Sodium Bicarbonate → Methyl 3-{[(2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl]amino}-5-fluoro-2-methylbenzoate

HRID 2208677Notes

Reaction equation

HRID 2208677 reaction equation
[NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:14]([N:21]1[C@@H:26]([CH3:27])[CH2:25][C:24](=O)[CH2:23][C@H:22]1[CH3:29])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=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>[CH2:14]([N:21]1[C@H:26]([CH3:27])[CH2:25][CH:24]([NH:1][C:2]2[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:23][C@H:22]1[CH3:29])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1

Participants

7

Reactant 4

HCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 53419617Methyl 3-amino-5-fluoro-2-methylbenzoateHCID 59342390(2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-one

Product 1

HCID 70873973Methyl 3-{[(2R,6R)-1-benzyl-2,6-dimethylpiperidin-4-yl]amino}-5-fluoro-2-methylbenzoateYield 30.3%

Reagents, catalysts & solvents 2

HCID 6422Trifluoroacetic acidSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a stirred solution of methyl 3-amino-5-fluoro-2-methylbenzoate (520 mg, 2.84 mmol) in THF (20 mL) and TFA (813 uL) was added (2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-one (679 mg, 3.12 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 (1.27 g, 5.68 mmol) was added. The reaction mixture was stirred at rt 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=5/1) to give titled compound as a colorless oil (331 mg, 30% yield.). 1H-NMR (400 MHz, CDCl3) δppm; 7.35-7.39 (m, 2H), 7.27-7.30 (m, 2H), 7.21-7.26 (m, 1H), 6.76 (dd, J=2.4, 9.2 Hz, 1H), 6.45 (dd, J=2.4, 11.2 Hz, 1H), 3.94 (d, J=14.4 Hz, 1H), 3.87 (s, 3H), 3.58-3.65 (m, 2H), 3.46 (d, J=14.4 Hz, 1H), 3.06-3.12 (m, 1H), 2.94-3.01 (m, 1H), 2.21 (s, 3H), 2.02-2.07 (m, 1H), 1.82-1.89 (m, 1H), 1.15-1.22 (m, 1H), 1.12 (d, J=6.0 Hz, 3H), 1.09 (d, J=7.2 Hz, 3H).

Workup

  1. temperatureThen the mixture was cooled to 0° C. in an ice bath
  2. stirringThe reaction mixture was stirred at rt 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=5/1)

Sources & evidence

ORD record
ord-9628d1b858d04b85b588c1a98eefe12c
Source dataset
uspto-grants-2016_06
Patent number
US09376422B2

Reaction notes

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