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 Dorzolamide hydrochloride;MK-507;L-671152;Trusopt
Chemical Name 4(S)-(Ethylamino)-6(S)-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide hydrochloride
CAS 130693-82-2
Related CAS
Formula C10H17ClN2O4S3
Structure
Formula Weight 360.90299
Stage 上市-1995
Company Banyu (Originator), Merck & Co. (Originator)
Activity/Mechanism Antiglaucoma Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Carbonic Anhydrase Inhibitors
Syn. Route 2
Route 1
reaction of (i) with acetic anhydride-sulfuric acid in methylene chloride provided the sulfonic acid in 98% yield. conversion to the sulfonyl chloride with phosphorous pentachloride in methylene chloride followed by treatment with aqueous ammonia gave the sulfonamide (ii). reduction of the carbonyl function with sodium borohydride and oxidation of the thiopyran sulfur with oxone(r) yielded (iv). the 4-hydroxy substituent was converted to the acetylamino functionality under ritter conditions. reduction of (v) with borane-dimethylsulfide complex yielded (vi) as a mixture of diasteriomers. chromatography on silica gel gave the trans-racemate, which was resolved into its individual enantiomers through the di-p-toluoyl-l-tartaric acid salt. the absolute configuration of the s,s-enantiomer, mk-507, was established by single crystal x-ray analysis.
List of intermediates No.
1-[2-hydroxy-5-(1h-1,2,3,4-tetraazol-5-yl)phenyl]-1-ethanone (i)
2-(3-methoxyphenyl)-2-methyl-1-propanamine; 2-(3-methoxyphenyl)-2-methylpropylamine (ii)
n-[2-(3-methoxyphenyl)-2-methylpropyl]-n,n-dimethylamine; 2-(3-methoxyphenyl)-n,n,2-trimethyl-1-propanamine (iii)
3-[2-(dimethylamino)-1,1-dimethylethyl]phenol (iv)
4-(4-morpholinyl)butyl isocyanate; 4-(4-isocyanatobutyl)morpholine (v)
4-(4-morpholinyl)-1-butanamine; 4-(4-morpholinyl)butylamine (vi)
Reference 1:
    baldwin, j.j.; ponticello, g.s.; christy, m.e. (merck & co., inc.); thienothiopyran sulfonamide derivs., pharmaceutical compsns. and use. au 8818387; ep 0296879; jp 1989100174; us 4797413; us 4863922 .
Reference 2:
    baldwing, j.j.; ponticello, g.s.; sugrue, m.f.; mk-507. drugs fut 1990, 15, 4, 350.
Reference 3:
    ponticello, g.s.; freedman, m.b.; habecker, c.n.; et al.; utilization of alpha,beta-unsaturated acids as michael acceptors for the synthesis of thieno[2,3-b]thiopyrans. j org chem 1988, 53, 1, 9-13.

Route 2
a new synthesis of mk-0507 has been described:the condensation of 3(r)-(tosyloxy)butyric acid methyl ester (i) with lithium 2-thienylmercaptide (ii) in formamide-thf gives 3(s)-(2-thienylthio)butyric acid methyl ester (iii), which is hydrolyzed with aqueous hcl to the corresponding free acid (iv). the intramolecular friedel-craftscyclization of (iv) with trifluoroacetic anhydride yields 6(s)-methyl-5,6-dihydro-4h-thieno[2,3-b]thiopyran-4-one (v), which is reduced with lialh4 in toluene to afford 4(r)-hydroxy-6(s)-methyl-5,6-dihydro-4h-thieno[2,3-b]thiopyran (vi). epimerization of (vi) with sulfuric acid gives the alcohol (vii) in a cis:trans ratio of 24:76%. oxidation of (vii) with h2o2 and sodium tungstate yields the 7,7-dioxide (viii; cis-trans mixture), which is acetylated with acetic anhydride to the acetate (ix). the reaction of (ix) with acetonitrile and sulfuric acid affords n-[6(s)-methyl-5,6-dihydro-4h-thieno[2,3-b]thiopyran-4-yl]acetamide 7,7-dioxide (x; cis-trans mixture), which is sulfonated with chlorosulfonic acid and then treated with socl2 to give 4-acetamide-6(s)-methyl-5,6-dihydro-4h-thieno[2,3-b]thiopyran-2-sulfonyl chloride 7,7-dioxide (xi; cis-trans mixture). the reaction of (xi) with concentrated aqueous nh4oh in thf yields the corresponding sulfonamide (xii), which by reduction with bh3-dimethylsulfide in thf affords 4-(ethylamino)-6(s)-methyl-5,6-dihydro-4h-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide (xiii; cis-trans mixture). finally, this mixture is treated with maleic acid in acetone and the resulting maleates are submitted to fractionated crystallization, giving the maleate of the (4s,6s)-isomer, which is treated first with nahco3 and then with hcl to give mk-0507; [alpha](25)589 -17.1 c (c 1, h2o).
List of intermediates No.
2-phenylacetyl chloride (i)
(2r)-3-(2-naphthyl)-2-[(2-phenylacetyl)amino]propionic acid (ii)
(2r)-2-[methyl(2-phenylacetyl)amino]-3-(2-naphthyl)propionic acid (iii)
(2r)-2-[methyl(2-phenylacetyl)amino]-3-(2-naphthyl)propanamide (iv)
n-[(1r)-1-amino-2-(2-naphthyl)ethyl]-n-methyl-2-phenylacetamide (v)
(1r,2s)-2-[(1h-indol-3-ylcarbonyl)amino]cyclohexanecarboxylic acid (vi)
propanal n-phenylhydrazone (vii)
benzenediazonium chloride (viii)
1-[(e)-2-phenyldiazenyl]-1-propanone n-phenylhydrazone (ix)
3-ethyl-1,2,4-benzotriazine (x)
(2r,3s,4s,5r)-2-[(1r)-4-amino-6-oxo-2,4-cyclohexadien-1-yl]-4-hydroxy-5-(hydroxymethyl)tetrahydro-3-furancarbonitrile (xi)
(9r)-2,2-dimethyl-6,12-dioxo-9-(palmitoyloxy)-5,7,11-trioxa-2-azonia-6lambda(5)-phosphaheptacosan-6-olate (xii)
1h-indol-5-yl methyl ether; 5-methoxy-1h-indole; 5-methoxyindole (xiii)
Reference 1:
    sohar, p.; grabowski, e.j.j.; lamanec, t.; blacklock, t.j.; butcher, j.w.; an enantioselective synthesis of the topically-active carbonic anhydrase inhibitor mk-0507 - 5,6-dihydro-(s)-4-(ethylamino)-(s)-6-methyl-4h-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride. j org chem 1993, 58, 7, 1672.

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多佐胺;英文名Dorzolamide hydrochloride;MK-507;L-671152;Trusopt;CAS[130693-82-2]

 
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
新型“超分子纳米囊”可减少农药
苯胺跌势难改
诺普信等3家国内企业首登三氟苯
华南地区己二酸行情持稳
华北地区丁二烯市场行情弱势
华东地区苯酚市场稳定
华南地区己二酸行情小幅走低
华南地区BDO市场整理运行
华东地区丁二烯市场弱势盘整
山东地区二氯甲烷市场价格动态
山东地区木薯酒精市场稳定
浙江地区醋酸价格
山东地区醋酸价格
浙江地区醋酸价格
河南地区醋酸价格下调
杀线虫剂tioxazafen应
2018年1月451项农药产品
甘肃省明确5种农药在温室和露地
2018年全国冬小麦春季田管技
江苏地区二氯甲烷价格上调
 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