药物Fosnetupitant（福奈妥匹坦）合成检索总结报告
一、Fosnetupitant（福奈妥匹坦）分子结构式
英文名称：Fosnetupitant 英文名称：Fosnetupitant hydrochloride 中文名称：福奈妥匹坦 中文名称：福奈妥匹坦盐酸盐 二、Fosnetupitant（福奈妥匹坦）合成路线
Fosnetupitant（福奈妥匹坦）中间体7其他合成方法如下：
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三、Fosnetupitant（福奈妥匹坦）合成检索总结报告 (一) Fosnetupitant（福奈妥匹坦）中间体2的合成
合成方法 操作方法一 操作方法二 实验步骤 2-Chloro-4-methoxy-5-nitropyridine 1 (1.02 g, 5.40 mmol) and K2CO3 (895 mg, 6.48 mmol) were purged with argon, treated with DMF (10 mE) followed by 1-methylpiperazine (0.66 ml, 5.94 mmol). The reaction mixture was then heated to 60°C. for 3 h. The reaction mixture was cooled to RT and treated with water, extracted with EtOAc (2×100 ml), washed with brine (2×25 ml) and dried over MgSO4, filtered and concentrated affording crude 1-(4-methoxy-5-nitropyri- din-2-yl)-4-methylpiperazine 2 (1.36 g, 5.39 mmol, 99% yield). Charged 2-chloro-4-methoxy-5-nitro pyridine 1 (100 g) N-methyl piperazine (175 mL) and tetrahydrofuran (1200 mL) and stirred for 10 hrs at room temperature. Charged reaction mixture in 720 mL of water and extracted in ethyl acetate. Organic layer washed with brine solution and treated with sodium sulphate. Distilled off organic layer under reduced pressure; crystallisation with diisopropyl ether gave 1-(4-methoxy-5-nitropyridin-2-yl)-4-methylpiperazine 2 (115.0 gms). 参考文献 US2014/249131; (2014); (A1) English US2015/315149; (2015); (A1) English (二) Fosnetupitant（福奈妥匹坦）中间体3的合成
合成方法 实验步骤 Charged 1-(4-methoxy-5-nitropyridin-2-yl)-4-methyl- piperazine 2 (100 g), 38% HBr in acetic acid (500 mL) and
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参考文献 US2015/315149; 操作方法一 acetic acid (500 mL). Stirred for 8 hrs. at 105°C. Cooled to (2015); (A1) room temperature, filtered the solid and washed with 100 mL English acetic acid. Dried the solid at 70°C. for 10 hrs to give 145 g of 2-(4-methylpiperazin-1-yl)-5-nitropyridin-4-ol 3. (三) Fosnetupitant（福奈妥匹坦）中间体4的合成
合成方法 操作方法一 实验步骤 Charged 2-(4-methylpiperazin-1-yl)-5-nitropyridin-4-ol 3 (100.0 g) and N,N-dimethylaniline (92 mL) at 10°C. to 20°C. Added phosphorus oxychloride slowly (180 mL) at 10°C. to 20°C. Refluxed for 2.0 hrs. Cooled to room temperature and dumped reaction mixture in ice and extracted in ethyl acetate after adjusting the pH to around 10 to 12. Treated the organic layer with brine solution and dried over sodium sulphate. Distilled off under reduced pressure to yield 60.0 gms of 1-(4-chloro-5-nitropyridin-2-yl)-4-methyl- piperazine 4. 参考文献 US2015/315149; (2015); (A1) English (四) Fosnetupitant（福奈妥匹坦）中间体6的合成
合成方法 操作方法一 实验步骤 Charged 1-(4-chloro-5-nitropyridin-2-yl)-4-methylpiperazine 4 (100 g), toluene (1 lit.) 2M Na2CO3 Solution (436 ml), boronic acid 5 (60 gm.), tetrakis (13 g) were refluxed reaction mass for 2 hrs. Cooled reaction mass to room temperature and quenched reaction mass in a mixture of ethyl acetate and process water medium. Extracted product in ethyl acetate layer. Dried the ethyl acetate layer with sodium sulphate and distilled to get thick mass which on crystallisation with di-isopropyl ether gave 80 g of the of 1-methyl-4-(5-nitro-4-(o-tolyl)pyridin-2-yl)piperazine 6. 参考文献 US2015/315149; (2015); (A1) English (五) Fosnetupitant（福奈妥匹坦）中间体7的合成方法一
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药物Fosnetupitant(福奈妥匹坦)合成检索总结报告
