* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 1 h; Stage #2: With hydrogenchloride In water
c) 4-Chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid A solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmol) in tetrahydrofuran (18 ml) was treated at room temperature with a solution of lithium hydroxide (135 mg, 5.6 mmol) in a 1:1-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was dissolved in water (10 ml) and acidified with hydrochloric acid (2M). Extraction with ethyl acetate, drying of the organic layer over sodium sulphate, and evaporation at reduced pressure yielded a white solid (555 mg) which was triturated with pentane (10 ml). The solid material was filtered, washed with pentane and dried. After drying at reduced pressure the 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid was obtained as a white solid (477 mg, 95percent of theory). MS (ISP): m/z=195.0 [M-H]-.
95%
Stage #1: With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 1 h; Stage #2: With hydrogenchloride In water
A solution of 4-chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmol) in tetrahydrofuran (18 ml) was treated at room temperature with a solution of lithium hydroxide (135 mg, 5.6 mmol) in a l : l-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was dissolved in water (10 ml) and acidified with hydrochloric acid (2M). Extraction with ethyl acetate, drying of the organic layer over sodium sulphate, and evaporation at reduced pressure yielded a white solid (555 mg) which was triturated with pentane (10 ml). The solid material was filtered, washed with pentane and dried. After drying at reduced pressure the 4- chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid was obtained as a white solid (477 mg, 95percent of theory). MS (ISP): m/z = 195.0 [M-H]\\
95%
With lithium hydroxide In tetrahydrofuran; methanol; water at 20℃; for 1 h;
c) 4-Chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acidA solution of 4-chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmol) in tetrahydrofuran (18 ml) was treated at room temperature with a solution of lithium hydroxide (135 mg, 5.6 mmol) in a l: l-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was dissolved in water (10 ml) and acidified with hydrochloric acid (2M). Extraction with ethyl acetate, drying of the organic layer over sodium sulphate, and evaporation at reduced pressure yielded a white solid (555 mg) which was triturated with pentane (10 ml). The solid material was filtered, washed with pentane and dried. After drying at reduced pressure the 4-chloro-l- difluoromethyl-lH-pyrazole-3-carboxylic acid was obtained as a white solid (477 mg, 95percent); (calculated) C5H3CIF2N2O2 [196.540]; (found) [M-H]~ = 195.
95%
Stage #1: With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 1 h; Stage #2: With hydrogenchloride In water
c) 4-Chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid A solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmol) in tetrahydrofuran (18 ml) was treated at room temperature with a solution of lithium hydroxide (135 mg, 5.6 mmol) in a 1:1-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was dissolved in water (10 ml) and acidified with hydrochloric acid (2M). Extraction with ethyl acetate, drying of the organic layer over sodium sulphate, and evaporation at reduced pressure yielded a white solid (555 mg) which was triturated with pentane (10 ml). The solid material was filtered, washed with pentane and dried. After drying at reduced pressure the 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid was obtained as a white solid (477 mg, 95percent); (calculated) C5H3ClF2N2O2 [196.540]; (found) [M'H]-=195.
95%
Stage #1: With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 1 h; Stage #2: With hydrogenchloride In water
c) 4-Chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acidA solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmol) in tetrahydrofuran (18 ml) was treated at room temperature with a solution of lithium hydroxide (135 mg, 5.6 mmol) in a 1:1-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was dissolved in water (10 ml) and acidified with hydrochloric acid (2M). Extraction with ethyl acetate, drying of the organic layer over sodium sulphate, and evaporation at reduced pressure yielded a white solid (555 mg) which was triturated with pentane (10 ml). The solid material was filtered, washed with pentane and dried. After drying at reduced pressure the 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid was obtained as a white solid (477 mg, 95percent of theory). MS (ISP): m/z=195.0 [M-H]-.
