CN115974891B - Preparation method of norcantharidin - Google Patents
Preparation method of norcantharidin Download PDFInfo
- Publication number
- CN115974891B CN115974891B CN202310060878.3A CN202310060878A CN115974891B CN 115974891 B CN115974891 B CN 115974891B CN 202310060878 A CN202310060878 A CN 202310060878A CN 115974891 B CN115974891 B CN 115974891B
- Authority
- CN
- China
- Prior art keywords
- dehydronorcantharidin
- norcantharidin
- reaction
- preparation
- hydrogenation reduction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a preparation method of norcantharidin, and relates to the technical field of organic synthesis. The invention mixes dehydronorcantharidin, diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridine dicarboxylic acid, organic solvent and palladium-carbon catalyst, and carries out hydrogenation reduction reaction in protective atmosphere to obtain the norcantharidin; the hydrogenation reduction reaction is carried out under normal pressure. The invention takes diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridine dicarboxylic acid as hydrogen source for catalytic hydrogenation reduction of dehydronorcantharidin, and prepares norcantharidin through normal pressure hydrogenation reduction. The invention adopts 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridine dicarboxylic acid diethyl ester to replace hydrogen, adopts a more stable hydrogen source, is normal pressure reaction, has improved reaction safety and operability, and is beneficial to industrial scale production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of norcantharidin.
Background
Norcantharidin (norcantharidin), the chemical name of which is exo-7-oxabicyclo [2, 1] heptane-2, 3 dicarboxylic anhydride, is an antitumor drug which is developed by China, is mainly used for treating primary liver cancer clinically, and has certain curative effects on stomach cancer, esophageal cancer, lung cancer, breast cancer, intestinal cancer, skin cancer and the like. The traditional preparation method of norcantharidin (the synthetic route is shown as formula A) takes furan (compound 1) and maleic anhydride (compound 2) as starting materials, and the dehydronorcantharidin (compound 3) is prepared by Diels-Alder addition reaction, and then the norcantharidin (compound 3) is subjected to catalytic hydrogenation reduction to obtain the norcantharidin (compound 4). Wherein the catalytic hydrogenation reduction step requires pressurization and the presence of hydrogen makes the operation safe.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing norcantharidin. The preparation method provided by the invention takes the diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridine dicarboxylic acid as a hydrogen source, and performs hydrogenation reduction at normal pressure, so that the reaction safety is high.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of norcantharidin, which comprises the following steps:
mixing dehydronorcantharidin (compound 3), diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridine dicarboxylic acid, an organic solvent and a palladium-carbon catalyst, and carrying out hydrogenation reduction reaction in a protective atmosphere to obtain norcantharidin; the hydrogenation reduction reaction is carried out under normal pressure.
Preferably, the molar ratio of the dehydronorcantharidin to the diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylic acid is 1:2 to 4.
Preferably, the mass of the palladium-carbon catalyst is 2-5% of the mass of the dehydronorcantharidin.
Preferably, the organic solvent comprises one or more of acetone, tetrahydrofuran, methanol and ethanol.
Preferably, the hydrogenation reduction reaction is carried out at a temperature of 25-35 ℃ for 2-4 hours.
Preferably, the protective atmosphere is a nitrogen atmosphere.
Preferably, after the hydrogenation reduction reaction, the method further comprises post-treatment of the obtained reaction liquid, wherein the post-treatment comprises:
carrying out solid-liquid separation on the reaction liquid, and collecting filtrate;
evaporating the filtrate to dryness, and then dissolving the filtrate with ethyl acetate to obtain a mixed solution;
washing the mixed solution with hydrochloric acid, and separating to obtain an ethyl acetate phase;
and washing the ethyl acetate phase with saturated saline water and drying to obtain norcantharidin.
Preferably, the dosage ratio of the ethyl acetate to the dehydronorcantharidin is (3-4) mL:1g.
Preferably, the mass fraction of the hydrochloric acid is 5%; the times of the hydrochloric acid washing are 2 times, and the dosage ratio of the hydrochloric acid used for single washing to the dehydronorcantharidin is (1.1-1.5) mL:1g.
