CN111518024A - 两种高纯度非洛地平杂质的制备方法 - Google Patents

两种高纯度非洛地平杂质的制备方法 Download PDF

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CN111518024A
CN111518024A CN202010339026.4A CN202010339026A CN111518024A CN 111518024 A CN111518024 A CN 111518024A CN 202010339026 A CN202010339026 A CN 202010339026A CN 111518024 A CN111518024 A CN 111518024A
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felodipine
impurity
compound
cooling
impurities
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任业明
段崇刚
赵思太
王金虎
张宁
邓玉晓
刘宜辉
龚艳艳
樊志萍
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Shandong Academy of Pharmaceutical Sciences
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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
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • 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
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation

Abstract

本发明涉及两种非洛地平杂质4‑(2,4‑二氯苯基)‑1,4‑二氢‑2,6‑二甲基‑3,5‑吡啶二羧酸甲酯乙酯(I)和4‑(3,4‑二氯苯基)‑1,4‑二氢‑2,6‑二甲基‑3,5‑吡啶二羧酸甲酯甲酯乙酯(II)的制备方法。通过对非洛地平杂质的制备，为非洛地平的质量研究提供杂质对照品。

Description

两种高纯度非洛地平杂质的制备方法
技术领域
本发明属于药物化学领域，具体来讲，涉及两种非洛地平制备过程中的杂质4-(2,4-二氯苯基)-2,6-二甲基-3,5-吡啶二羧酸甲酯乙酯和4-(3,4-二氯苯基)-2,6-二甲基-3,5-吡啶二羧酸甲酯乙酯的制备方法。
背景技术
非洛地平(clevidipine butyrate)，是一种新型经脉注射用二氢吡啶类钙通道阻滞药，选择性抑制动脉血管平滑肌细胞外的钙离子内流。由瑞典阿斯特拉(Astra)公司研制开发，并于1988年作为抗高血压药首次在丹麦上市。其化学名为4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二甲酸甲乙酯，结构式如下，目前临床上大多采用其缓释片，可持续释放非洛地平。临床研究结果表明，非洛地平用于治疗原发性高血压疗效显著，具有长效、不良反应少等优点。非洛地平结构如下：
Figure BDA0002467681700000011
目前国内报道的非洛地平的合成工艺路线较多，一般均以2,3-二氯苯甲醛为原料与乙酰乙酸甲酯经Knoevenagel缩合，再与β-氨基巴豆酸甲酯经Michael反应制得非洛地平产物。而2,3-二氯苯甲醛中含有2,4-二氯苯甲醛或3,4-二氯苯甲醛两种杂质，在后续的反应中可分别生成4-(2,4-二氯苯基)-2,6-二甲基-3,5-吡啶二羧酸甲酯乙酯和4-(3,4-二氯苯基)-2,6-二甲基-3,5-吡啶二羧酸甲酯乙酯两种非洛地平的杂质。所以对非洛地平杂质(I、II)的研究是十分必要的。结果如下所示：
Figure BDA0002467681700000012
发明内容
为了提高非洛地平的质量，降低临床用药的风险，本发明提供了两种制备高纯度非洛地平杂质的方法，对非洛地平的质量研究做出贡献。
本发明提供了两种高纯度非洛地平杂质的制备方法，其优势在于，该方法采用的原料及试剂均廉价易得，操作简单，无高温高压等特殊要求，制得的非洛地平杂质(I、II)纯度达到99.5％以上。
本发明提供了两种制备高纯度非洛地平杂质(I、II)的方法，其特征在于，该方法包括如下步骤：
Figure BDA0002467681700000021
第一步：在氮气保护下，以式(1)化合物(2,4-二氯苯甲醛或3,4-二氯苯甲醛)、乙酰乙酸乙酯和3-氨基巴豆酸甲酯在异丙醇中经环合反应生成目标化合物(I或II)粗品。
第二步：非洛地平杂质(I或II)粗品采用甲醇、乙醇、异丙醇等醇类溶剂或乙酸乙酯、二氯甲烷等溶剂，回流溶清，活性炭脱色，降温至0℃析晶1小时，得到非洛地平杂质(I或II)纯品。
进一步地，第一步所采用的醇可以为甲醇、乙醇、异丙醇等醇类溶剂。
进一步地，第二步所采用的精制溶剂可选为甲醇、乙醇、异丙醇等醇类溶剂，以及乙酸乙酯、二氯甲烷、甲苯等溶剂。精制得到的非洛地平杂质(I或II)纯度达到99.9％以上，收率为90％以上。
附图说明
图1非洛地平杂质I的HPLC图谱
图2非洛地平杂质II的HPLC图谱
具体实施方式
下面通过具体实施例，对本发明的方案作进一步的说明，但所述的进一步阐述和举例并不以任何方式限定本发明的专利保护范围。
实施例1
在氮气保护下，以2,4-二氯苯甲醛为起始原料，取该化合物(6.8g)加入250ml反应瓶中，加入异丙醇(50ml)溶解，再分别加入乙酰乙酸乙酯(6.3g)和3-氨基巴豆酸甲酯(5.5g)，加毕，混合溶液加热至回流搅拌16小时，再降温至10℃，出现大量固体，再搅拌析晶1h，过滤，冷异丙醇洗涤，得淡黄色固体非洛地平杂质I粗品：12.1g；收率：81.2％。
非洛地平杂质I粗品加入100ml反应瓶中，加乙醇(36ml)加热回流溶解，活性炭脱色15分钟，降温至0℃析晶30分钟，析出淡黄色固体非洛地平杂质I纯品10.9g，收率：90.0％。ESI-MS，m/z：385；[M+H]+；1H NMR(500MHz,DMSO-d6)δ8.95(s,1H),7.43(d,1H),7.26–7.05(m,2H),5.58(dd,1H),4.27(m,1H),3.95(m,1H),3.44(s,3H),2.23(d,6H),1.12(t,3H).
实施例2
在氮气保护下，以3,4-二氯苯甲醛为起始原料，取该化合物(6.8g)加入250ml反应瓶中，加入异丙醇(50ml)溶解，再分别加入乙酰乙酸乙酯(6.3g)和3-氨基巴豆酸甲酯(5.5g)，加毕，混合溶液加热至回流搅拌16小时，再降温至10℃，出现大量固体，再搅拌析晶1h，过滤，冷异丙醇洗涤，得淡黄色固体非洛地平杂质II粗品：11.9g；收率：79.9％。
非洛地平杂质II粗品加入100ml反应瓶中，加乙醇(36ml)加热回流溶解，活性炭脱色15分钟，降温至0℃析晶30分钟，析出淡黄色固体非洛地平杂质II纯品11.0g，收率：92.4％。收率：92.3％。ESI-MS，m/z：385；[M+H]+；1H-NMR(500MHz,DMSO-d6)δ8.97(s,1H),7.51(dd,1H),7.41(d,1H),7.25(m,1H),5.07–5.02(m,1H),4.32(m,1H),3.75(m,1H),3.45(s,3H),2.22(d,6H),1.15(t,3H).

