A process for the preparation of a crystalline form of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-b]pyridine-3-carbonitrile

Abstract

The present application relates to the technical field of medicine and chemical industry, and in particular to a preparation method of a 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolyl[3,4-B]pyridine-3-carbonitrile crystal form, which comprises the following steps: mixing 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolyl[3,4-B]pyridine-3-carbonitrile solid with isopropyl ether, and then stirring and dissolving; cooling and crystallizing, and then drying after filtration and washing to obtain the product. The preparation method of the 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolyl[3,4-B]pyridine-3-carbonitrile crystal form solves 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 and easy electrostatic effect, and the crystal form is easy to form a group and wrap impurities, which is not conducive to subsequent API purification.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical and chemical technology, specifically to a method for preparing the crystalline form of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile. Background Technology

[0002] Different crystal forms of the same drug may exhibit significant differences in appearance, solubility, melting point, dissolution rate, and bioavailability, thus affecting the drug's stability, bioavailability, and efficacy. This phenomenon is particularly pronounced in oral solid dosage forms. Drug polymorphism is a significant factor affecting drug quality and clinical efficacy; therefore, special attention should be paid to crystal form analysis when developing and reviewing drugs with polymorphism.

[0003] In the research and development and production of new drugs, the crystal form of the drug itself is extremely crucial. Polymorphic drugs can be classified into stable, metastable, and unstable types based on their stability. Stable drugs have high melting points and good chemical stability, but slow dissolution rates and low solubility; unstable drugs have fast dissolution rates and high solubility, but relatively poor chemical stability; metastable drugs fall between stable and unstable types, and will transform into stable types after a period of storage. In the research and development and production of new drugs, it is necessary to focus on the crystal form of the drug, explore the mechanisms of drug crystal form polymorphism, and adopt necessary process technologies based on the stability characteristics of each crystal form to ensure the consistency of crystal form between raw materials and formulations during production and storage.

[0004] In recent years, with the large-scale launch of the new drug veliciguat, the demand for its intermediate 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile has surged, and the requirements for its content and quality standards have become increasingly stringent. At the same time, it is also necessary to better meet the standards for large-scale production.

[0005] As an important intermediate for veliciguat, the original crystal form of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone-[3,4-B]pyridine-3-carboxynitrile has low density, large volume, and is prone to electrostatic effects. Furthermore, this crystal form easily aggregates and encapsulates impurities, which is detrimental to subsequent API purification. The original process also suffers from low crystal melting points, leading to sticking and impaction problems during production; moreover, the original crystal form has poor solubility, which is unfavorable for subsequent reactions.

[0006] In view of the above-mentioned defects, the inventors of this invention have finally obtained this invention after a long period of research and practice. Summary of the Invention

[0007] The purpose of this invention is to solve the problems of the low density, large volume, and easy electrostatic effect of the original crystal form of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone-[3,4-B]pyridine-3-carboxylonitrile, which is not conducive to subsequent API purification. The invention provides a method for preparing the crystal form of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone-[3,4-B]pyridine-3-carboxylonitrile.

[0008] To achieve the above objectives, this invention discloses a method for preparing the crystalline form of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile, comprising the following steps:

[0009] S1, 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile solid is mixed with isopropyl ether and stirred to dissolve;

[0010] 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.

[0011] 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.

[0012] 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.

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

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

[0015] In step S2, the crystal growth temperature is 10~20℃ and the crystal growth time is 0.5~1h.

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

[0017] The mechanism of this invention is as follows:

[0018] 5-Fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxynitrile was dissolved in a specific solvent, and the target product was brought to a supersaturated state by cooling. Small seed crystals then gradually precipitated in the solvent. Under specific temperature and time conditions, the small seed crystals gradually grew to obtain the target product crystals.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0020] 1. This invention optimizes the crystallization process of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxylonitrile crystal form I, and investigates the effects of different crystallization methods and solvent dosage on product yield and product content. Finally, the optimized crystallization process conditions of 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone[3,4-B]pyridine-3-carboxylonitrile crystal form I are determined. The product obtained by the optimized crystallization process has a larger diameter and more uniform crystal distribution, and the product purity and content are extremely high.

[0021] 2. The 5-fluoro-1-(2-fluorophenyl)-1H-pyrazolone-[3,4-B]pyridine-3-carboxynitrile synthesized in this invention has a uniform particle size distribution, good antistatic effect, and is not prone to flash explosion; the melting point of the original crystalline form and amorphous product is about 260℃. The S obtained in this invention... IPE The product has a melting point of around 280℃, which is 20℃ higher than the original crystalline and amorphous forms. This reduces the risk of sticking and impact during production and solves the problem of softening and adhering to shearing blades or hammers under mechanical force during the micronization process. At the same time, the solubility of this crystalline form is greatly improved compared to the original crystalline form. After crystallization, the product content is extremely high, the yield is considerable, and the operation is convenient, making it suitable for large-scale industrial production. Attached Figure Description

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

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

[0024] Figure 3 S obtained in Example 1 IPE Crystallographic image magnified 400 times under a microscope;

[0025] Figure 4 S obtained in Comparative Example 1 THF Crystallographic image magnified 400 times under a microscope;

[0026] Figure 5 The original irregular crystal form, S obtained in Comparative Example 1 THF The irregular crystal form and the S obtained in Example 1IPE 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 used. 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. Four sets of tests were conducted for each sample. 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; 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.

2. 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.

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 stirring temperature is 65~75℃ and the stirring speed is 300rpm.

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 S2, the cooling rate is 0.5℃ / min, and the temperature is reduced to 10~20℃.

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 crystal growth temperature is 10~20℃ and the crystal growth time is 0.5~1h.

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 drying temperature is 40~50℃.

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