PROCESS AND A NOVEL INTERMEDIATE FOR THE PREPARATION OF FLECAINIDE

Abstract: The present invention provides a process for the preparation of a compound of formula (A) wherein R is a 2-piperidyl or 2-pyridyl radical, and pharmaceutically acceptable salts thereof, which process comprises the steps of: a) reacting 2,5 bis (2,2,2,-trifluoroethoxy) benzoic acid or a salt thereof, with a haloacetonitrile of the formula XCH2CN, where X is C1, Br or I, if necessary in the presence of an inorganic or organic base, to form the cyanomethyl ester of formula (II); b) reacting the ester of formula (II) with an amine of the formula RCH2NH2, where R is as defined above and, if desired; c) converting the compound of the formula (A) to a pharmaceutically acceptable salt thereof.

Description: PROCESS AND A NOVEL INTERMEDIATE FOR THE PREPARATION OF FLECAINIDE FIELD OF THE INVENTION This invention relates to a novel process for the preparation of Recainide and a precursor thereof, to a novel intermediate used in this process and its preparation. BACKGROUND OF THE- INVENTION Flecainide (2,5 -bis(2,2,2-trifluoroethoxy)-N-(2- piperidylmethyl)benzamide is an effective antiarrythmic drug that acts on the cell membrane to reduce fast inward depolarization current. One prior art method for preparing Flecainide, disclosed inter alia, in British Patent Application No 2,045,760 A, starts from 2-5-bis(2-2,2-tri- fiuoroethoxy)ber__oic acid. This starting material is prepared by a multistage process, comprising the conversion of 1,4-dibromobεnzene or hydroquinone to l,4-bis(2,2,2-trifluoroethoxy)benzene, which is acetylated to form 2,5-bis(2,2,2-trifluoroethoxy)acetophenone. The acetophenone is then oxidized to form the corresponding benzoic acid derivative, which is then converted to its acid chloride and reacted either with 2-(am_αo- methyl)piperidi_ιe to form the Recainide product in one step or with 2- (aminomethyl)pyridine, followed by catalytic hydrogenation of the pyridine ring, to form the Recainide product in two steps. The one step process has a serious disadvantage in that the acid chloride reacts non-selectively with both nitrogen atoms of the 2- (aminomethyl) piperidine, resulting in a mixture of the two acylated isomers. This is the main reason why the two-step process via the pyridine intermediate is commercially preferred. A further disadvantage is due to the fact that the acid chloride mtermediate disclosed in GB 2,045,760A is a lϊc-ic which an no: be stored for long period, cf ___._ _ _. ____.. _ς iimnediaieiy after it is prepared. OBJECTS OF THE INVENTION It is an object of this invention to provide a novel process for the preparation of Flecainide and its pharmaceutically acceptable salts, which is free of the above-mentioned disadvantages, starting with commercially available halobenzoic acids and involving the use of simple reagents and low cost solvents, to afford high overall yield of the Flecainide product It is a farther object of this invention to provide a novel reactive intermediate, i.e. the cyanomethyl ester of 2 -bis(2,2,2-trifiuoroetho- xy)benzoic acid, which is capable of reacting selectively with the primary amino group of 2-(aminomethyl)piperidine, so as to form the Recainide product i high yield and free pf the above mentioned isomeric by-product SUMMARY OF THE INVENTION The above objects are achieved in accordance with the present invention which, in one aspect thereof, provides a process for preparing a compound of formula (A): wherein R is a 2-piperidy 1 or 2-pyridyl radical, and pharmaceutically acceptable salts thereof, which process comprises the steps of: a) reacting 2,5-bis(2^2,2-trrQuoroethoxy)benzoic acid or a salt thereof, with a haloacetonitrile of the formula XCH 2 CN, where X is Cl, Br or I, if necessary in the presence of an inorganic or organic base, to form the cyanomethyl ester of the formula (H): b) reacting the ester of the formula (II) with an amine of the formula RCH 2 NH 2 , where R is as defined above and, if desired, c) converting the compound of the formula (A) to a pharmaceutically acceptable salt thereof. In accordance with another aspect of this invention, there is provided the novel cyanomethyl ester of 2,5-bis(2,2,2-trifluoroethoxy)- benzoic