Acetic Acid → Benzoic acid, 2-bromo-5-chloro-3-[(tetrahydro-2H-pyran-4-yl)amino]-, methyl ester

HRID 2208838Notes

Reaction equation

HRID 2208838 reaction equation
[NH2:1][C:2]1[C:3]([Br:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Br:13][C:3]1[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[CH:11][C:10]([Cl:12])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 121599Tetrahydro-4H-pyran-4-one2×HCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydride2×HCID 86719566HCID 86719566, compound

Product 1

HCID 70873931Benzoic acid, 2-bromo-5-chloro-3-[(tetrahydro-2H-pyran-4-yl)amino]-, methyl esterYield 68.2%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 962WaterSolvent

Procedure

To a solution of methyl 3-amino-2-bromo-5-chlorobenzoate (1.0 g, 3.8 mmol) in 1,2-dichloroethane (15 ml) at room temperature under nitrogen was added oxan-4-one (0.7 ml, 7.6 mmol) followed by acetic acid (1.3 ml, 23 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (2.4 g, 11 mmol) at room temperature. After 21 h, additional oxan-4-one (0.7 ml, 7.6 mmol) was added to the reaction mixture, with stirring for 10 minutes before adding sodium triacetoxyborohydride (2.4 g, 11 mmol). After stirring for 20 h, deionized water (30 ml) was added and the mixture was neutralised with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (2×30 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (25 g silica, Isolute cartridge, gradient of eluents; 9:1 Heptane:EtOAc to 8:2 Heptane:EtOAc) to give 903 mg (68%) of the title compound as a white solid. LC-MS 92%, 2.11 min (3 minute LC-MS method), m/z=348.2/350.2/351.9, 1H NMR (500 MHz, Chloroform-d) δ 6.94-7.07 (1H, m), 6.70 (1H, d, J=2.36 Hz), 4.72 (1H, d, J=7.57 Hz), 3.96-4.15 (2H, m), 3.87-3.96 (3H, m), 3.40-3.67 (3H, m), 2.05 (2H, d, J=13.08 Hz), 1.49-1.69 (2H, m).

Workup

  1. stirringAfter stirring for 20 h
  2. customThe phases were separated
  3. extractionthe aqueous layer was extracted with EtOAc (2×30 ml)
  4. dry with materialThe combined organic extracts were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by FCC (25 g silica, Isolute cartridge, gradient of eluents; 9:1 Heptane:EtOAc to 8:2 Heptane:EtOAc)

Sources & evidence

ORD record
ord-c96ea45d1ee54c7ba19a1c5eab2dac8e
Source dataset
uspto-grants-2016_06
Patent number
US09376422B2

Reaction notes

Loading…