CN110804017A - Salt forming of sulfonylurea compound and metformin, preparation method and application - Google Patents

Abstract

The present invention relates to sulfonylurea compound and metformin salt formation, preparation method and application; the sulfonylurea compound and metformin are dissolved in a solvent according to a molar ratio of 1:0.9-1:1.1 to obtain a mixture; the mixture is reacted at 25-50 DEG C Crystallization for 12-48 hours; solid-liquid phase separation of the obtained product, drying to obtain a salt-type solid product. The sulfonylurea compound is glibanone or glyburide. The glyquinone-metformin salt and glyburide-metformin salt of the present invention are used in medicines for preventing and treating diabetes. Compared with metformin, the salt type product provided by the present invention has greatly improved hygroscopicity: when the relative humidity is 75%, the weight gain of metformin is 35%, and the weight gain of the salt type product is less than 1%. The solubility of the sulfonylurea compound is greatly improved: the solubility of the sulfonylurea compound in water is less than 0.02 mg/ml, and after salt formation, it is 10.61 and 16.78 mg/ml, respectively.

Description

Salt formation, preparation method and application of sulfonylurea compound and metformin

technical field

The invention belongs to the technical field of chemical synthesis and crystallization, and in particular relates to salt formation of a sulfonylurea compound and metformin, a preparation method and an application; the sulfonylurea compound includes glibanone and glyburide, and the formed salt is glibanone - Metformin salts and glyburide-metformin salts.

Background technique

According to statistics, about 70-80% of drug candidates fail to be marketed due to defects in physicochemical properties. Therefore, improving the physicochemical properties of drugs is of great significance for the development of new drugs. In the pre-clinical research and development stage of drugs, new drug research and development companies usually use the active ingredients of drugs to form salts to improve the solubility, dissolution rate, hygroscopicity, stability and bioavailability of drugs and other pharmaceutical properties. In the first half of 2017, the US Food and Drug Administration (FDA) approved a total of 23 new drugs, including 16 new molecular entities and 7 new biological products, and 8 of the 16 chemical drugs were marketed in the form of salts. Drug salt type refers to the introduction of new substances (salt-former) through proton transfer. When selecting these new substances, the traditional way is to introduce sodium, potassium, calcium, ammonium ions, etc. into acidic drugs, and hydrochloric acid. , sulfuric acid, maleic acid, etc. are introduced into basic drugs to form salts to improve the druggability, such as improving the stability of the drug to prolong the shelf life, and improving the solubility of the drug to improve the bioavailability. But in most cases, these new substances introduced are redundant and not pharmacologically active for the patient.

Gliquizone (C ₂₇ H ₃₃ N ₃ O ₆ S) and Glyburide (C ₂₃ H ₂₈ ClN ₃ O ₅ S) are both currently commonly used second-generation sulfonylurea anti-type 2 diabetes drugs. An insulin secretagogue, with better therapeutic effect and fewer side effects than the first-generation sulfonylurea drug tolbutamide. However, Gliquizone and Glyburide are Class II drugs (BCSII) in the biopharmaceutical classification system, with low solubility, so their pharmaceutical properties are not good. According to literature reports, different preparation methods can be used to improve their solubility. But the final result is not ideal. Metformin (C ₄ H ₁₁ N ₅ ) is a biguanide oral hypoglycemic drug against type 2 diabetes. However, metformin is unstable and easily hygroscopic, which is not conducive to the storage and transportation of drugs. It is common to form salts with hydrochloric acid to improve stability. However, the oral dose of metformin hydrochloride is relatively large, with a daily dose of about 500-1000 mg, and patients have to take an equimolar ratio of hydrochloride ions without hypoglycemic effect while taking metformin. Therefore, the problems of glibenclamide, glyburide and metformin themselves have not been well solved.

If the two are combined together, the acid ions that have no pharmacological activity in the traditional metformin hydrochloride are removed, and the two components are synthesized into a new salt-type compound, which not only preserves the respective therapeutic effects of the two drugs, but also helps to improve the single The stability and solubility of the drug will be of great value in the field of diabetes treatment.

SUMMARY OF THE INVENTION

One of the objectives of the present invention is to provide a simple, reproducible preparation method for salifying a sulfonylurea compound with metformin, which is suitable for industrial production.

The second purpose of the present invention is to provide a new, crystalline, stable, highly soluble salt-type product of sulfonylurea compound and metformin, including glyquinone-metformin salt and glyburide - Metformin salt.

In order to solve the problems of the prior art, the present invention proposes a salt formation, preparation method and application of a sulfonylurea compound and metformin.

The specific technical solutions are as follows:

A preparation method of sulfonylurea compound and metformin salt formation, comprising the following steps:

(1) dissolving the sulfonylurea compound and the metformin raw material in a solvent according to a molar ratio of 1:0.9 to 1:1.1 to obtain a mixture;

(2) reacting the mixture obtained in step (1) at 25-50° C. for 12-48 hours;

(3) solid-liquid phase separation of the product obtained in step (2) and drying to obtain a sulfonylurea compound and metformin salt-forming solid product.

The sulfonylurea compound is glibanone or glyburide.

The solvent is one or more of ethanol, acetone, acetonitrile or methyl acetate mixed in any proportion.

The sulfonylurea compound and metformin salt-forming product prepared by the method of the present invention is characterized in that its chemical structural formula is:

磺酰脲化合物为格列喹酮；Wherein: R substituent group is

The sulfonylurea compound is Gliquidone;

磺酰脲化合物为格列本脲。When the R substituent group is

The sulfonylurea compound is glyburide.

时，形成的盐为格列喹酮-二甲双胍盐，分子式为C₃₁H₄₄N₈O₆S，分子量为656.80，化学结构式为：Said sulfonylurea compound forms a salt with metformin, when the R substituent group is

When , the salt formed is Gliquizone-Metformin salt, the molecular formula is C ₃₁ H ₄₄ N ₈ O ₆ S, the molecular weight is 656.80, and the chemical structural formula is:

The Gliquizone-Metformin salt is in a crystalline state, and the diffraction angles represented by the 2θ angle are at 3.82±0.20°, 5.48±0.20°, 8.80±0.20°, 11.18±0.20°, 14.34±0.20°, 16.42±0.20 °, 17.40±0.20°, 17.84±0.20°, 20.42±0.20°, 23.38±0.20°, 27.02±0.20°, 28.00±0.20°, 29.22±0.20°, 30.78±0.20° have characteristic peaks;

Liquid ^1H -NMR (DMSO-d ₆ ) δ of the Gliquizone-Metformin salt: 7.62(d, 2H), 7.59(s, 1H), 7.54(d, 1H), 7.29( dd, 1H), 7.18(m, 4H), 6.63(s, 4H), 5.62(s, 1H), 4.09(m, 2H), 3.84(s, 3H), 3.16(s, 1H), 2.92(s , 6H), 2.83(m, 2H), 1.59(m, 4H), 1.46(m, 6H), 1.06(m, 6H); the differential scanning calorimetry analysis pattern of the Gliquizone-Metformin salt is in There is a characteristic melting peak at 183.5±5.0℃.

The sulfonylurea compound forms a salt with metformin, when the substituent , the formed salt is Glyburide-Metformin salt, the molecular formula is C ₂₇ H ₃₉ ClN ₈ O ₅ S, the molecular weight is 623.17, and the chemical structural formula is:

The glibenclamide-metformin salt is in a crystalline state and has diffraction angles expressed as 2θ angles at 7.36±0.20°, 10.72±0.20°, 11.14±0.20°, 12.34±0.20°, 13.94±0.20°, 15.05±0.20 degrees °, 26.90±0.20°, 29.12±0.20°.

Liquid ^1H -NMR (DMSO-d ₆ ) δ of the Glyburide-Metformin salt: 8.25(t, 1H), 7.66(m, 3H), 7.50(dd, 1H), 7.22( m, 4H), 7.14(d, 1H), 6.59(s, 4H), 5.60(s, 1H), 3.79(s, 3H), 3.50(dd, 2H), 3.17(s, 1H), 2.92(s , 6H), 2.83 (t, 2H), 1.15 (m, 10H); the differential scanning calorimetry analysis pattern of the glibenclamide-metformin salt has a characteristic melting peak at 176.8±5.0°C.

The Glyburide-Metformin salt and the Glyburide-Metformin salt provided by the present invention are also Glyburide, Glyburide and Metformin, and the pharmacodynamic groups are respectively a sulfonylurea group and a guanidine group. , and it still exists in the salt, and Gliquidone, Glyburide and Metformin have certain applications in the prevention or treatment of diabetes drugs, because their effects have been disclosed, Gliquidone-Metformin salt and Glycine The application of lebenclamide-metformin salt in the above diseases will not be repeated here.

The application of the glibenclamide-metformin salt and the glyburide-metformin salt of the present invention in the preparation of a medicament for preventing and treating diabetes.

The beneficial effects of the present invention are:

Compared with the single product of metformin, the hygroscopic stability of the glyquinone-metformin salt and glyburide-metformin salt provided by the invention is greatly improved: at 75% relative humidity, the salt has almost no hygroscopic weight gain. , Glyburide-Metformin salt is only 0.7%; Glyburide-Metformin salt is only 0.4%; and Metformin single product is wetted at 75% relative humidity and the weight gain is as high as 35%; and in terms of solubility, the present invention After the provided sulfonylurea compound is formed into a salt with metformin, compared with the single products of glibenclamide and glyburide, its solubility is greatly improved: the glibanone-metformin salt is dissolved in pure water. The solubility of Glyburide-Metformin salt in pure water is 16.783 mg/ml, and the solubility of Glyburide-Metformin salt in pure water is 16.783 mg/ml. The solubility of the single product of this urea in pure water is less than 0.001 mg/ml; at the same time, the preparation method of the salt is simple to operate, the crystallization process is easy to control, and the salt has good reproducibility.

Description of drawings

FIG. 1 is an X-ray powder diffraction (XRPD) pattern of the preparation of the Gliquizone-Metformin salt in acetonitrile;

Figure 2 is an X-ray powder diffraction (XRPD) pattern of the preparation of Gliquizone-Metformin salt in ethanol;

Figure 3 is an X-ray powder diffraction (XRPD) pattern of the preparation of the Gliquizone-Metformin salt in acetone;

Fig. 4 is the X-ray powder diffraction (XRPD) pattern of the preparation of Gliquizone-Metformin salt in acetonitrile-methyl acetate mixed solvent;

Figure 5 is an X-ray powder diffraction (XRPD) pattern of the preparation of glyburide-metformin salt in acetonitrile;

Figure 6 is an X-ray powder diffraction (XRPD) pattern of the preparation of glyburide-metformin salt in acetone;

Fig. 7 is the dynamic moisture adsorption (DVS) diagram of Gliquizone-Metformin salt;

Figure 8 is a dynamic moisture adsorption (DVS) graph of glibenclamide-metformin salt;

Figure 9 is a dynamic moisture adsorption (DVS) diagram of metformin feedstock;

Fig. 10 is the thermogravimetric analysis (TG) graph of Gliquizone-Metformin salt;

Figure 11 is a thermogravimetric (TG) graph of Glyburide-Metformin salt;

Figure 12 is a Differential Scanning Calorimetry (DSC) graph of Gliquizone-Metformin salt;

Figure 13 is a differential scanning calorimetry (DSC) graph of glyburide-metformin salt;

FIG. 14 is a liquid nuclear magnetic resonance ( ¹ H-NMR) image of Gliquizone-Metformin salt;

Figure 15 is a liquid state nuclear magnetic resonance ( ¹ H-NMR) diagram of gliquidone;

Figure 16 is a liquid nuclear magnetic resonance ( ¹ H-NMR) image of Glyburide-Metformin salt;

Fig. 17 is the liquid state nuclear magnetic ( ¹ H-NMR) image of glyburide raw material;

Figure 18 is the powder dissolution of Gliquizone-Metformin salt and Gliquizone raw material in simulated intestinal fluid (measured pH 6.9) within 240 minutes;

Figure 19 is the powder dissolution of glyburide-metformin salt and glyburide raw material in simulated intestinal fluid (measured pH 6.9) within 240 minutes.

Detailed ways

The present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention, but not to limit the present invention. Any improvements and changes made on the basis of the present invention still fall within the protection scope of the present invention.

Example 1

Take 52.7 mg of Glictazone and 13.0 mg of metformin (molar ratio of 1:1) into a 4 mL sample bottle, add 2 mL of acetonitrile, sonicate to dissolve and supersaturate, and react for crystallization at room temperature for 24 hours. The suspension was centrifuged, the supernatant was discarded, and the centrifuged solid was dried in a blast drying oven at 40°C for 3 hours to obtain the Gliquizone-Metformin salt. The diffraction angle represented by the 2θ angle in the XRPD results was in 3.82±0.20°, 5.48±0.20°, 8.80±0.20°, 11.18±0.20°, 14.34±0.20°, 16.42±0.20°, 17.40±0.20°, 17.84±0.20°, 20.42±0.20°, 23.38±0.20°, There are characteristic peaks at 27.02±0.20°, 28.00±0.20°, 29.22±0.20°, and 30.78±0.20°, as shown in Figure 1. The chemical structural formula is as follows:

Example 2

Take 52.7 mg of Gliquidone and 13.0 mg of metformin (molar ratio of 1:1) into a 4 mL sample bottle, add 2 mL of ethanol, sonicate to decompose and supersaturate, and react and crystallize at room temperature for 24 hours. The suspension was centrifuged, the supernatant was discarded, and the centrifuged solid was dried in a blast drying oven at 40°C for 3 hours to obtain the Gliquizone-Metformin salt. The diffraction angle represented by the 2θ angle in the XRPD results was in 3.82±0.20°, 5.48±0.20°, 8.80±0.20°, 11.18±0.20°, 14.34±0.20°, 16.42±0.20°, 17.40±0.20°, 17.84±0.20°, 20.42±0.20°, 23.38±0.20°, There are characteristic peaks at 27.02±0.20°, 28.00±0.20°, 29.22±0.20°, and 30.78±0.20°, as shown in Figure 2.

Example 3

Take 52.7mg of Gliquidone and 12.0mg of Metformin (molar ratio is 1:0.92) in a 4mL sample bottle, add 2mL of acetone, sonicate to dissolve and supersaturate, react and crystallize at 40°C for 12 hours, Centrifuge the suspension, discard the supernatant, and dry the centrifuged solid in a blast drying oven at 60°C for 1 hour to obtain the Gliquizone-Metformin salt. The diffraction angle represented by the 2θ angle in the XRPD results At 3.82±0.20°, 5.48±0.20°, 8.80±0.20°, 11.18±0.20°, 14.34±0.20°, 16.42±0.20°, 17.40±0.20°, 17.84±0.20°, 20.42±0.20°, 23.38±0.20° , 27.02±0.20°, 28.00±0.20°, 29.22±0.20°, 30.78±0.20° have characteristic peaks, as shown in Figure 3.

Example 4

Take 52.7mg of glitazone and 14.3mg of metformin (molar ratio is 1:1.1) in a 4mL sample bottle, add 2mL of acetonitrile-methyl acetate mixed solvent, ultrasonically, make it dissolved and supersaturated, at room temperature The reaction crystallized for 48 hours, the suspension was centrifuged, the supernatant was discarded, and the centrifuged solid was dried at room temperature and 25°C for 12 hours to obtain Gliquizone-Metformin salt, which is represented by the 2θ angle in the XRPD results. Diffraction angles are at 3.82±0.20°, 5.48±0.20°, 8.80±0.20°, 11.18±0.20°, 14.34±0.20°, 16.42±0.20°, 17.40±0.20°, 17.84±0.20°, 20.42±0.20°, 23.38± There are characteristic peaks at 0.20°, 27.02±0.20°, 28.00±0.20°, 29.22±0.20°, and 30.78±0.20°, as shown in Figure 4.

Example 5

Take 49.4 mg of glyburide and 13.0 mg of metformin (molar ratio of 1:1) into a 4 mL sample bottle, add 2 mL of acetonitrile, sonicate to dissolve and supersaturate, and react for crystallization at room temperature for 24 hours. The suspension was centrifuged, the supernatant was discarded, and the centrifuged solid was dried in a blast drying oven at 40°C for 3 hours to obtain glyburide-metformin salt. The diffraction angle represented by the 2θ angle in the XRPD results was 7.36±0.20°, 10.72±0.20°, 11.14±0.20°, 12.34±0.20°, 13.94±0.20°, 15.05±0.20°, 15.86±0.20°, 16.94±0.20°, 17.28±0.20°, 18.08±0.20°, There are characteristic peaks at 18.92±0.20°, 19.28±0.20°, 20.36±0.20°, 21.99±0.20°, 22.84±0.20°, 24.24±0.20°, 26.90±0.20°, and 29.12±0.20°, as shown in Figure 5. The chemical structural formula is as follows:

Example 6

Take 49.4 mg of glibenclamide and 12.0 mg of metformin (molar ratio is 1:0.92) in a 4 mL sample bottle, add 2 mL of acetone, ultrasonically, dissolve and supersaturate, react and crystallize at 40 ° C for 12 hours, Centrifuge the suspension, discard the supernatant, and dry the centrifuged solid in a blast drying oven at 50°C for 1 hour to obtain Glyburide-Metformin salt. The diffraction angle represented by the 2θ angle in the XRPD results At 7.36±0.20°, 10.72±0.20°, 11.14±0.20°, 12.34±0.20°, 13.94±0.20°, 15.05±0.20°, 15.86±0.20°, 16.94±0.20°, 17.28±0.20°, 18.08±0.20° , 18.92±0.20°, 19.28±0.20°, 20.36±0.20°, 21.99±0.20°, 22.84±0.20°, 24.24±0.20°, 26.90±0.20°, 29.12±0.20° have characteristic peaks, as shown in Figure 6.

Example 7

10 mg of the solid samples of glyburide-metformin salt and glyburide ^- metformin salt prepared in Examples 1-6 were taken for dynamic moisture adsorption analysis. The temperature is 25°C and the relative humidity range is 1-95%. When the relative humidity is 75%, the salt has almost no wet weight gain, and the wet weight gain of glibenclamide-metformin salt is about 0.7%, as shown in Figure 7; the wet weight gain of glyburide-metformin salt is about 0.4 %, as shown in Figure 8; while the weight gain of metformin single product at 75% relative humidity is as high as 35%, as shown in Figure 9.

The Gliquizone-Metformin salt and Glyburide-Metformin salt provided by the present invention are analyzed by X-ray powder diffraction (XRPD), thermogravimetric analysis (TG), differential scanning calorimetry (DSC), dynamic moisture adsorption (DVS), liquid nuclear magnetic resonance ( ¹ H-NMR) and other solid-state methods for characterization.

电压为40千伏，电流为100毫安，扫描速度为8度/分钟，扫描范围是2-40°。结果如图1-6。The salt-type solid samples prepared in Examples 1-6 were subjected to X-ray powder diffraction analysis using a D/MAX 2500 diffractometer from Rigaku Corporation, using Cu-Kα rays

The voltage was 40 kV, the current was 100 mA, the scan speed was 8 degrees/min, and the scan range was 2-40°. The result is shown in Figure 1-6.

The salt-type solid samples prepared in Examples 1-6 were subjected to dynamic vapor adsorption experimental analysis, which used a VTI-SA ⁺ DVS dynamic vapor adsorption instrument from TA Company in the United States, the atmosphere was nitrogen, the temperature was 25°C, and the relative humidity range was 1 -95%. The result is shown in Figure 7-9.

The salt-type solid samples prepared in Examples 1-6 were subjected to thermogravimetric analysis using a TGA/DSC1 thermogravimetric analyzer from Mettler Toledo, Switzerland, the atmosphere was nitrogen, and the heating rate was 10°C/min. The results show that there is no obvious weight loss phenomenon in the thermal gravimetric analysis chromatograms of the glibenclamide-metformin salt and the glyburide-metformin salt of the present invention before heating to decomposition. Figure 10 and Figure 11.

Differential scanning calorimetry analysis was performed on the salt-type solid samples prepared in Examples 1-6, which were detected by a DSC1 differential calorimeter from Mettler Toledo, Switzerland, the atmosphere was nitrogen, and the heating rate was 10°C/min . The results show that the differential scanning calorimetry analysis pattern of the gliquizone-metformin salt of the present invention has a characteristic melting peak at 183.5±5°C. Figure 12. The differential scanning calorimetry analysis pattern of the glyburide-metformin salt of the present invention has a characteristic melting peak at 176.8±5°C. Figure 13.

The salt-type solid samples prepared in Examples 1-6 were analyzed by proton nuclear magnetic resonance spectroscopy, which was analyzed by Bruker ADVANCEIII NMR instrument under the condition of 400 MHz, and DMSO-d ₆ was used as the nuclear magnetic reagent. The results show that the liquid ¹ H-NMR (DMSO-d ₆ )δ of the Gliquizone-Metformin salt: 7.62(d, 2H), 7.59(s, 1H), 7.54(d, 1H) ,7.29(dd,1H),7.18(m,4H),6.63(s,4H),5.62(s,1H),4.09(m,2H),3.84(s,3H),3.16(s,1H), 2.92(s, 6H), 2.83(m, 2H), 1.59(m, 4H), 1.46(m, 6H), 1.06(m, 6H). As shown in Figure 14 of the description. The liquid-phase hydrogen NMR spectrum of the raw material of glipaquinone is shown in Figure 15 of the description. Liquid hydrogen nuclear magnetic resonance spectrum of the salt ¹ H-NMR (DMSO-d ₆ ) δ: 8.25 (t, 1H), 7.66 (m, 3H), 7.50 (dd, 1H), 7.22 (m, 4H), 7.14 (d, 1H), 6.59(s, 4H), 5.60(s, 1H), 3.79(s, 3H), 3.50(dd, 2H), 3.17(s, 1H), 2.92(s, 6H), 2.83( t, 2H), 1.15 (m, 10H). Figure 16. The liquid H NMR spectrum of the glyburide raw material is shown in Figure 17.

Example 8

Solubility Experiment of Gliquizone-Metformin Salt and Glyburide-Metformin Salt

Experimental conditions: Dissolve glibenclamide and the glibenclamide-metformin salt, glibenclamide and the glibenclamide-metformin salt in 2 mL of pure water, control the rotational speed at 400 rpm and the temperature at 37 °C to make the experiment. It dissolves and is in a supersaturated state, where the test samples used are sieved through an 80 mesh screen to prevent particle size from affecting the dissolution results. Samples were taken after 24 hours, filtered through a 0.45 μm microporous membrane, and quantified by high performance liquid chromatography after appropriate dilution. The results showed that the solubility of glyquinone in pure water was 0.018 mg/ml, and the solubility of the glyquinone-metformin salt in pure water was 10.611 mg/ml; the solubility of glyburide in pure water Less than 1 mg/ml, the solubility of the glyburide-metformin salt in pure water is 16.783 mg/ml.

Example 9

Powder Dissolution Experiment of Gliquizone-Metformin Salt and Glyburide-Metformin Salt

Experimental conditions: Dissolution experiments were carried out using a RC-6 type dissolution tester. The dissolution medium was simulated intestinal fluid (measured pH 6.9), 200 mL. The control speed is 100rpm, and the temperature is 37°C. The samples used in the present invention are the glibenclamide-metformin salt and the glyburide raw material, the glyburide-metformin salt and the glyburide raw material respectively, which are passed through an 80-mesh sieve to prevent the particle size from affecting the dissolution result. After 2min, 5min, 10min, 15min, 20min, 30min, 40min, 60min, 80min, 100min, 120min, 150min, 180min, 210min, and 240min, 1.5ml was sampled, and the sample was filtered through a 0.45μm microporous membrane. Quantitation was performed by high performance liquid chromatography after dilution. The dissolution results of Gliquizone-Metformin salt are shown in Figure 18, and the dissolution results of Glyburide-Metformin salt are shown in Figure 19. The dissolution rate of Gliquizone-Metformin salt described in the present invention is much greater than The glyburide raw material, the dissolution rate of the glyburide-metformin salt described in the present invention is far greater than that of the glyburide raw material.

The above descriptions are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements and improvements made within the spirit and principles of the present invention shall be included in the protection of the present invention. within the range.

Claims (9)

1. a preparation method of sulfonylurea compound and metformin salify, is characterized in that, comprises the following steps: (1) Dissolving the sulfonylurea compound and the metformin raw material in a solvent according to a molar ratio of 1:0.9 to 1:1.1 to obtain a mixture; (2) reacting the mixture obtained in step (1) at 25-50° C. for 12-48 hours; (3) solid-liquid phase separation of the product obtained in step (2) and drying to obtain a sulfonylurea compound and metformin salt-forming solid product. 2 . The method of claim 1 , wherein the sulfonylurea compound is gliquinone or glibenclamide. 3 . 3. method as claimed in claim 1 is characterized in that described solvent is the solvent that one or more of ethanol, acetone, acetonitrile or methyl acetate mixes according to any ratio. 4. the sulfonylurea compound and the metformin salt-forming product prepared by the method of claim 1 or 2 are characterized in that the chemical structural formula is:

Wherein: R substituent group is

The sulfonylurea compound is Gliquidone; When the R substituent group is

The sulfonylurea compound is glyburide. 5. the sulfonylurea compound as claimed in claim 4 is salified with metformin; it is characterized in that when R substituent group is

When , the salt formed is Gliquizone-Metformin salt, the molecular formula is C ₃₁ H ₄₄ N ₈ O ₆ S, the molecular weight is 656.80, and the chemical structural formula is:

6. The sulfonylurea compound as claimed in claim 5 forms a salt with metformin; it is characterized in that the gliquinone-metformin salt is in a crystalline state, and the diffraction angle represented by 2θ angle is at 3.82±0.20°, 5.48± 0.20°, 8.80±0.20°, 11.18±0.20°, 14.34±0.20°, 16.42±0.20°, 17.40±0.20°, 17.84±0.20°, 20.42±0.20°, 23.38±0.20°, 27.02±0.20°, 28.00± There are characteristic peaks at 0.20°, 29.22±0.20°, and 30.78±0.20°; the liquid ^1H -NMR (DMSO-d6)δ of the Gliquizone-Metformin salt: 7.62(d,2H), 7.59(s, 1H), 7.54(d, 1H), 7.29(dd, 1H), 7.18(m, 4H), 6.63(s, 4H), 5.62(s, 1H), 4.09(m, 2H), 3.84 (s,3H), 3.16(s,1H), 2.92(s,6H), 2.83(m,2H), 1.59(m,4H), 1.46(m,6H), 1.06(m,6H); The differential scanning calorimetry analysis pattern of quinone-metformin salt has a characteristic melting peak at 183.5±5.0℃. 7. the sulfonylurea compound as claimed in claim 4 forms a salt with metformin; it is characterized in that, when R substituent group is

, the formed salt is Glyburide-Metformin salt, the molecular formula is C ₂₇ H ₃₉ ClN ₈ O ₅ S, the molecular weight is 623.17, and the chemical structural formula is:

8. The sulfonylurea compound according to claim 7 forms a salt with metformin; it is characterized in that the glibenclamide-metformin salt is in a crystalline state, and the diffraction angles expressed by 2θ angle are at 7.36±0.20°, 10.72± 0.20°, 11.14±0.20°, 12.34±0.20°, 13.94±0.20°, 15.05±0.20°, 15.86±0.20°, 16.94±0.20°, 17.28±0.20°, 18.08±0.20°, 18.92±0.20°, 19.28± 0.20°, 20.36±0.20°, 21.99±0.20°, 22.84±0.20°, 24.24±0.20°, 26.90±0.20°, 29.12±0.20°; the liquid ^1H nuclear magnetic resonance spectrum of the glibenclamide-metformin salt -NMR(DMSO-d ₆ )δ: 8.25(t, 1H), 7.66(m, 3H), 7.50(dd, 1H), 7.22(m, 4H), 7.14(d, 1H), 6.59(s, 4H) ), 5.60(s, 1H), 3.79(s, 3H), 3.50(dd, 2H), 3.17(s, 1H), 2.92(s, 6H), 2.83(t, 2H), 1.15(m, 10H) ; The differential scanning calorimetry analysis pattern of the glyburide-metformin salt has a characteristic melting peak at 176.8±5.0°C. 9. Use of the sulfonylurea compound of claim 4 to form a salt with metformin in the preparation of a medicament for preventing and treating diabetes.

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