Uses
Nortropinone hydrochloride is a metabolite of Tropinone. It is also used as an inhibitor in reactions that involve 11 beta-hydroxysteroid dehydrogenase type 1 enzyme. It plays an important role in the process of drug discovery, as it is an excellent linker component or building block and is useful in exploring a vast range of therapeutics and drugs.
Synthesis
1. 8-Methyl-8-azabicyclo[3.2.1]octan-3-one (tropinone, 10.0 g, 71.84 mmol) was dissolved in dichloroethane (DCE, 60 mL), and 1-chloroethyl chloroformate (ACE-C1, 14.5 mL, 19.11 g, 133.7 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature overnight and subsequently diluted with ether (Et2O, 400 mL) and filtered. The filtrate was concentrated under reduced pressure to give crude chloroethyl carbamate.
2. The above crude product was dissolved in methanol (MeOH, 200 mL) and stirred at room temperature for 1 h. Subsequently, it was concentrated under reduced pressure at 55 °C to obtain crude desmethyltropinone hydrochloride (brown solid, 11.4 g, 98% yield).
3. The crude product was recrystallized by acetonitrile to afford purified demethyltophenone hydrochloride (white crystalline solid, 5 g, 43% yield).
4. Demethyltophenone (5.10 g, 31.55 mmol) was dissolved in dichloromethane (CH2Cl2, 50 mL) and benzyl chloroformate (4.29 mL, 5.11 g, 29.98 mmol) and diisopropylethylamine (DIPEA, 16.48 mL, 12.23 g, 94.66 mmol) were added slowly and dropwise (note exothermic reaction). The reaction mixture was stirred at room temperature for 30 min and subsequently diluted with dichloromethane (100 mL). The organic phase was washed with 1N hydrochloric acid (2 x 100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product (7.2 g, 88% yield).
References
[1] Patent: WO2006/23852, 2006, A2. Location in patent: Page/Page column 84
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 10, p. 1817 - 1820
[3] Patent: WO2010/126163, 2010, A1. Location in patent: Page/Page column 38
[4] Patent: WO2007/100670, 2007, A1. Location in patent: Page/Page column 47
