WO2014121383A1

WO2014121383A1 - A process for the preparation of rufinamide and intermediates thereof

Info

Publication number: WO2014121383A1
Application number: PCT/CA2014/000097
Authority: WO
Inventors: Prabhudas Bodhuri; Stuart P. GREEN; Avedis KARADEOLIAN; Eduardo Gustavo Cammisa
Original assignee: Apotex Technologies Inc.
Priority date: 2013-02-11
Filing date: 2014-02-11
Publication date: 2014-08-14

Abstract

Provided are processes for the preparation of rutinamide and compounds which are intermediate compounds used in the processes for the preparation of rutinamide. Rutinamide is an anticonvulsant drug that is used in combination with other antiepileptic medicaments for the treatment of a rare form of epilepsy, Lennox-Gastaut syndrome. Formula (I)

Description

A PROCESS FOR THE PREPARATION OF RUFINAMIDE AND

INTERMEDIATES THEREOF

TECHNICAL FIELD

The present invention relates to the field of synthesis of organic compounds and in particular to a method for the synthesis of rufinamide and intermediates thereof.

BACKGROUND

Rufinamide of formula (1 ) is an anticonvulsant drug that is used in the combination therapy with other antiepileptic medicaments for the treatment of a rare form of epilepsy called Lennox-Gastaut syndrome. Rufinamide is a triazole derivative with the chemical name 1 -(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4- carboxamide.

(1 )

US 4789,680 discloses 1-phenyl-lower alkyl-1 H-1 ,2,3-triazole compounds of the formula (I) in which Ph represents phenyl substituted by up to and including 3 substituents selected from lower alkyl, halogen and trifluoromethyl, alk represents lower alkylidene, and wherein either R represents hydrogen, lower alkyl, lower alkoxy, amino, N-lower alkylamino, N,N-di-lower alkylamino, N- lower alkanoylamino, carbamoyl, N-lower alkanoylcarbamoyi, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl and R² represents carbamoyl, N- lower alkanoylcarbamoyi, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl or R¹ represents carbamoyl, N-lower alkanoylcarbamoyi, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl and R² represents hydrogen or lower alkyl, have anti-convulsive properties and can be used as medicaments.

WO 98/02423 discloses a process for the preparation of a compound of Formula:

in which R¹ is an aromatic or heteroaromatic radical, aromatic-aliphatic or heteroaromatic-aliphatic radical, a heterocyclic radical, a cycloaliphatic radical, a cycloaliphatic-aliphatic radical or an aliphatic radical, which comprises reacting a compound of the formula R1 -N3 in which R-i is defined as indicated above, with the compound of Formula:

in a two-phase system.

US 8,198,459 discloses a novel process for the regioselective preparation of rufinamide.

WO 2010/043849 discloses a process for the preparation of rufinamide, which process comprises: i) reacting a 2,6-difluorobenzyl halide of the Formula:

wherein X is chloride, bromide or iodide, with an azide to obtain 2-(azidomethyl)- 1 ,3-difluorobenzene; ii) reacting 2-(azidomethyl)-1 ,3-difluorobenzene with methyl propiolate to obtain methyl 1-(2,6-difluorobenzyl)-1H-1 ,2,3-triazole-4-carboxylic acid; and iii) reacting methyl 1 -(2,6-difluorobenzyl)-1H-1 ,2,3-triazole-4-carboxylic acid with ammonia to obtain rufinamide. WO 2012/025936 discloses a process for the preparation of 1 -(2,6- difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide commonly known as rufinamide and intermediates thereof.

WO 2012/032540 discloses a process for the preparation of 1-[(2,6- difluorophenyl)methyl]-1 H-1 ,2,3-triazole-4-carboxamide, comprising

regioselective cycloaddition of 2,6-difluorobenz l halide of the Formula:

wherein X is chloride, bromide or iodide; with a compound of the Formula:

in which R is -COOR-i, wherein Ri is hydrogen, C1 -C4 linear or branched alkyl group, or -CN, or -CONH₂, or -CH₂OR₂ wherein R₂ is hydrogen or hydroxyl protecting group; in presence of an azide, Cu(l) species and a catalyst.

WO 2011/135105 discloses a method for the preparation of compound 1- (2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxylic acid substantially free of its 3H-I isomer. The invention also refers to the use of said intermediate for the preparation of rufinamide and for obtaining a new polymorphic form of rufinamide, designed as Form R-5. The invention also refers to said new polymorph of rufinamide, and to the composition containing it and its use as medicament. The new polymorph of rufinamide shows good stability and appropriate physico-chemical properties for its manipulation on industrial scale. Polymorph Form R-5 will be suitable to use as pharmaceutical for the treatment of convulsions, especially for the treatment of epilepsy.

Stevens et al. report in Tet. Lett, 2010, 51, 3229 a two-step, one-pot synthesis of rufinamide, an antiepileptic drug. 2,6-Difluorobenzyl azide reacts with methyl 3-methoxyacrylate followed by methanolic ammonia to afford rufinamide in 89% yield.

Arava et al. report in Der Pharma Chemica, 201 1 , 3, 7, 381 a new protocol for the facile synthesis of rufinamide and allopurinol medicaments by the utilization of Λ/,/V-dimethylamino acrylate derivatives.

Wang et al. report in Progress in Natural Science, 2006, 16, 9, 925, that substituted benzyl azids were synthesized through the reaction of substituted benzyl chloride and sodium azid, which subsequently underwent cyclization with ethyl propiolate and amidation to give thirteen 1 -substituted

benzyl-N-substituted-1 ,2,3-triazole-4-formamide derivatives. The structure of the synthesized compounds was confirmed by IR, H-NMR, MS and elemental analysis. Their anticonvulsant activity against maximal electrolshock (MES) induced seizure was tested and the result showed that all these compounds possess anticonvulsant activity in different degrees. Among those, the compounds containing chloro atoms on the phenyl ring were less potent in anticonvulsant activity, while introducing one or two fluorin atoms on benzyl system increased its activity. Furthermore, their activity decreased when there was substituent on the nitrogen atom of carboxamide, and the larger the substituent, the lower the activity.

SUMMARY

The present invention is based, at least in part, on processes for preparation of rufinamide and/or compounds that are intermediate compounds with such processes and/or preparation of such intermediates.

In illustrative embodiments of the present invention, there is provided a process for the preparation of rufinamide comprising: i. reacting a compound of Formula 2:

thereby forming a compound of Formula 4: 4 wherein A is an activated carboxylic acid group; and ii. converting the compound of Formula 4 to rufinamide.

In illustrative embodiments of the present invention, there is provided a process described herein wherein the activated carboxylic acid group is selected from the group consisting of: a reactive ester group, a reactive anhydride group, a reactive cyclic amide group and a halomethyl carbonyl group.

In illustrative embodiments of the present invention, there is provided a process described herein wherein A is selected from the group consisting of: a /V-hydroxy ester group, a substituted aryl ester group, an alkenyl ester group, a substituted alkenyl ester group, a carbonyloxydioxoborolane group and a thioester group.

In illustrative embodiments of the present invention, there is provided a process described herein wherein A is a /V-hydroxy ester group.

In illustrative embodiments of the present invention, there is provided a process described herein wherein the /V-hydroxy ester group is selected from the roup consisting

In illustrative embodiments of the resent invention, there is provided a

process described herein wherein A is:

In illustrative embodiments of the present invention, there is provided a process described herein wherein A is a substituted aryl ester group.

In illustrative embodiments of the present invention, there is provided a process described herein wherein A is COOB(R¹)_n , n is 1 or 2, wherein when n is 1 , R forms a ring group with the boron to which it is bonded and A is of the

fc) I

I L _A

Formula: 0~^R , R is selected from the group consisting of: alkyl, substituted alkyl, aryl, substituted aryl, arylalkyi and substituted arylalkyi; and when n is 2, each R¹ is independently selected from the group consisting of -O-alkyl, substituted -O-alkyl, -O-aryl, substituted -O-aryl, -O-arylalkyl substituted -O-arylalkyl. In illustrative embodiments of the present invention, there is provided a process described herein wherein A is COSG and G is selected from the group consisting of: phenyl, nitro-substituted phenyl and lower alkyi.

In illustrative embodiments of the present invention, there is provided a process described herein wherein A is COOG and G is selected from the group consisting of: 4-nitrophenyl, 4-methylsulfonylphenyl, 2,4,5-trichlorophenyl and 2,3,4,5,6-pentachlorophenyl.

In illustrative embodiments of the present invention, there is provided a process described herein wherein A is selected from the group consisting of: a disubstituted phosphoric acid anhydride group, an organic acid anhydride group, a carbonic ester anhydride group and an organic sulfonic acid anhydride group.

In illustrative embodiments of the present invention, there is provided a process described herein wherein A is COOG, G is selected from the group consisting of: COR², S0₂R² and PO(OR³)₂, R² is selected from the group consisting of: alkyi, substituted alkyi, aryl, substituted aryl, arylalkyi, substituted arylalkyi, alkyloxy, substituted alkyloxy ethynyl and alkenyloxy; and R³ is lower alkyi.

In illustrative embodiments of the present invention, there is provided a process described herein wherein G is COR² and R² is selected from the group consisting of: lower alkyi, alkyloxy and alkenyloxy.

In illustrative embodiments of the present invention, there is provided a process described herein wherein the reacting of the compound of Formula 2 with the compound of Formula 3 is performed in a solvent selected from the group consisting of: alkyi esters, Λ/,/V-dialkylamides and sulfoxides.

In illustrative embodiments of the present invention, there is provided a process described herein wherein the compound of Formula 3 is prepared from propiolic acid.

In illustrative embodiments of the present invention, there is provided a process described herein wherein rufinamide is the only compound isolated. In illustrative embodiments of the present invention, there is provided a process described herein wherein the reacting of the compound of Formula 2 with the compound of Formula 3 is conducted in the presence of a copper (I) catalyst.

In illustrative embodiments of the present invention, there is provided a process described herein wherein the copper (I) catalyst is selected from the group consisting of: Cul, CuCI, CuBr, CuF, Cu₂0 and CuSCN.

In illustrative embodiments of the present invention, there is provided a process described herein wherein the copper (I) catalyst is generated in situ by reacting a copper (II) salt with a reducing agent.

In illustrative embodiments of the present invention, there is provided a process described herein wherein the copper (II) salt is selected from the group consisting of: CuS0₄, CuCI₂, CuBr₂, CuF₂, Cu(OH)₂, Cu(N0₃)₂, Cu(CI0₄)₂, Cu(ll)-D-gluconate and CuO.

In illustrative embodiments of the present invention, there is provided a process described herein wherein the copper (II) salt is CuS0₄.5H₂0.

In illustrative embodiments of the present invention, there is provided a

compound of Formula 4: ⁴ wherein A is selected from the group consisting of: a reactive ester group, a reactive anhydride group, a reactive cyclic amide group and a halomethylcarbonyl group.

In illustrative embodiments of the present invention, there is provided a compound described herein wherein A is selected from the group consisting of: a /V-hydroxy ester group, a substituted aryl ester group, an alkenyl ester group, a substituted alkenyl ester group, a carbonyloxydioxoborolane group and a thioester group. In illustrative embodiments of the present invention, there is provided a compound described herein wherein the compound is selected from the group consisting of:

In illustrative embodiments of the present invention, there is provided a compound described herein wherein A is COOG, G is COR²; and R² is selected from the group consisting of: lower alkyl, alkyloxy and alkenyloxy.

Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying figures.

DETAILED DESCRIPTION

As used herein, the term "alkyl" by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, having the number of carbon atoms designated (for example, C-I-C-I O or 1- to 10-membered means one to ten carbons). In the absence of a designated number of carbon atoms, the value of 1- 10 may be inferred Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

The term "lower alkyl" comprises straight chain or branched chain saturated hydrocarbon groups having 1 to 4 carbon atoms, for instance, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and t-butyl. Lower alkyls may be substituted or unsubstituted.

As used herein, the term "aryl" by itself or as part of another substituent, means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (often from 1 to 3 rings) which are fused together or linked covalently. "Aryl" includes, but is not limited to, "heteroaryl" groups. "Heteroaryl" refers to an aryl group that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally

quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl and heteroaryl groups include: phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4- oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,

2- thiazolyl, 4-thiazolyl, 5-thazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridinyl,

3- pyridinyl, 4-pyridinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1- isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6- quinolyl. The term "aryl" when used in combination with other terms (for example, aryloxy, arylthioxy, arylalkyi) includes both aryl and heteroaryl rings as defined herein. Thus, the term "arylalkyi" is meant to include those radicals in which an aryl group is attached to an alkyl group (for example, benzyl, phenylethyl, pyridylmethyl, etc.) including those alkyl groups in which a carbon atom containing group (for example, a methylene group) has been replaced by, for example, an oxygen atom (for example, phenoxymethyl, 2-pyridyloxymethyl, 3-(1 -naphthyloxy)propyl, etc).

As used herein, the term "substituted" refers to the replacement of a hydrogen atom on a compound with a substituted group. A substituent may be a non-hydrogen atom or multiple atoms of which at least one is a non-hydrogen atom and one or more may or may not be hydrogen atoms. For example, without limitation, substituted compounds may comprise one or more substituent's selected from the group consisting of: OR", NR"R", SR", halogen, OC(0)R", C(0)R", C0₂R", CONR"R"', NR'"C(0)₂R", S(0)R", S(0)₂R", CN, and N0₂. As used herein, each R", R'", and R"" may be selected, independently, from the group consisting of: hydrogen, halogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkyl and arylalkyi groups.

As used herein, the term "activated carboxylic acid group" is a COOH group that has been made more reactive to nucleophilic displacement compared to the free carboxy by the replacement of the OH group with an activating group and which does not include hydrocarbyl ester groups such as alkyl ester groups, arylalkyi ester groups and aryl ester groups. In some embodiments, the activated carboxylic acid group is a reactive ester group, a reactive anhydride group, a reactive cyclic amide group or a halomethyl carbonyl group.

