* 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 n-butyllithium In tetrahydrofuran at -78 - 20℃; for 3 h; Inert atmosphere Stage #2: at 20℃; for 1.08333 h;
Under room temperature, the 1-methyl -1H-pyrazole (2.0g, 24.4 mmol) dissolved in THF in (30 ml). Under the protection of the nitrogen of the obtained mixture to lower the temperature to -78 °C, then slowly dripping n-BuLi to the (10.72 ml, 26.8 mmol). Then the resulting mixture at -78 ° C stirring 2 hours, to room temperature, then the stirring is performed for 1 hour. Then to the reaction solution to maintain this temperature in drying CO2gas, approximately through 5 minutes. After stirring at room temperature, to 1 hours. To the obtained water is added in the mixture of (30 ml) the reaction quenching and diluting. The resulting mixture is extracted with methylene chloride. After acid aqueous phase precipitating a large amount of solid, filtered. The resulting filter cake is dried to obtain 1.5 g of white solid (yield: 48.8percent).
45.4%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 2 h; Stage #2: at -78℃; for 0.5 h; Stage #3: With hydrogenchloride In water at 2 - 3℃;
To a stirred solution of 1 -methyl- lH-pyrazole (609 mmol) in dry ether (600 mL) under an atmosphere of nitrogen is added a solution of n-BuLi in hexane (2.6 M, 670 mmol) dropwise at -78°C over a period of Ih. The reaction mixture is then stirred at this temperature for a further 1 h, and then dry carbon dioxide gas is passed through the mixture at -78°C for 30 min. The reaction mixture is then allowed to warm to room temperature and quenched with water (500 mL). The aqueous phase is separated, washed with ether (500 mL) and cooled to 2-3 0C. To the stirred mixture is added concentrated aqueous hydrochloric acid until a pη of 3 is obtained. The resulting precipitate is collected by filtration, washed with ice-cold water (20 mL), dried first in open air, and then in a vacuum desiccator over P2O5 to afford 2-methyl-2H-pyrazole-3-carboxylic acid as a white powder.[00249] Compound wt: 35.3g, 45.4percent yield. 1H NMR (400 MHz, OMSO-d6) δ: 13.31 (IH, bs);7.50 (IH, d); 6.81 (IH, d); 4.07 (3H, s).
45.4%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 2 h; Stage #2: at -78℃; for 0.5 h; Stage #3: With hydrogenchloride In water at 2 - 3℃;
To a stirred solution of 1 -methyl- lH-pyrazole (609 mmol) in dry ether (600 mL) under an atmosphere of nitrogen is added a solution of n-BuLi in hexane (2.6 M, 670 mmol) dropwise at -78°C over a period of Ih. The reaction mixture is then stirred at this temperature for a further 1 h, and then dry carbon dioxide gas is passed through the mixture at -78°C for 30 min. The reaction mixture is then allowed to warm to room temperature and quenched with water (500 mL). The aqueous phase is separated, washed with ether (500 mL) and cooled to 2-3 0C. To the stirred mixture is added concentrated aqueous hydrochloric acid until a pη of 3 is obtained. The resulting precipitate is collected by filtration, washed with ice-cold water (20 mL), dried first in open air, and then in a vacuum desiccator over P2O5 to afford 2-methyl-2H-pyrazole-3-carboxylic acid as a white powder.[0232] Compound wt: 35.3g, 45.4percent yield. 1H NMR (400 MHz, DMSOi6) δ: 13.31 (IH, bs);7.50 (IH, d); 6.81 (IH, d); 4.07 (3H, s).
45.4%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 2 h; Stage #2: at -78 - 20℃; for 0.5 h; Stage #3: With hydrogenchloride In water at 2 - 3℃;
To a stirred solution of 1-methyl-1H-pyrazole (609 mmol) in dry ether (600 mL) under an atmosphere of nitrogen was added a solution of n-BuLi in hexane (2.6M, 670 mmol) dropwise at -78oC over a period of 1 h. The reaction mixture was stirred at this temperature for a further 1 hour, and then dry carbon dioxide gas was passed through the mixture at -78oC for 30 min. The reaction mixture was then allowed to warm to room temperature and quenched with water (500 mL). The aqueous phase was separated, washed with ether (500 mL) and cooled to 2-3oC. To the stirred mixture was added concentrated aqueous hydrochloric acid until a pH of 3 was obtained. The resulting precipitate was collected by filtration, washed with ice-cold water (20 mL), dried first in open air, and then in a vacuum desiccator over phosphorus pentoxide to afford 2-methyl-2H-pyrazole-3-carboxylic acid as a white powder. Compound wt: 35.3 g, 45.4percent yield. 1H NMR (400 MHz, DMSO-d6) δ: 13.31(1H, bs); 7.50 (1H, d); 6.81 (1H, d); 4.07 (3H, s).
Stage #1: With sodium hydroxide In water at 40 - 80℃; for 2.75 h; Stage #2: With hydrogenchloride In water
Dimethyl sulfate (236 g, 177 mL, 1.87 mol) was added dropwise over 45 min to a stirred solution of pyrazole-3-carboxylic acid (200 g, 1.78 mol) in 20percent aqueous sodium hydroxide (850 mL) at 40 °C. The reaction mixture was heated at 80 °C for 2 h, cooled to room temperature, filtered, the filtrate acidified to pH 1 with concentrated HCI, the precipitate filtered, washed with water, and dried under vacuum to yield 1-methylpyrazole-5-carboxylic acid (85 g, 38percent). The filtrate was concentrated in vacuo to 800 ML, extracted with chloroform (15X400 mL), the organic phase dried over anhydrous magnesium sulfate, concentrated in vacuo, and the residue recrystallized from isopropanol to yield 1-METHYLPYRAZOLE-3-CARBOXYLIC acid (74 g) as a white crystalline solid.
38%
Stage #1: With sodium hydroxide In water at 40 - 80℃; for 2 h; Stage #2: With hydrogenchloride In water
A stirred solution of 3-methylpyrazole (82.1 g, 1.0 mol) in water (3.5 L) was heated to 70 °C. Potassium permanganate (111 g, 0.70 mol) was added in one portion, keeping the temperature near 70 °C. The reaction mixture was stirred for 1 h at 70 °C, and then a second portion of potassium permanganate (111 g) was added at 70 °C. After 1 h, a final portion of potassium permanganate (111 g) was added at 70 °C. The reaction mixture was stirred a further 2 h at 70 °C, and any unreacted oxidant was reduced by the dropwise addition of isopropanol. The reaction mixture was cooled to room temperature, filtered, the solid was rinsed with water, and the filtrate evaporated to 500 mL. The aqueous was chilled to 0 °C, acidified with concentrated HC1, filtered, the solid product washed with water, and dried under vacuum to provide pyrazole- 3-carboxylic acid as a white solid (64.4 g, 57percent). Dimethyl sulfate (236 g, 177 ML, 1.87 mol) was added dropwise over 45 min to a stirred solution of pyrazole-3-carboxylic acid (200 g, 1.78 mol) in 20percent aqueous sodium hydroxide (850 ML) at 40 °C. The reaction mixture was heated at 80 °C for 2 h, cooled to room temperature, filtered, the filtrate acidified to pH 1 with concentrated HC1, the precipitate filtered, washed with water, and dried under vacuum to yield 1-METHYLPYRAZOLE-5-CARBOXYLIC acid (85 g, 38percent). The filtrate was concentrated in vacuo to 800 ML, extracted with chloroform (15X400 mL), the organic phase dried over anhydrous magnesium sulfate, concentrated in vacuo, and the residue recrystallized from isopropanol to yield 1-METHYLPYRAZOLE-3-CARBOXYLIC acid (74 g) as a white crystalline solid. A suspension of the acid (90 g, 0.71 mol) and DMF (1 drop) in thionyl chloride (250 ML) was stirred at reflux under nitrogen for 2 h. The solvent was evaporated from the reaction mixture, the residue azeotroped with toluene (3X200 mL), diluted into toluene (250 mL), added to a suspension of Pd-C (10 wtpercent, 9.3 g) in toluene (500 ML), and the mixture stirred at reflux for 8 h with a gentle flow of hydrogen gas through the suspension. After cooling to room temperature, the suspension was filtered through celite, washed with toluene, and concentrated in vacuo. The residue was fractionally distilled under vacuum to provide the title compound (50 g, 63percent) as a low melting white solid (bp = 92 °C COMMAT; 8 MMHG).
