A Short Review on Synthetic Advances toward the Synthesis of

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A Short Review on Synthetic Advances towards the Synthesis of Rufinamide, an Antiepileptic Drug R D Padmaja, and Kaushik Chanda Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 26 Mar 2018 Downloaded from http://pubs.acs.org on March 26, 2018

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Organic Process Research & Development

A Short Review on Synthetic Advances towards the Synthesis of Rufinamide, an Antiepileptic Drug R D Padmaja, Kaushik Chanda* Department of Chemistry, School of Advanced Sciences, VIT University, Vellore-632014, India Email: [email protected]

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Graphical Abstract O

O

OH

O

O OH

F O N N N NH2 F Rufinamide

H2C N Cl

MeO O MeO

O COOR

NH2

OMe

2


CCl3

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Abstract: Chronic neurological disorder of the brain is the main reason for the disease, epilepsy which is almost affecting people of all ages. According to the World Health Organization (WHO) estimates, particularly in developing regions of the world nearly 80% people are suffering from different forms of epilepsy. The majority of epileptic seizures are controlled by the use of antiepileptic drugs (AEDs) which are often associated with related side-effects such as blurry vision, fatigue, sleepiness, and stomach upset. Lennox–Gastaut syndrome (LGS) is childhoodonset epilepsy with multiple different types of seizures that impair intellectual development. To treat Lennox-Gastaut syndrome, Novartis developed an antiepileptic drug known as rufinamide containing 1,2,3-triazole ring and manufactured by Eisai as a brand name of Banzel or Inovelon. This review article provides a brief background on the Lennox–Gastaut syndrome (LGS) and summarizes the works of literature on different synthetic routes of an antiepileptic drug, rufinamide that was approved by U.S. FDA in Nov 2008.

Keywords:

Epilepsy,

Lennox–Gastaut

syndrome (LGS),

cycloaddition, Rufinamide,

3


Click

chemistry,

1,3-dipolar


1. Introduction Epilepsy is a group of neurological disorders of the brain, which is affecting people of almost all ages.1 Nearly 80% people of low and medium income countries have suffered from different forms of epilepsy.2 According to the data obtained from World Health Organization (WHO), particularly in developed countries the epileptic seizures occur most commonly in babies and elderly whereas in developing countries the trend is observed mostly in older children and young adults.3 Due to the epileptic seizures, the number of deaths considerably increased recently. In majority of the cases epilepsy can be effectively treated by the use of anticonvulsants4, which are cost-effective.5 However, the cause for the increase in a large number of untreated epilepsy cases could be due to the poor knowledge and humiliation coupled with low importance within the health system, diagnostic facilities, and drug supply.6 Among different forms of epilepsy, Lennox–Gastaut syndrome (LGS) is childhood-onset epilepsy with multiple different types of seizures that impair intellectual development in the early stage of young children.7 The main problem of Lennox–Gastaut syndrome seizures is often treatment resistant. One of the first-line orphan drugs that treats the patients suffering from Lennox–Gastaut syndrome (LGS) seizures is a 1,2,3-triazole ring containing the antiepileptic drug known as rufinamide. The drug obtained by click chemistry approach has been developed by Novartis and manufactured by Eisai as a brand name of Banzel or Inovelon to treat the Lennox-Gastaut syndrome.8 In 2012, sales of Banzel or Inovelon and rufinamide generics stood at $43.3m in US and EU pharmaceutical market.9 Most of the antiepileptic drugs are classified according to their mechanism of actions such as sodium channel blockers, calcium current inhibitors, gamma-aminobutyric acid (GABA) enhancers, glutamate blockers, and carbonic anhydrase inhibitors. However, some antiepileptic drugs work 4


