357336-20-0

Basic information

• Product Name: brivaracetam
• Synonyms: brivaracetam;(alphaS,4R)-alpha-Ethyl-2-oxo-4-propyl-1-pyrrolidineacetamide;UCB-34714;1-PyrrolidineacetaMide, α-ethyl-2-oxo-4-propyl-, (αS,4R)-;(S)-2-((R)-2-oxo-4-propylpyrrolidin-1-yl)butanaMide;2(S)-[2-Oxo-4(R)-propylpyrrolidin-1-yl]butyramide;(2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide;API-Anti Epilepsy
• CAS NO: 357336-20-0
• Molecular Formula: C₁₁H₂₀N₂O₂
• Molecular Weight: 703.83
• EINECS: 1592732-453-0
• Product Categories: APIs;Brain health drug;Nootropic;API
• Mol File: 357336-20-0.mol
• Article Data: 52

Chemical Properties

• Melting Point: 76.38°
• Boiling Point: 409.3±28.0 °C(Predicted)
• Appearance: /
• Density: 1.062
• Storage Temp.: Refrigerator
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 15.74±0.50(Predicted)
• CAS DataBase Reference: brivaracetam(CAS DataBase Reference)
• NIST Chemistry Reference: brivaracetam(357336-20-0)
• EPA Substance Registry System: brivaracetam(357336-20-0)

Safety Data

• Hazardous Substances Data: 357336-20-0(Hazardous Substances Data)

Usage

Description

Different sources of media describe the Description of 357336-20-0 differently. You can refer to the following data:
1. Brivaracetam, a chemical analog of Levetiracetam, is a racetam derivative with anticonvulsant effect. It is used for the treatment of partial-onset seizures with or without secondary generalisation, in combination with other antiepileptic drugs. The exact mechanism of brivaracetam's anti-epileptogenic activity is unknown. What is known is thatbrivaracetam binds SV2A with high affinity. SV2A is known to play a role in epileptogenesis through modulation of synaptic GABA release. It is thought that brivaracetam exerts its anti-epileptogenic effects through its binding to SV2A. Brivaracetam can also inhibit Na+ channels which may also contribute to its anti-epileptogenic action.
2. Brivaracetam, a novel oral antiepileptic drug with a high affinity for synaptic vesicle protein 2A (SV2A), was approved in Europe and the US as an adjunctive therapy for the treatment of partial onset seizures with or without secondary generalization in patients aged 16 or older.42 Brivaracetam is very closely related to levetiracetam, an antiepileptic treatment whose immediate release formulation has been available in the United States as a generic drug since 2008, but whose extended release formulation is under patent protection until 2028. The two drugs, which were both developed by UCB Pharma, are structurally similar with brivaracetam having an n-propyl group at the C-4 position of the pyrrolidinone ring and levetiracetam having a hydrogen at this same position. A systematic investigation of the various substitutions of levetiracetam resulted in the identification of more potent and selective SV2A ligands and ultimately culminated in the discovery of brivaracetam, which has greater affinity for SV2A, improved selectivity, more rapid brain penetration, and faster onset of action against seizures than levetiracetam.

Overview and History

Brivaracetam is an orally bioavailable levetiracetam derivative, with anticonvulsant activity. It can be used in the treatment of partial-onset seizures[1-3]. Brivaracetam binds SV2A with 20 times higher affinity than levetiracetam. It is available under the brand name Briviact made by UCB. It was approved by the federal drug administration of USA[FDA] on Feb 19th 2016[1-3].

Application

Brivaracetam is indicated for the treatment of partial-onset seizures in patients 4 years of age and older[4,5]. It provides a new monotherapy treatment option for epilepsy patients 16 years of age and older who suffering partial-onset[focal] seizures, which can be initiated at a therapeutic dose at day one[5].

Mode of action

The accurate mode of action of brivaracetam remains unclear. It is known that Brivaracetam can strongly bind to SV2A[6-8], which is known to play a role in epileptogenesis through modulation of synaptic GABA release. It is thought that brivaracetam exerts its anti-epileptogenic effects through its binding to SV2A[6-8]. It may access the luminal side of recycling synaptic vesicles during vesicular endocytosis, which may reduce excitatory neurotransmitter release and enhance synaptic depression during trains of high-frequency activity, such as is believed to occur during epileptic activity. Brivaracetam is also known to inhibit Na+ channels which may also contribute to its anti-epileptogenic action[9].

