Synthesis method of pregn-5-ene-3, 7, 20-triketone divinyl ketal

Abstract

The invention discloses a synthesis method of pregn-5-ene-3, 7, 20-triketone divinyl ketal, which comprises the following steps: dissolving a raw material pregn-5-ene-3, 20-diketone divinyl ketal as shown in a formula (I) in an organic solvent, adding a catalyst, stirring under the action of air or oxygen and under the irradiation of light with a certain wavelength to carry out oxidation reaction, and after the reaction is finished, separating and purifying to obtain the pregn-5-ene-3, 7, 20-triketone divinyl ketal as shown in the formula (I), thereby obtaining the pregn-5-ene-3, 7, 20-triketone divinyl ketal. The reaction formula is as follows: # imgabs0 #. According to the invention, light is used as a reaction energy source, and the method has the characteristics of mild reaction conditions, small catalyst dosage, low process cost, simplicity and convenience in operation and the like.

Description

Technical Field

[0001] The invention relates to a method for synthesizing pregnen-5-ene-3,7,20-trione divinyl ketal. Background Art

[0002] Dydrogesterone is a synthetic progestogen, mainly used to treat diseases caused by endogenous progesterone deficiency, such as dysmenorrhea, endometriosis, secondary amenorrhea, habitual abortion, infertility, etc. Pregnant-5-ene-3,7,20-trione divinyl ketal is a key intermediate for the synthesis of dydrogesterone. The existing methods for synthesizing pregnant-5-ene-3,7,20-trione divinyl ketal mainly include the following two methods: 1. Through N-hydroxyphthalimide / initiator / air oxidation (CN202410644170.7); 2. Through transition metal / peroxide oxidation system to achieve 7-position oxidation (CN201180045623.5). The above strategies all require the addition of metals, free radical initiation catalysts, peroxides, etc., which not only have high process costs, but also have certain safety risks. Summary of the invention

[0003] In view of the problems existing in the existing oxidation technology, the present invention aims to provide a green, efficient and clean method for synthesizing pregn-5-ene-3,7,20-trione divinyl ketal. The CAS number of pregn-5-ene-3,7,20-trione divinyl ketal is 71379-22-1.

[0004] The technical solution adopted by the present invention is as follows:

[0005] A method for synthesizing pregn-5-ene-3,7,20-trione divinyl ketal comprises dissolving a raw material of pregn-5-ene-3,20-dione divinyl ketal shown in formula (I) in an organic solvent, stirring and performing an oxidation reaction under the action of air or oxygen and irradiation of light of a certain wavelength, and after the reaction is completed, the reaction liquid is post-treated to obtain a target product shown in formula (II); the reaction equation is as follows:

[0006]

[0007] Furthermore, the reaction temperature under light irradiation is room temperature, and the reaction time is 2 to 10 hours, preferably 2 to 6 hours.

[0008] Furthermore, the catalyst is one of the following: lithium bromide, sodium bromide, potassium bromide, tetrabutylammonium bromide, and the molar ratio of the catalyst to the raw material is 0.05 to 0.2:1, preferably 0.1 to 0.2:1.

[0009] Further, the organic solvent is one of the following: 1,2-dichloroethane, 1,2-dibromoethane, acetone, and acetonitrile. The volume of the organic solvent used is 10 - 25 mL / mmol based on the molar amount of the raw material pregn-5-ene-3,20-dione divinyl ketal.

[0010] Further, the wavelength of the light source is 380 - 430 nm, preferably 390 - 415 nm, and the light irradiation power is 40 - 100 W.

[0011] Further, when the organic solvent is 1,2-dichloroethane or 1,2-dibromoethane, the post-treatment steps are as follows: directly add water to the reaction solution, wash, extract, and separate layers. After the organic layer is dried over anhydrous sodium sulfate, add acetic anhydride and triethylamine to the organic layer, let it stand at 0 °C for 10 - 15 h, then concentrate under reduced pressure to recover the solvent, and recrystallize the concentrated residue with an organic solvent to obtain the product.

[0012] When the organic solvent is acetonitrile or acetone, the post-treatment steps are as follows: add water and dichloromethane to the reaction solution, extract and separate layers. After the dichloromethane layer is dried over anhydrous sodium sulfate, add acetic anhydride and triethylamine to the organic layer, let it stand at 0 °C for 10 - 15 h, then concentrate under reduced pressure to recover the solvent, and recrystallize the concentrated residue with an organic solvent to obtain the product.

