3-Bromopyridine → HCID 68058278, compound

Temperature

-78 °C

To a magnetically stirred solution of 2,2,6,6-tetramethylpiperidine (2.50 g, 17.70 mmol) in dry THF (80 mL) under argon at −78° C. was slowly added over 2 min n-butyllithium (2.50 M in hexanes; 5.6 ml, 14.0 mmol). The reaction mixture was stirred at −78° C. for 5 min and then allowed to warm to about 0° C. over 10 min. The reaction mixture was cooled to −78° C. and slowly over 10 min was added dropwise neat 3-bromopyridine (1.335 ml, 13.61 mmol). The reaction mixture was stirred at −78° C. for 15 min, and then slowly treated with neat oxetan-3-one (870 mg, 12.07 mmol) over 2-3 min. The reaction mixture was then allowed to warm to room temperature slowly over 18 h. The reaction mixture was concentrated in vacuo, then partitioned with ethyl acetate/aqueous saturated NH4Cl and solid sodium bicarbonate until pH ˜8-9 was achieved. The aqueous layers were saturated with sodium chloride and back extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and evaporated to dryness to give a red oil. The crude material was purified by Biotage Silica gel chromatography on a 80 g Thompson Single Step™ silica cartridge using a linear gradient from 100% CH2Cl2 to 100% ethyl acetate over 12 column volumes to give to give 860 mg (31%) of the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.75 (1 H, s), 8.58 (1 H, d, J=5.0 Hz), 7.24 (1 H, d, J=5.0 Hz), 5.16 (2 H, m), 4.91 (2 H, m), 3.12 (1 H, br.s). LC/MS (Condition B): ret. T=1.1 min, (M+H)+ 229.89, 231.89.

1. temperatureto warm to about 0° C. over 10 min
2. temperatureThe reaction mixture was cooled to −78° C. and slowly over 10 min
3. stirringThe reaction mixture was stirred at −78° C. for 15 min
4. temperatureto warm to room temperature slowly over 18 h
5. concentrationThe reaction mixture was concentrated in vacuo
6. custompartitioned with ethyl acetate/aqueous saturated NH4Cl and solid sodium bicarbonate until pH ˜8-9
7. extractionback extracted with ethyl acetate
8. washwashed with brine
9. dry with materialdried over Na2SO4
10. filtrationfiltered
11. customevaporated to dryness
12. customto give a red oil
13. customThe crude material was purified by Biotage Silica gel chromatography on a 80 g Thompson Single Step™ silica cartridge
14. customto give

ORD record

ord-ac45277530114adb9873fd7094e3898a

Source dataset

uspto-grants-2014_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08673922B2