Purification method of high-purity progesterone

Abstract

The invention discloses a preparation method of high-purity progesterone. According to the method, by-product aldehyde impurities in progesterone are subjected to a reductive amination reaction to generate amine compounds, and the amine compounds are dissolved in acid water to be removed. Comprising the following steps: dissolving a progesterone crude product in an organic solvent, adding an amine compound to generate Schiff base, controlling the temperature, adding a reducing agent, controlling the temperature, carrying out stirring reaction for a certain time, adding an acid aqueous solution into the obtained reaction solution, quenching, adding water, crystallizing, and centrifuging to obtain the progesterone with the purity of higher than 99.5% and the content of by-product aldehydes of lower than 0.3%. The method is simple in process, safe and reliable, the byproduct aldehyde impurities can be effectively controlled, and the prepared progesterone is high in yield and purity, economical, green and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of steroid medicines, and in particular relates to a method for purifying high-purity progesterone. Background Art

[0002] Progesterone, also known as progesterone, pregnenedione, and gestagen, is the main biologically active progestogen secreted by the corpus luteum of the ovary, the adrenal cortex, and the placenta, and plays a very important role in maintaining pregnancy. Under the synergistic effect of estrogen, progesterone causes the endometrium to complete the change from the proliferation phase to the secretion phase, so that the fertilized egg can implant safely; it promotes the relaxation of the muscles of the pregnant uterus and reduces its activity, reduces the sensitivity of the pregnant uterus, and is beneficial to the growth and development of the fertilized egg in the uterus; it also has an immune effect, directly participates in regulating the environment in the mother and fetus, and promotes maternal and fetal tolerance.

[0003] At present, the mainstream route for synthesizing progesterone is as follows. All of them use BA as the starting material. After oxidation to aldehyde, there are two routes to generate progesterone; Route 1, reported in patent CN112110971, is first prepared into enamine, and then oxidized into progesterone. The main by-product in the reaction process is enamine degradation to aldehyde and its isomers; Route 2, reported in patent CN104109183, is directly oxidized to prepare progesterone by aldehyde, and its main by-product is aldehyde and its isomers. Therefore, the removal of aldehyde impurities in progesterone has the greatest impact on its product quality, and aldehyde impurities must exist in the BA route, so the development of a method for removing by-product aldehyde impurities is an urgent problem to be solved.

[0004]

[0005] The aldehyde impurities in progesterone are recrystallized from solvents such as methanol and ethanol, which has almost no removal effect. Its removal requires multiple recrystallizations, which is cumbersome and difficult to operate. In addition, the EU standard limit for such aldehyde impurities is no more than 0.6%. When the crude progesterone is prepared by the above BA process, the aldehyde impurities are about 2%. Summary of the invention

[0006] In order to solve the problem of difficult removal of by-product aldehyde impurities in progesterone, the present invention avoids the technical bottleneck of progesterone purification in the prior art and provides a high-purity progesterone purification method. The process is simple, safe and efficient, simplifies the synthesis operation, reduces costs, and improves purity and yield. The synthesis route is as follows:

[0007]

[0008] Where R 1 :H or CH 3 , R 2 :H or CH 3 .

[0009] The specific plan is as follows:

[0010] The by-product aldehyde impurities in progesterone are converted into amine impurities by reduction amination, and the amine impurities are converted into quaternary ammonium salts by adding acid and dissolved in the aqueous phase for removal. The preparation method thereof is as follows:

[0011] The crude progesterone is added to 1 to 10 times the volume of an organic solvent, 0.05 to 1.0 eq of an amine compound is added, the temperature is controlled at -20 to 50° C. and stirred for reaction for 0.1 to 36 hours, 0.01 to 0.10 eq of a reducing agent is added, the temperature is controlled at -20 to 50° C. and stirred for reaction for 0.1 to 36 hours, the mixed solution is quenched with acid, the by-product aldehyde impurities are converted into amine impurities and then react with the acid to form a quaternary ammonium salt, which is dissolved in the aqueous solution system for removal; post-treatment: the mixed solution is added with 2 to 15 times the volume of water for crystallization, filtered, and the filter layer is vacuum dried at 40 to 50° C. for 12 to 24 hours to obtain high-purity progesterone; post-treatment: when the solvent is tetrahydrofuran or dichloromethane, the mixed solution is added with 2 to 15 times the volume of water and concentrated under reduced pressure at 40 to 50° C. to remove the organic solvent, cooled to ambient temperature, filtered, and the filter layer is vacuum dried at 40 to 50° C. for 12 to 24 hours to obtain high-purity progesterone.

[0012] The specific reaction conditions of the purification method of high-purity progesterone as described above are as follows:

[0013] Further, the reaction organic solvent is methanol, ethanol, tetrahydrofuran or dichloromethane;

[0014] Furthermore, the amine compounds are ammonia methanol solution, methylamine and dimethylamine;

[0015] Furthermore, the reducing agent is sodium borohydride, potassium borohydride or sodium triacetoxyborohydride.

[0016] In summary, the beneficial effects of the present invention are:

[0017] The preparation method of the invention is simple, safe and efficient, and avoids the multiple recrystallization operations using alcohol solvents in the patent, and avoids the use of heavy metal reagents for oxidation and impurity removal; the post-treatment is simple, the yield is stable at more than 95%, the purity obtained is more than 99.5%, and the by-product aldehyde impurities are less than 0.3%, which is convenient for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Attached Figure 1 This is the HPLC spectrum of the progesterone product of Example 1

[0019] Attached Figure 2 The HPLC spectrum of the reaction solution of Comparative Example 1

[0020] Attached Figure 3 This is the HPLC spectrum of the progesterone finished product of Comparative Example 1 DETAILED DESCRIPTION

[0021] In order to enable those skilled in the art to better understand the present invention, the technical solution of the present invention is further described below through specific examples. It should be understood that the following examples are only given to better illustrate the present invention and are not intended to limit the content of the present invention.

[0022] Example 1

[0023] Crude progesterone (50 g, containing by-product aldehyde impurities: 2.5%) and ammonia methanol solution (0.1 eq, 7 mol / L) were added with methanol (100 ml) and stirred at ambient temperature for 1 hour; the mixture was cooled to 0-10°C, potassium borohydride (0.02 eq) was added, and the mixture was stirred for 1 hour at this temperature; the reaction solution was quenched with dilute hydrochloric acid (0.25 eq), the temperature was raised to ambient temperature, and water (150 ml) was added for crystallization; the mixture was stirred for 1 hour, filtered, and the filter layer was dried to obtain 48.5 g of finished progesterone, with a yield of 97%, a HPLC purity of 99.55%, and a by-product aldehyde impurity of 0.27%.

[0024] Example 2

[0025] Crude progesterone (50 g, containing by-product aldehyde impurities: 2.5%) and ammonia methanol solution (0.1 eq, 7 mol / L) were added with methanol (100 ml) and stirred at ambient temperature for 1 hour; the mixture was cooled to 0-10°C, sodium triacetoxyborohydride (0.05 eq) was added, and the mixture was stirred at this temperature for 1 hour; the reaction solution was quenched with dilute hydrochloric acid (0.25 eq), stirred at ambient temperature for 1 hour, water (150 ml) was added to the mixture and concentrated in a 40°C water bath until there was almost no DCM, cooled to ambient temperature and stirred for 1 hour, filtered, and the filter layer was dried to obtain 48.7 g of progesterone, with a yield of 97.4%, an HPLC purity of 99.62%, and a by-product aldehyde impurity of 0.25%.

[0026] Example 3

[0027] Crude progesterone (50 g, containing by-product aldehyde impurities: 2.5%) and ammonia methanol solution (0.1 eq) were added with methanol (100 ml) and stirred at ambient temperature for 1 hour; the mixture was cooled to 0-10°C, sodium borohydride (0.01 eq) was added, and the mixture was stirred for 1 hour at this temperature; the reaction solution was quenched with dilute hydrochloric acid (0.25 eq), the temperature was raised to ambient temperature, and water (150 ml) was added for crystallization; the mixture was stirred for 1 hour, filtered, and the filter layer was dried to obtain 48.4 g of progesterone, with a yield of 96.8%, a HPLC purity of 99.54%, and a by-product aldehyde impurity of 0.23%.

[0028] Example 4

[0029] Crude progesterone (30 g, containing by-product aldehyde impurities: 2.5%) and methylamine methanol solution (0.1 eq) were added with dichloromethane (100 ml) and stirred at ambient temperature for 1 hour; the mixture was cooled to 0-10 ° C, sodium triacetoxyborohydride (0.05 eq) was added, and the mixture was stirred for 1 hour at this temperature; the reaction solution was quenched with dilute hydrochloric acid (0.25 eq), stirred at ambient temperature for 1 hour, water (150 ml) was added to the mixture and concentrated in a 40 ° C water bath until there was almost no DCM, cooled to ambient temperature and stirred for 1 hour, filtered, and the filter layer was dried to obtain 29 g of progesterone, with a yield of 96.7%, HPLC purity of 99.63%, and by-product aldehyde impurities of 0.17%.

[0030] Example 5

[0031] Crude progesterone (30 g, containing by-product aldehyde impurities: 2.5%) and methylamine methanol solution (0.2 eq) were added with THF (100 ml) and stirred at ambient temperature for 1 hour; the mixture was cooled to 0-10°C, sodium triacetoxyborohydride (0.05 eq) was added, and the mixture was stirred at this temperature for 1 hour; the reaction solution was quenched with dilute hydrochloric acid (0.35 eq), stirred at ambient temperature for 1 hour, water (150 ml) was added to the mixture and concentrated in a 40°C water bath until there was almost no THF, cooled to ambient temperature and stirred for 1 hour, filtered, and the filter layer was dried to obtain 28.9 g of progesterone, with a yield of 96.4%, an HPLC purity of 99.82%, and a by-product aldehyde impurity of 0.12%.

[0032] Example 6

[0033] Crude progesterone (40 g, containing by-product aldehyde impurities: 2.5%) and dimethylamine ethanol solution (0.1 eq) were added with ethanol and stirred at ambient temperature for 1 hour; the mixture was cooled to 0-10°C, potassium borohydride (0.02 eq) was added, and the mixture was stirred for 1 hour at this temperature; the reaction solution was quenched with dilute hydrochloric acid (0.25 eq), the temperature was raised to ambient temperature, and water (150 ml) was added for crystallization; the mixture was stirred for 1 hour, filtered, and the filter layer was dried to obtain 38.0 g of progesterone with a yield of 95%, a purity of 99.52% by HPLC, and a by-product aldehyde impurity of 0.26%.

[0034] Comparative Example 1

[0035] Add enamine intermediate (20g), CuCl (0.2g), DMF (60ml) and DCM (200ml) to the reaction flask and cool it in a 5℃ cold bath. Control the internal temperature at 5-10℃, let air flow and react for 16 hours. TLC monitoring: enamine intermediate <1%, HPLC detection: by-product aldehyde impurities in the reaction solution are 1.49%. Add acetic acid (10ml) to quench the reaction solution, concentrate until almost no liquid drips out of the system, add water (100ml), a large amount of solid precipitates in the system, stir and crystallize. Filter, rinse the filter layer with water (20ml), and dry the filter layer in a vacuum oven at 50℃ for 16 hours to obtain 15.05g of light yellow solid crude product, with a yield of 94.7%. The crude product was recrystallized once with methanol (30 ml), crystallized at 5 ° C for 1 h, and filtered; methanol (30 ml) and activated carbon (0.6 g) were added to the filter layer for dissolution and decolorization, filtered while hot, and the filtrate was crystallized at 5 ° C for 1 h, filtered, and the filter layer was dried at 50 ° C for 16 hours to obtain progesterone as a white solid: 10.5 g, with a yield of 66.1%. The progesterone content in the finished product was 99.30%, and the by-product aldehyde impurity was 0.54%, which met the EU Pharmacopoeia standards.

Claims

1. A method for purifying high-purity progesterone, the reaction scheme of the method is as follows: Features: The crude progesterone is added to an organic solvent, an amine compound is added, the internal temperature is controlled and stirred to react for a certain period of time, and then a reducing agent is added, the temperature is controlled and stirred to react for a certain period of time, the reaction solution is quenched by adding acid, and the by-product aldehyde impurities are converted into amine impurities and then react with acid to form quaternary ammonium salts that are dissolved in an aqueous solution system and separated and removed; a high-purity progesterone solid is obtained through this purification method.

2. The method for purifying high-purity progesterone according to claim 1, characterized in that The reaction organic solvent is methanol, ethanol, tetrahydrofuran or dichloromethane.

3. The method for purifying high-purity progesterone according to claim 1, characterized in that The amine compound is ammonia, methylamine or dimethylamine.

4. The method for purifying high-purity progesterone according to claim 1, characterized in that The temperature range of the two temperature controls is -20 to 50°C.

5. The method for purifying high-purity progesterone according to claim 1, characterized in that The two reaction times are 0.1 to 36 hours.

6. The method for purifying high-purity progesterone according to claim 1, characterized in that The reducing agent is sodium borohydride, potassium borohydride or sodium triacetoxyborohydride.

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