CN117534699A

CN117534699A - Silicon-containing impurity compound of taxane compound, and preparation method and application thereof

Info

Publication number: CN117534699A
Application number: CN202210916085.2A
Authority: CN
Inventors: 吴修艮; 李召广; 刘俊; 李�远
Original assignee: Jiangsu Jibeier Pharmaceutical Co ltd
Current assignee: Jiangsu Jibeier Pharmaceutical Co ltd
Priority date: 2022-08-01
Filing date: 2022-08-01
Publication date: 2024-02-09

Abstract

The invention provides a silicon-containing impurity compound of a taxane compound, a preparation method and application thereof, wherein the silicon-containing impurity compound of the taxane compound has a structure shown in a formula I:the compound provided by the invention can be used for detecting impurities of taxane compounds, and can provide a reference substance for quality control of taxane compounds; the control of the content of the compound provided by the invention can obviously improve and reduce the toxicity or side effect of the taxane compound when the taxane compound is used as a medicine, and has obvious benefit for improving the pharmacological activity of the taxane compound when the taxane compound is used as the medicine.

Description

Silicon-containing impurity compound of taxane compound, and preparation method and application thereof

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a taxane compound silicon-containing impurity compound, and a preparation method and application thereof.

Background

Malignant tumor is a major disease seriously threatening the health of residents in China, according to the data counted by cancer centers in China, the incidence and death of malignant tumor in recent ten years are continuously increased, the incidence rate of malignant tumor is increased by about 3.9 percent each year, the death rate is increased by about 2.5 percent each year, the death rate of malignant tumor in 2019 accounts for about 24 percent of the total death factors of residents, and the medical cost caused by malignant tumor exceeds 2200 hundred million. Lung cancer, liver cancer, upper digestive system tumor, colorectal cancer, female breast cancer and the like are main malignant tumors in China, wherein the lung cancer is located at the 1 st position of male morbidity, and the breast cancer is the first position of female morbidity. The 5-year relative survival rate of malignant tumor patients in China is about 41%, and the malignant tumor patients are improved by about 10% compared with the malignant tumor patients before 10 years, but the malignant tumor patients still have a great gap compared with developed countries. In general, the prevention and control situation of malignant tumors in China is severe, and the national and resident economic burden is great.

At present, drug therapy has become one of the important means for clinical tumor therapy, and more than 80 kinds of clinically used antitumor drugs are roughly classified into the following 6 kinds: cytotoxic drugs, hormonal drugs, biological response modifiers, monoclonal antibody drugs, adjuvant drugs, and other drugs.

The taxane medicine is a kind of high-efficiency spectrum cytotoxic antineoplastic medicine extracted from bark or leaf of yew or semisynthetic, and is a microtubulin inhibitor. Research shows that the medicine acts on microtubule/tubulin system to promote the assembly of microtubule dimer and inhibit the polymerization process to stabilize microtubule, retard cell in G2 and M phase and inhibit the mitosis and proliferation of tumor cell.

Currently, three kinds of taxane medicines are clinically used, namely paclitaxel, docetaxel and cabazitaxel, and the specific structures are as follows:

the taxane antitumor drug has multi-drug resistance in the use process, so that the antitumor effect is reduced. Therefore, the development of the novel taxane medicine has great clinical value. Based on the structure of docetaxel, the applicant performs structure optimization, and a novel taxane compound is obtained through preliminary drug effect screening, and the code number of the taxane compound is JJH201601, the compound is disclosed and authorized in the patent with the application number of CN201810185012.4, and the specific structure of the taxane compound is as follows:

according to the preliminary efficacy research results, the efficacy of the nude mouse model is obviously improved, the toxic and side effects are obviously reduced, tumors can be eliminated (the tumor inhibition rate reaches more than 99 percent), no tumor recurrence is found in the observation period after drug withdrawal, the results are verified on lung cancer A549, liver cancer HepG2 and pancreatic cancer Panc-1 models, and the compound is expected to be widely applied to the clinical quality of related diseases at present in the administrative approval stage.

The research of impurities is a necessary and important link in the process of developing, copying and declaring medicines, and the international association for registration of medicines (ICH) is required to define the impurities as follows: any component present in the drug that is not chemically identical to the drug. The impurity content is a key quality attribute of medicine quality, most of impurities contained in the medicine have potential biological activity and possible interaction among components, so that the safety and the efficacy of the medicine are affected, and even toxic and side effects are generated. In order to ensure medication safety, each impurity in the active pharmaceutical ingredient must be subjected to a safety assessment, i.e. an impurity limit is established which ensures safety. According to the requirements of the International Coordination (ICH) of human drug registration technical standards, if the single impurity amount in the bulk drug or the preparation composition thereof exceeds 0.05%, reporting is required; if the single impurity amount exceeds 0.1%, confirmation is required; if the single impurity amount exceeds 0.15%, security data support is required. In the process of drug development, the structure, source and direction of impurities are required to be clarified, the process impurities, degraded impurities and the like are required to be comprehensively understood and controlled, and an effective theoretical basis is provided for controlling the quality of the drug. In the development process of JJH201601 bulk drug, the applicant finds that JJH201601 molecules can be degraded or configuration converted through forced degradation test and stability test, partial impurities have an increasing trend along with the increase of storage time, and the impurities have the characteristics of unexpected biological activity and toxicity and can greatly influence the quality of the bulk drug.

The relation between impurities and medicine safety is very complex, the influence of optical isomers of chiral compounds on medicine safety is particularly complex, some enantiomer pharmacological actions are the same but have different degrees, some actions have complementarity, but the existence of different optical isomers of a plurality of optical isomer medicines can influence the medicine effect and even possibly cause serious adverse reactions. For example, the racemate of ofloxacin for the treatment of infections is only half as effective as the levorotatory form, and for example the R-enantiomer and S-enantiomer of zacopride are opposite, and the S-isomer of thalidomide has strong embryotoxic and teratogenic effects, while its R-isomer is safe and effective.

Disclosure of Invention

After a lot of studies on the taxane compound (JJH 201601) as described above, the applicant found that the taxane compound is critical for toxicity and effect, and completed the present invention.

The technical scheme adopted by the invention for achieving the purpose is as follows: a silicon-containing impurity compound of taxane compounds has a structural formula shown in formula (I):

further, the taxane compound has a structure as shown in formula (II):

the invention also discloses a preparation method of the silicon-containing impurity compound of the taxane compound, which comprises the specific steps of dissolving the compound of the formula III by using a polar aprotic solvent to obtain a mixture, adding the mixture into the polar protic solvent containing an acidic reagent under the condition of heating or not, stirring or not under the condition of heating or not until the reaction is finished, and carrying out post-treatment to obtain the silicon-containing impurity compound of the taxane compound shown as the formula I

Further, the polar aprotic solvent is any one of dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, acetone and N, N-dimethylformamide;

still further, the polar aprotic solvent is dichloromethane;

further, the acidic reagent is any one of hydrochloric acid, hydrobromic acid or sulfuric acid;

still further, hydrochloric acid.

Further, the polar protic solvent is an alcoholic solvent;

still further, the solvent is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol and tert-butanol;

still further, it is methanol.

Further, the reaction temperature is 0-40 ℃, and the volume ratio of the acidic reagent to the polar proton solvent is 0.01-0.2:1;

still further, the reaction temperature is 5-15 ℃, and the volume ratio of the acidic reagent to the polar proton solvent is 0.02-0.05:1.

Further, the post-treatment is extraction and column chromatography after slowly adding saturated sodium bicarbonate solution to adjust the pH=7-9;

still further, the column chromatography is silica gel column chromatography separation;

still further, the column chromatography separation uses 100-400 mesh silica gel.

Further, when the column chromatography is used for separation, the eluent is a mixture of ethyl acetate/n-hexane, a mixture of dichloromethane/methanol or a mixture of ethyl acetate/petroleum ether;

still further, the eluent is a mixture of ethyl acetate and n-hexane;

still further, the volume ratio of the ethyl acetate to the n-hexane is 1:1-6;

still further, the volume ratio of ethyl acetate to n-hexane was 1:3.

The invention also discloses the application of the silicon-containing impurity compound of the taxane compound in controlling the quality of the taxane compound or the pharmaceutical composition containing the taxane compound.

Further, the content of the silicon-containing impurity compound of the taxane compound shown in the formula (I) in the taxane compound is lower than 0.5%;

still further, the control of the quality of the taxane or the pharmaceutical composition containing the taxane is specifically the control of the pharmacological activity, toxicity or metabolic rate thereof.

According to the JJH201601 synthesis route (shown below), in the DTX2 hydrolysis reaction step, the side chain triethylsilyl group is more easily removed, resulting in an intermediate (molecule of formula I). As process impurities, the molecules shown in the formula I have certain residues in the finished product, and the control of the content of the compound shown in the formula (I) in the JJH201601 bulk drug or the pharmaceutical composition thereof has great significance in improving the pharmacological activity, toxicity and the like of the JJH 201601.

Advantageous effects

Due to the adoption of the technical scheme, the invention has the beneficial effects that:

1) The impurity shown in the formula I in the technical scheme of the invention is a process impurity, and the content of the impurity in raw materials or preparations is not further increased. Through forced degradation and stability tests, the impurity content shown in the formula I cannot be increased. According to the pilot plant results, the impurities remain in each batch of finished products, and limit control is necessary.

2) The compound provided by the invention can be used for detecting impurities of taxane compounds, and can provide a reference substance for quality control of taxane compounds; the control of the content of the compound provided by the invention can obviously improve and reduce the toxicity or side effect of the taxane compound when the taxane compound is used as a medicine, and has obvious benefit for improving the pharmacological activity of the taxane compound when the taxane compound is used as the medicine.

Drawings

FIG. 1 is a diagram of a precise molecular mass measurement of ESI (+) -TOFMS of the structure shown in formula I;

FIG. 2 shows the structure of formula I in CDCl ₃ In (a) and (b) ¹ H-NMR spectrum;

FIG. 3 is a high performance liquid chromatography of JJH201601 and a compound of formula I.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The technical solutions in the embodiments of the present invention will be clearly and completely described below in connection with the embodiments of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

Example 1

Preparation of Compounds of formula I

Under the condition of room temperature, 20mL of 2% hydrochloric acid methanol solution is prepared and added into a 100mL three-necked flask, and the temperature is controlled to about 5 ℃. 500mg of DTX2 is weighed, dissolved by 1mL of dichloromethane and added into a hydrochloric acid methanol solution in a dropwise manner, and the temperature is controlled to be 5-10 ℃. The reaction was monitored by TLC after completion of the dropwise addition and stirring at a constant temperature. After the reaction was completed, a saturated sodium bicarbonate solution was added dropwise to the reaction until ph=7 to 8, and 20mL of ethyl acetate was added to extract twice. The organic phases are combined, dried by a proper amount of anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain a crude product. Separating the crude product by column chromatography (200-300 mesh silica gel), eluting with ethyl acetate/n-hexane (1:4-1:3). The desired eluate was concentrated to dryness under reduced pressure to give 393mg of a white powder in a molar yield of 87%.

Example 2

Under the condition of room temperature, 20mL of 2% hydrochloric acid methanol solution is prepared and added into a 100mL three-necked flask, and the temperature is controlled to about 0 ℃. 500mg of DTX2 is weighed, dissolved by 1mL of dichloromethane and added into a hydrochloric acid methanol solution in a dropwise manner, and the temperature is controlled to be 0-5 ℃. The reaction was monitored by TLC after completion of the dropwise addition and stirring at a constant temperature. After the reaction was completed, a saturated sodium bicarbonate solution was added dropwise to the reaction until ph=7 to 8, and 20mL of ethyl acetate was added to extract twice. The organic phases are combined, dried by a proper amount of anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain a crude product. Separating the crude product by column chromatography (200-300 mesh silica gel), eluting with ethyl acetate/n-hexane (1:4-1:3). The desired eluate was concentrated to dryness under reduced pressure to give 340mg of a white powder in 75% molar yield.

Example 3

Under the condition of room temperature, 20mL of 2% hydrochloric acid methanol solution is prepared and added into a 100mL three-necked flask, and the temperature is controlled to about 10 ℃. 500mg of DTX2 is weighed, dissolved by 1mL of dichloromethane and added into a hydrochloric acid methanol solution in a dropwise manner, and the temperature is controlled to be 10-15 ℃. The reaction was monitored by TLC after completion of the dropwise addition and stirring at a constant temperature. After the reaction was completed, a saturated sodium bicarbonate solution was added dropwise to the reaction until ph=7 to 8, and 20mL of ethyl acetate was added to extract twice. The organic phases are combined, dried by a proper amount of anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain a crude product. Separating the crude product by column chromatography (200-300 mesh silica gel), eluting with ethyl acetate/n-hexane (1:4-1:3). The desired eluate was concentrated to dryness under reduced pressure to give 407mg of a white powder in 90% molar yield.

Example 4

Under the condition of room temperature, 20mL of 2% hydrochloric acid methanol solution is prepared and added into a 100mL three-necked flask, and the temperature is controlled to about 25 ℃. 500mg of DTX2 is weighed, dissolved by 1mL of dichloromethane and added into a hydrochloric acid methanol solution in a dropwise manner, and the temperature is controlled at 25-30 ℃. The reaction was monitored by TLC after completion of the dropwise addition and stirring at a constant temperature. After the reaction was completed, a saturated sodium bicarbonate solution was added dropwise to the reaction until ph=7 to 8, and 20mL of ethyl acetate was added to extract twice. The organic phases are combined, dried by a proper amount of anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain a crude product. Separating the crude product by column chromatography (200-300 mesh silica gel), eluting with ethyl acetate/n-hexane (1:4-1:3). The desired eluate was concentrated to dryness under reduced pressure to give 298mg of a white powder in 66% molar yield.

Example 5

Under the condition of room temperature, 20mL of 5% hydrochloric acid methanol solution is prepared and added into a 100mL three-necked flask, and the temperature is controlled to about 5 ℃. 500mg of DTX2 is weighed, dissolved by 1mL of dichloromethane and added into a hydrochloric acid methanol solution in a dropwise manner, and the temperature is controlled to be 5-10 ℃. The reaction was monitored by TLC after completion of the dropwise addition and stirring at a constant temperature. After the reaction was completed, a saturated sodium bicarbonate solution was added dropwise to the reaction until ph=7 to 8, and 20mL of ethyl acetate was added to extract twice. The organic phases are combined, dried by a proper amount of anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain a crude product. Separating the crude product by column chromatography (200-300 mesh silica gel), eluting with ethyl acetate/n-hexane (1:4-1:3). The desired eluate was concentrated to dryness under reduced pressure to give 411mg of a white powder in 91% molar yield.

Example 6

Under the condition of room temperature, 20mL of 5% hydrochloric acid methanol solution is prepared and added into a 100mL three-necked flask, and the temperature is controlled to about 5 ℃. 500mg of DTX2 is weighed, dissolved by 1mL of tetrahydrofuran and then added into a hydrochloric acid methanol solution in a dropwise manner, and the temperature is controlled to be 5-10 ℃. The reaction was monitored by TLC after completion of the dropwise addition and stirring at a constant temperature. After the reaction was completed, a saturated sodium bicarbonate solution was added dropwise to the reaction until ph=7 to 8, and 20mL of ethyl acetate was added to extract twice. The organic phases are combined, dried by a proper amount of anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain a crude product. Separating the crude product by column chromatography (200-300 mesh silica gel), eluting with ethyl acetate/n-hexane (1:4-1:3). The desired eluate was concentrated to dryness under reduced pressure to give 375mg of a white powder in 83% molar yield.

Example 7

Under the condition of room temperature, 20mL of 5% hydrochloric acid methanol solution is prepared and added into a 100mL three-necked flask, and the temperature is controlled to about 5 ℃. 500mg of DTX2 is weighed, dissolved by 2mL of acetone and then added into a hydrochloric acid methanol solution in a dropwise manner, and the temperature is controlled to be 5-10 ℃. The reaction was monitored by TLC after completion of the dropwise addition and stirring at a constant temperature. After the reaction was completed, a saturated sodium bicarbonate solution was added dropwise to the reaction until ph=7 to 8, and 20mL of ethyl acetate was added to extract twice. The organic phases are combined, dried by a proper amount of anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain a crude product. Separating the crude product by column chromatography (200-300 mesh silica gel), eluting with ethyl acetate/n-hexane (1:4-1:3). The desired eluate was concentrated to dryness under reduced pressure to give 375mg of a white powder in 83% molar yield.

Example 8

Under the condition of room temperature, 30mL of 5% hydrochloric acid methanol solution is prepared and added into a 100mL three-necked flask, and the temperature is controlled to about 5 ℃. 500mg of DTX2 is weighed, dissolved by 1mL of dichloromethane and added into a hydrochloric acid methanol solution in a dropwise manner, and the temperature is controlled to be 5-10 ℃. The reaction was monitored by TLC after completion of the dropwise addition and stirring at a constant temperature. After the reaction was completed, a saturated sodium bicarbonate solution was added dropwise to the reaction until ph=7 to 8, and 20mL of ethyl acetate was added to extract twice. The organic phases are combined, dried by a proper amount of anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain a crude product. Separating the crude product by column chromatography (200-300 mesh silica gel), eluting with ethyl acetate/n-hexane (1:4-1:3). The desired eluate was concentrated to dryness under reduced pressure to give 389mg of a white powder in 86% molar yield.

Example 9

Under the condition of room temperature, 20mL of 5% hydrochloric acid methanol solution is prepared and added into a 100mL three-necked flask, and the temperature is controlled to about 5 ℃. 500mg of DTX2 is weighed, dissolved by 2mL of dichloromethane and then added into a hydrochloric acid methanol solution in a dropwise manner, and the temperature is controlled to be 5-10 ℃. The reaction was monitored by TLC after completion of the dropwise addition and stirring at a constant temperature. After the reaction was completed, a saturated sodium bicarbonate solution was added dropwise to the reaction until ph=7 to 8, and 20mL of ethyl acetate was added to extract twice. The organic phases are combined, dried by a proper amount of anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain a crude product. Separating the crude product by column chromatography (200-300 mesh silica gel), eluting with ethyl acetate/n-hexane (1:4-1:3). The desired eluate was concentrated to dryness under reduced pressure to give 398mg of a white powder in 88% molar yield.

Example 10

Structure confirmation of the compound of formula (I):

(1) High resolution mass spectrometry (ESI (+) -TOFMS):

the molecular formula of the product is C ₅₈ H ₇₄ N ₂ O ₁₆ Si, exact is 1082.4808. In the high-resolution mass spectrum positive ion mode, the molecular ion peak is 1105.4617, namely [ M+Na ]] ⁺ The molecular formula is consistent with the molecular formula shown in the formula I, and is shown in figure 1.

(2) Nuclear magnetic resonance spectroscopy (NMR):

instrument model: 500M nmr, solvent: CDCl ₃ 。

The structural atomic numbers of formula I are shown below:

the results of the nuclear magnetic analysis are shown in table 1:

TABLE 1 Structure shown in I ¹ H NMR ¹³ C NMR assignment

As shown in FIG. 2, in ¹ In the H NMR spectrum, in the NMR spectrum, the product ¹ There are a total of 32 groups of peaks (except solvent and water peaks) in H NMR, the integration ratio is 2:2:1:4:4:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:1:2:3:3:3:9:6:9:6 from low to high, 73 protons in total, and the sample is consistent with the impurity structure shown in formula I.

In conclusion, the product is prepared by HRMS, ¹ The HNMR method confirms that the structural formula of the sample is consistent with that of the formula I.

Example 11

JJH201601 and silicon-containing impurity compound of formula (I):

chromatographic conditions: octadecylsilane chemically bonded silica as filler (AgilentEclipse Plus,4.6 mm. Times.150 mm,3.5 μm or column with comparable performance); ammonium formate buffer (5 mM ammonium formate in water, 10% formic acid to adjust pH to 4.0) -acetonitrile (30:70) as mobile phase A, ammonium formate buffer (5 mM ammonium formate in water, 10% formic acid to adjust pH to 4.0) -acetonitrile (5:95) as mobile phase B; the flow rate is 1.2mL/min; column temperature is 40 ℃; the detection wavelength was 232nm. Gradient elution was performed as follows.

TABLE 2 specific conditions

As shown in fig. 3, JJH201601 retention time was 2.571 minutes, and the compound of formula I retention time was 15.856 minutes, with specific parameters shown in table 3.

TABLE 3 Table 3

< Peak Table >

Detector A232 nm

Peak number	Retention time	Area of	Area percent	Theoretical plate number (USP)	Degree of separation (USP)	Tailing factor
							1	2.571	18157612	99.820	4826	--	1.123
2	4.894	16436	0.090	11890	14.184	1.066
							3	15.856	16325	0.090	60564	50.140	1.189
Totals to		18190374	100.000

Example 12

Acute toxicity study of JJH201601 drug substance with different content of impurity shown in formula I in ICR mice given intravenously once:

a total of 60 ICR mice of SPF grade were taken and weighing approximately 20-25g,6-8 weeks of age. 6 groups of 10 groups of male and female halves are arranged, and the groups are respectively:

test group 1: contains 0.1% of impurity group represented by formula I: dissolving compound JJH201601 in appropriate amount of Tween-80 and ethanol, and diluting with 5% glucose injection to desired concentration;

test group 2: contains 0.25% of impurity group represented by formula I: dissolving compound JJH201601 in appropriate amount of Tween-80 and ethanol, and diluting with 5% glucose injection to desired concentration;

test group 3: contains 0.50% of impurity group represented by formula I: dissolving compound JJH201601 in appropriate amount of Tween-80 and ethanol, and diluting with 5% glucose injection to desired concentration;

test group 4: contains 0.75% of impurity group represented by formula I: dissolving compound JJH201601 in appropriate amount of Tween-80 and ethanol, and diluting with 5% glucose injection to desired concentration;

test group 5: contains 1.0% of impurity group represented by formula I: dissolving compound JJH201601 in appropriate amount of Tween-80 and ethanol, and diluting with 5% glucose injection to desired concentration;

vehicle control group: 5% glucose injection solution;

the test groups 1-5 were each injected with the drug via ICR mice tail vein at a dose of 25mg/kg at a concentration of 5mg/mL. Animals were observed at any time the day after dosing and continuously for 14 days, reporting animal mortality. The results are shown in Table 4 below:

TABLE 4 Table 4

Group of	Impurity content shown in formula I	Animal death rate
			Test group 1	0.1％	0/10
Subject group 2	0.25％	0/10
			Subject group 3	0.5％	0/10
Test group 4	0.75％	0/10
			Subject group 5	1.0％	2/10
Vehicle control group	0％	0/10

From the above results, it was found that when the impurity content of formula I in the compound JJH201601 exceeds 0.75%, a single intravenous injection of ICR mice may cause death of some animals due to acute toxicity. Thus, the maximum tolerance of the compound JJH201601 for rodents of the impurity of formula I is 0.75% and the control limit for the impurity of formula I is less than or equal to 0.5% in combination with the quality achievable by the preparation process.

The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and variations could be made by those skilled in the art without departing from the principles of the present invention, which is also considered to be within the scope of the invention.

Claims

1. The silicon-containing impurity compound of the taxane compound is characterized in that the structural formula of the compound is shown as a formula (I):

2. the silicon-containing impurity compound of the taxane compound according to claim 1, wherein the taxane compound has a structure represented by formula (II):

3. the process for producing a silicon-containing impurity compound of a taxane according to claim 1 or 2, which comprises the steps of dissolving a compound of formula III in a polar aprotic solvent to obtain a mixture, adding the mixture to a polar protic solvent containing an acidic reagent with or without heating, stirring or not stirring until the reaction is completed with or without heating, and post-treating to obtain a silicon-containing impurity compound of a taxane of formula I

4. The method for producing a silicon-containing impurity compound according to claim 3, wherein the polar aprotic solvent is any one of dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, acetone, N-dimethylformamide;

preferably dichloromethane;

the acidic reagent is any one of hydrochloric acid, hydrobromic acid or sulfuric acid;

hydrochloric acid is preferred.

5. The method for producing a silicon-containing impurity compound according to claim 3, wherein the polar protic solvent is an alcoholic solvent;

preferably methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol or tert-butanol;

preferably methanol.

6. The method for producing a silicon-containing impurity compound according to claim 3, wherein the reaction temperature is 0 to 40 ℃, and the volume ratio of the acidic reagent to the polar protic solvent is 0.01 to 0.2:1;

preferably, the reaction temperature is 5-15 ℃, and the volume ratio of the acidic reagent to the polar proton solvent is 0.02-0.05:1.

7. The method for producing a silicon-containing impurity compound according to claim 3, wherein the post-treatment is extraction and column chromatography after the pH is adjusted to 7-9 by slowly adding saturated sodium bicarbonate solution;

preferably, the column chromatography is silica gel column chromatography separation;

still preferably, the column chromatography separation uses 100-400 mesh silica gel.

8. The method for producing a silicon-containing impurity compound according to claim 7, wherein the eluent is a mixture of ethyl acetate/n-hexane, a mixture of methylene chloride/methanol or a mixture of ethyl acetate/petroleum ether at the time of the column chromatography separation;

preferably, the eluent is a mixture of ethyl acetate and n-hexane;

still preferably, the volume ratio of the ethyl acetate to the n-hexane is 1:1-6;

still preferably, the volume ratio of ethyl acetate to n-hexane is 1:3.

9. Use of a silicon-containing impurity compound of a taxane according to claim 1 or 2 for controlling the quality of the taxane or a pharmaceutical composition containing the taxane.

10. The use according to claim 9, wherein the content of silicon-containing impurity compounds of the taxane compounds of formula (I) is less than 0.5%;

preferably, the control of the quality of the taxane or the pharmaceutical composition containing the taxane is specifically the control of the pharmacological activity, toxicity or metabolic rate thereof.