JPH0342270B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to N-chlorosulfonyl-2-oxindole-1-carboxamide compounds.
More specifically, the present invention relates to a novel N-chlorosulfonyl-2-oxindole-1-carboxamide produced by reacting 2-oxindole with chlorosulfonyl isocyanate. The 2-oxindole-1-carboxamide is useful as an intermediate for analgesic and anti-inflammatory agents. BACKGROUND OF THE INVENTION The reaction of chlorosulfonyl isocyanate with various nucleophiles, including amines, produces N-chlorosulfonylamide (ClSO ₂ NHCO) derivatives, which are then hydrolyzed to form amides, as shown in the graph. (Graf.) by Angew.Chem.
Internat.Edit., 7, 175 (1968), Chem.Rev. by Rassmussen et al., 389-390
(1976) and by Szabo.
Aldrichimica Acta, 10 , 23 (1977). For example, the appropriate (2-ureidophenyl) using trifluoroacetic anhydride/trifluoroacetic acid
The production of 2-oxindole-1-carboxamide by cyclization of acetic acid is called “3-Substituted 2-
Oxindole−1−carboxamidesas Analgestic
and Anti-inflammatory Agents” in co-filed U.S. Patent Application DPC(Ph) 6795A to Saul B. Kadin.Problem Solved by the InventionThe invention is readily available. N-chlorosulfonyl-2 obtained in good yield and high purity from the starting material
-oxindole-1-carboxamide. Means for Solving the Problem The present invention provides a new intermediate N-chlorosulfonyl-2-oxindole-1-carboxyamide obtained by reacting 2-oxindole with chlorosulfonyl isocyanate. The method for producing the above intermediate (), its intermediate () and the final product () are shown below. (In the formula, X is hydrogen, halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or
4 alkylthio, trifluoromethyl, or nitro, and Y is hydrogen, halogen, or has 1 or more carbon atoms.
4 alkyl, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, or trifluoromethyl; R is hydrogen or -CO-R ¹ and R ¹ is thienyl. R is hydrogen) is the formula are useful intermediates for the preparation of analgesic and anti-inflammatory compounds of the formula (where R', have (i) One of X and Y is hydrogen and the other is 5- or 6-chloro, fluoro or trifluoromethane. or (ii) X is 5-chloro or 5-
fluoro, and Y is 6-chloro or 6-fluoro. Said compound exhibits higher levels of analgesic anti-inflammatory activity than other compounds of said formula. As described above, the compounds of the present invention are among the intermediates useful in the preparation of analgesic anti-inflammatory compounds of the formula, where X, Y and R ¹ are as previously defined. These compounds are 2-oxindole derivatives, i.e. bicyclic amides of the formula: Compounds of formula are prepared from the appropriate 2-oxindole of formula by the two steps described above. The required 2-oxindole (R=H) is prepared by methods known to those skilled in the art. The following documents contain various 2
- describes the production of oxindole. Edited by Houihan, “The Chemistry of
“Heterocyclic Compounds”, Indoles, Part 2,
Wiley-Interscence, NYpp.142-143, (1973),
Edited by S. Coffey, “Rodd’s Chemistry”
of Carbon Compounds”, 2nd edition, Volume-A,
Elsevier Scientific Publishing Company,
pp.448-450, (1973), Walker,
J.Am.Chem.Soc., 77 , 3844-3850 (1955), Wright et al., J.Am.Chem.Soc., 78 , 221-
224 (1956), Mc Evoy et al., J.Org.
Chem., 38 , 3350 (1973), Gassman
et al., J.Org.Chem., 42 , 1340 (1977), Beckett et al., Tetrahedron, 24 , 6093 (1968),
Protiva et al., Coll.Czech, Chem.
Comm., 44, 2108 (1979) and U.S. Pat.
