A preparation method of dehydrogriseofulvin

Abstract

The invention discloses a preparation method of dehydrogenation griseofulvin, comprising the steps of: 1) adding an alcohol mixture into an autoclave, then sequentially adding griseofulvin, an oxidant, a platinum-carbon catalyst, a reaction temperature of 160 DEG C, and a reaction time of 68-72h; 2) after the reaction is completed, cooling to 80-90 DEG C, filtering while hot; the mother liquor is distilled under reduced pressure at 60-70 DEG C, a vacuum degree of 0.09Mpa, and a mixed alcohol liquid is recovered. After being steamed to solid precipitation, it is transferred to pure water, stirred for cooling, and dried after liquid filtering to obtain a crude product; 3) 25g of the crude product is taken, 120g of a mixed solvent is added, the temperature is slowly increased to dissolve, filtered while hot, and petroleum ether is added dropwise in the filtrate until a solid precipitate occurs. Crystallization is placed at low temperature for 3 hours, and solid is filtered out by suction to obtain dehydrogenation griseofulvin. The inventive method is short in time consumption, simple in process, and hydrogen is removed by the principle of catalytic oxidation. The dehydrogenation griseofulvin prepared has high purity and high reaction yield.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceuticals, and particularly relates to a method for preparing dehydrogriseofulvin. Background Art

[0002] Griseofulvin is a white to light cream crystalline powder with the chemical formula C 17 H 17 ClO6. Griseofulvin is a non-polyene antifungal antibiotic that strongly inhibits fungal cell mitosis and interferes with fungal DNA synthesis. It also binds to tubulin, preventing fungal cell division. First used in clinical practice in 1958, it has been widely used to treat fungal infections of the skin and stratum corneum, demonstrating strong inhibitory activity against Trichophyton rubrum, Trichophyton tonsurans, and Trichophyton liuocomodis. Griseofulvin is not only a widely used antibiotic for the clinical treatment of fungal infections of the skin and stratum corneum, but is also used in agriculture to control fungal diseases. It is particularly effective against a type of apple candidiasis that can cause infection during pollination.

[0003] Griseofulvin is produced by fermentation of strains such as Penicillium patulin, and the fermentation process inevitably produces process impurities. The main known impurities produced during griseofulvin production include griseofulvin acid, dechlorogriseofulvin, and dehydrogriseofulvin. Control of known and unknown impurities is particularly stringent during finished product testing, particularly with the implementation of European Pharmacopoeia EP10.0 and above. Impurity limits have been further lowered, with the limit for the impurity dehydrogriseofulvin being ≤ 0.75. This has led to an increase in the amount of impurity reference substances required during testing.

[0004] However, few reports exist on the preparation of this impurity, dehydrogrizofulvin, both domestically and internationally. Most manufacturers must purchase expensive impurity standards, currently priced at approximately RMB 300,000 per gram, or continuously accumulate the impurity during the production process, requiring isolation and purification only when the impurity concentration reaches a high level. Therefore, a method for preparing dehydrogrizofulvin with a shorter production time, simpler process, and higher yield is urgently needed. Summary of the Invention

[0005] The purpose of the present invention is to overcome the deficiencies in the prior art and provide a method for preparing dehydrogriseofulvin with short time consumption, simple process and high yield.

[0006] The present invention is achieved through the following technical solution: a method for preparing dehydrogriseofulvin, comprising the following steps:

[0007] 1) Add 100-160 parts of alcohol mixture to a high-pressure reactor, then add 6 parts of griseofulvin, 1.2-3 parts of oxidant, and 0.3 parts of platinum-carbon catalyst in sequence. The reaction temperature is 160°C, the pressure is 0.8-0.9 MPa, and the reaction time is 68-72 hours.

[0008] 2) After the reaction is completed, the temperature is lowered to 90°C and filtered while hot; the mother liquor is distilled under reduced pressure at 60-70°C and a vacuum degree of -0.09 MPa to recover the mixed alcohol liquid, evaporated until solids precipitate, and then transferred to pure water, stirred and cooled to 5°C, the liquid is filtered and dried to obtain a crude product;

[0009] 3) Take 5 parts of the crude product, add 24 parts of a mixed solvent, slowly raise the temperature to 60°C, dissolve, filter while hot, add petroleum ether dropwise to the filtrate until a solid precipitate appears, and place at low temperature for 3 hours to crystallize. Filter the solid and dry it to obtain dehydrogriseofulvin.

[0010] The alcohol mixture is a mixture of tert-butyl alcohol and isopropyl alcohol, and the weight ratio of the two is 1:1.4.

[0011] The oxidant is a mixed powder of lead tetraacetate and selenium oxide, and the weight ratio of lead tetraacetate to selenium oxide is 5:1.

[0012] The mixed solvent is a mixture of ethyl acetate and ethanol, and the weight ratio of the two is 4:1.

[0013] The beneficial effects of the present invention are: the present invention is time-saving and simple in process, hydrogen is removed by utilizing the principle of catalytic oxidation, the prepared dehydrogriseofulvin has high purity and high reaction yield, thus filling a technical gap and greatly reducing the detection cost of enterprises. DETAILED DESCRIPTION

[0014] The present invention is described in detail below.

[0015] Example 1

[0016] 620 g of the alcohol mixture, 30 g of griseofulvin, 12 g of an oxidant, and 1.5 g of a platinum-carbon catalyst (product name: platinum-carbon, produced by Shaanxi Ruike New Materials Co., Ltd.) were sequentially added into a closed autoclave for reaction at 160°C, a pressure of 0.8-0.9 MPa, and a reaction time of 72 h.

