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 (-)-Cetirizine;Levocetirizine;Xusal;Xyzal
Chemical Name (R)-2-[2-[4-[1-(4-Chlorophenyl)-1-phenylmethyl]piperazin-1-yl]ethoxy]acetic acid
CAS 130018-77-8
Related CAS
Formula C21H25ClN2O3
Structure
Formula Weight 388.898
Stage 上市-2001
Company Sepracor (Originator), UCB (Licensee)
Activity/Mechanism Allergic Skin Disorders, Treatment for, Asthma Therapy, DERMATOLOGIC DRUGS, Drugs for Allergic Rhinitis, RESPIRATORY DRUGS, Treatment of Upper Respiratory Tract Disorders, Urticaria, Treatment for, Histamine H1 Antagonists, IL8 Expression Inhibitors, TNF Expression Inhibitors
Syn. Route 3
Route 1
the resolution of racemic 1-[(4-chlorophenyl)phenylmethyl]piperazine (i) with l-tartaric acid provided the required (r)-enantiomer (ii), which was condensed with (2-chloroethoxy)acetonitrile (iii) in the presence of na2co3 and ki in refluxing n-butanol to give the alkylated piperazine (iv). the nitrile group of (iv) was finally hydrolyzed by means of concentrated hydrochloric acid to yield the target carboxylic acid.
List of intermediates No.
(4as,6r,8as)-6-hydroxy-11-methyl-5,6,9,10,11,12-hexahydro-4ah-[1]benzofuro[3a,3,2-ef][2]benzazepin-3-yl pivalate (i)
(ii)
(iii)
(iv)
Reference 1:
    cossement, e.; motte, g.; gobert, j.; bodson, g. (ucb sa); process for preparation of a 1-piperazine-ethoxyacetic acid. gb 2225321 .

Route 2
in a further procedure, racemic (4-chlorophenyl)phenylmethyl amine (v) was resolved by means of l-tartaric acid. the undesired (s)-enantiomer (vii) could be recovered by racemization to (v) upon treatment with 2-hydroxybenzaldehyde and naome. the required (r)-enantiomer (vi) was condensed with n,n-bis(chloroethyl)-p-toluenesulfonamide (viii) in refluxing diisopropylethylamine to provide the n-tosyl piperazine (ix). deprotection of the p-toluenesulfonamide of (ix) was achieved by treatment with hbr in the presence of 4-hydroxybenzoic acid. the resulting piperazine (x) was alkylated with either (2-chloroethoxy)acetamide (xi) or methyl (2-chloroethoxy)acetate (xiii), affording the n-alkylated piperazines (xii) and (xiv), respectively. the title carboxylic acid was then obtained by hydrolysis of amide (xii) with aqueous hcl or, alternatively, by hydrolysis of ester (xiv) with ethanolic koh.
List of intermediates No.
3-[(carboxymethyl)(hydroxy)phosphoryl]alanine (xi)
benzhydryl 4-(benzhydryloxy)-4,6-dioxo-1,4lambda(5)-azaphosphinane-2-carboxylate (xiii)
(x)
(v)
(vi)
(viii)
(ix)
(xii)
methyl (2s)-2-amino-5-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)pentanoate (xiv)
methyl (2s)-5-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)-2-[(4-formylbenzoyl)amino]pentanoate (vii)
Reference 1:
    bodson, g.; gobert, j.; cossement, e. (ucb sa); enantiomers of 1-[4-(chlorophenyl)phenylmethyl]-4-(methylphenyl)sulfonyl piperazine. ep 0617028 .

Route 3
the reaction of racemic cetiricine (i) with socl2 in toluene gives the acyl chloride (ii), which is treated with ammonia to yield the corresponding racemic amide (iii). the optical resolution of (iii) by preparative chiral chromatography on a chiralpak ad column affords the (r)-isomer (iv), which is treated with hcl in refluxing methanol to provide the chiral methyl ester (v). finally, ester (v) is hydrolyzed with aqueous hcl to provide the chiral target compound. the hydrolysis of amide (iv) is not performed directly to the target acid owing to purification problems (separation of the ammonium chloride formed in the hydrolysis with hcl).
List of intermediates No.
(iv)
methyl (2s)-2-amino-5-(1,3-dioxo-1,3-dihydro-2h-isoindol-2-yl)pentanoate (v)
(6as,10as)-9-(bromomethyl)-3-(1,1-dimethylheptyl)-6,6-dimethyl-6a,7,10,10a-tetrahydro-6h-benzo[c]chromen-1-ol (i)
(1r,2s,4r,5r,8r,9s,11r)-2-({[(2r,3s,4s,5s,6r)-3,4-dihydroxy-5-methoxy-6-methyltetrahydro-2h-pyran-2-yl]oxy}methyl)-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylic acid (ii)
benzhydryl (1r,2s,4r,5r,8r,9s,11r)-2-({[(2r,3s,4s,5s,6r)-3,4-dihydroxy-5-methoxy-6-methyltetrahydro-2h-pyran-2-yl]oxy}methyl)-9-formyl-13-isopropyl-5-methyltetracyclo[7.4.0.0~2,11~.0~4,8~]tridec-12-ene-1-carboxylate (iii)
Reference 1:
    pflum, d.a.; et al.; a large-scale synthesis of enantiomerically pure cetirizine dihydrochloride using preparative chiral hplc. org process res dev 2001, 5, 2, 110.

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左西替利嗪;英文名(-)-Cetirizine;Levocetirizine;Xusal;Xyzal;CAS[130018-77-8]

 
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
因抗药性,这些农药已失效了,怎
当前我国小麦主要病虫害发生面积
2019年农药市场谁主沉浮?
必须知道!这些问题在农药登记申
用药拌干稻种可减轻恶苗病和干尖
检察机关:农资打假绝不手软!
这29条环境违法行为可举报!奖
安道麦推出新产品,并将致力于完
原药登记中环境试验项目:环境归
2018年我国农药发展回顾与对
具有应用前景的新型杀线虫剂
涉及21家农化企业,山东省公布
联化科技2019年第一季度净利
2018年我国农药标准发布概况
山东省农作物病虫预报:小麦/玉
草甘膦再评审即将开始!欧盟提议
偷排废液2650吨!公司被罚款
十大典型!2018年共挽回1.
农业农村部×中化集团:携手共促
重磅!2019年全球化工企业5
 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