Cesium carbonate → 6-Cyclopropylmethoxy-5-(2-methyl-pyrrolidin-1-yl)-pyridine-2-carboxylic acid

HRID 632010

Reaction equation

HRID 632010 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH3:16][CH:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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:10]1([CH2:9][O:8][C:7]2[N:6]=[C:5]([C:13]([OH:15])=[O:14])[CH:4]=[CH:3][C:2]=2[N:18]2[CH2:19][CH2:20][CH2:21][CH:17]2[CH3:16])[CH2:12][CH2:11]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 130032-MethylpyrrolidineHCID 634876Binap, (A+-)-HCID 710875435-Bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid

Product 1

HCID 710879326-Cyclopropylmethoxy-5-(2-methyl-pyrrolidin-1-yl)-pyridine-2-carboxylic acidYield 36.9%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

Under an atmosphere of nitrogen, a solution of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (Example 9 d, 0.4 g, 1.5 mmol), 2-methylpyrrolidine (CAN 765-38-8, 188 mg, 2.2 mmol), R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (CAN 76189-55-4, 183 mg, 0.3 mmol), tris-(dibenzylidene-acetone)dipalladium (CAN 51364-51-3, 135 mg, 0.15 mmol) and cesium carbonate (1.9 g, 6 mmol) in toluene (50 mL) was heated to 90° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (10 mL) and extracted with ethyl acetate (30 mL), the pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid and the resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 10 g, 50% ethyl acetate in petroleum ether) to yield the title compound (0.15 g, 36.9%) as yellow solid; MS (EI): m/e=277.2 [M+H]+.

Workup

  1. customwas heated to 90° C. overnight
  2. concentrationThe reaction mixture was concentrated under reduced pressure
  3. dissolutionThe residue was dissolved in water (10 mL)
  4. extractionextracted with ethyl acetate (30 mL)
  5. additionthe pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid
  6. extractionthe resulting mixture was extracted with ethyl acetate (3×30 mL)
  7. washThe combined organic extracts were washed with water and brine
  8. dry with materialdried over sodium sulfate
  9. customevaporated
  10. customThe residue was purified by column chromatography (silica gel, 10 g, 50% ethyl acetate in petroleum ether)

Sources & evidence

ORD record
ord-ffe41ccebcac497db6f9346aec012aac
Source dataset
uspto-grants-2016_04
Patent number
US09321727B2

Linked notes

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