FR2531424A1 - 3,3,3-TRIFLUORO-2-TRIFLUOROMETHYLPROPYLBENZENE AND ITS PREPARATION - Google Patents

Abstract

THE SUBJECT OF THE INVENTION IS A NEW COMPOUND, 3,3,3-TRIFLUORO-2-TRIFLUOROMETHYLPROPYLBENZENE, WHICH IS AN INTERMEDIATE COMPOUND IN THE MANUFACTURE OF MEDICINAL PRODUCTS AND A PROCESS FOR MANUFACTURING THIS NEW COMPOUND. THE FIGURE REPRESENTS THE IR SPECTRUM OF THIS COMPOUND.

Description

3,3,3-trifluoro-2-trifluoromethylpropylbenzene

and its preparation.

  The present invention relates to a novel compound and a process for producing it.

  The present invention relates to a new compound, 3,3,3-

  trifluoro-2-trifluoromethylpropylbenzene which is useful as a raw material or as an intermediate compound in the

drug synthesis.

  It is an object of this invention to provide a novel compound, 3,3,3-trifluoro-2-trifluoromethylpropylbenzene. It is further intended to provide a process for making

this new compound.

  The novel compound of the present invention

  (hereinafter referred to as "the present compound") is 3,3,3-

  trifluoro-2-trifluoromethylpropylbenzene corresponding to the following formula: C Hr-CH-CF 3 CF 3 The present compound can be obtained synthetically by reacting benzene with 1,1-bis (trifluoromethyl) ethylene in the presence of a catalyst acid in an autoclave

  for 1 to 30 hours at a predetermined temperature.

  The 1,1-bis (trifluoromethyl) ethylene for use as a raw material in the present invention may be prepared by any of a variety of known methods, for example, a method described by M H Kaufman and J D Braun in J Org.

Chem. 31, 3090 (1966).

  The catalyst to be used is chosen from the group

253 1,424

  consisting of hydrogen fluoride, boron trifluoride and fluoboric acid. The amount of catalyst used is preferably greater than 0.5 equivalent relative to 1,1-bis (trifluoromethyl) ethylene. The temperature of the reaction may advantageously be chosen in the range from -20 to -150 ° C. It is preferable that the reaction temperature be from 0 to 60 ° C. in the case where boron trifluoride or acid is used. fluoroboric catalyst, and that the temperature of the reaction is 80 to 120 C in the case where the

hydrogen fluoride.

  When the reaction is complete, the autoclave is

  clave the remaining gas and the catalyst is separated from the reaction mixture according to conventional methods, for example by washing with water and then distilling the reaction mixture to obtain the present compound in the form of a liquid

transparent colorless.

  The present compound thus obtained can be used as a raw material or as an intermediate compound for

  drug synthesis, for example 2- / 4- (trifluoro-

  Methyl-3,3,3-trikluoropropyl) phenylpropionic acid which has excellent anti-inflammatory activity (ID 50:25 mg / kg orally, examined according to the method of CA Winter) and low toxicity (LD 50: 1100 mg / kg), which is a compound useful as a medicament for treating various inflammations. Thus, the present compound is reacted with propionyl chloride in carbon bisulfide in the presence of aluminum chloride.

  anhydrous to form 4- (2-trifluoromethyl-3,3,3-trifluoro-

propyl) propiophenone, and then

  react the 4- (2-trifluoromethyl-3,3,3-trifluoropropyl) propionic acid

  phenone thus formed with methanol in the presence of thallium (III) nitrate, then hydrolyzed to obtain the acid

  2- [4- (2-trifluoromethyl-3,3,3-trifluoropropyl) phenyl] propionic acid

Picnic.

253 1,424

  The present invention will be described in more detail

  in the following nonlimiting examples.

Synthesis of the present compound,

EXAMPLE 1

  In a 1-liter autoclave equipped with a mechanical stirrer, 156 g (2.0 moles) of benzene and 328 g (2.0 moles) of 1,1-bis (trifluoromethyl) ethylene are introduced. Next, boron trifluoride is introduced. in the autoclave from a pressurized cylinder until the internal pressure of the autoclave reaches approximately 5 '106 Pa (50 kg / cm). The contents of the autoclave are reacted with

  heating the autoclave to 50 C and stirring for 15 hours.

