CS256044B1 - Process for producing cyclohexyl benzyl cyanide - Google Patents

Abstract

The method for producing cyclohexyl benzyl cyanide of formula I <G6H11ÍG6H5 GHG1í by alkylation of benzyl cyanide of formula II c6h5ch2cn ♦ (II), with cyclohexyl bromide in the presence of a quaternary ammonium salt consists in that the alkylation is carried out in a two-phase system in an iodine-organic phase environment in the presence of phase transfer catalysts based on quaternary ammonium salts, for example tetra-n-butylammonium hydrogen sulfate in a molar ratio of the reacting components benzyl cyanide with cyclohexy bromide with catalyst 1 t 1.2 to 1.8 with 0.02 to 0.1 and an excess of approximately 50% aqueous sodium or potassium hydroxide solution at a temperature of 60 to 120 °C and preferably 70 to 90 °C for 2 to 8 hours, after which the product of formula I is obtained from the organic phase after phase separation. The compound of formula I is used in the production of pharmacologically active substances.

Description

The present invention relates to a process for the preparation of cyclohexyl benzyl cyanide of formula I ^{c 6h} 5 ' _from CHCN (1)

CgH11

The compound of formula I is used in the manufacture of pharmacologically active substances [Kleemann A., Engel J. in Pharmazeutische Wirkstoffe, Synthesen, Patente, Anwendungen; Thieme Verlag Stuttgart, 1978 / for example, methylthioethyl cyclohexylphenyl acetate thiospasmin methoiodide spasmolytics. / List of MS. pharmaceutical preparations 1980' 1984, Spofa Praha 1980 /.

The compound of formula I is prepared according to the prior art by alkylation of the sodium salt of benzyl cyanide of formula II, (C ₆ H ₅ CH ₂ CN (11)) prepared by treatment with various basic reagents, by reaction with cyclohexyl bromide. In most cases, sodium amide is used in various media such as liquid ammonia and toluene / J to prepare the sodium salt. Amer. Chem. Soc. 65, 1999 (1943), ether-benzene, ether-toluene, xylene and the like. obšč. Chim. 7, 2823 (1937); J. Amer. Chem. Sco. 64, 970 (1942); J. Chem. Soc.

1949, 3156; Org. Synth. Coll, Vol. III, 219 (1955); U.S. Pat. U.S. Pat. 2 265 184 (1939). A disadvantage of these processes is the work with liquid ammonia and aggressive sodium amide, which therefore requires special precautions. Another process disclosed in AO 200 438 protects the preparation of a compound of formula I using an alkali metal hydroxide using catalysis of quaternary ammonium salts in an environment of aprotic polar solvents such as dimethylformamide or dimethylsulfoxide. In another AO 202 448 it was shown that the reaction proceeds even in the absence of quaternary 254 044

- 2 of them ammonium salts. According to said AO, the product is obtained in yields of 60 to 85% with a boiling point in the wide range of 160 to 180 ° C at 1 353 Pa as an oil of defined purity.

It can therefore be assumed that it is not a pure compound of formula (I) and therefore the yields are substantially lower. A further disadvantage is the use of relatively expensive solvents, which are very difficult to remove from wastewater.

These known processes are followed in a positive way by the process according to the invention. A process for preparing a compound of formula I by alkylating a benzyl cyanide with cyclohexyl bromide in the presence of a quaternary ammonium salt catalyst comprises mixing a mixture of benzyl cyanide of formula II, cyclohexyl bromide, quaternary ammonium salt and about 50% alkali metal hydroxide and organic solvent at 60-120 ° C. for 2 to 8 hours. The molar ratio of reactants, compound II: cyclohexyl bromide: quaternary salt is 1: 1.2 to 1.8: 0.02 to 0.1. The progress of the reaction is monitored by chromatographic methods, preferably by gas chromatography. Particularly preferred quaternary ammonium salt catalysts are tetra-n-butylammonium hydrogen sulphate and methyltrioctylammonium chloride. Organic solvents which are immiscible or to a limited extent miscible with water, such as aromatic hydrocarbons benzene, toluene, xylene or halogenated derivatives such as dichloromethane, are used as organic phases. After completion of the reaction, the solution is filtered, the organic phases are separated, the aqueous phases are extracted with the solvent used above, the combined organics are washed with ice water, dried and the solvents are distilled off. Distillation of the residue yields, after cooling, a crystalline product which, according to gas-chromatographic analysis, contains above 97% by weight. It is also possible to proceed by distilling off only a small amount of unreacted cyclohexyl bromide and benzyl cyanide from the distillation residue. The product of formula (I) thus obtained contains over 97% by weight and can be used without further difficulty in further reaction steps.

An advantage of the process according to the invention is that the distilled solvents can be easily recovered and reused in the reaction cycle. Furthermore, simple reaction,

256 minimum requirements for the solvents used, good product yields without undesirable impurities make this process economically advantageous.

The invention and its effects are illustrated by the following examples which demonstrate the applicability of the methodology and do not limit the scope of the invention in any way.

Example 1

A mixture of 129 g of the benzyl cyanide of the formula II, 215 g of cyclohexyl bromide, 550 ml of toluene, 16.5 g of tetra-n-butylammonium hydrogen sulphate and 400 l of about 50% sodium hydroxide was heated at 90-100 ° C. After three hours of heating, 66 g of cyclohexyl bromide were added to the reaction mixture and heated with vigorous stirring for a further two hours. After cooling, the solution was filtered, the aqueous phase separated and extracted with toluene, the combined organics were washed with water, dried over magnesium sulfate, and after evaporation of the toluene, distillation of the residue yielded 132 g of the compound of formula I, b.p. 164-168 ° C at 1.3 kPa, which upon cooling crystallized to m.p. Mp 53-56 ° C.

Example 2

To a mixture of 258 g of benzyl cyanide of formula II, 350 g of cyclohexyl bromide, 1000 ml of xylene and 20 g of methyltrioctylammonium chloride 750 ml of about 50% potassium hydroxide was added after 1 hour at 60 ° C 50 g of cyclohexyl bromide. . After stirring for a further 3 hours, the reaction mixture was worked up as in Example 1 to obtain 275 g of the product of formula I, b.p. 165-169 ° C at 1.3 kPa, m.p. Mp 54-58 ° C.

Claims (2)

2S6 044 - 4 - OBJECT OF THE INVENTION A process for the preparation of cyclohexyl benzyl cyanide of formula I c6H5. CHCN / 1, C6H11 by alkylation of a benzyl cyanide of formula II with C6h5ch2cn (11), cyclohexyl bromide in the presence of a quaternary ammonium salt characterized in that the alkylation is carried out in a biphasic system in a water-organic phase in the presence of quaternary ammonium salt phase transfer catalysts , for example tetra-n-butylammonium hydrogen sulphate, in the molar ratio of the reactants benzyl cyanide: cyclohexyl bromide :: catalyst 1: 1.2 to 1.8: 0.02 to 0.1 and an excess of about 50% aqueous sodium or potassium hydroxide at a temperature of 60 to 120 ° Preferably C is 70 to 90 ° C for 2 to 8 hours, after which phase separation is obtained from the organic phase of formula I. 2. Process according to claim 1, wherein the organic phase is an organic solvent which is immiscible or miscible with water, for example an aromatic hydrocarbon such as benzene, toluene, xylene or chloroalkane such as 1,2-dichloroethane.