Reference：
[1] J. Gen. Chem. USSR (Engl. Transl.), 1982, vol. 52, # 11, p. 2291 - 2296[2] Zhurnal Obshchei Khimii, 1982, vol. 52, # 11, p. 2592 - 2598
[3] J. Gen. Chem. USSR (Engl. Transl.), 1982, vol. 52, # 11, p. 2291 - 2296[4] Zhurnal Obshchei Khimii, 1982, vol. 52, # 11, p. 2592 - 2598
[5] Patent: WO2004/58702, 2004, A2, . Location in patent: Page 30-31; 24
[6] Patent: WO2004/58763, 2004, A1, . Location in patent: Page 39-40
3
[ 930-36-9 ]
[ 201230-82-2 ]
[ 16034-46-1 ]
Yield
Reaction Conditions
Operation in experiment
27%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.5 h; Stage #2: at 20℃; for 1 h;
1-Methyl-1H-pyrazole (5.00 g, 60.9 mmol) was dissolved in diethyl ether (anhydrous; 150 mL), n-butyllithium (2.5 M hexane solution, 26.8 mL, 67.0 mmol) was added while cooling to -78°C, and the mixture was stirred for 30 min at -78°C. The reaction mixture was added to finely pulverized dry ice (500 g), the mixture was heated to room temperature, and further stirred at room temperature for 1 hr. To the reaction mixture was added water (200 mL), and the aqueous layer was separated and washed with diethyl ether (3 x 100 mL). The aqueous layer was acidified by adding concentrated hydrochloric acid to pH 3, and the precipitate was collected by filtration, and dried to give the title compound (2.10 g) as a white solid (yield 27percent). 1H NMR (400 MHz, DMSO-d6) δ 4.05 (3H, s), 6.79 (1H, d, J = 2.0 Hz), 7.47 (1H, d, J = 2.0 Hz), 13.29 (1H, s).
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1984, vol. 20, # 5, p. 976 - 980[2] Zhurnal Organicheskoi Khimii, 1984, vol. 20, # 5, p. 1073 - 1078
[3] J. Gen. Chem. USSR (Engl. Transl.), 1982, vol. 52, # 11, p. 2291 - 2296[4] Zhurnal Obshchei Khimii, 1982, vol. 52, # 11, p. 2592 - 2598
[5] Journal of the Chemical Society, 1903, vol. 83, p. 469
[6] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1980, vol. 29, # 5, p. 778 - 784[7] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1980, # 5, p. 1071 - 1077
5
[ 15226-74-1 ]
[ 16034-46-1 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 3, p. 419 - 425
6
[ 15226-74-1 ]
[ 16034-46-1 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 3, p. 419 - 425
7
[ 930-36-9 ]
[ 16034-46-1 ]
Reference：
[1] Journal of the American Chemical Society, 1958, vol. 80, p. 6271,6273
[2] Justus Liebigs Annalen der Chemie, 1959, vol. 625, p. 55,60
8
[ 27258-33-9 ]
[ 16034-46-1 ]
Reference：
[1] Russian Chemical Bulletin, 2012, vol. 61, # 6, p. 1148 - 1153[2] Izv. Akad. Nauk, Ser. Khim., 2012, vol. 61, # 6, p. 1139 - 1143,5
9
[ 1621-91-6 ]
[ 77-78-1 ]
[ 16034-46-1 ]
[ 25016-20-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1369 - 1375
10
[ 930-36-9 ]
[ 109-72-8 ]
[ 60-29-7 ]
[ 16034-46-1 ]
Reference：
[1] Journal of the American Chemical Society, 1958, vol. 80, p. 6271,6273
[2] Justus Liebigs Annalen der Chemie, 1959, vol. 625, p. 55,60
11
[ 930-36-9 ]
[ 60-29-7 ]
[ 591-51-5 ]
[ 16034-46-1 ]
Reference：
[1] Journal of the American Chemical Society, 1958, vol. 80, p. 6271,6273
[2] Justus Liebigs Annalen der Chemie, 1959, vol. 625, p. 55,60
12
[ 16034-46-1 ]
[ 84547-84-2 ]
Reference：
[1] J. Gen. Chem. USSR (Engl. Transl.), 1982, vol. 52, # 11, p. 2291 - 2296[2] Zhurnal Obshchei Khimii, 1982, vol. 52, # 11, p. 2592 - 2598
13
[ 1621-91-6 ]
[ 77-78-1 ]
[ 16034-46-1 ]
[ 25016-20-0 ]
Yield
Reaction Conditions
Operation in experiment
38%
Stage #1: With sodium hydroxide In water at 40 - 80℃; for 2.75 h; Stage #2: With hydrogenchloride In water
Dimethyl sulfate (236 g, 177 mL, 1.87 mol) was added dropwise over 45 min to a stirred solution of pyrazole-3-carboxylic acid (200 g, 1.78 mol) in 20percent aqueous sodium hydroxide (850 mL) at 40 °C. The reaction mixture was heated at 80 °C for 2 h, cooled to room temperature, filtered, the filtrate acidified to pH 1 with concentrated HCI, the precipitate filtered, washed with water, and dried under vacuum to yield 1-methylpyrazole-5-carboxylic acid (85 g, 38percent). The filtrate was concentrated in vacuo to 800 ML, extracted with chloroform (15X400 mL), the organic phase dried over anhydrous magnesium sulfate, concentrated in vacuo, and the residue recrystallized from isopropanol to yield 1-METHYLPYRAZOLE-3-CARBOXYLIC acid (74 g) as a white crystalline solid.
38%
Stage #1: With sodium hydroxide In water at 40 - 80℃; for 2 h; Stage #2: With hydrogenchloride In water
A stirred solution of 3-methylpyrazole (82.1 g, 1.0 mol) in water (3.5 L) was heated to 70 °C. Potassium permanganate (111 g, 0.70 mol) was added in one portion, keeping the temperature near 70 °C. The reaction mixture was stirred for 1 h at 70 °C, and then a second portion of potassium permanganate (111 g) was added at 70 °C. After 1 h, a final portion of potassium permanganate (111 g) was added at 70 °C. The reaction mixture was stirred a further 2 h at 70 °C, and any unreacted oxidant was reduced by the dropwise addition of isopropanol. The reaction mixture was cooled to room temperature, filtered, the solid was rinsed with water, and the filtrate evaporated to 500 mL. The aqueous was chilled to 0 °C, acidified with concentrated HC1, filtered, the solid product washed with water, and dried under vacuum to provide pyrazole- 3-carboxylic acid as a white solid (64.4 g, 57percent). Dimethyl sulfate (236 g, 177 ML, 1.87 mol) was added dropwise over 45 min to a stirred solution of pyrazole-3-carboxylic acid (200 g, 1.78 mol) in 20percent aqueous sodium hydroxide (850 ML) at 40 °C. The reaction mixture was heated at 80 °C for 2 h, cooled to room temperature, filtered, the filtrate acidified to pH 1 with concentrated HC1, the precipitate filtered, washed with water, and dried under vacuum to yield 1-METHYLPYRAZOLE-5-CARBOXYLIC acid (85 g, 38percent). The filtrate was concentrated in vacuo to 800 ML, extracted with chloroform (15X400 mL), the organic phase dried over anhydrous magnesium sulfate, concentrated in vacuo, and the residue recrystallized from isopropanol to yield 1-METHYLPYRAZOLE-3-CARBOXYLIC acid (74 g) as a white crystalline solid. A suspension of the acid (90 g, 0.71 mol) and DMF (1 drop) in thionyl chloride (250 ML) was stirred at reflux under nitrogen for 2 h. The solvent was evaporated from the reaction mixture, the residue azeotroped with toluene (3X200 mL), diluted into toluene (250 mL), added to a suspension of Pd-C (10 wtpercent, 9.3 g) in toluene (500 ML), and the mixture stirred at reflux for 8 h with a gentle flow of hydrogen gas through the suspension. After cooling to room temperature, the suspension was filtered through celite, washed with toluene, and concentrated in vacuo. The residue was fractionally distilled under vacuum to provide the title compound (50 g, 63percent) as a low melting white solid (bp = 92 °C COMMAT; 8 MMHG).
