1H-pyrazolo [3, 4-B] pyridine-3-formonitrile crystal form A and preparation method thereof
The 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crude product was added to the 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile and the alcohol solvent, and the temperature was increased and the cooling and drying process was carried out to increase the temperature and stir, and the temperature was reduced and dried. The 1H-pyrazolo[3,4- B] Pyridine-3-forminitrile crystal form A solves the problems of poor product properties and impurity packaging, achieves high-quality and efficient production, and is suitable for commercial production.
Patent Information
- Application Number
- CN202411350897.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-26
- Publication Date
- 2024-12-31
AI Technical Summary
In the prior art, the product properties of 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile are coalesced particles, which are not easy to dry, and the impurities are wrapped in low purity, which affects the quality and commercialization of Leoscigua. Chemical production.
The 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crude product, drinking water and alcohol solvent were used to keep warm and stir after heating, and then cool down and filtered to dry. The 1H-pyrazolo[3,4] -B] Pyridine-3-carbonitrile crystal form A, has blocky crystals, good fluidity, large particle size, reduces electrostatic adsorption and coalescence, is easy to dry, and has low impurity content.
The obtained 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystal A product has higher quality, shortening production time, improving production capacity, reducing production costs, and reducing the impact of impurities on downstream product quality. .
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Figure CN119219630A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystal form A and a preparation method thereof. Background Art
[0002] Riociguat is a drug used to treat pulmonary hypertension (PH), mainly for chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Its chemical name is: N-[4,6-diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl]-N-methylcarbamic acid methyl ester, and its structural formula is shown in II below:
[0003]
[0004] The key fragment pyrazolopyridine in the structural formula of riociguat usually requires the use of the intermediate 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile, the structural formula of which is shown below:
[0005]
[0006] There are multiple synthetic routes for 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile. U.S. Patents US20100113507 and US20100004235 both disclose synthetic processes for preparing 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile using 3-(trifluoromethyl)-1H-pyrazolo[3,4-B]pyridine; WO2011149921 discloses preparing 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile by reacting 3-iodo-1H-pyrazolo[3,4-B]pyridine with highly toxic zinc cyanide; WO201525025 reports preparing 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile by reacting 3-bromo-1H-pyrazolo[3,4-B]pyridine with highly toxic zinc cyanide, etc.
[0007] Among the various synthetic routes of 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile, there are two post-treatment methods after the reaction of 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile is completed. One is to extract with an organic solvent (such as ethyl acetate, etc., US20100113507) and then evaporate to dryness under reduced pressure to obtain 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile. This treatment method has certain feasibility in the pilot research stage, but in industrial production, the product obtained by evaporation under reduced pressure is a solid, which is not easy to carry out the next step of treatment. At the same time, because it has not been crystallized and purified, the purity of the obtained product is often low, which is not conducive to the subsequent reaction and the quality of the finished product riociguat. The second method is to add or not add a solvent after the reaction is completed, and then distill. After removing part of the solvent, the solution is cooled for crystallization purification. The quality of the product obtained by this method is improved to a certain extent, but the particle size of the product obtained by this method is small, and it is easy to produce electrostatic adsorption and agglomeration. The appearance of agglomerated particles is formed by encapsulating the mother liquor. The mother liquor is encapsulated inside the particles of this agglomerated form, which makes it difficult to dry the product and remove impurities. The product quality is not high, which affects the quality of the downstream finished product Riociguat. The product cannot meet market demand when it is commercially sold, and often requires multiple refining and purification, which has high costs, low production capacity, and complicated processes, and is not conducive to long-term large-scale production.
[0008] In view of the above-mentioned defects, the inventors of the present invention finally obtained the present invention after a long period of research and practice. Summary of the invention
[0009] The purpose of the present invention is to solve the problem that the product produced by the prior art is in the form of agglomerated particles, is not easy to dry, and has low content due to impurities wrapped, and provides a 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystal form A and a preparation method thereof.
[0010] In order to achieve the above-mentioned object, the present invention provides a method for preparing the above-mentioned 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystal form A, comprising the following steps:
[0011] S1, adding crude 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile, drinking water and alcohol solvent into a reactor, heating and then maintaining the temperature with stirring;
[0012] S2, after the heat preservation is completed, the feed liquid is cooled, filtered, and dried to obtain a 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystalline form A finished product.
[0013] In step S1, the alcohol solvent is any one or a combination of methanol, ethanol, isopropanol, n-butanol, and tert-butanol.
[0014] In the step S1, the alcohol solvent is methanol.
