NO144148B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BIS (3,4,5-TRIMETHOXY-BENZOATE) OF PYRIDINE-2,6-DIMETHANOL - Google Patents

Description

The present invention relates to an analogous process for the production of therapeutically active bis(3,4,5-trimethoxybenzoate) from pyridine-2,6-dimethanol of the formula: which process is characterized by the fact that 3,4,5-trimethoxybenzoic acid chloride is reacted with pyridine- 2,6-dimethanol according to the reaction scheme:

in that the reaction takes place in an inert organic solvent in the presence of a tertiary amine as an acid acceptor for the hydrochloric acid formed during reaction, and that the impure product is separated by adding the reaction mixture to water, after which the product is recrystallized from solvents that are miscible with water.

The starting material, 3,4,5-trimethoxybenzoic acid chloride, is obtained by reacting the corresponding acid and an excess of thionyl chloride. The resulting chloride of the acid can be used directly in its impure state and does not require purification by distillation.

In practice, 3 moles of 3,4,5-trimethoxybenzoic acid chloride are used in the reaction for each mole of pyridine-2,6-dimethanol. The reaction can be carried out in various inert solvents and in the presence of a tertiary amine, such as e.g. triethylamine, pyridine, tri-n-butylamine etc, which are able to absorb the hydrochloric acid formed during the reaction. Good results are obtained by using pyridine, because this simultaneously acts as a solvent as well as an acid acceptor, in an amount that can vary between 9 and 10.8 liters per kg of pyridine-2,6-dimethanol.

It is preferred that the reaction is carried out by mixing the solution of pyridine-2,6-dimethanol with the chloride of the acid at ambient temperature, after which the temperature of the reaction mixture is raised to 80°C by means of a heat bath, during the time necessary to complete the reaction which normally finds place within between 2 and 3 hours.

As soon as the reaction is complete, water is added, after which the reaction mixture is filtered, and the impure product is collected on the filter and recrystallized. In this way, yields varying between 60 and 68% are achieved.

In order to obtain a product of good quality, it is important to wash the impure product with water to remove color impurities which usually accompany the reaction and which are difficult to remove later by recrystallization, even when using activated carbon.

The final recrystallization of the impure product is carried out in different types of solvents, preferably methanol, ethanol and isopropanol are used for this purpose, the solubility of the product increasing with increasing temperature from methanol to isopropanol.

The structure of the bis-ester obtained was determined on the basis of its nuclear magnetic resonance spectrum and infrared spectrum.

Pyridine-2,6-dimethanol-di-(3,4,5-trimethoxybenzoate)

(PTB) is a new compound which is described for the first time in the present application. Clinical investigations have shown that the compound exhibits surprising and valuable properties in that it exhibits a strong hypolipidemic activity while at the same time reducing platelet aggregation. The hypolipidemic activity

is indicated by a specific reduction of low-density lipoproteins.

This property is not exhibited by the compounds described in Norwegian patent documents 116,851 and 116,913 which describe compounds with analgesic and vasodilatory properties. The compounds described in Chemical Abstract 76. (1972, 63476) and J. Med. Che. 10 (1976) 491-495 works through other biological mechanisms by antagonizing bradykinin and inhibiting the permeability of the arterial wall, which is completely different from the activities exhibited by PTB.

In an experimental investigation, the hypolipidemic effect of PTB was compared with the effect of 3,6-pyridinedimethanol bis-(N-methylcarbamate) (PMC), which is the most representative compound described in the latter two publications -cations. 80 white New-Zealand male rabbits, 6 months old and weighing 3212 - 480 g were divided into 4 groups. The active ingredients were used in suspension in 30% ethanol. The control groups (1 and 2) were given 1 ml of 30% ethanol daily by gavage. Blood samples for cholesterol determination were taken every four weeks from ear veins. A lipid and lipoprotein analysis was carried out after the end of the experiment. After 12 weeks, the rabbits were bled and killed.

Lipids were extracted as described by Folch et al (J. Biol. Chem. 226, 497, 1957), and cholesterol was determined in these extracts. Total cholesterol (TCh), esterified cholesterol (ECh) and free cholesterol (Ch) were measured using an enzymatic method (På Rochlan et al Z. Klin. Chem. Klin. Biochem 12, 403 (1974). Serum lipoproteins (LP) was separated by density gradient ultracentrifugation (F.T. Hatsch. Adv. Lipid. Res. 6, 1, 1968). LP with d 1.063 g/ml was termed LDL or Ø-zone LP after chylomicrons. LP of d> 1.06 3 g/ml was considered HDL or α-LP. Purity control of LP fractions was performed by polyacrylamide disc electrophoresis. For quantitative comparisons, means were tested using Student's t-test for independent groups. Distribution of the sample values were expressed in upper and lower 95% confidence limits.

