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Synthetic Approaches toward the Synthesis of Brivaracetam: An Antiepileptic Drug

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.


INTRODUCTION
"Epilepsy" is the condition of repeated, unjustifiable seizures, 1 or a group of neurological disorders, affecting the nervous system of individuals of all age groups. 2 Nearly 1% of the world population (∼50 million) is affected by seizure disorder, 3 of which about 80% of the patients are from underdeveloped and developing countries, 4 such as focal seizures, generalized seizures, and a combination of generalized and focal seizures. 5 In India alone, ∼10 million people suffer from these disorders. 6 According to World Health Organization (WHO), in poor and developing countries, epileptic seizures occur most commonly in juvenile and young adults, while in developed countries, the trend is observed in toddlers and elders. 7 A recent study has shown that the occurrence of epilepsy is slightly higher in elderly men as compared to that in women, which is reflected by higher possibilities of strong stroke, neurodegenerative diseases, and tumors in this age group. 8 In poor countries, owing to the lack of proper treatment, the number of deaths due to epilepsy seizures has exponentially increased, whereas insufficient knowledge and myths among people in developing countries make the treatment of epilepsy complicated. 9 However, timely treatment by an anticonvulsant drug can treat epilepsy efficiently. 10 Among the different forms of epilepsy, focal-onset seizures with or without secondary generalization are commonly seen in patients aged 16 years onward. 11 Unfortunately, most of the initially approved antiepileptic drugs (AEDs) 12 were only effective over 50% of the patients. Then, in 2000, the first effective drug, levetiracetam, was approved for the treatment of adults. An overview analysis revealed that in the last 3 decades, >30% of patients failed to achieve freedom from prolonged seizures following treatment with ∼14 conventional drugs AEDs. 13,14 In 2004, brivaracetam was introduced as an AED, which proved to be an unusual success of rational drug discovery in clinical development by exhibiting 13-fold more affinity toward synaptic vesicle glycoprotein (SV2A) than levetiracetam and 400-fold more affinity than piracetam. 15 Piracetam is a nootropic drug used in the treatment of central nervous system disorders. 16 Brivaracetam is an n-propyl analogue of levetiracetam developed by the Belgian company Union Chemique Belge (UCB Pharma). In 2016, brivaracetam was approved in the United States and Europe, and it is manufactured under the brand name Briviact to treat focalonset seizures and generalized seizures. 17 AEDs are majorly differentiated according to their mode of action such as calcium current inhibitors, sodium channel blockers, glutamate blockers, carbonic anhydride inhibitors, and γ-aminobutyric acid (GABA) enhancer. 18 Brivaracetam shows a higher affinity toward SV2A in the brain, which is believed to contribute to the anti-seizure effect. 19 The main function of SV2A is in epileptogenesis through the modulation of synaptic GABA release 20 and inhibiting Na + channels, thereby leading to its anti-epileptogenic action. 21 The precise mode of action of brivaracetam is still unknown, but it plays an important role in regulating neurotransmitter release. 22 However, its metabolism proceeds through hydrolysis of the acetamide group into the carboxylic acid metabolite. 23 The potential of brivaracetam caught the attention of researchers around the world to synthesize in several ways such as through exercising enzymatic resolution, chiral pool synthesis, and asymmetric synthesis. Brivaracetam is the first AED that was discovered through optimization of pharmacodynamic activity of the molecular target. 24

BRIVARACETAM MECHANISM OF ACTION
SV2A is a prototype protein that specifically recognizes the synaptic vesicles of endocrine granules and neurons. 25,26 Brivaracetam is an analogue of levetiracetam; both bind to the human SV2A protein at nearly the same site. However, they interact with different conformational states of proteins. 25 Various animal model studies state that the affinity of SV2A increased due to brivaracetam than levetiracetam in drugresistant, focal, and generalized seizures. 27 Unlike levetiracetam, brivaracetam does not inhibit high-voltage-gated-calcium current channels and is not believed to contribute to anticonvulsant properties. 28 The proposed mechanism of action is illustrated in Figure 1. 29 In order to synthesize brivaracetam, numerous different synthetic routes have been explored, and subsequently, a considerable number of literature studies have been published. The common approaches for the synthesis of brivaracetum are shown in Figure 2. The aim of the present review is to encourage medicinal chemists to develop new synthetic approaches for synthesizing brivaracetam. In the present review, we underline the merits and limitations of approaches employed for the synthesis of brivaracetam. 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 3 which is disclosed by Liao et al. 30 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: (i) Separation by chiral high-performance liquid chromatography (HPLC), (ii) Chiral pool/enantiomeric scaffold method, (iii) Asymmetric method, and (iv) Resolution methods.
2.1. Separation by Chiral HPLC. In this section, we illustrate the synthesis and purification of brivaracetam (1) by using separation through chiral HPLC reported in the literature.
2.1.1. Synthesis of Brivaracetam (1) by Morpholine-Catalyzed Condensation. In 2003, an initial strategy for the synthesis of brivaracetam was described in the US patent US2003120080A1. 31 At the beginning, morpholine-catalyzed condensation 32 of valeraldehyde (2) and glyoxylic acid (3) was carried out to form a hydroxy furanone (4) (Scheme 1). Intermediate 4 was subjected to reductive amination to obtain intermediate 6 as a crude orange oil, followed by reduction of the double bond to form a diastereomeric mixture of crude pyrrolidone as a white solid. Two diastereomers are separated by preparative HPLC on the chiral phase with EtOH/heptane (1:1) to afford brivaracetam (1) with a moderate yield. Brivaracetam (1) has been observed in two solid states, which is characterized by diffraction peaks. A further improved route to brivaracetam (1) is disclosed in the US patent US7629474-(B2), 33 in which synthesis of brivaracetam (1) was published by minimizing one step and improving the yield using two different methods for reductive amination, followed by hydrogenation in one pot. Later, in 2017, UCB Biopharma Sprl reported a continuous flow process for the synthesis of brivaracetam (1 ) disclosed in the p ubli cation WO2017076737A1. 34 The diastereomers are separated by a multi-column continuous (MCC) technique in an n-heptane/ ethanol (45:55%) mixture, followed by crystallization from 2-PrOAc. In the modern era of drug discovery, flow chemistry is playing a crucial role in API process development and bulk manufacture in the pharmaceutical plants and chemical industries. 35 In different aspects of the slight modification in the scheme, some other groups also filed a batch process patent. 36 The drawback accompanying these schemes is separation of diastereomers by using chiral HPLC which is not industrially viable for large-scale synthesis of brivaracetam.
Brivaracetam (1) was recrystallized in di-isopropyl ether and separated by chiral HPLC.
2.2. Chiral Pool/Enantiomeric Scaffold Method. Recently, several synthetic advancements have been introduced to the synthesis of brivaracetam using commercially available chiral starting materials to increase the chiral purity of brivaracetam.
2.3. Asymmetric Method. In this section, we demonstrate the synthesis of brivaracetam (1) by using various organochiral catalysts and chiral auxiliaries reported in the literature.
2.3.1. Using Catalyst. Generally, organocatalysis has a diverse range of activities, having cost effective starting materials and good moisture and air stability along with recovery. It is proven to be more economical and fruitful in synthetic chemistry.
2.3.1.1. Stereoselective Synthesis of Brivaracetam (1) by Using AD Mix-β. In 2007, an unconventional synthetic route of brivaracetam (1) with high stereoselectivity was developed by UCB pharma disclosed in PCT WO2007065634. 55 It is granted in US patent US8076493B2 56 (Scheme 12). The synthetic route begins with the asymmetric catalyst sharpless asymmetric dihydroxylation, 57 which makes high enantiomeric enrichment in the field of synthetic chemistry. Pent-1-ene (64) was used with the catalyst AD Mix-β to furnish the required enantiomerically pure (R)-pentane-1,2-diol (65). Further, compound (R)-4-propyl-1,3,2-dioxathiolane-2,2-dioxide (66) 2.3.2. Using Chiral Auxiliary. Stereoselective generation of chiral center was performed by using the temporarily incorporated chiral substrate (chiral auxiliary) with diastereofacial control in the reaction. Chiral auxiliaries can be recycled to minimize the cost of the chiral reagents used routinely. The major drawback is that one enantiomer is readily available but the other one is far more expensive; both the enantiomers of chiral auxiliaries are usually not available, and hence, chiral auxiliaries need to be synthesized. 2.4. Resolution Method. With the help of a single enantiomer of a chiral reagent conversion of a racemic mixture into a mixture of diastereomers, this can be easily separated by recrystallization or chromatographic technique. The limitation of the method is to lose another 50% undesired isomer; however, it can be recycled by racemization. Further hydrogenolysis was carried out using ammonium formate, 10% Pd/C, to obtain (2S)-methyl 2-(2-oxo-4-propyl pyrrolidin-1-yl)butanoate (23). Later, ester hydrolysis was carried out in the presence of sodium hydroxide along with methanol, water, and THF at a ratio of 1:1:1 to afford the acid intermediate (24). Stereochemical resolution of intermediate 24 by using (R)-1 shown-phenyl-ethanamine (110) obtained chiral acid amine salt 111. The yielded amine salt 111 dissolves in water and adjusts the pH to 10 by using the base to afford (S)-2-((R)-2-oxo-4-propyl pyrrolidin-1-yl)butanoic acid (112). In the last step, conversion of acid 112 by using DIPEA, ammonium chloride, and HATU obtained brivaracetam (1). The overall yield is good; however, the loss of half undesired isomer is observed. Later on, the synthesis of brivaracetam was also shown by many research groups using stereochemical resolution of the racemic acid intermediate  The aimed (R)-2-(2-(tert-butoxy)-2-oxoethyl)pentanoic acid (100) was synthesized by using enzymatic resolution of racemic compound 128, for which they screened four families of enzymes and found protease B and C from B. subtilis that exhibit excellent enzymatic performance. Shanghai Yikelai Biomedical Technology Co. Ltd. also reported enzymecatalyzed reaction by hydrolysis of ester to acid in the patent CN109266630A. 79 The enantiomerically pure (R)-succinic acid 100 was selectively reduced to alcohol 57, followed by the addition of TFA to afford butyrolactone (45). Compound 45 further undergoes ring-opening by the nucleophilic substitution reaction in the presence of bromine in acetic acid to afford acid intermediate 122. Intermediate 122 was introduced by esterification to obtain (R)-ethyl 3-(bromomethyl)hexanoate (123). Finally, compound 123 coupled with (S)-2-aminobutanamide (5) yielded aimed at brivaracetam (1).

CONCLUSIONS
In this review, we summarized all the available synthetic strategies reported in the literature. Especially in the last few years, by an enantiomeric scaffold, chiral pool, chiral organocatalysts, and metal complex catalysts, chemical resolution and enzymatic resolution are developed for synthetic approaches used in the method by which chirality is introduced in the brivaracetam molecule. Therefore, with the advancement in catalytic approaches, an impressive progress has been made in the synthesis of brivaracetam.

FUTURE RESEARCH PERSPECTIVE
In the class of AEDs, brivaracetam exhibits 13-fold more affinity toward SV2A than levetiracetam and 400-fold more affinity than piracetam. This rationale converted the interest of the scientific community toward a potent drug, brivaracetam, which boosted the synthesis of brivaracetam involving 24 different routes by using racemic and asymmetric moieties. The explained four different categorizations of synthetic approaches will surely encourage medicinal chemists to develop novel synthetic approaches with higher yields for synthesizing brivaracetam. It has been shown that for brivaracetam, the chiral pool/enantiomeric scaffold method proved to be the best approach in making this drug molecule conveniently. These approaches are even proven to be modest and efficient for brivaracetam synthesis. Using commercially available chiral starting materials to achieve excellent regioselectivity, excellent yield, and minimum chemical waste, further future improvements and modifications in the existing routes or development of novel synthetic routes are required. This review must be obliging for the future development of brivaracetam synthetic novel methodologies and for industrial process chemistry.