Process for the preparation of high purity gelsevines and pharmaceutically acceptable salts thereof based on separation of chiral organic acids

Abstract

The application discloses a preparation method of high-purity gelsemiumine and pharmaceutically acceptable salt thereof based on chiral organic acid separation, and comprises the following steps: obtaining gelsemiumine crude product by rapid column chromatography after total gelsemium alkaloids are obtained by extraction from gelsemium elegans Benth powder; obtaining chiral organic acid salt of gelsemiumine by reaction of the gelsemiumine crude product with chiral organic acid; obtaining high-purity gelsemiumine by dissociation after alkali is added; and obtaining pharmaceutically acceptable salt of high-purity gelsemiumine by salt formation with acid. The method has the advantages of large preparation amount, high yield up to hundreds of grams or even kilograms, simple and efficient operation, stable and environment-friendly process, mild reaction condition, low production cost, high product yield and high quality (purity is higher than 99.0%, total impurities are not higher than 1.0%, and the maximum single impurity is not higher than 0.1%), and is suitable for industrial large-scale production and can be used for preparation of gelsemiumine and pharmaceutically acceptable salt thereof.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of high-purity gelsemium and pharmaceutically acceptable salts thereof based on chiral organic acid separation, and belongs to the technical field of pharmacy. BACKGROUND

[0002] Gelsemium elegans Benth. is a perennial evergreen climbing vine of Gelsemium family, which is highly toxic and has been used as a traditional medicine for a long time. It is also a traditional Chinese medicine for promoting the growth of livestock such as pigs and sheep. In 1887, Gerrad et al. prepared it into Green's preparation, which was included in the vice-pharmacopoeia of some countries. The American Drug Index and Japanese World Folk Medicine also record Gelsemium elegans Benth. The main effective component of Gelsemium elegans Benth. is indole alkaloid, and gelsemium is an effective component with the highest content and less toxicity in the total alkaloid, with a molecular formula of C 20 H 22 N2O and a molecular weight of 306.4. Literature reports that gelsemium has significant pharmacological effects such as treating rheumatoid arthritis, anti-neuropathic pain, and anti-anxiety. No obvious toxicity is observed at the therapeutic dose, and it has strong safety. The mechanism of action is novel, and it has a good prospect for medical use.

[0003] Nearly half of the active drug molecules exist and are administered in the form of salts. The molecules or ions with opposite charges are combined with drugs to form salts, which can change some physical, chemical or biological properties of drugs. Therefore, the preparation of gelsemium and its pharmaceutically acceptable salts can meet the needs of different administration routes. It has the potential for large-scale industrial production. The preparation method of gelsemium and its pharmaceutically acceptable salts is of great significance for further clinical research and quality control.

[0004] Through literature retrieval, the preparation method of koumine can be extracted from the plant of Gelsemium elegans Benth. [Zhang L, Wang Z, Huang C, Zhang Z, Lin J. Extraction and separation of koumine from total alkaloids of Gelsemium elegans. Journal of the First Military Medical University, 2004, 24(9): 1006-1008], and some literatures report the artificial synthesis [Yang Z, Tan Q, Jiang Y, Yang J, Su X, Qiao Z, Zhou W, He L, Qiu H, Zhang M. Asymmetric Total Synthesis of Sarpagine and Koumine Alkaloids. Angew Chem Int Ed. 2021, 60(23): 13105-13111]. At the same time, several patents also disclose the methods related to the extraction of total gelsemium alkaloids and the preparation of koumine. Patent CN201711041508.6 discloses a method for preparing gelsemium alkaloids from Gelsemium elegans by ion exchange method, which can be used for the preparation of crude koumine in the preparation method of the present patent. Patent CN201710444073.3 discloses a method for preparing koumine by preparing Gelsemium acid water extract and then purifying by silica gel column chromatography for multiple times. This method is time-consuming and complicated to operate, and the yield is low due to the adsorption of the stationary phase. Patent CN201110081565.3 discloses a method for preparing koumine (i.e. koumine) from Gelsemium extract by ethyl acetate extraction and silica gel column chromatography, but the obtained koumine is only 2.8 grams, and the purity is only above 96%. Patent CN201410580093.X discloses a method for preparing koumine from Gelsemium medicinal materials by CO2 supercritical extraction technology. The operation steps are complicated, and related instruments and equipment are required. Subsequently, reverse phase silica gel column chromatography is also needed for separation and purification, and the obtained koumine is only 6.2 grams. Patents CN200810071469.9 and CN202010399671.5 disclose a method for separating koumine from Gelsemium alkaloids by using high-speed counter-current chromatography or high-speed counter-current chromatography combined with preparative liquid chromatography. The instrument and equipment have high requirements, and are not suitable for industrial production. In addition, the inventors' research group has also developed various preparation methods for koumine, such as pH zone refining counter-current chromatography and column chromatography combined with dynamic axial compression chromatography, which also require related instruments and equipment.

[0005] In the existing literature or patents, there is no report on the use of chiral organic acid separation method for the industrialized preparation of koumine and its pharmaceutically acceptable salt. Therefore, the present application discloses a preparation method of koumine and its pharmaceutically acceptable salt based on chiral organic acid separation. SUMMARY

[0006] In order to overcome the shortcomings of the prior art industrial preparation technology of gelsemid and pharmaceutically acceptable salts thereof, the present application aims to provide a preparation method which is simple, controllable, environmentally friendly, low in cost and suitable for the production of crude drugs, i.e. a preparation method of gelsemid and pharmaceutically acceptable salts thereof based on chiral organic acid separation.

[0007] The method for preparing high-purity gelsemid based on chiral organic acid separation provided by the present application is characterized by comprising the following steps: reacting gelsemid crude product with a chiral organic acid to obtain a gelsemid-chiral organic acid diastereomeric salt, and then adding an alkali to free the gelsemid-chiral organic acid diastereomeric salt to obtain high-purity gelsemid.

[0008] Further, in the above technical solution, the purity of the product is greater than or equal to 99.0%, the total impurities are not higher than 1.0%, and the maximum single impurity is not higher than 0.1%.

[0009] Further, in the above technical solution, the purity of gelsemid in the gelsemid crude product is greater than or equal to 40%.

[0010] Further, in the above technical solution, the gelsemid crude product can be obtained from gelsemium extract or artificial synthetic product.

[0011] Further, in the above technical solution, the gelsemid crude product is obtained by using gelsemium total alkaloids as raw material, and using ethyl acetate / methanol, dichloromethane / methanol or dichloromethane / acetone as eluent, and then performing rapid silica gel column chromatography.

[0012] Further, in the above technical solution, the purity of gelsemid in the gelsemium total alkaloids is not less than 10%, and the gelsemium total alkaloids are obtained by using gelsemium powder as raw material and using ethanol as solvent.

[0013] Further, in the above technical solution, the chiral organic acid is D-DTTA (D-diphenylmethanol tartaric acid) or D-DBTA (D-diphenylmethanol tartaric acid).

[0014] Further, in the above technical solution, the feeding equivalent ratio of the gelsemid crude product and the chiral organic acid is 1:0.3-1.0, and preferably 1:0.6; and the gelsemid and the D-DTTA in the salt product are salified in the form of 2:1.

[0015] Further, in the above technical solution, the alkali used for the dissociation of the gelsemid-chiral organic acid salt is sodium hydroxide aqueous solution or potassium hydroxide aqueous solution; and the alkali washing is performed for 1-3 times, and preferably 3 times.

[0016] Further, in the above technical solution, the gelsemid is salted with an acid, which can be an inorganic acid or an organic acid. The inorganic acid includes but is not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, hydrogen chloride / methanol solution, hydrogen bromide / methanol solution, and the organic acid includes but is not limited to methanesulfonic acid and acetic acid.

[0017] Further, in the above technical solution, the pharmaceutically acceptable salt of the gelsemid is selected from one of hydrochloride, sulfate, hydrobromide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, citrate, acetate, oxalate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate, preferably one of hydrochloride, sulfate, phosphate and hydrobromide, and more preferably hydrochloride.

[0018] Further, in the above technical solution, the acid for salting with the gelsemid is hydrogen chloride / ethanol solution, wherein the equivalent ratio of hydrogen chloride to gelsemid is 0.5-2.0:1, and preferably the ratio of the two is 1.0-1.1:1.

[0019] Further, in the above technical solution, the typical preparation method of the gelsemid hydrochloride is as follows: taking gelsemium powder as raw material, hot extracting with ethanol, concentrating the ethanol to obtain gelsemium extract; adding dilute hydrochloric acid to adjust pH value to 2-3, filtering, adding sodium hydroxide aqueous solution to adjust pH value to 9-10, extracting with ethyl acetate, concentrating the extract, and vacuum drying to obtain gelsemium total alkaloids; performing rapid column chromatography to obtain gelsemid crude product; adding D-DTTA to obtain gelsemid D-DTTA salt; adding sodium hydroxide aqueous solution to dissociate, and extracting with dichloromethane to obtain high-purity gelsemid; and adding hydrogen chloride / ethanol solution to salt to obtain high-purity gelsemid hydrochloride.

[0020] Further, in the above technical solution, the method has large preparation capacity, and the yield can reach hundreds of grams or even kilograms; the preparation operation is simple and efficient, the process is stable, environmentally friendly, the reaction condition is mild, and the production cost is low; the product has high yield and high quality, and can be used for the preparation of gelsemid and pharmaceutically acceptable salt of gelsemid.

[0021] Further, in the above technical solution, the preparation process of gelsemid hydrochloride is as follows Figure 1 .

[0022] Advantages of the application

[0023] 1、The chiral organic acid separation method greatly improves the efficiency of gelsemiumine separation. The chiral organic acid D-DTTA can form salt with gelsemiumine in the crude product with high selectivity, which "selects" gelsemiumine from the mixture. After separation, the purity of gelsemiumine can be increased from about 40% of the crude product to more than 99.0% at one time, thereby realizing efficient separation of gelsemiumine and other impurities.

[0024] 2、The present application is suitable for the preparation of gelsemiumine and its pharmaceutically acceptable salt. The method has the advantages of large preparation amount, gelsemiumine medicinal material powder feeding amount of hundreds of kilograms to tons, yield of hundreds of grams or even kilograms, compared with other disclosed chromatographic separation methods of grams or milligrams, simple and efficient operation, stable and environmentally friendly process, mild reaction conditions, low production cost, high product yield and quality (purity of more than 99.0%, total impurities not more than 1.0%, maximum single impurity not more than 0.1%), suitable for industrial large-scale production, and can meet the production requirements of raw materials.

[0025] 3、The method of the present application also lays the foundation for the production of gelsemiumine and its acceptable salt in the preparation of health products and feed and other applications. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 The preparation process flow chart of gelsemiumine hydrochloride;

[0027] Figure 2 The high performance liquid chromatogram of gelsemiumine in Example 2;

[0028] Figure 3 The high performance liquid chromatogram of gelsemiumine in Example 2;

[0029] Figure 4 The high performance liquid chromatogram of gelsemiumine in Example 2;

[0030] Figure 5 The high performance liquid chromatogram of gelsemiumine in Example 2;

[0031] Figure 6 The high performance liquid chromatogram of gelsemiumine in Example 2. DETAILED DESCRIPTION

[0032] Example 1

[0033] 1) Optimization of gelsemiumine crude product preparation process parameters

[0034] The total gelsemium alkaloids were purified by fast column chromatography, and the gelsemium alkaloids were collected. A certain amount of silica gel was used as the stationary phase, and the purity of gelsemidine in the crude product obtained by different elution systems (ethyl acetate / methanol system, dichloromethane / methanol system and dichloromethane / acetone system) was investigated. The results showed that the purity of gelsemidine was higher and the time was shorter when dichloromethane / methanol system (80:1, W / W) was used as the eluent.

[0035] The effect of different amounts of silica gel on the purity of gelsemidine in the crude product and the time of purification was investigated when dichloromethane / methanol system (80:1, W / W) was used as the eluent. The results showed that when the weight ratio of gelsemium alkaloids to silica gel was 1:8, the enrichment effect of gelsemidine was more obvious, the pigment removal effect was more ideal, and the time of purification was moderate.

[0036] 2) Selection of chiral organic acid

[0037] A parallel reactor was taken, and a certain amount of gelsemidine was added. Acetone was used as the solvent, and heating was used to make it fully dissolved. Then various chiral organic acids (L-camphorsulfonic acid, D-camphorsulfonic acid, L-mandelic acid, L-malic acid, D-malic acid, D-DTTA and L-DTTA) were added to the solution. After all were dissolved, cooling was carried out, and it was observed that the solution with D-DTTA precipitated quickly, and a small amount of solid precipitated after 3 hours with L-DTTA. The rest did not precipitate solid, so D-DTTA was selected as the chiral organic acid to separate gelsemidine (D-DBTA and D-DTTA had similar results).

[0038] 3) Selection of the purity of gelsemidine crude product

[0039] The gelsemidine crude product with different purity (20.86%, 41.00%, 57.52% and 86.36%) was reacted with D-DTTA, and the salting effect and the residual gelsemidine in the mother liquor after salting were investigated. The results showed that when the purity of gelsemidine in the crude product was about 20%, the salting effect of D-DTTA was poor because of the excessive amount of impurities, and most of the gelsemidine was in the mother liquor. When the purity of gelsemidine in the crude product was ≥40%, the selective salting with D-DTTA could be achieved, and there was almost no gelsemidine in the mother liquor. Therefore, the purity of gelsemidine in the crude product for salting with D-DTTA was selected to be ≥40%.

[0040] 4) Selection of the amount of chiral organic acid

[0041] The different amounts of D-DTTA (0.3, 0.6 and 1.0 equivalents) were reacted with the crude gelsemidine to investigate the product yield and D-DTTA residue after salification. The results showed that when the amount of D-DTTA was 0.3 equivalent of the weight of gelsemidine in the crude product, the yield of chiral organic acid salt was low, and part of the gelsemidine in the mother liquor was not completely salified; when the amount of D-DTTA was 1.0 equivalent, the product yield was high, but there was excessive D-DTTA residue, which brought difficulties to the subsequent treatment; when the amount of D-DTTA was 0.6 equivalent, the gelsemidine could be completely salified, and the yield was consistent with the theoretical value. Therefore, 0.6 equivalent of D-DTTA was preferred for the reaction.

[0042] 5) Optimization of the number of alkali washing times

[0043] The chiral organic acid salt of gelsemidine was dissociated with 2% sodium hydroxide aqueous solution. The results showed that after 1-3 times of washing of the chiral organic acid salt with 2% sodium hydroxide, no D-DTTA was detected in the organic phase, and the purity of gelsemidine was 99.92%. It was preferred that the washing times were 3 times to ensure the complete removal of D-DTTA.

[0044] 6) Optimization of the salt type of gelsemidine

[0045] An appropriate amount of gelsemidine was weighed, and the salification of gelsemidine with common inorganic acids (hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, hydrogen chloride / methanol solution, hydrogen bromide / methanol solution) and organic acids (methanesulfonic acid and acetic acid) in different solvents (acetone, methanol and dichloromethane) was investigated with the salification yield as the index. The results showed that when acetone was used as the solvent, the gelsemidine hydrochloride, sulfate, hydrobromide and phosphate were well crystallized after salification. The results of physicochemical properties and stability showed that the gelsemidine hydrochloride had high salification yield, no or almost no hygroscopicity, good solubility in different pH aqueous solutions and solid stability, and therefore the gelsemidine hydrochloride was preferred.

[0046] 7) Optimization of the equivalent amount of hydrogen chloride in the salification of gelsemidine

[0047] Different amounts of hydrogen chloride ethanol solution (1.0, 1.1, 1.2 and 1.5 equivalents) were reacted with gelsemidine to investigate the yield, purity and chloride ion content of gelsemidine hydrochloride. The results showed that after the salification of gelsemidine with the above amounts of hydrogen chloride, the product yield was ≥95%, and the purity was ≥99.0%; when the amount of hydrogen chloride was 1.0-1.1 equivalent, the chloride ion content in the product was close to the theoretical value, and with the increase of the amount of hydrogen chloride to 1.5 equivalent, the chloride ion content in the product was also increased. Therefore, the amount of hydrogen chloride was preferably 1.0-1.1 equivalent.

