CN110981903A - Refining method for improving optical purity of eribulin intermediate compound - Google Patents
Refining method for improving optical purity of eribulin intermediate compound Download PDFInfo
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- CN110981903A CN110981903A CN201911188501.6A CN201911188501A CN110981903A CN 110981903 A CN110981903 A CN 110981903A CN 201911188501 A CN201911188501 A CN 201911188501A CN 110981903 A CN110981903 A CN 110981903A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- 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
Abstract
The invention discloses a refining method for improving optical purity of eribulin intermediate compound, which comprises the following steps: (1) reacting free compound (I) with sodium bisulfite to obtain solid compound (II); (2) recrystallizing the compound (II), and then dissociating to form the compound (I); the reaction of the invention is a process of recrystallization after dissolution, avoids column chromatography, is safe, environment-friendly, fast in speed, clean in reaction process, free of redundant products, high in optical purity of products and suitable for large-scale production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a refining method for improving optical purity of eribulin intermediate compounds.
Background
Eribulin mesylate (Eribulin mesylate) blocks the G2/M cell circuit through the tubulin antimitotic pathway, affects the mitotic spindle, and finally blocks the mitotic process and dies cells, and is suitable for treating metastatic breast cancer patients who have been treated with at least 2 chemotherapeutic regimens. Developed by japanese toilet paper (Eisa) under the trade name HALAVENTM. Eribulin mesylate (Eribulin mesylate) contains 19 chiral centers, has a plurality of isomers and large synthesis difficulty, and most intermediates are oily liquids, so that industrial production and refining are extremely difficult. Therefore, it is particularly important to improve the optical purity of eribulin mesylate by controlling the chiral purity of eribulin mesylate intermediate.
Patent WO2014183211 and patent CN104024237B disclose a process for the preparation of eribulin mesylate, as a key intermediate (I) of the following formula provides a side chain for eribulin mesylate in the route.
Intermediate (I) is an oily liquid at room temperature and is unstable to heat, and is difficult to purify by conventional distillation or the like. In the prior art, the method is used for purification and refining by means of repeated column chromatography, although the method is simple, the reproducibility is not high, the amplification is difficult, and a large amount of organic solvent is used in the column chromatography process, so that the cost is high and the waste liquid is large.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a safe and environment-friendly refining method for improving the optical purity of eribulin intermediate compounds, which is suitable for large-scale production.
The technical scheme is as follows: the invention relates to a refining method for improving optical purity of eribulin intermediate compound, which is shown in general formula (I), wherein PG is an alcohol protecting group, and the synthetic route is as follows:
the method specifically comprises the following steps:
(1) reacting free compound (I) with sodium bisulfite to obtain solid compound (II);
(2) the compound (II) is recrystallized and then dissociated into the compound (I).
Further, the reaction process of the step (1) is as follows:
(a) adding a free compound (I) into a reaction bottle, adding a first solvent and a sodium bisulfite solution, and heating and stirring for reaction;
(b) and after the reaction is completed, carrying out suction filtration, washing a filter cake by using a second solvent, carrying out suction filtration, and drying to obtain a compound (II).
Further, the reaction process of the step (2) is as follows:
(c) adding a third solvent into the compound (II), heating for dissolving, cooling, recrystallizing to separate out a solid, and performing suction filtration to obtain a compound (II);
(d) and adding a base into the compound (II) in a fourth solvent, and dissociating to obtain the compound (I).
Further, the first solvent and the second solvent are respectively one or more of water, methanol, ethanol, isopropanol, tert-butanol, N, -dimethylformamide, N, -dimethylacetamide, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dichloromethane, ethyl acetate, isopropyl acetate, toluene and xylene.
Further, the temperature in the step (a) is increased to 20-80 ℃ and stirring is carried out.
Further, the third solvent and the fourth solvent are respectively one or more of water, methanol, ethanol, isopropanol, tert-butanol, N, -dimethylformamide, N, -dimethylacetamide, acetone, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, toluene, xylene, petroleum ether, N-pentane, N-hexane and N-heptane.
Further, in step (c), the third solvent is ethyl acetate and/or n-heptane.
Further, in the step (c), the temperature is reduced to 20-80 ℃ for recrystallization.
Further, in the step (d), the base is one or more of trimethylamine, triethylamine, tetramethylethylenediamine, pyridine, 2-methylpyridine, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.
Further, the base in step (d) is preferably potassium carbonate.
Has the advantages that: the reaction of the invention is a process of recrystallization after dissolution, avoids column chromatography, is safe, environment-friendly, fast in speed, clean in reaction process, free of redundant products, high in optical purity of products and suitable for large-scale production.
Detailed Description
For a further understanding of the contents of the present invention, reference will now be made in detail to the following examples.
Example 1
(1) Preparation of the Compound of formula (IIA)
(a) Respectively adding 100 g of compound formula (IA), 500 g of methanol, 200 g of water and 100 g of sodium bisulfite into a 2L reaction bottle, starting stirring, and reacting at 25-30 ℃;
(b) the reaction is complete, the filtration is carried out, the filter cake is leached by 20 g of methanol, the filtration is carried out, the filter cake is collected and dried in vacuum at the temperature of 30 ℃, 114.1 g of white solid compound (IIA) is obtained, and the yield is 92.0%.
(2) Preparation of the Compound of formula (IA)
(c) Respectively adding 100 g of the compound shown as the formula (IIA) and 400 g of ethyl acetate into a reaction bottle, heating and refluxing until the solid is dissolved clearly, slowly adding 120 g of n-heptane, continuously stirring for 30 minutes after the addition is finished, closing the heating, slowly cooling to 25 ℃, recrystallizing and separating out the solid, performing suction filtration, and collecting a filter cake.
(d) Adding the filter cake and 500 g of ethyl acetate into a reaction bottle, adding 120 g of water and 60 g of potassium carbonate under stirring, stirring for reaction, completely reacting, separating, washing an organic phase with saturated saline solution, separating again, and concentrating the organic phase under reduced pressure to obtain 68.1 g of a colorless liquid compound (IA), wherein the yield is as follows: 84.3 percent.
Example 2
(1) Preparation of the Compound of formula (IIA)
(a) Respectively adding 100 g of compound formula (IA), 500 g of toluene, 200 g of water and 100 g of sodium bisulfite into a 2L reaction bottle, starting stirring, and reacting at 20 ℃;
(b) the reaction is complete, the filtration is carried out, the filter cake is leached by 20 g of tetrahydrofuran, the filtration is carried out, the filter cake is collected and dried in vacuum at the temperature of 30 ℃, 114.1 g of white solid compound (IIA) is obtained, and the yield is 91.0%.
(2) Preparation of the Compound of formula (IA)
(c) Respectively adding 100 g of the compound shown as the formula (IIA) and 400 g of water into a reaction bottle, heating and refluxing until the solid is dissolved clearly, slowly adding 120 g of n-hexane, continuously stirring for 30 minutes after the addition is finished, closing the heating, slowly cooling to 20 ℃, recrystallizing and separating out the solid, performing suction filtration, and collecting a filter cake.
(d) Adding the filter cake and 500 g of ethanol into a reaction bottle, adding 120 g of water and 60 g of potassium carbonate under stirring, stirring for reaction, completely reacting, separating liquid, washing an organic phase with saturated saline solution, separating liquid again, and concentrating the organic phase under reduced pressure to obtain 68.1 g of a colorless liquid compound (IA), wherein the yield is as follows: 82.3 percent.
Example 3
(1) Preparation of the Compound of formula (IIA)
(a) Respectively adding 100 g of the compound shown as the formula (IA), 500 g of N, N-dimethylformamide, 200 g of water and 100 g of sodium bisulfite into a 2L reaction bottle, starting stirring, and reacting at 80 ℃;
(b) and (3) completely reacting, performing suction filtration, leaching a filter cake with 20 g of isopropanol, performing suction filtration, collecting the filter cake, and performing vacuum drying at 30 ℃ to obtain 114.1 g of a white solid compound (IIA), wherein the yield is 91.8%.
