Method for purifying camptothecin derivatives

Abstract

The present invention discloses a method for purifying camptothecin derivatives. Specifically, the present invention discloses a method for purifying camptothecin derivatives as shown in formula III, which comprises the following steps: solid-liquid separation of a mixture of a crude camptothecin derivative as shown in formula III, component A and component B; wherein component A is one or more of petroleum ether, n-heptane, n-pentane and n-hexane; component B is one or more of ether, isopropyl ether and methyl tert-butyl ether; the volume ratio of component A to component B is (4-100):1. The purification method of the present invention is simple and easy to operate, economical and convenient, and the obtained product has high purity, greatly reduced impurity content, high yield, and is suitable for commercial production.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical purification, and particularly relates to a method for purifying camptothecin derivatives. Background Art

[0002] Camptothecin is an alkaloid isolated from the Davidia involucrata plant, which is unique to my country. It has strong cytotoxicity and good therapeutic effects on various malignant tumors, but its drugability is poor. Camptothecin derivatives obtained by structural modification have characteristics such as good solubility, which provides a new approach for the clinical application of camptothecin drugs.

[0003] The products obtained by the preparation methods of camptothecin derivatives involved in the prior art have low purity and most of them require silica gel column chromatography purification, which may cause product loss during the purification process, has low yield and cumbersome operation, and is not suitable for commercial production.

[0004] According to the current literature, there is no method for preparing high-purity camptothecin derivatives suitable for commercial production. In view of the drug safety of camptothecin derivatives, it is necessary to provide a purification process for preparing high-purity camptothecin derivatives suitable for commercial production. Summary of the invention

[0005] In order to solve the problem that there is a lack of purification methods for preparing high-purity camptothecin derivatives suitable for commercial production in the prior art, the present invention provides a purification method that can prepare high-purity camptothecin derivatives and is suitable for commercial production. The present invention uses a mixed solvent to treat the crude camptothecin derivatives to obtain high-purity camptothecin derivative products, eliminating purification technology operations such as column chromatography and reverse phase preparative chromatography, which is convenient, fast, time-saving and labor-saving.

[0006] The present invention solves the above technical problems through the following methods.

[0007] The present invention provides a method for purifying a camptothecin derivative as shown in formula III, which comprises the following steps: solid-liquid separation of a mixture of a crude camptothecin derivative as shown in formula III, component A and component B; wherein the component A is one or more of petroleum ether, n-heptane, n-pentane and n-hexane; the component B is one or more of ethyl ether, isopropyl ether and methyl tert-butyl ether; the volume ratio of the component A to the component B is (4-100):1, preferably (5-75):1, preferably (25-60):1, more preferably (30-60):1, for example 30:1, 40:1, 50:1 or 60:1;

[0008]

[0009] In formula III, R1 is hydrogen or C 1-5Alkyl, preferably C 1-3 Alkyl, more preferably ethyl;

[0010] R2 is hydrogen or C 1-5 Alkyl, preferably C 1-3 Alkyl, more preferably ethyl;

[0011] R3 is C 1-5 Alkyl, preferably C 1-4 Alkyl, such as tert-butyl or ethyl, preferably tert-butyl;

[0012] R4 is C 1-5 Alkyl, preferably C 1-3 Alkyl, such as methyl or ethyl, preferably methyl;

[0013] R5 is C 1-5 Alkyl, preferably C 1-3 The alkyl group is, for example, methyl or ethyl, preferably methyl.

[0014] Preferably, the mixture consists of a crude camptothecin derivative as shown in Formula III, component A and component B.

[0015] Preferably, the mixture is obtained by mixing a crude camptothecin derivative as shown in Formula III with component A and component B, and stirring.

[0016] Wherein, the stirring time is preferably 1 to 3 hours, for example 2 hours.

[0017] Wherein, the specific step of mixing the crude camptothecin derivative as shown in formula III with component A and component B preferably comprises: first mixing the crude camptothecin derivative as shown in formula III with component B, and then mixing with component A. Preferably, the specific step of mixing the crude camptothecin derivative as shown in formula III with component A and component B comprises: first dissolving the crude camptothecin derivative as shown in formula III with component B, and then adding component A.

[0018] The component B is preferably methyl tert-butyl ether.

[0019] The composition and ratio of component A and component B are preferably one of the following:

[0020]

[0021]

[0022] Preferably, the composition and ratio of component A and component B are one of those shown in the following table:

[0023]

[0024]

[0025] Further preferably, the composition and ratio of component A and component B are one of those shown in the following table:

[0026]

[0027]

[0028] The solid-liquid separation may be carried out by a conventional solid-liquid separation method in the art. Preferably, the specific step of the solid-liquid separation comprises filtering the mixture of the crude camptothecin derivative as shown in Formula III, component A and component B. More preferably, the specific step of the solid-liquid separation further comprises: treating the filter cake obtained by the filtration under reduced pressure to remove the residual solvent.

[0029] Wherein, the mass ratio of the crude camptothecin derivative as shown in Formula III to component B is preferably 1:(1-5), more preferably 1:(2-4), and even more preferably 1:3.

[0030] In the present invention, the crude camptothecin derivative may be solid or liquid (such as oil), preferably solid. The purity of the crude camptothecin derivative is preferably above 80%, more preferably above 85%.

[0031] In the present invention, preferably, the method for preparing the crude camptothecin derivative as shown in Formula III comprises: reacting the compound as shown in Formula II and the compound as shown in Formula IV in an organic solvent, and concentrating the obtained reaction solution to obtain the crude camptothecin derivative as shown in Formula III;

[0032]

[0033] Where R1 is C 1-5 Alkyl, preferably C 1-3 Alkyl, more preferably ethyl;

[0034] R2 is C 1-5 Alkyl, preferably C 1-3 Alkyl, more preferably ethyl;

[0035] R3 is C 1-5 Alkyl, preferably C 1-4 Alkyl, such as tert-butyl or ethyl, preferably tert-butyl;

[0036] R4 is C 1-5 Alkyl, preferably C 1-3 Alkyl, such as methyl or ethyl, preferably methyl;

[0037] R5 is C 1-5 Alkyl, preferably C 1-3 Alkyl, such as methyl or ethyl, preferably methyl;

[0038] X is halogen, preferably chlorine.

[0039] Wherein, the reaction can be carried out under the action of a base.

[0040] Preferably, in the compound as shown in Formula IV, R3, R4 and R5 are not methyl groups at the same time.

[0041] Wherein, the compound as shown in Formula II is preferably (SN38), the compound as shown in formula IV is preferably Accordingly, the compound shown in formula III is preferably (Compound I).

[0042] Wherein, the base is preferably N,N-diisopropylethylamine. The equivalent ratio of the base to the compound shown in Formula II is preferably (2.3-3.5):1, for example 3:1.

[0043] Wherein, the equivalent ratio of the compound represented by Formula IV to the compound represented by Formula II is preferably (2-3):1, for example 2.4:1.

[0044] The reaction temperature is preferably room temperature, such as 25-35° C. The reaction time may be 1-3 h, such as 2 h.

[0045] The organic solvent may be a water-soluble organic solvent or a first water-insoluble organic solvent, and the first water-insoluble organic solvent is preferably dichloromethane. The mass ratio of the organic solvent to the compound shown in Formula II is preferably (10-25):1, more preferably (10-15):1.

[0046] Preferably, the method for preparing the crude camptothecin derivative as shown in formula III further comprises: before concentrating the obtained reaction solution, washing the obtained reaction solution with a water washing agent, wherein the water washing agent is water and / or saturated saline. When the water washing agent is water, it is preferably purified water. The ratio of the mass of the water washing agent to the mass of the compound as shown in formula II in the reaction is preferably (10-25):1, more preferably (10-15):1.

[0047] Preferably, when the organic solvent is a first water-insoluble organic solvent, the step of washing the obtained reaction solution with a water washing agent comprises: mixing the obtained reaction solution with the water washing agent to obtain a mixture, and separating the layers to obtain an organic layer and an aqueous layer.

[0048] Preferably, when "the method for preparing the crude camptothecin derivative as shown in Formula III further includes: washing the obtained reaction solution with a water washing agent before concentrating the obtained reaction solution", the organic solvent is a water-soluble organic solvent, and the step of "washing the obtained reaction solution with a water washing agent" includes: mixing the obtained reaction solution with the water washing agent and a second water-insoluble organic solvent to obtain a mixture, and layering to obtain an organic layer and an aqueous layer. The first water-insoluble organic solvent and the second water-insoluble organic solvent may be the same or different. The ratio of the mass of the second water-insoluble organic solvent to the mass of the compound as shown in Formula II in the reaction is preferably (10-25):1, more preferably (10-15):1. The second water-insoluble organic solvent is preferably dichloromethane. Preferably, the step of "washing the obtained reaction solution with a water washing agent" also includes: concentrating the obtained reaction solution before mixing the obtained reaction solution with the water washing agent and the second water-insoluble organic solvent to obtain a mixture. Preferably, the step of washing the obtained reaction solution with a water washing agent comprises: concentrating the obtained reaction solution, mixing it with a water-insoluble organic solvent, and then mixing it with the water washing agent to obtain a mixture, and separating the layers to obtain an organic layer and an aqueous layer.

[0049] Preferably, the step of "washing the obtained reaction solution with a water washing agent" further comprises: stirring the obtained mixture before the stratification. The stirring time is preferably 1 to 2 hours, such as 1 hour. The stirring is preferably carried out at 15 to 35°C, such as 25°C.

[0050] Preferably, the step of "concentrating the obtained reaction solution" comprises: concentrating the organic layer to obtain a crude camptothecin derivative as shown in Formula III.

[0051] Preferably, the step of "washing the obtained reaction solution with a water washing agent" further comprises: washing the organic layer with water (preferably purified water) and / or saturated brine. The mass of the water (preferably purified water) and / or saturated brine is preferably 10 to 25 times the amount of the compound shown in Formula II in the reaction. The number of washings is preferably 2 to 5 times, preferably 2 to 3 times, for example 3 times.

[0052] Preferably, when "the method for preparing the crude camptothecin derivative as shown in Formula III also includes: washing the obtained reaction solution with a water detergent before concentrating the obtained reaction solution", the method for preparing the crude camptothecin derivative as shown in Formula III also includes: drying the reaction solution (i.e., the organic layer) after washing with the water detergent before concentrating the obtained reaction solution, and the drying is preferably drying with anhydrous sodium sulfate.

[0053] Preferably, the concentration temperature is preferably 30-50°C, such as 35-45°C, preferably 40°C.

[0054] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0055] The reagents and raw materials used in the present invention are commercially available.

[0056] Compared with the prior art, the method for purifying camptothecin derivatives provided by the present invention has the following beneficial effects:

[0057] 1. The present invention can obtain high-purity camptothecin derivatives by only mixing the crude camptothecin derivatives with component A and component B once and performing solid-liquid separation. The addition of component B greatly improves the purity and yield of the camptothecin derivatives. The operation is simple and easy, economical and convenient, suitable for commercial production, and reduces the exposure risk of the crude camptothecin derivatives. The product is in good condition, the obtained product has high purity, greatly reduced impurity content, and high yield.

[0058] 2. The present invention does not require column chromatography or chromatographic purification, which greatly improves the purification efficiency of camptothecin derivatives and avoids operational losses when the product is purified by column chromatography or chromatographic purification.

[0059] 3. After the crude camptothecin derivative shown in Formula III, component A and component B are mixed, the product can be obtained by simply performing a solid-liquid separation operation, thereby improving the purification efficiency.

[0060] 4. The present invention further reduces impurities and improves purity by washing the reaction solution with water.

[0061] 5. The present invention greatly reduces the use of environmentally unfriendly solvents to achieve maximum environmental protection. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1 This is the chromatogram of the compound I product obtained after purification by treatment with the solvent combination No. 2-4 in Table 3 of Example 2 in Example 2. The chromatographic purity of the product is 99.79%. DETAILED DESCRIPTION

[0063] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0064] Unless otherwise specified, all material ratios in the following examples are by mass ratios.

[0065] Unless otherwise specified, the term "C i-j "Alkyl" is used to represent a straight or branched chain alkyl group containing ij carbon atoms, wherein i and j are integers and i is less than j. For example, C 1-5 The alkyl group is a straight chain or branched alkyl group containing 1 to 5 carbon atoms, such as methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, s-butyl, t-butyl) and pentyl (such as n-pentyl, isopentyl, neopentyl) and the like.

[0066] Unless otherwise specified, the "room temperature" referred to in the present invention refers to 15-35°C.

[0067] The purity in the present invention is measured by HPLC, and the HPLC analysis conditions are as follows:

[0068] Analytical column: Waters XBridge C18, size 250×4.6 mm, filler particle size 5 mm.

[0069] Mobile phase: A—sodium acetate / water=20mmol / L; B—acetonitrile. Elution gradient is shown in Table 1.

[0070] Table 1. HPLC elution gradient

[0071] Time(min) A vol% B vol% 0 90 10 30 10 90 35 10 90 38 90 10 45 90 10

[0072] (column temperature: 30°C, flow rate: 1.0 mL / min, detection wavelength: 220 nm)

[0073] Example 1: Pretreatment of the reaction solution to obtain a crude compound I

[0074] This example seeks a method for obtaining a crude compound I with high purity and good recovery rate by studying the amount of solvent used in the reaction, the amount of water used in the pretreatment process, and the ratio of the two.

[0075] The reaction for preparing compound I was performed as follows: SN38 (1.0 equivalent) was dissolved in dichloromethane (the mass was 10 to 25 times the mass of SN38), and then N,N-diisopropylethylamine (3.0 equivalent) and tert-butyldimethylsilyl chloride (2.4 equivalent) were added. The resulting mixture was stirred at room temperature for 2.0 hours, and the reaction endpoint was monitored by TLC.

[0076] After the reaction is completed, the obtained reaction solution is pretreated by the following steps:

[0077] Step 1. Add purified water with a mass of 10 to 25 times the amount of SN38 reaction feed to the reaction solution obtained according to the above operation steps, stir at 25°C for 1 hour and then stand to separate the layers to obtain an organic layer and an aqueous layer;

[0078] Step 2. The separated organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo at a concentration temperature of 35-45° C. to obtain a pretreated crude solid.

[0079] The amount of solvent used in the above reaction and the amount of water used in the pretreatment process, as well as the purity and recovery rate of the pretreated crude product obtained after pretreatment are shown in Table 2.

[0080] Table 2. Effect of solvent dosage on purity and recovery of pretreated crude product

[0081]

[0082]

[0083] It can be seen that when the amount (mass) of dichloromethane, the reaction solvent, is 10 to 15 times the amount of SN38 feed and the amount (mass) of water used in the pretreatment process is 10 to 15 times the amount of SN38 feed, a crude compound I with good purity (>87.5%) can be obtained with a good recovery rate (>80%).

[0084] Examples 2-1 to 2-8 and Comparative Examples 2-1 to 2-5: Selection of solvent type for further purification of the crude pre-treated product of Compound I

[0085] In this example, based on the pretreatment of the reaction solution using the solvent ratio obtained in Example 1, a solvent combination suitable for pulping and further purifying the solid obtained from the pretreatment was sought. The specific steps are as follows:

[0086] Step 1. The reaction solution obtained by the method of Example 1 is pretreated according to the method of pretreatment step 1 of Example 1 to obtain a stratified two-phase system (the amount of solvent used in the reaction and the amount of water used in the pretreatment process are the same as those of Example 1 No. 1-2);

[0087] Step 2. The organic layer obtained by separation was washed three times with purified water or saturated brine in an amount 15 times the amount of SN38 fed, and then dried over anhydrous sodium sulfate and concentrated in vacuo at a concentration temperature of 40° C. to obtain a pale yellow solid crude product (purity of 89.90%);

[0088] Step 3. First add an organic solvent of component B to the pale yellow solid crude product obtained in step 2 to completely dissolve it (wherein the mass ratio of the pale yellow solid crude product to component B is 1:3), then add an organic solvent of component A to the resulting solution under stirring, continue stirring for 2 hours and filter, and treat the resulting filter cake under reduced pressure to remove the solvent residue to obtain a purified compound I product. Component A is one or more of petroleum ether, n-heptane, n-pentane, n-hexane, acetonitrile, ethyl acetate, and butyl acetate. Component B is one or more of ether, isopropyl ether, methyl tert-butyl ether, methanol, isopropanol, and dichloromethane.