[0048] Example 2

[0049] 1) Extraction of gelsemium total alkaloids from gelsemium herb powder

[0050] 500 kg of Gouqi medicinal material powder was added to 95% ethanol in a glass reaction kettle and extracted by heating and stirring. After cooling and filtration, the residue was extracted again by the same method twice. The three extraction solutions were combined and concentrated to obtain Gouqi extract. 95% ethanol and purified water were added to the Gouqi extract, and the system was cooled to precipitate a large amount of solid. The filtrate was obtained by filtration and concentrated to dryness. The pH of the system was adjusted to 2-3 with dilute hydrochloric acid, and the organic phase impurities were removed by adding ethyl acetate. The pH of the acid-water phase was adjusted to 9-10 by adding dilute NaOH aqueous solution, and the Gouqi alkaloids were extracted with ethyl acetate. The extract was concentrated to dryness, and vacuum dried to constant weight to obtain Gouqi total alkaloids, which were brown paste-like solids with a weight of 2.899 kg and a Gouqi sub-purity of 26.5%. The HPLC spectrum is shown in Figure Figure 2 .

[0051] 2) Gouqi total alkaloids were obtained by rapid column chromatography to obtain Gouqi sub-rough product

[0052] 2.834 kg of Gouqi total alkaloids was added to a glass rotary evaporator flask, dissolved with dichloromethane and methanol, and then mixed with 200-300 mesh silica gel. 16.0 kg of 200-300 mesh silica gel was added to a stainless steel low-pressure preparation column, and the Gouqi total alkaloids were mixed with the sample. The mixed solvent of dichloromethane / methanol=80 / 1 (W / W) was used for elution, and TLC was used for monitoring. The fractions containing Gouqi sub were collected, concentrated under reduced pressure, and oil pump dried to constant weight to obtain 1.276 kg of Gouqi sub-rough product with a Gouqi sub-purity of 52.14%. The HPLC spectrum is shown in Figure Figure 3 .

[0053] 3) D-DTTA selectively forms a salt with Gouqi sub to obtain a chiral organic acid salt

[0054] 1.007 kg of Gouqi sub-rough product was added to a glass reaction kettle, and acetone was added under nitrogen protection. The stirring was started to dissolve the solid completely. 0.6 equivalent of D-DTTA solution was added dropwise, and the system was incubated at 20-30°C for 0.5-1 h with stirring. The filter cake was added to acetone for slurry, and the impurities were removed to obtain Gouqi sub-chiral organic acid salt rough product. The rough product was added to a glass reaction kettle, and recrystallized and vacuum dried to constant weight to obtain 630.1 g of Gouqi sub-chiral organic acid salt fine product. The HPLC spectrum is shown in Figure Figure 4 .

[0055] 4) Gouqi sub-chiral organic acid salt was dissociated by alkali washing and recrystallized to obtain Gouqi sub

[0056] The 600.2g of gelsemicidine chiral organic acid salt was put into a glass reactor, dichloromethane and purified water were added and stirred uniformly, 2% sodium hydroxide aqueous solution was added dropwise for washing, and after the dropwise addition was completed, the mixture was kept stirring, and then was allowed to stand and separate into two layers, the water phase was extracted with dichloromethane again, and the organic phases were combined; the above operation was repeated twice, and the combined organic phase was washed for 3 times. The organic phase was washed with 5% sodium chloride aqueous solution, dried with anhydrous sodium sulfate, filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated to dryness under reduced pressure, and dried with an oil pump to obtain gelsemicidine crude product. The gelsemicidine crude product was recrystallized with acetone, and dried with an oil pump to constant weight to obtain white solid, which was gelsemicidine product, with a weight of 346.7g, a purity of 99.98%, total impurities ≤1.0%, and maximum single impurity ≤0.1%, and the HPLC spectrum is shown in Figure 1. Figure 5 .

[0057] 5) Recrystallization of gelsemicidine salt with acid to obtain pharmaceutically acceptable salt thereof

[0058] The 320.0g of gelsemicidine was put into a glass reactor, dissolved in acetone, and 1.03 equivalent of hydrogen chloride ethanol solution was added dropwise under nitrogen protection, and solid was precipitated. After the mixture was kept stirring and slowly cooled, it was filtered, the filter cake was washed with ice acetone, and then was dried with an oil pump to constant weight to obtain gelsemicidine hydrochloride crude product. The crude product was dissolved in anhydrous ethanol and purified water, filtered to remove impurities, the filtrate was concentrated under reduced pressure, recrystallized with ethyl acetate, and white solid was obtained, which was gelsemicidine hydrochloride product, with a weight of 332.8g, a purity of 99.98%, total impurities ≤1.0%, and maximum single impurity ≤0.1%, and the HPLC spectrum is shown in Figure 2. Figure 6 .

[0059] Example 3

[0060] In this example, the method was the same as that in Example 2, and the amount of gelsemium medicinal material powder was increased to 1.5 times to prepare gelsemicidine hydrochloride. Gelsemicidine was obtained from 750kg of gelsemium medicinal material powder; gelsemicidine crude product was obtained by rapid column chromatography; chiral organic acid salt was obtained by high selectivity reaction of D-DTTA and gelsemicidine; gelsemicidine was obtained by recrystallization after dissociation of the chiral organic acid salt by alkaline washing, with a purity of ≥99.0%, total impurities ≤1.0%, and maximum single impurity ≤0.1%; gelsemicidine hydrochloride was obtained by recrystallization of gelsemicidine and hydrochloric acid, with a weight of 511.4g, a purity of 99.97%, total impurities ≤1.0%, and maximum single impurity ≤0.1%.

[0061] The above shows and describes the basic principles and main features of the present application and the advantages of the present application. Those skilled in the art should understand that the present application is not limited by the above examples, and the above examples and descriptions in the specification are only to illustrate the principles of the present application, and various changes and improvements can be made without departing from the spirit and scope of the present application, and these changes and improvements all fall within the scope of the claimed present application.

Claims

1. A method for separating high-purity gelseminates based on chiral organic acids, characterized in that, The process includes the following steps: reacting crude gelsemium with a chiral organic acid to obtain a gelsemium-chiral organic acid diastereomer salt, followed by alkali addition to liberate the salt and obtain high-purity gelsemium. The chiral organic acid is selected from D-dibenzoyl tartaric acid or D-di-p-methylbenzoyl tartaric acid. The purity of gelsemium in the crude gelsemium is ≥40%, and the ratio of the chiral organic acid to the equivalent of gelsemium in the crude gelsemium is 0.3-1.0:

1.

2. The method for separating high-purity gelseminates based on chiral organic acids according to claim 1, characterized in that: The crude gelseminin was obtained by rapid silica gel column chromatography using total alkaloids of Gelsemium elegans, with ethyl acetate / methanol, dichloromethane / methanol, or dichloromethane / acetone as the eluent.

3. The method for separating high-purity gelseminates based on chiral organic acids according to claim 2, characterized in that: The total alkaloids of Gelsemium elegans contain a purity of not less than 10% for Gelsemium elegans extract; the extract is obtained by extraction using Gelsemium elegans powder as raw material, but not limited to ethanol solvent.

4. The method for separating high-purity gelseminates based on chiral organic acids according to claim 1, characterized in that: The ratio of chiral organic acid feed amount to the equivalent amount of gelsemium ions in the crude product was 0.6:

1.

5. The method for separating high-purity gelseminates based on chiral organic acids according to claim 1, characterized in that: The base is selected from aqueous solutions of sodium hydroxide or potassium hydroxide.

6. A method for preparing a pharmaceutically acceptable salt of gelsemium seeds, characterized in that: High-purity gelsemin is obtained by any one of the methods of claims 1-5, and then the high-purity gelsemin is reacted with inorganic acid salts, sulfuric acid, hydrobromic acid or phosphoric acid to obtain pharmaceutically acceptable salts of high-purity gelsemin.

7. The method for preparing a pharmaceutically acceptable salt of gelsemium according to claim 6, characterized in that: The pharmaceutically acceptable salt is selected from hydrochloride, sulfate, hydrobromide or phosphate.

8. The method for preparing a pharmaceutically acceptable salt of gelsemium according to claim 7, characterized in that: The pharmaceutically acceptable salt is hydrochloride, which is obtained by reacting high-purity gelseminol with hydrogen chloride / ethanol solution.

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