CN111892526A - Novel preparation method of brivaracetam - Google Patents
Novel preparation method of brivaracetam Download PDFInfo
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- CN111892526A CN111892526A CN201910370852.2A CN201910370852A CN111892526A CN 111892526 A CN111892526 A CN 111892526A CN 201910370852 A CN201910370852 A CN 201910370852A CN 111892526 A CN111892526 A CN 111892526A
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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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Abstract
The invention provides a preparation method of brivaracetam, which takes (R) -4-propyl dihydro-2 (3H) -ketone which is purchased from the market as a raw material to synthesize the brivaracetam in four steps under certain conditions. The preparation method provided by the invention can directly obtain the high-optical-purity brivaracetam without adopting a chiral preparation chromatographic column separation step. The method has the advantages of high yield, simple and convenient post-treatment, low production cost and suitability for industrial production.
Description
Technical Field
The invention relates to a novel preparation method of brivaracetam.
Background
Epilepsy, commonly known as epilepsy, is a disease of paroxysmal motor, sensation, consciousness, mental and autonomic nerve dysfunction caused by paroxysmal abnormal discharge of neuron groups in the brain due to various reasons. The total prevalence rate of domestic epilepsy is 7.0%, the annual incidence rate is 28.8/10 ten thousand, and the prevalence rate of active epilepsy with seizures within 1 year is 4.6%. The Brivaracetam is a sitan derivative, is a novel high-affinity synaptobrevin 2A ligand, can inhibit a neuron voltage-dependent sodium channel, and plays a role in resisting epilepsy. Brivaracetam is a 3 rd generation antiepileptic drug developed by belgium time ratio (UCB) corporation.
The chemical name of the Buvalsartan is (2S) -2- [ (4R) -2-oxo-4-propyltrahydro-1H-pyrrol-1-yl ] butanamide.
Structural formula of it
The brivaracetam can be prepared in various ways, and is mainly prepared by the following two methods:
the method comprises the following steps: in the form of racemic 4-propyl-bisHydrogen furan-2-ketone as raw material, through ring opening, acyl chlorination reaction, and final ring closing with BRT-2 to obtain BRT and its diastereoisomer mixture ((J.Med.Chem.,2004,47,530）。
The target molecule is obtained only by silica gel column separation and purification and chiral resolution, and the method has high production cost and poor industrial feasibility.
The second method comprises the following steps: the (R) -4-propyl-dihydrofuran-2-ketone is used as a raw material, and the steps of ring opening, halogenation, condensation, ring closing and the like are carried out to prepare the brivaracetam (WO 2018152950).
The method can obtain the product with high chiral purity by ring closing reaction only by using non-nucleophilic strong base at low temperature.
Therefore, it is necessary to find a synthetic route of the brivaracetam, which has the advantages of few steps, high yield, simple post-treatment, high purity and suitability for industrial production.
Disclosure of Invention
Aiming at the defects of the prior art, the technical scheme of the invention is to provide a novel method for synthesizing the brivaracetam. The preparation method provided by the invention can directly obtain the high-optical-purity brivaracetam without adopting a chiral preparation chromatographic column separation step. The method has the advantages of high yield, simple and convenient post-treatment, low production cost and suitability for industrial production.
The invention provides a preparation method of brivaracetam, which takes (R) -4-propyl dihydro-2 (3H) -ketone (compound 1) which is purchased from the market as a raw material to synthesize the brivaracetam (compound 5) through four steps of ring opening, acylation, esterification and ring closing.
Synthetic route [1]
The step of synthesizing the brivaracetam mainly comprises four steps, wherein in the first step, (R) -4-propyl dihydro-2 (3H) -ketone (compound 1) is subjected to ring opening reaction under certain conditions to generate a compound 2, in the second step, the compound 2 is subjected to halogenation reaction to generate a compound 3, in the third step, the compound 3 is subjected to esterification reaction to generate a compound 4, and in the fourth step, the compound 4 is subjected to ring closing to prepare a target compound brivaracetam (compound 5).
In the first step of synthesizing the brivaracetam, the ring-opening reagent is trimethyl iodosilane, trimethyl bromosilane, trimethyl chlorosilane, hydrobromic acid and the like, and preferably trimethyl iodosilane.
In the second step of synthesizing the brivaracetam, the chlorinated reagent is phosphorus trichloride, phosphorus pentachloride, phosgene, thionyl chloride and the like, and the thionyl chloride is preferably thionyl chloride.
In the second step of synthesizing the brivaracetam, the catalyst is N, N-Dimethylformamide (DMF), N-dimethylaniline or pyridine, and the like, and the N, N-dimethylformamide is preferred.
In the third step of synthesizing the brivaracetam, the preferable reagent is methanol, ethanol and the like, and the preferable reagent is methanol.
In the fourth step of the synthesis of the brivaracetam, the preferable reaction solvent is acetonitrile, toluene, ethyl acetate, isopropyl acetate and the like, and the preferable reaction solvent is isopropyl acetate.
In the fourth step of synthesizing the brivaracetam, the preferable reaction temperature is 50-120 DEGoC, preferably 90oC。
In the fourth step of synthesizing the brivaracetam, the preferable reaction time is 20-40 hours, and the preferable reaction time is 28 hours.
In the synthesis of the bravaracetam, the progress of the reaction can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and is generally the end point of the reaction when the starting material disappears.
The crude product of the brivaracetam is preferably dissolved, filtered, dried and the solvent is removed. The suction filtration, the water washing, the drying and the solvent removal adopt the conventional method of the operation in the field, the dissolution is preferably dichloromethane dissolution, the water washing adopts tap water preferentially, the drying adopts anhydrous sodium sulfate or magnesium sulfate preferentially, and the solvent removal is preferably decompression concentration.
The crude product of the brivaracetam is subjected to pulping and recrystallization preferentially to obtain the brivaracetam. The pulping and recrystallization can adopt a conventional method operated in the field, the solvent adopted for pulping is preferably a mixed solvent of a lipid solvent and an alcohol solvent, and the volume ratio of the lipid solvent to the alcohol solvent in the mixed solvent of the lipid solvent and the alcohol solvent is preferably 5: 1-12: 1, such as 8: 1. The lipid solvent is preferably ethyl acetate; the alcohol solvent is preferably isopropanol. The solvent used for recrystallization is preferably an aprotic solvent; the aprotic solvent is preferably one or more of ethyl acetate, acetone, dichloromethane, methyl tert-butyl ether, isopropyl ether and diethyl ether.
The HPLC purity of the brivaracetam is more than 99.70%.
The starting materials or reagents described in the present invention are commercially available unless otherwise specified.
The preparation method provided by the invention has the advantages of few steps, suitability for industrial production, no need of chiral high-pressure liquid phase preparation column resolution, simple post-treatment and high purity. The other single impurities of the brivaracetam are less than 0.1 percent, reach the level of raw material medicines (API), and are suitable for industrial production. The invention relates to a green synthesis process.
Detailed Description
The following examples further illustrate the present invention without, however, limiting the scope of the invention thereto. The experimental methods in the following examples, which do not indicate specific conditions, were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
The preparation method of the Buvartan comprises the following process steps
(1) Compound 1 (5.0 g, 39 mmol) and 50ml of dichloromethane were added to a single-neck flask and stirring was turned on. TMSI (6.7 mL, 46.8 mmol) was measured and dissolved in 10 mL of dichloromethane and added dropwise to the system, and after completion of the dropwise addition, the reaction was stopped at room temperature for 3 hours. 50mL of 1M hydrochloric acid solution was added, stirred for 20 minutes, and transferred toIn a 250 mL separatory funnel, the liquid was extracted, the lower organic phase was collected, and the aqueous phase was extracted with dichloromethane (30 mL × 2). The organic phases were collected, washed with 50mL of 10% sodium thiosulfate solution, the organic phases were collected, the aqueous phase was washed with dichloromethane (30 mL × 1), and the organic phases were combined. The organic phases were combined and anhydrous Na was added2SO4Drying for 2 hours. Filtering, removing anhydrous Na2SO4The filtrate was concentrated at 40 ℃. 9.4g of a reddish brown oil was obtained in a yield of 94.0%.
