CN106995397A - R Amisulprides pharmaceutical salts, preparation method, crystal formation and application thereof - Google Patents

Abstract

The present invention relates specifically to R - amisulpride medicinal salt, preparation method, crystal form and its application in the preparation of medicines for treating diabetes. The preparation method is as follows: 2 - aminomethyl - N - ethylpyrrolidine As a raw material, use L -tartaric acid to resolve to obtain ( R )-2-aminomethyl- N -ethylpyrrolidine; amiic acid is directly combined with ( R )-2 under the catalysis of isopropyl chloroformate and triethylamine Aminomethyl- N -ethylpyrrolidine is condensed to obtain R -amisulpride; the R -amisulpride obtained in step (2) is reacted with an acid to obtain R -amisulpride medicinal salt, the preparation method It has the advantages of simple operation, high safety, good product quality and low cost, and is convenient for large-scale production.

Description

R-amisulpride medicinal salt, preparation method, crystal form and use thereof

technical field

The invention relates to the field of medicines, in particular to R -amisulpride medicinal salt, preparation method, crystal form and application thereof.

Background technique

Amisulpride, English name: Amisulpride, chemical name: 4-amino- N -[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxy benzamide. It is a new type of non-classic antipsychotic drug developed by Sanofi-Synthelabo (Sanofi-Synthelabo) in France. Listed in China, the current domestic market demand is relatively wide, which has far-reaching economic and social significance. However, compared with traditional antipsychotic drugs, amisulpride has a low risk of inducing weight gain, diabetes and extrapyramidal side effects. At present, the clinical drug form of amisulpride is administered as a racemate.

Studies have shown that S -amisulpride, the active isomeric form of racemic amisulpride, is twice as potent as the racemic form and is more effective in its ability to bind to dopamine D2 and dopamine _{D3 receptors} 19 to 38 times larger than R -amisulpride. Due to the weak affinity of R-amisulpride for dopamine D2 and dopamine _{D3 receptors} , R -amisulpride is considered to have no antipsychotic activity. At present, there are few researches on R-amisulpride, and no research on the medicinal salt of R-amisulpride has been carried out in the prior art.

Contents of the invention

The technical problem to be solved by the present invention is to provide R -amisulpride medicinal salt, and at the same time provide the preparation method of the salt to be used and the crystal form and the use of R-amisulpride medicinal salt in the preparation of medicines for treating diabetes.

In order to solve the above problems, the technical solution of the present invention is as follows:

On the one hand, the present invention provides a pharmaceutically acceptable salt of R -amisulpride shown in formula 1:

1

Wherein: n is 1/2 or 1; X is an acid radical, and the acid radical is selected from hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, formic acid, benzoic acid, maleic acid, fumaric acid, Acid radical of malic, tartaric, dibenzoyltartaric or citric acid.

Preferably, the acid group is selected from tartaric acid, hydrochloric acid, sulfuric acid or fumaric acid.

Preferably, the acid group is selected from L -tartaric acid, hydrochloric acid or sulfuric acid.

Another aspect of the present invention provides the preparation method shown in formula 1, specifically comprising the following steps:

(1) Using 2-aminomethyl- N -ethylpyrrolidine as raw material, adopting L -tartaric acid resolution to obtain ( R )-2-aminomethyl- N -ethylpyrrolidine;

(2) Aminoic acid is directly condensed with ( R )-2-aminomethyl- N -ethylpyrrolidine obtained in step (1) under the catalysis of isopropyl chloroformate and triethylamine to obtain R -amisulfuridine profit;

(3) Reaction of R -amisulpride obtained in step (2) with an acid to obtain formula 1.

The synthetic route is shown in formula I:

Preferably, the step (1) specifically includes: using 2-aminomethyl- N -ethylpyrrolidine as a raw material, adding L -tartaric acid, reacting at a temperature of 25-30°C for 1-3 hours, and then adding NaOH, obtained by hydrolysis.

Preferably, the molar ratio of L -tartaric acid to 2-aminomethyl- N -ethylpyrrolidine is 0.5-1.3:1.

Preferably, the mol ratio of L -tartaric acid and 2-aminomethyl- N -ethylpyrrolidine is 0.6～0.9:1

Preferably, recrystallization is performed with methanol prior to addition of NaOH.

