Harmless recovery treatment method for ketoconazole synthesis by-products

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a harmless recycling treatment method for ketoconazole synthesis by-products. The method comprises the following steps: 1, synthesizing ketoconazole by taking cis-bromo-ester, imidazole, potassium carbonate, potassium hydroxide, dichloromethane, ethyl acetate, paratoluensulfonyl chloride, tri-n-propylamine, sodium hydroxide and a ketoconazole side chain as raw materials, and generating wastewater; 2, adding the wastewater in the step 1 into a pH adjusting kettle, adding a proper amount of a pH regulator into the pH adjusting kettle, pumping into a decolorizing kettle, stirring for 1 hour for decolorizing, and pumping into a filter press; step 3, putting the liquid generated in the step 2 into an azeotropic distillation kettle, adding a proper amount of methylbenzene, and heating, refluxing and separating water completely under normal pressure until the water content is less than 0.1%; the byproduct produced in the ketoconazole synthesis process is subjected to innocent treatment, and the production raw materials are recycled, so that the method is energy-saving and environment-friendly, and no waste liquid is discharged.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis, and particularly to a method for harmless recovery and treatment of by-products in the synthesis of ketoconazole. Background Art

[0002] Ketoconazole is a broad-spectrum imidazole antifungal drug, which is commonly used clinically to treat superficial and deep fungal diseases, including tinea corporis and onychomycosis, gastrointestinal yeast infections, vaginal candidiasis that is ineffective with topical medications, etc., and has broad market prospects. The ketoconazole product produced from cis-bromoester, imidazole, potassium carbonate, potassium hydroxide, dichloromethane, ethyl acetate, p-toluenesulfonyl chloride, tri-n-propylamine, sodium hydroxide and the ketoconazole side chain as raw materials is trusted by domestic and foreign customers due to its stable quality and high purity. However, due to the large amount of by-products sodium p-toluenesulfonate and sodium hydroxide waste lye produced by the condensation of ketoconazole in this process, and the need for complex advanced oxidation methods for treatment, it brings great pressure to environmental protection sewage treatment. Summary of the Invention

[0003] The purpose of the present invention is to provide a method for harmless recovery and treatment of by-products in the synthesis of ketoconazole, so as to solve the problems raised in the above background art.

[0004] To achieve the above purpose, the present invention provides the following technical solution: A method for harmless recovery and treatment of by-products in the synthesis of ketoconazole, including the following steps; Step 1: Using cis-bromoester, imidazole, potassium carbonate, potassium hydroxide, dichloromethane, ethyl acetate, p-toluenesulfonyl chloride, tri-n-propylamine, sodium hydroxide and the ketoconazole side chain as raw materials, synthesize ketoconazole and generate wastewater; Step 2: Add the wastewater in Step 1 into a pH adjustment kettle, add an appropriate amount of pH regulator in the pH adjustment kettle, then pump it into a decolorization kettle, stir for 1 hour for decolorization, and then pump it into a filter press; Step 3: Put the liquid produced in Step 2 into an azeotropic distillation kettle, add an appropriate amount of toluene, heat and reflux to separate water under normal pressure until complete, until the water content is less than 0.1%; Step 4: Cool the product in Step 3 to 40 - 50 °C, add an appropriate amount of thionyl chloride, and keep it warm and stir for 1 - 2 hours; Step 5: Heat the product in Step 4 to reflux under normal pressure, slowly dropwise add a little DMF, and keep it warm and reflux for reaction until complete, so that the residual sodium p-toluenesulfonate is less than 0.1%; Step 6: After cooling the product in Step 5 to 40 - 50 °C, wash it with water 1 - 2 times, and wait for stratification after standing; Step 7: Cool and crystallize the organic liquid produced in Step 6, and after centrifugation, washing and vacuum drying, obtain white crystalline solid p-toluenesulfonyl chloride; Step 8: Sample and analyze the product obtained in Step 7. The content of p-toluenesulfonyl chloride is 99.5%, reaching the first-class product standard and meeting the process quality requirements.

[0005] Preferably, for the wastewater produced by ketoconazole condensation, the content of sodium p-toluenesulfonate is 10.5% and the content of free base is 6.8%.

[0006] Preferably, adjust the pH value in the pH adjustment kettle to 6 - 7.

[0007] Preferably, add activated carbon to the decolorization kettle and heat it up to 80 - 90 °C, and then remove the activated carbon with a filter press.

[0008] Compared with the prior art, the beneficial effects of the present invention are as follows: The present invention uses cis-bromoester, imidazole, potassium carbonate, potassium hydroxide, dichloromethane, ethyl acetate, p-toluenesulfonyl chloride, tri-n-propylamine, sodium hydroxide and the side chain of ketoconazole as raw materials. During the synthesis of ketoconazole, the mixture of sodium p-toluenesulfonate and sodium hydroxide, which are by-products of ketoconazole condensation, is reasonably utilized to carry out harmless treatment with p-toluenesulfonic acid and thionyl chloride to recover qualified p-toluenesulfonyl chloride, sodium chloride and water. The recovered p-toluenesulfonyl chloride is then used in the synthesis of ketoconazole active ester, solving the problem of difficult environmental protection treatment of waste liquid in production enterprises. It converts the mixed waste alkali liquid of sodium p-toluenesulfonate and sodium hydroxide, which are by-products of ketoconazole production, into pure p-toluenesulfonyl chloride, sodium chloride and water. The p-toluenesulfonyl chloride can be recycled as a raw material for the production of ketoconazole active ester, saving energy and protecting the environment without waste liquid discharge. Description of the Drawings

[0009] Figure 1 Source of ketoconazole by-products.

[0010] Figure 2 Harmless treatment process of ketoconazole by-products. Detailed Embodiments

[0011] In order to deepen the understanding and recognition of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described and introduced in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments, and no formal restrictions are imposed on this embodiment. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the scope of protection of the present invention. Embodiment

[0012] Please refer to Figure 1-2 , the present invention provides a technical solution: A method for harmless recovery and treatment of ketoconazole by-products, including the following steps; Step 1: Using cis-bromoester, imidazole, potassium carbonate, potassium hydroxide, dichloromethane, ethyl acetate, p-toluenesulfonyl chloride, tri-n-propylamine, sodium hydroxide and ketoconazole side chain as raw materials, synthesize ketoconazole and generate wastewater; Step 2: Add the wastewater from Step 1 into a pH adjustment kettle, add an appropriate amount of pH regulator into the pH adjustment kettle, then pump it into a decolorization kettle, stir for 1 hour for decolorization, and then pump it into a filter press; Step 3: Put the liquid produced in Step 2 into an azeotropic distillation kettle, add an appropriate amount of toluene, heat under reflux at atmospheric pressure to separate water completely until the water content is less than 0.1%; Step 4: Cool the product from Step 3 to 40 °C, add an appropriate amount of thionyl chloride, and keep stirring for 1 - 2 hours; Step 5: Heat the product from Step 4 to reflux at atmospheric pressure, slowly dropwise add a little DMF, and keep refluxing for reaction until complete after the addition, so that the residual p-toluenesulfonate is less than 0.1%; Step 6: After cooling the product from Step 5 to 40 °C, wash it with water 1 - 2 times, let it stand and wait for stratification; Step 7: Cool and crystallize the organic liquid produced in Step 6, and after centrifugation, washing and vacuum drying, obtain white crystalline solid p-toluenesulfonyl chloride; Step 8: Take a sample and analyze the product obtained in Step 7. The content of p-toluenesulfonyl chloride is 99.5%, reaching the first-class product standard and meeting the process quality requirements.

[0013] The wastewater produced by the condensation of ketoconazole contains 10.5% of p-toluenesulfonate and 6.8% of free base.

[0014] Adjust the pH value in the pH adjustment kettle to 6.

