Preparation method of esculene mesylate intermediate
By optimizing chemical reaction conditions and reagent selection, and using a series of refined chemical reaction steps, the purity and quality control of the eriprin mesylate intermediate was successfully improved, and the problem of difficulty in controlling three-dimensional selective chiral carbon atoms in the prior art was solved, and an efficient preparation method suitable for industrial applications was realized.
Patent Information
- Application Number
- CN202411860485.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-17
- Publication Date
- 2025-05-09
AI Technical Summary
The prior art is difficult to effectively control the stereoselectivity of chiral carbon atoms in the Eribrin methanesulfonate intermediate, resulting in poor product purity and complex preparation process and not suitable for industrial applications.
Using mild reaction conditions and widely accessible economic reagents, the esilbringer methanesulfonate intermediate is gradually synthesized and refined through a series of optimized chemical reaction steps, including oxidation reaction, Wittig reaction, debenzyl protecting reaction and reduction reaction, to ensure high-quality control of chiral carbon atoms.
The high purity (over 99.5%) and low impurity content (single impurity content is less than 0.1%) of the eriprin mesylate intermediate was achieved, which simplified the drug synthesis route, reduced R&D costs, and improved the stability and control of product quality.
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Figure CN119954751A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to a method for preparing an eribulin mesylate intermediate, and in particular to a method for preparing an eribulin mesylate intermediate with excellent product quality and conducive to industrialization. Background Art
[0002] Eribulin mesylate (Formula A) is a derivative of the macrolide compound halichondrin B extracted from the marine sponge Halichondria okadai. As a tubulin inhibitor, it is used to treat patients with metastatic breast cancer who have received at least two chemotherapy regimens. It can directly bind to tubulin to inhibit mitosis, thereby inhibiting microtubule growth and inhibiting cancer cell growth, providing a new treatment for patients with locally advanced breast cancer or metastatic breast cancer to improve survival and quality of life. It is also used to treat liposarcoma (STS, a specific type of soft tissue sarcoma) and tumors that cannot be surgically removed or are advanced (metastatic), and is the first drug to treat liposarcoma.
[0003]
[0004] Eribulin mesylate contains 19 chiral carbon atoms in its structure, and its total synthesis route research and preparation process development are very difficult, especially the stereoselective control of each chiral carbon atom in the preparation process is extremely challenging. The compound of formula I is a key intermediate for the preparation of Eribulin mesylate, and the preparation of this intermediate involves the introduction or construction of 5 chiral carbon atoms, which are numbered as C29, C30, C31, C32 and C34 according to the carbon atom numbering, wherein the chiral carbon atoms C31 and C32 are introduced from the original chiral natural product sugar source structure, and the chiral carbon atoms C29, C30 and C34 are constructed through subsequent chemical reactions, especially the diastereoisomer impurities related to the chiral carbon atoms C29 and C30, and there is no effective control method.
[0005]
[0006] CN101899026 discloses a method for preparing a compound of formula I (R is H). The method is reproduced and analyzed in depth, and it is found that the method is not conducive to industrialization. First, the oxidation reaction conditions for preparing a compound of formula III from a compound of formula II are complicated, and the reaction temperature needs to be controlled at about -20°C, which is cumbersome to operate and has certain requirements on the reaction equipment; second, the phosphoester reagent used in the Wittig reaction for preparing a compound of formula IV from a compound of formula III is expensive and difficult to obtain; third, the trimethyl iodosilane reagent used in the reaction for removing the benzyl protecting group from the compound of formula IV to prepare the compound of formula V is also expensive, has poor stability, is easily decomposed in moisture, and is difficult to operate; fourth, the purity of the product after purification of the compound of formula I is poor, especially the residual content of the related diastereoisomer impurities is high, which cannot be effectively removed and controlled, increasing the difficulty of subsequent research and preparation of raw materials.
[0007] Summary of the invention Purpose of the invention: The present invention aims to provide an industrialized method for preparing an eribulin mesylate intermediate with stable and readily available raw materials, convenient operation, and controllable product quality.
[0009] Technical solution: The preparation method of the intermediate of eribulin mesylate having the structure of formula I (R is selected from H or methyl) of the present invention,
[0010]
[0011] The following steps are involved:
[0012] (1) using dichloromethane as a reaction solvent, the compound of formula II is subjected to an oxidation reaction with a Dess-Martin reagent to obtain a compound of formula III;
[0013]
[0014] (2) using tetrahydrofuran as the reaction solvent and reacting anisyl sulfone or p-methyl anisyl sulfone with n-butyl lithium reagent at a reaction temperature of 0 to 5° C., followed by adding diisopropyl chlorophosphate to in situ generate Wittig reagent, which then reacts with a toluene solution of the compound of formula III to obtain a compound of formula IV;
[0015]
[0016] (3) using dichloromethane as the reaction solvent, and removing the benzyl protecting group from the compound of formula IV under the action of Lewis acid to obtain a compound of formula V;
[0017]
[0018] (4) using ethylene glycol dimethyl ether and toluene as solvents, in the presence of tetrabutylammonium chloride and sodium acetate borohydride, the compound of formula V is subjected to a reduction reaction to obtain a compound of formula VI;
[0019]
[0020] (5) removing the Bz protecting group from the compound of formula VI to obtain a crude compound of formula I, which is then recrystallized from isopropanol and toluene to obtain a refined compound of formula I;
[0021]
[0022] For the synthesis research of drugs with multiple chiral carbon atoms, if the effective quality control of chiral carbon atoms can be achieved at the front end of the synthesis route, especially for extremely complex structures such as eribulin mesylate, it will greatly simplify the difficulty of drug quality research and reduce unnecessary tedious impurity synthesis research work, further save drug research and development costs, and better improve and achieve stable control of drug quality. The present invention designs a method suitable for large-scale amplification with milder reaction conditions, extensive and economical reagent sources, and higher product purity for the key intermediate of eribulin mesylate of formula I.
[0023] Specifically, the compound of formula II is used as a raw material, firstly an oxidation reaction is performed to obtain an intermediate of formula III, then an intermediate of formula IV is obtained through a Wittig reaction, then the benzyl protecting group is removed through the action of Lewis acid to obtain an intermediate of formula V, and then an intermediate of formula VI is obtained through a stereoselective reduction reaction, and finally the Bz protecting group is removed and the intermediate is purified to obtain an eribulin mesylate intermediate of formula I, wherein the purity reaches more than 99.5%, the content of a single impurity is less than 0.1%, and in particular, the impurity contents of three diastereoisomers C29 (R), C30 (S) and C34 (R) are all less than 0.1%.
[0024] Preferably, the molar ratio of the compound of formula II to the Dess-Martin reagent in step (1) is 1:(1-2).
[0025] More preferably, the molar ratio of the compound of formula II to the Dess-Martin reagent is 1:1.1.
[0026] Preferably, in step (2), the molar ratio of the compound of formula III, phenyl sulfone or p-methyl phenyl sulfone, n-butyl lithium and diisopropyl chlorophosphate is 1:(1.2-2):(2.4-4):(1.2-2).
[0027] More preferably, the molar ratio of the compound of formula III, phenyl sulfone or p-methyl phenyl sulfone, n-butyl lithium and diisopropyl chlorophosphate is 1:1.6:3.2:1.6.
[0028] Preferably, in step (5), the mass ratio of the crude product of the compound of formula I, isopropanol and toluene is 1:(0.3-1):(3-5).
[0029] Further preferably, the mass ratio of the crude product of the compound of formula I, isopropanol and toluene is 1:0.6:4.
[0030] Preferably, the recrystallization method in step (5) is to mix the crude compound of formula I with isopropanol and toluene, dissolve it at 75-85°C, and then cool it to 0-5°C for crystallization.
[0031] Preferably, in step (3), the Lewis acid is selected from ferric chloride or aluminum chloride.
[0032] More preferably, the Lewis acid is ferric chloride.
[0033] Preferably, tetrabutylammonium chloride and sodium acetate borohydride are used as reducing agents in step (4).
[0034] Preferably, potassium carbonate is used as a deprotecting agent in step (5).
[0035] Preferably, in the eribulin mesylate intermediate prepared by the preparation method, the contents of C29(R), C30(S) and C34(R) diastereoisomer impurities are all lower than 0.1%.
[0036] Preferably, the purity of the eribulin mesylate intermediate prepared by the preparation method is greater than 99.5%.
