Tetrahydrofuran → Isopropanol

To a solution of 2-[(4-bromobenzyl)oxy]pyridine (789 g, 2.99 mol) in heptane (2603 g) were added heptane (939 mL) and tetrahydrofuran (1199 mL), which was cooled slowly with dry ice/ethanol bath under a nitrogen atmosphere, while stirring. After 45 minutes, cooling was stopped and 2-[(4-bromobenzyl)oxy]pyridine (0.9 g) was added thereto at an internal temperature of −12° C. Cooling was resumed, with cooling at −20° C./h. Approximately 3 hours later, 1.66M n-butyllithium hexane solution (1980 mL, 3.29 mol) was added thereto dropwise (80 min,−67.0 to 61.4° C.). After stirring for 0.5 hours, at the same temperature, triisopropoxy borane (674 g, 3.56 mol) was added thereto dropwise (134min, −68.2 to 60.3° C.). At the same temperature, after stirring for 0.5 hours, switching to an ice water bath cooling, the solution was stirred overnight (external temperature: 0° C.). On the next day, water (5600 mL) was added thereto dropwise, the solution was transferred to a separator vessel and was extracted into the aqueous layer (pH: 11.2). Ethyl acetate (4800 mL) was added thereto and concentrated hydrochloric acid (approximately 280 mL) was added thereto dropwise (at an internal temperature of 20° C. or lower) while stirring, to adjust the solution to pH: 7.1. The organic layer was separated and washed with 5% sodium chloride water (approximately 900 g) and then concentrated under a reduced pressure. To the residue was added isopropyl alcohol (3300 mL), concentrated under a reduced pressure, isopropyl alcohol (3300 mL) was further added thereto and concentrated under a reduced pressure to obtain a solution of {4-[(pyridin-2-yloxy)methyl]phenyl}boronic acid (646 g) in isopropyl alcohol (2671 g) (yield: 94.4%). The obtained solution was heated to 60° C., which was added to a container containing 2,2-dimethyl-1,3-propanediol (354 g, 3.41 mol) while eliminating insoluble matter by suction-filtration, and then which was washed thereto down with isopropyl alcohol (685 mL). After confirming dissolution, the solution was stirred at a bath temperature of 20° C. and crystal precipitation was observed at an internal temperature of 28.8° C. After 1.5 hours, the bath temperature was set to −20° C., and the solution was stirred overnight. The precipitated crystal was filtered, and the crystal was washed with a small amount of isopropyl alcohol cooled to 0° C. The crystal was dried under a reduced pressure, so as to obtain the title compound (779 g) as a white crystal (yield: 92.2%).

1. temperaturewas cooled slowly with dry ice/ethanol bath under a nitrogen atmosphere
2. temperaturecooling
3. customat an internal temperature of −12° C
4. temperatureCooling
5. temperaturewith cooling at −20° C./h
6. customdropwise (80 min,−67.0 to 61.4° C.)
7. additionwas added
8. customdropwise (134min, −68.2 to 60.3° C.)
9. stirringAt the same temperature, after stirring for 0.5 hours
10. customswitching to an ice water bath
11. temperaturecooling
12. stirringthe solution was stirred overnight (external temperature: 0° C.)
13. customdropwise, the solution was transferred to a separator vessel
14. extractionwas extracted into the aqueous layer (pH: 11.2)
15. additionEthyl acetate (4800 mL) was added
16. additionconcentrated hydrochloric acid (approximately 280 mL) was added
17. stirringdropwise (at an internal temperature of 20° C. or lower) while stirring
18. customThe organic layer was separated
19. washwashed with 5% sodium chloride water (approximately 900 g)
20. concentrationconcentrated under a reduced pressure
21. additionTo the residue was added isopropyl alcohol (3300 mL)
22. concentrationconcentrated under a reduced pressure, isopropyl alcohol (3300 mL)
23. additionwas further added
24. concentrationconcentrated under a reduced pressure

ORD record

ord-8927335e5fe5416d9518d2b75f850413

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08410277B2