1-Bromo-3-chloropropane → Ethyl 1-azabicyclo[3.3.1]nonane-5-carboxylate

Temperature

-35 °C

A cooled (-50° C.) solution of 1,3-piperidinedicarboxylic acid 1-(1,1-dimethylethyl) 3-ethyl ester (12.9 g, 50 mmol) in anhydrous tetrahydrofuran (60 mL) was treated (via syringe) with 1.15N lithium diisopropylamide/tetrahydorfuran (52 mmol), stirred for one hour at -15°±5° C., cooled (-35° C.), treated with 1-bromo-3-chloropropane (10.2 g, 65 mmol), warmed to room temperature over one hour, and stirred for 30 minutes. Most of the solvent was removed in vacuo, replaced with ether, and the organic solution was washed with saturated sodium bicarbonate (150 mL). The aqueous solution was extracted with ether (2×50 mL), and the combined organic solution was dried (MgSO4), concentrated in vacuo, and passed through a short column of alumina (eluted with methylene chloride). The concentrated filtrate was dissolved in anhydrous methylene chloride (25 mL), cooled (10° C.), and treated dropwise with trifluoroacetic acid (15 mL). The solution was stirred for one hour at room temperature, 15 minutes at 45° C., and concentrated in vacuo. The residue was partitioned between 1.25N sodium carbonate (75 mL) and methylene chloride (100 mL), and the organic layer was separated. The aqueous solution was extracted with methylene chloride (2×50 mL), and the combined organic solution was dried (Na2SO4), concentrated in vacuo, taken up in warm hexane, treated with a little charcoal, and filtered. The filtrate was concentrated in vacuo and the residue was distilled (bp 0.6 83°-85° C.) to give 7.2 g (73%) of the product.

1. temperaturewarmed to room temperature over one hour
2. stirringstirred for 30 minutes
3. customMost of the solvent was removed in vacuo
4. washthe organic solution was washed with saturated sodium bicarbonate (150 mL)
5. extractionThe aqueous solution was extracted with ether (2×50 mL)
6. dry with materialthe combined organic solution was dried (MgSO4)
7. concentrationconcentrated in vacuo
8. dissolutionThe concentrated filtrate was dissolved in anhydrous methylene chloride (25 mL)
9. temperaturecooled (10° C.)
10. additiontreated dropwise with trifluoroacetic acid (15 mL)
11. stirringThe solution was stirred for one hour at room temperature, 15 minutes at 45° C.
12. concentrationconcentrated in vacuo
13. customThe residue was partitioned between 1.25N sodium carbonate (75 mL) and methylene chloride (100 mL)
14. customthe organic layer was separated
15. extractionThe aqueous solution was extracted with methylene chloride (2×50 mL)
16. dry with materialthe combined organic solution was dried (Na2SO4)
17. concentrationconcentrated in vacuo
18. additiontreated with a little charcoal
19. filtrationfiltered
20. concentrationThe filtrate was concentrated in vacuo
21. distillationthe residue was distilled (bp 0.6 83°-85° C.)

ORD record

ord-06f5c13d44cb4445b1c0ad64e71f27b9

Source dataset

uspto-grants-1993_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05244907