Acetic Acid → methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate

HRID 1616408Notes

Reaction equation

HRID 1616408 reaction equation
[NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]([OH:17])(=O)[CH3:15].C(O[BH-](O[C:28](=O)[CH3:29])OC(=O)C)(=O)C.[Na+].[C:32](=O)(O)[O-].[Na+]>ClC(Cl)C>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:32]2[CH2:15][CH2:14][O:17][CH2:29][CH2:28]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 24729181Methyl 3-Amino-5-bromo-2-methylbenzoate

Product 1

HCID 70872676methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoateYield 69%

Reagents, catalysts & solvents 1

HCID 63651,1-DichloroethaneSolvent

Procedure

To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (15 g, 61.5 mmol) and dihydro-2H-pyran-4(3)-one (9.2 g, 92 mmol) in dichloroethane (300 mL) was added acetic acid (22 g, 369 mmol) and the reaction mixture stirred at room temperature for 15 minutes, then the reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (39 g, 184 mmol) was added. The reaction mixture was stirred overnight at room temperature. Upon completion of the reaction as determined by TLC, aqueous sodium bicarbonate solution was added to the reaction mixture until a pH of 7-8 was obtained. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel) eluting with ethyl acetate:hexane to afford the desired compound as a solid (14 g, 69%). 1H NMR (DMSO-d6, 400 MHz) δ 7.01 (s, 1H), 6.98 (s, 1H), 5.00 (d, 1H, J=7.6 Hz), 3.84-3.87 (m, 2H), 3.79 (s, 3H), 3.54-3.56 (m, 1H), 3.43 (t, 2H, J=12 Hz), 2.14 (s, 3H), 1.81-1.84 (m, 2H), 1.47-1.55 (m, 2H).

Workup

  1. temperaturethe reaction mixture was cooled to 0° C.
  2. stirringThe reaction mixture was stirred overnight at room temperature
  3. customUpon completion of the reaction
  4. additionwas added to the reaction mixture until a pH of 7-8
  5. customwas obtained
  6. customThe organic phase was separated
  7. extractionthe aqueous phase was extracted with ethyl acetate
  8. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe crude compound was purified by column chromatography (100-200 mesh silica gel)
  12. washeluting with ethyl acetate

Sources & evidence

ORD record
ord-1697c0ec9de74ad9828c7fc79128d9c5
Source dataset
uspto-grants-2014_07
Patent number
US08765732B2

Reaction notes

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