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0 °C

To a suspension of 6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylic acid (8.50 g, 22 mmol) in methylene chloride (300 mL) at 0° C. was added oxalyl chloride (2.25 mL, 26 mmol) and 1 drop of anhydrous DMF. The reaction was stirred at 0° C. for 15 minutes during which time no bubbling was observed. The reaction was then allowed to warm to room temperature and stirred for 40 minutes. At this time bubbling had ceased, and all material was in solution. An aliquot of the solution was quenched with dimethylamine and checked by LCMS to confirm completion. To the solution of the acid chloride starting material at 0° C. was added dimethylamine in THF (43.56 mL, 87 mmol, 2.0 M). The green/yellow reaction was allowed to stir at room temperature overnight although the reaction appeared to proceed immediately by LCMS. The solvent was removed in vacuo, and the resulting residue was dissolved in chloroform. The solution was washed with water and 5% aqueous HCl solution and back extracted to recover the product. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting iridescent green/yellow residue was examined in several TLC solvent systems (95:5 CH2Cl2:MeOH, 2:1 acetone:hexanes, 1:1 EtOAc:hexanes) with the most efficient separation of some early running impurities achieved in the CH2Cl2:MeOH system. The material was purified by silica gel flash column chromatography, loaded as a solution in methylene chloride onto a 330 g RediSep column. Gradient elution consisted of 1.5 L each of neat CH2Cl2, 1% MeOH:CH2Cl2, 2% MeOH:CH2Cl2, 3% MeOH:CH2Cl2, 4% MeOH:CH2Cl2, and 5% MeOH:CH2Cl2, in sequential order. The desired material began to elute with 3% and was pushed off the column with 4% and 5%, yielding two sets of fraction. The earlier set afforded of the desired product plus a fluorescent green contaminant. The later set afforded clean material.

1. temperatureto warm to room temperature
2. stirringstirred for 40 minutes
3. customAt this time bubbling
4. customAn aliquot of the solution was quenched with dimethylamine
5. customThe green/yellow reaction
6. stirringto stir at room temperature overnight although the reaction
7. customThe solvent was removed in vacuo
8. dissolutionthe resulting residue was dissolved in chloroform
9. washThe solution was washed with water and 5% aqueous HCl solution
10. extractionback extracted
11. customto recover the product
12. washThe combined organic layers were washed with brine
13. dry with materialdried over sodium sulfate
14. filtrationfiltered
15. concentrationconcentrated in vacuo
16. customThe resulting iridescent green/yellow residue was examined in several TLC solvent systems (95:5 CH2Cl2:MeOH, 2:1 acetone:hexanes, 1:1 EtOAc:hexanes) with the most efficient separation of some early running impurities
17. customThe material was purified by silica gel flash column chromatography
18. washGradient elution
19. washto elute with 3%
20. customyielding two sets of fraction