Nos. 3882236, 4006161 and 4160032. Furthermore,
The preparation of a representative 2-oxindole is shown here. Starting materials of the formula in which R is -CO-R ¹ with R ¹ as defined above may be acylated by methods known to those skilled in the art from suitable compounds of the formula in which R is hydrogen. Manufactured by. For example, the acyl moiety -CO-R ¹ is converted into a compound of the formula R ¹ - in a lower alkanal solvent (e.g. ethanol) in the presence of an alkali metal salt of a lower alkanal (e.g. sodium ethoxide) according to a conventional method. C(=
Coupling is carried out by reaction with an activated derivative of the appropriate acid of O)--OH. Formulas that can be used R ¹ −
Typical derivatives of C(=O)OH acids include acid chlorides, formulas R ¹ -C(=O)-R ¹ , R ¹ -C(=O)-O-C(=
O) ^-R3 , and ^R1 -C(=O)-O-C(=O)-
Anhydrides of R ⁴ and simple alkyl esters of the formula R ¹ -C(=O)-OR ⁴ where R ³ is a bulky low molecular weight alkyl group such as t-butyl;
R ⁴ is a low molecular weight alkyl group). Usually, derivatives of the formula R ¹ -C(=O)-OH are used in slight excess, and alkoxide salts of the formula R ¹ -C(=O)-
1 to 2 molar equivalents are used based on the said derivative of the acid OH. The reaction between derivatives of formula R ¹ -C(=O)-OH and compounds of formula where R is hydrogen is usually initiated at 0-25°C, but the reaction mixture is then heated at 50-130°C to complete the reaction. ℃ (approximately 80℃ is preferred). Under these conditions, reaction times of several hours (eg, 2 hours) to several days (eg, 2 days) are usually required. The reaction mixture is then cooled, diluted with excess water and made acidic. Products of the formula where R is -CO-R ¹ are recovered by filtration or solvent extraction using standard techniques. The process for preparing compounds of the invention (reaction of a suitable 2-oxindole with chlorosulfonyl isocyanate) does not react with a reaction inert solvent (i.e., chlorosulfonyl isocyanate or a 2-oxindole-1-chlorosulfonylamide of formula solvent). The solvent need not completely dissolve the reaction components. Typical solvents are dialkyl ethers (diethyl ether), isopropyl ether, aromatic hydrocarbons (benzene, xylene and toluene), chlorinated hydrocarbons (methylene chloride and chloroform) and acetonitrile. The reaction is generally carried out at a temperature range from -20°C to the boiling point of the solvent used. Generally temperatures between 25°C and 110°C are suitable. Temperatures below -70°C can also be used if desired. However, temperatures below 0° C. are generally avoided for practical reasons. 2-oxindole and chlorosulfonyl isocyanate are generally in equimolar to 30% excess of chloroisocyanate (i.e. 1:1 to 1:1.3)
The reaction is carried out at a molar ratio in the range of . Large excesses of chlorosulfonyl isocyanate have no advantage and are not used for economic reasons. The chlorosulfonylamide derivatives of the formula thus prepared can be isolated if desired and
It is also possible to convert the compound of the formula directly in the same reaction vessel without isolation. Isolation of the intermediate chlorosulfonamide compound of formula is accomplished by procedures known in the art such as filtration, evaporation, or extraction. Hydrolysis of the chlorosulfonamide derivatives of the formula is carried out in isolation or without treatment of the compound of the formula with water, aqueous acids or bases. Water is generally preferred as the hydrolyzing agent even when the hydrolysis step involves a bilayer system. The rate of hydrolysis is fast enough to overcome solubility problems of the reactants. Moreover, from the standpoint of large-scale reactions, the use of water alone is more economical than other hydrolysis methods. The use of aqueous inorganic or organic acids as hydrolyzing agents sometimes overcomes the occurrence of two-phase reaction systems. This often occurs when using aqueous acetic acid solutions. The amount of acid is not critical to the hydrolysis process. It ranges from less than equimolar to more than equimolar. The concentration of acid used is also not critical. Generally, when an aqueous acid solution is used in the hydrolysis step, about 0.1 to 3 moles of acid are used per mole of compound of formula. Acid concentrations of about 1 molar to 6 molar are commonly used for ease of handling. The use of aqueous acids is often used when an intermediate of the formula is isolated and a monolayer reaction mixture is desired. Typical acids are hydrochloric, sulfuric, phosphoric, acetic, formic, citric and benzoic acids. Compounds of formula are prepared from suitable 2-oxindole-1-carboxyamide compounds of formula where R is hydrogen and X and Y are as defined above. This is achieved by attaching the substituent -C(=O)-R ¹ to the 3-position of the 2-oxindole nucleus. The -C(=O)-R ¹ substituent is attached by reacting a compound of the above formula with an activated derivative of a carboxylic acid of the formula R ¹ -C(=O)OH. The reaction involves reacting a compound of the above formula with 1 molar equivalent or a slight excess of an activated derivative of a compound of formula R ¹ -C(=O)OH in the presence of 1 to 4 equivalents of a basic reagent in an inert solvent. Let me do it. An inert solvent is one that dissolves at least one reaction component and does not interact with either the reaction component or the product.