As used herein, the term "reactive ester group" refers to /V-hydroxy ester groups (obtainable, for example, from reaction of the acid, in the presence of a suitable coupling agent, with an /V-hydroxyamino compound, an /V-hydroxyamido compound or an /V-hydroxyimido compound, for example A/-hydroxysuccinimide, /V-hydroxyphthalimide, /V-hydroxypiperidine, 1 -hydroxybenzotriazole, 3-hydroxy- 3,4-dihydrobenzotriazin-4-one, 7-aza-1 ,2,3-benzotriazol-1 -ol or N- hydroxysuccinimide-3-sulfonic acid), substituted aryl ester groups (obtainable, for example, from reaction of the acid, in the presence of a suitable coupling agent, with a suitably substituted phenol, for example, 4-nitrophenol, 4- methylsulfonylphenol, 2,4,5-trichlorophenol or 2,3,4,5,6-pentachlorophenol), alkenyl ester groups (obtainable, for example, from transesterification of a corresponding ester of the acid with an alkenyl ester, for example, vinyl acetate), substituted alkenyl ester groups (obtainable, for example, from reaction of the acid with a lower alkyloxyacetylene, for example methoxyacetylene), thioester groups (obtainable, for example, from reaction of the acid with a substituted or unsubstituted thiol, for example, nitro-substituted thiophenol) and

carbonyloxydioxoborolane groups (obtainable, for example, from reaction of the acid with a borane compound, for example, catechol borane).

As used herein, the term "reactive anhydride group" refers to anhydrides with disubstituted phosphoric acid (obtainable, for example, from reaction of the acid with, for example, phosphorus oxychloride), anhydrides with organic acids such as mixed anhydrides with organic carboxylic acids (obtainable, for example, from reaction of the acid with an organic carboxylic acid halide, for example, phenylacetic acid chloride, pivalic acid chloride, trifluoroacetic acid chloride or propiolic acid chloride), anhydrides with carbonic acid derivatives, such as carbonic acid esters (obtainable, for example, by treatment of the acid with haloformic acid ester, for example ethyl chloroformate or isopropenyl

chloroformate) and anhydrides with organic sulfonic acids (obtainable from reaction of the acid with a suitable sulfonic acid halide, for example, methane sulfonic acid halide or p-toluene sulfonic acid halide).

As used herein, the term "reactive cyclic amide group" refers to cyclic amide groups (obtainable from reaction of the acid, in the presence of a suitable coupling agent, with a suitable cyclic amine, for example, benzotriazole, pyrrole, triazole, tetrazole or indole).

As used herein, the term "alkenyl" refers to an alkyl group in which the atom bearing the radical electron also forms a double bond with another carbon atom, which carbon atom is part of the alkenyl moiety. In other words, the 'linking atom' in an alkenyl is a carbon atom that forms a bond with another moiety (often to an oxygen atom on the other moiety) and also forms a double bond with another carbon atom in the alkenyl moiety. Examples of alkenyls include, but are not limited to, vinyl, 1 -methyl vinyl and cyclopentenyl.

In illustrative embodiments of the present invention, there is provided a a process for the preparation of rufinamide comprising:

i. reacting a compound of Formula 2:

with a compound of Formula 3:

H— thereby forming a compound of Formula 4:

wherein A is an activated carboxylic acid group; and

ii. converting the compound of Formula 4 to rufinamide.

The reaction between the compound of Formula 2 and the compound of Formula 3 may be conducted in a first solvent. The first solvent may be selected from the group consisting of: ethers (for example, tetrahydrofuran, dioxane, diethyl ether, methyl t-butyl ether, diisopropyl ether, butyl ether, diphenyl ether, and/or methylphenyl ether), alcohols (for example, methanol, and/or ethanol), alkyl esters (for example, ethyl acetate, and/or isopropyl acetate), alkyl ketones (for example, acetone, methyl ethyl ketone, and/or methyl isobutyl ketone), aromatic

hydrocarbons and aliphatic hydrocarbons (for example, toluene, xylenes, hexanes, and/or heptanes), nitriles (for example, acetonitrile, propionitrile, butyronitnle, and/or benzonitrile), Λ/,/V-dialkylamides (for example, Λ/,/V-dimethylformamide, N,N- dimethylacetamide, and/or /V-methyl-2-pyrrolidinone), sulfoxides and sulfones (for example, dimethyl sulfoxide and/or sulfolane), halogenated hydrocarbons (for example,dichloromethane and/or dichloroethane), and mixtures thereof.

In illustrative embodiments of the present invention, a process is provided wherein the compound of Formula 3 is prepared from propiolic acid.

Compounds of Formula 3 wherein A is a /V-hydroxy ester group or a cyclic amide group may be produced by a reaction between propiolic acid and a corresponding hydroxyamine, hydroxyamide, hydroxyimide or cyclic amine in the presence of an appropriate amide coupling reagent. Appropriate amide coupling reagents may be selected from the group consisting of: dicyclohexylcarbodiimide (DCC), ethyldimethylaminopropylcarbodiimide (EDC), propylphosphonic anhydride (®T3P), BOP-CI, TBTU, HBTU and HATU.

Compounds of Formula 3 wherein A is a substituted aryl ester group may be produced by a reaction between propiolic acid and a corresponding phenol wherein, if necessary, generated water is removed using a suitable mechanism, such as a Dean-Stark apparatus. Alternatively, the compounds may be prepared by a reaction between propiolic acid and the corresponding phenol in the presence of a suitable coupling reagent such as dicyclohexylcarbodiimide (DCC).

Compounds of Formula 3 wherein A is a halomethyl carbonyl group may be formed by a reaction between lithium acetylide and trihaloacetic anhydride or between lithium acetylide and trihaloacid halide.

In illustrative embodiments of the present invention, the reacting of the compound of Formula 2 with the compound of Formula 3 is conducted in the presence of a copper (I) catalyst. The copper (I) catalyst may be a compound of copper (I) having the formula CuX, wherein X is a monovalent anion. The monovalent anion may be organic or inorganic. An inorganic anion may be, for example, a halide or hexafluorophosphate. An organic anion may be acetate, cyanide, thiocyanate, thiophenolate or trifluoromethanesulfonate. The copper (I) catalyst may be Cu₂0. The copper (I) catalyst may be generated in situ by reaction between a copper (II) salt of the formula CuX_n and a suitable reducing agent, wherein n is 1 or 2 and X is a monovalent anion (when n is 2) or a bivalent anion (when n is 1 ). A monovalent anion may be, for example, a halide, nitrate, hydroxide, perchlorate, tetrafiuoroborate, trifluoroacetate, formate, acetate, acetylacetonate, trifluoromethanesulfonate, cyanide or D-gluconate. A bivalent anion may be, for example, sulfate, tartrate or carbonate. The copper (II) catalyst may be CuO. A suitable reducing agent may be selected from the group consisting of: ascorbic acid, ascorbic acid salts, fructose, glucose, sodium bisulfate and sodium metabisulfite.

The catalyst to substrate molar ratio may be from about 0.01 % to about 2%. In some embodiments, the molar ratio is from about 0.1 % to about 1 %.

The molar ratio of reducing agent to copper (II) salt is at least

stoichiometric and may range from about 1 : 1 to about 10: 1.

The compound of Formula 4 may be further converted to rufinamide by treatment with a suitable ammonia source. The suitable ammonia source may be neat ammonia or it may be a solution of ammonia in an aqueous solvent or an organic solvent. The suitable ammonia source may be ammonia gas or liquid ammonia. The suitable ammonia source may be diaminomethane dihydrochloride in the presence of a base or ammonium chloride in the presence of a base. The reaction of the compound of Formula 4 with a suitable ammonia source may be conducted in a second solvent. The second solvent may be water or a suitable protic organic solvent or aprotic organic solvent. The second solvent may be selected from the group consisting of: alcohols (for example, methanol, ethanol, propanol, isopropanol, and/or butanol), ethers (for example, tetrahydrofuran, dioxane, diethyl ether, methyl t-butyl ether, diisopropyl ether, butyl ether, diphenyl ether, and/or methylphenyl ether), alkyl esters (for example, ethyl acetate, and/or isopropyl acetate), alkyl ketones (for example, acetone, methyl ethyl ketone, and/or methyl isobutyl ketone), aromatic hydrocarbons and aliphatic hydrocarbons (for example, toluene, xylenes, hexanes, and/or heptanes), nitriles (for example, acetonitrile, propionitrile, butyronitrile, and/or benzonitrile), N,N- dialkylamides (for example, A/,A/-dimethylformamide, A/,A/-dimethylacetamide, and/or A/-methyl-2-pyrrolidinone), sulfoxides and sulfones (for example, dimethyl sulfoxide and/or sulfolane), halogenated hydrocarbons (for

example.dichloromethane and/or dichloroethane), and mixtures thereof.

In illustrative embodiments of the present invention, the processes described herein may be conducted in a single pot. Such one-pot processes are processes in which the starting matierials and various reagents used are added to the reaction mixture in a manner that results in the isolation only of rufinamide and no other compounds ae isolated. For example, such one-pot processes may start from propiolic acid and proceed through to preparation of rufinamide without isolation of any intermediates. Alternatively, one-pot processes may start from the compound of Formula 4 and proceed through to rufinamide without isolation of intermediates.

In illustrative embodiments of the present invention, rufinamide and intermediates thereof may be prepared by exemplary processes as set out in Scheme 1. Exemplary reagents and conditions for these reactions are disclosed herein.

^■*^■ Rufinamide

wherein X is a halogen and A is an activated carboxylic acid group.

Scheme 1

In illustrative embodiments of the present invention, there is provided a process disclosed in Scheme 1 , in a one-pot process conducted without isolation of intermediates. Examples

The following examples are illustrative of some of the embodiments of the invention described herein. These examples do not limit the spirit or scope of the invention in any way.

Example 1 - Preparation of 2,6-difluorobenzyl azide:

Sodium azide (120.62 g, 1.855 moles, 1.12 eq) was added in portions to a solution of 2,6-difluorobenzyl chloride (269.3 g, 1.657 moles), in water (2.5 L) at 35-40°C. The reaction mixture was heated to 70-75°C for 14 hours and then cooled to room temperature. The organic phase was separated to yield 2,6- difluorobenzyl azide (270.76 g; 97%) as a liquid.

¹HNMR (400MHz, CDCI₃) δ ppm: 4.42 (s, 2H), 6.93-6.98 (m, 2H), 7.28- 7.36 (m, 1 H).

Example 2 - Preparation of 2.6-difluorobenzyl azide:

Sodium azide (4.38 g, 67.4 mmol) was added to a solution of 2,6- difluorobenzyl chloride (10.54 g, 64.8 mmol) in dimethylformamide (10 mL). The mixture was stirred at room temperature for 45 minutes and then cooled to 5°C. Water (40 mL) was added slowly over ca. 15 minutes. The biphasic mixture was warmed to room temperature and the organic phase was separated to yield 2,6- difluorobenzyl azide (10.73 g; 94%) as a liquid containing 1.5 wt% of

dimethylformamide.

HNMR (400MHz, CDCI3) δ ppm: 4.42 (s, 2H), 6.93-6.98 (m, 2H), 7.28- 7.36 (m, 1 H).

Example 3 - Preparation of succinimidyl-3-propiolate:

A solution of dicyclohexylcarbodiimide (29.8 g, 142.74 mmol) in ethyl acetate (260 mL) was added drop-wise over ca. 1 hour to a cooled (0-5°C) suspension of 95% propiolic acid (10.53 g, 142.74 mmol) and N- hydroxysuccinimide (16.77 g, 142.74 mmol) in ethyl acetate (780 mL). The reaction mixture was stirred at 0-5°C over 6 hours and the byproduct dicyclohexyl urea was removed by filtration. The filtrate was concentrated to ca. 200 mL and washed with brine (2x50 mL). The organic layer was dried (anhydrous Na₂S0₄), concentrated to ca. 30 mL and cooled to -5°C. Heptanes (12 mL) was added to the precipitated solids and the mixture was further cooled to -10°C. The solids were stirred at -10°C for 2 hours, filtered and dried under vacuum to yield succinimidyl-3-propiolate (18.32 g, 77 %) as a white solid.

¹HNMR (400MHz, CDCI₃) δ ppm: 2.87 (s, 4H), 3.31 (s, 1 H).

Example 4 - Preparation of /V-succinimidyl 1-(2,6-difluorobenzyl)-1 H-1 ,2,3- triazole-4-carboxylate from succinimidyl propiolate:

Succinimidyl propiolate (2.77 g, 16.55 mmol) was added to a solution of 2,6-difluorobenzyl azide (2.0 g, 11.825 mmol) in methanol (10 mL) at room temperature. L-Ascorbic acid (208 mg, 1.183 mmol) and CuS0 .5H₂0 (30 mg, 0.118 mmol) were added and the reaction mixture was stirred at room

temperature for 3 hours. The precipitated solids were filtered off, washed with methanol (2x7 mL) and dried under vacuum (15 hours) to yield /V-succinimidyl 1- (2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxylate (3.97 g, 99%) as a crystalline off-white solid.

¹HNMR (400MHz, DMSO-d₆) δ ppm: 2.91 (s, 4H), 5.84 (s, 2H), 7.18-7.24 (m, 2H), 7.52-7.60 (m, 1 H), 9.35 (s, 1 H).

Example 5 - Preparation of /V-succinimidyl 1-(2,6-difluorobenzyl)-1 /-/-1 ,2,3- triazole-4-carboxylate from succinimidyl propiolate:

Succinimidyl propiolate (5.54 g, 33. 1 mmol) was added to a solution of 2,6-difluorobenzyl azide (4.0 g, 23.65 mmol) in ethanol (24 mL) at room temperature. L-Ascorbic acid (417 mg, 2.365 mmol) and CuS0₄.5H₂0 (60 mg, 0.237 mmol) were added and the reaction mixture was stirred at room

temperature overnight. The precipitated solids were filtered off, washed with ethanol (2x12 mL) and dried under vacuum (15 hours) to yield /V-succinimidyl 1- (2,6-difluorobenzyl)-1/-/-1 ,2,3-triazole-4-carboxylate (7.94 g, 99%) as a crystalline off-white solid.

Example 6 - Preparation of /V-succinimidyl 1-(2,6-difluorobenzyl)-1H-1 ,2,3- triazole-4-carboxylate from propiolic acid:

Diisopropylcarbodiimide (4.5 mL, 28.55 mmol) was added drop wise over ca. 3 minutes to a cooled (0-5°C) suspension of 95% propiolic acid (2.1 g, 28.55 mmol) and /V-hydroxysuccinimide (3.35 g, 28.55 mmol) in ethyl acetate (20 mL). The reaction mixture was stirred at 0-5°C for 5 hours and the by-product diisopropyl urea was removed by filtration. The filtrate was cooled to 10-12°C and 2,6-difluorobenzyl azide and L-ascorbic acid (505 mg, 2.855 mmol) were added. A solution of CuS0₄.5H₂0 (71 mg, 0.285 mmol) in dimethylformamide (6 mL) was added. The reaction mixture was stirred for 2 hours and ethyl acetate was removed on a rotary evaporator. Methanol (20 mL) was added to the residue and the precipitated solids were filtered, washed with methanol (2x8 mL) and dried under vacuum (15 hours) to yield /V-succinimidyl 1-(2,6-difluorobenzyl)-1/-/-1 ,2,3- triazole-4-carboxylate (8.82 g, 92%) as a crystalline pale yellow solid.

Example 7 - Preparation of 1-(2,6-difluorobenzyl)-1H-1 ,2,3-triazole-4- carboxamide (rufinamide) from succinimidyl propiolate:

Succinimidyl propiolate (2.05 g, 11.99 mmol), L-ascorbic acid (156 mg, 0.89 mmol) and CuS0₄.5H₂0 (23 mg, 0.09 mmol) were added in this sequence to a stirred solution of 2,6-difluorobenzyl azide (1.5 g, 8.868 mmol) in methanol (7.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours and methanol (1 1 mL) and ca. 15 wt% ammonia in methanol (2.02 g, 17.74 mmol) were added. After stirring for 5 minutes, water (6 mL) was added. The reaction mixture was stirred for another 30 minutes, filtered, washed with methanol (2x8 mL) and dried under vacuum at 42°C (15 hours) to yield rufinamide (1.80 g, 85%) as a crystalline white solid.

HPLC purity = 99.14 % area.

¹HNMR (400MHz, DMSO-d₆) δ ppm: 5.73 (s, 2H), 7.17-7.23 (m, 2 H), 7.40 (br s, 1 H), 7.40-7.57 (m, 1 H), 7.85 (br s, 1 H), 8.55 (s, 1 H).

Example 8 - Preparation of 1-(2,6-difluorobenzvQ-1 /-/-1 ,2,3-triazole-4- carboxamide (rufinamide) from succinimidyl propiolate:

Succinimidyl propiolate (1.1 1 g, 6.5 mmol) was added to a solution of 2,6- difluorobenzyl azide (1.0 g, 5.913 mmol), L-ascorbic acid (105 mmol, 0.59 mmol) and CuS0₄.5H20 (23 mg, 0.09 mmol) in dimethylformamide (5 mL). The reaction was complete in 20 minutes. The reaction mixture was cooled to 0-5°C and methanol (10 mL) and a solution of ca. 15 wt% ammonia in methanol (1.35 g, 1 1.83 mmol) was added. After 5 minutes, water (5 mL) was added and the reaction mixture was brought to room temperature. The precipitated solids were filtered, washed with methanol (2x5 mL), water (2x5 mL) and finally with methanol (4 mL). The damp cake was dried under vacuum at 42°C (15 hours) to yield rufinamide (1.33 g, 95%) as a crystalline white solid.

HPLC purity = 99.85 % area.

¹ HNMR (400MHz, DMSO-d₆) δ ppm: 5.73 (s, 2H), 7.17-7.23 (m, 2 H), 7.40 (br s, 1 H), 7.40-7.57 (m, 1 H), 7.85 (br s, 1 H), 8.55 (s, 1 H).

Example 9 - Preparation of 1 -(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4- carboxamide (rufinamide) from propiolic acid:

Dicyclohexylcarbodiimide (5.96 g, 28.55 mmol) was added to a cooled (0- 5°C) suspension of 95% propiolic acid (2.1 g, 28.55 mmol) and N- hydroxysuccinimide (3.35 g, 28.55 mmol) in ethyl acetate (40 mL). The suspension was stirred at 0-5°C for 8 hours and the dicyclohexyl urea by-product was removed by filtration. The filtrate was concentrated to ca. 24 mL and 2,6- difluorobenzyl azide (4.83 g, 28.55 mmol) followed by L-ascorbic acid (505 mg, 2.85 mmol) were added. A solution of CuS0₄.5H₂0 (72 mg, 0.286 mmol) in dimethylformamide (10 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and cooled to 0-5°C. Methanol (35 mL) and a solution of 15 wt% ammonia in methanol (6.5 g, 57.1 mmol) was added. After 5 minutes, water (10 mL) was added and the reaction mixture was warmed to room temperature. The precipitated solids were filtered, washed with methanol (2x8 mL), water (2x8 mL) and finally with methanol (2x8 mL). The damp cake was dried under vacuum at 42°C (15 hours) to yield rufinamide (5.69 g, 84%) as a crystalline white solid.

HPLC purity = 99.88 % area.

Example 10 - Preparation of 1-(2,6-difluorobenzyl)-1H-1 ,2,3-triazole-4- carboxamide (rufinamide) from propiolic acid:

A solution of dicyclohexylcarbodiimide (5.96 g, 28.55 mmol) in ethyl acetate (24 mL) was added over ca. 12 minutes to a cooled (0-5°C) suspension of 95% propiolic acid (2.1 g, 28.55 mmol) and /V-hydroxysuccinimide (3.35 g, 28.55 mmol) in ethyl acetate (5 mL). The suspension was stirred at 0-5°C for 6 hours and the by-product dicyclohexyl urea was removed by filtration. The filtrate was cooled to 0-5°C and 2,6-difluorobenzyl azide (4.83 g, 28.55 mmol) followed by L-ascorbic acid (505 mg, 2.85 mmol) were added. A solution of CuS0₄.5H₂0 (71 mg, 0.285 mmol) in dimethylformamide (5 mL) was added. The reaction mixture was stirred at 0-5°C for 8 hours. Methanol (20 mL) and a solution of aqueous 28 wt% ammonium hydroxide (2.6 g, 42.83 mmol) were added. After 5 minutes, water (10 mL) was added and the reaction mixture was warmed to room temperature. The precipitated solids were filtered, washed with methanol (2x8 mL), water (2x8 mL) and finally with methanol (2x8 mL). The damp cake was dried under vacuum at 42°C (15 hours) to yield rufinamide (5.58 g, 82%) as a crystalline white solid.

HPLC purity = 99.73 % area.

