JPH0149695B2 - - 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(2,2 , 2-trifluoroethoxy)acetophenone and its manufacturing method.

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 process of the present invention offers various practical advantages over the prior art processes described above, such as relatively low starting materials, ease of carrying out unit operations, and relatively high yields of the desired product. This is a preferred method because of its high cost.

Specifically, the present invention includes the following steps; (1) Formula [However, X (plural) is the same and selected from OH and Br] A compound of the following formula is suitably alkylated with the following formula CF ₃ CH ₂ O-A [However, A is -SO ₂ CF ₃ or an alkali metal] By reacting with the agent, the formula (2) This compound is acetylated in the presence of a Lewis acid catalyst to obtain the formula (3) (a) The substituted acetophenone is chlorinated to form the following formula: (b) By adding a buffer base and further chlorination, the formula or (c) reacting the substituted acetophenone with hypochlorite to give the formula (d) react this acid compound with an inorganic chloride to form the formula and then (4) convert the product of step 3(b) or 3(d) above into 2-
(aminomethyl)hyperidine to produce the desired product in one step, or in two steps.
-(aminomethyl)pyridine and subsequent reduction to produce the desired product, or optionally as the free base.

The above steps (1), (1)-(2); (3)(a); (3)(c); (1),
(2)
and (3)(c); (3)(b); (3)(a) and (3)(b); and methods including the steps of (4) are intermediate compounds of the following formula: B constitutes another characteristic aspect of the generic invention relating to the production of B, wherein B is selected from _-CH3 , _-CHC2 and _CC3 .

The reaction sequence of the comprehensive method of the present invention is shown in the following formula; In the first step of the process, when X is OH, A is preferably -SO ₂ CF ₃ and the reactant(s).
is a base such as an alkali metal carbonate, in a solvent such as acetone or N,N-dimethylformamide,
They are preferably co-heated in the presence of a weak base such as, for example, potassium carbonate or soda carbonate.

When the above X is Br, 1,4-dibromobenzene () and 2,2,2-trifluoroethoxide ion are mixed in a strongly polar mixed solvent 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 at a temperature of . To obtain the 2,2,2-trifluoroethoxide ion, the corresponding alcohol is reacted with a strong base, such as caustic soda or preferably sodium hydride. Suitable mixed solvents include dimethyl sulfoxide,
N,N-dimethylacetamide and preferably N,N-dimethylformamide, each of about 10 to 50
%, preferably about 20%, of 2,2,2-trifluoroethanol. Cuprous ions include, for example, cuprous halides, such as cuprous iodides.
Supplied by copper or cuprous bromide. Cupric ions are provided, for example, by cupric bromide, cupric sulfate or cupric acetate.

In step (2), 1,4-bis(2,2,2-trifluoroethoxy)-benzene () [which is produced in step (1)] is added under mild conditions to a Lewis acid catalyst such as tin chloride, Acetylation is carried out by reaction with an acetylating agent such as acetyl chloride or acetic anhydride in the presence of ferric chloride or preferably aluminum chloride. The acetylation is carried out in suitable non-reactive solvents such as chlorinated hydrocarbons such as dichloromethane, trichloroethylene or 1,2-dichloroethane, diethyl ether, tetrahydrofuran and the like. It is unexpected that this reaction provides the desired acetophenone () in high yield.

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

The product () can be isolated if desired. Alternatively, chlorination is carried out as in step (3)(b), and while the chlorination is continued, a buffer such as an acetate such as sodium acetate is added to lower the temperature slightly, e.g.
Intermediate () by raising to 100℃
get.

The reaction of step (3)(c) is carried out using an alkali metal hydroxide or 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.

In step (3)(d), the above acid is converted to the corresponding acyl chloride, and this conversion is carried out using an inorganic chloride in the presence or absence of a suitable non-reactive solvent such as benzene or toluene or a halogenated hydrocarbon. For example, by reaction of the acid with thionyl chloride, phosphorus trichloride or phosphorus pentachloride (preferably phosphorus trichloride) under reflux.

The method of step (4) can be carried out directly from the saturated diamine 2-(aminoethyl)piperidine or indirectly from the non-reduced diamine 2-(aminoethyl)pyridine. That is, 2-aminomethylpiperidine is converted into trichloroacetophenone [product of step (3)(b)].
Alternatively, the compound 2-aminomethylpyridine can be reacted with trichloroacetophenone [product of step (3)(b))]. In each case, the reaction proceeds readily in nonreactive solvents such as toluene, benzene, isopropyl alcohol, cyclohexane, and the like without external heating. The reaction proceeds particularly easily and in high yields when unreduced diamines are reacted in a mixture of toluene and cyclohexane.

