L-Hydroxyproline → tert-butyl 4-((1R,2R)-2-((4-amino-3-fluorobenzyloxy)methyl)cyclopropyl)piperidine-1-carboxylate

Temperature

85 °C

Ammonium hydroxide (14.9 mL, 107 mmol) was quickly added to a solution of tert-butyl 4-((1R,2R)-2-((4-bromo-3-fluorobenzyloxy)methyl)cyclopropyl)piperidine-1-carboxylate (Step A product, 1.58 g, 3.57 mmol), (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (1.3 g, 7.86 mmol), Copper(I) iodide (1.36 g, 7.14 mmol), and potassium carbonate (1.53 g, 11.1 mmol) in DMSO (12 mL) that had been placed under an inert atmosphere in a sealed tube. The reaction mixture was subsequently heated at 85° C. for 48 hrs in the sealed tube. The solution was cooled to rt and diluted with EtOAc (25 mL) and water (25 mL). The layers were cut and the aqueous phase extracted with EtOAc (25 mL×2). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was loaded onto a silica column (KP-Sil 50 g SNAP column, Biotage system) initially eluting with a range of 10-20% EtOAc/Hex over 6 CV, followed by a range of 25-60% EtOAc/Hex over 7 CV to give the desired compound (802 mg, 59%). LC/MS (m/z): 379 (M+H)+.

1. customhad been placed under an inert atmosphere in a sealed tube
2. temperatureThe solution was cooled to rt
3. extractionthe aqueous phase extracted with EtOAc (25 mL×2)
4. dry with materialThe combined organic layers were dried over MgSO4
5. filtrationfiltered
6. concentrationconcentrated under reduced pressure
7. washinitially eluting with a range of 10-20% EtOAc/Hex over 6 CV

ORD record

ord-479d5e8bcc2f408b912b5d22ca5b28d6

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09006228B2