CP-226269 synthesis

Yield:-

Reaction Conditions:

with lithium aluminium tetrahydride in tetrahydrofuran;

Steps:

17.17B Example 17B [ 5-FLUORO-2-F R4-(2-PYRIDINYL)-1-PIPERAZINYLLMETHYL}-1H-INDOLE]

The product from Example 17A (3.50 g) in tetrahydrofuran (50 mL) was treated with lithium aluminum hydride (30 mmol). The mixture was was treated by sequential addition of 1.14 [ML] of water, 1.14 mL of 15% aqueous sodium hydroxide, and 3.42 mL of water. The slurry was filtered and the filtrate diluted with ethanol and then concentrated under reduced pressure. The residue was filtered through a plug of silica gel, then purified by chromatography on silica gel, eluting with ethyl acetate containing [0.] 1% ammonium hydroxide to provide the title [COMPOUND. 1H] NMR (d6-DMSO, 300 MHz) [6] 2.55 [(M,] 4H), 3.50 (t, 4H, J=4. [5HZ),] 3.65 (s, 2H), 6.30 (s, 1H), 6.63 (dd, [1H,] J=7.5, 4.8Hz), 6.80 (d, [1H,] J=7. [5HZ),] 6. [85 (M, 1H),] 7.20 (dd, [1H, J=10.] 5,2. 4Hz), 7. [30] (dd, [1H,] J=9,5. 4Hz), 7. [50 (M,] 1H), 8.09 (dd, [1H,] J=4.5, 1. 8Hz), 11.72 (bs, 1H). MS (DCI/NH3) m/z 311 [(M+H) +.] The free base was dissolved in 45 mL of methanol, along with 1.0 equivalent of maleic acid. Addition of toluene, then evaporation under reduced pressure gave a glass, which was covered with 25 mL of ether, which yielded crystals when a small amount of methanol was added. Evaporation of solvent, followed by recrystallization of the resulting solid from 15 mL of methanol, 15 mL of toluene, and 200 mL of ether, gave 3. 11 g (88% from the free base) of 5- [FLUORO-2- (4-PYRIDIN-2-YL-PIPERAZIN-1-YLMETHYL)-1H-INDOLE MALEATE.] Anal. Calcd for [CL8HI9N4F. C4H404] : C, 61.96 ; H, 5.44 ; N, 13.14. Found: C, 61.89 ; H, 5. [36 ;] N, 13.12.

References:

WO2003/101994,2003,A1 Location in patent:Page 86