乙酰氧肟酸

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

实验步骤: To a mixed solution of 4-hydroxybenzoic acid (1.0 g) in a mixed solution (15 mL) of toluene and THF (toluene:THF=2:1, v/v) was added carbonyldiimidazole (1.29 g), and the mixture was stirred at room temperature for 1 hour. Subsequently, N-hydroxyacetamide (644 mg) was added thereto, and the mixture was further heated at 150° C. for 2 hours under reflux. The reaction solution was allowed to stand for cooling down to room temperature, diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1, v/v) to give the title compound (132 mg). the mixture was further heated at 150° C. for 2 hours under reflux for cooling down to room temperature washed successively with water and saturated brine dried over anhydrous sodium sulfate concentrated in vacuo The residue was purified by column chromatography on silica gel (ethyl acetate

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

实验步骤: To an ice-bath cooled and stirred solution of 5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2,3-difluorobenzonitrile (Intermediate 6, 500 mg, 0.96 mmol) in DMF was added t-BuOK (161 mg, 1.4 mmol) followed by acetohydroxamic acid (108 mg, 1.4 mmol). The mixture was brought to room temperature and stirred for 12 hours. The reaction mixture was diluted with EtOAc and washed successively with 1 N HCl (1×250 mL), water and brine. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified over silica gel flash column using a gradient of ethyl acetate in pet. ether to give the title compound as a white solid. Yield: 200 mg, (70%). To an ice-bath cooled was brought to room temperature washed successively with 1 N HCl (1×250 mL), water and brine The organic layer was dried (Na2SO4) filtered concentrated The residue was purified over silica gel flash column

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

实验步骤: To an ice-bath cooled and stirred solution of 5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2,3-difluorobenzonitrile (Intermediate 6, 500 mg, 0.96 mmol) in DMF was added t-BuOK (161 mg, 1.4 mmol) followed by acetohydroxamic acid (108 mg, 1.4 mmol). The mixture was brought to room temperature and stirred for 12 hours. The reaction mixture was diluted with EtOAc and washed successively with 1 N HCl (1×250 mL), water and brine. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified over silica gel flash column using a gradient of ethyl acetate in pet. ether to give the title compound as a white solid. Yield: 200 mg, (70%). To an ice-bath cooled was brought to room temperature washed successively with 1 N HCl (1×250 mL), water and brine The organic layer was dried (Na2SO4) filtered concentrated The residue was purified over silica gel flash column

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

实验步骤: Alternately, acid (XXXa) is prepared by first converting 2-fluoro-6-iodobenzoic acid to the acid chloride by reaction with a chlorinating agent such as oxalyl chloride, in a solvent such as DCM, with a catalytic amount of DMF, at a temperature of 0° C. Subsequent reaction of the acid chloride with N-hydroxyacetamide in a solvent such as CH2Cl2 provides (Z)—N′-((2-fluoro-6-iodobenzoyl)oxy)acetimidamide. 5-(2-Fluoro-6-iodophenyl)-3-methyl-1,2,4-oxadiazole is prepared by reacting (Z)—N′-((2-fluoro-6-iodobenzoyl)oxy)acetimidamide with sodium acetate, in a solvent such as tert-butanol, at temperatures ranging from 100° C. to 110° C. 3-Fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (XXXa) is prepared by reacting 5-(2-fluoro-6-iodophenyl)-3-methyl-1,2,4-oxadiazole with a grignard reagent such as i-PrMgCl, in a suitable solvent such as THF and the like, at a temperature of −78° C. Subsequent addition of CO2 gas, at a temperature of −78° C. provides 3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (XXXa). Alternately, acid (XXXa) is prepared at a temperature of 0° C

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

实验步骤: Alternately, acid (XXXa) is prepared by first converting 2-fluoro-6-iodobenzoic acid to the acid chloride by reaction with a chlorinating agent such as oxalyl chloride, in a solvent such as DCM, with a catalytic amount of DMF, at a temperature of 0° C. Subsequent reaction of the acid chloride with N-hydroxyacetamide in a solvent such as CH2Cl2 provides (Z)—N′-((2-fluoro-6-iodobenzoyl)oxy)acetimidamide. 5-(2-Fluoro-6-iodophenyl)-3-methyl-1,2,4-oxadiazole is prepared by reacting (Z)—N′-((2-fluoro-6-iodobenzoyl)oxy)acetimidamide with sodium acetate, in a solvent such as tert-butanol, at temperatures ranging from 100° C. to 110° C. 3-Fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (XXXa) is prepared by reacting 5-(2-fluoro-6-iodophenyl)-3-methyl-1,2,4-oxadiazole with a grignard reagent such as i-PrMgCl, in a suitable solvent such as THF and the like, at a temperature of −78° C. Subsequent addition of CO2 gas, at a temperature of −78° C. provides 3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (XXXa). Alternately, acid (XXXa) is prepared at a temperature of 0° C

