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 Lopinavir;A-157378.0;RS-346;ABT-378;Aluviran
Chemical Name N-[1(S)-Benzyl-3(S)-hydroxy-4(S)-[2-(2,6-dimethylphenoxy)acetamido]-5-phenylpentyl]-3-methyl-2(S)-(2-oxohexahydropyrimidin-1-yl)butyramide
CAS 192725-17-0
Related CAS
Formula C37H48N4O5
Structure
Formula Weight 628.81891
Stage 上市-2000
Company Abbott (Orphan Drug), Abbott (Originator), Gilead (Comarketer)
Activity/Mechanism AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors
Syn. Route 3
Route 1
the reaction of l-phenylalanine (i) with benzyl bromide and k2co3 in hot ethanol/water gives n,n,o-tribenzyl derivative (ii), which is condensed with acetonitrile (iii) by means of nanh2 in thf yielding the pentanenitrile (iv). the reaction of nitrile (iv) with benzylmagnesium chloride (v) in thf affords the diphenylhexenone (vi), which is reduced with nabh4 in thf to give the diphenylhexanol (vii). the protection of the amino group of (vii) with boc2o and k2co3 in methyl tert-butyl ether yields the carbamate (viii), which is debenzylated with ammonium formate over pd/c in methanol affording the amino compound (ix). the condensation of (ix) with 2-(2,6-dimethylphenoxy)acetic acid (x) by means of edac in dmf provides the corresponding amide (xi), which is deprotected at the carbamate group with tfa in dichloromethane to give (xii) with a free amino group. finally, this compound is condensed with 3-methyl 2(s)-(2-oxoperhydropyrimidin-1-yl)butyric acid (xiii) by means of edac in dmf or socl2 and imidazole to furnish the target compound.the intermediate 2-(2,6-dimethylphenoxy)acetic acid (x) has been obtained by condensation of 2,6-dimethylphenol (xiv) with ethyl 2-bromoacetate (xv) by means of cs2co3 in refluxing dioxane to give the acetate ester (xvi), which is hydrolyzed with lioh ethanol/water to afford the target intermediate (x).
List of intermediates No.
(2s)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid (i)
[(2r,3s,4s,5r)-5-(6-amino-2-fluoro-9h-purin-9-yl)-3,4-dihydroxytetrahydro-2-furanyl]methyl diethyl phosphate (xv)
(2s)-1,4-dimethoxy-1,4-dioxo-2-butanaminium chloride (v)
3-(1,1-dimethylheptyl)-6,6-dimethyl-9-methylene-6a,7,8,9,10,10a-hexahydro-6h-benzo[c]chromen-1-ol
2-(chloromethyl)-1-benzofuran (iii)
benzyl 4-[2-(1,2,3,5-cyclohexatetraen-1-yl)-6-fluoro-1h-indol-3-yl]-3,6-dihydro-1(2h)-pyridinecarboxylate (ii)
benzyl 4-(6-fluoro-2-phenyl-1h-indol-3-yl)-3-hydroxy-1-piperidinecarboxylate (vi)
7,7-dimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride (vii)
methyl (2s)-1-((2s)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoyl)-2-pyrrolidinecarboxylate (iv)
(2s)-1-((2s)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoyl)-2-pyrrolidinecarboxylic acid (xiii)
tert-butyl (1r,2s)-1-formyl-2-methylbutylcarbamate (x)
(xiv)
2-([(2r)-3-[1-([[(benzyloxy)carbonyl]amino][[(benzyloxy)carbonyl]imino]methyl)-4-piperidinyl]-2-[(benzylsulfonyl)amino]propanoyl]amino)acetic acid (viii)
(ix)
(2r)-n-[2-([(3s)-1-[amino(imino)methyl]-2-ethoxypiperidinyl]amino)-2-oxoethyl]-3-[1-[amino(imino)methyl]-4-piperidinyl]-2-[(benzylsulfonyl)amino]propanamide (xvi)
benzyl (2s,3r,4r,5s,6r)-4-(benzyloxy)-5-hydroxy-6-(hydroxymethyl)-2-methoxytetrahydro-2h-pyran-3-ylcarbamate (xi)
n-acetylimidazole; 1-acetylimidazole (xii)
Reference 1:
    stoner, e.j.; et al.; synthesis of abt-378, an hiv protease inhibitor candidate: avoiding the use of carbodiimides in a difficult peptide coupling. org process res dev 1999, 3, 2, 145.
Reference 2:
    sham, h.l.; stewart, k.d.; kempf, d.j. (abbott laboratories inc.); retroviral protease inhibiting cpds.. ep 0876353; jp 2000502997; wo 9721683 .
Reference 3:
    retroviral protease inhibiting cpds.. ep 0882024; jp 2000502085; us 5914332; wo 9721685 .

Route 2
the intermediate 3-methyl 2(s)-(2-oxoperhydropyrimidin1-yl)butyric acid (xiii) has been obtained as follows: the oxidation of 3-(benzyloxycarbonylamino)-1-propanol (xvii) with oxalyl chloride in dichloromethane gives the corresponding aldehyde (xviii), which is reductocondensed with l-valine methyl ester (xix) by means nabh3cn in methanol yielding the n-substituted valine (xx). the cyclization of (xx) by elimination of the benzyloxycarbonyl group by hydrogenation with h2 over pd/c in dichloromethane, followed by reaction with carbonyldiimidazole (cdi) affords the 3-methyl 2(s)-(2-oxoperhydropyrimidin-1-yl)butyric acid methyl ester (xxi). finally, this compound is hydrolyzed with lioh in dioxane/water to afford the target intermediate (xiii).
List of intermediates No.
1-(tert-butyl) 4-[6-(7-chloro[1,8]naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5h-[1,4]dithiino[2,3-c]pyrrol-5-yl] 1,4-piperazinedicarboxylate (xix)
(2s)-1-((2s)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoyl)-2-pyrrolidinecarboxylic acid (xiii)
((2r,3s,4r,5r,6s)-4-(benzyloxy)-5-[[(benzyloxy)carbonyl]amino]-3-hydroxy-6-methoxytetrahydro-2h-pyran-2-yl)methyl acetate (xvii)
methyl (3ar,5r,6s,7s,7ar)-7-(benzyloxy)-2-(tert-butoxy)-6-[(2-chloroacetyl)oxy]-2-methyltetrahydro-3ah-[1,3]dioxolo[4,5-b]pyran-5-carboxylate (xviii)
2,6-dimethylpyridinium perchlorate (xx)
methyl (2r,3s,4r,5r,6r)-5-(acetoxy)-6-[((2r,3s,4r,5r,6s)-2-[(acetoxy)methyl]-4-(benzyloxy)-5-[[(benzyloxy)carbonyl]amino]-6-methoxytetrahydro-2h-pyran-3-yl)oxy]-4-(benzyloxy)-3-[(2-chloroacetyl)oxy]tetrahydro-2h-pyran-2-carboxylate (xxi)
Reference 1:
    retroviral protease inhibiting cpds.. ep 0882024; jp 2000502085; us 5914332; wo 9721685 .
Reference 2:
    sham, h.l.; stewart, k.d.; kempf, d.j. (abbott laboratories inc.); retroviral protease inhibiting cpds.. ep 0876353; jp 2000502997; wo 9721683 .

Route 3
the reaction of l-phenylalanine (i) with benzyl bromide and k2co3 in hot etoh/h2o gives n,n,o-tribenzyl derivative (ii), which is condensed with acetonitrile (iii) by means of nanh2 in thf yielding the pentanenitrile (iv). the reaction of nitrile (iv) with benzylmagnesium chloride (v) in thf affords the diphenylhexenone (vi), which is reduced with nabh4 in thf to give the diphenylhexanol (vii) (slightly impurified (~10%) with other diastereomers that are not eliminated at this stage). the condensation of (vii) with acid chloride (viii) (obtained by reaction of acid (ix) with socl2) in the presence of imidazole yields the amide (x), which is debenzylated with ammonium formate over pd/c in methanol affording the amine (xi). at this stage the purification (elimination of the diastereomers) has been performed by crystallization of its salt with l-pyroglutamic acid (xii) in etoh/dmf, pure salt (xiii) being obtained. finally, this compound is condensed with the acid chloride (xiv) (obtained by reaction of acid (xv) with socl2) by means of nahco3 in ethyl acetate/water.the intermediates, the acids (ix) and (xv), have been obtained as indicated in schemes 24659001a and 24659001b (intermediates (xiii) and (x) of these schemes, respectively).
List of intermediates No.
(2s)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid (i)
(2s)-1,4-dimethoxy-1,4-dioxo-2-butanaminium chloride (v)
[(2,2-dimethylpropanoyl)oxy]methyl 4-oxo-4lambda(5)-piperazine-1-carboxylate (xii)
2-(chloromethyl)-1-benzofuran (iii)
benzyl 4-[2-(1,2,3,5-cyclohexatetraen-1-yl)-6-fluoro-1h-indol-3-yl]-3,6-dihydro-1(2h)-pyridinecarboxylate (ii)
benzyl 4-(6-fluoro-2-phenyl-1h-indol-3-yl)-3-hydroxy-1-piperidinecarboxylate (vi)
7,7-dimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride (vii)
methyl (2s)-1-((2s)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoyl)-2-pyrrolidinecarboxylate (iv)
(2s)-1-((2s)-2-[[tert-butyl(dimethyl)silyl]oxy]propanoyl)-2-pyrrolidinecarboxylic acid (ix)
(2r)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoic acid (viii)
2-(trimethylsilyl)ethyl (2r)-2-[[(benzyloxy)carbonyl](methyl)amino]-4-methylpentanoate (x)
2-(trimethylsilyl)ethyl (2r)-4-methyl-2-(methylamino)pentanoate (xi)
(2r,3s)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid (xiii)
ethyl (4r,5s)-4-[(tert-butoxycarbonyl)amino]-5-methyl-3-oxoheptanoate (xiv)
tert-butyl (1r,2s)-1-formyl-2-methylbutylcarbamate (xv)
Reference 1:
    stoner, e.j.; et al.; synthesis of hiv protease inhibitor abt-378 (lopinavir). org process res dev 2000, 4, 4, 264.

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洛匹那韋;英文名Lopinavir;A-157378.0;RS-346;ABT-378;Aluviran;CAS[192725-17-0]

 
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
作物保護領域新熱點——植物生物
第15批!通過認定的農藥登記試
海利爾獲“金質量·持續成長獎”
安道麥推出新產品,并將致力于完
失效農藥如何鑒別?過期農藥如何
新修訂發布的《產業結構調整指導
麥田雜草發生加重,春季化除壓力
涉及21家農化企業,山東省公布
這29條環境違法行為可舉報!獎
10年時間成為大豆殺菌劑市場領
全球食品安全指數:中國進步明顯
2018年我國農藥標準發布概況
山東省農作物病蟲預報:小麥/玉
檢察機關:農資打假絕不手軟!
全國農技推廣中心:小麥條銹病發
土壤調理劑市場規模已達482億
2019農業令人矚目十大事件!
因抗藥性,這些農藥已失效了,怎
立足預防,主動出擊,全面做好油
中農立華+紅太陽,市場占有率或
 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
在手机上赚钱的有哪些方法