3-Chloro-5-fluorobenzaldehyde → 2-(6-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chloro-5-fluorophenyl)-4-oxoquinazolin-3(4H)-yl)-N-isopropylacetamide

HRID 77400Notes

Reaction equation

HRID 77400 reaction equation
[NH2:1][C:2]1[CH:17]=[CH:16][C:15]([N:18]2[CH:24]3[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]3)[CH2:20][CH2:19]2)=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[O:5].[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH:31]=O>C(O)C.C(O)(=O)C.CO.[O-2].[O-2].[Mn+4]>[N:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[N:18]([C:15]1[CH:14]=[C:3]3[C:2](=[CH:17][CH:16]=1)[N:1]=[C:31]([C:30]1[CH:33]=[C:34]([F:36])[CH:35]=[C:28]([Cl:27])[CH:29]=1)[N:6]([CH2:7][C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])[C:4]3=[O:5])[CH2:19][CH2:20]2

Participants

7

Reactant 2

HCID 27348393-Chloro-5-fluorobenzaldehydeHCID 671150572-amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-(2-(isopropylamino)-2-oxoethyl)benzamide2×

Product 1

HCID 699290602-(6-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chloro-5-fluorophenyl)-4-oxoquinazolin-3(4H)-yl)-N-isopropylacetamideYield 9%

Reagents, catalysts & solvents 4

HCID 176Acetic AcidCatalystHCID 178418406HCID 178418406, compoundCatalystHCID 702EthanolSolventHCID 887MethanolSolvent

Conditions

Temperature
95 °C

Procedure

2-Amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-N-(2-(isopropylamino)-2-oxoethyl)benzamide (Intermediate 7A) (70 mg, 0.20 mmol) was dissolved in ethanol (2 mL) before addition of 3-chloro-5-fluorobenzaldehyde (46.3 mg, 0.29 mmol) followed by 2 drops of acetic acid. The resulting solution was sealed in a Reactivial® and heated at 95° C. for 24 hours. Reaction mixture was then cooled to room temperature and diluted with methanol before loading directly onto a 1 g SCX cartridge. The crude material was purified by SCX and concentrated under reduced pressure. The resultant product was re-dissolved in dichloromethane (2 mL), manganese dioxide (33.8 mg, 0.39 mmol) was added and reaction stirred overnight. The sample was then washed with water (5 mL) and extracted into dichloromethane. The organics were separated using a hydrophobic frit. The solvent was removed under reduced pressure and then re-dissolved in methanol (1 mL) and purified by preparative-HPLC. Purified sample was free-based using 500 mg SCX cartridge to afford 2-(6-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chloro-5-fluorophenyl)-4-oxoquinazolin-3(4H)-yl)-N-isopropylacetamide (9.0 mg, 0.018 mmol) 9% yield.

Workup

  1. customThe resulting solution was sealed in a Reactivial®
  2. customReaction mixture
  3. temperaturewas then cooled to room temperature
  4. customThe crude material was purified by SCX
  5. concentrationconcentrated under reduced pressure
  6. dissolutionThe resultant product was re-dissolved in dichloromethane (2 mL)
  7. customreaction
  8. washThe sample was then washed with water (5 mL)
  9. extractionextracted into dichloromethane
  10. customThe organics were separated
  11. customThe solvent was removed under reduced pressure
  12. dissolutionre-dissolved in methanol (1 mL)
  13. custompurified by preparative-HPLC
  14. customPurified sample

Sources & evidence

ORD record
ord-664e9408d3104579bc2a43c559f68d12
Source dataset
uspto-grants-2014_09
Patent number
US08841289B2

Reaction notes

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