CA1103679A - 4-(5- and 7-) benzoylindolin-2-ones - Google Patents

Abstract

Abstract of the Disclosure Novel 4-(5- and 7-) benzoylindolin-2-ones are described having the formula

Description

This application is a divisional of our copending Canadian Patent Application Serial No. 248,319 filed March lg, 1976.
The present invention relates to novel 4- (5- and 7-) benzoylindolin-2-ones of formula ~

~ C ~ ~ R

wherein R is hydrogen or lower alkyl, R2 is hydrogen, fluorine, chlorine, bromine, iodine or lower alkoxy, Z is hydrogen or SCH3, and X and Y are the same or different and represent hydrogen atoms or lower alkyl, lower alkoxy, fluorine, chlorine, bromine, iodine, nitro or trifluoromethyl groups, or together form a lower alkylenodioxy group.
The compounds of the present invention are precursors in the production of 2-amino-3-(5- and 6-) benzophenylacetic acids, esters, alkali metal salts and alkaline earth metal salts claimed in our copending Canadian Patent Application Serial No.
248,319. These latter compounds possess valuable pharmacological properties and are useful as pharmaceutical agents in that they exhibit anti-inflammatory activity, lower cholesterol levels in hyperlipemic rats and inhibit blood platelet aggregation.
In the definition of symbols in the formulae used above and where they appear elsewhere throughout this specific-ation, the terms have the following significance.

The term "lower alkyl" as used herein includes straight and branched chain radicals of up to six carbons inclusive, preferably no more than four carbon atoms and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, tertiary butyl, amyl, isoamyl and hexyl. The term "lower alkoxy"
has the formula -0-lower alkyl.
The term "halogen" when referred to herein designates one of the stable halogens, fluorine, chlorine, bromine and iodine and is preferably but not necessarily a halogen of atomic weight less than eighty.
The substituents which can be attached to the mono-substituted benzoyl radical and the disubstituted benzoyl radical can be a lower alkyl, halogen, nitro or trifluoromethyl radical or a combination thereof, said monosubstituted and disubstituted benzoyl radicals therefor including but not being limited to lower alkyl benzoyl, halobenzoyl such as chlorobenzoyl, bromo-benzoyl and fluorobenzoyl, nitrobenzoyl and trifluoromethyl-benzoyl, 3,5-dichlorobenzoyl, 2,4-dichlorobenzoyl, 3-trifluoro-methyl-4-chlorobenzoyl, 2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 3-nitro-4-chlorobenzoyl or 2-methyl-4-chlorobenzoyl, 3-methoxy-4-chlorobenzoyl or 3,4-methylenedioxybenzoyl.
When used hereinafter the term "benzoyl" refers to the unsubstituted benzoyl radical, the monosubstituted benzoyl radical or the disubstituted benzoyl radical.
Preferred compounds according to the present invention are those of formula II

-~*~679 C ~ H oR Il wherein R, R2, X and Y are as previously defined.
Also preferred are compounds of formula XII

X~ 3 ¦ SCH3 wherein R, R2, X and Y are as previously defined.
The invention also relates to a process for the pre-paration of compounds of formula A which comprises:
(a) reacting an aminobenzophenone of formula X

X C {~RJ2/NH2 X

wherein R2, X and Y are as defined above, with a methylthio acetate of formula XX

CHR(SCH3)COORl XX

wherein Rl is hydrogen, lower alkyl or alkali metal cation and R is as defined above, in the presence of t-butylhypochlorite, and subjecting the intermediates to the action of an acid to obtain a compound of formula A wherein Z is SCH3, and if desired, subsequently reacting the said compound with Raney nickel to obtain a compound of formula A wherein Z is hydrogen; or (b) for preparing compounds of formula A wherein Z is hydrogen and R2 is lower alkoxy, subjecting a corresponding 7-carboxy-5-~lower alkoxy)istatin to catalytic reduction and react-ing the resulting 7-carboxy-5-(lower alkoxy)-indolin-2-one with phenyllithium; or (c) for preparing compounds of formula A wherein Z is hydrogen and R2 is fluorine, chlorine, bromine, or iodine, react-ing the corresponding 5-halogeno-indolin-2-one with benzoyl chloride in the presence of aluminum chloride; or ~ d) for preparing 5-benzoylindolin-2-ones of formula A
wherein Z is hydrogen reacting an indolin-2-one of formula III

~ ~ R I I I

wherein R and R2 are as defined above, with a benzoyl chloride of formula ~/ ~ COC1 x~ IJ
~

wherein X and Y are as defined above, in the presence of aluminum chloride; or (e) for preparing 7-benzoylindolin-2-ones of formula A
wherein Z is hydrogen, reacting a l-aminoindolin-2-one of formula IV

R2 ~N~ - R IV

wherein R and R2 are as defined above, with a phenylacetone of formula ~, ~ CH2cocH3 wherein X and Y are as defined above, cyclizing the intermediate and treating the resulting indolyl-ester with ozone.
The S-benzoylindolin-2-ones can be prepared by react-ing an indolin-2-one of formula III with a benzoyl chloride in the presence of aluminum chloride to give an indolin-2-one of formula II.

COCl ~ C ~ ~ ~ R

(III) (Il) i~ 679 The indolin-2-ones ~III) are either commercially available or they can be prepared by methods known to the art such as are disclosed by Wenkert et al., J. Am. Chem. Soc. 81, 3763-3768 (1959).
The 7-benzoylindolin-2-ones of formula II are prepared by the following reaction sequence.

7g ~ CH2COCEI3 ~ r IV ~

x ~x CHR H 2 ) H CHR H

VIII VI

1H+,3 1H+~ 3 R ~3 ~ CHRCOOH ~ NHCOCH

C=O C=O

X

C=O H
~X

II Y

ilg~3~79 The l-aminoindolin-2-one starting materials (IV) can be prepared by suitable methods known to the art such as are disclosed by Baumgarten et al., J. Am. Chem. Soc. 82, 3977-82 (1960). The l-aminoindolin-2-one (IV) is leacted with an appropriately substituted phenylacetone to give a l-(-methyl-phenethylindenimino)indolin-2-one (V) which is cyclized in ethanolic hydrogen chloride to an ethyl -(2-methyl-3-phenylindol-7-yl)acetate (VI). The indolyl-ester is treated with ozone in acetic acid solution to give an ethyl 2-acetamido-3-benzoylphenyl-acetate (VII) which is hydrolyzed and cyclized in dilutemineral acid to a 7-benzoylindolin-2-one (II).
Alternatively, an ethyl -(2-methyl-3-phenylindol-7-yl)acetate (VI) is hydrolyzed in aqueous basic solution to an -(2-methyl-3-phenylindol-7-yl)acetic acid (VIII) which is treated with ozone in acetic acid solution to give a 2-acetamido-3-benzoylphenylacetic acid (IX). The acid is hydrolyzed and cyclized in dilute acid to the 7-benzoylindolin-2-one (II).
Compounds of formula II wherein R2 is lower alkoxy, especially methoxy are prepared by catalytic reduction of the corresponding 7-carboxy-5-(lower alkoxy)isatin, to the required 7-carboxy-5-(lower alkoxy)indolin-2-one and reaction of the latter compound with phenyllithium. For example, 7-carboxy-5-methoxyisatin is a known compound and is prepared by a modific-ation of the procedure of Cragoe, E. J. et al., J. Org. Chem. 18, 561 (1953). These products and their process of preparation form part of the present invention.

Compounds of formula Il wherein R2 is halogen, especially chlorine, are prepared by reacting the corresponding 5-halogeno-indolin-2-one with a benzoyl chloride in the presence of aluminum chloride. These products and their process of pre-paration also form part of the present invention. 5-Chloroindolin-

2-one is a known compound described in the chemical literature.
The 4-(5- and 7-)benzoylindolin-2-ones of formula XII
are prepared from appropriately substituted aminobenzophenones (X) by the following reaction sequence, wherein R, R2, X and Y
have the values hereinabove defined and Rl is hydrogen, lower alkyl or alkali metal cation. The reaction conditions employed are more fully set forth hereinafter in the specific preparations which follow.

~ 3~79 C 1~ 1 X I t -BuOC 1 X3~ ~ ~CR(SCH3)COOR

XI
11+
~ /
X O R

Y ~ ~0 XII

X H ~RaNi C ~ R

II

This reaction sequence and the compounds of formula XII are new and form part of the present in~ention. As can be seen from the above reaction sequence, the compounds of formula XII can subsequently be converted into compounds of formula II
by a novel process involving reaction with Raney nickel.
This invention is illustrated by the following Examples.
Example 1 5-Benzoylindolin-2-one A stirred slurry of 66 g. ~0.5 mole) of aluminum chloride and 42.5 g. (0.3 mole) of benzoyl chloride was heated to 150 C. and then 133 g. (0.1 mole) of indolin-2-one was slowly added at a rate so that the temperature of the stirred reaction mixture was maintained at 180-185 C. After addition the reaction mixture was stirred for five minutes at 185 C., cooled and poured into ice water. The 5-benzoylindolin-2-one which precipitated was collected and recrystallized from methanol; it melted at 204-205 C. The yield was 17.5 g. (73~).
Analysis: Calculated for C15HllNlO2: C, 75.94; H, 4.67; N, 5.90 Found : C, 75.76; H, 4.69; N, 5.82 Example 2 5-Benzoyl-3-methylindolin-2-one When, in the procedure of Example 1, an equal molar amount of 3-methylindolin-2-one is used in place of indolin-2-one, there is obtained 5-benzoyl-3-methylindolin-2-one.
Example 3 -Methylphenethylidenimino)indolin-2-one A mixture of 10 g. (0.07 mole~ of 1-aminoindolin-2-one ~ 7 9 and 9.05 g. (0.07 mole) of phenylacetone in 65 ml. of absolute ethanol was heated until all the l-aminoindolin-2-one dissolved.
The solution was treated with 0.5 ml. of acetic acid and heated on a steam bath an additional 15 minutes. After cooling~ the product was filtered off and the filtrate was treated with water.
The additional product which precipitated from the filtrate was combined with the original material and recrystallized from absolute alcohol; yield 16 g. ~90~); m.p. 102-104C.
Analysis: Calculated for C17H16N20: C, 77.25; H, 6.10; N, 10.60 Found : C, 77.26; H, 6.16; N, 10.58 Example 4 Ethyl -~2-methyl-3-~enylindol-7-yl)acetate A solution of ethanolic hydrogen chloride was prepared by bubbling dry hydrogen chloride into 100 ml. of absolute ethanol until the solution began to boil. At this point 10 g. ~0.04 mole) of l-~-methylphenethylidenimino)indolin-2-one ~prepared e.g. as described in Example 3) was added and the mixture was stirred for 30 minutes. Additional hydrogen chloride was bubbled into the hot mixture until thin layer chromatography showed no starting material remained. The reaction was allowed to cool and the solid which separated from the cooled reaction mixture was filtered off and was shown to be l-aminoindolin-2-one. The filtrate was concentrated and the residual brown oil was shown by nuclear magnetic resonance to be a mixture of phenylacetone and product~ The mixture was distilled at 165-175C. ~0.5 mm.); the oily distillate solidified upon cooling. The solid was recrystal-lized from ligroin to gi~e ethyl ~-~2-methyl-3-phenylindol-7-yl) acetate which melted at 108-109C. and weighed 2.2 g. (21%).

Analysis: Calculated for ClgHlgN02: C, 77.79; H, 6.53; N, 4.77 Found : C, 77.60; H, 6.54; N, 4.77 Example 5 -(2-Methyl-3-phenylindol-7-yl)acetic acid To a solution of 8 g. of potassium hydroxide in 100 ml.
of water was added 6. g. (0.02 mole) of ethyl a-(2-methyl-3-phenylindol-7-yl)acetate (prepared e.g. as described in Example 4).
The mixture was refluxed for two hours. The cooled reaction mixture was filtered and the filtrate diluted with an equal volume of water. Acidification of the basic solution with 3N
hydrochloric acid gave ~-(2-methyl-3-phenylindol-7-yl)acetic acid which was recrystallized from benzene; yield 3.7 g. (67%); m.p.
165C (dec.).
Analysis: Calculated for C17H15NO2: C, 76.96; H, 5.70; N, 5.28 Found : C, 77.09; H, 5.70; N, 5.22 Example 6 Ethyl 2-acetamido-3-benzoylphenylacetate A solution of 5 g. (0.017 mole) of ethyl ~-(2-methyl-3-phenylindol-7-yl)acetate (prepared e.g. as described in Example 4) and 75 ml. of acetic acid was treated with ozone for 25 minutes.
After ozonation, the acetic acid solution was diluted with water and extracted with ether. The ether extracts were washed with water, 5% sodium carbonate, dried (magnesium sulfate) and con-centrated. Recrystallization from isopropanol gave 2.6 g. (47%) of product which melted at 133-134C.
Analysis: Calculated for ClgHlgNO4 C, 70.14; H, 5.89; N, 4.30 Found : C, 69.95; H, 5.99; N, 4.12 Example 7 2-Acetamido-3-benzoylphenylacetic acid A solution of 2 g. of ~-~2-methyl-3-phenylindol-7-yl) acetic acid (prepared e.g. as described in Example 5) in 60 ml.
of acetic acid was treated with ozone for 15 minutes. The reaction mixture was treated with 10 ml. of water and allowed to evaporate overnight. The residue (1.7 g.) was recrystallized from isopropanol; yield 1.6 g. ~71%); m.p. 188-190C.
Analysis: Calculated for C17H15NO4: C, 68.68; H, 5.08; N, 4.71 Found : C, 68.33; H, 5.11; N, 4.58 Example 8 7-Benzoylindolin-2-one Method A
A mixture of 2.5 g. (0.0077 mole) of ethyl 2-acetamido-

3-benzoylphenylacetate (prepared e.g. as described in Example 6) in 50 ml. of 3N hydrochloric acid was refluxed for one hour. The reaction mixture was filtered and the filtrate was poured into a mixture of ice and water. The precipitate was collected and recrystallized from acetone; yield 1 g. (55%); m.p. 154C.
Analysis: Calculated for C15HllNO2: C, 75.94; H, 4.67; N, 5.90 ~ound : C, 75.84; H, 4.76; N, 5.78 Method B
A solution of 1.3 g. (0.0044 mole) of 2-acetamido-3-benzoylphenylacetic acid (prepared e.g. as described in Example 7) in 15 ml. of 3N hydrochloric acid and 15 ml. of acetic acid was refluxed for three hours. The cooled solution was poured into ice water and the 7-benzoylindolin-2-one which precipitated was collected and dried.
Example 9 Other 5-benzoylindolin-2-ones. -5-~p-chlorobenzoyl) indolin-2-one, 5-(o-fluorobenzoyl)indolin-2-one, 5-(p-methoxy-benzoyl)indolin-2-one and 5-(m-trifluoromethylbenzoyl)indolin-2-one are prepared in the manner of Example 1 from indolin-2-one and the corresponding substituted benzoyl chloride.
Example 10 Other l-(a-methylphenethylidenimino)indolin-2-ones.
-1-(a-methyl-p-chlorophenethylidenimino)indolin-2-one, 1-(~-methyl-o-fluorophenethylidenimino)indolin-2-one and l-(a-meth m-trifluoromethylphenethylidenimino)indolin-2-one are prepared in the same manner of Example 2 from 1-amino-indolin-2-one and the corresponding substituted phenylacetone.
Example 11 Other ethyl a- (2-methyl-3-phenylindol-7-yl)acetates.
-Ethyl a-[2-methyl-3-(p-chlorophenyl)indol-7-yl]acetate~ ethyl a-[2-methyl-3-(o-fluorophenyl)indol-7-yl]acetate and ethyl a-l2-methyl-3-(m-trifluoromethylphenyl)indol-7-yl]acetate are prepared in the same manner of Example 3 from the corresponding l-(a-methylphenethylidenimino)indolin-2-one.
Example 12 Other a - (2-methyl-3-phenylindol-7-yl)acetic acids.
-a- [2-methyl-3-~p-chlorophenyl)indol-7-yl]acetic acid, ~-[2-methyl-3-(o-fluorophen~l)indol-7-yl]acetic acid and a-[2-meth 3-~m-trifluoromethylphenyl)indol-7-yl)~acetic acid are prepared in the same manner of Example 4 from the corresponding ethyl ~-(2-methyl-3-phenyl-indol-7-yl)acetate.
Example 13 Other ethyl 2-acetamido-3-benzoylacetates. -Ethyl 2-acetamido-3-~p-chlorobenzoyl)phenylacetate, ethyl 2-acetamido-3-(o-fluorobenzoyl)phenylacetate and ethyl 2-acetamido-3-(m-tri-fluoromethylbenzoyl)phenylacetate are prepared in the same manner of Example 5 by ozonation of the corresponding ethyl ~-(2-methyl-3-phenylindol-7-yl)acetates.
Example 14 Other 2-acetamido-3-benzoylphenylacetic acids. 2-Acet-amido-3-(p-chlorobenzoyl)phenylacetic acid, 2-acetamido-3-(o-fluorobenzoyl)phenylacetic acid and 2-acetamido-3-(m-trifluoro-methylbenzoyl)phenylacetic acid are prepared in the same manner of Example 6 by ozonation of the corresponding a- (2-methyl-3-phenylindol-7-yl)acetic acids.
Example 15 Other 7-benzolindolin-2-ones. -7-(p-chlorobenzoyl) indolin-2-one, 7-(o-fluorobenzoyl)indolin-2-one and 7-(m-trifluoromethylbenzoyl~indolin-2-one are prepared in the same manner of Example 7 by cyclization of the corresponding ethyl 2-acetamido-3-benzoylphenylacetate or 2-acetamido-3-benzoyl-phenylacetic acid.
Example 16 7-Benzoyl-5-chloroindclin-2-one A mixture of 162.5 g. (1.0~ mole) of benzoyl chloride and 260 g. of aluminum chloride (1.80 mole) heated to 200C. with stirring was treated with 65 g. (.360 mole) of recrystallized 5-chloroindolin-2-one. This mixture was stirred 15 min. and 1~3G79 poured over ice. The resulting precipitate was triturated with boiling water and then chloroform. The chloroform solution was washed with 5% sodium bicarbonate, water, dried over sodium sul-fate, and stripped to yield approximately 55 g. of a glassy solid.
This material was then triturated with hot methanol and the methanol evaporated under vacuum to yield approximately 20 g. of a solid yellow material. Extraction of a benzene solution of this material removed any starting 5-chloroindolin-2-one present and after washing with water and drying the benzene yielded on evapor-ation 3 g. of a blue-gray material. Trituration of this material with room temperature methanol gave a residue which on recrystal-lization from methanol yielded 2.5 g. of a tan solid identified as product, m.p. 186-187C.
Analysis: Calculated for C15HloClNO2: C, 66.31; H, 3.71; N, 5.16 Found : C, 66.27; H, 3.83; N, 5.07 Example 17 5-Methoxy-7-benzoylindolin-2-one A suspension of 1.0 g. (4.9 mmole) of 5-methoxy-7-carboxyindolin-2-one in 20 ml. of tetrahydrofuran was treated dropwise with 12 ml. of commercially prepared phenyllithium solution (2.3 molar ether: benzene; 0.28 moles). After stirring for two hours the reaction mixture was poured into water and extracted several times with ethyl ether and benzene. The combined extracts were washed with water, dried over sodium sulfate and concentrated using a rotary evaporator to a solid residue which on recrystallization from acetone-water gave 259 mg. (21~) of a yellow powder which melted at 154C.

&79 Example 18

4-Benzoyl-3-methylthioindolin-2-one A solution of 30.6 ~0.152 mole) of 3-aminobenzophenone in 160 ml. of methylene chloride was cooled to -78C. in a dry ice/acetone bath and treated dropwise under a nitrogen atmosphere with a solution of 16.5 g. ~0.152 mole) of t-butylhypochlorite in 60 ml. of methylene chloride. After stirring for 1 hr. after addition was complete, thin layer chromatography showed no start-ing material. A solution of 20.2 g. ~0.152 mole) of ethyl ~ -~methylthio) acetate in 60 ml. of methylene chloride was added dropwise and stirring continued at -78C. for 2.5 hr. A solution of 15.4 g. ~0.152 mole) of triethylamine in 60 ml. of methylene chloride was added dropwise at -78C. and the reaction mixture allowed to warm to room temperature while stirring for 16 hre ~overnight). The dark brown solution was treated with 100 ml.
of 3N hydrochloric acid and stirred for 3 hrs. at room temperature.
Precipitation of a tan solid began after 15-30 minutes. Filtra-tion gave 18.5 g. of solid, m.p. 224-228C. ~dec.). The layers of the filtrate were separated, the organic phase dried over magnesium sulfate, evaporated under reduced pressure, and the residue triturated in isopropyl ether ~25 g.). The gummy solid was triturated in cold methanol to give 8.3 g. of product, m.p.
222-225C. ~dec.). The total yield was 26.8 g. (62%). A 7.0 g. sample recrystallized from methanol weighed 5.6 g. and melted at 235-237C. (dec.).
Analysis: Calculated for C16H13NO2S: C, 67.823; H, 4.625; N, 4.943 Found : C, 67.86; H, 4.71 ; N, 4.85 7~

