CA1289556C - 1- or 3-monosubstituted 2-oxindole compound intermediates useful for the production of analgesic and anti-inflammatory agents - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Disclosed are novel 1- or 3-monosubstituted 2-oxindole compounds useful as intermediates for the preparation of analgesic and anti-inflammatory 1,3-disubstituted 2-oxindole compounds.
The intermediates have the formulae:

and The 1,3-disubstituted 2-oxindole compounds have the formula:

Description

l~asss6 This is a divisional application of Serial Number 473,576 filed February 5, 1985 and is directed to intermediates of formulae (II) and (IV) described hereinafter and useful for the production of novel compounds of the parent application.
The parent application relates to new chemical compounds which are of value as new medicinal agents. More particularly the new chemical compounds are derivatives of 2-oxindole-1-carboxamide, and they are further substituted at the 3-position and on the carboxamide nitrogen by an acyl group. These new chemical compounds are inhibitors of boththe cyclooxygenase (CO) and lipoxygenase (LO) enzymes.
The compounds of the parent application possess analgesic activity in mammals, particularly man, and they are useful there-fore for acute administration for ameliorating or eliminating pain, such as the pain experienced by patients recovering from surgery or trauma.
In addition to their usefulness for acute administration to combat pain, the compounds of the parent application are useful for chronic administration to mammals, particularly man, to alleviate the symptoms of chronic diseases, such as the inflam-mation and pain associated with rheumatoid arthritis and osteo-arthritis.
In the specification hereinafter, the expression "this invention" includes both the subject matter of the parent applica-tion and that of this divisional application.

. _ This invention provides novel 2-oxindole compounds of the formula X ~ ,c y ~ N ~ 0 ODC-NH-~--R
o and the pharmaceutically-acceptable base salts thereof;
s wherein X i8 selected from the group consisting of hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbon~, alkoxy having 1 to 4 carbons, alkylthio having 1 to 4 carbons, trifluoro-methyl, alkylsulfinyl having 1 to 4 carbons, alkyl-sulfonyl having 1 to 4 carbons, nitro, phenyl, alkanoyl having 2 to 4 carbons, benzoyl, thenoyl, alkanamido having 2 to 4 carbons, benzamido and N,N-dialkylsulfamoyl having 1 to 3 carbons in each of said alkylst and Y i~
- lS selected from the group consisting of hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbons, alkoxy having 1 to 4 carbons, alkylthio having 1 to 4 carbons and trifluoromethyl;
or X and Y when taken together are a 4,5-, 5,6-or 6,7-methylenedioxy group or a 4,5-, 5,6- or 6,7-ethylenedioxy group;
or X and Y when taken together and when attached to adjacent carbon atoms, form a divalent radical Z, wherein Z is selected from the group consi~ting of ~ ` ~ 1;~89556 C ' C ' ~ ' - zl z2 z3 ~W_ W_ and \ \
z4 zS
wherein W is oxygen or sulfur;
Rl i~ selected from the group consisting of alkyl having l to 6 carbons, cycloalkyl having 3 to 7 carbons, phenyl, substituted phenyl, phenylalkyl having l to 3 carbons in said alkyl, (substituted phenyl)alkyl having l to 3 carbons in said alkyl, phenoxyalkyl having l to 3 carbons in said alkyl, (substituted - phenoxy)alkyl having l to 3 carbons in said alkyl, naphthyl and -lCH2)n-Q-R ;
wherein the substituent on said substituted phenyl, said (substituted phenyl)alkyl and said (substituted phenoxy)alkyl is selected from the group consisting of fluoro, chloro, alkyl having 1 to 3 carbons, alkoxy having l to 3 carbons and trifluoro-methyl; n 18 zero, l or 27 Q is a divalent radical derived from a compound selected from the group consisting of furan, thiophene, pyrrole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, l,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, pyridine, pyrimidine, pyrazine, benzolblfuran and benzolb]thiophene; and R is hydrogen or alkyl having l to 3 carbons;

'~ s~ --and R2 is selected from the group consisting of alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, phenoxymethyl, furyl, thienyl, pyridyl and ~ R4 wherein R3 and R4 are each selected from the group consisting of hydrogen, fluoro, chloro, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons and tri-fluoromethyl.
Said compounds of formula I are active as analgesic agents, and a~ agents for treating inflammatory diseases, such as the arthritides. Accordingly this invention also provides a method of eliciting an analgesic response in a mammalian subject, especially man a method of treating an inflammatory disease in a mammalian subject, especially man; and pharmaceutical compositions comprising a compound of formula I and a pharmaceutically-acceptable carrier.
A first preferred group of compounds of this invention consists of the compounds of formula I, wherein X and Y are each hydrogen and Rl is selected from the group consisting of 2-furyl, 2-thienyl and (2-thienyl)methyl. Among this first preferred group, particularly preferred compounds are those wherein R
is phenyl.
A second preferred group of compounds of this invention consists of the compounds of formula I, wherein X is 5-chloro, Y is hydrogen and Rl i9 selected from the group consisting of 2-furyl, 2-thienyl and (2-thienyl)methyl. Among thi8 second preferred group, particularly preferred compounds are tho8e wherein R2 is cyclohexyl.
Especially preferred individual compounds of the invention are:
N-benzoyl-3-(2-furoyl)-2-oxindole-1-carboxamide (I:X is hydrogen Y is hydrogen; Rl is 2-furyl; R2 is phenyl) and N-cyclohexylcarbonyl-5-chloro-3-(2-thenoyl)-2-~10 oxindole-l-carboxamide (I:X is 5-chloro; Y is hydrogen;
Rl is 2-thienyl; R2 is cyclohexyl).
Yet further thi8 invention provides novel com-pounds Of the formula X ~ N ~ O ---(II) OzC-NH-C-R

wherein X, Y and R2 are as defined previously. The compounds of formula II are useful as intermediates to the compounds of formula I.
Also useful as intermediates to the compounds of the formula I are the compounds of the formula ~ ~0 ---(IV) -5a-and the base salts thereof, wherein X, Y and Rl are as defined previously. A preferred sub-group of compounds of the formula IV consists of those compounds in which X is hydrogen, 5-fluoro or 5-chloro; Y is hydrogen, 6-fluoro or 6-chloro; and Rl is benzyl, furyl, thienyl or thienylmethyl; provided that when X
and Y are both hydrogen, Rl is not benzyl. The compounds of formula IV in said latter preferred sub-group are novel, and as such they form part of this invention.
The analgesic and antiinflammatory compounds of this invention are the compounds of formula I, wherein X, Y, Rl and R2 are as defined previously. Thus, the compounds of this invention are derivatives of 2-oxindole, the bicyclic amide of the formula 895~fi More particularly, the analgesic and antiinflammatory agents of this invention have an N-acylcarboxamido substituent, -C(=O)-NH-C(=O)-~2, at the l-position and an acyl substituent, -C(=O)-Rl, at the 3-position of 2-oxindole, and the benzo ring can be further substi-tuted by X and Y groups. X and Y can be certain monovalent substituents as defined previously, or X
and Y when on adjacent carbon atoms on the benzo ring can represent a methylenedioxy group, -OCH2O-, or ethylenedioxy group, -OCH2CH2O-. Yet further, X and Y, when they are attached to adjacent carbon atoms of the benzo ring of the 2-oxindole, can form a divalent unit, Z, such that when Z is taken with the carbon atoms to which it is attached it forms a fused carbo-lS cyclic or heterocyclic ring. Certain divalent groupsfor Z (i.e. zl_Z5) have been listed earlier. Thus, when Z is zl, X and Y when taken with the carbons to which they are attached represent a fused cyclopentene ring; and when Z is Z5, X and Y when taken with the carbons to which they are attached represent a fused furan or thiophene ring. Moreover, it is to be understood that when Z is Z4 or Z5, the Z group can be _ attached in either of two possible ways. Thus, for example, when X and Y are at C-5 and c-6 and they are Z , the formula I embraces both of the following formulae:

~-R

O=C-NH-C-R
o ~89556 Rl O-C-NH-Il-R
.

