Hydrochloric Acid → (3S,5S,6R)-6-Methyl-2-oxo-5-(o-tolyl)-1-(2,2,2-trifluoroethyl)piperidin-3-aminium 4-methylbenzoate

HRID 706385Notes

Reaction equation

HRID 706385 reaction equation
[CH3:1][C@H:2]1[N:7]([CH2:8][C:9]([F:12])([F:11])[F:10])[C:6](=[O:13])[CH:5]([NH:14]C(=O)OC(C)(C)C)[CH2:4][C@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].Cl.[CH3:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=1>C1COCC1.OC1C=CC([N+]([O-])=O)=CC=1C=O>[CH3:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([O-:37])=[O:36])=[CH:33][CH:32]=1.[CH3:1][C@H:2]1[N:7]([CH2:8][C:9]([F:11])([F:12])[F:10])[C:6](=[O:13])[C@@H:5]([NH3+:14])[CH2:4][C@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28]

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 7470P-Toluic AcidHCID 89821825tert-Butyl ((5S,6R)-6-methyl-2-oxo-5-(o-tolyl)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)carbamate

Product 1

HCID 118023940(3S,5S,6R)-6-Methyl-2-oxo-5-(o-tolyl)-1-(2,2,2-trifluoroethyl)piperidin-3-aminium 4-methylbenzoateYield 52%

Reagents, catalysts & solvents 2

HCID 668085-NitrosalicylaldehydeCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of 38 (2.0 g, 5.0 mol) in THF (10 mL) was added 6N HCl (10 mL, 59.9 mmol) dropwise. The reaction was aged at 20-25° C. for 5 h then concentrated to remove THF. The residue was diluted with MTBE and basified with K2CO3. A total of 3 mL of H2O was added to dissolve all solids. The organic layer was separated, washed with brine, and solvent-switched to IPAC. To one-third of the organic layer was added 4-methylbenzoic acid (0.27 g, 2.00 mmol). The solution was heated to 50° C. and 2-hydroxy-5-nitrobenzaldehyde (0.0028 g, 0.017 mmol) was added. The reaction was aged at 20-25° C. for 16 h. The resulting slurry was chilled in an ice bath to 2° C. and filtered. The solids were washed with IPAC and dried to give product 39 (0.38 g, 52%) as crystals. 1H NMR (500 MHz, DMSO-d6): δ 7.82 (d, J=8.0 Hz, 2H), 7.26 (d, J=7.9 Hz, 2H), 7.18-7.19 (m, 3H), 7.12 (d, J=7.5 Hz, 1H), 4.67 (dq, J=15.2, 9.7 Hz, 1H), 3.72-3.74 (m, 2H), 3.61-3.63 (m, 1H), 3.55 (dd, J=11.3, 6.7 Hz, 1H), 2.40 (dd, J=25.2, 12.9 Hz, 1H), 2.35 (s, 3H), 2.32 (s, 3H), 2.02 (dd, J=12.6, 6.7 Hz, 1H), 0.91 (d, J=6.4 Hz; 3H); 13C NMR (100 MHz, DMSO-d6): δ 172.7, 168.3, 142.4, 139.1, 136.1, 130.9, 130.5, 129.7, 129.3, 127.4, 127.2, 126.5, 125.6 (q, J=281 Hz), 56.2, 52.1, 45.0 (q, J=32.3 Hz), 38.5, 29.1, 21.5, 18.7, 14.2

Workup

  1. concentrationthen concentrated
  2. customto remove THF
  3. additionThe residue was diluted with MTBE and basified with K2CO3
  4. additionA total of 3 mL of H2O was added
  5. dissolutionto dissolve all solids
  6. customThe organic layer was separated
  7. washwashed with brine, and solvent-switched to IPAC
  8. waitThe reaction was aged at 20-25° C. for 16 h
  9. temperatureThe resulting slurry was chilled in an ice bath to 2° C.
  10. filtrationfiltered
  11. washThe solids were washed with IPAC
  12. customdried

Sources & evidence

ORD record
ord-717d1dde30f14a61989f66023951cc57
Source dataset
uspto-grants-2015_11
Patent number
US09174989B2

Reaction notes

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