CN109678919B - Preparation method of methylprednisolone succinate impurity - Google Patents
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- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
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Abstract
The invention belongs to the technical field of chemical synthesis, and relates to a preparation method of methylprednisolone succinate impurity, in particular to a preparation method of 11 beta, 17 alpha, 21-trihydroxy-6 beta-methylpregna-1, 4-diene-3, 20-diketone-21-succinate. The 11 beta, 17 alpha, 21-trihydroxy-6 beta-methyl pregna-1, 4-diene-3, 20-diketone-21-succinate is prepared by taking 11 beta, 17 alpha, 21-trihydroxy-6-methylene pregna-4-ene-3, 20-diketone as a raw material and carrying out a series of reduction reactions, esterification reactions, oxidation reactions, hydrolysis reactions and the like. The invention discloses a preparation method of the impurity for the first time, and the preparation method has the advantages of clear synthetic route, simple and convenient operation, high purity of the prepared product and the like.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of 11 beta, 17 alpha, 21-trihydroxy-6 beta-methyl pregna-1, 4-diene-3, 20-diketone-21-succinate.
Background
11 beta, 17 alpha, 21-trihydroxy-6 beta-methylpregna-1, 4-diene-3, 20-dione-21-succinate, which is an impurity of methylprednisolone succinate, and has the following structural formula according to the European pharmacopoeia:
methylprednisolone succinate with the structural formula as follows:
methylprednisolone succinate is an artificially synthesized glucocorticoid. Glucocorticoids diffuse across the cell membrane and bind to specific receptors within the cytoplasm. Has antiinflammatory, immunity enhancing and antiallergic activities, and can be used for symptomatic treatment of rheumatic diseases, collagen diseases, skin diseases, allergy symptoms, eye diseases, gastrointestinal diseases, respiratory system diseases, edema state, etc., and as immunosuppressant for treating tumor, shock, etc.
The impurity has great significance for the research of the methylprednisolone succinate, and can be used for qualitative and quantitative analysis of the impurity in the production of the methylprednisolone succinate, so that the quality standard of the methylprednisolone succinate is improved, and important guiding significance is provided for safe medication.
In order to better control the quality of methylprednisolone succinate products and ensure the medication safety of methylprednisolone succinate, a method for verifying impurities of methylprednisolone succinate is needed, but no relevant report discloses a preparation method of 11 beta, 17 alpha, 21-trihydroxy-6 beta-methylpregna-1, 4-diene-3, 20-dione-21-succinate at present, so that a synthesis process of the impurities needs to be deeply researched.
Disclosure of Invention
In view of the above, the present invention is directed to a method for preparing 11 β,17 α, 21-trihydroxy-6 β -methylpregna-1, 4-diene-3, 20-dione-21-succinate.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a preparation method of 11 beta, 17 alpha, 21-trihydroxy-6 beta-methyl pregna-1, 4-diene-3, 20-diketone-21-succinate takes 11 beta, 17 alpha, 21-trihydroxy-6-methylene pregna-4-ene-3, 20-diketone (a compound in a formula II) as a raw material, and a target compound (the formula I) is prepared through a series of chemical reactions such as reduction, esterification, oxidation, hydrolysis and the like, wherein the compound in the formula II can be prepared through esterification of hydrocortisone, mannich reaction and hydrolysis of potassium carbonate, and is not repeated herein. The specific reaction steps are as follows:
1) catalyzing the compound of the formula II in a solvent to perform a reduction reaction to obtain a compound of a formula III;
2) carrying out esterification reaction on the compound shown in the formula III and an esterification reagent in a solvent to obtain a compound shown in a formula IV; 3)
carrying out oxidation reaction on the compound of the formula IV in a solvent to obtain a compound of a formula V;
4) carrying out hydrolysis reaction on the compound of the formula V and alkali in a solvent to obtain a compound of a formula VI;
5) carrying out esterification reaction on the compound shown in the formula VI and an esterification reagent in a solvent to obtain a compound shown in the formula I;
the structural formula and the reaction flow of the reacted compound are as follows:
in the reaction route, the compound of formula II is 11 beta, 17 alpha, 21-trihydroxy-6-methylene pregn-4-ene-3, 20-dione, the compound of formula III is 11 beta, 17 alpha, 21-trihydroxy-6 beta-methyl pregn-4-ene-3, 20-dione, the compound of formula IV is 11 beta, 17 alpha-dihydroxy-6 beta-methyl pregn-4-ene-3, 20-dione-21-acetate, the compound of formula V is 11 beta, 17 alpha-dihydroxy-6 beta-methyl pregn-1, 4-diene-3, 20-dione-21-acetate, the compound of formula VI is 11 beta, 17 alpha, 21-trihydroxy-6 beta-methyl pregn-1, 4-diene-3, 20-dione.
Further, in the step (1), the reaction solvent is one or more of absolute methanol/cyclohexene and absolute ethanol/cyclohexene; the ratio of the alcohol to the cyclohexene is 10v/1 v-1 v/1 v.
As a preference, the solvent of the reaction in step (1) is absolute ethanol/cyclohexene in a ratio of 5v/1 v.
Further, the catalyst in the step (1) comprises 5% or 10% of one or more Pd/C by mass; the reaction temperature is 50-80 ℃.
Preferably, the catalyst in step (1) is 10% by mass of Pd/C, so that the reaction progress can be accelerated and the reaction time can be shortened.
Further, in the step (2), the esterification reagent is one or more of formic acid, acetic acid and acetic anhydride; the reaction temperature is 0-50 ℃; triethylamine was also added to the reaction.
Further, in the step (2), the molar ratio of the compound shown in the formula III to the esterifying reagent is 1: 1-1: 1.5.
Preferably, in step (2), the acylating agent is acetic anhydride; the molar ratio of the compound shown in the formula III to the acetic anhydride is 1: 1.2; the reaction temperature is 22-28 ℃.
Further, in the step (3), the reaction oxidant is dichlorodicyanobenzoquinone (DDQ), and the pro-oxidant is N, O-bis (trimethylsilyl)Trifluoroacetamide(BSTFA) in a molar ratio of 1:1.0:3.0 to 1:2.0:6.0 of the compound of formula IV to DDQ and BSTFA.
Further, in the step (3), the reaction solvent is 1, 4-dioxane, and the reaction temperature is 70-120 ℃.
Preferably, in step (3), the molar ratio of the compound of formula IV to DDQ and BSTFA is 1: 1.1: 4.7; the reaction temperature is 100-105 ℃.
Further, in the step (4), the alkali is one or more of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, and the molar ratio of the compound shown in the formula V to the alkali is 1: 5-1: 15.
Further, in the step (4), the reaction solvent is dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 1v/1 v-1 v/5 v; the reaction temperature is 0-50 ℃.
Preferably, in step (4), the base is potassium carbonate; the molar ratio of the compound of formula V to the base is 1: 10; the reaction solvent is dichloromethane/methanol with the ratio of 1v/2 v; the reaction temperature is 25-30 ℃.
Further, in the step (5), the esterifying reagent is succinic anhydride; the molar ratio of the compound of formula VI to succinic anhydride is 1: 1-1: 5.
Further, in the step (5), DMF is used as a solvent; the reaction temperature is 0-50 ℃; triethylamine was also added to the reaction.
Preferably, in step (5), the molar ratio of the compound of formula VI to succinic anhydride is 1: 3; the reaction temperature is 15-20 ℃; after the reaction is finished, the compound of the formula I is obtained by extraction, washing and purification of a preparation column, and the purity is over 95 percent.
The invention has the beneficial effects that:
1) the invention discloses a method for preparing an impurity of methylprednisolone succinate, namely 11 beta, 17 alpha, 21-trihydroxy-6 beta-methylpregna-1, 4-diene-3, 20-diketone-21-succinate for the first time, has a great significance for the impurity research of methylprednisolone succinate, can be used for qualitative and quantitative analysis of the impurity in the production of methylprednisolone succinate, and improves the quality standard of methylprednisolone succinate, thereby providing an important guiding significance for safe medication.
2) The invention provides a preparation method of 11 beta, 17 alpha, 21-trihydroxy-6 beta-methyl pregna-1, 4-diene-3, 20-diketone-21-succinate, which takes 11 beta, 17 alpha, 21-trihydroxy-6-methylene pregna-4-ene-3, 20-diketone as a raw material to obtain a target compound through reduction reaction, esterification reaction, oxidation reaction, hydrolysis reaction, esterification reaction and the like.
Drawings
FIG. 1 reaction scheme
Detailed Description
Hereinafter, preferred embodiments of the present invention will be described in detail. The experimental methods of the preferred embodiments, which do not indicate specific conditions, are generally performed according to conventional conditions, and the examples are given for better illustration of the present invention, but the present invention is not limited to the examples. Those skilled in the art can make insubstantial modifications and adaptations to the embodiments described above while remaining within the scope of the invention.
Example 1
The method comprises the following steps: preparation of 11 beta, 17 alpha, 21-trihydroxy-6 beta-methylpregna-4-ene-3, 20-dione (formula III)
To N2Adding 10.0g of 11 beta, 17 alpha, 21-trihydroxy-6-methylene pregn-4-ene-3, 20-dione, 250ml of absolute ethyl alcohol and 50ml of cyclohexene into a protected reaction bottle, stirring, adding 0.68g of triethylamine and 4.0g of 10% Pd/C, and heating to 65-70 ℃. And reacting for 3 hours at the temperature of 65-70 ℃. The reaction solution was filtered to remove the catalyst Pd/C, and the filtrate was evaporated to dryness under reduced pressure to give a white-like solid 9.4g, with a yield of 93.5% and a 6 β -isomer content of 94.7%.
Step two: preparation of 11 beta, 17 alpha-dihydroxy-6 beta-methylpregna-4-ene-3, 20-dione-21-acetate (formula IV)
To N2Adding 9.0g of 11 beta, 17 alpha, 21-trihydroxy-6 beta-methyl pregn-4-ene-3, 20-diketone (formula III) and 135ml of dichloromethane into a protected reaction bottle, stirring, adding 3.6g of triethylamine and 2.93g of acetic anhydride, keeping the temperature at 25 ℃ after the addition is finished, pouring the reaction system into 180ml of ice water, stirring, standing for liquid separation, extracting an aqueous phase twice by 200ml of dichloromethane, combining organic phases, and washing three times by 200ml of saturated saline; the organic phase was evaporated to dryness under reduced pressure to give 9.8g of a pale yellow solidThe yield thereof was found to be 98.0%.
Step three: preparation of 11 beta, 17 alpha-dihydroxy-6 beta-methylpregna-1, 4-diene-3, 20-dione-21-acetate (formula V)
Adding 9.5g of 11 beta, 17 alpha-dihydroxy-6 beta-methyl pregna-4-ene-3, 20-dione-21-acetate (formula IV) and 190ml of 1, 4-dichloromethane into a reaction bottle at room temperature, stirring, adding 5.7g of DDQ and 27.5g of BSTFA, heating to 100-105 ℃, and carrying out heat preservation reaction for 4 hours. The reaction system was cooled to room temperature, and 400ml of methylene chloride and 400ml of 1% NaHSO were poured into the reaction system3Stirring, standing, separating, extracting the water phase with 400ml dichloromethane twice, combining the organic phases, and washing with 300ml saturated saline twice; the organic phase is evaporated to dryness under reduced pressure and purified by column chromatography. Eluent: n-hexane/ethyl acetate 3/1; the purer product eluent was collected and evaporated to dryness under reduced pressure to give 7.2g of a pale yellow oil with a yield of 75.4%.
Step four: preparation of 11 beta, 17 alpha, 21-trihydroxy-6 beta-methylpregna-1, 4-diene-3, 20-dione (formula VI)
To N27.0g of 11 beta, 17 alpha-dihydroxy-6 beta-methylpregna-1, 4-diene-3, 20-dione-21-acetate (formula V), 140ml of dichloromethane and 280ml of methanol are added into a protected reaction flask, stirred and added dropwise with 23.2g of K at 25-30 DEG C2CO3Solution prepared by 140ml of water is dripped and reacted for 1 hour at the temperature of 25-30 ℃. Pouring the reaction solution into 700ml of saturated saline and 1120ml of dichloromethane, stirring, standing, separating, extracting the water phase twice by using 700ml of dichloromethane, combining the organic phases, and washing twice by using 800ml of saturated saline; the organic phase was evaporated to dryness under reduced pressure to give 6.2g of a pale yellow solid with a yield of 98.4%.
Step five: preparation of 11 beta, 17 alpha, 21-trihydroxy-6 beta-methylpregna-1, 4-diene-3, 20-dione-21-succinate (formula I)
To N26.0g of 11 beta, 17 alpha, 21-trihydroxy-6 beta-methyl pregna-1, 4-diene-3, 20-dione (formula VI) and 120ml of DMF are added into a protected reaction bottle, stirred, added with 1.9g of triethylamine and 4.8g of succinic anhydride, and reacted for 1.5h at the temperature of 15-20 ℃. The reaction mixture was poured into 600ml of ice water, stirred, and extracted with 900ml of dichloromethaneTwice, the organic phases were combined and washed twice with 700ml of saturated brine; the organic phase is evaporated to dryness under reduced pressure, purified by a preparative column, and purer eluent is collected and evaporated to dryness under reduced pressure to obtain 4.3g of off-white solid with the yield of 56.6 percent.
Purity by HPLC was 95.4%.
MS(ESI)：[M+H]+＝475.4，[2M+H]+＝949.8。
IR：3520，3482，2957～2839，1746～1653，1610～1595，1458～1238，1172～1136。
Example 2
Preparation of 11 beta, 17a, 21-trihydroxy-6 beta-methylpregna-4-ene-3, 20-dione (formula III)
To N2Adding 10.0g of 11 beta, 17a, 21-trihydroxy-6-methylene pregn-4-ene-3, 20-dione, 250ml of absolute ethyl alcohol and 50ml of cyclohexene into a protected reaction bottle, stirring, adding 0.68g of triethylamine and 4.0g of 10% Pd/C, and heating to 65-70 ℃. And reacting for 3 hours at the temperature of 65-70 ℃. The reaction solution was filtered to remove the catalyst Pd/C, and the filtrate was evaporated to dryness under reduced pressure to give a white-like solid 9.4g, with a yield of 93.5% and a 6 β -isomer content of 94.7%.
Example 3
Preparation of 11 beta, 17 alpha-dihydroxy-6 beta-methylpregna-4-ene-3, 20-dione-21-acetate (formula IV)
To N2Adding 9.0g of 11 beta, 17 alpha, 21-trihydroxy-6 beta-methyl pregn-4-ene-3, 20-diketone (formula III) and 135ml of dichloromethane into a protected reaction bottle, stirring, adding 3.6g of triethylamine and 2.93g of acetic anhydride, keeping the temperature at 25 ℃ after the addition is finished, pouring the reaction system into 180ml of ice water, stirring, standing for liquid separation, extracting an aqueous phase twice by 200ml of dichloromethane, combining organic phases, and washing three times by 200ml of saturated saline; the organic phase was evaporated to dryness under reduced pressure to give 9.8g of a pale yellow solid with a yield of 98.0%.
Example 4
Preparation of 11 β,17 α -dihydroxy-6 β -methylpregna-1, 4-diene-3, 20-dione-21-acetate (formula V) 9.5g of 11 β,17 α -dihydroxy-6 β -methylpregna-4-ene-3, 20-dione-21-acetate (formula IV) and 190ml of 1, 4-dichloromethane were added to a reaction flask at room temperature, and stirredStirring, adding 5.7g of DDQ and 27.5g of BSTFA, heating to 100-105 ℃, and reacting for 4 hours under the condition of heat preservation. The reaction system was cooled to room temperature, and 400ml of methylene chloride and 400ml of 1% NaHS0 were poured into the reaction system3Stirring, standing, separating, extracting the water phase with 400ml dichloromethane twice, combining the organic phases, and washing with 300ml saturated saline twice; the organic phase is evaporated to dryness under reduced pressure and purified by column chromatography. Eluent: n-hexane/ethyl acetate 3/1; the purer product eluent was collected and evaporated to dryness under reduced pressure to give 7.2g of a pale yellow oil with a yield of 75.4%.
