Preparation method and application of caspofungin acetate impurity III
During the synthesis of caspofungin acetate, the directional reduction and substitution reactions were successfully prepared by using a reaction system of phenylboric acid, N,O-bis(trimethylsilyl)trifluoroacetamide and hydroborohydrogenated reducing agent. The high-purity caspofenin acetate impurity III solves the problem of low purity in the prior art.
Patent Information
- Application Number
- CN202411626756.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-14
- Publication Date
- 2025-02-14
AI Technical Summary
The lack of the preparation method of caspofenin acetate impurity III in the prior art has resulted in its low purity and cannot meet the demand of enterprises and the market for high-purity reference products.
Heating reflux and directional reduction reactions were carried out by using a reaction system of phenylboric acid, N,O-bis(trimethylsilyl)trifluoroacetamide and hydroborohydrogenation reducing agent, followed by a substitution reaction to obtain a high-purity casporin acetate Fungin Impurities III.
The high-purity preparation of caspofenin acetate impurity III was achieved, with a purity of more than 99.3%, meeting the requirements of reference products in drug testing.
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Figure CN119431511A_ABST
Abstract
Description
Technical Field
[0001] The present application belongs to the field of chemical pharmaceutical technology, and in particular relates to a preparation method and application of caspofungin acetate impurity III. Background Art
[0002] Caspofungin Acetate is a lipopeptide chemical drug developed through fermentation semi-synthesis technology. It is mainly used for the empirical treatment of suspected fungal infections in patients with neutropenia and fever, as well as the treatment of invasive Aspergillus that is resistant to or intolerant of other treatments. It belongs to the echinocandin class of antifungal agents.
[0003] The synthesis process of caspofungin acetate first obtains the key raw material of caspofungin, nemocandin B0, through fermentation extraction of Glarealozoyensis filamentous fungi, and then modifies and purifies the structure through three steps of chemical synthesis to obtain the target compound caspofungin acetate; after the synthesis of the target compound caspofungin acetate, in order to ensure the effectiveness and safety of caspofungin acetate, it is necessary to conduct drug testing on caspofungin acetate. The components of caspofungin acetate can be detected and analyzed by instruments such as liquid chromatography, gas chromatography, and mass spectrometry. Caspofungin acetate peaks and impurity peaks will appear in the chromatographic peaks and mass spectrometry peaks; the impurity peaks of caspofungin acetate appear because side reactions will occur and impurities will be generated during the synthesis of caspofungin acetate. Since the side reactions are difficult to control, a variety of impurities of caspofungin acetate will be generated; for example, during the synthesis of caspofungin acetate, side reactions will occur and over-reduction by-products will be generated, which will further react to produce impurity III of caspofungin acetate.
[0004] In order to investigate the quality of research drugs, impurity III of caspofungin acetate needs to be used as a reference substance during drug testing of caspofungin acetate. The current impurity III of caspofungin acetate is mainly separated from various impurities of caspofungin acetate. Since the impurity structure and physicochemical properties of caspofungin acetate are similar, other impurities may be mixed in the impurity III of caspofungin acetate during the separation process, resulting in low purity of impurity III of caspofungin acetate. Therefore, it is necessary to develop a preparation method of impurity III of caspofungin acetate and provide high-purity impurity III of caspofungin acetate to meet the needs of enterprises and the market for impurity reference substances of caspofungin acetate. Summary of the invention
[0005] In view of this, the present application provides a preparation method and application of caspofungin acetate impurity III, which are used to solve the technical problem of lack of a preparation method of caspofungin acetate impurity III in the prior art.
[0006] In a first aspect, the present application provides a method for preparing caspofungin acetate impurity III, the preparation method comprising the steps of:
[0007] Step S1, adding the compound represented by formula I and phenylboronic acid into an organic solvent for heating and refluxing reaction to obtain a heating and refluxing reaction liquid;
[0008] Step S2, adding N,O-bis(trimethylsilyl) trifluoroacetamide and a borohydride reducing agent to a heated reflux reaction solution cooled to 35-40° C. to carry out a directional reduction reaction to obtain a directional reduction reaction solution;
[0009] Step S3, sequentially purifying and freeze-drying the directed reduction reaction solution to obtain a freeze-dried powder of the compound represented by Formula II;
[0010] Step S4, adding ethylenediamine dropwise to a methanol solution of a freeze-dried powder of the compound represented by Formula II at a temperature of -5 to 0°C, and heating the solution to 25 to 35°C to carry out a substitution reaction to obtain a substitution reaction solution;
[0011] Step S5, sequentially purifying and freeze-drying the substitution reaction solution to obtain the compound caspofungin acetate impurity III represented by formula III;
[0012] In step S1, the compound represented by formula I is:
[0013] Formula I, R is selected from hydrogen, hydroxyl or methyl;
[0014] In step S3, the compound represented by formula II is:
[0015] Formula II, R is selected from hydrogen, hydroxyl or methyl;
[0016] In step S5, the compound represented by formula III is:
[0017] Formula III.
[0018] Preferably, in step S2, the hydroboration reducing agent is selected from borane tetrahydrofuran or borane dimethyl sulfide.
[0019] Preferably, in step S2, the reaction time of the directional reduction reaction is 12 to 24 hours.
[0020] Preferably, in step S4, the substitution reaction time is 12 to 36 hours.
[0021] Preferably, in steps S1-S2, the molar ratio of the compound represented by formula I, the phenylboric acid, the N,O-bis(trimethylsilyl)trifluoroacetamide, and the reducing agent is 1:0.8-1.5:2-4:5-7.
[0022] Preferably, the molar ratio of the compound represented by formula I, the phenylboric acid, the N,O-bis(trimethylsilyl)trifluoroacetamide, and the reducing agent is 1:1.1:3:6.
[0023] Preferably, in step S4, the molar ratio of the ethylenediamine to the lyophilized powder of the compound represented by formula II is 1-3:1.
[0024] Preferably, the molar ratio of the ethylenediamine to the lyophilized powder of the compound represented by Formula II is 1-1.1:1.
[0025] Preferably, in step S3, the purification step comprises:
[0026] Step S31, adding hydrochloric acid solution to the directional reduction reaction solution for acidification to obtain an acidified directional reduction reaction solution;
[0027] Step S32, using a vacuum decompression concentrator to decompress and concentrate the acidified directional reduction reaction liquid to dryness, to obtain a directional reduction reaction powder block;
[0028] Step S33, dissolving the directional reduction reaction powder block with methanol and filtering to obtain a directional reduction reaction filtrate;
[0029] Step S34, using liquid chromatography to elute the directional reduction reaction filtrate to obtain a purified directional reduction reaction eluate;
[0030] The freeze-drying step comprises: freeze-drying the purified directional reduction reaction eluate using a vacuum freeze dryer to obtain a freeze-dried powder of the compound represented by formula II.
[0031] Preferably, in step S31, the concentration of the hydrochloric acid solution is 0.5-2 mol / L, and the volume is 30-50 mL;
[0032] In step S33, the amount of methanol used is 100-150 mL;
[0033] In step S34, during the elution process, the mobile phase A used was acetonitrile, and the mobile phase B was 0.2% acetic acid aqueous solution.
[0034] Preferably, in step S5, the purification step comprises:
[0035] Step S51, adding acetic acid solution to the substitution reaction solution for acidification to obtain an acidified substitution reaction solution;
[0036] Step S52, using a vacuum decompression concentrator to decompress and concentrate the acidified substitution reaction solution to dryness to obtain a substitution reaction powder block;
[0037] Step S53, dissolving the substitution reaction powder block with methanol and filtering to obtain a substitution reaction filtrate;
[0038] Step S54, using liquid chromatography to elute the acidified substitution reaction solution to obtain a purified substitution reaction eluate;
[0039] The freeze-drying step comprises: freeze-drying the purified substitution reaction eluate using a vacuum freeze dryer to obtain the compound caspofungin acetate impurity III represented by formula III.
[0040] Preferably, in step S51, the volume of the acetic acid solution is 100-200 ml, and the concentration is 30%-70% V / V;
[0041] In step S53, the amount of methanol used is 100-150 mL;
[0042] In step S54, during the elution process, the mobile phase A used was acetonitrile, and the mobile phase B was 0.2% acetic acid aqueous solution.
[0043] Preferably, in step S1, the organic solvent is selected from tetrahydrofuran.
[0044] The second aspect of the present application provides a use of the caspofungin acetate impurity III described in the first aspect in the detection of caspofungin acetate drugs.
[0045] In summary, the present application provides a preparation method and application of caspofungin acetate impurity III. In the preparation method of caspofungin acetate impurity III provided by the present application, in the process of reducing the carbonyl group with a borohydride reducing agent, the carbonyl group at a specific position of the compound represented by formula I is successfully reduced to an alkyl group by adjusting the reaction temperature to 35-40° C., thereby obtaining a compound represented by formula II; subsequently, ethylenediamine is used for a substitution reaction to obtain the compound represented by formula III, caspofungin acetate impurity III, and a synthesis method of caspofungin acetate impurity III is developed, thereby solving the technical problem of the lack of a preparation method of caspofungin acetate impurity III in the prior art. BRIEF DESCRIPTION OF THE DRAWINGS
[0046] In order to more clearly illustrate the specific implementation methods of the present application or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.
[0047] Figure 1 This is a liquid chromatogram of the impurity III of caspofungin acetate of the compound represented by formula III provided in Example 1 of the present application;
[0048] Figure 2 The mass spectrum of the impurity III of caspofungin acetate of the compound represented by formula III provided in Example 1 of the present application;
[0049] Figure 3 This is a hydrogen nuclear magnetic resonance spectrum of the impurity III of caspofungin acetate of the compound represented by formula III provided in Example 1 of the present application;
[0050] Figure 4 This is the carbon nuclear magnetic resonance spectrum of the impurity III of caspofungin acetate of the compound represented by formula III provided in Example 1 of the present application;
[0051] Figure 5 This is a spectrum of the system adaptability solution of the caspofungin acetate impurity III of the compound represented by Formula III provided in Example 1 of the present application for use in the caspofungin acetate analysis method. DETAILED DESCRIPTION
[0052] The present application provides a preparation method and application of caspofungin acetate impurity III, which are used to solve the technical problem of lack of a preparation method of caspofungin acetate impurity III in the prior art.
[0053] The technical solution of the present application will be described clearly and completely below in conjunction with the accompanying drawings. Obviously, the described embodiments are part of the embodiments of the present application, rather than all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present application.
[0054] In view of the lack of a preparation method for caspofungin acetate impurity III, it is difficult to meet the needs of enterprises and the market for caspofungin acetate impurity reference substances. The present application provides a preparation method for caspofungin acetate impurity III; the preparation method comprises first pretreating a compound shown in formula I with phenylboronic acid; then subjecting the compound shown in formula I to directed reduction with N,O-bis(trimethylsilyl) trifluoroacetamide and a borohydride reducing agent to obtain a compound shown in formula II, wherein R in the compounds shown in formula I and formula II is selected from hydrogen, hydroxyl or methyl; then purifying the compound shown in formula II and freeze-drying it to obtain a lyophilized powder of the compound shown in formula II; then dissolving the lyophilized powder of the compound shown in formula II with methanol, and adding ethylenediamine for substitution reaction to obtain a compound shown in formula III, caspofungin acetate impurity III; then purifying the compound shown in formula II and freeze-drying it to obtain a lyophilized powder of the compound shown in formula III.
[0055] In the preparation method provided in the present application, a reaction system of phenylboric acid, N,O-bis(trimethylsilyl) trifluoroacetamide and a borohydride reducing agent is used. By adjusting the temperature of the reaction system to 35-40° C., the carbonyl group at a specific position of the compound represented by Formula I can be directionally reduced to an alkyl group to obtain a compound represented by Formula II. Subsequently, ethylenediamine is used to replace the thiophenyl group in the compound represented by Formula II to obtain a compound represented by Formula III, caspofungin acetate impurity III; it can be qualitatively seen from the nuclear magnetic hydrogen spectrum, nuclear magnetic carbon spectrum, mass spectrum and liquid chromatogram that the preparation method provided in the present application can prepare the compound represented by Formula III, caspofungin acetate impurity III, and it can be quantitatively seen that the preparation method provided in the present application can prepare caspofungin acetate impurity III with a purity of more than 99.3%.
[0056] Preferably, in the preparation method provided in the present application, during the directional reduction of the compound represented by formula I and the substitution reaction of the compound represented by formula II, the process parameters such as the reducing agent, reaction time, and the amount of reaction substrate used are optimized to improve the yield of caspofungin acetate impurity III. The total yield of caspofungin acetate impurity III in the preparation method provided in the present application is 67%.
[0057] Wherein, in the directional reduction of the compound represented by formula I, the borohydride reducing agent used is preferably borane tetrahydrofuran or borane dimethyl sulfide, and in the substitution reaction of the compound represented by formula II, the substituent used is ethylenediamine; and the reaction time for the directional reduction of the compound represented by formula I is 12 to 24 hours, and the time for the substitution reaction of the compound represented by formula II is 12 to 36 hours;
[0058] At the same time, for the amount of reaction substrate, the molar ratio of the compound represented by formula I, phenylboronic acid, N, O-bis (trimethylsilyl) trifluoroacetamide, and the reducing agent is 1: 0.8 ~ 1.5: 2 ~ 4: 5 ~ 7; and in the process of the substitution reaction of the compound represented by formula II, the amount of the substituent ethylenediamine used needs to be greater than the compound represented by formula II, and the molar ratio of ethylenediamine to the lyophilized powder of the compound represented by formula II is 1 ~ 3: 1, and in order to reduce the subsequent separation of excess ethylenediamine, the amount of ethylenediamine needs to be controlled to be slightly greater than the compound represented by formula II.
[0059] Preferably, in the preparation method provided in the present application, a step of purifying the product is performed after the directed reduction reaction of the compound represented by Formula I and after the substitution reaction of the compound represented by Formula II.
[0060] Among them, after the directed reduction reaction of the compound shown in formula I is carried out, the purification step of the directed reduction reaction liquid includes first using hydrochloric acid to acidify the directed reduction reaction liquid, then concentrating and drying under reduced pressure, and then dissolving and filtering with methanol, eluting with liquid chromatography, collecting the eluate and freeze-drying to obtain a purified lyophilized powder of the compound shown in formula II; and in the purification step after the substitution reaction of the compound shown in formula II, acetic acid is used in the acidification stage, and the remaining steps are similar to the purification step of the directed reduction reaction liquid.
[0061] The caspofungin acetate impurity III provided in the present application will be specifically described below with reference to the examples.
[0062] Example 1
[0063] Example 1 of the present application provides a method for preparing caspofungin acetate impurity III, which comprises the steps of heating under reflux, performing a directed reduction reaction, purifying an intermediate product, performing a substitution reaction, and purifying a target product.
[0064] The step of heating and reflux comprises: adding 20 g (0.017 mol) of the compound represented by formula I (R is methyl), 2.28 g (0.019 mol) of phenylboric acid and 440 ml of tetrahydrofuran into a 1000 ml dry three-necked flask, heating to 68° C. and refluxing for 1.5 hours to dissolve, thereby obtaining a heating and reflux reaction solution.
[0065] The steps of carrying out the directional reduction reaction include: cooling the heated reflux reaction solution to 35°C, adding 13.18g (0.051mol) of N,O-bis(trimethylsilyl) trifluoroacetamide BSTFA, controlling the temperature at 35-40°C and adding dropwise 85.4ml (0.085mol) of borane tetrahydrofuran, and after the addition is complete, keeping the temperature for 18h for the directional reduction reaction to obtain a directional reduction reaction solution.
[0066] The step of purifying the intermediate product comprises: adding 41 ml of 1 mol / L hydrochloric acid to the directional reduction reaction solution for acidification, then using a vacuum decompression concentrator to reduce pressure and concentrate to dryness, adding 120 ml of methanol to dissolve, filtering, eluting the filtrate by liquid chromatography (mobile phase A is acetonitrile, mobile phase B is 0.2% acetic acid aqueous solution; gradient elution: 0 min, 20% acetonitrile; 10 min, 25% acetonitrile; 20 min, 30% acetonitrile; 70 min, 70% acetonitrile; 72 min, 95% acetonitrile; 95 min, 100% acetonitrile), collecting the eluent that meets the requirements, concentrating and freeze-drying using a vacuum freeze dryer to obtain a freeze-dried powder of the compound shown in formula II (R is methyl).
[0067] The steps of performing the substitution reaction include: adding 7 g of freeze-dried powder of the compound represented by formula II (R is methyl) and 28 ml of methanol into a 100 ml three-necked flask, stirring to dissolve and then cooling to -5~0°C, adding 35 ml of ethylenediamine dropwise and then heating to 30~35°C to react for 24 hours to obtain a substitution reaction liquid.
[0068] The step of purifying the target product comprises: adding the substitution reaction solution dropwise to an acetic acid solution (35 ml of water, 35 ml of methanol and 70 ml of glacial acetic acid) precooled to -5°C for acidification, then concentrating and drying under reduced pressure using a vacuum decompression concentrator, adding 120 ml of methanol for dissolution, filtering, and subjecting the filtrate to preparative liquid separation (mobile phase A is acetonitrile, mobile phase B is 0.2% acetic acid aqueous solution; gradient elution: 0 min, 10% acetonitrile; 15 min, 10% acetonitrile; 16 min, 22% acetonitrile; 85 min, 22% acetonitrile; 87 min, 95% acetonitrile; 100 min, 100% acetonitrile), collecting the eluate that meets the requirements, concentrating and freeze-drying using a vacuum freeze dryer to obtain a compound represented by formula III, caspofungin acetate impurity III (R is methyl) freeze-dried powder; the total yield of the product is 67%.
[0069] In this embodiment 1, the compound shown in formula I used is:
[0070] Formula I, R is selected from hydrogen, hydroxyl or methyl;
[0071] The compound shown in formula II is:
[0072] Formula II, R is selected from hydrogen, hydroxyl or methyl;
[0073] The compound shown in formula III is:
[0074] Formula III.
[0075] Experimental Example 1
[0076] Experimental Example 1 of the present application conducted an experimental test on the lyophilized powder of caspofungin acetate impurity III (R is methyl) of the compound represented by Formula III prepared in Example 1. The experiment included qualitative and quantitative analysis experiments and application experiments on the lyophilized powder of caspofungin acetate impurity III (R is methyl) of the compound represented by Formula III.
[0077] The qualitative and quantitative analysis experiments were performed using liquid chromatography, mass spectrometry and nuclear magnetic resonance spectrometers. The obtained liquid chromatography, mass spectrometry, nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum were as follows: Figure 1-4 shown; from Figure 1-4It can be qualitatively seen that the preparation method provided in Example 1 of the present application successfully reduces the carbonyl group at a specific position of the compound represented by Formula I to an alkyl group in a reaction system using phenylboric acid, N,O-bis(trimethylsilyl) trifluoroacetamide and a borohydride reducing agent by adjusting the temperature of the reaction system to 35-40°C to obtain a compound represented by Formula II, and replaces the thiophenyl group of the compound represented by Formula II with ethylenediamine to obtain a compound represented by Formula III, caspofungin acetate impurity III. It can also be quantitatively seen that the purity of the compound represented by Formula III, caspofungin acetate impurity III, is above 99.3%, reaching 99.37%, which is a high-purity caspofungin acetate impurity III, overcoming the defect of the current lack of a preparation method for caspofungin acetate impurity III.
[0078] After obtaining high-purity caspofungin acetate impurity III, the present application also used caspofungin acetate impurity III for caspofungin acetate analysis and detection, and the results are as follows: Figure 5 shown; from Figure 5 It can be seen that the high-purity caspofungin acetate impurity III provided in Example 1 of the present application can meet the drug detection requirements of caspofungin acetate and be used as a reference substance to distinguish impurities produced by side reactions.
[0079] The above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit them. Although the present application has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some or all of the technical features thereof may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the scope of the technical solutions of the embodiments of the present application.
Claims
1. A method for preparing caspofungin acetate impurity III, characterized in that: Includes steps: Step S1, adding the compound represented by formula I and phenylboronic acid into an organic solvent for heating and refluxing reaction to obtain a heating and refluxing reaction liquid; Step S2, adding N,O-bis(trimethylsilyl) trifluoroacetamide and a borohydride reducing agent to a heated reflux reaction solution cooled to 35-40° C. to carry out a directional reduction reaction to obtain a directional reduction reaction solution; Step S3, sequentially purifying and freeze-drying the directed reduction reaction solution to obtain a freeze-dried powder of the compound represented by Formula II; Step S4, adding ethylenediamine dropwise to a methanol solution of a freeze-dried powder of the compound represented by Formula II at a temperature of -5 to 0°C, and heating the solution to 25 to 35°C to carry out a substitution reaction to obtain a substitution reaction solution; Step S5, sequentially purifying and freeze-drying the substitution reaction solution to obtain the compound caspofungin acetate impurity III represented by formula III; In step S1, the compound represented by formula I is: Formula I, R is selected from hydrogen, hydroxyl or methyl; In step S3, the compound represented by formula II is: Formula II, R is selected from hydrogen, hydroxyl or methyl; In step S5, the compound represented by formula III is: Formula III.
2. The method for preparing caspofungin acetate impurity III according to claim 1, characterized in that: In step S2, the hydroboration reducing agent is selected from borane tetrahydrofuran or borane dimethyl sulfide.
3. The method for preparing caspofungin acetate impurity III according to claim 1, characterized in that: In step S2, the reaction time of the directional reduction reaction is 12 to 24 hours; In step S4, the substitution reaction time is 12 to 36 hours.
4. The method for preparing caspofungin acetate impurity III according to claim 1, characterized in that: In steps S1-S2, the molar ratio of the compound represented by formula I, the phenylboronic acid, the N,O-bis(trimethylsilyl)trifluoroacetamide, and the reducing agent is 1:0.8-1.5:2-4:5-7.
5. The method for preparing caspofungin acetate impurity III according to claim 4, characterized in that: The molar ratio of the compound represented by formula I, the phenylboric acid, the N,O-bis(trimethylsilyl)trifluoroacetamide, and the reducing agent is 1:1.1:3:
6.
6. The method for preparing caspofungin acetate impurity III according to claim 1, characterized in that: In step S4, the molar ratio of the ethylenediamine to the lyophilized powder of the compound represented by formula II is 1-3:
1.
7. The method for preparing caspofungin acetate impurity III according to claim 6, characterized in that: The molar ratio of the ethylenediamine to the lyophilized powder of the compound represented by formula II is 1-1.1:
1.
8. The method for preparing caspofungin acetate impurity III according to claim 1, characterized in that: In step S3, the purification step includes: Step S31, adding hydrochloric acid solution to the directional reduction reaction solution for acidification to obtain an acidified directional reduction reaction solution; Step S32, using a vacuum decompression concentrator to decompress and concentrate the acidified directional reduction reaction liquid to dryness, to obtain a directional reduction reaction powder block; Step S33, dissolving the directional reduction reaction powder block with methanol and filtering to obtain a directional reduction reaction filtrate; Step S34, using liquid chromatography to elute the directional reduction reaction filtrate to obtain a purified directional reduction reaction eluate; The freeze-drying step comprises: freeze-drying the purified directional reduction reaction eluate using a vacuum freeze dryer to obtain a freeze-dried powder of the compound represented by formula II.
9. The method for preparing caspofungin acetate impurity III according to claim 1, characterized in that: In step S5, the purification step includes: Step S51, adding acetic acid solution to the substitution reaction solution for acidification to obtain an acidified substitution reaction solution; Step S52, using a vacuum decompression concentrator to decompress and concentrate the acidified substitution reaction solution to dryness to obtain a substitution reaction powder block; Step S53, dissolving the substitution reaction powder block with methanol and filtering to obtain a substitution reaction filtrate; Step S54, using liquid chromatography to elute the acidified substitution reaction solution to obtain a purified substitution reaction eluate; The freeze-drying step comprises: freeze-drying the purified substitution reaction eluate using a vacuum freeze dryer to obtain the compound caspofungin acetate impurity III represented by formula III.
10. Use of the caspofungin acetate impurity III according to any one of claims 1 to 9 in the detection of caspofungin acetate drugs.