反应详情

To a suspension of 6-((benzyloxy)carbonyl)-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid (intermediate 9) (0.1240 g, 0.298 mmol) in CH2Cl2 with of DMF (2 mL) was added 2M (CH2Cl2) oxalyl chloride (0.298 mL, 0.595 mmol) and the solution stirred at room temperature. After 1 h, the mixture was concentrated and azeotroped with toluene 3 times to remove unreacted oxalyl chloride. The residue was taken up in CH2Cl2 (2.0 mL). iPr2NEt (0.156 mL, 0.893 mmol) and 1-(cyanomethyl)tetrahydro-1H-thiophen-1-ium, bromide salt (0.081 g, 0.387 mmol) were added and the solution stirred at room temperature for 20 h. The mixture was washed with water, then dried (Na2SO4), filtered and concentrated to give an amber oil. The oil was dissolved in MeOH (4 mL). a solution of oxone (0.366 g, 0.595 mmol) dissolved in water (1.5 mL) was added. The resulting suspension was stirred at room temperature for 2 h. Methanol was concentrated was removed under vacuum and the remaining solution extracted with EtOAc (3×'s). The organic layers were combined and washed with brine, dried (Na2SO4), filtered and concentrated. The resulting brown residue was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane) to provide benzyl 3-(2-methoxy-2-oxoacetyl)-2-methyl-4-(p-tolyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (0.063 g, 32% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.14-7.51 (m, 7H), 6.92-7.11 (m, 2H), 5.13 (br. s., 2H), 4.28-4.52 (m, 2H), 3.44 (s, 3H), 3.25-3.38 (m, 2H), 3.11 (br. s., 2H), 2.50-2.63 (m, 3H), 2.41 (s, 3H). LCMS (M+H) calcd for C27H27N2O5: 459.19. found: 459.3.

1. concentrationthe mixture was concentrated
2. customazeotroped with toluene 3 times
3. customto remove unreacted oxalyl chloride
4. stirringthe solution stirred at room temperature for 20 h
5. washThe mixture was washed with water
6. dry with materialdried (Na2SO4)
7. filtrationfiltered
8. concentrationconcentrated
9. customto give an amber oil
10. additionwas added
11. stirringThe resulting suspension was stirred at room temperature for 2 h
12. concentrationMethanol was concentrated
13. customwas removed under vacuum
14. extractionthe remaining solution extracted with EtOAc (3×'s)
15. washwashed with brine
16. dry with materialdried (Na2SO4)
17. filtrationfiltered
18. concentrationconcentrated
19. customThe resulting brown residue was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane)