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 (+)-Fluprostenol isopropyl ester;Travoprost;AL-6221;Travatan
Chemical Name 7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[3(R)-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1(E)-butenyl]cyclopentyl]-5(Z)-heptenoic acid isopropyl ester
      (+)-16-[3-(Trifluoromethoxy)phenoxy]-17,18,19,20-tetranorprostaglandin F2alpha isopropyl ester
CAS 157283-68-6
Related CAS
Formula C26H35F3O6
Structure
Formula Weight 500.56045
Stage 上市-2001
Company Alcon (Originator)
Activity/Mechanism Antiglaucoma Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Prostaglandins, Prostanoid FP Agonists
Syn. Route 5
Route 1
the condensation of 2-[3-(trifluoromethyl)phenoxy]acetyl chloride (i) with methylphosphonic acid dimethyl ester (ii) by means of buli in thf gives 2-oxo-3-[3-(trifluoromethyl)phenoxy]propylphosphonic acid dimethyl ester (iii), which is condensed with the known bicyclic aldehyde (iv) by means of buli in dimethoxyethane, yielding the unsaturated ketone (v). the reduction of (v) with zinc borohydride in dimethoxyethane affords the unsaturated alcohol (vi), which is treated with k2co3 to give a diastereomeric mixture of unsaturated diols, resolved by chromatography to yield the chiral unsaturated diol (vii). the protection of (vii) with dihydropyran and tsoh in dichloromethane provides the bis(tetrahydropyranyl) ether (viii), which by reduction of the lactone ring with diisobutylaluminum hydride in thf gives the lactol (ix). the condensation of (ix) with the phosphonium bromide (x) by means of nah in dmso yields the prostenoic acid (xi), which is esterified with isopropyl iodide and 1,8-diazabicyclo[5.4.0]undec-7-ene (dbu) in acetone to afford the corresponding isopropyl ester (xii). finally, this compound is deprotected with acetic acid in hot thf/water.
List of intermediates No.
2-[[3-(phenethyloxy)propyl]sulfonyl]acetaldehyde (ii)
2-bromo-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one (x)
(1s,2s)-2-amino-1-phenyl-1,3-propanediol (xii)
phenyl (3s,6r,7s,8s)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate (iv)
methyl 4-formylbenzoate (i)
methyl 4-[(z)-2-nitro-1-propenyl]benzoate (iii)
methyl 4-(2-oxopropyl)benzoate (v)
methyl 4-((2r)-2-[[(2r)-2-hydroxy-2-phenylethyl]amino]propyl)benzoate (vi)
guanidine (vii)
thiourea (viii)
ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetate (ix)
1-(2-amino-1,3-thiazol-4-yl)-2-(1h-1,2,3-benzotriazol-1-yloxy)-2-oxo-1-ethanone oxime (xi)
1-[((6r,7r)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl]-1-methylpyrrolidinium (xiii)
Reference 1:
    klimko, p.g.; bishop, j.a.; desantis, l. jr.; sallee, v.l. (alcon laboratories, inc.); use of cloprostenol, fluprostenol and their analogues for the manufacture of a medicament for the treatment of glaucoma and ocular hypertension. ep 0639563; jp 1995165703; jp 1998182465; us 5665773 .
Reference 2:
    casta?er, j.; sorbera, l.a.; travoprost. drugs fut 2000, 25, 1, 41.
Reference 3:
    bowler, j.; crossley, n.s. (astrazeneca plc); method of inducing luteolysis using 16-aryloxy-17,18,19,20-tetranor-prostanoic acid derivs. us 4321275 .

Route 2
the alkylation of 2-iodo-5-(trifluoromethyl)phenol (i) with ethyl 2-bromoacetate (ii) and k2co3 in acetone gives the phenyl ether (iii), which is condensed with the phosphonate (iv) by means of buli in thf to yield the ketophosphonate (v). the condensation of the corey aldehyde (vi) with phosphonate (v) by means of clli and tea in thf affords the ketonic intermediate (vii), which is reduced with (-)-chlorodiisopinocampheylborane [(-)-dipcl] in thf to produce c-15 hydroxy epimer predominantly with the desired stereochemistry (viii).the hydrolysis of the benzoate group of (viii) with k2co3 in methanol gives the dihydroxylactone (ix), which is protected with dhp and ts-oh in dichloromethane to yield the bis-tetrahydropyranyl ether (x). the lactone group of (x) is reduced with dibal in thf to yield the lactol (xi), which is submitted to a wittig condensation with 4-carboxybutyltriphenylphosphonium bromide (xii) by means of tbu-ok in thf to afford the carboxylic acid (xiii). the esterification of (xiii) with isopropyl iodide and dbu in acetone affords the isopropyl ester (xiv), which is deprotected (elimination of the thp protecting groups) with hcl in methanol/water and purified by chromatography (elimination of the unwanted c15-epimer) to afford the precursor (xv). finally the iodine atom of (xv) is eliminated by hydrogenation with hydrogen over pd/c in ethyl acetate.
List of intermediates No.
2-[[3-(phenethyloxy)propyl]sulfonyl]acetaldehyde (iv)
2-bromo-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one (xii)
[(2r,3s,4s,5r)-5-(6-amino-2-fluoro-9h-purin-9-yl)-3,4-dihydroxytetrahydro-2-furanyl]methyl diethyl phosphate (ii)
(1s)-2-(benzyloxy)-1-[(2r,5r)-5-(1-hydroxy-1-methylethyl)-2-methyltetrahydro-2-furanyl]ethyl acetate (vi)
Reference 1:
    selliah, r.; et al.; synthesis of [phenyl-2-h-3]-travoprost: isopropyl ester prodrug of a selective prostaglandin fp receptor agonist. j label compd radiopharm 2001, 44, 3, 173.

Route 3
the alkylation of 2-iodo-5-(trifluoromethyl)phenol (i) with ethyl 2-bromoacetate (ii) and k2co3 in acetone gives the phenyl ether (iii), which is condensed with the phosphonate (iv) by means of buli in thf to yield the ketophosphonate (v). the condensation of the corey aldehyde (vi) with phosphonate (v) by means of clli and tea in thf affords the ketonic intermediate (vii), which is reduced with (-)-chlorodiisopinocampheylborane [(-)-dipcl] in thf to produce c-15 hydroxy epimer (viii) predominantly with the desired stereochemistry. the hydrolysis of the benzoate group of (viii) with k2co3 in methanol gives the dihydroxylactone (ix), which is protected with dhp and ts-oh in dichloromethane to yield the bis-tetrahydropyranyl ether (x). the lactone group of (x) is reduced with dibal in thf to yield the lactol (xi), which is submitted to a wittig condensation with 4-carboxybutyltriphenylphosphonium bromide (xii) by means of tbu-ok in thf to afford the carboxylic acid (xiii). the esterification of (xiii) with isopropyl iodide and dbu in acetone affords the isopropyl ester (xiv), which is deprotected (elimination of the thp protecting groups) with hcl in methanol/water and purified by chromatography (elimination of the unwanted c15-epimer) to afford the precursor (xv). finally the iodine atom of (xv) is substituted with tritium by hydrogenation with tritium gas over pd/c in ethyl acetate.
List of intermediates No.
2-[[3-(phenethyloxy)propyl]sulfonyl]acetaldehyde (iv)
2-bromo-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one (xii)
[(2r,3s,4s,5r)-5-(6-amino-2-fluoro-9h-purin-9-yl)-3,4-dihydroxytetrahydro-2-furanyl]methyl diethyl phosphate (ii)
(1s)-2-(benzyloxy)-1-[(2r,5r)-5-(1-hydroxy-1-methylethyl)-2-methyltetrahydro-2-furanyl]ethyl acetate (vi)
Reference 1:
    selliah, r.; et al.; synthesis of [phenyl-2-h-3]-travoprost: isopropyl ester prodrug of a selective prostaglandin fp receptor agonist. j label compd radiopharm 2001, 44, 3, 173.

