CN109251230B - Method for preparing 16a, 21-diacetyl oxygen prednisolone - Google Patents
Method for preparing 16a, 21-diacetyl oxygen prednisolone Download PDFInfo
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- CN109251230B CN109251230B CN201811343103.2A CN201811343103A CN109251230B CN 109251230 B CN109251230 B CN 109251230B CN 201811343103 A CN201811343103 A CN 201811343103A CN 109251230 B CN109251230 B CN 109251230B
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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
- C07J5/0061—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 method for preparing 16a, 21-diacetyl oxygen group prednisolone, which comprises the steps of adopting 17 a-dehydroxy prednisolone as a raw material, firstly, carrying out epoxidation reaction on the starting raw material 17 a-dehydroxy prednisolone and organic peroxy acid at 16,17 positions in a first organic solvent to prepare an epoxy substance; and reacting the epoxy compound with glacial acetic acid in a second organic solvent under the catalysis of an acid catalyst for ring opening to obtain the target product 16a, 21-diacetyl oxygen prednisolone. The intermediate 16a, 21-diacetyl oxygen group prednisolone of the 16 alpha-hydroxy prednisolone is prepared by an efficient, environment-friendly and flat method.
Description
Technical Field
The invention belongs to a preparation process technology of a steroid hormone drug intermediate, and particularly relates to a method for preparing 16a, 21-diacetyl oxygen prednisolone.
Background
16 a-hydroxy prednisolone (molecular formula C)21H28O6) The chemical name is 11b, 16a, 17a, 21-tetrahydroxy-pregna-1, 4-diene-3, 20-diketone, which is a key intermediate for producing a nedesteroid adrenocortical hormone medicament, the nedeyne is prepared by taking the nedeyne as a raw material and carrying out one-step condensation reaction with acetone, and the nedeyne is prepared by carrying out one-step condensation with n-butyl aldehyde. The traditional production method of 16 a-hydroxy prednisolone takes prednisolone as raw material, and is prepared by four steps of reaction of 17, 21-position double esterification, 17-position ester elimination, 16, 17-position double bond oxidation, 21-position ester hydrolysis and the like, the 16a hydroxy prednisolone synthesized by the method has low total synthesis yield, and the main reason is that: on one hand, when 16, 17-bit double bonds are oxidized by potassium permanganate, 11-bit hydroxyl in molecules can be oxidized due to the oxidizing property of 6a hydroxyl prednisolone of potassium permanganate, and 16-bit hydroxyl in the molecules of the product 16a hydroxyl prednisolone acetate can be oxidized, so that more impurities are generated, the purification is difficult, and the yield of the oxidation step is low; on the other hand, the fourth step 16 a-prednisolone glycolate after hydrolysis with strong alkali such as sodium hydroxide or sodium carbonate or strong acid such as hydrochloric acid or sulfuric acid will produce ring-opening rearrangement and ring-expansion reaction of D ring in the molecule to produce two very large impurities, which are difficult to remove, resulting in low yield of the fourth step hydrolysis reaction. Therefore, the production cost of the 16 a-hydroxy prednisolone by the method is high, so thatGreatly improves the production cost and the market price of the budesonide medicaments, and greatly increases the medication cost of patients in treatment.
Patents such as chinese patent applications CN201610060609, CN201410455522, and CN201010106918 all use potassium permanganate oxidation to produce 16a hydroxyprednisolone.
In addition, patent CN201010205878 provides a method for synthesizing 16 α -hydroxyprednisolone, which comprises the following steps: taking prednisolone with a structure shown as a formula (I) as a raw material, performing dehydration reaction in an acidic ionic liquid with a structure shown as a formula (II) to generate double bonds, adding hydrogen peroxide water solution for reaction, adding water for further hydrolysis after full reaction, and finally obtaining the 16 alpha-hydroxy prednisolone; the synthesis method utilizes the property of the acidic ionic liquid serving as both a reaction medium and a catalyst, achieves the purposes of reducing cost, saving energy and reducing emission by changing the process conditions such as reaction time, reaction temperature and the like, and is suitable for industrial production. And patent CN201210364257 also provides a synthetic method of 16 α -hydroxy prednisolone. The method comprises the steps of taking prednisolone with a structure shown in a formula (I) as a raw material, carrying out dehydration reaction under the action of a gemini surfactant shown in a formula (II) to generate a double-bond compound, then adding aqueous hydrogen peroxide for further reaction, adding water for hydrolysis after the reaction is finished, and obtaining the target product 16 alpha-hydroxy prednisolone, wherein the gemini surfactant is a diphenylmethane gemini surfactant. The gemini surfactant is simultaneously used as a reaction medium and a catalyst, can be recycled and reused after the reaction is finished, and has the advantages of simple process, convenient post-treatment, high yield of the obtained product, good efficiency, less three wastes, high yield up to more than 85 percent, repeated use of the gemini surfactant, economy, practicability, environmental protection and suitability for popularization and application.