95%
Stage #1: With water; lithium hydroxide In tetrahydrofuran at 20℃; for 1 h; Stage #2: With hydrogenchloride In water
c) 4-Chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid A solution of 4-chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmol) in tetrahydrofuran (18 ml) was treated at room temperature with a solution of lithium hydroxide (135 mg, 5.6 mmol) in a l : l-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was dissolved in water (10 ml) and acidified with hydrochloric acid (2M). Extraction with ethyl acetate, drying of the organic layer over sodium sulphate, and evaporation at reduced pressure yielded a white solid (555 mg) which was triturated with pentane (10 ml). The solid material was filtered, washed with pentane and dried. After drying at reduced pressure the 4- chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid was obtained as a white solid (477 mg, 95percent of theory). MS (ISP): m/z = 195.0 [M-H]".
c) 4-Chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid A solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmol) in tetrahydrofuran (18 ml) was treated at room temperature with a solution of lithium hydroxide (135 mg, 5.6 mmol) in a 1:1-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was dissolved in water (10 ml) and acidified with hydrochloric acid (2M). Extraction with ethyl acetate, drying of the organic layer over sodium sulphate, and evaporation at reduced pressure yielded a white solid (555 mg) which was triturated with pentane (10 ml). The solid material was filtered, washed with pentane and dried. After drying at reduced pressure the 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid was obtained as a white solid (477 mg, 95% of theory). MS (ISP): m/z=195.0 [M-H]-.
95%
A solution of 4-chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmol) in tetrahydrofuran (18 ml) was treated at room temperature with a solution of lithium hydroxide (135 mg, 5.6 mmol) in a l : l-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was dissolved in water (10 ml) and acidified with hydrochloric acid (2M). Extraction with ethyl acetate, drying of the organic layer over sodium sulphate, and evaporation at reduced pressure yielded a white solid (555 mg) which was triturated with pentane (10 ml). The solid material was filtered, washed with pentane and dried. After drying at reduced pressure the 4- chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid was obtained as a white solid (477 mg, 95% of theory). MS (ISP): m/z = 195.0 [M-H]
95%
With lithium hydroxide; In tetrahydrofuran; methanol; water; at 20℃; for 1h;
c) 4-Chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acidA solution of 4-chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmol) in tetrahydrofuran (18 ml) was treated at room temperature with a solution of lithium hydroxide (135 mg, 5.6 mmol) in a l: l-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was dissolved in water (10 ml) and acidified with hydrochloric acid (2M). Extraction with ethyl acetate, drying of the organic layer over sodium sulphate, and evaporation at reduced pressure yielded a white solid (555 mg) which was triturated with pentane (10 ml). The solid material was filtered, washed with pentane and dried. After drying at reduced pressure the 4-chloro-l- difluoromethyl-lH-pyrazole-3-carboxylic acid was obtained as a white solid (477 mg, 95%); (calculated) C5H3CIF2N2O2 [196.540]; (found) [M-H]~ = 195.
95%
c) 4-Chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid A solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmol) in tetrahydrofuran (18 ml) was treated at room temperature with a solution of lithium hydroxide (135 mg, 5.6 mmol) in a 1:1-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was dissolved in water (10 ml) and acidified with hydrochloric acid (2M). Extraction with ethyl acetate, drying of the organic layer over sodium sulphate, and evaporation at reduced pressure yielded a white solid (555 mg) which was triturated with pentane (10 ml). The solid material was filtered, washed with pentane and dried. After drying at reduced pressure the 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid was obtained as a white solid (477 mg, 95%); (calculated) C5H3ClF2N2O2 [196.540]; (found) [M'H]-=195.
95%
c) 4-Chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acidA solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmol) in tetrahydrofuran (18 ml) was treated at room temperature with a solution of lithium hydroxide (135 mg, 5.6 mmol) in a 1:1-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was dissolved in water (10 ml) and acidified with hydrochloric acid (2M). Extraction with ethyl acetate, drying of the organic layer over sodium sulphate, and evaporation at reduced pressure yielded a white solid (555 mg) which was triturated with pentane (10 ml). The solid material was filtered, washed with pentane and dried. After drying at reduced pressure the 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid was obtained as a white solid (477 mg, 95% of theory). MS (ISP): m/z=195.0 [M-H]-.
95%
c) 4-Chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid A solution of 4-chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmol) in tetrahydrofuran (18 ml) was treated at room temperature with a solution of lithium hydroxide (135 mg, 5.6 mmol) in a l : l-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was dissolved in water (10 ml) and acidified with hydrochloric acid (2M). Extraction with ethyl acetate, drying of the organic layer over sodium sulphate, and evaporation at reduced pressure yielded a white solid (555 mg) which was triturated with pentane (10 ml). The solid material was filtered, washed with pentane and dried. After drying at reduced pressure the 4- chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid was obtained as a white solid (477 mg, 95% of theory). MS (ISP): m/z = 195.0 [M-H]".
