CN107746408B - Purification method of vinblastine sulfate - Google Patents
Purification method of vinblastine sulfate Download PDFInfo
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- CN107746408B CN107746408B CN201710958580.9A CN201710958580A CN107746408B CN 107746408 B CN107746408 B CN 107746408B CN 201710958580 A CN201710958580 A CN 201710958580A CN 107746408 B CN107746408 B CN 107746408B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
Abstract
The invention discloses a vinblastine sulfate purification method which comprises a formylation step, a recrystallization step, an acidification and salification step and a methanol pulping step. The purification method of the invention has simple operation, can obtain the vinblastine sulfate with the purity of more than 98% without column chromatography, simultaneously, the yield can reach 35-50%, the production cost is greatly reduced, and the method has high economic value.
Description
Technical Field
The invention relates to a purification method, in particular to a vinblastine sulfate purification method.
Background
Catharanthus roseus is an important medicinal plant of the genus Catharanthus of the family Apocynaceae, native south Asia, eastern Africa, tropical America and Hainan China. The whole herb of catharanthus roseus can relieve pain, diminish inflammation, promote sleep, relax bowels and promote urination, and the whole herb has toxicity, and can cause symptoms such as leukopenia, thrombocytopenia, myasthenia, limb paralysis and the like after being taken by mistake. Vinca rosea contains dozens of indole alkaloids, of which Vinblastine (LVB) is one of them, has anticancer effect, is an antitumor drug widely used in clinic, and has high medicinal value. Vinblastine Sulfate (Vinblastine Sulfate) is a national basic drug, is mainly suitable for treating hodgkin's disease and malignant lymphoma, can be used for treating choriocarcinoma, breast cancer and other symptoms, can also be used for bronchogenic carcinoma, soft tissue sarcoma, testicular tumor, ovarian cancer, digestive tract cancer, malignant circulating melanoma, neuroblastoma and other symptoms, and is one of the most widely used natural plant anticancer drugs in the world at present.
Because the vinblastine content in the catharanthus roseus is very low and is only a few ten-thousandth, the vinblastine sulfate crude product after extraction and primary salification is only about 60 percent, and the use requirement cannot be met. At present, the purity of vinblastine produced by only a few catharanthus roseus extract manufacturers in China can reach the international standard, but the production cost is high and the profit is low; the crude product of vinblastine produced by most manufacturers cannot meet the requirement of high purity (more than or equal to 98%), and needs to be further purified. The existing purification method mainly removes most impurities by column (silica gel column or alumina column, etc.) purification to obtain relatively high purity, and then obtains a high-purity product (more than or equal to 98 percent) by recrystallization, etc.; but the method has complicated operation steps and low yield (less than 30 percent), and reduces the value of the process production.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide the vinblastine sulfate purification method which is simple to operate, can obtain the vinblastine sulfate with the purity of more than 98% without column chromatography, has the yield of 35% -50%, greatly reduces the production cost and has high economic value.
The purpose of the invention is realized by adopting the following technical scheme:
a method for purifying vinblastine sulfate comprises the following steps:
a formylation step: taking a vinblastine crude product at normal temperature, adding formic acid and acetic anhydride, dissolving, cooling to 0-5 ℃, adding purified water, dropwise adding alkali liquor to adjust the pH to 7-9 to obtain a mixed solution, extracting the mixed solution for three times, combining extraction solutions of the three times, washing with purified water until the pH is neutral, drying with anhydrous sodium sulfate, and concentrating to dryness to obtain a first vinblastine;
a recrystallization step: dissolving the first vinblastine in methanol under heating, cooling to-15 deg.C to-7 deg.C, separating out solid, maintaining the temperature for 2 hr, rapidly filtering to obtain filtrate, and concentrating to dry to obtain second vinblastine;
acidifying and salifying: adding purified water into the second vinblastine, slowly dropwise adding an anhydrous ethanol solution of sulfuric acid under stirring at room temperature until the solution is clear, then adding anhydrous ethanol, stirring at 10-15 deg.C for 4-6h, filtering, washing the filter cake with anhydrous ethanol, and draining to obtain a third vinblastine;
pulping with methanol: adding methanol into the third vinblastine, stirring at 15-20 deg.C for 3 hr, filtering, adding methanol repeatedly, stirring, filtering at least twice, and vacuum drying the filter cake at 55-60 deg.C to obtain vinblastine sulfate.
Further, in the formylation step, the mass-to-volume ratio of the crude vinblastine to formic acid is 1: (1-2) g/mL.
Further, in the formylation step, the mass-to-volume ratio of the crude product of vinblastine to acetic anhydride is 1: (0.5-1) g/mL.
Further, in the formylation step, the mass-to-volume ratio of the crude vinblastine to the purified water is 1: (8-15) g/mL.
Further, in the formylation step, the alkali liquor is ammonia water, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate.
Further, in the formylation step, dichloromethane or trichloromethane is adopted to extract the mixed solution, and the volume ratio of the dichloromethane or trichloromethane to the mixed solution is 1: (40-60).
Further, in the recrystallization step, the mass-to-volume ratio of the first vinblastine to methanol is 1: (2-5) g/mL.
Further, in the step of acidification and salt formation, the mass-volume ratio of the second vinblastine to the purified water is 1: (2-4) g/mL.
Further, in the step of acidification and salt formation, the mass-to-volume ratio of the second vinblastine to the absolute ethyl alcohol solution is 1: (22-26) g/mL.
Further, in the methanol pulping step, the mass volume ratio of the third vinblastine to methanol is 1: (1-5) g/mL.
The invention has the beneficial effects that:
1. the vinblastine sulfate purification method provided by the invention is simple to operate, the vinblastine sulfate with the purity of more than 98% can be obtained without column chromatography, meanwhile, the yield can reach 35% -50%, the production cost is greatly reduced, and the vinblastine sulfate purification method has high economic value;
2. the purification method of the invention does not need to pass through columns (silica gel column, alumina column, chromatographic column, etc.) for separation and purification, about 40 percent of impurities can be removed by methanol recrystallization, and the method provides a premise for obtaining high-purity vinblastine sulfate; meanwhile, the operation is simple, the production is convenient, and the used reagent is environment-friendly;
3. the purification method of the invention adopts the step of pulping methanol, can well remove impurities with properties similar to the properties of vinblastine sulfate, and provides guarantee for obtaining high-purity vinblastine sulfate.
Detailed Description
The present invention is further described below with reference to specific embodiments, and it should be noted that, without conflict, any combination between the embodiments or technical features described below may form a new embodiment.
A method for purifying vinblastine sulfate comprises the following steps:
a formylation step: taking a vinblastine crude product at normal temperature, adding formic acid and acetic anhydride, dissolving, cooling to 0-5 ℃, adding purified water, dropwise adding alkali liquor to adjust the pH to 7-9 to obtain a mixed solution, extracting the mixed solution for three times, combining extraction solutions of the three times, washing with purified water until the pH is neutral, drying with anhydrous sodium sulfate, and concentrating to dryness to obtain a first vinblastine;
a recrystallization step: dissolving the first vinblastine in methanol under heating, cooling to-15 deg.C to-7 deg.C, separating out solid, maintaining the temperature for 2 hr, rapidly filtering to obtain filtrate, and concentrating to dry to obtain second vinblastine;
acidifying and salifying: adding purified water into the second vinblastine, slowly dropwise adding an anhydrous ethanol solution of sulfuric acid under stirring at room temperature until the solution is clear, then adding anhydrous ethanol, stirring at 10-15 deg.C for 4-6h, filtering, washing the filter cake with anhydrous ethanol, and draining to obtain a third vinblastine;
pulping with methanol: adding methanol into the third vinblastine, stirring at 15-20 deg.C for 3 hr, filtering, adding methanol repeatedly, stirring, filtering at least twice, and vacuum drying the filter cake at 55-60 deg.C to obtain vinblastine sulfate.
As a further embodiment, in the formylation step, the mass-to-volume ratio of the crude vinblastine to formic acid is 1: (1-2) g/mL.
As a further embodiment, in the formylation step, the mass-to-volume ratio of the crude vinblastine to acetic anhydride is 1: (0.5-1) g/mL.
As a further embodiment, in the formylation step, the mass-to-volume ratio of the crude vinblastine to the purified water is 1: (8-15) g/mL.
In a further embodiment, the alkali solution in the formylation step is ammonia, sodium carbonate, sodium hydrogen carbonate, potassium carbonate or potassium hydrogen carbonate.
In a further embodiment, in the formylation step, the mixed solution is extracted with dichloromethane or trichloromethane, and the volume ratio of the dichloromethane or trichloromethane to the mixed solution is 1: (40-60).
As a further embodiment, in the recrystallization step, the mass to volume ratio of the first vinblastine to methanol is 1: (2-5) g/mL.
As a further embodiment, in the step of acidifying to form salts, the mass-to-volume ratio of the second vinblastine to the purified water is 1: (2-4) g/mL.
