CN112552319A - Preparation method of vinorelbine tartrate - Google Patents
Preparation method of vinorelbine tartrate Download PDFInfo
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- CN112552319A CN112552319A CN202011535083.6A CN202011535083A CN112552319A CN 112552319 A CN112552319 A CN 112552319A CN 202011535083 A CN202011535083 A CN 202011535083A CN 112552319 A CN112552319 A CN 112552319A
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Abstract
The invention discloses a preparation method of vinorelbine tartrate, which comprises the following steps: 1) the preparation method of the dehydrated vinblastine comprises the following steps: the method comprises the following steps of (1) taking vinblastine sulfate and vindoline as initial raw materials, and obtaining dehydrated vinblastine through iron trichloride catalysis and sodium borohydride reduction; 2) bromo-dehydrated vinblastine preparation steps: carrying out bromination reaction on the dehydrated vinblastine and N-bromosuccinimide to obtain a brominated dehydrated vinblastine crude product; purifying the bromo-dehydrated vinblastine crude product by a column to improve the purity of the bromo-dehydrated vinblastine crude product to obtain bromo-dehydrated vinblastine; 3) the preparation method of vinorelbine comprises the following steps: carrying out debromination rearrangement on the bromo-dehydrated vinblastine and the aqueous solution of silver tetrafluoroborate to obtain a crude product of vinorelbine; recrystallizing the crude product of vinorelbine to obtain a pure product of vinorelbine; 4) the preparation method of the vinorelbine tartrate comprises the following steps: and carrying out salt forming reaction on the pure vinorelbine and tartaric acid to obtain the vinorelbine tartrate. The method has the advantages of simple operation and less side reaction, greatly improves the purity and the yield, reduces the production cost, 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 vinorelbine tartrate.
Background
Vinorelbine tartrate is a cell cycle specific broad-spectrum antitumor drug, and is first marketed in france in 1989. Its main role is to bind tubulin, thus making the cell mitotically microtubule-forming dysfunctional. Vinorelbine is a vinblastine derivative, and has similar effect to vincristine. Vinorelbine is a cycle specific drug, is clinically used for treating non-small cell lung cancer (NSCLC), breast cancer, ovarian cancer, head and neck phosphorus cancer and leukemia, and also has strong inhibiting effect on small cell lung cancer, colon cancer, brain tumor, malignant melanoma and the like.
At present, the vinorelbine tartrate is reported to be prepared from dehydrated vinblastine (3 ', 4' -anhydrovinblastine), namely, the vinorelbine tartrate is obtained by taking the vinorelbine tartrate as an intermediate through oxidation, ring-opening condensation or rearrangement and the like, and then salifying the vinorelbine tartrate with tartaric acid. The dehydrated Vinblastine can be extracted from natural plant vinca rosea, but because the dehydrated Vinblastine is not stable enough and is difficult to prepare and purify on a large scale, the dehydrated Vinblastine is generally obtained by semi-synthesis by using Vinblastine (Vinblastine) or Vindoline (Vindoline) and Catharanthine (Catharanthine) extracted from the vinca rosea as raw materials.
By combining the existing preparation method, basically, the reaction process has more byproducts which are difficult to control, so that the obtained vinorelbine has low purity and high purification difficulty, thereby having high cost and difficult industrial production.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide the preparation method of the vinorelbine tartrate, which has the advantages of simple operation, less side reaction, greatly improved purity and yield, reduced production cost and suitability for large-scale production.
The purpose of the invention is realized by adopting the following technical scheme:
a preparation method of vinorelbine tartrate is characterized by comprising the following steps:
1) the preparation method of the dehydrated vinblastine comprises the following steps: the method comprises the following steps of (1) preparing dehydrated vinblastine by taking vinblastine sulfate and vindoline as initial raw materials and carrying out iron trichloride catalysis and sodium borohydride reduction;
2) the preparation method of the bromo-dehydrated vinblastine comprises the following steps: carrying out bromination reaction on the dehydrated vinblastine and N-bromosuccinimide (NBS) to obtain a brominated dehydrated vinblastine crude product; purifying the bromo-dehydrated vinblastine crude product by a column to improve the purity of the bromo-dehydrated vinblastine crude product to obtain bromo-dehydrated vinblastine;
3) the preparation method of the vinorelbine comprises the following steps: carrying out debromination rearrangement on the bromo-dehydrated vinblastine and the aqueous solution of silver tetrafluoroborate to obtain a crude product of vinorelbine; recrystallizing the crude product of vinorelbine to obtain a pure product of vinorelbine;
4) the preparation method of the vinorelbine tartrate comprises the following steps: and carrying out salt forming reaction on the pure vinorelbine and tartaric acid to obtain the vinorelbine tartrate.
Further, in the preparation steps of the dehydrated vinblastine, the specific preparation process is as follows:
1-1) preparation of solution A: taking vinblastine sulfate and vindoline, adding an organic solvent a, adding a hydrochloric acid solution, slightly heating, and dissolving at 35-40 ℃ to obtain a solution A; wherein the mass ratio of the vinblastine sulfate to the vindoline is 1: (1-1.2), the mass-volume ratio of the vinblastine sulfate to the organic solvent a is 1: (8-10) g/ml, wherein the mass-volume ratio of the vinblastine sulfate to the hydrochloric acid solution is 1: (3-5) g/ml;
1-2) preparation of liquid B: adding purified water into ferric trichloride, adding a hydrochloric acid solution, and using nitrogen to drive oxygen for 10 minutes; wherein the mass ratio of the vincristine sulfate to the ferric chloride is 1: (4-4.5), the mass-volume ratio of the vinblastine sulfate to the purified water is 1: (100-110) g/ml, wherein the mass-volume ratio of the vincristine sulfate to the hydrochloric acid solution is 1: (2-3) g/ml;
1-3) preparation of solution C: adding purified water into ammonium chloride for dissolving, and using nitrogen to expel oxygen for 10 minutes; wherein the mass ratio of the vincristine sulfate to the ammonium chloride is 1: (5-6), wherein the mass-to-volume ratio of the vincristine sulfate to the purified water is 1: (20-21) g/ml;
1-4) preparation of liquid D: weighing sodium borohydride, and dissolving the sodium borohydride with dilute ammonia water; wherein the mass ratio of the vincristine sulfate to the sodium borohydride is 1: (0.3-0.5), the mass-volume ratio of the vinblastine sulfate to the dilute ammonia water is 1: (15-16) g/ml;
1-5) reaction step: adding the solution A into a stainless steel barrel filled with the solution B in advance, preserving heat in a water bath at 38-40 ℃, stirring and reacting for 60 minutes at 35-40 ℃ under the protection of nitrogen, adding the solution C, mixing uniformly, adding the solution D, and reacting for 10 minutes under continuous stirring; adding dilute ammonia water to pH 7.0-8.0, extracting with organic solvent b for three times, mixing organic solvent extractive solutions, washing with purified water for 1 time, filtering with anhydrous sodium sulfate layer, dewatering, recovering solvent under reduced pressure, and draining to obtain dehydrated vinblastine, charging nitrogen gas, and storing in frozen place with shelf life not longer than 48 hr.
Further, in the step of 1) preparing the dehydrated vinblastine, the organic solvent a is tetrahydrofuran or trifluoroethanol; the organic solvent b is any one of ethyl acetate, dichloromethane, trichloromethane, a mixed solution of methyl tert-butyl ether of dichloromethane with the concentration of 20% and a mixed solution of methyl tert-butyl ether of trichloromethane with the concentration of 20%; the dilute ammonia water is mixed aqueous solution prepared by ammonia water in a volume ratio of 1: 1.
Further, in the step 2) of preparing the bromo-dehydrated vinblastine, the specific preparation process is as follows:
2-1) preparation steps of bromo-dehydrated vinblastine crude product: dissolving the dehydrated vinblastine with dichloromethane to obtain a dichloromethane solution of the dehydrated vinblastine; stirring and cooling to (-5) -0 deg.C, adding precooled dichloromethane solution of trifluoroacetic acid, keeping the temperature for 5 minutes, adding liquid nitrogen to cool to (-70) - (-75) deg.C, adding dichloromethane solution of N-bromosuccinimide, controlling the temperature of the reaction solution to (-70) - (-75) deg.C, after the dichloromethane solution of N-bromosuccinimide is added, keeping the temperature and stirring at (-70) - (-75) deg.C for 60 minutes, sampling, detecting by silica gel GF254 thin-layer chromatography, sucking 5ml of reaction solution by a suction pipe, quickly adding into a mixed solution containing 10ml of saturated sodium bicarbonate solution in advance, shaking to alkalize, detecting by thin-layer chromatography, using a developing agent which is a mixed solution of petroleum ether, diethyl ether and diethylamine with the volume ratio of 2:10:0.5, and taking the raw solution as a self control, respectively sucking 40 mul, 20 mul, 10 mul and 5 mul of alkalized sample liquid on the same thin-layer plate, observing under an ultraviolet lamp with the wavelength of 254nm, finishing the reaction when the strength of the dehydrated alkali spots in 40 mul is less than the strength of the main spots in 5 mul, when the reaction is finished, quickly introducing the reaction liquid into a proper amount of saturated sodium bicarbonate solution, simultaneously stirring and uniformly mixing, controlling the pH value of a water layer to be more than or equal to 7.0, separating a lower organic layer, washing for 1 time by using purified water with the volume equal to 1/3 of the total volume of the reaction liquid, filtering and dehydrating by using anhydrous sodium sulfate, recovering a solvent under reduced pressure, concentrating to be dry, vacuumizing and filling nitrogen and sealing to obtain a crude product of bromo-dehydrated vinblastine, and storing the crude product of the bromo-dehydrated vinblastine in a freezing place.
Further, in the step of 2-1) preparing the crude product of bromo-dehydrated vinblastine,
the addition amount of the dehydrated vinblastine is 0.72 times of the total weight of the vindoline and the vinblastine sulfate;
in the dichloromethane solution of the dehydrated vinblastine, the mass-volume ratio of the dehydrated vinblastine to the dichloromethane is 1: (25-30) g/ml;
in a dichloromethane solution of trifluoroacetic acid, the mass volume ratio of the dehydrated vinblastine to the trifluoroacetic acid is 1 (0.8-1) g/ml; the mass-volume ratio of the dehydrated vinblastine to the dichloromethane is 1: (5-6) g/ml;
in a dichloromethane solution of N-bromosuccinimide, the mass ratio of the dehydrated vinblastine to the N-bromosuccinimide is 1: (0.25-0.30); the mass-volume ratio of the dehydrated vinblastine to the dichloromethane is 1: (15-17) g/ml.
Further, the step of 2) preparing bromo-dehydrated vinblastine also comprises:
2-2) column chromatography purification step of bromo-dehydrated vinblastine crude product:
weighing chromatographic silica gel according to a proportion, stirring uniformly by using dichloromethane to remove bubbles, pouring into a glass column, winding and cooling the chromatographic column at room temperature or by using an ice water circulating hose to cool the chromatographic column, and adding a proper amount of anhydrous sodium sulfate on the top of the column after the column surface is stabilized; the weight ratio of the total weight of vindoline and vinblastine sulfate to silica gel is 1: (10-12);
adding the bromo-dehydrated vinblastine crude product into dichloromethane, slowly adding the top of a silica gel column, eluting with a mixed solution of dichloromethane and methanol after sample liquid is completely discharged, collecting fractions in sections, detecting the fractions by silica gel GF254 thin-layer chromatography, collecting the fractions containing the bromo-dehydrated vinblastine with a developing agent which is a mixed solution of dichloromethane and methanol in a volume ratio of 40:1 by taking a raw liquid as a self control, combining, recovering the solvent under reduced pressure, controlling the water bath temperature below 35 ℃, drying, introducing nitrogen for protection, and storing the obtained pure bromo-dehydrated vinblastine in a freezing place.
Further, 2-2) in the step of column chromatography purification of the crude bromo-dehydrated vinblastine, the mass volume ratio of the crude bromo-dehydrated vinblastine to dichloromethane is 1 (2-3) g/ml; in the mixed liquid of dichloromethane and methanol, the volume ratio of dichloromethane to methanol is gradually increased from 80:1 to 40: 1.
Further, in the step of 3) preparing vinorelbine, the specific preparation process is as follows:
3-1) preparation of crude vinorelbine: dissolving bromo-dehydrated vinblastine with tetrahydrofuran, preheating to 30-35 ℃ under the protection of nitrogen, adding a tetrafluoroborate silver aqueous solution, stirring in a water bath at 30-35 ℃ for reaction for 60 minutes, sampling, detecting by using silica gel GF254 thin-layer chromatography, taking petroleum ether, diethyl ether and diethylamine as developing agents, taking stock solution before reaction as self-contrast, and finishing the reaction when a raw material point basically disappears; vacuum filtering the reaction solution through a Buchner funnel filled with diatomite, introducing a proper amount of saturated sodium bicarbonate solution into the filtrate to enable the pH value of the aqueous solution to be more than or equal to 7.0, extracting the aqueous solution for three times by using an organic solvent c, combining the extracting solutions, washing the extracting solutions once by using purified water, filtering and dehydrating the extracting solutions by using anhydrous sodium sulfate, recovering the solvent under reduced pressure, pumping the solvent to dry, filling nitrogen for protection, and storing the obtained vinorelbine crude product in a freezing place.
Further, in the 3-1) preparation step of the crude vinorelbine product, the mass ratio of the brominated dehydrated vinblastine to the silver tetrafluoroborate in the aqueous solution of the silver tetrafluoroborate is 1: (0.1-0.15), the mass volume ratio of the brominated dehydrated vinblastine to tetrahydrofuran is 1: (30-35) g/ml, wherein the mass-volume ratio of the brominated dehydrated vinblastine to water in the aqueous solution of the silver tetrafluoroborate is 1: 30g/ml, and the organic solvent c is ethyl acetate, dichloromethane or trichloromethane.
Further, in the 3) preparation step of vinorelbine, the method also comprises the following steps:
3-2) a crude product purification step of vinorelbine: weighing a crude product of vinorelbine, dissolving the crude product in acetone under the protection of nitrogen, dropwise adding a first part of diethyl ether at room temperature, standing at 0-10 ℃ for full crystallization for 10-12 h after dropwise adding, filtering, and washing with cold absolute ethyl alcohol; dissolving the crystals with the first part of ethyl acetate, concentrating to dryness, dissolving with the second part of ethyl acetate, dropwise adding the second part of diethyl ether at room temperature, standing at 0-10 deg.C for fully crystallizing for 10-12 h, filtering, and washing with cold anhydrous ethanol to obtain pure vinorelbine.
Further, in the step of 3-2) purifying the crude vinorelbine, the mass ratio of the crude vinorelbine to acetone is 1: (2-5), the mass-to-volume ratio of the crude vinorelbine to the first part of diethyl ether is 1: (10-15) g/ml, wherein the mass ratio of the crude vinorelbine to the first part of ethyl acetate is 1: (1.5-2), the mass ratio of the crude vinorelbine to the second part of ethyl acetate is 1: (1-1.5), the mass-to-volume ratio of the crude vinorelbine to the second part of diethyl ether is 1: 10 g/ml.
