4,4-二氟-1-苯基-1,3-丁二酮

反应条件: temp:24.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a clean and dry nitrogen purged 22 L round bottom flask under nitrogen atmosphere was charged: 500 g of 5-(methylsulfonyl)-2-hydrazinyl-pyridine (2.67 moles), 10 L water (20 volumes) and 579 mL of concentrated H2SO4 (0.063 volumes). In a separate 12 L 3-neck round-bottomed flask was prepared a solution of 7500 mL of isopropanol (15 volumes) and 508 g (2.56 moles) of 4,4-difluoro-1-phenyl-1,3-butanedione. The isopropanol/4,4-difluoro-1-phenyl-1,3-butanedione solution was added to the mixture containing the 5-(methylsulfonyl)-2-hydrazinyl-pyridine, keeping the pot temperature below 30° C. After addition of the 4,4-difluoro-1-phenyl-1,3-butanedione solution, the mixture was stirred at 24° C. for 1.0 hour and sampled for disappearance of 5-(methylsulfonyl)-2-hydrazinyl-pyridine by HPLC. The pot was then heated to 40° C. for 2 hours until disappearance of the intermediate compound of formula 4 and the resulting slurry was filtered and washed with water to achieve a pH of the filtrate of from about 6-7. The solids were then charged to a 5L 3-neck round-bottom flask. To the flask was added 1250 mL water (2.5 volumes) and 1250 mL isopropanol (2.5 volumes). The mixture was heated to reflux (85° C.) for 2 hours. The pot was then cooled to 40° C. and then stirred overnight. The solids were isolated by filtration, washed with 2 L isopropanol, and dried in a vacuum oven at 45° C. The compound of formula 6 was present at a level of 1.2% by HPLC (retention time 5.1 minutes). Analytical data: HPLC retention time (title compound) 8.4 minutes; MS: 349.36 (calc), M+1=350.1; 1H NMR in CDCl3: 8.75 doublet, (1H), 8.26 Quartet (1H), 7.38 multiplet (3H), 7.36 doublet (2H), 6.70 multiplet (2H), 3.08, Singlet, (3H); 13C NMR in CDCl3: 15.3, 149.3, 147.9, 146.6, 138.1, 130.27, 133.5, 130.0, 129.1, 128.7, 117.9, 113.4, 111.1, 108.1, 107.7, 45. To a clean and dry nitrogen purged 22 L round bottom flask under nitrogen atmosphere was charged the pot temperature below 30° C the resulting slurry was filtered washed with water The solids were then charged to a 5L 3-neck round-bottom flask To the flask was added 1250 mL water (2.5 volumes) and 1250 mL isopropanol (2.5 volumes) The mixture was heated to reflux (85° C.) for 2 hours The pot was then cooled to 40° C. stirred overnight The solids were isolated by filtration washed with 2 L isopropanol dried in a vacuum oven at 45° C HPLC retention time (title compound) 8.4 minutes

反应条件: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a clean and dry nitrogen purged 1 L round-bottom flask under nitrogen atmosphere was charged 25.6 g of 5-(methylsulfonyl)-2-hydrazinyl-pyridine (0.14 moles), 512 mL water (20 volumes) and 16 mL of concentrated H2SO4 (0.063 volumes). In a separate 500 mL 1-neck round-bottom flask, was prepared a solution of 384 mL of isopropanol (15 volumes) and 26.01 g (0.13 moles) of 4,4-difluoro-1-phenyl-1,3-butanedione. The isopropanol/4,4-difluoro-1-phenyl-1,3-butanedione solution was added to the 5-(methylsulfonyl)-2-hydrazinyl-pyridine reaction mixture keeping the pot temperature less than 25° C. After addition, the mixture was stirred at 22° C. for 2.0 hours and sampled for disappearance of starting material. When the starting materials had disappeared (less than 15 remaining), the pot was then heated to 40° C. for 5.5 hours until disappearance of the intermediate. The resulting slurry was filtered and washed with water to achieve a pH 6-7 of the filtrate. The solids were then charged to a 250 mL 3-neck round-bottom flask. To the flask was added: 31.25 mL water (1.2 volumes) and 31.25 mL isopropanol (1.2 volumes). The mixture was heated to reflux (85° C.) for 30 minutes. The pot was allowed to cool to 28° C. and the solids were isolated by filtration and washed with 20 mL isopropanol. The solids were dried in a vacuum oven at 45° C. The product was obtained with 87% yield and contained 0.54% of the compound of formula 6 (retention time 5.1 minutes). Analytical data: HPLC retention time (title compound) 8.4 minutes; MS: 349.36 (calc), M+1=350.1; 1H NMR in CDCl3: 8.75 doublet, (1H), 8.26 Quartet (1H), 7.38 multiplet (3H), 7.36 doublet (2H), 6.70 multiplet (2H), 3.08, Singlet, (3H); 13C NMR in CDCl3: 15.3, 149.3, 147.9, 146.6, 138.1, 130.27, 133.5, 130.0, 129.1, 128.7, 117.9, 113.4, 111.1, 108.1, 107.7, 45. To a clean and dry nitrogen purged 1 L round-bottom flask under nitrogen atmosphere the pot temperature less than 25° C After addition sampled for disappearance of starting material pot was then heated to 40° C. for 5.5 hours until disappearance of the intermediate The resulting slurry was filtered washed with water The solids were then charged to a 250 mL 3-neck round-bottom flask To the flask was added The mixture was heated to reflux (85° C.) for 30 minutes to cool to 28° C. the solids were isolated by filtration washed with 20 mL isopropanol The solids were dried in a vacuum oven at 45° C The product was obtained with 87% yield

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 120 g of 5-(methylsulfonyl)-2-hydrazinyl-pyridine [CP-675,775] (0.641 moles) was charged isopropanol (900 mL) followed by 4,4-difluoro-1-phenyl-1,3-butanedione (122 g, 0.615 moles, 0.96 eq.) as a melt, followed by 900 mL of isopropanol. The slurry was stirred for 15 minutes, then 36 mL of concentrated sulfuric acid was added (slight exotherm) (15 volumes of isopropanol total). The reaction was stirred for 6 hours at 20-30° C., 2.4 L (20 volumes) of water was added (slight exotherm, reaction temperature kept below 45° C.) and the reaction was granulated for 2 days. The product was filtered and was rinsed with water. The product contained less than 0.5% of compound 6 (retention time 5.1 minutes). Analytical data: HPLC retention time (title compound) 8.4 minutes; MS: 349.36 (calc), M+1=350.1; 1H NMR in CDCl3: 8.75 doublet, (1H), 8.26 Quartet (1H), 7.38 multiplet (3H), 7.36 doublet (2H), 6.70 multiplet (2H), 3.08, Singlet, (3H); 13C NMR in CDCl3: 15.3, 149.3, 147.9, 146.6, 138.1, 130.27, 133.5, 130.0, 129.1, 128.7, 117.9, 113.4, 111.1, 108.1, 107.7, 45. The reaction was stirred for 6 hours at 20-30° C. (slight exotherm, reaction temperature kept below 45° C.) the reaction was granulated for 2 days The product was filtered was rinsed with water HPLC retention time (title compound) 8.4 minutes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 120 g of 5-(methylsulfonyl)-2-hydrazinyl-pyridine [CP-675,775] (0.641 moles) was charged isopropanol (900 mL) followed by 4,4-difluoro-1-phenyl-1,3-butanedione (122 g, 0.615 moles, 0.96 eq.) as a melt, followed by 900 mL of isopropanol. The slurry was stirred for 15 minutes, then 36 mL of concentrated sulfuric acid was added (slight exotherm) (15 volumes of isopropanol total). The reaction was stirred for 6 hours at 20-30° C., 