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 Ketorolac;RS-37619
Chemical Name (±)-5-Benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid;(±)-5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
CAS 74103-06-3
Related CAS 74103-07-4 (tromethamine salt)
Formula C15H13NO3
Structure
Formula Weight 255.27576
Stage 上市-1991
Company Roche (Originator), Allergan (Licensee), Recordati (Licensee)
Activity/Mechanism ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Non-Opioid Analgesics, Non-Steroidal Antiinflammatory Drugs
Syn. Route 2
Route 1
the benzoylation of 2-methylthiopyrrole (i) with n,n-dimethylbenzamide (ii) by means of pocl3 in refluxing ch2cl2 gives 5-benzoyl-2-methylthiopyrrole (iii), which is condensed with spiro[2.5]-5,7-dioxa-6,6-dimethyloctane-4,8-dione (iv) by means of nah in dmf yielding compound (v). the oxidation of (v) with m-chloroperbenzoic acid in ch2cl2 affords the sulfone (vi), which is submitted to methanolysis with methanol and hcl giving 1-(3,3-dimethoxycarbonylpropyl)-2-methanesulfonyl-5-benzoylpyrrole (vii). the cyclization of (vii) with nah in dmf yields dimethyl 5-benzoyl-1,2-dihydro-3h-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylate (viii), which is finally hydrolyzed and decarboxylated with koh in refluxing methanol.compound (iii) can be oxidized with m-chloroperbenzoic acid as before giving 2-methanesulfonyl-5-benzoylpyrrole (ix), which is then condensed with spiro compound (iv) as before to afford compound (vi), already obtained.
List of intermediates No.
4-(4-pyridinyl)heptanedioic acid (iv)
2-pyrazinecarboxylic acid; pyrazinoic acid (i)
tert-butyl (4s)-3-oxopyrazolidinylcarbamate (ii)
diethyl 1-cyanovinylphosphonate (iii)
diethyl 2-[(4s)-4-[(tert-butoxycarbonyl)amino]-3-oxopyrazolidinyl]-1-cyanoethylphosphonate (v)
allyl (6s)-6-[(tert-butoxycarbonyl)amino]-2-cyano-5-oxo-6,7-dihydro-1h,5h-pyrazolo[1,2-a]pyrazole-3-carboxylate (vi)
diethyl 1-(methylsulfonyl)vinylphosphonate (vii)
diethyl 2-[(4s)-4-[(tert-butoxycarbonyl)amino]-3-oxopyrazolidinyl]-1-(methylsulfonyl)ethylphosphonate (viii)
allyl (6s)-6-[(tert-butoxycarbonyl)amino]-2-(methylsulfonyl)-5-oxo-6,7-dihydro-1h,5h-pyrazolo[1,2-a]pyrazole-3-carboxylate (ix)
Reference 1:
    muchowski, j.m.; franco, f.; greenhouse, r.; novel syntheses of 5-aryl-1,2-dihydro-3h-pyrrolo[1,2-a]pyrrole-1-carboxylic acids. j org chem 1982, 47, 9, 1682-88.
Reference 2:
    arrigoni-martelli, e.; castaner, j.; blancafort, p.; serradell, m.n.; rs-37,619. drugs fut 1983, 8, 10, 871.

Route 2
the condensation of dimethylacetone-1,3-dicarboxylate (x) with ethanolamine (xi) yields methyl 3-(methoxycarbonylmethyl)-3-(2-hydroxyethylamino)acrylate (xii), which is cyclized with bromoacetaldehyde diethylacetal (xiii) affording methyl 1-(2-hydroxyethyl)-3-methoxycarbonylpyrrol-2-acetate (xiv). acylation of (xiv) with methanesulfonyl chloride (xv) and triethylamine in ch2cl2 yields the corresponding mesylate (xvi), which by treatment with methyl iodide in refluxing acetonitrile is converted into methyl 1-(2-iodoethyl)-3-methoxycarbonylpyrrole-2-acetate (xvii). the cyclization of (xvii) with nah in dmf yields dimethyl 1,2-dihydro-3h-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate (xviii), which is hydrolyzed with koh in refluxing methanol - water to the corresponding diacid (xix). partial esterification of (xix) with isopropanol and hcl gives isopropyl 1,2-dihydro-3h-7-carboxypyrrolo[1,2-a]pyrrole-1-carboxylate (xx), which is decarboxylated by heating at 270 c affording isopropyl 1,2-dihydro-3h-pyrrolo[1,2-a]pyrrole-1-carboxylate (xxi). benzoylation of (xxi) with n,n-dimethylbenzamide (xxii) and pocl3 in refluxing ch2cl2 yields isopropyl 5-benzoyl-1,2-dihydro-3h-pyrrolo[1,2-a]pyrrole-1-carboxylate (xxiii), which is finally hydrolyzed with k2co3 or naoh in methanol - water.
List of intermediates No.
(1s,2s,3r,4s,7r,9s,10s,12r,15s)-4-(acetoxy)-1,12,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate (xi)
2,2,3-trimethyloxirane (xiii)
(2s,5r)-2-[[(benzyloxy)carbonyl]amino]-5-[(2r,4r)-4-(methoxycarbonyl)-1,3-thiazolidin-2-yl]hexanoic acid (x)
tert-butyl (4s)-3-oxopyrazolidinylcarbamate (xxii)
methyl 2-[(tert-butoxycarbonyl)amino]-3-[[(4-methylphenyl)sulfonyl]oxy]propanoate (xii)
(xiv)
allyl (e)-4-oxo-3-(phenylsulfonyl)-2-pentenoate (xvi)
allyl 2-acetyl-6-[(tert-butoxycarbonyl)amino]-5-oxo-6,7-dihydro-1h,5h-pyrazolo[1,2-a]pyrazole-3-carboxylate (xvii)
tert-butyl 3-oxo-4-pyrazolidinylcarbamate (xviii)
2-(2-methylphenyl)-4,5-dihydro-1h-imidazole (xix)
(xx)
methyl 4-(3,4,5-trimethoxyphenethyl)benzoate (xxi)
5-[4-(3,4,5-trimethoxyphenethyl)phenyl]-2,3,5,6-tetrahydroimidazo[2,1-a]isoquinolin-5-ol (xxiii)
Reference 1:
    blancafort, p.; serradell, m.n.; hillier, k.; castaner, j.; bppc. drugs fut 1981, 6, 11, 669.
Reference 2:
    muchowski, j.m.; kluge, a.f. (roche bioscience); 1,2-dihydro-3h-pyrrolo[1,2-a]pyrrole-1-carboxylic acids derivatives and process for the production thereof. de 2731678; es 460706; es 470214; fr 2358406; fr 2375234; gb 1554075 .
Reference 3:
    arrigoni-martelli, e.; castaner, j.; blancafort, p.; serradell, m.n.; rs-37,619. drugs fut 1983, 8, 10, 871.

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酮咯酸;英文名Ketorolac;RS-37619;CAS[74103-06-3]

 
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
中国农科院启动“农业纳米药物靶
先正达开发的吡唑酰胺类杀菌剂—
人大代表罗金仁:农药企业应向农
2020年第3批!101个农药
内蒙古元正拟建年产5000吨草
先正达集团和扬农化工协同效应几
长青股份年产13700吨农药原
富美实推出全新精准农业平台--
新型抑酸药物:伏诺拉生Vono
2020年第4批!54个农药产
红太阳正式控股坤宁生物,合作开
未来已至,只是分布不均
两会声音:推进农药包装废弃物有
中农立华原药价格指数20200
中化助力新疆“大国棉仓”升级!
农业农村部种植业管理司:这10
红太阳全球首家拥有敌草快二氯盐
先正达在意大利推出杀虫剂Min
国内创制的植物免疫激活抗病毒新
近期我国农药制造业十大规模项目
 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