Identification, characterization, synthesis and strategy for minimization of potential impurities observed in the synthesis of brivaracetam

Liao, Shouzhu; Chen, Hongjun; Wang, Guifei; Wu, S. X.; Yang, Zaiyou; Luo, Weihe; Liu, Zhuanfeng; Gao, Xun; Qin, Junhai; Li, Chuanhua; Wang, Zhongqing

doi:10.1016/j.tet.2020.131273

Cited by 13 publications

(9 citation statements)

References 7 publications

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“…The crude intermediate 62 further used for epoxidation with potassium carbonate yielded (S)-2-(oxiran-2-yl)acetonitrile (63). Later, epoxideopening was performed in the presence of triisopropoxy titanium chloride in toluene, and n-propyl magnesium bromide was further added to obtain (R)-3-(hydroxyl-methyl)-hexanenitrile (60). Hydrolysis of nitrile functionality of 60 was performed by using sodium hydroxide to obtain (R)-3-(hydroxymethyl)hexanoic acid (61).…”

Section: Brivaracetam Mechanism Of Actionmentioning

confidence: 99%

“…Later, the next step involves the homoconjugate 58 reaction for ring-opening of the spiro acylal 59 with amine 5, followed by intramolecular cyclization 15 to afford the mixture of (4R)-1-((S)-1-amino-1oxobutan-2-yl)-2-oxo-4-propyl pyrrolidine-3-carboxylic acid (70) and as an impurity 1-((S)-1-amino-1-oxobutan-2-yl)-2oxo-5-propyl pyrrolidine-3-carboxylic acid (71). 60 In the last step, decarboxylation of compound (70) in MIBK at 120 °C obtained brivaracetam (1). The use of the expensive asymmetric chiral catalyst AD Mix-β limits the general utility of the protocol.…”

Section: Brivaracetam Mechanism Of Actionmentioning

confidence: 99%

“…In the beginning, generation of a stereogenic center through alkylation of (S)-4-benzyl-3-pentanoyl oxazolidin-2one (97) by using 2-bromoaceto-nitrile (101) in the presence of LiHMDS obtained alkylated intermediate 102. Compound 102 undergoes cleavage of the chiral auxiliary, followed by reduction of acid, by using sodium borohydride to afford (R)- 3-(hydroxymethyl)hexanenitrile (60). Protection of the hydroxyl group was carried out via benzyl bromide to form a protected intermediate (R)-3-((benzyloxy)-methyl)hexanenitrile (103).…”

Section: Brivaracetam Mechanism Of Actionmentioning

confidence: 99%

“…Realizing the presence of impurities is important for studying the efficacy and safety of the drug. A literature review reveals that the synthetic routes of brivaracetam have nine impurities, illustrated in Figure which is disclosed by Liao et al Apart from that, we include four different categorization of synthetic approaches through which chirality can be introduced in the brivaracetam molecule. The categories are as follows: Separation by chiral high-performance liquid chromatography (HPLC), Chiral pool/enantiomeric scaffold method, Asymmetric method, and Resolution methods. …”

Section: Brivaracetam Mechanism Of Actionmentioning

confidence: 99%

“…Further protection of dioic acid was performed with acetone in the presence of acetic anhydride and sulfuric acid to afford ( S )-6,6-dimethyl-1-propyl-5,7-dioxaspiro[2.5]octane-4,8-dione ( 69 ). Later, the next step involves the homoconjugate reaction for ring-opening of the spiro acylal with amine 5 , followed by intramolecular cyclization to afford the mixture of (4 R )-1-(( S )-1-amino-1-oxobutan-2-yl)-2-oxo-4-propyl pyrrolidine-3-carboxylic acid ( 70 ) and as an impurity 1-(( S )-1-amino-1-oxobutan-2-yl)-2-oxo-5-propyl pyrrolidine-3-carboxylic acid ( 71 ) . In the last step, decarboxylation of compound ( 70 ) in MIBK at 120 °C obtained brivaracetam ( 1 ).…”

Section: Brivaracetam Mechanism Of Actionmentioning

confidence: 99%

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Synthetic Approaches toward the Synthesis of Brivaracetam: An Antiepileptic Drug

et al. 2022

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Epilepsy is a chronic neurological disorder in the brain, affecting individuals of all age groups. Nearly 1% of the world population is affected by seizure disorder, of which 80% of the patients are observed in underdeveloped and developing countries. The predominant treatment option for epilepsy includes an antiepileptic drug named brivaracetam. This drug emerged as an unusual success of rational drug discovery in clinical development by exhibiting magnificent affinity toward synaptic vesicle glycoprotein as compared to conventional drug levetiracetam and piracetam. Given its efficiency in limiting the progression of epilepsy, this drug has drawn considerable attention of researchers to devise novel routes of its synthesis. The present review encapsulates the reported literature on synthetic strategies for brivaracetam, which will assist medicinal chemists in the further progress of its synthesis.

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Section: Brivaracetam Mechanism Of Actionmentioning

confidence: 99%

Section: Brivaracetam Mechanism Of Actionmentioning

confidence: 99%

Section: Brivaracetam Mechanism Of Actionmentioning

confidence: 99%

Section: Brivaracetam Mechanism Of Actionmentioning

confidence: 99%

Section: Brivaracetam Mechanism Of Actionmentioning

confidence: 99%

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Synthetic Approaches toward the Synthesis of Brivaracetam: An Antiepileptic Drug

et al. 2022

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Identification of degradation products of brivaracetam using liquid chromatography quadrupole time‐of‐flight tandem mass spectrometry: Degradation pathway elucidation

Xu,

Ning,

et al. 2023

Rapid Comm Mass Spectrometry

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RationalePyrrolidone‐based drugs find widespread use in treating conditions such as epilepsy and Alzheimer's disease, and in various other medical applications. Brivaracetam, the latest generation of pyrrolidone drugs, has exhibited significant promise owing to chemical structure modifications. Its affinity to the SV2A receptor is double that of the previous‐generation drug, levetiracetam. Consequently, brivaracetam holds substantial potential for diverse applications. As a novel drug not yet included in the pharmacopeias of developed nations, comprehensive analysis and research are necessary to guarantee its safe utilization in clinical settings.MethodsA liquid chromatography quadrupole time‐of‐flight tandem mass spectrometry (LC/QTOFMS) method has been developed to effectively separate, identify and characterize both the degradation products and process‐related substances of brivaracetam. Stress testing of the sample was carried out following the guidelines outlined in ICH Q1A(R2). The structures of these impurities were identified through positive electrospray ionization QTOF high‐resolution MS and NMR spectroscopy. Additionally, the formation mechanism of each degradation product is thoroughly discussed.ResultsUnder the analytical conditions outlined in this paper, brivaracetam and its degradation products were effectively separated. Thirteen degradation products were detected and characterized, shedding light on their origins and degradation pathways. Among these, three degradation products align with previously reported impurities, and two unreported degradation products were synthesized and confirmed through NMR spectroscopy. The stress testing results revealed the instability of brivaracetam under acidic, alkaline, oxidative and thermal stress conditions, while it exhibited relative stability under photolytic stress conditions.ConclusionThe study developed an analytical method for brivaracetam that enabled the effective detection and separation of brivaracetam and its 13 degradation products. This method addresses a gap in both current domestic and foreign drug standards. The structures of all the major degradation products were characterized by high‐resolution LC/QTOFMS, which is essential for quality control during the drug production process, stability evaluation and the establishment of proper storage conditions.

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Engineering of an ene-reductase for producing the key intermediate of antiepileptic drug Brivaracetam

Sun

Liu

Song

et al. 2023

Appl Microbiol Biotechnol

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Identification, characterization, synthesis and strategy for minimization of potential impurities observed in the synthesis of brivaracetam

Cited by 13 publications

References 7 publications

Synthetic Approaches toward the Synthesis of Brivaracetam: An Antiepileptic Drug

Synthetic Approaches toward the Synthesis of Brivaracetam: An Antiepileptic Drug

Identification of degradation products of brivaracetam using liquid chromatography quadrupole time‐of‐flight tandem mass spectrometry: Degradation pathway elucidation

Engineering of an ene-reductase for producing the key intermediate of antiepileptic drug Brivaracetam

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