2.4 L (20 volumes) of water was added (slight exotherm, reaction temperature kept below 45° C.) and the reaction was granulated for 2 days. The product was filtered and was rinsed with water. The product contained less than 0.5% of compound 6 (retention time 5.1 minutes). Analytical data: HPLC retention time (title compound) 8.4 minutes; MS: 349.36 (calc), M+1=350.1; 1H NMR in CDCl3: 8.75 doublet, (1H), 8.26 Quartet (1H), 7.38 multiplet (3H), 7.36 doublet (2H), 6.70 multiplet (2H), 3.08, Singlet, (3H); 13C NMR in CDCl3: 15.3, 149.3, 147.9, 146.6, 138.1, 130.27, 133.5, 130.0, 129.1, 128.7, 117.9, 113.4, 111.1, 108.1, 107.7, 45. The reaction was stirred for 6 hours at 20-30° C. (slight exotherm, reaction temperature kept below 45° C.) the reaction was granulated for 2 days The product was filtered was rinsed with water HPLC retention time (title compound) 8.4 minutes

反应条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 12.2 kg of 5-(methylsulfonyl)-2-hydrazinyl-pyridine (64.1 moles) was charged isopropanol (45 gallons) followed by 4,4-difluoro-1-phenyl-1,3-butanedione (12.0 kg, 61.5 moles, 0.96 eq.) as a melt, followed by 45 gallons of isopropanol. The slurry was stirred for 15 minutes, then 3.6 L of concentrated sulfuric acid was added (slight exotherm) (30V of isopropanol total). The reaction was heated to 75° C. and held for 1 hour. The pot was then cooled to 20-30° C. After reaction completion assay, 126 gallons (40V) of water was added (slight exotherm, reaction temp kept below 45° C.) and the reaction product was granulated for 2 hours. The product was filtered on a 36-inch nutche filter dressed with a poly cloth in less than 2 hours. The filter cake was rinsed with an additional 12 gallons (4V) of water, and the cake was blown dry for 12 hours. The product contained 2.2% of compound 6 as the major impurity (by HPLC; retention time 5.1 minutes). Analytical data: HPLC retention time (title compound) 8.4 minutes; MS: 349.36 (calc), M+1=350.1; 1H NMR in CDCl3: 8.75 doublet, (1H), 8.26 Quartet (1H), 7.38 multiplet (3H), 7.36 doublet (2H), 6.70 multiplet (2H), 3.08, Singlet, (3H); 13C NMR in CDCl3: 15.3, 149.3, 147.9, 146.6, 138.1, 130.27, 133.5, 130.0, 129.1, 128.7, 117.9, 113.4, 111.1, 108.1, 107.7, 45.). held for 1 hour The pot was then cooled to 20-30° C was added (slight exotherm, reaction temp kept below 45° C.) the reaction product was granulated for 2 hours The product was filtered on a 36-inch nutche filter dressed with a poly cloth in less than 2 hours The filter cake was rinsed with an additional 12 gallons (4V) of water the cake was blown dry for 12 hours HPLC retention time (title compound) 8.4 minutes

反应条件: temp:24.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a clean and dry nitrogen purged 22 L round bottom flask under nitrogen atmosphere was charged: 500 g of 5-(methylsulfonyl)-2-hydrazinyl-pyridine (2.67 moles), 10 L water (20 volumes) and 579 mL of concentrated H2SO4 (0.063 volumes). In a separate 12 L 3-neck round-bottomed flask was prepared a solution of 7500 mL of isopropanol (15 volumes) and 508 g (2.56 moles) of 4,4-difluoro-1-phenyl-1,3-butanedione. The isopropanol/4,4-difluoro-1-phenyl-1,3-butanedione solution was added to the mixture containing the 5-(methylsulfonyl)-2-hydrazinyl-pyridine, keeping the pot temperature below 30° C. After addition of the 4,4-difluoro-1-phenyl-1,3-butanedione solution, the mixture was stirred at 24° C. for 1.0 hour and sampled for disappearance of 5-(methylsulfonyl)-2-hydrazinyl-pyridine by HPLC. The pot was then heated to 40° C. for 2 hours until disappearance of the intermediate compound of formula 4 and the resulting slurry was filtered and washed with water to achieve a pH of the filtrate of from about 6-7. The solids were then charged to a 5L 3-neck round-bottom flask. To the flask was added 1250 mL water (2.5 volumes) and 1250 mL isopropanol (2.5 volumes). The mixture was heated to reflux (85° C.) for 2 hours. The pot was then cooled to 40° C. and then stirred overnight. The solids were isolated by filtration, washed with 2 L isopropanol, and dried in a vacuum oven at 45° C. The compound of formula 6 was present at a level of 1.2% by HPLC (retention time 5.1 minutes). Analytical data: HPLC retention time (title compound) 8.4 minutes; MS: 349.36 (calc), M+1=350.1; 1H NMR in CDCl3: 8.75 doublet, (1H), 8.26 Quartet (1H), 7.38 multiplet (3H), 7.36 doublet (2H), 6.70 multiplet (2H), 3.08, Singlet, (3H); 13C NMR in CDCl3: 15.3, 149.3, 147.9, 146.6, 138.1, 130.27, 133.5, 130.0, 129.1, 128.7, 117.9, 113.4, 111.1, 108.1, 107.7, 45. To a clean and dry nitrogen purged 22 L round bottom flask under nitrogen atmosphere was charged the pot temperature below 30° C the resulting slurry was filtered washed with water The solids were then charged to a 5L 3-neck round-bottom flask To the flask was added 1250 mL water (2.5 volumes) and 1250 mL isopropanol (2.5 volumes) The mixture was heated to reflux (85° C.) for 2 hours The pot was then cooled to 40° C. stirred overnight The solids were isolated by filtration washed with 2 L isopropanol dried in a vacuum oven at 45° C HPLC retention time (title compound) 8.4 minutes

反应条件: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a clean and dry nitrogen purged 1 L round-bottom flask under nitrogen atmosphere was charged 25.6 g of 5-(methylsulfonyl)-2-hydrazinyl-pyridine (0.14 moles), 512 mL water (20 volumes) and 16 mL of concentrated H2SO4 (0.063 volumes). In a separate 500 mL 1-neck round-bottom flask, was prepared a solution of 384 mL of isopropanol (15 volumes) and 26.01 g (0.13 moles) of 4,4-difluoro-1-phenyl-1,3-butanedione. The isopropanol/4,4-difluoro-1-phenyl-1,3-butanedione solution was added to the 5-(methylsulfonyl)-2-hydrazinyl-pyridine reaction mixture keeping the pot temperature less than 25° C. After addition, the mixture was stirred at 22° C. for 2.0 hours and sampled for disappearance of starting material. When the starting materials had disappeared (less than 15 remaining), the pot was then heated to 40° C. for 5.5 hours until disappearance of the intermediate. The resulting slurry was filtered and washed with water to achieve a pH 6-7 of the filtrate. The solids were then charged to a 250 mL 3-neck round-bottom flask. To the flask was added: 31.25 mL water (1.2 volumes) and 31.25 mL isopropanol (1.2 volumes). The mixture was heated to reflux (85° C.) for 30 minutes. The pot was allowed to cool to 28° C. and the solids were isolated by filtration and washed with 20 mL isopropanol. The solids were dried in a vacuum oven at 45° C. The product was obtained with 87% yield and contained 0.54% of the compound of formula 6 (retention time 5.1 minutes). Analytical data: HPLC retention time (title compound) 8.4 minutes; MS: 349.36 (calc), M+1=350.1; 1H NMR in CDCl3: 8.75 doublet, (1H), 8.26 Quartet (1H), 7.38 multiplet (3H), 7.36 doublet (2H), 6.70 multiplet (2H), 3.08, Singlet, (3H); 13C NMR in CDCl3: 15.3, 149.3, 147.9, 146.6, 138.1, 130.27, 133.5, 130.0, 129.1, 128.7, 117.9, 113.4, 111.1, 108.1, 107.7, 45. To a clean and dry nitrogen purged 1 L round-bottom flask under nitrogen atmosphere the pot temperature less than 25° C After addition sampled for disappearance of starting material pot was then heated to 40° C. for 5.5 hours until disappearance of the intermediate The resulting slurry was filtered washed with water The solids were then charged to a 250 mL 3-neck round-bottom flask To the flask was added The mixture was heated to reflux (85° C.) for 30 minutes to cool to 28° C. the solids were isolated by filtration washed with 20 mL isopropanol The solids were dried in a vacuum oven at 45° C The product was obtained with 87% yield

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 120 g of 5-(methylsulfonyl)-2-hydrazinyl-pyridine [CP-675,775] (0.641 moles) was charged isopropanol (900 mL) followed by 4,4-difluoro-1-phenyl-1,3-butanedione (122 g, 0.615 moles, 0.96 eq.) as a melt, followed by 900 mL of isopropanol. The slurry was stirred for 15 minutes, then 36 mL of concentrated sulfuric acid was added (slight exotherm) (15 volumes of isopropanol total). The reaction was stirred for 6 hours at 20-30° C., 2.4 L (20 volumes) of water was added (slight exotherm, reaction temperature kept below 45° C.) and the reaction was granulated for 2 days. The product was filtered and was rinsed with water. The product contained less than 0.5% of compound 6 (retention time 5.1 minutes). Analytical data: HPLC retention time (title compound) 8.4 minutes; MS: 349.36 (calc), M+1=350.1; 1H NMR in CDCl3: 8.75 doublet, (1H), 8.26 Quartet (1H), 7.38 multiplet (3H), 7.36 doublet (2H), 6.70 multiplet (2H), 3.08, Singlet, (3H); 13C NMR in CDCl3: 15.3, 149.3, 147.9, 146.6, 138.1, 130.27, 133.5, 130.0, 129.1, 128.7, 117.9, 113.4, 111.1, 108.1, 107.7, 45. The reaction was stirred for 6 hours at 20-30° C. (slight exotherm, reaction temperature kept below 45° C.) the reaction was granulated for 2 days The product was filtered was rinsed with water HPLC retention time (title compound) 8.4 minutes

反应条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 12.2 kg of 5-(methylsulfonyl)-2-hydrazinyl-pyridine (64.1 moles) was charged isopropanol (45 gallons) followed by 4,4-difluoro-1-phenyl-1,3-butanedione (12.0 kg, 61.5 moles, 0.96 eq.) as a melt, followed by 45 gallons of isopropanol. The slurry was stirred for 15 minutes, then 3.6 L of concentrated sulfuric acid was added (slight exotherm) (30V of isopropanol total). The reaction was heated to 75° C. and held for 1 hour. The pot was then cooled to 20-30° C. After reaction completion assay, 126 gallons (40V) of water was added (slight exotherm, reaction temp kept below 45° C.) and the reaction product was granulated for 2 hours. The product was filtered on a 36-inch nutche filter dressed with a poly cloth in less than 2 hours. The filter cake was rinsed with an additional 12 gallons (4V) of water, and the cake was blown dry for 12 hours. The product contained 2.2% of compound 6 as the major impurity (by HPLC; retention time 5.1 minutes). Analytical data: HPLC retention time (title compound) 8.4 minutes; MS: 349.36 (calc), M+1=350.1; 1H NMR in CDCl3: 8.75 doublet, (1H), 8.26 Quartet (1H), 7.38 multiplet (3H), 7.36 doublet (2H), 6.70 multiplet (2H), 3.08, Singlet, (3H); 13C NMR in CDCl3: 15.3, 149.3, 147.9, 146.6, 138.1, 130.27, 133.5, 130.0, 129.1, 128.7, 117.9, 113.4, 111.1, 108.1, 107.7, 45.). held for 1 hour The pot was then cooled to 20-30° C was added (slight exotherm, reaction temp kept below 45° C.) the reaction product was granulated for 2 hours The product was filtered on a 36-inch nutche filter dressed with a poly cloth in less than 2 hours The filter cake was rinsed with an additional 12 gallons (4V) of water the cake was blown dry for 12 hours HPLC retention time (title compound) 8.4 minutes