Example 19 7-~4-Chlorobenzoyl)-3-methylthioindolin-2-one A solution of 23.1 g. ~0.1 mole) of 2-amino-4'-chlorobenzophenone in 400 ml. of methylene chloride was cooled to -65~C. and treated dropwise with 12.4 g. (0.1 mole) of t-butyl hypochlorite. After 15 min., 13.4 g. of ethyl ~-(methylthio) acetate ~0.1 mole) was added dropwise maintaining -65C. temper-ature. After 1-1/2 hr. 10.1 g. of triethylamine ~0.1 mole) was added and the reaction mixture allowed to come to room temperature.
~he solution was then washed with water and stripped. The residue was taken into methanol and brought to reflux at which time lN hydrochloric acid was added and the resulting mixture refluxed overnight. The mixture was cooled, resulting precipitate filtered off and recrystallized from toluene, giving 10 g. of a cream colored solid. The product (33% yield) melted at 186-188C.
Analysis: Calculated for C16 H12ClNO2S: C, 60.47; H, 3.81; N, 4.41 Found : C, 60.29; H, 3.76; N, 4.43 Example 20 7-~enzoyl-3-methyl-3-methylthioindolin-2-one A stirred solution of 3.94 g. (0.02 mole) of 2-amino-benzophenone in methylene chloride at -65C. was treated with 2.16 g. (0.02 mole) of t-butylhypochlorite. After 15 min. 2.96 g. ethyl ~-(methylthio)propionate was added dropwise and stirring continued for 1 hr. At the end of this time 2.02 g. of tri-ethylamine (0.02 mole) was added dropwise and thc reaction solution was allowed to warm to room temperature. This was followed by treatment with lN hydrochloric acid and stirred for '79 15 min. The methylene chloride solution was then separated and stripped under vacuum. The yellow oil residue was triturated with isopropyl ether and 3 g. of a yellow solid was filtered off (51%). Recrystallization from absolute ethanol gave a cream color solid, m.p. 135-137C.
Analysis: Calculated for C17H15NO2S: C, 68.66; H, 5.08; N, 4.71 Found : C, 68.54; H, 5.08; N, 4.63 Example 21 7-Benzoyl-3-methylthioindolin-2-one A solution of 300 g. ~1.52 mole) of 2-aminobenzophenone in 4 liters of methylene chloride was chilled to -40C. and then treated with 204 g. (1.52 mole) of the ethyl ~-(methylthio) acetate in 5 liters of methylene chloride. The reaction mixture was then cooled to -65C. and treated dropwise with 500 ml. of a methylene chloride solution containing 164 g. (1.52 mole) of t-butylhypochlorite. After addition was complete, stirring was continued for 2 hr. at -70C. The solution was then treated with 182 g. (1.8 mole) of triethylamine and allowed to come to room temperature overnight. The methylene chloride solution was washed twice with 3 liters of ice water followed by drying over sodium sulfate and concentrating the dried solution to a yellow oil under reduced pressure. The oil was taken into 1.5 liters of methanol treated with 1 liter of lN hydrochloric acid and refluxed for 2 hrs. After cooling in an ice bath 343 g.
(79.9) of crude product was recovered after filtering and drying. Two recrystallizations from toluene gave creamy white flakes; m.p. 130C.

` ``:
i79 Analysis: Calculated for C16H13NO2S: C, 67.82; H, 4.62; N, 4.97 Found : C, 68.06; H, 4.68; N, 4.87 Example 22 4-Benzoylindolin-2-one A stirred suspension of 7.0 g. (0.0248 mole) of 4-benzoyl-3-methylthioindolin-2-one prepared as described in Example 18 in 400 ml. of tetrahydrofuran was treated portionwise under a nitrogen atmosphere with 35.0 g. of Raney nickel over a 2.5 hr. period. The reaction mixture was stirred for 1.5 hr.
after addition was complete and the catalyst removed by filtration. The filter cake was washed well with tetrahydro-furan and methylene chloride and the filtrate evaporated under reduced pressure. The residue (5.6 g.) was recrystallized from methanol and gave 4.45 g. (76%) of product m.p. 210-212C.
Analysis: Calculated for C15HllNO2: C, 75.937; H, 4.673; N, 5.904 ~ound : C, 75.85; H, 4.59; N, 5.92 Example 23 7-(4-Chlorobenzoyl)indolin-2-one A stirred solution of 9 g. ~0.028 mole) of 7-(4-chlorobenzoyl)-3-methylthionindolin-2-one prepared as described in Example 19 in 180 ml. of tetrahydrofuran was treated over a two-hour period with 45 g. of a commercial Raney nickel water suspension. After the addition was complete the mixture was filtered. A drop of concentrated hydrochloric acid was added to the filtrate which removed some color and the resulting solution was then stripped under water pump vacuum to yield a cream color material. Recrystallization from toluene gave needles, (93O

~1~3679 yield); the material sintered at 177GC. and melted at 185C.
Analysis: Calculated for C15HloClNO: C, 66.31; H, 3.71; N, 5.16 Found : C, 65.97; H, 3.56; N, 5.11 Example 24 7-Benzoyl-3-methylindolin-2-one A stirred solution of 8 g. (0.027 mole) of 7-benzoyl-3-methyl-3-methylthioindolin-2-one prepared as described in Example 20 in 80 ml. of tetrahydrofuran was treated under N2 with 40 g. of a commercial Raney nickel-water mixture over a 2 hr. period. At the end of this period the mixture was filtered and the residue washed thoroughly with tetrahydrofuran. One drop of concent-rated hydrochloric acid was added to the filtrate and the dark orange solution turned pale yellow. The solution was stripped under vacuum to a yellow oil which crystallized on seeding. The material was recrystallized from toluene petroleum ether to give a white crystalline material. The solid ~6.0 g., 89% yield) melted at 125-127~C.
Analysis: Calculated for C16H13NO2: C, 76.43; H, 5.22; N, 5.57 Found : C, 76.38; H, 5.22; N, 5.52 Example 25 7-(4-Fluorobenzoyl)indolin-2-one A stirred suspension of 12.3 g. (0.41 mole) of 7-(4-fluorobenzoyl)-3-methylthioindolin-2-one prepared in a similar manner to that described in Example 19 by reacting 2-amino-4'-~luorobenzophenone with ethyl ~-(methylthio)acetate in the presence of t-butyl hypochlorite in 250 ml. of tetrahydrofuran was treated over a two hour period with 60 g. of a commercial '79 Raney-nickel water suspension. The mixture was filtered under nitrogen and the residue washed with tetrahydrofuran and methylene chloride. The filtrate was treated with a few drops of conc.
hydrochloric acid and concentrated under reduced pressure to give 9.5 g. (91%) of 7-(4-fluorobenzoyl)indolin-2-one.
Example 26 2-Amino-5-benzoylphenylacetic Acid A mixture of 1.0 g. (0.004 mole) of 5-benzoylindolin-2-one prepared, for example, as described in Example 1 and 30 ml.
of 3N sodium hydroxide was refluxed for 0.5 hour. The reaction mixture was cooled, acidified to pH 6 with 3N hydrochloric acid and slightly acidic solution was extracted with chloroform. The chloroform extracts were dried (magnesium sulfate~ and concent-rated to a solid. Recrystallization from ethanol-water gave 0.9 g. (84.5%) of pure product which melted at 143-145C.
Analysis: Calculated for C15H13NO3: C, 70.57; N, 5.13; N, 5.49 Found : C, 70.80; N3 5.18; N, 5.55 Example 27 2-Amino-5-benzoyl-a-methylphenylacetic Acid When, in the procedure of Example 26, an equal molar amount of 5-benzoyl-3-methylindolin-2-one prepared, for example, as described in Example 2 is used in place of 5-benzoylindolin-2-one, there is obtained 2-amino-5-benzoyl-~-methylphenylacetic acid .
Example 2_ 2-Amino-3-benzoylphenylacetic Acid - ~3 A mixture of 1.0 g. ~0.004 mole) of 7-benzoylindolin-2-one prepared, for example, as described in Example 8 was added to 30 ml. of 3N sodium hydroxide and the basic solution was refluxed for 45 minutes under nitrogen. The mixture was filtered and the filtrate was neutralized with glacial acetic acid. The precipitate was filtered off, washed with water and dried. The material melted at 122C. (dec.). The yield was 0.8 g. (72~).
Analysis: Calculated for C15H13NlO3: C, 70.58; H, 5.13; N, 5.49 Found : C, 70.36; H, 5.11; N, 5.48 Example 29 In the same manner as given in Example 26, 2-amino-5-(p-chlorobenzoyl)phenylacetic acid, 2-amino-5-(o-fluorobenzoyl)phenylacetic acid, 2-amino-S-(p-methoxybenzoyl)phenylacetic acid, and 2-amino-5-(m-trifluoromethylbenzoyl)phenylacetic acid are prepared from

5-(p-chlorobenzoyl)indolin-2-one, 5-(o-fluorobenzoyl)indolin-2-one, 5-(p-methoxybenzoyl)indolin-2-one, and 5-(m-trifluoromethylbenzoyl)indolin-2-one.
Example 30 In the same manner as given in Example 27, 2-amino-3-(p-chlorobenzoyl)phenylacetic acid, 2-amino-3-(o-fluorobenzoyl)phenylacetic acid, and 2-amino-3-(m-trifluoromethylhenzoyl)phenylacetic acid are prepared from 7-(p-chlorobenzoyl)indolin-2-one, 7-(o-fluorobenzoyl)indolin-2-one, and 7-(m-trifluoromethylbenzoyl)indolin-2-one.

