Trifluoroacetic acid → Omarigliptin

HRID 1619907Notes

Reaction equation

HRID 1619907 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[C:25](=[N:26][N:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=3)[CH2:24]2)[CH2:11][O:10]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH2:15])[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[C:25](=[N:26][N:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=3)[CH2:24]2)[CH2:11][O:10]1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 71486978tert-butyl {(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate

Product 1

HCID 46209133Omarigliptin

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Removal of the BOC group in the product from Step A (13.78 g, 27.67 mmol) was accomplished with trifluoroacetic acid (100 ml) in dichloromethane (200 mL) at room temperature. After stirring for 2 h, the reaction was concentrated and neutralized with 25% MeOH and 2.5% ammonium hydroxide in dichloromethane. Solvents were removed under reduced pressure and the resulting crude material was purified on a 65i Biotage™ column eluting with 1.25-5% MeOH and 0.125-0.5% ammonium hydroxide in dichloromethane. The isolated material was further purified by recrystallization from 5:1 EtOAc/CH2Cl2 at 60° C. The crystalline product was washed with cold 2:1 EtOAc/hexanes to give the title compound as a light brown solid. 1H NMR (500 MHz, CD3OD): 1.71 (q, 1H, J=12 Hz), 2.56-2.61 (m, 1H), 3.11-3.18 (m, 1H), 3.36-3.40 (m, 1H), 3.48 (t, 1H, J=12 Hz), 3.88-3.94 (m, 4H), 4.30-4.35 (m, 1H), 4.53 (d, 1H, J=12 Hz), 7.14-7.23 (m, 2H), 7.26-7.30 (m, 1H), 7.88 (s, 1H). LC-MS: 399.04 (M+1).

Workup

  1. concentrationthe reaction was concentrated
  2. customSolvents were removed under reduced pressure
  3. customthe resulting crude material was purified on a 65i Biotage™ column
  4. washeluting with 1.25-5% MeOH and 0.125-0.5% ammonium hydroxide in dichloromethane
  5. customThe isolated material was further purified by recrystallization from 5:1 EtOAc/CH2Cl2 at 60° C
  6. washThe crystalline product was washed with cold 2:1 EtOAc/hexanes

Sources & evidence

ORD record
ord-f74f8b09cdc14840bc9b7ed7d0a02c70
Source dataset
uspto-grants-2014_07
Patent number
US08772328B2

Reaction notes

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