反应条件: temp:24.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a clean and dry nitrogen purged 22 L round bottom flask under nitrogen atmosphere was charged: 500 g of 5-(methylsulfonyl)-2-hydrazinyl-pyridine (2.67 moles), 10 L water (20 volumes) and 579 mL of concentrated H2SO4 (0.063 volumes). In a separate 12 L 3-neck round-bottomed flask was prepared a solution of 7500 mL of isopropanol (15 volumes) and 508 g (2.56 moles) of 4,4-difluoro-1-phenyl-1,3-butanedione. The isopropanol/4,4-difluoro-1-phenyl-1,3-butanedione solution was added to the mixture containing the 5-(methylsulfonyl)-2-hydrazinyl-pyridine, keeping the pot temperature below 30° C. After addition of the 4,4-difluoro-1-phenyl-1,3-butanedione solution, the mixture was stirred at 24° C. for 1.0 hour and sampled for disappearance of 5-(methylsulfonyl)-2-hydrazinyl-pyridine by HPLC. The pot was then heated to 40° C. for 2 hours until disappearance of the intermediate compound of formula 4 and the resulting slurry was filtered and washed with water to achieve a pH of the filtrate of from about 6-7. The solids were then charged to a 5L 3-neck round-bottom flask. To the flask was added 1250 mL water (2.5 volumes) and 1250 mL isopropanol (2.5 volumes). The mixture was heated to reflux (85° C.) for 2 hours. The pot was then cooled to 40° C. and then stirred overnight. The solids were isolated by filtration, washed with 2 L isopropanol, and dried in a vacuum oven at 45° C. The compound of formula 6 was present at a level of 1.2% by HPLC (retention time 5.1 minutes). Analytical data: HPLC retention time (title compound) 8.4 minutes; MS: 349.36 (calc), M+1=350.1; 1H NMR in CDCl3: 8.75 doublet, (1H), 8.26 Quartet (1H), 7.38 multiplet (3H), 7.36 doublet (2H), 6.70 multiplet (2H), 3.08, Singlet, (3H); 13C NMR in CDCl3: 15.3, 149.3, 147.9, 146.6, 138.1, 130.27, 133.5, 130.0, 129.1, 128.7, 117.9, 113.4, 111.1, 108.1, 107.7, 45. To a clean and dry nitrogen purged 22 L round bottom flask under nitrogen atmosphere was charged the pot temperature below 30° C the resulting slurry was filtered washed with water The solids were then charged to a 5L 3-neck round-bottom flask To the flask was added 1250 mL water (2.5 volumes) and 1250 mL isopropanol (2.5 volumes) The mixture was heated to reflux (85° C.) for 2 hours The pot was then cooled to 40° C. stirred overnight The solids were isolated by filtration washed with 2 L isopropanol dried in a vacuum oven at 45° C HPLC retention time (title compound) 8.4 minutes

