Pyridine → HCID 86619619, compound

Pyridine (21 mg, 0.022 mL, 0.268 mmol) and cyclopentanecarbonyl chloride (30 mg, 0.223 mmol) were added to an ice-water cooled solution of 4-{4-amino-3-[(tert-butylcarbamoylmethyl)carbamoyl]phenyl}perhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (INTERMEDIATE V.38) (100 mg, 0.223 mmol) in THF (1 mL) and the reaction mixture stirred for 15 min. Solvent was removed in vacuo and the residue partitioned between DCM (10 mL) and water (10 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude material was dissolved in 1,2-dichloroethane (5 mL) and triethylamine (1.04 g, 1.39 mL, 10.28 mmol) and trimethylsilyl chloride (364 mg, 0.428 mL, 3.35 mmol) added. The reaction mixture was heated at reflux temperature for 3 h. The reaction mixture was diluted with EtOAc (10 mL), washed with 1M HCl (aq.) and sodium bicarbonate (aq.) solution. The organic phase was dried (MgSO4) and solvent removed in vacuo. Crude product was purified by chromatography on silica gel with a gradient of DCM to DCM:EtOAc (1:4, v/v) as eluent. The product was dissolved in DCM (5 mL), TFA (0.5 mL) added and the reaction stirred at room temperature for 2 h. The solution was poured directly onto an SCX cartridge and product eluted with 2N NH3/MeOH. Solvent was removed under reduced pressure to afford N-tert-butyl-2-(2-cyclopentyl-4-oxo-6-perhydro-1,4-diazepin-1-yl-4H-quinazolin-3-yl-acetamide (EXAMPLE 7a) (35 mg, 0.082 mmol, 37%).

1. customSolvent was removed in vacuo
2. customthe residue partitioned between DCM (10 mL) and water (10 mL)
3. dry with materialThe organic phase was dried (Na2SO4)
4. concentrationconcentrated in vacuo
5. dissolutionThe crude material was dissolved in 1,2-dichloroethane (5 mL)
6. temperatureThe reaction mixture was heated
7. temperatureat reflux temperature for 3 h
8. washwashed with 1M HCl (aq.) and sodium bicarbonate (aq.) solution
9. dry with materialThe organic phase was dried (MgSO4) and solvent
10. customremoved in vacuo
11. customCrude product was purified by chromatography on silica gel with a gradient of DCM to DCM:EtOAc (1:4, v/v) as eluent
12. dissolutionThe product was dissolved in DCM (5 mL)
13. additionTFA (0.5 mL) added
14. stirringthe reaction stirred at room temperature for 2 h
15. additionThe solution was poured directly onto an SCX cartridge and product
16. washeluted with 2N NH3/MeOH
17. customSolvent was removed under reduced pressure

ORD record

ord-5fcd2fa167714436823408979d5d626b

Source dataset

uspto-grants-2010_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07820649B2