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

HRID 2208808Notes

Reaction equation

HRID 2208808 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].[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+]>ClCCCl>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]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 121599Tetrahydro-4H-pyran-4-oneHCID 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 71.2%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a stirred solution of methyl 3-amino-2-methyl-5-bromobenzoate (4.06 g, 16.6 mmol) in DCE (60 ml) under a nitrogen atmosphere was added oxan-4-one (3.07 ml, 33.3 mmol) followed by acetic acid (5.71 ml, 99.8 mmol) and the reaction was left to stir for 5 min before the addition of sodium triacetoxyborohydride (10.6 g, 49.9 mmol). The reaction was stirred for 3 h at room temperature whereupon distilled water (50 ml) was added and the solution was neutralised with solid NaHCO3. The phases were separated and then the aqueous phase was washed with EtOAc (2×100 ml), the combined organics were then dried using Na2SO4, filtered and evaporated. The residue was purified by FCC using silica and eluting with a 10% to 40% EtOAc in heptane gradient to afford the title compound as an off-white solid (3.88 g, 71%). LC-MS 100%, 2.10 min (3.5 minute LC-MS method), m/z=327.9/329.8, 1H NMR (500 MHz, Chloroform-d) δ 7.23 (d, J=1.9 Hz, 1H), 6.84 (d, J=1.7 Hz, 1H), 4.02 (dt, J=11.7, 3.5 Hz, 2H), 3.87 (s, 3H), 3.65 (d, J=7.2 Hz, 1H), 3.59-3.45 (m, 3H), 2.23 (s, 3H), 2.05 (d, J=13.8 Hz, 2H), 1.51 (ddd, J=24.1, 10.8, 4.2 Hz, 2H).

Workup

  1. waitthe reaction was left
  2. distillationwhereupon distilled water (50 ml)
  3. additionwas added
  4. customThe phases were separated
  5. washthe aqueous phase was washed with EtOAc (2×100 ml)
  6. customthe combined organics were then dried
  7. filtrationfiltered
  8. customevaporated
  9. customThe residue was purified by FCC
  10. washeluting with a 10% to 40% EtOAc in heptane gradient

Sources & evidence

ORD record
ord-b937d99b65be421cb5e39f0de239ed07
Source dataset
uspto-grants-2016_06
Patent number
US09376422B2

Reaction notes

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