CN115490701B - Method for synthesizing cantharidin - Google Patents
Method for synthesizing cantharidin Download PDFInfo
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- CN115490701B CN115490701B CN202211193208.0A CN202211193208A CN115490701B CN 115490701 B CN115490701 B CN 115490701B CN 202211193208 A CN202211193208 A CN 202211193208A CN 115490701 B CN115490701 B CN 115490701B
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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Abstract
Aiming at the problems that the existing cantharidin ring synthesis requires ultra-high pressure harsh reaction conditions, has low conversion rate and the like, the invention provides a novel synthesis process of cantharidin, the synthesis of cantharidin is completed through a simple three-step method of nordehydrocantharidin, norcantharidin and cantharidin by maleic anhydride and tetrahydrofuran, when metal-loaded ionic liquid is adopted, the catalyst and the solvent are equivalent to the catalyst and the solvent in a reaction system, the yield of the reaction can be improved, the ionic liquid can be recovered, and the green chemical flow of the step is realized; after the separation and the re-methylation of the cantharidin derivative, the full utilization of the reaction materials is realized, and the mode is beneficial to industrial production.
Description
Technical Field
The invention belongs to the field of medicine synthesis and preparation, and relates to a method for synthesizing cantharidin, in particular to a synthesis process for preparing cantharidin and derivatives thereof under the condition of organic alkali.
Background
Cantharidin (formula 1) is mainly derived from dried body of Cantharis or Mylabris flavicans of Melanin of Melaninaceae of Melanin of Arthropoda. Pharmacological studies show that the cantharis has anti-tumor activity and has inhibition effect on liver cancer, cervical cancer, skin cancer, bone marrow cancer, leukemia and the like. The cantharidin has the advantages of less damage to normal cells of cancer patients, increased white blood cells, no inhibition of immune system and the like, so the cantharidin is always a research and development hot spot of anti-tumor drugs. Because of the lack of natural resources, tablets and injection such as cantharidin, sodium cantharidate, methyl cantharidimide and the like cannot be produced in large quantity.
After the structure of cantharidin has been confirmed by Gadamer in 1914, pharmaceutical synthesizers in various countries have been working on the chemical synthesis of cantharidin.
Stork first synthesized cantharidin through 11 steps (formula 2) in 1951.
Schenk was synthesized in 1953 in 7 steps (formula 3).
Dauben underwent 2-step synthesis in 1976 (formula 4).
Although cantharidin can be synthesized by the above method, the reaction conditions are very harsh when the intermediate is prepared, the specific operation is complex, and the cantharidin yield is low. In particular, the reaction of Dauben needs to be carried out under 15000 atmospheres, which has very high equipment requirements and is difficult to realize industrial production.
In the past, how to reduce the harsh conditions during the key cycloaddition reaction of the preparation of cantharidin and improve the yield of cantharidin is a research and development hot spot for scientific researchers in various countries. In 1990 Grico et al, it was proposed to shorten the reaction time and increase the yield of the target product by using lithium perchlorate, but lithium perchlorate has strict requirements on the anhydrous condition of the reaction and is difficult to handle. In 2016, cantharidin (formula 5) is synthesized under normal pressure, but the process uses ionic liquid in key reaction, the ionic liquid is difficult to separate from a target object, and meanwhile, the used ionic liquid is expensive, so that industrial mass production cannot be realized. It is therefore desirable to develop a new process with mild reaction conditions to prepare the spot-chelant.
Disclosure of Invention
Aiming at the problems of the existing synthesis of cantharidin ring that ultra-high pressure harsh reaction condition is needed, the conversion rate is low and the like, the invention provides a novel synthesis process of cantharidin.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a method for synthesizing cantharidin comprises the following steps:
s1: preparing nordehydrocantharidin;
s2: preparing norcantharidin;
s3: and (3) preparing cantharidin.
Still further, the step S1: the nordehydrocantharidin is obtained by the slow stirring reaction of maleic anhydride and tetrahydrofuran at room temperature.
Still further, the step S1: the nordehydrocantharidin is obtained by slowly stirring maleic anhydride, tetrahydrofuran and metal-loaded ionic liquid at room temperature, wherein the metal-loaded ionic liquid is Ni-loaded ionic liquid, and the ionic liquid structure is thatThe metal loading is 0.1wt% to 0.3wt% of the ionic liquid.
When the metal-loaded ionic liquid is used as a catalyst and a solvent in a reaction system, the yield of the reaction can be improved, and meanwhile, the recovery of the ionic liquid can be realized, so that the green chemical flow of the step is realized.
Still further, the step S2: adding nordehydrocantharidin and organic solvent into hydrogenation bottle, and heating to react to obtain norcantharidin.
Still further, the step S3: dissolving norcantharidin in an organic solvent, extracting hydrogen at low temperature, dripping methyl iodide, quenching with pure water after the reaction at low temperature is completed, and separating to obtain the product cantharidin.
Further, after the product is obtained by separation in the step S3, the obtained cantharidin derivative is combined with norcantharidin obtained in the step S2, and then the step S3 is performed.
After extracting hydrogen at low temperature, methyl iodide is dripped to complete methylation, cantharidin and cantharidin derivatives are obtained through product separation, and after the derivatives are subjected to methylation again, the full utilization of reaction materials is realized.
Still further, S1: adding maleic anhydride and tetrahydrofuran, diethyl ether or ionic liquid into a dry reaction bottle, slowly stirring at room temperature for reaction for 45-50 h, and removing diethyl ether by vacuum suction filtration to obtain white powder which is nordehydrocantharidin;
s2: norcantharidin preparation: adding nordehydrocantharidin and ethyl acetate into a hydrogenation bottle, heating to 50-60 ℃ for reaction for 5 hours, carrying out suction filtration, and recrystallizing with ethyl acetate to obtain white powder norcantharidin;
s3: preparing cantharidin: dissolving norcantharidin in tetrahydrofuran, dropwise adding butyllithium at-78 ℃, reacting for 30min after dropwise adding, dropwise adding methyl iodide, reacting for 15min at minus 78 ℃ after dropwise adding, naturally and slowly heating to room temperature for 2h, cooling, quenching with purified water, separating liquid, extracting water phase with ethyl acetate for three times, mixing organic phases, evaporating the organic phases to dryness, and separating and purifying with silica gel column to obtain cantharidin.
Still further, S1: adding maleic anhydride, tetrahydrofuran and metal-loaded ionic liquid into a dried reaction bottle, slowly stirring at room temperature for reaction for 5-10 hours, adding maleic anhydride, tetrahydrofuran and metal-loaded ionic liquid into the dried reaction bottle, stirring at room temperature for reaction for 5-10 hours, and recovering the metal-loaded ionic liquid to obtain white powder which is nordehydrocantharidin;
s2: norcantharidin preparation: adding nordehydrocantharidin and ethyl acetate into a hydrogenation bottle, heating to 50-60 ℃ for reaction for 5 hours, carrying out suction filtration, and recrystallizing with ethyl acetate to obtain white powder norcantharidin;
s3: preparing cantharidin: dissolving norcantharidin in tetrahydrofuran, dropwise adding butyllithium at-78 ℃, reacting for 30min after dropwise adding, dropwise adding methyl iodide, reacting for 15min at minus 78 ℃ after dropwise adding, naturally and slowly cooling to room temperature, reacting for 2h, cooling, quenching with purified water, separating liquid, extracting water phase with ethyl acetate for three times, mixing organic phases, evaporating the organic phases to dryness, and separating and purifying with silica gel column to obtain cantharidin and cantharidin derivatives;
s4: combining the cantharidin derivative with norcantharidin in the step S2, and performing the step S3 to prepare cantharidin.
Compared with the prior art, the invention has the beneficial effects that:
1. the synthesis of the cantharidin is completed by the simple three-step method of nordehydrocantharidin, norcantharidin and cantharidin through maleic anhydride and tetrahydrofuran;
2. when the metal-loaded ionic liquid is used as a catalyst and a solvent in a reaction system, the yield of the reaction can be improved, and meanwhile, the recovery of the ionic liquid can be realized, so that the green chemical flow of the step is realized.
3. After the separation and the re-methylation of the cantharidin derivative, the full utilization of the reaction materials is realized, and the mode is beneficial to industrial production.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1:
s1 preparation of nordehydrocantharidin
Maleic anhydride 50g,250mL tetrahydrofuran and 100mL diethyl ether are added into a dry reaction bottle, the mixture is slowly stirred at room temperature for reaction for 50 hours, diethyl ether is removed by vacuum filtration, 80g of white powder is obtained after drying, and the yield is 93%; 1 H NMR(600MHz,CDCl 3 )δ,ppm:2.16(s,2H),3.16(s,2H),5.45(s,2H)。
s2 norcantharidin preparation
Adding 20g of nordehydrocantharidin, 200mL of ethyl acetate and catalytic amount of Raney Ni into a hydrogenation bottle, heating to 50-60 ℃ for reaction for 5h, carrying out suction filtration, and recrystallizing with ethyl acetate to obtain 16g of white powder, wherein the yield is 80%; m.p. 113-116 ℃; 1 H NMR(600MHz,CDCl 3 )δ,ppm:1.62(m,2H),1.88(m,2H),3.17(s,2H),5.02(m,2H)； 13 C NMR(600MHz,CDCl 3 )δppm:28.1,50.6,80.2,171.2.
s3 preparation of cantharidin
Dissolving 10g norcantharidin in 200In the method, 80mL of 2.5M butyl lithium is dropwise added at minus 78 ℃, after the dropwise addition, the temperature is kept at minus 78 ℃ for 30min, 17g of methyl iodide/50 mL of THF solution is dropwise added, after the dropwise addition, the temperature is kept at minus 78 ℃ for 15min, the reaction is naturally and slowly carried out at room temperature for 2h, the temperature is reduced, the reaction is quenched by purified water, the liquid is separated, the aqueous phase is extracted three times by 50mL of ethyl acetate, the organic phases are combined, a proper amount of organic phases are evaporated to dryness, and the cantharidin is obtained by separating and purifying by a silica gel column. m.p. 210-212 ℃; 1 H NMR(600MHz,CDCl 3 )δ,J＝6.0Hz,2H)； 13 C NMR(600MHz,CDCl 3 )δ,ppm:12.7,23.4,55.2,84.7,175.9；ESI-MS:m/z 197.08(M+H+,100％).
example 2
S1: preparing nordehydrocantharidin;
the nordehydrocantharidin is obtained by slowly stirring maleic anhydride, tetrahydrofuran and metal-loaded ionic liquid at room temperature, wherein the metal-loaded ionic liquid is Ni-loaded ionic liquid, and the ionic liquid structure is thatThe metal loading is 0.1wt% to 0.3wt% of the ionic liquid.
500g of maleic anhydride, 250mL of tetrahydrofuran and 500mL of Ni metal-loaded ionic liquid are added into a dry reaction bottle, the metal loading is 0.1wt% of the ionic liquid, the reaction is slowly stirred at room temperature for 5h, the Ni metal-loaded ionic liquid is recovered, and 85g of white powder is obtained, and the yield is 99%.
The recycled metal load is the ionic liquid, and the yield still reaches about 98 percent.
When the metal-loaded ionic liquid is used as a catalyst and a solvent in a reaction system, the reaction dosage is increased, the reaction time is reduced, the yield of the reaction is improved, post-treatment separation is basically not needed, and the recycling of the ionic liquid is realized. Meanwhile, the ionic liquid can be recovered, and the green chemical flow of the step is realized.
S2: preparing norcantharidin;
200g of nordehydrocantharidin, 200mL of ethyl acetate and catalytic amount of Raney Ni are added into a hydrogenation bottle, the mixture is heated to 60 ℃ to react for 5 hours, the mixture is filtered by suction, and the white powder is obtained by recrystallization, wherein 165g of white powder is obtained, and the yield is 82%.
S3: and (3) preparing cantharidin.
Dissolving norcantharidin in an organic solvent, extracting hydrogen at low temperature, dripping methyl iodide, quenching with pure water after the reaction at low temperature is completed, and separating to obtain the product cantharidin. And (3) after the product is obtained through separation in the step (S3), combining the obtained cantharidin derivative with norcantharidin obtained in the step (S2), and then carrying out the step (S3).
Dissolving 150g norcantharidin in 500mL tetrahydrofuran, dropwise adding 80mL of 2.5M butyl lithium at minus 78 ℃, preserving heat for 30min after the dripping, reacting for 15min at minus 78 ℃ after the dripping, naturally and slowly heating to room temperature for 2h, cooling, adopting purified water quenching reaction, separating liquid, extracting, separating and purifying by a silica gel column to obtain 102g of cantharidin, 59% and 52.5g of cantharidin derivative, 35%. After extracting hydrogen at low temperature, methyl iodide is dripped to complete methylation, cantharidin and cantharidin derivatives are obtained through product separation, and after the derivatives are subjected to methylation again, the full utilization of reaction materials is realized.
S4: combining the cantharidin derivative with norcantharidin in the step S2, and performing the step S3 to prepare cantharidin.
100g norcantharidin and 52.5g cantharidin derivative are dissolved in 500mL tetrahydrofuran, 80mL of 2.5M butyl lithium is dripped at minus 78 ℃, after dripping, the temperature is kept at minus 78 ℃ for 30min, methyl iodide/THF solution is dripped, after dripping, the temperature is kept at minus 78 ℃ for 15min, the reaction is naturally and slowly carried out at room temperature for 2h, the temperature is reduced, the purified water quenching reaction is adopted, the liquid separation and the extraction are carried out, and the separation and the purification are carried out by adopting a silica gel column to obtain 120g of cantharidin, 74% and 37.2g of cantharidin derivative, 22%.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (5)
1. A method for synthesizing cantharidin is characterized in that: the preparation method comprises the following steps:
s1: the nordehydrocantharidin preparation: the nordehydrocantharidin is obtained by slowly stirring maleic anhydride and tetrahydrofuran at room temperature for reaction;
s2: norcantharidin preparation: adding nordehydrocantharidin and an organic solvent into a hydrogenation bottle, and heating for reaction to obtain norcantharidin;
s3: preparing cantharidin: dissolving norcantharidin in an organic solvent, extracting hydrogen at a low temperature by using butyl lithium, dripping methyl iodide, quenching by pure water after the reaction is completed at a low temperature, and separating to obtain a product;
the chemical reaction formula is as follows:
2. the method for synthesizing cantharidin according to claim 1, wherein the method is characterized in that: the step S1: the nordehydrocantharidin is obtained by slowly stirring maleic anhydride, tetrahydrofuran and metal-loaded ionic liquid at room temperature, wherein the metal-loaded ionic liquid is Ni-loaded ionic liquid, and the ionic liquid structure is thatThe metal loading is 0.1wt% to 0.3wt% of the ionic liquid.
3. The method for synthesizing cantharidin according to claim 1, wherein the method is characterized in that: and (3) after the product is obtained through separation in the step (S3), combining the obtained cantharidin derivative with norcantharidin obtained in the step (S2), and then carrying out the step (S3).
4. The method for synthesizing cantharidin according to claim 1, wherein the method is characterized in that:
s1: the nordehydrocantharidin preparation: adding maleic anhydride and tetrahydrofuran, diethyl ether or ionic liquid into a dry reaction bottle, slowly stirring at room temperature for reaction for 40-50 h, and removing diethyl ether by vacuum suction filtration to obtain white powder which is nordehydrocantharidin;
s2: norcantharidin preparation: adding nordehydrocantharidin and ethyl acetate into a hydrogenation bottle, heating to 50-60 ℃ for reaction for 5 hours, carrying out suction filtration, and recrystallizing with ethyl acetate to obtain white powder norcantharidin;
s3: preparing cantharidin: dissolving norcantharidin in tetrahydrofuran, dropwise adding butyllithium at-78 ℃, reacting for 30min after dropwise adding, dropwise adding methyl iodide, reacting for 15min at minus 78 ℃ after dropwise adding, naturally and slowly heating to room temperature for 2h, cooling, quenching with purified water, separating liquid, extracting water phase with ethyl acetate for three times, mixing organic phases, evaporating the organic phases to dryness, and separating and purifying with silica gel column to obtain cantharidin.
5. The method for synthesizing cantharidin according to claim 1, wherein the method is characterized in that:
s1: the nordehydrocantharidin preparation: adding maleic anhydride, tetrahydrofuran and metal-loaded ionic liquid into a dry reaction bottle, stirring and reacting for 5-10 hours at room temperature, and recovering the metal-loaded ionic liquid to obtain white powder which is nordehydrocantharidin;
s2: norcantharidin preparation: adding nordehydrocantharidin and ethyl acetate into a hydrogenation bottle, heating to 50-60 ℃ for reaction for 5 hours, carrying out suction filtration, and recrystallizing with ethyl acetate to obtain white powder norcantharidin;
s3: preparing cantharidin: dissolving norcantharidin in tetrahydrofuran, dropwise adding butyllithium at-78 ℃, reacting for 30min after dropwise adding, dropwise adding methyl iodide, reacting for 15min at minus 78 ℃ after dropwise adding, naturally and slowly cooling to room temperature, reacting for 2h, cooling, quenching with purified water, separating liquid, extracting water phase with ethyl acetate for three times, mixing organic phases, evaporating the organic phases to dryness, and separating and purifying with silica gel column to obtain cantharidin and cantharidin derivatives;
s4: combining the cantharidin derivative with norcantharidin in the step S2, and performing the step S3 to prepare cantharidin.
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| CN106674248A (en) * | 2016-12-17 | 2017-05-17 | 重庆市中药研究院 | Novel green environment-friendly synthesis process of cantharidin |
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| CN106674248A (en) * | 2016-12-17 | 2017-05-17 | 重庆市中药研究院 | Novel green environment-friendly synthesis process of cantharidin |
| CN111269242A (en) * | 2020-03-17 | 2020-06-12 | 遵义医科大学 | Norcantharidin carboxylic acid monofluorobenzyl ester and synthesis method and anti-tumor application thereof |
| CN111362962A (en) * | 2020-03-17 | 2020-07-03 | 遵义医科大学 | Tetrafluorobenzyl norcantharidin carboxylate and synthesis method thereof |
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