KR870000231B1 - Process for preparing 2,6-pyridine methanol bis (3,4,5,-trimethoxy benzoate) - Google Patents

Abstract

The title compds. (I) were prepd. by the reaction of 2,6pyridinemethanol(II) and 3,4,5-trimethoxy benzoic acid ester in the presence of base. Thus, 6.95kg 2,6-pyridinedimethanol and 339g NaH were reacted with 26.4286Kg 3,4,5-trimethoxy benzoic acid ester at 160≰C for 6hr to give 19.4kg 2,6-pyridinedimethanol bis (3,4,5- trimethoxybenzoate) (73% yield).

Description

Method for preparing 2,6-pyridinedimethanol bis (3, 4, 5-trimethoxybenzoate)

The present invention relates to a process for producing the novel 2, 6-pyridinethanol bis (3, 4, 5-trimethoxybenzoate) of the following formula.

The reaction consists of a transesterification reaction by reacting 2, 6-pyridinedimethanol with 3, 4, 5-trimethoxybenzoic acid in the presence of a base as shown in the table below.

As esters of the raw material, ie, 3, 4, 5-trimethoxymentoic acid, it is preferable to use alkyl esters having a small molecular weight as described in the literature.

The reaction is carried out in the absence of solvent. 2.2 moles of ester per mole of 2, 6-pyridinedimethane are used. Sodium hydride is used as the base. Usually, even when a sufficient amount of catalyst is present, the reaction can be rapidly advanced by using an excess amount of base, that is, 100 to 200 moles with respect to 2,6-pyridinedimethanol.

This reaction proceeds in two steps. In the first step, 2, 6-pyridinedimethanol is partially modified with the corresponding alcoholate. Appropriate external temperature at this time is about 130 degreeC. Then, an alkyl ester of 3, 4, 5-trimethoxybenzoic acid is added to the obtained reactant, and a transesterification reaction is carried out. Suitable external temperature at this time is 160 degreeC-170 degreeC. The resulting alcohol is distilled off under standard pressure (preferably in vacuo) to prevent severe reaction of the reaction mass.

The heating time is 6 to 12 hours.

As a result of this, 2, 6-pyridine diethanol bis (3, 4, 5-trimethoxybenzoate) is obtained with high purity of 70 to 90%. The goose of this material has been confirmed by nuclear magnetic resonance spectra and infrared spectroscopy.

The above method according to the present invention is characterized in that industrial mass production is easy and the final product can be separated from any kind of impurities. In addition, 2, 6-pyridinedimethanol bis (3, 4, 5-trimethoxybenzoate) has an advantageous pharmacological action.

The effect of 2, 6-pyridinedimethanol bis (3, 4, 5-trimethoxybiszoate) on hyperlipidemia and atherosclerosis caused by administration of atheromatous foods to rabbits is tested. 2, 6-pyridinedimethanol bis (3, 4, 5-trimethoxybenzoate) was orally administered to one group of animals at an amount of 50 mg / kg / day for 12 weeks and another group was untreated. The above food is administered (control).

The following two groups are measured.

Treatment of Atherosclerosis: Enlargement of lesions in the aortic site and light, relationship of free cholesterol / esterified cholesterol and cholesterol content in the aortic wall.

Cholesterol-lowering effect: Relationship between total ratio of seric cholesterol, degree of LDL-cholesterol and HDL / LDL cholesterol.

The results obtained above are summarized in the table below.

2, 6-pyridindimethanol bis (3, 4, 5-trimethoxybenzoate) is a remarkable activity as a therapeutic agent for atherosclerosis which reduces the infection rate of aortic part and tubelite by 24.6% and 48.6%, respectively Indicates. It also shows a potent alleviation of 21.2% of total aortic cholesterol compared to the values obtained in the control group. 2, 6-pyridinedi methanolic bis (3, 4, 5-trimethoxybenzoate) increases the relationship of free cholesterol / esterified cholesterol by 166% and cholesterol lowering of blood vessel walls with a 21.2% reduction rate Very preferred pharmacological action against.

2, 6-pyridindimethanol bis (3, 4, 5-trimethoxybenzoate) reduces the total ceric cholesterol by 32.4% and LDL-cholesterol ratio (B cholesterol) by 37.9%.

This increases the relationship between HDL / LDL-cholesterol by 52%, resulting in unusually large values as a result of the significant decrease in LDL-cholesterol rate.

To further illustrate the method, the following examples are actually shown. This does not limit the scope of the present invention.

When 2, 6-pyridine dimethane was administered to rabbits with bamboo oil-producing plants, bis (3, 4, 5-trimethoxybenzoate) (50 mg / kg po) lowered cholesterol and hemorrhage (same food) Compared to the results of the untreated group administered).

Example 1

A mixture of 6.95789 (50 moles) of 2, 6-pyridinedimethanol and 339 g of NaH (about 50% in paraffin: 7.06 moles) is heated to 130 ° C. for 1 hour. To obtain a homogeneous substance, 26.4286 kg (110 mol) of ethyl ester of 3, 4, 5-trimethoxybenzoic acid are added thereto. Vacuum at 14 mm Hg and heat it to 160 ° C. for 6 hours. After heating to room temperature, 120 ml of isopropanol and 20 ml of water are added to the opaque material. The precipitate is filtered off and washed with water and isopropanol in turn. This gave 19.4 kg (36.7 mol: 73%) of 2, 6-pyridinedimethanol bis (3, 4, 5-trimethoxybenzoate) having a melting point of 110 to 122 ° C. Crystallization with acetonitrile gives a sample having a melting point of 127-8 ° C.

Calculated Value: (C ₂₇ H ₂₉ NO ₁₀ ): 61.47% C 5.54% H 2.65% N

Found: 61.58% C 5.71% H 2.79% N

Example 2

A mixture of 6.9578 kg (50 moles) of 2, 6-pyridinedimethanol and 339 g of NaH (about 50%: 7.06 moles in paraffin) is treated in the same manner as in Example 1. 24.8856 kg (110 mol) of methyl ester of 3, 4, 5-trimethoxybenzoic acid are added to the homogeneous material obtained. Under vacuum of 14 mmHg, it is heated to 160 ° C. for 7 hours. The reaction mixture was crystallized with isopropanol / water to give 23.74 kg (45 mol: 90%) of bis- (3, 4, 5-trimethoxybenzoate) of pyridine-2, 6-dimethanol having a melting point of 126-8 ° C. do.

Claims (4)

2, 6-pyridinedimethane of formula (2) is reacted with 3, 4, 5-trimethoxy benzoic acid ester of formula (3) in the presence of a base to undergo transesterification. A process for producing 2, 6-pyridinedimethanol bis (3, 4, 5-trimethoxy benzoate) of formula (A).

The method according to claim 1, wherein alkyl esters having a low molecular weight are used as the 3, 4, 5-trimethoxybenzoic acid esters. The process of claim 1 wherein sodium hydride is used as the basic catalyst. The process according to claim 1, wherein the transesterification is carried out by distilling off the alcohol produced.