WO2021136491A1 - Crystalline form of dipeptidyl peptidase iv inhibitor and preparation method therefor and use thereof - Google Patents

Abstract

The present invention provides a crystalline form of a dipeptidyl peptidase IV inhibitor and a preparation method therefor and use thereof. The obtained crystalline form has the characteristics of high purity, regular crystal particle morphology, large particle size, good stability, etc., and is suitable for a direct compression formulation process, and facilitates the preparation of a pharmaceutical formulation, and the preparation method is simple and convenient, and is suitable for industrial large-scale production.

Description

Crystal form of dipeptidyl peptidase IV inhibitor and preparation method and application thereof Technical field

The invention belongs to the technical field of medicine, and specifically relates to a crystal form of a dipeptidyl peptidase IV (DPP-IV) inhibitor, and a preparation method and application thereof.

Background technique

The chemical name of compound I is (2S,4S)-1-[2-(1,1-dimethyl-3-oxo-3-pyrrolidin-1-yl-propylamino)-acetyl]-4 -Fluoro-2-cyano-pyrrolidine, the structural formula is shown in formula I:

Compound I is a dipeptidyl peptidase IV (DPP-IV) inhibitor, which can inhibit DPP-IV and DPP-VIII, causing DPP-IV and DPP-VIII not to degrade glucagon-like peptide 1 (glucagon-like peptide-1, GLP-1), thereby promoting insulin secretion, reducing plasma glucose concentration and enhancing the function of pancreatic β-cells, and can be used clinically to treat type II diabetes.

Patent CN101970402B discloses compound I and its preparation method. The crude reaction product is separated by column chromatography to obtain a white solid, and its purity is not disclosed. Jiang Guoyou et al. [Chinese Journal of New Drugs, 2016, Volume 25, Issue 13, Pages 1531-1534] made a new exploration of the synthetic route of compound I, using acetone recrystallization instead of column chromatography to obtain a white solid with purity 99.5%. Neither of the two prior art studies explored the existence of other crystal forms and the properties of the crystal forms after synthesis and purification, nor did they conduct in-depth research on the possible defects of compound I in the subsequent drug development process. In view of the huge application prospect of compound I in the treatment of diabetes, seeking a crystal form of compound I with excellent properties has become an urgent problem for those skilled in the art.

This application prepared compound I according to the method in CN101970402B and evaluated its properties. It was found that, on the one hand, the product prepared by CN101970402B had the defects of irregular crystal particle appearance, small particle size, and poor fluidity, which made the formulation development process limited by raw materials. On the other hand, the separation method of column chromatography cannot be scaled up and used in industry. The compound I samples prepared according to the method disclosed in the article by Jiang Guoyou et al. [Chinese Journal of New Drugs, 2016, Volume 25, Issue 13, Pages 1531-1534] also have the defects of small particle size and poor fluidity.

Summary of the invention

【technical problem】

A technical problem to be solved by the present invention is to provide a new crystal form of Compound I that can be directly used and stored as a raw material medicine and is suitable for industrial scale-up production.

Another technical problem to be solved by the present invention is to provide a crystal particle with a more regular microscopic morphology and a _{larger particle size value (D 90} ), which can be directly used as a raw material medicine and long-term storage, suitable for preparation process operation, and suitable for industrial scale-up. A new crystalline form of Compound I produced.

【Technical solutions】

In the process of continuous research on the desired crystalline form of Compound I, the inventors of the present application have conducted rigorous experiments and have found a crystalline form that can solve the above technical problems, thereby completing the present invention.

Specifically, this application provides the following technical solutions:

One aspect of the present invention provides a DPP-IV inhibitor compound I crystal form, the structural formula of which is shown in the following formula I:

It is characterized in that, using Cu-Kα radiation, powder X-ray diffraction expressed in 2θ angles (°) has characteristic peaks at the following positions: 8.0±0.2°, 8.8±0.2°, 14.0±0.2°, 17.5±0.2°, 19.6±0.2°, 21.8±0.2°.

Preferably, the relative intensity of the above-mentioned characteristic peak is:

2θ(°)	Relative Strength(%)
8.0	15～30
8.8	100
14.0	15～40
17.5	60～80
19.6	20～40
21.8	20～55

；

More preferably, the relative intensity of the above characteristic peak is:

2θ(°)	Relative Strength(%)
8.0	15～30
8.8	100
14.0	15～30

17.5	60～80
19.6	20～40
21.8	20～41

；

Further preferably, the relative intensity of the above-mentioned characteristic peak is:

2θ(°)	Relative Strength(%)
8.0	17～30
8.8	100
14.0	17～30
17.5	60～80
19.6	20～40
21.8	22～41

.

In some aspects of the present invention, the DPP-IV inhibitor compound I crystal form is characterized in that, using Cu-Kα radiation, powder X-ray diffraction expressed in 2θ angles (°) has characteristic peaks at the following positions: 8.0±0.2°, 8.8±0.2°, 14.0±0.2°, 16.4±0.2°, 17.5±0.2°, 18.7±0.2°, 19.6±0.2°, 20.5±0.2°, 21.8±0.2°.

Preferably, the relative intensity of the above-mentioned characteristic peak is:

2θ(°)	Relative Strength(%)
8.0	15～30
8.8	100
14.0	15～40
16.4	10～40
17.5	60～80
18.7	10～30
19.6	20～40
20.5	10～25
21.8	20～55

；

More preferably, the relative intensity of the above characteristic peak is:

2θ(°)	Relative Strength(%)
8.0	15～30
8.8	100
14.0	15～30

16.4	10～20
17.5	60～80
18.7	10～20
19.6	20～40
20.5	10～25
21.8	20～41

；

Further preferably, the relative intensity of the above-mentioned characteristic peak is:

2θ(°)	Relative Strength(%)
8.0	17～30
8.8	100
14.0	17～30
16.4	10～20
17.5	60～80
18.7	10～20
19.6	20～40
20.5	10～25
21.8	22～41

.

In some aspects of the present invention, the DPP-IV inhibitor compound I crystal form uses Cu-Kα radiation, which has a powder X-ray diffraction pattern substantially as shown in FIG. 2. The term "substantially as shown in the drawings" means that a certain crystal form that is substantially pure has at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of its powder X-ray diffraction pattern. %, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99% of the peaks appear in the given powder X-ray diffraction pattern. When the content of a certain crystal form in the sample gradually decreases, some diffraction peaks in the powder X-ray diffraction pattern attributable to the crystal form may be reduced due to the detection sensitivity of the instrument.

In some aspects of the present invention, the melting point of the DPP-IV inhibitor compound I crystal form is 160-170°C, preferably 166-169°C.

In some aspects of the present invention, the crystal particles of the DPP-IV inhibitor compound I have a columnar shape.

In some aspects of the present invention, the crystal size D _{90 of} the DPP-IV inhibitor compound I is ≥165 μm, preferably ≥ 170 μm, more preferably ≥ 180 μm, further preferably ≥ 220 μm, and even more preferably ≥ 300 μm. The diameter distribution range is 0.9～600μm.

On the other hand, the present invention also provides a method for preparing the above-mentioned DPP-IV inhibitor compound I crystal form, which comprises: (1) adding the crude product to a single solvent system, heating and stirring to dissolve, cooling and stirring for crystallization, and filtering to obtain The crystal form of the DPP-IV inhibitor compound I; or (2) the crude product is added to solvent A and heated to dissolve, concentrated under reduced pressure, ethyl acetate is added, and the crystal form of the DPP-IV inhibitor compound I is filtered to obtain the crystal form of the DPP-IV compound I inhibitor; or ( 3) After adding the crude product to solvent A for heating and dissolving, it is concentrated under reduced pressure to remove part of the solvent and filtered to obtain the crystal form of the DPP-IV compound I inhibitor.

In some aspects of the present invention, in the above preparation method, the single solvent in method (1) is selected from ethanol, isopropanol, tetrahydrofuran, preferably ethanol; preferably, the heating temperature is 20°C to reflux temperature, It is preferably 50°C to reflux temperature; preferably, the crystallization temperature is -10 to 50°C, preferably 0 to 50°C, and more preferably 30 to 50°C; preferably, between the crude product and the single solvent The mass-volume ratio is 1:5-50, preferably 1:5-30.

Or, preferably, in the above preparation method, the single solvent in the method (1) is selected from ethanol, anhydrous ethanol, isopropanol, and tetrahydrofuran, preferably ethanol, more preferably anhydrous ethanol; preferably, the heating The temperature is 20°C to reflux temperature, preferably 50°C to reflux temperature; preferably, the crystallization temperature is -10 to 50°C, preferably 0 to 50°C, more preferably 30 to 50°C; preferably The mass-volume ratio between the crude product and the single solvent is 1:5-50, preferably 1:5-30.

In some aspects of the present invention, in the above preparation method, the solvent A in the method (2) and the method (3) is selected from methanol, dichloromethane, and acetonitrile, preferably methanol, dichloromethane; preferably, the crude product The mass-volume ratio with solvent A is 1:1-10, preferably 1:2-5; preferably, the heating temperature is 20°C to reflux temperature, preferably 20-40°C; preferably, it is concentrated under reduced pressure to 2/3 volume to 1/6 volume, preferably 1/2 volume to 1/6 volume, more preferably 1/3 volume to 1/6 volume, still more preferably 1/4 volume to 1/6 volume, and further It is preferably 1/5 volume, specifically, the degree of concentration under reduced pressure is concentrated until the volume of the remaining solution in the bottle is 2/3 to 1/6 volume of the volume of the originally added solvent A, preferably 1/2 volume ~1/6 volume, more preferably 1/3 volume to 1/6 volume, still more preferably 1/4 volume to 1/6 volume, still more preferably 1/5 volume.

In some embodiments of the present invention, the above preparation method further includes a separation step before obtaining the DPP-IV inhibitor compound I crystals. The separation step includes filtering, centrifugation and other suitable methods to remove the obtained compound I crystals from the crystal solution. separate from.

In some schemes of the present invention, considering the removal of free solvent from the product, after the separation step, it also includes a solvent washing step, such as ethyl acetate, n-hexane, cyclohexane, etc., and a drying step. The drying method can be any suitable A known method is preferably drying under reduced pressure (vacuum). The specific drying conditions are, for example, the temperature is preferably 40-60°C, more preferably 50-60°C; the pressure is preferably vacuum>0.090MPa; the drying time is preferably 5-20h, more preferably 5-8h. Regardless of the drying method used, it is advisable that the solvent residue in the product obtained meets the quality standard. The crude DPP-IV inhibitor compound I described in the present invention is prepared by the known method disclosed in CN101970402B, and can also be prepared by any known method disclosed in other prior art.

Another aspect of the present invention also provides a pharmaceutical composition comprising the above-mentioned DPP-IV inhibitor compound I crystal form. Optionally, the pharmaceutical composition may further comprise other therapeutic components, and the other therapeutic components refer to Other active ingredients or drugs for the treatment of diabetes, such as insulin, metformin or a pharmaceutically acceptable salt thereof, and sulfonylurea and/or thiazolidinedione hypoglycemic agents, preferably metformin or a pharmaceutically acceptable salt thereof, More preferably, it is metformin hydrochloride. Preferably, the other therapeutic components can have a synergistic effect with the DPP-IV inhibitor compound I. Optionally, the compound I crystal form and other therapeutic components are administered in the form of a single preparation or a combined preparation.

Another aspect of the present invention also provides a pharmaceutical composition comprising the above-mentioned DPP-IV inhibitor compound I crystal form and a pharmaceutically acceptable carrier. Optionally, the pharmaceutical composition may also include other therapeutic components, so The other therapeutic components refer to other active ingredients or drugs for the treatment of diabetes, such as insulin, metformin or a pharmaceutically acceptable salt thereof, and sulfonylureas and/or thiazolidinedione hypoglycemic agents, preferably metformin or its The pharmaceutically acceptable salt is more preferably metformin hydrochloride. Preferably, the other therapeutic components can have a synergistic effect with the DPP-IV inhibitor compound I. Optionally, the compound I crystal form and other therapeutic components are administered in the form of a single preparation or a combined preparation.

The above-mentioned pharmaceutical composition is prepared into clinically accepted preparations, such as oral preparations, injection preparations, topical administration preparations, topical preparations and the like. The oral preparations are preferably solid preparations, such as tablets, capsules, granules and the like. These preparations can be prepared by using adjuvants known to those of ordinary skill in the art and using conventional pharmaceutical preparation techniques.

Another aspect of the present invention also provides the application of the above-mentioned DPP-IV inhibitor compound I crystal form or a pharmaceutical composition containing the same in the preparation of DPP-IV inhibitor drugs, especially for the treatment of type II diabetes drugs.

Another aspect of the present invention also provides the above-mentioned DPP-IV inhibitor compound I crystal form or a pharmaceutical composition containing the same for the treatment of type II diabetes.

In still another aspect of the present invention, there is also provided a method for treating type II diabetes, which comprises administering the above-mentioned DPP-IV inhibitor compound I crystal form or a pharmaceutical composition containing the same to a patient or subject in need.

The aforementioned "subject" and "patient" include all members of the animal kingdom, including, but not limited to, mammals (for example, mice, rats, cats, monkeys, dogs, horses, pigs, etc.) and humans.

The beneficial effects of the crystal form of the DPP-IV inhibitor compound I of the present invention are: (1) The crystal form of the DPP-IV inhibitor compound I of the present invention can be directly used as a raw material medicine, and the instruments, equipment and operations used in the preparation process There are no special and harsh requirements, and it is more suitable for industrial scale-up production; (2) The crystal particles of the crystal form of the DPP-IV inhibitor compound I of the present invention have a more regular microscopic morphology and a _{larger particle size value (D 90} ). The preparation process operation, especially the direct compression tableting process, can greatly simplify the preparation process of the preparation; (3) The crystal form of the DPP-IV inhibitor compound I of the present invention also has excellent stability. In the accelerated experiment and long-term stability test, the investigated crystal form did not undergo a crystal form transformation, and the maximum single impurities, content, moisture, etc. have no obvious changes, and it is more suitable for storage as a raw material drug.

Description of the drawings

Figure 1: Appearance of the crystal particles of the compound I sample obtained in Preparation Example 1.

Figure 2: Powder X-ray diffraction pattern of the crystal form of Compound I obtained in Example 1.

Figure 3: Appearance morphology of the crystal particles of the compound I crystal form obtained in Example 1.

Figure 4: Appearance of the crystal particles of the compound I crystal form obtained in Example 3.

Figure 5: Appearance morphology of the crystal particles of the compound I sample obtained in Comparative Example 1.

Detailed ways

1. The powder X-ray diffraction pattern detection conditions of the samples obtained in the following examples are as follows:

Equipment name: D/MAX-2500X-ray diffractometer

Target: Cu (40KV, 150mA)

Step angle: 0.02°

Scan range: 1.5～40.0°.

2. The particle size detection conditions of the samples obtained in the following examples are as follows:

Equipment name: Malvern laser particle size analyzer (Malvern 2000)

Measurement method: dry method

Shading degree: 0.5%～5%

Measuring air pressure: 2.0bar

Measurement time: background measurement time 10s, sample measurement time 7s.

3. The observation conditions of the crystal shape of the sample obtained in the following examples are as follows:

Equipment name: Olympus microscope (microscope frame wit CX31)

Capture resolution: 3072*2048

Set the scale: 1

Selection ruler: 4X

Set the line width: 2.

The present invention will be described in detail below through some embodiments, but the present invention is not limited to the following embodiments. Modifications obvious to those skilled in the art are intended to fall within the scope of the claims of the present invention.

If no specific conditions are indicated in the examples, it shall be carried out in accordance with the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used without the manufacturer's indication are all conventional products that can be purchased on the market. Unless otherwise defined, the meanings of all professional and scientific terms used in the text are the same as those familiar to those skilled in the art.

The crude compound I of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by its combination with other chemical synthesis methods, and those skilled in the art. Well-known equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.

In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the existing embodiments.

Preparation Example 1: Preparation of crude compound I (refer to CN101970402B method for preparation)

Potassium carbonate (110g, 800mmol) was added to 3-amino-3-methyl-1-pyrrolidin-1-yl-butan-1-one trifluoroacetic acid (56g, 200mmol) dissolved in dry tetrahydrofuran (1000mL) ) Stir the solution. After stirring at room temperature for 1 hour, the mixture was filtered through Celite, and washed with ethyl acetate (1000 mL). (2S,4S)-1-(2-bromoacetyl)-4-fluoro-2-cyano-pyrrolidine (24g, 100mmol) was added to the filtrate, and the reaction mixture was stirred under nitrogen at room temperature 12 hour. Under reduced pressure, most of the solvent was removed, and the residue was separated using CH ₂ Cl ₂ (4000 mL) and H ₂ O (1000 mL). The aqueous layer _{was extracted with CH 2} Cl ₂ (2000 mL). The combined organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a thick oily crude product. The crude oil product was purified by chromatography (silica gel, 4%-10% CH ₃ OH/CH ₂ Cl ₂ gradient) to obtain a white solid compound (24 g, total yield 74%, liquid phase purity 99.5%, Melting point: 163.1-164.4°C). A sample is taken for particle size detection, and the particle size D ₉₀ of the sample powder is 145.487 μm. The appearance of the sample powder particles is shown in Figure 1, irregular.

Example 1 Preparation of Compound I Crystal Form

Add the crude compound I (10g, 30.83mmol) prepared according to the method of Preparation Example 1 to 60mL of methanol, dissolve at 25±5℃ with stirring, and concentrate under reduced pressure to obtain about 40mL of methanol. Stop the concentration under reduced pressure, and stir at 25±5℃. After 1h, the temperature was lowered to 0～5℃ and the crystallization was continued for 1h and filtered, and the solid was washed with ethyl acetate. After vacuum drying, 6.74 g of white crystalline powder was obtained. The yield is 67.4%, the liquid phase purity is 99.88%, and the melting point is 166.3-167.8°C. A sample was taken for X-ray powder diffraction, and it was shown as a crystalline solid. The results are shown in Table 1, and the spectrum is shown in Figure 2. Samples were taken for particle size testing, and the results of crystal particle size testing are shown in Table 2. The appearance of the crystal particles is shown in Figure 3, showing columnar crystals.

Table 1 Powder-X-ray diffraction peak data of compound I crystal form obtained in Example 1

Serial number	2θ angle (°)	Relative Strength	Serial number	2θ angle (°)	Relative Strength
1	8.020	17.0%	8	18.741	19.2%
2	8.822	100.0%	9	19.699	31.4%
3	14.047	17.8%	10	20.491	10.6%
4	14.639	5.8%	11	21.875	24.1%
5	15.970	6.9%	12	23.130	8.5%
6	16.365	15.4%	13	26.010	9.1%
7	17.566	74.6%	To	To	To

Note: The data presented in the table are diffraction peaks with relative peak intensity> 5%.

Table 2 Particle size test results of compound I crystal form obtained in Example 1

D 10 (μm)	D 50 (μm)	D 90 (μm)
12.103	101.174	316.909

Example 2 Preparation of Compound I Crystal Form

The crude compound I (10 g, 30.83 mmol) prepared according to the method of Preparation Example 1 was added to 50 mL of dichloromethane, and dissolved under stirring at room temperature. Concentrate under reduced pressure to obtain 40 mL of dichloromethane, add 50 mL of ethyl acetate, filter, and wash the solid with ethyl acetate. After vacuum drying, 7.30 g of white crystalline powder was obtained. The yield is 73.0%, the purity of the liquid phase is 99.7%, and the melting point is 167.0-168.2°C. Samples were taken for particle size testing, and the results of crystal particle size testing are shown in Table 3. The appearance of the crystal particles is columnar crystals.

Table 3 Particle size test results of compound I crystal form obtained in Example 2

D 10 (μm)	D 50 (μm)	D 90 (μm)
12.138	64.452	181.096

Example 3 Preparation of Compound I Crystal Form

The crude compound I (20 g, 61.65 mmol) prepared according to the method of Preparation Example 1 was added to 160 mL of absolute ethanol, heated to reflux to dissolve, and the temperature was lowered to 30° C., and stirring was continued for 1 h. After filtration, the solid was washed with ethyl acetate and dried in vacuum to obtain 11.56 g of white crystalline powder with a yield of 57.8%, a liquid phase purity of 99.9%, and a melting point of 166.7-167.9°C. A sample was taken for X-ray powder diffraction, and it was shown as a crystalline solid. The results are shown in Table 4. Samples were taken for particle size testing, and the results of crystal particle size testing are shown in Table 5. The appearance of the crystal particles is shown in Figure 4, showing columnar crystals.

Table 4 Compound I crystal form powder-X-ray diffraction characteristic peak data obtained in Example 3

Serial number	2θ angle (°)	Relative Strength	Serial number	2θ angle (°)	Relative Strength
1	7.981	18.8%	7	18.664	14.2%
2	8.764	100.0%	8	19.630	20.8%
3	13.993	20.9%	9	20.449	13.3%
4	15.908	5.1%	10	21.844	24.3%
5	16.298	10.6%	11	25.994	6.5%
6	17.517	65.3%	To	To	To

Note: The data presented in the table are diffraction peaks with relative peak intensity> 5%.

Table 5 Particle size test results of compound I crystal form obtained in Example 3

D 10 (μm)	D 50 (μm)	D 90 (μm)
8.019	43.457	168.990

Example 4 Preparation of Compound I Crystal Form

The crude compound I (20 g, 61.65 mmol) prepared according to the method of Preparation Example 1 was added to 160 mL of absolute ethanol, heated to reflux and dissolved, cooled to 0° C., and stirring was continued for 1 h. After filtration, the solid was washed with ethyl acetate, and dried in vacuum to obtain 16.04 g of white crystalline powder with a yield of 80.2%, a liquid phase purity of 99.8%, a melting point of 168.1-169.4°C, and all single impurities below 0.1%. Samples were taken for particle size testing, and the results of crystal particle size testing are shown in Table 6. The appearance of the crystal particles showed columnar crystals.

Table 6 Particle size test results of compound I crystal form obtained in Example 4

D 10 (μm)	D 50 (μm)	D 90 (μm)
16.293	71.874	220.06

Comparative Example 1: Preparation of Compound I

Prepared by referring to the method disclosed in the literature "Chinese Journal of New Drugs, 2016, Volume 25, Issue 13, Pages 1531-1534", a white solid 2.2g was obtained, the sample powder particle size D ₉₀ was 67.237μm, and the melting point: 163.4-164.7°C . See Figure 5 for the appearance morphology of the sample powder particles.

Example 5: The influence of different samples on the preparation process

In order to investigate whether the above-mentioned products meet the requirements of the preparation process operation, the influence of Preparation Example 1, Comparative Example 1, and Examples 1 to 4 on the direct compression process of the preparation was compared. The results are shown in Table 7.

Table 7 The influence of different samples of compound I on the preparation process of direct compression

Note: The formulation components and weight percentages are as follows: microcrystalline cellulose (66.55%), sodium starch glycolate (1.0%), magnesium stearate (1.2%), the balance is compound I crystals; premix: compound I Mix with microcrystalline cellulose and sodium starch glycolate to obtain a premix; total mixing: mix the premix with magnesium stearate.

Therefore, in the above preparation examples, comparative examples and examples, the crystal form (particle size ≥165μm) obtained in Examples 1-4 meets the requirements of the preparation direct compression process, while the preparation example 1 and comparative example 1 (particle size <150μm) It cannot meet the preparation process requirements.

Example 6: Influencing factor test

Take an appropriate amount of the compound I crystal form sample of Example 1, and place it under the conditions of high temperature (40℃±2℃, 60℃±2℃), high humidity (92.5%RH, 75%RH), and light (4500Lx±500Lx). Days and 10 days, the experimental results are shown in Table 8.

Table 8 Experimental data results of compound I crystal form samples under different conditions

Take appropriate amounts of the compound I crystal form samples of Example 3, Preparation Example 1 and Comparative Example 1, respectively, at high temperature (40℃±2℃, 60℃±2℃), high humidity (92.5%RH, 75% RH) and light (4500Lx±500Lx) were placed for 5 days and 10 days. The experimental results are shown in Table 9-10.

Table 9 Experimental data results of the compound I crystal form samples of Example 3 under different conditions

Table 10 Experimental data results of samples obtained in Preparation Example 1 and Comparative Example 1 under different conditions

The test results of influencing factors show that, compared with the samples of Preparation Example 1 and Comparative Example 1, the maximum single impurity and total impurity content of the samples of the compound I crystal form obtained in Example 1 and Example 3 of the present invention at day 0 are both lower. That is, the sample has higher purity and is more suitable for direct use as an API; the samples obtained in Example 1 and Example 3 are at high temperature (40℃±2℃, 60℃±2℃) and high humidity (92.5%RH, 75%RH). ), and placed under the conditions of light (4500Lx±500Lx) for 10 days, compared with the data of 0 days, there is no significant change in all the detection indicators, indicating that the properties of the samples obtained in these two examples are stable and suitable for storage as bulk drugs.

Example 7: Accelerated test

Take an appropriate amount of compound I crystal form samples of Examples 1 and 3, and place them in a medicinal low-density polyethylene bag + polyester/aluminum/polyethylene composite bag at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% They were placed for 6 months under the conditions, and samples were taken at the end of the 0th, 1, 2nd, and 6th months respectively. The sample of Example 1 after 6 months was subjected to powder X-ray diffraction analysis to observe whether it was consistent with the 0-day crystal form. The experimental results are shown in Table 12.

Table 11 Experimental data results of the accelerated test stability of the samples obtained in Examples 1 and 3

Table 12 Powder-X-ray diffraction data of the crystalline sample in Example 1 after being placed for 6 months

Serial number	2θ angle (°)	Relative Strength	Serial number	2θ angle (°)	Relative Strength
1	7.975	25.1%	9	19.645	36.5%
2	8.762	100.0%	10	20.448	22.8%
3	13.991	28.7%	11	21.807	40.5%
4	14.700	10.3%	12	23.267	15.6%
5	15.884	7.2%	13	25.951	10.4%
6	16.313	15.8%	14	27.039	5.7%
7	17.515	75.1%	15	28.115	5.9%
8	18.686	26.2%	To	To	To

Note: The data presented in the table are diffraction peaks with relative peak intensity> 5%.

The accelerated test results show that the crystal form samples of Example 1 and Example 3 have been placed for 6 months at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%, the appearance of the samples has not changed, and the related substances have no significant growth. , And the crystal form has not changed, the stability of the sample is good, and the packaging used has no obvious influence on the stability of the product, and it is suitable for storage as a bulk drug.

Example 8: Long-term test

Take an appropriate amount of compound I crystal form samples of Examples 1 and 3, and place them in a medicinal low-density polyethylene bag + polyester/aluminum/polyethylene composite bag at a temperature of 25°C ± 2°C and a relative humidity of 60% ± 5% Placed under the conditions for 36 months, samples were taken at the end of the 0th, 1, 3, 6, 12, 18, 24, 34, and 36 months respectively. The experimental results are shown in Table 13.

Table 13: Accelerated Test Stability Test Data Results of the Samples Obtained in Examples 1 and 3

Note: / is not tested.

The long-term test results show that the crystal form samples of Example 1 and Example 3 have been placed for 36 months at a temperature of 25°C ± 2°C and a relative humidity of 60% ± 5%, and the appearance of the samples has no significant change, and there is no significant related substance. Growth, and the crystal form has not changed, the stability of the sample is good, the packaging used has no obvious effect on the stability of the product, and it is suitable for long-term storage as a bulk drug.

In summary, the compound I of the present invention has good crystal form stability, can be used directly as a raw material drug and stored for a long time. The crystal particles have regular appearance and a _{larger particle size value (D 90} ), which is suitable for the preparation process operation, and the purification process is suitable for industry. The scale-up production provides a new way for the preparation of compound I drugs.

Claims (14)

1. A crystal form of a DPP-IV inhibitor, the DPP-IV inhibitor has the following structural formula:

   

   It is characterized in that, using Cu-Kα radiation, powder X-ray diffraction expressed in 2θ angles (°) has characteristic peaks at the following positions: 8.0±0.2°, 8.8±0.2°, 14.0±0.2°, 17.5±0.2°, 19.6±0.2°, 21.8±0.2°.
2. The crystalline form of the DPP-IV inhibitor according to claim 1, wherein the relative intensity of the characteristic peaks has the following characteristics:

   2θ(°) Relative Strength(%) 8.0 15～30 8.8 100 14.0 15～40 17.5 60～80 19.6 20～40 21.8 20～55 ；

   Preferably, the relative intensity of the above-mentioned characteristic peak is:

   2θ(°) Relative Strength(%) 8.0 15～30 8.8 100 14.0 15～30 17.5 60～80 19.6 20～40 21.8 20～41 ；

   Further preferably, the relative intensity of the above-mentioned characteristic peak is:

   2θ(°) Relative Strength(%) 8.0 17～30 8.8 100 14.0 17～30

   17.5 60～80 19.6 20～40 21.8 22～41 .
3. The crystalline form of the DPP-IV inhibitor according to claim 1, wherein the powder X-ray diffraction expressed in 2θ angle (°) using Cu-Kα radiation has a characteristic peak at the following position: 8.0±0.2° , 8.8±0.2°, 14.0±0.2°, 16.4±0.2°, 17.5±0.2°, 18.7±0.2°, 19.6±0.2°, 20.5±0.2°, 21.8±0.2°.
4. The crystalline form of the DPP-IV inhibitor according to claim 3, wherein the relative intensity of the characteristic peaks has the following characteristics:

   2θ(°) Relative Strength(%) 8.0 15～30 8.8 100 14.0 15～40 16.4 10～40 17.5 60～80 18.7 10～30 19.6 20～40 20.5 10～25 21.8 20～55 ；

   Preferably, the relative intensity of the above-mentioned characteristic peak is:

   2θ(°) Relative Strength(%) 8.0 15～30 8.8 100 14.0 15～30 16.4 10～20 17.5 60～80 18.7 10～20 19.6 20～40 20.5 10～25 21.8 20～41 ；

   Further preferably, the relative intensity of the above-mentioned characteristic peak is:

   2θ(°) Relative Strength(%) 8.0 17～30 8.8 100 14.0 17～30 16.4 10～20 17.5 60～80 18.7 10～20 19.6 20～40 20.5 10～25 21.8 22～41 . .
5. The crystalline form of the DPP-IV inhibitor according to any one of claims 1 to 4, characterized in that Cu-Kα radiation is used, which has a powder X-ray diffraction pattern substantially as shown in FIG. 2.
6. The crystal form of the DPP-IV inhibitor according to any one of claims 1 to 5, wherein the melting point of the crystal form is 160-170°C, preferably 166-169°C.
7. The crystal form of the DPP-IV inhibitor according to any one of claims 1 to 6, wherein the crystal particles of the DPP-IV inhibitor have a columnar shape.
8. The crystal form of the DPP-IV inhibitor according to any one of claims 1 to 7, wherein the crystal particle size D ₉₀ of the inhibitor is ≥165 μm, preferably ≥ 170 μm, and more preferably ≥ 180 μm, It is more preferably ≥ 220 μm, and still more preferably ≥ 300 μm.
9. A method for preparing the crystal form of the DPP-IV inhibitor according to any one of claims 1 to 8, specifically: (1) adding the crude product to a single solvent system, heating and stirring to dissolve, cooling and stirring to crystallize , Filter to obtain the crystal form of the DPP-IV inhibitor; or (2) add the crude product to solvent A and heat to dissolve, concentrate under reduced pressure, add ethyl acetate, and filter to obtain the crystal form of the DPP-IV inhibitor; or (3 ) After adding the crude product to solvent A and heating to dissolve it, concentrating under reduced pressure, removing part of the solvent, and filtering to obtain the crystal form of the DPP-IV compound I inhibitor.
10. The preparation method according to claim 9, wherein the single solvent in the method (1) is selected from ethanol, absolute ethanol, isopropanol, tetrahydrofuran, preferably ethanol, more preferably absolute ethanol; preferably , The heating temperature is 20°C to reflux temperature, preferably 50°C to reflux temperature; preferably, the crystallization temperature is -10 to 50°C, preferably 0 to 50°C, more preferably 30 to 50 °C; Preferably, the mass-volume ratio between the crude product and the single solvent is 1:5-50, preferably 1:5-30.
11. The preparation method according to claim 9, wherein the solvent A in the method (2) and the method (3) is selected from methanol, dichloromethane, acetonitrile, preferably dichloromethane or methanol; preferably, the solvent A is selected from the group consisting of methanol, dichloromethane, and acetonitrile; The mass-volume ratio of the crude product and solvent A is 1:1-10, preferably 1:2-5; preferably, the heating temperature is 20°C to reflux temperature, preferably 20-40°C; preferably, reduced pressure Concentrated to 2/3 volume to 1/6 volume, preferably 1/2 volume to 1/6 volume, more preferably 1/3 volume to 1/6 volume, still more preferably 1/4 volume to 1/6 volume, More preferably, it is 1/5 volume.
12. A pharmaceutical composition comprising the DPP-IV inhibitor compound I crystal form according to any one of claims 1 to 8. Optionally, the pharmaceutical composition may further comprise other therapeutic components, the other therapeutic Components refer to other active ingredients or drugs for the treatment of diabetes, such as insulin, metformin or pharmaceutically acceptable salts thereof, and sulfonylureas and/or thiazolidinedione hypoglycemic agents, preferably metformin or its pharmaceutically acceptable The accepted salt is more preferably metformin hydrochloride; preferably, the other therapeutic components can produce a synergistic effect with the DPP-IV inhibitor compound I; preferably, the pharmaceutical composition is made into a clinically accepted preparation, and the preparation Including oral preparations, injection preparations, topical preparations, topical preparations, etc.; oral preparations are preferred, and tablets and capsules are more preferred.
13. A pharmaceutical composition comprising the DPP-IV inhibitor compound I crystal form according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier. Optionally, the pharmaceutical composition may also include other treatments Components, the other therapeutic components refer to other active ingredients or drugs for the treatment of diabetes, such as insulin, metformin or a pharmaceutically acceptable salt thereof, and sulfonylureas and/or thiazolidinedione hypoglycemic agents, preferably Is metformin or a pharmaceutically acceptable salt thereof, more preferably metformin hydrochloride; preferably, the other therapeutic component can have a synergistic effect with the DPP-IV inhibitor compound I; optionally, the compound I crystal form and Other therapeutic components are administered in the form of a single preparation or a combined preparation.
14. The crystal form of the DPP-IV inhibitor according to any one of claims 1 to 8, or the crystal form of the DPP-IV inhibitor prepared by the method of any one of claims 9-11, or the crystal form of claim 12 or 13 The pharmaceutical composition is used in the preparation of DPP-IV inhibitor drugs, especially in the treatment of type II diabetes drugs.

Images