CN113861134A

CN113861134A - Industrial synthesis method of water-soluble docetaxel derivative

Info

Publication number: CN113861134A
Application number: CN202111179652.2A
Authority: CN
Inventors: 陈开云; 柏凤静
Original assignee: Individual
Current assignee: Individual
Priority date: 2021-10-11
Filing date: 2021-10-11
Publication date: 2021-12-31

Abstract

The invention provides an industrial synthesis method of a water-soluble docetaxel derivative, which is used for synthesizing the water-soluble docetaxel derivative with (R) -4-dimethylamino-2-fluoro-butyric acid hydrochloride by taking l 0-deacetylbaccatin III as a substrate. The method adopts two-step synthesis technology, centrifugal extraction separation technology, recrystallization technology and supercritical CO₂The fluid drying technology and the full-automatic control technology are combined, synthesis and purification are carried out under the synergistic effect of the fluid drying technology and the full-automatic control technology, the water solubility of the water-soluble docetaxel derivative produced by the combined technology can reach more than 12mg/ml, and is increased by about 2000 times compared with docetaxel in water, and the docetaxel injection prepared by the method does not use absolute ethanol and tween-80 cosolvent, so that the water-soluble docetaxel derivative is high-efficiency, has no anaphylactic reaction and has small toxic and side effects. Therefore, the product has the characteristics of small toxic and side effects, low production cost, high product purity, high product yield and stable quality, and is suitable for industrial large-scale production.

Description

Industrial synthesis method of water-soluble docetaxel derivative

Technical Field

The invention belongs to the technical field of medicine synthesis, and particularly relates to an industrial synthesis method of a water-soluble docetaxel derivative.

Background

Docetaxel is also known as docetaxel, and has a molecular formula: C43H53NO14 molecular weight: 807.87922, respectively; is a lipophilic taxane antitumor drug, belongs to a cell inhibitor drug, and forms a stable non-functional microtubule bundle by enhancing tubulin polymerization and inhibiting microtubule depolymerization, thereby destroying mitosis of tumor cells to achieve antitumor effect. Docetaxel has intracellular concentration 3 times higher than that of taxol and long intracellular retention time, so that docetaxel has stronger antitumor activity than taxol. The traditional Chinese medicine composition is mainly used for treating advanced breast cancer, ovarian cancer, non-small cell lung cancer, head and neck cancer and small cell lung cancer clinically; it also has therapeutic effect on gastric cancer, pancreatic cancer, and melanoma. Clinical research shows that docetaxel has higher effective rate than paclitaxel for anthracycline drug-resistant breast cancer. Docetaxel is by far the most effective drug in the second-line treatment of anthracycline-resistant breast cancer; docetaxel is one of the most effective drugs in single drug therapy and combination chemotherapy for non-small cell lung cancer.

Although docetaxel has good anticancer activity, due to poor water solubility, tween-80 and absolute ethyl alcohol are required to be added for dissolution assistance in clinical application, alcohol-free docetaxel for injection of Teikoku company is approved by FDA in 2015 12 months and is used for treating breast cancer, prostate cancer, non-small cell lung cancer and the like, anhydrous ethyl alcohol and tween-80 are adopted for dissolution assistance in the injection, tween-80 has a plurality of side effects such as hemolysis, allergy, nerve and cardiovascular toxicity and the like, and when docetaxel is administered to clinical patients, antiallergic drugs are often required to be firstly used, so that great inconvenience and pain are brought to the patients. Therefore, there is a need to develop a water-soluble docetaxel derivative having high efficacy and small toxic and side effects.

Chinese patent 201510624350.X "water-soluble docetaxel anticancer drug compound and its preparation method and application" adopts docetaxel, methoxypolyethylene glycol, diglycolate, etc. dissolved in anhydrous toluene to react to prepare water-soluble docetaxel compound, however, this method adopts carcinogenic toluene solvent, and the reaction substrate is finished product docetaxel, which has the disadvantage of high production cost.

Disclosure of Invention

The invention aims to provide an industrial synthesis method of water-soluble docetaxel derivatives aiming at the defects of the prior art, and the industrial synthesis method of the water-soluble docetaxel derivatives can well solve the problems.

In order to meet the requirements, the technical scheme adopted by the invention is as follows: provides an industrial synthesis method of water-soluble docetaxel derivatives, which comprises the following steps: a step of synthesis of (R) -4-dimethylamino-2-fluoro-butanoate hydrochloride; and a step of synthesizing water-soluble docetaxel.

The synthesis steps of (R) -4-dimethylamino-2-fluoro-butyric acid hydrochloride are as follows:

s1, putting alpha (-S) -hydroxy-gamma-phthalimide-butyric acid into a No. 1 reaction kettle of 2000L, pumping methanol, stirring for 30min, adding thionyl chloride, and stirring at normal temperature until the reaction is complete;

s2, feeding the reaction solution into a No. 1 concentrator for concentration, centrifuging and desolventizing, and recovering the solvent to obtain a dry filter cake A;

s3, filling the dry filter cake A into a No. 1 extraction kettle of 3000L, pumping ethyl acetate for extraction, pumping saturated sodium bicarbonate solution for washing for 2 times, and collecting and combining washing liquid;

s4, pumping the washing solution into a No. 1 liquid-liquid centrifugal extractor, and separating an organic phase and a water phase;

s5, filtering the organic phase, concentrating the filtrate by a No. 2 concentrator, centrifugally desolventizing, and recovering the solvent to obtain 2a white solid with the yield of 98.5 percent;

s6, removing water from tetrahydrofuran by a solvent dehydrator for later use;

s7, putting the diethylaminosulfur trifluoride into a 2000L rotary dissolving tank, pumping the anhydrous tetrahydrofuran, and stirring and dissolving for later use;

s8, putting the 2a white solid into a No. 2 reaction kettle of 5000L, pumping anhydrous tetrahydrofuran, vacuumizing, pumping nitrogen for protection, slowly pumping the diethylamino sulfur trifluoride tetrahydrofuran solution prepared in the step 2 at room temperature, and reacting for 48 hours at room temperature until the reaction is complete;

s9, feeding the reaction solution in the step 3 into a No. 3 concentrator for concentration, centrifuging and desolventizing, and recovering a tetrahydrofuran solvent to obtain a dry filter cake B;

s10, putting the dry filter cake B into No. 2 extraction kettle of 5000L, pumping dichloromethane for extraction, washing the organic layer for 3 times by using saturated sodium bicarbonate water solution respectively, and collecting washing liquid;

s11, pumping the washing solution into a No. 2 liquid-liquid centrifugal extractor, and separating an organic phase and a water phase;

s12, pumping the organic phase into a No. 4 concentrator for concentration, centrifuging and desolventizing, and recovering a dichloromethane solvent to prepare a dry filter cake C;

s13, putting the dry filter cake C into a No. 1 crystallization kettle, and recrystallizing by methanol to obtain 3a white solid with the yield: 92.6 percent;

s14, pumping concentrated hydrochloric acid into a 2000L No. 1 hydrochloric acid concentration preparation tank, pumping a proper amount of purified water, and preparing 6N (20%) hydrochloric acid for later use;

s15, putting the 3a white solid into a No. 3 reaction kettle of 2000L, pumping 6N (20%) hydrochloric acid, heating to 90 ℃ for reaction for 24h, stopping heating, and cooling to room temperature; stirring at 0-10 deg.C for 2 hr to obtain white solid;

s16, filtering the reaction precipitate, pumping the filtrate into a 3000L No. 3 extraction kettle, extracting with diethyl ether for 4 times, and collecting and mixing the extractive solutions;

s17, pumping the extract into No. 3 liquid-liquid centrifugal extractor, and separating organic phase and water phase;

s18, pumping the organic phase into a No. 5 concentrator for concentration, and recovering the ether solvent;

s19, pumping the water phase into a No. 6 concentrator for concentration and centrifugal desolventizing to obtain 4a white solid with the yield of 94.1 percent;

s20, putting the 4a white solid into a No. 4 reaction kettle of 3000L, pumping purified water, adding formic acid and formaldehyde water solution, slowly heating to 60 ℃ for reaction for 4 hours, then heating to 80 ℃, continuing the reaction for 24 hours, stopping heating, cooling to room temperature, adding concentrated hydrochloric acid, and stirring for 0.5 hour to obtain a reaction solution;

s21, pumping the reaction solution into a No. 4 extraction kettle of 3000L, and adjusting the pH value to 6-8;

s22, pumping the neutralized reaction solution into a No. 7 concentrator for concentration, centrifuging and desolventizing to obtain a dry filter cake D;

s23, putting the dry filter cake D into a No. 5 extraction kettle of 3000L, pumping methanol to dissolve, and filtering to obtain filtrate;

s24, concentrating the filtrate by a No. 8 concentrator, centrifugally desolventizing, and recovering a methanol solvent to obtain a dry filter cake E;

s25, filling the dry filter cake E into a No. 2 crystallization kettle, recrystallizing with acetonitrile, and filtering crystals to obtain wet crystals and crystallization mother liquor;

s26, pumping the crystallized mother liquor into a No. 9 concentrator for concentration, centrifuging and desolventizing, and recovering the acetonitrile solvent to obtain a mother liquor extract;

s27, putting the prepared wet crystal into a microwave vacuum drying oven for drying to obtain the (R) -4-dimethylamino-2-fluoro-butyric acid hydrochloride with the yield of 92 percent.

The synthesis method of the water-soluble docetaxel derivative specifically comprises the following steps:

s1: removing residual water in tetrahydrofuran solvent by using a pervaporation membrane solvent dehydrator to prepare anhydrous tetrahydrofuran for later use;

s2: putting benzyl chloroformate into a 3000L rotary dissolving tank, pumping anhydrous tetrahydrofuran solvent, and uniformly stirring and mixing for later use;

s3: filling L0-deacetylbaccatin III and 4-dimethylamino pyridine with the purity of more than or equal to 98 percent into a 1000L first reaction kettle, pumping anhydrous tetrahydrofuran, stirring, heating to 50 ℃ and keeping the temperature constant, slowly pumping the benzyl chloroformate anhydrous tetrahydrofuran solution prepared in the step S2, reacting for 2 hours at the constant temperature of 50 ℃, and monitoring the reaction process by HPLC (high performance liquid chromatography) until the reaction is finished;

s4: filtering the reaction solution by using a bag filter, concentrating the filtrate by using a No. 1 concentrator, centrifuging, desolventizing, and recovering the solvent to obtain a dry filter cake A;

s5: putting the dry filter cake A into a No. 1 extraction kettle of 3000L, pumping ethyl acetate, stirring and extracting, and then washing with saturated ammonium chloride for 1 time and saturated salt solution for 1 time in sequence;

s6: performing liquid-liquid centrifugal extraction on the washing liquid, and separating an organic phase and a water phase to obtain the organic phase and the water phase;

s7: filtering the organic phase by a bag filter, concentrating the filtrate by a No. 2 concentrator, centrifuging, desolventizing, and recovering the solvent to obtain a dry filter cake B;

s8: and (3) putting the dry filter cake B into a No. 1 crystallization kettle, and pumping ethyl acetate and petroleum ether 1: 1, recrystallizing the mixed solvent, filtering mother liquor, concentrating the mother liquor by a No. 13 concentrator, centrifugally desolventizing, and recovering the solvent to obtain a white wet crystal III with the yield of 96 percent;

s9: white wet crystals III and (3R, 4S) -3- (1-ethoxyethoxy) -2-oxo-4 phenyl-azetidinecarboxylic acid tert-butyl ester are put into a 1000L reaction kettle II, tetrahydrofuran is pumped in, the temperature in the kettle is controlled to be-15 to-5 ℃, 60% sodium hydride is added, the reaction is stirred and reacted for 1 hour, and the reaction progress is monitored by HPLC;

s10: pumping the reaction liquid after the reaction into an extraction kettle No. 2, adding a saturated ammonium chloride solution into the extraction kettle, stirring and washing;

s11: sending the washing liquid into a No. 2 liquid-liquid centrifugal extractor to separate an organic phase and a water phase;

s12: feeding the organic phase into a No. 3 concentrator for concentration, centrifuging for desolventizing, and recovering the solvent to obtain a dry filter cake C;

s13: putting the dry filter cake C into a No. 2 extraction kettle of 2000L, pumping ethyl acetate, stirring and dissolving, and then washing with saturated ammonium chloride for 1 time and saturated salt solution for 1 time in sequence;

s14: performing liquid-liquid centrifugal extraction on the washing liquid, and separating an organic phase and a water phase;

s15: concentrating the organic phase by a No. 3 concentrator, centrifuging, desolventizing, and recovering the solvent to obtain a dry filter cake D;

s16: and (3) putting the dry filter cake D into a No. 2 crystallization kettle, and pumping ethyl acetate and petroleum ether 1: 2, recrystallizing the mixed solvent, filtering the mother liquor, concentrating the mother liquor by a No. 12 concentrator, centrifugally desolventizing, and recovering the solvent to obtain white wet crystals IV and a mother liquor dry extract with the yield of 91 percent;

s17: filling the white wet crystal IV into a third reaction kettle of 2000L, pumping acetic acid, slowly adding purified water, reacting for 2h at the temperature of 25 ℃, monitoring the reaction process by HPLC,

s18: after the reaction is finished, adding purified water into a third reaction kettle, stirring for 10 minutes, and then precipitating at normal temperature to obtain a white solid precipitate, and filtering the white solid precipitate by using a bag filter to obtain a white solid filter cake and a filtrate; concentrating the filtrate in No. 4 concentrator, and recovering purified water;

s19: putting the white solid filter cake into a No. 3 extraction kettle of 3000L, adding purified water, stirring and washing for 2 times, and filtering the washing liquid by a bag filter to obtain a white solid filter cake and filtrate; concentrating the filtrate in No. 5 concentrator, and recovering purified water;

s20: sending the filter cake into a microwave vacuum drying oven for reduced pressure drying to obtain a white solid V with the yield of 96%;

s21: putting (R) -4-dimethylamino-2-fluoro-butyric acid hydrochloride into a No. four reaction kettle of 1000L, pumping thionyl chloride, heating to 30 ℃, stirring and reacting for 4 hours, and finishing the reaction;

s22: concentrating the reaction solution by a No. 6 concentrator, centrifuging, desolventizing, and recovering thionyl chloride to prepare a dry filter cake;

s23: putting the dry filter cake into a 3000L No. 4 extraction kettle, adding anhydrous dichloromethane, stirring and dissolving for later use;

s24: pumping anhydrous dichloromethane into a No. five reaction kettle of 5000L, reducing the temperature in the reaction kettle to-15 to-5 ℃, keeping the temperature constant, then adding a compound V and 4-dimethylaminopyridine, stirring to dissolve the compound V and the 4-dimethylaminopyridine, slowly adding a dichloromethane solution of (R) -4-dimethylamino-2-fluoro-butyryl chloride hydrochloride prepared by S23, reacting for 2 hours, and monitoring the reaction process by HPLC;

s25: filling sodium chloride into a 3000L sodium chloride aqueous solution preparation tank, pumping purified water, stirring and dissolving to prepare a saturated sodium chloride aqueous solution, and then cooling the temperature in the tank to-10 to-5 ℃ for later use;

s26: pumping the obtained reaction solution into a No. 5 extraction kettle of 6000L, and stirring and washing the obtained reaction solution to be neutral by using the prepared frozen saturated sodium chloride aqueous solution;

s27: pumping the washing liquid into a liquid-liquid centrifugal extractor, and separating an organic phase and a water phase;

s28: concentrating the water phase with No. 7 concentrator, centrifuging, removing solvent, and recovering purified water;

s29: filtering the organic phase with bag filter, concentrating the filtrate with No. 8 concentrator, centrifuging, removing solvent, and recovering solvent to obtain filter cake;

s30: and (3) feeding the filter cake obtained in the step S29 into a No. 1 crystallization kettle, and reacting with acetone: recrystallizing methyl tert-butyl ether with a 1:8 mixed solvent, filtering crystals by using a bag filter, concentrating a mother solution by using a No. 11 concentrator, centrifugally desolventizing, and recovering the solvent to obtain a wet white solid VI with the yield of 85%;

s31: putting the compound VI into a No. six reaction kettle of 3000L, pumping tetrahydrofuran, adding palladium-carbon with the mass fraction of 10%, vacuumizing, introducing hydrogen, reacting at the temperature of 25 ℃ for 1.5h, and adding 1000L of tetrahydrofuran to dilute reaction liquid after the reaction is finished;

s32: filtering the reaction solution, concentrating in a No. 12 concentrator, centrifuging to remove solvent, and recovering solvent to obtain dry filter cake;

s33: sending the dry filter cake into a No. 2 crystallization kettle, and adding acetone: methyl t-butyl ether 1: 6, recrystallizing the mixed solvent, filtering crystals by using a bag filter, concentrating the mother liquor by using a No. 13 concentrator, centrifugally desolventizing the mother liquor extract, and recovering the solvent to obtain wet crystals and a mother liquor filter cake;

s34: and (3) conveying the wet crystal into a supercritical drying device for drying and desolventizing to obtain a white crystal I product, wherein the yield is 90%, the purity is 99.2% (HPLC), and the molecular formula is as follows: c₄₉H₆₄FN₂O₁₅。

The industrial synthesis method of the water-soluble docetaxel derivative has the following advantages:

1) adopts two-step synthesis technology, recrystallization technology and supercritical CO₂The fluid drying technology and the full-automatic control technology are combined, synthesis and purification are carried out under the synergistic effect of the fluid drying technology and the full-automatic control technology, and the product produced by utilizing the combined technology has the characteristics of high product purity, stable quality, high product yield and high industrial automation degree.

2) The automatic control system is adopted to accurately control the solvent filling quantity of the reaction kettle, the heating and cooling of the reaction kettle and the reaction time, thereby reducing the generation of byproducts, saving the energy consumption and reducing the environmental pollution; the product yield is ensured.

3) The MVR evaporator or the full-electric evaporator is adopted for vacuum concentration or membrane concentration, the automatic scraper centrifuge is adopted for desolventizing, and the solvent is recovered, so that the solvent recovery rate is improved and reaches over 95 percent, and the energy consumption and the environmental pollution are greatly reduced.

4) The automatic control system is adopted to accurately control the solvent filling quantity of the crystallization kettle, the heating and cooling time and the crystallization time of the crystallization kettle, so that the energy consumption is saved, the solvent consumption is reduced, and the product yield and the product quality are guaranteed.

5) The preparation, filling, crystallization temperature and crystallization time of the crystallization solvent are accurately controlled by an automatic control system, so that the consumption of the solvent is reduced and stable product quality is obtained.

6) The automatic control system is adopted to accurately control the drying pressure, the CO2 flow, the heating temperature of the drying kettle and the drying time of the supercritical drying device, so that the energy consumption is saved, the solvent residue in the product is greatly reduced, and the product quality is ensured.

7) Because the solvent filling, the temperature control, the pressure control, the reaction time control and the like are accurately controlled by an automatic control system, a large amount of labor force is saved, the product yield is stable, the product quality is stable, and the product production cost is greatly reduced. Therefore, the water-soluble docetaxel derivative product prepared by the invention has the advantages of low residual solubility, few byproducts, high purity, high yield, stable product quality, low cost, low energy consumption, high productivity and good economic benefit and application prospect.

8) The water-soluble docetaxel derivative has water solubility up to 12.4mg/mL, and the water solubility is increased by about 2000 times compared with docetaxel.

9) The docetaxel injection produced by the water-soluble docetaxel derivative prepared by the method does not use absolute ethanol and tween-80 cosolvent, and has high efficiency and small toxic and side effects.

10) The water-soluble docetaxel derivative crystal prepared by the process with the raw materials can meet the production of 100 ten thousand docetaxel injection in 5 working days, and has the characteristic of large production scale.

Drawings

The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the application and together with the description serve to explain the application and not to limit the application. In the drawings:

fig. 1 schematically shows a structural diagram of a water-soluble docetaxel derivative according to one embodiment of the present application.

Fig. 2 schematically shows a schematic of a water-soluble docetaxel derivative synthesis scheme in accordance with one embodiment of the present application.

Figure 3 schematically shows a schematic of a synthetic route for (R) -4-dimethylamino-2-fluoro-butyric acid hydrochloride according to one embodiment of the present application.

Detailed Description

In order to make the objects, technical solutions and advantages of the present application more apparent, the present application will be described in further detail with reference to the accompanying drawings and specific embodiments.

