DD232265A5 - PROCESS FOR THE PREPARATION OF 2-OXINDOL-1-CARBOXAMIDES AND INTERMEDIATE DAFUER - Google Patents

Abstract

The preparation of 2-oxindole-1-carboxamides by reacting 2-oxindoles with chlorosulfonyl isocyanate to give new N-chlorosulfonyl-2-oxindole-1-carboxamides which then become 2-oxindole-1-carboxamides, useful as intermediates for analgesic and antiperspirant Agent, be hydrolyzed.

Description

Process for the preparation of 2-oxindole-1-carboxamides and

Intermediates for that

Field of application of the invention

This invention relates to a process for the preparation of 2-oxindole-1-carboxamides which comprises reacting a 2-oxindole with chlorosulfonyl isocyanate to produce a novel N-chlorosulfonyl-2-oxindole-1-carboxamide, which is then converted to a 2-oxindole 1-carboxamide is hydrolyzed. The 2-oxindole-1-carboxamides are useful as intermediates for analgesic and anti-inflammatory agents.

Characteristic of the known technical solutions

The reactions of chlorosulfonyl isocyanate with various nucleophiles, including amines for the preparation of its N-chlorosulfonylamido (ClSO ₉ NHCO) derivatives and the following

The hydrolysis of the derivatives to amides is described by Graf, Angew. Chem. Boarding school. Edit. ] _, 175 (1968); Rasmussen et al., Cherrf. Rev. 389-390 (1976) and Szabo, Aldrichimica Acta j_0, 23 (1977).

The preparation of 2-oxindole-1-carboxamides by cyclization of the appropriate (2-ureidophenyl) acetic acid by means of e.g. Trifluoroacetic anhydride / trifluoroacetic acid is described in co-pending US patent application DPC (Ph) 6795A to Saul B. Kadin entitled 3-substituted 2-oxindole-1-carboxamides as analgesic and antiinflammatory agents.

Aim and presentation of the essence of the invention

The process of the present invention provides an improved process for preparing 2-0-oxindole-1-carboxamides of the formula ITI in good yield and purity from readily available starting materials.

This invention provides a convenient method of preparing 2-oxindole T-carboxamides by reacting a 2-oxindole with chlorosulfonyl isocyanate to produce a new intermediate, N-chlorosulfonyl-2-oxindole-i-carboxamide which is then converted to a 2-oxindole 1-carboxamide is hydrolyzed. The process, the intermediate and the end products are shown below:

ClSQ ₂ NCO

..I Il

hydrolysis

III

1 1

wherein R is hydrogen or -CO-R, wherein R is as defined below, and

X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbons, cycloalkyl of 3 to 7 carbons, alkoxy of 1 to 4 carbons, alkylthio of 1 to 4 carbons, trifluoromethyl, alkylsulfinyl of 1 to 4 carbons, alkylsulfonyl of 1 to 4 carbons, nitro, phenyl, alkanoyl of 2 to 4 carbons, benzoyl, thenoyl, alkanamido of 2 to 4 carbons, benzamido and Ν, Ν-dialkylsulfamoyl of 1 to 3 carbons in each of the alkyls; and Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbons, cycloalkyl of 3 to 7 carbons, alkoxy of 1 to 4 carbons, alkylthio of 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 carbons form a bivalent radical Z wherein Z is selected from the group consisting of

and

where W is oxygen or sulfur.

Compounds of the formula III in which R is hydrogen are valuable intermediates for the preparation of analgesic and antiinflammatory compounds of the formula IV

O = C-NH.

wherein X and Y are as defined above; and

R is selected from the group consisting of alkyl of 1 to 6 carbons, cycloalkyl of 3 to 7 carbons, cycloalkenyl of 4 to 7 carbons, phenyl, substituted phenyl, phenylalkyl of 1 to 3 carbons in the alkyl, (substituted phenyl) alkyl having 1 to 3 carbons in the alkyl, phenoxyalkyl having 1 to 3 carbons

in the alkyl, (substituted phenoxy) alkyl having 1 to 3 carbon atoms in the alkyl, (thiophenoxy) alkyl having 1 to 3 carbon atoms in the alkyl, naphthyl, bicyclo / 2 .2.1 / heptan-2-yl, bicyclo / 2.2.1 / -hept-5-en-2-yl and - (CH ₂ ) _n ~ Q ~ ^R ° ''

wherein the substituent on the substituted phenyl, on the (substituted phenyl) alkyl and on the (substituted phenoxy) alkyl is selected from the group consisting of fluorine, chlorine, bromine, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 Carbons and trifluoromethyl; η is zero, 1 or 2; Q is a divalent radical derived from a compound selected from the group consisting of furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1, 3,4-thiadiazole , 1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo / b / furan and benzo / b / thiophene; and R ° is hydrogen or alkyl of 1 to 3 carbons.

Preferred compounds of formula IV are those wherein (i) one of X and Y is hydrogen and the other is 5- or 6-chloro, fluoro or trifluoromethyl; or (ii) X is 5-chloro or 5-fluoro and Y is 6-chloro or 6-fluoro. The compounds show a higher level of analgesic and anti-inflammatory activity than other compounds of formula IV.

Thus, the method of the invention is useful for the preparation of analgesic and anti-inflammatory compounds of formula IV wherein X, Y and R are as previously defined. These compounds are derivatives of 2-oxindole, remote bicyclic amide of the formula

More specifically, the analgesic and anti-inflammatory agents have a carboxamide substituent, -C (= O) -NH _? , in the 1-position and an acyl substituent, -C (= O) -R, in the 3-position of the 2-oxindole, and the benzo ring may be further substituted by X and Y groups. X and Y may be certain monovalent substituents as previously defined, or X and Y, when on adjacent carbon atoms on the benzo ring, may represent a methylenedioxy group, -OCH ₂ O-, or an ethylenedioxy group, -OCH ₂ CH ₂ O-. Still further, when X and Y are attached to adjacent carbon atoms of the benzo ring of the 2-0-oxindole, they can form a divalent unit Z such that when Z is taken together with the carbon atoms to which it is attached, it forms a fused carbocyclic or heterocyclic ring , Certain divalent groups for Z (ie Z-Z) have been listed earlier. So when ZZ is X and Y, when combined with the carbons to which they are attached mean

taken, a condensed cyclopentene ring, and

when Z is Z, X and Y, when taken together with the carbons to which they are attached, represent a fused furan or thiophene ring. It is further understood that

4 p

if Z is Z or Z, the group Z can be appended in one of two possible ways. Thus, for example, when X and Y are C-5 and C-6 and Z is the formula IV both of the following formulas

CR ^J

and

The compounds of formula III are prepared from the appropriate 2-oxindoles of formula I according to the two-step sequence shown above. The required 2-oxindoles (R = H) are prepared by methods known to those skilled in the art. The following references describe the preparation of various 2-oxindoles: "The Chemistry of Heterocyclic Compounds", Indoles, Part 2, Editor Houlihan, Wiley-Interscience, NY, pp. 142-143 (1973); Rodd's Chemistry of Carbon Compounds, 2nd edition, S. Coffey; Vol. IV-A, Elsevier Scientific Publishing Company, pp. 448-450 (1973); Walker, J. Am. Chem. Soc. Jl ' 3844-3850 (1955); Wright et al., J. Am. Chem. Soc. 7_8 '221-224 (1956); McEvoy et al., J. Org. Chem. 38 , 3350 (1973); Gassman et al., J. Org. Chem. 4j2, 1340 (1977); Beckett et al., Tetrahedron 2_4, 6093 (1968); Protiva et al., Coll. Czech. Chem. Comm. _4_4, 2108 (1979); and U.S. Patent 3,882,236; 4,006,161 and 4,160,032. In addition, preparations of representative substituted 2-oxindoles are presented herein.

