Preparation method of gabapentin impurity compound

Abstract

The invention provides a preparation method of a gabapentin impurity compound, which comprises the following steps of: adding 3, 4-diphenyl-1, 3, 4-triazole-3-carboxylic acid as shown in a formula 2 into a solvent, the preparation method comprises the following steps: mixing 3, 3 '-pentenyl-4-butyrolactam, dimethyl sulfoxide and a solvent, adding a catalyst, reacting, removing the solvent and the dimethyl sulfoxide, and purifying to obtain the gabapentin impurity compound as shown in a formula 1, and the reaction structural formula is as follows: # imgabs0. The gabapentin impurity compound prepared by the preparation method disclosed by the invention is relatively high in purity; the requirements of reference substances for drug research and declaration are met, and the cost is greatly lower than the price sold in the market.

Description

Technical Field

[0001] The present invention relates to the technical field of gabapentin impurity preparation, and in particular to a method for preparing a gabapentin impurity compound. Background Art

[0002] Epilepsy is a brain disorder characterized by persistent changes in the brain that can produce epileptic seizures, and the corresponding neurobiological, cognitive, psychological, and sociological consequences, which can be motor, sensory, mental, or autonomic, with or without changes in consciousness or alertness. At present, clinical treatment for epilepsy patients is mostly given drugs such as carbamazepine and topiramate. Although these drugs have certain application value, they can only relieve the condition of patients with refractory partial epilepsy, but cannot control the disease. Long-term use can also lead to memory and reaction decline, and even adverse events such as impaired cognitive function, and the long-term efficacy is poor.

[0003] Gabapentin is one of the most commonly used drugs in neurology for the treatment of epilepsy and neuralgia caused by herpes zoster. It has an anticonvulsant effect. When used in the routine anti-epileptic treatment of patients with refractory partial epilepsy, it can enhance the efficacy of conventional anti-epileptic drugs, inhibit epileptic seizures, and have anti-epileptic and anti-convulsant effects. Oral administration is not affected by food and does not require blood drug concentration monitoring. It is suitable for epilepsy patients who are ineffective or cannot be satisfactorily controlled by conventional anti-epileptic drugs; epilepsy patients who cannot tolerate the adverse reactions of traditional anti-epileptic drugs; severe epilepsy patients with complex partial seizures or secondary systemic seizures, and children with Lennox-Gostaut syndrome.

[0004] Impurity research is an important part of the drug development process, which is directly related to the quality control and drug safety of the drug. By controlling the impurities in the drug product, the quality and safety of the product can be guaranteed. The impurities in the drug mainly come from by-products in the synthesis process and the degradation of the drug.

[0005] 2-[(3-oxo-2-azaspiro[4.5]decan-2-yl)methyl]-2-azaspiro[4.5]decan-3-one is a gabapentin bisamide impurity and a major impurity produced in the gabapentin production process. It was retrieved from the Reaxys database and included in PubChem (National Center for Biotechnology Information's organic small molecule biological activity database) on October 14, 2021, with CID number 169444120, and its name is Methylene bis(Gabapentinlactam). The content of gabapentin bisamide impurity is related to the quality of gabapentin finished products.

[0006] At present, 2-[(3-oxo-2-azaspiro[4,5]decane-2-yl)methyl]-2-azaspiro[4,5]decane-3-one is generally separated from gabapentin raw materials by separation methods. However, since the content of this substance in gabapentin raw materials is extremely low, usually below 0.5%, it is difficult to obtain 2-[(3-oxo-2-azaspiro[4,5]decane-2-yl)methyl]-2-azaspiro[4,5]decane-3-one in large quantities by separation and preparation methods. The commercially available 2-[(3-oxo-2-azaspiro[4,5]decane-2-yl)methyl]-2-azaspiro[4,5]decane-3-one is usually expensive. However, there is no report on the synthesis method at present. There is no CAS number found in the SciFinder database search, and there is no literature report on the synthesis of this impurity. Summary of the invention

[0007] In view of the above-mentioned shortcomings of the prior art, the object of the present invention is to provide a method for preparing a gabapentin impurity compound, so as to solve the problem that the gabapentin impurity compound 2-[(3-oxo-2-azaspiro[4,5]decane-2-yl)methyl]-2-azaspiro[4,5]decane-3-one cannot be produced in large quantities in the prior art.

[0008] To achieve the above objectives and other related objectives, the present invention is achieved through the following technical solutions.

[0009] The present invention provides a method for preparing a gabapentin impurity compound, comprising the following steps: mixing 3,3'-pentenyl-4-butyrolactam shown in formula 2 with a solvent, adding a catalyst, reacting, removing the solvent and dimethyl sulfoxide, purifying, and obtaining

[0010] The gabapentin impurity compound shown in Formula 1 has the following reaction structure:

[0011]

[0012] As described above, the method for preparing a gabapentin impurity compound of the present invention has the following beneficial effects:

[0013] The invention designs a preparation method route of the gabapentin impurity compound 2-[(3-oxo-2-azaspiro[4,5]decane-2-yl)methyl]-2-azaspiro[4,5]decane-3-one, and synthesizes the target impurity in a targeted manner. After testing, the synthesized target impurity has a purity of more than 98%, which meets the requirements of reference substances for drug research and declaration, and the cost is much lower than the market price. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 Shown is the HPLC spectrum of the gabapentin impurity compound of the present invention.

[0015] Figure 2 Shown is the LC-MS spectrum of the gabapentin impurity compound of the present invention.

[0016] Figure 3 It is shown as the impurity compound of gabapentin of the present invention 1 H-NMR spectrum.

[0017] Figure 4 It is shown as the impurity compound of gabapentin of the present invention 13 C-NMR spectrum.

[0018] Figure 5 Shown is a synthetic route for the gabapentin impurity compound of the present invention. DETAILED DESCRIPTION

[0019] In order to make the purpose of the invention, technical solutions and beneficial technical effects of the present invention clearer, the present invention is further described in detail below in conjunction with embodiments. People familiar with this technology can easily understand other advantages and effects of the present invention from the contents disclosed in this specification.

[0020] The extended part of this application and the effect description of the extended part, including but not limited to subsequent data analysis, mechanism description, etc.

[0021] The control of drug impurities is the key to drug quality control, because impurities in drugs may reduce the efficacy of drugs and even cause harm to human health. Therefore, scientific and rigorous analysis and research should be conducted on impurities generated during the production and storage of raw materials.

[0022] In the study of impurities, the use of impurity reference substances for detection is a scientific and effective method. In addition to the characteristics of general reference substances, impurity reference substances also have their own characteristics: difficult preparation, small sample quantity and high price. For example, the price of the impurity reference substance of the present invention is 100mg / 14000RMB. The sources of impurity reference substances include: preparation of liquid phase enrichment and directional synthesis. The World Health Organization stipulates that the purity of impurity reference substances should not be less than 95%.

[0023] The present invention provides a specific implementation method of a method for preparing a gabapentin impurity compound.

[0024] The inventors of the present invention have found through a large number of experiments that formaldehyde can be prepared by reacting dimethyl sulfoxide with a catalyst oxalyl chloride, and then the prepared formaldehyde is further reacted with 3,3'-pentenylene-4-butyrolactam shown in Formula 2 under the action of oxalyl chloride to prepare a gabapentin impurity compound, namely 2-[(3-oxo-2-azaspiro[4,5]decane-2-yl)methyl]-2-azaspiro[4,5]decane-3-one. At present, a method for synthesizing 2-[(3-oxo-2-azaspiro[4,5]decane-2-yl)methyl]-2-azaspiro[4,5]decane-3-one has not been reported. Therefore, the preparation method of the present invention can mass-produce the gabapentin impurity compound 2-[(3-oxo-2-azaspiro[4,5]decane-2-yl)methyl]-2-azaspiro[4,5]decane-3-one, thereby improving the quality and safety of gabapentin drugs.

[0025] Definition of terms

[0026] Unless otherwise specified, the following words, phrases and symbols used in this specification generally have the meanings described below.

[0027] In general, the nomenclature used herein (e.g., IUPAC nomenclature) and the laboratory procedures described below (including for cell culture, organic chemistry, analytical chemistry, and pharmacology, etc.) are those well known and commonly used in the art. Unless otherwise defined, all scientific and technical terms used herein in conjunction with the present disclosure described herein have the same meanings as commonly understood by those skilled in the art. In addition, in the claims and / or the specification, when the term "one" or "an" is used in conjunction with the term "comprising" or a noun, its meaning may be "one", but it is also consistent with the meaning of "one or more", "at least one" and "one or more than one". Similarly, the term "another" or "other" can mean at least a second or more.

[0028] It should be understood that whenever various aspects are described herein with the terms "including" or "comprising," other similar aspects described by "consisting of" and / or "consisting essentially of" are also provided.

[0029] The present invention provides a method for preparing a gabapentin impurity compound, comprising the following steps: mixing 3,3'-pentenyl-4-butyrolactam, dimethyl sulfoxide and a solvent as shown in formula 2, dropping a catalyst, reacting, removing the solvent and dimethyl sulfoxide, and purifying to obtain a compound as shown in formula 1, and the reaction structure is as follows:

[0030]

[0031] In some embodiments of the present invention, the catalyst is oxalyl chloride.

[0032] The compound represented by Formula 1 of the present invention is 2-[(3-oxo-2-azaspiro[4,5]decane-2-yl)methyl]-2-azaspiro[4,5]decane-3-one.

[0033] The dimethyl sulfoxide of the present invention reacts with the catalyst oxalyl chloride to obtain formaldehyde, and then the formaldehyde reacts with the 3,3'-pentenyl-4-butyrolactam shown in formula 2 under the action of the catalyst oxalyl chloride to obtain the compound shown in formula 1.

[0034] In some embodiments of the present invention, the equivalent of dimethyl sulfoxide is 2-3 e.q. of 3,3'-pentenyl-4-butyrolactam shown in Formula 2.

[0035] In some specific embodiments of the present invention, the equivalent of dimethyl sulfoxide can be 2-2.5 eq, 2.5-3 e.q. of 3,3'-pentenylene-4-butyrolactam shown in Formula 2; typically but not limiting, for example, 2 e.q., 2.5 eq, 3 e.q.

[0036] In some embodiments of the present invention, the equivalent weight of the catalyst is 0.2-0.5 eq of 3,3'-pentenylene-4-butyrolactam shown in Formula 2.

[0037] In some specific embodiments of the present invention, the equivalent weight of the catalyst may be 0.2-0.4 eq, 0.4-0.5 eq of 3,3'-pentenylene-4-butyrolactam shown in Formula 2, typically but not limitingly, for example, 0.2 eq, 0.4 eq, 0.5 eq.

[0038] In some embodiments of the present invention, the reaction temperature is 50-110°C.

[0039] In some specific embodiments of the present invention, the reaction temperature can be 50-60°C, 60-70°C, 70-85°C, 85-95°C, 95-110°C; typical but non-limiting examples are 50°C, 60°C, 70°C, 85°C, 95°C, 110°C.

[0040] In some embodiments of the present invention, the reaction time is 4-8 hours.

[0041] In some specific embodiments of the present invention, the reaction time may be 4-6 h, 6-7 h, 6-8 h; typically but not limiting, for example, it may be 4 h, 6 h, 7 h, 8 h.

[0042] In some embodiments of the present invention, the solvent is selected from any one of 1,4-dioxane, toluene and xylene.

[0043] In some embodiments of the present invention, the purification is performed by column chromatography; preferably, the eluent of the column chromatography is selected from one or more of ethyl acetate and n-heptane; further preferably, the eluent consists of ethyl acetate and n-heptane in a mass ratio of (1-3): (1-10); further preferably, the eluent consists of ethyl acetate and n-heptane in a mass ratio of 1:6.

[0044] In some embodiments of the present invention, the removal of the solvent and dimethyl sulfoxide is carried out by vacuum distillation; preferably, the temperature of the vacuum distillation is 90-98°C, specifically, 90-95°C, 95-98°C, typically but not limitatively, for example, 90°C, 95°C, 98°C.

[0045] In some embodiments of the present invention, the purity of the gabapentin impurity compound is >98%.

[0046] The present invention is further described below by way of examples, but the scope of the present invention is not limited thereto.

[0047] When the embodiment gives a numerical range, it should be understood that, unless otherwise specified in the present invention, the two endpoints of each numerical range and any numerical value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those generally understood by those skilled in the art. If specific conditions are not specified in the embodiment, they are carried out according to normal conditions or conditions recommended by the manufacturer. If the manufacturer is not specified for all reagents or instruments, they are conventional products that can be purchased commercially. In addition to the specific methods, equipment, and materials used in the embodiments, according to the grasp of the prior art by those skilled in the art and the record of the present invention, any method, equipment, and material of the prior art similar or equivalent to the method, equipment, and material in the embodiments of the present invention can also be used to realize the present invention.

[0048] The yield calculation method in the following examples is actual yield / theoretical yield × 100%, and the purity is determined by high performance liquid chromatography. NMR spectra were obtained on a BRUKER400.

[0049] Example

[0050] Example 1

[0051] A preparation method of a gabapentin impurity compound of this embodiment comprises the following steps: 10.00 g of the compound 3,3'-pentenyl-4-butyrolactam shown in Formula 2, 12.75 g of dimethyl sulfoxide and 30 ml of 1,4-dioxane are mixed to obtain a mixed solution 1. 3.31 g of oxalyl chloride is mixed with 20 ml of 1,4-dioxane to obtain a mixed solution 2; the mixed solution 2 is added dropwise to the mixed solution 1, and after the addition is completed for 30 minutes, the temperature is raised to 85° C. and the reaction is carried out for 6 hours. After the reaction, 1,4-dioxane and dimethyl sulfoxide were removed by reduced pressure distillation at 95°C to obtain 17.24g of brown oil with a yield of 83.0%. The brown oil was purified by column chromatography to obtain 14.60g of white powder, wherein the eluent for column chromatography consisted of ethyl acetate and n-heptane in a mass ratio of 1:6. The white powder was 2-[(3-oxo-2-azaspiro[4,5]decane-2-yl)methyl]-2-azaspiro[4,5]decane-3-one as shown in Formula 1, with a purity of 99.03%.

[0052] The characterization data are as follows:

[0053] Proton spectrum

[0054]

[0055] Combination Figure 3 It can be seen that

[0056] 1, 2, 3, 4, 5 and 1', 2', 3', 4', 5' δ (1.44, m), multiple peaks with 20 protons, representing the methylene proton peak -CH2 of the cyclohexyl group in the spirocyclic structure, and it is a symmetrical structure;

[0057] 6, 6'δ (3.12, s), single peak with 4 protons, representing the proton peak -CH2 on the methylene group of the cyclic amine in the spirocyclic structure, and it is a symmetrical structure;

[0058] 7, 7'δ (2.24, s), single peak with 4 protons, representing the proton peak -CH2 on the methylene group of cyclopentylamine in the spiro ring structure, and it is a symmetrical structure;

[0059] 8δ (4.74, s), a single peak with 2 protons, represents the proton peak -CH2 on the methylene connecting the two spiro rings.

[0060] Theoretically, this product contains 30 hydrogen atoms. Figure 3 of 1 Analysis of the H NMR spectrum shows that the compound has 30 hydrogen atoms, and the chemical shift assignments are completely consistent with the molecular structure.

[0061] Carbon spectrum

[0062]

[0063] Combination Figure 4 It can be seen that

[0064] 13 C NMR analysis (δ36.81) is the methylene proton peak -CH2 with carbon numbers 1, 1', 5, 5' on the cyclohexyl group in the spiro ring structure;

[0065] 13 C NMR analysis (δ22.70) is the methylene proton peak -CH2 with carbon numbers 2, 2', 4, 4' on the cyclohexyl group in the spiro ring structure;

[0066] 13 C NMR analysis (δ25.48) is the methylene proton peak -CH2 with carbon numbers 3,3' on the cyclohexyl group in the spiro ring structure;

[0067] 13 C NMR analysis (δ36.36) is the methylene proton peak -CH2 with carbon numbers 6, 6' on the cyclohexyl group in the spiro ring structure;

[0068] 13 C NMR analysis (δ48.75) is the methylene proton peak -CH2 with carbon number 7,7' on the cyclopentylamine in the spiro ring structure;

[0069] 13 C NMR analysis (δ43.92) is the methylene proton peak -CH2 with carbon number 8, 8' on the cyclopentylamine in the spiro ring structure;

[0070] 13 C NMR analysis (δ175.05) is the acyl proton peak -C=O- with carbon numbers 9, 9' on the cyclopentylamine in the spiro ring structure;

[0071] 13 C NMR analysis (δ57.46) showed that it was a methylene group -CH2 with carbon number 10 connecting two spiro rings.

[0072] from 13 Analysis of the C NMR spectrum shows that the compound has a total of 19 carbon atoms, and the number and position of high-field and low-field carbon atoms are completely consistent with the molecular structure.

[0073] Example 2

[0074] A method for preparing a gabapentin impurity compound of the present embodiment comprises the following steps: mixing 10.00 g of the compound 3,3'-pentenyl-4-butyrolactam represented by Formula 2 with 120 ml of toluene to obtain a mixed solution 1, mixing 10.2 g of dimethyl sulfoxide with 60 ml of toluene to obtain a mixed solution 2, adding the mixed solution 2 dropwise to the mixed solution 1 to obtain a mixed solution 3, mixing 2.73 g of oxalyl chloride with 60 ml of toluene to obtain a mixed solution 4, adding the mixed solution 4 dropwise to the mixed solution 3, and after the addition is completed for 30 minutes, heating to 70° C. and reacting for 6 hours. After the reaction, toluene and dimethyl sulfoxide were removed by reduced pressure distillation at 95°C to obtain 16.78g of brown oil with a yield of 80.7%. The brown oil was purified by column chromatography to obtain 13.40g of white powder, wherein the eluent for column chromatography consisted of ethyl acetate and n-heptane in a mass ratio of 1:6. The white powder was 2-[(3-oxo-2-azaspiro[4,5]decane-2-yl)methyl]-2-azaspiro[4,5]decane-3-one as shown in Formula 1, with a purity of 98.26%.

[0075] Example 3

[0076] The preparation method of a gabapentin impurity compound of the present embodiment comprises the following steps: 10.00 g of the compound 3,3'-pentenyl-4-butyrolactam shown in formula 2, 12.75 g of dimethyl sulfoxide and 60 ml of xylene are mixed to obtain a mixed solution 1, 2.73 g of oxalyl chloride and 30 ml of xylene are mixed to obtain a mixed solution 2, the mixed solution 2 is added dropwise to the mixed solution 1, after the addition is completed for 30 minutes, the temperature is raised to 95° C., and the reaction is performed for 6 hours. After the reaction is completed, the xylene and dimethyl sulfoxide are removed by reduced pressure distillation at 95° C. to obtain 15.48 g of a brown oily substance, with a yield of 74.5%. The brown oil was purified by column chromatography to obtain 10.97 g of white powder, wherein during the column chromatography, the eluent consisted of ethyl acetate and n-heptane in a mass ratio of 1:6, and the white powder was 2-[(3-oxo-2-azaspiro[4,5]decane-2-yl)methyl]-2-azaspiro[4,5]decane-3-one as shown in Formula 1, with a purity of 98.79%.

[0077] Performance Testing

[0078] 1. High performance liquid chromatography

[0079] The purity of the gabapentin impurity compound obtained in Example 1 was measured, and the spectrum was as follows: Figure 1 shown.

[0080] Detection instrument: Waters e2695 high performance liquid chromatograph; detection wavelength: 210nm, mobile phase A: mixed solution (phosphate buffer 94%, acetonitrile 6%), phosphate buffer (94:6); mobile phase B: acetonitrile flow rate: 1.5ml / min; mobile phase gradient is shown in Table 1. Among them, the preparation method of phosphate buffer is: take 1.2g of potassium dihydrogen phosphate, add 940ml of water to dissolve, and adjust the pH value to 6.6 with 5mol potassium hydroxide solution, and obtain, chromatographic column: use octadecylsilane bonded silica gel as filler (chromatographic column: Waters Atlantis T3 4.6x250mm, 5um); column temperature: 40℃.

[0081] Table 1 Chromatographic mobile phase gradient elution program

[0082]

[0083] 2. Liquid chromatography, mass spectrometry

[0084] The molecular weight of the gabapentin impurity compound obtained in Example 1 was measured, and the spectrum is as follows: Figure 2 shown.

[0085] Detection instrument: Agilent LC-MS / MS chromatograph Qtof 1290-6546;

[0086] Detection method: Refer to "Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0431 Mass Spectrometry".

[0087] 3. Nuclear Magnetic Resonance

[0088] Detection instrument: Swiss Bruker AVANCE AV 400 superconducting pulse Fourier transform nuclear magnetic resonance spectrometer;

[0089] The gabapentin impurity compound prepared in Example 1 was tested by hydrogen spectrum and carbon spectrum using 400 MHz nuclear magnetic resonance, the solvent was deuterated chloroform, and the spectrum was as follows: Figure 3 and Figure 4 shown.

[0090] Results Analysis

[0091] 1. High performance liquid chromatography analysis

[0092] Combination Figure 1 It can be seen that after high performance liquid chromatography detection, the purity of 2-[(3-oxo-2-azaspiro[4,5]decane-2-yl)methyl]-2-azaspiro[4,5]decane-3-one prepared by the preparation method of the present invention is 99.03%.

[0093] 2. Liquid chromatography and mass spectrometry analysis

[0094] Combination Figure 2 It can be seen that according to the analysis of the LC-MS spectrum, the following structural information can be obtained, see Table 2.

[0095] Table 2

[0096] m / z Fragment ions Remark 319.2415 <h2 style=";text-align:left;direction:ltr"><![CDATA[C <h2 style=";text-align:left;direction:ltr"> 19 <h2 style=";text-align:left;direction:ltr"> H<h2 style=";text-align:left;direction:ltr"> 30 <h2 style=";text-align:left;direction:ltr"> N2O2<h2 style=";text-align:left;direction:ltr"> +. <h2 style=";text-align:left;direction:ltr"> ]]><h2 style=";text-align:left;direction:ltr"> Molecular ion peak

[0097] Combination 1 H NMR, 13 C NMR and LC-MS confirmed that the molecular composition of the compound was C 19 H 30 The structure of N2O2 is shown below.

[0098]

[0099] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical concept disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. A method for preparing a gabapentin impurity compound, characterized in that: The method comprises the following steps: mixing 3,3'-pentenyl-4-butyrolactam, dimethyl sulfoxide and a solvent as shown in formula 2, adding a catalyst, reacting, removing the solvent and dimethyl sulfoxide, and purifying to obtain a gabapentin impurity compound as shown in formula 1, and the reaction structure is as follows:

2. The method for preparing the gabapentin impurity compound according to claim 1, characterized in that: The catalyst is oxalyl chloride.

3. The method for preparing the gabapentin impurity compound according to claim 2, characterized in that: The equivalent weight of the catalyst is 0.2-0.5 eq of 3,3'-pentenylene-4-butyrolactam shown in Formula 2.

4. The method for preparing the gabapentin impurity compound according to claim 1, characterized in that: The equivalent weight of the dimethyl sulfoxide is 2-3 e.q. of 3,3'-pentenylene-4-butyrolactam shown in Formula 2.

5. The method for preparing the gabapentin impurity compound according to claim 1, characterized in that: The reaction time is 4-8 hours; preferably, the reaction time is 6-7 hours.

6. The method for preparing the gabapentin impurity compound according to claim 1, characterized in that: The reaction temperature is 50-110°C; preferably, the reaction temperature is 70-95°C.

7. The method for preparing the gabapentin impurity compound according to claim 1, characterized in that: The purity of the gabapentin impurity compound is greater than 98%.

8. The method for preparing the gabapentin impurity compound according to claim 1, characterized in that: Also includes any one or more of the following features: 11) The solvent is selected from any one of 1,4-dioxane, toluene and xylene; 12) The purification is performed by column chromatography; 13) The removal of the solvent and dimethyl sulfoxide is carried out by vacuum distillation.

9. The method for preparing the gabapentin impurity compound according to claim 8, characterized in that: Also includes any one or more of the following features: 121) The eluent for column chromatography is selected from one or more of ethyl acetate and n-heptane; 131) The temperature of the reduced pressure distillation is 90-98°C.

10. The method for preparing the gabapentin impurity compound according to claim 9, characterized in that: The eluent is composed of ethyl acetate and n-heptane in a mass ratio of 1-3:1-10.

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