2-Amino-6-fluorobenzoic acid → 2-(1-(Tert-butoxycarbonyl)piperidin-4-ylamino)-6-fluorobenzoic acid

HRID 2378967Notes

Reaction equation

HRID 2378967 reaction equation
[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].O=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[B-]C#N.[Na+]>CO>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=2[C:4]([OH:6])=[O:5])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]

Participants

5

Reactant 3

HCID 5211422-Amino-6-fluorobenzoic acidHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 20587905Sodium cyanoborohydride [MI]

Product 1

HCID 590063302-(1-(Tert-butoxycarbonyl)piperidin-4-ylamino)-6-fluorobenzoic acidYield 92%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

2-Amino-6-fluorobenzoic acid (2.01 g, 12.93 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (5.15 g, 25.9 mmol) were combined and dissolved in methanol (50 mL). Sodium cyanotrihydroborate (1.625 g, 25.9 mmol) was added in one portion at room temperature. Reaction stirred at room temperature for 1 hour. The solvent was removed in vacuo. The resulting foam was partitioned between dichloromethane (170 mL) and 1N sodium hydroxide (65 mL). Layers were separated. The dichloromethane layer was extracted with water (2×65 mL). The aqueous layers were combined and acidified with citric acid to pH around 3. The aqueous layer was extracted with ethyl acetate (3×100 mL). The ethyl acetate layers were combined, dried (Na2SO4), filtered and concentrated to dryness. Title compound was obtained as off-white solid in 92% yield. 1H NMR (400 MHz, MeOD) δ ppm 7.18-7.28 (m, 1 H) 6.57 (d, J=8.56 Hz, 1 H) 6.27 (dd, J=11.58, 8.06 Hz, 1 H) 3.83-3.95 (m, 2 H) 3.56-3.67 (m, 1 H) 3.00-3.15 (m, 2 H) 1.93-2.04 (m, 2 H) 1.44 (s, 9 H) 1.31-1.43 (m, 2 H).

Workup

  1. customReaction
  2. customThe solvent was removed in vacuo
  3. customThe resulting foam was partitioned between dichloromethane (170 mL) and 1N sodium hydroxide (65 mL)
  4. customLayers were separated
  5. extractionThe dichloromethane layer was extracted with water (2×65 mL)
  6. extractionThe aqueous layer was extracted with ethyl acetate (3×100 mL)
  7. dry with materialdried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-1d7627157879491d8d0ca30b49b001ba
Source dataset
uspto-grants-2008_12
Patent number
US07470680B2

Reaction notes

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