Dimethylformamide → (1R,5S)-3-(4-methyl-5-(6-(trifluoromethyl)-1H-indazol-4-yl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide

HRID 58122Notes

Reaction equation

HRID 58122 reaction equation
[CH3:1][C:2]1[C:7]([C:8]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)=[CH:6][N:5]=[C:4]([N:21]2[CH2:26][C@@H:25]3[C@@H:23]([CH2:24]3)[CH:22]2[C:27]([OH:29])=O)[N:3]=1.[NH4+].[Cl-].C[N:33](C([O:39]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.CN([CH:66]=[O:67])C>>[C:66]([OH:67])([C:17]([F:20])([F:19])[F:18])=[O:39].[CH3:1][C:2]1[C:7]([C:8]2[CH:16]=[C:15]([C:17]([F:19])([F:18])[F:20])[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)=[CH:6][N:5]=[C:4]([N:21]2[CH2:26][C@@H:25]3[C@@H:23]([CH2:24]3)[CH:22]2[C:27]([NH2:33])=[O:29])[N:3]=1

Participants

7

Reactant 5

HCID 6228DimethylformamideHCID 8471TriethylamineHCID 25517Ammonium ChlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 89794893(1R,5S)-3-(4-methyl-5-(6-(trifluoromethyl)-1H-indazol-4-yl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

Product 2

HCID 6422Trifluoroacetic acidHCID 89794848(1R,5S)-3-(4-methyl-5-(6-(trifluoromethyl)-1H-indazol-4-yl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamideYield 3.2%

Procedure

In a 4 mL vial equipped with a magnetic stir bar were mixed (1R,5S)-3-(4-methyl-5-(6-(trifluoromethyl)-1H-indazol-4-yl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (80 mg, 0.198 mmol), NH4Cl (21.22 mg, 0.397 mmol), HATU (90 mg, 0.238 mmol) and Et3N (0.083 mL, 0.595 mmol) in DMF (2 mL). The resulting brown solution was stirred overnight. The product was purified by preparative HPLC, eluting with a gradient of 25-50% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA). The pure fractions were lyophilized to give a TFA salt of the title compound as a white solid (3.3 mg, 3.2%). 1H NMR (400 MHz, CD3OD) δ ppm 0.78-0.86 (m, 2H), 1.88 (ddd, J=12.06, 7.26, 4.67 Hz, 1H), 2.09-2.15 (m, 1H), 2.25-2.29 (m, 3H), 3.82 (dd, J=10.61, 5.05 Hz, 1H), 3.92-3.96 (m, 1H), 4.61 (d, J=5.31 Hz, 1H), 7.28 (d, J=1.01 Hz, 1H), 7.93-7.95 (m, 2H), 8.27 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C19H17F3N6O, 403.2. found 403.4.

Workup

  1. customIn a 4 mL vial equipped with a magnetic stir bar
  2. customThe product was purified by preparative HPLC
  3. washeluting with a gradient of 25-50% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA)

Sources & evidence

ORD record
ord-4ffd930c775c4774ad4539256ff2549f
Source dataset
uspto-grants-2016_09
Patent number
US09434743B2

Reaction notes

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