CS252499B2 - Method of 3-substituted 2-oxindoles production - Google Patents

Abstract

Process for producing 3-substituted 2-oxindoles of formula IV O wherein X is a hydrogen atom, an atom fluorine or chlorine, Y represents a hydrogen atom, a fluorine atom or an atom chlorine and R1 is furyl, thienyl or thienylmethyl a group, and their base salts, characterized by by providing a general compound of Formula III (lil) with an acid derivative general formula R1-C (= O) -OH and the resulting product is optionally converted to its base salt. New made the compounds are used as starting compounds, analgesically effective substances 1,3-disubstituted 2-oxindoles.

Description

The invention discloses novel chemical compounds which are useful as starting materials for the manufacture of new drugs.

The related Czechoslovak patents Nos. 252,480 and 252,498 disclose novel 1,3-disubstituted 2-oxindole derivatives which are inhibitors of cyclooxygenase and lipoxygenase enzymes. Furthermore, these compounds exhibit analgesic efficacy in mammals, particularly humans, and are therefore useful for acute administration to alleviate or eliminate pain, such as that occurring in patients following surgery or trauma.

In addition to their utility for acute administration to alleviate or eliminate pain, the compounds can be used for chronic administration to mammals, particularly humans, to alleviate the symptoms of chronic diseases such as inflammation and pain associated with rheumatoid arthritis and osteoarthritis.

The above-cited Czechoslovak patents also disclose methods for making these compounds. In one method, the compounds of the invention are used as starting materials.

Accordingly, the invention relates to novel 3-substituted 2-oxindoles of formula IV wherein:

O

(IV)

X represents a hydrogen atom, a fluorine atom or a chlorine atom,

Y represents an atom, a hydrogen atom, a fluorine atom or a chlorine atom and

R f represents a furyl group, a thienyl group or a thienylmethyl group, and their base salts. The compounds of the invention are derivatives of 2-oxindole, which is a bicyclic amide of formula: ## STR2 ##

The present invention provides a process for the preparation of compounds of the above formula (IV) and their salts with bases, characterized in that the compound of the formula (XII)

(III) wherein

X and Y are as defined above, reacted with an acid derivative of the formula

R = -C (= O) -OH in which r 1 is as defined above, and the resulting product is optionally converted to its base salt.

Thus, the side chain -C (= O) -R ^ is introduced into the compound of formula III by reaction with a derivative of the corresponding acid of formula

R ¹ -C (= O) -OH in a lower alkanol solvent (e.g. ethanol) in the presence of an alkali metal salt of a lower alkanol solvent (e.g. sodium ethoxide) according to standard methods. Typical useful derivatives of the acid of formula R 1 -C (= O) -OH include acid chlorides, acid anhydrides of formula

R ¹ -C (= O) -O-C (= O-R ^X R ¹ -C (= O) -O-C (= O) -R ⁵ and R ^X -C (= O) -O-C (= O) -OR ⁶ and simple alkyl esters of formula

R ¹ -C (= O) -OR ⁶ in which formulas R represents a bulky lower alkyl group such as a tert-butyl group and R ° represents a lower alkyl group.

Typically, a small excess of an acid derivative of the formula R ^-C (= O) -OH is used and the alkoxide is generally present in an amount of from one to two molectivalents based on the above-mentioned acid derivative of the formula R-C (= O) OH. The reaction between an acid derivative of the formula RC (= O) OH and a compound of the formula III is usually initiated at a temperature of 0 to 25 ° C, but the reaction mixture is then generally heated to a temperature of 50 to 130 ° C to complete the reaction. preferably to a temperature of about 80 ° C. Under these conditions, reaction times ranging from several hours, for example two hours, to several days, for example two days, are usually used. The reaction mixture was then cooled, diluted with excess water and acidified. The product of formula (IV) can then be isolated by filtration or standard solvent extraction methods.

The 2-oxindole compounds of formula III are prepared by known methods or by methods analogous to those known in the art, see Rod's Chemistry of Carbon Compounds, 2, Ed.