The starting materials of formula I, wherein R is -CO-R, wherein R is as defined above, are prepared by acylating the appropriate compound of formula I, wherein R is hydrogen, by methods known to those skilled in the art. For example, the acyl radical -CO-R is prepared by reacting a compound of formula I with an activated derivative of the appropriate acid of the formula R -C (= O) -OH in a lower alkanol solvent (eg, ethanol) in the presence of an alkali metal salt of the lower alkanol Solvent (eg, sodium ethylate) according to standard procedures. Typical derivatives of the acid of the formula R -C (= O) OH which may be used include acid chlorides, acid anhydrides of the formula R -C (= O) -O-C (= O) -R ¹ , R ¹ -C ( = O) -OC (= O) -R ³ and R ¹ -C (= O) -O-C (= O) -OR ⁴ and simple alkyl esters of the formula R ¹ -C (= O) -O-R where R ³ one

4 is a bulky, low molecular weight alkyl group such as t-butyl, and R is a low molecular weight alkyl group. Usually, a small excess of the derivative of the acid of the formula R'-C (= O) -OH is used, and the alkoxide is usually present in an amount of from 1 to 2 molar equivalents, based on the amount of

derivative of the acid of the formula R -C (= O) OH. The reaction between the derivative of the acid of formula R -C (= O) OH and the compound of formula I wherein R is hydrogen is usually started at 0 to 25 ° C, but it is then usual to bring the reaction mixture to a temperature in the range of 50 to 130 C, preferably about 80 C, to heat to complete the reaction. Under these circumstances, reaction times of a few hours, e.g. 2 hours, up to a few days, e.g. 2 days, applied. The reaction mixture is then cooled, diluted with an excess of water and acidified. The product of formula I wherein R is -CO-R can then be recovered by filtration or by the standard procedure of solvent extraction. .

The first step of the process of the invention, the reaction of the appropriate 2-oxindole with chlorosulfonyl isocyanate, is carried out in a reaction-inert solvent medium, i. a solvent which does not react with the chlorosulfonyl isocyanate or the 2-oxindol-1-chlorosulfonylamide product of formula II. The solvent does not necessarily completely dissolve the reaction components. Representative solvents are dialkyl ethers such as diethyl ether; diisopropylether; aromatic hydrocarbons, such as benzene, xylene and toluene; chlorinated hydrocarbons, such as methylene chloride and chloroform; and acetonitrile.

The reaction is generally carried out at temperatures in the range of -20 C to the reflux temperature of the solvent used. In general, temperatures of 2 5 C to 110 ° C are favored. Temperatures as low as -70 ° C may be used if desired. However, temperatures below ⁰ C are generally avoided for practical reasons.

The 2-oxindole and chlorosulfonyl isocyanate are generally

in molar ratios ranging from equimolar up to 30% excess of chlorosulfonyl isocyanate, i. 1: 1 to 1: 1.3, implemented. Larger excesses of chlorosulfonyl isocyanate appear to be of no benefit and are not used for economic reasons.

The chlorosulfonamide derivatives of the formula II thus prepared may, if desired, be isolated or may be converted directly into the same reaction vessel without isolation to give compounds of the formula III. Isolation of the chlorosulfonamido intermediate compounds of formula II is carried out by procedures known to those skilled in the art, e.g. by filtration, evaporation of the solvent or extraction.

The second stage of the process, the hydrolysis of the Chlorsulfonamido derivatives (formula II), is carried out by treating the compounds of formula II with or without their isolation with water, aqueous acid or aqueous base. Water alone is generally favored as a hydrolyzing agent even in cases where the hydrolysis step comprises a two-phase system. The rate of hydrolysis is fast enough to overcome any solubility problems of the reaction components. Moreover, from the viewpoint of large-scale conversions, the use of water alone is more economical than the other hydrolysis methods.

The use of an aqueous inorganic or organic acid as a hydrolyzing agent sometimes overcomes the development of biphasic reaction systems. This is often the case when using aqueous acetic acid. The amount of acid is not critical for the hydrolysis step. It can range from less than equimolar amounts to more than equimolar amounts. Also not critical is the concentration of the acid used. In general, when aqueous acid is used for the hydrolysis step, about 0.1 mole of acid per mole of compound of formula II is used up to 3 moles of acid per mole of compound of formula II.

Acid concentrations of about 1 molar to 6 molar are generally used for ease of handling. Frequently, the use of aqueous acid is chosen when the intermediate of formula II is isolated and a single phase hydrolysis mixture is desired. Representative acids are hydrochloric, sulfuric, phosphoric, acetic, formic, citric and benzoic acid.

The compounds of formula IV are prepared from the appropriate 2-oxindole-1-carboxamide compound of formula III wherein R is hydrogen and X and Y are as previously defined. This is done by appending the substituent -C (= O) -R to the 3-position of the 2-oxindole nucleus. The -C (= O) -R substituent is added by reacting a compound of Formula III with an activated derivative of a carboxylic acid of the formula R -C (= O) OH. The reaction is carried out by treating the compound of formula III in an inert solvent with one molar equivalent or one small

Excess of an activated derivative of a compound of formula R -C (= O) OH in the presence of 1 to 4 equivalents of a basic agent. An inert solvent is one which dissolves at least one of the reaction components and does not detrimentally interact with any of the reactioncomponents or product in practice, but in practice a polar, aprotic solvent such as N, N-dimethylformamide, Ν, is usually used Conventional methods for activating the acid of the formula R -C (= O) OH are used, for example acid halides, eg acid chlorides, symmetrical acid anhydrides, R -C (= O) -O -C (= O) R, mixed acid anhydrides with a hindered low molecular weight

1 3 3

gular carboxylic acid, R -C (= O) -O-C (= O) -R, wherein R is a bulky lower alkyl group such as t-butyl, and mixed

1 4

Carboxylic acid-carbonic anhydrides, R -C (= O) -O-C (= O) -OR, where

Rin R is a low molecular weight alkyl group can be used. In addition, N-hydroxyimide esters (such as N-hydroxysuccinimide and N-hydroxyphthalimide esters), 4-nitrophenyl esters, thiol

ester (such as thiolphenyl ester) and 2,4,5-trichlorophenyl ester and the like. Further, in those cases where R is a heteroaryl group (e.g., furyl),

1 4 4

simple alkyl esters of the formula R -C (= O) -OR, wherein R is a low molecular weight alkyl group (eg ethyl), sometimes used as an activated derivative of the acid of the formula R -C (= O) -OH, when the -C ( = O) -R substituent at the 3-position of the 2-oxindole compound of the formula in which RH is.

A wide variety of basic agents can be used in the reaction between a compound of formula III wherein R is H "and the activated derivative of the acid of formula R -C (= O) OH. However, preferred basic agents are tertiary amines such as trimethylamine , Triethylamine, tributylamine, N-methylmorpholine, N-methylpiperidine and 4- (N, N-dimethylamino) pyridine.

The reaction between a compound of formula III wherein R is H, and the activated derivative of the acid of the formula R -C (= 0) -OHwird usually carried out in the temperature range of -10 to 25 ^0C. Reaction times from 30 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 recrystallization.

The analgesic activity of compounds of formula IV was demonstrated in mice by demonstrating blocking of the abdominal lining 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., 9_5, 729-731 (1957), adapted for high throughput (see also Milne and Twomey, Agents and Actions K), 31-37 (198O)). The mice used in these experiments were Carworth males, albino CF-1 strain, weighing 18 to 20 g. All mice were fasted overnight prior to drug administration and testing.

The compounds of formula IV were dissolved or suspended in a carrier consisting of ethanol (5%), Emulphor 620 (a mixture of polyoxyethylene fatty acid esters, 5%) and saline (90%). This carrier also served as a control. Doses were on a logarithmic scale (i.e. ... 0.32, 1.0, 3.2, 10, 32 ... mg / kg). The route of administration was oral, with concentrations varied to allow for a constant injection volume of 10 ml / kg of mouse. The aforementioned method of Milne and Twomey was used to determine potency and potency. Mice were treated orally with compounds and received PBQ, 2 mg / kg intraperitoneally one hour later. Individual mice were then immediately placed in a heated lucite chamber and, starting 5 min after PBQ administration, the number of abdominal contractions was recorded during the following 5 min. The level of analgesic protection (% MPE) was calculated based on suppression of abdominal contraction relative to counts of concurrent daytime control animal passage. At least four such determinations (N J5) yielded dose-responsive data to produce an MPE ^ Q value, the best dose detection that reduced abdominal contractions to 50% of control values.

The anti-inflammatory activity of the compounds of formula IV has been demonstrated in rats by a method based on the carrageenin-induced rat paw edema standard test (Winter et al., Proc. Soc. Exp. Biol. Med., 111, 544 (1963)). ,

Non-anesthetized adult male albino rats of 150-190 g body weight were numbered, weighed and a color mark applied to the right lateral ankle. Each paw was dipped in mercury exactly to the color mark. The mercury was contained in a glass cylinder connected to a Statham pressure transducer. The output of the transducer was fed through a control unit to a microvoltameter. The volume of the dive through the submerged

The displaced mercury was read. Drugs were given by force-feeding. One hour after drug administration, the edema was injected by injecting 0.05 ml of a 1% carrageenin solution into the plantar tissue of the labeled paw. Immediately thereafter, the volume of the injected paw was measured. The increase in foot volume 3 hours after injection of carrageenin represents the individual inflammatory response.

The analgesic activity of the compounds of formula IV makes them suitable for acute administration to mammals for the control of pain, e.g. postoperative pain and traumatic pain, useful. The anti-inflammatory activity of the compounds makes them useful for chronic administration to mammals, including humans, for the control of inflammatory diseases such as arthritis, especially rheumatoid arthritis.

When a compound of formula IV is to be used for any of these purposes, it may be administered to a mammal alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition according to standard pharmaceutical practice, oral or parenteral (including intravenous, intramuscular, intraperitoneal, subcutaneous and topically) routes are administered.

In a pharmaceutical composition containing a compound of formula IV, the weight ratio of carrier to active ingredient will normally be in the range of 1: 4 to 4: 1 and preferably 1: 2 to 2: 1. In any given case, however, the chosen ratio will depend on such factors as the solubility of the active ingredient, the dosage considered, and the exact route of administration.

For oral use, a compound of formula IV may be administered in the form of tablets or capsules or as an aqueous solution or suspension. Carriers commonly used for tablets include lactose and corn starch. Lubricants such as magnesium stearate are usually added. Useful diluents for capsule dosage forms are lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared and the pH of the solutions is adjusted and buffered appropriately. For intravenous use, the total solute concentration should be controlled so that the preparation becomes isotonic. ,

When a compound of formula IV is used in humans, the daily dosage, usually determined by the prescriber, will vary according to the age, weight and response of the individual patient, as well as the severity of the patient's symptoms. However, for acute administration for pain relief, an effective dose in most cases will be 0.1 to 1.0 g, as needed (e.g., every 4 to 6 hours). For chronic administration as an anti-inflammatory agent, in most cases an effective dose will be from 0.5 to 3.0 g / day in single or divided doses. On the other hand, it may be necessary in some cases to apply dosages outside these limits.

embodiments

The following examples and preparations are given solely for the purpose of further illustration. It was

no attempt was made to optimize the yield of the examples and preparations.

example 1

2-0xindol-1-carboxamide

Chlorosulfonyl isocyanate (1.20 g, 8.4 mmol) was added to a mixture of 2-oxindole (0.94 g, 7.1 mmol) in ether (30 ml) and the reaction stirred at room temperature for 20 h. The ether was removed in vacuo and the residue was treated with water (10 ml) and 1 N HCl (10 ml). Ethyl acetate (125 ml) was added and the mixture was stirred for 1 h. The ethyl acetate phase was separated, washed with 1N HCl (1 × 50 ml), brine (2 × 100 ml) and dried (over MgSO 4). Concentration provided 0.97 g (77%) of crude product. Recrystallization from ethanol gave 0.18 g, mp 178-18O ° C.

Example 2

2-0xindol-1-carboxamide

A mixture of 2-0xindole (5.86 g, 44.0 mmol) in toluene (160 mL) was azeotroped for 1 h to dry the toluene. Then chlorosulfonyl isocyanate (7.47 g, 52.8 mmol) was added. Hydrogen chloride was developed immediately. The mixture was stirred and refluxed for 15 minutes and then cooled to room temperature. Water (50 ml) was added to the cooled mixture (some HCl was first developed) and the mixture was stirred for 1.5 h. The solid that formed was collected by filtration and dried (4.10 g). The filtrate was extracted with ethyl acetate (100 ml), the resulting extract was washed with brine (2 × 100 ml) and dried (over MgSO 4). Evaporation of the extract under reduced pressure gave 4.16 g of solid. The combined solids were dissolved by dissolving in acetonitrile (200 mL) and concentration

the solution recrystallized under reduced pressure to about 7 5 ml. The small amount of amorphous material which separated out was filtered off, the filtrate was destained and concentrated under reduced pressure to about 50 ml volume, then inoculated. The dark red crystals that separated were filtered and dried (3.0 g, 38%). It was identical to the product of Example 1.

Example 3

2-Qxindol-1-carboxamide

To a slurry of 2-oxindole (13.3 g, 0.10 mol) in toluene (150 mL) was added chlorosulfonyl isocyanate (15.6 g, 0.11 mol) and the reaction mixture heated on a steam bath for 10 min (within about 3 minutes, a clear solution formed, almost immediately followed by the formation of a precipitate). It was then cooled in an ice bath for 30 minutes, the solid filtered off and air dried.

The chlorosulfonamido intermediate thus obtained was added to a 2: 1 mixture of acetic acid / water (240 ml) and the resulting slurry was heated on a steam bath for 10 minutes. It was cooled in an ice bath and the nearly white solid that formed filtered off and air dried. Concentration of the mother liquor to a slurry and filtration gave 1.2 g of product. The combined solids were recrystallized from about 250 ml of ethanol, yield = 11.48 g (65%). It was identical to the product of Example 1.

Example 4

6-fluoro-5-methyl-2-oxindole-1-carboxamide

Following the procedure of Example 2 /, the title compound was prepared from 6-fluoro-5-methyl-2-oxindole (1.0 g, 6.0 mmol),

Chlorosulfonyl isocyanate (1.03 g, 7.3 mmol), toluene (30 mL). Water (5 ml) was used for the hydrolysis step. Yield = 0.58 g, 46%. M.p. 2OO-2O3 ° C.

Analysis for C _in HQN ₂ O ₂ F,%

Calculated: C 57.69 H 4.36 N 13.46

Found: C 57.02 H 4.41 N 12.85

A sample of the chlorosulfonamide intermediate was removed prior to hydrolysis and subjected to mass spectrum analysis for accurate mass assays:

C ₁₀ HgN ₂ O ₄ SCI: 307.9848.

Examples 5 to 13 Substituted 2-0xindole-1-carboxamides

The following compounds were prepared according to the procedure of Example 3 from suitably substituted 2-oxindoles.

