Hydrochloric Acid → HCID 178483086, compound

HRID 1984913Notes

Reaction equation

HRID 1984913 reaction equation
N([O-])=O.[Na+].N[C:6]1[CH:33]=[CH:32][C:9]([CH2:10][NH:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19]3[N:28]=[C:27]([N:29]([CH3:31])[CH3:30])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:14][CH2:13]2)=[C:8]([O:34][C:35]([F:38])([F:37])[F:36])[CH:7]=1.C([O-])(O)=O.[Na+].[ClH:44]>CC(O)=O.CCOC(C)=O.Cl[Cu]>[ClH:44].[ClH:44].[Cl:44][C:6]1[CH:33]=[CH:32][C:9]([CH2:10][NH:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18][C:19]3[N:28]=[C:27]([N:29]([CH3:31])[CH3:30])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:14][CH2:13]2)=[C:8]([O:34][C:35]([F:38])([F:37])[F:36])[CH:7]=1

Participants

8

Reactant 4

HCID 313Hydrochloric Acid3×HCID 516892Sodium BicarbonateHCID 23668193Sodium NitriteHCID 178483087HCID 178483087, compound

Product 1

HCID 178483086HCID 178483086, compoundYield 29%

Reagents, catalysts & solvents 3

HCID 62652Cuprous chlorideCatalystHCID 176Acetic AcidSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
70 °C

Procedure

A mixture of conc. HCl (420 μL) and NaNO2 (44 mg, 0.64 mmol) were stirred at 70° C. for 10 min. To the reaction mixture was added a solution of cis-N2-[4-(4-amino-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N4,N4-dimethyl-quinazoline-2,4-diamine (free) obtained in step A of example 77 in AcOH (15 mL), and stirred at ambient temperature for 10 min. To the reaction mixture was added a solution of CuCl (146 mg, 1.47 mmol) in conc. HCl (1 mL), and stirred at 80° C. for 6 hr. The reaction mixture was alkalized with saturated aqueous NaHCO3, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, purified by medium-pressure liquid chromatography (NH-silica gel, 50% EtOAc in hexane) to give a yellow oil. To a solution of above oil in EtOAc (2 mL) was added 4 M hydrogen chloride in EtOAc (10 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated. A solution of the residue in Et2O (20 mL) was stirred at ambient tempareture for 1 hr. The precipitate was collected by filtration, washed with Et2O, and dried under reduced pressure to give cis-N2-[4-(4-chloro-2-trifluoromethoxy-benzylamino)-cyclohexyl]-N4,N4-dimethyl-quinazoline-2,4-diamine dihydrochloride (70 mg, 29%) as a white solid.

Workup

  1. stirringstirred at ambient temperature for 10 min
  2. stirringstirred at 80° C. for 6 hr
  3. extractionthe aqueous layer was extracted with CHCl3 (three times)
  4. dry with materialThe combined organic layer was dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. custompurified by medium-pressure liquid chromatography (NH-silica gel, 50% EtOAc in hexane)
  8. customto give a yellow oil
  9. stirringThe mixture was stirred at ambient temperature for 1 hr
  10. concentrationconcentrated
  11. stirringA solution of the residue in Et2O (20 mL) was stirred at ambient tempareture for 1 hr
  12. filtrationThe precipitate was collected by filtration
  13. washwashed with Et2O
  14. customdried under reduced pressure

Sources & evidence

ORD record
ord-262f199d686d485a8b9c4925ce8c0008
Source dataset
uspto-grants-2009_06
Patent number
US07544690B2

Reaction notes

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