Diisopropyl Ether → N-Boc-sitagliptin

HRID 590636Notes

Reaction equation

HRID 590636 reaction equation
[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(C[C@@H](N)CC([N:38]2[CH2:50][C:42]3=[N:43][N:44]=[C:45]([C:46]([F:49])([F:48])[F:47])[N:41]3[CH2:40][CH2:39]2)=O)=C(F)C=C(F)C=1F.O.OP(O)(O)=O.Cl.FC(F)(F)C1N2CCNCC2=NN=1.C1(B(O)O)C=CC=CC=1.C(OC(C)C)(C)C>O.C(N(CC)CC)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][C:11](=[O:13])[N:38]1[CH2:39][CH2:40][N:41]2[C:45]([C:46]([F:49])([F:47])[F:48])=[N:44][N:43]=[C:42]2[CH2:50]1)[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])([CH3:2])([CH3:3])[CH3:4]

Participants

9

Reactant 5

HCID 7914Diisopropyl EtherHCID 66827Phenylboronic AcidHCID 11591741Sitagliptin phosphate monohydrateHCID 119613713-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochlorideHCID 21911205Boc-(R)-3-Amino-4-(2,4,5-trifluoro-phenyl)-butyric acid

Product 1

HCID 46836576N-Boc-sitagliptin

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8471TriethylamineSolvent

Procedure

100 g of 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butyric acid of formula (II) was charged with 800 ml of toluene into a 2 liter 4 necked round bottom flask attached with dean stark apparatus followed by 70 ml of triethyl amine at room temperature. Then 100 g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine HCl was charged and stirred for 5 minutes. 7.5 g of phenyl boronic acid was charged to the reaction mass. After 48 hours of stirring at reflux temperature, the reaction was complete. The reaction mass was cooled to room temperature and 1000 ml of water was added to it. The organic layer was separated and washed twice with 500 ml of 1N HCl. The organic layer was separated and washed with 500 ml of water followed by 6% NaHCO3 and finally by 500 ml of water. The organic layer was then separated, treated with sodium sulfate and then with charcoal and filtered. The solvent was distilled out under vacuum. The solid obtained was stirred with 500 ml of diisopropyl ether for 2 hours, filtered, washed with diisopropyl ether and then dried under vacuum at 50° C. for 12-15 hours.

Workup

  1. stirringAfter 48 hours of stirring
  2. temperatureat reflux temperature
  3. customThe organic layer was separated
  4. washwashed twice with 500 ml of 1N HCl
  5. customThe organic layer was separated
  6. washwashed with 500 ml of water
  7. customThe organic layer was then separated
  8. additiontreated with sodium sulfate
  9. filtrationwith charcoal and filtered
  10. distillationThe solvent was distilled out under vacuum
  11. customThe solid obtained
  12. filtrationfiltered
  13. washwashed with diisopropyl ether
  14. customdried under vacuum at 50° C. for 12-15 hours

Sources & evidence

ORD record
ord-afc94577d3ec4fcebdeb4f74e69a31df
Source dataset
uspto-grants-2016_01
Patent number
US09233967B2

Reaction notes

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