NL8001551A - PROCESS FOR THE PREPARATION OF 2,5-BIS (2,2,2-TRIFLUORETHOXY) -N- (2-PIPERIDYMETHYL) -BENAMIDE. - Google Patents

Description

N / 2 9.5 2 8-Kp / vdM A 4 - 1 -

Process for the preparation of 2,5-bis- (2,2,2-trifluoro-ethoxy) -N- (2-piperidylmethyl) -benzamide.

The invention relates to an improved process for the preparation of the anti-arrhythmically active compound 2,5-bis- (2,2,2-trifluoroethoxy) -N- (2-piperidyl-methyl) -benzamide (flecainide) and salts thereof of bromo-5 or hydroxy-substituted benzene compounds. The invention also relates to certain intermediates obtained in the process.

U.S. Pat. No. 3,900,481 discloses the anti-arrhythmically active compound flecainide having formula 1 of the formula sheet, the salts of this compound and a method of preparation.

The method according to the invention is preferred over the known method because of various practical advantages, eg the relatively low cost of the starting materials, the ease with which the different steps can be carried out and the relatively high yields of the desired product.

The present invention is characterized in that: a compound of formula 2, in which both X's are equal and hydroxy or bromine, is reacted with a suitable alkylating agent of formula 3, in which: A is -SO-jCFg or an alkali metal, to prepare a compound of formula 4, 25 (2) this compound acetylates in the presence of a Lewis acid as a catalyst, to prepare a substituted acetophenone of formula 5, (3) or (a) converting the substituted acetophenone by chlorination to the corresponding α, α-dichloroacetophenone and (b) adding a base as a buffer and further chlorinating the compound to the α, α, α-trifluoroacetophenone of formula 7, Or (c) deprotected the substituted acetophenone with hypo-800 1 5 51-2-chlorite into the corresponding benzoic acid and (d) convert the acid with an inorganic acid chloride to the corresponding acid chloride of formula 9 and then (4) the compound obtained from the step 3 (b) or 3 (d) reacts either in one step with 2- (aminomethyl) -piperidine to the desired product, or with 2- (aminomethyl) -pyridine, followed by reduction to the desired product, optionally as free base.

The methods using steps (1), (1) - (2); (3) (a); (3) (c)? (1), (2) and (3) (c)? (3) (b); (3) (a) and (3) (b); and (4) include, as described above, separate aspects of the overall invention. The same applies to the intermediates of formula 10, in which B is -CH 2, -CHCl 2 or -CCl 2.

The total method according to the invention is shown in the reaction scheme.

In the first step of the process, A is preferably -SC ^ CF ^ when X is hydroxy. The starting compounds are heated together in a solvent, e.g. acetone or N, N-dimethylformamide in the presence of a base, preferably a weak base, such as an alkali metal carbonate, e.g. potassium or sodium carbonate.

If X is bromine, 1,4-dibromobenzene of formula 2 is reacted with the 2,2,2-trifluoroethoxide ion in a highly polar solvent mixture at a temperature up to the boiling temperature of the solution in the presence of cuprous or cupric ions to prepare the desired product of formula IV in 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 preferably sodium hydride. Suitable solvent mixtures include dimethylsulfoxide, Ν, Ν-dimethylacetamide and preferably N, N-35 dimethylformamide, each containing about 10-50%, preferably 20%, of 2,2,2-trifluoroethanol. For example, cupro ions can be provided by a cupro halide, such as cuproiodide or cuprobromide. For example, cupric ions are provided by cupric bromide, cupric sulfate or cupric acetate.

In step (2), the 1,4-bis- (2,2,2-trifluoro-ethoxy) -benzene of formula 4, which is prepared in the first step, is acetylated by leaving the compound under mild reaction conditions react with an acetylating agent, e.g., acetyl chloride or acetic anhydride in the presence of a Lewis acid as a catalyst, e.g., tin chloride, ferric chloride, or preferably, aluminum chloride. The acetylation is carried out in a suitable inert solvent, such as chlorinated hydrocarbon, eg dichloromethane, trichlorethylene or 1,2-dichloroethane, diethyl ether, tetrahydrofuran and the like.

