CN112724061A - 一种左乙拉西坦杂质pbba及其制备方法 - Google Patents
一种左乙拉西坦杂质pbba及其制备方法 Download PDFInfo
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- 239000012535 impurity Substances 0.000 title claims abstract description 26
- 229960004002 levetiracetam Drugs 0.000 title claims abstract description 22
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 2
- 238000003908 quality control method Methods 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 238000004458 analytical method Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000000337 buffer salt Substances 0.000 description 2
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 208000003078 Generalized Epilepsy Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 201000001993 idiopathic generalized epilepsy Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种左乙拉西坦杂质PBBA及其制备方法，该杂质结构如下式所示。本发明通过确定该杂质的结构，以及提供定向合成该杂质的方法，并建立该杂质的分析方法，可有效控制左乙拉西坦原料药的质量。
Description
技术领域
本发明涉及药物化学领域，具体涉及4-(2-(2-吡咯烷酮-1-基)丁酰胺基)丁酰胺(PBBA，一种左乙拉西坦杂质)及其制备方法。
发明背景
左乙拉西坦(英文名Levetiracetam)，化学名为(S)-2-(2-吡咯烷酮-1-基)丁酰胺，其结构式如下：
左乙拉西坦是比利时UCB公司开发的一种高效的、毒副作用小的广谱抗癫痫药，主要用于治疗局限性及继发性全身癫痫。
左乙拉西坦的最大日剂量为3000mg/天，根据ICH相关指导原则的规定，对于超过每日主成分最大日剂量为2g/天的产品，杂质的界定限为0.05％。超越界定限的杂质含量已经达到足以对人造成危害的数量。高于该限度的杂质应进行动物毒理研究，确定临床使用的安全限，且药品中的杂质含量应在效期内不大于该限度。
发明内容
在左乙拉西坦生产过程中，发明人发现某些异常批次有未知杂质水平较高，因此鉴定并且合成该杂质，建立该杂质的分析方法，对左乙拉西坦原料药的质量控制有重要意义。
本发明的一方面提供了一种左乙拉西坦杂质，其结构如下式所示：
另一方面提供了一种操作简便，成本低廉的合成4-(2-(2-吡咯烷酮-1-基)丁酰胺基)丁酰胺的方法。
该方法以化合物4-(2-(2-吡咯烷酮-1-基)丁酰胺基)丁酸甲酯为起始原料，与氨化试剂反应得到PBBA。
其中，反应可以在无溶剂或有溶剂中进行，优选在溶剂中进行反应，溶剂进一步优选为甲醇、乙醇或DMF；溶剂用量与4-(2-(2-吡咯烷酮-1-基)丁酰胺基) 丁酸甲酯的质量比为1:1～10:1，优选为2:1～5:1。
所述的氨化试剂为氨气或甲酰胺；
反应可以在含碱或碱性的条件下进行，优选在碱性条件下进行，进一步优选所述碱为甲醇钠、乙醇钠。所述碱用量与4-(2-(2-吡咯烷酮-1-基)丁酰胺基)丁酸甲酯的摩尔比为0:1～5:1，优选为1.5:1～2.5:1；反应温度为-20～70℃。
本发明提供的杂质PBBA为主要工艺杂质，较难精制去除，本发明通过确定该杂质的结构，以及提供定向合成该杂质的方法，并建立该杂质的分析方法，可有效控制左乙拉西坦原料药的质量。
附图说明
图1：左乙拉西坦PBBA杂质检测图谱。
图2：左乙拉西坦样品检测图谱。
具体实施方式
下面结合实施例对本发明做进一步阐述，但是这些实例不对本发明构成任何限制。
实施例1：
4-(2-(2-吡咯烷酮-1-基)丁酰胺基)丁酰胺(PBBA)的合成：
向500mL的高压反应釜中，依次加入27.0g(0.10mol)4-(2-(2-吡咯烷酮-1- 基)丁酰胺基)丁酸甲酯，100g的甲醇，关闭釜盖，搅拌降温至-20℃，通入氨气至饱和，关闭阀门，升温至60℃，反应20h，降温至20～25℃，泄压，出料，蒸干溶剂，真空抽干得PBBA，收率85％。1H NMR(CDCl3)δ＝0.85(t,3H), 1.63-1.81(m,3H),1.91-1.98(m,3H),2.20(t,2H),2.39(t,2H),3.21-3.50(m,4H), 4.35-4.39(m,1H),6.07(bs,1H),6.48(bs,1H),7.10(bs,1H)；13C NMR(CDCl3)δ＝ 10.6 18.1,21.5,25.2,31.1,32.8,38.6,44.1,56.7,170.6,175.5,176.2.MS-ESI(m/z): [M+H]+256.2.
