CN109651475B - Novel method for preparing 16 a-hydroxy prednisolone - Google Patents
Novel method for preparing 16 a-hydroxy prednisolone Download PDFInfo
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- CN109651475B CN109651475B CN201910050781.8A CN201910050781A CN109651475B CN 109651475 B CN109651475 B CN 109651475B CN 201910050781 A CN201910050781 A CN 201910050781A CN 109651475 B CN109651475 B CN 109651475B
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- C—CHEMISTRY; METALLURGY
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- 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
- C07J5/0061—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 substituted in position 16
- C07J5/0092—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 substituted in position 16 by an OH group free esterified or etherified
Abstract
The invention provides a novel method for preparing 16 a-hydroxy prednisolone, which comprises the following steps: at first, prednisolone acetate and trimethylchlorosilane are subjected to 11-site silicon etherification reaction under the catalysis of organic baseA protective substance should be obtained; step B, dehydration, hydrolysis deprotection and refining: the protective substance and SO3Carrying out 17-position dehydration reaction under the catalysis of organic base, directly adding acid to carry out deprotection on 11 positions after the reaction, and obtaining a 17 a-dehydroxyacetate prednisolone crude product; then the crude product is refined to obtain a 17 a-dehydroxyacetic acid prednisolone product; and step C, preparing the 17 a-dehydroxy acetate prednisolone product as a raw material to obtain 16 a-hydroxy prednisolone. The invention overcomes the problems of more side reactions, more impurities, difficult refining of the impurities and the like in the traditional production process of the 17 a-dehydroxy acetate prednisolone, greatly improves the total synthesis yield of the 16 a-dehydroxy prednisolone, and reduces the production cost.
Description
Technical Field
The invention belongs to a preparation process technology of a steroid hormone drug intermediate, and particularly relates to a production process technology for synthesizing 16 a-hydroxy prednisolone by taking prednisolone acetate as a raw material.
Background
17 a-prednisolone dehydroxyacetate (molecular formula C)23H26O6) The chemical name of the compound is 11b, 21-dihydroxypregna-1, 4, 16-triene-3, 20-diketone-21-acetate, which is a key intermediate for producing the deflazacort and nede steroid adrenocortical hormone medicaments, and the deflazacort can be synthesized by 3 steps of reaction by taking the deflazacort as a raw material, and the desonide and the budesonide can be prepared by 3 steps of reaction. Deflazacort is a third-generation steroid glucocorticoid medicine, is mainly used for clinically treating primary and secondary renal epithelial hypofunction, rheumatism, collagenous diseases, skin diseases, explosive and disseminated tuberculosis, diseases of a hematopoietic system, ulcerative colitis, nausea and tumors of the hematopoietic system and other diseases, and has low side effect and good effect; the nednide steroid adrenocortical hormone medicine is a strong local anti-inflammatory agent, such as budesonide, which is mainly used for clinically treating various diseases such as rhinitis, acute bronchitis and chronic bronchitis, and has low side effect and good effect, so the 17 a-prednisolone dehydroxyacetate is developed and produced, and the market prospect is wide. 1The traditional production method of 7 a-dehydroxyacetic acid prednisone is characterized by using prednisolone acetate as raw material and making it undergo the processes of 17-position esterification and 17-position ester elimination reaction so as to obtain the invented product. The method for synthesizing the 17 a-dehydroxyacetic acid prednisolone has low total synthesis yield and is mainly caused by the following steps: on one hand, when 17-position hydroxyl is esterified by acetic anhydride, 11-position hydroxyl in molecules can be partially esterified to generate an impurity with the 11-position hydroxyl esterified, so that the purification is difficult, and the reaction yield of the esterification step is low; on the other hand, the second step 17 a-prednisolone acetate-17-acetate, when the elimination reaction is carried out at high temperature by the catalysis of a base such as sodium hydroxide or lithium carbonate, causes the elimination reaction in which the hydroxyl group at the 11-position in the molecule is also dehydrated to form two impurities, which are also difficult to remove, resulting in a low yield of the second elimination reaction. Therefore, the production cost of the 17 a-dehydroxyacetic acid prednisolone is very high, so that the production cost of deflazacort and budesonide drugs is also high, the market price of the deflazacort and budesonide drugs is greatly increased, and the medication cost of patients in treatment is greatly increased.
