CN112592357B - Preparation method of vindesine sulfate - Google Patents
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- CN112592357B CN112592357B CN202011535351.4A CN202011535351A CN112592357B CN 112592357 B CN112592357 B CN 112592357B CN 202011535351 A CN202011535351 A CN 202011535351A CN 112592357 B CN112592357 B CN 112592357B
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Abstract
The invention discloses a preparation method of vindesine sulfate, which comprises the following steps: 1) the preparation method of the crude product of vindesine comprises the following steps: reacting vinblastine sulfate serving as a raw material with an ammonia methanol solution and a methanol solution of methoxy magnesium in a sealed system to obtain a crude product of vindesine; 2) and (3) purifying the crude product of vindesine: purifying the crude product of the vinblastine by a column to obtain a pure product of the vinblastine; 3) the preparation method of the vindesine sulfate comprises the following steps: and carrying out salt forming reaction on the pure vindesine and sulfuric acid to obtain the vindesine sulfate. The method has the advantages of few reaction byproducts, simple operation, low price of required reagents, high product yield and high purity, and is suitable for large-scale production.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of vindesine sulfate.
Background
Vindesine is a semi-synthetic derivative of vinblastine, and has a wider anticancer spectrum than vinblastine and vincristine, high curative effect and low toxicity. The action principle of the compound mainly is to inhibit the polymerization of tubulin in cells, thereby preventing the formation of spindles in mitosis of proliferating cells, stopping the division of tumor cells in the metaphase of mitosis and further achieving the anti-tumor effect. Therefore, the compound has a wide anti-tumor spectrum and is effective on malignant tumors such as non-small cell lung cancer, lymphomelanoma, malignant lymphoma, breast cancer, esophageal cancer and the like. The vindesine structure contains four nitrogen atoms, wherein two of the four nitrogen atoms are alkaline, and the vindesine sulfate can be salified with sulfuric acid to obtain the vindesine sulfate. Vindesine sulfate is white or off-white block or powder, and is easily discolored by light or heat.
The structure of the vindesine sulfate is as shown in formula 1:
the existing vindesine synthesis generally adopts high-purity vinblastine as a raw material, and desacetyl vindesine hydrazide is synthesized first and then the vindesine is obtained. The series of reaction conditions have high requirements and a large number of byproducts, and provide great difficulty for obtaining high-purity vindesine, so the production cost is high, and the industrial production is difficult to realize.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide the preparation method of the vindesine sulfate, which has the advantages of few reaction byproducts, simple operation, low price of required reagents, high product yield and high purity and is suitable for large-scale production.
The purpose of the invention is realized by adopting the following technical scheme:
a method for preparing vindesine sulfate comprises the following steps:
1) the preparation method of the crude product of vindesine comprises the following steps: reacting vinblastine sulfate serving as a raw material with an ammonia methanol solution and a methanol solution of methoxy magnesium in a sealed system to obtain a crude product of vindesine;
2) and (3) purifying the crude product of vindesine: purifying the crude product of the vinblastine by a column to obtain a pure product of the vinblastine;
3) the preparation method of the vindesine sulfate comprises the following steps: and carrying out salt forming reaction on the pure vindesine and sulfuric acid to obtain the vindesine sulfate.
Further, 1) in the preparation step of the crude product of vindesine, the specific preparation process is as follows: adding vinblastine sulfate, ammonia methanol solution and methoxy magnesium methanol solution into a pressure-resistant bottle blown by nitrogen in sequence, sealing after nitrogen replacement, reacting for 12 hours at 73-78 ℃, distilling the reaction system under reduced pressure until the reaction system is dry after the reaction is finished, adding an organic solvent a and a half-saturated ammonium chloride solution for extraction to obtain an organic phase, washing the organic phase once with purified water, drying with anhydrous sodium sulfate, filtering, and concentrating until the organic phase is dry to obtain a crude product of vindesine.
Further, in 1) the preparation step of the crude product of vindesine, the mass-to-volume ratio of the vinblastine sulfate to the methanolic ammonia solution is 1: (9-12) g/ml, wherein the molar volume ratio of ammonia to methanol in the ammonia-methanol solution is 7:500 mol/ml; the mass volume ratio of the vinblastine sulfate to the methoxy magnesium in the methanol solution is 1: (2-3) g/ml; the concentration of the methanolic magnesium methoxide solution is 7-8 wt%.
Further, in 1) the preparation step of the crude product of vindesine, the organic solvent a refers to dichloromethane, chloroform or ethyl acetate, and the mass-to-volume ratio of the vinblastine sulfate to the organic solvent a is 1: (20-25) g/ml.
Further, in 1) the preparation step of the crude product of vindesine, the mass-to-volume ratio of the vinblastine sulfate to the semi-saturated ammonium chloride solution is 1: (10-20) g/ml.
Further, 1) during the preparation step of the crude product of vindesine, silica gel GF254 thin-layer chromatography is used for detection, 1ml of reaction solution is absorbed by a suction pipe, the thin-layer chromatography is used for detection, a developing agent is a mixed solution of dichloromethane, methanol and ethyl acetate in a volume ratio of 8:1:1, vinblastine sulfate is used as a self control, about 20 mul and 20 mul of sample solution are respectively absorbed and spotted on the same thin-layer plate, and the reaction is finished when the control cannot be basically seen in a sample spot under an ultraviolet lamp with the wavelength of 254 nm.
Further, in 1) the preparation step of the crude product of vindesine, the purity of the vinblastine sulfate is more than or equal to 90%.
Further, 2) in the purification step of the crude product of vindesine, the preparation process comprises the following steps: loading 100-mesh 200-mesh silica gel into a column, wherein the using amount of the silica gel is 15-18 times of the mass of the crude product of the vindesine, washing the column by using dichloromethane, dissolving a sample by using dichloromethane, then loading the sample, adopting a mixed solution of dichloromethane and methanol chloride as an eluent, wherein the volume ratio of the dichloromethane to the methanol chloride is gradually increased from 80:1 to 40:1, washing, determining the position of a target product by using thin-layer chromatography, using a mixed solution of dichloromethane, ethyl acetate and methanol in the volume ratio of 1:1:0.1 as a developing agent, combining collected liquids of the vindesine, and carrying out reduced pressure distillation to obtain a pure product of the vindesine.
Further, 3) the preparation steps of vindesine sulfate include the following specific preparation processes: under the protection of nitrogen, dissolving the pure vindesine sulfate with 8-10 times of absolute ethyl alcohol, slowly dropwise adding a sulfuric acid absolute ethyl alcohol solution in an ice water bath until the pH value of the solution is 3.8-4.0, heating to 25-30 ℃, stirring for 1h, dropwise adding 20-25 times of organic solvent b into the system at the temperature, cooling to 0-5 ℃, stirring for 2h at the temperature, performing suction filtration, and drying under reduced pressure at room temperature to obtain the vindesine sulfate.
Further, 3) in the step of preparing vindesine sulfate, the organic solvent b is ethyl acetate, methyl tert-butyl ether or diethyl ether.
Compared with the prior art, the invention has the beneficial effects that:
1. the preparation method of vindesine sulfate comprises the steps of taking vinblastine sulfate as a raw material, reacting the vindesine sulfate with an ammonia methanol solution and a methoxy magnesium methanol solution in a sealed system, directly obtaining vindesine through one-step reaction, purifying the vindesine through a column to obtain a pure vindesine sulfate product, and salifying the vindesine sulfate product with sulfuric acid to obtain the vindesine sulfate product, wherein the purity of the product is up to more than 98.5%. The method has the advantages of few reaction byproducts, simple operation, low price of required reagents and easy realization of enterprise production.
2. The vinblastine sulfate adopted by the invention is a raw material, and the purity requirement is wide and easy to achieve; the adopted reagent has low price, can effectively reduce the production cost and is easy to realize enterprise production. The method adopts a one-step method to directly synthesize the vinblastine, is simple and easy to obtain, has few reaction byproducts and high purity, and provides guarantee for obtaining the high-purity vinblastine; in addition, impurities can be removed more effectively through simple column purification. The invention adopts absolute ethyl alcohol and methyl tert-butyl ether system to form salt, which can play a certain impurity removing effect, and the quality of the final product is far higher than the standard of Chinese pharmacopoeia.
Drawings
FIG. 1 is a liquid chromatogram of vindesine sulfate of example 1.
FIG. 2 is a liquid chromatogram of vindesine sulfate of example 2.
FIG. 3 is a liquid chromatogram of vindesine sulfate from example 3.
Detailed Description
The present invention will be further described with reference to the accompanying drawings and the detailed description, and it should be noted that any combination of the embodiments or technical features described below can be used to form a new embodiment without conflict. Except as specifically noted, the materials and equipment used in this example are commercially available.
A method for preparing vindesine sulfate comprises the following steps:
1) the preparation method of the crude product of vindesine comprises the following steps: reacting vinblastine sulfate serving as a raw material with an ammonia methanol solution and a methanol solution of methoxy magnesium in a sealed system to obtain a crude product of vindesine;
2) and (3) purifying the crude product of vindesine: purifying the crude product of the vinblastine by a column to obtain a pure product of the vinblastine;
3) the preparation method of the vindesine sulfate comprises the following steps: and carrying out salt forming reaction on the pure vindesine and sulfuric acid to obtain the vindesine sulfate.
As a preferred embodiment, 1) the preparation process of the crude vindesine product comprises the following steps: adding vinblastine sulfate, ammonia methanol solution and methoxy magnesium methanol solution into a pressure-resistant bottle blown by nitrogen in sequence, sealing after nitrogen replacement, reacting for 12 hours at 73-78 ℃, distilling the reaction system under reduced pressure until the reaction system is dry after the reaction is finished, adding an organic solvent a and a half-saturated ammonium chloride solution for extraction to obtain an organic phase, washing the organic phase once with purified water, drying with anhydrous sodium sulfate, filtering, and concentrating until the organic phase is dry to obtain a crude product of vindesine.
As a preferred embodiment, 1) in the step of preparing the crude vindesine, the mass-to-volume ratio of the vinblastine sulfate to the methanolic ammonia solution is 1: (9-12) g/ml, wherein the molar volume ratio of ammonia to methanol in the ammonia-methanol solution is 7:500 mol/ml; the mass volume ratio of the vinblastine sulfate to the methoxy magnesium in the methanol solution is 1: (2-3) g/ml; the concentration of the methanolic magnesium methoxide solution is 7-8 wt%.
As a preferred embodiment, 1) in the step of preparing the crude product of vindesine, the organic solvent a refers to dichloromethane, chloroform or ethyl acetate, and the mass-to-volume ratio of the vinblastine sulfate to the organic solvent a is 1: (20-25) g/ml.
As a preferred embodiment, 1) in the step of preparing the crude vindesine, the mass-to-volume ratio of the vinblastine sulfate to the semi-saturated ammonium chloride solution is 1: (10-20) g/ml.
As a preferred embodiment, 1) the preparation step of the crude vindesine product comprises the steps of detecting by silica gel GF254 thin-layer chromatography, sucking 1ml of reaction solution by a pipette, detecting by the thin-layer chromatography, using a mixed solution of dichloromethane, methanol and ethyl acetate with the volume ratio of 8:1:1 as a developing agent, using vinblastine sulfate as a self control, sucking about 20 mul and 20 mul of sample solution respectively, spotting the sample solution on the same thin-layer plate, observing under an ultraviolet lamp with the wavelength of 254nm, and obtaining the reaction when the control is basically not seen in the sample spot.
As a preferred embodiment, 1) in the preparation step of the crude vindesine sulfate, the purity of the vinblastine sulfate is more than or equal to 90%.
