Trifluoroacetic acid → Fotagliptin

HRID 524117Notes

Reaction equation

HRID 524117 reaction equation
[C:1]([C:3]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]([CH3:13])=[N:9][N:8]=[C:7]1[N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20]C(=O)OC(C)(C)C)[CH2:15]1)#[N:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH2:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:7]2[N:6]([CH2:5][C:4]3[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:3]=3[C:1]#[N:2])[C:11](=[O:12])[C:10]([CH3:13])=[N:9][N:8]=2)[CH2:15]1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 516892Sodium BicarbonateHCID 58328541(R)-tert-butyl 1-(4-(2-cyano-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate

Product 1

HCID 53258570Fotagliptin

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (R)-tert-butyl 1-(4-(2-cyano-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate (20, 37 mg) in dichloromethane (1 mL) was added TFA (0.5 mL) and the mixture was stirred at RT for 1 h. The mixture was carefully neutralized with NaHCO3 (aq, saturated), and extracted with CH2Cl2 (10 mL×3). The combined extracts were dried over Na2SO4 and concentrated to give the crude product, which was purified by column chromatography on silica gel, and eluted with 92:6:2 dichloromethane-methanol-ammonia to provide (R)-2-((3-(3-aminopiperidin-1-yl)-6-methyl-5-oxo-1,2,4-triazin-4(5H)-yl)methyl)-4-fluorobenzonitrile (21). 1H NMR (400 MHz, DMSO, ppm): δ 7.96 (m, 1H), 7.36 (br, 1H), 7.29 (d, 1H), 5.23 (s, 2H), 3.15 (m, 3H), 2.72 (m, 2H), 2.23 (s, 3H), 1.78 (d, 1H), 1.64 (d, 1H), 1.47 (m, 1H), 1.12 (m, 1H). MS: m/z, 343 (100%, M+1);

Workup

  1. extractionextracted with CH2Cl2 (10 mL×3)
  2. dry with materialThe combined extracts were dried over Na2SO4
  3. concentrationconcentrated
  4. customto give the crude product, which
  5. customwas purified by column chromatography on silica gel
  6. washeluted with 92:6:2 dichloromethane-methanol-ammonia

Sources & evidence

ORD record
ord-ef8a7e5f6f404bc59ece264f9660fc73
Source dataset
uspto-grants-2016_05
Patent number
US09340523B2

Reaction notes

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