Preparation method of AR-13324
A technology of AR-13324 and t-bu, which is applied in the field of preparation of AR-13324 inhibitors, can solve the problems of low yield, high cost, and high cost of chiral stationary phase
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Embodiment 1
[0056] Synthesis of compound 2
[0057]
[0058] Dissolve 50g of compound 1 (4-methylphenylacetic acid) in 200ml of carbon tetrachloride, heat to reflux, and add NBS (N-bromosuccinimide) (62g, 0.35mol) in batches under heating After the addition, continue to maintain the reflux state for 3 hours, a large amount of solids are precipitated, TLC shows that the raw materials are completely reacted, the reaction solution is cooled to room temperature, poured into 500 ml of ice water under stirring, continue to stir for 20 minutes, filter, filter cake Wash 3 times with water (300 ml each time) to obtain a white solid, dry the white solid at 50 ° C for 10 hours to obtain 51 g of compound 2 (4-bromomethylphenylacetic acid), compound 2 is directly carried out to the next step without further purification .
[0059] Synthesis of compound 3
[0060]
[0061] Compound 2 (50 g) was added to 200 ml of water, stirred and heated to reflux and maintained for 2 hours, the reaction becam...
Embodiment 2
[0097] In this example, except that the treatment steps of compound 12 are different, the others are the same as in Example 1.
[0098] The treatment steps of compound 12 are as follows: Dissolve compound 12 (3.9g) in 40ml of dichloromethane, then add methanesulfonic acid (2g, 21.6mmol) dropwise, stir overnight at room temperature, rotary evaporate under reduced pressure, add 100ml of diethyl ether was stirred to produce a large amount of white solid, which was filtered and dried to obtain a white solid (4.54g), with a yield of 97.8% and a purity of 98.2%. The obtained substance was AR-13324 methanesulfonate as detected by 1HNMR.
Embodiment 3
[0100] In this example, except that the synthesis steps of compound 5 are different, the others are the same as in Example 1.
[0101] Synthesis of compound 5A (chiral ligand)
[0102]
[0103] Compound 4 (50g, 178.3mmol) was dissolved in anhydrous tetrahydrofuran (500ml), the temperature was cooled to -10°C with dry ice acetone, and oxalyl chloride (13g) was slowly added dropwise, keeping the dropping temperature not higher than -10°C to obtain the acid chloride; At the same time, in another three-necked flask, 28.7g (R)-4-benzyl-2-oxazolidinone was added to 500ml of anhydrous tetrahydrofuran, replaced with nitrogen, cooled to -78 degrees with dry ice acetone, and slowly added dropwise 7.2ml n-Butyllithium solution (concentration is 2.5mol / L) and keep the temperature at -78 degrees, after the dropwise addition is completed, continue to stir at -78 degrees for 1 hour, and slowly add the acid chloride prepared in front to the solution through a constant pressure funnel. In ...
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