[0015] In the step S1, the mass ratio of the crude 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile to drinking water is 1:2-20, and the mass volume ratio of the crude 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile to the alcohol solvent is 1:0.05-1.0.
[0016] In the step S1, the mass ratio of the crude 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile to drinking water is 1:4, and the mass volume ratio of the crude 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile to the alcohol solvent is 1:0.5.
[0017] In the step S1, the temperature of the heat preservation and stirring is 40 to 80° C., and the heat preservation and stirring time is 0.5 to 5 hours.
[0018] In the step S1, the temperature of the heat preservation and stirring is 70° C., and the heat preservation and stirring time is 1 hour.
[0019] In the step S2, the cooling temperature is 0-30°C.
[0020] In step S2, the cooling temperature is 5°C.
[0021] The present invention also discloses 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystal form A prepared by the preparation method.
[0022] Compared with the prior art, the present invention has the following beneficial effects: the present invention provides a new crystal form A of 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile, the crystal form A product is a block crystal, has a large particle size, good fluidity, is not easy to produce electrostatic adsorption and agglomeration between particles, is not easy to contain mother liquor in the separation process after crystallization, the product is easy to dry, has a low impurity content, and has higher quality, which can not only shorten the production time, improve the production capacity, and reduce the production cost, but also reduce the influence of impurities on the quality of downstream products. BRIEF DESCRIPTION OF THE DRAWINGS
[0023] Figure 1 This is the HPLC purity spectrum of the crude 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile in Example 1 of the present invention;
[0024] Figure 2 The XRPD spectrum of 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystalline form A in Example 1 of the present invention;
[0025] Figure 3 The HPLC purity spectrum of 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystalline form A in Example 1 of the present invention;
[0026] Figure 4This is a microscope photograph of 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystal form A in Example 1 of the present invention;
[0027] Figure 5 The XRPD spectrum of the granular 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile in Comparative Example 1 of the present invention;
[0028] Figure 6 This is a microscope photograph of granular 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile in Comparative Example 1 of the present invention. DETAILED DESCRIPTION
[0029] The above and other technical features and advantages of the present invention are described in more detail below in conjunction with the accompanying drawings. The crude 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile used in the present invention is prepared according to Example 1 in reference patent US201001135073, and the crude purity is 95.04%.
[0030] Example 1
[0031] Add 10 g of crude 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile, 40 g of drinking water and 5 mL of methanol to the reaction bottle, start stirring and heat to 70°C. After heating, keep stirring at 70°C for 1 hour. After keeping warm, cool the liquid to 5°C. After cooling, filter. Collect the wet filter cake and dry it in an oven at 60°C for 4 hours. 9.7 g of 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystalline form A was obtained, with a yield of 97%, a product moisture content of 0.2% and a purity of 99.2%. Figures 1 to 4 As shown, the crystal form is a block crystal, and its X-ray powder diffraction spectrum has characteristic diffraction peaks at 2θ angles of 10.18±0.2°, 11.88±0.2°, 12.98±0.2°, 13.42±0.2°, 14.50±0.2°, 15.50±0.2°, 18.32±0.2°, 20.38±0.2°, 24.60±0.2°, 26.22±0.2°, 26.88±0.2°, 27.58±0.2°, 28.32±0.2°, 30.70±0.2°, and 31.93±0.2°. The product of this crystal form has good fluidity, large particle size, is not easy to agglomerate, has little mother liquor residue during centrifugation or filtration, is easy to dry, has low impurity content, is of high quality, and is suitable for commercial production.
[0032] Example 2
[0033] Add 10g of crude 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile, 20g of drinking water, and 0.5mL of ethanol to the reaction bottle, start stirring, and heat to 40°C. After heating, keep stirring at 40°C for 5 hours. After keeping warm, cool the liquid to 30°C. After cooling, filter. Collect the wet filter cake and put it in an oven at 60°C to dry for 8 hours. 9.4g of 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystal form A was obtained, with a yield of 94%, a product moisture of 0.4%, and a purity of 98.7%.
[0034] Example 3
[0035] Add 10g of crude 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile, 200g of drinking water, and 10mL of isopropanol to the reaction bottle, start stirring, and heat to 80°C. After heating, keep stirring at 80°C for 1 hour. After keeping warm, cool the liquid to 0°C. After cooling, filter. Collect the wet filter cake and put it in an oven at 60°C to dry for 6 hours. 9.5g of 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystal form A was obtained, with a yield of 95%, a product moisture of 0.4%, and a purity of 98.8%.
[0036] Example 4
[0037] Add 10g of crude 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile, 100g of drinking water, and 8mL of tert-butanol to the reaction bottle, start stirring, and heat to 60°C. After heating, keep stirring at 60°C for 1 hour. After keeping warm, cool the liquid to 15°C. After cooling, filter. Collect the wet filter cake and put it in an oven at 80°C to dry for 4 hours. 9.6g of 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystal form A was obtained, with a yield of 96%, a product moisture of 0.3%, and a purity of 98.4%.
[0038] Comparative Example 1
[0039] Refer to patent US201001135073 Example 1 to prepare 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile.
[0040] Add 5 g (26.7 mmol) of 3-(trifluoromethyl)-1H-pyrazolo[3,4-B]pyridine and 100 mL of 33% ammonia water to the reaction bottle, heat to 140°C in a microwave for 10 minutes, and concentrate under reduced pressure to dryness after the reaction is complete. Add 1000 mL of ethyl acetate and 200 mL of methyl tert-ether, stir to dissolve, filter to remove insoluble matter, and concentrate the filtrate to obtain a yellow granular solid 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile. Take out the solid and vacuum dry it at 60°C for 8 hours to obtain 3.5 g of the product, with a yield of 90%, a moisture content of 1.7%, and a purity of 95.04%. Figures 5-6As shown, the X-ray powder diffraction spectrum of the product crystal form prepared by the method has characteristic diffraction peaks at 2θ angles of 11.84°, 14.46°, 15.18°, 23.96°, 24.60°, 26.20°, 26.89°, 27.64°, and 27.96°. The crystal form has an agglomerated granular appearance, poor fluidity, and low purity.
[0041] Comparative Example 2:
[0042] Add 10g of crude 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile, 250g of drinking water, and 20mL of methanol to the reaction bottle, start stirring, and heat to 70°C. After heating, keep stirring at 70°C for 1 hour. After keeping warm, cool the liquid to 5°C. After cooling, filter. Collect the wet filter cake and put it in an oven at 80°C to dry for 4 hours. Obtain 2.6g of 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystal form A finished product, with a yield of 26%, a product moisture of 0.6%, and a purity of 99.3%.
[0043] The above description is only a preferred embodiment of the present invention, which is only illustrative and not restrictive of the present invention. Those skilled in the art understand that many changes, modifications, and even equivalences may be made to the present invention within the spirit and scope defined by the claims of the present invention, but all of them will fall within the scope of protection of the present invention.
Claims
1. A 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystalline form A, characterized in that: The X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ angles of 10.18±0.2°, 11.88±0.2°, 12.98±0.2°, 13.42±0.2°, 14.50±0.2°, 15.50±0.2°, 18.32±0.2°, 20.38±0.2°, 24.60±0.2°, 26.22±0.2°, 26.88±0.2°, 27.58±0.2°, 28.32±0.2°, 30.70±0.2°, and 31.93±0.2°.
2. A method for preparing 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystalline form A as claimed in claim 1, characterized in that: The following steps are involved: S1, adding crude 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile, drinking water and alcohol solvent into a reactor, heating and then maintaining the temperature with stirring; S2, after the heat preservation is completed, the feed liquid is cooled, filtered, and dried to obtain a 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystal form A finished product.
3. The method for preparing a 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystal form A according to claim 2, characterized in that: In step S1, the alcohol solvent is any one or a combination of methanol, ethanol, isopropanol, n-butanol, and tert-butanol.
4. The method for preparing 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystalline form A according to claim 2, characterized in that: In the step S1, the alcohol solvent is methanol.
5. The method for preparing 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystal form A according to claim 2, characterized in that: In the step S1, the mass ratio of the crude 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile to drinking water is 1:2-20, and the mass volume ratio of the crude 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile to the alcohol solvent is 1:0.05-1.
0.
6. The method for preparing 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystal form A according to claim 2, characterized in that: In the step S1, the mass ratio of the crude 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile to drinking water is 1:4, and the mass volume ratio of the crude 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile to the alcohol solvent is 1:0.
5.
7. The method for preparing 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystal form A according to claim 2, characterized in that: In the step S1, the temperature of the heat preservation and stirring is 40 to 80° C., and the heat preservation and stirring time is 0.5 to 5 hours.
8. The method for preparing 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystal form A according to claim 2, characterized in that: In the step S1, the temperature of the heat preservation and stirring is 70° C., and the heat preservation and stirring time is 1 hour.
9. The method for preparing 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystal form A according to claim 2, characterized in that: In the step S2, the cooling temperature is 0-30°C.
10. The method for preparing 1H-pyrazolo[3,4-B]pyridine-3-carbonitrile crystal form A according to claim 2, characterized in that: In step S2, the cooling temperature is 5°C.