Example 5
Preparation of 11 beta, 17 alpha, 21-trihydroxy-6 beta-methylpregna-1, 4-diene-3, 20-dione (formula VI)
To N27.0g of 11 beta, 17 alpha-dihydroxy-6 beta-methylpregna-1, 4-diene-3, 20-dione-21-acetate (formula V), 140ml of dichloromethane and 280ml of methanol are added into a protected reaction flask, stirred and added dropwise with 23.2g of K at 25-30 DEG C2CO3Solution prepared by 140ml of water is dripped and reacted for 1 hour at the temperature of 25-30 ℃. Pouring the reaction solution into 700ml of saturated saline and 1120ml of dichloromethane, stirring, standing, separating, extracting the water phase twice by using 700ml of dichloromethane, combining the organic phases, and washing twice by using 800ml of saturated saline; the organic phase was evaporated to dryness under reduced pressure to give 6.2g of a pale yellow solid with a yield of 98.4%.
Finally, it should be noted that the above-mentioned embodiments are only for illustrating the technical solutions of the present invention and not for limiting, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, which should be covered by the claims of the present invention.
Claims (6)
1. The preparation method of methylprednisolone succinate impurity is characterized in that the impurity is 11 beta, 17 alpha, 21-trihydroxy-6 beta-methylpregna-1, 4-diene-3, 20-dione-21-succinate; the method comprises the following specific steps: (1) the method takes a compound 11 beta, 17 alpha, 21-trihydroxy-6-methylene pregn-4-alkene-3, 20-diketone shown in a formula II as a raw material, and the compound is catalyzed in a solvent to carry out reduction reaction, and triethylamine is also added in the reaction to obtain a compound shown in a formula III; (2) carrying out esterification reaction on the compound shown in the formula III and an esterification reagent in a solvent, wherein the molar ratio of the compound shown in the formula III to the esterification reagent is 1: 1-1: 1.5, and triethylamine is added in the reaction to obtain a compound shown in the formula IV; (3) the compound shown in the formula IV is subjected to oxidation reaction in a solvent to obtain a compound shown in the formula V, wherein an oxidant is DDQ, and an auxiliary oxidant is BSTFA; the molar ratio of the compound shown in the formula IV to DDQ and BSTFA is 1:1.0: 3.0-1: 2.0: 6.0; (4) the compound of the formula V and alkali are subjected to hydrolysis reaction in a solvent to obtain a compound of a formula VI, wherein the alkali comprises one or more of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, and the molar ratio of the compound of the formula V to the alkali is 1: 5-1: 15; (5) the compound of formula VI and an esterification reagent are subjected to esterification reaction in a solvent to obtain a compound of formula I, namely 11 beta, 17 alpha, 21-trihydroxy-6 beta-methyl pregna-1, 4-diene-3, 20-diketone-21-succinate, triethylamine is further added in the reaction, and the esterification reagent is succinic anhydride; the molar ratio of the compound in the formula VI to the succinic anhydride is 1: 1-1: 5;
2. the preparation method according to claim 1, wherein the solvent in step (1) is one or more of absolute methanol/cyclohexene and absolute ethanol/cyclohexene, and the volume ratio of the alcohol to the cyclohexene is 10v/1 v-1 v/1 v; the catalyst comprises 5% or 10% by mass of one or more Pd/C; the reaction temperature is 50-80 ℃.
3. The method according to claim 1, wherein the esterification reagent in step (2) is one or more selected from the group consisting of formic acid, acetic acid, and acetic anhydride; the solvent for the reaction is dichloromethane; the reaction temperature is 0-50 ℃.
4. The method according to claim 1, wherein the reaction solvent in the step (3) is 1, 4-dioxane, and the reaction temperature is 70 ℃ to 120 ℃.
5. The process according to claim 1, wherein the reaction solvent in the step (4) is dichloromethane and methanol at a volume ratio of 1v/1v to 1v/5 v; the reaction temperature is 0-50 ℃.
6. The method according to claim 1, wherein the reaction solvent in step (5) is DMF; the reaction temperature is 0-50 ℃.
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