Synthesis method of key intermediate of contrast agent iodixanol impurity E
A technology of iodixanol and its synthesis method, which is applied in the fields of chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., and can solve the problems of little difference in physical and chemical properties and polarity of substances, and difficulty in removal
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Embodiment 1
[0022] Preparation of 5-amino-N-(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide
[0023] 70g of 5-amino-N,N-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide was added to a 500ml reaction flask, and 420g of Ionized water, add 5g of 98% concentrated sulfuric acid, 17g of iodine, and 22g of iodic acid, heat up to 90°C, keep stirring for 25h, take samples of the reaction solution, and detect by HPLC, where the content of the target product is about 40%, cool down to 60°C , 10% hydrazine hydrate was added dropwise, adjusted until the reaction solution KI-starch test paper did not develop color, the pH was adjusted to 7.5 with liquid alkali, cooled to 10 °C for crystallization and stirred for 24 h, suction filtration to obtain a yellow-brown solid, 60 °C normal pressure Drying to obtain 18 g of solid, HPLC detected, the content of the target product was 70%, and the yield was 30%.
Embodiment 2
[0025] Separation and purification of 5-amino-N-(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide
[0026] Add 18g of the product of Example 1 into a 500ml reaction flask, add 200ml of deionized water, heat up to 60°C to dissolve, cool down to room temperature, add it to the LX-18 resin column, use deionized water to elute, and elute to the target After the product begins to flow out, use 30v / v% methanol aqueous solution to elute, elute until the target product content in the effluent is less than 80%, stop elution, evaporate the eluent containing the target product to dryness under reduced pressure, slip out After methanol, a white solid was obtained, 100 g of deionized water was added to dissolve the temperature, the temperature was lowered to 7 °C for crystallization for 20 hours, and the white solid was obtained by suction filtration.
Embodiment 3
[0028] Preparation of 5-amino-N-(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide
[0029] Add 70g of 5-amino-N,N-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide into a 500ml reaction flask, add 300g of Deionized water, add 9g of 98% concentrated sulfuric acid, 15g of iodine, and 19g of iodic acid, heat up to 85°C, keep stirring for 24h, take samples of the reaction solution, and detect by HPLC, where the content of the target product is about 74%, cool down to 60 ℃, add 10% hydrazine hydrate to adjust until the reaction solution KI-starch test paper does not develop color, use liquid alkali to adjust pH to 7.5, cool to 10 ℃ for crystallization and stir for 24 hours, suction filtration to obtain golden yellow solid, 65 ℃ normal pressure Drying to obtain 40 g of solid, HPLC detected, the content of the target product was 83%, and the yield was 66%.
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