When carrying out the final step method using the acid chloride (), which is the product of step (3)(d), as a starting material, this method can be carried out directly from 2-(aminomethyl)piperidine or from 2-(aminomethyl)piperidine. It can also be accomplished openly from methyl)pyridine. The acid chloride (product of step (3)(d)) is reacted by heating in a non-reactive solvent such as glyme, benzene, toluene or diethyl ether (preferably glyme). Alternatively, 2-aminomethylpyridine and acid chloride [process
(3) (d) product] 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 (eg, a tertiary amine such as triethylamine). The desired product is produced by catalytic hydrogenation of the adduct obtained from the reaction of either compound () or () with 2-(aminomethyl)pyridine in the presence of platinum oxide or (preferably) platinum on carbon. Return to. The solvent used in this reaction is notanol or a lower alkanoic acid such as (and preferably) glacial acetic acid and the preferred temperature range is from 15 to
It is 30℃. The product obtained when acetic acid is used is flecainide acetate.

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

Example 1 (Reference example) Method of step (1): A=SO ₂ CF ₃ , X=OH 2.42 mol (334.4 g) potassium carbonate, 2.2 mol (510.6 g) 2,2,2-tri- 1.0 mole (110 g) of hydroquinone in 1.1 part of acetone to fluoroethyl trifluoromethanesulfonate was added slowly over 2 hours. The reaction was then heated under reflux for 24 hours before the reaction mixture was evaporated and the residue was dissolved in 2 parts of chloroform and 2 parts of chloroform.
of water was added. The chloroform layer was separated, the aqueous layer was washed twice with 1 part of chloroform, and the chloroform solution was combined and washed with 1 part of water. The chloroform solution was dried over magnesium sulfate and then concentrated under vacuum. Hexane was added to the residue and the solid product was collected by filtration and washed with hexane. Additional material was collected from the concentrated residue. 241 g of 1,4-bis(2,2,2-trifluoroethoxy)benzene (melting point 75-77°C), yield 88%, was obtained.

Example 2 Step (1): A=Na, Then 0.034 moles (8.0 g) of 1,4-dibromobenzene and 0.006 moles (1.0 g) of cuprous iodide were added. 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 was 7.3 g (80
%).

The above reaction was repeated with different conditions and proportions of the components used and using cupric bromide as a catalyst as follows; a mixture of 4.8 g of sodium hydrogen in 40 ml of N,N-dimethylformamide. against 20
ml (27.4 g) of 2,2,2-trifluoroethanol was added. 0.034 mol (8.0g) in this mixture
of 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 1,4-bis(2,2,2-trifluoroethoxy)-benzene as a white solid. The chemical structure was confirmed by infrared spectroscopy.

Example 3 Step (2); Using acetic anhydride as the acetylating agent A mixture of 2.43 mol (324 g) of aluminum chloride in 648 ml of dichloromethane and 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 0°C. The reaction mixture was then heated to reflux temperature and stirred under reflux for 5 hours. The concentration of the reaction was followed by the use of 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. Reduce the temperature of the reaction mixture to 25
The temperature was not allowed to rise above ℃. 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. After drying, 250 g of pale yellow crystalline 2,5-bis(2,2,2-trifluoroethoxy)acetophenone was obtained.
Melting point: 84-86°C, yield: 90%.

Example 4 Expansion of the operation scale of Example 3 above. 4,367 g (32.75 mol) of aluminum chloride and
3,267 g of 1,4 in 1.3 of dichloromethane for a mixture at 0°C with 8.8 of dichloromethane
A solution of -bis(2,2,2-trifluoroethoxy)benzene and 1.399 Kg (13.7 moles) of acetic anhydride 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. Ice was added to the mixture to maintain the temperature 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 two harvests was 3.088 Kg of 2,5
-bis(2,2,2-trifluoroethoxy)acetophenone (melting point 84-88°C, yield 82%).

Example 5 Step (2): Using acetyl chloride as the acetylating agent 0.022 mol (2.8 g) of aluminum chloride and 1,
For a mixture of 2 and 100 ml of 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-dichloroethane (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 6 (Reference example) 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 to 50°C, Chlorine gas was bubbled into the solution and the temperature was gradually increased to 55°C. Adjust chlorine addition rate to 55-60
The temperature was maintained at ℃. After about 75 minutes the temperature began to decrease (indicating that chlorination was no longer occurring). The total amount of chlorine added was 35.5g. The product obtained is 2,5-bis(2,
2,2-trifluoroethoxy)-α,α-dichloroacetophenone.

Example 7 (Reference Example) Step (3)(b) Product of Example 6 above (not isolated or purified)
0.35 mol (28.7 g) of sodium acetate was added to the solution. The temperature rose to about 80°C and the solution was heated to 85°C.
It was heated to ℃. Continue adding chlorine to raise the temperature.
Raise the temperature to 100℃. After about 20 minutes the theoretical amount of chlorine was consumed and the mixture was poured into a mixture of ice and water. The resulting precipitate was collected by filtration, rinsed with water, dissolved in dichloromethane and dried. The residue obtained by evaporation was micronized using hexane to obtain a white solid. A yield of 94 g (90%) of 2,5-bis(2,2,2-trifluoroethoxy)α,α,α-trichloroacetophenone (melting point 45-48°C) was obtained.

Example 8 (Reference Example) Step (3)(c) Ice was added to a 7.3 mol (292 g) caustic soda solution 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 maintaining the temperature below 10°C. 2.19 moles (87.6 g) of caustic soda dissolved in 200 ml of water were 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 9 (Reference example) Step (3)(d) 0.688 mol (219 g) of 2,5 in 657 ml of benzene
-To a solution of bis(2,2,2-trifluoroethoxy)benzoic acid, 1.376 M (100 ml) of thionyl chloride was gradually added over 1 hour while heating to about 60°C. The mixture was then heated at reflux for about 8 hours and then evaporated to give 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 10 (Reference example) Step (4): Performing a two-step reaction using intermediate () as starting material 0.05 mol (21.0 g) of 2,5 in 60 ml of toluene
-bis(2,2,2-trifluoroethoxy)-
A solution of 0.055 mol (6.0 g) of 2-aminomethylpyridine in 50 ml of cyclohexane and 10 ml of toluene was added dropwise to the solution of α,α,α-trichloroacetophenone. The reaction was exothermic and a precipitate formed immediately. Additional toluene and cyclohexane were added to reach a stirrable mixture consistency and stirring continued for 2 hours at about 25°C. The resulting solid is then filtered off, washed with a mixture of toluene and cyclohexane, and dried to produce a white solid, i.e. 2,5-bis(2,2,2-trifluoroethoxy)-N-(2
-pyridylmethyl)benzamide (melting point 104-106
17.8 g (yield: 89%) of

A ternary mixture, i.e. 0.33 mol (134.7 g) of 2,5-
Bis(2,2,2-trifluoroethoxy)-N
A mixture of -(2-pyridylmethyl)benzamide, 1.347 g of glacial acetic acid, and 13.5 g of 5% platinum on carbon was reduced to about 30 pounds of hydrogen pressure at room temperature in a Parr apparatus. The reaction is 6~
It was completed in 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. 2,5 with a yield of 71%
-bis(2,2,2-trifluoroethoxy)-
N-(2-piperidylmethyl)-benzamide acetate (melting point 150-152°C) was obtained. Concentration of the residual liquid gave an additional 18% yield of product (melting point 148-150°C) as a second crop.

Example 11 (Reference example) Step (4): Performing a single reaction using intermediate () as starting material 0.01 mol (4.19 g) of 2,5-bis(2,2,2- 0.01 mol (1.2 g) of 2-aminomethylpiperidine was added to the solution of (trifluoroethoxy)-α,α,α-trichloroacetophenone. The mixture gradually solidified over 30 minutes. The mixture was allowed to stand for approximately 16 hours, then 0.01 M acetic acid and 5 ml of isopropyl alcohol were added and the solution was warmed to dissolve all solids. Upon cooling, 3.0 g of white solid was obtained. Evaporation of the filtrate and recondensation of the residue from isopropyl alcohol gave additional product as a white solid. The infrared spectrum and nuclear magnetic resonance spectrum indicate that this product is 2,5-bis(2,2,2-trifluoroethoxy)-N-(2
-piperidylmethyl)benzamide acetate.

Example 12 (Reference example) Step (4): Performing a two-step reaction using intermediate () as a starting material 0.77 mol (83.3 g) of 2-aminomethylpyridine,
0.70 moles (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 500 ml of benzene and the organic phases were combined, dried over magnesium sulfate and evaporated under vacuum.
Reconsolidation from a mixture of benzene and hexane is
240g (86%) off-white 2,5-bis(2,2,
2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide (melting point 100-102°C) was obtained.

2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide
0.33 mol (134.7 g), glacial acetic acid 1.347 and 5 on carbon
A mixture of 13.5 g of platinum (approximately 4.5 Kg of platinum (approximately 10
The mixture was reduced to room temperature under a hydrogen pressure of 1 pound). The reaction is 6
It was completed in ~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. 2,5 with a yield of 71%
-bis(2,2,2-trifluoroethoxy)-
N-(2-piperidylmethyl)benzamide acetate (melting point 150-152°C) was obtained. Concentration of the residue gave additional product in 18% yield (mp 148-150
°C) was obtained as a second crop.

Claims (1)

[Claims] 1. Compound 2,5-bis(2,2,2-trifluoroethoxy)acetophenone. 2. 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,
Compound 2,5 characterized by producing 2,2-trifluoroethoxy)acetophenone
-bis(2,2,2-trifluoroethoxy)
Method for producing acetophenone.