CN101875681B - Synthetic method of 16alpha-hydroxy prednisonlone - Google Patents

Abstract

The invention discloses a method for synthesizing 16α-hydroxyprednisolone with a structure as shown in formula (III), comprising the following steps: using prednisolone with a structure as shown in formula (I) as a raw material, in the structure as shown in In the acidic ionic liquid shown in formula (II), the dehydration reaction is carried out first to generate double bonds, and then an aqueous hydrogen peroxide solution is added for the reaction. After sufficient reaction, water is added for further hydrolysis, and finally the 16α-hydroxyprednisolone is obtained. The synthetic method of the present invention utilizes the properties of the acidic ionic liquid as both a reaction medium and a catalyst, and realizes the purpose of cost reduction, energy saving and emission reduction by changing process conditions such as reaction time and reaction temperature, and is suitable for industrial production.

Description

A kind of synthetic method of 16α-hydroxyprednisolone

(1) Technical field

The invention relates to a method for synthesizing 16α-hydroxyprednisolone.

(2) Background technology

16α-Hydroxyprednisolone, chemical formula: C ₂₁ H ₂₈ O ₆ , molecular weight: 376.44. It is an important intermediate of ciclesonide, a drug for the treatment of asthma. Regarding the synthesis of 16α-hydroxyprednisolone, the methods reported at present all use prednisolone as a raw material, and form a ring with triethyl orthoacetate under the catalysis of pyridinium p-toluenesulfonate, and selectivity under weakly acidic conditions Ring-opening to obtain acetylated products, and then reacting with acetic anhydride under alkaline conditions to form diacetylated products, heating in the presence of potassium acetate to remove a molecule of acetic acid to obtain (11β)-hydroxy-21-acetoxy-1,4, 16-Pregnatriene-3,20-dione compound. The compound is selectively dihydroxylated under the action of potassium permanganate, and deacetylated in the presence of sodium hydroxide to obtain the product 16α-hydroxyprednisolone. In the existing synthetic routes, the synthetic steps are long and the product post-processing is complicated.

In recent years, we are committed to the application research of various ionic liquids in the synthesis of hormone drugs and intermediates. Ionic liquids are ionic systems composed of organic cations and inorganic or organic anions, which are liquid at room temperature and adjacent temperatures. Ionic liquids have many advantages that other substances cannot match, such as wide liquid temperature range, no significant vapor pressure, good thermal stability, acidic or super acidic, and acidity can be adjusted according to needs, and it is suitable for many inorganic compounds and organic compounds. Compounds have good solubility, wide electrochemical window, can overcome the separation and recovery difficulties of homogeneous catalysts, and cause environmental pollution. At the same time, they have the advantages of high reactivity of homogeneous catalysts and easy separation of heterogeneous catalysts from products. Based on these characteristics, ionic liquids have been widely used in extraction and separation, catalytic reaction, electrochemistry and so on. The acidity of acidic ionic liquids is determined by the nature of the anions. Acidic ionic liquids are divided into "Lewis acidic ionic liquids" and "Brōnsted acidic ionic liquids". The advantages of acidic ionic liquids are that ionic liquids, as a new type of environmentally friendly acid catalyst, are less corrosive; the reaction conditions are mild; the acidity can be adjusted; and they can be recycled. It overcomes the environmental pollution problems caused by traditional Lewis acid catalysts, and exhibits good activity and selectivity in acid-catalyzed reactions. It is expected to become one of the most promising green solvents and catalysts in the 21st century.

(3) Contents of the invention

The technical problem to be solved in the present invention is to provide a method for synthesizing 16α-hydroxyprednisolone by using an acidic ionic liquid simultaneously as a reaction medium and a catalyst. Ionic liquids are reusable, economical and practical.

In order to solve the problems of the technologies described above, the present invention adopts the following technical solutions:

A kind of synthetic method of the 16 alpha-hydroxy prednisolone shown in formula (III) of structure, comprises the steps: be raw material with the prednisolone shown in formula (I) of structure, in formula (II) In the acidic ionic liquid shown, first carry out dehydration reaction and generate double bond, then add hydrogen peroxide aqueous solution to react, add water after sufficient reaction and further hydrolyze, finally obtain described 16α-hydroxy prednisolone;

In formula (II), R is a C1-C10 substituted alkyl group, the substituent of the substituted alkyl group is a sulfonic acid group or a carboxyl group, and L is HSO ₄ , COO, CH ₃ COO, BF ₄ , PF ₆ or CF ₃ SO ₃ ; or R is a C1-C10 alkyl group, and L is HSO ₄ , COO or CF ₃ SO ₃ .