2-oxindole X Y 8th " CSI Ißsungsr Zv • Si tfischen- hydrolysis - 2-oxindole oxamld. - Ausb., Z • 1-carb product analysis C H N found H N β ml 8th Cc) ml of HOAC / H ₂ O 8th Mp CC) calculated C example

5 5-CH ₃ H 11.51 12.2 150 16 149-50 6 5-OCH I! 8.15 7.78 100 8.4 163 7 4-Cl H 5.03 4.67 85 165-6 (Zerd 8th 5-C1 H 10.0 9.3 200 15.8 9 6-Cl H 4.18 3.89 85 O 5-F H 10.0 10.3 100 16 1 5-CF ₃ H 4.4 3.4 λ 45 6.5 2 4-CH ₃ 5-CH ₃ 4.8 4.7 45 8.8 3 5-CH ₃ 6-CH 1.6 1.6 15 2.8

120/160 7,3 49 215-6

80/40 7,3 70 191-2

45/25 3,64 58 201-2 * 51,32 3,35 13,30 51,04 3,26 13,24

50/5 9.8 46.8 211. ^ ₃₂ ^ _{35 U3Q} ^ ^ ^ ^ ^ _n

41/21 4.09 78 221-2,. _{32 3} " _{13 3Q 51 0? 3 3Q 13 31}

Cf.J * * * '. '

50/100 6,7 52,3 198 ^b 55,67 3,64 14,43 56,25 3,79 14,53 20/40 3,4 63,3 214,5 ^b 49,19 2,89 11, 48 48.90 3.05 11.50

25/50 4.08 66.6 222 64.69 5.92 13.72 64.57 5.94 13.64

Ctirs)

8/17 1,3 63,7 214,5 ^C 64,69 5,92 13,72 64,52 6,67 13,68

a recrystallized from ethanol b crystallized from acetonitrile c recrystallized from acetic acid

Example 14

5,6-methylenedioxy-2-oxindole-1-carboxamide

5,6-Methylenedioxy-2-oxindole-1-carboxamide was prepared by reacting 5,6-methylenedioxy-2-oxindole with chlorosulfonyl isocyanate and subsequent hydrolysis using the procedure of Example 3. The product melted at 237-238 C (dec.) After recrystallization from acetic acid.

Example 15

By reacting the appropriate 2-oxindole with chlorosulfonyl isocyanate and subsequent hydrolysis using the procedure of Example 3, the following tricyclic compounds can be prepared:

X country Y *

4-CH ₂ -CH ₂ -CH ₂ -5 5-CH ₂ -CH ₂ -CH ₂ -6

5-CH »CH-CH = CH-6

5-O-CH ₂ -CH ₂ -6

5-CH ₂ -CH ₂ -O-6

5-S-CH ₂ -CH ₂ -6

5-0-CH = CH-6

5-S-CH "CH-6

5-CH = CH-S-6

In this column, the figure at the left of the formula indicates the point of attachment of this end of the formula with the 2-oxindole nucleus, and the number on the right indicates the point of attachment of this end of the formula with the 2-0xindole nucleus.

Example 16

6-methylthio-2-oxindole-1-carboxamide

Chlorosulfonyl-isocyanate (5.66 g, 0.04 mol) was added to a slurry of 6-methylthio-2-oxindole (6.0 g, 0.033 mol) in acetonitrile (60 ml) at 5 to 10 ⁰ C. The reaction mixture was stirred for 1 h. Water (100 ml) was then added to the mixture with good stirring for 10 min. The aqueous solution was extracted with ethyl acetate (600 ml), washed successively with water and brine, dried (over MgSO 4) and concentrated under reduced pressure to give a gray solid, which was recrystallized from acetonitrile. Yield = 3.0 g. Another 0.71 g of product was obtained from the mother liquor. Total yield = 3.71 g (50.6%), mp 176-179 ° C.

Example 17 -.

5,6-Dimethoxy-2-oxindole-1-carboxamide

Following the procedure of Example 16, the title compound was prepared from 5,6-dimethoxy-2-oxindole (8.0 g, 0.042 mol), chlorosulfonyl isocyanate (7.08 g, 0.05 mol) and acetonitrile (75 mL). The crude product obtained after evaporation of the ethyl acetate extract was recrystallized from acetonitrile / acetic acid (1: 1). Yield = 6.02 g (60%), m.p. 206.5-2O9 ° C.

Similarly, 5,6-methylenedioxy-2-oxindole-1-carboxamide is prepared from 5,6-methylenedioxy-2-oxindole.

Example 18

6-trifluorine thy 1-2 -oxindole-1-carboxamide

To a slurry of 6-trifluoromethyl-2-oxindole (8.0 g, 0.04 mol) in acetonitrile (80 mL) was added chlorosulfonyl isocyanate (6.65 g, 0.047 mol) and the mixture stirred for 45 min. Water (100 ml) was then added and the aqueous mixture was stirred for one hour. The precipitate that formed was filtered off and recrystallized from acetonitrile to give 0.92 g of the title product. Extraction of the filtration from the aqueous reaction mixture with ethyl acetate (300 ml) followed by drying of the extract over MgSO4 and then evaporation under reduced pressure gave further product. Recrystallization from acetonitrile gave further (2.2 g) product.

Additional product (1.85 g) was recovered by combining the mother liquors from the acetonitrile recrystallizations and concentrating them under reduced pressure. Total yield = 4.97 g (51%), m.p. 207.5 to 210 ° C.

Examples 19 to 24

Repeat the. Procedure of Example 18 but using the appropriately substituted 2-oxindole afforded the following compounds.

CONH.

2-oxindole X Y G CSI Solv. Interm. Hydrolyae-ϊ 2-oxindole - 1-carboxaraid product 8th Y. X Dchmp. cc) example 8th ml Schmp. (* C) Medium: Water (ml)

19 4-SCH. H 2 25 2.26 25 141.5 to 143 * 20 1.62 56 181-4 20 6-F H 1 , 06 0.99 15 158-161 · 15 1.21 94.5 191.5-194 21 6-Br H 3 75 2.97 40 232-235 · 40 2.50 58 205-8 22 5-NO ₂ H 1 Λ 1.13 30 5 0.52 38.5 201-5 23 5-F 6-Cl 1 , 59 1.42 55 ^a 20 l, 02 ^b 52 ^C 229-31 24 5-F 6-F 3 , 0 2.98 13 15 2.60 72 198-201

a used toluene as a solvent

b NMR shows that the isanere 4-chloro-5-fluoro-2-oxindole-1-carboxamide was also formed (starting material an isaneren mixture) c evaporation of the solvent toluene yielded another 0.59 g for 84% yield.

Example 25

3- (2-furoyl) -6-fluoro-2-oxindole-1-carboxamide

In substantial accordance with the procedure of Example 18, the title compound was prepared in 17% yield from 3- (2-furoyl) -6-fluoro-2-oxindole (0.30 g, 1.2 mmol), chlorosulfonyl isocyanate (0.20 g , 1.4 mmol), acetonitrile (15 ml) and water (10 ml), yield = 0.060 g, mp = 231-235 ° C.

Example 26 Substituted 2-0xindole-1-chlorosulfonamides

The procedure of Example 16 was followed using the appropriate substituted 2-oxindole as the reaction component. Before the hydrolysis step, the intermediate chlorosulfonyl derivative was recovered by filtration when a solid was present; or by evaporation from a small volume of the reaction mixture when no precipitate formed. A sample of the resulting intermediates was then subjected to more accurate mass determination.

