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Preparation method of sodium valproate

A technology of sodium valproate and halopropane, applied in the field of pharmaceutical synthesis, can solve the problems of low utilization rate of equipment, long synthesis route, low total reaction yield and the like

Pending Publication Date: 2020-06-30
SICHUAN CREDIT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] This method synthetic route is long, needs to use larger reactor during reaction decarboxylation, and the utilization rate of unit equipment is low; Reaction total yield is low

Method used

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  • Preparation method of sodium valproate
  • Preparation method of sodium valproate
  • Preparation method of sodium valproate

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0033] Embodiment 1, the method for synthesizing sodium valproate of the present invention

[0034] (1) Preparation of compound II

[0035] 2kg of ethyl valerate (compound I) was dissolved in 20kg of methyl tert-butyl ether, under the protection of nitrogen, the temperature was lowered to -25°C, and then 6.77kg (8.46L, density 0.8kg / L) 2mol / L was added dropwise The methyl tert-butyl ether solution of the pyrrole lithium reagent was added dropwise. After stirring for 2 hours, the temperature of the reaction system was controlled at -30°C, and 2.08 kg of bromopropane was added dropwise. The 10% ammonium chloride solution of 5kg terminated the reaction, and after standing still for 20 minutes, the aqueous phase was separated; the organic phase was washed once with 3kg of saturated saline; the aqueous phase was separated, and the organic solvent was concentrated under reduced pressure to obtain compound II .

[0036] (2) Preparation of compound III

[0037] Dissolve the compoun...

Embodiment 2

[0038] Embodiment 2, the method for synthesizing sodium valproate of the present invention

[0039] (1) Preparation of compound II

[0040]3kg of ethyl valerate (compound I) was dissolved in 24kg of methyl tetrahydrofuran, under the protection of nitrogen, the temperature was lowered to -40°C, and then 13.85kg (17.31L, density 0.8kg / L) of 2mol / L lithium pyrrole was added dropwise The methyl tert-butyl ether solution of the reagent was added dropwise, and after stirring for 3 hours, the temperature of the reaction system was controlled at -30°C, and 3.97 kg of bromopropane was added dropwise. After the reaction of the raw materials was completed, 8 kg of 10 % ammonium chloride solution to terminate the reaction, and after standing still for 30 minutes, the aqueous phase was separated; the organic phase was washed once with 5 kg of saturated brine; the aqueous phase was separated, and the organic solvent was concentrated under reduced pressure to obtain compound II.

[0041] (2...

Embodiment 3

[0043] Embodiment 3, the method for synthesizing sodium valproate of the present invention

[0044] (1) Preparation of compound II

[0045] 5kg of ethyl valerate (compound I) was dissolved in 45kg of tetrahydrofuran, under the protection of nitrogen, the temperature was lowered to -35°C, and then 20kg (25.0L, density 0.8kg / L) of 2mol / L pyrrole lithium reagent was added dropwise. Base tert-butyl ether solution, after the dropwise addition, after stirring for 3 hours, the temperature of the reaction system was controlled at -15°C, and 6.15kg of bromopropane was added dropwise. Ammonium chloride solution was used to terminate the reaction, and after standing still for 30 minutes, the aqueous phase was separated; the organic phase was washed once with 8.2 kg of saturated brine; the aqueous phase was separated, and the organic solvent was concentrated under reduced pressure to obtain compound II.

[0046] (2) Preparation of compound III

[0047] Dissolve compound II obtained in t...

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Abstract

The invention provides a preparation method of sodium valproate, and belongs to the technical field of medicine synthesis. The method comprises the following steps: by taking ethyl valerate as a raw material, adding a methyl tert-butyl ether solution of a pyrrole metal reagent into an ether solution of ethyl valerate, then adding halopropane, carrying out an alkylation reaction, adding a weakly acidic solution in a dropwise manner to terminate the reaction after the reaction is finished, and washing with water to obtain an intermediate product; and adding a sodium hydroxide solution into the alcohol solvent of the intermediate product, carrying out a saponification reaction, and purifying to obtain sodium valproate after the saponification reaction is finished. The method is short in reaction route, high in total yield, easily available in raw materials, low in cost, high in operability and suitable for industrialization. The total molar yield of sodium valproate prepared by the methodis greater than or equal to 86.0%, and the purity of the final product is greater than or equal to 99.5%.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of sodium valproate. Background technique [0002] Sodium valproate (sodium valproate), chemically named 2-valproate sodium, is a nitrogen-free broad-spectrum antiepileptic drug, which has different degrees of resistance to convulsions caused by various reasons. It is effective for various types of human epilepsy such as various types of petit mal seizures, myoclonic epilepsy, partial seizures, grand mal seizures and mixed epilepsy. Sodium valproate oral tablet is absorbed quickly and completely, mainly distributed in the extracellular fluid, most of which is combined with plasma protein in the blood, and is mostly used for various types of epilepsy patients who are ineffective with other antiepileptic drugs, especially for small hairs. [0003] At present, the commonly used method for preparing valproic acid is as follows: [0004] T...

Claims

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Application Information

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IPC IPC(8): C07C53/128C07C27/02C07C51/41C07C69/24C07C67/343
CPCC07C51/412C07C67/343C07C53/128C07C69/24
Inventor 刘卫国黄正功阳海龙道兵陈刚
Owner SICHUAN CREDIT PHARMA
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