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-(4-Chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-fluorobenzonitrile 15 (90 mg, 0.299 mmol) was added to a mixture of acetohydroxamic acid, CH3C(O)NHOH (0.0675 g, 0.899 mmol) and potassium carbonate (0.145 g, 1.049 mmol) in 4 mL dimethylformamide and the resultant reaction mixture was heated for 2 hours at 50° C. The solvent was removed, diluted with ethyl acetate and washed with saturated sodium bicarbonate (1×20 mL) followed by brine (1×20 mL), dried over anhydrous sodium sulfate, concentrated and purified by a Biotage purification system eluting with ethyl acetate and hexanes to obtain 17 (35 mg, 40%). the resultant reaction mixture The solvent was removed diluted with ethyl acetate washed with saturated sodium bicarbonate (1×20 mL) dried over anhydrous sodium sulfate concentrated purified by a Biotage purification system eluting with ethyl acetate and hexanes

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-(4-Chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-fluorobenzonitrile 15 (90 mg, 0.299 mmol) was added to a mixture of acetohydroxamic acid, CH3C(O)NHOH (0.0675 g, 0.899 mmol) and potassium carbonate (0.145 g, 1.049 mmol) in 4 mL dimethylformamide and the resultant reaction mixture was heated for 2 hours at 50° C. The solvent was removed, diluted with ethyl acetate and washed with saturated sodium bicarbonate (1×20 mL) followed by brine (1×20 mL), dried over anhydrous sodium sulfate, concentrated and purified by a Biotage purification system eluting with ethyl acetate and hexanes to obtain 17 (35 mg, 40%). the resultant reaction mixture The solvent was removed diluted with ethyl acetate washed with saturated sodium bicarbonate (1×20 mL) dried over anhydrous sodium sulfate concentrated purified by a Biotage purification system eluting with ethyl acetate and hexanes

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

实验步骤: To a stirred solution of acetohydroxamic acid (3.88 g) in N,N-dimethylformamide (DMF) (120 ml) was added potassium tertiarybutoxide (tBuOK) (5.80 g) under N2. After one hour of stirring 2-fluoro-4-(methoxymethoxy)-benzonitrile (6.0 g) was added. Stirring continued for 16 hours. TLC (silica gel) in 10% acetone/CHCl3 showed the presence of starting material. An additional 1 equivalent of acetohydroxamic acid and tBuOK were added in DMF (120 ml). After one hour the reaction was diluted with EtOAc (2 l), filtered, washed filtrate with brine (4×11), dried (MgSO4), and concentrated in vacuo. Flash column chromatography (silica gel) was performed eluting with 2.5% acetone/CH2Cl2 solution affording 8.1 g of the product, m.p. 88°-89° C. filtered washed filtrate with brine (4×11) dried (MgSO4) concentrated in vacuo Flash column chromatography (silica gel) was performed eluting with 2.5% acetone/CH2Cl2 solution

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

实验步骤: Acetohydroxamic acid (54 mg, 0.72 mmol) and K2CO3 (0.2 g, 1.45 mmol) were added to 8 mL of DMF and 4 mL of H2O. The mixture was stirred at rt for 15 min, followed by addition of a solution of 2-fluoro-5-[7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl]benzonitrile (0.12 g, 0.24 mmol) in DMF(2 mL). The mixture was stirred at rt overnight. The mixture was then partitioned between ethylacetate (40 mL) and water (20 mL), washed with H2O (20 mL×3) and brine (20 mL), dried over Na2SO4, filtered, and concentrated. HPLC (C18 RP., 0.5% TFA, H2O/MeCN gradient) purification gave 100 mg (67% yield) of the title compound as its TFA salt. LRMS (ESI−): 623.4 (M+TFA−H)−. 1H NMR (CDCl3) δ 7.80 (s, 1H), 7.72 (d, 1H), 7.44 (d, 1H), 7.34-7.24 (m, 4H), 4.16 (t, 2H), 3.98 (br, 2H), 3.61 (br, 2H), 3.20 (t, 2H), 2.60 (br, 2H), 1.98-1.89 (m, 4H). The mixture was stirred at rt overnight The mixture was then partitioned between ethylacetate (40 mL) and water (20 mL) washed with H2O (20 mL×3) and brine (20 mL) dried over Na2SO4 filtered concentrated HPLC (C18 RP., 0.5% TFA, H2O/MeCN gradient) purification

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

实验步骤: Acetohydroxamic acid (54 mg, 0.72 mmol) and K2CO3 (0.2 g, 1.45 mmol) were added to 8 mL of DMF and 4 mL of H2O. The mixture was stirred at rt for 15 min, followed by addition of a solution of 2-fluoro-5-[7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl]benzonitrile (0.12 g, 0.24 mmol) in DMF(2 mL). The mixture was stirred at rt overnight. The mixture was then partitioned between ethylacetate (40 mL) and water (20 mL), washed with H2O (20 mL×3) and brine (20 mL), dried over Na2SO4, filtered, and concentrated. HPLC (C18 RP., 0.5% TFA, H2O/MeCN gradient) purification gave 100 mg (67% yield) of the title compound as its TFA salt. LRMS (ESI−): 623.4 (M+TFA−H)−. 1H NMR (CDCl3) δ 7.80 (s, 1H), 7.72 (d, 1H), 7.44 (d, 1H), 7.34-7.24 (m, 4H), 4.16 (t, 2H), 3.98 (br, 2H), 3.61 (br, 2H), 3.20 (t, 2H), 2.60 (br, 2H), 1.98-1.89 (m, 4H). The mixture was stirred at rt overnight The mixture was then partitioned between ethylacetate (40 mL) and water (20 mL) washed with H2O (20 mL×3) and brine (20 mL) dried over Na2SO4 filtered concentrated HPLC (C18 RP., 0.5% TFA, H2O/MeCN gradient) purification

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

实验步骤: To a stirred solution of acetophydroxamic acid (3.88 g) in N,N-dimethylformamide (DMF) (120 ml) was added potassium tertiarybutoxide (tBuOK) (5.80 g) under N2. After one hour of stirring 2-fluoro-4-(methoxymethoxy)-benzonitrile (6.0 g) was added. Stirring continued for 16 hours. TLC (silica gel) in 10% acetone/CHCl3 showed the presence of starting material. An additional 1 equivalent of acetohydroxamic acid and tBuOK were added in DMF (120 ml). After one hour the reaction was diluted with EtOAc (2 l), filtered, washed filtrate with brine (4×11), dried (MgSO4), and concentrated in vacuo. Flash column chromatography (silica gel) was performed eluting with 2.5% acetone/CH2Cl2 solution affording 8.1 g of the product, m.p. 88-89° C. filtered washed filtrate with brine (4×11) dried (MgSO4) concentrated in vacuo Flash column chromatography (silica gel) was performed eluting with 2.5% acetone/CH2Cl2 solution

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

实验步骤: To a stirred solution of acetophydroxamic acid (3.88 g) in N,N-dimethylformamide (DMF) (120 ml) was added potassium tertiarybutoxide (tBuOK) (5.80 g) under N2. After one hour of stirring 2-fluoro-4-(methoxymethoxy)-benzonitrile (6.0 g) was added. Stirring continued for 16 hours. TLC (silica gel) in 10% acetone/CHCl3 showed the presence of starting material. An additional 1 equivalent of acetohydroxamic acid and tBuOK were added in DMF (120 ml). After one hour the reaction was diluted with EtOAc (2 l), filtered, washed filtrate with brine (4×11), dried (MgSO4), and concentrated in vacuo. Flash column chromatography (silica gel) was performed eluting with 2.5% acetone/CH2Cl2 solution affording 8.1 g of the product, m.p. 88-89° C. filtered washed filtrate with brine (4×11) dried (MgSO4) concentrated in vacuo Flash column chromatography (silica gel) was performed eluting with 2.5% acetone/CH2Cl2 solution