Preparation method of fused ring compound crystal

Abstract

The invention relates to the technical field of medicine, and discloses a preparation method of a fused ring compound crystal, # imgabs0 # crystal is an A-type crystal form of a compound of formula 1, and the preparation method comprises the following steps: suspending a compound of formula I in any form in a solvent, heating for dissolving, filtering while hot, cooling the obtained filtrate, adding purified water, continuously cooling and stirring to cure the crystal, and drying to obtain the fused ring compound crystal. And centrifuging and drying in vacuum to obtain the crystal of the crystal form A with high purity and high stability. According to the method, the high-yield preparation method of the cap dependent endonuclease inhibitor which is used for preventing and treating influenza A and has high purity and high stability is provided.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a method for preparing condensed ring compound crystals. Background Art

[0002] The fused ring compound (Formula I) is a cap-dependent endonuclease inhibitor used for the prevention and treatment of influenza A. Its chemical structure is as follows: .

[0003] Patent WO2023088370 reports the stability of the crystalline form A of the compound of formula I. The test results show that the crystalline form A of the compound of formula I has good stability under high temperature (60°C, open), high humidity (RH 92.5%, open), and strong light (5000lx, open) conditions. At the same time, the crystalline form A of the compound of formula I showed a protective effect in the animal model efficacy test.

[0004] Patent WO2023088370 reports a method for preparing the crystalline form A of compound formula I, wherein any crystalline form of formula I is added to methyl tert-butyl ether, n-heptane, ethanol-water mixture, acetone-water mixture, methyl tert-butyl ether-ethyl acetate mixture to prepare a suspension, and the suspension is kept warm and stirred to obtain formula I as crystalline form A. However, the crystalline purity of the crystals obtained by the above preparation method is low, and the introduction of amorphous or other crystalline forms to form mixed crystals cannot be commercially scaled up for production, and the bioavailability of the drug in the body cannot be ensured.

[0005] Patent CN118206567B uses ethyl acetate (5 times the volume, 4.5 times the mass) for beating and crystallizing to prepare compound I. This preparation method fails to completely dissolve compound I, introduces amorphous or other crystalline forms to form mixed crystals, cannot be commercially scaled up for production, and cannot ensure the bioavailability of the drug in the body.

[0006] Therefore, the market is in urgent need of a method for large-scale commercial purification of condensed ring compounds (Formula I) to meet the needs of prevention and treatment in response to frequent influenza outbreaks. Summary of the invention

[0007] The present invention aims to solve at least one of the technical problems existing in the related art. To this end, the present invention provides a method for preparing a condensed ring compound crystal.

[0008] A method for preparing a condensed ring compound crystal, The crystal is type A of the compound of formula 1, The preparation steps include: S1. Add any form of the compound of formula I into a solvent, heat to dissolve, and filter while hot to obtain a filtrate; S2, after cooling the filtrate, add purified water, keep warm and stir; S3, continuing to cool and stir to ripen the crystals, to obtain a compound of formula I in the form of crystal form A.

[0009] Furthermore, the solvent used in step S1 is ethyl acetate, and the amount used is 5-20 times the mass of the compound of formula I.

[0010] Furthermore, the temperature for heating and dissolving in step S1 is 50 to 80°C.

[0011] Furthermore, the amount of purified water added in step S2 is 0.5-1.5 times the mass of the compound of formula I.

[0012] Furthermore, in step S2, the cooling and heat preservation temperature is 40 to 65° C., and the heat preservation and stirring time is 1 hour.

[0013] Furthermore, the temperature for cooling, stirring and aging in step S3 is -5 to 30°C.

[0014] Furthermore, the aging time in step S3 is 1 to 5 hours.

[0015] Furthermore, the crystalline form is the compound of formula I in crystalline form A, Its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 6.859°±0.200°, 10.557°±0.200°, 13.059°±0.200°, 13.782°±0.200°, 16.381°±0.200°, 16.900°±0.200°, 20.780°±0.200°, 21.480°±0.200°, 23.420°±0.200°, 24.401°±0.200°, 25.679°±0.200°, 27.500°±0.200°, 28.181°±0.200°, 29.062°±0.200°, and 29.661°±0.200°.

[0016] The above one or more technical solutions in the embodiments of the present invention have at least one of the following technical effects: 1. The crystals obtained by the preparation method have high crystal purity and are in the form of crystal A. The crystal form has cap-dependent endonuclease inhibition ability, can ensure the bioavailability of the drug in the body, and can be used for the prevention and treatment of influenza A. 2. The crystals obtained by this preparation method have high purity and high yield, and have considerable economic value. 3. The preparation method is simple in process, mild in preparation conditions, and the cost of the raw materials used is controllable, and has broad application prospects.

[0017] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] In order to more clearly illustrate the technical solutions in the present invention or the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0019] Figure 1 is the powder X-ray diffraction pattern of the crystals prepared in Example 1 of the present invention; Figure 2 is a comparison chart of X-ray diffraction patterns of the crystalline powder prepared in Example 1 of the present invention after being treated under different temperature conditions; Figure 3 is the powder X-ray diffraction pattern of the crystals prepared in Example 2 of the present invention; Figure 4 is the powder X-ray diffraction pattern of the crystals prepared in Example 3 of the present invention; Figure 5 is the powder X-ray diffraction pattern of the crystal prepared in the comparative example of the present invention; Figure 6 It is a comparison chart of the powder X-ray diffraction patterns of the crystals prepared in Example 1 of the present invention and the comparative example. DETAILED DESCRIPTION

[0020] In order to make the purpose, technical scheme and advantages of the present invention clearer, the technical scheme of the present invention will be clearly and completely described below in conjunction with the drawings in the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention. The following embodiments are used to illustrate the present invention, but cannot be used to limit the scope of the present invention.

[0021] Example 1 Any form of the compound of formula I (10.00 g) was added to ethyl acetate (70 ml, 63 g, 20°C), the resulting suspension mixture was heated to 80°C to fully dissolve, and filtered while hot.

[0022] The filtrate was cooled to 65°C and purified water (5 ml, 5 g) was added while maintaining the temperature at 65°C. The mixture was stirred for 1 hour.

[0023] The mixture was cooled to 30°C, stirred and matured at 30°C for 1 hour, filtered and vacuum dried to obtain white crystalline particles (7.50 g) with a yield of 75.0%.

[0024] The powder X-ray diffraction analysis showed that the product was in Form A. Its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 6.859°±0.200°, 10.557°±0.200°, 13.059°±0.200°, 13.782°±0.200°, 16.381°±0.200°, 16.900°±0.200°, 20.780°±0.200°, 21.480°±0.200°, 23.420°±0.200°, 24.401°±0.200°, 25.679°±0.200°, 27.500°±0.200°, 28.181°±0.200°, 29.062°±0.200°, and 29.661°±0.200°.

[0025] X-ray diffraction spectrum is shown in the attached Figure 1 .

[0026] The batch of crystalline samples is subjected to variable temperature powder X-ray diffraction detection. A certain mass of samples is weighed and tested on an X-ray diffraction testing device. The samples are processed before each test, and the processing process is carried out on the X-ray diffraction testing device.

[0027] The specific processing and test sequence before each test are as follows: After sample preparation, X-ray diffraction test was performed. After the test, nitrogen was purged for 20 minutes and the test was repeated. After the test, the test was performed again after heating to 120°C under nitrogen conditions. After the test, cool down to 30℃ and test again. After the test, expose to air for 30 minutes and test again.

[0028] Finally, the X-ray diffraction comparison patterns of the crystalline powder prepared in Example 1 after being treated under different temperature conditions are obtained, as shown in FIG. Figure 2 As shown in the figure, it can be seen that the crystals prepared in Example 1 have strong stability. After being treated with variable temperature and exposed to the environment, the structure of the crystals remains stable.

[0029] The results compared with the starting sample of Form A showed that The diffraction peaks of the sample did not change after nitrogen purging for 20 minutes; When the sample is heated to 120°C, some diffraction peaks shift slightly, which is presumably caused by the expansion of the lattice after heating; When the temperature was lowered to 30°C, the diffraction peaks of the samples did not change; After exposure to air for 30 minutes, the diffraction peaks of the sample did not change.

[0030] Example 2 Any form of the compound of formula I (6.83 kg) was added to ethyl acetate (68.3 L, 61.47 kg, 20° C.), and the resulting suspension mixture was heated to 70° C. and filtered while hot.

[0031] The filtrate was cooled to 50°C and purified water (6.83 L, 6.83 kg) was added while maintaining the temperature at 50°C, and the mixture was stirred for 1 hour.

[0032] The mixture was cooled to 5°C, stirred and matured at 5°C for 3 hours, centrifuged and vacuum dried to obtain white crystalline particles (5.77 kg) with a yield of 84.5%.

