Benzylamine → 1,1-Dimethylethyl (3R,4S)-4-amino-3-fluoro-1-piperidinecarboxylate

HRID 877668Notes

Reaction equation

HRID 877668 reaction equation
[F:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C([NH2:23])C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:12]([O:11][C:9]([N:4]1[CH2:5][CH2:6][C@H:7]([NH2:23])[C@H:2]([F:1])[CH2:3]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]

Participants

5

Reactant 3

HCID 7504BenzylamineHCID 5049666Sodium triacetoxyborohydrideHCID 10560711TERT-BUTYL 3-FLUORO-4-OXOPIPERIDINE-1-CARBOXYLATE

Product 1

HCID 112644351,1-Dimethylethyl (3R,4S)-4-amino-3-fluoro-1-piperidinecarboxylateYield 60.3%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

A mixture of (+/−)-tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (0.33 g, 1.52 mmol), benzylamine (0.16 mL, 1.52 mmol) and sodium triacetoxyborohydride (0.382 g, 1.8 mmol) in dry 1,2-dichloroethane (6 mL) was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aq. K2CO3 solution (25 mL) and extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried over anhyd. Na2SO4 and concentrated under vacuum. The crude product obtained was purified by flash chromatography to give the cis isomer of the title compound (200 mg, 42.6%) as the major product and the trans isomer of the title compound (20 mg, 4.26%) as the minor product. Cis isomer: HPLC (condition D): retention time=10.20 min. LCMS (condition E): m/z 308.4 +ve with retention time=1.84 min. 1H-NMR (400 MHz, CDCl3) δ ppm: 7.32-7.37 (m, 4H), 7.24-7.29 (m, 2H), 4.69-4.82 (m, 1H), 4.32 (s, 1H), 4.11-4.16 (m, 1H), 3.88 (s 2H), 2.91-3.04 (dd, J=35.6 Hz, J=14 Hz, 1H), 2.66-2.80 (m, 2H), 1.78 (bs, 1H), 1.63-1.72 (m, 1H), 1.47 (s, 9H). 19F-NMR (400 MHz in CDCl3): δ ppm: −204.51 (1F). Trans isomer: HPLC (condition D): retention time=11.05 min. LCMS (condition E): m/z 308.4 +ve with retention time=1.99 min. 1H-NMR (400 MHz, CDCl3) δ ppm: 7.31-7.37 (m, 4H), 7.25-7.28 (m, 1H), 4.25-4.30 (m, 2H), 3.89-3.93 (d, J=13.6 Hz, 2H), 2.93 (bs, 1H), 2.80-2.89 (m, 2H), 1.96-2.01 (m, 1H), 1.48 (s, 9H), 1.37-1.40 (d, J=13 Hz, 1H). 19F-NMR (400 MHz in CDCl3): δ ppm: −189.58 (1F).

Workup

  1. customThe reaction mixture was quenched with saturated aq. K2CO3 solution (25 mL)
  2. extractionextracted with ethyl acetate (2×40 mL)
  3. customThe combined organic extracts were dried over anhyd
  4. concentrationNa2SO4 and concentrated under vacuum
  5. customThe crude product obtained
  6. customwas purified by flash chromatography

Sources & evidence

ORD record
ord-b374c883f35846f8b4e92155875853c8
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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