Recovery method of tetramisole hydrochloride resolving agent N-p-toluenesulfonyl-L-proline

Abstract

The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a method for recovering N-p-toluenesulfonyl-L-proline serving as a tetramisole hydrochloride resolving agent. The recovery method comprises the following steps: dissolving a levamisole-N-p-toluenesulfonyl-L-proline compound by using an alkaline solution, extracting levamisole from the obtained mixed solution by using an organic solvent, and carrying out acidification, crystal growing and solid-liquid separation on the residual water phase to obtain the N-p-toluenesulfonyl-L-proline, the crystal growing temperature is-5 to 20 DEG C; the method comprises the following steps: dissolving a levamisole-N-p-toluenesulfonyl-L-proline compound by adopting an alkaline solution, extracting levamisole alkali by using an organic solvent, adding acid to the residual water phase to adjust the residual water phase to be acidic, controlling the temperature to separate out N-p-toluenesulfonyl-L-proline crystals, and carrying out solid-liquid separation to obtain the recovered N-p-toluenesulfonyl-L-proline, thereby obtaining the levamisole-N-p-toluenesulfonyl-L-proline. The method can be directly fed and used in production, and the cost of splitting tetramisole hydrochloride is greatly reduced.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical industry, and particularly relates to a method for recovering a hydrochloric acid tetraimidazole resolving agent N-toluenesulfonyl-L-proline. Background Art

[0002] Levamisole hydrochloride is a general anthelmintic drug that has good efficacy against roundworms, hookworms, pinworms and strongyloides. It is highly effective and low in toxicity. It can be used as a veterinary drug, as well as a drug for adults or children, and has good medicinal value. Its structural formula is as follows:

[0003]

[0004] At present, the mainstream production process of levamisole hydrochloride is to use tetramisole hydrochloride racemate as raw material, and use glutamic acid derivatives as chiral resolving agents to split and obtain high-purity levamisole base, which is further converted into hydrochloride to obtain medicinal levamisole hydrochloride products. In order to reduce production costs, the chiral resolving agent can be recycled and reused.

[0005] Chinese patent CN 117800881 A discloses a method for recovering N-toluenesulfonyl-L-(+)-glutamic acid from tetramisole hydrochloride resolution agent, wherein levamisole and N-toluenesulfonyl-L-(+)-glutamic acid monosodium salt monohydrate aqueous solution are treated with alkali, and the levamisole alkali is precipitated at a pH value of about 9, and the N-toluenesulfonyl-L-(+)-glutamic acid aqueous solution is obtained after filtration, and the solution is heated to 70°C and adjusted to a pH value of about 10 with alkali for 2 hours, and then acidified to a pH value of about 1.5 after cooling to room temperature, and qualified crystal seeds are added, and the temperature is reduced for crystallization for about 7 hours, and the N-toluenesulfonyl-L-(+)-glutamic acid solid is obtained after filtration. However, the N-toluenesulfonyl-L-(+)-glutamic acid recovered by the above method needs to be reacted in an alkaline high temperature environment for about 2 hours, and the recovered product is yellow, and the yield is low, which is only about 92%. Summary of the invention

[0006] In view of this, the object of the present invention is to provide a method for recovering N-toluenesulfonyl-L-proline, a hydrochloric acid tetraimidazole resolution agent. The recovery method of the present invention has a high recovery rate of the resolution agent N-toluenesulfonyl-L-proline, and the dry yield is above 96%.

[0007] The present invention provides a method for recovering a hydrochloric acid tetraimidazole resolution agent N-toluenesulfonyl-L-proline, comprising the following steps:

[0008] dissolving the levamisole-N-p-toluenesulfonyl-L-proline complex with an alkaline solution to obtain a mixed solution;

[0009] The mixed solution is extracted with an organic solvent to extract levamisole, the remaining aqueous phase is acidified, crystallized, and solid-liquid separated to obtain N-toluenesulfonyl-L-proline; the crystallization temperature is -5 to 20°C.

[0010] 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.

[0011] Preferably, the mass concentration of the alkaline solution is 3-50%, and the weight ratio of the levamisole-N-toluenesulfonyl-L-proline complex to the alkaline solution is 1:1-10.

[0012] 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.

[0013] Preferably, the extraction is performed 1 to 5 times, and the volume ratio of the organic solvent to the alkaline solution in each extraction is 20 to 50:22 to 25.

[0014] Preferably, the acid used for the acidification includes one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid and oxalic acid.

[0015] Preferably, the pH value of the acidified system is 0-5.

[0016] Preferably, the crystal growing temperature is 0-5°C, and the crystal growing time is 1-20h.

[0017] Preferably, the solid-liquid separation method is suction filtration.