In addition, patent application CN201811343271.1 invented and published by the present applicant discloses a method for preparing 16 a-hydroxyprednisolone from 17 a-prednisolone dehydroxyacetate, wherein it is necessary to use 17 a-prednisolone dehydroxyacetate as a raw material. Therefore, there is a need in the art to develop new processes for preparing 17 a-dehydroprednisolone acetate and 16 a-hydroxyprednisolone.
Disclosure of Invention
The invention aims to provide a new method for synthesizing 17 a-dehydroxyacetate prednisolone and 16 a-hydroxyprednisolone aiming at the defects of more side reactions, low synthesis yield, high production cost and the like in the traditional 17 a-dehydroxyacetate prednisolone synthesis process so as to overcome the defects of the existing production process.
The invention provides a novel method for preparing 16 a-hydroxy prednisolone, which comprises the following steps,
step A, preparing a protective substance: prednisolone acetate is used as a raw material, and is dissolved in a first organic solvent, and subjected to 11-site silicon etherification reaction with trimethylchlorosilane under the catalysis of organic base to selectively protect 11-site hydroxyl to obtain a protector;
step B, dehydration, hydrolysis deprotection and refining: in a second organic solvent, the protecting substance is mixed with SO3Carrying out 17-position dehydration reaction under the catalysis of organic base, directly adding acid to carry out deprotection on 11 positions after the reaction, and obtaining a 17 a-dehydroxyacetate prednisolone crude product; decolorizing and recrystallizing the crude product of the 17 a-dehydroxy acetate prednisolone in the presence of lower alcohol with the carbon number below C4 and activated carbon to obtain a refined 17 a-dehydroxy acetate prednisolone product;
step C, carrying out epoxidation reaction on the 17 a-dehydroxy acetate prednisolone product and organic peroxy acid at 16 and 17 positions in an organic solvent to prepare an epoxy substance; reacting the epoxy compound with glacial acetic acid in an organic solvent under the catalysis of an acid catalyst to open a ring, so as to prepare 16a, 21-diacetyl oxygen prednisolone; and then dissolving 16a, 21-diacetyl oxygen prednisolone into an organic solvent, and hydrolyzing the acetic esters on two positions under the catalytic action of a solid-phase base catalyst to prepare the 16 a-hydroxy prednisolone, wherein the solid-phase base catalyst is a catalyst which takes alumina, silica gel or calcium carbonate as a carrier and adsorbs sodium carbonate or sodium hydroxide on the carrier.
In a specific embodiment, the step a is a stirring reaction at 10-50 ℃ for 3-4 hours, the first organic solvent is one selected from toluene, dichloromethane, acetone, chloroform, DMF, DME, and dioxane, and the organic base is pyridine.
In a specific embodiment, the ratio of prednisolone acetate in step a: organic base: chlorotrimethylsilane ═ 1 g: 0.6-1.5 g: 0.5-1.2 g, wherein the ratio of the reactants to the solvent is prednisolone acetate: first organic solvent ═ 1 g: 2-10 ml.
In a specific embodiment, the step B comprises introducing SO at 10-100 ℃3And (3) performing gas dehydration reaction for 6-12 hours, preferably 40-45 ℃, completing hydrolysis deprotection at 10-100 ℃, preferably 60-65 ℃, wherein the second organic solvent is one of toluene, acetone, chloroform, DMF, DME and dioxane, and the organic base is pyridine.
In a specific embodiment, the acid in step B is one of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and trifluoroacetic acid.
In a particular embodiment, the protective in step B: organic base catalyst: SO (SO)31 g: 0.4-1.0 g: 0.5-1.2 g; protection: second organic solvent ═ 1 g: 5-15 ml, protective substance: acid 1 g: 0.5 to 1.5 g.
In a specific embodiment, the lower alcohol used for purification in step B is alcohol.