Claims (9)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of compounds of formula A

A

wherein R is hydrogen or lower alkyl, R2 is hydrogen, fluorine, chlorine, bromine, iodine or lower alkoxy, Z is hydrogen or SCH3 and X and Y are the same or different and represent hydrogen atoms or lower alkyl, lower alkoxy, fluorine, chlorine, bromine, iodine, nitro or trifluoromethyl groups, or together form a lower alkylenedioxy group, which comprises:
(a) reacting an aminobenzophenone of formula X

X

wherein R2, X and Y are as defined above, with a methylthio acetate of formula XX
CHR(SCH3)COOR1 XX
wherein R1 is hydrogen, lower alkyl or alkali metal cation and R is as defined above, in the presence of t-butylhypochlorite, and subjecting the intermediates to the action of an acid to obtain a compound of formula A wherein Z is SCH3, and if desired, subsequently reacting the said compound with Raney nickel to obtain a compound of formula A wherein Z is hydrogen; or (b) for preparing compounds of formula A wherein Z is hydrogen and R2 is lower alkoxy, subjecting a corresponding 7-carboxy-5-(lower alkoxy)istatin to catalytic reduction and reacting the resulting 7-carboxy-5-(lower alkoxy)-indolin-2-one with phenyllithium; or (c) for preparing compounds of formula A wherein Z
is hydrogen and R2 is fluorine, chlorine, bromine, or iodine, reacting the corresponding 5-halogeno-indolin-2-one with benzoyl chloride in the presence of aluminum chloride; or (d) for preparing 5-benzoylindolin-2-ones of formula A
wherein Z is hydrogen, reacting an indolin-2-one of formula III

III

wherein R and R2 are as defined above, with a benzoyl chloride of formula wherein X and Y are as defined above, in the presence of aluminum chloride; or (e) for preparing 7-benzoylindolin-2-ones of formula A wherein Z is hydrogen, reacting a l-aminoindolin-2-one of formula IV

IV

wherein R and R2 are as defined above, with a phenylacetone of formula wherein X and Y are as defined above, cyclizing the intermediate and treating the resulting indolyl-ester with ozone.

2. A compound of formula A as defined in claim 1 when-ever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

3. A process for the preparation of compounds of formula II

II

wherein R, R2, X and Y are as defined in claim 1, which com-prises subjecting a corresponding 3-methylthio-indolin-2-one of formula XII

XII

wherein R, R2, X and Y are as defined in claim 1, to reaction with Raney nickel.

4. A process for the preparation of compounds of formula XII

XII

wherein R, R2, X and Y are as defined in claim 1, which com-prises reacting an aminobenzophenone of formula X as defined in claim 1 with a methylthio acetate of formula XX as defined in claim 1 in the presence of t-butylhypochlorite, and subjecting the intermediates to the action of an acid.

5. A compound of formula XII as defined in claim 4 whenever prepared by the process of claim 4 or by an obvious chemical equivalent thereof.

6. A process for the preparation of compounds of formula II

II

wherein R, X and Y are as defined in claim 1 and R2 is fluorine, chlorine, bromine or iodine, which comprises reacting the corresponding 5-halogenoindolin-2-one with benzoyl chloride in the presence of aluminum chloride.

7. A compound of formula II as defined in claim 6 when-ever prepared by the process of claim 6 or by an obvious chemical equivalent thereof.

8. A process for the preparation of compounds of formula II

II

wherein R, X and Y are as defined in claim 1 and R2 is lower alkoxy, which comprises subjecting a corresponding 7-carboxy-5-(lower alkoxy)istatin to catalytic reduction and reacting the resulting 7-carboxy-5-(lower alkoxy)-indolin-2-one with phenyllithium.

9. A compound of formula II as defined in claim 8, when-ever prepared by the process of claim 8 or by an obvious chemical equivalent thereof.