[0015] Add activated carbon into the decolorization kettle and heat it up to 80 °C, and the filter press removes the activated carbon. Example

[0016] Please refer to Figure 1-2 , the present invention provides a technical solution: a method for harmless recovery and treatment of by-products in the synthesis of ketoconazole, including the following steps; Step 1: Using cis-bromoester, imidazole, potassium carbonate, potassium hydroxide, dichloromethane, ethyl acetate, p-toluenesulfonyl chloride, tri-n-propylamine, sodium hydroxide and ketoconazole side chain as raw materials, synthesize ketoconazole and generate wastewater; Step 2: Add the wastewater from Step 1 into a pH adjustment kettle, add an appropriate amount of pH regulator into the pH adjustment kettle, then pump it into a decolorization kettle, stir for 1 hour for decolorization, and then pump it into a filter press; Step 3: Put the liquid produced in Step 2 into an azeotropic distillation kettle, add an appropriate amount of toluene, heat under reflux at atmospheric pressure to separate water completely until the water content is less than 0.1%; Step 4: Cool the product from Step 3 to 50°C, add an appropriate amount of thionyl chloride, and keep stirring for 1 - 2 hours at a constant temperature; Step 5: Heat the product from Step 4 to reflux under normal pressure, slowly add a little DMF dropwise, and keep refluxing until the reaction is complete after the addition, so that the residual sodium toluenesulfonate is less than 0.1%; Step 6: After cooling the product from Step 5 to 50°C, wash it with water 1 - 2 times, and wait for layering after standing; Step 7: Cool and crystallize the organic liquid produced in Step 6, and then carry out centrifugation, washing, and vacuum drying to obtain white crystalline solid p-toluenesulfonyl chloride; Step 8: Take a sample of the product obtained in Step 7 for analysis. The content of p-toluenesulfonyl chloride is 99.5%, reaching the excellent product standard and meeting the process quality requirements.

[0017] The wastewater produced by ketoconazole condensation contains 10.5% of sodium toluenesulfonate and 6.8% of free base.

[0018] Adjust the pH value in the pH adjustment kettle to 7.

[0019] Add activated carbon to the decolorization kettle and heat it up to 90°C, and then remove the activated carbon with a filter press.

[0020] Although the embodiments of the present invention have been shown and described, it should be emphasized that the above description is only an introduction and description of the usage mode of the embodiments of the present invention, and does not impose any form of limitation on the present invention. For those of ordinary skill in the art, it can be understood that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principle and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A harmless recycling treatment method for by-products of synthetic ketoconazole, characterized in that: Including the following steps; Using cis-bromoester, imidazole, potassium carbonate, potassium hydroxide, dichloromethane, ethyl acetate, p-toluenesulfonyl chloride, tri-n-propylamine, sodium hydroxide and ketoconazole side chain as raw materials to synthesize ketoconazole and generate wastewater; Adding the wastewater in Step 1 into a pH adjustment kettle, adding an appropriate amount of pH adjuster in the pH adjustment kettle, then pumping it into a decolorization kettle, stirring for 1 hour for decolorization, and then pumping it into a filter press; Putting the liquid produced in Step 2 into an azeotropic distillation kettle, adding an appropriate amount of toluene, heating under reflux at atmospheric pressure to separate water completely until the water content is less than 0.1%; Cooling the product in Step 3 to 40 - 50 °C, adding an appropriate amount of thionyl chloride, and keeping warm and stirring for 1 - 2 hours; Heating the product in Step 4 to reflux at atmospheric pressure, slowly dropping a little DMF, and keeping warm and refluxing until the reaction is complete, so that the residual amount of sodium p-toluenesulfonate is less than 0.1%; After cooling the product in Step 5 to 40 - 50 °C, washing it with water 1 - 2 times, and standing for layering; Cooling and crystallizing the organic liquid produced in Step 6, and then centrifuging, washing and vacuum drying to obtain white crystalline solid p-toluenesulfonyl chloride; Sampling and analyzing the product obtained in Step 7, the content of p-toluenesulfonyl chloride is 99.5%, reaching the first-class product standard and meeting the process quality requirements.

2. The harmless recycling treatment method for by-products of ketoconazole synthesis according to claim 1, characterized in that: The wastewater produced by the condensation of ketoconazole contains 10.5% of sodium p-toluenesulfonate and 6.8% of free base.

3. A method for harmless recycling of by-products of ketoconazole synthesis according to claim 1, characterized in that: Adjusting the pH value in the pH adjustment kettle to 6 - 7.

4. A method for harmless recovery and treatment of by-products of ketoconazole synthesis according to claim 1, characterized in that: Adding activated carbon into the decolorization kettle and heating it to 80 - 90 °C, and the filter press removes the activated carbon.

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