CN108409648A - 一种甲苯磺酸索拉非尼相关中间体的制备方法 - Google Patents
一种甲苯磺酸索拉非尼相关中间体的制备方法 Download PDFInfo
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- CN108409648A CN108409648A CN201810238567.0A CN201810238567A CN108409648A CN 108409648 A CN108409648 A CN 108409648A CN 201810238567 A CN201810238567 A CN 201810238567A CN 108409648 A CN108409648 A CN 108409648A
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- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical group [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/86—Hydrazides; Thio or imino analogues thereof
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明公开了一种甲苯磺酸索拉非尼相关中间体的制备方法,属于医药技术领域。本发明先由‑COOH生成‑CONHCH3,之后常温下在吡啶环上接上卤素原子合成化合物3,能耗降低。并且本发明后处理简单、易操作,处理后的每一步产物纯度都能达到95%,可直接用于下一步,适合工业化生产。
Description
技术领域
本发明涉及一种甲苯磺酸索拉非尼相关中间体的制备方法,属于医药技术领域。
背景技术
索拉非尼(Sorafenib,BAY43-9006,商品名Nexevar)是拜尔和OnyxPHarmaceuticals公司开发的一种新型的双芳基脲类小分子口服多靶点受体酪氨酸激酶抑制剂,分别于2005年12月和2007年10月被美国FDA快速审批用于治疗晚期肾细胞癌和晚期肝癌。它具有双重的抗肿瘤作用,一方面通过抑制Ras/Raf/MEK信号转导通路直接抑制肿瘤生长,另一方面通过抑制VEGF和血小板衍生生长因子(PDGF)受体而阻断肿瘤新生血管的形成,间接地抑制肿瘤细胞的生长。在体外研究中发现索拉非尼还可以作用于c-Kit、Flt-3和RET等多种酪氨酸激酶。该药是近10多年来世界上被批准用于治疗晚期肾癌的第一个新药,也是医疗界第一次找到能够延长晚期肝癌患者生命的药物。
甲苯磺酸索拉非尼,化学名称:4-{4[-3(-4-Chloro-3-rifluoromethylphenyl)ureido]phenoxy}-N 2-methy1pyridine-2-carboxamide mono(4-methylbenzenesulfonate)。分子式:C21H16ClF3N403·C7H8O3S,分子量637.03。化学结构式如下所示:
4-(4-氨基苯氧基)-N-甲基-2-吡啶甲酰胺是制备索拉非尼的重要中间体,其结构式如下:
现有技术中4-(4-氨基苯氧基)-N-甲基-2-吡啶甲酰胺的制备方法主要有相转移催化法和Williamson合成法,具体如下:
孙超:《索拉非尼的合成工艺研究》,黑龙江大学,2011年硕士论文中公开了以四氢呋喃为溶剂,反应时间为12小时,催化剂为四丁基溴化铵时收率为51.9%,催化剂为聚乙醇600时,收率为48.6%,但是相转移催化法在产品提出阶段会析出一些焦油状的物质,影响提出,且提出的产品需要多次重结晶,才能得到较纯的产品,收率较低,因焦油状的物质可能由产品或一些杂质与相转移催化剂相互包杂所产生。