As a further embodiment, in the step of acidifying to form salts, the mass-to-volume ratio of the second vinblastine to the absolute ethanol solution is 1: (22-26) g/mL.
As a further embodiment, in the methanol pulping step, the mass-to-volume ratio of the third vinblastine to methanol is 1: (1-5) g/mL.
The following are specific examples of the present invention, and raw materials, equipments and the like used in the following examples can be obtained by purchasing them unless otherwise specified.
Example 1:
a method for purifying vinblastine sulfate comprises the following steps:
a formylation step: taking 10.0g (with the content of 34%) of crude vinblastine at normal temperature, adding 20mL of formic acid and 10mL of acetic anhydride, dissolving, cooling to 3 ℃, stirring for reaction for 30min, adding 100mL of purified water, dropwise adding ammonia water to adjust the pH value to 8, extracting for three times by using 500mL of dichloromethane, combining extract liquor, washing with purified water until the pH value is neutral, drying by using anhydrous sodium sulfate, and concentrating to dryness to obtain 11.8g of first vinblastine;
a recrystallization step: dissolving the first vinblastine in 25mL of methanol under stirring and heating, cooling to-15 deg.C to-7 deg.C to precipitate solid, maintaining the temperature for 2 hr, rapidly filtering to obtain filtrate, and concentrating to dry to obtain 5.8g of second vinblastine with purity of 73.7%;
acidifying and salifying: adding 15mL of purified water into the second vinblastine, and slowly dropwise adding a 5% sulfuric acid absolute ethyl alcohol solution at room temperature while stirring until the vinblastine solution becomes clear; adding 140mL of absolute ethyl alcohol, stirring for 5 hours at 12 ℃, filtering, washing a filter cake with a small amount of absolute ethyl alcohol, and pumping to dry to obtain 5.1g of third vinblastine;
pulping with methanol: taking the third vinblastine, adding 10mL of methanol, stirring for 3h at 15 ℃, filtering, adding 8mL of methanol for the second time, adding 5mL of methanol for the third time, filtering to obtain a filter cake, and vacuum drying for 4h at 55 ℃ to obtain 1.4g of vinblastine sulfate, wherein the purity is 98.2%, and the yield is 36.8%.
Example 2:
a method for purifying vinblastine sulfate comprises the following steps:
a formylation step: taking 10.1g (the content is 35%) of crude vinblastine, adding 11mL of formic acid and 6mL of acetic anhydride, dissolving, cooling to 0 ℃, stirring for reaction for 50min, adding 110mL of purified water, dropwise adding ammonia water to adjust the pH value to 9, extracting for three times by using 500mL of dichloromethane, combining extract liquids, washing with purified water until the pH value is neutral, drying by using anhydrous sodium sulfate, and concentrating to dryness to obtain 10.9g of first vinblastine;
a recrystallization step: dissolving the first vinblastine in 22mL of methanol under stirring and heating, cooling to-12 deg.C to precipitate solid, maintaining the temperature for 2 hr, rapidly filtering to obtain filtrate, and concentrating to dry to obtain second vinblastine 5.3g with purity of 74.7%;
acidifying and salifying: adding 12mL of purified water into the second vinblastine, and slowly dropwise adding an 8% sulfuric acid absolute ethyl alcohol solution at room temperature while stirring until the vinblastine solution becomes clear; adding 130mL of absolute ethyl alcohol, stirring for 6 hours at 12 ℃, filtering, washing a filter cake with a small amount of absolute ethyl alcohol, and draining to obtain 4.6g of third vinblastine;
pulping with methanol: taking the third vinblastine, adding 10mL of methanol, stirring at 18 ℃ for 3h, filtering, adding 8mL of methanol for the second time, adding 4mL of methanol for the third time, filtering to obtain a filter cake, and vacuum drying at 58 ℃ to obtain 1.5g of vinblastine sulfate, wherein the purity is 98.4%, and the yield is 37.8%.
Example 3:
a method for purifying vinblastine sulfate comprises the following steps:
a formylation step: taking 10.1g (the content is 40%) of crude vinblastine, adding 15mL of formic acid and 7mL of acetic anhydride, dissolving, cooling to 5 ℃, stirring for reaction for 60min, adding 150mL of purified water, dropwise adding ammonia water to adjust the pH value to 9, extracting for three times by using 600mL of dichloromethane, combining extract liquids, washing with purified water until the pH value is neutral, drying by using anhydrous sodium sulfate, and concentrating to dryness to obtain 11.8g of first vinblastine;
a recrystallization step: dissolving the first vinblastine in 25mL of methanol under stirring and heating, cooling to-7 deg.C to precipitate solid, maintaining the temperature for 2 hr, rapidly filtering to obtain filtrate, and concentrating to dry to obtain second vinblastine 5.8g with purity of 78.1%;
acidifying and salifying: adding 13mL of purified water into the second vinblastine, and slowly dropwise adding an 8% sulfuric acid absolute ethyl alcohol solution at room temperature while stirring until the vinblastine solution becomes clear; adding 150mL of absolute ethyl alcohol, stirring for 6 hours at 15 ℃, filtering, washing a filter cake with a small amount of absolute ethyl alcohol, and pumping to dryness to obtain 5.1g of third vinblastine;
pulping with methanol: adding 10mL of methanol into the third vinblastine, stirring at 20 ℃ for 3h, filtering, adding 8mL of methanol into the second time and 5mL of methanol into the third time, and vacuum drying the filter cake obtained by filtering at 60 ℃ to obtain 1.8g of vinblastine sulfate, wherein the purity is 98.5% and the yield is 40.0%.
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.
Claims (4)
1. A method for purifying vinblastine sulfate is characterized by comprising the following steps:
a formylation step: taking a vinblastine crude product at normal temperature, adding formic acid and acetic anhydride, dissolving, cooling to 0-5 ℃, adding purified water, dropwise adding alkali liquor to adjust the pH to 7-9 to obtain a mixed solution, extracting the mixed solution for three times by adopting dichloromethane or trichloromethane, combining extracted solutions for three times, washing with purified water until the pH is neutral, drying by using anhydrous sodium sulfate, and concentrating to dryness to obtain first vinblastine; wherein the mass volume ratio of the crude product of vinblastine to formic acid is 1: (1-2) g/mL; the mass volume ratio of the vinblastine crude product to the acetic anhydride is 1: (0.5-1) g/mL; the volume ratio of the dichloromethane or the trichloromethane to the mixed solution is 1: (40-60);
a recrystallization step: dissolving the first vinblastine in methanol under heating, cooling to-15 deg.C to-7 deg.C, separating out solid, maintaining the temperature for 2 hr, rapidly filtering to obtain filtrate, and concentrating to dry to obtain second vinblastine; the mass volume ratio of the first vinblastine to the methanol is 1: (2-5) g/mL;
acidifying and salifying: adding purified water into second vinblastine, slowly dropwise adding a sulfuric acid absolute ethyl alcohol solution under stirring at room temperature until the solution is clear, and then adding absolute ethyl alcohol, wherein the mass-to-volume ratio of the second vinblastine to the absolute ethyl alcohol solution is 1: (22-26) g/mL, stirring for 4-6h at 10-15 ℃, filtering, washing a filter cake with absolute ethyl alcohol, and draining to obtain a third vinblastine;
pulping with methanol: adding methanol into the third vinblastine, stirring at 15-20 deg.C for 3 hr, filtering, repeatedly adding methanol, stirring, filtering at least twice, and vacuum drying the filter cake at 55-60 deg.C to obtain vinblastine sulfate; wherein the mass volume ratio of the third vinblastine to the methanol is 1: (1-5) g/mL.
2. The process for the purification of vinblastine sulfate according to claim 1, characterized in that: in the formylation step, the mass-to-volume ratio of the vinblastine crude product to the purified water is 1: (8-15) g/mL.
3. The process for the purification of vinblastine sulfate according to claim 1, characterized in that: in the formylation step, the alkali liquor is ammonia water, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate.
4. The process for the purification of vinblastine sulfate according to claim 1, characterized in that: in the step of acidification and salt formation, the mass-volume ratio of the second vinblastine to the purified water is 1: (2-4) g/mL.
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Citations (2)
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| CN1724539A (en) * | 2005-07-13 | 2006-01-25 | 东北林业大学 | Purification method of catharanthine and vincristine |
| CN101638413A (en) * | 2009-08-28 | 2010-02-03 | 广州汉方现代中药研究开发有限公司 | Separation and purification method for vinca alkaloids |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1724539A (en) * | 2005-07-13 | 2006-01-25 | 东北林业大学 | Purification method of catharanthine and vincristine |
| CN101638413A (en) * | 2009-08-28 | 2010-02-03 | 广州汉方现代中药研究开发有限公司 | Separation and purification method for vinca alkaloids |
Non-Patent Citations (4)
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| 醛基长春碱的一种新来源;荘有才;《药学学报》;19820131;第17卷(第1期);第38-40页 * |
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