A kind of preparation method of fludrocortisone acetate

Abstract

The invention relates to the technical field of chemical drug preparation and purification, and in particular to a method for preparing fludrocortisone acetate. The method comprises the following steps: S1, fluorinating and ring-opening 9β,11β-epoxy-17α-hydroxypregnane-4-ene-3,20-dione-21-acetate to obtain a product, fludrocortisone acetate fluoride; S2, acetylating the fludrocortisone acetate fluoride and acetic anhydride to obtain a fludrocortisone acetate crude product; and S3, recrystallizing the fludrocortisone acetate crude product to obtain high-standard fludrocortisone acetate. The preparation method of the present invention uses 9β,11β-epoxy-17α-hydroxypregnane-4-ene-3,20-dione-21-acetate as a substrate for fluorination ring opening, and then adds an acetylation reaction. The impurity fludrocortisone in the fluoride on fludrocortisone acetate is acetylated to generate the target product fludrocortisone acetate, which is then recrystallized and refined to obtain high-standard fludrocortisone acetate, with a chromatographic purity of more than 99.5% and any impurities less than 0.10%.

Description

Technical Field

[0001] The invention relates to the technical field of chemical drug preparation and purification, in particular to a method for preparing fludrocortisone acetate. Background Art

[0002] Fludrocortisone acetate, also known as fludrocortisone acetate, 9α-fluorocortisol acetate, 9α-fluorocortisone acetate, etc., has the chemical name: 9-fluoro-11β,17-dihydroxy-3,20-dioxopregnan-4-en-21-yl acetate. It is a synthetic glucocorticoid and an adrenal cortex hormone drug with anti-inflammatory and anti-allergic effects. It is clinically used for adrenal cortex hormone deficiency in Addison's disease, and is used topically to treat seborrheic eczema, contact dermatitis, and anal and genital itching.

[0003] The traditional preparation method is to directly purify and refine 9β,11β-epoxy-17α-hydroxypregnane-4-ene-3,20-dione-21-acetate after fluorination ring opening. However, in the process of fluorination ring opening, in addition to generating the target product fludrocortisone acetate, there will be side reactions. A part of the 21-acetate will undergo hydrolysis reaction to generate impurity fludrocortisone with a content of up to 20-30%. The chromatographic purity of the target product fludrocortisone acetate is only 60-70%, which seriously affects the chromatographic purity of the finished product. The content of the target product in the reaction solution after the fluorination ring opening reaction in patent US2894007A is 50-65%, and the content of the target product in the reaction solution after the fluorination ring opening reaction in patent CN107915766A is 70%. Therefore, the subsequent purification steps generally require multiple refinings, and the chromatographic purity is only about 98.5% after continuous refining for more than 5 times.

[0004] In view of this, the present invention is proposed. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing fludrocortisone acetate, which can solve the problems raised by the above-mentioned background technology.

[0006] The first aspect of the present invention provides a method for preparing fludrocortisone acetate, comprising the following steps:

[0007] S1. 9β,11β-epoxy-17α-hydroxypregnane-4-ene-3,20-dione-21-acetate (with a structural formula as shown in Formula I) is subjected to fluorination ring-opening to obtain a product, fludrocortisone acetate fluoride, wherein the fludrocortisone acetate fluoride comprises: fludrocortisone acetate (with a structural formula as shown in Formula III) and fludrocortisone (with a structural formula as shown in Formula II);

[0008]

[0009] Specifically, the fluorination ring-opening reaction route is as follows:

[0010]

[0011] Specifically, the fluorination ring-opening side reaction route is as follows:

[0012]

[0013] S2, acetylation of the fluorine on fludrocortisone acetate with acetic anhydride to obtain a crude fludrocortisone acetate;

[0014] Specifically, the acetylation synthesis reaction route is as follows:

[0015]

[0016] S3. Recrystallize the crude fludrocortisone acetate to obtain high-standard fludrocortisone acetate.

[0017] Preferably, in step S2, the solvent for the acetylation synthesis is a dipolar aprotic solvent, and the catalyst is an organic amine.

[0018] Preferably, in step S2, the feed ratio of the solvent, the catalyst, the fluorinated substance on fludrocortisone acetate and the acetic anhydride is (3-10):(0.3-1):1:(1-2), wherein the fluorinated substance on fludrocortisone acetate is measured in g, and the solvent, the catalyst and the acetic anhydride are measured in mL.

[0019] Preferably, the dipolar aprotic solvent includes: one or more of dimethylformamide and dimethyl sulfoxide; the organic amine includes: one or more of piperidine, ethylenediamine, and triethylamine.

[0020] Preferably, step S2 comprises: pumping a dipolar aprotic solvent into an acetylation reaction vessel, adding fluorine on fludrocortisone acetate, adding acetic anhydride and an organic amine, controlling the temperature range to react at 10-15°C, filtering after the reaction, washing with water, and drying to obtain a crude fludrocortisone acetate.

[0021] Preferably, in step S3, the solvent used for the recrystallization includes: one or more of dichloromethane, chloroform, methanol, ethanol, acetone, ethyl acetate, and dimethylformamide, more preferably methanol or acetone.

[0022] Preferably, step S3 comprises: adding a solvent into a refining reaction vessel, adding a crude fludrocortisone acetate, heating to 30-40°C for dissolution, decolorizing and refluxing after dissolution, filtering, concentrating the filtrate under reduced pressure to a viscous state, cooling to 0-5°C, filtering, washing with water, and drying to obtain a refined fludrocortisone acetate. The above refining steps are performed continuously for several times and then dried to obtain a high-standard fludrocortisone acetate.

[0023] Preferably, the refining step is performed continuously 2-4 times.

[0024] The second aspect of the present invention provides a high-standard fludrocortisone acetate, which is prepared by the above-mentioned fludrocortisone acetate preparation method.

[0025] The present invention has at least the following beneficial effects:

[0026] The preparation method of fludrocortisone acetate of the present invention uses 9β,11β-epoxy-17α-hydroxypregnane-4-ene-3,20-dione-21-acetate as a substrate for fluorination ring opening and then adds an acetylation reaction. The impurity fludrocortisone in the fluorine on the fludrocortisone acetate is acetylated to generate the target product fludrocortisone acetate, and the chromatographic purity of the fludrocortisone acetate crude product can be increased from 60%-70% to about 95%. Then, the fludrocortisone acetate with high standard is obtained by recrystallization and purification, and the chromatographic purity can reach more than 99.5%, and any impurity is less than 0.10%. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0028] Figure 1 This is the HPLC spectrum of fludrocortisone acetate prepared in Example 1 of the present invention.

[0029] Figure 2 This is the HPLC spectrum of fludrocortisone acetate prepared in Example 2 of the present invention.

[0030] Figure 3 This is the HPLC spectrum of fludrocortisone acetate prepared in Example 3 of the present invention.

[0031] Figure 4 This is the HPLC spectrum of fludrocortisone acetate prepared in Example 4 of the present invention.

[0032] Figure 5 The HPLC spectrum of fludrocortisone acetate prepared as a comparative example of the present invention. DETAILED DESCRIPTION

[0033] It should be noted that the following detailed descriptions are illustrative and are intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present application belongs.

[0034] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular form also includes the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.

[0035] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0036] Example 1

[0037] S1. Pump 120 ml of hydrogen fluoride solution into the fluorine reaction tank, control the temperature to -35 to -45°C, add 30 g of 9β,11β-epoxy-17α-hydroxypregnane-4-ene-3,20-dione-21-acetate, react at -35 to -45°C for 3 hours, add 300 ml of ammonia water / 1500 ml of ice water to dilute, then add appropriate amount of ammonia water to adjust the pH to 6-7, filter the material, wash with water for 30 minutes, drain, and dry at 60-70°C for about 10 hours to obtain the product fludrocortisone acetate fluoride, about 21.5 g.

[0038] S2. Pump 60 ml of dimethylformamide into the acetylation tank, add 20 g of fludrocortisone acetate, control the temperature to 10-15 ° C, stir for 5-10 minutes, slowly add 20 ml of acetic anhydride and 6 ml of triethylamine, keep the temperature at 10-15 ° C and react for 3 hours. Filter the material, wash it with water for 30 minutes, and drain it to obtain about 22.1 g of fludrocortisone acetate crude product with a chromatographic purity of 93.8%.

[0039] S3. Put 80ml of dichloromethane and 80ml of methanol into the refining tank, add the crude fludrocortisone acetate, heat to 35℃ to dissolve, add 2g of activated carbon after dissolving, decolorize and reflux at 35℃ for 0.5h. Filter, decompress and concentrate the filtrate until it is viscous, add 20ml of methanol twice each time, concentrate until it is viscous, and stop concentrating. Cool down to 0-5℃, filter the material, wash it with methanol, and drain it to obtain the first refined product of fludrocortisone acetate.

[0040] According to the refining step S3, the product was purified twice continuously, and then dried at 90-100°C for about 10 hours to obtain about 15.3g of high-standard fludrocortisone acetate product, with a yield of 76.5%, a chromatographic purity of 99.6%, and any impurity less than 0.10%. The HPLC spectrum of high-standard fludrocortisone acetate is shown in Figure 1 .

[0041] Example 2

[0042] S1. Pump 120 ml of hydrogen fluoride solution into the fluorine reaction tank, control the temperature to -35 to -45°C, add 30 g of 9β,11β-epoxy-17α-hydroxypregnane-4-ene-3,20-dione-21-acetate, react at -35 to -45°C for 3 hours, add 300 ml of ammonia water / 1500 ml of ice water to dilute, then add appropriate amount of ammonia water to adjust the pH to 6-7, filter the material, wash with water for 30 minutes, drain, and dry at 60-70°C for about 10 hours to obtain the product fludrocortisone acetate fluoride, about 21.5 g.

[0043] S2. Pump 80 ml of dimethylformamide into the acetylation tank, add 20 g of fludrocortisone acetate, control the temperature to 10-15 ° C, stir for 5-10 minutes, slowly add 30 ml of acetic anhydride and 8 ml of triethylamine, keep the temperature at 10-15 ° C and react for 3 hours. Filter the material, wash it with water for 30 minutes, and drain it to obtain about 22.6 g of fludrocortisone acetate crude product with a chromatographic purity of 94.8%.

[0044] S3. Put 500ml of methanol into the refining tank, add the crude fludrocortisone acetate, heat to 65-70℃ to dissolve, add 2g of activated carbon after dissolving, decolorize and reflux for 0.5h. Filter, concentrate the filtrate under reduced pressure, concentrate until it is viscous, and stop concentrating. Cool down to 0-5℃, filter the material, wash it with methanol, and drain it to obtain about 20.6g of the first refined product of fludrocortisone acetate.

[0045] According to the refining step S3, the product was purified twice continuously, and then dried at 90-100°C for about 10 hours to obtain about 15.4g of high-standard fludrocortisone acetate product, with a yield of 77.0%, a chromatographic purity of 99.8%, and any impurity less than 0.10%. The HPLC spectrum of high-standard fludrocortisone acetate is shown in Figure 2 .

[0046] Example 3

[0047] S1. Pump 120 ml of hydrogen fluoride solution into the fluorine reaction tank, control the temperature to -35 to -45°C, add 30 g of 9β,11β-epoxy-17α-hydroxypregnane-4-ene-3,20-dione-21-acetate, react at -35 to -45°C for 3 hours, add 300 ml of ammonia water / 1500 ml of ice water to dilute, then add appropriate amount of ammonia water to adjust the pH to 6-7, filter the material, wash with water for 30 minutes, drain, and dry at 60-70°C for about 10 hours to obtain the product fludrocortisone acetate fluoride, about 21.5 g.

[0048] S2. Pump 100 ml of dimethylformamide into the acetylation tank, add 20 g of fludrocortisone acetate, control the temperature to 10-15°C, stir for 5-10 minutes, slowly add 40 ml of acetic anhydride and 10 ml of triethylamine, keep the temperature at 10-15°C and react for 3 hours. Filter the material, wash it with water for 30 minutes, and drain it to obtain about 22.4 g of fludrocortisone acetate crude product with a chromatographic purity of 95.1%.

[0049] S3. Put 400ml acetone and 40ml drinking water into the refining tank, add the crude fludrocortisone acetate, heat to 65-70℃ to dissolve, add 2g activated carbon after dissolving, decolorize and reflux for 0.5h. Filter, concentrate the filtrate under reduced pressure, concentrate to about 3 times the residual volume, and stop concentrating. Cool to 0-5℃, filter the material, wash with acetone, and drain to obtain about 20.2g of fludrocortisone acetate.

[0050] According to the refining step S3, the product was purified twice continuously, and then dried at 90-100°C for about 10 hours to obtain about 15.1g of high-standard fludrocortisone acetate, with a yield of 75.5%, a chromatographic purity of 99.7%, and any impurity less than 0.10%. The HPLC spectrum of high-standard fludrocortisone acetate is shown in Figure 3 .

[0051] Example 4

[0052] S1. Pump 120 ml of hydrogen fluoride solution into the fluorine reaction tank, control the temperature to -35 to -45°C, add 30 g of 9β,11β-epoxy-17α-hydroxypregnane-4-ene-3,20-dione-21-acetate, react at -35 to -45°C for 3 hours, add 300 ml of ammonia water / 1500 ml of ice water to dilute, then add appropriate amount of ammonia water to adjust the pH to 6-7, filter the material, wash with water for 30 minutes, drain, and dry at 60-70°C for about 10 hours to obtain the product fludrocortisone acetate fluoride, about 21.5 g.

[0053] S2. Pump 100 ml of dimethylformamide into the acetylation tank, add 20 g of fludrocortisone acetate, control the temperature to 10-15°C, stir for 5-10 minutes, slowly add 30 ml of acetic anhydride and 8 ml of triethylamine, keep the temperature at 10-15°C and react for 3 hours. Filter the material, wash it with water for 30 minutes, and drain it to obtain about 22.2 g of fludrocortisone acetate crude product with a chromatographic purity of 95.9%.

[0054] S3. Put 400ml acetone and 60ml drinking water into the refining tank, add the crude fludrocortisone acetate, heat to 65-70℃ to dissolve, add 2g activated carbon after dissolving, decolorize and reflux for 0.5h. Filter, and concentrate the filtrate under reduced pressure until the residual volume is about 4 times, and stop concentrating. Cool down to 0-5℃, filter the material, wash it with acetone, and drain it to obtain about 20.2g of the first refined product of fludrocortisone acetate.

[0055] According to the refining step S3, the product was purified twice continuously, and then dried at 90-100°C for about 10 hours to obtain about 15.6g of high-standard fludrocortisone acetate product, with a yield of 78.0%, a chromatographic purity of 99.8%, and any impurity less than 0.10%. The HPLC spectrum of high-standard fludrocortisone acetate is shown in Figure 4 .

[0056] Comparative Example (Fluorination ring opening followed by direct recrystallization)

[0057] S1. Pump 120 ml of hydrogen fluoride solution into the fluorine reaction tank, control the temperature to -35 to -45°C, add 30 g of 9β,11β-epoxy-17α-hydroxypregnane-4-ene-3,20-dione-21-acetate, react at -35 to -45°C for 3 hours, add 300 ml of ammonia water / 1500 ml of ice water to dilute, then add appropriate amount of ammonia water to adjust the pH to 6-7, filter the material, wash with water for 30 minutes, drain, and dry at 60-70°C for about 10 hours to obtain the product fludrocortisone acetate fluoride, about 21.5 g.

[0058] S2. Put 80ml of dichloromethane and 80ml of methanol into a refining tank, add 20g of fluorine on fludrocortisone acetate, heat to 35℃ to dissolve, add 2g of activated carbon after dissolving, decolorize and reflux at 35℃ for 0.5h. Filter, decompress and concentrate the filtrate until it is viscous, add 20ml of methanol twice each time, concentrate until it is viscous, and stop concentrating. Cool down to 0-5℃, filter the material, wash it with methanol, and drain it to obtain the first refined product of fludrocortisone acetate.

[0059] According to the refining step S2, the product was purified for five times continuously, and then dried at 90-100°C for about 10 hours to obtain about 10.2 g of fludrocortisone acetate, with a yield of 51.0%, a chromatographic purity of 98.5%, and a maximum impurity of 0.60%. The HPLC spectrum of fludrocortisone acetate is shown in Figure 5 The results showed that the yield and purity of fludrocortisone acetate obtained by direct recrystallization after fluorination ring opening were low, and the impurity content was high.

[0060] In summary, the preparation method of fludrocortisone acetate of the present invention uses 9β,11β-epoxy-17α-hydroxypregnane-4-ene-3,20-dione-21-acetate as a substrate for fluorination and ring-opening, and then adds an acetylation reaction. The impurity fludrocortisone in the fluorine on fludrocortisone acetate is acetylated to generate the target product fludrocortisone acetate, and the chromatographic purity of the crude fludrocortisone acetate can be increased from 60%-70% to about 95%. Then, it is recrystallized and refined to obtain high-standard fludrocortisone acetate, and the chromatographic purity can reach more than 99.5%, and any impurity is less than 0.10%.

[0061] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein by equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing fludrocortisone acetate, characterized in that: The steps include: S1, fluorinating and ring-opening 9β,11β-epoxy-17α-hydroxypregnane-4-ene-3,20-dione-21-acetate to obtain the product fludrocortisone acetate fluoride; S2, acetylation of the fluorine on fludrocortisone acetate with acetic anhydride to obtain a crude fludrocortisone acetate; S3. Recrystallize the crude fludrocortisone acetate to obtain high-standard fludrocortisone acetate.

2. The method for preparing fludrocortisone acetate according to claim 1, characterized in that: In step S1, the fluorine-containing substance on fludrocortisone acetate includes: fludrocortisone acetate and fludrocortisone.

3. The method for preparing fludrocortisone acetate according to claim 1, characterized in that: In step S2, the solvent for the acetylation synthesis is a dipolar aprotic solvent, and the catalyst is an organic amine.

4. The method for preparing fludrocortisone acetate according to claim 3, characterized in that: In step S2, the feed ratio of the solvent, the catalyst, the fluorinated substance on fludrocortisone acetate and the acetic anhydride is (3-10):(0.3-1):1:(1-2), wherein the fluorinated substance on fludrocortisone acetate is measured in g, and the solvent, the catalyst and the acetic anhydride are measured in mL.

5. The method for preparing fludrocortisone acetate according to claim 3, characterized in that: The dipolar aprotic solvent includes: one or more of dimethylformamide and dimethyl sulfoxide; the organic amine includes: one or more of piperidine, ethylenediamine and triethylamine.

6. The method for preparing fludrocortisone acetate according to claim 1, characterized in that: Step S2 comprises: pumping a dipolar aprotic solvent into an acetylation reaction vessel, adding fluorine on fludrocortisone acetate, adding acetic anhydride and an organic amine, controlling the temperature range to react at 10-15° C., filtering after the reaction is completed, washing with water, and drying to obtain a crude fludrocortisone acetate.

7. The method for preparing fludrocortisone acetate according to claim 1, characterized in that: In step S3, the solvent used for the recrystallization includes: one or more of dichloromethane, chloroform, methanol, ethanol, acetone, ethyl acetate, and dimethylformamide.

8. The method for preparing fludrocortisone acetate according to claim 1, characterized in that: Step S3 comprises: adding a solvent into a refining reaction vessel, adding a crude fludrocortisone acetate, heating to 30-40°C for dissolution, decolorizing and refluxing after dissolution, filtering, concentrating the filtrate under reduced pressure to a viscous state, cooling to 0-5°C, filtering, washing with water, and drying to obtain a refined fludrocortisone acetate. The above refining steps are performed several times continuously and then dried to obtain a high-standard fludrocortisone acetate.

9. The method for preparing fludrocortisone acetate according to claim 8, characterized in that: The refining step is performed continuously 2-4 times.

10. A high-standard fludrocortisone acetate, characterized in that: The fludrocortisone acetate is prepared by the preparation method of fludrocortisone acetate according to any one of claims 1 to 9.

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