As a preferred embodiment, 2) the purification step of the crude vindesine comprises the following specific preparation processes: loading 100-mesh 200-mesh silica gel into a column, wherein the using amount of the silica gel is 15-18 times of the mass of the crude product of the vindesine, washing the column by using dichloromethane, dissolving a sample by using dichloromethane, then loading the sample, adopting a mixed solution of dichloromethane and methanol chloride as an eluent, wherein the volume ratio of the dichloromethane to the methanol chloride is gradually increased from 80:1 to 40:1, washing, determining the position of a target product by using thin-layer chromatography, using a mixed solution of dichloromethane, ethyl acetate and methanol in the volume ratio of 1:1:0.1 as a developing agent, combining collected liquids of the vindesine, and carrying out reduced pressure distillation to obtain a pure product of the vindesine.
As a preferred embodiment, 3) the preparation step of vindesine sulfate comprises the following specific preparation processes: under the protection of nitrogen, dissolving the pure vindesine sulfate with 8-10 times of absolute ethyl alcohol, slowly dropwise adding a sulfuric acid absolute ethyl alcohol solution in an ice water bath until the pH value of the solution is 3.8-4.0, heating to 25-30 ℃, stirring for 1h, dropwise adding 20-25 times of organic solvent b into the system at the temperature, cooling to 0-5 ℃, stirring for 2h at the temperature, performing suction filtration, and drying under reduced pressure at room temperature to obtain the vindesine sulfate.
As a preferred embodiment, 3) the step of preparing vindesine sulfate, the organic solvent b is ethyl acetate, methyl tert-butyl ether or diethyl ether.
The purity detection method of all products in the invention is high performance liquid chromatography, and the specific conditions are as follows: a chromatographic column: pH value enomexLCColumn 250X 4.6 mm; mobile phase: 0.02mol/L dipotassium hydrogen phosphate solution (pH adjusted to 6.6 with phosphoric acid) -methanol (35: 65); flow rate: 1 ml/min; detection wavelength: 270 nm; detecting the temperature: 35 ℃ is carried out.
Example 1:
a method for preparing vindesine sulfate comprises the following steps:
1) the preparation method of the crude product of vindesine comprises the following steps: 1.0g of vinblastine sulfate (purity: 97%), 10ml of methanolic ammonia solution and 2ml of methanolic methoxy magnesium solution were sequentially added to a 50ml pressure-resistant bottle blown with nitrogen, sealed after nitrogen substitution, and reacted at 75 ℃ for 12 hours. The reaction was monitored by thin layer chromatography (dichloromethane: methanol: ethyl acetate 8:1:2) with essentially no starting point. After the reaction is finished, distilling the reaction system under reduced pressure, adding 20ml of dichloromethane and 10ml of half-saturated ammonium chloride solution for extraction, drying the obtained organic phase with anhydrous sodium sulfate, filtering and concentrating to obtain 0.9g of crude product of vinblastine, with purity: 94.4 percent;
2) and (3) purifying the crude product of vindesine: and (3) taking 15g of 100-one 200-mesh silica gel to fill a column, washing the column by using dichloromethane, dissolving the crude vindesine obtained in the step by using dichloromethane, and then loading the crude vindesine. Washing by using an eluent system of dichloromethane/methanol (the mixture ratio is that dichloromethane: methanol is 80:1/40:1), determining the position of a target product by using thin-layer chromatography (a developing agent is that dichloromethane: ethyl acetate: methanol is 2:1:0.4), combining collected liquid of the vindesine, and distilling under reduced pressure to obtain a pure product of the vindesine, wherein the purity is as follows: 98.5 percent.
