CN115872913A - Preparation method of brivaracetam and intermediate thereof - Google Patents

Preparation method of brivaracetam and intermediate thereof Download PDF

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CN115872913A
CN115872913A CN202211307468.6A CN202211307468A CN115872913A CN 115872913 A CN115872913 A CN 115872913A CN 202211307468 A CN202211307468 A CN 202211307468A CN 115872913 A CN115872913 A CN 115872913A
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brivaracetam
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郭思远
稂琪伟
丁小兵
张紫恒
胡洋
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Shenzhen Catalys Technology Co Ltd
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Abstract

A preparation method of brivaracetam and an intermediate thereof relates to the field of medicinal chemical synthesis, and comprises a method for preparing a key intermediate of brivaracetam, namely a chiral pyrrolidone derivative, through asymmetric reduction reaction catalyzed by a chiral copper catalyst.

Description

Preparation method of brivaracetam and intermediate thereof
Technical Field
The invention belongs to the field of medicinal chemical synthesis, and relates to a preparation method of brivaracetam and an intermediate thereof.
Background
Brivaracetam (Brivaracetam) with the chemical name of (2S) -2- [ (4R) -2-oxo-4-n-propyl-1-pyrrolidinyl]Butyrylamide, CAS 357336-20-0, molecular formula C 11 H 20 N 2 O 2 317.38 of molecular weight, and the structural formula is as follows:
Figure RE-GDA0004022309790000011
the united states Food and Drug Administration (FDA) and European Medicine Administration (EMA) in 2016 approved the third generation of the antiepileptic drug brivaracetam developed by UCB for the adjuvant treatment of partial seizures in patients with epilepsy in adolescents and adults 16 years old and older, with or without secondary generalized seizures. The U.S. Food and Drug Administration (FDA) in 2021 further approved the escalating indications of brivaracetam as a monotherapy or an adjunct therapy for patients with epilepsy as young as 1 month old. With good pharmacological activity, clinical efficacy and safety, the global sales of brivaracetam has been greatly increased from 1800 ten thousand euros in 2016 to 3.55 hundred million euros in 2021, and thus has a considerable prospect of sales in the future.
The patent WO 01/62726 firstly discloses a route for synthesizing brivaracetam, and the specific method is as follows:
Figure RE-GDA0004022309790000012
the method firstly prepares a dihydropyrrolone intermediate (II) through condensation/reduction reaction of (S) -2-aminobutanamide and 5-hydroxy-4-n-propyl-2-furanone (II). Subsequent hydrogenation of intermediate (II) using palladium/carbon catalysis produced a mixture of diastereomers (V)/epi- (V) in a ratio of 50/50. Finally, the mixture (V)/epi- (V) is subjected to resolution by a chiral chromatographic column to finally obtain the brivaracetam (V). It was found by study (patent EP 1659191B) that the diastereomer epi- (V) is not active in the treatment of epilepsy. Therefore, in the route, the byproduct epi- (V) generated in the synthesis of brivaracetam greatly reduces the total yield, greatly increases the production cost and is not beneficial to scale-up production.
Similar brivaracetam synthetic routes as disclosed in patent WO 01/62726, including patents WO2007065634A1, WO2018042393, US8338621B2, US20080009638A1, WO 01/62726 A2, WO2005028435 and WO2017076738 and literature Tetrahedron Letters,2019,60,46,151249 and Journal of Medicinal Chemistry,2004,47,53, all suffer from the same problem that chiral intermediates or final products need to be resolved by chiral chromatographic columns, greatly reducing the industrial application value of these synthetic routes.
Document org.process res.dev.2016,20,1566 reports that although the brivaracetam chiral lactone intermediate can be obtained and synthesized into brivaracetam by using enzyme-catalyzed chiral resolution, the enzyme-catalyzed chiral resolution also wastes more than half of the material, resulting in a decrease in the overall yield. Moreover, the synthetic route is long, and is not beneficial to the large-scale production of brivaracetam.
Figure RE-GDA0004022309790000021
Because the chiral resolution method can suffer from the problem of serious material waste, the research and development of asymmetric reaction to obtain the brivaracetam chiral intermediate becomes a research hotspot for developing related synthetic routes in recent years. In the process of implementing the invention, the inventor finds that at least the problems exist in the prior art, so that a method which is simple to operate, environment-friendly and efficient is urgently needed to be developed in the field of industrial synthesis of brivaracetam to solve a series of problems or at least one technical problem of complex process, long steps, raw material waste and greatly increased preparation time and cost caused by chiral resolution of racemate, generation of environmentally-unfriendly waste materials and the like in the existing brivaracetam preparation.
Disclosure of Invention
On one hand, a method for preparing a chiral pyrrolidone derivative (IV) which is a key intermediate of brivaracetam by asymmetric reduction reaction of dihydropyrrolidone (III) catalyzed by a chiral copper catalyst is provided; in another aspect, a process for preparing brivaracetam (V) via a key intermediate chiral pyrrolidone derivative (IV) is provided.
The invention is realized by the following technical scheme.
A method for preparing a brivaracetam intermediate pyrrolidone (IV), comprising: carrying out 1, 4-reduction reaction on the gamma-lactam intermediate (III) and a hydrogen source under the catalysis of a chiral copper metal catalyst to generate a pyrrolidone Intermediate (IV);
Figure RE-GDA0004022309790000031
wherein, the R group is alkyl and aryl, preferably C1-C6 alkyl.
In some embodiments, the copper metal in the chiral copper catalyst is selected from anhydrous copper acetate or copper acetate hydrate.
In some embodiments, the chiral ligand in the chiral copper catalyst is selected from the group consisting of (S) -SEGPHOS, (S) -DM-SEGPHOS, (S) -DTBM-SEGPHOS, (S) -BINAP, (S) -Tol-BINAP, (S) -H 8 -BINAP、 (S)-MeO-BIPHEP、(S)-3,5-Xyl-MeOBIPHEP、(S)-3,5-t-Bu-MeOBIPHEP、 (S)-3,5-t-Bu-4-MeO-MeOBIPHEP、(S)-C 3 -TunePhos、(S)-DTBM-C 3 * -TunePhos, (S, S) -Me-DUPHOS, (S) -ZhaoPhos, (S) - (R) -Josiphos, josiphos SL-J007-2, (S, S) -Me-DUPHOS, (S, S) -Et-DUPHOS, (S, S) -i-Pr-DUPHOS, (S, S) -Et-Ferrocelane, or (S, S) -Ph-BPE, and in some embodiments, the chiral ligand in the chiral copper catalyst is (S) -DTBM-SEGPS.
In some embodiments, the molar ratio of copper to chiral ligand in the chiral copper catalyst is 1 to 1, or is 1; the molar ratio of the compound (III) to the chiral copper catalyst is from about 1.001 to about 1.
In some embodiments, the hydrogen source is selected from the group consisting of polymethylhydrosiloxane, 1, 3-tetramethyldisiloxane, phenylsilane, diphenylsilane, triphenylsilane, dimethylphenylsilane, methylphenylsilane, diethylsilane, triethylsilane, triethoxysilane, methyldiethoxysilane, pinacolborane, catecholborane, tributyltin hydride, preferably polymethylhydrosiloxane.
In some embodiments, the reduction reaction solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, cyclopentylmethyl ether, 1, 4-dioxane, diisopropyl ether, di-n-butyl ether, ethylene glycol dimethyl ether, n-hexane, and preferably tetrahydrofuran.
In some embodiments, the reduction reaction temperature is from about-20 ℃ to about 50 ℃, in some embodiments, from about 10 ℃ to about 40 ℃, and in some embodiments, the reduction reaction temperature is about-10 ℃, or about 0 ℃, or about 10 ℃, or about 20 ℃, or about 25 ℃, or about 30 ℃, or about 40 ℃.
In some embodiments, a process for preparing the gamma-lactam intermediate (III) comprises condensing/reducing a derivative of L-2-aminobutyrate or a salt thereof (I) and 5-hydroxy-4-propyl-2 (5H) -furanone (II) in the presence of an organic amine, a reducing agent to form a dihydropyrrolone intermediate (III);
Figure RE-GDA0004022309790000041
in some embodiments, the molar ratio of the derivative of L-2-aminobutyrate or salt thereof (I) to 5-hydroxy-4-propyl-2 (5H) -furanone (II) is 1.
In some embodiments, the organic amine is selected from triethylamine, diisopropylethylamine, pyridine, and the reducing agent is a borohydride or hydride selected from potassium borohydride, sodium cyanoborohydride.
