有機化學人才網 | 最新人才 | 最新職位 | 技術交易 | 藥物合成 |
   
全站搜索: |
  您當前位置:網站首頁 >> 藥物合成路線圖解
 

藥物詳細合成路線

Name Pergolide mesylate;LY-141-B(free base);LY-127809;Pharken;Nopar;Parkotil;Celance;Permax
Chemical Name 8beta-[(Methylthio)methyl]-6-propylergoline monomethanesulfonate;9beta-(Methylthiomethyl)-7-propyl-4,6,6abeta,7,8,9,10,10aalpha-octahydroindolo[4,3-fg]quinoline methanesulfonate
CAS 66104-23-2
Related CAS 66104-22-1 (free base)
Formula C20H30N2O3S2
Structure
Formula Weight 410.6017
Stage 上市-1989
Company Lilly (Originator), Amarin (Licensee), Draxis Health (Licensee), Elan (Licensee), Shire Pharmaceuticals (Licensee)
Activity/Mechanism Antiparkinsonian Drugs, Extrapyramidal Disorders, Treatment of, NEUROLOGIC DRUGS, Dopamine Receptor Agonists
Syn. Route 4
Route 1
a new synthesis of pergolide has been reported:the alkylation of 8,9-dihydroelymoclavine (i) with propyl iodide and na2co3 in n-methylpyrrolidone gives the quaternary compound (ii), which is mesylated with meso2cl in pyridine yielding the mesyl ester (iii). finally, (iii) is treated with sodium methylmercaptide in n-methylpyrrolidone.
List of intermediates No.
(2s,4s,5s,6s,6r,7s,11r,13s,15s,17ar,20r,20ar,20bs)-20-(tert-butyldimethylsilyloxy)-7-[4-o-[4-o-(tert-butyldimethylsilyl)-2,6-dideoxy-3-o-methyl-beta-l-mannopyranosyl]-2,6-dideoxy-3-o-methyl-beta-l-mannopyranosyloxy]-4,4-difluoro-5,6,8,19-tetramethyl-6-(1-methylpropyl)-20b-(trimethylsilyloxy)-3,4,5,6,6,7,10,11,14,15,17,17a,20a,20b-tetradecahydro-spiro[11,15-methano-2h,13h,20h-furo[4,3,2-pq][2,6]benzodioxacyclooctadecino-13,2-2h-pyran]-17-one; (2s,4s,5s,6s,6r,7s,11r,13s,15s,17ar,2 (i)
7-methyl-2h-chromen-2-one (ii)
7-(bromomethyl)-2h-chromen-2-one (iii)
Reference 1:
    misner, j.w. (eli lilly and company); one-pot process for preparing pergolide. ep 0571202 .
Reference 2:
    misner, j.w.; et al.; integration of a highly selective demethylation of a qaternized ergoline into a one-pot synthesis of pergolide. org process res dev 1997, 1, 1, 77.

Route 2
the reaction of methyl dihydro-lysergate (i) with cyanogen bromide in methylene chloride gives 6-cyano-8beta-methoxycarbonylergoline (ii), which is treated with zn dust and acetic acid - water to afford 8beta-methoxycarbonylergoline (iii). the alkylation of (iii) with propyl bromide (a) and potassium carbonate in dmf yields 6-n-propyl-8beta-methoxycarbonylergoline (iv), which is reduced with nabh4 in dioxane - methanol to 6-n-propyl-8beta-hydroxymethylergoline (v). the mesylation of (v) with mesyl chloride in pyridine gives 6-n-propyl-8beta-mesyloxymethylergoline (vi), which is finally treated with sodium methylmercaptide in dimethylacetamide and with methanesulfonic acid.
List of intermediates No.
ethyl 2-(1-piperazinyl)phenyl ether; 1-(2-ethoxyphenyl)piperazine (iii)
3-cyclopenten-1-ylmethyl 4-methylbenzenesulfonate (a)
5-chloro-6-(4-methyl-1-piperazinyl)indoline (i)
7-bromo-4-methyl-1h-indole (ii)
4-methyl-1h-indole-7-carboxylic acid (iv)
6-hydroxy-1-[(z)-3-pyridinylmethylidene]-3,4-dihydro-2-naphthalenone (v)
(5r,6s)-6-amino-5-(3-pyridinylmethyl)-5,6,7,8-tetrahydro-2-naphthalenol (vi)
Reference 1:
    kornfeld, e.c.; bach, n.j. (eli lilly and company); 6-n-propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds. at 371817b; dd 141928; ep 0003667; fr 2416891; gb 2014140; us 4166182 .
Reference 2:
    serradell, m.n.; castaner, j.; blancafort, p.; owen, r.t.; pergolide mesylate. drugs fut 1981, 6, 4, 231.

