JPH01125341A - 2, 5-bis (2, 2, 2-trifluoroethoxy)acetophenone and its production - Google Patents

Abstract

NEW MATERIAL: 2,5-Bis(2,2,2trifluoroethoxy)acetophenone.

USE: Useful as an inteymediate for synthesizing a bromo- or hydroxy-substituted benzene of a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide and its salt useful as an antiarrhythmic agent.

PROCESS: 1,4-Bis(2,2,2-trifluoroethoxy)benzene is obtained by allowing 1,4- dibromobenzene to contact with alkali metal 2,2,2-trifluoroethoxide in the presence of a cuprous ion or a cupric ion and in a strongly polar solvent containing 2,2,2-trifluoroethanol. Then the novel compd. is obtained by treating the product with an acetylating agent in the presence of a Lewis acid catalyst.

COPYRIGHT: (C)1989,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an antiarrhythmic agent, 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide [flecainide].
) and its salts from promoter or hydroxy-substituted Hensen, intermediate compound 2.5-
The present invention relates to bis(2,2,2-)lifluoroethoxy)acetophenone and a method for producing the same.

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: This is the preferred method due to its ease and relatively high yield of the desired product.

Specifically, the present invention includes the following steps: (11) [wherein 8O□CF, or an alkali metal] to form a compound of the formula;
d) acetylate in the presence of a catalyst to produce a substituted acetophenone of the formula; (3) chlorinate the substituted acetophenone (al) to produce the corresponding α,α dichloroacetophenone of the formula; In addition, further chlorination produces an α,α,α-trichloroacetophenone of the formula, or alternatively fc) reacting the substituted acetophenone with hypochlorite to produce the corresponding benzoic acid compound of the formula; And +dl
This acid compound is reacted with an inorganic chloride to form an acid chloride of formula, and then (4) the product of step 3(b) or 3(d) above is converted into 2
-(aminomethyl)hyperidine to produce the desired product in one step, or by reaction with 2-(aminomethyl)pyridine followed by reduction, or optionally with the free base. Create the desired product.

The above steps (11, fil - (21; (3Hal
; (31(C1; (1), (21 and f31
[01; (31(b); f31 [al and f3
1bli and the processes comprising steps (4) constitute another characteristic aspect of the generic invention for the preparation of intermediate compounds of the formula: do.

The reaction sequence of the generic process of the present invention is shown below: In the essential first step, when X is OH, A is preferably -3O□CF3 and the reactants are solvents such as The mixture is heated in acetone or N,N-dimethylformamide in the presence of a base such as an alkali metal carbonate, preferably a weak base such as potassium carbonate or soda carbonate.

When the above X is Br, 1,4-dibromobenzene (I) and 2,2,2-trifluoroethoxide ion are mixed in a strongly polar mixed solvent at the reflux temperature of this solution. The desired product (
II).

2.2.2-) To obtain the refluoroethoxide 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 preferred N, N-
Mixtures of each of dimethylformamide and about 10-50%, preferably about 20%, of 2.2.2-1 refluoroethanol are included. Cuprous ions are provided, for example, by cuprous halides such as cuprous iodide or cuprous bromide. Examples of cupric ions include cupric bromide and cupric sulfate.
Supplied by copper or cupric acetate.

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

The reaction of step (31) is a simple chlorination of intermediate (1) in a suitable solvent such as ethyl acetate, a chlorinated hydrocarbon, or preferably in an acetic acid solution. Preferably it is carried out at 50-60°C.

The product (TV) can be isolated if desired. Or process (3
The intermediate is prepared by carrying out the chlorination as in 1 (bl) and increasing the temperature slightly, e.g. to 80-100'C, by adding a buffer e.g. an acetate salt such as sodium acetate while continuing the chlorination. (V) is obtained.

Step (31) (C1) is a reaction in which a cold solution of an alkali metal hydroxide or alkaline earth metal hydroxide (e.g. caustic soda, caustic potash or calcium hydroxide) is saturated with hydrochloric acid to a pH of 7 (the corresponding hypochlorite). The reaction is most conveniently carried out by adding acetophenone (IIT) to the chlorate (forming chlorate). The reaction is accelerated by warming the reaction mixture.
,2-)lifluoroethoxy)benzoic acid (Vl) is obtained in significantly high yields.

In step 31 (dl) the acid described above is converted to the corresponding acyl chloride, this conversion being carried out using an inorganic chloride, e.g. By reaction of thionyl, phosphorus trichloride or phosphorus pentachloride (preferably phosphorus trichloride) with a nucleic acid under reflux.

The method of step (4) is to use saturated diamine 2-(aminoethyl)
It can be accomplished directly from piperidine or indirectly from the non-reduced diamine 2-(aminoethyl)pyridine. That is, 2-aminomethylpiperidine can be reacted with trichloroacetophenone [the product of step (3)(g))], or the compound 2-aminomethylpyridine can be reacted with trichloroacetophenone [the product of step (3)(b)]. product (
■)] can be reacted with. In both cases, a non-reactive solvent such as toluene, without external heating,
The reaction proceeds easily in benzene, isopropyl alcohol, cyclohexane and other solvents. 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 (31 (dl)), as a starting material, this method
-(aminomethyl)piperidine directly or 2-
It is also accomplished indirectly from (aminomethyl)pyridine.

The acid chloride [step 31 (product of dl)] is reacted by heating in a non-reactive solvent such as glyme, benzene, toluene or diethyl ether (preferably glyme). Alternatively, 2- Aminomethylpyridine and the acid chloride [product of step (3) (dl)] can be reacted 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). By catalytically hydrogenating the adduct obtained from the reaction of either compound (V) or (■) with 2-(aminomethyl)pyridine in the presence of platinum oxide or (preferably) platinum on carbon. Return to desired product ■. 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.
It is. 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.

Example 1 (Reference example) Step (method of 11: A=SO□CF3, X=OH 2.42 mol (334.4 g) in acetone 1.02
) Potassium carbonate, 262 mol (510,6 g) of 2. 2.
For 2-trifluoroethyl trifluoromethanesulfonate], 1.0 mol (110 g
) was gradually added over 2 hours.

The reaction was then heated under reflux for 24 hours before the reaction mixture was evaporated and the residue was treated with 21 parts of chloroform and 27 parts of chloroform. of water was added. Separate the chloroborum layer and separate the aqueous layer into 17!
The mixture was washed twice with chloroform, and the chloroform solution was combined and washed with 11 portions 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. 1.
241 g of 4-bis(2,2,2-trifluoroethoxy)benzene (melting point 75-77°C) was obtained in a yield of 88%.

0.20 in 40mj2 of N,N-dimethylformamide
40 for mol (9,6 g) of 50% sodium hydride
mA of 2.2.2-trifluoroethanol was added followed by 0.034 mol (8.0 g) of 1°4-dibromobenzene and 0.006 mol (1.0 g) of cuprous iodide. Ta. The mixture was heated to its reflux temperature for 4 hours, then cooled to about 25°C and filtered. The residue is N,N
- Washed with 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 1,4-bis(2°2.2
-)rifluoroethoxy)benzene (melting point 77-79℃
) is 7.3g (80%).

The above reaction was carried out as follows by changing the conditions and proportions of the components used and using cupric bromide as a catalyst.4.
20m7 for 8g of sodium hydrogen mixture! (27,
4 g) of 2.2.2-trifluoroethanol was added. To this mixture was added 0.034 mol (8.0 g) 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(2,2,2-1-lifluoroethoxy)-benzene as a white solid. The chemical structure was confirmed by infrared spectroscopy.

2.43 mol (324 g) in 648 mρ dichloromethane
) 880 mp for a mixture of aluminum chloride.

of 0.88 mol (274 g) of 1.
A solution of 4-bis(2,2,2-trifluoroethoxy)benzene and 0.97 mol (92n+4) acetic anhydride was added over 3 hours while maintaining the temperature at about 0°C.The reaction mixture was then added. It was heated to reflux temperature and stirred under reflux for 5 hours.The progress of the reaction was followed by the use of thin layer chromatography.

The reaction mixture was placed in a water bath and ice, and 10% hydrochloric acid was gradually added 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 and washed once with 211 parts of 10% hydrochloric acid and then with 21 parts of water. 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-)lifluoroethoxy)acetophenone was obtained. Melting point 84-86℃, yield 90
%.

Example 4 For a mixture at 0'C with dichloromethane of A solution of .399 kg (13.7 mol) 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 8.76 kg 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 3.08
8 kg of 2,5-bis(2,2,2-1-lifluoroethoxy)acetophenone (melting point 84-88°C, yield 82
%)Met.

0.022 mol (2.8 g) of aluminum chloride and 1.
For a mixture with 100 mj2 of 2-dichloroethane, 0
．． 020 moles (5,6 g) of 1,4-bis(2,2,2
-) fluoroethoxy)benzene and 0.022 mol (
A warm solution of 1.7 g) of acetyl chloride in 1°2-dichloroethane (20 mj2) was added dropwise at 25°C. After stirring for 4 hours, 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). ) was given.

Example 6 (Reference Example) Step (31) 0.25 mol (79.1 g) of 2.
A mixture of 5-bis(2,2,2-trifluoroethoxy)acetophenone was heated to 50°C, chlorine gas was bubbled into the solution and the temperature was gradually increased to 55°C. The chlorine addition rate was adjusted to maintain a temperature of 55-60°C. After about 75 minutes the temperature began to decrease (indicating that chlorination was no longer occurring)
. The total amount of chlorine added was 35.5 g. The product obtained is 2,5-bis(2,2,2-)lifluoroethoxy)-α,α-dichloroacetophenone.

Example 7 (Reference Example) Step (31 (bl) 0 for the product of Example 6 above (not isolated or purified)
．． 35 mol (28.7 g) of sodium acetate were added.

The temperature rose to about 80°C and the solution was heated to 85°C. Continue adding chlorine and increase the temperature to 100°C. After about 20 minutes, the theoretical amount of chlorine is consumed,
This 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. Yield 94g (90
%) of 2.5-bis(2,2,2-)lifluoroethoxy)α,α,α-trichloroacetophenone (melting point 45
~48°C) was obtained.

I Example 8 (Reference Example) Step (3) tel Ice was added to a 7.3 mol (292 g) caustic soda solution in 600 nl of water to make a total volume of 1.75 #. Chlorine gas was passed into the solution until it became neutral to lidomas while maintaining the temperature below 10°C. 2
2,19 mol (87,6 g) dissolved in water at 00 mA
of caustic soda was added.

The combined solution was warmed to 50°C and 0.73 mol (230
g) 2,5-bis(2,2,2-)lifluoroethoxy)acetophenone was slowly added. The reaction mixture was heated with stirring until an exotherm of about 75°C began, 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 the reaction was monitored by thin layer chromatography. Next is 250ml! The excess hypochlorite was destroyed by the addition of 75 g of sodium bisulfite in water and the mixture was cooled to about 25°C to give a 10%
Carefully acidified with hydrochloric acid. A yellow solid product was collected by filtration, washed with water and dried. 2 with a yield of 94.5%
,5-bis(2,2,i)lifluoroethoxy)benzoic acid (melting point 120-122°C) was obtained.

Example 9 (Reference Example) Step +31 +dl For a solution of 0.688 mol (219 g) of 2,5-bis(2,2,2-)lifluoroethoxy)benzoic acid in 651 ml of benzene, 1.376 M (100 mjl) of thionyl chloride was slowly added over an hour while heating to about 60°C. The mixture was then heated to reflux for about 8 hours before evaporation to give the desired product 2,5-bis(2,2,2 −
) trifluoroethoxy) benzoic acid chloride was obtained as a residue. The chemical structure was developed by infrared spectrum analysis.

