Echinocandin drug impurity compound, preparation method therefor and use thereof
By employing chemical synthesis and resin purification methods, the problem of efficient preparation and purification of impurities in micafungin sodium was solved, providing high-purity echinocandin impurities for drug quality control and improving the quality standards of micafungin sodium.
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- SHANGHAI TECHWELL BIOPHARMACEUTICALS CO LTD
- Filing Date
- 2025-04-02
- Publication Date
- 2026-05-21
AI Technical Summary
In the existing technology, impurities generated during the synthesis of micafungin sodium are difficult to prepare and purify efficiently, affecting drug quality and safety, and there is a lack of effective preparation and purification methods.
A specific chemical synthesis method was used to react the active ester of micafungin sodium side chain with FR179642 under an alkaline catalyst, followed by a purification step using a combination of ion exchange resin and macroporous adsorption resin to prepare high-purity echinocandin drug impurities.
This method enables the preparation of high-purity (over 90%) impurities in echinocandins, provides a reference standard for drug quality control, and improves the quality standard of micafungin sodium.
Smart Images
Figure CN2025086918_21052026_PF_FP_ABST
Abstract
Description
A drug impurity compound of echinocandin, its preparation method and application
[0001] Cross-references to related applications
[0002] This application claims priority to Chinese Patent Application No. 202411642606.5, filed on November 15, 2024, entitled "An Echinocandin Drug Impurity Compound and Its Preparation Method and Application", the entire contents of which are incorporated herein by reference. Technical Field
[0003] This application belongs to the field of biomedical technology, specifically relating to a new echinocandin drug impurity compound, and further discloses its preparation method and application. Background Technology
[0004] Micafungin sodium is a new generation of echinocandin antifungal drug, primarily used to treat fungemia, respiratory fungal infections, and gastrointestinal fungal infections caused by Aspergillus and Candida. It is also used to prevent Aspergillus and Candida infections in hematopoietic stem cell patients. Micafungin sodium is a type of echinocandin antifungal drug that inhibits the synthesis of β(1,3)-glucan in filamentous fungi and yeasts. In recent years, the incidence and mortality rates of fungal infections have been rising, especially among critically ill patients, posing a fatal threat. As an echinocandin drug, micafungin sodium, with its excellent antifungal activity, is the first-line treatment for infections caused by Candida or Aspergillus. It not only has good therapeutic effects but also minimal impact on human cells, exhibiting low toxicity and high efficacy in clinical practice.
[0005] In existing technologies, micafungin sodium is a semi-synthetic antibacterial drug, which can be prepared by microbial transformation of fermentation intermediate FR901379 to remove fatty acid side chains, yielding FR179642, followed by chemical synthesis. Due to the unique structure of FR179642, which is a polypeptide parent ring containing multiple amino and hydroxyl functional groups, it generates various byproducts when reacting with side-chain acids or active side-chain esters. By tracking the fermentation process of FR901379, it was found that impurities with structures similar to the FR901379 parent core are produced at this stage. These impurities can then undergo cleavage of fatty acid side chains by acyltransferases to form fatty amine impurities with structures similar to FR179642, which in turn undergo condensation reactions with active ester side chains to form micafungin sodium impurities. Ohigashi et al. (Journal of Synthetic Organic Chemistry, vol 64, No. 12, 2006) reported in 2006 that due to the large number of active groups in micafungin, side reactions of monoacylation could be detected during the acylation reaction to prepare echinocandin, suggesting the possible presence of diacylated impurities. However, they did not report the structures of these potential diacylated impurities, nor did they report any related preparation or purification methods.
[0006] Impurity analysis is crucial in drug development. Impurities are closely related to the quality, safety, and stability of drugs. Preparing and structurally confirming impurities can reveal their formation pathways, providing a basis for improving drug synthesis routes and manufacturing processes. Impurities can also be used in drug quality control, serving as reference standards for establishing analytical methods. For pharmaceutical manufacturers, strict control over impurities is essential. Therefore, research on impurities in echinocandins can be used for the qualitative and quantitative analysis of impurities in micafungin sodium production, thereby providing technical support for subsequent quality research of micafungin sodium and improving its quality standards.
[0007] Therefore, there is a need in the field to develop an efficient and convenient method for preparing impurities in echinocandin drugs, which would be of positive significance for the development of echinocandin drugs. Summary of the Invention
[0008] Therefore, the technical problem to be solved by this application is to provide an echinocandin drug impurity, wherein the HPLC purity of the echinocandin drug impurity reaches more than 90%, which can be used for the quality control of echinocandin drugs and as a reference for establishing analytical methods.
[0009] The second technical problem to be solved by this application is to provide a method for preparing the above-mentioned echinocandin drug impurities, including a synthesis method and a separation and purification method.
[0010] To solve the above-mentioned technical problems, this application provides an echinocandin drug impurity compound or an acceptable salt thereof, wherein the echinocandin drug impurity compound has the structure shown in formula (Ⅰ):
[0011] The echinocandin drug impurity compound with the structure shown in formula (Ⅰ) provided in this application has the chemical name: 5-[(1S,2S)-1-[4-[5-(4-pentoxyphenyl)isoxazol-3-yl]benzoyloxo]-2-[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S)-3-[(R)-2-carbamoyl-1-hydroxyethyl] -11,20,21,25-Tetrahydroxy-15-[(R)-1-hydroxyethyl]-2,5,8,14,17,23-Hexaoxo-18-[4-[5-(4-pentoxyphenyl)isoxazol-3-yl]benzoylamino]-1,4,7,13,16,22-Hexaazatricyclo[22.3.0.09,13]hexadecyl-6-yl]-2-hydroxyethyl]-2-hydroxyphenyl sulfate sodium.
[0012] This application also discloses a high-purity echinocandin drug impurity, comprising the echinocandin drug impurity compound or an acceptable salt thereof, having an HPLC purity of 90% or higher.
[0013] This application also discloses a method for preparing the high-purity echinocandin drug impurity, comprising the following steps:
[0014] (1) Add the active ester of micafungin sodium side chain selected from the structure shown in formula (II) or formula (III) to the first solvent and mix;
[0015] (2) Continue to add organic base and compound FR179642 with the following formula (IV) and mix them to obtain the echinocandin drug impurity with the structure shown in formula (I) after reaction;
[0016] Specifically, in the method for preparing the high-purity echinocandin drug impurity, in step (1), the first organic solvent includes at least one of N,N-dimethylformamide, N,N-diethylacetamide, tetrahydrofuran, or dimethyl sulfoxide.
[0017] Specifically, in the method for preparing the high-purity echinocandin drug impurity, in step (2), the amount of compound FR179642 added is 0.2-1.0 equivalents.
[0018] Specifically, in the method for preparing the high-purity echinocandin drug impurity, in step (2), the organic base includes at least one of DIPEA, TEA, DMAP, Pyridine, or NMM.
[0019] Specifically, in the method for preparing the high-purity echinocandin drug impurity, the reaction temperature in step (2) is -10 to 20°C, or optionally -10 to 10°C.
[0020] Specifically, the method for preparing the high-purity echinocandin drug impurity further includes a step of purifying the echinocandin drug impurity, comprising the following steps:
[0021] (3) Collect the reactants from step (2) and add them to an ion exchange resin for the first purification process;
[0022] (4) Collect the purified product, add it to a macroporous adsorption resin for a second adsorption treatment, and add a second solvent for elution treatment to obtain the product.
[0023] Specifically, in the method for preparing the high-purity echinocandin drug impurity, in step (3), the ion exchange resin includes a strongly acidic cation exchange resin.
[0024] Optionally, the ion exchange resin includes at least one of UBK530, UBK550, or UBK555.
[0025] Specifically, in the method for preparing the high-purity echinocandin drug impurity, in step (4), the macroporous adsorption resin includes a resin with styrene and / or divinylbenzene as the matrix;
[0026] Optionally, the macroporous adsorption resin includes at least one of HP20, HP20SS, SP70, SP700, SP850, CHP20, or CHP55.
[0027] Specifically, in the method for preparing the high-purity echinocandin drug impurity, in step (4), the second solvent includes at least one of methanol, ethanol, acetone or acetonitrile.
[0028] Optionally, the volume percentage of the second solvent is 1%-90%.
[0029] Specifically, in the method for preparing the high-purity echinocandin drug impurity, the temperatures of the first purification step and the second purification step are independent of each other and are 10-30℃, optionally 15-25℃.
[0030] Specifically, in the method for preparing the high-purity echinocandin drug impurity, step (4) further includes the step of collecting the eluent and adjusting the pH value to 4.0-6.0.
[0031] Specifically, in the preparation method of the high-purity echinocandin drug impurity, step (4) further includes a step of collecting and concentrating the eluent. Optionally, the eluent is concentrated at a temperature below 20°C and then freeze-dried to obtain the solid echinocandin drug impurity (compound of formula I).
[0032] This application also discloses the application of the echinocandin drug impurity compound or its acceptable salt or the high-purity echinocandin drug impurity in the field of echinocandin drug quality control.
[0033] This application also discloses a method for analyzing impurities in echinocandin drugs, including the step of using the echinocandin drug impurity compound or its acceptable salt or the high-purity echinocandin drug impurity as a reference standard for establishing the analytical method.
[0034] In previous research on echinocandin-related drugs, diacylated impurities were detected during condensation reaction studies, but their content was low and enrichment and purification were difficult. This application presents a surprising discovery: by first dissolving the active side-chain ester in a solvent, adding a basic catalyst, and then adding an appropriate amount of FR179642, echinocandin drug impurities can be efficiently generated under certain conditions. After separation and purification, compound of formula I is obtained.
[0035] The echinocandin drug impurity compound described in this application has an additional hydrophobic acyl side chain compared to the micafungin drug structure. This is based on in-depth research into the preparation process of echinocandin drugs. By first dissolving the active ester of the side chain in a solvent, adding a basic catalyst, and then adding an appropriate amount of compound FR179642, the echinocandin drug impurity initially detected can be monitored by HPLC. With optimization of conditions, the proportion of this impurity compound in the HPLC spectrum continuously increases. The high-purity echinocandin drug impurity of formula I provided in this application can be used for the quality control of echinocandin drugs and as a reference standard for establishing analytical methods.
[0036] The preparation method for the echinocandin drug impurity compound described in this application suffers from poor water solubility due to the presence of an additional hydrophobic acyl side chain compared to micafungin, resulting in unsatisfactory purification effects using conventional column chromatography. This application, by sequentially using ion exchange resin and macroporous adsorption resin, efficiently purifies and separates the echinocandin drug impurity, effectively solving the problem of inefficient separation of compounds with Formula I under various conditions.
[0037] The purification method for echinocandin drug impurities described in this application involves first purifying with an ion exchange resin, followed by purification with a macroporous adsorption resin. The HPLC purity of the echinocandin drug impurities reaches over 90%, providing a new approach for industrial production. This application is the first to prepare echinocandin drug impurities with a purity exceeding 90%, which can be used as a reference standard for drug quality control. Attached Figure Description
[0038] To make the content of this application easier to understand, the following detailed description is provided based on specific embodiments and accompanying drawings.
[0039] Figure 1 is a high-resolution mass spectrum (HRMS) of the echinocandin drug impurities in Example 5;
[0040] Figure 2 is the HPLC chromatogram of the impurities in the echinocandin drug in Example 5. Detailed Implementation
[0041] The present application provides a method for preparing high-purity echinocandin drug impurities in the following embodiments, comprising the following steps:
[0042] (1) Add the active ester of micafungin sodium side chain selected from the structure shown in formula (II) or formula (III) to the first solvent and mix;
[0043] (2) Continue to add organic base and compound FR179642 with the following formula (IV) and mix them to obtain the echinocandin drug impurity with the structure shown in formula (I) after reaction;
[0044] (3) Collect the reactants from step (2) and add them to an ion exchange resin for the first purification process;
[0045] (4) Collect the purified product, add it to a macroporous adsorption resin for a second adsorption treatment, and add a second solvent for elution treatment to obtain the product.
[0046] As an implementable approach, in step (1), the first organic solvent includes at least one of N,N-dimethylformamide, N,N-diethylacetamide, tetrahydrofuran, or dimethyl sulfoxide.
[0047] As an feasible option, in step (2), the amount of compound FR179642 added is 0.2-1.0 equivalents.
[0048] As an feasible option, in step (2), the organic base includes at least one of DIPEA, TEA, DMAP, Pyridine, or NMM.
[0049] As an feasible option, the reaction temperature in step (2) is -10 to 20°C.
[0050] As an feasible option, in step (3), the ion exchange resin includes a strongly acidic cation exchange resin.
[0051] Optionally, the ion exchange resin includes at least one of UBK530, UBK550, or UBK555.
[0052] As an feasible option, in step (4), the macroporous adsorption resin includes a resin based on styrene and / or divinylbenzene;
[0053] Optionally, the macroporous adsorption resin includes at least one of HP20, HP20SS, SP70, SP700, SP850, CHP20, or CHP55.
[0054] As an feasible option, in step (4), the second solvent includes at least one of methanol, ethanol, acetone or acetonitrile.
[0055] As an feasible approach, the temperatures of the first purification step and the second purification step are independent of each other and are 10-30°C.
[0056] As an feasible option, step (4) also includes the step of collecting the eluent and adjusting the pH value to 4.0-6.0.
[0057] As an feasible option, step (4) also includes a step of collecting and concentrating the eluent.
[0058] The present application will be further described below with reference to specific embodiments.
[0059] Example 1
[0060] 1.0 g of the active ester of the side chain acid (compound of formula II) was added to a reaction flask containing 20 ml of N,N-dimethylformamide solvent. The mixture was stirred and cooled to -10℃ to 0℃ for 15 min. DIPEA was added and stirred for 5 min. Then, approximately 1.0 g (0.5 equivalent) of FR179642 (compound of formula IV) was added. The temperature was controlled at 0-10℃, and the reaction was continued for 20 h. HPLC analysis confirmed that the echinocandin drug impurity compound with the structure of formula I could be obtained.
[0061] Add 50 ml of water to the above reaction solution, perform ion exchange using UBK530 resin (50 ml), elute with reverse osmosis water, adjust the pH of the collected solution to 5.5 using 0.2 M sodium bicarbonate, and then purify using HP20SS macroporous adsorption resin. Elute with 80% ethanol for two column volumes, followed by elution with 90% methanol. Collect the fraction with a purity of over 90%, concentrate and lyophilize to obtain 0.3 g of a white powder containing echinocandin drug impurity according to formula (I), with a purity of 93.5%.
[0062] Example 2
[0063] 1.0 g of the active ester of the side chain acid (such as compound III) was added to a reaction flask containing 20 ml of N,N-dimethylacetamide solvent. 0.2 g of TEA was added and stirred for 10 min. Then, approximately 0.4 g (0.2 equivalents) of FR179642 (such as compound IV) was added. The temperature was controlled at -10 °C, and the reaction was continued for 2 h. HPLC analysis confirmed that the echinocandin drug impurity compound with the structure of formula (I) could be obtained.
[0064] Add 50 ml of water to the above reaction solution, perform ion exchange using UBK550 resin (50 ml), elute with reverse osmosis water, adjust the pH of the collected solution to 5.5 using 0.2 M sodium bicarbonate, and then purify using HP20 macroporous adsorption resin. First, elute with 80% acetonitrile for 2 column volumes, then elute with 90% methanol. Collect the fraction with a purity of over 90%, concentrate and freeze-dry to obtain approximately 0.1 g of echinocandin drug impurity of formula (I) as a white powder, with a purity of 90.8%.
[0065] Example 3
[0066] 1.0 g of the active ester of the side chain acid (such as compound II) was added to a reaction flask containing 20 ml of dimethyl sulfoxide solvent. 0.2 g of DMM was added and stirred for 10 min. Then, approximately 2.0 g (1.0 equivalent) of FR179642 (such as compound IV) was added. The temperature was controlled at 0-5 °C, and the reaction was continued for 20 h. HPLC analysis revealed the echinocandin drug impurity compound with the structure of formula (I).
