Resolution method of tetramisole hydrochloride

Abstract

The invention belongs to the technical field of chiral material resolution, and particularly relates to a resolution method of tetramisole hydrochloride. The resolution method comprises the following steps: mixing a tetramisole hydrochloride solution with N-p-toluenesulfonyl-L-proline for reaction, carrying out solid-liquid separation, mixing the obtained compound with an alkaline solution, extracting with an organic solvent, acidifying an organic phase to obtain levamisole hydrochloride, and realizing resolution of tetramisole hydrochloride. The method comprises the following steps: adding a chiral reagent N-p-toluenesulfonyl-L-proline into a tetramisole hydrochloride solution to obtain a precipitate, and carrying out solid-liquid separation to obtain a high-purity key intermediate levamisole-N-p-toluenesulfonyl-L-proline compound solid with an ee value of 99% or more. The compound is dissolved by adding alkali, the compound is extracted and separated by using an organic solvent without re-purification, the medicinal levamisole hydrochloride product can be obtained after hydrochloride is formed, the liquid phase purity is more than 99%, the yield can reach 44.2%, the product quality is improved, and the production cost is reduced.

Description

Technical Field

[0001] The invention belongs to the technical field of chiral material separation, and particularly relates to a separation method of tetraimidazole hydrochloride. Background Art

[0002] Almost all natural or semi-synthetic drugs are chiral. At least half of the commonly used drugs contain chiral centers, of which 90% are racemates. Single enantiomer drugs often show higher activity and lower adverse reactions than their racemates, so the preparation of high-purity chiral monomers is of great research significance. Levamisole hydrochloride is the active ingredient of tetramisole hydrochloride, and dexamidisole hydrochloride has no biological activity. Therefore, the preparation of high-purity levamisole hydrochloride by splitting tetramisole hydrochloride has high pharmaceutical value.

[0003] Chinese patent CN 114307991 A discloses a method for resolving tetramisole hydrochloride using a chiral separation column. However, the method has complicated steps and the specific rotation of the obtained levamisole hydrochloride product is -85°, which is of poor quality and cannot meet the quality requirements of pharmaceutical products (specific rotation is required to be not less than -121.5°).

[0004] Chinese patent CN117466916A discloses a method for splitting tetramisole hydrochloride, wherein a chiral metal organic framework material is added as a nucleating agent to a saturated solution of tetramisole hydrochloride racemization to induce preferential crystallization of levamisole hydrochloride, thereby splitting tetramisole hydrochloride. However, the ee value of levamisole hydrochloride obtained by splitting tetramisole hydrochloride by this method is 90.25-97.26%, and the purity of the obtained levamisole hydrochloride is low, and the yield is not high, and further purification is required to meet the demand of more than 98% for medicinal use.

[0005] The chiral resolving agents reported in US Pat. No. 3,579,530 include N-p-toluenesulfonic acid-D(-)-glutamic acid, N-p-toluenesulfonic acid-L(+)-glutamic acid, etc.; US Pat. No. 4,672,126 reports the chiral resolving agent N-p-methoxybenzenesulfonic acid-L-glutamic acid; however, when the chiral glutamic acid derivative is used as the resolving agent of tetraimidazole hydrochloride, the chiral glutamic acid derivative-levorotatory (or dextrorotatory) imidazole complex obtained has a certain solubility in aqueous solution, and the product yield obtained after one resolution is low, generally 30-35%, and the mother liquor needs to be recycled to improve the yield. Summary of the invention

[0006] In view of this, the object of the present invention is to provide a method for splitting tetramisole hydrochloride. The present invention uses N-p-toluenesulfonyl-L-proline to split tetramisole hydrochloride, and the yield of one split is high, and the yield is between 41% and 45%.

[0007] The present invention provides a method for splitting tetramisole hydrochloride, comprising the following steps:

[0008] The solution of tetramisole hydrochloride and N-p-toluenesulfonyl-L-proline are mixed to react, and the solid-liquid separation is performed to obtain a levamisole-N-p-toluenesulfonyl-L-proline complex;

[0009] The levamisole-N-p-toluenesulfonyl-L-proline complex is mixed with an alkaline solution, the obtained mixed solution is extracted with an organic solvent, the obtained organic phase is acidified, and the solid-liquid separation is performed to obtain levamisole hydrochloride, thereby achieving the resolution of tetramisole hydrochloride.

[0010] Preferably, the solvent in the tetramisole hydrochloride solution includes one or more of ethanol, methanol, 1,4-dioxane, isopropanol, acetone, acetonitrile, tetrahydrofuran and water.

[0011] Preferably, the concentration of tetramisole hydrochloride in the tetramisole hydrochloride solution is 0.1 to 0.5 g / mL.

[0012] Preferably, the weight ratio of the N-toluenesulfonyl-L-proline to tetramisole hydrochloride is 0.6 to 2:1.

[0013] Preferably, the reaction temperature is -5 to 70°C and the reaction time is 10 to 120 minutes.

[0014] Preferably, the alkaline solution comprises one or more of sodium hydroxide solution, potassium hydroxide solution, lithium hydroxide solution, sodium carbonate solution, potassium carbonate solution, lithium carbonate solution and ammonia solution.

[0015] Preferably, the concentration of the alkaline solution is 3-50 wt %, and the dosage ratio of the levamisole-N-toluenesulfonyl-L-proline complex to the alkaline solution is 110-115 g:200-400 mL.

[0016] Preferably, the organic solvent includes one or more of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, methyl acetate, ethyl acetate, butyl acetate, toluene, xylene, methyl tert-butyl ketone and diethyl ether.

[0017] Preferably, the acidifying solution used in the acidification includes one or more of hydrogen chloride ethanol solution, hydrogen chloride methanol solution, hydrogen chloride ether solution, hydrogen chloride ethyl acetate solution, hydrogen chloride butyl acetate solution and hydrogen chloride methyl acetate solution.

[0018] Preferably, the mass concentration of HCl in the acidified solution is 5-50%, and the dosage ratio of the levamisole-N-toluenesulfonyl-L-proline complex to the acidified solution is 110-115 g:40 mL.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] The invention provides a tetramisole hydrochloride splitting method, comprising the following steps: mixing a tetramisole hydrochloride solution and N-toluenesulfonyl-L-proline for reaction, and performing solid-liquid separation to obtain a levamisole-N-toluenesulfonyl-L-proline complex; mixing the levamisole-N-toluenesulfonyl-L-proline complex and an alkaline solution, extracting the obtained mixed solution with an organic solvent, acidifying the obtained organic phase, and performing solid-liquid separation to obtain levamisole hydrochloride, thereby realizing the splitting of the tetramisole hydrochloride.

[0021] The invention uses N-toluenesulfonyl-L-proline as a chiral resolving agent; a levamisole-N-toluenesulfonyl-L-proline complex formed by N-toluenesulfonyl-L-proline and levamisole has low water solubility, can improve the yield of one-time resolution to 44.2%, and reduces production costs; the obtained high-purity key intermediate levamisole-N-toluenesulfonyl-L-proline complex has an ee value of more than 99%; after adding alkali to dissolve the complex, extracting and separating N-toluenesulfonyl-L-proline salt with an organic solvent, a levamisole alkaline solution is obtained, and no purification is required, and further hydrochloride is formed to obtain a levamisole hydrochloride product that meets medical use, and the purity is more than 99%. DETAILED DESCRIPTION

[0022] The present invention provides a method for splitting tetramisole hydrochloride, comprising the following steps:

[0023] The solution of tetramisole hydrochloride and N-p-toluenesulfonyl-L-proline are mixed to react, and the solid-liquid separation is performed to obtain a levamisole-N-p-toluenesulfonyl-L-proline complex;

[0024] The levamisole-N-p-toluenesulfonyl-L-proline complex is mixed with an alkaline solution, the obtained mixed solution is extracted with an organic solvent, the obtained organic phase is acidified, and the solid-liquid separation is performed to obtain levamisole hydrochloride, thereby achieving the resolution of tetramisole hydrochloride.

[0025] In the present invention, unless otherwise specified, the materials and equipment used are commercially available products in the art.

[0026] The invention comprises the following steps: mixing a tetramisole hydrochloride solution and N-toluenesulfonyl-L-proline for reaction, and performing solid-liquid separation to obtain a levamisole-N-toluenesulfonyl-L-proline complex.

[0027] In the present invention, the tetramisole hydrochloride is a racemate, including levamisole hydrochloride and dexamisole hydrochloride.

[0028] In the present invention, the solvent in the tetramisole hydrochloride solution preferably includes one or more of ethanol, methanol, 1,4-dioxane, isopropanol, acetone, acetonitrile, tetrahydrofuran and water, and is more preferably a mixture of water and methanol. The volume ratio of water to methanol in the mixture is preferably 1.5:10.

[0029] The present invention dissolves tetramisole hydrochloride to obtain a solution of tetramisole hydrochloride; the weight ratio of the dissolved solvent to tetramisole hydrochloride is preferably 0.1 to 100:1, more preferably 2.5 to 9.6:1, and even more preferably 4.2 to 8.3:1. The concentration of tetramisole hydrochloride in the solution of tetramisole hydrochloride is preferably 0.1 to 0.5 g / mL, more preferably 0.2 to 0.4 g / mL, and specifically can be 0.24 g / mL or 0.3 g / mL. The dissolving temperature is preferably 20 to 70°C, and specifically can be 60°C.

[0030] In the present invention, the N-toluenesulfonyl-L-proline is preferably used in the form of a solid or a solution, and the solvent in the solution preferably includes one or more of anhydrous ethanol, methanol, isopropanol, acetone, acetonitrile, tetrahydrofuran and water; when used in the form of a solution, the weight ratio of the N-toluenesulfonyl-L-proline to the solvent is preferably 1:1 to 20, more preferably 1:7.4; the preparation temperature of the solution is preferably 20 to 70°C, more preferably 60°C.

[0031] In the present invention, the weight ratio of the N-toluenesulfonyl-L-proline to the tetramisole hydrochloride in the tetramisole hydrochloride solution is preferably 0.6 to 2:1, more preferably 0.8 to 1.6:1, and specifically may be 1:1.

[0032] The present invention preferably adds N-toluenesulfonyl-L-proline to the tetramisole hydrochloride solution in batches, and the present invention has no special requirements on the number of batches. During the adding process, the temperature of the tetramisole hydrochloride solution is preferably controlled to be 20-70°C, more preferably 60°C.

[0033] In the present invention, the reaction temperature is preferably -5 to 70°C, more preferably 0 to 60°C; the reaction is preferably carried out under stirring, and the stirring time is preferably 10 to 120 minutes, more preferably 30 to 90 minutes. The reaction is a reaction of levamisole and N-toluenesulfonyl-L-proline to form a complex, and the reaction formula is as follows:

[0034]

[0035] In the present invention, the reaction preferably further comprises cooling to allow the levamisole-N-toluenesulfonyl-L-proline complex to crystallize and precipitate, and the temperature after cooling is preferably -5 to 5°C.

[0036] In the present invention, the solid-liquid separation method is preferably suction filtration, and after the solid-liquid separation, it is preferably further included: washing and drying the obtained solid to obtain a levamisole-N-toluenesulfonyl-L-proline complex; after the solid-liquid separation, dexamisole hydrochloride is retained in the solution, and the obtained solid is a levamisole-N-toluenesulfonyl-L-proline complex, achieving the crystallization separation of levamisole and dexamisole. The washing reagent is preferably anhydrous ethanol; the drying temperature is preferably 60°C, and the drying time is preferably 2h.

[0037] The invention obtains a levamisole-N-toluenesulfonyl-L-proline complex and dexamisole hydrochloride, and the resolution ee value is above 99%.

[0038] After obtaining the levamisole-N-toluenesulfonyl-L-proline complex, the present invention mixes the levamisole-N-toluenesulfonyl-L-proline complex with an alkaline solution, extracts the obtained mixed solution with an organic solvent, acidifies the obtained organic phase, separates the solid and the liquid, obtains levamisole hydrochloride, and realizes the resolution of tetramisole hydrochloride.

[0039] In the present invention, the alkaline solution preferably includes one or more of sodium hydroxide solution, potassium hydroxide solution, lithium hydroxide solution, sodium carbonate solution, potassium carbonate solution, lithium carbonate solution and ammonia solution; the concentration of the alkaline solution is preferably 3-50wt%, specifically 50wt% or 10wt%, and the dosage ratio of the levamisole-N-toluenesulfonyl-L-proline complex to the alkaline solution is preferably 110-115g:200-400mL.

[0040] In the present invention, the pH value of the mixed solution is preferably greater than 9, more preferably greater than 10. The present invention has no special requirements on the mixing method of the levamisole-N-toluenesulfonyl-L-proline complex and the alkaline solution, as long as the complex is dissolved.

[0041] In the present invention, the levamisole-N-toluenesulfonyl-L-proline complex is mixed with an alkaline solution to obtain a mixed solution containing levamisole and N-toluenesulfonyl-L-proline salt. Taking the alkaline solution as a sodium hydroxide solution as an example, the reaction formula is as follows:

[0042]

[0043] In the present invention, the organic solvent preferably includes one or more of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, methyl acetate, ethyl acetate, butyl acetate, toluene, xylene, methyl tert-butyl ketone and ether, more preferably dichloromethane. The organic solvent is preferably an organic solvent that is immiscible with water and can dissolve levamisole. The purpose of the organic solvent extraction in the present invention is to extract levamisole into the organic solvent, and N-toluenesulfonyl-L-proline salt is left in the remaining aqueous phase, so as to achieve the separation of levamisole and N-toluenesulfonyl-L-proline salt.

[0044] In the present invention, the number of extractions is preferably 1 to 5 times, more preferably 2 to 3 times, and the volume ratio of the organic solvent to the alkaline solution used in each extraction is preferably 1:1 to 2.

[0045] In the present invention, after the extraction, the step preferably further comprises: washing the obtained organic phase and drying with a desiccant; the washing agent is preferably saturated salt water; and the desiccant is preferably anhydrous sodium sulfate.

[0046] In the present invention, the acidification solution used in the acidification preferably includes one or more of hydrogen chloride ethanol solution, hydrogen chloride methanol solution, hydrogen chloride ether solution, hydrogen chloride ethyl acetate solution, hydrogen chloride butyl acetate solution and hydrogen chloride methyl acetate solution. The mass concentration of HCl in the acidification solution is preferably 5-50%, more preferably 10-40%, and specifically 30%. The amount ratio of the levamisole-N-toluenesulfonyl-L-proline complex to the acidification solution is preferably 110-115g:40mL. After the acidification, levamisole generates levamisole hydrochloride and precipitates, and the reaction formula is as follows:

[0047]

[0048] In the present invention, after the solid-liquid separation, the process preferably further comprises: washing and drying the obtained solid; the solid-liquid separation method is preferably suction filtration; the washing reagent is preferably anhydrous ethanol; the drying temperature is preferably 60°C and the drying time is preferably 2h.

[0049] The levamisole hydrochloride obtained by the invention has high yield and purity, with the yield being above 40% and the purity being above 99%.

[0050] The invention adds a chiral reagent N-toluenesulfonyl-L-proline to a tetraimidazole hydrochloride racemic solution to obtain a precipitate, and obtains a high-purity key intermediate levamisole-N-toluenesulfonyl-L-proline complex solid after solid-liquid separation, and the ee value is above 99%. After the complex is dissolved with alkali, and N-toluenesulfonyl-L-proline salt is extracted and separated by an organic solvent, a high-purity levamisole alkaline solution is obtained, and no further purification is required. The hydrochloride can be further formed to obtain a levamisole hydrochloride product that meets medical use, and the liquid phase purity is above 99%, thereby improving product quality and reducing production costs at the same time.

[0051] In order to further illustrate the present invention, the resolution method of tetramisole hydrochloride provided by the present invention is described in detail below in conjunction with examples, but they should not be construed as limiting the scope of protection of the present invention.

[0052] Example 1

[0053] Preparation of the resolving agent N-toluenesulfonyl-L-proline: In a 2000mL three-necked glass bottle, add 1000mL of dichloromethane, add 115g of L-proline, drop 130g of triethylamine and stir to dissolve, drop a dichloromethane solution of p-toluenesulfonyl chloride (weigh 210g of p-toluenesulfonyl chloride, add 600mL of dichloromethane to dissolve), control the temperature at 20±5℃ and react for 16 hours. Add 500mL of water to extract twice, combine the aqueous phases, adjust the pH value to 3-4 with hydrochloric acid, control the temperature at 0-5℃ to grow crystals for 1 hour, filter, wash with ethanol, and vacuum dry at 50℃ for 2 hours to obtain 225g of N-toluenesulfonyl-L-proline as a white solid.

[0054] The reaction equation for preparing N-tosyl-L-proline is as follows:

[0055]

[0056] Example 2

[0057] Weigh 120g of tetramisole hydrochloride racemate into a 1000L three-necked glass bottle, add 500mL of water, and stir to dissolve. Control the temperature at 60°C, and add 120g of N-toluenesulfonyl-L-proline. Stir for 90min after addition, cool to 5°C, filter, wash the solid with anhydrous ethanol, and vacuum dry at 60°C for 2 hours to obtain 115g of white solid, with a molar yield of 97.1% and an ee value of 99.2% in liquid phase detection.

[0058] Dissolve 115g of white solid in 200mL 10wt% sodium hydroxide solution, add 200mL dichloromethane to extract, and collect the organic phase. The aqueous phase is extracted once with 200mL dichloromethane, the organic phase is combined, the organic phase is washed once with saturated brine, 10g of anhydrous sodium sulfate is added, stirred for 1 hour, filtered, the filtrate is placed in a 1000mL three-necked flask, stirred, 40mL of 30wt% hydrogen chloride ethanol solution is added dropwise, and white crystals are precipitated. Filter by suction, wash with anhydrous ethanol, and vacuum dry at 60°C for 2 hours to obtain 53g of levamisole hydrochloride white crystals. The liquid phase detection purity is 99.5%, and the yield is 44.2%.

[0059] Example 3

[0060] Weigh 120g of tetramisole hydrochloride racemate into a 3000L three-necked glass bottle, add 150mL of water and 1000mL of methanol, and stir to dissolve. Control the temperature at 60°C, and slowly add N-toluenesulfonyl-L-proline solution (120g N-toluenesulfonyl-L-proline, dissolved in 1000mL of tetrahydrofuran, controlled at 60°C). After adding, stir for 30 minutes, cool to 5°C, filter, wash the solid with anhydrous ethanol, and vacuum dry at 60°C for 2 hours to obtain 110g of white solid, and the ee value of liquid phase detection is 99.3%.

[0061] Dissolve 110g of white solid with 400mL 5wt% potassium hydroxide solution, add 200mL dichloromethane to extract, and collect the organic phase. The aqueous phase is extracted once with 200mL dichloromethane, the organic phase is combined, the organic phase is washed once with saturated brine, 10g of anhydrous sodium sulfate is added, stirred for 1 hour, filtered, the filtrate is placed in a 1000mL three-necked flask, stirred, 40mL of 30wt% hydrogen chloride ethanol solution is added dropwise, and white crystals are precipitated. Filter by suction, wash with anhydrous ethanol, and vacuum dry at 60°C for 2 hours to obtain 50g of levamisole hydrochloride white crystals. The liquid phase detection purity is 99.4%, and the yield is 41.7%.

[0062] The method for splitting tetramisole hydrochloride provided by the present invention uses N-toluenesulfonyl-L-proline as a chiral splitting agent, which is added to a tetramisole hydrochloride racemic solution to induce levamisole and N-toluenesulfonyl-L-proline to form a high-purity complex crystal precipitation, while dexamisole does not precipitate, and the purpose of splitting with dexamisole is achieved after solid-liquid separation. The splitting ee value of tetramisole hydrochloride is above 99%. After the complex is dissolved with alkali and N-toluenesulfonyl-L-proline is separated by organic solvent extraction, a high-purity levamisole alkaline solution is obtained, which does not need to be purified again, and further hydrochloride can be obtained to obtain a levamisole hydrochloride product that meets medical use, and the liquid phase purity is above 99%.

[0063] Although the above-mentioned embodiments have made a detailed description of the present invention, they are only some embodiments of the present invention, rather than all embodiments. People can also obtain other embodiments based on the embodiments of the present invention without creative work, and these embodiments all fall within the scope of protection of the present invention.

Claims

1. A method for resolving tetramisole hydrochloride, characterized in that: The following steps are involved: The solution of tetramisole hydrochloride and N-p-toluenesulfonyl-L-proline are mixed to react, and the solid-liquid separation is performed to obtain a levamisole-N-p-toluenesulfonyl-L-proline complex; The levamisole-N-p-toluenesulfonyl-L-proline complex is mixed with an alkaline solution, the obtained mixed solution is extracted with an organic solvent, the obtained organic phase is acidified, and the solid-liquid separation is performed to obtain levamisole hydrochloride, thereby achieving the resolution of tetramisole hydrochloride.

2. The splitting method according to claim 1, characterized in that: The solvent in the tetramisole hydrochloride solution includes one or more of ethanol, methanol, 1,4-dioxane, isopropanol, acetone, acetonitrile, tetrahydrofuran and water.

3. The splitting method according to claim 1 or 2, characterized in that: The concentration of tetramisole hydrochloride in the tetramisole hydrochloride solution is 0.1-0.5 g / mL.

4. The splitting method according to claim 1, characterized in that: The weight ratio of the N-toluenesulfonyl-L-proline to tetramisole hydrochloride is 0.6 to 2:

1.

5. The splitting method according to claim 1 or 4, characterized in that: The reaction temperature is -5 to 70°C and the reaction time is 10 to 120 minutes.

6. The splitting method according to claim 1, characterized in that: The alkaline solution includes one or more of a sodium hydroxide solution, a potassium hydroxide solution, a lithium hydroxide solution, a sodium carbonate solution, a potassium carbonate solution, a lithium carbonate solution and an ammonia solution.

7. The splitting method according to claim 6, characterized in that: The concentration of the alkaline solution is 3-50 wt %, and the dosage ratio of the levamisole-N-toluenesulfonyl-L-proline complex to the alkaline solution is 110-115 g: 200-400 mL.

8. The splitting method according to claim 1, characterized in that: The organic solvent includes one or more of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, methyl acetate, ethyl acetate, butyl acetate, toluene, xylene, methyl tert-butyl ketone and ether.

9. The splitting method according to claim 1, characterized in that: The acidification solution used in the acidification includes one or more of hydrogen chloride ethanol solution, hydrogen chloride methanol solution, hydrogen chloride ether solution, hydrogen chloride ethyl acetate solution, hydrogen chloride butyl acetate solution and hydrogen chloride methyl acetate solution.

10. The splitting method according to claim 9, characterized in that: The mass concentration of HCl in the acidified solution is 5-50%, and the dosage ratio of the levamisole-N-toluenesulfonyl-L-proline complex to the acidified solution is 110-115 g:40 mL.

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