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by acting on the combination of channels or through some unknown mechanism of action. Voltage-gated sodium channels (VGSCs) are a family of membrane proteins which play a crucial role in controlling cellular excitement by selectively regulating sodium ions in and out of cell's plasma membranes in response to deviations of membrane potentials. Recent evidence suggested that the abnormal VGSCs are primarily responsible for epileptic seizures. Most of the antiepileptic drugs such as lamotrigine, carbamazepine, and phenytoin act as sodium channel blockers, thus preventing the revisit of the channels to the active state by stabilizing the inactive form. The mechanism of action of rufinamide is not known. However, from the results of in-vitro studies, it has been suggested that the principal mechanism of action of rufinamide is modulation of the activity of Na channels and in particular, the persistence of the inactive state of the channel. Further, the drug significantly slowed down the Na channel recovery from inactivation after a prolonged prepulse in cultured cortical neurons, and limited persistent frequent firing of sodium dependent action potentials. Click chemistry based strategy in drug discovery is becoming an important component of the pharmaceutical drug market, which offers the coupling of molecular fragments under mild reaction conditions through efficient and chemoselective synthetic pathway.10 Almost 50 years ago, Huisgen and his coworkers developed the triazole ring via 1,3-dipolar cycloaddition reaction between azides and terminal alkynes under thermal conditions.11 However, the cycloaddition reaction is thermodynamically favored and did not show any regioselectivity which involved the formation of both 1,4- and 1,5-regioisomers. After the discovery of click chemistry in 2001, Cu(I) catalyzed 1,3-dipolar cycloaddition reaction is extremely regioselective towards the formation of the 1,4-disubstituted triazole and this approach has been broadly used to construct diverse chemotypes in chemical, biological and material fields.12 Initially, it was believed that the mechanism of the click reaction proceeds via only the 5



mononuclear Cu(I) complex but the recent studies suggested the participation of both the mono and dinuclear copper intermediate. The dinuclear copper pathway is kinetically favored for the click reaction as evidenced by the isolation and spectroscopic characterization of dinuclear copper intermediate.13 Recently, we have observed the ruthenium or silver-catalyzed azidealkyne cycloaddition reaction,14 or copper-free click chemistry15 development in the click chemistry field. 1,2,3-triazole rings formed from azides and terminal acetylenes via Cu(I) catalyzed cycloaddition reaction are often found to have a variety of biological properties which includes the anti-HIV,16 antiallergic,17 antifungal,18 anticancer19 and antibiotic properties. In the past two decades, a large number of scientific reports have appeared in the literature depicting the synthesis of an antiepileptic drug known as rufinamide which clearly states the importance of this type of drug molecule in the pharmaceutical industry for the treatment of Lennox-Gastaut syndrome. Since then several routes have been reported for the synthesis of rufinamide both in industrial as well as in academic arena (Figure 1).

Figure 1. Schematic representation for the synthesis of rufinamide The present synthetic industrial technique for rufinamide synthesis suffers from low yields and complex processes. The synthetic pathway that is commercially used to obtain rufinamide is required to meet many criteria in terms of environmental safety while dealing with hazardous chemicals, control of regioselectivity, and the environmental law issue. Unfortunately, there is no single review which describes the different synthetic pathway both in the commercial and academic arena among those that were published in the literature. The present review deals with 6


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the main innovations regarding the synthesis of rufinamide through industrial and academic approaches which will pave the way to the synthesis of antiepileptic drug rufinamide. The click based core 1,2,3-triazoles moiety in drug molecule described here is a highly diverse entity formed via 1,3-dipolar Huisgen cycloaddition of 2,6-difluorobenzyl bromide/azide with different dipolarophiles. As part of our recent report on the diversity-oriented synthesis of bioactive heterocycles,20 we have highlighted the key developments and challenges to the future design of antiepileptic drug molecule in this review. The discussion and forethought in this review provide key solutions to resolve the current synthetic problems. The content of the review aims to demonstrate the full account of the development activities for the synthesis of rufinamide including the catalyst screening, chemical yield, selectivity, solvents, toxicity, and efficiency. Furthermore, we believe that by assembling all the synthetic techniques on one platform will also provide knowledge about current synthetic progress in the field of antiepileptic drug rufinamide, and from that knowledge, it may be possible to develop new concepts and increase the diversity of rufinamide synthetic processes.

2. Medicinal Chemistry Route to Rufinamide The medicinal chemistry route to rufinamide was first developed by Ciba-Geigy Corporation of United States which after the merger with Sandoz later known as Novartis Corporation. The synthesis of rufinamide was first described in U.S. Patent 4,789,680 starts with 2,6difluorobenzyl bromide 1 (Scheme 1).21 2,6-difluorobenzyl bromide 1 was reacted with sodium azide in presence of DMSO as solvent at room temperature for 2 h to obtain 2,6-difluorobenzyl azide 2 which further underwent 1,3-dipolar cycloaddition reaction with propiolic acid 3 to obtain the 1-(2,6-Difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid 4 at 70 oC for several 7



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hours in toluene as solvent. The choice of propiolic acid as dipolarophile is based on its less toxicity and high reactivity owing to the higher electronic deficiency. Further, the compound 4 is reacted with SOCl2 and distilling out the excess of SOCl2 to get 1-(2,6-difluorobenzyl)-1H-1,2,3triazole-4-carbonyl chloride 5 which subsequently reacted with aqueous ammonia in toluene solution obtained the rufinamide 7. The patent described another process of reacting the 1-(2,6difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid 4 with methanol in presence of H2SO4 to get methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate 6 in good yield which further reacted with methanolic ammonia solution to obtain the corresponding rufinamide 7 in moderate yield. The 1,3-dipolar cycloaddition reaction of 2,6-difluorobenzyl azide 2 with propiolic acid 3 was carried out on a 36 gm scale. The reason behind the moderate yield of rufinamide 7 could be attributed to the formation of a mixture of 1,4- and 1,5-regioisomeric cycloadduct. F

F Br F

NaN3/DMSO

N3

toluene, 70 C

N N N F

24 h

F 2

O

o

OH

+

r.t., 2 h

1

F

O

3

OH

4

F O F O N N N F 4

N N N F

lux ref , l 2 C SO 1h

Methanolic NH3 Toluene, 50 oC for 3 days O

5

OH M co eOH nc Re H2 S f lu x, O4 1h

Cl

F N N N F

F O N N N F

NH2

7 (Moderate yield)

O

6

Scheme 1. Medicinal chemistry route to rufinamide 7 developed by Novartis. In 1998, the further patent application WO1998002423 A1 related to the synthesis of rufinamide has been published by the same innovator company to improve the yield and streamlining the process using different dipolarophile.22 The 2-chloroacrylonitrile 8 has been used as a 8


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dipolarophile which reacts with 2,6-difluorobenzyl azide 2 for 24 h using H2O as the solvent to obtain the intermediate 9 (Scheme 2). The yield of intermediate 9 was varied depending upon the reaction temperature, time, and mol equivalent of 2-chloroacrylonitrile 8. The best condition suited for the 98% yield of intermediate 9 was obtained using 1.5 equivalent of 2chloroacrylonitrile 8 at 80 oC for 24 h on a 34 gm scale. The use of higher equivalents of 2chloroacrylonitrile, solvents like heptane, ethanol, toluene, and N,N-dimethyl formamide did not increase the yield. Further, the excess of 2-chloroacrylonitrile 8 was distilled out from the reaction mixture followed by the hydrolysis of intermediate 9 with NaOH in the presence of toluene as a solvent to obtain the rufinamide 7 in good yield. Although the dipolarophile 2chloroacrylonitrile results in a 1,4-regioisomeric product in good yield yet it is highly toxic and flammable substance.

Scheme 2. Novartis improved route to rufinamide 7. In 2010, Kankan et al of Cipla Limited identified the synthesis of rufinamide on a 5 gram scale using methyl propiolate as dipolarophile in U.S. Patent 8,183,269 (Scheme 3).23 The one-pot synthetic procedure involved the SN2 reaction of 2,6-difluoro benzyl halide 1 with NaN3 in water at 70 oC for 30 h resulted the 2,6-difluorobenzyl azide 2 which further underwent 1,3-dipolar cycloaddition reaction with methyl propiolate 10 to obtain the methyl 1-(2,6-Difluorobenzyl)1H-1,2,3-triazole-4-carboxylate 11 at 60 oC for 3-4 h. Without isolating the intermediate 11, to the same reaction mixture was added with 25% aqueous NH3 solution dropwise and heated the reaction mixture at 75 oC for 4-5 h to obtain the rufinamide 7 in 60% yield. However, on 9



applying the multistep synthetic sequence the yield of the rufinamide was dramatically reduced to 36% as calculated over three steps.

It is to be noted that apart from toxicity and

regioselectivity issues, the high cost of methyl propiolate as a dipolarophile is an obstacle for the large scale production cycle.

Scheme 3. Cipla’s one-pot route to rufinamide 7 using methyl propiolate as a dipolarophile. However, all those patented methods as discussed above have some drawbacks such as poor reaction yield, poor regioselectivity leading to the formation of both 1,4- and 1,5- regioisomers (Figure 2), and multistep synthetic sequence and overheating of the reagents leading to the poor yield

Figure 2. 1,4- and 1,5-regioisomers of rufinamide 7 and 7a prompted the scientists to discover new strategies to synthesize exclusively 1,4-regioisomer of 7. In 2010, an alternative industrial route to the synthesis of rufinamide 7 on a 100 gm scale with safety and high regioisomeric selectivity has been developed.24 The industrial route to the synthesis of rufinamide has been disclosed in the European patent application EP 2,230,234 A1 10


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by the Dipharma Francis S.r.l. of Italy. For the first time, 1,3-dipolar cycloaddition reaction was carried out using monovalent Cu(I) salt or divalent Cu(II) species reduced to Cu(I) by a suitable reducing agent (Scheme 4). The synthetic scheme comprises of the synthesis of 2,6difluorobenzyl azide 2 using NaN3 and tetrabutyl ammonium bromide (TBAB) 2,6-difluoro benzyl halide 1 in water at 40 oC for 1 h. Subsequently, the compound 2 underwent 1,3-dipolar cycloaddition reaction with propiolic acid 3 on a 7 gram scale, methyl propiolate 10 on a 1.5 gram scale, and proiolamide 12 on a 100 gm scale separately using CuSO4 as the catalyst and ascorbic acid as a reducing agent in H2O-tBuOH (1:1) as the solvent for a specified period of time and temperature. In all the three cases, the product rufinamide 7 was obtained in high yields. F O N N N F 4

CuSO4, Ascorbic acid t H2O- BuOH (1:1) Yield=80%

F

F X=Cl, Br, I 1

3

SOCl2, reflux, 1 h 30% aq NH3 r.t Yield= 91%

OH

O

NaN3/H2O TBAB 40 oC 1h

O

o

F X

OH

N3 F 2, 88% yield

NH2 12 CuSO4, Ascorbic acid H2O-tBuOH (1:1)

F

o

Yield=87% O

H2O-tBuOH (1:1)

O 10 CuSO4, Ascorbic acid

o

Yield=87%

O N N N F 7

NH2

30 % aq NH3 MeOH, reflux, 4 h Yield=87%

F O N N N F 11

O

Scheme 4. Dipharma Francis S.r.ls. the highly regioselective route to rufinamide 7

11



In 2012, the further patent application WO2012032540 A1 related to the synthesis of rufinamide on a 10 gram scale published by the Indoco Remedies limited to improve the regioselectivity using propargyl alcohol as a dipolarophile in presence of CuSO4.5H2O, and sodium ascorbate.25 (Scheme 5) The synthetic scheme comprises of the synthesis of l-(2,6-difluorobenzyl)-lH-l,2,3triazol-4-yl methanol 14 using NaN3, tetrabutyl ammonium bromide (TBAB), KI, 2,6-difluoro benzyl bromide 1, and propargyl alcohol 13 using Cu(II) as catalyst in H2O-tBuOH (1:1) as solvent in water at 30 oC for 4 h. The next step involves the oxidation of alcohol to carboxylic acid to introduce the second functional diversity in a bid to obtain the rufinamide. Subsequently, the compound 14 underwent oxidation reaction with ΤΕΜΡΟ as an oxidizing agent in PBS buffer solution for 15 min at 35 oC to obtain the intermediate 4. Finally, the intermediate 4 was refluxed with SOCl2 for 2 h followed by reaction with aqueous ammonia maintaining the temperature at 5-10°C to obtain the rufinamide 7 in excellent yield. The same methodology was applied with other dipolarophiles such as methyl propiolate 10, and propiolamide 12 to obtain the rufinamide in the excellent yield on a 100 gm scale.

Scheme 5. Indoco Remedies new route to rufinamide using propargyl alcohol as dipolarophile. In 2014, Laboratories Lesvi S. L demonstrated an improved method for the preparation of compound 1-(2,6-difuorobenzyl)-1H-1,2,3triazole-4-carboxylic acid 4 which is substantially free 12


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from its 1,5-regioisomer (Scheme 6) on a 10 gram scale. The synthetic methodology was described in U.S. Patent US 8,884,026.26 The invention disclosed the further use of intermediate 4 for the preparation of rufinamide and the new polymorphic form of rufinamide, known as Form R-5. The new polymorph of rufinamide showed good stability along with appropriate physicochemical properties for its synthesis on the industrial scale. Polymorph Form R-5 will be appropriate for the treatment of epilepsy. 2,6-difuorobenzyl chloride 1 was reacted with sodium azide and TBAB using isopropyl acetate as solvent at room temperature for 14 h to obtain the 2,6-difluorobenzyl azide 2 which further underwent 1,3-dipolar cycloaddition reaction with propiolic acid 3 at 50° C for 8 h. Upon completion of the reaction and aqueous workup obtained the

Scheme 6. Laboratories Lesvi S. Ls the new improved route to new polymorphic form of rufinamide R-5. (2,6-difuorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid 4 in 57% yield along with 99.94% UPLC purity. Subsequently, the intermediate 4 was reacted with oxalyl chloride at 0-5 oC under N2 atmosphere using anhydrous THF as a solvent for 2 h. After completion of the reaction, the reaction mixture was treated with 25% aqueous NH3 and NH4Cl in water at 0-5oC for 2 h to

13



obtain the new polymorphic form of rufinamide in 68% yield, known as Form R-5 with only 1,4regioisomer. Subsequently, they have extended the methodology to 200 gram scale also. Later on in the same year, Davuluri et al developed a novel process for the preparation of rufinamide and its intermediates in U.S. Patent 8,871,945 (Scheme 7) on a 100 gram scale.27 Alkyl 2-bromoacrylate 15 was chosen as dipolarophile instead of expensive reagents such as methyl propiolate and propiolamide, which reacted with 2,6-difluorobenzyl azide 2 prepared from 2,6-difluoro benzyl halide 1 with NaN3 in water at 75-80° C for 24 h to obtain the alkyl 1(2,6-difuorobenzyl)-1H-1,2,3-triazole-4-carboxylate 11. Further hydrolysis of the intermediate 11 with aq NaOH at room temperature and refluxed with SOCl2 for 2 h followed by reaction with aqueous ammonia at room temperature to obtain the rufinamide 7 in excellent yield. The invention also highlights the synthesis of alkyl 2-bromoacrylate 15 in presence of a brominating reagent followed by treatment with base.

Scheme 7. Davuluri’s approach to the synthesis of rufinamide using alkyl 2-bromoacrylate as dipolarophile. 3. Synthetic developments Route to Rufinamide

14


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The first synthesis of Rufinamide in academic arena was carried out by Stevens and his coworkers.28 The synthetic method was adopted from earlier reports of Stevens and his group in 2005 where 1,2,3-Triazoles were prepared in good to modest yields by cycloaddition of alkyl azides onto enol ethers under neat conditions.29 Because of poor electron density, the alkenes of enol ethers are less reactive as compared to enamine alkenes which makes them unsuitable for azide cycloaddition reaction. However, to enhance the reactivity of alkenes of enol ethers and cycloaddition rate, the azide–enol ether cycloadditions were performed at 200 °C in a sealed tube without solvent for 6 h to obtain the desired triazole products in modest yield. Prompted by this observation, methyl 3-methoxyacrylate 16 was chosen as dipolarophile which reacted with 2,6difluorobenzyl azide 2 to obtain the methyl 1-(2,6-difuorobenzyl)-1H-1,2,3-triazole-4carboxylate 11 (Scheme 8). Interestingly, the use of 3-methoxy acrylonitrile as dipolarophile in 1,3-dipolar cycloaddition resulted in the generation of two regioisomers.

Scheme 8. Stevens’s two-pot and one-pot syntheses of rufinamide 7. The azide–enol ether cycloaddition reaction was carried out under solvent less condition at 135 o

C for 28 h to obtain the intermediate 11 in 85% yield. Subsequently, the ammonolysis of ester

11 proceeds smoothly in 7M methanolic NH3 solution at room temperature for 18 h to obtain the rufinamide 7 in 79% overall yields. Further, it has been observed that the most of the waste is 15



generated during the second step of ammonolysis of intermediate 11. However, in order to avoid the waste generation, the ammonolysis reaction was tried by reducing the volume of methanolic ammonia which resulted in the lengthening of the reaction time. Interestingly the same synthetic sequence was applied for 35 gm scale of 2,6-difluorobenzyl azide 2 as a one-pot process which obtained the rufinamide in 89% overall yields. Furthermore, the E-factor which determines the amount of waste generated per kilogram of the product was 14.6 for the one-step synthetic process as compared to the nitrile route with an estimated overall E-factor of 20.2. The use of nontoxic and inexpensive methyl 3-methoxyacrylate as a dipolarophile resulted in the exclusive formation of 1,4-cycloaddition adduct owing to the presence of a methoxy leaving group. In 2013, Hessel and co-workers developed an alternative methodology to 1,3-dipolar cycloaddition to the rufinamide precursor using continuous-flow reaction technology which can considerably enhance the catalyst-free synthesis of the rufinamide precursor in high yields.30 The advantages associated with continuous-flow reaction technology over conventional batch chemistry are safer reaction profile involving hazardous materials, gas evolution, high pressure reaction, followed by the rapid route to scale-up, and integrating the downstream process and reagent screening. However, in view of the instability of the azide component, there is always a serious safety issue in a conventional batch experiment as the 1,3-dipolar cycloaddition reaction required the intense heating of 28 h for 135 oC without using any solvent. To ensure the safety and to fulfill the requirements of industry, a catalyst-free and solvent-free continuous-flow methodology was developed which involves the purging of reactants methyl 3-methoxyacrylate 16 and 2,6-difluorobenzyl azide 2 into the reactor. In an effort to maintain the homogeneous reaction condition, the entire reactor coil was heated above the melting point of the product at 210 °C accompanied by a residence time of 10 min (Scheme 9). The final product of rufinamide 16


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precursor 11 was obtained in 30 min for 83% yield from cooling zone after a slow stream of MeOH or MeCN was introduced into the mixing zone of the reactor. The reaction was carried out on a 34 gram scale.

Scheme 9. Catalyst and solvent-free continuous-flow methodology for the synthesis of rufinamide precursor 11. In the same year, Huang et al reported the synthesis of rufinamide 7 on a 1mM scale catalyzed by rhombic dodecahedral Cu2O nanocrystals in a one-pot synthetic pathway.31 The aim of this study was to demonstrate the facet dependent catalytic activity of different shapes of Cu2O nanocrystals for 1,3-dipolar cycloaddition to triazole formation. For the purpose, cubic, octahedra, and rhombic dodecahedral shapes of Cu2O nanocrystals were prepared by the procedure developed by Huang group.32 In this report, rhombic dodecahedral Cu2O nanocrystals bounded by {110} facets were shown catalytically active than Cu2O octahedra revealing {111}

17



facets, whereas Cu2O nanocubes displayed the slowest catalytic activity for the multicomponent synthesis of 1,2,3-triazoles.

Scheme 10. Cu2O rhombic dodecahedral nanocrystal catalyzed synthesis of rufinamide 7. For the first time, rufinamide 7 could be synthesized through a multi-component coupling reaction by employing 2,6-difluorobenzyl bromide 1, NaN3, and propiolamide 12 (Scheme 10). In this multicomponent reaction, Cu2O rhombic dodecahedra bounded by {110} facets were selected as the catalysts. Interestingly, the multicomponent cycloaddition reaction obtained rufinamide 7 at 55 ºC in EtOH as the solvent for 2.5 h with 95% yield. The next year, Jamison et al developed the continuous flow total synthesis of rufinamide 7 on a 1M scale using commonly available chemicals.33 The aim of this study was to develop the continuous flow technology using benzyl bromide as the primary precursor. Initially, 2,6difluorobenzyl azide 2 was obtained in a continuous flow via SN2 substitution reaction of benzyl bromide 1 with azide nucleophiles in 1 min using DMSO as a solvent (Scheme 11). Next sequence of the reaction involves the continuous flow synthesis of propiolamide 12 where as both the propiolamide 12 and methyl propiolate 10 have a very high tendency to polymerization.34 Using an optimum condition, propiolamide 12 was synthesized by reacting methyl propiolate 10 with 4 equiv of NH4OH at 0 °C for 5 min in continuous flow technique. Mixing the two reaction-streams did not cause any solid formation whereas the increase in

18


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reaction temperature to 140 oC for 6 min obtained the rufinamide 7 in 10% yield with the formation of 1,5-regioisomers.

Scheme 11. Continuous flow total synthesis of rufinamide 7. Nevertheless, to obtain the regioselective formation of rufinamide 7 in high yield, Cu tubing as the reactor material was used. Interestingly, the yield of the rufinamide 7 was increased dramatically to 82% under identical reaction conditions with greater than 20:1 regioselectivity. Further, screening of the reaction temperature and pressure identified as the optimal temperature should be at 110 °C for 100 psi BPR in 6.2 min residence time resulting in the 98% yield of rufinamide 7. The main advantages of this methodology involve the in-line synthesis of costly and unstable propiolamide free from polymerization or storage and also without the need for further functional group transformation. In 2015, Wang and Li disclosed better methodology for accessing rufinamide 7 via an organocatalytic 1,3-dipolar cycloaddition reaction of α,β- unsaturated esters with azides (Scheme 12).35 Initial investigation of 1,3-dipolar cycloaddition reaction of α,β- unsaturated esters with azides revealed the tertiary amine DBU, which serves as the best catalyst among various primary amines and phosphine catalysts. 2,6-difluoro benzyl azide 2 again serves as the starting material, which underwent the 1,3-dipolar cycloaddition reaction with α,β- unsaturated ester 16 under the 19



neat condition to furnish rufinamide precursor 11 in 85% yield. The 1,3-dipolar cycloaddition reaction was catalyzed by 10 mol% of the DBU. The next step of the synthetic sequence involves the ammonolysis of the intermediate 11 under room temperature condition for 24 h obtained the corresponding rufinamide 7 in 89% yield.

Scheme 12. DBU catalyzed synthesis of rufinamide 7. Interestingly, the mechanism of the reaction involves the formation of zwitterion by reacting DBU with methyl acrylate. Next, the zwitterion reacted with organic azide followed by elimination of MeOH and successive cascade sequence of electrocyclization obtained the cycloaddition product. In the same year, Bonacorso pursued a novel method for the synthesis of rufinamide 7 on a 170 mg scale.36 Starting from 2,6-difluoro benzyl azide 2, within two steps the desired moiety is achieved in 42% overall yield. The methodology based on the use of trichloroacetyl group substituted enones 17 as dipolarophile under the neat condition for 2 days at 135 oC reacted with 2,6-difluoro benzyl azide 2 to obtain the triazoles 18. Further, the triazole derivative 18 was subjected to a reaction with an aqueous solution of NH4OH obtained rufinamide 7 in 42% yields (Scheme 13).

20


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F

F

O N3

+ MeO

17

One-pot strategy

O + MeO

CCl3 25 oC, 30 min

N N N F

O NH2

7 (42 % yield)

F

1. Neat, 135 oC, 48 h CCl3

F 2

NH3 in MeOH

18 (42 % yield)

F N3

O

N N N F

CCl3

F 2

F

neat, 135 oC, 48 h

2. NH4OH, MeOH 25 oC, 30 min

N N N F

O NH2

7 (50% yield)

17

Scheme 13. Synthesis of rufinamide 7 using trichloroacetyl group substituted enones under neat condition. In an attempt to improve the yield and to reduce the synthetic steps, the domino process was employed which involves the synthesis of rufinamide 7 directly, without isolation of the trichloroacetyl-substituted 1H-1,2,3-triazole 18. After the initial cycloaddition to trichloroacetylsubstituted 1H-1,2,3-triazole 18, 33% aqueous solution of NH4OH was added to the reaction mixture in the presence of MeOH at room temperature for 30 min produced rufinamide 7 in 50% yield. Again in the year 2016, Hessel and his coworkers developed an uninterrupted continuous flow process towards rufinamide precursor using 2,6-difluoro benzyl alcohol on a 25 gram scale.37 In an attempt to minimize the waste formation, and to develop the green protocol 2,6-difluoro benzyl alcohol 19 was chosen as a starting material instead of using 2,6-difluoro benzyl bromide/chloride. 2,6-difluoro benzyl alcohol 19 was converted to chloride intermediate by using pure hydrogen chloride gas which generates water as the sole by-product which further converted to azide derivative 2. The rufinamide precursor 11 was obtained in 88% isolated yield by reacting 2,6-difluorobenzyl azide 2 with 3-methoxyacrylate 16 via 1,3-dipolar cycloaddition. The uninterrupted continuous flow process shows chemical and process-design amplification 21



aspects covered by novel process windows where single reaction steps are chemically strengthened via a variety of conditions available in a microreactor environment.38 Scheme 14 demonstrates the 5-stage 3-step continuous synthesis with integrated separation steps resulting in a total yield of 82% based on 2,6-difluoro benzyl alcohol 19 used and productivity of 9 g h−1 for rufinamide precursor 11.

