Synthetic method of phenytoin sodium

A synthetic method, the technology of phenytoin sodium, applied in the field of biomedicine, can solve the problems of reducing the yield of phenytoin, low yield of phenytoin, and low purity, so as to inhibit the formation of by-product diphenylacetylene diurea and promote the process of amidation reaction , the effect of reducing the reaction concentration

Active Publication Date: 2019-03-12
NINGBO POLYTECHNIC
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Problems solved by technology

[0007] In the existing method for synthesizing phenytoin sodium, the biggest problem is that the reaction time of the condensation process is too long, the side reactions are more, and the impurity toluene diurea is not easy to remove, resulting in low yield of phenytoin, low purity, and poor appearance crystal form , the color is deep, the post-treatment requires activated carbon decolorization, and even the crude phenytoin needs to be recrystallized and purified with ethanol solution, which further reduces the yield of phenytoin; in the process of salt formation, the precipitation of phenytoin sodium is difficult, the crystallization rate is slow, and the yield is low

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  • Synthetic method of phenytoin sodium

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Effect test

Embodiment 1

[0032] Oxidation reaction: Weigh 2.18g of benzoin, 5.4g of ferric chloride hexahydrate, measure 13mL of glacial acetic acid, and 5.2mL of distilled water, pour them into a three-necked flask in turn, stir, heat and reflux for 50min, and stop heating completely after the reaction; after cooling, put Pour the reaction solution into a 100mL beaker, add 40mL of distilled water, and bathe in ice-salt for 15min, wait for the precipitation of yellow needle-like crystals, filter with suction, wash the filter cake with distilled water several times, and obtain 2.14g of dibenzoyl;

[0033] Condensation reaction: Add 2.14g dibenzoyl, 1.80g urea, 2.13g potassium hydroxide, 0.06g 4-dimethylaminopyridine, 22mL n-butanol, 22mL distilled water into a 250mL three-neck round bottom flask, stir magnetically, and Reflux at ℃ for 30 minutes, stop heating completely; cool the reaction solution to room temperature, pour into a 500mL separatory funnel, extract 3 times with 3×100mL distilled water, com...

Embodiment 2

[0036] Oxidation reaction: Weigh 8.67g of benzoin, 24.5g of ferric chloride hexahydrate, measure 50mL of glacial acetic acid, and 22mL of distilled water, pour them into a three-neck flask in turn, start stirring, and heat to reflux for 52 minutes, then stop heating completely; after cooling, Pour the reaction solution into a 500mL beaker, add 173mL of distilled water, and bathe in ice-salt for 16 minutes, yellow needle-like crystals precipitate, filter with suction, and wash the filter cake with distilled water several times to obtain 8.5g of dibenzoyl;

[0037] Condensation reaction: Add 8.5g of dibenzoyl, 7.4g of urea, 9g of potassium hydroxide, 0.26g of 4-dimethylaminopyridine, 71mL of n-butanol, and 85mL of distilled water into a 250mL three-necked round-bottomed flask, stir magnetically, and heat to reflux at 118°C 35min, stop heating after the reaction is complete. The reaction solution was cooled to room temperature, poured into a 500mL separatory funnel, extracted 3 t...

Embodiment 3

[0040] Oxidation reaction: Weigh 10.71g of benzoin, 28g of ferric chloride hexahydrate, measure 64mL of glacial acetic acid, and 25mL of distilled water, pour them into a three-neck flask in turn, start stirring, heat and reflux for 55min, and stop heating completely after the reaction; after cooling, the reaction Pour the solution into a 500mL beaker, add 210mL distilled water, and ice-salt bath for 18 minutes, yellow needle-like crystals precipitated, filtered with suction, and washed the filter cake with distilled water several times to obtain bibenzoyl;

[0041] Condensation reaction: Add 10.5g dibenzoyl, 9g urea, 10.64g potassium hydroxide, 0.305g 4-dimethylaminopyridine, 105mL n-butanol, 125mL distilled water into a 500mL three-neck round bottom flask, stir magnetically, and heat to 119 ℃ reflux for 40min, stop heating after the reaction is complete. The reaction solution was cooled to room temperature, poured into a 500mL separatory funnel, extracted 3 times with 3×100m...

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Abstract

The invention relates to a synthetic method of phenytoin sodium, belonging to the technical field of biomedicine. The synthetic method of the phenytoin sodium comprises the following steps of oxidation reaction, condensation reaction and salt formation reaction, wherein a amidation reaction process is promoted through adding a phase transfer catalyst 4-dimethylamiopryidine in the condensation reaction; a two-phase system of n-butanol and water is adopted, so that the generation of diphenylacetylene diurea is greatly inhibited, and reaction time is obviously shortened; ethanol serves as a solvent in the salt formation reaction, after a sodium hydroxide ethanol solution reacts with phenytoin, cyclohexane with defective solvent ice is added to promote the phenytoin sodium to precipitate as white crystal, and compared with the salt formation reaction with water as a solvent, the phenytoin sodium is faster in precipitation rate and high in precipitation degree and purity.

Description

technical field [0001] The invention relates to a method for synthesizing phenytoin sodium, which belongs to the technical field of biomedicine. Background technique [0002] Phenytoin is the drug of choice for the treatment of epilepsy. It is clinically used for the treatment of grand mal seizures, psychomotor seizures and arrhythmia diseases. It can also be used for the treatment of trigeminal neuralgia, recessive dystrophic epidermolysis bullosa, paroxysmal Choreoathetosis, seizure control disorder, myotonia, and cardiac conduction disturbance in tricyclic antidepressant overdose. After more than half a century of clinical use, it has been proved to be one of the effective antiepileptic drugs, especially the most effective for grand mal seizures. [0003] At present, the synthesis method of phenytoin sodium mostly adopts benzoin as raw material, and synthesizes phenytoin sodium through three steps of oxidation, condensation, and salt formation, specifically: [0004] (1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/74
CPCC07D233/74
Inventor 史海波陈艳君蒋梦吉邵柯妹袁道远文志强
Owner NINGBO POLYTECHNIC
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