CN115734964A - 一种左乙拉西坦中间体的制备方法 - Google Patents
一种左乙拉西坦中间体的制备方法 Download PDFInfo
- Publication number
- CN115734964A CN115734964A CN202180041072.9A CN202180041072A CN115734964A CN 115734964 A CN115734964 A CN 115734964A CN 202180041072 A CN202180041072 A CN 202180041072A CN 115734964 A CN115734964 A CN 115734964A
- Authority
- CN
- China
- Prior art keywords
- ethyl
- oxo
- process according
- alpha
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960004002 levetiracetam Drugs 0.000 title description 8
- 238000002360 preparation method Methods 0.000 title description 7
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 230000008569 process Effects 0.000 claims abstract description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 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 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 238000005886 esterification reaction Methods 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- IODGAONBTQRGGG-LURJTMIESA-N Levetiracetam acid Chemical compound CC[C@@H](C(O)=O)N1CCCC1=O IODGAONBTQRGGG-LURJTMIESA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 239000000243 solution Substances 0.000 description 14
- HPHUVLMMVZITSG-LURJTMIESA-N levetiracetam Chemical compound CC[C@@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-LURJTMIESA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- IODGAONBTQRGGG-ZCFIWIBFSA-N (2r)-2-(2-oxopyrrolidin-1-yl)butanoic acid Chemical compound CC[C@H](C(O)=O)N1CCCC1=O IODGAONBTQRGGG-ZCFIWIBFSA-N 0.000 description 1
- YAQLSKVCTLCIIE-UHFFFAOYSA-M 2-bromobutanoate Chemical compound CCC(Br)C([O-])=O YAQLSKVCTLCIIE-UHFFFAOYSA-M 0.000 description 1
- 208000003078 Generalized Epilepsy Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 201000001993 idiopathic generalized epilepsy Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000019837 monoammonium phosphate Nutrition 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
Abstract
一种制备α‑乙基‑2‑氧代‑1‑吡咯烷乙酸酯的方法，特别是通过优化后处理过程，使反应收率和产品纯度得到显著提升。
Description
PCT国内申请，说明书已公开。
Claims (11)
- PCT国内申请，权利要求书已公开。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2020106120712 | 2020-06-30 | ||
| CN202010612071.2A CN113861090A (zh) | 2020-06-30 | 2020-06-30 | 一种左乙拉西坦中间体的制备方法 |
| PCT/CN2021/100021 WO2022001649A1 (zh) | 2020-06-30 | 2021-06-15 | 一种左乙拉西坦中间体的制备方法 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115734964A true CN115734964A (zh) | 2023-03-03 |
Family
ID=78981132
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010612071.2A Pending CN113861090A (zh) | 2020-06-30 | 2020-06-30 | 一种左乙拉西坦中间体的制备方法 |
| CN202180041072.9A Pending CN115734964A (zh) | 2020-06-30 | 2021-06-15 | 一种左乙拉西坦中间体的制备方法 |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010612071.2A Pending CN113861090A (zh) | 2020-06-30 | 2020-06-30 | 一种左乙拉西坦中间体的制备方法 |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN113861090A (zh) |
| WO (1) | WO2022001649A1 (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023178538A1 (zh) * | 2022-03-23 | 2023-09-28 | 浙江华海药业股份有限公司 | 一种纯化左乙拉西坦中间体的方法 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080146819A1 (en) * | 2005-03-10 | 2008-06-19 | Rubamin Limited | Process for Preparing Levetiracetam |
| CN101511786A (zh) * | 2006-07-25 | 2009-08-19 | Zach系统股份公司 | 制备左乙拉西坦的方法 |
| CN102617436A (zh) * | 2012-03-20 | 2012-08-01 | 浙江洪波化工有限公司 | 2-(2-氧代吡咯烷基）丁酰胺的制备方法 |
| CN102851238A (zh) * | 2012-08-10 | 2013-01-02 | 上海应用技术学院 | 一种鞘氨醇杆菌及利用其制备左乙拉西坦酸的方法 |
| CN110590635A (zh) * | 2019-10-11 | 2019-12-20 | 山东理工职业学院 | 左乙拉西坦及其中间体的制备方法 |
-
2020
- 2020-06-30 CN CN202010612071.2A patent/CN113861090A/zh active Pending
-
2021
- 2021-06-15 CN CN202180041072.9A patent/CN115734964A/zh active Pending
- 2021-06-15 WO PCT/CN2021/100021 patent/WO2022001649A1/zh active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080146819A1 (en) * | 2005-03-10 | 2008-06-19 | Rubamin Limited | Process for Preparing Levetiracetam |
| CN101511786A (zh) * | 2006-07-25 | 2009-08-19 | Zach系统股份公司 | 制备左乙拉西坦的方法 |
| CN102617436A (zh) * | 2012-03-20 | 2012-08-01 | 浙江洪波化工有限公司 | 2-(2-氧代吡咯烷基）丁酰胺的制备方法 |
| CN102851238A (zh) * | 2012-08-10 | 2013-01-02 | 上海应用技术学院 | 一种鞘氨醇杆菌及利用其制备左乙拉西坦酸的方法 |
| CN110590635A (zh) * | 2019-10-11 | 2019-12-20 | 山东理工职业学院 | 左乙拉西坦及其中间体的制备方法 |
Non-Patent Citations (2)
| Title |
|---|
| 丁小莉: "抗癫痫药物左乙拉西坦的合成与工艺研究", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》, no. 07, 15 July 2012 (2012-07-15), pages 016 - 556 * |
| 刘跃金等: "左乙拉西坦及其衍生物的合成", 《中国新药杂志》, vol. 16, no. 11, 31 December 2007 (2007-12-31), pages 860 - 864 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2022001649A1 (zh) | 2022-01-06 |
| CN113861090A (zh) | 2021-12-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113045471B (zh) | 一种改进的酮咯酸中间体的制备方法 | |
| CN110467519B (zh) | 一种乙炔化方法 | |
| CN115734964A (zh) | 一种左乙拉西坦中间体的制备方法 | |
| CN111606851B (zh) | 一种高纯度高收率的硫酸羟氯喹产业化制备方法 | |
| CN108947774B (zh) | 一种分离异丙醇的方法及装置 | |
| CN104140410A (zh) | 鲁比前列酮的制备方法 | |
| CN112047883A (zh) | 顺苯磺酸阿曲库铵的制备方法 | |
| CN113372271A (zh) | 一种顺苯磺酸阿曲库铵的制备方法 | |
| CN109553610B (zh) | 一种恩曲他滨异构体的制备方法 | |
| CN110483317A (zh) | 高纯度3-异丁基戊二酸二甲酯的制备方法及应用 | |
| CN111285782A (zh) | 一种1-氰基环己基乙腈的制备方法 | |
| CN110255656B (zh) | 三嗪酮工业生产废水的处理方法 | |
| EP2168943B1 (en) | Method for producing optically active trans-2-aminocyclohexanol and intermediate of optically active trans-2-aminocyclohexanol | |
| CN113004300A (zh) | 一种稳定同位素标记的展青霉素及其合成方法 | |
| CN112481319A (zh) | 一种氨基甲酸酯的绿色合成方法 | |
| CN112430197A (zh) | 一种3-氧代-5-羟基-6-氰基己酸叔丁酯的合成方法 | |
| CN115974659B (zh) | 一种1-(1-乙氧基乙氧基)-4-乙烯基苯的合成方法 | |
| CN115636742B (zh) | 一种重结晶的方法 | |
| CN113061084B (zh) | 一种制备阿魏酸的新方法 | |
| CN109761950B (zh) | 一种制备4,4-二甲基-1,3-二氧六环的方法 | |
| CN113735755B (zh) | 一种氨磺必利的制备方法 | |
| CN113336636B (zh) | 一种高收率的dl-扁桃酸的合成工艺 | |
| CN114940676B (zh) | 一种假尿嘧啶核苷的合成方法 | |
| CN113544113B (zh) | 一种坎地沙坦酯中间体的合成方法 | |
| US6617463B2 (en) | Method for the production of L-ascorbic acid by lactonization of 2-keto-L-gulonic acid or s2-keto-L-gulonate esters |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |