JPH01125344A - Production of 2, 5-bis (2, 2, 2-trifluoroethoxy)benzoate - Google Patents

Abstract

PURPOSE: To produce in high yield the subject compd. for an intermediate of a Flecainide being an antiarrhythmic agent from an inexpensive starting material and by a facilitate operation by alkylating 1,4-dibromobenzene, then acetylating the alkylated compd. in the presence of a Lewis acid catalyst, moreover, allowing the acetylated compd. to react with hypochlorite.

CONSTITUTION: 1,4-Bis(trifluoroethoxy)benzene is obtained by allowing the 1,4- dibromobenzene to react with alkali metal 2,2,2-trifluoroethoxide in the presence of a cuprous ion or a cupric ion and in a polar solvent to alkylate. Then 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is obtained by treating the alkylated compd. with an acetylating agent in the presence of the Lewis acid catalyst, then 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid is obtained by allowing the acetylated compd. to react moreover with the hypochlorite.

COPYRIGHT: (C)1989,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the antiarrhythmic agent 2,5-bis(2,2,2=trifluoroethoxy)-N-(2-piperidylmethyl)henzamide (flecainide) and its salts. Intermediate compound 2.5-bis(2
, 2,2-)rifluoroethoxy)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: 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: (1) A compound of the formula [wherein -5O2CF3 or an alkali metal] to form a compound of the formula;
d) acetylate in the presence of a catalyst to form a 1m acetophenone of the formula (31(al), chlorinate the substituted acetophenone to form the corresponding α,α dichloroacetophenone of the formula (31(al), and add fbl a buffer base. and further chlorination to produce the α,α,α-trichloroacetophenone of the formula, or alternatively (c) reacting the substituted acetophenone with hypochlorite to form the corresponding benzoic acid compound of the formula ( So, and ((fl
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 form the desired product in a Lee step, or reaction with 2-(aminomethyl)pyridine followed by reduction to form the desired product, or optionally free Create the desired product as a base.

The above steps (11, (11-+21; (31(a)
) ; (3Hc) ; (1), (21 and [31
fc); (31(b); (31(al and f3
Hb), and methods including the steps (4) are intermediate compounds of the following formula: [where B is -CH3+ CHCj2 z
and CC7!3] constitutes another characteristic aspect of the generic invention.

The reaction sequence of the generic process of the invention is shown below: In the essential first step, when X is OH, A is preferably -S O2CF3 and the reactants are a solvent such as acetone or The mixture is heated in 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 (1) and 2,2,2-)lifluoroethoxide ion are mixed in a strongly polar mixed solvent, and the solution is refluxed. The desired product (
Create I[).

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.

Included are N-dimethylacetamide and, suitably, mixtures of each of N,N-dimethylformamide with about 10-50%, preferably about 20%, of 2.2.2-) refluoroethanol. 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 (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 (I[[) in high yield.

Step +31 The reaction of (a) is a simple chlorination of intermediate (III) 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.

Product (IV) can be isolated if desired. Or process +3
The intermediate can be prepared by carrying out the chlorination as in 1(b) and, while continuing the chlorination, adding a buffer, e.g. an acetate salt such as sodium acetate, and raising the temperature slightly, e.g. (V) is obtained.

The reaction of step (31(c)) consists of saturating a cold solution of an alkali metal hydroxide or alkaline earth metal hydroxide (e.g. caustic soda, caustic potash or calcium hydroxide) with hydrochloric acid to give p) 17 (corresponding (forms hypochlorite)
This is most conveniently accomplished by adding acetophenone (I) to the reaction mixture. This reaction is accelerated by warming the reaction mixture. desired 2.5-bis(2,2,
2-1-Lifluoroethoxy)benzoic acid (VI) is obtained in significantly higher yields.

