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 Nelfinavir mesilate;LY-312857;AG-1346(free base);AG-1343;Viracept
Chemical Name N-tert-Butyl-2-[2(R)-Hydroxy-3(R)-[(3-hydroxy-2-methylbenzoyl)amino]-4-(phenylsulfanyl)butyl]decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide monomethanesulfonate
CAS 159989-65-8
Related CAS 159989-64-7 (free base)
Formula C33H49N3O7S2
Structure
Formula Weight 663.90238
Stage 上市-1997
Company Agouron (Originator), Japan Tobacco (Licensee), Mitsubishi Pharma (Licensee), Roche (Licensee)
Activity/Mechanism AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors
Syn. Route 7
Route 1
the addition of thiophenol (ii) to n-(benzyloxycarbonyl)-l-serine beta-lactone (i) by means of nah in thf gives n-(benzyloxycarbonyl)-(s-phenyl)-l-cysteine (iii), which is treated with isobutyl chloroformate, diazomethane and n-nitro-n-nitrosoguanidine in ethyl acetate/ethyl ether to yield the diazo intermediate (iv). the treatment of (iv) with dry hcl in ethyl ether affords the chloromethyl derivative (v), which is reduced with nabh4 in thf giving the secondary alcohol (vi). the dehydrochlorination of (vi) with koh in ethanol yields the corresponding epoxide (vii), which is submitted to ring opening with (3s,4as,8as)-n-(tert-butyl)decahydroisoquinoline-3-carboxamide (viii) in hot isopropanol to afford the condensation product (ix). the deprotection of (ix) with 30% hbr in acetic acid gives compound (x) with a free amino group, which is finally acylated with 3-hydroxy-2-methylbenzoic acid (xi) by means of dicyclohexylcarbodiimide (dcc) and hydroxybenzotriazole (hobt) in thf.the benzoic acid (xi) has been obtained by the following sequence: the condensation of 3-methoxybenzoyl chloride (xii) with aniline (xiii) gives the corresponding anilide (xiv), which is methylated with butyllithium and methyl iodide in thf yielding 2-methyl-3-methoxybenzanilide (xv). finally, this compound is treated with 5n hcl and 30% hbr in refluxing acetic acid.
List of intermediates No.
1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (xiii)
2-[(2r)-2-(2-chlorobenzyl)-3,6-dioxo-4-(3-phenylpropyl)piperazinyl]acetic acid (ii)
tert-butyl (2s)-2-[[(2s,4r)-2-amino-4-methyloctanoyl](methyl)amino]-4-methylpentanoate (viii)
5-(2-ethoxyethyl)-4-hydrazino-6-phenyl-2-pyrimidinamine (i)
4-chloro-5-(2-ethoxyethyl)-6-phenyl-2-pyrimidinylamine (iii)
(3ar,5s,6s,6ar)-5-[(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (iv)
3-([(3ar,5s,6s,6ar)-5-[(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl]oxy)-n,n-dimethyl-1-propanamine (v)
(2s,3s,4r,5r)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]-2-cyanotetrahydro-3-furanyl benzoate (vi)
(2r,3s,4r,5r)-2-(aminocarbothioyl)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate (vii)
4,6-dimethyl-2-oxo-2h-chromen-7-yl acetate (ix)
8-acetyl-7-hydroxy-4,6-dimethyl-2h-chromen-2-one (x)
ethyl 2-[(8-acetyl-4,6-dimethyl-2-oxo-2h-chromen-7-yl)oxy]acetate (xi)
2-[(8-acetyl-4,6-dimethyl-2-oxo-2h-chromen-7-yl)oxy]acetic acid (xii)
5h-dibenzo[a,d]cyclohepten-5-one; dibenzosuberenone (xiv)
ethyl 2-(5h-dibenzo[a,d]cyclohepten-5-ylidene)acetate (xv)
Reference 1:
    rabasseda, x.; martel, a.m.; casta?er, j.; nelfinavir mesylate. drugs fut 1997, 22, 4, 371.
