A process for the decolorization of a steroidal intermediate dihydroxy compound

Abstract

The application provides a method for decoloring a steroid intermediate dihydroxyl, relates to the technical field of medicine and chemical industry, and comprises the following steps: dissolving a dihydroxyl crude product in a halogenated hydrocarbon solvent, adding an inorganic base to adjust the pH of the system to 8.0-9.5; under the condition of keeping the pH value, adding a sodium hypochlorite aqueous solution to perform chemical oxidation decoloring; the reaction end point is monitored and judged through color change or oxidation-reduction potential; after the reaction is completed, the pH is adjusted back through a weak acid, and the product is obtained through liquid separation, concentration and crystallization; the selective oxidation of sodium hypochlorite under a specific pH buffer system is utilized, the traditional activated carbon physical adsorption decoloring is replaced, the fermentation pigment is effectively removed, the oxidation damage of 11-hydroxyl in the steroid skeleton is avoided, the product has high purity, no waste activated carbon solid waste is generated, the operation is simple, and the industrialization amplification is easy.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical technology, and specifically relates to a method for decolorizing steroid intermediate dihydroxy compounds. Background Technology

[0002] 11α,17α-Dihydroxyprogesterone (CAS No.: 603-98-5) is a key intermediate in the synthesis of active pharmaceutical ingredients (APIs) for steroidal corticosteroids such as prednisolone acetate and methylprednisolone. Industrially, this compound is typically obtained by bio-fermentation of 17α-hydroxyprogesterone using Aspergillus ochraceus.

[0003] During the cultivation of Aspergillus ochraceus, pigments are produced by various culture medium components during high-temperature sterilization, and pigments are also produced during the bio-fermentation process. After fermentation, the collected Aspergillus ochraceus mycelia are extracted with organic solvents, which extracts crude dihydroxy compounds, pigments, and other impurities. This results in a darker color for the crude dihydroxy compounds, which is brownish-red. A large amount of activated carbon is required for decolorization to obtain a white finished product. The use of large amounts of activated carbon causes the product to be adsorbed into the activated carbon, resulting in product loss. The use of activated carbon also leads to the generation of a large amount of hazardous solid waste. Summary of the Invention

[0004] To overcome the problems in the prior art, this invention develops a method for decolorizing steroid intermediate dihydroxy compounds. This method uses sodium hypochlorite in a specific pH buffer system for chemical oxidation decolorization, replacing traditional physical adsorption. This effectively removes pigments while avoiding damage to the steroid skeleton, thereby increasing product yield and reducing the generation of hazardous solid waste.

[0005] To achieve the above objectives, the present invention is implemented through the following technical solution: A method for decolorizing a steroidal intermediate dihydroxy compound includes the following steps: S1. Dissolution: Dissolve the crude dihydroxy compound in a haloalkane solvent to obtain a substrate solution; S2. pH pre-adjustment: Add an inorganic base to the substrate solution to adjust the pH of the system to 8.0-9.5; S3. Decolorization: Under the condition of maintaining the pH value of the system greater than 8.0, add sodium hypochlorite aqueous solution with an effective chlorine concentration of 10%-15% to the system to carry out the oxidation reaction. The reaction temperature is 20℃-25℃ until the system color no longer changes or reaches the predetermined color standard. S4. Post-treatment: Adjust the pH of the system to 6.0-6.5 using a weak acid; S5. Discharge: After adding water and stirring thoroughly, the mixture separates into layers. The lower layer of halogenated hydrocarbon solvent is separated, concentrated under reduced pressure to a small volume, cooled to crystallize, and discharged to obtain the product.

[0006] Furthermore, the haloalkane solvent in step S1 is selected from either dichloromethane or trichloromethane. These two types of solvents have good solubility for dihydroxy compounds and a density greater than that of water, which is beneficial for the layering operation after the reaction.

[0007] Furthermore, the inorganic base in step S2 is sodium bicarbonate or potassium bicarbonate. Using bicarbonate can construct a mild buffer system to prevent excessive local alkalinity from causing steroid degradation.

[0008] Furthermore, in step S3, when the pH of the system decreases, the inorganic base described in step S2 is added to maintain the pH of the system at 8.0-9.5.

[0009] Furthermore, in step S3, the flow rate of sodium hypochlorite is controlled by real-time monitoring of the redox potential of the reaction system, so that the redox potential of the reaction system is maintained between +550 mV and +700 mV.

[0010] Furthermore, in step S3, when the redox potential reading decreases by ≤20 mV within 15 minutes after stopping the addition of sodium hypochlorite, the reaction is considered complete. At this point, the reducing pigments in the system have been completely consumed, and there is no need to consume oxidant anymore, thus accurately determining the endpoint and avoiding over-oxidation.

[0011] Furthermore, the weak acid in step S4 is acetic acid. Acetic acid has a mild effect on pH adjustment and the generated sodium acetate is readily soluble in water, making it easy to remove in subsequent water washing.

[0012] The beneficial effects of this invention are: 1. This invention utilizes chemical selective oxidation instead of physical adsorption. It employs a liquid-liquid two-phase system of halogenated hydrocarbons and water to protect the steroid substrate in the organic phase, while the sodium hypochlorite oxidant is mainly present in the aqueous phase. By controlling the pH buffer zone and adjusting the ratio of hypochlorous acid to hypochlorite ions, the oxidizing power is sufficient for decolorization while avoiding the oxidative damage of C11-secondary hydroxyl groups in the steroid skeleton inside the organic phase. Thus, decolorization is achieved without the need for activated carbon, and the color of the finished product meets the requirements. 2. This invention avoids the entrainment loss of activated carbon in the product, increases the yield of dihydroxy compounds, eliminates the generation of hazardous solid waste such as waste activated carbon, and the reaction byproducts are only sodium chloride and water-soluble small molecules that are easy to handle, providing technical support for the high-quality and green production of downstream pharmaceutical raw materials. Detailed Implementation

[0013] To make the objectives, technical solutions, and beneficial effects of the present invention clearer, the preferred embodiments of the present invention will be described in detail below to facilitate understanding by those skilled in the art.

[0014] Example 1 Dissolution: In a 1L four-necked flask equipped with a mechanical stirrer and a thermometer, add 100g of crude 11α,17α-dihydroxyprogesterone (dark brown in appearance), add 1L of dichloromethane, heat and stir until completely dissolved, then cool to 20-25℃. Pre-adjust pH: Add 1-6g of solid sodium bicarbonate to the bottle, stir for 10 minutes, and adjust the pH of the aqueous phase to 8.5; Decolorization: Slowly add 1-10g of sodium hypochlorite solution with an effective chlorine concentration of 12%. During the addition process, check the pH value every 30 minutes. If it is lower than 8.0, add a small amount of sodium bicarbonate. React at 20-25℃ for about 4 hours. Observe the color of the system from dark brown to light brown by using a pre-set colorimetric card. Post-treatment: Add glacial acetic acid to adjust the pH of the system to 6.2, add 150g of tap water, stir for 15 minutes, and let stand to separate into layers; Discharge: The lower dichloromethane phase was separated, concentrated under reduced pressure to about 150 mL, cooled to 0-5 °C to crystallize, filtered, and dried to obtain 97.2 g of the dihydroxy compound product.

[0015] The obtained product, analyzed by HPLC, had a purity of 99.2%, with no 11-keto impurities detected, and met the data of the standard.

[0016] Example 2 Dissolution: In a 1L four-necked flask equipped with a mechanical stirrer and a thermometer, add 100g of crude 11α,17α-dihydroxyprogesterone (dark brown in appearance), add 1L of dichloromethane, heat and stir until completely dissolved, then cool to 20-25℃. Pre-adjust pH: Add 1-6g of solid sodium bicarbonate to the bottle, stir for 10 minutes, and measure the pH of the aqueous phase to be approximately 8.0; Decolorization: Slowly add 1-10g of sodium hypochlorite solution with an effective chlorine concentration of 10%. During the addition process, check the pH value every 30 minutes. If it is lower than 8.0, add a small amount of sodium bicarbonate. React at 20-25℃ for about 4 hours. Observe the color of the system from dark brown to light brown by using a pre-set colorimetric card. Post-treatment: Add glacial acetic acid to adjust the pH of the system to 6.0, add 100g of tap water, stir for 15 minutes, and let stand to separate into layers; Discharge: The lower dichloromethane phase was separated, concentrated under reduced pressure to about 100 mL, cooled to 0-5 °C for crystallization, filtered, and dried to obtain 97.0 g of the dihydroxy compound product.

[0017] The obtained product, analyzed by HPLC, had a purity of 99.0% and 11-keto impurities of <0.1%, which met the data of the standard.

[0018] Example 3 Dissolution: In a 1L four-necked flask equipped with a mechanical stirrer and a thermometer, add 100g of crude 11α,17α-dihydroxyprogesterone (dark brown in appearance), add 1L of dichloromethane, heat and stir until completely dissolved, then cool to 20-25℃. pH pre-adjustment: Add 1-6g of solid sodium bicarbonate to the bottle, stir for 10 minutes, and measure the pH of the aqueous phase to be approximately 9.5; Decolorization: Slowly add 1-10g of sodium hypochlorite solution with an effective chlorine concentration of 15%. During the addition process, check the pH value every 30 minutes. If it is lower than 8.0, add a small amount of sodium bicarbonate. React at 20-25℃ for about 4 hours. Observe the color of the system from dark brown to light brown by using a pre-set colorimetric card. Post-treatment: Add glacial acetic acid to adjust the pH of the system to 6.5, add 200g of tap water, stir for 15 minutes, and let stand to separate into layers; Discharge: The lower dichloromethane phase was separated, concentrated under reduced pressure to about 200 mL, cooled to 0-5 °C for crystallization, filtered, and dried to obtain 96.8 g of the dihydroxy compound product.

[0019] The obtained product, analyzed by HPLC, had a purity of 99.1% and 11-keto impurities of <0.1%, which met the data of the standard.

[0020] Example 4 Dissolution: In a 1L four-necked flask equipped with a mechanical stirrer and a thermometer, add 100g of crude 11α,17α-dihydroxyprogesterone (dark brown in appearance), add 1L of dichloromethane, heat and stir until completely dissolved, then cool to 20-25℃ and insert an online ORP electrode. Pre-adjust pH: Add 1-6g of solid sodium bicarbonate to the bottle, stir for 10 minutes, and adjust the pH to 8.5. At this point, the ORP reading will be approximately +200 mV.

[0021] Decolorization: Turn on the automatic drip pump and slowly add 1-10g of sodium hypochlorite solution with an effective chlorine concentration of 12%. During the dripping process, check the pH value every 30 minutes. If it is lower than 8.0, add a small amount of sodium bicarbonate. The reaction temperature is 20-25℃. Configure control logic: When the system ORP < +600 mV, the pump flow rate increases; when the ORP approaches +650 mV, the flow rate decreases; when the ORP > +700 mV, the pump stops. During the reaction, the ORP value of the system remained between +580 mV and +680 mV. After 2.5 hours of reaction, the pump automatically stopped feeding. Stirring continued for 15 minutes. The ORP reading dropped by only 10 mV, indicating that the pigment was no longer consuming the oxidant. The reaction was then considered complete. The color of the system changed from dark brown to light brown by observing the color of the system through the pre-set colorimetric card.

[0022] Post-treatment: Add glacial acetic acid to adjust the pH of the system to 6.2, add 150g of tap water, stir for 15 minutes and let stand to separate into layers.

[0023] Discharge: The lower dichloromethane phase was separated, concentrated under reduced pressure to about 150 mL, cooled to 0-5 °C to crystallize, filtered, and dried to obtain 98.1 g of the dihydroxy compound product.

[0024] The obtained product, analyzed by HPLC, had a purity of 99.5%, with no 11-keto impurities detected, and met the data of the standard.

[0025] Comparative Example 1: Traditional activated carbon decolorization process Take 100g of crude dihydroxy compound from the same batch, dissolve it in 1L of dichloromethane, add 5g of pharmaceutical activated carbon, heat and reflux to decolorize for 1 hour, use a filter aid to filter while hot to remove activated carbon, wash the filter cake with a small amount of hot dichloromethane, concentrate the filtrate to crystallize; obtain 93.5g of finished product, and generate about 10g of waste activated carbon solid waste containing the product.

[0026] The obtained product, analyzed by HPLC, had a purity of 98.8% and 11-keto impurities of <0.10%, which met the data of the standard.

[0027] Table 1 Product Analysis Table Finally, it should be noted that the above preferred embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should understand that various changes can be made to it in form and detail without departing from the scope defined by the claims of the present invention.

Claims

1. A method for decolorizing a steroidal intermediate dihydroxy compound, characterized in that, Includes the following steps: S1. Dissolution: Dissolve the crude dihydroxy compound in dichloromethane or trichloromethane solvent to obtain a substrate solution; S2. pH adjustment: Add an inorganic base to the substrate solution to adjust the pH of the system to 8.0-9.

5. The inorganic base is sodium bicarbonate or potassium bicarbonate. S3. Decolorization: While maintaining the pH of the system at 8.0-9.5, add an aqueous solution of sodium hypochlorite with an effective chlorine concentration of 10%-15% to the system to carry out an oxidation reaction. Control the reaction temperature at 20℃-25℃ until the system color no longer changes or reaches the predetermined color standard. S4. Post-treatment: Adjust the pH of the system to 6.0-6.5 using a weak acid; S5. Discharge: After adding water and stirring thoroughly, the mixture separates into layers. The lower layer of halogenated hydrocarbon solvent is separated, concentrated under reduced pressure to a small volume, cooled to crystallize, and discharged to obtain the product.

2. The method for decolorizing the steroidal intermediate dihydroxy compound according to claim 1, characterized in that, In step S3, the pH value is monitored in real time during the reaction. When the pH value of the system decreases, the inorganic base described in step S2 is added to maintain the pH value of the system at 8.0-9.

5.

3. The method for decolorizing the steroidal intermediate dihydroxy compound according to claim 1, characterized in that, In step S3, the flow rate of sodium hypochlorite is controlled by real-time monitoring of the redox potential of the reaction system, so that the redox potential of the reaction system is maintained between +550 mV and +700 mV.

4. The method for decolorizing the steroidal intermediate dihydroxy compound according to claim 3, characterized in that, When the addition of sodium hypochlorite is stopped in step S3, the reaction is considered complete when the redox potential reading decreases by ≤20 mV within 15 minutes.

5. The method for decolorizing the steroidal intermediate dihydroxy compound according to claim 1, characterized in that, The weak acid in step S4 is acetic acid.

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