Ethyl Acetate → HCID 131729737, compound

HRID 1928531Notes

Reaction equation

HRID 1928531 reaction equation
[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].C(OCC)(=O)C.[C:35]([OH:43])(=[O:42])[C@H:36]([CH2:38][C:39]([OH:41])=[O:40])[OH:37]>C(O)C>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:35]([O-:43])(=[O:42])[C@H:36]([CH2:38][C:39]([O-:41])=[O:40])[OH:37]

Participants

5

Reactant 3

HCID 8857Ethyl AcetateHCID 222656L-Malic AcidHCID 4369359Sitagliptin

Product 1

HCID 131729737HCID 131729737, compoundYield 87%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
60 °C

Procedure

To a 250 ml round bottom flask, equipped with a magnetic stirrer and a reflux condenser, was added Sitagliptin base (12.0 g) and ethyl acetate (120 ml). The mixture was heated to 60° C. for dissolution. A solution of L-malic acid (3.95 g) in absolute ethanol (24 ml) was added to the above solution dropwise over 15 minutes. During the addition, the heating was stopped and the mixture was cooled slowly. When the addition was completed the temperature in the oil bath was 43° C. The solution was cooled to room temperature (˜20° C.) and stirred overnight. After 3 days about 60 g of solvents were distilled out and the solution was stirred at room temperature over 10 days, during this time precipitation as a soft white block occurred. Ethyl acetate (110 ml) was added in order to facilitate filtration and the mixture was stirred for several minutes. The product was isolated by vacuum filtration, washed with ethyl acetate (40 ml) and dried in a vacuum oven at 50° C. for 24 hours and then for additional 48 hours at room temperature (15-25° C.) to obtain Sitagliptin L-malate crystalline form I3 (13.86 g, 87% yield).

Workup

  1. customTo a 250 ml round bottom flask, equipped with a magnetic stirrer and a reflux condenser
  2. additionDuring the addition
  3. temperaturethe mixture was cooled slowly
  4. additionWhen the addition
  5. customwas 43° C
  6. temperatureThe solution was cooled to room temperature (˜20° C.)
  7. distillationAfter 3 days about 60 g of solvents were distilled out
  8. stirringthe solution was stirred at room temperature over 10 days, during this time precipitation as a soft white block
  9. additionEthyl acetate (110 ml) was added in order
  10. filtrationfiltration
  11. stirringthe mixture was stirred for several minutes
  12. customThe product was isolated by vacuum filtration
  13. washwashed with ethyl acetate (40 ml)
  14. customdried in a vacuum oven at 50° C. for 24 hours

Sources & evidence

ORD record
ord-fa6faafb4d2241c9a7727e9bf09c3123
Source dataset
uspto-grants-2012_05
Patent number
US08183373B2

Reaction notes

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