Adverse reactions

The most frequently reported adverse reactions associated with brivaracetam treatment are somnolence and dizziness (both somnolence and fatigue are reported with a higher incidence with increasing dose). Preliminary metaanalytic data comparing the incidence of behavioural problems in brivaracetam and levetiracetam trials (used as adjunctive therapy in adults with uncontrolled partial- onset epilepsy) showed that the incidence of non- psychotic behavioural treatment emergent adverse effects was considerably lower with brivaracetam treatment (6.8%) compared with levetiracetam (10.9%), whereas the incidences in placebo arms were similar (4.2 and 4.8%, respectively). The placebo- adjusted incidence rates were 2.6% for brivaracetam and 6.8% for levetiracetam, resulting in a brivaracetam/levetiracetam Odds Ratio of 0.68. Brivaracetam has a low interaction potential, although it is not recommended for use with concomitant levetiracetam.

Dose titration

Brivaracetam is known under the proprietary name of Briviact? (UCB Pharma, Slough) in the UK and USA. Brivaracetam is available in different pharmaceutical forms (10-25-50-75-100 mg film- coated tablets and 10 mg/ mL oral solution). Brivaracetam is initially prescribed at the dose of 50–100 mg daily, divided into two doses. Based on individual patient response and tolerability, the dose may be adjusted within the dose range of 50– 200 mg daily. Brivaracetam is recommended as an adjunctive AED treatment for partial- onset seizures with or without secondary generalization. Brivaracetam exhibits greater antiepileptic properties than levetiracetam in animal models, but with a somewhat smaller (although still high) therapeutic range. Moreover, brivaracetam requires no up- titration to reach therapeutic doses and there is no recommendation for specific monitoring. Exposure to brivaracetam is increased in patients with chronic liver disease. A starting dose of 50 mg daily should be considered and a maximum daily dose of 150 mg administered, divided into two doses, is recommended for all stages of hepatic impairment. If patients missed one dose or more, it is recommended that they take a single dose as soon as they remember and take the following dose at the usual morning or evening time, in order to avoid the brivaracetam plasma concentration falling below the efficacy level and prevent breakthrough seizures from occurring. If brivaracetam has to be discontinued, it is recommended to withdraw it gradually by 50 mg daily on a weekly basis. After 1 week of treatment at 50 mg daily, a final week of treatment at the dose of 20 mg daily is recommended.

Warning

It is possible that BRIVIACT can cause the following severe adverse effects, special attention should pay immediately once those following cases occur[4, 10, 11]. Suicidal Behavior and Ideation: Antiepileptic drugs can increase the risk of suicidal behavior and ideation. Monitor patients taking BRIVIACT for the emergence or worsening of depression; unusual changes in mood or behavior; or suicidal thoughts, behavior, or self-harm. Advise patients, their caregivers, and/or families to be alert for these behavioral changes and report them immediately to a healthcare provider[4]. Psychiatric Adverse Reactions: BRIVIACT can also cause psychiatric adverse reactions, including non-psychotic and psychotic symptoms. These events were reported in approximately 13% of patients taking at least 50 mg per day of BRIVIACT compared to 8% of patients taking placebo. A total of 1.7% of adult patients taking BRIVIACT discontinued treatment due to psychiatric reactions compared to 1.3% of patients taking placebo. Advise patients to report these symptoms immediately to a healthcare provider[10]. Hypersensitivity: BRIVIACT can cause hypersensitivity reactions such as bronchospasm and angioedema. The patients should discontinue BRIVIACT if a he/she develops a hypersensitivity reaction after treatment. BRIVIACT should not be applied in patients with a prior hypersensitivity reaction to brivaracetam or any of the inactive ingredients[10]. Neurological Adverse Reactions: BRIVIACT causes somnolence, fatigue, dizziness, and disturbance in coordination. Somnolence and fatigue-related adverse reactions were reported in 25% of patients taking at least 50 mg per day of BRIVIACT compared to 14% of patients taking placebo. Dizziness and disturbance in gait and coordination were reported in 16% of patients taking at least 50 mg per day of BRIVIACT compared to 10% of patients taking placebo. The risk is greatest early in treatment but can occur at any time. Monitor patients for these signs and symptoms and advise them not to drive or operate machinery until they have gained sufficient experience on BRIVIACT[4]. Withdrawal of Antiepileptic Drugs: BRIVIACT should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus[4].

Precaution

You should not use brivaracetam if you are allergic to it[4, 11, 12]. Brivaracetam may become habit-forming for people administrate. Therefore, it is of risk to share brivaracetam with another person, especially avoid sharing with someone with a history of drug abuse or addiction. You should keep the medication in a place where others cannot get to it. Selling or giving away this medicine is against the law. Before administrate the brivaracetam, tell your doctor if you have ever had one or several of the following symptom for your own safety: Depression or a mood disorder; Suicidal thoughts or actions; liver disease; or alcoholism or drug addiction. Follow your doctor's instructions about taking seizure medication if you are pregnant. Seizure control is very important during pregnancy, and having a seizure could harm both mother and baby. Do not start or stop taking this medicine without your doctor's advice, and tell your doctor right away if you become pregnant. If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of brivaracetam on the baby. It is not known whether brivaracetam passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby. Brivaracetam is not approved for use by anyone younger than 16 years old[4]. Patients of hepatic impairment should subject to dose adjustment[4].

References

https://www.ncbi.nlm.nih.gov/pubmed/21575627 https://www.ucb.com/stories-media/press-releases/article/U-S-FDA-approves-UCB-s-new-epilepsy-treatment-BRIVIACT-for-patients-with-partial-onset-seizures https://www.drugbank.ca/drugs/DB05541 https://www.briviact.com/briviact-PI.pdf https://www.ucb.com/stories-media/Press-Releases/article/New-indication-for-BRIVIACT-brivaracetam-UCB-s-newest-antiepileptic-drug-approved-by-FDA-as-monotherapy-treatment-of-partial-onset-seizures-in-adults Gillard, Michel, et al. "Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: Relationship to anti-convulsant properties." European Journal of Pharmacology664.1(2011]:36-44. Yang, X., et al. "Brivaracetam augments short-term depression and slows vesicle recycling. " Epilepsia 56.12(2016]:1899-1909. Nicolas, J. M., et al. "Brivaracetam, a selective high-affinity synaptic vesicle protein 2A[SV2A] ligand with preclinical evidence of high brain permeability and fast onset of action. " Epilepsia 57.2(2016]:201-209. Vogl, Christian, et al. "The SV2A Ligand Levetiracetam Inhibits Presynaptic Ca2+ Channels Via an Intracellular Pathway."[2012]. Briviact? US Prescribing Information. Brussels, Belgium: UCB, 2016. https://www.rxlist.com/briviact-side-effects-drug-center.htm https://www.everydayhealth.com/drugs/brivaracetam

Uses

Different sources of media describe the Uses of 357336-20-0 differently. You can refer to the following data:
1. Treatment ofTreatment of epilepsy, neuropathic pain and essential tremor.
2. Brivaracetam, is a 4-n-propyl analog of levetiracetam (L331500), and a racetam derivative with anticonvulsant properties.

Definition

ChEBI: A non-proteinogenic amino acid derivative that is butanamide in which the pro-S hydrogen at position 2 is replaced by a (4R)-2-oxo-4-propylpyrrolidin-1-yl. Used for treatment of partial onset seizures related to epilepsy.

Clinical Use

Antiepileptic agent

Synthesis

Two enantioselective routes have been reported, one employing an enzymatic resolution and the other utilizing (R)- (-)-epichlorohydrin as a chiral starting material. The route involves an enzymatic resolution, is the only kilogram-scale route disclosed in the literature to date and reportedly permits the production of brivaracetam within the required commercial quality specifications. However, the authors note that the development of this route for commercial purposes has been stopped. Commercial dimethyl n-propylmalonate 108 was first alkylated with tertbutyl- 2-bromoacetate. The resulting product underwent Krapcho decarboxylation to afford racemic succinate derivative 109 in 94% yield over the two steps. Optimized conditions for the key enzymatic resolution employed protease C from Bacillus subtilis type 2 at 30 °C for 18 h to resolve ester 109 and provide the acid enantiomer 110. This biocatalytic process allowed for residual unreacted diester 109 to be washed away with cyclohexane at pH 9 (adjusted with 0.5 M NaOH), and the desired acid 110 could be isolated upon lowering the pH (～1) and extracting with isopropyl acetate (42% yield, 97% ee). The transformation of acid 110 into propyllactone 111 proceeded in nearly quantitative yield by a three-step sequence: activation of the acid with ethyl chloroformate, reduction to the alcohol with sodium borohydride, and cyclization upon acidic workup with TFA. Exposure of 111 to HBr in acetic acid followed by esterification of the resulting acid-generated bromoester 112. Finally, TBAI-catalyzed alkylation of 112 with commercial (S)-2-aminobutanamide (113) in refluxing isopropyl acetate introduced the n-butylamide moiety while facilitating lactamization. Addition of MTBE followed by filtration and recrystallization from isopropyl acetate afforded brivaracetam (IX) in 32% yield and 96% ee.

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: concentration reduced by rifampicin. Antidepressants: antagonism of anticonvulsant effect (convulsive threshold lowered). Antimalarials: mefloquine antagonises anticonvulsant effect. Antipsychotics: antagonism of anticonvulsant effect (convulsive threshold lowered). Orlistat: possibly increased risk of convulsions.

Metabolism

Brivaracetam is mainly metabolised by hydrolysis of the amide moiety to form the corresponding carboxylic acid (approximately 60% the elimination), and secondarily by hydroxylation on the propyl side chain (approximately 30% the elimination). The hydrolysis of the amide moiety leading to the carboxylic acid metabolite (34% of the dose in urine) is supported by hepatic and extra-hepatic amidase. The metabolites are inactive. Greater than 95% of the dose is excreted in the urine as brivaracetam and its metabolites.

Synthetic route

(2S)-4,5-dehydro-(2-oxo-4-n-propyl-1-pyrrolidinyl)-2-butanamide (357338-13-7) → brivaracetam (357336-20-0)

Conditions	Yield
With (R)-((4,4’-bi-1,3-benzodioxole)-5,5’-diyl)bis(bis(3,5-di-t-butyl-4-methoxyphenyl))phosphine; copper(l) chloride; sodium t-butanolate In toluene at -40℃; for 24h; Inert atmosphere;	99.3%
With 5% Pd-CaCO3; hydrogen In methanol; water at -10 - 0℃; Temperature; Reagent/catalyst; Solvent;	70.2%

(R)-N-((S)-1-amino-1-oxobutan-2-yl)-3-(chloromethyl)hexanamide → brivaracetam (357336-20-0)

Conditions	Yield
With potassium tert-butylate In tetrahydrofuran	93%
With sodium hydroxide In dichloromethane at -15 - -10℃; Concentration; Reagent/catalyst; Temperature; Solvent;	90%
With lithium hexamethyldisilazane In tetrahydrofuran at -15 - -5℃; for 4h;	69.8%

ethyl (R)-γ-bromo-3-propylbutyrate + (S)-2-amino-butanamide hydrochloride (53726-14-0) → brivaracetam (357336-20-0)

Conditions	Yield
With sodium carbonate In ethanol at 50℃; for 24h; Temperature;	93%

(S)-2-amino-butanamide (7324-11-0, 53726-14-0, 104652-77-9, 143164-46-9) + C7H13IO2 → brivaracetam (357336-20-0)

Conditions	Yield
Stage #1: C7H13IO2 With 1,1'-carbonyldiimidazole In toluene at 10 - 20℃; for 0.166667h; Inert atmosphere; Stage #2: (S)-2-amino-butanamide In toluene at 10 - 20℃;	92%

(S)-2-amino-butanamide (7324-11-0, 53726-14-0, 104652-77-9, 143164-46-9) + ethyl (R)-γ-bromo-3-propylbutyrate → brivaracetam (357336-20-0)

Conditions	Yield
With potassium carbonate In ethanol at 60℃; for 8h; Reagent/catalyst; Solvent; Temperature;	91%
With tetra-(n-butyl)ammonium iodide; sodium carbonate In Isopropyl acetate at 88.8℃; for 28h; Inert atmosphere; Cooling;	32%
Stage #1: (S)-2-amino-butanamide; ethyl (R)-γ-bromo-3-propylbutyrate With tetra-(n-butyl)ammonium iodide; sodium carbonate In Isopropyl acetate for 28h; Reflux; Stage #2: With acetic acid In Isopropyl acetate at 60℃; for 1.83h;	12.66%

