Primidone (link:https://www.bloomtechz.com/synthetic-chemical/api-researching-only/primidone-powder-cas-125-33-7.html) is an antiepileptic drug that contains an isoprene ring and two carboxyl functional groups in its structure. The synthetic method of Primidone will be introduced below.
1. Ethyl acetoacetate and urea method
This is the earliest synthesis method of Primidone. The method is to react Ethyl acetoacetate and urea to prepare Primidone, and the steps are as follows:
(1) Heat Ethyl acetoacetate and urea in absolute ethanol and dissolve under stirring.
(2) Under heating conditions, add 0.5 moles of lead acetate and potassium nitrate respectively, and react for 24 hours.
(3) Acidification, distillation, extraction, cooling, and separation of Primidone crystals.
This method has certain advantages: the raw material is easy to get, the operation is simple, but the reaction time is long and the yield is not high.
2. β-carbolinone method
This method is one of the most important synthetic methods of Primidone, and the steps are as follows:
2.1. Synthesis of β-carbolinone
First of all, it is necessary to synthesize β-carbolinone, and its synthetic route is as follows:
(1) Prepare oxane-2,5-dione (1,3-cyclohexanedione) through condensation reaction of benzaldehyde and acetone.
(2) React cyclohexanedione with acetic anhydride and sulfuric acid to form 4-oxo-4-benzoylcyclohexane-1,3-dione (molecular formula C13H12O4), also known as 4-(benzoyl) -4-oxo-1,3-cyclohexanedione or butyrolactone.
(3) Knoevenagel condensation reaction of butyrolactone under the catalysis of potassium carbonate, reaction with acetophenone to form β-benzylidene butyrolactic acid, and hydrogenation reduction to obtain β-benzylidene-γ-butyrolactic acid .
(4) According to the Claisen condensation reaction, β-benzylidene-γ-butyrolactic acid and octyl acetate were reacted by heating to obtain ethyl β-(2-octyl acetate)carbazole-5-carboxylate (4,5 - ethyl diphenyl-2,3-carbazoledione-5-carboxylate).
(5) Finally, ethyl β-(2-octyl acetate)carbazole-5-carboxylate was hydrolyzed by base catalysis to obtain β-carbolinone. This step is a key step in the synthesis of Primidone in this method.
2.2. Synthesis of Primidone
The synthesis of Primidone can be achieved through the following steps:
(1) An intermediate is obtained by condensation reaction of β-carbolinone and cymenophenone.
(2) Catalyzed by phosphorus pentachloride to react the intermediate with 1,3-dioxane-2,5-dione to obtain a new intermediate.
(3) Finally, a catalyst is used to catalyze the second condensation to generate Primidone.
In the above steps, the first step is to condense β-carbolinone and cymenophenone to obtain an intermediate. Sodium carbonate needs to be used as a catalyst in this reaction, and the reaction is carried out in methanol. In this reaction, the carbonyl groups of β-carbolinone and cumenone react with sodium carbonate to form an alcohol. This alcohol contains two merged rings, which are the two β-carbolinone rings contained in the Primidone molecule. The alcohol can continue to participate in the next reaction as a new reactant.
The second step is catalyzed by phosphorus pentachloride, so that a new intermediate is formed. In the molecular structure of this intermediate, an oxygen atom is shared between the β-carbolinone ring and the cumenone group, forming a ring. This ring is the precursor to the reaction in step 3.
The third step is the synthesis of Primidone. In this step, sodium hydroxide or potassium hydroxide is used to catalyze a second condensation reaction to form Primidone from the above intermediate. During this process, the intermediate undergoes an intracyclic condensation reaction, thus completing the synthesis of Primidone.
In general, the β-carbolinone synthesis method is a common synthesis method of Primidone, which successfully utilizes various reactions such as Claisen condensation, Knoevenagel reaction and intracyclic condensation to realize the synthesis of Primidone.
