CS200438B1 - Method of preparing phenylcyclohexyl acetonitrile - Google Patents

Description

The invention relates to a process for the preparation of phenylcyclohexylaetonitrile, an important intermediate of the synthesis of basic and sulfuric esters of phenylcyclohexylacetic acid, in particular a spasmolytically active methylthioethyl ester, which is produced as a clinically used medicinal specialty.

On a production scale, phenylcyclohexylacetonitrile is obtained by alkylating phenylacetonitrile with cyclohexyl bromide in inert organic solvents in the presence of powdered sodium amide (JHBiel et al., J. Am. Chem. Soc. 74, 1487, 1952), which is a very unpleasant reagent . Another method of successfully carrying out alkylae is not described, and attempts to make the reaction more operationally safe, up to 3 using alkali metal or sodium hydroxides, have so far failed.

The aforementioned disadvantages are eliminated by a process for the preparation of phenylcyclohexylaoetonitrile by alkylation of phenylacetonitrile with cyclohexyl bromide in the presence of a solid alkali metal hydroxide according to the invention, characterized in that the alkylation is carried out under catalysis with a quaternary ammonium salt of the general formula

200 438

200 430 wherein R 1 and R 6 are C 1 -C 4 alkyl, R 1 C 1 -C 4 alkyl or benzyl, R 2 C 2 -C 16 alkyl and X inorganic anion, especially hydrohalic acid, in an amount of 1 to 4 5% by weight, based on the amount of starting phenylacetonitrile, and in the presence of a polar aprotic solvent, preferably dimethylformamide or dimethylsulphoxide, in 0.5 and 1.5 times the amount of starting phenylacetonitrile, at a temperature of 50 to 70 ^° C.

The described reaction proceeds in a two-phase system, in the presence of quaternary ammonium salts of the general formula as a phase transfer catalyst. In principle, it is the formation of a carbanion from phenylacetonitrile (organic phase) with an alkali metal hydroxide (aqueous phase), which is made possible by the presence of a catalyst. The quaternary salt forms the appropriate quaternary base, which comes into the organic phase, where the reaction with phenylacetonitrile forms an ion pair substrate. Substitution reaction of the carbanion with cyclohexyl bromide produces the desired product and recombines the appropriate quaternary ammonium salt.

Another possible mechanism assumes the formation of a carbanion directly at the phase interface, and the role of the quaternary ammonium cation consists only in the transport of the carbanion (in the ion feather blower) into the interior of the organic phase, where the desired product is formed by the substitution reaction.

It has been found that instead of the aqueous phase, it is preferable to use a solid phase, for example a pulverized solid hydroxide instead of a 50% aqueous alkali metal borohydride solution. It has further been found that the addition of a polar aprotic solvent (for example dimethylformamide or dimethylsulfoxide) accelerates the reaction and increases yields. A series of tetraalkylammonium, trialkylarlylammonium and trialkylaralkylammonium salts of any anion can be used as the phase transfer catalyst. For example, tetrabutylammonium iodide and cetyltrlmethylammonium bromide were preferably used.

The process according to the invention is very simple, preparatively feasible and, in contrast to the sodium amide processes used hitherto, completely safe. It also provides very good yields of about 80% of theory and the product is very pure in contrast to the products obtained by nitramidamide condensation, which are always contaminated by the corresponding double alkylation product.

Further details will be apparent from the examples which illustrate the method according to the invention but do not limit it in any way.

Example 1

To a stirred mixture of 17.55 g (0.15 mol) phenylacetonitrile, 26.90 g (0.165 ml) of cyclohexyl bromide, 18.0 g (0.45 mol) of powdered sodium hydroxide and 2.8 g (0.0075 mol, 5 15 g of dimethylsulphoxide was added dropwise over a period of 3 minutes, based on the amount of phenylaetonitrile) tetrabutylammonium iodide. The temperature of the mixture spontaneously rises to 60 ^° C and is maintained at this level by cooling for 20 to 30 minutes. After stirring for an additional 30 to 40 minutes at 50 ⁰ 0 and then heated again at 65 ° 0 4-5 hours. 150 ml of water are added, stirred and shaken 3 times with 80 ml of toluene each. The toluene fractions are washed first with 5% hydrochloric acid and then thoroughly with water. After drying over magnesium sulfate and evaporation of the solvent, the residue is distilled under reduced pressure and a fraction boiling in the range of 160-180 ^° C / 1333 Pa is collected. Yield: 25.4 g (85.1% of theory).

200 430

Example 3

The procedure was as in Example 1 except that an equimolar amount of tetrabutylammonium bromide and 15 g of dimethylformamide were used instead of tetrabutylammonium bromide. Yield: 80%.

Example 4

The procedure was as in Example 1 except that equimolar amounts of triethylbenzylammonium chloride and 15 g of dimethylformamide were used instead of tetrabutylammonium iodide. The yield is 78.5% of theory »

Example 5

The procedure was as in Example 1 except that an equimolar amount of cetyltrimethylammonium bromide was used instead of tetrabutylammonium iodide. Yield: 83%.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of phenylcyclohexylacetonitrile by alkylation of phenylacetonitrile with cyclohexyl bromide, in the presence of a solid alkali metal hydroxide, characterized in that the alkylation is carried out under quaternary catalysis with an ammonium salt of the general formula. and an inorganic, especially hydrohalic acid, in an amount of 1 to 5% by weight, based on the amount of the starting phenylacetonitrile, and in the presence of a polar aprotic solvent, preferably dimethylformamide or dimethylsulfoxide. in 0.5 to 1.5 times the weight of starting phenylaetonitride, at a temperature of 50 to 70 ^° C.