Lithium hydroxide, monohydrate → HCID 46908610, compound

Participants

Reaction Steps

Acetic acid 2-(5-{tert-butoxycarbonyl-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-amino}-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzyl ester (1.5 g, 1.92 mmol) was dissolved in 19 ml of dioxane. Lithium hydroxide monohydrate (404 mg, 9.62 mmol) was dissolved in 19 ml of water and added dropwise. The reaction was heated at 50 degrees centigrade for 2 hrs. The reaction was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried and concentrated. The residue was dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (20 ml) and heated in a microwave reactor at 140 degrees for 30 min. The reaction was concentrated and the residue was purified by flash chromatography using a gradient of 0% to 15% methanol in DCM. The residue was diluted with DCM and concentrated again. Isopropyl acetate was added and the mixture was heated in a water bath to form a solution. The solution was cooled to room temperature and allowed to stand at room temperature overnight. The solid that formed was filtered and dried to give 185 mg of 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-phthalazin-1-one. A second crop of crystals yielded 88 mg of product for a combined yield of 273 mg (22.3%). MS: (M+H)+=638; MP=235.0-238.0° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (s, 9 H) 2.12 (s, 3 H) 2.19-2.41 (m, 8 H) 3.60 (s, 3 H) 4.32-4.40 (m, 2 H) 4.58-4.63 (m, 1 H) 4.60-4.61 (m, 1 H) 7.25 (d, J=8.59 Hz, 1 H) 7.34-7.44 (m, 3 H) 7.52 (s, 2 H) 7.52-7.54 (m, 1 H) 7.74 (dd, J=13.14, 1.52 Hz, 1 H) 7.87 (d, J=1.52 Hz, 1 H) 8.04 (d, J=2.02 Hz, 1 H).

Provenance & Evidence