* 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.
Reference：
[1] Journal of Medicinal Chemistry, 2010, vol. 53, # 2, p. 855 - 866
[2] Patent: US5064851, 1991, A,
[3] Patent: EP1176140, 2002, A1, . Location in patent: Page 46
2
[ 138907-68-3 ]
[ 187949-90-2 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With lithium hydroxide; water In methanol for 17 h; Heating / reflux Stage #2: With hydrogenchloride In water
Ethyl 5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylate (22.18 g, 89 mmol) was suspended in 1 N aqueous solution of LiOH (178 ml_, 178 mmol) and methanol (200 ml_). The reaction mixture was refluxed for 17 hours, allowed to cool to room temperature and filtered. The filtrate was acidified to pH=7 with 2N HCI. A solid was collected by filtration and allowed to dry under reduced pressure to afford the title compound as a pale yellow solid (18.64 g, 95 percent yield), which was used without further purification.
Reference：
[1] Patent: WO2008/53136, 2008, A1, . Location in patent: Page/Page column 36
[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 20, p. 5032 - 5038
[3] Journal of Medicinal Chemistry, 2006, vol. 49, # 5, p. 1562 - 1575
[4] Patent: WO2008/74814, 2008, A1, . Location in patent: Page/Page column 56
[5] Patent: WO2008/777, 2008, A2, . Location in patent: Page/Page column 58-59
[6] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 23, p. 6886 - 6889
[7] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 81 - 87
[8] Patent: WO2007/144327, 2007, A2, . Location in patent: Page/Page column 70-71
3
[ 823-85-8 ]
[ 94-05-3 ]
[ 138907-68-3 ]
Yield
Reaction Conditions
Operation in experiment
72%
With triethylamine In ethanol for 2.5 h; Heating / reflux
Ethyl(ethoxymethylene)cyanoacetate (20.80 g, 123 mmol) and triethylamine (17.1 ml_, 123 mmol) were added to a solution of 4-fluorophenylhydrazine hydrochloride (20.00 g, 123 mmol). The reaction mixture was refluxed for 2.5 hours and allowed to cool to room temperature. A solid was collected by filtration, washed with small amounts of ethanol and EPO <DP n="37"/>heptane and allowed to dry under reduced pressure to afford the title compound as a beige solid (22.18 g, 72 percent yield). m/z 250 [M+H]+. 1H NMR (300 MHz, CDCI3) 7.80 (1 H, s), 7.58-7.51 (2H, m), 7.27 (2H, m), 5.27 (2H, br s), 4.33 (2H1 q, J=7.2 Hz), 1.39 (2H, t, J=7.2 Hz).
65%
With triethylamine In ethanol at 20 - 80℃; for 8 h;
General procedure: To ethyl 2-cyano-3-ethoxyacrylate (2.00 g, 11.8 mmol) and 4-methoxyphenyl hydrazine hydrochloride (2.06 g, 11.8 mmol) in ethanol (75 mL) at room temperature was added triethylamine (1.65 mL, 11.8 mmol). The mixture was stirred at 80 °C for 8 h. After cooling the reaction mixture to room temperature, ethanol was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column with a mixture of n-hexane and ethyl acetate (3:1) to give the desired product 2b (2.42 g, 78 percent). 1H NMR (300 MHz, CDCl3): δ=7.76 (s, 1H), 7.42 (d, J=6.9Hz, 2H), 7.01 (d, J=6.9Hz, 2H), 5.19 (br s, 2H), 4.30 (q, J=7.1Hz, 2H), 3.82 (s, 3H), 1.36 (t, J=7.1Hz, 3H) ppm; MS (ESI): m/z: 262 [M+H+].
PREPARATION A Ethyl-5-Amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylate A stirred mixture of 11.38 g (70.0 mmole) of a commercially available sample of 4-fluorophenylhydrazine hydrochloride, 11.84 g (70.0 mmole) of ethyl (ethoxymethylene)cyanoacetate and 9.67 g (70.0 mmole) of potassium carbonate in 100 ml of ethanol was refluxed overnight and then treated with 300 ml of water. The precipitate was filtered and dried in vacuo to furnish 12.87 g (74percent yield) of pale yellow crystalline solid. The sample was recrystallized from ethanol m.p. 151-2° C. Analysis: Calculated for C12 H12 FN3 O2: C, 57.82; H, 4.85; N, 16.86percent. Found: C, 57.82; H, 4.78; N, 16.79percent.