Scheme 14. Schematic illustration of 5-stage 3-step continuous flow synthesis of rufinamide precursor 11. The major advantages associated with this process are the reduction of operating time, higher yields, use of cheaper, greener and more readily available starting material, outwitting the solvent use, demand-based production capacity, and inline separation results in a more concentrated intermediate. This year our group developed a novel method for the synthesis of rufinamide 7 on a 1 gram scale using 2,6-difluro benzyl bromide 1 as a substrate and propiolamide 12 as a dipolarophile in the presence of 0.5 mol% [Cu(phen)(PPh3)2]NO3.39 The study was carried out initially with 2,6difluro benzyl azide 2 with propiolamide 12 using 0.5 mol% Cu(I) as homogeneous catalyst in refluxing EtOH as solvent which resulted in the yield of rufinamide 7 upto 70%. By changing the 22


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reaction solvent system to H2O, the yield was increased upto 75%. However, in order to avoid the potentially explosive organic azides, we used the one-pot multicomponent strategy. The onepot synthetic sequence involves the reaction of 2,6-difluoro benzyl bromide 1 with NaN3 in water at 60 oC for 1 h to generate the in-situ 2,6-difluoro benzyl azide 2 which further reacted with propiolamide 12 using 0.5 mol % of [Cu(phen)(PPh3)2]NO3 for 1 h as catalyst to obtain the rufinamide 7 in 95 % overall yield (Scheme 15). F

F

F Br F 1

NaN3 H2O, 60 oC, 1 h

N3 + F 2 Not isolated

N

NH2

Cu(I) catalyst

O

H2O, 60 oC, 1 h

12

F

N

N NH2

O 7 (95% yield)

Cu(I) catalyst=[Cu(phen)(PPh3)2]NO3

Scheme 15. Novel Cu(I) catalyzed one-pot multicomponent synthetic strategy to rufinamide 7.

4. Conclusions & future research direction

This review summarizes all the available synthetic techniques for rufinamide. The aim of this review is to point out recent advances in the field of synthesis of rufinamide and to encourage chemists to design and develop new synthetic routes to rufinamide. Here we first give a smart summary of all the techniques which involve the seven routes to rufinamide in patents and journal articles. It has been shown that for rufinamide, the best overall yield 95% is obtained from the multicomponent Cu(I) catalyzed 1,3-dipolar cycloaddition, while the Novartis synthesis technique produces moderate yield with a mixture of 1,4 and 1,5-regioisomers. The multi component Cu(I) catalyzed approach for rufinamide is the most modern and efficient green synthetic approach because it offers the highest flexibility in making drug molecule using green pathway without generating highly explosive organic azides. In an attempt to achieve excellent 23



yield, excellent regioselectivity, and minimum chemical waste, further improvement and modification of these methodologies are required. The review should be very helpful for the further development of rufinamide synthetic methodologies and for process chemistry.

5. Acknowledgements The authors thank the Chancellor and Vice Chancellor of VIT University for providing opportunity to carry out this study. Further the authors wish to thank the management of this university for providing seed money as the research grant. Kaushik Chanda thanks, CSIR-Govt of India for funding through Grant no 01(2913)/17/EMR-II.

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Biographies

R D Padmaja received her MSc degree in 2012 from the VIT University, Vellore Tamilnadu In 2012, She started her Ph.D. in organic chemistry under the supervision of Prof.Kaushik Chanda from 2016. Her current research efforts are focused on green organic synthesis, nanoparticle synthesis and the synthesis of biologically active heterocycles.

Dr Kaushik Chanda, obtained his MSc in Organic Chemistry from Guwahati University, Assam India in 2001. Subsequently worked as a Senior Research Fellow in ICAR-NATP funded project

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in St Anthonys College, Shillong, India from 2002-2005. In 2006, he moved to Taiwan for pursuing PhD in Applied Chemistry from National Chiao Tung University under the guidance of Prof Chung Ming Sun on a topic of Combinatorial Chemistry. After finishing his PhD in 2010, he moved to Department of Chemistry, National Tsing Hua University, Taiwan for NSCpostdoctoral fellowship in facet dependent organic catalysis with Prof Michael H Y Huang. Now he is working as an Assistant Professor in Department of Chemistry, VIT University, Vellore. His research interest includes the diversity oriented synthesis, anticancer drug design, drug delivery and nanocatalysis.

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A Short Review on Synthetic Advances toward the Synthesis of

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