FR2468576A1 - PROCESS FOR THE PREPARATION OF 2,5-BIS (2,2,2-TRIFLUORETHOXY) -BENZOIC ACID - Google Patents

Abstract

The invention relates to the preparation of 2,5-bis (2,2,2-trifluorethoxy) -benzoic acid. This preparation process comprises reacting 2,5-bis (2,2,2-trifluorethoxy) -acetophenone with a hypochlorite. The acid thus obtained is used for the economical synthesis of 2,5-bis (2,2,2-trifluorethoxy) -N- (2-piperidylmethyl) benzamide, which is a known antiarrhythmic drug.

Description

The present invention relates to a method of

  improved preparation of the antiarrhythmic agent

  consisting of 2,5-bis (2,2,2-trifluoroethoxy) - B- (2-p-

  peridylmethyl) benzamide (flecainide) and its salts from bromo- or hydroxy-substituted benzenes. The invention also relates to intermediate compounds

obtained during this process.

  The antiarrhythmic compound, flecainide, and its salts and a method of preparation have been described

  in U.S. Patent No. 3,900,481.

  The structure of this compound is as follows:

OH

CF CH 0 0 C-N-CH 2 - -

OCH2 F30

  The process according to the present invention is preferable to that presented by this prior patent because of various practical advantages, for example the relatively low cost of the starting materials, the ease of implementation of the operating phases of this process.

  and the relatively high yields of the desired product.

  The process according to the present invention

  takes the following steps: (1) the reaction of a compound of the formula: X X

  in which the symbols X are identical and are chosen

2468576 -

  among the OH and Br radicals, with an alkylating agent

  appropriate formula corresponding to the formula:

CF3CH20-A

  wherein A represents the -SO 2 CF 3 group or an alkali metal to form a compound of the formula:

CF3CH2O

OCH 2CF 3

  (2) acetylation in the presence of a Lewis acid catalyst to prepare a substituted acetophenone of the formula:

CF3 CH20

  (3) one or the other of the following operating phases:

  (a) the chlorination of acetophenone

  to form the corresponding α,--dichloroacetophenone

  dante of the formula: o It CF3CH 20, CCICl2

OCHI2CF

  and (b) the addition of a buffering base and

  then the chlorination to obtain the ati-trichloro-

ketophenone of the formula: -

CF3CH20

3 2,

  (c) the reaction of the substituted acetophenone

  killed with hypochlorite to form the corresponding benzoic acid: Or o

CF CH 20 COH

 2 3 and

  (d) the reaction of the acid with a chlorine

  re of mineral acid to form the acid chloride:

CF3CH20

  O He j. CCl and then (4) the reaction of the product of phase 3 (b)

  or phase 3 (d) with either 2- (aminomethyl) piperine

  to form the desired product in a single step.

  eg with 2- (aminomethyl) pyridine, and then

  reduction to form the desired product, possibly

the free base of it.

  Processes comprising the operating phases: (1); (1) - (2); (3) (a); (3) (c); (1), (2) and (3) (c);

  (3) (b); (3) (a) and (3) (b); and (4) constitute

  distinct aspects of the invention as a whole, from

  as are the intermediary compounds corresponding to the formula:

CF3CH20 CI

10 OCOI2CF3

  wherein B is -CH3, -CI1Cl2-or CCl3.

  The overall process according to the invention follows the sequence of reactions below; l OC112F CF3 Ci 0 CCH3 X (l)) X (2) 0

X 2CF3 IOCH CF3

  (3) (a) 2 o (0a) (3) (c) It It CF3CH20 CCC13 CF3Cl2> 0 CCHC12 - X> - (b.L 'Y W V OCi2CF3 IV OCH 2CF3

- 2 3 - 2 3

(4)

O O

he He.

- CF3CHi20 CCl CF3CIO COH (4)

VII OC "! CF VI OCH CF

2 3 2 3

  VIII] During the first operational phase of the

  process, when X represents the OH radical, A is

  the group -S02CF3 and the reactants are heated in a solvent, such as acetone or N, N-dimethylformamide, in the presence of a base, preferably

  a weak base, such as an aluminum metal carbonate

  hull, for example potassium or sodium carbonate.

  When X represents bromine, reacts

  1,4-dibromobenzene I with 2,2,2-trifluoroethyl-

  late in a strongly polar solvent mixture at a temperature up to the reflux temperature of

  the solution in the presence of the cuprous or copper ion

  only to give with a good yield the desired product II. The 2,2,2-trifluoroethylate ion is obtained from the corresponding alcohol by reaction with a strong base, such as sodium hydroxide or preferably sodium hydroxide.

  sodium hydride. Appropriate solvent mixtures

  include dimethylsulfoxide, N, N-

  dimethylacetamide and preferably N, N-dimethylformate

  mide, each with about 10 to 50%, preferably about

  20%, 2,2,2-trifluoroethanol. The cuprous ion is provided for example by a cuprous halide, such as

  cuprous iodide or cuprous bromide. The copper ion

  that is provided for example by cupric bromide, the

  cupric sulfate or cupric acetate.

  In phase (2), 1,4-bis (2,2,2-trifluorene)

  thoxy) benzene II produced in the first phase is

  tyled by reaction, under mild conditions, with any acetylating agent, such as acetyl chloride or acetic anhydride, in the presence of a

  a catalyst formed by a Lewis acid, such as chlorine

  tin chloride, ferric chloride or preferably aluminum chloride. The acetylation is carried out in a suitable non-reactive solvent, such as a chlorinated hydrocarbon, such as dichloromethane, trichlorethylene or

  1,2-dichloroethane, diethyl ether, tetrahydrofuran

  ranne, etc. This reaction gives, unexpectedly,

  high yields of the desired acetophenone III.

  The reaction of phase (3) (a) is a simple chlorination of intermediate III in a solvent

  appropriate, such as ethyl acetate, a hydrocarbon

  chlorinated or preferably a solution of acetic acid.

  This reaction is carried out at a moderate temperature,

preferably from 50 to 60 C.

  The product IV can be isolated if desired or chlorination is carried out according to the phase (3) (b) to obtain the intermediate V by the addition of a buffering agent, for example an acetate salt, such as sodium acetate, and raising the temperature slightly, for example up to 80-100 C, while

continuing chlorination.

  The reaction of phase (3) (c) is carried out

  most conveniently by adding acetophenic

  none III to a cold solution of a metal hydroxide

  alkaline or alkaline-earth metal (for example hy-

  sodium hydroxide, potassium hydroxide or hydroxide

  of calcium), which has been saturated with chlorine to pH 7 (forming the corresponding hypochlorite). This

  reaction is facilitated by heating the reaction mixture

  tion. A very high yield of the acid is obtained

  Desired 2,5-bis (2,2,2-trifluoroethoxy) benzoic VI.

  In step (3) (d), the acid is converted to the corresponding acyl chloride by reaction with

  a mineral acid chloride, such as thio

  nitrogen, phosphorus trichloride or phosphorus pentachloride (preferably phosphorus trichloride)

  reflux, with or without an appropriate non-reactive solvent

  such as benzene or toluene, or a hy-

';. -

- .. - _

halocarbon.

  Phase (4) of the process can be carried out

  right from the saturated diamine, 2- (amino-

  methyl) piperidine, or indirectly from the dia-

  unreduced mine, 2- (aminomethyl) pyridine. Thus, 2-aminomethylpiperidine can be reacted with the trichloroacetophenone produced according to the phase

  (3) (b) or that the 2-amino compound can be reacted

  methylpyridine with trichloroacetophenone forming product V of phase (3) (b). In both cases,

  the reaction develops easily without external heating

  in an inert solvent, such as toluene, benzene, isopropyl alcohol, cyclohexane, etc. The reaction develops particularly easily

  and with a high yield when the non-reducing diamine

  It is reacted in a mixture of toluene and cyclohexane. When the final phase of the process is carried out, starting from the acid chloride forming the product VII of

  phase (3) (d), we also proceed directly to the de-

  2- (aminomethyl) piperidine or indirectly

  starting from 2- (aminomethyl) pyridine. Acid chloride

  obtained as the product of step (3) (d) is reacted by heating in a non-reactive solvent, such as