Reference：
[1] Patent: US5064851, 1991, A,
5
[ 42466-67-1 ]
[ 823-85-8 ]
[ 138907-68-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2010, vol. 53, # 2, p. 855 - 866
[2] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 81 - 87
6
[ 68350-76-5 ]
[ 371-14-2 ]
[ 138907-68-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 23, p. 6886 - 6889
7
[ 371-14-2 ]
[ 94-05-3 ]
[ 138907-68-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 5, p. 1562 - 1575
[2] Patent: EP1176140, 2002, A1, . Location in patent: Page 45 - 46
Ethyl 5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylate (22.18 g, 89 mmol) was suspended in 1 N aqueous solution of LiOH (178 ml_, 178 mmol) and methanol (200 ml_). The reaction mixture was refluxed for 17 hours, allowed to cool to room temperature and filtered. The filtrate was acidified to pH=7 with 2N HCI. A solid was collected by filtration and allowed to dry under reduced pressure to afford the title compound as a pale yellow solid (18.64 g, 95 % yield), which was used without further purification.
Intermediate 9: 5-Amino-1-(4-fluorophenyl)-1 H-pyrazole-4-carboxylic acid. To a suspension of ethyl 5-amino-1-(4-fluorophenyl)-1 H-pyrazole-4-carboxylate (12.1g, 48.5mmol) in ethanol (250ml) was added a solution of lithium hydroxide(5.8g, 242mmol) in water (100ml). The mixture was stirred at reflux for 2.5hr. It was allowed to cool and concentrated to 50% of its volume before 5M hydrochloric acid(47ml) was added. After stirring for 15mins, the resulting white solid was filtered off and further 5M hydrochloric acid (3ml) was added. This was filtered and the combined solids were washed with water and diethyl ether and then dried under vacuum to give the title compound (10.27g).1 H NMR (400 MHz, DMSO-d6) deltappm 12.09 (br. s., 1 H) 7.67 (s, 1 H) 7.54 - 7.60 (m, 2H) 7.34 - 7.41 (m, 2 H) 6.29 (br. s., 2 H).LC-MS Retention Time 2.20mins, MH+ 222.
Intermediate 9; 5-Amiotano-1-(4-fluorophenyl)-1 /-/-pyrazole-4-carboxyliotac acid; To a suspension of ethyl 5-amiotano-1-(4-fluorophenyl)-1 /-/-pyrazole-4-carboxylate (12 1g, 48 5mmol) in ethanol (250ml) was added a solution of lithium hydroxide (5 8g, 242mmol) in water (100ml) The mixture was stirred at reflux for 2 5 hours It was allowed to cool <n="61"/>and concentrated to 50% of its volume before 5M hydrochloric acid (47ml) was added. After stirring for 15 minutes, the resulting white solid was filtered off and further 5M hydrochloric acid (3ml) was added to the filtrate and the resulting solid was filtered and the combined solids were washed with water and diethyl ether and then dried under vacuum to give the title compound (10.27g).1H NMR (400 MHz, DMSOd6) delta ppm 12.09 (br. s., 1 H) 7.67 (s, 1 H) 7.54 - 7.60 (m, 2H) 7.34 - 7.41 (m, 2H) 6.29 (br. s., 2H). LC-MS Retention Time 2.20mins, MH+ 222.
With water; In ethanol;Reflux;
General procedure: Intermediates 13 6 was synthesized according to the literature by ML Bender [28]. Intermediates 5 was dissolved in a solution of 15 ethanol and 16 potassium hydroxide and refluxed for 2h. After cooling, the pH of the mixture was adjusted to 5-6by the dropwise addition of 10% 17 HCl solution to give an intermediate 13 6, which was filtered under vacuum and recrystallized from ethanol to give the pure products.
To a suspension of ethyl 5-amino-1-(4-fluorophenyl)-1/-/-pyrazole-4-carboxylate (12.1g, 48.5mmol) in ethanol (250ml) was added a solution of lithium hydroxide (5.8g, 242mmol) in water (100ml). The mixture was stirred at reflux for 2.5 hours. It was allowed to cool and concentrated to 50% of its volume before 5M hydrochloric acid (47ml) was added. After stirring for 15 minutes, the resulting white solid was filtered off and further 5M hydrochloric acid (3ml) was added to the filtrate and the resulting solid was filtered and the combined solids were washed with water and diethyl ether and then dried under vacuum to give the title compound (10.27g).1H NMR (400 MHz, DMSO-Cf6) delta ppm 12.09 (br. s., 1 H) 7.67 (s, 1 H) 7.54 - 7.60 (m, 2H) 7.34 - 7.41 (m, 2H) 6.29 (br. s., 2H).LC-MS Retention Time 2.20mins, MH+ 222.
1.8 g
With potassium hydroxide; In isopropyl alcohol; at 80℃; for 5h;
To a stirred solution of Step 2 intermediate (2.6 g, 10.42 mmol) in isopropyl alcohol (35 mL) was added potassium hydroxide (880 mg, 15.62 mmol) at RT. The mixture was stirred at 80 C for 5h. The solvent was evaporated under reduced pressure and the residue was acidified with nitric acid till pH 2-3. The precipitated solid was filtered, washed with water (40 mL x 2) and dried under vacuum to yield 1.80 g of the titled product as a solid. lH NMR (300 MHz, DMSO- d6): delta 6.27 (s, 2H), 7.36 (t, = 8.4 Hz, 2H), 7.54-7.60 (m, 2H), 7.66 (s, 1H), 12.07 (br s, 1H); APCI (m/z) 220 (M-H)".
In methanol;
The solid was filtered off and dried to give <strong>[138907-68-3]5-amino-4-ethylcarboxy-1-(4-fluorophenyl)pyrazole</strong> (28 g) which was suspended in a mixture of 1N lithium hydroxide (100 ml) and methanol (250 ml). The reaction mixture was heated at reflux. After 16 h, the reaction mixture was filtered through a sinter funnel and the filtrate was acidified with 2 N hydrochloric acid (65 ml). The solid was filtered off and dried to give 5-amino-4-carboxy-1-(4-fluorophenyl)pyrazole (21 g).
With triethylamine; In ethanol; for 2.5h;Heating / reflux;
Ethyl(ethoxymethylene)cyanoacetate (20.80 g, 123 mmol) and triethylamine (17.1 ml_, 123 mmol) were added to a solution of 4-fluorophenylhydrazine hydrochloride (20.00 g, 123 mmol). The reaction mixture was refluxed for 2.5 hours and allowed to cool to room temperature. A solid was collected by filtration, washed with small amounts of ethanol and EPO <DP n="37"/>heptane and allowed to dry under reduced pressure to afford the title compound as a beige solid (22.18 g, 72 % yield). m/z 250 [M+H]+. 1H NMR (300 MHz, CDCI3) 7.80 (1 H, s), 7.58-7.51 (2H, m), 7.27 (2H, m), 5.27 (2H, br s), 4.33 (2H1 q, J=7.2 Hz), 1.39 (2H, t, J=7.2 Hz).
65%
With triethylamine; In ethanol; at 20 - 80℃; for 8h;
General procedure: To ethyl 2-cyano-3-ethoxyacrylate (2.00 g, 11.8 mmol) and 4-methoxyphenyl hydrazine hydrochloride (2.06 g, 11.8 mmol) in ethanol (75 mL) at room temperature was added triethylamine (1.65 mL, 11.8 mmol). The mixture was stirred at 80 C for 8 h. After cooling the reaction mixture to room temperature, ethanol was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column with a mixture of n-hexane and ethyl acetate (3:1) to give the desired product 2b (2.42 g, 78 %). 1H NMR (300 MHz, CDCl3): delta=7.76 (s, 1H), 7.42 (d, J=6.9Hz, 2H), 7.01 (d, J=6.9Hz, 2H), 5.19 (br s, 2H), 4.30 (q, J=7.1Hz, 2H), 3.82 (s, 3H), 1.36 (t, J=7.1Hz, 3H) ppm; MS (ESI): m/z: 262 [M+H+].
With triethylamine; In ethanol; for 3.5h;Heating / reflux;
Intermediate 8: Ethyl 5-amino-1-(4-fluorophenyl)-1 H-pyrazole-4-carboxvlate. To a stirred suspension of 4-fluorophenylhydrazine hydrochloride (9.76g, 60mmol) in ethanol (250ml) was added triethylamine (9.2ml, 62mmol) and to the resulting amber solution was added ethyl 2-cyano-3-ethoxyacrylate (10.15g, 60mmol). The solution was heated at reflux temperature for 3.5hr. The solution was allowed to cool to room temperature and after standing overnight the resultant solid was filtered off, washed with small amount of ethanol and then ether before being dried under vacuum to give the title compound (12.1 g) as an off white solid. 1 H NMR (400 MHz, DMSOd6) deltappm 7.70 (s, 1 H) 7.55 (s, J=5.0 Hz, 2 H) 7.34 - 7.41 (m, 2 H) 6.34 (br. s., 2 H) 4.21 (q, J=7.0, 7.0 Hz, 2 H) 1.26 (t, J=7.0 Hz, 3 H).
With triethylamine; In ethanol; for 3.5h;Heating / reflux;
Intermediate 8; Ethyl 5-amiotano-1-(4-fluorophenyl)-1/-/-pyrazole-4-carboxylateTo a stirred suspension of 4-fluorophenylhydraziotane hydrochloride (9 76g, 60mmol) in ethanol (250ml) was added triethylamine (9 2ml, 62mmol) and to the resulting amber solution was added ethyl 2-cyano-3-ethoxyacrylate (10 15g, 60mmol) The solution was heated at reflux temperature for 3 5 hours The solution was allowed to cool to room temperature and after standing overnight the resultant solid was filtered off, washed with small amount of ethanol and then ether before being dried under vacuum to give the title compound (12 1g) as an off white solid1H NMR (400 MHz, DMSO-d6) delta ppm 7 70 (s, 1 H) 7 55 (s, J=5 0 Hz, 2H) 7 34 - 7 41 (m, 2 H) 6 34 (br s , 2H) 4 21 (q, J=I 0, 7 0 Hz, 2H) 1 26 (t, J=I 0 Hz, 3H)
With triethylamine; In ethanol; for 3.5h;Heating / reflux;
To a stirred suspension of 4-fluorophenylhydrazine hydrochloride (9.76g, 60mmol) in ethanol (250ml) was added triethylamine (9.2ml, 62mmol) and to the resulting amber solution was added ethyl 2-cyano-3-ethoxyacrylate (10.15g, 60mmol). The solution was heated at reflux temperature for 3.5 hours. The solution was allowed to cool to room temperature and after standing overnight the resultant solid was filtered off, washed with small amount of ethanol and then ether before being dried under vacuum to give the title compound (12.1 g) as an off white solid.1H NMR (400 MHz, DMSO-cfe) delta ppm 7.70 (s, 1 H) 7.55 (s, J=5.0 Hz, 2 H) 7.34 - 7.41 (m, 2 H) 6.34 (br. s., 2 H) 4.21 (q, J=7.0, 7.0 Hz, 2 H) 1.26 (t, J=7.0 Hz, 3 H).
With sodium acetate; In ethanol; at 95℃; for 3.5h;
(i) Ethyl-2-cyano-3-(ethyloxy)-2-propenoate (5.0 g, 29.56 mmol), (4- fluorophenyl)hydrazine hydrochloride (4.81 g, 29.56 mmol) and sodium acetate (2.43 g, 29.56 mmol) were dissolved in ethanol (100 ml) and heated for 3.5 hrs at 95C. The mixture was then cooled to room temperature and diluted with dichloromethane (-150 ml) and water (50 ml). The organic layer was separated using a hydrophobic <n="105"/>frit, dried over anhydrous sodium sulphate, filtered and to give ethyl 5-amino-1-(4- fluorophenyl)-1 H-pyrazole-4-carboxylate (6.83 g) as an orange solid. This was used in the next step without further purification.
PREPARATION G Ethyl 1-(4-fluorophenyl)-1H-pyrazole-4-carboxylate A stirred suspension of ethyl 5-amino-1-(4-fluoro-phenyl)-1H-pyrazole-4-carboxylate (7.48 g, 30.0 mmole), prepared as described in Preparation A, above, and isopentyl nitrite (7.03 g, 60.0 mmole) in 80 ml of tetrahydrofuran was refluxed for twenty-four hours and then evaporated in vacuo. The residue was triturated with 50 ml of methanol and filtered to furnish 5.18 g (74% yield) of off-white solid. The sample was recrystallized from ethanol, m.p. 119-21 C. Analysis: Calculated for C12 H11 FN2 O2: C, 61.53; H, 4.73; N, 11.96%. Found: C, 61.41; H, 4.51; N, 11.95%.