Reference 2:
    dressman, b.a.; fritz, j.e.; hammond, m.; hornback, w.j.; kaldor, s.w.; kalish, v.j.; munroe, j.e.; reich, s.h.; tatlock, j.h.; shepherd, t.a.; rodriguez, m.j. (agouron pharmaceuticals, inc.); hiv protease inhibitors. ep 0889036; jp 1997501443; jp 1999310573; us 5484926; wo 9509843 .
Reference 3:
    jungheim, l.n.; shepherd, t.a. (eli lilly and company); intermediate and process for making. wo 9521164 .

Route 2
a new synthesis of nelfinavir has been described: the protection of the amino group of the dioxolane derivative (i) with benzyl chloroformate and k2co3 in toluene gives the carbamate (ii), which is mesylated with mscl and triethylamine in toluene yielding the mesylate (iii). reaction of compound (iii) with thiophenol (iv) by means of tetrabutylammonium bromide and naoh in toluene/water affords the thioether (v), which is treated with hcl in methanol/water to provide diol (vi). protection of the primary oh group of (vi) with p-nitrobenzoyl chloride and 2-picoline yields the p-nitrobenzoate (vii), which is mesylated as before to afford the protected compound (viii). the reaction of (viii) with koh in dioxane gives epoxide (ix), which is condensed with n-tert-butylperhydroisoquinoline-3-carboxamide (x) in refluxing methanol to yield the addition product (xi). this compound (xi) can also be obtained by direct condensation of compound (viii) with isoquinoline (x) by means of k2co3 in methanol/water. removal of the benzyloxycarbonyl group of (xi) with koh in hot isopropanol affords compound (xii), which is condensed with 3-acetoxy-2-methylbenzoyl chloride (xiii) by means of nahco3 in ethyl acetate to give the corresponding amide (xiv). finally, this compound is deacetylated with ammonia in methanol.
List of intermediates No.
2-[(2r)-2-(2-chlorobenzyl)-3,6-dioxo-4-(3-phenylpropyl)piperazinyl]acetic acid (iv)
tert-butyl (2s)-2-[[(2s,4r)-2-amino-4-methyloctanoyl](methyl)amino]-4-methylpentanoate (x)
(2r,3s,4r,5r)-2-(aminocarbothioyl)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate (ix)
4,6-dimethyl-2-oxo-2h-chromen-7-yl acetate (xi)
8-acetyl-7-hydroxy-4,6-dimethyl-2h-chromen-2-one (xii)
1-[(e)-3-chloro-1-propenyl]-3-methoxy-2-nitrobenzene; 3-[(e)-3-chloro-1-propenyl]-2-nitrophenyl methyl ether
1-(2-hydroxyethyl)-2-imidazolidinone (i)
1-{2-[4-[5-chloro-1-(4-fluorophenyl)-1h-indol-3-yl]-3,6-dihydro-1(2h)-pyridinyl]ethyl}-2-imidazolidinone (ii)
2-isopropyl-1,3-dioxane-5-carbonyl chloride (iii)
2,4,6-triiodo-5-{[(2-isopropyl-1,3-dioxan-5-yl)carbonyl]amino}isophthaloyl dichloride (v)
2,3-dihydroxy-n-methylpropylamine; n-methyl-3-amino-1,2-propanediol; 3-methylamino-1,2-propanediol (vi)
n~1~,n~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-{[(2-isopropyl-1,3-dioxan-5-yl)carbonyl]amino}-n~1~,n~3~-dimethylisophthalamide (vii)
n~4~-(6-methoxy-8-quinolinyl)-1,4-pentanediamine; n-(4-amino-1-methylbutyl)-n-(6-methoxy-8-quinolinyl)amine (viii)
n-(4-{2-[6,7-dimethoxy-3,4-dihydro-2(1h)-isoquinolinyl]ethyl}phenyl)-4,5-dimethoxy-2-nitrobenzamide (xiii)
2-amino-n-(4-{2-[6,7-dimethoxy-3,4-dihydro-2(1h)-isoquinolinyl]ethyl}phenyl)-4,5-dimethoxybenzamide (xiv)
Reference 1:
    schaus, s.e.; et al.; practical synthesis of enantiopure cyclic 1,2-amino alcohols via catalytic asymmetric ring opening of meso epoxides. j org chem 1997, 62, 12, 4197.