Preferably, the volume-mass ratio of L -tartaric acid to methanol is 1:5-1:7, the crystallization temperature is 10-15°C, and the crystallization time is 1-2 hours.

Preferably, the mass percentage of the sodium hydroxide is 25-40%, the hydrolysis temperature is 25-30°C, and the volume-mass ratio of sodium hydroxide to 2-aminomethyl-N-ethylpyrrolidine is 1:0.5- 0.9.

Preferably, the hydrolysis time is 1 to 3 hours.

Preferably, the mol ratio of amamiic acid, triethylamine, isopropyl chloroformate and R -2-aminomethyl-N-ethylpyrrolidine in the step (2) is 1:1.0~2.0:1.2~ 1.6:1.1~1.7.

Preferably, the mol ratio of amamiic acid, triethylamine, isopropyl chloroformate and R -2-aminomethyl-N-ethylpyrrolidine in the step (2) is 1:1.27~1.8:1.34~ 1.5:1.30~1.5.

Preferably, the reaction temperature in the step (2) is 10-15° C., the reaction time is 0.5-1 hour, and then moved to room temperature and stirred for 1-3 hours.

Preferably, the step (3) is to react R -amisulpride with an acid in an organic solvent, then cool down and stir to crystallize to obtain a pharmaceutically acceptable salt of R -amisulpride.

Preferably, the molar ratio of R -amisulpride and acid in the step (3) is 1:1~1.5.

Preferably, the organic solvent is selected from methanol/ether mixed solvent, methanol/acetone mixed solvent or methanol.

Preferably, the crystallization temperature in the step (3) is 0-5°C, and the crystallization time is 3-5 hours.

Preferably, the crystallization temperature in the step (3) is -10~-20°C, and the crystallization time is 0.5~1.5 hours.

Another aspect of the present invention provides the crystalline or amorphous form of the pharmaceutically acceptable salt represented by Formula 1.

Preferably, the crystalline or amorphous form of the pharmaceutically acceptable salt represented by Formula 1 is selected from:

Crystal form A of R -amisulpride- L -tartrate;

Amorphous form of R -amisulpride hydrochloride;

Amorphous form of R -amisulpride sulfate.

The crystal form A of the R -amisulpride L -tartrate salt has characteristic peaks at the following positions: 10.25 ± 0.2, 12.69 ± 0.2, 13.70 ±0.2, 13.95±0.2, 15.49±0.2, 15.84±0.2, 16.06±0.2, 16.32±0.2, 19.13±0.2, 19.36±0.2, 21.42±0.2, 22.08±0.2, 22.48±0.2; preferably expressed in degrees 2θ The X-ray powder diffraction pattern has characteristic peaks at the following positions: 10.25±0.2, 12.69±0.2, 13.70±0.2, 13.95±0.2, 15.49±0.2, 15.84±0.2, 16.06±0.2, 16.32±0.2, 17.11±0.2, 17.54 ±0.2, 17.77±0.2, 19.13±0.2, 19.36±0.2, 21.42±0.2, 22.08±0.2, 22.48±0.2, 23.07±0.2, 24.36±0.2, 25.22±0.2, 26.92±0.2.

The powder X-ray diffraction pattern of the crystal form A of the R -amisulpride- L -tartrate salt is shown in Figure 1.

The powder X-ray diffraction spectrum of the amorphous form of the R -amisulpride hydrochloride is shown in Figure 2.

The powder X-ray diffraction spectrum of the amorphous form of the R -amisulpride sulfate is shown in Figure 3.

The preparation method of the crystalline or amorphous R -amisulpride medicinal salt is as follows: R -amisulpride medicinal salt is added to methanol, dissolved by heating, hot-filtered, cooled to crystallize, and kept stirring , filtered, and dried, the volume-to-mass ratio of R-amisulpride medicinal salt to methanol is 1g:4-6ml.

The temperature-rising dissolution means heating to 55-60°C for dissolution.

The heat preservation and stirring system is stirred for 1.5-2.5 hours at 10-15°C.

The last aspect of the present invention provides the use of the pharmaceutically acceptable salt represented by formula 1 in the preparation of a medicament for treating diabetes.

The use of the pharmaceutically acceptable salt represented by formula 1 in the preparation of medicines for treating diabetes is to use it as an active ingredient, plus pharmaceutically acceptable adjuvants or auxiliary ingredients to prepare a preparation.

The administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include, but are not limited to: oral administration, parenteral administration or topical administration. For oral administration, including but not limited to capsules, tablets, pills, powders, granules, emulsions, solutions, suspensions, syrups or tinctures. For parenteral administration, including but not limited to injection solutions, dispersions or powders. For topical administration, it includes but is not limited to ointments, powders, patches, sprays and inhalants.

The beneficial effects produced by adopting the above-mentioned technical scheme are:

The pharmaceutically acceptable salt of R -amisulpride provided by the invention can significantly lower blood sugar and has better curative effect on treating diabetes.

The preparation method of R -amisulpride medicinal salt of the present invention solves the problem of avoiding the use of a large amount of expensive chiral reagents in the preparation process of R-amisulpride-medicinal salt, and has the advantages of simple operation, high safety and high product quality. The advantages of good quality, high optical purity and low cost are convenient for large-scale production.

The crystalline or amorphous form of R -amisulpride medicinal salt provided by the present invention has the characteristics of stable properties and good solubility, and can be conveniently applied in various dosage forms in pharmacy.

Description of drawings

Accompanying drawing 1 is the powder X-ray diffraction spectrum of the crystal form A of R -amisulpride- L -tartrate;

Accompanying drawing 2 is the powder X-ray diffraction spectrum of the amorphous form of R -amisulpride hydrochloride;

Accompanying drawing 3 is the powder X-ray diffraction spectrum of the amorphous form of R -amisulpride sulfate;

Accompanying drawing 4 is R, the high performance liquid phase chromatogram of S -amisulpride optical purity determination;

Accompanying drawing 5 is S -amisulpride- D -tartrate optical purity determination high performance liquid phase chromatogram;

Accompanying drawing 6 is R -amisulpride- L -tartrate optical purity determination high performance liquid chromatography.

detailed description

In order to make the object, technical solution and advantages of the present invention clearer, the invention will be clearly and completely described below in conjunction with specific embodiments.

Example 1 Synthesis of R -2-aminomethyl- N -ethylpyrrolidine- L -tartrate

Add 45.6 g of L -tartaric acid into 60 mL of distilled water, stir until it is completely dissolved, slowly add 30 g of 2-aminomethyl-N-ethylpyrrolidine dropwise, and keep the temperature between 25°C and 30°C during the dropwise addition After the addition, stir at room temperature for 1 h, then add 260 ml of methanol to the reaction flask, stir at 12±2°C for 2 h, filter, and wash the filter cake once with 20 ml of methanol. Filter, add the filter cake to 190 ml of 75% methanol, heat until clarified, naturally cool down to 20±2°C, stir for 1 h, filter with suction, rinse with 15 ml of methanol, and dry to obtain a colorless solid.

Dissolve 11 g of R -2-aminomethyl- N -ethylpyrrolidine- L -tartrate in 60 ml of distilled water, add 36 g of 30% sodium hydroxide solution dropwise, after the drop is completed, store at 20±2°C Stir for 1 h, extract with dichloromethane (30 ml×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and rotary evaporate to dryness.

The synthesis of embodiment 2 R -amisulpride

Dissolve 10 g of amimic acid and 4.96 g of triethylamine in 50 ml of acetone, cool down to 5°C, slowly add 5.6 g of isopropyl chloroformate dropwise, after the dropwise completion, keep stirring for 0.5 h, then slowly add in Example 1 Prepare 6.42 g of R -2-aminomethyl- N -ethylpyrrolidine in 25 mL of acetone solution, after dropping, stir at 12°C for 0.5 h, then move to room temperature and stir for 1 h. After rotary evaporation, water was added and extracted with dichloromethane (25 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness to obtain a yellow-brown oil.