Reference：
[1] J. Gen. Chem. USSR (Engl. Transl.), 1982, vol. 52, # 11, p. 2291 - 2296[2] Zhurnal Obshchei Khimii, 1982, vol. 52, # 11, p. 2592 - 2598
[3] J. Gen. Chem. USSR (Engl. Transl.), 1982, vol. 52, # 11, p. 2291 - 2296[4] Zhurnal Obshchei Khimii, 1982, vol. 52, # 11, p. 2592 - 2598
[5] Patent: WO2004/58702, 2004, A2, . Location in patent: Page 30-31; 24
[6] Patent: WO2004/58763, 2004, A1, . Location in patent: Page 39-40
14
[ 1621-91-6 ]
[ 77-78-1 ]
[ 16034-46-1 ]
[ 25016-20-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1369 - 1375
15
[ 67-56-1 ]
[ 16034-46-1 ]
[ 17827-60-0 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 0 - 20℃; for 12 h; Inert atmosphere
To a stirred solution of 1 -methyl- lH-pyrazole-5-carboxylic acid (5 g, 39.7 mmol) in methanol (100 mL) was added thionyl chloride (103.2 mmol) under argon atmosphere at 0 °C. The reaction mixture was stirred to room temperature over 12 h. The reaction mixture was cone, in vacuo, then diluted with water (100 mL), carefully quenched with sat'd aqueous NaHCC"3, and extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried with anhydrous sodium sulphate, filtered and the filtrate was concentrated to give afford the title compound as a white solid which was used without further purification (5 g, 90 percent) m/z 240.
Reference：
[1] Patent: WO2014/151142, 2014, A1, . Location in patent: Paragraph 0092
[2] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1980, vol. 29, # 5, p. 778 - 784[3] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1980, # 5, p. 1071 - 1077
16
[ 16034-46-1 ]
[ 18107-18-1 ]
[ 17827-60-0 ]
Yield
Reaction Conditions
Operation in experiment
94%
for 1 h;
Example 92: 2-Methyl-2H-pyrazole-3-carboxylic acid methyl ester; o \\ MeO \\J2-Methyl-2H-pyrazole-3-carboxylic acid (3.0 g, 24 mmol, 1.0 equiv) was dissolved in methanol (100 mL) and toluene (100 mL). The clear solution was slowly treated with (trimethylsilyl)diazomethane (24 mL of 2.0M in ether, 48 mmol, 2.0 equiv), stirred for 1 hour, concentrated in vacuo, and gave a clear oil (3.1 g, 94percent yield): 1H NMR (400 MHz, DMSO- d6) δ 7.52 (d, J = 2.0Hz, 1 H), 6.86 (d, J = 2.0Hz, 1 H), 4.07 (s, 3H), 3.82 (s, 3H).
Reference：
[1] Russian Chemical Bulletin, 2014, vol. 63, # 2, p. 360 - 367[2] Izv. Akad. Nauk, Ser. Khim., 2014, # 2, p. 360 - 367
[3] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1980, vol. 29, # 5, p. 778 - 784[4] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1980, # 5, p. 1071 - 1077
[5] Russian Chemical Bulletin, 2013, vol. 62, # 4, p. 1044 - 1051[6] Izv. Akad. Nauk, Ser. Khim., 2013, vol. 62, # 4, p. 1043 - 1050,8
18
[ 16034-46-1 ]
[ 92534-69-5 ]
Yield
Reaction Conditions
Operation in experiment
50%
at 60℃; for 1 h;
Oleum (1977mmol) is slowly added to fuming nitric acid (777 mmol) followed by the addition of 2-methyl-2H-pyrazole-3-carboxylic acid (277 mmol) in small portions maintaining the reaction temperature below 6O0C. Stirring at this temperature is then continued for a further 1 h. On completion, the reaction mixture is poured onto crushed ice and extracted with ethyl acetate (300 mL x 3). The combined organic phases are washed with water (250 mL x 2) and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to afford 2-methyl-4-nitro-2H-pyrazole-3- carboxylic acid as a light yellow solid. Compound wt: 23.6g, 50percent.[00251] 1H NMR (400 MHz, OMSO-d6) δ: 8.29 (lH,s); 3.95 (3H, s).
50%
at 60℃; for 1 h;
Oleum (1977mmol) is slowly added to fuming nitric acid (777 mmol) followed by the addition of 2-methyl-2H-pyrazole-3-carboxylic acid (277 mmol) in small portions maintaining the reaction temperature below 600C. Stirring at this temperature is then continued for a further 1 h. On completion, the reaction mixture is poured onto crushed ice and extracted with ethyl acetate (300 mL x 3). The combined organic phases are washed with water (250 mL x 2) and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to afford 2-methyl-4-nitro-2H-pyrazole-3- carboxylic acid as a light yellow solid. Compound wt: 23.6g, 50percent. [0234] 1H NMR (400 MHz, OMSO-d6) δ: 8.29 (lH,s); 3.95 (3H, s).
50%
at 60℃; for 1 h;
Oleum (1977 mmol) was slowly added to fuming nitric acid (777 mmol) followed by the addition of 2-methyl-2H-pyrazole-3-carboxylic acid (277 mmol) in small portions maintaining the reaction temperature below 60oC. Stirring at this temperature was continued for a further 1 h. On completion, the reaction mixture was poured onto crushed ice and extracted with ethyl acetate (300 mL*3). The combined organic phases were washed with water (250 mL*2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 2-methyl-4-nitro-2H-pyrazole-3-carboxylic acid as a light yellow solid. Compound wt: 23.6 g, 50percent. 1H NMR (400 MHz, DMSO-d6) δ: 8.29 (1H, s); 3.95 (3H, s).
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1983, vol. 19, # 12, p. 1326 - 1330[2] Khimiya Geterotsiklicheskikh Soedinenii, 1983, vol. 19, # 12, p. 1676 - 1679
[3] Journal of Organic Chemistry USSR (English Translation), 1984, vol. 20, # 5, p. 976 - 980[4] Zhurnal Organicheskoi Khimii, 1984, vol. 20, # 5, p. 1073 - 1078
[5] Patent: WO2009/71705, 2009, A1, . Location in patent: Page/Page column 39
[6] Patent: WO2009/71706, 2009, A1, . Location in patent: Page/Page column 48-49
[7] Patent: US2008/242661, 2008, A1, . Location in patent: Page/Page column 25-26
[8] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1369 - 1375
[9] Patent: US4317823, 1982, A,
[10] Patent: US4381303, 1983, A,
19
[ 16034-46-1 ]
[ 137890-05-2 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2012, vol. 49, # 6, p. 1422 - 1424
[2] Patent: WO2018/160878, 2018, A1,
20
[ 16034-46-1 ]
[ 84547-61-5 ]
Yield
Reaction Conditions
Operation in experiment
67%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 2 h; Inert atmosphere
To a solution of 1 -methyl- lH-pyrazole-5-carboxylic acid (2 g, 15.86 mmol) in tetrahydrofuran (50 mL) was added L1AIH4 (720 mg, 18.97 mmol) in portions at 0 °C under an inert atmosphere of nitrogen. The reaction was stirred for 2 hours at room temperature then quenched by the addition of water (2 mL). The mixture was dried over by anhydrous sodium sulfate and the solids were filtered out. The filtrates were concentrated under reduced pressure to afford (1 -methyl- lH-pyrazol- 5-yl)methanol as colorless oil (1.2 g, 67 ). (ES, m/z) [M+H]+ 113.0 *H NMR (300 MHz, CDC13) δ 7.36 (d, 7 = 1.8 Hz, 1H), 6.18 (d, 7 = 1.8 Hz, 1H), 4.66 (s, 2H), 3.88 (s, 3H)
Reference：
[1] Patent: WO2014/66795, 2014, A1, . Location in patent: Paragraph 0175
[2] J. Gen. Chem. USSR (Engl. Transl.), 1982, vol. 52, # 11, p. 2297 - 2303[3] Zhurnal Obshchei Khimii, 1982, vol. 52, # 11, p. 2598 - 2605
[4] Patent: WO2014/151142, 2014, A1,
[5] Patent: WO2016/29454, 2016, A1, . Location in patent: Page/Page column 64
With thionyl chloride; In ethyl acetate; at 80℃; for 5h;
A mixture of 1-methyl-1H-pyrazole-5-carboxylic acid (1.26 g, 10 mmol) obtained in Example 1-A), thionyl chloride (3.65 mL, 50 mmol) and ethyl acetate (10 mL) was stirred at 80C for 5 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (1.45 g) as an oil (yield 100%) . 1H NMR (300 MHz, CDCl3) delta 4.14 (3H, s), 7.13 (1H, d, J = 1.9 Hz), 7.52 (1H, d, J = 2.3 Hz).
