2-Chloro-5-(oxiran-2-yl)pyridine → 9-Chloro-5-{3-[2-(6-chloropyridin-3-yl)-2-hydroxyethylamino]cyclohexyl}-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one

Participants

Reaction Steps

To a stirred solution of 6-chloronicotinic acid (900 mg, 5.7 mmol) in THF (7 mL) was added BH3 (16 mL, 17.1 mmol, 1M in THF) under N2 atmosphere. The reaction mixture was stirred for 5 h. It was quenched with methanol (5 mL) and then concentrated. The crude was dissolved in EtOAc (30 mL), washed with 1N NaOH (15 mL×3), brine, dried and concentrated. Yield: 615 mg (75%) of 6-chloro-pyridin-3-yl-methanol. To this alcohol (615 mg, 4.28 mmol) solution in CH2Cl2 (8 mL) was added Dess-Martin reagent (5.4 mg, 12.8 mmol). It was stirred at rt. for 2 h and then diluted with CH2Cl2. The resulting solution was washed with NaOH (1N, 2×5 mL), brine, dried and concentrated. 516 mg (85%) of yellow solid as the desired 6-chloro-pyridine-3-carbaldehyde. To a solution of above aldehyde (401 mg, 2.82 mmol) in CH2Cl2 (10 mL) was added 50% NaOH solution (9.3 mL), trimethylsulfonium iodide (1.15 g, 5.64 mmol) and tetrabutylammonium iodide (11 mg). It was refluxed for 48 h and poured onto ice water. The organic layer was extracted with CH2Cl2, washed with brine, dried and concentrated. The crude epoxide was chromatographed (gradient, hexanes: EtOAc) and 190 mg (43%) yellow oil was yielded as desired 2-Chloro-5-oxiranyl-pyridine. To the solution of 2-chloro-5-oxiranyl-pyridine (118.4 mg, 0.76 mmol) in absolute ethanol (40 mL) was added a compound from Example 660 (252 mg, 0.76 mmol). The reaction mixture was refluxed for 24 h and concentrated.

Provenance & Evidence