CN110684069B - Preparation method of pregn-4-ene-17 alpha-alcohol-3, 11, 20-trione - Google Patents
Preparation method of pregn-4-ene-17 alpha-alcohol-3, 11, 20-trione Download PDFInfo
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- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
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Abstract
The invention relates to a preparation method of pregn-4-ene-17 α -ol-3, 11, 20-trione, which comprises the following steps of taking a compound I as a raw material, adding a bromination reagent, carrying out a reaction of 9, 11-bromine hydroxyl to obtain a compound II, and mixing the compound II with an oxidant for carrying outOxidizing 11-hydroxy in a compound II to form a ketone group through an oxidation reaction to obtain a compound III, and carrying out reduction dehalogenation reaction on the compound III to obtain pregn-4-ene-17 α -ol-3, 11, 20-trione, wherein the structural formulas of the compound I, the compound II and the compound III are as follows:
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a preparation method of pregna-4-ene-17 alpha-alcohol-3, 11, 20-trione.
Background
Methylprednisolone is a middle-acting glucocorticoid, has similar action to prednisolone, has anti-inflammatory action 3 times that of prednisolone, glucose metabolism 10 times stronger than that of hydrocortisone, and has weak water and sodium retention action and no potassium discharge side effect. Methylprednisolone has strong pharmacological actions of resisting inflammation, immunosuppression, antianaphylaxis, antishock and the like, and is widely applied to respiratory diseases, endocrine disorders, rheumatic diseases, collagenous diseases, blood diseases, skin diseases, nervous system diseases and the like in clinic. Compared with prednisone, the prednisone has the characteristics of quick response, strong anti-inflammatory effect, short half-life period, weak influence on adrenal cortex function and the like. Has good curative effect, is a new substitute product of prednisone, and represents the clinical medication direction of glucocorticoid.
The methylprednisolone medicine is a technically intensive product due to the complex production process and the long production period. The major manufacturer is Puqiang, USA. Pregnenolone acetate is used as an initial raw material by Puqiang company, pregn-4-ene-17 alpha-alcohol-3, 11, 20-trione is obtained through epoxidation, Wolff reaction, mold oxidation, Prader oxidation reaction, bromine addition and debromination, and then iodine replacement, reductive dehydrogenation, methylation and hydrolysis are carried out to obtain methylprednisolone. The process can synthesize pregna-4-ene-17 alpha-alcohol-3, 11, 20-trione by five steps of chemical reaction and one step of mould fermentation, and has the advantages of long synthesis route, difficult control of reaction process technology, low yield and high cost.
Therefore, there is a need for an improved method for the industrial production of pregn-4-en-17 α -ol-3, 11, 20-trione.
Disclosure of Invention
Based on the above, a preparation method of pregna-4-ene-17 alpha-ol-3, 11, 20-trione, which has a short synthetic route and a high conversion rate and is suitable for industrial production, is needed.
A preparation method of pregn-4-ene-17 alpha-alcohol-3, 11, 20-trione comprises the following steps:
taking a compound I as a raw material, adding a brominating reagent, and carrying out a 9-position and 11-position hydroxyl bromide reaction to obtain a compound II;
carrying out oxidation reaction on the compound II, and oxidizing the 11-position hydroxyl in the compound II into a ketone group to obtain a compound III;
carrying out reduction dehalogenation reaction on the compound III to obtain pregn-4-ene-17 alpha-alcohol-3, 11, 20-trione;
the structural formulas of the compound I, the compound II and the compound III are as follows:
the reaction of the 9-and 11-bromo hydroxyl groups refers to a reaction of the 9-bromo group and the 11-hydroxy group, that is, a bromination reaction is carried out by adding a bromination reagent to the compound I as a raw material, so that the 9-bromo group and the 11-hydroxy group are simultaneously present.