PREPARATION A Ethyl-5-Amino-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylate A stirred mixture of 11.38 g (70.0 mmole) of a commercially available sample of 4-fluorophenylhydrazine hydrochloride, 11.84 g (70.0 mmole) of ethyl (ethoxymethylene)cyanoacetate and 9.67 g (70.0 mmole) of potassium carbonate in 100 ml of ethanol was refluxed overnight and then treated with 300 ml of water. The precipitate was filtered and dried in vacuo to furnish 12.87 g (74% yield) of pale yellow crystalline solid. The sample was recrystallized from ethanol m.p. 151-2 C. Analysis: Calculated for C12 H12 FN3 O2: C, 57.82; H, 4.85; N, 16.86%. Found: C, 57.82; H, 4.78; N, 16.79%.
With bromine; isopentyl nitrite; In chloroform; at 20℃; for 1.5h;
(ii) Ethyl 5-amino-1-(4-fluorophenyl)-1 H-pyrazole-4-carboxylate (6.83 g, 27.40 mmol) was dissolved in chloroform (180 ml) and bromine (3.23 ml, 63.03 mmol) was added to give a dark red/brown solution. To this isoamyl nitrite (5.52 ml, 41.10 mmol) was added dropwise and the mixture was then stirred at room temperature for 1.5 hrs. The solvent was evaporated to give ethyl 5-bromo-1-(4-fluorophenyl)-1 H-pyrazole-4- carboxylate (15.56 g) as an orange/brown oil which solidified on standing. This was used in the subsequent step without further purification.
General procedure: Intermediates 5 was synthesized based on the literature of Stephane L.etal. [27] Dissolve phenylhydrazine hydrochloride with 1.5 equivalents of sodium acetate in ethanol, stir and reflux for 1h, filter to obtain filtrate, then add ethyl (E)-2-cyano-3-ethoxyacrylate, stir and reflux for 1h, then the solution was rotary evaporated until the volume of the solution was reduced by half. After cooling, solids intermediate 5 can be precipitated, then filtered under vacuum. The resulting crude products are subjected to recrystallization purification.
2.65 g
In ethanol; at 110℃;
To a stirred solution of Step 1 intermediate (2.0 g, 10.14 mmol) in ethanol (20 mL), 4- fluorophenylhydrazine hydrochloride (1.97 g, 12.17 mmol) was added at RT and the reaction mixture was stirred overnight at 110 C. The rection mixture was cooled to RT, solvent were evaporated under reduced pressure and the residue was basified with saturated aqueous sodium bicarbonate solution till pH 9- 10. The mixture was extracted with ethyl acetate (100 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained product was purified by silica gel column chromatography to afford 2.65 g of the titled product as a solid. lH NMR (300 MHz, DMSO-d6): delta 1.26 (t, = 7.2 Hz, 3H), 4.21 (q, = 7.2 Hz, 2H), 6.31 (s, 2H), 7.37 (t, = 8.1 Hz, 2H), 7.54-7.57 (m, 2H), 7.69 (s, 1H); APCI (m/z) 250 (M+H)+.
methyl 1-(4-fluorophenyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With hydrogenchloride; In 1,4-dioxane; at 100℃; for 14h;
General procedure: To ethyl 5-amino-1-phenyl-1H-pyrazole-4-carboxylate (2a, 1.60 g, 6.92 mmol) in 4N HCl in 1,4-dioxane (35 mL) at room temperature was added methyl cyanoformate (1.77 g, 20.8 mmol). The mixture was stirred at 100 C for 14 h and was cooled to room temperature. After 1,4-dioxane was removed in vacuo and the residue was partitioned between methylene chloride and water. The organic layer was dried over magnesium sulfate and was evaporated in vacuo. The residue was chromatographed on a silica gel column with a mixture of methylene chloride and ethyl acetate (7:1) to give the desired product 3a (1.47 g, 78 %).
