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
菜青虫和小菜蛾绿色防控技术
飞防应用场景为导向的制剂研究
久易农业、托球股份、快达农化、
泰禾旗下公司拟投建年产1万吨2
精甲霜灵、甲酰胺磺隆、苯霜灵、
希腊植保公司Alfa完整融入安
我国成功研制一种提升Bt和球孢
山东绿霸子公司拟投资3.8亿建
毒死蜱、百草枯等农药在泰国遭到
飞防植保正迈进新时代
国内杀菌剂龙头企业——利民股份
中农立华原药价格指数20200
印度发布农药禁令,或重塑全球供
南京农大在杀菌剂调控赤霉病菌D
未来已至,只是分布不均
辉丰股份多个原药项目将复产,公
利民股份子公司拟投资10.4亿
阿根廷农药和肥料销售无限期暂停
蝗灾卷土重来,印度“史无前例”
中化助力新疆“大国棉仓”升级!
 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