Crystal form a and crystal form b of (r)-terbutaline benzenesulfonate and preparation methods therefor

Abstract

Disclosed are a crystal form A and a crystal form B of (R)-terbutaline benzenesulfonate and preparation methods therefor. An (R)-terbutaline free base and benzenesulfonic acid are crystallized in different solvents to obtain a crystal form A and a crystal form B of (R)-terbutaline benzenesulfonate, which crystal forms exhibit good stability and solubility. The method is simple and reliable, and involves an inexpensive preparation cost. The ee of the product remains unchanged at 99.9% during the crystallization process, and the purity reaches as high as 99.8%.

Description

(R)-Terbutaline benzenesulfonate crystal form A and crystal form B and preparation method thereof Technical Field

[0001] The present invention relates to multiple crystal forms of (R)-terbutaline benzenesulfonate as a β2 receptor agonist, and in particular to (R)-terbutaline benzenesulfonate crystal form A and crystal form B and a preparation method thereof. Background Art

[0002] Terbutaline is a potent, selective β2-receptor agonist that relaxes bronchial smooth muscle, inhibits the release of endogenous spasmodics, and suppresses edema caused by increased clearance of endogenous transmitters and mucociliary membranes. Clinically, it is primarily used to dilate the trachea and increase lung ventilation, and can be used to treat symptoms such as asthma, obstructive pneumonia, smooth muscle spasm, and shock.

[0003] Terbutaline has a chiral center, but the racemic sulfate salt is currently used clinically. Studies have shown that the R-form of terbutaline (usually the levorotatory form) is the active ingredient in the drug (J. Med. Chem., 1972, 15, 1182-1183). The S-form (usually the dextrorotatory form) lacks affinity for β-adrenergic receptors, making it ineffective and potentially toxic. Therefore, exploring and optimizing the preparation of (R)-terbutaline, systematically studying the various salt forms of this chiral form, and re-marketing it are of great clinical value.

[0004] There are many studies on the crystal forms of racemic terbutaline sulfate, including literature (CRYSTAL GROWNTH & DESIGN. 2008, 18(1), 80-90) and patent applications (CN101391965A, CN112250586A, CN109988074A). So far, only the crystal forms of (R)-terbutaline hydrochloride have been studied, but only one crystal form has been involved. It is well known that the stability of different crystal forms of different salt forms of the same drug may be different. Moreover, the solubility of the same salt form of the racemate and chiral form of the same drug often varies greatly. For example, the sulfate of racemic terbutaline is a good crystal, while the sulfate of (R)-terbutaline is difficult to form crystals. Therefore, the disclosed technology for forming the crystal form of racemic terbutaline has no guiding value for the current research on the crystal form of (R)-terbutaline. Therefore, preparing multiple crystal forms of different salt forms of (R)-terbutaline and studying the differences in their physical and chemical properties are of great significance for obtaining advantageous crystal forms for clinical use. Technical Solutions

[0005] The present invention provides a new crystalline form of (R)-terbutaline besylate with high optical and chemical purity, namely Form A and Form B. The product has an enantiomeric excess (ee) of greater than 99.9% and a chemical purity greater than 99.8%. The present invention improves the stability and solubility of existing (R)-terbutaline salt forms, providing a foundation for the clinical research and application of (R)-terbutaline.

[0006] The present invention adopts the following technical solutions:

[0007] A (R)-terbutaline benzenesulfonate crystal form A has an X-ray powder diffraction pattern using Cu-Kα radiation, with characteristic diffraction peaks at 2θ=8.81°, 10.29°, 12.23°, 13.36°, 16.99°, 18.55°, 18.89°, 19.17°, 19.94°, 21.08°, 22.31°, 22.76°, 23.75°, 25.49°, 26.81°, 27.70°, 30.29°, 33.41°, and 36.69°, wherein the 2θ value error range is ±0.2°.

[0008] A (R)-terbutaline benzenesulfonate crystal form B has an X-ray powder diffraction pattern using Cu-Kα radiation, with characteristic diffraction peaks at 2θ=9.10°, 10.63°, 12.21°, 13.36°, 16.16°, 17.05°, 18.00°, 18.71°, 20.37°, 21.54°, 21.91°, 22.88°, 26.83°, and 28.85°, wherein the 2θ value error range is ±0.2°.

[0009] The present invention also discloses a method for preparing (R)-terbutaline benzenesulfonate crystal form A, comprising the steps of reacting (R)-terbutaline free base and benzenesulfonic acid in acetone for 0.5 to 1.5 hours, followed by crystallization, and then separating the solid to obtain (R)-terbutaline benzenesulfonate crystal form A. Preferably, the reaction temperature is 40 to 60° C., more preferably 45 to 50° C.

[0010] In the present invention, the ratio of (R)-terbutaline free base to acetone is 30-60 mg:1 mL, preferably 40-50 mg:1 mL.

[0011] The present invention also discloses a method for preparing (R)-terbutaline benzenesulfonate Form B, comprising the steps of reacting (R)-terbutaline free base and benzenesulfonic acid in isopropyl alcohol for 1 to 2.5 hours, followed by crystallization, and then separating the solid to obtain (R)-terbutaline benzenesulfonate Form B. Preferably, the reaction temperature is 40 to 60° C., preferably 50 to 55° C.

[0012] In the present invention, the ratio of (R)-terbutaline free base to isopropyl alcohol is 30-60 mg:1 mL, preferably 40-50 mg:1 mL.

[0013] In the present invention, the crystallization temperature is -10°C to 10°C. Preferably, in the preparation method of the (R)-terbutaline benzenesulfonate crystal form, the crystallization temperature is -5°C to 5°C; more preferably, the crystallization temperature is 0°C. Beneficial effects

[0014] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0015] The present invention uses (R)-terbutaline and benzenesulfonic acid to crystallize in different solvents to obtain (R)-terbutaline benzenesulfonate crystal form A and crystal form B, which have good stability and solubility, improve the stability and solubility of existing (R)-terbutaline salt forms, and provide a basis for clinical research and application of (R)-terbutaline. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG1 is an XRPD pattern of (R)-terbutaline benzenesulfonate Form A;

[0017] Figure 2 shows the appearance of (R)-terbutaline benzenesulfonate Form A and its aqueous solution (100 mg / mL);

[0018] FIG3 is an XRPD pattern of (R)-terbutaline benzenesulfonate Form B;

[0019] Figure 4 shows the appearance of (R)-terbutaline benzenesulfonate Form B and its aqueous solution (100 mg / mL). Modes for Carrying Out the Invention

[0020] The applicant previously disclosed a technique for preparing (R)-terbutaline (i.e., levorotatory terbutaline) using a chiral prosthetic group (CN113264839A), with the product exhibiting an ee value of up to 99.9%. The present invention utilizes this previously reported technique to prepare (R)-terbutaline free base, which is then salted with benzenesulfonic acid and crystallized in various solvents. However, this method for preparing a novel crystalline form of (R)-terbutaline benzenesulfonate has not been previously reported.

[0021] In the present invention, (R)-terbutaline benzenesulfonate is a compound with the chemical name {(R)-5-(2-(tert-butylamino)-1-hydroxyethyl)benzene-1,3-diol}benzenesulfonate, which is represented by formula (I):

[0022]

[0023] The present invention also discloses a method for preparing (R)-terbutaline benzenesulfonate crystal form A, comprising the following steps: reacting (R)-terbutaline free base and benzenesulfonic acid in acetone for 1 hour, followed by crystallization, and then separating the solid to obtain (R)-terbutaline benzenesulfonate crystal form A. Specifically:

[0024] (1) (R)-terbutaline free base and benzenesulfonic acid were mixed in acetone and reacted for 1 hour;

[0025] (2) cooling the reaction solution to crystallize;

[0026] (3) The solid and liquid are separated by filtration, and the solid is dried to obtain (R)-terbutaline benzenesulfonate Form A.

[0027] The present invention also discloses a method for preparing (R)-terbutaline benzenesulfonate crystal form B, comprising the following steps: reacting (R)-terbutaline free base and benzenesulfonic acid in isopropyl alcohol for 2 hours, followed by crystallization, and then separating the solid to obtain (R)-terbutaline benzenesulfonate crystal form B. Specifically:

[0028] (1) (R)-terbutaline free base and benzenesulfonic acid were mixed in isopropanol and reacted for 2 hours;

[0029] (2) cooling the reaction solution to crystallize;

[0030] (3) The solid and liquid are separated by filtration, and the solid is dried to obtain (R)-terbutaline benzenesulfonate Form B.

[0031] In some embodiments, the crystallization temperature of (R)-terbutaline benzenesulfonate in step (2) is -10°C to 10°C; in a preferred embodiment, the crystallization temperature is 0°C.

[0032] The XRPD pattern of the (R)-terbutaline besylate form A of the present invention is shown in Figure 1 of the accompanying drawings of the specification. The XRPD pattern of the (R)-terbutaline besylate form B of the present invention is shown in Figure 3 of the accompanying drawings of the specification.

[0033] In the present invention, the chemical structural formula of (R)-terbutaline free base is as follows:

[0034]

[0035] The previously reported (R)-terbutaline hydrochloride (CN113264839A, compound 8, 26.2 g) was dissolved in 100 mL of water and added with 1 M sodium bicarbonate aqueous solution (110 mL). The mixture was stirred for 1 hour and then extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated to dryness to obtain 21.4 g of (R)-terbutaline free base, a yield of 96%. The free base had an ee of 99.9%. The crystallization process of the present invention does not result in loss of ee, and all products have an ee of 99.9%.

[0036] The specific preparation and testing methods of the present invention are conventional methods, such as the purity and ee value tested by conventional high performance liquid chromatography (HPLC + chiral column) (Daicel Chiralpak OJ-H, EtOH: hexane: TFA: Et3N = 5: 95: 0.05: 0.02, flow rate = 1.0 mL min −1 , λ = 254 nm):t major = 20.16 min,t minor = 29.34 min, ee = 99.9%. X-ray diffraction (XRPD) test conditions used: instrument model: Bruker D8 Focus X-ray powder diffractometer, radiation: monochromatic Cu-Kα radiation (λ = 1.5406), scanning mode: θ / 2θ, scanning range: 2-40°, voltage: 40 kV, current: 40 mA, scanning speed: 20° / min.

[0037] The present invention is further described below with reference to the examples. (R)-terbutaline free base is obtained by referring to the method of Example 1 of CN113264839A, and further reacting with sodium bicarbonate.

[0038] Example 1, Preparation of (R)-Terbutaline Besylate Form A

[0039] (R)-Terbutaline free base (2.25 g) was dissolved in 50 mL of acetone. Benzenesulfonic acid (1.58 g) was then added at 50°C. The reaction was stirred at 50°C for 1 hour, then naturally cooled to 0°C to allow crystallization. The mixture was then filtered and the filter cake was dried under vacuum at room temperature to obtain 3.33 g of (R)-terbutaline benzenesulfonate Form A, with a yield of 87%. High-performance liquid chromatography (HPLC) analysis revealed an ee of 99.9% and a purity of 99.8%. The XRPD spectrum of this crystal form is shown in Figure 1, with characteristic diffraction peaks at 2θ=8.81°, 10.29°, 12.23°, 13.36°, 16.99°, 18.55°, 18.89°, 19.17°, 19.94°, 21.08°, 22.31°, 22.76°, 23.75°, 25.49°, 26.81°, 27.70°, 30.29°, 33.41°, and 36.69°, where the error range of the 2θ value is ±0.2°; the product and its aqueous solution are shown in Figure 2.

[0040] Example 2

[0041] Based on Example 1, the amount of benzenesulfonic acid (1.58 g) was replaced with (2.37 g), and the rest remained unchanged, to obtain 3.26 g of (R)-terbutaline benzenesulfonate Form A. HPLC determination of the product showed an ee of 99.9% and a purity of 99.7%.

[0042] Based on Example 1, the amount of benzenesulfonic acid (1.58 g) was replaced with (1.26 g), and the rest remained unchanged, to obtain 2.72 g of (R)-terbutaline benzenesulfonate Form A. HPLC determination of the product showed an ee of 99.9% and a purity of 99.5%.

[0043] Example 3

[0044] Based on Example 1, the amount of acetone was changed to 40 mL, and the rest remained unchanged to obtain 3.52 g of (R)-terbutaline benzenesulfonate Form A with a yield of 92%. HPLC determination showed that the ee of the product was 99.9% and the purity was 98.5%.

[0045] Based on Example 1, the amount of acetone was changed to 60 mL, and the rest remained unchanged to obtain 2.99 g of (R)-terbutaline benzenesulfonate Form A with a yield of 78%. HPLC determination showed that the product had an ee of 99.9% and a purity of 99.8%.

[0046] Example 4

[0047] Based on Example 1, the crystallization temperature was changed from 0°C to 10°C, while the other parameters remained unchanged, to obtain 2.83 g of (R)-terbutaline benzenesulfonate Form A with a yield of 74%. HPLC determination showed that the product had an ee of 99.9% and a purity of 99.8%.

[0048] Based on Example 1, the crystallization temperature was changed from 0°C to -10°C, while other parameters remained unchanged, to obtain 3.51 g of (R)-terbutaline benzenesulfonate Form A. HPLC determination showed that the product had an ee of 99.9% and a purity of 98.9%.

[0049] Example 5, Preparation of (R)-Terbutaline Besylate Form B

[0050] (R)-Terbutaline free base (2.25 g) was dissolved in 50 mL of isopropanol. Benzenesulfonic acid (1.58 g) was then added at 55°C. The reaction was stirred and maintained at 55°C for 2 hours. The mixture was then naturally cooled to 0°C for crystallization. The filter cake was filtered and dried under vacuum at room temperature to obtain 3.03 g of (R)-terbutaline benzenesulfonate Form B, with a yield of 79%. High-performance liquid chromatography (HPLC) analysis revealed an ee of 99.9% and a purity of 99.6%. The XRPD spectrum of this crystal form is shown in Figure 3, with characteristic diffraction peaks at 2θ=9.10°, 10.63°, 12.21°, 13.36°, 16.16°, 17.05°, 18.00°, 18.71°, 20.37°, 21.54°, 21.91°, 22.88°, 26.83°, and 28.85°, where the error range of the 2θ value is ±0.2°; the product and its aqueous solution are shown in Figure 4.

[0051] Example 6

[0052] A humidity stability test and a light stability test were conducted using a Sino HQH-400 artificial climate chamber. A 10mg sample of (R)-terbutaline benzenesulfonate was spread flat in a weighing bottle and placed in the chamber with the bottle open. The sample was exposed to 5000L of light for 7 days at a normal temperature and humidity. During the humidity test, the humidity was 85% for 7 days at a normal temperature. The purity of the hydrochloride of R-terbutaline prepared in Example 1 and Example 5, as well as in Example 1 of CN113264839A, after the light test was 98.5%, 96.7%, and 95.9%, respectively. The purity of the products in Example 1 and Example 5 after the humidity test was 98.3% and 97.2%, respectively.

[0053] The method provided by the present invention is to crystallize (R)-terbutaline free base with an ee value of 99.9% and benzenesulfonic acid in different solvents to obtain (R)-terbutaline benzenesulfonate crystal form A and crystal form B. The crystals have good stability and solubility, provide support for further dosage form research, and are beneficial to the application of (R)-terbutaline.

Claims

1. A (R)-terbutaline benzenesulfonate crystalline form A, using Cu-Kα radiation, whose X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ=8.81°, 10.29°, 12.23°, 13.36°, 16.99°, 18.55°, 18.89°, 19.17°, 19.94°, 21.08°, 22.31°, 22.76°, 23.75°, 25.49°, 26.81°, 27.70°, 30.29°, 33.41°, and 36.69°, wherein the 2θ value error range is ±0.2°.

2. The (R)-terbutaline besylate crystal form A according to claim 1, characterized in that Acetone crystallization was used to obtain the (R)-terbutaline benzenesulfonate Form A.

3. The method for preparing the (R)-terbutaline benzenesulfonate crystal form A according to claim 1, characterized in that: The following steps are involved: (R)-terbutaline free base and benzenesulfonic acid are reacted in acetone for 0.5 to 1.5 hours, followed by crystallization, and then the solid is separated to obtain (R)-terbutaline benzenesulfonate form A.

4. The method for preparing the (R)-terbutaline benzenesulfonate crystal form A according to claim 3, characterized in that: The ratio of (R)-terbutaline free base to acetone is 30-60 mg:1 mL.

5. A (R)-terbutaline benzenesulfonate crystalline form B, using Cu-Kα radiation, whose X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ=9.10°, 10.63°, 12.21°, 13.36°, 16.16°, 17.05°, 18.00°, 18.71°, 20.37°, 21.54°, 21.91°, 22.88°, 26.83°, and 28.85°, wherein the 2θ value error range is ±0.2°.

6. The (R)-terbutaline besylate crystalline form B according to claim 5, characterized in that The (R)-terbutaline benzenesulfonate Form B is obtained by crystallization using isopropyl alcohol.

7. The method for preparing the (R)-terbutaline benzenesulfonate crystal form B according to claim 5, characterized in that: The following steps are involved: (R)-terbutaline free base and benzenesulfonic acid are reacted in isopropyl alcohol for 1 to 2.5 hours, followed by crystallization, and then the solid is separated to obtain (R)-terbutaline benzenesulfonate Form B.

8. The method for preparing the (R)-terbutaline benzenesulfonate crystal form B according to claim 7, characterized in that: The ratio of (R)-terbutaline free base to isopropyl alcohol is 30-60 mg:1 mL.

9. The preparation method according to claim 3 or 7, characterized in that: The reaction temperature is 40 to 60°C, and the crystallization temperature is -10 to 10°C.

10. Use of the (R)-terbutaline besylate crystal form A according to claim 1 or the (R)-terbutaline besylate crystal form B according to claim 5 in the preparation of a medicament containing terbutaline as an active ingredient.

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