Reference 2:
    busse, j.k.; borer, b.c.; zook, s.e.; a concise synthesis of the hiv-protease inhibitor nelfinavir via an unusual tetrahydrofuran rearrangement. tetrahedron lett 2000, 41, 36, 7017.

Route 3
a new concise synthesis of nelfinavir has been reported: the asymmetric desymmetrization of the meso-epoxide (i) by means of azidotrimethylsilane and a chiral (r,r)-(salen)chromium(iii) complex as catalyst gives the chiral 3-(trimethylsilyloxy)-4-azidotetrahydrofuran (ii), which is deprotected with tfa in methanol yielding the chiral 4-azidotetrahydrofuran-3-ol (iii). hydrogenation of (iii) with h2 over pto2 affords the chiral 4-aminotetrahydrofuran-3-ol (iv), which is condensed with 3-acetoxy-2-methylbenzoyl chloride (v) by means of nahco3 in dichloromethane to provide amide (vi). the mesylation of the oh group of (vi) with ms-cl gives mesylate (vii), which is isomerized with ac2o and h2so4 to yield oxazoline (viii). condensation of compound (viii) with the perhydroisoquinoline-3-carboxamide derivative (ix) by means of k2co3 in methanol affords the oxazoline-adduct (x). finally, the oxazoline-ring opening of compound (x) is performed with thiophenol (xi) and khco3.
List of intermediates No.
2-[(2r)-2-(2-chlorobenzyl)-3,6-dioxo-4-(3-phenylpropyl)piperazinyl]acetic acid (xi)
tert-butyl (2s)-2-[[(2s,4r)-2-amino-4-methyloctanoyl](methyl)amino]-4-methylpentanoate (ix)
n-(4-{2-[6,7-dimethoxy-3,4-dihydro-2(1h)-isoquinolinyl]ethyl}phenyl)-4,5-dimethoxy-2-nitrobenzamide (v)
3-quinolinecarboxylic acid; quinoline-3-carboxylic acid (i)
3-quinolinecarbonyl chloride (ii)
3-methoxy-4-(2-oxiranylmethoxy)benzaldehyde (iii)
4-[3-(tert-butylamino)-2-hydroxypropoxy]-3-methoxybenzaldehyde (iv)
n-[(3s,4r)-3-bromo-4-hydroxy-2,2-dimethyl-7-nitro-3,4-dihydro-2h-chromen-6-yl]-2-(4-methoxyphenyl)acetamide (vi)
2-chloro-n-(3-chlorophenyl)-9h-purin-6-amine; n-(3-chlorophenyl)-n-(2-chloro-9h-purin-6-yl)amine (vii)
2-chloro-n-(3-chlorophenyl)-9-ethyl-9h-purin-6-amine; n-(2-chloro-9-ethyl-9h-purin-6-yl)-n-(3-chlorophenyl)amine (viii)
methyl (2r,3s)-2-[(3,5-dinitrobenzoyl)amino]-3-hydroxybutanoate (x)
Reference 1:
    inaba, t.; cho, h.; yamada, y.; sagawa, s.; abe, h.; (1s)-1-[(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethylammonium benzoate, a versatile building block for chiral 2-aminoalkanols: concise synthesis and application to nelfinavir, a potent hiv-protease inhibitor. j org chem 2000, 65, 6, 1623.

Route 4
the oxidative cleavage of sodium erythorbate (i) with h2o2 and nahco3 gives the chiral dihydroxytetrahydrofuranone (ii), which is regioselectively monotosylated with ts-cl and pyridine to yield tosylate (iii). the cyclization of (iii) by means of naome in methanol affords the epoxide (iv), which is opened with naoh and nh3 in methanol to provide the dihydroxy aminoester (v). the reaction of (v) with cbz-cl and nahco3, followed by hydrolysis with hcl, gives the n-protected amino acid (vi), which is treated with ts-oh in water to yield the lactone (vii). the reduction of (vii) with ca(bh4)2 in methanol affords the trihydroxy compound (viii), which is acetalyzed with acetone and ppts to provide the protected alcohol (ix). the reaction of (ix) with ms-cl and tea in toluene gives the mesylate (x), which by reaction with thiophenol and k2co3 in dmf yields the thioether (xi). the hydrolysis of (xi) with hcl in hot methanol affords the glycol (xii), which is treated with socl2 and tea in dichloromethane to provide the cyclic sulfite (xiii). finally, this compound is cleaved with licl in dmf and hydrolyzed with aqueous hcl to give rise to the target (2s,3r)-3-(benzyloxycarbonylamino)-1-chloro-4-(phenylsulfanyl)-2-butanol (xiv).
List of intermediates No.
(2s,3s,4r,5r)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]-2-cyanotetrahydro-3-furanyl benzoate (xiv)
Reference 1:
    ikunaka, m.; et al.; an enantioselective synthesis of (2s,3r)-(n-benzyloxycarbonyl)amino-1-chloro-4-phenylthiobutan-2-ol, a central intermediate of nelfinavir. org process res dev 2002, 6, 1, 49.

Route 5
the reaction of d-tartaric acid (i) with 2,2-dimethoxypropane (ii) and ts-oh gives the acetonide (iii), which is reduced with nabh4 in ethanol to yield the diol (iv). the reaction of (iv) with ts-oh and tea affords the ditosylate (v), whose acetonide is cleaved with hcl to provide the diol (vi). the reaction of (vi) with socl2 in dichloromethane gives the cyclic sulfite (vii), which is oxidized with naio4 and rucl3 to yield the cyclic sulfate (viii). the reaction of (viii) with sodium azide in acetone/water affords the azide (ix), which is treated with sulfuric acid in thf/water to provide the azido alcohol (x). the reduction of the azido group of (x) with h2 over pd/c affords the amino alcohol (xi), which is condensed with 3-acetoxy-2-methylbenzoyl chloride (xii) by means of tea in thf, providing the intermediate amide (xiii). spontaneous cyclization of the amide (xiii) under the reaction conditions gives the oxazoline (xiv), which is condensed with the perhydroisoquinoline (xv) by means of k2co3 in isopropanol to yield the oxazoline intermediate (xvi). finally, the cleavage of the oxazoline ring of (xvi) by means of thiophenol (xvii) affords the target compound.
List of intermediates No.
(2r,3s,4r,5r)-2-(hydroxymethyl)-5-[6-[[2-(methylsulfanyl)ethyl]amino]-2-[(3,3,3-trifluoropropyl)sulfanyl]-9h-purin-9-yl]tetrahydro-3,4-furandiol (ii)
2-[(2r)-2-(2-chlorobenzyl)-3,6-dioxo-4-(3-phenylpropyl)piperazinyl]acetic acid (xvii)
tert-butyl (2s)-2-[[(2s,4r)-2-amino-4-methyloctanoyl](methyl)amino]-4-methylpentanoate (xv)
2,3-dichloro-6-nitrobenzonitrile (i)
n-(4-{2-[6,7-dimethoxy-3,4-dihydro-2(1h)-isoquinolinyl]ethyl}phenyl)-4,5-dimethoxy-2-nitrobenzamide (xii)
methyl (2r,3s)-2-[(3,5-dinitrobenzoyl)amino]-3-hydroxybutanoate (xvi)
Reference 1:
    albizati, k.f.; et al.; a synthesis of the hiv-protease inhibitor nelfinavir from d-tartaric acid. tetrahedron lett 2001, 42, 37, 6481.

Route 6
alternatively, the reaction of the cyclic sulfate (viii) with potassium phthalimide (xviii) gives the n-substituted phthalimide (xix), whose sulfate group is cleaved with sulfuric acid to yield the alcohol (xx). the reaction of (xx) with the perhydroisoquinoline (xv) by means of k2co3 in acetonitrile/methanol affords the oxazoline (xxi), whose ring is opened with thiophenol (xvii) and khco3 in thf, providing a mixture of the two sulfides (xxii) and (xxiii) that are not isolated. the cleavage of the phthalimido group with refluxing ethanolamine followed by a treatment with benzoic acid gives a mixture of ammonium salts that is separated by crystallization, yielding the desired isomer (xxiv). the reaction of (xxiv) with acid chloride (xii) affords the precursor (xxv), which is finally deacetylated with naoh to provide the target compound.
List of intermediates No.
2-[(2r)-2-(2-chlorobenzyl)-3,6-dioxo-4-(3-phenylpropyl)piperazinyl]acetic acid (xvii)
tert-butyl (2s)-2-[[(2s,4r)-2-amino-4-methyloctanoyl](methyl)amino]-4-methylpentanoate (xv)
octahydropyrrolo[1,2-a]pyrazine (xviii)
ethyl 5-((3s)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxybutyl)-2-thiophenecarboxylate (xxv)
n-(4-{2-[6,7-dimethoxy-3,4-dihydro-2(1h)-isoquinolinyl]ethyl}phenyl)-4,5-dimethoxy-2-nitrobenzamide (xii)
Reference 1:
    albizati, k.f.; et al.; a synthesis of the hiv-protease inhibitor nelfinavir from d-tartaric acid. tetrahedron lett 2001, 42, 37, 6481.

Route 7
the reaction of the unsaturated acetonide (i) with ammonia gives a diastereomeric, not separable mixture, of amino derivatives (ii) + (iii), which is reduced with bf3/et2o and nai to yield a mixture of sulfanyl derivatives (iv)+ (v). the condensation of this mixture with 3-acetoxy-2-methylbenzoic acid (vi) by means of edc and hobt affords a separable mixture of amides, from which the desired diastereomer (vii) is isolated. the hydrolysis of the acetonide group of (vii) by means of hcl in methanol provide the dihydroxyamide (viii), which is finally condensed with the perhydroisoquinoline (ix) by means of tes-cl and tea to furnish the target nelfinavir.
List of intermediates No.
tert-butyl (2s)-2-[[(2s,4r)-2-amino-4-methyloctanoyl](methyl)amino]-4-methylpentanoate (ix)
3-amino-1-methyl-4(1h)-quinolinone (vi)
Reference 1:
    ma, d.; et al.; a short synthesis of the hiv-protease inhibitor nelfinavir via a diastereoselective addition of ammonia to the alpha,beta-unsaturated sulfoxide derived from (r)-glyceraldehyde acetonide. tetrahedron lett 2002, 43, 47, 8511.

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甲磺酸奈非那韦;英文名Nelfinavir mesilate;LY-312857;AG-1346(free base);AG-1343;Viracept;CAS[159989-65-8]

 
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
史丹利进军农药市场,药-肥市场
国光股份与重庆双丰签署投资备忘
恭喜!拜耳、成都新朝阳、极飞科
克拉维酸、舒巴坦、他唑巴坦有什
商务部:今日起,对原产于这些国
江山股份布局东北制剂市场,收购
德国决定自2023年起全面禁用
华东地区醋酸市场整体稳定
华中地区甲苯行情暂稳
江苏地区顺酐市场行情整理
拜耳氟吡呋喃酮或将在我国首获正
山东地区顺酐市场行情整理
华东地区丁二烯市场价格走高
华北地区顺酐市场行情整理
河北地区甲醛价格持稳
华北地区顺酐市场行情整理
华东苯酐市场行情
浙江地区二氯甲烷价格暂稳
山东地区醋酸价格
河北地区醋酸价格
 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