CN108707099B - Preparation method of levetiracetam intermediate - Google Patents
Preparation method of levetiracetam intermediate Download PDFInfo
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- CN108707099B CN108707099B CN201810629772.XA CN201810629772A CN108707099B CN 108707099 B CN108707099 B CN 108707099B CN 201810629772 A CN201810629772 A CN 201810629772A CN 108707099 B CN108707099 B CN 108707099B
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- levetiracetam
- isomer
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- mother liquor
- heating
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- 229960004002 levetiracetam Drugs 0.000 title claims abstract description 30
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 title claims abstract 9
- 238000002360 preparation method Methods 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000012452 mother liquor Substances 0.000 claims abstract description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 239000007788 liquid Substances 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000003651 drinking water Substances 0.000 claims description 4
- 235000020188 drinking water Nutrition 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 239000012065 filter cake Substances 0.000 claims description 2
- 238000011084 recovery Methods 0.000 abstract description 2
- HPHUVLMMVZITSG-LURJTMIESA-N levetiracetam Chemical compound CC[C@@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-LURJTMIESA-N 0.000 description 25
- 239000000243 solution Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- IODGAONBTQRGGG-LURJTMIESA-N Levetiracetam acid Chemical compound CC[C@@H](C(O)=O)N1CCCC1=O IODGAONBTQRGGG-LURJTMIESA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- 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 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000005915 ammonolysis reaction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- QRQVFVYABBZXFO-ZETCQYMHSA-N methyl (2s)-2-(2-oxopyrrolidin-1-yl)butanoate Chemical compound COC(=O)[C@H](CC)N1CCCC1=O QRQVFVYABBZXFO-ZETCQYMHSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- IODGAONBTQRGGG-UHFFFAOYSA-N 2-(2-oxopyrrolidin-1-yl)butanoic acid Chemical compound CCC(C(O)=O)N1CCCC1=O IODGAONBTQRGGG-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 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
- 235000011114 ammonium hydroxide Nutrition 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
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229940062717 keppra Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000019837 monoammonium phosphate Nutrition 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a method for converting levetiracetam and/or isomers thereof into (+/-) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid, and the method is applied to recovery of levetiracetam mother liquor. The method provided by the invention has the advantages of simple operation steps, good yield and good economic benefit.
Description
Technical Field
The invention relates to a method for preparing a levetiracetam intermediate, in particular to a method for recovering and obtaining the intermediate from levetiracetam mother liquor, and belongs to the field of pharmaceutical chemicals.
Background
Levetiracetam (marketed under the name Keppra) is a novel antiepileptic drug developed by UCB, belgium, under the chemical name (S) -2- (2-oxopyrrolidin-1-yl) butanamide, having the structural formula shown in formula I:
CN85105301A reports that levetiracetam is obtained by splitting (+/-) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (II) to obtain (S) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (III), then obtaining a levetiracetam crude product through esterification and ammonolysis, and finally refining to obtain levetiracetam, wherein the synthetic route is shown as follows:
in the levetiracetam refining process, a large amount of waste liquid is generated, and the waste liquid contains more complex components, and the main components are as follows: the method is characterized in that the method comprises the following steps of preparing levetiracetam (I), levetiracetam isomer (I '), levetiracetam methyl ester (IV) and isomer (IV ') thereof, (S) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (III) and isomer (R) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (III '), and how to treat the waste liquid is one of core problems of the process.
Disclosure of Invention
In a first aspect of the present invention, there is provided a process for preparing (±) - α -ethyl-2-oxo-1-pyrrolidineacetic acid (II), comprising the steps of: heating levetiracetam (I) and/or isomer (I') thereof in strong alkali solution for reaction to obtain a compound shown in a formula II,
preferably:
wherein the base is selected from: sodium hydroxide or potassium hydroxide;
the percentage concentration range of the alkali solution is 25-40%;
the dosage of the alkali is 2 to 4 times, preferably 2.5 times of the total molar amount of the levetiracetam (I) and the isomer (I') thereof;
the temperature of the heated reaction solution: 80 to 120 ℃, preferably 90 to 95 ℃.
