One-pot synthesis method of praziquantel

Abstract

The invention discloses a one-pot synthesis method of praziquantel, which belongs to the field of medicine, and is characterized by comprising the following steps: firstly, adding aminoacetaldehyde dimethyl acetal, an alkaline reagent 1 and process water into an organic solvent A, controlling the temperature to be 0-10 DEG C, dropwise adding cyclohexyl formyl chloride, reacting to obtain a compound shown as a formula I, directly washing with water for layering, and separating to obtain a compound shown as a formula II; directly adding chloroacetic acid into an organic layer to react under an alkaline reagent 2, adding process water, adjusting the pH value to be 3-5 by using 10% hydrochloric acid to obtain a compound shown as a formula II, adding a condensing agent HATU, an acid-binding agent and phenylethylamine to obtain a compound shown as a formula III, washing once by using a 10% sodium carbonate solution after the reaction, washing once again, adding a cyclization reagent to react, and purifying to obtain a compound shown as a formula III. And washing, layering, distilling and crystallizing by using an organic solvent B to obtain praziquantel. The method has the effects of simple operation, one-pot continuous reaction of the intermediate, mild reaction, low toxicity, low risk, low cost and high yield synthesis of praziquantel, conformity to the requirements of industrial mass production, and significant application value.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and more specifically to a one-pot synthesis method of praziquantel. Background Art

[0002] Praziquantel is a synthetic pyrazine isoquinoline derivative, which is recognized worldwide as a highly effective and broad-spectrum antiparasitic drug. It is widely used to treat diseases such as Schistosoma japonicum, Schistosoma haematobium, Schistosoma mansoni, Clonorchiasis, Paragonimiasis, Sparganosis mengidii, Fasciola zingiberensis, Echinococcosis, Tapeworms and Cysticercosis. It has the advantages of a broad antiparasitic spectrum, high efficacy, low toxicity, short course of treatment and easy use. In addition to being used in humans, it is also widely used in antiparasitic treatment of animals, poultry, etc. Praziquantel is the preferred drug for the treatment of various parasitic diseases on the market. The chemical structure of praziquantel is as follows:

[0003]

[0004] There are many synthetic routes for praziquantel. The routes currently in production at home and abroad are:

[0005] Route 1: Patent CN201911418638.6 uses 2-phenylethylamine and chloroacetyl chloride to carry out acylation reaction under alkaline conditions, then adds aminoacetaldehyde dimethyl acetal to carry out chlorination reaction, then carries out cyclization reaction, and finally adds cyclohexanecarboxylic acid chloride to obtain praziquantel. The reaction route is as follows:

[0006]

[0007]

[0008] Route 2: Patent CN20120251997.9, 2-phenylethylamine and chloroacetaldehyde dimethyl acetal are synthesized under alkaline conditions to form formula IV, cyclohexanecarbonyl chloride and glycine are synthesized under alkaline conditions to form formula II, formula II and formula IV are reacted with methyl chloroformate and triethylamine to form amide, and then a strong acid is added to cyclize to obtain praziquantel. The reaction route is shown below:

[0009]

[0010] Route 3: Using isoquinoline as the starting material, praziquantel is prepared through Reissert reaction, catalytic hydrogenation, acylation, cyclization, hydrolysis and acylation. The reaction route is as follows:

[0011]

[0012] The above routes are currently used in industrial production at home and abroad. Although the direct method has fewer steps, the yield is low. Although the above methods are mature and the raw materials are readily available, the amount of "three wastes" is relatively large and the yield is low, which is not conducive to industrial production. In summary, the process for preparing praziquantel in the prior art has defects and shortcomings that are not suitable for large-scale industrialization. Summary of the invention

[0013] In view of the shortcomings of the prior art, the object of the present invention is to provide a one-pot synthesis method of praziquantel, which has the advantages that the method not only has a simple operation process, but also has a high yield and high efficiency, and is suitable for large-scale, industrial preparation of high-purity praziquantel to meet the requirements of industrial production of praziquantel.

[0014] To achieve the above object, the present invention provides the following technical solution: a one-pot synthesis method of praziquantel, comprising the following steps:

[0015] S1. In an organic solvent A, aminoacetaldehyde dimethyl acetal, alkaline reagent 1, process water, control the temperature at 0-10 ° C, and add cyclohexanecarbonyl chloride dropwise to react to obtain a compound of formula I;

[0016] S2. After the compound of formula I is obtained in step S1, the layers are washed directly with water, and then chloroacetic acid is directly added to the organic layer to react under alkaline reagent 2, process water is added, and the pH is adjusted to 3-5 with 10% hydrochloric acid to obtain a compound of formula II;

[0017] S3. After the compound of formula II is obtained in step S2, a condensing agent HATU and an acid binding agent, phenethylamine are added to obtain a compound of formula III;

[0018] S4. After the reaction of the compound of formula III obtained in step S3, the compound was washed once with 10% sodium carbonate solution, then washed once with water, a cyclization reagent was added to react, and the mixture was washed, layered, distilled, and crystallized with an organic solvent B to obtain praziquantel;

[0019] The reaction equation is as follows:

[0020]

[0021] Preferably, the organic solvent A in step S1 is any one of toluene or ethylene dichloride.

[0022] Preferably, the alkaline reagent 1 in step S1 is any one of triethylamine, sodium hydroxide and sodium carbonate.

[0023] Preferably, the alkaline reagent 2 in step S2 is any one of sodium methoxide and sodium ethoxide.

[0024] Preferably, the condensing agent HATU in step S3 is a commonly used peptide condensation agent, which is mainly used in the reaction of synthesizing peptide bonds between carboxyl groups and amino groups. Its system name is 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and its structural formula is as follows:

[0025]

[0026] Preferably, the acid binding agent in step S3 is selected from triethylamine or diethylamine.

[0027] Preferably, the organic solvent B in step S4 is any one of ethanol or acetone.

[0028] Preferably, the cyclization reagent in step S4 is at least one of concentrated sulfuric acid and methanesulfonic acid.

[0029] Preferably, the molar ratio of the cyclization reagent in step S4 to the compound of formula III is 2 to 10:1.

[0030] Preferably, the molar ratio of aminoacetaldehyde dimethyl acetal: cyclohexanecarbonyl chloride: chloroacetic acid: phenylethylamine: condensation agent HATU is 1:1.2-2:1-2:0.8-1:1-1.1.

[0031] In summary, the present invention has the following advantages:

[0032] The preparation method of the invention is simple to operate and combines the intermediate one-pot continuous reaction and mild reaction. Firstly, aminoacetaldehyde dimethyl acetal, alkaline reagent 1 and process water are added to an organic solvent A, and cyclohexanecarbonyl chloride is added dropwise at a temperature of 0-10 DEG C to react to obtain a compound of formula I, and the compound is directly washed with water and layered. Chloroacetic acid and alkaline reagent 2 are directly added to the organic layer, and the temperature is raised to 70-110 DEG C for insulation reaction for 4 hours, and the temperature is lowered and process water is added. The pH is adjusted to 3-5 with 10% hydrochloric acid, and the compound of formula II is layered. A condensation agent HATU and an acid binding agent and phenethylamine are added to obtain a compound of formula III. After the reaction, the compound is washed once with 10% sodium carbonate solution, and then washed once with water, and a cyclization reagent is added to react. After washing, layering, distillation and crystallization with an organic solvent B, praziquantel is obtained, thereby achieving the purpose of synthesizing praziquantel with low toxicity, low danger, low cost and high yield, meeting the requirements of large-scale industrial production and having significant application value. DETAILED DESCRIPTION

[0033] The technology of the present invention is further described below in conjunction with specific examples.

[0034] Example 1

[0035] A one-pot synthesis method of praziquantel comprises the following steps:

[0036] In a 500ml four-necked reaction bottle, add 150ml of dichloroethane, aminoacetaldehyde dimethyl acetal (10.5g, 0.1mol), sodium hydroxide (4g, 0.1mol), and 50ml of process water, and slowly add cyclohexanecarbonyl chloride (14.66g, 0.1mol) at 0-10℃. After the addition is complete, keep warm for 2 hours. After the reaction is completed, add 50ml of process water to the organic layer, wash and separate the layers, add chloroacetic acid (11.34g, 0.12mol) and sodium methoxide (16.2g, 0.3mol) to the organic layer, raise the temperature to 70-80℃ and keep warm for reaction for 4 hours. After the reaction is completed, cool to 20-30℃, add 50ml of process water, separate the layers, continue to add 50ml of process water to the organic layer, adjust with 10% hydrochloric acid PH = 3-5, layering to obtain an organic layer, adding phenylethylamine (12.1g, 0.1mol), HATU (38.0g, 0.1mol), diethylamine (22g, 0.3mol), heating to 40-50°C, keeping warm for 4 hours, after the reaction is completed, washing once with 10% sodium carbonate solution and 100ml of process water respectively, layering to obtain an organic layer, adding concentrated sulfuric acid (19.6g, 0.2mol), keeping warm for 4 hours, after the reaction is completed, adding 100ml of process water to wash twice, the organic layer is distilled under reduced pressure at less than 80°C, evaporated to dryness, adding 50ml of acetone, heating to dissolve, then cooling to 5-10°C, filtering and drying to obtain praziquantel dry product (21.9g, 0.0701mol) with a purity of more than 99.5%.

[0037] Example 2

[0038] A one-pot synthesis method of praziquantel comprises the following steps:

[0039] In a 500ml four-necked reaction bottle, add 150ml of toluene, aminoacetaldehyde dimethyl acetal (10.5g, 0.1mol), sodium hydroxide (4.4g, 0.11mol), and 50ml of process water, and slowly add cyclohexanecarbonyl chloride (16.13g, 0.11mol) at 0-10℃. After the addition is complete, keep warm for 2 hours. After the reaction is completed, wash the organic layer with 50ml of process water and separate the layers. Add chloroacetic acid (18.9g, 0.2mol) and sodium methoxide (127g, 0.5mol) to the organic layer, heat to 80-90℃ and keep warm for 4 hours. After the reaction is completed, cool to 20-30℃, add 50ml of process water, separate the layers, continue to add 50ml of process water to the organic layer, adjust with 10% hydrochloric acid PH = 3-5, layering to obtain an organic layer, adding phenylethylamine (12.1g, 0.1mol), HATU (41.8g, 0.11mol), diethylamine (24.1g, 0.33mol), heating to 40-50°C, keeping warm for 4 hours, after the reaction is completed, washing once with 10% sodium carbonate solution and 100ml of process water respectively, layering to obtain an organic layer, adding concentrated sulfuric acid (49g, 0.5mol), keeping warm for 4 hours, after the reaction is completed, adding 100ml of process water to wash twice, the organic layer is distilled under reduced pressure at less than 80°C, evaporated to dryness, adding 50ml of acetone, heating to dissolve, cooling to 5-10°C, filtering and drying, to obtain a dry product of praziquantel (22g, 0.0705mol), with a purity of more than 99.5%

[0040] Example 3

[0041] A one-pot synthesis method of praziquantel comprises the following steps:

[0042] In a 500ml four-necked reaction bottle, add 150ml of toluene, aminoacetaldehyde dimethyl acetal (10.5g, 0.1mol), sodium hydroxide (4.4g, 0.11mol), and 50ml of process water, and slowly add cyclohexanecarbonyl chloride (19.06g, 0.13mol) at 0-10℃. After the addition is complete, keep warm for 2 hours. After the reaction is completed, wash the organic layer with 50ml of process water and separate the layers. Add chloroacetic acid (18.9g, 0.2mol) and sodium ethoxide (34g, 0.5mol) to the organic layer, heat to 70-80℃ and keep warm for 4 hours. After the reaction is completed, cool to 20-30℃, add 50ml of process water, separate the layers, continue to add 50ml of process water to the organic layer, and adjust the pH with 10% hydrochloric acid =3-5, layering to obtain an organic layer, adding phenylethylamine (10.9 g, 0.09 mol), HATU (41.8 g, 0.11 mol), triethylamine (30.3 g, 0.3 mol), heating to 40-50 ° C, keeping warm for 4 hours, after the reaction is completed, washing once with 10% sodium carbonate solution and process water 100 ml each, layering to obtain an organic layer, adding methanesulfonic acid (48 g, 0.5 mol), keeping warm for 4 hours, after the reaction is completed, adding process water 100 ml to wash twice, the organic layer is distilled under reduced pressure below 80 ° C, evaporated to dryness, adding 50 ml of ethanol, heating to dissolve, cooling to 5-10 ° C, filtering and drying to obtain praziquantel dry product (22.2 g, 0.0711 mol) with a purity of more than 99.5%.

[0043] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the design concept of the present invention should be included in the protection scope of the present invention.

Claims

1. A one-pot synthesis method of praziquantel, characterized in that: The following steps are involved: S1. In an organic solvent A, aminoacetaldehyde dimethyl acetal, alkaline reagent 1, process water, control the temperature at 0-10 ° C, and add cyclohexanecarbonyl chloride dropwise to react to obtain a compound of formula I; S2. After the compound of formula I is obtained in step S1, the layers are washed directly with water, and then chloroacetic acid is directly added to the organic layer to react under alkaline reagent 2, process water is added, and the pH is adjusted to 3-5 with 10% hydrochloric acid to obtain a compound of formula II; S3. After the compound of formula II is obtained in step S2, a condensing agent HATU and an acid binding agent, phenethylamine are added to obtain a compound of formula III; S4. After the reaction of the compound of formula III obtained in step S3, the compound was washed once with 10% sodium carbonate solution, then washed once with water, a cyclization reagent was added to react, and the mixture was washed, layered, distilled, and crystallized with an organic solvent B to obtain praziquantel; The reaction equation is as follows:

2. A one-pot synthesis method of praziquantel according to claim 1, characterized in that: The organic solvent A in step S1 is any one of toluene or ethylene dichloride.

3. A one-pot synthesis method of praziquantel according to claim 1, characterized in that: The alkaline reagent 1 in step S1 is any one of triethylamine, sodium hydroxide and sodium carbonate.

4. A one-pot synthesis method of praziquantel according to claim 1, characterized in that: The alkaline reagent 2 in step S2 is any one of sodium methoxide and sodium ethoxide.

5. A one-pot synthesis method of praziquantel according to claim 1, characterized in that: The condensing agent HATU in step S3 is a commonly used peptide condensation reagent, which is mainly used in the reaction of synthesizing peptide bonds between carboxyl groups and amino groups. Its system name is 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and its structural formula is as follows:

6. A one-pot synthesis method of praziquantel according to claim 1, characterized in that: The acid binding agent in step S3 is selected from any one of triethylamine or diethylamine.

7. A one-pot synthesis method of praziquantel according to claim 1, characterized in that: The organic solvent B in step S4 is any one of ethanol or acetone.

8. A one-pot synthesis method of praziquantel according to claim 1, characterized in that: The cyclization reagent in step S4 is at least one of concentrated sulfuric acid and methanesulfonic acid.

9. A one-pot synthesis method of praziquantel according to claim 1, characterized in that: The molar ratio of the cyclization reagent in step S4 to the compound of formula III is 2 to 10:

1.

10. The one-pot synthesis method of praziquantel according to claim 1, characterized in that: The molar ratio of aminoacetaldehyde dimethyl acetal: cyclohexanecarbonyl chloride: chloroacetic acid: phenylethylamine: condensation agent HATU is 1:1.2-2:1-2:0.8-1:1-1.1.

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