Dichloromethane → BI-135585 monohydrate

Participants

Reaction Conditions

Reaction Steps

A reaction flask is charged with (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (19.66 g, 45.47 mmol) (see Ex. 588 of WO/2009/017664), compound 1 (7.65 g, 50.02 mmol), [1,1′-bis(diphenylphosphino)ferroncene]dichloropalladium(II), complex with dichloromethane (37.40 mg, 0.046 mmol), potassium carbonate (18.85 g, 136.42 mmol) and 2-propanol (100 mL). The flask is evacuated and refilled with argon three times. The contents of the reactor are heated to 80° C. and held for about 6 hours at which time compound 1 is completely consumed. The contents of the reactor are then treated with a solution of N-acetyl-L-cysteine (0.75 g, 4.58 mmol) in 2-propanol (100 mL) and stirred at 80° C. for 2 hours. The resultant suspension is then filtered. (The suspension is maintained at 50° C. to 70° C. during the filtration step.) The resultant solids are then rinsed with 2-propanol (50 mL pre-heated to 70° C.). The combined filtrate and washes is heated to 70° C., maintained at reduced pressure until about 150 ml of volatiles are removed, cooled to 65° C., and seeded with compound 2. The resultant suspension is stirred at 60-65° C. for 0.5 hours, cooled to 0° C. over about 2 hours, and maintained at 0° C. for 1 hour. The resultant solids are collected by filtration and washed with cold 2-propanol (50 mL). The solids are then recrystallized from a mixture of 2-propanol (40 mL) and water (200 mL) to provide compound 2 (monohydrate) as a white solid. Yield: 19.38 g, 88.2% yield based on BI135541. Purity: 98.96 wt %. Analysis of the product agrees with the data reported in Example 48, Method 2 of WO/2009/134400 which describes the synthesis of the monohydrate of compound 1 by reacting 4-iodo-1-methylpyridin-2(1H)-one with (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one.

Provenance & Evidence