The invention provides a preparation method of norcantharidin, which comprises the following steps: mixing dehydronorcantharidin, diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridine dicarboxylic acid, an organic solvent and a palladium-carbon catalyst, and carrying out hydrogenation reduction reaction in a protective atmosphere to obtain norcantharidin; the hydrogenation reduction reaction is carried out under normal pressure. The invention takes diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridine dicarboxylic acid as hydrogen source for catalytic hydrogenation reduction of dehydronorcantharidin, and prepares norcantharidin through normal pressure hydrogenation reduction. The invention adopts 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridine dicarboxylic acid diethyl ester to replace hydrogen, adopts a more stable hydrogen source, is normal pressure reaction, has improved reaction safety and operability, and is beneficial to industrial scale production. The results of the embodiment show that the norcantharidin prepared by the method provided by the invention has the product yield of 75-96%.
Detailed Description
The invention provides a preparation method of norcantharidin, which comprises the following steps:
mixing dehydronorcantharidin, diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridine dicarboxylic acid, an organic solvent and a palladium-carbon catalyst, and carrying out hydrogenation reduction reaction in a protective atmosphere to obtain norcantharidin; the hydrogenation reduction reaction is carried out under normal pressure.
In the present invention, unless otherwise specified, the starting materials are known compounds, and can be prepared by commercially available products or by methods well known to those skilled in the art.
In the present invention, the molar ratio of dehydronorcantharidin to diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylic acid, i.e., hans ester (1, 4-dihydropyridine), is preferably 1:2 to 4, more preferably 1:2 to 3. In the present invention, the mass of the palladium-carbon (Pd/C) catalyst is preferably 2 to 5% of the mass of dehydronorcantharidin, more preferably 3 to 4%; in the embodiment of the invention, the palladium-carbon catalyst adopts palladium-carbon with the content of 10 weight percent of palladium. In the invention, the organic solvent preferably comprises one or more of acetone, tetrahydrofuran, methanol and ethanol, more preferably acetone, and the dosage of the organic solvent is not particularly required, so that the raw materials can be dissolved and the reaction can be smoothly carried out; in the embodiment of the invention, the dosage ratio of the organic solvent to the dehydronorcantharidin is preferably (4-6) mL:1g, more preferably 5mL:1g. In the present invention, the mixing method is preferably: sequentially adding dehydronorcantharidin, diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridine dicarboxylic acid and an organic solvent into a reaction device, stirring, and then adding a palladium-carbon catalyst into the solution. The invention has no special requirement on the stirring speed and time, and ensures that the dehydronorcantharidin and the diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridine dicarboxylic acid are fully dissolved in an organic solvent.
In the present invention, the protective atmosphere is preferably a nitrogen atmosphere, and the present invention preferably involves performing a nitrogen substitution reaction in the reaction apparatus so that the hydrogenation reduction reaction is performed in the nitrogen atmosphere. In the present invention, the hydrogenation reduction reaction is preferably carried out at a temperature of 25 to 35 ℃, more preferably 25 to 30 ℃, for a time of preferably 2 to 4 hours, more preferably 2 hours; the hydrogenation reduction reaction is carried out under normal pressure. The invention adopts the diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridine dicarboxylic acid to replace hydrogen, the hydrogen source is more stable, the reaction is carried out under normal pressure, and the safety is high.
After the hydrogenation reduction reaction is completed, the invention also comprises the step of preferably carrying out post-treatment on the obtained reaction liquid, wherein the post-treatment preferably comprises the following steps:
carrying out solid-liquid separation on the reaction liquid, and collecting filtrate;
evaporating the filtrate to dryness, and then dissolving the filtrate with ethyl acetate to obtain a mixed solution;
washing the mixed solution with hydrochloric acid, and separating to obtain an ethyl acetate phase;
and washing the ethyl acetate phase with saturated saline water and drying to obtain norcantharidin.
In the invention, the solid-liquid separation method is preferably suction filtration, the solid phase obtained by the solid-liquid separation is palladium-carbon catalyst, the palladium-carbon catalyst is recovered by the solid-liquid separation, and the filtrate is collected. In the invention, the dosage ratio of the ethyl acetate to the dehydronorcantharidin is preferably (3-4) mL:1g. Hydrochloric acid is preferably added into the mixed solution for hydrochloric acid washing, and the mass fraction of the hydrochloric acid is preferably 5%; the number of times of hydrochloric acid washing is preferably 2, and the dosage ratio of hydrochloric acid to dehydronorcantharidin used in single washing is preferably (1.1-1.5) mL:1g. In the invention, the hydrochloric acid washing function is to remove the by-product obtained after the reaction of the diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridine dicarboxylic acid and the excessive diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridine dicarboxylic acid by hydrochloric acid treatment to form hydrochloride; the effect of the saturated brine wash was to remove hydrochloric acid and wash the hydrochloric acid remaining in the ethyl acetate phase. In the invention, the drying is preferably reduced pressure distillation drying, the temperature of the reduced pressure distillation drying is preferably 40-50 ℃, and the time is based on the drying by distillation; and (3) removing ethyl acetate through drying to obtain norcantharidin.
The following examples are provided to illustrate the preparation of norcantharidin according to the present invention in detail, but they should not be construed as limiting the scope of the present invention.
Example 1
34g (0.2046 mol) of dehydronorcantharidin, 155.47g (0.6138 mol) of diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylate and 170mL of acetone were added to the reaction vessel, dissolved by stirring, and then 1.36g of palladium on carbon (Pd/C, 10wt% palladium content) was added thereto, the reaction vessel was replaced with nitrogen protection, and the reaction was carried out at 25℃for 2 hours. After the reaction is finished, suction filtration is carried out, palladium carbon is recovered, filtrate is collected and evaporated to dryness to obtain a mixture, then 102mL of ethyl acetate is added for dissolution, 40mL of 5wt% hydrochloric acid is added for washing twice, the ethyl acetate phase is obtained after separation, saturated saline water is used for washing, and 33.03g of crude norcantharidin is obtained after decompression and evaporation at 40-50 ℃, and the yield is 96% and the purity is over 99%.
Example 2
34g (0.2046 mol) of dehydronorcantharidin, 103.64g (0.4092 mol) of diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylate and 170mL of acetone were added to the reaction vessel, dissolved by stirring, and then 1.36g of palladium on carbon (Pd/C, 10wt% palladium content) was added thereto, the reaction vessel was replaced with nitrogen protection, and the reaction was carried out at 25℃for 2 hours. After the reaction is finished, suction filtration is carried out, palladium carbon is recovered, filtrate is collected and evaporated to dryness to obtain a mixture, then 102mL of ethyl acetate is added for dissolution, 40mL of 5wt% hydrochloric acid is added for washing twice, an ethyl acetate phase is obtained by separation, saturated saline water is used for washing, and 25.80g of crude norcantharidin is obtained after decompression and evaporation at 40-50 ℃, and the yield is 75% and the purity is more than 99%.
Example 3
34g (0.2046 mol) of dehydronorcantharidin, 207.29g (0.8184 mol) of diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylate and 170mL of acetone were added to the reaction vessel, dissolved by stirring, and then 1.36g of palladium on carbon (Pd/C, 10wt% palladium content) was added thereto, the reaction vessel was replaced with nitrogen protection, and the reaction was carried out at 25℃for 2 hours. After the reaction is finished, suction filtration is carried out, palladium carbon is recovered, filtrate is collected and evaporated to dryness to obtain a mixture, then 102mL of ethyl acetate is added for dissolution, 40mL of 5wt% hydrochloric acid is added for washing twice, an ethyl acetate phase is obtained by separation, saturated saline water is used for washing, and 32.09g of crude norcantharidin is obtained after decompression evaporation at 40-50 ℃, and the yield is 93.24% and the purity is more than 99%.
