Description
Scopine-2,2-dithienyl glycolate is an organic compound. It is off-white solid. The melting point is 138-140°C. The storage temperature is -20°C. Scopine-2,2-dithienyl glycolate is one of the reaction intermediates in the preparation of tiotropium bromide, which is a highly effective anticholinergic agent and widely used for treatment of asthma and/or chronic obstructive pulmonary disease (COPD) (chronic obstructive pulmonary disease).
Synthesis
Example 1: 7 mol% NHC (relative to compound (1)) in THF at room temperature. In an anhydrous flask containing about 7.85 g of activated 4A molecular sieves, methyl 2,2-dithienylglycolate (2) (R = Me, 3.97 g, 15.6 mmol) and rel-(1R,2R,4S,5S,7s)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-ol (1) (2.61 g. 16.8 mmol) was dissolved in THF (14 mL). Another flask was taken and 1-butyl-3-methylimidazolium tetrafluoroborate (210 μL, 1.12 mmol), KOtBu/THF solution (960 μL, 0.96 mmol), and THF (1.0 mL) were added, and stirred for 15 min at room temperature. Subsequently, this mixture was transferred to a flask containing rel-(1R,2R,4S,5S,7s)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-ol solution using a syringe. The syringe and flask were washed with THF (2 x 0.5 mL) and the reaction mixture was stirred at room temperature for 18 h. HPLC analysis showed 86% yield of the expected product.After 18 h, the mixture was filtered and the molecular sieves were washed with THF (2 x 20 mL). The filtrate was concentrated to dryness and the residue was dissolved in toluene (30 mL) and 1M HCl (30 mL). Solid precipitation was observed during phase separation; the suspension was filtered and the solids were washed with toluene (30 mL) and redissolved in the separated aqueous phase. The aqueous phase suspension was cooled to 0 °C and alkalized to the proper pH by adding solid K2CO3. The mixture was stirred at 0 °C for about 30 min, and the resulting solid was filtered, washed with cold water, and dried first on a filter, followed by vacuum drying at 45 °C for 18 h to give the white solid product (3) (4.30 g, 73%, HPLC purity = 99.89%).
References
[1] Patent: WO2013/46138, 2013, A1. Location in patent: Page/Page column 9; 10
[2] Patent: US2004/242622, 2004, A1. Location in patent: Page 29
[3] ChemMedChem, 2017, vol. 12, # 15, p. 1173 - 1182
[4] Patent: US2014/303373, 2014, A1. Location in patent: Paragraph 0034; 0035; 0036; 0037