0-C-NH-SO ₂ Cl

2-oxindole CSI _ml intermediate

Solvent formula exact mass

6-FH 1.5 1.70 15 C ₉ H ₆ N ₂ O ₄ FSCl 291 _T 9721 6-CF ₃ H 0.5 0.35 10 ^a C ₁₀ H ₆ N ₂ O ₄ F ₃ SCl 341.3693

5-F 6-Cl 1.59 1.42 55 ^a C ₉ HgN ₂ O ₄ FSCl ₂ 326.9340

5-NO ₂ H 1.75 0.35 55 ^a C ₉ H ₆ H ₃ O ₆ SCI 318.9675

6-Br H 0.40 0.31 5 ^a ^ C ₉ H ₆ N ₂ O ₄ SBrCl 351.8863

_5-OCH3 6-OCH3 _t l 0 0.85 12 C ₁₁ H _n N ₂ O ₆ SCl 344.0034

6-SCH ₃ H 0.20 0.18 3 ^a C ₁₀ H ₉ N ₂ O ₄ S ₂ Cl 319.9636

4-SCH ₃ H 0.20 0.18 3 ^a C ₁₀ H ₉ N ₂ O ₄ S ₂ Cl 319.9696

6-F 5-CH ₃ 0.16 0.14 10 ^a C ₁₀ HgN ₂ O ₄ FClS 307.9848

a = toluene used as solvent

Example 27 6-Phenyl-2-oxindole-1-carboxamide

To 4.5 g (21.5 mmol) of 6-phenyl-2-oxindole in a mixture of 100 ml of toluene and 25 ml of tetrahydrofuran was added 2.2 ml (25.8 mmol) of chlorosulfonyl isocyanate with stirring at 5 ° C. Stirring was continued for 1 h at 0 to 5 ° C and then 100 ml of water was added. The solid was collected by filtration and added to a mixture of 40 ml of glacial acetic acid and 80 ml of water. The resulting mixture was heated to 10O ⁰ C for 1 h, cooled and filtered. The residue was dried to give 3.1 g of the title compound, mp. 18 8-189 ⁰ C to give.

Example 28 5-Benzoyl-2-oxindole-1-carboxamide

A mixture of 10.1 g (42 mmol) of 5-benzoyl-2-oxindole, 4.4 ml (51 mmol) of chlorosulfonyl isocyanate and 300 ml of tetrahydrofuran

was stirred at room temperature for 6 h, and then the solvent was evaporated in vacuo. The residue was added to 150 ml of glacial acetic acid and 300 ml of water and the resulting mixture heated to reflux for 2 h. The reaction mixture was cooled and the supernatant decanted. The remaining resinous residue was triturated under acetonitrile to give a solid which was recovered by filtration and then recrystallized from a 1: 1 mixture of n-propanol and acetonitrile. This yielded 4.1 g of the title compound as a solid, mp. 210-211 ⁰ C.

Example 29

Reaction of 5-acetyl-2-oxindole and 5- (2-thenoyl) -2-oxindole with chlorosulfonyl isocyanate and subsequent hydrolysis with aqueous acetic acid, essentially following the procedure of Example 28, afforded the following compounds:

5-acetyl-2-oxindole-1-carboxamide, 34% yield, mp. 225 ⁰ C (dec.) (From CI ^ CN) or

5- (2-Thenoyl) -2-oxindole-1-carboxamide, 51% yield, mp 200 ° C (dec.) (From CH 3 OH / CH 3 CN).

Example 30

3- (2-thenoyl) -5-chloro-2-oxindole-1-carboxamide

To a stirred slurry of 1.5 g (5.4 mmol) of 3- (2-thenoyl) -5-chloro-2-oxindole in 15 mL of dry acetonitrile was added 0.52 mL (5.9 mmol) of chlorosulfonyl isocyanate, and Reaction mixture stirred for 2 h at room temperature. A small sample was taken, filtered and evaporated in vacuo to give a small sample of N-chlorosulfonyl-3- (2-thenoyl) -5-chloro-2-oxindole-1-carboxamide, mp 166-169 ° C , To the remainder of the reaction mixture, 30 ml of water were added slowly while stirring, and stirring was continued for one hour.

stir. The reaction mixture was then poured into 50 ml of 1N hydrochloric acid containing ice chips, and the resulting mixture was stirred for 20 minutes. The yellow solid was collected by filtration, washed with water and diisopropyl ether, and recrystallized from glacial acetic acid to give 200 mg of a first crop of the title compound, mp 213-215 ° C. The mother liquors from which this yield was recovered deposited another yellow solid. The latter solid was recovered by filtration to give 4,770 mg of a second crop of the title compound. The second crop was recrystallized from glacial acetic acid and combined with the first crop and recrystallized from glacial acetic acid. This yielded 280 mg of the title compound, mp. 232-234 ⁰ C.

Preparation 1 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 mol) of hydrazine hydrate, resulting in a red solution. The solution was heated at reflux for 3.5 hours to give a precipitate. The reaction mixture was stirred overnight, and then the precipitate was filtered off to give 5-chloro-3-hydrazone-2-oxindole as a yellow solid, which was dried in a vacuum oven. The dried solid weighed 105.4 g.

The dried solid was then added portionwise over 10 minutes to a solution of 12.5 g of sodium ethoxide in 900 ml of absolute ethanol. The resulting solution was heated at reflux for 10 minutes and then concentrated in vacuo to a resinous solid. The resinous solid was dissolved in 400 g of water, and the resulting aqueous solution was decolorized with charcoal and then poured into a mixture of 11 g of wasj and 180 ml of concentrated hydrochloric acid, ice chips. A yellow-brown solid separated

was collected by filtration and washed thoroughly with water. The solid was dried and then washed with diethyl ether. Finally it was recrystallized from ethanol to give 48.9 g of the title compound, mp. 19 3-195 ⁰ C (dec.) Yield.

Analogously, 5-methylisatin was converted to 5-methyl-2-oxindole by treatment with hydrazine hydrate and then with sodium ethylate in ethanol. The product melted at 173-1 "74 ⁰ C.

Production 2

4,5-dimethyl-2-oxindole and 5,6-dimethyl-2-oxindole

3,4-Dimethylaniline was converted to 3,4-dimethylisonitrosoacetanilide by reaction with chloral hydrate and hydroxylamine using the method described in "Organic Syntheses", Vol. I, p. 327. The 3,4-dimethylisonitrosoacetanilide was treated with sulfuric acid according to the method of Baker et al., Journal of Organic Chemistry YJ_, 149 (1952) to 4,5-dimethylisatin (mp 225-226 ⁰ C) and 5,6- Dimethylisatin (mp 217-218 ° C) cyclized.

4,5-Dimethylisatin was converted to 4,5-dimethyl-2-oxindole, m.p. 245.5-247.5 ° C, by treatment with hydrazine hydrate, then with sodium ethylate in ethanol, essentially according to the procedure of Preparation 1.

Similarly, 5,6-dimethylisatin was converted to 5,6'-dimethyl-2-oxindole, mp 196.5-198 ° C, by treatment with hydrazine hydrate, then with sodium ethylate in ethanol, essentially according to the procedure of Preparation 1.

Production 3

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

A. Isonitroso S-chloroacetanilide

To a stirred solution of 113.23 g (0.686 mol) chloral hydrate in 2 L water was added 419 g (2.95 mol) sodium sulfate, then a solution prepared from 89.25 g (0.70 mol) 3 Chloroaniline, 62 ml of concentrated hydrochloric acid and 500 ml of water. It formed a thick precipitate. 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 slowly warmed and maintained at between 60 and 75 ° C for about 6 hours, during which time a further liter of water was added to facilitate stirring. The reaction mixture was then cooled and the precipitate recovered by filtration. The wet solid was dried to give 136.1 g of isonitroso-3-chloroacetanilide.

