Triethylamine → Bms-681

HRID 1374290Notes

Reaction equation

HRID 1374290 reaction equation
[NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][CH2:19][CH3:20])[C:3]1=[O:21].C(N(CC)CC)C.Cl[C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=2)[N:33]=[CH:32][N:31]=1>CCO.O.C(#N)C>[CH:15]([N:13]([CH3:14])[C@@H:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:42])([F:43])[F:41])[CH:38]=4)[N:33]=[CH:32][N:31]=3)[C:3]2=[O:21])[C@H:8]([CH2:18][CH2:19][CH3:20])[CH2:9]1)([CH3:16])[CH3:17]

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 210750954-Chloro-6-(trifluoromethyl)quinazolineHCID 68767742(S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)pyrrolidin-2-one

Product 1

HCID 68764898Bms-681

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 18373917Acetonitrile--water (1/1)Solvent

Conditions

Temperature
75 °C

Procedure

To a solution of (S)-3-amino-1-[(1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl]pyrrolidin-2-one (7.0 mmol) in EtOH (23 mL) was added triethylamine (2.5 mL, 17.5 mmol) and 4-chloro-6-(trifluoromethyl)quinazoline (2.03 g, 8.75 mmol). The mixture was heated at 75° C. for 14 h and then concentrated in vacuo. [Note: on smaller reaction scales, this residue could be diluted in water/acetonitrile, filtered, and purified directly by RP-HPLC.] The residue was dissolved in 60 mL of 2:1 H2O/AcOH and extracted with Et2O twice. The aqueous phase was basified to pH 14 with solid NaOH (the temperature of this exothermic process was controlled through the intermittent use of an external ice bath) and then extracted with EtOAc thrice. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give a solid. The material was recrystallized from EtOAc twice to provide the title compound, (S)-1-[(1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl]-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one, as a white microcrystalline solid (1.83 g, 52% yield). MS found: (M+H)+=492.4. [Note: Purification of the the mother liquors using RP-HPLC provided more of the title compound as its bis-TFA salt.]

Workup

  1. concentrationconcentrated in vacuo
  2. custom[Note: on smaller reaction scales
  3. filtrationfiltered
  4. custompurified directly by RP-HPLC
  5. dissolution] The residue was dissolved in 60 mL of 2:1 H2O/AcOH
  6. extractionextracted with Et2O twice
  7. customwas controlled through the intermittent use of an external ice bath
  8. extraction) and then extracted with EtOAc thrice
  9. washwashed with brine
  10. dry with materialdried (Na2SO4)
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customto give a solid
  14. customThe material was recrystallized from EtOAc twice

Sources & evidence

ORD record
ord-b1404fcca88f4a2389f8f1d4a372e9ac
Source dataset
uspto-grants-2007_01
Patent number
US07163937B2

Reaction notes

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