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃;Product distribution / selectivity;
Oxalyl chloride (11.3 g, 89.5 mmol) was added to a slurry of 1-methyl-1H-pyrazole-5-carboxylic acid (7.5 g, 59.5 mmol) in dichloromethane (100 ml). One drop dimethylformamide was added and the reaction left to stir at room temperature for 7 hours. Another 7 ml oxalyl chloride was added followed by 1 drop dimethylformamide, and the reaction left to stir at room temperature overnight. The reaction was concentrated in vacuo and azeotroped with dichloromethane. The residue was dissolved in CH3CN (20 ml) and added to a solution of the 3-(2-chloro-5-methoxy-phenyl)-pyrazine-2,6-diamine (Preparation 6, 9.0 g, 35.9 mmol) and lutidine (5.2 ml, 46.7 mmol) in CH3CN (100 ml). The reaction was stirred at room temperature for 4 hours before concentration in vacuo. The residue was taken up in 200 ml ethyl acetate and washed with 100 ml water. The organic layer was collected and washed again with 50 ml water and 50 ml brine, before drying over MgSO4 and concentrating in vacuo to afford a sticky gum. The residue was purified by silica gel column chromatography, eluding with ethyl acetate:heptane 2:1, to afford the product as a white solid. 1H-NMR (d6-DMSO): 3.8 (3H, s), 4.1 (3H, s), 5.85 (2H, br s), 6.95 (1H, m), 7.05 (1H, m), 7.25 (1H, m), 7.45 (1H, m), 7.5 (1H, m), 8.55 (1H, s). LCMS Rt=3.35 min MS m/z 359 [MH]+ ; EXAMPLE 3 N-[6-Amino-5-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)pyrazin-2-yl]-1-methyl-1H-pyrazole-5-carboxamide Method C Oxalyl chloride (36 mul, 0.41 mmol) was added to a slurry of 1-methyl-1H-pyrazole-5-carboxylic acid (40 mg, 0.32 mmol) in dichloromethane (2 ml). One drop dimethylformamide was added and the reaction left to stir at room temperature for 3 hours before concentrating in vacuo and azeotroping with dichloromethane. The resulting acid chloride was dissolved in 1 ml anhydrous pyridine and added to a solution of 3-(7-chloro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-pyrazine-2,6-diamine (Preparation 13, 50 mg, 0.18 mmol) in 2 ml anhydrous pyridine. The reaction was heated to 60 C. overnight before concentrating in vacuo and partitioning between 5 ml dichloromethane and 5 ml water. The layers were separated using a phase separation cartridge and the organic layer collected and concentrated in vacuo. The residue was dissolved in 1 ml dimethylsulfoxide and purified using preparative HPLC. LCMS Rt=3.14 min MS m/z 388 [MH]+; Preparation 2 N-(6-Amino-5-chloropyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide Oxalyl chloride (0.288 ml, 3.32 mmol) was added to a suspension of 1-methyl-1H-pyrazole-5-carboxylic acid (0.279 g, 2.21 mmol) in dichloromethane (5 ml) followed by 1 drop of dimethylformamide. The mixture was stirred at room temperature for 4 hours before concentrating in vacuo and azeotroping with dichloromethane. The residue was taken up in pyridine (1 ml) and added to a solution of 3-chloro-pyrazine-2,6-diamine (Preparation 1) (0.16 g, 1.11 mmol) and the mixture heated at 60 C. for 3 hours before cooling to room temperature and concentrating in vacuo. The residue was purified by silica gel column chromatography, eluting with ethylacetate:heptane 1:1, to afford the product as a pale solid (100 mg). 1HNMR (d6-DMSO): 4.05 (s, 3H), 6.60 (br s, 2H), 7.20 (d, 1H), 7.50 (d, 1H), 8.30 (s, 1H), 10.60 (br s, 1H). MS m/z 255 [MH]+
With thionyl chloride; at 79℃; for 2h;
The 2-Methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide was prepared from 3-nitrobenzoyl chloride using the following multiple step procedure: Step 1: 2-Methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide.; A dry 25 mL flask was charged with 2-Methyl-2H-pyrazole-3-carboxylic acid (0.110 g, 0.873 mmol) and thionyl chloride (5 mL) and allowed to stir at 79 C. for 2 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.794 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 2 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The tan solids were filtered to afford the pure 2-Methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.160 g, 0.444 mmol, 56%).
850 mg
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;
A suspension of 800 mg (6.03 mmol) of 2-methyl-2H-pyrazole-3-carboxylic acid in 30 mL of DCM is placed under argon and cooled to 0C. When the temperature is reached, 1.32 mL (15.07 mmol) of oxalyl chloride and a catalytic amount of DMF are added. The reaction mixture is stirred at room temperature for 2 hours and then evaporated to dryness and the residue is taken up in DCM and evaporated again to give 850 mg of 2-methyl-2H-pyrazole-3-carbonyl chloride, the characteristics of which are as follows: 1H NMR (300 MHz, delta in ppm, CDCl3): 4.10 (s, 3H), 6.82 (s, 1 H), 7.50 (s, 1 H).
850 mg
With oxalyl dichloride; N,N-dimethyl-formamide; at 0 - 20℃; for 2h;Inert atmosphere;
A suspension of 800 mg (6.03 mmol) of 2-methyl-2H-pyrazole-3-carboxylic acid in 30 mL of DCM is placed under argon and cooled to 0 C. When the temperature is reached, 1.32 mL (15.07 mmol) of oxalyl chloride and a catalytic amount of DMF are added. The reaction mixture is stirred at room temperature for 2 hours and then evaporated to dryness and the residue is taken up in DCM and evaporated again to give 850 mg of 2-methyl-2H-pyrazole-3-carbonyl chloride, the characteristics of which are as follows: 1H NMR (300 MHz, delta in ppm, CDCl3): 4.10 (s, 3H), 6.82 (s, 1H), 7.50 (s, 1H).
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 4.5h;
To a suspension of 2-methyl-1H-pyrazole-3-car- boxylic acid (126 mg, 1 mmol) in dry dichloromethane (5 mE) was added oxalyl chloride (0.423 mE, 5 mmol) and DMF (2 drops). The mixture was stirred at room temperature for 4.5 hours and evaporated. The residue was azeotroped twice with dry chloroform then dried under vacuum to give crude acid chloride. This was dissolved in dry dichloromethane (2 mE). Half of this solution (0.5 mmol) was added to a solution of 3-(4-ethylpyridin-3-yl)-N1 ,N1 -bis-(4- methoxybenzyl)-[2,7]naphthyridine- 1 ,6-diamine (126 mg, 0.25 mmol) in dichloromethane (2 mE), followed by pyridine (0.1 mE, 1.24 mmol). The mixture was stirred at room temperature for 4.5 hours, then water (approx. 5 mE) was added and the phases separated. The aqueous phase was extracted with dichloromethane (3x). The combined organic fractions were dried (Na2504) and evaporated. The crudeproduct was chromatographed on silica gel eluted with 50-100% ethyl acetate/cyclohexane to give the title compound (61 mg, 40% yield). LCMS (ESI): RT (min)=3.26, [M+H]6 14, method=K.
With sulfuric acid; sulfur trioxide; nitric acid; at 60℃; for 1h;
Oleum (1977mmol) is slowly added to fuming nitric acid (777 mmol) followed by the addition of 2-methyl-2H-pyrazole-3-carboxylic acid (277 mmol) in small portions maintaining the reaction temperature below 6O0C. Stirring at this temperature is then continued for a further 1 h. On completion, the reaction mixture is poured onto crushed ice and extracted with ethyl acetate (300 mL x 3). The combined organic phases are washed with water (250 mL x 2) and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to afford 2-methyl-4-nitro-2H-pyrazole-3- carboxylic acid as a light yellow solid. Compound wt: 23.6g, 50%.[00251] 1H NMR (400 MHz, OMSO-d6) delta: 8.29 (lH,s); 3.95 (3H, s).
50%
With sulfuric acid; sulfur trioxide; nitric acid; at 60℃; for 1h;
Oleum (1977mmol) is slowly added to fuming nitric acid (777 mmol) followed by the addition of 2-methyl-2H-pyrazole-3-carboxylic acid (277 mmol) in small portions maintaining the reaction temperature below 600C. Stirring at this temperature is then continued for a further 1 h. On completion, the reaction mixture is poured onto crushed ice and extracted with ethyl acetate (300 mL x 3). The combined organic phases are washed with water (250 mL x 2) and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to afford 2-methyl-4-nitro-2H-pyrazole-3- carboxylic acid as a light yellow solid. Compound wt: 23.6g, 50%. [0234] 1H NMR (400 MHz, OMSO-d6) delta: 8.29 (lH,s); 3.95 (3H, s).
