Background and overview[1]
Anterior gastrointestinal motility disorder is considered to be the main cause of functional dyspepsia, so gastrointestinal motility drugs are currently the main drugs for the treatment of FD. Commonly used gastrointestinal motility drugs include dopamine receptor antagonists metoclopramide, domperidone, itopride, levosulpiride, 5-HT4 receptor agonists mosapride, cisapride and motilin receptor agonists agents, and the acetylchoesterase (AChE) inhibitor acotiamide, etc. Among them, acotiamide is a new type of FD treatment drug approved in the world. 2,4,5-trimethoxybenzoic acid is its important pharmaceutical synthesis intermediate. It is a white solid and its Chinese alias is mandel. Acid, mandelic acid, etc., the English name is 2,4,5-trimethoxybenzoic acid. During the synthesis process, the oxidant is still an effective substance for converting aromatic aldehydes into aromatic acids. Traditionally, heavy metal salts (such as potassium dichromate, picolinate chromic acid) are mainly used. Salt, etc.) and peracid are used as oxidizing agents. However, it not only has severe reaction conditions and expensive oxidants, but also has shortcomings such as complicated post-processing and difficulty in completely purifying the product. It also causes environmental pollution. Therefore, it is necessary to find an ideal way to prepare p-toluic acid for para-toluic acid. The foundation was laid for the industrial production of methylbenzoic acid. Asaral is a synthetic intermediate of 2,4,5-trimethoxybenzoic acid.
Preparation[1]
A synthesis method of pharmaceutical intermediate 2,4,5-trimethoxybenzaldehyde (asaraldehyde), the method includes the following steps:
Step 1. Add 4.42g of 1,2,4-trimethoxybenzene and 10ml of DMF to the reaction bottle in sequence, take an ice-water bath, control the temperature to 10°C, and add dropwise a DMF solution containing 1.47g of phosphorus oxychloride into the solution. After the dropwise addition is completed, the mixture is heated to 60°C and stirred for 1 hour;
Step 2, control the reaction by TLC. If the reaction is complete, pour the reaction solution into 30 ml of cold water, add 30% potassium hydroxide solution dropwise to adjust pH=7, lower the temperature by 5°C, crystallize for 30 minutes, filter and wash, to obtain 2,4,5-trimethoxybenzaldehyde (asaraldehyde);
Apply[1]
Asaraldehyde can be used to prepare 2,4,5-trimethoxybenzoic acid
1) Add 5g 2,4,5-trimethoxybenzaldehyde (asaraldehyde), 1.5g ZrO2/MCM-41 nanocatalyst, 10mol% silver nitrate and 50ml acetonitrile in sequence into the reaction bottle, and add dropwise at room temperature After the dripping of 8.7g of 30% hydrogen peroxide solution is completed, the reaction system is heated to 50°C and reacts for 3 hours;
2) After the reaction is completed, add the reaction solution to 50ml of 10% cold alkali solution and stir, filter the insoluble substances, adjust the filtrate to pH=3.5 with concentrated sulfuric acid, extract with ethyl acetate (2×50ml), and combine the organic phases. Wash once with saturated sodium chloride, dry with magnesium sulfate, concentrate, and recrystallize with benzene and petroleum ether to obtain the white crystal product 2,4,5-trimethoxybenzoic acid.
The preparation method of the ZrO2/MCM-41 nanocatalyst is as follows:
Step 1. 50g MCM-41 zeolite powder is activated at 500°C and dispersed in 50ml of ethanol. After ball milling, transfer the mixture of activated zeolite and ethanol to a three-necked flask containing 20ml of ammonia water and raise the temperature. to 60°C, heat for 1 hour, then add 10 ml of TEOS, continue stirring for 6 minutes, filter the obtained slurry, wash with ethanol 3 times, and finally obtain the short-chain modifier modified MCM-41 filter cake;
Step 2. Add 0.8 mol ZrO2 to a mixed alkali solution of 1.5 mol sodium hydroxide and 1.2 mol anhydrous sodium carbonate and sonicate for 30 minutes. Add 50 mL of the above mixed solution under vigorous stirring at room temperature to contain 0.75 mol nickel nitrate and aluminum nitrate. A suspension was obtained in 0.25 mol salt solution;
Step 3. Disperse 35g of the short-chain modifier-modified MCM-41 filter cake obtained in step 1 into ethanol, add 80 ml of the suspension obtained in step 2, stir for 1 hour, filter, and wash with ethanol three times. The prepared mixture was then placed in an oven at 110°C for 2 hours to remove the solvent, and the modified ZrO2/MCM-41 catalyst was obtained.
Main reference materials
[1] CN201810279852.7 A synthesis method of pharmaceutical intermediate 2,4,5-trimethoxybenzoic acid
