CN116354976B - Purification method of camptothecin derivatives - Google Patents
Purification method of camptothecin derivatives Download PDFInfo
- Publication number
- CN116354976B CN116354976B CN202111617331.6A CN202111617331A CN116354976B CN 116354976 B CN116354976 B CN 116354976B CN 202111617331 A CN202111617331 A CN 202111617331A CN 116354976 B CN116354976 B CN 116354976B
- Authority
- CN
- China
- Prior art keywords
- water
- component
- formula iii
- camptothecin derivative
- washing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了一种喜树碱衍生物的纯化方法。具体地，本发明公开了一种如式III所示的喜树碱衍生物的纯化方法，其包括以下步骤：将如式III所示的喜树碱衍生物粗品、组分A和组分B的混合物进行固液分离，即可；其中，所述组分A为石油醚、正庚烷、正戊烷和正己烷的一种或多种；所述组分B为乙醚、异丙醚和甲基叔丁基醚的一种或多种；所述组分A和组分B的体积比为(4～100):1。本发明所述的纯化方法操作简单易行、经济方便，所得产品纯度高、杂质含量大大降低，收率高，适合商业化生产。
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
The invention belongs to the technical field of chemical purification, and particularly relates to a purification method of a camptothecin derivative.
Background
The camptothecine is alkaloid separated from the specific Chinese Davidiaceae camptotheca acuminata, has stronger cytotoxicity and better curative effect on various malignant tumors, but has poor pharmacy, and the camptothecine derivative obtained by modifying the structure of the camptothecine has the characteristics of good solubility and the like, thereby providing a new method for clinical application of camptothecine medicines.
The purity of the product obtained by the preparation method of the camptothecin derivative in the prior art is low, and most of the product needs silica gel column chromatography purification, so that the product loss can be caused in the purification process, the yield is low, the operation is complex, and the method is not suitable for commercial production.
From the current literature, there is no production method for preparing camptothecin derivatives with high purity suitable for commercial production. In view of the safety of the administration of camptothecin derivatives, it is desirable to provide a purification process for preparing camptothecin derivatives of high purity suitable for commercial production.
Disclosure of Invention
In order to solve the problem of the prior art that a purification method for preparing a high-purity camptothecin derivative suitable for commercial production is lacking, the invention provides a purification method capable of preparing a high-purity camptothecin derivative and suitable for commercial production. The invention adopts the mixed solvent to treat the crude product of the camptothecin derivative, thus obtaining the camptothecin derivative product with high purity, omitting the purification technical operations such as column chromatography, reversed phase preparation chromatography and the like, and being convenient, quick, time-saving and labor-saving.
The present invention solves the above-mentioned problems by the following method.
The invention provides a purification method of a camptothecin derivative shown in a formula III, which comprises the following steps of carrying out solid-liquid separation on a mixture of a crude camptothecin derivative shown in the formula III, a component A and a 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 diethyl ether, isopropyl ether and methyl tert-butyl ether, and 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;
In formula III, R 1 is hydrogen or C 1-5 alkyl, preferably C 1-3 alkyl, further preferably ethyl;
r 2 is hydrogen or C 1-5 alkyl, preferably C 1-3 alkyl, more preferably ethyl;
R 3 is C 1-5 alkyl, preferably C 1-4 alkyl, such as tert-butyl or ethyl, preferably tert-butyl;
R 4 is C 1-5 alkyl, preferably C 1-3 alkyl, such as methyl or ethyl, preferably methyl;
R 5 is C 1-5 alkyl, preferably C 1-3 alkyl, such as methyl or ethyl, preferably methyl.
Preferably, the mixture consists of a crude camptothecin derivative represented by formula III, a component A and a component B.
Preferably, the mixture is obtained by mixing and stirring the crude camptothecin derivative represented by formula III with component a and component B.
Wherein the stirring time is preferably 1 to 3 hours, for example 2 hours.
Wherein the specific step of mixing the crude camptothecin derivative represented by formula III with the component A and the component B preferably comprises mixing the crude camptothecin derivative represented by formula III with the component B first and then with the component A. Preferably, the specific step of mixing the crude camptothecin derivative shown in the formula III with the component A and the component B comprises the steps of dissolving the crude camptothecin derivative shown in the formula III with the component B, and then adding the component A.
The component B is preferably methyl tert-butyl ether.
The components and proportions of the component A and the component B are preferably one of the following tables:
preferably, the components and proportions of the component A and the component B are one of the following tables:
Further preferably, the components and proportions of the component A and the component B are one of the following tables:
Wherein, the solid-liquid separation can adopt a solid-liquid separation method conventional in the art, and preferably, the specific step of the solid-liquid separation comprises the step of filtering the mixture of the crude camptothecin derivative shown in the formula III, the component A and the component B. More preferably, the specific step of solid-liquid separation further comprises the step of treating the filter cake obtained by filtration under reduced pressure to remove solvent residues.
Wherein the mass ratio of the crude product of the camptothecin derivative shown in the formula III and the component B is preferably 1 (1-5), more preferably 1 (2-4), and even more preferably 1:3.
In the present invention, the crude camptothecin derivative may be solid or liquid (e.g., oil), preferably solid. The crude product of the camptothecin derivative has a purity of preferably 80% or more, more preferably 85% or more.
In the invention, preferably, the preparation method of the camptothecin derivative crude product shown in the formula III comprises the steps of carrying out the following reaction on a compound shown in the formula II and a compound shown in the formula IV in an organic solvent, and concentrating the obtained reaction liquid to obtain the camptothecin derivative crude product shown in the formula III;
Wherein R 1 is C 1-5 alkyl, preferably C 1-3 alkyl, further preferably ethyl;
R 2 is C 1-5 alkyl, preferably C 1-3 alkyl, more preferably ethyl;
R 3 is C 1-5 alkyl, preferably C 1-4 alkyl, such as tert-butyl or ethyl, preferably tert-butyl;
R 4 is C 1-5 alkyl, preferably C 1-3 alkyl, such as methyl or ethyl, preferably methyl;
R 5 is C 1-5 alkyl, preferably C 1-3 alkyl, such as methyl or ethyl, preferably methyl;
x is halogen, preferably chlorine.
Wherein the reaction can be carried out under the action of alkali.
Preferably, in the compound shown in formula IV, R 3、R4 and R 5 are not simultaneously methyl.
Wherein the compound of formula II is preferably(SN 38), the compound of formula IV is preferablyAccordingly, the compound of formula III is preferably(Compound I).
Wherein the base is preferably N, N-diisopropylethylamine. The equivalent weight of the base to the compound of formula II is preferably (2.3-3.5): 1, e.g. 3:1.
Wherein the equivalent weight of the compound shown in the formula IV and the compound shown in the formula II is preferably (2-3): 1, for example, 2.4:1.
The reaction temperature is preferably room temperature, for example 25-35 ℃. The reaction time may be 1 to 3 hours, for example 2 hours.
Wherein 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 of the organic solvent is preferably (10-25): 1, more preferably (10-15): 1, as compared with the mass of the compound represented by formula II.
Preferably, the preparation method of the crude camptothecin derivative shown in the formula III further comprises the step of washing the obtained reaction liquid with a water washing agent before concentrating the obtained reaction liquid, wherein the water washing agent is water and/or saturated saline water. When the water wash agent is water, purified water is preferable. The mass of the water washing agent is preferably (10-25): 1, more preferably (10-15): 1, to the mass of the compound of formula II in the reaction.
Preferably, when the organic solvent is a first water-insoluble organic solvent, the step of washing the obtained reaction liquid with a water washing agent comprises mixing the obtained reaction liquid with the water washing agent to obtain a mixture, and layering to obtain an organic layer and an aqueous layer.
Preferably, when the preparation method of the crude camptothecin derivative shown in the formula III further comprises the step of washing the obtained reaction liquid with a water-washing agent before concentrating the obtained reaction liquid, the organic solvent is a water-soluble organic solvent, and the step of washing the obtained reaction liquid with the water-washing agent comprises the steps of mixing the obtained reaction liquid 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 mass of the second water-insoluble organic solvent is preferably (10-25): 1, more preferably (10-15): 1, as compared with the mass of the compound of formula II fed in the reaction. The second water-insoluble organic solvent is preferably dichloromethane. Preferably, the step of washing the obtained reaction liquid with a water-washing agent further comprises concentrating the obtained reaction liquid before mixing the obtained reaction liquid with the water-washing agent and the second water-insoluble organic solvent to obtain a mixture. Preferably, the step of washing the obtained reaction liquid with a water washing agent comprises the steps of concentrating the obtained reaction liquid, mixing the concentrated reaction liquid with a water-insoluble organic solvent, mixing the mixture with the water washing agent to obtain a mixture, and layering to obtain an organic layer and a water layer.
Preferably, the step of washing the obtained reaction liquid with a water washing agent further comprises stirring the obtained mixture before the delamination. The stirring time is preferably 1 to 2 hours, for example 1 hour. The stirring is preferably carried out at 15-35 ℃, for example 25 ℃.
