Yield:7554-65-6 84%

Reaction Conditions:

Stage #1:1,1,3,3-tetraethoxy-2-methyl-propane with hydrazinium sulfate in water at 80; for 3 h;
Stage #2: with sodium hydroxide in water; pH=4 - 6 at 3 - 30;
Stage #3: with sodium hydrogencarbonate in water; pH=7 at 27 - 30;

Steps:

4
Into a 5 liter flask equipped with a mechanical stirrer were added 1750 ml of sterile USP water to which 266.7 g (2.05 moles) of hydrazine hydrosulfate were added gradually over one hour with stirring. To the above mixture was added dropwise 481 g (2.053 moles) of 3 and the reaction mixture was warmed to 80°C. Heating and stirring were maintained for 3 hours, the flask was cooled to 40°C, and the volatile components were distilled off under a reduced pressure of about 125 mm. The resulting mixture was EPO cooled to 10⁰C first with water and then with glycol; 20 ml of water were added to the flask, and cooling was continued to a temperature of 3°C. Thereafter 50% sodium hydroxide solution was added with cooling so as to maintain the temperature below 30°C. The pH of the reaction mixture should be between 4 and 6. A solution of sodium bicarbonate containing 4.9 g of sodium bicarbonate to 55 ml of water was added to the flask. Additional sodium bicarbonate solution was added until the pH reached 7.0. The flask temperature was allowed to rise to 27°C with continued stirring. The contents of the flask were extracted with ethyl acetate and the aqueous layer was separated. The organic layer was dried over magnesium sulfate, filtered, and the extract was distilled under vacuum. The light fraction was removed at a pot temperature of 55-60°C at 125 mm pressure. The vacuum was improved to 5 mm for the remainder of the distillation; pot temperatures were permitted to rise to 100-110°C to produce 134.8 g (84% based on 3) of 4-methylpyrazole, bp 77-80°C at 5 mm, as a clear, colorless to yellow liquid. Gas chromatographic analysis showed less than 0.1% pyrazole and less than 10 ppm hydrazine.

References:

ORPHAN MEDICAL, INC. WO2006/115626, 2006, A2 Location in patent:Page/Page column 8-9

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