50%
With sulfuric acid; sulfur trioxide; nitric acid; at 60℃; for 1h;
Oleum (1977 mmol) was slowly added to fuming nitric acid (777 mmol) followed by the addition of 2-methyl-2H-pyrazole-3-carboxylic acid (277 mmol) in small portions maintaining the reaction temperature below 60oC. Stirring at this temperature was continued for a further 1 h. On completion, the reaction mixture was poured onto crushed ice and extracted with ethyl acetate (300 mL*3). The combined organic phases were washed with water (250 mL*2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 2-methyl-4-nitro-2H-pyrazole-3-carboxylic acid as a light yellow solid. Compound wt: 23.6 g, 50%. 1H NMR (400 MHz, DMSO-d6) delta: 8.29 (1H, s); 3.95 (3H, s).
1-Methyl-4-nitropyrazole-5-carboxylic acid 18.8 g of 1-methylpyrazole-5-carboxylic acid (mp 227 to 228 C.) are stirred in a mixture consisting of 23.5 of 100% strength nitric acid and 17 ml of 25% strength oleum for 8 hours at from 55 to 60 C. and for 4.5 hours at from 70 to 75 C. The mixture is poured onto ice and extracted with 9:1 methylene chloride/ethanol. The extract is concentrated. This yields 27 g of 1-methyl-4-nitropyrazole-5-carboxylic acid, mp 162 to 164 C., with decomposition (from ethyl acetate).
With sulfuric acid;
(a) 1-Methyl-4-nitro-1H-pyrazole-5-carboxylic acid A quantity comprising 69.0 gm (0.547 mol) of 1-methyl-1H-pyrazole-5-carboxylic acid of m.p.: 227-228 C. (R. Huttel and M. E. Schon, Liebigs Ann. Chem 625, 55 [1959]) was added in small portions to a mixture of 200 ml of concentrated sulfuric acid and 60 ml of 90% fuming nitric acid under stirring. The temperature of the mixture rose from 75 C. at the beginning to a maximum temperature of 95 C. After the exothermal reaction was finished, heating was continued for 30 minutes up to 95 C. The cold mixture was stirred into 300 gm of cracked ice, and the resulting ice-cold suspension was filtered off by suction filtration. The filtration residue was washed with water, and after recrystallization from ethyl acetate, 44.0 gm (47% of theory) of pale yellow crystals were obtained. M.p.: 169-170 C. (decomp.).
Dimethyl sulfate (236 g, 177 mL, 1.87 mol) was added dropwise over 45 min to a stirred solution of pyrazole-3-carboxylic acid (200 g, 1.78 mol) in 20% aqueous sodium hydroxide (850 mL) at 40 C. The reaction mixture was heated at 80 C for 2 h, cooled to room temperature, filtered, the filtrate acidified to pH 1 with concentrated HCI, the precipitate filtered, washed with water, and dried under vacuum to yield 1-methylpyrazole-5-carboxylic acid (85 g, 38%). The filtrate was concentrated in vacuo to 800 ML, extracted with chloroform (15X400 mL), the organic phase dried over anhydrous magnesium sulfate, concentrated in vacuo, and the residue recrystallized from isopropanol to yield 1-METHYLPYRAZOLE-3-CARBOXYLIC acid (74 g) as a white crystalline solid.
38%
A stirred solution of 3-methylpyrazole (82.1 g, 1.0 mol) in water (3.5 L) was heated to 70 C. Potassium permanganate (111 g, 0.70 mol) was added in one portion, keeping the temperature near 70 C. The reaction mixture was stirred for 1 h at 70 C, and then a second portion of potassium permanganate (111 g) was added at 70 C. After 1 h, a final portion of potassium permanganate (111 g) was added at 70 C. The reaction mixture was stirred a further 2 h at 70 C, and any unreacted oxidant was reduced by the dropwise addition of isopropanol. The reaction mixture was cooled to room temperature, filtered, the solid was rinsed with water, and the filtrate evaporated to 500 mL. The aqueous was chilled to 0 C, acidified with concentrated HC1, filtered, the solid product washed with water, and dried under vacuum to provide pyrazole- 3-carboxylic acid as a white solid (64.4 g, 57%). Dimethyl sulfate (236 g, 177 ML, 1.87 mol) was added dropwise over 45 min to a stirred solution of pyrazole-3-carboxylic acid (200 g, 1.78 mol) in 20% aqueous sodium hydroxide (850 ML) at 40 C. The reaction mixture was heated at 80 C for 2 h, cooled to room temperature, filtered, the filtrate acidified to pH 1 with concentrated HC1, the precipitate filtered, washed with water, and dried under vacuum to yield 1-METHYLPYRAZOLE-5-CARBOXYLIC acid (85 g, 38%). The filtrate was concentrated in vacuo to 800 ML, extracted with chloroform (15X400 mL), the organic phase dried over anhydrous magnesium sulfate, concentrated in vacuo, and the residue recrystallized from isopropanol to yield 1-METHYLPYRAZOLE-3-CARBOXYLIC acid (74 g) as a white crystalline solid. A suspension of the acid (90 g, 0.71 mol) and DMF (1 drop) in thionyl chloride (250 ML) was stirred at reflux under nitrogen for 2 h. The solvent was evaporated from the reaction mixture, the residue azeotroped with toluene (3X200 mL), diluted into toluene (250 mL), added to a suspension of Pd-C (10 wt%, 9.3 g) in toluene (500 ML), and the mixture stirred at reflux for 8 h with a gentle flow of hydrogen gas through the suspension. After cooling to room temperature, the suspension was filtered through celite, washed with toluene, and concentrated in vacuo. The residue was fractionally distilled under vacuum to provide the title compound (50 g, 63%) as a low melting white solid (bp = 92 C @ 8 MMHG).
With thionyl chloride; at 0 - 20℃; for 12.0h;Inert atmosphere;
To a stirred solution of 1 -methyl- lH-pyrazole-5-carboxylic acid (5 g, 39.7 mmol) in methanol (100 mL) was added thionyl chloride (103.2 mmol) under argon atmosphere at 0 C. The reaction mixture was stirred to room temperature over 12 h. The reaction mixture was cone, in vacuo, then diluted with water (100 mL), carefully quenched with sat'd aqueous NaHCC"3, and extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried with anhydrous sodium sulphate, filtered and the filtrate was concentrated to give afford the title compound as a white solid which was used without further purification (5 g, 90 %) m/z 240.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere;
To a solution of 1 -methyl- lH-pyrazole-5-carboxylic acid (2 g, 15.86 mmol) in tetrahydrofuran (50 mL) was added L1AIH4 (720 mg, 18.97 mmol) in portions at 0 C under an inert atmosphere of nitrogen. The reaction was stirred for 2 hours at room temperature then quenched by the addition of water (2 mL). The mixture was dried over by anhydrous sodium sulfate and the solids were filtered out. The filtrates were concentrated under reduced pressure to afford (1 -methyl- lH-pyrazol- 5-yl)methanol as colorless oil (1.2 g, 67 ). (ES, m/z) [M+H]+ 113.0 *H NMR (300 MHz, CDC13) delta 7.36 (d, 7 = 1.8 Hz, 1H), 6.18 (d, 7 = 1.8 Hz, 1H), 4.66 (s, 2H), 3.88 (s, 3H)
With dimethylsulfide borane complex; In tetrahydrofuran;Reflux;
A mixture of 1-methyl-1 H-pyrazole-5-carboxylic acid (1.0 g, 7.93 mmol), BH3. DMS (39.6 mL, 79 mmol) in THF (40 mL) was stirred at reflux overnight. The mixture was diluted with MeOH (30 mL) and stirred for 30 min, and the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with CH2Cl2/MeOH. The residue was dissolved in DCM (20 mL) and to the solution was added SOCl2(5 mL, 68.5 mmol) at room temperature. The mixture was stirred for 3 h then concentrated to afford the product as an oil which was used in the next step without further purification. MS (ESI) calc? d for (C5H7ClN2) [M+H]+, 131.0, found, 131.0
Under room temperature, the 1-methyl -1H-pyrazole (2.0g, 24.4 mmol) dissolved in THF in (30 ml). Under the protection of the nitrogen of the obtained mixture to lower the temperature to -78 C, then slowly dripping n-BuLi to the (10.72 ml, 26.8 mmol). Then the resulting mixture at -78 C stirring 2 hours, to room temperature, then the stirring is performed for 1 hour. Then to the reaction solution to maintain this temperature in drying CO2gas, approximately through 5 minutes. After stirring at room temperature, to 1 hours. To the obtained water is added in the mixture of (30 ml) the reaction quenching and diluting. The resulting mixture is extracted with methylene chloride. After acid aqueous phase precipitating a large amount of solid, filtered. The resulting filter cake is dried to obtain 1.5 g of white solid (yield: 48.8%).
