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
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
新农药登记需要注意哪些问题?
2018年除草剂登记数量领先,
江苏省严查严管危废处置,保障环
年报!正邦科技净利润或同比下降
中山化工嘧菌酯/灭草松/啶酰菌
红太阳子公司重庆华歌生化投资设
吲唑磺菌胺化合物专利已经届满,
2019年上海市推荐农药品种及
预增!江山/新安2018年净利
国光股份募集资金投资项目变更实
安道麦与辉丰签署备忘录,拟收购
恭喜!这3家企业入围第25批国
科迪华旗下喹禾灵除草剂产品线被
民族骄傲!氰烯菌酯再获国家科学
BMS 白血病药物组合 Spr
增加至7000万!国光股份子公
农药领域的行政许可事项相互之间
暂停?不存在的!2019年将全
多个植保农药类项目拟提名201
又有多项植保农药类成果拟提名2
 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