Crystal form of compound (ZZ0312R) with STSA3 inhibitory activity and preparation method thereof

Abstract

The invention discloses a crystal form of a compound (ZZ0312R) with STSA3 inhibitory activity and a preparation method, and belongs to the field of synthesis of medical intermediates. PXRD, DSC, HNMR and TGA detection confirms that the crystal forms I and II are simple in preparation operation, low in cost and easy for large-scale production, and a new choice is provided for preparation research and development.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical intermediate synthesis, and specifically relates to a crystal form of a compound (ZZ0312R) having STSA3 inhibitory activity and a preparation method. Background Art

[0002] Compound ZZ0312R has a chemical name of N-(1-(R-1-(6-fluoropyridin-3-yl)ethyl)piperidin-3-yl)-2-(methylsulfonyl)-2,3,4-5-tetrahydro-1H-benzo[c]azepan-7-amine and has the following structure:

[0003]

[0004] Compound ZZ0312R is a newly developed chemical entity with STSA3 inhibitory activity. STAT3 is transiently activated under physiological conditions but exhibits persistent activation in many cancers. Two amino acid residues of STAT3, Tyr705 and Ser727, are phosphorylated upon activation. Phosphorylation of STAT3 Tyr705 (p-Tyr705) mediates the classical activation pathway of STAT3. Several clinical studies have shown that high expression of p-Tyr705 and p-Ser727 is closely associated with poor prognosis in pancreatic cancer patients. Therefore, simultaneous blocking of STAT3 phosphorylation at Tyr705 and Ser727 is a promising therapeutic strategy for pancreatic cancer.

[0005] The crystalline form of a drug substance significantly affects its solubility, further impacting the absorption, distribution, metabolism, and other physiological activities of oral drug formulations. Developing new crystalline forms of chemical entities is a key component of setting quality standards for drug substances, providing new options for formulation development. Currently, no literature has been published on the preparation of this crystalline form of the compound (ZZ0312R). Summary of the Invention

[0006] In response to the shortcomings of the existing technology, the present invention provides two crystal forms and preparation methods of a compound (ZZ0312R) with STSA3 inhibitory activity, both of which have been confirmed by PXRD, DSC, HNMR, and TGA detection. The preparation of crystal forms I and II is simple, low-cost, and easy to scale up, providing new options for formulation research and development.

[0007] The compound (ZZ0312R) crystalline form I provided by the present invention has an X-ray powder diffraction angle 2θ of 14.4°±0.2°, 15.2°±0.2°, 19.6°±0.2°, 20.0°±0.2°, 23.7°±0.2°, 24.6°±0.2°, 25.8°±0.2°, 26.0°±0.2°, 28.2°±0.2°, 29.5°±0. 2°, 30.7°±0.2°, 31.0°±0.2°, 31.8°±0.2°, 33.1°±0.2°, 33.9°±0.2°, 35.0°±0.2°, 35.6°±0.2°, 37.3°±0.2°, 38.1°±0.2°, 38.8°±0.2°, 38.9°±0.2°, 39.6°±0.2°, and one or more characteristic peaks.

[0008] The crystalline form I of compound (ZZ0312R) was confirmed to be the free base by nuclear magnetic resonance.

[0009] A method for preparing Form I of a compound (ZZ0312R) is characterized by obtaining the free base crystalline form of the compound from an amorphous solid starting material in a solvent of ethanol, acetone, or acetone / ethanol / n-heptane. Changing the solvent type is not conducive to obtaining the free base crystalline form I.

[0010] This preparation method has the following advantages:

[0011] (1) Good purification effect and high product purity:

[0012] (2) The preparation method is simple and easy to produce:

[0013] (3) The preparation can be done using a single solvent, acetone or ethanol, which makes solvent recovery easy and avoids the increase in solvent recovery costs caused by the use of mixed solvents:

[0014] Preparation method of compound (ZZ0312R) type I

[0015] Method 1:

[0016] The compound (ZZ0312R) solid (amorphous) was dissolved in 2 to 10 volumes of acetone and stirred at 35 to 60°C for 0.5 to 48 hours until completely dissolved. The temperature was then lowered to 0 to 35°C to allow solid to precipitate. The solution was kept warm for 1 to 10 hours and filtered to obtain Form I of the compound (ZZ0312R).

[0017] The volume of the reaction solvent is preferably 3 to 6 volumes; the reaction temperature is preferably 50 to 60° C.; the stirring time is preferably 1 to 3 hours; the crystallization temperature is preferably 20 to 25° C.; and the crystallization time is preferably 2 to 4 hours.

[0018] Method 2:

[0019] The compound (ZZ0312R) solid (amorphous) was dissolved in 2 to 10 volumes of ethanol, heated to 5 to 80°C and kept warm for 1 hour until completely dissolved, cooled to 0 to 30°C and allowed to stand for 3 to 10 hours until a large amount of solid precipitated, and filtered to obtain compound (ZZ0312R) Form I.

[0020] The volume of the reaction solvent is preferably 3 to 8 volumes, the reaction temperature is preferably 70 to 80° C., the cooling and crystallization temperature is preferably 20 to 25° C., and the crystallization time is preferably 2 to 4 hours.

[0021] Method 3:

[0022] The compound (ZZ0312R) solid (amorphous) was dissolved in 3-50 volumes of acetone or 1-5 volumes of ethanol, and 0.5-3 volumes of n-heptane were added at 5-80°C. The mixture was stirred until solid precipitated. The temperature was lowered to 0-30°C and filtered to obtain compound (ZZ0312R) Form I.

[0023] The volume of the reaction solvent acetone is preferably 3 to 6 volumes, the volume of the solvent ethanol is preferably 1 to 2 volumes, and the volume of n-heptane is preferably 0.5 to 1 volume; the reaction temperature is preferably 50 to 60° C.; the crystallization temperature is preferably 15 to 25° C.; and the stirring time is preferably 1 to 3 hours.

[0024] The crystal form I of the present invention has the following beneficial effects:

[0025] (1) Provided is a method for preparing a free base crystalline form of a compound (ZZ0312R);

[0026] (2) This method is simple to operate and easy to scale up;

[0027] (3) The crystal form has good stability: the crystal form I has no change in crystal form after being placed at 50°C for 7 days, the crystal form has no change in crystal form at high temperature of 80°C for 8 hours, and the crystal form has no change in crystal form at high humidity of 25°C and 80% RH for 48 hours, indicating that the crystal form has good stability and provides a new option for formulation development.

[0028] The compound (ZZ0312R) provided by the present invention has a second crystalline form II, and the diffraction angle 2θ of the X-ray powder diffraction of the crystalline form II using Cu-Ka radiation is: 8.7°±0.2°, 9.5°±0.2°, 10.1°±0.2°, 12.3°±0.2°, 12.7°±0.2°, 12.9°±0.2°, 13.1°±0.2°, 15.1°±0. 2°, 15.7°±0.2°, 16.0°±0.2°, 16.8°±0.2°, 17.0°±0.2°, 17.6°±0.2, 18.2°±0.2°, 18.6°±0.2°, 19.1°±0.2°, 19.9°±0.2°, 20.6°±0.2°, 21.0°±0.2, 21.8°±0.2°, 22.7°±0.2°, 23.7°±0.2°. 2°, 23.9°±0.2°, 24.2°±0.2°, 24.9°±0.2°, 25.2°±0.2°, 25.6°±0.2°, 25.8°±0.2°, 26.0°±0.2°, 27.2°±0.2°, 27.6°±0.2°, 28.1°±0.2°, 28.9°±0.2°, 29.9°±0.2°, 30.4°±0.2°, 30.6°±0. 2°, 30.9°±0.2°, 31.3°±0.2°, 31.8°±0.2°, 32.1°±0.2°, 33.0°±0.2°, 33.4°±0.2°, 34.5°±0.2°, 35.8°±0.2°, 36.2°±0.2°, 36.7°±0.2°, 36.9°±0.2°, 38.5°±0.2°, and 38.8°±0.2°.

[0029] The crystalline form II of compound (ZZ0312R) was confirmed to be the free base by nuclear magnetic resonance.

[0030] The compound (ZZ0312R) solid (amorphous or Form I) is dissolved in 3 to 10 volumes of isopropanol, n-propanol, n-butanol, ethyl acetate, butanone, methyl isobutyl ketone solvent, or a mixed solvent of any two or more thereof, stirred at 5 to 80° C. until completely dissolved, cooled to 0 to 30° C., crystallized for 1 to 10 hours, and filtered to obtain Form II of the compound (ZZ0312R).

[0031] Preparation method of Form II of compound (ZZ0312R):

[0032] The compound (ZZ0312R) solid (amorphous or crystalline form I) is dissolved in 3 to 10 volumes of ethanol, isopropanol, n-propanol, n-butanol, ethyl acetate, butanone, methyl isobutyl ketone, acetone solvent, or a mixed solvent of any two or more thereof, stirred at 5 to 80° C. until completely dissolved, cooled to 0 to 30° C., crystallized for 1 to 10 hours, and filtered to obtain crystalline form II of the compound (ZZ0312R).

[0033] The volume of the reaction solvent is preferably 5 to 8 volumes, the reaction temperature is preferably 50 to 60° C., the crystallization temperature is preferably 15 to 25° C., and the stirring time is preferably 1 to 3 hours.

[0034] The crystalline form II of the compound of the present invention (ZZ0312R) has beneficial effects:

[0035] (1) Provided is a method for preparing a free base crystalline form of a compound (ZZ0312R);

[0036] (2) This method is simple to operate and easy to scale up;

[0037] (3) The crystal form has good stability: the crystal form II has no change in crystal form after being placed at 50°C for 7 days, at a high temperature of 80°C for 8 hours, and at a high humidity of 25°C and 80% RH for 48 hours, indicating that the crystal form has good stability and provides a new option for formulation development. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 is the HNMR spectrum of the crystalline form I and the crystalline form II;

[0039] Figure 2 The PXRD pattern of the Form I Example 1 is shown in FIG.

[0040] Figure 3 is the DSC spectrum of the crystalline form I;

[0041] Figure 4 is the TGA spectrum of the crystalline form I;

[0042] Figure 5 This is the PXRD pattern of the Form II Example 4;

[0043] Figure 6 is the DSC spectrum of the crystalline form II;

[0044] Figure 7 It is the TGA spectrum of the crystalline form II. DETAILED DESCRIPTION

[0045] The present invention will be further described below in conjunction with specific examples. These examples should be understood to be merely illustrative of the present invention and not intended to limit the scope of protection of the present invention. After reading the contents described herein, those skilled in the art may make various changes or modifications to the present invention, and these equivalent variations and modifications also fall within the scope defined by the claims of the present invention.

[0046] Example 1

[0047] 20.0 g of compound (ZZ0312R) solid (amorphous) was dissolved in 80 mL of acetone at 15-30°C, heated to 50-60°C, stirred at this temperature for 2 hours, cooled to 20-25°C, stirred at this temperature for 2 hours, filtered, and the filter cake was vacuum dried at 40°C to obtain 17.6 g of Form I solid of compound (ZZ0312R) with a purity of 99.7%.

[0048] The compound (ZZ0312R) crystalline form I provided by the present invention has an X-ray powder diffraction angle 2θ of 14.4°±0.2°, 15.2°±0.2°, 19.6°±0.2°, 20.0°±0.2°, 23.7°±0.2°, 24.6°±0.2°, 25.8°±0.2°, 26.0°±0.2°, 28.2°±0.2°, 29.5°±0. 2°, 30.7°±0.2°, 31.0°±0.2°, 31.8°±0.2°, 33.1°±0.2°, 33.9°±0.2°, 35.0°±0.2°, 35.6°±0.2°, 37.3°±0.2°, 38.1°±0.2°, 38.8°±0.2°, 38.9°±0.2°, 39.6°±0.2°, and one or more characteristic peaks.

[0049] Example 2

[0050] 20.0 g of compound (ZZ0312R) solid (amorphous) was added to 160 mL of ethanol, the temperature was raised to 50-60°C, and the mixture was stirred for 0.5 hour. The temperature was then lowered to 20-25°C, and the mixture was stirred for 2 hours. The mixture was filtered, and the filter cake was dried under vacuum at 40°C to obtain 18.8 g of Form I solid of compound (ZZ0312R) with a purity of 99.2%.

[0051] Example 3

[0052] 20.0 g of compound (ZZ0312R) solid (amorphous) was added to 60 mL of acetone, the temperature was raised to 50-60°C, 20 mL of n-heptane was added dropwise, and the mixture was stirred at this temperature for 0.5 hour. The temperature was then lowered to 20-25°C, stirred at this temperature for 2 hours, and filtered. The filter cake was vacuum dried at 40°C to obtain 172 g of Form I solid of compound (ZZ0312R) with a purity of 99.5%.

[0053] Example 4

[0054] To 20.0 g of compound (ZZ0312R) solid (amorphous or Form I) was added 60 mL of ethyl acetate, and the temperature was raised to 50-60°C until the system clarified. 20 mL of butanone was added dropwise, and the temperature was maintained at 50-60°C for 1 hour. The temperature was then lowered to 20-25°C, and the mixture was stirred for 2 hours. The mixture was filtered, and the filter cake was vacuum dried at 40°C to obtain 10.7 g of Form II solid of compound (ZZ0312R) with a purity of 99.2%.

[0055] The second crystalline form II of the compound (ZZ0312R) provided by the invention, using Cu-Ka radiation, the diffraction angle 2θ of the X-ray powder diffraction of the crystalline form II is: 8.7°±0.2°, 9.5°±0.2°, 10.1°±0.2°, 12.3°±0.2°, 12.7°±0.2°, 12.9°±0.2°, 13.1°±0.2°, 15.1°±0 2°, 15.7°±0.2°, 16.0°±0.2°, 16.8°±0.2°, 17.0°±0.2°, 17.6°±0.2, 18.2°±0.2°, 18.6°±0.2°, 19.1°±0.2°, 19.9°±0.2°, 20.6°±0.2°, 21.0°±0.2, 21.8°±0.2°, 22.7°±0.2°, 23.7°±0.2°. 2°, 23.9°±0.2°, 24.2°±0.2°, 24.9°±0.2°, 25.2°±0.2°, 25.6°±0.2°, 25.8°±0.2°, 26.0°±0.2°, 27.2°±0.2°, 27.6°±0.2°, 28.1°±0.2°, 28.9°±0.2°, 29.9°±0.2°, 30.4°±0.2°, 30.6°±0. 2°, 30.9°±0.2°, 31.3°±0.2°, 31.8°±0.2°, 32.1°±0.2°, 33.0°±0.2°, 33.4°±0.2°, 34.5°±0.2°, 35.8°±0.2°, 36.2°±0.2°, 36.7°±0.2°, 36.9°±0.2°, 38.5°±0.2°, and 38.8°±0.2°.

Claims

1. Form I of compound (ZZ0312R), characterized in that The X-ray powder diffraction patterns at diffraction angles 2θ are: 14.4°±0.2°, 15.2°±0.2°, 19.6°±0.2°, 20.0°±0.2°, 23.7°±0.2°, 24.6°±0.2°, 25.8°±0.2°, 26.0°±0.2°, 28.2°±0.2°, 29.5°±0.2°, 30.7°±0.2°, 31. .0°±0.2°, 31.8°±0.2°, 33.1°±0.2°, 33.9°±0.2°, 35.0°±0.2°, 35.6°±0.2°, 37.3°±0.2°, 38.1°±0.2°, 38.8°±0.2°, 38.9°±0.2°, 39.6°±0.2°, and one or more characteristic peaks.

2. The method for preparing the crystalline form I of the compound (ZZ0312R) according to claim 1, wherein The free base crystalline form of compound (ZZ0312R) was obtained from an amorphous solid starting material in ethanol, acetone, or acetone / ethanol / n-heptane solvent.

3. Form II of compound (ZZ0312R), characterized in that The X-ray powder diffraction at the diffraction angle 2θ is: 8.7°±0.2°, 9.5°±0.2°, 10.1°±0.2°, 12.3°±0.2°, 12.7°±0.2°, 12.9°±0.2°, 13.1°±0.2°, 15.1°±0 2°, 15.7°±0.2°, 16.0°±0.2°, 16.8°±0.2°, 17.0°±0.2°, 17.6°±0.2, 18.2°±0.2°, 18.6°±0.2°, 19.1°±0.2°, 19.9°±0.2°, 20.6°±0.2°, 21.0°±0.2, 21.8°±0.2°, 22.7°±0.2°, 23.7°±0.2°. 2°, 23.9°±0.2°, 24.2°±0.2°, 24.9°±0.2°, 25.2°±0.2°, 25.6°±0.2°, 25.8°±0.2°, 26.0°±0.2°, 27.2°±0.2°, 27.6°±0.2°, 28.1°±0.2°, 28.9°±0.2°, 29.9°±0.2°, 30.4°±0.2°, 30.6°±0. 2°, 30.9°±0.2°, 31.3°±0.2°, 31.8°±0.2°, 32.1°±0.2°, 33.0°±0.2°, 33.4°±0.2°, 34.5°±0.2°, 35.8°±0.2°, 36.2°±0.2°, 36.7°±0.2°, 36.9°±0.2°, 38.5°±0.2°, and 38.8°±0.2°.

4. The method for preparing the crystalline form II of the compound (ZZ0312R) according to claim 3, wherein The amorphous solid or crystal form I of compound (ZZ0312R) is used as a raw material, the temperature is raised to 50-60° C. in ethanol, isopropanol, n-propanol, n-butanol, ethyl acetate, butanone, methyl isobutyl ketone, acetone solvent or any two or more mixed solvents thereof, the mixture is dissolved by maintaining the temperature, and the crystal form II is crystallized by cooling.

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