4-Methylmorpholine → Benzyl 4-oxopiperidine-1-carboxylate

Temperature

15 °C

A mixture of 40 kg of N-benzyloxycarbonyl) succinimide and 26 kg (175 mol) of 4-piperidone hydrochloride hydrate in 38.8 kg of water and 88 kg of tetrahydrofuran is stirred at about 15° C. until dissolution is complete (˜15 minutes). N-methylmorpholine (22.8 kg) is added to the agitated mixture (exothermic) while maintaining the temperature at or below 20° C. The reaction mixture is agitated at about 20° C. for 2.5 hours, at which point HPLC indicates complete reaction. The mixture is diluted with 115.2 kg of methyl tert-butyl ether and 38.8 kg of water and is agitated at about 20° C. for 5 minutes. Agitation is stopped, the layers are allowed to separate, and the aqueous (lower) layer is removed and discarded. The organic layer is washed twice with 129.6 kg of water (agitate 5 minutes, separate phases, remove/discard aqueous [lower] phase). The organic layer is washed with 5.2 kg of NaCl in 46.8 kg of water (agitate 5 minutes, separate phases, remove/discard aqueous [lower] layer). The organic layer is treated with 11.5 kg of MgSO4, with agitation for 1 hour, then the mixture is filtered. The reactor is rinsed with 8 kg of methyl tert-butyl ether (filtered, combined with main filtrate; total filtrate water content: 0.52%). The filtrate volume is reduced by half via distillation at reduced pressure at 30° C. Vacuum is broken to nitrogen and the residue is cooled to 20° C. (pot residue water content: 0.43%). The residue is diluted with 57.6 kg of methyl tert-butyl ether, then mixture volume is reduced again by half via distillation under vacuum at 30° C. Vacuum is released to nitrogen and the mixture is cooled to 20° C. (pot residue water content: 0.25%). This is repeated 5 additional times. The final pot residue is diluted with 28.8 kg of methyl tert-butyl ether and mixed for 5 minutes, then assayed for water content and content of 1-phenylmethoxycarbonyl-4-piperidone (water: 0.05%; wt/wt assay 1-phenylmethoxycarbonyl-4-piperidone: 22.66 wt%, 35.36 kg, 155 mole, 88.6% yield.).

1. custom(˜15 minutes)
2. temperaturewhile maintaining the temperature at or below 20° C
3. stirringThe reaction mixture is agitated at about 20° C. for 2.5 hours, at which point HPLC
4. customreaction
5. stirringis agitated at about 20° C. for 5 minutes
6. customto separate
7. customthe aqueous (lower) layer is removed
8. washThe organic layer is washed twice with 129.6 kg of water (agitate 5 minutes, separate phases, remove/discard aqueous [lower] phase)
9. washThe organic layer is washed with 5.2 kg of NaCl in 46.8 kg of water (agitate 5 minutes, separate phases, remove/discard aqueous [lower] layer)
10. additionThe organic layer is treated with 11.5 kg of MgSO4, with agitation for 1 hour
11. filtrationthe mixture is filtered
12. washThe reactor is rinsed with 8 kg of methyl tert-butyl ether (filtered, combined with main filtrate; total filtrate water content: 0.52%)
13. distillationThe filtrate volume is reduced by half via distillation at reduced pressure at 30° C
14. temperaturethe residue is cooled to 20° C. (pot residue water content: 0.43%)
15. additionThe residue is diluted with 57.6 kg of methyl tert-butyl ether
16. distillationmixture volume is reduced again by half via distillation under vacuum at 30° C
17. temperaturethe mixture is cooled to 20° C. (pot residue water content: 0.25%)
18. additionThe final pot residue is diluted with 28.8 kg of methyl tert-butyl ether
19. additionmixed for 5 minutes

ORD record

ord-c8de6e8ff1ae49fdad79e30b8ab504b9

Source dataset

uspto-grants-2001_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06180759B2