Cesium carbonate → 6-Cyclopropylmethoxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

HRID 927779Notes

Reaction equation

HRID 927779 reaction equation
[CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[NH:32]1[CH2:35][CH:34]([OH:36])[CH2:33]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:32]2[CH2:35][CH:34]([OH:36])[CH2:33]2)=[C:15]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3]

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 27592903-Hydroxyazetidine hydrochlorideHCID 710935455-Bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide

Product 1

HCID 710936646-Cyclopropylmethoxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amideYield 54.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

5-Bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (150 mg, 380 μmol) was dissolved in toluene (6.0 mL) to give a colorless solution. This solution was degassed under an Argon stream for 5 minutes. Cesium carbonate (371 mg, 1.14 mmol), Pd2(dba)3CHCl3 (39.3 mg, 38.0 μmol), [rac]-BINAP (47.3 mg, 75.9 μmol) and 3-azetidinol hydrochloride (1:1) (CAN 18621-18-6; 49.9 mg, 455 μmol) were added and the mixture was heated for 18 hours in a microwave oven to 100° C. After cooling to room temperature the mixture was diluted with ethyl acetate (5 mL) and water (3 mL), filtered through Celite® and the filter pad was washed with water (10 mL) and ethyl acetate (30 mL). Phases were separated and the aqueous phase was extracted with ethyl acetate (20 mL). Organic phases were combined, dried with Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel. 20 g, 0% to 100% ethyl acetate in heptane) to give the title compound (80 mg, 54%) as yellow solid; NMR complies.

Workup

  1. customto give a colorless solution
  2. customThis solution was degassed under an Argon stream for 5 minutes
  3. temperatureAfter cooling to room temperature the mixture
  4. filtrationfiltered through Celite®
  5. washthe filter pad was washed with water (10 mL) and ethyl acetate (30 mL)
  6. customPhases were separated
  7. extractionthe aqueous phase was extracted with ethyl acetate (20 mL)
  8. dry with materialdried with Na2SO4
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by flash chromatography (silica gel. 20 g, 0% to 100% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-360df197a05a473c948d7eee29e90b4b
Source dataset
uspto-grants-2016_03
Patent number
US09290451B2

Reaction notes

Loading…