-methoxyphenyl)-n-methyl-1-ethanamine (iv)
1-[(e)-2-methyl-3-phenyl-2-propenyl]hydrazine (v)
2-oxopropionic acid (vi)
Reference 1:
    shiragami, h.; shirae, h.; irie, y.; yokozeki, k.; yasuda, n.; the synthesis of 2,3-dideoxyadenosine and 2,3-dideoxyinosine. nucl acid res symp ser 1988, 20, 20, 17-18.

Route 3
the hydrolysis of (v) affords 2,3-dideoxyuridine (vi), which is finally submitted to transdeoxyribosilation with adenine (vii) by means of escherichia coli aj-2595 microorganisms.
List of intermediates No.
1-iodo-4-nitrobenzene (ii)
2-oxopropionic acid (i)
Reference 1:
    shiragami, h.; shirae, h.; irie, y.; yokozeki, k.; yasuda, n.; the synthesis of 2,3-dideoxyadenosine and 2,3-dideoxyinosine. nucl acid res symp ser 1988, 20, 20, 17-18.

Route 4
a new synthesis of 2,3-dideoxyadenosine has been described:the stereospecific deamination - lactonization of l-glutamic acid (i) with nano2 - hcl in water gives (s)-(+)-gamma-carboxy-gamma-butyrolactone (ii), which is esterified with ethanol - p-toluenesulfonic acid to the ester (iii). the selective reduction of (iii) with nabh4 in ethanol yields (s)-(+)-gamma-(hydroxymethyl)-gamma-butyrolactone (iv), which is benzoylated with benzoyl chloride as usual, affording the benzoate (v). the selective reduction of (v) with disiamyl borane in thf gives the alcohol (vi), which is acetylated with acetic anhydride in pyridine to the acetate (vii). the reaction of (vii) with trimethylsilyl bromide in dichloromethane yields the tetrahydrofuryl bromide (viii), which is condensed with the silylated adenine (ix) to afford 5-o-benzoyl-2,3-dideoxyadenosine (x). finally, this compound is deprotected with nh3 in methanol.
List of intermediates No.
3-[(2-methoxyphenyl)sulfanyl]propionic acid (i)
8-methoxy-2,3-dihydro-4h-thiochromen-4-one (ii)
8-thiochromanol (iii)
2-[(3,4-dihydro-2h-thiochromen-8-yloxy)methyl]oxirane (iv)
2-chloropyrazine (v)
heptyl hydroxy(phenyl)carbamate (vi)
heptyl 4-(5-oxo-4,5-dihydro-2-pyrazinyl)phenylcarbamate (vii)
4-(4,5-dihydro-2-pyrazinyl)aniline (viii)
n-hydroxy-n-phenylacetamide (ix)
2-[[2-(tert-butoxy)-2-oxoethoxy]imino]-2-(1,3-thiazol-4-yl)acetic acid (x)
Reference 1:
    farina, v.; benigni, d.a.; 2,3-dideoxynucleosides for aids chemotherapy. tetrahedron lett 1988, 29, 11, 1239-42.

Route 5
a new method for the synthesis of title compound has been reported:the reaction of 5-o-triphenylmethyl-2-deoxyadenosine (i) with cs2, methyl iodide and nah gives the corresponding xanthate (ii), which is reduced with tributyl hydrogen stannide to 5-o-triphenylmethyl-2,3-dideoxyadenosine (iii). finally, this compound is deprotected in the usual way.
List of intermediates No.
(3r)-3-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1h-inden-5-yl 1,2-dimethyl-1-hydrazinecarboxylate (i)
(3r)-3-amino-2,3-dihydro-1h-inden-5-yl 1,2-dimethyl-1-hydrazinecarboxylate (ii)
4-nitrobenzyl (4s,5r,6s)-6-[(1r)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (iii)
Reference 1:
    samukov, v.v.; ofitserov, v.i.; synthesis od 2,3-dideoxynucleosides. bioorg khim 1983, 9, 1, 52-59.

