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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).
(E)-1-(4-fluorophenyl)-5-(((2-phenyl-1H-indol-3-yl)methylene)amino)-1H-pyrazole-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In ethanol; water; at 80℃;
General procedure: Intermediate 4 (1mmol) and the intermediate 7 (1mmol) were dissolved in ethanol to the glass flask, then HCl solution was added as a catalyst refluxed at 80C for 15-18h. After the TLC monitoring reaction was completed, the mixture was vacuum filtered and concentrated. Finally, the above crude product can be isolated and purified by column chromatography (Hexane/EtOAc=8:1) to obtain target compounds.
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