Methyl iodide → Tert-butyl {1-[5-chloro-2-methoxy-4-methyl-3-(1-methyl-5-oxopyrrolidin-3-yl)phenyl]ethyl}carbamate

HRID 511019Notes

Reaction equation

HRID 511019 reaction equation
[Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH:20]2[CH2:24][C:23](=[O:25])[NH:22][CH2:21]2)[C:5]([O:18][CH3:19])=[C:6]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:7]=1.[H-].[Na+].[CH3:29]I>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH:20]2[CH2:24][C:23](=[O:25])[N:22]([CH3:29])[CH2:21]2)[C:5]([O:18][CH3:19])=[C:6]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])[CH3:9])[CH:7]=1

Participants

5

Reactant 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 86666939Tert-butyl {1-[5-chloro-2-methoxy-4-methyl-3-(5-oxopyrrolidin-3-yl)phenyl]ethyl}carbamate

Product 1

HCID 86666940Tert-butyl {1-[5-chloro-2-methoxy-4-methyl-3-(1-methyl-5-oxopyrrolidin-3-yl)phenyl]ethyl}carbamate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
60 °C

Procedure

Solutions of the individual diastereoisomers of tert-butyl {1-[5-chloro-2-methoxy-4-methyl-3-(5-oxopyrrolidin-3-yl)phenyl]ethyl}carbamate (0.31 g, 0.80 mmol [peak 1 from Examples 192, step 3]; 0.31 g, 0.80 mmol [peak 2 from Examples 192, step 3]) in DMF (4 mL) at 0° C. were each treated individually with sodium hydride dispersed in mineral oil (80 mg, 2.0 mmol). The ice bath was removed and the reaction mixtures were stirred for 30 min and heated at 60° C. for 30 minutes. The reaction mixtures were cooled down to 0° C., treated with methyl iodide (0.060 mL, 0.96 mmol) in DMF (2 mL, 26 mmol), and stirred at room temperature for 16 hours. The reaction mixtures were cooled to 0° C., quenched with saturated ammonium chloride, and extracted with EtOAc. The organic extract was concentrated to give a crude oil which was purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give diastereoisomer from peak 1 (28 mg, 9%, retention time: 2.52 min) and diastereoisomer from peak 2 (56 mg, 18%, retention time: 2.51 min). Peak 1: LCMS for C20H29ClN2O4Na (M+Na)+: m/z=419.2. Found: 419.1. Peak 2: LCMS for C20H29ClN2O4Na (M+Na)+: m/z=419.2. Found: 419.1.

Workup

  1. customat 0° C.
  2. customThe ice bath was removed
  3. customthe reaction mixtures
  4. customThe reaction mixtures
  5. temperaturewere cooled down to 0° C.
  6. stirringstirred at room temperature for 16 hours
  7. customThe reaction mixtures
  8. temperaturewere cooled to 0° C.
  9. customquenched with saturated ammonium chloride
  10. extractionextracted with EtOAc
  11. extractionThe organic extract
  12. concentrationwas concentrated
  13. customto give a crude oil which
  14. customwas purified by preparative LCMS (XBridge C18 column
  15. washeluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min)
  16. customto give diastereoisomer from peak 1 (28 mg, 9%, retention time: 2.52 min) and diastereoisomer from peak 2 (56 mg, 18%, retention time: 2.51 min)

Sources & evidence

ORD record
ord-71ea921e266f44a7be40d2e047bdb9fb
Source dataset
uspto-grants-2015_08
Patent number
US09096600B2

Reaction notes

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