  glyme, benzene, toluene or diethyl ether

  thyline (preferably glyme). Alternatively, the 2-aminomethylpyridine can be reacted with the acid chloride produced according to step (3) (d) in the presence of a non-reactive solvent, such as toluene or

  benzene. This mixture is heated to reflux

  it is an acid acceptor (for example a tertiary amine

  re, such as triethylamine). The addition product obtained from the reaction of a 2- (aminomethyl) pyridine with the compound V or the compound VII is reduced in the product

  desired by catalytic hydrogenation in the form of

  it is a platinum oxide or, preferably, platinum on charcoal. The solvent used for this reaction is methanol or a lower alkanoic acid, such as glacial acetic acid, which is preferred.

  The preferred temperature range is 15 to 30 C.

  that acetic acid is used, the product obtained is

flecainide acetate.

  The following Examples illustrate the processes of the invention and the preparation of the intermediates but they do not constitute any limitation whatsoever

of the scope of the invention.

Example 1

  Phase (1) of the process: A = S 02CF3 and X = OH

  To a mixture of 2.42 moles (334.4 g) of carbon

  potassium nitrate and 2.2 moles (510.6 g) of trifluoro-

  2,2,2-trifluoroethyl methanesulphonate in 1.02 liters of acetone, a solution of 1.0 mol (110 g) of hydroquinone in 1.1 liters of acetone is slowly added.

  over a period of 2 hours. Then heat up

  flow for 24 hours, the reaction mixture is evaporated and the remainder is added 2 liters of chloroform and 2 liters of water. The chloroform layer is separated, the aqueous layer is washed twice with 1 liter of chloroform, and the combined chloroform solutions are washed with 1 liter of water. Then dry on sulphate of

  magnesium and concentrated in vacuo. We add hexagon

  the rest, the solid product is collected by filtration

  and washed with hexane. We collect a quantity

  additional material starting from the concentrated remains.

  88% yield, 241 g, of 1,4-bis (2,2,2

  trifluorethoxy) benzene with a melting point of 75-77 C.

Example 2

  Phase (1): A = Na and X = Br A 0.20 mol (9.6 g) of 50% sodium hydride in 40 ml of N, N-dimethylformamide, 40 ml of 2.2 are added. , 2-trifluorethanol, then 0.034 mole (8.0 g) of 1,4-

  dibromobenzene and 0.006 mole (1.0 g) of cuprous iodide.

  The mixture is heated to its reflux temperature during

  4 hours, then cooled to about 25 ° C and filtered.

  The residue is washed with N, N-dimethylformamide. We will

  then the solution in water and separate the pre-

  filtered by filtration. The product is dissolved in

  diethyl ether and filter, and then evaporate the solution.

  filtrate to obtain a solid residue which is washed with hexane and dried. The product is formed by 7.3 g (80%) of 1,4-bis (2,2,2-trifluoroethoxy) benzene from one point

melting from 77 to 79 C.

  The reaction is repeated as follows

  by modifying the conditions and proportions of the constituents and using cupric bromide as catalyst: to a mixture of 4.8 g of sodium hydride in 40 ml of N, N-dimethylformamide, 20 ml is added

  (27.4 g) 2,2,2-trifluoroethanol. We add to this mixture

  0.034 mole (8.0 g) of 1,4-dibromobenzene and 1.0 g of cupric bromide. The reaction mixture is heated at about 100 ° C for 2 hours, then the reaction is quenched.

  with ice water. Acidification with chloroacid

  hydrogen chloride and filtration give 9.2 g (99%) of 1,4-

  bis (2,2,2-trifluoroethoxy) benzene in the form of a

  white solid. This structure is confirmed by

  an infrared spectrum analysis.

Example 3

  Phase (2) using acetic anhydride as an acetylating agent

  To a mixture of 2.43 moles (324 g) of chlorine

  re aluminum in 648 ml of dichloromethane, add ...

  a solution of 0.58 mole (274 g) of 1,4-bis (2,2,2-tris)

  fluorethoxy) benzene E of 0.97 mole (92 ml) of acetic anhydride

  in 880 ml of dichloromethane over a period of 3 hours while maintaining the temperature above 0 ° C. The reaction mixture is then heated to

  its reflux temperature and stirred at reflux for

  hours. We follow the progress of the reaction using - - =

  thin layer chromatography. We place the mixture

  reaction in an ice bath and slowly add-

  10% hydrochloric acid to decompose the aluminum chloride complex. The temperature of the reaction mixture is not allowed to exceed 25 C.

  organic phase is separated and washed once with 2

  10% hydrochloric acid and then with 2

  very water. The combined aqueous phase is extracted with several liters of dichloromethane. The organic phase is dried over magnesium sulfate and then evaporated to obtain a moist residue. Hexane is added to the residue and the resulting solid is collected by

  filtration and washed with hexane. By drying, we obtain

  holds 250 g of 2,5-bis (2,2,2-trifluoroethoxy) acetophenone -

  crystalline of a pale yellow color. The yield is ..

  90% and the melting point is 84-860C.

  Example 4 Treatment of Example 3 on a larger scale.

  To a mixture of 4.367 g (32.75 moles) of chlorine

  aluminum chloride and 8.8 liters of dichloromethane at

  0 C, a solution of 3.267 g of 1,4-bis (2,2,2-trifluoroethoxy) benzene and 1.399 kg is gradually added

  (13.7 moles) of acetic anhydride in 1.3 liters of

  chloromethane. We maintain the reaction temperature -

  at 5-10 ° C while stirring the mixture for about 16 hours.

  hours. This reaction mixture is then heated up to

  at its reflux temperature and is maintained at

  flow for 4 hours. The reaction mixture is then acidified with 8.76 kg of 10% hydrochloric acid. Ice is added to the mixture to maintain the temperature.

  under 20 C. The organic layer is separated

  The aqueous layers are extracted several times with dichloromethane. The organic layers are dried and then evaporated to give a residue which is triturated with

  hexane to give a solid product of the same color

  born. We get two crops of product, which gives

  a total production of 3,088 kg of 2,5-bis (2,2,2-tri-

  fluorethoxy) acetophenone with a melting point of 84-88 C,

the yield being 82%.

  Example 5 Phase (2) Using Acetyl Chloride as Acetylating Agent

  To a mixture of 0.022 mole (2.8 g) chlorine

  1 ml of aluminum and 100 ml of 1,2-dichloroethane are added dropwise, at 25 ° C., a solution of 0.020 mol (5.6 g) of 1,4-bis (2,2,2-trifluoroethoxy) benzene. and 0.022 mole (1.7 g) of acetyl chloride in 20 ml of 1,2-dichloroethane. After stirring for 4 hours, the reaction mixture is washed with ice water and with

  hydrochloric acid, and then the organic layer is dried.

  Evaporation gives a residue which is recrystallized from hexane to give 4.1 g (71%) of

  pale yellow color of 2,5-bis (2,2,2-trifluoroethoxy) acetone

  tophenone (the structure is verified by an analysis of

spectrum in the infrared).

Example 6

  Phase (3) (a) A mixture of 0.25 mole (79.1 g) of 2,5 bis (2,2,2-trifluoroethoxy) acetophenone q7 - is heated to 50 ° C. in 150 ml of acetic acid. Chlorine gas is bubbled into the solution and the temperature is raised

  gradually up to 550C. The rate of addition of chlorine

  re is set to maintain the temperature between 55 and _60 C. After about 75 minutes, the temperature begins to decrease, indicating that no more chlorination occurs. The total amount of chlorine added is

  , 5 g. The resulting product is 2,5-bis (2,2,2-tri-

  fluoroethoxy) -a, -dichloracétophénone. Example 7 Phase (3) (b)

  To the product of the preceding Example (without the iso-

  or purify it), 0.35 moles (28.7 g) of

  sodium tate. The temperature rises to about 800C and the solution is heated to 850C. The addition of chlorine is resumed and the temperature rises to 1000C. After about 20 minutes, the theoretical amount of chlorine was set and the mixture was poured into a mixture of ice and water. The precipitate formed is filtered off, rinsed with water, dissolved in

  dichloromethane and dried. Evaporation gives a resi-

  triturated with hexane to obtain a

  white solid. We obtain a production of 94 g

  (90% yield) of 2,5-bis (2,2,2-trifluoroethoxy) -α, α, α-

  trichloroacetophenone with a melting point of 45 to 48 C.

Example 8

Phase (3) (c)

  To a solution of 7.3 moles (292 g) of

  of sodium in 600 ml of water, ice is added to bring the total volume to 1.75 liter. Chlorine gas is passed into the solution while maintaining the temperature below 100 ° C until the reaction is neutral to sunflower, then 2.19 moles are added.

  (87.6 g) of sodium hydroxide dissolved in 200 ml of water.

  The combined solution is heated to 50 C, and added

  slowly 0.73 moles (230 g) of 2,5-bis (2,2,2-trifluorene)

  methoxy) acetophenone. The reaction mixture is stirred by heating until an exothermic reaction commences at about 75 ° C and then maintained at about C by cooling. The mixture is stirred for about 16 hours at about 80-90 ° C while monitoring

  the degree of the reaction by chromatography

  thin hair. The excess hypochlorite is then destroyed by addition of 75 g of sodium bisulfite in 250 ml of water, and the mixture is cooled to about 25 ° C.

  and acidified with care using hydrochloric acid

  than 10%. The solid product of yellow color is harvested

  it is not filtered, washed with water and sieved.

  che. A yield of 94.5% of 2.5% acid is obtained.

* bis (2,2,2-trifluoroethoxy) benzoic acid with a melting point

from 120-122 C.

Example 9

  Phase (3) (d) To a solution of 0.688 mole (219 g) of acid

  2,5-bis (2,2,2-trifluoroethoxy) benzoic acid in 657 ml of benzene

  zene, 100 ml of thionyl chloride (1.376 M) is added slowly over a period of one hour while

  heating up to about 60 C. The mixture is

  The mixture is refluxed for about 8 hours and then evaporated to obtain the desired product, namely

  2,5-bis (2,2,2-trifluoroethoxy) ben-

  zoic in the form of a remainder. The structure is verified

  by infrared spectrum analysis.

  EXAMPLE 10 Phase (4) carried out in two reactions starting from intermediate V

  To a solution of 0.05 mole (21.0 g)

  bis (2,2,2-trifluoroethoxy) -ct, CL, α-trichloroacetophenone in ml of toluene, a solution of 0.055 mole (6.0 g) of 2-aminomethylpyridine in 50 ml is added dropwise;

  cyclohexane and 10 ml of toluene. The reaction is exo-

  thermal and a precipitate forms immediately. An additional amount of toluene and cyanide are added.

  clohexane to obtain a mixing consistency that allows

  as the stirring, and this is continued for 2 hours at about 25 C. The solid material is then separated by filtration, washed with a mixture of toluene

  and cyclohexane and dried to give a solid material

  white. The product obtained is 2,5-bis (2,2,2-tri-

  fluorethoxy) -N- (2-pyridylmethyl) benzamide with a melting point of 104 ° C, yield of 17.8 g, 89% yield.

  A mixture of 0.33 mole (134.7 g)

  bis (2,2,2-trifluoroethoxy) -N- (2-pyridylmethyl) benzamide, 1.347 liters of glacial acetic acid and 13.7 g of 5% platinum on charcoal is reduced in a Parr apparatus to a pressure of about 20.6 N / cm 2 of hydrogen and at room temperature. The reaction ends in 6-7

  hours. The reaction mixture is filtered and the catalyst

  It is washed with isopropyl alcohol. The solution and the washings are evaporated to give a

  remainder to which hexane is added. We harvest the

  resulting solid white and is recrystallized

  in a mixture of acetone and hexane. We obtain a

  71% of 2,5-bis (2,2,2-trifluoroethoxy) acetate -

  N- (2-piperidylmethyl) benzamide with a melting point of -152 C. By concentration of the residual liquid, an additional 18% of product is obtained as a secondary crop, having a melting point of

148-150C

Example 11

  Phase (4) carried out in a single reaction from intermediate V

  To a solution of 0.01 mole (4.19 g)

  bis (2,2,2-trifluoroethoxy) -acL, α-trichloroacetophenone in 50 ml of isopropyl alcohol is added 0.01 mole

  (1.2 g) 2-aminomethylpiperidine. The mixture is

  gradually forms into a solid material over a period

  from 30 minutes. This mixture is allowed to stand for

  about 16 hours, then 0.01 M acetic acid is added.

  and 5 ml of isopropyl alcohol, the solution being

  heated suite to dissolve all of the material

  solid. On cooling, 3.0 g of a

  white solid. The filtrate is evaporated and the resi-

  It is recrystallized from isopropyl alcohol to give an additional amount of product as a white solid. According to its spectrum in

  infrared and its nu-

  the product is 2,5-bis (2,2,2-trihydroxyl) acetate.

  fluoroethoxy) -N- (2-piperidylmethyl) benzamide.

Example 12

  Phase (4) carried out in two reactions starting from intermediate VII

  To a mixture of 0.77 mole (83.3 g) of 2-amino

  Methylpyridine, 0.77 mole (106.7 ml) triethylamine and 300 ml benzene, 0.70 mole (236 g)

  2,5-bis (2,2,2-trifluoroethoxy) benzoic acid chloride

  than in 472 ml of benzene over a period of 1 hour.

  The reaction mixture is stirred for about

  After 16 hours at 25 ° C., it is refluxed for 1 hour and washed twice with 2 liters of water. The aqueous phase is washed with 2 liters of benzene and the combined organic phases are dried over sulphate.

  of magnesium, then evaporated under vacuum. A recrystalli-

  in a mixture of benzene and hexane gives

  240 g (86%) of 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-pyrrolidine)

  dylmethyl) benzamide of a dirty white color of a

melting point of 100-102WC.

  A mixture of 0.33 moles (134.7 g) of 2,5-bis (2,2,2-trifluoroethoxy) -N- (2-pyridylmethyl) benzamide, 1.347 liters of glacial acetic acid and 13.5 g of a 5% platinum catalyst on charcoal is reduced in a Parr apparatus at a pressure of about 6.8 N / m 2

  at room temperature. The reaction is completed

  in 6-7 hours. The reaction mixture is filtered and

  the catalyst is washed with isopropyl alcohol.

  The solution and the washings are evaporated to

  give a residue to which hexane is added, the material

  resultant white solid being collected and recreated

  in a mixture of acetone and hexane. We ob-

  has a yield of 71% of 2,5-bis (2,2,2

  trifluoroethoxy) -N- (2-piperidylmethyl) benzamide from one point

  melting point of 150-152 C. By concentration of the liquid

  siduary, we obtain a second harvest of 18% of the

  duit, having a melting point of 148'150 C.

Claims (4)

  1. Process for the preparation of 2,5   bis (2,2,2-trifluoroethoxy) benzoic acid, characterized in that   includes the reaction of 2,5-bis (trifluoroethoxy) -   acetophenone with hypochlorite.   2. Process for the preparation of 2.5   bis (2,2,2-trifluoroethoxy) benzoic acid, characterized in that it comprises: (1) the reaction of a compound of the formula: X X   in which the two symbols X are identical and represent   smell the hydroxyl radical or bromine, with an appropriate alkylating agent of the formula: CF3CH20-A   in which A represents the group -SO2CF3 or a metal   alkaline to obtain 1,4-bis (2,2,2-trifluoroethoxy) -   benzene, (2) acetylation in the presence of a Lewis acid   as a catalyst to obtain 2,5-bis (2,2,2-trifluoride)   ethoxy) acetophenone, and (3) the reaction of substituted acetophenone   with hypochlorite to form the desired acid.   3. Method according to claim 1 or 2,   characterized in that 2,5-bis (2,2,2-trifluoride) is   ethoxy) acetophenone in a cold solution of an alkali or alkaline earth metal hydroxide which has been saturated with chlorine to form the corresponding hypochlorite and the reaction mixture is heated.   4. Process according to any one of the claims   tions, characterized in that hypochlorite is   sodium, potassium or calcium hypochlorite.