DE3328371A1 - 3,3,3-TRIFLUOR-2-TRIFLUORMETHYLPROPYLBENZOL AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Description

-ΒΙΟ The present invention relates to a new chemical compound and a method for their production. In particular, the present invention relates to the new compound 3,3,3-trifluoro-2-trifluoromethylpropylbenzene, the is a valuable starting material or intermediate product for the manufacture of pharmaceuticals.

It is an object of the present invention to provide the new compound 3,3,3-trifluoro-2-trifluoromethylpropylbenzene create. It is also an object of this invention to provide a simple process for making this new compound to accomplish.

According to the present invention there is provided the new compound 3,3,3-trifluoro-2-trifluoromethylpropylbenzene which is represented by the chemical formula below:

\ O / -CH ₉ -CH-CF.
\ / ~!

c? _

^J

The compound of the invention can be prepared by adding benzene and 1,1-bis (trifluoromethyl) ethylene in the presence of an acidic catalyst in an autoclave at a preselected temperature for a period of

-4-1 to 30 hours together.

The starting compound used, 1,1-bis (trifluoromethyl) ethylene can be prepared by any of several known methods, for example by the Method used by M.H. Kaufman and J.D. Braun in J. Org. Chem., 31, 3090 (1966).

The catalyst used is selected from the group consisting of hydrogen fluoride, boron trifluoride and fluoroboric acid consists. It is preferably used in an amount of more than 0.5 equivalents based on 1,1-bis (trifluoromethyl) ethylene used.

The Reaktxonstemperatür can be selected within a range of -20 to +150 ⁰ C in a suitable manner. A reaction temperature of 0 to 60 ^° C. is usually advantageous when boron trifluoride or fluoroboric acid is used as the catalyst, while a reaction ^{temperature of 80 to 120 °} C. is advantageous when hydrogen fluoride is used.

After completion of the reaction, the gas in the autoclave is removed with a purge gas stream, and the Catalyst is removed from the reaction mixture by conventional methods, for example by washing with Water, after which the reaction mixture is distilled to the compound of the invention as colorless transparent To get liquid.

The compound of the present invention thus obtained can be used as a starting material or as an intermediate for the synthesis of drugs such as 2- (4- (2-trifluoromethyl-3,3,3-trifluoropropyl) phenyl] propionic acid, which has excellent anti-inflammatory activity ( ID ₅₀ : 25mg / kg orally, determined according to the

-δι method of CA. Winter) as well as a low toxicity (LD ^ _n : 1100 mg / kg), and which is a useful compound in medicine for the treatment of various inflammations. For this purpose, the present invention is reacted with propionyl chloride in carbon disulfide in the presence of anhydrous aluminum chloride, with 4- (2-trifluoromethyl-3,3,3-trifluoropropyl) propiophenone being formed, after which the 4- (2-trifluoromethyl-3 , 3,3-trifluoropropyl) propiophenone ^{reacts with methanol in the presence of} thallium (III) nitrate, followed by hydrolysis of the compound obtained with formation of 2-C4- (2-trifluoromethyl-3,3,3-trifluoropropyl) phenylpropionic acid.

The present invention is explained in more detail below with reference to the following examples.

example 1

Preparation of the compound of the invention.

156 g (2.0 mol) of benzene and 328 g (2.0 mol) of 1,1-bis (trifluoromethyl) ethylene were placed in a 11-liter autoclave equipped with a mechanical stirrer. Boron trifluoride was then added to the autoclave from a pressure cylinder until the internal pressure in the autoclave reached a value of 50 kg / cm ² .G. At a temperature of 5O ⁰ C you brought the contents of the autoclave to implementation,

3Q stirring for 15 hours.