45.4%
To a stirred solution of 1 -methyl- lH-pyrazole (609 mmol) in dry ether (600 mL) under an atmosphere of nitrogen is added a solution of n-BuLi in hexane (2.6 M, 670 mmol) dropwise at -78C over a period of Ih. The reaction mixture is then stirred at this temperature for a further 1 h, and then dry carbon dioxide gas is passed through the mixture at -78C for 30 min. The reaction mixture is then allowed to warm to room temperature and quenched with water (500 mL). The aqueous phase is separated, washed with ether (500 mL) and cooled to 2-3 0C. To the stirred mixture is added concentrated aqueous hydrochloric acid until a peta of 3 is obtained. The resulting precipitate is collected by filtration, washed with ice-cold water (20 mL), dried first in open air, and then in a vacuum desiccator over P2O5 to afford 2-methyl-2H-pyrazole-3-carboxylic acid as a white powder.[00249] Compound wt: 35.3g, 45.4% yield. 1H NMR (400 MHz, OMSO-d6) delta: 13.31 (IH, bs);7.50 (IH, d); 6.81 (IH, d); 4.07 (3H, s).
45.4%
To a stirred solution of 1 -methyl- lH-pyrazole (609 mmol) in dry ether (600 mL) under an atmosphere of nitrogen is added a solution of n-BuLi in hexane (2.6 M, 670 mmol) dropwise at -78C over a period of Ih. The reaction mixture is then stirred at this temperature for a further 1 h, and then dry carbon dioxide gas is passed through the mixture at -78C for 30 min. The reaction mixture is then allowed to warm to room temperature and quenched with water (500 mL). The aqueous phase is separated, washed with ether (500 mL) and cooled to 2-3 0C. To the stirred mixture is added concentrated aqueous hydrochloric acid until a peta of 3 is obtained. The resulting precipitate is collected by filtration, washed with ice-cold water (20 mL), dried first in open air, and then in a vacuum desiccator over P2O5 to afford 2-methyl-2H-pyrazole-3-carboxylic acid as a white powder.[0232] Compound wt: 35.3g, 45.4% yield. 1H NMR (400 MHz, DMSOi6) delta: 13.31 (IH, bs);7.50 (IH, d); 6.81 (IH, d); 4.07 (3H, s).
45.4%
To a stirred solution of <strong>[930-36-9]1-methyl-1H-pyrazole</strong> (609 mmol) in dry ether (600 mL) under an atmosphere of nitrogen was added a solution of n-BuLi in hexane (2.6M, 670 mmol) dropwise at -78oC over a period of 1 h. The reaction mixture was stirred at this temperature for a further 1 hour, and then dry carbon dioxide gas was passed through the mixture at -78oC for 30 min. The reaction mixture was then allowed to warm to room temperature and quenched with water (500 mL). The aqueous phase was separated, washed with ether (500 mL) and cooled to 2-3oC. To the stirred mixture was added concentrated aqueous hydrochloric acid until a pH of 3 was obtained. The resulting precipitate was collected by filtration, washed with ice-cold water (20 mL), dried first in open air, and then in a vacuum desiccator over phosphorus pentoxide to afford 2-methyl-2H-pyrazole-3-carboxylic acid as a white powder. Compound wt: 35.3 g, 45.4% yield. 1H NMR (400 MHz, DMSO-d6) delta: 13.31(1H, bs); 7.50 (1H, d); 6.81 (1H, d); 4.07 (3H, s).
In tetrahydrofuran; N,N-dimethyl acetamide; ethyl acetate; N,N-dimethyl-formamide;
Example 259 Production of N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1-methyl-1H-pyrazole-5-carboxamide To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (106 mg, 0.84 mmol) in tetrahydrofuran (5 mL) were added N,N-dimethylformamide (1 drop), oxalyl chloride (91 muL, 1.0 mmol), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, and the obtained <strong>[84547-59-1]1-methyl-1H-pyrazole-5-carbonylchloride</strong> was dissolved in N,N-dimethylacetamide (2 mL). This was added to a solution of N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (210 mg, 0.65 mmol) in N,N-dimethylacetamide (5 mL), and the mixture was stirred at room temperature for 30 min. To the mixture were added ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogencarbonate solution, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (*4). Combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70?90/10) to give the title compound (230 mg, 83%) as a white solid. 1H-NMR (DMSO-d6, 300 MHz) delta 0.73-0.85 (4H, m), 1.87-1.97 (1H, m), 2.25 (3H, s), 4.05 (3H, s), 7.00-7.07 (2H, m), 7.11 (1H, dd, J=8.3, 2.3 Hz), 7.28 (1H, d, J=2.7 Hz), 7.36 (1H, d, J=8.3 Hz), 7.53 (1H, d, J=2.3 Hz), 7.93 (1H, s), 8.03 (1H, d, J=9.5 Hz), 9.91 (1H, s), 11.07 (1H, s).
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 19h;
19.1 1) 1-Methyl-N′-[4-(trifluoromethyl)benzoyl]-1H-pyrazol-5-carbohydrazide
1) 1-Methyl-N'-[4-(trifluoromethyl)benzoyl]-1H-pyrazol-5-carbohydrazide 4-(Trifluoromethyl)benzohydrazide (583 mg) was added to a dimethylformamide (6.8 mL) solution that contained 1-methyl-1H-pyrazol-5-carboxylic acid (300 mg), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.09 g) and diisopropylethylamine (830 μL) at a room temperature, and the obtained solution was then stirred for 19 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with water and a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The obtained solid was washed with ethyl acetate/hexane (1:1), so as to obtain the title compound (598 mg) in the form of a colorless solid. The filtrate was concentrated under a reduced pressure, and the residue was then purified by column chromatography (silica gel cartridge, chloroform:methanol=10:0 to 9:1), so as to further obtain the title compound (109 mg) in the form of a colorless solid.
109 mg
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 19h;
12.1 1) 1-Methyl-N′-[4-(trifluoromethyl)benzoyl]-1H-pyrazol-5-carbohydrazide
1) 1-Methyl-N'-[4-(trifluoromethyl)benzoyl]-1H-pyrazol-5-carbohydrazide 4-(Trifluoromethyl)benzohydrazide (583 mg) was added to an N,N-dimethylformamide (6.8 mL) solution that contained 1-methyl-1H-pyrazol-5-carboxylic acid (300 mg), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.09 g) and diisopropylethylamine (830 μL) at a room temperature, and the obtained solution was then stirred for 19 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with water and a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The obtained solid was washed with ethyl acetate/hexane (1:1), so as to obtain the title compound (598 mg) in the form of a colorless solid. The filtrate was concentrated under a reduced pressure, and the residue was then purified by column chromatography (silica gel cartridge, chloroform:methanol=10:0 to 9:1), so as to further obtain the title compound (109 mg) in the form of a colorless solid.
With N,N-dimethyl-formamide; In tetrahydrofuran; at 20℃; for 2h;
General procedure: To a solution of 2,5-dimethyl-1,3-thiazole-4-carboxylic acid (107mg, 0.681mmol) in THF (5mL) was added thionyl chloride (118muL, 1.36mmol) and two drops of DMF. The mixture was stirred at room temperature for 2h and concentrated under reduced pressure. The residue was dissolved in DMA (6mL), and 27b (200mg, 0.619mmol) was added to the solution at 0C. The mixture was stirred at room temperature for 2h. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with AcOEt. The extract was washed with saturated aqueous sodium hydrogen carbonate, brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residual solid was recrystallized from EtOH to give 29a (248mg, 87%) as white crystals: mp 239-240C; 1H NMR (DMSO-d6) delta 0.78-0.86 (4H, m), 2.04 (1H, br s), 2.23-2.28 (3H, m), 2.65 (3H, s), 2.70 (3H, s), 6.82 (1H, dd, J=8.3, 2.7Hz), 7.27 (1H, d, J=8.7Hz), 7.50 (1H, dd, J=9.5, 2.3Hz), 7.66 (1H, d, J=2.7Hz), 7.69-7.75 (1H, m), 8.82 (1H, dd, J=2.3, 0.8Hz), 9.66 (1H, s), 11.02 (1H, s); Anal. Calcd for C23H22N6O3S: C, 59.73; H, 4.79; N, 18.17. Found: C, 59.48; H, 4.80; N, 18.00.