Route 6
the elimination reaction of (iii) with sodium ethoxide in dmf gives 2,3-dideoxy-2,3-didehydroadenosine (v), which is hydrogenated with h2 over pd/c in ethanol.
List of intermediates No.
2-[2-(4-fluorophenyl)-1,3-benzoxazol-5-yl]propionic acid (v)
(3r)-3-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1h-inden-5-yl 1,2-dimethyl-1-hydrazinecarboxylate (i)
n-benzyl-2-(5-fluoro-2-methyl-1h-inden-3-yl)acetamide (ii)
2-(5-fluoro-2-methyl-1h-inden-3-yl)acetyl chloride (iii)
Reference 1:
    mccarthy, j.r.; et al.; purine nucleosides. xiv. unsaturated furanosyl adenine nucleosides prepared via base-catalysed elimination reactions of 2-deoxyadenosine derivatives. j am chem soc 1966, 88, 7, 1549-53.
Reference 2:
    castaner, j.; hopkins, s.j.; serradell, m.n.; blancafort, p.; 2,3-dideoxyadenosine. drugs fut 1982, 7, 4, 244.

Route 7
the reaction of 5-triphenylmethyl-2-deoxyadenosine (i) with p-toluenesulfonyl chloride in pyridine gives 5-triphenylmethyl-3-(p-toluenesulfonyl)-2-deoxyadenosine (ii), which by partial hydrolysis with acetic acid yields 3-p-toluenesulfonyl)-2-deoxyadenosine (iii). the reaction of (iii) with ethylmercaptane (a) by means of sodium ethoxide affords 3-ethylthio-2,3-dideoxyadenosine (iv), which is finally desulfurized by treatment with raney-ni in refluxing methyl cellosolve - ethanol (100 c).
List of intermediates No.
2-methyl-1-sulfanyl-2-heptanol (a)
(3r)-3-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1h-inden-5-yl 1,2-dimethyl-1-hydrazinecarboxylate (i)
n-benzyl-2-(5-fluoro-2-methyl-1h-inden-3-yl)acetamide (ii)
2-(5-fluoro-2-methyl-1h-inden-3-yl)acetyl chloride (iii)
5-(5-fluoro-2-methylphenyl)-1,3-cyclohexanedione (iv)
Reference 1:
    robins, m.j.; et al.; the synthesis of 2,3-dideoxyadenosine from 2-deoxyadenosine. j am chem soc 1964, 86, 17, 3585-86.
Reference 2:
    robins, m.j.; et al.; purine nucleosides. xii. the preparation of 2,3-dideoxyadenosine, 2,5dideoxyadenosine and 2,3,5-trideoxyadenosine from 2-deoxyadenosine. biochem j 1966, 5, 1, 224-231.
Reference 3:
    castaner, j.; hopkins, s.j.; serradell, m.n.; blancafort, p.; 2,3-dideoxyadenosine. drugs fut 1982, 7, 4, 244.

Route 8
the reaction of 2,3-dideoxy-2chloro-3-ethylthioadenosine (vi) with potassium thiocyanate gives 2,3-dideoxy-2-thiocyanato-3-ethylthioadenosine (vii), which by treatment with ni sponge in dmf at 100 c under h2 atmosphere is converted into compound (iv), which is finally treated with raney-ni in refluxing methyl cellosolve-ethanol (100 c).
List of intermediates No.
5-(5-fluoro-2-methylphenyl)-1,3-cyclohexanedione (iv)
3-amino-5-(5-fluoro-2-methylphenyl)-2-cyclohexen-1-one (vi)
acetoacetaldehyde dimethylacetal; 1,1-dimethoxy-3-butanone; 3-ketobutyraldehyde dimethyl acetal; 3-ketobutyric aaldehyde 1-dimethylacetal; 3-oxobutyraldehyde dimethylacetal; 4,4-dimethoxy-2-butanone (vii)
Reference 1:
    tong, l.; et al.; an alternative synthesis of 2,3-dideoxyadenosine. j org chem 1965, 30, 8, 2854-55.
Reference 2:
    castaner, j.; hopkins, s.j.; serradell, m.n.; blancafort, p.; 2,3-dideoxyadenosine. drugs fut 1982, 7, 4, 244.

