Triisopropyl borate → (6-Fluoropyridin-3-yl)boronic acid

Temperature

6 °C

To stirred and cooled (dry ice-acetone bath) anhydrous [TBME] (620 mL; in a 3 L three-necked round-bottomed flask equipped with mechanical stirrer, temperature probe with adapter, and nitrogen inlet) was added (via syringe) 2 M BuLi (352 mL, 0.704 mol, 1.2 eq). To this rapidly stirred and cooled (<−75° C.) mixture was added a solution of 3 (102.2 g, 0.581 mol) in anhydrous TBME (100 mL) over a period of 13 min during which time the internal temperature rose to −62° C. The reaction was stirred for another 45 min (the temperature was maintained between −62° C. and −80° C.), followed by the rapid and sequential addition of four portions of triisopropylborate (total of 180 g, 0.957 mol, 1.65 eq). At the end of the addition the internal temperature had risen to −33° C. After stirring an additional 45 min over the cold bath (internal temperature lowered from −33° C. to −65° C.), the cold bath was removed and the stirred mixture on its own rose to −22° C. over a period of 50 min. After warming (via water bath) to 6° C. over a period of 15 min, the stirred reaction mixture was placed in an ice-water bath and then quenched under nitrogen with a cooled solution of NaOH (160 g) in water (500 mL). Once the addition was complete, the internal temperature was 20° C. This mixture was stirred at room temperature for 1.5 h. The aqueous layer was removed, neutralized to pH 7 with ˜350 mL concentrated HCl, and then extracted with EtOAc (3×1 L). Because the pH was now 8-9, the aqueous layer was adjusted to pH 7 using ˜15 mL concentrated HCl and extracted further (2×1 L) with ethyl acetate. The combined EtOAc extracts were dried (Na2SO4), filtered, and concentrated to a volume of ˜150 mL. With swirling of the concentrate, heptane was added in portions (total volume of 300 mL) resulting in the precipitation/crystallization of the product. Filtration, washing of the solid with heptane (100 mL, 300 mL, then another 300 mL), and air drying gave the title product as an off-white solid (68.6 g, yield of 79-90%*; LC purity of 96.4%, NMR showed an estimated 5.5% w/w of heptane), which was used successfully without further purification. LC/MS showed it to be a mixture of the two following entities, the intensity of the higher molecular weight entity being major (*Note: yield of reaction is 79% if the boronic acid is assumed to be the only constituent and is 90% if it is assumed that the cyclic borate is the only constituent):

1. temperaturecooled
2. stirringTo this rapidly stirred
3. temperaturecooled (<−75° C.) mixture
4. customrose to −62° C
5. stirringThe reaction was stirred for another 45 min (the temperature
6. temperaturewas maintained between −62° C. and −80° C.),
7. additionAt the end of the addition the internal temperature
8. customhad risen to −33° C
9. stirringAfter stirring an additional 45 min over the cold bath (internal temperature lowered from −33° C. to −65° C.)
10. customthe cold bath was removed
11. customthe stirred reaction mixture
12. customwas placed in an ice-water bath
13. customquenched under nitrogen with a cooled solution of NaOH (160 g) in water (500 mL)
14. additionOnce the addition
15. customwas 20° C
16. stirringThis mixture was stirred at room temperature for 1.5 h
17. customThe aqueous layer was removed
18. extractionextracted with EtOAc (3×1 L)
19. extractionextracted further (2×1 L) with ethyl acetate
20. dry with materialThe combined EtOAc extracts were dried (Na2SO4)
21. filtrationfiltered
22. concentrationconcentrated to a volume of ˜150 mL
23. additionwas added in portions (total volume of 300 mL)
24. customresulting in the precipitation/crystallization of the product
25. filtrationFiltration
26. washwashing of the solid with heptane (100 mL, 300 mL
27. customanother 300 mL), and air drying

ORD record

ord-115cfd14018340ae91c2de01c3877033

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08901297B2