A gliclazide oxalate and its crystal form, preparation method and application

Abstract

The present invention discloses a gliclazide oxalate, its crystal form, preparation method and application, relating to the technical field of pharmaceutical chemistry. The present invention provides a crystal form of gliclazide oxalate, which has not been reported in the prior art. Animal experiments show that, compared with gliclazide tartrate and gliclazide hydrochloride, the gliclazide oxalate prepared by the present invention has better pharmacokinetic properties, laying a foundation for the development and application of new dosage forms of gliclazide; the present invention also provides a simple and efficient salt-forming process for gliclazide. Compared with the method of removing the amino protecting group by acid treatment, the salt-forming process provided by the present invention does not need to add alkali to free the amino group, avoiding the generation of impurities caused by strong acids or strong bases, and the prepared gliclazide oxalate has high purity.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly relates to gilexentin oxalate, its crystal forms, preparation methods and applications. Background Art

[0002] Diabetes is a chronic metabolic disease, which is caused by the pancreas being unable to produce enough insulin, or the body being unable to effectively utilize insulin, thus leading to an increase in blood sugar levels. Prolonged high blood sugar can seriously damage organs such as the heart, blood vessels, kidneys, nerves and eyes. The latest statistics from the World Health Organization show that approximately 422 million people worldwide suffer from diabetes, of which approximately 90% are patients with type 2 diabetes mellitus (T2DM). Type 2 diabetes is characterized by the gradual deterioration of pancreatic beta cell function, and currently drug intervention has become an important part of the treatment of type 2 diabetes.

[0003] Gilexentin is a potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, which was launched in 2012 under the brand name "Zemiglo" by LG Life Sciences Co., Ltd. in South Korea. Compared with other oral antidiabetic drugs, whether used alone or in combination with other oral hypoglycemic drugs, gilexentin has obvious advantages in the treatment of type 2 diabetes patients. For example, gilexentin has a better tendency to protect against cardiovascular diseases and kidneys in clinical practice, and requires a lower dose when used in combination with metformin. In addition, gilexentin is more effective than other oral antidiabetic drugs in reducing glycated hemoglobin (HbA1c) and improving islet beta cell function (HOMA-β).

[0004] However, the drug active ingredient can exist in different crystalline forms of salts. Different crystalline forms of the same drug molecule will have significant differences in aspects such as color, solubility, dissolution performance, melting point, mechanical properties, and stability, which will directly affect the efficacy and developability of the drug. The Korean patent document with the publication number KR1020220048952A discloses an oral compound for treating type 2 diabetes, which relates to the tartrate salt of gemigliptin, but this invention does not mention the crystalline form of gemigliptin salt, nor does it analyze and study the crystalline form of pharmaceutically acceptable salts of gemigliptin. The Australian patent document with the publication number AU2013330679A8 discloses a compound drug composed of gemigliptin tartrate and metformin as active ingredients and its preparation method. Similarly, this patent does not analyze and study any salt form crystalline form of gemigliptin. Currently, the research reports on gemigliptin mainly involve the tartrate salt and hydrochloride salt of gemigliptin. There are few research reports on the oxalate salt of gemigliptin, and there is no research report on the crystalline form of gemigliptin oxalate. Therefore, the present invention provides a new and general salt-forming process for gemigliptin, prepares gemigliptin oxalate, and studies this new crystalline form, laying a foundation for the development and application of a new dosage form of the hypoglycemic drug - gemigliptin. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a preparation method of pharmaceutically acceptable gemigliptin oxalate. Using this preparation method, gemigliptin oxalate and its crystalline form that have not been reported currently can be obtained, and a salt-forming process for gemigliptin can also be provided based on this preparation method, so as to be applicable to the preparation of other salt forms of gemigliptin.

[0006] The technical problem to be solved by the present invention is achieved by adopting the following technical solutions:

[0007] The first object of the present invention is to provide a gemigliptin oxalate, and its structural formula is shown as follows:

[0008]

[0009] The second object of the present invention is to provide a preparation method of gemigliptin oxalate, including the following steps:

[0010] (1) Use ammonium cerium nitrate to carry out deprotection of the amino group on the gemigliptin intermediate to obtain gemigliptin;

[0011] (2) Make gemigliptin undergo a salt-forming reaction with oxalic acid to obtain gemigliptin oxalate.

[0012] The structural formula of the gemigliptin intermediate is shown as follows:

[0013]

[0014] Among them, R is selected from any one of

[0015] The third object of the present invention is to provide a vildagliptin oxalate crystal form, the X-ray powder diffraction pattern of which has characteristic peaks at 2θ values of 24.71±0.2°, 15.63±0.2°, and 19.69±0.2°.

[0016] The fourth object of the present invention is to provide the application of the vildagliptin oxalate in the preparation of dipeptidyl peptidase-4 (DPP-4) inhibitors, hypoglycemic drugs, angiogenesis and regeneration drugs.

[0017] The fifth object of the present invention is to provide a vildagliptin salt formation process, which comprises the following steps:

[0018] (1) The amino deprotection of the vildagliptin intermediate is carried out by using ammonium cerium nitrate to obtain vildagliptin;

[0019] (2) Vildagliptin reacts with an acid to carry out a salt formation reaction to obtain a vildagliptin salt.

[0020] The structural formula of the vildagliptin intermediate is as follows:

[0021]

[0022] Among them, R is selected from any one of

[0023] The beneficial effects of the present invention are:

[0024] 1. The present invention provides a vildagliptin oxalate crystal form, which has not been reported in the prior art, laying a foundation for the development and application of new dosage forms of vildagliptin.

[0025] 2. The present invention provides a simple and efficient vildagliptin salt formation process. Compared with the method of removing the amino protecting group by acid treatment, the salt formation process provided by the present invention does not need to add an alkali to free the amino group, avoiding the generation of impurities caused by strong acids or strong bases, and the purity of the prepared vildagliptin oxalate is high. Description of the Drawings

[0026] Figure 1 is the nuclear magnetic resonance hydrogen spectrum (H-NMR) diagram of the vildagliptin oxalate crystal form prepared by the present invention;

[0027] Figure 2 is the X-ray powder diffraction (XRPD) diagram of the vildagliptin oxalate crystal form prepared by the present invention;

[0028] Figure 3 is the thermogravimetric analysis (TGA) diagram of the vildagliptin oxalate crystal form prepared by the present invention;

[0029] Figure 4 The high performance liquid chromatography (HPLC) diagram of the sitagliptin oxalate crystal form prepared by the present invention;

[0030] Figure 5 The high performance liquid chromatography (HPLC) diagram of the sitagliptin hydrochloride prepared by the present invention;

[0031] Figure 6 The high performance liquid chromatography (HPLC) diagram of the sitagliptin tartrate prepared by the present invention;

[0032] Figure 7 The in vivo pharmacokinetic curves of sitagliptin oxalate, sitagliptin hydrochloride and sitagliptin tartrate prepared by the present invention in mice. Detailed implementation manners

[0033] In order to make the technical means, creative features, achieved purposes and functions of the present invention easy to understand, the present invention will be further described below in conjunction with specific embodiments and diagrams.

[0034] The present invention provides a sitagliptin oxalate, and its structural formula is shown as follows:

[0035]

[0036] The present invention provides a preparation method of sitagliptin oxalate, which comprises the following steps:

[0037] (1) Carry out deprotection of the amino group on the sitagliptin intermediate with ammonium cerium nitrate to obtain sitagliptin;

[0038] (2) Carry out a salt formation reaction between sitagliptin and oxalic acid to obtain sitagliptin oxalate.

[0039] The structural formula of the sitagliptin intermediate is shown as follows:

[0040]

[0041] Among them, R is selected from any one of.

[0042] In some specific implementation manners, the HPLC purity of the sitagliptin oxalate is greater than 99.4%, and the maximum single impurity content is less than 0.2%.

[0043] The present invention provides a sitagliptin oxalate crystal form, and its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 24.71±0.2°, 15.63±0.2°, and 19.69±0.2°.

[0044] In some specific embodiments, the X-ray powder diffraction pattern of the vildagliptin oxalate crystal form has characteristic peaks at 2θ values of 10.38±0.2°, 15.63±0.2°, 17.28±0.2°, 19.69±0.2°, 22.20±0.2°, 23.13±0.2°, and 24.71±0.2°.

[0045] In some specific embodiments, the X-ray powder diffraction pattern of the vildagliptin oxalate crystal form has characteristic peaks at 2θ values of 10.38±0.2°, 15.63±0.2°, 16.61±0.2°, 17.28±0.2°, 19.69±0.2°, 20.54±0.2°, 22.20±0.2°, 23.13±0.2°, 24.71±0.2°, 29.88±0.2°, and 35.15±0.2°.

[0046] Furthermore, the X-ray powder diffraction pattern of the vildagliptin oxalate crystal form is measured using Cu-Kα radiation.

[0047] Furthermore, when the vildagliptin oxalate crystal form is heated to 90°C, the weight loss is 0.77%; when heated from 90°C to 136°C, the weight loss is 3.01%; when heated from 136°C to 173°C, the weight loss is 3.50%; and when heated from 173°C to 503°C, the weight loss is 62.57%.

[0048] The present invention provides the use of the vildagliptin oxalate in the preparation of dipeptidyl peptidase-4 (DPP-4) inhibitors, hypoglycemic drugs, angiogenesis and regeneration drugs.

[0049] The present invention provides a process for forming a salt of vildagliptin, comprising the following steps:

[0050] (1) Deprotecting the amino group of the vildagliptin intermediate using ammonium cerium(IV) nitrate to obtain vildagliptin;

[0051] (2) Reacting vildagliptin with an acid to form a vildagliptin salt.

[0052] The structural formula of the vildagliptin intermediate is as follows:

[0053]

[0054] Wherein, R is selected from any one of.

[0055] Furthermore, the acid is an inorganic acid or an organic acid. The inorganic acid includes but is not limited to one of hydrochloric acid and sulfuric acid. The organic acid includes but is not limited to one of tartaric acid, oxalic acid, malic acid, fumaric acid, benzenesulfonic acid, benzoic acid, hippuric acid, adipic acid, succinic acid, and maleic acid.

[0056] Furthermore, the gliclazide salts include, but are not limited to, one of gliclazide hydrochloride, gliclazide sulfate, gliclazide tartrate, gliclazide oxalate, gliclazide malate, gliclazide fumarate, gliclazide benzenesulfonate, gliclazide benzoate, gliclazide hippurate, gliclazide adipate, gliclazide succinate, and gliclazide maleate.

[0057] Example 1

[0058] Synthesis of gliclazide oxalate:

[0059]

[0060] Weigh 100 g (Compound II, CAS: 911637-18-8, 0.170 mol) into a reaction flask, add 1 kg of ethanol to dissolve it completely, add 95 g (0.179 mol) of ammonium cerium(IV) nitrate at room temperature, and heat the mixture to 70 °C for reaction. Monitor the reaction progress by HPLC. After the raw materials disappear, cool the mixture to room temperature, add 1 kg of methyl tert-butyl ether and stir well. Orange-red ammonium cerium(IV) nitrate solid will precipitate. Filter and rotary evaporate the filtrate to obtain the crude product of Compound I. Dissolve the crude product of Compound I in 300 mL of ethanol, slowly add dropwise 50 mL of an aqueous solution containing 15 g (0.170 mol) of oxalic acid, heat the mixture to 70 °C for 3 h, cool it to room temperature and continue to stir overnight. A large amount of white solid will precipitate. Filter, collect the filter cake, and dry it to obtain a white solid, which is Compound III, with a yield of 60%.

[0061] 1H-NMR data of Compound III: 1 H NMR (400 MHz, D 2 O) δ 5.01 - 4.89 (m, 2H), 4.12 - 3.68 (m, 6H), 3.63 - 3.52 (m, 1H), 3.34 - 3.13 (m, 2H), 3.10 - 2.86 (m, 2H), 2.73 - 2.52 (m, 2H), 2.46 - 2.23 (m, 2H); See the specific spectrum in Figure 1 .

[0062] The XRPD data of the Compound III sample prepared in Example 1 was measured by a Bruker D8 ADVANCE analyzer, and the detection parameters are shown in Table 1. See the XRPD spectrum in Figure 2 .

[0063] Table 1 XRPD test parameters of gliclazide oxalate

[0064]

[0065] From Figure 2It can be seen that the XRPD pattern of the vildagliptin oxalate crystal form has characteristic peaks at 2θ values of 24.71±0.2°, 15.63±0.2°, 19.69±0.2°, 10.38±0.2°, 23.13±0.2°, 17.28±0.2°, 22.20±0.2°, 29.88±0.2°, 20.54±0.2°, 35.15±0.2°, 16.61±0.2°, and the height % of these diffraction peaks is greater than 10.

[0066] The thermogravimetric analysis (TGA) data of the compound III sample prepared in Example 1 were collected by TGA / DSC 3+, and the specific experimental parameters are shown in Table 2. The TGA graph is shown in Figure 3 .

[0067] Table 2 TGA test parameters of vildagliptin oxalate

[0068] Item Parameter Sample tray Aluminum oxide ceramics Temperature range 30-500℃ Heating rate 10K / min Protective gas Nitrogen Flow rate of protective gas 20mL / min

[0069] From Figure 3 it can be seen that when the vildagliptin oxalate crystal form is heated to 90°C, the weight loss is 0.77%; from 90°C to 136°C, the weight loss is 3.01%; from 136°C to 173°C, the weight loss is 3.50%; from 173°C to 503°C, the weight loss is 62.57%.

[0070] The high performance liquid chromatography (HPLC) data of the compound III sample prepared in Example 1 were collected on an Agilent 1260 HPLC, and the specific instrument and experimental parameters are shown in Table 3. The HPLC graph is shown in Figure 4 .

[0071] Table 3 HPLC test parameters of vildagliptin oxalate

[0072] Item Parameter Chromatographic column Hypeisil ODS2 4.6*150mm,5μm Detection wavelength 210nm Injection volume 2μL Flow rate 1ml / min Elution mode Gradient elution Column temperature 35℃ Mobile phase Acetonitrile / water = 50:50(V / V) Time 30min

[0073] From Figure 4 it can be seen that the purity of vildagliptin oxalate is 99.49%, and the maximum single impurity is 0.19%.

[0074] Example 2

[0075] Synthesis of vildagliptin hydrochloride:

[0076]

[0077] Weigh 100 g (Compound II, CAS: 911637-18-8, 0.170 mol) into a reaction flask, add 1 kg of ethanol to dissolve it completely. At room temperature, add 95 g (0.179 mol) of ammonium cerium(IV) nitrate, and heat the mixture to 70 °C for reaction. Monitor the reaction progress by HPLC. After the raw materials disappear, cool the mixture to room temperature, add 1 kg of methyl tert-butyl ether and stir well. Orange-red ammonium cerium(IV) nitrate solid precipitates out. Filter and rotary evaporate the filtrate to obtain the crude product of Compound I. Dissolve the crude product of Compound I in 300 mL of ethanol, slowly add 170 mL (1 M, 0.170 mol) of hydrochloric acid aqueous solution at room temperature, and continue to stir the reaction at room temperature for 1 h. A large amount of white solid precipitates out. Filter, collect the filter cake, and dry it to obtain a white solid, namely Compound IV, with a yield of 50%.

[0078] The high performance liquid chromatography (HPLC) data of the Compound IV sample prepared in Example 2 were collected on an Agilent 1260 HPLC. The specific instruments and experimental parameters are the same as those shown in Table 3. The HPLC chromatogram is shown in Figure 5 。

[0079] From Figure 5 it can be seen that the purity of vildagliptin hydrochloride is 98.33%, and the maximum single impurity is 0.73%.

[0080] Example 3

[0081] Synthesis of vildagliptin tartrate:

[0082]

[0083] Weigh 100 g (Compound II, CAS: 911637-18-8, 0.170 mol) into a reaction flask, add 1 kg of ethanol to dissolve it completely. At room temperature, add 95 g (0.179 mol) of ammonium cerium(IV) nitrate, and heat the mixture to 70 °C for reaction. Monitor the reaction progress by HPLC. After the raw materials disappear, cool the mixture to room temperature, add 1 kg of methyl tert-butyl ether and stir well. Orange-red ammonium cerium(IV) nitrate solid precipitates out. Filter and rotary evaporate the filtrate to obtain the crude product of Compound I. Dissolve the crude product of Compound I in 300 mL of ethanol, slowly dropwise add 50 mL of an aqueous solution containing 26 g (0.170 mol) of oxalic acid, and heat the mixture to 70 °C for reaction for 3 h. Cool to room temperature and continue to stir the reaction overnight. A large amount of white solid precipitates out. Filter, collect the filter cake, and dry it to obtain a white solid, namely Compound V, with a yield of 57%.

[0084] The high performance liquid chromatography (HPLC) data of the Compound V sample prepared in Example 3 were collected on an Agilent 1260 HPLC. The specific instruments and experimental parameters are the same as those shown in Table 3. The HPLC chromatogram is shown in Figure 6 。

[0085] From Figure 6It can be seen that the purity of gliclazide tartrate is 99.65%, and the maximum single impurity is 0.09%.

[0086] Pharmacokinetic study

[0087] BALB / c mice (purchased from Jiangsu Jicui Yakang Biotechnology Co., Ltd., 5 - 6 weeks old, body weight about 20 g) were randomly divided into three groups with 5 mice in each group. The three groups of mice were respectively injected with PBS solutions of gliclazide tartrate, gliclazide oxalate, and gliclazide hydrochloride via the tail vein, and the concentration was 10 μM for all. Blood samples were collected from the submandibular vein at predetermined time points (0, 1, 2, 3, 4, 5, 6, 7, 8, and 9 h after injection). The samples were centrifuged at 16000 r / min for 15 min to obtain plasma. The concentration changes of gliclazide salts in plasma were determined by HPLC, and the relationship curve of blood drug concentration changing with time was plotted according to the ratio of the peak area of each sample to the peak area at 0 h.

[0088] Figure 7 The in - vivo (tail vein injection) pharmacokinetic curves of gliclazide oxalate, gliclazide tartrate, and gliclazide hydrochloride prepared by the present invention are respectively shown. From Figure 7 It can be seen that the metabolic clearance rate of gliclazide oxalate prepared by the present invention in mice is slower than that of gliclazide tartrate and gliclazide hydrochloride. This indicates that gliclazide oxalate can play a hypoglycemic function more persistently. Therefore, gliclazide oxalate prepared by the present invention has great clinical transformation value.

[0089] The above shows and describes the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above - mentioned embodiments. What is described in the above - mentioned embodiments and the specification only illustrates the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of the present invention claimed. The scope of the present invention claimed is defined by the appended claims and their equivalents.

Claims

1. A crystalline form of gemagliptin oxalate, characterized in that: The X-ray powder diffraction pattern of the gemagliptin oxalate crystalline form is shown in FIG2 .

2. The gemagliptin oxalate crystalline form according to claim 1, characterized in that: The X-ray powder diffraction pattern of the gemagliptin oxalate crystalline form is measured using Cu-Kα radiation.

3. The gemagliptin oxalate crystalline form according to claim 1, characterized in that: The gemagliptin oxalate crystalline form is heated to 90 o C, the weight loss is 0.77%; from 90 o Heat to 136°C o C, weight loss is 3.01%; from 136 o Heat to 173°C o C, weight loss is 3.50%; from 173 o Heat to 503°C o C, weight loss is 62.57%.

4. Use of the gemagliptin oxalate crystalline form according to any one of claims 1 to 3 in the preparation of dipeptidyl peptidase-4 inhibitors, hypoglycemic drugs, angiogenesis and regeneration drugs.

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