CN112375114A - Preparation method of prednisolone acetate - Google Patents
Preparation method of prednisolone acetate Download PDFInfo
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- CN112375114A CN112375114A CN202011260971.1A CN202011260971A CN112375114A CN 112375114 A CN112375114 A CN 112375114A CN 202011260971 A CN202011260971 A CN 202011260971A CN 112375114 A CN112375114 A CN 112375114A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—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
- C07J5/0046—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
- 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
Abstract
The invention relates to a preparation method of prednisolone acetate and prednisolone, which takes anecortave acetate as a raw material, and sequentially carries out biological fermentation, esterification reaction, bromination reaction and debromination reaction to prepare the prednisolone acetate, and the prednisolone acetate is subjected to hydrolysis reaction to prepare the prednisolone, wherein the overall yield is up to 81.75 percent, and the HPLC area normalization content of the prednisolone is up to 99.5 percent. The preparation method has short synthetic route and low cost, is suitable for industrial production and has high industrial value.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of prednisolone acetate.
Background
Prednisolone acetate is named as 11 beta, 17 alpha, 21-trihydroxy pregna-1, 4-diene-3, 20-dione-21-acetate, is a glucocorticoid medicine, and is used externally to treat allergic and non-infectious dermatosis and some hyperplastic skin diseases, such as dermatitis, eczema, neurodermatitis, seborrheic dermatitis, pruritus, etc. Prednisolone acetate can also be used for treating allergic and autoimmune inflammatory diseases and collagen diseases, such as rheumatism, rheumatoid arthritis, lupus erythematosus, severe bronchial asthma, nephrotic syndrome, thrombocytopenic purpura, granulocytopenia, acute lymphatic leukemia, various adrenal cortex insufficiency, exfoliative dermatitis, herpetic neurodermatitis and eczema.
The traditional preparation method of prednisolone acetate is divided into biological conversion and chemical synthesis. The preparation method has the defects of high substrate cost, low substrate feeding concentration, long production period, difficult separation in the post-treatment process, low purity and the like. Chemical synthesis is carried out by taking 17 alpha-hydroxy-1, 4, 9-triene-pregna-3, 20-diketone as raw material, brominating, debrominating, adding iodine and replacing to obtain prednisolone acetate; or prednisolone acetate is taken as a raw material, and is prepared by the methods of 3-position and 20-position ketosemicarbazone protection, 11-position ketoreduction, 3-position and 20-position deprotection and 21-position esterification; but the production process is complex, the steps are complicated, the overall yield is low, and the cost is high.
Therefore, the development of the preparation method of the prednisolone acetate, which can effectively improve the yield and the purity, is suitable for industrial production and effectively reduces the cost, has important significance.
Disclosure of Invention
Therefore, a preparation method of prednisolone acetate is needed, and the synthesis method has the advantages of easily available starting materials, effectively improved yield and purity, suitability for industrial production and effectively reduced cost.
A preparation method of prednisolone acetate comprises the following steps:
carrying out bromination reaction on the compound of the formula (I) to obtain a compound of a formula (II);
carrying out debromination reaction on the compound shown in the formula (II), and carrying out aftertreatment to obtain prednisolone acetate shown in the formula (III);
the structures of the compound of formula (I), the compound of formula (II) and the compound of formula (III) are as follows:
the post-treatment comprises adding at least one of sodium thiosulfate, sodium sulfite, and sodium hypochlorite.
In some embodiments, in the preparation method of prednisolone acetate, the mass ratio of the sodium salt added in the post-treatment to the compound of formula (II) is (0.15-0.35): 1.
In some embodiments, the prednisolone acetate preparation method includes that the compound of formula (i) is obtained by esterification of a compound of formula (IV), and the structure of the compound of formula (IV) is as follows:
in some embodiments, the esterification reaction uses at least one catalyst selected from 4-dimethylaminopyridine, triethylamine, pyridine and p-toluenesulfonic acid, and the esterification reaction uses at least one acetylation reagent selected from acetic anhydride, acetyl chloride and isopropenyl acetate.
In some embodiments, the prednisolone acetate preparation method, the compound of formula (IV) is obtained by biofermentation of anecortave acetate which is a compound of formula (V), and the structure of the compound of formula (V) is as follows:
in some embodiments, in the preparation method of prednisolone acetate, the bacteria used in the biological fermentation is selected from one of nocardia and arthrobacter simplex.
In some embodiments, the bromination reaction uses a bromination reagent selected from at least one of dibromohydantoin and N-bromosuccinimide in the preparation method of prednisolone acetate.
In some embodiments, the catalyst used in the bromination reaction is at least one selected from the group consisting of sulfuric acid, phosphoric acid, perchloric acid, and fluoroboric acid.
In some embodiments, in the preparation method of prednisolone acetate, the solvent used in the bromination reaction is a mixture of an organic solvent and water, the organic solvent is at least one selected from dichloromethane, dichloroethane, tetrahydrofuran, dioxane and acetone, and the reaction temperature of the bromination reaction is-20 ℃ to 15 ℃.
In some embodiments, the reducing agents used in the debromination reaction are zinc and chromium trichloride.
In some embodiments, the solvent used in the debromination reaction is at least two selected from tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dichloromethane, toluene and acetone, and the reaction temperature of the debromination reaction is 10 ℃ to 25 ℃.
The invention has the following beneficial effects:
in the preparation method of prednisolone acetate provided by the invention, a compound of a formula (I) is subjected to bromination reaction to obtain a compound of a formula (II); carrying out debromination reaction on the compound shown in the formula (II), and carrying out aftertreatment to obtain prednisolone acetate shown in the formula (III); the sodium salt is added in the post-treatment, the mercaptoacetic acid and other solvents are destroyed, a good impurity removal effect is achieved, the special smell of the system is greatly reduced, the process is not harsh, the process is more environment-friendly, the subsequent operation is convenient, the obtained prednisolone acetate is good in physical state, suitable for suction filtration, white in product color and high in yield; if the post-treatment is not carried out, part of the prednisolone acetate product is wrapped or dissolved by the system, the product has poor color state, the yield is reduced, and the taste is sharp.
The synthesis method has the advantages of easily available and cheap raw materials, few reaction steps, high yield, simple operation and capability of effectively reducing the cost, is economic and environment-friendly when being applied to industrial production, and has better application prospect.
Drawings
FIG. 1 is a mass spectrum of a compound of formula (I) prepared in step 2) of example 1;
FIG. 2 shows the compound of formula (I) prepared in step 2) of example 11H NMR spectrum;
FIG. 3 shows the compound of formula (I) prepared in step 2) of example 113A C NMR spectrum;
FIG. 4 shows prednisolone prepared in step 5) of example 11H NMR spectrum;
FIG. 5 shows prednisolone prepared in step 5) of example 113C NMR spectrum.
Detailed Description
The compounds of the present invention, methods for their preparation and their use are described in further detail in the following examples. The present invention may be embodied in many different forms and is not limited to the embodiments described 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.
An embodiment of the present invention provides a method for synthesizing prednisolone acetate, which includes the following steps S10-S20.
Step S10: carrying out bromination reaction on the compound of the formula (I) to obtain a compound of a formula (II); wherein the structures of the compound of formula (I) and the compound of formula (II) are as follows:
step S20: carrying out debromination reaction on the compound shown in the formula (II), and carrying out aftertreatment to obtain prednisolone acetate shown in the formula (III); wherein the post-treatment comprises adding a sodium salt selected from at least one of sodium thiosulfate, sodium sulfite and sodium hypochlorite, and the compound of formula (III) has the following structure:
sodium salt is added in the post-treatment to destroy solvents such as thioglycolic acid and the like, so that a better impurity removal effect is achieved, the special smell of the system is greatly reduced, no irritation is caused, the process is more environment-friendly, the subsequent operation is convenient, the obtained prednisolone acetate is good in physical state, dry and suitable for suction filtration, and the product is white in color, high in yield, white in color and free of irritation; if the post-treatment is not carried out, part of the prednisolone acetate product is wrapped or dissolved by a zinc and chromium trichloride system, the product has poor color state, the yield is reduced, and the taste is sharp.
In some of the examples, in step S20, the mass ratio of the sodium salt added in the post-treatment to the compound of formula (I) is (0.15-0.35): 1.
It is understood that when the amount of sodium salt added is too small, the effect of destroying thioglycolic acid and other reagents is not obtained, whereas when the amount of sodium salt added is too large, the purity and appearance of the product are affected.
Preferably, the sodium salt is selected from sodium thiosulfate in a mass ratio of 0.2:1 to the compound of formula (I).
In some embodiments, in step S10, the concentration of the compound of formula (I) is 0.05-0.3 g/mL-1。
In some of these embodiments, the bromination reaction uses a bromination reagent selected from at least one of dibromohydantoin and N-bromosuccinimide in step S10.
Preferably, the brominating reagent is dibromohydantoin.
In some embodiments, in step S10, the mass ratio of the brominating agent to the compound of formula (I) used in the bromination reaction is (0.4-0.9): 1.
Preferably, the mass ratio of dibromohydantoin to compound of formula (I) is 0.45: 1.
In some of these embodiments, in step S10, the bromination reaction uses a catalyst selected from at least one of sulfuric acid, phosphoric acid, perchloric acid, and fluoroboric acid.
Preferably, the catalyst used in the bromination reaction is sulfuric acid.
In some examples, in step S10, the mass ratio of the catalyst to the compound of formula (I) used in the bromination reaction is (0.03-0.2): 1.
Preferably, the mass ratio of sulfuric acid to the compound of formula (I) is 0.08: 1.
In some embodiments, in step S10, the solvent used in the bromination reaction is a mixture of an organic solvent and water, and the volume ratio of the organic solvent to the water is 1 (0.1-0.5).
It can be understood that when the bromination reaction is carried out by using a mixed solvent of water and an organic solvent, the reaction time is short, the substrate reaction is more thorough, and the product purity and yield are high.
In some of these embodiments, in step S10, the organic solvent in the bromination reaction is selected from at least one of dichloromethane, dichloroethane, tetrahydrofuran, dioxane, and acetone.
Preferably, the solvent used for the bromination reaction is a mixture of acetone and water in a volume ratio of 1: 0.15.
In some of these embodiments, the bromination reaction is conducted at a temperature of from-20 ℃ to 15 ℃ in step S10.
Preferably, the reaction temperature of the bromination reaction is from 1 ℃ to 5 ℃.
In some embodiments, step S10, after the bromination step, includes a step S11 of purifying the product of the bromination step.
Step S11: and (3) putting the bromination reaction system into water to separate out solid, and filtering.
It will be appreciated that the reaction system may be quenched by adding a small amount of water to the reaction system and then transferred to another portion of water as a whole.
The filter cake obtained by filtration may be washed with water in order to obtain a higher purity product from the bromination reaction.
In some embodiments, the reducing agents used in the debromination reaction in step S20 are zinc and chromium trichloride.
Alternatively, the mass ratio of zinc, chromium trichloride to compound of formula (i) is 0.2:0.2: 1.
In some of the embodiments, in step S20, the debromination reaction uses a solvent selected from at least two of tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dichloromethane, toluene, and acetone.
It can be understood that if only a single solvent is used, the heat release in the debromination process is large, the reaction system is easy to cure and explode, and when two different solvents are mixed, the reaction system is not easy to cure, so that the reaction reagents are fully contacted, the using amount of the solvent is small, and the reaction is thorough.
Preferably, the solvent used for the debromination reaction is dimethyl sulfoxide and acetone.
In some of these embodiments, the reaction temperature for the debromination reaction in step S20 is from 10 ℃ to 25 ℃.
Preferably, the reaction temperature for the debromination reaction is 15 ℃ to 20 ℃.
In some embodiments, step S20 further comprises adding an activator, wherein the activator is thioglycolic acid.
Alternatively, thioglycolic acid may be added dissolved in acetone.
In some embodiments, step S20 further includes post-treatment steps S21-23 after the end of the debromination reaction.
Step S21: the reaction system was poured into an aqueous solution containing hydrochloric acid and stirred.
It will be appreciated that the purpose of the hydrochloric acid is to react with the excess zinc to remove it.
Step S22: sodium thiosulfate solution is added and stirred.
Step S23: concentrating and filtering to obtain the prednisolone acetate crude product.
In some of the examples, in step S23, the mixture is concentrated to an acetone-free fraction and filtered with suction at 10 ℃ to 15 ℃.
In some embodiments, step S20 further involves refining steps S24-S29 after obtaining the crude prednisolone acetate.
Step S24: and (3) putting the prednisolone acetate crude product into a mixed solvent of dichloromethane and methanol, and heating to slightly reflux to dissolve the prednisolone acetate crude product.
In some of these embodiments, the volume ratio of dichloromethane to methanol in step S24 is 2: 1.
Step S25: adding active carbon, slightly refluxing, filtering and collecting filtrate.
In some embodiments, in step S25, the micro-reflow time is 0.5-2 h.
Preferably, the duration of the micro-reflux is 1 h.
It is understood that the purpose of adding activated carbon is to decolorize the system, remove part of the pigments of the system, purify the product, and adsorb part of the impurities.
