WO2017008684A1 - Α-crystal form of compound a, preparation method thereof, and pharmaceutical composition comprising same - Google Patents

Abstract

The present invention relates to the field of chemical drug preparation, in particular to an α-crystal form of compound A, preparation method thereof, and pharmaceutical composition comprising the same, wherein the compound A is a dipeptidyl peptidase-IV inhibitor.

Description

Form A of Compound A, preparation method thereof and pharmaceutical composition containing the same Technical field

The invention belongs to the field of chemical drug preparation, and particularly relates to a crystal form α of a dipeptidyl peptidase-IV inhibitor compound A, a preparation method thereof, and a pharmaceutical composition containing the same.

Background technique

Dipeptidyl peptidase IV (DPP-IV) is a serine protease that specifically hydrolyzes the Xaa-Pro or Xaa-Ala dipeptide of the N-terminus of a polypeptide or protein. DPP-IV is an atypical serine protease with a Ser-Asp-His catalytic triad at the C-terminal region that differs from a typical serine protease in a reverse order.

DPP-IV has a variety of physiologically relevant substrates, such as inflammatory chemokines, regulated on activation normal T-cell expressed and secreted (RANTES), eosinophilic chemokines and macrophages. Cell-derived chemokines, neuropeptides such as neuropeptide Y (NPY) and P5 substances, vasoactive peptides, incretins such as glucagon-like peptide-l (GLP-1) And glucose-dependent insulinotropic polypeptide (GIP).

Inhibition of DPP-IV in vivo can increase the level of endogenous GLP-1 (7-36) and reduce the production of its antagonist GLP-1 (9-36). Therefore, DPP-IV inhibitors may be effective against diseases associated with DPP-IV activity, such as type 2 diabetes, diabetic dyslipidemia, impaired glucose tolerance (IGT), and impaired fasting plasma Glucose (IFG). ), metabolic acidosis, ketosis, appetite regulation and obesity.

The DPP-IV inhibitor Alogliptin has a clinically good therapeutic effect on type 2 diabetes and is approved for marketing in the United States. Therefore, DPP-IV inhibitors are currently considered to be the new treatment route for the treatment of type 2 diabetes.

PCT/CN2010/080370 describes a series of DPP-IV inhibitors of new mother core structures. Among them, including compound A, its chemical name is: (R)-2-((3-(3-aminopiperidin-1-yl)-6-methyl-5-oxo-1,2,4-tri Pyrazin-4(5H)-yl)methyl)-4-fluorobenzonitrile (the product obtained by this prior art process is a yellow oil), molecular formula: C ₁₇ H ₁₉ FN ₆ O, molecular weight: 342, chemical structural formula The following formula (I):

In order to improve the pharmaceutical properties of the compound, studies with advantageous stability properties can be effectively used in pharmaceutical compositions for treating morbid patients by inhibiting DPP-IV.

Summary of the invention

One of the objects of the present invention is to provide a stable crystalline form of a stable dipeptidyl peptidase-IV (DPP-IV) reversible competitive inhibitor Compound A.

The chemical name of Compound A is: (R)-2-((3-(3-Aminopiperidin-1-yl)-6-methyl-5-oxo-1,2,4-triazine-4 ( 5H)-yl)methyl)-4-fluorobenzonitrile, molecular formula: C ₁₇ H ₁₉ FN ₆ O, molecular weight: 342, the chemical structural formula of compound A is the following formula (I),

The crystal form α of the above-mentioned dipeptidyl peptidase-IV inhibitor compound A has a characteristic peak at 9.41° in an X-ray diffraction diagram at an angle of 2θ with an error of ±0.2°. Further, there are characteristic peaks at 15.66°, 16.33° and 22.68° with an error of ±0.2°. The characteristic peak of the displacement is the strongest characteristic peak of the crystal X-ray, which can fully represent the crystal form.

Specifically, in more detail, Compound A is represented by an angle of 2θ in the X-ray diffraction diagram at 8.87°, 9.41°, 13.91°, 15.66°, 16.33°, 18.37°, 22.68°, 23.55°, 24.00°, 24.41°, and There is a characteristic peak at 24.92° with an error of ±0.2°. It should be noted that different samples of a particular crystal form have the same major XRPD peak, but small peaks in the powder pattern may vary. In addition, when used by those of ordinary skill in the art When the isomorphous samples obtained by the corresponding methods are detected by the same instrument and detection method, the error of each 2θ angle is usually within ±0.2° (the meaning of each 2θ angle error is usually within ±0.2° refers to most characteristic peaks. If more than 80% of the characteristic peak errors are within this range, and occasionally there are a few minor characteristic peaks whose error exceeds the range, they should all be considered to belong to the same crystal form of the XRPD spectrum); moreover, the characteristics of the displacements The peaks are medium intensity absorption peaks, while other weak absorption peaks may vary significantly due to experimental operational errors. Other absorption peaks are those that are not necessary for characterizing the crystal form.

Specifically, the X-ray diffraction pattern of the crystal form α of the compound A is shown in Table 1 or Table 2, and the error is ±0.2°.

More specifically, the X-ray diffraction pattern of the crystal form α of the compound A is shown in Fig. 1 or Fig. 2 .

X-ray diffraction detection conditions:

X-ray diffraction using Empyean X-ray diffractometer, Cu target Kα ray, voltage: 40.0kV, current: 40.0mA, divergence slit 1/32°, anti-scatter slit 1/16°, anti-scattering narrow The slit is 7.5 mm, the step length is 0.02°, and the 2θ range is determined under the condition of 40s per step: 3°-50°.

The stability of the crystal form α of the compound A is high, and it has better stability with respect to the yellow oil obtained by PCT/CN2010/080370, and is more advantageous for the clinical application of the compound A, and sufficiently ensures the safety and effectiveness of the drug.

Another object of the present invention is to provide a process for preparing the crystal form α of the above compound A, which is simple in process and can be realized under normal temperature conditions.

Among them, the compound A can be prepared according to the method disclosed in PCT/CN2010/080370, and the specific synthesis route and main reaction conditions are as follows:

The preparation method of the crystal form α of the compound A includes the following steps:

(1) using methanol or a mixed solution of methanol and water as a solvent, respectively dissolving benzoic acid and the above process to obtain compound A, and adding an equimolar amount of benzoic acid solution to a solution of compound A at a specific temperature, after the dropwise addition is completed , stirring at 15 ~ 25 ° C for more than 10 hours, and then placed at 0 ~ 10 ° C for several hours, filtered to obtain a solid product;

(2) taking the product of step (1), adding dichloromethane, stirring and dissolving, adding ice water, adjusting pH 9.0 to 10.0 with sodium carbonate/water solution, stirring, phase separation, collecting the lower dichloromethane layer, and dichlorochloric acid in the water layer. The methane was extracted, and the methylene chloride layer was combined, washed with water, and then evaporated.

Further, the crystallization step (3) is optimized, the oil is obtained in the step (2), methanol is added, stirred and dissolved, and the mixture is stirred, water is added dropwise, stirred until a large amount of solids are precipitated, water is continuously added dropwise, stirred, filtered, washed with water, and dried at room temperature under vacuum.

Specifically, it is preferred that the crystallization step (3) takes 5 g of the oil of the step (2), 2.5 ml of methanol is added, and the mixture is stirred and dissolved. Under stirring, 5 ml of water is added dropwise, and the mixture is stirred until a large amount of solid is precipitated. Continue to drip 10-15 ml of water, stir for 3 hours, filter, wash 3 times with water, and dry at room temperature under vacuum to obtain about 4.1 to 4.3 g.

The yellow oil product of the prior art PCT/CN2010/080370, although having a good purity, is always difficult to obtain the crystal form of the compound A by various crystallization methods, and it is not easy to further prepare for use due to its physical form. The invention adopts a large number of experiments, and obtains a yellow oil-like benzoate by synthesis, and a weak alkali to convert a new alkali oil, and optimizes the crystallization process to obtain the novel crystal form of the compound A for the first time, which is excellent. Purity and quality stability.

A further object of the present invention is to provide a pharmaceutical composition comprising the above-mentioned Compound A Form A or a crystalline form of the Compound A to be converted into a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

The carrier comprises various medicinal excipients, packaging materials, delivery tools, etc., and is selected according to the needs of the preparation, for example, the auxiliary materials include a filler, a disintegrating agent, a binder, a lubricant, etc., and can be applied to oral, inhalation, non-gastrointestinal. Dosing or topical use; dosage forms include, but are not limited to, injections, solution preparations, tablets, capsules, granules and the like.

The pharmaceutical composition can be used for the preparation of a medicament for causing DPP-IV to cause a related disease, particularly type 2 diabetes.

Compared with the prior art, the present invention has the following outstanding advantages and beneficial effects:

1. The crystal form α of the compound A of the present invention has a high purity and is a solid form having a stable quality, and is easier to arrange and use the pharmaceutical composition.

2. The crystal form α of the compound A of the present invention is obviously more stable than the yellow oil obtained by PCT/CN2010/080370, and is more favorable for ensuring the clinical efficacy and safe use of the compound A.

3. The method for preparing the crystal form α of the compound A of the invention is simple, rapid, and can be prepared under normal temperature conditions, and is more easily industrialized.

DRAWINGS

1 is an X-ray diffraction pattern of the crystal form α of the compound A obtained in Example 2 of the present invention.

2 is an X-ray diffraction pattern of the crystal form α of the compound A obtained in Example 3 of the present invention.

detailed description

The present invention will be further described in detail below with reference to the embodiments and drawings, but the embodiments of the invention are not limited thereto.

Example 1 Preparation of Compound A

Compound A was prepared by the following synthetic route according to the procedures of Examples 2 and 3 of PCT/CN2010/080370:

The obtained compound A, ¹ H-NMR (400 MHz, DMSO, ppm): δ 7.96 (m, 1H), 7.36 (br, 1H), 7.29 (d, 1H), 5.23 (s, 2H), 3.15 (m, 3H), 2.72 (m, 2H), 2.23 (s, 3H), 1.78 (d, 1H), 1.64 (d, 1H), 1.47 (m, 1H), 1.12 (m, 1H). MS: m/z , 343 (100%, M+1).

The specific preparation steps are as follows:

Step A. 1-Bromo-4-fluoro-2-(isothiocyanatomethyl)benzene (2)

To a solution of 1-bromo-2-(bromomethyl)-4-fluorobenzene (1, 5.36 g, 20.0 mmol) in DMF (20 mL), sodium iodide (1.20 g, 8.00 mmol) and potassium thiocyanate (3.88 g, 40.0 mmol). The mixture was heated to 80 ° C for 12 h under a nitrogen atmosphere, and then cooled to room temperature, and then, 100 mL of water was added thereto, and the mixture was extracted with ethyl acetate (50 mL × 2). The crude product was concentrated by suction-lu~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Step B. N-(2-Bromo-5-fluorobenzyl)hydrazinothiocarboxamide (3)

The 1,4-dioxane solution (20 mL) of hydrazine hydrate (80%, 2.22 g, 35.5 mmol) was cooled to 0 ° C, and 1-bromo-4-fluoro-2-(isothiocyanate) was added thereto. A solution of benzene (2, 3.16 g, 12.8 mmol) in 1,4-dioxane (5 mL). The mixture was stirred at room temperature for 2 h, 100 mL of ice water was added thereto, and a solid was precipitated, suction filtered, washed with water, and dried over phosphorus pentoxide overnight to obtain N-(2-bromo-5-fluorobenzyl)thiolthiocarbamate. Amide (3). MS: m/z, 278 (100%, M+1), 280 (100%), 300 (10%, M+23), 302 (10%).

Step C. Methyl 2-(2-(2-bromo-5-fluorobenzylthiocarbamide) decyl)propionate (4)

Add N-(2-bromo-5-fluorobenzyl)hydrazinothiocarboxamide (3, 1.112 g, 4.00 mmol) to a solution of pyruvic acid (352 mg, 4.00 mmol) in methanol (15 mL) 5 drops of sulfuric acid, heat the mixture to After refluxing for 7 h, the solvent was evaporated. EtOAc (EtOAc m. -(2-(2-Bromo-5-fluorobenzylaminothiocarboxamide) decyl)propionate (4). MS: m/z, 362 (100%, M+1), 364 (100%), 384 (60%, M+23), 386 (60%).

Step D. 4-(2-Bromo-5-fluorobenzyl)-6-methyl-3-thio-3,4-dihydro-1,2,4-triazin-5(2H)-one (5)

Sodium methoxide (0.4 M) freshly prepared from sodium (273 mg, 11.88 mmol) and dry methanol (30 mL) was dissolved in methanol 30 mL, and methyl 2-(2-(2-bromo-5-fluorobenzylamino)sulfide was added thereto. To a carboxamide) mercapto)propionate (4, 1.434 g, 3.96 mmol), the mixture was heated to reflux for 22 h, and the solvent was evaporated. The residue was diluted with water (100 mL). The mixture was extracted with ethyl acetate (50 mL×2). EtOAc (EtOAc) ～30%), 4-(2-bromo-5-fluorobenzyl)-6-methyl-3-thio-3,4-dihydro-1,2,4-triazine-5 (2H) )-ketone (5), MS: m/z, 330 (65%, M+1), 332 (60%, M+23).

Step E. 4-(2-Bromo-5-fluorobenzyl)-6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (6)

4-(2-Bromo-5-fluorobenzyl)-6-methyl-3-thio-3,4-dihydro-1,2,4-triazin-5(2H)-one (5,914 The mg, 2.77 mmol) was suspended in 15 mL of ethanol, followed by sodium hydroxide (111 mg, 2.77 mmol) and methyl iodide (787 mg, 5.54 mmol). The mixture was stirred at room temperature for 10 minutes to give a EtOAc (EtOAc). Purification by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20 to 25%) to give 4-(2-bromo-5-fluorobenzyl)-6-methyl-3-(methylthio)- 1,2,4-triazin-5(4H)-one (6). ¹ H NMR (400MHz, DMSO, ppm): δ 7.73 (m, 1H), 7.16 (br, 1H), 7.05 (d, 1H), 5.09 (s, 2H), 2.56 (s, 3H), 2.32 (s, 3H). MS: m/z, 344 (100%, M+1), 346 (100%).

Step F. (R)-tert-Butyl 1-(4-(2-bromo-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4 -three Pyrazin-3-yl)piperidin-3-carbamate (8)

4-(2-Bromo-5-fluorobenzyl)-6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (6,180 mg, 0.523 mmol And (R)-tert-butylpiperidine-3-carbamate (7,208 mg, 1.04 mmol) was milled for 5 minutes, heated to 135 ° C for 13 h under nitrogen atmosphere, and the reaction mixture was purified by silica gel column chromatography Agent: ethyl acetate / petroleum ether = 10 ~ 50%) to give (R)-tert-butyl 1-(4-(2-bromo-5-fluorobenzyl)-6-methyl-5-oxo- 4,5-Dihydro-1,2,4-triazin-3-yl)piperidin-3-carbamate (8). MS: m/z, 496 (100%, M+1), 498 (100%).

Step G. (R)-tert-Butyl 1-(4-(2-cyano-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4 -three Pyrazin-3-yl)piperidin-3-carbamate (9)

To a mixture of sodium carbonate (53 mg, 0.50 mmol), palladium acetate (3 mg, 0.013 mmol) and N-methylpyrrolidone 0.5 mL, 3 drops of isopropanol and 2 drops of water were added, and the mixture was stirred at room temperature for 5 minutes, and added thereto. (R)-tert-butyl 1-(4-(2-bromo-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazine -3-yl)piperidin-3-carbamate (8,246 mg, 0.496 mmol) in NMP (1.0 mL), and heated to 140 ° C, then K ₄ [Fe(CN) ₆ ].3H ₂ O (209 mg, 0.496 mmol), heated at 140 ° C for 12 h, cooled to room temperature, EtOAc (EtOAc) (EtOAc) The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 20 to 35%) to give (R)-tert-butyl 1-(4-(2-cyano-5-fluorobenzyl)- 6-Methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-carbamate (9). MS: m/z, 418 (20%), 443 (100%, M+1), 465 (95%, M+23).

Step H. (R)-2-((3-(3-Aminopiperidin-1-yl)-6-methyl-5-oxo-1,2,4-triazin-4(5H)-yl ) 4-fluorobenzonitrile (10, compound A)

To (R)-tert-butyl 1-(4-(2-cyano-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-tri 1 mL of a solution of pyrazin-3-yl)piperidine-3-carbamate (9,37 mg) in dichloromethane, 0.5 mL of trifluoroacetic acid, stirred at room temperature for 1 h, neutralized with saturated sodium bicarbonate, dichloromethane The organic layer was dried over anhydrous sodium sulfate, and then filtered and evaporated to ethylamine. )-2-((3-(3-Aminopiperidin-1-yl)-6-methyl-5-oxo-1,2,4-triazin-4(5H)-yl)methyl)- 4-fluorobenzonitrile (10, yellow oil).

^{1 H NMR (400MHz, DMSO,} ppm): δ7.96 (m, 1H), 7.36 (br, 1H), 7.29 (d, 1H), 5.23 (s, 2H), 3.15 (m, 3H), 2.72 ( m, 2H), 2.23 (s, 3H), 1.78 (d, 1H), 1.64 (d, 1H), 1.47 (m, 1H), 1.12 (m, 1H). MS: m/z, 343 (100% , M+1).

Example 2 Preparation of Form A of Compound A

(1) Configure 95% methanol solution: Add 91.2 mL of methanol to a 200 mL beaker, add 4.8 mL of water, stir well, and set aside. Take 2.14g of benzoic acid, add 10mL of 95% methanol at room temperature, stir and dissolve, and reserve (methanol solution of benzoic acid); add 60g of compound A obtained by the above method to a 50mL reaction flask, stir and dissolve with 32mL of methanol, 32mL; keep the internal temperature at Adding benzoic acid at 15 to 25 ° C The alcohol solution is dripped at 0.5 to 1 hour; after the addition is completed, the mixture is stirred at about 15 to 25 ° C for 16 hours, and then left at about 0 to 10 ° C for 6 hours, and filtered to obtain a solid product.

(2) Take 30 g of the product of the step (1), add 150 ml of dichloromethane, stir to dissolve, add 100 ml of ice water, adjust the pH to 9.0 to 10.0 with sodium carbonate/water solution 150 ml, and stir for 5 minutes to separate the phases. The lower dichloromethane layer was collected, the aqueous layer was extracted with 50 ml of dichloromethane, and the methylene chloride layer was combined, washed with water (100 ml), and the phases were separated. It was concentrated to dryness under reduced pressure at 30 ° C to give an oily product of about 22 g.

(3) 5 g of an oily substance was taken, 2.5 ml of methanol was added, and the mixture was stirred and dissolved. Under stirring, 5 ml of water was added dropwise, and the mixture was stirred until a large amount of solid was precipitated. 10 ml of water was continuously added dropwise, stirred for 3 hours, filtered, washed 3 times with water, and dried under vacuum at normal temperature to obtain about 4.1 to 4.3 g of Compound A crystal form α.

The X-ray diffraction pattern of the crystal form α of the obtained Compound A is shown in Fig. 1 . The specific characteristic absorption peaks are shown in Table 1 below, and the error is ±0.2°.

Table X X-ray diffraction absorption peak data of the crystal form α of the compound A

Among them, No.= serial number, Rel.Int.=Relative Intensity, Pos.[ ^. 2Th.]=Position[ ^. 2Theta], the error is ±0.2°. Rel.Int.=Relative Intensity is only the general strength of the characteristic peak intensity and should not be defined as a specific crystal form.

X-ray diffraction detection conditions:

X-ray diffraction using Empyean X-ray diffractometer, Cu target Kα ray, voltage: 40.0kV, current: 40.0mA, divergence slit 1/32°, anti-scatter slit 1/16°, anti-scattering narrow The slit is 7.5 mm, the step length is 0.02°, and the 2θ range is determined under the condition of 40s per step: 3°-50°.

Example 3 Preparation of Form A of Compound A

(1) Configure 95% methanol solution: Add 91.2 mL of methanol to a 200 mL beaker, add 4.8 mL of water, stir well, and set aside. Take 2.14g of benzoic acid, add 10mL of 95% methanol at room temperature, stir and dissolve, and reserve (methanol solution of benzoic acid); add 60g of compound A obtained by the above method to a 50mL reaction flask, stir and dissolve with 32mL of methanol, 32mL; keep the internal temperature at The methanol solution of benzoic acid was added dropwise at 15 to 25 ° C, and the dropping was completed in 0.5 to 1 hour. After the dropwise addition was completed, the mixture was stirred at about 15 to 25 ° C for 16 hours, and then left at about 0 to 10 ° C for 6 hours, and filtered to obtain a solid product.

(2) Take 30 g of the product of the step (1), add 150 ml of dichloromethane, stir to dissolve, add 100 ml of ice water, adjust the pH to 9.0 to 10.0 with sodium carbonate/water solution 150 ml, and stir for 5 minutes to separate the phases. The lower dichloromethane layer was collected, the aqueous layer was extracted with 50 ml of dichloromethane, and the methylene chloride layer was combined, washed with water (100 ml), and the phases were separated. It was concentrated to dryness under reduced pressure at 30 ° C to give an oily product of about 22 g.

(3) 5 g of an oily substance was taken, 2.5 ml of methanol was added, and the mixture was stirred and dissolved. Under stirring, 5 ml of water was added dropwise, and the mixture was stirred until a large amount of solid was precipitated. 15 ml of water was continuously added dropwise, stirred for 3 hours, filtered, washed three times with water, and dried under vacuum at normal temperature to obtain about 4.1 to 4.3 g of Compound A crystal form α.

The X-ray diffraction pattern of the crystal form α of the obtained Compound A is shown in Fig. 2 . The specific characteristic absorption peaks are shown in Table 2 below, with an error of ±0.2°.

Table 2 X-ray diffraction absorption peak data of the crystal form α of the compound A

Among them, No.= serial number, Rel.Int.=Relative Intensity, Pos.[ ^. 2Th.]=Position[ ^. 2Theta], the error is ±0.2°. Rel.Int.=Relative Intensity is only the general strength of the characteristic peak intensity and should not be defined as a specific crystal form.

X-ray diffraction detection conditions:

X-ray diffraction using Empyean X-ray diffractometer, Cu target Kα ray, voltage: 40.0kV, current: 40.0mA, divergence slit 1/32°, anti-scatter slit 1/16°, anti-scattering narrow The slit is 7.5 mm, the step length is 0.02°, and the 2θ range is determined under the condition of 40s per step: 3°-50°.

Summary: According to the XRD spectrum and characteristic peak data of Figures 1 and 2, the strongest characteristic absorption peak at 9.41 ° ± 0.2 ° with an angle of ± 0.2 ° at 2θ angle can clearly represent the crystal form.

Further, the crystal form has characteristic peaks at 15.66°, 16.33° and 22.68° with an error of ±0.2° and a relative absorption intensity of more than 20%, which can fully represent the crystal form.

Specifically, in more detail, Compound A is represented by an angle of 2θ in the X-ray diffraction diagram at 8.87°, 9.41°, 13.91°, 15.66°, 16.33°, 18.37°, 22.68°, 23.55°, 24.00°, 24.41°, and 24.92° has characteristic peaks with an error of ±0.2° and a relative absorption intensity greater than 10%, which can distinguish other material generations in more detail. Table crystal form.

While other weak absorption peaks may change significantly due to experimental operational errors, other absorption peaks for those skilled in the art are absorption peaks that can be considered unnecessary when characterizing the crystal form.

Example 4 Stability Comparison Experiment

According to the Chinese Pharmacopoeia 2010 edition, the second appendix XIXC "Guidelines for the stability test of drug substance in pharmaceutical preparations", the crystal form α of compound A obtained in Examples 2 and 3 and the method disclosed in PCT/CN2010/080370 The prepared yellow oil was subjected to the high-humidity test under the same conditions. After several days of storage, the experimental methods and results were as follows:

High humidity experiment

According to the Chinese Pharmacopoeia 2010 edition second appendix XIXC "Guidelines for the stability test of drug substance in pharmaceutical preparations", compound A (yellow oil) of Example 1 and compound A obtained in Examples 2 and 3 were accurately weighed. The crystal form α was 5 parts each, 100 mg each, placed in a container, exposed to an environment having a relative humidity of 92.5% and a temperature of 25 ± 2 °C. The samples were taken after 0, 1, 2, and 13 days, respectively, and the results are shown in Table 3.

Table 3 High-humidity test results (25 ° C ± 2 ° C, RH 92.5%)

Relative content of sample (%) 0 days 1 day 2 days 13 days Compound A (yellow oil) 100.00% 96.776% 96.712% 96.707% Example 2 Compound A (Form α) 100.00% 98.554% 98.308% 98.160% Example 3 Compound A (Form α) 100.00% 98.552% 98.306% 98.159%

From the above results, it can be seen that the crystal form α of the compound A obtained in Examples 2 and 3 was placed at 25 ° C ± 2 ° C under RH 92.5% for 1, 2 and 13 days, and the relative content thereof was obtained relative to the prior art. The yellow oil has significantly better stability.

Purity detection method refers to the Chinese Pharmacopoeia 2010 edition second appendix VD high performance liquid chromatography, instrument: Agilent high performance liquid chromatography, C18 column, 5μm, flow rate: 1mL / min, detection wavelength: 229nm, mobile phase : 0.1% phosphoric acid - acetonitrile: water = 3:7.

Example 5 Preparation of a pharmaceutical composition

Compound A (crystal form α) 6.78g

Dextrin 84.00g

The above materials were uniformly mixed according to a conventional method, and then divided into 1000 equal portions and filled into ordinary gelatin capsules to obtain 1000 capsules.

The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and combinations thereof may be made without departing from the spirit and scope of the invention. Simplifications should all be equivalent replacements and are included in the scope of the present invention.

Claims (10)

a crystal form α of the compound A, the chemical structural formula of the compound A is the following formula (I),

The crystal form α of the compound A according to claim 1, wherein the crystal form α of the compound A has a characteristic peak at 9.41° in an X-ray diffraction diagram at an angle of 2θ with an error of ±0.2°. The crystal form α of the compound A according to claim 1, wherein the crystal form α of the compound A is represented by an angle of 2θ in the X-ray diffraction pattern at 9.41°, 15.66°, 16.33° and 22.68°. Characteristic peak with an error of ±0.2°. The crystal form α of the compound A according to claim 1, wherein the crystal form α of the compound A is represented by an angle of 2θ in the X-ray diffraction diagram at 8.87°, 9.41°, 13.91°, 15.66°, 16.33. Characteristic peaks at °, 18.37°, 22.68°, 23.55°, 24.00°, 24.41°, and 24.92° with an error of ±0.2°. The crystal form α of the compound A according to claim 1, wherein the X-ray diffraction pattern of the crystal form α of the compound A is as shown in Table 1 or Table 2, and the error is ±0.2°. The crystal form α of the compound A according to claim 1, wherein the X-ray diffraction pattern of the crystal form α of the compound A is as shown in Fig. 1 or Fig. 2 . A method for preparing a crystal form α of the compound A according to any one of claims 1 to 6, which comprises the steps of: (1) using methanol or a mixed solution of methanol and water as a solvent, respectively dissolving benzoic acid and the above process to obtain compound A, and adding an equimolar amount of benzoic acid solution to a solution of compound A at a specific temperature, after the dropwise addition is completed , stirring at 15 ~ 25 ° C for more than 10 hours, and then placed at 0 ~ 10 ° C for several hours, filtered to obtain a solid product; (2) taking the product of step (1), adding dichloromethane, stirring and dissolving, adding ice water, adjusting pH 9.0 to 10.0 with sodium carbonate/water solution, stirring, phase separation, collecting the lower dichloromethane layer, and dichlorochloric acid in the water layer. The methane was extracted, and the methylene chloride layer was combined, washed with water, and then evaporated. Further comprising optimizing the crystallization step (3): taking the step (2) oil, adding methanol, stirring and dissolving Solution, stirring, adding water, stirring to a large amount of solid precipitation, continue to add water, stirring, filtration, washing with water, vacuum drying at room temperature. The method for preparing the crystal form α of the compound A according to claim 7, wherein the crystallization step (3) comprises: taking 5 g of the oil of the step (2), adding 2.5 ml of methanol, stirring and dissolving, stirring. Next, 5 ml of water was added dropwise, and the mixture was stirred until a large amount of solid was precipitated. Continue to drip 10-15 ml of water, stir for 3 hours, filter, wash 3 times with water, and dry at room temperature under vacuum. A pharmaceutical composition comprising the crystalline form α of the compound A according to any one of claims 1 to 8 or the use of the crystalline form α of the compound A for medicinal use in the pharmaceutical composition Salt, and more than one pharmaceutically acceptable carrier. A pharmaceutical use, characterized in that the pharmaceutical composition according to claim 9 is used for the preparation of a medicament for preventing or treating diabetes.

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