Hydrochloric Acid → (R)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole-6-carboxylic acid

Participants

Reaction Steps

A solution of (R)-ethyl 2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole-6-carboxylate (Example 53, 1.38 g, 3.85 mmol) in tetrahydrofuran (50 mL) and methanol (25 mL) was added to a stirred solution of lithium hydroxide monohydrate (0.504 g, 12.00 mmol) in water (20 mL). The reaction mixture was stirred at ambient temperature for 19 hours. An aliquot was checked by TLC (99:1 ethyl acetate/methanol). A lower Rf spot was apparent, however, considerable starting ester remained, so the reaction mixture was heated to 40° C. for 7 hours. Starting ester was still present so the reaction mixture was stirred at ambient temperature for approximately 65 hours. Starting ester appeared to be consumed so the reaction mixture was concentrated under reduced pressure. The residue was treated with methanol (100 mL), water (200 mL), and three equivalents (3.0 mL, 12.0 mmol) of 4 M HCl in dioxane. This mixture was stirred overnight at ambient temperature. A precipitate had formed overnight. Most of the methanol was removed under reduced pressure, then the mixture was diluted with additional water and the precipitate was collected by filtration. This solid was azeotroped with benzene to remove residual water then dried in a vacuum oven to provide the title compound as the dihydrate. 1H NMR (300 MHz, CD3OD) δ ppm 8.27 (s, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 3.96-3.83 (m, 1H), 3.81-3.68 (m, 1H), 3.62-3.36 (m, 3H), 2.94-2.69 (m, 4H), 2.51-2.36 (m, 1H), 2.23-2.06 (m, 1H), 1.83-1.68 (m, 4H), 1.66-1.50 (m, 2H); MS (DCI/NH3) m/z 332 (M+H)+.

Provenance & Evidence