Trifluoroacetic acid → 4-((3S,4S)-3-Amino-4-hydroxypyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-3-(1H-pyrazol-5-yl)benzamide

HRID 525751Notes

Reaction equation

HRID 525751 reaction equation
O1CCCCC1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.[NH2:21][C@@H:22]1[C@@H:26]([OH:27])[CH2:25][N:24]([C:28]2[CH:47]=[CH:46][C:31]([C:32]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]([Cl:45])([F:44])[F:43])=[CH:37][CH:36]=3)=[O:33])=[CH:30][C:29]=2Br)[CH2:23]1.C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O>COCCOC>[NH2:21][C@@H:22]1[C@@H:26]([OH:27])[CH2:25][N:24]([C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:34][C:35]3[CH:36]=[CH:37][C:38]([O:41][C:42]([Cl:45])([F:43])[F:44])=[CH:39][CH:40]=3)=[O:33])=[CH:46][C:47]=2[C:11]2[NH:7][N:8]=[CH:9][CH:10]=2)[CH2:23]1

Participants

6

Reactant 4

HCID 6422Trifluoroacetic acidHCID 10340Sodium CarbonateHCID 115872081-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 899064294-((3 S,4S)-3-amino-4-hydroxypyrrolidin-1-yl)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)benzamide

Product 1

HCID 1180450264-((3S,4S)-3-Amino-4-hydroxypyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-3-(1H-pyrazol-5-yl)benzamide

Reagents, catalysts & solvents 1

HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
80 °C

Procedure

1-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (82 mg, 0.288 mmol) and PdCl2(dppf)-(CH2Cl2) (10.07 mg, 12 μmol) were added to a mixture of 4-((3S,4S)-3-amino-4-hydroxypyrrolidin-1-yl)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)benzamide (Stage 76.1, 100 mg, 0.206 mmol), Na2CO3 (0.308 mL, 0.617 mmol) in DME (2 mL) under argon atmosphere and the RM was heated at 80° C. for 4 h. 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, DCM/EtOH from 98:2 to 8:2). The resulting intermediate was dissolved in DCM (2 mL), treated with TFA (0.198 mL, 2.57 mmol) and the RM was stirred for RT for 3 h. The solvent was evaporated off under reduced pressure and the residue was treated with sat. aq. Na2CO3, and extracted with EtOAc. The combined extracts were washed with brine (20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 12 g, DCM/MeOH from 95:5 to 7:3) and crystallized from n-hexane/DCM to give the title product as a beige solid. HPLC (Condition 7) tR=5.774 min, UPLC-MS (Condition 3) tR=0.77 min, m/z=464.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.73-2.99 (m, 2H) 3.22-3.44 (m, 3H) 3.93-4.04 (m, 1H) 5.33 (br. s, 1H) 6.39 (s, 1H) 6.74-6.94 (m, 1H) 7.31 (d, J=8.60 Hz, 2H) 7.76-8.03 (m, 4H) 10.17 (br. s, 1H).

Workup

  1. filtrationThe RM was filtered through Hyflo®
  2. customthe solvent was evaporated off under reduced pressure
  3. customto give a residue which
  4. customwas purified by flash chromatography (Silica gel column, 12 g, DCM/EtOH from 98:2 to 8:2)
  5. dissolutionThe resulting intermediate was dissolved in DCM (2 mL)
  6. customThe solvent was evaporated off under reduced pressure
  7. additionthe residue was treated with sat. aq. Na2CO3
  8. extractionextracted with EtOAc
  9. washThe combined extracts were washed with brine (20 mL)
  10. dry with materialdried over Na2SO4
  11. customthe solvent was evaporated off under reduced pressure
  12. customto give the crude product which
  13. customwas purified by flash chromatography (Silica gel column, 12 g, DCM/MeOH from 95:5 to 7:3)
  14. customcrystallized from n-hexane/DCM

Sources & evidence

ORD record
ord-9ebbe338fe2b4dfc930b970df00bb44f
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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