CH643829A5 - METHOD FOR PRODUCING 2,5-BIS (2,2,2-TRIFLUORAETHOXY) -N- (2-PIPERIDYLMETHYL) BENZAMIDE. - Google Patents

Description

65 The invention relates to a process for the preparation of 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-piperidylmethyl) benzamide (flecainide) and its salts from bromine- or hydroxy-substituted benzenes. This connection is

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suitable for the treatment of cardiac arrhythmias.

The antiarrhythmic compound flecainides and their salts and a process for their preparation are described in US Pat. No. 3,900,481. The connection corresponds to the formula:

cf3ch2o

0 h

1 i c-n-ch.

och2of3

-O

10th

CF3CH20

och_cf_

and ^ o b) adding a base as a buffer and further chlorination to form the a, a, a-trichloroacetophenone viiiis

The method according to the invention is superior to the known method for various practical reasons. It is based on relatively simple, inexpensive starting materials, the individual process steps can be carried out very easily and the desired product is obtained in high yields.

The method according to the invention comprises the following stages:

1. Implementation of a compound of the formula cf3ch2o

20th

och2cf3

25 or c) reaction of the substituted acetophenone with hypochlorite to form the corresponding benzoic acid in which the radicals X are the same and each represent a hydroxyl group or a bromine atom, with an alkylating agent of the formula

CF3CH20-A

in which A represents the group -S02CF3 or an alkali atom, with the formation of a compound of the formula cf3ch2 °

och2cf3

40

and cf3ch20

och2cf3

2. Acetylation of this compound in the presence of a Lewis acid as a catalyst to form a substituted acetophenone of the formula cp3ch2o d) reaction of the acid with an inorganic acid chloride to form the acid chloride cf3ch2 °

och2cf,

50

och2cf,

and then 55 4. Implementation of the product of stage 3 b) or 3 d) optionally with

2- (aminomethyl) piperidine

60 to form the desired product in one step or with

2- (aminomethyl) pyride

3. optionally a) chlorination of the substituted acetophenone to form the corresponding a, a-dichloroaceto-phenone of the formula

65 and subsequent reduction to form the desired product, optionally as a free base.

The entire process according to the invention proceeds according to the following scheme:

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O

In the first stage of the process, when X is OH, A is conveniently -S02CF3 and the reactants are combined together in a solvent such as acetone, N, N-dimethylformamide and in the presence of a base, preferably a weak base such as alkali carbonate, e.g. Potassium or sodium carbonate, heated.

If X is Br, the 1,4-dibromobenzene I is expediently mixed with the 2,2,2-trifluoroethoxide ion in a strongly polar solvent mixture at a temperature up to the reflux temperature of the solution in the presence of copper I or copper II ions reacted to obtain the desired product II 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 dimethyl sulfoxide, N, N-dimethylacetamide and preferably N, N-dimethylformamide, each together with about 10 to 50% and preferably about 20% 2,2,2-trifluoroethanol. The copper-I-ions are supplied, for example, by a copper-I-halo genide such as copper-I-iodide or copper-I-bromide. The copper-II ions are supplied by, for example, copper-II-bromide, copper-II-sulfate or copper-II-acetate.

In step (2), the 1,4-bis (2,2,2-trifluoroethoxy) benzene II formed in step (1) is reacted with an acetylating agent such as acetyl chloride or acetic anhydride in the presence of a Lewis acid such as tin chloride, Iron III chloride or, preferably, aluminum chloride as the catalyst, preferably acety-lated under mild conditions. The acetylation is usually carried out in a suitable non-reactive solvent, such as a chlorinated hydrocarbon such as dichloromethane, trichlorethylene or 1,2-dichloroethane, diethyl ether, tetrahydrofuran and the like. Surprisingly, this reaction leads to high yields of the desired aceto-phenone III.

The reaction of step (3) (a) is a simple chlorination of intermediate III, generally in a solvent such as ethyl acetate, a chlorinated hydrocarbon or preferably in acetic acid. This reaction is carried out at a moderate temperature of preferably 50 to 60 ° C.

