CN104710354A - 高纯度索拉非尼的制备方法 - Google Patents

高纯度索拉非尼的制备方法 Download PDF

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CN104710354A
CN104710354A CN201310690301.7A CN201310690301A CN104710354A CN 104710354 A CN104710354 A CN 104710354A CN 201310690301 A CN201310690301 A CN 201310690301A CN 104710354 A CN104710354 A CN 104710354A
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methylene dichloride
thf
tetrahydrofuran
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陈安丰
杨勇
张亮
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Jiangsu Hansoh Pharmaceutical Co Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic 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
    • C07D213/02Heterocyclic 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
    • C07D213/04Heterocyclic 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
    • C07D213/60Heterocyclic 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
    • C07D213/78Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81Amides; Imides

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Abstract

本发明涉及高纯度索拉非尼的制备方法。该方法包括将4-(4-氨基苯氧基)-N-甲基吡啶-2-甲酰胺与4-氯-3-三氟甲基异氰酸苯酯在反应溶剂中反应后,加入后处理溶剂,过滤,得到如式(I)所示的索拉非尼,再成盐,得到甲苯磺酸索拉非尼。该制备方法操作简单,收率高,产品纯度高,适合工业化生产。

Description

高纯度索拉非尼的制备方法
技术领域
本发明涉及有机化学和药物化学领域,具体涉及索拉非尼的制备方法。
背景技术
如下式(I)所示的索拉非尼(Sorafenib)是由拜耳和Onyx两家公司联合研制的口服多激酶抑制剂,既靶向RAF/MEK/ERK信号传导通路阻滞肿瘤细胞增殖,又靶向VEGFR-2/PDGFR-β信号转导级联抑制肿瘤血管新生。化学名为4-(4-{3-[4-氯-3-(三氟甲基)苯基]脲基}苯氧基)-N2-甲基吡啶-2-甲酰胺,商品名为多吉美,适应症为晚期肾细胞癌和无法手术的肝细胞癌。
有关索拉非尼的合成已揭示在专利WO0042010、WO0041698、WO2006034796、WO2007/059154A2、CN10105269A、WO2007/053574A2、WO2009/034308A2等中。利用4-(4-氨基苯氧基)-N-甲基吡啶-2-甲酰胺(如式III)与4-氯-3-三氟甲基异氰酸苯酯在有机溶剂下可制得索拉非尼,或利用化合物III与4-氯-3-三氟甲基苯胺在1,1-羰基二咪唑及有机溶剂存在下反应可制得索拉非尼。
但是在上述相关方法中所使用的有机溶剂中反应实际上很难获得高纯度的索拉非尼。基于这点考虑,我们提出一种制备高纯度索拉非尼的方法。
发明内容
本发明的目的在于克服现有技术的缺陷,提供一种高纯度索拉非尼的制备方法。
本发明的工艺步骤如下所示:
本发明所述的高纯度索拉非尼是指产物纯度在99.9%以上。
本发明是通过下列技术方案实现的:
式(III)化合物4-(4-氨基苯氧基)-N-甲基吡啶-2-甲酰胺与式(II)化合物4-氯-3-三氟甲基异氰酸苯酯在反应试剂中反应后,加入处理试剂,经后处理,过滤,得到目标产物。
优选的,所述反应试剂选自二氯甲烷、环己烷和/或四氢呋喃,更优选四氢呋喃;所述处理试剂选自丙酮、二氯甲烷、三氯乙烯和/或氯仿,更优选二氯甲烷。
优选的,所述制备方法具体包括如下步骤:
a)4-(4-氨基苯氧基)-N-甲基吡啶-2-甲酰胺与4-氯-3-三氟甲基异氰酸苯酯在反应试剂中于30~100℃保温反应0.5~7小时;
b)降至室温,加入处理试剂,搅拌反应至少1小时;
c)过滤,得目标产物。
优选的,所述反应试剂选自二氯甲烷、环己烷和/或四氢呋喃;所述处理试剂选自丙酮、二氯甲烷、三氯乙烯和/或氯仿;更优选的,所述反应试剂选自四氢呋喃,所述处理试剂选自二氯甲烷。
优选的,所述步骤a)中控温为30~100℃,更优选控温30~70℃。
优选的,所述步骤a)中反应时间为0.5~5小时,更优选控温0.5~2小时。
优选的,所述步骤b)中搅拌时间为1~5小时,更优选控温1~2小时。
优选的,所述反应中四氢呋喃与二氯甲烷的体积比为1:1~1:10,优选1:1~1:5,特别优选1:1-1:3。
优选的,所述制备方法包括如下步骤:
a)4-(4-氨基苯氧基)-N-甲基吡啶-2-甲酰胺与4-氯-3-三氟甲基异氰酸苯酯在四氢呋喃中于30~50℃保温反应0.5~2小时;
b)降至室温,加入二氯甲烷,搅拌反应至少1-2小时;所述四氢呋喃与二氯甲烷的体积比为1:1~1:3;
c)过滤,得目标产物。
本发明的制备方法操作简单,收率高,产品纯度高,适合工业化生产。
附图说明
图1是甲苯磺酸索拉非尼的1H-核磁共振谱图。
具体实施方式
应该理解,本领域技术人员基于此处公开的内容,可以对本发明进行各种不偏离本发明精神和范围内的各种修改和改进。它们应当都落在本申请的权利要求定义的专利保护范围内。此外,应该理解,此处提供的实施例仅用于说明本方面的目的,而不应解释为对本发明的限制。
实施例1:
向1L三口瓶中,加入化合物III[4-(2-(N-甲基氨基甲酰基)吡啶-4-基氧基)苯胺]21.4g,四氢呋喃(100ml),于40~50℃油浴下搅拌10分钟,使溶清得红棕色液体。将化合物II(4-氯-3-三氟甲基异氰酸苯酯)20g溶于四氢呋喃(100ml)中,滴加入反应液中,保温反应1小时,反应液冷却至内温为20-30℃,加入二氯甲烷400ml,保温搅拌2小时。过滤,得化合物I粗品33.5g,HPLC:99.92%,最大单杂:0.03%。
实施例2:
向1L三口瓶中,加入化合物III[4-(2-(N-甲基氨基甲酰基)吡啶-4-基氧基)苯胺]21.4g,四氢呋喃(100ml),于40~50℃油浴下搅拌10分钟,使溶清得红棕色液体。将化合物II(4-氯-3-三氟甲基异氰酸苯酯)20g溶于四氢呋喃(100ml)中,滴加入反应液中,保温反应1小时,反应液冷却至内温为20-30℃,旋干,过滤,得化合物I粗品26.8g,HPLC:91.05%,最大单杂:4.51%。
实施例3:
将化合物III[4-(2-(N-甲基氨基甲酰基)吡啶-4-基氧基)苯胺]21.4g,二氯甲烷(100ml),于40~50℃油浴下搅拌10分钟,使溶清得红棕色液体。将化合物II(4-氯-3-三氟甲基异氰酸苯酯)20g溶于二氯甲烷(100ml)中,滴加入反应液中,保温反应1小时,反应液冷却至内温为20-30℃,旋干,过滤,得化合物I粗品24.66g,HPLC:87.87%,最大单杂:5.78%。
实施例4:
向1L三口瓶中,加入化合物III[4-(2-(N-甲基氨基甲酰基)吡啶-4-基氧基)苯胺]21.4g,四氢呋喃(100ml),于20℃下搅拌。将化合物II(4-氯-3-三氟甲基异氰酸苯酯)20g溶于四氢呋喃(100ml)中,滴加入反应液中,保温反应1小时,反应液冷却至内温为20-30℃,加入二氯甲烷400ml,保温搅拌2小时。过滤,得化合物I粗品25.1g,HPLC:96.97%,最大单杂:2.52%。
实施例5:
向1L三口瓶中,加入化合物III[4-(2-(N-甲基氨基甲酰基)吡啶-4-基氧基)苯胺]21.4g,四氢呋喃(100ml),于40~50℃油浴下搅拌10分钟,使溶清得红棕色液体。将化合物II(4-氯-3-三氟甲基异氰酸苯酯)20g溶于四氢呋喃(100ml)中,滴加入反应液中,保温反应1小时,反应液冷却至内温为20-30℃,加入二氯甲烷300ml,保温搅拌2小时。过滤,得化合物I粗品33.5g,HPLC:99.97%,最大单杂:0.01%。
实施例6:
将化合物I(12.6g)放入500ml圆底烧瓶中,加入异丙醇(150ml)和一水合对甲苯磺酸(6.2g),室温搅拌15小时,过滤,烘干,得类白色固体16.4g。
1H-NMR(DMSO-d6)δ:2.31(s,3H),2.84-2.85(d,3H),7.16-7.18(d,2H),7.21-7.23(d,2H),7.29-7.31(m,1H),7.58-7.62(m,3H),7.65-7.68(d,2H),7.69-7.72(m,2H),8.14-8.15(d,1H),8.60-8.61(d,1H),9.05-9.06(d,1H),9.30(s,1H),9.48(s,1H),9.74(br,1H).

