WO2015043404A1 - (-)-huperzine-a salt - Google Patents

Abstract

The present invention relates to a salt of (-)-huperzine-a, which is prepared from the reaction of huperzine-a and a corresponding acid. The huperzine-a salt is selected from huperzine-a hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, trifluoroacetate, lactate, citrate, oxalate, maleate, succinate, tartrate, fumarate, mandelate, mesylate, benzene sulfonate, gluconate, ascorbate, acetonate, alanine salt, aspartate, lysinate and arginine salt.

Description

(-)-huperzine methyl salt Technical field

The invention belongs to the field of medicinal chemistry, in particular to a salt of huperzine A, which is prepared by reacting (-)-huperzine A with a corresponding acid.

technical background

Huperzine A is a highly active alkaloid isolated from Huperzia serrata (Thunb) Thev., and (-)-huperzine A is a pharmaceutically active ingredient.

(-)- Huperzine A has the following structural formula:

Chemical name: (5R, 9R, 11E)-5-amino-11-ethylidene-5,6,9,10-tetrahydro-7-methyl-5,9-methylenecyclooctatetetraeno[ b]pyridine-2-(1H)-one

Huperzine A

Molecular weight: 242.32

It is white or off-white to slightly yellow crystalline powder, melting point: 228-231 ° C, soluble in methanol, chloroform, soluble in ethanol, insoluble in water.

The preparation process of Huperzine A has pure natural plant extracts obtained by extraction and isolation from plants, and also compounds obtained by chemical synthesis. Natural (-)-huperzine A is only about one-tenth of a million in the kelp plant of the genus Huperaceae. Because the growth cycle of the galaxies is as long as 8-10 years, plant extraction alone is far from satisfying the market. Demand, chemical synthesis (-) - Huperzine A has a long-term market prospects.

(-)-Huperzine A is a highly effective and highly selective reversible acetylcholinesterase inhibitor, which has the functions of improving learning and memory effects, and can be used for the treatment of benign memory disorders and various neuropsychiatric diseases. The patient's ability to point to memory, association learning, image recall, meaningless graphics recognition and portrait recall also improves memory impairment caused by dementia patients and brain organic diseases.

Huperzine A is China's first drug. Currently, in addition to the Chinese Pharmacopoeia (2010), USP (33), EP (7.0), Both BP (2010) and the Japanese Pharmacopoeia (XV) are not included.

(-)-Huperzine A injection was launched in China in 1985, clinically used for myasthenia gravis. (-)-Huperzine A tablet was launched in 1995, clinically used for Alzheimer's disease (AD) and memory. The treatment of obstacles; in foreign countries, Huperzine A is widely used as a food additive and functional beverage active ingredient, mainly used to improve the memory function of the elderly and improve the brain reaction speed of athletes.

(-)-Huperzine A preparation has the functions of improving learning and memory efficiency and repairing neuronal damage. It is mainly used for the treatment of myasthenia gravis, schizophrenia, senile dementia, benign memory impairment and other symptoms, especially for senile forgetfulness. Symptoms and Alzheimer's disease are effective and effective in improving children's memory.

(-)-Huperzine A is highly toxic, and acute toxicity test showed that the LD50 of mice injected intraperitoneally was 1.8 mg/kg, and that of rats was 5 mg/kg. Excessive dose can cause dizziness, nausea, gastrointestinal discomfort, fatigue and other reactions.

The existing (-)-huperzine tablets and capsules and injections are marketed, and the specifications are: 0.05 mg/tablet or granules, and the injection is 0.2 mg/ampule.

(-)-Huperzine A oral absorption is good, the dosage is: oral, 0.1mg ~ 0.2mg (2 ~ 4 tablets), 2 times a day, but the maximum amount of no more than 9 tablets a day.

(-)-Huperzine A has a darker color, and under certain conditions of acid, alkali and oxidation forced destruction test, it shows a certain degree of degradation. Accelerated stability test and long-term stability test results show that the related substances are on the rise. (The maximum increase of 1.5% in 24 months); The Chinese Pharmacopoeia 2010 edition stipulates: Huperzine A [check] the relevant substance limit should not exceed 2.5%, in the production of conventional tablets and capsules, (-)-stone If the process of preparing granules without diluting hydrochloric acid into salt and adjusting the pH value of the solution, the preparation of granules by direct dilution with ethanol will often result in the sum of the peak areas of the impurity of the final product being larger than the main peak area of the control (4.0%). ), that is, does not meet the quality requirements of the Chinese Pharmacopoeia 2010 version of huperzine tablets and capsules [check] related substances, indicating that huperzine A has a storage process and granulation, drying and other preparation processes Significant degradation, affecting product quality.

In the prior art, there are not many studies on huperzine methyl salt, but many patents mention the salt of huperzine A. For example, Chinese Patent 200710038007.2 describes a huperzine A and its derivatives or their salts. Release the nanoparticles. Its particle size is between 20 and 500 nm. The drug can be slowly released in the body. The blood concentration is stable and long-lasting, which can improve bioavailability and reduce the number of administrations. Among them, huperzine A and its derivatives or salts thereof may be mentioned, and may be a salt combined with hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, lactic acid, citric acid or maleic acid. China Patent 200710037550.0 describes a huperzine A and its derivatives or salts thereof, referred to as Huperzine A and its derivatives or salts thereof, which may be with hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, lactic acid, citric acid or malay The acid is combined into a salt. Chinese Patent No. 200510014685.6 describes a compound of formula (I) for use in the treatment of pain, functional pain syndrome or organ pain and various pharmaceutically acceptable inorganic or organic acid salts thereof, and Chinese Patent 200410078207.7 describes the cedar The base a compound may be in the form of a free base or an acid addition salt, and examples of the acid forming the acid addition salt include hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, lactic acid or citric acid. Chinese Patent 200310108852.4 describes a salt of Huperzine A, which is a compound of the formula (I), the formula (II), the formula (III), the formula (IV) and the formula (IV) with hydrochloric acid, acetic acid, phosphoric acid, a salt of sulfuric acid, lactic acid, citric acid or maleic acid combined. Chinese Patent No. 01119952.0 describes a sustained release microsphere of Huperzine A and derivatives thereof or a salt thereof according to the general formula (1), characterized in that it is 0.2 to 50% of the weight of the microspheres of Huperzine A and The derivative or its salt and the weight of the microspheres are 50-99.8% of a biodegradable medicinal polymer excipient having a molecular weight ranging from 5,000 to 1,000,000, wherein the acid forming the salt is hydrochloric acid, acetic acid, phosphoric acid, Sulfuric acid, lactic acid, citric acid.

However, the above patents only mention that huperzine A can form the above salts, and no actual preparation and study of these salts have been conducted.

Based on the prior art, the (-)-huperzine A is prepared as a sulfadipine methyl salt having better quality stability than huperzine A, in order to improve (-)-huperzine A. The quality and quality stability of its preparation products.

The invention also studies the physicochemical properties of the Huperzine M salt, and finds that it has good crystal stability, good water solubility, and is particularly suitable for preparing liquid preparations or soluble preparations.

The present inventors have found that the quality stability of (-)-huperzine methyl salt is superior to (-)-huperzine methyl free base. In order to ensure the quality of the Huperzine A preparation product, the acid-to-salt process step becomes an important step in the preparation of the preparation.

Summary of the invention:

The present invention provides a pharmaceutically acceptable huperzine methyl salt, which is selected from the group consisting of the hydrochloride salt of huperzine A, a hydrobromide salt, a nitrate salt, a citrate salt, an acetate salt, Trifluoroacetate, lactate, phosphate, sulfate, oxalate, maleate, succinate, tartrate, fumarate, mandelate, methanesulfonate, besylate , gluconate, ascorbate, pyruvate, alaninate, aspartate An acid salt, a lysine salt or an arginine salt.

A preferred huperzine methyl salt is selected from the group consisting of the hydrochloride salt of huperzine A, hydrobromide, citrate, acetate, lactate, phosphate, sulfate, fumarate.

The invention also includes a method for preparing a huperzine methyl salt, the method comprising the steps of:

(1) (-)-huperzine A is reacted with an acid in a solvent to obtain a solution of huperzine methyl salt;

(2) Distilling the Huperzine Methyl Salt Solution under reduced pressure, adding the recrystallization solvent after evaporation of the solvent, heating and dissolving, cooling to room temperature, then adding acetone, combining to form a mixed solvent for crystallization, cooling to about 0 ° C, filtering, The acetone was washed, and the crystals were dried under vacuum to obtain the Huperzine salt.

Wherein the solvent in the step (1) is selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, acetone, tetrahydrofuran, water; and the molar ratio of (-)-huperzine A to acid is 1:1 to 1: 2. The solvent is selected from the group consisting of water, acetone and water or a mixed solvent of ethanol and water, the ratio of acetone to water is 1:1 to 5:1, and the ratio of ethanol to water is 1:1 to 5:1; (-)- The weight ratio of Huperzine A to the solvent is 1:1 to 10.

Preferably, the acid in the step (1) is hydrochloric acid or hydrobromic acid, the molar ratio of (-)-huperzine to the acid is 1:1 to 1:1.05, and the pH of the reaction liquid is 3.5 to 5.5.

Wherein the recrystallization solvent in the step (2) is selected from the group consisting of methanol, absolute ethanol, isopropanol and ethyl acetate; and the amount thereof is 3 to 20 times the weight of (-)-huperzine A, and the amount of acetone is ( -) - 10 to 50 by weight of Huperzine A.

A preferred method of preparation of the invention comprises the steps of:

(1) (-)-Huperzine A is reacted with hydrochloric acid or hydrobromic acid in a solvent to obtain a solution of huperzine methyl salt; wherein the solvent is selected from the group consisting of water, acetone and water or a mixed solvent of ethanol and water. The ratio of acetone to water is 1:1-5:1, the ratio of ethanol to water is 1:1-5:1; the weight ratio of (-)-huperzine A to solvent is 1:1-10, ( -) - the molar ratio of Huperzine A to hydrobromic acid is 1:1 to 1:1.05, and the pH of the reaction solution is 3.5 to 5.5;

(2) Distilling the Huperzine Methyl Salt Solution under reduced pressure, adding the recrystallization solvent after evaporation of the solvent, heating and dissolving, cooling to room temperature, then adding acetone, cooling to about 0 ° C, filtering, acetone washing, and crystallization by vacuum drying. Obtaining a huperzine methyl salt, wherein the recrystallization solvent is selected from the group consisting of methanol, absolute ethanol, isopropanol, and ethyl acetate; and the amount thereof is 3 to 20 times the weight of (-)-huperzine A, and the amount of acetone is used. It is 10 to 50 times the weight of (-)-huperzine A.

The present invention has been studied in the form of a polymorphic form, in particular, some specific crystal forms have excellent physical and chemical properties. To this end, the present invention also provides a solid of (-)-huperzine methyl salt. crystallization.

The solid crystal of the (-)-huperzine methyl salt of the present invention includes the following crystal forms:

Huperzine methyl hydrochloride an amorphous crystalline form.

Huperzine hydrobromide crystal form, X-ray diffraction pattern of the crystal, expressed as degrees 2θ of 8.720, 10.560, 11.957, 13.381, 14.506, 15.253, 16.109, 17.074, 17.488, 18.102, 18.932, 19.339 , 20.249, 20.863, 21.218, 21.968, 22.677, 23.074, 23.944, 24.437, 24.851, 25.343, 25.713, 25.974, 26.350, 26.943, 27.204, 28.028, 28.945, 30.318, 31.087, etc. have obvious characteristic absorption peaks, as shown in the figure 1b. The DSC thermogram, infrared spectrum and Raman spectrum of the crystal are shown in Figures 1c, 1d, and 1e.

Huperzine methyl sulfate crystal form, respectively named huperzine methyl sulfate crystal form I, huperzine methyl sulfate form II.

X-ray diffraction pattern of Huperzine Methanesulfate Form I, the 2θ angle expressed in degrees has obvious characteristic absorption peaks at 7.442, 14.863, 21.693, etc., as shown in Figure 2b. The DSC thermogram, infrared spectrum and Raman spectrum of the crystal are shown in Figures 2c, 2d, and 2e.

X-ray diffraction pattern of Huperzine Methionine Form II, in terms of degrees of 2θ, at 4.573, 6.434, 8.330, 9.512, 10.597, 12.279, 13.577, 14.270, 15.161, 15.989, 16.968, 18.042, 18.475, 19.248 There are obvious characteristic absorption peaks at 20.116, 21.160, 22.585, 22.974, 24.081, 24.674, 25.858, 26.985, 27.476, 28.598, etc., see Figure 3b. The DSC thermogram, infrared spectrum and Raman spectrum of the crystal are shown in Figures 3c, 3d, and 3e.

Huperzine methyl phosphate crystal form, X-ray diffraction pattern of the crystal, the 2θ angle expressed in degrees is 4.677, 6.613, 7.363, 8.033, 9.869, 11.338, 11.924, 13.112, 13.519, 14.843, 16.955, 17.862, 19.048 , 19.934, 21.297, 22.346, 23.567, 24.198, 25.049, 25.957, 27.674, 28.661, 31.582, etc. have obvious characteristic absorption peaks, see Figure 4b. The DSC thermogram, infrared spectrum and Raman spectrum of the crystal are shown in Figures 4c, 4d, 4e.

The three crystal forms of Huperzine mesylate are named as Huperzine Methionate Form I, Huperzine Formate Form II, and Huperzine Formate Form III.

X-ray diffraction pattern of Huperzine mesylate Form I, the 2θ angle expressed in degrees is obviously at 5.210, 9.238, 10.363, 13.579, 14.944, 15.829, 18.356, 20.332, 20.942, 22.225, etc. The characteristic absorption peak is shown in Figure 5b. The DSC thermogram, infrared spectrum and Raman spectrum of the crystal are shown in Figures 5c, 5d, 5e.

X-ray diffraction pattern of Huperzine Methacetate Form II, expressed as 27.7 angles in degrees 7.737, 9.259, 11.332, 11.745, 12.811, 13.797, 14.568, 15.535, 16.935, 17.942, 18.652, 19.363, 20.054, 20.507 There are obvious characteristic absorption peaks at 21.158, 21.989, 22.424, 23.411, 24.733, 25.722, 27.418, 29.113, 29.588, 30.201, etc., see Figure 6b. The DSC thermogram, infrared spectrum and Raman spectrum of the crystal are shown in Figures 6c, 6d, and 6e.

X-ray diffraction pattern of Huperzine Methionate Form III, expressed as degrees 2441 at 5.444, 9.356, 10.797, 12.376, 14.547, 15.497, 16.167, 18.121, 18.713, 19.502, 21.830, 22.502, 23.074, 23.628 , 24.416, 24.871, 26.213, 26.668, 27.319, 30.477, 32.844, 34.721, 35.194, 36.042, etc. have obvious characteristic absorption peaks, see Figure 7b. The DSC thermogram, infrared spectrum and Raman spectrum of the crystal are shown in Figures 7c, 7d, and 7e.

Huperzine form of fumarate, the X-ray diffraction pattern of the crystal, expressed as degrees 2θ of 7.837, 11.033, 12.221, 12.611, 13.185, 14.785, 15.711, 17.134, 19.068, 19.778, 20.765, 21.416 There are obvious characteristic absorption peaks at 22.187, 22.780, 23.607, 24.477, as shown in Figure 8b. The DSC thermogram, infrared spectrum and Raman spectrum of the crystal are shown in Figures 8c, 8d, and 8e.

Huperzine form of the huperzine, the X-ray diffraction pattern of the crystal, expressed as degrees 2θ at 5.980, 9.316, 10.934, 12.356, 13.895, 14.880, 15.733, 16.185, 17.646, 18.260, 18.949, 21.456, There are obvious characteristic absorption peaks at 22.344, 22.937, 23.905, 24.656, 25.956, as shown in Figure 9b. The DSC thermogram, infrared spectrum and Raman spectrum of the crystal are shown in Figures 9c, 9d, and 9e.

Huperzine formamidine crystal form, respectively named as Huperzine Methionate Form I, Huperzine Formate Form II.

X-ray diffraction pattern of huperzine formamidine Form I, in terms of degrees 2θ, at 8.227, 9.492, 10.936, 12.887, 13.478, 13.699, 14.270, 15.278, 16.699, 17.370, 18.633, 19.0228, 20.803 , 21.495, 22.029, 22.560, 23.075, 24.774, 25.480, 26.767, 27.576, 28.106, 28.521, 29.312, 30.515, 31.265, 32.036, 33.299, 34.541, etc. have obvious characteristic absorption peaks, see Figure 10b. The DSC thermogram, infrared spectrum and Raman spectrum of the crystal are shown in Figures 10c, 10d, and 10e.

X-ray diffraction pattern of huperzine formamidine crystal form II, the 2θ angle expressed in degrees is 4.836, 8.113, 9.475, 12.691, 13.935, 14.784, 17.015, 18.495, 20.311, 23.232, 24.062, 24.712, 27.158, 27.668, 28.245 have significant characteristic absorption peaks, see Figure 11b. The infrared spectrum and Raman spectrum of the crystal are shown in Figures 11d and 11e.

Huperzine methyl hydrochloride crystals, which are amorphous powders.

The infrared absorption spectrum, X-ray diffraction pattern and DSC thermogram of Huperzine Hydrochloride are shown in Figures 12a, 112b, and 112c.

The invention additionally provides a method for preparing polymorphs of four huperzine methyl salts, specifically:

Method 1: Huperzine methyl salt was added to an organic solvent, dissolved by heating to dissolve, slowly lowered to 25 ° C, crystals were precipitated and stirred for 12 hours; filtered, and the solid was collected and dried under reduced pressure for 24 hours.

