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Trifluoroacetic acid → 6-(3-Hydroxyazetidin-1-yl)-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 525697
Notes
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Reaction equation

HRID 525697 reaction equation
O1CCCCC1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:30]1[C:31]([N:50]2[CH2:53][CH:52]([OH:54])[CH2:51]2)=[N:32][CH:33]=[C:34]([CH:49]=1)[C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=1)=[O:36].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:54][CH:52]1[CH2:53][N:50]([C:31]2[C:30]([C:11]3[NH:7][N:8]=[CH:9][CH:10]=3)=[CH:49][C:34]([C:35]([NH:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:42][CH:43]=3)=[O:36])=[CH:33][N:32]=2)[CH2:51]1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 5

HCID 6422Trifluoroacetic acidHCID 10340Sodium CarbonateHCID 62657Potassium Phosphate, TribasicHCID 115872081-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 899062825-bromo-6-(3-hydroxyazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 118044918
6-(3-Hydroxyazetidin-1-yl)-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
110 °C

Procedure

1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (209 mg, 0.752 mmol), K3PO4 (368 mg, 1.735 mmol) and Pd(PPh3)4 (33.4 mg, 0.029 mmol) were added to a mixture of 5-bromo-6-(3-hydroxyazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 37.1, 250 mg, 0.578 mmol) in toluene (2.5 mL) in a vial, which was sealed, purged with argon and the RM was stirred at 110° C. for 3 h. The cooled mixture was treated with brine (25 mL) and extracted with EtOAc. The combined extracts were washed with brine (25 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The residue (100 mg, 0.199 mmol) was dissolved in DCM (0.5 mL), treated with TFA (0.3 mL, 3.89 mmol) and stirred at RT for 8 h. Aq. Na2CO3 (0.5 mL) was added and the solvent was evaporated off under reduced pressure to give a crude product which was purified by SFC (Column NH2, from 21% to 26% over 6 min) and lyophilized in water/MeCN to give the title product. UPLC-MS (Condition 3) tR=0.86 min, m/z=420.2 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 3.53-3.59 (m, 2H) 3.91-4.00 (m, 2H) 4.35-4.42 (m, 1H) 6.43 (d, J=1.88 Hz, 1H) 7.35 (d, J=8.66 Hz, 2H) 7.79 (br. s, 1H) 7.86 (d, J=9.03 Hz, 2H) 8.09 (d, J=2.07 Hz, 1H) 8.71 (d, J=2.07 Hz, 1H) 10.26 (s, 1H).

Workup

  1. customwas sealed
  2. custompurged with argon
  3. additionThe cooled mixture was treated with brine (25 mL)
  4. extractionextracted with EtOAc
  5. washThe combined extracts were washed with brine (25 mL)
  6. dry with materialdried over Na2SO4
  7. customthe solvent was evaporated off under reduced pressure
  8. stirringstirred at RT for 8 h
  9. customthe solvent was evaporated off under reduced pressure
  10. customto give a crude product which
  11. customwas purified by SFC (Column NH2, from 21% to 26% over 6 min)

Sources & evidence

ORD record
ord-9f192665862f484c845add79a9d5068e
Source dataset
uspto-grants-2016_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09340537B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes