A fused heterocyclic derivative crystal form C and its preparation method

Abstract

This invention provides a crystalline form C of a fused heterocyclic derivative of formula (Ⅰ), whose XRPD pattern exhibits characteristic peaks at diffraction angles 2θ at 6.87°±0.2°, 8.43°±0.2°, 15.36°±0.2°, 15.91°±0.2°, 16.32°±0.2°, 20.95°±0.2°, 23.73°±0.2°, and 28.07°±0.2°. The fused heterocyclic derivative crystalline form C provided by this invention possesses properties such as simple preparation process, high purity, good stability, low hygroscopicity, and good mechanical stability.

Description

Technical Field

[0001] This invention relates to a crystal form of a fused heterocyclic derivative, specifically, to a crystal form C of a fused heterocyclic derivative and its preparation method. Technical Background

[0002] Uterine fibroids, adenomyosis, and endometriosis are all serious disorders of endometrial growth. These diseases are associated with hypertrophy and proliferation of the uterine myometrial cells, which may ultimately lead to changes in the size and shape of the uterus. Currently, treatment options for patients with these diseases are limited. Minimally invasive surgery is rarely performed on patients with adenomyosis; hysterectomy is often considered the only treatment option, and there are currently no approved drugs for treating adenomyosis or its related symptoms. Similar to adenomyosis, drug treatment for endometriosis is either ineffective or has significant side effects. Therefore, it is essential to develop new and effective treatments that can alleviate the symptoms of these diseases and treat their underlying pathology.

[0003] A fused heterocyclic derivative, chemically named 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid, has the structural formula shown in formula (I). Developed by Kissei Pharmaceutical, this novel oral non-peptide small molecule gonadotropin-releasing hormone (GnRH; LHRH) receptor antagonist prevents endogenous GnRH from activating its pituitary receptors, ultimately reducing estrogen production by the ovaries. It can maintain estradiol within the normal range and alleviate symptoms while avoiding severe bone loss or other adverse reactions associated with excessive estrogen suppression, possessing potential best-in-class characteristics. It can be used for the prevention or treatment of sex hormone-dependent diseases such as uterine fibroids, adenomyosis, and endometriosis.

[0004]

[0005] Currently, there are few patent reports on the crystal forms of fused heterocyclic derivatives. Patent document CN101331134B discloses a method for preparing fused heterocyclic derivatives of formula (I): the solid crystal form (hereinafter referred to as "crystal form G4") obtained by silica gel column chromatography purification (elution buffer: n-hexane / ethyl acetate = 1 / 2-ethyl acetate) is a solvate crystal form, which is unstable. Moreover, its preparation method has a long cycle, many elution solvents, and complicated operation, which is not conducive to large-scale production.

[0006] Patent CN102753557B discloses a crystalline form of a fused heterocyclic derivative compound (hereinafter referred to as "crystalline form A"), which has poor solubility and will further affect the absorption, efficacy and safety of the drug.

[0007] 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. Therefore, developing new crystal forms with more advantageous properties is crucial for the production and application of fused heterocyclic derivatives (I). Summary of the Invention

[0008] This invention discloses a novel crystalline form of the fused heterocyclic derivative shown in formula (I) and its preparation method. This novel crystalline form exhibits high crystallinity, higher purity, is less hygroscopic, has better stability, and is easy to store. Its preparation method is simple and conducive to industrial production.

[0009]

[0010] The novel crystalline form of the fused heterocyclic derivative described in this invention is crystalline form C (hereinafter referred to as "crystalline form C"). The X-ray powder diffraction (XRPD) pattern detected using Cu-Kα radiation shows characteristic peaks at diffraction angles 2θ at 6.87°±0.2°, 8.43°±0.2°, 15.36°±0.2°, 15.91°±0.2°, 16.32°±0.2°, 20.95°±0.2°, 23.73°±0.2°, and 28.07°±0.2°.