Example 1 1 - Preparation of 1-(2,6-difluorobenzyl)-1H-1 ,2,3-triazole-4- carboxamide (rufinamide) from propiolic acid:

A solution of dicyclohexylcarbodiimide (5.96 g, 28.55 mmol) in ethyl acetate (20 mL) was added over ca. 8 minutes to a cooled (0-5°C) suspension of 95% propiolic acid (2.1 g, 28.55 mmol) and /V-hydroxysuccinimide (3.35 g, 28.55 mmol) in ethyl acetate (5 mL). The suspension was stirred at 0-5°C for 5 hours and the by-product dicyclohexyl urea was removed by filtration. The filtrate was cooled to 10-15°C and 2,6-difluorobenzyl azide (4.83 g, 28.55 mmol) followed by L-ascorbic acid (505 mg, 2.85 mmol) were added. A solution of CuS0₄.5H₂0 (71 mg, 0.285 mmol) in dimethylformamide (5 mL) was added. The reaction mixture was stirred at 10-15°C for 4 hours. A solution of aqueous 28 wt% ammonium hydroxide (2.6 g, 42.83 mmol) in methanol (20 mL) was added over ca. 5 minutes. After 5 minutes, water (10 mL) was added and the reaction mixture was warmed to room temperature. The precipitated solids were filtered, washed with methanol (2x8 mL), water (2x8 mL) and finally with methanol (2x8 mL). The damp cake was dried under vacuum at 42°C (15 hours) to yield rufinamide (5.71 g, 84%) as a crystalline white solid.

HPLC purity = 99.59 % area.

¹HNMR (400MHz, DMSO-d₆) δ ppm: 5.73 (s, 2H), 7.17-7.23 (m, 2 H), 7.40 (br s, 1 H), 7.40-7.57 (m, 1 H), 7.85 (br s, 1 H), 8.55 (s, 1 H). Example 12 - Preparation of 1 -(2,6-difluorobenzyl)-1 /-/-1 ,2,3-triazole-4- carboxamide (rufinamide) from propiolic acid using /V-hvdroxyphthalimide:

A solution of dicyclohexylcarbodiimide (5.96 g, 28.55 mmol) in ethyl acetate (20 mL) was added over ca. 8 minutes to a cooled (0-5°C) suspension of 95% propiolic acid (2.1 g, 28.55 mmol) and A/-hydroxyphthalimide (4.81 g, 28.55 mmol) in ethyl acetate (10 mL). The suspension was stirred at 0-5°C for 5 hours and the dicyclohexyl urea was removed by filtration. [Phthalimidyl propiolate peaks in ¹H NMR (400 MHz, DMSO-d₆) δ 5.46 (s, 1 H), 7.95-8.03 (m, 4 H)]. The filtrate was cooled to 10-15°C and 2,6-difluorobenzyl azide (4.83 g, 28.55 mmol) followed by L-ascorbic acid (505 mg, 2.85 mmol) were added. A solution of CuS0₄.5H₂0 (71 mg, 0.285 mmol) in dimethylformamide (6 mL) was added. The reaction mixture was stirred at 10-15°C for 4 hours. A solution of aqueous 28 wt% ammonium hydroxide (2.6 g, 42.83 mmol) in methanol (20 mL) was added over ca. 5 minutes. After 5 minutes, water (10 mL) was added and the reaction mixture was warmed to room temperature. The precipitated solids were filtered, washed with methanol (2x8 mL), water (2x8 mL) and finally with methanol (2x8 mL). The damp cake was dried under vacuum at 42°C (15 hours) to yield a solid that contained a mixture of rufinamide and /V-hydroxyphthalimide derivate (5.45 g, ratio by ¹H NMR = 1 : 0.88). The solid was pulped at room temperature in a mixture of methanol (53 mL) and water (27 mL). The solids were filtered and the cake was dried under vacuum at 42°C (15 hours) to yield rufinamide (3.55 g, 52 %) as a crystalline white solid.

Example 13 - Preparation of 1 -(2,6-difluorobenzvD-1 H-1 ,2,3-triazole-4- carboxamide (rufinamide) from propiolic acid using 1 -hvdroxybenzotriazole:

Part a - Preparation of Benzotriazol-1 -yl-propiolate:

A solution of dicyclohexylcarbodiimide (14.9 g, 71.37 mmol) in

tetrahydrofuran (70 mL) was added drop-wise over ca. 15 minutes to a cooled (0- 5°C) suspension of propiolic acid (5.1 g, 71.37 mmol) and 1-hydroxybenzotriazol (9.65 g, 71.37 mmol) in tetrahydrofuran (70 mL). The reaction mixture was stirred at 0-5°C over 4 hours and the by-product dicyclohexyl urea was removed by filtration. The filtrate was concentrated to ca. 30 mL and ethyl acetate (20 mL) was added. The precipitated solids were cooled to -5°C (overnight), filtered and dried under vacuum to yield benzotriazol-1 -yl-propiolate (6.55 g, 49 %) as a light brown solid.

¹HNMR (400MHz, DMSO-d₆) δ ppm: 5.39 (s, 1 H), 7.71 (t, J=7.6 Hz, 1 H), 7.94 (t, J=7.6 Hz), 8.07 (d, J=8.3 Hz), 8.28 (d, J=8.3 Hz).

Part b - Preparation of rufinamide from benzotriazol-1-yl-propiolate:

Benzotriazol-1-yl-propiolate (2.7 g, 13.01 mmol, ca. 90% purity) and L-ascorbic acid (208 mg, 1.183 mmol) were added to a stirred and cooled (5-10°C) solution of 2,6-difluorobenzyl azide (2.0 g, 11.82 mmol) in dimethylformamide (6 mL). A solution of CuS0₄.5H₂0 (30 mg, 0.1 18 mmol) in dimethylformamide (4 mL) was added. The reaction mixture was stirred at 5-10°C for 2 hours. [Benzotriazolyl-1- (2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxylate peaks in ¹HNMR (400MHz, DMSO-d₆) δ ppm: 5.93 (s, 2 H), 7.20-7.26 (m, 2H), 7.52-7.59 (m, 1 H), 7.71-7.75 (m, 1 H), 7.96-7.98 (m, 1 H), 8.11 (d, J=8.3 Hz, 1 H), 8.47 (d, J=8.3 Hz, 1 H), 9.22 (s, 1 H)]. A 28% solution of ammonium hydroxide (1.44 g, 23.65 mmol) was added and a thick white suspension formed. The mixture was stirred at room temperature overnight and diluted with methanol (5 mL) and water (3 mL). The reaction mixture was filtered, washed with methanol (2x10 mL), water (10 mL) and finally with methanol (10 mL) and then dried under vacuum at 60°C (5 hours) to yield rufinamide (2.55 g, 90%) as a crystalline white solid.

¹HNMR (400MHz, DMSO-d₆) δ ppm: 5.73 (s, 2H), 7.17-7.23 (m, 2 H), 7.40 (br s, 1 H), 7.40-7.57 (m, 1 H), 7.85 (br s, 1 H), 8.55 (s, 1 H). Example 14 - Preparation of 1-(2,6-difluorobenzyl)-1 /-/-1 ,2,3-triazole-4- carboxamide (rufinamide) from 2,6-difluorobenzyl chloride:

A mixture of 2,6-difluorobenzyl chloride (5.0 g, 30.756 mmol), sodium azide (2.24 g, 34.44 mmol) in water (25 mL) was heated at 70-75°C over 15 hours and cooled to room temperature. A portion (20 mL) of the supernatant aqueous layer was removed and discarded. To the remaining biphasic mixture was added a filtrate derived from a reaction of dicyclohexylcarbodiimide (5.96 g, 28.55 mmol), 95% propiolic acid (2.1 g, 28.55 mmol) and /V-hydroxysuccinimide (3.35 g, 28.55 mmol) in ethyl acetate (25 mL). L-Ascorbic acid (542 mg, 3.07 mmol) and CuS0₄.5H₂0 (78 mg, 0.31 mmol) were added and the reaction mixture was stirred at room temperature overnight. Succinimidyl propiolate (3.6 g, 21.5 mmol) was added and stirring was continued for another 4 hours. The reaction mixture was cooled to 0-5°C and a solution of aqueous 28% ammonium hydroxide (5.7 g, 92.27 mmol) in methanol ( 15 mL) was added over ca. 5 minutes. The reaction mixture was stirred for 5 minutes and water (15 mL) was added. The reaction mixture was brought to room temperature and the precipitated solids were filtered, washed with methanol (2x8 mL), water (2x8 mL) and finally with methanol (2x8 mL). The damp cake was dried under vacuum at 42°C (15 hours) to yield rufinamide (4.95 g, 68 %) as a crystalline white solid.

Example 15 - Preparation of 1-(2,6-difluorobenzyl)-1H-1 ,2,3-triazole-4- carboxamide (rufinamide) from succinimidyl propiolate without the use of a copper catalyst:

A solution of 2,6-difluorobenzyl azide (2.0 g, 1 1.82 mmol) and succinimidyl propiolate (2.32 g, 13.60 mmol) in dimethylformamide (10 mL) was heated at 45°C for 9 hours. (Crude HNMR analysis revealed ca. 4 % of the 1 ,5- regioisomer formation). The reaction mixture was cooled to 0-5°C and a solution of 28% ammonium hydroxide in methanol (14 mL) was added. After stirring for 5 minutes, water (8 mL) was added. The reaction mixture was stirred for another 5 minutes, filtered, washed with methanol (2x8 mL), water (8 mL) and finally with methanol (8 mL) and dried under vacuum at 60°C (2 hours) to yield rufinamide (2.68 g, 95%) as a crystalline white solid.

HPLC purity = 99.60 % area.

¹HNMR (400MHz, DMSO-d₆) δ ppm: 5.73 (s, 2H), 7.17-7.23 (m, 2 H), 7.40 (br s, 1 H), 7.40-7.57 (m, 1 H), 7.85 (br s, 1 H), 8.55 (s, 1 H). (1 ,5-regioisomer was not detected by ¹HNMR).

Example 16 - Purification of 1-(2,6-difluorobenzyl)-1/-/-1 ,2,3-triazole-4- carboxamide (rufinamide):

Rufinamide (4.0 g, 16.79 mmol) was dissolved in acetic acid (28 mL) at 100°C and then was cooled to 80°C. Methanol (24 mL) was added and the resulting suspension was cooled to 23-25°C over 4 hours. The solids were filtered, washed with methanol (3x8 mL) and dried at 60°C under vacuum (8 hours) to yield rufinamide (3.83 g, 95 %) as a crystalline white solid.

HPLC purity: 99.94 % area.

Example 17 - Purification of 1-(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4- carboxamide (rufinamide):

Rufinamide (4.0 g, 16.79 mmol) was dissolved in acetic acid (28 mL) at 100°C and then was cooled to 80°C. Methanol (12 mL) was added and the resulting suspension was cooled to 23-25°C over 4 hours. The solids were filtered, washed with methanol (2x8 mL) and dried at 45°C under vacuum (12 hours) to yield rufinamide (3.68 g, 92 %) as a crystalline white solid.

HPLC purity: 99.99 % area.

¹HNMR (400MHz, DMSO-d₆) δ ppm: 5.73 (s, 2H), 7.17-7.23 (m, 2 H), 7.40 (br s, 1 H), 7.40-7.57 (m, 1 H), 7.85 (br s, 1 H), 8.55 (s, 1 H). Example 18 - Preparation of 1 -(2,6-difluorobenzyl)-1 /-/-1 ,2,3-triazole-4- carboxamide (rufinamide) from propiolic acid and 4-nitrophenol:

A solution of dicyclohexylcarbodiimide (5.96 g, 28.55 mmol) and 4- nitrophenol (3.97 g, 28.55 mmol) in ethyl acetate (18 mL) was added over ca. 8 minutes to a cooled (0-5°C) suspension of 98.5% propiolic acid (2.03 g, 28.55 mmol) in ethyl acetate (5 mL). The suspension was stirred at 0-5°C for 3.5 hours and the by-product dicyclohexyl urea was filtered off. The filtrate was cooled to 10-15°C and 2,6-difluorobenzyl azide (4.85 g, 28.68 mmol) followed by a solution of CuS0₄.5H₂0 (0.14 g, 0.51 mmol) in dimethylformamide (10 mL) and L- ascorbic acid (0.50 g, 2.85 mmol) were added. The reaction mixture was stirred at 10-15°C for 16 hours. The suspension was cooled to 0-5°C and an aqueous solution of 28 wt% ammonium hydroxide (3.47 g, 57.10 mmol) was added. After 2.5 hours, methanol (35 mL) was added and the reaction mixture was filtered and the solids were washed with methanol (3x10 mL). The damp cake was dried under vacuum at 22-25°C (15 hours) to yield rufinamide (4.52 g, 66%) as a crystalline off-white solid.

¹ HNMR (400MHz, DMSO-d₆):

4-nitrophenyl propiolate δ ppm: 4.98 (s, 1 H), 7.57-7.61 (m, 2H), 8.31 -8.35 (m, 2H).

4-nitrophenyl 1 -(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxylate δ ppm: 5.82 (s, 1 H), 7.19-7.25 (m, 2 H), 7.52-7.56 (m, 1 H), 7.59-7.65 (m, 2H), 8.34-8.38 (m, 2H), 9.17 (s, 1 H).

1 -(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide (rufinamide) δ ppm: 5.73 (s, 2H), 7.17-7.23 (m, 2 H), 7.40 (br s, 1 H), 7.40-7.57 (m, 1 H), 7.85 (br s, 1 H), 8.55 (s, 1 H). Example 19 - Preparation of 1 -(2,6-difluorobenzyl)-1 /-/-1 ,2,3-triazole-4- carboxamide (rufinamide) from propiolic acid and benzotriazole:

A solution of dicyclohexylcarbodiimide (5.96 g, 28.55 mmol) and benzotriazole (3.40 g, 28.55 mmol) in ethyl acetate (24 mL) was added over ca. 16 minutes to a cooled (0-5°C) suspension of 98.5% propiolic acid (2.03 g, 28.55 mmol) in ethyl acetate (5 mL). The suspension was stirred at 0-5°C for 2 hours and the by-product dicyclohexyl urea was filtered off. The solid was washed with cold ethyl acetate (3x4 vol) and the filtrate was concentrated to 24 mL. The filtrate was cooled to 10-15°C and 2,6-difluorobenzyl azide (4.83 g, 28.56 mmol) followed by a solution of CuS0₄.5H₂0 (0.14 g, 0.51 mmol) in dimethylformamide (10 mL) and L-ascorbic acid (0.50 g, 2.85 mmol) were added. The reaction mixture was stirred at 10-15°C for 16 hours. The suspension was cooled to 0-5°C and an aqueous solution of 28 wt% ammonium hydroxide (3.47 g, 57.10 mmol) was added. After ca. 8 minutes, methanol (35 mL) was added and the reaction mixture was filtered and the solids were washed with methanol (2x10 mL). The damp cake was dried under vacuum at 22-25°C ( 5 hours) to yield rufinamide (3.65 g, 54%) as a crystalline grey-red solid.

