DK164857B - METHOD FOR PREPARING 2,5-BIS (2,2,2-TRIFLUORETHOXY) -N- (2-PIPERIDYLMETHYL) BENZAMIDE - Google Patents

Description

in

DK 164857 B

The present invention relates to an improved process for the preparation of the antiarrhythmic agent 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-piperidylmethyl) benzamide (flecainide) and its salts.

5

The antiarrhythmic compound, flecainide, its salts and a process for its preparation are described in U.S. Patent No. 3,900,481. It has the following formula

10 OH

crane, in I Γ)

3 2 -C-N-CH-, J VIII

Xoch2cf3 15

The method according to the invention is preferred over the known method because of various practical advantages, e.g. the relatively low cost of the starting materials, the ease of carrying out the unit operations included in the process, and the relatively high yields of the desired product.

The process according to the invention is characterized by the characterizing part of claim 1 and comprises the following 25 steps: (1) Reaction of 1,4-dibromobenzene of formula ΒΓ

Br with a suitable alkylating agent of the formula wherein A is an alkali metal to give 1,4-bis (2,2,2-trifluoroethoxy) benzene of formula 5

DK 164857 B

CF3CH20-A

CF, CH_0

X

och2cf3 10 (2) acetylation in the presence of a Lewis acid catalyst to give a substituted acetophenone of formula 0 (3) either (a) chlorinating the substituted acetophenone to give the corresponding α, α-dichloro-30 acetophenone of formula 0

xoch2cf3 IV

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DK 164857 B

3 and (b) addition of a buffer base and further chlorination to give a, a, a-trichloroacetophenone of formula 0

II

CF, CH 0 CCC1, 10 3 2 3

W

XOCH 2 CF 3 or (c) reacting the substituted acetophenone of step (2) with hypochlorite to give the corresponding benzoic acid of formula 20

ISLAND

•IN

* VI

CF CH O yCOE

^ SK

XOCH 2 CF 3 and 3Q (d) reacting the acid with an inorganic acid chloride to give the acid chloride of the formula

ISLAND

! i C- CH_0, CC1 3 2 35 [Q) VI1 'OCIL.CF.

4

DK 164857 B

and then (4) reacting the product of step 3 (b) or step 3 (d) either with 5 2- (aminomethyl) piperidine to give the desired product in one step 10 or with 2- (aminomethyl) pyridine followed by reduction to form the desired product as a free base or optionally in the form of the acetate salt.

The overall process of the invention follows the reaction scheme: 20 25 30 35

DK 164857 B

5

ISLAND

II

Li

Br OCH_CF_ CF „CH_0 XCtf

JL Z Δ ύ Z \ J

5 ^ TIT ^ ~ ΈΓ ~: 'S \ i BTj OCK2CF3 III 0ca2c? 3 (3) U) 10 O' 'O · * f 3 \ fc \ il i! (CF_CH_0 CCC1_ CFoCH_0 CCKCl, 3 2 V-v / 3 2 V-s / 2 _ [O), (3) {b) Ιοί v - ^ OCH-CF-IV ^ AND-jCF ^

15 2 3 2 J

(4)

0 O

1 li

20 r-CF, CH_O CC1 CF ^ Cri-O COH

J Z \ S £ N.

(p [<-Z3UåL · 1 ^ 0! ^ _I

1 * VII ^ '' 'ΟΟΗ ^ γ VI ^^ OCH, CF „Z Δ Z o 25 QT VIII 30 35 6

DK 164857 B

In the first process step, the reactants are heated together in a solvent such as acetone or N, N-dimethylformamide, and in the presence of a base, preferably a weak base such as an alkali metal carbonate, e.g. potassium or sodium carbonate.

Conveniently, the 1,4-dibromobenzene I is reacted with the 2,2,2-trifluoroethoxide ion in a highly polar solvent mixture at a temperature of up to reflux temperature for the solution in the presence of cuprous or cuprous ions to give the desired product II. good yield. The 2,2,2-trifluoroethoxide ion is obtained from the corresponding alcohol by reaction with a strong base such as sodium hydroxide or preferred sodium hydride. Suitable solvent mixtures include dimethyl sulfoxide, Ν, Ν-dimethylacetamide and preferably Ν, Ν-dimethylformamide, each having about 10 to 50%, and preferably about 10%. 20%, 2,2,2-trifluoroethanol. The cup rion is provided e.g. by means of a cuprohalide such as cuproiodide or 20 cuprobromide. The cup rion is provided e.g. with cupri bromide, cupris sulphate or cupri acetate.

In step (2), the compound 1,4-bis (2,2,2-trifluoroethoxy) benzene II prepared in the first step is acetylated by reaction under mild conditions with any acetylating agent such as acetyl chloride or acetic anhydride. in the presence of a Lewis acid catalyst such as tin chloride, ferric chloride or, preferably, aluminum chloride. The acetylation is carried out in an appropriate non-reactive solvent, e.g. a chlorinated hydrocarbon such as dichloromethane, trichlorethylene or 1,2-dichloroethane, diethyl ether and tetrahydrofuran. This reaction yields unexpectedly high yields of the desired aceto-phenone III.

Reaction step (3) (a) is a simple chlorination of intermediate III in a suitable solvent such as

DK 164867 B

7 ethyl acetate, a chlorinated hydrocarbon or, preferably, in acetic acid solution. This reaction is carried out at a moderate temperature, preferably 50 to 60 ° C.

If desired, the product IV may be isolated or the chlorination may be carried out as in step (3) (b) to obtain the intermediate V by the addition of a buffering agent, e.g. an acetate salt, such as sodium acetate, and by slightly increasing the temperature, e.g. to 80 to 100 ° C, with continued chlorination.

The reaction of step (3) (c) is most conveniently carried out by adding the acetophenone III to a cold solution of an alkali metal or alkaline earth metal hydroxide (such as 15 nitrile hydroxide, potassium hydroxide or calcium hydroxide) which has been saturated with chlorine to pH 7 ( the corresponding hypochlorite is formed). The reaction is facilitated by heating the reaction mixture. A very high yield of the desired 2,5-bis (2,2,2-trifluoroethoxy) -20 benzoic acid VI is obtained.

In step (3) (d), the acid is transferred to the corresponding acyl chloride by reaction with an inorganic acid chloride such as thionyl chloride, phosphorus trichloride or phosphorus pentachloride (preferably phosphorus trichloride) by refluxing with or without an appropriate non-reactive solvent such as benzene or toluene or a halogenated hydrocarbon.

Step (4) of the process of the invention can be performed directly from the saturated compound 2- (aminomethyl) -piperidine or indirectly from the unsaturated compound 2- (aminomethyl) pyridine. Thus, 2-aminomethylpiperidine can be reacted with the trichloroacetophenone product of step 35 (3) (b) or the compound 2-aminomethylpyridine can be reacted with the trichloroacetophenone product V of step (3) (b). In each case, the reaction proceeds easily without external reaction.

DK 164857 B

In an inert solvent such as toluene, benzene, isopropyl alcohol, cyclohexane and the like. The reaction proceeds particularly easily and yields a high yield when the pyridine is reacted in a mixture of toluene and cyclohexane.

When the final step of the process is carried out by starting with the acid chloride VII from step (3) (d), it is also carried out directly from 2- (aminomethyl) piperidine or indirectly from 2- (aminomethyl) pyridine. The acid chloride of step (3) (d) is reacted by heating in a non-reactive solvent such as glycol, benzene, toluene or diethyl ether (preferred glycol). Alternatively, 2-aminomethylpyridine may be reacted with the acid chloride of step (3) (d) in the presence of a non-reactive solvent such as toluene or benzene. This mixture is heated at reflux in the presence of an acid acceptor (e.g., a tertiary amine such as triethylamine). The resulting product from the reaction of 2- (aminomethyl) pyridine with either compound V or the compound ice VII is reduced to the desired product VIII by catalytic hydrogenation in the presence of platinum oxide or (preferably) platinum-on-charcoal. The solvent used for this reaction is methanol or a lower alkanoic acid, such as (and preferably) glacial acetic acid, and the preferred temperature range is 15 to 30 ° C. When acetic acid is used, the product obtained is flecainide acetate.

The following examples further explain the invention.

EXAMPLE 1

Step (1): A = Na

To 0.20 mole (9.6 g) of 50% sodium hydride in 40 ml of N, N-35 dimethylformamide is added 40 ml of 2,2,2-trifluoroethanol followed by 0.034 mole (8.0 g) of 1,4-dibromobenzene. and 0.006 mole (1.0 g) of cuprous iodide. The mixture is heated at reflux temperature for 4 hours, then cooled to ca. 25 ° C and filtered. The residue is washed with N, N-dimethylformamide. The solution is then poured into water and the precipitate is separated by filtration. The product is dissolved in diethyl ether and filtered and the filtrate solution is evaporated to give a solid residue which is washed with hexane and dried. The product is 7.3 g (80%) of 1,4-bis (2,2,2-trifluoroethoxy) benzene, m.p. 77 to 79 ° C.

