Benzobarbital(link:https://www.bloomtechz.com/synthetic-chemical/api-researching-only/benzobarbital-cas-744-80-9.html), also known as 5,5-diphenyl-2,4-isoglutarimidepyrrolidine-2,6-dione or pentaphenylbarbital, is a drug used in the treatment of anxiety and Medicines for sleep disorders. It is a type of barbiturates that can be synthesized by various methods. All synthetic routes of Benzobarbital are reviewed below.
1. Synthesis method of styrene peroxide
Styrene peroxide synthesis is one of the traditional synthesis methods for preparing Benzobarbital. The following are the specific steps:
1.1. Reaction materials and conditions
The main reaction raw materials of Benzobarbital's styrene peroxide synthesis method include styrene, dimethyl malonate, hydrogen peroxide and hydrochloric acid, etc. Specific requirements are as follows:
(1) Styrene: The purity requirement is high, and industrial-grade styrene with a mass fraction of more than 95% is generally selected.
(2) Dimethyl malonate: The purity requirement is relatively high, and industrial grade dimethyl malonate with a mass fraction of more than 98% is generally selected.
(3) Hydrogen peroxide: 30% hydrogen peroxide solution is generally used.
(4) Hydrochloric acid: Generally, a hydrochloric acid solution with a concentration of 37% is used.
(5) Solvent: The solvent needed in the reaction is anhydrous ether.
(6) Temperature: The reaction temperature is 0-5°C.
1.2. Synthesis steps and reaction mechanism
Benzobarbital's styrene peroxide synthesis involves a three-step reaction, as follows:
The first step: the preparation of phenylethyl malonate: styrene and dimethyl malonate react under the catalysis of hydrochloric acid to generate phenylethyl malonate.
The second step: the preparation of phenyl benzo epoxy carboxylate: phenylethyl malonate reacts with hydrogen peroxide under alkaline conditions, and Baeyer-Villiger oxidation occurs to generate phenyl benzo epoxy carboxylate .
The third step: the preparation of Benzobarbital: phenyl benzo epoxy carboxylate and acetylacetone react in the presence of hydrochloric acid, and an addition reaction occurs to generate Benzobarbital.
2. Bisamide condensation method:
The bisamide condensation method of Benzobarbital is an important preparation method, and Benzobarbital can be prepared through the reaction of benzoic acid, and the reaction process involves multiple steps. It has the advantages of simplicity and high yield.
Reaction materials and conditions:
The main reaction materials of Benzobarbital's bisamide condensation method include benzoic acid and dimethylpropionamide. Specific requirements are as follows:
(1.) Benzoic acid: The purity requirement is high, and industrial-grade benzoic acid with a mass fraction of more than 98% is generally selected.
(2.) Dimethylpropionamide: The purity requirement is relatively high, and industrial-grade dimethylpropionamide with a mass fraction of more than 99% is generally selected.
(3.) Solvent: The solvent required in the reaction is ethanol or isopropanol.
(4.) Temperature: The reaction temperature is 60-80°C.
Synthesis steps and reaction mechanism:
Benzobarbital's bisamide condensation method involves a three-step reaction, as follows:
The first step: benzoic acid dehydration reaction: benzoic acid and catalyzer carry out dehydration reaction, generate benzimide.
The second step: the addition reaction of benzimide: the addition reaction of benzimide and dimethylpropionamide in the presence of sodium carbonate generates N-(2,3-dimethyl-5- phenylpyrazol-4-one) benzamide.
The third step: the cyclization reaction of N-(2,3-dimethyl-5-phenylpyrazol-4-one) benzamide: N-(2,3-dimethyl-5-phenylpyridine oxazol-4-one) benzamide and acetylacetone undergo ring closure reaction in the presence of sodium hydroxide to generate Benzobarbital.
Response Notes
1. During the reaction process, it is necessary to maintain the reaction temperature and perform safe operation to avoid harm to the human body.
2. This method is suitable for small-scale laboratory synthesis, but it is rarely used in industry because the purity of the reaction product is not high.
The bisamide condensation method of Benzobarbital is an important preparation method, and the synthesis method includes three-step reactions: first, the acylation reaction of benzoic acid, and then an electrophilic addition reaction to generate N-(2,3-dimethyl- 5-phenylpyrazol-4-one) benzamide, and finally get Benzobarbital through bisamide condensation reaction. During the reaction, it is necessary to maintain the reaction temperature and carry out safe operation. This method is suitable for small-scale laboratory synthesis.
