Diisopropylamine → 2-Fluoro-5-(1-morpholinoethyl)pyridin-3-ylboronic acid

Temperature

-78 °C

A solution of LDA was prepared by addition of n-butyllithium (1.6 M in hexanes, 9.60 mL, 15.35 mmol) to a solution of diisopropylamine (2.152 mL, 15.35 mmol) in THF (20 mL) at −40° C. The LDA solution was cooled to −78° C. and a solution of 4-(1-(6-fluoropyridin-3-yl)ethyl)morpholine (2.69 g, 12.79 mmol) in THF (15 mL) was added slowly over 20 min. The deep-red mixture was stirred at −78° C. for 1.5 h. A solution of triisopropyl borate (4.41 mL, 19.19 mmol) in THF (10 mL) was added slowly. The resulting mixture was stirred at −78° C. for 30 min and then the cooling bath was removed. After the reaction mixture had warmed up to room temperature, the tan mixture was quenched with 1 N NaOH (aq) (15 mL). The separated aqueous layer was removed and the flask was rinsed with 1 N NaOH(aq) (2×20 mL) and the organic layer was extracted with 1 N NaOH (2×10 mL). The aqueous layer was collected and carefully acidified with 5N HCl until acidic (pH 5 to about 6). The aqueous layer was frozen and the water was removed by lyophilization. The mixture was diluted with 1:1 MeOH/DCM and placed into a sonicator for 5 min. The mixture was filtered through a fine-fritted funnel. The filtrate was concentrated in vacuo to give 2-fluoro-5-(1-morpholinoethyl)pyridin-3-ylboronic acid (3.120 g, 12.28 mmol, 96% yield) as a yellow solid. 1H NMR (400 MHz, d4-MeOH) δ 8.00 (dd, J=8.22, 2.54 Hz, 1H); 7.88 (d, J=2.35 Hz, 1H); 3.68 (t, J=4.69 Hz, 4H); 3.40-3.54 (m, 1H); 2.56 (d, J=10.76 Hz, 2H); 2.35-2.50 (m, 2H); 1.41 (t, J=6.65 Hz, 3H). m/z (ESI, +ve) 255.1 (M+H)+.

1. stirringThe resulting mixture was stirred at −78° C. for 30 min
2. customthe cooling bath was removed
3. temperatureAfter the reaction mixture had warmed up to room temperature
4. customthe tan mixture was quenched with 1 N NaOH (aq) (15 mL)
5. customThe separated aqueous layer was removed
6. washthe flask was rinsed with 1 N NaOH(aq) (2×20 mL)
7. extractionthe organic layer was extracted with 1 N NaOH (2×10 mL)
8. customThe aqueous layer was collected
9. temperatureThe aqueous layer was frozen
10. customthe water was removed by lyophilization
11. additionThe mixture was diluted with 1:1 MeOH/DCM
12. waitplaced into a sonicator for 5 min
13. filtrationThe mixture was filtered through a fine-fritted funnel
14. concentrationThe filtrate was concentrated in vacuo

ORD record

ord-c6d728577651481f83101faf89c368e1

Source dataset

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08772480B2