(2) Adding SOCl2(9.6 mL, 0.1406 mol) and 270 mL of methylene chloride were added to a 500 mL single-neck flask, and 3 drops of DMF were added dropwise with stirring. Under the condition of ice-water bath, compound 2 (30.0 g, 0.117 mol) is measured and dissolved in 30 mL dichloromethane and added into the system dropwise, after the dropwise addition is finished, the ice-water bath is removed, and the temperature is room temperature (20-25 parts by weight)oC) The reaction was carried out for 4 hours. After the reaction is finished, 40 times ofoConcentrating under C, removing dichlorine, and raising temperature to 55 deg.CoConcentration under C, to remove excess thionyl chloride, gave 32.0 g of a tan liquid in a yield of 99.7%.
(3) Under the condition of ice-water bath, compound 3 (30.0 g, 0.109 mol) was added dropwise to 150mL of methanol solution, and after completion of the dropwise addition, the ice-water bath was removed and reacted at room temperature for 2 hours. After the reaction was completed, methanol was removed by concentration, the mixture was extracted with 150mL of water and 150mL of methylene chloride, the organic phase was collected, the aqueous phase was extracted with methylene chloride (100 mL. times.2), and anhydrous Na2SO4Drying for 2 hours, filtering by suction, removing Na2SO4The organic phase was concentrated to give 26.5 g, yield 95.0%.
(4) S-2-aminobutanamide hydrochloride (4.0 g, 29.2 mmol) was added to 40 mL of isopropyl acetate, stirred, potassium carbonate (8.1 g, 58.5 mmol) was added and heated under reflux for 8 hours, and a solution of Compound 4 (5 g, 19.5 mmol) in isopropyl acetate was added dropwise and refluxed for 28 hours. After the reaction, the solution was filtered, diluted 5 times, and acetic acid (1.8 mL, 5.9 mmol) was added dropwise at 60 ℃ to react for 2 hours, and the pH was adjusted to about 7 with a saturated sodium bicarbonate solution, followed by liquid separation and concentration to obtain a crude BRT product. The crude product is crystallized by ethyl acetate and methyl tert-butyl ether, filtered and dried to obtain 2.6g of compound with yield of 63.4%, HPLC purity of more than 99.70% and ee value of more than 20: 1.
Example 2
(1) Compound 1 (5.0 g, 39 mmol) and 50ml of dichloromethane were added to a single-neck flask and stirring was turned on. Zinc chloride (2.6 g, 29.5 mmol) was added in portions, TMSBr (10.3 mL, 78 mmol) was dissolved in 10 mL of dichloromethane and added dropwise to the system, and after the addition was completed, the reaction was stopped at room temperature for 28 hours. 50mL of 1M hydrochloric acid solution was added, stirred for 20 minutes, transferred to a 250 mL separatory funnel, the separated liquid was extracted, the lower organic phase was collected, and the aqueous phase was extracted with dichloromethane (30 mL. times.2). The organic phases were collected, washed with 50mL of 10% sodium thiosulfate solution, the organic phases were collected, the aqueous phase was washed with dichloromethane (30 mL × 1), and the organic phases were combined. The organic phases were combined and anhydrous Na was added2SO4Drying for 2 hours. Filtering, removing anhydrous Na2SO4The filtrate was concentrated at 40 ℃. 6.8 g of a reddish brown oil was obtained in 89.0% yield.
(2) Adding SOCl2(9.6 mL, 0.1406 mol) and 270 mL of toluene were added to a 500 mL single-neck flask, and 3 drops of DMF were added dropwise with stirring. Under the condition of ice-water bath, compound 6 (30.0 g, 0.153 mol) is measured and dissolved in 30 mL of toluene alkane and is added into the system in a dropwise manner, after the dropwise addition is finished, the ice-water bath is removed, and the temperature is room temperature (20-25 parts by weight)oC) The reaction was carried out for 4 hours. The reaction is complete at 70oC. Concentration by evaporation at-0.1 MPa removed toluene to give 31.4 g of a tan liquid in 95.7% yield.
(3) Under the condition of ice-water bath, compound 7 (30.0 g, 0.140 mol) was added dropwise to 150mL of ethanol solution, and after the dropwise addition, the ice-water bath was removed and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, ethanol was removed by concentration, the mixture was extracted with 150mL of water and 150mL of methylene chloride, the organic phase was collected, the aqueous phase was extracted with methylene chloride (100 mL. times.2), and anhydrous Na2SO4Drying for 2 hours, filtering by suction, removing Na2SO4The organic phase was concentrated to give 29.8 g, yield 94.8%.
(4) S-2-aminobutanamide hydrochloride (4.7 g, 33.6 mmol) was added to 40 mL of isopropyl acetate, stirred, potassium carbonate (9.3 g, 67.2 mmol) was added and heated under reflux for 8 hours, and a solution of Compound 8 (5 g, 22.4 mmol) in isopropyl acetate was added dropwise and refluxed for 28 hours. After the reaction is finished, filtering, diluting by 5 times, and reacting at 60%oAnd (3) dropwise adding acetic acid (0.96 mL, 16.8 mmol) under the condition of C, reacting for 1.5 hours, adjusting the pH to be about 7 by using a saturated sodium bicarbonate solution, separating, and concentrating to obtain a BRT crude product. The crude product is crystallized by ethyl acetate and methyl tert-butyl ether, filtered and dried to obtain 3.2 g of compound with yield of 68.0%, HPLC purity of more than 99.75% and ee value of more than 20: 1.
1H NMR(400MHz, CDCl3): 0.83-0.91 (m, 6H), 1.26-1.34 (m, 2H), 1.31-1.45(m, 2H), 1.67-1.72 (m, 1H), 2.59 (dd, 1H, JA=16.8 Hz, JB= 8.4 Hz), 3.03 (dd,1H, JA=9.6 Hz, JB= 7.2 Hz), 3.49 (dd, 1H, JA=9.6 Hz, JB= 8.4 Hz), 4.45 (dd,1H, JA=8.4 Hz, JB= 7.2 Hz), 5.30(s, br, 1H), 6.20 (s, br, 1H)。
Claims (10)
1. A preparation method of the brivaracetam is characterized by comprising the following steps: the preparation method is prepared by the following synthetic route: the first step is that (R) -4-propyldihydro-2 (3H) -ketone (compound 1) generates ring-opening reaction under certain conditions to generate compound 2, the second step generates halogenation reaction to generate compound 3, the third step generates esterification reaction to generate compound 4, and the fourth step generates compound 4 to close ring to prepare target compound, namely, the compound 5
2. The process according to claim 1, wherein in the first step of the synthesis of brivaracetam, the ring-opening reagent is selected from the group consisting of iodotrimethylsilane, bromotrimethylsilane, chlorotrimethylsilane, hydrobromic acid, and the like, preferably iodotrimethylsilane.
3. The process according to claim 1, wherein in the second step of the synthesis of bravaracetam, the chlorinating agent is phosphorus trichloride, phosphorus pentachloride, phosgene, thionyl chloride or the like, preferably thionyl chloride.
4. The process according to claim 1, wherein in the second step of the synthesis of bravaracetam the catalyst is N, N-Dimethylformamide (DMF), N-dimethylaniline or pyridine or the like, preferably N, N-dimethylformamide.
