tert-butyl 4-(3-nitro-2-pyridinyl)tetrahydro-1(2H)-pyrazinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】16159

【品名】tert-butyl 4-(3-nitro-2-pyridinyl)tetrahydro-1(2H)-pyrazinecarboxylate

【CA登记号】

【分子式】C₁₄H₂₀N₄O₄

【分子量】308.33736

【元素组成】C 54.54% H 6.54% N 18.17% O 20.76%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(III)

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.

参考文献中间体

合成目标

【1】 Richman, D.D.; Fischl, M.A.; Grieco, M.H.; et al.; The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: A double-blind, placebo-controlled trial. New Engl J Med 1987, 317, 4, 192-7.
【2】 Tan, C.-K.; Busso, M.; Romero, D.L.; et al.; Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication. Proc Natl Acad Sci USA 1991, 88, 19, 8806-10.
【3】 Romero, D.L.; Atevirdine Mesylate. Drugs Fut 1994, 19, 1, 9.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	10355	Diethylenediamine; Piperazine	110-85-0	C₄H₁₀N₂	详情	详情
(II)	10321	2-Chloro-3-nitropyridine	5470-18-8	C₅H₃ClN₂O₂	详情	详情
(III)	16159	tert-butyl 4-(3-nitro-2-pyridinyl)tetrahydro-1(2H)-pyrazinecarboxylate		C₁₄H₂₀N₄O₄	详情	详情
(IV)	14880	tert-butyl 4-[3-(ethylamino)-2-pyridinyl]tetrahydro-1(2H)-pyrazinecarboxylate		C₁₆H₂₆N₄O₂	详情	详情
(V)	63849	{4-[3-(ethylamino)-2-pyridinyl]-1-piperazinyl}(1H-indol-2-yl)methanone		C₂₀H₂₃N₅O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

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.

参考文献中间体

合成目标

【1】 Romero, D.L.; Atevirdine mesylate (U-87201E). Drugs Fut 1994, 19, 1, 7-12.
【2】 Aristoff, P.A.; Romero, D.L.; Palmer, J.R.; Thomas, R.C.; Smith, H.W. (Pharmacia Corp.); Diaromatic substd. cpds. as anti-HIV-1 agents. US 5563142 .
【3】 Busso, M.; Romero, D.L.; Biles, C.; Genin, M.J.; Tarpley, W.G.; Morge, R.A.; Reusser, F.; Althaus, I.W.; Thomas, R.C.; Resnick, L.; Bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors: Structure-activity relationships of novel substituted indole analogues and the identification oF (U-90152S), a second-generation clinical candidate. J Med Chem 1993, 36, 10, 1505-8.
【4】 Romero, D.L.; Delavirdine Mesylate. Drugs Fut 1994, 19, 3, 238.
【5】 Tan, C.-K.; Busso, M.; Romero, D.L.; et al.; Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication. Proc Natl Acad Sci USA 1991, 88, 19, 8806-10.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	10355	Diethylenediamine; Piperazine	110-85-0	C₄H₁₀N₂	详情	详情
(II)	10321	2-Chloro-3-nitropyridine	5470-18-8	C₅H₃ClN₂O₂	详情	详情
(III)	16159	tert-butyl 4-(3-nitro-2-pyridinyl)tetrahydro-1(2H)-pyrazinecarboxylate		C₁₄H₂₀N₄O₄	详情	详情
(IV)	16160	tert-butyl 4-[3-(isopropylamino)-2-pyridinyl]tetrahydro-1(2H)-pyrazinecarboxylate		C₁₇H₂₈N₄O₂	详情	详情
(V)	16161	[4-[3-(isopropylamino)-2-pyridinyl]piperazino](5-nitro-1H-indol-2-yl)methanone		C₂₁H₂₄N₆O₃	详情	详情

Extended Information