KR800001181B1 - Preparation method of indolyl acetic acid derivative - Google Patents

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Description

Preparation method of indolyl acetic acid derivative

The present invention relates to fresh 1-aroyl-3-indolyl acetic acid. It is known that 1-aroyl and heteroaroyl-3-indolyl-lower fatty acid compounds are highly anti-inflammatory and effective in preventing or inhibiting granuloma tissue formation. Some of these compounds are effective in treating gout, skin disorders and similar symptoms, and are used as anti-inflammatory agents in these treatments. Among the most effective compounds, the compound known under the trade name “Indomethacin” is 1-P-chlorobenzoyl-5-methoxy-2-methyl-5-indolyl-acetic acid.

The present invention relates to 1- (P-azidobenzoyl) -5-methoxy-2-methyl-3-indolyl acetic acid, ie compounds having the following formula and salts which are excellent as medicaments.

The presence of azido substituents in benzoyl groupings has revealed that the compounds are pharmaceutically effective, such as indomethacin, but with far less toxicity and unwanted side effects.

This new compound itself is a yellow crystal with a melting point of 170-172 ° C., soluble in dimethylformamide and dimethyl sulfoxide, somewhat soluble in methanol and ethanol, and insoluble in water.

The present invention also provides a method for synthesizing the agent.

One easy method of preparation is from the corresponding P-amino compounds. This compound is described in British Patent No. 1,159,626, which standardizes, for example, acylating sodium P-methoxy-phenylhydrazine-sulfonate with P-nitrobenzoylchloride, resulting in unbalanced N '-(P-nitbenzoyl)- It can synthesize | combine by setting it as P-methoxyphenyl hydrazine.

1- (P-aminobenzoyl) -5-methoxy-2-methyl-3-indoleacetic acid is obtained in two steps by Fischer after indole condensation with levulinic acid followed by reduction of P-nitro groove. . P-azido grooves are made by diazotization following hydronitride treatment.

Formula II of another indolyl acetate ester,

Where R is lower alkyl and aralkyl or vinyl groupings may be used. For example, by esterifying a known free acid with an alcohol, the desired ester of levulinic acid can be produced during the initial synthesis of the ring. By direct synthesis or by transesterification of other esters.

Acylation of indool nitrogen is rather employed, which treats the compound of formula II with an alkali metal hydride to form a metal salt and then reacts with the P-nitrobenzoylhalogen compound in P-azidobenzoyl or anhydrous sorbent media. By close contact. And ester groupings can be removed in several ways.

The anti-inflammatory action of the compounds of the present invention is characterized by the use of cartonferils used in the granuloma test (Meyer R, Schuler W. and Desauls-Experientia 1950. 6,469) while orally administering the compound for 7 days. cotton pellets) to evaluate rats.

The anti-edema effect of this compound was evaluated by accurately administering carrageenan before injecting the rat plantar surface and measuring inhibition of edema. (Winter CA, Risley EA and GW-J pharmacol. Exp. Ther. 1963 141. 369), the compound resists granuloma and edema (usually 29% each, with oral single dose of 3 mg / kg bw). In the granuloma test, the compound was slightly less active than indomethacin but acted like indomethacin in suppressing edema formation.

Analgesic activity was evaluated by measuring the rate of prevention of struggling caused by injecting phenylkinone into the peritoneum using mice. (Henders LC Forsaith J.-J. Pharmacol. Exp. Ther. 1953, 125, 237). Oral ED ₅₀ (single dose preventing strangulation in 50% of mice) was 1.25 mg / kg bw for indomethacin, about 2.5 mg / kg bw.

The LD ₅₀ values after the correct dose of this compound in males and mice were 250 mg / kg bw and 85 mg / kg bw, respectively. The corresponding LD ₅₀ values for indomethacin were 13.5 mg / kg bw and 10 mg / kg bw. LD ₅₀ values of female mice and rats were 240 mg / kg bw and 105 mg / kg bw for the compounds of the present invention, respectively, and 23 mg / kg bw and 17 mg / kg bw for indomethacin. As a result of administering this compound, it was found that the ulcer was about 10 times less than indomethacin. Therefore, the present invention can be used as a therapeutic agent in the form of tablet capsules, ampoules or suppositories having a dosage unit ranging from 25 mg to 150 mg.

The following examples illustrate the invention.

Example 1

Method A

Preparation of 1- (P-azidobenzoyl) -5-methoxy-2-methyl-3-indolylacetic acid.

A hot solution of 5.2 g (15.4 moles) of 1- (P-aminobenzoyl) -5-methoxy-2-methyl-3-indolylacetic acid was added to 65 ml of acetic acid and 25-30 ° C being careful not to crystallize. Cool rapidly to This cooled solution and 1.145 g (16.6 mol) of sodium nitrite dissolved in 40 ml of water are poured simultaneously into 18 ml of concentrated hydrochloric acid while stirring at -5 ° C. The resulting solution (25 ° C) is reddish, and when cooled to 0 ° C the crystals begin to separate. After 10 minutes at 0 ° C., 1.057 g (16.25 moles) ice cold solution dissolved in 40 ml of water is added in small portions. Immediately following a rich nightfall of nitrogen, a cream colored precipitate is formed. The reaction is complete when the red light is no longer visible. If necessary, a further solution of NaN ₃ may be added.

After stirring was continued for 10 minutes at 0 ° C., the mixture was extracted with ethyl acetate. The organic phase was separated, washed with water, dried over Na ₂ SO ₄ and aggregated in vacuo, then 5.67 g (100%) of 1- (P-azidobenzoyl) -5-methoxy-2-methyl-3-indole Reel acetic acid is obtained. Light layer chromatography on silica gel shows a spot in the system of chloroform-ethanol 95: 5. Analytical samples are obtained by crystallizing methanol-water.

Melting Point 170-172 ° C Releases Gas.

IR (KBr) was midline at 4.69-4.76 μ (N ₃ ), 5.85 μ (acid C = 0), 5.97 μ (amide C = 0).

Method B

950 g (2.808 mol) of 1- (P-amino benzoyl) -5-methoxy-2-methyl-3-indolylacetic acid dissolved in 10 L water is poured into NaOH 2.5N with pH 8 and stirred until the solid is released. . To this solution, slowly pour over a well stirred solution of 3 L of concentrated hydrochloric acid over 2 and a half hours. A dark red precipitate is formed. After 20 minutes at 0 ° C., 250 g (3.85 moles) of sodium azide are added in portions over 60 minutes with stirring.

Nitrogen is released and solids are accompanied by dissolution. The reaction is complete until no more red light is visible. The organic phase is separated, washed with 120 L of water, dried over Na ₂ SO ₄ , filtered through Gelite® and condensed to 7-8 L in vacuo. 40 L of petroleum ether was added and stirred for 2 hours at room temperature, the solid was filtered, washed with petroleum in ether and dried in vacuo at a temperature of 40 ° C. The prepared powder is pure close to the desired product (product 921 g, 90%). The different amount (30 g) is obtained by filtration after condensation.

Example 2

Preparation of methyl 1- (P-nitrobenzoyl) -5-methoxy-2-methyl-3-indolyl acetate.

3 g of 80% sodium hydride is added to 23.3 g (0.1 mol) of methyl-5-methoxy-2-methyl-3-indolyl acetate solution mixed with 50 ml of dry toluene. After the mixture was stirred at room temperature for 4 hours, a solution of 18.56 g (0.1 mol) of P-nitrobenzoyl chloride mixed with 80 ml of dry toluene was slowly added over a period of 30 minutes or longer.

The reaction mixture is boiled for 30 hours, cooled, and then poured into 400 ml of ice water or 15 ml of acetic acid. The separated toluene solution is washed with a large amount of water, dried over sodium sulfate and evaporated to a syrup that is dissolved in ether.

When the solution is placed in a beaker and evaporated slowly, 10 g of methyl-1 (P-nitrobenzoyl) -5-methoxy-2-methyl-2-indolyl acetate is obtained in the form of a yellow column.

After chromatographic analysis with silica gel column, a different fraction is obtained from the rest of the oil (eluted with benzene). Melting point 134-135 ° C. (on-crystallization in MeOH).

