Potassium Phosphate, Tribasic → 2,6-Difluoro-3-[4-(4-methoxy-phenyl)-5-pyridin-4-yl-thiazol-2-ylmethoxy]-benzamide

HRID 538516Notes

Reaction equation

HRID 538516 reaction equation
Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:19][C:10]1[C:9]([O:8][CH2:7][C:5]2[S:6][C:2]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)=[C:3]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:4]=2)=[CH:17][CH:16]=[C:15]([F:18])[C:11]=1[C:12]([NH2:14])=[O:13]

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 2734379(Pyridin-4-yl)boronic acidHCID 594026583-[5-Bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide

Product 1

HCID 594028852,6-Difluoro-3-[4-(4-methoxy-phenyl)-5-pyridin-4-yl-thiazol-2-ylmethoxy]-benzamideYield 49%

Reagents, catalysts & solvents 2

HCID 21584511triphenylphosphine palladium (II)CatalystHCID 21962138N,N-Dimethylformamide--water (1/1)Solvent

Conditions

Temperature
120 °C

Procedure

To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.2 g, 0.43 mmol) in 5 ml of anhydrous DMF:H2O (2:1) 4-pyridine boronic acid (0.108 g, 0.87 mmol), potassium phosphate (0.112 g, 0.51 mmol) was added. Then degassed the reaction mixture for the 10 minutes, and added dichlorobis [(triphenylphosphine)-palladium (II) (0.046 g, 0.06 mmol) and again degassed for 10 min. The reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. DMF was distilled off, after cooling to r.t. water was added into reaction mixture and extracted with ethyl acetate, The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by chromatography on silica (230-400μ) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.045 g, 49%). 1H NMR (DMSO-d6, 400 MHz): δ 3.80 (s, 3H), 5.59 (s, 2H), 6.94 (d, 2H, J=8.8 Hz (o-coupling), 7.14 (dt, 1H), 7.34 (d, 1H, J=6.0 Hz (o-coupling), 7.38 (d, 2H, J=8.8 Hz (o-coupling), 7.41-7.45 (m, 1H), 7.89 (broad s, 1H), 8.17 (s, 1H), 8.60 (dd, 1H) MS ES+ (454.12), HPLC (method 5) Rt=13.55 min.

Workup

  1. customThen degassed the reaction mixture for the 10 minutes
  2. customagain degassed for 10 min
  3. distillationDMF was distilled off
  4. temperatureafter cooling to r.t. water
  5. additionwas added into reaction mixture
  6. extractionextracted with ethyl acetate
  7. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  8. customevaporated to dryness under reduced pressure
  9. customThe compound was purified by chromatography on silica (230-400μ)

Sources & evidence

ORD record
ord-7dba9d90efd84e3ca207234258b831c2
Source dataset
uspto-grants-2014_10
Patent number
US08865736B2

Reaction notes

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