A process for the preparation of amorphous evocarnide

Abstract

This invention provides a method for preparing amorphous evokort, which has high yield, simple and feasible process, high stability, good reproducibility and low cost. The obtained amorphous evokort and amorphous evokort products are of excellent quality and have low solvent residue.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology and relates to a method for preparing amorphous evokalose. Background Technology

[0002] Hyperparathyroidism (SHPT) is a significant manifestation of mineral metabolism disorders and a common and serious complication of chronic kidney disease (CKD). It can lead to adverse consequences such as bone disease, cardiovascular calcification, and ectopic soft tissue calcification. Cardiovascular calcification, in particular, often results in cardiovascular and cerebrovascular events that lead to death in end-stage renal disease patients. Calcium mimics are allosteric agonists that act on calcium-sensitive receptors (CaSRs), increasing the sensitivity of CaSRs to calcium ions and directly inhibiting the secretion of parathyroid hormone (PTH) and the proliferation of parathyroid cells.

[0003] Evocalcet is a calcium receptor agonist (calcimimetic agent). In May 2018, it was approved in Japan for the treatment of secondary hyperparathyroidism (SHPT) patients on maintenance dialysis, and for the treatment of hypercalcemia in patients with parathyroid cancer, those who are ineligible for parathyroidectomy, or those with recurrent primary hyperparathyroidism after parathyroidectomy. In December 2019, it received partial approval in Japan for the treatment of hypercalcemia in patients with parathyroid cancer or primary hyperparathyroidism who are ineligible for parathyroidectomy or have recurrent parathyroid cancer after parathyroidectomy. Evocalcet's chemical name is 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidine-1-yl)phenylacetic acid, and its molecular formula is shown below:

[0004]

[0005] Solid chemical substances can be classified into crystalline, amorphous, and eutectic states. Different states of the same solid drug often exhibit different physicochemical properties, such as solubility and dissolution rate. Research on the states and polymorphisms of drugs is of paramount importance for ensuring stability during drug production and storage, as well as safety and efficacy in clinical use. The states and polymorphs of drugs are related to their molecular structure and the crystallization method used during preparation. Amorphous drugs, due to their long-range disorder and short-range order, possess higher surface free energy, making them easier to disperse in water. This significantly improves the solubility and dissolution rate of poorly soluble drugs, thereby enhancing their bioavailability.

[0006] There are currently inventions relating to evokasse crystal forms and their preparation methods. CN105517992A discloses evokasse crystal forms A and B, wherein crystal form A, with diffraction angles expressed in 2θ, shows peaks at 12.7°±0.2°, 14.6°±0.2°, 14.8°±0.2°, 17.3°±0.2°, 18.6°±0.2°, 19.1°±0.2°, 20.5°±0.2°, 22.6°±0.2°, 24.5°±0.2°, and 28.1°±0.2°, and crystal form B, with diffraction angles expressed in 2θ, shows peaks at 12.6°±0.2°, 14.4°±0.2°, 14.4°±0.2°, and 14.4°±0.2°. Peaks appeared at °±0.2°, 15.9°±0.2°, 18.6°±0.2°, 19.1°±0.2°, 19.7°±0.2°, 21.4°±0.2°, 23.8°±0.2°, 24.3°±0.2°, and 28.0°±0.2°. Reference Example 1 discloses the preparation of amorphous form, but this method involves complex steps, uses solvents such as tetrahydrofuran, acetone, and diethyl ether, and has a yield of only 8.7%, with the tetrahydrofuran content in the solvent residue exceeding the standard (tetrahydrofuran content is approximately 1.9%–3.7%).

[0007] The inventors prepared amorphous products using spray drying, vacuum concentration, freeze drying, or grinding (including pulverization). The results showed that the yield and purity of the product decreased to some extent during spray drying, and the product had high solvent residue. The product prepared by vacuum concentration had high solvent residue and could not be industrialized. The product prepared by freeze drying also had high solvent residue and could not be completely removed. The product prepared by grinding (including pulverization) had solvent residue that could not be removed and was prone to crystallization. Summary of the Invention

[0008] The first objective of this invention is to provide a method for preparing amorphous evokortide that has a high yield, is simple and feasible, has good reproducibility, low cost, and produces amorphous evokortide of excellent quality with low solvent residue. To achieve the above objective, this invention provides the following technical solution:

[0009] A method for preparing amorphous evokine includes the following steps:

[0010] (1) Dissolve crude evokine in trifluoroethanol;

[0011] (2) Add the solution obtained in step (1) to water and control the crystallization temperature to 0-30℃ to carry out crystallization;

[0012] The mass-to-volume ratio of crude evokalse to trifluoroethanol is 1:20-30, with units of g / ml.

[0013] Furthermore, in the above preparation method, the dissolution temperature of the trifluoroethanol in step (1) is 10-55℃, and examples can be 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, 50℃, and 55℃.

[0014] Furthermore, in the above preparation method, the dissolution temperature of the trifluoroethanol in step (1) is 10-30℃, and examples can be 10℃, 15℃, 20℃, 25℃, or 30℃.

[0015] Furthermore, in the above preparation method, the crystallization temperature in step (2) is 0-30℃, and examples can be 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, or 30℃.

[0016] Furthermore, in the above preparation method, the crystallization temperature in step (2) is 0-10℃, and examples can be 0℃, 5℃, or 10℃.

[0017] Furthermore, in the above preparation method, when the solution obtained in step (1) is added to water in step (2), the mass-to-volume ratio of the crude evokalose to water is 1:50-500, with units of g / ml.

[0018] Furthermore, in the above preparation method, when the solution obtained in step (1) is added to water in step (2), the mass-to-volume ratio of the crude evokine to water is 1:100-320, with units of g / ml.

[0019] Furthermore, in the above preparation method, the crude evokalse is dissolved in trifluoroethanol and then added to water in a conventional manner, including slow dropwise addition, rapid dropwise addition, or one-time addition.

[0020] In a preferred embodiment, the above preparation method further includes the steps of filtration and drying after crystallization.

[0021] Furthermore, in the above preparation method, filtration and drying are carried out using conventional methods in the art.

[0022] In a preferred embodiment, the present invention provides a method for preparing amorphous evokalse: crude evokalse is dissolved in a solution of trifluoroethanol, added to water, and crystallization is carried out under controlled crystallization temperature. The sample is then filtered and dried to obtain an amorphous sample. The crystallization temperature is 0-30°C. The mass-to-volume ratio of crude evokalse to trifluoroethanol is 1:20-30, with units of g / ml.

[0023] The second objective of this invention is to provide an amorphous evokine, which is prepared by the method described in the first objective of this invention.

[0024] Furthermore, the present invention also provides a pharmaceutical composition comprising the above-mentioned amorphous evokalose and a pharmaceutically acceptable carrier.

[0025] In addition, the present invention also provides an amorphous evokalse article containing no more than 1.5% residual solvent, preferably no more than 1.0%, more preferably no more than 0.5%, wherein the residual solvent is trifluoroethanol.

[0026] Furthermore, the aforementioned amorphous evokalose product is prepared by the preparation method described in the first objective of this invention.

[0027] Furthermore, the present invention also provides a pharmaceutical composition comprising the above-described amorphous evokalose product and a pharmaceutically acceptable carrier.

[0028] The present invention also provides the use of amorphous evokalose, amorphous evokalose articles, or pharmaceutical compositions comprising said amorphous evokalose or amorphous evokalose articles in the preparation of a medicament for the prevention or treatment of diseases improved by inhibiting CaSR activation and / or PTH production.

[0029] The positive effects of the amorphous evokalose prepared by this invention and its preparation method are as follows: the preparation method of this invention is simple and feasible, low in cost, and has good reproducibility. It can stably precipitate amorphous samples and obtain a high product yield of over 85%, which is suitable for industrial production. In addition, the preparation method of this invention can effectively reduce the residual solvent content of the product (hereinafter referred to as "solvent residue"). The solvent residue of the amorphous evokalose or amorphous evokalose product is no more than 1.5%, more preferably no more than 1.0%, and even more preferably no more than 0.5%. Detailed Implementation

[0030] The present invention will be further described below with reference to embodiments, enabling those skilled in the art to better understand the invention. These embodiments are merely illustrative and are in no way intended to limit the scope of the invention.

[0031] The preparation of crude evokorbutol as described in the experiment is provided: crude evokorbutol prepared according to CN105517992A.

[0032] Example 1

[0033] Evocascide crude product was dissolved in different solvents at temperatures ranging from 10 to 30°C, and the apparent solubility was tested. Approximately 10 mg of sample was weighed into centrifuge tubes, and 100 μL of solvent was added each time, followed by shaking until a clear solution was observed. The maximum amount added was 1 mL; if no clear solution was found, the experiment was stopped. The approximate apparent solubility was calculated based on the amount of solvent added. The clear solution was allowed to slowly evaporate, and the precipitated solid was collected for XRPD detection. The undissolved system was suspended and stirred at 20°C for one day, then centrifuged to collect the solid for crystalline XRPD detection. The results are shown in the table below.

[0034]

[0035]

[0036] Experimental results show that evokine has good solubility in dimethyl sulfoxide, dimethylformamide and trifluoroethanol, but crystal form A is obtained in dimethyl sulfoxide and dimethylformamide, and the crystallinity of the sample obtained in the trifluoroethanol system is low; while crystal form A is obtained in the undissolved suspension system.

[0037] Example 2

[0038] At a temperature of 10-30℃, 10 mg of crude evokine was dissolved in a good solvent to obtain a clear solution. Different antisolvents were added to the clear solution at a low temperature (<5℃), and the mixture was shaken and stirred for 5 min before sampling to detect the crystal form of XRPD. The test results are shown in the table below.

[0039]

[0040]

[0041] Experimental results show that after dissolving crude evokalse in trifluoroethanol, adding different antisolvents yields a single amorphous sample; adding water yields a mixed sample of crystal form A and amorphous form.

[0042] Example 3

[0043] At 10-30℃, 0.1 g of crude evokalse was dissolved in 2.5 mL of trifluoroethanol (25V, g / mL). Different amounts of methyl tert-butyl ether (MTBE) were added dropwise to the system at 0-10℃ to induce crystallization. The samples were then dried to prepare the final samples, and the XRPD crystal form and solvent residue were detected. The results are shown in the table below.

[0044]

[0045] Experimental conclusion: Amorphous samples can be obtained by crystallization using a mixed solvent of trifluoroethanol and methyl tert-butyl ether (MTBE), but the controllability of residual trifluoroethanol is poor, and the content of MTBE is high.

[0046] Example 4

[0047] 0.2 g of crude evokalse was dissolved in 5 ml of trifluoroethanol at different temperatures, and then added dropwise to water with different concentrations. After post-processing, the crystal form XRPD and residual solvent of the samples were detected. The results are shown in the table below.

[0048]

[0049]

[0050] Experimental results show that amorphous samples can be obtained by crystallization using a trifluoroethanol / water system with a high yield, all above 85%; however, the higher the dissolution temperature, the higher the relative amount of trifluoroethanol remaining.

[0051] Example 5

[0052] 0.2 g of crude evokalse was dissolved in 2 ml of trifluoroethanol at 55 °C, then added to water. Crystals were precipitated at different temperatures. After post-processing, the crystal form XRPD and residual solvent of the samples were determined. The results are shown in the table below.

[0053]

[0054] Experimental results show that amorphous samples can be obtained by using a trifluoroethanol / water system for crystallization, but the residual amount of trifluoroethanol is relatively high, and reducing the amount of trifluoroethanol still cannot reduce the residual amount. In addition, after reducing the trifluoroethanol content, when the crystallization temperature exceeds 20℃, the crystal stability of the sample is poor and it transforms into crystal form A.

[0055] Example 6

[0056] 0.2 g of crude evokalse was dissolved in different amounts of trifluoroethanol at different temperatures, and then added to water with different concentrations at different temperatures. After filtration and drying, the crystal form XRPD and residual solvent of the samples were determined. The results are shown in the table below.

[0057]

[0058]

[0059] Experimental results show that: 1) Amorphous samples can be obtained when the trifluoroethanol dissolution temperature is within the range of 10-30℃ and the amount of trifluoroethanol used is equivalent to 20-30V (g / ml) of crude evocarbate. Further reduction in the amount of trifluoroethanol will result in the product not dissolving completely at 10-30℃. 2) Amorphous samples can be obtained when the amount of water used is equivalent to 50-500V (g / ml) of crude evocarbate. However, lower amounts will lead to an increasing residual solution. Excessive water usage will result in a larger post-processing system, increasing the cost of industrial production and hindering the scale-up of the product. 3) Amorphous samples can be obtained at crystallization temperatures of 0-10℃. The crystal form of the samples is stable. When the temperature reaches 20℃, the crystallization time is extended, and the samples transform into crystal form A.

[0060] Example 7

[0061] Different concentrations of crude evokalose were dissolved in trifluoroethanol at 25°C, and then added to water of different concentrations at crystallization temperatures ranging from 0 to 10°C. After drying, the crystal form XRPD and residual solvent content of the samples were measured at different time points. The results are shown in the table below.

[0062]

[0063] Note: In the table above, for examples 7-1 to 7-17, the slow dripping duration is approximately 5 minutes, the rapid dripping duration is approximately 2.5 minutes, and the single-drop duration is approximately 10 seconds; for example 7-18, due to the increased amount of crude product, the rapid dripping duration is approximately 5 minutes.

[0064] Experimental results show that under the above conditions, amorphous samples can be stably precipitated. The method and speed of adding trifluoroethanol solution have no effect on the crystal form of the product. The residual content can be controlled within 0.5%. The preparation process of this amorphous sample is relatively stable and there is no crystal transformation. Stable samples with low residual content can also be obtained in high yield in scale-up production.

Claims

1. A method for preparing amorphous evokalose, comprising the following steps: (1) Dissolve crude evokine in trifluoroethanol; (2) Add the solution obtained in step (1) to water and control the crystallization temperature to 0-30℃ to carry out crystallization; wherein The mass-to-volume ratio of crude evokalse to trifluoroethanol is 1:20-30, expressed in g / ml.

2. The method according to claim 1, wherein the crude evokine in step (1) is dissolved in trifluoroethanol at a temperature of 10-55°C, preferably 10-30°C.

3. The method as described in claim 1 or 2, wherein the crystallization temperature in step (2) is 0-10°C.

4. The method according to any one of claims 1 to 3, wherein when the solution obtained in step (1) is added to water in step (2), the mass-to-volume ratio of the crude evokort to water is 1:50-500, preferably 1:100-320, in g / ml.

5. Amorphous evokase obtained by the method of any one of claims 1 to 4.

6. An amorphous evocaptide article, characterized by: It contains no more than 1.5% residual solvent, preferably no more than 1.0%, more preferably no more than 0.5%, wherein the residual solvent is trifluoroethanol; and even more preferably, the amorphous evokase article is prepared by the method according to any one of claims 1 to 4.

7. A pharmaceutical composition comprising amorphous evokalose as claimed in claim 5 or amorphous evokalose as claimed in claim 6, and a pharmaceutically acceptable carrier.

8. Use of the amorphous evokalose of claim 5, the amorphous evokalose article of claim 6, or the pharmaceutical composition of claim 7 in the preparation of a medicament for the prevention or treatment of diseases improved by inhibiting CaSR activation and / or PTH production.

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