JPH0339498B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an antiarrhythmic agent 2,5-bis(2,2,2
Intermediate compound 2,5-bis(2,-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide [flecainide] and its salts in the improved preparation from bromo- or hydroxy-substituted benzenes. The present invention relates to a method for producing (2,2-trifluoroethoxy)benzoic acid.

Antiarrhythmic compounds, flecainide and its salts, and methods for their preparation are described in US Pat. No. 3,900,481. The chemical structure of the compound is as shown in the following formula; The synthetic intermediate produced by the method of the present invention is used to produce the above-mentioned flecainide and its salts.
Various practical benefits, such as the relatively low cost of the starting materials, the ease of carrying out the unit operations, and the relatively high yields of the desired product, make them superior to the prior art processes described above. This provides a suitable method.

Specifically, the invention includes the following steps: (a) in the presence of cuprous ions or cupric ions;
1,4-bis( (b) treating the 1,4-bis(2,2,2-trifluoroethoxy)benzene with an acetylating agent in the presence of a Lewis acid catalyst; 2,5-bis(2,
(c) producing 2,5-bis(2,2,2-trifluoroethoxy)acetophenone by reacting the 2,5-bis(2,2,2-trifluoroethoxy)acetophenone with hypochlorite; Bis (2, 2,
The 2,5-bis(2,5-bis(2,
2,2-trifluoroethoxy)benzoic acid is produced.

The reaction sequence of the method of the present invention is shown in the following formula: In step (a) of this method, 1,4-dibromobenzene () and 2,2,2-trifluoroethoxide ion are mixed in a strongly polar mixed solvent at a temperature below the reflux temperature of this solution. The desired product () is prepared in good yield by reaction in the presence of cuprous or cupric ions. 2,
To obtain the 2,2-trifluoroethoxide ion, the corresponding alcohol is reacted with a strong salt, such as caustic soda or preferably sodium hydride. Suitable mixed solvents include dimethyl sulfoxide, N,N-dimethylacetamide, and preferably N,N-dimethylformamide, each with about 10 to 50%, preferably about 20%, of 2,2,2-trifluorocarbon. Mixtures with ethanol are included. Cuprous ions are provided, for example, by cuprous halides such as cuprous iodide or cuprous bromide. Cupric ions are provided, for example, by cupric bromide, cupric sulfate or cupric acetate.

In step (b), 1,4-bis(2,2,2
-trifluoroethoxy)-benzene () produced in step (a) is acetylated under mild conditions in the presence of a Lewis acid catalyst such as tin chloride, ferric chloride or preferably aluminum chloride. Acetylation by reaction with agents such as acetyl chloride or acetic anhydride. This acetylation is carried out using a suitable non-reactive solvent such as a chlorinated hydrocarbon such as dichloromethane, trichloroethylene or 1,2-
Worked in dichloroethane, diethyl ether, tetrahydrofuran and the like. It is unexpected that this reaction provides the desired acetophenone () in high yield.

The reaction of step (c) is carried out using an alkali metal hydroxide or an alkaline earth metal hydroxide (e.g. caustic soda,
This is most conveniently accomplished by adding acetophenone () to a cold solution of caustic potash (or calcium hydroxide) saturated with hydrochloric acid to a pH of 7 (forming the corresponding hypochlorite). This reaction is accelerated by warming the reaction mixture. The desired 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid () is obtained in significantly high yields.

Furthermore, 2,5- obtained by the method of the present invention
Flecainide ( ) can be produced using bis(2,2,2-trifluoroethoxy)benzoic acid ( ).

An example of the reaction sequence is shown below: In step (d), the acid described above is converted to the corresponding acyl chloride, which is carried out using an inorganic chloride such as thionyl chloride in the presence or absence of a suitable non-reactive solvent such as benzene or toluene or a halogenated hydrocarbon. , by reaction of the acid with phosphorus trichloride or phosphorus pentachloride (preferably phosphorus trichloride) under reflux.

The process of step (e) can be carried out directly from the saturated diamine 2-(aminoethyl)piperidine or indirectly from the non-reduced diamine 2-(aminoethyl)pyridine.