The product IV can optionally be isolated or the chlorination can be carried out as in step (3) (b) in order to obtain the intermediate product V by adding a buffer substance, e.g. An acetate such as sodium acetate and preferably a slight increase in temperature e.g. to 80 to 100 ° C while the chlorination is continued. 65 The reaction of step (3) (c) is most conveniently carried out by adding acetophenone III to a cold solution of an alkali or alkaline earth hydroxide (such as sodium, potassium or calcium hydroxide)

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Value of 7 has been saturated with chlorine (to form the corresponding hypochlorite). The reaction is advantageously facilitated by heating the reaction mixture. A very high yield of the desired 2,5-bis (2,2,2-trifluoroethoxy) benzoic acid VI is obtained.

In step (3) (d) the acid is reacted with an inorganic acid chloride such as thionyl chloride, phosphorus trichloride or phosphorus pentachloride (preferably phosphorus trichloride), generally at reflux temperature in the presence of a suitable non-reactive solvent such as benzene or toluene or a halogenated hydrocarbon or without a solvent, converted to the corresponding acyl chloride.

Step (4) of the process can be carried out directly, starting from the saturated diamine 2- (aminomethyl) piperidine, or indirectly from the unreduced amine 2- (aminomethyl) pyridine. For example, 2- (aminomethyl) pipe-ridine can be reacted with the trichloroacetophenone product of stage (3) (b) or the compound 2- (A.minomethyl) -pyridine can be reacted with the trichloroacetophenone product V of stage (3) ( b) implemented. In any case, the reaction proceeds easily without external heating, usually in an inert solvent such as toluene, benzene, isopropyl alcohol, cyclohexane and the like. The reaction is particularly easy and high yields are obtained if the unreduced diamine reacts in a mixture of toluene and cyclohexane.

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

The following examples explain the process according to the invention and the preparation of the intermediates required for this.

Example 1 Step (1): A = S02CF3 and X = OH

To a mixture of 334.4 g (2.42 mol) of potassium carbonate, 510.6 g (2.2 mol) of 2,2,2-trifluoroethyltrifluoromethanesulfonate in 1.02 liters of acetone was added a solution of 110 g ( 1.0 mol) hydroquinone in 1.1 liters of acetone slowly added within 2 hours. The reaction mixture was then heated to reflux for 24 hours, evaporated and 2 liters of chloroform and 2 liters of water were added to the residue. The chloroform layer was separated, the aqueous layer washed twice with 1 liter of chloroform and the combined chloroform solution washed with 1 liter of water. The chloroform solution was dried over magnesium sulfate and evaporated in vacuo.

Hexane was added to the residue and the solid product was filtered off and washed with hexane. Additional product was obtained from the restricted residues. A yield of 241 g (88%) of 1,4-bis (2,2,2-trifluoro-ethoxy) benzene, mp 75 to 77 ° C., was obtained.

Example 2 Step (1): A = Na and X = Br 40 ml of 2,2,2-trifluoroethanol and 9.6 g (0.20 mol) of 50% sodium hydride in 40 ml of N, N-dimethylformamide Then 8.0 g (0.034 mol) of 1,4-dibromobenzene and 1.0 g (0.006 mol) of copper i-iodide were added. The mixture was heated to reflux for 4 hours, then cooled to approximately 25 ° C and filtered. The residue was washed with N, N-dimethylformamide. The solution was then poured into water and the precipitate filtered off. The product was dissolved in diethyl ether and filtered and the filtrate evaporated to a solid which was washed with hexane and dried. 7.3 g (80%) of 1,4-bis (2,2,2-trifluoroethoxy) benzene, mp 77 to 79 ° C., were obtained.

