CS240935B1 - Production method of 2-(substitute-2-naphtyl)-alkannitriles - Google Patents

Abstract

A process for the preparation of 2-substituted-2-naphthyl / alkane nitriles of formula I, wherein R is methyl or ethyl, R 1 is hydrogen or C 1 to C 5 alkyl, X is hydrogen, chloro or bromo, reacting an alcohol of formula II wherein R 1 R1, X are as defined above and Y is chlorine or bromine, with cyanide, the reaction being carried out in the presence of a quaternary ammonium or phosphonium salt, wherein the molar ratio of alkyl halide, cyanide and quaternary ammonium salt is 1: 1 to 5 : 0.01 to 0.1, in an organic solvent environment, - optionally an aqueous phase-orhanic phase in a two-phase system, at a temperature of 40 to 120 ° C, after which the organic phase is separated off, the solvents are evaporated off and the product is crystallized. The compounds are intermediates in the manufacture of medicaments having anti-inflammatory, analgesic and antipyretic properties.

Description

The present invention relates to a process for the preparation of 2- (substituted-2-naphthyl) alkanenitriles of the general formula I wherein R is methyl or ethyl; X is hydrogen, chloro or bromo. Said compounds are important intermediates in the preparation of 2- (substituted-2-naphthyl) alkanoic acids. Compounds of this type have found widespread use in human medicine as drugs with significant anti-inflammatory analgesic and antipyretic effects. They are mainly used in the treatment of rheumatoid diseases of joints and tissues, especially rheumatoid arthritis and osteoarthritis. The best known representative of this group of substances is 2- (6-methoxy-2-naphthyl) propionic acid, which is an active ingredient in Naproxen.

Methods for the preparation of certain compounds of formula (I) are described both in the literature and protected in patents, e.g. of formula I wherein R = CH 3, R ^{1 =} H, X = Br (from the corresponding chloromethyl derivative) (see Bull.soc.chim. France 1942, 58) by the action of potassium cyanide in aqueous ethanol. An analogous process for the preparation of the above nitrile, by reacting the chloromethyl derivative with sodium cyanide in a solution of dimethyl sulfoxide, is protected in Polish patent no.

201. In the first process, an aqueous ethanol solution greatly reduces the specificity of this substitution reaction and the by-products formed are relatively difficult to remove from the desired nitrile. High isolation effort together with low product yields make this process relatively disadvantageous. The second method uses an expensive and, in terms of work safety, dimethylsulfoxide. On the technological scale, it brings both the difficult isolation of the pure product and the problems associated with waste water treatment.

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Furthermore, in the above-mentioned patent, the conversion of a substituted acetonitrile of formula (I) wherein RCH 3, R ^{1 =} H, X = Br, to 2- / 5-bromo-6- methoxy-2-naphthyl (propanenitrile) of formula I wherein R = R ^{1 =} CH 2, X = Br) by sequential treatment with tert. potassium butylate in dimethylsulfoxide and methyl iodide under an inert nitrogen atmosphere with substantially no yield. The use of expensive solvents and reagents, the requirement of an anhydrous environment and an inert atmosphere make this process considerably disadvantageous both from a technological and economic point of view.

Another method for preparing a nitrile of the formula I where R = R ¹ = C H5, X = H, is protected by Japanese Pat. No. 58 25 162. The essence of this process is the transmetallation 6-methoxy-2-naphthyl magnesium halide and cuprous halide subsequent coupling the resulting organo-copper compound with 2- (p-toluenesulfonyloxy) propionitrile. The disadvantage of this process is a difficult technological solution requiring special apparatuses, as well as difficulties in recovering the copper compounds from the waste water. This also implies its economic disadvantage.

These processes are followed in a positive way by the method according to the invention, which partially or completely removes the above mentioned deficiencies.

The process of the invention starts from readily available substituted alkyl halides of formula II wherein R, X, X are as defined above, and Y is chloro or bromo, which by reaction with cyanide in the presence of a catalytic amount of quaternary ammonium or phosphonium 5: 0.01 to 0.1 in an organic solvent environment, optionally in a two-phase aqueous-organic phase system, yields a product of Formula I in high yields of 70 to 95% and purity. The reaction is carried out with vigorous stirring at a temperature of 40 to 120 ° C, preferably 60 to 100 ° C, and its progress is controlled by thin layer chromatography or gas chromatography. After completion of the reaction, the solids (a mixture of cyanides and halides) are filtered off, the organic phase is washed with a little cold water, the solvents are distilled off and the product is purified by crystallization. The quaternary salt can be recovered from the wash aqueous solution and used in the next reaction.