Further, in the step of 4) preparing vinorelbine tartrate, the specific preparation process is as follows:
weighing a pure vinorelbine product, dissolving the pure vinorelbine product by using acetone, wherein the mass-volume ratio of the pure vinorelbine product to the acetone is 1: (8-10) g/ml, adding a mixed solution of tartaric acid and acetone with the concentration of 2% in an ice bath under stirring until the pH value of the solution is 3.8-4.0, standing at 0-10 ℃ for about 2-4 hours, then moving to the freezing temperature for continuously standing for 10-16 hours to completely crystallize, filtering, washing, and drying under reduced pressure at 40-45 ℃ to obtain the vinorelbine tartrate.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention takes vinblastine sulfate and vindoline as initial raw materials, and prepares dehydrated vinblastine through ferric trichloride catalysis and sodium borohydride reduction; then carrying out bromination reaction with NBS to obtain bromo-dehydrated vinblastine, and purifying by a column to improve the purity of the vinblastine; debrominating and rearranging with a silver tetrafluoroborate aqueous solution to obtain vinorelbine; recrystallizing the vinorelbine to obtain high-purity vinorelbine, and salifying the vinorelbine with tartaric acid to obtain the vinorelbine tartrate. The method is simple to operate, has few side reactions, greatly improves the purity and the yield, reduces the production cost, and is suitable for large-scale production.
2. The invention increases the concentration of reactants and the reaction temperature in the preparation of the dehydrated vinblastine, can effectively improve the reaction speed and the purity of the product, the purity of the product reaches more than 81 percent, and the operation is simplified. Because the dehydrated vinblastine is a diindolyl polymeric alkaloid, has a plurality of halogenated active sites, and the specificity of the reaction is difficult to control, different halides exist, and the post-treatment is influenced. After the process, most of halogenated impurities are removed by adsorption and impurity removal of chromatographic silica gel, so that the purity of the bromo-dehydrated vinblastine is effectively improved, the efficiency of the next rearrangement reaction is improved, the HPLC content of the crude vinorelbine is averagely more than 85%, the dosage of a noble reagent of silver tetrafluoroborate is greatly reduced, and the production cost is reduced. The purification of the vinorelbine adopts a recrystallization method, so that the purity of the vinorelbine reaches more than 99 percent, the impurities can be effectively removed, and the method is simple and easy to operate, and is beneficial to production amplification. The vinorelbine is salified, and a certain impurity removal effect can be achieved by adopting a single organic solvent, namely acetone; and is also beneficial to the recovery of the solvent, so that the production cost is reduced, and the pollution to the environment is further reduced.
Drawings
FIG. 1 is a liquid chromatogram of vinorelbine tartrate of example 1.
FIG. 2 is a liquid chromatogram of vinorelbine tartrate of example 2.
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 preparation method of vinorelbine tartrate comprises the following steps:
1) the preparation method of the dehydrated vinblastine comprises the following steps: the method comprises the following steps of (1) preparing dehydrated vinblastine by taking vinblastine sulfate and vindoline as initial raw materials and carrying out iron trichloride catalysis and sodium borohydride reduction;
2) the preparation method of the bromo-dehydrated vinblastine comprises the following steps: carrying out bromination reaction on the dehydrated vinblastine and N-bromosuccinimide (NBS) to obtain a brominated dehydrated vinblastine crude product; purifying the bromo-dehydrated vinblastine crude product by a column to improve the purity of the bromo-dehydrated vinblastine crude product to obtain bromo-dehydrated vinblastine;
3) the preparation method of the vinorelbine comprises the following steps: carrying out debromination rearrangement on the bromo-dehydrated vinblastine and the aqueous solution of silver tetrafluoroborate to obtain a crude product of vinorelbine; recrystallizing the crude product of vinorelbine to obtain a pure product of vinorelbine;
4) the preparation method of the vinorelbine tartrate comprises the following steps: and carrying out salt forming reaction on the pure vinorelbine and tartaric acid to obtain the vinorelbine tartrate.
In a preferred embodiment, the preparation process of the dehydrated vinblastine comprises the following steps:
1-1) preparation of solution A: taking vinblastine sulfate and vindoline, adding an organic solvent a, adding a hydrochloric acid solution, slightly heating, and dissolving at 35-40 ℃ to obtain a solution A; wherein the mass ratio of the vinblastine sulfate to the vindoline is 1: (1-1.2), the mass-volume ratio of the vinblastine sulfate to the organic solvent a is 1: (8-10) g/ml, wherein the mass-volume ratio of the vinblastine sulfate to the hydrochloric acid solution is 1: (3-5) g/ml;
1-2) preparation of liquid B: adding purified water into ferric trichloride, adding a hydrochloric acid solution, and using nitrogen to drive oxygen for 10 minutes; wherein the mass ratio of the vincristine sulfate to the ferric chloride is 1: (4-4.5), the mass-volume ratio of the vinblastine sulfate to the purified water is 1: (100-110) g/ml, wherein the mass-volume ratio of the vincristine sulfate to the hydrochloric acid solution is 1: (2-3) g/ml;
1-3) preparation of solution C: adding purified water into ammonium chloride for dissolving, and using nitrogen to expel oxygen for 10 minutes; wherein the mass ratio of the vincristine sulfate to the ammonium chloride is 1: (5-6), wherein the mass-to-volume ratio of the vincristine sulfate to the purified water is 1: (20-21) g/ml;
1-4) preparation of liquid D: weighing sodium borohydride, and dissolving the sodium borohydride with dilute ammonia water; wherein the mass ratio of the vincristine sulfate to the sodium borohydride is 1: (0.3-0.5), the mass-volume ratio of the vinblastine sulfate to the dilute ammonia water is 1: (15-16) g/ml;
1-5) reaction step: adding the solution A into a stainless steel barrel filled with the solution B in advance, preserving heat in a water bath at 38-40 ℃, stirring and reacting for 60 minutes at 35-40 ℃ under the protection of nitrogen, adding the solution C, mixing uniformly, adding the solution D, and reacting for 10 minutes under continuous stirring; adding dilute ammonia water to pH 7.0-8.0, extracting with organic solvent b for three times, mixing organic solvent extractive solutions, washing with purified water for 1 time, filtering with anhydrous sodium sulfate layer, dewatering, recovering solvent under reduced pressure, and draining to obtain dehydrated vinblastine, charging nitrogen gas, and storing in frozen place with shelf life not longer than 48 hr.
As a preferred embodiment, 1) the step of preparing dehydrated vinblastine, the organic solvent a is tetrahydrofuran or trifluoroethanol; the organic solvent b is any one of ethyl acetate, dichloromethane, trichloromethane, a mixed solution of methyl tert-butyl ether of dichloromethane with the concentration of 20% and a mixed solution of methyl tert-butyl ether of trichloromethane with the concentration of 20%; the dilute ammonia water is mixed aqueous solution prepared by ammonia water in a volume ratio of 1: 1.
As a preferred embodiment, 2) the preparation step of bromo-dehydrated vinblastine comprises the following specific preparation processes:
2-1) preparation steps of bromo-dehydrated vinblastine crude product: dissolving the dehydrated vinblastine with dichloromethane to obtain a dichloromethane solution of the dehydrated vinblastine; stirring and cooling to (-5) -0 deg.C, adding precooled dichloromethane solution of trifluoroacetic acid, keeping the temperature for 5 minutes, adding liquid nitrogen to cool to (-70) - (-75) deg.C, adding dichloromethane solution of N-bromosuccinimide, controlling the temperature of the reaction solution to (-70) - (-75) deg.C, after the dichloromethane solution of N-bromosuccinimide is added, keeping the temperature and stirring at (-70) - (-75) deg.C for 60 minutes, sampling, detecting by silica gel GF254 thin-layer chromatography, sucking 5ml of reaction solution by a suction pipe, quickly adding into a mixed solution containing 10ml of saturated sodium bicarbonate solution in advance, shaking to alkalize, detecting by thin-layer chromatography, using a developing agent which is a mixed solution of petroleum ether, diethyl ether and diethylamine with the volume ratio of 2:10:0.5, and taking the raw solution as a self control, respectively sucking 40 mul, 20 mul, 10 mul and 5 mul of alkalized sample liquid on the same thin-layer plate, observing under an ultraviolet lamp with the wavelength of 254nm, finishing the reaction when the strength of the dehydrated alkali spots in 40 mul is less than the strength of the main spots in 5 mul, when the reaction is finished, quickly introducing the reaction liquid into a proper amount of saturated sodium bicarbonate solution, simultaneously stirring and uniformly mixing, controlling the pH value of a water layer to be more than or equal to 7.0, separating a lower organic layer, washing for 1 time by using purified water with the volume equal to 1/3 of the total volume of the reaction liquid, filtering and dehydrating by using anhydrous sodium sulfate, recovering a solvent under reduced pressure, concentrating to be dry, vacuumizing and filling nitrogen and sealing to obtain a crude product of bromo-dehydrated vinblastine, and storing the crude product of the bromo-dehydrated vinblastine in a freezing place.