3) The preparation method of the vindesine sulfate comprises the following steps: under the protection of nitrogen, 0.72mg of pure vindesine and 7ml of absolute ethyl alcohol are added into a 50ml round-bottom flask and stirred until the pure vindesine and the 7ml of absolute ethyl alcohol are dissolved, the system is placed under an ice water bath, 10 percent sulfuric acid absolute ethyl alcohol solution is slowly dripped until the pH value of the solution is 3.8 to 4.0, the temperature is increased to 30 ℃, the stirring is carried out for 1h, 15ml of ethyl acetate is dripped into the system, after the dripping is finished, the temperature is reduced to 0 to 5 ℃, the stirring is carried out for 2h at the temperature, the suction filtration and the reduced pressure drying at room temperature are carried out, and the 0.71mg of the vindesine sulfate is obtained.
In this example, the yield by weight is 100% of the product weight/vinblastine sulfate weight; the weight yield was 0.71 ÷ 1 × 100% ═ 71%.
Referring to fig. 1, the specific test conditions are: a chromatographic column: pH value enomexLCColumn 250X 4.6 mm; mobile phase: 0.02mol/L dipotassium hydrogen phosphate solution (pH adjusted to 6.6 with phosphoric acid) -methanol (35: 65); flow rate: 1 ml/min; detection wavelength: 270 nm; detecting the temperature: 35 ℃ is carried out. The purity of vindesine sulfate is calculated by an area normalization method and is 98.79 percent.
Example 2:
a method for preparing vindesine sulfate comprises the following steps:
1) the preparation method of the crude product of vindesine comprises the following steps: 2.0g of vinblastine sulfate (94% purity), 22ml of methanolic ammonia and 5ml of methanolic methoxy magnesium solution were sequentially added into a 100ml pressure-resistant bottle blown with nitrogen, sealed after nitrogen substitution, and reacted at 75 ℃ for 12 hours. The reaction was monitored by thin layer chromatography (dichloromethane: methanol: ethyl acetate 8:1:2) until no starting material remained. After the reaction is finished, concentrating the reaction system under reduced pressure, adding 50ml of dichloromethane and 20ml of half-saturated ammonium chloride solution for extraction, drying the obtained organic phase with anhydrous sodium sulfate, filtering and concentrating to obtain 1.6g of crude product of vinblastine, with the purity: 92.1 percent;
2) and (3) purifying the crude product of vindesine: and (3) loading 20g of 100-one 200-mesh silica gel into a column, washing the column by using dichloromethane, dissolving the crude vindesine obtained in the step by using dichloromethane, and then loading the crude vindesine. Washing by using a system with eluent dichloromethane/methanol (the mixture ratio is that dichloromethane: methanol is 80:1/40:1), determining the position of a target product by using thin-layer chromatography (the developing agent is dichloromethane: ethyl acetate: methanol is 2:1:0.4), combining collected liquid of the vindesine, and distilling under reduced pressure to obtain 1.2g of pure vindesine product with the purity: 98.4 percent.
3) The preparation method of the vindesine sulfate comprises the following steps: under the protection of nitrogen, 1.2g of pure vindesine and 13mL of absolute ethyl alcohol are added into a 50mL round-bottom flask and stirred until the pure vindesine and the absolute ethyl alcohol are dissolved, the system is placed under an ice water bath, 10% sulfuric acid absolute ethyl alcohol solution is slowly dripped until the pH value of the solution is 3.8-4.0, the temperature is raised to 28 ℃, the stirring is carried out for 1h, 30mL of methyl tert-butyl ether is dripped into the system, then the temperature is reduced to 0-5 ℃, the dripping is finished, the stirring is carried out for 2h at the temperature, the suction filtration is carried out, and the reduced pressure drying is carried out at the room temperature, so that 1.2g of the vindesine sulfate is obtained.
In this example, the yield by weight is 100% of the product weight/vinblastine sulfate weight; the weight yield was 1.2 ÷ 2 × 100% ═ 60%.
Referring to fig. 2, the specific test conditions are: a chromatographic column: pH value enomexLCColumn 250X 4.6 mm; mobile phase: 0.02mol/L dipotassium hydrogen phosphate solution (pH adjusted to 6.6 with phosphoric acid) -methanol (35: 65); flow rate: 1 ml/min; detection wavelength: 270 nm; detecting the temperature: 35 ℃ is carried out. The purity of vindesine sulfate is calculated by an area normalization method and is 98.61%.
