875515-76-7

To a stirred solution of 2,2,6,6-tetramethylpiperidine (1.484 mL, 8.79 mmol) in anhydrous THF (15 mL) was added slowly and dropwise 2.5 M n-butyllithium hexane solution (3.52 mL, 8.79 mmol) at 0 °C and under nitrogen protection. The reaction mixture was continued to be stirred at 0 °C for 30 min. Subsequently, the mixture was slowly added to a solution of anhydrous THF (15 mL) of 4-chlorothieno[3,2-d]pyrimidine (Compound 12; 1.00 g, 5.86 mmol) in a controlled dropwise manner over 30 min and the reaction temperature was maintained at -78 °C. After the reaction continued to stir at -78 °C for 1 h, dry ice (2.58 g, 58.6 mmol) was added to the reaction system. Subsequently, the reaction mixture was allowed to slowly warm up to room temperature over a period of 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with 0.1 M hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to afford 4-chlorothieno[3,2-d]pyrimidine-6-carboxylic acid (Compound 13; 1.1 g, 83% yield). Mass spectrometry (ESI) data: calculated value for C7H3ClN2O2 was 213.96; measured value was 215.0 [M + H].

[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 9, p. 3666 - 3679
[2] Patent: WO2014/138562, 2014, A1. Location in patent: Page/Page column 63