The method takes the compound I as a raw material, and the pregna-4-ene-17 alpha-alcohol-3, 11, 20-trione can be prepared by three steps of reactions of hydroxyl bromide, oxidation and reduction dehalogenation in sequence, and has the advantages of short synthetic route, easily controlled reaction conditions, easily obtained raw materials, low cost, higher reaction yield and suitability for industrial production.
In one embodiment, the brominating reagent is selected from at least one of dibromohydantoin, dibromodimethylhydantoin, and bromosuccinimide; the mass ratio of the bromination reagent to the compound I is (0.5-1): 1.
In one embodiment, the reaction conditions of the hydroxyl bromide are as follows: reacting for 2-5 h at-20-40 ℃ under the catalysis of a catalyst.
In one embodiment, the catalyst is selected from at least one of perchloric acid, fluoroboric acid, sulfuric acid, and p-toluenesulfonic acid.
In one embodiment, the temperature of the oxidation reaction is between-10 ℃ and 50 ℃.
In one embodiment, the oxidizing agent is selected from at least one of chromium trioxide, PDC, PCC, manganese dioxide, sodium chlorite, and sodium hypochlorite; the mass ratio of the oxidant to the compound II is (0.1-1): 1.
In one embodiment, the oxidizing agent is selected from at least one of chromium trioxide, PDC (pyridinium dichlorochromate), PCC (pyridinium chlorochromate), manganese dioxide, sodium chlorite, and sodium hypochlorite; the mass ratio of the oxidant to the compound II is (0.1-1): 1.
In one embodiment, the oxidizing agent is chromium trioxide, the oxidation reaction temperature is 0-10 ℃, and the oxidation reaction time is 1-3 hours.
In one embodiment, the conditions for the reductive dehalogenation reaction are: and reacting for 5-10 h at 0-80 ℃ in an acidic environment by adopting a metal reducing agent.
In one embodiment, the pH value of the acidic environment is 2-4;
the metal reducing agent is at least one selected from zinc powder, tin powder and aluminum powder, and the mass ratio of the metal reducing agent to the compound III is (0.1-1): 1.
In one embodiment, the acidic environment contains an organic acid, the organic acid is selected from at least one of acetic acid, formic acid and trifluoroacetic acid, and the mass ratio of the organic acid to the compound III is (0.5-2): 1.
Detailed Description
In order that the invention may be more fully understood, a more particular description of the invention will now be rendered by reference to specific embodiments thereof that are illustrated in the appended drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The conventional method takes pregnene diketene acetate as a starting material, and pregnene-4-alkene-17 alpha-alcohol-3, 11, 20-trione is obtained through multi-step reaction, and the specific synthetic route is as follows:
the process has long synthesis route, needs five-step chemical reaction and one-step mould fermentation, and has the disadvantages of complicated operation process, low process yield and high cost.
One embodiment of the invention provides a preparation method of pregn-4-ene-17 alpha-ol-3, 11, 20-trione, which comprises the following steps of S1-S3, and the specific synthetic route is as follows:
step S1, carrying out hydroxyl bromine reaction: taking a compound I as a raw material, adding a brominating agent, and carrying out a reaction of 9-position and 11-position bromine hydroxyl to obtain a compound II.
Specifically, the compound I and a brominating reagent are dissolved in a first organic solvent, and under the catalysis of a catalyst, bromine hydroxyl reaction is carried out at the temperature of minus 20 ℃ to 40 ℃ to obtain a compound II.
In one embodiment, the first organic solvent is selected from ketone solvents.
Further, the first organic solvent is selected from at least one of acetone and butanone.
In one embodiment, the mass ratio of the first organic solvent to the compound I is (2-10): 1.
Further, the mass ratio of the first organic solvent to the compound I is (2-5): 1.
In one embodiment, the brominating reagent is selected from at least one of dibromohydantoin, dibromodimethylhydantoin, and bromosuccinimide.
Further, the brominating reagent is at least one of dibromohydantoin and bromosuccinimide.
In one embodiment, the mass ratio of the brominating agent to the compound I is (0.5-1): 1.
In one embodiment, the catalyst is selected from at least one of perchloric acid, fluoroboric acid, sulfuric acid, and p-toluenesulfonic acid.
Further, the catalyst is selected from at least one of perchloric acid and fluoroboric acid.
In one embodiment, the reaction time of the hydroxyl bromide is 2 to 5 hours.
In one embodiment, after completion of the hydroxyl bromide reaction, the reaction is quenched, crystallized, filtered, washed with water to remove impurities, and compound II is obtained.
Specifically, a catalyst is put into a first organic solvent, a compound I and a brominating agent are added in batches at the temperature of minus 20-40 ℃, the temperature is kept for reaction, after the reaction is finished, a sodium sulfite solution is added for quenching reaction, water is separated out, the temperature is reduced, filtration is carried out, and washing and impurity removal are carried out, so that a compound II is obtained.
Further, under the condition of inert gas atmosphere at-20-40 ℃, adding the compound I and a brominating reagent into a mixed system of a first organic solvent and a catalyst in batches, and after the addition is finished, carrying out heat preservation reaction at-20-40 ℃ for 2-5 hours.
It is understood that the compound I and the brominating agent are fed in batches, namely the compound I and the brominating agent are added into a mixed system according to a certain proportion for each time and are added for multiple times. For example, 100g of compound I and 52g of the brominating agent are added to the mixed system in four portions, that is, 25g of compound I and 13g of the brominating agent are added each time.
Further, the temperature of the bromine hydroxyl reaction is-5 ℃ to 5 ℃.
Therefore, by selecting a specific brominating agent and a catalyst and controlling the reaction temperature of the hydroxyl bromide and the using amounts of the brominating agent, the solvent and the catalyst, the smooth reaction of the hydroxyl bromide can be ensured, the reaction speed is high, the generation of impurities is less and the yield is high.
Step S2, oxidation reaction: and (4) mixing the compound II prepared in the step (S1) with an oxidant for oxidation reaction, and oxidizing the hydroxyl at the 11-position in the compound II into a ketone group to obtain a compound III.
Specifically, the compound II prepared in the step S1 is mixed with a second organic solvent, an oxidant is added, and oxidation reaction is carried out at-10 ℃ to 50 ℃ to obtain a compound III.
In one embodiment, the second organic solvent is selected from at least one of acetone, butanone, chloroform, dichloromethane, tetrahydrofuran, and 1, 4-dioxane.
Further, the second organic solvent is selected from at least one of acetone and tetrahydrofuran.
In one embodiment, the mass ratio of the second organic solvent to the compound II is (2-10): 1.
Further, the mass ratio of the second organic solvent to the compound II is (3-6): 1
In one embodiment, the oxidizing agent is selected from at least one of chromium trioxide, PDC (pyridinium dichromate), PCC (pyridinium chlorochromate), manganese dioxide, sodium chlorite, and sodium hypochlorite.
Further, the oxidizing agent is chromium trioxide.
In one embodiment, the mass ratio of the oxidant to the compound II is (0.1-1): 1.
In one embodiment, the time of the oxidation reaction is 1 to 3 hours.
Specifically, dissolving the compound II in a second organic solvent, cooling to-10-50 ℃, slowly adding an oxidant, and then carrying out heat preservation reaction at-10-50 ℃ for 1-3 hours.
Further, the oxidizing agent is added dropwise.
Further, the temperature of the oxidation reaction is 0-10 ℃.
In one embodiment, after the oxidation reaction is complete, the reaction is quenched, crystallized, and filtered to provide compound ii.
Specifically, propanol is added to quench the reaction, and crystallization is carried out by a water separation method.
Step S3, reductive dehalogenation reaction: and (3) carrying out reduction dehalogenation reaction on the compound III prepared by S2 to obtain pregn-4-ene-17 alpha-alcohol-3, 11, 20-trione.
Specifically, the compound III prepared in the step S2 is mixed with a third organic solvent, a metal reducing agent is added, reduction reaction is carried out under the conditions that the pH value is 2-4 and the temperature is 0-80 ℃, and after the reaction is finished, filtration, crystallization and purification are carried out to obtain pregna-4-ene-17 alpha-alcohol-3, 11, 20-trione.
In one embodiment, the third organic solvent is selected from at least one of dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, acetone, butanone, and 1, 4-dioxane.
Further, the third organic solvent is selected from at least one of dimethylformamide and tetrahydrofuran.
In one embodiment, the pH is adjusted with an organic acid selected from at least one of acetic acid, formic acid, and trifluoroacetic acid.
Further, the organic acid is acetic acid.
In one embodiment, the mass ratio of the organic acid to the compound III is (0.5-2): 1.
In one embodiment, the metal reducing agent is selected from at least one of zinc powder, tin powder, and aluminum powder.
Further, the metal reducing agent is zinc powder.
In one embodiment, the mass ratio of the metal reducing agent to the compound III is 0.1-1: 1.
In one embodiment, the temperature of the reduction reaction is 0-60 ℃.
In one embodiment, the compound III and a third organic solvent are mixed, organic acid is added in an inert gas atmosphere, the mixture is cooled to 10-20 ℃, a metal reducing agent is slowly added, the mixture is uniformly mixed and reacts at room temperature for 0.5-2 hours, then the temperature is increased to 50-60 ℃ to react for 8-13 hours, and the mixture is filtered and crystallized to obtain a crude product, and the crude product is recrystallized to obtain a refined pregna-4-ene-17 alpha-alcohol-3, 11, 20-trione product.
Specifically, different crystallization methods may be adopted for different third organic solvents, for example, when dimethylacetamide is used as the third organic solvent, crystallization may be performed by a water crystallization method, and then a crude product is obtained by filtration and water washing, while when a low-boiling-point solvent such as tetrahydrofuran is used as the third organic solvent, the filtrate may be concentrated first to remove a part of tetrahydrofuran, and then cooled for crystallization and filtered to obtain the crude product, or crystallization may be performed by a water crystallization method. The crude product may be recrystallized from ethyl acetate.
The method for preparing pregna-4-ene-17 alpha-alcohol-3, 11, 20-trione has the advantages of short synthetic route, low cost, yield of over 80 percent and product purity of over 98 percent, and is very suitable for industrial production.
The following are specific examples
The various chemicals and reagents used in the examples of the present invention were all commercially available.
Example 1
1) Hydroxyl reaction of bromine
500mL (394g) of acetone and 20g of water are added into a 1L three-necked flask, the flask is cooled to 0-5 ℃, 5mL (8.8g) of perchloric acid is added, nitrogen is introduced to discharge air, and the compound I and the dibromohydantoin are added in four times, wherein 25g of the compound I and 13g of the dibromohydantoin are added at intervals of 30 minutes. After the addition, the reaction was incubated for 3 hours. After the raw materials are completely reacted by thin-layer chromatography (TLC) detection, sodium sulfite solution is added to quench the reaction, then 1000g of water is poured into the reaction product for water precipitation, the temperature is reduced, the reaction product is filtered and washed, and a light yellow solid compound II is obtained, wherein the wet weight is 192g, and the detection purity is 96.7%.
2) Oxidation reaction
Preparation of a Jones reagent: weighing 40g of chromic anhydride (chromic anhydride), adding into 120g of water, stirring to dissolve, slowly dripping 60g of concentrated sulfuric acid with the mass concentration of 98%, and cooling to room temperature for later use.
