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【结 构 式】 
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【药物名称】Atevirdine mesylate, U-87201E 【化学名称】1-[3-(Ethylamino)-2-pyridyl]-4-(5-methoxy-1H-indol-2-ylcarbonyl)piperazine monomethanesulfonate 【CA登记号】138540-32-6, 136816-75-6 (free base) 【 分 子 式 】C22H29N5O5S 【 分 子 量 】475.57093 |
【开发单位】Pfizer (Originator) 【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Reverse Transcriptase Inhibitors |
合成路线1
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.
| 【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
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.
| 【1】 Perrault, W.R.; et al.; Production scale synthesis of the non-nucleoside recverse transcriptase inhibitor atervirdine mesylate (U-87,201E). Org Process Res Dev 1997, 1, 2, 106. |
| 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) | 11160 | 2-Chloro-3-pyridinamine; 2-Chloro-3-pyridinylamine; 3-Amino-2-chloropyridine; 2-Chloro-3-aminopyridine | 6298-19-7 | C5H5ClN2 | 详情 | 详情 |
| (II) | 36531 | 1,1,1-trimethoxypropane; 1,1-dimethoxypropyl methyl ether | C6H14O3 | 详情 | 详情 | |
| (III) | 36532 | methyl N-(2-chloro-3-pyridinyl)ethanimidoate | C8H9ClN2O | 详情 | 详情 | |
| (IV) | 36533 | N-(2-chloro-3-pyridinyl)-N-ethylamine; 2-chloro-N-ethyl-3-pyridinamine | C7H9ClN2 | 详情 | 详情 | |
| (V) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (VI) | 36534 | N-ethyl-N-[2-(1-piperazinyl)-3-pyridinyl]amine; N-ethyl-2-(1-piperazinyl)-3-pyridinamine | C11H18N4 | 详情 | 详情 | |
| (VII) | 28885 | 5-methoxy-1H-indole-2-carboxylic acid | 4382-54-1 | C10H9NO3 | 详情 | 详情 |