Piperidine → L-Tartaric acid

Temperature

65 °C

A round bottomed flask was charged with copper (1) iodide (0.102 g, 0.536 mmol), bis(tripheynlphosphine)palladium(II)dichloride (1.128 g, 1.608 mmol), and (1R,3R)-methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate, 0.5 L-tartaric acid 2 (20 g, 53.6 mmol) (that had been free based by partitioning between EtOAc and saturated NaHCO3. The organic layer was separated, dried (NaSO4), filtered and concentrated) THF (150 mL) was added and the reaction mixture was purged with nitrogen. After 5 min piperidine (23.88 mL, 241 mmol) and 7-methoxyhept-1-yne (6.0 g, 54 mmol) was added. The reaction mixture was heated to about 65° C. After about 8 hours additional 7-methoxyhept-1-yne (3.1 g, 27 mmol) was added. After about 20 hours total the reaction mixture was cooled to about room temperature and partitioned between EtOAc/NaHCO3. The organic layer was separated dried (Na2SO4) filtered and concentrated. The crude mixture was purified by chromatography on silica gel (eluting with EtOAc/MeOH). The fractions containing the desired product were concentrated in vacuo. The dark brown oil was dissolved in MeOH (50 mL) and a solution of (2R,3R)-2,3-dihydroxysuccinic acid (9.65 g, 64.3 mmol) in MeOH (15 mL) was added. The solution was concentrated in vacuo and the resulting solid was slurried in isopropyl alcohol (approx 100 mL), filtered and dried in vacuo to provide (1R,3R)-methyl 1-amino-3-(4-(6-methoxyhex-1-ynyl)phenyl)cyclopentanecarboxylate, L-tartaric acid (25 g, 52.1 mmol, 97% yield) as a colorless solid.

1. customby partitioning between EtOAc and saturated NaHCO3
2. customThe organic layer was separated
3. dry with materialdried (NaSO4)
4. filtrationfiltered
5. concentrationconcentrated) THF (150 mL)
6. additionwas added
7. customthe reaction mixture was purged with nitrogen
8. temperaturethe reaction mixture was cooled to about room temperature
9. custompartitioned between EtOAc/NaHCO3
10. customThe organic layer was separated
11. dry with materialdried (Na2SO4)
12. filtrationfiltered
13. concentrationconcentrated
14. customThe crude mixture was purified by chromatography on silica gel (eluting with EtOAc/MeOH)
15. additionThe fractions containing the desired product
16. concentrationwere concentrated in vacuo
17. dissolutionThe dark brown oil was dissolved in MeOH (50 mL)
18. concentrationThe solution was concentrated in vacuo
19. filtrationfiltered
20. customdried in vacuo

ORD record

ord-42f7ff60a0324b24aa9284d4ecc3a622

Source dataset

uspto-grants-2012_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08217027B2