Echinocandin drug impurity compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of biological medicine, particularly relates to a novel echinocandin drug impurity compound, and further discloses a preparation method and application thereof. Compared with a micafungin medicine structure, the echinocandin medicine impurity compound has the advantages that a hydrophobic acyl side chain is additionally arranged, side chain active ester is dissolved in a solvent firstly, a basic catalyst is added, and then a proper amount of FR179642 compound is added for reaction. The high-purity echinocandin drug impurity provided by the invention can be applied to quality control of echinocandin drugs, and can be used as a reference substance for establishing an analysis method.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to a new echinocandin drug impurity compound, and further discloses a preparation method and application thereof. Background Art

[0002] Micafungin sodium is a new generation of echinocandin antifungal drugs, mainly used to treat fungemia, respiratory fungal diseases, gastrointestinal fungal diseases caused by Aspergillus and Candida, and is also used to prevent Aspergillus and Candida infections in hematopoietic stem cell patients. Micafungin sodium is a type of echinocandin antifungal drug that can inhibit the synthesis of β(1,3)-glucan in filamentous fungi and yeasts. In recent years, the incidence and mortality of fungal infections have also been on the rise, especially for critically ill patients, which is a deadly threat. As a type of echinocandin drug, micafungin sodium is the first choice for the treatment of infections caused by Candida or Aspergillus due to its good antifungal activity. It not only has good therapeutic effects, but also has little effect on human cells, and has low toxicity and high efficiency clinical effects.

[0003] In the prior art, micafungin sodium is a semi-synthetic antibacterial drug, which can be obtained by removing the fatty acid side chain from the fermentation intermediate FR901379 through microbial transformation to obtain FR179642, and then prepared by a chemical synthesis method. Due to the structural specificity of FR179642, it is a polypeptide mother ring and contains multiple amino and hydroxyl functional groups, and different by-products will be generated when reacting with side chain acids or side chain active esters. By tracking the fermentation process of FR901379, it can be found that impurities with a structure similar to the FR901379 mother nucleus will be produced at this stage. Such impurities can also remove the fatty acid side chain under the action of acyltransferase to form fatty amine impurities with a structure similar to FR179642, and then undergo condensation reaction with the active ester side chain 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, when the acylation reaction was performed to prepare the echinocandin drug, the side reaction of the monoacylation reaction could be monitored, and diacylated impurities might be present. However, the structure of the possible diacylated impurities was not reported, nor were there any reports on the relevant preparation and purification methods.

[0004] In the process of drug development, the analysis of impurities is key. Impurities are closely related to the quality, safety and stability of drugs. The preparation and structural confirmation of impurities can understand the pathway of impurity generation and provide a basis for the improvement of drug synthesis process routes and production processes. Impurities can be used in drug quality control as reference substances for establishing analytical methods. For drug manufacturers, strict control of impurities is required. Therefore, the relevant research on impurities of echinocandin drugs can be used for the qualitative and quantitative analysis of impurities in the production of micafungin sodium, thereby providing technical support for subsequent quality research of micafungin sodium and improving the quality standard of micafungin sodium.

[0005] Therefore, the art expects to develop an efficient and convenient method for preparing echinocandin drug impurities, which has positive significance for the development of echinocandin drugs. Summary of the invention

[0006] To this end, the technical problem to be solved by the present invention is to provide an echinocandin drug impurity, the HPLC purity of the echinocandin drug impurity reaches more than 90%, which can be applied to the quality control of echinocandin drugs as a reference substance for establishing an analytical method.

[0007] The second technical problem to be solved by the present invention is to provide a method for preparing the above-mentioned echinocandin drug impurities, including a synthesis method and a separation and purification method.

[0008] In order to solve the above technical problems, the present invention provides an echinocandin drug impurity compound or an acceptable salt thereof, wherein the echinocandin drug impurity compound has a structure shown in the following formula (I):

[0009]

[0010] The echinocandin drug impurity compound with the structure shown in the above formula (I) provided by the present invention has a chemical name: 5-[(1S,2S)-1-[4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoyloxy]-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-pentyloxyphenyl)isoxazol-3-yl]benzoylamino]-1,4,7,13,16,22-hexaazatricyclo[22.3.0.09,13]heptacos-6-yl]-2-hydroxyethyl]-2-hydroxyphenyl sodium sulfate.

[0011] The invention also discloses a high-purity echinocandin drug impurity, comprising the echinocandin drug impurity compound or an acceptable salt thereof, and the HPLC purity thereof reaches more than 90%.

[0012] The present invention also discloses a method for preparing the high-purity echinocandin drug impurities, comprising the following steps:

[0013] (1) adding a side chain active ester of micafungin sodium selected from the structure represented by the following formula (II) or formula (III) to a first solvent and mixing;

[0014]

[0015] (2) adding an organic base and a compound FR179642 having the following formula (IV) to mix, and reacting to obtain an echinocandin drug impurity having a structure shown in formula (I);

[0016]

[0017] Specifically, in the method for preparing high-purity echinocandin drug impurities, in the step (1), the first organic solvent includes at least one of N,N-dimethylformamide, N,N-diethylacetamide, tetrahydrofuran or dimethyl sulfoxide.

[0018] Specifically, in the method for preparing high-purity echinocandin drug impurities, in the step (2), the added amount of the compound FR179642 is 0.2-1.0 equivalents.

[0019] Specifically, in the method for preparing high-purity echinocandin drug impurities, in the step (2), the organic base includes at least one of DIPEA, TEA, DMAP, Pyridine or NMM.

[0020] Specifically, in the method for preparing high-purity echinocandin drug impurities, the reaction temperature in step (2) is -10 to 20°C, preferably -10 to 10°C.

[0021] Specifically, the method for preparing high-purity echinocandin drug impurities, the method also includes the step of purifying the echinocandin drug impurities, comprising the following steps:

[0022] (3) collecting the reactants from step (2) and adding them to an ion exchange resin for a first purification treatment;

[0023] (4) Collect the purified product, add a macroporous adsorption resin to perform a second adsorption treatment, and add a second solvent to perform an elution treatment to obtain the product.

[0024] Specifically, in the method for preparing high-purity echinocandin drug impurities, in the step (3), the ion exchange resin comprises a strongly acidic cation exchange resin;

[0025] Preferably, the ion exchange resin includes at least one of UBK530, UBK550 or UBK555.

[0026] Specifically, in the method for preparing high-purity echinocandin drug impurities, in the step (4), the macroporous adsorption resin includes a resin with styrene and / or divinylbenzene as a matrix;

[0027] Preferably, the macroporous adsorption resin includes at least one of HP20, HP20SS, SP70, SP700, SP850, CHP20 or CHP55.

[0028] Specifically, in the method for preparing high-purity echinocandin drug impurities, in the step (4), the second solvent includes at least one of methanol, ethanol, acetone or acetonitrile.

[0029] Preferably, the volume percentage of the second solvent is 1%-90%.

[0030] Specifically, in the method for preparing high-purity echinocandin drug impurities, the temperatures of the first purification step and the second purification step are independently 10-30°C, preferably 15-25°C.

[0031] Specifically, in the method for preparing high-purity echinocandin drug impurities, the step (4) also includes the step of collecting the eluate and adjusting the pH value to 4.0-6.0.

[0032] Specifically, in the method for preparing high-purity echinocandin drug impurities, the step (4) also includes the step of collecting the eluate for concentration, preferably concentrating the eluate at below 20° C., and freeze-drying to obtain the echinocandin drug impurity (compound of formula I) solid.

[0033] The present invention 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.

[0034] The present invention also discloses a method for analyzing echinocandin drug impurities, comprising the step of using the echinocandin drug impurity compound or its acceptable salt or the high-purity echinocandin drug impurity as a reference substance for establishing an analysis method.

[0035] In the previous research on echinocandin drug-related topics, the present invention was able to monitor diacylated impurities during the condensation reaction research, but the content was low and the enrichment and purification were difficult. The present application surprisingly found that the side chain active ester was first dissolved in a solvent, an alkaline catalyst was added, and then an appropriate amount of FR179642 was added, and the echinocandin drug impurities could be efficiently generated under certain conditions, and the compound of formula I was obtained after separation and purification.

[0036] The echinocandin drug impurity compound of the present invention has one more hydrophobic acyl side chain than the drug structure of micafungin. It is based on the in-depth study of the preparation process of echinocandin drugs. The side chain active ester is first dissolved in a solvent, a basic catalyst is added, and then an appropriate amount of FR179642 compound is added. The echinocandin drug impurities discovered for the first time can be monitored by HPLC. With the optimization of conditions, the proportion of this impurity compound in the HPLC spectrum continues to increase. The high-purity echinocandin drug impurities of formula I structure provided by the present invention can be applied to the quality control of echinocandin drugs as a reference substance for establishing an analytical method.

[0037] The preparation method of the echinocandin drug impurity compound of the present invention, in the separation and purification of the impurity compound, because it has one more hydrophobic acyl side chain in the drug structure compared with micafungin, its water solubility is worse than micafungin, and the effect of conventional column purification is not ideal. The present invention uses ion exchange resin and macroporous adsorption resin in sequence to efficiently purify and separate the echinocandin drug impurities, effectively solving the problem that different conditions cannot efficiently separate the compound of formula I.

[0038] The purification method of the echinocandin drug impurity compound of the present invention first uses an ion exchange resin for purification; and then uses a macroporous adsorption resin for purification. The HPLC purity of the echinocandin drug impurity can reach more than 90%, providing a new idea for industrial production. The present invention prepares echinocandin drug impurities with a purity of more than 90% for the first time, which can be used as a drug quality control reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] In order to make the content of the present invention more clearly understood, the present invention is further described in detail below according to specific embodiments of the present invention in conjunction with the accompanying drawings, wherein:

[0040] Figure 1 is the high resolution mass spectrum (HRMS) of the echinocandin drug impurities in Example 5;

[0041] Figure 2 It is the HPLC spectrum of the echinocandin drug impurities in Example 5. DETAILED DESCRIPTION

[0042] In the following embodiment of the present invention, a method for preparing high-purity echinocandin drug impurities is provided, comprising the following steps:

[0043] (1) adding a side chain active ester of micafungin sodium selected from the structure represented by the following formula (II) or formula (III) to a first solvent and mixing;

[0044]

[0045] (2) adding an organic base and a compound FR179642 having the following formula (IV) to mix, and reacting to obtain an echinocandin drug impurity having a structure shown in formula (I);

[0046]

[0047] (3) collecting the reactants from step (2) and adding them to an ion exchange resin for a first purification treatment;

[0048] (4) Collect the purified product, add a macroporous adsorption resin to perform a second adsorption treatment, and add a second solvent to perform an elution treatment to obtain the product.

[0049] As an practicable solution, in step (1), the first organic solvent includes at least one of N,N-dimethylformamide, N,N-diethylacetamide, tetrahydrofuran or dimethyl sulfoxide.

[0050] As an implementable solution, in the step (2), the amount of compound FR179642 added is 0.2-1.0 equivalent.

[0051] As an practicable solution, in the step (2), the organic base includes at least one of DIPEA, TEA, DMAP, Pyridine or NMM.

[0052] As an practicable solution, the reaction temperature in step (2) is -10 to 20°C.

[0053] As an practicable solution, in step (3), the ion exchange resin comprises a strongly acidic cation exchange resin;

[0054] Preferably, the ion exchange resin includes at least one of UBK530, UBK550 or UBK555.

[0055] As an practicable solution, in step (4), the macroporous adsorption resin comprises a resin having styrene and / or divinylbenzene as a matrix;

[0056] Preferably, the macroporous adsorption resin includes at least one of HP20, HP20SS, SP70, SP700, SP850, CHP20 or CHP55.

[0057] As an practicable solution, in step (4), the second solvent includes at least one of methanol, ethanol, acetone or acetonitrile.

[0058] As an practicable solution, the temperatures of the first purification step and the second purification step are independently 10-30°C.

[0059] As an implementable solution, the step (4) further comprises the step of collecting the eluate and adjusting the pH value to 4.0-6.0.

[0060] As an implementable solution, the step (4) further comprises the step of collecting the eluate for concentration.

[0061] The present invention will be further described below in conjunction with specific embodiments.

[0062] Example 1

[0063] Take 1.0g of the active ester of the side chain acid (such as the compound of formula II) and add it to a reaction bottle filled with 20ml of N,N-dimethylformamide solvent, cool it down to -10℃~0℃ and stir for 15min under stirring, add DIPEA and stir for 5min, then add about 1.0g (0.5 equivalent) of FR179642 (such as the compound of formula IV), control the temperature at 0-10℃, and continue the reaction for 20h. HPLC detection proves that the echinocandin drug impurity compound with the structure of formula I can be obtained.

[0064] Continue to add 50ml of water to the above reaction solution, use UBK530 resin (50ml) for ion exchange, use reverse osmosis water for elution, use 0.2M sodium bicarbonate to adjust the pH of the collected solution to 5.5, and then use HP20SS macroporous adsorption resin for purification, first elute with 80% ethanol for 2 times the column volume, and then use 90% methanol for elution. Collect components with a purity of more than 90%, concentrate and freeze-dry to obtain 0.3g of white powder of echinocandin drug impurities with a structure of formula (I), and the detection purity is 93.5%.

[0065] Example 2

[0066] 1.0 g of the active ester of the side chain acid (such as the compound of formula III) was added to a reaction bottle containing 20 ml of N, N-dimethylacetamide solvent, 0.2 g of TEA was added and stirred for 10 min, and then about 0.4 g (0.2 equivalent) of FR179642 (such as the compound of formula IV) was added, the temperature was controlled at -10°C, and the reaction was continued for 2 h. HPLC detection proved that the echinocandin drug impurity compound of the structure of formula (I) could be obtained.

[0067] Continue to add 50 ml of water to the above reaction solution, use UBK550 resin (50 ml) for ion exchange, use reverse osmosis water for elution, use 0.2 M sodium bicarbonate to adjust the pH of the collected solution to 5.5, and then use HP20 macroporous adsorption resin for purification, first 80% acetonitrile for elution after 2 times the column volume, and then use 90% methanol for elution, collect components with a purity of more than 90%, and concentrate and freeze-dry to obtain about 0.1 g of white powder of echinocandin drug impurities with a structure of formula (I), and the detection purity is 90.8%.

[0068] Example 3

[0069] 1.0 g of the active ester of the side chain acid (such as the compound of formula II) was added to a reaction bottle containing 20 ml of dimethyl sulfoxide solvent, 0.2 g of DMM was added and stirred for 10 min, and then about 2.0 g (1.0 equivalent) of FR179642 (such as the compound of formula IV) was added, the temperature was controlled at 0-5°C, and the reaction was continued for 20 h. The echinocandin drug impurity compound of the structure of formula (I) was obtained by HPLC detection.

[0070] Continue to add 50ml of water to the above reaction solution, use UBK555 resin (50ml) for ion exchange, use reverse osmosis water for elution, use 0.2M sodium bicarbonate to adjust the pH of the collected solution to 5.5, and then use CHP20 macroporous adsorption resin for purification, first 50% methanol for elution after 2 times the column volume, and then use 80% ethanol for elution. Collect components with a purity of more than 90%, concentrate and freeze-dry to obtain 0.2g of white powder of echinocandin drug impurities with a structure of formula (I), and the detection purity is 91.2%.

[0071] Example 4

[0072] Take 1.0 g of the side chain acid active ester (such as the compound of formula III) and add it to a reaction bottle containing 20 ml of dimethyl sulfoxide solvent, add 0.2 g of DMAP and stir for 10 minutes, then add about 1.0 g (0.5 equivalent) of FR179642 (such as the compound of formula IV), control the temperature at -10 to -5°C, and continue the reaction for 20 hours.

[0073] Continue to add 50ml of water to the above reaction solution, use UBK530 resin (50ml) for ion exchange, use reverse osmosis water for elution, use 0.2M sodium bicarbonate to adjust the pH of the collected solution to 5.5, and then use HP20 macroporous adsorption resin for purification, first 30% methanol for elution after 2 times the column volume, and then use 90% methanol for elution. Collect components with a purity of more than 90%, concentrate and freeze-dry to obtain 0.1g of white powder of echinocandin drug impurities with a structure of formula (I), and the detection purity is 93.8%.

[0074] Example 5

[0075] 1.0 g of active ester of side chain acid (such as compound of formula II) was added to a reaction bottle containing 20 ml of tetrahydrofuran solvent, 0.2 g of pyridine was added and stirred for 10 min, and then about 1.2 g (0.6 equivalent) of FR179642 (such as compound of formula IV) was added, the temperature was controlled at 0-5°C, and the reaction was continued for 20 h. HPLC detection proved that the impurity compound of echinocandin drug with the structure of formula I could be obtained.

[0076] Add 50 ml of water to the above reaction solution, use UBK530 resin (50 ml) for ion exchange, use reverse osmosis water for elution, adjust the pH of the collected solution to 5.5 using 0.2 M sodium bicarbonate, and then use HP20SS macroporous adsorption resin for purification, first use 50% methanol for elution after 2 times the column volume, and then use 80% methanol for elution. Collect components with a purity of more than 90%, concentrate and freeze-dry to obtain 0.35 g of white powder of echinocandin drug impurities with a structure of formula (I), with a purity of 96.09%.

[0077] In this embodiment, the high resolution mass spectrometry (HRMS) of the impurity compounds of the echinocandin drug was collected as shown in the attached Figure 1 , the HPLC spectrum of the impurity compounds of the echinocandin drug is attached Figure 2 In this example, the product identification data was collected as follows:

[0078] 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);

[0079] 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;

[0080] HRMS(ES - ):calcd.For C 77 H 89 N 10 O 26 NaS(M-Na + ):1601.5670,Found:1601.5667.

[0081] It can be seen that the product prepared in this example has a correct structure.

[0082] Example 6

[0083] 1.0 g of active ester of side chain acid (such as compound of formula III) was added to a reaction bottle containing 20 ml of tetrahydrofuran solvent, 0.2 g of pyridine was added and stirred for 10 min, and then about 1.6 g (0.8 equivalent) of FR179642 (such as compound of formula IV) was added, the temperature was controlled at 10-20° C., and the reaction was continued for 3 h. The echinocandin drug impurity compound of formula (I) was obtained by HPLC.

[0084] 50 ml of water was added to the reaction solution, 20 ml of UBK530 resin and 30 ml of UBK555 resin were used for ion exchange, reverse osmosis water was used for elution, 0.2 M sodium bicarbonate was used to adjust the pH of the collected solution to 5.5, and then HP20SS macroporous adsorption resin was used for purification, 50% acetone was used for elution for 2 times of column volume, and then 90% ethanol was used for elution. Components with a purity of more than 90% were collected, and 0.15 g of micafungin drug impurity white powder with a structure of formula (I) was obtained after concentration and freeze drying, and the purity was 93.2%.

[0085] Example 7

[0086] 1.0 g of the active ester of the side chain acid (such as the compound of formula II) was added to a reaction bottle containing 20 ml of N, N-dimethylformamide solvent, 0.2 g of DIPEA was added and stirred for 10 min, and then about 1.0 g (0.5 equivalent) of FR179642 (such as the compound of formula IV) was added, the temperature was controlled at 15-20° C., and the reaction was continued for 3 h. The echinocandin drug impurity compound of the structure of formula (I) was obtained by HPLC.

[0087] Continue to add 50ml of water to the above reaction solution, use 10ml of UBK530 resin and 10ml of UBK550 resin for ion exchange, use reverse osmosis water for elution, and use 0.2M sodium bicarbonate to adjust the pH of the collected solution to 5.5; then use CHP20 macroporous adsorption resin for adsorption, control the temperature below 10°C, first use 50% methanol for elution for 2 times the column volume, and then use 80% methanol for elution. Collect components with a purity of more than 90%, concentrate and freeze-dry to obtain 0.09g of micafungin drug impurity white powder with a structure of formula (I), and the detection purity is 91.7%.

[0088] Comparative Example 1

[0089] This comparative example was tested with reference to the literature (Journal of Synthetic Organic Chemistry, vol 64, No. 12, 2006), 1.0 g of side chain acid active ester (such as compound of formula II) was added to a reaction bottle containing 20 ml of DMF solvent, 0.2 g of DIPEA was added and stirred for 10 min, and then about 2.0 g (1.0 equivalent) of FR179642 (such as compound of formula IV) was added, the temperature was controlled at 25 ° C, and the reaction was continued for 2.5 h. HPLC detection obtained a component with the same retention time as the structure of formula (I), accounting for 0.2%, and the reaction liquid of this component accounted for a low proportion and was not further purified for the reaction.

[0090] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. An echinocandin drug impurity compound or an acceptable salt thereof, characterized in that: The echinocandin drug impurity compound has a structure shown in the following formula (I):

2. A high-purity echinocandin drug impurity, characterized in that: The echinocandin drug impurity compound or an acceptable salt thereof as claimed in claim 1 has an HPLC purity of more than 90%.

3. A method for preparing high-purity echinocandin drug impurities as claimed in claim 2, characterized in that: The steps include: (1) adding a side chain active ester of micafungin sodium selected from the structure represented by the following formula (II) or formula (III) to a first solvent and mixing; (2) adding an organic base and a compound FR179642 having the following formula (IV) to mix, and reacting to obtain an echinocandin drug impurity having a structure shown in formula (I); 4. The method for preparing high-purity echinocandin drug impurities according to claim 3, characterized in that: In the 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 the step (2), the added amount of the compound FR179642 is 0.2-1.0 equivalent.

6. The method for preparing high-purity echinocandin drug impurities according to any one of claims 3 to 5, characterized in that: In the 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 to 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 to 7, characterized in that: The method further comprises the step of purifying the echinocandin drug impurities, comprising the following steps: (3) collecting the reactants from step (2) and adding them to an ion exchange resin for a first purification treatment; (4) Collect the purified product, add a macroporous adsorption resin to perform a second adsorption treatment, and add a second solvent to perform an elution treatment to obtain the product.

9. The method for preparing high-purity echinocandin drug impurities according to claim 8, characterized in that: In the step (3), the ion exchange resin comprises 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 the step (4), the macroporous adsorption resin comprises a resin having styrene and / or divinylbenzene as a matrix; 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 to 10, characterized in that: In the 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 to 11, characterized in that: The temperatures of the first purification step and the second purification step are independently 10-30°C.

13. The method for preparing high-purity echinocandin drug impurities according to any one of claims 8 to 12, characterized in that: The step (4) also includes the step of collecting the eluate 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 to 13, characterized in that: The step (4) also includes the step of collecting the eluate for concentration.

15. Use of the echinocandin drug impurity compound or an acceptable salt thereof according to claim 1 or the high-purity echinocandin drug impurity according to claim 2 in the field of echinocandin drug quality control.

16. A method for analyzing impurities in echinocandin drugs, characterized in that: The method comprises the step of using the echinocandin drug impurity compound or an acceptable salt thereof as described in claim 1 or the high-purity echinocandin drug impurity as described in claim 2 as a reference substance for establishing an analytical method.

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