tert-butyl 3-((((1-methyl-1H-pyrazol-5-yl)carbonyl)amino)methyl)morpholine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
756 mg
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 45.0h;
A mixture of 1-methyl-1H-pyrazole-5-carboxylic acid (277 mg), <strong>[475106-18-4]tert-butyl 3-(aminomethyl)morpholine-4-carboxylate</strong> (433 mg), HATU (913 mg), DIEA (0.699 ml) and DMF (8 mL) was stirred at room temperature for 5 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (756 mg). 1H NMR (300 MHz, CDCl3) δ 1.38 (9H, s), 3.13-3.54 (3H, m), 3.64 (1H, dd, J = 11.9, 2.8 Hz), 3.73 (1H, brs), 3.81-3.96 (2H, m), 3.99-4.40 (5H, m), 6.50 (1H, d, J = 2.3 Hz), 6.55-6.88 (1H, m), 7.41 (1H, d, J = 2.3 Hz).
methyl 3-methyl-4-(1-methyl-1H-pyrazole-5-carboxamido)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (compound 4A, 4.58 g, 36.3 mmol), DIEA (13.7 g, 106 mmol) in CH2Cl2 (30 mL) was added EDCI (11.6 g, 60.5 mmol) and DMAP (4.44 g, 36.3 mmol) at -5 C., the mixture was stirred at -5 C. for 30 min. Then <strong>[18595-14-7]methyl 4-amino-3-methylbenzoate</strong> (compound 11, 5.00 g, 30.3 mmol) was added, stirred at -5 C. for 30 min. The mixture was warmed to 25 C., stirred for 11 hrs. TLC (petroleum ether:ethyl acetate=1:1, Rf=0.52) showed starting material consumed completely. The mixture was concentrated in vacuum to give light yellow oil. The oil was purified by silica gel column chromatography (petroleum ether:ethyl acetate=90:10 to 50:50) to give methyl 3-methyl-4-(1-methyl-1H-pyrazole-5-carboxamido)benzoate (compound 12, 5.70 g, 69% yield) as light yellow solid.
N-(4-bromo-2-methylphenyl)-1-methyl-1H-pyrazole-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
Stage #1: 1-methyl-1H-pyrazole-5-carboxylic acid With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at -5℃; for 0.5h; Inert atmosphere;
Stage #2: 4-Bromo-2-methylaniline In dichloromethane at -5 - 25℃; for 11.5h; Inert atmosphere;
9.1 Step 1 N-(4-bromo-2-methylphenyl)-1-methyl-1H-pyrazole-5-carboxamide
To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (compound 4A, 4.07 g, 32.2 mmol), DIEA (12.2 g, 94.1 mmol) in CH2Cl2 (30 mL) was added EDCI (10.3 g, 53.7 mmol) and DMAP (3.94 g, 32.2 mmol) at -5° C., the mixture was stirred at -5° C. for 30 min under N2. Then 4-bromo-2-methylaniline (compound 7, 5.00 g, 26.9 mmol) was added, the mixture was stirred at -5° C. for 30 min, then warmed to 25° C., stirred for 11 hrs. TLC (petroleum ether:ethyl acetate=1:1, Rf=0.27) showed one new point formed. The mixture was concentrated in vacuum to give light yellow oil. The oil was purified by silica gel column chromatography (petroleum ether: ethyl acetate=80:20 to 50:50) to give N-(4-bromo-2-methylphenyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 8, 6.40 g, 81% yield) as light yellow solid. 1H NMR (400 MHz, CDCl3) δ δ ppm 7.72 (d, J=8.2 Hz, 1H), 7.47-7.58 (m, 2H), 7.33-7.41 (m, 2H), 6.64 (s, 1H), 4.20 (s, 3H), 2.28 (s, 3H); ES-LCMS m/z 294.1 [M+H]+.
N-(4-cyano-2-methyl-phenyl)-2-methyl-pyrazole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; at 15℃; for 1.5h;
To a solution of <strong>[78881-21-7]4-amino-3-methyl-benzonitrile</strong> (1.5 g, 11.12 mmol, 1 eq) and 2-methylpyrazole-3-carboxylic acid (1.54 g, 12.23 mmol, 1.1 eq) in pyridine (15 mL) was added T3P (21.23 g, 33.37 mmol, 19.84 mL, 50%, 3 eq). The mixture was stirred at 15 C. for 1.5 h. The reaction mixture was concentrated under reduced pressure to remove pyridine (15 mL). The residue was dissolved in water (100 mL), extracted with EtOAc (50 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield crude N-(4-cyano-2-methyl-phenyl)-2-methyl-pyrazole-3-carboxamide (2.3 g, 8.71 mmol, 78.3% yield, 91.0% purity) as a pink solid which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) delta ppm 8.26 (d, J=8.5 Hz, 1H), 7.71 (s, 1H), 7.60-7.49 (m, 3H), 6.69 (d, J=2.0 Hz, 1H), 4.23 (s, 3H), 2.37 (s, 3H); ES-LCMS m/z 241.1 [M+H]+.
N-(4-iodo-2-methyl-phenyl)-2-methyl-pyrazole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33.1%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 60℃; for 19h;
To a solution of <strong>[13194-68-8]4-iodo-2-methyl-aniline</strong> (200 mg, 858.19 mumol, 1 eq) and 2-methylpyrazole-3-carboxylic acid (129.87 mg, 1.03 mmol, 1.2 eq) in EtOAc (10 mL) was added T3P (1.64 g, 2.57 mmol, 1.53 mL, 50%, 3.0 eq) and DIEA (332.74 mg, 2.57 mmol, 448.44 muL, 3.0 eq). The mixture was stirred at 60 C. for 3 h. The mixture was stirred at 60 C. for 16 h. The reaction mixture was diluted with NaHCO3 solution (20 mL), extracted with ethyl acetate (20 mL*3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified on silica gel column chromatography (from PE/EtOAc=1/0 to 10/3, TLC: PE/EtOAc=3/1, Rf=0.49) to give the product of N-(4-iodo-2-methyl-phenyl)-2-methyl-pyrazole-3-carboxamide (100 mg, 284.34 mumol, 33.1% yield, 97.0% purity) as a white solid. 1H NMR (400 MHz, CDCl3) delta ppm 7.69 (d, J=8.4 Hz, 1H), 7.63-7.56 (m, 2H), 7.53 (d, J=2.2 Hz, 1H), 7.45 (br s, 1H), 6.64 (d, J=2.0 Hz, 1H), 4.23 (s, 3H), 2.28 (s, 3H); ES-LCMS m/z 341.8 [M+H]+.
(5-bromoindolin-1-yl)-(2-methylpyrazol-3-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95.1%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In ethyl acetate at 60℃; for 3h;
28.1 Step 1: (5-Bromoindolin-1-yl)-(2-methylpyrazol-3-yl)methanone
To a solution of 5-bromoindoline (200 mg, 1.01 mmol, 1 eq) and 2-methylpyrazole-3-carboxylic acid (127.35 mg, 1.01 mmol, 1.0 eq) in EtOAc (10 mL) was added T3P (1.93 g, 3.03 mmol, 1.80 mL, 50%, 3.0 eq) and DIEA (652.54 mg, 5.05 mmol, 879.44 μL, 5.0 eq). The mixture was stirred at 60° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue which was purified on silica gel column chromatography (from PE/EtOAc=1/0 to 10/3, TLC: PE/EtOAc=3/1, Rf=0.42) to give the product (5-bromoindolin-1-yl)-(2-methylpyrazol-3-yl)methanone (300 mg, 960.29 μmol, 95.1% yield, 98.0% purity) as a white solid 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (s, 1H), 7.52 (d, J=2.2 Hz, 1H), 7.30-7.37 (m, 2H), 6.53 (d, J=2.0 Hz, 1H), 4.24 (t, J=8.3 Hz, 2H), 4.08 (s, 3H), 3.18 (t, J=8.3 Hz, 2H); ES-LCMS m/z 306.0, 308.0 [M+H]+.