[0018] Preferably, the solid-liquid separation further includes drying, and the drying temperature is 40 to 80° C. and the drying time is 2 to 10 hours.

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

[0020] The invention provides a method for recovering a hydrochloric acid tetramisole resolution agent N-toluenesulfonyl-L-proline. The method comprises the following steps: dissolving a levamisole-N-toluenesulfonyl-L-proline complex with an alkaline solution to obtain a mixed solution; extracting levamisole with an organic solvent from the mixed solution, acidifying the remaining aqueous phase, growing crystals, and performing solid-liquid separation to obtain N-toluenesulfonyl-L-proline; and the temperature for growing crystals is -5 to 20 DEG C.

[0021] The invention adopts an alkaline solution to dissolve a levamisole-N-toluenesulfonyl-L-proline complex to obtain levamisole and N-toluenesulfonyl-L-proline salt, extracts the levamisole with an organic solvent, adds acid to the remaining water phase to adjust it to acidity, controls the temperature to precipitate N-toluenesulfonyl-L-proline crystals, and obtains N-toluenesulfonyl-L-proline after solid-liquid separation. The invention controls the crystal growing temperature to be -5 to 20 DEG C, and the obtained N-toluenesulfonyl-L-proline has high yield and purity, the dry yield is above 96%, and the purity after drying is above 99.5%.

[0022] The recovered N-toluenesulfonyl-L-proline is directly used in the resolution of tetraimidazole hydrochloride, and the one-time resolution yield can reach 44%, which can greatly reduce the production cost of the resolution of tetraimidazole hydrochloride. DETAILED DESCRIPTION

[0023] The present invention provides a method for recovering a hydrochloric acid tetraimidazole resolution agent N-toluenesulfonyl-L-proline, comprising the following steps:

[0024] dissolving the levamisole-N-p-toluenesulfonyl-L-proline complex with an alkaline solution to obtain a mixed solution;

[0025] The mixed solution is extracted with an organic solvent to extract levamisole, the remaining aqueous phase is acidified, crystallized, and solid-liquid separated to obtain N-toluenesulfonyl-L-proline; the crystallization temperature is -5 to 20°C.

[0026] In the present invention, unless otherwise specified, the materials and equipment used are commercially available products in the art.

[0027] The invention dissolves the levamisole-N-toluenesulfonyl-L-proline complex with an alkaline solution to obtain a mixed solution.

[0028] In the present invention, the levamisole-N-toluenesulfonyl-L-proline complex is preferably obtained by a method comprising the following steps:

[0029] The tetramisole hydrochloride solution and N-p-toluenesulfonyl-L-proline are mixed for reaction, and the solid-liquid separation is performed to obtain a levamisole-N-p-toluenesulfonyl-L-proline complex.

[0030] In the present invention, the tetramisole hydrochloride is a racemate, including levamisole hydrochloride and dexamisole hydrochloride.

[0031] 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.

[0032] 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 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, more preferably 70°C.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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:

[0037]

[0038] 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.

[0039] In the present invention, the solid-liquid separation method is preferably suction filtration, and after the solid-liquid separation, the method preferably further comprises: washing and drying the obtained solid to obtain a levamisole-N-toluenesulfonyl-L-proline complex; after the solid-liquid separation, dexvamisole hydrochloride remains in the solution, and the obtained solid is a levamisole-N-toluenesulfonyl-L-proline complex. The washing reagent is preferably anhydrous ethanol; the drying temperature is preferably 60°C, and the drying time is preferably 2h.

[0040] 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.

[0041] In the present invention, the mass concentration of the alkaline solution is preferably 1% to saturation concentration, more preferably 3 to 50%, specifically 5%, 15% or 20%.

[0042] In the present invention, the weight ratio of the levamisole-N-toluenesulfonyl-L-proline complex to the alkaline solution is preferably 1:1-10, more preferably 118 g:220-250 mL.

[0043] In the present invention, the dissolution is preferably carried out at room temperature and under stirring. The present invention has no special requirements on the stirring time and speed, as long as the complex is dissolved. The pH value of the mixed solution after the dissolution is preferably above 9, more preferably above 10.

[0044] Taking the alkaline solution as sodium hydroxide solution as an example, after the levamisole-N-toluenesulfonyl-L-proline complex is dissolved, the mixed solution contains levamisole and N-toluenesulfonyl-L-proline sodium salt, and the reaction formula is as follows:

[0045]

[0046] After obtaining the mixed solution, the present invention uses an organic solvent to extract levamisole from the mixed solution, acidifies the remaining aqueous phase, grows crystals, and separates the solid and liquid to obtain N-toluenesulfonyl-L-proline; the temperature of the growing crystals is -5 to 20°C.

