Methanol → 5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-methyl-N-[3-(1-methyl-4-piperidinyl)-propyl]-2-pyrimidinamine phosphate

Participants

Reaction Steps

To a 50 mL Erlenmeyer flask which contained 500.32 mg (1.275 mmol) of 5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-methyl-N-[3-(1-methyl-4-piperidinyl)propyl]-2-pyrimidinamine), Compound 2 and a stir bar, was added about 20 mL of hot 50:50 MeOH:EtOH solvent. In some embodiments, hot MeOH:EtOH was used at a temperature of about 50° C. to 60° C. A clear yellow solution was obtained. The solution was brought to boiling temperature on a hot plate with stirring, and 96 μL of phosphoric acid (85% in water, 1.1 equivalent) was added dropwise. The reaction mixture became cloudy as the acid was added but quickly changed to a clear yellow solution as it was stirred. The reaction mixture was left to heat on the hot plate at low temperature for another 10 min before being removed and allowed to cool down to rt on the bench top. The flask was left at room temperature overnight to allow crystals to precipitate. For this experiment, small spatula of the phosphate salt was added to the reaction mixture as seeded and left open at rt overnight to form crystals. Very fine crystalline needles are formed in the bottom of the flask after 2 days. 531.3 mg (85% yield) of the off white, light yellow solid crystalline 5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-methyl-N-[3-(1-methyl-4-piperidinyl)-propyl]-2-pyrimidinamine phosphate (1:1), compound 5 were collected by vacuum filter. Precipitation will occur at rt after 2 days or more without seeding, but it forms an oil layer in the bottom of the flask if left at cold temperature (5° C.). Significant losses in the mother liquor were observed in some embodiments. Furthermore, this phosphate salt tended to form a sticky oil on the reactor walls, which makes it more difficult to handle than any of Compounds 2.1 and 3. XRD profiles confirmed the pattern of the desired phosphate salt. As to purity, this phosphate salt did not show improved impurity segregaton ability with respect to that of Compound 2.1.

Provenance & Evidence