Hydrochloric Acid → HCID 117776761, compound

Temperature

-78 °C

N-Boc-4-cyanopiperidine (5.35 g, 25.4 mmol) was dissolved in tetrahydrofuran (100 mL) and cooled to −78° C. Thereafter, to this, a cyclohexane solution (1.5 M, 16.5 mL, 24.8 mmol) of a lithium diisopropylamide/tetrahydrofuran complex was added while maintaining the inside temperature at −70° C. or less. The reaction mixture was stirred at −78° C. for 20 minutes. To the resultant reaction mixture, a THF solution (10 mL) of 2-bromo-6-(bromomethyl)-3-fluoropyridine (6.28 g, 23.4 mmol) was added while maintaining the inside temperature at −70° C. or less and then stirred at −78° C. for 20 minutes. To the reaction solution, a mixture of hydrochloric acid (5 M, 4.95 mL, 24.8 mmol) and a saturated aqueous ammonium chloride solution (95 mL) was added. After stirred at room temperature, the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, then filtered and concentrated. A tar-like residue was dissolved in ethyl acetate (6 mL). To the mixture, heptane (50 mL) was added dropwise while stirring. A seed crystal was added and stirred at room temperature for one hour. To the resultant light yellow suspension solution, heptane (50 mL) was further added dropwise and stirred overnight. The resultant solid substance was collected by filtration, washed with a heptane solution of ethyl acetate and dried under reduced pressure to obtain the target product as an off-white solid substance (7.10 g, 17.8 mmol) (yield 76%). Note that the seed crystal was obtained from the tar-like residue by a purification method routinely used in silica gel column chromatography. Physical property values are shown below.

1. temperaturewhile maintaining the inside temperature at −70° C. or less
2. customTo the resultant reaction mixture
3. temperaturewhile maintaining the inside temperature at −70° C. or less
4. stirringstirred at −78° C. for 20 minutes
5. stirringAfter stirred at room temperature
6. extractionthe mixture was extracted with ethyl acetate
7. washThe extract was washed with saturated saline
8. dry with materialdried over anhydrous sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated
11. dissolutionA tar-like residue was dissolved in ethyl acetate (6 mL)
12. additionTo the mixture, heptane (50 mL) was added dropwise
13. stirringwhile stirring
14. additionA seed crystal was added
15. stirringstirred at room temperature for one hour
16. additionTo the resultant light yellow suspension solution, heptane (50 mL) was further added dropwise
17. stirringstirred overnight
18. filtrationThe resultant solid substance was collected by filtration
19. washwashed with a heptane solution of ethyl acetate
20. customdried under reduced pressure

ORD record

ord-98857275b7ac48dda94df04eeade8625

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09012475B2