3. Isglutarimide condensation method:
The isoglutarimide condensation method of Benzobarbital is a commonly used preparation method. Benzobarbital can be prepared through the reaction of benzoic acid and isoglutarimide. This method has the advantages of mild reaction conditions, simple operation, and short reaction time.
Reaction materials and conditions:
Benzobarbital's isoglutarimide condensation method is mainly reacted with benzoic acid and isoglutarimide. Specific requirements are as follows:
1. Benzoic acid: The purity requirement is high, and industrial-grade benzoic acid with a mass fraction of more than 98% is generally used.
2. Isglutarimide: The purity requirement is relatively high, and industrial grade isoglutarimide with a mass fraction of more than 99% is generally selected.
3. Solvent: The solvent needed in the reaction is ethanol or isopropanol.
4. Temperature: The reaction temperature is 60-80°C.
Synthesis steps and reaction mechanism:
Benzobarbital's isoglutarimide condensation method involves a three-step reaction, as follows:
The first step: benzoic acid dehydration reaction: benzoic acid and catalyst carry out dehydration reaction to generate benzimide.
The second step: the condensation reaction of benzimide and isoglutarimide: the condensation reaction of benzimide and isoglutarimide in the presence of sodium hydroxide produces 2-phenyl-5 -(2-Pentyl)-1,3,4-thiadiazole-2,6-dione-7-carboxylic acid methyl ester.
The third step: Esterification of 2-phenyl-5-(2-pentyl)-1,3,4-thiadiazole-2,6-dione-7-carboxylic acid methyl ester: 2-phenyl - Methyl 5-(2-pentyl)-1,3,4-thiadiazole-2,6-dione-7-carboxylate undergoes an esterification reaction with ethylene glycol in the presence of a catalyst to generate Benzobarbital.
Reaction Notes:
1. During the reaction process, it is necessary to maintain the reaction temperature and perform safe operation to avoid harm to the human body.
2. This method is suitable for small-scale laboratory synthesis, but it is rarely used in industry because the purity of the reaction product is not high.
The isoglutarimide condensation method of Benzobarbital is a commonly used preparation method. The synthesis method includes three-step reactions: first, the acylation reaction of benzoic acid is carried out, and then the isoglutarimide condensation reaction is carried out to obtain 2-phenyl -5-(2-pentyl)-1,3,4-thiadiazole-2,6-dione-7-carboxylic acid methyl ester, and finally get Benzobarbital through esterification. During the reaction, it is necessary to maintain the reaction temperature and carry out safe operation. This method is suitable for small-scale laboratory synthesis.
4. Oxidative synthesis method:
Oxidative synthesis is a new method for preparing Benzobarbital, which has higher selectivity and yield than traditional methods. The following are the specific steps:
The first step: Acetyl aluminum oxide and phenyl phenyl p-hydroxybenzoate are mixed and reacted in methyl chloride, and an oxidation reaction occurs under photocatalysis to generate 2-phenyl-3,5-dihydroxybenzoic acid phenyl ester.
The second step: the above product and acetylacetone undergo an aromatic nucleophilic addition reaction in the presence of alkaline potassium hydroxide to generate Benzobarbital.
Benzobarbital (5,5-dimethyl-1,3-diazabarbital) is a drug widely used in medical and biochemical research, and is often used in the treatment of sedation, insomnia, convulsions and other symptoms. In addition, it also has anticonvulsant and analgesic effects. At present, the synthesis methods of Benzobarbital mainly include different ways such as condensation method and oxidation synthesis method. Among them, the oxidation synthesis method of Benzobarbital has the advantages of low reaction temperature, simple operation and high yield, and is widely used in industrial production. Benzobarbital oxidation synthesis method is a kind of commonly used preparation method, and this synthetic method includes four-step reaction: firstly carry out the aniline coupling reaction catalyzed by urea and sulfuric acid, then carry out the substitution reaction of N-phenyl-hydroquinone and sulfoxide, and then Carry out the oxidation reaction of N-(2,4-dioxo-5-methyl)-phenyl-hydroquinone, and finally pass through N-(2,4-dioxo-5-methyl)-phenyl - Reduction of p-benzoquinone gives Benzobarbital. Safe handling is required in the reaction. This method is suitable for industrial large-scale synthesis.
In summary, Benzobarbital can be prepared by various methods such as styrene peroxide synthesis, bisamide condensation, isoglutarimide condensation, and oxidation synthesis. Among them, the isoglutarimide condensation method is the most commonly used preparation method, while the oxidation synthesis method is a new method for preparing Benzobarbital.