A solution of 4-chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmole) in THF (18 ml) was treated at 22C with a solution of lithium hydroxide (135 mg, 5.6 mmole) in a 1 : 1-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was partitioned between 2 M aqueous HCl and AcOEt, the organic layer was dried, evaporated, the residue was triturated with pentane and the solid was dried to give the title compound (477 mg) as a white solid. MS: m/z = 195.0 [M-H]
c) 4-Chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid A solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmole) in THF (18 ml) was treated at 22 C. with a solution of lithium hydroxide (135 mg, 5.6 mmole) in a 1:1-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was partitioned between 2 M aqueous HCl and AcOEt, the organic layer was dried, evaporated, the residue was triturated with pentane and the solid was dried to give the title compound (477 mg) as a white solid. MS: m/z=195.0 [M-H]-.
A solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmole) in THF (18 ml) was treated at 22 C. with a solution of lithium hydroxide (135 mg, 5.6 mmole) in a 1:1-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was partitioned between 2 M aqueous HCl and AcOEt, the organic layer was dried, evaporated, the residue was triturated with pentane and the solid was dried to give the title compound (477 mg) as a white solid. MS: m/z=195.0 [M-H]-.
c) 4-Chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acidA solution of 4-chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmole) in THF (18 ml) was treated at 22C with a solution of lithium hydroxide (135 mg, 5.6 mmole) in a l: l-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was partitioned between 2 M aqueous HCl and AcOEt, the organic layer was dried, evaporated, the residue was triturated with pentane and the solid was dried to give the title compound (477 mg) as a white solid. MS: m/z = 195.0 [M-H]"
c) 4-Chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid A solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmole) in THF (18 ml) was treated at 23 C. with a solution of lithium hydroxide (135 mg, 5.6 mmole) in a 1:1-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was partitioned between 2 M aqueous HCl and AcOEt, the organic layer was dried, evaporated, the residue was triturated with pentane and the solid was dried to give the title compound (477 mg) as a white solid. MS: m/z=195.0 [M-H]-.
c) 4-Chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acidFA solution of 4-chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmole) in THF (18 ml) was treated at 23 C with a solution of lithium hydroxide (135 mg, 5.6 mmole) in a l : l-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was partitioned between 2 M aqueous HCl and AcOEt, the organic layer was dried, evaporated, the residue was triturated with pentane and the solid was dried to give the title compound (477 mg) as a white solid. MS: m/z = 195.0 [M-H]".
c) 4-Chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acidA solution of 4-chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmol) in tetrahydrofuran (18 ml) was treated at 23 C with a solution of lithium hydroxide (135 mg, 5.6 mmol) in a l: l-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was partitioned between 2 M aqueous hydrochloric acid and ethyl acetate. The organic layer was dried, evaporated, the residue was triturated with pentane and the solid was dried to give the title compound (477 mg) as a white solid. MS (ISP): m/z = 195.0 [M-H]~.
With water; lithium hydroxide; In tetrahydrofuran; methanol; at 23℃; for 1h;
c) 4-Chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid A solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (540 mg, 2.6 mmol) in tetrahydrofuran (18 ml) was treated at 23 C. with a solution of lithium hydroxide (135 mg, 5.6 mmol) in a 1:1-mixture of water and methanol (12 ml). After 1 hour the reaction was complete, and the solvents were evaporated at reduced pressure. The residue was partitioned between 2 M aqueous hydrochloric acid and ethyl acetate. The organic layer was dried, evaporated, the residue was triturated with pentane and the solid was dried to give the title compound (477 mg) as a white solid. MS (ISP): m/z=195.0 [M-H]-.
a) 1-Difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester A solution of <strong>[1310350-99-2]1-difluoromethyl-1H-pyrazole-3-carboxylic acid</strong> (CAS925179-02-8) (500 mg, 3.1 mmole) in methanol (18 ml) was cooled to 0 C. and treated with sulphuric acid (98%, 0.2 ml, 3.1 mmol). The mixture was heated to reflux for 2 hours, cooled to 22 C. and concentrated at reduced pressure. The residue was partitioned between AcOEt and water, the organic layer was washed with water until the water phase showed a neutral pH, dried and evaporated to give the title compound (535 mg) as a colorless liquid which was used without further purification. MS: m/z=177.1 [M+H]+.
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
d) 4-Chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid methoxy-methyl-amide A suspension of 4-chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid (880 mg, 4.5 mmol) and Nu,Omicron-dimethylhydroxylamine hydrochloride (459 mg, 4.7 mmol) in dichloromethane (30 ml) was treated at room temperature with N-methylmorpholine (476 mg, 4.7 mmol). Thereafter, in three portions l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (901 mg, 4.7 mmol) was added. The solution was stirred at room temperature overnight. For the workup, the reaction mixture was treated dropwise with hydrochloric acid (1M, 30 ml) and stirred for 10 minutes. The organic layer was separated, washed with water, then dried over sodium sulphate and evaporated. The crude material was purified by chromatography on silica gel using a 2: 1- mixture of cyclohexane and ethyl acetate as the eluent. The 4-chloro-l-difluoromethyl-lH- pyrazole-3-carboxylic acid methoxy-methyl-amide was obtained as a colourless oil (930 mg, 87%).
87%
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
d) 4-Chloro-<strong>[1310350-99-2]1-difluoromethyl-1H-pyrazole-3-carboxylic acid</strong> methoxy-methyl-amide A suspension of <strong>[1310350-99-2]4-chloro-<strong>[1310350-99-2]1-difluoromethyl-1H-pyrazole-3-carboxylic acid</strong></strong> (880 mg, 4.5 mmol) and N,O-dimethylhydroxylamine hydrochloride (459 mg, 4.7 mmol) in dichloromethane (30 ml) was treated at room temperature with N-methylmorpholine (476 mg, 4.7 mmol). Thereafter, in three portions 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (901 mg, 4.7 mmol) was added. The solution was stirred at room temperature overnight. For the workup, the reaction mixture was treated dropwise with hydrochloric acid (1M, 30 ml) and stirred for 10 minutes. The organic layer was separated, washed with water, then dried over sodium sulphate and evaporated. The crude material was purified by chromatography on silica gel using a 2:1-mixture of cyclohexane and ethyl acetate as the eluent. The <strong>[1310350-99-2]4-chloro-<strong>[1310350-99-2]1-difluoromethyl-1H-pyrazole-3-carboxylic acid</strong></strong> methoxy-methyl-amide was obtained as a colourless oil (930 mg, 87%).
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 22℃; for 16h;
A solution of <strong>[1310350-99-2]4-chloro-<strong>[1310350-99-2]1-difluoromethyl-1H-pyrazole-3-carboxylic acid</strong></strong> (150 mg, 0.76 mmole) in dichloromethane (5 ml) was subsequently treated at 22 C. with N,O-dimethylhydroxylamine hydrochloride (78 mg, 0.80 mmole), N-methylmorpholine (0.09 ml, 0.8 mmole) and EDCI.HCl (154 mg, 0.8 mmole) and stirring was continued for 16 h. The mixture was washed with 1 M aqueous HCl and H2O, the organic layer was dried, evaporated and the residue purified by chromatography on silica gel using cyclohexane/AcOEt (2:1) to give the title compound (164 mg) as a colorless oil. MS: m/z=240.1 [M]+.
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; for 16h;
d) 4-Chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid methoxy-methyl- amideA solution of 4-chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid (150 mg, 0.76 mmole) in dichloromethane (5 ml) was subsequently treated at 22C with Nu,Omicron- dimethylhydroxylamine hydrochloride (78 mg, 0.80 mmole), N-methylmorpholine (0.09 ml, 0.8 mmole) and EDCI.HC1 (154 mg, 0.8 mmole) and stirring was continued for 16 h. The mixture was washed with 1 M aqueous HCl and H20, the organic layer was dried, evaporated and the residue purified by chromatography on silica gel using cyclohexane/ AcOEt (2: 1) to give the title compound (164 mg) as a colorless oil. MS: m/z = 240.1 [M]+.
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 23℃; for 16h;
d) 4-Chloro-<strong>[1310350-99-2]1-difluoromethyl-1H-pyrazole-3-carboxylic acid</strong> methoxy-methyl-amide A solution of <strong>[1310350-99-2]4-chloro-<strong>[1310350-99-2]1-difluoromethyl-1H-pyrazole-3-carboxylic acid</strong></strong> (150 mg, 0.76 mmole) in dichloromethane (5 ml) was subsequently treated at 23 C. with N,O-dimethylhydroxylamine hydrochloride (78 mg, 0.80 mmole), N-methylmorpholine (0.09 ml, 0.8 mmole) and EDCI.HCl (154 mg, 0.8 mmole) and stiffing was continued for 16 h. The mixture was washed with 1 M aqueous HCl and H2O, the organic layer was dried, evaporated and the residue purified by chromatography on silica gel using cyclohexane/AcOEt (2:1) to give the title compound (164 mg) as a colorless oil. MS: m/z=240.1 [M]+.
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 23℃; for 16h;
d) 4-Chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid methoxy-methyl-amideF A solution of 4-chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid (150 mg, 0.76 mmole) in dichloromethane (5 ml) was subsequently treated at 23 C with N,0- dimethylhydroxylamine hydrochloride (78 mg, 0.80 mmole), N-methylmorpholine (0.09 ml, 0.8 mmole) and EDCI.HC1 (154 mg, 0.8 mmole) and stirring was continued for 16 h. The mixture was washed with 1 M aqueous HCl and H20, the organic layer was dried, evaporated and the residue purified by chromatography on silica gel using cyclohexane/AcOEt (2: 1) to give the title compound (164 mg) as a colorless oil. MS: m/z = 240.1 [M]+.
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 23℃; for 16h;
d) 4-Chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid methoxy-methyl- amideA solution of 4-chloro-l-difluoromethyl-lH-pyrazole-3-carboxylic acid (150 mg, 0.76 mmol) in dichloromethane (5 ml) was subsequently treated at 23 C with N,0- dimethylhydroxylamine hydrochloride (78 mg, 0.80 mmol), N-methylmorpholine (0.09 ml, 0.8 mmol) and N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (154 mg, 0.8 mmol) and stirring was continued for 16 hours. The mixture was washed with 1 M aqueous hydrochloric acid and water, the organic layer was dried, evaporated and the residue purified by chromatography on silica gel using cyclohexane/ethyl acetate (2: 1) as the eluent to give the title compound (164 mg) as a colorless oil. MS (ISP): m/z = 240.1 [M]+.
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;
Step 1: 4-chloro-1-(difluoromethyl)-N-methoxy-N-methyl-1H-pyrazole-3-carboxamide To a solution of <strong>[1310350-99-2]4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid</strong> (0.38 g, 1.933 mmol) in DCM (12.89 ml) was added N-methylmorpholine (0.234 ml, 2.127 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.408 g, 2.127 mmol), and N,O-dimethylhydroxylamine hydrochloride (0.207 g, 2.127 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was then partitioned between ethyl acetate and water. The organic portion was concentrated and the crude product was purified by silica-gel chromatography, eluting with a gradient of 10-40% Ethyl Acetate/Heptanes to give the title compound (270 mg, 1.127 mmol, 58.3% yield) as a white solid. LC/MS (ESI+) m/z=240 (M+H).
Example 196 N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4,5-difluorophenyl)-4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide The title compound was synthesized by procedures and steps analogous to those described in Method Z, Example 186 above, but using <strong>[1310350-99-2]4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid</strong> (WO201169934). MS m/z=488.1 [M+H]+. Calculated for C17H13ClF7N5O2: 487.76 1H NMR (400 MHz, CHLOROFORM-d) delta=8.57 (br. s., 1H), 8.12-8.04 (m, 1H), 7.93 (s, 1H), 7.31-6.99 (t, 1H), 6.99-6.95 (m, 1H), 4.06 (m, 1H), 2.80 (dd, J=2.2, 13.7 Hz, 1H), 1.92 (t, J=13.1 Hz, 1H), 1.65 (s, 3H)
Example 72 Synthesis of N-(5-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-6-fluoropyridin-3-yl)-4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide The title compound was synthesized using steps and procedures analogous to those described in Method H (Example 66) above, but using <strong>[1310350-99-2]4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid</strong> (WO2011069934) in step 2. MS m/z=471.0 [M+H]+. Calculated for C16H13ClF6N6O2: 470.8 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.63 (s, 3H) 1.91 (t, J=13.30 Hz, 1H) 2.81 (dd, J=13.99, 2.25 Hz, 1H) 3.99 (m, J=9.88, 5.38 Hz, 1H) 4.41 (br. s., 2H) 7.14 (s, 1H) 7.93 (s, 1H) 8.04 (dd, J=8.80, 2.54 Hz, 1H) 8.54-8.67 (m, 2H).
Example 88 Synthesis of N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide The title compound was synthesized by procedures and steps analogous to those described in Example 84, but using <strong>[1310350-99-2]4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid</strong> (WO2011069934) in step 1. MS m/z=471 [M+H]+. Calculated for C16H13ClF6N6O2: 470.8. 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.64 (s, 3H) 1.77 (t, J=13.01 Hz, 1H) 2.97 (dd, J=13.50, 3.13 Hz, 1H) 4.45 (ddd, J=12.18, 6.02, 2.93 Hz, 1H) 7.00-7.36 (m, 1H) 7.48 (dd, J=10.37, 9.00 Hz, 1H) 7.94 (s, 1H) 8.27 (dd, J=8.80, 2.93 Hz, 1H) 9.05 (br. s., 1H).
Synthesis of 4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide The title compound was prepared according to Method AA starting from <strong>[1310350-99-2]4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid</strong> (WO201169934). MS m/z=196 (M+H).
(R)-6-(5-amino-2-fluorophenyl)-6-methyl-6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazin-4-amine[ No CAS ]
N-{3-[(6R)-4-amino-6-methyl-6,7-dihydro[1,2,3 ]triazolo[1,5-a]pyrazin-6-yl]-4-fluorophenyl}-4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
4-Chloro-l -(difluoromethyl)- 1 H-pyrazole-3 -carboxylic acid (0.083 g, 0.423 mmol) was added to DMTMM (0.117 g, 0.423 mmol) in MeOH (2 mL). After stirring the mixture for 5 minutes, a solution of intermediate 1-12 (0.1 g, 0.384 mmol) in MeOH (2 mL) was added at 0 C, and the mixture was stirred for 24 hours. The solvent was evaporated in vacuo. The residue was then suspended in DCM and treated with sat. aq. Na2C03 sol. The organic layer was separated, dried (MgS04), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 7 M ammonia in MeOH/DCM 0/100 to 5/95). The desired fractions were collected and concentrated in vacuo. The product was purified further by preparative HPLC (RP, C18 XBridge 30x100 5 urn), mobile phase (gradient 90% 0.1% to 0% 0.1% NH4HCO3/NH4OH pH 9 solution in water, 10% MeCN). The desired fractions were collected and the product was extracted with DCM. The organic layer was separated, dried (MgS04), filtered and concentrated in vacuo. The residue was dried overnight (vacuum oven, 50C) yielding compound 5 (53 mg, 31% yield) as a pale yellow solid.
With water; lithium hydroxide; In tetrahydrofuran; methanol; at 20℃; for 1h;
General procedure: To a solution of C16 (18 g, 1 10 mmol) in tetrahydrofuran (150 mL) was added a solution of lithium hydroxide (5.42 g, 226 mmol) in a mixture of methanol and water (1 : 1 , 500 mL). The reaction mixture was stirred at room temperature for 1 hour, whereupon it was concentrated in vacuo. After the residue had been dissolved in water (500 mL), it was acidified to a pH of 2 by addition of 2 M aqueous hydrochloric acid. The aqueous layer was then extracted with ethyl acetate (2 x 100 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure, providing the product as a yellow solid. Yield: 13 g, 90 mmol, 82%. LCMS m/z 144.0 [M-H+]. 1 H NMR (400 MHz, CD3OD) delta 8.61 (s, 1 H), 5.47 (d, JHF=47 HZ, 2H).
