Sodium Bicarbonate → Methyl 3-{[(2R*,6R*)-1-benzyl-2,6-dimethylpiperidin-4-yl]amino}-2-methyl-5-(trifluoromethyl)benzoate

HRID 2208670Notes

Reaction equation

HRID 2208670 reaction equation
[NH2:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:17]([N:24]1[C@@H:29]([CH3:30])[CH2:28][C:27](=O)[CH2:26][C@H:25]1[CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(O)(C(F)(F)F)=O>[CH2:17]([N:24]1[C@H:29]([CH3:30])[CH2:28][CH:27]([NH:1][C:2]2[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:26][C@H:25]1[CH3:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1

Participants

7

Reactant 4

HCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 59342390(2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-oneHCID 68295733Methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate

Product 1

HCID 86719532Methyl 3-{[(2R*,6R*)-1-benzyl-2,6-dimethylpiperidin-4-yl]amino}-2-methyl-5-(trifluoromethyl)benzoateYield 37%

Reagents, catalysts & solvents 2

HCID 6422Trifluoroacetic acidSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a stirred solution of methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate (400 mg, 1.72 mmol) in THF (15 mL) and TFA (491 uL) was added (2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-one (410 mg, 1.89 mmol) at 0° C. The mixture was stirred at 60° C. for 1 hour under nitrogen atmosphere. Then the mixture was cooled to 0° C. in an ice bath, sodium triacetoxyborohydride (765 mg, 3.43 mmol) was added. The reaction mixture was stirred at 23° C. for 2 hours. Then aq. NaHCO3 was added at 0° C. until pH8-9, and the content was extracted with ethylacetate. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=3/1) to give the titled compound as a colorless oil. (278 mg, 37% yield). 1H-NMR (400M Hz, CDCl3) δppm; 7.21-7.40 (m, 6H), 6.90 (s, 1H), 3.95 (d, J=14.0 Hz, 1H), 3.90 (s, 3H), 3.60-3.73 (m, 2H), 3.46 (d, J=14.0 Hz, 1H), 3.08-3.12 (m, 1H), 2.98-3.03 (m, 1H), 2.30 (s, 3H), 2.02-2.08 (m, 1H), 1.83-1.88 (m, 1H), 1.52-1.60 (m, 1H), 1.17-1.26 (m, 1H), 1.11 (d, J=6.8 Hz, 3H), 1.13 (d, J=6.4 Hz, 3H).

Workup

  1. temperatureThen the mixture was cooled to 0° C. in an ice bath
  2. stirringThe reaction mixture was stirred at 23° C. for 2 hours
  3. extractionthe content was extracted with ethylacetate
  4. dry with materialThe organic layer was dried over MgSO4
  5. filtrationfiltered
  6. concentrationThe filtrate was concentrated in vacuo
  7. customThe residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=3/1)

Sources & evidence

ORD record
ord-3f04278d7b5b4e02b5bbd136b2b9db37
Source dataset
uspto-grants-2016_06
Patent number
US09376422B2

Reaction notes

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