CN113105517A - Synthesis method of androstane-1, 4, 9-triene-3, 17-diketone - Google Patents
Synthesis method of androstane-1, 4, 9-triene-3, 17-diketone Download PDFInfo
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- CN113105517A CN113105517A CN202110391988.9A CN202110391988A CN113105517A CN 113105517 A CN113105517 A CN 113105517A CN 202110391988 A CN202110391988 A CN 202110391988A CN 113105517 A CN113105517 A CN 113105517A
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- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
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Abstract
The invention discloses a method for synthesizing androstane-1, 4, 9-triene-3, 17-diketone, (1) dispersing androstane-4, 9-triene-3, 17-diketone, alkali and a phenyl selenizing reagent which are raw materials shown in a formula (I) in an organic solvent, and carrying out phenyl selenizing reaction in a tubular reactor; (2) carrying out gas-liquid mixing on the obtained phenyl selenization reaction raw material liquid, a photocatalyst dissolved in an organic solvent and oxygen in a mixer, and carrying out a selenization reaction in a tubular reactor containing blue lamp illumination equipment; (3) the material liquid after being desalinized is post-processed to prepare androstane-1, 4, 9-triene-3, 17-diketone (III), and the reaction formula is as follows:
Description
Technical Field
The invention belongs to the technical field of chemical drug synthesis, and particularly relates to a method for synthesizing androstane-1, 4, 9-triene-3, 17-diketone.
Background
Androstane-1, 4, 9-triene-3, 17-diketone is an important intermediate for synthesizing steroid hormone drugs betamethasone and dexamethasone. Clinically, betamethasone or dexamethasone is mainly applied to the treatment of diseases such as anti-inflammation, anti-allergy, eczema, disseminated dermatitis and the like. Androsta-1, 4, 9-triene-3, 17-dione is prepared from androsta-4, 9-triene-3, 17-dione by dehydrogenation of the steroid ring at the 1, 2-position.
The existing preparation method is mainly realized by biological conversion, for example, the invention application with the Chinese patent application number of 201710437594.6 discloses a method for preparing a target compound, and the dehydrogenation reaction of the 1 and 2 sites of the steroid ring is realized by inoculating Nocardia strains into a culture medium and adopting a microbial fermentation method. However, the biological method has problems that the fermentation solution is difficult to handle, the content of active ingredients is low, and the production efficiency is low. Therefore, the development of a method for synthesizing androstane-1, 4, 9-triene-3, 17-dione, which is efficient, environment-friendly and easy to industrialize, is urgently needed.
Disclosure of Invention
The invention aims to provide a preparation method of androstane-1, 4, 9-triene-3, 17-dione, which is simple to operate, environment-friendly, low in production cost and suitable for industrialization, and solves the problems of difficult treatment of fermentation liquid, low content of effective components, low production efficiency and the like in a biological method.
In order to achieve the above object, the present invention provides a method for synthesizing androstane-1, 4, 9-triene-3, 17-dione, comprising the following steps: (1) dispersing androstane-4, 9-triene-3, 17-diketone, alkali and a phenyl selenizing reagent which are raw materials shown in the formula (I) in an organic solvent, and carrying out phenyl selenizing reaction in a tubular reactor; (2) carrying out gas-liquid mixing on the obtained phenyl selenization reaction raw material liquid, a photocatalyst dissolved in an organic solvent and oxygen in a mixer, and carrying out a selenization reaction in a tubular reactor containing blue lamp illumination equipment; (3) the material liquid after being desalinized is post-processed to prepare androstane-1, 4, 9-triene-3, 17-diketone (III), and the reaction formula is as follows:
further, dissolving the raw materials androstane-4, 9-triene-3, 17-dione (I) and alkali in an organic solvent S1, placing the mixture into a storage bottle A, dissolving phenyl selenium chloride in an organic solvent S2, placing the phenyl selenium chloride in a storage bottle B, conveying the solutions in the storage bottles A and B into a first mixer T1 through metering pumps P1 and P2 respectively, mixing, and continuously feeding the mixed solution into a tubular reactor R1 for a phenyl selenization reaction; and dissolving a photocatalyst in an organic solvent S3, placing the solution into a storage bottle C, conveying the solution into a second mixer T2 through a metering pump P3, mixing the solution with the reaction solution subjected to benzene selenylation and oxygen conveyed through a pump P4, continuously feeding the mixture into a tubular reactor R2 with illumination equipment for a selenium removal reaction, and carrying out post-treatment on the mixed solution after the reaction to obtain the androstane-1, 4, 9-triene-3, 17-dione (III).
Further, the organic solvents S1, S2, and S3 are respectively one of ethyl acetate, methyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, and dichloromethane.
Further, the alkali is lithium diisopropylamide or butyl lithium, and the reaction temperature of the benzene selenylation is-50-25 ℃.
Further, the retention time of the benzene selenylation reaction is 15mins-2 h.
Further, the mass ratio of the androstane-4, 9-triene-3, 17-dione (I) to the phenyl selenium chloride is 1: 1-5.
Further, the structure of the photocatalyst is as shown in the following formula (1-12) arbitrary one of twelve; the mass ratio of the photocatalyst to the androstane-4, 9-triene-3, 17-dione (I) is 0.01-0.1: 1,
further, the retention time of the selenium removal reaction is 15mins-3h, and the temperature is 0-60 ℃.
Further, the post-processing step is: adding water for quenching, extracting by using an organic solvent, carrying out reduced pressure distillation to recover the organic solvent, and recrystallizing the obtained concentrate to obtain a yellowish crystal, namely the product androstane-1, 4, 9-triene-3, 17-diketone (III).
The invention has the beneficial effects that:
(1) the androstane-1, 4, 9-triene-3, 17-diketone is prepared by using a continuous tubular reaction technology, so that the automatic control of the process is easy to realize, the continuous production is convenient, and the stability of the process is improved; (2) through the tubular multi-step series reaction mode, the intermediate separation step is omitted, the process flow is simplified, and the reaction yield is improved; (3) the method combining visible light and tubular reaction technology is adopted to realize the selenium removal reaction, the conditions are mild, and the process is green and clean. (4) Good reaction selectivity, easy product separation, high yield and easy industrialization. Therefore, the method for preparing the androstane-1, 4, 9-triene-3, 17-diketone by adopting the tubular reaction method is essentially different from the traditional kettle type fermentation method, and the continuous flow tubular technology adopted by the invention has better reaction effect; (5) the invention adopts a tubular reaction series connection mode similar to plug flow, has high mass and heat transfer efficiency, no separation of intermediates and simple and convenient operation, and simultaneously has the advantages of high product yield and purity, less three wastes, easy industrialization and the like.
Drawings
FIG. 1 is a process flow diagram of one embodiment of the present invention.
In the figure: a-storage bottle A, B-storage bottle B, C-storage bottle C, P1-first metering pump, P2-second metering pump, P3-third metering pump, P4-gas metering pump, T1-first mixer, T2-second mixer, R1-tubular reactor 1, R2-tubular reactor R2 and D-receiving bottle.
Detailed Description
The present invention will now be described in detail with reference to the accompanying drawings.
Example 1
As shown in FIG. 1, androsta-4, 9-diene-3, 17-dione (I) (10mmol,2.84g), phenylselenium chloride (15mmol,2.87g) were dissolved in 50mL of ethyl acetate and placed in flask A; LDA (2mol/L, tetrahydrofuran solution) (7.5mL) was made into 50mL ethyl acetate solution and placed in reservoir B. The materials in the storage bottle A and the storage bottle B are respectively conveyed by a metering pump and enter a mixer for mixing, the mixed raw material liquid continuously enters a tubular reactor R1 for phenyl selenization reaction (the inner diameter of the pipeline is 0.2cm, the length of the pipeline is 3m, the feeding molar flow ratio of androstane-4, 9-diene-3, 17-diketone I to LDA is controlled to be 1:1.5), the temperature of the tubular reactor R1 is kept at 25 ℃, and the retention time is 30 mins. The reacted feed liquid enters a mixer T2, is mixed with photocatalyst 1 solution (0.1mmol is dissolved in 0.5mL dichloromethane, the flow rate ratio of the mixed liquid to the phenyl selenization reaction liquid is 1:100) and oxygen gas through a pump to carry out gas-liquid mixing, then the mixed liquid enters a tubular reactor R2 containing blue light equipment to carry out the selenization reaction (the inner diameter of a pipeline is 0.2cm, the length of the pipeline is 2.5m), the temperature of the tubular reactor R2 is kept at 25 ℃, and the retention time is 1 h. And (3) feeding the reacted feed liquid into a receiving bottle C, adding distilled water to quench and react after the feed liquid in the receiving bottle is received, extracting by using dichloromethane, directly distilling and concentrating an organic layer, and recrystallizing the residual oily concentrate by using a mixed solvent of methanol and water to obtain 2.45g of yellowish crystals, wherein the yield is 87%, and the content is 99%.
Example 2
As shown in FIG. 1, androsta-4, 9-diene-3, 17-dione (I) (10mmol,2.84g), phenylselenium chloride (12mmol,2.30g) were dissolved in 50mL of ethyl acetate and placed in a storage bottle A; LDA (2.0mol/L, tetrahydrofuran solution) (6.0mL) was made into 50mL ethyl acetate solution and placed in reservoir B. The materials in the storage bottle A and the storage bottle B are respectively conveyed by a metering pump and enter a mixer for mixing, the mixed raw material liquid continuously enters a tubular reactor R1 for phenyl selenization reaction (the inner diameter of the pipeline is 0.2cm, the length of the pipeline is 5m, the feeding molar flow ratio of androstane-4, 9-diene-3, 17-diketone I to LDA is controlled to be 1:1.2), the temperature of the tubular reactor R1 is kept at 0 ℃, and the retention time is 45 mins. The reacted feed liquid enters a mixer T2, is mixed with photocatalyst 1 solution (0.2mmol is dissolved in 1.0mL of dichloromethane and the flow rate ratio of the solution to the phenyl selenization reaction liquid is 1:50) and oxygen gas through a pump to carry out gas-liquid mixing, then the mixed liquid enters a tubular reactor R2 containing blue light equipment to carry out the selenization reaction (the inner diameter of a pipeline is 0.2cm, the length of the pipeline is 2m), the temperature of the tubular reactor R2 is kept at 40 ℃, and the retention time is 30 mins. And (3) feeding the reacted feed liquid into a receiving bottle C, adding distilled water to quench and react after the feed liquid in the receiving bottle is received, extracting by using ethyl acetate, directly distilling and concentrating an organic layer, and recrystallizing the residual oily concentrate by using a mixed solvent of ethanol and water to obtain 2.20g of yellowish crystals with the yield of 78% and the content of 99%.
Example 3
As shown in FIG. 1, androsta-4, 9-diene-3, 17-dione (I) (50mmol,14.2g), phenylselenium chloride (100mmol,19.2g) were dissolved in 200mL of ethyl acetate and placed in a storage bottle A; LDA (2.0mol/L, tetrahydrofuran solution) (37.5mL) was made up into 200mL ethyl acetate solution and placed in reservoir B. The materials in the storage bottle A and the storage bottle B are respectively conveyed by a metering pump and enter a mixer for mixing, the mixed raw material liquid continuously enters a tubular reactor R1 for phenyl selenization reaction (the inner diameter of the pipeline is 0.1cm, the length of the pipeline is 5m, the feeding molar flow ratio of androstane-4, 9-diene-3, 17-diketone I and LDA is controlled to be 1:1.5), the temperature of the tubular reactor R1 is kept at-25 ℃, and the retention time is 1.5 h. The reacted feed liquid enters a mixer T2, is mixed with photocatalyst 3 solution (1mmol is dissolved in 4mL of 2-methyltetrahydrofuran and the flow rate ratio of the reacted feed liquid to the phenyl selenization reaction liquid is 1:50) and oxygen gas through a pump to carry out gas-liquid mixing, then the mixed liquid enters a tubular reactor R2 containing blue light equipment to carry out the selenization reaction (the inner diameter of a pipeline is 0.1cm, the length of the pipeline is 5m, the feeding molar flow ratio of androstane-4, 9-diene-3, 17-diketone I to the photocatalyst 3 is controlled to be 1:0.02), the temperature of the tubular reactor R2 is kept at 50 ℃, and the retention time is 30 mins. And (3) feeding the reacted feed liquid into a receiving bottle C, adding distilled water to quench and react after the feed liquid in the receiving bottle is received, extracting by using ethyl acetate, directly distilling and concentrating an organic layer, and recrystallizing the residual oily concentrate by using a mixed solvent of petroleum ether and ethyl acetate to obtain yellowish crystals 11.3g, wherein the yield is 80%, and the content is 99%.
Example 4
Following the procedure and procedure of example 1, except using methyl acetate as the phenyl selenization reaction solvent, yellowish crystals were obtained in the amount of 2.14g, yield 76%, content 98%.
Example 5
Following the procedure and procedure of example 1, except adjusting the base of the phenyl selenization reaction to butyl lithium, yellowish crystals of 1.44g were obtained in 51% yield with a content of 97%.
Example 6
Following the procedure and procedure of example 1, except using catalyst 12 as the photocatalyst, 2.57g of yellowish crystals were obtained in a yield of 91% and a content of 99%.
Example 7
Following the procedure of example 1, except for adjusting the mass ratio of androsta-4, 9-diene-3, 17-dione (I) to phenylselenium chloride to 1:3, yellowish crystals of 2.40g were obtained in a yield of 85% and a content of 99%.
Example 8
Following the procedure of example 1, except adjusting the oxygen in the de-selenation reaction to air, 2.0g of yellowish crystals were obtained in 71% yield and 98% content.