Route 9
the bromination of 2-deoxyadenosine (viii) with br2 in dioxane - water by means of caco3 or sodium acetate gives 8-bromo-2-deoxyadenosine (ix), which by reaction with triphenylmethyl chloride in pyridine - dmf is converted into 8-bromo-2-deoxy-5-o-triphenylmethyladenosine (x). the reaction of (x) with p-toluenesulfonyl chloride in pyridine affords 8-bromo-5-o-triphenylmethyl-3-o-(p-toluenesulfonyl)-2-deoxyadenosine (xi), which by reaction with thiourea (a) in refluxing butanol and treatment with propanol-ammonia-water is converted into 2,3-dideoxy-8-mercapto-8,3-anhydroadenosine (xii). finally, this compound is desulfurized by treatment with raney-ni in refluxing water.
List of intermediates No.
methyl (1s,3as,4s,5s,7as)-4-(cyanomethyl)-7a-methyl-5-[(1r,3r,6r)-3-methyl-2-oxo-7-oxabicyclo[4.1.0]hept-3-yl]octahydro-1h-indene-1-carboxylate (a)
(2s)-1-[(9h-fluoren-9-ylmethoxy)carbonyl]octahydro-1h-indole-2-carboxylic acid (viii)
7-(5-fluoro-2-methylphenyl)-4-methyl-7,8-dihydro-5(6h)-quinolinone (ix)
methyl 2-(3-formyl-4-hydroxyphenyl)acetate (x)
methyl 2-(3-bromo-5-formyl-4-hydroxyphenyl)acetate (xi)
methyl 2-[3-bromo-5-formyl-4-[(2-methoxyethoxy)methoxy]phenyl]acetate (xii)
Reference 1:
    morio, i.; masakatsu, k.; nucleosides and nucleotides. xliv. purine cyclonucleosides. 2. synthesis of cyclonucleosides having 8,3-o- and -s-anhydro linkage derived from 2-deoxyadenosine. chem pharm bull 1970, 18, 12, 2441-46.
Reference 2:
    castaner, j.; hopkins, s.j.; serradell, m.n.; blancafort, p.; 2,3-dideoxyadenosine. drugs fut 1982, 7, 4, 244.

Route 10
the reaction of adenosine (xiii) with 2-acetoxyisobutyryl bromide (xiv) in acetonitrile gives 3-deoxy-3-bromo-2-o-acetyl-5-(2,5,5-trimethyl-1,3-dioxolan-4-on-2-yl)adenosine (xv), which is submitted to hydrogenolysis with h2 over pd/c in methanol containing triethylamine.
List of intermediates No.
n-butyl-2-(3,4-dimethoxyphenyl)-n-propylacetamide (xiii)
(2s)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid (xiv)
methyl 2-[5-formyl-6-[(2-methoxyethoxy)methoxy]-3-nitro[1,1-biphenyl]-3-yl]acetate (xv)
Reference 1:
    russell, a.f.; et al.; reaction of 2-acyloxyisobutyryl halides with nucleosides. ii. reactions of adenosine. j am chem soc 1973, 95, 12, 4025-30.
Reference 2:
    castaner, j.; hopkins, s.j.; serradell, m.n.; blancafort, p.; 2,3-dideoxyadenosine. drugs fut 1982, 7, 4, 244.

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2',3'-双脱氧腺苷;英文名Dideoxyadenosine;NSC-98700;ddA;CAS[4097-22-7]

 
推荐VIP企业
无锡景耀生物科技有限公司
杭州卢普生物科技有限公司
宁波赛伦化工有限公司
苏州昊赛生物科技有限公司
北京嘉盛扬医药科技有限公司
上海泽涵生物医药科技有限公司
河北固安三利化工公司
郑州凯普瑞生物技术有限公司
上海药谷药业有限公司
兰州康寓信生物科技有限公司
湖北朗昕生化药业有限公司
武汉福鑫化工有限公司
嘉兴市英南化工有限公司
苏州迪飞医药科技有限公司
北京富安凯科技有限公司
上海盛中医药化工有限公司
连云港天和化学有限公司
南京晨瑞医药科技有限公司
南京苏如化工有限公司
常州瑞盛化工有限公司
热门文章
山东地区醋酸价格
陕西地区醋酸价格
江苏地区醋酸价格
浙江地区醋酸价格
山东地区醋酸价格
华北地区醋酸价格
河北地区醋酸价格
华北地区BDO市场低位整理
华东地区BDO市场偏弱运行
江苏地区醋酸价格
华北地区顺酐市场行情整理
河南地区醋酸价格
华北地区醋酸价格
华北地区醋酸价格
江苏地区醋酸价格
华北地区BDO市场低位整理
河北地区醋酸价格
江苏地区醋酸价格
浙江地区醋酸价格
华南地区BDO市场走势偏弱
 友情链接
有机化学人才网  
首页 | 广告服务 | 建站服务 | 关于我们 | 联系我们 | 版权声明