S. Coffey, Vol. IV Part A, Elsevier Scientific Publishing Company, 1973, pp. 448-450? Gassman et al., Journal of Organic Chemistry, 42 1340 (1977); Wright et al., Journal of the American Chemical Society, 78, 221 (1956); Beckett et al., Tetrahedron, 24, 6,093 (1968); U.S. Patent Nos. 3,882,236, 4,006,161 and 4,160,032? Walker, Journal of the American Chemical Society, 77 3,844 (1955); Protiva et al., Collection of Czechoslovakian Chemical Communications, 44 2 108 (1979)? McEvoy et al., Journal of Organic Chemistry, 38, 3,350 (1973); Simet, Journal of Organic Chemistry, 28, 3580- (1963) Wieland et al., Chemische Berichte, 96, 253 (1963) and references cited therein.

The compounds of formula IV are acidic and form salts with bases. All such base salts, which can be prepared by conventional methods, are within the scope of the invention. For example, salts can be prepared simply in a way that e £ acidic basic entities, usually in a stoichiometric ratio, either brought into contact in ftevodněm, _to an aqueous or partially aqueous medium, as is in the case where appropriate. The resulting salts are isolated either by filtration, by precipitation with a non-solvent followed by filtration, or by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization. Typical salts of the compounds of formula (IV) which may be prepared are salts with primary, secondary or tertiary amines, alkali metal salts and alkaline earth metal salts. Especially valuable are the salts with ethanolamine, diethanolamine and triethanolamine.

Both organic and inorganic basic reagents can be used to produce salts, including organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, alkaline earth metal hydroxides, alkaline earth metal carbonates hydrides alkaline earth metal and alkaline earth metal alkoxides. Representative bases include primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine ethanolamine and glucamine, secondary amines such as diethylamine, diethanolamine, N-methylglucamine, N-methylaniline, morpholine, pyrrolidine and piperidine, tertiary amines such as triethylamine, triethanolamine, Ν, Ν-dimethylaniline, N-ethylpiperidine and N-methylmorpholine, hydroxides such as sodium hydroxide, alkoxides such as sodium ethoxide and sodium methoxide and potassium methoxide, hydrides such as calcium hydride and sodium hydride, and carbonates such as potassium carbonate and sodium carbonate.

The invention is illustrated by the following non-limiting examples.

Example 1

3- (2-furoyl) -2-oxindole

To a solution of 5.5 g (0.24 mol) of sodium in 150 ml of ethanol was added under stirring at room temperature 13.3 g (0.10 mol) of 2-oxindole. The resulting suspension was cooled in ice and 15.7 g (0.12 mol) of 2-furoyl chloride was added dropwise over 10-15 minutes. The cooling bath was removed, after the addition of 100 ml of ethanol, the reaction mixture was refluxed for 7 hours and allowed to stand overnight. The solid material was filtered off, taken up in 400 ml of water and the resulting mixture acidified with concentrated hydrochloric acid. After cooling in ice, the solid product is filtered off and recrystallized from 150 ml of acetic acid. 8.3 g of a yellow crystalline material are obtained, melting at 209 DEG-210 DEG C. with decomposition.

For C 6 HHgO ^N: C, 68.72; H, 3.99; N, 6.17. Found: C, 68.25; H, 4.05; N, 6.20.

Example 2

By analogy to Example +, the following additional products are obtained by reacting 2-oxindole with the appropriate acid chloride:

3- (2-thenoyl) -2-oxindole, m.p. 189-190 ° C (17% yield);

3- [2- (2-thienyl) acetyl] -2-oxindole, m.p. 191-192.5 ° C (yield 38%); and

5-chloro-3- [2- (2-thienyl) acetyl] -2-oxindole, m.p. 228-230 ° C (yield 22%).

