Synthesis method of crilimidazole hydrochloride

Abstract

The invention belongs to the technical field of organic synthesis, and particularly discloses a synthesis method of crilimidazole hydrochloride, which comprises the following steps: mixing methyl chloroacetate, potassium carbonate, dichloromethane and pyrrolidine, reacting to obtain a compound III, mixing the compound III, a compound IV and hydrochloric acid, reacting to obtain a compound V crude product, and purifying to obtain crilimidazole hydrochloride. The synthesis method provided by the invention has the advantages of few process steps and simple operation, and is more beneficial 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

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing clemizole hydrochloride. Background Art

[0002] Clemizole Hydrochloride (generic name: Clemizole Hydrochloride), chemical name: 1-[(4-chlorophenyl)methyl]-2-(pyrrolidin-1-ylmethyl)benzimidazole hydrochloride. Clemizole hydrochloride is an amine antihistamine and a strong H1 receptor antagonist. Its main dosage forms are tablets and injections. Clemizole hydrochloride has a moderate sedative effect and a strong antipruritic effect. The latest research shows that it has anti-hepatitis C virus effects.

[0003] In the prior art, the following synthesis method of clemizole hydrochloride has been disclosed:

[0004]

[0005] The chloroacetic acid used in the first step of the method is highly toxic and can easily cause allergies in operators, making it less safe. The third step requires the use of NaH, which is highly alkaline and reductive, unstable in the air, and less safe. At the same time, when reacting with 4-chlorobenzyl chloride, it will definitely replace the chlorine on the benzene ring, thereby producing more by-products. Therefore, it is necessary to develop a new synthesis route that is safe, efficient, has fewer by-products, and is suitable for commercialization. Summary of the invention

[0006] Purpose of the invention: In view of the shortcomings of the prior art, the present invention provides a new synthesis method of clemizole hydrochloride.

[0007] Technical solution: The synthesis method of clemizole hydrochloride described in the present invention has the following reaction scheme:

[0008]

[0009] The synthesis method of clemizole hydrochloride, the synthesis steps are as follows:

[0010] 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.

[0011] Step 2) Compound III, compound IV and hydrochloric acid are added to a reaction container, refluxed for reaction, cooled to room temperature, and the pH is adjusted to alkaline with an aqueous potassium carbonate solution, and filtered with suction. The filter cake is a crude compound V.

[0012] 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 by suction to obtain a white solid, which is clemizole hydrochloride.

[0013] Specifically, in the step 1), the molar ratio of methyl chloroacetate to tetrahydropyrrole is 1:0.95-1, preferably 1:0.98;

[0014] Specifically, in the step 1), the molar ratio of methyl chloroacetate to potassium carbonate is 1:1.2-2, preferably 1:1.5;

[0015] Specifically, in the step 1), the weight ratio of methyl chloroacetate to dichloromethane is 1:5-10, preferably 1:7;

[0016] Specifically, in step 1), the reaction time is: 6 to 10 hours, preferably 8 hours;

[0017] Specifically, in step 1), the reaction temperature is: 20-50°C, preferably 30-35°C;

[0018] Specifically, in step 1), the concentration of hydrochloric acid is: 5% to 20%, preferably 10%;

[0019] Specifically, in step 1), the potassium carbonate aqueous solution is adjusted to pH 8 to 12, preferably pH 9 to 10;

[0020] Specifically, in the step 2), the molar ratio of compound III to compound IV is 1:0.95-1, preferably 1:0.98;

[0021] Specifically, in the step 2), the molar ratio of compound III to hydrogen chloride in hydrochloric acid is 1:5-7, preferably 1:6;

[0022] Specifically, in step 2), the concentration of hydrochloric acid is: 10% to 30%, preferably 20%;

[0023] Specifically, in step 2), the reaction time is: 4 to 8 hours, preferably 6 hours;

[0024] Specifically, in step 2), the pH of the potassium carbonate aqueous solution is adjusted to 8 to 11, preferably 9 to 10;

[0025] Specifically, in the step 3), the weight ratio of the crude compound V to toluene is 1:4 to 8, preferably 1:6;

[0026] Specifically, in step 3), the reaction temperature is: 0 to 20°C, preferably 5 to 10°C;

[0027] Beneficial effects: The synthesis method of the present invention has fewer process steps, simple operation, and is more conducive to industrial production. Compared with the prior art, it reduces production costs, improves product yield and purity, and the maximum single impurity in the product is less than 0.1%. DETAILED DESCRIPTION

[0028] The following are embodiments to illustrate the scheme of the present invention in detail, but the protection scope of the present invention is not limited to the embodiments.

[0029] Embodiment 1:

[0030] Into a 2000ml reaction flask, methyl chloroacetate (108.5g, 1mol), potassium carbonate (207.0g, 1.5mol), dichloromethane 760.0g, pyrrole (69.6g, 0.98mol) were added, and the temperature was controlled at 30°C and stirred for 8 hours; after the reaction was completed, the mother liquor was filtered and washed with 760g of 10% hydrochloric acid aqueous solution, and the aqueous phase was extracted once with 200ml of dichloromethane; 760g of dichloromethane was added to the aqueous phase, and the pH was adjusted to 9-10 with saturated potassium carbonate aqueous solution; the organic phase was separated, washed once with 300g of saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and the solvent was removed to obtain 128.5g of compound III with a yield of 92.3% and a purity of 99.4%.

[0031] Into a 2000 ml reaction bottle, 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 added, and the reaction was refluxed at 100 ° C for 6 hours. The temperature was cooled to room temperature and the pH was adjusted to 10 with potassium carbonate aqueous solution. The filter cake was washed with 400 ml of water to obtain a crude compound V. 273.0 g of an off-white solid was obtained by drying. The yield was 95.2% and the purity was 98.9%.

[0032] Into a 2000 ml reaction bottle, add 273 g of crude compound V and 1638 g of toluene, stir to dissolve, then add 3.2 g of activated carbon for decolorization, filter the mother liquor, cool to 10°C, add isopropanol solution of hydrogen chloride dropwise until pH = 3-4, keep at 5-10°C and stir for 1 hour, then filter and dry to obtain 251.7 g of white solid clemizole hydrochloride, with a yield of 92.1% and a purity of 99.7%.

[0033] Embodiment 2:

[0034] Into a 2000ml reaction flask, methyl chloroacetate (108.5g, 1mol), potassium carbonate (207.0g, 1.5mol), dichloromethane 760.0g, tetrahydropyrrole (70.3g, 0.99mol) were added, and the temperature was controlled at 30°C and stirred for 9 hours; after the reaction was completed, the mother liquor was filtered and washed with 760g of 10% hydrochloric acid aqueous solution, and the aqueous phase was extracted once with 200ml of dichloromethane; 760g of dichloromethane was added to the aqueous phase, and the pH was adjusted to 9-10 with saturated potassium carbonate aqueous solution; the organic phase was separated, washed once with 300g of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was removed to obtain 129.1g of compound III with a yield of 91.8% and a purity of 99.3%.

[0035] Into a 2000 ml reaction bottle, 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 added, and the reaction was refluxed at 100 ° C for 6 hours. The temperature was cooled to room temperature and the pH was adjusted to 9 with potassium carbonate aqueous solution. The filter cake was washed with 400 ml of water to obtain the crude compound V, which was dried to obtain 274.0 g of an off-white solid with a yield of 95.5% and a purity of 99.1%.

[0036] Into a 2000 ml reaction bottle, add 274 g of crude compound V and 1644 g of toluene, stir to dissolve, then add 3.2 g of activated carbon for decolorization, filter the mother liquor, cool to 10°C, add isopropanol solution of hydrogen chloride dropwise until pH = 3-4, keep at 5-10°C and stir for 1 hour, then filter and dry to obtain 253.2 g of white solid clemizole hydrochloride, with a yield of 92.4% and a purity of 99.7%.

[0037] Embodiment 3:

[0038] Methyl chloroacetate (434 g, 4 mol), potassium carbonate (829 g, 6 mol), 3000 g of dichloromethane and tetrahydropyrrole (278.3 g, 3.92 mol) were added to a 10 L reaction bottle and stirred at 30 ° C for 8 hours; after the reaction was completed, the mother liquor was filtered and washed with 3000 g of 10% hydrochloric acid aqueous solution, and the aqueous phase was extracted once with 1000 ml of dichloromethane; 3000 g of dichloromethane was added to the aqueous phase, and the pH was adjusted to 9 with saturated potassium carbonate aqueous solution; the organic phase was washed once with 1000 g of saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was removed to obtain 527 g of compound III with a yield of 94.6% and a purity of 99.5%.

[0039] Into a 10L reaction bottle, 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 added, and the reaction was refluxed at 100°C for 6 hours. The mixture was cooled to room temperature and the pH was adjusted to 10 with an aqueous potassium carbonate solution. The mixture was filtered and the filter cake was washed with 1500 ml of water to obtain a crude compound V. The off-white solid of 1089 g was obtained by drying. The yield was 95.5% and the purity was 99.0%.

[0040] Into a 10L reaction bottle, 1080 g of crude compound V and 6480 g of toluene were added, stirred and dissolved, and then 50 g of activated carbon was added for decolorization. The mother liquor was filtered and cooled to 10°C. An isopropanol solution of hydrogen chloride was added dropwise until the pH value was 3-4. The mixture was stirred at 5-10°C for 1 hour and filtered. After drying, 1010 g of white solid clemizole hydrochloride was obtained with a yield of 93.5% and a purity of 99.8%.

[0041] The above description is only a preferred embodiment of the present application and is not intended to limit the present application.

Claims

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 for reaction, 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 by suction to obtain a white solid, which is 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%; the pH 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 above 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%; the pH 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.

Images