acid having the formula (II) above. As contrasted to the liquid acid chloride intermediate disclosed in GB 2,045,760A, the novel intermediate of the present invention is a stable, solid compound, obtainable in high yield, which can be easily purified by cristallisation and stored for long periods of time. DETAILED DESCRIPTION OF THE INVENTION It was shown by Schwyzer et al. (Helvetica Chimica Acta, 1955, v. 38, 69; 80; 83) that the carboxylic group ' of aliphatic amino acids, activated by their conversion to their cyanomethyl esters, react selectively with primary amino groups. The present invention is based on the the unexpected finding that this type of activation may be used with aromatic carboxylic acids, specifically 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid. Accordingly, the cyanomethyl ester (II) is prepared in high yield, starting with 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid which is reacted with a haloacetonitrile of the formula XCH 2 CN wherein X is Cl, Br or I, preferably Cl, in the presence of an inorganic or organic base. Alternatively, the ester (II) can be prepared by reacting a salt of 2,5-bis(2,2,2-trifiuo- roethoxy)benzoic acid with a haloacetonitrile. Suitable organic bases for use in the above process are primarily tertiary amines, e.g. triethylamine, diisopropylethylamine, ethylpiperidine and the like, preferably triethylamine. Inorganic bases which may also be used are, e.g., alkali metal or alkaline earth metal carbonates or bicarbonates. In the second step of the process ., the cyanomethyl ester (II) is reacted with an amine of the formula RCH 2 NH 2 , where R is as defined above, optionally in a suitable, inert solvent. Thus, the reaction may be carried out by mixing together 2-(aminomethyl)piperidine with the ester (II) in a solvent such as 1,2-dimethoxyethane or ethyl acetate, to yield Flecainide (I) in a high yield. The optional conversion of Flecainide into a pharmaceutically acceptable salt such as the acetate salt, is carried out by conventional methods. The starting material 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid is preferably prepared by the process described in co-pending Israel Application No. 120715. Accordingly, this benzoic acid derivative is prepared by contacting a halobenzoic acid of the formula (Til): or a salt thereof, wherein X 1 is selected from Br or I, and X 2 is selected from Cl, Br or I, or one of X 1 and X 2 may also be CF 3 CH 2 0-, with 2,2,2-trifluoroethanol in the presence of a strong base and copper iodide and/or copper bromide, in an aprotic solvent. Suitable solvents are dipolar aprotic solvents or N-containing heterocycles or their mixtures, such as N,N-dimethylformamide, l-methyl-2-pyrrolidinone, N,N-dimethyIacet- amide, DMSO, pyridine, picolines, lutidines, collidines, methylethylpyridine (MEP), quinoline and substituted quinolines. As the strong base there may be used Na, NaH, NaNH 2 , Na- and K-alcoholates, NaOH, KOH and the like, most preferably NaH. For example, 5-bromo-2-chlorobenzoic acid is reacted while heating, with 2,2,2-trifluoroethanol and a strong base, e.g. sodium hydride in a dipolar aprotic solvent, e.g. N,N-dimethylformamide, in the presence of copper iodide. The present invention will be described in more detail with the aid of the following non-limiting examples. EXAMPLE 1 Synthesis of 2,5-bis(2^,2-trifluoroethoxy)benzoic acid A I L round-bottomed flask equipped with a magnetic stixrεr, a thermometer pocket, dropping funnel and a reflux condenser, was charged with 51.0 g of a 60 % strength suspension of sodium hydride in mineral oil (equivalent to a total of 30.6 g (1.28 mole) of pure NaH) and 570 mL of anhydrous N^-dimemylformamide. The iruxture was cooled to room temperature in an ice-water bath and 189.5 g (1.90 mole) of anhydrous 2^,2-trifiuoroethanol were added dropwise during 40 minutes. The mixture was cooled to room temperature and 24.8 g (0.13 mole) of anhydrous copper iodide and 59.5 g (0.25 mole) of 5-bromo-2-chlorobenzoic acid were added. The black reaction Diixture was heated to about 110 - 115 °C and kept at this temperature for 2 hours. The reaction mixture was cooled to room temperature and poured into a rnixturε of crushed ice (3 kg) and cone, hydrochloric acid (0.78 L). The mixture was vigorously stirred for 1 hour, the black precipitate was filtered off and washed at once with 200 mL of water. The obtained solid was suspended at room temperature in 1 L of 5 % aqueous KOH under vigorous stirring for 15 min, followed by filtration through a Ceiite modified filter and washing with 100 mL of 5 % aqueous KOH. The transparent clear alkaline solution was thrice extracted with 150 mL of dichloromethane. The alkaline solution was added dropwise under vigorous stirring to πiixture of O.