The synthesis of embodiment 3 R -amisulpride maleic acid

Heat 10 g of R -amisulpride prepared in Example 2 and 35 ml of methanol to dissolve it, add 4.06 g of maleic acid in methanol solution 15 ml, stir at 45°C for 5h, cool to 3°C and stir for 3h, and precipitate A large number of crystals were suction filtered and dried to obtain 10.9 g of the product with a yield of 83% and an optical purity of ee%=100%.

Example 4 Synthesis of R -amisulpride L -tartaric acid

Add R-amisulpride (50g, 0.135mol) and 190ml of methanol prepared in Example 2 into a 500ml reaction bottle, heat up and stir, and add L-tartaric acid (21.3g, 0.142mol) and 90ml of methanol dropwise at a temperature of 40~50°C. After the dropwise addition, keep stirring for 2 hours, lower the temperature to -10~-20°C and stir for 1 hour, filter, wash the filter cake with a small amount of cold methanol, and dry it with air at 45°C to obtain 61.11g of the product. The yield is 87%, and the optical purity is ee %=100%.

The synthesis of embodiment 5 R -amisulpride hydrochloride

Add the R-amisulpride (5g, 0.0135mol) prepared in Example 2 into the 50ml reaction bottle, dissolve 10ml of ether in 2ml of methanol and dilute it, stir at room temperature, add the mixture of 2g of saturated hydrogen chloride ether solution and 10ml of ether dropwise under temperature control, drop After the addition, keep stirring for 2 hours, lower the temperature to -10~-20°C and stir for 1 hour, filter, wash the filter cake with a small amount of cold ether, and blow dry at 45°C to obtain 4.12g of the product. The yield is 75%, and the optical purity ee%=100% .

The synthesis of embodiment 6 R -amisulpride sulfate

Add R-amisulpride (5g, 0.0135mol) prepared in Example 2 into a 50ml reaction bottle, dilute with 2ml of methanol and 10ml of ether, stir at 0~5°C, add 9g of 15% diethyl ether sulfate solution and 5ml of ether dropwise under temperature control After the dropwise addition, keep stirring for 2 hours, cool down to -10~-20°C and stir for 1 hour, filter, wash the filter cake with a small amount of cold ether, and dry at 45°C to obtain 5.43g of the product. The yield is 86%, and the optical purity is ee %=100%.

Example 7 Crystal form A of R -amisulpride- L -tartrate

Add 10 g of R -amisulpride L-tartrate obtained in Example 4 into 50 mL of methanol, heat up to 55-60 ° C, dissolve the solid, filter, and crystallize the filtrate at cooling temperature, stir at 10-15 ° C for 2 h, filter, and methanol The filter cake was washed and air-dried at 45°C to obtain 9.23 g of R -amisulpride- L -tartrate salt with a yield of 92.3%.

The X-ray powder diffraction pattern obtained by measuring the obtained R -amisulpride sulfate using Cu-Kα rays is shown in Figure 1.

Example 8 Amorphous Form of R -Amisulpride Hydrochloride

Add 1 g of R -amisulpride hydrochloride obtained in Example 5 into 5 mL of methanol, heat up to 55-60°C, dissolve the solid, filter, cool the filtrate to crystallize, stir at 10-15°C for 2h, filter, and wash with methanol The filter cake was air-dried at 45°C to obtain 0.8 g of R-amisulpride hydrochloride with a yield of 80%.

The X-ray powder diffraction pattern obtained by measuring the obtained R-amisulpride hydrochloride using Cu-Kα rays is shown in Figure 2.

Example 9 Amorphous Form of R -Amisulpride Sulfate

Add 1 g of R -amisulpride sulfate obtained in Example 6 into 5 mL of methanol, heat up to 55~60°C, dissolve the solid, filter, cool the filtrate to crystallize, stir at 10~15°C for 2h, filter, wash and filter with methanol The cake was blown-dried at 45°C to obtain 0.65 g of R -amisulpride sulfate with a yield of 65%.

The X-ray powder diffraction pattern obtained by measuring the obtained R-amisulpride sulfate using Cu-Kα rays is shown in Figure 2.

Test Example 1 Determination of Optical Purity

Instrument: high performance liquid chromatography

Reagents and solvents: diethylamine AR, chromatographic n-hexane, chromatographic ethanol

Chromatographic conditions:

Chromatographic column: ChiralpakAD-H (250mm×4.6mm, 5um)

Detection wavelength: 224nm

Flow rate: 0.6ml/min

Column temperature: 23°C

Mobile phase preparation: n-hexane solution (add 0.05 ml of diethylamine to 650 ml of n-hexane solution)-ethanol (65:35:0.05).

R,S -amisulpride reference substance solution: Accurately weigh 10 mg of R,S -amisulpride sample and place it in a 10ml volumetric flask, dissolve it in ethanol, and dilute to volume with ethanol as the stock solution, take 2ml of the stock solution in In a 10ml volumetric flask, dilute to volume, and prepare a 200μg/ml solution of the test product.

S -amisulpride- D -tartrate reference substance solution: Weigh 10 mg of the sample and place it in a 10 ml volumetric flask, dissolve it in ethanol, and dilute to volume with ethanol as the stock solution. Take 2 ml of the stock solution in a 10 ml volumetric flask, dilute to volume, and prepare a 200 μg/ml test solution.

The R -amisulpride- L -tartaric acid test solution prepared in Example 4: Weigh 10 mg of the sample and place it in a 10 ml volumetric flask, dissolve it in ethanol, and dilute to volume with ethanol as the stock solution. Take 2 ml of the stock solution in a 10 ml volumetric flask, dilute to volume, and prepare a 200 μg/ml test solution.

The R,S -amisulpride reference substance solution was measured and analyzed using the above-mentioned measuring conditions and instruments, and the retention time and optical purity were analyzed. The spectrum is shown in Figure 4.

The S -amisulpride- D -tartrate reference substance solution was measured and analyzed using the above-mentioned measuring conditions and instruments, and the retention time and optical purity were analyzed. The spectrum is shown in Figure 5.

Adopt above measuring condition and instrument to measure and analyze R -amisulpride- L -tartaric acid need testing solution, retention time and optical purity analysis, its collection of illustrative plates is shown in accompanying drawing 6, calculates the optical purity of sample by area normalization method is 100%.

R,S -Amisulpride reached the baseline separation, and the resolution was greater than 1.5. Compared with the chromatogram of the S -amisulpride- D -tartrate reference substance, it was determined that RT=8.237 was the S configuration, and RT=9.471 was the R configuration. structure.

Test example 2 Stability study of R -amisulpride- L -tartaric acid

1. Illumination experiment

Take the solid R -amisulpride- L -tartaric acid obtained in Example 4 and the R -amisulpride- L -tartaric acid crystal form A prepared in Example 7 and spread them in an appropriate amount on a petri dish (about 2 mm thick), place Place it under the condition of 4500Lx±500Lx strong light for 10 days, take samples on the 5th and 10th day, and use HPLC to detect the content and optical purity.

Table 1 Lighting experiment results

2. High temperature experiment

Take the solid R -amisulpride- L -tartaric acid obtained in Example 4 and the R -amisulpride- L -tartaric acid crystal form A prepared in Example 7 and spread them in an appropriate amount on a petri dish (about 2 mm thick), place Place it in a constant temperature box at 60°C for 10 days, take samples for detection on the 5th and 10th days, and use high performance liquid chromatography to detect the content and optical purity.

Table 2 Results of high temperature experiments

3. High humidity experiment

Take the solid R -amisulpride- L -tartaric acid obtained in Example 4 and the R -amisulpride- L -tartaric acid crystal form A prepared in Example 7 and spread them in an appropriate amount on a petri dish (about 2 mm thick), place Store at room temperature 25°C±2°C and relative humidity RH90±5% for 10 days, take samples for testing on the 5th and 10th days, and use HPLC to detect the content and optical purity.

Table 3 Results of high humidity experiment

4. Accelerated experiment

Take an appropriate amount of the solid R -amisulpride- L -tartaric acid obtained in Example 4 and the crystal form A of R -amisulpride- L -tartaric acid prepared in Example 7, and place it at 40°C and 75%RH for 6 months, at the end of the 1st, 2nd, 3rd, and 6th months, samples were taken for testing, and high performance liquid chromatography was used to detect the content and optical purity.

Table 4 accelerated test results

From the above experimental data, it can be known that the crystal form A of R -amisulpride- L -tartaric acid of the present invention is more stable than that of Example 4 under the conditions of light, high temperature, high humidity and accelerated experiments.

Test Example 3 Solubility of R -amisulpride- L -tartaric acid

The solubility of R -amisulpride- L -tartaric acid crystal form A in water is greater than that of R -amisulpride- L -tartaric acid obtained in Example 4 according to the 2005 edition of the Chinese Pharmacopoeia.

Stability study of test example 4 R -amisulpride hydrochloride

1. Illumination experiment

Take the solid R -amisulpride hydrochloride obtained in Example 5 and the amorphous form of R -amisulpride hydrochloride prepared in Example 8 and spread them on a petri dish (about 2mm thickness), place Place it under the condition of 4500Lx±500Lx strong light for 10 days, take samples on the 5th and 10th day, and use HPLC to detect the content and optical purity.

Table 5 Lighting experiment results

2. High temperature experiment

Take the solid R -amisulpride hydrochloride obtained in Example 5 and the amorphous form of R -amisulpride hydrochloride prepared in Example 8 and spread them on a petri dish (about 2mm thickness), place Place it in a 60°C incubator for 10 days, take samples for testing on the 5th and 10th days, and use high performance liquid chromatography to detect the content and optical purity.

Table 6 High temperature experiment results

3. High humidity experiment

Take the solid R -amisulpride hydrochloride obtained in Example 5 and the amorphous form of R -amisulpride hydrochloride prepared in Example 8 and spread them on a petri dish (about 2mm thickness), place Store at room temperature 25°C±2°C and relative humidity RH90±5% for 10 days, take samples for testing on the 5th and 10th days, and use HPLC to detect the content and optical purity.

Table 7 High humidity test results

4. Accelerated experiment

Take an appropriate amount of the solid R -amisulpride hydrochloride obtained in Example 5 and the amorphous form of R -amisulpride hydrochloride prepared in Example 8, and place 6 under the conditions of 40° C. and 75% RH month, at the end of the first, second, third, and sixth months, samples were taken for testing, and the content and optical purity were detected by high-performance liquid chromatography.

Table 8 accelerated experiment results

From the above experimental data, it can be seen that the stability of the amorphous form of R -amisulpride hydrochloride prepared in the present invention is better than that of Example 5 under the conditions of light, high temperature, high humidity and accelerated experiments.

Test example 5 Solubility of R -amisulpride hydrochloride

According to the 2005 edition of the Chinese Pharmacopoeia, the second general example seven (2) stipulates that the solubility of the R -amisulpride hydrochloride amorphous form in water is greater than that of the R -amisulpride hydrochloride obtained in Example 5.

Test example 6 Stability study of R -amisulpride sulfate

1. Illumination experiment

Take the solid R -amisulpride sulfate obtained in Example 6 and the amorphous form of the R -amisulpride sulfate prepared in Example 9 and spread it in a petri dish (about 2mm thickness), and place it at 4500Lx± Place it under the condition of 500Lx strong light for 10 days, take samples for detection on the 5th and 10th days, and use high performance liquid chromatography to detect the content and optical purity.

Table 9 Lighting experiment results

2. High temperature experiment

Take the solid R -amisulpride sulfate obtained in Example 6 and the amorphous form of R -amisulpride sulfate prepared in Example 9 and spread it on a petri dish (about 2mm thickness), and place it at 60°C Place in the incubator for 10 days, take samples for detection on the 5th and 10th days, and use high-performance liquid chromatography to detect the content and optical purity.

Table 10 High temperature test results

3. High humidity experiment

Take the solid R -amisulpride sulfate obtained in Example 6 and the amorphous form of the R -amisulpride sulfate prepared in Example 9 and spread them on a petri dish (about 2mm thickness), and place them at room temperature for 25 ℃±2℃ and relative humidity RH90±5% for 10 days, take samples on the 5th and 10th day, and use HPLC to detect the content and optical purity.

Table 11 High humidity test results

4. Accelerated experiment

Get the solid R -amisulpride sulfate obtained in Example 6 and the amorphous form of the R -amisulpride sulfate prepared in Example 9 in an appropriate amount, and place it at 40° C. and 75% RH for 6 months. At the end of the 1st, 2nd, 3rd, and 6th months, samples were taken for testing, and high performance liquid chromatography was used to detect the content and optical purity.

Table 12 accelerated test results

From the above experimental data, it can be seen that the stability of the amorphous form of R -amisulpride sulfate prepared by the present invention is better than that of Example 6 under the conditions of light, high temperature, high humidity and accelerated experiments.

Test example 7 Solubility of R -amisulpride sulfate

According to the 2005 edition of the Chinese Pharmacopoeia, the second general example seven (2) stipulates that the solubility of the R -amisulpride sulfate amorphous form in water is greater than that of the R -amisulpride sulfate obtained in Example 6.

Test Example 8 Oral Glucose Tolerance Test in Normal Mice

Eight-week-old Kunming mice, male, were randomly divided into 4 groups, with 10 mice in each group, and their body weights were recorded. Respectively blank control group: give 1.5ml normal saline orally; test group 1: give R -amisulpride- L -tartrate (3.0 μmol/kg) prepared in Example 4, dissolve with 1.5ml normal saline; Test group 2: administer the R -amisulpride hydrochloride (3.0 μmol/kg) prepared in Example 5, dissolve it orally with 1.5 ml of normal saline; test group 3: administer the R -amisulpride prepared in Example 5 Lisulfate (3.0 μmol/kg), dissolved in 1.5ml saline orally.

Before the experiment, the mice were fasted without food and water for 12 hours, and each group was administered orally by gavage, blood was taken from the tail vein, and the blood sugar value was measured (denoted as 0 min). Then the 4 groups of mice were given normal saline, R -amisulpride L-tartrate, R -amisulpride hydrochloride and R -amisulpride sulfate by intragastric administration respectively, and the blood glucose value was measured after 30 minutes and recorded as 30 minutes , and then immediately administered a glucose solution with a concentration of 3g/10ml by intragastric administration at 10ml/kg, and after 15min (recorded as 45min), after 30min (recorded as 60min), after 45min (recorded as 75min), after 60min (recorded as 90min), after 120min (recorded as 150min), measure the blood glucose level (mmol/L). The results are shown in Table 13.

Table 13 Changes in blood sugar levels

According to the oral glucose tolerance test of mice, the compounds in the test groups 1-3 can obviously improve the glucose tolerance of mice, showing a more significant hypoglycemic effect.

It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than limiting them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: it can still be Modifications are made to the technical solutions described in the foregoing embodiments, or equivalent replacements are made to some of the technical features; these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims (10)

1. A medicinal salt of R-amisulpride shown in formula 1: 1 Wherein: n is 1/2 or 1; X is an acid radical, and the acid radical is selected from hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, formic acid, benzoic acid, maleic acid, fumaric acid, Acid radical of malic, tartaric, dibenzoyltartaric or citric acid. 2. the preparation method of R-amisulpride medicinal salt as claimed in claim 1, is characterized in that, specifically comprises the steps: (1) Using 2-aminomethyl-N-ethylpyrrolidine as raw material, adopting L-tartaric acid resolution to obtain (R)--2-aminomethyl-N-ethylpyrrolidine; (2) Aminoic acid is directly condensed with the (R)-2-aminomethyl-N-ethylpyrrolidine obtained in step (1) under the catalysis of isopropyl chloroformate and triethylamine to obtain R-amisulfuridine profit; (3) react the R-amisulpride obtained in step (2) with an acid to obtain formula 1. 3. the preparation method of R-amisulpride medicinal salt as claimed in claim 1, is characterized in that, described step (1) is specifically: take 2-aminomethyl-N-ethylpyrrolidine as raw material , add L-tartaric acid, react at a temperature of 25-30°C for 1-3 hours, then add NaOH, and hydrolyze to obtain; Preferably, the molar ratio of L-tartaric acid and 2-aminomethyl-N-ethylpyrrolidine is 0.5~1.3:1; Preferably, the mol ratio of L-tartaric acid and 2-aminomethyl-N-ethylpyrrolidine is 0.6～0.9:1; Preferably, recrystallization with methanol prior to addition of NaOH; Preferably, the volume-to-mass ratio of the L-tartaric acid to methanol is 1:5-1:7, the crystallization temperature is 10-15°C, and the crystallization time is 1-2 hours; Preferably, the mass percentage of the sodium hydroxide is 25-40%, the hydrolysis temperature is 25-30°C, and the volume-mass ratio of sodium hydroxide to 2-aminomethyl-N-ethylpyrrolidine is 1:0.5- 0.9; Preferably, the hydrolysis time is 1 to 3 hours. 4. the preparation method of R-amisulpride medicinal salt as claimed in claim 1, is characterized in that, in described step (2), amic acid, triethylamine, isopropyl chloroformate and R-2 - The molar ratio of aminomethyl-N-ethylpyrrolidine is 1:1.0~2.0:1.2~1.6:1.1~1.7; Preferably, the mol ratio of amamiic acid, triethylamine, isopropyl chloroformate and R-2-aminomethyl-N-ethylpyrrolidine in the step (2) is 1:1.27~1.8:1.34~ 1.5:1.30~1.5; Preferably, the reaction temperature in the step (2) is 10-15° C., the reaction time is 0.5-1 hour, and then moved to room temperature and stirred for 1-3 hours. 5. the preparation method of R-amisulpride medicinal salt as claimed in claim 1, is characterized in that, described step (3) is that R-amisulpride and acid react in organic solvent, cooling and stirring crystallization , to obtain the pharmaceutically acceptable salt of R-amisulpride. 6. Preferably, the mol ratio of R-amisulpride and acid described in the step (3) is 1:1～1.5; Preferably, the organic solvent is selected from a mixed solvent of methanol/ether, a mixed solvent of methanol/acetone or methanol; Preferably, the crystallization temperature in the step (3) is 0-5°C, and the crystallization time is 3-5 hours; Preferably, the crystallization temperature in the step (3) is -10~-20°C, and the crystallization time is 0.5~1.5 hours; The crystalline or amorphous form of the pharmaceutically acceptable salt of R-amisulpride as claimed in claim 1. 7. The crystalline or amorphous form of the pharmaceutically acceptable salt of R-amisulpride according to claim 5, characterized in that it is selected from: Crystal form A of R-amisulpride-L-tartrate; Amorphous form of R-amisulpride hydrochloride; Amorphous form of R-amisulpride sulfate. 8. The crystallization or amorphous form of the medicinal salt of R-amisulpride according to claim 5, characterized in that, the crystal form A of the R-amisulpride-L-tartrate is used Cu-Ka radiation, X-ray powder diffraction pattern represented by 2θ has characteristic peaks at the following positions: 10.25±0.2, 12.69±0.2, 13.70±0.2, 13.95±0.2, 15.49±0.2, 15.84±0.2, 16.06±0.2, 16.32 ±0.2, 19.13±0.2, 19.36±0.2, 21.42±0.2, 22.08±0.2, 22.48±0.2; preferably, the X-ray powder diffraction pattern expressed in degrees 2θ has characteristic peaks at the following positions: 10.25±0.2, 12.69±0.2 , 13.70±0.2, 13.95±0.2, 15.49±0.2, 15.84±0.2, 16.06±0.2, 16.32±0.2, 17.11±0.2, 17.54±0.2, 17.77±0.2, 19.13±0.2, 19.36±0.2, 21.42±0.2, 22.08 ±0.2, 22.48±0.2, 23.07±0.2, 24.36±0.2, 25.22±0.2, 26.92±0.2. 9. The crystallization or amorphous form of the medicinal salt of R-amisulpride according to claim 5, characterized in that, the preparation method of the crystallization or amorphous form of the pharmaceutical salt of R-amisulpride As follows: R-amisulpride medicinal salt is added to methanol, dissolved by heating, hot filtered, cooled to crystallize, kept stirring, filtered, and dried. The R-amisulpride medicinal salt and methanol The volume to mass ratio is 1g:4-6ml; Preferably, the temperature-rising dissolution system is heated to 55-60°C for dissolution; Preferably, the insulated stirring system is stirred at 10-15°C for 1.5-2.5 hours. 10. The use of R-amisulpride medicinal salt as claimed in claim 1 in the preparation of a medicament for treating diabetes.