Hydrochloric Acid → (S)-2-Amino-3-(4-fluoro-phenyl)-1-(4-hydroxy-piperidin-1-yl)-propan-1-one hydrochloride

HRID 1693361Notes

Reaction equation

HRID 1693361 reaction equation
C(OC(=O)[NH:7][C@@H:8]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:27].O1CCOCC1>CO>[ClH:27].[NH2:7][C@@H:8]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:9]([N:11]1[CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH2:16]1)=[O:10]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 10808894[(S)-1-(4-Fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester

Product 1

HCID 67278381(S)-2-Amino-3-(4-fluoro-phenyl)-1-(4-hydroxy-piperidin-1-yl)-propan-1-one hydrochloride

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Route A: To a solution of [1(S)-(4-fluorobenzyl)-2-(4-hydroxypiperidin-1-yl)-2-oxoethyl]carbamic acid tert-butyl ester (Preparation 19, 11.6 g, 31.7 mmol) in methanol (40 mL) was added hydrochloric acid in dioxane (24 mL, 4N, 95.0 mmol) and the reaction mixture stirred at rt for 6 h. The solvent was removed in vacuo and the residue was dissolved in water (100 mL) and extracted into ethyl acetate (2×50 mL). The aqueous phase was evaporated to dryness to give the title compound as a white solid. δH (D2O): 0.52-0.63 (0.5H, m), 1.12-1.23 (0.5H, m), 1.26-1.38 (1H, m), 1.42-1.50 (0.5H, m), 1.59-1.69 (0.5H, m), 1.72-1.82 (1H, m), 2.61-2.71 (0.5H, m), 2.91-3.15 (4H, m), 3.33-3.47 (1H, m), 3.69-3.78 (1H, m), 3.88-3.96 (1H, m), 4.60-4.72 (1H, m), 7.02-7.11 (2H, m), 7.14-7.26 (2H, m). Route B: To a solution of 4-hydroxypiperidine (40 mg, 0.4 mmol) in anhydrous THF (3 mL) under an argon atmosphere was added a solution of 4(S)-(4-fluorobenzyl)oxazolidine-2,5-dione (Preparation 117, 100 mg, 0.48 mmol) in THF (2 mL) dropwise over 15 min. The resulting mixture was stirred for 40 h at rt before removal of the solvent in vacuo. The crude material was purified by column chromatography (SiO2, 9:1 dichloromethane/methanol) to afford an oil. The free amine was dissolved in methanol (2 mL) and a solution of 4M HCl in dioxane (0.3 mL) was added and stirring was continued for 15 min. The solvent was removed in vacuo and the material partitioned between ethyl acetate (5 mL) and water (5 mL). The aqueous layer was concentrated in vacuo to give the title compound. δH (CD3OD): 7.36-7.29 (2H, m), 7.17-7.10 (2H, m), 4.70 (1H, t), 4.09-4.00 (0.5H, m), 3.91-3.74 (1.5H, m), 3.64-3.56 (0.5H, m), 3.43-3.31 (1H, m), 3.26-3.07 (3H, m), 2.89-2.80 (0.5H, m), 1.87-1.69 (1.5H, m), 1.56-1.36 (2H, m), 1.09-0.99 (0.5H, m).

Workup

  1. customThe solvent was removed in vacuo
  2. dissolutionthe residue was dissolved in water (100 mL)
  3. extractionextracted into ethyl acetate (2×50 mL)
  4. customThe aqueous phase was evaporated to dryness

Sources & evidence

ORD record
ord-a53a19990fd64eaa814812752ed91db5
Source dataset
uspto-grants-2012_04
Patent number
US08158622B2

Reaction notes

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