This reaction surprisingly gives high yields of the desired acetophenone of formula 5.

The reaction of step (3) (a) is simply a chlorination of the intermediate of formula 5, in a suitable solvent, such as ethyl acetate, a chlorinated hydrocarbon or, preferably, a solution of acetic acid. This reaction is carried out at an elevated temperature, preferably 50-60 ° C.

The compound of formula 6 can be isolated if desired, but chlorination can also be continued, carrying out step (3) (b), to obtain the intermediate of formula 7 by adding a buffer, eg an acetate, such as sodium acetate, and slightly raise the temperature, e.g., to 80-100 ° C, while chlorination is continued.

The reaction of step (3) (c) is preferably carried out by adding the acetophenone of formula 5 to a cold solution of an alkali or alkaline earth metal hydroxide (such as sodium hydroxide, potassium hydroxide or calcium hydroxide) which is saturated with chlorine to pH 7 to form the corresponding hypochlorite). The reaction is then facilitated by heating the reaction mixture. A very high yield of the desired 2,5-bis- (2,2,2-35 trifluoroethoxy) -benzoic acid of formula 8 is thus obtained.

In step (3) (d), the acid is converted to the corresponding acyl chloride by reaction with an inorganic acid chloride, such as thionyl chloride, phosphorus trichloride or phosphorus pentachloride (preferably phosphorus trichloride) at reflux temperature at boiling temperature with or without a suitable inert solvent, such as benzene or toluene or a halogenated hydrocarbon.

Step (4) of the process can be carried out directly from the saturated diamine 2- (aminomethyl) -piperidine or indirectly from the non-reduced diamine 2- (aminomethyl) -pyridine. Thus, 2-amino-methylpiperidine can be reacted with the trichloroacetophenone compound 10 from step (3) (b) or the compound 2-aminomethylpyridine can be reacted with the trichloroacetophenone compound of formula 7 from step (3) (b). In both cases, the reaction proceeds easily without external heating in an inert solvent such as toluene, benzene, isopropyl alcohol, cyclohexane and the like.

The reaction takes place especially easily and in high yield when the unreduced diamine is used in a mixture of toluene and cyclohexane.

If the last step of the process is carried out starting from the acid chloride of formula 9 from step 20 (3) (d), it can also be carried out directly starting from 2- (aminomethyl-piperidine or "Indirectly, starting from 2- (aminomethyl) -pyridine The acid chloride compound from step (3) (d) is reacted by heating it in an inert solvent such as glym, benzene, toluene or diethyl ether (preferably 25 glym). Also 2-aminomethylpyridine reacting with the acid chloride compound of step (3) (d) in the presence of an inert solvent such as toluene or benzene This mixture is refluxed in the presence of an acid binding agent (eg a tertiary amine such as triethylamine). adduct obtained from the reaction of a 2- (aminomethyl) -pyridine with compound 7 or compound 9 is reduced to the desired compound of formula 1 by catalytic hydrogenation in the presence of platinum oxide or (e.g. or preference) platinum-on-carbon. The solvent used for this reaction is methanol or a lower alkane carboxylic acid, such as (and preferably) glacial acetic acid, the temperature preferably being in the range of 15 to 30 ° C. If acetic acid is used, the resulting compound is 800 1 5 51 t-5-bond flecainide acetate.

The following non-limiting examples illustrate the methods of the invention and the preparation of the intermediates obtained thereby.

EXAMPLE I

Step (1) of the method: A = SC ^ CF ^ and X = OH

To a mixture of 2.42 mol. (334.4 g) potassium carbonate, 2.2 mol. (510.6 g) 2,2,2-trifluoroethyl-trifluoromethane sulfonate in 1.02 L of acetone is slowly dissolved in 1.0 mole over 2 hours. (110 g) hydroquinone in 1.1 liters of acetone was added. The mixture is then refluxed for 24 hours and then evaporated, after which 2 liters of chloroform and 2 liters of water are added to the residue. The chloroform layer is separated, the water layer is washed twice with 1 liter of chloroform and the combined chloroform solution is washed with 1 liter of water. The chloroform solution is dried over magnesium sulfate and then concentrated under reduced pressure. Hexane is added to the residue and the solid product is collected by filtration and washed with hexane. Additional material is collected from the concentrated residues. 241 g (88%) of 1,4-bis- (2,2,2-trifluoroethoxy) -benzene, m.p. 75-77 ° C.

EXAMPLE II

Step (1): A = Na and X = Br.

To 0.20 mol. (9.6 g) 50% sodium hydride in 40 ml of Ν, Ν-dimethylformamide, 40 ml of 2,2,2-trifluoroethanol are added, followed by 0.034 mol. (8.0 g) 1,4-dibromobenzene and 0.006 mol. (1.0 g) cuprous iodide. The mixture is refluxed for 4 hours, then cooled to about 25 ° C and filtered. The residue is washed with Ν, Ν-dimethylformamide. The solution is then poured into water and the precipitate is separated by filtration. The product is dissolved in diethyl ether and filtered, the filtrate is evaporated, leaving a solid residue, which is washed with hexane and then dried.

The product is 1,4-bis- (2,2,2-trifluoroethoxy) -benzene in a yield of 7.3 g (80%), m.p. 77-79 ° C.

80 0 1 5 5 ^ - 6 -

The reaction is run again as follows, changing the conditions and properties of the starting compounds and using cupribromide as a catalyst: to a mixture of 4.8 g of sodium hydride in 5 40 ml of ΙΊ / Ν-dimethylformamide, 20 ml (27 , 4 g) 2,2,2-trifluoroethanol. 0.034 mol. Is added to this mixture. (8.0 g) 1,4-dibromobenzene and 1.0 g cupric bromide added. The reaction mixture is heated at about 100 ° C for 2 hours and then quenched with ice water. Acidification with hydrochloric acid and filtration yields 9.2 g (99%) of the white solid 1,4-bis- (2,2,2-trifluoroethoxy) -benzene. The structure is confirmed by IR spectroscopy.

EXAMPLE III

Step (2) using acetic anhydride as the acetylation ring agent.

To a mixture of 2.43 mol. (324 g) aluminum chloride in 648 ml of dichloromethane becomes a solution of 0.88 mol. (274 g) 1,4-bis- (2,2,2-trifluoroethoxy) -benzene and 0.97 mol. (92 ml) acetic anhydride in 880 ml dichloromethane 20 over a period of 3 hours, keeping the temperature above 0 ° C. The reaction mixture is then heated to boiling temperature and refluxed for 5 hours with stirring. The progress of the reaction is monitored by thin layer chromatography. The reaction mixture is then placed in an ice bath and ice and 10% hydrochloric acid are slowly added to decompose the aluminum chloride complex. Care is taken that the temperature of the reaction mixture does not 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 leave a moist residue. Hexane is added to this 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) acetophenone are obtained. The yield is 90%, the mp. 84-86 ° C.

800 1 5 51 λ * - 7 -

EXAMPLE IV

Scaling up the method of Example III.

To a mixture of 4,367 g (32.75 mol.) Of aluminum chloride and 8.8 liters of dichloromethane, a solution of 3,267 g of 1,4-bis- (2,2,2-trifluoroethoxy) is slowly added at 0 ° C. ) benzene and 1,399 kg (13.7 mol.) acetic anhydride in 1.3 liters of dichloromethane are added. The reaction temperature is kept at 5-10 ° C while the mixture is stirred for about 16 hours. The reaction mixture is then heated to boiling temperature and refluxed for 4 hours. The reaction mixture is then acidified with 8.76 kg of 10% hydrochloric acid. Ice is added to the mixture to keep the temperature below 20 ° C. The organic layer is separated and the water layers are extracted several times with dichloromethane. The organic layers are dried and then evaporated, yielding a residue, which is triturated with hexane to yield a yellow solid product. Two yields of the product are obtained, with a total yield of 3.088 kg of 20 (32%) 2,5-bis- (2,2,2-trifluoroethoxy) acetophenone, m.p. 84-88 ° C.

EXAMPLE V

Step (2), using acetyl chloride as the acetylating agent.

To a mixture of 0.022 mol. (2.8 g) aluminum-25 chloride and 100 ml 1,2-dichloroethane are added dropwise at 25 ° C to a solution of 0.020 mol. (5.6 g) 1,4-bis- (2,2,2-trifluoroethoxy) -benzene and 0.022 mol. (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. After evaporation, a residue is recrystallized from hexane to give 4.1 g (71%) of light yellow needles of 2,5-bis- (2,2,2-trifluoroethoxy) -acetophenone. The structure is confirmed by IR spectroscopy.

EXAMPLE VI

Step (3) (a).

A mixture of 0.25 mol. (79.1 g) of 2,5-bis- (2,2,2-trifluoroethoxy) acetophenone in 150 ml of acetic acid is heated 800 1 5 51-8 to 50 ° C. Chlorine gas is bubbled into this solution and the temperature gradually rises to 55 ° C. The rate of the chlorine addition is controlled by keeping the temperature between 55 and 60 ° C. After about 75 minutes, the temperature begins to drop, indicating that chlorination is no longer taking place. The total amount of chlorine added is 35.5 g. The product obtained is 2,5-bis- (2,2,2-trifluoroethoxy) -α, α-dichloroacetophenone.

EXAMPLE VII

10 Step (3) (b).

0.35 mol. Is added to the compound of the previous example (without isolation or purification). (28.7 g) sodium acetate added. The temperature rises to about 80 ° C and the solution is heated to 85 ° C. The chlorine addition 15 is resumed and the temperature rises to 100 ° C. After about 20 minutes the theoretical amount of chlorine is taken up, after which the mixture is poured into a mixture of ice and water. The resulting precipitate is collected by filtration, rinsed with water, dissolved in dichloromethane and dried.

Evaporation yields a residue, which is triturated with hexane to a white solid. 94 g (90%) of 2,5-bis- (2,2,2-trifluoroethoxy) -a, a, a-trichloroacetophenone, m.p. 45-48 ° C.

EXAMPLE VIII Step (3) (c).

To a solution of 7.3 mol. (292 g) sodium hydroxide in 600 ml water, ice is added to a total volume of 1.75 liters. Chlorine gas is passed through the solution, keeping the temperature below 10 ° C until the solution is neutral on litmus, after which 2.19 mol. (87.6 g) sodium hydroxide dissolved in 200 ml of water is added. The combined solution is heated to 50 ° C after which 0.73 mol. (230 g) 2,5-bis- (2,2,2-trifluoroethoxy) -aceto-phenone is added slowly. The reaction mixture is stirred with heating until an exothermic reaction starts at about 75 ° C, after which it is kept at about 80 ° C by cooling. The mixture is stirred at about 80-90 ° C for about 16 hours, following the course by thin layer chromatography of 800 1 5 51-9. Subsequently, the excess hypochlorite is destroyed by adding 75 g of sodium bisulfite in 250 ml of water, after which the mixture is cooled to about 25 ° C and carefully acidified with 10% hydrochloric acid. The light yellow solid product is collected by filtration, washed with water and dried. 2,5-bis- (2,2,2-trifluoroethoxy) -benzoic acid is obtained, in a yield of 94.5%, m.p. 120-122 ° C.

EXAMPLE IX 10 Step (3) (d).

To a solution of 0.688 mol. (219 g) 2,5-bis- (2,2,2-trifluoroethoxy) -benzoic acid in 657 ml of benzene slowly becomes 1,376 mol for 1 hour at about 60 ° C. (100 ml) thionyl chloride added. The mixture is then refluxed for about 8 hours, then evaporated, yielding the desired product 2,5-bis- (2,2,2-trifluoroethoxy) -benzoic acid chloride as residue. The structure is confirmed by IR spectroscopy.

EXAMPLE X

Step (4), performed in two reactions, starting from the intermediate of formula 7.

To a solution of 0.05 mol. (21, Og) 2,5-bis- (2,2,2-trifluoroethoxy) -α, α, α-trichloroacetophenone in 60 ml of toluene is added dropwise to a solution of 0.055 mol.

25 (6.0 g) of 2-aminomethylpyridine in 50 ml of cyclohexane and 10 ml of toluene are added. The reaction is exothermic and a precipitate forms immediately. Then an additional amount of toluene and cyclohexane is added to obtain a mixture that can be stirred and stirred at about 25 ° C for 2 hours. The solid is then separated by filtration, washed with a mixture of toluene and cyclohexane and dried to yield a white solid. The compound is 2,5-bis- (2,2,2-trifluoroethoxy) -N- (2-pyridylmethyl) -benzamide, m.p. 104-106 ° C, yield 17.8 g of 35 (89%).

A mixture of 0.33 mol. (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-carbon is reduced t 800 1 5 51 - 10 - in an apparatus according to Parr at approx. 200 kPa of hydrogen at room temperature. The reaction is completed in 6-7 hours. The reaction mixture is filtered and the catalyst is washed with isopropyl alcohol. The solution and the washing liquid are evaporated to leave a residue. Hexane is added to this residue and the resulting white solid is collected and recrystallized from a mixture of acetone and hexane. A 71% yield of 2,5-bis- (2,2,2-trifluoro-ethoxy) -N- (2-piperidylmethyl) -benzamide acetate with m.p.

10 of 150-152 ° C is obtained. By concentrating the residual liquid, an additional 18% of the compound is obtained as a second yield with a mp. from 148-150 ° C. EXAMPLE XI

Step (4), performed in a single reaction, starting from the intermediate of formula 7.

To a solution of 0.01 mol. (4.19 g) 2,5-bis- (2,2,2-trifluoroethoxy) -a, a, a-trichloroacetophenone in 50 ml of isopropyl alcohol becomes 0.01 mol. (1.2 g) of 2-aminomethylpiperidine added. The mixture solidifies gradually over a period of 30 minutes. The mixture settles for about 16 hours, after which 0.01 mol. acetic acid and 5 ml of isopropyl alcohol are added and the solution is heated to dissolve any solid. After cooling, 3.0 g of a white solid are obtained. The filtrate is evaporated and the residue is recrystallized from isopropyl alcohol to obtain an additional amount of product in the form of a white solid. The product is 2,5-bis- (2,2,2-trifluoroetho-xy) -N- (2-piperidylmethyl) -benzamide acetate according to the IR and NMR spectra.

EXAMPLE XII

Step (4), performed in two reactions, starting from the intermediate of formula 9.

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

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

A mixture of 0.33 mol. (134.7 g) of 2,5-bis-10 (2,2,2-trifluoroethoxy) -N- (2-pyridylmethyl) -benzamide, 1,347 liters of glacial acetic acid and 13.5 g of 5% platinum-on-charcoal are a Parr device reduced at a hydrogen pressure of approximately 70 kPa at room temperature. The reaction is completed in 6-7 hours. The reaction mixture is filtered and the catalyst is washed with isopropyl alcohol. The solution and washings are evaporated to leave a residue. Hexane is added to this residue and the resulting white solid is collected and recrystallized from a mixture of acetone and hexane. 2,5-Bis- (2,2,2-trifluoro-20-ethoxy) -N- (2-piperidylmethyl) -benzamide acetate in yield of 71%, mp. 150-152 ° C. By concentrating the residual liquid, an additional 18% of the compound is obtained as a second yield, m.p. 148-150 ° C.

25 80 0 1 5 51

Claims (10)

Process for preparing a compound of the formula 1, characterized in that (1) a compound of the formula 2, in which the two X's are equal and represent OH or bromine, reacts with a suitable alkylating agent of the formula 3, wherein A is -SO 2 CF 3 or an alkali metal, to 1,4-bis- (2,2,2-trifluoroethoxy) -benzene, (2) the resulting compound acetylates in the presence of a Lewis acid as a catalyst, to 2,5-bis- (2,2,2-trifluoroethoxy) -acetophenone, (3) or (a) the substituted acetophenone compound chlorinates in acetic acid to form 2,5-bis- (2,2,2-trifluoroethoxy) - a, a-dichloroacetophenone and (b) adding a base as a buffer and the compound further chlorinating to 2,5-bis- (2,2,2-trifluoroethoxy) -α, α, α-trichloroacetophenone or (c) the substituted acetophenone reacts with hypochlorite to form 2,5-bis- (2,2,2-tri ------------ - ,, __ fluorethoxy) benzoic acid and (d) the acid with an ariorgari is ctT converts chi ori into the acid chloride, (4) and then the ve The bond from step (3) (b) or step (3) (d) reacts in one step either with 2- (aminomethyl) piperidine to the desired product or with 2- (aminomethyl) pyridine and the resulting compound reduces to the desired product, optionally as a free base. 2. Process for the preparation of the compound 1,4-bis- (2,2,2-trifluoroethoxy) -benzene, characterized in that a compound of formula 2, in which the two X's are equal and OH or bromine, reacts with a suitable alkylating agent of formula 3, wherein A is -SO 2 CF 2 or an alkali metal. 3. Process for preparing the compound 2,5-bis- (2,2,2-trifluoroethoxy) -acetophenone, characterized in that (1) a compound of formula 2, in which both 800 1 5 51 - 13 - X's being equal and representing OH or bromine, reacts with a suitable alkylating agent of formula 3, wherein A is -SO2CF2 or an alkali metal, to form 1,4-bis (2,2,2-trifluoroethoxy) -benzene and 5 (2) this compound acetylates in the presence of a Lewis acid as a catalyst. 4. Process for preparing the compound 2.5-bis- (2,2,2-trifluoroethoxy) -ct, α-dichloroacetophenone, characterized in that 2,5-bis- (2,2,2-trifluoroetho) - 10 xy) acetophenone chlorides. 5. Process for preparing 2,5-bis- (2,2,2-trifluoroethoxy) -α, α, α-trichloroacetophenone, characterized in that a base is added as a buffer to 2.5-bis- (2, 2,2-trifluoroethoxy) -a, α-dichloroacetophenone and this compound chlorides. 6. Process for preparing 2,5-bis- (2,2,2-trifluoroethoxy) -α, α, α-trichloroacetophenone, characterized in that (1) 2,5-bis- (2,2 , 2-trifluoroethoxy) -acetophenone 20 chlorinates to the corresponding ct, α-dichloroetophenone ~ en- ----------------- (2) - add a base as buffer and further chlo -Rates to 2,5-bis- (2,2,2-trifluoroethoxy) -α, α, α-trichloroaceto-phenone. 7. Process for preparing 2,5-bis- (2,2,2-25-trifluoroethoxy) -benzoic acid, characterized in that 2,5-bis- (trifluoroethoxy) -acetophenone is reacted with hypchlorite. 8. Process for preparing 2,5-bis- (2,2,2-trifluoroethoxy) -benzoic acid, characterized in that (1) a compound of formula 2, wherein both X's are equal and OH or bromine, reacts with a suitable alkylating agent of formula 3, wherein A is -SC ^ CF ^ or an alkali metal, to form 1,4-bis- (2,2,2-trifluoroethoxy) -benzene, (2) de compound in the presence of a Lewis acid as a catalyst acetylates to 2,5-bis- (2,2,2-trifluoroethoxy) -acetophenone and 800 1 5 51 - 14 - (3) the substituted acetophenone reacts with hypochlorite to the desired acid. 9. Process for preparing 2,5-bis- (2,2,2-trifluoroethoxy) -N- (2-piperidylmethyl) -benzamide / characterized in that 2,5-bis- (2,2, 2-trifluoroetho-xy) -a, a, a-trichloroacetophenone reacts in one step either with 2- (aminomethyl) -piperidine to the desired product or with 2- (aminomethyl) -pyridine and reduces the resulting compound to the desired product , optionally as a free base. 10. A compound of formula 10, wherein B is -CH2, ~ CHCl2, or “CC13. 15 80 0 1 5 51