Salt forms of capivasertib and preparation method therefor

Abstract

The present invention relates to salt forms of Capivasertib and a preparation method therefor. Specifically, the present invention provides a malate crystal form and a succinate crystal form of Capivasertib, and the two crystal forms can be used as intermediates for preparing the crystal form A of Capivasertib. The preparation method for the two intermediate salt crystal forms of the present invention is simple, and the two crystal forms have a high yield and a high purity, and can be used for the industrial preparation of the crystal form A.

Description

Carpicrite salt type and its preparation method Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to the malate and succinate of cappicetide, methods for their preparation, and uses for preparing cappicetide crystal form A. Background Technology

[0002] Capivasertib is the world's first small molecule inhibitor targeting protein kinase AKT, exhibiting high inhibitory activity against AKT1 / 2 / 3. On November 16, 2023, the drug received marketing approval from the U.S. Food and Drug Administration (FDA) under the brand name TRUQAP. It is indicated for use in combination with fulvestrant for the treatment of hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative, locally advanced or metastatic breast cancer in adult patients who have been found to have one or more PIK3CA / AKT1 / PTEN mutations in FDA-approved trials. These patients must have progressed in a metastatic setting after receiving at least one endocrine-based therapy or relapsed within 12 months of completing adjuvant therapy.

[0003] Currently, the existing technology CN104203953B discloses different crystal forms, preparation methods, and applications of carpicrite. Specifically, it discloses crystal forms A, B, and C of carpicrite, among which crystal form B is a stable crystal form. Under certain conditions, crystal form A can be converted into crystal form B, but crystal form B has a lower dissolution rate than crystal form A. In practice, it has also been found that crystal form A can also exist stably under certain conditions, showing potential medicinal value. However, the existing technology for preparing carpicrite crystal form A is unstable, resulting in the inability to stably obtain carpicrite crystal form A and the low purity of the obtained carpicrite crystal form A, which hinders the further application of carpicrite crystal form A.

[0004] Therefore, there is a need in this field to develop a more stable process for preparing carpicret crystal form A for better application. Summary of the Invention

[0005] One object of the present invention is to provide the crystalline forms of carpicroside intermediate malate and succinate.

[0006] Another object of the present invention is to provide a method for preparing carpicret crystal form A.

[0007] Another objective of this invention is to provide a cappiseti crystal form A with higher stability and purity.

[0008] In a first aspect of the invention, an intermediate is provided, said intermediate being carpicrite malate and carpicrite succinate:

[0009] Carpicrite malate

[0010] Capisothiazolinone diphosphate.

[0011] In another preferred embodiment, the carpicrite malate is selected from the group consisting of carpicrite L-malate, carpicrite D-malate, or carpicrite DL-malate.

[0012] In another preferred embodiment, the carpicrite malate is carpicrite DL-malate.

[0013] In another preferred embodiment, the carpicroti malate has two or more (three, four, five, or six) characteristic peaks (2θ) selected from the group consisting of: 5.8°±0.2°, 22.4°±0.2°, 22.1°±0.2°, 19.0°±0.2°, 17.5°±0.2°, and 23.2°±0.2°.

[0014] In another preferred embodiment, the carpicetil diphosphate has two or more (three, four, five, or six) characteristic peaks (2θ) selected from the group consisting of: 14.1°±0.2°, 24.7°±0.2°, 15.6°±0.2°, 31.8°±0.2°, 22.7°±0.2°, 18.5°±0.2°, 17.4°±0.2°, and 26.7°±0.2°.

[0015] In another preferred embodiment, the said carpicroti malate has characteristic peaks (2θ) selected from the group consisting of: 21.0°±0.2°, 16.6°±0.2°, 17.7°±0.2°, 25.5°±0.2°, 27.1°±0.2°, 16.0°±0.2°, 26.3°±0.2°, 7.5°±0.2°, 19.9°±0.2°, and 27.7°±0.2°.

[0016] In another preferred embodiment, the said carpicretinoic acid salt also has characteristic peaks (2θ) selected from the group consisting of: 22.9°±0.2°, 6.3°±0.2°, 28.2°±0.2°, 13.1°±0.2°, 21.7°±0.2°, 20.5°±0.2°, 17.9°±0.2°, 28.7°±0.2°, 14.9°±0.2°, 27.3°±0.2°, and 25.7°±0.2°.

[0017] In another preferred embodiment, the said carpicote malate further has characteristic peaks (2θ) selected from the group consisting of: 19.9°±0.2°, 36.2°±0.2°, 11.4°±0.2°, 28.5°±0.2°, 33.5°±0.2°, 24.2°±0.2°, and 3.4°±0.2°.

[0018] In another preferred embodiment, the carpicretinoic acid salt further has characteristic peaks (2θ) selected from the group consisting of: 23.3°±0.2°, 26.2°±0.2°, 24.0°±0.2°, 38.6°±0.2°, 31.0°±0.2°, 16.9°±0.2°, 35.0°±0.2°, 45.5°±0.2°, 19.3°±0.2°, 19.7°±0.2°, 12.0°±0.2°. 0.2°, 12.7°±0.2°, 40.0°±0.2°, 10.7°±0.2°, 11.6°±0.2°, 12.4°±0.2°, 41.2°±0.2°, 32.2°±0.2°, 13.6°±0.2°, 29.1°±0.2°, 8.7°±0.2°, 16.5°±0.2°, 48.4°±0.2°, 35.6°±0.2°, 46.3°±0.2°.

[0019] In another preferred embodiment, the carpicroside malate has one or more features selected from the group consisting of:

[0020] (1) The carpicroside malate has the basic XRPD characteristic map shown in Figure 1; and / or

[0021] (2) The carpicroside malate has XRPD characteristic peaks as shown in Table 1; and / or

[0022] (3) The carpicroside malate has the PLM diagram shown in Figure 2; and / or

[0023] (4) The carpicroti malate has a TGA diagram as shown in Figure 5.

[0024] In another preferred embodiment, the carpicretinoic acid salt has one or more features selected from the group consisting of:

[0025] (1) The carpicetil diphosphate has the basic XRPD characteristic map shown in Figure 3; and / or

[0026] (2) The carpicetil diphosphate has XRPD characteristic peaks as shown in Table 2; and / or

[0027] (3) The carpicetil diphosphate has the PLM diagram shown in Figure 4; and / or

[0028] (4) The carpicetidine diphosphate has a TGA graph as shown in Figure 6.

[0029] In a second aspect of the invention, the use of the intermediate described in the first aspect of the invention is provided, the intermediate being used to prepare carpicretinoic acid form A; wherein the carpicretinoic acid form A has the following characteristic peaks: 14.3°±0.2°, 18.9°±0.2° and 19.6°±0.2°.

[0030] In another preferred embodiment, the cappise type A has the following characteristic peaks: 23.9°±0.2°, 25.9°±0.2°, 15.5°±0.2°, 3.1°±0.2°, 17.4°±0.2°, 16.5°±0.2°, and 9.2°±0.2°.

[0031] In another preferred embodiment, the cappise type A has a basic XRPD feature map as shown in Figure 7.

[0032] In another preferred embodiment, the kapisitet crystal form A has characteristic peaks as shown in Table 3.

[0033] In another preferred embodiment, the purity of the cappisete crystal form A is ≥90%, more preferably ≥95%, more preferably ≥99%, and even more preferably ≥99.5%.

[0034] In a third aspect of the invention, a method for preparing the intermediate described in the first aspect of the invention is provided.

[0035] (I) The intermediate is capiprosete malate, comprising the following steps:

[0036] (a-1) Dissolve the carpicrin raw material in inert solvent A at 50℃~70℃ to obtain a clear liquid;

[0037] (b-1) The clear liquid obtained from stirring step (a-1);

[0038] (c-1) Add a solution of malic acid in inert solvent A to the supernatant from step (b-1);

[0039] (d-1) Cool down to 5℃~10℃ and keep warm for crystallization for 18h~36h;

[0040] (e-1) Filter and dry to obtain capiprite malate;

[0041] Or (II) the intermediate is capiste succinate, comprising the following steps:

[0042] (a-2) Dissolve the carpicrin raw material in inert solvent B at 50℃~70℃ to obtain a clear liquid;

[0043] (b-2) The clear liquid obtained from stirring step (a-2);

[0044] (c-2) Add a solution of succinic acid in inert solvent B to the supernatant from step (b-2);

[0045] (d-2) Cool down to 5℃~10℃ and keep warm for 4~8h to allow crystals to precipitate.

[0046] (e-2) Filter and dry to obtain carpicrate diisocyanate.

[0047] In another preferred embodiment, in step (a-1), the temperature is 50°C to 60°C.

[0048] In another preferred embodiment, step (d-1) involves cooling at a rate of 1.0 °C / min.