In the following description, references to "one embodiment," "an embodiment," "one example," "an example," etc., indicate that the embodiment or example so described may include a particular feature, structure, characteristic, property, element, or limitation, but every embodiment or example does not necessarily include the particular feature, structure, characteristic, property, element, or limitation. Moreover, repeated use of the phrase "in accordance with an embodiment of the present application" although it may possibly refer to the same embodiment, does not necessarily refer to the same embodiment.

Certain features that are well known to those skilled in the art have been omitted from the following description for the sake of simplicity.

An industrial synthesis method of water-soluble docetaxel derivatives comprises the following steps:

a step of synthesis of (R) -4-dimethylamino-2-fluoro-butanoate hydrochloride; and a step of synthesizing water-soluble docetaxel.

s1, putting alpha (-S) -hydroxy-gamma-phthalimide-butyric acid into a No. 1 reaction kettle of 2000L, pumping methanol, stirring for 30min, adding thionyl chloride, and stirring at normal temperature to react completely;

s2, feeding the reaction solution into a No. 1 concentrator for concentration, centrifuging and desolventizing, and recovering the solvent to obtain dry extract A;

s3, putting the dry extract A into a No. 1 extraction kettle of 3000L, pumping ethyl acetate for extraction, pumping saturated sodium bicarbonate solution for washing for 2 times, and collecting and combining washing liquid;

s6, removing water from tetrahydrofuran by a solvent dehydrator for later use;

s9, feeding the reaction solution in the step 3 into a No. 3 concentrator for concentration, centrifuging and desolventizing, and recovering a tetrahydrofuran solvent to obtain a dry filter cake A;

s10, putting the dry filter cake A into No. 2 extraction kettle of 5000L, pumping dichloromethane for extraction, washing the organic layer with saturated sodium bicarbonate water solution for 3 times, and collecting the washing liquid;

s12, pumping the organic phase into a No. 4 concentrator for concentration, centrifugally desolventizing, and recovering a dichloromethane solvent to prepare a dry filter cake B;

s13, putting the dry filter cake B into a No. 1 crystallization kettle, and recrystallizing by methanol to obtain 3a white solid with the yield: 92.6 percent;

s15, putting the 3a white solid into a No. 3 reaction kettle of 2000L, pumping in (20%) 6N hydrochloric acid, heating to 90 ℃ for reaction for 24h, stopping heating, and cooling to room temperature; stirring at 0-10 deg.C for 2 hr to obtain white solid;

s22, pumping the neutralized reaction solution into a No. 7 concentrator for concentration, centrifuging and desolventizing to obtain dry filter cake paste C;

s23, filling the dry filter cake C into a No. 5 extraction kettle of 3000L, pumping methanol for dissolving, and filtering to obtain filtrate;

s24, concentrating the filtrate by a No. 8 concentrator, centrifugally desolventizing, and recovering a methanol solvent to prepare a dry filter cake D;

s25, putting the dry extract D into a No. 2 crystallization kettle, recrystallizing with acetonitrile, and filtering to obtain wet crystals and crystallization mother liquor;

s26, pumping the crystallized mother liquor into a No. 9 concentrator for concentration, centrifuging and desolventizing, and recovering the acetonitrile solvent to obtain a mother liquor dry filter cake;

3. The industrial synthesis method of water-soluble docetaxel derivatives according to claim 1, wherein the steps of synthesizing (R) -4-dimethylamino-2-fluoro-butyric acid hydrochloride are as follows:

putting alpha (-S) -hydroxy-gamma-phthalimide-butyric acid into a No. 1 reaction kettle of 2000L, pumping methanol, stirring for 30min, adding thionyl chloride, and stirring at normal temperature to react completely;

feeding the reaction solution into a No. 1 concentrator for concentration, centrifuging and desolventizing, and recovering the solvent to prepare a dry filter cake A;

putting the dry filter cake A into a No. 1 extraction kettle of 3000L, pumping ethyl acetate for extraction, pumping saturated sodium bicarbonate solution for washing for 2 times, and collecting and combining washing liquid;

pumping the washing liquid into a No. 1 liquid-liquid centrifugal extractor, and separating an organic phase from a water phase;

filtering the organic phase, concentrating the filtrate by a No. 2 concentrator, centrifugally desolventizing, and recovering the solvent to obtain 2a white solid with the yield of 98.5%;

removing water from tetrahydrofuran by a solvent dehydrator for later use;

putting the diethylaminosulfur trifluoride into a 2000L rotary dissolving tank, pumping anhydrous tetrahydrofuran, and stirring for dissolving for later use;

putting the 2a white solid into a No. 2 reaction kettle of 5000L, pumping in anhydrous tetrahydrofuran, vacuumizing, pumping in nitrogen gas for protection, slowly pumping in the diethylamino sulfur trifluoride tetrahydrofuran solution prepared in the step 2 at room temperature, and reacting for 48 hours at room temperature until the reaction is complete;

feeding the reaction liquid into a No. 3 concentrator for concentration, centrifuging and desolventizing, and recovering a tetrahydrofuran solvent to prepare a dry filter cake A;

putting the dry filter cake A into No. 2 extraction kettle of 5000L, pumping dichloromethane for extraction, washing the organic layer with saturated sodium bicarbonate water solution for 3 times, and collecting the washing liquid;

pumping the washing liquid into a No. 2 liquid-liquid centrifugal extractor, and separating an organic phase from a water phase; pumping the organic phase into a No. 4 concentrator for concentration, centrifuging for desolventizing, and recovering a dichloromethane solvent to prepare a dry filter cake B;

and (3) putting the dry filter cake B into a No. 1 crystallization kettle, and recrystallizing by using methanol to obtain a 3a white solid with the yield: 92.6 percent;

pumping concentrated hydrochloric acid into a hydrochloric acid concentration preparation tank of No. 2000L 1, pumping a proper amount of purified water, and preparing 6N (20%) hydrochloric acid for later use; putting the 3a white solid into a No. 3 reaction kettle of 2000L, pumping 20% of 6N hydrochloric acid, heating to 90 ℃ for reaction for 24h, stopping heating, and cooling to room temperature;

stirring at 0-10 deg.C for 2 hr to obtain white solid;

filtering the reaction precipitate, pumping the filtrate into 3000L No. 3 extraction kettle, extracting with diethyl ether for 4 times, and collecting the combined extractive solutions;

pumping the extract into No. 3 liquid-liquid centrifugal extractor, and separating organic phase and water phase;

pumping the organic phase into a No. 5M concentrator for concentration, and recovering the ether solvent; pumping the water phase into a No. 6 concentrator for concentration, centrifuging and desolventizing to obtain 4a white solid with the yield of 94.1 percent;

putting the 4a white solid into a No. 4 reaction kettle of 3000L, pumping purified water, adding formic acid and formaldehyde water solution, slowly heating to 60 ℃ for reaction for 4h, then heating to 80 ℃, continuing the reaction for 24h, stopping heating, cooling to room temperature, adding concentrated hydrochloric acid, and stirring for 0.5h to obtain a reaction solution;

pumping the reaction solution into a No. 4 extraction kettle of 3000L, and adjusting the pH value to 6-8; pumping the neutralized reaction solution into a No. 7 concentrator for concentration, centrifuging and desolventizing to prepare a dry filter cake C;

putting the dry filter cake C into a No. 5 extraction kettle of 3000L, pumping methanol for dissolving, and filtering to obtain filtrate;

concentrating the filtrate by a No. 8 concentrator, centrifugally desolventizing, and recovering a methanol solvent to prepare a dry filter cake D;

putting the dry extract D into a No. 2 crystallization kettle, recrystallizing with acetonitrile, and filtering to obtain wet crystals and crystallization mother liquor;

pumping the crystallized mother liquor into a No. 9 concentrator, concentrating, centrifugally desolventizing, and recovering an acetonitrile solvent to obtain a mother liquor filter cake;

the prepared wet crystal is put into a microwave vacuum drying oven for drying to prepare (R) -4-dimethylamino-2-fluoro-butyric acid hydrochloride with the yield of 92 percent.

s16: and (3) putting the dry filter cake paste D into a No. 2 crystallization kettle, and pumping ethyl acetate and petroleum ether 1: 2, recrystallizing the mixed solvent, filtering the mother liquor, concentrating the mother liquor by a No. 12 concentrator, centrifugally desolventizing, and recovering the solvent to obtain white wet crystals IV and a mother liquor dry filter cake with the yield of 91 percent;

s26: pumping the reaction liquid prepared in the step 4 into a No. 5 extraction kettle of 6000L, and stirring and washing the reaction liquid to be neutral by using the frozen saturated sodium chloride aqueous solution prepared in the step 5;

s31: putting the compound VI into a No. six reaction kettle of 3000L, pumping tetrahydrofuran, adding palladium-carbon with the mass fraction of 10%, vacuumizing, introducing hydrogen, reacting at the temperature of 25 ℃ for 1.5h, and adding tetrahydrofuran to dilute reaction liquid after the reaction is finished;

s33: sending the dry filter cake into a No. 2 crystallization kettle, and adding acetone: methyl t-butyl ether 1: 6, recrystallizing the mixed solvent, filtering crystals by using a bag filter, concentrating the mother liquor by using a No. 13 concentrator, centrifugally desolventizing, and recovering the solvent to obtain wet crystals and a mother liquor filter cake;

s34: will be in a wet stateThe crystal is sent into a supercritical drying device for drying and desolventizing to prepare a white crystal I product, the yield is 90%, the purity is 99.2% (HPLC), and the molecular formula is as follows: c₄₉H₆₄FN₂O₁₅。

removing residual water in tetrahydrofuran solvent by using a pervaporation membrane solvent dehydrator to prepare anhydrous tetrahydrofuran for later use;

putting benzyl chloroformate into a 3000L rotary dissolving tank, pumping anhydrous tetrahydrofuran solvent, and uniformly stirring and mixing for later use;

filling L0-deacetylbaccatin III and 4-dimethylamino pyridine with the purity of more than or equal to 98 percent into a 1000L first reaction kettle, pumping anhydrous tetrahydrofuran, stirring, heating to 50 ℃ and keeping the temperature constant, slowly pumping the prepared benzyl chloroformate anhydrous tetrahydrofuran solution, reacting for 2 hours at the constant temperature of 50 ℃, and monitoring the reaction process by HPLC (high performance liquid chromatography) until the reaction is finished;

filtering the reaction solution by using a bag filter, concentrating the filtrate by using a No. 1 concentrator, centrifuging, desolventizing, and recovering the solvent to obtain a dry filter cake A;

putting the dry filter cake A into a No. 1 extraction kettle of 3000L, pumping ethyl acetate, stirring and extracting, and then washing with saturated ammonium chloride for 1 time and saturated salt solution for 1 time in sequence;

performing liquid-liquid centrifugal extraction on the washing liquid, and separating an organic phase and a water phase to obtain the organic phase and the water phase; filtering the organic phase by a bag filter, concentrating the filtrate by a No. 2 concentrator, centrifuging, desolventizing, and recovering the solvent to obtain a dry filter cake B; and (3) putting the dry filter cake B into a No. 1 crystallization kettle, and pumping ethyl acetate and petroleum ether 1: 1, recrystallizing the mixed solvent, filtering mother liquor, concentrating the mother liquor by a No. 13 concentrator, centrifugally desolventizing, and recovering the solvent to obtain a white wet crystal III with the yield of 96 percent;

white wet crystals III and (3R, 4S) -3- (1-ethoxyethoxy) -2-oxo-4 phenyl-azetidinecarboxylic acid tert-butyl ester are put into a 1000L reaction kettle II, tetrahydrofuran is pumped in, the temperature in the kettle is controlled to be-15 to-5 ℃, 60% sodium hydride is added, the reaction is stirred and reacted for 1 hour, and the reaction progress is monitored by HPLC;

pumping the reaction liquid after the reaction into an extraction kettle No. 2, adding a saturated ammonium chloride solution into the extraction kettle, stirring and washing;

sending the washing liquid into a No. 2 liquid-liquid centrifugal extractor to separate an organic phase and a water phase;

feeding the organic phase into a No. 3 concentrator for concentration, centrifuging for desolventizing, and recovering the solvent to obtain a dry filter cake C;

putting the dry filter cake C into a No. 2 extraction kettle of 2000L, pumping ethyl acetate, stirring and dissolving, and then washing with saturated ammonium chloride for 1 time and saturated salt solution for 1 time in sequence;

performing liquid-liquid centrifugal extraction on the washing liquid, and separating an organic phase and a water phase; concentrating the organic phase by a No. 3 concentrator, centrifuging, desolventizing, and recovering the solvent to obtain a dry filter cake D;

and (3) putting the dry filter cake D into a No. 2 crystallization kettle, and pumping ethyl acetate and petroleum ether 1: 2, recrystallizing the mixed solvent, filtering the mother liquor, concentrating the mother liquor by a No. 12 concentrator, centrifugally desolventizing, and recovering the solvent to obtain white wet crystals IV and a mother liquor dry filter cake with the yield of 91 percent;

putting the white wet crystal IV into a third reaction kettle of 2000L, pumping acetic acid, slowly adding purified water, reacting for 2 hours at the temperature of 25 ℃, monitoring the reaction process by HPLC (high performance liquid chromatography), after the reaction is finished, adding the purified water into the third reaction kettle, stirring for 10 minutes, and then precipitating at normal temperature to obtain a white solid precipitate, and filtering the white solid precipitate by a bag filter to obtain a white solid filter cake and filtrate;

concentrating the filtrate in No. 4 concentrator, and recovering purified water; putting the white solid filter cake into a No. 3 extraction kettle of 3000L, adding purified water, stirring and washing for 2 times, and filtering the washing liquid by a bag filter to obtain a white solid filter cake and filtrate;

concentrating the filtrate in No. 5 concentrator, and recovering purified water; sending the filter cake into a microwave vacuum drying oven for reduced pressure drying to obtain a white solid V with the yield of 96%;

putting (R) -4-dimethylamino-2-fluoro-butyric acid hydrochloride into a No. four reaction kettle of 1000L, pumping thionyl chloride, heating to 30 ℃, stirring and reacting for 4 hours, and finishing the reaction;

concentrating the reaction solution by a No. 6 concentrator, centrifuging, desolventizing, and recovering thionyl chloride to prepare a dry filter cake; putting the dry filter cake into a 3000L No. 4 extraction kettle, adding anhydrous dichloromethane, stirring and dissolving for later use;

pumping anhydrous dichloromethane into a No. five reaction kettle of 5000L, reducing the temperature in the reaction kettle to-15 to-5 ℃, keeping the temperature constant, then adding a compound V and 4-dimethylaminopyridine, stirring to dissolve the compound V and the 4-dimethylaminopyridine, slowly adding the prepared dichloromethane solution of (R) -4-dimethylamino-2-fluoro-butyryl chloride hydrochloride, reacting for 2 hours, and monitoring the reaction process by HPLC;

filling sodium chloride into a 3000L sodium chloride aqueous solution preparation tank, pumping purified water, stirring and dissolving to prepare a saturated sodium chloride aqueous solution, and then cooling the temperature in the tank to-10 to-5 ℃ for later use;

pumping the reaction solution prepared in the step 4 into a No. 5 extraction kettle of 6000L, and stirring and washing the reaction solution to be neutral by using the prepared frozen saturated sodium chloride aqueous solution; pumping the washing liquid into a liquid-liquid centrifugal extractor, and separating an organic phase and a water phase;

concentrating the water phase with No. 7 concentrator, centrifuging, removing solvent, and recovering purified water;

filtering the organic phase with bag filter, concentrating the filtrate with No. 8 concentrator, centrifuging, removing solvent, and recovering solvent to obtain filter cake;

and (3) feeding the prepared filter cake into a No. 1 crystallization kettle, and adding acetone:

recrystallizing methyl tert-butyl ether with a 1:8 mixed solvent, filtering crystals by using a bag filter, concentrating a mother solution by using a No. 11 concentrator, centrifugally desolventizing, and recovering the solvent to obtain a wet white solid VI with the yield of 85%;

putting the compound VI into a No. six reaction kettle of 3000L, pumping tetrahydrofuran, adding palladium-carbon with the mass fraction of 10%, vacuumizing, introducing hydrogen, reacting at the temperature of 25 ℃ for 1.5h, and adding 1000L of tetrahydrofuran to dilute reaction liquid after the reaction is finished;

filtering the reaction solution, concentrating in a No. 12 concentrator, centrifuging the fluid extract for desolventizing, and recovering the solvent to obtain a dry filter cake;

sending the dry filter cake into a No. 2 crystallization kettle, and adding acetone: methyl t-butyl ether 1: 6, recrystallizing the mixed solvent, filtering crystals by using a bag filter, concentrating the mother liquor by using a No. 13 concentrator, centrifugally desolventizing, and recovering the solvent to obtain wet crystals and a mother liquor filter cake;

and (3) conveying the wet crystal into a supercritical drying device for drying and desolventizing to obtain a left white crystal I product with the yield of 90 percent and the purity of 99.2 percent (HPLC), wherein the molecular formula is as follows: c₄₉H₆₄FN₂O₁₅。

6. The industrial synthesis method of water-soluble docetaxel derivatives according to claim 1, wherein the steps of synthesizing (R) -4-dimethylamino-2-fluoro-butyric acid hydrochloride are as follows:

the 2a synthesis process comprises the following steps:

a. putting alpha (-S) -hydroxy-gamma-phthalimide-butyric acid into a No. 1 reaction kettle of 2000L, pumping methanol, stirring for 30min, adding thionyl chloride, and stirring at normal temperature to react completely;

b. feeding the reaction solution into a No. 1 concentrator for concentration, centrifuging and desolventizing, and recovering the solvent to prepare a dry filter cake A;

c. putting the dry filter cake A into a No. 1 extraction kettle of 3000L, pumping ethyl acetate for extraction, pumping saturated sodium bicarbonate solution for washing for 2 times, and collecting and combining washing liquid;

d. pumping the washing liquid into a No. 1 liquid-liquid centrifugal extractor, and separating an organic phase from a water phase;

e. filtering the organic phase, concentrating the filtrate by a No. 2 concentrator, centrifuging, desolventizing, and recovering the solvent to obtain a white solid (2a) with the yield of 98.5 percent;

the synthesis process of 3a comprises the following steps:

a. removing water from tetrahydrofuran by a solvent dehydrator for later use;

b. putting the diethylaminosulfur trifluoride into a 2000L rotary dissolving tank, pumping anhydrous tetrahydrofuran, and stirring for dissolving for later use;

c. putting the 2a into a No. 2 reaction kettle of 5000L, pumping in anhydrous tetrahydrofuran, vacuumizing, pumping in nitrogen gas for protection, slowly pumping in the diethylamino sulfur trifluoride tetrahydrofuran solution prepared in the step 2 at room temperature, and reacting for 48 hours at room temperature until the reaction is complete;

d. feeding the reaction liquid into a No. 3 concentrator for concentration, centrifuging and desolventizing, and recovering a tetrahydrofuran solvent to prepare a dry filter cake A;

e. putting the dry filter cake A into No. 2 extraction kettle of 5000L, pumping dichloromethane for extraction, washing the organic layer with saturated sodium bicarbonate water solution for 3 times, and collecting the washing liquid;

f. pumping the washing liquid into a No. 2 liquid-liquid centrifugal extractor, and separating an organic phase from a water phase;

g. pumping the organic phase into a No. 4 concentrator for concentration, centrifuging for desolventizing, and recovering a dichloromethane solvent to prepare a dry filter cake B;

h. the dry cake B was charged into a crystallization vessel No. 1 and recrystallized from methanol to give a white solid (3a) in yield: 92.6 percent;

the 4a synthesis process comprises the following steps:

a. pumping concentrated hydrochloric acid into a 2000L No. 1 hydrochloric acid concentration preparation tank, pumping a proper amount of purified water, and preparing 20% of 6N hydrochloric acid for later use;

b. putting the 3a into a 2000L No. 3 reaction kettle, pumping 20% of 6N hydrochloric acid, heating to 90 ℃ for reaction for 24h, stopping heating, and cooling to room temperature; stirring for 2 hours at the temperature of 0 to minus 10 ℃ to separate out white solid;

c. filtering the reaction precipitate, pumping the filtrate into 3000L No. 3 extraction kettle, extracting with diethyl ether for 4 times, and collecting the combined extractive solutions;

d. pumping the extract into No. 3 liquid-liquid centrifugal extractor, and separating organic phase and water phase;

e. pumping the organic phase into a No. 5 concentrator for concentration, and recovering the ether solvent;

f. pumping the water phase into a No. 6 concentrator for concentration, centrifuging and desolventizing to obtain a white solid (4a) with the yield of 94.1 percent; the synthesis process of (R) -4-dimethylamino-2-fluoro-butyrate hydrochloride comprises the following steps:

a. putting the compound (4a) into a No. 4 reaction kettle of 3000L, pumping purified water, adding formic acid and formaldehyde water solution, slowly heating to 60 ℃ for reaction for 4h, then heating to 80 ℃, continuing the reaction for 24h, stopping heating, cooling to room temperature, adding concentrated hydrochloric acid, and stirring for 0.5h to obtain a reaction solution;

b. pumping the reaction solution into a No. 4 extraction kettle of 3000L, and adjusting the pH value to 6-8;

c. pumping the neutralized reaction solution into a No. 7 concentrator for concentration, centrifuging and desolventizing to prepare a dry filter cake C;

d. putting the dry filter cake C into a No. 5 extraction kettle of 3000L, pumping methanol for dissolving, and filtering to obtain filtrate;

e. concentrating the filtrate by a No. 8 concentrator, centrifugally desolventizing, and recovering a methanol solvent to prepare a dry filter cake D;

f. putting the dry filter cake D into a No. 2 crystallization kettle, recrystallizing with acetonitrile, and filtering crystals to obtain wet crystals and crystallization mother liquor;

g. pumping the crystallized mother liquor into a No. 9 concentrator for concentration, centrifuging for desolventizing, and recovering acetonitrile solvent to obtain mother liquor extract;

h. the prepared wet crystal is put into a microwave vacuum drying oven for drying to prepare (R) -4-dimethylamino-2-fluoro-butyrate hydrochloride with the yield of 92 percent;

7. the industrial synthesis method of water-soluble docetaxel derivatives according to claim 1, wherein the synthesis of (R) -4-dimethylamino-2-fluoro-butyrate hydrochloride is characterized in that:

2 a-4 a, (R) -4-dimethylamino-2-fluoro-butyrate hydrochloride,

the No. 1 concentrator is a double-effect vacuum concentrator or a fully-automatically controlled 500L-2000L/h MVR evaporator or a full-electric evaporator or a membrane concentrator;

the reaction kettle is a fully-automatically controlled 2000L-5000L stainless steel open type reaction kettle;

the crystallization kettle is a 8000L full-automatic control crystallization kettle;

heating and cooling related to the reaction kettle, the concentrator and the crystallization kettle adopt full-automatic control refrigeration heating circulation temperature control equipment;

the centrifugal desolventizing equipment adopts a full-automatic control PZG-400-1200 full-automatic scraper centrifuge;

the 3a crystallization solvent is methanol-water; the concentration of the crystallization solvent is 70-95%;

the (R) -4-dimethylamino-2-fluoro-butyric acid hydrochloride crystallization solvent is acetonitrile-water; the concentration of the crystallization solvent is 50-90 percent;

the crystallization temperature is 50-60 ℃ to-15-0 ℃; the crystallization time is 12-24 h;

the supercritical drying device is a 200-400L double-extraction double-separation electric heating full-automatic control supercritical drying device;

the supercritical drying device is used for drying and desolventizing at the pressure of 20-28 MPa;

the crystallization temperature is 40-60 ℃; the flow rate of the CO2 is 1500-3000L/h; the drying time is 300-420 min.

8. The industrial synthesis method of water-soluble docetaxel derivatives as claimed in claim 1, wherein the step of synthesizing the water-soluble docetaxel derivatives specifically comprises:

the synthesis steps of the compound III comprise:

a. removing residual water in tetrahydrofuran solvent by using a pervaporation membrane solvent dehydrator to prepare anhydrous tetrahydrofuran for later use;

b. putting benzyl chloroformate into a 3000L rotary dissolving tank, pumping anhydrous tetrahydrofuran solvent, and uniformly stirring and mixing for later use;

c. filling L0-deacetylbaccatin III and 4-dimethylaminopyridine with the purity of more than or equal to 98% into a 1000L first reaction kettle, pumping anhydrous tetrahydrofuran, stirring, heating to 50 ℃ and keeping the temperature constant, slowly pumping the benzyl chloroformate anhydrous tetrahydrofuran solution prepared in the step 2, reacting for 2 hours at the constant temperature of 50 ℃, and monitoring the reaction process by HPLC (high performance liquid chromatography) until the reaction is finished;

d. filtering the reaction solution by using a bag filter, concentrating the filtrate by using a No. 1 concentrator, centrifuging, desolventizing, and recovering the solvent to obtain a dry filter cake A;

e. putting the dry filter cake A into a No. 1 extraction kettle of 3000L, pumping ethyl acetate, stirring and extracting, and then washing with saturated ammonium chloride for 1 time and saturated salt solution for 1 time in sequence;

f. performing liquid-liquid centrifugal extraction on the washing liquid, and separating an organic phase and a water phase to obtain the organic phase and the water phase;

g. filtering the organic phase by a bag filter, concentrating the filtrate by a No. 2 concentrator, centrifuging, desolventizing, and recovering the solvent to obtain a dry filter cake B;

h. and (3) putting the dry filter cake B into a No. 1 crystallization kettle, and pumping ethyl acetate and petroleum ether 1: 1, recrystallizing the mixed solvent, filtering mother liquor, concentrating the mother liquor by a No. 13 concentrator, centrifugally desolventizing, and recovering the solvent to obtain a white wet crystal III with the yield of 96 percent;

the synthesis of compound iv comprises the following steps:

a. white wet crystals III g and (3R, 4S) -3- (1-ethoxyethoxy) -2-oxo-4 phenyl-azetidinecarboxylic acid tert-butyl ester were charged into a 1000L reaction vessel II, tetrahydrofuran was pumped in, the temperature in the vessel was controlled to-15 to-5 ℃, and 60% sodium hydride was added thereto and the reaction was stirred for 1 hour. Monitoring the reaction process by HPLC;

b. pumping the reaction liquid after the reaction into an extraction kettle No. 2, adding a saturated ammonium chloride solution into the extraction kettle, stirring and washing;

c. sending the washing liquid into a No. 2 liquid-liquid centrifugal extractor to separate an organic phase and a water phase;

d. feeding the organic phase into a No. 3 concentrator for concentration, centrifuging for desolventizing, and recovering the solvent to obtain a dry filter cake A;

e. putting the dry filter cake A into a No. 2 extraction kettle of 2000L, pumping ethyl acetate, stirring and dissolving, and then washing with saturated ammonium chloride for 1 time and saturated salt solution for 1 time in sequence;

f. performing liquid-liquid centrifugal extraction on the washing liquid, and separating an organic phase and a water phase;

g. concentrating the organic phase by a No. 3 concentrator, centrifugally desolventizing, and recovering the solvent to prepare a dry filter cake B;

h. and (3) putting the dry filter cake B into a No. 2 crystallization kettle, and pumping ethyl acetate and petroleum ether 1: 2, recrystallizing the mixed solvent, filtering the mother liquor, concentrating the mother liquor by a No. 12 concentrator, centrifugally desolventizing, and recovering the solvent to obtain white wet crystals IV and a mother liquor dry filter cake with the yield of 91 percent;

procedure for synthesis of compound V:

a. and (3) putting the white wet crystal IV into a third reaction kettle of 2000L, pumping acetic acid, slowly adding purified water, and reacting for 2h at the temperature of 25 ℃. The reaction progress was monitored by HPLC and,

b. after the reaction is finished, adding purified water into a third reaction kettle, stirring for 10 minutes, and then precipitating at normal temperature to obtain a white solid precipitate, and filtering the white solid precipitate by using a bag filter to obtain a white solid filter cake and a filtrate; concentrating the filtrate in a No. 4 concentrator, and discharging into a sewage pipe;

c. putting the white solid filter cake into a No. 3 extraction kettle of 3000L, adding cold water, stirring and washing for 2 times, and filtering the washing liquid by a bag filter to obtain a white solid filter cake and filtrate; concentrating the filtrate by a No. 5 concentrator, collecting the wastewater, and discharging the wastewater into a sewage pipeline;

d. and (3) sending the filter cake into a microwave vacuum drying oven for reduced pressure drying to obtain a white solid V with the yield of 96%.

The synthesis of compound vi was performed as follows:

a. putting (R) -4-dimethylamino-2-fluoro-butyric acid hydrochloride into a No. four reaction kettle of 1000L, pumping thionyl chloride, heating to 30 ℃, stirring and reacting for 4 hours, and finishing the reaction;

b. concentrating the reaction solution by a No. 6 concentrator, centrifuging, desolventizing, and recovering thionyl chloride to prepare a dry filter cake;

c. putting the dry extract into a No. 4 extraction kettle of 3000L, adding anhydrous dichloromethane, stirring and dissolving for later use;

d. pumping anhydrous dichloromethane into a No. five reaction kettle of 5000L, reducing the temperature in the reaction kettle to-15 to-5 ℃, keeping the temperature constant, then adding a compound V and 4-dimethylaminopyridine, stirring to dissolve the compound V and the 4-dimethylaminopyridine, slowly adding the dichloromethane solution of the (R) -4-dimethylamino-2-fluoro-butyryl chloride hydrochloride prepared in the step 3, reacting for 2 hours, and monitoring the reaction process by HPLC;

e. filling sodium chloride into a 3000L sodium chloride aqueous solution preparation tank, pumping purified water, stirring and dissolving to prepare a saturated sodium chloride aqueous solution, and then cooling the temperature in the tank to-10 to-5 ℃ for later use;

f. pumping the reaction solution prepared in the step 4 into a No. 5 extraction kettle of 6000L, and stirring and washing the reaction solution to be neutral by using the prepared frozen saturated sodium chloride aqueous solution;

g. pumping the washing liquid into a liquid-liquid centrifugal extractor, and separating an organic phase and a water phase;

h. concentrating the water phase by a No. 7 concentrator, centrifugally desolventizing, collecting wastewater, and discharging to a sewage pipeline;

i. filtering the organic phase with bag filter, concentrating the filtrate with No. 8 concentrator, centrifuging, removing solvent, and recovering solvent to obtain filter cake;

j. and (3) feeding the prepared filter cake into a No. 1 crystallization kettle, and adding acetone: recrystallizing methyl tert-butyl ether with a 1:8 mixed solvent, filtering crystals by using a bag filter, concentrating a mother solution by using a No. 11 concentrator, centrifugally desolventizing, and recovering the solvent to obtain a wet white solid VI with the yield of 85%;

the synthesis of compound I was as follows:

a. and (3) putting the compound VI into a 3000L number six reaction kettle, pumping tetrahydrofuran, adding 10 mass percent of palladium carbon, vacuumizing, introducing hydrogen, and reacting at the temperature of 25 ℃ for 1.5 h. After the reaction is finished, adding tetrahydrofuran to dilute the reaction solution;

b. filtering the reaction solution, concentrating in a No. 12 concentrator, centrifuging to remove solvent, and recovering solvent to obtain dry filter cake;

c. sending the dry filter cake into a No. 2 crystallization kettle, and adding acetone: methyl t-butyl ether 1: 6, recrystallizing the mixed solvent, filtering the crystals by using a bag filter, concentrating by using a No. 13 concentrator, centrifugally desolventizing, and recovering the solvent to obtain wet crystals and a mother liquor filter cake;

d. and (3) conveying the wet crystal into a supercritical drying device for drying and desolventizing to obtain a left white crystal I product with the yield of 90 percent and the purity of 99.2 percent (HPLC), wherein the molecular formula is as follows: c₄₉H₆₄FN₂O₁₅。

The synthesis of the water-soluble docetaxel derivative is characterized in that:

in the process step of synthesizing the water-soluble docetaxel derivatives,

the capacity of the pervaporation membrane solvent dehydrator is 100/h;

the capacity of the microwave vacuum drying oven is 30 kg/h;

the crystallization solvent of the compound III is ethyl acetate and petroleum ether 1: 1, mixing a solvent;

the compound IV crystallization solvent is ethyl acetate and petroleum ether 1: 2, mixing the solvent;

the crystallization solvent of the compound VI is acetone: methyl tert-butyl ether 1:8 mixed solvent;

the crystallization solvent of the compound I is acetone: methyl t-butyl ether 1: 6, mixing a solvent;

the concentration temperature of the concentrator is 55-60 ℃;

the supercritical drying device is a 200-400L double-extraction double-separation electric heating full-automatic control supercritical drying device; the supercritical drying device is used for drying, desolventizing and sterilizing under the pressure of 20-28 MPa; the crystallization temperature is 40-60 ℃; the flow rate of the CO2 is 1500-3000L/h; the drying time is 300-420 min.

According to an embodiment of the present application, there is provided an industrial synthesis method of a water-soluble docetaxel derivative, including 2 synthesis steps, the first step being (R) -4-dimethylamino-2-fluoro-butyrate hydrochloride synthesis; the second step is the synthesis of water-soluble docetaxel derivatives.

(R) -4-dimethylamino-2-fluoro-butyric acid hydrochloride synthesis: putting alpha (-S) -hydroxy-gamma-phthalimide-butyric acid into a No. 1 reaction kettle of 2000L, pumping methanol, stirring for 30min, adding thionyl chloride, and stirring at normal temperature to react completely; feeding the reaction solution into a No. 1 concentrator for concentration, centrifuging and desolventizing, and recovering the solvent to prepare a dry filter cake A; putting the dry filter cake A into a No. 1 extraction kettle of 3000L, pumping ethyl acetate for extraction, pumping saturated sodium bicarbonate solution for washing for 2 times, and collecting and combining washing liquid; pumping the washing liquid into a No. 1 liquid-liquid centrifugal extractor, and separating an organic phase from a water phase; filtering the organic phase, concentrating the filtrate by a No. 2 concentrator, centrifugally desolventizing, and recovering the solvent to obtain 2a white solid with the yield of 98.5%; removing water from tetrahydrofuran by a solvent dehydrator for later use; putting the diethylaminosulfur trifluoride into a 2000L rotary dissolving tank, pumping anhydrous tetrahydrofuran, and stirring for dissolving for later use; putting the 2a white solid into a No. 2 reaction kettle of 5000L, pumping in anhydrous tetrahydrofuran, vacuumizing, pumping in nitrogen gas for protection, slowly pumping in the diethylamino sulfur trifluoride tetrahydrofuran solution prepared in the step 2 at room temperature, and reacting for 48 hours at room temperature until the reaction is complete; feeding the reaction liquid into a No. 3 concentrator for concentration, centrifuging and desolventizing, and recovering a tetrahydrofuran solvent to prepare a dry filter cake A; putting the dry filter cake A into No. 2 extraction kettle of 5000L, pumping dichloromethane for extraction, washing the organic layer with saturated sodium bicarbonate water solution for 3 times, and collecting the washing liquid; pumping the washing liquid into a No. 2 liquid-liquid centrifugal extractor, and separating an organic phase from a water phase; pumping the organic phase into a No. 4 concentrator for concentration, centrifuging for desolventizing, and recovering a dichloromethane solvent to prepare a dry filter cake B; and (3) putting the dry filter cake B into a No. 1 crystallization kettle, and recrystallizing by using methanol to obtain a 3a white solid with the yield: 92.6 percent; pumping concentrated hydrochloric acid into a hydrochloric acid concentration preparation tank of No. 2000L 1, pumping a proper amount of purified water, and preparing 6N (20%) hydrochloric acid for later use; putting the 3a white solid into a No. 3 reaction kettle of 2000L, pumping 6N (20%) hydrochloric acid, heating to 90 ℃ for reaction for 24h, stopping heating, and cooling to room temperature; stirring at 0-10 deg.C for 2 hr to obtain white solid; filtering the reaction precipitate, pumping the filtrate into 3000L No. 3 extraction kettle, extracting with diethyl ether for 4 times, and collecting the combined extractive solutions; pumping the extract into No. 3 liquid-liquid centrifugal extractor, and separating organic phase and water phase; pumping the organic phase into a No. 5M concentrator for concentration, and recovering the ether solvent; pumping the water phase into a No. 6 concentrator for concentration, centrifuging and desolventizing to obtain 4a white solid with the yield of 94.1 percent; putting the 4a white solid into a No. 4 reaction kettle of 3000L, pumping purified water, adding formic acid and formaldehyde water solution, slowly heating to 60 ℃ for reaction for 4h, then heating to 80 ℃, continuing the reaction for 24h, stopping heating, cooling to room temperature, adding concentrated hydrochloric acid, and stirring for 0.5h to obtain a reaction solution; pumping the reaction solution into a No. 4 extraction kettle of 3000L, and adjusting the pH value to 6-8; pumping the neutralized reaction solution into a No. 7 concentrator for concentration, centrifuging and desolventizing to prepare a dry filter cake C; putting the dry filter cake C into a No. 5 extraction kettle of 3000L, pumping methanol for dissolving, and filtering to obtain filtrate; concentrating the filtrate by a No. 8 concentrator, centrifugally desolventizing, and recovering a methanol solvent to prepare a dry filter cake D; putting the dry extract D into a No. 2 crystallization kettle, recrystallizing with acetonitrile, and filtering to obtain wet crystals and crystallization mother liquor; pumping the crystallized mother liquor into a No. 9 concentrator, concentrating, centrifugally desolventizing, and recovering an acetonitrile solvent to obtain a mother liquor filter cake; the prepared wet crystal is put into a microwave vacuum drying oven for drying to prepare (R) -4-dimethylamino-2-fluoro-butyric acid hydrochloride with the yield of 92 percent.

The synthesis method of the water-soluble docetaxel derivative specifically comprises the following steps: removing residual water in tetrahydrofuran solvent by using a pervaporation membrane solvent dehydrator to prepare anhydrous tetrahydrofuran for later use; putting benzyl chloroformate into a 3000L rotary dissolving tank, pumping anhydrous tetrahydrofuran solvent, and uniformly stirring and mixing for later use; filling L0-deacetylbaccatin III and 4-dimethylamino pyridine with the purity of more than or equal to 98 percent into a 1000L first reaction kettle, pumping anhydrous tetrahydrofuran, stirring, heating to 50 ℃ and keeping the temperature constant, slowly pumping the prepared benzyl chloroformate anhydrous tetrahydrofuran solution, reacting for 2 hours at the constant temperature of 50 ℃, and monitoring the reaction process by HPLC (high performance liquid chromatography) until the reaction is finished; filtering the reaction solution by using a bag filter, concentrating the filtrate by using a No. 1 concentrator, centrifuging, desolventizing, and recovering the solvent to obtain a dry filter cake A; putting the dry filter cake A into a No. 1 extraction kettle of 3000L, pumping ethyl acetate, stirring and extracting, and then washing with saturated ammonium chloride for 1 time and saturated salt solution for 1 time in sequence; performing liquid-liquid centrifugal extraction on the washing liquid, and separating an organic phase and a water phase to obtain the organic phase and the water phase; filtering the organic phase by a bag filter, concentrating the filtrate by a No. 2 concentrator, centrifuging, desolventizing, and recovering the solvent to obtain a dry filter cake B; and (3) putting the dry filter cake B into a No. 1 crystallization kettle, and pumping ethyl acetate and petroleum ether 1: 1, recrystallizing the mixed solvent, filtering mother liquor, concentrating the mother liquor by a No. 13 concentrator, centrifugally desolventizing, and recovering the solvent to obtain a white wet crystal III with the yield of 96 percent; white color is obtainedThe wet crystal III and (3R, 4S) -3- (1-ethoxyethoxy) -2-oxo-4 phenyl-azetidinecarboxylic acid tert-butyl ester are put into a 1000L reaction kettle II, tetrahydrofuran is pumped in, the temperature in the kettle is controlled to be-15 to-5 ℃, 60% sodium hydride is added, the reaction is stirred for 1 hour, and the reaction progress is monitored by HPLC; pumping the reaction liquid after the reaction into an extraction kettle No. 2, adding a saturated ammonium chloride solution into the extraction kettle, stirring and washing; sending the washing liquid into a No. 2 liquid-liquid centrifugal extractor to separate an organic phase and a water phase; feeding the organic phase into a No. 3 concentrator for concentration, centrifuging for desolventizing, and recovering the solvent to obtain a dry filter cake C; putting the dry filter cake C into a No. 2 extraction kettle of 2000L, pumping ethyl acetate, stirring and dissolving, and then washing with saturated ammonium chloride for 1 time and saturated salt solution for 1 time in sequence; performing liquid-liquid centrifugal extraction on the washing liquid, and separating an organic phase and a water phase; concentrating the organic phase by a No. 3 concentrator, centrifuging, desolventizing, and recovering the solvent to obtain a dry filter cake D; and (3) putting the dry filter cake D into a No. 2 crystallization kettle, and pumping ethyl acetate and petroleum ether 1: 2, recrystallizing the mixed solvent, filtering the mother liquor, concentrating the mother liquor by a No. 12 concentrator, centrifugally desolventizing, and recovering the solvent to obtain white wet crystals IV and a mother liquor dry filter cake with the yield of 91 percent; putting the white wet crystal IV into a third reaction kettle of 2000L, pumping acetic acid, slowly adding purified water, reacting for 2 hours at the temperature of 25 ℃, monitoring the reaction process by HPLC (high performance liquid chromatography), after the reaction is finished, adding the purified water into the third reaction kettle, stirring for 10 minutes, and then precipitating at normal temperature to obtain a white solid precipitate, and filtering the white solid precipitate by a bag filter to obtain a white solid filter cake and filtrate; concentrating the filtrate in No. 4 concentrator, and recovering purified water; putting the white solid filter cake into a No. 3 extraction kettle of 3000L, adding purified water, stirring and washing for 2 times, and filtering the washing liquid by a bag filter to obtain a white solid filter cake and filtrate; concentrating the filtrate in No. 5 concentrator, and recovering purified water; sending the filter cake into a microwave vacuum drying oven for reduced pressure drying to obtain a white solid V with the yield of 96%; putting (R) -4-dimethylamino-2-fluoro-butyric acid hydrochloride into a No. four reaction kettle of 1000L, pumping thionyl chloride, heating to 30 ℃, stirring and reacting for 4 hours, and finishing the reaction; concentrating the reaction solution by a No. 6 concentrator, centrifuging, desolventizing, and recovering thionyl chloride to prepare a dry filter cake; the dry filter cake is loaded into a No. 4 extraction kettle of 3000LAdding anhydrous dichloromethane, stirring and dissolving for later use; pumping anhydrous dichloromethane into a No. five reaction kettle of 5000L, reducing the temperature in the reaction kettle to-15 to-5 ℃, keeping the temperature constant, then adding a compound V and 4-dimethylaminopyridine, stirring to dissolve the compound V and the 4-dimethylaminopyridine, slowly adding the prepared dichloromethane solution of (R) -4-dimethylamino-2-fluoro-butyryl chloride hydrochloride, reacting for 2 hours, and monitoring the reaction process by HPLC; filling sodium chloride into a 3000L sodium chloride aqueous solution preparation tank, pumping purified water, stirring and dissolving to prepare a saturated sodium chloride aqueous solution, and then cooling the temperature in the tank to-10 to-5 ℃ for later use; pumping the reaction solution prepared in the step 4 into a No. 5 extraction kettle of 6000L, and stirring and washing the reaction solution to be neutral by using the prepared frozen saturated sodium chloride aqueous solution; pumping the washing liquid into a liquid-liquid centrifugal extractor, and separating an organic phase and a water phase; concentrating the water phase with No. 7 concentrator, centrifuging, removing solvent, and recovering purified water; filtering the organic phase with bag filter, concentrating the filtrate with No. 8 concentrator, centrifuging, removing solvent, and recovering solvent to obtain filter cake; and (3) feeding the prepared filter cake into a No. 1 crystallization kettle, and adding acetone: recrystallizing methyl tert-butyl ether with a 1:8 mixed solvent, filtering crystals by using a bag filter, concentrating a mother solution by using a No. 11 concentrator, centrifugally desolventizing, and recovering the solvent to obtain a wet white solid VI with the yield of 85%; putting the compound VI into a No. six reaction kettle of 3000L, pumping tetrahydrofuran, adding palladium-carbon with the mass fraction of 10%, vacuumizing, introducing hydrogen, reacting at the temperature of 25 ℃ for 1.5h, and adding 1000L of tetrahydrofuran to dilute reaction liquid after the reaction is finished; filtering the reaction solution, concentrating in a No. 12 concentrator, centrifuging the fluid extract for desolventizing, and recovering the solvent to obtain a dry filter cake; sending the dry filter cake into a No. 2 crystallization kettle, and adding acetone: methyl t-butyl ether 1: 6, recrystallizing the mixed solvent, filtering crystals by using a bag filter, concentrating the mother liquor by using a No. 13 concentrator, centrifugally desolventizing, and recovering the solvent to obtain wet crystals and a mother liquor filter cake; and (3) conveying the wet crystal into a supercritical drying device for drying and desolventizing to obtain a left white crystal I product with the yield of 90 percent and the purity of 99.2 percent (HPLC), wherein the molecular formula is as follows: c₄₉H₆₄FN₂O₁₅。

(I) Synthesis of Compound III

c. putting L0-deacetylbaccatin III with the purity of more than or equal to 98 percent and 4-dimethylaminopyridine into a 1000L first reaction kettle, pumping anhydrous tetrahydrofuran, stirring, heating to 50 ℃ and keeping the temperature constant, slowly pumping the benzyl chloroformate anhydrous tetrahydrofuran solution prepared in the step 2, and reacting for 2 hours at the constant temperature of 50 ℃. Monitoring the reaction process by HPLC until the reaction is finished;

h. and (3) putting the dry filter cake B into a No. 1 crystallization kettle, and pumping ethyl acetate and petroleum ether 1: 1 recrystallizing the mixed solvent, filtering mother liquor, concentrating the mother liquor by a No. 13 concentrator, centrifugally desolventizing, and recovering the solvent to obtain white wet crystal III with the yield of 96 percent.

(II) Synthesis of Compound IV

h. and (3) putting the dry filter cake B into a No. 2 crystallization kettle, and pumping ethyl acetate and petroleum ether 1: 2 recrystallizing the mixed solvent, filtering the mother liquor, concentrating the mother liquor by a No. 12 concentrator, centrifugally desolventizing, and recovering the solvent to obtain white wet crystals IV and a mother liquor dry filter cake with the yield of 91 percent.

(III) Synthesis of Compound V

(IV) Synthesis of Compound VI

c. and putting the dry extract into a 3000L No. 4 extraction kettle, adding anhydrous dichloromethane, stirring and dissolving for later use.

d. Pumping anhydrous dichloromethane into a fifth reaction kettle of 5000L, reducing the temperature in the fifth reaction kettle to-15 to-5 ℃, keeping the temperature, adding a compound V and 4-dimethylaminopyridine, and stirring to dissolve the compound V and the 4-dimethylaminopyridine. Slowly adding the dichloromethane solution of the (R) -4-dimethylamino-2-fluoro-butyryl chloride hydrochloride prepared in the step 3, reacting for 2 hours, and monitoring the reaction process by HPLC;

j. and (3) feeding the prepared filter cake into a No. 1 crystallization kettle, and adding acetone: recrystallizing methyl tert-butyl ether with a 1:8 mixed solvent, filtering crystals by a bag filter, concentrating a mother solution by a No. 11 concentrator, centrifugally desolventizing, and recovering the solvent to obtain a wet white solid VI with the yield of 85 percent.

(V) Synthesis of Compound I

Example (b):

(I) and 2a synthesis process step

a. 83.66kg of alpha (-S) -hydroxy-gamma-phthalimide-butyric acid is put into a No. 1 reaction kettle of 2000L, 1004L of methanol is pumped in and stirred for 30min, and then 36.42L of thionyl chloride is added and stirred at normal temperature to react completely;

c. putting the dry filter cake A into a No. 1 extraction kettle of 3000L, pumping 1673L of ethyl acetate for extraction, pumping 502L of saturated sodium bicarbonate solution for washing for 2 times, and collecting and combining washing liquid;

e. the organic phase was filtered, the filtrate was concentrated by a No. 2 concentrator, centrifuged to desolventize, and the solvent was recovered to obtain 87kg of a white solid (2a) with a yield of 98.5%.

(II) and 3a synthesis process step

a. Removing water from tetrahydrofuran 3915L by using a solvent dehydrator for later use;

b. 174.87kg of diethylaminosulfur trifluoride is put into a 2000L rotary dissolving tank, 435L of anhydrous tetrahydrofuran is pumped in and stirred for dissolving for later use;

c. putting 2a 87kg into a No. 2 reaction kettle of 5000L, pumping 3480L of anhydrous tetrahydrofuran, vacuumizing, pumping nitrogen for protection, slowly pumping the diethylamino sulfur trifluoride tetrahydrofuran solution prepared in the step 2 at room temperature, and reacting for 48 hours at room temperature until the reaction is complete;

d. feeding the reaction liquid in the step 3 into a No. 3 concentrator for concentration, centrifuging and desolventizing, and recovering a tetrahydrofuran solvent to prepare a dry filter cake B;

e. putting the dry filter cake B into a No. 2 extraction kettle of 5000L, pumping 3480L of dichloromethane for extraction, washing an organic layer for 3 times by using 435L of saturated sodium bicarbonate aqueous solution respectively, and collecting washing liquid;

g. pumping the organic phase into a No. 4 concentrator for concentration, centrifuging for desolventizing, and recovering a dichloromethane solvent to prepare a dry filter cake C;

h. and (3) putting the dry extract C into a No. 1 crystallization kettle, and recrystallizing with methanol to obtain 80.91kg of white solid (3a), wherein the yield is as follows: 92.6 percent.

(III) and 4a synthesis process step

a. Pumping concentrated hydrochloric acid into a 2000L No. 1 hydrochloric acid concentration preparation tank, pumping a proper amount of purified water, and preparing 1123.8L6N (20%) hydrochloric acid for later use;

b. putting 3a 80.91kg of the mixed solution into a 2000L No. 3 reaction kettle, pumping 1123.8L6N (20%) hydrochloric acid, heating to 90 ℃ for reaction for 24 hours, stopping heating, and cooling to room temperature; stirring for 2 hours at the temperature of 0 to minus 10 ℃ to separate out white solid;

c. filtering the reaction precipitate, pumping the filtrate into 3000L No. 3 extraction kettle, extracting with ethyl ether 337.14L for 4 times, and collecting the combined extractive solutions;

f. pumping the water phase into a No. 6 concentrator for concentration, centrifuging and desolventizing to obtain 44.95kg of white solid (4a) with the yield of 94.1%;

(IV), (R) -4-dimethylamino-2-fluoro-butyric acid hydrochloride synthesis process steps

a. 44.95g of the compound (4a) is put into a No. 4 reaction kettle of 3000L, 168.6L of purified water is pumped, 561.9L of formic acid and 450L of formaldehyde water solution are added, then the temperature is slowly raised to 60 ℃ for reaction for 4 hours, then the temperature is raised to 80 ℃, the reaction is continued for 24 hours, the heating is stopped, the temperature is cooled to the room temperature, 112.38L of concentrated hydrochloric acid is added, and the mixture is stirred for 0.5 hour to prepare reaction liquid;

c. pumping the neutralized reaction solution into a No. 7 concentrator for concentration, centrifuging and desolventizing to prepare a dry filter cake D;

d. putting the dry filter cake D into a No. 5 extraction kettle of 3000L, pumping 281L of methanol for dissolving, and filtering to obtain filtrate;

e. concentrating the filtrate by a No. 8 concentrator, centrifuging, desolventizing, and recovering a methanol solvent to obtain a dry filter cake E;

f. putting the dry filter cake E into a No. 2 crystallization kettle, recrystallizing with acetonitrile, and filtering crystals to obtain wet crystals and crystallization mother liquor;

h. the prepared wet crystal is put into a microwave vacuum drying oven for drying to prepare 48.32kg of (R) -4-dimethylamino-2-fluoro-butyrate hydrochloride with the yield of 92 percent;

(I) Synthesis of Compound III

b. putting 99.73L of benzyl chloroformate into a 3000L rotary dissolving tank, pumping 138.27L of anhydrous tetrahydrofuran solvent, and uniformly stirring and mixing for later use;

c. putting 38.61kg of L0-deacetylbaccatin III with the purity of more than or equal to 98 percent and 86.42kg of 4-dimethylaminopyridine into a 1000L first reaction kettle, pumping 535L of anhydrous tetrahydrofuran, stirring, heating to 50 ℃ for constant temperature, slowly pumping the benzyl chloroformate anhydrous tetrahydrofuran solution prepared in the step 2, and reacting for 2 hours at the constant temperature of 50 ℃. Monitoring the reaction process by HPLC until the reaction is finished;

e. putting the dry filter cake A into a No. 1 extraction kettle of 3000L, pumping 890L of ethyl acetate, stirring and extracting, and then washing 1 time by using 700L of saturated ammonium chloride and 1 time by using 700L of saturated salt water in sequence;

h. and (3) putting the dry filter cake B into a No. 1 crystallization kettle, and pumping ethyl acetate and petroleum ether 1: 1 mixed solvent recrystallization, mother liquor filtration, mother liquor concentration by a No. 13 concentrator, centrifugal desolventizing and solvent recovery, 55.24kg of white wet crystal III is prepared, and the yield is 96%.

(II) Synthesis of Compound IV

a. White wet crystals III 55.24kg and (3R, 4S) -3- (1-ethoxyethoxy) -2-oxo-4 phenyl-azetidinecarboxylic acid tert-butyl ester 29.64kg were charged in a 1000L reaction vessel II, 606.25L of tetrahydrofuran was pumped in, the temperature in the vessel was controlled to-15 to-5 ℃ and 4.04kg of 60% sodium hydride was added thereto, and the reaction was stirred for 1 hour. Monitoring the reaction process by HPLC;

b. pumping the reaction solution after the reaction into an extraction kettle No. 2, adding 67.36L of saturated ammonium chloride solution into the extraction kettle, stirring and washing;

d. feeding the organic phase into a No. 3 concentrator for concentration, centrifuging for desolventizing, and recovering the solvent to obtain a dry filter cake C;

e. putting the dry filter cake C into a No. 2 extraction kettle of 2000L, pumping 673.62L ethyl acetate, stirring for dissolving, and sequentially washing with 680L saturated ammonium chloride for 1 time and 680L saturated saline solution for 1 time;

g. concentrating the organic phase by a No. 3 concentrator, centrifuging, desolventizing, and recovering the solvent to obtain a dry filter cake D;

h. and (3) putting the dry filter cake D into a No. 2 crystallization kettle, and pumping ethyl acetate and petroleum ether 1: 2 recrystallizing the mixed solvent, filtering the mother liquor, concentrating the mother liquor by a No. 12 concentrator, centrifugally desolventizing, and recovering the solvent to obtain 70.73kg of white wet crystal IV and a mother liquor dry extract with the yield of 91 percent.

(III) Synthesis of Compound V

a. White wet crystal IV 70.73kg is put into a third reaction kettle of 2000L, 452.70L of acetic acid is pumped in, 70.75L of purified water is slowly added, and the reaction is carried out for 2h at the temperature of 25 ℃. The reaction progress was monitored by HPLC and,

b. after the reaction is finished, 990L of purified water is added into the third reaction kettle, stirred for 10 minutes and then precipitated at normal temperature to prepare white solid precipitate, and the white solid precipitate is filtered by a bag filter to prepare a white solid filter cake and filtrate; concentrating the filtrate in a No. 4 concentrator, and discharging into a sewage pipe;

c. putting the white solid filter cake into a No. 3 extraction kettle of 3000L, adding 425L of cold water, stirring and washing for 2 times, and filtering washing liquid by a bag filter to obtain a white solid filter cake and filtrate; concentrating the filtrate by a No. 5 concentrator, collecting the wastewater, and discharging the wastewater into a sewage pipeline;

d. the filter cake was dried under reduced pressure in a microwave vacuum drying oven to give 63.66kg of white solid V with a yield of 96%.

(IV) Synthesis of Compound VI

a. 48.32kg of (R) -4-dimethylamino-2-fluoro-butyric acid hydrochloride is put into a No. four reaction kettle of 1000L, 289.35L of thionyl chloride is pumped, the temperature is heated to 30 ℃, the mixture is stirred and reacts for 4 hours, and the reaction is finished;

c. putting the dry extract into 3000L No. 4 extraction kettle, adding 1736.12L anhydrous dichloromethane, stirring and dissolving for use.

d. 1736.12L of anhydrous dichloromethane is pumped into a fifth reaction kettle of 5000L, the temperature in the fifth reaction kettle is reduced to minus 15 to minus 5 ℃, then the temperature is kept constant, and then 63.66kg of compound V and 40.51kg of 4-dimethylamino pyridine are added and stirred to be dissolved. Slowly adding the prepared dichloromethane solution of the (R) -4-dimethylamino-2-fluoro-butyryl chloride hydrochloride to react for 2 hours, and monitoring the reaction process by HPLC;

e. putting 72kg of sodium chloride into a 3000L sodium chloride water solution preparation tank, pumping 2000L of purified water, stirring and dissolving to prepare a saturated sodium chloride water solution, and then reducing the temperature in the tank to-10 to-5 ℃ for later use;

j. and (3) feeding the prepared filter cake into a No. 1 crystallization kettle, and adding acetone: recrystallizing methyl tert-butyl ether with a 1:8 mixed solvent, filtering crystals by a bag filter, concentrating a mother solution by a No. 11 concentrator, centrifugally desolventizing, and recovering the solvent to obtain 62.5kg of wet white solid VI with the yield of 85 percent.

(V) Synthesis of Compound I

a. 62.5kg of compound VI is put into a No. six reaction kettle of 3000L, 1500L of tetrahydrofuran is pumped, 6kg of palladium carbon with the mass fraction of 10 percent is added, then the vacuum pumping is carried out, hydrogen is introduced, and the reaction is carried out for 1.5h at the temperature of 25 ℃. After the reaction, 1000L of tetrahydrofuran is added to dilute the reaction solution;

d. and (3) conveying the wet crystals into a supercritical drying device for drying and desolventizing to obtain about 44kg of white crystals I, wherein the yield is 90%, the purity is 99.2% (HPLC), and the molecular formula is as follows: c₄₉H₆₄FN₂O₁₅。

e. Feeding the three batches of white crystals I with the concentration of more than or equal to 99% into a batch V-1000 type mixer for mixing to obtain a water-soluble docetaxel derivative crystal powder product with the concentration of more than or equal to 99%;

the above-mentioned embodiments only show some embodiments of the present invention, and the description thereof is more specific and detailed, but should not be construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the claims.

Claims

1. An industrial synthesis method of a water-soluble docetaxel derivative is characterized by comprising the following steps:

2. The industrial synthesis method of water-soluble docetaxel derivatives according to claim 1, wherein the synthesis steps of (R) -4-dimethylamino-2-fluoro-butyric acid hydrochloride are as follows:

s6, removing water from tetrahydrofuran by a solvent dehydrator for later use;

removing water from tetrahydrofuran by a solvent dehydrator for later use;

stirring at 0-10 deg.C for 2 hr to obtain white solid;

4. The industrial synthesis method of water-soluble docetaxel derivatives as claimed in claim 1, wherein the step of synthesizing water-soluble docetaxel derivatives specifically comprises:

5. The industrial synthesis method of water-soluble docetaxel derivatives as claimed in claim 1, wherein the step of synthesizing water-soluble docetaxel derivatives specifically comprises:

the 2a synthesis process comprises the following steps:

the synthesis process of 3a comprises the following steps:

a. removing water from tetrahydrofuran by a solvent dehydrator for later use;

the 4a synthesis process comprises the following steps:

2 a-4 a, (R) -4-dimethylamino-2-fluoro-butyrate hydrochloride,

the synthesis steps of the compound III comprise:

the synthesis of compound iv comprises the following steps:

procedure for synthesis of compound V:

d. and (3) sending the filter cake into a microwave vacuum drying oven for reduced pressure drying to obtain a white solid V with the yield of 96%. The synthesis of compound vi was performed as follows:

the synthesis of compound I was as follows:

9. The industrial synthesis method of water-soluble docetaxel derivatives as claimed in claim 1, wherein the synthesis of water-soluble docetaxel derivatives is characterized in that:

in the process step of synthesizing the water-soluble docetaxel derivatives,

the capacity of the pervaporation membrane solvent dehydrator is 100/h;

the capacity of the microwave vacuum drying oven is 30 kg/h;

the concentration temperature of the concentrator is 55-60 ℃;