160596-25-8

122320-73-4

[1] Preparation of catalyst: 1.2 g of cobalt(II) chloride hexahydrate was dissolved in 120 ml of N,N-dimethylformamide (DMF), followed by the addition of 8.0 g of dimethylethylene dioxime. Stirring was done until a clarified blue-green solution was formed. [2] Preparation of reducing agent solution: 27.2 g of sodium borohydride was slowly dissolved in 300 ml of 0.1 M sodium hydroxide solution at room temperature with continuous stirring. [3] Reduction reaction: 16.8 g of sodium hydroxide was dissolved in 1200 ml of distilled water, followed by the addition of 120 g of rosiglitazone EPO benzylidene derivative. The mixture was stirred until complete dissolution and heated to 55±5°C. Once the temperature was reached, the catalyst solution (1/5 volume of the solution prepared in step [1] for about 1 min) was added dropwise, followed by the reductant solution (1/5 volume of the solution prepared in step [2] for about 2 min). The reaction was maintained at 55 ± 5 °C with stirring for 50 min. The addition of catalyst and reducing agent (1/5 of the previous volume each time) was repeated four times, maintaining 55±5°C stirring for 50 min after each addition. [4] Crude product isolation: the reaction mixture was kept at 55±5°C and 300 ml of ethyl acetate was added with vigorous stirring, followed by the slow addition of 260 ml of 1:1 hydrochloric acid. No external heating was required and 55±5°C was maintained. Slowly add 600 ml of 10% sodium bicarbonate solution. The suspension was stirred and slowly cooled to 30-40°C for about 20 minutes and filtered. The filter cake was washed sequentially with 6 x 200 ml of water and 3 x 200 ml of ethanol. Vacuum dried to constant weight to obtain crude rosiglitazone base I, melting point 153-155°C, yield 93% (HPLC purity 99.0%, cobalt residue 11 μg/g). [5] Crystallization and purification: 110 g of crude rosiglitazone base I was dissolved in 200 ml of acetic acid and heated at 70-80°C for 15 min. Add ethanol according to the following procedure: add 250 ml of ethanol within 5 min and filter at 65°C; slowly cool the filtrate to 57°C and stir for 15 min; continue to cool to 50°C and stir for 20 min; quickly add 250 ml of ethanol and stir at 45°C for 10 min; repeat the rapid addition of 250 ml of ethanol and stir at 38°C for 10 min; and finally add 250 ml of ethanol quickly and stir at 30°C for 10 minutes. In total, 1000 ml of ethanol was added over 70 minutes and the suspension was cooled to 30 °C. Filtration, the filter cake was washed with 2 x 150 ml ethanol and vacuum dried to give 90-95 g of white crystalline product with melting point 155-156°C (HPLC purity 99.90%, cobalt residue 1 μg/g). [6] Alternative crystallization method: 10110g of crude rosiglitazone base I was dissolved in 200ml acetic acid, and ethanol was added under stirring at 70-80°C according to the following procedure: 250ml ethanol was added within 5 minutes, and stirred at 75-70°C for 10 minutes; 250ml ethanol was added within 5 minutes, and stirred at 65-60°C for 20 minutes; 250ml ethanol was added quickly, and stirred at 55-50°C for 10 minutes; rapid addition of 250 ml ethanol, 45-40 ℃ stirring 10 minutes. In total, 1000 ml of ethanol was added over 1 hour and the suspension was cooled to 40°C. Filtration, the filter cake was washed with 2×150 ml ethanol and vacuum dried to give 92.2 g of white crystalline product in 83.8% yield (HPLC purity >99.95%, cobalt residue 1.5 μg/g). [7] Small scale crystallization: 12 g of crude rosiglitazone base I was dissolved in 200 ml of acetic acid and 250 ml of ethanol (75-78°C) was added within 5 min at 80°C with stirring.