Benzaldehyde → HCID 21480461, compound

A mixture of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (J. Org. Chem., 1987, 52, 3232) (1 g), benzaldehyde (408 mg) and anhydrous magnesium sulphate (3 g) in anhydrous dichloromethane (25 ml) was stirred at room temperature for 21 hours, under nitrogen. 4 Å Molecular sieves (2 g) were added to the above mixture and it was refluxed for 19 hours and finally stirred at room temperature for a further 23 hours. Solids were filtered off, washed with anhydrous dichloromethane (15 ml) and the solvent was removed under vacuum. The remaining residue was azeotroped with toluene (2×15 ml) and further dried under high vacuum to give a yellow foam. This material was dissolved in anhydrous tetrahydrofuran (10 ml) and it was added via cannula to a cooled (-72° C.) and stirred solution of sodium bis(trimethylsilyl)amide (1M in tetrahydrofuran; 4.2 ml) in anhydrous tetrahydrofuran (10 ml) over 7 minutes, under a nitrogen atmosphere. The resulting dark blue solution was stirred at -72° C. for 5 minutes before iodomethane (0.27 ml) was added dropwise and stirring was continued at -70° C. for 2 hours and at room temperature for 17 hours. Brine (20 ml) was added and the organic solvent was removed under vacuum. The aqueous residue was diluted with 2N hydrochloric acid (10 ml) and methanol (5 ml) and it was stirred at room temperature for 10 minutes before it was extracted with diethyl ether (2×25 ml). The acidic aqueous solution was basified with 2N sodium hydroxide and products were extracted with ethyl acetate (3×65 ml). The combined organic solutions were washed with brine (1×25 ml), dried (Na2 SO4) and concentrated. Flash chromatography (silica gel, dichloromethane-methanol, 92:8) of the residue gave the title compound (577 mg) as a solid; δH (250 MHz, CDCl3) 7.66-7.26 (8H, m, Ar--H), 7.15 (1H, dt, J=8.0 and 1.1 Hz, Ar--H), 3.52 (3H, s, --NMe), 1.00 (3H, s, --Me); m/z (CI) 280 (M+ +1).

1. addition4 Å Molecular sieves (2 g) were added to the above mixture and it
2. temperaturewas refluxed for 19 hours
3. stirringfinally stirred at room temperature for a further 23 hours
4. filtrationSolids were filtered off
5. washwashed with anhydrous dichloromethane (15 ml)
6. customthe solvent was removed under vacuum
7. customThe remaining residue was azeotroped with toluene (2×15 ml)
8. customfurther dried under high vacuum
9. customto give a yellow foam
10. additionit was added via cannula to
11. temperaturea cooled (-72° C.)
12. additionwas added dropwise
13. stirringstirring
14. waitwas continued at -70° C. for 2 hours and at room temperature for 17 hours
15. customthe organic solvent was removed under vacuum
16. additionThe aqueous residue was diluted with 2N hydrochloric acid (10 ml) and methanol (5 ml) and it
17. stirringwas stirred at room temperature for 10 minutes before it
18. extractionwas extracted with diethyl ether (2×25 ml)
19. extractionwere extracted with ethyl acetate (3×65 ml)
20. washThe combined organic solutions were washed with brine (1×25 ml)
21. customdried (Na2 SO4)
22. concentrationconcentrated

ORD record

ord-e6d55619a7e444ddb1e7487b3ef05cb7

Source dataset

uspto-grants-1997_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05681833