Route 4
synthesis of the tricyclic ketone intermediate (vi): optical resolution of racemic bicyclo[3.2.0]hept-2-en-6-one (i) by reaction with so2 and (+)-a-methylbenzylamine (ii) yields a mixture of diastereomeric salts of the a-hydroxysulfonic acid with the chiral amine (ii), which are separated by crystallization. treatment of the purified salt (iii) with aqueous na2co3 results in the pure enantiomer (-)-(i). reaction of (-)-(i) with 1,3-dibromo-5,5-dimethylhydantoin (dbdmh) in acetone/water affords the bromohydrin (iv), which is treated with tbdms-cl and imidazole to provide the silyl ether (v). finally, reaction of the protected bromohydrin (v) with potassium tert-butoxide in toluene gives the target tricyclic ketone intermediate (vi).
List of intermediates No.
2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran (ii)
methyl (2s)-2-[[(benzyloxy)carbonyl]amino]-2-(hydroxymethyl)-4-pentenoate (--i)
Reference 1:
    boulton, l.t.; brick, d.; fox, m.e.; et al.; synthesis of the potent antiglaucoma agent, travoprost. org process res dev 2002, 6, 2, 138.

Route 5
synthesis of the alkenyl cuprate (xvii): enzymatic acylation of the racemic acetylenic alcohol (vii) with vinyl butyrate (viii) by means of chirazyme l9 gives a mixture of the ester (r)-(ix) and the alcohol (s)-(x). reaction of this mixture with ms-cl and tea yields a mixture of ester (r)-(ix) and the mesylate (s)-(xi). treatment of this mixture with butyric acid and tea results in the acylation of mesylate (s)-(xi) with optical inversion, providing pure ester (r)-(ix). enzymatic hydrolysis of (r)-(ix) with chirazyme l2 affords the enantiomerically pure alcohol (r)-(xiii). silylation of alcohol (xiii) with tbdms-cl and imidazole gives the silyl ether (xiv), which is iodinated with cp2zrcl2 and i2 to yield the iodovinyl derivative (xv). finally, the reaction of compound (xv) with the lithium cuprate (xvi) -prepared by lithiation of thiophene with buli followed by treatment with copper (i) cyanide- affords the alkenyl cuprate (xvii).condensation of the alkenyl cuprate (xvii) with the tricyclic ketone (vi) in toluene provides the bicyclic ketone (xviii), which is submitted to a baeyer-villiger oxidation with peracetic acid to give a mixture of the regioisomeric lactones (xix) and (xx). the minor and unwanted regioisomer (xix) is selectively hydrolyzed by treatment with aqueous na2co3 and separated by crystallization. reduction of lactone (xx) with dibal in toluene gives lactol (xxi), which is submitted to a wittig condensation with (4-carboxybutyl)triphenylphosphonium bromide and t-buok in thf, followed by esterification with isopropyl iodide and dbu, yielding a mixture of the monosilylated compounds (xxiii) and (xxiv) due to migration of the silyl group on the cyclopentane ring. finally, this mixture is deprotected with hcl in isopropanol.
List of intermediates No.
2-bromo-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one (xxii)
Reference 1:
    boulton, l.t.; brick, d.; fox, m.e.; et al.; synthesis of the potent antiglaucoma agent, travoprost. org process res dev 2002, 6, 2, 138.

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曲沃前列素;英文名(+)-Fluprostenol isopropyl ester;Travoprost;AL-6221;Travatan;CAS[157283-68-6]

 
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
唐山盛源泽兴化工有限公司
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
欧盟农药年销量为3.6亿公斤
辉瑞重磅:PDE4湿疹新药Cr
双丙环虫酯——巴斯夫刺向刺吸口
不顾议会反对,欧盟正式批准延长
最易引起药害的农药排行榜!这些
美国国家环境保护局拟批准登记哒
本周中农立华原药价格指数与市场
芦笋农药登记“捉襟见肘”,氟吡
河北将建立116个省级农作物病
注意!农业农村部发布农药混配制
我国批准登记首个草地贪夜蛾防治
南方水稻防涝抗灾技术指导意见
住友化学的SDHI类新型杀菌剂
9月成都,2020“西部地区仿
巴斯夫与隆平高科携手合作,助力
农药制剂行业的发展方向和未来趋
火热的吸入剂,三联:布地格福审
墨西哥宣布将逐步淘汰并在202
全球最大的植物源杀虫剂类别——
昆虫性信息素——4-氧代-反-
 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