Ammonium Hydroxide → Sitagliptin enamine

HRID 2053032Notes

Reaction equation

HRID 2053032 reaction equation
[O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)[CH2:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14].C([O-])(=O)C.[NH4+:33].[OH-].[NH4+]>CO>[O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)/[CH:3]=[C:4](\[NH2:33])/[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14]

Participants

5

Reactant 3

HCID 14923Ammonium HydroxideHCID 517165Ammonium AcetateHCID 98875881-(3-(trifluoromethyl)-5,6-dihydro(1,2,4)triazolo(4,3-a)pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione

Product 1

HCID 29986152Sitagliptin enamineYield 90.2%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent3×

Procedure

A 5 L round-bottom flask was charged with methanol (100 mL), the ketoamide 2-3 (200 g), and ammonium acetate (110.4 g). Methanol (180 mL) and 28% aqueous ammonium hydroxide (58.6 mL) were then added keeping the temperature below 30° C. during the addition. Additional methanol (100 mL) was added to the reaction mixture. The mixture was heated at reflux temperature and aged for 2 h. The reaction was cooled to room temperature and then to about 5° C. in an ice-bath. After 30 min, the solid was filtered and dried to afford 2-4 as a solid (180 g); m.p. 271.2° C.

Workup

  1. customthe temperature below 30° C.
  2. additionduring the addition
  3. temperatureThe mixture was heated
  4. temperatureat reflux temperature
  5. customto about 5° C.
  6. waitAfter 30 min
  7. filtrationthe solid was filtered
  8. customdried

Sources & evidence

ORD record
ord-f12ab6b0b72a497780f8cf060b56f36f
Source dataset
uspto-grants-2008_02
Patent number
US07326708B2

Reaction notes

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