[0047] In the present invention, the organic solvent is preferably an organic solvent that is immiscible with water and can dissolve levamisole, and 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.

[0048] 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 in each extraction is preferably 20 to 50:22 to 25, more preferably 30:22 to 25. After the organic solvent extraction, levamisole is extracted into the organic phase and can be used for the preparation of levamisole hydrochloride; the salt formed by N-toluenesulfonyl-L-proline remains in the aqueous phase, and N-toluenesulfonyl-L-proline is recovered.

[0049] In the present invention, the acid solution used for acidification preferably includes one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid and oxalic acid; the total mass concentration of the acid solution is preferably 1 to 99%, more preferably 3 to 20%, and even more preferably 15 to 18%.

[0050] In the present invention, the pH value of the acidified system is preferably 0 to 5, more preferably 1 to 4, and even more preferably 3 to 3.5.

[0051] Taking the sodium salt of N-toluenesulfonyl-L-proline as an example, the acidified N-toluenesulfonyl-L-proline sodium salt generates N-toluenesulfonyl-L-proline, and the reaction formula is as follows:

[0052]

[0053] In the present invention, the crystal growing temperature is preferably 0-5°C, specifically 0-2°C or 3-5°C, and the time is preferably 1-20h, more preferably 2-3h; during the crystal growing process, N-toluenesulfonyl-L-proline is precipitated in the form of crystals.

[0054] In the present invention, the solid-liquid separation method is preferably suction filtration, and the suction filtration process is preferably accompanied by washing. The present invention has no special requirements for the suction filtration conditions, and the conditions commonly used by those skilled in the art can be used. After the suction filtration, a wet product of N-toluenesulfonyl-L-proline is obtained, and the water content of the wet product of N-toluenesulfonyl-L-proline is preferably 5-10%, and more preferably 5.5-7.2%.

[0055] In the present invention, the solid-liquid separation preferably includes drying, the drying temperature is preferably 40-80°C, more preferably 60-70°C, the time is preferably 2-10 hours, more preferably 1 hour. The drying method preferably includes normal pressure drying, blast drying or vacuum drying.

[0056] The invention adopts an alkaline solution to dissolve the levamisole-N-toluenesulfonyl-L-proline complex, and then uses an organic solvent to extract the levamisole base (which can be directly used in the production of levamisole hydrochloride), and then adds acid to the remaining water phase to adjust it to acidity, and controls the temperature to precipitate N-toluenesulfonyl-L-proline crystals. After solid-liquid separation, N-toluenesulfonyl-L-proline is obtained. The yield and purity of N-toluenesulfonyl-L-proline are high, the dry yield is above 96%, and the purity after drying is above 99.5%.

[0057] To further illustrate the present invention, the method for recovering the tetraimidazole hydrochloride resolution agent N-toluenesulfonyl-L-proline provided by the present invention is described in detail below in conjunction with the examples, but they should not be construed as limiting the scope of protection of the present invention.

[0058] In the examples or comparative examples of the present invention, the levamisole-N-toluenesulfonyl-L-proline complex is prepared according to the following steps (can be prepared multiple times):

[0059] 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℃, and add 120g of N-toluenesulfonyl-L-proline. After adding, stir for 90min, cool to 5℃, filter, wash the solid with anhydrous ethanol, and vacuum dry at 60℃ for 2 hours. The obtained white solid is the levamisole-N-toluenesulfonyl-L-proline complex.

[0060] Example 1

[0061] Weigh 118g of levamisole-N-toluenesulfonyl-L-proline complex into a 1000L three-necked glass bottle, add 220mL of 5wt% sodium hydroxide aqueous solution, and stir to dissolve completely. Add 300mL of dichloromethane, stir for 10min, let stand for 30min, separate the phases, and transfer the dichloromethane phase. Add another 300mL of dichloromethane to the aqueous phase, stir for 10min, let stand for 30min, separate the phases, and transfer the dichloromethane phase. Collect the remaining aqueous phase in a 500mL three-necked flask, stir, adjust the pH value to 3.5 with 18wt% hydrochloric acid, cool to 0-2℃ and grow the crystals for 2 hours.

[0062] The mixture was filtered to dryness to obtain 70 g of a white crystalline wet product with a water content of 7.2% and a dry yield of 96.8%.

[0063] The sample was vacuum dried at 70°C for 1 hour, and the content of N-toluenesulfonyl-L-proline was measured by chemical titration to be 99.8%.

[0064] Example 2

[0065] In a 1000L three-necked glass bottle, add 250mL of 20wt% potassium carbonate solution, stir, weigh 118g of levamisole-N-toluenesulfonyl-L-proline complex, and add in batches. After dissolving, add 300mL of dichloromethane, stir for 10min, let stand for 30min, separate the phases, and transfer the dichloromethane phase. Add another 300mL of dichloromethane to the aqueous phase, stir for 10min, let stand for 30min, separate the phases, and transfer the dichloromethane phase. Collect the remaining aqueous phase in a 500mL three-necked flask, stir, adjust the pH value to 3.0 with 15wt% sulfuric acid, cool to 3-5℃ and grow the crystal for 2 hours.

[0066] The mixture was filtered to dryness to obtain 68.6 g of a white crystalline wet product with a water content of 5.5% and a dry yield of 96.6%.

[0067] The sample was vacuum dried at 70°C for 1 hour, and the content of N-toluenesulfonyl-L-proline was measured by chemical titration to be 99.7%.

[0068] Application Example 1

[0069] Weigh 120g of tetramisole hydrochloride racemate into a 1000L three-necked glass bottle, add 493mL of water, and stir to dissolve. Control the temperature at 60°C, and add 127g (5.5% water content) of wet N-toluenesulfonyl-L-proline recovered in Example 2 in several portions. After adding, stir for 30min, cool to 5°C, filter, wash the solid with anhydrous ethanol, and vacuum dry at 60°C for 2 hours to obtain 114.5g of white solid, with an ee value of 99.3% detected by liquid phase.

[0070] Dissolve 114.5g of white solid with 200mL 10wt% sodium hydroxide solution, add 200mL dichloromethane to extract, and collect the organic phase. Extract the aqueous phase with 200mL dichloromethane again, combine the organic phases, wash once with saturated brine, add 10g of anhydrous sodium sulfate, stir for 1 hour, filter, place the filtrate in a 1000mL three-necked flask, stir, drop 40mL of 30wt% hydrogen chloride ethanol solution, and precipitate white crystals. Filter by suction, wash with anhydrous ethanol, and vacuum dry at 60℃ for 2 hours to obtain 52.8g of levamisole hydrochloride white crystals, with a liquid phase detection purity of 99.5% and a total resolution yield of 44%.

[0071] Comparative Example 1

[0072] Weigh 118g of levamisole-N-toluenesulfonyl-L-proline complex into a 1000L three-necked glass bottle, add 220mL of 5wt% sodium hydroxide aqueous solution, and stir to dissolve completely. Add 300mL of dichloromethane, stir for 10min, let stand for 30min, separate the phases, and transfer the dichloromethane phase. Add 300mL of dichloromethane to the aqueous phase, stir for 10min, let stand for 30min, separate the phases, and transfer the dichloromethane phase. Collect the remaining aqueous phase in a 500mL three-necked flask, stir, adjust the pH to 3.5 with 18wt% hydrochloric acid, and control the temperature at 25-30℃ to grow the crystal for 2 hours.

[0073] The mixture was filtered to dryness to obtain 52.1 g of a white crystalline wet product with a water content of 5.7% and a dry yield of 73.2%.

[0074] 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 recovering N-tosyl-L-proline, a hydrochloric acid tetraimidazole resolving agent, characterized in that: The following steps are involved: dissolving the levamisole-N-p-toluenesulfonyl-L-proline complex with an alkaline solution to obtain a mixed solution; The mixed solution is extracted with an organic solvent to extract levamisole, the remaining aqueous phase is acidified, crystallized, and solid-liquid separated to obtain N-toluenesulfonyl-L-proline; the crystallization temperature is -5 to 20°C.

2. The recycling 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.

3. The recovery method according to claim 1 or 2, characterized in that: The mass concentration of the alkaline solution is 3-50%, and the weight ratio of the levamisole-N-toluenesulfonyl-L-proline complex to the alkaline solution is 1:1-10.

4. The recycling 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.

5. The recovery method according to claim 1 or 4, characterized in that: The extraction is performed 1 to 5 times, and the volume ratio of the organic solvent to the alkaline solution in each extraction is 20 to 50:22 to 25.

6. The recycling method according to claim 1, characterized in that: The acid used for the acidification includes one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid and oxalic acid.

7. The recycling method according to claim 1 or 6, characterized in that: The pH value of the acidified system is 0-5.

8. The recycling method according to claim 1, characterized in that: The crystal growing temperature is 0-5°C, and the crystal growing time is 1-20h.

9. The recycling method according to claim 1, characterized in that: The solid-liquid separation method is suction filtration.

10. The recycling method according to claim 1 or 9, characterized in that: The solid-liquid separation is followed by drying, wherein the drying temperature is 40 to 80° C. and the drying time is 2 to 10 hours.

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