Trifluoroacetic acid → N-(4-(Chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-3-(1H-pyrazol-5-yl)benzamide

HRID 525754Notes

Reaction equation

HRID 525754 reaction equation
O1CCCCC1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.Br[C:22]1[CH:23]=[C:24]([CH:39]=[CH:40][C:41]=1[N:42]1[CH2:46][C@H:45]([OH:47])[C@@H:44]([OH:48])[CH2:43]1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([Cl:38])([F:37])[F:36])=[CH:30][CH:29]=1)=[O:26].C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO>[Cl:38][C:35]([F:36])([F:37])[O:34][C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:41]([N:42]3[CH2:43][C@H:44]([OH:48])[C@@H:45]([OH:47])[CH2:46]3)=[C:40]([C:11]3[NH:7][N:8]=[CH:9][CH:10]=3)[CH:39]=2)=[CH:33][CH:32]=1

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 10340Sodium Carbonate2×HCID 115872081-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 899064003-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((3 S,4S)-3,4-dihydroxypyrrolidin-1-yl)benzamide

Product 1

HCID 118045025N-(4-(Chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-3-(1H-pyrazol-5-yl)benzamide

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 702EthanolSolventHCID 80711,2-DimethoxyethaneSolvent

Procedure

1-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (126 mg, 0.451 mmol) and PdCl2(PPh3)2 (15.84 mg, 23 μmol) were added to a mixture of 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)benzamide (Stage 77.1, 110 mg, 0.226 mmol) and Na2CO3 (0.451 mL, 0.903 mmol) in DME (1.5 mL)/EtOH (0.3 mL) in a vial, which was sealed, purged with argon and the RM was subjected to MW irradiation at 125° C. for 30 min. The RM was filtered through Hyflo® and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 12 g, n-hexane/EtOAc from 20% to 100% EtOAc). The resulting intermediate was dissolved in DCM (2 mL), treated TFA (0.314 mL, 4.07 mmol) and stirred at RT for 2 h. The solvent was evaporated off under reduced pressure to give a residue which was treated with sat. aq. Na2CO3 and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative HPLC (Condition 10). Fractions containing pure product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure to give an aq. residue which was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 4 g, DCM/EtOH from 98:2 to 92:8) to give the title product as a white solid. HPLC (Condition 7) tR=6.105 min, UPLC-MS (Condition 8) tR=0.91 min, m/z=465.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.81 (d, J=10.56 Hz, 2H) 3.24-3.38 (m, 2H) 3.81-3.91 (m, 2H) 4.99 (br.s, 1H) 5.04 (br.s, 1H) 6.26-6.36 (m, 1H) 6.72-6.87 (m, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.47-7.94 (m, 5H) 10.10 (s, 1H) 12.75-13.04 (m, 1H).

Workup

  1. customwas sealed
  2. custompurged with argon
  3. customthe RM was subjected to MW irradiation at 125° C. for 30 min
  4. filtrationThe RM was filtered through Hyflo®
  5. customthe solvent was evaporated off under reduced pressure
  6. customto give a residue which
  7. customwas purified by flash chromatography (Silica gel column, 12 g, n-hexane/EtOAc from 20% to 100% EtOAc)
  8. dissolutionThe resulting intermediate was dissolved in DCM (2 mL)
  9. customThe solvent was evaporated off under reduced pressure
  10. customto give a residue which
  11. extractionextracted with EtOAc
  12. washThe combined extracts were washed with brine
  13. dry with materialdried over Na2SO4
  14. customthe solvent was evaporated off under reduced pressure
  15. customto give the crude product which
  16. customwas purified by preparative HPLC (Condition 10)
  17. additionFractions containing pure product
  18. additiontreated with sat. aq. Na2CO3
  19. customthe MeCN was evaporated off under reduced pressure
  20. customto give an aq. residue which
  21. extractionwas extracted with EtOAc
  22. washThe combined extracts were washed with brine
  23. dry with materialdried over Na2SO4
  24. customthe solvent was evaporated off under reduced pressure
  25. customto give a residue which
  26. customwas purified by flash chromatography (Silica gel column, 4 g, DCM/EtOH from 98:2 to 92:8)

Sources & evidence

ORD record
ord-2249c40215924f31883bab8b088b5da5
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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