Example 10 (Reference example) 0.05 mol (21.0 g) of 2 in 60 mβ of toluene
,5-bis(2,2,2-)lifluoroethoxy)-α
, α, 50 for a solution of α-trichloroacetophenone
0 in ml cyclohexane and 10ml toluene
．． A solution of 0.55 mol (6.0 g) of 2-aminomethylpyridine was added dropwise.

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-)lifluoroethoxy)-N-(2-pyridylmethyl)benzamide (melting point 104-106°C) in 17.
8 g (yield 89%) was obtained.

Three types of mixture i.e. 0.33 mol (134,7 g>2゜5
-bis(2,2,2-4lifluoroethoxy)-N-(
A mixture of 2-pyridylmethyl)benzamide, 1.347 β of glacial acetic acid and 13.5 g of 5% platinum on carbon was added in a Parr apparatus to approx.
kg (approximately 30 pounds) of hydrogen pressure at 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.

2.5-bis(2,2,2-1-lifluoroethoxy)-N-(2-piperidylmethyl)-benzamide acetate (melting point 150-152°C) was obtained in a yield of 71%. The residual liquid was concentrated to give a yield of 18% (melting point 148
˜150° C.) was additionally obtained as a second crop.

Example 11 (Reference example) 0.01 mol (4
, 19 g) of 2,5-bis(2,2,2-)lifluoroethoxy)-α,α,α-trichloroacetophenone to a solution of 0.01 mol (1,2 g) of 2-aminomethylpiperidine. added. The mixture gradually solidified over 30 minutes. Let this mixture stand for about 16 hours, then
．． OIM acetic acid and 5mI! of isopropyl alcohol was 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 product is 2,5-bis(2,2,2-)lifluoroethoxy)-N-(2-piperidylmethyl)benzamide acetate from the infrared spectrum and nuclear magnetic resonance spectrum.

Example 12 (Reference example) 2-aminomethylpyridine 0.77 mol (83.3 g)
, 472 ml for a mixture consisting of 0.77 mol (106,7 mρ) of triethylamine and 300 nl of benzene.
0.70 mol (236 g) of 2.5- in l of benzene
Bis(2,2,1-)lifluoroethoxy)benzoic acid chloride was added over 1 hour.

The reaction mixture was stirred at 25° C. for approximately 16 hours, refluxed for 1 hour, and then washed twice with 21 portions of water.

The aqueous phase was washed with 2i 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%)
This gave off-white 2,5-bis(2°2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide (melting point 100-102°C).

2.5-bis(2,2,2-)lifluoroethoxy)-
N-(2-pyridylmethyl)benzamide 0.33 mol (
A mixture of 134.7 g), 1.347 A of glacial acetic acid, and 13.5 g of 5% platinum on carbon was reduced at room temperature with hydrogen pressure in a Pal apparatus width of about 4.5 kg (about 10 pounds). 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-bis(2,2,2-)lifluoroethoxy)-N-(2-piperidylmethyl)benzamide acetate (melting point 150-152°C) was obtained in a yield of 71%. Concentration of the residue yielded additional product in 18% yield (melting point 14
8-150'c) was obtained as the 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, 2.
1,4-dibromobenzene and an alkali metal 2,2,2-trifluoroethoxide are contacted in a strongly polar solvent containing 2,2-trifluoroethanol.
, 4-bis(2,2,2-trifluoroethoxy)benzene, and (b) acetylating the 1,4-bis(2,2,2-trifluoroethoxy)benzene in the presence of a Lewis acid catalyst. 2,5-bis(2-trifluoroethoxy)acetophenone is produced by treatment with a compound 2,5-bis(2-trifluoroethoxy)acetophenone.
, 2,2-trifluoroethoxy)acetophenone.