The reaction was carried out again, the following conditions and properties of the constituents varying and copper-II-bromide being used as a catalyst: 27.4 g (20 ° C.) were added to a mixture of 4.8 g of sodium hydride in 40 ml of N, N-dimethylformamide ml) of 2,2,2-tri-fluoroethanol. 8.0 g (0.034 mol) of 1,4-dibromobenzene and 1 g of copper-II-bromide were added to this mixture. The reaction mixture was heated to approximately 100 ° C for 2 hours and then the reaction was stopped with ice water. It was acidified with hydrochloric acid and filtered. 9.2 g (99%) of 1,4-bis (2,2,2-trifluoroethoxy) benzene were obtained as a white solid. The structure was confirmed by IR analysis.

Example 3

Step (2) using acetic anhydride as acetylating agent. A solution of 274 g (0.88 mol) 1,4-bis (2,2,2 .mu.l) was added to a mixture of 324 g (2.43 mol) aluminum chloride in 648 ml dichloromethane trifluoroethoxy) benzene and 92 ml (0.97 mol) of acetic anhydride in 880 ml of dichloromethane were added over the course of 3 hours, the temperature being kept above 0 ° C. The reaction mixture was then heated to reflux temperature and stirred under reflux for 5 hours. The progress of the reaction was followed by thin layer chromatography. The reaction mixture was placed in an ice bath and 10% hydrochloric acid was added slowly to decompose the aluminum chloride complex. The temperature of the reaction mixture was not allowed to rise above 25 ° C. The organic phase was separated, washed once with 2 liters of 10% hydrochloric acid and then with 2 liters of water. The combined aqueous phase was extracted with several liters of dichloromethane. The organic phase was dried over magnesium sulfate and evaporated to a moist residue. Hexane was added to the residue and the resulting solid was filtered off and washed with hexane. After drying, 250 g of 2,5-bis (2,2,2-trifluoroethoxy) acetophenone were obtained as a light yellow crystalline solid. The yield was 90% mp 84 to 86 ° C.

Example 4

Transfer of Example 3 to a Larger Scale A solution of 3267 gL, 4-bis (2.2.2.) Was gradually added to a mixture of 4367 g (32.75 mol) of aluminum chloride and 8.8 liters of dichloromethane at 0.degree -trifluoro-ethoxy) benzene and 1399 g (13.7 mol) acetic anhydride in

5

10th

15

20th

25th

30th

35

40

45

50

55

60

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6

Given 1.3 liters of dichloromethane. The reaction temperature was kept at 5 to 10 ° C while the mixture was stirred for about 16 hours. The reaction mixture was then heated to reflux and held under reflux for 4 hours. The reaction mixture was acidified with 8760 g of 10% hydrochloric acid. Ice was added to the mixture to keep the temperature below 20 ° C. The organic layer was separated and the aqueous layers extracted several times with dichloromethane. The organic layers were dried and evaporated to give a residue which was triturated with hexane. A yellow solid was formed. Two parts of the product were obtained, corresponding to a total yield of 3088 g of 2,5-bis (2,2,2-trifluoroethoxy) acetophenone, mp 84 to 88 ° C, yield 82%.

Example 5

Step (2) using acetyl chloride as an acetylating agent

A solution of 5.6 g (0.020 mol) of 1,4-bis (2,2,2-trifluoroethoxy) was added to a mixture of 2.8 g (0.022 mol) of aluminum chloride and 100 ml of 1,2-dichloroethane at 25 ° C. ) -benzene and 1.7 g (0.022 mol) of acetyl chloride in 20 ml of 1,2-dichloroethane were added dropwise. After stirring for 4 hours, the reaction mixture was washed with ice water and hydrochloric acid, and the organic layer was dried. Evaporation gave a residue which was recrystallized from hexane. 4.1 g (71%) of 2,5-bis (2,2,2-trifluoroethoxy) acetophenone were obtained as pale yellow needles (the structure was confirmed by IR analysis).

Example 6

Level (3) (a)

A mixture of 79.1 g (0.25 mol) of 2,5-bis (2,2,2-trifluoro-ethoxy) acetophenone in 150 ml of acetic acid was heated to 50 ° C. Chlorine gas was bubbled into the solution and the temperature gradually rose to 55 ° C. The rate of chlorine addition was adjusted so that the temperature was maintained between 55 and 60 ° C. After about 75 minutes, the temperature started to drop (a sign that no further chlorination is taking place). The total amount of chlorine added was 35.5 g. The resulting product was 2,5-bis (2,2,2-trifluoroethoxy) a, a-di-chloroacetophenone.

Example 7

Level (3) (b)

28.7 g (0.35 mol) of sodium acetate were added to the product obtained according to the previous example (without isolation and purification). The temperature rose to approximately 80 ° C and the solution was further heated to 85 ° C. Chlorine was further added and the temperature rose to 100 ° C. After about 20 minutes the theoretical amount of chlorine had been absorbed and the mixture was poured into a mixture of ice and water. The resulting precipitate was filtered off, washed with water, dissolved in dichloromethane and dried. Evaporation gave a residue which was triturated with hexane. 94 g (90%) of 2,5-bis (2,2,2-trifluoroethoxy) a, a, a-trichloroacetophenone were obtained as a white solid. Mp 45 to 48 C.

Example 8

Level (3) (c)

Ice was added to a solution of 292 g (7.3 mol) of sodium hydroxide in 600 ml of water to a total volume of 1.75 liters. Chlorine gas was passed into the solution while the temperature was kept below 10 ° C. until the solution was neutral to litmus and a further 87.6 g (2.19 mol) of sodium hydroxide in 200 ml of water were added. The combined solution was heated to 50 ° C. and 230 g (0.73 mol) of 2,5-bis (2,2,2-trifluoroethoxy) aceto-phenone were added slowly. The reaction mixture was stirred with heating until an exothermic reaction started at about 75 ° C and then kept at 80 ° C by cooling. The mixture was stirred at about 80 to 90 ° C for about 16 hours, the extent of the reaction being followed by thin layer chromatography, io. The excess hypochlorite was then destroyed by adding 75 g of sodium bisulfite in 250 ml of water and the mixture was cooled to about 25 ° C and carefully acidified with 10% hydrochloric acid. The light yellow solid was filtered off, washed with water and dried. He-15 was kept 94.5% 2,5-bis (2,2,2-trifluoroethoxy) benzoic acid, mp 120 to 122 ° C.

Example 9 Step (3) (d)

20 To a solution of 219 g (0.688 mol) of 2,5-bis (2,2,2-tri-fluoroethoxy) benzoic acid in 657 ml of benzene was added 100 ml (1.376 m) of thionyl chloride slowly over the course of an hour, the mixture being about 60 ° C. The mixture was then heated to reflux temperature for about 8 hours and evaporated. The desired product, 2,5-bis (2,2,2-trifluoroethoxy) benzoic acid chloride, was obtained as a residue. The structure was confirmed by the IR spectrum.

30 Example 10

Stage (4) (two-stage reaction starting from intermediate V)

To a solution of 21.0 g (0.05 mol) of 2,5-bis (2,2,2-tri-fluoroethoxy) a, a, a-trichloroacetophenone in 60 ml of toluene was added a solution of 6. 0 g (0.055 mol) of 2-aminomethylpyridine in 50 ml of cyclohexane and 10 ml of toluene were added dropwise. The reaction was exothermic and a precipitate formed immediately. Additional toluene and cyclohexane were added to obtain a mixture with a consistency such that it could be stirred and stirring was continued at approximately 25 ° C for 2 hours. The solid was then filtered off, washed with a mixture of toluene and cyclohexane and dried. 17.8 g (89%) of 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-pyridylmethyl) benzamide 45 were obtained as a white solid, mp 104 to 106 ° C.