In the technical scheme of the present invention, the raw material prednisolone is first dehydrated to form double bonds, then the oxidation reaction is carried out with hydrogen peroxide as the oxidant, and the hydrolysis reaction is carried out after the oxidation to finally obtain the target product.

Further, the acidic ionic liquid represented by the formula (II), preferably: R is a C1-C10 substituted alkyl group, and the substituent of the substituted alkyl group is a sulfonic acid group; furthermore, preferably L is HSO ₄ , CH ₃ COO or BF ₄ .

Further, the dehydration reaction is preferably carried out at a temperature of 100-150°C, more preferably 110-130°C. Follow and monitor the reaction process by TLC until the raw material point disappears. It is recommended to use a mixed solvent of cyclohexane:acetone (volume ratio)=5:5 as a developing solvent.

Furthermore, the oxidation reaction and hydrolysis reaction are preferably carried out at a temperature of 10-60°C, more preferably the oxidation reaction and hydrolysis reaction are carried out at a temperature of 40-60°C. Preferably after adding aqueous hydrogen peroxide solution, react for 5-50 hours, then add water for further hydrolysis; more preferably after adding aqueous hydrogen peroxide solution, react for 10-40 hours, then add water for further hydrolysis. The present invention tracks and monitors the above-mentioned reaction process through TLC, and recommends a mixed solvent of cyclohexane:acetone (volume ratio)=5:5 as a developer.

Further, the mass ratio of prednisolone and acidic ionic liquid according to the present invention is 1:1-20, preferably 1:8-15, more preferably 1:10.

Further, the molar ratio of prednisolone to hydrogen peroxide in the present invention is 1:1-10, preferably 1:3-5. The present invention has no special requirement on the concentration of the hydrogen peroxide aqueous solution used, for example, the hydrogen peroxide aqueous solution with a mass concentration of 30-70% is applicable to the present invention.

The present invention has no special requirements on the amount of water added in the reaction process for further hydrolysis, and those skilled in the art can adjust it according to actual conditions. In the present invention, water with 40 to 60 times the mass of prednisolone is generally added for further hydrolysis.

The present invention specifically recommends that the synthetic method be carried out according to the following steps: adding prednisolone to the acidic ionic liquid, reacting at 100-150°C, tracking by TLC until the raw material point disappears, cooling to room temperature, adding hydrogen peroxide Aqueous solution, reacted at 10-60°C for 5-50h, then added water for further hydrolysis, TLC followed the reaction process, after the reaction, the reaction solution obtained was post-processed to obtain the 16α-hydroxyprednisolone product; the prednisolone The feeding mass ratio of nisolone and acidic ionic liquid is 1:1-20; the feeding molar ratio of prednisolone and hydrogen peroxide is 1:1-10.

The post-treatment adopts the following steps: the reaction solution is extracted with toluene, the toluene layer is taken, washed with distilled water, dried with anhydrous magnesium sulfate, and the toluene is evaporated under reduced pressure to obtain the 16α-hydroxyprednisolone product. The raffinate obtained after toluene extraction can be directly added to the reaction system for reaction, and after repeated use for 3 to 5 times, it can be washed with water, extracted with dichloromethane, dried and concentrated, and then reused.

Compared with the prior art, the synthesis method of the present invention utilizes the properties of the acidic ionic liquid as both the reaction medium and the catalyst, and by changing the process conditions such as reaction time and reaction temperature, the purposes of cost reduction, energy saving and emission reduction are achieved. Suitable for industrial production. Specifically, the technology of the present invention is easy to operate, high in production capacity, good in efficiency, less in three wastes, convenient in post-processing, and reusable in ionic liquids, and is an economical and practical green technology.

(4) Specific implementation methods

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

The hydrogen peroxide described in the examples of the present invention is added in the form of an aqueous hydrogen peroxide solution with a mass concentration of 30%, and the quality and amount of substances in the examples are all calculated by hydrogen peroxide itself.

Example 1

Add 0.1 g of prednisolone (I) (2.77×10 ^-4 mol) and 1 g of methyl butyl sulfoimidazolium bisulfate acidic ionic liquid into the reaction flask, keep the temperature at 120 ° C, and track the reaction process with TLC For monitoring, a mixed solvent of cyclohexane:acetone (volume ratio)=5:5 was used as a developing solvent until the raw material point disappeared. Then, cool to room temperature, add hydrogen peroxide 0.028g (8.31 * 10 ^-4 mol), react at 50 ℃ for 20 hours, then add 5 milliliters of water, thin-layer plate (by cyclohexane: acetone (volume ratio) = 5:5 mixed solvent as developing agent) after tracking the reaction, add 3×5mL toluene for extraction, combine the extracts, wash with 3×5mL distilled water, separate the organic layer, dry over anhydrous magnesium sulfate, and distill under reduced pressure To constant weight, 0.09 g of 16α-hydroxyprednisolone product as shown in formula (III) was obtained, and the yield was 90%. Mp: 238-241°C. H ¹ NMRδ: 0.98(s, 3H), 1.49(s, 3H), 4.24-4.68(dd, 2H, J=20.1, Hz). 4.50(d, 1H, J=2.5Hz), 5.08(d, 1H , J=8.2Hz), 6.03(s, 3H), 6.28(d, 1H, 9.3Hz), 7.25(d, 1H, J=10.1Hz).

Example 2

Add 0.1 g (2.77×10 ^-4 mol) of prednisolone (I) and 1 g of methyl butylsulfoimidazole acetate acidic ionic liquid into the reaction flask, keep the temperature at 150 ° C, and track and monitor the reaction process with TLC , using a mixed solvent of cyclohexane: acetone (volume ratio) = 5:5 as a developing solvent until the raw material point disappears. Then, cool to room temperature, add hydrogen peroxide 0.009g (2.77 * 10 ^-4 mol), react at 50 ℃ for 10 hours, then add 5 milliliters of water, thin-layer plate (by cyclohexane: acetone (volume ratio) = 5:5 mixed solvent as developing agent) after tracking the reaction, add 3×5mL toluene for extraction, combine the extracts, wash with 3×5mL distilled water, separate the organic layer, dry over anhydrous magnesium sulfate, and distill under reduced pressure To constant weight, 0.08 g of 16α-hydroxyprednisolone product as shown in formula (III) was obtained, and the yield was 80%.

Example 3

Add 0.1 g of prednisolone (I) (2.77×10 ^-4 mol) and 1 g of methyl butylsulfoimidazolium tetrafluoroborate acidic ionic liquid into the reaction flask, keep the temperature at 100 ° C, and use TLC to monitor the reaction process Tracking and monitoring, using a mixed solvent of cyclohexane: acetone (volume ratio) = 5: 5 as a developing solvent until the raw material point disappears. Then, cool to room temperature, add hydrogen peroxide 0.094g (2.77 * 10 ^-3 mol), react at 50 ℃ for 20 hours, then add 5 milliliters of water, thin-layer plate (by cyclohexane: acetone (volume ratio) = 5:5 mixed solvent as developing agent) after tracking the reaction, add 3×5mL toluene for extraction, combine the extracts, wash with 3×5mL distilled water, separate the organic layer, dry over anhydrous magnesium sulfate, and distill under reduced pressure To constant weight, 0.092 g of 16α-hydroxyprednisolone product as shown in formula (III) was obtained, and the yield was 92%.

Example 4

Add 0.1 g (2.77×10 ^-4 mol) of prednisolone (I) and 0.8 g of methyl butylsulfoimidazolium bisulfate acidic ionic liquid into the reaction flask, keep the temperature at 120 °C, and use TLC to monitor the reaction process. Tracking and monitoring, using a mixed solvent of cyclohexane: acetone (volume ratio) = 5: 5 as a developing solvent until the raw material point disappears. Then, cool to room temperature, add hydrogen peroxide 0.047g (13.85 * 10 ^-4 mol), react at 10 ℃ for 30 hours, then add 5 milliliters of water, thin-layer plate (by cyclohexane: acetone (volume ratio) = 5:5 mixed solvent as developing agent) after tracking the reaction, add 3×5mL toluene for extraction, combine the extracts, wash with 3×5mL distilled water, separate the organic layer, dry over anhydrous magnesium sulfate, and distill under reduced pressure To constant weight, 0.089 g of 16α-hydroxyprednisolone product as shown in formula (III) was obtained, and the yield was 89%.

Example 5

Add 0.1 g (2.77×10 ^-4 mol) of prednisolone (I) and 1.5 g of methyl butylsulfoimidazolium bisulfate acidic ionic liquid into the reaction flask, keep the temperature at 120°C, and use TLC to monitor the reaction process. Tracking and monitoring, using a mixed solvent of cyclohexane:acetone (volume ratio)=5:5 as a developing solvent until the raw material point disappears. Then, cool to room temperature, add hydrogen peroxide 0.038g (11.08 * 10 ^-4 mol), react at 40 ℃ for 25 hours, then add 5 milliliters of water, thin-layer plate (by cyclohexane: acetone (volume ratio) = 5:5 mixed solvent as developing agent) after tracking the reaction, add 3×5mL toluene for extraction, combine the extracts, wash with 3×5mL distilled water, separate the organic layer, dry over anhydrous magnesium sulfate, and distill under reduced pressure To constant weight, 0.09 g of 16α-hydroxyprednisolone product as shown in formula (III) was obtained, and the yield was 90%.

Claims (10)

1. a kind of synthetic method of the 16α-hydroxy prednisolone shown in formula (III) of structure, comprises the steps: be raw material with the prednisolone shown in formula (I) with structure, in structure such as formula ( In the acidic ionic liquid shown in II), first carry out dehydration reaction to generate double bonds, then add hydrogen peroxide aqueous solution to react, add water after fully reacting and further hydrolyze, finally obtain described 16α-hydroxy prednisolone;

In formula (II), R is a C1-C10 substituted alkyl group, the substituent of the substituted alkyl group is a sulfonic acid group or a carboxyl group, and L is HSO ₄ , CH ₃ COO, BF ₄ , PF ₆ or CF ₃ SO ₃ ; or R is a C1-C10 alkyl group, and L is HSO ₄ or CF ₃ SO ₃ . 2. the synthetic method of 16α-hydroxyprednisolone as claimed in claim 1 is characterized in that the acidic ionic liquid shown in described formula (II), R is the substituted alkyl of C1～C10, described The substituent of the substituted alkyl group is a sulfonic acid group, and L is HSO ₄ , CH ₃ COO or BF ₄ . 3. the synthetic method of 16α-hydroxyprednisolone as claimed in claim 1 or 2 is characterized in that described dehydration reaction is carried out under the temperature condition of 100～150 ℃. 4. the synthetic method of 16α-hydroxyprednisolone as claimed in claim 3 is characterized in that described dehydration reaction is carried out under the temperature condition of 110～130 ℃. 5. The synthetic method of 16α-hydroxyprednisolone as claimed in claim 1 or 2, is characterized in that: react at 10～60 ℃ after adding hydrogen peroxide aqueous solution, add water again at 10～60 ℃ after fully reacting °C for further hydrolysis. 6. The synthetic method of 16α-hydroxyprednisolone as claimed in claim 2, characterized in that: after adding hydrogen peroxide aqueous solution, react at 10～60°C for 5～50h, then add water for further hydrolysis. . 7. the synthetic method of 16α-hydroxy prednisolone as claimed in claim 1 or 2 is characterized in that the mass ratio of feeding intake of described prednisolone and acidic ionic liquid is 1: 1～20. 8. the synthetic method of 16α-hydroxy prednisolone as claimed in claim 1 or 2 is characterized in that the molar ratio of described prednisolone and hydrogen peroxide is 1: 1～10. 9. the synthetic method of 16α-hydroxy prednisolone as claimed in claim 1 or 2 is characterized in that described synthetic method is carried out according to the following steps: prednisolone is added in the acidic ionic liquid, at 100 ~ Carry out the reaction at 150°C, follow TLC until the raw material point disappears, cool to room temperature, add aqueous hydrogen peroxide solution, react at 10-60°C for 5-50 hours, then add water to continue the reaction, track the reaction process by TLC, and obtain the reaction after the end of the reaction The liquid obtains the described 16α-hydroxy prednisolone product through aftertreatment; The mass ratio of the feed intake of the described prednisolone and the acidic ionic liquid is 1: 1～20; The described prednisolone and hydrogen peroxide The molar ratio of feed is 1:1~10. 10. the synthetic method of 16α-hydroxyprednisolone as claimed in claim 9 is characterized in that described aftertreatment adopts the following steps: reaction solution extracts with toluene, gets the toluene layer, washes with distilled water, with anhydrous sulfuric acid The toluene layer was dried with magnesium, and the solvent was evaporated to dryness under reduced pressure to obtain the 16α-hydroxyprednisolone product.