RU2549566C2 - Method for producing methyl 1-[(1,3-dioxo-2,3-dihydro-1h-inden-2-yl)-(4-methylphenyl)methyl]cyclohexane carboxylate showing analgesic activity - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a method for producing methyl 1-[(1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-(4-methylphenyl)methyl]cyclohexane carboxylate (I)

consisting in the fact that 1-bromcyclohexane carboxylic acid methyl ester is boiled with zinc and 2-(4-methylbenzylidene)-1H-indene-1,3(2H)-dione in the medium of benzol - ethylacelate - hexamethylphosphotriamide (10:5:1) for 8 hours with 67% yield.

EFFECT: prepared compound possesses analgesic activity.

1 tbl, 2 ex

Description

The invention relates to the field of organic chemistry, namely to oxo esters, and to a method for producing methyl 1 - [(1,3-dioxo-2,3-dihydro-1H-inden-2-yl) - (4-methylphenyl) not described previously methyl] cyclohexanecarboxylate of the formula

exhibiting analgesic activity, and which may find application in various organic syntheses.

Reformatsky's reagents can join the activated carbon-carbon double bond of unsaturated ketones with the formation of carboxylic acid oxoesters [1]. Oxoacids have analgesic activity [2].

The purpose of the invention is the development of a method for producing methyl 1 - [(1,3-dioxo-2,3-dihydro-1H-inden-2-yl) - (4-methylphenyl) methyl] cyclohexanecarboxylate, which exhibits analgesic activity and which would be widely used as an intermediate in various organic syntheses.

This goal is achieved by the fact that 1-bromocyclohexanecarboxylic acid methyl ester is boiled with zinc and 2- (4-methylbenzylidene) -1H-indene-1,3 (2H) -dione in benzene - ethyl acetate - HMFTA (10: 5: 1) within 8 hours. The target product is isolated by known methods with a yield of 67%.

The process proceeds according to the scheme

Example 1. Synthesis of methyl 1 - [(1,3-dioxo-2,3-dihydro-1H-inden-2-yl) - (4-methylphenyl) methyl] cyclohexanecarboxylate (I).

Into a round-bottom flask were placed 1.5 g of zinc pulverized into fine chips, a catalytic amount of HgCl ₂ , 12 mmol of 1-bromocyclohexanecarboxylic acid methyl ester, 10 mmol of 2- (4-methylbenzylidene) -1H-indene-1,3 (2H) -dione , 10 ml of anhydrous benzene, 5 ml of anhydrous ethyl acetate, 1 ml of HMFTA. The reaction mixture was boiled for 8 h, cooled, poured from excess zinc, hydrolyzed with a 5% solution of acetic acid, the organic layer was separated, and the reaction products were extracted twice with ethyl acetate from the aqueous layer. After the extract was dried with anhydrous sodium sulfate, the solvents were distilled off, and methyl 1 - [(1,3-dioxo-2,3-dihydro-1H-inden-2-yl) - (4-methylphenyl) methyl] cyclohexanecarboxylate was recrystallized twice from ethanol. Yield 2.62 g (67%), mp. 136-137 ° C. IR spectrum, ν, cm ^-1 : 1709 (С = O) _ket. 1740 (C = O) _eff. . ¹ H NMR, δ, ppm .: 1,07-2,40 m [10H, (CH _{2) 5],} 2.33 s (3H, Me), 3.57 d (1H, C H Ar, J 2.1 Hz ), 3.69 s (3H, OMe), 4.18 d (1H, HCO, J2.1 Hz), 6.91-7.87 m (8H, Ar). Found,%: C 77.03; H, 6.64. C ₂₅ H ₂₆ O ₄ . Calculated,%: C 76.90; H, 6.71.

Example 2. Pharmacological study of methyl 1 - [(1,3-dioxo-2,3-dihydro-1H-inden-2-yl) - (4-methylphenyl) methyl] cyclohexanecarboxylate (I) for the presence of analgesic activity.

The analgesic activity of compound (I) was determined by the “hot plate” method on white outbred mice weighing 18-22 g [3]. The test substance was administered intraperitoneally in the form of a suspension in 2% starch mucus at a dose of 50 mg / kg 0.5 h before the animals were placed on a metal plate heated to 53.5 ° C. An indicator of pain sensitivity was the duration of the animal’s stay on the hot plate until the hind legs were licked, measured in seconds. The reference standard was metamizole sodium, administered intraperitoneally at a dose of 93 mg / kg (ED ₅₀ ). Statistical processing of the experimental material was performed using Student's t test [4]. The test results are presented in the table. As can be seen from the table, the named compound significantly increased the threshold of pain sensitivity in animals under thermal exposure, exceeding metamizole sodium in activity. Acute toxicity (LD ₅₀ , mg / kg) of compound (I) was determined by the method of G.N. Pershine [5]. Compound (I) was administered intraperitoneally to white mice weighing 16-18 g in the form of a suspension in 2% starch mucus. For test compound (I), LD ₅₀ > 500 mg / kg. According to the classification of drug toxicity [6], compound (I) belongs to class V of practically non-toxic drugs. Data on the pharmacological activity of analogues of the claimed compounds are not available in the available literature. The inventive compound (I) may find application in medical practice as an analgesic drug.

Table Analgesic activity of methyl 1 - [(1,3-dioxo-2,3-dihydro-1H-inden-2-yl) - (4-methylphenyl) methyl] cyclohexanecarboxylate (I) The time of the defensive reflex at the peak of action, s No. p / p Connection Name Dose mg / kg Methyl 1 - [(1,3-dioxo-2,3-dihydro-1H-inden-2-yl) - (4-methylphenyl) methyl] cyclohexanecarboxylate 23.86 ± 4.65 p <0.01 one fifty 93 [ED ₅₀ ] 16.33 ± 3.02 P <0.1 2 Metamizole sodium 3 Control, 2% starch. slime 10.75 ± 1.64 p - in relation to control

Information sources

1. Dubois J.C., Guette J.P., Kagan H. B. / Adition 1-4 du reactifde Reformatsky sur les cetones α, β-ethyleniques // Bull. Soc. Chim. Fr 1966. No9. P.3008-3013.

2. Kleeman A., Engel J. Pharmazeutische Wirkstoffe. Stuttgart-NewYork. 1982. S. 386.

3. Radell Z.O., Selitto J.J. A method for measurement of analgesic activity on inflamed tissue // Arch. Intermat. Pharmacodun Et ther. 1957. Vol. 11. Number 4. S.409-419.

4. Belenky M.L. Elements of a quantitative assessment of the pharmacological effect. 2nd ed. L. 1963. P.152.

5. Pershin G.N. Methods of experimental chemotherapy // M., 1971. S. 100, 109-117.

6. Izmerov N.F., Sanotsky I.V., Sidorov K.K. Parameters of toxicometry of industrial poisons // M .: Medicine, 1977. P.196.

Claims (1)

The method of obtaining methyl 1 - [(1,3-dioxo-2,3-dihydro-1H-inden-2-yl) - (4-methylphenyl) methyl] cyclohexanecarboxylate (I)

consisting in the fact that methyl ester of 1-bromocyclohexanecarboxylic acid is boiled with zinc and 2- (4-methylbenzylidene) -1H-indene-1,3 (2H) -dione in a medium of benzene - ethyl acetate - HMFTA (10: 5: 1) in within 8 hours.