Bicyclo[2.2.2]octane-1,4-dicarboxylic acid hemimethyl ester

Uses

4-(Methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic Acid has been used as a reactant for the preparation of bicyclo-octyltriazole inhibitors of HSD1 for metabolic syndrome treatment.

Synthesis

General procedure for the synthesis of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1,4-dicarboxylic acid from dimethyl bicyclo[2.2.2]octane-1-carboxylate: a mixture of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (20 g) and potassium hydroxide (5.5 g) in methanol/water (10:1, 106 mL) was heated to reflux overnight. After the reaction was completed, it was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate and extracted with 1N aqueous sodium hydroxide (2 x 100mL). The organic phase was dried with magnesium sulfate, filtered and concentrated to give the starting material as a white solid. The combined aqueous phases were adjusted to pH 1-2 with 2N aqueous hydrochloric acid and extracted with ethyl acetate (4 x 250mL). The combined turbid organic phases were filtered through a slot filter, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated to afford 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid as a colorless solid (13.1 g, 70% yield). Mass spectral analysis showed [MH]+ = 213.

References

[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 24, p. 5731 - 5737
[2] Patent: WO2006/128184, 2006, A2. Location in patent: Page/Page column 164-165
[3] Patent: WO2008/63671, 2008, A2. Location in patent: Page/Page column 177-178
[4] Patent: WO2014/159802, 2014, A1. Location in patent: Paragraph 00189
[5] Journal of Medicinal Chemistry, 2009, vol. 52, # 6, p. 1558 - 1568