Diethyl Ether → HCID 19970250, compound

Two solutions containing the reactants were prepared separately as follows. To a stirred solution of N-carbobenzyloxyproline (D or L, 3.10 g, 12.4 mmol, 1 eq) or N-carbobenzyloxyazetidine-2-carboxylic acid (R or S or racemate, 12.4 mmol) or N-carbobenzyloxypipecolinic acid (R or S or racemate, 12.4 mmol) in anhydrous methylene chloride (7 mL) with one drop dimethylformamide was added oxalyl chloride (1.60 mL, 18.4 mmol, 1.5 eq), and the resulting effervescing solution was stirred at room temperature under nitrogen for 1.5 hours. The solution was then evaporated under reduced pressure, and any remaining solvent was removed from the residual oil using high vacuum to afford the N-benzyloxycarbonylproline acid chloride. At the same time, a solution of ethylmagnesium bromide (3.0M in ether, 4.13 mL, 12.4 mmol, 1 eq) was added to a stirred solution of the indole (12.4 mmol) in anhydrous ether (50 mL), and this cloudy solution was heated at reflux under nitrogen for 1.5 hours to form the indole magnesium bromide salt. The proline acid chloride was then dissolved in methylene chloride or ethyl ether (3 mL), and this solution was added dropwise to the stirred solution of the indole magnesium bromide salt at room temperature, and the resultant reaction mixture was stirred at room temperature under nitrogen for 1 hour. A saturated solution of sodium hydrogen carbonate (25 mL) and ethyl acetate (50 mL) was then added to the reaction mixture, and this mixture was vigorously stirred for 15 minutes. The resulting mixture was filtered through diatomaceous earth (Celite (trademark)), the solids washed with copious amounts of ethyl acetate, and the ethyl acetate layer was separated from the aqueous layer which was extracted with ethyl acetate (2×25 mL). All ethyl acetate extracts were combined, dried, and evaporated under reduced pressure. The residual oil/solid was flash chromatographed using silica gel (250 g) and eluted with an appropriate solvent system to afford the desired 3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)indole,3-(N-benzyloxycarbonylazetidin-2-ylcarbonyl)-1H-indole, or 3-(N-benzyloxycarbonylpiperidin-2-ylcarbonyl)-1H-indole.

1. customthe resultant reaction mixture
2. stirringthis mixture was vigorously stirred for 15 minutes
3. filtrationThe resulting mixture was filtered through diatomaceous earth (Celite (trademark))
4. washthe solids washed with copious amounts of ethyl acetate
5. customthe ethyl acetate layer was separated from the aqueous layer which
6. extractionwas extracted with ethyl acetate (2×25 mL)
7. customdried
8. customevaporated under reduced pressure
9. customchromatographed
10. washeluted with an appropriate solvent system

ORD record

ord-c5fbea250c4a4dadb2c10e341dc59519

Source dataset

uspto-grants-1996_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05559246