Preparation method of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone [3, 4-B] pyridine-3-formonitrile crystal form

Abstract

The invention relates to the technical field of pharmaceutical chemical engineering, in particular to a preparation method of a 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone [3, 4-B] pyridine-3-formonitrile crystal form, which comprises the following steps: mixing a 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone [3, 4-B] pyridine-3-formonitrile solid with isopropyl ether, and stirring for dissolving; and cooling, growing crystals, performing suction filtration, washing and drying. The preparation method of the 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone [3, 4-B] pyridine-3-formonitrile crystal form solves the problems that the original crystal form of the existing 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone [3, 4-B] pyridine-3-formonitrile is small in density, large in volume and easy to generate electrostatic effect, and the crystal form is easy to agglomerate to wrap impurities and is not beneficial to subsequent API (American Petroleum Institute) purification.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine and chemical industry, and particularly relates to a preparation method of a 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile crystal form. BACKGROUND

[0002] Different crystal forms of the same drug can be significantly different in appearance, solubility, melting point, dissolution rate, biological effectiveness, etc., thereby affecting the stability, bioavailability and efficacy of the drug, and such a phenomenon is particularly obvious in oral solid preparations. The polymorphism of a drug is one of the important factors affecting the quality of a drug and the clinical efficacy, and therefore, special attention should be paid to the analysis of the crystal form of a drug with polymorphism during the research and development and evaluation of the drug.

[0003] In the process of research and development and production of a new drug, the crystal form type of the drug is extremely crucial. Polymorphic drugs can be divided into stable, metastable and unstable types according to their stability. The stable type has a high melting point and good chemical stability, but has a slow dissolution rate and small solubility; the unstable type has a fast dissolution rate and large solubility, but has relatively poor chemical stability; the metastable type is between the stable type and the unstable type, and will change to the stable type after being stored for a period of time. In the process of research and development and production of a new drug, the crystal form type of the drug should be focused on, the mechanism of the polymorphism of the crystal form of the drug should be explored, and necessary process technologies should be adopted according to the stability characteristics of each crystal form type to ensure the consistency of the crystal form of the raw material and the preparation during the production and storage.

[0004] In recent years, with the large-scale marketing of the new drug velixibane, the demand for the intermediate 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile has increased dramatically, and the requirements for the content and quality standards of the intermediate are higher and higher, and it is also necessary to better meet the large-scale production standards.

[0005] As an important intermediate of velixibane, the original crystal form of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carbonitrile has a small density and a large volume, and is prone to electrostatic effect. Meanwhile, the crystal form is easy to form a group and wrap impurities, which is not conducive to the subsequent purification of API. The original process crystal has a low melting point, and is prone to sticking and clashing problems during the production process. In addition, the original crystal form has poor solubility, which is not conducive to the subsequent reaction.

[0006] In view of the above defects, the present inventors have finally obtained the present application after a long period of research and practice. SUMMARY

[0007] The present application aims to solve the problems of the original crystal form of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolyl[3,4-B]pyridine-3-carbonitrile, such as small density, large volume, easy to cause electrostatic effect, easy to form a group of impurities, and not conducive to subsequent API purification, and provides a preparation method of a crystal form of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolyl[3,4-B]pyridine-3-carbonitrile.

[0008] In order to achieve the above-mentioned purpose, the present application discloses a preparation method of a crystal form of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolyl[3,4-B]pyridine-3-carbonitrile, comprising the following steps:

[0009] S1, mixing 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolyl[3,4-B]pyridine-3-carbonitrile solid with isopropyl ether, and stirring to dissolve;

[0010] S2, after complete dissolution in step S1, maintaining the stirring rate, cooling and crystallizing, and after washing by filtration and drying, obtaining 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolyl[3,4-B]pyridine-3-carbonitrile.

[0011] The crystal form is S IPE , and the XRD diffraction pattern of the S IPE has characteristic absorption peaks at the following 2θ angles: 12.0±0.3, 15.0±0.3, 16.0±0.3, 18.0±0.3, 19.0±0.3, 21.0±0.3, 23.0±0.3, and 29.0±0.3.

[0012] In the step S1, the use ratio of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolyl[3,4-B]pyridine-3-carbonitrile to isopropyl ether is 1g:3-10mL.

[0013] In the step S1, the stirring temperature is 65-75℃, and the stirring rate is 300rpm.