[0013] Further, for the acetic anhydride and triethylamine added during the post-treatment process, the molar ratio of acetic anhydride to the raw material pregn-5-ene-3,20-dione divinyl ketal is 2 - 3:1, and the molar ratio of triethylamine to the raw material pregn-5-ene-3,20-dione divinyl ketal is 4 - 6:1.

[0014] Further, the recrystallization organic solvent is one of the following: methanol, ethanol, and isopropanol.

[0015] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0016] 1) The present invention uses light energy as the energy source, the reaction conditions are mild, the amount of catalyst used is small and inexpensive, and the oxidation process cost is low. The method of the present invention does not require the participation of reagents such as transition metals and peroxides, the process is clean, and the atom economy is high.

[0017] 2) Lithium bromide, sodium bromide, potassium bromide, tetrabutylammonium bromide, etc. are introduced as catalysts in the reaction of the present invention, which can significantly improve the reaction rate and product yield.

[0018] 3) The post-treatment method of the present invention is simple and low-cost. The selection of the recrystallization solvent during the post-treatment process can also greatly improve the product yield.

[0019] 4) The method of the present invention is easy to operate, the product is easy to separate, and it is easy to industrialize. Detailed implementation mode

[0020] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0021] Example 1

[0022] Pregnant-5-ene-3,20-dione divinyl ketal (0.2mmol) and LiBr (0.02mmol) were added to a 10mL reaction bottle, acetone (5.0mL) was added to dissolve, 415nm wavelength light was irradiated (light power 40W), and air was continuously introduced into the above reaction solution. After stirring and reacting for 4h, water and dichloromethane were added to the reaction solution, and the layers were extracted. After the organic layer was dried with anhydrous sodium sulfate, acetic anhydride (0.4mmol) and triethylamine (0.8mmol) were added. The reaction solution was allowed to stand at 0℃ for 12, and the solvent was removed by vacuum distillation and concentration to obtain a yellow oil. The yellow oil was recrystallized from methanol to obtain the product, pregnant-5-ene-3,7,20-trione divinyl ketal, with a yield of 80%.

[0023] Characteristic data: White solid. 1 H NMR (400 MHz, CDCl 3 )δ5.71-5.65(m,1H),4.05–3.85(m,8H),2.72-2.65(m,1H),2.50-2.43(m,1H),2.38-2.32(m,1H),2.20–2.00(m,1H) ,1.94–1.85(m,2H),1.84–1.72(m,4H),1.72–1.33(m,7H),1.31(s,3H),1.22(s,3H),1.20–1.14(m,1H),0.80(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ201.7,164.6,126.6,112.0,108.9,64.9,64.6,64.5,63.3,56.8,50.0,49.6 ,45.0,42.6,41.7,38.4,38.3,35.6,31.1,25.9,24.6,23.5,21.0,17.0,13.0.

[0024] Example 2

[0025] Pregnant-5-ene-3,20-dione divinyl ketal (0.5mmol) and tetrabutylammonium bromide (0.025mmol) were added to a 10mL reaction bottle, 1,2-dibromoethane (5.0mL) was added to dissolve, 400nm wavelength light was irradiated (light power 100W), and air was continuously introduced into the above reaction solution. After stirring and reacting for 2h, water was added to the reaction solution, and the layers were extracted. After the organic layer was dried with anhydrous sodium sulfate, acetic anhydride (1.5mmol) and triethylamine (3mmol) were added. The reaction solution was allowed to stand at 0℃ for 12, and the solvent was removed by vacuum distillation and concentration to obtain a yellow oil. The yellow oil was recrystallized from ethanol to obtain the product, pregnant-5-ene-3,7,20-trione divinyl ketal, with a yield of 70%.

[0026] Example 3

[0027] The catalyst in the system was replaced with an equal molar amount of NaBr, and other operations were the same as in Example 1. The yield of the target product was 68%.

[0028] Example 4

[0029] The illumination reaction time in the system was extended to 6 h, and other operations were the same as in Example 1. The yield of the target product was 88%.

[0030] Example 5

[0031] The light source in the system was replaced with 390 nm (power 100 W), and other operations were the same as in Example 1. The yield of the target product was 85%.

[0032] Example 6

[0033] The amount of catalyst in the system was adjusted to 0, and other operations were the same as in Example 1. The yield of the target product was 32%.