After the completion of the reaction, the remaining gas became flushed from the autoclave, and the contents of the autoclave were washed with water and dried, whereby 435 g of a reaction mixture were obtained. The reaction mixture obtained in this way was

-C-

Distilled under reduced pressure, 170 σ of a colorless transparent liquid fraction with a boiling point of 7 9 to 80 ⁰ C at a reduced pressure of 4 0 mmHg were obtained, which as 3,3,3-trifluoro-2-trifluoromethylpropylbenzene a purity of more than 99% was identified based on the following analytical data:

1) mass spectrum (at 20 eV):
m / e = 242

(see Fig. 1)

2) Infrared absorption spectrum
(see Fig. 2);

3) ¹ H-NMR spectrum (at 60 MHz, measured in carbon tetrachloride and against TMS):

7.35 ppm. (S, 5H, Ar-H)
2.7-3.6 ppm (m, 3H, Ar-CH ₂ -Ci ^ '}
(see Fig. 3);

4) refractive index:
n ^ ⁵ = 1.4031

Example 2

Into a flask equipped with a mechanical stirrer 100 ml autoclave were added 20 g (0.256 mol) of benzene, 14 g (0.085 mol) 1 1 r-bis (trifluoromethyl) ethylene, and 5.2 g (0.26 mol)

Hydrogen fluoride. Boron trifluoride was then fed into the autoclave from a pressure cylinder until
the internal pressure of the autoclave reached a value of 12 kg / cm ² .G. With heating at 30 ⁰ C and under lOstündigem stirring, the contents of the autoclave were reacted.

According to deir. The completion of the work was done in the autoclave the remaining gas was purged and the contents of the autoclave were poured into an aqueous 5% solution of sodium hydroxide, in which ice cubes floated. The separated oily layer was washed with water and dried, whereby 32 g of a reaction mixture were obtained.

The composition of the reaction mixture thus obtained was determined by gas chromatographic mass spectroscopy as follows:

Composition of the product

Component content m / e

(% By weight) *

/ Q

40.9

^1: 55.4 242

CF-

other 3.7

* Determined by comparing the areas of the corresponding peaks appearing in the gas chromatogram.

The following is the use of the compound according to the invention explained in more detail.

Synthesis of 2-4 - (2-trifluoromethyl-3,3,3-trifluoropropyl) phenyl propionic acid

1.) Synthesis of the intermediate compound

In a 500 ml three-necked round bottom flask fitted with a mechanical With a stirrer and a dropping funnel, 100 ml of carbon disulfide was added and stirring was continued Add 32.0 g (0.24 moles) of anhydrous aluminum chloride dispersed in the carbon disulfide. Subsequently was a solution of 22.2 g (0.24 mol) of propionyl chloride, dissolved in 20 ml of carbon disulfide, within 15 min. added dropwise to the flask, after which, while maintaining an internal temperature of 0 to 5 ° C, a solution of 48.4 g (0.20 mol) of the 3,3,3-trifluoro-2-trifluoromethylpropylbenzene according to the invention in 50 ml of carbon disulfide was added dropwise over a period of 2 hours. After the addition was complete, the contents of the flask were stirred for an additional 7 hours and then poured into a Poured dilute hydrochloric acid, in which ice cubes floated.

After the separation of the carbon disulfide layer, it was extracted with ether. The extract was washed with water, dried over calcium chloride, and then distilled to remove carbon disulfide, whereby 59 g of the reaction mixture was obtained as a light yellow liquid. In the distillation of this mixture under reduced pressure, 42 g of a fraction boiling at a reduced pressure of 5 mmHg at 135 to 138 ⁰ C. An analysis of this fraction by gas chromatography, mass spectroscopy, H-NMR spectroscopy and IR spectroscopy confirmed that the fraction is an isomer mixture of (2-trifluoromethyl-3,3,3-

trifluorpropy1) propiophenone with a content of 90% by weight of the para-isomer (the actual intermediate compound) was,

2.) Synthesis of the final product

2-1) Preparation of the thallium reagent

In a 500 ml round bottom flask, 106 g (1.0 mol) of methyl orthoformate and 80 g (2.5 mol) of methanol were mixed with one another at room temperature, and 48.9 g (0.11 mol) of thallium nitrate trihydrate, Tl (NO ₃ ) -. 3H ₂ O dissolved in this mixture. In addition, 100 g of silica gel was added to the solution thus formed. After stirring the solution for 20 min. The solvent was distilled off from the solution, and the residue was ^{dried at 4 0 0} C under a reduced pressure of 10 mmHg for 2 hours, so that 161 g of the thallium reagent in the form of a white Powder were obtained.

2-2) Oxidative rearrangement

Into an 11-round flask fitted with a mechanical stirrer and a reflux condenser, 161 g of the tha11ium reagent prepared in 2-1) above, 750 ml Carbon tetrachloride and 29.8 g (0.1 mol) of the intermediate compound prepared according to 1) entered, and the The mixture was heated to reflux for 8 hours, during which time the reaction proceeded. After completing the implementation, the solid material present in the reaction mixture was filtered off, and the filtrate became the solvent distilled off, 42 g of a yellow liquid being obtained.

After dissolving the liquid in 150 ml of ether, this solution was mixed with water, a 5% aqueous sodium

-ΙΟΙ bicarbonate solution and washed again with water, and then distilled to remove the ether, 30.8 g of a yellow transparent liquid were obtained. When this yellow liquid was distilled, 18.1 g of a fraction were obtained which had a boiling range from 76 to 78 ^° C. at a reduced pressure of 3 mmHg.

2-3) hydrolysis

18.1 g of the fraction obtained in 2-2) were added 150 ml of ethanol and 4.4 g of sodium hydroxide and this mixture was refluxed for 2 hours. After graduation After the reaction, the solvent was distilled off from the reaction mixture and the residue became mixed with 150 ml of water, after which the mixture was washed twice with 150 ml of ether each time. With the addition a dilute hydrochloric acid solution to the aqueous phase for the purpose of acidifying it appeared in the aqueous phase sin oily precipitate. After extracting the precipitate the ether was distilled off with ether, 10 g of a reddish-brown liquid being obtained.

The liquid was then purified by chromatography on silica gel using benzene as the eluting solvent, 6.7 g of a pale yellow oily substance being obtained, which were then dissolved in 70 ml of η-hexane. When this solution was left to stand in a refrigerator, crystals separated out from the solution, which were collected and dried. 2.6 g of the purified crystals were obtained, which based on their melting point, the mass spectrum, the IR absorption spectrum and the NMR spectrum as 2- [4- (2-trifluoromethyl- -3,3,3-trifluoropropyl) phenyl ^] propionic acid were identified.

Claims (8)

KADOR KLUNKER · SCHMITT-NILSON HIRSCH PATENTANWÄLTE KlKOl ¹ K-VN I) VTKNT ATIX) RNKVS Kureha Kagaku Kogyo Kabushiki Kaisha, 9-11 Horidome-cho 1-chome, Nihonbashi, Chuo-ku, Tokyo, Japan 3,3, I-tritluoro-2-trifluoromethyl propybenzene and method for its manufacture Claims 1 . y 3, 3, 3-Trifluor-2-trifluorTiechylpropylbenzol ie: ■ - / following formula: 2. Process for the preparation of 3,3,3-trifluor-2- triflucme-hvlOroovlbeazole of the formula characterized in that one benzene and 1,1-bis (trifluoromethyl) ethylene in the presence of a acidic catalyst reacts with each other. 3. The method according to claim 2, characterized in that the acidic catalyst is selected from a group those of hydrogen fluoride, boron trifluoride and fluoroboric acid consists. 4. The method according to claim 2, characterized in that the reaction temperature is in the range -20 to + 150 ⁰ C. 5. The method according to any one of claims 2 to 4, characterized in that the reaction ^{temperature is in the range from 0 to 60 0} C and the catalyst is boron trifluoride or fluoroboric acid. 6. The method according to any one of claims 2 to 4, characterized in that the reaction ^{temperature is in the range from 80 to 120 0} C and the catalyst is hydrogen fluoride. 7. The method according to claim 2 or 3, characterized in that the catalyst in an amount of more than 0.5 equivalents based on 1,1-bis (trifluoromethyl) ethylene is used. 8. The method according to claim 2, characterized in that the reaction time is in the range from 1 to 30 hours.