Step (31fdl) converts the acid described above 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 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 [product of step (31fb)], or the compound 2-aminomethylpyridine can be reacted with trichloroacetophenone [product of step (3) (bl) (■
)]. The reaction proceeds readily in non-reactive solvents such as toluene, benzene, isopropyl alcohol, cyclohexane and the like, in both cases without external heating. When allowed to react, the reaction proceeds particularly easily and in high yields.

Step (2) When carrying out the final step method using the acid chloride (■), which is the product of 31fdl, as a starting material,
-(aminomethyl)piperidine directly or 2-
It is also accomplished indirectly from (aminomethyl)pyridine.

The acid chloride [product of 31 fdl] is reacted by heating in a non-reactive solvent such as glyme, benzene, toluene or diethyl ether (preferably glyme). Alternatively, 2-aminomethyl Pyridine and the acid chloride [step (3) (product of d+)] 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.

■-1 (Reference example) Process (1) Method: A = S Oz CF 3
, X = 2.42 mol (334,4 g) potassium carbonate in OH acetone 1.02 A, 2.2 mol (510,6
g) 2. 2. 1.1 in acetone for 2-trifluoroethyl trifluoromethanesulfonate.
0 mole (110 g) of hydroquinone was added slowly over 2 hours. The reaction was then heated under reflux for 24 hours before the reaction mixture was evaporated and 21 parts of chloroform and 21 parts of water were added to the residue. The chloroform layer was separated, the aqueous layer was washed twice with 17+ chloroform, and the chloroform solution was combined and washed with 11+ 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(2,2,2-1-lifluoroethoxy)benzene (melting point 75-77°C)
A yield of 88% was obtained.

N,N-dimethylformamide 40m7! 0.20 inside
mol (9.6 g) (40 ml of 2.2.2- to 7350% sodium hydride) is added, then 0.034 mol (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 is N
, N-dimethylformamide. The solution was poured into water and the precipitate was filtered off. The product was dissolved in diethyl ether and filtered, and the filtrate was evaporated to form a solid residue, which was washed with hexane and dried. The product is 1,4-bis(2゜2
．． 2-)Lifluoroethoxy)benzene (melting point 77-7
7.3g (80%) of 9°C).

The above reaction was carried out using cupric bromide as a catalyst, varying the conditions and proportions of the components used, as follows: 4.8 g of sodium hydrogen in 40 mj2 of N, N-dimethylformamide. 20 mj for the mixture!
(27.4 g) of 2.2.2-)lifluoroethanol was added. To this mixture was added 0.034 moles (8,0g) of 1,4-dibromobenzene and 1.0 g of cupric bromide. The reaction mixture was heated to about 100° C. for 2 hours and then quenched with ice water.

Acidification with hydrochloric acid and filtration produced 9.2 g (99%) of 1,4-bis(2,2,2-)lifluoroethoxy)-benzene as a white solid. The chemical structure was confirmed by infrared spectroscopy.

Example 3 Step (2) Anhydrous vinegar as niacetylating agent used A mixture of 2.43 moles (324 g) of aluminum chloride in 648 mA of dichloromethane and 0.88 moles (274 g) of 1,4-bis( 2,
A solution of 2,2-)lifluoroethoxy)benzene and 0.97 mol (92 ml) of acetic anhydride was added over 3 hours while maintaining the temperature at about O'C. The reaction mixture was then heated to reflux temperature and stirred under reflux for 5 hours. The progress of the reaction was followed using 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 21 portions of 10% hydrochloric acid and then with 21 portions 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. When dried, 250g of pale yellow crystalline 2
5-bis(2,2,2-)lifluoroethoxy)acetophenone was obtained. Melting point 84-86℃, yield 90%
It is.

Example 4 3.267 g of 1°4 hebis(2,2,2-1-lifluoroethoxy)benzene in 1.3/dichloromethane and 1° A solution of .399 kg (13.7 liters) 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-trifluoroethoxy)acetophenone (melting point 84-88°C, yield 82%)
)Met.

0.022 mol (2.8 g) of aluminum chloride and 1.
For 100 m6 of 2-dichloroethane and a mixture, 0.
020 moles (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 (
The solution in 20 mA') 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-)lifluoroethoxy)acetophenone (corroborated by infrared spectroscopy) was given.

(1)-E (Reference Example) Step (31) 0.25 mol (79.1 g) of 2.
A mixture of 5-bis(2,2,2-)lifluoroethoxy)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 (9) 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 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. Yield 94g (90%
) of 2,5-bis(2,2,2-)trifluoroethoxy)α,α,α-trichloroacetophenone (melting point 45~
48°C) was obtained.

Water 600mI! Ice was added to 7.3 mol (292 g) of caustic soda solution in the solution to make the total amount 1.75 ρ. Chlorine gas was passed into the solution until it became neutral to lidomas, while the temperature was maintained below 10°C. 20
2,19 moles (87,6 g) dissolved in 0 mj2 water
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 reaction was monitored by thin layer chromatography. The excess hypochlorite was then destroyed by the addition of 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. A yellow solid product was collected by filtration, washed with water and dried. 2 with a yield of 94.5%.
5-bis(2,2,2-)lifluoroethoxy)benzoic acid (melting point 120-122°C) was obtained.

Example 9 Process (0.688 mol (219 g) in 31 fdl benzene 657 mj!
2,5-bis(2,2,2-)lifluoroethoxy)
To a solution of benzoic acid, 100 ml of 1.376 M thionyl chloride was slowly added over 1 hour while heating to about 60°C. The mixture was then heated to reflux for about 8 hours and then evaporated to give the desired amount. Product 2,5-bis(2,2,2
-)trifluoroethoxy)benzoic acid chloride was obtained as a residue. The chemical structure was confirmed by infrared spectrum analysis.

Example 10 (Reference example) 0.05 mol (21.0 g) of 2 in 60 mf of toluene
．． 5-bis(2,2,2-)lifluoroethoxy)-α
, α, 50 for a solution of α-trichloroacetophenone
1 of cyclohexane and 10 ml of cyclohexane. of toluene.
A solution of 0.055 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-)lifluoroe)oxy)-N-(2-pyridylmethyl)benzamide (melting point 104-106°C) 17
．． 8 g (yield 89%) was obtained.

2°5 of a ternary mixture i.e. 0.33 mol (134.7 g)
-bis(2,2,2-trifluoroethoxy)-N-(
A mixture of 2-pyridylmethyl)benzamide, 1.347 N glacial acetic acid, and 13.5 g of 5% platinum on carbon was added in a Parr apparatus to about 13.6 g of 5% platinum on carbon.
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-trifluoroethoxy)-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 148-1
50° 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
．． 01M acetic acid and 5ml 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 product is 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide acetate from infrared and nuclear magnetic resonance spectra.

2-aminomethylpyridine 0.77 mol (83.3 g)
, triethylamine 0.77 mol (106,7mj2)
and 472 m for a mixture consisting of 300 ml of benzene.
0.70 mol (236 g) of 2.5- in benzene of 4
Bis(2,2,2-)lifluoroethoxy)benzoic acid chloride was added over 1 hour.

The reaction mixture was stirred at 25° C. for about 16 hours, refluxed for 1 hour, then 21! Washed twice with water.

27! 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 was 240g (86%
) of gray-white 2,5-bis(2゜2.2-1lifluoroethoxy)-N-(2-pyridylmethyl)benzamide (
melting point 100-102°C).

2.5-bis(2,2,2-trifluoroethoxy)
-N-(2-pyridylmethyl)benzamide 0.33 mol (134,7 g), glacial acetic acid 1.34711 and 5 on carbon
A mixture of 13.5 g of platinum was put into a Pal device with a width of approximately 4.5 kg.
(approximately 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.

2.5-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] The following steps include (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. (c) treating the 2,5-bis(2,2,2-trifluoroethoxy)acetophenone with hypochlorite; The 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid is produced by reacting with an acid salt.
- A method for producing bis(2,2,2-trifluoroethoxy)benzoic acid.