4-chloroisatin and 6-chloroisatin

To 775 ml of concentrated sulfuric acid, preheated to 10 ° C, with stirring 136 g of isonitroso-S-chloroacetanilide were added at such a rate that the reaction medium was maintained at a temperature between 75 and 85 ° C. After addition of the entire solid, the reaction mixture was heated at 90 ° C. for a further 30 minutes. The reaction mixture was then cooled and poured slowly onto about 2 liters of ice with stirring. Additional ice was added, if necessary, to keep the temperature below room temperature. A red-orange precipitate formed which was collected by filtration, washed with water and dried. The resulting solid was slurried in 2 liters of water and then dissolved in water by addition of about 700 ml of 3N sodium hydroxide.

introduced. The solution was filtered, and then the pH was adjusted to 8 with concentrated hydrochloric acid. Then 120 ml of a mixture of 8O parts of water and 20 parts of concentrated hydrochloric acid were added. The solid which separated out was recovered by filtration, washed with water and dried to give 50 g of crude 4-chloroisatin. The filtrate from which the 4-chloroisatin was recovered was further acidified to pH 0 with concentrated hydrochloric acid, whereupon a further precipitate formed. It was collected 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 258-259 ° C melting material.

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

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 hydrate, and then the reaction mixture was heated at 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-hydrazone-2-oxindole, m.p. 235-236 ° C.

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-3-oxindole, and the resulting solution was heated at reflux for 30 minutes.

The cooled solution was then concentrated to a resin which

dissolved in 400 ml of water and decolorized with "activated charcoal.

The resulting solution was poured onto a mixture of 1 liter of water and 45 ml of concentrated hydrochloric acid. The low

impact that formed was recovered by filtration, dried and recrystallized from ethanol to give 22.4 g of 4-chloro-2-oxindole, mp. 216-218 showed ⁰ C (dec.).

D. 6-chloro-2-oxindole

Reacting 36.2 g of 6-chloroisatin with Hydräzinhydrat, then with sodium ethoxide in ethanol, substantially according to the above C, 14.2 g gave 6-chloro-2-oxindole, mp. 196-198 ⁰ C.

Production 4

5,6-difluoro-2-oxindole

Reaction of 3,4-difluoroaniline with chloral hydrate and hydroxylamine followed by cyclization with sulfuric acid in a manner analogous to parts A and B of Preparation 3 gave 5,6-difluoroisatin reacted with hydrazine hydrate then with sodium methylate in ethanol in a manner analogous to Preparation 1 to give the title compound, mp 187-190 ° C.

Preparation 5 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 -65 ° C was added a solution of 10.8 g (0.1 mol) of t-butyl hypochlorite in 25 ml Dropped dichloromethane. The mixture was stirred for a further 10 minutes at -60 to -65 ° C and then a solution of 13.4 g (0.1 mol) of ethyl 2- (methylthio) acetate in 25 ml of dichloromethane was added dropwise. Stirring was continued for one hour at -60 ° C and then at -60 to -65 ° C a solution of 11.1 g (0.11 mol) of triethylamine in x 25. ml of dichloromethane is added dropwise. The cooling batch was removed, and when the reaction mixture warmed to room temperature, 100 ml of water was added. The

Phases were separated and the organic phase was washed with saturated sodium chloride solution, dried over Na 2 SO /, and evaporated in vacuo. The residue was dissolved in 350 ml of diethyl ether, to which was added 40 ml of 2N hydrochloric acid. This mixture was stirred at room temperature overnight. The phases were separated and the ether phase washed with water, then with saturated sodium chloride. The ether phase (dried over Na ₂ SO ₄₎ was evaporated in vacuo to give 17 g of an orange-brown solid which was triturated under isopropyl ether The solid was then recrystallized from ethanol to give 5.58 g of 5-fluoro-3-methylthio 2-oxindole, mp 151.5-152.5 ° C.

Analysis for C ₉ HgONFS,%

Calc .: 54.80 H 4.09 N 7.10 gef. : 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 teaspoons full of Raney nickel under 50 mL absolute ethanol, and then the reaction mixture was heated at reflux for 2 h. The catalyst was removed by decantation and washed with absolute ethanol. The combined ethanol solutions were evaporated in vacuo and the residue dissolved in dichloromethane. The dichloromethane solution was dried (over Na 2 SO 3) and evaporated in vacuo to give 4 75 mg of 5-fluoro-2-oxindole, m.p. 121-134 ° C.

In an analogous manner, 4-trifluoromethylaniline was reacted with t-butyl hypochlorite, ethyl 2- (methylthio) acetate and triethylamine, followed by reduction of the thus obtained 3-thiomethyl-5-trifluoromethyl-2-oxindole with Raney nickel to give 5- Trifluoromethyl-2-oxindole, m.p. 189.5-1 90 ,,. 5. ⁰ C, to surrender.

Production 6

6-fluoro-5-methyl-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 to 22O ° C , After 4 hours, the reaction mixture was cooled and then added to 100 ml of 1N hydrochloric acid and 50 ml of ice. A tan solid formed, which was collected by filtration and recrystallized from aqueous ethanol. Three yields were obtained, 4.49 g, 2.28 g. Weighing 1.0g. The first two yields involved a mixture of isomers (4-fluoro-5-methyl- and 6-fluoro-5-methyl-2-oxindole). The yield 1.0g vast was further C to result from Wasser.umkristallisiert to 280 mg of the title compound, mp. 168.5 to 171 ^0th

Production 7

6-Pheny1-2-oxindole

To 3.46 g (0.072 mol) of sodium hydride was added 50 ml of dimethylsulfoxide, followed by dropwise addition of a solution of 8.2 ml (0.072 mol) of dimethyl malonate in 10 ml of dimethyl sulfoxide with stirring. After completion of the addition, stirring was continued for 1 h, and then a solution of 10 g (0.036 mol) of 4-bromo-3-nitrodiphenyl in 50 ml of dimethyl sulfoxide was added. The reaction mixture was heated to 100 ° C for one hour, cooled, poured onto a mixture of ice / water containing 5 g of ammonium chloride. The resulting mixture was extracted with ethyl acetate, and the extracts were washed with sodium chloride solution and dried with magnesium sulfate. Evaporation in vacuo gave an oil which was chromatographed using silica gel and then recrystallized from methanol to provide 6 g of dimethyl 2- (S-nitro-diphenyl malonate, mp 82-83 ° C.

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 about 5 bar (about 5 kg / cm ² ) to give the corresponding amine to surrender. The latter compound was refluxed in ethanol for 16 h and then the product was recovered by evaporation of the solvent and recrystallized from methanol to give 1.1 g of ethyl 6-phenyl-2-oxindole-1-carboxylate, mp 115-117 ° C, to surrender.

The above ethyl ester (1.0 g) and 100 ml of 6N hydrochloric acid were heated at reflux for 3 hours and then allowed to stand at room temperature for 3 days. The solid was collected by filtration and dried to give 700 mg of 6-phenyl-2-oxindole, m.p. 175-176 ° C.

Preparation 8 5-ACe-ty 1, 2-oxindole

To 95 ml of carbon disulfide was added 2.7 g (0.202 mol) of aluminum chloride, followed by dropwise addition of a solution of 3 ml (0.042 mol) of acetyl chloride in 5 ml of carbon disulfide with stirring. Stirring was continued for 5 minutes and then 4.4 g (0.033 mole) of 2-oxindole was added. The resulting mixture was heated at reflux for 4 hours and cooled. The carbon disulfide was removed by decantation and the residue triturated under water and recovered by filtration. After drying, 3.2 g of the title compound were obtained, mp 225-22 7 ⁰ C.

Reaction of 2-0xindole with benzoyl chloride and with 2-thenoyl chloride in the presence of aluminum chloride, essentially by the same procedure gave the following compounds: ~

5-benzoyl-2-oxindole _/ mp. 203-205 ⁰ C (from _CH3 OH) and 5- (2-thenoyl) -2-oxindole, mp. 211-213 ° C (from _CH3 CN).

Production 9

5-bromo-2-oxindole can be prepared by brominating 2-oxindole; See also Beckett et al., Tetrahedron 24, 6093 (1968) and Sumpter et al., Journal of the American Chemical Society Sl_, 1656 (1945).

5-n-Butyl-2-oxindole can be prepared by reacting 5-n-butylisatin with hydrazine hydrate, then with sodium methylate in ethanol following the procedure of Preparation 1. 5-n-butylisatin can be prepared from 4-n-butylaniline by treatment with chloral hydrate and hydroxylamine, then by cyclization with sulfuric acid following the procedure of Part A and B of Preparation 3.

5-Ethoxy-2-oxindole can be prepared by converting 3-hydroxy-6-nitro-toluene into 3-ethoxy-6-nitrotoluene by standard methods (potassium carbonate and ethyl iodide in acetone), followed by conversion of 3-ethoxy-6-nitrotoluene in 5-ethoxy-2-oxindole according to the method described by Becket et al., Tetrahedron 24_, 6093 (1968), for the conversion of 3-methoxy-6-nitrotoluene in 5-methoxy-2-oxindole. 5-n-butoxy-2-oxindole can be prepared similarly, but substituting n-butyl iodide for the ethyl iodide.

5,6-dimethoxy-2-oxindole can be prepared by the method of Walker, Journal of the American Chemical Society, Jl., 3844 (1955).

7-Chloro-2-oxindole can be prepared by the method described in U.S. Patent 3,882,236.

4-Thiomethyl-2-oxindole and 6-thiomethyl-2-oxindole can be prepared by the method described in US Pat. No. 4,006,161. 5-n-butylthio-2-oxindole can be prepared similarly but replacing 3-methylthioaniline with 4-butylthioaniline.

5,6-Methylenedioxy-2-oxindole can be prepared by the method of McEvoy et al., Journal of Organic Chemistry 38. ' 3350 (1973). 5,6-ethylenedioxy-2-oxindole can be prepared in an analogous manner.

6-Fluoro-2-oxindole can be prepared according to Protiva et al., Collection of Czechoslovakian Chemical Communications 4_4_, 2108 (1979) and U.S. Patent 4,160,032.

6-trifluoromethyl-2-oxindole can be prepared according to Simet, Journal of Organic Chemistry, 28, 3580 (1963).

6-Methoxy-2-oxindole can be prepared according to Wieland et al., Chemische Berichte 9j5, 253 (1963).

5-nitro-2-oxindole can be prepared by the method of Sumpter et al., Journal of American Chemical Society 6J, 499 (1945).

5-Cyclopropyl-2-oxindole and 5-cycloheptyl-2-oxindole can be prepared by reacting 5-cyclopropylisatin or 5-cycloheptylisatin with hydrazine hydrate, then with sodium methylate in ethanol according to the procedure of Preparation 1. 5-Cyclopropylisotene and 5-cycloheptylisatin can be prepared from 4-cyclopropylaniline and 4-cycloheptylaniline, respectively, by treatment with chloral hydrate and hydroxylamine, followed by cyclization with sulfuric acid, according to part A and B of preparation 3.

Preparation 10 5-Amino-2-oxindole-1-carboxamide

To a solution of 5.0 g of 5-nitro-2-oxindole-1-carboxamide in 110 ml of Ν, Ν-dimethylformamide was added 0.5 g of 10% Pd / C, and the resulting mixture was added under an atmosphere of hydrogen an initial pressure of 5 bar (5 kg / cm ² ) shaken until the hydrogen uptake ceased. The catalyst was filtered off and the filtrate was diluted with brine and extracted with ethyl acetate. The extracts were dried (over MgSO 4) and evaporated in vacuo to a dark colored oil which solidified after trituration under water. This yielded 3.0 g of the title compound as a yellow solid, mp. 189-191 ⁰ C.

Production 11

3- (2-furoyl) -2-oxindole

To a stirred solution of 5.5 g (0.24 mol) of sodium in 150 ml of ethanol was added 13.3 g (0.10 mol) of 2-oxindole at room temperature. The resulting slurry was cooled to ice-bath temperature, and then 15.7 g (0.12 mol) of 2-furoyl chloride was added dropwise over a period of -10 to 15 minutes. The ice-bath was removed and an additional 100 ml of ethanol was added and then the reaction mixture was heated to 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 with concentrated hydrochloric acid. The mixture was cooled with ice and the solid collected by filtration. The solid residue was recrystallized from 150 ml of acetic acid to give 8.3 g of yellow crystals, mp. 209-21O ⁰ C (dec.) Afforded.

Analysis for C ₁₃ H ₉ O ₃ N,%

C 68.72 H 3.99 N 6.17 Found: C 68.25 H 4.05 N 6.20

Reaction of 2-oxindole with the appropriate acid chloride by the above method gave the following further products:

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

3- (2- / 2-thienyl / acetyl) -2-oxindole, mp. 191 to 192.5 ⁰ C, 38% yield, and

3- {2-phenoxyacetyl) -2-oxindole, m.p. 135-136 ° C, 42% yield.

Production 12

3- (3-furoyl) -2-oxindole

To a stirred solution of -2.8 g (0.12 mol) of sodium in 200 ml of ethanol was added 13.3 g (0.10 mol) of 2-0xindole then 16.8 g of ethyl 3-furoate. The mixture was heated at reflux for 47 h, cooled and then the solvent was removed by evaporation in vacuo. The residue was triturated under 200 ml of ether and the solid collected by filtration and discarded. The filtrate was evaporated in vacuo and the residue triturated under isopropyl alcohol 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, then from acetonitrile to give 705 mg of the title compound, mp. 185-186 ⁰ C.

analysis For ^C 13 H _g C 3 N,% N 6 / 1 7 About: C 68, 72 H 4 / 99 N 6 / 1 4 gef. : C 68, 72 H / 14

Production 13 !

5-chloro-3- (thenoyl) -2-oxindole-I-carboxamide

A stirred solution of 21.1 g (0.1 mol) of 5-chloro-2-oxindole-1-carboxamide and 26.9 g (0.22 mol) of 4- (N, N-dimethylamino) -pyridine in 200 ml Ν, Ν-Dimethylformamide was cooled to ice-bath temperature and then a solution of 16.1 x g (0.11 mol) of 2-thenoyl chloride in 50 ml of Ν, Ν-dimethylformamide was added dropwise. The mixture was stirred for about 30 minutes, and then the reaction mixture was poured into a mixture of 1 1 of water and 75 ml of 3 η hydrochloric acid. The resulting mixture was cooled in an ice bath and then the solid was collected by filtration. The solid was recrystallized from 1800 ml of acetic acid to give 2.6 g of the title compound as a pale yellow crystals, m.p. 23O ° C (dec.).

A sample of the title compound from a similar experiment gave the following results in the elemental analysis.

Analysis for C ₁₄ H ₉ ClN ₂ O ₃ S,%

About: C 52 42 H 2 , 83 N 8th , 74 Found .: C 52 22 H 2 , 81 N 8th , 53

Production 14

Reacting the appropriate 2-0xindole-1-carboxamide with the necessary acid chloride

1 of the formula R -CO-Cl essentially according to the procedure of preparation

provided the following connections:

0-C-NH

R ¹ 2- feryl Mp. I 55 C analysis N found(%) H N I 2- (2-thienyl) methyl CC) ¹ ' ² 53 , 18 calculated(%) 9.20 C 3.09 9.32 X 2-furyl 234d 55 , 81 H 8.37 55.06 3.31 8.37 5-Cl 2-iThienyl 24Od ³ 52 19 2.98 9.19 53.40 2.90 9.23 5-Cl 2- (2-thienyl) methyl 218-219 53 , 44 3.31 8.74 54.89 3.03 8.61 6-Cl 201-202 , 83 2.98 8 _t 37 51.86 3.45 8.38 6-Cl 219-220 2.83 53.70 6-Cl 3.31

R ¹ 2-Euryl Production 1 58 4 (continued) C 3 H Analysis i) 57 found(%) 3 H N I 2-thienyl Mp 1 2 55 calculated (ι _r 34 2 15 N 55 C 3 13 9.70 X 2- (2-thienyl) methyl 56 25 3 , 98 9.72 56 99 3 00 9.28 5-F 2-furyl 232d 58 , 59 3 48 9.21 57 t <9 3 48 8.81 5-F 2-thienyl 231d 55 , 33 2 13 8.80 55 , 76 2 , 04 9.72 5-F 2- (2-thienyl) methyl 243d 56 , 26 3 96 9.75 55 , 73 3 91 9.15 6-F 2-furyl 230.5-233.5 53 , 61 2 48 9.21 52 , 14 2 , 52 8.65 6-F 2-thienyl 117.5-120.5 50 , 26 2 , 68 8.80 50 97 2 > 6 8.17 6-F 2- (2-thienyl) roethyl 214.5-217 52 85 3 , 56 8.28 51 , 84 3 72 7.90 5-CFG 2-furyl 235.5d 53 17 2 , 01 7.91 52 , 43 3 , 37 7.45 5-CFG 2-thienyl 212.5d 50 , 26 2 , 68 7.61 50 72 2 , 03 8.27 5-CFG 223.5d , 86 , 56 8.28 , 87 75 7.96 6-CFG 206-208 7.91 , 69 6-CF ₃ 177-180

All compounds were recrystallized from acetic acid unless otherwise specified. The letter "d" in this column indicates that the compound melted under decomposition. Recrystallized from N, N-dimethylformamide.

Production 15

5-chloro-3-acety1-2-oxindole-1-carboxamide

A stirred slurry of 842 mg (4.0 mmol) of 5-chloro-2-oxindole-1-carboxamide and 1.08 g (8.8 mmol) of 4- (N, N-dimethylamino) pyridine in 15 ml of Ν, Ν Dimethylformamide was cooled to ice-bath temperature and then a solution of 449 mg (4.4 mmol) acetic anhydride in 5 ml N, N-dimethylformamide was added dropwise. Stirring was continued for about 30 minutes and then the reaction mixture became Mixture of 75 ml of water and 3 ml of 3 η hydrochloric acid poured. The resulting mixture was cooled in an ice bath and the solid recovered by filtration. The solid was recrystallized from acetic acid dissolved 600 mg, pale pink crystals, mp. 237.5 ⁰ C (dec.) Yield.

Analysis. For C ₁₁ H ₉ ClN ₂ O ₃ ,%

Calc .: C 52.29 H 3.59 N 11.09 Found: C 52.08 H 3.63 N 11.04

Claims (10)

invention claim 1. A process for the preparation of a compound of the formula -R wherein X is hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbons, cycloalkyl of 3 to 7 carbons, alkoxy of 1 to 4 carbons, alkylthio of 1 to 4 carbons, trifluoromethyl, alkylsulfinyl of 1 to 4 carbons, Alkylsulfonyl of 1 to 4 carbons, nitro, phenyl, alkanoyl of 2 to 4 carbons, benzoyl, thenoyl, alkanamido of 2 to 4 carbons, benzamido or N, N-dialkylsulfamoyl of 1 to 3 carbons in each of the alkyls; and Y is hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbons, cycloalkyl of 3 to 7 carbons, alkoxy of up to 4 carbons, alkylthio of 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 taken together and pendant from adjacent carbon atoms form a bivalent radical Z wherein Z is selected from and where W is oxygen or sulfur; R is H or -COR in which R is alkyl of 1 to 6 carbons, cycloalkyl of 3 to 7 carbons, cycloalkenyl of 4 to 7 carbons, phenyl, substituted phenyl, phenylalkyl of 1 to 3 carbons in the alkyl, (substituted phenyDalkyl of 1 to 3 carbons in the alkyl, Phenoxyalkyl having 1 to 3 carbons in the alkyl, (substituted phenoxy) alkyl having 1 to 3 carbons in the alkyl, (thiophenoxy) alkyl having 1 to 3 carbons in the alkyl, naphthyl, bicyclo / 2.2.1 / heptan-2-yl, Bicyclo / 2.2. Λ J- hept-5-en-2-yl or - (CH ₂ ) _n -QR °; - 3 wherein the substituent on the substituted phenyl, the (substituted phenyl) alkyl and the (substituted phenoxy) alkyl include fluoro, bromo, chloro, alkyl of 1 to 4 carbons, alkoxy with Is 1 to 4 carbons or trifluoromethyl, η is zero, 1 or 2, Q is a divalent radical derived from a compound selected from furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1 , 2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo / b / furan and benzo / b / -thiophene, and R ° is hydrogen or alkyl of 1 to 3 carbons; characterized in that a compound of the formula is hydrolyzed. 2. The method according to item 1, characterized in that X and Y are each hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, alkylthio of 1 to 4 carbons, nitro or trifluoromethyl, or X and Y taken together are a 4,5-, 5,6- or 6,7-methylenedioxy group and R is H or -COR wherein R is alkyl of 1 to 6 carbons, cycloalkyl of 3 to 7 carbons, phenyl, substituted phenyl, phenylalkyl of 1 to 3 carbons in alkyl, phenoxyalkyl of 1 to 3 carbons in alkyl, (substituted phenoxy) alkyl of 1 to 3 carbons in the alkyl, furyl, thienyl, Alkylfuryl having 1 to 3 carbons in the alkyl, alkylthienyl having 1 to 3 carbons in the alkyl, furylalkyl having 1 to 3 carbons in the alkyl, thienylalkyl having 1 to 3 carbons in the alkyl or bicyclo / 2.2.Vheptan-2-yl, wherein the substituent on the substituted phenyl group and on the substituted phenoxy group is selected from the group consisting of fluoro, chloro, bromo, alkyl of 1 to 4 carbons and alkoxy of 1 to 4 carbons. 3. The method according to item 1 or 2, characterized in that the hydrolysis is carried out practically alone with water. 4. The method according to item 1 or item 2, characterized in that the 'hydrolysis is carried out using an aqueous inorganic or organic acid. 5. The method according to item 4, characterized in that the inorganic or organic acid is selected from hydrochloric, sulfuric, phosphoric, acetic, formic, citric and benzoic acid. 6. The method according to item 4 or item 5, characterized in that the inorganic or organic acid is used in a concentration in the range of 1 molar to 6 molar. A process according to any one of items 1 to 6, characterized in that X is hydrogen, 5-chloro, 5-fluoro or 5-trifluoromethyl, Y is hydrogen, 6-chloro, 6-fluoro or 6-trifluoromethyl and R is hydrogen. 8. The method according to item 7, characterized in that X is 5-chloro and Y is hydrogen. -HB - 9. A process as claimed in any one of items 1 to 6, characterized in that X is hydrogen, 5-chloro, 5-fluoro or 5-trifluoromethyl, Y is hydrogen, 6-chloro, 6-fluoro or 6-trifluoromethyl and R is CO-R wherein R is benzyl, '2-furyl, 2-thienyl, (2-furyl) methyl or (2-thienyl) methyl. 10. The method according to item 9, characterized in that X is 5-chloro, Y is hydrogen and R 2-thienyl.