(2S)-2-[(4R)-2-oxo-4-n-propyl-1-pyrrolidinyl]butyric acid → brivaracetam (357336-20-0)

Conditions	Yield
With ammonium chloride; N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran at 20℃; for 2h; Time; Large scale;	90%
With ammonia; pivaloyl chloride; triethylamine In dichloromethane at 0 - 10℃; for 6h; Inert atmosphere;	88%
Stage #1: (2S)-2-[(4R)-2-oxo-4-n-propyl-1-pyrrolidinyl]butyric acid With chloroformic acid ethyl ester; triethylamine In dichloromethane at -10 - -5℃; for 1h; Stage #2: With ammonium bicarbonate In dichloromethane at -10 - -5℃;	67%

C11H22N2O3*C2H2O4 → brivaracetam (357336-20-0)

Conditions	Yield
In isopropyl alcohol for 6h; Reflux;	89.3%

isopropyl (2S)-2-[(4R)-2-oxo-4-propyl-1-pyrrolidinyl]butyrate → brivaracetam (357336-20-0)

Conditions	Yield
With ammonium hydroxide; ammonia In water at 5℃; under 750.075 - 1125.11 Torr; for 15h;	88.7%

(S)-2-amino-butanamide (7324-11-0, 53726-14-0, 104652-77-9, 143164-46-9) + C7H12ClIO → brivaracetam (357336-20-0)

Conditions	Yield
With potassium hydroxide In dichloromethane at 0 - 5℃; for 2h; Molecular sieve;	87%

methyl (2S)-2-[(4R)-2-oxo-4-propyl-1-pyrrolidinyl]butyrate → brivaracetam (357336-20-0)

Conditions	Yield
With ammonium hydroxide In N,N-dimethyl-formamide at 20℃; for 15h;	86.4%
With ammonium hydroxide; ammonia In water at 5℃; under 750.075 - 1125.11 Torr; for 15h;	34 g
With ammonia In tetrahydrofuran at 20℃; for 20h;	0.91 g

(2S)-2-((3R)-2-hydroxy-5-oxo-3-propylpyrrolidin-1-yl)butanamide → brivaracetam (357336-20-0)

Conditions	Yield
With triethylsilane; trifluoroacetic acid In dichloromethane at -25 - 20℃; for 4.51667h;	81.3%
With triethylsilane; boron trifluoride diethyl etherate In dichloromethane at 0℃; for 18h;

(2S)-2-(4-propylpyrrolidin-2-one)butanamide → brivaracetam (357336-20-0)

Conditions	Yield
In ethanol; n-heptane at 23 - 27℃; Product distribution / selectivity; Resolution of racemate;	80%
In dichloromethane Resolution of racemate;

(R)-3-hydroxymethylhexanoic acid [(S)-1-carbamoylpropyl]amide → brivaracetam (357336-20-0)

Conditions	Yield
With sulfuric acid In toluene at 90 - 100℃; for 15h; Solvent; Reagent/catalyst; Temperature; Green chemistry;	77.95%
Multi-step reaction with 2 steps 1: thionyl chloride / tetrahydrofuran / 2 h / 0 - 20 °C 2: lithium hexamethyldisilazane / tetrahydrofuran / 4 h / -15 - -5 °C View Scheme
With tributylphosphine; di-tert-butyl-diazodicarboxylate In tetrahydrofuran at 20℃; for 18h;

C14H24N2O4 → brivaracetam (357336-20-0)

Conditions	Yield
With sodium chloride In water; N,N-dimethyl-formamide at 100℃; for 16h; Solvent; Temperature; Reagent/catalyst;	75.47%

(S)-2-amino-butanamide (7324-11-0, 53726-14-0, 104652-77-9, 143164-46-9) + C7H12Br2O → brivaracetam (357336-20-0)

Conditions	Yield
Stage #1: (S)-2-amino-butanamide; C7H12Br2O With tetrabutylammomium bromide; potassium hydroxide In dichloromethane at 0℃; for 10h; Stage #2: In tert-butyl methyl ether at 20℃; for 22h; Reagent/catalyst; Temperature; Inert atmosphere;	75%

(3R)-3-(bromomethyl)-N-[(1S)-1-carbamoylpropyl]hexanamide → brivaracetam (357336-20-0)

Conditions	Yield
With sodium hexamethyldisilazane In tetrahydrofuran at -10 - 10℃; for 1h; Reagent/catalyst; Temperature;	75%
With potassium tert-butylate In tetrahydrofuran at -30℃;	69.06%

C15H20N2O5S + n-propylmagnesium bromide (927-77-5) → brivaracetam (357336-20-0)

Conditions	Yield
With potassium bromide In dichloromethane at 5℃; for 2.5h; Temperature; Reagent/catalyst; Inert atmosphere;	74.8%

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) + (S)-2-aminobutanamide hydrochloride → brivaracetam (357336-20-0)

Conditions	Yield
Stage #1: (S)-2-aminobutyramide hydrochloride With sodium hydroxide In ethanol for 1h; Reflux; Green chemistry; Stage #2: (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one In ethanol for 9h; Green chemistry; Stage #3: With sulfuric acid In toluene at 95 - 100℃; for 15h; Green chemistry;	72.93%

(2S)-2-(2-hydroxy-5-oxo-3-propyl-2,5-dihydro-1H-pyrrole-1-yl)butanamide → brivaracetam (357336-20-0)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In isopropyl alcohol at -30 - -20℃;	72.4%

(S)-2-aminobutanamide hydrochloride + C8H15BrO2 → brivaracetam (357336-20-0)

Conditions	Yield
Stage #1: (S)-2-aminobutyramide hydrochloride With potassium carbonate In Isopropyl acetate for 8h; Reflux; Stage #2: C8H15BrO2 In Isopropyl acetate for 28h; Reflux;	68%

C7H12ClIO + (S)-2-amino-butanamide hydrochloride (53726-14-0) → brivaracetam (357336-20-0)

Conditions	Yield
With tetrabutylammomium bromide; sodium sulfate; potassium hydroxide In dichloromethane at 20 - 30℃; for 18h; Large scale;	64%
With tetrabutylammomium bromide; sodium sulfate; potassium hydroxide In dichloromethane at 20 - 30℃; for 18h; Molecular sieve;	543.5 g
With tetrabutylammomium bromide; sodium sulfate; potassium hydroxide In dichloromethane at 20 - 30℃; for 18h; Molecular sieve; Large scale;	543.5 g

(S)-2-amino-butanamide (7324-11-0, 53726-14-0, 104652-77-9, 143164-46-9) + C10H15BrN2O → brivaracetam (357336-20-0)

Conditions	Yield
With sodium hydroxide In acetonitrile at 0 - 25℃; for 12h; Solvent; Reagent/catalyst; Temperature;	64%

(S)-2-aminobutanamide hydrochloride + C7H13IO2 → brivaracetam (357336-20-0)

Conditions	Yield
Stage #1: (S)-2-aminobutyramide hydrochloride With potassium carbonate In Isopropyl acetate for 8h; Reflux; Stage #2: C7H13IO2 In Isopropyl acetate for 28h; Reflux;	63.4%

(+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one (63095-51-2) + (S)-2-amino-butanamide (7324-11-0, 53726-14-0, 104652-77-9, 143164-46-9) → brivaracetam (357336-20-0)

Conditions	Yield
With toluene-4-sulfonic acid In toluene for 24h; Reflux; enantioselective reaction;	60%
With sodium sulfate; potassium hydroxide at 160℃; for 18h; Temperature; Molecular sieve; Inert atmosphere;	60%
Stage #1: (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one; (S)-2-amino-butanamide In toluene at 20℃; for 2h; Inert atmosphere; Stage #2: With sodium tetrahydroborate; sodium hydroxide In water; toluene for 1h; Stage #3: With acetic acid In water; toluene at 50℃; for 20h;

(S)-2-amino-butanamide (7324-11-0, 53726-14-0, 104652-77-9, 143164-46-9) + C7H12BrClO → brivaracetam (357336-20-0)

Conditions	Yield
With tetrabutylammomium bromide; lithium isopropylamide; sodium sulfate In N,N-dimethyl-formamide at 10 - 20℃; for 10h; Large scale;	59%

