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Potassium Carbonate → 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

HRID 1011718
Notes
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Reaction equation

HRID 1011718 reaction equation
[F:1][CH:2]([F:24])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([OH:23])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12])[CH3:6].[N:25]1([C:29]([C:31]2[CH:32]=[C:33]([Cl:38])[C:34](Cl)=[N:35][CH:36]=2)=[O:30])[CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:25]1([C:29]([C:31]2[CH:32]=[C:33]([Cl:38])[C:34]([O:23][C:21]3[CH:20]=[C:10]([CH:9]=[C:8]([O:7][C@@H:5]([CH3:6])[CH2:4][O:3][CH:2]([F:1])[F:24])[CH:22]=3)[C:11]([NH:13][C:14]3[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=3)=[O:12])=[N:35][CH:36]=2)=[O:30])[CH2:28][CH2:27][CH2:26]1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 536296165-(Azetidin-1-ylcarbonyl)-2,3-dichloropyridineHCID 591271223-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-hydroxy-N-(1-methylpyrazol-3-yl)benzamide

Product 1

HCID 160396463-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamideYield 53.6%

Reagents, catalysts & solvents

1
HCID 6342AcetonitrileSolvent

Conditions

Temperature
160 °C

Procedure

A mixture of 3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (110 mg, 0.32 mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (75 mg, 0.32 mmol) and potassium carbonate (89 mg, 0.64 mmol) in acetonitrile (5 mL) was stirred in a ‘Biotage initiator Microwave’ at 160° C. for 3 hours. The solvent was removed in vacuo and ethyl acetate (50 mL) added to the residue which was washed with water (20 mL), brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow oil. The residue was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (92 mg). 1H NMR δ (CDCl3): 1.40 (d, 3H), 2.41 (quin, 2H), 3.81 (s, 3H), 4.01 (mult, 2H), 4.26 (t, 2H), 4.38 (t, 2H), 4.67 (sextet, 1H), 6.29 (t, 1H), 6.82 (d, 1H), 6.96 (t, 1H), 7.27 (t, 1H), 7.31 (d, 1H), 7.38 (t, 1H), 8.18 (d, 1H), 8.26 (d, 1H), 8.77 (s, 1H), m/z 536 (M+H)+

Workup

  1. customThe solvent was removed in vacuo and ethyl acetate (50 mL)
  2. additionadded to the residue which
  3. washwas washed with water (20 mL), brine (50 mL)
  4. dry with materialdried (MgSO4)
  5. filtrationfiltered
  6. customthe solvent removed in vacuo
  7. customto give a yellow oil
  8. customThe residue was chromatographed on silica
  9. washeluting with a gradient of 50-100% ethyl acetate in isohexane

Sources & evidence

ORD record
ord-385ec12a537e4ce793c3b9732b106ad9
Source dataset
uspto-grants-2011_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07977328B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes