CN103819406A - 艾曲波帕的制备方法 - Google Patents
艾曲波帕的制备方法 Download PDFInfo
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- 229960001827 eltrombopag olamine Drugs 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- ZXLYSSHNDUXXIN-UHFFFAOYSA-N 3-(3-amino-2-hydroxyphenyl)benzoic acid Chemical compound NC1=CC=CC(C=2C=C(C=CC=2)C(O)=O)=C1O ZXLYSSHNDUXXIN-UHFFFAOYSA-N 0.000 claims abstract description 15
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- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- -1 isobutyl- Chemical group 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
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- XDXWLKQMMKQXPV-QYQHSDTDSA-N eltrombopag Chemical compound CC1=NN(C=2C=C(C)C(C)=CC=2)C(=O)\C1=N/NC(C=1O)=CC=CC=1C1=CC=CC(C(O)=O)=C1 XDXWLKQMMKQXPV-QYQHSDTDSA-N 0.000 abstract description 2
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- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
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- 229940126460 thrombopoietin receptor agonist Drugs 0.000 description 2
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- MGKIRGBIZJFKPD-UHFFFAOYSA-N C1(=CC(=C(C=C1)C)C)C1(C(=O)O)CC(C(=O)O)(CC=C1)C Chemical compound C1(=CC(=C(C=C1)C)C)C1(C(=O)O)CC(C(=O)O)(CC=C1)C MGKIRGBIZJFKPD-UHFFFAOYSA-N 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- PLILLUUXAVKBPY-SBIAVEDLSA-N NCCO.NCCO.CC1=NN(C=2C=C(C)C(C)=CC=2)C(=O)\C1=N/NC(C=1O)=CC=CC=1C1=CC=CC(C(O)=O)=C1 Chemical compound NCCO.NCCO.CC1=NN(C=2C=C(C)C(C)=CC=2)C(=O)\C1=N/NC(C=1O)=CC=CC=1C1=CC=CC(C(O)=O)=C1 PLILLUUXAVKBPY-SBIAVEDLSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 102000005763 Thrombopoietin Receptors Human genes 0.000 description 1
- 108010070774 Thrombopoietin Receptors Proteins 0.000 description 1
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
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- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 1
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- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 230000001361 thrombopoietic effect Effects 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
- C07D231/46—Oxygen atom in position 3 or 5 and nitrogen atom in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
Abstract
本发明揭示了一种艾曲波帕(Eltrombopag)的制备方法，其制备包括如下步骤：用3’-氨基-2’-羟基联苯基-3-羧酸(II)和乙酰乙酸烷基酯发生重氮偶联反应得到(Z)-2-[3’-(2’-羟基-3-羧酸联苯基)亚肼基]-3-氧代丁酸烷基酯(III)，中间体(III)与3，4-二甲基苯肼进行缩合环化反应制得艾曲波帕(I)。该工艺过程简洁，原料易得，经济环保，有利于实现工业化，可促进艾曲波帕原料药的经济技术发展。
Description
技术领域
本发明属于有机合成路线设计及其原料药和中间体制备技术领域，特别涉及一种血小板减少性紫癜的治疗药物艾曲波帕的制备方法。
背景技术
艾曲波帕(Eltrombopag)是英国葛兰素史克公司开发的口服血小板生成因子类药物，是小分子血小板生成素受体激动剂，它可与人体跨膜区的血小板生成素受体相互作用，产生信号级联放大作用，从而诱导骨髓巨核细胞的增殖和分化。该药于2008年11月获得美国食品药品管理局(FDA)批准在美国上市，用于治疗经糖皮质激素类药物、免疫球蛋白治疗无效或脾切除术后慢性特发性血小板减少性紫癜(ITP)患者的血小板减少。商品名为Promacta。艾曲波帕为首个获准治疗成人慢性ITP患者的口服非肽类血小板生成素受体激动剂，其批准治疗ITP患者是一重要里程碑。目前，该药还在进行治疗丙型肝炎病毒、慢性肝病以及和肿瘤相关的引起的血小板减少症的临床研究。
艾曲波帕的化学名为：3′-{(2Z)-2-[1-(3，4-二甲苯基)-3-甲基-5-氧代-1，5-二氢-4H-吡唑-4-亚基]肼基}-2′-羟基-3-联苯基甲酸。
世界专利第WO2001／089457号、第WO2002／057300号、第WO2003／098992号、第WO2010／114943号、第WO2013／072921号和第WO2013／04960号等报道了艾曲波帕的合成路线和制备方法。虽然反应条件或工艺参数有所差别，但合成路线基本相同，即通过3′-氨基-2′-羟基联苯基-3-羧酸(中间体A)和1-(3，4-二甲苯基)-3-甲基-1H-吡唑-5(4H)-酮(中间体B)间的缩合偶联反应制得艾曲波帕(I)。
其中，中间体A是以2-溴苯酚和邻卤素苯甲酸为起始原料，经过硝化、保护、还原、Suzuki偶联和脱保护等反应制备得到。
中间体B则是以3，4-二甲基苯胺为原料经重氮化和还原成肼，再与乙酰乙酸乙酯缩合环化制得吡唑酮衍生物。
分析己公开的艾曲波帕及其中间体的制备方法，普遍存在反应步骤多、环保压力大、成本较高等弊端，因而寻求更加简洁方便、绿色环保及成本可控的工艺路线，对于该原料药的经济技术发展至关重要。
发明内容
本发明的目的在于克服现有技术的缺陷，按照绿色化学的合成理念，提供一种改进的艾曲波帕制备方法，该制备方法简便、经济和环保，有利于该药品的工业化生产，并能促进该原料药的经济技术发展。
为了实现上述目的，本发明所提供的主要技术方案如下：一种艾曲波帕(I)的制备方法，
该制备方法包括如下步骤：用3’-氨基-2’-羟基联苯基-3-羧酸(II)和乙酰乙酸烷基酯发生重氮偶联反应得到中间体(Z)-2-[3’-(2’-羟基-3-羧酸联苯基)亚肼基]-3-氧代丁酸烷基酯(III)，中间体(III)与3,4-二甲基苯肼进行缩合环化反应制得艾曲波帕(I)。
此外，本发明还提供如下附属技术方案：
原料乙酰乙酸烷基酯和相应的产物(Z)-2-[3’-(2’-羟基-3-羧酸联苯基)亚肼基]-3-氧代丁酸烷基酯(III)中的烷基R为甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、烯丙基或环己基，优选甲基或乙基。
重氮偶联反应原料3’-氨基-2’-羟基联苯基-3-羧酸(II)和乙酰乙酸烷基酯的投料摩尔比为1∶1.0-2.0，优选1∶1.2-1.5。
重氮偶联反应的溶剂为有机溶剂与水的混合溶剂，有机溶剂与水的体积比为1∶0.5-2.0，优选1∶0.75-1.5；该有机溶剂为甲醇、乙醇、丙醇、异丙醇、叔丁醇、环己醇、乙腈、N,N-二甲基甲酰胺、或二甲亚砜，优选甲醇或乙醇。
缩合环化反应的原料(Z)-2-[3’-(2’-羟基-3-羧酸联苯基)亚肼基]-3-氧代丁酸烷基酯(III)与3,4-二甲基苯肼的投料摩尔比为1∶0.5-1.5，优选1∶1.0-1.2。
缩合环化反应的温度为50-150℃，优选80-120℃。
缩合环化反应的溶剂为冰醋酸、二甲亚砜、甲苯、二甲苯、二氧六环、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺，优选冰醋酸。
本发明所涉及的艾曲波帕制备方法，通过重氮偶联和缩合环化等步骤，使其制备过程原料易得、快捷方便、经济环保，产品收率及产品纯度高，适于大规模工业化生产。
具体实施方式
以下结合数个较佳实施例对本发明技术方案作进一步非限制性的详细说明。其中，原料3’-氨基-2’-羟基联苯基-3-羧酸(II)和3,4-二甲基苯肼的制备可参考文献WO200I／089457和CN101481352的相关描述。
实施例一：
于反应瓶中加入3’-氨基-2’-羟基联苯基-3-羧酸(II)(2.29g，10mmol)和1N盐酸50mL，搅拌溶解。冰浴下滴加亚硝酸钠(0.76g，11mmol)的25mL水溶液，滴毕，搅拌下加入含有乙酰乙酸乙酯(1.63g，12.5mmol)和醋酸钠(8.2g，0.1mol)的乙醇75mL溶液，升至室温，反应10小时，TLC检测反应完成。过滤，粗品用甲醇重结晶得淡黄色固体(Z)-2-[3’-(2’-羟基-3-羧酸联苯基)亚肼基]-3-氧代丁酸乙酯(III)2.7g，收率73.0％。
实施例二：
室温下，于反应瓶中加入3,4-二甲基苯肼(0.75g，5.5mmol)和冰醋酸(25mL)，搅拌溶解。加入(Z)-2-[3’-(2’-羟基-3-羧酸联苯基)亚肼基]-3-氧代丁酸乙酯(III)(1.85g，5mmol)，升温至100℃，搅拌反应24小时，TLC检测反应完成。减压除去溶剂。粗品用甲醇重结晶，得类白色固体艾曲波帕(I)1.8g，收率81.4％。
需要指出的是，上述较佳实施例仅为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。