However, in practice polar non-aqueous solvents such as N , N -dimethylformamide, N , N -dimethylacetamide, N -methylpyrrolidone or dimethylsulfoxide are usually used. Formula R ¹ -C
Conventional methods are used to activate the (=O)OH acid. For example, acid halides such as acid chlorides, symmetric acid anhydrides (R ¹ -C(=O)-O-
C(=O)-R ¹ ) mixed acid anhydride of a hindered low molecular weight carboxylic acid (R ¹ -C(=O)-O-C(=
O)-R ³ , where R ³ is a bulky lower alkyl group such as t-butyl) and mixed carboxylic-carbonic anhydride (R ¹ -C(=O)
-O-C(=O) ^-OR4 , where ^R4 is a low molecular weight alkyl group) is always used. In addition,
N-hydroxyimide esters (e.g. N -hydroxysuccinimide and N -hydroxyphthalimide esters), 4-nitrophenyl esters, thiol esters (e.g. thiol phenyl esters), 2,4,5-trichlorophenyl esters and the like. things can be used. formula
A simple alkyl ester of R ¹ -C(=O)-O-R ⁴ (where R ⁴ is a low molecular weight alkyl group such as ethyl) is a 2-oxindole compound of the formula where R is hydrogen. When a -C(=O) ^-R1 substituent is attached to the 3-position, it is sometimes used as an activated derivative of an acid of the formula ^R1 -C(=O)-OH. A variety of basic reagents are used in the reaction between a compound of formula where R is hydrogen and an activated derivative of an acid of formula R ¹ --C(=O)OH. However, suitable basic reagents are trimethylamine, triethylamine, tributylamine, N -methylmorpholine, N -methylpiperidine and 4-( N , N -dimethylamino)
Tertiary amines such as pyridine. Compounds of the formula in which R is hydrogen and compounds of the formula R ¹ -C(=
The reaction between O)-OH and the activated derivative of the acid is usually carried out in the temperature range from -10 to 25°C. Reaction times of 30 minutes to several hours are common. At the end of the reaction, the reaction medium is usually diluted with water and made acidic, and the product is then recovered by filtration. Purify by standard techniques such as recrystallization. The following examples and preparations are presented solely for the purpose of illustrating the invention. No attempt was made to maximize the yield of the Examples and Preparations. Reference Example 1 2-oxindole-1-carboxyamide Chlorosulfonyl isocyanate (1.20 g, 8.4 mmole) was added to 2-oxindole (0.94 g, 7.1 mmole) in ether (30 ml), and the mixture was heated at room temperature for 20 hours. Stirred. The ether was removed under vacuum and the residue was treated with water (10ml) and 1N HCl (10ml). Ethyl acetate (125ml) was added and the mixture was stirred for 1 hour. Separate the ethyl acetate layer and add 1N
Washed with HCl (1 x 50 ml), brine (2 x 100 ml),
Dry with _MgSO4 . 0.97g (77%) crude product
Obtained. 0.18g (m.) by recrystallization from ethanol.
p.178° to 180°C) was obtained. Reference Example 2 2-oxindole-1-carboxamide 2-oxindole (5.86 g, 44.0 mmole) in toluene (160 ml) was azeotroped for 1 hour to dry the toluene. Chlorosulfonyl isocyanate (7.47 g, 52.8 mmole) was then added and hydrogen chloride was immediately released. The mixture was stirred for 15 minutes at reflux and cooled to room temperature. Water (50ml) was added to the cold mixture (HCL was released first) and stirred for 1.5 hours. The resulting solid was collected by filtration and dried (4.10 g). Dilute the solution with ethyl acetate (100
ml), and the resulting extract was diluted with salt water (2 x 100ml).
ml) and dried with _MgSO4 . The extract was distilled off under reduced pressure to obtain 4.16 g of solid matter. The solids were combined and recrystallized by dissolving in acetonitrile (200ml) and then concentrating the solution to about 75ml under reduced pressure. A small amount of separated amorphous material was removed by filtration, and the solution was decolorized, concentrated under reduced pressure to about 50 ml, and seeded with crystals. The dark red crystals separated were filtered and dried (3.0 g, 38%). This was the same product as Reference Example 1. Reference Example 3 2-Oxindole-1-Carboxamide To a slurry of 2-oxindole (13.3 g, 0.10 mmole) in toluene (150 ml) was added chlorosulfonyl isocyanate (15.6 g, 0.11 mmole) and the mixture was Heated on a steam bath for 10 minutes (clear solution within about 3 minutes, then a precipitate formed almost immediately). Cooled in an ice bath for 30 minutes, filtered the solids and dried with air. The obtained chlorosulfonamide intermediate was mixed with acetic acid/
A 2:1 mixture of water (240ml) was added and the resulting slurry was heated on a steam bath for 10 minutes. Cooled in an ice bath and the resulting white solid was filtered and dried with air. When the mother liquor is made into soft sludge and filtered, it yields 1.2g.
of product was obtained. Combine the solids and make approx.
