Trifluoroacetic acid → Methyl 5-bromo-2-methyl-3-[(oxan-4-yl)(2,2,2-trifluoroethyl)amino]benzoate

HRID 2208873Notes

Reaction equation

HRID 2208873 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:20](O)([C:22]([F:25])([F:24])[F:23])=O.[BH4-].[Na+].[OH-].[Na+]>Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:20][C:22]([F:25])([F:24])[F:23])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acid3×HCID 14798Sodium HydroxideHCID 4311764Sodium borohydride4×HCID 70872676methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate

Product 1

HCID 70872517Methyl 5-bromo-2-methyl-3-[(oxan-4-yl)(2,2,2-trifluoroethyl)amino]benzoateYield 91%

Reagents, catalysts & solvents 1

HCID 313Hydrochloric AcidSolvent

Procedure

To a solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)amino]benzoate (500 mg, 1.5 mmol) and TFA (15 ml), was added NaBH4 (1.0 g, 26 mmol) portionwise over 5 minutes. The reaction mixture was stirred at room temperature for 2 hours and then heated to 50° C. for 3 hours and treated with a further aliquot of NaBH4 (300 mg) over 25 minutes. The reaction mixture was then heated to 60° C. for 2 hours and left to stir at room temperature for 17 hours. The reaction mixture was treated with TFA (5 ml) and NaBH4 (200 mg) and heated back up to 60° C. for 3.5 hours. A further aliquot of NaBH4 (200 mg) was added over 15 minutes, along with TFA (5 ml) and heating continued for a further 3 hours, before being left to stand at room temperature overnight. The reaction mixture was poured over ice (75 ml) and stirred until the ice had melted. The reaction mixture was then basified by the addition of 6M NaOH (aq) (40 ml) and re-adjusted to pH 7 using 1M HCl (aq) (40 ml). The resulting white suspension was collected by filtration, the solid washed with water (20 ml) and dried in-vacuo at 40° C. for 3 hours to give the title compound (577 mg, 91%) as a white solid. LC-MS 98%,), m/z=409.90, 410.9, 411.90, 412.9; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.80 (d, J=1.73 Hz, 1H) 7.41 (d, J=1.73 Hz, 1H) 4.01 (dd, J=11.51, 4.10 Hz, 2H) 3.91 (s, 3H) 3.64 (d, J=5.20 Hz, 2H) 3.32 (t, J=11.82 Hz, 2H) 2.99 (tt, J=11.43, 3.63 Hz, 1H) 2.48 (s, 3H) 1.80 (dd, J=12.53, 1.50 Hz, 2H) 1.54-1.62 (m, 2H).

Workup

  1. temperatureheated to 50° C. for 3 hours
  2. temperatureThe reaction mixture was then heated to 60° C. for 2 hours
  3. waitleft
  4. stirringto stir at room temperature for 17 hours
  5. temperatureheated back up to 60° C. for 3.5 hours
  6. temperatureheating
  7. waitcontinued for a further 3 hours
  8. waitbefore being left
  9. waitto stand at room temperature overnight
  10. filtrationThe resulting white suspension was collected by filtration
  11. washthe solid washed with water (20 ml)
  12. customdried in-vacuo at 40° C. for 3 hours

Sources & evidence

ORD record
ord-11beb2d3e7c64a2f928cafb74baec329
Source dataset
uspto-grants-2016_06
Patent number
US09376422B2

Reaction notes

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