Additionally, as will be appreciated by one skilled in the art, the analgesic and anti-inflammatory compounds of this invention of formula I, wherein X, Y, Rl and R2 are defined previously, are capable of enolization, and therefore they can exist in one or more tautomeric (enolic) forms. All such tautomeric (enolic) forms of the compounds of formula I are considered to be within the scope of this invention.
The compounds of formula I are prepared from the appropriate 2-oxindole compound of the formula K ~ 1 o ---(III) H

wherein X and Y are as defined previously. This is accomplished by attaching the substituent -C(sO)-NH-C(=O)-R2 to the l-position and the substituent -C(~O)-Rl to the 3-position. These substituents can be attached in either order, and~this leads to two vari-ations in the method for making the compounds of formula I, as ~hown in the Scheme.

1~895~6 ., --8--SCHEME

X~,_, y ~N~) ~ III ) /

IE y ~ O
OnC--NH-C-R2 ( IV ) ( I I ) ~C--Rl O~C-NH-~-R2 . (I) Thus the first variation involves the sequence:
compound III to compound IV to compound I, while the second varlation involves the qequence: compound III
S to compound II to compound I.

~ 895S~i --~ he -Cl=0)-NH-C(~0)-R2 group is attached by reacting a compound of the formula III or a compound of the formula IV with an acyl isocyanate of the formula R2-C(50)-N=C-O. Most commonly, the reaction 5 i8 carried out by contacting substantially equimolar quantities of the reactants in an inert solvent at a temperature in the range from 50 to 150C., and preferably from 100 to 130C. In this context an inert solvent is one which will dissolve at least one of the reactants, and which does not adversely interact with either of the reactants or the product. Typical solvents which can be used include aliphatic hydro-carbons, such as octane, nonane, decane and decalin:
aromatic hydrocarbons, such as benzene, chlorobenzene, lS toluene, xylenes and tetralin; chlorinated hydrocarbons, such as 1,2-dichloroethane; ethers, such as tetra-hydrofuran, dioxane, 1,2-dimethoxyethane and di(2-methoxyethyl)ether; and polar, aprotic solvents such ag N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide. The reactiontime varies according to the reaction temperature, but at a temperature from 100 to 130C , reaction times of - a few hourc, e.g., 5 to 10 hours are commonly used.
When a relatively non-polar reaction solvent is used for the reaction of a compound of formula III or IV with an acyl isocyanate of formula R2-C(=0)-N-C~0, the product (I or II) i8 usually out of solution at the end of the reaction when the reaction mixture is cooled to room temperture. Under these circumstances the product is usually recovered by filtration.
~owever, if relatively polar solvents are used and the product is not out of solution at the end of the reaction, the product can be recovered by solvent evaporation or, in the case of water-miscible solvents, ~895~

by dilution of the reaction medium with water. This causes the product to precipitate and again it can be recovered by filtrat$on. The reaction product (I
or II) can be purified by standard methods, e.g., S recrystallization.
The reaction between a compound of formula ~V
and an acyl isocyanate of formula R2-C( 80 )-N-CSO can be speeded up by the addition of a base, such as a tertiary amine, e.g., trimethylamine, triethylamine, tributylamine, N-methylpiperidine, N-methylmorpholine or N,N-dimethylaniline. From about one to about four equivalents of the basic agent is usually added, and this permits the use of reaction temperature from 20 to 50C. At the end of the reaction, the reaction medium must be neutralized (or made acidic) and then the product is isolated as described earlier.
The -C(-O)-Rl side-chain can be attached to a compound of the formula II by reaction with an activated derivative of a carboxylic acid of the formula Rl-C(~OlOH. The reaction is carried out by treating saidcompound of formula II in an inert solvent with one molar equivalent, or a slight exce~s, of an activated ~ derivative of a compound of formula Rl-C(-O)OH, in the presence of from one to four equivalents of a basic agent. An inert solvent is one which will dissolve at least one of the reactants, and will not adversely interact with either of the reactants or the product.
However, in practice, a polar, aprotic solvent, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide, is commonlyused. Conventional methods for activating the acid of formula Rl-C~O)OH are used. For example, acid halides, e.g., acid chlorides; symmetrical acid anhydrides, Rl-C~=O)-O-Ct=O)-Rl mixed acid anhydrides with a hindered low-molecular weight carboxylic acid, R -C(=o)-o-C~=o)-R5, where R5 is a bul~y lower-al~yl group such as t-butyl; and mixed carboxylic-carbonic S anhydrides, Rl-C(=O)-O-C~-O)-OR6, wherein R5 is a lower-alkyl group, can all be used. In addition, N-hydroxyimide esters (such as N-hydroxysuccinimide and N-hydroxyphthalimide esters), 4-nitrophenyl esters, thiol esters ~such as thiol phenyl esters) and 2,4,5-trichlorophenyl e~ters, and the like, can be used.
A wide variety of basic agents can be used in thereaction between a compound of formula II and the activated derivative of the acid of the formula Rl-C(~O)OH. However, preferred basic agents are tertiary amines, such as trimethylamine, triethylamine, tri-butylamine, N-methylmorpholine, N-methylpiperidine and 4-(N,N-dimethylamino)pyridine.
The reaction between a compound of the formula II
and thé activated derivative of the acid of formula Rl-C(-O)-OH is usually carried out in the temperature range from -10 to 25C. Reaction times of from ~0 minutes to a few hours are common. At the end of the ~ reaction, the reaction medium is usually diluted with water and acidified, and then the product can be recovered by filtration. It can be purified by standard methods, such as recrystallizatlon.
The -C(~O)-Rl side-chain can be attached to a compound of the formula III by reaction w-th a derivative of the appropriate acid of the formula Rl-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 ~ 12~95S6 ~

formula Rl-C(=O)OH which can be used include acid chlorides, acid anhydrides of the formula Rl-C(=O)-O-c(=o)-Rl Rl-C(=o)-o-C(=o)-R5 and Rl-c(=o)-o-c(=o)-OR , and simple alkyl esters of the formula Rl-C(=O)-OR6, wherein R5 and R6 are as defined previously. Usually, a small excess of the derivative of the acid of formula Rl-C(=O)-OH 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 Rl-C(=O)OH. The reaction between the derivative of the acid of the formula Rl-C(=O)OH and the compound of formula III is usually started at 0 to 25C., but it is then usual to heat the reaction mixture at a temperature in the range from 50 to 130C., and preferably at about 80C., 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 days, are commonly used. The reaction mixture is then cooled, diluted with an excess of water, and acidified.
The product of formula IV can then be recovered by filtration or by the standard procedure of solvent extraction.
The acyl isocyanates of the formula R2-C(=O)-N=C=O which are known can be prepared by the published procedures. Those which are analogs of known compounds can be prepared by analogous procedures. In general, the corresponding amide of the formula R2-C(=O)-NH2 reacts with oxalyl chloride, or the acid chloride of formula R2-C(=O)-Cl reacts with silver cyanate.
Consult: Speziale et al., Journal of Organic Chemistry, 28, 1805 (1963) and 30, 4306 (1965); Ramirez et al., Journal of Orqanic Chemistry, 34, 376 (1969); and 1~8~556 Naito et al., Journal of Antibiotics (Japan), 18, 145 ~1965).
The 2-oxindole compounds of formula III are prepared by known methods, or methods analogous to known methods. Consult: ~Rodd's Chemistry of Carbon Compounds,~ Second Edition, S. Coffey editor, Volume IV Part A, Elsevier Scientific Publishing Company, 1973, pp. 448-450; Gassman et al., Journal of Oraanic Chemistry, 42, 1340 (1977); Wright et al., Journal of the American Chemical SocietY, 78, 221 (1956); Beckett et al., Tetrahedron, 24, 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 Czechoslovakian Chem$cal Communications, 44, 2108 (1979); McEvoy et al., Journal of Or~anic Chemistrv, 38, 3350 (1973); Simet, Journal of Orqanic ChemistrY, 28, 3580 tl963);
Wieland et al., Chemische Berichte, 96, 253 (1963);
and references cited therein.
The compounds of the formula I are acidic and they form base salts. All such base salts are within the scope of this invention and they can be prepared ~ by conventional methods. For example, they can be prepared simply by contacting the acidic and basic entities, usually in a stoichiometric ratio, in either an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salt~ are recovered either by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, as appropriate, or, in the case of aqueous solutions, by lyophilization. Typical salts of the compounds of formula I which can be prepared are primary, secondary `~ 8~556 and tertiary amine salts, alkali metal salts and alkaline earth metal salts. Especially valuable are the ethanolamine, diethanolamine and triethanolamine salts.
~asic agents suitably employed in salt formation belong to both the organic and inorganic types, and they include organic amines, al~ali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, al~ali metal hydrides, alkali metal alkoxides, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal hydrides and alkaline earth metal alkoxides. Representative examples of such bases are primary amines, such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, ~-toluidine, ethanolamine and glucamine; secondary amines, such as diethylamine, diethanolamine, N-methylqlucamine, N-methylaniline, morpholine, pyrrolidine and piperidine;
tertiary amines, such as triethylaminq, triethanol-amine, N,N-dimethylaniline, N-ethylpiperidine and N-methylmorpholine; hydroxides, such as sodium hydroxide;
al~oxides, such as sodium ethoxide and potassium methoxide; hydrides, such as calcium hydride and sodium hydride; and carbonates, such as potassium carbonate and sodium carbonate.
The compounds of formula I possess analgesic activity. This activity has been demonstrated in mice by showing blockade of the abdominal stretching induced by administration of 2-phenyl-1,4-benzoquinone (PBQ). The method used was based on that of Siegmund et al., Proc. Soc. Exp. Biol. Med., 95: 729-731, 1957, as adapted for high throughput (see further Milne and Twomey, ents and Actions, 10: 31-37, 1~8955g~

., 1980). The mice used in these experiments were Carworth males, albino CF-l strain, weighing 18-20 g.
All mice were fasted overnight prior to drug adminis-tration and testing.
The compounds of formula I were dissolved or suspended in a vehicle consisting of ethanol (5%), emulphor 620 (a mixture of polyoxyethylene fatty acid esters, 5%) and saline (90%). This vehicle also served as control. Doses were on a logarithmic scale (i.e., ... 0.32, 1.0, 3.2, 10, 32... mg/~g), and were calculated from weights of the salt when applicable, and not of the acid. The route of administration was oral, with concentrations varied to allow a constant dosage volume of 10 ml/kg of body weight. The afore-said method of Milne and Twomey was used to determine efficacy and potency. Mice were treated with com-pounds orally, and one hour later received PBQ, 2 mg~kg, intraperitoneally. Individual mice were then lmmediately placed in a warmed ~ucite (transparent plastic) chamber, and, starting five minutes after PBQ administration, the number of abdominal constrictions during the subsequent 5 minutes was recorded. The ~ degree of analgesic protection (% MPE) was calculated on the basis of suppression of abdominal constriction relative to counts from concurrent control animals run on the same day. At least four such determinations (N > S) provided dose-response data for generation of an MPE50, the best estimate of the dose that reduces abdominal constriction to 50% of control levels.
The compounds of formula I also posses~ anti-inflammatory activity. This activity has been demonstrated in rats by a method based on the standard carrageenin-induced rat-foot edema test. (Winter et al., Proc.
Soc. Exp. Biol. Med., 111: 544, 1963).

~ nanesthetized, adult, male, albino rats of 150 g to 190 g body weight were numbered, weighed, and an ink mark placed on the right lateral malleolus. Each paw was immersed in mercury exactly to the ink mark.
The mercury was contained in a glass cylinder, connected to a Statham Pressure Transducer. The output from the transducer was fed through a control unit to a micro-voltameter. The volume of mercury displaced by the immersed paw was read. Drugs were given by gavage.
One hour after drug administration, edema was induced by injection of 0.05 ml of 1% solution of carrageenin into the plantar tissue of the marked paws. Immediately thereafter, the volume of the injected foot was measured. The increase in foot volume 3 hours after the injection of carrageenin constitutes the individual inflammatory response.
The analgesic activity of the compounds of formula I makes them useful for acute adm~nistration to mammals for the control of pain, e.g., post-operative pain and the pain of trauma. Additionally the compounds of formula I are useful for chronic administration to mammals for the alleviation of the symptoms of chronic diseases, such as the inflammation of rheumatoid arthritis, and the pain associated with osteoarthritis and other musculoskeletal disorders.
When a compound of the formula I or a pharma-ceutically acceptable salt thereof is to be used as either an analgesic agent or an anti-inflammatory agent, it can be administered to a mammalian subject either alone, or, preferably, in combination with pharmaceutically-acceptable carriers or diluents in a pharmaceutical composition, according to standard pharmaceutical practice. A compound can be administered .

1~8~556 orally or parenterally. Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous and topical administration.
In a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically-acceptable salt thereof, the weight ratio of carrier to active ingredient will normally be in the range from 1:4 to 4:1, and preferably 1:2 to 2:1. However, $n any given case, the.ratio chosen will depend on such factors as the solubility of the active component, the dosage contemplated and the precise route of administration.
For oral use of a compound of formula I of this $nvention, the compound can be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents are lactose and dried corn starch.
When aqueous suspensions are required for oral use, the active ingredient is co~bined with emulsifiying and suspending agents. If desired, certain sweetening and/or flavoring agents can be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic.
When a compound of formula I or salt thereof is used in a human subject, the daily dosage will normally be determined by the prescribing physician. Moreover, 1~89556 the dosage will vary according to the age, weight and response of the individual patient, as well as the severity of the patient's symptoms and the potency of the particular compound being administered. However, for acute administration to relieve pain, an effective analgesic response eliciting dose in most instances will be 0.1 to 1.0 g as needed (e.g., every four to six hours). For chronic administration to alleviate (treat) inflammation and pain, in most instances an effective dose will be from 0.5 to 3.0 g per day, and preferably 0.5 to 1.5 g per day, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
The following examples and preparations are being provided solely for the purpose of further illustration.

1~8955~ --N-Benzoyl-3-~2-furoyl)-2-oxindolc-1-carboxamide =~
A mixture of 909 mg ~4.0 mmole) of 3-(2-furoyl)-2-oxindole and 706 mg (4.8 mmole) of benzoyl iso-! cyanate in 25 ml of toluene was heated to reflux and then it was heated at reflux temperature for 7 hours.
The mixture was allowed to stand at room temperature overnight and then the precipitate which had formed wa~ removed by filtration, giving 1.3 g of crude product. The crude product was recrystallized from ca 30 ml of acetic acid, giving 920 mg of the title compound, mp 184C (dec).
Analvsis: Calcd. for C21H14O5N2: C, 67.37; H, 3.77;
N, 7.49~. Found- C, 66.90; H, 4.02; N, 7.38%.

1;~895~6 N-Benzoyl-3-(2-furoyl)-2-oxindole-1-carboxamide To 30 ml of N,N-dimethylformamide was added, with stirring, 2.8 g (10 mmole) of N-benzoyl-2-oxindole-l-carboxamide, followed by 2.9 g 124 mmole) of 4-(N,N-dimethylamino)pyridine. The mixture was cooled in an ~ce-bath and then to it was added, dropwise, with stirring, during 10 minutes, a solution of 1.6 g (12 mmole) of 2-furoyl chloride in 10 ml of N,N-dimethylformamide. Stirring was continued for 30 minutes and then the reaction mixture was poured into a mixture prepared from 250 ml of water and 8.5 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice-bath and the solid was removed by filtration. The solid was recrystallized from ca. 75 ml of acetic acid to give 2.94 g of the title compound as yellow-brown crystals, mp 190C.
The ultraviolet spectrum of the title compound ~howed absorptions as follows:

SolventWavelenqth Epsilon (nanometers) C~30H 245 6,920 375 2,530 CH OH + 1 drop 249 7,200 0.~N NaOH 372 2,710 C~ OH ~ 1 drop 241 9,070 0.~N HCl N-~enzoyl-3-acetyl-2-oxindole-l-carboxamide To a stirred slurry of 841 mg (3.0 mmole) of N-benzoyl-2-oxindole-1-carboxamide in 5 ml of N,N-dimethylformamide was added 806 mg (6.6 mmole) of 4-(N,N-dimethylamino)pyridine. Stirring was continued for a few minutes, and then the slurry was cooled in an ice-bath and a solution of 337 mg ~3.3 mmole) of acetic anhydride in 2 ml of N,N-dimethylformamide was added dropwise. Stirring was continued for 1 hour, and then the reaction mixture was poured onto a mixture of 65-70 ml. of ice-water and 2.2 ml of 3N
hydrochloric acid. The solid which precipitated was lS recovered by filtration. It was recrystallized from cthanol to give 385 mg of the title compound as tan crystals, mp 198C.

Analysis Calcd. for C18H14O4N2:
C, 67.07; H, 4.38; N, 8.69%.
- 20 Found: C, 66.78; H, 4.65; N, 8.62%.

N-Benzoyl-3-l2-thenoyl)-2-oxindole-1-carboxamide To a stirred solution of 486 mg ~2.0 mmole) of 3-~2-thenoyl)-2-oxindole and 445 mg (4.4 mmole) of triethylamine in 5 ml of dimethyl sulfoxide was added 324 mg (2.2 mmole) of benzoyl isocyanate. Stirring wa~ continued for 1 hour, and then the mixture was poured into a mixture of 50 ml of water and 1.7 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice-bath and the solid was removed by filtration. The solid was recrystallized from ca. 30 ml of 2:1 ethanol:water to give 190 mg of the title compound as fluffy, yellow crystals, mp 165-166C.
(dec).
AnalYsi5: Calcd. for C21H1404N2S c~ 64-60; H~
3.615 N, 7.18~. Found: C, 64.53; H, 3.75; N, 7.10~.

Reaction of the appropriate N-substituted-2-oxindole-l-carboxamide with the requisite acid chloride of the formula Rl-CO-Cl, substantially according to the procedure of Example 2, afforded the following compounds:

X ~-Rl O=C-NH-ICl-R2 o _ ._ O
_ ~ ~ U~ ~ ~ _ t` ~ U~ ~
Z . ...
I~
1: Il'~~ _ ~N ~I` ~~:1 0 1`~
~ ~` O~ ~ ~~O ~ ~ ~ CO 0 0 ~3: ~
~ ~ ~ o ~ _ I~
Uu~ ~ o r oa~
.U7 _ ~1 ~ ~ u~ a~ co1~r~ ~u~ o o _ o~ ~ ~ O ~ I` U
~¢ Z . . . . . . . . . -~1 _ ~ O Q~r Oa~ O ~ ~ D
1~ ~ocn ~ o ~ ~ o _:~ . . . . .
~ ~ ~ r~
O
n~ O1'1 O ~rt O ~ I~ O ~ ~
U
C~
~ _ ~ o ~ r o ~ cn C ~ O
_ ~ o ~ C ~ _ O o 1~ W ~D O 1'~ 0 ~ ~ 1 O ~ O ~ O ~ O--1 0 _ O _~
. C: C C C C ~1 ~
2: C~ U X U X U X U X U X U X
S C S S S ~ ~
.p~ t) s u s u s u s u s u s _ ~ _ ~1 _I ~1 _ :b C ~ c ~c ~ C
0~C ~ _~ C

~~ S >~)~ ''I S ~ ~ S ~ S :~
,C J~ C :1 C ~ S :~ S J~ S :~ S ~ S
N --6 ~ ~`1 --E ~`1~ --E ~ ~ E
X ~ U C~
u~

1;~8~55~S

I` o co ~ u~
0~ ~D ~ O O 11-1 N C~
Z . - - - - - - ~U
I~
C ~ u~ C
O ~ ~ o o ~ ~ O
O-~ 11'1 ~r ~ ~ ~ ~eo o ~ o~
~ ~ O
11~ ~ o ~ o E
_l ~ O
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N-Benzoyl-3-(2-thenoyl)-2-oxindole-1-carboxamide was also prepared by reaction of 3-(2-ther.oyl)-2-oxindole with benzoyl i~ocyanate u~ing the method of Example 1.
N-Ben.zoyl-3-(2-12-thienyl]acetyl)-2-oxindole-1-carboxamide was prepared by reaction of 3-(2-[2-thienyl]acetyl)-2-oxindole with benzoyl isocyanate u~ing the method of Example 1.

Following the method of Example 1 (Method A), Example 2 or 3 (Method B), or Example 4 IMethod C), the following compounds were made:

X ~-Rl N

o-C-NH--C--R2 . ~
1~89556 Method Melting 1 2 of Prepl Poin~
X R R aration ~C) H methyl phenyl A,B 198-200d H isopropylphenyl ~ 165d - ~ cyclohexylphenyl B 181d S~5-Cl methyl phenyl B 215-217d ~S-Cl isopropyl phenyl B 185.5-187.5d 5-Cl cyclohexylphenyl B 192-194d H phenoxymethyl phenyl A 202d H 3-furyl phenyl C 187d ; S-Cl cyclopropyl phenyl B 213-215d H cyclopropyl phenyl B 173d i~opropyl phenyl B 165d H l-phenylethyl phenyl B 173d 5-Cl benzyl phenyl B 239-240d lS 5-CH3 2-furyl phenyl B 204-205d (3-thienyl)-methyl phenyl B 195-lg7d 6-C1 2-thienylphenyl 8 192-193d 6-F 2-furyl phenyl B 189-190 6-F 2-thienylphenyl B 190-194 20 S-Cl S-ethyl-2-furyl phenyl B 202-203.5d H S-ethyl-2-furyl phenyl B 174-175 5-F 2-furyl phenyl B 172d 5-F (2-thienyl)-methyl phenyl B 189d '6-C1 2-furyl phenyl B 199-200 5-F (2-thienyl)-methyl phenyl B 167d ~-Cl (2-thienyl)-methyl phenyl B 199-200d ~89556 Method Melting , of Prep- Poin~
X R' . . R2 arationl (C)' H 2-thienyl 4-fluoro- C 163.5-phenyl 164.5d 2-furyl 4-fluoro- C 164.Sd phenyl H . methyl 4-fluoro- A 205-207d phenyl ~ benzyl 4-fluoro- ~ 207-209d phenyl H cyclopropyl 4-fluoro- B 167.5d phenyl (2-thienyl)- 4-fluoro-methyl phenyl A 216-217d 5-CH3 2-thienyl 4-fluoro- B 178-179d phenyl S-Cl 2-furyl 4-fluoro- B 197-199d phenyl 10S-CH3 2-furyl 4-fluoro- B 179-181d phenyl 5-C1 2-thienyl 4-fluoro- B 191.5-phenyl 192.5d H 12-thienyl)- 4-methoxy-methyl phe4yl A 197-198d - ~ 2-thienyl 4-methoxy- B 173d phenyl 2-furyl 4-methoxy- B 146d phenyl H cyclopropyl 4-methoxy- B 193d phenyl H isopropyl 4-methoxy- B 125d phenyl 2-furyl 4-chloro- B 180-181d phenyl H 2-thienyl 4-chloro- B 170-17ld phenyl H isopropyl 4-chloro- B 164-165d phenyl H propyl 4-chloro- B 184-185d 2-thienyl 2-methyl- B 173.5d phenyl 1~8~5~ --Method Melting 1 2 of Prepl Poin~
X R R aration (C) H 2-furyl 2-methyl- B 167-168d phenyl R (2-thienyl)- 2-methyl-methyl phenyl B 179.5d ~ cyclopropyl cyclohexyl B 153-154d H methyl cyclohexyl B 167-168d l-phenylethyl cyclohexyl B l9ld H 5-methyl-2-furyl cyclohexyl B 163-165d S-Cl S-methyl-2-furyl cyclohexyl B 197.Sd 5-Cl methyl cyclohexyl B 214.Sd S-Cl propyl cyclohexyl B 162-163d 5-Cl isopropyl cyclohexyl B 205-206d S-CH3 2-furyl cyclohexyl B 170-171 S-CH3 2-thienyl cyclohexyl B 153-154.Sd H 5-ethyl-2-. furyl cyclohexyl B 146-147 lS S-CH3 S-ethyl-2-furyl cyclohexyl B 190-191 5-C~3 (2-th~enyl)-- methyl cyclohexyl B 158-lS9 5-Cl S-ethyl-2-furyl cyclohexyl B 210-211d 6-C1 2-furyl cyclohexyl B 183-184 S-F 2-furyl cyclohexyl B 186.5-187.Sd S-F 2-thienyl cyclohexyl B 145 5-S-F (2-thienyl)-methyl cyclohexyl B 164-165 ' -29- .