It was recrystallized from 250ml of ethanol. yield,
11.48g (65%). This was the same product as Reference Example 1. Example 1 N-chlorosulfonyl-6-fluoro-5-methyl-2-oxindole-1-carboxamide Following the procedure of Reference Example 2, the title compound was prepared with 6-
Fluoro-5-methyl-2-oxindole (1.0 g, 6.0 mmole), chlorosulfonyl isocyanate (1.03 g, 7.3 mmole), toluene (30 ml)
Manufactured from. Water (5 ml) was used for the hydrolysis step. Yield, 0.58g (46%). MP200~203℃. Elemental analysis C ₁₀ H ₉ N ₂ O ₂ F Calculated value, C, 57.69; H, 4.36; N, 13.46% Actual value, C, 57.02; H, 4.41; N, 12.85% N-chlorosulfonyl-6-fluoro- A sample of 5-methyl-2-oxindole-1-carboxamide was taken before hydrolysis and subjected to mass spectrometry using accurate mass determination. C ₁₀ H ₈ N ₂ O ₄ SCl: 307.9848 Examples 2 to 4 Substituted-2-oxindole-1-carboxamide The following compounds were produced from appropriate substituted-2-oxindole according to the procedure of Reference Example 3. . [Table] [Table] Reference example 4 6-methylthio-2-oxindole-1-
Carboxamide 6-methylthio- in acetonitrile (60ml)
To a slurry of 2-oxindole (6.0 g, 0.033 mole) at 5°-10° C. was added chlorosulfonyl isocyanate (5.66 g, 0.04 mole) and the mixture was stirred for 1 hour. Then water (100ml) was added,
Stir well for 10 minutes. The aqueous solution was diluted with ethyl acetate (600
ml), washed successively with water and brine,
After drying with MgSO ₄ and removing the solvent under reduced pressure, a gray solid was obtained. This solid was recrystallized from acetonitrile. Yield, 3.0g. An additional 0.71 g of product was obtained from the mother liquor. Overall yield, 3.71g
(50.6%), mp176°~179°C. Reference Example 5 6-Trifluoromethyl-2-oxindole-1-carboxamide 6-trifluoromethyl-2-oxindole (8.0 g, 0.04 mole) in acetonitrile (80 ml)
Chlorosulfonyl isocyanate (6.65 g, 0.047 mole) was added to the slurry and the mixture was stirred for 45 minutes. Water (100ml) was then added and the aqueous mixture was stirred for 1 hour. The resulting precipitate was filtered and recrystallized from acetonitrile to obtain 0.92 g of the title product. Dilute the liquid with ethyl acetate (300ml)
Additional product was obtained after extraction with , drying with MgSO ₄ and evaporation under reduced pressure. Further product (2.2 g) was obtained by recrystallization from acetonitrile. Further mother liquors from recrystallization with acetonitrile are combined and concentrated under reduced pressure to give the product (1.85 g)
was recovered. Overall yield, 4.97g (51%), m.
p.207.5゜～210℃. Examples 5-7 The following compounds were produced by repeating the procedure of Reference Example 5 using the appropriate substituted 2-oxindole. [Table] Example 8 Substituted 2-oxindole-1-chlorosulfonamide The procedure of Reference Example 4 was followed using a suitable substituted-2-oxindole as a reaction component. Prior to the hydrolysis step, the intermediate chlorosulfonyl derivative was recovered by filtration if a solid was present or by distillation from a small amount of the reaction mixture if no precipitate formed. A sample of the intermediate thus obtained was subjected to accurate mass spectrometry. [Table] Example 9 N-chlorosulfonyl-3-(2-thenoyl)-
5-Chloro-2-oxindole-1-carboxamide A slurry of 3-(2-thenoyl)-5-chloro-2-oxindole (1.5 g, 5.4 mmole) in anhydrous acetonitrile (15 ml) was added with stirring to a slurry of chloro-2-oxindole-1-carboxyamide. Sulfonylisocyanate (0.52ml,
5.9 mmole) was added and the reaction mixture was stirred at room temperature for 2 hours. A small sample is taken, filtered and distilled under vacuum to release a small amount of N-chlorosulfonyl-3-
A sample of (2-thenoyl)-5-chloro-2-oxindole-1-carboxamide, mp 166-169°C was obtained. Preparation Example 1 5-Chloro-2-oxindole Hydrazine hydrate (40 ml, 0.826 mole) was added to a stirred slurry of 5-chloroisatin (100 g, 0.55 mole) in ethanol (930 ml), the solution turned red; A precipitate formed while the solution was refluxed for 3.5 hours. The reaction mixture was stirred overnight and the precipitate was collected by filtration to give 5-chloro-3-hydrazino-2-oxindole as a yellow solid, which was dried in a vacuum oven and the solid
105.4g was obtained. Convert the dry solids into sodium ethoxide (125.1g)
in absolute ethanol (900 ml) in portions over 10 minutes. The resulting solution was refluxed for 10 minutes and concentrated under vacuum to give a sticky solid. The sticky solid was dissolved in water (400 ml), the resulting aqueous solution was decolorized with activated carbon and poured into a mixture of water (1) containing ice chips and concentrated hydrochloric acid (180 ml). A tan solid precipitated and was collected by filtration, washed exhaustively with water, dried, and then washed with diethyl ether. Finally, recrystallization from ethanol gave the title compound (48.9 g, mp 193-195°C (decomposed)). In a similar manner, treatment of 5-methylisatin with hydrazine hydrate followed by sodium ethoxide in ethanol gave 5-methyl-2-oxindole. The product exhibited a melting point of 173-174°C. Production Example 2 4,5-dimethyl-2-oxindole and 5,6-dimethyl-2-oxindole “Orgnic Syntheses”, Collection Vol. 1, p.
3,4-dimethylaniline was converted to 3,4-dimethylisonitrosoacetanilide using the method described in 327. According to Baker et al.
Journal of Organic Chemistry , 17 , 149
(1952), cyclization of 3,4-dimethylisonitroacetanilide with sulfuric acid yields 4,5
-dimethylisatin (mp 225-226°C) and 5,6-dimethylisatin (mp 217-218°C) were obtained. Substantially following the procedure of Preparation 1, treatment of 4,5-dimethylisatin with hydrazine hydrate followed by sodium ethoxide in ethanol yields 4,5-dimethyl-2-oxindole, m-
p.245.5-247.5°C was obtained. Similarly, following substantially the procedure of Preparation Example 1, 5,
Treatment of 6-dimethylisatin with hydrazine hydrate followed by sodium ethoxide in ethanol yields 5,6-dimethyl-2-oxindole,
mp196.5-198°C was obtained. Production example 3 4-chloro-2-oxindole and 6-
Chloro-2-oxindole A Isonitroso-3-chloroacetanilide Chloral hydrate (113.23) in water (2)
Sodium sulfate (419 g, 2.95 mole), followed by 3-chloroaniline (89.25 g, 0.70 mole) and concentrated hydrochloric acid (62 ml) were added to a stirring solution of
and water (500ml) was added. A thick precipitate formed and an aqueous solution (500 ml) of hydroxylamine (155 g, 2.23 mole) was added to the reaction mixture with stirring. Stirring was continued and more water (1) was added to facilitate stirring while the reaction mixture was slowly warmed and held at 60-75°C for about 6 hours. The reaction mixture was then cooled and the precipitate was collected by filtration. Drying of the wet solid gave isonitroso-3-chloroacetanilide (136.1 g). B 4-chloroisatin and 6-chloroisatin 75% in concentrated sulfuric acid (775ml) pre-warmed to 70℃
at a rate that maintains the reaction solution at a temperature of ~85 °C.
Isonitroso-3-chloroacetanilide (136
g) was added with stirring. After all solids were added, the reaction mixture was heated to 90° C. for an additional 30 minutes.
The reaction mixture was then cooled and slowly poured onto ice (approximately 2 g) with stirring. Additional ice was added as necessary to maintain the temperature below room temperature. A red-orange precipitate formed and was collected by filtration, washed with water and dried. The obtained solid was slurried with water (2), and 3N sodium hydroxide (about 700 ml) was added to form a solution. Filter the solution and PH with concentrated hydrochloric acid.
8 and a mixed solution (120 ml) of water/concentrated hydrochloric acid (70:20) was added. The precipitated solid was collected by filtration, washed with water and dried to obtain crude 4-chloroisatin (50 g). When the liquid from which 4-chloroisatin was recovered was made acidic to pH 0 using concentrated hydrochloric acid, further precipitation occurred. The residue was collected by filtration, washed with water, and dried to obtain crude 6-chloroisatin (43 g). Recrystallization of crude 4-chloroisatin from acetic acid yields 4-chloroisatin (43.3g, mp258-259
°C) was obtained. Recrystallization of crude 6-chloroisatin from acetic acid yields 6-chloroisatin (36.2 g, m.p261-262
°C) was obtained. C 4-Chloro-2-oxindole To a stirred slurry of 4-chloroisatin (43.3 g) in ethanol (350 ml), hydrazine hydrate (17.3 ml) was added and the reaction mixture was then refluxed for 2 hours. The reaction mixture was cooled and the precipitate was collected by filtration to give 4-chloro-3-hydrazino-2-oxindole (43.5 g, mp235
~236°C) was obtained. Sodium (22%) in absolute ethanol (450ml)
While stirring the solution of g), 4-chloro-2-hydrazono-2-oxindole (43.5 g) was added in portions and the resulting solution was refluxed for 30 minutes.
The cooled solution was then concentrated to give a gummy material, which was dissolved in water (400ml) and decolorized using activated charcoal. The resulting solution was poured into a mixture of water (1) and concentrated hydrochloric acid (45 ml). The resulting precipitate was collected by filtration, dried, and recrystallized from ethanol to yield 4-chloro-2-oxindole (22.4 g, mp 216-218°C (decomposed)). D 6-Chloro-2-oxindole When 6-chloroisatin is reacted with hydrazine hydrate and then sodium methoxide in ethanol essentially according to C above, 6-chloro-2-oxindole
-Oxindole (14.2g, mp196-198℃)
was gotten. Production Example 4 5,6-difluoro-2-oxindole 3, in the same manner as Steps A and B of Production Example 3.
Reaction of 4-difluoroaniline with chloral hydrate and hydroxylamine followed by reflux with sulfuric acid yields 5,6-difluoroisatin, which is treated in the same manner as in Preparation Example 1 with hydrazine hydrate and then sodium chloride. Reaction with ethoxide gave the title compound (mp 187-190°C). Preparation Example 5 5-Fluoro-2-oxindole A solution of 4-fluoroaniline (11.1 g, 0.1 mole) in dichloromethane (200 ml) was prepared from -60 to -65
While stirring at <0>C, a solution of t-butyl hypochlorite (10.8 g, 0.1 mole) in dichloromethane (25 ml) was added dropwise. Stirring was continued for 10 minutes at -60 to -65°C, then a solution of ethyl 2-(methylthio)acetate (13.4 g, 0.1 mole) in dichloromethane (25 ml) was added dropwise. Stirring was continued for 1 hour at -60°C, then triethylamine (11.1 g,
A solution of 0.11 mole) in dichloromethane (25 ml) was added dropwise. The cooling bath was removed and once the reaction mixture had warmed to room temperature, water (100ml) was added. The layers separate,
The organic layer was washed with saturated brine, dried over Na ₂ SO ₄ and evaporated under vacuum. The residue was dissolved in diethyl ether (350ml) and 2N hydrochloric acid (40ml) was added.
The mixture was stirred overnight at room temperature and the layers separated;
The ether layer was washed with water and then with saturated brine.
The ether layer dried over Na ₂ SO ₄ was evaporated under vacuum and triturated under isopropyl ether to give an orange-brown solid (17 g). Recrystallization of the solid from ethanol yielded 5-fluoro-3-methylthio-2-oxindole (5.58 g, mp151.5~
152.5℃) was obtained. Elemental analysis C ₉ H ₈ ONFS Calculated value, C, 54.80; H, 4.09; N, 7.10% Actual value, C, 54.74; H, 4.11; N, 7.11% Above 5-fluoro-3-methylthio-2-oxindole (986 mg, 5.0 mmole) was added to 2 teaspoons of Raney nickel in absolute ethanol (50 ml) and the reaction mixture was refluxed for 2 hours. The catalyst was decanted off and washed with absolute ethanol. The ethanol solutions were combined and evaporated under vacuum, the residue was dissolved in dichloromethane, dried over Na ₂ SO ₄ and evaporated under vacuum to give 5-fluoro-2-oxindole (475 mg, mp 121-134 °C) was gotten. In a similar manner, 4-trifluoromethylaniline was reacted with t-butylhypochlorite, ethyl 2-(methylthio)acetate and triethylamine, and the resulting 3-thiomethyl-5-trifluoromethyl-2-oxindole When reduced with Raney nickel, 5-trifluoromethyl-2-
Oxindole (mp189.5-190.5) was obtained. Production example 6 6-fluoro-5-methyl-2-oxindole N-(2-chloroacetyl)-3-fluoro-4
- A mixture of methylaniline (11.62 g, 57.6 mmole) and anhydrous aluminum chloride (30.6 g, 229.5 mmole) is heated to 210-220°C and after 4 hours the reaction mixture is cooled and mixed with 1N hydrochloric acid (100 ml) and ice ( 50ml) was added. A tan solid formed, which was collected by filtration and recrystallized from aqueous ethanol. Three products were obtained, weighing 4.49g, 2.28g and 1.0g respectively. The first two products were a mixture of isomers (4-fluoro and 6-fluoro-5-methyl-2-oxindole). Further recrystallization of the product weighing 1.0 g from water gave the title compound (280 mg, mp 168.5-171°C). Production Example 7 6-Phenyl-2-oxindole Dimethyl sulfoxide (50 ml) was added to sodium hydride (3.46 g, 0.072 mole), and then a solution of dimethyl malonate (8.2 ml, 0.072 mole) in dimethyl sulfoxide (10 ml) was added. Add dropwise with stirring. After the addition, stirring was continued for 1 hour, then 4-
Bromo-3-nitro-diphenyl (10g,
A solution of 0.036 mole) in dimethyl sulfoxide (50 ml) was added. The reaction mixture was heated to 100° C. for 1 hour, cooled and poured into ice water containing aluminum chloride (5 g). The mixture was extracted with ethyl acetate, and the extract was washed with brine and dried over _MgSO4 .
Evaporation under vacuum gave an oil which was chromatographed on silica gel and recrystallized from methanol to give dimethyl 2-(3-nitro-4-diphenyl)malonate (6 g, mp 82-83°C).
was gotten. A portion (5 g) of the above nitro compound was reduced with hydrogen in a mixture of tetrahydrofuran (50 ml) and methanol (10 ml) using a palladium catalyst at a pressure of about 5 kg/cm ² to obtain the corresponding amine.
The amine compound was refluxed in ethanol for 16 hours, the product was recovered by evaporation, and recrystallized from methanol to yield ethyl 6-phenyl-2-oxindole-1-carboxylate (1.1 g, m.
p.115-117℃) was obtained. The above ethyl ester (1.0g) and 6N hydrochloric acid (100g)
ml) was refluxed for 3 hours and left at room temperature for 3 days. The solid was collected by filtration and dried to give 6-phenyl-2-
Oxindole (700 mg, mp 175-176°C) was obtained. Production example 8 5-acetyl-2-oxindole Carbon disulfide (95 ml) and aluminum chloride (27
g, 0.202 mole) and then acetyl chloride (3 ml, 0.042 mole) of carbon disulfide (5 ml).
The solution was added dropwise with stirring. Stirring was continued for 5 minutes, then 2-oxindole (4.4 g,
0.033 mole) was added. The resulting mixture was refluxed for 4 hours and cooled. The carbon disulfide was decanted off and the residue was triturated in water and recovered by filtration. After drying, the title compound (3.2 g, mp 225-227°C) was obtained. The following compound was produced from the reaction of 2-oxindole with benzoyl chloride and 2-thenoyl chloride in the presence of aluminum chloride, essentially following the procedure described above. 5-benzoyl-2-oxindole, m.
p.203-205℃ (from CH ₃ OH) and 5-(2-thenoyl)-2-oxindole,
mp211~213℃ (from _CH3CN ). Production Example 9 5-bromo-2-oxindole is produced by bromination of 2-oxindole. Furthermore, Beckett et al., Tetrahedron , 24 ,
6093 (1968) and Sumpter et al.
Journal of the American Chemical
See Society, 67 , 1656 (1945). 5-n-Butyl-2-oxindole is prepared according to the procedure of Preparation Example 1 by reacting 5-n-butyl isatin with hydrazine hydrate and then sodium methoxide in ethanol. 5-n
-Butylisatin is prepared by treating 4-n-butylaniline with chloral hydrate and hydroxylamine and cyclizing with sulfuric acid according to the procedure of Steps A and B of Preparation Example 3. 5-Ethoxy-2-oxindole was prepared using 3-hydroxy-6-nitro-toluene using the standard method (potassium carbonate and ethyl iodide in acetone).
to 3-ethoxy-6-nitro-toluene and then convert 3-methoxy-6-nitro-toluene to 5-methoxy-2-oxindole according to Beckett et al.
3-ethoxy-6-nitrotoluene was prepared by the method described in Tetrahedron, 24 , 6093 (1968).
-Ethoxy-2-oxindole.
5-n-Butoxy-2-oxindole is also produced in a similar manner by replacing ethyl iodide with butyl iodide. 5,6-dimethoxy-2-oxindole is described in Walker's Journal of the
American Chemical Society , 77 , 3844
(1955). 7-chloro-2-oxindole is prepared by the method described in US Pat. No. 3,882,236. 4-thiomethyl-2-oxindole and 6-thiomethyl-2-oxindole are prepared by the method described in US Pat. No. 4,006,161. 5-n-Butyloxy-2-oxindole is produced in a similar manner by replacing 3-methylthioaniline with 4-butylthioaniline. 5,6-methylenedioxy-2-oxindole is described in the Journal of McEvoy et al.
Organic Chemistry , 38 , 3350 (1973). 5,6-ethylenedioxy-2-
Oxindoles are also produced in a similar manner. 6-Fluoro-2-oxindole is available from the Collection of Protiva et al.
Czechoslovakian Chemical Communication ,
44, 2108 (1979) and U.S. Patent No. 4160032. 6-Trifluoromethyl-2-oxindole is described in Simet's Journal of Organic
Chemistry , 28 , 3580 (1963). 6-Methoxy-2-oxindole is described by Wieland et al.
96, 253 (1963). 5-nitro-2-oxindole is described by Sumptre et al. in the Journal of the
American Chemical Society , 67 , 499 (1945)
manufactured by the method. 5-Cyclopropyl-2-oxindole and 5-cycloheptyl-2-oxindole were prepared by preparing 5-cyclopropylisatin and 5-cycloheptylisatin, respectively, in hydrazine hydrate and then ethanol according to the procedure of Preparation Example 1. Produced by reacting with sodium methoxide.
5-Cyclopropylisatin and 5-cycloheptylisatin are obtained by treating 4-cyclopropylaniline and 4-cycloheptylaniline with chloral hydrate and hydroxylamine, respectively, according to steps A and B of Production Example 3, and then adding sulfuric acid to It is produced by cyclization. Preparation Example 10 5-Amino-2-oxindole-1-carboxamide To a solution of 5-nitro-2-oxindole (50 g) in N , N -dimethylformamide (110 ml) was added 10% palladium on carbon, The mixture was shaken under a hydrogen atmosphere at an initial pressure of 5 Kg/cm ² until hydrogen absorption ceased. The catalyst was removed by filtration and the solution was diluted with brine and extracted with ethyl acetate. The extract was dried over _MgSO4 and evaporated under vacuum to give a dark oil, which was solidified by trituration in water to give the title compound (3.0 g, mp189) as a yellow solid.