[0049] In another preferred embodiment, the inert solvent A is selected from the group consisting of: water-miscible organic solvents, and mixtures of water and water-miscible organic solvents.

[0050] In another preferred embodiment, the water-miscible organic solvent is selected from acetonitrile, 1,4-dioxane, and tetrahydrofuran.

[0051] In another preferred embodiment, the volume ratio of the water-miscible organic solvent and water in the inert solvent A is 10:1 to 60:1; more preferably 20:1 to 50:1; and even more preferably 30:1 to 50:1.

[0052] In another preferred embodiment, the molar ratio of malic acid to capiprine raw material is 1:1 to 1:2, more preferably 1:1.0 to 1:1.6; and even more preferably 1:1.0 to 1:1.4.

[0053] In another preferred embodiment, the molar volume ratio (mol / L) of the capiprine raw material to the inert solvent A is (0.04-0.15):1; more preferably (0.04-0.1):1.

[0054] In another preferred embodiment, step (b-1) further includes stirring at 50°C to 60°C for 10 min to 30 min; more preferably, step (b-1) is stirring at 55°C for 15 min.

[0055] In another preferred embodiment, step (c-1) further includes: (i) dissolving malic acid in an inert solvent A to obtain a liquid A; (ii) adding the liquid A dropwise to the clear liquid in step (b-1) at a temperature of 50°C to 60°C.

[0056] In another preferred embodiment, the inert solvent B is a mixture of water and a water-miscible organic solvent.

[0057] In another preferred embodiment, the water-miscible organic solvent is selected from acetonitrile, 1,4-dioxane, and tetrahydrofuran.

[0058] In another preferred embodiment, the volume ratio of the water-miscible organic solvent and water in the inert solvent B is 80:1 to 1:1; more preferably 60:1 to 5:1; and even more preferably 50:1 to 10:1.

[0059] In another preferred embodiment, the molar ratio of succinic acid to carpicret raw material is 1:1 to 2:1; more preferably 1.2:1.0 to 1.8:1.0; and even more preferably 1.2:1.0 to 1.5:1.0.

[0060] In another preferred embodiment, the molar volume ratio (mol / L) of the carpicrotening material to the inert solvent B is (0.05-0.2):1; more preferably (0.06-0.15):1.

[0061] In another preferred embodiment, step (b-2) further includes stirring at 50°C to 60°C for 10 min to 30 min; more preferably, step (b-2) is stirring at 55°C for 15 min.

[0062] In another preferred embodiment, step (c-2) further includes: (i) heating and dissolving succinic acid in an inert solvent B until the solution is clear, to obtain a liquid B, wherein the heating temperature is 50°C to 60°C; (ii) adding the liquid B dropwise to the clear solution obtained in step (b-2), wherein the dropwise addition temperature is 50°C to 60°C.

[0063] In a fourth aspect of the present invention, a method for preparing kapisitet crystal form A is provided, comprising the following steps:

[0064] (1) A solution of capiprite malate or capiprite succinate as described in the first aspect of the present invention in a C2-C6 ether solvent is provided as mixture 1;

[0065] (2) Add Na2CO3 aqueous solution to the mixture 1 to obtain mixture 2;

[0066] (3) Stir mixture 2 at room temperature and separate the liquids;

[0067] (4) Take the organic phase obtained in step (3) and add water and stir, then separate the liquids;

[0068] (5) At 0-10℃, C1-C6 alcohol solvents are added to the organic phase obtained in step (4) to obtain mixture 3;

[0069] (6) The mixture 3 is kept at a constant temperature to crystallize and obtain Capsicentiate crystal type A.

[0070] In another preferred embodiment, the stirring time is 10 min to 30 min; more preferably, it is 10 min to 15 min.

[0071] In another preferred embodiment, the molar volume ratio (mol / L) of capiste malate or succinate to C2-C6 ether solvent in the mixture 1 is 1:20 to 1:50; more preferably 1:25 to 1:35.

[0072] In another preferred embodiment, the molar volume ratio (mol / L) of capiste malate or succinate to C1-C6 alcohol solvent is 1:2 to 1:6; more preferably 1:4 to 1:5.

[0073] In another preferred embodiment, the Na2CO3 aqueous solution is a 10% Na2CO3 aqueous solution.

[0074] In another preferred embodiment, the Na2CO3 aqueous solution is a 10% Na2CO3 aqueous solution, and the molar volume ratio (mol / L) of capiste malate or succinate to the Na2CO3 aqueous solution is 1:8 to 1:12; more preferably 1:9 to 1:11.

[0075] In another preferred embodiment, in step (6), the crystallization time is 8h to 24h; more preferably 12h to 18h.

[0076] In another preferred embodiment, the C2-C6 ether solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, or combinations thereof.

[0077] In another preferred embodiment, the C1-C6 alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, or combinations thereof.

[0078] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0079] Figure 1 shows the XRPD spectrum of capiste malate.

[0080] Figure 2 shows the PLM diagram of capiste malate.

[0081] Figure 3 shows the XRPD spectrum of capiste succinate.

[0082] Figure 4 shows the PLM diagram of capiste succinate.

[0083] Figure 5 shows the TGA graph of capiste malate.

[0084] Figure 6 shows the TGA graph of capiste succinate.

[0085] Figure 7 shows the XRPD pattern of Cappiseta crystal form A. Detailed Implementation

[0086] Through extensive and in-depth research, the inventors have, for the first time, provided two salt forms of carpicrite: carpicrite malate and carpicrite succinate. These two salt forms can be used to prepare carpicrite crystal form A with higher purity and better stability, making them suitable for industrial production. Based on this, the inventors completed this invention.

[0087] the term

[0088] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0089] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

[0090] As used in this article, the term "optionally" means that it may or may not be added.

[0091] As used in this article, the term "room temperature" generally refers to 4℃ to 30℃, and preferably 20℃ ± 5℃.

[0092] As used in this article, the term "carpicolor raw material" generally refers to carpicolor amorphous or crystalline form.

[0093] Carpi Color

[0094] The chemical name of capiprine (I) is: 4-amino-N-[(1S)-1-(4-chlorobenzyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinecarboxamide, and its structural formula is:

[0095] Carpicrite is a compound with low solubility, almost insoluble in water. Existing technologies disclose carpicrite in crystal forms A, B, and C. Crystal form B is a stable crystal form. Under certain conditions, crystal form A can be converted to crystal form B, but crystal form B has a lower dissolution rate than crystal form A. Furthermore, it has been found in practice that crystal form A can also exist stably under certain conditions, possessing potential medicinal value. However, the existing process for preparing carpicrite crystal form A is unstable, resulting in the inability to stably obtain carpicrite crystal form A and the low purity of the obtained carpicrite crystal form A, hindering its further application.

[0096] This invention provides an intermediate carpicrite salt form, which can be used to prepare high-purity carpicrite crystal form A, providing a better option for the application of carpicrite. Furthermore, this high-purity crystal form A is also more conducive to the preparation of pharmaceutical crystal form B. Specifically, the intermediate salt form is selected from carpicrite malate and carpicrite succinate forms.

[0097] Carpicrite malate, its molecular formula is: C 25 H 31 ClN6O7, its chemical structural formula is shown in formula (I):

[0098] Capisothiazoline diphosphate, its molecular formula is: C 25 H 31 ClN6O7, its chemical structural formula is shown in formula (II):

[0099] The purity of the kapisitet crystal form A obtained by preparing the intermediate salt form of the present invention is ≥90%, preferably ≥95%, more preferably ≥99%, and even more preferably ≥99.5%.

[0100] Preparation method of carpicrite salt type

[0101] There are many existing reports on the salt forms of carpicrite. For example, US2024 / 0051964 A1 discloses preparation processes for various carpicrite salt forms, including hydrochloride, dihydrochloride, glutarate, and sebacic acid salt. However, the salt formation process provided is cumbersome and has a long crystallization time (up to 72 hours).

[0102] In response, this invention provides a calpicot salt type with a simpler salt formation process and shorter crystallization time, and its preparation method.

[0103] Specifically, the preparation method of the aforementioned carpicroside malate includes the following steps:

[0104] (a-1) Dissolve the carpicrin raw material in inert solvent A at 50℃~70℃ to obtain a clear liquid;

[0105] (b-1) The clear liquid obtained from stirring step (a-1);

[0106] (c-1) Add a solution of malic acid in inert solvent A to the supernatant from step (b-1);

[0107] (d-1) Cool to 5℃~10℃ and keep warm for crystallization for 12h~36h; preferably 18h~24h.

[0108] (e-1) Filter and dry to obtain carpicrate malate.

