Introduction to the Application of Efficient Catalyst DMAP
Acylation is one of the most common organic chemical reactions, and the commonly used catalysts for acylation reactions are pyridine and triethylamine. In 1967, Litvinenko et al. found that 4-dimethylaminopyridine (DMAP) was used to catalyze the benzoylation reaction of m-chloroaniline, and the reaction rate increased by about 104-105 times compared with pyridine as a catalyst. Therefore, 4-dimethylaminopyridine, as a new type of high-efficiency acylation catalyst, has attracted more and more people's favor. In addition, DMAP has a significant catalytic effect on many reactions such as etherification reaction, esterification reaction, alkylation reaction and hydroxyl protection reaction of alcohols. It has broad application prospects in the fields of analytical chemistry, organic synthesis, drug synthesis, pesticides, dyes, fragrance chemistry, polymer chemistry, etc.
DMAP is dubbed as a "super catalyst" because DMAP, as a catalyst, has many advantages such as fast reaction speed, mild reaction conditions, high reaction yield, wide range of solvent selection, and less catalyst dosage .
As a catalyst, DMAP can be applied to the following types of reactions:
1. Acylation reaction
DMAP can not only catalyze the acylation reaction of simple reactants, but also significantly increase the reaction rate and yield of some high-steric hindrance, low-activity alcohol and phenol acylation reactions. DMAP as a catalyst can increase the yield of many acylation reactions It can reach more than 90%, and the reaction conditions are mild, which can be realized at room temperature.
2. Esterification reaction
The esterification reaction of carboxylic acid and alcohol needs to be carried out at higher temperature. Under the action of DMAP catalyst, it can proceed rapidly at room temperature. For example, when the esterification reaction of amino acid needs to be carried out at high temperature, but the racemization product is easy to be obtained at high temperature, when DMAP is added, not only the rapid esterification at low temperature, but also avoid the racemization of raw materials and products during the reaction process , greatly increasing the reaction yield.
3. Etherification of Alcohols and Phenols
DMAP can also be used to catalyze the etherification reaction of alcohols and phenols.
For example, using DMAP as a catalyst to catalyze the etherification reaction of alcohol and trityl chloride, the yield can be increased by 20% to 30%.
Using DMAP as a catalyst to catalyze the reaction of phenol and dimethyl carbonate can not only avoid the use of highly toxic dimethyl sulfate, but also complete the reaction. In addition to the target product, the by-products are CO2 and methanol, and no three wastes are produced. Its reaction formula is as follows:
4. Synthesis of Macrocycles
DMAP catalyzed the synthesis of some natural macrocyclic compounds, not only can significantly improve the reaction conditions, but also significantly improve the yield and product purity.
5. Isocyanate Reaction
The reaction of carboxylic acids with isocyanates is much faster with DMAP than with pyridine . For example, when phenylacetic acid and phenylisocyanate react in dichloromethane at 24 °C, DMAP is used to catalyze the reaction for 5 minutes, and the yield can reach 66%; while pyridine is used to catalyze the reaction, the reaction lasts for 2 hours, and the yield is only 53%. %.
Utilizing this reaction, it has broad application prospects in the synthesis of ampicillin series antibiotics.
Application of DMAP in Synthesis of Antitumor Drugs
Gambogic acid (Gambogic acid) is one of the main active ingredients of traditional Chinese medicine Gambogic. It has anti-tumor activity against a variety of tumors, has very high selectivity for tumor cell inhibition, and has no obvious effect on normal hematopoietic system and immune function. influences. However, the solubility of gambogic acid in water is very small, which affects its medicinal value. Matrine is one of the main active ingredients of traditional Chinese medicine Sophora flavescens. It has obvious inhibitory effect on tumor cells, not only has no damage to normal cells, but can even increase the number of white blood cells and improve the immune function of the body. The modified derivatives of matrine also have better water solubility. For this reason, Hou Xuefeng, Chu Zhusheng, et al. used gambogic acid and N-benzylmatrine to react with DMAP and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Under the esterification reaction, N-benzyl matrine gambogic acid ester was synthesized. The reaction can proceed smoothly, thanks to the catalytic effect of DMAP, and the reaction conditions are mild, and the product yield is high.
Vitamin E succinate , the molecular formula is C33H54O5, can inhibit the growth of various tumor cells such as breast cancer and prostate cancer, but has no cytotoxicity and inhibitory effect on normal cell growth. Zheng Yansheng and Mo Qian used DMAP as a catalyst to synthesize vitamin E succinate from vitamin E and succinic anhydride. DMAP is used as a catalyst in the synthesis process, which has low consumption, high catalytic activity, no corrosion to equipment, no pollution to the environment, few side reactions, simple production process, and can reduce costs. It is an excellent catalyst for the synthesis of vitamin E succinate. It has good industrial development value and application prospect.
Methylerythromycin is a macrolide anti-inflammatory and antibacterial drug. Compared with erythromycin, it is more stable to gastric acid, has good oral absorption, high blood concentration, reaches the peak value quickly (1h~2h), and has a long half-life. Blue-positive bacteria have a strong antibacterial effect. Therefore, it has the laudatory title of "golden stomach medicine". The preparation of tri-O-acetylated erythromycin derivatives is one of the key steps in the synthesis of methylerythromycin. The traditional synthesis method is to react at 25°C for 10 days in the presence of pyridine and acetic anhydride, and the yield is 95.2%. Liang Ya, Gao Suhua and others used the DMAP catalyst to react with stirring at 25°C for 24 hours, and catalyzed the synthesis of tri-O-acetylated erythromycin derivatives with a yield of 95.7%. Compared with the traditional method, it only needs 24h at the same temperature, and the reaction rate is increased by 10 times. It can be seen that the catalytic synthesis of tri-O-acetylated erythromycin by DMAP has the advantages of simplicity, rapidity and high yield compared with traditional methods.
Benzoylphenobarbital, chemically known as 1-benzoyl-5-ethyl-5-phenylbarbituric acid, is a prodrug of the sedative phenobarbital, which is itself an antiepileptic drug [4 ]. Compared with phenobarbital, it has the characteristics of less toxicity, less side effects and less dosage. Using phenobarbital silver salt and benzoyl chloride to synthesize benzoylphenobarbital under the condition of no catalyst, the yield is only 20%. Fan Chongguang and Ma Feng used phenobarbital and benzoyl chloride as raw materials, DMAP as a catalyst, and triethylamine as an acid-binding agent. When other experimental conditions were the same, the yield was 64% and the content was 99%.
With the improvement of people's requirements for herbicides, it is necessary to find better synthetic methods to increase the yield of pesticides and achieve high-efficiency production. Because of their low toxicity, no pollution, and no residue, amino acid amide derivatives have gradually attracted people's close attention and attention. According to relevant literature reports, N-acylalanine derivatives have high-efficiency insecticidal, bactericidal and herbicidal biological activities, and have attracted more and more interest because of their wide range of biological activities. Among them, 5-aryl-2-furancarboxylic acid and its derivatives are groups with relatively high herbicidal activity. In order to find the lead compounds of new pesticides with higher activity, insert 5-o-chlorophenyl-2-furancarboxylic acid at the N-terminal of alanine, connect substituted aniline at its C-terminal, and use N,N'-dicyclohexyl carbon Diimine (DCC) was used as dehydrating agent for acylation , and 4-dimethylaminopyridine (DMAP) was used as dehydration accelerator to speed up the reaction rate. Ten compounds were synthesized. Preliminary results showed that the compound had certain of herbicide. DMAP acts as a catalyst in its synthesis process, plays a catalytic role, shortens the reaction time and improves the reaction rate.
Benzimidazoles and their derivatives are widely used agricultural fungicides, plant virus inhibitors, fungicides and insect repellents. my country's Chen Hong and others chose triethylamine as the acid-binding agent and DMAP as the catalyst to synthesize three benzimidazole phenoxylactose ester compounds. Relevant experimental results show that the DMAP/Et3N system makes the product yield more than 52.7%, and has the advantages of lowering the reaction temperature and shortening the reaction time. The biological activity shows that its anti-tobacco mosaic virus activity reaches 52.2%. It can be seen that DMAP is a highly efficient catalyst compared with the phase transfer method.
The acaricide and fungicide dinitrocrotonate is a mixture of two isomers. This product is developed and commercially produced by Rohm&Hass. The main formulations of the product are WP, EC and DF, and it is used in conjunction with systemic fungicides. In 2005, Dow Chemical Company of the United States applied for registration of this product in Europe, and its sales market is mainly concentrated in Europe, America and the Middle East. In the synthesis process of dinitrocrotonate, when the reaction temperature is 30~40°C, compared with catalysts such as dimethylformamide and triethylamine, 4-dimethylaminopyridine is used as the catalyst , and the reaction result is better. Good, the product content can reach 95.4%, and the product yield can reach 85.6%.
As an acylation catalyst, DMAP has a strong catalytic effect on the acylation reaction, and is widely used in the synthesis process of pesticides.
Acetophos, researched and developed by Sandoz. AG in 1972, is mainly used in crops such as fruit trees, corn, vegetables, alfalfa and potatoes to control Diptera, Hemiptera, Lepidoptera, Coleoptera and other crops. It is a kind of high-efficiency, broad-spectrum, non-systemic contact and stomach toxicity organophosphorus insecticide with low toxicity . Due to its high efficiency and low toxicity, it is very in line with the current situation of my country's pesticide industry and has broad market prospects. In the early reports on the synthesis of pyrimethion, the synthetic route is long, there are many intermediate steps, and there is no supply of key intermediates in the market, which makes its industrial production difficult. In the later study, the factors affecting the yield of pyrimethion were investigated through single factor experiments, and the optimal process conditions for the synthesis of pyrimethion were obtained. In the synthesis process, when 4-dimethylaminopyridine is used as a catalyst, compared with the catalytic effects of catalysts such as dodecylbenzyl ammonium chloride and tetrabutylammonium bromide, the reaction yield increases rapidly, making the product The yield reached 91%, and the product purity was 74.0% under the process conditions, which reached the best effect of catalytic effect. The use of 4-dimethylaminopyridine makes the synthesis of pyrimethion reach high efficiency and high yield.
Although there are many reports on the method of synthesizing the organophosphorus insecticide and acaricide quinalphos, industrial production is very difficult , because either the yield is low, resulting in difficulty in post-processing, and a large amount of solvent loss; The efficiency is high, expensive solvents are needed in the synthesis process, and industrial production is also limited. In the research on the synthesis of Quetiaphos, it was found that one of the main reasons for the low yield of Quetiaphos is the decomposition of Quetiaphos when the non-polar solvent is recovered. Considering that the solvent of Quetiaphos emulsion is xylene, so we focus on the research A synthetic method using DMAP as a catalyst. Relevant experimental results show that the reaction cycle of the method is short, the conditions are mild, and the yield of Quetiaphos is over 90%. The synthesis method no longer needs to distill the solvent, greatly reduces the loss of the solvent and the pollution to the environment, and the synthesis process is simple to operate, effectively avoids the decomposition of the product at high temperature, and reduces the production cost.
With the improvement of acylation synthesis technology, the scope and amount of DMAP are also gradually increasing. Due to the characteristics of easy-to-obtain raw materials, simple synthesis, low cost, low toxicity, no bad smell, convenient use, outstanding catalytic effect, and stable storage in ultra-efficient acylation catalysts, DMAP is increasingly used in organic synthesis reaction. The main problem at present in the country is
DMAP is expensive, and its application in industry is not high, and its economic benefits are not significant. Therefore, it is necessary to strengthen the research on its synthetic technology, in order to reduce the production cost, broaden the use, and expand its application range in organic synthesis to meet the needs of chemical production.
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