NO744293L - - Google Patents

Description

The present invention relates to a method for

preparation of new acyl-substituted benzyl and dibenzyl ethers of formula I

in which R 1 and R_ are the same or different and in each case stand for hydrogen, a straight-chain alkyl group with 1-4

carbon atoms, a straight-chain alkoxy group with 1-4 carbon atoms,

fluorine or chlorine, and and R^ are the same or different and mean in the individual case an alkyl group with one or two carbon atoms,

and n stands for 0 or 1, with the condition that if R3 and R4 simultaneously stand for methyl, R2 stands for hydrogen because n stands for 0, R1 has

a meaning other than the meaning of a methoxy group in the 4-position.

The peculiarity of the method according to the invention is that

in which R^/R3 and R^ have the above meaning and X stands for chlorine or bromine, are reacted with compounds of formula III

in which M stands for sodium, potassium or lithium and R1 and n have the above meaning.

The reaction of the compounds of formula II with the compounds of formula III conveniently takes place in an inert organic solvent, e.g. an aromatic hydrocarbon such as benzene, toluene or xylene, dimethylformamide or dimethylacetamide, the latter being preferred. The reaction takes place preferably at temperatures from 0 to 60°C, preferably from 20 to 30°G, with the reaction duration being 2 to 36 hours and preferably 15 to 20 hours. For the reaction, compounds of formula II in which X stands for bromine are preferred.

The obtained compounds of formula I can be isolated and purified in a manner known per se.

The compounds of formula II used as starting compounds in the above method can be prepared by

wherein , R3 and R. have the above meaning, in the presence of a

organic solvent is brominated or chlorinated by reaction with N a brominating or chlorinating agent.

The bromination or chlorination of the compounds of formula IV is initiated by means of free radicals. For the bromination and chlorination, bromine, chlorine, N-bromo- or N-chlorophthalimide/N-bromo- or N-chloroacetamide and N-bromo or N-chlorosuccinimide are suitably used as bromination and chlorination agents, the latter being preferred. The reaction is triggered by free radicals: such as organic peroxides, e.g. benzoyl peroxide, or by irradiation with ultraviolet light. Suitable solvents are aromatic hydrocarbons, e.g. benzene, and preferably halogenated hydrocarbons such as methylene dichloride, chloroform or carbon tetrachloride. The reaction is preferably carried out at the reflux temperature of the reaction mixture, suitably over the course of 12 to 48 hours, preferably over the course of 18 to 25 hours. In some cases, a mixture of mono- and dihalogenated compounds is obtained: after which the monohalogenated compounds, if desired, are separated and purified using known means. If in the compounds of formula IV R^ stands for an alkyl group, especially a methyl group, that group can be halogenated to a certain extent. This happens especially when this group is in the ortho position to the methyl group. In this way, you arrive at a mixed reaction product that must be separated in a manner known per se.

The obtained compounds of formula II can be isolated and purified

in and of itself known manner.

The compounds of formulas III and IV used as starting compounds in the above process are either known or can be prepared in a manner known per se from known starting compounds.

Thus, e.g. compounds of formula III are obtained by

a corresponding phenol or a corresponding benzyl alcohol is treated with an inorganic base, e.g. an alkali metal hydroxide, especially sodium hydroxide or potassium hydroxide, an alkali metal alkoxide, e.g. sodium methoxide, sodium ethoxide, or potassium ethoxide, or an alkali metal hydride such as potassium hydride, the latter being preferred. The compounds of formula III are thereby formed in situ and can then be used for the preparation of the compounds of formula I.

The compounds of formula I are characterized by favorable

pharmacodynamic effect. In particular, the compounds have down formula I

a blood lipid-lowering, especially a lipoprotein gel-lowering effect, as this can be inferred from the results of experiments in which the lowering of the blood cholesterol level and blood triglyceride level in male albino rats is measured by exposure to the compounds of formula I.

The compounds of formula I can therefore be used as blood fat-lowering agents, especially lipoprotein-lowering agents.

The daily administered dose of the compounds of formula I in which n stands for 0 is between 250 and 3000 mg, this amount being suitably administered in smaller doses of 62.5 to 1500 mg 2-4 times a day or in slow-release form. The daily added dose of the compounds of formula I, in which n stands for 1, is between 150 and 2500 mg,

as this amount is suitably administered in smaller doses of 37.5 to 1250 mg 2-4 times a day or in slow-release form.

The compounds of formula I can be administered together with per se common pharmaceutical diluents or carriers.

possibly other additives in the form of tablets or capsules.

The compounds that are preferred are those in which stands for

hydrogen and/or each of the substituents R^ and R^ stands for methyl. If R^ has a meaning other than hydrogen, this substituent is preferably in the 4-position of the phenyl ring. The particularly preferred compounds are p-(4-methylphenoxymethyl)-pivalophenone and p-(benzyloxymethyl)-pivalophenone.

The invention shall be illustrated in more detail by means of the following exemplary and preferred embodiments.

Example 1: p-(phenoxymethyl)-pivalophenone.

■§l_a=brom=p=pivalgiltgluen_

■To a suspension of 28.5 g of magnesium shavings in 150 ml of tetrahydrofuran, which is under a nitrogen atmosphere, add 10 ml

4-bromotoluene dissolved in 600 ml of dry tetrahydrofuran. Upon addition of the first portions of the 4-bromotoluene-16s, the reaction begins. The remaining portions of the bromotoluene solution are then added dropwise at a rate which causes the system to be kept at a gentle boil. After the addition is complete, the mixture is heated to boiling for a further 1% hour. The resulting deogrignard solution is added dropwise to a cold solution of 128 g of pivaloyl chloride in 500 ml of dry tetrahydrofuran at such a rate that the temperature remains at 0 to -5°C. The solution is then stirred further for 1^ hours at 0°C and the stirring is then continued at room temperature for 18 hours. The mixture is then cooled to 0°C and hydrolysed by adding 100 ml of 2N hydrochloric acid. The layers formed are separated and 200 ml of ether is added to the organic phase. The organic phase is then washed with water with 100 ml of 2N hydrochloric acid, 100 ml of a 10% aqueous sodium bicarbonate solution and finally 100 ml of a saturated aqueous sodium chloride solution. The organic solution is then dried over anhydrous sodium sulphate, filtered and the solvent is freed of solvent in a vacuum. This gives p-pivaloyltoluene (boiling point 80-84 C/0.7 mm, n 1.5108). A mixture of

D

156.3 g of the obtained p-pivaloyltoluene is then added to a mixture of 127.8 g of N-bromosuccinimide, 4 g of benzoyl peroxide and 150 ml of carbon tetrachloride and the resulting mixture is heated for 18 hours to boiling. The mixture is then cooled and the precipitate formed is filtered off and washed with carbon tetrachloride. The filtrate is freed of solvent in vacuum and the remaining oil is distilled in vacuum. This yields a-bromo-p-pivaloyltoluene with a boiling point of 124-132 C (0.17 ram n^1.5546. (Vapor phase chromatography: 96% monobromo and 4% dibromo compound).

b) P-^phenoxymethyl)_-pivalophenone

To a suspension of 6.73 g of sodium hydride (57% suspension in mineral oil - 0.165 mol) in 200 ml of dry dimethylacetamide, 14.1 g of phenol dissolved in 50 ml of dimethylacetamide is added dropwise, keeping the temperature below 25°C. After the addition is complete, the resulting mixture is stirred for 1^ hours at room temperature. A solution of 38.3 g of cc-bromide-p-pivaloyltoluene in 50 ml of dimethylacetamide is added dropwise to the mixture at room temperature and the resulting mixture is stirred for 18 hours at room temperature. 10 ml of methanol is then added to the mixture. The mixture is then evaporated in vacuo and the residue obtained is distributed between ether and water. The ether layer is washed twice with 200 ml of a 2N aqueous sodium hydroxide solution,

once with water and once with an aqueous saline solution. The organic layers are combined and dried over anhydrous magnesium sulfate, decolorized and freed from solvent by evaporation. The solid residue obtained is mixed with petroleum ether. It thus obtained clean

p-(phenoxymethyl)-pivalophenone melts at 79.5 - 80°C.

Example 2:

Using the method described in example 1 and corresponding starting compounds in roughly equivalent amounts, the following compounds of formula I can be prepared:

a) p-(phenoxymethyl)-2-chloro-pivalophenone,

b) p-(phenoxymethyl)-2-methoxy-pivalophenone,

c) p-(phenoxymethyl)-3-methyl-pivalophenone,

d) p-(4-chlorophenoxymethyl)-pivalophenone, melting point 55-57°C,

e) p-(3-chlorophenoxymethyl)-pivalophenone,

f) p-(4-methylphenoxymethyl)-pivalophenone, melting point 39-42°C, g) p-(benzyloxymethyl)pivalophenone, melting point 39.5 - 40.5°C,

h) p-(benzyloxymethyl)-2-chloro-pivalophenone,

i) p-(benzyloxymethyl)-2-methoxy-pivalophenone, v

j) p-(benzyloxymethyl)-3-methyl-pivalophenone,

k) p-(4-chlorobenzyloxymethyl)-pivalophenone,

1) p-(4-methoxybenzyloxymethyl)-pivalophenone, and

m) p-(4-methylbenzyloxymethyl)-pivalophenone.

Claims (1)

Process for the preparation of new acyl-substituted benzyl and dibenzyl ethers of formula I in which and R2 are the same or different and in each case stand for hydrogen, a straight-chain alkyl group with 1-4 carbon atoms, a straight-chain alkoxy group with 1-4 carbon atoms, fluorine or chlorine, and R^ and R^ are the same or different and mean in in the individual case an alkyl group with 1 or 2 carbon atoms, and n stands for 0 or 1, with the condition that if R 3 e and ■ .- R 4 simultaneously stand for methyl, R 2 means hydrogen and n means 0, R^ has a meaning other than the meaning of a methoxy group in the 4-position, characterized in that in which R2, R3 and R^ have the above meaning and X represents bromine or chlorine, is reacted with compounds of formula III, in which M represents sodium, potassium or lithium and R ^and n have the above meaning.