Related impurities of olmesartan medoxomil and preparation method thereof
A technology for olmesartan medoxomil and impurities, which is applied to the new olmesartan medoxomil-related impurities and the field of preparation thereof, can solve problems such as the need for further research on the synthesis method, and achieve the effect of improving quality control technology
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Embodiment 1
[0057] The preparation of embodiment 1 olmesartan medoxomil degradation impurity AMST-Z8
[0058] Add 20g of olmesartan medoxomil, 2.01g of p-toluenesulfonic acid and 100ml of toluene into a 250ml three-necked flask at room temperature, raise the temperature to 95°C for 3.5h, and the system is two-phase. Let the reaction solution stand still, separate the oily substance in the lower layer, stir with 50ml 5% sodium hydroxide aqueous solution at room temperature for 30min, then use glacial acetic acid to adjust the pH of the system to 3~4, a brown solid precipitates, continue to stir for 20min, then filter, and filter the cake with 30ml×5 After washing with water once, it was blown-dried at 60° C. for 4 hours to obtain 11.5 g of brown solid AMST-Z8 with a yield of 75%.
Embodiment 2
[0059] Embodiment 2 Preparation of Olmesartan Medoxomil Degradation Impurity AMST-Z8
[0060] Dissolve 15g of olmesartan medoxomil in 90ml of 1,4-dioxane solution at room temperature, stir to dissolve, add 10ml of 6% hydrogen chloride in 1,4-dioxane solution into a 250ml three-necked flask, heat up to 90 ℃ reaction 3h, the system is two-phase. Let the reaction solution stand still, separate the oily substance in the lower layer, stir with 40ml of 5% sodium hydroxide aqueous solution at room temperature for 30min, then adjust the pH of the system to 3-4 with glacial acetic acid, a brown solid precipitates, continue to stir for 20min, then filter, and filter the cake with 30ml×5 times After washing with water, it was air-dried at 60° C. for 4 hours to obtain 7.7 g of brown solid AMST-Z8 with a yield of 67%.
[0061] AMST-Z8 structure confirmation:
[0062] 1 H NMR (400MHz, d 6 -DMSO): δ7.63-7.59(m, 2H), 7.54-7.47(m, 2H), 7.07(d, J=8.0Hz, 2H), 6.93(d, J=8.0Hz, 2H), 5.50( s...
Embodiment 3
[0063] The preparation of embodiment 3 olmesartan medoxomil impurity AMST-Z5 and AMST-Z7
[0064] (1) 11.1 g of AMST-SM2, 4.5 g of AMST-SM1-Z1 and 0.6 g of LiOH were sequentially added to 60 ml of DMA at room temperature, kept at 65 °C and stirred for 2 h. Slowly add the reaction solution dropwise to 500ml of water with stirring, and a solid precipitates, and is filtered, and the filter cake is washed with 100ml×3 times of water. The obtained solid was separated and purified by chromatographic column to obtain impurities 3.2g AMST1-Z6 (yield 22.85%), 9.5g AMST1-Z7 (yield 67.8%), total yield: 90.65%.
[0065] (2) Dissolve 3.0g AMST1-Z6 in 20ml of acetonitrile at room temperature, then add 0.16g of purified water, 4.2g of cesium carbonate, stir at room temperature for 5 hours, then add 4-chloromethyl-5-methyl-1,3- Dioxol-2-one 1.2g, add and stir at room temperature for 6h, the reaction system is extracted with EA and water, the organic phase is washed with saturated aqueous sod...
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