Method Melting 1 ~of Prep- Poin~
X R R~arationl ~C)~
6-C1 2-thienyl cyclohexyl B 172-173 6-Cl (2-thienyl)-methyl cyclohexyl B 173-175d 4-C1 2-thienyl cyclohexyl B 189-190 S 4-Cl t2-th$enyl)-methyl cyclohexyl B 172-173 4-Cl methyl cyclohexyl B 131-132 S-CF3 2-fUrYl cyclohexyl B 194-195d 5-CF3 2-thienyl cyclohexyl B 171-172d 6-F 2-furyl cyclohexyl B 164-166 6-F 2-thienyl cyclohexyl B
5-C~3 2-thienyl t-butyl B 189.5d S-CH3 Methyl t-butyl B 194d S-Cl methyl t-butyl B 211.5d S-CH S-ethyl-2-3 furyl t-butyl B 214-215 5-C1 5-ethyl-2-furyl t-butyl 8 224-225 5-F 2-furyl t-butyl B 212.5d S-F 2-thienyl t-butyl B 183.Sd - S-F l2-thienyl)-methyl t-butyl B 161d 6-C1 2-thienyl t-butyl B 191-192 S-C~3 2-thienyl isopropyl B 146-147d 5-C~3 2-furYl isopropyl B 166-167d 5-CH3 phenoxymethyl isopropyl B 184-186 5-Cl phenoxymethyl isopropyl B 186-188d S-Cl benzyl isopropyl B 184-185 5-Cl cyclohexyl isopropyl B 206-208d 5-CH 5-methyl-2-3 furyl isopropyl B 194d 5-C~3 methyl isopropyl B 158-159 Method Melting 1 2 of Prep- Poin~
X R R arationl (C) 5-C1 5-methyl-2- isopropyl B 198.5-furyl 199.5 5-Cl methyl isopropyl B 215-216 ~ methyl isopropyl B 170-172 h cyclohexyl isopropyl B 188-189 8 benzyl isopropyl B 145-146 B phenoxymethyl isopropyl B 157-158 S-Cl 5-ethyl-2-furyl isopropyl 8 20g-211d 5-Cl isopropyl isopropyl B 142-143 6-C1 2-furyl isopropyl B 184-185d 6-Cl. 2-thienyl isopropyl B 174.5-175 6-Cl (2-thienyl)-methyl isopropyl B 157-158d 8 2-thienyl phenoxy- B 161-162 methyl S-Cl 2-thienyl phenoxy- B 182-183 . methyl 8 2-furyl phenoxy- ~ 173-175d methyl B 12-thienyl)- phenoxy-_ methyl methyl B 193-194 S-Cl 2-furyl phenoxy- B 194-195.5 methyl lThe letter A in this column indicates that the compound was p~epared substantially according to Example 1~ the letter B indicates that the compound wa~ prepared substantially according to Example 2 or 3; and the letter C indicates that the compound was prepared substant$ally according to Example 4.
2The letter "d" indicates that the compound melted with decomposition.

Ethanolamine Salt of N-Benzoyl-3-(2-furoyl)-_ _ __ 2-oxindole-1-carboxamide To a slurry of 562 mg (1.5 mmole) of N-benzoyl-3-(2-furoyl)-2-oxindole-1-carboxamide in 10 ml of methanol was added 101 mg (1.65 mmole) of ethanolamine.
The re~ulting mixture was heated to boiling for a few minutes and then it was allowed to cool. The solid which precipitated was reco~ered by f~ltration to give 524 mg of the title salt, mp 165-166C. Yield:
80%.
AnalYsis: Calcd. for C23H21O6N3: C, 63.44; H, 4.86;
N, 9.65%. Found: C, 63.27; H~ 4.95; N, 9.58%.

The diethanolamine salt of N-benzoyl-3-(2~
furoyl)-2-oxindole-1-carboxamide was prepared by substituting diethanolamine for ethanolamine in the procedure of Example 8 . The product melted at 157-158C. Yield: 74%.
AnalYsis: Calcd. for C25H25O7N3: C, 62.62; H, 5.26;
N, 8.76%. Found: C, 62.53; H, 5.31; N, 8.74%.

The triethanolamine salt of N-benzoyl-3-(2-furoyl)-2-oxindole-1-carboxamide was prepared by substituting triethanolamine for ethanolamine in the procedure of Example 8 . The product melted at 154-155C. Yield: 60%.
AnalYsis: Calcd. for C27H29O8N3: C, 61.94; H, 5.58;
N, 8.03~. Found: C, 61.84; H, 5.61; N, 7.99%.

1;~89556 N-8enzoyl-2-oxindole-1-carboxamide . . .
To a stirred slurry of 399 mg (3.0 mmole) of 2-oxindole in 7 ml of toluene was added 485 mg l3.3 mmole) of benzoyl ~socyanate. The mixture was heated under reflux for 2.2 hours and then lt was cooled to room temperature. The 501 id was recovered by fil-tration and it was then dissolved in ca. 10 ml of hot acetonitrile. ~he acetonitrile solution was decolorized using activated carbon and then allowed to cool and the precipitate was recovered by filtration. Recrystal-lization of the precipitate from acetonitrile gave 131 mg of the title compound, mp 183.5-184.5C.
Anal~sis: Calcd. for C16H12O3N2:
N, 9.99~. Found: C, 68.37; H, 4.58; N, 10.16%.

1~89556 .. -33-Reaction of the appropriate 2-oxindole with the requi~ite acyl isocyanate, substantially according to the procedure of Example 11, afforded the following compounds:
' X~

O~C--NH--IC-R2 2 Melting 1 X R Point(0C) Yield~%) S-Clphenyl 193-195 43 5-CH3phenyl 202-203 68 6-Clphenyl 206-207 59 6-F phenyl 174-175.5 5-F phenyl 187d 37 H 4-fluorophenyl 177-178d 21 __ S-C~3 4-fluorophenyl 209-211d 78 5-C1 4-fluorophenyl 198-199d 59 R 4-methoxyphenyl 180d 72 H 4-chlorophenyl 186.5-187.5d 53 R 2-methylphenyl 166.5-167.5 59 H cyclohexyl 144.5-145.5 62 5-Cl cyclohexyl 172-174 63 5-CH3 cyclohexyl 140-141.~ 68 6-Cl cyclohexyl 181-182 56 5-F cyclohexyl 163.5-164.5 63 ; ~

1~89556 ' -34-Melting X R2 Point(0C)1 Yield(%~
4-Cl cyclohexyl 173-174 69 5-CF3 cyclohexyl 177.5-178.5d 40 6-F cyclohexyl 203-206 43 S H t-butyl 151-152 35 S-CH3 t-butyl 202.Sd 34 5-Cl t-butyl 176.5-177.5d 43 5-F t-butyl 161.5-162.5d 31 6-Cl t-butyl 146-147 42 ~ isopropyl 114-llS 23 S-CH3 isopropyl 169-171 38 5-Cl isopropyl 164-165 77 6-Cl isopropyl 128-129 69 H phenoxymethyl 187-188 78 5-Cl phenoxymethyl 218-219 51 . ..
lThe letter ~d~ in this column indicates that the material melted with decomposition.

1~8~55~

3-(2-Furoyl)-2-oxindole To a stirred solution of 5.5 9 (0.24 moleJ of sodium in 150 ml of ethanol was added 13.3 9 (0.10 mole) of 2-oxindole at room temperature. The resulting slurry was cooled to ice-bath temperature, and then 15.7 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 ~olid was collected by filtration. The solid residue was recrystallized from 150 ml of acetic acid, affording 8.3 9 of yellow crystal~, mp 209-210C.
(dec).
Analvsis: Calcd. for C13~9O3N: C, 68.72; ~, 3.99;
N, 6.17%. Found: C, 68.25; ~, 4.05; N, 6.20%.

