pazopanib 中间体的合成工艺研究
【摘 要】pazopanib 是葛兰素史克公司研制的一种口服小分子多靶点受体酪氨酸激酶抑制剂的抗肿瘤药[1],选择性抑制VEGFR-1, 2, 3, PDGFR-α, PDGFR-β, c-Kit 。目前,pazopanib 已进入Ⅲ期临床研究。但是目前合成pazopanib 以3-甲基-6-硝基-1H-吲唑(化合物4)为原料合成,不易购买且成本较高,中间处理过程也比较复杂,通过比较与优化,为其中间体设计了一条方便高效的合成路线。2-乙基苯胺经混酸硝化,亚硝酸叔丁酯成环生成3-甲基-6-硝基-1H-吲唑,再经硫酸二甲酯甲基化制得2,3-二甲基-6-硝基-2H-吲唑。探索了不同条件对合成中间体的产率的影响,找出合适的反应条件,使之更适于工业生产。最终产物的结构由核磁共振谱、元素分析等波谱进行了表征和确认。
【关键词】Pazopanib ;多靶点受体酪氨酸激酶抑制剂;抗肿瘤药;合成 Synthesis of Pazopanib Intermedium
【Abstract 】Pazopanib is one kind of anti-drugs of tumour from GlaxoSmithKline company,which is multiple target point tyrosine kinase Inhibitor of small molecule for eaten, selectively restrainting VEGFR-1, 2, 3, PDGFR-α, PDGFR-β, c -Kit.Pazopanib now is in the Ⅲ stage of Clinical Research. But at present synthesizes Pazopanib used 3-methyl-6-nitro-1H-indazole(compound 4)for feedstock is hard to buy and cost to be high, and the production rate is low, the middle treating processes quite are also complex. Through the comparison and the optimization, has designed a highly effective process of synthesis. 2-ethyl phenylamine nitrating by violet acid production 3-methyl-6-nitro-1H-indazole, then methylation by DMSO production 2,3-double methyl-6-nitro-2H-indazole.The effects of difference reaction conditions on the yield of product in each step have been investigated and optimal reaction condition has been found. The final product was identified by 1HNMR, element analysis spectra.
【Key words】Synthesis ;VEGF inhibitors;Tyrosine kinase inhibitor;Synthesis 酪氨酸激酶是最常见的生长因子受体, 通过阻断酪氨酸激酶可破坏肿瘤细胞的信号传递, 从而达到抗肿瘤的目的[1]。受体酪氨酸激酶抑制剂包括单靶点酪氨酸激酶抑制剂和多靶点酪氨酸激酶抑制剂。Pazopanib 属第二代多靶点酪氨酸激酶抑制剂对抑制血管内皮细胞生长因子受体(VEGFR-1,-2,-3), 血小板源生长因子受体( PDGFR )以及c-kit 效果明显。
中间体1的合成线路
1 实验部分
1.1 实验仪器与设备
Varian Mercury VS 300核磁共振仪 美国Varian 公司
2-乙基苯胺 上海海曲化工有限公司,浓硫酸,冰醋酸,发烟硝酸,环己烷,亚硝酸叔丁酯,乙酸乙酯,二甲基亚砜,均为市售分析纯
1.2 合成步骤
1.2.1 2-乙基-5-硝基苯胺(3)的合成
36.9mL(0.3mol) 2-乙基苯胺(化合物2) 溶解于150mL 浓H2SO4中并冷却至0℃,滴加19.0mL(0.45mol)发烟硝酸,温度不超过5℃。滴加后于室温搅拌反应30min ,再倒入冰水(约1500mL) 中,用NaOH 小心中和并过滤,粗品用环己烷重
pazopanib 中间体的合成工艺研究
【摘 要】pazopanib 是葛兰素史克公司研制的一种口服小分子多靶点受体酪氨酸激酶抑制剂的抗肿瘤药[1],选择性抑制VEGFR-1, 2, 3, PDGFR-α, PDGFR-β, c-Kit 。目前,pazopanib 已进入Ⅲ期临床研究。但是目前合成pazopanib 以3-甲基-6-硝基-1H-吲唑(化合物4)为原料合成,不易购买且成本较高,中间处理过程也比较复杂,通过比较与优化,为其中间体设计了一条方便高效的合成路线。2-乙基苯胺经混酸硝化,亚硝酸叔丁酯成环生成3-甲基-6-硝基-1H-吲唑,再经硫酸二甲酯甲基化制得2,3-二甲基-6-硝基-2H-吲唑。探索了不同条件对合成中间体的产率的影响,找出合适的反应条件,使之更适于工业生产。最终产物的结构由核磁共振谱、元素分析等波谱进行了表征和确认。
【关键词】Pazopanib ;多靶点受体酪氨酸激酶抑制剂;抗肿瘤药;合成 Synthesis of Pazopanib Intermedium
【Abstract 】Pazopanib is one kind of anti-drugs of tumour from GlaxoSmithKline company,which is multiple target point tyrosine kinase Inhibitor of small molecule for eaten, selectively restrainting VEGFR-1, 2, 3, PDGFR-α, PDGFR-β, c -Kit.Pazopanib now is in the Ⅲ stage of Clinical Research. But at present synthesizes Pazopanib used 3-methyl-6-nitro-1H-indazole(compound 4)for feedstock is hard to buy and cost to be high, and the production rate is low, the middle treating processes quite are also complex. Through the comparison and the optimization, has designed a highly effective process of synthesis. 2-ethyl phenylamine nitrating by violet acid production 3-methyl-6-nitro-1H-indazole, then methylation by DMSO production 2,3-double methyl-6-nitro-2H-indazole.The effects of difference reaction conditions on the yield of product in each step have been investigated and optimal reaction condition has been found. The final product was identified by 1HNMR, element analysis spectra.
【Key words】Synthesis ;VEGF inhibitors;Tyrosine kinase inhibitor;Synthesis 酪氨酸激酶是最常见的生长因子受体, 通过阻断酪氨酸激酶可破坏肿瘤细胞的信号传递, 从而达到抗肿瘤的目的[1]。受体酪氨酸激酶抑制剂包括单靶点酪氨酸激酶抑制剂和多靶点酪氨酸激酶抑制剂。Pazopanib 属第二代多靶点酪氨酸激酶抑制剂对抑制血管内皮细胞生长因子受体(VEGFR-1,-2,-3), 血小板源生长因子受体( PDGFR )以及c-kit 效果明显。
中间体1的合成线路
1 实验部分
1.1 实验仪器与设备
Varian Mercury VS 300核磁共振仪 美国Varian 公司
2-乙基苯胺 上海海曲化工有限公司,浓硫酸,冰醋酸,发烟硝酸,环己烷,亚硝酸叔丁酯,乙酸乙酯,二甲基亚砜,均为市售分析纯
1.2 合成步骤
1.2.1 2-乙基-5-硝基苯胺(3)的合成
36.9mL(0.3mol) 2-乙基苯胺(化合物2) 溶解于150mL 浓H2SO4中并冷却至0℃,滴加19.0mL(0.45mol)发烟硝酸,温度不超过5℃。滴加后于室温搅拌反应30min ,再倒入冰水(约1500mL) 中,用NaOH 小心中和并过滤,粗品用环己烷重