Acetic Acid → Sitagliptin Phosphate Monohydrate

HRID 1261629Notes

Reaction equation

HRID 1261629 reaction equation
[O:1]=[C:2]([N:24]1[CH2:29][CH2:28][N:27]2[C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][N:32]=[C:26]2[CH2:25]1)[CH2:3][C@H:4]([NH:15][C@@H](C1C=CC=CC=1)C)[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:39])C.[H][H].[P:43](=[O:47])([OH:46])([OH:45])[OH:44]>CO.[Pd]>[CH:11]1[C:6]([CH2:5][C@@H:4]([NH2:15])[CH2:3][C:2]([N:24]2[CH2:25][C:26]3=[N:32][N:31]=[C:30]([C:33]([F:36])([F:35])[F:34])[N:27]3[CH2:28][CH2:29]2)=[O:1])=[C:7]([F:14])[CH:8]=[C:9]([F:13])[C:10]=1[F:12].[OH2:39].[OH:45][P:43]([OH:47])([OH:46])=[O:44]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 1004Phosphoric AcidHCID 51001609(R)-3-[(R)-1-Phenylethylamino]-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine-7-yl]-4-(2,4,5-trifluorophenyl)-1-butanoneHCID 178418361HCID 178418361, compound

Product 1

HCID 11591741Sitagliptin Phosphate MonohydrateYield 81.5%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Conditions

Temperature
5 °C

Procedure

(2R)-4-oxo-N-[(1R)-1-phenylethyl]-1-(2,4,5-trifluorophenyl)-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]butan-2-amine [F] (25 g, 0.049 mol) was subjected to hydrogenolysis in methanol (75 ml) containing acetic acid (3.0 ml, 0.052 mol) using 5% palladium on charcoal as catalyst at 52±2° C. at hydrogen pressure of 2.0±0.5 kg/cm2. After completion on reaction the catalyst was removed by filtration and reaction mass was concentrated under vacuum. Obtained residue was suspended in water and pH was set to 10.0±0.4 with solution of potassium carbonate. Product was extracted into dichloromethane. The extract was concentrated and degassed. The obtained syrupy mass was dissolved in ethanol, phosphoric acid (3.5 ml, 0.060 mol) was added and the solution refluxed for 30 min. Cooled to 5±3° C., filtered the solid and dried to obtain 20.9 g sitagliptin phosphate, chromatographic purity was 99.8%; chiral purity (determined by chiral HPLC) was 100%.

Workup

  1. customat 52±2° C.
  2. customAfter completion on reaction the catalyst
  3. customwas removed by filtration and reaction mass
  4. concentrationwas concentrated under vacuum
  5. extractionProduct was extracted into dichloromethane
  6. concentrationThe extract was concentrated
  7. customdegassed
  8. dissolutionThe obtained syrupy mass was dissolved in ethanol
  9. temperaturethe solution refluxed for 30 min
  10. filtrationfiltered the solid
  11. customdried

Sources & evidence

ORD record
ord-df33ff095e67401c818d894384035882
Source dataset
uspto-grants-2013_06
Patent number
US08471016B2

Reaction notes

Loading…