In some embodiments, a process for the preparation of gamma-lactam intermediate (III) comprising the condensation/reduction of derivative of L-2-aminobutyrate or salt thereof (I) and 5-hydroxy-4-propyl-2 (5H) -furanone (II) in the presence of triethylamine, sodium borohydride and glacial acetic acid to form pyrrolidoneintermediate (III);
in some embodiments, the molar ratio of the derivative of L-2-aminobutyrate or salt thereof (I) to 5-hydroxy-4-propyl-2 (5H) -furanone (II) is from about 1 to about 1.5, preferably about 1.
In some embodiments, a method of preparing brivaracetam comprises converting pyrrolidone (IV) to an amide and forming brivaracetam (V) under aminolysis conditions, in some embodiments, by adding aqueous ammonia to tetrahydrofuran and performing aminolysis at room temperature, in some embodiments, in a mixture of aqueous ammonia and tetrahydrofuran under reflux conditions; in some embodiments, the aminolysis is performed in an ammonia methanol solution, and the aminolysis reaction temperature can be room temperature or under the heating reflux condition; in some embodiments, the aminolysis is a reaction by passing aqueous ammonia through DMF at room temperature to about 80 ℃; in some embodiments, the aminolysis may also be reacted in a DMF solution of ammonium carbonate at room temperature; in some embodiments, the aminolysis is heated to reflux in an aqueous ammonia and tetrahydrofuran system.
A compound represented by the formulae (I), (III) and (IV):
Figure RE-GDA0004022309790000051
wherein, the R group is alkyl, aryl or aralkyl with the length of 1-6 carbons.
In another aspect, a method for preparing brivaracetam is provided:
Figure RE-GDA0004022309790000052
which comprises the following steps:
a, performing condensation/reduction on a derivative (I) of L-2-aminobutyric acid ester hydrochloride and 5-hydroxy-4-propyl-2 (5H) -furanone (II) in the presence of triethylamine, sodium borohydride and glacial acetic acid to generate a pyrrolidon intermediate (III);
in the reaction b, the gamma-lactam intermediate (III) and a hydrogen source are subjected to 1, 4-reduction reaction under the catalysis of a chiral copper metal catalyst to generate a pyrrolidone Intermediate (IV);
reaction c conversion of the ester group in pyrrolidone (IV) to the amide under suitable ammonolysis conditions and formation of brivaracetam (V).
The reaction a is that the L-2-aminobutyrate hydrochloride derivative (I) and 5-hydroxy-4-propyl-2 (5H) -furanone (II) are subjected to condensation/reduction reaction under the action of triethylamine, sodium borohydride and glacial acetic acid. After the reaction solution is washed by 1M HCl, the water phase is extracted by dichloromethane, and the organic phase is dried by anhydrous sodium sulfate and then concentrated to obtain the dihydropyrrolone intermediate (III).
Figure RE-GDA0004022309790000053
According to the process for preparing the pyrrolidoneintermediate (III), the R group in the general formula is selected from alkyl (1-6 carbons in length), aryl, preferably methyl.
According to the preparation method of the dihydropyrrolone intermediate (III), the molar ratio of L-2-aminobutyric acid methyl ester hydrochloride (I) to 5-hydroxy-4-propyl-2 (5H) -furanone (II) is 1.
And b, preparing the chiral copper catalyst in situ in a solvent, and adding the dihydropyrrolone intermediate (III) into the reactor for reduction reaction. Stirring in the presence of a hydrogen source, washing after complete reaction, extracting with dichloromethane, drying with anhydrous sodium sulfate, filtering and concentrating to obtain the pyrrolidone (IV) intermediate.
Figure RE-GDA0004022309790000061
According to the process for the preparation of pyrrolidones (IV) of the invention, the R group in the general formula is selected from alkyl (1-6 carbons in length), aryl, arylalkyl, preferably methyl.
According to the preparation method of the pyrrolidone (IV), in the in-situ preparation of the chiral copper catalyst, the copper metal source is selected from anhydrous copper acetate, copper acetate hydrate, copper sulfate, cuprous chloride/potassium tert-butoxide, cuprous chloride/sodium tert-butoxide, copper chloride, copper fluoride, copper bromide, cuprous fluorotris (triphenylphosphine), copper oxide, copper hydroxide and copper carbonate, and is preferably anhydrous copper acetate.
