Triethylamine → (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone

Temperature

17.5 °C

Triethylamine (4.65 kg, 46 mol) was added over a period of 1 h to a mixture of (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone hydrochloride (4.8 kg, 22 mol) and acetonitrile (48 L), maintaining a temperature of 15-20° C. The mixture was held at that temperature for 30 min, then was warmed to 38-42° C. 6-Chloro-3-nitropyridin-2-amine (3.8 kg, 22 mol) was added portion-wise, and the mixture was held at 38-42° C. for 3 h. The mixture was then cooled to 15-20° C. and an aqueous solution of ammonium chloride (prepared from 6.24 kg ammonium chloride and 48 L water) and ethyl acetate (48 L) were added sequentially, and the layers were stirred and then separated. The aqueous layer was further extracted with ethyl acetate (2×24 L). The combined organic layers were washed with an aqueous solution of sodium chloride (prepared from 4.8 kg sodium chloride and 24 L water) and then were dried with sodium sulfate (1.92 kg). The organic layer was removed and solvent was evaporated under reduced pressure at 40° C. Ethyl acetate (14.4 L) was added to the crude product, and the mixture was heated to 35-40° C. and was held at that temperature for 15 min. The mixture was cooled to 20-25° C. and held at that temperature for 6 h, then cooled to 10-15° C. and held at that temperature for 1 h. The suspension was centrifuged and the mother liquor was removed. The resulting cake was washed with chilled ethyl acetate (4.8 L) and then was dried at 40-50° C. to afford (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (4.6 kg, 66%). HPLC retention time: 5.30 min (Column: Halo C18, 4.6×150 mm, 2.7 μm; Mobile Phase A: 0.1% orthophosphoric acid and 2% acetonitrile in water, Mobile Phase B: acetonitrile; Gradient: 20% B to 90% B over 7 min, then held for 3 min; Flow: 0.8 mL/min; Temperature: 25° C.; UV detection at 210 and 226 nM). Melting point: 118.5-123.5° C. Water content by Karl Fischer titration: 0.36% by weight.

1. temperaturewas warmed to 38-42° C
2. waitthe mixture was held at 38-42° C. for 3 h
3. temperatureThe mixture was then cooled to 15-20° C.
4. customseparated
5. extractionThe aqueous layer was further extracted with ethyl acetate (2×24 L)
6. washThe combined organic layers were washed with an aqueous solution of sodium chloride (prepared from 4.8 kg sodium chloride and 24 L water)
7. dry with materialwere dried with sodium sulfate (1.92 kg)
8. customThe organic layer was removed
9. customsolvent was evaporated under reduced pressure at 40° C
10. additionEthyl acetate (14.4 L) was added to the crude product
11. temperaturethe mixture was heated to 35-40° C.
12. waitwas held at that temperature for 15 min
13. temperatureThe mixture was cooled to 20-25° C.
14. waitheld at that temperature for 6 h
15. temperaturecooled to 10-15° C.
16. waitheld at that temperature for 1 h
17. customthe mother liquor was removed
18. washThe resulting cake was washed with chilled ethyl acetate (4.8 L)
19. customwas dried at 40-50° C.

ORD record

ord-40b104044b674e67ba057ec0b2460593

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09296745B2