A process for the synthesis of clemizole hydrochloride

Abstract

The application belongs to the technical field of organic synthesis, and specifically discloses a synthesis method of clemizole hydrochloride, which comprises the following steps: mixing methyl chloroacetate, potassium carbonate, dichloromethane and tetrahydro-pyrrole to obtain compound III through reaction; mixing the compound III, compound IV and hydrochloric acid to obtain compound V crude product through reaction; and then purifying the compound V crude product to obtain clemizole hydrochloride. The synthesis method has the advantages of fewer process steps, simple operation and being more conducive to industrialized production. Compared with the prior art, the synthesis method reduces production cost, improves product yield and purity, and the maximum single impurity in the product is less than 0.1%.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for synthesizing crimimidazole hydrochloride. Background Technology

[0002] Clemizole hydrochloride (generic name: Clemizole Hydrochloride), chemical name: 1-[(4-chlorophenyl)methyl]-2-(pyrrolidone-1-ylmethyl)benzimidazole hydrochloride. Clemizole hydrochloride is an amine antihistamine, a strong H1 receptor antagonist, mainly available in tablet and injection forms. Clemizole hydrochloride also has moderate sedative effects and strong antipruritic effects. Recent studies have shown that it has anti-hepatitis C virus activity.

[0003] In the prior art, the following synthetic methods for crimimidazole hydrochloride have been disclosed:

[0004]

[0005] The first step of this method uses chloroacetic acid, which is highly toxic and can easily cause allergic reactions in operators, resulting in poor safety. The third step requires the use of NaH, which is a strong base and reducing agent, unstable in air, and also has poor safety. Furthermore, its reaction with 4-chlorobenzyl chloride will inevitably replace the chlorine on the benzene ring, generating numerous byproducts. Therefore, a new synthetic route that is safe, efficient, produces fewer byproducts, and is suitable for commercialization needs to be developed. Summary of the Invention

[0006] Purpose of the invention: To address the shortcomings of existing technologies, this invention provides a novel method for synthesizing crimimidazole hydrochloride.

[0007] Technical solution: The synthesis method of crimimidazole hydrochloride according to the present invention has the following reaction route:

[0008]

[0009] The method for synthesizing crimimidazole hydrochloride includes the following steps:

[0010] Step 1) Add methyl chloroacetate, potassium carbonate, dichloromethane, and tetrahydropyrrole to the reaction vessel and stir under controlled temperature. After the reaction is completed, filter the mixture, wash the mother liquor with hydrochloric acid aqueous solution and separate the liquid. Extract the aqueous phase with dichloromethane and add dichloromethane. Adjust the pH to alkaline with potassium carbonate aqueous solution and separate the liquid. Wash the organic phase with saturated sodium chloride aqueous solution and dry to obtain compound III.

[0011] Step 2) Compound III, Compound IV and hydrochloric acid are added to the reaction vessel, the reaction is refluxed, the temperature is cooled to room temperature, the pH is adjusted to alkaline with potassium carbonate aqueous solution, and the mixture is filtered. The filter cake is the crude product of Compound V.

[0012] Step 3) Add crude compound V and toluene to the reaction vessel, stir to dissolve and decolorize. After cooling the mother liquor, add isopropanol solution of hydrogen chloride dropwise until pH = 3-4. Filter to obtain white solid crimiazole hydrochloride.

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

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

[0015] Specifically, in step 1), the weight ratio of methyl chloroacetate to dichloromethane is 1:5 to 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 pH of the potassium carbonate aqueous solution is adjusted to 8-12, preferably pH=9-10;

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

[0021] Specifically, in step 2), the molar ratio of compound III to hydrogen chloride in hydrochloric acid is 1:5 to 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 8-11, preferably 9-10;

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

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

[0027] Beneficial effects: The synthesis method described in this invention has fewer process steps, is simpler to operate, and is more conducive to industrial production. Compared with existing technologies, it reduces production costs, improves product yield and purity, and the maximum single impurity in the product is less than 0.1%. Detailed Implementation

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

[0029] Example 1:

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

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

[0032] 273g of crude compound V and 1638g of toluene were added to a 2000ml reaction flask and stirred until dissolved. 3.2g of activated carbon was added for decolorization. The mother liquor was filtered and cooled to 10℃. A solution of hydrogen chloride in isopropanol was added dropwise until the pH reached 3-4. The mixture was kept at 5-10℃ and stirred for 1 hour. After filtration and drying, 251.7g of white solid crimimidazole hydrochloride was obtained, with a yield of 92.1% and a purity of 99.7%.

[0033] Example 2:

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

[0035] 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 to a 2000 ml reaction flask. The mixture was refluxed at 100 °C for 6 hours. After cooling to room temperature, the pH was adjusted to 9 with potassium carbonate aqueous solution. The mixture was filtered, and the filter cake was washed with 400 ml of water to obtain crude compound V. After drying, 274.0 g of off-white solid was obtained, with a yield of 95.5% and a purity of 99.1%.

[0036] 274 g of crude compound V and 1644 g of toluene were added to a 2000 ml reaction flask and stirred until dissolved. 3.2 g of activated carbon was added for decolorization. The mother liquor was filtered and cooled to 10 °C. A solution of hydrogen chloride in isopropanol was added dropwise until the pH reached 3-4. The mixture was kept at 5-10 °C and stirred for 1 hour. After filtration and drying, 253.2 g of white solid crimimidazole hydrochloride was obtained, with a yield of 92.4% and a purity of 99.7%.

[0037] Example 3:

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

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

[0040] 1080g of crude compound V and 6480g of toluene were added to a 10L reaction flask and stirred until dissolved. 50g of activated carbon was added for decolorization. The mother liquor was filtered and cooled to 10℃. A solution of hydrogen chloride in isopropanol was added dropwise until the pH reached 3-4. The mixture was kept at 5-10℃ and stirred for 1 hour. After filtration and drying, 1010g of white solid crimidazole hydrochloride was obtained, with a yield of 93.5% and a purity of 99.8%.

[0041] The above description is merely a preferred embodiment of this application and is not intended to limit this application.

Claims

1. A process for the synthesis of clemizole hydrochloride, characterized in that, The synthetic line is as follows: Step 1) Put methyl chloroacetate, potassium carbonate, dichloromethane and tetrahydro-pyrrole into a reaction container, and stir under temperature control; after the reaction is completed, perform suction filtration, wash the mother liquor with hydrochloric acid aqueous solution, separate the phases, extract the aqueous phase with dichloromethane, add dichloromethane, adjust the pH to be alkaline with potassium carbonate aqueous solution, separate the phases, and then wash the organic phase with saturated sodium chloride aqueous solution, dry and desolventize to obtain compound III; Step 2) Put compound III, compound IV and hydrochloric acid into a reaction container, and reflux to react; after cooling to room temperature, adjust the pH to be alkaline with potassium carbonate aqueous solution, perform suction filtration, and the filter cake is a crude compound V; Step 3) Put the crude compound V and toluene into a reaction container, stir to dissolve, decolorize, drop hydrochloric acid isopropanol solution into the mother liquor until the pH is 3-4 after cooling, and perform suction filtration to obtain white solid, which is clomipridine hydrochloride; wherein compound III is ; compound IV is ; compound V is ; In the step 1), the concentration of hydrochloric acid is 5%-20%; and the pH adjusted by potassium carbonate aqueous solution is 8-12. In the step 2), the concentration of hydrochloric acid is 10%-30%; and the pH adjusted by potassium carbonate aqueous solution is 8-11.

2. The process for the synthesis of clemizole hydrochloride according to claim 1, characterized in that, In the step 1), the molar ratio of methyl chloroacetate to tetrahydro-pyrrole is 1:0.95-1; the molar ratio of methyl chloroacetate to potassium carbonate is 1:1.2-2; and the weight ratio of methyl chloroacetate to dichloromethane is 1:5-10.

3. The process for the synthesis of clemizole hydrochloride according to claim 1, characterized in that, In the step 1), the reaction time is 6-10 hours; and the reaction temperature is 20-50℃.

4. The process for the synthesis of 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; and the molar ratio of compound III to hydrogen chloride in hydrochloric acid is 1:5-7.

5. The process for the synthesis of clemizole hydrochloride according to claim 1, characterized in that, In the step 2), the reaction time is 4-8 hours.

6. The process for the synthesis of clemizole hydrochloride according to claim 1, characterized in that, In the step 3), the weight ratio of crude compound V to toluene is 1:4-8.

7. The process for the synthesis of clemizole hydrochloride according to claim 1, characterized in that, In the step 3), the reaction temperature is 0-20℃.

Images