Citric Acid → 4-Amino-5-cyclobutyloxy-6,7-dimethoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinoline

HRID 1004023Notes

Reaction equation

HRID 1004023 reaction equation
C([N-:4]C(C)C)(C)C.[Li+].[CH:9]1([O:13][C:14]2[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[C:18]([N:26]=[C:27]([N:29]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[O:37])[CH2:31][CH2:30]3)[CH3:28])[C:15]=2[C:16]#[N:17])[CH2:12][CH2:11][CH2:10]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[NH3:4].[NH2:17][C:16]1[C:15]2[C:18](=[CH:19][C:20]([O:24][CH3:25])=[C:21]([O:22][CH3:23])[C:14]=2[O:13][CH:9]2[CH2:10][CH2:11][CH2:12]2)[N:26]=[C:27]([N:29]2[CH2:35][CH2:34][CH2:33][N:32]([C:36]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:37])[CH2:31][CH2:30]2)[CH:28]=1

Participants

6

Reactant 3

HCID 311Citric AcidHCID 2724682Lithium diisopropylamideHCID 177736302-Cyclobutyloxy-3,4-dimethoxy-6-{1-[4-(morpholinecarbonyl)-1,4-diazepan-1-yl]ethylideneamino}benzonitrile

Product 2

HCID 222AmmoniaHCID 187941994-Amino-5-cyclobutyloxy-6,7-dimethoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1-yl]quinolineYield 67%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of lithium diisopropylamide in tetrahydrofuran (10 ml, 0.5M, 0.005 mol) was added to a solution of 2-cyclobutyloxy-3,4-dimethoxy-6-{1-[4-(morpholinecarbonyl)-1,4-diazepan-1-yl]ethylideneamino}benzonitrile (950 mg, 0.002 mol) in tetrahydrofuran (25 ml) at -70° C. and the reaction allowed to warm to room temperature under a nitrogen atmosphere. 1N aqueous citric acid solution (25 ml) was then added and the mixture extracted once with ethyl acetate (25 ml). The aqueous phase was basified using 1N aqueous sodium hydroxide solution and the mixture extracted with further ethyl acetate (60 ml) and these combined organic extracts dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with dichloromethane:methanol:0.880 aqueous ammonia (97:3:1 v/v) and trituration with diethyl ether gave the title compound as a foam (680 mg, 67%). Rf 0.31 (dichloromethane:methanol:0.880 aqueous ammonia, 97:3:1, v/v). MS m/z 486 (MH)+. 1H-NMR (CDCl3): δ=1.45 (1H, m), 1.70 (1H, m), 2.03 (2H, m), 2.30 (4H, m), 3.30 (4H, m), 3.35 (2H, m), 3.60 (8H, m), 3.80 (3H, s), 3.92 (5H, br.s), 4.80 (1H, m), 5.60 (2H, m), 570 (1H, s), 6.73 (1H, s). Found: C, 61.27; H, 7.39; N, 13.92; C25H35N5O5 1(C2H5)2O 0.3 H2O requires C, 61.21; H, 7.40; N, 14.05%.

Workup

  1. extractionthe mixture extracted once with ethyl acetate (25 ml)
  2. extractionthe mixture extracted with further ethyl acetate (60 ml)
  3. dry with materialthese combined organic extracts dried (MgSO4)
  4. filtrationfiltered
  5. customevaporated under reduced pressure
  6. customThe crude product was purified on silica gel eluting with dichloromethane

Sources & evidence

ORD record
ord-552995bfbe36458f9dc307dc67aacea5
Source dataset
uspto-grants-2000_04
Patent number
US06048864

Reaction notes

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