[0034] Example 7

[0035] The recrystallization solvent in the system was replaced with isopropanol, and other operations were the same as in Example 1. The yield of the target product was 68%.

[0036] Example 8

[0037] When the amount of LiBr was adjusted to 0.04 mmol and the molar ratio of the catalyst to the raw material in the system was adjusted to 0.2:1, the other operations were the same as in Example 1, and the yield of the target product was 90%.

[0038] Example 9

[0039] The catalyst in the system was replaced with an equal molar amount of KBr, and other operations were the same as in Example 1. The yield of the target product was 79%.

[0040] Example 10

[0041] The catalyst in the system was replaced with an equal molar amount of tetrabutylammonium bromide, and other operations were the same as in Example 1. The yield of the target product was 72%.

[0042] Comparative Example 1

[0043] The catalyst in the system was replaced with an equal molar amount of LiCl, and other operations were the same as in Example 1. The yield of the target product was 41%.

[0044] Comparative Example 2

[0045] The catalyst in the system was replaced with an equal molar amount of LiI, and other operations were the same as in Example 1. The yield of the target product was 35%.

[0046] The contents described in this specification are merely an enumeration of implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as being limited to the specific forms described in the embodiments.

Claims

1. A method for synthesizing pregnen-5-ene-3,7,20-trione divinyl ketal, characterized in that The raw material of formula (I) is dissolved in an organic solvent, and an oxidation reaction is carried out by stirring under the action of air or oxygen and irradiation with light of a certain wavelength. After the reaction is completed, the reaction solution is post-treated to obtain the target product shown in formula (II); the reaction equation is as follows:

2. The method for synthesizing pregnen-5-ene-3,7,20-trione divinyl ketal according to claim 1, characterized in that The reaction temperature under light irradiation is room temperature, and the reaction time is 2 to 10 hours, preferably 2 to 6 hours.

3. The method for synthesizing pregnen-5-ene-3,7,20-trione divinyl ketal according to claim 1, characterized in that The catalyst is one of the following: lithium bromide, sodium bromide, potassium bromide, tetrabutylammonium bromide, and the molar ratio of the catalyst to the raw material is 0.05 to 0.2:1, preferably 0.1 to 0.2:

1.

4. The method for synthesizing pregn-5-ene-3,7,20-trione divinyl ketal according to claim 1, characterized in that The organic solvent is one of the following: 1,2-dichloroethane, 1,2-dibromoethane, acetone, acetonitrile, and the volume dosage of the organic solvent is 10-25 mL / mmol based on the molar dosage of the raw material pregn-5-ene-3,20-dione divinyl ketal.

5. The method for synthesizing pregnen-5-ene-3,7,20-trione divinyl ketal according to claim 1, characterized in that The wavelength of the light source is 380-430nm, preferably 390-415nm, and the illumination power is 40-100W.

6. The method for synthesizing pregn-5-ene-3,7,20-trione divinyl ketal according to claim 4, characterized in that When the organic solvent is 1,2-dichloroethane or 1,2-dibromoethane, the post-treatment step is: directly adding water to the reaction solution, washing the extraction layer with water, drying the organic layer with anhydrous sodium sulfate, adding acetic anhydride and triethylamine to the organic layer, standing at 0°C for 10-15h, and then recovering the solvent by vacuum concentration, and recrystallizing the concentrated residue with an organic solvent to obtain the product; When the organic solvent is acetonitrile or acetone, the post-treatment step is: adding water and dichloromethane to the reaction solution, extracting and stratifying, drying the dichloromethane layer over anhydrous sodium sulfate, adding acetic anhydride and triethylamine to the organic layer, standing at 0°C for 10-15h, and then recovering the solvent by concentrating under reduced pressure, and recrystallizing the concentrated residue with an organic solvent to obtain the product.

7. The method for synthesizing pregn-5-ene-3,7,20-trione divinyl ketal according to claim 6, characterized in that The acetic anhydride and triethylamine added in the post-treatment process have a molar ratio of acetic anhydride to the raw material 5-pregnane-3,20-dione divinyl ketal of 2 to 3:1, and a molar ratio of triethylamine to the raw material 5-pregnane-3,20-dione divinyl ketal of 4 to 6:

1.

8. The method for synthesizing pregn-5-ene-3,7,20-trione divinyl ketal according to claim 7, characterized in that The recrystallization organic solvent is one of the following: methanol, ethanol, isopropanol.

Images