According to the preparation method of the pyrrolidone (IV), the chiral ligand in the in-situ preparation of the chiral copper catalyst is selected from (S) -SEGPHOS, (S) -DM-SEGPHOS, (S) -DTBM-SEGPHOS, (S) -BINAP, (S) -Tol-BINAP, (S) -H 8 -BINAP、(S)-MeO-BIPHEP、(S)-3,5-Xyl-MeOBIPHEP、(S)-3,5-t-Bu-MeOBIPHEP、 (S)-3,5-t-Bu-4-MeO-MeOBIPHEP、(S)-C 3 -TunePhos、(S)-DTBM-C 3 * -TunePhos, (S, S) -Me-DUPHOS, (S) -ZhaoPhos, (S) - (R) -Josiphos, josiphos SL-J007-2, (S, S) -Me-DUPHOS, (S, S) -Et-DUPHOS, (S, S) -i-Pr-DUPHOS, (S, S) -Et-Ferrocelane, (S, S) -Ph-BPE, preferably (S) -DTBM-SEHOGPS.
According to the preparation method of pyrrolidone (IV), the molar ratio of copper and chiral ligand in the chiral copper catalyst is 1.
According to the process for producing pyrrolidone (IV) of the present invention, the molar ratio of pyrrolidone (IV) to copper catalyst is 1.
According to the process for the preparation of pyrrolidones (IV) according to the invention, the hydrogen source is selected from hydrogen, polymethylhydrosiloxane, 1, 3-tetramethyldisiloxane, phenylsilane, diphenylsilane, triphenylsilane, dimethylphenylsilane, methylphenylsilane, diethylsilane, triethylsilane, triethoxysilane, methyldiethoxysilane, pinacolborane, catecholborane, tributyltin hydride, preferably polymethylhydrosiloxane.
According to the process for the preparation of pyrrolidone (IV) of the present invention, the solvent is selected from dichloromethane, toluene, tetrahydrofuran, dimethyltetrahydrofuran, methyl t-butyl ether, cyclopentylmethyl ether, 1, 4-dioxane, diisopropyl ether, di-n-butyl ether, ethylene glycol dimethyl ether, n-hexane, preferably tetrahydrofuran.
According to the process for the preparation of pyrrolidone (IV) of the present invention, the reduction reaction temperature is-20 ℃ to 50 ℃, preferably room temperature.
Reaction c: and (3) ammonolyzing the pyrrolidone Intermediate (IV) under proper conditions, washing after the reaction is finished, extracting by using dichloromethane, drying by using anhydrous sodium sulfate, filtering and concentrating to obtain a crude product, and recrystallizing to obtain the pure product of the brivaracetam (V).
Figure RE-GDA0004022309790000071
According to the preparation method of brivaracetam (Ia), in some embodiments, the ammonolysis is performed at room temperature by adding ammonia water into tetrahydrofuran, and in some embodiments, the ammonolysis is performed in a mixture of ammonia water and tetrahydrofuran under heating reflux conditions; in some embodiments, the aminolysis is performed in an ammonia methanol solution, and the aminolysis reaction temperature can be room temperature or under heating reflux; in some embodiments, the aminolysis is a reaction by passing aqueous ammonia into DMF at room temperature to about 80 ℃; in some embodiments, the aminolysis may also be reacted in a DMF solution of ammonium carbonate at room temperature; in some embodiments, the aminolysis is heated to reflux in an aqueous ammonia and tetrahydrofuran system.
One of the above technical solutions has the following advantages or beneficial effects: the pyrrolidon (IV) can be prepared with high optical purity and high yield by carrying out asymmetric 1, 4-reduction on the dihydropyrrolidon intermediate (III) through a chiral copper catalyst and screening an optimal chiral ligand, and the reaction condition is mild, so that the method is suitable for industrial scale-up production. The preparation of brivaracetam by utilizing high-optical-purity pyrrolidone (IV) only needs three steps, and has the advantages of short synthetic route, high total yield, good stereoselectivity and huge industrial application prospect.
"Room temperature" in the present invention refers to ambient temperature, ranging from about 10℃ to about 40℃. In some embodiments, "room temperature" refers to a temperature of from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to a temperature of from about 25 ℃ to about 30 ℃; in still other embodiments, "room temperature" refers to 10 ℃,15 ℃,20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, etc.
"aryl" means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, the aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzenes, naphthalenes, anthracenes, biphenyls, and the like.
"arylalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom) is replaced with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenyleth-1-yl, naphthylmethyl, 2-naphthyleth-1-yl, naphthobenzyl, 2-naphthophenyleth-1-yl, and the like. Arylalkyl groups can include 7 to 20 carbon atoms, for example, the alkyl portion is I to 6 carbon atoms, and the aryl portion is 6 to 14 carbon atoms.
Detailed Description
The following provides a specific embodiment of the present invention for preparing brivaracetam (V).
The reagents and raw materials used in the present invention are commercially available.
EXAMPLE 1 preparation of dihydropyrrolone intermediate (III)
Figure RE-GDA0004022309790000081
In a 100mL round-bottomed flask, methyl L-2-aminobutyric acid hydrochloride (Ia) (7.6805 g) was dissolved in methanol (50 mL), and NEt was added 3 (17.5 mL) was dissolved at room temperature with stirring. 5-hydroxy-4-propyl-2 (5H) -furanone (II) (7.1077 g) was added and the mixture was stirred at room temperature for 2H. Cooling the reaction liquid to 0 ℃, and adding NaBH in batches 4 (1.8915 g). After the addition was complete, stirring was continued for 30min at 0 ℃. Glacial acetic acid (12 mL) was added at 0 ℃. The reaction was warmed to 50 ℃ and stirred overnight. Cooled to room temperature and concentrated to dryness. The crude product was dissolved in dichloromethane (50 mL) and 1M HCl added to pH<3. After separation of the organic phase, the aqueous phase is extracted three times with dichloromethane. The organic phases were combined, washed three times with saturated brine and dried over anhydrous sodium sulfate. Filtered and concentrated to dryness. Crude product column(petroleum ether/ethyl acetate 4).
MS(m/z):[M+H] + ＝226.14
1 H NMR(600MHz,Chloroform-d)δ5.70(s,1H),4.60(dt,J＝10.7,5.4Hz,1H),4.00 -3.97(m,1H),3.69(d,J＝19.0Hz,1H),3.55(s,3H),2.23(q,J＝8.2,6.0Hz,2H),1.89(dq,J ＝13.9,7.0,6.5Hz,1H),1.60(ddt,J＝14.7,7.7,3.7Hz,1H),1.47(tt,J＝16.1,13.2,5.9Hz, 2H),0.83(dd,J＝10.4,5.1Hz,3H),0.78-0.75(m,3H)ppm.
EXAMPLE 2 preparation of pyrrolidone Intermediate (IV)
Figure RE-GDA0004022309790000091
In a 20mL round-bottom flask, anhydrous copper acetate (3.6 mg) and (S) -DTBM-SEGPHOS (23.6 mg) were dissolved in THF (degassed) (10 mL), and stirred at room temperature for 15min. Polymethylsiloxane (4.8 mL) was added and the reaction stirred at room temperature for 1 h, turning a red-brown color. A solution of the intermediate dihydropyrrolone (IIIa) (4.5058 g) in THF (degassed) (10 mL) was slowly added dropwise. After the addition was complete, stirring was continued at room temperature overnight. The reaction was quenched by the addition of water (10 mL). Dichloromethane (10 mL) was added and after separation of the organic phase, the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, washed three times with saturated brine and dried over anhydrous sodium sulfate. Filtered and concentrated to dryness. Column chromatography, mobile phase ethyl acetate/petroleum ether (1. Diastereomer dr determined by HPLC: daicel Chiralpak IB N-3column (0.46x25cm), hexane/iPrOH =95, flow rate =1.0 mL/min, λ =210nm, t = R 8.206min (major) and 9.227min (minor). Diastereomer (dr) means (2S) -2- [ (4R) -2-oxo-4-n-propyl-1-pyrrolidinyl)]Butanamide and (2S) -2- [ (4S) -2-oxo-4-n-propyl-1-pyrrolidinyl]Ratio of butyramide.
MS(m/z):[M+H] + ＝228.16
1 H NMR(600MHz,Chloroform-d)δ4.67(dd,J＝10.9,5.1Hz,1H),3.70(s,3H),3.41 (t,J＝8.6Hz,1H),3.11(dd,J＝9.4,6.8Hz,1H),2.55(dd,J＝16.7,8.5Hz,1H),2.34-2.29(m, 1H),2.12(dd,J＝16.7,7.8Hz,1H),2.01-1.97(m,1H),1.69-1.64(m,1H),1.45(p,J＝10.0, 8.8Hz,2H),1.37-1.31(m,2H),0.93-0.89(m,6H)ppm.
