CN117624099A - Preparation method of dehydrogriseofulvin - Google Patents
Preparation method of dehydrogriseofulvin Download PDFInfo
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- CN117624099A CN117624099A CN202311764030.5A CN202311764030A CN117624099A CN 117624099 A CN117624099 A CN 117624099A CN 202311764030 A CN202311764030 A CN 202311764030A CN 117624099 A CN117624099 A CN 117624099A
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- dehydrogriseofulvin
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- ISLYVROQSJYFAZ-KRWDZBQOSA-N Dehydrogriseofulvin Chemical compound COC1=CC(=O)C=C(C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 ISLYVROQSJYFAZ-KRWDZBQOSA-N 0.000 title claims abstract description 18
- ISLYVROQSJYFAZ-UHFFFAOYSA-N dl-dehydrogriseofulvin Natural products COC1=CC(=O)C=C(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 ISLYVROQSJYFAZ-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 238000001914 filtration Methods 0.000 claims abstract description 19
- 239000011259 mixed solution Substances 0.000 claims abstract description 19
- 239000007787 solid Substances 0.000 claims abstract description 15
- 239000000243 solution Substances 0.000 claims abstract description 15
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 claims abstract description 14
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 claims abstract description 13
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 claims abstract description 13
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229960002867 griseofulvin Drugs 0.000 claims abstract description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000012043 crude product Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000012046 mixed solvent Substances 0.000 claims abstract description 11
- 239000007800 oxidant agent Substances 0.000 claims abstract description 11
- 230000001590 oxidative effect Effects 0.000 claims abstract description 11
- 238000001816 cooling Methods 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 9
- 230000035484 reaction time Effects 0.000 claims abstract description 9
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 239000000706 filtrate Substances 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- 239000010413 mother solution Substances 0.000 claims abstract description 6
- 239000003208 petroleum Substances 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000002425 crystallisation Methods 0.000 claims abstract description 3
- 230000008025 crystallization Effects 0.000 claims abstract description 3
- 238000000643 oven drying Methods 0.000 claims abstract description 3
- 238000001556 precipitation Methods 0.000 claims abstract description 3
- 238000010025 steaming Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 7
- JEHCHYAKAXDFKV-UHFFFAOYSA-J lead tetraacetate Chemical compound CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O JEHCHYAKAXDFKV-UHFFFAOYSA-J 0.000 claims description 7
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 claims description 7
- 239000011812 mixed powder Substances 0.000 claims description 5
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 abstract description 6
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 239000012535 impurity Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 7
- 239000013558 reference substance Substances 0.000 description 4
- 208000031888 Mycoses Diseases 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000010812 external standard method Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 206010017533 Fungal infection Diseases 0.000 description 2
- ZRWPUFFVAOMMNM-UHFFFAOYSA-N Patulin Chemical compound OC1OCC=C2OC(=O)C=C12 ZRWPUFFVAOMMNM-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 108020000949 Fungal DNA Proteins 0.000 description 1
- 241000223238 Trichophyton Species 0.000 description 1
- 241000223229 Trichophyton rubrum Species 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000004291 polyenes Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of dehydrogriseofulvin, which comprises the following steps: 1) Adding an alcohol mixed solution into a high-pressure reaction kettle, and then sequentially adding griseofulvin, an oxidant and a platinum-carbon catalyst, wherein the reaction temperature is 160 ℃, and the reaction time is 68-72 hours; 2) Cooling to 80-90 ℃ after the reaction is finished, and filtering while the mixture is hot; distilling the mother solution at 60-70deg.C under vacuum degree-0.09 Mpa to recover mixed alcohol solution, steaming until solid is separated out, transferring into pure water, stirring, cooling, suction filtering, and oven drying to obtain crude product; 3) And (3) taking 25g of crude product, adding 120g of mixed solvent, slowly heating to dissolve, filtering while the solution is hot, reversely dripping petroleum ether into the filtrate until solid precipitation appears, standing at a low temperature for crystallization for 3 hours, filtering out the solid, and drying to obtain the griseofulvin. The method has the advantages of short time consumption, simple process, high purity of the prepared dehydrogriseofulvin and high reaction yield, and hydrogen is removed by utilizing the principle of catalytic oxidation.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a preparation method of dehydrogriseofulvin.
Background
Griseofulvin is a white to pale cream crystalline powder with chemical formula C 17 H 17 ClO 6 . Griseofulvin belongs to the class of non-polyene antifungal antibiotics, it can strongly inhibit the mitosis of fungal cells, interfere with fungal DNA synthesis, and it binds to tubulin, preventing the division of fungal cells. The composition is used for medical clinic in 1958, has been widely used for treating fungal infection of skin and horny layer, and has strong inhibition effect on trichophyton rubrum, trichophyton atroviride and the like. Griseofulvin is not only an antibiotic commonly used in clinical treatment of skin and cuticle fungal infections, but also in agricultureIn industry, it is also used for fungal disease control, an apple candidiasis can cause infection when pollinated, and it has a particular therapeutic effect on this.
Griseofulvin is obtained by fermenting strain such as patulin, and the like, and process impurities are inevitably produced in the fermentation process. The main known impurities produced in the griseofulvin production process are griseofulvin acid, dechlorinated griseofulvin and dehydrogriseofulvin. In the finished product detection, the control of known impurities and unknown impurities is particularly strict, especially after the application of European pharmacopoeia EP10.0 and above, the impurity limit is further reduced, the limit of impurity dehydrogriseofulvin is less than or equal to 0.75, and the dosage of an impurity reference substance required in the detection process is increased.
However, there are few reports on the preparation method of the impurity dehydrogriseofulvin at home and abroad at present, most manufacturers purchase high impurity standard substances, the market price of the impurity standard substances is about 30 ten thousand per gram at present, or the impurity is continuously enriched in the production process, and the impurity is separated and purified when the content is high. Therefore, there is a need in the art for a method for preparing dehydrogriseofulvin that is time-consuming, simple in process, and high in yield.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a preparation method of dehydrogriseofulvin, which is short in time consumption, simple in process and high in yield.
The invention is realized by the following technical scheme: a preparation method of dehydrogriseofulvin, which comprises the following steps:
1) Adding 100-160 parts of alcohol mixed solution into a high-pressure reaction kettle, sequentially adding 6 parts of griseofulvin and 1.2-3 parts of oxidant, and 0.3 part of platinum-carbon catalyst, wherein the reaction temperature is 160 ℃, the pressure is 0.8-0.9MPa, and the reaction time is 68-72h;
2) Cooling to 90 ℃ after the reaction is finished, and carrying out suction filtration while the reaction product is hot; distilling the mother solution at 60-70deg.C under vacuum degree-0.09 Mpa to recover mixed alcohol solution, steaming until solid is separated out, transferring into pure water, stirring, cooling to 5deg.C, vacuum filtering, and oven drying to obtain crude product;
3) Taking 5 parts of crude product, adding 24 parts of mixed solvent, slowly heating to 60 ℃, dissolving, filtering while the solution is hot, reversely dripping petroleum ether into the filtrate until solid precipitation appears, standing at a low temperature for crystallization for 3 hours, filtering out the solid by suction, and drying to obtain the dehydrogriseofulvin.
The alcohol mixed solution is a mixed solution of tertiary butanol and isopropanol, and the weight ratio of the tertiary butanol to the isopropanol is 1:1.4.
The oxidant is mixed powder of lead tetraacetate and selenium oxide, and the weight ratio of the lead tetraacetate to the selenium oxide is 5:1.
the mixed solvent is a mixed solution of ethyl acetate and ethanol, and the weight ratio of the ethyl acetate to the ethanol is 4:1.
The beneficial effects of the invention are as follows: the method has the advantages of short time consumption, simple process, high purity of the prepared dehydrogriseofulvin by utilizing the principle of catalytic oxidation, high reaction yield, filling in the technical blank and greatly reducing the detection cost of enterprises.
Detailed Description
The present invention is described in detail below.
Example 1
620g of alcohol mixed solution, 30g of griseofulvin, 12g of oxidant and 1.5g of platinum-carbon catalyst (product name platinum-carbon, produced by Shaanxi Ruida New Material Co., ltd.) are sequentially added into a high-pressure reaction kettle for airtight reaction, wherein the reaction time is 160 ℃, the pressure is 0.8-0.9MPa, and the reaction time is 72 hours;
wherein the alcohol mixed solution is 258.33g of tertiary butanol and 361.67g of isopropanol; the oxidant is mixed powder of 10g of lead tetraacetate and 2g of selenium oxide;
cooling to 80 ℃ after the reaction is finished, and carrying out suction filtration while the reaction product is hot; concentrating the mother solution at 70deg.C under vacuum degree of-0.09 Mpa, evaporating to obtain alcohol solution, separating out solid, immediately transferring into pure water, stirring, cooling to 5deg.C, crystallizing, vacuum filtering to obtain crude product, and drying;
taking 25g of crude product, adding 120g of mixed solvent (the mixed solvent is a mixed solution of 96g of ethyl acetate and 24g of ethanol), slowly heating to 60 ℃, dissolving, filtering while the solution is hot, reversely dripping 26ml of petroleum ether into the filtrate, standing for 3 hours in a refrigerator, filtering out solid by suction, and drying to obtain 24.2g of product with the yield of 80.7%.
The high performance liquid chromatograph detects the sample, the peak time is not different from the reference substance, and the calculated content is 98% by an external standard method.