Preferably, the step of concentrating the obtained reaction solution comprises concentrating the organic layer to obtain a crude camptothecin derivative shown in a formula III.
Preferably, the step of washing the obtained reaction liquid 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 the saturated saline water is preferably 10-25 times that of the compound shown as the formula II in the reaction. The number of times of washing is preferably 2 to 5 times, preferably 2 to 3 times, for example 3 times.
Preferably, when the preparation method of the crude camptothecin derivative shown in the formula III further comprises washing the obtained reaction solution with a water washing agent before concentrating the obtained reaction solution, the preparation method of the crude camptothecin derivative shown in the formula III further comprises drying the reaction solution (namely, the organic layer) washed with the water washing agent, preferably, drying with anhydrous sodium sulfate, before concentrating the obtained reaction solution.
Preferably, the temperature of the concentration is preferably 30-50 ℃, for example 35-45 ℃, preferably 40 ℃.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
Compared with the prior art, the purification method of the camptothecin derivative provided by the invention has the following beneficial effects:
1. The invention can obtain the high-purity camptothecin derivative by only carrying out once mixing and solid-liquid separation on the crude product of the camptothecin derivative, the component A and the component B, the addition of the component B greatly improves the purity and the yield of the camptothecin derivative, the operation is simple, easy, economical and convenient, the method is suitable for commercial production, the exposure risk of the crude product of the camptothecin derivative is reduced, the product state is good, the purity of the obtained product is high, the impurity content is greatly reduced, and the yield is high.
2. The invention does not need column chromatography or chromatographic purification, greatly improves the purification efficiency of the camptothecin derivative, and simultaneously avoids the operation loss of the product when the product is purified by column chromatography or chromatographic purification.
3. According to the invention, after the crude product of the camptothecin derivative shown in the formula III, the component A and the component B are mixed, the product can be obtained only through simple and easy solid-liquid separation operation, and the purification efficiency is improved.
4. The invention further reduces impurities and improves purity by washing the reaction liquid.
5. The invention greatly reduces the use of environment-friendly solvents so as to protect the environment to the greatest extent.
Drawings
FIG. 1 is a chromatogram of the compound I product obtained after purification by treatment with the solvent combination of Table 3 Nos. 2-4 in example 2, with a purity of 99.79%.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
The proportions of the substances referred to in the following examples are mass ratios unless otherwise specified.
The term "C i-j alkyl" as used herein, unless otherwise specified, is intended to mean a straight or branched chain alkyl group containing i-j carbon atoms, where i and j are integers, i is less than j, e.g., C 1-5 alkyl is a straight or branched chain alkyl group containing 1 to 5 carbon atoms, such as methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
Unless otherwise indicated, "room temperature" as used herein means 15-35 ℃.
The purity in the invention is measured by HPLC, and the analysis conditions of the HPLC are as follows:
Analytical column Waters XBidge C18, 250X 4.6mm, filler size 5mm.
Mobile phase A-sodium acetate/water=20 mmol/L and B-acetonitrile. The elution gradient is shown in table 1.
TABLE 1 HPLC elution gradient
| Time(min) | A vol% | B vol% |
| 0 | 90 | 10 |
| 30 | 10 | 90 |
| 35 | 10 | 90 |
| 38 | 90 | 10 |
| 45 | 90 | 10 |
(Column temperature: 30 ℃ C., flow rate: 1.0mL/min, detection wavelength: 220 nm)
EXAMPLE 1 pretreatment of the reaction solution to give crude Compound I
In the embodiment, the method for obtaining the crude product of the compound I with higher purity and good recovery rate is searched through researching the solvent consumption of the reaction, the water consumption in the pretreatment process and the consumption proportion of the solvent and the water.
The reaction for preparing compound I was carried out by dissolving SN38 (1.0 equivalent) in methylene chloride (mass 10 to 25 times the mass of SN 38), then adding N, N-diisopropylethylamine (3.0 equivalent) and t-butyldimethylchlorosilane (2.4 equivalent), and stirring the resulting mixture at room temperature for 2.0 hours, and monitoring the reaction end point by TLC.
After the reaction, the obtained reaction solution was pretreated by the following steps:
step1, adding purified water with the mass of 10-25 times of the SN38 reaction feeding amount into the reaction liquid obtained according to the operation steps, stirring for 1h at 25 ℃, and standing for layering to obtain an organic layer and a water layer;
And step 2, drying the separated organic layer by using anhydrous sodium sulfate, and concentrating in vacuum at the concentration temperature of 35-45 ℃ to obtain a pretreated crude solid.
The solvent amount and the water amount in the pretreatment process of the above reaction, and the purity and recovery rate of the pretreated crude product obtained after the pretreatment are shown in Table 2.
TABLE 2 influence of the amount of solvent used on the purity and recovery of the pretreated crude product
The method can obtain the crude product of the compound I with better purity (87.5%) with better recovery rate (> 80%) under the conditions that the dosage (mass) of the reaction solvent methylene dichloride is 10-15 times of the dosage of the SN38 and the dosage (mass) of water in the pretreatment process is 10-15 times of the dosage of the SN 38.
Examples 2-1 to 2-8 and comparative examples 2-1 to 2-5 selection of the kind of solvent for further purification of crude pretreatment of Compound I
In this example, a solvent composition suitable for further purification by beating the solid obtained by pretreatment was found on the basis of pretreatment of the reaction solution with the solvent ratio obtained in example 1. The method comprises the following specific steps:
Step 1, pretreating the reaction solution obtained according to the method of the example 1 according to the method of the pretreatment step 1 of the example 1 to obtain a layered two-phase system (the solvent consumption of the reaction and the water consumption in the pretreatment process are the same as those of the numbers 1-2 of the example 1);
Step 2, washing the organic layer obtained by liquid separation with purified water or saturated saline water with the mass which is 15 times of the feeding amount of SN38 for 3 times, drying the organic layer by anhydrous sodium sulfate, and concentrating the organic layer in vacuum at the concentration temperature of 40 ℃ to obtain a light yellow solid crude product (the purity is 89.90 percent);
And 3, adding an organic solvent with a component B into the light yellow solid crude product obtained in the step 2 to enable the light yellow solid crude product to be completely dissolved (wherein the mass ratio of the light yellow solid crude product to the component B is 1:3), then adding the organic solvent with a component A into the obtained solution under the stirring condition, continuously stirring for 2 hours, filtering, and treating the obtained filter cake under reduced pressure to remove solvent residues to obtain a purified compound I product. Wherein the component A is one or more of petroleum ether, n-heptane, n-pentane, n-hexane, acetonitrile, ethyl acetate and butyl acetate. The component B is one or more of diethyl ether, isopropyl ether, methyl tertiary butyl ether, methanol, isopropanol and dichloromethane.
Step 3 of this example by fixing the mixing ratio of the organic solvent component a and component B (component a: component b=50:1), mixed solvent conditions of optimal purity and optimal yield are obtained and thus a compound I product of high purity is obtained. The specific solvent selections and corresponding purity and recovery results of the product obtained in step 3 of this example are shown in Table 3.
TABLE 3 solvent selection and purity and recovery of the resulting product
It can be seen that when the component A of the organic solvent is one or more of petroleum ether, n-heptane, n-pentane and n-hexane, and the component B of the organic solvent is one or more of diethyl ether, isopropyl ether and methyl tert-butyl ether, a compound I sample with purity of 99% or more can be obtained with a recovery rate of 95% or more. In particular, when the organic solvent A component is n-heptane, petroleum ether or n-pentane and the organic solvent B component is methyl tert-butyl ether, a compound I sample having a purity of 99.5% or more can be obtained at a recovery rate of 95% or more.
EXAMPLE 3 solvent ratio selection for further purification of crude Compound I pretreatment
This example further investigated the effect of solvent ratio on compound I purity and recovery based on the preferred solvent combination of example 2. The method comprises the following specific steps:
Step 1. The reaction solution obtained according to the method of example 1 is pretreated according to the method of the pretreatment step 1 of example 1 to obtain a layered two-phase system (the solvent amount of the reaction and the water amount in the pretreatment process are the same as those of the numbers 1-2 in the table 2 of example 1);
Step 2, treating the organic phase obtained in the step 1 according to the method of the step 2 of the embodiment 2 to obtain a light yellow solid crude product;
Step 3. Further processing of the crude compound of formula I according to the procedure of step 3, example 2, table 3, solvent combinations numbered 2-3/4/5;
In the embodiment, the mixing proportion of the component A and the component B methyl tertiary butyl ether of different types of organic solvents is adjusted, and the proportion condition of the best purity and the best yield is obtained through screening, so that the camptothecin derivative product with high purity is obtained. The mixing ratio of the solvents studied in this example ranges from component a to component b=100:1 to 5:1, tables 4 and 5 being specific.
