Hydrochloric Acid → N-(piperidin-4-ylmethyl)-3,5-bis(trifluoromethyl)benzamide

To a solution of 1-Boc-4-(aminomethyl)piperidine (18.0 g, 84.1 mmol) and DIPEA (12.9 g, 100 mmol) in anhydrous CH2Cl2 (200 mL) at 15° C. was added 3,5-bis-(trifluoromethyl)benzoyl chloride (23.4 g, 85.0 mmol) slowly. After the reaction mixture was stirred at room temperature for 30 min, water (50 mL) was added followed by adding aqueous HCl (0.5 N, 100 mL). The organic fraction was collected. The aqueous fraction was extracted with CH2Cl2 (100 mL). The combined organic solution was dried over anhydrous Na2SO4 and passed through a silica gel plug. The desired compound was eluted off with EtOAc/petroleum ether (1:3 in v/v). Solvents were removed and the product was dissolved in EtOAc (200 mL). To the solution HCl (g) bubbled for 5 min to form a white suspension. The suspension was stirred at room temperature for 30 min, and then concentrated to around 100 mL. Diethyl ether (150 mL) was added and the suspension was cooled at 7° C. for 1 h. A white HCl salt was collected by filtration. The salt was dissolved in a mixture of methanol/water (30/300 mL), and aqueous NaOH (2 N) was added until pH=˜11. The mixture was extracted with CH2Cl2 (5×200 ML) and the combined organic solution was dried over anhydrous Na2SO4. After filtration the filtrate was concentrated in vacuo to give pale yellow sticky foam (28.8 g, 97%).).

1. customThe organic fraction was collected
2. extractionThe aqueous fraction was extracted with CH2Cl2 (100 mL)
3. dry with materialThe combined organic solution was dried over anhydrous Na2SO4
4. washThe desired compound was eluted off with EtOAc/petroleum ether (1:3 in v/v)
5. customSolvents were removed
6. dissolutionthe product was dissolved in EtOAc (200 mL)
7. customTo the solution HCl (g) bubbled for 5 min
8. customto form a white suspension
9. stirringThe suspension was stirred at room temperature for 30 min
10. concentrationconcentrated to around 100 mL
11. additionDiethyl ether (150 mL) was added
12. temperaturethe suspension was cooled at 7° C. for 1 h
13. filtrationA white HCl salt was collected by filtration
14. dissolutionThe salt was dissolved in a mixture of methanol/water (30/300 mL), and aqueous NaOH (2 N)
15. additionwas added until pH=˜11
16. extractionThe mixture was extracted with CH2Cl2 (5×200 ML)
17. dry with materialthe combined organic solution was dried over anhydrous Na2SO4
18. filtrationAfter filtration the filtrate
19. concentrationwas concentrated in vacuo

ORD record

ord-e9888ede3ce84f87a367332fa086ebed

Source dataset

uspto-grants-2013_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08377968B2