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Chemical synthesis of compound 16677. For synthesis of compound 16677, 1-methyl-3-trifluoromethyl-5-pyrazolecarboxylic acid 3 (Scheme 1, FIG. 10) was prepared from commercially available compound 1 as previously described (Schlosser et al., (2002) Eur. J. Org. Chem. 2002(17), 2913-2920). Compound 3 (820 mg, 4.2 mmol) in dichloromethane (10 ml) was treated with oxalyl chloride (2.0 M in CH2Cl2, 8.5 mmol, 4.2 ml) and a catalytic amount of DMF. The reaction mixture was incubated at room temperature for 5 hours. Evaporation of solvent delivered yellow acyl chloride 4 in quantitative yield.
To a mixture of 8.71 g of l-methyl-3-trifIuoromethyl-1H-' pyrazole and 130 ml of tetrahydrofuran was added dropwise 32 ml of a 2.0 mol/L lithium diisopropylamide solution in heptane/tetrahydrofuran/ethylbenzene at -78C. The mixture of stirred at -780C for 2 hours and then poured into a mixture was dry ice and 50 ml of tetrahydrofuran. The mixture was stirred for 2 hours while allowing it to rise to around room temperature. Water and diethyl ether were poured into the reaction mixture. The aqueous layer was adjusted to pH 10-12 by an addition of a 2N aqueous sodium hydroxide solution, and then layers were separated. The resulting aqueous layer was washed with diethyl ether two times, adjusted to around pH 3 by an addition of 2N hydrochloric acid, and then extracted with methyl tert-butyl ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 8.19 g of l-methyl-3- tri f luoromethyl- lH-pyra zole- 5-carboxylic acid of the formula :l-Methyl-3-trifluoromethyl-lH-pyrazole-S-carboxylic acid EPO <DP n="488"/>1H-NMR (CDCl3, TMS) delta (ppm) : 4.13 (3H, s) , 7.22 (IH, s).
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