KR790001195B1 - Process for preparing substituted imino methylene-di-tert-alkyl phenones - Google Patents

Abstract

Alkylphenones [I; R1 = H, F or Cl, R2,R3 = C1-2 alkyl, R4 = C1-4 alkyl , useful as blood lipid lowering agents at 300-2000mg, were prepd. by reaction of halo derivs. (II; X = Cl or Br) with R4NH2. Thus, a mixt. of 300ml MeNH2 and C6H6 was added to II, prepd. by acylation of ρ-Me C6H4Br with Me3CCOCl followed by bromination with NBS, and the mixt. heated to boiling for 24hr to give I as HCl salt.

Description

Process for preparing substituted iminodimethylene-di-tert-alkylphenone

The present invention relates to a process for preparing substituted iminodimethylene-di-tert-alkyl phenones of the following structural formula (I), which are effective as blood fat reducing agents.

In the above structural formula,

R ₁ is hydrogen, fluorine or chlorine,

R ₂ and R ₃ may be the same or different from each other and each represents C ₁ -C ₂ alkyl,

R ₄ represents C ₁ -C ₄ alkyl.

The compound of formula (I) is prepared by reacting a compound of formula (II) with a compound of formula (III) in the presence of an inert organic solvent.

Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as in formula (I) and X represents chlorine or bromine.

Suitable solvents include halogenated hydrocarbons such as methylene dichloride or chloroform, benzenes of ethers such as tetrahydrofuran or diethyl ether, aromatic hydrocarbons such as toluene (preferably benzene) and the like. The reaction proceeds well at temperatures between 25 ° and 150 ° C., preferably at the reflux temperature of the reaction mixture, with a reaction time of 10 to 48 hours, usually 20 to 26 hours. In this reaction, the amine of formula (III) and the carbonyl group of formula (II) condense to form an imine by-product. In this case, the compound of the desired structural formula (I) can be separated according to a conventional method.

The compound of formula (I) obtained can be separated and purified by conventional techniques. If necessary, the free base form of this compound can be converted to the acid addition salt form according to a conventional method, and vice versa.

The compound of formula (II) used as a starting material in the reaction may be prepared by chlorination or bromination of the compound of formula (IV) with a chlorinating or brominating agent in the presence of an organic solvent, and the reaction may be initiated by free radical initiation. do.

Suitable chlorination / bromination agents include chlorine, bromine, N-chloro / bromophthalimide, N-chloro / bromoacetamide and N-chloro / bromosuccinamide, with the latter being preferred. This reaction can be started in the presence of a chemical free radical initiator such as an organic peroxide such as benzoyl peroxide or can be initiated under ultraviolet light. Suitable solvents include aromatic hydrocarbons such as benzene and halogenated hydrocarbons such as methylene dichloride, chloroform or carbon tetrachloride. The reaction is preferably run for 12 to 48 hours (18 to 25 hours is more suitable) at the reflux temperature of the reaction mixture. In some cases, mono-halo can be separated and purified according to conventional methods if necessary to produce a mixture of monohalo and dihalo products. In addition, when R ₁ is alkyl, in particular methyl, and this group is halogenated to some extent, in particular halogenated at the ortho position relative to the methyl group, a mixed product results, which is usually again possible to separate the desired product.

The compound of formula II obtained can be separated and purified according to a conventional method.

The compounds of the formulas (III) and (IV) used as starting materials in the reaction are known compounds or compounds which can be obtained according to conventional methods.

Substituted iminodimethylene-di-tert-alkylphenones of formula (I) prepared according to the invention can be used as blood fat reducing agents, in particular blood fat protein reducing agents. That is, it can be seen that cholesterol and triglyceride concentrations are lowered in male Wistar rats of 110-130 g in the first weight. These mice are fed for 7 days with no drug-feeding and then divided into groups of 8-10 animals. Each group was orally administered with 120 mg / kg for 6 days, except for the control group, followed by anesthesia with sodium hexobarbital and bleeding in the carotid artery. Serum or plasma samples are collected and 1.0 ml of serum is added to 9.0 ml of re-distilled isopropanol. A mixture of zeolite-copper hydroxide and Lloydds reagents (Kassler, Z. and Redler, H., 1965, Technicon Symposium, Median Inc., New York, 345-347) was used as a glass of the automatic analyzer. Add two glasses and shake the mixture for 1 hour. Cholesterol and triglyceride concentrations are measured simultaneously on the same sample using the Technicon N 24 A (cholesterol) and N-78 (triglyceride) test methods. The average total serum cholesterol concentration is calculated and the blood cholesterol reduction effect is expressed as% of cholesterol lowering relative to the control concentration. Change in serum triglyceride concentration by drug is calculated as the control triglyceride concentration%.

A suitable daily dose of the compound of formula (I) is 300 to 2,000 mg, and it is appropriate to administer 75 to 1,000 mg twice or four times a day or sustained release.

The compound of formula (I) may be mixed with conventional pharmaceutically innocuous diluents or carriers and any other excipients or may be administered in the form of a formulation such as a capsule.

The compound of formula (I) can be administered as a free base or in the form of a pharmaceutically toxic acid addition salt, which salts have the same degree of activity as the free base.

Acids used for salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, succinic acid, benzoic acid and maleic acid.

Therefore, the compound of formula (I) in the form of free base or pharmaceutically harmless acid addition salt obtained according to the present invention may be mixed with a pharmaceutically harmless diluent or carrier to form a pharmaceutical composition.

Preferred among the compounds according to the present invention are compounds wherein R ₂ and R ₃ are each methyl, and more preferred are compounds wherein R ₄ is methyl. Other important compounds are those wherein R ₁ is the same and each is hydrogen or chlorine. Most preferred compounds are the title compounds of the following Example 1.

The following examples are some examples that specifically illustrate the present invention.

Example 1

4 ", 4" '-methyliminodimerene-dipivalophenone

A) Bromo-P-pivaloyltoluene (Compound II)

=1.5108)을 얻는다. 이렇게 얻은 P-피발로일톨루엔 156.3g(0.886몰)dmf 157.8g(0.886몰)의 N-브로모석신이미드, 4.0g(0.016몰)의 벤조일 퍼옥사이드와 150㎖의 사염화탄소의 혼합물에 가하고 이 혼합물을 18시간 가열 환류시킨다. 이 혼합물을 냉각, 여과하고 수득된 오일을 진공 증류하여 α-브로모-P-피발로일톨루엔(비점 124 내지 132℃/0.7mm,

=1.5546-V.P.C. 96%-모노브로모 4%-디브로모)을 얻는다.10 ml 4-bromo-toluene (1.17 moles) dissolved in 650 ml of anhydrous tetrahydrofuran was added to a suspension in which 28.5 g (1.17 g atoms) magnesium pieces were suspended in 150 ml of tetrahydrofuran under nitrogen atmosphere. Start with and add the rest of the bromo toluene solution dropwise to maintain the proper reflux. After completion of the dropwise addition, the mixture is refluxed for another 1 1/2 hours. The resulting Grignard solution is added dropwise to a cold solution in which 128.0 g of pivaloyl chloride (1.06 mole) is dissolved in 500 ml of anhydrous tetrahydrofuran at a rate such that the temperature can be maintained between 0 ° and -5 ° C. The solution is stirred for further 1 1/2 hours at 0 ° C. and then for 18 hours at room temperature. The mixture was cooled to 0 ° C., hydrolyzed by addition of 100 mL of 2N hydrochloric acid and the layers separated, followed by addition of 200 mL of ether to the organic phase, followed by 100 mL of 2N hydrochloric acid, 100 mL of 10% sodium carbonate solution and 100 mL. Wash with mL of saturated sodium chloride. The layer thus obtained was dehydrated with anhydrous sodium sulfate, filtered and the solvent was removed in vacuo to give P-pivaloyltoluene (boiling point 80-84 ° C./0.7 mm,

= 1.5108). 156.3 g (0.886 mole) dmf 157.8 g (0.886 mole) N-bromosuccinimide, 4.0 g (0.016 mole) benzoyl peroxide and 150 ml of carbon tetrachloride were added to the P-pivaloyl toluene thus obtained. The mixture is heated to reflux for 18 hours. The mixture was cooled, filtered and the oil obtained was vacuum distilled to give α-bromo-P-pivaloyltoluene (boiling point 124 to 132 ° C./0.7 mm,

1.51.5-VPC 96% -monobromo 4% -dibromo).

B) 4 ", 4" '-methyliminodimethylene-dipivalophenone

300 ml of benzene and anhydrous methylamine mixture were added dropwise to 6.0 g (0.235 mol) of α-bromo-P-pivaloyltoluene dissolved in 600 ml of benzene and excess anhydrous methylamine was bubbled through the solution. ) After the timely completion, the inflow of methylamine is continued and the mixture is refluxed for 6 hours. The influx of methylamine is stopped and the mixture is refluxed for another 18 hours, then cooled in ice and the solvent is evaporated in vacuo. The resulting residue is treated with water and diethyl ether, the layers are separated and water is extracted with diethyl ether. The combined diethyl ether layers are washed twice with 2N hydrochloric acid, the acid layer is cooled, basified by addition of solid sodium hydroxide and extracted with ether. The ether solution is washed with water and brine, dehydrated on anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is dissolved in ethanol and treated with anhydrous hydrochloric acid. The mixture is cooled with ice and the resulting crystals are filtered and washed with cold ethanol to obtain 4 ", 4" 'methyl iminodimethylene-dipivallophenone hydrochloride at melting point 238-236 ° C.

Example 2

The following compounds can be obtained by a method analogous to Example 1 using approximately the same amount of suitable starting material.

A) 4 ", 4" '-ethyliminodimethylene-dipivallophenone, melting | fusing point 106-108 degreeC

B) 3 ", 3" '-dichloro-4 ", 4"'-methyliminodimethylene-dipivalophenone

C) 3 ", 3" '-difluoro-4 ", 4"'-methyliminodimethylene-dipivalophenone, melting point 205-206 degreeC

Claims (1)

A process for preparing a substituted iminodimethylene-di-tert-alkylphenone of formula (I), characterized by reacting a compound of formula (II) with a compound of formula (III) in the presence of an inert organic solvent.

In the above structural formula, R ₁ is hydrogen, fluorine or chlorine, R ₂ and R ₃ may be the same or different from each other and each represents C ₁ -C ₂ alkyl, R ₄ is C ₁ -C ₄ alkyl X represents chlorine or bromine.