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 Albaconazole;UR-9825
Chemical Name (1R,2R)-7-Chloro-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4(3H)-one
CAS 187949-02-6
Related CAS
Formula C20H16ClF2N5O2
Structure
Formula Weight 431.83262
Stage I 期临床
Company Uriach (Originator)
Activity/Mechanism Antifungal Agents, ANTIINFECTIVE THERAPY
Syn. Route 2
Route 1
the condensation of the chiral oxazolidinone (i) with 2,4-difluorophenacyl bromide (ii) by means of nahmds in thf/et2 o gives the chiral oxirane (iii), which is treated with lioh and h2o2 to eliminate the chiral auxiliary, yielding the carboxylic acid (iv). the cleavage of the oxirane ring of (iv) with 1,2,4-triazole (v) and nah in hot dmf affords the chiral hydroxyacid (vi), which is submitted to curtius rearrangement by means of dppa in hot pyridine to provide the chiral oxazolidinone (vii). the cleavage of the oxazolidinone ring of (vii) by means of refluxing aq. hcl gives the chiral aminoalcohol (viii), which is condensed with 2-amino-4-chlorobenzoic acid (ix) by means of dcc and hobt to yield the corresponding amide (x). finally, this compound is cyclized to the target quinazolinone by reaction with triethyl orthoformate in hot dioxane/nmp.
List of intermediates No.
5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione (v)
2-(benzyloxy)-5-nitro-1h-isoindole-1,3(2h)-dione (i)
1-[(2r,3r,4r,5r)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydro-2-furanyl]-5-(5h-dibenzo[a,d]cyclohepten-5-yl)-4-thioxo-3,4-dihydro-2(1h)-pyrimidinone (ii)
Reference 1:
    bartroli, j.; et al.; aldol condensation of evans chiral enolates with acetophenones. its application to the stereoselective synthesis of homochiral antifungal agents. j org chem 1995, 60, 10, 3000.
Reference 2:
    bartroli, j.; et al.; new azole antigungals. 3. synthesis and antifungal activity of 3-substituted-4(3h)-quinazolinones. j med chem 1998, 41, 11, 1869.
Reference 3:
    bartrolí, j.; turmo, e.; anguita, m. (j. uriach & cía., sa); new pyrimidone derivs. with antifungal activity. ep 0783501; es 2107376; es 2120885; jp 1998508317; us 5807854; wo 9705130 .

Route 2
the condensation of (r)-lactic acid (i) with morpholine (ii) gives the corresponding morpholide (iii), which is protected at the hydroxyl position with dihydropyran (iv) to yield the tetrahydropyranyl ether (v). the grignard reaction of (v) with 2,4-difluorophenylmagnesium bromide (vi) affords the chiral 1-propanone (vii), which by a coreys diastereoselective epoxidation with trimethylsulfoxonium iodide is converted into the oxirane (viii). the opening of the oxirane ring of (viii) by means of 1,2,4-triazole (ix) and nah provides the tertiary alcohol (x), which is treated with pyridine p-toluenesulfonate to give the deprotected diol (xi) as a (2r,3r) and (2r,3s) 4:1 diastereomeric mixture, from which the desired (2r,3r)-isomer (xii) was isolated by crystallization. the reaction of (xii) with ms-cl and tea, followed by cyclization with naome, yields the oxirane (xiii), which is finally condensed with 7-chloroquinazolin-4(3h)-one (xiv) by means of k2co3 in hot nmp.
List of intermediates No.
2-(4-benzhydryl-1-piperazinyl)ethyl (z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate (ii)
(2r)-2-[([(2s)-1-[(2s,5s,8r,11s,14s,17r,20r)-20-(4-chlorobenzyl)-2,8-bis(4-[[(ethylamino)(ethylimino)methyl]amino]butyl)-11-(4-hydroxybenzyl)-14-(hydroxymethyl)-5-isobutyl-24,24-dimethyl-4,7,10,13,16,19,22-heptaoxo-17-(3-pyridinylmethyl)-23-oxa-3,6, (i)
4-([[3-(4-morpholinyl)propyl]imino]methyl)-2-pyrimidinamine (xii)
5-ethyl-5-hydroxy-1,4,5,8-tetrahydrooxepino[3,4-c]pyridine-3,9-dione (ix)
methyl (2s,3s,4s,5r,6r)-6-[5-(4-[[2,4-dimethyl-7-oxo-6,7-dihydropyrido[2,3-d]pyrimidin-8(5h)-yl]methyl][1,1-biphenyl]-2-yl)-2h-1,2,3,4-tetraazol-2-yl]-3,4,5-trihydroxytetrahydro-2h-pyran-2-carboxylate (iv)
2-[(dichlorophosphoryl)oxy]benzoyl chloride (vi)
(2r)-5-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid (xiii)
methyl 2-[3-(3-bromopropoxy)phenyl]acetate (v)
2-bromoethyl trifluoromethanesulfonate (xiv)
Reference 1:
    tasaka, a.; tamura, n.; matsushita, y.; teranishi, k.; hayashi, r.; okonogi, k.; itoh, k.; optically active antifungal azoles. i. synthesis and antifungal activity of (2r,3r)-2-(2,4-difluorophenyl)-3-mercapto-1-(1h-1,2,4-triazol-1-yl)-2-butanol and stereoisomers. chem pharm bull 1993, 41, 6, 1035-42.
Reference 2:
    bartroli orpi, j.; anguita lopez, m. (j. uriach & cia., sa); method for preparing pyrimidone derivs. with antifungal activity. es 2159488; wo 0166519 .

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阿巴康唑;英文名Albaconazole;UR-9825;CAS[187949-02-6]

 
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
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
华东地区邻苯市场行情上涨
华北地区醋酸价格
华北地区正丁醇市场行情
新型“超分子纳米囊”可减少农药
苯胺跌势难改
华东地区BDO市场僵持整理
诺普信等3家国内企业首登三氟苯
华东地区BDO市场持续僵持
华南地区苯酚市场窄幅上行
PTA止跌在眼前
华北苯酐市场行情
江苏地区顺酐市场行情整理
华东苯酐市场行情
山东地区三氯甲烷价格
山东地区辛醇市场行情
山东地区二氯甲烷市场价格动态
华东地区醋酸价格
河南地区醋酸价格
山东地区醋酸价格
浙江地区醋酸价格
 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