Water → Sitagliptin Phosphate Monohydrate

HRID 1432132Notes

Reaction equation

HRID 1432132 reaction equation
O.[O:2]=[C:3]([N:17]1[CH2:22][CH2:21][N:20]2[C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=[C:19]2[CH2:18]1)[CH2:4][C@H:5]([NH2:16])[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15].[P:30](=[O:34])([OH:33])([OH:32])[OH:31]>C(O)(C)C>[OH2:2].[P:30]([OH:34])([OH:33])([OH:32])=[O:31].[O:2]=[C:3]([N:17]1[CH2:22][CH2:21][N:20]2[C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=[C:19]2[CH2:18]1)[CH2:4][C@H:5]([NH2:16])[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15]

Participants

5

Reactant 3

HCID 962WaterHCID 1004Phosphoric AcidHCID 4369359Sitagliptin

Product 1

HCID 11591741Sitagliptin Phosphate Monohydrate

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent2×

Conditions

Temperature
75 °C

Procedure

A 250 mL round bottom flask equipped with an overhead stirrer, heating mantle and thermocouple, was charged with 31.5 mL of isopropanol (IPA), 13.5 mL water, 15.0 g (36.9 mmol) of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine freebase and 4.25 g (36.9 mmol) of 85% aqueous phosphoric acid. The mixture was heated to 75° C. A thick white precipitate formed at lower temperatures but dissolved upon reaching 75° C. The solution was cooled to 68° C. and then held at that temperature for 2 h. A slurry bed of solids formed during this age time [the solution can be seeded with 0.5 to 5 wt % of small particle size (alpine milled) monohydrate]. The slurry was then cooled at a rate of 4° C./h to 21° C. and then held overnight. 105 mL of IPA was then added to the slurry. After 1 h the slurry was filtered and washed with 45 mL EPA. The solids were dried on the frit with open to air. The solids were found to greater than 99.8% pure by HPLC area percentage (HPLC conditions same as those given above).

Workup

  1. customA 250 mL round bottom flask equipped with an overhead stirrer
  2. temperatureheating mantle
  3. customA thick white precipitate formed at lower temperatures
  4. dissolutiondissolved
  5. customupon reaching 75° C
  6. temperatureThe solution was cooled to 68° C.
  7. customA slurry bed of solids formed during this age time [the solution
  8. temperatureThe slurry was then cooled at a rate of 4° C./h to 21° C.
  9. waitheld overnight
  10. filtrationAfter 1 h the slurry was filtered
  11. washwashed with 45 mL EPA
  12. customThe solids were dried on the frit with open to air

Sources & evidence

ORD record
ord-202c634caa4342888ce95494ce8da698
Source dataset
uspto-grants-2009_11
Patent number
US07612072B2

Reaction notes

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