Method for researching and controlling impurity E in Valsartan
A technology of valsartan and valine ester, which is applied in the field of impurity VLSI-E research and control, and can solve the problem of inability to use gas chromatography to detect isoleucine ester, inconvenient transportation and storage, and detectors such as evaporative light Low sensitivity, failure to meet detection requirements, etc.
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Embodiment 1
[0023] Embodiment 1. The preparation of valsartan
[0024] In a 1000ml three-necked flask, add 118g N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester and 400ml toluene, 44g sodium bicarbonate, stir, and cool to 0 ℃. Add 52ml of valeryl chloride dropwise, keeping the temperature below 10°C. After the addition was complete, it was stirred at room temperature for 10 hours; TLC and HPLC showed that the reaction was complete. Add 100ml×2 water, stir for 0.5 hours, separate the water phase; wash the toluene phase with 50ml 1N hydrochloric acid, 50ml 5% sodium bicarbonate and 50ml×2 brine, and dry with 40g anhydrous sodium sulfate. After filtration, the filtrate was rotary evaporated to obtain a light yellow oily substance, namely N-[(2'-cyanobiphenyl-4-yl)methyl]-N-pentanoyl-(L)-valine methyl ester.
[0025] Add 135ml of tributyltin chloride, 40g of sodium azide, 400ml of xylene and N-[(2'-cyanobiphenyl-4-yl)methyl]-N-pentanoyl-( L)-Valine methyl ester, heat up to 140°C ...
example 2
[0026] Example 2. Refining of Valsartan
[0027] Add the obtained valsartan crude product into 460ml of ethyl acetate, and heat until completely dissolved. After cooling to room temperature, continue to cool to 0°C for 2 hours, filter, and wash the filter cake with a small amount of cold ethyl acetate. Dry to obtain 80g valsartan primary crystallization product. Add the primary crystallization product of valsartan to 400ml ethyl acetate, heat to dissolve, stir and cool to room temperature, filter, wash the filter cake with a small amount of ethyl acetate, and dry to obtain 60g secondary crystallization product of valsartan, HPLC purity >99.7%.
example 3
[0028] Preparation of Example 3.VLSI-E
[0029] Add 12.5g of potassium carbonate and 85mL of acetonitrile into a 250ml three-necked flask, add 5.1g of L-isoleucine methyl ester hydrochloride, add 16.7g of VLS-02, and heat to 50-55°C. Reacted for 7.5h, filtered, and the filtrate was rotary evaporated under reduced pressure. The oil was dissolved in 70mL of toluene, 4.1g of sodium bicarbonate was added, and 4.6ml of valeryl chloride was added dropwise. After the addition, stir at room temperature for 3 to 4 hours. The toluene layer was washed with 30ml×2 brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 21g of oil. The above oil was dissolved in 90ml of methanol, and 1ml of hydrochloric acid was added dropwise. After the addition, stir at room temperature for 3 to 4 hours. After filtration, the filtrate was spin-dried under reduced pressure to obtain 14.4 g of oil. 60ml of toluene was added to the above oil, and a solution of 5.6g of potassium hydroxide d...
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