PYRROLO[3,2-d]PYRIMIDINE COMPOUNDS AND THEIR USE AS PI3 KINASE AND mTOR KINASE INHIBITORS

General Procedure

Preparation of 2-[3-(benzyloxy)phenyl]-4-morpholin-4-yl-5H-pyrrolo[3,2-d]pyrimidine

[0232]Step 1: Synthesis of 4-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)morpholine

[0233]To a stirred solution of 2,4-dichloro-6-methyl-5-nitro-pyrimidine (5.0 g, 24.15 mmol) in CH2Cl2 (50 mL) was added a solution of morpholine (2.1 mL, 24.15 mmol) in CH2Cl2 (20 mL), followed by the addition of triethylamine (6.7 mL, 48.3 mmol) at 0° C. The resulting mixture was stirred at room temperature overnight and diluted with CH2Cl2. The organic solution was washed with water and brine, and dried over MgSO4. The solvent was removed by evaporation under reduced pressure, and the residue was purified by flash chromatography to give the titled compound as yellow solid (6.17 g, 99% yield). MS (ESI) m / z 259.0

Step 2: Synthesis of 4-{2-[3-(benzyloxy)phenyl]-6-methyl-5-nitropyrimidin-4-yl}morpholine

[0234]To a stirred solution of 4-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)morpholine (400 mg, 1.55 mmol) in 8

Preparation of 3-(4-morpholin-4-yl-5H-pyrrolo[3,2-d]pyrimidin-2-yl)phenol

[0237]To a solution of 2-[3-(benzyloxy)phenyl]-4-morpholin-4-yl-5H-pyrrolo[3,2-d]pyrimidine (249 mg, 0.64 mmol) in 20 mL of methanol was added 10% Pd / C (40 mg) and acetic acid (1 mL). The resulting mixture was shaken under hydrogen (H2, 50 psi) at room temperature overnight. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuum. The obtained residue was purified by flash column chromatography (EtOAc:Hexanes=80:20) to give the title compound as off-white solid (180 mg, 95% yield); MS (ESI) m / z 297.1

Preparation of [3-(4-morpholin-4-yl-5H-pyrrolo[3,2-d]pyrimidin-2-yl)phenyl]methanol

[0238]Following the procedure as described as in Example 1 step 2, Suzuki coupling of 4-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)morpholine (1.1 g, 4.26 mmol) and 3-(hydroxymethyl)phenylboronic acid (0.882 g, 6.39 mmol) gave the intermediate 3-(4-methyl-6-morpholino-5-nitropyrimidin-2-yl)phenyl)methanol (1.41 g, 99% yield, MS (ESI): m / z 331.2), which was converted to the title compound (by following the procedure as described as in Example 1 step 3 and 4) as off-white solid (Yield: 542 mg, 41%). MS (ESI) m / z 311.2