β kg of ice and 0.2 L of cone, hydrochloric acid, at a temperature not higher than 0°C and a pH 1. The irdxture was stirred Jfor 0.5 hours at these conditions. The obtained precipitate was filtered off, washed with water, collected and dried under vacuum to a constant weight Yield: 64.7 " g (81.4%) of crude 2,5-bis(2 ,2 ,2 -trifiuoroethoxy)benzoic acid, m.p. 116 -1 I8°C. After recrystaUisaiton from an ethanol/water system, a product with m.p. 120-121°C was obtained. EXAMPLE 2 Synthesis of cyanomethyl estεr of 2,5-bis(2^,2-trifiuoroethoxy)benzoic acid Et 3 N π A I L two-neck round-bottomed flask equipped with a heating mantle, a magnetic stirrer and a reflux condenser was charged under argon with a mixture of 62.8g (197.4 mmole) of 2,5-bis(2,2,2-trifluoroetho- xy)benzoic acid, 22.4g (296.1 mmole) of chloroacεtonitrile and 29.9g (296.1 mmole) of triethylamine in 250 mL ethyl acetate (EtOAc). The obtained mixture was rεfiuxed for 3 hours. After cooling to 10°C, the mixture was filtered through a column containing 50g of silica gel to remove the formed triethylammonium chloride. The filtrate was evaporated in vacuo and the product was dried under high vacuum for 1 hour at 50°C. The resulting colourless solidified oil was stirred with 200 mL of cold hexane. to obtain white crystals. The crystals were filtered off, washed with cold hexane and dried at reduced pressure to give 60.0 g (85% yield) of cyanomethyl ester (IT), having a purity of 99.5 % (GC), m.p. 50-51°C, one spot on TLC. Η NMR (CDC1 3 ) δ 4.37 (4H, m); 4.93 (2H, s); 7.00 (1H, d); 7.17 (1H, dd); 7.44 (lH,d); HRMS: M ÷ 357.0433, Cι 3 H 9 Nθ 4 F 6 . EXAMPLE 3 Synthesis of Flecainide (I) from the cyanomethyl εstεr of 2,5-bis(2,2,- 2-trifiuoroethGxy)benzoic acid (II) and 2-(aminomεthyl)piperidinε π 1,2-Dimethoxyethane A mixture of compound (II) (2.1 g, 5.9 mmole) and 2-(aminomethyl)- piperidine (0.8 g, 7 mmole) in 1,2-dimethoxy ethane (10 mL) was charged under argon into a 50 mL round-bottomed flask equipped with a magnetic stirrer. After stirring for 2.5 hours at room temperature, additional 2- (aminomethyl)piperidine (0.5 g, 4.7 mmole) was aded. The mixture was stirred for additional 24 hours at room temperature. The solvent was removed in vacuo and the residue was dissolved in 10 mL methylene chloride. The obtained solution was extracted with water and the aqueous layer was extracted with additional 5 mL of methylene chloride. The combined organic layers were dried over sodium sulphate and evaporated under reduced pressure to give 1.9 g (77.6 % yield) of white crystals of Flecainide (I), purity 99.1 % (GC). Example 4: SYNTHESIS OF FLECAINIDE ACETATE (TV) A rmxture of compound (H) (95.0g, 0.27 mole) and 2-(amϊnomethyl) piperidine (35.4 g, 0.31 mole) in 450 mL ethyl acetate (max water content: 0.05%) was charged under argon into a 1 L round-bottomed flask equipped with a dropping funnel and magnetic stirrer. After stirring for 2 hours at room temperature, the additional amount (24.2g. 0.21 mole) of 2-(aminomethyl)piperidine was added and the mixture was stirred for an additional period of 12 hours at room temperature. The solvent was evaporated under reduced pressure. The residue was dissolved in 250 mL of dichloromethane. The obtained solution was treated with water (3X 50 mL). dried with anhydrous Na 2 SO4. filtered and concentrated under reduced pressure. The residue was dissolved in boiling ethyl acetate (800 mL). and 30g (0.5 mole) of glacial acetic acid was added dropwise to the obtained solution. The mixture was stirred under reflux for an additional 10 minutes and allowed to cool to room temperature overnight followed by cooling into an ice bath for 4 hours. The crystalline product was filtered off, washed with cooled to 0 ° C ethyl acetate (2 X 100 mL) and dried at 50 ° C under reduced pressure, to obtain 103.0 g (82% from theoretical yield) of Flecainide acetate, m.p. 147-148 ° C. EXAMPLE 5 Synthesis of 2.5-bis(2.2.2-trifluoroethoxy)-N-(2-pyridvlmethyl)- benzamide (V) Eώvl Acεtate To a solution of 8.93 g (2.5 mmole) of compound (IT) in 80 mL of ethyl acetate under argon, 2-(aminomethyl)ρyridine (3.2 g, 3.0 mmole) were added with stirring and the mixture was refluxed for 4 hours. An additional 1 g of 2-(aminomethyl)ρyridine was added and the mixture was refluxed for two more hours. The ethyl acetate was evaporated under reduced pressure and the residue was passed through a 12 cm column containing silica gel with a mixture of methylene chloride : hexane (1:1) as eluent. The column was washed with methylene chloride and the combined solutions were evaporated under reduced pressure. The residue was crystallised from CH 2 C : hexane (1 : 2) to give 7 g (69 % yield) of 2.5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide (V) m.p. 104-106°C, purity 99.8 % (GC). 0 5 0 _

Claims: CLAIMS 12 1. A process for the preparation of a compound of formula (A) wherein R is a 2-ρiperidyl or 2-pyridyl; radical, and pharmaceutically acceptable salts thereof, which process comprises the steps of: a) reacting 2 -bis(2,2 -trifluorσethoxy)be___oic acid or a salt thereof, with a haloacetonitrile of the formula XCH 2 CN, where X is Cl, Br or I, if necessary in the presence of an inorganic or organic base, to form the cyanomethyl ester of the formula (U): b) reacting the ester of the formula (IT) with an amrαe of the formula CH 2 NH 2 , where R is as defined above and, if desired, c) converting the compound of the formula (A) to a pharmaceutically acceptable salt thereof. 2. A process according to claim 1, wherein the reactions in steps a) and/or b) and/or c) are carried out in a suitable inert solvent 3. A process according to claim 2, wherein ethyl acetate is used as the solvent in steps a) and/or b), and /or c). 4. A process according to claim 1, wherein the free 2,5-bis(2,2,2- trifiuoroethoxy)benzoic acid is used as the starting material in step a) and the reaction is conducted in the presence of a base. 5. A process according to claim 4 wherein a tertiary a∑r±ie is used in step a) as a base. 6. A process according to Claim 5, wherein the tertiary amine is selected from triethylamine, dώoprαpylemylamiαe, ethylpiperidine. 7. A process according to claim 1, wherein R is 2-piperidyl to obtain Flecainide (I). 8. A process according to claim 7 further comprising the conversion of the Flecainide product to its acetate in step c) of claim 1. 9. Cyanomethyl ester of 2-5-bis(2,2,2-trifluoroethoxy)benzoic acid of the formula (II) in claim 1. 10. A process for the preparation of the cyanomethyl ester of the formula (IT) ia claim 1, which comprises reacting roethoxy)ber__σic acid or a salt thereof, with a haloacetonitrile of the formula XCH 2 CN wherein X is as defined in claim 1 and, if necessary, in the presence of an inorganic or organic base. 11. A process according to claim 10, .carried out in a suitable inert solvent. 12. A process according to claim 10,. wherein 2,5-bis(2,2,2-trifluo- roethoxy)benzoic acid is prepared fay contacting a halobenzoic acid of the formula (HI): or a salt thereof, wherein X 1 is selected from Br or I, and X 2 is selected from Cl, Br or I, or one of X 1 and X 2 may also be CF 3 CH 2 0-, with 2,2,2-trif oroethanol in the presence of a strong base and copper iodide and/or copper bromide, in an aprotic solvent 13. A process for the preparation of Flecainide (I) or a pharmaceutically acceptable salt thereof, substantially as herein described, with reference to the Examples.

Inventors: GUTMAN ARIE L, NISNEVICH GENADY, SHKOLNIK ELEONORA, ZALTZMAN IGOR, GUTMAN, ARIE, L., NISNEVICH, GENADY, SHKOLNIK, ELEONORA, ZALTZMAN, IGOR
Applicants: FINETECH LTD, GUTMAN ARIE L, NISNEVICH GENADY, SHKOLNIK ELEONORA, ZALTZMAN IGOR, FINETECH LTD., GUTMAN, ARIE, L., NISNEVICH, GENADY, SHKOLNIK, ELEONORA, ZALTZMAN, IGOR
Application year: 1998
Main classification: C07D213
IPC codes: C07C255, C07D211, C07D213