A method for preparing levamisole hydrochloride

Abstract

The application discloses a preparation method of levamisole hydrochloride and belongs to the technical field of medical intermediates. (R)-epoxyphenylalkane is used as raw material, and is subjected to ring opening with 2-chloroethylamine hydrochloride in water to obtain (R)-1-phenyl-2-aminoethanol; then, ring closure is carried out with thiourea to obtain (R)-3-(2'-hydroxy-2'-phenylethyl)-2-thiazolidine imine; finally, intramolecular Mitsunobu ring closure reaction is carried out, and after treatment, levamisole hydrochloride is obtained. The preparation method has the advantages of short reaction steps, simple and coherent operation, easy control, low corrosion to equipment, and the like, and simultaneously improves the yield and quality of the product.

Description

Technical Field

[0001] This invention relates to a method for preparing levamisole hydrochloride, belonging to the field of pharmaceutical synthesis technology. Background Technology

[0002] Levamisole hydrochloride is a raw material pharmaceutical product with broad-spectrum, highly effective, and low-toxicity anthelmintic activity, as well as immunomodulatory and immune-stimulating functions. Levamisole hydrochloride, in its solid dosage form, is mainly taken orally and is effective in treating parasites, hookworms, pinworms, and strongyloides stercoralis infections, such as levamisole hydrochloride tablets and levamisole hydrochloride pagoda-shaped sugar tablets. Levamisole hydrochloride, in its liquid dosage form, is mainly used for topical application and is used to treat recurrent upper respiratory tract infections, allergic asthma, allergic rhinitis, chronic hepatitis B, recurrent oral mucosal ulcers, and malignant tumors caused by immunodeficiency, such as levamisole hydrochloride liniment.

[0003] There are two main methods for preparing levamisole hydrochloride as reported in existing literature:

[0004] The first method, as reported in the literature [Tetrahedron, 1985, vol. 41, #12, pp. 2465-2470], involves resolving and dissociating Tetramisole with 0.5 eq D-(-)-dibenzoyl tartaric acid (monohydrate) to prepare levamisole hydrochloride. Another configuration in the mother liquor can be racemiced under the action of potassium tert-butoxide, which can further resolve the configuration and improve atom utilization. However, the actual operation is relatively complicated, requiring not only excessive instrumentation but also control over impurities in the active pharmaceutical ingredient.

[0005] The second method, as reported in the literature [Tetrahedron Letters, 1989, vol. 30, #3, pp. 363-366], uses 2,3-pyridine-α-bromoacetophenone as a starting material, reacting it with 2-chloroethylamine via amination, followed by asymmetric catalytic hydrogenation to give (S)-1-phenyl-2-aminoethanol hydrochloride. This is then cyclized with potassium thiocyanate in ethanol-water under reflux to give (S)-3-(2'-hydroxy-2'-phenethyl)-2-thiazolidinylimine hydrochloride, and finally further cyclized under thionyl chloride to give levamisole hydrochloride. This method requires a large amount of 2-chloroethylamine for the first step of amination, and only multi-substituted impurities will decrease. The second step uses a rhodium catalyst for asymmetric catalytic hydrogenation, which is expensive. Furthermore, the active pharmaceutical ingredient requires final heavy metal residue testing. While this method has a high yield (up to 96%), it is practically unsuitable for this particular active pharmaceutical ingredient's reaction route. The reaction route is shown below:

[0006]

[0007] To overcome the shortcomings of existing literature methods, it is necessary to optimize and improve the preparation route of levamisole hydrochloride, and develop a synthetic route that is consistent in operation, has a considerable yield, is concise in steps, and is more suitable for industrial production. Summary of the Invention

[0008] To better address the aforementioned problems, this invention discloses a method for preparing levamisole hydrochloride. Using (R)-epoxyphenylethane as a starting material, it undergoes ring-opening with 2-chloroethylamine hydrochloride in water to obtain (R)-1-phenyl-2-aminoethanol; subsequently, it undergoes ring-closure with thiourea to obtain (R)-3-(2'-hydroxy-2'-phenylethyl)-2-thiazolidinylimine; finally, an intramolecular Mitsunobu ring-closure reaction is performed, followed by treatment to obtain levamisole hydrochloride. This preparation method features a short reaction sequence, simple and continuous operation, easy control, low corrosivity to equipment, and improved product yield and quality.

[0009] The present invention discloses a method for preparing levamisole hydrochloride, comprising the following steps:

[0010] Step 1: 2-Chloroethylamine hydrochloride and water are mixed, and an aqueous solution of inorganic base and (R)-epoxyphenyl ethane are added dropwise in both directions. Then, the reaction is heated in the presence of a catalyst to obtain (R)-1-phenyl-2-aminoethanol, which is then purified to obtain (R)-1-phenyl-2-aminoethanol hydrochloride.

[0011] Step 2: (R)-1-phenyl-2-aminoethanol hydrochloride, thiourea, ethanol and water are mixed and heated to react, yielding (R)-3-(2'-hydroxy-2'-phenylethyl)-2-thiazolidinimine;

[0012] Step 3: (R)-3-(2'-hydroxy-2'-phenylethyl)-2-thiazolidinylimine, triphenylphosphine, azodicarbonate diester and organic solvent are mixed, and intramolecular cyclization is performed to obtain levamisole base. After treatment with hydrogen chloride solution, levamisole hydrochloride is obtained.

[0013] The reaction route is shown below:

[0014]

[0015] Furthermore, in the first step, the inorganic base is selected from lithium hydroxide or potassium carbonate.

[0016] Furthermore, in the first step, the catalyst is triphenylborone; the reaction temperature is 50-80℃.

[0017] Furthermore, in the first step, the molar ratio of (R)-epoxyphenylethane to 2-chloroethylamine hydrochloride is 1:2.1-2.5.

[0018] Furthermore, in the second step, the ratio of ethanol to water is 30:70, and the volume is 6 times the weight of (R)-1-phenyl-2-aminoethanol hydrochloride.

[0019] Furthermore, in the second step, the temperature is raised to reflux conditions.

[0020] Furthermore, in the second step, the molar ratio of (R)-1-phenyl-2-aminoethanol hydrochloride to thiourea is 1:1.2-1.4.

[0021] Furthermore, in the third step, the azodicarbonate diester is selected from diethyl azodicarbonate (DEAD) or diisopropyl azodicarbonate (DIAD).

[0022] Furthermore, in the third step, the organic solvent is selected from tetrahydrofuran or dichloromethane.

[0023] Furthermore, in the third step, the molar ratio of (R)-3-(2'-hydroxy-2'-phenylethyl)-2-thiazolidinylimine, triphenylphosphine, and azodicarbonate diester is 1:1.2-1.3:1.25-1.35.

[0024] Compared with the prior art, the method for preparing levamisole hydrochloride provided by this invention has a higher yield, shorter steps, continuous operation, and is more equipment-friendly.

[0025] Specific implementation methods

[0026] The embodiments of the present invention are described in detail below. Examples are listed below to illustrate the present invention. However, it should be understood that the present invention is not limited to these embodiments, but merely provides a method for practicing the present invention.

[0027] Preparation method of levamisole hydrochloride

[0028] Example 1 (step 1)

[0029]

[0030] Under nitrogen protection, 290 g (2.5 mol) of 2-chloroethylamine hydrochloride and 2800 mL of water were added to a reaction flask. A mixture of 5% lithium hydroxide aqueous solution and (R)-epoxyphenyl ethane 120.2 g (1.0 mol), BPh3 12.1 g (0.05 mol), and 100 mL of methanol was added dropwise at room temperature. The pH was maintained at 11.0-11.5 until the addition was complete. The reaction was then carried out at 60-70 °C for 8 hours. HPLC analysis showed that 3.6% of the starting material remained. The mixture was heated to 10-15℃, and concentrated hydrochloric acid was added to adjust the pH to 2-3. Most of the methanol and water were concentrated under reduced pressure. Dichloromethane was added to extract impurities. Sodium hydroxide solution was added to the aqueous phase to adjust the pH to 11-12. The product was extracted with dichloromethane. The organic phase was concentrated under reduced pressure to remove dichloromethane. Acetone was added to replace the dichloromethane. Concentrated hydrochloric acid was added under increased temperature, and the solid precipitated. The solid was cooled, filtered, and dried to obtain 179.2 g of (R)-1-phenyl-2-aminoethanol hydrochloride, with a yield of 75.9% and an HPLC yield of 97.8%. 1 H-NMR(400MHz,DMSO-d6)δ:9.82(s,1H),8.20-7.50(m,5H),5.73(t,1H),4.86-4. 82(m,1H),4.71(s,1H),4.52-4.48(m,2H),4.03-3.99(m,2H),3.47-3.43(m,2H).

[0031] Example 2 (step 1)

[0032]

[0033] Under nitrogen protection, 243.6 g (2.1 mol) of 2-chloroethylamine hydrochloride and 2400 mL of water were added to a reaction flask. A mixture of 10% potassium carbonate aqueous solution and (R)-epoxyphenyl ethane, 12.1 g (0.05 mol) of BPh3 and 50 mL of methanol was added dropwise at room temperature, maintaining a pH of 11.0-11.5 until the addition was complete. The reaction was then carried out at 60-65 °C for 10 hours. HPLC analysis showed that 4.2% of the starting material remained. The temperature was lowered to 10-15 °C, and concentrated hydrochloric acid was added to adjust the pH to 2-3. Most of the methanol and water were concentrated under reduced pressure. Dichloromethane was added to extract impurities. Sodium hydroxide aqueous solution was added to the aqueous phase to adjust the pH to 11-12. The product was extracted with dichloromethane. The organic phase was concentrated under reduced pressure to remove dichloromethane, which was replaced with acetone. Concentrated hydrochloric acid was added at elevated temperature, causing the solid to precipitate. The solid was cooled, filtered, and dried to obtain 157.7 g of (R)-1-phenyl-2-aminoethanol hydrochloride, with a yield of 66.8% and an HPLC yield of 95.7%.

[0034] Example 3 (step 2)

[0035]

[0036] Under nitrogen protection, 153.5 g (0.65 mol) of (R)-1-phenyl-2-aminoethanol hydrochloride, 64 g (0.85 mol) of thiourea, and 920 mL of 30% ethanol solution were added to a reaction flask. The mixture was heated to reflux for 6 h, cooled, and concentrated under reduced pressure to remove most of the ethanol. MTBE was added to extract impurities. The pH of the aqueous phase was adjusted to 9-10 with 20% potassium carbonate aqueous solution. The mixture was then heated to 40-45 °C and stirred for 1.5 h. After cooling, 300 mL of dichloromethane was added four times for extraction. The organic phases were combined, washed with saturated brine, and mixed with anhydrous sodium sulfate and 20 g of silica gel. The mixture was filtered, and the filtrate was concentrated until no liquid flow was observed to give 129.1 g of (R)-3-(2'-hydroxy-2'-phenylethyl)-2-thiazolidinylimine, with a yield of 89.34% and an HPLC yield of 99.4%. MS (ESI+1) 223. 1 H-NMR(400MHz,DMS O-d6)δ:9.34(s,1H),7.55-7.44(m,5H),5.73(t,1H),5.15-5.12(m,1H),4 .26-4.20(m,1H),3.97-3.88(m,2H),3.75-3.70(m,1H),3.46-3.43(m,2H).

[0037] Example 4 (step 3)

[0038]

[0039] Under nitrogen protection, 111.2 g (0.5 mol) of (R)-3-(2'-hydroxy-2'-phenylethyl)-2-thiazolidinylimine, 170.5 g (0.65 mol) of triphenylphosphine, and 1300 mL of dichloromethane (KF < 500 ppm) were added to the reaction flask. The temperature of the reaction system was controlled within 0-5℃, and 117.6 g (0.675 mol) of diethyl azodicarbonate was added dropwise. After the addition was complete, the temperature was maintained and the reaction was stirred for 3 hours. The reaction of the starting material was completed by TLC.

[0040] Add saturated sodium bicarbonate aqueous solution, allow to stand and separate into layers, concentrate the organic phase at room temperature to remove dichloromethane, resulting in solid precipitation. Filter, wash the filter cake with a small amount of cold dichloromethane, concentrate the filtrate under reduced pressure, replace with acetone, and slowly add the acetone solution dropwise to a 6M hydrogen chloride-isopropanol solution at 22-25℃. After the addition is complete, raise the temperature to 35℃ and stir for 2 hours, then lower the temperature to 15-20℃, filter, wash the filter cake with acetone, and dry to obtain 94.5 g of levamisole hydrochloride, HPLC 99.7% (consistent with the peak of the standard sample), yield 78.5%. 1H-NMR (400MHz, DMSO-d6)δ:11.2(s,1H),7.48-7.40(m,5H),5.78-5.74(m,1H),4.26-4.22(m,1H),4.02(dd,2H),3.76-3.67(m,2H),3.67(dd,1H).

[0041] Example 5 (step 3)

[0042]

[0043] Under nitrogen protection, 111.2 g (0.5 mol) of (R)-3-(2'-hydroxy-2'-phenylethyl)-2-thiazolidinylimine, 170.5 g (0.65 mol) of triphenylphosphine, and 1300 mL of tetrahydrofuran (KF < 300 ppm) were added to the reaction flask. The temperature of the reaction system was controlled within 0-5℃, and 136.5 g (0.675 mol) of diisopropyl azodicarbonate was added dropwise. After the addition was complete, the temperature was maintained and the reaction was stirred for 3 hours. The TLC showed that almost no raw material remained.

[0044] Add saturated sodium bicarbonate solution and saturated saline solution, allow to stand and separate into layers, cool the organic phase to 5-10℃, add zinc chloride, heat to room temperature and stir for 3 hours, filter, wash the filter cake with tetrahydrofuran, concentrate the filtrate under reduced pressure to remove tetrahydrofuran, replace with acetone, slowly add the acetone solution dropwise to 6M hydrogen chloride-isopropanol solution at 22-25℃, after the addition is complete, heat to 35℃ and stir for 2 hours, then cool to 15-20℃, filter, wash the filter cake with acetone, dry to obtain 84.7g of levamisole hydrochloride, HPLC 99.6%, yield 70.4%.

[0045] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the methods and techniques disclosed above without departing from the scope of the present invention to create equivalent embodiments. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A process for the preparation of levamisole hydrochloride, characterized in that, The process comprises the following steps: Step 1: 2-chloroethylamine hydrochloride and water were mixed, aqueous solution of inorganic base was added dropwise in both directions and (R)-epoxystyrene was added, then the reaction was heated in the presence of a catalyst to obtain intermediate 2, which was purified to obtain the hydrochloride salt of intermediate 2; the catalyst was triphenylboron; the intermediate 2 was ; Step 2: Intermediate 2 hydrochloride, thiourea, ethanol and water were mixed and reacted at elevated temperature to give intermediate 3; said intermediate 3 is ; Step 3: Intermediate 3, triphenylphosphine, diethyl azodicarboxylate and an organic solvent are mixed to give intramolecular cyclization to give levamisole base, and then treated with hydrogen chloride solution to give levamisole hydrochloride.

2. The process for the preparation of levamisole hydrochloride according to claim 1, characterized by the fact that: In the first step, the inorganic base is selected from lithium hydroxide or potassium carbonate.

3. The process for the preparation of levamisole hydrochloride according to claim 1, characterized by the fact that: In the first step, the reaction temperature is 50-80°C.

4. The process for the preparation of levamisole hydrochloride according to claim 1, characterized by the fact that: In the first step, the molar ratio of (R)-epoxyphenylmethane to 2-chloroethylamine hydrochloride is 1:2.1-2.

5.

5. The process for the preparation of levamisole hydrochloride according to claim 1, characterized by the fact that: In the second step, the molar ratio of the hydrochloride salt of intermediate 2 to thiourea is 1:1.2-1.

4.

6. The process for the preparation of levamisole hydrochloride according to claim 1, characterized by the fact that: In the first step, the reaction is carried out under heating to reflux conditions.

7. The process for the preparation of levamisole hydrochloride according to claim 1, characterized by the fact that: In the third step, the diethyl azodicarboxylate is selected from diethyl azodicarboxylate or diisopropyl azodicarboxylate.

8. The process for the preparation of levamisole hydrochloride according to claim 1, characterized by: In the third step, the organic solvent is selected from tetrahydrofuran or dichloromethane.

9. The process for the preparation of levamisole hydrochloride according to claim 1, characterized by the fact that: In the third step, the molar ratio of intermediate 3, triphenylphosphine and diethyl azodicarboxylate is 1:1.2-1.3:1.25-1.35.

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