[0011] More specifically, the X-ray powder diffraction pattern (XRPD) of crystal form C, detected by Cu-Kα radiation, shows characteristic peaks at diffraction angles 2θ at 6.87°±0.2°, 8.43°±0.2°, 12.46°±0.2°, 13.76°±0.2°, 15.36°±0.2°, 15.91°±0.2°, 16.32°±0.2°, 18.46°±0.2°, 20.95°±0.2°, 23.73°±0.2°, 26.13°±0.2°, and 28.07°±0.2°.

[0012] More specifically, the X-ray powder diffraction pattern (XRPD) of crystal form C, detected using Cu-Kα radiation, shows diffraction angles 2θ at 6.87°±0.2°, 8.43°±0.2°, 12.46°±0.2°, 13.76°±0.2°, 14.29°±0.2°, 15.36°±0.2°, 15.91°±0.2°, and 16.32°±0.2°. Characteristic peaks are observed at 18.46°±0.2°, 20.42°±0.2°, 20.95°±0.2°, 22.16°±0.2°, 22.73°±0.2°, 23.73°±0.2°, 24.18°±0.2°, 24.98°±0.2°, 26.13°±0.2°, 26.78°±0.2°, and 28.07°±0.2°.

[0013] More specifically, the crystal form C has the same properties as... Figure 3 The XRPD patterns are basically the same.

[0014] The crystal form C described in this invention has the following unit cell parameters: α=105.962(11)°; β=105.859(10)°; γ=92.622(10)°.

[0015] The crystal form C described in this invention has the same properties as... Figure 4 The DSC / TGA spectra are basically the same. The weight loss is about 0.2% in the temperature range of 30℃ to 100℃. There is a melting endothermic peak at 245℃ to 247℃. The melting point is 246.93℃. It begins to decompose after about 250℃.

[0016] The fused heterocyclic derivative crystal form C described in this invention can be further used to produce gonadotropin-releasing hormone antagonist drugs.

[0017] This invention provides a method for preparing the above-mentioned crystal form C, the method comprising the following steps: suspending the fused heterocyclic derivative (I) raw material in a solvent, optionally with or without seed crystals, stirring the suspension, filtering and drying to obtain crystal form C.

[0018] Furthermore, the solvent is selected from any one or two or more solvents of alcohols, esters, ketones, ethers, nitriles, and water, mixed in any proportion.

[0019] More preferably, the alcohol is selected from one or more of methanol, isopropanol, n-butanol, isoamyl alcohol, and sec-amyl alcohol; the ester is selected from one or more of ethyl acetate, methyl acetate, ethyl formate, and isopropyl acetate; the ketone is selected from one or more of acetone, 2-butanone, and 4-methyl-2-pentanone; the ether is selected from one or more of methyl tert-butyl ether and diethyl ether; the nitrile is selected from acetonitrile; and the water is selected from purified water, deionized water, and ultrapure water.

[0020] Furthermore, the reaction temperature of the stirring is 10℃~60℃.

[0021] More preferably, the reaction temperature of the stirring is 20°C to 50°C.

[0022] Furthermore, the reaction time for stirring is ≥8 hours.

[0023] Preferably, the reaction time for stirring is ≥24 hours.

[0024] More preferably, the reaction time of the stirring is ≥48 hours.

[0025] The method for preparing crystal form C provided by this invention is simple and easy to operate, requires no special preparation conditions, and is suitable for industrial production. The obtained crystal form C has the following properties:

[0026] (1) High crystallinity and good fluidity.

[0027] (2) High purity, the obtained crystal form C has higher purity than the patented crystal form A.

[0028] (3) It has good stability. After being placed for four weeks under the conditions of 25℃ / 60%RH and 40℃ / 75%RH, the crystal form, crystallinity and purity remain basically unchanged. It has better physical and chemical stability compared with the patented crystal form A.

[0029] (4) It has low hygroscopicity. After being placed at 25℃ / 80%RH for one day, it only gained 0.04% of its weight, and has virtually no hygroscopicity.

[0030] (5) It has good mechanical stability. The crystal form did not change after grinding, only the crystallinity decreased slightly. The mechanical stability is better than that of crystal form A in patent CN102753557B.

[0031] (6) The preparation process is simple, does not use high-boiling-point or non-volatile solvents, the crystals are easy to dry, and solvent residue is not easily generated. The yield is high, about 80% or more, and the amount of solvent used is small, making it economical and environmentally friendly.

[0032] In summary, compared with crystal form A disclosed in patent CN102753557B, crystal form C has better purity and stability, making it the superior crystal form for fused heterocyclic derivatives. Attached Figure Description

[0033] Figure 1 XRPD pattern of crystal form G4 obtained in Comparative Example 1.

[0034] Figure 2 DSC / TGA spectra of crystal form G4 obtained in Comparative Example 1.

[0035] Figure 3 XRPD pattern of crystal form C obtained in Example 1.

[0036] Figure 4 DSC / TGA spectrum of crystal form C obtained in Example 1.

[0037] Figure 5 XRPD comparison spectra of crystal form A after one week, two weeks, and four weeks of storage at 25℃ / 60%RH and 40℃ / 75%RH.

[0038] Figure 6 XRPD comparison spectra of crystal form C before and after one week, two weeks and four weeks of storage at 25℃ / 60%RH and 40℃ / 75%RH.

[0039] Figure 7 XRPD comparison images of crystal form A before and after grinding.

[0040] Figure 8 Comparison of XRPD spectra before and after grinding of crystal form C.

[0041] Specific implementation examples:

[0042] The following specific preparation examples are provided to illustrate the present invention in detail. These examples are for more detailed and specific explanation only and are not intended to limit the present invention in any way.

[0043] The abbreviations used in this invention are explained as follows:

[0044] XRPD: X-ray powder diffraction

[0045] DSC: Differential Scan Calorimetry

[0046] TGA: Thermogravimetric Analysis

[0047] The analytical instruments and methods used in this invention:

[0048] (1) X-ray powder diffractometer

[0049] Instrument model: Bruker D8 ADVANCE; Test method: The sample is filled into the groove of the glass plate. After scraping the sample plane flush with the glass surface with a glass slide, the sample is placed in the sample injector. A Cu-Kα ray source with a voltage and current of 40kV and 40mA is used. The scanning range is 3 to 40° (2θ), the step size is 0.02° (2θ), the counting time per step is 0.2s, and the total scanning time is 390s.

[0050] (2) Thermal analyzer

[0051] Instrument model: Mettler TGA / DSC 2; Test method: Place the sample to be tested (about 5-10 mg) in the sample pan, maintain equilibrium at 30°C, and then heat to 300°C at a rate of 10°C / min.

[0052] Comparative Example 1: Solid crystal form prepared according to compound patent CN101331134B

[0053] Using the preparation method of Example 233 in compound patent CN101331134B, a fused heterocyclic derivative solid was obtained. Upon testing, the obtained solid was found to be crystal form G4, which is an ethyl acetate solvate.

[0054] Its XRPD map is as follows Figure 1 DSC / TGA spectra as follows Figure 2 The TGA spectrum shows a weight loss of approximately 7.8% between 30℃ and 150℃.

[0055] After being placed at 25℃ / 60%RH for two weeks, crystallization of G4 occurred as a mixed crystal of crystallization A and G4. After being placed at 40℃ / 75%RH for two weeks, crystallization completely occurred as crystallization A, indicating that crystallization G4 has poor stability.

[0056] Comparative Example 2: Crystal form A prepared in crystal form patent CN102753557B

[0057] Using the preparation method of Comparative Example 2 in the crystal form patent CN102753557B, a fused heterocyclic derivative solid was obtained. After testing, it was found to be consistent with the XRPD pattern disclosed in the patent, and it was named crystal form A here.