The invention has the beneficial effects that: the invention adopts prednisolone acetate as raw material, firstly, the prednisolone acetate and trimethyl chlorosilane are subjected to 11-site etherification reaction in an organic solvent under the catalysis of alkali to selectively protect 11-site hydroxyl, and then the prednisolone acetate and SO are subjected to etherification reaction in the organic solvent3And (2) carrying out 17-position dehydration reaction under the catalysis of alkali, directly adding acid to carry out deprotection on 11 positions after the reaction to obtain 17 a-dehydroxy acetate prednisolone, and further preparing the 16 a-hydroxy prednisolone by using the 17 a-dehydroxy acetate prednisolone as a raw material. The method for producing the 17 a-dehydroxyacetic acid prednisolone has the advantages that although two steps of protection and deprotection are added, the unit reaction yield of each step is high, the latter two steps of reaction can be boiled in one pot, the production operation is simple and convenient, and the production process is economic and environment-friendly. And the problems of more side reactions, more impurities, difficult refining of the impurities and the like in the traditional production process of the 17 a-dehydroxyacetate prednisolone are solved, the total synthesis yield is greatly improved, and the production cost is reduced. Compared with the preparation method of the 17 a-dehydroxy prednisolone acetate of the traditional production method, the preparation cost of the method for preparing the 17 a-dehydroxy prednisolone acetate of the invention is reduced by 20-25%, and the corresponding process for preparing the 16 a-hydroxy prednisolone also reduces the production cost. The solvent used in the production of the method can be recycled and reused, and the method is easy to implement industrial production.
Drawings
FIG. 1 is a schematic diagram of the prior art preparation of 17 a-dehydroxyprednisolone acetate from prednisolone acetate.
FIG. 2 is a schematic diagram of the preparation of 16 a-hydroxyprednisolone after 17 a-dehydroxyacetate prednisolone is prepared from prednisolone acetate in the present invention.
Detailed Description
Specifically, the technical scheme of the invention is as follows: a process for preparing 17 a-dehydroxy acetate prednisolone includes such steps as etherifying prednisolone acetate with trimethylchlorosilane in organic solvent under the catalysis of alkali to selectively protect 11-hydroxy, and reacting with SO in organic solvent3Carrying out 17-site dehydration reaction under the catalysis of alkali, directly adding acid to carry out deprotection on 11 sites after the reaction, and obtaining 17 a-dehydroxy acetate prednisolone;
further, the preparation method of the 17 a-prednisolone dehydroxyacetate comprises the following specific operation steps:
step A, preparing a protective substance: dissolving prednisolone acetate in an organic solvent, adding an alkali catalyst and trimethylchlorosilane, stirring and reacting at 10-50 ℃ for 3-4 hours, after the reaction is finished, evaporating the organic solvent under reduced pressure, adding tap water for elutriation, filtering, washing and drying to obtain a protective substance: 11-trimethylsilyletherified prednisolone acetate, the weight yield is about 120-125%;
step B, preparing 17 a-prednisolone dehydroxyacetate: dissolving the protective substance prepared by the step A in an organic solvent, adding an organic base catalyst, keeping the temperature at 10-100 ℃, and introducing SO3Carrying out gas dehydration reaction for 6-12 hours, confirming a reaction end point by TLC, directly adding an acid aqueous solution to carry out hydrolysis deprotection at 10-100 ℃ after the reaction is finished, confirming the hydrolysis reaction end point by TLC, carrying out reduced pressure concentration to recover 90-95% of organic solvent after the hydrolysis reaction is finished, then cooling, adding tap water to carry out hydration, centrifuging, discharging filtrate into a wastewater treatment tank, washing and drying a filter cake to obtain a 17 a-dehydroxy acetate prednisolone crude product; the crude product is decolored and recrystallized by lower carbon alcohol with the carbon number below 4 to obtain a refined product of 17 a-dehydroxy acetate prednisolone, the HPLC content is more than 99.0 percent, the weight yield is 65 to 70 percent, and the total yield of the two-step preparation weight is 82 to 88 percent;
the specific conditions for synthesizing 17 a-prednisolone dehydroxyacetate are further described as follows:
the organic solvent in the preparation of the protective substance in the step A can be selected from: one of toluene, dichloromethane, acetone, chloroform, DMF, DME, dioxane, etc.; the alkali catalyst can be one of aromatic organic alkali such as pyridine and aliphatic organic alkali; the etherification reaction temperature can be 10-50 ℃; the weight ratio of the reactants can be selected as follows: prednisolone acetate: organic base: chlorotrimethylsilane ═ 1 g: 0.6-1.5 g: 0.5-1.2 g, and the ratio of the reactants to the solvent can be selected as follows: prednisolone acetate: first organic solvent ═ 1 g: 2-10 ml.
The organic solvent in the synthesis of the 17 a-prednisolone dehydroxyacetate of the step B can be selected from: one of toluene, acetone, chloroform, DMF, DME, dioxane, etc.; the alkali catalyst can be one of aromatic organic alkali such as pyridine and aliphatic organic alkali; the dehydration reaction temperature can be selected from 10 to 100 ℃; the acid used in the hydrolysis reaction can be one of inorganic acid such as hydrochloric acid and sulfuric acid or organic acid such as p-toluenesulfonic acid and trifluoroacetic acid; the hydrolysis reaction temperature can be 10-100 ℃; the weight ratio of the reactants can be selected as follows: protection: organic base catalyst: SO (SO)31 g: 0.4-1.0 g: 0.5-1.2 g; the ratio of the reactant to the second solvent is selectable: protection: second organic solvent ═ 1 g: 5-15 ml, the proportion of the reactant of the hydrolysis reaction and the acid can be selected as follows: protection: acid 1 g: 0.5 to 1.5 g.
The preferred conditions for synthesizing 17 a-prednisolone dehydroxyacetate are as follows:
the organic solvent in the preparation of the protective substance in the previous step A is preferably dichloromethane; the base catalyst is preferably pyridine; the etherification reaction temperature is preferably 20-25 ℃; the weight ratio of the reactants is preferably as follows: prednisolone acetate: alkali: chlorotrimethylsilane ═ 1 g: 1.0 g: 0.8 g; the ratio of reactants to solvent is preferably: prednisolone acetate: organic solvent ═ 1 g: 6 ml.
The organic solvent in the synthesis of the 17 a-prednisolone dehydroxyacetate of the step B is preferably: DMF; the base catalyst is preferably pyridine; the dehydration reaction temperature is preferably 40-45 ℃; the acid used in the hydrolysis reaction is preferably hydrochloric acid; the hydrolysis reaction temperature is preferably 60-65 ℃; the weight ratio of the reactants is preferably as follows: protection: alkali catalyst: SO3 ═ 1 g: 0.6 g: 0.8 g; the ratio of reactants to solvent is preferably: protection: second organic solvent ═ 1 g: 10ml, the proportion of hydrolysis reactant and acid is preferably as follows: protection: acid 1 g: 0.8 g.