Example 3

3- (3-furoyl) -2-oxindole

To a solution of 2.8 g (0.12 mol) of sodium in 200 ml of ethanol was added with stirring first 13.3 g (0.10 mol) of 2-oxindole and then 16.8 g of ethyl 3-furoate. The mixture was refluxed for 47 hours, cooled, and the solvent evaporated in vacuo. The residue was triturated with 200 ml of ether, the solid material was filtered off and discarded. The filtrate was evaporated in vacuo, the residue triturated with diisopropyl ether and filtered. The solid is suspended in 250 ml of water, acidified with concentrated hydrochloric acid, and the resulting mixture is stirred to precipitate a solid which is isolated by filtration and recrystallized first from acetic acid and then from acetonitrile. 705 mg of the title compound are obtained, m.p. 185-186 ° C.

H, 3.99; H, 6.17. Found: C, 68.72; H, 4.14; N, 6.14.

Example 3A

In analogy to Example 3, the following compounds are obtained by reacting the corresponding 2-oxindole with the ethyl ester of the corresponding carboxylic acid:

5-chloro-3- (2-thenoyl) -2-oxindole, m.p. 190-192 ° C (yield 36%),

5-chloro-3- (2-furoyl) -2-oxindole, m.p. 234-235 ° C (yield%),

5-chloro-3- (2-phenylacetyl) -2-oxindole, m.p. 241-243 ° C (yield 61%),

5-fluoro-3- (2-furoyl) -2-oxindole, m.p. 222-224 ° C (yield 51%),

5-fluoro-3- (2-thenoyl) -2-oxindole, m.p. 200-203 ° C (26% yield),

6-fluoro-3- (2-furoyl) -2-oxindole, m.p. 239-242 ° C (26% yield); and

6-chloro-5-fluoro-3- (2-thenoyl) -2-oxindole, m.p. 212 DEG-215 DEG C. (yield 20%).

Example 4

5-chloro-2-oxindole

To a suspension of 100 g (0.55 mol) of 5-chloroisatin in 930 ml of ethanol was added 40 ml (0.826 mol) of hydrazine hydrate with stirring to form a red solution. The solution was heated at reflux for 3.5 hours, whereupon a precipitate formed. The reaction mixture was stirred overnight and then the precipitate was filtered off. 5-Choro-3-hydrazono-2-oxindole is obtained as a yellow solid.

This material, which after drying in a vacuum oven weighs 105.4 g, is added portionwise over a period of 10 minutes to a solution of 125.1 g of sodium methoxide in 900 ml of absolute ethanol. The resulting solution was heated to reflux for 10 minutes and then concentrated in vacuo. The resinous solid residue was dissolved in 400 ml of water, the aqueous solution was decolorized with charcoal and poured into a mixture of 1 liter of water and 180 ml of concentrated hydrochloric acid containing chunks of ice. The precipitated red-yellow solid is filtered off, washed thoroughly with water, dried, washed with diethyl ether and finally recrystallized from ethanol. 48.9 g of the title compound, melting at 193-195 ° C, decomposes.

Example 5

4-chloro-2-oxindole and 6-chloro-2-oxindole

A. 3-Chloro-isonitrosoacetanilide

To a solution of 113.23 g (0.686 mol) of chloral hydrate in 2 liters of water was added with stirring first 419 g (2.95 mol) of sodium sulfate and then a solution prepared from 89.25 g (0.70 mol) of 3-chloroaniline, ml of concentrated hydrochloric acid and 500 ml of water, whereupon a thick precipitate formed. A solution of 155 g (2.23 mol) of hydroxylamine in 50 ml of water is added to the mixture while stirring, the reaction mixture is slowly warmed with stirring and maintained at a temperature between 60 and 70 ° C for about 6 hours. add 1 liter of water to facilitate stirring. The resulting mixture was cooled, the precipitate formed was filtered off and dried. 136.1 g of 3-chloro-isonitrosoacetanilide are obtained.