[0089] In step 3 of this embodiment, by fixing the mixing ratio of organic solvent component A and component B (component A: component B = 50:1), a mixed solvent condition with both optimal purity and optimal yield was obtained, thereby obtaining a high-purity compound I product. The specific solvent selection in step 3 of this embodiment and the corresponding purity and recovery rate of the obtained product are shown in Table 3.

[0090] Table 3. Solvent selection and product purity and recovery rate

[0091]

[0092] It can be seen that when the organic solvent component A is one or more of petroleum ether, n-heptane, n-pentane, and n-hexane, and the organic solvent component B is one or more of diethyl ether, isopropyl ether, and methyl tert-butyl ether, a sample of compound I with a purity of more than 99% can be obtained at a recovery rate of more than 95%. In particular, when the organic solvent component A is n-heptane, petroleum ether, or n-pentane, and the organic solvent component B is methyl tert-butyl ether, a sample of compound I with a purity of more than 99.5% can be obtained at a recovery rate of more than 95%.

[0093] Example 3: Selection of solvent ratio for further purification of the crude pre-treated compound I

[0094] This example further studies the effect of solvent ratio on the purity and recovery rate of compound I based on the preferred solvent combination in Example 2. The specific steps are as follows:

[0095] Step 1. The reaction solution obtained by the method of Example 1 is pretreated according to the method of pretreatment step 1 of Example 1 to obtain a stratified two-phase system (the amount of solvent used in the reaction and the amount of water used in the pretreatment process are the same as those numbered 1-2 in Table 2 of Example 1);

[0096] Step 2. Treat the organic phase obtained in step 1 according to the method of step 2 of Example 2 to obtain a pale yellow solid crude product;

[0097] Step 3. Further treat the crude compound of formula I according to the method of step 3 of Example 2 and the solvent combination numbered 2-3 / 4 / 5 listed in Table 3 of Example 2;

[0098] In this example, the mixing ratio of different types of organic solvent component A and component B methyl tert-butyl ether is adjusted to screen the ratio conditions for obtaining both the best purity and the best yield, thereby obtaining a high-purity camptothecin derivative product. The mixing ratio of the solvent studied in this example is component A: component B = 100:1 to 5:1, as shown in Table 4 and Table 5.

[0099] Table 4. Effect of solvent ratio on the purity and recovery of compound I

[0100]

[0101] Table 5. Effect of other solvent ratios on the purity and recovery of compound I

[0102]

[0103]

[0104] From the results obtained (see Table 4 and Table 5), it can be seen that when the organic solvent component A is petroleum ether, n-heptane or n-pentane and component B is methyl tert-butyl ether and the mixed component ratio is 75:1 to 5:1, compound I with a purity of more than 98% can be obtained; when the organic solvent component A is petroleum ether, n-heptane or n-pentane and component B is methyl tert-butyl ether and the mixing ratio is 60:1 to 30:1, compound I with a purity of more than 99.5% and the best recovery rate (>95%) can be obtained.

[0105] The specific embodiments of the present invention are described in detail above, but they are only examples, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modification and substitution of the present invention is also within the scope of the present invention. Therefore, the equivalent transformation and modification made without departing from the spirit and scope of the present invention should be included in the scope of the present invention.

Claims

1. A method for purifying a camptothecin derivative as shown in formula III, comprising the following steps: The mixture of the crude camptothecin derivative as shown in Formula III, component A and component B is subjected to solid-liquid separation; wherein the component A is one or more of petroleum ether, n-heptane, n-pentane and n-hexane; the component B is one or more of diethyl ether, isopropyl ether and methyl tert-butyl ether; the volume ratio of the component A to the component B is (5-75):1; In formula III, R1 is hydrogen or C 1-5 Alkyl; R2 is hydrogen or C 1-5 Alkyl; R3 is C 1-5 Alkyl; R4 is C 1-5 Alkyl; R5 is C 1-5 alkyl.

