2-Cyclobutyloxy-4-methoxy-6-{1-[4-(morpholinecarbonyl)-1,4-diazepan-1-yl]ethylideneamino}benzonitrile → 4-Amino-5-cyclobutyloxy-7-methoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinoline

HRID 1004032Notes

Reaction equation

HRID 1004032 reaction equation
CC(C)([O-])C.[K+].[CH:7]1([O:11][C:12]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([N:22]=[C:23]([N:25]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:33])[CH2:27][CH2:26]3)[CH3:24])[C:13]=2[C:14]#[N:15])[CH2:10][CH2:9][CH2:8]1>COCCOC>[NH3:15].[NH2:15][C:14]1[C:13]2[C:16](=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=2[O:11][CH:7]2[CH2:8][CH2:9][CH2:10]2)[N:22]=[C:23]([N:25]2[CH2:31][CH2:30][CH2:29][N:28]([C:32]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[O:33])[CH2:27][CH2:26]2)[CH:24]=1

Participants

5

Reactant 2

HCID 177736272-Cyclobutyloxy-4-methoxy-6-{1-[4-(morpholinecarbonyl)-1,4-diazepan-1-yl]ethylideneamino}benzonitrileHCID 23665647Potassium tert-butoxide

Product 2

HCID 222AmmoniaHCID 184706234-Amino-5-cyclobutyloxy-7-methoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinolineYield 112.5%

Reagents, catalysts & solvents 1

HCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
90 °C

Procedure

Potassium tert-butoxide (810 mg, 0.00725 mol) was added to a solution of 2-cyclobutyloxy-4-methoxy-6-{1-[4-(morpholinecarbonyl)-1,4-diazepan-1-yl]ethylidene-amino}benzonitrile (1.65 g, 0.00363 mol) in 1,2-dimethoxyethane (250 ml) and the reaction stirred at 90° C. under a nitrogen atmosphere for 1 hour. On cooling, the reaction mixture was washed with 1N aqueous citric acid solution (100 ml) and extracted with ethyl acetate (100 ml). The aqueous layer was then basified with 2N aqueous sodium hydroxide solution and extracted with dichloromethane (2×100 ml). These combined organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with a solvent gradient of dichloromethane:methanol:0.880 aqueous ammonia (100:0:0 to 91:9:1 v/v) gave the title compound as a foam (0.93 g, 56%). Rf 0.27 (dichloromethane:methanol:0.880 aqueous ammonia, 97:2:1, v/v). MS m/z 456 (MH)+. 1H-NMR (CDCl3): δ=1.75 (1H, m), 1.92 (1H, m), 2.05 (2H, m), 2.24 (2H, m), 2.54 (2H, m), 3.14 (4H, t), 3.34 (2H, t), 3.57 (2H, t), 3.64 (4H, t), 3.70 (2H, t), 3.88 (3H, s), 3.94 (2H, bm), 4.62 (1H, m), 5.55 (2H, bs), 5.70 (1H, s) 5.96 (1H, s), 6.56 (1H, bs). Found: C, 60.87; H, 7.45; N, 14.79; C24H33N5O4H2O, requires C, 60.67; H, 7.08; N, 14.51%.

Workup

  1. temperatureOn cooling
  2. washthe reaction mixture was washed with 1N aqueous citric acid solution (100 ml)
  3. extractionextracted with ethyl acetate (100 ml)
  4. extractionextracted with dichloromethane (2×100 ml)
  5. dry with materialThese combined organic extracts were dried (MgSO4)
  6. filtrationfiltered
  7. customevaporated under reduced pressure
  8. customThe crude product was purified on silica gel eluting with a solvent gradient of dichloromethane

Sources & evidence

ORD record
ord-048b9015c5fc402a97cf4cf5743fbde2
Source dataset
uspto-grants-2000_04
Patent number
US06048864

Reaction notes

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