As a preferred embodiment, in the 2-1) preparation step of the crude bromo-dehydrated vinblastine,
the addition amount of the dehydrated vinblastine is 0.72 times of the total weight of the vindoline and the vinblastine sulfate;
in the dichloromethane solution of the dehydrated vinblastine, the mass-volume ratio of the dehydrated vinblastine to the dichloromethane is 1: (25-30) g/ml;
in a dichloromethane solution of trifluoroacetic acid, the mass volume ratio of the dehydrated vinblastine to the trifluoroacetic acid is 1 (0.8-1) g/ml; the mass-volume ratio of the dehydrated vinblastine to the dichloromethane is 1: (5-6) g/ml;
in a dichloromethane solution of N-bromosuccinimide, the mass ratio of the dehydrated vinblastine to the N-bromosuccinimide is 1: (0.25-0.30); the mass-volume ratio of the dehydrated vinblastine to the dichloromethane is 1: (15-17) g/ml.
As a preferred embodiment, the step of 2) preparing bromodehydrated vinblastine further comprises:
2-2) column chromatography purification step of bromo-dehydrated vinblastine crude product:
weighing chromatographic silica gel according to a proportion, stirring uniformly by using dichloromethane to remove bubbles, pouring into a glass column, winding and cooling the chromatographic column at room temperature or by using an ice water circulating hose to cool the chromatographic column, and adding a proper amount of anhydrous sodium sulfate on the top of the column after the column surface is stabilized; the weight ratio of the total weight of vindoline and vinblastine sulfate to silica gel is 1: (10-12);
adding the bromo-dehydrated vinblastine crude product into dichloromethane, slowly adding the top of a silica gel column, eluting with a mixed solution of dichloromethane and methanol after sample liquid is completely discharged, collecting fractions in sections, detecting the fractions by silica gel GF254 thin-layer chromatography, collecting the fractions containing the bromo-dehydrated vinblastine with a developing agent which is a mixed solution of dichloromethane and methanol in a volume ratio of 40:1 by taking a raw liquid as a self control, combining, recovering the solvent under reduced pressure, controlling the water bath temperature below 35 ℃, drying, introducing nitrogen for protection, and storing the obtained pure bromo-dehydrated vinblastine in a freezing place.
Further, 2-2) in the step of column chromatography purification of the crude bromo-dehydrated vinblastine, the mass-volume ratio of the crude bromo-dehydrated vinblastine to dichloromethane is 1: (2-3) g/ml; in the mixed liquid of dichloromethane and methanol, the volume ratio of dichloromethane to methanol is gradually increased from 80:1 to 40: 1.
As a preferred embodiment, 3) the preparation step of vinorelbine specifically comprises the following steps:
3-1) preparation of crude vinorelbine: dissolving bromo-dehydrated vinblastine with tetrahydrofuran, preheating to 30-35 ℃ under the protection of nitrogen, adding a tetrafluoroborate silver aqueous solution, stirring in a water bath at 30-35 ℃ for reaction for 60 minutes, sampling, detecting by using silica gel GF254 thin-layer chromatography, taking petroleum ether, diethyl ether and diethylamine as developing agents, taking stock solution before reaction as self-contrast, and finishing the reaction when a raw material point basically disappears; vacuum filtering the reaction solution through a Buchner funnel filled with diatomite, introducing a proper amount of saturated sodium bicarbonate solution into the filtrate to enable the pH value of the aqueous solution to be more than or equal to 7.0, extracting the aqueous solution for three times by using an organic solvent c, combining the extracting solutions, washing the extracting solutions once by using purified water, filtering and dehydrating the extracting solutions by using anhydrous sodium sulfate, recovering the solvent under reduced pressure, pumping the solvent to dry, filling nitrogen for protection, and storing the obtained vinorelbine crude product in a freezing place.
As a preferred embodiment, in 3-1) the step of preparing the crude vinorelbine product, the mass ratio of the brominated dehydrated vinblastine to the silver tetrafluoroborate in the aqueous solution of silver tetrafluoroborate is 1: (0.1-0.15), the mass volume ratio of the brominated dehydrated vinblastine to tetrahydrofuran is 1: (30-35) g/ml, wherein the mass-volume ratio of the brominated dehydrated vinblastine to water in the aqueous solution of the silver tetrafluoroborate is 1: 30g/ml, and the organic solvent c is ethyl acetate, dichloromethane or trichloromethane.
As a preferred embodiment, 3) the step of preparing vinorelbine further comprises:
3-2) a crude product purification step of vinorelbine: weighing a crude product of vinorelbine, dissolving the crude product in acetone under the protection of nitrogen, dropwise adding a first part of diethyl ether at room temperature, standing at 0-10 ℃ for full crystallization for 10-12 h after dropwise adding, filtering, and washing with cold absolute ethyl alcohol; dissolving the crystals with the first part of ethyl acetate, concentrating to dryness, dissolving with the second part of ethyl acetate, dropwise adding the second part of diethyl ether at room temperature, standing at 0-10 deg.C for fully crystallizing for 10-12 h, filtering, and washing with cold anhydrous ethanol to obtain pure vinorelbine.
As a preferred embodiment, in 3-2) the step of purifying the crude vinorelbine, the mass ratio of the crude vinorelbine to acetone is 1: (2-5), the mass-to-volume ratio of the crude vinorelbine to the first part of diethyl ether is 1: (10-15) g/ml, wherein the mass ratio of the crude vinorelbine to the first part of ethyl acetate is 1: (1.5-2), the mass ratio of the crude vinorelbine to the second part of ethyl acetate is 1: (1-1.5), the mass-to-volume ratio of the crude vinorelbine to the second part of diethyl ether is 1: 10 g/ml.
As a preferred embodiment, in 4) the preparation step of vinorelbine tartrate, the specific preparation process is as follows:
weighing a pure vinorelbine product, dissolving the pure vinorelbine product by using acetone, wherein the mass-volume ratio of the pure vinorelbine product to the acetone is 1: (8-10) g/ml, adding a mixed solution of tartaric acid and acetone with the concentration of 2% in an ice bath under stirring until the pH value of the solution is 3.8-4.0, standing at 0-10 ℃ for about 2-4 hours, then moving to the freezing temperature for continuously standing for 10-16 hours to completely crystallize, filtering, washing, and drying under reduced pressure at 40-45 ℃ to obtain the vinorelbine tartrate.
As a preferred embodiment, 4) the step of preparing vinorelbine tartrate, the tartaric acid is L- (+) tartaric acid.
Example 1:
a preparation method of vinorelbine tartrate comprises the following steps:
1) the preparation method of the dehydrated vinblastine comprises the following steps: the preparation process comprises the following steps:
1-1) preparation of solution A: taking 4.4g of vindoline and 4g of vincristine sulfate, adding 40ml of tetrahydrofuran, adding 20ml of hydrochloric acid solution, slightly heating, and dissolving at 35-40 ℃.
