Method for preparing crystal form of didarcib

Abstract

The invention relates to a method for preparing a didarcib crystal form, which comprises the following steps: dissolving didarcib in a first organic solvent, cooling to separate out part of didarcib crystals, and adding a second organic solvent to further separate out crystals; according to the method, potential safety hazards and health risks caused by adding a low-boiling-point solvent (methyl tert-butyl ether) at a high temperature are avoided; the selected solvent is safe, low in cost and easy to obtain, the obtained crystal is high in purity and yield, and industrial production is facilitated.

Description

Technical Field

[0001] This invention belongs to the field of drug crystal forms, and specifically relates to a method for preparing didacini crystal forms. Background Technology

[0002] Didacinib, chemically named 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][1,4]benzodiazepine-6-one, is a partial agonist / partial positive allosteric modulator (pPAM) of the γ-aminobutyric acid A (GABAA) receptor. It selectively acts on the α1 subtype of (GABA)A receptors, both activating the receptor and rapidly inhibiting the nervous system, while avoiding excessive activation of the receptor that could lead to deep inhibition and neurological side effects. It has been developed for the treatment of insomnia and represents a significant improvement over traditional insomnia medications, improving the daytime mental state of users.

[0003] Patent documents CN1350538A, CN113045574A, and CN111620834A have successively disclosed methods for preparing didacinib and its intermediates, as well as its non-sedative therapeutic effects on insomnia. These documents did not investigate polymorphisms. Patent document CN109134471A discloses the solid form of didacinib and its corresponding preparation method, but it did not conduct a detailed study of the preparation method for didacinib crystal forms. Summary of the Invention

[0004] From an industrial production perspective, pharmaceuticals used in pharmaceuticals are required to have high-quality and stable crystal forms, as well as safe, simple, high-yield, high-purity production methods that can be sustained for large-scale production. However, the method for preparing didacini crystal forms in patent document CN109134471A has some shortcomings. For example, it does not address the chemical purity, yield, or reproducibility of these crystal forms in industrial production. Furthermore, the preparation method in Example 1 involves a step of adding methyl tert-butyl ether at high temperature, which poses serious safety hazards when applied to industrial production. It is prone to splashing and explosion accidents, and the large-scale volatilization of methyl tert-butyl ether at high temperatures can seriously affect the health of workers.

[0005] The preparation method of the present invention can overcome the shortcomings of the prior art, is safe to operate, worker-friendly, and suitable for industrial production.

[0006] This invention provides a method for preparing didacini crystal form (preferably crystal form A), which includes the following steps:

[0007] (1) Dissolve didacinib in a first organic solvent;

[0008] (2) Cool down to precipitate some didacini crystals, then add a second organic solvent to further precipitate crystals;

[0009] In step (1), the first organic solvent is selected from one or more of ethyl formate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate; preferably, the first organic solvent is isopropyl acetate or butyl acetate.

[0010] In step (1), the weight ratio of didacini to the first organic solvent is 1:(3-15), preferably 1:(7-12), specifically 1:9.6 or 1:12, etc.

[0011] In step (1), optionally, didacini is dissolved in a first organic solvent by heating; the heating temperature is preferably 30-60°C.

[0012] In step (2), the temperature is preferably reduced to 0-10℃;

[0013] In step (2), the second organic solvent is preferably n-heptane;

[0014] In step (2), the weight of the second organic solvent is 0.1-0.5 times that of the first organic solvent in step (1), preferably 0.3-0.4 times, and more preferably 0.3-0.32 times.

[0015] Optionally, a decolorization step may be included between step (1) and step (2); the decolorization is preferably performed using activated carbon.

[0016] In some embodiments, the weight ratio of activated carbon to didacini is (0.01-0.02):1, preferably 0.015:1;

[0017] In some implementations, the activated carbon decolorization time is 15-45 minutes, preferably 30 minutes;

[0018] In some implementations, the decolorization step further includes operations such as filtration;

[0019] In some implementations, step (2) also includes filtering, washing, and drying;

[0020] In some embodiments, the preparation method of the present invention prepares deltacenide crystal form A;

[0021] In some embodiments, didacini crystal form A, in the X-ray powder diffraction pattern determined using Cu-Kα ray morphology analysis, has at least the following diffraction angles 2θ being 6.6±0.2°, 9.1±0.2°, 16.9±0.2°, 19.6±0.2°, 19.8±0.2°, 21.0±0.2°, 22.9±0.2°, 23.7±0.2°, and 27.4±0.2°. The diffraction angle has a characteristic peak at the specified location, and preferably also has a characteristic peak at at least the following diffraction angles 2θ: 12.5±0.2°, 12.9±0.2°, 14.7±0.2°, 15.9±0.2°, 18.5±0.2°, 20.0±0.2°, 20.5±0.2°, 22.6±0.2°, 23.4±0.2°, and 24.5±0.2°. More preferably, the deviation of the diffraction angle is ±0.1°.

[0022] In a specific embodiment of the present invention, the characteristic spectral lines of the X-ray powder diffraction pattern of didacini crystal form A are shown in Table 1; preferably, the X-ray powder diffraction pattern of didacini crystal form A shown is substantially as follows: Figure 1 As shown;

[0023] All reagents used in this invention are commercially available.

[0024] The positive and progressive effects of this invention are as follows:

[0025] (1) The didacini crystal form A prepared by the method of the present invention has good color, is easy to filter, has low hygroscopicity during storage, is stable, and does not contain other mixed crystals, making it suitable for long-term storage.

[0026] (2) The method for preparing didacini crystal form of the present invention has a high yield, preferably higher than 90%; high purity, preferably above 99.9%; and less than 0.1% single impurities, which meets the requirements for pharmaceutical use.

[0027] (3) The method for preparing didacini crystal form of the present invention is simple, safe and easy to operate, avoiding the safety hazards and health risks caused by adding low-boiling-point solvent (methyl tert-butyl ether) at high temperature; the selected solvent is safe, inexpensive and readily available, and the obtained crystal has high purity (including crystal form purity and chemical purity), which is conducive to industrial production. Attached Figure Description

[0028] Figure 1 This is the X-ray powder diffraction (PXRD) pattern of didacini crystal form A. Detailed Implementation

[0029] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0030] In the following examples, the didacini used can be prepared by referring to the method described in patent CN1350538A.

[0031] The instruments used in this invention for detecting drug crystal forms and properties are as follows:

[0032] Powder X-ray diffraction (XRD) characterization instrument: Rigaku D / Max-2550PC, CuKα radiation, power 40kV×250mA, scanning range 2θ3~50°, step width 0.02°, scanning speed 5° / min.

[0033] Example 1

[0034] 2000g of didacinib was added to 19200g of butyl acetate, heated until dissolved, and 30g of activated carbon was added. The mixture was kept warm and stirred for 30 minutes. The solution was filtered through a 0.45-micron filter membrane to obtain the filtrate. The filtrate was cooled to 5-10℃, and didacinib crystals precipitated. 5800g of n-heptane was added for further dissolution and crystallization. The solution was filtered, washed with cold n-heptane, and dried under vacuum at 50℃ for 4 hours to obtain a white solid. The yield was 94.6%. The PXRD pattern of the prepared didacinib is shown in the figure below. Figure 1 The image shows didacini crystal form A; HPLC analysis showed its purity to be 99.96%, with a maximum single impurity of 0.01%.

[0035] The stability of didacini crystal form A was studied, and the results are shown in Table 2-3. Under accelerated test (0-6 months) and long-term test (0-9 months) conditions, there were no changes in appearance, maximum single impurity, total impurities, loss on drying, and crystal form. This indicates that the prepared didacini crystal form A has good chemical stability, is suitable for preparation of formulations, can be stored for a long time, and has high application value in medicine.

[0036] Table 1 Powder X-ray diffraction data of didacini crystal form A

[0037]

[0038]

[0039]

[0040] Table 2 Accelerated Experiment (Conditions: 40±2℃, RH 75±5%)

[0041]

[0042] Table 3 Long-term test (under investigation conditions: 25±2℃, RH 60±5%)

[0043]

[0044] Example 2

[0045] 1000g of didacinib was added to 12000g of butyl acetate, heated until dissolved, and 15g of activated carbon was added. The mixture was kept warm and stirred for 30 minutes. The solution was filtered through a 0.45-micron filter membrane to obtain the filtrate. The filtrate was cooled to 5-10℃, and didacinib crystals precipitated. 3600g of n-heptane was added for further dissolution and crystallization. The solution was filtered, washed with cold n-heptane, and dried under vacuum at 50℃ for 4 hours to obtain a white solid dry product with a yield of 90.1%. PXRD analysis showed that the PXRD pattern of the prepared didacinib was similar to... Figure 1 It is basically consistent with the didacini crystal form A; according to HPLC analysis, its purity is 99.96% and the maximum single impurity is 0.01%.

Claims

1. A method for preparing a dedacinyl crystal form, comprising the following steps: (1) Dissolve didacinib in a first organic solvent; (2) Cool down to precipitate some didacini crystals, then add a second organic solvent to further precipitate crystals; In step (1), the first organic solvent is selected from one or more of ethyl formate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate; preferably, the first organic solvent is isopropyl acetate or butyl acetate. In step (2), the weight of the second organic solvent is 0.1-0.5 times that of the first organic solvent in step (1); In step (1), the weight ratio of didacini to the first organic solvent is 1:(3-15).

2. The method for preparing the didacini crystal form according to claim 1, wherein, The second organic solvent is n-heptane.

3. The method for preparing the didacini crystal form according to claim 1, wherein, In step (1), didacini is dissolved in a first organic solvent by heating; the preferred heating temperature is 30-60°C.

4. The method for preparing the didacini crystal form according to claim 1, wherein, In step (2), the temperature is reduced to 0-10℃.

5. The method for preparing the didacini crystal form according to claim 1, wherein, The weight ratio of didacini to the first organic solvent is 1:(7-12).

6. The method for preparing the didacini crystal form according to claim 1, wherein, In step (2), the weight of the second organic solvent is 0.3-0.4 times that of the first organic solvent in step (1), more preferably 0.3-0.32 times.

7. The method for preparing the didacini crystal form according to claim 1, wherein, Between step (1) and step (2), there is also a decolorization step; the decolorization is preferably carried out using activated carbon.

8. The method for preparing the didacini crystal form according to claim 7, wherein, The weight ratio of activated carbon to didacini is (0.01-0.02):1, preferably 0.015:

1.

9. The method for preparing the didacini crystal form according to claim 8, wherein, The decolorization time for activated carbon is 15-45 minutes, preferably 30 minutes.

10. The method for preparing the didacini crystal form according to any one of claims 1-9, wherein, The prepared didacini crystal form is didacini crystal form A.

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