Claims (7)

1.一种制备如式(I)所示的4-(4-{3-[4-氯-3-(三氟甲基)苯基]脲基}苯氧基)-N2-甲基吡啶-2-甲酰胺的方法,
其特征在于:式(III)化合物4-(4-氨基苯氧基)-N-甲基吡啶-2-甲酰胺与式(II)化合物4-氯-3-三氟甲基异氰酸苯酯在反应试剂中反应后,加入处理试剂,经后处理,过滤,得到目标产物,
2.根据权利要求1所述的方法,其特征在于:所述反应试剂选自二氯甲烷、环己烷和/或四氢呋喃,优选四氢呋喃;所述处理试剂选自丙酮、二氯甲烷、三氯乙烯和/或氯仿,优选二氯甲烷。
3.根据权利要求1所述的方法,其具体包括如下步骤:
a)4-(4-氨基苯氧基)-N-甲基吡啶-2-甲酰胺与4-氯-3-三氟甲基异氰酸苯酯在反应试剂中于30~100℃保温反应0.5~7小时;
b)降至室温,加入处理试剂,搅拌反应至少1小时;
c)过滤,得目标产物。
4.根据权利要求3所述的方法,其特征在于:所述反应试剂选自二氯甲烷、环己烷和/或四氢呋喃;所述处理试剂选自丙酮、二氯甲烷、三氯乙烯和/或氯仿;优选的,所述反应试剂选自四氢呋喃,所述处理试剂选自二氯甲烷。
5.根据权利要求4所述的方法,其特征在于:所述四氢呋喃与二氯甲烷的体积比为1:1~1:10,优选1:1~1:5,特别优选1:1-1:3。
6.根据权利要求3所述的方法,其特征在于,其包括如下步骤:
a)4-(4-氨基苯氧基)-N-甲基吡啶-2-甲酰胺与4-氯-3-三氟甲基异氰酸苯酯在四氢呋喃中于30~50℃保温反应0.5~3小时;
b)降至室温,加入二氯甲烷,搅拌反应至少1-3小时;所述四氢呋喃与二氯甲烷的体积比为1:1~1:5;
c)过滤,得目标产物。
7.根据权利要求6所述的制备方法,其特征在于,所述四氢呋喃与二氯甲烷的体积比为1:1~1:3。
CN201310690301.7A 2013-12-13 2013-12-13 高纯度索拉非尼的制备方法 Pending CN104710354A (zh)

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