CN115260130A - Preparation method of 10-deacetylated paclitaxel - Google Patents
Preparation method of 10-deacetylated paclitaxel Download PDFInfo
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- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Epoxy Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of 10-deacetyl paclitaxel, relating to the technical field of chemical synthesis; the method takes 10-deacetyl baccatin III extracted and purified from taxus chinensis plants as a raw material, and takes the reactions of protection, esterification, hydrolysis, deprotection and the like in the participation of chloroformic acid-2, 2-trichloroethyl ester to obtain a 10-deacetyl taxol crude product, and the 10-deacetyl taxol crude product is further purified by column chromatography and recrystallization to obtain a 10-deacetyl taxol finished product; the preparation method provided by the invention reduces the synthesis difficulty, is simple and easy to operate, and has high purification efficiency and high yield.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of 10-deacetyl taxol.
Background
Paclitaxel is a diterpene alkaloid compound with anticancer activity, and a chemotherapeutic drug with cytotoxic effect on a plurality of tumor cells, and multiple studies prove clinically that the paclitaxel is often used in combination with other chemotherapeutic drugs, and the paclitaxel is mainly used for treating breast cancer, ovarian malignant tumor and lung malignant tumor, and can also be used for treating malignant tumors of the urinary system, such as bladder cancer, prostatic cancer and the like. It also has therapeutic effect on malignant tumor of head and neck, and paclitaxel of late stage gastric cancer patients.
The diterpenoid compound with unique anticancer activity is extracted from the bark of Pacific yew (Taxus brevifolia), and can be used for treating ovarian cancer and breast cancer which are ineffective in conventional chemotherapy.
Paclitaxel is a diterpenoid compound which is separated from taxus plants in taxus family and has a taxane unique skeleton, is a high-efficiency cytotoxin and has a unique anticancer mechanism, is a new anticancer drug which has a unique anticancer mechanism and follows doxorubicin and cisplatin, acts on tubulin, promotes the tubulin to polymerize into microtubules, the microtubules are different from common microtubules, the microtubules are fibrin of eukaryotic cells, the microtubules can depolymerize after mitosis to regenerate the tubulin and are closely related to the mitosis of the cells, and for rapidly dividing tumor cells, the paclitaxel 'freezes' mitotic spindle, so that the tumor cells stop at G2 phase and M phase, and the cancer cells die.
The 10-deacetyl taxol is taken as an analogue of taxol, is included as taxol impurity by United states pharmacopoeia and European Union pharmacopoeia, is strictly controlled, a large amount of 10-deacetyl taxol is needed to be calibrated in the links of taxol research, development, production, detection and the like, the 10-deacetyl taxol in a taxus mountain is low in content and high in extraction difficulty and is not beneficial to commercial production, and the method for synthesizing the 10-deacetyl taxol by using the 10-deacetyl baccatin III seat starting raw material with high content in the taxus is simple in process, operated and beneficial to commercial amplification production.
The 10-deacetyltaxol is white powder substance with English name of 10-O-deacetylpaclitaxel and CAS number of 78432-77-6 and molecular formula of C45H49NO13811.86946, structural formula:
disclosure of Invention
The present invention is directed to a method for preparing 10-deacetyl paclitaxel, which solves the problems of the background art mentioned above.
In order to achieve the purpose, the invention provides the following technical scheme:
a method for preparing 10-deacetyl paclitaxel, comprising the steps of:
(1) Dissolving 10-deacetylbaccatin III as a raw material by using anhydrous dichloromethane, adding pyridine, and dropwise adding 2, 2-trichloroethyl chloroformate at the temperature of between 20 ℃ below zero and 3 ℃ under the stirring condition; after the dropwise addition, naturally heating to room temperature for reaction; after the reaction is finished, sequentially using water and saturated salt solution to extract and wash a reaction mixture system, and sequentially drying, filtering, decompressing, concentrating and drying the reaction mixture system subjected to extraction and washing treatment by adopting anhydrous sodium sulfate to obtain powder I;
(2) Putting the powder I obtained in the step (1) into anhydrous dichloromethane, and stirring at normal temperature; adding a paclitaxel side chain, stirring until the solution is white slurry, continuously adding a catalyst DMAP-DCC into the solution, and gradually converting the solution from the white slurry into a light yellow turbid solution; filtering with diatomite as a filter aid after the reaction is finished, washing a filter cake with dichloromethane, combining the filtrate and a washing solution, and sequentially treating the filtrate and the washing solution as follows: extracting with water and saturated saline solution, washing, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and draining to obtain powder II;
(3) Dissolving the powder II in the step (2) by using anhydrous acetone, stirring at normal temperature, adding hydrochloric acid to adjust the pH value, reacting for 1-2h, adding a saturated sodium acetate solution, and adjusting the pH value; sequentially adding glacial acetic acid and zinc powder, and continuously reacting for 3-4h; filtering zinc powder, washing a filter cake by using acetone, combining a filtrate and a washing solution, adding the filtrate and the washing solution into ice water in a stirring state, and standing; after 3.5-4.5h, filtering and drying a filter cake to obtain a 10-deacetyl taxol crude product;
(4) Dissolving the 10-deacetyl taxol crude product in the step (3) by using chloroform, then carrying out column chromatography separation by using a mixed solvent of chloroform and isopropanol, and carrying out reduced pressure concentration and suction drying on the obtained fraction to obtain a dry distillation product; dissolving the dry distillate with acetonitrile, adding n-hexane, and standing; filtering the mixture system of acetonitrile, normal hexane and dry distillate, and drying the filter cake under reduced pressure to obtain the finished product of 10-deacetylated taxol.
As a preferable technical scheme of the invention, the dosage ratio of the 10-deacetylbaccatin III, the anhydrous dichloromethane, the pyridine and the chloroformic acid-2, 2-trichloroethyl ester in the step (1) is 1.10 ml to 1.2 ml.
As a preferable technical scheme of the invention, the dosage ratio of the powder I, the anhydrous dichloromethane, the paclitaxel side chain, the DMAP and the DCC in the step (2) is 1g.
As a preferable technical scheme of the invention, the dosage ratio of the powder II, the acetone, the glacial acetic acid and the zinc powder in the step (3) is 1g; and (4) adding hydrochloric acid to adjust the pH value to be 0.9-1.0 in the step (3), and adding saturated sodium acetate to adjust the pH value to be 5.0-5.4.
As a preferable technical scheme of the invention, the dosage ratio of the powder II to the ice water in the step (3) is 1g.
In a preferred embodiment of the present invention, in the step (4), the volume ratio of chloroform to isopropanol is 80.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a preparation method of 10-deacetyl taxol, which takes 10-deacetylbaccatin III extracted and purified from taxus chinensis plants as a raw material, and performs protection, esterification, hydrolysis, deprotection and other reactions in the presence of chloroformic acid-2, 2-trichloroethyl ester to obtain a 10-deacetyltaxol crude product, and the 10-deacetyltaxol crude product is further purified through column chromatography and recrystallization to obtain a 10-deacetyltaxol finished product. The method reduces the synthesis difficulty, is simple and easy to operate, and has high purification efficiency and high yield.
Detailed Description
In order to make those skilled in the art better understand the technical solutions of the embodiments of the present application, the following will clearly and completely describe the technical solutions in the embodiments of the present application, and it is obvious that the described embodiments are only a part of the embodiments of the present application, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
It should be noted that, in the present application, the embodiments and features of the embodiments may be combined with each other without conflict, and the present application will be described in detail with reference to the embodiments.
Dissolving 150g of 10-deacetylbaccatin III with the content of 99.7% in a 5000ml reactor by using 3000ml of anhydrous dichloromethane, stirring for 5min, adding 150ml of pyridine, continuing stirring, adjusting the temperature, cooling the temperature of the material to-10 ℃, slowly dripping 180ml of chloroformic acid-2, 2-trichloroethyl ester at a controlled flow rate, naturally heating to room temperature after dripping is finished, monitoring the reaction process by TLC, and after 2.2 hours, removing the raw materials, wherein the reaction is finished; then, the reaction mixture system is sequentially extracted and washed by 1500ml of water and 1500ml of saturated salt solution, the reaction mixture system subjected to extraction and washing treatment is dried and filtered by 100g of anhydrous sodium sulfate, and is decompressed, concentrated and dried to obtain 236.1g of white-like powder I, the content of the intermediate product I is 97.1 percent, and the yield of the intermediate product I is 95.8 percent by HPLC detection;
weighing 230g of off-white powder I produced in the steps, dissolving in a 5000ml reactor by 3500ml of anhydrous dichloromethane, stirring uniformly at normal temperature, continuously adding 230g of paclitaxel side chain, stirring for 10min, continuously adding 5.75g of DMAP and 230g of DCC, monitoring by TLC, and after 1.8h, the raw material disappears, at the moment, the reaction is finished; filtering with filter aid diatomite after the reaction is finished; washing the filter cake with 2000ml dichloromethane, combining the filtrate and the washing liquid, extracting and washing with 2000ml water and 2000ml saturated salt solution in turn, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure and pumping to obtain light yellow powder II of 308.2g; detecting the powder II by HPLC, wherein the content of the second intermediate product is 94.3 percent, and the yield of the second intermediate product is 93.7 percent;
weighing 300g of light yellow powder (V), dissolving the light yellow powder (V) in a 5000ml reactor by using 3000ml of acetone, stirring at normal temperature, adding 104ml of hydrochloric acid, adjusting the pH value to 1.0, reacting for 1.9h, and detecting the disappearance of the raw materials by TLC (thin layer chromatography); adding 320ml of saturated sodium acetate solution, adjusting the pH value to 5.2, then sequentially adding 600ml of glacial acetic acid and 300g of zinc powder, continuing to react for 3.6h, and detecting the disappearance of the raw materials through TLC (thin layer chromatography) to complete the reaction; filtering, filtering to remove zinc powder, washing the filter cake with 1000ml of acetone, combining the filtrate and the washing liquid, adding into 4500ml of ice water under the stirring state, and crystallizing by water; after 4h, filtering and drying a filter cake to obtain 274.4g of 10-deacetyl taxol crude product, wherein HPLC detection shows that the 10-deacetyl taxol content in the 10-deacetyl taxol crude product is 82.3 percent, and the 10-deacetyl taxol yield is 88.7 percent;
weighing 270g of 10-deacetylated taxol crude product, dissolving the crude product with 3000ml of chloroform, and then carrying out column chromatography separation by adopting a mixed solvent, wherein the total mass of silica gel of the mixed solvent is 4000g, the particle size of silica gel particles is 200-300 meshes, and the solvent is a mixed solvent of chloroform and isopropanol in a volume ratio of 80ml; and carrying out vacuum concentration and pumping drying on fractions obtained by the mixed solvent column chromatography separation to obtain a dry distillate, dissolving the dry distillate by using 3000ml of acetonitrile, then adding 300ml of n-hexane, standing for 8 hours, filtering a mixture system of the acetonitrile, the n-hexane and the dry distillate, and carrying out vacuum drying on an obtained filter cake to obtain 188.9g of 10-deacetylated taxol, wherein the content of the 10-deacetylated taxol is 98.9 percent and the yield is 84.1 percent through HPLC detection.
Therefore, the present invention is not limited to the above embodiments, and any person skilled in the art can substitute or change the technical solution of the present invention and the inventive concept within the technical scope of the present invention.
Claims (6)
1. A preparation method of 10-deacetyl taxol is characterized by comprising the following steps:
(1) Dissolving 10-deacetylbaccatin III as a raw material by using anhydrous dichloromethane, adding pyridine, and dropwise adding 2, 2-trichloroethyl chloroformate at the temperature of-20-3 ℃ under the stirring condition; after the dropwise addition, naturally heating to room temperature for reaction; after the reaction is finished, sequentially using water and saturated salt solution to extract and wash a reaction mixture system, and sequentially drying, filtering, decompressing, concentrating and drying the reaction mixture system subjected to extraction and washing treatment by adopting anhydrous sodium sulfate to obtain powder I;
(2) Putting the powder I obtained in the step (1) into anhydrous dichloromethane, and stirring at normal temperature; adding a paclitaxel side chain, stirring until the solution is white slurry, continuously adding a catalyst DMAP-DCC into the solution, and gradually converting the solution from the white slurry into a light yellow turbid solution; filtering with diatomite as a filter aid after the reaction is finished, washing a filter cake with dichloromethane, combining the filtrate and a washing solution, and sequentially treating the filtrate and the washing solution as follows: extracting with water and saturated saline solution, washing, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and draining to obtain powder II;
(3) Dissolving the powder II in the step (2) by using anhydrous acetone, stirring at normal temperature, adding hydrochloric acid to adjust the pH value, reacting for 1-2h, and adding a saturated sodium acetate solution to adjust the pH value; sequentially adding glacial acetic acid and zinc powder, and continuously reacting for 3-4h; filtering zinc powder, washing a filter cake by using acetone, combining a filtrate and a washing solution, adding the filtrate and the washing solution into ice water in a stirring state, and standing; after 3.5-4.5h, filtering and drying a filter cake to obtain a 10-deacetyl taxol crude product;
(4) Dissolving the 10-deacetyl taxol crude product in the step (3) by using chloroform, then carrying out column chromatography separation by using a mixed solvent of chloroform and isopropanol, and carrying out reduced pressure concentration and suction drying on the obtained fraction to obtain a dry distillation product; dissolving the dry distillate with acetonitrile, adding n-hexane, and standing; filtering the mixture system of acetonitrile, normal hexane and dry distillate, and drying the filter cake under reduced pressure to obtain the finished product of 10-deacetylated taxol.
2. The method for preparing 10-deacetyl paclitaxel according to claim 1, wherein the dosage ratio of 10-deacetyl baccatin III, anhydrous dichloromethane, pyridine, chloroformic acid-2, 2-trichloroethyl ester in step (1) is 1.0ml to 1.2 ml.
3. The method for preparing 10-deacetyl paclitaxel according to claim 1, wherein in step (2), the ratio of powder I, anhydrous dichloromethane, paclitaxel side chains, DMAP, and DCC is 1g to 20 ml.
4. The method for preparing 10-deacetyl taxol according to claim 1, wherein in the step (3), the ratio of the powder II, acetone, glacial acetic acid and zinc powder is 1.1 g-1.3 g; and (3) adding hydrochloric acid to adjust the pH value to be 0.9-1.0, and adding saturated sodium acetate to adjust the pH value to be 5.0-5.4.
5. The method for preparing 10-deacetyl paclitaxel according to claim 1, wherein the amount ratio of powder II to ice water in step (3) is 1 g.
6. The method for preparing 10-deacetyl taxol according to claim 1, wherein in the step (4), the volume ratio of chloroform to isopropanol is 80.
Priority Applications (1)
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