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

HRID 2208671
Notes
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Reaction equation

HRID 2208671 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)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl>[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
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 59342390(2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-oneHCID 68295733Methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate

Product 1

HCID 70874011Methyl 3-{[(2R*,6S*)-1-benzyl-2,6-dimethylpiperidin-4-yl]amino}-2-methyl-5-(trifluoromethyl)benzoateYield 62%

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Procedure

To a stirred mixture of MS3A (1.0 g), methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate (350 mg, 1.50 mmol) and (2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-one (359 mg, 1.65 mmol) in chloroform (10 mL) was added acetic acid (500 uL) at 0° C. and stirred at r.t. for 7 hours. To the reaction mixture was added sodium triacetoxyborohydride (670 mg, 3.00 mmol) at 0° C. The reaction mixture was stirred at 23° C. for 1.5 hours. Then the reaction mixture was quenched with aq. NaHCO3 until pH8-9. The MS 3 Å was removed by Celite filtration and the content was extracted with ethylacetate, dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane/ethylacetate=5/1 to 3/1). Target fractions were collected and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=5/1) to give the titled compound as a light yellow oil (223 mg, 62% yield.). For major isomer; 1H-NMR (400 MHz, CDCl3) δppm; 7.40-7.21 (m, 6H), 6.85 (s, 1H), 4.00-3.95 (m, 1H), 3.91 (s, 3H), 3.88 (d, 2H), 3.84-3.76 (m, 1H), 2.83-2.73 (m, 2H), 2.25 (s, 3H), 1.83-1.69 (m, 4H), 1.13 (d, J=6.4 Hz, 6H).

Workup

  1. stirringThe reaction mixture was stirred at 23° C. for 1.5 hours
  2. customThen the reaction mixture was quenched with aq. NaHCO3 until pH8-9
  3. customThe MS 3 Å was removed by Celite filtration
  4. extractionthe content was extracted with ethylacetate
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationthe filtrate was concentrated in vacuo
  8. customThe residue was purified by silica gel column chromatography (heptane/ethylacetate=5/1 to 3/1)
  9. customTarget fractions were collected
  10. concentrationconcentrated in vacuo
  11. customThe residue was purified by silica gel column chromatography (NH—SiO2; heptane/ethylacetate=5/1)

Sources & evidence

ORD record
ord-346c22af2de44ed39dcbaacc6d82b582
Source dataset
uspto-grants-2016_06
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09376422B2

Reaction notes

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