B. 4-Chloroisatin and 6-Chloroisatin

AND

Κ 775 ml of concentrated sulfuric acid, preheated to 70 ° C, is added with stirring 136 g

3-chloro-isonitrosoacetanilide at a rate such that the temperature of the reaction medium is maintained between 75-85 ° C. After all solid material has been added, the reaction mixture is heated at 90 ° C for a further 30 minutes, then cooled and poured slowly into about 2 liters of ice with stirring. Additional ice is added as necessary to keep the temperature below room temperature. The red-orange precipitate formed is filtered off and dried after washing with water. The solid material is suspended in liters of water and dissolved in about 700 ml of 3N sodium hydroxide. The solution is filtered and adjusted to pH 8 with concentrated hydrochloric acid. 120 ml of a mixture of 80 parts of water and 20 parts of concentrated hydrochloric acid are added, the precipitated solid product is filtered off and dried after washing. 50 g of crude 4-chloroisatin are obtained. After isolation of the 4-chloroisatin with concentrated hydrochloric acid, the filtrate is acidified to pH 0, whereupon a further precipitate is formed which, after filtration, washed with water and dried, yields 43 g of crude 6-chloroisatin.

The crude 4-chloroisatin was recrystallized from acetic acid to give 43.3 g of a melting point at 258-259 ° C.

The crude 6-chloroisatin was recrystallized from acetic acid to give 36.2 g of a melting point at 261-262 ° C.

C. 4-Chloro-2-oxindole

To a suspension of 43.3 g of 4-chloroisatin in 350 ml of ethanol is added 17.3 hydrazine hydrate, the reaction mixture is heated under reflux for 2 hours, then cooled and the precipitate formed is filtered off. 43.5 g of 4-chloro-3-hydrazono-2-oxindole, m.p. 235 DEG-236 DEG C., are obtained.

To a solution of 22 g of sodium in 450 ml of anhydrous ethanol, 43.5 g was added portionwise with stirring

Of 4-chloro-3-hydrazono-2-oxindole, the resulting solution was heated to reflux for 30 minutes, then cooled and concentrated to a gummy residue which was dissolved in 400 ml of water. The solution was decolorized with charcoal and poured into a mixture of 1 liter of water and 45 ml of concentrated hydrochloric acid. The precipitate formed is filtered off and, after drying, recrystallized from ethanol. 22.4 g of 4-chloro-2-oxindole are obtained, melting at 216 DEG-218 DEG C. with decomposition.

D. 6-Chloro-2-oxindole

Analogous to the procedure described in Part C, 14.2 g of 6-chloro-2-oxindole, m.p. 196 DEG-198 DEG C., are obtained by reaction of 6-chloroisatin with hydrazine hydrate.

Example 6

5,6-difluoro-2-oxindole

In analogy to the steps A and B of Example 5, the reaction of 3,4-difluoroaniline with chloral hydrate and hydroxylamine followed by cyclization with sulfuric acid affords 5,6-difluoroisatin which is reacted with hydrazine hydrate and then sodium methoxide. ethanol, analogously to Example 4. The title compound is obtained, m.p. 187-190 ° C.

? k i and .1

5-Fluoro-2-oxindole

To a solution of 11.1 g (0.1 mol) of 4-fluoroaniline in 200 ml of dichloromethane at -60 ° C to -65 ° C is added dropwise a solution of 10.8 g (0.1 mol) of tert-butyl hypochlorite in stirring. 25 ml of dichloromethane. Stirring is continued at -60 to -65 ° C for 10 minutes, after which a solution of 13.4 g (0.1 mol) of ethyl 2- (methylthio) acetate in 25 ml of dichloromethane is added dropwise.

The mixture was stirred at -60 ° C for 1 h and then added dropwise at -60 to -65 ° C to a solution of 11.1 g (0.11 mol) of triethylamine in 25 mL of dichloromethane. The cooling bath was removed and after the reaction mixture was warmed to room temperature, 100 ml of water was added. The phases are separated, the organic phase is washed with saturated sodium chloride solution and evaporated in vacuo. The residue was dissolved in 350 ml of diethyl ether, to which 40 ml of 2N hydrochloric acid was added. The mixture is stirred at room temperature overnight, then the phases are separated and the ether phase is washed first with water and then with a saturated sodium chloride solution. After drying over sodium sulfate, the ethereal phase is evaporated in vacuo. 17 g of an orange-brown solid are obtained, which is triturated with isopropyl ether. The solid material was recrystallized from ethanol to give 5.58 g of 5-fluoro-3-methylthio-2-oxindole, m.p. 151.5-152.5 ° C.

