反应详情

The nitrogen purged vessel containing about 4-oxo-1,3-piperidinedicarboxylic acid 1-(1,1-dimethylethyl) 3-methyl ester (prepared according to Preparation Five, Step C, 53 kg, 49 L, 1.0 eq.) was charged with tetrahydrofuran (THF, 536 L) and potassium carbonate (72 kg, 2.5 eq.). The slurry was treated with benzyl bromide (36.0 kg, 1.01 eq.) over 10 to 15 minutes. The reaction mixture was heated at reflux temperature until reaction was complete (generally between 12 and 18 hours). The mixture was cooled to between 20° C. and 25° C., filtered to remove the salts, and the filter cake washed with THF (134 L). The THF was removed from the mixture by partial vacuum distillation and replaced with heptanes (402 L). The resulting slurry was cooled to between −5° C. and 5° C. and stirred for about one hour. The solids were collected by filtration, washed with heptanes (57 L) cooled between 0° C. to 10° C., and dried under vacuum between 45° C. to 55° C. to give 50.1 kg of 4-oxo-3-(phenylmethyl)-1,3-piperidinedicarboxylic acid 1-(1,1-dimethylethyl) 3-methyl ester (69.2% yield). HPLC assay showed a product peak of 99.2% at about 12 minutes. HPLC conditions: Intersil C-8 column, 4.6×150 mm; mobile phase: 50%acetonitrile/water; aqueous phase: 1 L water, 3 mL triethylamine and 1 mL H3PO4 at pH 6.5; flow rate 1.0 mL/min.; detected by UV at 210 nm.

1. temperatureThe reaction mixture was heated
2. temperatureat reflux temperature
3. customuntil reaction
4. customgenerally between 12 and 18 hours
5. temperatureThe mixture was cooled to between 20° C. and 25° C.
6. filtrationfiltered
7. customto remove the salts
8. washthe filter cake washed with THF (134 L)
9. customThe THF was removed from the mixture by partial vacuum distillation
10. temperatureThe resulting slurry was cooled to between −5° C. and 5° C.
11. filtrationThe solids were collected by filtration
12. washwashed with heptanes (57 L)
13. temperaturecooled between 0° C. to 10° C.
14. customdried under vacuum between 45° C. to 55° C.