DE2514960A1 - NEW SUBSTITUTED IMIMODIMETHYLENE DITERT.ALKYLPHENONE AND METHOD FOR THEIR PRODUCTION - Google Patents

Description

New substituted iminodimethylene-di-tert-alkylphenones
and methods of making them

The invention relates to substituted iminodimethylenedi-tert-alkylphenols of formula I,

R.

R ₀ OC

W /

² y

V7orin R represents hydrogen, fluorine / chlorine or a straight-chain alkoxy group with 1-4 carbon atoms, R
and R are the same or different and are each one
Denote alkyl group having 1 or 2 carbon atoms, and R ^ denotes an alkyl group having 1-4 carbon atoms, and processes for their preparation.

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The compounds of the formula I can be converted into their salts and vice versa.

According to the invention, compounds of the formula I are obtained by using compounds of the formula II,

II

C = O

^R 2- <r- ^CH 3

wherein R ₁ , R and R_ have the above meaning, and X stands for chlorine or bromine, with compounds of the formula III,

R ₄ NH ₂ III

v / orin R _{4 has the} above meaning.

The reaction of compounds of the formula II with compounds of the formula III is expediently carried out in one inert organic solvent, for example a halogenated hydrocarbon such as methylene dichloride or chloroform, an ether such as tetrahydrofuran or diethyl ether, or aromatic hydrocarbons such as

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Benzene or toluene. However, the reaction is preferably carried out in benzene. The reaction can take place at temperatures of 25 to 150 ° C, especially at the boiling point of the reaction mixture, take place, the reaction time expediently 10 to 48 hours, in particular 20 to 26 hours. During the reaction, an imino by-product can also be produced by condensation of the amine of formula III with the carbonyl group of the compound of formula II. In this case, the desired compounds of the formula I are separated off in a manner known per se.

The compounds of the formula I obtained by the above process can be isolated and in a manner known per se getting cleaned.

The compounds of the formula II used as starting compounds in the above process can be obtained by chlorination or bromination of compounds of the formula IV,

IV

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wherein R ₁ , R and R have the above meanings, are formed with the aid of chlorinating or brominating agents in an inert organic solvent, the reaction being triggered by free radicals.

For the above chlorination or bromination can be used as Chlorinating or brominating agents, in particular chlorine, bromine, N-chlorine or N-bromophthalimide, N-chlorine or N-bromoacetamide and N-chloro- or N-bromosuccinimide can be used, the latter being preferred. The reaction is triggered either by the presence of chemical free radicals, such as organic peroxides, in particular benzoyl peroxide, or the reaction can also be triggered by irradiation with ultra-violet light. Suitable solvents for the reaction are, for example, aromatic hydrocarbons, such as Benzene, and preferably halogenated hydrocarbons such as methylene dichloride, chloroform or carbon tetrachloride. The reaction is conveniently carried out at the boiling point of the reaction mixture for 12 to 48 hours Hours, especially 18 to 25 hours. In some cases a mixture of mono- and dihalogenates is obtained Links. In this case, the monohalogenated compounds must, if desired, in a manner known per se separated and cleaned. In addition, compounds of the formula IV, if R, for alkyl, but in particular stands for methyl, are halogenated on this group, especially if they are ortho to the methyl

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group stands. In this case, a product mixture is obtained from which the desired compounds of the formula II are separated off Need to become.

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

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

The compounds of formula I have an extremely high
favorable pharmacodynamic effect. In particular, the compounds of the formula I are distinguished by a blood lipid-lowering effect, and they can therefore be used to lower the blood lipid level.

The amount of these compounds to be administered daily is from 300 to 2000 mg, which are expediently divided up in doses of 75 to 1000 mg 2-4 times a day or in sustained release form.

The compounds of formula I can be used together with customary pharmaceutically acceptable diluents or Carriers and optionally other additives are mixed and administered in the form of capsules.

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The compounds of the formula I can also be used in the form of their pharmaceutically acceptable acid addition salts, which have the same degree of effect as the free bases, are administered, in particular for salt formation the hydrochloric acid, hydrobromic acid, sulfuric acid, succinic acid, benzoic acid and Maleic acid are suitable.

The present invention also relates to a pharmaceutical composition which is characterized by the content of compounds of the formula I in the form of the free bases or in the form of their pharmaceutically acceptable bases Acid addition salts together with a pharmaceutically acceptable diluent or carrier.

The preferred compounds of the formula I are those in which R ₂ and R_ each represent methyl. However, particular preference is given to compounds of the formula I in which R _{4 is} methyl. Other compounds of the formula I which are also important are those in which both R 1 are identical and each is hydrogen or chlorine.

The particularly preferred compound is that of Example 1 below.