A mixture of 134.7 g (0.33 mol) of 2,5-bis (2,2,2-trifluoro-ethoxy) -N- (2-pyridylmethyl) benzamide, 1.347 liters of glacial acetic acid and 13.5 g of 5% platinum on carbon was hydrogenated in a Parr device at room temperature and at a water pressure of 0.2 bar (30 pounds). The reaction was complete in about 6 to 7 hours. The reaction mixture was filtered and the catalyst was washed with isopropyl alcohol. The solution and the washing liquids were evaporated. Hess xan was added to the residue and the resulting white solid was collected and recrystallized from a mixture of acetone and hexane. 71% of 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-piperidylmethyl) benzamide acetate, mp 150 ° to 152 ° C., were obtained. By concentrating the remaining liquid, a further 60 18% of the product with a melting point of 148 to 150 ° C. was obtained.

Example 11

Stage (4) (one-stage implementation based on 65 intermediate V)

To a solution of 4.19 g (0.01 mol) of 2,5-bis (2,2,2-tri-fluoroethoxy) a, a, a-trichloroacetophenone in 50 ml of isopropyl alcohol was added 1.2 g (0 , 01 mol) 2-aminomethylpiperidine

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given. The mixture gradually solidified within 30 minutes. It was left to stand for about 16 hours and then 0.01 M acetic acid and 5 ml of isopropyl alcohol were added and the solution was heated to dissolve all of the solid. Cooling gave 3.0 g of a white solid. The filtrate was evaporated and the residue was recrystallized from isopropyl alcohol. Another product was obtained as a white solid. The product was 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-piperidyimethyl) benzamide acetate according to the IR spectrum and the nuclear magnetic resonance spectrum.

Example 12

Level (4) (two-stage implementation based on the

Intermediate VII)

To a mixture of 83.3 g (0.77 mol) of 2-aminomethylpyridine 106.7 ml (0.77 mol) of triethylamine and 300 ml of benzene were added 236 g (0.70 mol) of 2,5-bis (2.2 , 2-trifluoro-ethoxy) benzoic acid chloride in 472 ml of benzene added within one hour. The reaction mixture was stirred at 25 ° C for about 16 hours and refluxed for 1 hour and washed twice with 2 liters of water. The watery

The phase was washed with 2 liters of benzene and the combined organic phases were dried over magnesium sulfate and evaporated under vacuum. Recrystallization from a mixture of benzene and hexane gave 240 g of 5 (86%) 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-pyridylmethyl) benzamide, mp 100 to 102 ° C as whitish solid.

A mixture of 134.7 g (0.33 mol) of 2,5-bis (2,2,2-trifluoro-ethoxy) -N- (2-pyridylmethyl) benzamide, 1.347 liters of glacial acetic acid and 13.5 g of 5% platinum on carbon was hydrogenated in a Parr device at a pressure of approximately 10 pounds of hydrogen at room temperature. The reaction was complete after 6 to 7 hours. The reaction mixture was filtered and the catalyst washed with isopropyl alcohol. The solution and the washing liquids were evaporated i5. Hexane was added to the residue and the resulting white solid was collected and recrystallized from a mixture of acetone and hexane. 71% of 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-piperidyl-methyl) benzamide acetate were obtained, mp 150 ° to 152 ° C. Concentrating 20 of the remaining liquid gave a further 18% of the product with a melting point of 148 to 150 C.

s

Claims (6)

