Reaction Steps
A 250 mL 3-necked round bottom flask equipped with a magnetic stir bar, a condenser topped with a nitrogen outlet, a stopper, and a rubber septum was flushed with nitrogen and charged with 24.38 g (50 mmol, 1 eq) of 3-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-hydroxyphenyl)methyl]-N-(3-fluorophenyl)-N-methylbenzamide {DPI-3290; U.S. Pat. No. 5,574,159, Example 16}, 7.5 mL (58.5 mmol, 1.17 eq) of 1,4-dioxa-8-azaspiro-[4.5]decane, and 100 mL of anhydrous tetrahydrofuran. While stirring briskly, 55 mL (110 mmol, 2.2 eq) of 2.0 M isopropylmagnesium chloride in THF was added by syringe over 5 minutes. A vigorous, exothermic reaction ensued. After addition was completed, a heating mantle was attached and the reaction was heated to reflux for 4 hours. The reaction was cooled to room temperature overnight under nitrogen. The reaction was quenched by careful addition of 15 mL of saturated aqueous NH4Cl solution and stirred vigorously for 30 minutes. Approximately 15 g of anhydrous magnesium sulfate was added and the mixture was filtered, rinsing the solids with THF (2×25 mL). The filtrate was concentrated in vacuo and the residue was partitioned between 100 mL ethyl acetate and water. The aqueous solution was adjusted to pH=8-9 using saturated sodium bicarbonate solution. The layers were separated and the organic phase was washed with water and then brine. The organic extract was dried over sodium sulfate/magnesium sulfate and the solvent was removed in vacuo, leaving 31.85 g of crude product as an amber-colored foam. Chromatography of this material on ˜300 g of silica gel eluting with dichloromethane/ethyl acetate with 2% ammonium hydroxide yielded 23.93 g (91.5%) of {3-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-hydroxyphenyl)methyl]-phenyl}-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)methanone as an off-white foam. Calculated for C30H39N3O4 0.1 CH2Cl2 0.1 C4H8O2: %C, 70.05; H, 7.71; N, 8.04. Found: %C, 69.95; H, 7.80; N, 8.05. 1H NMR (300 MHz, CDCl3): {tilde over (□)}□d, J=7.6 Hz, 1H), 7.45 (s, 1H), 7.33-7.23 (m, 2H), 7.05 (t, J=7.7 Hz, 1H), 6.56 (t, J=8.3 Hz, 2H), 6.53 (s, 1H), 5.95-5.82 (m, 1H), 5.21 (d, J=9.3Hz, 1H), 5.16 (s, 2H), 3.97 (s, 4H), 3.82 (br s, 2H), 3.45-3.38 (m, 3H), 2.90-2.80 (m, 2H), 2.63-2.45 (m, 3H), 2.13 (dd, J=1.1, 10.9 Hz, 1H), 1.91 (dd, J=1.0, 11.2 Hz, 1H), 1.78 (br s, 2H), 1.60 (br s, 2H), 1.14 (d, J=6.0 Hz, 3H), 0.99 (d, J=6.1 Hz, 3H).