Example 3

Preparation of Methyl-1- (P-azidobenzoyl) -5-methoxy-2-methyl-3-indolyl acetate.

The compound was prepared by condensing 18.16 g (0.1 mole) of P-azidobenzoyl chloride with 0.1 mole of methyl-5-methoxy-2-methyl-3-indolyl acetate, according to the method described in Example 2. do.

The reaction mixture is stirred under nitrogen at a temperature of 50-60 ° C. for 48 hours. This product is isolated as described in Example 2 to obtain substantially pure yellow methyl-1- (P-azidobenzoyl) -5-methoxy-2-methyl-3-indoleyl acetate.

In the infrared spectrum, there is no NH absorption near the 2.9-3.0 μ range, the strong doublet at 4.7-4.75 μ still indicates the grouping, and the strong C = 0 absorption at 5.75 and 5.98 μ indicates ester and amide functionality. Learn to display the characteristics of each.

Example 4

Preparation of 1- (P-nitrobenzoyl) -5-methoxy-2-methyl-3-indolylacetic acid.

A solution of 4.9 g (12.8 moles) of methyl-1- (P-nitrobenzoyl) -5-methoxy-2-methyl-3-indolyl acetate in 40 ml of acetic acid containing 400 mg of P-toluene-sulfonic acid Was refluxed for 20 hours and then condensed in vacuo.

The rubbery residue is extracted with ethyl acetate. The extract is filtered to remove insolubles, washed with water and dried over sodium sulfate. Removal of the solvent under reduced pressure gives the desired product as yellow crystals. Melting point 185-186 ° C. (crystallization by Et OH)

Example 5

Preparation of 1- (P-aminobenzoyl) -5-methoxy-2-methyl-3-indolylacetic acid

Method A

20 g (54.3 moles) of 1- (P-aminobenzoyl) -5-methoxy-2-methyl-3-indolyl acetic acid is dissolved in 1200 ml of hot methanol and in the presence of 2.64 g of 10% palladium on charcoal as a catalyst. Compound with hydrogen. Hydrogenation is stopped after 164 moles of hydrogen have run out. The solution is filtered to remove the catalyst. The filtrate is condensed in vacuo to give a nearly theoretical product P-amino derivative.

Samples are obtained by crystallization by methanol-number. Melting point 198-200 ° C. (dec.) Determination by MeOH-H ₂ O.

Method B

2.36 kg (6.4 moles) of 1- (P-nitrobenzoyl) -5-methoxy-2-methyl-3-indolylacetic acid mixed with 23.6 kg of water and 28 l of methanol and 230 g of 10% palladium charcoal Stir and cool to maintain about 15 ° C. To this mixture, 1.1 L of 100% (22.0 mol) hydrazine hydrate dissolved in 3 L of water is slowly added for a time of 60 minutes or longer. Thus, the mixture is stirred for one hour while allowing the temperature to rise to 30 ° C, and for three hours at this temperature. The catalyst is filtered off and the pH of the solution is corrected from 8 to 2 with 15% hydrochloric acid (˜3.2 L Hce 15%). The mixture is stirred for 2 hours at room temperature. The precipitate is filtered off, washed with water and dried to pH 5 (25 L). The white solid weighs 1.955 kg (90.2%) and is essentially pure 1- (P-aminobenzoyl) -5-methoxy-2-methyl-3-indolylacetic acid.

Claims (1)

As described above in the text, a method for preparing an indolyl acetic acid derivative comprising a step of diazotizing 1- (P-aminobenzoyl) -5-methoxy-2-methyl-3-indolyl acetic acid with triazoic acid. 1- (P-aminobenzoyl) -5-methoxy-2-methyl-3-indolylacetic acid was dissolved in water / NαOH, an aqueous solution of sodium nitrite was added, and the whole solution was layered with ethyl acetate. Indoleyl acetic acid derivative formed by separating an organic layer containing 1- (P-azidobenzoyl) -5-methoxy-2-methyl-3-indolylacetic acid derivative by adding sodium azide after injection into hydrochloric acid Recipe.