实施例2：
4-(2-(2-吡咯烷酮-1-基)丁酰胺基)丁酰胺(PBBA)的合成：
向500mL的高压反应釜中，依次加入27.0g(0.10mol)4-(2-(2-吡咯烷酮-1- 基)丁酰胺基)丁酸甲酯，125g的乙醇，关闭釜盖，搅拌降温至-20℃，通入氨气至饱和，关闭阀门，升温至70℃，反应24h，降温至20～25℃，泄压，出料，蒸干溶剂，真空抽干得PBBA，收率81％。1H NMR(CDCl3)δ＝0.85(t,3H), 1.63-1.81(m,3H),1.91-1.98(m,3H),2.20(t,2H),2.39(t,2H),3.21-3.50(m,4H), 4.35-4.39(m,1H),6.07(bs,1H),6.48(bs,1H),7.10(bs,1H)；13C NMR(CDCl3)δ＝ 10.6 18.1,21.5,25.2,31.1,32.8,38.6,44.1,56.7,170.6,175.5,176.2.MS-ESI(m/z): [M+H]+256.2.
实施例3：
4-(2-(2-吡咯烷酮-1-基)丁酰胺基)丁酰胺(PBBA)的合成：
向500mL的高压反应釜中，依次加入27.0g(0.10mol)4-(2-(2-吡咯烷酮-1- 基)丁酰胺基)丁酸甲酯，125g的DMF，9g(0.20mol)的甲酰胺，搅拌升温至 40℃，加入10.8g(0.20mol)的甲醇钠，40～50℃搅拌反应4～5小时，蒸干溶剂，柱层析分离主产物得PBBA，收率74％。1H NMR(CDCl3)δ＝0.85(t,3H), 1.63-1.81(m,3H),1.91-1.98(m,3H),2.20(t,2H),2.39(t,2H),3.21-3.50(m,4H), 4.35-4.39(m,1H),6.07(bs,1H),6.48(bs,1H),7.10(bs,1H)；13C NMR(CDCl3)δ＝10.6 18.1,21.5,25.2,31.1,32.8,38.6,44.1,56.7,170.6,175.5,176.2.MS-ESI(m/z): [M+H]+256.2.
实施例4：
4-(2-(2-吡咯烷酮-1-基)丁酰胺基)丁酰胺(PBBA)和左乙拉西坦样品的检测：
检测条件：
进样浓度：PBBA 0.5μg/mL和左乙拉西坦样品10μg/mL分别进样
色谱仪：高效液相色谱仪配备紫外检测器配备鬼峰捕集小柱
色谱柱：Inertsil ODS-3 150×4.6mm,5μm
缓冲盐：2.7g磷酸二氢钾溶于1000mL水中，用磷酸调节pH至4.5。
流动相A:缓冲盐：乙腈＝19:1(％V/V)
流动相B:乙腈
波长：205nm 柱温：30℃ 流速：0.9mL/min
进样量：10μL 运行时间：40min
梯度表：
| 时间(min) | 流动相A(％V/V) | 流动相B(％V/V) |
| 0 | 100 | 0 |
| 10 | 100 | 0 |
| 20 | 71 | 29 |
| 25 | 71 | 29 |
| 28 | 100 | 0 |
| 40 | 100 | 0 |
PBBA和左乙拉西坦样品的检测结果分别见图1和图2。
Claims (10)
1.一种左乙拉西坦杂质PBBA，其结构如下所示：
2.一种制备如权利要求1所述的左乙拉西坦杂质PBBA的方法，该方法以化合物4-(2-(2-吡咯烷酮-1-基)丁酰胺基)丁酸甲酯为起始原料，与氨化试剂反应得到PBBA，
3.根据权利要求2所述的制备方法，其特征在于，反应在溶剂中进行，所述溶剂选自甲醇、乙醇或DMF。
4.根据权利要求3所述的制备方法，所述溶剂用量与4-(2-(2-吡咯烷酮-1-基)丁酰胺基)丁酸甲酯的质量比为1:1～10:1，优选为2:1～5:1。
5.根据权利要求2所述的制备方法，其特征在于所述的氨化试剂为氨气或甲酰胺。
6.根据权利要求2所述的制备方法，其特征在于所述反应在碱性条件下进行。
7.根据权利要求6所述的制备方法，所述碱为甲醇钠或乙醇钠。
8.根据权利要求6所述的制备方法，碱用量与4-(2-(2-吡咯烷酮-1-基)丁酰胺基)丁酸甲酯的摩尔比为0:1～5:1，优选为1.5:1～2.5:1。
9.根据权利要求2的制备方法，反应温度为-20～70℃。
10.权利要求1所述左乙拉西坦杂质PBBA，作为左乙拉西坦产品质量控制研究的杂质对照品的用途。
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