Hydrochloric Acid → (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone hydrochloride

Temperature

22.5 °C

Over a period of 1 h, hydrochloric acid (9.8 kg) was added to the solution of (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate in isopropanol from the previous step, maintaining a temperature of 20-25° C. The reaction mixture was heated to 50-55° C. and was held at that temperature for 6 h. Solvent was removed by distillation under reduced pressure at 50° C. Four cycles of solvation and then distillation under reduced pressure at 50° C. were conducted sequentially: isopropanol (2×14.5 L), toluene (18.5 L), and tetrahydrofuran (12.0 L). Another portion of tetrahydrofuran (12.0 L) was added and the mixture was stirred at 25-30° C. for 1 h. The mixture was centrifuged and the mother liquor was removed; the resulting cake was washed with tetrahydrofuran (3.7 L), then was dried at 40-50° C. to afford (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone hydrochloride (4.8 kg, 84% over two steps). HPLC retention time: 1.67 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).

1. temperatureThe reaction mixture was heated to 50-55° C.
2. waitwas held at that temperature for 6 h
3. customSolvent was removed by distillation under reduced pressure at 50° C
4. distillationFour cycles of solvation and then distillation under reduced pressure at 50° C.
5. additionAnother portion of tetrahydrofuran (12.0 L) was added
6. customthe mother liquor was removed
7. washthe resulting cake was washed with tetrahydrofuran (3.7 L)
8. customwas dried at 40-50° C.

ORD record

ord-a86621db5b1c4bc88701ef682623653a

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09296745B2