Diisopropylethylamine → Racemic 3-{(E)-2-[5-(tetrahydropyran-4-yloxy)pyridin-3-yl]vinyl}pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 472777Notes

Reaction equation

HRID 472777 reaction equation
[Cl-].[Li+].C(N(C(C)C)C(C)C)C.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([O:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:18]=1.[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH:35]([CH:38]=[CH2:39])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:26]([O:30][C:31]([N:33]1[CH2:37][CH2:36][CH:35](/[CH:38]=[CH:39]/[C:13]2[CH:14]=[N:15][CH:16]=[C:17]([O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:18]=2)[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 433294Lithium ChlorideHCID 219640263-Bromo-5-((tetrahydro-2H-pyran-4-yl)oxy)pyridineHCID 53302213tert-Butyl 3-ethenylpyrrolidine-1-carboxylate

Product 1

HCID 66883192Racemic 3-{(E)-2-[5-(tetrahydropyran-4-yloxy)pyridin-3-yl]vinyl}pyrrolidine-1-carboxylic acid tert-butyl esterYield 72.3%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
110 °C

Procedure

Palladium acetate (0.117 g, 0.52 mmol), 0.678 g (16 mmol) of lithium chloride and 7.25 cm3 (42 mmol) of ethyldiisopropylamine were added in succession to a solution under argon of 1.33 g (5.17 mmol) of 3-bromo-5-(tetrahydropyran-4-yloxy)pyridine and 1.2 g (5.17 mmol) of racemic 3-vinylpyrrolidine-1-carboxylic acid tert-butyl ester in 15 cm3 of dimethylformamide. After 3 hours of heating at 110° C. with stirring, the reaction mixture was stirred for 2 hours at a temperature in the region of 22° C. and then concentrated to dryness under reduced pressure (2.7 kPa). The oily residue was taken up in 50 cm3 of ethyl acetate and the resulting solution was washed in succession with 2 times 25 cm3 of water, 25 cm3 of saturated bicarbonate solution, 2 times 25 cm3 of water and 25 cm3 of saturated sodium chlorine solution and then was dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.4 g of brown oil. This residue was purified by chromatography on silica gel [eluent: cyclohexane/ethyl acetate (8/2 by volume)]. Concentration of the fractions under reduced pressure (2.7 kPa) gave 0.44 g of yellow oil which was used without further purification in the remainder of the synthesis.

Workup

  1. stirringthe reaction mixture was stirred for 2 hours at a temperature in the region of 22° C.
  2. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)
  3. washthe resulting solution was washed in succession with 2 times 25 cm3 of water, 25 cm3 of saturated bicarbonate solution, 2 times 25 cm3 of water and 25 cm3 of saturated sodium chlorine solution
  4. dry with materialwas dried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)

Sources & evidence

ORD record
ord-4173fe14480f4d73bbcf3d671daeb8fa
Source dataset
uspto-grants-2014_01
Patent number
US08633222B2

Reaction notes

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