[0017] The alcohol mixture is a mixture of 258.33 g of tert-butyl alcohol and 361.67 g of isopropyl alcohol; the oxidant is a mixed powder of 10 g of lead tetraacetate and 2 g of selenium oxide;

[0018] After the reaction is completed, the temperature is lowered to 80°C and filtered while hot; the mother liquor is concentrated under reduced pressure at 70°C and a vacuum degree of -0.09 MPa, the alcohol liquid is evaporated, and the precipitated solid is immediately transferred to pure water, stirred and cooled to 5°C for crystallization, and the liquid is filtered to obtain a crude product, which is dried for later use;

[0019] Take 25 g of the crude product, add 120 g of a mixed solvent (a mixture of 96 g of ethyl acetate and 24 g of ethanol), slowly heat to 60 ° C, dissolve, filter while hot, add 26 ml of petroleum ether to the filtrate, place in the refrigerator for 3 hours, filter out the solid and dry it to obtain 24.2 g of the product with a yield of 80.7%.

[0020] The sample was tested by high performance liquid chromatography, and the peak time was the same as that of the reference substance. The content calculated by external standard method was 98%.

[0021] Example 2

[0022] 800 g of the alcohol mixture, 30 g of griseofulvin, 15 g of an oxidant, and 1.5 g of a platinum-carbon catalyst (product name: platinum-carbon, produced by Shaanxi Ruike New Materials Co., Ltd.) were sequentially added into a closed autoclave for reaction at 160°C, a pressure of 0.08 MPa, and a reaction time of 72 h.

[0023] The alcohol mixture is a mixture of 333.3 g of tert-butyl alcohol and 466.7 g of isopropyl alcohol; the oxidant is a mixed powder of 12.5 g of lead tetraacetate and 2.5 g of selenium oxide;

[0024] After the reaction is completed, the temperature is lowered to 80-90°C and filtered while hot; the mother liquor is concentrated under reduced pressure at 70°C and a vacuum degree of -0.09Mpa, the alcohol liquid is evaporated, and the precipitated solid is immediately transferred to pure water, stirred and cooled by 5°C for crystallization, and the crude product is obtained by filtration and dried for later use;

[0025] Take 25g of the crude product, add 120g of a mixed solvent (a mixture of 96g of ethyl acetate and 24g of ethanol), slowly heat to 60°C to dissolve, filter while hot, add 26ml of petroleum ether to the filtrate, place in the refrigerator for 3 hours, filter out the solid and dry it to obtain 24.6g of the product with a yield of 82%.

[0026] The sample was tested by high performance liquid chromatography, and the peak time was the same as that of the reference substance. The content calculated by external standard method was 98.5%.

[0027] Example 3

[0028] 650 g of the alcohol mixture, 30 g of griseofulvin, 11 g of an oxidant, and 1.5 g of a catalyst (platinum carbon, manufactured by Shaanxi Ruike New Materials Co., Ltd.) were sequentially added into a closed autoclave for reaction at 160°C, a pressure of 0.08 MPa, and a reaction time of 70 h.

[0029] The alcohol mixture is a mixture of 270.8 g of tert-butyl alcohol and 379.2 g of isopropyl alcohol; the oxidant is a mixed powder of 9.2 g of lead tetraacetate and 1.8 g of selenium oxide;

[0030] After the reaction is completed, the temperature is lowered to 80-90°C and filtered while hot; the mother liquor is concentrated under reduced pressure at 70°C and a vacuum degree of -0.09Mpa, the alcohol liquid is evaporated, and the precipitated solid is immediately transferred to pure water, stirred and cooled by 5°C for crystallization, and the crude product is obtained by filtration and dried for later use;

[0031] Take 25g of the crude product, add 120g of a mixed solvent (a mixture of 96g of ethyl acetate and 24g of ethanol), slowly heat to 60°C to dissolve, filter while hot, add 26ml of petroleum ether to the filtrate, place in the refrigerator for 3 hours, filter out the solid and dry it to obtain 24g of the product with a yield of 80%.

[0032] The sample was tested by high performance liquid chromatography, and the peak time was the same as that of the reference substance. The content calculated by external standard method was 98.1%.

[0033] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing dehydrogriseofulvin, characterized in that The steps include: 1) Add 100-160 parts of an alcohol mixture to an autoclave, then sequentially add 6 parts of griseofulvin, 1.2-3 parts of an oxidant, and 0.3 parts of a platinum-carbon catalyst. The reaction temperature is 160°C, the pressure is 0.8-0.9 MPa, and the reaction time is 68-72 hours. The oxidant is a mixed powder of lead tetraacetate and selenium oxide, with a weight ratio of lead tetraacetate to selenium oxide of 5:

1. 2) After the reaction is completed, the temperature is lowered to 90°C and filtered while hot; the mother liquor is distilled under reduced pressure at 60-70°C and a vacuum degree of -0.09 MPa to recover the mixed alcohol liquid, evaporated until solids precipitate, and then transferred to pure water, stirred and cooled to 5°C, the liquid is filtered and dried to obtain a crude product; 3) Take 5 parts of the crude product, add 24 parts of a mixed solvent, slowly raise the temperature to 60°C, dissolve, filter while hot, add petroleum ether dropwise to the filtrate until a solid precipitate appears, and place at low temperature for 3 hours to crystallize. Filter the solid and dry it to obtain dehydrogriseofulvin.

2. The method for preparing dehydrogriseofulvin according to claim 1, wherein: The alcohol mixture is a mixture of tert-butyl alcohol and isopropyl alcohol, and the weight ratio of the two is 1:1.

4.

3. The method for preparing dehydrogriseofulvin according to claim 1, wherein: The mixed solvent is a mixture of ethyl acetate and ethanol, and the weight ratio of the two is 4:1.