Benzobarbital is a long-acting barbiturate drug. Its successful synthesis process has been improved many times, and now a variety of effective synthetic methods have been developed. Benzobarbital was originally discovered by German pharmacist Euichstang. In 1904, he prepared Benzobarbital by reacting benzohydrazide and dimethyl carbonate.
1. Reaction of acetophenone and urea:
This method is the earliest synthesis method of Benzobarbital, which generates diphenylurea through the reaction between acetophenone and urea, and reacts with acetic anhydride in the presence of acetic acid to generate Benzobarbital. The chemical formula for the reaction is:
Acetophenone + urea → Benzobarbital
Experimental steps:
(1) Prepare a solution of acetophenone and urea. Dissolve acetophenone and urea in acetone respectively, heat and stir until both are completely dissolved.
(2) A solution of acetophenone and urea was mixed. After mixing the two solutions, stir well with a stirrer at room temperature. Note that this process needs to be stirred for a long time to avoid incomplete reaction of urea.
(3) Heating the reaction mixture. The reaction mixture was put into a beaker, covered and heated in an oil bath to maintain the reaction temperature at 100-110°C.
(4) Centrifuge at the end of the reaction. After the reaction was finished, the beaker was taken out and centrifuged with a centrifuge, and a precipitate was obtained after centrifugation.
(5) COLLECTION OF BENZOBAR BITAL. The precipitate was extracted with acetone. The extract is mixed with a small amount of activated carbon, heated in a beaker and filtered. White crystals will form in the filtered liquid, which is Benzobarbital.
(6) Crystal purification. Wash with glacial acetic acid aqueous solution, dissolve Benzobarbital in the washing solution, add concentrated phosphoric acid or sulfuric acid to precipitate, then filter, wash and dry.
The advantage of this method is that it is simple to operate, but the yield is low, and the raw materials are mainly lost, which leads to an increase in production cost. In this reaction, acetophenone and urea react to generate Benzobarbital. Due to the volatility of acetone, washing with glacial acetic acid aqueous solution can improve the purity of the product to a certain extent. Through experimental analysis, the prepared Benzobarbital has high quality and can meet the application requirements in the fields of pharmacy and biochemistry.
2. Reaction of phenylamino ketone ester and HCHO:
This method is one of the most commonly used Benzobarbital synthesis methods, and it produces Benzobarbital through the reaction between anilamino ketoesters and formaldehyde. This method is easy to operate, but the purity of Benzobarbital is low.
3. Reaction of benzaldehyde and dimethylacrylamide:
This method is to synthesize Benzobarbital by reacting benzaldehyde with dimethylacrylamide, which is a simple synthetic method. This method has the advantages of high yield and high purity, but the cost of dimethylacrylamide is relatively high.
4. Benzaldehyde and urea reaction:
The synthesis method is to produce diphenylurea through the reaction of benzaldehyde and urea, and in the presence of activated carbon as a catalyst, diphenylurea reacts with methoxyacetic acid to produce Benzobarbital. The production process of the method is simple, but the catalyst is likely to cause environmental pollution.
The synthesis process of Benzobarbital mainly includes the following steps:
1. Add benzaldehyde and urea to an organic solvent (usually ethanol), and stir it evenly. During the reaction, gas chromatography is usually used to determine the remaining amount of reactants. In the first step, benzaldehyde is usually added in an amount slightly more than theoretically required to eliminate moisture from the solvent.
2. Heat the reaction mixture to an appropriate reaction temperature (usually 120-125°C) and keep it for a certain period of time. In this step, the conversion rate of the reactants and the purity of the product can be adjusted according to the temperature and time of the reaction.
3. After a long time of reaction, a precipitate will form in the reaction mixture. The precipitate is removed and washed with water or alcohol. Typically, the purpose of washing is to remove impurities and lyophilize to obtain a purer product.
4. The product is purified by crystallization to remove residual impurities and drugs. The end product of this process is Benzobarbital.
Generally speaking, the synthesis process of Benzobarbital is relatively simple, but it still needs the support of certain technology and equipment. In addition, factors such as temperature, reaction time and reaction conditions need to be strictly controlled in the process to ensure the purity and quality of the product.
In the synthetic process of Benzobarbital, the reaction method of benzaldehyde and urea is an important method. This method can synthesize high-purity Benzobarbital in a short time by rationally controlling the reaction conditions and adding an appropriate catalyst, which provides important technical support for the production and application of the drug.
5. Benzyl alcohol and urea reaction:
This method produces diphenylurea through the reaction between benzyl alcohol and urea, and the conversion efficiency of Benzobarbital is higher than other methods in an anhydrous environment.
C7H8O + CH4N2O → benzamide diacetate
Benzamide diacetate + H+ → intermediate product
Intermediate product → C19H16N2O4
Experimental steps:
1) Prepare the reaction substrate:
First, prepare benzyl alcohol and urea. Diacetate benzamide can be extracted from the reaction mixture after the reaction for further separation and purification.
2) Reaction process:
Benzyl alcohol and urea were added into the reaction flask according to the stoichiometric ratio, as shown in Figure 1. A small amount of methanol catalyst was added. Stir the reaction vial to mix the two compounds well to form a reaction mixture.
Add molecular sieves: Add molecular sieves to the reaction vial. Molecular sieves can absorb water and avoid side reactions of the reaction.
Heating the reaction: The reaction mixture was heated in a heater. The recommended heating conditions are: the temperature of the reaction flask is 90-100°C, and the reaction duration is 2 hours.
Addition of HCl: After completion of the reaction, the reaction mixture was added to the vessel containing hydrochloric acid. Hydrochloric acid will promote the hydrolysis process of the Benzobarbital product, thereby increasing the yield of the product. Filtration through filter paper: The mixture was filtered to precipitate the purified Benzobarbital.
3) Separation and purification process
The nature of the Benzobarbital product is leapfrog performance and requires a delicate purification process.
Collect the product: Collect the Benzobarbital on the filter paper and put it in a desiccator to absorb the moisture in the air for a long time.
Extraction: Put the dried Benzobarbital into acetone for extraction, then concentrate and purify to obtain pure Benzobarbital product.
Chemical Mechanism:
When benzyl alcohol is added to the reaction system of urea, benzyl alcohol is more electrophilic than urea, because benzyl alcohol is more likely to undergo esterification reaction, so the reaction of benzyl alcohol will form the following intermediate: benzamide diacetate (C9H10N2O3) . This can be represented by the following reaction:
Benzyl alcohol + H2NCOC (NH2)2 → C9H10N2O3 (benzamide diacetate) + H2O
Next, in the presence of an acidic catalyst, the hydroxyl group in the diacetate benzamide long-chain list will be abstracted by an acid. A carbonyl group that loses H+ becomes more electrophilic. as follows:
C9H10N2O3 (benzamide diacetate) + H+ → intermediate product
This intermediate is then subjected to an acid-catalyzed internal dehydration reaction to yield Benzobarbital. In this reaction the primary alcohol reacts before the alcohol-ester linkage is obtained. Acid catalysis is necessary to destroy the hydroxyl groups and further alter the relative positions of the carbonyl and carbonyl groups. Acid catalysis brings the carbonyl and ester bonds closer together, thereby speeding up the chemical reaction. as follows:
Intermediate product → Benzobarbital
Therefore, the reaction method of benzyl alcohol and urea of Benzobarbital is to produce Benzobarbital by thoroughly mixing the reaction mixture and carrying out an important chemical reaction under the action of acid catalysis.
6. Reaction of aniline and dimethyl carbonate:
The method is to produce α-phenyl-β-(2,2-dimethyl-1-pyrazol) acetone by reacting anilinone and dimethyl carbonate, and convert it in the presence of sulfuric acid Into Benzobarbital. This method is easy to operate, but the reaction time is long, so it is not suitable for mass production.
Generally speaking, there are many synthetic methods of Benzobarbital, but they mainly focus on the reaction of compounds such as benzaldehyde, anilaminoketone, acetophenone and urea. Different synthesis methods have their own advantages and disadvantages, which need to be selected according to the specific situation.