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Stage #1: With methanol; lithium hydroxide; water In tetrahydrofuran at 25℃; for 12 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran; methanol; ethyl acetate
Method 66; 1 -fert-Butyl- lH-pyrazole-4-carboxylic acid; A solution of ethyl l-ter^butyl-lH-pyrazole-3-carboxylate (Method 65; 327 mg, 1.66 mmol) in THF-MeOH-H2O (3:1:1, 8 ml) was treated with LiOH (120 mg, 5.0 mmol). The reaction mixture was stirred at 25 0C for 12 h. H2O and EtOAc were added to the reaction mixture and the resulting solution was acidified with 10percent HCl. The organics were dried with Na2SO4(s) and concentrated under reduced pressure to yield 217 mg (78 percent). m/z 168.
With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h;
To a -78 0C solution of 4-bromo-l -7-butyI-lH-pyrazole (15 g, 74.3 mmol) in anhydrous THF (100 mL) was added /7-BuLi (2.5 M in hexane, 53 mL, 132 mmol) under N2, and the resulting mixture was stirred at -78°C for 30 min. Excess dry ice was added at -78 0C, and the mixture was warmed slowly to RT and stirred overnight. The reaction was concentrated in vacuo, water was added and the pH was adjusted to pH 3 by the addition of 2N aq HCI. The aqueous solution was extracted with EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was recrystallized (EtO Ac-pet, ether) to give 1 -/-butyl- lH-pyrazole-4-carboxylic acid (8.0 g, 67 percent yield). 1H NMR (300 MHz, CDCl3): ^ 8.10 (s, 1 H), 8.03 (s, 1 H), 1.64 (s, 9 H); MS (ESI) m/z: 168.9 [M+Hf.
Formyl-3-oxo-propionic acid ethyl ester (75.85 g, 525.6 mmol) was dissolved in ethanol (1 L) at room temp. Tert-butylhydrazine hydrochloride (65.5 g, 525.6 mmol) was added at room temp and the reaction temperature gradually increased to 32° C. The flask was then placed in an ice-bath to cool it back to 20° C. It took ca. 1 h for t-butylhydrazine to fully dissolve. The solution was stirred at room temp. for 3 h. The reaction mixture was cooled in an ice-bath. Sodium hydroxide (4N, 152.4 g) was added to neutralize the hydrochloric acid. Most of the ethanol was then removed in vacuo and methanol (300 ml) was added followed by additional sodium hydroxide (4N, 304.8 g, 1.05 mol). The internal temperature gradually rose to 32° C. The reaction flask was then placed in a water bath to cool it back to room temp. and the reaction was allowed to stir at room temp. for 18 h. Methanol (300 ml) was then removed in vacuo with the water bath temperature kept below 30° C. The reaction mixture was then cooled to 0° C. and hydrochloric acid (6N, 190 ml) was added slowly to keep internal temperature below 15° C. The solution was adjusted to pH=2. The resulting suspension was allowed to stir in the ice-bath for 2 h, and the solid was filtered. After drying at 60° C. in vacuo for 2.5 days, 1-tert-butyl-1H-pyrazole-4-carboxylic acid (56.06 g) of off-white solid was collected. The mother liquor was extracted 3 times with dichloromethane (200 ml.x.3). The combined organic layer was washed once with brine (100 ml) and dried over magnesium sulfate. After concentrating in vacuo and drying, 16.5 g of yellowish solid was collected. The crude material was crystallized in hot iso-propyl acetate (25 ml) and heptane (25 ml). After cooling to room temp, the solid was filtered off and the cake was washed with mixed solvent of isopropyl acetate and heptane (1/1 (v/v, 14 ml) and dried in oven at 60° C. in vacuo for 5 h. A second crop of 1-tert-butyl-1H-pyrazole-4-carboxylic acid (7 g) was collected as a white solid.
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