TABLE 4 influence of solvent ratio on purity and recovery of Compound I
TABLE 5 influence of other solvent ratios on the purity and recovery of Compound I
From the results (see Table 4 and Table 5), it was found that when the organic solvent component A was petroleum ether, n-heptane or n-pentane and the component B was methyl t-butyl ether and the mixing ratio was 75:1 to 5:1, a compound I having a purity of 98% or more was obtained, and when the organic solvent component A was petroleum ether, n-heptane or n-pentane and the component B was methyl t-butyl ether and the mixing ratio was 60:1 to 30:1, a compound I having a purity of 99.5% or more and an optimal recovery (> 95%) was obtained.
The above description of the specific embodiments of the present invention has been given by way of example only, and the present invention is not limited to the above described specific embodiments. Any equivalent modifications and substitutions for this invention will occur to those skilled in the art, and are intended to be within the scope of this invention. Accordingly, equivalent changes and modifications are intended to be included within the scope of the present invention without departing from the spirit and scope thereof.
Claims (25)
1. A purification method of a camptothecin derivative shown in a formula III comprises the following steps of carrying out solid-liquid separation on a mixture of a crude camptothecin derivative shown in the formula III, a component A and a 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 diethyl ether, isopropyl ether and methyl tertiary butyl ether, and the volume ratio of the component A to the component B is (5-75): 1;
in formula III, R 1 is hydrogen or C 1-5 alkyl, R 2 is hydrogen or C 1-5 alkyl, R 3 is C 1-5 alkyl, R 4 is C 1-5 alkyl, and R 5 is C 1-5 alkyl.
2. The method of purifying a camptothecin derivative represented by formula III according to claim 1, wherein it meets one or more of the following conditions:
(1) The volume ratio of the component A to the component B is (25-60): 1;
(2) R 1 is C 1-3 alkyl;
(3) R 2 is C 1-3 alkyl;
(4) R 3 is C 1-4 alkyl;
(5) R 4 is C 1-3 alkyl;
(6) R 5 is C 1-3 alkyl;
(7) The mixture consists of a camptothecine derivative crude product shown in a formula III, a component A and a component B;
(8) The mixture is obtained by mixing and stirring a camptothecin derivative crude product shown in a formula III with a component A and a component B;
(9) The solid-liquid separation step comprises filtering the mixture of the crude camptothecin derivative shown in the formula III, the component A and the component B;
(10) The mass ratio of the crude product of the camptothecin derivative shown in the formula III to the component B is 1 (1-5);
(11) The purity of the crude product of the camptothecin derivative shown in the formula III is more than 80 percent.
3. The method of purifying a camptothecin derivative represented by formula III according to claim 2, wherein one or more of the following conditions are satisfied:
(1) The volume ratio of the component A to the component B is (30-60): 1;
(2) The mixture is obtained by mixing and stirring a camptothecin derivative crude product shown in a formula III with a component A and a component B, wherein the stirring time is 1-3h;
(3) The solid-liquid separation step comprises the steps of filtering the mixture of the crude camptothecin derivative shown in the formula III, the component A and the component B, and the solid-liquid separation step further comprises the step of treating a filter cake obtained by filtering under reduced pressure to remove solvent residues.
4. A process for purifying a camptothecin derivative represented by formula III according to claim 3, wherein one or both of the following conditions are satisfied:
(1) The volume ratio of the component A to the component B is 30:1, 40:1, 50:1 or 60:1;
(2) The mixture is obtained by mixing and stirring the crude product of the camptothecin derivative shown in the formula III with the component A and the component B, wherein the stirring time is 2 hours.
5. The method for purifying a camptothecin derivative represented by formula III according to claim 2, wherein the mixture is obtained by mixing a crude camptothecin derivative represented by formula III with component A and component B and stirring, and the step of mixing a crude camptothecin derivative represented by formula III with component A and component B comprises mixing a crude camptothecin derivative represented by formula III with component B and then with component A.
6. The method of purifying a camptothecin derivative represented by formula III according to claim 2, wherein one or more of the following conditions are satisfied:
(1) R 1 is ethyl;
(2) R 2 is ethyl;
(3) R 3 is tert-butyl or ethyl;
(4) R 4 is methyl or ethyl;
(5) R 5 is methyl or ethyl;
(6) The components and the proportion of the component A and the component B are one of the following tables:
;
(7) The mass ratio of the crude product of the camptothecin derivative shown in the formula III to the component B is 1 (2-4);
(8) The purity of the crude product of the camptothecin derivative shown in the formula III is more than 85%.
7. The method for purifying a camptothecin derivative represented by formula III according to claim 6, wherein the mass ratio of the crude camptothecin derivative represented by formula III to component B is 1:3.
8. The method of purifying a camptothecin derivative represented by formula III according to claim 6, wherein one or more of the following conditions are satisfied:
(1) R 3 is tert-butyl;
(2) R 4 is methyl;
(3) R 5 is methyl;
(4) The components and the proportion of the component A and the component B are one of the following tables:
9. the method for purifying a camptothecin derivative represented by formula III according to claim 8,
The components and the proportion of the component A and the component B are one of the following tables:
。
10. The method for purifying a camptothecin derivative represented by formula III according to any one of claims 1 to 9, wherein the preparation method of the crude camptothecin derivative represented by formula III comprises the steps of reacting a compound represented by formula II with a compound represented by formula IV in an organic solvent, concentrating the obtained reaction solution to obtain the crude camptothecin derivative represented by formula III;
wherein R 1、R2、R3、R4 and R 5 are as defined in any one of claims 1 to 9;
X is halogen.
11. The method for purifying a camptothecin derivative represented by formula III according to claim 10, wherein the compound represented by formula II isThe compound shown in the formula IV isThe compound shown in the formula III is
12. The method of purifying a camptothecin derivative represented by formula III according to claim 10, wherein it meets one or more of the following conditions:
(1) The reaction is carried out under the action of alkali;
(2) X is chlorine;
(3) In the compound shown in the formula IV, R 3、R4 and R 5 are not methyl at the same time;
(4) The compound shown in the formula II is
(5) The equivalent ratio of the compound shown in the formula IV to the compound shown in the formula II is (2-3) 1;
(6) The temperature of the reaction is room temperature;
(7) The reaction time is 1-3 h;
(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 shown in the formula II is (10-25) 1;
(10) The preparation method of the crude product of the camptothecin derivative shown in the formula III further comprises the steps of washing the obtained reaction liquid with a water lotion before concentrating the obtained reaction liquid, wherein the water lotion is water and/or saturated saline water;
(11) The temperature of concentration is 30-50 ℃.
13. The method for purifying a camptothecin derivative represented by formula III according to claim 12, wherein the concentration temperature is 35 to 45 ℃.
14. The method for purifying a camptothecin derivative represented by formula III according to claim 13, wherein the concentration temperature is 40 ℃.
15. The method for purifying a camptothecin derivative according to any one of claims 12 to 14, wherein one or more of the following conditions are satisfied:
(1) When the reaction is carried out under the action of alkali, the alkali is N, N-diisopropylethylamine;
(2) When the reaction is carried out under the action of alkali, the equivalent ratio of the alkali to the compound shown in the formula II is (2.3-3.5): 1;
(3) The compound shown in the formula IV is
(4) The equivalent ratio of the compound shown in the formula IV to the compound shown in the formula II is 2.4:1;
(5) The reaction temperature is 25-35 ℃;
(6) The reaction time is 2h;
(7) The organic solvent is dichloromethane;
(8) The mass ratio of the organic solvent to the compound shown in the formula II is (10-15) 1;
(9) The preparation method of the camptothecin derivative crude product shown in the formula III further comprises the steps of washing the obtained reaction liquid with a water washing agent before concentrating the obtained reaction liquid, wherein the water washing agent is purified water;
(10) When the preparation method of the crude camptothecin derivative shown in the formula III further comprises the step of washing the obtained reaction liquid with a water washing agent before concentrating the obtained reaction liquid, the ratio of the mass of the water washing agent to the mass of the compound shown in the formula II in the reaction is (10-25): 1.
16. The method of purifying a camptothecin derivative represented by formula III according to claim 15, wherein one or both of the following conditions are satisfied:
(1) When the reaction is carried out under the action of alkali, the equivalent ratio of the alkali to the compound shown as the formula II is 3:1;
(2) When the preparation method of the crude camptothecin derivative shown in the formula III further comprises the step of washing the obtained reaction liquid with a water washing agent before concentrating the obtained reaction liquid, the ratio of the mass of the water washing agent to the mass of the compound shown in the formula II in the reaction is (10-15): 1.
17. The method for purifying a camptothecin derivative represented by the formula III according to claim 11, wherein when the method for preparing a crude product of the camptothecin derivative represented by the 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 layering to obtain an organic layer and an aqueous layer;
Or when the preparation method of the crude camptothecin derivative shown in the formula III further comprises the steps of washing the obtained reaction liquid with a water-washing agent before concentrating the obtained reaction liquid, wherein the organic solvent is a water-soluble organic solvent, and the step of washing the obtained reaction liquid with the water-washing agent comprises the steps of mixing the obtained reaction liquid with the water-washing agent and a second water-insoluble organic solvent to obtain a mixture after concentrating the obtained reaction liquid for the first time, and layering to obtain an organic layer and a water layer;
Or when the preparation method of the crude camptothecin derivative shown in the formula III further comprises the step of washing the obtained reaction liquid with a water washing agent before concentrating the obtained reaction liquid, the preparation method of the crude camptothecin derivative shown in the formula III further comprises the step of drying the reaction liquid washed with the water washing agent before concentrating the obtained reaction liquid.
18. The method for purifying a camptothecin derivative represented by the formula III according to claim 17, wherein, when the method for preparing a crude product of the camptothecin derivative represented by the 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 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 a water layer, wherein the ratio of the mass of the second water-insoluble organic solvent to the mass of the compound represented by the formula II in the reaction is (10-25): 1;
or when the preparation method of the crude camptothecin derivative shown in the formula III further comprises the step of washing the obtained reaction liquid with water lotion before concentrating the obtained reaction liquid, the preparation method of the crude camptothecin derivative shown in the formula III further comprises the step of drying the reaction liquid washed with water lotion before concentrating the obtained reaction liquid, wherein the drying is drying with anhydrous sodium sulfate.
19. The method for purifying a camptothecin derivative represented by the formula III according to claim 18, wherein the organic solvent is a water-soluble organic solvent when the obtained reaction solution is washed with a water-washing agent before concentrating the obtained reaction solution, 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 the concentrated reaction solution with the water-washing agent and a second water-insoluble organic solvent to obtain a mixture, and layering the mixture to obtain an organic layer and a water layer, wherein the ratio of the mass of the second water-insoluble organic solvent to the mass of the compound represented by the formula II in the reaction is (10-15): 1.
20. The method for purifying a camptothecin derivative represented by the formula III according to claim 17, wherein when the method for preparing a crude product of the camptothecin derivative represented by the 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 the concentrated 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, and the second water-insoluble organic solvent is dichloromethane.
21. The method for purifying a camptothecin derivative represented by the formula III according to any one of claims 17 to 20, wherein the step of washing the obtained reaction solution with a water washing agent further comprises stirring the obtained mixture for 1 to 2 hours before the delamination;
Or the step of "washing the obtained reaction liquid with a water washing agent" further comprises washing the obtained organic layer with water and/or saturated brine.
22. The method for purifying a camptothecin derivative represented by the formula III according to claim 21, wherein the step of washing the reaction solution with a water washing agent further comprises stirring the mixture before the delamination, wherein the stirring time is 1-2 hours, and the stirring temperature is 15-35 ℃;
Or the step of washing the obtained reaction liquid with a water washing agent further comprises the step of washing the obtained organic layer with water and/or saturated saline water, wherein the mass of the water and/or the saturated saline water is 10-25 times of the feeding amount of the compound shown as the formula II in the reaction.
23. The method for purifying a camptothecin derivative represented by the formula III according to claim 22, wherein the step of washing the obtained reaction solution with a water washing agent further comprises washing the obtained organic layer with water and/or saturated saline water, wherein the number of washing times is 2 to 5.
24. The method for purifying a camptothecin derivative represented by the formula III according to claim 23, wherein the step of washing the obtained reaction solution with a water washing agent further comprises washing the obtained organic layer with water and/or saturated saline water, wherein the number of washing times is 2 to 3.
