Dimethylformamide → Trifluoroacetic acid

HRID 45100Notes

Reaction equation

HRID 45100 reaction equation
[N:1]1[C:6]2[CH2:7][NH:8][CH2:9][C:5]=2[C:4]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[O:21])[CH:15]=[CH:14]3)=[N:3][CH:2]=1.Br[CH2:34][C:35]([O:37]C(C)(C)C)=[O:36].CN([CH:45]=[O:46])C>>[C:45]([OH:46])([C:29]([F:32])([F:31])[F:30])=[O:36].[F:32][C:29]([F:31])([F:30])[C:25]1[CH:24]=[C:23]([NH:22][C:20]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][C:4]4[C:5]5[CH2:9][N:8]([CH2:34][C:35]([OH:37])=[O:36])[CH2:7][C:6]=5[N:1]=[CH:2][N:3]=4)=[CH:19][CH:18]=3)[CH:14]=[CH:15]2)=[O:21])[CH:28]=[CH:27][CH:26]=1

Participants

5

Reactant 3

HCID 6228DimethylformamideHCID 79177tert-Butyl bromoacetateHCID 593944295-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide

Product 2

HCID 6422Trifluoroacetic acidYield 0.1%HCID 59394030{4-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-yl}-acetic acid

Procedure

5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide (121.9 mg, 0.277 mmol) is dissolved in DMF (5 mL) and TEA (200 μl, 1.435 mmol) is added followed by t-butyl bromoacetate (101 μl, 0.693 mmol). The solution is stirred at rt overnight. The reaction is concentrated and then diluted with DCM (10 mL) and cooled to 0° C. TFA (5 mL) is then added and the ice bath is removed and the reaction is stirred at room temperature. The reaction is concentrated, basified with ammonium hydroxide, and diluted with ethyl acetate. The solution is then treated with 1N HCl. The ethyl acetate is removed, dried and concentrated to a residue. The residue is dissolved in DMSO and purified via HPLC (C18; 20-100% I/H2O with 0.1% TFA to obtain {4-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro-pyrrolo[3,4-d]pyrimidin-6-yl}-acetic acid. MS (ESI) m/z 498.9 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.50 (s, 1 H)8.32 (d, J=8.84 Hz, 1 H)8.06 (s, 1 H)7.88-7.95 (m, 2 H)7.57 (t, J=7.96 Hz, 1 H)7.40-7.45 (m, 2 H)7.12 (dd, J=9.09, 2.02 Hz, 1 H)6.74 (d, J=3.79 Hz, 1 H)4.19 (d, J=9.35 Hz, 4 H), 3.43 (s, 2H).

Workup

  1. concentrationThe reaction is concentrated
  2. additiondiluted with DCM (10 mL)
  3. temperaturecooled to 0° C
  4. additionTFA (5 mL) is then added
  5. customthe ice bath is removed
  6. stirringthe reaction is stirred at room temperature
  7. concentrationThe reaction is concentrated
  8. additiondiluted with ethyl acetate
  9. additionThe solution is then treated with 1N HCl
  10. customThe ethyl acetate is removed
  11. customdried
  12. concentrationconcentrated to a residue
  13. dissolutionThe residue is dissolved in DMSO
  14. custompurified via HPLC (C18

Sources & evidence

ORD record
ord-73a39c32266f4d999a002c6507e44e38
Source dataset
uspto-grants-2013_09
Patent number
US08541432B2

Reaction notes

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