In order to more conveniently explain the gist and spirit of the present invention, the following examples are given:
example 1
Step A, preparing a protective substance:
adding 100g of prednisolone acetate, 600ml of dichloromethane and 100g of pyridine into a 1000ml three-necked bottle, stirring to completely dissolve the solid, slowly dropwise adding 80g of trimethylchlorosilane at 20-25 ℃, completing the addition within 1.5-2 hours, continuing to keep the temperature at 20-25 ℃ after completing the dropwise addition, stirring and reacting for 3-4 hours under heat preservation, confirming the reaction end point by TLC, recovering 90-95% of dichloromethane serving as an organic solvent by reduced pressure distillation at the temperature of below 30 ℃ after completing the reaction, then adding 600ml of tap water, stirring and crystallizing for 3-4 hours at the temperature of 10-15 ℃, filtering, sending the filtrate to a wastewater treatment pool for treatment, washing a filter cake, and drying at the temperature of below 60 ℃ to obtain a protective substance: 123.6g of 11-trimethylsilyletherified prednisolone acetate, 97.6 percent of HPLC content and 123.6 percent of weight yield;
B. preparation of 17 a-prednisolone dehydroxyacetate:
adding 100g of the protective substance prepared from the A, 1000ml of DMF and 60g of pyridine into a 2000ml three-necked flask, stirring to completely dissolve the protective substance, keeping the temperature, and introducing 80g of SO at 40-45 DEG C3The gas is completely introduced after about 2-3 hours, after introduction, the dehydration reaction is continuously carried out for 6-12 hours at the temperature of 40-45 ℃, the TLC confirms the reaction end point, after the reaction is finished, 450g of 6N hydrochloric acid aqueous solution is directly added, the temperature is raised to 60-65 ℃, the hydrolysis reaction is carried out for 3-4 hours, the TLC confirms the hydrolysis reaction end point, after the hydrolysis reaction is finished, a proper amount of liquid caustic soda is used for adjusting the pH to 6-7, then the pressure is reduced below 80 ℃ for concentrating and recovering 90-95% DMF, the temperature is reduced, 600ml of tap water is added for elutriating, the filtrate is discharged into a waste water treatment tank, and the filter cake is washed and dried to obtain 75.6g of 17 a-dehydroxy; placing the crude product into a 1000ml three-necked bottle, adding 600ml of alcohol and 5g of activated carbon, refluxing and decoloring for 1-1.5 hours, filtering while hot, washing with 100ml of alcohol, sending the filter cake to a manufacturer for recycling, combining the filtrate and the washing liquid, carrying out reduced pressure concentration to recycle 80-85% of alcohol, cooling to-5-0 ℃, stirring and crystallizing for 2-3 hours, filtering, recycling the alcohol from the filtrate and mother liquor materials for use in the next refining process, rinsing the filter cake with 5ml of cold alcohol, and drying to obtain 17 a-prednisolone dehydroxyacetate refined product 68.8g, HPLC content 99.2%, weight yield 68.8%.
Step C, preparing 16 a-hydroxy prednisolone:
the method for preparing 16 a-hydroxyprednisolone from 17 a-dehydroxyacetic acid prednisolone product is the same as in example 1 of patent application CN 201811343271.1.
Example 2
A. Preparing a protective substance:
adding 100g of prednisolone acetate, 600ml of trichloromethane and 80g of triethylamine into a 1000ml three-neck flask, stirring to completely dissolve the solid, slowly dropwise adding 80g of trimethylchlorosilane at 20-25 ℃, completing the addition within 1.5-2 hours, continuing to perform heat preservation and stirring at 20-25 ℃ for reaction for 3-4 hours after completing the addition, confirming the reaction end point by TLC, recovering 90-95% of trichloromethane as an organic solvent by reduced pressure distillation below 30 ℃ after the reaction is completed, then adding 600ml of tap water, stirring at 10-15 ℃ for crystallization for 3-4 hours, filtering, sending the filtrate to a wastewater treatment pool for treatment, washing a filter cake, and drying at the temperature of below 60 ℃ to obtain a protective substance: 123.2g of 11-trimethylsilyletherified prednisolone acetate, 97.2 percent of HPLC content and 123.2 percent of weight yield;
B. preparation of 17 a-prednisolone dehydroxyacetate:
adding 100g of the protective substance prepared from the A, 1000ml of acetone and 60g of triethylamine into a 2000ml three-necked bottle, stirring to completely dissolve the protective substance, keeping the temperature at 40-45 ℃, and introducing 80g of SO3The gas is completely introduced after about 2-3 hours, after introduction, the dehydration reaction is continuously carried out for 6-12 hours at the temperature of 40-45 ℃, the TLC confirms the reaction end point, 400g of 20% sulfuric acid aqueous solution is directly added after the reaction is finished, the temperature is raised to 60-65 ℃, the hydrolysis reaction is carried out for 3-4 hours, the TLC confirms the hydrolysis reaction end point, after the hydrolysis reaction is finished, a proper amount of liquid alkali is used for adjusting the pH value to 6-7, then 90-95% acetone is recovered by decompression concentration at the temperature of 40 ℃, the temperature is reduced, 600ml of tap water is added for elutriation, the filtrate is discharged into a waste water treatment tank, and the filter cake is washed and dried to obtain 74.8g of 17 a-dehydroxy prednisolone; the crude product was decolorized and recrystallized as described in step B of example 1 to obtain 67.5g of a 17 a-prednisolone dehydroacetate crude product with HPLC content of 99.4% and weight yield of 67.5%.
