A taxane derivative, a preparation method and application thereof

Abstract

The present application provides a taxane derivative, a preparation method and application thereof, the taxane derivative has a structure as shown in formula I: The compound provided by the present application can be used for detecting impurities of taxane anticancer compounds, and can provide a control sample for quality control of the taxane anticancer compounds; controlling the content of the taxane derivative provided by the present application can obviously improve the toxicity or side effects of the taxane anticancer compounds when used as a drug, improve the long-term stability thereof, and has obvious benefits for improving the pharmacological activity of the taxane derivative when used as a drug.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a taxane derivative and a preparation method and application thereof. BACKGROUND

[0002] One of the biggest problems plaguing mankind is cancer, and a huge number of people die of cancer every year, and cancer is one of the main causes of death. There are many methods for treating cancer, and one of the most important treatment methods is chemotherapy. Chemotherapy inhibits the proliferation of cancer cells by inhibiting the division of rapidly growing cells, but at the same time, it also affects the rapid proliferation of normal cells, such as hair follicles, bone marrow and gastrointestinal cells. And many chemotherapy drugs have the disadvantages of poor solubility, lack of targeting, short residence time in the body, high toxicity to normal healthy tissues, etc., which limit their application.

[0003] Taxane drugs are one of the most concerned anti-tumor drugs at present, and although taxanes have the disadvantages of side effects and poor solubility, they are still the first choice for treating metastatic cancer. There are three kinds of taxane drugs currently used in clinical, which are paclitaxel, docetaxel (docetaxel) and cabazitaxel, and the specific structures are as follows:

[0004]

[0005] Taxanes are not only widely used in the treatment of ovarian cancer, prostate cancer and breast cancer, but also widely used in the treatment of bladder cancer, gastric cancer and non-small cell lung cancer. However, because the above compounds have high lipophilicity and are not easy to dissolve in water, a surfactant is usually added when they are made into pharmaceutical preparations, and the surfactant can easily produce side effects. Therefore, it has great clinical value to develop new taxane drugs. On the basis of the structure of docetaxel, the applicant has carried out structural optimization, and a new taxane derivative, code JJH201601, has been obtained through preliminary drug screening. The compound has been disclosed and authorized in the patent with the application number CN201810185012.4, and the specific structure is as follows:

[0006]

[0007] According to the preliminary efficacy research results, the drug efficacy of the nude mouse model is significantly improved, and the toxic side effects are obviously reduced, the tumor can be eliminated (the tumor inhibition rate reaches more than 99%), and 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. At present, the compound has entered the administrative approval stage. In April 2023, the State Drug Administration approved the clinical trial of JJH201601 liposome injection for single drug in advanced solid tumors, notice number: 2023LP00637. In July 2023, clinical phase I research was started, and it is expected to be widely used in the clinical treatment of related diseases.

[0008] The study of impurities is a necessary and important part in the development, imitation and declaration process of drugs. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) defines impurities as: any component present in a drug that has a chemical structure different from the drug. Impurity content is a key quality attribute of drug quality. Most impurities contained in drugs have potential biological activity and possible interactions between components, affecting the safety and efficacy of drugs, and even producing toxic side effects. In order to ensure drug safety, each impurity in the active pharmaceutical ingredient must be safety evaluated, that is, the impurity limit ensuring safety is established. According to the requirements of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), if the single impurity content in the raw material drug or its preparation composition exceeds 0.05%, it should be reported; if the single impurity content exceeds 0.1%, it needs to be confirmed; if the single impurity content exceeds 0.15%, it needs to have safety data support. In the drug development process, the structure, source and destination of impurities need to be clarified, and process impurities, degradation impurities and the like need to be fully understood and controlled to provide effective theoretical basis for drug quality control. During the development of JJH201601 raw material drug, the applicant found through experiments that JJH201601 molecules can undergo hydrolysis, and part of the impurities have an increasing trend with increasing storage time. Impurities have unpredictable characteristics of biological activity and toxicity, and have a great impact on the quality of raw materials. SUMMARY

[0009] After a large amount of research on the taxane derivative (JJH201601) as described above, the applicant found one of the keys to the toxicity of the taxane derivative and completed the present application.

[0010] The technical scheme adopted by the present application to achieve the above-mentioned purpose is: a taxane derivative, whose structural formula is shown as formula (I):

[0011]

[0012] The present application also provides a preparation method of the taxane derivative as described above, which is prepared by reacting a compound shown in formula (II) in the presence of an acid reagent and post-treatment, wherein the formula (II) is shown as follows:

[0013]

[0014] Further, the specific steps are as follows: dissolving the compound shown in formula (II) with a polar organic solvent, adding an acid reagent, stirring or not stirring under heating or not heating, and then post-treatment to obtain the taxane derivative.

[0015] Further, the organic solvent is any one or more of dichloromethane, ethyl acetate, methanol, ethanol, tetrahydrofuran, acetone, acetonitrile, dimethyl sulfoxide, and N,N-dimethylformamide;

[0016] Preferably, the organic solvent is dichloromethane or tetrahydrofuran;

[0017] More preferably, the organic solvent is dichloromethane.

[0018] Further, the acid reagent is any one or more of formic acid, trifluoroacetic acid, hydrochloric acid, and hydrobromic acid;

[0019] Preferably, the acid reagent is formic acid or trifluoroacetic acid;

[0020] More preferably, the acid reagent is formic acid.

[0021] Further, the volume ratio of the organic solvent to the acid reagent is (0-1):1;

[0022] Preferably, the volume ratio of the organic solvent to the acid reagent is (0.1-0.5):1.

[0023] Further, the reaction temperature is 0-60℃;

[0024] Preferably, the reaction temperature is 0-20℃.

[0025] Further, the post-treatment is column chromatography or preparative chromatography separation;

[0026] Preferably, the post-treatment is column chromatography, and the eluent is a mixture of ethyl acetate, n-hexane and triethylamine, dichloromethane, a mixture of methanol and triethylamine, or a mixture of ethyl acetate, petroleum ether and triethylamine;

[0027] Preferably, the eluent is a mixture of ethyl acetate, n-hexane and triethylamine;

[0028] More preferably, the volume ratio of ethyl acetate to n-hexane is 1:1-6, and the amount of triethylamine is 0.05%-1% of the volume of the mixture of ethyl acetate and n-hexane.

[0029] The present application also provides the use of the taxane derivative as described above in controlling the quality of the compound of formula (II) or the pharmaceutical composition containing the compound of formula (II).

[0030] Further, the content of the taxane derivative of formula (I) in the compound of formula (II) is less than 0.5% or in the pharmaceutical composition containing the compound of formula (II) is less than 0.6%;

[0031] Further, the content of the impurity compound of the taxane derivative of formula (I) in the taxane derivative is less than 0.3%

[0032] Further, the control of the quality of the taxane derivative or the pharmaceutical composition containing the taxane derivative is specifically the control of the pharmacological activity, toxicity or metabolic rate.

[0033] The control of the content of the compound of formula (I) in the JJH201601 bulk drug or the pharmaceutical composition thereof is of great significance for improving the pharmacological activity, toxicity, etc. of JJH201601.

[0034] Advantages

[0035] Due to the adoption of the above technical solutions, the present application has the following advantages:

[0036] The compound provided by the present application can be used for the detection of impurities of taxane compounds, and can provide a control sample for the quality control of taxane compounds; the control of the content of the compound provided by the present application can significantly improve the toxicity or side effects of taxane compounds when used as drugs, and has obvious benefits for improving the pharmacological activity of taxane compounds when used as drugs BRIEF DESCRIPTION OF DRAWINGS

[0037] Figure 1 ESI(+)-TOF MS precise molecular weight determination spectrum of the structure of formula I;

[0038] Figure 2 CD3OD in the structure of formula I 1 H-NMR spectrum;

[0039] Figure 3 High performance liquid chromatogram of JJH201601 and the compound of formula I;

[0040] Figure 4 High performance liquid chromatogram of JJH201601 and the compound of formula I;

[0041] Figure 5 HPLC of JJH201601 and its base destroyed forced degradation of test solution;

[0042] Figure 6 JJH201601 10 days related substances test results spectrum;

[0043] Figure 7 JJH201601 25℃ long-term two years related substances test results spectrum. DETAILED DESCRIPTION

[0044] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present application.

[0045] Example 1

[0046] Preparation of the compound shown in formula I

[0047]

[0048] At room temperature, 500 mg of JJH201601 raw material was weighed into a 50 mL three-necked flask, then 2 mL of dichloromethane was added to stir and dissolve and control the temperature to about 5℃, 10 mL of formic acid was added dropwise, and the temperature was controlled at 5-10℃. After the dropwise addition was completed, the reaction was stirred to completion. To the reaction solution, saturated sodium bicarbonate solution was added dropwise, the pH was adjusted to 7-8, and 10 mL of ethyl acetate was added for extraction twice. The organic phase was combined, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (200-300 mesh silica gel), and the eluent was ethyl acetate / n-hexane (1:4-1:1 containing 0.1% triethylamine). The desired eluent was concentrated to dryness under reduced pressure to obtain 220 mg of the compound shown in formula I (white powder), with a molar yield of 49%. 1HNMR (CD3OD, 500M) δ: 8.06 (d, J = 7.9 Hz, 2H), 7.95 (d, J = 8.8 Hz, 2H), 7.71 (t, J1= 7.4 Hz, J1= 7.5 Hz, 1H), 7.65-7.58 (m, 4H), 7.46-7.37 (m, 4H), 7.29-7.25 (m, 1H), 6.42 (s, 1H), 6.07 (t, J1= 8.8 Hz, J2= 9.0 Hz, 1H), 5.63 (d, J = 7.2 Hz, 1H), 4.99 (d, J = 9.4 Hz, 1H), 4.37-4.34 (m, 1H), 4.28 (d, J = 7.8 Hz, 1H), 4.22 (d, J = 7.9 Hz, 1H), 4.19-4.16 (m, 2H), 3.78 (d, J = 7.2 Hz, 1H), 2.56 (s, 3H), 2.50-2.45 (m, 1H), 2.23 (s, 3H), 2.02-1.98 (m, 1H), 1.95 (s, 3H), 1.84-1.78 (m, 1H), 1.72-1.68 (m, 1H), 1.66 (s, 3H), 1.21 (s, 3H), 1.18 (s, 3H). TOF-MS: calcd for C 47 H 52 N2O 14

[0049] 869.3491[M+H] + , found 869.3431.

[0050] Example 2

[0051] Preparation of the compound shown in Formula I

[0052] At room temperature, 500 mg of JJH201601 raw material was weighed into a 50 mL three-necked flask, then 2 mL of tetrahydrofuran was added to stir and dissolve and control the temperature to about 5°C, 8 mL of formic acid was added dropwise, and the temperature was controlled at 5-10°C. After the dropwise addition was completed, the reaction was stirred to completion. To the reaction solution, saturated sodium bicarbonate solution was added dropwise, and the pH was adjusted to 7-8. 20 mL of ethyl acetate was added for extraction twice. The organic phase was combined, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (200-300 mesh silica gel), and the eluent was ethyl acetate / n-hexane (1:4-1:1 containing 0.1% triethylamine). The desired eluent was concentrated to dryness under reduced pressure to obtain 206 mg of the compound shown in Formula I (white powder), with a molar yield of 46%.

[0053] Example 3

[0054] Preparation of the compound shown in Formula I

[0055] JJH201601 was weighed into a 50 mL flask, then 2 mL of dichloromethane was added to dissolve the material and the temperature was controlled at about 15°C. 10 mL of formic acid was added dropwise while the temperature was controlled at 15-20°C. After the addition was completed, the reaction was stirred until it was completed. Saturated sodium bicarbonate solution was added dropwise to the reaction solution to adjust the pH to 7-8, and 20 mL of ethyl acetate was added to extract twice. The organic phase was combined, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain a crude product. The crude product was separated by column chromatography (200-300 mesh silica gel), and the eluent was ethyl acetate / n-hexane (1:4-1:1, containing 0.1% triethylamine). The desired eluent was concentrated under reduced pressure to dryness to obtain 177 mg of the compound of formula I (white powder), with a molar yield of 40%.

[0056] Example 4

[0057] Preparation of the compound of formula I

[0058] JJH201601 was weighed into a 50 mL flask, then 2 mL of dichloromethane was added to dissolve the material and the temperature was controlled at about 15°C. 10 mL of formic acid was added dropwise while the temperature was controlled at 15-20°C. After the addition was completed, the reaction was stirred until it was completed. Saturated sodium bicarbonate solution was added dropwise to the reaction solution to adjust the pH to 7-8, and 20 mL of ethyl acetate was added to extract twice. The organic phase was combined, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain a crude product. The crude product was separated by column chromatography (200-300 mesh silica gel), and the eluent was ethyl acetate / n-hexane (1:4-1:1, containing 0.1% triethylamine). The desired eluent was concentrated under reduced pressure to dryness to obtain 177 mg of the compound of formula I (white powder), with a molar yield of 40%.

[0059] Example 5

[0060] Preparation of the compound of formula I

[0061] JJH201601 was weighed into a 50 mL flask, then 2 mL of dichloromethane was added to dissolve the material and the temperature was controlled at about 15°C. 10 mL of formic acid was added dropwise while the temperature was controlled at 15-20°C. After the addition was completed, the reaction was stirred until it was completed. Saturated sodium bicarbonate solution was added dropwise to the reaction solution to adjust the pH to 7-8, and 20 mL of ethyl acetate was added to extract twice. The organic phase was combined, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain a crude product. The crude product was separated by column chromatography (200-300 mesh silica gel), and the eluent was ethyl acetate / n-hexane (1:4-1:1, containing 0.1% triethylamine). The desired eluent was concentrated under reduced pressure to dryness to obtain 177 mg of the compound of formula I (white powder), with a molar yield of 40%.

[0062] Example 6

[0063] Preparation of the compound of formula I

[0064] JJH201601 was dissolved in 5 mL of THF and stirred at room temperature. 10 mL of trifluoroacetic acid was added dropwise to the solution. The reaction was stirred at 5-10 °C until completion. The reaction was quenched by the addition of saturated NaHC03 solution. The pH was adjusted to 7-8. The reaction was extracted twice with 20 mL of ethyl acetate. The organic phase was combined and dried over anhydrous NaS04. The filtrate was concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (200-300 mesh silica gel) using ethyl acetate / hexane (1:4-1:1 with 0.1% triethylamine) as the eluent. The desired fractions were combined and concentrated to dryness under reduced pressure to give 116 mg of the compound of formula I (white powder) with a molar yield of 26%.

[0065] Example 7

[0066] Preparation of the compound of formula I

[0067] JJH201601 was dissolved in 5 mL of THF and stirred at room temperature. 10 mL of trifluoroacetic acid was added dropwise to the solution. The reaction was stirred at 5-10 °C until completion. The reaction was quenched by the addition of saturated NaHC03 solution. The pH was adjusted to 7-8. The reaction was extracted twice with 20 mL of ethyl acetate. The organic phase was combined and dried over anhydrous NaS04. The filtrate was concentrated to dryness under reduced pressure. The crude product was separated by column chromatography (200-300 mesh silica gel) using ethyl acetate / hexane (1:4-1:1 with 0.1% triethylamine) as the eluent. The desired fractions were combined and concentrated to dryness under reduced pressure to give 116 mg of the compound of formula I (white powder) with a molar yield of 26%.

[0068] Example 8

[0069] Preparation of the compound of formula I

[0070] JJH201601 raw material was weighed 500 mg and added to a 50 mL flask, then 3 mL of methanol was added to stir and dissolve and control the temperature to about 5°C, 6 mL of formic acid was added dropwise, the temperature was controlled at 5-10°C. After the end of the dropwise addition, the reaction was stirred to completion. To the reaction solution, saturated sodium bicarbonate solution was added dropwise, adjusted to pH = 7-8, extracted twice with 20 mL of ethyl acetate. The organic phase was combined, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (200-300 mesh silica gel), eluent ethyl acetate / n-hexane (1:4-1:1, containing 0.1% triethylamine). The desired eluent was concentrated to dryness under reduced pressure to obtain 177 mg of the compound of formula I (white powder), with a molar yield of 39.5%.

[0071] Example 9

[0072] Preparation of the compound of formula I

[0073] JJH201601 raw material was weighed 500 mg and added to a 50 mL flask, then 3 mL of methanol was added to stir and dissolve and control the temperature to about 5°C, 6 mL of formic acid was added dropwise, the temperature was controlled at 5-10°C. After the end of the dropwise addition, the reaction was stirred to completion. To the reaction solution, saturated sodium bicarbonate solution was added dropwise, adjusted to pH = 7-8, extracted twice with 20 mL of ethyl acetate. The organic phase was combined, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (200-300 mesh silica gel), eluent ethyl acetate / n-hexane (1:4-1:1, containing 0.1% triethylamine). The desired eluent was concentrated to dryness under reduced pressure to obtain 177 mg of the compound of formula I (white powder), with a molar yield of 39.5%.

[0074] Example 10

[0075] Preparation of the compound of formula I

[0076] JJH201601 raw material was weighed 500 mg and added to a 50 mL flask, then 3 mL of methanol was added to stir and dissolve and control the temperature to about 5°C, 6 mL of formic acid was added dropwise, the temperature was controlled at 5-10°C. After the end of the dropwise addition, the reaction was stirred to completion. To the reaction solution, saturated sodium bicarbonate solution was added dropwise, adjusted to pH = 7-8, extracted twice with 20 mL of ethyl acetate. The organic phase was combined, dried over an appropriate amount of anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (200-300 mesh silica gel), eluent ethyl acetate / n-hexane (1:4-1:1, containing 0.1% triethylamine). The desired eluent was concentrated to dryness under reduced pressure to obtain 177 mg of the compound of formula I (white powder), with a molar yield of 39.5%.

[0077] Example 11

[0078] JJH201601 and the impurity compound represented by formula (I) were detected

[0079] Chromatographic conditions: octadecylsilane-bonded silica gel as the filler (Agilent Eclipse Plus, 4.6 mm x 150 mm, 3.5 μm or a performance equivalent chromatographic column); ammonium formate buffer (5 mM ammonium formate aqueous solution, adjusted to pH 4.0 with 10% formic acid)-acetonitrile (65:35) as mobile phase A, ammonium formate buffer (5 mM ammonium formate aqueous solution, adjusted to pH 4.0 with 10% formic acid)-acetonitrile (30:70) as mobile phase B; flow rate was 1.2 mL / min; injection tray temperature was 20°C; column temperature was 40°C; detection wavelength was 232 nm. Gradient elution was carried out according to Table 1.

[0080] Table 1 Specific conditions

[0081] Time (min) Mobile phase A (%) Mobile phase B (%) 0 100 0 15 0 100 20 0 100 20.1 100 0 25 100 0

[0082] As shown in Figure 3 , the retention time of JJH201601 was 13.092 minutes, and the retention time of the compound represented by formula I was 3.707 minutes, and the specific parameters are shown in Table 2.

[0083] Table 2 JJH201601 and the retention time of each impurity

[0084] Detector A 232 nm

[0085] Peak number Retention time Area Height Area % Height % Theoretical plates (USP) Separation (USP) Tailing factor 1 3.707 43982 4511 0.218 0.134 3348 -- 0.978 2 9.564 12232 2229 0.061 0.066 57513 28.176 1.153 3 13.092 19980205 3337994 99.184 99.251 97035 21.539 1.099 4 14.682 71640 12549 0.356 0.373 130638 9.617 -- 5 14.865 18910 3040 0.094 0.090 113175 1.081 -- 6 17.130 17694 2859 0.088 0.085 153507 12.880 1.117 Total 20144663 3363183 100.000 100.000

[0086] The compound represented by formula I was detected in each batch of pilot production, and the specific conditions are shown in Table 3.

[0087] Table 3 Detection of the compound represented by formula I in each batch of pilot production

[0088]

[0089] Example 12

[0090] According to the forced degradation test, the product is easy to generate the characteristic impurity represented by formula I under the conditions of acid destruction and alkali destruction. Figure 4 In the table, a is a blank solvent, b is a 0.15% self-control, c is JJH201601, d is acid destruction, and e is a system suitability solution. Figure 5 In the table, a is a blank solvent, b is a 0.15% self-control, c is JJH201601, d is alkali destruction, and e is a system suitability solution.

[0091] As shown in Figure 5 , Figure 6As shown, the acid breakdown produced 1.56% of the impurity shown in Formula I, and the base breakdown produced 1.09% of the impurity shown in Formula I.

[0092] Example 13

[0093] As shown, the 25°C long-term stability data indicated that the impurity shown in Formula I increased over time, from 0.14% at 0 days to 0.27% at 0.27%. Figure 7

[0094] Table 4 Long-term two-year stability data for the impurity shown in Formula I

[0095] Time 0 days 730 days Impurity content of structure shown in Formula I 0.14％ 0.27％

[0096] Example 14

[0097] Acute toxicity study of intravenous administration of JJH201601 drug substance with different amounts of impurity shown in Formula I to ICR mice:

[0098] A total of 60 SPF ICR mice, weighing about 20-25 g, 6-8 weeks old, were used. A total of 7 groups were set up, 10 in each group, half male and half female, and were set up as follows:

[0099] Test group 1: 5% glucose injection solution of compound JJH201601 containing 0.1% of the impurity shown in Formula I;

[0100] Test group 2: 5% glucose injection solution of compound JJH201601 containing 0.2% of the impurity shown in Formula I;

[0101] Test group 3: 5% glucose injection solution of compound JJH201601 containing 0.4% of the impurity shown in Formula I;

[0102] Test group 4: 5% glucose injection solution of compound JJH201601 containing 0.6% of the impurity shown in Formula I;

[0103] Test group 5: 5% glucose injection solution of compound JJH201601 containing 0.8% of the impurity shown in Formula I;

[0104] Test group 6: 5% glucose injection solution of compound JJH201601 containing 1.0% of the impurity shown in Formula I;

[0105] Vehicle control group: 5% glucose injection solution;

[0106] ​The test groups 1-6 were respectively injected with the drug through the tail vein of ICR mice at a dose of 25 mg / kg, and the concentration of the drug was 5 mg / mL. The animals were observed at any time on the day of administration, and continuously observed for 14 days, and the death of the animals was reported. The dose of 25 mg / kg of the animals was calculated according to the human equivalent dose of compound JJH201601 (the human clinical equivalent dose was 75 mg / m 2 The results are shown in Table 5 below:

[0107] Table 5

[0108] Group Impurity content of Formula I Animal mortality rate Test group 1 0.1％ 0 / 10 Test group 2 0.2％ 0 / 10 Test group 3 0.4％ 0 / 10 Test group 4 0.6％ 0 / 10 Test group 5 0.8％ 1 / 10 Test group 6 1.0％ 2 / 10 Vehicle control group 0％ 0 / 10

[0109] From the above results, it can be seen that when the content of the impurity represented by Formula I in compound JJH201601 exceeds 0.6%, a single intravenous injection of ICR mice can cause some animals to die due to acute toxicity. Therefore, the maximum tolerable content of the impurity represented by Formula I in compound JJH201601 in rodents is 0.6%, and the content of the impurity represented by Formula I should be controlled to be ≤0.6% in the synthesis process.

[0110] The above only describes the preferred embodiments of the present application, and it should be noted that those skilled in the art can make several improvements or refinements without departing from the principles of the present application, and these improvements and refinements should also be considered within the protection scope of the present application.

Claims

1. Use of the taxane derivative of formula (I) in controlling the quality of a compound of formula (II) or a pharmaceutical composition containing a compound of formula (II), as shown below: (I) Equation (II) is shown below: (II); The content of the taxane derivative as shown in formula (I) in the compound of formula (II) is less than 0.5% or in the pharmaceutical composition containing the compound as shown in formula (II) is less than 0.6%.

2. The use as described in claim 1, wherein controlling the quality of the compound as shown in formula (II) or the pharmaceutical composition containing the compound as shown in formula (II) specifically involves controlling its pharmacological activity, toxicity, or metabolic rate.

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