1-Butanol → HCID 178522431, compound

Participants

Reaction Conditions

Reaction Steps

7-Morpholin-4-ylmethyl-2,4-dihydro-1,2,4,5a,10-pentaaza-cyclopenta[α]fluoren-5-one (1.0 wt, prepared as outlined above in Example 66A) and a solvent such as n-butanol, butyronitrile, glycol or toluene (3.0 vol) can be charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. Cyclopropylamine (0.351 wt) can be added at temperature such as 15 to 30° C. under an inert atmosphere e.g. nitrogen. The contents can be heated to 40 to 105° C., in particular 40-80° C. and stirred at this temperature for 16 to 24 hours. Reaction completion can be determined by 1H NMR analysis. The reaction mixture can then be cooled to 10 to 20° C. The product can then be isolated by organic-aqueous extraction method as outlined above in Example 66A, or an alternative method of isolation may be employed such as the addition of an anti-solvent, for example n-heptanes, to the reaction mixture. This could allow the reaction product to precipitate with subsequent isolation by filtration. The solid can then be dried under vacuum at 35 to 45° C. to yield 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea. At this stage the solid can be purified by recrystallisation from an appropriate solvent, preferably a Class 2 or 3 solvent1. In addition, alternative methods of purification aside from recrystallisation may be employed for purification of the product such as flash column chromatography or filtration through a plug of silica gel or reverse-phase silica gel. 1 Class 3 and Class 2 solvents are as outlined Q3C—Tables and List in Guidance for Industry Q3C Impurities: Residual Solvents (November 2003, CDER, CBER, FDA, ICH) and as further outlined in Impurities: Guideline for Residual Solvents (1997, ICH).

Provenance & Evidence