[0037] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:
[0038] The present invention optimizes the reaction conditions by optimizing the reaction reagents, thereby avoiding the restriction of the reaction conditions on the equipment, improving the accessibility and operability of the reaction reagents, improving the economy of the preparation method, and facilitating industrial application. The refining method can not only effectively remove conventional process impurities, but also remove multiple diastereoisomer impurities generated in the reaction, and the product quality is stable and controllable. At the same time, the front-end quality control of multiple chiral carbon atoms is achieved, which is more conducive to the quality control of the subsequent prepared raw materials and related preparations. BRIEF DESCRIPTION OF THE DRAWINGS
[0039] Figure 1 is the hydrogen spectrum of the compound of formula I when R is H;
[0040] Figure 2 is the HPLC spectrum of the crude product of the compound of formula I when R is H;
[0041] Figure 3 The HPLC spectrum of the purified product of the compound of formula I when R is H. DETAILED DESCRIPTION
[0042] The technical solution of the present invention is further described below in conjunction with embodiments.
[0043] Example 1
[0044] 30.0 kg of dichloromethane and 5.0 kg of the compound of formula II (R is H) were added to the reactor in sequence, and stirred to dissolve; the temperature inside the reaction system was cooled to 0°C; 4.5 kg of Dess-Martin reagent was added; after the addition, the internal temperature was raised to 25-35°C and stirred to react; after the reaction was completed, an aqueous solution of sodium thiosulfate and sodium carbonate was added, and the mixture was stirred to quench; the liquids were separated and the organic phase was retained; the organic phase was concentrated to obtain 5.5 kg of the compound of formula III (R is H).
[0045] Example 2
[0046] 25.0 kg of tetrahydrofuran and 2.62 kg (16.8 mol, 1.6 eq) of phenyl sulfone were sequentially added to the reactor, and stirred to dissolve; the temperature in the reaction system was cooled to 0°C; 9.4 kg (33.6 mol, 3.2 eq) of 2.5 M n-butyl lithium hexane solution and 3.37 kg (16.8 mol, 1.6 eq) of diisopropyl chlorophosphate were sequentially added dropwise; after the addition, the mixture was stirred for 0.5 hours (Wittig reagent solution was prepared in situ); 18.9 kg of toluene and 5.4 kg (10.5 mol, 1.0 eq) of the compound of formula III (R is H) were sequentially added to another reactor, and stirred to dissolve; the Wittig reagent solution prepared above was added to the reaction system of the latter reactor, and stirred to react; after the reaction was completed, a dilute aqueous hydrochloric acid solution was added, and the mixture was stirred to quench; the liquids were separated, and the organic phase was retained; the organic phase was concentrated to obtain 6.17 kg of the compound of formula IV (R is H).
[0047] Example 3
[0048] Add 21.0 kg of dichloromethane and 6.0 kg of the compound of formula IV (R is H) to the reactor in sequence, and stir to dissolve; cool the temperature in the reaction system to 0°C; add 2.24 kg of ferric chloride; after the addition, keep warm and stir; after the reaction is completed, filter; add purified water to the filtrate and stir; separate the liquids and retain the organic phase; concentrate the organic phase to obtain 4.65 kg of the compound of formula V (R is H).
[0049] Example 4
[0050] 21.6 kg of ethylene glycol dimethyl ether, 8.6 kg of toluene, 6.23 kg of tetrabutylammonium chloride, and 7.04 kg of sodium borohydride acetate were added to the reactor in sequence and stirred to mix; the temperature in the reaction system was controlled at 20 to 30 degrees and stirred for 0.5 hours; 4.6 kg of the compound of formula V (R is H) and 2.3 kg of toluene were mixed evenly and added to the aforementioned reaction system; the temperature in the reaction system was raised to 80 to 90°C and stirring was continued for 1 hour; after the reaction was completed, sodium bicarbonate aqueous solution was added and stirred to quench; the liquids were separated and the organic phase was retained; the organic phase was concentrated to obtain 4.22 kg of the compound of formula VI (R is H).
[0051] Example 5
[0052] 8.4 kg of methanol, 4.2 kg of the compound of formula VI (R is H), and 1.0 kg of potassium carbonate were added to the reactor in sequence and stirred evenly; the temperature in the reaction system was raised to 40-50° C., and the reaction was stirred; after the reaction was completed, the system was concentrated; dichloromethane and purified water were added, stirred, and separated; dichloromethane was added to the aqueous phase for extraction; the organic phases were combined and concentrated to obtain 2.6 kg of a crude product of the compound of formula I (R is H) with an HPLC purity of 74.68% ( Figure 2 , Table 1). 1.56 kg of isopropanol and 10.4 kg of toluene were added to the crude product; the system was heated to 75-85°C, stirred to dissolve; the temperature was slowly lowered to 0-5°C, and the stirring was continued; suction filtration was performed to obtain 2.21 kg of a refined product of the compound of formula I (R is H), with an HPLC purity of 99.87%, an unknown single impurity of less than 0.1%, and the impurity contents of the three diastereoisomers C29 (R), C30 (S) and C34 (R) were all less than 0.1% ( Figure 3 , Table 2).
[0053] Table 1 HPLC detection results of crude product
[0054]
[0055] Table 2 HPLC test results of refined products
[0056]
[0057] Example 6
[0058] The compound of formula VI (R is methyl) was prepared by referring to the methods of Examples 1 to 4. 9.2 kg of methanol, 4.6 kg of the compound of formula VI (R is methyl), and 1.1 kg of potassium carbonate were added to the reactor in sequence and stirred evenly; the temperature in the reaction system was raised to 40-50° C., and the reaction was stirred; after the reaction was completed, the system was concentrated; dichloromethane and purified water were added, stirred, and separated; dichloromethane was added to the aqueous phase for extraction; the organic phases were combined and concentrated to obtain 2.7 kg of a crude product of the compound of formula I (R is methyl). 1.62 kg of isopropanol and 10.8 kg of toluene were added to the crude product; the system was heated to 75-85° C., stirred to dissolve; the temperature was slowly lowered to 0-5° C., and stirring was continued at the temperature; suction was filtered to obtain 2.38 kg of a refined product of the compound of formula I (R is methyl) with an HPLC purity of 99.62%, an unknown single impurity of less than 0.1%, and the impurity contents of three diastereoisomers, C29 (R), C30 (S) and C34 (R), were all less than 0.1%.
Claims
1. A method for preparing an eribulin mesylate intermediate, wherein the intermediate has a structure of formula I, wherein R is selected from H or methyl, It is characterized in that The preparation method comprises the following steps: (1) using dichloromethane as a reaction solvent, the compound of formula II is subjected to an oxidation reaction with a Dess-Martin reagent to obtain a compound of formula III; (2) using tetrahydrofuran as the reaction solvent and reacting anisyl sulfone or p-methyl anisyl sulfone with n-butyl lithium reagent at a reaction temperature of 0 to 5° C., followed by adding diisopropyl chlorophosphate to in situ generate Wittig reagent, which then reacts with a toluene solution of the compound of formula III to obtain a compound of formula IV; (3) using dichloromethane as the reaction solvent, in the presence of ferric chloride, the compound of formula IV undergoes a benzyl protecting group removal reaction to obtain a compound of formula V; (4) using ethylene glycol dimethyl ether and toluene as solvents, in the presence of tetrabutylammonium chloride and sodium acetate borohydride, the compound of formula V is subjected to a reduction reaction to obtain a compound of formula VI; (5) removing the Bz protecting group from the compound of formula VI to obtain a crude compound of formula I, which is then recrystallized from isopropanol and toluene to obtain a refined compound of formula I; 2. The preparation method according to claim 1, characterized in that: In step (1), the molar ratio of the compound of formula II to the Dess-Martin reagent is 1:(1-2).
3. The preparation method according to claim 2, characterized in that: The molar ratio of the compound of formula II to the Dess-Martin reagent is 1:1.
1.
4. The preparation method according to claim 1, characterized in that: In step (2), the molar ratio of the compound of formula III, phenyl sulfone or p-methyl phenyl sulfone, n-butyl lithium and diisopropyl chlorophosphate is 1:(1.2-2):(2.4-4):(1.2-2).
5. The preparation method according to claim 4, characterized in that: The molar ratio of the compound of formula III, anisyl sulfone or p-methyl anisyl sulfone, n-butyl lithium and diisopropyl chlorophosphate is 1:1.6:3.2:1.
6.
6. The preparation method according to claim 1, characterized in that: In step (5), the mass ratio of the crude product of the compound of formula I, isopropanol and toluene is 1:(0.3-1):(3-5).
7. The preparation method according to claim 6, characterized in that: The mass ratio of the crude product of the compound of formula I, isopropanol and toluene is 1:0.6:
4.
8. The preparation method according to claim 1, characterized in that: The recrystallization method in step (5) is to mix the crude product of the compound of formula I with isopropanol and toluene, dissolve it at 75-85°C, and then cool it to 0-5°C for crystallization.
9. The preparation method according to claim 1, characterized in that: In the prepared eribulin mesylate intermediate, the contents of C29(R), C30(S) and C34(R) diastereoisomer impurities are all lower than 0.1%.
10. The preparation method according to claim 1, characterized in that: The purity of the prepared eribulin mesylate intermediate is greater than 99.5%.