Example 4
34g (0.2046 mol) of dehydronorcantharidin, 155.47g (0.6138 mol) of diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylate and 170mL of acetone were added to the reaction vessel, stirred and dissolved, then 0.68g of palladium on carbon (Pd/C, 10wt% palladium content) was added thereto, the reaction vessel was replaced with nitrogen protection, and the reaction was carried out at 25℃for 2 hours. After the reaction is finished, suction filtration is carried out, palladium carbon is recovered, filtrate is collected and evaporated to dryness to obtain a mixture, then 102mL of ethyl acetate is added for dissolution, 40mL of 5wt% hydrochloric acid is added for washing twice, an ethyl acetate phase is obtained by separation, saturated saline water is used for washing, and 28.72g of crude norcantharidin is obtained after decompression and evaporation at 40-50 ℃, and the yield is 83.47% and the purity is more than 99%.
Example 5
34g (0.2046 mol) of dehydronorcantharidin, 155.47g (0.6138 mol) of diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylate and 170mL of acetone were added to the reaction vessel, stirred and dissolved, then 1.02g of palladium on carbon (Pd/C, 10wt% palladium content) was added thereto, the reaction vessel was replaced with nitrogen protection, and the reaction was carried out at 25℃for 2 hours. After the reaction is finished, suction filtration is carried out, palladium carbon is recovered, filtrate is collected and evaporated to dryness to obtain a mixture, then 102mL of ethyl acetate is added for dissolution, 40mL of 5wt% hydrochloric acid is added for washing twice, an ethyl acetate phase is obtained by separation, saturated saline water is used for washing, and 30.10g of crude norcantharidin is obtained after decompression evaporation at 40-50 ℃, and the yield is 87.47% and the purity is more than 99%.
Example 6
34g (0.2046 mol) of dehydronorcantharidin, 155.47g (0.6138 mol) of diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylate and 136mL of acetone were added to the reaction vessel, stirred and dissolved, then 1.36g of palladium on carbon (Pd/C, 10wt% palladium content) was added thereto, the reaction vessel was replaced with nitrogen protection, and the reaction was carried out at 25℃for 2 hours. After the reaction is finished, suction filtration is carried out, palladium carbon is recovered, filtrate is collected and evaporated to dryness to obtain a mixture, then 102mL of ethyl acetate is added for dissolution, 40mL of 5wt% hydrochloric acid is added for washing twice, an ethyl acetate phase is obtained by separation, saturated saline water is used for washing, and 31.09g of crude norcantharidin is obtained after decompression evaporation at 40-50 ℃, and the yield is 90.35% and the purity is more than 99%.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (9)
1. The preparation method of norcantharidin is characterized by comprising the following steps:
mixing dehydronorcantharidin, diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridine dicarboxylic acid, an organic solvent and a palladium-carbon catalyst, and carrying out hydrogenation reduction reaction in a protective atmosphere to obtain norcantharidin; the hydrogenation reduction reaction is carried out under normal pressure.
2. The preparation method according to claim 1, wherein the molar ratio of dehydronorcantharidin to diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylic acid is 1:2 to 4.
3. The preparation method according to claim 1, wherein the mass of the palladium-carbon catalyst is 2-5% of the mass of dehydronorcantharidin.
4. The preparation method according to claim 1, wherein the organic solvent is one or more selected from the group consisting of acetone, tetrahydrofuran, methanol and ethanol.
5. The method according to claim 1, wherein the hydrogenation reduction reaction is carried out at a temperature of 25 to 35 ℃ for a time of 2 to 4 hours.
6. The method of claim 1, wherein the protective atmosphere is a nitrogen atmosphere.
7. The method according to claim 1 or 5, wherein the method further comprises subjecting the obtained reaction solution to a post-treatment after the hydrogenation reduction reaction, the post-treatment comprising:
carrying out solid-liquid separation on the reaction liquid, and collecting filtrate;
evaporating the filtrate to dryness, and then dissolving the filtrate with ethyl acetate to obtain a mixed solution;
washing the mixed solution with hydrochloric acid, and separating to obtain an ethyl acetate phase;
and washing the ethyl acetate phase with saturated saline water and drying to obtain norcantharidin.
8. The preparation method of claim 7, wherein the dosage ratio of ethyl acetate to dehydronorcantharidin is (3-4) mL:1g.
9. The preparation method according to claim 7, wherein the mass fraction of the hydrochloric acid is 5%; the times of the hydrochloric acid washing are 2 times, and the dosage ratio of the hydrochloric acid used for single washing to the dehydronorcantharidin is (1.1-1.5) mL:1g.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310060878.3A CN115974891B (en) | 2023-01-16 | 2023-01-16 | Preparation method of norcantharidin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310060878.3A CN115974891B (en) | 2023-01-16 | 2023-01-16 | Preparation method of norcantharidin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115974891A CN115974891A (en) | 2023-04-18 |
| CN115974891B true CN115974891B (en) | 2023-07-25 |
Family
ID=85957927
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310060878.3A Active CN115974891B (en) | 2023-01-16 | 2023-01-16 | Preparation method of norcantharidin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115974891B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006041921A2 (en) * | 2004-10-05 | 2006-04-20 | Auspex Pharmaceuticals, Inc. | Preparation and uses of rhodanine derivatives |
| CN111170949B (en) * | 2018-11-09 | 2021-07-27 | 中国科学院大连化学物理研究所 | Method for synthesizing 3, 4-dihydropyrimidinone compound by asymmetric transfer hydrogenation |
| CN111253415B (en) * | 2020-03-17 | 2022-08-09 | 遵义医科大学 | Norcantharidin carboxylic acid trifluoro benzyl ester and synthetic method and application thereof |
-
2023
- 2023-01-16 CN CN202310060878.3A patent/CN115974891B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN115974891A (en) | 2023-04-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113943336B (en) | Method for synthesizing cholesterol by taking BA as raw material | |
| CN1803801A (en) | Method for preparing ellagic acid by pomegranate rind | |
| CN114524856B (en) | Synthesis method of high-purity plant-derived cholesterol | |
| CN114292256A (en) | Preparation method and purification method of watermelon ketone crude product suitable for industrial production | |
| CN113135971B (en) | Carbon-loss cholesterin and preparation method and application thereof | |
| CN109651473A (en) | A kind of preparation method of androstane -2- alkene -17- ketone | |
| CN115974891B (en) | Preparation method of norcantharidin | |
| CN114644547A (en) | Preparation method of cannabidiol and/or hypocannabidiol | |
| CN114213496B (en) | Method for separating lanosterol and dihydro lanosterol | |
| CN110698335A (en) | Synthesis method of terbutaline intermediate | |
| CN112679512B (en) | Trabectedin intermediate and preparation method thereof | |
| WO2023000636A1 (en) | Method for synthesis of (3-fluorooxetan-3-yl)methyl 4-methylbenzenesulfonate | |
| CN111592491B (en) | Preparation method of levo-hydrochloric acid demethyl phencynonate | |
| CN113292542A (en) | Rosuvastatin calcium intermediate impurity and preparation method thereof | |
| CN102399255B (en) | Preparation method for betulinic acid | |
| CN115010573B (en) | Method for reducing chromium content in lycopene crystal | |
| CN113929726B (en) | Mogrol derivative compound and preparation method and application thereof | |
| CN114249352B (en) | Method for treating wastewater generated in production of 6-methoxy tetralone | |
| CN111517985B (en) | Preparation method of 4- [ (1R) -1-amino-2-hydroxyethyl ] -3-fluoro-benzonitrile | |
| CN113754538B (en) | Vigabatrin acid intermediate and preparation method thereof | |
| CN112679513B (en) | Method for preparing key intermediate of koji Bei Ti | |
| CN116354929A (en) | Preparation method of 6-bromo-2- (2, 6-dioxopiperidine-3-yl) 4-fluoroisoindoline-1, 3-dione | |
| CN115057767A (en) | Preparation method of phthalic acid | |
| CN116903633A (en) | Preparation method of high-purity gelsemium seed and pharmaceutically acceptable salt thereof based on chiral organic acid separation | |
| CN112707918A (en) | Preparation method of polycyclic diketone fused ring molecule |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |