WO2024131603A1 - Procédé de préparation de brivaracétam et d'un intermédiaire de celui-ci - Google Patents

Procédé de préparation de brivaracétam et d'un intermédiaire de celui-ci Download PDF

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Publication number
WO2024131603A1
WO2024131603A1 PCT/CN2023/138256 CN2023138256W WO2024131603A1 WO 2024131603 A1 WO2024131603 A1 WO 2024131603A1 CN 2023138256 W CN2023138256 W CN 2023138256W WO 2024131603 A1 WO2024131603 A1 WO 2024131603A1
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compound
brivaracetam
reaction
preparing
formula
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PCT/CN2023/138256
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English (en)
Chinese (zh)
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孟金鹏
张其峰
周婷
赫亚征
王磊
庄程翰
李开波
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浙江普洛家园药业有限公司
普洛药业股份有限公司
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Publication of WO2024131603A1 publication Critical patent/WO2024131603A1/fr

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  • the invention belongs to the field of drug synthesis, and specifically relates to a method for preparing brivaracetam.
  • Brivaracetam (compound of formula V) is a third-generation antiepileptic drug used to treat partial-onset seizures in patients aged 16 years and above, and as an adjuvant treatment for seizures with or without secondary generalized seizures. Compared with previous antiepileptic drugs, its mechanism of action is unique, especially its good tolerance in the central nervous system is the main reason why it is superior to other antiepileptic drugs. Brivaracetam is a highly selective and high-affinity ligand for synaptic vesicle protein 2A, which affects synaptic function by binding to it, and can also be used as a high-affinity sodium channel inhibitor to enhance antiepileptic activity.
  • the previously reported synthetic route of Buvaracetam has two very obvious shortcomings.
  • CN108503610A and CN108503609A mentioned that (R)-4-propyl-dihydrofuran-2-one is used as a key intermediate, and then Buvaracetam is obtained through several steps of reaction.
  • This type of preparation method is extremely complicated for the preparation of intermediates alone.
  • the present invention provides a preparation method of brivaracetam and its intermediates.
  • the method does not require chiral separation of intermediates and products, and can directly obtain high-purity brivaracetam.
  • the brivaracetam of the present invention has a structure shown in Formula V:
  • C2 has S configuration and C7 has R configuration
  • a method for preparing a brivaracetam intermediate comprising:
  • R 1 is a C 1 -C 8 alkyl group, including a straight chain or branched chain alkyl group, preferably a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group or a tert-butyl group.
  • the hydrolase is an esterase, an amide hydrolase, etc., including but not limited to protease CAS No.: 9014-01-1; 9074-07-1, etc., lipase CAS: 9001-62-1, etc., specifically: Aladdin protease (CAS: 9014-01-1) is derived from Bacillus, Bacillus licheniformis, Aspergillus oryzae, Bacillus amyloliquefaciens and 2.5L; Amano protease (CAS: 9074-07-1) is derived from Bacillus and Aspergillus oryzae; Aladdin lipase (CAS: 9001-62-1) is derived from Aspergillus oryzae and Aspergillus niger, etc.
  • the amount of enzyme used is 15-20% by weight of compound II.
  • the temperature of the hydrolysis reaction is 20-35°C, preferably 30°C.
  • the hydrolysis reaction is carried out in a phosphate buffer having a pH of 6.5-7.5, preferably 7.0.
  • the pH value is adjusted to 8-10 by using ammonia water, and more preferably to 9.
  • the pH range of the hydrochloric acid adjustment is 2-4, more preferably 3.
  • the present invention also provides a method for preparing brivaracetam, comprising the following steps:
  • the carboxyl derivatization is halogenation, esterification or anhydride
  • Compound IV is subjected to an aminolysis reaction to obtain Compound V, which is the aforementioned brivaracetam;
  • X is a halogen, preferably Cl, Br or I;
  • R 2 is halogen, C 1 ⁇ C 8 alkoxy or C 1 ⁇ C 8 alkoxyacyloxy, preferably -OCOOMe, -OCOOC 2 H 5 , -OCOOCH 2 CH 2 CH 3 , -OCOOCH(CH 3 ) 2 or -OCOOCH 2 CH 2 CH 2 CH 3 .
  • step (1) the reaction formula is as follows:
  • the nucleophilic substitution reaction is carried out under the action of a base, wherein the base is preferably sodium tert-butoxide, sodium methoxide, sodium ethoxide, sodium hydride or potassium tert-butoxide. Sodium methoxide is preferred.
  • the nucleophilic substitution reaction is carried out in one or more of the following solvents: toluene, N,N-dimethylformamide or 1,4-dioxane, preferably toluene.
  • the reaction temperature is 70-80°C.
  • step (1) is as follows:
  • the compound represented by formula I-B and a base are dissolved in an organic solvent, and then the compound represented by formula I-A is added, and the reaction is carried out at 70-80°C for 4 hours.
  • the system is cooled to room temperature, and water is added to quench the reaction. Saturated brine and ethyl acetate are added, and the organic phase is separated and concentrated to obtain compound II.
  • step (3) the reaction formula is as follows:
  • step (3) there are three derivatization methods.
  • the first derivatization method is to derive the carboxyl group into an ester, wherein R 2 is a C 1 -C 8 alkoxy group, the derivatization reagent used is an alcohol compound, and the reaction is carried out in the presence of a catalyst.
  • the alcohol compound is one of methanol, ethanol, propanol, isopropanol, butanol, isobutanol and tert-butanol
  • the catalyst is concentrated sulfuric acid or thionyl chloride, more preferably thionyl chloride.
  • step (3) is as follows:
  • the alcohol solvent is cooled, and then the catalyst is added. After the addition is complete, the reaction is kept warm.
  • the compound of formula III is then added to the reaction solution, and the reaction is kept warm.
  • a sodium carbonate solution is added, the pH is adjusted to neutral, the solvent is removed by vacuum distillation, and the mixture is extracted with ethyl acetate, concentrated and dried to obtain a crude product of the compound of formula IV.
  • the second derivatization method is to derive the carboxyl group into an acyl halide, wherein R 2 is a halogen and the derivatization reagent used is thionyl chloride.
  • step (3) is as follows:
  • the compound represented by formula III is added to thionyl chloride to carry out reaction. After the reaction is completed, the thionyl chloride is removed by reduced pressure distillation to obtain a crude product of the compound represented by formula IV.
  • the third derivatization method is to derive the carboxyl group into anhydride, the R 2 is a C 1 -C 8 alkoxy acyloxy group, and the derivatization agent used is a chloroformate compound.
  • the R 2 is -OCOOMe, -OCOOC 2 H 5 , -OCOOCH 2 CH 2 CH 3 , -OCOOCH(CH 3 ) 2 or -OCOOCH 2 CH 2 CH 2 CH 3 ; and the derivatization agent is methyl chloroformate, ethyl chloroformate, isopropyl chloroformate or butyl chloroformate.
  • reaction process is as follows:
  • the compound represented by formula III and the chloroformate compound are dissolved in an organic solvent, and a base is added to react. After the reaction is completed, water and ethyl acetate are added to extract, and the organic phases are combined and distilled under reduced pressure to obtain a crude product of the compound represented by formula IV.
  • step (4) the reaction formula is as follows:
  • step (4) the aminolysis reaction is carried out in an alcohol solvent of ammonia, and the concentration of ammonia should be 8-15%, preferably 10%.
  • the alcohol solvent is methanol, ethanol or isopropanol, more preferably methanol.
  • the reaction temperature in step (4) is 0-10°C, more preferably 5°C.
  • the post-processing process is as follows:
  • the reaction solution is distilled under reduced pressure to remove methanol and ammonia, and then recrystallized to obtain a compound represented by formula V.
  • the solvent for recrystallization is tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, diisopropyl ether, isopropyl acetate, etc., and more preferably methyl tert-butyl ether.
  • the beneficial effects of the present invention are as follows: the present invention uses a completely new route, the reaction of the new route is simple and easy to operate, the entire reaction route has a high yield and low cost, and there is no need to use a chiral splitting agent for chiral splitting, the optical purity is high, and it is suitable for industrial production.
  • protease derived from Bacillus, with an enzyme activity of 8 u/g, purchased from Aladdin Reagent Company, CAS No.: 9014-01-1, item No.: P298996
  • 54 g of the compound shown in Formula II were added to 300 mL of phosphate buffer with a pH of 7, and stirred at 30°C for 24 h. After the reaction was completed, 200 mL of ethyl acetate was added, and the pH was adjusted to 9-10 with aqueous ammonia. The organic phase was separated, and the aqueous phase was retained.
  • the aqueous phase was adjusted to pH 2-3 with 10% hydrochloric acid, and extracted twice with 200 mL of ethyl acetate and concentrated to obtain 21.4 g of the compound shown in Formula III, with a yield of 45% and an optical purity of 99.2 %.
  • the crude product of the compound of formula IV was dissolved in 100 mL of methanol, cooled to 0°C, and ammonia gas was introduced into the reaction solution to a concentration of 10%. The reaction was kept warm for 6 hours and monitored by HPLC. After the conversion of the raw materials was completed, methanol and ammonia gas were removed by vacuum distillation to obtain a crude product. The crude product was dissolved in 80 mL of acetic acid. The mixture was added to isopropyl ester, heated to reflux, stirred for 1 hour, cooled to 10°C, and filtered to obtain a white solid. 17 g of the compound represented by formula V was obtained, with a yield of 80%, a purity of 99.5%, and an optical purity of 99.8%.
  • the pH of the aqueous phase was adjusted to 3 with 10% hydrochloric acid, and extracted twice with 200 mL of ethyl acetate and concentrated to obtain 17.6 g of the compound shown in Formula III with a yield of 37.7% and an optical purity of 99.1%.
  • the crude product of the compound of formula IV was dissolved in 100 mL of methanol, cooled to 0°C, and added to the reaction solution. Ammonia gas was introduced to a concentration of 8%, and the reaction was kept warm for 6 hours. The reaction was monitored by HPLC. After the conversion of the raw materials was completed, methanol and ammonia were removed by vacuum distillation to obtain a crude product.
  • the crude product was dissolved in 80 mL of methyl tert-butyl ether, heated to reflux, stirred for 1 hour, and then cooled to 10°C. A white solid was filtered to obtain 14.9 g of the compound represented by formula V, with a yield of 85%, a purity of 99.6%, and an optical purity of 99.7%.
  • the pH of the aqueous phase was adjusted to 3 with 10% hydrochloric acid, and extracted twice with 200 mL of ethyl acetate and concentrated to obtain 17.8 g of the compound represented by formula III with a yield of 38.1% and an optical purity of 99.4%.
  • the crude product of the compound of formula IV was dissolved in 80 mL of methanol, cooled to 0°C, ammonia was introduced into the reaction solution to a concentration of 15%, and the reaction was kept warm for 6 hours. The reaction was monitored by HPLC. After the conversion of the raw materials was completed, methanol and ammonia were removed by vacuum distillation to obtain a crude product.
  • the crude product was dissolved in 80 mL of diisopropyl ether, heated to reflux, stirred for 1 hour, and then cooled to 10°C. White precipitate was obtained by suction filtration. Solid, to obtain 13.3 g of the compound represented by formula V, with a yield of 75%, a purity of 98.9%, and an optical purity of 99.6%.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation de brivaracétam. La (R)-4-propyl pyrrole-2-cétone et le 2-bromobutyrate d'éthyle sont utilisés comme matières premières, et le brivaracétam est synthétisé par une réaction en quatre étapes. Le procédé de préparation ne nécessite pas l'utilisation d'un agent de résolution pour la résolution chirale, et opte plutôt pour une hydrolase pour l'hydrolyse stéréosélective. L'invention concerne également un procédé de préparation d'un intermédiaire de brivaracétam.
PCT/CN2023/138256 2022-12-22 2023-12-12 Procédé de préparation de brivaracétam et d'un intermédiaire de celui-ci WO2024131603A1 (fr)

Applications Claiming Priority (2)

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CN202211656940.7 2022-12-22
CN202211656940.7A CN115851866A (zh) 2022-12-22 2022-12-22 一种布瓦西坦及其中间体的制备方法

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CN116891879A (zh) * 2023-09-08 2023-10-17 山东静远药业有限公司 一种布瓦西坦关键中间体的合成方法

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