CN108409592B - 一种左乙拉西坦的杂质及其合成方法 - Google Patents
一种左乙拉西坦的杂质及其合成方法 Download PDFInfo
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- 239000012535 impurity Substances 0.000 title abstract description 11
- 229960004002 levetiracetam Drugs 0.000 title abstract description 8
- 238000010189 synthetic method Methods 0.000 title abstract description 3
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 title abstract 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- IODGAONBTQRGGG-UHFFFAOYSA-N 2-(2-oxopyrrolidin-1-yl)butanoic acid Chemical compound CCC(C(O)=O)N1CCCC1=O IODGAONBTQRGGG-UHFFFAOYSA-N 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 5
- VLGWOCOMICKAPO-UHFFFAOYSA-N 2-(3-carboxypropylamino)butanoic acid Chemical compound CCC(C(O)=O)NCCCC(O)=O VLGWOCOMICKAPO-UHFFFAOYSA-N 0.000 description 8
- HPHUVLMMVZITSG-LURJTMIESA-N levetiracetam Chemical compound CC[C@@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-LURJTMIESA-N 0.000 description 7
- 238000001035 drying Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 3
- 238000011109 contamination Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- IODGAONBTQRGGG-LURJTMIESA-N Levetiracetam acid Chemical compound CC[C@@H](C(O)=O)N1CCCC1=O IODGAONBTQRGGG-LURJTMIESA-N 0.000 description 1
- -1 acetylpyrrolidine compound Chemical class 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940062717 keppra Drugs 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/22—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种式I所示的左乙拉西坦新杂质以及该杂质的合成方法，
Description
技术领域
本发明涉及一种左乙拉西坦的新杂质以及合成方法，属于医药化工领域。
背景技术
左乙拉西坦(Levetiracetam，商品名为Keppra)是由比利时公司UCB研制的一种新型的抗癫痫药物，它是一种乙酰吡咯烷类化合物，其化学名称为(S)-α-乙基-2-氧合-1-乙酰胺吡咯烷，结构如下所示：
其中式II所示的化合物α-乙基-2-氧代-1-吡咯烷乙酸为其关键中间体，例如专利US4696943报道将其通过拆分获得(S)-α-乙基-2-氧代-1-吡咯烷乙酸，再进一步氨化得到左乙拉西坦：
发明内容
发明人在研究左乙拉西坦的制备过程中发现式II所示的α-乙基-2-氧代-1-吡咯烷乙酸存在一种未曾被报道过的新杂质，该杂质可由中间体带到成品中去，对成品质量造成影响。该杂质命名为2-[(3-羧基丙基)氨基]丁酸，结构式如式I所示：
本发明还提供了式I所示化合物的制备方法，包括以下步骤：
(a)加热条件下，使式II的化合物α-乙基-2-氧代-1-吡咯烷乙酸在强碱条件下在水或者有机溶剂中反应，
(b)反应结束后，在步骤(a)的反应液中加酸，分离得到式I所示化合物，
其中所述碱优选为：氢氧化钠、氢氧化钾、甲醇钠、叔丁醇钠、叔丁醇钾或丁基锂。所述碱与式II所示化合物的投料摩尔比优选为1～20：1。
所述有机溶剂优选为：四氢呋喃、甲苯、甲基叔丁基醚或乙腈。所述水或有机溶剂体积用量相对于每克式II所示化合物优选为1.5ml～10ml。
步骤(b)所述酸优选为盐酸。
步骤(b)加入酸调节pH至0.5～5.0，进一步优选调节pH至3.0。
本发明发现的新杂质对于左乙拉西坦成品的质量控制方面具有非常有用的价值，例如：研究该杂质及其衍生物对于成品的污染程度，以及研究如何控制该杂质的生成，降低对成品污染的风险。
具体实施方式
下面结合实施例，对本发明的具体实施方式作进一步详细描述。以下实施例仅用于说明本发明，但不用于限制本发明的范围。
实例1：
取α-乙基-2-氧代-1-吡咯烷乙酸20g于三口瓶中，加入水60ml，然后加入氢氧化钠9.4g，于90～120℃下搅拌反应9小时，加入盐酸调节pH至3.0，降温析晶得到2-[(3-羧基丙基)氨基]丁酸，烘干称重得20.1g，收率为90％，纯度为95.8％。
结构鉴定如下：
MS-ESI(M+1)＝190.1；MS-ESI(M-1)＝188.1。
H-NMR(DMSO-d6):δ:12.38(S,1H),12.01(S,1H),3.43-3.37(m,1H),3.35-3.27(m,1H),2.57-2.49(m,2H),2.33-3.27(m,2H),1.75-1.60(m,4H),0.89-0.83(m,3H)。
实例2：
取α-乙基-2-氧代-1-吡咯烷乙酸20g于三口瓶中，加入四氢呋喃30ml，然后加入氢氧化钾39.4g，于90～120℃下搅拌反应8小时，浓缩掉溶剂，加入水和精制盐酸调节pH至1.0，降温析晶，过滤得到2-[(3-羧基丙基)氨基]丁酸，烘干后称重为15.3g，收率为69.2％，纯度为97.2％。
实例3：
取α-乙基-2-氧代-1-吡咯烷乙酸20g于三口瓶中，加入甲苯100ml，然后加入甲醇钠50.5g，于95～110℃下搅拌反应6小时，浓缩掉溶剂，加入水和精制盐酸调节pH至4.0，降温析晶，过滤得到2-[(3-羧基丙基)氨基]丁酸，烘干后称重为15.3g，收率为57％，纯度为93.5％。
实例4：
取α-乙基-2-氧代-1-吡咯烷乙酸20g于三口瓶中，加入甲基叔丁基醚70ml，然后加入叔丁醇钠168.4g，于50～70℃下搅拌反应9小时，浓缩掉溶剂，加入水和精制盐酸调节pH至2.0，降温析晶，过滤得到2-[(3-羧基丙基)氨基]丁酸，烘干后称重为17.3g，收率为78.3％，纯度为89.5％。
实例5：
取α-乙基-2-氧代-1-吡咯烷乙酸20g于三口瓶中，加入乙腈180ml，然后加入叔丁醇钾91.7g，于50～70℃下搅拌反应8小时，浓缩掉溶剂，加入水和精制盐酸调节pH至4.5，降温析晶，过滤得到2-[(3-羧基丙基)氨基]丁酸，烘干后称重为19.2g，收率为86.9％，纯度为92.5％。
实例6：
取α-乙基-2-氧代-1-吡咯烷乙酸20g于三口瓶中，加入四氢呋喃80ml，然后加入丁基锂142.2g，于50～70℃下搅拌反应3小时，浓缩掉溶剂，加入水和精制盐酸调节pH至3.5，降温析晶，过滤得到2-[(3-羧基丙基)氨基]丁酸，烘干后称重为17.6g，收率为80.0％，纯度为93.9％。
Claims (5)
1.式I所示化合物的制备方法，包括以下步骤：
(a)加热条件下，使式II的化合物α-乙基-2-氧代-1-吡咯烷乙酸在强碱条件下在水或者有机溶剂中反应，
(b)反应结束后，在步骤(a)的反应液中加酸调节pH至0.5～5.0，降温析晶分离得到式I所示化合物，
其中所述碱选自：氢氧化钠、氢氧化钾、甲醇钠、叔丁醇钠、叔丁醇钾或丁基锂，
其中当所述碱为氢氧化钠、氢氧化钾时，反应温度为90～120℃；当所述碱为甲醇钠时，反应温度为95～110℃；当所述碱为叔丁醇钠、叔丁醇钾或丁基锂，反应温度为50～70℃，
所述有机溶剂选自：四氢呋喃、甲苯、甲基叔丁基醚或乙腈。
2.根据权利要求1所述的方法，所述碱与式II所示化合物的投料摩尔比为1～20：1。
3.根据权利要求1所述的方法，所述水或有机溶剂体积用量相对于每克式II所示化合物为1.5ml～10ml。
4.根据权利要求1所述的方法，步骤(b)所述酸为盐酸。
5.根据权利要求1所述的方法，步骤(b)加入酸调节pH至3.0。
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| CN103304464B (zh) * | 2013-05-10 | 2014-06-11 | 成都合迅医药技术有限公司 | 一种制备左乙拉西坦的方法 |
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| Title |
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| "β-Hydroxypiperidinecarboxylates: additions to the chiral pool from bakers’ yeast reductions of β-ketopiperidinecarboxylates";David W. Knight等，;《J. Chem. Soc., Perkin Trans.1》;19980101;第3673-3683页 * |
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