Example 9
Following the procedure and procedure of example 1, except that the oxygen in the selenium removal reaction was adjusted to nitrogen, the desired product could not be obtained.
The nuclear magnetic data of the final product obtained in each of the above examples are as follows:
1HNMR(CDCl3400MHz) delta 0.88(s,3H),0.92-2.61(m,15H),5.56(m,1H),6.05(s,1H),6.26(m,1H),7.16(d, 1H). This data is consistent with androsta-1, 4, 9-triene-3, 17-dione.
Comparative example
Chinese patent CN104328159A discloses a method for preparing androstane-1, 4, 9-triene-3, 17-dione by using 19 alpha-OH-4 AD as an initial raw material and through elimination and biological fermentation. The 1, 2-position dehydrogenation of the steroid ring can be realized by inoculating Nocardia strains, but the biological fermentation needs to be subjected to the steps of inoculation, seed transfer and the like, the fermentation period is long, and generally needs about one week of time.
The method has high reaction efficiency, can completely react in 2-3 hours generally, and greatly shortens the production period.
In light of the foregoing description of the preferred embodiment of the present invention, many modifications and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.
Claims (9)
1. The method for synthesizing androstane-1, 4, 9-triene-3, 17-diketone is characterized by comprising the following steps: (1) dispersing androstane-4, 9-triene-3, 17-diketone, alkali and a phenyl selenizing reagent which are raw materials shown in the formula (I) in an organic solvent, and carrying out phenyl selenizing reaction in a tubular reactor; (2) carrying out gas-liquid mixing on the obtained phenyl selenization reaction raw material liquid, a photocatalyst dissolved in an organic solvent and oxygen in a mixer, and carrying out a selenization reaction in a tubular reactor containing blue lamp illumination equipment; (3) the material liquid after being desalinized is post-processed to prepare androstane-1, 4, 9-triene-3, 17-diketone (III), and the reaction formula is as follows:
2. the method for synthesizing androsta-1, 4, 9-triene-3, 17-dione as claimed in claim 1, characterized in that the starting materials androsta-4, 9-triene-3, 17-dione (I) and alkali are dissolved in organic solvent S1 and placed in a storage bottle a, phenylselenium chloride is dissolved in organic solvent S2 and placed in a storage bottle B, the solutions in the storage bottles a and B are respectively fed into a first mixer T1 through metering pumps P1 and P2 for mixing, and the mixed solution is continuously fed into a tubular reactor R1 for phenyl selenization; and dissolving a photocatalyst in an organic solvent S3, placing the solution into a storage bottle C, conveying the solution into a second mixer T2 through a metering pump P3, mixing the solution with the reaction solution subjected to benzene selenylation and oxygen conveyed through a pump P4, continuously feeding the mixture into a tubular reactor R2 with illumination equipment for a selenium removal reaction, and carrying out post-treatment on the mixed solution after the reaction to obtain the androstane-1, 4, 9-triene-3, 17-dione (III).
3. The method of claim 2, wherein the organic solvents S1, S2 and S3 are selected from ethyl acetate, methyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran and dichloromethane.
4. The method of synthesizing androsta-1, 4, 9-triene-3, 17-dione of claim 2 wherein the base is lithium diisopropylamide or butyllithium and the temperature of the phenylselenization reaction is-50 ℃ to 25 ℃.
5. The method of synthesizing androsta-1, 4, 9-triene-3, 17-dione of claim 2 wherein the benzoselenylation reaction has a retention time of 15mins "2 h.
6. The method for synthesizing androsta-1, 4, 9-triene-3, 17-dione as claimed in claim 2 wherein the mass ratio of androsta-4, 9-triene-3, 17-dione (I) to phenylselenium chloride is 1: 1-5.
7. The method for synthesizing androsta-1, 4, 9-triene-3, 17-dione as claimed in claim 2, wherein the structure of the photocatalyst is any one of twelve compounds selected from the following formulae (1-12); the mass ratio of the photocatalyst to the androstane-4, 9-triene-3, 17-dione (I) is 0.01-0.1: 1,
8. the method of synthesizing androsta-1, 4, 9-triene-3, 17-dione as in claim 2 wherein the selenium removal reaction has a retention time of 15mins "3 h and a temperature of 0 ℃ to 60 ℃.
9. The method of synthesizing androsta-1, 4, 9-triene-3, 17-dione of claim 2 wherein the post-treatment step is: adding water for quenching, extracting by using an organic solvent, carrying out reduced pressure distillation to recover the organic solvent, and recrystallizing the obtained concentrate to obtain a yellowish crystal, namely the product androstane-1, 4, 9-triene-3, 17-diketone (III).
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