Example 3:
a method for preparing vindesine sulfate comprises the following steps:
1) the preparation method of the crude product of vindesine comprises the following steps: 2g of vinblastine sulfate (purity: 98.5%), 23mL of methanolic ammonia, and 6mL of methyloxy-magnesium in methanol were sequentially added to a 100mL pressure-resistant bottle purged with nitrogen, sealed after nitrogen substitution, and reacted at 76 ℃ for 12 hours. The reaction was monitored by thin layer chromatography (dichloromethane: methanol: ethyl acetate 8:1:2) until no starting material remained. After the reaction is finished, concentrating the reaction system under reduced pressure, adding 50mL of dichloromethane and 40mL of half-saturated ammonium chloride solution for extraction, drying the obtained organic phase with anhydrous sodium sulfate, filtering and concentrating to obtain 1.7g of crude product of vinblastine, with the purity: 93.2 percent;
2) and (3) purifying the crude product of vindesine: and (3) loading 30g of 100-one 200-mesh silica gel into a column, washing the column by using dichloromethane, dissolving the crude vindesine obtained in the step by using dichloromethane, and then loading the crude vindesine. Washing by using a system with eluent dichloromethane/methanol (the mixture ratio is that dichloromethane: methanol is 80:1/40:1), determining the position of a target product by using thin-layer chromatography (the developing agent is dichloromethane: ethyl acetate: methanol is 2:1:0.4), combining collected liquid of the vindesine, and distilling under reduced pressure to obtain 1.4g of pure vindesine product with the purity: 98.6 percent.
3) The preparation method of the vindesine sulfate comprises the following steps: under the protection of nitrogen, 1.4g of pure vindesine and 15mL of absolute ethyl alcohol are added into a 50mL round-bottom flask and stirred until the pure vindesine and the absolute ethyl alcohol are dissolved, the system is placed under an ice water bath, the absolute ethyl alcohol solution of sulfuric acid is slowly dripped until the pH value of the solution is 3.8-4.0, the temperature is raised to 30 ℃, the stirring is carried out for 1h, 32mL of diethyl ether is dripped into the system, the temperature is reduced to 0-5 ℃, the temperature is stirred for 2h after the dripping is finished, the filtration is carried out at the temperature, and the reduced pressure drying is carried out at room temperature, so that 1.4g of the vindesine sulfate is obtained.
In this example, the yield by weight is 100% of the product weight/vinblastine sulfate weight; the weight yield was 1.4 ÷ 2 × 100% ═ 70%.
Referring to fig. 3, the specific test conditions are: a chromatographic column: pH value enomexLCColumn 250X 4.6 mm; mobile phase: 0.02mol/L dipotassium hydrogen phosphate solution (pH adjusted to 6.6 with phosphoric acid) -methanol (35: 65); flow rate: 1 ml/min; detection wavelength: 270 nm; detecting the temperature: 35 ℃ is carried out. The purity of vindesine sulfate is calculated by an area normalization method and is 98.73 percent.
And (3) performance detection:
the vindesine sulfate prepared in the examples 1-3 was tested according to the Chinese pharmacopoeia 2020 edition, and the specific results are shown in Table 1.
