Acetic Acid → HCID 178484155, compound

Participants

Reaction Steps

A mixture of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone (100 g, 2.51 mmol), (3R)-(+)-3-(dimethylamino)pyrrolidine (0.86 g, 7.5 mmol), and acetic acid (0.43 mL, 7.5 mmol) in 1,2-dichloroethane (45 mL) was stirred at ambient temperature under an atmosphere of nitrogen for 30 minutes. Sodium triacetoxyborohydride (0.689 g, 3.26 mmol) was added and the mixture stirred at ambient temperature for 22 hours. Water (50 mL) and sodium bicarbonate (1.35 g, 16.1 mmol) were added and the mixture was stirred for 3 hours. The reaction mixture was transferred to a separatory funnel and the organic layer was separated. The aqueous layer was extracted with CH2Cl2(20 mL), and the combined organic extracts were dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure to yield a red oil. The cis and trans isomers were purified by flash chromatography on silica gel (1 L 5% MeOH in CH2Cl2, then 1 L 10% MeOH in CH2Cl2, 1 L 20% MeOH in CH2Cl2, 1 L 30% MeOH in CH2Cl2, 1 L 40% MeOH in CH2Cl2, and 1 L 50% MeOH in CH2Cl2) to yield cis-7-{4-[(3R)-3-(dimethylamino)tetrahydro-1H-1-pyrrolyl]cyclohexyl}-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a pink solid (0.558 g, 1.12 mmol) and trans-7-{4-[(3R)-3-(dimethylamino)tetrahydro-1H-1-pyrrolyl]cyclohexyl}-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a pink solid (0.210 g, 0.422 mmol). The cis-7-{4-[(3R)-3-(dimethylamino)tetrahydro-1H-1-pyrrolyl]cyclohexyl}-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.330 g, 0.670 mmol) was dissolved in warm ethanol (5 mL) then maleic acid (0.233 g, 2.01 mmol) in ethanol (5 mL) was added. The mixture was cooled to ambient temperature and the solid was collected by filtration and dried to give cis-7-{4-[(3R)-3-(dimethylamino)tetrahydro-1H-1-pyrrolyl]cyclohexyl}-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine trimaleate salt (0.622 g) as a beige solid: 1H NMR (d6 DMSO, 400 MHz): δ H 8.20(1H, s), 7.41-7.48(4H, m), 7.35(1H, s), 7.08-7.19 (5H, m), 6.45(2H, bs), 6.16(6H, s), 4.70(1H, m), 4.30(2H, bs), 3.80(1H, bs), 3.08(3H, m), 2.76(6H, s), 2.00-2.21(6H, m), 1.74-1.72(4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 13.94 min. MS: MH+ 497.

Provenance & Evidence