C13H26N2O3 → brivaracetam (357336-20-0)

Conditions	Yield
With 2-hydroxypyridin In toluene at 90℃; for 3h; Reagent/catalyst;	58%
With acetic acid In tetrahydrofuran at 25 - 65℃; for 4h;	28 g

(2S)-2-((4S)-2-oxo-4-propyl-3-tosylpyrrolidin-1-yl)butanamide → brivaracetam (357336-20-0)

Conditions	Yield
With methanol; chloro-trimethyl-silane; magnesium at 20℃; for 24h; Reagent/catalyst; Temperature;	47.6%

C11H20N2O2 → ((2R)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide) (357337-00-9) + brivaracetam (357336-20-0)

Conditions	Yield
Purification / work up; Resolution of diastereomeric mixture;	A 45% B 44%

2-(2-oxo-4-propylpyrrolidin-1-yl)butanamide (357335-87-6) → brivaracetam (357336-20-0)

Conditions	Yield
With Chiralpak AD In ethanol; n-heptane Resolution of racemate;	44%

tert-butyl (3R)-3-({[(2S)-1-amino-1-oxobutan-2-yl]amino}methyl)hexanoate → brivaracetam (357336-20-0)

Conditions	Yield
With benzotriazol-1-ol In toluene at 90℃; for 3h;	40%
With acetic acid In toluene at 80 - 85℃; for 14h; Reagent/catalyst; Temperature; Solvent;	0.3 g

Upstream product

• 7324-11-0 (S)-2-amino-butanamide 
• 78920-10-2 5-hydroxy-4-n-propyl-2,5-dihydrofuran-2-one 
• 2163-48-6 diethyl propylmalonate 
• 112106-16-8 (R)-2-((tert-butoxycarbonyl)methyl)pentanoic acid 
• 63095-51-2 (+)-(R)-4-propyl-4,5-dihydrofuran-2(3H)-one 
• 14035-96-2 dimethyl 2-propylmalonate 
• 110-62-3 pentanal 
• 357338-13-7 (2S)-4,5-dehydro-(2-oxo-4-n-propyl-1-pyrrolidinyl)-2-butanamide 
• 927-77-5 n-propylmagnesium bromide 
• 117039-60-8 (R)-2-n-propylpent-4-en-1-ol 

Relevant articles and documents

Chiral resolution method of brivaracetam

The invention relates to a chiral resolution method of brivaracetam. The chiral resolution method comprises the following steps: 1) in a solvent, co-crystallizing a compound (R,S)-2-((R)-2-oxo-4-propyl pyrrolidin-1-yl)butyramide as shown in a formula 2 and D-tartaric acid to obtain a compound as shown in a formula 3; 2) performing alkali dissociation on the compound as shown in the formula 3 to obtain a compound as shown in a formula 1; and 3) carrying out epimerization on the other diastereoisomer compound as shown in the formula 4 in the step 1) under the action of alkali to obtain a compound as shown in the formula 2, and continuously preparing the compound as shown in the formula 1. According to the method, brivaracetam and diastereoisomers can be separated easily and conveniently, so high-purity brivaracetam is prepared.

PROCESS FOR THE PREPARATION OF BRIVARACETAM

The present invention relates to a process for the preparation of brivaracetam, a compound of formula I and salts thereof. The present invention also relates to a compound of formula II and a compound of formula IIA, process for its preparation and conversion thereof to brivaracetam, the compound of formula I.

Preparation methods of brivaracetam and intermediate thereof

The invention discloses a preparation method of a brivaracetam intermediate as shown in a formula B-R. The preparation method comprises the following steps: reacting a compound as shown in a formula B-P with a resolution reagent to prepare a compound as shown in a formula B-Q; and converting the compound as shown in the formula B-Q into the brivaracetam intermediate as shown in the formula B-R. The resolution reagent is a (1S, 2S)-(+)-1, 2-cyclohexanediamine compound. The invention also provides a preparation method of brivaracetam. According to the methods, a mixture of two diastereoisomers of (S)-2-3-propylpyrrolidine-1-yl butyric acid can be conveniently and effectively split, a chiral chromatographic column is not used, the process time is greatly shortened, the operation is simplified, the process cost is reduced, and industrial production and environmental protection are facilitated.