Methylamine → HCID 178485523, compound

Participants

Reaction Conditions

Reaction Steps

A suspension of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (300 mg, 0.63 mmol) and 6-(methyloxy)-1-(1-methyl-L-prolyl)-1,2,3,4-tetrahydro-7-quinolinamine 217 mg, 0.75 mmol) in THF (50 ml) was heated at 65° C. for 4 hrs. The reaction was diluted with ethyl acetate (200 ml) and washed with saturated NaHCO3 (300 ml). Organic layer was removed, concentrated by rotary evaporation, solids triturated from ethyl acetate/hexanes, and dried under house vacuum prior to next step. The solids were then added to THF (50 ml) followed by a solution of methylamine (2M in THF, 7.40 ml, 3.7 mmol) and the resulting mixture was stirred at rt overnight. Next, the crude reaction was adsorbed onto silica gel and purified by silica gel chromatography (DCM to 10% MeOH/DCM over 30 min). ESIMS (M+H)+=727. The isolated pure amide was redissolved in 1,4-dioxane (10 ml), potassium hydroxide (2.497 ml, 12.49 mmol) added and the reaction was heated in the microwave at 120° C. for 20 min. The resulting solution was adsorbed onto silica gel and purified by silica gel chromatography (DCM to 10% MeOH/DCM) to afford 2-fluoro-N-methyl-6-[(2-{[6-(methyloxy)-1-(1-methyl-L-prolyl)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (0.1 g, 28% over three steps). ESIMS (M+H)+=573; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72-1.98 (m, 6 H) 2.06 (s, 3 H) 2.11-2.20 (m, 1 H) 2.58-2.73 (m, 2 H) 2.78 (d, J=4.41 Hz, 3 H) 2.85-2.97 (m, 1 H) 3.41-3.52 (m, 2 H) 3.88 (s, 3 H).

Provenance & Evidence