CS243153B1 - Process for producing 176 alkoxy-2-naphthyl / -1-alkanols - Google Patents

Abstract

The method of producing 1-(6-alkoxy-2-naphthyl)-1- -alkanols of the general formula I, where R denotes methyl or ethyl, R1 denotes up to C2 alkyl, consists in treating the halogenophenone of the general formula II, where R and R1 have the above-mentioned meaning, with a complex hydride and in one step reducing the halogen and reducing the ketone to an alcohol in an organic solvent environment in an equimolar ratio of components 1:2 to 4 at a temperature of 35 °C to the boiling point of the solvent, after which the aqueous phase is extracted with an organic solvent after decomposition of the reaction mixture, the combined organic fractions are evaporated and the product of the general formula I is purified by simple crystallization. The invention is useful in the production of drugs based on arylalkanoic acids with anti-inflammatory effects and in the production of insecticides that are part of pyrethroids.

Description

The invention relates to a process for the preparation of 1- (6-alkoxy-2-naphthyl) -1-alkanols of the general formula I, wherein R is methyl or ethyl, R 1 is alkyl having 1 to 2 carbon atoms. Said compounds of formula I are important intermediates in the preparation of 2- (substituted aryl) alkanoic acids.

Compounds of this type have found wide application in human medicine as drugs with anti-inflammatory, analgesic and antipyretic effects. E.g. U.S. Pat. No. 3,904,682 discloses 2- (6-methoxy-2-naphthyl) propionic acid, which is known as the active ingredient of the drug Naproxen. Similar compounds are disclosed in Belgian Pat. In addition, some acids of this type are part of insecticidal preparations of the pyrethroid type.

According to the prior art, compounds of the formula I in which R represents methyl and methyl are still known. methyl or ethyl, prepared by reduction of 6-methoxy-2-naphthylmethyl (ethyl) ketone. As the reducing agent used of aluminum isopropylate in isopropanol medium (J. Chem. Soc. 1955, 2398), or catalytic hydrogenation using mědnatochromitých oxides (Cu _x Cr _y O _z) at elevated temperature and pressure. In the first case, the disadvantage of the aluminum isopropylate process is the disadvantage, in the second case (see J. Org. Chem. 19, 1 205 (1954)) that undesired by-products are formed which are difficult to remove from the reaction mixture. Another disadvantage is working at elevated pressure and temperature in pressure vessels, which require special safety devices.

Another method of preparing compounds of formula I wherein R = R ^{1 =} CH ₃ is protected by U.S. Pat. No. 3,651,106 where the starting 6-methoxy-2-naphthyl methyl ketone is reduced with sodium borohydride in ethanol and the product is isolated from the reaction mixture by extraction ether.

On an industrial scale, the use of ether as solvent requires special precautions and the design of relatively complex devices. A common disadvantage of the preparation of alcohols of formula I, wherein R is methyl and R1 is methyl or ethyl, according to the above procedures, is the difficulty of preparing the starting phenones, which consists in Friedel-Crafts acylation of 2-methoxynaphthalene in nitrobenzene (see e.g. Org. 53, 5 (1973), J. Chem. Soc., 1966, 181).

The use of nitrobenzene as a solvent presents a number of problems in terms of occupational safety (toxicity) and ecology (waste water treatment). In addition, unwanted substances are formed in the reaction which are difficult to remove from the desired phenone. This also shows the economic disadvantage of these processes.

These known processes are followed in a positive way by the process according to the invention, which partially or completely removes the disadvantages. The process according to the invention starts from readily available halophenones (see, for example, J. Chem. Soc. 1941, 394, Annales de Chimie 1, 395 (1946), Ger. Offen. 3 212 172) of the general formula II, wherein R a R1 is as defined above and X is halogen, preferably chloro or bromo.

In this process, halogen is reduced in one reaction step and the ketone is reduced to an alcohol. The reducing agent used is a complex hydride, preferably sodium bis- (2-methoxyethoxy) aluminum hydride, lithium aluminum hydride in aromatic hydrocarbons such as benzene, toluene, xylene, or ether, or sodium borohydride, potassium borohydride in alcohols such as methanol, ethanol. In this reaction, the complex hydride to the phenone of formula II is used in an equimolar ratio of 1: 2 to 4. The reduction is carried out at a temperature of 35 ° C to the boiling point of the solvent, preferably 20 to 100 ° C, for 1 to 7 hours. The progress of the reaction can be monitored by thin layer chromatography. Upon completion of the reaction, the reaction mixture is quenched with either a dilute mineral acid such as hydrochloric or sulfuric acid or with a dilute aqueous alkali hydroxide solution. After the decomposition is complete, the organic phase is separated and the aqueous layer is extracted with an aromatic hydrocarbon such as benzene, toluene or a halogenated hydrocarbon such as dichloroethane, chloroform and the like. After evaporation of the solvents, the product of formula I is purified by simple crystallization.

The advantage of the process according to the invention is that it is simple to carry out the reaction, easy isolation of the product obtained in high yields and purity. A further advantage is that cheap, readily available and realistically safe reagents and solvents are used. The process according to the invention brings about substantial technical progress and is therefore very advantageous from an economic point of view.

He did.

To a solution of 38 g of a phenone of formula II wherein R is CH ₃ , r ¹ = CH 3 and X = Br in 300 ml of toluene was added with stirring 50 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene. The mixture was heated to boiling for 4 h, quenched with 70 ml of hydrochloric acid (1: 1) after cooling, the organic layer was separated, washed with water and the volume of the solution was reduced by evaporation to 100 ml. After cooling, the crystals were collected by filtration and washed with toluene. 21.8 g of product of formula I were obtained, where R = CH3, R1 ⁼ CH3, mp 112-113 [deg.] C, yield 80%.

Example 2

A mixture of 2.7 g of a phenone of formula II wherein R = CH ₃ and R ^{1 =} CH ₃ , 0.37 g of sodium borohydride and 10 ml of ethanol was heated at 60 ° C for 7 h, quenched with 1 ml of concentrated hydrochloric acid after cooling, precipitate filtered, washed with ethanol. The solution was evaporated to dryness and crystallized from benzene to give 1.52 g of the product of formula (I) wherein R ¹ and R ^{1 were} CH 3, mp 111-113 ° C, yield 75%.

Example 3

To a mixture of 3.8 g of lithium aluminum hydride and 100 ml of benzene with stirring over 30 min, dropwise a solution of 23.5 g benzophenone of formula II wherein R = CH _3, R ^ C ^ CH, and X = C1, in 100 ml of benzene, the reaction the mixture was then heated to boiling for 4 h, quenched with 15 ml of 4% NaOH solution after cooling, the organic layer was separated, washed with water, and the solution was concentrated to a volume of 75 ml. After cooling, the crystals were filtered and washed with benzene. 17.9 g of product of formula I were obtained, where R = CH ₃ and R ^X = CH ₂ CH ₃ , mp 86-87 ° C, yield 83%.

Example 4

To a suspension of 28.5 g of lithium aluminum hydride in 500 ml of ether is added dropwise over 1 h a solution of 100 g of phenone of formula II, where R = R = = CH ₃ and X = Br, in 500 ml of ether. The reaction mixture was then heated to boiling for 7 h and, after cooling, was quenched with 100 mL of 1: 1 hydrochloric acid, decanted from the precipitate, washed with water, 5% sodium bicarbonate solution, water and dried over anhydrous sodium sulfate. After evaporation of the ether, crystallization from benzene yielded 58.5 g of the product of formula I, where R = R = = CH ₃ , yield 81%, mp 110-112 ° C.

The invention is useful in the manufacture of arylalkanoic acid medicaments having anti-inflammatory effects as well as in the manufacture of insecticides which are part of pyrethroids.

Claims (4)

object of the invention A process for the preparation of 1- (6-alkoxy-2-naphthyl) -1-alkanols of formula I wherein R is methyl or ethyl is alkyl having 1 to 2 carbon atoms, characterized in that it is converted to a halophenone of formula II wherein R and R '' are as defined above and X is halogen, acts with the complex hydride in an organic solvent medium at an equimolar ratio of components of 1: 2 to 2: After the reaction mixture is quenched, the aqueous phase is extracted with an organic solvent, the combined organics are evaporated and the product of formula I is purified by simple crystallization. 2. The process according to claim 1, wherein the complex hydride is sodium bis- (2-methoxyethoxy) aluminum hydride, lithium aluminum hydride, sodium borohydride, potassium borohydride. 3. A method according to claim 1, characterized in that: The use of benzene and its methyl derivatives or alcohols C1 is used as solvents in the reduction after C1 or ether. 4. The process uses benzene according to any one of Claims 1 to 3 and its methyl derivatives. It can be used as a solvent in the extraction