JPH01104045A - Manufacture of 2,5-bis(2,2,2-trifluoroethoxy)- n-(2-piperidylmethyl)benzamide - Google Patents

Abstract

PURPOSE: To easily obtain the subject compd. with high yield useful for antiarrhythmic agent by using a relatively cheap starting material, allowing to react with an alkylating agent, and after acetylating the obtained compd. then chlorinating, etc.

CONSTITUTION: The compd. represented by formula I (where X is OH or Br) is allowed to react with an alkylating agent represented by the formula; CF₃CH₂ O-A (A is -SO₂CF₃ when X=OH or an alkali metal when X=Br) to obtain 1,4-bis(2,2,2-trifluoroethoxy)benzene represented by formula II, and the resultant is acetylated in the presence of a Lewis acid catalyst to obtain a substd. acetophenone represented by formula III. And the resultant is allowed to react with a hypochlorite to obtain a benzoic acid compd. represented by formula VI, then the resultant is allowed to react with an inorganic chloride to form acid chlorides, etc., to obtain the compd. represented by formula VIII.

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 bromo- or hydroxy-substituted benzenes. The invention also relates to certain intermediate compounds produced in the process.

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: = (Formula 11 [wherein 3O2CF3 or an alkali metal] to form a compound of the formula; (2) This compound is treated with a Lewis acid.
d) acetylation in the presence of a catalyst to produce a substituted acetophenone of formula T3) (a) chlorination of the substituted acetophenone to produce the corresponding α,α dichloroacetophenone of formula; and further chlorination to form the α,α,α-trichloroacetophenone of the formula, or alternatively (C1, the substituted acetophenone is reacted with hypochlorite to form the corresponding benzoic acid compound of the formula making, and (d)
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. Collect the desired product.

The above steps (1), (1)-(2); (3)(
a) ; (3) (c) ; (1), f2) and (
3) (c); (31(b)'; (3) (a
) and (3)(b); and methods including the steps (4) are intermediate compounds of the following formula: [where B is -CHff,
selected from CHC1z and CClx] constitutes another characteristic aspect of the generic invention.

The reaction sequence of the general process of the invention is shown in Figure 2: In the essential first step, when X is OH, A is preferably -SO□CF and the reactant(s) is a solvent such as acetone. or 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 (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-dimethylacemide and preferred N, N-
Mixtures of each dimethylformamide with about 10-50%, preferably about 20%, of 2,2,2-trifluoroethanol 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 (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, e.g. 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
, 2-dichloroethane, diethyl ether, tetrahydrofuran and the like. It is unexpected that this reaction provides the desired acetophenone (Ilr) in high yield.

Step (3) 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
1 (b) and continue the chlorination by adding a buffer, e.g. an acetate salt such as sodium acetate, and increasing the temperature slightly, e.g. Obtain body (V).

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

Step (3) In step (d), the acid described above is converted to the corresponding acyl chloride, which is carried out in the presence or absence of a suitable non-reactive solvent such as benzene or toluene or a halogenated hydrocarbon. For example, thionyl chloride,
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 [the product of step (3) (b)], or the compound 2-aminomethylpyridine can be reacted with trichloroacetophenone [the product of step (3) (b)]. thing(
V)]. In both cases, a non-reactive solvent such as toluene, without external heating,
The reaction proceeds easily in benzene and isopropyl alcohol. The reaction proceeds particularly easily and in high yields when unreduced diamines are reacted in a mixture of toluene and cyclohexane.

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

2.42 mol (334.4 g) in 1.021 acetone
2.2.2- of potassium carbonate, 2.2 mol (510,6 g)
1.0 mole (110 g) of hydroquinone in 1.11 parts of acetone to trifluoroethyl trifluoromethanesulfonate 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 11 parts of chloroform, and the chloroform solution was combined with 1 part of the chloroform solution.
Washed with 1 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. 1.4-bis(
2,2,2-trifluoroethoxy)benzene (melting point 7
5-77°C), yield 88%.

40 m for 0.20 mol (9,6 g) of 50% sodium hydride in 40 ml of N,N-dimethylformamide
1 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 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 (80%) of 1,4-bis(2°2,2-trifluoroethoxy)benzene (mp 77-79°C).

The above reaction was carried out as follows, varying the conditions and proportions of the components used and using cupric bromide as a catalyst: 4.
20 ml for 8 g of sodium hydrogen mixture (27,
4 g) of 2.2.2-1-lifluoroethanol 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 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.

2.43 mol (324 g) in 648 ml dichloromethane
) for a mixture of aluminum chloride 880+nj! of 0.88 mol (274 g) of 1.4 in dichloromethane
A solution of -bis(2,2,2-trifluoroethoxy)benzene and 0.97 molar (92 mf) 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 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. The solid obtained by adding hexane to this residue was collected by filtration and washed with hexane. When dried, 250 g of pale yellow crystals of 2°5-bis(2,2,2-)lifluoroethoxy)acetophenone were obtained. Obtained. Melting point 84-86°C, yield 90
%.

4.367 g (32,75 mol) of aluminum chloride
3.267 g of 1°4 in 1.3f dichloromethane for a mixture of 8.81 and dichloromethane at 0°C
A solution of -bis(2,2,2-trifluoroethoxy)benzene and 1.399 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 3.088k
g 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 ml of 2-dichloroethane, 0
．． 020 moles (5,6 g) of 1,4-bis(2,2,2
-) fluoroethoxy)benzene and 0.022 mol (
A solution of 1.7 g) of acetyl chloride in 1°2-dichloroethane (20 nl) 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(
2.2.2-1-lifluoroethoxy)acetophenone (corroborated by infrared spectroscopy) was obtained.

Charcoal-tan (reference example) 0.25 mol (79.1 g) of 2.
A mixture of 5-bis(2,2,2-1-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.

Separate-7 (Reference Example) Engineering (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 194g (90%
) of 2,5-bis(2,2,2-trifluoroethoxy)α,α,α-trichloroacetophenone (melting point 45~
48°C) was obtained.

Example 8 Step (31 (C1) Ice was added to a solution of 7.3 mol (292 g) of caustic soda in 600 nj of water to make a total of 11.751. Chlorine gas was introduced into the solution to make it neutral to lidomas. The temperature was maintained below 10°C while passing through the room until the temperature reached 2.
2.19 mol (87.6 g) dissolved in 00 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-trifluoroethoxy)acetophenone was gradually added. The reaction mixture was heated with stirring until it began to reach an exothermic temperature of 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. 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. 2.5 with a yield of 94.5%
-bis(2,2,2-)lifluoroethoxy)benzoic acid (melting point 120-122°C) was obtained.

Hanadori step (3) (d) 0.688 mol (219 g) in benzene 657 nji
2,5-bis(2,2,2-trifluoroethoxy)
1.376M (100mj2) for a solution of benzoic acid
of thionyl chloride was gradually added over 1 hour while heating to about 60°C. The mixture is then heated at reflux for about 8 hours before evaporation to yield the desired product 2,5-bis(2,2,
2-)Lifluoroethoxy)benzoic acid chloride was obtained as a residue. The chemical structure was confirmed by infrared spectrum analysis.

■-Earthworks (reference example) 0.05 mol (21.0 g) of 2 in 60 ml of toluene
．． 5-bis(2,2,2-trifluoroethoxy)-α
, α, 50 for a solution of α-trichloroacetophenone
0 in mj2 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
, 17. of 2-1-lifluoroethoxy)-N-(2-pyridylmethyl)benzamide (melting point 104-106°C).
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-(
2-pyridylmethyl)benzamide, 1,3471 glacial acetic acid and 13.5 g of 5% platinum on carbon in a Parr apparatus.
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.

0.01 mol (1 , 2g) of 2-aminomethylpiperidine was added. The mixture gradually solidified over 30 minutes. This mixture was allowed to stand for about 16 hours, then 0. OIM acetic acid and 5nj? 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 infrared spectrum and nuclear magnetic resonance spectrum indicate that this product is 2,5-
Bis(2,2,2-trifluoroethoxy)-N~(2
-piperidylmethyl)benzamide acetate.

Suga 112 2-aminomethylpyridine 0.77 mol (83.3 g)
, triethylamine 0.77 mol (106,7+yl)
and 472 m for a mixture consisting of 300 ml of benzene.
0.70 mol (236 g) of 2.5- in l of benzene
Bis(2,2,2-)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 21 g 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-)lifluoroethoxy)-N-(2-pyridylmethyl)benzamide (melting point 100-102°C).

2.5-bis(2,2,2-)lifluoroethoxy”)
-N-(2-pyridylmethyl)benzamide 0.33 mol (134,,7 g), glacial acetic acid 1.347/and a mixture of 13.5 g of 5% platinum on carbon in a Pal apparatus width of approximately 4.5 k
g (approximately 10 bonds) of hydrogen pressure to reduce the temperature 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(2,2,2-1-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.

Procedural amendment (formality) was also submitted by the Commissioner of the Japan Patent Office.
Item 3: Relationship with the person making the amendment Applicant 4: Agent

Claims (1)

[Claims] 1. The following steps, namely (a) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [However, X (plurality) is the same and is selected from OH and Br] A compound of the formula CF_3CH_2O -A [However, A is -SO_2CF_3 when X is OH,
or A is an alkali metal when X is Br] to form 1,4-bis(2,2,2-
(b) This product is acetylated in the presence of a Lewis acid catalyst to produce 2,5-bis(2,2,2-trifluoroethoxy).
(c) reacting the substituted acetophenone with hypochlorite to form 2,5-bis(2,2,2
-trifluoroethoxy)benzoic acid, (d) reacting this acid compound with inorganic chloride to form the acid chloride, and (e) converting the product of step (d) above into 2-(aminomethyl )
2,5-bis(2,2,2 -Trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide. 2. In the presence of cuprous ions or cupric ions, 2.2
, 2-trifluoroethanol by reacting 1,4-dibromobenzene with a suitable alkylating agent of the formula CF_3CH_2O-A, where A is an alkali metal. A method according to claim 1, wherein the substance 1,4-bis(2,2,2-trifluoroethoxy)benzene is produced.