ETHYL 1-ISOPROPYL-3-METHYL-6-OXO-6,7-DIHYDRO-1H-PYRAZOLO[3,4-B]PYRIDINE-4-CARBOXYLATE synthesis

Yield:-

Reaction Conditions:

Stage #1:3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine;Diethyl ketomalonate in toluene at 62;
Stage #2: with acetic acid for 2 h;Reflux;

Steps:

2.2
Step 2:To a solution of diethyl 2-oxobutanedione (176 g, 0.94 mol) in toluene (2 L) was added 3 -methyl- l-(l-methylethyl)-lH-pyrazol-5 -amine (82.5 g, 0.59 mol), and the mixture stirred at 62 °C, overnight. After cooling to room temperature, the mixture was concentrated in vacuo and the crude residue dissolved into acetic acid (1.5 L). The mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was concentrated in vacuo to afford a solid residue, which was recrystallized from DCM to afford the desired product as a yellow colored solid. The collected solid was suspended in ethanol (1510 niL) and THF (216 mL) followed by addition of 3N NaOH (334 mL) and the reaction mixture was stirred at 40 °C for 40 min. The mixture was concentrated in vacuo to remove the volatiles and the aqueous phase acidified using IN HC1. The resulting precipitate was collected by filtration and dried under high vacuum to give the title compound, 3-methyl-l-(l-methylethyl)-6-oxo-6,7-dihydro-lH-pyrazolo[3,4-?]pyridine-4- carboxylic acid, as 51.38 g. LCMS E-S (?+?) = 236.1. 1H NMR (400 MHz, DMSO-d₆) ? ppm 1.35 (d, J=6.8 Hz, 6 H), 2.41 (s, 3H), 4.84-4.91 (m, 1H), 6.64 (s, 1H). Carboxylic acid proton not observed.

References:

GLAX0SMITHKLINE LLC;BURGESS, Joelle, Lorraine;JOHNSON, Neil, W.;KNIGHT, Steven, David;LAFRANCE, Louis, Vincent, III;MILLER, William, H.;NEWLANDER, Kenneth, Allen;ROMERIL, Stuart, Paul;ROUSE, Meagan, B.;SUAREZ, Dominic;TIAN, Xinrong;VERMA, Sharad, Kumar WO2013/39988, 2013, A1 Location in patent:Page/Page column 46-47