Step C, preparing 16 a-hydroxy prednisolone:
the process for the preparation of 16 a-hydroxyprednisolone from the 17 a-dehydroxyacetate prednisolone product is in accordance with example 2 of patent application CN 201811343271.1.
Example 3
A: preparing a protective substance:
adding 100g of prednisolone acetate, 600ml of DME and 80g of 4-hydroxypyridine into a 1000ml three-necked bottle, stirring to completely dissolve solids, slowly dropwise adding 80g of trimethylchlorosilane at 20-25 ℃, completing the addition within about 1.5-2 hours, continuing to perform heat preservation and stirring reaction at 20-25 ℃ for 3-4 hours after completing the addition, confirming the reaction end point by TLC, recovering 90-95% of organic solvent DME by reduced pressure distillation at the temperature of below 30 ℃ after completing the reaction, then adding 600ml of tap water, stirring and crystallizing at 10-15 ℃ for 3-4 hours, filtering, sending filtrate to a wastewater treatment tank for treatment, washing filter cakes, and drying at the temperature of below 60 ℃ to obtain a protective substance: 122.6g of 11-trimethylsilyletherified prednisolone acetate, 98.4 percent of HPLC content and 122.6 percent of weight yield;
B. preparation of 17 a-prednisolone dehydroxyacetate:
adding 100g of the protective substance prepared from the A, 1000ml of toluene and 60g of diisopropylamine into a 2000ml three-necked flask, stirring to completely dissolve the protective substance, keeping the temperature at 40-45 ℃, and introducing 80g of SO3Completing gas introduction within 2-3 hours, continuing to perform dehydration reaction at 40-45 ℃ for 6-12 hours after the gas introduction, confirming the reaction end point by TLC (thin layer chromatography), directly adding 400g of 20% p-toluenesulfonic acid aqueous solution after the reaction is completed, heating to 60-65 ℃, performing hydrolysis reaction for 3-4 hours, confirming the hydrolysis reaction end point by TLC, adjusting the pH to 6-7 by using a proper amount of liquid alkali after the hydrolysis reaction is completed, then performing reduced pressure concentration at 60 ℃ to recover 90-95% toluene, cooling, adding 600ml of tap water for elutriation, centrifuging, discharging filtrate into a wastewater treatment tank, washing and drying a filter cake to obtain 74.2g of a 17 a-dehydroxyacetic acid prednisolone crude product; the crude product was decolorized and recrystallized as described in step B of example 1 to obtain 66.8g of a 17 a-prednisolone dehydroacetate refined product with HPLC content of 99.6% and weight yield of 66.8%.
Step C, preparing 16 a-hydroxy prednisolone:
the process for the preparation of 16 a-hydroxyprednisolone from the 17 a-dehydroxyacetate prednisolone product is in accordance with example 3 of patent application CN 201811343271.1.
The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions and substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.
Claims (7)
1. A method for preparing 16 a-hydroxy prednisolone, which is characterized by comprising the following steps,
step A, preparing a protective substance: prednisolone acetate is used as a raw material, and is dissolved in a first organic solvent, and subjected to 11-site silicon etherification reaction with trimethylchlorosilane under the catalysis of organic base to selectively protect 11-site hydroxyl to obtain a protector;
step B, dehydration, hydrolysis deprotection and refining: in a second organic solvent, the protecting substance is mixed with SO3Carrying out 17-position dehydration reaction under the catalysis of organic base, directly adding acid to carry out deprotection on 11 positions after the reaction, and obtaining a 17 a-dehydroxyacetate prednisolone crude product; decolorizing and recrystallizing the crude product of the 17 a-dehydroxy acetate prednisolone in the presence of lower alcohol with the carbon number below C4 and activated carbon to obtain a refined 17 a-dehydroxy acetate prednisolone product;
step C, carrying out epoxidation reaction on the 17 a-dehydroxy acetate prednisolone product and organic peroxy acid at 16 and 17 positions in an organic solvent to prepare an epoxy substance; reacting the epoxy compound with glacial acetic acid in an organic solvent under the catalysis of an acid catalyst to open a ring, so as to prepare 16a, 21-diacetyl oxygen prednisolone; and then dissolving 16a, 21-diacetyl oxygen prednisolone into an organic solvent, and hydrolyzing the acetic esters on two positions under the catalytic action of a solid-phase base catalyst to prepare the 16 a-hydroxy prednisolone, wherein the solid-phase base catalyst is a catalyst which takes alumina, silica gel or calcium carbonate as a carrier and adsorbs sodium carbonate or sodium hydroxide on the carrier.
2. The method according to claim 1, wherein the step A is a stirring reaction at 10-50 ℃ for 3-4 hours, the first organic solvent is one selected from toluene, dichloromethane, acetone, chloroform, DMF, DME and dioxane, and the organic base is pyridine.
3. The method of claim 1, wherein the ratio of prednisolone acetate in step a: organic base: chlorotrimethylsilane ═ 1 g: 0.6-1.5 g: 0.5-1.2 g, wherein the ratio of the reactants to the solvent is prednisolone acetate: first organic solvent ═ 1 g: 2-10 ml.
4. The method according to claim 1, wherein the step B comprises introducing SO at 10-100 ℃3And (3) carrying out gas dehydration reaction for 6-12 hours, wherein the hydrolysis deprotection is completed at 10-100 ℃, the second organic solvent is one of toluene, acetone, chloroform, DMF, DME and dioxane, and the organic base is pyridine.
5. The method of claim 1, wherein the acid in step B is one of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and trifluoroacetic acid.
6. The method of claim 1, wherein the guard in step B: organic base catalyst: SO (SO)31 g: 0.4-1.0 g: 0.5-1.2 g; protection: second organic solvent ═ 1 g: 5-15 ml, protective substance: acid 1 g: 0.5 to 1.5 g.
7. The method according to claim 1, wherein the lower alcohol used for the purification in step B is an alcohol.
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Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4036831A (en) * | 1975-10-28 | 1977-07-19 | Steroid Development Company Establishment | Trimethyl siloxane steroid intermediates |
| WO2001079255A1 (en) * | 2000-04-12 | 2001-10-25 | Genaera Corporation | A process for the preparation of 7.alpha.-hydroxy 3-aminosubstituted sterols using intermediates with an unprotected 7.alpha.-hydroxy group |
| WO2003048181A1 (en) * | 2001-12-01 | 2003-06-12 | Glaxo Group Limited | 17.alpha. -cyclic esters of 16-methylpregnan-3,20-dione as anti-inflammatory agents |
| US7732432B2 (en) * | 2003-01-21 | 2010-06-08 | Merck Sharp & Dohme Corp. | 17-carbamoyloxy cortisol derivatives as selective glucocorticoid receptor modulators |
| CN101759760B (en) * | 2008-11-28 | 2013-02-13 | 天津金耀集团有限公司 | Preparation of fluorine-containing steroid hormone |
| CN103724396A (en) * | 2013-12-18 | 2014-04-16 | 成都医路康医学技术服务有限公司 | Preparation method of R-budesonide |
| CN104262440B (en) * | 2014-09-10 | 2016-08-17 | 江西赣亮医药原料有限公司 | A kind of preparation method of 16-hydroxy prednisonlone |
| CN107573398B (en) * | 2017-09-07 | 2021-02-26 | 山东泰华生物科技股份有限公司 | Preparation method of halcinonide and derivatives thereof |
| CN109081861A (en) * | 2018-11-13 | 2018-12-25 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of 16a- hydroxy prednisonlone |
| CN109232697B (en) * | 2018-11-13 | 2020-07-14 | 湖南科瑞生物制药股份有限公司 | Method for preparing 16 a-hydroxy prednisolone product |
| CN109232696A (en) * | 2018-11-13 | 2019-01-18 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of 16a- hydroxy prednisonlone product |
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