Hydrochloric Acid → 2-[(1R,5R,6S)-6-(aminomethyl)-6-bicyclo[3.2.0]heptanyl]acetic acid

Temperature

70 °C

The cyclohexylamine salt of the nitro acid from example 1 (100 g; 320 mmol) was added to a mixture of ethyl acetate (680 ml) and a 2M aqueous solution of hydrochloric acid (340 ml). The mixture was stirred vigorously for 10 minutes and the phases were separated. The organic layer was further washed with demineralised water (340 ml). The organic layer was separated and demineralised water (1360 ml) was added. To this two phase mixture 5% platinum on carbon as a 50% water wet catalyst (13.65 g) was added. The reaction mixture was then hydrogenated at 50° C. and a hydrogen pressure of 150 psi for 24 hours. The hydrogen was purged with nitrogen and the reaction mixture was heated to 70° C. The reaction mixture was filtered through Celite at 70° C. and the filter pad was washed with hot demineralised water (50 ml). The filtrate was allowed to settle, the phases were separated at 70° C. and the lower aqueous phase was removed and concentrated by distillation at atmospheric pressure to a sixth of its original volume. The white slurry was cooled to 50° C. and isopropanol (705 ml) was then added over a period of 1.7 hours. The white slurry was then cooled to between +5° C. and +10° C. over 90 minutes and stirred for 2.5 hours. The solid was collected by filtration and the damp filter cake washed with isopropanol (60 ml). The isolated solid was then dried in vacuo at 45° C. for 18 hours to give the title compound in high purity as a white crystalline solid (36.3 g) in 62% yield.

1. customthe phases were separated
2. washThe organic layer was further washed with demineralised water (340 ml)
3. customThe organic layer was separated
4. additiondemineralised water (1360 ml) was added
5. additionTo this two phase mixture 5% platinum on carbon as a 50% water wet catalyst (13.65 g) was added
6. customwas then hydrogenated at 50° C.
7. waita hydrogen pressure of 150 psi for 24 hours
8. customThe hydrogen was purged with nitrogen
9. filtrationThe reaction mixture was filtered through Celite at 70° C.
10. washthe filter pad was washed with hot demineralised water (50 ml)
11. customthe phases were separated at 70° C.
12. customthe lower aqueous phase was removed
13. concentrationconcentrated by distillation at atmospheric pressure to a sixth of its original volume
14. temperatureThe white slurry was cooled to 50° C.
15. additionisopropanol (705 ml) was then added over a period of 1.7 hours
16. temperatureThe white slurry was then cooled to between +5° C. and +10° C. over 90 minutes
17. stirringstirred for 2.5 hours
18. filtrationThe solid was collected by filtration
19. washthe damp filter cake washed with isopropanol (60 ml)
20. customThe isolated solid was then dried in vacuo at 45° C. for 18 hours

ORD record

ord-fe67844f43174180860cf39521ba63de

Source dataset

uspto-grants-2005_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06911555B2