Hydrochloric Acid → methyl 4-methyl-3-(4-oxo-6-piperazin-1-ylquinazolin-3(4H)-yl)benzoate

HRID 641974Notes

Reaction equation

HRID 641974 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:15]([O:17][CH3:18])=[O:16])[C:5]2=[O:23].C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([N:83]1[CH2:88][CH2:87][NH:86][CH2:85][CH2:84]1)(OC(C)(C)C)=O.Cl>C1(C)C=CC=CC=1.CO.O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:22][C:21]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[N:6]1[C:5](=[O:23])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([N:83]3[CH2:88][CH2:87][NH:86][CH2:85][CH2:84]3)[CH:3]=2)[N:8]=[CH:7]1

Participants

10

Reactant 5

HCID 313Hydrochloric Acid2×HCID 10796Cesium carbonateHCID 143452tert-Butyl piperazine-1-carboxylateHCID 634876Binap, (A+-)-HCID 66919066Methyl 3-(6-bromo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate

Product 1

HCID 68604387methyl 4-methyl-3-(4-oxo-6-piperazin-1-ylquinazolin-3(4H)-yl)benzoateYield 69.5%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 887MethanolSolventHCID 1140TolueneSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
100 °C

Procedure

Methyl 3-(6-bromo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoate (2 g), Cs2CO3 (4.4 g), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.67 g), palladium acetate (0.12 g) in anhydrous toluene (20 ml) at ambient temperature was added N-boc piperazine (2.5 g). The mixture was heated to 100° C. and stirred for 16 hours. Inorganic solids were removed via a hot filtration and the filtrate concentrated to give an oil. The oil was resuspended in MeOH (16 ml), 4N HCl in dioxane (10 ml) was added and the reaction mixture stirred at 50° C. for 1 hour when additional 4N HCl in dioxane (2 ml) was added and heating continued for a further 30 minutes. The reaction mixture was cooled to room temperature and the solid collected by filteration, washed with ethyl acetate (×2) and ether and dried. The resultant solid was suspended in saturated K2CO3 solution and extracted with ethyl acetate (×5). The organic layers combined, dried (magnesium sulphate) and concentrated to yield methyl 4-methyl-3-(4-oxo-6-piperazin-1-ylquinazolin-3(4H)-yl)benzoate as a yellow foam (1.41 g); NMR Spectrum: (DMSOd6) 2.17 (s, 3H), 2.31 (m, 1H), 2.87 (m, 4H), 3.19 (m, 4H), 3.87 (s, 3H), 7.46 (s, 1H), 7.61 (m, 3H), 7.97 (s, 1H), 8.02 (d, 1H), 8.08 (s, 1H); Mass Spectrum: M+H+ 379.

Workup

  1. customInorganic solids were removed via a hot filtration
  2. concentrationthe filtrate concentrated
  3. customto give an oil
  4. additionwas added
  5. temperatureheating
  6. waitcontinued for a further 30 minutes
  7. temperatureThe reaction mixture was cooled to room temperature
  8. customthe solid collected by filteration
  9. washwashed with ethyl acetate (×2) and ether
  10. customdried
  11. extractionextracted with ethyl acetate (×5)
  12. dry with materialdried (magnesium sulphate)
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-74dd4906a32f40829566b4c2c69c0a90
Source dataset
uspto-grants-2010_04
Patent number
US07696215B2

Reaction notes

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