In carrying out the final step method starting from the acid chloride (), which is the product of step (d), the method directly converts 2-(aminomethyl)piperidine into
or indirectly from 2-(aminomethyl)pyridine. The acid chloride [product of step (d)] is dissolved in a non-reactive solvent such as glyme, benzene,
The reaction is heated in toluene or diethyl ether (preferably glyme). Or alternatively 2
-Aminomethylpiperidine and the acid chloride [product of step (d)] can be reacted in the presence of a non-reactive solvent such as toluene or benzene. The mixture is heated to reflux temperature in the presence of an acid acceptor (eg, a tertiary amine such as triethylamine). The adduct obtained from the reaction of compound () with 2-(aminomethy)pyridine is reduced to the desired product () by catalytic hydrogenation in the presence of platinum oxide or (preferably) platinum on carbon. The solvent used in this reaction is methanol or a lower alkanoic acid such as (and preferably) glacial acetic acid and the preferred temperature range is 15-30°C. The product obtained when acetic acid is used is flecainide acetate.

The following examples illustrate the methods of the invention and the preparation of intermediate products therein, but are not intended to limit the scope of the invention described above.

Examples Example 1 Step (a) 0.20 mol (9.6) g of 50% sodium hydride in 40 ml of N,N-dimethylformamide to 40 ml
of 2,2,2-trifluoroethanol was added followed by 0.034 mole (8.0 g) of 1,4-dibromobenzene and 0.006 mole (1.0 g) of cuprous iodide. The mixture was heated to its reflux temperature for 4 hours, then cooled to about 25°C and filtered. The residue was washed with N,N-dimethylformamide. The solution was poured into water and the precipitate was filtered off. The product was dissolved in diethyl ether and filtered, the filtrate was evaporated and the resulting solid residue was washed with hexane and dried. The product is 7.3 g of 1,4-bis(2,2,2-trifluoroethoxy)benzene (melting point 77-79°C)
(80%).

The above reaction was repeated with different conditions and proportions of the components used and using cupric bromide as solvent as follows: a mixture of 4.8 g of sodium hydrogen in 40 ml of N,N-dimethylformamide. against
20ml (27.4g) of 2,2,2-trifluoroethanol was added. This mixture contains 0.034 mol (8.0
g) 1,4-dibromobenzene and 1.0 g of cupric bromide were added. The reaction mixture was heated to about 100° C. for 2 hours and then quenched with ice water. Acidification with hydrochloric acid and filtration yielded 9.2 g (99%) of a white solid of 1,4
-bis(2,2,2-trifluoroethoxy)-
produced benzene. The chemical structure was confirmed by infrared spectroscopy.

Example 2 Step (b): Using acetic anhydride as the acetylating agent A mixture of 2.43 mol (324 g) of aluminum chloride in 648 ml of dichloromethane to 0.88 mol (274 g) of 1,4-bis(2,2) in 880 ml of dichloromethane , 2-trifluoroethoxy)benzene and 0.97 mol (92 ml) of acetic anhydride was added over 3 hours while maintaining the temperature at about 0°C. The reaction mixture was then heated to reflux temperature and refluxed for 5
Stir for hours. The progress of the reaction was followed using thin layer chromatography. The reaction mixture was placed in an ice bath and ice, and 10% hydrochloric acid was gradually added to decompose the aluminum chloride complex. temperature of reaction mixture
The temperature was not allowed to rise above 25℃. The organic phase was separated and washed once with 10% hydrochloric acid (2) and then with water (2). The aqueous phases were combined and extracted with several liters of dichloromethane. The organic phase was dried over magnesium sulfate and then evaporated to give a wet residue. Hexane was added to this residue, and the resulting solid was collected by filtration and washed with hexane. 250g when dried
A pale yellow crystalline 2,5-bis(2,2,2-trifluoroethoxy)acetophenone was obtained. Melting point: 84-86°C, yield: 90%.

Example 3 Expansion of the operation scale of Example 2 above 4367 g (32.76 mol) of aluminum chloride and 8.8
1.3 for a mixture of dichloromethane at 0°C
A solution of 3267 g of 1,4-bis(2,2,2-trifluoroethoxy)benzene and 1.399 Kg (13.7 moles) of acetic anhydride in dichloromethane was added gradually. The mixture was stirred for about 16 hours while maintaining the reaction temperature at 5-10°C. The reaction mixture was then heated to its reflux temperature and kept under reflux for 4 hours. The reaction mixture was then acidified using 8.76Kg of 10% hydrochloric acid. Add ice to this mixture to bring the temperature to
The temperature was kept below 20°C. The organic layer was separated and the aqueous layer was extracted several times with dichloromethane. The organic layer was dried and the resulting residue was triturated with hexane to give a yellow solid product. The total yield of this product over the two crops was 3.088 Kg of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (mp 84-88°C, 82% yield).

