Chloroselenobenzene → (7R)-benzyl 3-chloro-1-azaspiro[4.4]nonane-7-carboxylate

Temperatur

80 °C

To phenylselenyl chloride (0.199 g, 1.041 mmol) was added (1R)-benzyl 3-allyl-3-aminocyclopentanecarboxylate (example 2, step A, 0.090 g, 0.347 mmol) dissolved in acetonitrile (2 mL). The contents were heated at 80° C. for 18 hours. The reaction mixture was concentrated and partitioned between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (10 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated. To the residue was added methanol (5 mL). The solid that separates was filtered and washed with methanol (2 mL). To the filtrate was added 4.0N hydrogen chloride in dioxane (1 mL) and the contents concentrated. Ethyl acetate was added and the resulting mixture was concentrated under reduced pressure. Methanol (5 mL) was added and a solid separates out The liquid was carefully pipetted out into a HPLC vial and subjected to preparative HPLC (Phenomex Luna AXIA 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). Fractions corresponding to the desired product were isolated and concentrated. The residue was partitioned between dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution (3 mL). The dichloromethane layer was dried over sodium sulfate and concentrated to yield (7R)-benzyl 3-chloro-1-azaspiro[4.4]nonane-7-carboxylate (0.051 g, 0.174 mmol, 50.0% yield) as an oil. It was used as such for the subsequent step. MS (ESI) m/z 294.14 (M+H)+

1. concentrationThe reaction mixture was concentrated
2. custompartitioned between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (10 mL)
3. dry with materialThe ethyl acetate layer was dried over sodium sulfate
4. concentrationconcentrated
5. additionTo the residue was added methanol (5 mL)
6. filtrationThe solid that separates was filtered
7. washwashed with methanol (2 mL)
8. additionTo the filtrate was added 4.0N hydrogen chloride in dioxane (1 mL)
9. concentrationthe contents concentrated
10. additionEthyl acetate was added
11. concentrationthe resulting mixture was concentrated under reduced pressure
12. additionMethanol (5 mL) was added
13. customsubjected to preparative HPLC (Phenomex Luna AXIA 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA)

ORD-Eintrag

ord-2ad639262bdd42d282561845a3bd8e4a

Quelldatensatz

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09221819B2