¹HNMR (400MHz, DMSO-d₆):

N-benzotriazolyl propiolate: δ ppm: 5.43 (s, 1 H), 7.64-7.67 (m, 1 H), 7.80- 7.84 (m, 1 H), 8.19 (d, J=8.2 Hz, 1 H), 8.29 (d, J=8.4 Hz, 1 H).

N-benzotriazolyl 1 -(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxylate: δ ρριττ. 5.92 (s, 1 H), 7.20-7.25 (m, 2 H), 7.52-7.59 (m, 1 H), 7.65-7.69 (m, 1 H), 7.82-7.86 (m, 1 H), 8.32 (d, J=8.4 Hz), 8.35 (d, J=8.4 Hz, 1 H), 9.39 (s, 1 H).

1 -(2,6-difluorobenzyl)-1 H-1 ,2,3-triazole-4-carboxamide (rufinamide): 5 ppm: 5.73 (s, 2H), 7.17-7.23 (m, 2 H), 7.40 (br s, 1 H), 7.40-7.57 (m, 1 H), 7.85 (br s, 1 H), 8.55 (s, 1 H).

Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. Numeric ranges are inclusive of the numbers defining the range. Furthermore, numeric ranges are provided so that the range of values is recited in addition to the individual values within the recited range being specifically recited in the absence of the range. The word "comprising" is used herein as an open-ended term, substantially equivalent to the phrase "including, but not limited to", and the word "comprises" has a corresponding meaning. As used herein, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a thing" includes more than one such thing. Citation of references herein is not an admission that such references are prior art to the present invention. Furthermore, material appearing in the background section of the specification is not an admission that such material is prior art to the invention. Any priority document(s) are incorporated herein by reference as if each individual priority document were specifically and individually indicated to be incorporated by reference herein and as though fully set forth herein. The invention includes all embodiments and variations substantially as hereinbefore described and with reference to the examples and drawings.

Claims

What is Claimed is:

1. A process for the preparation of rufinamide comprising:

i. reacting a compound of Formula 2:

with a compound of Formula 3:

H—≡— A

3

thereby forming a compound of Formula 4:

wherein A is an activated carboxylic acid group; and

ii. converting the compound of Formula 4 to rufinamide.

2. The process of claim 1 wherein the activated carboxylic acid group is selected from the group consisting of. a reactive ester group, a reactive anhydride group, a reactive cyclic amide group and a halomethyl carbonyl group.

3. The process of claim 1 wherein A is selected from the group consisting of: a /V-hydroxy ester group, a substituted aryl ester group, an alkenyl ester group, a substituted alkenyl ester group, a carbonyloxydioxoborolane group and a thioester group.

4. The process of claim 1 wherein A is a /V-hydroxy ester group.

5. The process of claim 4 wherein the A/-hydroxy ester group is selected from the group consisting of:

6. The process of claim 1 wherein A is:

7. The process of claim 1 wherein A is a substituted aryl ester group.

8. The process of claim 1 wherein A is COOB(R¹)_n

n is 1 or 2

wherein

when n is 1 ,

R¹ forms a ring group with the boron to which it is bonded and A is of the Formula:

R^A is selected from the group consisting of: alkyl, substituted alkyl, aryl, substituted aryl, arylalkyi and substituted arylalkyi; and when n is 2,

each R¹ is independently selected from the group consisting of -O-alkyl, substituted -O-alkyl, -O-aryl, substituted -O-aryl, -O-arylalkyl substituted -O-arylalkyl.

9. The process of claim 1 wherein A is COSG and G is selected from the group consisting of: phenyl, nitro-substituted phenyl and lower alkyl.

10. The process of claim 1 wherein A is COOG and G is selected from the group consisting of: 4-nitrophenyl, 4-methylsulfonylphenyl, 2,4,5-trichlorophenyl and 2,3,4,5,6-pentachlorophenyl.

11. The process of claim 1 wherein A is selected from the group consisting of: a disubstituted phosphoric acid anhydride group, an organic acid anhydride group, a carbonic ester anhydride group and an organic sulfonic acid anhydride group.

12. The process of claim 1 wherein

A is COOG,

G is selected from the group consisting of: COR², S0₂R² and

PO(OR³)₂,

R² is selected from the group consisting of: alkyl, substituted alkyl, aryl, substituted aryl, arylalkyi, substituted arylalkyi, alkyloxy, substituted alkyloxy ethynyl and alkenyloxy; and R³ is lower alkyl.

13. The process of claim 12 wherein G is COR² and R² is selected from the group consisting of: lower alkyl, alkyloxy and alkenyloxy.

14. The process of claim 3 wherein the reacting of the compound of Formula 2 with the compound of Formula 3 is performed in a solvent selected from the group consisting of: alkyl esters, A/JV-dialkylamides and sulfoxides.

15. The process of claim 1 wherein the compound of Formula 3 is prepared from propiolic acid.

16. The process of claim 15 wherein rufinamide is the only compound isolated.

17. The process of any one of claims 1 to 16 wherein the reacting of the compound of Formula 2 with the compound of Formula 3 is conducted in the presence of a copper (I) catalyst.

18. The process of claim 17 wherein the copper (I) catalyst is selected from the group consisting of: Cul, CuCI, CuBr, CuF, Cu₂0 and CuSCN.

19. The process of claim 17 wherein the copper (I) catalyst is generated in situ by reacting a copper (II) salt with a reducing agent.

20. The process of claim 19 wherein the copper (II) salt is selected from the group consisting of: CuS0₄, CuCI₂, CuBr₂, CuF₂, Cu(OH)₂, Cu(N0₃)₂, Cu(CI0₄)₂, Cu(ll)-D-gluconate and CuO.

21. The process of claim 19 wherein the copper (II) salt is CuS0₄.5H₂0.

A compound of Formula 4:

wherein A is selected from the group consisting of: a reactive ester group, a reactive anhydride group, a reactive cyclic amide group and a

halomethylcarbonyl group.

23. The compound of claim 22 wherein A is selected from the group consisting of: a A/-hydroxy ester group, a substituted aryl ester group, an alkenyl ester group, a substituted alkenyl ester group, a carbonyloxydioxoborolane group and a thioester group.

24. The compound of claim 22 wherein the compound is selected from the group consisting of:

25. The compound of claim 22 wherein

A is COOG,

G is COR²; and

R² is selected from the group consisting of: lower alkyl, alkyloxy and alkenyloxy.