  When the reaction is complete, the autoclave is

  clave the residual gas, then the contents of the autoclave are washed with water and dried to obtain 435 g of reaction mixture The reaction mixture thus obtained is distilled under a reduced pressure to obtain 170 g of a transparent liquid fraction colorless boiling at 79 to 80 ° C. under a reduced pressure of 40 mm Hg, which is identified as 3,3,3-trifluoro-2-trifluoromethylpropylbenzene having purity greater than 99% according to the following analysis 1) Mass Spectrum (at 20 eV) m / e = 242 refer to Figure 1 2) Infrared Absorption Spectrum; shown in FIG. 3) H-NMR spectrum (at 60MHz, in carbon tetrachloride and based on TM 6) refer to FIG. 7.35 ppm (s, 5H, Ar-H) 2 3.6 ppm (m, 3H, Ar-CH 2-CH) 4) Refractive index; n D = 1.4031

EXAMPLE 2

  In a 100 ml autoclave equipped with a stirrer

253 1,424

  20 g (0.256 moles) of benzene, 15 g (0.085 moles) of 1,1-bis (trifluoromethyl) ethylene and 5.2 g (0.26 moles) of hydrogen fluoride are then introduced. boron trifluoride in the autoclave from a pressurized cylinder until the internal pressure gauge of the autoclave reached approximately 12 105 Pa (12 kg / cm 2). The contents of the autoclave were reacted with heating at 30 C and

stirring for 10 hours.

  When the reaction is complete, the autoclave is

  clave of the residual gas, and the contents of the autoclave are poured into a 5% aqueous solution of sodium hydroxide in which blocks of ice float. The oily layer thus separated is washed with water and then dried to

  obtain 32 g of reaction mixture.

  The composition of the reaction mixture was

  determined by gas chromatography and spectrophotometric

  mass scopie and was found as follows: Product composition Components content% wt%) m / e

K @ II 40.9

CH-CH-CF 55 Z 4

  21 3 CF 3 -30 other products 3.7 Determined by comparing the respective peak areas in the chromatogram

in the gas phase.

Application:

  Synthesis of 2- / 4 (2-trifluoromethyl-3,3,3-trifluoro-

  propyl) phenylpropionic. 1) Synthesis of the Intermediate Compound In a 500 ml three-necked round bottom flask equipped with a mechanical stirrer and a separatory funnel, 100 ml of carbon disulfide and all

  with stirring, 32.0 g (0.24 mol) of aluminum chloride are added.

  anhydrous material to be dispersed in carbon disulphide.

  A solution of 22.2 g (0.24 mol) of propionyl chloride dissolved in 20 ml of carbon disulfide is then added dropwise to the flask for 15 minutes, and then the internal temperature is maintained at 0 to 5 hours. C, a solution of 48.4 g (0.20 mol) of 3,3,3-trifluoro-2-trifluoromethylpropylbenzene is added dropwise to the flask for 2 hours.

  of the present compound, dissolved in 50 ml of carbon disulfide.

  When the addition is complete, the mixture is stirred for 7 hours and then the contents of the flask are poured into dilute hydrochloric acid in which blocks of ice float. After separating the layer of carbon disulphide, an extraction is carried out. The extract is washed with water, dried over calcium chloride, and distilled to remove the carbon disulfide and obtain 59 g of reaction mixture as a pale yellow liquid by distilling the mixture. under reduced pressure, 42 g of the fraction boiling at 135 to 138 ° C. under a reduced pressure of 5 mmHg are obtained by analyzing the fraction by gas chromatography, mass spectroscopy, H-NMR spectroscopy and absorption spectroscopy infra. Red, it has been confirmed that

  the fraction is a mixture of isomers of (2-trifluoro-

  methyl-3,3,3-trifluoropropyl) propiophenone containing 90%

  weight of the para isomer (the intermediate compound).

