Hydrochloric Acid → 2-[3-(4,6-Dichloroindol-2-ylmethylamino)prop-1-ylamino]-1H-quinolin-4-one

HRID 430097

Reaction equation

HRID 430097 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12](OCC)=O)[NH:6]2.[H-].C(N([Al](N(CC)CC)N(CC)CC)CC)C.[Na+].Cl.[NH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]1[NH:42][C:43]2[C:48]([C:49](=[O:51])[CH:50]=1)=[CH:47][CH:46]=[CH:45][CH:44]=2.C([BH3-])#N.[Na+]>C1COCC1.CO.CC(O)=O.C(OCC)C.O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:12][NH:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]1[NH:42][C:43]3[C:48]([C:49](=[O:51])[CH:50]=1)=[CH:47][CH:46]=[CH:45][CH:44]=3)[NH:6]2

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 2736407ethyl 4,6-dichloro-1H-indole-2-carboxylateHCID 5003444Sodium cyanoborohydrideHCID 108569252-[(3-Aminopropyl)amino]-1,4-dihydroquinolin-4-oneHCID 16706599Sodium tris(diethylamino)aluminium hydride

Product 1

HCID 445339602-[3-(4,6-Dichloroindol-2-ylmethylamino)prop-1-ylamino]-1H-quinolin-4-one

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolventHCID 10129899Acetic acid methanolSolvent

Procedure

To ethyl 4,6-dichloroindole-2-carboxylate (0.258 g, 1 mmol) in THF (1 ml) at −78° C. under argon was added 1 ml of a solution of sodium tris(diethylamino)aluminium hydride (prepared from NaAlH4 (1 M in THF, 6 ml) and diethylamine (1.86 ml, 18 mmol), 70 min/0° C.). After 20 min at −78° C. the reaction was allowed to warm to 0° C. over 1 h before addition of 5 M HCl (1.5 ml), water (10 ml) and diethyl ether (50 ml). The phases were separated and the organic layer washed with brine, dried (MgSO4) and evaporated to dryness under reduced pressure to give a pink solid (200 mg; comparison of NMR integrals indicated the presence of approx 40% aldehyde). To this material (132 mg) was added a solution of 0.125 M 2-(3-aminoprop-1-ylamino)-1H-quinolin-4-one in MeOH/HOAc (2 ml, prepared as in example 4a) and sodium cyanoborohydride (0.031 g, 0.5 mmol). After 2.5 h, the reaction mixture was applied to a Varian Bond Elute 1 g SCX cartridge which was flushed with MeOH then eluted with 0.2 M NH3 in MeOH. Product containing fractions were combined and purified by chromatography on silica gel eluting with 0-12% (9:1 MeOH/20 M NH3) in CH2Cl2 to give the title compound, isolated as a colourless solid, (0.050 g, 48%). δH (Methanol-D4) 8.1 (1H, dd, J=8.1, 1.3 Hz), 7.5 (1H, dt, J=1.3, 7.7), 7.2-7.3 (3H, m), 7.0 (1H, d, J=1.6 Hz), 6.5 (1H, s), 5.7 (1H, s), 3.95 (2H, s), (2H, t, J=6.7 Hz), 2.8 (2H, t, J=6.8 Hz), 1.9 (2H, m). MS (ES+) 415, 417 (35%, 25%, MH+), 218 (100%).

Workup

  1. customThe phases were separated
  2. washthe organic layer washed with brine
  3. dry with materialdried (MgSO4)
  4. customevaporated to dryness under reduced pressure
  5. customto give a pink solid (200 mg
  6. waitAfter 2.5 h
  7. washElute 1 g SCX cartridge which
  8. customwas flushed with MeOH
  9. washthen eluted with 0.2 M NH3 in MeOH
  10. additionProduct containing fractions
  11. custompurified by chromatography on silica gel eluting with 0-12% (9:1 MeOH/20 M NH3) in CH2Cl2

Sources & evidence

ORD record
ord-57ecc031f11c4e848daea732afa1069f
Source dataset
uspto-grants-2001_11
Patent number
US06320051B1

Linked notes

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