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Example II 4 ", 4 '" -Methyliminodimethylene-dipivalophenone

10 ml of 4-bromotoluene in 650 ml of tetrahydrofuran are added to a suspension of 28.5 g of magnesium turnings in 150 ml of tetrahydrofuran, which is in a nitrogen atmosphere. When the addition of the 4-bromotoluene solution begins, the reaction is initiated and the remaining portion of the bromotoluene solution is added dropwise at a rate that will keep the system at a low boil. After the addition is complete, the reaction mixture is heated to boiling for a further 11/2 hours. The Grignard solution thus obtained is added dropwise to a cold solution of 128 g of pivaloyl chloride in 500 ml of dry tetrahydrofuran at a rate such that the temperature of the reaction mixture remains at 0 to -5 ° C. After the addition is complete, the resulting solution ^{is stirred for 11/2 hours at 0 °} C. and then for 18 hours at room temperature. The mixture is then cooled to 0 ° C. and hydrolyzed by adding 100 ml of 2N hydrochloric acid. The layers formed are separated and 200 ml of ether are added to the organic phase. Thereafter, the organic phase with 100 ml of a 2N hydrochloric acid, 100 ml of a 10 % aqueous sodium bicarbonate solution and with 100 ml of a saturated aqueous sodium chloride

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Solution washed. It is then dried over anhydrous sodium sulfate, filtered and the solvent im Vacuum removed. This gives p-pivaloyltoluene

2: D

from Sdpkt. 80 to 84 ° C / 0.7 mm Hg, η ^ = 1.5108.

A mixture consisting of 156.3 g of the p-pivaloyltoluene obtained above, 157.8 g of N-bromosuccinimide, 4 g of benzoyl peroxide and 150 ml of carbon tetrachloride is heated to boiling temperature for 18 hours. It is then cooled, filtered and the solvent evaporated. The residual oil is distilled in vacuo to the fields over at 124-132 ° C / 0.1 mm Hg fraction. This consists of cc-bromo-p-pivaloyltoluene,

η = 1.5546 (thin layer chromatography: 96% monobromine compound, 4% dibromine compound).

b) 4 " _£ 4"'""

A mixture of 300 ml of benzene and anhydrous methylamine is added dropwise to 6 g of cc-bromo-ppivaloy / toluene in 600 ml of benzene added, with anhydrous gaseous methylamine through the solution is directed. After the addition is complete, the bubbling of methylamine is continued and the mixture is continued during Heated to the boil for 6 hours. The methylamine flow is then switched off and the mixture is removed heated to boiling for a further 18 hours. It is then cooled in ice and the solvents in vacuo evaporates. The remaining residue is treated with water and diethyl ether, and the resulting layers

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separated. The aqueous layer is extracted with diethyl ether. The combined diethyl ether layers are washed with 2N hydrochloric acid 2 times. The acidic extract is cooled and added by adding solid sodium hydroxide made alkaline. Then it is extracted with ether, the Aetherextrakt'with water and saturated Washed sodium chloride solution, dried over anhydrous magnesium sulfate, filtered off and evaporated in vacuo. The residue is dissolved in ethanol and anhydrous hydrogen chloride gas is passed through the solution. The received The mixture is cooled in ice and the crystals formed are filtered off and washed with cold ethanol. Here the 4 ", 4 '" methyliminodimethylene-dipivalophenone hydrochloride is obtained from m.p. 238-239 ° C.

Example 2;

Using the procedure described in Example 1 and appropriate starting material in approximately equivalents The following compounds of the formula I are obtained in proportions:

a) 4 ", 4" '-Aethyliminodimethylene-dipivalophenon of m.p. 106-108 ° C,

b) 3 ", 3 ^ -Dichlor-4", 4 ⁿⁱ -methyliminodimethylene-dipivalophenon,

c) 3 ", 3 '" -Dimethoxy-4 ", 4'" -methylimino-dimethylene-dipivalophenone and

d) 3 ^If , 3 ^HI -difluoro-4 ", 4 ^MI -methyliminodimethylene-dipivalophenone with a melting point of 205-206 ° C.

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Claims (3)

Claims; 1. Process for the preparation of substituted iminodimethylene-di-tert-alkylphenones of the formula I, wherein R _{1 represents} hydrogen, fluorine, chlorine or a straight-chain alkoxy group with 1-4 carbon atoms, R_ and R_ are identical or different and are each one
Denote an alkyl group with 1 or 2 carbon atoms, and R4 denotes an alkyl group with 1-4 carbon atoms, characterized in that compounds of the formula II, II wherein R ₁ , R ₃ and R- have the above meaning, and X is
Is chlorine or bromine, with compounds of the formula III, R ₄ NH, III wherein R. has the above meaning, converts. 5098U / 1 075 600-6642 Germany 25Η96Θ 2. Substituted iminodimethylene-di-tert-alkylphenones Formula I, where R _{1 represents} hydrogen, fluorine, chlorine or a straight-chain alkoxy group with 1-4 carbon atoms, R and R_ are identical or different and each represent an alkyl group with 1 or 2 carbon atoms, and R _{4 represents} an alkyl group with 1-4 carbon atoms . 3. Therapeutic compositions containing compounds of the formula I. 3700 / ST / SE SANDOZ-PATENT-GMBH Lu 509844/1075