Sulfuric Acid → HCID 71724478, compound

HRID 711290Notes

Reaction equation

HRID 711290 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].[OH:29][S:30]([OH:33])(=[O:32])=[O:31]>C(O)C.O>[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].[S:30]([O-:33])([O-:32])(=[O:31])=[O:29]

Participants

5

Reactant 2

HCID 1118Sulfuric AcidHCID 4369359Sitagliptin

Product 1

HCID 71724478HCID 71724478, compound

Reagents, catalysts & solvents 2

HCID 702EthanolSolvent2×HCID 962WaterSolvent

Conditions

Temperature
22.5 °C

Procedure

100.0 g (245.5 mmoles) of sitagliptin base were dissolved at 20-22° C. in a mixture of 750 ml of absolute ethanol and 120 ml of water. A previously prepared solution of 98.1% H2SO4 (24.9 g, 240.9 mmoles) in ethanol (760 ml) was slowly added to said solution, maintaining the temperature between 20-25° C. When approximately ⅔ of the total volume of the acid solution had been added, the addition was stopped and 1.0 g (1.978 mmoles) of crystalline form M of sitagliptin sulfate obtained by means of any of the processes described in Examples 1 and 3-5 was added to the reaction mixture. The presence of a white precipitate that remains undissolved was immediately noticed. The addition of the acid solution was continued and once this ended, the mixture obtained was maintained at a temperature of 20-25° C. for 4 hours. The solid obtained was filtered and washed in the filter with absolute ethanol (2×100 ml). The wet product was dried in a vacuum oven at 40° C. for 22 hours to yield 97.1 g (192.1 mmoles) of a white crystalline solid (77.6%). XRPDs both of the wet product (FIG. 3) and of the dry product (FIG. 2) which correspond with form M of sitagliptin sulfate were performed. The DSC of the wet product (FIG. 9) shows an endothermic signal at 216.7° C. whereas the dry product showed an endothermic signal at 215.5° C. (FIG. 8). The water content determined by TGA (FIG. 13) is 0.02%. The product thus obtained had a particle size distribution (PSD) corresponding to D90: 254.21 μm, D50: 141.64 μm, D10: 5.32 μm. By adjusting the grinding conditions a product with a particle size distribution (PSD) corresponding to D90 120.84 μm, D50: 6.01 μm, D10: 1.50 μm could be obtained and it was found that the ground product is still the crystalline form of sitagliptin sulfate object of the present invention.

Workup

  1. additionWhen approximately ⅔ of the total volume of the acid solution had been added
  2. additionthe addition

Sources & evidence

ORD record
ord-8e43fd8423ae4407856628d87b43c05b
Source dataset
uspto-grants-2015_11
Patent number
US09181260B2

Reaction notes

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