The reaction is then repeated as follows, varying the conditions and ratios of the components and using cupribromide as catalyst: to a mixture of 4.8 g of sodium hydride in 40 ml of Ν, Ν-dimethylformamide is added 20 ml (27.4 g) 2.2 , 2-trifluoroethanol. To this mixture is added 15.034 moles (8.0 g) of 1,4-dibromobenzene and 1.0 g of cupribromide.

The reaction mixture is heated at ca. 100 ° C for two hours, then quenched with ice water. Acidification with hydrochloric acid and filtration give 9.2 g (99%) of white solid 1,4-bis (2,2,2-trifluoroethoxy) benzene. The structure is confirmed by 20 IR spectral analysis.

EXAMPLE 2

Step (2) using acetic anhydride as acetylating agent

To a mixture of 2.43 mole (324 g) of aluminum chloride in 648 ml of dichloromethane is added a solution of 0.88 mole (274 g) of 1,4-bis (2,2,2-trifluoromethoxy) benzene and 0.97 mole ( 92 (30 ml) of acetic anhydride in 880 ml of dichloromethane over a period of 3 hours while maintaining the temperature above 0 ° C. The reaction mixture is then heated to reflux temperature and stirred under reflux for 5 hours. The progress of the reaction is monitored using thin layer chromatography. The reaction mixture is placed in an ice bath, and ice and 10% hydrochloric acid are added slowly to decompose the aluminum chloride complex. Reaction bias 10

DK 164857 B

the temperature of the thing is not allowed to exceed 25 ° C. The organic phase is separated and washed once with 2 liters of 10% hydrochloric acid and then with 2 liters of water. The combined aqueous phase is extracted with several liters of dichloromethane.

The organic phase is dried over magnesium sulfate and then evaporated to give a moist residue. Hexane is added to the residue and the resulting solid is collected by filtration and washed with hexane. After drying, 250 g of pale yellow crystalline 2,5-bis (2,2,2-trifluoroethoxy) aceto-phenone are obtained. The yield is 90%, m.p. 84 to 96 ° C.

EXAMPLE 3

Example 2 performed on a larger scale 15

To a mixture of 4.367 g (32.75 moles) of aluminum chloride and 8.8 liters of dichloromethane at 0 ° C is gradually added a solution of 3,267 g, 4-bis (2,2,2-trifluoroethoxy) benzene and 1,399 kg (13, 7 moles of acetic anhydride in 1.3 liters of dichloromethane. The reaction mixture is maintained at 5 to 10 ° C with stirring of the mixture for 16 hours. The reaction mixture is then heated to reflux temperature and kept under reflux for 4 hours. The reaction mixture is then acidified with 8.76 kg of 10% hydrochloric acid. Ice 25 is added to the mixture to keep the temperature below 20 ° C. The organic layer is separated and the aqueous layers are extracted several times with dichloromethane. The organic layers are dried, then evaporated to give a residue which is triturated with hexane to give a yellow solid product. Two portions of the product are obtained, giving a total yield of 3,088 kg of 2,5-bis (2,2,2-trifluoroethoxy) acetopheone, m.p. 84-88 ° C, yield 82%.

35 11

DK 164857 B

EXAMPLE 4

Step (2) using acetyl chloride as acetylating agent 5

To a mixture of 0.022 mole (2.8 g) of aluminum chloride and 100 ml of 1,2-dichloroethane is added dropwise at 25 ° C a solution of 0.020 mole (5.6 g) of 1,4-bis (2.2,2 g). trifluoroethoxy) benzene and 0.022 mole (1.7 g) of acetyl chloride in 20 ml of 1,2-dichloroethane. After stirring for 4 hours, the reaction mixture is washed with ice water and hydrochloric acid and the organic layer is dried. Evaporation gives a residue which is recrystallized from hexane to give 4.1 g (71%) of light yellow needles of 2,5-bis (2,2,2-trifluoroethoxy) acetophenone (as shown by IR spectral analysis).

EXAMPLE 5

Step (3) (a) 20

A mixture of 0.25 mole (79.1 g) of 2,5-bis (2,2,2-trifluoroethoxy) acetophenone in 150 ml of acetic acid is heated to 50 ° C. Gaseous chlorine is bubbled into the solution and the temperature gradually rises to 55 ° C. The chlorine addition rate is adjusted so that the temperature is maintained between 55 and 60 ° C. After approx. After 75 minutes, the temperature begins to drop (indicating that no chlorination is taking place anymore). The total amount of chlorine added is 35.5 g.

30

The resulting product is 2,5-bis (2,2,2-trifluoroethoxy) -α, α-dichloroacetophenone.

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DK 164857 B

EXAMPLE 6 Step (3) (b) 5 To the product of the preceding example is added (without isolation or purification) 0.35 mole (28.7 g) of sodium acetate. The temperature is increased to approx. 80 ° C and the solution is heated to 85 ° C. The chlorine addition is repeated and the temperature rises to 100 ° C. After approx. For 20 minutes 10, the theoretical amount of chlorine has been absorbed and the mixture is poured into a mixture of ice and water. The precipitate formed is collected by filtration, rinsed with water, dissolved in dichloromethane and dried. Evaporation gives a residue which is triturated with hexane to give a white solid. A yield of 94 g (90%) of 2,5-bis (2,2,2-trifluoroethoxy) -α, α, α-trichloroacetophenone, m.p. 45-48 ° C is obtained.

EXAMPLE 7 20

Step (3) (c)

To a solution of 7.3 moles (292 g) of sodium hydroxide in 600 ml of water is added ice so that the total volume becomes 1.75 25 liters. Gaseous chlorine is added to the solution while the temperature is kept below 10 ° C, the addition lasting until the reaction mixture is neutral to litmus and 2.19 mol (87.6 g) of sodium hydroxide dissolved in 200 ml of water is added. The combined solution is heated to 50 ° C, and 0.73 mole (230 g) of 2,5-bis (2,2,2-trifluoroethoxyacetophenone) is slowly added. The reaction mixture is stirred under heating until an exothermic reaction begins at about 75 And the reaction mixture is then maintained at ca.

80 ° C on cooling. The mixture is stirred for approx. 16 hours at 35 approx. 80 to 90 ° C, while the reaction rate is followed by thin-layer chromatography. The excess hypochlorite is then destroyed by the addition of 75 g of sodium bisulfite in 250 ml

DK 164857 B

13 water and the mixture is cooled to ca. 25 ° C and carefully acidified with 10% hydrochloric acid. The pale yellow solid product is collected by filtration, washed with water and dried. A yield of 94.5% of 2,5-bis (2,2,2-trifluoroethoxy) benzoic acid is obtained, m.p. 120-122 ° C.

EXAMPLE 8

Step (3) (d) 10

To a solution of 0.688 mole (219 g) of 2,5-bis (2,2,2-trifluoroethoxy) benzoic acid in 657 ml of benzene, slowly add 1.376 mole (100 ml) of thionyl chloride over 1 hour while heating to ca. 60 ° C. The mixture is then heated at reflux for approx. For 8 hours, it is evaporated to give the desired product 2,5-bis (2,2,2-trifluoroethoxy) benzoic acid chloride as a residue. The structure is confirmed by IR spectral analysis.

EXAMPLE 9

Step (4) performed in two reactions starting with the intermediate V

To a solution of 0.05 mole (21.0 g) of 2,5-bis (2,2,2-trifluoroethoxy) -α, α, o-trichloroacetophenone in 60 ml of toluene is added dropwise a solution of 0.055 mole (6.0 g) of 2-aminomethylpyridine in 50 ml of cyclohexane and 10 ml of toluene. The reaction is exothermic and a precipitate-30 drop is formed immediately. More toluene and cyclohexane are added to obtain a mixing consistency which allows stirring, and stirring is continued for 2 hours at ca. 25 ° C. The solid is then separated by filtration, washed with a mixture of toluene and cyclohexane and dried to give a white solid. The product is 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-pyridylmethyl) benzamide, m.p. 104-106 ° C, 17.8 g, 89% yield.

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DK 164857 B

A mixture of 0.33 moles (134.7 g) of 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-pyridylmethyl) benzamide, 1.347 liters of glacial acetic acid and 13.5 g of 5% s palladium-on-coal is reduced in Parr's apparatus by approx. 30 pounds of hydrogen at room temperature.

5

The reaction is complete in 6-7 hours. The reaction mixture is filtered and the catalyst is washed with isopropyl alcohol. The solution and the wash water are evaporated to give a residue. Hexane is added to the residue and the resulting white solid solid is collected and recrystallized from a mixture of acetone and hexane. A yield of 71% of 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-piperidylmethyl) benzamide acetate is obtained, m.p. 150-152 ° C. By concentrating the residual liquid, an additional 18% product is obtained as a second portion, with a melting point of 148-150 ° C.

EXAMPLE 10

Step (4) is carried out in a single reaction from intermediate V

To a solution of 0.01 mole (4.19 g) of 2,5-bis (2,2,2-trifluoroethoxy) -α, α, α-trichloroacetophenone in 50 ml of isopropyl alcohol is added 0.01 mol ( 1.2 g) 2-Aminomethylpiperidine.

The mixture gradually solidifies over a period of 30 minutes. The mixture is allowed to settle for approx. 16 hours, then 0.01 M acetic acid and 5 ml of isopropyl alcohol are added and the solution is heated to dissolve all solid. After cooling, 3.0 g of white solid are obtained. The filtrate is evaporated and the residue is recrystallized from isopropyl alcohol to give more product as a white solid. The product is 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-piperidylmethyl) benzamide acetate, which was shown by IR and NMR spectra.

EXAMPLE 11

Step (4) is performed in two reactions from the intermediate VII 5

To a mixture of 0.77 mole (83.3 g) of 2-aminomethylpyridine, 0.77 mole (106.7 ml) of triethylamine and 300 ml of benzene is added 0.70 mole (236 g) of 2,5-bis ( 2,2,2-trifluoroethoxy) benzoic acid chloride in 472 ml of benzene over 1 hour.

10

The reaction mixture is stirred for 16 hours at 25 ° C, refluxed for 1 hour and then washed twice with 2 liters of water. The aqueous phase is washed with 2 liters of benzene and the combined organic phases are dried over 15 magnesium sulfate and evaporated under vacuum. Recrystallization from a mixture of benzene and hexane gives 240 g, 86%, off-white 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-pyridylmethyl) benzamide, m.p. 100-102 ° C.

A mixture of 0.33 moles (134.7 g) of 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-pyridylmethyl) benzamide, 1.347 liters of glacial acetic acid and 13.5 g of 5% platinum-on-coal is reduced in Parr's apparatus at a hydrogen pressure of approx. 10 pounds at room temperature. The reaction is complete in 6 to 7 hours.

The reaction mixture is filtered and the catalyst is washed with isopropyl alcohol. The solution and washings are evaporated to give a residue. Hexane is added to the residue and the resulting white solid is collected and recrystallized from a mixture of acetone and hexane. A yield of 71% of 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-piperidylmethyl) benzamide acetate is obtained in m.p. 150-152 ° C. Concentrating the remaining liquid gives an additional 18% product as a second portion, mp 148-150 ° C.

35

Claims (2)

A process for the preparation of 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-piperidylmethyl) benzamide of the formula 0 15 / N CF 2 C 2 N VIII 10. K and 2cf3 characterized by reacting 1,4 (dibromobenzene) of the formula for R Br - 20 with a suitable alkali metal 2,2,2-trifluoroethoxide of the formula CF3CH20-A wherein A is an alkali metal to give 1,4-bis (2,2,2-trifluoroethoxy) benzene of the formula 30 tsi XOCH2CF3 35 (2) in the presence of a Lewis acid catalyst acetylates it to give 2 5-bis (2,2,2-trifluoroethoxy) aceto-phenone of the formula DK Ί648ϋ / b OI! (OC) (10) either 10 (a) chlorines the substituted acetophenone in acetic acid to give 2,5-bis (2,2,2-trifluoroethoxy) -α, α-di-chloroacetophenone and 15 (b) adds a buffering base and further chlorates to give 2,5-bis (2,2,2-trifluoroethoxy) -α, α, α-tri-chloroacetophenone of the formula 020 | V CF, CH_O CCCI, OCH-CF, or z (c) react the substituted acetophenone with hypochlorite to give 2,5-bis (2,2,2-trifluoroethoxy) benzoic acid and 30 (d) reacting the acid with an inorganic chloride to give the acid chloride of formula 0 II C? 3CH2 ° W ^ Ca 35 TO! VI1 0C »2 ^ · 3 DK 164857 B (4) and then reacting the product of step (3) (b) or step (3) (d) with either 2- (aminomethyl) piperidine to form the desired final product in one step or with 2- (aminomethyl) pyridine followed by reduction to form the desired final product, optionally in the form of the acetate salt. Process according to claim 1, characterized in that 1,4-bis (2,2,2-trifluoroethoxy) benzene is prepared by reaction between 1,4-dibromobenzene and alkali metal-2,2,2-trifluoroethoxide in the presence of cupro - or cuprions in a highly polar solvent. 15 20 25 30 35