Purification method of progesterone crude product

Abstract

The invention discloses a purification method of a progesterone crude product, and belongs to the technical field of purification of organic compounds. The purification method of the progesterone crude product comprises the following steps: adding acid into a progesterone crude product reaction solution, dropwise adding a sodium hypochlorite solution at 0-30 DEG C for reaction, quenching, separating liquid, washing an organic phase with a sodium hydroxide solution after liquid separation, and concentrating a water precipitation material under reduced pressure by the organic phase to obtain purified progesterone. According to the method, the impurity I and the impurity L are efficiently removed under the mild reaction condition.

Description

Technical Field

[0001] This invention relates to the field of organic compound purification technology, and specifically to a method for purifying crude progesterone. Background Technology

[0002] Progesterone, also known as luteal hormone or progesterone, is a white crystalline powder. It is a natural progestin secreted by the corpus luteum of the ovary with a melting point of 128–131°C. In vivo, it has a significant morphological effect on stimulated endometrium and is essential for maintaining pregnancy. Clinically, it is used for threatened abortion and recurrent miscarriage. Progesterone is also a key intermediate for steroidal drugs such as corticosteroids and androgens.

[0003] Progesterone can be administered orally or by injection. The large dosage and trace amounts of related substances can affect the efficacy and safety of the final product. Therefore, understanding the entire production process and identifying and controlling impurities at the source is crucial for providing high-quality progesterone. Currently, in the synthesis of progesterone, the crude product contains high levels of impurities, which are difficult to remove, resulting in progesterone that does not meet the quality standards for progesterone products.

[0004] Numerous methods for synthesizing progesterone have been reported in the literature, involving different starting materials. One method uses BA (dinorrolidone) as the starting material: BA is oxidized to dinoraldehyde, dinoraldehyde reacts with cyclohexenepiperidine to form a dinorpiperidine ring, which is then oxidized in air to finally yield progesterone. The dinorpiperidine ring is unstable and degrades to form dinoraldehyde and its isomer impurities (EP impurity I). Simultaneously, EP impurity L is generated during the reaction. The EP impurity I content in crude progesterone is 1-3%, and the EP impurity L content is 0.25-0.35%. Because EP impurity I and EP impurity L have similar physicochemical properties to progesterone, the progesterone product obtained using conventional purification methods such as recrystallization and adsorption is difficult to meet standards. This poses a significant obstacle to obtaining high-purity progesterone in industrial production (the European Pharmacopoeia stipulates that EP impurity I < 0.6% and EP impurity L < 0.15% in progesterone raw materials; otherwise, it is considered an unqualified product). The synthetic route and impurity structures are as follows:

[0005] Chinese patent CN 112062801A reports a method for removing impurity I: sodium bisulfite is added to react with it, and after some post-treatment, the purity of progesterone reaches more than 99%, the single impurity is less than 0.2%, and the total impurity is less than 1.0%. The operation is cumbersome, and although EP-I meets the standard, it is still not completely removed, and it has no effect on removing impurity L.

[0006]

[0007] Chinese patent CN 113880905A describes a process involving the addition of a Girald reagent to react with impurity I at high temperature, followed by water washing, and finally concentration and purification. The result shows that impurity I is less than 0.15% and progesterone is greater than 99.6%. Girald reagent is an ammonium catalyst that reacts with impurity I to produce a secondary amine. The high-temperature reaction carries the risk of introducing genotoxic nitrogen oxide impurities and also poses a residual risk. Furthermore, the patent does not mention its effectiveness in removing impurity L.

[0008]

[0009] How to efficiently remove impurities I and L under mild reaction conditions is a technical problem that needs to be solved by existing technologies. Summary of the Invention

[0010] The purpose of this invention is to overcome the above-mentioned technical deficiencies and provide a method for purifying crude progesterone, solving the technical problem in the prior art of how to efficiently remove impurities I and L under mild reaction conditions.

[0011] To achieve the above-mentioned technical objectives, the present invention provides a method for purifying crude progesterone, comprising the following steps:

[0012] Acid was added to the reaction solution containing crude progesterone, and sodium hypochlorite solution was added dropwise at 0-30℃ to react. The reaction was then quenched, followed by separation. The organic phase was washed with sodium hydroxide solution after separation, and the organic phase was concentrated under reduced pressure to obtain purified progesterone.

[0013] In any embodiment, the acid is one or more of acetic acid, dilute hydrochloric acid, and dilute sulfuric acid.

[0014] In any embodiment, the content of active chlorine in the sodium hypochlorite solution is ≥10%, and the amount of sodium hypochlorite solution added is 15%-20% of the crude progesterone mass.

[0015] In any embodiment, the reaction time for adding the sodium hypochlorite solution dropwise at 0-30°C is 0.5-1 h.

[0016] In any embodiment, the quenching is achieved by adding sodium thiosulfate solution dropwise.

[0017] In any embodiment, the mass concentration of the sodium thiosulfate solution is 10-12%, and the amount of sodium thiosulfate solution added is 2.2-2.5 times the mass of the crude progesterone.

[0018] In any embodiment, the sodium hydroxide solution has a mass concentration of 0.7-0.9% and is added at an amount 2-2.2 times the mass of the crude progesterone.

[0019] In any embodiment, the impurities removed include one or both of impurity I and impurity L.

[0020] In any embodiment, the concentration of the acid is 3-5%, and the amount added is 4%-5% of the crude progesterone mass.

[0021] In any embodiment, the reaction solution containing crude progesterone is a dichloromethane solution containing crude progesterone.

[0022] Compared with the prior art, the beneficial effects of the present invention include: The present invention proposes a simple and efficient method for removing impurities I and L: a catalytic amount of acid is added to the crude progesterone reaction solution, and sodium hypochlorite solution is added dropwise under controlled temperature (0-30℃) to react and oxidize impurities I and L to the corresponding carboxylic acids. Sodium thiosulfate is added dropwise to quench the oxidation. After separation, the organic phase is washed with sodium hydroxide solution and reacts with the corresponding carboxylic acids to form sodium salts, which are dissolved in water to remove impurities I and L. The organic phase is concentrated under reduced pressure and water is precipitated to obtain crude progesterone. The crude product has an HPLC filtration efficiency >99%, impurity I is not detected, and impurity L is <0.1% (the crude product meets the EP standard). The reaction temperature is relatively low. The present invention achieves efficient removal of impurities I and L under mild reaction conditions. Attached Figure Description

[0023] Figure 1 This is a high-performance liquid chromatogram of crude progesterone from Example 1 of the present invention.

[0024] Figure 2 This is a high-performance liquid chromatogram of progesterone purified in Example 1 of this invention.

[0025] Figure 3 This is a high-performance liquid chromatogram of progesterone purified in Comparative Example 1 of this invention.

[0026] Figure 4 This is a high-performance liquid chromatogram of progesterone purified in Comparative Example 2 of this invention. Detailed Implementation

[0027] The "range" disclosed in this application is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. Ranges defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60~120 and 80~110 are listed for a specific parameter, it is also expected that ranges of 60~110 and 80~120 are also included. Furthermore, if minimum range values ​​of 1 and 2 are listed, and if maximum range values ​​of 3, 4, and 5 are listed, then the following ranges are all expected: 1~3, 1~4, 1~5, 2~3, 2~4, and 2~5. In this application, unless otherwise stated, the numerical range "a~b" represents a shortened representation of any combination of real numbers between a and b, where a and b are real numbers. For example, the numerical range "0~5" indicates that all real numbers between "0~5" have been listed in this article; "0~5" is simply a shortened representation of these numerical combinations. Furthermore, when a parameter is stated as an integer ≥2, it is equivalent to disclosing that the parameter is, for example, an integer such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0028] Unless otherwise specified, the terms "comprising" and "including" as used in this application can be open-ended or closed-ended. For example, "comprising" and "including" can mean that other components not listed may also be included, or that only the listed components may be included.

[0029] Unless otherwise specified, the term "or" is inclusive in this application. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, the condition "A or B" is satisfied by any of the following conditions: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); or both A and B are true (or exist).

[0030] This specific embodiment provides a method for purifying crude progesterone, including the following steps:

[0031] An acid is added to the reaction solution containing crude progesterone, and sodium hypochlorite solution is added dropwise at 0-30℃ for 0.5-1 h. The reaction is then quenched by adding sodium thiosulfate solution. The mixture is separated into liquid and liquid phases. The organic phase is washed with sodium hydroxide solution, and the organic phase is concentrated under reduced pressure to obtain purified progesterone. The acid is one or more of acetic acid, dilute hydrochloric acid, and dilute sulfuric acid. The active chlorine content in the sodium hypochlorite solution is ≥10%, and the amount of sodium hypochlorite added is 15%-20% of the crude progesterone mass. The concentration of the acid is 3-5%, and the amount added is 4%-5% of the crude progesterone mass. The mass concentration of the sodium thiosulfate solution is 10-12%, and the amount added is 2.2-2.5 times the crude progesterone mass. The mass concentration of the sodium hydroxide solution is 0.7-0.9%, and the amount added is 2-2.2 times the crude progesterone mass.

[0032] In some embodiments, the impurities removed include one or both of impurity I and impurity L.

[0033] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0034] In this invention, the terms "some embodiments," "this embodiment," and examples are used to describe a subset of all possible embodiments. However, it is understood that "some embodiments" can be the same subset or different subsets of all possible embodiments and can be combined with each other without conflict.

[0035] If the application documents contain similar descriptions such as "first / second", the following explanation shall be added: In the following description, the terms "first / second / third" are used only to distinguish similar objects and do not represent a specific ordering of objects. It is understood that "first / second / third" may be interchanged in a specific order or sequence where permitted, so that the embodiments described herein can be implemented in an order other than that illustrated or described herein.

[0036] In this embodiment, the term "and / or" is merely a description of the relationship between related objects, indicating that there can be three relationships. For example, object A and / or object B can represent three situations: object A exists alone, object A and object B exist simultaneously, and object B exists alone.

[0037] The following describes embodiments of this application. The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Reagents or instruments used, unless otherwise specified, are all conventional products that can be obtained commercially.

[0038] The preparation methods of crude progesterone in the following examples or comparative examples are from the prior art, and are as follows: Preparation method of crude progesterone:

[0039] 60g BA (dichloroaldehyde), 200g dichloromethane, and 0.05g TEMPO were added to a reaction flask. 10g of 2% sodium bicarbonate solution was added while stirring. The temperature was lowered to 5-10℃, and 120g of sodium hypochlorite solution (active chlorine >10%) was slowly added dropwise while maintaining the system temperature <10℃. After the addition was complete, the reaction was allowed to proceed for 20min. Then, 50g of 10% sodium thiosulfate was added dropwise to quench the reaction. The mixture was stirred for 10min, and 200g of water was added. The water was concentrated under reduced pressure to precipitate the solid. The solid was filtered, dried under vacuum, and dried at 50-55℃ to obtain 58.8g of pale yellow solid dichloroaldehyde.

[0040] 58.8g of dinoraldehyde, 200g of acetonitrile, and 45g of cyclohexenepiperidine were added to a reaction flask and heated to 50℃ with stirring to dissolve. The reaction was maintained at 50℃ for 8 hours, then cooled to -10℃ and stirred to crystallize for 0.5 hours. The mixture was filtered, and the solid was washed with a small amount of acetonitrile and dried at 40℃ to obtain 65.9g of white solid dinorpiperidine ring.

[0041] 65.9g of di-norpiperidine ring, 250g of dichloromethane, and 50g of DMF were added to a reaction flask. The mixture was cooled to about 0°C, and 3g of cuprous chloride was added with stirring. The reaction was carried out under air, and the reaction system was kept below 25°C. The reaction was completed in about 8 hours. 100ml of 5% sulfuric acid solution was added dropwise to quench the reaction. The mixture was separated, and the organic phase was washed once more with 5% sulfuric acid solution. The organic phase was then separated, and it was the dichloromethane solution of crude progesterone.

[0042] The crude progesterone contained 1.162% EP impurity I and 0.176% EP impurity L. The relevant chromatograms are shown below. Figure 1 As shown.

[0043] Example 1

[0044] This embodiment proposes a method for purifying crude progesterone, including the following steps:

[0045] Add 2g of 4% acetic acid to a dichloromethane solution (300g dichloromethane) containing crude progesterone (50g). Add 0.15w (7.5g) of sodium hypochlorite solution (active chlorine ≥10%) dropwise at 0-30℃. After the addition is complete, maintain the reaction temperature at 0-30℃ for 0.5h to oxidize impurities I and L to their corresponding carboxylic acids. Quench the oxidation by adding 110g of 10% sodium thiosulfate solution. After separation, wash the organic phase with sodium hydroxide solution (100g 0.9% sodium hydroxide solution) (which reacts with the corresponding carboxylic acids to form sodium salts, which dissolve in water to remove impurities I and part of impurity L). Separate the organic phase, wash twice with 100g of water each time, add 8w of water to the organic phase, concentrate under reduced pressure to precipitate the water, filter, and dry at 50℃ to constant weight to obtain 49.5g of purified progesterone. Figure 2 Progesterone HPLC >99%, impurity I not detected, impurity L <0.1% (compliant with EP standard).

[0046] Comparative Example 1

[0047] This comparative example presents a method for purifying crude progesterone, comprising the following steps:

[0048] 0.15w (7.5g) of sodium hypochlorite solution (active chlorine ≥10%) was added dropwise to a dichloromethane solution containing 50g of crude progesterone (300g) at a controlled temperature of 0-30℃. After the addition was complete, the reaction was maintained at 0-30℃ for 0.5h. The reaction was then quenched by adding 110g of 10% sodium thiosulfate solution. After separation, the organic phase was washed with sodium hydroxide solution (100g of 0.9% sodium hydroxide solution), separated, and the organic phase was washed twice with 100g of water each time. The organic phase was then concentrated under reduced pressure with 8w of water to precipitate the water, filtered, and dried at 50℃ to constant weight to obtain purified progesterone. The chromatogram of progesterone is shown below. Figure 3 As shown, impurity I (0.359%) is less than 0.6%, and a single impurity I meets the EP standard. However, an unknown impurity (44min) has been added, causing progesterone to fail the test. The removal effect on impurity I is poor, and an unknown single impurity has been added.

[0049] Comparative Example 2

[0050] This comparative example presents a method for purifying crude progesterone, comprising the following steps:

[0051] Add 2g of 4% acetic acid to a dichloromethane solution (300g dichloromethane) containing 50g crude progesterone. Add 0.15w (7.5g) of sodium chlorite solution (active chlorine ≥10%) dropwise at 0-30℃. After the addition is complete, maintain the reaction at 0-30℃ for 0.5h. Then quench the reaction by adding 110g of 10% sodium thiosulfate solution. After separation, wash the organic phase with sodium hydroxide solution (100g 0.9% sodium hydroxide solution). Separate the organic phase and wash it twice with water (100g water each time). Add 8w of water to the organic phase and concentrate the water under reduced pressure to precipitate the product. Filter and dry at 50℃ to constant weight to obtain purified progesterone. The relevant chromatograms are shown below. Figure 4 As shown, impurity I is 0.394% < 0.6%, and the single impurity I meets the EP standard. However, an unknown impurity of 44min has been added, which makes progesterone unqualified. The removal effect of impurity I is poor, and an unknown single impurity has been added.

[0052] The specific embodiments of the present invention described above do not constitute a limitation on the scope of protection of the present invention. Any other corresponding changes and modifications made in accordance with the technical concept of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A method for purifying crude progesterone, characterized in that, Includes the following steps: Acid was added to the reaction solution containing crude progesterone, and sodium hypochlorite solution was added dropwise at 0-30℃ to react. The reaction was then quenched, followed by separation. The organic phase was washed with sodium hydroxide solution after separation, and the organic phase was concentrated under reduced pressure to obtain purified progesterone.

2. The purification method for crude progesterone according to claim 1, characterized in that, The acid is one or more of acetic acid, dilute hydrochloric acid, and dilute sulfuric acid.

3. The purification method for crude progesterone according to claim 1, characterized in that, The sodium hypochlorite solution contains ≥10% active chlorine, and the amount of sodium hypochlorite solution added is 15%-20% of the crude progesterone mass.

4. The purification method for crude progesterone according to claim 1, characterized in that, The sodium hypochlorite solution is added dropwise at 0-30℃, and the reaction time is 0.5-1h.

5. The purification method for crude progesterone according to claim 1, characterized in that, The quenching is achieved by adding sodium thiosulfate solution dropwise.

6. The purification method for crude progesterone according to claim 5, characterized in that, The sodium thiosulfate solution has a mass concentration of 10-12%, and the amount of sodium thiosulfate solution added is 2.2-2.5 times the mass of crude progesterone.

7. The purification method for crude progesterone according to claim 1, characterized in that, The sodium hydroxide solution has a mass concentration of 0.7-0.9% and is added at a rate of 2-2.2 times the mass of the crude progesterone.

8. The purification method for crude progesterone according to claim 1, characterized in that, The impurities removed include one or both of impurity I and impurity L.

9. The purification method for crude progesterone according to claim 1, characterized in that, The concentration of the acid is 3-5%, and the amount added is 4%-5% of the crude progesterone mass.

10. The purification method for crude progesterone according to claim 1, characterized in that, The reaction solution containing crude progesterone is a dichloromethane solution containing crude progesterone.

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