Claims (7)
1.一种艾曲波帕(I)的制备方法，
其特征在于该制备方法包括如下步骤：用3’-氨基-2’-羟基联苯基-3-甲酸(II)和乙酰乙酸烷基酯发生重氮偶联反应得到中间体(Z)-2-[3’-(2’-羟基-3-羧酸联苯基)亚肼基]-3-氧代丁酸烷基酯(III)，中间体(III)与3，4-二甲基苯肼进行缩合环化反应制得艾曲波帕(I)。
2.根据权利要求1所述艾曲波帕的制备方法，其特征在于：乙酰乙酸烷基酯和(Z)-2-[3’-(2’-羟基-3-羧酸联苯基)亚肼基]-3-氧代丁酸烷基酯(III)中的烷基R分别为甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、烯丙基或环己基。
3.根据权利要求1所述艾曲波帕的制备方法，其特征在于：3’-氨基-2’-羟基联苯基-3-羧酸(II)和乙酰乙酸烷基酯的投料摩尔比为1∶1.0-2.0。
4.根据权利要求1所述艾曲波帕的制备方法，其特征在于：重氮偶联反应的溶剂为有机溶剂与水的混合溶剂，有机溶剂与水的体积比为1∶0.5-2.0，该有机溶剂为甲醇、乙醇、丙醇、异丙醇、叔丁醇、环己醇、乙腈、N,N-二甲基甲酰胺、或二甲亚砜。
5.根据权利要求1所述艾曲波帕的制备方法，其特征在于：缩合环化反应的原料(Z)-2-[3’-(2’-羟基-3-羧酸联苯基)亚肼基]-3-氧代丁酸烷基酯(III)与3,4-二甲基苯肼的投料摩尔比为1∶0.5-1.5。
6.根据权利要求1所述艾曲波帕的制备方法，其特征在于：缩合环化反应的温度为50-150℃。
7.根据权利要求1所述艾曲波帕的制备方法，其特征在于：缩合环化反应的溶剂为冰醋酸、二甲亚砜、甲苯、二甲苯、二氧六环、N，N-二甲基甲酰胺或N，N-二甲基乙酰胺。
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Cited By (5)
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| CN106146330A (zh) * | 2015-04-21 | 2016-11-23 | 江苏威凯尔医药科技有限公司 | 一种制备艾曲波帕中间体的新方法 |
| CN107021928A (zh) * | 2017-04-01 | 2017-08-08 | 常州制药厂有限公司 | 艾曲波帕新的中间体及其制备方法和应用 |
| CN108101845A (zh) * | 2016-11-25 | 2018-06-01 | 苏州科伦药物研究有限公司 | 一种艾曲泊帕的制备方法 |
| US10336706B2 (en) | 2014-09-05 | 2019-07-02 | Hetero Research Foundation | Crystalline form of Eltrombopag free acid |
| CN112321454A (zh) * | 2020-11-25 | 2021-02-05 | 湖南华腾制药有限公司 | 一种艾曲泊帕中间体及其制备方法以及用该中间体制备艾曲泊帕的方法 |
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Cited By (8)
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| US10336706B2 (en) | 2014-09-05 | 2019-07-02 | Hetero Research Foundation | Crystalline form of Eltrombopag free acid |
| CN106146330A (zh) * | 2015-04-21 | 2016-11-23 | 江苏威凯尔医药科技有限公司 | 一种制备艾曲波帕中间体的新方法 |
| CN106146330B (zh) * | 2015-04-21 | 2018-04-06 | 江苏威凯尔医药科技有限公司 | 一种制备艾曲波帕中间体的方法 |
| CN108101845A (zh) * | 2016-11-25 | 2018-06-01 | 苏州科伦药物研究有限公司 | 一种艾曲泊帕的制备方法 |
| CN108101845B (zh) * | 2016-11-25 | 2020-05-15 | 苏州科伦药物研究有限公司 | 一种艾曲泊帕的制备方法 |
| CN107021928A (zh) * | 2017-04-01 | 2017-08-08 | 常州制药厂有限公司 | 艾曲波帕新的中间体及其制备方法和应用 |
| CN107021928B (zh) * | 2017-04-01 | 2022-11-18 | 常州制药厂有限公司 | 艾曲波帕新的中间体及其制备方法和应用 |
| CN112321454A (zh) * | 2020-11-25 | 2021-02-05 | 湖南华腾制药有限公司 | 一种艾曲泊帕中间体及其制备方法以及用该中间体制备艾曲泊帕的方法 |
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| KR101919097B1 (ko) | 2018-11-15 |
| CN103819406B (zh) | 2015-04-08 |
| KR20170005404A (ko) | 2017-01-13 |
| WO2015139536A1 (zh) | 2015-09-24 |
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