Prednisolone hemisuccinate impurity control method

Abstract

The invention belongs to the technical field of chemical medicines, and particularly relates to a prednisolone hemisuccinate impurity control method, which comprises the following steps: by taking prednisolone acetate as an initial raw material, condensing, reducing, hydrolyzing and refining to obtain prednisolone. The method comprises the following steps: dissolving refined prednisolone in a succinic anhydride, pyridine and ethyl acetate system, carrying out an esterification reaction to obtain a prednisolone hemisuccinate crude product, dissolving the prednisolone hemisuccinate crude product in an organic solvent, carrying out reflux decoloration, carrying out rotary evaporation to remove the organic solvent, carrying out elutriation, filtering, and drying to obtain a prednisolone hemisuccinate refined product. According to the invention, the variety and content of 11-epihydrocortisone, prednisone, hydrocortisone and other key impurities doped in prednisolone hemisuccinate can be effectively controlled, so that the content of the obtained product is greater than 99%, the weight loss on drying is less than or equal to five thousandths, the content of all impurities is controlled to be less than 2.5 thousandths, and the purity of the prednisolone hemisuccinate is greatly improved. And a powerful quality guarantee is provided for competition of the product in the international market.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical medicine, and particularly relates to a method for controlling impurities of prednisolone hemisuccinate. Background Art

[0002] The CAS number of prednisolone succinate is 2920 - 86 - 7, and its molecular formula is C 25 H 32 O8. It is a synthetic glucocorticoid, a derivative of cortisol, and an important compound widely used in the medical field. It is mainly used for the treatment of allergic and autoimmune inflammatory diseases, such as active rheumatism, rheumatoid arthritis, lupus erythematosus, severe bronchial asthma, nephrotic syndrome, thrombocytopenic purpura, granulocytopenia, various adrenocortical insufficiency diseases, severe dermatitis, acute leukemia, etc. At the same time, it can also be used for the comprehensive treatment of certain infections; in addition, the topical form of prednisolone succinate has also shown significant efficacy in the treatment of allergic, non - infectious skin diseases and some proliferative skin disorders, such as dermatitis, eczema, neurodermatitis, seborrheic dermatitis and pruritus; its eye - drop form is used for the short - term treatment of eye inflammation sensitive to corticosteroids and can exclude viral, fungal and bacterial pathogen infections.

[0003] At present, the synthesis process of prednisolone succinate uses prednisolone acetate as the raw material, and is prepared through four - step reactions of condensation, reduction, hydrolysis and esterification. It will be doped with impurities such as 11 - epi - hydrocortisone, prednisolone, hydrocortisone, etc. These impurities not only affect the yield and purity of the final product prednisolone succinate, but also limit its application effect in the medical field. Therefore, it is particularly important to develop a synthesis method of prednisolone succinate that can strictly control the content and types of impurities according to the quality standards of the pharmacopoeia and customer requirements.

[0004] In the prior art, there are purification methods for prednisolone or its analogues. For example, in patent application CN113801183A - A method for purifying prednisolone, which uses prednisolone acetate and semicarbazide as raw materials to obtain high - quality prednisolone through condensation - reduction reaction, hydrolysis reaction and two - step purification reactions. Although it can improve the purity of prednisolone to a certain extent, it is very difficult to effectively control the content and types of key impurities such as 11 - epi - hydrocortisone, prednisolone, hydrocortisone, etc. in the current synthesis process of prednisolone succinate, thus seriously affecting the purity and loss on drying of prednisolone succinate. Moreover, the existing prednisolone purification methods also have certain limitations in terms of process steps, reaction conditions and solvent selection, and it is difficult to meet the requirements of large - scale production and high quality. Therefore, a new technical solution is needed to solve the above technical problems. Summary of the Invention

[0005] The object of the present invention is to provide a method for controlling impurities of prednisolone hemisuccinate, so as to solve the problems proposed in the above-mentioned background technology. At present, it is very difficult to effectively control the types and contents of key impurities such as 11-epihydrocortisone, prednisone, and hydrocortisone doped in prednisolone hemisuccinate by the refining methods of prednisolone or its analogs. This has seriously affected the purity and loss on drying of prednisolone hemisuccinate. Moreover, the existing refining methods also have certain limitations in terms of process steps, reaction conditions, and solvent selection, and it is difficult to meet the requirements of large-scale production and high quality.

[0006] To achieve the above object, the present invention provides the following technical solution: A method for controlling impurities of prednisolone hemisuccinate. First, use prednisolone acetate as the starting material, and obtain prednisolone through condensation, reduction, hydrolysis, and refining. Then, esterify and refine prednisolone to obtain high-quality prednisolone hemisuccinate. The specific steps for impurity control are as follows: S1. Condense prednisolone acetate with semicarbazide hydrochloride in an alcohol solvent system to prepare the intermediate product, bis-semicarbazide-protected prednisolone acetate. Among them, the molar ratio of semicarbazide hydrochloride to prednisolone acetate is 1:2.2 - 1:2.5. The alcohol solvent is one or more of methanol, ethanol, and isopropanol. The temperature of the condensation reaction is 65 - 80 °C, and the time of the condensation reaction is 6 - 8 h. S2. Add a reducing agent to the solution of bis-semicarbazide-protected prednisolone acetate prepared in S1 for a reduction reaction to prepare the intermediate product, bis-semicarbazide-protected prednisolone. Among them, the molar ratio of bis-semicarbazide-protected prednisolone acetate to the reducing agent is 1:2 - 1:3. The reducing agent is one of potassium borohydride and sodium borohydride. The solvent system used for the reduction reaction is one or more of tetrahydrofuran, methanol, and ethanol. The temperature of the reduction reaction is 40 - 50 °C, and the time of the reduction reaction is 10 - 15 h. S3. Add the bis-semicarbazide-protected prednisolone prepared in S2 to hydrochloric acid and distilled water, and add solid sodium nitrite in batches to prepare the crude product of prednisolone. Among them, the mass ratio of bis-semicarbazide-protected prednisolone to hydrochloric acid is 1:2 - 1:3, and the concentration of hydrochloric acid is 36 - 38%. The mass ratio of bis-semicarbazide-protected prednisolone to sodium nitrite is 1:1 - 1:1.2. The temperature of the hydrolysis reaction is 30 - 50 °C, and the time of the hydrolysis reaction is 4 - 6 h. S4. Dissolve the crude prednisolone obtained in S3 in a low-polarity solvent, heat it to reflux, and then cool it to precipitate solid prednisolone. Among them, the mass ratio of prednisolone to the low-polarity solvent is 1:5 - 1:6, the low-polarity solvent is one or several of methanol, dichloromethane, ethyl acetate, or petroleum ether, and the refining time is 2 - 3 h; S5. Dissolve the prednisolone obtained in S4 in a system of succinic anhydride, pyridine, and ethyl acetate for an esterification reaction to obtain crude prednisolone hemisuccinate. Among them, the molar ratio of prednisolone to succinic anhydride added is 1:1.2 - 1:1.4, the temperature of the esterification reaction is 60 - 80 °C, and the time of the esterification reaction is 10 - 15 h; S6. Dissolve the crude prednisolone hemisuccinate obtained in S5 in an organic solvent, perform reflux decolorization, rotary evaporate the organic solvent, perform water precipitation, filtration, and drying to obtain high-quality prednisolone hemisuccinate. Among them, the organic solvent is one or several of tetrahydrofuran, chloroform, and ethanol, the decolorization is treated with activated carbon, and the mass ratio of the activated carbon to the crude prednisolone hemisuccinate is 1:10 - 1:15; The specific reaction synthesis route derived from the above steps is as follows: 。

[0007] Compared with the prior art, the beneficial effects of the present invention are: 1. The present invention adopts six synthesis steps of condensation - reduction - hydrolysis - refining - esterification - re - refining, so that the types and contents of key impurities such as 11 - epi - hydrocortisone, prednisone, and hydrocortisone doped in prednisolone hemisuccinate can be effectively controlled. Compared with the prior art, this impurity control method can significantly reduce the content of impurities, thereby improving the purity and quality of the final product. Through the condensation and reduction reactions, the control of 11 - epi - hydrocortisone and prednisone impurities is achieved, and the secondary refining realizes the control of hydrocortisone impurities. The esterification and refining steps realize the control of the oxidized impurities of prednisolone hemisuccinate, so that the content of the obtained product prednisolone hemisuccinate is greater than 99%, the loss on drying is less than or equal to five per thousand, and the content of all impurities is controlled below two point five per thousand. This index far exceeds the average level of the prior art and fully meets the requirements of international standards such as the European Pharmacopoeia, effectively improving the safety and effectiveness of the drug and providing a strong quality guarantee for the product's competition in the international market; 2. The present invention finely optimizes the conditions for each reaction step, including reaction temperature, time, solvent system, and material ratio, etc., ensuring the efficient progress of the reaction and the maximum yield of the product, reducing the generation of by-products, further improving the quality of the product. By selecting a specific solvent system and process conditions, effective separation of impurities and purification of the product are achieved, improving the efficiency and stability of the overall process; 3. In the refining step of the present invention, recrystallization is carried out using low-polarity solvents (such as methanol, dichloromethane, ethyl acetate, petroleum ether, etc.) and reflux decolorization is carried out using organic solvents (such as tetrahydrofuran, chloroform, ethanol, etc.). This not only helps in the separation and removal of impurities, but also improves the purity and stability of the product. At the same time, this makes the process step more concise, easy to operate and control, and the raw materials and solvents used are all common commercially available chemicals, which are easy to obtain and have low costs. Thus, this process is not only applicable to laboratory-scale research, but also very suitable for large-scale industrial production, helping to reduce production costs and improve economic benefits; 4. The method for controlling impurities of prednisolone hemisuccinate provided by the present invention not only improves the quality and purity of the product, but also provides the possibility for expanding its application in the treatment of more diseases. Especially in the treatment of allergic and autoimmune inflammatory diseases, skin diseases, and eye inflammations, etc., it is expected to bring better treatment effects and medication experiences to relevant patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 It is the liquid phase diagram of prednisolone hemisuccinate of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0009] The following examples are used to further illustrate the content of the present invention and do not limit the application of the present invention. Example 1:

[0010] Please refer to Figure 1 , this example provides a method for controlling impurities of prednisolone hemisuccinate. This method first uses prednisone acetate as the starting material, and successively undergoes condensation, reduction, hydrolysis, and the first refining to obtain prednisolone, and then prednisolone is esterified and the second refining is carried out to obtain the high-quality prednisolone hemisuccinate; the specific reaction synthesis route is as follows: .

[0011] The specific impurity control steps according to the above synthesis route are as follows: First, add 121 kg (1.1 mol) of semicarbazide hydrochloride and 44 kg (1.1 mol) of sodium hydroxide to 2000 mL of methanol solvent. After stirring at room temperature for 1 h, add 200 kg (0.5 mol) of prednisone acetate, heat up to 65 °C and react for 8 h. Rotavaporize the methanol solvent, wash with water, filter, and dry to obtain 234 kg of semicarbazide-protected prednisone acetate with a yield of 91%; Second, add 257 kg (0.5 mol) of semicarbazide-protected prednisone acetate to 3000 mL of tetrahydrofuran solvent. After stirring and dissolving, add 57 kg (1.5 mol) of sodium borohydride, heat up to 50 °C and react for 15 h. After the reaction, add glacial acetic acid to adjust the pH value to 6.0, rotavaporize the tetrahydrofuran solvent, wash with water, filter, and dry to obtain 225 kg of semicarbazide-protected prednisolone with a yield of 95%; Third, add 237 kg (0.5 mol) of semicarbazide-protected prednisolone to 700 kg of concentrated hydrochloric acid and 1400 kg of distilled water. Add 240 kg of solid sodium nitrite under vigorous stirring and react at 40 °C for 5 h. Filter, wash with water, and dry to obtain 158 kg of crude prednisolone with a yield of 88%; Then, dissolve 180 kg of prednisolone in 900 mL of dichloromethane and 100 mL of methanol, heat up to reflux and react for 1 h, then cool down to -10 °C and react for 1 h. Filter and dry to obtain 144 kg of prednisolone solid with a yield of 80%; Next, add 36 kg (0.1 mol) of prednisolone to a mixed solvent of 360 mL of ethyl acetate and 50 mL of pyridine, add 12 kg (0.12 mol) of succinic anhydride in batches, heat up to 70 °C and react for 14 h. After the reaction, rotavaporize 2 / 3 of the volume of the mixed solvent under reduced pressure, add water to precipitate, and filter to obtain crude prednisolone hemisuccinate; Finally, dissolve 30 kg of crude prednisolone hemisuccinate in 300 mL of tetrahydrofuran, add 2 kg of activated carbon, heat up to reflux and react for 2 h, filter while hot, concentrate under reduced pressure to 1 / 4 of the volume, add 900 mL of water to precipitate solid, filter and dry to obtain 27 kg of high-quality prednisolone hemisuccinate with a yield of 90%. The liquid phase diagram of the product is as Figure 1 shown. Example 2:

[0012] This example provides a method for controlling impurities in prednisolone hemisuccinate. This method uses prednisone acetate as the starting material, and successively obtains prednisolone through condensation, reduction, hydrolysis, and first purification, and then obtains high-quality prednisolone hemisuccinate through esterification and second purification; The specific impurity control steps are as follows: First, add 138 kg (1.25 mol) of semicarbazide hydrochloride and 50 kg (1.25 mol) of sodium hydroxide to 2000 mL of isopropanol solvent. After stirring at room temperature for 80 min, add 200 kg (0.5 mol) of prednisolone acetate, heat up to 80 °C and react for 6 h. Rotavaporize the isopropanol solvent, wash with water, filter, and dry to obtain 239 kg of semicarbazide-protected prednisolone acetate with a yield of 93%; Second, add 257 kg (0.5 mol) of semicarbazide-protected prednisolone acetate to 2500 mL of methanol solvent. After stirring to dissolve, add 54 kg (1 mol) of potassium borohydride, heat up to 40 °C and react for 12 h. After the reaction, add glacial acetic acid to adjust the pH value to 6.0, rotavaporize the methanol solvent, wash with water, filter, and dry to obtain 221 kg of semicarbazide-protected prednisolone with a yield of 93%; Third, add 237 kg (0.5 mol) of semicarbazide-protected prednisolone to 550 kg of concentrated hydrochloric acid and 1600 kg of distilled water. Add 280 kg of solid sodium nitrite under vigorous stirring and react at 50 °C for 4 h. Filter, wash with water, and dry to obtain 150 kg of crude prednisolone with a yield of 83%; Then, dissolve 180 kg of prednisolone in 1080 mL of petroleum ether and 100 mL of ethyl acetate, heat up to reflux and react for 1 h, then cool down to -5 °C and react for 1 h. Filter and dry to obtain 137 kg of prednisolone solid with a yield of 76%; Next, add 36 kg (0.1 mol) of prednisolone to a mixed solvent of 360 mL of ethyl acetate and 50 mL of pyridine, add 14 kg (0.14 mol) of succinic anhydride in batches, heat up to 75 °C and react for 10 h. After the reaction, rotavaporize under reduced pressure 7 / 9 of the volume of the mixed solvent, add water to precipitate, and filter to obtain crude prednisolone hemisuccinate; Finally, dissolve 30 kg of crude prednisolone hemisuccinate in 300 mL of chloroform, add 3 kg of activated carbon, heat up to reflux and react for 3 h, filter while hot, concentrate under reduced pressure to 1 / 5 of the volume, add 800 mL of water to precipitate solids, filter and dry to obtain 28 kg of high-quality prednisolone hemisuccinate with a yield of 93%. Example 3:

[0013] This example provides a method for controlling impurities in prednisolone hemisuccinate. This method uses prednisolone acetate as the starting material, and successively undergoes condensation, reduction, hydrolysis, and the first purification to obtain prednisolone, and then prednisolone undergoes esterification and the second purification to obtain high-quality prednisolone hemisuccinate; The specific impurity control steps are as follows: First, add 126 kg (1.15 mol) of semicarbazide hydrochloride and 46 kg (1.15 mol) of sodium hydroxide to 2000 mL of ethanol solvent. After stirring at room temperature for 90 min, add 200 kg (0.5 mol) of prednisolone acetate, heat up to 75 °C and react for 7 h. Rotavaporize the ethanol solvent, wash with water, filter, and dry to obtain 232 kg of semicarbazide-protected prednisolone acetate with a yield of 90%; Second, add 252 kg (0.5 mol) of semicarbazide-protected prednisolone acetate to a mixed solvent of 2800 mL of ethanol and tetrahydrofuran (volume ratio 1:1). After stirring to dissolve, add 63 kg (1.65 mol) of sodium borohydride, heat up to 45 °C and react for 13 h. After the reaction, add glacial acetic acid to adjust the pH value to 6.5, rotavaporize the mixed solvent, wash with water, filter, and dry to obtain 228 kg of semicarbazide-protected prednisolone with a yield of 96%; Third, add 240 kg (0.5 mol) of semicarbazide-protected prednisolone to 650 kg of 37% hydrochloric acid and 1500 kg of distilled water. Under vigorous stirring, add 260 kg of solid sodium nitrite in batches and react at 35 °C for 6 h. Filter, wash with water, and dry to obtain 155 kg of crude prednisolone with a yield of 86%; Then, dissolve 180 kg of prednisolone in a mixed solvent of 1000 mL of methanol and 80 mL of ethyl acetate, heat up to reflux and react for 2 h, then cool down to 0 °C and react for 2 h. Filter and dry to obtain 148 kg of prednisolone solid with a yield of 82%; Next, add 38 kg (0.1 mol) of prednisolone to a mixed solvent of 400 mL of ethyl acetate and 60 mL of pyridine. Add 13 kg (0.13 mol) of succinic anhydride in batches, heat up to 65 °C and react for 12 h. After the reaction, rotavaporize 3 / 4 of the volume of the mixed solvent under reduced pressure, add water to precipitate, and filter to obtain crude prednisolone hemisuccinate; Finally, dissolve 32 kg of crude prednisolone hemisuccinate in 320 mL of ethanol, add 2.5 kg of activated carbon, heat up to reflux and react for 2.5 h, filter while hot, concentrate under reduced pressure to 1 / 6 of the volume, add 950 mL of water to precipitate the solid, filter and dry to obtain 29 kg of high-quality prednisolone hemisuccinate with a yield of 94%.

Claims

1. A method for controlling impurities in prednisolone hemisuccinate, using prednisolone acetate as a starting material, and obtaining prednisolone through condensation, reduction, hydrolysis and purification, characterized in that: The refined prednisolone is dissolved in a succinic anhydride, pyridine and ethyl acetate system for esterification reaction to obtain a crude prednisolone hemisuccinate, and then the crude prednisolone hemisuccinate is dissolved in an organic solvent, subjected to reflux decolorization, rotary evaporation to remove the organic solvent, water separation, filtration, and drying to obtain a fine product of prednisolone hemisuccinate; The specific reaction synthesis route is as follows: 。 2. A method for controlling impurities of prednisolone hemisuccinate according to claim 1, characterized in that: The molar ratio of prednisolone to succinic anhydride is 1:1.2 to 1:1.

4.

3. A method for controlling impurities of prednisolone hemisuccinate according to claim 1, characterized in that: The temperature of the esterification reaction is 60-80° C., and the time of the esterification reaction is 10-15 hours.

4. A method for controlling impurities of prednisolone hemisuccinate according to claim 1, characterized in that: The organic solvent is one or more of tetrahydrofuran, chloroform and ethanol.

5. A method for controlling impurities of prednisolone hemisuccinate according to claim 1, characterized in that: The decolorization is carried out by activated carbon treatment, and the mass ratio of the activated carbon to the crude product of prednisolone hemisuccinate is 1:10 to 1:

15.

6. The method for controlling impurities of prednisolone hemisuccinate according to claim 1, characterized in that: The specific preparation steps of the prednisolone are as follows: S1, condensing prednisone acetate with semicarbazide hydrochloride in an alcohol solvent system to prepare an intermediate product, bis-semicarbazide-protected prednisone acetate; S2, adding a reducing agent to the bisaminozide-protected prednisolone acetate solution prepared in S1 to carry out a reduction reaction, thereby preparing an intermediate product, bisaminozide-protected prednisolone; S3, adding the bisaminozide-protected prednisolone obtained in S2 to hydrochloric acid and distilled water, and adding solid sodium nitrite in batches to prepare an intermediate product, a crude prednisolone; S4. Dissolve the crude prednisolone obtained in S3 in a low-polarity solvent, raise the temperature to reflux, and then cool to precipitate prednisolone solid.

7. A method for controlling impurities of prednisolone hemisuccinate according to claim 6, characterized in that: In S1, the molar ratio of the semicarbazide hydrochloride to the prednisone acetate is 1:2.2 to 1:2.5, the alcohol solvent is one or more of methanol, ethanol, and isopropanol, the temperature of the condensation reaction is 65 to 80° C., and the time of the condensation reaction is 6 to 8 hours.

8. The method for controlling impurities of prednisolone hemisuccinate according to claim 6, characterized in that: In S2, the molar ratio of the bisaminozide-protected prednisolone acetate to the reducing agent is 1:2 to 1:3, wherein the reducing agent is one of potassium borohydride and sodium borohydride, the solvent system used in the reduction reaction is one or more of tetrahydrofuran, methanol, and ethanol, the temperature of the reduction reaction is 40 to 50° C., and the time of the reduction reaction is 10 to 15 hours.

9. The method for controlling impurities of prednisolone hemisuccinate according to claim 6, characterized in that: In S3, the mass ratio of the bisaminozide-protected prednisolone to hydrochloric acid is 1:2-1:3, wherein the concentration of hydrochloric acid is 36-38%, the mass ratio of the bisaminozide-protected prednisolone to sodium nitrite is 1:1-1:1.2, the temperature of the hydrolysis reaction is 30-50°C, and the time of the hydrolysis reaction is 4-6h.

10. The method for controlling impurities of prednisolone hemisuccinate according to claim 6, characterized in that: In S4, the mass ratio of prednisolone to low-polarity solvent is 1:5-1:6, the low-polarity solvent is one or more of methanol, dichloromethane, ethyl acetate or petroleum ether, and the refining time is 2-3 hours.

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