Acetic Acid → Methyl 5-bromo-2-methyl-3-[methyl(oxan-4-yl)amino]benzoate

HRID 2208813Notes

Reaction equation

HRID 2208813 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C=O.[C:22](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:22])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 712Formaldehyde2×HCID 5049666Sodium triacetoxyborohydride2×HCID 70872676methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate

Product 1

HCID 70872508Methyl 5-bromo-2-methyl-3-[methyl(oxan-4-yl)amino]benzoateYield 58.1%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a stirred solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)amino]benzoate (1.20 g, 3.66 mmol) in DCE (10 ml) under a nitrogen atmosphere was added paraformaldehyde (659 mg, 21.9 mmol) followed by acetic acid (1.26 ml, 21.9 mmol) and the reaction was left to stir for 5 min before the addition of sodium triacetoxyborohydride (4.65 g, 21.9 mmol). The reaction was stirred for 16 h at room temperature after which time additional paraformaldehyde (325 mg, 10.8 mmol) and sodium triacetoxyborohydride (2.40 g, 11.3 mmol) was added and the reaction was stirred for a further 18 h whereupon distilled water (30 ml) was added and solid NaHCO3 was added until the aqueous phase was pH7 and the phases were separated, the aqueous phase was washed with EtOAc (3×50 ml), the combined organics were then washed with brine (50 ml), dried using Na2SO4, filtered and evaporated. The crude residue was purified using FCC over silica eluting with 0-10% EtOAc in heptane to afford the title compound as a colourless oil (728 mg, 52%). LC-MS 87%, m/z=341.9/343.9, 1H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J=2.0 Hz, 1H), 7.25 (d, J=1.9 Hz, 1H), 3.92 (d, J=11.1 Hz, 2H), 3.82 (s, 3H), 3.27 (td, J=11.5, 2.0 Hz, 2H), 2.94-2.79 (m, 1H), 2.57 (s, 3H), 2.36 (s, 3H), 1.74-1.52 (m, 4H).

Workup

  1. waitthe reaction was left
  2. additionwas added
  3. distillationwhereupon distilled water (30 ml)
  4. additionwas added
  5. additionsolid NaHCO3 was added until the aqueous phase
  6. customthe phases were separated
  7. washthe aqueous phase was washed with EtOAc (3×50 ml)
  8. washthe combined organics were then washed with brine (50 ml)
  9. customdried
  10. filtrationfiltered
  11. customevaporated
  12. customThe crude residue was purified

Sources & evidence

ORD record
ord-aac30b849acc48f4aedfa115e9d342f9
Source dataset
uspto-grants-2016_06
Patent number
US09376422B2

Reaction notes

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