Adding the wet compound II prepared in the step 1) and 600mL (473g) of acetone into a 1000mL three-necked bottle, cooling to 0-5 ℃, dropwise adding a Jones reagent, carrying out heat preservation reaction for 2 hours after dropwise adding, adding isopropanol after TLC detection raw materials react completely, carrying out quenching reaction, carrying out reduced pressure concentration to remove acetone, pouring into 400g of water, carrying out water precipitation, and carrying out suction filtration to obtain a white-like solid compound III, wherein the wet weight is 191g, and the detection purity is 93.9%.
3) Reduction dehalogenation reaction
Adding the wet compound III prepared in the step 2) and 400mL (380g) of dimethylformamide into a 1L three-necked bottle, introducing nitrogen to exhaust air, adding 200g of acetic acid, stirring to dissolve, cooling the system to 10-20 ℃, adding 50g of zinc powder in batches, and reacting at room temperature for 1 hour after the addition is finished; then heating to 55-60 ℃ for reaction for 10 hours, detecting by TLC that the raw materials react completely, filtering, pouring the filtrate into 2000g of water for water precipitation, filtering, and washing with water to obtain a crude product. The crude product is recrystallized by ethyl acetate to obtain 78.1g of a white solid compound pregn-4-ene-17 alpha-ol-3, 11, 20-trione, the detection purity is 98.7 percent, and the total yield in the three steps is 82.3 percent.
Example 2
1) Hydroxyl reaction of bromine
Adding 500ml (405g) of butanone and 30g of water into a 1L three-necked bottle, cooling to 0-5 ℃, adding 10g of fluoroboric acid, introducing nitrogen to discharge air, adding the compound I and the dibromohydantoin for four times, and adding 25g of the compound I each time; 13g of dibromohydantoin; the addition was carried out at 30 minute intervals. After the addition is finished, the temperature is kept between 0 and 5 ℃ for reaction for 3 hours. TLC detects that the raw material reacts completely, sodium sulfite solution is added to quench the reaction, then 1000g of water is poured into the mixture for elutriation, temperature reduction, filtration and washing are carried out, light yellow solid II is obtained, the wet weight is 186g, and the detection purity is 97.3%.
2) Oxidation reaction
Preparation of a Jones reagent: weighing 40g of chromic anhydride, adding into 120g of water, stirring to dissolve, slowly dripping 60g of concentrated sulfuric acid, and cooling to room temperature for later use. Adding 400ml (356g) of tetrahydrofuran and the wet compound II prepared in the step 1) into a 1000ml three-necked bottle, cooling to 0-5 ℃, dropwise adding a Jones reagent, reacting for 2 hours under a heat preservation condition after dropwise adding, detecting by TLC (thin layer chromatography), completely reacting raw materials, adding isopropanol, quenching, reacting, concentrating the tetrahydrofuran under reduced pressure, pouring 400g of water, performing elutriation, and performing suction filtration to obtain a white-like solid III, wherein the wet weight is 182g, and the detection purity is 95.4%.
3) Reduction dehalogenation reaction
Adding the wet compound III prepared in the step 2) and 800ml (712g) of tetrahydrofuran into a 2L three-necked bottle, introducing nitrogen to exhaust air, adding 150g of acetic acid, cooling the system to 20-25 ℃, adding 50g of zinc powder in batches, and keeping the temperature for reaction for 1 hour after the addition. And then heating to 50-55 ℃ for reaction for 10 hours, detecting by TLC that the raw materials completely react, filtering, concentrating the filtrate under reduced pressure to a small amount, cooling for crystallization, and filtering to obtain a crude product. The crude product was recrystallized from ethyl acetate to yield pregn-4-en-17 α -ol-3, 11, 20-trione as a white solid (80.6 g). The total yield of the three steps is 84.9 percent, and the detection purity is 98.2 percent.
Example 3
1) Hydroxyl reaction of bromine
Adding 400mL (315g) of acetone and 20g of water into a 1L three-necked bottle, cooling to-5-0 ℃, adding 3mL (5.3g) of perchloric acid, introducing nitrogen to exhaust air, adding the compound I and the brominated succinimide four times, adding 25g of the compound I and 15g of the brominated succinimide every time, and adding the compounds at intervals of 30 minutes. After the addition is finished, the temperature is kept between minus 5 ℃ and 0 ℃ for reaction for 3 hours. After the raw materials are completely reacted by thin-layer chromatography (TLC) detection, sodium sulfite solution is added to quench the reaction, then 1000g of water is poured into the reaction product for water precipitation, the temperature is reduced, the reaction product is filtered and washed, and a light yellow solid compound II is obtained, wherein the wet weight is 181g, and the detection purity is 97.1%.
2) Oxidation reaction
Preparing PDC: weighing 35g of chromic anhydride, adding 35g of water, cooling to 0-5 ℃ in an ice bath, slowly adding 28g of pyridine dropwise, stirring for 30min after adding 28g of pyridine dropwise, adding 105ml of acetone, stirring for 30min, cooling to-10-5 ℃, stirring for crystallization for 10h, and filtering to obtain a PDC solid.
Adding the wet compound II prepared in the step 1) and 500mL (394g) of acetone into a 1000mL three-necked bottle, cooling to 0-5 ℃, adding PDC solid in batches, keeping the temperature for reaction for 3 hours after the addition is finished, adding isopropanol after TLC detection raw materials react completely, quenching the reaction, decompressing and concentrating to remove the acetone, pouring the mixture into 400g of water for water precipitation, and performing suction filtration to obtain a white-like solid compound III, wherein the wet weight is 179g, and the detection purity is 96.2%.
3) Reduction dehalogenation reaction
Adding the wet compound III prepared in the step 2) and 350mL (385g) of dimethyl sulfoxide into a 1L three-necked bottle, introducing nitrogen to exhaust air, adding 150g of acetic acid, stirring to dissolve, cooling the system to 10-20 ℃, adding 50g of zinc powder in batches, and reacting at room temperature for 1 hour after the addition is finished; then heating to 55-60 ℃ for reaction for 10 hours, detecting by TLC that the raw materials react completely, filtering, pouring the filtrate into 2000g of water for water precipitation, filtering, and washing with water to obtain a crude product. The crude product is recrystallized by ethyl acetate to obtain 75.6g of a white solid compound pregn-4-ene-17 alpha-ol-3, 11, 20-trione, the detection purity is 96.7 percent, and the total yield in the three steps is 79.6 percent.
Example 4
1) Hydroxyl reaction of bromine
Adding 400ml (324g) of butanone and 40g of water into a 1L three-necked bottle, cooling to 5-10 ℃, adding 20g of fluoboric acid, introducing nitrogen to exhaust air, adding the compound I and the dibromohydantoin for four times, and adding 25g of the compound I each time; 13g of dibromohydantoin; the addition was carried out at 30 minute intervals. After the addition, the reaction is carried out for 1 hour at the temperature of 5-10 ℃. TLC detects that the raw material reacts completely, sodium sulfite solution is added to quench the reaction, then 1000g of water is poured into the mixture for elutriation, temperature reduction, filtration and washing are carried out, light yellow solid II is obtained, wet weight is 176g, and detection purity is 94.6%.
2) Oxidation reaction
Preparation of a Jones reagent: weighing 40g of chromic anhydride, adding into 120g of water, stirring to dissolve, slowly dripping 60g of concentrated sulfuric acid, and cooling to room temperature for later use. Adding 400ml (356g) of tetrahydrofuran and the wet compound II prepared in the example 2 into a 1000ml three-necked flask, cooling to 12-17 ℃, dropwise adding a Jones reagent, keeping the temperature for reaction for 2 hours after the dropwise adding, detecting the reaction of the raw materials by TLC (thin layer chromatography), adding isopropanol to quench the reaction, concentrating the tetrahydrofuran under reduced pressure, pouring 400g of water for elutriation, and performing suction filtration to obtain a white-like solid III, wherein the wet weight is 178g, and the detection purity is 90.6%.
3) Reduction dehalogenation reaction
Adding the wet compound III prepared in the step 2) and 800ml (712g) of tetrahydrofuran into a 2L three-necked bottle, introducing nitrogen to exhaust air, adding 150g of formic acid, cooling the system to 20-25 ℃, adding 50g of zinc powder in batches, and keeping the temperature for reaction for 1 hour after the addition. And then heating to 50-55 ℃ for reaction for 10 hours, detecting by TLC that the raw materials completely react, filtering, concentrating the filtrate under reduced pressure to a small amount, cooling for crystallization, and filtering to obtain a crude product. The crude product was recrystallized from ethyl acetate to yield 72.2g of pregn-4-en-17 α -ol-3, 11, 20-trione as a white solid. The total yield of the three steps is 76.1 percent, and the detection purity is 95.9 percent.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A preparation method of pregn-4-ene-17 alpha-alcohol-3, 11, 20-trione is characterized by comprising the following steps:
taking a compound I as a raw material, adding a brominating reagent, and carrying out a 9-position and 11-position hydroxyl bromide reaction to obtain a compound II;
carrying out oxidation reaction on the 11-position hydroxyl of the compound II, and oxidizing the 11-position hydroxyl in the compound II into a ketone group to obtain a compound III;
carrying out reduction dehalogenation reaction on the compound III to obtain pregn-4-ene-17 alpha-alcohol-3, 11, 20-trione;
the structural formulas of the compound I, the compound II and the compound III are as follows:
2. the method according to claim 1, wherein the brominating agent is at least one selected from the group consisting of dibromohydantoin, dibromodimethylhydantoin, and bromosuccinimide; the mass ratio of the bromination reagent to the compound I is (0.5-1): 1.
3. The method according to claim 1, wherein the reaction conditions of the hydroxyl bromide are as follows: reacting for 2-5 h at-20-40 ℃ under the catalysis of a catalyst.
4. The production method according to claim 3, wherein the catalyst is at least one selected from perchloric acid, fluoroboric acid, sulfuric acid and p-toluenesulfonic acid.
5. The method according to claim 1, wherein the temperature of the oxidation reaction is-10 ℃ to 50 ℃.
6. The method according to claim 5, wherein the oxidizing agent is at least one selected from the group consisting of chromium trioxide, PDC, PCC, manganese dioxide, sodium chlorite, and sodium hypochlorite; the mass ratio of the oxidant to the compound II is (0.1-1): 1.
7. The method according to claim 6, wherein the oxidizing agent is chromium trioxide, the oxidation reaction temperature is 0 to 10 ℃, and the oxidation reaction time is 1 to 3 hours.
8. The production method according to any one of claims 1 to 7, wherein the conditions of the reductive dehalogenation reaction are as follows: and reacting for 5-10 h at 0-80 ℃ in an acidic environment by adopting a metal reducing agent.
9. The method according to claim 8, wherein the acidic environment has a pH of 2 to 4;
the metal reducing agent is at least one selected from zinc powder, tin powder and aluminum powder, and the mass ratio of the metal reducing agent to the compound III is (0.1-1): 1.
10. The method according to claim 8, wherein the acidic environment contains an organic acid selected from at least one of acetic acid, formic acid and trifluoroacetic acid, and the mass ratio of the organic acid to the compound III is (0.5-2): 1.
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| CN102746370A (en) * | 2011-04-22 | 2012-10-24 | 天津金耀集团有限公司 | Novel technology for oxosynthesis of pregnane 11-bit ketonic group |
| CN103864872B (en) * | 2012-12-13 | 2016-12-21 | 天津金耀集团有限公司 | Polyhydroxy pregnant steroid 11 α hydroxyl process for selective oxidation |
| CN107400153B (en) * | 2017-04-23 | 2019-08-27 | 浙江仙琚制药股份有限公司 | A kind of preparation method of hydrocortisone acetate |
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