Tetrahydrofuran → N-({[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]-isobutyl-carbamoyl}-methyl)-N-cyano-2-phenyl-acetamide

HRID 1814738Notes

Reaction equation

HRID 1814738 reaction equation
[C:1]([NH:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:2].C1COCC1.Br[CH2:19][C:20]([N:22]([CH2:27][C:28]([N:30]1[CH2:39][CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31]1)=[O:29])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21]>CN(C=O)C.CC(C)([O-])C.[K+]>[CH2:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:38][CH2:39][N:30]1[C:28](=[O:29])[CH2:27][N:22]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:20]([CH2:19][N:3]([C:1]#[N:2])[C:4](=[O:12])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:21]

Participants

6

Reactant 3

HCID 8028TetrahydrofuranHCID 14174697HCID 14174697, compoundHCID 224987912-bromo-N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]-N-isobutyl-acetamide

Product 1

HCID 10388880N-({[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]-isobutyl-carbamoyl}-methyl)-N-cyano-2-phenyl-acetamideYield 12.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 23665647Potassium tert-butoxideSolvent

Conditions

Temperature
0 °C

Procedure

To a stirred solution of N-cyano-2-phenyl-acetamide (0.15 g, 0.9 mmol) (see Example 1) in DMF (5.0 mL), potassium tert-butoxide (0.9 mL of a 1.0 M THF solution, 0.9 mmol) was added dropwise at 0° C., under argon. The resulting mixture was stirred at 0° C. for 20 min, then at ambient temperature for 15 min. After this time, the resulting anion was added dropwise to a stirred solution of the 2-bromo-N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]-N-isobutyl-acetamide (0.34 g, 0.9 mmol) from above in DMF (5.0 mL) at room temperature, under argon. Upon complete addition, the reaction was stirred at room temperature for 1.5 h, then warmed to 40° C. for 6 h. The reaction was cooled to room temperature and stirred for 48 h after which time it was concentrated to dryness. The resulting residue was dissolved in EtOAc and washed with 5% citric acid (aqueous). The layers were separated and the aqueous phase was extracted with EtOAc (2×). The combined organics were dried (MgSO4), filtered and concentrated to give the crude product which was purified via reverse phase HPLC (C18 column, 20-100% CH3CN/H2O over 20 min at a flow rate of 20 mL/min, UV detection was at 220 nm). Retention time of the product was 16 min. Product-containing fractions were concentrated to give 49 mg (12%) of the title compound.

Workup

  1. waitat ambient temperature for 15 min
  2. additionUpon complete addition
  3. stirringthe reaction was stirred at room temperature for 1.5 h
  4. temperaturewarmed to 40° C. for 6 h
  5. temperatureThe reaction was cooled to room temperature
  6. stirringstirred for 48 h after which time it
  7. concentrationwas concentrated to dryness
  8. dissolutionThe resulting residue was dissolved in EtOAc
  9. washwashed with 5% citric acid (aqueous)
  10. customThe layers were separated
  11. extractionthe aqueous phase was extracted with EtOAc (2×)
  12. dry with materialThe combined organics were dried (MgSO4)
  13. filtrationfiltered
  14. concentrationconcentrated
  15. customto give the crude product which
  16. customwas purified via reverse phase HPLC (C18 column, 20-100% CH3CN/H2O over 20 min at a flow rate of 20 mL/min, UV detection
  17. waitRetention time of the product was 16 min
  18. concentrationProduct-containing fractions were concentrated

Sources & evidence

ORD record
ord-ef55a7b8ff13435d96c96ce3054d158c
Source dataset
uspto-grants-2005_04
Patent number
US06878706B1

Reaction notes

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