Malonic Acid → (+/-)-3-(4-Chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene malonate

To a stirred solution of 3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (2 g, 8.5 mmol) in anhydrous 1,2-dichloroethane (20 mL) under a nitrogen atmosphere was added 1-chloroethyl chloroformate (1.25 mL, 11.6 mmol). The reaction mixture was heated at reflux overnight, then added 1-chloroethyl chloroformate (1 mL, 9.3 mmol), once again the reaction mixture was heated at reflux overnight. The reaction mixture was concentrated to an oil, the oil was dissolved in methanol (25 mL), this solution was heated at reflux for 2 hours and then concentrated to an oil. The residue was dissolved in water and added concentrated NH4OH until pH=10, the water phase was extracted with diethyl ether. The organic phase was dried with magnesium sulphate and concentrated to dryness. The residue was chromatographed over silica gel (dichloromethane/acetone/methanol, 4/1/1 (v/v)). The product fractions was concentrated to an oil, the oil was dissolved in ethanol (96%) and malonic acid (0.55 g, 5.3 mmol) in ethanol (96%) was added, this solution was concentrated to an oil, the oil was trituated in diethyl ether, the title compound precipitated as powder and was isolated by filtration. Yield (1.32 g, 48%), m.p. 136.1-138° C.

1. temperatureThe reaction mixture was heated
2. temperatureat reflux overnight
3. temperatureat reflux overnight
4. concentrationThe reaction mixture was concentrated to an oil
5. dissolutionthe oil was dissolved in methanol (25 mL)
6. temperaturethis solution was heated
7. temperatureat reflux for 2 hours
8. concentrationconcentrated to an oil
9. dissolutionThe residue was dissolved in water
10. additionadded concentrated NH4OH until pH=10
11. extractionthe water phase was extracted with diethyl ether
12. dry with materialThe organic phase was dried with magnesium sulphate
13. concentrationconcentrated to dryness
14. customThe residue was chromatographed over silica gel (dichloromethane/acetone/methanol, 4/1/1 (v/v))
15. concentrationThe product fractions was concentrated to an oil
16. dissolutionthe oil was dissolved in ethanol (96%)
17. concentrationthis solution was concentrated to an oil
18. customthe title compound precipitated as powder
19. customwas isolated by filtration
20. customYield (1.32 g, 48%), m.p. 136.1-138° C.

ORD record

ord-21394ef4eb5e41448a7a360330833eef

Source dataset

uspto-grants-2000_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06100275