Method for preparing LCZ696
A compound, sodium hydroxide technology, applied in the directions of organic chemical methods, carboxylic acid amide preparation, chemical instruments and methods, etc., can solve the problems such as many aminolysis impurities and hydrolysis impurities, low yield of target products, and unfavorable scale-up production. , to achieve the effect of less hydrolysis impurities, good solid precipitation state, and reducing the generation of hydrolyzed products
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Embodiment 1
[0044] The preparation of embodiment 1 compound III
[0045]
[0046] Dissolve 230g of the compound of formula (II) in 2.3L of dichloromethane, add 90g of succinic anhydride, and stir; add 190g of sodium acetate and stir for 3 hours; concentrate the reaction solution under reduced pressure until there is no fraction, and add the residue to 3.6L of ethyl acetate Add 1N hydrochloric acid prepared with 230 g of concentrated hydrochloric acid and 2.3 L of water, discard the aqueous phase after stirring, and concentrate the organic phase under reduced pressure until there is no distillate; dissolve the residue in 5.7 L of methyl tert-butyl ether, add 2.9 L of water L, stir and cool down to 0-5°C; add 0.7L of 1N sodium hydroxide dropwise, stir for 1-2h, separate the liquids, add 5.7L of methyl tert-butyl ether to the water phase, and stir for 30min; add dropwise 1N chlorine dioxide to the water phase Calcium solution 0.7L, stirred and centrifuged; 80 ± 5 ° C air-dried for 10 hour...
Embodiment 2
[0047] The preparation of embodiment 2 compound I
[0048]
[0049] Add 250 g of the compound of formula (III) into 2N hydrochloric acid prepared from 2.8 L of isopropyl acetate, 130.5 g of concentrated hydrochloric acid and 0.57 L of water, stir until it dissolves, separate the liquids to remove the water phase, and concentrate the organic phase under reduced pressure until there is no distillate. Dissolve the substance in 4.8L of acetone, add 0.6L of n-heptane and 250g of valsartan, and stir to dissolve; stir to raise the temperature to 45°C, add dropwise a solution made of 68.5g of sodium hydroxide and 23.8g of water, and keep the temperature not exceeding 45°C; Distill under reduced pressure after the dropwise addition, concentrate the volume to about 4L; add isopropyl acetate, continue to concentrate under reduced pressure to 4L; add isopropyl acetate, continue to concentrate under reduced pressure to 4L; add isopropyl acetate to continue reducing Concentrate under pre...
Embodiment 3
[0050] The preparation of embodiment 3 compound I
[0051]
[0052] Add 3 g of compound of formula (III) to 30 ml of isopropyl acetate and 6.9 ml of 2N hydrochloric acid, stir until dissolved, separate liquids to remove the water phase, wash the organic phase twice with water; concentrate the organic phase under reduced pressure until there is no fraction, and dissolve the residue in Add 11ml of n-heptane and 3g of valsartan to 55ml of acetone, stir to dissolve; stir to raise the temperature to 35°C, add dropwise a solution made of 0.82g of sodium hydroxide and 1.5g of water, and keep the temperature of the system below 45°C ℃, drop the temperature down to 15-25 ℃ and stir for 3 hours; under the protection of nitrogen, suction filter, dry the filter cake at 20-25 ℃ under reduced pressure for 6 hours, open the box and turn over, weigh until constant weight, and obtain the compound of formula (I) 5.82g, yield 88.1%, purity 99.50% [HPLC method: chromatographic column: C18 (150...
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