  2) Synthesis of the final product 2-1 Preparation of the thallium reagent In a 500 ml round-bottomed flask, 106 g (1.0 mole) of methyl orthoformate and 80 g (2 g) are mixed at room temperature. 5 moles) of methanol and dissolved in the mixture of 48.9 g (0.11 mol) of thallium nitrate trihydrate, Tl (NO 3) 3 3H. In addition, 100 g of silica gel was added to The solution thus formed After stirring the solution for 20 minutes, the solvent was distilled off from the solution and the residue was dried.

  at 40 ° C under a reduced pressure of 10 mmHg for 2 hours.

  to obtain 161 g of white powder as a reagent

with thallium.

  2-2 Rearrangement by oxidation On the other hand, 161 g of thallium reagent thus prepared, 750 ml of tetrachloride, are introduced into a 1-liter round bottom flask equipped with a mechanical stirrer and a reflux condenser. of carbon and 29.8 g (0.1 mole) of the intermediate compound synthesized in 1) to react under reflux refrigerant for 8 hours. When the reaction is complete, the solid material present in the reaction medium is removed. the reaction mixture by filtration and the solvent was distilled off from the filtrate to obtain 42 g of

yellow liquid.

  After having dissolved the liquid in 150 ml of ether, it is washed with water with a 5% aqueous solution of sodium hydrogen carbonate and then with water, and subjected to distillation to remove the water. ether to obtain 30.8 g of a yellow transparent liquid. By distilling the yellow liquid, 18.1 g of a fraction boiling at 76 to 780 ° C. are obtained.

  under reduced pressure of 3 mmHg.

  2-3 Hydrolysis In 18.1 g of the fraction obtained in 2-2, ml of ethanol and 4.4 g of sodium hydroxide are added and the mixture is refluxed for 2 hours. When the reaction is complete, The solvent is distilled off from the reaction mixture and the residue is then mixed in 150 ml of water, and the mixture is then washed twice with 150 ml of ether each time by adding dilute hydrochloric acid to the aqueous phase to give acidify it, a precipitate appears

2531.42 4

  oily in the aqueous phase After extracting the precipitate with ether, the ether is distilled off by distillation for

  obtain I O g of a reddish brown liquid.

  The liquid is further purified by silica gel chromatography while using benzene as the eluting solvent to obtain 6.7 g of a yellow oily substance.

  pale, which is then dissolved in 70 ml of n-hexane.

  By leaving the solution in a refrigerator, crystals separate from the solution and are collected and dried to obtain 2.6 g of purified crystals, which are identified as

  being 2- [4- (2-trifluoromethyl) 3,3,3-trifluoromethyl]

  propyl) phenylpropionic by its melting point, by

  mass spectroscopy, absorption spectroscopy infra-

red, and NMR spectroscopy -z

Claims (10)

  3,3,3-trifluoro-2-trifluoromethylpropylbenzene represented by the following formula: CH-CHCF 21 3 CF 3   2 Process for producing 3,3,3-trifluoro-2-   trifluoromethylpropylbenzene represented by the following formula: CH 2 -CH-CF 3 CF 3 comprising the step of reacting benzene with 1,1-bis (trifluoromethyl) ethylene in the presence of a catalyst acid.   3. The process as claimed in claim 2, wherein the acidic catalyst is chosen from the group consisting of hydrogen fluoride and boron trifluoride. and fluoboric acid.   Process according to Claim 2, characterized in   that the temperature of the reaction is from -20 to + 150 C.   Process according to any one of the claims   2 to 4, characterized in that the reaction temperature is from 0 to 60 C and the catalyst is boron trifluoride or fluoboric acid.   Process according to any one of the claims   2 to 4, characterized in that the temperature of the reaction is   from 80 to 120 ° C. and the catalyst is hydrogen fluoride. 253 1,424   Process according to Claim 2 or 3, characterized in that the catalyst content is greater than 0.5 equivalent with respect to 1,1-bis (trifluoromethyl) ethylene -   Process according to one of Claims 2 to 7,   characterized in that the duration of the reaction is from 1 to hours.