1-2) preparation of liquid B: 17g of ferric trichloride is taken, 400ml of slightly heated purified water is added, 10ml of hydrochloric acid solution is added, and nitrogen is used for expelling oxygen for about 10 minutes.
1-3) preparation of solution C: taking 25g of ammonium chloride, adding 80ml of slightly heated purified water for dissolving, and adding nitrogen for removing oxygen for about 10 minutes.
1-4) preparation of liquid D: about 1.2g of sodium borohydride was weighed out and dissolved in 70ml of dilute ammonia. The dilute ammonia water is mixed aqueous solution prepared by ammonia water in a volume ratio of 1: 1.
1-5) reaction step: adding the solution A into a stainless steel barrel filled with the solution B in advance, stirring and reacting for 40 minutes at 35-40 ℃ under the protection of nitrogen in a water bath heat preservation at about 38-40 ℃, adding the solution C, mixing uniformly, adding the solution D, and reacting for 10 minutes under continuous stirring. Adding diluted ammonia water to make pH value be 7.0-8.0, extracting with ethyl acetate 300ml solution for three times, mixing upper layer extractive solutions, washing with 50ml purified water for 1 time, filtering and dehydrating with anhydrous sodium sulfate layer, recovering solvent under reduced pressure, and draining to obtain dehydrated vinblastine, which is called 8.5g, and has purity: and (4) filling 82.5% of nitrogen to store in a frozen place, wherein the storage life cannot exceed 48 hours.
2) The preparation method of the bromo-dehydrated vinblastine comprises the following steps:
calculating the amount of dehydrated vinblastine: 6.0 g. Wherein the addition amount of the dehydrated vinblastine is 0.72 times of the total weight of vindoline and vinblastine sulfate.
Preparing a reaction solution:
dehydrated vinblastine in dichloromethane: anhydrovinblastine (m): dichloromethane (v) ═ 6g: 160 ml.
Trifluoroacetic acid in dichloromethane: anhydrovinblastine (m): trifluoroacetic acid (v): dichloromethane (v) ═ 6g: 6 ml: 30 ml.
Dichloromethane solution of N-bromosuccinimide: anhydrovinblastine (m): n-bromosuccinimide (m): dichloromethane (v) ═ 6g:1.6g:90 ml.
2-1) preparation steps of bromo-dehydrated vinblastine crude product: taking 6.0g of dehydrated vinblastine, and dissolving with dichloromethane to obtain dichloromethane solution of the dehydrated vinblastine; stirring and cooling to (-5) -0 deg.C, adding precooled dichloromethane solution of trifluoroacetic acid, keeping the temperature for 5 minutes, adding liquid nitrogen to cool to (-70) - (-75) deg.C, adding dichloromethane solution of N-bromosuccinimide, controlling the temperature of the reaction solution to (-70) - (-75) deg.C, after the dichloromethane solution of N-bromosuccinimide is added, keeping the temperature and stirring at (-70) - (-75) deg.C for 60 minutes, sampling, detecting by silica gel GF254 thin-layer chromatography, sucking 5ml of reaction solution by a suction pipe, quickly adding into a mixed solution containing 10ml of saturated sodium bicarbonate solution in advance, shaking to alkalize, detecting by thin-layer chromatography, using a developing agent which is a mixed solution of petroleum ether, diethyl ether and diethylamine with the volume ratio of 2:10:0.5, and taking the raw solution as a self control, respectively sucking 40 mul, 20 mul, 10 mul and 5 mul of the alkalized sample liquid on the same thin-layer plate, observing under an ultraviolet lamp with the wavelength of 254nm, finishing the reaction when the strength of the dehydrated alkali spots in 40 mul is less than the strength of the main spots in 5 mul, when the reaction is finished, quickly introducing the reaction liquid into a proper amount of saturated sodium bicarbonate solution, simultaneously stirring and uniformly mixing, controlling the pH value of a water layer to be more than or equal to 7.0, separating a lower organic layer, washing for 1 time by using purified water with the volume equal to 1/3 of the total volume of the reaction liquid, filtering and dehydrating by using anhydrous sodium sulfate, recovering the solvent under reduced pressure, concentrating to be dry, vacuumizing and filling nitrogen and sealing to obtain 8.2g of crude bromo-dehydrated vinblastine, placing the crude bromo-dehydrated vinblastine in a freezing place for storage for 48 hours.
2-2) column chromatography purification step of bromo-dehydrated vinblastine crude product:
the loading ratio is that the total weight of the fed vindoline and the vinblastine sulfate is as follows: silica gel (200-300 mesh) (W/W) 8.2: 82 g.
Weighing chromatographic silica gel according to a proportion, stirring uniformly by using dichloromethane to remove bubbles, pouring into a glass column, winding and cooling the chromatographic column at room temperature or by using an ice water circulating hose to cool the chromatographic column, and adding a proper amount of anhydrous sodium sulfate on the top of the column after the column surface is stabilized;
adding a bromo-dehydrated vinblastine crude product into dichloromethane, slowly adding the crude product into a silica gel column top, eluting with a mixed solution of dichloromethane and methanol after a sample solution is completely poured, gradually increasing the volume ratio of dichloromethane to methanol from 80:1 to 40:1, collecting fractions in sections, detecting the fractions by silica gel GF254 thin-layer chromatography, collecting fractions containing the bromo-dehydrated vinblastine with a developing agent of a mixed solution of dichloromethane and methanol in a volume ratio of 40:1 by taking a raw solution as a self contrast, combining the fractions, recovering a solvent under reduced pressure, controlling the water bath temperature below 35 ℃, drying, filling nitrogen for protection, and storing 5.1g of the obtained pure bromo-dehydrated vinblastine in a freezing place. The mass volume ratio of the bromo-dehydrated vinblastine crude product to dichloromethane is 8.2 g: 18 g/ml.
3) The preparation method of the vinorelbine comprises the following steps:
3-1) preparation of crude vinorelbine: dissolving 5.1g of bromo-dehydrated vinblastine with 16ml of tetrahydrofuran, preheating to 30-35 ℃ under the protection of nitrogen, adding a tetrafluoro boron silver aqueous solution, stirring and reacting 0.51g of tetrafluoro boron silver and 15ml of water in the tetrafluoro boron silver aqueous solution in a water bath at 30-35 ℃ for 60 minutes, sampling, detecting by using silica gel GF254 thin-layer chromatography, taking petroleum ether, diethyl ether and diethylamine as developing agents, taking stock solution before reaction as self-contrast, and finishing the reaction when a raw material point basically disappears; vacuum filtering the reaction solution with a Buchner funnel filled with diatomite, introducing a proper amount of saturated sodium bicarbonate solution into the filtrate to ensure that the pH value of the aqueous solution is approximately equal to 9.0, extracting with 300ml of ethyl acetate for three times, combining the extracting solutions, extracting and washing with 60ml of purified water for 1 time, filtering and dehydrating with anhydrous sodium sulfate, recovering the solvent under reduced pressure, pumping out, filling nitrogen for protection, weighing and storing the obtained crude vinorelbine product 4.8g (the purity: 92.0%) in a freezing place.
3-2) a crude product purification step of vinorelbine: weighing a crude product of vinorelbine, dissolving the crude product with 10g of acetone under the protection of nitrogen, dropwise adding 50ml of first part of diethyl ether at room temperature, standing at 0-10 ℃ for full crystallization for 10-12 h after dropwise adding, filtering, and washing with 10ml of cold absolute ethyl alcohol; dissolving the crystal by using 8g of the first part of ethyl acetate, concentrating to be dry, adding 7g of the second part of ethyl acetate for dissolving, dropwise adding 55ml of the second part of ethyl ether at room temperature, standing at 0-10 ℃ after dropwise adding to fully crystallize for 10-12 h, filtering, washing by using 9ml of cold absolute ethyl alcohol to obtain 2.8g of pure vinorelbine product with the purity: 99.1 percent.
