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

HRID 1050462Notes

Reaction equation

HRID 1050462 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].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O.C([O-])([O-])=O.[Na+].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[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

8

Reactant 4

HCID 176Acetic AcidHCID 177Acetaldehyde2×HCID 5049666Sodium triacetoxyborohydrideHCID 70872676methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate

Product 1

HCID 70872485methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoateYield 107.3%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolventHCID 962WaterSolventHCID 10340Sodium CarbonateSolvent

Procedure

To a mechanically stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H -pyran-4-yl)amino)benzoate (15.3 g, 46.6 mmol) and acetaldehyde (7.90 mL, 140 mmol) in 1,2-dichloroethane (DCE) (150 mL) under nitrogen was added acetic acid (16.01 mL, 280 mmol). After 30 min, sodium triacetoxyborohydride (29.6 g, 140 mmol) was added to the reaction mixture. The reaction was stirred overnight, at which time the nitrogen was removed and acetaldehyde (7.90 mL, 140 mmol) was added. After 2 h, the reaction mixture was diluted with water and Na2CO3 (sat′d) and extracted with EtOAc (3×). The ethyl acetate layers were dried over Na2SO4, filtered, and concentrated to obtain methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (17.8 g, 50.0 mmol, 107% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.61 (d, J=2.02 Hz, 1 H), 7.54 (d, J=2.27 Hz, 1 H), 3.89-3.73 (m, 5 H), 3.26 (td, J=11.56, 1.89 Hz, 2 H), 3.15-2.86 (m, 3 H), 3.36 (s, 3 H). 1.66-1.55 (m, 2 H), 1.55-1.36 (m, 2 H), 0.79 (t, J=6.95 Hz, 3 H). MS(ES) [M+H]+ 358, 356.

Workup

  1. customwas removed
  2. waitAfter 2 h
  3. extractionextracted with EtOAc (3×)
  4. dry with materialThe ethyl acetate layers were dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-38bfbb99df7b4745a3ba4edfa7e81e5d
Source dataset
uspto-grants-2016_07
Patent number
US09382234B2

Reaction notes

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