[0058] Example 1: Preparation of Crystal Form C by Suspension Crystallization

[0059] Weigh about 20 mg of the fused heterocyclic derivative, add 1 mL of methanol to prepare a good suspension, stir for one week at room temperature, filter and dry to obtain 18 mg of white powder, with a yield of 90.0%.

[0060] Upon testing, the obtained solid was found to be crystal form C as described in this invention, and its XRPD pattern is as follows. Figure 3As shown in Table 1 below, the DSC / TGA spectra are as follows: Figure 4 It loses about 0.2% of its weight in the temperature range of 30℃ to 100℃, has a melting endothermic peak at 245℃ to 247℃, has a melting point of 246.93℃, and begins to decompose after about 250℃.

[0061] Table 1

[0062]

[0063]

[0064] Example 2: Preparation of Crystal Form C by Suspension Crystallization

[0065] Approximately 200 mg of the fused heterocyclic derivative was weighed and added to 5 ml of a mixed solvent of purified water and ethanol in a ratio of 1:4 (v:v) to prepare a good suspension. The suspension was stirred at 50°C for one week, filtered, and dried to obtain 184 mg of a white powder, with a yield of 92.0%. Analysis confirmed that the obtained solid was crystal form C as described in this invention.

[0066] Example 3: Preparation of Crystal Form C by Suspension Crystallization

[0067] Approximately 20 mg of the fused heterocyclic derivative was weighed and added to 1 ml of ethyl acetate to prepare a good suspension. The suspension was stirred at 50°C for one week, filtered, and dried to obtain a white powder. Analysis confirmed that the obtained solid was crystal form C as described in this invention.

[0068] Example 4: Preparation of Crystal Form C by Suspension Crystallization

[0069] Approximately 20 mg of the fused heterocyclic derivative was weighed and added to 1 ml of 2-butanone to prepare a good suspension. The suspension was stirred at 50°C for one week, filtered, and dried to obtain a white powder. Analysis confirmed that the obtained solid was crystal form C as described in this invention.

[0070] Example 5: Preparation of Crystallized C by Suspension Crystallization

[0071] Approximately 20 mg of the fused heterocyclic derivative was weighed and added to 1 ml of methanol to prepare a good suspension. A small amount of crystalline form C was added as a seed crystal. The mixture was stirred at 20°C for 8 hours, filtered, and dried to obtain a white powder. Analysis confirmed that the obtained solid was crystalline form C as described in this invention.

[0072] It should be noted that the characterization results of Examples 2-5 are consistent with those of Example 1, confirming that the substances prepared in Examples 2-5 are consistent with those in Example 1. Therefore, the characterization results of Examples 2-5 will not be described again here.

[0073] Example 6: Stability Comparison of Crystal Form C and Patented Crystal Form A

[0074] The crystal form C prepared by this invention and the patented crystal form A were placed in open conditions at 25℃ / 60%RH and 40℃ / 75%RH for one week, two weeks and four weeks respectively. Then samples were taken for XRPD and HPLC tests. The results of the changes in crystal form and purity are shown in Table 2.

[0075] Table 2

[0076]

[0077] The results showed that the purity of the prepared crystal form C was higher than that of crystal form A, and both crystal forms A and C exhibited good physical and chemical stability during storage.

[0078] As can be seen from Example 9, crystal form C is a more stable crystal form, and the obtained crystal form C has higher purity.

[0079] Example 7: Hygroscopicity test of crystal form C

[0080] 50 mg of the crystalline form C of this invention was weighed and placed at 25°C / 80% RH for one day. The mass change before and after placement was recorded, and the experimental results are shown in Table 3. The results show that crystalline form C has almost no hygroscopicity, and the weight gain at 80% relative humidity is 0.04%, which is considered to be almost non-hygroscopic.

[0081] Table 3

[0082] Crystal form condition Weight gain Hygroscopic Crystal form C 25℃ / 80%RH 0.04％ Almost no hygroscopicity

[0083] Example 8: Comparison of mechanical stability between crystal form C and patented crystal form A

[0084] XRPD was used to test the crystal forms of crystal form A and crystal form C before and after grinding. The spectra are shown below. Figure 7 , Figure 8 .

[0085] XRPD patterns showed that after grinding crystal form C for 3 minutes, the crystal form remained unchanged, and the crystallinity decreased only slightly; after grinding crystal form A for 30 seconds, although the crystal form remained unchanged, the crystallinity decreased significantly, indicating that crystal form C has better mechanical stability than crystal form A.

[0086] Example 9: Study on the transformation relationship between crystal form C and patented crystal form A

[0087] Crystal form A and crystal form C were uniformly mixed in a 1:1 mass ratio and suspension experiments were conducted in different solvents and at different temperatures. After a period of time, the mixture was filtered and dried to obtain a solid. The obtained solid was subjected to XRPD testing, and the results are shown in Table 4.

[0088] Table 4

[0089]

[0090] Under different solvents and temperatures, the solid obtained after a period of suspension of a mixture of crystal form A and crystal form C is always crystal form C. The results show that crystal form C is more stable than the patented crystal form A and is the preferred crystal form for fused heterocyclic derivatives.

[0091] The experimental results from Examples 6 and 9 show that the prepared crystal form C has a higher purity than crystal form A. Both crystal forms A and C have good physical and chemical stability during storage, but crystal form C is a more stable crystal form.

[0092] The above embodiments are intended to illustrate the substantive content of this application, but are not intended to limit the scope of protection of this application. Those skilled in the art should understand that any modifications, equivalent substitutions, or improvements made within the spirit and principles of this invention should be included within the scope of protection of this invention.

Claims

1. A fused heterocyclic derivative crystal form C of formula (I), characterized in that, The X-ray powder diffraction pattern of crystal form C shows characteristic peaks at diffraction angles 2θ at 6.87°±0.2°, 8.43°±0.2°, 15.36°±0.2°, 15.91°±0.2°, 16.32°±0.2°, 20.95°±0.2°, 23.73°±0.2°, and 28.07°±0.2°.

2. The fused heterocyclic derivative crystal form C according to claim 1, characterized in that, It has the following unit cell parameters: α=105.962(11)°; β=105.859(10)°; γ=92.622(10)°.

3. The fused heterocyclic derivative crystal form C according to claim 1, characterized in that, Its differential scanning calorimetry (DSC) curve shows an endothermic peak at 245℃ to 247℃.

4. The fused heterocyclic derivative crystal form C according to any one of claims 1-3, characterized in that, It has an XRPD pattern that is basically the same as that in Figure 3.

5. The fused heterocyclic derivative crystal form C according to any one of claims 1-3, characterized in that, It has a DSC / TGA spectrum that is basically the same as that in Figure 4.

6. Use of the fused heterocyclic derivative crystal form C of any one of claims 1-3 in the production of a medicament for use as a gonadotropin-releasing hormone antagonist.

7. A method for preparing crystal form C of the fused heterocyclic derivative as described in any one of claims 1-3, characterized in that, Includes the following steps: The fused heterocyclic derivative (I) raw material is suspended in a solvent, and the suspension is stirred with or without seed crystals, and then filtered and dried to obtain crystal form C. The solvent is selected from one or more of methanol, isopropanol, n-butanol, isoamyl alcohol, sec-amyl alcohol, methyl acetate, ethyl formate, isopropyl acetate, acetone, 2-butanone, 4-methyl-2-pentanone, purified water, deionized water, and high-purity water. The reaction temperature of the stirring is 20℃~50℃, and the reaction time of the stirring is ≥48 hours.

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