IE57742B1 - 2-oxindole intermediates - Google Patents

Description

This application is a divisional Of Parent Patent Specification Wo. It concerns synthetic intermediates of the formula: or a base salt thereof, wherein X is hydrogen, 5-fluoro or 5-chloro; Ύ is hydrogen, 6-fluoro or 6-chloro; and R^ is benzyl, furyl, thienyl or thienyImethy1; provided that when X and Y are both hydrogen, R·^ is not benzyl.

Preferred compounds of the formula (A) are those wherein (a) X is 5-chloro, Y is hydrogen and R^ is 2-thienyl and (b) X is 5-fluoro, Y is 6-chloro and R is 2-thienyl.

The compounds of the formula (A) are synthetic intermediates useful in the preparation of the N-substituted oxindole-l-carboxamide antiinflammatory agents of the Parent Patent Specification No. as is described in that application.

The compounds of formula (A) are prepared from the appropriate 2-oxindoie compound of the formulas wherein X and Y are as defined previously. This is accomplished by attaching the substituent -C(=0)~κ to the 3-position.

.The -C(=0)-R side-chaw can be attached to a compound of the formula (B) by reaction with a derivative of the appropriate acid of the formula R^-C{=O)-OH, in a lower-alkanol solvent (e.g. ethanol), in the presence of an alkali metal salt of the lower-alkanol solvent (e.g. sodium ethoxide), according to standard procedures. Typical derivatives of the acid of the xormula R -C(=O)OH which can be used include acid chlorides, acid anhydrides of the formula R1-C(=O)-O0(=0)--^, R1"C( =0) -0-C(=0) -R2 and R1-/: (=0)-0-C (=O)-0R3 , and simple alkyl esters of the formula ?3-C (-0) -OR3 , wherein R is a bulky lower alkyl group such as t-butyl, and R is a lower alkyl group. Usually, a small excess of the derivative of the acid of formula R3-C(=0)-0H is used, and the alkoxide salt is usually present in an amount from one to two molar equivalents, based on said derivative - of the acid of formula R^-c(=C) OH. The reaction between the derivative of the acid of the formula R^-C( =0)011 and the compound of formula (B) is usually started at 0 to 253C., but it is then usual to heat the reaction mixture at a temperature in the range from SO to 130°C„, and preferahly at about 80°C„, to complete the reaction.

Under these circumstances, reaction times of a few hours, e.g. two hours, up to a few days, e.g.,, two - y * days, are commonly used. The reaction mixture is then cooled, diluted with an excess of water, and acidified.

The product of formula (A) can then be recovered by filtration or by the standard procedure of solvent extraction.

The 2-oxindole compounds of formula (31 are prepared by known methods, or methods analogous to known methods. Consults Rodd’s Chemistry of Carbon Compounds, Second Edition, S. Coffey editor, Volume IV Part A, Elsevier Scientific Publishing Company, 1973, pp. 448-4.50; Gassman et al., Journal of Organic Chemistry·, 42, 1340 (1977); Wright et al., Journal of the American Chemical Society, 7 8 , 221 (1956); Beckett et al. , Tetrahedron, 2 4 , 6093 (1968); United States Patents Nos. 3,882,236, 4,006,161 and 4,160,032; Walker, Journal of the American Chemical Society, 77, 3844 (1955); Protiva et al. , Collection of CzechoslovakianChemical Communications, 44, 2108 (1979); McEvoy et al- , Journal of Organic Chemistry, 38 , .3350 (1973); Simet, Journal of Organic Chemistry z 2 3 , 3580 (1963); · Wieland et al., Chemische Berichte , 96 , 253 ( 1963); and references cited therein.

The following Examples illustrate the invention:5 EXAMPLE 1 3- (2-Furoyl) ~2»oxindQle To a stirred solution of 5.5 g (0,24 mole) of sodium in 150 ml of ethanol was added 13-3 g (0-10 mole) of 2-oxindole at room temperature- The resulting slurry was cooled to ice-bath temperature, and then ,7 g (0,12 mole) of 2-furoyl chloride was added, dropwise, during 10-15 minutes. The ice-bath was removed, and additional 100 ml of ethanol was added and then the reaction mixture was heated under reflux for 7 hours. The reaction mixture was allowed to stand overnight and then the solid was filtered off.

The solid was added to 400 ml of water and the resulting mixture was acidified using concentrated hydrochloric acid. The mixture was cooled with ice and the solid was collected by filtration. The solid residue was recrystallized from 150 ml of acetic acid, affording 8.3 g of yellow crystals, mp 209-210 (dec).