ethyl 1-(4-fluorophenyl)-5-(2-oxo-2H-chromene-3-carboxamido)-1H-pyrazole-4 carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With pyridine; trichlorophosphate;
General procedure: Intermediate 4 (0.001mol) and 5 (0.001mol) were dissolved in pyridine, phosphorus oxychloride is slowly added dropwise under ice bath conditions, then at 40-60C reacted for 5-8h. Finally, the mixture was poured into 30mL saturated Na2CO3 solution and stirred well. After the mixture was acidified, the saturated CuSO4 solution was used to remove pyridine, which greatly improved the purity and yield of the product. The data for compounds 8I-8VI are provided in the supporting information.
ethyl 5-(6-bromo-2-oxo-2H-chromene-3-carboxamido)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With pyridine; trichlorophosphate;
General procedure: Intermediate 4 (0.001mol) and 5 (0.001mol) were dissolved in pyridine, phosphorus oxychloride is slowly added dropwise under ice bath conditions, then at 40-60C reacted for 5-8h. Finally, the mixture was poured into 30mL saturated Na2CO3 solution and stirred well. After the mixture was acidified, the saturated CuSO4 solution was used to remove pyridine, which greatly improved the purity and yield of the product. The data for compounds 8I-8VI are provided in the supporting information.
ethyl 5-(6-chloro-2-oxo-2H-chromene-3-carboxamido)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With pyridine; trichlorophosphate;
General procedure: Intermediate 4 (0.001mol) and 5 (0.001mol) were dissolved in pyridine, phosphorus oxychloride is slowly added dropwise under ice bath conditions, then at 40-60C reacted for 5-8h. Finally, the mixture was poured into 30mL saturated Na2CO3 solution and stirred well. After the mixture was acidified, the saturated CuSO4 solution was used to remove pyridine, which greatly improved the purity and yield of the product. The data for compounds 8I-8VI are provided in the supporting information.
ethyl 1-(4-fluorophenyl)-5-(6-nitro-2-oxo-2H-chromene-3-carboxamido)-1H-pyrazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With pyridine; trichlorophosphate;
General procedure: Intermediate 4 (0.001mol) and 5 (0.001mol) were dissolved in pyridine, phosphorus oxychloride is slowly added dropwise under ice bath conditions, then at 40-60C reacted for 5-8h. Finally, the mixture was poured into 30mL saturated Na2CO3 solution and stirred well. After the mixture was acidified, the saturated CuSO4 solution was used to remove pyridine, which greatly improved the purity and yield of the product. The data for compounds 8I-8VI are provided in the supporting information.
ethyl 5-(7-(diethylamino)-2-oxo-2H-chromene-3-carboxamido)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With pyridine; trichlorophosphate;
General procedure: Intermediate 4 (0.001mol) and 5 (0.001mol) were dissolved in pyridine, phosphorus oxychloride is slowly added dropwise under ice bath conditions, then at 40-60C reacted for 5-8h. Finally, the mixture was poured into 30mL saturated Na2CO3 solution and stirred well. After the mixture was acidified, the saturated CuSO4 solution was used to remove pyridine, which greatly improved the purity and yield of the product. The data for compounds 8I-8VI are provided in the supporting information.
5-amino-N-(2[({2-[(difluoromethyl)oxy]-6-fluorophenyl}carbonyl)amino]methyl}-3,3,3-trifluoro-2-hydroxypropyl)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide[ No CAS ]
5-amino-N-(2-[({2-chloro-6-[(difluoromethyl)oxy]phenyl}carbonyl)amino]methyl}-3,3,3-trifluoro-2-hydroxypropyl)-1-(-fluorophenyl)-1H-pyrazole-4-carboxamide[ No CAS ]
5-amino-N-{2-[([2-chloro-6-(trifluoromethyl)phenyl]carbonyl}amino)methyl]-3,3,3-trifluoro-2-hydroxypropyl}-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide[ No CAS ]
5-amino-N-{2-[([2-bromo-6-(trifluoromethyl)phenyl]carbonyl}amino)methyl]-3,3,3-trifluoro-2-hydroxypropyl}-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide[ No CAS ]
5-amino-N-{2-[([2,6-bis(difluoromethyl)phenyl]carbonyl}amino)methyl]-3,3,3-trifluoro-2-hydroxypropyl}-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide[ No CAS ]
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