Aliskiren intermediate, and preparation method therefor and application thereof
An intermediate and reaction technology, applied in the field of compound intermediates and their preparation, can solve the problems of slow reaction, low yield, many impurities, etc., and achieve the effects of reducing power and labor costs and improving yield
- Summary
- Abstract
- Description
- Claims
- Application Information
AI Technical Summary
Problems solved by technology
Method used
Image
Examples
Embodiment 1
[0050] The preparation of embodiment 1 intermediate (d)
[0051]
[0052] The intermediate (c) (780g) was dissolved in 4L of ethanol, then added to the reactor, and the temperature was lowered to 5°C. Weigh 240g of lithium hydroxide monohydrate and dissolve in 2.5L of water, heat to 40°C to dissolve, add it dropwise to the above reactor, control the temperature at 0-10°C, after the dropwise addition, control the temperature at 5-10°C , The reaction was carried out for about 1h, until there was no raw material by TLC (thin layer chromatography). Concentrate to remove ethanol, add 4L water to the water phase, extract the water phase with 2.7L methyl tert-butyl ether, extract the water phase with ethyl acetate, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, and filtrate Concentrate to dryness to obtain 811 g of oil.
[0053] 811g of the obtained oil was washed into the reactor with 4L of ethanol and 4L of water, an...
Embodiment 2
[0057] The preparation of embodiment 2 intermediate (e)
[0058]
[0059] At room temperature, 5L of dichloromethane was added to the reactor, and then 750g of the compound shown in the substrate formula (d) prepared in Example 1, 74.7g of 4-dimethylaminopyridine (DMAP, 0.45 equivalents) and 344g of triethyl Add amine (2.5 equivalents) into the reactor, control the reaction temperature at about 25°C, add 194g of acetic anhydride (1.4 equivalents) dropwise, after the dropwise addition, keep stirring at 23-28°C for 30 minutes, take a sample TLC to monitor the disappearance of the raw material point.
[0060] Then, add 4L of water (no significant temperature rise) into the reactor, stir for 30 minutes; separate the liquid, extract the aqueous phase with dichloromethane, combine the organic phase, and use 1N hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride for the organic phase successively washed, dried over anhydrous sodium sulfate, filtered, and ...
Embodiment 3
[0063] The preparation of embodiment 3 intermediate (b)
[0064]
[0065] In the 10L there-necked flask, add the intermediate (e) solid 640g prepared in Example 2, dissolve with 5L ethanol / water (volume ratio is 8:1) mixed solvent, add palladium carbon 64g (water content 50%, dry basis 10% ), water 110mL, replace the system with nitrogen three times, then replace the nitrogen with hydrogen three times, stir, keep the internal temperature around 55°C, and the system pressure is about 1.2 atmospheres. After 16 hours of reaction, TLC monitors the reaction. Spin dry, add 5L ethyl acetate and 3L water, stir and separate the liquid, continue to extract the water phase with ethyl acetate twice, combine the organic phases, wash with saturated sodium chloride solution, dry, spin dry, add 1.2L n-heptane Slurry for 0.5 h and filter to obtain 598 g of a white solid, which was confirmed to be the compound represented by formula (b) through structure, with a HPLC purity of 99.3% and a me...
PUM
Login to View More Abstract
Description
Claims
Application Information
Login to View More