Dipropylmalonic acid diester preparation method

Abstract

The invention provides a preparation method of dipropylmalonic acid diester. The method comprises the following steps: in an organic reaction solvent, alkali is taken as a catalyst, diester malonate and 1-halogenated n-propane are reacted to prepare dipropylmalonic acid diester, a reaction equation is shown as a reaction equation (I), in the reaction equation, R1 and R2 are respectively and independently selected from straight chain or branched chain alkanes with 1-5 carbon atoms; X is halogen; the alkali is MO-R3, wherein the R3 is straight chain or branched chain alkanes with 1-4 carbon atoms, and M is sodium or potassium. Compared with the prior art, the dipropylmalonic acid diester preparation method has the following advantages and active effects: a phase-transfer catalyst is not added in the reaction, the reaction speed is fast, the postprocessing is simple, dipropylmalonic acid diester can be directly used in a next step, and is suitable for synthesis of pharmaceutical intermediates.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a preparation method of dipropylmalonate diester. Background technique [0002] Dipropylmalonate diester is an important class of chemical drug intermediates. Its structural formula is shown below. Dipropylmalonate diester can be used to synthesize sodium valproate and half valproate for the treatment of mental diseases. sodium. [0003] [0004] US Patent No. 5,856,569 describes the following preparation method: the starting material used is alkyl carbonyl acetate, and the double-alkylated product is hydrolyzed, followed by decarbonylation to obtain valproic acid. The reaction scheme is as follows: [0005] [0006] This method has the following disadvantages: [0007] 1. The reaction is carried out in an organic phase (bromopropane) and aqueous phase (sodium hydroxide, water) two-phase system, which requires the use of a large amount of phase transfer catal...

AI Technical Summary

Problems solved by technology

The use of phase transfer catalysts increases the workload of post-processing, and also affects the quality and yield of products. The phase transfer catalysts themselves also pollute the environment.

[0008] 2. the mol ratio of bromopropane and reactant alkyl carbonyl acetate in the reaction is (0.5+0.249): 0.05, and the consumption of bromopropane is about 15 times of reactant alkyl carbonyl acetate consumption, has used greatly Excessive halopropane wastes a lot of raw materials, increases production costs, and the post-treatment of excess bromopropane is complicated, affecting product quality and yield

[0009] 3. The reaction takes a long time, more than 45 hours

This method has the following disadvantages: cesium hydroxide is the most alkaline substance in inorganic substances, is extremely corrosive, belongs to dangerous goods, and is not suitable for use in industrialized production; this reaction is a solid / liquid two-phase reaction, and hydrogen The solubility of cesium in DMF is not good, so the reaction takes a long time; DMF has a high boiling point, it is difficult to remove it by rotary evaporation after the reaction, and a large amount of water washing is required, which increases the reaction cost and affects the product quality.

[0015] In this reaction, sodium metal is used, and tert-butanol is used as the reaction solvent. This method has the following disadvantages: sodium metal is very active in chemical properties, can react with oxygen and is flammable, is not convenient for storage and use, is not conducive to safe production, and is not suitable for production. Suitable for large-scale industrial production; the solubility of sodium metal in tert-butanol is not good, the reaction is a solid / liquid two-phase reaction, and the reaction takes a long time

The disadvantages of the above two methods are: sodium hydride is active in nature, sensitive to water, inconvenient to store and use, not suitable for large-scale industrial production, and unfavorable for safe production; sodium hydride has poor solubility in DMF, and the reaction is solid / liquid Two-phase reaction, the reaction takes a long time; DMF has a high boiling point, as a solvent, it is difficult to remove it by rotary evaporation after the reaction, and a large amount of water washing is required, which increases the reaction cost and affects the product quality.

[0026] The disadvantage of this method is: the reaction is carried out in an organic phase and an aqueous two-phase system, and a large amount of phase transfer catalyst is required. In this method, benzyltriethylammonium chloride (TEBAC) is used as a phase transfer catalyst. The transfer catalyst increases the workload of post-processing, which also affects the quality and yield of the product. The phase-transfer catalyst itself also pollutes the environment; the reaction requires the use of excessive halopropane, which wastes raw materials and increases costs, and the post-treatment of excessive bromopropane It is also very troublesome and affects product quality and yield; the reaction time is very long, and the two-phase reaction requires at least 25 hours

Images