H, 4.09; N, 7.10. Found: C, 54.74; H, 4.11; N, 7.11.

986 mg (5.0 mmol) of the above-prepared 5-fluoro-3-methylthio-2-oxindole was added to a mixture of two teaspoons of Raney-nickel and 50 ml of absolute ethanol, and the reaction mixture was heated under reflux for 2 hours. The catalyst was separated by decantation and washed with absolute ethanol. The combined ethanolic solutions were evaporated in vacuo and the residue was dissolved in dichloromethane. The dichloromethane solution was dried over sodium sulfate and evaporated in vacuo to give 475 mg

121 DEG-134 DEG C. 5-fluoro-2-oxindole.

Example 8

6-chloro-5-fluoro-2-oxindole

To 130 ml of toluene was added with stirring 24.0 g (0.165 mol) of 3-chloro-4-fluoroaniline and 13.5 ml (0.166 mol) of pyridine. The resulting solution was cooled to about 0 ° C and 2-chloroacetylchoride (13.2 mL, 0.166 mol) was added. The reaction mixture was stirred at room temperature for 5 hours and then extracted first twice with 100 ml of 1N hydrochloric acid each and then with 100 ml of saturated sodium chloride solution. The resulting toluene solution was dried (MgSO 4) and concentrated in vacuo. 32.6 g (88%) of N- (2-chloroacetyl) -3-chloro-4-fluoroaniline are obtained.

26.63 g of this N (2-chloroacetyl) -3-chloro-4-fluoroaniline are thoroughly mixed with 64 g of anhydrous aluminum chloride and the mixture is heated at 210-230 ° C for 8.5 hours. The reaction mixture was poured into ice / 1N hydrochloric acid with stirring, and the resulting mixture was stirred for an additional 30 minutes, after which the solid material was filtered off. 22.0 g of solid product are obtained, which is dissolved in a mixture of equal parts of ethyl acetate and hexane and chromatographed on 800 g of silica gel. Evaporation of the appropriate eluted fractions gave 11.7 g of N- (2-chloroacetyl) -2-chloro-4-fluoroaniline and then 3.0 g of 6-chloro-5-fluoro-2-oxindole. The latter product, after recrystallization from toluene, gave 1.70 g (7% yield) of the title compound, m.p. 196 DEG-206 DEG.

According to NMR spectroscopy, this product is contaminated with some 4-chloro-5-fluoro-2-oxindole. 0.8 g of product is obtained as a second crop.

Claims (5)

A process for the preparation of 3-substituted 2-oxindoles of general formula IV C— R * O (IV) in which X represents a hydrogen atom, a fluorine atom or a chlorine atom, Y represents a hydrogen atom, a fluorine atom or a chlorine atom; represents a furyl group, a thienyl group or a thienylmethyl group, and their base salts, characterized in that the compound of formula (III): X and Y are as defined above, reacted with an acid derivative of the formula R ¹ -C (= 0) -OH \ e kteivui has the above meaning, and the resulting product is optionally converted into its salt with a base. 2. The process of claim 1 wherein the reaction is carried out in a lower alkanol as a solvent in the presence of an alkali metal salt of the lower alkanol. 3. A process according to claim 2, wherein the acid derivative of the formula (I) is used R @ ¹ --C (.dbd.O) --OH uses the acid chloride, the acid anhydride of the formula R ¹ -C (= O) -OC- (= O) -R ¹ R ^X -C (= O) -OC (= O) -R ⁵ or R ¹ -C (= O) -OC (= O) -R ⁶ or an alkyl ester of formula R ¹ -C (= O) -OR ⁶ in which formulas r! is as defined above; c R represents a bulky lower alkyl group, such as a tert-butyl group, and r6 represents a lower alkyl group. AND 9 252499 4. A process according to claim 3, wherein the corresponding starting materials are used to form a compound of formula (IV) wherein Y is hydrogen and the remaining radicals are as defined above. 5. A method according to claim 4, characterized in that a starting material, to give a compound of formula IV in which X represents a hydrogen or chlorine atom in the 5-position, Y is hydrogen and R ¹ is 2-fluoro or 2 a thienyl group.