(S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4';6,7]indolo[1,2-b]quinolin-9-yl[1,4'-bipiperidin]-1'-carboxylic acids were synthesized using (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3. 4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl [1,4'-bipiperidin]-1'-carboxylate trihydrate in the following general procedure: irinotecan hydrochloride (4.8 g), water (30 mL), ethanol (10 mL), and 5% hydrochloric acid solution (0.3 mL) were added to the reaction flask. The reaction mixture was heated to 75-80°C with continuous stirring until complete dissolution. Subsequently, the solution was cooled to 65°C and crystallization was induced by the addition of crystal seeds. The rate of cooling was controlled so that the solution was slowly cooled to 50 °C over 10 hours and then continued to 20 °C over the next 10 hours. Upon completion of crystallization, the solid product was collected by filtration and washed with pure water (16 mL). The resulting product was dried at room temperature and under atmospheric pressure to give 4.6 g of irinotecan hydrochloride trihydrate in 87% yield. The purity of the product was 99.9% by high performance liquid chromatography (HPLC). The structure of the product was confirmed by X-ray diffraction and infrared spectroscopy (IR) analysis to be consistent with form b as described in WO 03/074527. Microscopic observation showed that the average length of the crystals ranged from 50 μm to 200 μm.
