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 nitrogen atmosphere 1-chloroethyl chloroformate (1.25 ml, 11.6 mmol) was added. The reaction mixture was heated at reflux overnight, then 1-chloroethyl chloroformate (1 ml, 9.3 mmol) was added and once again the reaction mixture was heated at reflux overnight. The reaction mixture was concentrated to an oil and 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 concentrated NH4OH was added until pH 10 was reached. 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/ace-tone/methanol, 4/1/1 (v/v)). The product fractions were 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 triturated in diethyl ether. The title compound precipitated as a 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. temperatureonce again the reaction mixture was heated
4. temperatureat reflux overnight
5. concentrationThe reaction mixture was concentrated to an oil
6. dissolutionthe oil was dissolved in methanol (25 ml)
7. temperatureThis solution was heated
8. temperatureat reflux for 2 hours
9. concentrationconcentrated to an oil
10. dissolutionThe residue was dissolved in water
11. additionconcentrated NH4OH was added until pH 10
12. extractionThe water phase was extracted with diethyl ether
13. dry with materialThe organic phase was dried with magnesium sulphate
14. concentrationconcentrated to dryness
15. customThe residue was chromatographed over silica gel (dichloromethane/ace-tone/methanol, 4/1/1 (v/v))
16. concentrationThe product fractions were concentrated to an oil
17. dissolutionthe oil was dissolved in ethanol (96%)
18. concentrationThis solution was concentrated to an oil
19. customthe oil was triturated in diethyl ether
20. customThe title compound precipitated as a powder
21. customwas isolated by filtration
22. customYield (1.32 g, 48%), m.p. 136.1-138° C.

ORDレコード

ord-635771e504d341e1bf88a05136cf8d0c

出典データセット

uspto-grants-2003_09

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US06617459B2