Reaction of 2-oxindole with the appropriate acid chloride, using the method of Preparation 1, gave the following additional products:
3-(2-thenoyl)-2-oxindole, mp 189-190C, 17%
yield;
3-(2-[2-thienyl]acetyl)-2-oxindole, mp 191-192.5C, 38% yield;
3-(2-phenoxyacetyl)-2-oxindole, mp ~35-136C, 42% yield; and 5-chloro-3-(2-12-thienyl]acetyl)-2-oxindole, mp 228-230C., 22% yield.

3-(3-Furovl)-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-furoate. 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 185-186C.
Analvsis: Calcd. for Cl3HgO3N: C, 68.72: H, 3.99;
N, 6.17%. Found: C, 68.72; H, 4.14; N, 6.14%.

Reaction of the appropriate 2-oxindole with the ethyl ester of the requisite carboxylic acid, ~ub-stantially according to the procedure of Preparation 3, gave the following compounds:
5-chloro-3-(2-thenoyl)-2-oxindole, mp 190.5-192C., 36% yield;
5-chloro-3-(2-furoyl)-2-oxindole, mp 234-235C., 54% yield;
5-chloro-3-(2-phenylacetyl)-2-oxindole, mp 241-243C., 61% yield;

8~55~ _ -36a-PREPARATION 3A (Cont.) S-fluoro-3-(2-furoyl)-2-oxindole, mp 222-224C., 51% yield;
5-fluoro-3-(2-thenoyl)-2-oxindole, mp 200-203C., 26% yield;
6-fluoro-3-(2-furoyl)-2-oxindole, mp 239-242C., 26~ yield; and 6-chloro-5-fluoro-3-(2-thenoyl)-2-oxindole, mp 212-215C., 20~ yield.

5-Chloro-2-oxindole To a stirred slurry of 100 g ~0.55 mol) of 5-chloroisatin in 930 ml of ethanol was added 40 ml (0.826 molJ of hydrazine hydrate, resulting in a red solution. The solution was heated under reflux for 3.5 hours, during which time a precipitate appeared.
The reaction mixture was stirred overnight, and then the precipitate was recovered by filtration to give 5-chloro-3-hydrazono-2-oxindole as a yellow solid, ; ~
~ 395S6 PREPARATION 4 (Cont. ?
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 hydro-chloric 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 to give 48.9 g of the title compound, mp 193-195C. (dec).
In an analogous fashion, 5-methylisatin was converted into 5-methyl-2-oxindole by treatment with hydrazine hydrate followed sodium ethoxide in ethanol.
The product melted at 173-174C.

4,5-Dimethyl-2-oxindole and 5,6-dimethvl-2-oxindole 3,4-Dimethylaniline was converted into 3,4-di-methyl-isonitrosoacetanilide by reaction with chloral hydrate and hydroxylamine, using the method described in ~Organic Syntheses," Collective Volume I, page 327. The 3,4-dimethyl-isonitrosoacetanilide was cyclized with sulfuric acid, according to the method of Baker et al., Journal of Orqanic Chemistry, 17, 149 (1952), to give 4,5-dimethylisatin (m.p. 225-226 C.) and 5,6-dimethylisatin (m.p. 217-218 C.).

~ 95S6 PREPARATION 5 (Cont.) 4,5-Dimethylisatin was converted into 4,5-dimethyl-2-oxindole, m.p. 245.5-247.5 C., by treatment with hydrazine hydrate, followed by sodium ethoxide in ethanol, substantially according to the procedure of Preparation 4.
In like manner, 5,6-dimethylisatin was converted into 5,6-dimethyl-2-oxindole, m.p. 196.5-198 C., by treatment with hydrazine hydrate, followed by sodium ethoxide in ethanol, substantially according to the procedure of Preparation 4.

4-Chloro-2-oxindole and 6-chloro-2-oxindole A. 3-Chloro-isonitrosoacetanilide To a stirred solution of 113.23 g (0.686 mol) of chloral hydrate in 2 liters of water was added 419 g (2.95 mol) of sodium sulfate, followed by a solution prepared from 89.25 g (0.70 mol) of 3-chloroaniline, 62 ml of concentrated hydrochloric acid and 500 ml of water. A thick precipitate formed. To the reaction mixture was then added, with stirring, a solution of 155 g (2.23 mol) of hydroxylamine in 500 ml of water.
Stirring was continued and the reaction mixture was warmed slowly and it was maintained between 60 and 75C. for approximately 6 hours, during which time an additional 1 liter of water had been added to facili-tate stirring. The reaction mixture was then cooled and the precipitate was recovered by filtration. The wet solid was dried to give 136.1 g of 3-chloro-isonitrosoacetanilide.

1~955~

PREPARATION 6 (Cont.) B. 4-Chloroisatin and 6-chloroisatin To 775 ml of concentrated sulfuric acid, preheated to 70C., was added, with stirring, 136 g of 3-chloro-isonitrosoacetanilide at such a rate as to maintain the reaction medium at a temperature between 75 and 85C. When all the solid had been added, the reaction mixture was heated at 90C. for an additional 30 m$nutes. The reaction mixture wa~ then cooled, and poured slowly onto ca 2 liters of ice, with stirring.
Additional ice was added as necessary to maintain the temperature below room temperature. A red-orange precipitate formed which was recovered by filtration, washed with water and dried. The resultant solid was slurried in 2 liters of water, and then it was brought into solution by the addition of ca 700 ml of 3N
sodium hydroxide. The solution was filtered, and then pH was adjusted to 8 with concentrated hydrochloric acid. At this point, 120 ml of a mixture of 80 parts water and 20 parts concentrated hydrochloric acid was added. The solid which precipitated was recovered by filtration, washed with water and dried to give 50 g of crude 4-chloroisatin. The filtrate from which the 4-chloroisatin had been recovered was further acidified to pH 0 using concentrated hydrochloric acid, whereupon a further prec$pitate formed. It was recovered by filtration, washed with water and dried, to give 43 g of crude 6-chloroisatin.
The crude 4-chloroisatin was recrystallized from acetic acid to give 43.3 g of material melting at 258-259 C .
The crude 6-chloroisatin was recrystallized from acetic acid to give 36.2 g of material melting at 261-262C.

PREPARATION 6 (Cont.) C. 4-Chloro-2-oxindole To a stirred slurry of 43.3 g of 4-chloroisatin in 350 ml of ethanol was added 17.3 ml of hydrazine S hydrate, and then the reaction mixture was heated under reflux for 2 hours. The reaction mixture was cooled, and the precipitate was recovered by filtration to give 43.5 g of 4-chloro-3-hydrazono-2-oxindole, mp 235-236C.
To a stirred solution of 22 g of sodium in 450 ml of anhydrous ethanol was added, portionwise, 43.5 g of 4-chloro-3-hydrazono-2-oxindole, and the resulting solution was heated under reflux for 30 minutes.
The cooled ~olution was then concentrated to a gum, lS which was dissolved in 400 ml of water and decolorized using activated carbon. The resulting solution was poured onto a mixture of 1 liter of water and 45 ml of concentrated hydrochloric acid. The precipitate which formed was recovered by filtration, dried and recrystal-lized from ethanol, giving 22.4 g of 4-chloro-2-oxindole, mp 216-218C (dec).
D. 6-Chloro-2-oxindole Reaction of 36.2 g of 6-chloroisatin with hydrazine hydrate followed by sodium ethoxide in ethanol, sub-stantially according to C above, afforded 14.2 g of 6-chloro-2-oxindole, mp 196-198C.

1~8~556 ! 41 5,6-Difluoro-2-oxindole Reaction of 3,4-difluoroaniline with chloral hydrate and hydroxylamine followed cyclization with sulfuric acid, in a manner analogous to Parts A and B
of Preparation 6, gave 5,6-difluoroisatin, which was reacted with hydrazine hydrate followed by sodium methoxide in ethanol, in a manner analogous to Preparation 4, to give the title compound, m.p. 187-190C.

