3-methylpiperidin-4-one

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium t-butoxide (1.56 g) was added portionwise to a stirred suspension of methoxymethyltriphenylphosphonium chloride (4.76 g) in tetrahydrofuran (30 ml) at 0° C. under argon. The resulting orange mixture was stirred at 0° C. for 30 min., then 1-(4-chlorocinnamyl)-3-methyl-piperidin-4-one (1.83 g, prepared by alkylation of 3-methyl-piperidin-4-one [CAS No 5773-58-0] with 4-chloro-cinnamyl chloride) dissolved in a minimum volume of tetrahydrofuran was added dropwise and the resulting solution was stirred at room temperature for 1 hour, poured into water and extracted twice with ether. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. The residue was purified by silica gel chromatography (cyclohexane:ethyl acetate 75:25) to afford 1-(4-chlorocinnamyl)-4-[1-methoxy-methylidene]-3-methyl-piperidine as a mixture of diastereoisomers. MS (ES+) 292/294 (M+H+). was added dropwise the resulting solution was stirred at room temperature for 1 hour extracted twice with ether The combined organic layers were dried over sodium sulphate concentrated in vacuo The residue was purified by silica gel chromatography (cyclohexane:ethyl acetate 75:25)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and 3-methylpiperidin-4-one (34 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 30-55% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (34 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J=6.57 Hz, 3H) 1.46 (s, 6H) 2.74-2.97 (m, 2H) 3.30 (t, J=11.87 Hz, 1H) 3.57-3.69 (m, 1H) 4.56-4.70 (m, 2H) 6.38 (d, J=2.27 Hz, 1H) 7.48 (s, 1H) 7.60 (d, J=8.59 Hz, 2H) 8.00 (d, J=8.59 Hz, 2H) 8.13 (d, J=2.27 Hz, 1H) 10.93 (s, 1H). ESI-MS: m/z 408.2 (M+H)+. was then purified by preparatory HPLC, 30-55% (MeCN/H2O gradient+0.01% TFA)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and 3-methylpiperidin-4-one (34 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 30-55% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (34 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J=6.57 Hz, 3 H) 1.46 (s, 6 H) 2.74-2.97 (m, 2 H) 3.30 (t, J=11.87 Hz, 1 H) 3.57-3.69 (m, 1 H) 4.56-4.70 (m, 2 H) 6.38 (d, J=2.27 Hz, 1 H) 7.48 (s, 1 H) 7.60 (d, J=8.59 Hz, 2 H) 8.00 (d, J=8.59 Hz, 2 H) 8.13 (d, J=2.27 Hz, 1 H) 10.93 (s, 1 H). ESI-MS: m/z 408.2 (M+H)+. was then purified by preparatory HPLC, 30-55% (MeCN/H2O gradient+0.01% TFA)