Claims (3)

1.两种非洛地平杂质(Ⅰ)和(II)的制备方法，其特征在于，通过一锅法环合制得：
Figure FDA0002467681690000011
第一步：在氮气保护下，以式(1)化合物(2,4-二氯苯甲醛或3,4-二氯苯甲醛)、乙酰乙酸乙酯和3-氨基巴豆酸甲酯在异丙醇中经环合反应生成目标化合物(I或II)[(4-(2,4-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸甲酯乙酯(I)或4-(3,4-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸甲酯甲酯乙酯(II)]；
第二步：非洛地平杂质(I或II)粗品采用甲醇、乙醇、异丙醇等醇类溶剂或乙酸乙酯、二氯甲烷、甲苯等溶剂，回流溶清，活性炭脱色，降温至0℃析晶30分钟，得到非洛地平杂质(I或II)纯品。
2.根据权利要求1所述的两种非洛地平杂质(Ⅰ)和(II)的制备方法，其特征在于经过如下步骤：
第一步：一锅法环合反应，在氮气保护下，式(1)化合物、乙酰乙酸乙酯和3-氨基巴豆酸甲酯在溶剂异丙醇中加热至回流反应16小时，降温至10℃搅拌析晶1h，过滤，得淡黄色固体非洛地平杂质(I或II)粗品；
第二步：非洛地平杂质(I或II)粗品，用乙醇加热回流溶解，降温至0℃，搅拌30分钟，得淡黄色固体非洛地平杂质(I或II)纯品。
3.根据权利要求1所述的两种非洛地平杂质(Ⅰ)和(II)的制备方法，其特征在于，步骤如下：
在氮气保护下，以式(1)化合物(2,4-二氯苯甲醛或3,4-二氯苯甲醛)为起始原料，取该化合物(6.8g)加入250ml反应瓶中，加入异丙醇(50ml)溶解，再分别加入乙酰乙酸乙酯(6.3g)和3-氨基巴豆酸甲酯(5.5g)，加毕，混合溶液加热至回流搅拌16小时，再降温至10℃，出现大量固体，再搅拌析晶1h，过滤，得淡黄色固体非洛地平杂质(I或II)粗品(12.1g)；
非洛地平杂质(I或II)粗品(12.1g)加入250ml反应瓶中，加乙醇(36ml)加热回流溶解，活性炭脱色15分钟，降温至0℃析晶30分钟，析出淡黄色固体非洛地平杂质(I或II)纯品(10.9g)。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN192858B (zh) * 2000-02-25 2004-05-22 Council Scient Ind Res
WO2010027113A2 (en) * 2008-09-04 2010-03-11 Ahn-Gook Pharmaceutical Co., Ltd Process for preparing (s)-(-)-felodipine
CN102285911A (zh) * 2011-07-12 2011-12-21 绍兴文理学院 非洛地平的制备方法
CN108164454A (zh) * 2017-12-15 2018-06-15 江苏联环药业股份有限公司 一种非洛地平的制备新工艺

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN192858B (zh) * 2000-02-25 2004-05-22 Council Scient Ind Res
WO2010027113A2 (en) * 2008-09-04 2010-03-11 Ahn-Gook Pharmaceutical Co., Ltd Process for preparing (s)-(-)-felodipine
CN102285911A (zh) * 2011-07-12 2011-12-21 绍兴文理学院 非洛地平的制备方法
CN108164454A (zh) * 2017-12-15 2018-06-15 江苏联环药业股份有限公司 一种非洛地平的制备新工艺

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