Acetic Acid → Methyl 2-methyl-3-[methyl(oxan-4-yl)amino]-5-(1-methylazetidin-3-yl)benzoate

HRID 2208819Notes

Reaction equation

HRID 2208819 reaction equation
[NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[C:7]([N:16]([CH3:23])[CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:8]([CH3:15])=[C:9]([CH:14]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:2]1.C=O.[C:26](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:15][C:8]1[C:7]([N:16]([CH3:23])[CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:6][C:5]([CH:3]2[CH2:2][N:1]([CH3:26])[CH2:4]2)=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 712Formaldehyde2×HCID 5049666Sodium triacetoxyborohydride2×HCID 70873962Methyl 5-(azetidin-3-yl)-2-methyl-3-[methyl(oxan-4-yl)amino]benzoate

Product 1

HCID 70873844Methyl 2-methyl-3-[methyl(oxan-4-yl)amino]-5-(1-methylazetidin-3-yl)benzoateYield 89%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a stirred solution of methyl 5-(azetidin-3-yl)-2-methyl-3-[methyl(oxan-4-yl)amino]benzoate (320 mg, 1.01 mmol) in DCE (10 ml) under a nitrogen atmosphere was added paraformaldehyde (151 mg, 5.03 mmol) followed by acetic acid (0.115 ml, 2.01 mmol) and the reaction was left to stir for 5 min before the addition of sodium triacetoxyborohydride (852 mg, 4.02 mmol). The reaction was stirred for 16 h at room temperature after which time additional paraformaldehyde (21 mg) and sodium triacetoxyborohydride (98 mg) was added and the reaction was stirred for a further 4 h whereupon distilled water (20 ml) was added and solid NaHCO3 was added until the aqueous phase was pH7. The phases were separated, the aqueous phase was washed with DCM (3×20 ml), the combined organic phases were then washed with brine (50 ml), dried using MgSO4, filtered and evaporated to afford the title compound as an oil (296 mg, 89%). LC-MS 100%, m/z=333.1, 1H NMR (500 MHz, Chloroform-d) δ 7.42 (d, J=1.4 Hz, 1H), 7.09 (s, 1H), 3.96 (d, J=11.2 Hz, 2H), 3.92-3.82 (m, 5H), 3.74 (d, J=7.2 Hz, 1H), 3.30 (dt, J=22.2, 15.0 Hz, 4H), 3.00-2.89 (m, 1H), 2.62 (s, 3H), 2.49-2.39 (m, 6H), 1.75-1.59 (m, 4H).

Workup

  1. waitthe reaction was left
  2. additionwas added
  3. distillationwhereupon distilled water (20 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 DCM (3×20 ml)
  8. washthe combined organic phases were then washed with brine (50 ml)
  9. customdried
  10. filtrationfiltered
  11. customevaporated

Sources & evidence

ORD record
ord-a93554e8263d44cf871905fad5487306
Source dataset
uspto-grants-2016_06
Patent number
US09376422B2

Reaction notes

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