oxolane-2,4-dione

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: At 0° C., 10.5 ml of cyclopropylamine (149.9 mmol) are added dropwise to 10.0 g of tetronic acid (99.9 mmol) in 57 ml of acetic acid, and the mixture is stirred at 120° C. for 2 h. After addition of 200 ml of toluene, the mixture is heated under reflux on a water separator for 3 hours. The reaction mixture is concentrated under reduced pressure and the residue is partitioned between 2.5 N of aqueous sodium hydroxide solution and dichloromethane. The aqueous phase is extracted a few more times with dichloromethane and the combined organic phases are dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by recrystallization from ethanol gives 5.2 g (37% of theory) of 4-(cyclopropylamino)furan-2(5H)-one. the mixture is heated The reaction mixture is concentrated under reduced pressure the residue is partitioned between 2.5 N of aqueous sodium hydroxide solution and dichloromethane The aqueous phase is extracted a few more times with dichloromethane the combined organic phases are dried over sodium sulphate Concentration of the organic phase under reduced pressure and purification of the residue by recrystallization from ethanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 120 μl (2.04 mmol) of acetic acid and 422 mg (2.04 mmol) of 1-(5,6-dichloropyridin-3-yl)-N-methoxymethanamine (III-3) are added to 224 mg (2.24 mmol) of tetronic acid in 50 ml of toluene, and the mixture is heated under reflux on a water separator for 3 hours. The reaction mixture is concentrated under reduced pressure, the residue is taken up in ethyl acetate and the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by recrystallization from ethyl acetate gives 360 mg (59% of theory) of 4-[[(5,6-dichloropyridin-3-yl)methyl](methoxy)amino]furan-2(5H)-one. the mixture is heated The reaction mixture is concentrated under reduced pressure the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and saturated sodium chloride solution dried over sodium sulphate Concentration of the organic phase under reduced pressure and purification of the residue by recrystallization from ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 24.80 g (248 mmol) of tetronic acid are added slowly to 41.40 g (225.3 mmol) of N-[(6-chloro-5-fluoropyridin-3-yl)methyl]methanamine (III-1) in 64 ml of acetic acid, and the mixture is stirred at room temperature for about 16 hours. The reaction mixture is concentrated under reduced pressure, the residue is taken up in ethyl acetate and the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by recrystallization from ethyl acetate gives 30.0 g (52% of theory) of 4-[[(6-chloro-5-fluoropyridin-3-yl)methyl](methyl)amino]furan-2(5H)-one. The reaction mixture is concentrated under reduced pressure the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and saturated sodium chloride solution dried over sodium sulphate Concentration of the organic phase under reduced pressure and purification of the residue by recrystallization from ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: On a water separator, 550 mg (4.97 mmol) of 2-fluoroethylamine hydrochloride, 547 mg (5.47 mmol) of tetronic acid, 408 mg (4.97 mmol) of sodium acetate and 9 mg (0.05 mmol) of 4-toluene-sulphonic acid in 50 ml of toluene are heated under reflux for 5 hours. The reaction mixture is concentrated under reduced pressure and then taken up in ethyl acetate and washed with 1 N aqueous sodium hydroxide solution. The aqueous phase is extracted repeatedly with ethyl acetate and the combined organic phase is dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by recrystallization from ethyl acetate/cyclohexane gives 300 mg (42% of theory) of 4-[(2-fluoroethyl)amino]furan-2(5H)-one. under reflux for 5 hours The reaction mixture is concentrated under reduced pressure washed with 1 N aqueous sodium hydroxide solution The aqueous phase is extracted repeatedly with ethyl acetate the combined organic phase is dried over sodium sulphate Concentration of the organic phase under reduced pressure and purification of the residue by recrystallization from ethyl acetate/cyclohexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: On a water separator, 5.00 g (35.1 mmol) of 1-(6-chloropyridin-3-yl)methylamine, 3.51 g (35.1 mmol) of tetronic acid and 20 mg (0.12 mmol) of 4-toluenesulphonic acid in 200 ml of toluene are heated under reflux for 24 hours. The reaction mixture is concentrated, and the residue that remains is then purified by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate. This gives 4.96 g (63% of theory) of 4-[[(6-chloropyridin-3-yl)methyl]amino]furan-2(5H)-one, which can be used for subsequent reactions. under reflux for 24 hours The reaction mixture is concentrated the residue that remains is then purified by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.52 g (5.18 mmol) of tetronic acid is initially charged in 1.13 ml of acetic acid, and 1.00 g (4.93 mmol) of N-[(6-chloropyridin-3-yl)methyl]-3-fluoropropane-1-amine (III-2) is added slowly at room temperature. The entire reaction mixture is then stirred at room temperature for approximately a further 18 hours. The reaction mixture is concentrated under reduced pressure, the residue is then taken up in dichloromethane and the mixture is washed with water. After phase separation, the aqueous phase is extracted twice with dichloromethane. The combined organic phases are then made alkaline (pH>9) with 1 N sodium hydroxide solution and the phases are separated. The aqueous phase is extracted twice with dichloromethane, and, after phase separation, the combined organic phases are dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (9:1) gives 191 mg (14% of theory) of 4-[[(6-chloropyridin-3-yl)methyl](3-fluoro-n-propyl)amino]furan-2(5H)-one. The entire reaction mixture The reaction mixture is concentrated under reduced pressure the mixture is washed with water After phase separation the aqueous phase is extracted twice with dichloromethane the phases are separated The aqueous phase is extracted twice with dichloromethane after phase separation the combined organic phases are dried over sodium sulphate Concentration of the organic phase under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: On a water separator, 21.90 g (106.0 mmol) of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethane-1-amine (III-1), 14.85 g (148.4 mmol) of tetronic acid and 183 mg (1.1 mmol) of 4-toluenesulphonic acid in 250 ml of toluene are heated under reflux for 2 hours. The reaction mixture is concentrated under reduced pressure, the residue is then taken up in ethyl acetate and the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate gives 15.9 g (52% of theory) of 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one. under reflux for 2 hours The reaction mixture is concentrated under reduced pressure the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and once with saturated sodium chloride solution The organic phase is dried over sodium sulphate concentrated under reduced pressure Purification of the residue by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100 mg (0.624 mmol) 3-methyl-1H-indazole-5-carbaldehyde (Example 1A) and 62.5 mg (0.624 mmol) furan-2,4(3H,5H)-dione were heated up to reflux in 1-pentanol (3 ml) for 1 h. After addition of 425 mg (3.120 mmol) 3-amino-4,4,4-trifluorobut-2-enenitrile [A. W. Lutz, U.S. Pat. No. 3,635,977], the reaction mixture was stirred at 100° C. for further 4 h. Then, conc. hydrochloric acid (115 μl) and water (350 μl) were added, and the mixture was stirred at 100° C. for another 1 h. After cooling, the mixture was directly purified by RP-HPLC (acetonitrile/water+0.1% TFA gradient) to give 33 mg (14% of th.) of the title compound. the mixture was stirred at 100° C. for another 1 h After cooling the mixture was directly purified by RP-HPLC (acetonitrile/water+0.1% TFA gradient)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from 600 mg (2.508 mmol) (2E)-2-[(3-ethyl-1H-indazol-5-yl)-methylidene]-3-oxobutanenitrile (Example 7A), 256 mg (2.508 mmol) furan-2,4(3H,5H)-dione and 232 mg (3.010 mmol) ammonium acetate in analogy to the procedure described in Example 1 yielding 98 mg (12% of th.) of the racemic compound after purification by flash chromatography (silica gel; dichloromethane/methanol gradient, final mixture 30:1 v/v). after purification by flash chromatography (silica gel; dichloromethane/methanol gradient, final mixture 30:1 v/v)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To tetronic acid (5.00 g, 49.9 mmol) in CH2Cl2 (250 mL) at 0° C. were added Et3N (8.3 mL, 59.6 mmol) and tosyl azide (7.37 g, 37.4 mmol). After a period of 2 h at r.t., the reaction mixture was partitioned between NH4OAc (25%) and CH2Cl2. The organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting mixture was purified by flash chromatography (20% to 35% EtOAc in Hexane) to provide 1.4 g of the title compound as a white solid. the reaction mixture was partitioned between NH4OAc (25%) and CH2Cl2 The organic phase was dried over Na2SO4 filtered evaporated under reduced pressure The resulting mixture was purified by flash chromatography (20% to 35% EtOAc in Hexane)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Triethylamine (0.75 mL, 5.5 mmol) was added to a suspension of tetronic acid (500 mg, 5.00 mmol) in dichloromethane (25 mL) to obtain a homogeneous solution. The solution was cooled to 0° C., mixed with 4-N,N-dimethylaminopyridine (200 mg, 1.7 mmol), 3-cyclohexne-1-carboxylic acid (0.65 mL, 5.6 mmol), and then, diisopropylcarbodiimide (1.0 mL, 6.3 mmol), followed by stirring for 30 min. The resulting mixture was removed from the ice bath, stirred for 14 hours at room temperature, and filtered to remove thus-produced insoluble diisopropyl urea; the reaction solution was washed twice with 5% hydrochloric acid (20 mL) and the water layer was extracted twice with dichloromethane (10 mL). The organic layers were combined, dried over sodium sulfate anhydride, and concentrated; the thus-obtained residue was purified by silica gel column chromatography (silica gel, ethyl acetate:methanol=15:1). The resultant was arranged to be a sodium salt by adding an excess amount of sodium hydrogencarbonate and distilled water (100 mL), and then washed with dichloromethane; the water layer was acidified by adding 5% hydrochloric acid and extracted four times with dichloromethane (20 mL). The resultant was dried over sodium sulfate anhydride and concentrated to give pale yellow crystals (394 mg, 38%). to obtain a homogeneous solution The resulting mixture was removed from the ice bath stirred for 14 hours at room temperature filtered to remove

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 300 ml of 6N hydrochloric acid solution was placed in a 1.5-liter flask equipped with a 250-ml dropping funnel, a mechanical stirrer and a thermometer. 57.6 g (0.61 mol) of distilled aniline was added with ice cooling. A solution of 43.92 g (0.64 mol) of sodium nitrite in 90 ml of ice water was added dropwise the resulting suspension and stirred for 40 min. The resultant diazonium salt solution was added dropwise to a solution of 60 g (0.6 mol) of tetronic acid and 120 g (0.88 mol) of sodium acetate trihydrate in 900 ml of water for 30 min. After this addition a yellow solid immediately precipitated. The reaction mixture was stirred at 10° C. for 1.5 hours, and filtered off; and the product was washed with 500 ml of cold methanol. It was dried at 35° C. in a vacuum. Concerning the product: Yield: 113.2 g = 92.4 percent. Melting point: 199°-200° C. (decomp.). equipped with a 250-ml After this addition a yellow solid immediately precipitated The reaction mixture was stirred at 10° C. for 1.5 hours filtered off and the product was washed with 500 ml of cold methanol It was dried at 35° C. in a vacuum