2. The method for purifying the camptothecin derivative as shown in formula III according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The volume ratio of component A to component B is (25-60):1; (2) The R1 is C 1-3 alkyl; (3) R2 is C 1-3 alkyl; (4) R3 is C 1-4 alkyl; (5) R4 is C 1-3 alkyl; (6) R5 is C 1-3 alkyl; (7) The mixture is composed of a crude camptothecin derivative as shown in Formula III, component A and component B; (8) The mixture is obtained by mixing a crude camptothecin derivative represented by Formula III with component A and component B, and stirring; (9) The solid-liquid separation step comprises: filtering the mixture of the crude camptothecin derivative represented by Formula III, component A and component B; (10) The mass ratio of the crude camptothecin derivative represented by formula III to component B is 1:(1-5); (11) The purity of the crude camptothecin derivative represented by formula III is above 80%.

3. The method for purifying the camptothecin derivative as shown in formula III according to claim 2, characterized in that: It meets one or more of the following conditions: (1) The volume ratio of component A to component B is (30-60):1; (2) The mixture is obtained by mixing a crude camptothecin derivative as shown in Formula III with component A and component B, and stirring; the stirring time is 1-3 hours; (3) The solid-liquid separation step comprises: filtering the mixture of the crude camptothecin derivative represented by Formula III, component A and component B; the solid-liquid separation step further comprises: treating the filter cake obtained by filtration under reduced pressure to remove the residual solvent.

4. The method for purifying the camptothecin derivative represented by formula III according to claim 3, characterized in that: It meets one or both of the following conditions: (1) The volume ratio of component A to component B is 30:1, 40:1, 50:1 or 60:1; (2) The mixture is obtained by mixing a crude camptothecin derivative as shown in Formula III with component A and component B, and stirring; the stirring time is 2 hours.

5. The method for purifying the camptothecin derivative represented by formula III according to claim 2, characterized in that: The mixture is obtained by mixing a crude camptothecin derivative as shown in formula III with component A and component B, and stirring; the step of mixing the crude camptothecin derivative as shown in formula III with component A and component B comprises: first mixing the crude camptothecin derivative as shown in formula III with component B, and then mixing with component A.

6. The method for purifying the camptothecin derivative represented by formula III according to claim 2, characterized in that: It meets one or more of the following conditions: (1) The R1 is ethyl; (2) R2 is ethyl; (3) R3 is tert-butyl or ethyl; (4) R4 is methyl or ethyl; (5) R5 is methyl or ethyl; (6) The composition and ratio of component A and component B are one of the following: ； (7) The mass ratio of the crude camptothecin derivative represented by formula III to component B is 1:(2-4); (8) The purity of the crude camptothecin derivative represented by formula III is above 85%.

7. The method for purifying the camptothecin derivative represented by formula III according to claim 6, characterized in that: The mass ratio of the crude camptothecin derivative represented by formula III to component B is 1:

3.

8. The method for purifying the camptothecin derivative represented by formula III according to claim 6, characterized in that: It meets one or more of the following conditions: (1) R3 is tert-butyl; (2) R4 is methyl; (3) R5 is methyl; (4) The composition and ratio of component A and component B are one of the following:

9. The method for purifying the camptothecin derivative represented by formula III according to claim 8, characterized in that: The composition and ratio of component A and component B are one of those shown in the following table: 。 10. The method for purifying a camptothecin derivative represented by formula III according to any one of claims 1 to 9, characterized in that: The preparation method of the crude camptothecin derivative as shown in formula III comprises: in an organic solvent, reacting a compound as shown in formula II and a compound as shown in formula IV as follows, concentrating the obtained reaction solution to obtain a crude camptothecin derivative as shown in formula III; Wherein, R1, R2, R3, R4 and R5 are defined as in any one of claims 1 to 9; X is halogen.

11. The method for purifying the camptothecin derivative represented by formula III according to claim 10, characterized in that: The compound shown in formula II is The compound shown in formula IV is The compound shown in formula III is 12. The method for purifying the camptothecin derivative represented by formula III according to claim 10, characterized in that: It meets one or more of the following conditions: (1) The reaction is carried out under the action of a base; (2) X is chlorine; (3) In the compound of formula IV, R3, R4 and R5 are not methyl groups at the same time; (4) The compound shown in formula II is (5) The equivalent ratio of the compound represented by Formula IV to the compound represented by Formula II is (2-3):1; (6) The reaction temperature is room temperature; (7) The reaction time is 1 to 3 hours; (8) The organic solvent is a water-soluble organic solvent or a first water-insoluble organic solvent; (9) The mass ratio of the organic solvent to the compound represented by formula II is (10-25):1; (10) The method for preparing the crude camptothecin derivative represented by Formula III further comprises: washing the obtained reaction solution with a water washing agent before concentrating the obtained reaction solution, wherein the water washing agent is water and / or saturated saline; (11) The concentration temperature is 30 to 50°C.

13. The method for purifying the camptothecin derivative represented by formula III according to claim 12, characterized in that: The concentration temperature is 35-45°C.

14. The method for purifying the camptothecin derivative represented by formula III according to claim 13, characterized in that: The concentration temperature was 40°C.

15. The method for purifying a camptothecin derivative represented by formula III according to any one of claims 12 to 14, characterized in that: It meets one or more of the following conditions: (1) When the reaction is carried out under the action of a base, the base is N,N-diisopropylethylamine; (2) When the reaction is carried out under the action of a base, the equivalent ratio of the base to the compound represented by Formula II is (2.3-3.5):1; (3) The compound shown in formula IV is (4) The equivalent ratio of the compound represented by Formula IV to the compound represented by Formula II is 2.4:1; (5) The reaction temperature is 25 to 35°C; (6) The reaction time is 2 hours; (7) The organic solvent is dichloromethane; (8) The mass ratio of the organic solvent to the compound represented by formula II is (10-15):1; (9) When "the method for preparing the crude camptothecin derivative represented by Formula III further comprises: washing the obtained reaction solution with a water washing agent before concentrating the obtained reaction solution", the water washing agent is purified water; (10) When "the method for preparing the crude camptothecin derivative as shown in Formula III further includes: washing the obtained reaction solution with a water washing agent before concentrating the obtained reaction solution", the ratio of the mass of the water washing agent to the mass of the compound as shown in Formula II in the reaction is (10-25):

1.

16. The method for purifying the camptothecin derivative represented by formula III according to claim 15, characterized in that: It meets one or both of the following conditions: (1) When the reaction is carried out under the action of a base, the equivalent ratio of the base to the compound represented by Formula II is 3:1; (2) When "the method for preparing the crude camptothecin derivative as shown in Formula III further includes: washing the obtained reaction solution with a water washing agent before concentrating the obtained reaction solution", the ratio of the mass of the water washing agent to the mass of the compound as shown in Formula II in the reaction is (10-15):

1.

17. The method for purifying the camptothecin derivative represented by formula III according to claim 11, characterized in that: When "the method for preparing the crude camptothecin derivative as shown in Formula III further comprises: washing the obtained reaction solution with a water washing agent before concentrating the obtained reaction solution", the organic solvent is a first water-insoluble organic solvent, and the step of "washing the obtained reaction solution with a water washing agent" comprises: mixing the obtained reaction solution with the water washing agent to obtain a mixture, and separating the layers to obtain an organic layer and an aqueous layer; Alternatively, when "the method for preparing the crude camptothecin derivative as shown in Formula III further comprises: washing the obtained reaction solution with a water washing agent before concentrating the obtained reaction solution", the organic solvent is a water-soluble organic solvent, and the step of "washing the obtained reaction solution with a water washing agent" comprises: concentrating the obtained reaction solution for the first time, mixing it with the water washing agent and a second water-insoluble organic solvent to obtain a mixture, and separating the layers to obtain an organic layer and an aqueous layer; Alternatively, when "the method for preparing the crude camptothecin derivative as shown in Formula III further includes: washing the obtained reaction solution with a water detergent before concentrating the obtained reaction solution", the method for preparing the crude camptothecin derivative as shown in Formula III further includes: drying the reaction solution after washing with the water detergent before concentrating the obtained reaction solution.

