Potassium Carbonate → 3-Cyclopropyl-6-{[4-(cyclopropylsulfonyl)phenyl](2,4-difluorophenoxy)methyl}-2-[(4-methoxybenzyl)oxy]pyridine

HRID 70716Notes

Reaction equation

HRID 70716 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(P(CCCC)CCCC)CCC.[CH:23]1([C:26]2[CH:27]=[CH:28][C:29]([CH:42]([C:44]3[CH:49]=[CH:48][C:47]([S:50]([CH:53]4[CH2:55][CH2:54]4)(=[O:52])=[O:51])=[CH:46][CH:45]=3)O)=[N:30][C:31]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH:23]1([C:26]2[C:31]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)=[N:30][C:29]([CH:42]([C:44]3[CH:45]=[CH:46][C:47]([S:50]([CH:53]4[CH2:54][CH2:55]4)(=[O:52])=[O:51])=[CH:48][CH:49]=3)[O:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 13831TributylphosphineHCID 1230512,4-DifluorophenolHCID 67400026{5-Cyclopropyl-6-[(4-methoxybenzyl)oxy]pyridin-2-yl}[4-(cyclopropylsulfonyl)phenyl]methanol

Product 1

HCID 673995783-Cyclopropyl-6-{[4-(cyclopropylsulfonyl)phenyl](2,4-difluorophenoxy)methyl}-2-[(4-methoxybenzyl)oxy]pyridineYield 77.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
86 °C

Procedure

2,4-Difluorophenol (219 mg), tributylphosphine (340 mg) and N,N,N′,N′-tetramethylazodicarboxyamide (289 mg) were sequentially added to a solution of {5-cyclopropyl-6-[(4-methoxybenzyl)oxy]pyridin-2-yl}[4-(cyclopropylsulfonyl)phenyl]methanol (390 mg) in tetrahydrofuran (12 mL). After replacement with nitrogen, the mixture was stirred under reflux at an external temperature of 86° C. for six hours, returned to room temperature and stirred overnight. The reaction solution was poured into water and a potassium carbonate solution was added, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=92:8→34:66) to give 3-cyclopropyl-6-{[4-(cyclopropylsulfonyl)phenyl](2,4-difluorophenoxy)methyl}-2-[(4-methoxybenzyl)oxy]pyridine as a yellow gum (373 mg, 77%).

Workup

  1. customreturned to room temperature
  2. stirringstirred overnight
  3. extractionfollowed by extraction with chloroform
  4. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  5. filtrationfiltered
  6. concentrationThe filtrate was concentrated under reduced pressure
  7. customThe resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=92:8→34:66)

Sources & evidence

ORD record
ord-76b163f3a3e44ff6913f39b830daeb8f
Source dataset
uspto-grants-2014_09
Patent number
US08822503B2

Reaction notes

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