Step S26: controlling the temperature to be less than or equal to 50 ℃, and concentrating the filtrate under negative pressure to be pasty without fraction.
It can be understood that the temperature is controlled to be less than or equal to 50 ℃ in order to control the crystallization speed and avoid new impurities generated due to high temperature.
Step S27: adding water, cooling to 35 deg.C, adding ethyl acetate, heating to reflux, and pulping.
In some embodiments, in the step S27, the beating time is 3-4 h.
Step S28: filtering and drying.
It will be appreciated that in order to obtain prednisolone acetate of higher purity, the filter cake obtained after filtration may be rinsed with ethyl acetate.
In some embodiments, in step S28, the temperature during filtration is controlled to be 0-5 ℃ and the drying temperature is controlled to be 55-60 ℃.
In some of these embodiments, the prednisolone acetate preparation method described herein, the compound of formula (i) is obtained in step S30.
Step S30: carrying out esterification reaction on the compound shown in the formula (IV) to obtain the compound shown in the formula (I), wherein the structure of the compound shown in the formula (IV) is as follows:
in some of the embodiments, in step S30, the esterification reaction uses a catalyst selected from at least one of 4-dimethylaminopyridine, triethylamine, pyridine, and p-toluenesulfonic acid.
Optionally, the mass ratio of the catalyst used in the esterification reaction to the compound of the formula (IV) is (0.02-0.06): 1.
Preferably, the catalyst used in the esterification reaction is 4-dimethylaminopyridine, the mass ratio of which to the compound of formula (IV) is 0.04: 1.
In some of the embodiments, in step S30, the esterification reaction uses an acetylation reagent selected from at least one of acetic anhydride, acetyl chloride, and isopropenyl acetate.
Preferably, the acetylating agent is acetic anhydride and the mass ratio of the acetylating agent to the compound of formula (IV) is 1: 1.
In some of the embodiments, in step S30, the solvent used for the esterification reaction is chloroform.
In some of the embodiments, step S30 further involves post-treatment steps S31-S32 after the esterification reaction is completed.
Step S31: cooling the reaction system to 0-5 ℃, and adding ethanol to quench the reaction.
Step S32: filtering, concentrating and drying.
In some embodiments, the prednisolone acetate preparation method includes the step of obtaining the compound of formula (IV) in step S40.
Step S40: anecortave acetate, a compound of formula (V), is subjected to biological fermentation to obtain a compound of formula (IV), wherein the structure of the compound of formula (V) is as follows:
in some of these embodiments, in step S40, the bacteria used in the biological fermentation are selected from one of nocardia and arthrobacter simplex.
Preferably, the bacterium used in the biological fermentation is nocardia.
In some preferred embodiments, step S40 includes the following steps S41-S49:
step S41:
preparing a slant culture medium, wherein the components of the culture medium comprise glucose, yeast extract and agar, culturing at the constant temperature of 30 ℃ for 3 days under the pH value of 7.0, and storing at the temperature of 3-5 ℃ for later use.
Preferably, in step S41, the slant culture medium comprises the following components by mass: glucose: yeast cream: agar 0.65:0.65: 1.
Step S42: preparing a first-class seed culture medium, wherein the components of the culture medium comprise beef extract and peptone, and the pH value is 6.8.
Preferably, in step S42, the primary seed culture medium comprises the following components by mass: beef extract: peptone ═ 3: 5.
Step S43: and (4) putting the half branch of the inclined plane prepared in the step S41 into 100 ml of the first-level seed culture medium prepared in the step S42, controlling the rotating speed of a shaking table to be 180-200 rpm, and culturing for 20-30 h at the temperature of 30-35 ℃.
Preferably, in step S43, the shaking table is rotated at 180rpm and incubated at 30 ℃ for 24 hours.
Step S44: preparing a secondary seed culture medium, wherein the components of the culture medium are glucose, corn steep liquor, peptone and potassium dihydrogen phosphate, the pH value is 7.0, the rotating speed of a shaking table is controlled to be 180-200 rpm, and the secondary seed culture medium is cultured for 20-30 h at the temperature of 30-35 ℃.
Preferably, in step S44, the mass ratio of each component of the secondary seed culture medium is glucose: corn steep liquor: peptone: potassium dihydrogen phosphate is 1:1:1: 0.01.
Preferably, in step S44, the shaking table is rotated at 180rpm and incubated at 30 ℃ for 25 hours.
Step S45: mixing the compound of formula (V), tween 80, methanol and water, and adding into secondary seed culture medium for biological fermentation.
In some of these embodiments, step S45 further involves adding a poult to the can prior to dosing.
Step S46: in the process of biological fermentation, the aeration quantity is 0.1Nm3The tank pressure is 0.05MPa, and the rotating speed of a shaking table is controlled to be 180-220 rpm; after 24h, the ventilation was adjusted to 0.2Nm3H, continue to turnAnd (4) transforming.
It can be understood that the initial foam after feeding is large, and the opening gas amount is 0.1Nm3H; after 24h, the foam fell and the aeration adjusted to 0.2Nm3And h, controlling the foaming speed by adjusting the ventilation quantity, increasing the dissolved oxygen of the system to a certain extent, and increasing the conversion rate.
Step S47: and (4) carrying out solid-liquid separation on the fermentation liquor, filtering and drying.
It can be understood that the fermentation liquor is directly filtered without inactivation after solid-liquid separation.
The compound of formula (II) is obtained by taking anecortave acetate as a raw material through biological fermentation, the impurity is less, and the yield can reach 98%. The method of fermentation and synthesis is adopted, the conditions are mild, and the overall yield is high.
An embodiment of the present invention provides a method for synthesizing prednisolone, including the following step S50.
Step S50: mixing prednisolone acetate, dichloromethane, methanol, water and alkali to perform hydrolysis reaction.
Alternatively, in step S50, the base is selected from at least one of potassium hydroxide and sodium hydroxide.
Preferably, in step S50, the base is at least one selected from potassium hydroxide and sodium hydroxide, and at least one selected from sodium carbonate and potassium carbonate.
It can be understood that the sodium carbonate and the potassium carbonate are weak in alkalinity, prednisolone acetate is not enough to completely react when the sodium carbonate and the potassium carbonate are used alone, and the raw materials are remained.
In some embodiments, in step S50, the hydrolysis reaction includes steps S51-S56.
Step S51: stirring prednisolone acetate, dichloromethane and methanol under the condition of nitrogen, and controlling the temperature to be 0-10 ℃.
Step S52: adding a mixed solution of alkali and water, and stirring.
Step S53: and after the hydrolysis reaction is finished, adjusting the pH value to be 6-7, concentrating, replacing with water, and filtering.
Step S54: mixing the prednisolone crude product with methanol, and heating to slightly reflux to dissolve.
Step S55: adding active carbon, slightly refluxing, filtering, collecting filtrate, and concentrating at 45-50 deg.C.
Step S56: filtering at 5 deg.C, and drying at 55-60 deg.C.
According to the invention, anecortave acetate is used as a raw material, and prednisolone acetate is prepared through fermentation, esterification, bromination reaction and dehydrobromination reaction in sequence, wherein the overall yield is up to 88.6%, and the HPLC area normalization content of the prednisolone acetate is up to 99.6%; the prednisolone acetate is further hydrolyzed to prepare the prednisolone, the overall yield is as high as 81.75%, and the prednisolone HPLC area normalization content is as high as 99.5%. The preparation method has short synthetic route and low cost, is suitable for industrial production and has high industrial value.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The preparation method of prednisolone acetate and the preparation method of prednisolone according to the present invention are exemplified herein, but the present invention is not limited to the following examples.
Example 1
1) Preparation of the Compound of formula (IV)
1.1 slant culture
The nocardia is used as a strain, the components and the mass fraction of a culture medium are 1.3 percent of glucose, 1.3 percent of yeast extract and 2 percent of agar, the pH value is 7.0, the nocardia is cultured for 3 days at the constant temperature of 30 ℃, and the nocardia is preserved for standby at the temperature of 3-5 ℃.
1.2 first order seed culture
The components of the culture medium are 0.3 percent of beef extract and 0.5 percent of peptone, the pH value is 6.8, half of the slant culture medium is put into 100 ml of first-level seed culture medium, the rotating speed of a shaking table is controlled to be 180rpm, and the culture is carried out for 24 hours at the temperature of 30 ℃.
1.3 Secondary seed culture
The culture medium comprises glucose 1%, corn steep liquor 1%, peptone 1% and potassium dihydrogen phosphate 0.01%, has pH of 7.0, and is cultured at 30 deg.C for 16h with shaking table rotation speed of 180 rpm.
1.4 charging
Pulverizing anecortave acetate (compound of formula V) to 200 mesh, weighing 120g, adding water 360mL, tween 803 g and methanol 60mL, mixing well, feeding into secondary seed culture medium for biological fermentation, and adding 0.2% of DIDET into the tank before feeding.
1.5 transformation
Initial aeration amount after feeding is 0.1Nm3Per hour, pot pressure 0.05MPa, stirring at 200rpm for 24 hours, and aeration rate adjusted to 0.2Nm3H, continuing the conversion.
1.6 working-up
And (4) performing solid-liquid separation on the fermentation liquor, filtering, and leaching a filter cake with clear water until the filtrate is colorless. The filter cake is directly dried to obtain a crude product of the compound shown in the formula (IV), the yield is 98 percent, and the purity is 95 percent.
Yield of compound of formula (IV) ═ molar amount of compound of formula (IV)/molar amount of anecortave acetate × 100%
343.2[ M + H ] in the formula (IV) compounds MS (ES)]+。
2) Preparation of Compounds of formula (I)
Adding 1.0g of crude compound of formula (IV), 0.04g of 4-dimethylaminopyridine and 5mL of chloroform into a reaction bottle, stirring for 10min, cooling to 10-15 ℃, slowly dropwise adding 1.0mL of acetic anhydride, returning to room temperature after dropwise adding, reacting until no raw material remains, cooling a system to 0-5 ℃, slowly dropwise adding 2.0mL of 95% ethanol, quenching, filtering by a Buchner funnel, concentrating the filtrate at normal pressure until no fraction is obtained, adding 2.0mL of ethanol, concentrating at 45-60 ℃ under negative pressure (the vacuum degree is less than or equal to 0.06MPa) to form slurry, filtering at 15 ℃, and drying to obtain the compound of formula (I), wherein the yield is 98%, and the purity is 95%.
Yield of compound of formula (i) ═ molar amount of compound of formula (i) × 100% per molar amount of compound of formula (IV)
384.9[ M + H ] compounds of the formula (I) MS (ES)]+。
3) Preparation of Compounds of formula (II)
Adding 8mL of acetone, 1.2mL of water and 0.08g of sulfuric acid into a reaction bottle, stirring for 10min, adding 1.0g of the compound of the formula (I) at one time, controlling the temperature to be 0-5 ℃, stirring for 30min, adding 0.45g of dibromohydantoin at one time, reacting at 0-5 ℃, and monitoring by TLC. After the raw materials completely react, controlling the temperature to be below 15 ℃, adding 3mL of water into the system, then transferring the system into 12mL of standing water, standing for 30min, stirring for 20min, standing for 1h, filtering, and washing a filter cake to obtain 1.2g of a wet product of the compound shown in the formula (II), wherein the purity is 97.5%.
480.8[ M + H ] in the formula (II) compounds MS (ES)]+。
4) Preparation of prednisolone acetate
Adding 2.5mL of dimethyl sulfoxide, 2mL of acetone, 0.2g of zinc powder and 0.2g of chromium trichloride into a reaction bottle, keeping the temperature at 15-25 ℃, dropwise adding a mixed solution of 0.5mL of thioglycolic acid and 0.5mL of acetone, keeping the temperature for reaction for 30min, controlling the temperature at 15-20 ℃, adding 1.2g of the wet product of the compound of the formula (II) prepared in the step 3) in 5 batches, after the TLC monitoring reaction is finished, pouring the system into 5mL of an aqueous solution containing 0.3g of concentrated hydrochloric acid, stirring for 1h, adding an aqueous solution (mass fraction is 5%) containing 0.2g of sodium thiosulfate, stirring for 20min, concentrating until no acetone fraction exists, and performing suction filtration at 10-15 ℃ to obtain a prednisolone acetate crude product.
Putting 12mL of dichloromethane, 6mL of methanol and the crude product of prednisolone acetate into a reaction bottle, and heating to slightly reflux and dissolve the crude product. Adding 0.1g of active carbon, slightly refluxing for 1h, filtering, and collecting filtrate. Controlling the temperature to be less than or equal to 50 ℃, concentrating under negative pressure until no fraction is contained in a paste, replacing with 0.5g of water once again, cooling to 35 ℃, adding 1mL of ethyl acetate, heating to reflux and pulping for 3-4 h, filtering at 0-5 ℃, leaching a filter cake with a small amount of ethyl acetate, and drying at 55-60 ℃ to obtain the prednisolone acetate white solid.
The total yield of the step 3) and the step 4) is 92 percent, and the purity is 99.6 percent.
Prednisolone acetate yield ═ molar weight of prednisolone acetate/molar weight of compound of formula (i) × 100%
Prednisolone acetate MS (ES) 403.0[ M + H ]]+。
5) Preparation of prednisolone
Under the protection of nitrogen, 1.0g of prednisolone acetate, 8mL of dichloromethane and 6mL of methanol are added into a reaction bottle and stirred until the prednisolone acetate, the dichloromethane and the methanol are dissolved clearly; controlling the temperature to be 0-10 ℃, dropwise adding the prepared mixed solution containing 0.02g of sodium hydroxide, 0.03g of potassium carbonate and 1mL of water into the reaction system, and stirring for 2 h; and monitoring by TLC until no raw material remains, adjusting the pH value to 6-7 by glacial acetic acid, concentrating under reduced pressure to be pasty, replacing the pasty raw material with 2mL of water, filtering at 5-10 ℃, and leaching a filter cake by water to obtain a prednisolone crude product.
Putting 8mL of methanol and the prednisolone crude product into a reaction bottle, and heating to slightly reflux and dissolve the prednisolone crude product. Adding 0.05g of activated carbon, carrying out micro-reflux for 0.5h, filtering, leaching a filter cake with a small amount of methanol, and collecting filtrate. Concentrating at 45-50 ℃, filtering at 5 ℃, leaching a filter cake with a small amount of methanol, and drying at 55-60 ℃ to obtain prednisolone white solid with the yield of 92.5% and the purity of 99.5%.
Prednisolone ═ prednisolone molar weight/prednisolone acetate molar weight × 100%
Prednisolone MS (ES) 361.5[ M + H ]]+。
Example 2
Example 2 is substantially the same as example 1 except that sodium thiosulfate was replaced with sodium hypochlorite in step 4) of example 2, and the other steps and process parameters are the same as those of example 1.
Through calculation, the total yield of the prednisolone acetate obtained in the steps 3) and 4) is 91%, and the purity is 99.3%.
Prednisolone acetate yield ═ molar weight of prednisolone acetate/molar weight of compound of formula (i) × 100%
Example 3
Example 3 is essentially the same as example 1 except that the mass ratio of sodium thiosulfate to the compound of formula (i) in step 4) of example 3 is 0.35:1, and the other steps and process parameters are the same as in example 1.
Through calculation, the total yield of the prednisolone acetate obtained in the steps 3) and 4) is 92%, and the purity is 99.4%.
Prednisolone acetate yield ═ molar weight of prednisolone acetate/molar weight of compound of formula (i) × 100%
Example 4
Example 4 is essentially the same as example 1 except that the mass ratio of sodium thiosulfate to the compound of formula (i) in step 4) of example 4 is 0.15:1 and the other steps and process parameters are the same as in example 1.
Through calculation, the total yield of the prednisolone acetate obtained in the steps 3) and 4) is 90%, and the purity is 99.3%.
Prednisolone acetate yield ═ molar weight of prednisolone acetate/molar weight of compound of formula (i) × 100%
Example 5
Example 5 is substantially the same as example 1 except that in step 3) of example 5, the bromination reagent dibromohydantoin is replaced with N-bromosuccinimide, and the other steps and process parameters are the same as those in example 1.
Through calculation, the total yield of the prednisolone acetate obtained in the steps 3) and 4) is 92%, and the purity is 99.5%.
Prednisolone acetate yield ═ molar weight of prednisolone acetate/molar weight of compound of formula (i) × 100%
Comparative example 1
Comparative example 1 is substantially the same as example 1 except that sodium thiosulfate was replaced with sodium carbonate in step 4) of comparative example 1 and the other steps and process parameters were the same as example 1.
Through calculation, the total yield of the prednisolone acetate obtained in the steps 3) and 4) is 86%, and the purity is 98.5%.
Prednisolone acetate yield ═ molar weight of prednisolone acetate/molar weight of compound of formula (i) × 100% comparative example 2
Comparative example 2 is substantially the same as example 1 except that sodium thiosulfate in step 4) of comparative example 2 is replaced with potassium bicarbonate and the other steps and process parameters are the same as example 1.
Through calculation, the total yield of the prednisolone acetate obtained in the steps 3) and 4) is 80%, and the purity is 98.1%.
Prednisolone acetate yield ═ molar weight of prednisolone acetate/molar weight of compound of formula (i) × 100%
Comparative example 3
Comparative example 3 is substantially the same as example 1 except that the solvent used in step 4) of comparative example 3 does not contain water and is replaced with an equal amount of organic reagent and the other steps and process parameters are the same as in example 1.
Through calculation, the total yield of the prednisolone acetate obtained in the steps 3) and 4) is 80%, and the purity is 98%.
Prednisolone acetate yield ═ molar weight of prednisolone acetate/molar weight of compound of formula (i) × 100%
Comparative example 4
Comparative example 4 is substantially the same as example 1 except that the mass ratio of sodium thiosulfate to the compound of formula (i) in step 4) of comparative example 4 is 0.6:1 and the other steps and process parameters are the same as in example 1.
Through calculation, the total yield of the prednisolone acetate obtained in the steps 3) and 4) is 85%, and the purity is 98%.
Prednisolone acetate yield ═ molar weight of prednisolone acetate/molar weight of compound of formula (i) × 100%
As can be seen from the above, compared with examples 1 to 5, the yield and purity of comparative examples 1 to 4 are both reduced, and the purity is reduced to below 98.5%, which does not meet the requirement that the purity of the commercial intermediate is more than or equal to 99%.
According to the invention, anecortave acetate is used as a raw material, and prednisolone acetate is prepared through fermentation, esterification, bromination reaction and dehydrobromination reaction in sequence, wherein the overall yield is up to 88.6%, and the HPLC area normalization content of the prednisolone acetate is up to 99.6%; the prednisolone acetate is further hydrolyzed to prepare the prednisolone, the overall yield is as high as 81.75%, and the prednisolone HPLC area normalization content is as high as 99.5%. The preparation method has short synthetic route and low cost, is suitable for industrial production and has high industrial value.
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. The preparation method of prednisolone acetate is characterized by comprising the following steps:
carrying out bromination reaction on the compound of the formula (I) to obtain a compound of a formula (II);
carrying out debromination reaction on the compound shown in the formula (II), and carrying out aftertreatment to obtain prednisolone acetate shown in the formula (III);
the structures of the compound of formula (I), the compound of formula (II) and the compound of formula (III) are as follows:
the post-treatment comprises adding a sodium salt selected from at least one of sodium thiosulfate, sodium sulfite and sodium hypochlorite.
2. The method for preparing prednisolone acetate according to claim 1, wherein the mass ratio of the sodium salt added in the post-treatment to the compound of formula (II) is (0.15-0.35): 1.
3. The method of preparing prednisolone acetate according to claim 1, wherein the compound of formula (i) is obtained by esterification of a compound of formula (IV) having the following structure:
4. the method of claim 3, wherein the esterification reaction uses a catalyst selected from at least one of 4-dimethylaminopyridine, triethylamine, pyridine and p-toluenesulphonic acid, and the esterification reaction uses an acetylating agent selected from at least one of acetic anhydride, acetyl chloride and isopropenyl acetate.
5. The method of claim 1, wherein the compound of formula (IV) is obtained by biofermentation of anecortave acetate, a compound of formula (V), and the structure of the compound of formula (V) is as follows:
6. the method for preparing prednisolone acetate according to claim 5, wherein the bacteria used in the biological fermentation are selected from one of nocardia and arthrobacter simplex.
7. The method for preparing prednisolone acetate according to any one of claims 1 to 6, wherein the bromination reaction uses a bromination reagent selected from at least one of dibromohydantoin and N-bromosuccinimide, and uses a catalyst selected from at least one of sulfuric acid, phosphoric acid, perchloric acid and fluoroboric acid.
8. The method for preparing prednisolone acetate according to any one of claims 1 to 6, wherein the solvent used in the bromination reaction is a mixture of an organic solvent and water, the organic solvent is at least one selected from the group consisting of dichloromethane, dichloroethane, tetrahydrofuran, dioxane and acetone, and the reaction temperature of the bromination reaction is from-20 ℃ to 15 ℃.
9. The method for preparing prednisolone acetate according to any one of claims 1 to 6, wherein the reducing agents used in the debromination reaction are zinc and chromium trichloride.
10. The method for preparing prednisolone acetate according to any one of claims 1 to 6, wherein the solvent used in the debromination reaction is at least two selected from the group consisting of tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dichloromethane, toluene and acetone, and the reaction temperature of the debromination reaction is 10 ℃ to 25 ℃.
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| CN113754713A (en) * | 2021-09-28 | 2021-12-07 | 丽江映华生物药业有限公司 | Method for decoloring and refining prednisone acetate |
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