3. 2-methyl-2-butenoic acid methyl ester method
This method is on the basis of 2-methyl-2-butenoic acid methyl ester, prepares Primidone by reaction, and the steps are as follows:
(1) Heat 2-methyl-2-butenoic acid methyl ester and urea in absolute ethanol to generate Primidone intermediate.
(2) Add sodium hydroxide to the resulting intermediate and perform hydrolysis to generate Primidone.
3.1. The synthetic route of 2-methyl-2-butenoic acid methyl ester is as follows:
(1) Reaction of isoprene and formic acid to obtain 3-methylfuran-2-carboxylic acid.
(2) Reaction of isopentene 3-formate and trimethylalumina at high temperature to generate functional hydroxypyridine (4-hydroxy-2-methylpyridine).
(3) In the presence of sodium hydroxide, add dimethyl phosphite (Diethyl phosphite) to react with functional hydroxypyridine under the catalysis of polyamide to generate 2-methyl-2-butenoic acid methyl ester (Ethyl 2- methyl-2-butenoate).
In the above steps, the first step is to firstly react isoprene with formic acid to obtain 3-isopentene formate, and then through two steps of reduction and acid catalysis to finally obtain a functional pyridine compound. Among them, the reduction step will convert the introduced carboxyl group into an alcohol group; the acid catalysis step can make the hydroxyl group on the ring dehydrate and eliminate while forming the pyridine compound. The 3rd step is then the key step of reacting 2-methyl-2-butenoic acid methyl ester.
3. 2. The synthesis process of Primidone is as follows:
(1) Methyl 2-methyl-2-butenoate and benzaldehyde undergo Claisen condensation reaction to generate β-benzylidene-γ-butyrolactate.
(2) In the presence of sodium hydroxide, β-benzylidene-γ-butyrolactate undergoes a lactonization reaction to generate 4-benzoyloxy-4-benzylidenecyclohexanedione.
(3) React 4-benzoyloxy-4-benzylidenecyclohexanedione and isomenthylidene piperidine in the presence of phosphorus pentafluoride to generate Primidone.
In the above steps, the first step is to generate β-benzylidene-γ-butyrolactate through Claisen condensation reaction of 2-methyl-2-butenoic acid methyl ester and benzaldehyde. This reaction needs to be carried out in the presence of sodium hydroxide, and the reaction product can be further lactonized.
In the second step, β-benzylidene-γ-butyrolactate undergoes a lactonization reaction to generate 4-benzoyloxy-4-benzylidenecyclohexanedione. This reaction is achieved by eliminating the alcohol molecule, and another effect of sodium hydroxide is to decarboxylate the butyrolactic acid moiety in β-benzylidene-γ-butyrolactate. The final product is 4-benzoyloxy-4-benzylidenecyclohexanedione. Its structure contains the precursors of two β-carbolinone rings.
In step 3, the key raw materials of Primidone: 4-benzoyloxy-4-benzylidenecyclohexanedione and isomenthylidenepiperidine are reacted by the catalysis of phosphorus pentafluoride to generate Primidone . In this reaction process, isomengthylidene piperidine plays an important role in promoting the intracyclic condensation reaction between the two reactants. Primidone is synthesized through this step.
Generally speaking, the synthetic method of 2-methyl-2-butenoic acid methyl ester is one of the important synthetic methods of Primidone. The method realizes the synthesis of Primidone through various reactions such as Claisen condensation, lactonization reaction and phosphorus pentafluoride catalysis. The raw materials required by the method are easy to obtain and easy to operate, and it is one of the important methods for the large-scale industrial production of Primidone.
4. Acid-catalyzed method:
The method is to carry out acid catalysis in β-carbolinone and acetic acid to obtain Primidone. Proceed as follows:
(1) Add β-carbolinone into acetic acid, add acidic catalyst, and stir until completely dissolved.
(2) Add sodium carbonate to the reaction system and continue stirring.
(3) The reaction system was separated, the solid was filtered, and Primidone crystals were extracted with ether.
This method is simple to operate and does not need to use sodium hydroxide hydrolysis, but the yield is low and it is not suitable for large-scale production.
The specific steps of the Primidone acid-catalyzed method are as follows:
The first step: preparing methyl 2-phenyl-2-butenoate.
The synthetic route of 2-phenyl-2-butenoic acid methyl ester is as follows:
(1) Trans-pentadienoic acid and vinyl methyl ether undergo Claisen condensation reaction to generate 2-methyl-2-butenoic acid methyl ester.
(2) In the presence of sodium hydroxide, 2-methyl-2-butenoic acid methyl ester and benzaldehyde undergo Claisen condensation reaction to generate 2-phenyl-2-butenoic acid methyl ester.
The Claisen condensation reaction is a class of reactions that link two molecules containing active methylene groups through the formation of carbon-carbon bonds. This reaction is one of the key steps in the synthesis of Primidone.
The second step: synthesis of Primidone.
The synthesis of Primidone requires two acid-catalyzed reactions. Specific steps are as follows:
(1) First, in an environment containing a catalyst (such as tetrahydrofuran or ethanol), 2-phenyl-2-butenoic acid methyl ester and benzaldehyde are subjected to an acid-catalyzed reaction to generate 2-(4-benzoyloxy Benzyl)-2-butenoic acid methyl ester. This reaction results in an acid-catalyzed condensation of the carbonyl group of benzaldehyde with the hydroxyl group of methyl 2-phenyl-2-butenoate to form the 4-benzoyloxybenzyl alcohol moiety.
(2) In the presence of the same catalyst, perform an acid-catalyzed reaction between the reaction product of the previous step and dimethylformamide to obtain Primidone. This reaction will make the 4-benzoyloxybenzyl alcohol part in the reaction product of the previous step combine with diformamide to form a structure of two β-carbolinone rings.
The reaction mechanism of the Primidone acid-catalyzed method is as follows:
First, 2-phenyl-2-butenoic acid methyl ester and benzaldehyde undergo an acid-catalyzed Claisen condensation reaction to generate 2-(4-benzoyloxybenzyl)-2-butenoic acid methyl ester. During the reaction, the carbonyl part of benzaldehyde and the hydroxyl part of 2-phenyl-2-butenoic acid methyl ester form an adduct in the five-membered ring, and at the same time generate 1,3-dehydration product, ie ketol.
Subsequently, 2-(4-benzoyloxybenzyl)-2-butenoic acid methyl ester and diformamide react under acid catalysis to form Primidone. Concrete reaction steps are as follows:
(1) The hydrogen atom of the ketone alcohol forms a hydrogen bond with the OH^- in the catalyst (such as tetrahydrofuran or ethanol), so that the carbonyl and other parts are transferred outward, making it a good leaving group.
(2) On this basis, the ketone alcohol is condensed to form a two-membered ring, and then a nucleophilic addition reaction occurs to produce the precursor of Primidone 3-(4-benzoyloxybenzyl)-4-hydroxy-2,5 - Dimethyl-β-carbolinone.
(3) In the last step, the ring dehydration reaction occurs again in the precursor molecule of Primidone to generate the final product Primidone.
Overall, in the acid-catalyzed synthesis of Primidone, two Claisen condensations are performed sequentially, thereby combining benzaldehyde and methyl 2-phenyl-2-butenoate to form the molecular precursor of Primidone. This process requires acid catalysis to promote the reaction. Through this method, Primidone can be obtained efficiently and simply, and it is a widely used synthetic method.
In short, the main methods for synthesizing Primidone are β-carbolinone method, 2-methyl-2-butenoic acid methyl ester method, acid-catalyzed method, etc., among which β-carbolinone method is the most important and commonly used. With the development of technology, researchers are constantly exploring and improving the synthesis method of Primidone in order to increase the yield, reduce the cost, and provide better drug options for clinical treatment.