25. The method for purifying a camptothecin derivative represented by formula III according to claim 24, wherein the step of washing the obtained reaction solution with a water washing agent further comprises washing the obtained organic layer with water and/or saturated saline water, wherein the number of washing times is 3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111617331.6A CN116354976B (en) | 2021-12-27 | 2021-12-27 | Purification method of camptothecin derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111617331.6A CN116354976B (en) | 2021-12-27 | 2021-12-27 | Purification method of camptothecin derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116354976A CN116354976A (en) | 2023-06-30 |
| CN116354976B true CN116354976B (en) | 2025-01-24 |
Family
ID=86937504
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111617331.6A Active CN116354976B (en) | 2021-12-27 | 2021-12-27 | Purification method of camptothecin derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116354976B (en) |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101376659B (en) * | 2008-09-27 | 2011-11-30 | 上海北卡医药技术有限公司 | Method for purifying camptothecine and derivative thereof |
| US9931417B2 (en) * | 2012-12-13 | 2018-04-03 | Immunomedics, Inc. | Antibody-SN-38 immunoconjugates with a CL2A linker |
| HRP20220399T1 (en) * | 2012-12-13 | 2022-05-13 | Immunomedics, Inc. | Dosages of immunoconjugates of antibodies and sn-38 for improved efficacy and decreased toxicity |
| EP3035938B1 (en) * | 2013-09-10 | 2020-08-19 | Madrigal Pharmaceuticals, Inc. | Targeted therapeutics |
| CN104530413B (en) * | 2014-10-01 | 2017-08-25 | 厦门赛诺邦格生物科技股份有限公司 | A kind of bio-related substance of multiple functionalized H types polyethyleneglycol derivative modification |
| CN106831853B (en) * | 2017-02-15 | 2019-02-22 | 浙江海正药业股份有限公司 | The preparation process of 7- ethyl -10-O- tert-butyl diphenyl silicon substrate camptothecine -20-O- glycine hydrochloride |
| CN109303780B (en) * | 2017-07-28 | 2021-09-21 | 烟台药物研究所 | Reduction response type amphiphilic polymer prodrug of 7-ethyl-10-hydroxycamptothecin and preparation method thereof |
| BR112020020466A2 (en) * | 2018-04-06 | 2021-01-12 | Seattle Genetics, Inc. | CAMPTOTECIN PEPTIDE CONJUGATES |
| CN111362990B (en) * | 2018-12-26 | 2021-08-17 | 联宁（苏州）生物制药有限公司 | Antitumor drug LND1026-034 and synthetic method thereof |
| CN111686259B (en) * | 2019-05-26 | 2023-08-08 | 成都百利多特生物药业有限责任公司 | SN 38-containing antibody drug conjugate |
| EP4066861A4 (en) * | 2019-11-28 | 2023-12-27 | Chongqing Upgra Biotechnology Co., Ltd. | Polyethylene glycol conjugate medicament, preparation method therfor and use thereof |
-
2021
- 2021-12-27 CN CN202111617331.6A patent/CN116354976B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN116354976A (en) | 2023-06-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3421503B1 (en) | Sugammadex preparation and purification method | |
| CN115505051A (en) | Method for refining sugammadex sodium | |
| CN101302190B (en) | Method for preparing 2,3-dichloropyridine | |
| CN102775387B (en) | Method for refining fasudil hydrochloride | |
| CN116354976B (en) | Purification method of camptothecin derivatives | |
| CN110078695B (en) | A kind of quercetin derivative and preparation method thereof | |
| CN114249711A (en) | Method for preparing nicotine by resolution | |
| CN111362990B (en) | Antitumor drug LND1026-034 and synthetic method thereof | |
| CN103450331A (en) | Method for refining bortezomib | |
| CN103172687B (en) | Nelarabine crystalline compound and preparation method thereof | |
| CN104530112A (en) | Method for preparing everolimus intermediate and ethylated impurities thereof | |
| CN106957247B (en) | Purification method of micro-protein indicator | |
| CN113683499B (en) | Method for preparing Du Weili siberian intermediate | |
| CN110229111B (en) | Ambroxol impurity and preparation method and application thereof | |
| EP4433058A1 (en) | Improved process for the preparation of lurbinectedin and its morphs thereof | |
| CN110698532B (en) | Method for extracting sea cucumber saponin Cladoloside A | |
| CN108864240B (en) | Method for purifying dexamethasone epoxy hydrolysate | |
| CN112679512A (en) | Tributine intermediate and preparation method thereof | |
| CN108707150B (en) | Preparation method of imidazopyrazine pharmaceutical intermediate | |
| CN110642862B (en) | Preparation method of ticagrelor ethylated impurity | |
| CN114621258B (en) | Purification method of vinorelbine tartrate | |
| CN114605357B (en) | Separation and purification method of taxol-oleic acid small molecules | |
| CN111440121B (en) | Method for splitting two key intermediates in total synthesis process of optical pure tetrandrine | |
| CN114907424A (en) | Synthesis method of glycated lysine and isotope labeled glycated lysine | |
| CN108586408B (en) | Preparation method of high-yield and high-purity Iguratimod intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20240520 Address after: 201210 Shanghai Zhangjiang High Tech Park of Pudong New Area Cailun Road No. 308 Applicant after: SHANGHAI FUDAN-ZHANGJIANG BIO-PHARMACEUTICAL Co.,Ltd. Country or region after: China Applicant after: TAIZHOU FUDAN ZHANGJIANG PHARMACEUTICAL Co.,Ltd. Address before: 201210 Shanghai Zhangjiang High Tech Park of Pudong New Area Cailun Road No. 308 Applicant before: SHANGHAI FUDAN-ZHANGJIANG BIO-PHARMACEUTICAL Co.,Ltd. Country or region before: China |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |