CS240715B1 - A method for producing 1- (6-methoxy-2-naphthyl alkyl halides) - Google Patents

Abstract

The method for producing 1-(6-Alkoxy, 2-naphthyl)alkylhalogens of the general formula '1, 'where R .denotes methyl or ethyl, R* 1 denotes C1 to C2 alkyl and .X denotes trichloro or bromo from the alcohol of the general formula II, where R and R 1 -have the above-mentioned meaning, consists in .that the alcohol of the general formula JI is treated with hydrochloric or hydrobromic acid in the presence of a phase transfer catalyst of the quaternary ammonium type in a molar ratio of components 1.: 2 to 10: 0.02 to 0.1, with intensive stirring in a two-phase system aqueous phase-organic solvent at a temperature of 20 to .80 ° C, after which the organic phase is separated after completion of the reaction and after evaporation the obtained solid product of the above formula is dissolved I purifies crystallization. The compounds mentioned are intermediates in the production of drugs with anti-inflammatory, analgesic and antipyretic effects.

Description

(54) A method for producing 1- (6-methoxy-2-naphthyl) alkyl halides

A process for the preparation of 1- (6-Alkox, γ 2 -naphthyl) alkyl halides of the general formula (1), wherein R is methyl or ethyl, R ¹ is C 1 to C ² -C 2 alkyl, and X is Cl, or bromo from alcohol II; wherein R and R1 are as defined above, wherein the alcohol of general formula (I) is treated with isotropic hydrochloric acid with bromic acid in the presence of a quaternary ammonium phase transfer catalyst, in molar ratios of the components of 1: 2 to 10: 0.02 to 0.1, with vigorous stirring in a two-phase aqueous phase-organic solvent system at a temperature of 20 to 80 ° C, after which the organic phase is separated after the reaction is completed and the solid product of formula I obtained after evaporation of the solvent. purifies crystallization.

Listed. the compounds are intermediates in the manufacture of drugs with anti-inflammatory, analgesic and antipyretic effects.

The invention relates to a process. l -. (6-alkoxy-, 2-naphthyl) alkyl halogenides of the general formula I wherein R is methyl or ethyl, R @ ¹ represents alkyl having 1 to. 2 carbon atoms and X is chlorine or bromine? The compounds of formula (I) are used as intermediates in the production of 1- (6-Alkoxy-2-naphthyl) alkanoic acids and derivatives thereof, so far, the compounds have been found to be highly effective and low toxicity pharmaceuticals in the treatment of inflammatory diseases such as (4 -) - 1- (6-methoxy-2-naphthyl) propionic acid, with the generic name Naproxen, which is an effective part of anti-inflammatory and analgesic agents such as Naprosyn (See, e.g., U.S. Pat. Nos. 3,904,682, 3,978 1H6, 3,958,012.) Recently, 2- (X-substituted aryl) alkanic acids, especially isovaleric acid derivatives, have been used as insecticides with a pronounced pyrethroid effect ( see Angew Chem Int 11: 460 (1972).

Synthesis of some compounds of formula I is described in the literature and patents. For example, U.S. Pat. No. 3,651,108 describes a process for preparing 1- (6-methoxy-2-naphthyl) ethyl chloride, a compound of formula I wherein R = R ¹ = CH 3 and X is Cl, starting from the corresponding substituted alcohols, from which, first by reaction with p-toluenesulfonyl chloride, the corresponding p-toluenesulfoester is prepared, and treatment with lithium halides gives the desired halide derivative of formula II wherein R = R ¹ = CH 3 and X = Cl. A significant disadvantage of this process is that the reaction is carried out in two reaction stages, wherein the preparation of the p-tosyl ester is carried out in an environment of excess pyridine. In the second step, a small amount of undesirable unsaturated derivative is formed which contaminates the product. It is obvious that this process has a number of disadvantages, the most important of which are the relatively high consumption of aggressive chemicals (p-toluenesulfonyl chloride and pyridine) and the problems of waste water treatment. It is therefore disadvantageous both from a technological and economic point of view. The preparation of the above-mentioned compound from the corresponding alcohol by treatment with dry hydrogen chloride or thionyl chloride with unrecognized yields and physicochemical characteristics is described in Bull. Chem. Soc. Japan 52, 3033 (1979). The disadvantage of this process is aggressive and expensive reagents, especially thionyl chloride, the use of which is considerably disadvantageous in terms of hygiene, safety and economy. ,

Bull. soc. chim. France, 1954, 511 discloses the preparation of l- (6-methoxy. Naftyljpropylchloridu ^J-2, compounds of formula I wherein R = CH3, ^{R1 =} C2H5, X = C1, from the corresponding alcohol by treatment with anhydrous HCl gas in the medium of benzene, The disadvantage of this process is the excessive consumption of hydrogen chloride gas associated with its capture and the use of hazardous class I combustibles in fire safety terms.

These known processes in the positive sense are followed by the process according to the invention, which partially or completely removes these disadvantages. The essence of the invention lies in the fact that the alcohol of formula II wherein R and R ¹ are as defined above, acts azeotropic hydrochloric acid or hydrobromic acid in the presence katalyzátru phase · transfer of quaternary ammonium salt in a two-phase system of aqueous phase-organic solvent at a temperature of 20 to 80 ° C, preferably 20 to 40 ° C with vigorous stirring. After completion of the reaction, the organic phase is separated, the aqueous phase is washed with the same solvent, and the combined extracts are distilled off and the solid product of the formula I obtained is recrystallized. The molar ratio of alcohol: acid: catalyst is 1: 2 to 10: 0.02 to 0.10. Phase transfer catalysts may be formulated with tertiary ammonium salts, such as trioctylmethylammonium chloride, triethylbenzylammonium chloride, cetyltrimethylammonium bromide, tetrabutylammonium hydrogen sulfate, or also phosphonium salts such as hexadecyltributylphosphonium bromide and other phosphonium bromide. The organic solvents used are halogenated hydrocarbons having 1 to 6 carbon atoms and 1 to 4 chlorine atoms, such as dichloromethane, 1,2-dichloroethane, chlorobenzene, carbon tetrachloride. and aromatic hydrocarbons such as benzene, toluene. xylene or mixtures thereof.

The process according to the invention has a number of advantages over the prior art. From a technological point of view, it is easy to do. in conventional simple apparatuses already reaction occurs rapidly under mild reaction conditions _t čn.ích .and its course is allowed to be easily monitored through chromatographic methods, and tím.šetřit energy. Uses Easily Available Cheap Reagents and Solvents. The product is obtained in high yield and purity. From the above-mentioned results also economic the process according to the invention.

The process of the present invention is illustrated by several specific exemplary embodiments, which are illustrative only and are not intended to limit the scope and scope of the invention in any way.

EXAMPLE complete, the mixture 20.2 g of an alcohol of formula II, wherein R = R ¹ = CH 3, 26 ml of concentrated hydrochloric acid, 100 ml of dichloroethane and 2.2 g triethylbenzylamoniumchloridp was vigorously stirred for 1 h at 20 C, the organic layer separated, washed with water and after evaporation the residue crystallized from toluene. Yield 210.3 g (92%) of an alkyl halide of general formula I, wherein R = R ¹ = CH 3 and X = C1, mp 82-84 ° C.

Example 2

A mixture of 6.5 g of the alcohol of formula II, where R = CH3, R1 ⁼ CH2CH3, 7.7 ml of concentrated hydrochloric acid, 15 ml of toluene and 0.3 g of hexadecyltrimethylammonium bromide was stirred for 1 hour at 40 ° C, the organic layer separated, washed with water. After concentrating the solution to half volume by cooling, crystals dropped, which were aspirated and washed with toluene. 6.54 g (93%) of an alkyl halide of formula I were obtained, wherein R = CH3, R1 = CH2CH3 and X = C1, mp 49-51 degrees Celsius.

Example 3

A mixture of 40.4 g of the alcohol of formula II wherein R = R ¹ = CH 3, 1114 ml of azeotropic hydrobromic acid, 200 ml of tetrachlorethylene and 2.5 g of trioctylmethylammonium chloride was stirred vigorously at 20 ° C for 2 h, the organic layer was separated, washed ice water, and after concentrating and cooling was isolated by filtration 47.2 g (89%) of an alkyl halide of general formula I, wherein R = R ¹ = CH 3 and X = Br, mp 95-97 ° C.

The invention is useful in the pharmaceutical industry for the synthesis of intermediate drug products based on substituted arylalkanoic acids as well as for the production of substances with pyrethroid effects.

Claims (3)

SUBJECT A process for the preparation of 1- (6-alkoxy-2-naphthyl) alkyl halides of the formula I, wherein R is methyl or ethyl, R ¹ is C 1 -C 2 alkyl and X is chlorine or bromine, from an alcohol of formula II, wherein R and R ¹ are as defined above, characterized in that the alcohol of formula II with azeotropic hydrochloric or hydrobromic acid in the presence of phase transfer catalyst of quaternary ammonium salt in a molar ratio of components of 1: 2 to 10: 0.2 to ! 0.1 with stirring in a biphasic aqueous-organic solvent system at 20 to the invention 80 ° C, after which the organic phase is separated after completion of the reaction, and after evaporation of the solvents, the solid product of the formula I obtained is purified by crystallization. 2. The process according to claim 1, wherein the quaternary ammonium salts are trioctylmethylammonium chloride, benzyltriethylammonium chloride. 3. A process according to claim 1, wherein the organic solvent is halogenated hydrocarbons having from 1 to 4 halogen atoms and from 1 to 6 carbon atoms or benzene and its methyl derivatives.