5. The process according to claim 1, wherein in the third step of the synthesis of bravaracetam, the reaction solvent is lower alcohol such as methanol, ethanol and the like, preferably methanol.
6. The process according to claim 1, wherein in the fourth step of the synthesis of bravaracetam the reaction solvent is acetonitrile, toluene, ethyl acetate or isopropyl acetate, preferably isopropyl acetate.
7. The process according to claim 1, wherein the reaction temperature in the fourth step of the synthesis of the bravaracetam is 50 to 120%oC, preferably 90oC。
8. The process according to claim 1, wherein in the fourth step of the synthesis of bravaracetam, the preferred reaction time is 20 to 40 hours, preferably 28 hours.
9. The crude product of the brivaracetam is subjected to pulping and recrystallization preferentially to obtain the brivaracetam; the pulping and recrystallization can adopt a conventional method operated in the field, the solvent adopted for pulping is preferably a mixed solvent of an ester solvent and an alcohol solvent, and the volume ratio of the ester solvent to the alcohol solvent in the mixed solvent of the ester solvent and the alcohol solvent is preferably 5: 1-12: 1, such as 8: 1; the ester solvent is preferably ethyl acetate; the alcohol solvent is preferably isopropanol.
10. The solvent used for recrystallization is preferably an aprotic solvent; the aprotic solvent is preferably one or more of ethyl acetate, acetone, dichloromethane, methyl tert-butyl ether, isopropyl ether and diethyl ether.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113651745A (en) * | 2021-09-09 | 2021-11-16 | 上海医药工业研究院 | Buvalracetam intermediate, preparation method and purification method thereof |
| CN114213305A (en) * | 2021-12-29 | 2022-03-22 | 苏州诚和医药化学有限公司 | Production process of brivaracetam |
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| CN1882535A (en) * | 2003-09-24 | 2006-12-20 | Ucb股份有限公司 | Process for preparing 2-oxo-1-pyrrolidine derivatives |
| CN105646319A (en) * | 2015-12-30 | 2016-06-08 | 佛山市隆信医药科技有限公司 | Preparation method of brivaracetam |
| CN108503573A (en) * | 2017-02-24 | 2018-09-07 | 北京艾百诺医药股份有限公司 | A kind of new preparation method of Bu Waxitan |
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2019
- 2019-05-06 CN CN201910370852.2A patent/CN111892526A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1882535A (en) * | 2003-09-24 | 2006-12-20 | Ucb股份有限公司 | Process for preparing 2-oxo-1-pyrrolidine derivatives |
| CN105646319A (en) * | 2015-12-30 | 2016-06-08 | 佛山市隆信医药科技有限公司 | Preparation method of brivaracetam |
| CN108503573A (en) * | 2017-02-24 | 2018-09-07 | 北京艾百诺医药股份有限公司 | A kind of new preparation method of Bu Waxitan |
Non-Patent Citations (3)
| Title |
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| ARNAUD SCHÜLÉ等: "A Biocatalytic Route to the Novel Antiepileptic Drug Brivaracetam", 《ORG. PROCESS RES. DEV.》, vol. 20, pages 1566 - 1575, XP055525783, DOI: 10.1021/acs.oprd.6b00094 * |
| 刘九知等: "布瓦西坦合成路线图解", 《中国药物化学杂志》, vol. 27, no. 3, pages 256 - 258 * |
| 周超: "抗癫痫药布瓦西坦的合成研究", 《中国医药工业研究总院硕士学位论文》, pages 46 - 47 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113651745A (en) * | 2021-09-09 | 2021-11-16 | 上海医药工业研究院 | Buvalracetam intermediate, preparation method and purification method thereof |
| CN114213305A (en) * | 2021-12-29 | 2022-03-22 | 苏州诚和医药化学有限公司 | Production process of brivaracetam |
| CN114213305B (en) * | 2021-12-29 | 2023-08-22 | 苏州诚和医药化学有限公司 | Production process of brivaracetam |
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