[0033] The powder X-ray diffraction analysis showed that the product was in Form A. Its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 6.839°±0.200°, 10.520°±0.200°, 13.041°±0.200°, 13.761°±0.200°, 16.398°±0.200°, 16.881°±0.200°, 20.761°±0.200°, 21.459°±0.200°, 23.401°±0.200°, 24.380°±0.200°, 26.279°±0.200°, 27.480°±0.200°, 28.180°±0.200°, 29.021°±0.200°, and 29.601°±0.200°.

[0034] X-ray diffraction spectrum is shown in the attached Figure 3 .

[0035] Example 3 Any form of the compound of formula I (10.00 g) was added to ethyl acetate (200 ml, 180 g, 20° C.), and the resulting suspension mixture was heated to 50° C. and filtered while hot.

[0036] The filtrate was cooled to 40°C and purified water (15 ml, 15 g) was added while maintaining the temperature at 40°C. The mixture was stirred for 1 hour.

[0037] The mixture was cooled to -5°C and stirred for 5 hours at -5°C. It was then filtered and dried under vacuum to obtain white crystalline particles (8.20 g). The yield was 82.0%. The powder X-ray diffraction analysis showed that the product was in Form A. Its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 6.876°±0.200°, 10.540°±0.200°, 13.079°±0.200°, 13.803°±0.200°, 16.399°±0.200°, 16.921°±0.200°, 20.835°±0.200°, 21.496°±0.200°, 23.417°±0.200°, 24.383°±0.200°, 25.642°±0.200°, 27.498°±0.200°, 28.198°±0.200°, 29.058°±0.200°, and 29.641°±0.200°.

[0038] X-ray diffraction spectrum is shown in the attached Figure 4 , Comparative Example According to the preparation method disclosed in patent CN118206567B, compound I (100.00 g) was added to ethyl acetate (500 ml), and the resulting suspension mixture was slurried and stirred for 2 hours, filtered, and vacuum dried to obtain a white powder (45.00 g) with a yield of 45%.

[0039] After powder X-ray diffraction detection, the X-ray diffraction spectrum is shown in the attached Figure 5 .

[0040] The powder X-ray diffraction superposition patterns of the crystals prepared in Example 1 and the crystals prepared in the comparative example are shown in the attached Figure 6 .from Figure 5 and Figure 6 It can be seen that the crystals prepared according to the scheme of patent CN118206567B have more overlapping peaks and bun peaks. Compared with the diffraction peaks of the sample prepared in Example 1, some characteristic peaks of Form A are not obvious, and there are more impurity peaks of other forms, indicating that the crystals prepared by the scheme of patent CN118206567B have lower purity and are mixed crystals containing Form A, and the yield is also lower.

[0041] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a condensed ring compound crystal, characterized in that: The crystal is type A of the compound of formula 1, The preparation steps include: S1. Add any form of the compound of formula I into a solvent, heat to dissolve, and filter while hot to obtain a filtrate; S2, after cooling the filtrate, add purified water, keep warm and stir; S3, continuing to cool and stir to ripen the crystals, to obtain a compound of formula I in the form of crystal form A.

2. The method for preparing a condensed ring compound crystal according to claim 1, characterized in that: The solvent used in step S1 is ethyl acetate, and the amount used is 5-20 times the mass of the compound of formula I.

3. The method for preparing a condensed ring compound crystal according to claim 1, characterized in that: The temperature for heating and dissolving in step S1 is 50 to 80°C.

4. The method for preparing a condensed ring compound crystal according to claim 1, characterized in that: The amount of purified water added in step S2 is 0.5-1.5 times the mass of the compound of formula I.

5. The method for preparing condensed ring compound crystals according to claim 1, characterized in that: In step S2, the cooling and heat preservation temperature is 40 to 65° C., and the heat preservation and stirring time is 1 hour.

6. The method for preparing condensed ring compound crystals according to claim 1, characterized in that: The temperature for cooling, stirring and aging in step S3 is -5 to 30°C.

7. The method for preparing condensed ring compound crystals according to claim 1, characterized in that: The aging time in step S3 is 1 to 5 hours.

8. The method for preparing condensed ring compound crystals according to claim 1, characterized in that: The crystalline form is the compound of formula I of Form A, Its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 6.859°±0.200°, 10.557°±0.200°, 13.059°±0.200°, 13.782°±0.200°, 16.381°±0.200°, 16.900°±0.200°, 20.780°±0.200°, 21.480°±0.200°, 23.420°±0.200°, 24.401°±0.200°, 25.679°±0.200°, 27.500°±0.200°, 28.181°±0.200°, 29.062°±0.200°, and 29.661°±0.200°.

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