Example 4 Step (b): Using acetyl chloride as the acetylating agent 0.022 mol (2.8 g) of aluminum chloride and 1,
For the mixture with 100 ml of 2-dichloroethane,
0.020 mol (5.6 g) of 1,4-bis(2,2,2
-trifluoroethoxy)benzene and 0.022 mol (1.7 g) of acetyl chloride in 1,2-dichloromethane (20 ml) was added dropwise at 25°C. 4
After stirring for an hour, the reaction mixture was washed with ice water and hydrochloric acid and the organic layer was dried. The residue obtained by evaporation was recrystallized from hexane to yield 4.1 g (71%) of pale yellow needles of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (confirmed by infrared spectroscopy). gave.

Example 5 Step (c) Ice was added to a 7.3 mol (292 g) solution of caustic soda in 600 ml of water to make a total volume of 1.75. Chlorine gas was passed into the solution until it became neutral to litmus, while the temperature was maintained below 10°C. 2.19 moles (87.6 g) dissolved in 200 ml of water
of caustic soda was added. The combined solution was warmed to 50°C and 0.73 mol (230 g) of 2,5-bis(2,
2,2-trifluoroethoxy)acetophenone was added slowly. The reaction mixture was heated with stirring until it began to exotherm to about 75°C and then maintained at about 80°C by cooling. The mixture was stirred at about 80-90° C. for about 16 hours, during which time the extent of reaction was monitored by thin layer chromatography. Then in 250ml of water
The excess hypochlorite is destroyed by the addition of 75 g of sodium bisulfite and the mixture is cooled to approximately 25°C to reduce the 10%
Carefully acidified with hydrochloric acid. A yellow solid product was collected by filtration, washed with water and dried. yield
94.5% of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid (melting point 120-122°C) was obtained.

Example 6 (Reference example) Step (d) 0.688 mol (219 g) of 2 in 657 ml of benzene,
5-bis(2,2,2-trifluoroethoxy)
To the benzoic acid solution, 1.376 M (100 ml) of thionyl chloride was gradually added over 1 hour while heating to about 60°C. The mixture was then refluxed for about 8 hours and evaporated to yield the desired product, 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride, as a residue. The chemical structure was confirmed by infrared spectrum analysis.

Example 7 (Reference Example) Step (e): Performing a two-step reaction using intermediate () as starting material 0.77 mol (83.3 g) of 2-aminomethylpyridine,
0.70 mole (236 g) of 2,5-bis(2,2,
2-trifluoroethoxy)benzoic acid chloride to 1
Added over time.

The reaction mixture was stirred at 25° C. for about 16 hours, refluxed for 1 hour, then washed twice with 2 portions of water. 2
The aqueous phase was washed with benzene and the organic phases were combined, dried over magnesium sulfate and evaporated under vacuum.
Reconsolidation from a mixture of benzene and hexane is 240
g (86%) of off-white 2,5-bis(2,2,2
-trifluoroethoxy)-N-(2-pyridimethyl)benzamide (melting point 100-102°C).

2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pitadylmethyl)benzamide
0.33 mol (134.7 g), 1.347 glacial acetic acid and 5 on carbon
Approximately 4.5 kg (approx.
10 pounds) of hydrogen pressure to room temperature. The reaction was completed in 6-7 hours. The reaction mixture was filtered and the catalyst was washed with isopropyl alcohol. Evaporation of the solution and washings gave a residue. Hexane was added to this residue, and the resulting white solid was collected and reconsolidated from a mixture of acetone and hexane. 2 with a yield of 71%,
5-bis(2,2,2-trifluoroethoxy)
-N-(2-piperidylmethyl)benzamide acetate (melting point 150-152°C) was obtained. Concentration of the residue yielded additional product (mp 148~) in 18% yield.
150°C) was obtained as the second crop.

Claims (1)

[Claims] 1. The following steps: (a) In the presence of cuprous ions or cupric ions,
1,4-bis( (b) treating the 1,4-bis(2,2,2-trifluoroethoxy)benzene with an acetylating agent in the presence of a Lewis acid catalyst; 2,5-bis(2,
(c) producing 2,5-bis(2,2,2-trifluoroethoxy)acetophenone by reacting the 2,5-bis(2,2,2-trifluoroethoxy)acetophenone with hypochlorite; Bis (2, 2,
The 2,5-bis(2,5-trifluoroethoxy)benzoic acid is
A method for producing 2,2-trifluoroethoxy)benzoic acid.