Substrate screening for chiral copper catalyst catalyzed dihydropyrrolone (III) asymmetric reduction reaction:
Figure RE-GDA0004022309790000101
Entry substrate Conversion rate a dr a
1 IIIa >99％ 99.5:0.5
2 IIIb <5％ b 95.6:4.4
3 IIIc <5％ c 98.0:2.0
4 IIId <5％ d /
a Conversion and diastereoratio (dr) were determined by HPLC; b the IIIb recovery rate is 92 percent; c the IIIc recovery rate is 97%; d the recovery of IIId was 96%.
The chiral ligand of the dihydropyrrolone (III) asymmetric reduction reaction catalyzed by the chiral copper catalyst is optimized:
Figure RE-GDA0004022309790000102
Figure RE-GDA0004022309790000103
Figure RE-GDA0004022309790000111
a conversion and diastereoratio (dr) were determined by HPLC.
The condition of copper catalyst loading capacity of the chiral copper catalyst catalyzed pyrrolidon (III) asymmetric reduction reaction is optimized:
Figure RE-GDA0004022309790000112
serial number x Conversion rate a dr a
1 1 >99％ 99.5:0.5
2 0.5 >99％ 99.5:0.5
3 0.25 >99％ 99.5:0.5
4 0.1 >99％ 99.5:0.5
a Conversion and diastereoratio (dr) were determined by HPLC.
Optimizing the condition of the reducing agent for chiral copper catalyst catalyzed pyrrolidon (III) asymmetric reduction reaction:
Figure RE-GDA0004022309790000113
Figure RE-GDA0004022309790000114
Figure RE-GDA0004022309790000121
a conversion and diastereoratio (dr) were determined by HPLC.
The solvent condition of the chiral copper catalyst catalyzed pyrrolidon (III) asymmetric reduction reaction is optimized:
Figure RE-GDA0004022309790000122
serial number Solvent(s) Conversion rate a dr a
1 Tetrahydrofuran (THF) >99％ 99.5:0.5
2 Toluene 36％ 99.4:0.6
3 N-heptane 22％ 99.4:0.6
4 Methyl tert-butyl ether 80％ 97.3:2.7
a Conversion and diastereoratio (dr) were determined by HPLC.
Example 3 preparation of brivaracetam (V)
Figure RE-GDA0004022309790000123
Pyrrolidone Intermediate (IV) (2.2715 g) was dissolved in tetrahydrofuran (20 mL), and 25% aqueous ammonia (20 mL) was added and the mixture was refluxed overnight. The temperature was reduced to room temperature, dichloromethane (10 mL) was added, the organic phase was separated and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, washed three times with saturated brine and dried over anhydrous sodium sulfate. Filtered and concentrated to dryness. The resulting crude solid was recrystallized from methyl tert-butyl ether/n-hexane (5 mL/20 mL) to give 2.0168g of a white solid in 95% yield, dr 99.9.
MS(m/z):[M+H] + ＝213.16
1 H NMR(600MHz,Chloroform-d)δ6.31(s,1H),5.56(s,1H),4.44(dd,J＝8.8,6.8 Hz,1H),3.48(dd,J＝9.8,7.9Hz,1H),3.02(dd,J＝9.8,7.1Hz,1H),2.57(dd,J＝16.8,8.7Hz, 1H),2.33(dq,J＝15.4,7.7Hz,1H),2.07(dd,J＝16.8,8.0Hz,1H),1.93(dp,J＝14.4,7.3Hz, 1H),1.71-1.64(m,1H),1.40(q,J＝7.5Hz,2H),1.31(tdd,J＝12.2,7.6,5.4Hz,2H),0.90(q, J＝7.0Hz,6H)ppm.
The above examples merely represent preferred embodiments of the present invention, and it should be noted that those skilled in the art should also understand that the modifications and amendments made by the conception and method of the present invention should also be considered as within the scope of the present invention.

Claims (10)

1. A method for preparing a brivaracetam intermediate pyrrolidone (IV), comprising: carrying out 1, 4-reduction reaction on the gamma-lactam intermediate (III) and a hydrogen source under the catalysis of a chiral copper metal catalyst to generate a pyrrolidone Intermediate (IV);
Figure FDA0003906473600000011
wherein, the R group is alkyl and aryl, preferably C1-C6 alkyl; copper metal in the chiral copper catalyst is selected from anhydrous copper acetate and copper acetate hydrate; the chiral ligand in the chiral copper catalyst is selected from (S) -SEGPHOS, (S) -DM-SEGPHOS, (S) -DTBM-SEGPHOS, (S) -MeO-BIPHEP, (S) -3,5-Xyl-MeOBIPHEP, (S) -3,5-t-Bu-4-MeO-C 3 * -TunePhos, structure represented as follows:
Figure FDA0003906473600000012
wherein Ar represents an aryl group selected from the group consisting of phenyl, 4-methylphenyl, 4-methoxyphenyl, 3, 5-dimethylphenyl, 3, 5-di-tert-butylphenyl, 3, 5-di-tert-butyl-4-methoxyphenyl; the hydrogen source is selected from one or more of polymethylhydrosiloxane, 1, 3-tetramethyldisiloxane, triethoxysilane and methyldiethoxysilane.
2. The method of claim 1, wherein the ratio of the molar amount of copper metal to the molar amount of the reactant compound (III) in the copper catalyst is 0.001 to 0.1, and the ratio of the molar amount of the chiral ligand to the molar amount of the reactant compound (III) in the copper catalyst is 0.0001 to 0.01.
3. The method according to claim 1, wherein the solvent for the reduction reaction is one selected from dichloromethane, tetrahydrofuran, dimethyltetrahydrofuran, methyl tert-butyl ether, cyclopentylmethyl ether, 1, 4-dioxane, diisopropyl ether, di-n-butyl ether, ethylene glycol dimethyl ether, n-hexane, or a mixture thereof in any ratio.
4. The method of claim 1, wherein the reduction reaction temperature is from-20 ℃ to 50 ℃.
5. A process for the preparation of a gamma-lactam intermediate (III) comprising the condensation/reduction of a derivative of L-2-aminobutyrate or a salt thereof (I) and 5-hydroxy-4-propyl-2 (5H) -furanone (II) in the presence of an organic amine, a reducing agent to form a dihydropyrrolone intermediate (III);
Figure FDA0003906473600000021
6. the preparation method according to claim 1, wherein the molar ratio of the derivative (I) of L-2-aminobutyrate or a salt thereof to 5-hydroxy-4-propyl-2 (5H) -furanone (II) is 1 to 1.5.
7. The preparation method according to claim 1, wherein the organic amine is selected from triethylamine, diisopropylethylamine and pyridine, and the reducing agent is borohydride or hydride selected from potassium borohydride, sodium borohydride and sodium cyanoborohydride.
8. A preparation method of brivaracetam comprises the steps of converting pyrrolidone (IV) into amide under ammonolysis conditions and generating brivaracetam (V),
Figure FDA0003906473600000022
the ammonolysis conditions are selected from ammonia water/tetrahydrofuran/room temperature reaction, ammonia water/tetrahydrofuran/heating reflux, ammonia methanol solution/room temperature reaction, ammonia methanol solution/heating reflux, ammonia water/DMF/room temperature reaction, ammonia water/DMF/80 ℃ reaction and ammonium carbonate/DMF/room temperature reaction.
9. A preparation method of brivaracetam comprises the following steps:
Figure FDA0003906473600000023
the method comprises the following steps:
a, performing condensation/reduction on a derivative (I) of L-2-aminobutyric acid ester hydrochloride and 5-hydroxy-4-propyl-2 (5H) -furanone (II) in the presence of triethylamine, sodium borohydride and glacial acetic acid to generate a pyrrolidon intermediate (III);
in the reaction b, the gamma-lactam intermediate (III) and a hydrogen source are subjected to 1, 4-reduction reaction under the catalysis of a chiral copper metal catalyst to generate a pyrrolidone Intermediate (IV);
reaction c-conversion of the ester group in pyrrolidone (IV) to the amide under appropriate aminolysis conditions and formation of brivaracetam (V).
10. The preparation process according to claim 9, wherein the reaction a comprises: and (2) carrying out condensation/reduction reaction on the L-2-aminobutyrate hydrochloride derivative (I) and 5-hydroxy-4-propyl-2 (5H) -furanone (II) under the action of triethylamine, sodium borohydride and glacial acetic acid, washing the reaction solution by 1M HCl, extracting a water phase by using dichloromethane, drying an organic phase by using anhydrous sodium sulfate, and concentrating to obtain a pyrrolidon intermediate (III).
CN202211307468.6A 2022-10-25 2022-10-25 Preparation method of brivaracetam and intermediate thereof Pending CN115872913A (en)

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