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

HRID 1468868Notes

Reaction equation

HRID 1468868 reaction equation
[OH-].[NH4+].Br[C:4]1[CH:28]=[CH:27][C:7]([CH2:8][O:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:6][C:5]=1[F:29].O[C@H]1C[NH:34][C@H](C(O)=O)C1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O.O.[Cu]I>[NH2:34][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][O:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:6][C:5]=1[F:29]

Participants

9

Reactant 4

HCID 5810L-HydroxyprolineHCID 11430Potassium CarbonateHCID 14923Ammonium HydroxideHCID 71116028tert-butyl 4-((1R,2R)-2-((4-bromo-3-fluorobenzyloxy)methyl)cyclopropyl)piperidine-1-carboxylate

Product 1

HCID 86717803tert-butyl 4-((1R,2R)-2-((4-amino-3-fluorobenzyloxy)methyl)cyclopropyl)piperidine-1-carboxylateYield 59.4%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 679Dimethyl SulfoxideSolventHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
85 °C

Procedure

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)+.

Workup

  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

Sources & evidence

ORD record
ord-479d5e8bcc2f408b912b5d22ca5b28d6
Source dataset
uspto-grants-2015_04
Patent number
US09006228B2

Reaction notes

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