CN119707828A - A kind of synthetic method of clemizole hydrochloride - Google Patents

Abstract

The invention belongs to the technical field of organic synthesis, and specifically discloses a method for synthesizing clemizole hydrochloride, wherein methyl chloroacetate, potassium carbonate, dichloromethane and tetrahydropyrrole are mixed to react to obtain compound III, compound III is mixed with compound IV and hydrochloric acid to react to obtain a crude compound V, and then purified to obtain clemizole hydrochloride. The synthesis method of the invention has fewer process steps, is simple to operate, and is more conducive to industrial production. Compared with the prior art, the production cost is reduced, the product yield and purity are improved, and the maximum single impurity in the product is less than 0.1%.

Description

Synthesis method of clemizole hydrochloride

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a synthesis method of clemizole hydrochloride.

Background

Clemizole hydrochloride (common name: clemizole Hydrochloride), chemical name: 1- [ (4-chlorophenyl) methyl ] -2- (pyrrolidin-1-ylmethyl) benzimidazole hydrochloride. The clemizole hydrochloride is an amine antihistamine, is a strong H1 receptor antagonist, and is mainly prepared into tablets and injections. The clemizole hydrochloride has moderate sedative effect and strong antipruritic effect. Recent studies have shown that it has an anti-hepatitis c virus effect.

In the prior art, clemizole hydrochloride has been disclosed as the following synthetic method:

The chloroacetic acid used in the first step of the method has high toxicity, is extremely easy to cause body allergy of operators and poor in safety, and the NaH used in the third step is required to have strong alkalinity and reducibility, is unstable in air and poor in safety, and can certainly replace benzene ring chlorine when reacting with 4-chlorobenzyl chloride, so that more byproducts are generated. Therefore, there is a need to develop a new synthetic route that is safe, efficient, has few byproducts and is suitable for commercialization.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides a novel synthesis method of clemizole hydrochloride.

The technical scheme is that the synthetic method of the clemizole hydrochloride comprises the following reaction routes:

The synthesis method of the clemizole hydrochloride comprises the following synthesis steps:

Step 1) adding methyl chloroacetate, potassium carbonate, methylene dichloride and tetrahydropyrrole into a reaction container, stirring at a controlled temperature, carrying out suction filtration after the reaction is finished, washing mother liquor with hydrochloric acid aqueous solution for separating liquid, extracting aqueous phase with methylene dichloride, adding methylene dichloride, regulating pH to be alkaline with potassium carbonate aqueous solution, separating liquid, washing organic phase with saturated sodium chloride aqueous solution, and drying for desolventizing to obtain a compound III.

And 2) adding the compound III, the compound IV and hydrochloric acid into a reaction vessel, carrying out reflux reaction, cooling to room temperature, regulating pH to be alkaline by using a potassium carbonate aqueous solution, and carrying out suction filtration, wherein a filter cake is a crude product of the compound V.

And 3) adding a crude product of the compound V and toluene into a reaction container, stirring, dissolving, decoloring, cooling the mother liquor, dropwise adding an isopropanol solution of hydrogen chloride until the pH value is 3-4, and carrying out suction filtration to obtain a white solid, namely the clemizole hydrochloride.

Specifically, in the step 1), the molar ratio of methyl chloroacetate to tetrahydropyrrole is 1:0.95-1, preferably 1:0.98;

specifically, in the step 1), the molar ratio of methyl chloroacetate to potassium carbonate is 1:1.2-2, preferably 1:1.5;

specifically, in the step 1), the weight ratio of methyl chloroacetate to dichloromethane is 1:5-10, preferably 1:7;

Specifically, in the step 1), the reaction time is 6-10 hours, preferably 8 hours;

Specifically, in the step 1), the reaction temperature is 20-50 ℃, preferably 30-35 ℃;

specifically, in the step 1), the concentration of hydrochloric acid is 5% -20%, preferably 10%;

specifically, in the step 1), the pH of the potassium carbonate aqueous solution is adjusted to 8-12, preferably pH=9-10;

specifically, in the step 2), the molar ratio of the compound III to the compound IV is 1:0.95-1, preferably 1:0.98;

specifically, in the step 2), the molar ratio of the compound III to the hydrogen chloride in the hydrochloric acid is 1:5-7, preferably 1:6;

Specifically, in the step 2), the concentration of hydrochloric acid is 10% -30%, preferably 20%;

Specifically, in the step 2), the reaction time is 4-8 hours, preferably 6 hours;

Specifically, in the step 2), the pH of the aqueous potassium carbonate solution is adjusted to 8-11, preferably 9-10;

Specifically, in the step 3), the weight ratio of the crude product of the compound V to toluene is 1:4-8, preferably 1:6;

Specifically, in the step 3), the reaction temperature is 0-20 ℃, preferably 5-10 ℃;

The synthesis method has the advantages of few process steps, simple operation and more contribution to industrial production. Compared with the prior art, the method reduces the production cost, improves the product yield and purity, and has the maximum single impurity of less than 0.1 percent.

Detailed Description

The following is a detailed description of the present invention, but the scope of the present invention is not limited to the examples.

Example 1:

Methyl chloroacetate (108.5 g,1 mol), potassium carbonate (207.0 g,1.5 mol), methylene dichloride 760.0g and tetrahydropyrrole (69.6 g,0.98 mol) are put into a 2000ml reaction bottle, stirred for 8 hours at a temperature of 30 ℃, after the reaction is finished, suction filtration is carried out, mother liquor is washed and separated by 760g of 10% hydrochloric acid aqueous solution, aqueous phase is extracted by 200ml of methylene dichloride once, 760g of methylene dichloride is added into aqueous phase, the aqueous phase is regulated to 9-10 by saturated potassium carbonate aqueous solution, separated liquid is dried by anhydrous sodium sulfate after the organic phase is washed once by 300g of saturated sodium chloride aqueous solution, and the compound III128.5g is obtained after desolventizing, the yield is 92.3%, and the purity is 99.4%.

Into a 2000ml reaction flask, compound III (128.0 g,0.9 mol), compound IV (205.6 g,0.88 mol) and 20% hydrochloric acid (996.5 g,5.46 mol) were put into a reaction flask, reflux reaction was carried out at 100℃for 6 hours, the temperature was lowered to room temperature, the pH was adjusted to 10 with an aqueous potassium carbonate solution, suction filtration was carried out, 400ml of water-washed cake was crude compound V, and then 273.0g of off-white solid was obtained by drying, the yield was 95.2%, and the purity was 98.9%.

Adding 273g of crude product of the compound V and 1638g of toluene into a 2000ml reaction bottle, stirring and dissolving, adding 3.2g of active carbon for decolorization, cooling the suction filtration mother liquor to 10 ℃, dropwise adding an isopropanol solution of hydrogen chloride to pH=3-4, preserving heat for 5-10 ℃, stirring for 1 hour, suction filtration, and drying to obtain 251.7g of white solid clemizole hydrochloride, wherein the yield is 92.1% and the purity is 99.7%.

Example 2:

Methyl chloroacetate (108.5 g,1 mol), potassium carbonate (207.0 g,1.5 mol), methylene dichloride 760.0g and tetrahydropyrrole (70.3 g,0.99 mol) are put into a 2000ml reaction bottle, stirred for 9 hours at a temperature of 30 ℃, after the reaction is finished, suction filtration is carried out, mother liquor is washed and separated by 760g of 10% hydrochloric acid aqueous solution, aqueous phase is extracted once by 200ml of methylene dichloride, 760g of methylene dichloride is added into aqueous phase, the aqueous phase is regulated to 9-10 by saturated potassium carbonate aqueous solution, separated liquid is dried by anhydrous sodium sulfate after the organic phase is washed once by saturated 300g of sodium chloride aqueous solution, and the compound III129.1g is obtained after desolventizing, the yield is 91.8%, and the purity is 99.3%.

Into a 2000ml reaction flask, compound III (129.0 g,0.91 mol), compound IV (209.4 g,0.9 mol) and 20% hydrochloric acid (985.5 g,5.4 mol) were put into a reaction flask, reflux reaction was performed for 6 hours at 100 ℃, the temperature was lowered to room temperature, the pH was adjusted to 9 with an aqueous potassium carbonate solution, suction filtration was performed, 400ml of water-washed filter cake was crude product of compound V, and then the crude product was dried to obtain 274.0g of off-white solid, yield 95.5%, purity 99.1%.

274G of crude product of the compound V and 1644g of toluene are put into a 2000ml reaction bottle, 3.2g of active carbon is added for decolorization after stirring and clearing, the suction filtration mother liquor is cooled to 10 ℃, isopropanol solution of hydrogen chloride is added dropwise until the pH value is 3-4, the temperature is kept for 5-10 ℃ and stirring is carried out for 1 hour, suction filtration is carried out, and 253.2g of white solid clemizole hydrochloride is obtained after drying, the yield is 92.4%, and the purity is 99.7%.

Example 3:

Methyl chloroacetate (433 g,4 mol), potassium carbonate (829 g,6 mol), dichloromethane 3000g and tetrahydropyrrole (278.3 g,3.92 mol) are put into a 10L reaction bottle, stirred for 8 hours at a temperature of 30 ℃, after the reaction is finished, suction filtration is carried out, a mother solution is washed and separated by a 10% hydrochloric acid aqueous solution of 3000g, an aqueous phase is extracted by 1000ml dichloromethane once, 3000g dichloromethane is added into the aqueous phase, the aqueous phase is adjusted to 9 by a saturated potassium carbonate aqueous solution, the separated solution is washed by a saturated sodium chloride aqueous solution of 1000g once, then dried by anhydrous sodium sulfate, and the compound III527g is obtained after desolventizing, the yield is 94.6%, and the purity is 99.5%.

Into a 10L reaction flask, compound III (500.0 g,3.52 mol), compound IV (814.5 g,3.5 mol) and 20% hydrochloric acid (3854 g,21.1 mol) were put for reflux reaction at 100℃for 6 hours, the temperature was lowered to room temperature, the pH was adjusted to 10 with an aqueous potassium carbonate solution, suction filtration was performed, 1500ml of a water-washed cake was a crude product of compound V, and the crude product was dried to give 1089g of an off-white solid with a yield of 95.5% and a purity of 99.0%.

Adding 1080g of crude compound V and 6480g of toluene into a 10L reaction bottle, stirring and dissolving, adding 50g of active carbon for decolorization, cooling the suction filtration mother liquor to 10 ℃, dripping an isopropanol solution of hydrogen chloride to pH=3-4, preserving heat, stirring for 1 hour at 5-10 ℃, suction filtration, and drying to obtain 1010g of white solid clemizole hydrochloride, wherein the yield is 93.5% and the purity is 99.8%.

The foregoing description is only of the preferred embodiments of the application and is not intended to limit the application.

Claims (10)

1. A method for synthesizing clemizole hydrochloride, characterized in that the synthesis route is as follows: 2. The method for synthesizing clemizole hydrochloride according to claim 1, characterized in that the specific steps are: Step 1) methyl chloroacetate, potassium carbonate, dichloromethane and tetrahydropyrrole are added to a reaction vessel, and the mixture is stirred under controlled temperature; after the reaction is completed, the mixture is filtered, the mother liquor is washed with an aqueous hydrochloric acid solution and separated, the aqueous phase is extracted with dichloromethane, dichloromethane is added, the pH is adjusted to alkaline with an aqueous potassium carbonate solution, and the mixture is separated; the organic phase is washed with a saturated sodium chloride aqueous solution, and then dried and desolvated to obtain compound III; Step 2) Compound III, Compound IV and hydrochloric acid are added to a reaction vessel, refluxed, cooled to room temperature, pH adjusted to alkaline with potassium carbonate aqueous solution, filtered, and the filter cake is a crude compound V; Step 3) Add the crude compound V and toluene into the reaction container, stir to dissolve and then decolorize. After cooling the mother liquor, add isopropanol solution of hydrogen chloride dropwise until the pH value is 3-4. Filter and obtain a white solid as clemizole hydrochloride. 3. The method for synthesizing clemizole hydrochloride according to claim 1, characterized in that, in the step 1), the molar ratio of methyl chloroacetate to tetrahydropyrrole is 1:0.95-1; the molar ratio of methyl chloroacetate to potassium carbonate is 1:1.2-2; the weight ratio of methyl chloroacetate to dichloromethane is 1:5-10, preferably 1:7. 4. The method for synthesizing clemizole hydrochloride according to claim 1, characterized in that in the step 1), the reaction time is 6 to 10 hours and the reaction temperature is 20 to 50°C. 5. The method for synthesizing clemizole hydrochloride according to claim 1, characterized in that in the step 1), the concentration of hydrochloric acid is 5% to 20%; and the pH value of the potassium carbonate aqueous solution is adjusted to 8 to 12. 6. The method for synthesizing clemizole hydrochloride according to claim 1, characterized in that, in the step 2), the molar ratio of compound III to compound IV is 1:0.95-1; the molar ratio of compound III to hydrogen chloride in hydrochloric acid is 1:5-7. 7. The method for synthesizing clemizole hydrochloride according to claim 1, characterized in that in the step 2), the reaction time is 4 to 8 hours. 8. The method for synthesizing clemizole hydrochloride according to claim 1, characterized in that in the step 2), the concentration of hydrochloric acid is 10% to 30%; and the pH value of the potassium carbonate aqueous solution is adjusted to 8 to 11. 9. The method for synthesizing clemizole hydrochloride according to claim 1, characterized in that in the step 3), the weight ratio of the crude compound V to toluene is 1:4-8. 10. The method for synthesizing clemizole hydrochloride according to claim 1, characterized in that in the step 3), the reaction temperature is 0-20°C.