Method 2: Huperzine methyl salt was added to an organic solvent, heated under reflux for 12 hours with stirring, and the temperature was slowly lowered to 25 ° C, filtered, and the solid was collected and dried under reduced pressure for 24 hours.

Method 3: Huperzine methyl salt was added to an organic solvent, dissolved by heating under stirring, concentrated to dryness under reduced pressure, and dried under vacuum for 24 hours.

Method 4: Add the huperzine methyl salt to dimethyl sulfoxide or N, N-dimethylformamide, stir to dissolve, slowly add organic solvent, precipitate crystals and stir for 12 hours; filter, collect The solid was dried under reduced pressure for 24 hours.

The organic solvent includes all organic solvents, as long as it has a certain solubility to the huperzine methyl salt and does not deteriorate. The organic solvent used in this patent uses acetone, ethanol, ethyl acetate, acetonitrile, and aqueous acetone.

The present invention also encompasses a pharmaceutical preparation comprising the huperzine methyl salt of the present invention or a polymorph thereof, which is selected from any of the pharmaceutical dosage forms suitable for administration, such as tablets, capsules, pills, granules. , powders, suppositories, films, oral solutions, sprays and injections.

The pharmaceutical preparation of the present invention is particularly suitable for preparation into a liquid preparation or a soluble preparation such as an oral solution, a large-volume injection, a small-volume injection, a dry powder injection, a freeze-dried injection or the like.

The invention is particularly suitable for the preparation of oral orally soluble preparations, such as dropping pills, orally disintegrating tablets, buccal tablets, granules, dispersible tablets and the like.

Compared with the prior art, the product (-)-huperzine methyl salt or its polymorph and its preparation, the salt-refining process further improves the product quality of the Huperzine methyl salt, and the content can be More than 99.9%, the total impurity content is less than 0.1%, and its quality stability is better than Huperzine A, which is beneficial to the quality stability of the product storage period and preparation production, improve the quality of the final preparation product, and is beneficial to patients. Medication safety Sexuality, effectiveness.

The above-mentioned huperzine A according to the present invention refers to (-)-huperzine A.

The beneficial effects of the present invention are illustrated by experimental data below:

First, the solubility experiment

Experimental method: Weigh the test powder into a fine powder, shake it vigorously for 5 seconds every 5 minutes in a solvent with a certain volume of 25±2°C; observe the dissolution within 30 minutes, if it is not visible. When solute particles,

It is considered to be completely dissolved.

Expressed in the following terms:

Very soluble, means that 1g of solute can be dissolved in less than 1ml;

Soluble means that 1 g of solute can be dissolved in 1 to less than 10 ml;

Dissolution means that 1 g of solute can be dissolved in 10 to less than 30 ml;

Slightly soluble means that 1 g of solute can be dissolved in 30 to less than 100 ml;

Microsolute means that 1g of solute can be dissolved in 100~ less than 1000ml;

Very slightly soluble means that 1g of solute can be dissolved in 1000~ less than 10000ml;

Almost insoluble or insoluble means that 1 g of solute can not be completely dissolved in 10,000 ml.

Experimental results:

Second, the dissolution rate experiment

Experimental method: Take 1g of the solubility test sample, shake it vigorously in a solvent of 10±25°C at 20±2°C, dissolve completely in 1 minute to be extremely fast, completely dissolve in 3 minutes, dissolve completely in 10 minutes, completely dissolve in 10 minutes. slow.

Experimental results:

The present invention also finds that huperzine methyl salt has an improved taste and is particularly suitable for the preparation of instant oral preparations such as dropping pills, orally disintegrating tablets, buccal tablets, oral liquids, dispersible tablets and the like.

According to the present invention, the following crystal forms of huperzine methyl salt, hydrobromide crystal, sulfate crystal form I, sulfate crystal form II, phosphate crystal, acetate crystal form I, B were found. Acid crystal form II, acetate crystal form III, fumarate crystal, lactate crystal, citrate crystal form I, citrate crystal form II, hydrochloride crystal.

Unexpectedly discovered by the present invention, the above crystal form has good stability, and stability test is carried out for this purpose. The test conditions are: temperature 40±2° C., RH 75±5%; test basis: “Chinese Pharmacopoeia” 2010 edition 2; number of tests: 0 months, 1 month, 2 months, 3 months, 6 months. The test results are as follows:

The experimental results show that the quality stability of the Huperzine M salt of the present invention is higher than that of Huperzine A.

DRAWINGS

Figure 1a ¹ H NMR of the Huperzine Hydrobromide Salt of the Invention

Figure 1b X-ray powder diffraction pattern of the Huperzine Hydrobromide salt of the present invention

Figure 1c DSC scan of the Huperzine Hydrobromide salt of the present invention

Figure 1d IR IR absorption spectrum of Huperzine hydrobromide salt of the present invention

Figure 1e shows the Raman spectrum of the Huperzine hydrobromide salt of the present invention

Figure 2a ¹ H NMR of the Huperzine Methyl Sulfate Salt of the Invention

Figure 2b X-ray powder diffraction pattern of Huperzine Methanesulfate Form I of the present invention

Figure 2c DSC scan of the Huperzine Methanesulfate Form I of the present invention

Figure 2d IR IR absorption spectrum of Huperzine Methane sulfate Form I of the present invention

Figure 2e shows the Raman spectrum of the Huperzine Methanesulfate Form I of the present invention

Figure 3b X-ray powder diffraction pattern of Huperzine Methanesulfate Form II of the present invention

Figure 3c DSC scan of the Huperzine Methanesulfate Form II of the present invention

Figure 3d IR IR absorption spectrum of Huperzine Methanesulfate Form II of the present invention

Figure 3e shows the Raman spectrum of the Huperzine Methanesulfate Form II of the present invention

Figure 4a ¹ H NMR of the Huperzine Methyl Phosphate of the Invention

Figure 4b X-ray powder diffraction pattern of the Huperzine Methyl Phosphate of the present invention

Figure 4c DSC scan of the Huperzine Methyl Phosphate of the present invention

Figure 4d IR IR absorption spectrum of the Huperzine Methyl Phosphate of the present invention

Figure 4e shows the Raman spectrum of the Huperzine Methyl Phosphate of the present invention

Figure 5a ¹ H NMR of the Huperzine Methacetate of the present invention

Figure 5b X-ray powder diffraction pattern of Huperzine Methyl Acetate Form I of the present invention

Figure 5c DSC scan of the crystalline form I of Huperzine Methacetate of the present invention

Figure 5d IR IR absorption spectrum of Huperzine meacetate crystal form I of the present invention

Figure 5e is a Raman spectrum of the crystalline form I of Huperzine meacetate of the present invention

Figure 6b X-ray powder diffraction pattern of Huperzine Methacetate Form II of the present invention

Figure 6c DSC scan of the Huperzine Methacetate Form II of the present invention

Figure 6d IR IR absorption spectrum of Huperzine meacetate crystal form II of the present invention

Figure 6e shows the Raman spectrum of the Huperzine meacetate crystal form II of the present invention

Figure 7b X-ray powder diffraction pattern of Huperzine Methyl Acetate Form III of the present invention

Figure 7c DSC scan of the crystalline form III of Huperzine Methacetate of the present invention

Figure 7d IR IR absorption spectrum of Huperzine meacetate crystal form III of the present invention

Figure 7e shows the Raman spectrum of the crystalline form III of Huperzine meacetate of the present invention

Figure 8a ¹ H NMR of the Huperzine Methyl Fumarate of the present invention

Figure 8b X-ray powder diffraction pattern of the Huperzine Methyl Fumarate of the present invention

Figure 8c DSC scan of the Huperzine Methyl Fumarate of the present invention

Figure 8d IR IR absorption spectrum of the huperzine methyl fumarate of the present invention

Figure 8e shows the Raman spectrum of the Huperzine Methyl Fumarate of the present invention

Figure 9a ¹ H NMR of the Huperzine Lactate of the present invention

Figure 9b X-ray powder diffraction pattern of the Huperzine Lactate of the present invention

Figure 9c DSC scan of the Huperzine Lactate of the present invention

Figure 9d IR IR absorption spectrum of the Huperzine Lactate of the present invention

Figure 9e shows the Raman spectrum of the Huperzine Lactate of the present invention

Figure 10a ¹ H NMR of the Huperzine Formate of the present invention

Figure 10b X-ray powder diffraction pattern of the huperzine formamidine crystal form I of the present invention

Figure 10c DSC scan of the huperzine formamidine crystal form I of the present invention

Figure 10d IR IR absorption spectrum of the huperzine formamidine crystal form I of the present invention

Figure 10e Raman spectrum of the huperzine formamidine crystal form I of the present invention

Figure 11b X-ray powder diffraction pattern of the Huperzine Formate Form II of the present invention

Figure 11c DSC scan of the Huperzine Formate Form II of the present invention

Figure 11d IR IR absorption spectrum of the huperzine formazan crystal form II of the present invention

Figure 11e shows the Raman spectrum of the huperzine formamidine crystal form II of the present invention

Figure 12a IR IR absorption spectrum of the Huperzine methyl hydrochloride of the present invention

Figure 12b X-ray powder diffraction pattern of the Huperzine Methyl Hydrochloride of the present invention

Figure 12c DSC scan of the Huperzine Methyl Hydrochloride of the present invention

detailed description:

The invention is further illustrated by the following examples without intending to limit the invention.

Experimental conditions:

XRPD: In the present invention, the XRPD spectrum was detected by a Bruker Advance X-ray diffractometer, and the 2θ angle scan was from 5 to 45 degrees, Cu-Ka radiation.

DSC: The DSC spectrum in the present invention was detected by a DSC8500 differential scanning calorimeter from a US PE company, the atmosphere was nitrogen, and the heating rate was 10 ° C / min.

IR: The infrared spectrum of the present invention is detected by a Bruker Tenso 227 infrared absorption spectrometer with a detection range of 4000-350 wave numbers.

Raman: In the present invention, the Raman spectrum is detected by a DXR micro-Raman spectrometer with a detection range of 3500-50 cm ^-1 Raman shift.

Example 1: Preparation of Huperzine Methyl Hydrochloride

12.1 g of (-)-huperzine A was reacted with about 8.5 ml of 1:1 hydrochloric acid in 60 ml of 1:1 ethanol-water (V/V) solution to form a Huperzine Hydrochloride solution, and the pH of the solution was adjusted to 3.5-5.5. Within the scope, the above-prepared huperzine methylamine solution was filtered (0.45 μ), washed with a small amount of ethanol-water solution, and the combined washings and filtrates were distilled off in a water bath (70-90 ° C) to remove the solvent, and then added. Anhydrous ethanol, dissolved by heating, cooled to room temperature, and then added about 200 ml of acetone, stirred to form a mixed solvent, cooled to about 0 ° C, filtered, washed with acetone, and crystallized by vacuum drying to obtain 11.8 g of Huperzine hydrochloride. The solid powder was determined by X-ray diffraction, and the specific spectrum is shown in Figure 12b.

Example 1: Preparation of Huperzine Hydrobromide

12.1 g of (-)-huperzine A was suspended in 120 ml of acetone, and after stirring uniformly, 17.7 g of hydrobromic acid (48%) was added, and the mixture was stirred for 10 minutes, and the mixture was clarified, stirring was continued for 1 hour, and the solution was added dropwise to 1200 ml of acetone. The white solid gradually precipitated, stirring was continued for 3 h, cooled to about 0 ° C, filtered, and the filter cake was rinsed with acetone and dried under vacuum at 45 ° C for 12 h to give a solid 12.8 g.

Example 2: Preparation of Huperzine Hydrobromide Crystal Form

0.3 g of Huperzine hydrobromide was added to 2.5 mL of dimethyl sulfoxide, stirred and dissolved, and 15 mL of acetone was slowly added dropwise. After the addition, the mixture was stirred for 4 hours, filtered, and the filter cake was rinsed with acetone. Drying at 45 ° C for 4 hours under vacuum gave 0.26 g of crystalline powder, which was determined by X-ray powder diffraction. The specific spectrum is shown in Figure 1b.

Example 3: Preparation of Huperzine Methyl Sulfate

The 12.1 g of Huperzine A crude product was suspended in 120 ml of acetone, and after stirring evenly, 5.2 g was slowly added dropwise. Sulfuric acid was added dropwise, stirring was continued for 1 hour, and filtration was carried out. The filter cake was rinsed with acetone and dried under vacuum at 45 ° C for 12 h to give a solid 11.6 g.

Example 4: Preparation of Huperzine Methylsulfate Form I

0.3 g of Huperzine methyl sulfate was added to 10 mL of ethanol, heated to reflux for 1 hour, the system was clarified, and the temperature was slowly lowered to room temperature with stirring. Stirring was continued for 2 hours, and the filter cake was rinsed with ethanol, and the solid was at 45 ° C. The mixture was vacuum dried for 4 hours to obtain 0.22 g of a crystalline powder, which was determined by X-ray powder diffraction, and the obtained crystalline powder was Huperzine Methanesulfate Form I, and the specific spectrum is shown in Fig. 2b.

Example 5: Preparation of Huperzine Methylsulfate Form II

0.3 g of Huperzine Methyl Sulfate was added to 10 mL of acetone/water (95/5), heated to reflux for 1 hour, the system was clarified, slowly cooled to room temperature with stirring, stirring was continued for 2 hours, and filtration was carried out, and the filter cake was acetone/water. (95/5) After washing once, the solid was vacuum dried at 45 ° C for 4 hours to obtain 0.20 g of a crystalline powder, which was determined by X-ray powder diffraction, and the obtained crystalline powder was Huperzine Methionite Form II, specifically The spectrum is shown in Figure 3b.

Example 6: Preparation of Huperzine Methyl Phosphate

12.10g of Huperzine A crude product was suspended in 100ml acetone/water (2/1), and after stirring evenly, 10.3g of phosphoric acid (85%) was slowly added dropwise, the system gradually thickened, and the addition was completed, and stirring was continued for 1 hour. For clarification, the above solution was added to 1500 mL of acetone, a large amount of solid was precipitated, stirring was continued for 4 hours, and filtration was carried out. The filter cake was rinsed with acetone and dried under vacuum at 45 ° C for 12 hours to obtain a solid (13.6 g).

Example 7: Preparation of Huperzine Methyl Phosphate Crystal Form

0.3 g of Huperzine Methyl Phosphate was added to 2.5 mL of NN-dimethylformamide, heated under reflux for 2 hours, slowly cooled to room temperature, stirring was continued for 2 hours, filtered, and the filter cake was rinsed with acetone, solid at 45 Drying under vacuum at °C for 4 hours gave 0.28 g of crystalline powder, which was measured by X-ray powder diffraction. The specific spectrum is shown in Fig. 4b.

Example 8: Preparation of Huperzine Methacetate and Form I

12.1 g of Huperzine A crude product was suspended in 120 ml of acetone, and after stirring uniformly, 12.6 g of acetic acid was slowly added dropwise, and the system was gradually clarified. Stirring was continued for 1 hour, a large amount of solid was precipitated, stirring was continued for 5 hours, and filtration was carried out, and the cake was filtered with acetone. Washing, vacuum drying at 45 ° C for 12 h, to obtain a solid 12.5 g, the X-ray powder diffraction measurement, the obtained crystalline powder is Huperzine mesylate crystal form I, the specific spectrum see Figure 5b.

Example 9: Preparation of Huperzine Methacetate Form II

Add 0.3 g of Huperzine Methacetate Form I to 10 mL of acetone, heat to reflux for 1 hour, slowly cool to room temperature with stirring, continue stirring for 2 hours, filter, filter cake with acetone, once again, solid at 45 ° C After drying in a vacuum for 4 hours, 0.25 g of a crystalline powder was obtained, which was determined by X-ray powder diffraction, and the obtained crystalline powder was Huperzine mesylate crystal form II, and the specific spectrum is shown in Fig. 6b.

Example 10: Preparation of Huperzine Methyl Acetate Form III

0.3 g of Huperzine Methacetate Form I was added to 10 mL of acetonitrile, heated to reflux for 1 hour, the system gradually clarified, slowly cooled to room temperature with stirring, and the solid was precipitated, stirring was continued for 2 hours, filtered, and the filter cake was rinsed with acetonitrile. Once again, the solid was vacuum dried at 45 ° C for 4 hours to obtain 0.23 g of a crystalline powder, which was determined by X-ray powder diffraction, and the obtained crystalline powder was Huperzine mesylate crystal form III, and the specific spectrum is shown in Fig. 7b.

Example 11: Preparation of Huperzine Methyl Fumarate

12.1 g of Huperzine A crude product was suspended in 60 ml of acetone/water (10/1), and after stirring uniformly, 12.95 g of fumaric acid was slowly added dropwise, the system was gradually thickened, 20 mL of acetone was added, stirring was continued for 5 hours, and filtration was carried out. The cake was rinsed with acetone and dried under vacuum at 45 ° C for 12 h to afford 16.2 g.

Example 12: Preparation of Huperzine Methyl Fumarate Crystal Form

0.3 g of huperzine methyl fumarate was added to 10 mL of ethyl acetate, heated under reflux for 1 hour, slowly cooled to room temperature with stirring, stirring was continued for 2 hours, filtered, and the filter cake was washed with ethyl acetate. Drying at 45 ° C for 4 hours under vacuum gave 0.27 g of crystalline powder, which was determined by X-ray powder diffraction. The specific spectrum is shown in Figure 8b.