[0067] Add 50 ml of water to the above reaction solution, perform ion exchange using UBK555 resin (50 ml), elute with reverse osmosis water, adjust the pH of the collected solution to 5.5 using 0.2 M sodium bicarbonate, and then purify using CHP20 macroporous adsorption resin. Elute with 2 column volumes of 50% methanol first, then with 80% ethanol. Collect the fraction with a purity of over 90%, concentrate and lyophilize to obtain 0.2 g of a white powder containing echinocandin of formula (I), with a purity of 91.2%.
[0068] Example 4
[0069] Take 1.0 g of the active ester of the side chain acid (such as compound III) and add it to a reaction flask containing 20 ml of dimethyl sulfoxide solvent. Add 0.2 g of DMAP and stir for 10 min. Then add about 1.0 g (0.5 equivalent) of FR179642 (such as compound IV). Control the temperature to -10 to -5 °C and continue the reaction for 20 h.
[0070] Add 50 ml of water to the above reaction solution, perform ion exchange using UBK530 resin (50 ml), elute with reverse osmosis water, adjust the pH of the collected solution to 5.5 using 0.2 M sodium bicarbonate, and then purify using HP20 macroporous adsorption resin. First, elute with 30% methanol for 2 column volumes, then elute with 90% methanol. Collect the fraction with a purity of over 90%, concentrate and lyophilize to obtain 0.1 g of a white powder containing echinocandin of formula (I), with a purity of 93.8%.
[0071] Example 5
[0072] 1.0 g of the active ester of the side chain acid (such as compound II) was added to a reaction flask containing 20 ml of tetrahydrofuran solvent. 0.2 g of pyridine was added and stirred for 10 min. Then, approximately 1.2 g (0.6 equivalents) of FR179642 (such as compound IV) was added. The temperature was controlled at 0-5 °C, and the reaction was continued for 20 h. HPLC analysis confirmed the yield of the echinocandin drug impurity compound with the structure of formula I.
[0073] Add 50 ml of water to the above reaction solution, perform ion exchange using UBK530 resin (50 ml), elute with reverse osmosis water, adjust the pH of the collected solution to 5.5 using 0.2 M sodium bicarbonate, and then purify using HP20SS macroporous adsorption resin. First, elute with 50% methanol for 2 column volumes, then elute with 80% methanol. Collect the fraction with a purity of over 90%, concentrate and lyophilize to obtain 0.35 g of a white powder containing echinocandin of formula (I) with a purity of 96.09%.
[0074] In this embodiment, the high-resolution mass spectra (HRMS) of the impurity compounds of echinocandin are shown in Figure 1, and the HPLC spectra of the impurity compounds of echinocandin are shown in Figure 2. In this embodiment, the product identification data are collected as follows:
[0075] 1 H NMR (DMSO- d6,600MHz)δ:0.12(t,J=6.0Hz,6H),0.98(d,J=6.6Hz,3H),1.09(d,J=6.0Hz,3H),1.36-1.44(m,8H),1.75~1.77(m,4H),1.80~1.85(m,3H),2.20-2.24(m,12H),2.30(m,1H),2.36-2.40(m,2H),2.45-2.49(m,1H),3.21(t,J=7.8Hz,1H),3.72(m,2H),3.80(m,12H),3.99(m,1H),4.02(m,1H),4.03-4.05(m,3H),4.05(t,J=6.0Hz,1H),4.10(d,J=12.6Hz,1H),4.12(d,J=9.6Hz,1H),4.21(d,J=7.2Hz,1H),4.29(m,1H),4.37(m,1H),4.41-4.42(m,2H),4.48(m,1H),4.70(m,1H),4.81(d,J=7.2Hz,1H),4.92(d,J=6.0Hz,1H),5.18(b,1H),5.23(b,1H),5.29(b,1H),5.33(b,1H),5.43(d,J=7.8Hz,1H),5.51(m,1H),5.96(b,1H),6.74(d,J=8.4Hz,1H),6.82(d,J=8.4Hz,1H),6.95(s,1H),7.02(s,1H),7.02~7.05(m,5H),7.31(b,1H),7.38(s,1H),7.41(s,1H),7.48(b,1H),7.73~7.75(m,4H),7.84~7.88(s,4H),7.98(d,J=8.4Hz,2H),8.22(d,J=7.8Hz,2H),8.39(b,1H),8.59(b,1H),8.85(b,1H),8.97(d,J=6.0Hz,1H);
[0076] 13 C NMR(DMSO- d6,400MHz)δ:10.8,13.8,13.9,21.8,27.6,28.2,31.1,37.1,38.0,50.8,51.0,53.2,53.9,55.1,5 6.2,60.3,65.5,67.6,68.2,69.0,72.3,72.7,73.2,74.8,69.9,97.0,114.9,116.5,119.0,119.1 ,121.9,123.6,125.9,126.2,127.0,128.2,130.4,131.0,133.7,134.8,135.0,140.2,148.3,160.3,161.6,161.7,164.3,165.3,166.2,168.1,169.5,169.8,170.0,170.3,170.4,171.2,172.9;
[0077] HRMS(ES - ):calcd.For C 77 H 89 N 10 O 26 NaS(M-Na + ):1601.5670,Found:1601.5667.
[0078] It is evident that the product prepared in this embodiment has the correct structure.
[0079] Example 6
[0080] 1.0 g of the active ester of the side chain acid (such as compound III) was added to a reaction flask containing 20 ml of tetrahydrofuran solvent. 0.2 g of pyridine was added and stirred for 10 min. Then, approximately 1.6 g (0.8 equivalents) of FR179642 (such as compound IV) was added. The temperature was controlled at 10-20 °C, and the reaction was continued for 3 h. The echinocandin drug impurity compound with the structure of formula (I) was obtained by HPLC analysis.
[0081] Add 50 ml of water to the above reaction solution, perform ion exchange using 20 ml of UBK530 resin and 30 ml of UBK555 resin, elute with reverse osmosis water, adjust the pH of the collected solution to 5.5 with 0.2 M sodium bicarbonate, and then purify using HP20SS macroporous adsorption resin. Elute with 50% acetone for two column volumes, followed by elution with 90% ethanol. Collect the fraction with a purity of over 90%, concentrate and lyophilize to obtain 0.15 g of micafungin drug impurity of formula (I) as a white powder, with a purity of 93.2%.
[0082] Example 7
[0083] 1.0 g of the active ester of the side chain acid (such as compound II) was added to a reaction flask containing 20 ml of N,N-dimethylformamide solvent. 0.2 g of DIPEA was added and stirred for 10 min. Then, approximately 1.0 g (0.5 equivalent) of FR179642 (such as compound IV) was added. The temperature was controlled at 15-20 °C, and the reaction was continued for 3 h. The echinocandin drug impurity compound with the structure of formula (I) was obtained by HPLC analysis.
[0084] Add 50 ml of water to the above reaction solution, perform ion exchange using 10 ml of UBK530 resin and 10 ml of UBK550 resin, elute with reverse osmosis water, and adjust the pH of the collected solution to 5.5 using 0.2 M sodium bicarbonate; then perform adsorption using CHP20 macroporous adsorption resin, controlling the temperature below 10°C, first eluting with 50% methanol for 2 column volumes, then eluting with 80% methanol. Collect the fraction with a purity of over 90%, concentrate and freeze-dry to obtain 0.09 g of micafungin drug impurity white powder with structure (I), with a purity of 91.7%.
[0085] Comparative Example 1
[0086] This comparative example was conducted according to the literature (Journal of Synthetic Organic Chemistry, vol 64, No. 12, 2006). 1.0 g of the active side-chain acid ester (as in compound II) was added to a reaction flask containing 20 ml of DMF solvent. 0.2 g of DIPEA was added and stirred for 10 min. Then, approximately 2.0 g (1.0 equivalent) of FR179642 (as in compound IV) was added, and the reaction was continued at 25 °C for 2.5 h. HPLC analysis revealed a component with the same retention time as the structure of formula (I), accounting for 0.2%. This component had a low proportion in the reaction solution, and further purification was not performed.
[0087] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.
Claims
1. A echinocandin drug impurity compound or an acceptable salt thereof, characterized in that, The echinocandin drug impurity compound has the structure shown in formula (Ⅰ):
2. A high-purity echinocandin drug impurity, characterized in that, The impurity compound of the echinocandin drug as described in claim 1, or an acceptable salt thereof, has an HPLC purity of 90% or higher.
3. A method for preparing high-purity echinocandin drug impurities as described in claim 2, characterized in that, Includes the following steps: (1) Add the active ester of micafungin sodium side chain selected from the structure shown in formula (II) or formula (III) to the first solvent and mix; (2) Continue to add organic base and compound FR179642 having the following formula (IV) and mix them to obtain the echinocandin drug impurity with the structure shown in formula (I) after reaction; 4. The method for preparing high-purity echinocandin drug impurities according to claim 3, characterized in that, In step (1), the first organic solvent includes at least one of N,N-dimethylformamide, N,N-diethylacetamide, tetrahydrofuran, or dimethyl sulfoxide.
5. The method for preparing high-purity echinocandin drug impurities according to claim 3 or 4, characterized in that, In step (2), the amount of compound FR179642 added is 0.2-1.0 equivalents.
6. The method for preparing high-purity echinocandin drug impurities according to any one of claims 3-5, characterized in that, In step (2), the organic base includes at least one of DIPEA, TEA, DMAP, Pyridine, or NMM.
7. The method for preparing high-purity echinocandin drug impurities according to any one of claims 3-6, characterized in that, The reaction temperature in step (2) is -10 to 20°C.
8. The method for preparing high-purity echinocandin drug impurities according to any one of claims 3-7, characterized in that, The method further includes a step of purifying the echinocandin drug impurities, including the following steps: (3) Collect the reactants from step (2) and add them to an ion exchange resin for the first purification process; (4) Collect the purified product, add it to a macroporous adsorption resin for a second adsorption treatment, and add a second solvent for elution treatment to obtain the product.
9. The method for preparing high-purity echinocandin drug impurities according to claim 8, characterized in that, In step (3), the ion exchange resin includes a strongly acidic cation exchange resin. Preferably, the ion exchange resin includes at least one of UBK530, UBK550, or UBK555.
10. The method for preparing high-purity echinocandin drug impurities according to claim 8 or 9, characterized in that, In step (4), the macroporous adsorption resin includes a resin based on styrene and / or divinylbenzene; Preferably, the macroporous adsorption resin includes at least one of HP20, HP20SS, SP70, SP700, SP850, CHP20, or CHP55.
11. The method for preparing high-purity echinocandin drug impurities according to any one of claims 8-10, characterized in that, In step (4), the second solvent includes at least one of methanol, ethanol, acetone or acetonitrile.
12. The method for preparing high-purity echinocandin drug impurities according to any one of claims 8-11, characterized in that, The temperatures for the first and second purification steps are independent of each other, ranging from 10 to 30°C.
13. The method for preparing high-purity echinocandin drug impurities according to any one of claims 8-12, characterized in that, Step (4) also includes the step of collecting the eluent and adjusting the pH value to 4.0-6.
0.
14. The method for preparing high-purity echinocandin drug impurities according to any one of claims 8-13, characterized in that, Step (4) also includes a step of collecting and concentrating the eluent.
15. The application of the echinocandin drug impurity compound of claim 1 or an acceptable salt thereof, or the high-purity echinocandin drug impurity of claim 2, in the field of echinocandin drug quality control.
16. A method for analyzing impurities in echinocandin drugs, characterized in that, The method includes the step of using the echinocandin drug impurity compound of claim 1 or an acceptable salt thereof, or the high-purity echinocandin drug impurity of claim 2, as a reference standard for establishing an analytical method.