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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.

全民突击安卓跟苹果系统可以PK吗 www.uxeea.icu 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]

 
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