4) The preparation method of the vinorelbine tartrate comprises the following steps:
weighing 2.8g of vinorelbine, dissolving the vinorelbine with 25ml of acetone, adding a mixed solution of 2% tartaric acid and acetone in an ice bath under stirring until the pH value of the solution is 3.8-4.0, standing the solution at 0-10 ℃ for about 2-4 hours, then moving the solution to a freezing temperature for continuously standing the solution for 14 hours to completely crystallize, filtering the solution, washing the solution with 20ml of acetone, and drying the solution at 40 ℃ under reduced pressure for 6 hours to obtain the vinorelbine tartrate: 3.0g.
In this example, the yield was 100% by weight of product/(vindoline weight + vinblastine sulfate). The weight yield was 3.0 ÷ (4+4) × 100% ═ 37.5%.
Referring to fig. 1, the specific test conditions are: according to the 2020 version of Chinese pharmacopoeia. The purity was calculated as area normalization with a purity of 99.54%.
Example 2:
a preparation method of vinorelbine tartrate comprises the following steps:
1) the preparation method of the dehydrated vinblastine comprises the following steps: the preparation process comprises the following steps:
1-1) preparation of solution A: 4.4g of vindoline and 4g of vincristine sulfate are taken, 40ml of trifluoroethanol is added, and 20ml of hydrochloric acid solution is added for dissolving by slight heating (35 ℃ -40 ℃).
1-2) preparation of liquid B: 17g of ferric trichloride is taken, 400ml of slightly heated purified water is added, 10ml of hydrochloric acid solution is added, and nitrogen is used for expelling oxygen for about 10 minutes.
1-3) preparation of solution C: taking 25g of ammonium chloride, adding 80ml of slightly heated purified water for dissolving, and adding nitrogen for removing oxygen for about 10 minutes.
1-4) preparation of liquid D: about 1.3g of sodium borohydride was weighed out and dissolved in 70ml of dilute ammonia. The dilute ammonia water is mixed aqueous solution prepared by ammonia water in a volume ratio of 1: 1.
1-5) reaction step: adding the solution A into a stainless steel barrel filled with the solution B in advance, stirring and reacting for 40 minutes at 35-40 ℃ under the protection of nitrogen in a water bath heat preservation at about 38-40 ℃, adding the solution C, mixing uniformly, adding the solution D, and reacting for 10 minutes under continuous stirring. Adding diluted ammonia water to make pH value be 7.0-8.0, extracting with ethyl acetate 300ml solution for three times, mixing upper layer extractive solutions, washing with 50ml purified water for 1 time, filtering and dehydrating with anhydrous sodium sulfate layer, recovering solvent under reduced pressure, and draining to obtain dehydrated vinblastine, which is called 9.0g, and has purity: the product is preserved in a frozen place by filling 83.9% nitrogen, and the preservation period is not more than 48 hours.
2) The preparation method of the bromo-dehydrated vinblastine comprises the following steps:
calculating the amount of dehydrated vinblastine: 6.0 g. Wherein the addition amount of the dehydrated vinblastine is 0.72 times of the total weight of vindoline and vinblastine sulfate.
Preparing a reaction solution:
dehydrated vinblastine in dichloromethane: anhydrovinblastine (m): dichloromethane (v) ═ 6g: 150 ml.
Trifluoroacetic acid in dichloromethane: anhydrovinblastine (m): trifluoroacetic acid (v): dichloromethane (v) ═ 6g: 6 ml: 30 ml.
Dichloromethane solution of N-bromosuccinimide: anhydrovinblastine (m): n-bromosuccinimide (m): dichloromethane (v) ═ 6g:1.8g:91 ml.
2-1) preparation steps of bromo-dehydrated vinblastine crude product: taking 6.0g of dehydrated vinblastine, and dissolving with dichloromethane to obtain dichloromethane solution of the dehydrated vinblastine; stirring and cooling to (-5) -0 deg.C, adding precooled dichloromethane solution of trifluoroacetic acid, keeping the temperature for 5 minutes, adding liquid nitrogen to cool to (-70) - (-75) deg.C, adding dichloromethane solution of N-bromosuccinimide, controlling the temperature of the reaction solution to (-70) - (-75) deg.C, after the dichloromethane solution of N-bromosuccinimide is added, keeping the temperature and stirring at (-70) - (-75) deg.C for 60 minutes, sampling, detecting by silica gel GF254 thin-layer chromatography, sucking 5ml of reaction solution by a suction pipe, quickly adding into a mixed solution containing 10ml of saturated sodium bicarbonate solution in advance, shaking to alkalize, detecting by thin-layer chromatography, using a developing agent which is a mixed solution of petroleum ether, diethyl ether and diethylamine with the volume ratio of 2:10:0.5, and taking the raw solution as a self control, respectively sucking 40 mul, 20 mul, 10 mul and 5 mul of the alkalized sample liquid on the same thin-layer plate, observing under an ultraviolet lamp with the wavelength of 254nm, finishing the reaction when the strength of the dehydrated alkali spots in 40 mul is less than the strength of the main spots in 5 mul, when the reaction is finished, quickly introducing the reaction liquid into a proper amount of saturated sodium bicarbonate solution, simultaneously stirring and uniformly mixing, controlling the pH value of a water layer to be more than or equal to 7.0, separating a lower organic layer, washing for 1 time by using purified water with the volume equal to 1/3 of the total volume of the reaction liquid, filtering and dehydrating by using anhydrous sodium sulfate, recovering the solvent under reduced pressure, concentrating to be dry, vacuumizing and filling nitrogen and sealing to obtain 8.5g of crude bromo-dehydrated vinblastine, placing the crude bromo-dehydrated vinblastine in a freezing place for storage for 48 hours.
2-2) column chromatography purification step of bromo-dehydrated vinblastine crude product:
the loading ratio is that the total weight of the fed vindoline and the vinblastine sulfate is as follows: silica gel (200-300 mesh) (W/W) 8.5: 100 g.
Weighing chromatographic silica gel according to a proportion, stirring uniformly by using dichloromethane to remove bubbles, pouring into a glass column, winding and cooling the chromatographic column at room temperature or by using an ice water circulating hose to cool the chromatographic column, and adding a proper amount of anhydrous sodium sulfate on the top of the column after the column surface is stabilized;
adding the bromo-dehydrated vinblastine crude product into dichloromethane, slowly adding the silica gel column top, eluting with a mixed solution of dichloromethane and methanol after sample liquid is completely discharged, gradually increasing the volume ratio of dichloromethane to methanol from 80:1 to 40:1, collecting fractions in sections, detecting the fractions by silica gel GF254 thin-layer chromatography, collecting fractions containing the bromo-dehydrated vinblastine with a developing agent being a mixed solution of dichloromethane and methanol in a volume ratio of 40:1 by taking a raw liquid as a self contrast, combining the fractions, recovering the solvent under reduced pressure, controlling the water bath temperature below 35 ℃, drying, charging nitrogen gas for protection, and storing the obtained pure bromo-dehydrated vinblastine 5.0g in a freezing place. The mass volume ratio of the crude bromo-dehydrated vinblastine to dichloromethane is 8.5:20 g/ml.