N-(6-bromo-2-naphthyl)-2-methyl-pyrazole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80.7%
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 25℃; for 19h;Inert atmosphere;
To a mixture of 6-bromonaphthalen-2-amine (100 mg, 450.29 mumol, 1 eq), 2-methylpyrazole-3-carboxylic acid (56.79 mg, 450.29 mumol, 1 eq), HATU (222.58 mg, 585.37 mumol, 1.3 eq) in DCM (10 mL) was added Et3N (136.69 mg, 1.35 mmol, 188.02 muL, 3 eq). The mixture was stirred at 25° C. under N2 atmosphere for 19 h. The mixture was concentrated and saturated NaHCO3 (10 mL) was added, extracted with EtOAc (10 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated to yield the residue which was purified on silica gel column chromatography (from PE/EtOAc=1/0 to 10/3, TLC: PE/EtOAc=3/1, Rf=0.45) to yield N-(6-bromo-2-naphthyl)-2-methyl-pyrazole-3-carboxamide (120 mg, 363.44 mumol, 80.7percent yield, 100.0percent purity) as a white solid. 1H NMR (400 MHz, CDCl3) delta ppm 8.29 (d, J=1.8 Hz, 1H), 7.98 (s, 1H), 7.84-7.75 (m, 2H), 7.71 (d, J=8.8 Hz, 1H), 7.61-7.49 (m, 3H), 6.71 (d, J 2.2 Hz, 1H), 4.26 (s, 3H); ES-LCMS m/z 332.0, 334.0 [M+H]+.
N-[4-iodo-2-(trifluoromethyl)phenyl]-2-methyl-pyrazole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; aniline; at 25℃; for 12h;Inert atmosphere;
A mixture of 2-methylpyrazole-3-carboxylic acid (145.00 mg, 1.15 mmol, 1.1 eq), <strong>[97760-97-9]4-iodo-2-(trifluoromethyl)aniline</strong> (300 mg, 1.05 mmol, 1 eq), T3P (2.00 g, 3.14 mmol, 1.86 mL, 50%, 3 eq) in pyridine (3 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 25 C. for 12 h under N2 atmosphere The reaction mixture was quenched by addition H2O (20 mL), extracted with EtOAc (30 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield N-[4-iodo-2-(trifluoromethyl)phenyl]-2-methyl-pyrazole-3-carboxamide (350 mg, 708.65 mumol, 67.8% yield, 80.0% purity) as a white solid which was used in the next step without further purification. 1H NMR (400 MHz, CD3OD) delta ppm 8.10-8.01 (m, 2H), 7.52 (d, J=2.0 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 6.92 (d, J=2.2 Hz, 1H), 4.12 (s, 3H); ES-LCMS m/z 396.0 [M+H]+.
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃;
005.2 Step 2: N-(4-bromo-2-fluoro-3- yl-lH-pyrazole-5-carboxamide
To a solution of 4-bromo-2-fluoro-3-methylaniline(3 g, 14.70 mmol, 1 equiv), 1- methyl-lH-pyrazole-5-carboxylic acid (2.2 g, 17.44mmol, 1.186equiv) and DIPEA(3.8 g, 29.3 mmol, 1.994 equiv) in DMF (60.0 mL,0.44 mmol,0.028equiv), HATU (8.4 g, 22.01 mmol, 1.497equiv) was added. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water (180 mL) and the aqueous layer extracted with EtOAc (2x100 mL). The organic layers were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, with EtOAc/PE (1 : 10) to afford N-(4-bromo-2-fluoro-3-methylphenyl)-l-methyl-lH-pyrazole-5- carboxamide as a yellow solid in 83% yield.
83%
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃;
5.2 Step 2: N-(4-bromo-2-fluoro-3-methylphenyl)-l-methyl-lH-pyrazole-5-carboxamide
To a solution of 4-bromo-2-fluoro-3 -methyl aniline(3 g, 14.70 mmol, 1 equiv), 1- methyl-lH-pyrazole-5-carboxylic acid (2.2 g, l7.44mmol, l.l86equiv) and DIPEA(3.8 g, 29.3 mmol, 1.994 equiv) in DMF (60.0 mL,0.44 mmol,0.028equiv), HATU (8.4 g, 22.01 mmol, l.497equiv) was added. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water (180 mL) and the aqueous layer extracted with EtOAc (2x100 mL). The organic layers were combined and concentrated under reduced pressure. (0878) The residue was purified by silica gel column chromatography, with EtO Ac/PE (1 : 10) to afford N-(4-bromo-2-fluoro-3-methylphenyl)-l-methyl-lH-pyrazole-5-carboxamide as a yellow solid in 83% yield.
N-(6-bromo-2,3-dihydro-1-benzofuran-3-yl)-1-methyl-1H-pyrazole-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: 1-methyl-1H-pyrazole-5-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.25h;
Stage #2: (rac)-6-bromo-2,3-dihydrobenzofuran-3-ylamine In N,N-dimethyl-formamide
8.2; 9.1 1. Synthesis of Intermediate 9-2:
To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (592 mg, 4.7 mmol, 1.0 equiv) in DMF (10 mL) were added DIEA (1.8 g, 13.9 mmol, 3.0 equiv) and HATU (2.7 g, 7.1 mmol, 1.5 equiv). The mixture was stirred for 15 min and 6-bromo-2,3-dihydro-1- benzofuran-3-amine (1 g, 4.7 mmol, 1.0 equiv) was then added. The mixture was then stirred overnight, diluted with ethyl acetate (200 mL), washed with brine (200 mL) three times, concentrated under reduced pressure, and purified by silica gel chromatography (EA/PE, 1/1) to give 1.3 g (86%) of N-(6-bromo-2,3-dihydro-1-benzofuran-3-yl)-1-methyl-1H-pyrazole-5- carboxamide as an off-white solid.
N-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-1-methyl-1H-pyrazole-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
Oxalyl chloride (191 muL) was added to a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (200 muL) in DCM (2 mL) and DMF (1 drop). After 1 hour, the reaction mixture was evaporated. A solution of 4-(1H-benzo[d]imidazol-2-yl)aniline (166 mg) and triethylamine (420 muL), in DCM (4 mL) was added to the initial reaction residue and stirred at ambient temp for 1 hour. The Reaction mixture was diluted with DCM and extracted sequentially with sat bicarb, water, brine, then dried over sodium sulfate, filtered and evaporated. The bis acylated material was purified on silica, eluting with a gradient of ethyl acetate (50-100%) in hexane. The pure bis acylated material was treated with ethylamine solution (2M in THF, 5 mL) for 18h. The reaction mixture was evaporated. Trituration with ethyl acetate / diethyl ether [1:4], afforded a solid which was collected by filtration (77mg, Y = 30%). UPLC-MS (Acidic Method, 4 min): rt 1.05 min, m/z 318.1 [M+H]+ 1H NMR (400 MHz, DMSO-d6) d ppm 12.83 (br s, 1H), 10.41 (s, 1H), 8.13-8.21 (m, 2H), 7.92 (d, J=8.8 Hz, 2H), 7.64 (br d, J=5.9 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.52 (br d, J=6.4 Hz, 1H), 7.19 (br d, J=4.3 Hz, 2H), 7.11 (d, J=2.0 Hz, 1H), 4.11 (s, 3H).
N-(4-(benzo[d]thiazol-2-yl)phenyl)-1-methyl-1H-pyrazole-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
Stage #1: 1-methyl-1H-pyrazole-5-carboxylic acid With triethylamine In tetrahydrofuran for 0.0833333h;
Stage #2: 2-(4-aminophenyl)benzothiazole With dmap In tetrahydrofuran at 65℃; for 18h;
21 N-(4-(benzo[d]thiazol-2-yl)phenyl)-1-methyl-1H-pyrazole-5-carboxamide
A solution of 1-methyl-1H-pyrazole-5-carboxylic acid (56 mg), HATU (168 mg), triethylamine (157 µL) were combined in THF (5 mL). After 5 min, 4-(benzo[d]thiazol-2-yl)aniline (100 mg) and a catalytic amount of DMAP were added and the resulting mixture was stirred at 65 °C for 18 h. The reaction mixture was diluted with DCM, washed with saturated solution of NaHCO3 and brine. The organic solution was, dried over Na2SO4, decanted and evaporated under reduced pressure. The crude was purified by column chromatography on silica gel using 1:4 to 1:2 EtOAc:Hexane as mobile phase to give N-(4-(benzo[d]thiazol-2-yl)phenyl)-1-methyl-1H-pyrazole-5-carboxamide (25 mg, 17%). UPLC-MS (Acidic Method, 4 min): rt 1.91 min, m/z 335.1 [M+H]+ 1H NMR (400 MHz, DMSO-d6) d ppm 10.49 (s, 1H), 8.07-8.18 (m, 3H), 8.04 (d, J=7.7 Hz, 1H), 7.92- 8.00 (m, 2H), 7.51-7.60 (m, 2H), 7.42-7.50 (m, 1H), 7.13 (d, J=2.1 Hz, 1H), 4.11 (s, 3H).
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