Example 13: Preparation of Huperzine Lactate and Crystal Form

12.1 g of Huperzine A crude product was suspended in 120 ml of acetone, and after stirring uniformly, 11.6 g of lactic acid was slowly added, the system gradually thickened, heated to 60 ° C, the system gradually clarified, stirring was continued for 1 hour, a large amount of solid precipitated, and stirring was continued. After filtration, the filter cake was rinsed with acetone and dried under vacuum at 45 ° C for 12 h to obtain a solid of 13.9 g. The crystalline powder obtained by X-ray powder diffraction was the crystal form of huperzine lactate. Figure 9b.

Example 14: Preparation of Huperzine Formate

20.3 g of citric acid was dissolved in 120 ml of acetone/water (2/1), and after stirring, 12.1 g of crude huperzine A was added, the system was gradually clarified, stirring was continued for 1 hour, and the above solution was added to 1200 mL of acetone. A large amount of solid precipitated, stirring was continued for 4 hours, filtered, and the filter cake was rinsed with acetone at 45 ° C. Drying for 12 h, gave a solid 20.6 g.

Example 15: Preparation of Huperzine Forminate Form I

0.3 g of huperzine formate was added to 10 mL of ethanol, heated to reflux for 1 hour, slowly cooled to room temperature with stirring, stirring was continued for 2 hours, filtered, and the filter cake was rinsed with ethanol, and the solid was vacuumed at 45 ° C. After drying for 4 hours, 0.27 g of a crystalline powder was obtained, and the obtained crystalline powder was determined by X-ray powder diffraction to be a huperzine formamidine crystal form I. The specific spectrum is shown in Fig. 10b.

Example 16: Preparation of Huperzine Formate Form II

0.3 g of huperzine formate was added to 10 mL of acetonitrile, heated to reflux for 1 hour, slowly cooled to room temperature with stirring, stirring was continued for 2 hours, filtered, and the filter cake was rinsed once with acetonitrile, and the solid was vacuumed at 45 ° C. After drying for 4 hours, 0.28 g of a crystalline powder was obtained, which was measured by X-ray powder diffraction, and the obtained crystalline powder was huperzine formate crystal form II, and the specific spectrum is shown in Fig. 11b.

Example 17: Preparation of Huperzine Methyl Hydrochloride

12.1 g of (-)-huperzine A was reacted with about 8.5 ml of 1:1 hydrochloric acid in 60 ml of 1:1 ethanol-water (V/V) solution to form a Huperzine Hydrochloride solution, and the pH of the solution was adjusted to 3.5-5.5. Within the scope, the above-prepared huperzine methylamine solution was filtered (0.45 μ), washed with a small amount of ethanol-water solution, and the combined washings and filtrates were distilled off in a water bath (70-90 ° C) to remove the solvent, and then added. Anhydrous ethanol, dissolved by heating, cooled to room temperature, and then added about 200 ml of acetone, stirred to form a mixed solvent, cooled to about 0 ° C, filtered, washed with acetone, and crystallized by vacuum drying to obtain 11.8 g of Huperzine hydrochloride. The solid powder was determined by X-ray diffraction, and the specific spectrum is shown in Figure 12b.

The preparation method of the huperzine hydrochloride tablet of Example 18 is as follows:

prescription:

The above ingredients were uniformly mixed, granulated by 20 mesh, sieved and sized, dried, and compressed into 1000 pieces.

Example 19

The preparation method of the Huperzine hydrochloride mouth-containing tablet is as follows:

prescription:

Method: fully dissolve the Huperzine Hydrochloride in dilute ethanol, and become a dispersion of Huperzine Hydrochloride. Spray the starch, maltose, tannic acid, sweet polysaccharide, and strontium which have been mixed and evenly passed through the 80 mesh sieve. In the auxiliary materials consisting of citric acid, vitamin C, honey and aspartame, stir well until uniform, add magnesium stearate to mix evenly, and compress it.

Example 20

The preparation method of huperzine hydrochloride mouth-breaking tablet is as follows:

prescription

Method: fully dissolve the Huperzine Hydrochloride in a solvent, add Polysorbate 80, stir evenly, and become a dispersion of Huperzine Hydrochloride. Spray the uniformly mixed croscarmellose sodium, A. In the auxiliary materials composed of cellulose, citric acid, mannitol and aspartame, stir well until uniform, add magnesium stearate to mix evenly, and compress it.

Example 21

The preparation method of huperzine hydrochloride granules is as follows:

System of law:

1. Pretreatment of raw materials: sucrose, citric acid, sodium citrate were crushed through a 100 mesh sieve and used.

2. The oxalipine hydrochloride A is sufficiently dissolved in dilute ethanol to prepare a dispersion of Huperzine Hydrochloride.

3. Preparation of the binder: Dissolve 5% PVP and K30 in 95% ethanol, stir well, and set aside.

4. The sifted sucrose powder, citric acid and citric acid are mixed and granulated by high-efficiency wet method.

Mix in the machine, then spray the dispersion of Huperzine Hydrochloride in separate portions, mix well, add the binder to make soft material, 12 mesh sieve, dry, 12 mesh sieve, 60 mesh The sieve is removed from the fine powder, the total mixture, after the particle inspection is qualified, the package is obtained, and the package is obtained.

Example 22

The preparation method of Huperzine Hydrochloride A capsule is as follows:

prescription:

The oxalipine hydrochloride and the solvent are dissolved into a solution, and the above components are added and stirred uniformly. After granulation by a wet granulation method, the granules are sieved, dried, microcrystalline cellulose is added, and 1000 capsules are obtained by capsule filling.

Example 23

The preparation method of Huperzine Hydrochloride A capsule is as follows:

prescription

The oxalipine hydrochloride and the solvent are dissolved into a solution, and the above components are added and stirred uniformly. After granulation by a wet granulation method, the granules are sieved, dried, microcrystalline cellulose is added, and 1000 capsules are obtained by capsule filling.

Example 24

The preparation method of the Huperzine Hydrochloride A Drop Pill is as follows:

prescription

Huperzine hydrochloride 0.058g

Polyethylene glycol 4000 60.0g

Ethanol

The oxalipine hydrochloride and the solvent are dissolved into a solution, and the above components are added, melted and mixed uniformly, and dropped into 5-10C liquid paraffin or dimethyl silicone oil to form a pellet, rubbed with oil, and dried to prepare 1000 pellets.

Example 25

The preparation method of the Huperzine Hydrochloride A Drop Pill is as follows:

prescription

Huperzine hydrochloride 0.058g

Polyethylene glycol 6000 60.0g

Ethanol

The huperzine hydrochloride A is dissolved uniformly with an appropriate amount of solvent, and mixed with the already melted polyethylene glycol 6000, the temperature is 60-90 ° C, melted and stirred uniformly, and then transferred into the drip irrigation of the dropping machine (insulation 70-90) °C), dripping into liquid paraffin or methyl silicone oil at 5-17 ° C, taking out the dropping pills, removing liquid paraffin or methyl silicone oil, washing the pellets, and drying, to obtain 1000 pills (pill weight 50-60 mg).

Example 26

The preparation method of the lyophilized injection is as follows:

prescription

Huperzine hydrochloride 0.058%

Mannitol 50%

Sodium chloride 0.5%

The rest is water for injection. (Each unit contains -(-) Huperzine A 30-100μg)

Take the above raw materials, add appropriate amount of water for injection, adjust the pH to 3.5 ~ 5.5 to dissolve, add water to the mark, add 0.1-0.5% activated carbon, stir at 20-50 ° C for 10-60 minutes, decarburization, using micropores The filter membrane is sterilized by filtration, the filtrate is divided and packaged, and the white loose block is obtained by freeze-drying method, and the seal is obtained.

Example 27

The preparation method of small volume injection is as follows:

Prescription

Huperzine hydrochloride 0.058g

Sodium chloride 0.5%

The rest is water for injection (30-100μg of huperzine hydrochloride per unit)

Take the above raw materials, add appropriate amount of water for injection, adjust the pH to 3.5 ~ 5.5 to dissolve, add water to the scale, add 0.1-0.5% activated carbon, stir at 20-50 ° C for 10-60 minutes, decarbonization, fine filtration, irrigation Sealed to 1-10ml ampoules and sterilized.

Example 28

The preparation method of large-volume injection is as follows:

prescription

Huperzine hydrochloride 0.116g

Sodium chloride 0.5%

The rest is water for injection (30-100μg per unit cell/bag containing -(-) Huperzine A)

Take the above raw materials, add appropriate amount of water for injection, adjust the pH to 3.5-5.5 to dissolve, add water to the mark, add 0.1-0.5% activated carbon, stir at 20-50 ° C for 10-60 minutes, decarbonize, finely filter, Potted into a 100-1000ml injection container and sterilized.

Example 29

The preparation method of Huperzine Hydrochloride Oral Liquid is as follows:

prescription

System of law

Weighing 0.058 g of huperzine hydrochloride and 0.5 g of citric acid, adding 200 ml of purified water to dissolve all of them, adding 65% syrup, filtering, adding purified water to the whole amount, potting, sterilizing, and packaging.

Claims (69)

1. Solid crystal of (-)-huperzine methyl salt selected from the group consisting of the hydrochloride salt of huperzine A, hydrobromide salt, sulfate salt, phosphate salt, nitrate salt, acetate salt, three Fluoroacetate, lactate, citrate, tartrate, fumarate, mandelate, methanesulfonate, besylate, gluconate, ascorbate, pyruvate, alanine An acid salt, an aspartic acid salt, a lysine salt or an arginine salt.
2. The solid crystal according to claim 1, wherein the huperzine methyl salt is selected from the group consisting of oxaliline A hydrochloride, hydrobromide, sulfate, phosphate, acetate, fumarate, lactate. Or citrate.
3. A crystal of (-)-huperzine hydrobromide salt characterized by an X-ray powder diffraction pattern represented by a 2θ angle comprising the following characteristic peaks: 8.720, 10.560, 11.957, 13.381, 14.506, 15.253.
4. The (-)-huperzine hydrobromide crystal according to claim 3, wherein the crystalline X-ray powder diffraction pattern further comprises the following characteristic peaks: 16.109, 17.074, 17.488, 18.102, 18.932, 19.339, 20.249, 20.863.
5. The (-)-huperzine hydrobromide crystal according to claim 4, wherein the crystalline X-ray powder diffraction pattern further comprises the following characteristic peaks: 21.218, 21.968, 22.677, 23.074, 23.944, 24.437, 24.851, 25.343, 25.713, 25.974, 26.350, 26.943, 27.204, 28.028, 28.945, 30.318, 31.087.
6. The (-)-huperzine hydrobromide crystal according to any one of claims 3 to 5, wherein the crystalline DSC scan has an endothermic peak between 140 and 160 °C.
7. The (-)-huperzine hydrobromide crystal according to any one of claims 3 to 6, characterized in that the infrared absorption spectrum of the crystal is measured by KBr tableting at about 3421.10 cm ^{- 1} ,2854.13cm ^-1 , 2123.24cm ^-1 ,1668.12cm ^-1 ,1612.20cm ^-1 ,1540.84cm ^-1 ,1438.64cm ^-1 ,1317.14cm ^-1 ,1118.51cm ^-1 ,1018.23cm ^-1 ,950.73cm ^{- 1} , 829.24cm ^-1 has an absorption peak.
8. The (-)-huperzine hydrobromide crystal according to any one of claims 3 to 7, characterized in that the Raman spectrum measured by the crystallization is about 3390.23 cm ^-1 , 3164.6 cm ^-1 , 3037.38 cm ^-1 , 2968.87 cm ^-1 , 2912.00 cm ^-1 , 1667.22 cm ^-1 , 1617.17 cm ^-1 , 1563.41 cm ^-1 , 1426.89 cm ^-1 , 1429.50 cm ^-1 , 1251.41 cm ^-1 , 712.27 cm ^-1 , 677.96 cm ^-1 , 555.79 cm ^-1 , 465.79 cm ^-1 , 341.25 cm ^-1 has an absorption peak.
9. a (-)-huperzine methyl sulfate crystal selected from one of the following crystal forms: Huperzine methyl sulfate crystal Form I and Huperzine Methionine Form II.
10. The huperzine methyl sulfate crystal form I according to claim 9, wherein the X-ray powder diffraction pattern represented by the 2θ angle contains the following characteristic peaks: 7.442, 14.863, 21.693.
11. The huperzine methyl sulfate form II according to claim 9, wherein the X-ray powder diffraction pattern expressed by the angle 2θ contains the following characteristic peaks: 4.573, 6.434, 8.330, 9.512, 10.597.
12. The (-)-huperzine methyl sulfate crystal form II according to claim 11, wherein the X-ray powder diffraction pattern of the crystal further comprises the following characteristic peaks: 12.279, 13.577, 14.270, 15.161, 15.989, 16.968, 18.042, 18.475, 19.248.
13. The (-)-huperlin methyl sulfate form II according to claim 12, wherein the X-ray powder diffraction pattern of the crystal further comprises the following characteristic peaks: 20.116, 21.160, 22.585, 22.974, 24.081, 24.674, 25.858, 26.985, 27.476, 28.598.
14. The (-)-huperlin methyl sulfate form I according to any one of claims 9 to 10, characterized in that the infrared absorption spectrum of the crystal is measured by KBr tableting at about 3415.31 cm ^{- 1} ,2911.98cm ^-1 ,1644.98cm ^-1 ,1602.56cm ^-1 ,1554.34cm ^-1 ,1440.56cm ^-1 ,1357.64cm ^-1 ,1116.58cm ^-1 ,1047.16cm ^-1 ,835.03cm ^-1 ,593.97cm ^- There is an absorption peak at ¹ place.
15. The (-)-huperzine methyl sulfate crystal form II according to any one of claims 9 to 11-13, characterized in that the infrared absorption spectrum of the crystal is measured by KBr tableting at about 3421.10. Cm ^-1 ,2938.98cm ^-1 ,1698.98cm ^-1 ,1656.55cm ^-1 ,1610.27cm ^-1 ,1538.92cm ^-1 ,1444.42cm ^-1 ,1359.57cm ^-1 ,1120.44cm ^-1 ,1041.37cm ^-1 ,833.10 cm ^-1, absorption peaks at 593.97cm ^-1.
16. The (-)-huperlin methyl sulfate crystal form I according to any one of claims 9 to 10, wherein the crystallization-measured Raman spectrum is about 3407.92 cm ^-1 . 3391.11cm ^-1 , 3163.86cm ^-1 , 3070.00cm ^-1 , 2928.62cm ^-1 , 2910.95cm ^-1 , 2984.40cm ^-1 , 1667.22cm ^-1 ,1681.67cm ^-1 , 1576.30cm ^-1 ,1439.01cm ^-1 , 1385.71cm ^-1 , 1288.92cm ^-1 , 1213.51cm ^-1 , 989.62cm ^-1 , 880.17cm ^-1 , 721.09cm ^-1 , 663.40cm ^-1 , 559.30cm ^-1 , 345.15cm ^-1 have absorption peaks.
17. The (-)-huperzine methyl sulfate crystal form II according to any one of claims 9, 11 to 13, and 15, wherein the crystallization is measured in a Raman spectrum at about 3388.76 cm ^{- 1} , 3316.78 cm ^-1 , 3018.61 cm ^-1 , 2925.75 cm ^-1 , 2923.33 cm ^-1 , 1686.30 cm ^-1 , 1613.70 cm ^-1 , 1560.08 cm ^-1 , 1450.71 cm ^-1 , 1260.14 cm ^-1 , 983.59 cm ^{- 1} , 714.93 cm ^-1 , 661.80 cm ^-1 , 606.15 cm ^-1 , 554.65 cm ^-1 , 461.93 cm ^-1 , 344.47 cm ^-1 , and 221.62 cm ^-1 have absorption peaks.
18. A (-)-huperzine methyl phosphate crystal characterized by an X-ray powder diffraction pattern represented by a 2 theta angle comprising the following characteristic peaks: 4.677, 6.613, 7.363, 8.033, 9.869.
19. The (-)-huperzine methyl phosphate crystal according to claim 18, wherein the crystalline X-ray powder diffraction pattern further comprises the following characteristic peaks: 11.338, 11.924, 13.112, 13.519, 14.843, 16.955 , 17.862, 19.048, 19.934.
20. The (-)-huperzine methyl phosphate crystal according to claim 19, wherein the crystalline X-ray powder diffraction pattern further comprises the following characteristic peaks: 21.297, 22.346, 23.567, 24.198, 25.049, 25.957 , 27.674, 28.661, 31.582.
21. The (-)-huperzine methyl phosphate crystal according to any one of claims 18 to 20, wherein the crystalline DSC scan has an endothermic peak between 155 and 180 °C.
22. The (-)-huperzine methyl phosphate crystal according to any one of claims 18 to 21, wherein the infrared absorption spectrum of the crystal is measured by KBr tableting at about 3421.10 cm ^-1 , 2935.13 cm ^-1 , 1165.55 cm ^-1 , 1610.27 cm ^-1 , 1552.42 cm ^-1 , 1437.71 cm ^-1 , 1307.50 cm ^-1 , 1116.58 cm ^-1 , 954.59 cm ^-1 , 512.97 cm ^-1 have absorption peaks.
23. The (-)-huperzine methyl phosphate crystal according to any one of claims 18 to 22, having a Raman spectrum measured, which is characterized by being about 3338.85 cm ^-1 , 3164.32 cm ^-1 , and 291.92 cm ^{- 1} ,1684.12cm ^-1 , 1560.29cm ^-1 , 1437.63cm ^-1 , 1268.43cm ^-1 , 722.70cm ^-1 , 661.55cm ^-1 , 559.39cm ^-1 , 340.37cm ^-1 There is an absorption peak.
24. a crystal of (-)-huperzine meacetate selected from one of the following crystal forms: Huperzine mesylate Form I, Huperzine Formate Form II, and Huperzine Formate Crystal form III
25. The Huperzine Methacetate Form I according to Claim 24, characterized in that the X-ray powder diffraction pattern represented by the 2θ angle contains the following characteristic peaks: 5.210, 9.238, 10.363, 13.579, 14.944.
26. The (-)-huperzine mesylate form I according to claim 25, wherein the crystalline X-ray powder diffraction pattern further comprises the following characteristic peaks: 15.829, 18.356, 20.332, 20.942, 22.225 .
27. The Huperzine Methacetate Form II according to Claim 24, characterized in that the X-ray powder diffraction pattern represented by the 2θ angle contains the following characteristic peaks: 7.737, 9.259, 11.332, 11.745, 12.811, 13.797, 14.568.
28. The (-)-huperzine mesylate form II according to claim 27, wherein the crystalline X-ray powder diffraction pattern further comprises the following characteristic peaks: 15.535, 16.935, 17.942, 18.652, 19.363 , 20.054, 20.507.
29. The (-)-huperzine mesylate salt form II according to claim 28, wherein the crystalline X-ray powder diffraction pattern further comprises the following characteristic peaks: 21.158, 21.989, 22.424, 23.411, 24.733 , 25.722, 27.418, 29.113, 29.588, 30.201.
30. The Huperzine Methacetate Form III according to Claim 24, characterized in that the X-ray powder diffraction pattern represented by the 2θ angle contains the following characteristic peaks: 5.444, 9.356, 10.797, 12.376, 14.547, 15.497.
31. The (-)-huperzine mesylate form III according to claim 30, wherein the crystalline X-ray powder diffraction pattern further comprises the following characteristic peaks: 16.167, 18.121, 18.713, 19.502, 21.830 , 22.502, 23.074, 23.628.
32. The (-)-huperzine mesylate form III according to claim 31, wherein the crystalline X-ray powder diffraction pattern further comprises the following characteristic peaks: 24.416, 24.871, 26.213, 26.668, 27.319 , 30.477, 32.844, 34.721, 35.194, 36.042.
33. The (-)-huperzine mesylate form I according to any one of claims 24 to 26, wherein the crystalline DSC scan has a first endothermic peak between 95 and 115 °C. There is a second endothermic peak between 220 and 230 °C.
34. The (-)-huperzine mesylate form II according to any one of claims 24, 27-29, wherein the crystalline DSC scan has a first draw between 130-140 °C The heat peak has a second endothermic peak between 220 and 240 °C.
35. The (-)-huperzine mesylate form III according to any one of claims 24, 30-32, wherein the crystalline DSC scan has a first endotherm between 110 and 130 °C. The peak has a second endothermic peak between 220 and 240 °C.
36. The (-)-huperzine mesylate crystal form I according to any one of claims 24 to 26, wherein the infrared absorption spectrum of the crystal is measured by KBr tableting. 3405.67cm ^-1 , 2933.20cm ^-1 , 1654.48cm ^-1 , 1612.20cm ^-1 , 1550.49cm ^-1 , 1455.99cm ^-1 , 1403.92cm ^-1 , 1307.50cm ^-1 , 1122.37cm ^-1 ,835.03cm ^-1 , There is an absorption peak at 659.54 cm ^-1 .
37. The (-)-huperzine mesylate salt form II according to any one of claims 24, 27-29, and 34, wherein the infrared absorption spectrum of the crystal is measured by KBr tableting, At about 3367.10cm ^-1 , 2925.48cm ^-1 , 1716.34cm ^-1 , 1666.20cm ^-1 , 1602.56cm ^-1 , 1554.34cm ^-1 , 1461.78cm ^-1 , 1303.64cm ^-1 , 1174.44cm ^-1 , 925.66cm ^{- 1} , 850.45cm ^-1 , 665.32cm ^-1 has an absorption peak.
38. The (-)-huperzine mesylate crystalline form III according to any one of claims 24, 30-32, and 35, wherein the infrared absorption spectrum of the crystal is measured by KBr tableting, At about 3428.81 cm ^-1 , 2929.34 cm ^-1 , 1662.34 cm ^-1 , 1608.34 cm ^-1 , 1548.56 cm ^-1 , 1455.99 cm ^-1 , 1409.71 cm ^-1 , 1305.57 cm ^-1 , 1122.37 cm ^-1 , 836.95 cm ^{- 1} , 657.61 cm ^-1 has an absorption peak.
39. The (-)-huperzine mesylate form I according to any one of claims 24-26, 33, 36, wherein the crystallization-measured Raman spectrum is at about 3333.30 cm ^-1 ,3164.15cm ^-1 ,2922.67cm ^-1 ,1681.23cm ^-1 ,1561.08cm ^-1 ,1458.68cm ^-1 ,1261.36cm ^-1 ,918.09cm ^-1 ,718.23cm ^-1 ,661.46cm ^-1 ,556.29cm There is an absorption peak at ^-1 .
40. The (-)-huperzine mesylate salt form II according to any one of claims 24, 27-29, 34, 37, wherein the crystallization-measured Raman spectrum is about 3392.02cm ^-1 ,3302.50cm ^-1 ,3164.45cm ^-1 ,3049.02cm ^-1 ,2928.21cm ^-1 ,2893.87cm ^-1 ,1683.93cm ^-1 ,1603.11cm ^-1 ,1552.50cm ^-1 ,1453.65cm ^-1 , 1426.19cm ^-1 , 1258.07cm ^-1 , 1216.94cm ^-1 , 712.34cm ^-1 , 663.04cm ^-1 , 556.53cm ^-1 , 346.39cm ^-1 have an absorption peak.
41. The (-)-huperzine mesylate form III according to any one of claims 24, 30-32, 35, 38, wherein the crystallization-measured Raman spectrum is about 3316.23cm ^-1 ,3164.44cm ^-1 ,3164.44cm ^-1 ,3016.49cm ^-1 ,2931.97cm ^-1 ,2908.91cm ^-1 ,2252.29cm ^-1 ,1679.66cm ^-1 ,1594.26cm ^-1 ,1563.70cm ^-1 , 1459.18cm ^-1 , 1431.31cm ^-1 , 1412.84cm ^-1 , 1264.15cm ^-1 , 939.14cm ^-1 , 718.92cm ^-1 , 662.04cm ^-1 , 342.25cm ^-1 have absorption peaks.
42. A (-)-huperzine methyl fumarate crystal characterized by an X-ray powder diffraction pattern represented by a 2θ angle comprising the following characteristic peaks: 7.837, 11.033, 12.221, 12.611, 13.185, 14.785.
43. The (-)-huperlin methyl fumarate crystal according to claim 42, wherein the crystalline X-ray powder diffraction pattern further comprises the following characteristic peaks: 15.711, 17.134, 19.068, 19.778, 20.765. There are obvious characteristic absorption peaks at 21.416, 22.187, 22.780, 23.607, 24.477.
44. The (-)-huperzine mfumarate crystal according to any one of claims 42-43, wherein the infrared absorption spectrum of the crystal is measured by KBr tableting at about 3496.31 cm ^-1 ,3235.97cm ^-1 , 2906.20cm ^-1 ,1666.20cm ^-1 ,1542.77cm ^-1 ,1463.71cm ^-1 ,1363.43cm ^-1 ,1295.93cm ^-1 ,1178.29cm ^-1 ,985.45cm ^-1 ,831.17cm ^-1 , 638.32cm ^-1 has an absorption peak.
45. The (-)-huperzine methyl fumarate crystal according to any one of claims 42 to 44, wherein the crystallization-measured Raman spectrum is at about 3338.42 cm ^-1 , 3164.31 Cm ^-1 ,3048.74cm ^-1 , 2957.30cm ^-1 ,2908.54cm ^-1 ,1679.25cm ^-1 ,1658.79cm ^-1 ,1554.66cm ^-1 ,1467.73cm ^-1 ,1258.83cm ^-1 ,720.88cm ^-1 Absorption peak.
46. A (-)-huperzine formyl lactate crystal characterized by an X-ray powder diffraction pattern represented by a 2 theta angle comprising the following characteristic peaks: 5.980, 9.316, 10.934, 12.356, 13.895, 14.880.
47. The (-)-huperzine methyl lactate crystal according to claim 46, wherein the crystalline X-ray powder diffraction pattern further comprises the following characteristic peaks: 15.733, 16.185, 17.646, 18.260, 18.949, 21.456, 22.344, 22.937, 23.905, 24.656, 25.956.
48. The (-)-huperzine formyl lactate crystal according to any one of claims 46 to 47, wherein the crystalline DSC scan has an endothermic peak between 170 and 180 °C.
49. The (-)-huperzine-methyl lactate crystal according to any one of claims 46 to 48, wherein the infrared absorption spectrum of the crystal is measured by KBr tableting at about 3141.46 cm ^{- 1} ,2937.05cm ^-1 ,1743.33cm ^-1 ,1658.48cm ^-1 ,1608.34cm ^-1 ,1554.34cm ^-1 ,1452.14cm ^-1 ,1122.37cm ^-1 ,833.10cm ^-1 , 661.46cm ^-1 has absorption peak .
50. The (-)-huperzine mesylate crystal according to any one of claims 46 to 49, wherein in the Raman spectrum measured by the crystallization, at about 3388.08 cm ^-1 , 3164.03 cm ^-1 ,3103.92cm ^-1 ,2937.89cm ^-1 ,1691.41cm ^-1 ,1678.33cm ^-1 ,1607.34cm ^-1 ,1560.42cm ^-1 ,1450.64cm ^-1 ,1422.18cm ^-1 ,1262.82cm ^-1 ,718.23cm There is an absorption peak at ^-1 .
51. A crystal of (-)-huperzine mesylate selected from one of the following crystalline forms: Huperzine Formate Form I and Huperzine Formate Form II.
52. The (-)-huperlin mesylate crystal form I according to claim 51, wherein the X-ray powder diffraction pattern expressed by the angle 2θ contains the following characteristic peaks: 8.227, 9.492, 10.936, 12.887 , 13.478, 13.699, 14.270, 15.278.
53. The (-)-huperlin mesylate crystal form I according to claim 52, wherein the crystalline X-ray powder diffraction pattern further comprises the following characteristic peaks: 16.699, 17.370, 18.633, 19.028, 20.803, 21.495, 22.029, 22.560, 23.075, 24.774.
54. The (-)-huperlin mesylate crystalline form I according to claim 53, wherein the crystalline X-ray powder diffraction pattern further comprises the following characteristic peaks: 25.480, 26.767, 27.576, 28.106 , 28.521, 29.312, 30.515, 31.265, 32.036, 33.299, 34.541.
55. The (-)-huperlin mesylate crystal form II according to claim 51, wherein the X-ray powder diffraction pattern represented by the 2θ angle contains the following characteristic peaks: 4.836, 8.113, 9.475, 12.691 , 13.935, 14.784.
56. The (-)-huperlin mesylate crystal form II according to claim 55, wherein the crystal X-ray powder diffraction pattern further comprises the following characteristic peaks: 17.015, 18.495, 20.311, 23.232 , 24.062, 24.712, 27.158, 27.668, 28.245.
57. The (-)-huperlin mesylate form I according to any one of claims 51-54, wherein the crystalline DSC scan has an endothermic peak between 200 and 220 °C.
58. The (-)-huperlin mesylate form II according to any one of claims 51, 55-56, wherein the crystalline DSC scan has an endotherm between 175 and 185 °C. peak.
59. The (-)-huperlin mesylate crystal form I according to any one of claims 51-54, 57, wherein the infrared absorption spectrum of the crystal is measured by KBr tableting, There are absorption peaks at about 3405.67 cm ^-1 , 3087.48 cm ^-1 , 2096.24 cm ^-1 , 1658.48 cm ^-1 , 1608.34 cm ^-1 , 1538.92 cm ^-1 , 1224.58 cm ^-1 , 885.17 cm ^-1 , 509.12 cm ^-1 . .
60. The (-)-huperlin mesylate crystal form II according to any one of claims 51, 55-56, and 58, wherein the infrared absorption spectrum of the crystal is measured by KBr tableting. Fig., at about 3384.46 cm ^-1 , 2944.77 cm ^-1 , 2541.72 cm ^-1 , 1716.34 cm ^-1 , 1163.41 cm ^-1 , 1577.49 cm ^-1 , 1407.78 cm ^-1 , 1344.14 cm ^-1 , 1216.15 cm ^-1 , 1132.01 cm ^-1, absorption peaks at 630.61cm ^-1.
61. The (-)-huperlin mesylate crystal form I according to any one of claims 51-54, 57, 59, wherein the crystallization-measured Raman spectrum is about 3407.75cm ^-1 ,3397.83cm ^-1 ,3386.28cm ^-1 ,3164.85cm ^-1 ,2936.09cm ^-1 ,2878.17cm ^-1 ,2836.09cm ^-1 ,1683.95cm ^-1 ,1561.16cm ^-1 ,1455.23cm ^-1 , 1283.47cm ^-1 ,1224.94cm ^-1 ,1174.39cm ^-1 ,1045.24cm ^-1 ,950.12cm ^-1 ,717.69cm ^-1 ,669.31cm ^-1 ,560.61cm ^-1 ,363.64cm ^-1 ,265.69cm ^-1 There are absorption peaks.
62. The (-)-huperlin mesylate crystal form II according to any one of claims 51, 55-56, 58 and 60, wherein in the Raman spectrum measured by the crystallization, There are absorption peaks at about 3324.13 cm ^-1 , 3313.76 cm ^-1 , 3290.48 cm ^-1 , 3255.24 cm ^-1 , 3164.72 cm ^-1 , 2946.53 cm ^-1 , 1448.17 cm ^-1 , 1287.52 cm ^-1 , 724.22 cm ^-1 . .
63. A crystal of (-)-huperlin hydrochloride, characterized by being an amorphous powder.
64. The (-)-huperzine mehydrochloride crystal according to claim 63, wherein the crystalline DSC scan has an endothermic peak between 130 and 140 °C.
65. The (-)-huperzine mehydrochloride crystal according to any one of claims 63 to 64, characterized in that the infrared absorption spectrum measured by KBr tableting is characterized by being about 3362.71 cm ^{- 1} ,2853.85cm ^-1 ,1700.61cm ^-1 ,1653.77cm ^-1 ,1600.93cm ^-1 ,1522.44cm ^-1 ,1437.21cm ^-1 ,1356.81cm ^-1 ,1304.73cm ^-1 ,1201.69cm ^-1 ,1120.79cm ^{- 1} , 832.33 cm ^-1 , 659.33 cm ^-1 , and 512.85 cm ^-1 have absorption peaks.
66. The method for producing (-)-huperzine methyl salt crystal according to any one of claims 1 to 5, wherein the method comprises the following steps:

    (1) Suspending a Huperzine A in an organic solvent, stirring uniformly, adding the corresponding acid, and continuing to stir, and solids are formed during the process; wherein the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, and acetic acid Ester, acetone, tetrahydrofuran, acetonitrile or a mixed solvent with water; (-)-huperzine methyl and acid molar ratio of 1:1 to 1:2.

    (2) filtration, the filter cake is rinsed with an organic solvent, and dried to obtain a huperzine methyl salt;

    (3) adding the Huperzine methyl salt to the solvent, heating to dissolve it under stirring, slowly cooling to 25 ° C, crystallizing, filtering, and drying; wherein the solvent is selected from the group consisting of: acetone, ethanol, ethyl acetate, Acetonitrile, aqueous acetone, dimethyl sulfoxide or N,N-dimethylformamide.
67. The preparation method according to Claim 66, wherein when the corresponding acid is hydrobromic acid, the preparation method of Huperzine Hydrobromide is as follows:

    (1) Suspending a Huperzine A in acetone, stirring uniformly, adding hydrobromic acid, and stirring for further 2 hours, during which a large amount of solid is formed; wherein the solvent is selected from the group consisting of: a mixed solvent of acetone and water, acetone and The ratio of water is 1:1-50:1, the weight ratio of (-)-huperzine A to solvent is 1:30-100, and the molar ratio of (-)-huperzine A to hydrobromic acid is 1:1. To 1:2;

    (2) Cooling to about 0 ° C, filtration, acetone washing, the amount of acetone is 10 to 50 times the weight of (-)-huperzine A, and the crystals are dried by vacuum to obtain the Huperzine hydrobromide salt.

    (3) adding huperzine hydrobromide to the solvent, heating to dissolve it under stirring, slowly cooling to 25 ° C, crystallizing, filtering, and drying; wherein the solvent is selected from the group consisting of: acetone, ethanol, acetic acid Ethyl ester, acetonitrile, aqueous acetone, dimethyl sulfoxide or N,N-dimethylformamide.
68. The preparation method according to claim 66, wherein when the corresponding acid is hydrochloric acid, the preparation method of huperzine methyl hydrochloride is as follows:

    0.1 mol(-)-huperzine A was reacted with about 8.5 ml of 1:1 hydrochloric acid in 60 ml of 1:1 ethanol-water (V/V) solution to form a Huperzine Hydrochloride solution, and the pH of the solution was adjusted to 3.5-5.5. Within the scope, the above-prepared huperzine methylamine solution was filtered (0.45 μ), washed with a small amount of ethanol-water solution, and the combined washings and filtrates were distilled off in a water bath (70-90 ° C) to remove the solvent, and then added. Anhydrous ethanol, dissolved by heating, cooled to room temperature, and then added about 200 ml of acetone, stirred to form a mixed solvent, cooled to about 0 ° C, filtered, washed with acetone, and crystallized by vacuum drying to obtain Huperzine Hydrochloride.
69. A pharmaceutical preparation containing solid crystals of (-)-huperzine methyl salt according to claim 1, wherein the pharmaceutical preparation is selected from the group consisting of tablets, capsules, pills, granules, powders, suppositories, and films. Agents, oral liquids, sprays and injections.

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