4) The preparation method of the vinorelbine comprises the following steps:
3-1) preparation of crude vinorelbine: dissolving 5.0g of bromo-dehydrated vinblastine with 17ml of tetrahydrofuran, preheating to 30-35 ℃ under the protection of nitrogen, adding a tetrafluoro boron silver aqueous solution, stirring and reacting 0.51g of tetrafluoro boron silver and 15ml of water in the tetrafluoro boron silver aqueous solution in a water bath at 30-35 ℃ for 60 minutes, sampling, detecting by using silica gel GF254 thin-layer chromatography, taking petroleum ether, diethyl ether and diethylamine as developing agents, taking stock solution before reaction as self-contrast, and finishing the reaction when a raw material point basically disappears; vacuum filtering the reaction solution with a Buchner funnel filled with diatomite, introducing a proper amount of saturated sodium bicarbonate solution into the filtrate to ensure that the pH value of the aqueous solution is approximately equal to 9.0, extracting with 300ml of ethyl acetate for three times, combining the extracting solutions, extracting and washing with 60ml of purified water for 1 time, filtering and dehydrating with anhydrous sodium sulfate, recovering the solvent under reduced pressure, pumping out, filling nitrogen for protection, weighing and storing the obtained crude vinorelbine product 4.5g (the purity: 94.3%) in a freezing place.
3-2) a crude product purification step of vinorelbine: weighing 4.5g of crude vinorelbine, dissolving with 10g of acetone under the protection of nitrogen, dropwise adding 50ml of first part of diethyl ether at room temperature, standing at 0-10 ℃ after dropwise adding, fully crystallizing for 12h, filtering, and washing with 10ml of cold anhydrous ethanol; dissolving the crystal by using 8g of the first part of ethyl acetate, concentrating to be dry, adding 6g of the second part of ethyl acetate for dissolving, dropwise adding 55ml of the second part of ethyl ether at room temperature, standing at 0-10 ℃ after dropwise adding to fully crystallize for 12h, filtering, and washing by using 10ml of cold absolute ethyl alcohol to obtain 2.5g of pure vinorelbine product with the purity: 99.3 percent.
4) The preparation method of the vinorelbine tartrate comprises the following steps:
weighing 2.5g of vinorelbine, dissolving the vinorelbine with 25ml of acetone, adding a mixed solution of 2% tartaric acid and acetone in an ice bath under stirring until the pH value of the solution is 3.8-4.0, standing the solution at 0-10 ℃ for about 2-4 hours, then moving the solution to a freezing temperature for continuously standing the solution for 16 hours to completely crystallize, filtering the solution, washing the solution with 20ml of acetone, and drying the solution at 40 ℃ under reduced pressure for 6 hours to obtain the vinorelbine tartrate: 2.8g.
In this example, the yield was 100% by weight of product/(vindoline weight + vinblastine sulfate). The weight yield was 2.8 ÷ (4.4+4) × 100% ═ 33%.
Referring to fig. 2, the specific test conditions are: according to the 2020 version of Chinese pharmacopoeia. The purity was calculated as area normalization with a purity of 99.57%.
And (3) performance detection:
the vinorelbine tartrate prepared in the example 1-2 was tested according to the United states pharmacopoeia 35 edition (usp 35), 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 (10)
1. A preparation method of vinorelbine tartrate is characterized by comprising the following steps:
1) the preparation method of the dehydrated vinblastine comprises the following steps: the method comprises the following steps of (1) preparing dehydrated vinblastine by taking vinblastine sulfate and vindoline as initial raw materials and carrying out iron trichloride catalysis and sodium borohydride reduction;
2) the preparation method of the bromo-dehydrated vinblastine comprises the following steps: carrying out bromination reaction on the dehydrated vinblastine and N-bromosuccinimide to obtain a brominated dehydrated vinblastine crude product; purifying the bromo-dehydrated vinblastine crude product by a column to improve the purity of the bromo-dehydrated vinblastine crude product to obtain bromo-dehydrated vinblastine;
3) the preparation method of the vinorelbine comprises the following steps: carrying out debromination rearrangement on the bromo-dehydrated vinblastine and the aqueous solution of silver tetrafluoroborate to obtain a crude product of vinorelbine; recrystallizing the crude product of vinorelbine to obtain a pure product of vinorelbine;
4) the preparation method of the vinorelbine tartrate comprises the following steps: and carrying out salt forming reaction on the pure vinorelbine and tartaric acid to obtain the vinorelbine tartrate.
2. The method for preparing vinorelbine tartrate as claimed in claim 1, wherein the preparation step of the anhydrovinblastine comprises the following steps:
1-1) preparation of solution A: taking vinblastine sulfate and vindoline, adding an organic solvent a, adding a hydrochloric acid solution, slightly heating, and dissolving at 35-40 ℃ to obtain a solution A; wherein the mass ratio of the vinblastine sulfate to the vindoline is 1: (1-1.2), the mass-volume ratio of the vinblastine sulfate to the organic solvent a is 1: (8-10) g/ml, wherein the mass-volume ratio of the vinblastine sulfate to the hydrochloric acid solution is 1: (3-5) g/ml;
1-2) preparation of liquid B: adding purified water into ferric trichloride, adding a hydrochloric acid solution, and using nitrogen to drive oxygen for 10 minutes; wherein the mass ratio of the vincristine sulfate to the ferric chloride is 1: (4-4.5), the mass-volume ratio of the vinblastine sulfate to the purified water is 1: (100-110) g/ml, wherein the mass-volume ratio of the vincristine sulfate to the hydrochloric acid solution is 1: (2-3) g/ml;
1-3) preparation of solution C: adding purified water into ammonium chloride for dissolving, and using nitrogen to expel oxygen for 10 minutes; wherein the mass ratio of the vincristine sulfate to the ammonium chloride is 1: (5-6), wherein the mass-to-volume ratio of the vincristine sulfate to the purified water is 1: (20-21) g/ml;
1-4) preparation of liquid D: weighing sodium borohydride, and dissolving the sodium borohydride with dilute ammonia water; wherein the mass ratio of the vincristine sulfate to the sodium borohydride is 1: (0.3-0.5), the mass-volume ratio of the vinblastine sulfate to the dilute ammonia water is 1: (15-16) g/ml;
1-5) reaction step: adding the solution A into a stainless steel barrel filled with the solution B in advance, preserving heat in a water bath at 38-40 ℃, stirring and reacting for 60 minutes at 35-40 ℃ under the protection of nitrogen, adding the solution C, mixing uniformly, adding the solution D, and reacting for 10 minutes under continuous stirring; adding dilute ammonia water to pH 7.0-8.0, extracting with organic solvent b for three times, mixing organic solvent extractive solutions, washing with purified water for 1 time, filtering with anhydrous sodium sulfate layer, dewatering, recovering solvent under reduced pressure, and draining to obtain dehydrated vinblastine, charging nitrogen gas, and storing in frozen place with shelf life not longer than 48 hr.
3. The process for the preparation of vinorelbine tartrate as claimed in claim 2, wherein in 1) the step of preparing vinblastine dehydrate, the organic solvent a is tetrahydrofuran or trifluoroethanol; the organic solvent b is any one of ethyl acetate, dichloromethane, trichloromethane, a mixed solution of methyl tert-butyl ether of dichloromethane with the concentration of 20% and a mixed solution of methyl tert-butyl ether of trichloromethane with the concentration of 20%; the dilute ammonia water is mixed aqueous solution prepared by ammonia water in a volume ratio of 1: 1.
4. The method for preparing vinorelbine tartrate as claimed in claim 1, wherein in the step of 2) preparing vinorelbine bromide dehydrate, the specific preparation process is as follows:
2-1) preparation steps of bromo-dehydrated vinblastine crude product: dissolving the dehydrated vinblastine with dichloromethane to obtain a dichloromethane solution of the dehydrated vinblastine; stirring and cooling to (-5) -0 deg.C, adding precooled dichloromethane solution of trifluoroacetic acid, keeping the temperature for 5 minutes, adding liquid nitrogen to cool to (-70) - (-75) deg.C, adding dichloromethane solution of N-bromosuccinimide, controlling the temperature of the reaction solution to (-70) - (-75) deg.C, after the dichloromethane solution of N-bromosuccinimide is added, keeping the temperature and stirring at (-70) - (-75) deg.C for 60 minutes, sampling, detecting by silica gel GF254 thin-layer chromatography, sucking 5ml of reaction solution by a suction pipe, quickly adding into a mixed solution containing 10ml of saturated sodium bicarbonate solution in advance, shaking to alkalize, detecting by thin-layer chromatography, using a developing agent which is a mixed solution of petroleum ether, diethyl ether and diethylamine with the volume ratio of 2:10:0.5, and taking the raw solution as a self control, respectively sucking 40 mul, 20 mul, 10 mul and 5 mul of alkalized sample liquid on the same thin-layer plate, observing under an ultraviolet lamp with the wavelength of 254nm, finishing the reaction when the strength of the dehydrated alkali spots in 40 mul is less than the strength of the main spots in 5 mul, when the reaction is finished, quickly introducing the reaction liquid into a proper amount of saturated sodium bicarbonate solution, simultaneously stirring and uniformly mixing, controlling the pH value of a water layer to be more than or equal to 7.0, separating a lower organic layer, washing for 1 time by using purified water with the volume equal to 1/3 of the total volume of the reaction liquid, filtering and dehydrating by using anhydrous sodium sulfate, recovering a solvent under reduced pressure, concentrating to be dry, vacuumizing and filling nitrogen and sealing to obtain a crude product of bromo-dehydrated vinblastine, and storing the crude product of the bromo-dehydrated vinblastine in a freezing place.
5. The method for preparing vinorelbine tartrate as claimed in claim 4, wherein in the step of 2-1) preparing the crude vinorelbine bromodehydrate,
the addition amount of the dehydrated vinblastine is 0.72 times of the total weight of the vindoline and the vinblastine sulfate;
in the dichloromethane solution of the dehydrated vinblastine, the mass-volume ratio of the dehydrated vinblastine to the dichloromethane is 1: (25-30) g/ml;
in a dichloromethane solution of trifluoroacetic acid, the mass volume ratio of the dehydrated vinblastine to the trifluoroacetic acid is 1 (0.8-1) g/ml; the mass-volume ratio of the dehydrated vinblastine to the dichloromethane is 1: (5-6) g/ml;
in a dichloromethane solution of N-bromosuccinimide, the mass ratio of the dehydrated vinblastine to the N-bromosuccinimide is 1: (0.25-0.30); the mass-volume ratio of the dehydrated vinblastine to the dichloromethane is 1: (15-17) g/ml.
6. The method of preparing vinorelbine tartrate as claimed in claim 4, wherein the step of 2) preparing vinorelbine bromide dehydrate further comprises:
2-2) column chromatography purification step of bromo-dehydrated vinblastine crude product:
weighing chromatographic silica gel according to a proportion, stirring uniformly by using dichloromethane to remove bubbles, pouring into a glass column, winding and cooling the chromatographic column at room temperature or by using an ice water circulating hose to cool the chromatographic column, and adding a proper amount of anhydrous sodium sulfate on the top of the column after the column surface is stabilized; the weight ratio of the total weight of vindoline and vinblastine sulfate to silica gel is 1: (10-12);
adding the bromo-dehydrated vinblastine crude product into dichloromethane, slowly adding the top of a silica gel column, eluting with a mixed solution of dichloromethane and methanol after sample liquid is completely discharged, collecting fractions in sections, detecting the fractions by silica gel GF254 thin-layer chromatography, collecting the fractions containing the bromo-dehydrated vinblastine with a developing agent which is a mixed solution of dichloromethane and methanol in a volume ratio of 40:1 by taking a raw liquid as a self control, combining, recovering the solvent under reduced pressure, controlling the water bath temperature below 35 ℃, drying, introducing nitrogen for protection, and storing the obtained pure bromo-dehydrated vinblastine in a freezing place.
7. The method for preparing vinorelbine tartrate as claimed in claim 6, wherein in the step of 2-2) column chromatography purification of the crude bromo-dehydrated vinblastine, the mass-to-volume ratio of the crude bromo-dehydrated vinblastine to dichloromethane is 1 (2-3) g/ml; in the mixed liquid of dichloromethane and methanol, the volume ratio of dichloromethane to methanol is gradually increased from 80:1 to 40: 1.
8. The method for preparing vinorelbine tartrate according to claim 1, wherein in the step of 3) preparing vinorelbine tartrate, the specific preparation process is as follows:
3-1) preparation of crude vinorelbine: dissolving bromo-dehydrated vinblastine with tetrahydrofuran, preheating to 30-35 ℃ under the protection of nitrogen, adding a tetrafluoroborate silver aqueous solution, stirring in a water bath at 30-35 ℃ for reaction for 60 minutes, sampling, detecting by using silica gel GF254 thin-layer chromatography, taking petroleum ether, diethyl ether and diethylamine as developing agents, taking stock solution before reaction as self-contrast, and finishing the reaction when a raw material point basically disappears; vacuum filtering the reaction solution through a Buchner funnel filled with diatomite, introducing a proper amount of saturated sodium bicarbonate solution into the filtrate to ensure that the pH value of the aqueous solution is more than or equal to 7.0, extracting for three times by using an organic solvent c, combining the extracting solutions, washing once by using purified water, filtering and dehydrating by using anhydrous sodium sulfate, recovering the solvent under reduced pressure, pumping out, filling nitrogen for protection, and storing the obtained crude vinorelbine in a freezing place; the mass ratio of the brominated dehydrated vinblastine to the boron-silver tetrafluoride in the boron-silver tetrafluoride aqueous solution is 1: (0.1-0.15), the mass volume ratio of the brominated dehydrated vinblastine to tetrahydrofuran is 1: (30-35) g/ml, wherein the mass-volume ratio of the brominated dehydrated vinblastine to water in the aqueous solution of the silver tetrafluoroborate is 1: 30g/ml, and the organic solvent c is ethyl acetate, dichloromethane or trichloromethane.
9. The method of preparing vinorelbine tartrate of claim 8, wherein the step of 3) preparing vinorelbine further comprises:
3-2) a crude product purification step of vinorelbine: weighing a crude product of vinorelbine, dissolving the crude product in acetone under the protection of nitrogen, dropwise adding a first part of diethyl ether at room temperature, standing at 0-10 ℃ for full crystallization for 10-12 h after dropwise adding, filtering, and washing with cold absolute ethyl alcohol; dissolving the crystals with a first part of ethyl acetate, concentrating to dryness, dissolving with a second part of ethyl acetate, dropwise adding a second part of diethyl ether at room temperature, standing at 0-10 ℃ for fully crystallizing for 10-12 h after dropwise adding, filtering, and washing with cold absolute ethanol to obtain a pure vinorelbine product; the mass ratio of the crude vinorelbine product to the acetone is 1: (2-5), the mass-to-volume ratio of the crude vinorelbine to the first part of diethyl ether is 1: (10-15) g/ml, wherein the mass ratio of the crude vinorelbine to the first part of ethyl acetate is 1: (1.5-2), the mass ratio of the crude vinorelbine to the second part of ethyl acetate is 1: (1-1.5), the mass-to-volume ratio of the crude vinorelbine to the second part of diethyl ether is 1: 10 g/ml.
10. The method for preparing vinorelbine tartrate according to claim 1, wherein the specific preparation process in the step of 4) preparing vinorelbine tartrate is as follows:
weighing a pure vinorelbine product, dissolving the pure vinorelbine product by using acetone, wherein the mass-volume ratio of the pure vinorelbine product to the acetone is 1: (8-10) g/ml, adding a mixed solution of tartaric acid and acetone with the concentration of 2% in an ice bath under stirring until the pH value of the solution is 3.8-4.0, standing at 0-10 ℃ for about 2-4 hours, then moving to the freezing temperature for continuously standing for 10-16 hours to completely crystallize, filtering, washing, and drying under reduced pressure at 40-45 ℃ to obtain the vinorelbine tartrate.
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