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The cyanides used are preferably ammonium cyanide or alkali metal cyanides, and preferably lithium, sodium, potassium cyanide. Preferred quaternary ammonium and phosphonium salts are cetyltrimethylammonium bromide, cetyltributylphosphonium bromide, trioctylmethylammonium chloride, dodecylbenzyldimethylammonium chloride, and tetrabutyl hydrogen sulphate. The organic solvents used are halogenated hydrocarbons having 1 to 4 chlorine atoms and 1 to 6 carbon atoms, preferably dichloromethane, 1,2-dichloroethane, tetrachloroethylene, chlorobenzene or aromatic hydrocarbons such as benzene, toluene, xylene.

The advantage of the process according to the invention is that it is simple to carry out the reaction and to easily isolate the product even under technological conditions. Furthermore, the use of inexpensive and available reagents and solvents. The process according to the invention brings technical progress and is very economically advantageous.

The process according to the invention is illustrated by means of several specific examples which are illustrative only and do not limit the scope of the invention in any way.

Example 1

A mixture of 2.62 g of an alkyl halide of the formula II wherein R-CH3, iBM1, X = Br, Y-Cl, 10 ml of benzene, 0.98 g of cyanide. sodium hydroxide, 2 ml of water and 0.1 g of triethylbenzylammonium chloride were heated at 85-90 ° C with vigorous stirring for 6 hours. After cooling, the organic phase was separated, washed with 3 ml of water, dried over magnesium sulphate, the solvents were evaporated and crystallization of the residue from ethanol gave 2.29 g (91%) of the nitrile of formula I wherein R-GH4, R-H3. M.p. 145-146 ° C.

Example 2

A mixture of 2.80 g .obecného halides of formula II wherein R₁ CIIj, R = G ₂ H 5, X = H, Y = Br, 1.16 g ammonium cyanide, 0.2 g of trioktylmethylamoniumchloridu in 10 ml of chlorobenzene was heated at stirring at 90-100 ° C for 8 hours. After cooling, the solids were aspirated, the organic phase washed with water, dried and the solvents distilled off under reduced pressure. Crystallization of the distillation residue

240 933 from acetone gave 1.69 g (72%) of the product of formula (I) wherein R = CH ₅ , R ¹ = C ₂ H ₅ , X = H, mp 74-76 ° C.

Example 5

A mixture of 40 g of the compound of formula II wherein R = R ¹ = CH _2> X = H, Y = C1, 35.5 g of sodium cyanide, 6.1 g of tetrabutylammonium hydrogen sulfate, 400 mL of toluene and 50 ml of water was heated to 90 100 ° C for 6 hours. After cooling, the aqueous phase was separated and the organic solution was evaporated to dryness. Crystallization of the residue from methanol gave 30.3 g (79%) of a nitrile of formula I wherein R = R R = GH5, X = H, mp 71-73 ° C.

Example 4

A mixture of 3.44 g of the halide of formula II wherein R @ 1 R @ 1 R @ CH3, X = Y = Br, 1.1 g of potassium cyanide, 0.1 g of cetyltributylphosphonium bromide, 10 ml of 1,2-dichloroethane and 2 ml of water was added. 4 hours of stirring and heating at 55 to 60 ° C was treated in an analogous manner to that of Example 1. 2.03 g (70%) of the product of formula I were obtained, where R @ 1 R @ 1 R @ 1 CH @ 1, X = Br. Mp 104-106 ° C.

Claims (3)

SUBJECT OF THE INVENTION A process for the preparation of 2- (substituted-2-naphthyl) alkanenitriles of formula I wherein R is methyl or ethyl, R 1 is hydrogen or C 1 -C 3 alkyl, X is hydrogen, chloro or bromo by reaction of substituted halides of formula II wherein R, R · ⁵ · X have the abovementioned meaning and Y represents chlorine or bromine, _a cyanide, characterized in that the reaction is carried out in the presence of a quaternary ammonium or phosphonium salt, wherein the molar ratio of alkyl halides, cyanide and the quaternary salt is 1: 1 to 5: 0.01 to 0.1, in an organic solvent environment, optionally in a two-phase aqueous-organic phase system, at a temperature of 40 to 120 ° C, after which the organic phase is reacted the solvents are evaporated off and crystallization of the residue yields the product of formula (I). 2. Method according to point 1 _? characterized in that a chlorinated hydrocarbon having 1 to 6 carbon atoms and 1 to 4 chlorine atoms or benzene and its methyl derivatives is used as the organic solvent. 3. Process according to claims 1-2 _(wherein the quaternary ammonium or phosphonium salts employed trioktylmethylamo · chloride, cetyltribůtylfosfoniumbromid, tetrabutylammonium hydrogensulfate, triethylbenzyl. 1 drawing