18. The method for purifying the camptothecin derivative represented by formula III according to claim 17, characterized in that: When "the method for preparing the crude camptothecin derivative as shown in Formula III further comprises: washing the obtained reaction solution with a water washing agent before concentrating the obtained reaction solution", the organic solvent is a water-soluble organic solvent, and the step of "washing the obtained reaction solution with a water washing agent" comprises: after concentrating the obtained reaction solution for the first time, mixing it with the water washing agent and a second water-insoluble organic solvent to obtain a mixture, and separating the layers to obtain an organic layer and an aqueous layer; the ratio of the mass of the second water-insoluble organic solvent to the mass of the compound as shown in Formula II in the reaction is (10-25):1; Alternatively, when "the method for preparing the crude camptothecin derivative as shown in Formula III also includes: washing the obtained reaction solution with a water detergent before concentrating the obtained reaction solution", the method for preparing the crude camptothecin derivative as shown in Formula III also includes: drying the reaction solution after washing with a water detergent before concentrating the obtained reaction solution, and the drying is drying with anhydrous sodium sulfate.

19. The method for purifying the camptothecin derivative represented by formula III according to claim 18, characterized in that: When "the preparation method of the crude camptothecin derivative as shown in Formula III also includes: washing the obtained reaction solution with a water washing agent before concentrating the obtained reaction solution", the organic solvent is a water-soluble organic solvent, and the step of "washing the obtained reaction solution with a water washing agent" includes: after concentrating the obtained reaction solution for the first time, mixing it with the water washing agent and a second water-insoluble organic solvent to obtain a mixture, and separating the layers to obtain an organic layer and an aqueous layer; the ratio of the mass of the second water-insoluble organic solvent to the mass of the compound as shown in Formula II in the reaction is (10-15):

1.

20. The method for purifying the camptothecin derivative represented by formula III according to claim 17, characterized in that: When "the method for preparing the crude camptothecin derivative as shown in Formula III further includes: washing the obtained reaction solution with a water washing agent before concentrating the obtained reaction solution", the organic solvent is a water-soluble organic solvent, and the step of "washing the obtained reaction solution with a water washing agent" includes: after concentrating the obtained reaction solution for the first time, mixing it with the water washing agent and a second water-insoluble organic solvent to obtain a mixture, and separating the layers to obtain an organic layer and an aqueous layer; the second water-insoluble organic solvent is dichloromethane.

21. The method for purifying a camptothecin derivative represented by formula III according to any one of claims 17 to 20, characterized in that: The step of "washing the obtained reaction solution with a water detergent" further comprises: stirring the obtained mixture before the stratification; the stirring time is 1 to 2 hours; Alternatively, the step of "washing the obtained reaction solution with a water detergent" further comprises: washing the obtained organic layer with water and / or saturated brine.

22. The method for purifying a camptothecin derivative as shown in formula III as claimed in claim 21, characterized in that: The step of "washing the obtained reaction solution with a water detergent" further comprises: stirring the obtained mixture before the stratification; the stirring time is 1 to 2 hours, and the stirring temperature is 15 to 35°C; Alternatively, the step of "washing the obtained reaction liquid with a water detergent" further includes: washing the obtained organic layer with water and / or saturated brine; the mass of the water and / or saturated brine is 10 to 25 times the amount of the compound shown in Formula II in the reaction.

23. The method for purifying a camptothecin derivative as shown in formula III as claimed in claim 22, characterized in that: The step of "washing the obtained reaction solution with a water detergent" also includes: washing the obtained organic layer with water and / or saturated brine; the number of washing times is 2 to 5 times.

24. The method for purifying a camptothecin derivative as shown in formula III as claimed in claim 23, characterized in that: The step of "washing the obtained reaction solution with a water detergent" also includes: washing the obtained organic layer with water and / or saturated brine; the number of washing times is 2 to 3 times.

25. The method for purifying a camptothecin derivative as shown in formula III as claimed in claim 24, characterized in that: The step of "washing the obtained reaction solution with a water detergent" also includes: washing the obtained organic layer with water and / or saturated brine; the number of washing times is 3 times.

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