Water → N-((1r,2s,5r)-5-(isopropyl(methyl)amino)-2-((s)-2-oxo-3-((6-(trifluoromethyl)quinazolin-4-yl)amino)pyrrolidin-1-yl)cyclohexyl)acetamide

HRID 2242318Notes

Reaction equation

HRID 2242318 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[NH:18][C:19](=[O:21])[CH3:20])[C:3]1=[O:22].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.C(N(CC)CC)C.O.[OH-].[Na+]>C(O)(C)C.ClCCl>[CH:15]([N:13]([CH3:14])[C@H:10]1[CH2:9][C@@H:8]([NH:18][C:19](=[O:21])[CH3:20])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:36])([F:37])[F:35])[CH:32]=4)[N:27]=[CH:26][N:25]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:17])[CH3:16]

Participants

8

Reactant 5

HCID 962WaterHCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 210750954-Chloro-6-(trifluoromethyl)quinazolineHCID 44185161N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexyl)acetamide

Product 1

HCID 23725177N-((1r,2s,5r)-5-(isopropyl(methyl)amino)-2-((s)-2-oxo-3-((6-(trifluoromethyl)quinazolin-4-yl)amino)pyrrolidin-1-yl)cyclohexyl)acetamideYield 99%

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexyl)acetamide (˜35 g, 0.115 mol) in isopropanol (600 mL) was added 4-chloro-6-(trifluoromethyl)quinazoline (32 g, 0.138 mol, 1.2 eq, see: P. H. Carter et al., PCT application WO 2005/021500). The mixture was stirred at room temperature overnight before being charged with triethylamine (46 g, 0.46 mol, 4 eq). The mixture was stirred at 60° C. for 10 h. The solvent was removed under reduced pressure to give an oil. Azeotropic distillation with isopropanol was performed twice. The residue was dissolved in dichloromethane (600 mL) and extracted with water (250 mL, containing 4 eq acetic acid). Dichloromethane (600 mL) was added to the combined aqueous washes, and the mixture was cooled to 0° C. Aqueous NaOH (50% by weight) was added with stirring until the pH reached 11. The water layer was extracted with dichloromethane twice (2×600 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give the amorphous free base of the title compound (99% purity by HPLC). LC/MS found [M+H]+=507.3. 1H-NMR (400 MHz, d4-MeOH): δ 8.82 (s, 1H), 8.59 (s, 1H), 8.05 (dd, J=8.8, 1.8 Hz, 1H), 7.9 (d, J=8.7 Hz, 1H), 5.28 (t, J=8.6 Hz, 1H), 4.58 (br s, 1H), 4.06 (m, 1H), 3.52-3.68 (m, 2H), 3.43 (m, 1H), 2.76 (br s, 1H), 2.55 (m, 1H), 2.28 (s, 3H), 2.1-2.3 (m, 3H), 2.0 (s, 3H), 2.0 (m, 1H), 1.65-1.8 (m, 3H), 1.09 (app. dd, J=24, 6.4 Hz, 6 H).

Workup

  1. stirringThe mixture was stirred at 60° C. for 10 h
  2. customThe solvent was removed under reduced pressure
  3. customto give an oil
  4. distillationAzeotropic distillation with isopropanol
  5. dissolutionThe residue was dissolved in dichloromethane (600 mL)
  6. temperaturethe mixture was cooled to 0° C
  7. stirringwith stirring until the pH
  8. extractionThe water layer was extracted with dichloromethane twice (2×600 mL)
  9. dry with materialThe combined organic extracts were dried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-c91c11ccb9f540dc9536e894070f53c2
Source dataset
uspto-grants-2010_03
Patent number
US07671062B2

Reaction notes

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