阅读说明：本技术 一种丙酸氟替卡松的精制方法 (Refining method of fluticasone propionate ) 是由 纪道玉 孙福锁 米奇 李�灿 刘芳 于 2019-10-30 设计创作，主要内容包括：本发明实施例提供了一种丙酸氟替卡松的精制方法,所述方法包括：溶解步骤：将丙酸氟替卡松粗品加入有机溶剂中,搅拌溶解；所述有机溶剂的体积(以毫升计)是丙酸氟替卡松粗品重量(以克计)的10-20倍；精制步骤：控制温度为30-60℃,缓慢滴加水,搅拌均匀；析出步骤：以每小时降温10-30℃的速度将反应温度降低至10-15℃,析出晶体；干燥步骤：将晶体过滤、干燥,得到丙酸氟替卡松精品。精制后的丙酸氟替卡松达到USP 41和EP9.0的质量要求,纯度在99.4％以上,本发明实施例提供的丙酸氟替卡松的精制方法,产品收率高,成本低,采用的有机溶剂毒性低,非常适合大规模工业应用。(The embodiment of the invention provides a refining method of fluticasone propionate, which comprises the following steps: a dissolving step: adding the crude fluticasone propionate into an organic solvent, and stirring for dissolving; the volume of the organic solvent (measured in milliliters) is 10 to 20 times of the weight of the crude fluticasone propionate (measured in grams); refining: controlling the temperature to be 30-60 ℃, slowly dripping water, and uniformly stirring; a precipitation step: reducing the reaction temperature to 10-15 ℃ at the speed of reducing the temperature by 10-30 ℃ per hour, and separating out crystals; and (3) drying: and filtering and drying the crystals to obtain the fine fluticasone propionate. The refined fluticasone propionate meets the quality requirements of USP 41 and EP9.0, and the purity is more than 99.4 percent.)

1. A refining method of fluticasone propionate, which is characterized by comprising the following steps:

a dissolving step: adding the crude fluticasone propionate into an organic solvent, and stirring for dissolving; the volume of the organic solvent (measured in milliliters) is 10 to 20 times of the weight of the crude fluticasone propionate (measured in grams);

refining: controlling the temperature to be 30-60 ℃, slowly dripping water, and uniformly stirring;

a precipitation step: reducing the reaction temperature to 10-15 ℃ at the speed of reducing the temperature by 10-30 ℃ per hour, and separating out crystals;

and (3) drying: and filtering and drying the crystals to obtain the fine fluticasone propionate.

2. The method according to claim 1, wherein the organic solvent is at least one of dichloromethane, ethyl acetate, butanone, acetone, and ethanol.

3. The process of claim 1, wherein the volume of organic solvent (in milliliters) is 14 to 18 times the weight of the crude fluticasone propionate (in grams).

4. The process of claim 1, wherein the volume of water (in milliliters) in the refining step is 7-12 times the weight (in grams) of the crude fluticasone propionate.

5. The method according to claim 1, wherein the reaction temperature is lowered to 10-15 ℃ at a rate of 10-15 ℃ per hour to precipitate crystals in the precipitation step.

6. The method according to claim 1, wherein in the refining step, the volume of the dropwise added water (in milliliters) is 6 to 14 times the weight of the crude fluticasone propionate (in grams).

Technical Field

The invention relates to the technical field of medicines, in particular to a refining method of fluticasone propionate.

Background

The fluticasone propionate is used for preventing and treating seasonal allergic rhinitis and perennial allergic rhinitis, and is a preferred medicament for treating the conventional rhinitis, the allergic rhinitis and asthma. China has a large population, the number of rhinitis patients is high in recent years, the existing commercial fluticasone propionate is imported and expensive, and the synthesis and refining method provided by the existing patent cannot achieve a refining means with high yield and good purity.

Patent document No. 200610161627.0 provides a method for refining fluticasone propionate, but the yield of fluticasone propionate obtained by the method is low, the purity of the fluticasone propionate is not high, and the method is not favorable for industrial production. Patent application No. 200810054277.7, which provides a method that although the refined fluticasone propionate reaches the pharmacopeia specifications, the unknown impurities contained in fluticasone propionate are still greater than 0.15%, and the yield situation is not specified. In the refining method provided by the patent document with the patent application number of 200810151322.0, although the refined fluticasone propionate meets the requirements of EP5, the technological process of the refining method is complicated to operate, and the refining method is not beneficial to industrial production.

Disclosure of Invention

In view of the above problems, embodiments of the present invention provide a method for refining fluticasone propionate that overcomes or at least partially solves the above problems.

In order to solve the above problems, an embodiment of the present invention discloses a refining method of fluticasone propionate, which includes:

a dissolving step: adding the crude fluticasone propionate into an organic solvent, and stirring for dissolving; the volume of the organic solvent (measured in milliliters) is 10 to 20 times of the weight of the crude fluticasone propionate (measured in grams);

refining: controlling the temperature to be 30-60 ℃, slowly dripping water, and uniformly stirring;

a precipitation step: reducing the reaction temperature to 10-15 ℃ at the speed of reducing the temperature by 10-30 ℃ per hour, and separating out crystals;

and (3) drying: and filtering and drying the crystals to obtain the fine fluticasone propionate.

Preferably, the organic solvent is at least one of dichloromethane, ethyl acetate, butanone, acetone and ethanol.

Preferably, the volume of the organic solvent (in ml) is 14 to 18 times the weight of the crude fluticasone propionate (in g).

Preferably, the volume of water (in ml) in the refining step is 7-12 times the weight (in g) of the crude fluticasone propionate.

Preferably, in the precipitation step, the reaction temperature is reduced to 10-15 ℃ at the speed of reducing the temperature by 10-15 ℃ per hour, and crystals are precipitated.

Preferably, in the refining step, the volume of the dropwise added water (in milliliters) is 6 to 14 times the weight (in grams) of the crude fluticasone propionate.

The embodiment of the invention has the following advantages:

the refining method of the fluticasone propionate provided by the embodiment of the invention comprises the steps of adding crude fluticasone propionate into an organic solvent with the weight part ratio of the crude fluticasone propionate to the crude fluticasone propionate being 10-20:1, and stirring for dissolving; wherein the organic solvent is one or a mixture of two of dichloromethane, ethyl acetate, butanone, acetone and ethanol; controlling the reaction temperature to be 30-60 ℃, slowly dripping water with the weight part ratio of 6-14:1 to the crude fluticasone propionate product, and uniformly stirring; reducing the reaction temperature to 10-15 ℃ at the speed of reducing the temperature by 10-30 ℃ per hour, and separating out crystals; and filtering and drying the crystals to obtain the fine fluticasone propionate. Because the reaction temperature is reduced to 10-15 ℃ at the speed of reducing the temperature by 10-30 ℃ per hour in the embodiment of the invention, crystals are separated out, so that the refined fluticasone propionate meets the quality requirements of USP 41 and EP9.0, and the purity is more than 99.4 percent.

Drawings

FIG. 1 shows the results of HPLC detection in example one;

FIG. 2 shows the HPLC detection results of example two;

FIG. 3 shows the HPLC detection results of example III;

FIG. 4 shows the HPLC detection results of example four;

FIG. 5 shows the HPLC detection results of example five;

FIG. 6 shows the HPLC detection results of example six;

FIG. 7 shows the HPLC detection results of example seven;

FIG. 8 shows the results of HPLC detection in example eight;

FIG. 9 shows the results of HPLC analysis of the control group.

Detailed Description

In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are described in further detail below.

The process of the present invention is illustrated in detail by the following examples.

The embodiment of the invention discloses a refining method of fluticasone propionate, which comprises the following steps:

a dissolving step: adding the crude fluticasone propionate into an organic solvent, and stirring for dissolving; the volume of the organic solvent (measured in milliliters) is 10 to 20 times of the weight of the crude fluticasone propionate (measured in grams);

refining: controlling the temperature to be 30-60 ℃, slowly dripping water, and uniformly stirring;

a precipitation step: reducing the reaction temperature to 10-15 ℃ at the speed of reducing the temperature by 10-30 ℃ per hour, and separating out crystals;

and (3) drying: and filtering and drying the crystals to obtain the fine fluticasone propionate.

In the embodiment of the invention, the crude fluticasone propionate product is added into an organic solvent with the weight 10-20 times of that of the crude product, water with the weight 6-14 times of that of the crude product is added for recrystallization at 30-60 ℃ to remove impurities in the crude fluticasone propionate product, then the reaction temperature is reduced to 10-15 ℃ at the speed of reducing the temperature by 10-30 ℃ per hour, crystals are separated out, and the filtration and the drying are carried out to obtain the high-purity refined fluticasone propionate product. Because the temperature of the system is reduced to 10-15 ℃ at the speed of reducing the temperature by 10-30 ℃ per hour, and crystals are separated out, the refining method of the fluticasone propionate provided by the embodiment of the invention has the advantages that the yield and the purity of the obtained fluticasone propionate refined product are higher, the content of impurities in the fluticasone propionate refined product is low, and the fluticasone propionate refined product meets related requirements. The embodiment of the invention realizes high refining yield of the fluticasone propionate and low cost, and is very suitable for large-scale industrial application.

In the embodiment of the invention, the reaction temperature is reduced to 10-15 ℃ in a staged cooling mode at the speed of reducing the temperature by 10-30 ℃ per hour, so that the precipitation of impurities is reduced, and the refining effect is improved, and the fine fluticasone propionate product prepared by the refining method of the fluticasone propionate provided by the embodiment of the invention has higher purity.

In the embodiment of the present invention, the organic solvent is at least one of dichloromethane, ethyl acetate, butanone, acetone, and ethanol.

In the embodiment of the invention, low-toxicity solvents such as dichloromethane, ethyl acetate, butanone, acetone, ethanol and the like are selected as the organic solvent in the refining method of the fluticasone propionate, so that the method has high safety and small harm to human bodies and the environment, the volume of the organic solvent is controlled to be 10-20 times of the weight of the crude fluticasone propionate, and impurities in the crude fluticasone propionate can be removed accurately and comprehensively.

In the present examples, the volume of the organic solvent (in ml) is 14 to 18 times the weight of the crude fluticasone propionate (in g).

In the present examples, the volume of water (in ml) in the refining step is 7-12 times the weight (in g) of the crude fluticasone propionate.

In the embodiment of the invention, in the precipitation step, the reaction temperature is reduced to 10-15 ℃ at the speed of reducing the temperature by 10-15 ℃ per hour, and crystals are precipitated.

In the present embodiment, in the refining step, the volume of the dropwise added water (in ml) is 6 to 14 times the weight (in g) of the crude fluticasone propionate.

In order to make the person skilled in the art better understand the present invention, the refining method of fluticasone propionate according to the present invention will be described below by using a plurality of specific examples.