赵乘有等人,对甲苯磺酸索拉菲尼的合成,中国医药工业杂质,2007,38(9):614-616中公开了4-(4-氨基苯氧基)-N-甲基-2-吡啶甲酰胺的制备方法,以四氢呋喃为溶剂溶解4-氯-N-甲基吡啶-2-甲酰胺,加入对-氨基苯酚、氢氧化钠、氢氧化钠水溶液、相转移催化剂聚乙醇600后,加热回流12小时,减压干燥溶剂后,用冷异丙醇重结晶,收率为72%。
中国发明专利CN101052619中公开了4-(4-氨基苯氧基)-N-甲基-2-吡啶甲酰胺的制备方法,首先加入4-氯-N-甲基吡啶-2-甲酰胺粗品和二甲基甲酰胺、对-氨基苯酚和叔丁醇钾获得4-(4-氨基苯氧基)-N-甲基-2-吡啶甲酰胺的棕色油状物,再将棕色油状物反应成盐酸盐溶于水,再以氢氧化钠中和使其析出白色固体,保证后续产物的质量。但是该方法操作复杂,收率低,为78%,不利于工业化大生产。
中国发明专利CN103408488A中公开了4-(4-氨基苯氧基)-N-甲基-2-吡啶甲酰胺的制备方法,将对氨基苯酚溶于DMF中,向其中加入NaH、Na0H、K0H中一种,室温反应2h后,加入4-氯-2-(甲基氨甲酰基)-吡啶,升温至85℃,反应2h。冷却到室温,获得4-(4-氨基苯氧基)-N-甲基-2-吡啶甲酰胺粗品,加入水,用乙酸乙酯萃取,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩,用乙酸乙酯-石油醚重结晶得4-(4-氨基苯氧基)-2-甲基氨甲酰基-吡啶纯品,收率在77.6%-87.9%之间。现有的制备方法主要采用合适的溶剂进行重结晶,操作比较复杂,收率基本较低,只能达到48.6%-88.2%左右。且生产成本较高,后处理时产生的废水废液较多,不符合环保要求。
中国发明专利CN104672129A公开了4-(4-氨基苯氧基)-N-甲基-2-吡啶甲酰胺的制备方法,在反应容器中加入4-氨基苯酚,N,N-二甲基甲酰胺,室温搅拌加入氢氧化钠,反应1小时后加入碳酸钾,N-甲基-4-氯-吡啶甲酰胺,升温至85℃,反应5-6小时,减压浓缩后加入水,在0℃时搅拌5小时,过滤,获得4-(4-氨基苯氧基)-N-甲基-2-吡啶甲酰胺,收率为88.2%,HPLC纯度为99.48%。但是该方法直接由索拉非尼中间体N-甲基-4-氯-吡啶甲酰胺为原料合成目标化合物4-(4-氨基苯氧基)-N-甲基-2-吡啶甲酰胺,成本很高。
发明内容
为解决上述问题,本发明提供一种条件温和、操作方便、反应时间短、收率高、质量好、成本低的适合工业化大生产的索拉菲尼中间体4-(4-氨基苯氧基)-N-甲基-2-吡啶甲酰胺的制备方法。
本发明的第一个目的是提供一种索拉菲尼关键中间体4-(4-氨基苯氧基)-N-甲基-2-吡啶甲酰胺的制备方法,所述方法的制备路线如下:
在本发明的一种实施方式中,所述方法包括如下步骤:
(1)2-烟酸(化合物1)先与氯化试剂反应,之后再与甲胺反应得到N-甲基吡啶酰胺(化合物2);
(2)化合物2在吡啶甲基酰胺基的间位接上一个氟原子得到4-氟-N-甲基吡啶酰胺(化合物3);
(3)化合物3和对硝基苯酚(化合物4)在催化剂存在下发生取代反应得到N-甲基-3-(4-硝基苯)苯甲酰胺(化合物5);
(4)化合物5在催化剂和氢源的存在下将硝基还原成氨基得到4-(4-氨基苯氧基)-N-甲基-2-吡啶甲酰胺(化合物6)。
在本发明的一种实施方式中,所述步骤(1)中氯化试剂为草酰氯、磺酰氯或者二氯亚枫。
在本发明的一种实施方式中,所述步骤(1)是以二氯甲烷、三氯甲烷、乙腈、乙酸乙酯、乙酸丁酯、甲醇、乙醇、丙醇、异丙醇、四氢呋喃、丙酮、乙醚、N-二甲基甲酰胺或二甲基亚砜中的一种或几种混合为溶剂进行反应。
在本发明的一种实施方式中,所述步骤(2)的反应温度为0~50℃,优选为20-30℃。
在本发明的一种实施方式中,所述步骤(3)中催化剂为碳酸铯、碳酸钾、碳酸钙、碳酸钠、碳酸镁、碳酸钡、三乙胺、碳酸氢钾、碳酸氢钠或碳酸氢钙。
在本发明的一种实施方式中,所述步骤(3)是以二氯甲烷、三氯甲烷、乙腈、乙酸乙酯、乙酸丁酯、甲醇、乙醇、丙醇、异丙醇、四氢呋喃、丙酮、乙醚、N-二甲基甲酰胺或二甲基亚砜中的一种或几种混合为溶剂进行反应。
在本发明的一种实施方式中,所述步骤(4)中催化剂为Pd(OH)2/C、Pd/C、PdCl2、Pd(OAc)2、Pd(OH)2或Raney镍。
在本发明的一种实施方式中,所述步骤(4)中氢源为H2、HCOOH、HCOONH4、水合肼或环已烯。
在本发明的一种实施方式中,所述步骤(4)是以甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、1,4-二氧六环、甲酸、乙酸、丁酸、戊酸、丙酮、丁酮、戊酮、环戊酮、己酮、环己酮、乙醚、乙酸乙酯、乙酸丁酯、四氢呋喃、乙腈、苯、甲苯、二甲苯、DMF、DMAC或DMSO的一种或几种为溶剂进行反应。
在本发明的一种实施方式中,所述步骤(4)中,化合物5与催化剂的质量比为1:0.001-100,优选为1:0.01-1,最优选为1:0.0125。
在本发明的一种实施方式中,所述步骤(4)中反应温度为30~50℃。
在本发明的一种实施方式中,所述步骤(4)在常压或者加压条件下进行反应。
本发明的优点和效果:
1、原研工艺是先在2-吡啶甲酸上接上-Cl,此步反应需要在70-80℃下反应,在和甲胺反应生成-CONHCH3。而我们先由-COOH生成-CONHCH3,之后常温下在吡啶环上接上卤素原子合成化合物3,能耗降低。
2本发明后处理简单、易操作,处理后的每一步产物纯度都能达到95%,可直接用于下一步,适合工业化生产。
具体实施方案
收率的计算方法:产品烘干后,收率=实际产量/理论产量*100%。
下面是对本发明进行具体描述。
实施例1:化合物2的制备
将化合物1(1.23g,10mmol)加入到二氯甲烷(20mL)中,将溶液降温到0℃,在搅拌下缓慢加入氯化亚砜(1.50g,13mmol),该反应温和放热,氯化亚砜加入过程中,溶液温度不超过5℃,待其加入完毕后0℃反应1h,之后将溶液在50℃下反应不少于6h或者TLC监测显示反应完全,将溶液温度降到25℃,将溶解在二氯甲烷(5mL)的甲胺(0.90g,30mmol)溶液缓慢滴加到其中,混合溶液35℃下反应0.5h或者TLC监测显示反应完全后停止反应,加入饱和食盐水(15mL),用乙酸乙酯(2x15mL)萃取,分层,合并有机层,用无水硫酸钠干燥,过滤,浓缩,干燥得到产物,产率88-93%。
实施例2:化合物3的制备
向装有冷凝回流管、气体导入管、温度计和搅拌器的100mL三口瓶中,加入化合物2(1.36g,10mmol)和浓度为15%的硫酸溶液(2.62g,4.0mmol)。搅拌,在温度25℃下,向其中连续通入氟气进行氟化反应,未反应氟气利用碱液吸收,反应期间从中定时取样分析以监控反应进行程度,当液相色谱分析取样结果中化合物3含量大于95.0%时,停止通入氟气,继续搅拌10-20分钟,氟化反应结束。将反应液倒入水中(30mL)稀释,然后用40%氢氧化钠水溶液中和调其PH≈10,搅拌,当液体温度到20℃以下时,将沉淀进行抽滤分离,滤饼用冷水洗涤、干燥,得到化合物3,产率82-85%。
实施例3:化合物5的制备
将化合物3(0.46g,3mmol)溶解在无水DMF(50mL)中,将碳酸铯(2.44g,6.45mmol)加入到该溶液中并将溶液升温到80℃,将溶解在DMF(5mL)的化合物4(0.46g,3.3mmol加入其中,80℃下反应3h停止反应,降至室温,加入纯水(30mL)搅拌0.5h,之后用乙酸乙酯(3x30mL)萃取。合并的有机层用无水硫酸钠干燥并减压浓缩,得到产物,产率90-92%。
实施例4:化合物6的制备
将化合物5(1.74g,6.4mmol)、10%Pd/C(0.25g,含50%的水,0.12mmol)加入到含有甲醇(60mL)的反应容器里。反应温度为35℃,氢气压力为40psi,在加氢反应器中反应2h后停止反应,在含有硅藻土层的过滤装置中将反应液过滤,甲醇(10mL)冲洗滤饼,减压旋蒸除去滤液,得到产物,产率92-95%,纯度98.3%。ESI-MS[M+H]m/z:244.1079;m.p.:105.9-107.3℃。
虽然本发明已以较佳实施例公开如上,但其并非用以限定本发明,任何熟悉此技术的人,在不脱离本发明的精神和范围内,都可做各种的改动与修饰,因此本发明的保护范围应该以权利要求书所界定的为准。
Claims (10)
1.一种索拉菲尼关键中间体4-(4-氨基苯氧基)-N-甲基-2-吡啶甲酰胺的制备方法,其特征在于,所述方法的制备路线如下:
2.根据权利要求1所述的方法,其特征在于,所述方法包括如下步骤:
(1)2-烟酸先与氯化试剂反应,之后再与甲胺反应得到N-甲基吡啶酰胺;
(2)N-甲基吡啶酰胺在吡啶甲基酰胺基的间位接上一个氟原子得到4-氟-N-甲基吡啶酰胺;
(3)4-氟-N-甲基吡啶酰胺和对硝基苯酚在催化剂存在下发生取代反应得到N-甲基-3-(4-硝基苯)苯甲酰胺;
(4)N-甲基-3-(4-硝基苯)苯甲酰胺在催化剂和氢源的存在下将硝基还原成氨基得到4-(4-氨基苯氧基)-N-甲基-2-吡啶甲酰胺。
3.根据权利要求2所述的方法,其特征在于,所述步骤(1)中氯化试剂为草酰氯、磺酰氯或者二氯亚枫。
4.根据权利要求2所述的方法,其特征在于,所述步骤(1)是以二氯甲烷、三氯甲烷、乙腈、乙酸乙酯、乙酸丁酯、甲醇、乙醇、丙醇、异丙醇、四氢呋喃、丙酮、乙醚、N-二甲基甲酰胺或二甲基亚砜中的一种或几种混合为溶剂进行反应。
5.根据权利要求2所述的方法,其特征在于,所述步骤(3)中催化剂为碳酸铯、碳酸钾、碳酸钙、碳酸钠、碳酸镁、碳酸钡、三乙胺、碳酸氢钾、碳酸氢钠或碳酸氢钙。
6.根据权利要求2所述的方法,其特征在于,所述步骤(3)是以二氯甲烷、三氯甲烷、乙腈、乙酸乙酯、乙酸丁酯、甲醇、乙醇、丙醇、异丙醇、四氢呋喃、丙酮、乙醚、N-二甲基甲酰胺或二甲基亚砜中的一种或几种混合为溶剂进行反应。
7.根据权利要求2所述的方法,其特征在于,所述步骤(4)中催化剂为Pd(OH)2/C、Pd/C、PdCl2、Pd(OAc)2、Pd(OH)2或Raney镍。
8.根据权利要求2所述的方法,其特征在于,所述步骤(4)中氢源为H2、HCOOH、HCOONH4、水合肼或环已烯。
9.根据权利要求2所述的方法,其特征在于,所述步骤(4)是以甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、1,4-二氧六环、甲酸、乙酸、丁酸、戊酸、丙酮、丁酮、戊酮、环戊酮、己酮、环己酮、乙醚、乙酸乙酯、乙酸丁酯、四氢呋喃、乙腈、苯、甲苯、二甲苯或二甲基亚砜的一种或几种为溶剂进行反应。
10.权利要求1~9任一所述方法在制备抗癌症药物中的应用。
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