反应详情

A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, gas bubbler, heating mantle and a water condenser, was charged with 545.73 g (1.19 mol) of (R)-{1-[(2-benzylcarbamoyl-5-chloro-phenylimino)-methyl]-2-methyl-propyl}-carbamic acid tert-butyl ester (a compound of Formula 106, obtained, for example, as described in Example 2.3), 520 mL of dimethoxymethane and 520 mL (2.492 mol) of HMDS. The mixture was heated to reflux for 24 hours and then allowed to cool. The volatiles were removed by rotary evaporation, leaving an oily residue that was then triturated with ethanol (3×125 mL) to remove residual HMDS or ammonia. To the resulting oil was added 400 mL of ethanol, and the mixture was heated until a homogeneous solution had been obtained. At refulx temperature, 60 mL of water was added and the solution was allowed to cool slowly with light stirring, overnight. The resulting white suspension was allowed to settle; an aliquot of the supernatant was removed and treated dropwise with water to confirm completion (no more solid was formed). The solid was filtered, washed (3×200 mL H2O/EtOH (1:4)), and dried in an oven at 50° C. for 48 hours to afford 260.23 g (51% yield) of the enantiomerically pure title compound of Formula 107, (R)-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester.

1. customA dry 3-necked, round bottomed flask, equipped with a magnetic stirrer
2. temperaturegas bubbler, heating mantle and a water condenser
3. temperatureThe mixture was heated
4. temperatureto reflux for 24 hours
5. temperatureto cool
6. customThe volatiles were removed by rotary evaporation
7. customleaving an oily residue that
8. customwas then triturated with ethanol (3×125 mL)
9. customto remove residual HMDS or ammonia
10. additionTo the resulting oil was added 400 mL of ethanol
11. temperaturethe mixture was heated until a homogeneous solution
12. customhad been obtained
13. temperatureto cool slowly with light stirring, overnight
14. customan aliquot of the supernatant was removed
15. additiontreated dropwise with water
16. customwas formed)
17. filtrationThe solid was filtered
18. washwashed (3×200 mL H2O/EtOH (1:4))
19. customdried in an oven at 50° C. for 48 hours