Analysis: Calcd. for C^HgO^N; C, 68.72; H, 3.99; N, 6.17¾. Found; C, 68.25; H, 4.05; N, 6.20%.

EXAMPLE 2 Reaction of 2-oxindole with the appropriate acid chloride using the method of Example 1, gave the following additional products: 3-(2-thenoyl)-2-oxindole, mp 189-19O°C, 17% yield; 3-(2-[2-thieny1]acety1)-2-oxindole, mp 191192.5°C, 38% yield; —3hloro-3-(2-[2-thienvl]acetyl)-2-oxindole, mp 228-23O°C., 22% yield. β EXAMPLE 3 3-(3-Furpyl)-2-oxindole To a stirred solution. of 2.8 g (0.12 mole) of sodium in 200 ml of ethanol was added 13.3 g (0.10 mole) of·2-oxindole, followed by 16.8 g of ethyl 3'Τ’ fur oat e. The mixture was heated under reflux for 47 hours, cooled and then the solvent was removed by evaporation in vacuo. The residue was triturated under 200 ml of ether, and the solid was collected by filtration and discarded. The filtrate was evaporated in vacuo, and the residue triturated under diisopropyl ether and recovered by filtration. The solid was suspended in 250 ml of water, which was then acidified with concentrated hydrochloric acid. This mixture was stirred to give a solid, which was recovered by filtration. This latter solid was recrystallized from acetic acid followed by acetonitrile to give 705 mg of the title compound, mp 185-186°C.

Analysis : Calcd. for. C-^HgO^N: C, 68.72; H, 3.99; N, 6.17%. Found: C, 68.72; H, 4.14; N, 6.14%.

EXAMPLE 4 Reaction of the appropriate 2-oxxndoXe with the ethyl ester of the requisite carboxylic acid, substantially according to the procedure of Exanple . 3, gave the following compounds: -chlorO"3-(2-thenoyl)-2-cxindole, mp 190.5192°C., 36% yield; -chlorc-3-(2-furoyl)-2-oxindole, mp 234-235°C., 54% yield; t -chloro-3-(2-phenylacetvl)-2-oxindcle, mp 241243°C., 61% yield; -fluoro-3-(2-furoyl)-2-oxindole, mp 222-224°C., 51% yield; - fluoro-3-(2-thenoyl)-2-oxindole, mp 200-203°C., 26% yield; 6- fluoro-3-(2—furoyl)-2-oxindole, mp 239-242°C., 26% yield; and 6-chloro-5-fIuoro-3-(2-thenoyl)-2-oxindole, mo 212-215°C., 20% yield.

The following Preparations describe the preparation of certain starting materials used in the previous Examples:PREPARATION 1 5-Chloro-2-oxindole To a stirred slurry of 100 g (0.55 mol) of 5chloroisatin in 930 ml of ethanol was added 40 ml (0.826 mol) of hydrazine hydrate, resulting in a red solution. The solution was heated under reflux for ’ 3.5 hours, during which time a crecioitate aooeared. ι The reaction mixture was stirred overnight, and then the orecioitate was recovered bv filtration to give 5-chloro-3-hydrazono-2-oxindoie as a veiiow solid, s which was dried in a vacuum oven». The dried solid weighed 105.4 g.

The dried solid was then added portionwise, during 10 minutes, to a solution of 125-1 g of sodium ’ > methoxide in 900 ml of absolute ethanol. The resultant solution was heated under reflux for 10 minutes and then it was concentrated in vacuo to a gummy solid.

The gummy solid was dissolved in 400 ml of water and the aqueous solution thus obtained was decolorized with activated carbon and then poured into a mixture of 1 liter of water and 180 ml of concentrated hydrochloric acid containing ice chips. A tan solid precipitated and it was collected by filtration and washed thoroughly with water. The solid was dried and then it was washed with diethyl ether. Finally it was recrystallized from ethanol fo give 48.9 g of the title compound, mp 193-195°C. (dec).

PREPARATION 25-Fluoro-2-oxindole To a stirred solution of 11.1 g (0,1 mol) of 4fluoroaniline in 200 ml of dichloromethane, at -60 to -65°C, was added, dropwise, a solution of 10.8 g (0.1 mol) of t-butyl hypochlorite in 25 ml of dichloromethane. Stirring was continued for 10 minutes at -60 to ~65°C, and then was added, dropwise, a solution of 13.4 g (0.1 mol) of ethyl 2-(methylthio)acetate in 25 ml of dichloromethane. Stirring was continued at -60°C. for 1 hour and then was added, dropwise, at -60 to -65°C, a solution of 11,1 g (0.11 mol) of triethylamine in 25 ml of dichloromethane. The cooling bath was removed, and when the reaction mixtur had warmed to room temperature, 100 ml of water was added. The chases were secarated, and the organic phase was washed with saturated sodium chloride solution, dried (Na^so^) and evaporated in vacuo. The residue was dissolved in 350 ml of diethyl ether, to which was added 40 ml of 2N hydrochloric acid. This mixture was stirred at room temperature overnight. The phases were separated and the ether phase was washed with water,' followed .saturated sodium chloride. The dried ίΝ&2δΟ^) ether phase was evaporated in vacuo to give 17 g of an orange-brown solid which was triturated under isopropyl ether. The solid was then recrystallized form ethanol, to give 5.58 g of 5"fluoro-3methylthio-2-oxindole, mp 151.5-152.5°C„ Analysis: Calcd for CQHgONFS: C, 54.80; H, 4.09; N, 7.10%. Found: C, 54.74; H, 4.11; Ν, 7.11%.

A sample of the above 5-fluoro-3-methylthio™2oxindole (986 mg, 5.0 mmol) was added to 2 teaspoonsful of Raney nickel under 50 ml of absolute ethanol, and then the reaction mixture was heated under reflux for 2 hours. The catalyst was removed by decantation and was washed with absolute ethanol. The combined ethanol solutions were evaporated in vacuo and the residue was dissolved in dichloromethane. The dichloromethane solution was dried (Na^SO^) and evaporated in vacuo to give 475 mg of 5-fluoro-2-oxindole, mp 121134°C.

PREPARATION 3. β-Chloro-S-f luoro-2-oxindole To 130 ml of toluene was added, with stirring, 24.0 g (0.165 mole) of 3-chloro-4-fluoroaniline and 513.5 ml (0.166 mole) of pyridine. The resulting solution was cooled to ca 0°C. and 13.2 ml (0.166 mole) of 2-chloroacetyl chloride was added. The reaction mixture was stirred at room temperature for 5 hours and then it was extracted twice with 100 ml of IN hydrochloric acid, followed by 100 ml of saturated sodium chloride solution. The resulting toluene solution was dried using magnesium sulfate, and then it was concentrated in vacuo to give 32.6 g (88% yield) of '!-(2-chloroacetyl)-3—chloro-4-fluoroaniline.

A 26.63-g sample of the N-(2-chloroacetyl)-3chloro-4-fluoroaniline was thoroughly mixed with 64 g of anhydrous aluminum chloride, and the mixture was heated at 210-230°C. for 8.5 hours. The reaction mixture was then poured onto a mixture of ice and IN hydrochloric acid, with stirring. Stirring was continued for 3 0 minutes, and then the solid was collected by filtration (22.0 g) . The solid was dissolved in 1:1 ethyl acetate-hexane and chromatographed on 800 g of silica gel.· Elution of the column, followed by evaporation of the fractions, produced 11.7 g of the N-(2-chloroacetyl)-3-chloro-4fluoroaniline, followed by 3.0 g of 6~chloro-5-fluoro2-oxindole. The latter material was recrystallized from toluene to give 1.70 g (7% yield) of the title compound, mp 196-206°C. Analysis by NMR spectroscopy indicated that the product was contaminated by some 4 chloro—5-fluoro-2—oxindole. A second crop weighing 0.8 g was obtained. i 1

Claims (6)

1. CLAIMS or a base salt thereof, wherein X is hydrogen, 55 fluoro or 5-chloro; Y is hydrogen, 6-fluoro or 6chloro; and R 1 is benzyl, furyl, thienyl or thienvlmethyl; provided that when X and Y are both hydrogen, is not benzyl.

2. The compound of claim 1 wherein X is 5-chloro, 10 Y is hydrogen and R^ is 2-thienyl.

3. The compound of claim 1 wherein X is 5-fluoro, Y is 6-chloro and R^ is 2-thienyl.

4. A compound of the formula (A) as claimed in claim 1 or a base salt thereof, which is any one of those 15 specifically hereinbefore mentioned.

5. A process for the preparation of a compound of the formula (A) as claimed in claim 1 or a base salt thereof, substantially as hereinbefore described and exemplified.

6. A compound of the formula (A) as claimed in claim 20 1 or a base salt thereof, whenever prepared by a process claimed in claim 5. Dated this tbe 8th nay of June, 1989 F. R. KELLY & CG.