CS252921B1 - Process for preparing 1-aryl-1-chloroethane - Google Patents

Abstract

The method of producing 1-aryl-1-chloroethanes of the general formula I Ar-CH-CH, Cl where Ar denotes a 4-isobutylphenyl, 6-methoxy- -2-naphthyl, 5-bromo-6-methoxy-2-naphthyl group consists in treating the methyl aryl ketone of the general formula II Ar-C0-CH3 (II) with 2-propanol with a maximum water content of 0.1% in the presence of aluminum-tris- -2-propanol while boiling the reaction mixture and simultaneously distilling off the resulting acetone with 2-propanol, after which, after the reduction is complete, the remaining solvents are distilled off under reduced pressure and, after dissolving the distillation residue in an organic solvent, extraction is carried out with an aqueous solution containing 10 to 30% by weight. sodium hydroxide or dilute hydrochloric acid to remove aluminum salts, after which the organic phase containing the crude hydroxy derivative is stirred at a temperature of 20 to 60 °C with an excess of conc. hydrochloric acid for 0.2 to 4 hours, the organic phase is separated, washed with a saturated solution of sodium or potassium chloride and after evaporation of the solvents, the product of general formula I is obtained.

Description

The invention relates to a process for the preparation of 1-aryl-1-chloroethanes of the formula I

Ar-CH-CH

Cl

wherein Ar represents a 4-isobutylphenyl-, 6-methoxy-2-naphthyl-, or 5-bromo-6-methoxy-2-naphthyl group.

These compounds are used as intermediates in the synthesis of pharmaceutically interesting arylpropionic acids, which form the active ingredient of non-steroidal anti-inflammatory drugs with antipyretic and analgesic effects. These are in particular 2- (4-isobutylphenyl) propionic acid (ibuprofen) and 2- (6-methoxy-2-naphthyl) propionic acid (naproxen).

To date, the compounds of formula (I) have been prepared in two reaction steps. In the first, the arylmethylketone of formula II

ArCOCH ₅ (11) wherein Ar is as defined above reduced with a complex hydride or alkali metal in ethanol or catalytically (Hol). U.S. Pat. prihl. 7603-693 (1976), Jap. U.S. Pat. 77 39-050 (1977), AO 219 752] to the corresponding alcohol which is isolated in a pure state by methods known to those skilled in the art. In the next step, this alcohol is treated with various halogenating agents such as thionyl chloride, phosphorus halides, hydrohalic acids / jap. U.S. Pat. 77, 2111-536 (1977), Ft. U.S. Pat. No. 2,015,725 (1970) provides the desired 1-aryl-1-haloethane. These processes have various disadvantages when carried out on an industrial scale. In some cases they use expensive, in others from the point of view of work safety, harmful reagents and solvents. Furthermore, they are economically disadvantageous in terms of technology and labor.

252 921

The aforementioned drawbacks are largely eliminated by the process of the present invention, wherein the aryl methyl ketone is reduced with 2-propanol in the presence of aluminum tris-2-propanoate / Neuesre Methoden der Praparativen Organischen Chemie, p. 136, 2nd edition, Verlag Chemie, Berlin 1944} Methoden der Organischen Chemie (Houben-Weyl), Alkohole III, Band 6 (lb p. 301, G. Thieme Verlag, Stuttgart 1984). According to the invention, an arylmethylketone of formula (II) is added to the aluminum tris-2-propanoate prepared in situ in a solution of 2-propanol while boiling the reaction mixture while distilling off the acetone formed together with the solvent 2-propanol. After 3-6 hours, the reaction is complete, the solvents are evaporated off under reduced pressure, and the distillation residue is dissolved in an organic solvent preferably of a C 6 to C 10 hydrocarbon such as benzene, toluene, xylene, cyclohexane, or mixtures thereof. By repeated extraction of the organic phase with dilute aqueous sodium or potassium hydroxide solution or dilute hydrochloric acid, the aluminum salts are removed, and conc. hydrochloric acid at 20 to 60 ° C. The progress of the reaction is monitored by chromatography, preferably by gas chromatography. The reaction is usually complete in 0.2 to 4 hours, depending not only on the acid concentration and temperature, but also on the reaction mixture stirring. Then, the organic phase is separated, washed with a saturated sodium chloride solution. In some cases, it is preferred to decolourize the organic phase with activated carbon. After evaporation of the solvents, the product of formula I is obtained in very good yield and purity, which is used without further purification in the following reaction steps (AO 219 732).

An advantage of the process according to the invention is that it is simple to carry out reactions which do not require expensive and safety-critical reagents. The reaction can be carried out on standard technological equipment and the waste products can be cleaned in a simple way, so that it is also very environmentally friendly.

252 921

The process of the invention is illustrated by several specific examples, which in no way limit the scope of the invention.

Example 1

To a solution of 152.0 g of a compound of formula II wherein Ar is 4-isobutylphenyl- in 1500 ml of anhydrous 2-propanol was added 40 g of aluminum tris-2-propanoate and after 1 hour heating to boiling, distilled on a packed column a mixture of acetone-2-propanol. The content of 1- (4-isobutylphenyl) -1-ethanol in the reaction mixture was monitored by gas chromatography, at a conversion of 99%, the remaining 2-propanol was distilled off from the reaction mixture under reduced pressure, was washed 5x with 100 ml of 5% aqueous sodium hydroxide solution and then stirred at 25 to 50 ° C with 400 ml of conc. hydrochloric acid. After separation of the aqueous phase, the organic layer was washed with 2x250 ml of saturated sodium chloride solution, 250 ml of water and the solvents were evaporated. 124 g of product were obtained which, according to gas-chromatographic analysis, contained 91.5% by weight. compounds of formula I wherein Ar is 4-isobutylphenyl, X is chlorine.

Example 2

To a solution of 100 g of the compound of formula II, Ar is 4-isobutylphenyl, in 1550 ml of 2-propanol was added 25 g of aluminum tris-2-propanoate. After analogous work-up of the reaction mixture as in Example 1, 118 g of product were obtained, which, according to gas-chromatographic analysis, contained 89.5% by weight. compounds of formula I wherein Ar is 4-isobutylphenyl and X is chloro.

Example 5

To 55 g of aluminum foil was added 100 ml of a 0.05 M solution of aluminum tris-2-propanoate in 2-propanol and after heating to boiling, 2500 ml of anhydrous 2-propanol was gradually added over 6 hours. A 100 ml sample was taken from the solution thus prepared for further operation. Then, 240 g of compound II, where Ar

252 921 is 4-isobutylphenyl, and the reaction mixture was worked up as in Example 1. The solvent residue was dissolved in 2400 ml of toluene and washed with 2400 ml of 5% hydrochloric acid. To the separated toluene layer was then added 250 mL conc. hydrochloric acid and proceeded as in Example 1, it is washed with 500 ml of saturated sodium chloride solution, 500 ml of water and the solvent evaporated on a rotary evaporator. 269 g of product were obtained which, according to gas chromatography analysis, contained 90.7 wt. the desired compounds of formula I wherein Ar is 4-isobutylphenyl.

Example 4

To a solution of 145 g of a compound of formula II wherein Ar is 6-methoxy-2-naphthyl in 1450 ml of anhydrous 2-propanol was added 42 g of aluminum tris-2-propanoate and distilled on a packed column after heating to boiling. successively a mixture of the resulting acetone with a solvent. After analogous work-up of the reaction mixture as in Example 1, 122.6 g of product were obtained, which, according to gas-chromatographic analysis, contained 99% by weight of 2 wt. m.p. 79-82 ° C / toluene.

Claims (4)

SUBJECT OF THE INVENTION 252 921 A process for the preparation of 1-aryl-1-chloroethanes of the general formula I A), wherein Ar represents a 4-isobutylphenyl-, 6-methoxy-2-naphthyl-, 5-bromo-6-methoxy-2-naphthyl- group, characterized in that the methylaryl ketone of the general formula XI is Ar-CO-CH3 Al) is treated with 2-propanol with a maximum water content of 0.1% in the presence of aluminum tris-2-propanoate while boiling the reaction mixture while distilling off the resulting acetone with 2-propanol, after which the remaining solvents are distilled off under reduced pressure. after dissolving the distillation residue in an organic solvent with extraction with an aqueous solution containing 10 to 30 wt. sodium hydroxide or dilute hydrochloric acid removed the aluminum salts, whereupon the organic phase containing the crude hydroxy derivative was stirred at 20 to 60 ° C with an excess of conc. hydrochloric acid for 0.2 to 4 hours, the organic phases are separated, washed with a saturated sodium or potassium chloride solution and evaporation of the solvents yields the product of formula I. 2. Method of claim l _y wherein 2-propanol contains less than 0.05% water. 3. A process according to claim 1, wherein the organic solvent is a hydrocarbon having from 6 to 10 carbon atoms, preferably benzene, toluene, xylene, hexane, cyclohexane, or a mixture thereof. 4. A process according to claim 1, characterized in that it is used in situ for genuine aluminum tris-2-propanoate.