阅读说明：本技术 一种妥洛特罗晶型及制备方法 (Tulobuterol crystal form and preparation method thereof ) 是由 郭伟 杨杰 何淑旺 王文笙 方亮 蔡琨 颜世强 梁林 解春文 景亚军 于 2020-12-25 设计创作，主要内容包括：本发明提供了一种妥洛特罗晶型及制备方法。其制备方法包括：将妥洛特罗溶解于乙酸乙酯等良溶剂后,再向体系中滴加正庚烷等不良溶剂,滴加完毕后过滤,取滤饼,干燥,得到所述妥洛特罗晶型晶体。该晶型纯度高,稳定性好,在工艺成产中具有优越性,适合制剂工艺过程长期储备。(The invention provides a tulobuterol crystal form and a preparation method thereof. The preparation method comprises the following steps: and dissolving tulobuterol in a good solvent such as ethyl acetate, dropwise adding a poor solvent such as n-heptane into the system, filtering after dropwise adding, taking a filter cake, and drying to obtain the tulobuterol crystal form crystal. The crystal form has high purity and good stability, has superiority in process production, and is suitable for long-term storage in a preparation process.)

1. A tulobuterol crystal characterized in that an X-ray powder of the crystal expressed in a 2 theta diffraction angle using Cu-Kalpha radiation has diffraction peaks at the 2 theta diffraction angles of 9.4384 + -0.2, 9.9474 + -0.2, 17.8258 + -0.2, 18.0469 + -0.2.

2. Tulobuterol crystals according to claim 1, having an X-ray powder diffraction pattern according to figure 1.

3. The method for producing tulobuterol crystals as claimed in claim 1 or claim 2, comprising the steps of: and dissolving tulobuterol in a good solvent, dropwise adding a poor solvent into the system, filtering after dropwise adding, taking a filter cake, and drying to obtain the tulobuterol crystal.

4. The method for producing tulobuterol crystals according to claim 3, wherein the ratio of the amount of tulobuterol to the good solvent is 1 g: 1-5 ml; in the dropwise adding step, the dosage of the good solvent is 2-6 times of the volume dosage of the poor solvent.

5. The method for producing tulobuterol crystals as claimed in claim 3, wherein the good solvent during the dissolving is selected from the group consisting of ethyl acetate, dichloromethane, acetone, acetonitrile, tetrahydrofuran; ethyl acetate and acetone are preferred; the poor solvent is selected from n-hexane, n-heptane, cyclohexane, isopropyl ether and methyl tert-butyl ether in the dropping process; n-hexane, n-heptane, cyclohexane are preferred.

6. The method for producing tulobuterol crystals according to claim 3, wherein the dissolution temperature in the dissolution step is 25 to 60 ℃; in the dropwise adding step, the temperature is 30-40 ℃.

7. The method for preparing tulobuterol crystal according to claim 3, wherein a certain amount of tulobuterol in the form of the crystal is added as seed crystal, the amount of the seed crystal being 1-10% of the mass of the charge.

8. The method for producing tulobuterol crystals according to claim 3, wherein in the dropping step, the dropping rate is 1 to 7ml/min, preferably 4 ml/min.

9. Use of tulobuterol crystals according to claim 1 or 2 in the manufacture of an antihistamine medicament.

10. A pharmaceutical composition comprising the tulobuterol crystal according to claim 1 or 2 as an active ingredient.

Technical Field

The invention belongs to the technical field of pharmaceutical chemical synthesis, and relates to a tulobuterol crystal form and a preparation method thereof.

Background

Tulobuterol (tulobuterol), a selective β 2 receptor agonist developed by Abbot corporation of japan, was approved for the market as an anti-asthmatic in japan in 1981. It was used in 1998 for asthma and chronic obstructive disease (COPD), and is currently used in children as a patch for relieving symptoms such as dyspnea caused by airway obstruction diseases such as bronchial peaks, acute bronchitis, chronic bronchitis, and emphysema. Tulobuterol, chemically known as 1- (2-chlorophenyl) -2-tert-butylaminoethanol, has the following structure:

there are several reports on tulobuterol: german patent DE2244737, application date 1973.3.22, discloses the compound tulobuterol, a process for its synthesis and the formation of salts of this compound with other pharmaceutically acceptable acids. The synthetic method of tulobuterol and its pharmacological action against asthma are reported in Japanese literature Synthesis and immunization activity of o-chloro- (tert-butyllaminomethyl) -benzylalcoholic chloride (C-78) and related compounds [ J ]. Yakugakuzu Zhiass, 1978, 98(9): 1198-. Spanish patent ES1985549752 discloses a process for the preparation of trogliol. The preparation process of tulobuterol reported in the Chinese journal of medicinal chemistry 2015, 25(2) is improved. The search of domestic and foreign documents shows that the tulobuterol crystal form is not reported.

Disclosure of Invention

The invention provides a new tulobuterol crystal form and a preparation method thereof.

The invention provides a tulobuterol crystal, which uses Cu-Kalpha radiation, and X-ray powder of the crystal expressed by a 2 theta diffraction angle has diffraction peaks at the 2 theta diffraction angles of 9.4384 +/-0.2, 9.9474 +/-0.2, 17.8258 +/-0.2 and 18.0469 +/-0.2.

The invention provides a tulobuterol crystal, which uses Cu-Kalpha radiation, and X-ray powder of the crystal expressed by a 2 theta diffraction angle has diffraction peaks at the 2 theta diffraction angles of 9.4384 +/-0.2, 9.9474 +/-0.2, 17.8258 +/-0.2, 18.0469 +/-0.2, 26.9933 +/-0.2 and 29.0322 +/-0.2.

The invention provides a tulobuterol crystal, which uses Cu-Kalpha radiation, and X-ray powder of the crystal expressed by a 2 theta diffraction angle has diffraction peaks at the 2 theta diffraction angles of 9.4384 +/-0.1, 9.9474 +/-0.1, 17.8258 +/-0.1, 18.0469 +/-0.1, 26.9933 +/-0.1 and 29.0322 +/-0.1.

The invention provides a tulobuterol crystal, which uses Cu-Kalpha radiation, and X-ray powder of the crystal expressed by a 2 theta diffraction angle has diffraction peaks at the 2 theta diffraction angles of 9.4384 +/-0.2, 9.9474 +/-0.2, 17.8258 +/-0.2, 18.0469 +/-0.2, 26.9933 +/-0.2 and 29.0322 +/-0.2. The tulobuterol new crystal form crystal provided by the invention has the advantages that Cu-Kalpha radiation is used, X-ray powder of the crystal expressed by a 2 theta diffraction angle has a diffraction peak at the 2 theta diffraction angle of 9.4384 +/-0.2, the relative intensity of the diffraction peak is 22.61%, and the corresponding interplanar spacing D is 9.37057;

a diffraction peak at a 2 theta diffraction angle of 9.9474 +/-0.2, wherein the relative intensity of the diffraction peak is 100 percent, and the corresponding interplanar spacing D is 8.89220;

a diffraction peak at a 2 theta diffraction angle of 17.8258 +/-0.2, wherein the relative intensity of the diffraction peak is 76.83 percent, and the corresponding interplanar spacing D is 4.97595;

a diffraction peak at a 2 theta diffraction angle of 18.0469 +/-0.2, wherein the relative intensity of the diffraction peak is 7.58 percent, and the corresponding interplanar spacing D is 4.91548;

a diffraction peak at a 2 theta diffraction angle of 26.9933 +/-0.2, wherein the relative intensity of the diffraction peak is 11.68 percent, and the corresponding interplanar spacing D is 3.30324;

a diffraction peak at a 2 theta diffraction angle of 29.0322 +/-0.2, wherein the relative intensity of the diffraction peak is 6.35 percent, and the corresponding interplanar spacing D is 3.07573;

the method for preparing the new tulobuterol crystal comprises the following steps: and dissolving tulobuterol in a good solvent such as ethyl acetate, dropwise adding a poor solvent such as n-heptane into the system, filtering after dropwise adding, taking a filter cake, and drying to obtain the new tulobuterol crystal form crystal.

In the method, the using amount ratio of the tulobuterol to the good solvent such as ethyl acetate is 1 g: 1-5 ml; in this case, a solution of a good solvent such as ethyl tulobuterol acetate can form a saturated solution at 20 to 50 ℃.

In the dropwise adding step, the dosage of good solvents such as ethyl acetate is 2-6 times of the volume dosage of poor solvents such as n-heptane.

Regardless of the form of tulobuterol before dissolution, whether tulobuterol is a solvent compound or not, the preparation method can obtain the tulobuterol crystal form. The form of the composition comprises oil tulobuterol, a low-purity crude tulobuterol product and amorphous tulobuterol.

The good solvent in the dissolving process comprises ethyl acetate, dichloromethane, acetone, acetonitrile and tetrahydrofuran, and preferably ethyl acetate and acetone.

The poor solvent in the dropping process comprises n-hexane, n-heptane, cyclohexane, isopropyl ether and methyl tert-butyl ether, and preferably n-hexane, n-heptane and cyclohexane.

The poor solvent may be added at a time or in portions during the dropwise addition.

In the dissolving step, the dissolving temperature is 25-60 ℃;

in the dropwise adding step, the temperature is 30-40 ℃. Since the process of dropping n-heptane into the ethyl acetate solution of tulobuterol to precipitate crystals is also a process of growing crystals from large to small, it is necessary to maintain the solution at 30 to 40 ℃.

During the dropping process, a certain amount of tulobuterol in the crystal form can be added as seed crystal. The dosage is 1-10% of the mass of the fed material.

In the dripping step, the dripping speed is 1-7 ml/min, preferably 4 ml/min;

the application of the new crystal form of tulobuterol provided by the invention in preparing an antihistamine medicine and the antihistamine medicine using the new crystal form of tulobuterol provided by the invention as an active ingredient also belong to the protection scope of the invention.

In the research process, the inventor finds a tulobuterol crystal form which is not reported in the literature, and obtains an X-ray powder diffraction spectrum. The crystal form has high purity and good stability, has superiority in process production, and is suitable for long-term storage in a preparation process.

The disclosed new crystal forms of tulobuterol have the same uses as known tulobuterol compounds per se.

The new crystal form has long-acting anti-asthma effect, and can be used for relieving dyspnea caused by airway obstruction diseases such as bronchial asthma, acute bronchitis, chronic bronchitis, and emphysema, and for preparing anti-asthma medicine.

Drawings

Fig. 1 is a tulobuterol crystal form X-ray powder diffraction pattern.

Fig. 2 is a DSC endotherm of tulobuterol crystals.

FIG. 3 is a contrast diagram of influence factor and accelerated sample crystal form XRD

FIG. 4 is a graph of the in vitro release profile of tulobuterol patch from a test article

FIG. 5 is a plot of Tulobuterol patch self-supporting animal pharmacokinetics

Detailed Description

The present invention will be further illustrated with reference to the following specific examples, but the present invention is not limited to the following examples. The method is a conventional method unless otherwise specified. The starting materials are commercially available from the open literature unless otherwise specified. The tulobuterol used as starting material in the following examples was prepared by itself according to the literature, modification of tulobuterol synthesis process [ J ]. gesneezuele 2015, 25(2), the chinese journal of pharmaceutical chemistry.

Example 1

(1) Synthesis of alpha-bromo-2-chloroacetophenone (3)

230.0g (1.5mol) of o-chloroacetophenone and 1188mL of water were added to a 3L three-necked flask, reacted at 20 ℃, and 84.4mL (1.6mol) of liquid bromine was added dropwise over 0.5h, and stirred for 15 min. The mixture was extracted with 400mL of dichloromethane, and the organic layer was washed with 4.7mol/L aqueous sodium carbonate solution and dried over anhydrous sodium sulfate. The mixture was filtered and the solvent was evaporated under reduced pressure to obtain 346.3g of a pale yellow oily liquid with a yield of 99%. ESI-MS M/z 234.0[ M + H ]]⁺，139.1[M－CH₂Br]⁺，111.1[M－COCH₂Br]⁺。

(2) Synthesis of 1- (2-chlorophenyl) -2-bromoethanol (4)

347.4g (1.5mol) of compound 3 is dissolved in 1626.9mL of absolute ethyl alcohol, 42.48g (0.74mol) of a solution prepared by water 244.6mL is added dropwise under ice bath conditions, the temperature is controlled below 20 ℃, and stirring is continued for 15min after dropwise addition. The ethanol was evaporated under reduced pressure, 760mL of water was added, the pH was adjusted to 2 with 2mol/L hydrochloric acid, and the mixture was extracted with 400mL of dichloromethane, the organic layer was separated, the aqueous layer was further extracted with 200mL of dichloromethane, and the organic layers were combined and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent under reduced pressure gave 333.19g of a pale yellow oily liquid in 95.1% yield. ESI-MSm/z 236.0[ M + H ]]⁺，141.1[M-CH₂Br]⁺，113.1[M－COCH₂Br]⁺。

(3) Synthesis of tulobuterol

333.0g (1.4mol) of Compound 4 was dissolved in 1426.3mL of absolute ethanol, 474.3mL (4.5mol) of tert-butylamine was added, and the mixture was refluxed for 6 hours. The solvent was evaporated under reduced pressure, 1500mL of 2mol/L hydrochloric acid was added thereto, the mixture was stirred well, the aqueous layer was separated and extracted with isopropyl ether (500mL × 3), and the aqueous layer was adjusted to pH 12 with 5mol/L sodium hydroxide solution. Suction filtration and drying to obtain 245g of crude product.

(3) Preparation of tulobuterol crystal form

Adding 50g of tulobuterol into 100mL of ethyl acetate, heating to 40-50 ℃, and stirring to dissolve. After dissolving, cooling the obtained ethyl acetate solution of tulobuterol to 30-40 ℃, slowly dripping 300mL of n-heptane at a dripping speed of 4mL/min while stirring, and keeping the temperature at 30-40 ℃. Stirring for more than 8 hours after the dropwise addition is finished, filtering crystals, and vacuum drying a filter cake for 12 hours to obtain 44.5 g of a product with yield; 89% and 99.8% HPLC purity.

The product obtained in this example was subjected to X-ray diffraction using Cu — ka radiation for crystals, and the results are shown in fig. 1, wherein with Cu — ka radiation, the X-ray powder of crystals expressed as 2 θ diffraction angle had a diffraction peak at 2 θ diffraction angle 9.4384 ± 0.2, the relative intensity of the diffraction peak was 22.61%, and the corresponding interplanar spacing D was 9.37057;

a diffraction peak at a 2 theta diffraction angle of 9.9474 +/-0.2, wherein the relative intensity of the diffraction peak is 100 percent, and the corresponding interplanar spacing D is 8.89220;

a diffraction peak at a 2 theta diffraction angle of 17.8258 +/-0.2, wherein the relative intensity of the diffraction peak is 76.83 percent, and the corresponding interplanar spacing D is 4.97595;

a diffraction peak at a 2 theta diffraction angle of 18.0469 +/-0.2, wherein the relative intensity of the diffraction peak is 7.58 percent, and the corresponding interplanar spacing D is 4.91548;

a diffraction peak at a 2 theta diffraction angle of 26.9933 +/-0.2, wherein the relative intensity of the diffraction peak is 11.68 percent, and the corresponding interplanar spacing D is 3.30324;

a diffraction peak at a 2 theta diffraction angle of 29.0322 +/-0.2, wherein the relative intensity of the diffraction peak is 6.35 percent, and the corresponding interplanar spacing D is 3.07573;

as can be seen from the literature, the crystal form of the product obtained in the example is not reported in the literature and is a new crystal form of tulobuterol.

The product is subjected to differential thermal analysis, the model of the used instrument is a NETZSCH STA 449F3 synchronous analyzer, and the test conditions are as follows: the temperature rise speed is 10.0 ℃/min, the temperature range is 30-150 ℃, and the obtained spectrogram is shown in figure 2. As can be seen from FIG. 2, the product has an endothermic peak at 94.0 ℃ which should be the melting peak temperature.

Example 2

Adding 50g of tulobuterol into 100mL of acetone, heating to 40-50 ℃, and stirring to dissolve. After dissolving, cooling the obtained tulobuterol acetone solution to 30-40 ℃, slowly dripping 300mL of normal hexane at a dripping speed of 4mL/min while stirring, and keeping the temperature at 30-40 ℃. Stirring for more than 8 hours after the dropwise addition is finished, filtering crystals, and vacuum drying a filter cake for 12 hours to obtain 43.2 g of a product with yield; 86.4% and 99.9% HPLC purity.

The XRD and structure confirmation results of the product obtained in this example are the same as those of example 1, and are not described again.

Example 3

Adding 50g of tulobuterol into 200mL of acetonitrile, heating to 40-50 ℃, and stirring to dissolve. After dissolving, cooling the obtained tulobuterol acetone solution to 30-40 ℃, slowly dripping 800mL of cyclohexane at a dripping speed of 4mL/min while stirring, and keeping the temperature at 30-40 ℃. Stirring for more than 8 hours after the dropwise addition is finished, filtering crystals, and vacuum drying a filter cake for 12 hours to obtain 47.2 g of a product with yield; 94.4% and 99.8% HPLC purity.

The XRD and structure confirmation results of the product obtained in this example are the same as those of example 1, and are not described again.

Example 4

Adding 50g of tulobuterol into 100mL of acetone, heating to 40-50 ℃, and stirring to dissolve. After dissolving, cooling the obtained tulobuterol acetone solution to 30-40 ℃, adding 5g of the tulobuterol seed crystal obtained in the example 1, slowly dropwise adding 300mL of n-hexane at a dropwise adding rate of 4mL/min while stirring, and keeping the temperature at 30-40 ℃. Stirring for more than 8 hours after the dropwise addition is finished, filtering crystals, taking filter cakes, drying for 12 hours in vacuum, and deducting seed crystals to obtain 47.9 g of a product with yield; 95.8% and 99.9% HPLC purity.

The XRD and structure confirmation results of the product obtained in this example are the same as those of example 1, and are not described again.

Example 5 preparation of tulobuterol in crystalline form according to example 1 for testing the stability of the crystalline form

The consistency of the continuously prepared three batches of crystal forms, the stability of the crystal forms in the influence factor test and the investigation of the accelerated stability test on the crystal forms are combined, so that the preparation method is verified to be capable of stably and repeatedly preparing the new tulobuterol crystal form, the crystal form is stable, and the crystal form cannot be changed by light, heat and humidity, which is shown in figure 3. In fig. 3, the XRD patterns are from top to bottom: 160301 (accelerated 3 months), 160301 (accelerated 6 months), 160302 (accelerated 3 months), 160302 (accelerated 6 months), 160303 (accelerated 3 months), 160303 (accelerated 6 months), 160301 (factor high temperature), 160301 (factor high humidity), 160301 (factor light).

Example 6 Tulobuterol obtained as in example 1 and tested for quality stability

The stability of the tulobuterol is inspected for 36 months, and the stability inspection result shows that the characteristics, the melting point, related substances, the content and other inspection indexes of the tulobuterol do not show obvious change trend compared with 0 month, which indicates that the product has good crystal form stability. The test data are shown in tables 6-1-6-3.

TABLE 6-1160301 results of the long-term tests of batches

TABLE 6-2160302 results of the long-term tests of batches

TABLE 6-3160303 results of the long-term tests of batches

Example 7 comparative study on patch stability prepared from tulobuterol crystal form raw material

The invention adopts the crystal form raw materials to prepare the tulobuterol patch self-ground product, and the stability comparison research is carried out on the tulobuterol patch self-ground product and the original commercially available product patch, and the result shows that the patch prepared by the crystal form raw materials provided by the invention has better stability, and the result is as follows:

example 8 in vitro Release Profile and in vivo animal pharmacokinetic Studies of Patches prepared with Tulobuterol Crystal form Material

The tulobuterol patch self-research product prepared from the crystal form raw materials is shown in figures 4-5 through in vitro release degree and in vivo animal pharmacokinetics research, and in vitro release degree curves and animal pharmacokinetics results show that the patch self-research product prepared from the tulobuterol crystal form can be effectively released in vivo and in vitro.