Control method for diovan foreign matter
A technology of valsartan and synthesis method, which is applied in the field of valsartan impurity control, and can solve problems such as valsartan impurity control methods that have not yet been seen
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Embodiment 1
[0024] Embodiment 1. The preparation of valsartan
[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 (VLSM-02), the temperature is raised to 140°C for 24-30 hours and the VLSM-02 is less than 2%. Cool at room temperature, add 560g of 10% potassium hydroxide solution and stir at 30-35°C for 8-16 hours. After the reaction is completed (VLSI-D is less than 0.5%), separate the xylene layer, add 200ml of xylene and 200ml of isopropyl ether to wash . Add 42g of sodium nitrite to the aqueous layer, slowly adjust the pH to 2-2.5 with concentrated hydrochloric acid, and stir. Extract with 500ml×2 ethyl acetate, combine the ethyl acetate layers, wash with brine, dry over anhydrous sodium sulfate, and recover the solvent under reduced pressure to obtain 115g of yellow viscous oil, which is crude valsartan.
Embodiment 2
[0026] Embodiment 2. The 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%.
Embodiment 3
[0028] The preparation of embodiment 3.VLSI-A
[0029] Add 12.5g of potassium carbonate and 85mL of acetonitrile into a 250ml three-necked flask, add 5.1g of D-valine 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 hydroxid...
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Abstract
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