Example 2
800g of alcohol mixed solution, 30g of griseofulvin, 15g of oxidant and 1.5g of platinum-carbon catalyst (product name platinum-carbon, produced by Shaanxi Ruida New Material Co., ltd.) are sequentially added into a high-pressure reaction kettle for airtight reaction, wherein the reaction time is 160 ℃, the pressure is 0.08Mpa, and the reaction time is 72 hours;
wherein the alcohol mixed solution is 333.3g of tertiary butanol and 466.7g of isopropanol mixed solution; the oxidant is mixed powder of 12.5g of lead tetraacetate and 2.5g of selenium oxide;
after the reaction is finished, the temperature is reduced to 80-90 ℃ and the mixture is filtered while the mixture is hot; concentrating the mother solution at 70deg.C under vacuum degree of-0.09 Mpa, evaporating to obtain alcohol solution, separating out solid, immediately transferring into pure water, stirring, cooling to 5deg.C, crystallizing, vacuum filtering to obtain crude product, and drying;
and (3) taking 25g of crude product, adding 120g of mixed solvent (the mixed solvent is a mixed solution of 96g of ethyl acetate and 24g of ethanol), slowly heating to 60 ℃ for dissolution, filtering while the solution is hot, reversely dripping 26ml of petroleum ether into the filtrate, standing for 3 hours in a refrigerator, filtering out solid by suction, and drying to obtain 24.6g of product with the yield of 82%.
The high performance liquid chromatograph detects the sample, the peak time is not different from the reference substance, and the calculated content is 98.5% by an external standard method.
Example 3
650g of alcohol mixed solution, 30g of griseofulvin, 11g of oxidant and 1.5g of catalyst (product name platinum carbon, produced by Shaanxi Ruicaceae new material Co., ltd.) are sequentially added into a high-pressure reaction kettle for airtight reaction, wherein the reaction time is 160 ℃, the pressure is 0.08Mpa, and the reaction time is 70h;
wherein the alcohol mixed solution is 270.8g of tertiary butanol and 379.2g of isopropanol; the oxidant is mixed powder of 9.2g of lead tetraacetate and 1.8g of selenium oxide;
after the reaction is finished, the temperature is reduced to 80-90 ℃ and the mixture is filtered while the mixture is hot; concentrating the mother solution at 70deg.C under vacuum degree of-0.09 Mpa, evaporating to obtain alcohol solution, separating out solid, immediately transferring into pure water, stirring, cooling to 5deg.C, crystallizing, vacuum filtering to obtain crude product, and drying;
taking 25g of crude product, adding 120g of mixed solvent (the mixed solvent is a mixed solution of 96g of ethyl acetate and 24g of ethanol), slowly heating to 60 ℃ for dissolution, filtering while the solution is hot, reversely dripping 26ml of petroleum ether into the filtrate, standing for 3 hours in a refrigerator, filtering out solid, and drying to obtain 24g of product with the yield of 80%.
The high performance liquid chromatograph detects the sample, the peak time is not different from the reference substance, and the calculated content is 98.1 percent by an external standard method.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.
Claims (4)
1. The preparation method of the dehydrogriseofulvin is characterized by comprising the following steps of:
1) Adding 100-160 parts of alcohol mixed solution into a high-pressure reaction kettle, sequentially adding 6 parts of griseofulvin and 1.2-3 parts of oxidant, and 0.3 part of platinum-carbon catalyst, wherein the reaction temperature is 160 ℃, the pressure is 0.8-0.9MPa, and the reaction time is 68-72h;
2) Cooling to 90 ℃ after the reaction is finished, and carrying out suction filtration while the reaction product is hot; distilling the mother solution at 60-70deg.C under vacuum degree-0.09 Mpa to recover mixed alcohol solution, steaming until solid is separated out, transferring into pure water, stirring, cooling to 5deg.C, vacuum filtering, and oven drying to obtain crude product;
3) Taking 5 parts of crude product, adding 24 parts of mixed solvent, slowly heating to 60 ℃, dissolving, filtering while the solution is hot, reversely dripping petroleum ether into the filtrate until solid precipitation appears, standing at a low temperature for crystallization for 3 hours, filtering out the solid by suction, and drying to obtain the dehydrogriseofulvin.
2. The method for preparing the dehydrogriseofulvin according to claim 1, characterized by comprising the following steps: the alcohol mixed solution is a mixed solution of tertiary butanol and isopropanol, and the weight ratio of the tertiary butanol to the isopropanol is 1:1.4.
3. The method for preparing the dehydrogriseofulvin according to claim 1, characterized by comprising the following steps: the oxidant is mixed powder of lead tetraacetate and selenium oxide, and the weight ratio of the lead tetraacetate to the selenium oxide is 5:1.
4. the method for preparing the dehydrogriseofulvin according to claim 1, characterized by comprising the following steps: the mixed solvent is a mixed solution of ethyl acetate and ethanol, and the weight ratio of the ethyl acetate to the ethanol is 4:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311764030.5A CN117624099A (en) | 2023-12-21 | 2023-12-21 | Preparation method of dehydrogriseofulvin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311764030.5A CN117624099A (en) | 2023-12-21 | 2023-12-21 | Preparation method of dehydrogriseofulvin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117624099A true CN117624099A (en) | 2024-03-01 |
Family
ID=90035661
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311764030.5A Pending CN117624099A (en) | 2023-12-21 | 2023-12-21 | Preparation method of dehydrogriseofulvin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117624099A (en) |
-
2023
- 2023-12-21 CN CN202311764030.5A patent/CN117624099A/en active Pending
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