5-Fluoro-2-oxindole To a stirred solution of 11.1 g (0.1 mol) of 4-fluoroaniline in 200 ml of dichloromethane, at -60 to lS -65C, was added, dropwise, a solution of 10.8 g (0.1 mol) of t-butyl hypochlorite in 25 ml of dichloro-methane. Stirring was continued for 10 minutes at -60 to -65C, and t~len was added, dropwise, a solution of 13.4 g (0.1 mol) of ethyl 2-(methylth~o)acetate in 25 ml of dichloromethane. Stirring was continued at -60C. for 1 hour and then was added, dropwise, at - -60 to -65C, 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 mixture had warmed to room temperature, lC0 ml of water was added. The phases were separated, and the organic phase was washed with saturated sodium chloride solution, dried (Na2SO4) 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 PREPARATION 8 (Cont.) with water, followed saturated sodium chloride. The dried (Na2S041 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 recrystal-lized form ethanol, to give 5.58 g of 5-fluoro-3-methylthio-2-oxindole, mp 151.5-152.5C.
Analysis: Calcd for CgH80NFS C, 54.80; ~, 4.09; N, 7.10~. Found: C, 54.74; H, 4.11; N, 7.11%.
A sample of the above 5-fluoro-3-methylthio-2-oxindole (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 hour~. 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 dichloro-methane solution was dried (Na2so4) and evaporated in vacuo to give 475 mg of 5-fluoro-2-oxindole, mp 121-1~4C.
In analogous fashion, 4-trifluoromethylaniline - was reacted with t-butyl hypochlorite, ethyl 2-(methyl-thio)acetate and triethylamine followed by reduction of the 3-thiomethyl-5-trifluoromethyl-2-oxindole thus obtained with Raney nickel, to give 5-trifluoromethyl-2-oxindole, mp 189.5-190.5C.

5-Methoxv-2-oxindole 5-Methoxy-2-oxindole was prepared from 4-methoxy-aniline in a manner similar to the procedure of Preparation 8, except that the initial chlorination step was carried out using a solution of chlorine gas in dichloromethane in place of t-butyl hypochlorite.
The title product melted at 150.5-151.5 C.

1~8~556 6-Chloro-5-fluoro-2-oxindole To 130 ml of toluene was added, with stirring, 24.0 g (0.165 mole) of 3-chloro-4-fluoroaniline and 13.5 ml ~0.166 mole) of pyridine. The resulting solution was cooled to ca 0C. 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 lN hydrochloric acid, followed by 100 ml of ~aturated 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 N-(2-chloroacetyl)-3-chloro-4-fluoroaniline.
lS A 26.63-g sample of the N-(2-chloroacetyl)-3-chloro-4-fluoroaniline was thoroughly mixed with 64 g of anhydrous aluminum chloride, and the mixture was heated at 210-230C. for 8.5 hours. The reaction mixture was then poured onto a mixture of ice and lN
hydrochloric acid, with stirring. Stirring was continued for 30 minutes, and then the solid was collected by filtration (22.0 g). The solid was dissolved in 1:1 ethyl acetate-hexane and chroma-tographed 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-4-fluoroaniline, followed by 3.0 g of 6-chloro-5-fluoro-2-oxindole. The latter material was recrystallized from toluene to give 1.70 g (7~ yield) of the title compound, mp 196-206C. 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.

3955~

6-Fluoro-5-methvl-2-oxindole An intimate mixture of 11.62 g (57.6 mmol) of N-~2-chloroacetyl)-3-fluoro-4-methylaniline and 30.6 g ~229.5 mmol) of anhydrous aluminum chloride was heated to 210-220C. After 4 hours, the reaction mixture was cooled and then added to 100 ml of lN hydrochloric acid and 50 ml of ice. A tan solid formed, which was collected by filtration and recrystallized from agueous ethanol. Three crops were obtained, weighing 4.49 g, 2.28 g and 1.0 g, respectively. The crop weighing 1.0 g was further recrystallized from water to give 280 mg of the title compound, mp 168.5-171C.

lS 6-Bromo-2-oxindole To 9.4 g of sodium hydr$de was added 195 ml of dimethyl sulfoxide, followed b~ the dropwi~e addition of 22.37 ml of dimethyl malonate. At the end of the addition, the mixture was heated to 100 C. and main-tained at that temperature for 40 minutes. At thispoint, 25 g of 1,4-dibromo-2-nitrobenzene was added all at once. The reaction mixture was maintained at 100 C. for 4 hours and then it was added to 1.0 liter of ~aturated ammonium chloride solution. The resulting mixture was extracted with ethyl acetate and the extracts were washed with ammonium chloride solution, water and saturated sodium chloride. The dried (MgSO4) solution was evaporated, and the residue was recrystal-lized from ethyl acetate-hexane to give 22.45 g of dimethyl 2-(4-bromo-2-nitrophenyl)malonate.
A solution of 17.4 g of dimethyl 2-(4-bromo-2-nitrophenyl)malonate and 4.6 g of lithium chloride in 150 ml of dimethyl sulfoxide was placed in an oil bath at 100 C. After 3 hours, the reactlon mixture was ~ ~8~55fi PREPARATION 12 (Contd) cooled to room temperature and then it was poured into a mixture of 500 ml of ethyl acetate and 500 ml of saturated sodium chloride solution. The layers were separated and the aqueous layer was extra~ted with further ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried using sodium sulfate, and then evaporated in vacuo.
The residue was chromatographed using silica gel as adsorbant and ethyl acetate-hexane mixture as eluant.
This afforded 9.4 g of methyl 2-14-bromo-2-nitrophenyl)-acetate.
To a solution of 7.4 g of methyl 2-(4-bromo-2-nitrophenyl)acetate in 75 ml of acetic acid was added 6.1 g of iron powder. The reaction mixture was placed in an oil bath at 100 C. After 1 hour, the solvent was removed by evaporation in vacuo, and the ~esidue was dissolved in 250 ml of ethyl acetate. The solution was filtered, washed with saturated sodium chloride solution, dried using sodium sulfate, decolorized using activated carbon, and evaporated in vacuo. This afforded 5.3 g of 6-bromo-2-oxindole as a white crystalline solid, m.p. 213-214 C.
In like manner, starting with 1,4,5-trichloro-2-nitrobenzene, 5,6-dichloro-2-oxindole was prepared, m.p. 209-210 C.

~ c ~9556 PF~EPARATION 1 3 6-PhenYl-2-oxindole To 3.46 g. (0.072 mole) of sodium hydride was added 50 ml. of dimethyl sulfoxide followed by the dropwise addition of a solution of 8.2 ml. (0.072 mole) of dimethyl malonate in 10 ml. of dimethyl sulfoxide, with stirring. After completion of the addition, stirring was continued for 1 hour, and then a solution of 10 g. (0.036 mole) of 4-bromo-3-nitro-diphenyl in 50 ml. of dimethyl sulfoxide was added.
The reaction mixture was heated to 100C. for 1 hour, cooled, and poured onto a mixture of ice-water containing 5 g. of ammonium chloride. The mixture thus obtained was extracted with ethyl acetate, and the extracts were washed with sodium chloride solution and dried using magnesium sulfate. Evaporation in vacuo to give an oil, which was chromatographed using ~ilica gel and then recrystallized from methanol to afford 6 g. of dimethyl 2-(3-nitro-4-diphenylyl)-malonate, m.p. 82-83C.
A portion (5 g.) of the above nitro compound was - reduced with hydrogen over a platinum catalyst, in a mixture of 50 ml. of tetrahydrofuran and 10 ml. of methanol, at a pressure of ca 5 kg/cm2, to give the corresponding amine. The latter compound was refluxed in ethanol for 16 hours, and then the product was recovered by solvent evaporation and recrystallized from methanol to give 1.1 g. of ethyl 6-phenyl-2-oxindole-l-carboxylate, m.p. 115-117C.
The above ethyl ester (1.0 g.) and 100 ml. of 6N
hydrochloric acid was heated under reflux for 3 hour~
and then allowed to stand at room temperature for 3 S5~i PREPARATION 13 (Cont.) days. The solid was collected by filtration and dried, to give 700 mg. of 6-phenyl-2-oxindole, m.p.
175-176C.

PREPARA~ION 14 S-Acetvl-2-oxindole To 95 ml. of carbon disulfide was added 27 g.
~0.202 mole) of aluminum chloride, followed by the dropwise addition of a solution of 3 ml. (0.042 mole) of acetyl chloride in 5 ml. of carbon disulfide, with stirring. Stirring was continued for 5 minutes and then ~.4 g. (0.03; mole) of 2-oxindole was added. The resulting mixture was heated under reflux for 4 hours and cooled. The carbon disulfide was removed by decantation and the residue was triturated under water and recovered by filtration. After drying, 3.2 g. of the title compound was obtained, m.p. 225-227C.
Reaction of 2-oxindole with benzoyl chloride and with 2-thenoyl chloride in the presence of aluminum chloride, substantially according to the above ~ procedure, afforded the following compounds:
5-benzoyl-2-oxindole, m.p. 203-205C. (from CH30H) and 5 (2-thenoyl)-2-oxindole, m.p. 211-213C. ~from CH3CN).

~ ~8'~55~

P~EPARATION 15 S-Bromo-2-oxindole, 5-nitro-2-oxindole and 5-amino-2-oxindole can be prepared as described in Beckett et al., Tetrahedron, 24, 6093 (1968). 5-S Amino-2-oxindole can be acylated to give 5-alkanamido-2-oxindole and 5-benzamido-2-oxindole, using standard procedures.
5-n-Butyl-2-oxindole can be prepared by reaction of 5-n-butylisatin with hydrazine hydrate followed by sodium methoxide in ethanol, according to the procedure of Preparation 4. 5-n-Butylisatin can be prepared from 4-n-butylaniline by treatment with chloral hydrate and hydroxylamine, followed by cyclization with sulfuric acld, according to the procedure of Parts A and B of Preparation 6.
5~Ethoxy-2-oxindole can be prepared by conversion of 3-hydroxy-6-nitro-toluene into 3-ethoxy-6-nitro-toluene by standard methods (potassium carbonate and ethyl iodide in acetone), followed by conversion of the 3-ethoxy-6-nitrotoluene into 5-ethoxy-2-oxindole by the method described by Beckett et al., (Tetrahedron, 24, 6093 [1968]), for the conversion of 3-methoxy-6-nitro-toluene intG 5-methoxy-2-oxindole. 5-n-Butoxy-2-oxindole can be prepared in like manner, but substituting n-butyl iodide for ethyl iodide.
5,6-Dimethoxy-2-oxindole can be prepared by the method of Walker, Journal of the American Chemical Soc~etY, 77, 3844 (1955).
7-Chloro-2-oxindole can be prepared by the method described in United States Patent No. 3,882,236.
4-Thiomethyl-2-oxindole and 6-thiomethyl-2-oxindole can be prepared by the method described in United States Patent No. 4,006,161. S-n-Butylthio-2-oxindole can be prepared in like manner, but substituting 4-butylthioaniline for the 3-methylthioaniline.

1i~89556 .

PREPARATION 15 (Cont.) 5,6-Methylenedioxy-2-oxindole can be prepared by the method of McEvoy et al., Journal of Orqanic Chemistrv, 38, 3350 (1973). 5,6-Ethylenedioxy-2-oxindole can be prepared in analogous fashion.
6-Fluoro-2-oxindole can be prepared according to Protiva et al., Collection of Czechoslovakian Chemical Communications, _ , 2108 (1979) and United States Patent No. 4,160,032.
6-~rifluoromethyl-2-oxindole can be prepared according to Simet, Journal of Orqanic Chemi~trv, 28, 3580 (1963).
6-Methoxy-2-oxindole can be prepared according to Wieland et al., Chemische Berichte, 96, 253 (1963).
5-Cyclopropyl-2-oxindole and 5-cycloheptyl-2-oxindole can be prepared by reaction of 5-cyclo-propylisatin and 5-cycloheptylisatin, respectively, with hydrazine hydrate followed by sodium methoxide in ethanol, according to the procedure of Preparation 4. 5-Cyclopropylisatin and 5-cycloheptylisatin can be prepared from 4-cyclopropylaniline and 4-cyclo-heptylaniline, respectively, by treatment wlth - chloral hydrate and hydroxylamine, followed by cyclization with sulfuric acid, according to Parts A
and B of Preparation 6.

Claims

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

1. A compound of the formula and the base salts thereof; wherein X is hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbons, alkoxy having 1 to 4 carbons, alkylthio having 1 to 4 carbons, trifluoromethyl, alkylsulfinyl having 1 to 4 carbons, alkylsulfonyl having 1 to 4 carbons, nitro, phenyl, alkanoyl having 2 to 4 carbons, benzoyl, thenoyl, alkanamido having 2 to 4 carbons, benzamido or N,N-dialkylsulfamoyl having 1 to 3 carbons in each of said alkyls; and Y is hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbons, alkoxy having 1 to 4 carbons, alkylthio having 1 to 4 carbons or trifluoro-methyl;
or X and Y when taken together are a 4,5-, 5,6-or 6,7-methylenedloxy group or a 4,5-, 5,6- or 6,7-ethylenedioxy group;
or X and Y when taken together and when attached to adjacent carbon atoms, form a divalent radical Z, wherein Z is selected from , , and wherein W is oxygen or sulfur;
and R2 in alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, phenoxymethyl, furyl, thienyl, pyridyl or wherein R3 and R4 are each hydrogen, fluoro, chloro, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons or trifluoromethyl.

2. A compound of the formula and the base salts thereof, wherein X is hydrogen, 5-fluoro or 5-chloro; Y is hydrogen, 6-fluoro or 6-chloro; and R1 is benzyl, furyl, thienyl or thienyl-methyl; provided that when X and Y are both hydrogen, R1 is not benzyl.
3. The compound according to claim 2, wherein X is 5-chloro, Y is hydrogen and R1 is 2-thienyl.

4. A process for preparing a compound of the formula or a base salt thereof, wherein X is hydrogen, 5-fluoro or 5-chloro; Y is hydrogen, 6-fluoro or 6-chloro; and R1 is benzyl, furyl, thienyl or thienyl-methyl; provided that when X and Y are both hydrogen, R1 is not benzyl;
characterized in that a compound of the formula is reacted with a derivative of an acid of the formula R1-C(=O)-OH.

5. The process according to claim 4, wherein X
is 5-chloro, Y is hydrogen and R1 is 2-thienyl.

6. A compound of the formula:

(wherein (1) R7 is hydrogen; R8 is [where R2 is alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, phenoxy-methyl, furyl, thienyl, pyridyl or (where R3 and R4 are each hydrogen, fluoro, chloro, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons or trifluoromethyl)];
[X is hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbons, alkoxy having 1 to 4 carbons, alkylthio having 1 to 4 carbons, trifluoromethyl, alkylsulfinyl having 1 to 4 carbons, alkylsulfonyl having 1 to 4 carbons, nitro, phenyl, alkanoyl having 2 to 4 carbons, benzoyl, thenoyl, alkan-amido having 2 to 4 carbons, benzamido or N,N-dialkylsulfamoyl having 1 to 3 carbons in each of said alkyls; and Y is hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbons, alkoxy having 1 to 4 carbons, alkylthio having 1 to 4 carbons or trifluoromethyl;
or X and Y when taken together are a 4,5-, 5,6- or 6,7-methylenedioxy group or a 4,5-, 5,6- or 6,7-ethylenedioxy group;
or X and Y when taken together and when attached to adjacent carbon atoms, form a divalent radical Z, wherein Z is selected from , , and wherein W is oxygen or sulfur]; or (2) R7 is -?-R1; R8 is hydrogen; [X is hydrogen, 5-fluoro or 5-chloro; Y is hydrogen, 6-fluoro or 6-chloro; and R1 is benzyl, furyl, thienyl or thienylmethyl; provided that when X and Y
are both hydrogen, R1 is not benzyl] and the base salts thereof.

7. The compound according to claim 1, wherein X and Y
are each hydrogen.

8. The compound according to claim 1, wherein X is 5-chloro and Y is hydrogen.

9. The compound according to claim 1 or 7, wherein R2 is phenyl.

10. The compound according to claim 1 or 8, wherein R2 is cyclohexyl.

11. The compound according to claim 2, wherein X and Y
are each hydrogen.

12. The compound according to claim 2, wherein X is 5-chloro and Y is hydrogen.

13. The compound according to claim 2 or 11, wherein R1 is 2-furyl, 2-thienyl or (2-thienyl)methyl.

14. The compound according to claim 12, wherein R1 is 2-furyl, 2-thienyl or (2-thienyl)methyl.