The heating reaction time is as follows: 8 to 12 hours.
According to the first aspect of the invention, the method can be applied to a levetiracetam mother liquor recovery process, and comprises the following specific steps:
(1) Concentrating a certain amount of levetiracetam mother liquor to be dry to obtain a solid-liquid mixture, wherein the mother liquor contains levetiracetam (I) and/or an isomer (I') thereof;
(2) Heating the solid-liquid mixture obtained in the step (1) in a strong alkali solution for reaction;
(3) After the reaction is finished, adding a proper amount of drinking water, and then adding hydrochloric acid to adjust the pH value to 0.5-4.5; preferably, the pH is adjusted to 1.0 to 2.0;
(4) Cooling the solution to 0-10 ℃, carrying out suction filtration, and drying a filter cake to obtain the (+/-) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid.
Simultaneously with the reaction in step (2), the tail gas can be absorbed by a secondary solvent absorption device, wherein the secondary solvent is selected from the following group: water, ethanol, methanol and dichloromethane, and the recovered ammonia gas can be prepared into ammonia solution required by ammonolysis reaction.
The invention provides a method for recovering levetiracetam mother liquor, which can recover (+/-) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid from levetiracetam mother liquor and can generate better economic benefit. The method has simple operation steps and good yield.
The specific implementation mode is as follows:
the following examples employ the detection method:
purity HPLC analytical method:
the instrument comprises the following steps: the high performance liquid chromatograph is provided with an ultraviolet detector and a chromatographic column: agilent Zobax Eclipse XDB C18150X 4.6mm 5 μm, wavelength: 205nm, mobile phase: 0.01mol/L ammonium dihydrogen phosphate aqueous solution: acetonitrile =1:9.
isomer HPLC analytical method:
the instrument comprises the following steps: the high performance liquid chromatograph is provided with an ultraviolet detector and a chromatographic column: CHIRALPAK AS-H250X 4.6mm 5 μm, mobile phase: n-hexane: trifluoroacetic acid =80:20, wavelength: 210nm.
Example 1
1000g of levetiracetam crude product and 4000g of acetone are taken and heated to 55-60 ℃, stirred for 1 hour under the condition of heat preservation, then slowly cooled to 0-5 ℃, and filtered to obtain 958g of levetiracetam wet product and 4019g of levetiracetam refined mother liquor.
Collecting 2500g of levetiracetam refined mother liquor, controlling the temperature at 50 ℃, and carrying out reduced pressure concentration at the pressure of less than or equal to-0.09 MPa until no liquid is evaporated out, and then continuously carrying out reduced pressure concentration for 0.5 hour to finally obtain 50.8g of a solid-liquid mixture.
50.8g of the obtained solid-liquid mixture is completely dissolved in 100g of 30 percent sodium hydroxide solution, slowly heated to 90-95 ℃, and continuously stirred for 10 hours under the temperature of 90-95 ℃.
After the reaction, 50g of drinking water was added, and then refined hydrochloric acid was added dropwise to the system until the pH of the reaction solution was 1.5. After the refined hydrochloric acid is dripped, stirring is continuously carried out for 0.5 hour, then the temperature of the system is slowly reduced to 5 ℃, the temperature is controlled to be 5 ℃, stirring is carried out for 0.5 hour, suction filtration is carried out, then the temperature of the solid is controlled to be 70-90 ℃, and drying is carried out under the pressure of more than or equal to 0.08 MPa. 47.9g of (+/-) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid is obtained, and the yield is 94.3 percent (the solid-liquid mixture is calculated by converting into the corresponding molar weight of levetiracetam). Purity (HPLC): 99.95%, other max monohetero (HPLC) 0.02%, (R) - α -ethyl-2-oxo-1-pyrrolidineacetic acid (isomer) (HPLC): 50.31 percent.
Examples 2 to 9
100g of levetiracetam isomer is dissolved in 30 percent aqueous alkali, slowly heated and then stirred at constant temperature. The specific conditions are as follows:
after the reaction, 100g of drinking water was added, and then refined hydrochloric acid was added dropwise to the system until the pH of the reaction solution became 1.5. After the refined hydrochloric acid is dripped, stirring is continuously carried out for 0.5 hour, then the temperature of the system is slowly reduced to 5 ℃, the temperature is controlled to be 5 ℃, stirring is carried out for 0.5 hour, suction filtration is carried out, then the temperature of the solid is controlled to be 70-90 ℃, and the pressure is not less than 0.08MPa for drying. Yield, purity, isomer data are as follows.
| Examples | Yield (%) | Purity (%) | Isomer (%) |
| 2 | 93.5 | 99.91 | 50.60 |
| 3 | 94.7 | 99.98 | 50.18 |
| 4 | 93.8 | 99.97 | 51.42 |
| 5 | 91.2 | 99.67 | 50.02 |
| 6 | 89.4 | 99.89 | 50.03 |
| 7 | 96.8 | 99.95 | 52.06 |
| 8 | 92.0 | 99.65 | 50.04 |
| 9 | 93.6 | 99.92 | 51.99 |
Claims (4)
1. A method for recovering (+/-) -alpha-ethyl-2-oxo-1-pyrrolidineacetic acid from levetiracetam mother liquor comprises the following steps:
(1) Concentrating a certain amount of levetiracetam mother liquor to dryness to obtain a solid-liquid mixture, wherein the mother liquor contains levetiracetam (I) and/or an isomer (I') thereof; the structure of levetiracetam (I) and/or its isomer (I') is shown below:
(2) Heating the solid-liquid mixture obtained in the step (1) in a strong alkali solution for reaction;
(3) After the reaction is finished, adding a proper amount of drinking water, and then adding hydrochloric acid to adjust the pH value to 0.5 to 4.5;
(4) Cooling the solution to 0 to 10 ℃, carrying out suction filtration, drying a filter cake to obtain (+/-) -alpha-ethyl-2-oxo-1-pyrrolidine acetic acid,
wherein the base is selected from: sodium hydroxide or potassium hydroxide, and the like,
wherein the percentage concentration range of the alkali solution is 25% -40%,
wherein the temperature of the heating reaction: 80 to 110 ℃,
wherein the heating reaction time is: the reaction time is 8 to 12 hours,
the dosage of the alkali is 2 to 4 times of the total molar quantity of the levetiracetam (I) and the isomer (I') thereof.
2. The process according to claim 1, wherein the amount of base is 2.5 times the total molar amount of levetiracetam (I) and its isomer (I').
3. The method of claim 1, wherein the heating the temperature of the reaction: 90 to 95 ℃.
4. The method according to claim 1, wherein hydrochloric acid is added in step (3) to adjust the pH to 1.0 to 2.0.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810629772.XA CN108707099B (en) | 2018-06-19 | 2018-06-19 | Preparation method of levetiracetam intermediate |
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| CN201810629772.XA CN108707099B (en) | 2018-06-19 | 2018-06-19 | Preparation method of levetiracetam intermediate |
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| CN108707099B true CN108707099B (en) | 2022-12-13 |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110003074A (en) * | 2019-04-23 | 2019-07-12 | 浙江华海药业股份有限公司 | A kind of preparation method of levetiracetam intermediate |
| CN112745254A (en) * | 2020-12-30 | 2021-05-04 | 江苏诚信药业有限公司 | Preparation method and application of 4-hydroxy-2-oxo-1-pyrrolidine acetic acid |
| CN114644586A (en) * | 2022-04-12 | 2022-06-21 | 江苏豪森药业集团有限公司 | Preparation method of lenalidomide related substance |
| CN114702426A (en) * | 2022-05-24 | 2022-07-05 | 雅本化学股份有限公司 | Synthesis method of levetiracetam intermediate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101511786A (en) * | 2006-07-25 | 2009-08-19 | Zach系统股份公司 | Process for the preparation of levetiracetam |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101511786A (en) * | 2006-07-25 | 2009-08-19 | Zach系统股份公司 | Process for the preparation of levetiracetam |
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