Potassium Carbonate → 4-[(6-tert-Butoxy-5-chloropyridin-3-yl)methy]-2,5-difluoro-N-(methylsulfonyl)benzamide

HRID 2048026Notes

Reaction equation

HRID 2048026 reaction equation
Br[CH2:2][C:3]1[C:15]([F:16])=[CH:14][C:6]([C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8])=[C:5]([F:17])[CH:4]=1.[C:18]([O:22][C:23]1[C:28]([Cl:29])=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1)([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>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.O1CCCC1>[C:18]([O:22][C:23]1[N:24]=[CH:25][C:26]([CH2:2][C:3]2[C:15]([F:16])=[CH:14][C:6]([C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8])=[C:5]([F:17])[CH:4]=2)=[CH:27][C:28]=1[Cl:29])([CH3:21])([CH3:19])[CH3:20]

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 666666512-Tert-butoxy-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-YL)pyridineHCID 666671114-(Bromomethyl)-2,5-difluoro-N-(methylsulfonyl)benzamide

Product 1

HCID 580425034-[(6-tert-Butoxy-5-chloropyridin-3-yl)methy]-2,5-difluoro-N-(methylsulfonyl)benzamideYield 23.1%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Procedure

4-(Bromomethyl)-2,5-difluoro-N-(methylsulfonyl)benzamide (Preparation 245, 70 mg, 0.21 mmol), 2-tert-butoxy-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 118, 72.9 mg, 0.234 mmol), tetrakistriphenylphosphinepalladium (24.3 mg, 0.021 mmol), aqueous potassium carbonate solution (1.8 M, 0.35 mL, 0.639 mmol) and tetrahydrofuran (15 mL) were combined and stirred under nitrogen at reflux for 5 hours. After cooling, the mixture was filtered through Celite™ and the filtrate evaporated. The residue was dissolved in water (20 mL) and acidified with aqueous potassium hydrogen sulphate solution (0.5 M) to pH 2 and the mixture extracted with ethyl acetate (30 mL). The organic layer was separated and washed with brine (3×20 mL), dried over sodium sulphate, filtered and evaporated to give an oil. The oil was purified using silica gel column chromatography eluting with heptane to ethyl acetate:heptane 1:1 to give a solid. The solid was further purified by reverse phase HPLC to give the title compound (21 mg, 23%) as a white solid.

Workup

  1. temperatureat reflux for 5 hours
  2. temperatureAfter cooling
  3. filtrationthe mixture was filtered through Celite™
  4. customthe filtrate evaporated
  5. dissolutionThe residue was dissolved in water (20 mL)
  6. extractionthe mixture extracted with ethyl acetate (30 mL)
  7. customThe organic layer was separated
  8. washwashed with brine (3×20 mL)
  9. dry with materialdried over sodium sulphate
  10. filtrationfiltered
  11. customevaporated
  12. customto give an oil
  13. customThe oil was purified
  14. washeluting with heptane to ethyl acetate:heptane 1:1
  15. customto give a solid
  16. customThe solid was further purified by reverse phase HPLC

Sources & evidence

ORD record
ord-3410ebda5f3b4bcda94db0c399689d5f
Source dataset
uspto-grants-2013_11
Patent number
US08592629B2

Reaction notes

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