(2-bromo-5-chloropyridin-3-yl)methanol Chemical Properties

Boiling point:

318.4±37.0 °C(Predicted)

Density 

1.785±0.06 g/cm3(Predicted)

storage temp. 

under inert gas (nitrogen or Argon) at 2-8°C

pka

12.59±0.10(Predicted)

(2-bromo-5-chloropyridin-3-yl)methanol Usage And Synthesis

Uses

(2-Bromo-5-chloropyridin-3-yl)methanol is used in preparation of Spiro[indene-pyrrolopyridine] compounds as AM2 receptor inhibitors.

Synthesis

General procedure for the synthesis of (2-bromo-5-chloropyridin-3-yl)methanol from 2,3-dibromo-5-chloropyridine: To a solution of 2,3-dibromo-5-chloropyridine (60 g, 221 mmol) in tetrahydrofuran (THF, 500 mL) was slowly added a THF solution of isopropylmagnesium chloride lithium chloride (1.3 M, 185 mL) at -40 °C. The reaction temperature was maintained at -40 °C and after stirring for 30 min, N,N-dimethylformamide (DMF, 50 mL) was added. The reaction mixture was gradually warmed to room temperature and stirring was continued for 30 min. The reaction was quenched with 1N hydrochloric acid (400 mL) and methyl tert-butyl ether (MTBE, 200 mL) was added. The organic layer was separated and washed twice with 5% aqueous sodium bicarbonate (200 mL). The solvent was removed by concentration under reduced pressure at 50 °C. The resulting aldehyde intermediate solid was dissolved in methanol (400 mL) and cooled to 5°C in an ice bath. Sodium borohydride (NaBH4, 3.6 g) was added slowly over 30 min, controlling the reaction temperature not to exceed room temperature. Stirring was continued for 30 minutes and then water (125 mL) was added. The reaction mixture was concentrated under reduced pressure to approximately 150 mL, with solids precipitating during the process. The suspension was stirred vigorously for 1 hour at room temperature and the solids were collected by filtration. The wet filter cake was dried in a vacuum oven at 60 °C overnight to afford the target product (2-bromo-5-chloropyridin-3-yl)methanol (45.6 g, 93% yield) as a white solid. The product was structurally confirmed by 1H NMR (CDCl3, 400 MHz) and 13C NMR (CDCl3, 100 MHz).

References

[1] Patent: US2016/130273, 2016, A1. Location in patent: Paragraph 0234; 0235
[2] Patent: WO2013/138413, 2013, A1
[3] Patent: WO2013/169348, 2013, A1
[4] Angewandte Chemie - International Edition, 2014, vol. 53, # 32, p. 8375 - 8378
[5] Angew. Chem., 2014, vol. 126, # 32, p. 8515 - 8518,4