Phosphoric Acid → (S)-Sitagliptin Phosphate

HRID 445980Notes

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][CH:4]([NH2:15])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14].[P:29](=[O:33])([OH:32])([OH:31])[OH:30]>C(O)(C)C>[P:29]([OH:33])([OH:32])([OH:31])=[O:30].[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@@H:4]([NH2:15])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14]

Participants

Conditions

Temperature: 72.5 °C

Procedure

In a 25 mL round bottom flask isopropanol (4.0 mL) was taken. Then (2R:2S, 70:30)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (2.0 g) was added. The reaction mixture was heated at 70-75° C. Subsequently 85% Phosphoric acid (481 mg, 0.33 mL) was added over a period of 15-20 mins. Solid mass was precipitated out during addition. After a solvent mixture of water (1.8 mL) and IPA (14.0 mL) was added into the reaction mixture, keeping the temperature between 68-70° C. The slurry was aged for 2-3 h at 68-70° C. Then the slurry was cooled to room temperature. Solid mass was filtered off and washed with cold IPA. Solid mass was dried and collected. Wt. of titled compound-1.8 g. % Purity by HPLC-99.7%, % chiral purity by HPLC of R-isomer 72.8%.

Workup

customSolid mass was precipitated out during addition
additionAfter a solvent mixture of water (1.8 mL) and IPA (14.0 mL)
additionwas added into the reaction mixture
custombetween 68-70° C
temperatureThen the slurry was cooled to room temperature
filtrationSolid mass was filtered off
washwashed with cold IPA
customSolid mass was dried
customcollected

Sources & evidence

ORD record: ord-3a64d3e1fb984b4a88bdc23a709717cd
Source dataset: uspto-grants-2013_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08476437B2

Reaction notes

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