Route 3
the reaction of dihydrolysergol (i) with brcn in dmf gives the n-cyano derivative (ii), which is treated with naoh in ethylene glycol yielding the demethylated compound (iii). the reductive alkylation of (iii) with propionaldehyde (iv) and formic acid in dmf affords the propyl derivative (v), which is mesylated with mscl and pyridine giving the mesylate (vi). finally, this compound is treated with sodium methylthiolate and msoh.
List of intermediates No.
(2s,4s,5s,6s,6r,7s,11r,13s,15s,17ar,20r,20ar,20bs)-20-(tert-butyldimethylsilyloxy)-7-[4-o-[4-o-(tert-butyldimethylsilyl)-2,6-dideoxy-3-o-methyl-beta-l-mannopyranosyl]-2,6-dideoxy-3-o-methyl-beta-l-mannopyranosyloxy]-4,4-difluoro-5,6,8,19-tetramethyl-6-(1-methylpropyl)-20b-(trimethylsilyloxy)-3,4,5,6,6,7,10,11,14,15,17,17a,20a,20b-tetradecahydro-spiro[11,15-methano-2h,13h,20h-furo[4,3,2-pq][2,6]benzodioxacyclooctadecino-13,2-2h-pyran]-17-one; (2s,4s,5s,6s,6r,7s,11r,13s,15s,17ar,2 (i)
(2r)-5-[[amino(imino)methyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid (iv)
6-hydroxy-1-[(z)-3-pyridinylmethylidene]-3,4-dihydro-2-naphthalenone (v)
(5r,6s)-6-amino-5-(3-pyridinylmethyl)-5,6,7,8-tetrahydro-2-naphthalenol (vi)
(3s,10r,13s,16r,17s)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(1s)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthrene-16,17-diol (ii)
(2s,3r,4r,5r)-2-([(2s,3r,4r,5s)-3-(acetoxy)-2-([(3s,10r,13s,16s,17s)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-hydroxy-17-[(1s)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-16-yl]oxy)-5-[(triethylsilyl)oxy]tetrahydro-2h-pyran-4-yl]oxy)-4,5-bis[(triethylsilyl)oxy]tetrahydro-2h-pyran-3-yl 4-methoxybenzoate (iii)
Reference 1:
    misner, j.w.; et al.; integration of a highly selective demethylation of a qaternized ergoline into a one-pot synthesis of pergolide. org process res dev 1997, 1, 1, 77.

Route 4
the reaction of dihydrolysergol (i) with propyl iodide (ii) in hot sulfolane gives the quaternary salt (iii), which is treated with na2s in the same solvent, yielding the propyl derivative (iv). the reaction of (iv) with mesyl chloride and pyridine affords the corresponding mesylate (v), which is finally treated with commercial na-s-ch3 in dmf to afford the target methylsulfanyl derivative.
List of intermediates No.
(2s,4s,5s,6s,6r,7s,11r,13s,15s,17ar,20r,20ar,20bs)-20-(tert-butyldimethylsilyloxy)-7-[4-o-[4-o-(tert-butyldimethylsilyl)-2,6-dideoxy-3-o-methyl-beta-l-mannopyranosyl]-2,6-dideoxy-3-o-methyl-beta-l-mannopyranosyloxy]-4,4-difluoro-5,6,8,19-tetramethyl-6-(1-methylpropyl)-20b-(trimethylsilyloxy)-3,4,5,6,6,7,10,11,14,15,17,17a,20a,20b-tetradecahydro-spiro[11,15-methano-2h,13h,20h-furo[4,3,2-pq][2,6]benzodioxacyclooctadecino-13,2-2h-pyran]-17-one; (2s,4s,5s,6s,6r,7s,11r,13s,15s,17ar,2 (i)
3-amino-1-[2-(3-azabicyclo[3.2.2]non-3-yl)-2-oxoethyl]-5-(2-fluorophenyl)-9-methyl-1,3-dihydro-2h-1,4-benzodiazepin-2-one (ii)
6-hydroxy-1-[(z)-3-pyridinylmethylidene]-3,4-dihydro-2-naphthalenone (iv)
Reference 1:
    anastasia, l.; et al.; simple and selective one-pot replacement of the n-methyl group of tertiary amines by quaternization and demethylation with sodium sulfide or potassium thioacetate: an application to the synthesis of pergolide. j chem soc - perkins trans i 2001, 19, 2398.

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名甲磺酸培高利特;英文名Pergolide mesylate;LY-141-B(free base);LY-127809;Pharken;Nopar;Parkotil;Celance;Permax;CAS[66104-23-2]

 
推薦VIP企業
無錫景耀生物科技有限公司
杭州盧普生物科技有限公司
寧波賽倫化工有限公司
蘇州昊賽生物科技有限公司
北京嘉盛揚醫藥科技有限公司
上海澤涵生物醫藥科技有限公司
河北固安三利化工公司
鄭州凱普瑞生物技術有限公司
上海藥谷藥業有限公司
蘭州康寓信生物科技有限公司
湖北朗昕生化藥業有限公司
武漢福鑫化工有限公司
嘉興市英南化工有限公司
蘇州迪飛醫藥科技有限公司
唐山盛源澤興化工有限公司
上海盛中醫藥化工有限公司
連云港天和化學有限公司
南京晨瑞醫藥科技有限公司
南京蘇如化工有限公司
常州瑞盛化工有限公司
熱門文章
農業農村部種植業管理司:這10
紅太陽全球首家擁有敵草快二氯鹽
解讀:新化學物質環境管理登記辦
先正達在意大利推出殺蟲劑Min
國際農藥分析協作委員會的農藥與
近期我國農藥制造業十大規模項目
主打植物生長調節劑和水溶性肥的
拉美非法農藥貿易有增無減,各國
“禾本綠色農藥研究院”被認定為
先正達以行動助力可持續農業!“
堅決禁止不必要環保執法! 違規
拜耳作物科學事業部2020一季
先正達將在阿根廷分銷Rizob
透過穎泰生物2019年報看行業
Amoeba與拜耳簽署關于生物
開發“專利到期”農藥,也要重視
巴西對252種已登記的制劑產品
解讀:中華人民共和國農業農村部
當今現代物理農業的四個高端技術
疫情下,農藥出口貿易公司如何突
 友情鏈接
有機化學人才網  
首頁 | 廣告服務 | 建站服務 | 關于我們 | 聯系我們 | 版權聲明
怎样才能在直播中赚钱 江西十一选五牛走势 福彩快乐十分预测 开通股票融资的条件 2019女篮总决赛直播 山西快乐十分必出规律 股票市场行情大盘指 广东36选7最新开奖 赛车pk10高手计划 十一运夺金概率制胜法宝 福建31选7历史开奖结果 百度