Cesium carbonate → 6-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid

HRID 624988Notes

Reaction equation

HRID 624988 reaction equation
[CH3:1][O:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:60]1[CH:61]=[CH:62][C:63]([C:71]([OH:73])=[O:72])=[N:64][C:65]=1[O:66][CH2:67][CH:68]1[CH2:70][CH2:69]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:68]1([CH2:67][O:66][C:65]2[N:64]=[C:63]([C:71]([OH:73])=[O:72])[CH:62]=[CH:61][C:60]=2[N:5]2[CH2:6][CH:3]([O:2][CH3:1])[CH2:4]2)[CH2:69][CH2:70]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 134019963-MethoxyazetidineHCID 710875435-Bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid

Product 1

HCID 902034536-(Cyclopropylmethoxy)-5-(3-methoxyazetidin-1-yl)picolinic acidYield 34%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

Under a nitrogen atmosphere, 3-methoxyazetidine (38 mg, 0.44 mmol), BINAP (23 mg, 0.037 mmol), Pd2(dba)3 (17 mg, 0.02 mmol) and Cs2CO3 (240 mg, 0.735 mmol) were added to a solution of 5-bromo-6-(cyclopropylmethoxy)pyridine-2-carboxylic acid (CAN 1415898-37-1, 100 mg, 0.37 mmol) in toluene (4 mL). The reaction mixture was stirred overnight at 110° C. and then concentrated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate (30 mL). The aqueous layer was adjusted to pH 2 by addition of 1N HCl. The resulting precipitate was collected by filtration and dried in vacuo. Chromatographical purification over silica gel using petroleum ether/ethyl acetate=1/2 provided the title compound (35 mg, 34%) as a yellow solid, LC-MS: 265.2 [MH+].

Workup

  1. concentrationconcentrated under reduced pressure
  2. dissolutionThe residue was dissolved in water
  3. extractionextracted with ethyl acetate (30 mL)
  4. additionThe aqueous layer was adjusted to pH 2 by addition of 1N HCl
  5. filtrationThe resulting precipitate was collected by filtration
  6. customdried in vacuo
  7. customChromatographical purification over silica gel

Sources & evidence

ORD record
ord-88c61143877140a5ac515560f069e2c0
Source dataset
uspto-grants-2016_04
Patent number
US09303012B2

Reaction notes

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