Preparation method of pregnadiene ketone

Abstract

According to the preparation method, 13beta-ethyl-15alpha-hydroxystane-4-ene-3, 17-diketone is taken as a raw material, after acylation and ethynylation elimination, the pregnadiene ketone is obtained, the product yield reaches 80%, and the HPLC (high performance liquid chromatography) purity is greater than or equal to 99.7%; the steps of the preparation method are obviously shortened, the solvent can be recycled, and the pollution of wastewater is small; the method has the advantages of simplicity and convenience in operation, short production period, low labor intensity, high yield, low production cost, environment friendliness and the like, and is suitable for industrial production to improve economic benefits.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, in particular to a preparation method of gestodene. BACKGROUND

[0002] Gestodene is a kind of progestin of norgestrel, which can inhibit the secretion of gonadotropin and has similar inhibitory effect on ovulation as norgestrel. It can inhibit the growth of endometrium and make the cervical mucus thick, so as to achieve the effects of anti-sperm penetration and anti-implantation. The mechanism of the product as a short-acting compound oral contraceptive is as follows: 1. Inhibition of ovulation: estrogen inhibits the release of gonadotropin-releasing hormone (GnRH) in the hypothalamus through negative feedback mechanism, thereby reducing the secretion of follicle-stimulating hormone, and the growth and maturation of follicle is inhibited. Progestin also inhibits the release of luteinizing hormone in the pituitary through negative feedback mechanism, thereby hindering the maturation and ovulation of oocytes. 2. Change of endometrial morphology: due to the anti-estrogen effect of progestin, the endometrium becomes thin, the gland is reduced, and the secretion phenomenon of poor secretory function appears prematurely, which is not conducive to the implantation of fertilized eggs. 3. Change of physical and chemical properties of cervical mucus: under the influence of progestin, the secretion of cervical glands is inhibited, the amount of cervical mucus is small, thick and turbid, and the biochemical properties are changed, which is not conducive to sperm penetration. The molecular structural formula of gestodene, CAS: 60282-87-3, is as follows:

[0003] The patent route of gestodene includes: 1. US5719300A discloses a route for synthesizing gestodene. The route is constructed from A ring and the formation of 15, 16 double bond. At present, the biological synthesis of 15-hydroxyl compound has obvious advantages, and the synthetic route is as follows:

[0004] 2. EP1586579B1 reports another synthetic route. 13β-ethyl-sterane-4-en-3, 17-dione is used as the starting material, ethylene glycol, 1, 3 propylene glycol or 2, 2-dimethyl propylene glycol is used as the protecting group, triethyl orthoformate is used as the dehydrating agent, and p-toluenesulfonic acid is used as the catalyst to selectively protect the 3-keto group. The synthetic route is shown as follows:

[0005] 3. WO2011098439A2 discloses that 13β-ethyl-15α-acetyloxy-sterane-4-en-3, 17-dione is used as the starting material, ethanol is used as the protecting group, triethyl orthoformate is used as the dehydrating agent, and p-toluenesulfonic acid is used as the catalyst to selectively protect the 3-keto group. The synthetic route is shown as follows:

[0006] 4. Chinese patent document CN103319558B discloses that 13beta-ethyl-15alpha-hydroxy- androstane-4-ene-3, 17-dione is used as a starting material, and a 15, 16 double bond is synthesized by a chemical method. At present, a 15-hydroxyl compound is synthesized by a biological method, and the method has obvious advantages:

[0007] 5. German patent document DE2546062C3 Schering AG discloses that 13beta-ethyl-15alpha-hydroxy-androstane-4-ene-3, 17-dione is used as a starting material, and a 15, 16 double bond is synthesized by a chemical method. At present, a 15-hydroxyl compound is synthesized by a biological method, and the method has obvious advantages:

[0008] At present, in the synthesis route of the gestodene, selective protection of ketones at the 3rd and 17th positions is one of key reactions, but the selective protection weakens electrophilicity of the conjugated carbonyl group, thereby increasing difficulty of acetylation. Therefore, under the premise of ensuring yield, how to simplify the preparation route of the gestodene and reduce cost becomes a problem that needs to be concerned in industrialization. SUMMARY

[0009] The present application provides a preparation method of gestodene, which shortens process steps, reduces environmental pressure and labor intensity under the premise of ensuring product yield, and is more suitable for industrial application.

[0010] Therefore, the present application provides the following scheme: A preparation method of gestodene, steps comprising: S1. 13beta-ethyl-15alpha-hydroxy-androstane-4-ene-3, 17-dione is mixed with a solvent and an acid-binding agent, an acylation reagent is added, and the mixture is stirred and reacted under heat preservation, then the reaction solution is added to a dilute hydrochloric acid aqueous solution to precipitate, filtered, and dried to obtain 13beta-ethyl-15alpha-acetylandrostane-4-ene-3, 17-dione; S2. A strong base is dissolved in a tetrahydrofuran solution, nitrogen is replaced, acetylene gas is introduced, and the mixture is reacted under heat preservation at 40-50 DEG C, then the temperature is lowered to-30-10 DEG C, the tetrahydrofuran solution of 13beta-ethyl-15alpha-acetylandrostane-4-ene-3, 17-dione obtained in step S1 is slowly added dropwise to the reaction solution, and the mixture is reacted under heat preservation at-30-10 DEG C for 1.5-6 hours, then dilute hydrochloric acid is added dropwise to the reaction solution until the solution is acidic, the mixture is concentrated, and then filtered, and the obtained solid is purified to obtain gestodene.

[0011] The reaction route of the preparation method is as follows:

[0012] Further, in step S1, the aprotic polar solvent is dichloromethane and / or ethyl acetate; and / or, the acylation agent is acetic anhydride or acetyl chloride.

[0013] Further, in step S1, the ratio of 13β-ethyl-15α-hydroxysterane-4-ene-3,17-dione to the acid-binding agent is 1g:(0.01~5)g; and / or, the ratio of the acylation agent to 13β-ethyl-15α-hydroxysterane-4-ene-3,17-dione is (1~5)ml:1g.

[0014] Furthermore, in step S1, the reaction temperature is 15~25℃ and the reaction time is 2~72h.

[0015] Further, in step S1: the concentration of the dilute hydrochloric acid is 1~10wt%; and / or, the ratio of the amount of dilute hydrochloric acid to 13β-ethyl-15α-hydroxysterane-4-ene-3,17-dione is (35~50):1g.

[0016] Further, in step S2: the strong base is selected from at least one of potassium hydroxide, potassium tert-butoxide, and n-butyllithium; And / or, the concentration process is carried out at a temperature of 40~50℃.

[0017] Further, in step S2, the dilute hydrochloric acid is added dropwise until the pH value is 1-6; and / or the concentration of the dilute hydrochloric acid is 5-20 wt%.

[0018] Furthermore, in step S2, the purification process involves washing and drying the filtered solid with water and then recrystallizing it.

[0019] Preferably, the drying process temperature is 40–90°C; and / or, the solvent used for recrystallization is selected from at least one of acetone, ethyl acetate, anhydrous ethanol, and isopropanol. The recrystallization process involves first heating to a clear solution and then cooling to -10–10°C, stirring for more than 4 hours, filtering, and drying to obtain a pregnadienone product with a purity of more than 99.7%.

[0020] Compared with the prior art, the present invention has the following beneficial effects: The preparation method provided by this invention uses 13β-ethyl-15α-hydroxysterane-4-ene-3,17-dione as raw material, and obtains pregnadienone after acylation and acetylation elimination. The product yield exceeds 80%, and the HPLC purity is ≥99.7%. The preparation method has significantly shortened steps, and the solvent can be recycled and reused, resulting in less wastewater pollution. It has the advantages of simple operation, short production cycle, low labor intensity, high yield, low production cost, and environmental friendliness, and is suitable for industrial production to improve economic efficiency. Attached Figure Description

[0021] Figure 1 The HPLC detection results of the pregnadienone prepared in Example 1 of this invention are shown.

[0022] Figure 2 The HPLC detection results of the pregnadienone prepared in Example 2 of this invention are shown.

[0023] Figure 3 The above is the 1H NMR spectrum of the pregnadienone prepared in Example 1 of this invention. Detailed Implementation

[0024] The technical solution of the present invention will now be clearly and completely described in conjunction with preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0025] Example 1 1) Add 10g of 13β-ethyl-15α-hydroxysterane-4-ene-3,17-dione, 35mL of pyridine, and 20mL of acetic anhydride to the reaction flask. Incubate the reaction at 20℃ for 5 hours. Monitor the reaction by TLC. Once the reaction is complete, add the reaction solution dropwise to 300mL of 7% hydrochloric acid aqueous solution at 5℃. After stirring, let stand for 2 hours, filter, wash with water until neutral, dry under vacuum, and dry at 50℃ to obtain 11.11g of 13β-ethyl-15α-acetylsterane-4-ene-3,17-dione, with a molar yield of 97.5%. 2) Under nitrogen protection, add 150 mL of tetrahydrofuran, 20 g of n-butyllithium, and 2 drops of acetone. Heat to 45 °C, maintain the temperature and stir, and purge with acetylene gas until no more acetylene gas is absorbed. Cool to -5 °C. Dissolve 10 g of 13β-ethyl-15α-acetylsterane-4-ene-3,17-dione obtained in step 1) in 250 mL of tetrahydrofuran and add it dropwise to the reaction flask. The addition is completed in about 30 min. Then, maintain the temperature at -5 °C and react for 4 hours. Monitor the reaction by TLC until complete. Stop purging with acetylene gas and start adding 18% hydrochloric acid dropwise until the pH reaches 4. After the addition is complete, maintain the temperature at 0–10 °C and react for 1 h. Concentrate until almost no liquid evaporates, cool to crystallize, filter, wash the solid with plenty of water until neutral, dry under vacuum, and dry at 80 °C to obtain 8.57 g of crude pregnadienone. The molar yield of this step is 95.1%. 3) Take 10g of the crude pregnadienone obtained in step 2) and add it to a reaction flask. Add 30mL of isopropanol, heat to dissolve, slowly cool down, and when the temperature drops to 30℃, slowly add 10mL of water dropwise. Keep the temperature at 25℃ and stir for 3 hours. Filter and dry to obtain pregnadienone extract I. Add pregnadienone extract I to a reaction flask, add 100mL of acetone, heat to 55℃, filter while hot, concentrate to 70mL of acetone, cool to 10℃, keep the temperature and stir for 2 hours, filter and dry to obtain 9.01g of pregnadienone product. The overall molar yield is 83.54%, and the HPLC purity is 99.74%.Figure 1 It meets the pharmacopoeia standards.

[0026] Example 2 1) Add 10g of 13β-ethyl-15α-hydroxysterane-4-ene-3,17-dione, 10mL of triethylamine, and 30mL of acetic anhydride to a reaction flask. Incubate the reaction at 25℃ for 4.5 hours. Monitor the reaction by TLC until complete. Add the reaction solution dropwise to 300mL of 7% hydrochloric acid aqueous solution at 5℃. After stirring, let stand for 2 hours, filter, wash with water until neutral, dry under vacuum, and dry at 50℃ to obtain 11.18g of 13β-ethyl-15α-acetylsterane-4-ene-3,17-dione, with a molar yield of 98.2%. 2) Under nitrogen protection, add 150 mL of tetrahydrofuran, 20 g of n-butyllithium, and 2 drops of acetone. Heat to 45 °C, maintain the temperature and stir, and purge with acetylene gas until no more acetylene gas is absorbed. Cool to 0 °C. Dissolve 10 g of 13β-ethyl-15α-acetylsterane-4-ene-3,17-dione obtained in step 1) in 250 mL of tetrahydrofuran and add it dropwise to the reaction flask. The addition is completed in about 30 minutes. Then, maintain the temperature at 0 °C and react for 2 hours. Monitor the reaction by TLC until it is complete. Stop purging with acetylene gas and start adding 18% hydrochloric acid until the pH reaches 4. After the addition is complete, maintain the temperature at 5 °C and react for 1 hour. Concentrate until almost no liquid evaporates, cool to crystallize, filter, wash the solid with plenty of water until neutral, dry under vacuum, and dry at 80 °C to obtain 8.67 g of crude pregnadienone. The molar yield of this step is 96.2%. 3) Take 10g of the crude pregnathione obtained in step 2) and add it to a reaction flask. Add 30mL of isopropanol, heat to dissolve, slowly cool down, and when the temperature drops to 30℃, slowly add 10mL of water dropwise. Keep the temperature at 30℃ and stir for 3 hours. Filter and dry to obtain pregnathione ester I. Add pregnathione ester I to a reaction flask, add 100mL of acetone, heat to 58℃, filter while hot, concentrate to 75mL of acetone, cool to 15℃, keep the temperature and stir for 2 hours, filter and dry to obtain 9.05g of pregnathione product. The overall molar yield is 85.49%, and the HPLC purity is 99.77%. Figure 2 It meets the pharmacopoeia standards.

[0027] Example 3 1) Add 10g of 13β-ethyl-15α-hydroxysterane-4-ene-3,17-dione, 35mL of pyridine, and 30mL of acetyl chloride to a reaction flask. Incubate at 20℃ for 5.5 hours. Monitor the reaction by TLC until complete. Add the reaction solution dropwise to 400mL of 5% hydrochloric acid aqueous solution at 2℃. After stirring, let stand for 2 hours, filter, wash with water until neutral, dry under vacuum, and dry at 50℃ to obtain 11.12g of 13β-ethyl-15α-acetylsterane-4-ene-3,17-dione, with a molar yield of 97.7%. 2) Under nitrogen protection, add 150 mL of tetrahydrofuran, 30 g of potassium tert-butoxide, and 2 drops of acetone. Heat to 40 °C, maintain the temperature and stir, and purge with acetylene gas until no more acetylene gas is absorbed. Cool to 3 °C, dissolve 10 g of 13β-ethyl-15α-acetylsterane-4-ene-3,17-dione obtained in step 1) in 250 mL of tetrahydrofuran, and add it dropwise to the reaction flask. The addition is completed in about 30 min. Then, maintain the temperature at -8 °C and react for 6 hours. Monitor the reaction by TLC until complete. Stop purging with acetylene gas and start adding 18% hydrochloric acid until the pH reaches 5. After the addition is complete, maintain the temperature at 5 °C and react for 1 h. Concentrate until almost no liquid evaporates, cool to crystallize, filter, wash the solid with plenty of water until neutral, dry under vacuum, and dry at 85 °C to obtain 8.12 g of crude pregnadienone, with a molar yield of 90.2%. 3) Take 10g of the crude pregnadienone obtained in step 2) and add it to the reaction flask. Using the purification method of Example 1, 9.03g of pregnadienone product was obtained. The overall molar yield was 79.57%, and the HPLC purity was 99.68%, which met the pharmacopoeia standard.

[0028] Example 4

[0029] 1) The preparation of 13β-ethyl-15α-acetylsterane-4-ene-3,17-dione was the same as in Example 1; 2) Under nitrogen protection, add 150 mL of tetrahydrofuran, 30 g of potassium tert-butoxide, and 2 drops of acetone. Heat to 45 °C, maintain the temperature and stir, and introduce acetylene gas until no more acetylene gas is absorbed. Cool to 5 °C, dissolve 10 g of 13β-ethyl-15α-acetylsterane-4-ene-3,17-dione obtained in step 1) in 250 mL of tetrahydrofuran, and add it dropwise to the reaction flask. The addition is completed in about 30 min. Then, control the temperature at -10 °C and react for 6 hours. Monitor the reaction by TLC until it is complete. Stop the acetylene gas supply and start adding 15% hydrochloric acid dropwise until the pH is 5. After the addition is complete, control the temperature at 2 °C and react for 1 h. Concentrate until almost no liquid evaporates, cool to crystallize, filter, wash the solid with a large amount of water until neutral, dry under vacuum, and dry at 85 °C to obtain 8.05 g of crude pregnadienone, with a molar yield of 89.4%. 3) Take 10g of the crude pregnadienone obtained in step 2) and add it to the reaction flask. Using the purification method of Example 2, 9.02g of pregnadienone product was obtained. The overall molar yield was 78.62%, and the HPLC purity was 99.62%, which met the pharmacopoeia standard.

[0030] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing pregnadienone, characterized in that the steps include... include: S1.13β-ethyl-15α-hydroxysterane-4-ene-3,17-dione was mixed with a solvent and an acid-binding agent, and an acylation reagent was added. The mixture was stirred and kept at a constant temperature. The reaction solution was added to a dilute hydrochloric acid aqueous solution to precipitate the precipitate. The solution was filtered and dried to obtain 13β-ethyl-15α-acetylsterane-4-ene-3,17-dione. S2. Dissolve a strong base in tetrahydrofuran solution, replace with nitrogen, introduce alkyne gas, and maintain the reaction temperature at 40~50℃. Cool the temperature to -30~10℃, and slowly add a tetrahydrofuran solution of 13β-ethyl-15α-acetylsterane-4-ene-3,17-dione obtained in step S1 to the reaction solution. Maintain the reaction temperature at -30~10℃ for 1.5~6 hours. After the reaction is complete, add dilute hydrochloric acid dropwise to the reaction solution until it becomes acidic. Concentrate the solution and filter. The solid obtained by filtration is purified to obtain pregnadienone.

2. The preparation method according to claim 1, characterized in that, In step S1, the aprotic polar solvent is dichloromethane and / or ethyl acetate; and / or, the acylating agent is acetic anhydride or acetyl chloride.

3. The preparation method according to claim 1 or 2, characterized in that, In step S1, the ratio of 13β-ethyl-15α-hydroxysterane-4-ene-3,17-dione to the acid-binding agent is 1g: (0.01~5)g; And / or, the ratio of the acylating agent to 13β-ethyl-15α-hydroxysterane-4-ene-3,17-dione is (1~5) ml: 1 g.

4. The preparation method according to claim 1, characterized in that, In step S1, the reaction temperature is 15~25℃ and the reaction time is 2~72h.

5. The preparation method according to claim 1, characterized in that, In step S1: the concentration of the dilute hydrochloric acid is 1~10wt%; And / or, the ratio of the amount of dilute hydrochloric acid to 13β-ethyl-15α-hydroxysterane-4-ene-3,17-dione is (35~50):1g.

6. The preparation method according to claim 1, characterized in that, In step S2: the strong base is selected from at least one of potassium hydroxide, potassium tert-butoxide, and n-butyllithium; And / or, the concentration process is carried out at a temperature of 40~50℃.

7. The preparation method according to claim 1, characterized in that, In step S2, dilute hydrochloric acid is added dropwise until the pH value is 1-6; And / or, the concentration of the dilute hydrochloric acid is 5~20wt%.

8. The preparation method according to claim 1, characterized in that, In step S2, the purification process involves washing and drying the filtered solid with water and then recrystallizing it.

9. The preparation method according to claim 8, characterized in that, The drying process temperature is 40–90°C; And / or, the solvent used for the recrystallization is selected from at least one of acetone, ethyl acetate, anhydrous ethanol, and isopropanol.

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