[0109] Specifically, the preparation method of the aforementioned carpicretinoic acid diphosphate includes the following steps:

[0110] (a-2) Dissolve the carpicrin raw material in inert solvent B at 50℃~70℃ to obtain a clear liquid;

[0111] (b-2) The clear liquid obtained from stirring step (a-2);

[0112] (c-2) Add acetonitrile-water solution of succinic acid dropwise to the clear solution from step (b-2);

[0113] (d-2) Cool down to 5℃~10℃ and keep warm for 4h~8h for crystallization.

[0114] (e-2) Filter and dry to obtain carpicrate diisocyanate.

[0115] Both the inert solvent A and the inert solvent B are independently selected from water-miscible organic solvents and mixtures of water and water-miscible organic solvents; the water-miscible organic solvents are selected from acetonitrile, 1,4-dioxane and tetrahydrofuran.

[0116] The stirring time in step (b) is 5 min to 60 min, 10 min to 50 min, 10 min to 40 min, 10 min to 30 min, 10 min to 15 min, etc.; in some preferred embodiments, heating (50-70℃) or other methods can be used to promote dissolution.

[0117] The heat preservation and crystallization time in step (d) is 1h-48h, 1h-24h, 1h-12h, 1h-8h, 2h-8h, 4h-8h, etc. Preferably, the heat preservation and crystallization is carried out at room temperature, for example, 20℃-35℃.

[0118] Preparation of Carpicrite Salt-Type Intermediates for Carpicrite Crystal Form A

[0119] The existing method for preparing capiprine crystal form A involves purifying the crude reaction solution for capiprine preparation by column chromatography to obtain capiprine in an amorphous state, and then converting it into crystal form A by removing the solvent ethyl acetate.

[0120] The preparation process has obvious defects. First, the chemical purity of crystal form A depends on the separation effect of column chromatography. If the chemical purity cannot be guaranteed, it is difficult for the related substances to meet the pharmaceutical purity requirements. The separation efficiency of column chromatography is low. In addition, the process is difficult to realize industrial production.

[0121] This invention provides a method for preparing carpicrite crystal form A using the above-mentioned carpicrite intermediate salt form. Specifically, it includes the following steps:

[0122] (1) Provide a solution of capiprite malate or capiprite succinate in a C2-C6 ether solvent, which is mixture 1;

[0123] (2) Add Na2CO3 aqueous solution to the mixture 1 to obtain mixture 2;

[0124] (3) Stir mixture 2 at room temperature and separate the liquids;

[0125] (4) Take the organic phase obtained in step (3) and add water and stir, then separate the liquids;

[0126] (5) At 0-10℃, C1-C6 alcohol solvents are added to the organic phase obtained in step (4) to obtain mixture 3;

[0127] (6) The mixture 3 is kept at a constant temperature to crystallize and obtain Capsicentiate crystal type A.

[0128] In the above steps, the addition of Na2CO3 aqueous solution is to release the free base of carpicrite.

[0129] The stirring time in steps (3)-(4) is 5 min to 60 min, 10 min to 50 min, 10 min to 40 min, 10 min to 30 min, and 10 min to 15 min, until the final reaction is complete or the solution is dissolved.

[0130] The crystallization time in step (6) is 1h~48h, 1h~24h, 1h~12h, 1h~8h, 2h~8h, 4h~8h, 8h~12h, 8h~18h, 8h~24h, 12h~18h, etc., of which 12h~18h is preferred.

[0131] The C2-C6 ether solvent is preferably one or a combination of tetrahydrofuran, 2-methyltetrahydrofuran, and tert-butyl methyl ether.

[0132] The C1-C6 alcohol solvent is preferably selected from one or a combination of methanol, ethanol, isopropanol and tert-butanol.

[0133] Compared with the prior art, the main advantages of the present invention include:

[0134] (1) The carpicetine malate and carpicetine succinate of the present invention have good stability and high purity, which is beneficial for formulation application.

[0135] (2) The preparation method of carpicroside malate and succinate of the present invention is safe and simple, the crystallization system does not form gel, it is feasible for scale-up, and the operation is simple and easy to carry out, which is convenient for industrial production.

[0136] (3) The malate and succinate of the carpicroten prepared by the method of the present invention have high purity (over 99.0%), reaching chemical purity and stable optical purity.

[0137] (4) The process of using the malate and succinate of the present invention to prepare the crystal form A of the carpicrite is simple, and the resulting carpicrite crystal form A has high purity and yield, which is conducive to industrial production.

[0138] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0139] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0140] All solvents used in this invention are of analytical grade, and all test methods used in this invention are general methods. The test parameters are as follows:

[0141] 1. XRPD spectral determination method:

[0142] Method 1: X-ray powder diffraction instrument: Bruker D2 Phaser X-ray powder diffractometer; radiation source Cu Generator kV: 30kV; Generator mA: 10mA; Initial 2θ: 2.0°; Scan range: 2.0~50.0°; Scan speed: 0.2s / step; Step size: 0.02° / step.

[0143] 2. HPLC determination method:

[0144] Detector: Ultraviolet absorbance spectrophotometer (measurement wavelength: 220 nm)

[0145] Chromatographic column: Brand: Waters; Model: XBridge C18; Specifications: 4.6mm × 250mm, 3.5μm

[0146] Mobile phase: (A) 20 mmol / L potassium dihydrogen phosphate buffer solution (pH 2.5)

[0147] (B) Methanol-acetonitrile (1:1 (volume ratio))

[0148] gradient scheme

[0149] Flow rate: 0.7 mL / min

[0150] Running time: 40 minutes

[0151] Column temperature: 40℃

[0152] Injection volume: 5 μl

[0153] Example 1: Preparation of the DL-malate crystal form of capiprite

[0154] At room temperature, 100.0 mg of crude capiprine was added to 3.0 ml of tetrahydrofuran (THF) solvent containing 2% water, and the mixture was heated to 55 °C and stirred for 15 min. Then, 1.0 ml of a tetrahydrofuran solution containing 23.0 mg of DL-malic acid containing 2% water was added, and the resulting mixture was stirred for 15 min. The temperature was then lowered to 5 °C–10 °C at a rate of 1.0 °C / min. Crystallization was maintained at this temperature for 24 h, followed by filtration. The solid was then vacuum dried at room temperature to obtain 106 mg of DL-malate capiprine. The PLM diagram is shown in Figure 2, with a purity of 97.6% and a yield of 90.0%. The preparation method of crude capiprine in this embodiment can refer to the methods disclosed in prior art CN101861321B or CN106661033B, which are incorporated herein by reference.

[0155] The obtained DL-malate carpicrite was subjected to XRPD testing, and the results are shown in Figure 1. The spectral data are shown in Table 1. The obtained DL-malate carpicrite was subjected to TGA testing, and the results are shown in Figure 5. The results show that the weight loss was 1.8% from room temperature to 123℃.

[0156] Table 1. XRPD data for DL-malate of capiprolol.

[0157] Example 2: Preparation of the DL-malate crystal form of capiprite

[0158] Under nitrogen protection, 7.0 g of crude cappicetil was added to tetrahydrofuran (210.0 ml), and the mixture was stirred and heated to 60℃~70℃. The mixture was kept at this temperature and stirred until the solution was clear. Then, the solution was allowed to cool naturally to 25℃~30℃. At 25℃~30℃, a prepared DL-malic acid / tetrahydrofuran solution (2.2 g of DL-malic acid dissolved in 22 ml of tetrahydrofuran at room temperature) was added dropwise. After the addition was complete, the mixture was stirred at 25℃~30℃ for 2 hours. The mixture was then filtered, and the filter cake was washed once with tetrahydrofuran (7.0 mL) to obtain 8.2 g of white powdered cappicetil DL-malate with a chemical purity of 97.7%.

[0159] XRPD testing was performed on the obtained capiste DL-malate, and the results showed that the crystal form of capiste DL-malate obtained in Example 2 was the same as that obtained in Example 1.

[0160] Example 3: Preparation of the crystal form of capiprate diphosphate

[0161] Weigh 1.0 g of crude carpicrate into a glass vial, then add 30.0 mL of acetonitrile solution containing 3% water, heat to 55°C, and stir for 15-30 min until completely dissolved. Then add 1.0 mL of acetonitrile solution containing 10% water and 413.6 mg of succinic acid. Gradually cool the resulting mixture to 5-10°C and keep it at this temperature for 4-6 h to allow crystallization. The resulting solid is then vacuum dried overnight at room temperature to obtain the dried solid, which is carpicrate succinate. The PLM diagram is shown in Figure 4. Its purity is 95.8% and the yield is 85%.

[0162] The obtained carpicetidine diphosphate was subjected to XRPD testing, and the results are shown in Figure 3. The spectral data are shown in Table 2. The obtained carpicetidine diphosphate was subjected to TGA testing, and the results are shown in Figure 6. The results show that the weight loss was 2.1% from room temperature to 75°C.

[0163] Table 2. XRPD data of capiprine succinate

[0164] Example 4: Preparation of Cappisitet Crystal Form A

[0165] At room temperature, 1.0 g of DL-malate of capiprine prepared in Example 2 was added to THF (60.0 ml), and 20 ml of prepared Na2CO3 aqueous solution (10%) was added to it. The mixture was stirred at room temperature for 10-15 min and then allowed to stand for 5 min to separate the layers. The separated organic phase was added to purified water (20 ml), stirred for 10-15 min and then allowed to stand for 5 min to separate the layers. Isopropanol (10.0 ml) was added dropwise to the separated organic phase at 0-10 °C. After crystallization at this temperature for 12 h, the mixture was filtered. The obtained solid was dried under vacuum at room temperature to obtain capiprine crystal form A (680 mg) with a purity of 99.5% and a yield of 97.0%.

[0166] The obtained capiste crystal form A was subjected to XRPD testing, and the results are shown in Figure 7. The spectral data are shown in Table 3.

[0167] Table 3. XRPD data for Cappisite crystal form A

[0168] Comparative Example 1: Preparation of Cappiseta Crystal Form A in the Existing Technology

[0169] This comparative example is based on the method disclosed in CN101861321B, specifically as follows: 10.0 g of crude cappicetil was added to anhydrous ethanol (100 ml) and stirred until completely dissolved. Silica gel (20 g, 100-200 mesh) was added to prepare silica gel. The sample was subjected to column chromatography separation, with pure ethyl acetate as the eluent. The ethyl acetate solution of the product with relatively high purity was collected, and the ethyl acetate was removed under vacuum to obtain cappicetil crystal form A (1.2 g, HPLC purity 95.0%), with a yield of 14.6%.

[0170] Test Example 1: Comparison of the effects of different methods in preparing cappicet crystal form A

[0171] The effects of the cappisetain crystal form A prepared in Comparative Example 1 and Example 4 were compared, and the results are shown in Table 4. The specific method for stability testing included: weighing appropriate amounts of cappisetain crystal form A prepared in Comparative Example 1 and Example 4, sealing them in double-layered PE bags with an outer layer of aluminum foil, and placing them under conditions of 40℃ / 75%RH and 60℃ / 93%RH, respectively. XRPD was used to determine the crystal form before and after placement.

[0172] Table 4 Comparison of the effects of Cappixelated Crystal Form A

[0173] The above comparative data results show that the process of preparing carpicrite crystal form A from carpicrite malate of the present invention is simple, the obtained crystal form A has good stability and high purity, reaching more than 99%, and the yield is also as high as 97%, which is conducive to realizing industrial production.

[0174] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. An intermediate, characterized in that, The intermediate is selected from: carpicrite malate and carpicrite succinate. Carpicrite malate; Capisothiazolinone diphosphate.

2. The intermediate as described in claim 1, characterized in that, The carpicroti malate has two or more characteristic peaks (2θ) selected from the group consisting of: 5.8°±0.2°, 22.4°±0.2°, 22.1°±0.2°, 19.0°±0.2°, 17.5°±0.2°, and 23.2°±0.2°. And / or the said carpicetidine diphosphate has two or more characteristic peaks (2θ) selected from the group consisting of: 14.1°±0.2°, 24.7°±0.2°, 15.6°±0.2°, 31.8°±0.2°, 22.7°±0.2°, 18.5°±0.2°, 17.4°±0.2°, and 26.7°±0.2°.

3. The intermediate as described in claim 1, characterized in that, The carpicroti malate has characteristic peaks (2θ) selected from the group consisting of: 21.0°±0.2°, 16.6°±0.2°, 17.7°±0.2°, 25.5°±0.2°, 27.1°±0.2°, 16.0°±0.2°, 26.3°±0.2°, 7.5°±0.2°, 19.9°±0.2°, and 27.7°±0.2°. And / or, the said carpicetidine diphosphate has characteristic peaks (2θ) selected from the group consisting of: 22.9°±0.2°, 6.3°±0.2°, 28.2°±0.2°, 13.1°±0.2°, 21.7°±0.2°, 20.5°±0.2°, 17.9°±0.2°, 28.7°±0.2°, 14.9°±0.2°, 27.3°±0.2°, and 25.7°±0.2°.

4. The intermediate as described in claim 1, characterized in that, The aforementioned carpicroside malate has one or more characteristics selected from the group consisting of: (1) The carpicroside malate has the basic XRPD characteristic map shown in Figure 1; and / or (2) The carpicroside malate has XRPD characteristic peaks as shown in Table 1; and / or (3) The carpicroside malate has the PLM diagram shown in Figure 2; and / or (4) The carpicroti malate has a TGA diagram as shown in Figure 5; And / or, the said carpicetidine diphosphate has one or more characteristics selected from the group consisting of: (1) The carpicetil diphosphate has the basic XRPD characteristic map shown in Figure 3; and / or (2) The carpicetil diphosphate has XRPD characteristic peaks as shown in Table 2; and / or (3) The carpicetil diphosphate has the PLM diagram shown in Figure 4; and / or (4) The carpicetidine diphosphate has a TGA graph as shown in Figure 6.

5. The use of the intermediate as described in claim 1, characterized in that, The intermediate is used to prepare carpicret crystal form A; wherein, carpicret crystal form A has the powder X-ray diffraction pattern shown in Figure 7.

6. The use as described in claim 5, characterized in that, The purity of the described carpiceter crystal form A is ≥90%.

7. A method for preparing the intermediate according to claim 1, characterized in that, (I) The intermediate is capiprosete malate, comprising the following steps: (a-1) Dissolve the carpicrin raw material in inert solvent A at 50℃~70℃ to obtain a clear liquid; (b-1) The clear liquid obtained from stirring step (a-1); (c-1) Add a mixed solution of malic acid and inert solvent A to the clear liquid from step (b-1); (d-1) Cool down to 5℃~10℃ and keep warm for crystallization for 18h-36h; (e-1) Filter and dry to obtain capiprite malate; Or (II) the intermediate is capiste succinate, comprising the following steps: (a-2) Dissolve the carpicrin raw material in inert solvent B at 50℃~70℃ to obtain a clear liquid; (b-2) The clear liquid obtained from stirring step (a-2); (c-2) Add a solution of succinic acid in inert solvent B to the supernatant from step (b-2); (d-2) Cool down to 5℃~10℃ and keep warm for 4h~8h to allow crystallization; (e-2) Filter and dry to obtain carpicrate diisocyanate.

8. The method as described in claim 7, characterized in that, The method for preparing the carpicrite malate intermediate includes one or more of the following features: In step (a-1), the inert solvent A is selected from water-miscible organic solvents and mixed solvents of water and water-miscible organic solvents; The water-miscible organic solvent is selected from one of acetonitrile, 1,4-dioxane and tetrahydrofuran; The volume ratio of the water-miscible organic solvent to water in the inert solvent A is 10:1 to 60:

1. The molar volume ratio (mol / L) of the carpicrotening material to the inert solvent A is 0.04:1 to 0.15:1; Step (b-1) further includes stirring at 50°C to 60°C for 10 min to 30 min; The molar ratio of malic acid to capiprine raw material in step (c-1) is 1:1 to 1:2; and The temperature conditions for the dripping are 50℃~60℃.

9. The method as described in claim 7, characterized in that, The method for preparing the carpicetil dicarboxylate intermediate includes one or more of the following features: In step (a-2), the inert solvent B is a mixture of water and a water-miscible organic solvent; The water-miscible organic solvent is selected from one of acetonitrile, 1,4-dioxane and tetrahydrofuran; The volume ratio of water-miscible organic solvent to water in the inert solvent B is 80:1 to 1:

1. The molar volume ratio (mol / L) of the carpicrotening material to the inert solvent B is 0.05:1 to 0.2:1; Step (b-2) further includes stirring at 50°C to 60°C for 10 min to 30 min; In step (c-2), the molar ratio of succinic acid to capiprine is 1:1 to 2:1; and The temperature conditions for the dripping are 50℃~60℃.

10. A method for preparing carpicret crystal form A, wherein carpicret crystal form A has a powder X-ray diffraction pattern as shown in Figure 7, characterized in that, Includes the following steps: (1) Provide a solution of capiprosete malate or succinate in a C2-C6 ether solvent, which is mixture 1; (2) Add Na2CO3 aqueous solution to the mixture 1 to obtain mixture 2; (3) Stir mixture 2 at room temperature and separate the liquids; (4) Take the organic phase obtained in step (3) and add water and stir, then separate the liquids; (5) At 0-10℃, C1-C6 alcohol solvents are added to the organic phase obtained in step (4) to obtain mixture 3; (6) The mixture 3 is kept at a constant temperature to crystallize and obtain Capsicentiate crystal type A.

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