Acetic Acid → 4-(3-Bromo-phenyl)-1-methyl-piperidine hydrochloride

온도

10 °C

A mixture of 4-(3-bromo-phenyl)-piperidine; hydrochloride (1.0 g, 3.6 mmol), 37% formaldehyde in water (3.7 mL, 120 mmol), Acetic acid (0.25 mL, 4.4 mmol) and methanol (20 mL) was stirred for 15 minutes at room temperature. The mixture was cooled to 10° C. in an ice/water bath. Sodium cyanoborohydride (3.0 g, 48 mmol) was added portionwise. A mild exotherm was noted. The mixture was stirred and warmed to room temperature over 18 hours. The mixture was poured into saturated aqueous ammonium chloride (200 mL) and stirred for 1 hour at room temperature. The mixture was extracted with dichloromethane (3×75 ml). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to an oil. The residue was triturated in ether (200 mL) and filtered. The filtrate was evaporated to an oil (0.585 g). The oil was dissolved in ether and stirred. Hydrogen chloride (2.0M in ether, 2.0 mL) was added dropwise and stirred for 30 minutes. The precipitate was filtered and rinsed with ether. 4-(3-Bromo-phenyl)-1-methyl-piperidine hydrochloride was isolated as a crude white solid (0.432 g, 41%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.52 (s, 1H), 7.47-7.41 (m, 2H), 7.37-7.21 (m, 2H), 3.52-3.41 (m, 2H), 3.10-2.95 (m, 2H), 2.85-2.78 (m, 1H), 2.75 (s, 3H), 2.15-2.78 (m, 4H). MS=254, 256 (MH)+. 129b) N-Methyl-N-(3-{2-[3-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 4-(3-bromo-phenyl)-1-methyl-piperidine; hydrochloride (76.0 mg, 0.262 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.093 g, 80%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (d, J=6.6 Hz, 1H), 8.10-8.07 (m, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.46-7.40 (m, 2H), 7.27 (t, J=7.9 Hz, 1H), 6.98 (t, J=7.1 Hz, 1H), 6.88 (d, J=7.7 Hz, 1H), 6.83 (s, 1H), 3.42 (s, 3H), 3.03-2.96 (m, 2H), 2.90 (s, 3H), 2.55-2.45 (m, 1H), 2.34 (s, 3H), 2.12-2.00 (m, 2H), 1.90-1.80 (m, 4H). MS=491 (MH)+.

1. temperaturewarmed to room temperature over 18 hours
2. stirringstirred for 1 hour at room temperature
3. extractionThe mixture was extracted with dichloromethane (3×75 ml)
4. dry with materialThe combined organic layers were dried over magnesium sulfate
5. filtrationfiltered
6. customevaporated to an oil
7. customThe residue was triturated in ether (200 mL)
8. filtrationfiltered
9. customThe filtrate was evaporated to an oil (0.585 g)
10. dissolutionThe oil was dissolved in ether
11. stirringstirred
12. additionHydrogen chloride (2.0M in ether, 2.0 mL) was added dropwise
13. stirringstirred for 30 minutes
14. filtrationThe precipitate was filtered
15. washrinsed with ether

ORD 기록

ord-d3ad9fd7f02e4a6396d612a268149409

출처 데이터셋

uspto-grants-2013_08

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08501936B2