反应条件: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a clean and dry nitrogen purged 1 L round-bottom flask under nitrogen atmosphere was charged 25.6 g of 5-(methylsulfonyl)-2-hydrazinyl-pyridine (0.14 moles), 512 mL water (20 volumes) and 16 mL of concentrated H2SO4 (0.063 volumes). In a separate 500 mL 1-neck round-bottom flask, was prepared a solution of 384 mL of isopropanol (15 volumes) and 26.01 g (0.13 moles) of 4,4-difluoro-1-phenyl-1,3-butanedione. The isopropanol/4,4-difluoro-1-phenyl-1,3-butanedione solution was added to the 5-(methylsulfonyl)-2-hydrazinyl-pyridine reaction mixture keeping the pot temperature less than 25° C. After addition, the mixture was stirred at 22° C. for 2.0 hours and sampled for disappearance of starting material. When the starting materials had disappeared (less than 15 remaining), the pot was then heated to 40° C. for 5.5 hours until disappearance of the intermediate. The resulting slurry was filtered and washed with water to achieve a pH 6-7 of the filtrate. The solids were then charged to a 250 mL 3-neck round-bottom flask. To the flask was added: 31.25 mL water (1.2 volumes) and 31.25 mL isopropanol (1.2 volumes). The mixture was heated to reflux (85° C.) for 30 minutes. The pot was allowed to cool to 28° C. and the solids were isolated by filtration and washed with 20 mL isopropanol. The solids were dried in a vacuum oven at 45° C. The product was obtained with 87% yield and contained 0.54% of the compound of formula 6 (retention time 5.1 minutes). Analytical data: HPLC retention time (title compound) 8.4 minutes; MS: 349.36 (calc), M+1=350.1; 1H NMR in CDCl3: 8.75 doublet, (1H), 8.26 Quartet (1H), 7.38 multiplet (3H), 7.36 doublet (2H), 6.70 multiplet (2H), 3.08, Singlet, (3H); 13C NMR in CDCl3: 15.3, 149.3, 147.9, 146.6, 138.1, 130.27, 133.5, 130.0, 129.1, 128.7, 117.9, 113.4, 111.1, 108.1, 107.7, 45. To a clean and dry nitrogen purged 1 L round-bottom flask under nitrogen atmosphere the pot temperature less than 25° C After addition sampled for disappearance of starting material pot was then heated to 40° C. for 5.5 hours until disappearance of the intermediate The resulting slurry was filtered washed with water The solids were then charged to a 250 mL 3-neck round-bottom flask To the flask was added The mixture was heated to reflux (85° C.) for 30 minutes to cool to 28° C. the solids were isolated by filtration washed with 20 mL isopropanol The solids were dried in a vacuum oven at 45° C The product was obtained with 87% yield

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 120 g of 5-(methylsulfonyl)-2-hydrazinyl-pyridine [CP-675,775] (0.641 moles) was charged isopropanol (900 mL) followed by 4,4-difluoro-1-phenyl-1,3-butanedione (122 g, 0.615 moles, 0.96 eq.) as a melt, followed by 900 mL of isopropanol. The slurry was stirred for 15 minutes, then 36 mL of concentrated sulfuric acid was added (slight exotherm) (15 volumes of isopropanol total). The reaction was stirred for 6 hours at 20-30° C., 2.4 L (20 volumes) of water was added (slight exotherm, reaction temperature kept below 45° C.) and the reaction was granulated for 2 days. The product was filtered and was rinsed with water. The product contained less than 0.5% of compound 6 (retention time 5.1 minutes). Analytical data: HPLC retention time (title compound) 8.4 minutes; MS: 349.36 (calc), M+1=350.1; 1H NMR in CDCl3: 8.75 doublet, (1H), 8.26 Quartet (1H), 7.38 multiplet (3H), 7.36 doublet (2H), 6.70 multiplet (2H), 3.08, Singlet, (3H); 13C NMR in CDCl3: 15.3, 149.3, 147.9, 146.6, 138.1, 130.27, 133.5, 130.0, 129.1, 128.7, 117.9, 113.4, 111.1, 108.1, 107.7, 45. The reaction was stirred for 6 hours at 20-30° C. (slight exotherm, reaction temperature kept below 45° C.) the reaction was granulated for 2 days The product was filtered was rinsed with water HPLC retention time (title compound) 8.4 minutes