TABLE 1
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention should not be 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 (5)
1. A preparation method of vindesine sulfate is characterized by comprising the following steps:
1) the preparation method of the crude product of vindesine comprises the following steps: reacting vinblastine sulfate serving as a raw material with an ammonia methanol solution and a methanol solution of methoxy magnesium in a sealed system to obtain a crude product of vindesine; the preparation process comprises the following steps: sequentially adding vinblastine sulfate, an ammonia methanol solution and a methanol solution of methoxy magnesium into a pressure-resistant bottle blown by nitrogen, sealing after nitrogen replacement, reacting at 73-78 ℃ for 12 hours, after the reaction is finished, distilling the reaction system under reduced pressure to dryness, adding an organic solvent a and a half-saturated ammonium chloride solution for extraction to obtain an organic phase, washing the organic phase once with purified water, drying with anhydrous sodium sulfate, filtering, and concentrating to dryness to obtain a crude product of vindesine; the mass volume ratio of the vinblastine sulfate to the ammonia methanol solution is 1: (9-12) g/ml, wherein the molar volume ratio of ammonia to methanol in the ammonia-methanol solution is 7:500 mol/ml; the mass volume ratio of the vinblastine sulfate to the methoxy magnesium in the methanol solution is 1: (2-3) g/ml; the concentration of the methanol solution of the methoxyl magnesium is 7-8 wt%;
2) and (3) purifying the crude product of vindesine: purifying the crude product of the vinblastine by a column to obtain a pure product of the vinblastine; the preparation process comprises the following steps: loading 100-mesh 200-mesh silica gel into a column, wherein the using amount of the silica gel is 15-18 times of the mass of the crude product of the vindesine, washing the column by using dichloromethane, dissolving a sample by using dichloromethane, then loading the sample, adopting a mixed solution of dichloromethane and methanol chloride as an eluent, wherein the volume ratio of the dichloromethane to the methanol chloride is gradually increased from 80:1 to 40:1, washing, determining the position of a target product by using thin-layer chromatography, using a mixed solution of dichloromethane, ethyl acetate and methanol in the volume ratio of 1:1:0.1 as a developing agent, combining collected liquids of the vindesine, and carrying out reduced pressure distillation to obtain a pure product of the vindesine;
3) the preparation method of the vindesine sulfate comprises the following steps: carrying out salt forming reaction on the pure product of the vindesine and sulfuric acid to obtain the vindesine sulfate; the preparation process comprises the following steps: under the protection of nitrogen, dissolving pure vindesine with 8-10 times of anhydrous ethanol, slowly dropwise adding a sulfuric acid anhydrous ethanol solution in an ice water bath until the pH value of the solution is 3.8-4.0, heating to 25-30 ℃, stirring for 1h, dropwise adding 20-25 times of organic solvent b into the system at the temperature, cooling to 0-5 ℃, stirring for 2h at the temperature, performing suction filtration, and drying under reduced pressure at room temperature to obtain vindesine sulfate; the organic solvent b is ethyl acetate, methyl tert-butyl ether or diethyl ether.
2. The process for the preparation of vindesine sulfate as claimed in claim 1, wherein, in 1) the step of preparing the crude vindesine sulfate, the organic solvent a is dichloromethane, chloroform or ethyl acetate, and the mass-to-volume ratio of the vinblastine sulfate to the organic solvent a is 1: (20-25) g/ml.
3. The process for the preparation of vindesine sulfate as claimed in claim 1, wherein, in 1) the step of preparing the crude vindesine sulfate, the mass-to-volume ratio of vinblastine sulfate to the solution of semi-saturated ammonium chloride is 1: (10-20) g/ml.
4. The process for preparing vindesine sulfate as claimed in claim 1, wherein, in 1) the step of preparing the crude vindesine sulfate, silica gel GF254 thin layer chromatography is used for detection, 1ml of reaction solution is absorbed by a pipette, the detection is carried out by the thin layer chromatography, a developing agent is a mixed solution of dichloromethane, methanol and ethyl acetate with the volume ratio of 8:1:1, vinblastine sulfate is used as a self control, about 20 μ l and 20 μ l of sample solution are respectively absorbed and spotted on the same thin layer plate, and the reaction is finished when the control substance is not substantially seen in the sample spot under an ultraviolet lamp with the wavelength of 254 nm.
5. The process for the preparation of vindesine sulfate as claimed in claim 1, wherein in 1) the step of preparing the crude vindesine sulfate, the purity of vindesine sulfate is not less than 90%.
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| CN101638413B (en) * | 2009-08-28 | 2011-12-14 | 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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