Atevirdine mesylate, U-87201E
1-[3-(乙胺基)-2-吡啶基]-4-(5-甲氧基-1H-吲哚-2-基羰基)哌嗪单甲磺酸酯 阿替韦啶 Chemical Name: 1-[3-(Ethylamino)-2-pyridyl]-4-(5-methoxy-1H-indol-2-ylcarbonyl)piperazine monomethanesulfonate
CAS No. 138540-32-6, 136816-75-6 (free base)
项目整合开发状态: Phase III
项目研究机构: Pfizer (Originator)
合成路线:Nucleophilic aromatic substitution of 2-chloro-3-nitropyridine (II) with excess piperazine (I) in acetonitrile at room temperature produces 1-(3-nitro-2-pyridyl)piperazine.Protection of the free piperazine nitrogen by treatment with di-tert-butyldicarbonate affords nitropyridine (III).Reduction of the nitro group to the amine is accomplished via hydrogenation (40 psi) over palladium on carbon.Treatment of the aminopyridine with acetaldehyde and sodium cyanoborohydride in methanol affords the (ethylamino)pyridine (IV).Removal of the BOC protecting group with trifluoroacetic acid and coupling of the resulting 1-[3-(ethylamino)pyridyl]piperazine with 5-methoxyindole-2-carboxylic acid using 1-ethyl-3-(dimethylaminopropyl)carbodiimide (EDC) or 1,1'-carbonyldiimidazole (CDI) affords U-87201 (V).Dissolution of (V) in methanol,treatment with 1 eq of methanesulfonic acid,and the addition of diethyl ether results in the precipitation of atevirdine mesylate.
合成路线:The synthesis of delavirdine mesylate is depicted in Scheme 19654001a:The first three chemical steps are the same as those used for the synthesis of atevirdine mesylate (ATV,U-87201E) (2,3).Nucleophilic aromatic substitution of 2-chloro-3-nitropyridine (II) with excess piperazine in acetonitrile at room temperature produces 1-(3-nitro-2-pyridyl)piperazine.Protection of the free piperazine nitrogen by treatment with di-tert-butyldicarbonate affords nitropyridine (III).Reduction of the nitro group to the amine is accomplished via hydrogenation (40 psi) over palladium on carbon.Treatment of the aminopyridine with acetone and sodium cyanoborohydride in methanol affords the 3-(1-methylethylamino)pyridine (IV).Removal of the BOC protecting group with trifluoroacetic acid and coupling of the resulting 1-[3-(1-methylethylamino)pyridyl]piperazine with 5-nitroindole-2-carboxylic acid using 1-ethyl-3-(dimethylaminopropyl)carbodiimide (EDC) or 1,1'-carbonyldiimidazole (CDI) affords (V).Catalytic reduction of the nitro group and treatment of the resulting amine with methanesulfonyl chloride provides U-90152.Dissolution of U-90152 in acetonitrile and treatment with 1 eq of methanesulfonic acid results in the precipitation of delavirdine mesylate.
📌 参考资料/链接：
参考文献标题:Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication
文献作者:Romero,D.L.; Busso,M.; Tan,C.-K.; Reusser,F.; Palmer,J.R.; Poppe,S.M.; Aristoff,P.A.; Downey,K.M.; So,A.G.; Resnick,L.; et al.
参考来源:Proc Natl Acad Sci USA 1991,88(19),8806-10
📄 详细内容
合成路线:Nucleophilic aromatic substitution of 2-chloro-3-nitropyridine (II) with excess piperazine (I) in acetonitrile at room temperature produces 1-(3-nitro-2-pyridyl)piperazine.Protection of the free piperazine nitrogen by treatment with di-tert-butyldicarbonate affords nitropyridine (III).Reduction of the nitro group to the amine is accomplished via hydrogenation (40 psi) over palladium on carbon.Treatment of the aminopyridine with acetaldehyde and sodium cyanoborohydride in methanol affords the (ethylamino)pyridine (IV).Removal of the BOC protecting group with trifluoroacetic acid and coupling of the resulting 1-[3-(ethylamino)pyridyl]piperazine with 5-methoxyindole-2-carboxylic acid using 1-ethyl-3-(dimethylaminopropyl)carbodiimide (EDC) or 1,1'-carbonyldiimidazole (CDI) affords U-87201 (V).Dissolution of (V) in methanol,treatment with 1 eq of methanesulfonic acid,and the addition of diethyl ether results in the precipitation of atevirdine mesylate.
参考文献标题:Atevirdine Mesylate
文献作者:Romero,D.L.
参考来源:Drugs Fut 1994,19(1),9
合成路线:The reaction of 3-amino-2-chloropyridine (I) with triethyl orthoacetate (II) catalyzed by TsOH gives the acetimidate (III),which is reduced to 3-(ethylamino)-2-chloropyridine (IV) by means of DIBAL in toluene.The reaction of (IV) with piperazine (V) by means of Na2CO3 by heating at 144 C affords 3-(ethylamino)-2-(1-piperazinyl)pyridine (VI),which is finally condensed with 5-methoxy-1H-indole-2-carboxylic acid (II) by means of CDI in dichloromethane and treated with CH3SO3H in methanol to provide the target mesylate.
参考文献标题:Production scale synthesis of the non-nucleoside recverse transcriptase inhibitor atervirdine mesylate (U-87,201E)
文献作者:Perrault,W.R.; et al.
参考来源:Org Process Res Dev 1997,1(2),106
合成路线:Nucleophilic aromatic substitution of 2-chloro-3-nitropyridine (II) with excess piperazine (I) in acetonitrile at room temperature produces 1-(3-nitro-2-pyridyl)piperazine.Protection of the free piperazine nitrogen by treatment with di-tert-butyldicarbonate affords nitropyridine (III).Reduction of the nitro group to the amine is accomplished via hydrogenation (40 psi) over palladium on carbon.Treatment of the aminopyridine with acetaldehyde and sodium cyanoborohydride in methanol affords the (ethylamino)pyridine (IV).Removal of the BOC protecting group with trifluoroacetic acid and coupling of the resulting 1-[3-(ethylamino)pyridyl]piperazine with 5-methoxyindole-2-carboxylic acid using 1-ethyl-3-(dimethylaminopropyl)carbodiimide (EDC) or 1,1'-carbonyldiimidazole (CDI) affords U-87201 (V).Dissolution of (V) in methanol,treatment with 1 eq of methanesulfonic acid,and the addition of diethyl ether results in the precipitation of atevirdine mesylate.
参考文献标题:The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: A double-blind,placebo-controlled trial
文献作者:Richman,D.D.; Fischl,M.A.; Grieco,M.H.; Gottlieb,M.S.; Volberding,P.A.; Laskin,O.L.; Leedom,J.M.; Groopman,J.E.; Mildvan,D.; Hirsch,M.S.; et al.
参考来源:New Engl J Med 1987,317(4),192-7
产品链接: CAS No. 138540-32-6›› 产品链接: CAS No.136816-75-6››