~191°C) was obtained. Preparation Example 11 3-(2-furoyl)-2-oxindole Sodium (5.5 g,
2-oxindole (13.3 g, 0.10 mole) was added at room temperature while stirring the solution. The resulting slurry was cooled to ice bath temperature and 2-
10-15 Furoyl chloride (15.7g, 0.12mole)
Added dropwise over minutes. The ice bath was removed, more ethanol (100ml) was added and the reaction mixture was refluxed for 7 hours. The reaction mixture was allowed to stand overnight and the solids were filtered off. The solid was added to water (400ml), the mixture acidified with concentrated hydrochloric acid, cooled with ice and the solid collected by filtration. The solid residue was recrystallized from acetic acid (150ml) to give yellow crystals (8.3g, mp209-210℃ (decomposition)).
was generated. Elemental analysis C ₁₃ H ₉ O ₃ N Calculated value C, 68.72; H, 3.99; N, 6.17% Actual value C, 68.25; H, 4.05; N, 6.20% Using the above method, 2-oxindole was When reacted with acid chloride, the following addition product was obtained. 3-(2-thenoyl)-2-oxindole,
mp189-190℃, yield 17%, 3-(2-[2-thienyl]acetyl)-2-oxindole, mp191-192.5℃, yield 38%,
and 3-(2-phenoxyacetyl)-2-oxindole, mp 135-136°C, yield 42%. Preparation Example 12 3-(3-furoyl)-2-oxindole 12.8 g of sodium in ethanol (200 ml),
While stirring a solution of 2-oxindole (13.3 g, 0.10 mole), ethyl 3
- Float (16.8g) was added. 47 mixture
After refluxing for an hour and cooling, the solvent was distilled off under vacuum.
The residue was triturated under ether (200ml) and the solid collected by filtration and discarded. Distill the liquid under vacuum,
The residue was triturated under isopropyl alcohol and collected by filtration. The solid was suspended in water (250ml) and then acidified with concentrated hydrochloric acid. The mixture was stirred to yield a solid, which was collected by filtration. This solid was recrystallized from acetic acid and then from acetonitrile to give the title compound (705 mg, mp 185-186°C). Elemental analysis C ₁₃ H ₉ O ₃ N Calculated value C, 68.72; H, 3.99; N, 6.17% Actual value C, 68.72; H, 4.14; N, 6.14% Production example 13 5-chloro-3-(2-thenoyl )-2-oxindole-1-carboxamide 5-chloro-2-oxindole-1-carboxamide (21.1 g, 0.1 mole) and 4-(N,
N-dimethylamino)pyridine (26.9g,
A slurry of 2-thenoyl chloride (16.1 g,
A solution of 0.11 mole) in N,N-dimethylformamide (50 ml) was added dropwise. Continue stirring for about 30 minutes,
The reaction mixture was poured into a mixture of water (1) and 3N hydrochloric acid (75ml). The resulting mixture was cooled in an ice bath and the solids were collected by filtration. Recrystallization of the solid from acetic acid (1800ml) gave the title compound (26.6g, mp 230°C (decomposed)) as fluffy yellow crystals. A sample of the title compound from a similar experiment gave the following elemental analysis results. Elemental analysis C ₁₄ H ₉ ClN ₂ O ₃ S Calculated value C, 52.42; H, 2.83; N, 8.74% Actual value C, 52.22; H, 2.81; N, 8.53% Production example 14 Substantially the same as the procedure of Production example 13 Therefore, a suitable 2-oxindole-1-carboxamide can be defined as having the formula R ¹
Reaction of -CO-Cl with the required acid chloride produced the following compounds. [Table] [Table] Production example 15 5-chloro-3-acetyl-2-oxindole-1-carboxamide 5 in N,N-dimethylformamide (15 ml)
-chloro-2-oxindole-1-carboxamide (842 mg, 4.0 mmnle) and 4-(N,
N-dimethylamino)pyridine (1.08g,
A slurry of acetic anhydride (449 mg, 4.4 mmole) was stirred, cooled to ice bath temperature, and
A solution of N-dimethylformamide (5 ml) was added dropwise. Stirring was continued for approximately 30 minutes, then the reaction mixture was poured into a mixture of water (75 ml) and 3N hydrochloric acid (3 ml).
The resulting mixture was cooled in an ice bath and the solids were collected by filtration. Recrystallization of the solid from acetic acid yields fluffy pale red crystals (600 mg, mp237.5 (decomposed))
was gotten. Elemental analysis C ₁₁ H ₉ ClN ₂ O ₃ Calculated value C, 52.29; H, 3.59; N, 11.09% Actual value C, 52.08; H, 3.63; N, 11.04%

Claims (1)

[Claims] 1 formula (In the formula, X is hydrogen, halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or
4 alkylthio, trifluoromethyl, or nitro, and Y is hydrogen, halogen, or has 1 to 1 carbon atoms.
4 alkyl, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, or trifluoromethyl; R is hydrogen or -CO-R ¹ , and R ¹ is thienyl). 2 X is hydrogen, 5-chloro-, 5-fluoro, or 5-trifluoromethyl, Y is hydrogen,
2. A compound according to claim 1, wherein R is 6-chloro, 6-fluoro or 6-trifluoromethyl and R is hydrogen. 3. The compound according to claim 2, wherein X is 5-chloro and Y is hydrogen. 4 X is hydrogen, 5-chloro, 5-fluoro or 5-trifluoromethyl, Y is hydrogen, 6-
2. A compound according to claim 1, which is chloro, 6-fluoro or 6-trifluoromethyl, and R is -CO-R ¹ with the proviso that R ¹ is 2-thienyl. 5. The compound according to claim 4, wherein X is 5-chloro and Y is hydrogen.