有机化学人才网 | 最新人才 | 最新职位 | 有机化学论坛 | 技术交易 | 药物合成 | 企业大全 | CAS大全 注册 | 登陆
   
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 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 未确定
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.

 
推荐VIP企业
杭州卢普生物科技有限公司
宁波赛伦化工有限公司
无锡景耀生物科技有限公司
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
2018年第12届韩国国际实验
2017上海国际污泥处理处置设
2017年泰国国际石油天然气展
华中地区醋酐市场行情暂稳
2018年欧洲精细化工展览会(
2018年第十六届俄罗斯国际实
2018年第69届美国匹兹堡实
2017’中国国际石墨烯创新大
广东醋酸丁酯市场平稳运行
华东醋酸丁酯市场整理运行
华北地区醋酐市场行情稳定
2018年埃及国际化工染料展
2017(第十三届)中国国际水
2017上海国际航空航天材料展
2017年欧洲德国制药原料展
2017年第十九届中东迪拜水处
2017中国国际化工科学仪器、
广东醋酸乙酯市场盘整运行
2018上海环保展览会|201
2018沈阳国际润滑油、脂展览
 友情链接
有机化学人才网  有机化学论坛
首页 | 会员级别 | 广告服务 | 建站服务 | 关于我们 | 联系我们 | 版权声明