(2) Preparation of the Compound of formula (IA)
(c) Respectively adding 100 g of compound formula (IIA) and 400 g of dimethylbenzene into a reaction bottle, heating and refluxing until the solid is clear, slowly adding 120 g of n-pentane, continuously stirring for 30 minutes after the addition is finished, closing the heating, slowly cooling to 80 ℃, recrystallizing and separating out the solid, performing suction filtration, and collecting a filter cake.
(d) Adding the filter cake and 500 g of ethanol into a reaction bottle, adding 120 g of water and 60 g of potassium carbonate under stirring, stirring for reaction, completely reacting, separating liquid, washing an organic phase with saturated saline solution, separating liquid again, and concentrating the organic phase under reduced pressure to obtain 68.1 g of a colorless liquid compound (IA), wherein the yield is as follows: 82.9 percent.
Claims (10)
1. A refining method for improving optical purity of eribulin intermediate compound, wherein the compound is shown as a general formula (I), PG is an alcohol protecting group, and the synthetic route is as follows:
the method specifically comprises the following steps:
(1) reacting free compound (I) with sodium bisulfite to obtain solid compound (II);
(2) the compound (II) is recrystallized and then dissociated into the compound (I).
2. The purification method for improving optical purity of eribulin intermediate compound according to claim 1, wherein the reaction process in step (1) is:
(a) adding a free compound (I) into a reaction bottle, adding a first solvent and a sodium bisulfite solution, and heating and stirring for reaction;
(b) and after the reaction is completed, carrying out suction filtration, washing a filter cake by using a second solvent, carrying out suction filtration, and drying to obtain a compound (II).
3. The purification method for improving optical purity of eribulin intermediate compound according to claim 1, wherein the reaction process in step (2) is:
(c) adding a third solvent into the compound (II), heating for dissolving, cooling, recrystallizing to separate out a solid, and performing suction filtration to obtain a compound (II);
(d) and adding a base into the compound (II) in a fourth solvent, and dissociating to obtain the compound (I).
4. The method according to claim 2, wherein the first solvent and the second solvent are one or more selected from water, methanol, ethanol, isopropanol, tert-butanol, N, -dimethylformamide, N, -dimethylacetamide, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dichloromethane, ethyl acetate, isopropyl acetate, toluene, and xylene.
5. The purification method of eribulin intermediate compound for improving optical purity of claim 2, wherein in step (a), said heating to 20-80 ℃ is performed with stirring.
6. The purification method of eribulin intermediate compound for increasing optical purity of claim 3, wherein said third and fourth solvents are water, methanol, ethanol, isopropanol, t-butanol, N-dimethylformamide, N-dimethylacetamide, acetone, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl t-butyl ether, ethyl acetate, isopropyl acetate, toluene, xylene, petroleum ether, N-pentane, N-hexane, and N-heptane, respectively.
7. The purification method of claim 6, wherein the third solvent in step (c) is one or both of ethyl acetate and n-heptane.
8. The purification method for improving optical purity of eribulin intermediate compound as claimed in claim 3, wherein in step (c), the temperature is reduced to 20-80 deg.C for recrystallization.
9. The refining method of eribulin intermediate compound for improving optical purity of claim 3, wherein in step (d), said base is one or more of trimethylamine, triethylamine, tetramethylethylenediamine, pyridine, 2-methylpyridine, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate.
10. The purification method for improving optical purity of an eribulin intermediate compound as claimed in claim 9, wherein said base in step (d) is potassium carbonate.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114671905A (en) * | 2020-12-24 | 2022-06-28 | 苏州正济药业有限公司 | Derivative of eribulin intermediate and salt thereof, and preparation and purification methods and application thereof |
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| CN114671905B (en) * | 2020-12-24 | 2023-10-20 | 苏州正济药业有限公司 | Derivative of eribulin intermediate and salt thereof, and preparation, purification method and application thereof |
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