[0014] In the step S2, the cooling rate is 0.5℃ / min, and the temperature is cooled to 10-20℃.

[0015] In the step S2, the crystallization temperature is 10-20℃, and the crystallization time is 0.5-1h.

[0016] In the step S2, the drying temperature is 40-50℃.

[0017] The mechanism of the present application is as follows:

[0018] 5-Fluoro-1-(2-fluorophenyl)-1H-pyrazolyl[3,4-B]pyridine-3-carbonitrile is dissolved in a specific solvent, and the target product is made to reach a supersaturated state by cooling, and then small crystal seeds are gradually precipitated in the solvent. Under specific temperature and time, the small crystal seeds gradually grow to obtain the target product crystal.

[0019] The beneficial effects of the present application compared with the prior art are:

[0020] 1. The crystallization process of 5-Fluoro-1-(2-fluorophenyl)-1H-pyrazolyl[3,4-B]pyridine-3-carbonitrile crystal form I is optimized, the effects of different crystallization methods and solvent amount on product yield and product content are investigated, and the optimal crystallization process conditions of 5-Fluoro-1-(2-fluorophenyl)-1H-pyrazolyl[3,4-B]pyridine-3-carbonitrile crystal form I are determined. The product obtained by the optimized crystallization process has larger diameter and more uniform crystal distribution, and the product has very high purity and content.

[0021] 2. The 5-Fluoro-1-(2-fluorophenyl)-1H-pyrazolyl[3,4-B]pyridine-3-carbonitrile crystal form synthesized by the present application has uniform particle size distribution, good antistatic effect, and is not prone to flash explosion. The melting point of the original crystal form and amorphous product is about 260℃, and the S IPE The melting point of the product obtained by the present application is about 280℃, which is 20℃ higher than that of the original crystal form and amorphous product, reducing the risk of sticking and collision in production, solving the problem of softening and adhering to the shear cutter or hammer under the action of mechanical force in the process of micronization; at the same time, the solubility of this crystal form is greatly improved compared with the original crystal form; the product obtained after crystallization has very high content, considerable yield, and convenient operation, and can be used for large-scale industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 The XRD diffraction pattern of S IPE obtained in Example 1;

[0023] Figure 2 The XRD diffraction pattern of S THF obtained in Comparative Example 1;

[0024] Figure 3 The crystal form pattern of S IPE obtained in Example 1 under a microscope at 400 times magnification;

[0025] Figure 4 The crystal form pattern of S THF obtained in Comparative Example 1 under a microscope at 400 times magnification;

[0026] Figure 5 The irregular crystal form of S THF obtained in Comparative Example 1 and the SIPE Crystal form comparison diagram;

[0027] Figure 6 The original irregular crystal form, S obtained in Comparative Example 1 THF The irregular crystal form and the S obtained in Example 1 IPE Comparison of solubility of crystal forms. Detailed Implementation

[0028] The above-mentioned and other technical features and advantages of the present invention will be described in more detail below with reference to the accompanying drawings.

[0029] Example 1

[0030] Solvent compound S IPE Preparation:

[0031] Weigh 20 g of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile and measure 100 mL of isopropyl ether. Add both to a 250 mL single-necked flask. Set the temperature to 65℃ and the stirring rate to 300 rpm to dissolve. After complete dissolution, maintain the stirring rate and cool to 20℃ at a rate of 0.5℃ / min. Allow to crystallize at 10-20℃ for 1 h. After filtration and washing, dry at 40-50℃ to obtain compound S of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile. IPE The product yield was 93%, and the product content was 99.9%. The obtained S... IPE The XRD diffraction pattern is as follows Figure 1 As shown, the crystal form diagram is as follows: Figure 3 As shown, by Figure 3 It can be seen that S IPE Under a microscope, the crystal form can be observed to be a complete and orderly arrangement of regular needle-like crystals.

[0032] Example 2

[0033] Solvent compound S IPE Preparation:

[0034] Weigh 20 g of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile and measure 100 mL of isopropyl ether. Add both to a 250 mL single-necked flask. Set the temperature to 65℃ and the stirring rate to 300 rpm to dissolve. After complete dissolution, maintain the stirring rate and cool to 20℃ at a rate of 0.5℃ / min. Allow crystals to crystallize at 10-20℃ for 0.5 h. After filtration, washing, and drying at 40-50℃, obtain compound S of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile. THF The product has a yield of 86% and a purity of 99%.

[0035] Example 3

[0036] Solvent compound S IPE Preparation:

[0037] Weigh 20 g of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile and measure 60 mL of isopropyl ether. Add both to a 250 mL single-necked flask. Set the temperature to 65℃ and the stirring rate to 300 rpm to dissolve. After complete dissolution, maintain the stirring rate and cool to 20℃ at a rate of 0.5℃ / min. Allow to crystallize at 10-20℃ for 1 h. After filtration, washing, and drying at 40-50℃, obtain compound S of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile. THF The product has a yield of 90% and a purity of 99.2%.

[0038] Example 4

[0039] Solvent compound S IPE Preparation:

[0040] Weigh 20 g of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile and measure 100 mL of isopropyl ether. Add both to a 250 mL single-necked flask. Set the temperature to 65℃ and the stirring rate to 300 rpm to dissolve. After complete dissolution, maintain the stirring rate and cool to 10℃ at a rate of 0.5℃ / min. Allow to crystallize at 0-10℃ for 1 h. After filtration, wash, and drying at 40-50℃, obtain compound S of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile. THF The product yield is 93%, and the product content is 99.78%.

[0041] Example 5

[0042] Solvent compound S IPE Preparation:

[0043] Weigh 20 g of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile and measure 200 mL of isopropyl ether. Add both to a 250 mL single-necked flask. Set the temperature to 65℃ and the stirring rate to 300 rpm to dissolve. After complete dissolution, maintain the stirring rate and cool to 20℃ at a rate of 0.5℃ / min. Allow to crystallize at 10-20℃ for 1 h. After filtration and washing, dry at 40-50℃ to obtain compound S of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile. THF The product has a yield of 80% and a purity of 99.9%.

[0044] Example 6

[0045] Solvent compound S IPE Preparation:

[0046] Weigh 20 g of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile and measure 200 mL of isopropyl ether. Add both to a 250 mL single-necked flask. Set the temperature to 75℃ and the stirring rate to 300 rpm to dissolve. After complete dissolution, maintain the stirring rate and cool to 20℃ at a rate of 0.5℃ / min. Allow to crystallize at 10-20℃ for 1 h. After filtration and washing, dry at 40-50℃ to obtain compound S of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile. THF The product has a yield of 85% and a purity of 99.5%.

[0047] Comparative Example 1

[0048] Solvent compound S THF Preparation:

[0049] Weigh 20 g of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile and measure 60 mL of tetrahydrofuran. Add both to a 250 mL single-necked flask. Set the temperature to 65℃ and the stirring rate to 300 rpm to dissolve. After complete dissolution, maintain the stirring rate and cool to 20℃ at a rate of 0.5℃ / min. Allow crystals to crystallize at 10-20℃ for 1 h. After filtration and washing, dry at 40-50℃ to obtain compound S of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile. THF The product yield was 88%, and the product content was 99.5%. The obtained S... THF The XRD diffraction pattern is as follows Figure 2 As shown, the crystal form diagram is as follows: Figure 4 As shown, by Figure 4 It can be seen that S THF Under a microscope, the crystal form appears as an irregular arrangement of granular and platy crystals.

[0050] Comparative Example 2

[0051] Solvent compound S IPE / THF Preparation:

[0052] Weigh 20 g of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile, measure 50 mL of isopropyl ether and 50 mL of tetrahydrofuran, and add them together to a 250 mL single-necked flask. Set the temperature to 65℃ and the stirring rate to 300 rpm to dissolve. After complete dissolution, maintain the stirring rate and cool down to 20℃ at a rate of 0.5℃ / min. Crystallize at 10-20℃ for 1 h. After filtration and washing, dry at 40-50℃ to obtain compound S of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile. IPE / THF The product has a yield of 99.6% and a content of 90%.

[0053] Table 1. Product effects obtained in Examples 1-6 and Comparative Examples 1-2

[0054]

[0055] The original irregular crystal form and the irregular S synthesized in Comparative Example 1 were used. THF Crystal form, rule S of synthesis in Example 1 IPE The crystal form was tested as follows:

[0056] (1) Comparison of antistatic properties:

[0057] like Figure 5 As shown, Figure 5 In the middle, the left side shows the original irregular crystal form. Due to strong electrostatic agglomeration, the product consists of large, irregular particles. The middle part shows the irregular S synthesized in Comparative Example 1. THF The crystal form also exhibits electrostatic agglomeration, resulting in irregular particles as the product. The right image shows S synthesized in Example 1. IPE The product has a crystalline form, strong antistatic properties, is not prone to clumping, and is a loose and uniform solid.

[0058] (2) Comparison of solubility:

[0059] Weigh out the original irregular crystal form and the irregular S synthesized in Comparative Example 1, respectively. THF Crystal form, rule S of synthesis in Example 1 IPE 0.2g of the crystalline form was dissolved in 1mL of methanol and sonicated at 25℃ for 10min. The dissolution was then observed. Undissolved samples were filtered, the filter cake was dried and weighed. The more undissolved solids remaining, the worse the solubility.

[0060] The results are as follows Figure 6 As shown, Figure 6 In the middle, the left side shows the original irregular crystal form, and the center shows the synthesized irregular S crystal. THF Crystal form, right is the synthetic rule S IPE Crystal form. Comparison revealed that the original irregular crystal form had the worst solubility, and the synthesized S... THFSecondly, the synthesized S crystal form IPE The crystal form has the best solubility.

[0061] (3) Melting point comparison:

[0062] 0.1g of the original irregular crystal form and the irregular S synthesized in Comparative Example 1 were respectively synthesized. THF Crystal form, rule S of synthesis in Example 1 IPE After grinding the crystal, it is placed into a wool tube and inverted to pack it tightly; then the capillary tube is inserted into the melting point apparatus, the instrument is run, and the data is recorded.

[0063] The results are shown in Table 2. In the table, TA represents the initial melting temperature and TC represents the complete melting temperature. Each sample was tested in 4 groups. As shown in Table 2, compared with the original irregular crystal form and the synthesized S THF Crystal form and synthesized S IPE The crystal form, after multiple measurements and averaging, yielded a melting point (TC) of 266.8℃ for the original crystal form and a synthesized S crystal form. THF The crystalline form has a melting point (TC) of 255.3℃, and S... IPE The crystalline form has a melting point (TC) of 286.9℃, and the synthesized S IPE The melting point of the crystal form is higher than that of the original irregular crystal form and S. THF The crystal form has a melting point above 20°C.

[0064] Table 2. Original irregular crystal form, S obtained in Comparative Example 1 THF Crystal form and S obtained in Example 1 IPE Comparison of melting points of crystal forms

[0065]

[0066] The above description is merely a preferred embodiment of the present invention and is illustrative rather than restrictive. Those skilled in the art will understand that many changes, modifications, and even equivalents can be made within the spirit and scope defined by the claims of the present invention, all of which will fall within the protection scope of the present invention.

Claims

1. A method for preparing the crystalline form of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile, characterized in that, Includes the following steps: S1, 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile solid is mixed with isopropyl ether and stirred to dissolve; S2. After the solution in step S1 is completely dissolved, maintain the stirring rate, cool down to grow crystals, filter, wash and dry to obtain 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxylonitrile.

2. The method for preparing the crystalline form of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile according to claim 1, characterized in that, The crystal form is S. IPE The S IPE The XRD diffraction patterns show characteristic absorption peaks at the following 2θ angles: 12.0±0.3, 15.0±0.3, 16.0±0.3, 18.0±0.3, 19.0±0.3, 21.0±0.3, 23.0±0.3, and 29.0±0.

3.

3. The method for preparing the crystalline form of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile as described in claim 1, characterized in that, In step S1, the ratio of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile to isopropyl ether is 1g:3~10mL.

4. The method for preparing the crystalline form of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile as described in claim 1, characterized in that, In step S1, the stirring temperature is 65~75℃ and the stirring speed is 300rpm.

5. The method for preparing the crystalline form of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile as described in claim 1, characterized in that, In step S2, the cooling rate is 0.5℃ / min, and the temperature is reduced to 10~20℃.

6. The method for preparing the crystalline form of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile as described in claim 1, characterized in that, In step S2, the crystal growth temperature is 10~20℃ and the crystal growth time is 0.5~1h.

7. The method for preparing the crystalline form of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile as described in claim 1, characterized in that, In step S2, the drying temperature is 40~50℃.

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