643 829 2nd PATENT CLAIMS 1. Process for the preparation of the 2,5-bis (2,2,2-trifluoro-ethoxy) -N- (2-piperidylmethyl) benzamide of the formula: cf3ch2 ° given formula and its salts, characterized in that a compound of the formula: och2cf3 and its salts, characterized in that a compound of the formula: 10th in which the two radicals X are identical and each represent hydroxyl groups or bromine atoms, with an alkylating agent of the formula: CF ^ CH ^ O-A in which the two radicals X are identical and each represent hydroxyl groups or bromine atoms, with an alkylating agent of the formula: cf3ch2o-a in which A denotes the group -S02CF3 or an alkali atom, alkylates the resulting 1,4-bis (2,2 * 2-trifluoroethoxy) benzene in the presence of a Lewis acid as a catalyst, which acety-lates The resulting 2,5-bis (2,2,2-trifluoro-ethoxy) aceto-phenone is chlorinated and the resulting 2,5-bis (2,2,2-trifluoro-ethoxy) -a, a-dichloroacetophenone after adding a buffering base chlorinated further to form 2,5-bis (2,2,2-tri-fluoroethoxy) -a, a, a-trichloroacetophenone, reacting the product with 2-aminomethylpiperidine to form the desired product and adjusting the pH accordingly Value isolated as a free base or acid addition salt. 2. The method according to claim 1, characterized in that 2,5-bis (2,2,2-trifluoroethoxy) acetophenone in acetic acid to 2,5-bis (2,2,2-trifluoroethoxy) -a, a-dichloroaceto -phenon chlorinated. 3. A process for the preparation of 2,5-bis (2,2,2-trifluoro-ethoxy) -N- (2-piperidylmethyl) benzamide of the formula given in claim 1 and its salts, characterized in that a compound of the formula : in which A denotes the group -S02CF3 or an alkali atom, alkylates the resulting 1,4-bis (2,2,2-trifluoroethoxy) benzene in the presence of a Lewis acid as a catalyst, the resulting 2nd , 5-bis (2,2,2-trifluoroethoxy) -aceto-phenone chlorinated and the resulting 2,5-bis (2,2,2-trifluoro-ethoxy) -a, a-dichloroacetophenone further chlorinated after adding a buffering base to form 2,5-bis (2,2,2-tri-20 fluoroethoxy) -a, a, a-trichloroacetophenone, the product is reacted with 2-aminomethylpyridine and then reduced to the desired product and this is adjusted by adjusting the pH accordingly -Values isolated as free base or acid addition salt. 25 5. The method according to claim 4, characterized in that the reaction with the 2-aminomethylpyridine is carried out in a mixture of toluene and cyclohexane. 6. The method according to claim 4, characterized in that the reduction of the reaction product of 2-amino methylpyridine is carried out by catalytic hydrogenation. 7. A process for the preparation of 2,5-bis (2,2,2-trifluoro-ethoxy) -N- (2-piperidylmethyl) benzamide which in claim 1 35 given formula and its salts, characterized in that a compound of the formula: jy- 45 in which the two radicals X are identical and each represent hydroxyl groups or bromine atoms, with an alkylating agent of the formula: CF, CH, 0-A in which the two radicals X are identical and each represent hydroxyl groups or bromine atoms, with an alkylating agent of the formula: cf3ch2o-a in which A denotes the group S02CF3 or an alkali atom, alkylates the resulting 1,4-bis (2,2,2-trifluoroethoxy) benzene in the presence of a Lewis acid as a catalyst, which acety-lates the resulting 2,5-bis (2,2,2-trifluoroethoxy) aceto-phenone is reacted with hypochlorite and the resulting 2,5-bis (2,2,2-trifluoroethoxy) benzoic acid is reacted with an inorganic acid chloride to give the acid chloride which Reacting the product with 2-aminomethylpiperidine to form the desired product and isolating it as a free base or acid addition salt by adjusting the pH. 4. A process for the preparation of the 2,5-bis (2,2,2-trifluoro-ethoxy) -N- (2-piperidylmethyl) benzamide which in claim 1 in which A denotes the group S02CF3 or an alkali atom, alkylates the resulting 1,4-bis (2,2,2-trifluoroethoxy) benzene in the presence of a Lewis acid as a catalyst, the resulting 2nd , 5-bis (2,2,2-trifluoroethoxy) aceto-phenone is reacted with hypochlorite, the resulting 2,5-bis (2,2,2-trifluoroethoxy) benzoic acid is reacted with an inorganic acid chloride to form the acid chloride, the pro 55 product is reacted with 2-aminomethylpyridine and then reduced to the desired product and this is isolated as a free base or acid addition salt by appropriate adjustment of the pH. 60