Sodium Carbonate → 4-(2-Amino-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-fluorobenzoic acid

HRID 596062Notes

Reaction equation

HRID 596062 reaction equation
Br[C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[C:20]([F:27])[CH:19]=1)(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[NH2:14][C:3]1[C:2]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[C:20]([F:27])[CH:19]=2)=[CH:7][C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:5][N:4]=1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 27632014-Carboxy-3-fluorophenylboronic acidHCID 1180451843-bromo-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine

Product 1

HCID 1180457744-(2-Amino-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-fluorobenzoic acidYield 137%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
125 °C

Procedure

To a microwave vial were charged with 3-bromo-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine (500 mg, 1.95 mmol), 4-borono-2-fluorobenzoic acid (1.07 g, 5.83 mmol), aqueous Na2CO3 (2 M, 4.86 mL) and DME (10 mL). The mixture was purged with argon, then followed by addition of Pd(PPh3)4 (225 mg, 0.194 mmol). The mixture was purged with argon, sealed and heated via microwave reactor at 125° C. for 20 min, and then at 130° C. for another 40 min. The DME layer of the reaction mixture was collected, and the solid precipitates were triturated with methanol (2×10 mL). Methanol supernatants were combined with DME layer, and concentrated. The obtained residue was stirred with Et2O (2×60 mL), and the Et2O supernatants were discarded. The solid residue was partitioned between EtOAc (20 mL) and aq. HCl (1 N, 20 mL). The EtOAc layer was stripped with 1N HCl (2×5 mL), and the aqueous layers were combined. The aqueous layer was concentrated under reduced pressure, and the obtained light yellow solid was triturated with methanol (8 mL). The supernant was isolated via filtration and concentrated. 4-(2-Amino-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-fluorobenzoic acid (0.844 g, 2.67 mmol, 137% yield) was obtained as light yellow foam. LCMS (m/z) 317.2 (MH+) 0.46 min.

Workup

  1. customThe mixture was purged with argon
  2. customThe mixture was purged with argon
  3. customsealed
  4. customThe DME layer of the reaction mixture was collected
  5. customthe solid precipitates
  6. customwere triturated with methanol (2×10 mL)
  7. concentrationconcentrated
  8. customThe solid residue was partitioned between EtOAc (20 mL) and aq. HCl (1 N, 20 mL)
  9. concentrationThe aqueous layer was concentrated under reduced pressure
  10. customthe obtained light yellow solid was triturated with methanol (8 mL)
  11. customThe supernant was isolated via filtration
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-e8b865acecab4916b4cf06e0058c4bce
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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