21
[ 1310350-99-2 ]
N-(6-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide[ No CAS ]
N-(6-((3aR,4S,8S)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-5-fluoropyridin-2-yl)-4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide[ No CAS ]
4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carbonyl chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; toluene; at 0 - 20℃; for 3.5h;
4-Chloro- l-(difluoromethyl)-lH-pyrazole-3-carboxylic acid (111 mg, 565 muiotaetaomicron) was suspended in dichloromethane (5 mL), the suspension was cooled to 0-5C (ice bath) and oxalyl chloride (100 mg, 791 muiotaetaomicron) as well as dimethylformamide (0.308 M in toluene, 76 mu^, 23 muiotaetaomicron) were added. The mixture was stirred for 3.5 h at room temperature. Then, it was concentrated in vacuo (40C, 5 mbar) and dried azeotropically by addition of toluene (5 mL) followed by concentration in vacuo to afford 4-chloro-l-(difluoromethyl)-lH-pyrazole-3-carbonyl chloride as light yellow oil (121 mg, quant.). After that, tert-butyl ((3aS,4R,8R)-4-(6-amino-3-fluoropyridin- 2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a][l,4]thiazin-6- yl)carbamate (Int-39AB, 100 mg, 235 muiotaetaomicron) was dissolved in dichloromethane (5 mL), the solution cooled to 0-5C (ice bath) and N,N-diisopropylethylamine (46 mg, 62 muL, 353 mupiiotaomicron) and 4-(dimethylamino)pyridine (2.9 mg, 23.5 muiotatauiotaomicron) were added, followed by a solution of 4- chloro-l-(difluoromethyl)- lH-pyrazole-3-carbonyl chloride (vide supra, 61 mg, 282 muiotaetaomicron) in dichloromethane (5 mL). The reaction mixture was stirred for 75 min at room temperature. Then, additional portions of N,N-diisopropylethylamine (46 mg, 62 muL, 353 muiotatauiotaomicron) and a solution of 4- chloro-l-(difluoromethyl)- lH-pyrazole-3-carbonyl chloride (vide supra, 60 mg, 280 muiotaetaomicron) in dichloromethane (5 mL) were added, the mixture was stirred for 16 h at room temperature. After that, a third portion of N,N-diisopropylethylamine (46 mg, 62 mu, 353 mupiiotaomicron) and a solution of 4- chloro-l-(difluoromethyl)- lH-pyrazole-3-carbonyl chloride (vide supra, 61 mg, 282 muiotaetaomicron) in dichloromethane (5 mL) were added, the mixture was stirred for a further 1 h at room temperature. Aqueous sodium carbonate solution (10% m/m, 25 mL) was added, the aqueous phase was extracted with dichloromethane (2 x 25 mL), the combined organic extracts were dried (sodium sulfate) and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 24 g, eluting with ethyl acetate / dichloromethane, gradient 35:65 to 100:0) to yield, after drying in vacuo (40C, 5 mbar), the title compound as an off-white solid (71 mg, 50% yield). HPLC (method LCMS_fglm) tR = 1.31 min. MS (ES+) m/z 604.4 [M+H] .
100%
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; toluene; at 0 - 20℃; for 2.5h;
4-Chloro- l-(diflouromethyl)- lH-pyrazole-3-carboxylic acid (63 mg, 320 muetaiotaomicron) was suspended in dichloromethane (5 mL), the suspension was cooled to 0-5C (ice bath) and oxalyl chloride (56.9 mg, 39.3 mu, 448 muiotaetaomicron) as well as dimethylformamide (0.308 M in toluene, 51.9 mu, 16 muiotaetaomicron) were added. The mixture was stirred for 2.5 h at room temperature. Then, it was concentrated in vacuo (40C, 5 mbar) and dried azeotropically by two cycles of addition of toluene (3 mL) followed by concentration in vacuo to afford 4-chloro- l-(diflouromethyl)-lH- pyrazole-3-carbonyl chloride as yellow oil (69 mg, quant.). After that, tert-butyl ((3aS,4R,8R)-4- (5-amino-2-fluorophenyl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5- a][l,4]thiazin-6-yl)carbamate (Int-16ABp, 80 mg, 188 muiotaetaomicron) was dissolved in dichloromethane (5 mL), the solution cooled to 10C and N,N-diisopropylethylamine (36.5 mg, 49.4 mu, 283 muiotaetaomicron) was added, followed by a solution of 4-chloro- l-(diflouromethyl)- lH-pyrazole-3-carbonyl chloride (vide supra, 55 mg, 256 muiotaetaomicron) in dichloromethane (4 mL). The reaction mixture was stirred for 15 min at 10C. Then, methanol (2 mL) was added, the mixture was stirred for 5 min at room temperature and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 35:65 to 100:0) to yield, after drying in vacuo (40C, 5 mbar), the title compound as a white solid (77 mg, 68%). HPLC (method LCMS_fglm) tR = 1.26 min. MS (ES+) m/z 603.5 [M+H] .
tert-butyl ((3aS,4R,8R)-4-(6-(4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamido)-3-fluoropyridin-2-yl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-6-yl)carbamate[ No CAS ]
tert-butyl ((3aS,4R,8R)-4-(5-(4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamido)-2-fluorophenyl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-6-yl)carbamate[ No CAS ]
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide[ No CAS ]
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