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 Conivaptan hydrochloride;CI-1025;YM-087
Chemical Name N-[4-(2-Methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-ylcarbonyl)phenyl]biphenyl-2-carboxamide hydrochloride
CAS 168626-94-6
Related CAS 210101-16-9 (free base)
Formula C32H27ClN4O2
Structure
Formula Weight 535.05059
Stage 上市-2006
Company Yamanouchi (Originator), Pfizer (Licensee)
Activity/Mechanism CARDIOVASCULAR DRUGS, Diuretics, Heart Failure Therapy, RENAL-UROLOGIC DRUGS, Oxytocin Antagonists, Vasopressin V1a Antagonists, Vasopressin V2 Antagonists
Syn. Route 3
Route 1
acylation of 2,3,4,5-tetrahydro-1h-1-benzazepin-5-one (i) with 4-nitrobenzoyl chloride (ii) by means of tea in ch2cl2 gives 1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1h-1-benzazepin-5-one (iii), which is hydrogenated with h2 over raney-ni in meoh, yielding the corresponding amine derivative (iv). acylation of (iv) with biphenyl-2-carboxylic acid (v) by means of oxalyl chloride in ch2cl2 affords the expected amide (vi) which is brominated with either br2 or cubr2, providing the alpha-bromo ketone (vii). this ketone (vii) is cyclized with acetamidine hydrochloride (viii) by means of k2co3 in mecn, furnishing a mixture of conivaptan and oxazolo[4,5-d][1]benzodiazepine compound. finally, conivaptan is separated by column chromatography over silica gel and is treated with 4n hcl to provide the desired hydrochloride.
List of intermediates No.
ethyl 3-(3-hydroxy-2-pyridinyl)propanoate (viii)
tert-butyl (2s)-2-[(tert-butoxycarbonyl)amino]-5-isothiocyanatopentanoate (v)
1-[(e)-3-chloro-1-propenyl]-3-methoxy-2-nitrobenzene; 3-[(e)-3-chloro-1-propenyl]-2-nitrophenyl methyl ether (ii)
n-(3-chloro-4-fluorophenyl)-6-(methylsulfinyl)pyrimido[5,4-d]pyrimidin-4-amine; n-(3-chloro-4-fluorophenyl)-n-[6-(methylsulfinyl)pyrimido[5,4-d]pyrimidin-4-yl]amine (i)
n-(3-chloro-4-fluorophenyl)-6-(methylsulfonyl)pyrimido[5,4-d]pyrimidin-4-amine; n-(3-chloro-4-fluorophenyl)-n-[6-(methylsulfonyl)pyrimido[5,4-d]pyrimidin-4-yl]amine (iii)
1-methyl-4-piperidinamine; 1-methyl-4-piperidinylamine (iv)
1-fluoro-4-iodobenzene; 4-fluoroiodobenzene; 4-iodofluorobenzene; p-fluoroiodobenzene (vi)
4-fluorobenzoic acid (vii)
Reference 1:
    casta?er, r.m.; norman, p.; rabasseda, x.; leeson, p.a.; casta?er, j.; conivaptan hydrochloride. drugs fut 2000, 25, 11, 1121.
Reference 2:
    tanaka, a.; koshio, h.; taniguchi, n.; matsuhisa, a.; sakamoto, k.; yamazaki, a.; yatsu, t. (yamanouchi pharmaceutical co., ltd.); fused benzazepine deriv. and pharmaceutical compsn. containing the same. ep 0709386; jp 1995505056; us 5723606; wo 9503305 .
Reference 3:
    koshio, h.; taniguchi, n.; tanaka, a.; yatsu, t.; matsuhisa, a.; nonpeptide arginine vasopressin antagonists for both v1a and v2 receptors: synthesis and pharmacological properties of 4-(1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)benzanilide derivatives and 4-(5,6-dihydro-4h-thiazolo[5,4-d][1]benzoaze. chem pharm bull 2000, 48, 1, 21.

Route 2
the bromination of 1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1h-1-benzazepin-5-one (ix) with br2 in chcl3 gives the alpha-bromo ketone (x), which is cyclized with acetamidine hydrochloride (viii) by means of k2co3, yielding the expected imidazo-benzazepine (xi). this compound is detosylated with hot h2so4 to provide 2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine (xii). acylation of (xii) with 4-nitroben-zoic acid (xiii) by means of pyridine in either hot mecn or dmf affords the 6-(4-nitro-benzoyl) derivative (xiv), which is reduced with h2 and raney-ni in meoh to the corres-ponding 6-(4-aminobenzoyl) compound (xv). finally, this compound is condensed with biphenyl-2-carbonyl chloride (xvi) [ obtained by treatment of biphenyl-2-carboxylic acid (v) with oxalyl chloride in ch2cl2/dmf] by means of pyridine in acetonitrile and treated with 4n hcl.
List of intermediates No.
3-[[tert-butyl(dimethyl)silyl]oxy]-2-[1-(1-hydroxy-1-methyl-2-propynyl)cyclopropyl]-5-(trimethylsilyl)-4-pentyn-2-ol (ix)
ethyl 3-(3-hydroxy-2-pyridinyl)propanoate (viii)
11-[[11-(acetoxy)undecanoyl]peroxy]-11-oxoundecyl acetate (xiii)
tert-butyl (2s)-2-[(tert-butoxycarbonyl)amino]-5-isothiocyanatopentanoate (v)
tert-butyl (2s)-2-[(tert-butoxycarbonyl)amino]-5-[[(hydroxyamino)carbothioyl]amino]pentanoate (xvi)
4-fluorobenzonitrile (x)
4-fluorobenzoic acid (xi)
n-[(3r,4s)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2h-chromen-4-yl]-2,5-dibromo-4-fluorobenzamide (xii)
percyanoethylene; tetracyanoethylene (xiv)
2-amino-5-bromo-1h-pyrrole-3,4-dicarbonitrile (xv)
Reference 1:
    casta?er, r.m.; norman, p.; rabasseda, x.; leeson, p.a.; casta?er, j.; conivaptan hydrochloride. drugs fut 2000, 25, 11, 1121.
Reference 2:
    yamazaki, a.; tanaka, a.; tsunoda, t. (yamanouchi pharmaceutical co., ltd.); novel preparation method of condensed benzazepine derivs.. jp 1996198879 .

Route 3
alternatively, treatment of biphenyl-2-carboxylic acid (v) with socl2 and dmf in ch2cl2 provides the acyl chloride (xvi), which is condensed with 4-aminobenzoic acid (xvii) by means of n,n-dimethylaniline in acetone to give the corresponding 4-(2-phenylbenzamido)benzoic acid (xviii). treatment of (xviii) with socl2 and dmf in dry thf affords the acyl chloride (xix), which is finally condensed with the inmidazobenzazepine (xii) by means of pyridine in mecn and treated with 4n hcl.
List of intermediates No.
tert-butyl (2s)-2-[(tert-butoxycarbonyl)amino]-5-isothiocyanatopentanoate (v)
tert-butyl (2s)-2-[(tert-butoxycarbonyl)amino]-5-[[(hydroxyamino)carbothioyl]amino]pentanoate (xvi)
1h-1,2,3,4-tetraazole; tetrazole (xvii)
(5r,9s)-2,9-dimethyl-10-[(triisopropylsilyl)oxy]-3-decyne-2,5-diol (xix)
n-[(3r,4s)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2h-chromen-4-yl]-2,5-dibromo-4-fluorobenzamide (xii)
ethyl 5-bromo-3,4-dicyano-1h-pyrrol-2-yliminoformate (xviii)
Reference 1:
    casta?er, r.m.; norman, p.; rabasseda, x.; leeson, p.a.; casta?er, j.; conivaptan hydrochloride. drugs fut 2000, 25, 11, 1121.
Reference 2:
    yamazaki, a.; tanaka, a.; tsunoda, t. (yamanouchi pharmaceutical co., ltd.); novel preparation method of condensed benzazepine derivs.. jp 1996198879 .

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盐酸考尼伐坦;英文名Conivaptan hydrochloride;CI-1025;YM-087;CAS[168626-94-6]

 
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
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
作物保护领域新热点——植物生物
海利尔获“金质量·持续成长奖”
辉丰公示原药车间停产进展,山东
简析甲氧基丙烯酸酯类杀菌剂登记
诺华MEK/BRAF国内价格不
化学、生物化学及微生物农药制造
我国农药产品质量情况统计分析
供应、需求、出口——全方位了解
第15批!通过认定的农药登记试
2019农业令人瞩目十大事件!
先正达受让中化、中化工农业板块
麦田杂草发生加重,春季化除压力
土壤调理剂市场规模已达482亿
呋虫胺市场现状与未来展望
预计小麦重大病虫害总体偏重发生
从应用现状看市场发展:小麦田除
2020年重大病虫害发生将重于
全球作物保护行业发展趋势
新修订发布的《产业结构调整指导
中农立华+红太阳,市场占有率或
 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