Results - The results of the experiment are listed in Table I.

A very marked reduction of low density lipoproteins (LDL) is shown for the compound PTB compared to the low effect of the compound PMC.

Clinical studies have established the specific effect of the compound PTB on low-density 3-lipoproteins. Dis-se's role in the pathophysiology of lipid transport disorders has been clearly demonstrated (Post-graduate Medical Journal 41 (Suppl. 8), 1-101, 1975 ( .

Another unexpected property of the compound PTB is its effect on platelet aggregation, which has been shown in several clinical trials. The use of drugs that exhibit anti-platelet aggregation to prevent thrombosis has been described in (H.J. Weiss, American Heart Journal, 92, 86, 1976).

Example 1

15 kg (70.8 mol) 3,4,5-trimethoxybenzoic acid and 65 1

benzene was introduced into a reactor to which a mixture of 27.4 liters of thionyl chloride had been added. The mass was heated to 56 - 70°C within five hours. The excess of benzene and thionyl chloride was distilled off under vacuum. The residue was kept under vacuum at 120 - 123°C for one hour, whereby a hard crystalline solid was thus obtained.

A solution composed of 3.24 kg (23.3 moles) of pyridine-2,6-dimethanol in 35 liters of pure pyridine was added to the mixture, and the reaction mixture was heated to 80°C for 2 1/2 hours. The reaction mixture turned brown. The pyridine hydrochloride formed was cooled and crystallized. The reaction mixture was then poured into water, filtered, after which the precipitate was repeatedly washed with water, then dissolved in 400 liters of methanol, after which the resulting solution was filtered with activated carbon. Over 50 liters of methanol were distilled from this filtrate at normal pressure, after which the product was crystallized. An amount of 8.35 kg (15.8 mol) of pyridine-2,6-dimethanol-trimethoxybenzoate was obtained, which was a yield of 68%.

The product was present as white solid crystals melting at 119-126°C. Recrystallized from methanol, a product was obtained which melted at 126-127°C and whose elemental analysis was as follows: C = 61.2^, H = 5A6#, N = 2.82$

while the calculated quantities for the formula 02^2^0-^ are:

C = 61.^7$, H = 5.5^%, N = 2.65%.

Infrared spectrum: The ester structure was confirmed by the C=0 absorption at 1720 cm and strong absorption of C-O-C. The band at 760 cm""'" was attributed to the three hydrogens in the pyridine ring.

Nuclear magnetic resonance spectrum: (CDCl^, TMS):

3-9"+^ singlet -0CH3; 5. 52f singlet -0CH2; 8.00

- 7.27^ multiplet aromatic protons.

Example 2.

15 kilograms (70.7 mol) of 3 A, 5-trimethoxybenzoic acid and

65 liters of benzene were introduced into a reactor after which 27.<*>+ liters of thionyl chloride were introduced. Reaction mixture none was heated to 65 - 70°C

in the course of five hours. The excess of benzene and thionyl chloride was evaporated under vacuum. The residue was heated under vacuum for 1 hour at 120-123°C, whereby a crystalline solid material was obtained.

The residue obtained was dissolved in 60 liters of benzene, to which 3.2 kg were added. (23.3 mol) pyridine-2,6-dimethanol and 8 liters of pyridine. None of the reaction mixtures were heated under reflux for 5 hours. The solvents were then removed by distillation under vacuum and the residue was poured into water, the precipitate was filtered and washed repeatedly with water, after which it was then diluted in h00 liters of methanol and filtered with activated carbon.

From the filtrate it was distilled from 10 liters of methanol at normal pressure whereby the remaining product was crystallized. 8.98 kg was thus obtained. (17 mol) pyridine-2,6-dimethanol trimethoxybenzoate, which yielded 73% - On recrystallization from methanol, a product was obtained which melted at 126-127 C, for which the elemental analysis was as follows: C = 61.2^56, H = 5A6$, N = 2.82$

which when calculating the formula C2<r7H2>^N<0>10 gives:

C = 6l,V7$, H = 5.5^%, N = 2.65%

Claims (1)

Analogous procedure in the preparation of therapeutically active bis(3,4,5-trimethoxybenzoate) from pyridine-2,6-dimethanol of the formula: characterized in that 3,!+, 5-trimethoxybenzoic acid chloride is reacted with pyridine-2,6-dimethanol according to the reaction scheme: in that the reaction takes place in an inert organic solvent in the presence of a tertiary amine as an acid acceptor for the hydrochloric acid formed during the reaction, and that the impure product is separated by adding the reaction mixture to water, after which the product is recrystallized from solvents that are miscible with water.