However, in the above patent, although the use of a strong oxidizing agent such as potassium permanganate is avoided, prednisolone is used as a raw material, and dehydration is performed to generate a double bond-containing substance, if the double bond-containing substance is 17-dehydroxy prednisolone, the process of preparing 16 α -hydroxy prednisolone by using 17-dehydroxy prednisolone as a raw material, oxidizing with hydrogen peroxide, and then hydrolyzing with water is difficult to implement and repeat. It is not indicated in these two patents what the intermediate formed during the reaction is, and it is therefore not clear what route and route the inventors of these two patents specifically obtained 16 α -hydroxy prednisolone, but it can be seen that acetic acid was not used in these two patents, and thus the process of acetic acid ring opening is not involved at all.
Therefore, in general, no technology which can avoid using potassium permanganate and other strong oxidants and can efficiently, environmentally and cheaply prepare 16 alpha-hydroxy prednisolone exists in the prior art. There is a need in the art to develop a new method for preparing 16 alpha-hydroxy prednisolone and its intermediates.
Disclosure of Invention
In order to efficiently and environmentally prepare the 16 alpha-hydroxy prednisolone, the 16 alpha, 21-diacetyl oxygen prednisolone is prepared by a specific method, and then the 16 alpha-hydroxy prednisolone is obtained by a method of alkali hydrolysis of the 16 alpha, 21-diacetyl oxygen prednisolone under specific conditions.
The invention firstly provides a method for preparing 16a, 21-diacetyl oxygen group prednisolone, which comprises the steps of adopting 17 a-dehydroxy prednisolone as a raw material, firstly, carrying out epoxidation reaction on the starting raw material 17 a-dehydroxy prednisolone and organic peroxy acid at 16,17 positions in a first organic solvent to prepare epoxy; and reacting the epoxy compound with glacial acetic acid in a second organic solvent under the catalysis of an acid catalyst for ring opening to obtain the target product 16a, 21-diacetyl oxygen prednisolone.
In a specific embodiment, the first organic solvent is one or more of toluene, dichloromethane, chloroform, ethyl acetate, DME, dioxane, and the organic peroxyacid is one or more of o-peroxybenzoic acid, m-methylperoxybenzoic acid, m-chloroperoxybenzoic acid, peroxyacetic acid, and peroxybutyric acid.
In a specific embodiment, the first organic solvent is ethyl acetate and the organic peroxyacid is o-peroxybenzoic acid.
In one embodiment, the epoxidation reaction temperature is from 10 ℃ to 60 ℃; 17 a-dehydroxyprednisolone: organic peroxy acid ═ 1 g: 0.1-0.8 g, 17 a-dehydroxyprednisolone: first organic solvent ═ 1 g: 10 to 25 ml.
In one embodiment, the epoxidation reaction temperature is from 25 ℃ to 30 ℃; 17 a-dehydroxyprednisolone: organic peroxy acid ═ 1 g: 0.3-0.5 g, 17 a-dehydroxyprednisolone: first organic solvent ═ 1 g: 13-17 ml.
In a specific embodiment, the second organic solvent is one or more of dichloromethane, glacial acetic acid, chloroform, ethyl acetate, DME, THF, C4 and the following lower alcohols, and the acid catalyst is one or more of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and trifluoroacetic acid.
In a specific embodiment, the second organic solvent is dichloromethane and the acid catalyst is p-toluenesulfonic acid.
In one embodiment, the ring-opening reaction temperature is from 10 to 80 ℃, and the epoxide: acid catalyst: glacial acetic acid ═ 1 g: 0.02-0.20 g: 0.2 to 1.6g, and epoxy: second organic solvent ═ 1 g: 2-15 ml.
In one embodiment, the ring-opening reaction temperature is from 40 ℃ to 45 ℃, and the epoxide: acid catalyst: glacial acetic acid ═ 1 g: 0.04-0.08 g: 0.8 to 1.2g, and epoxy: second organic solvent ═ 1 g: 4-6 ml.
The invention also provides a method for preparing the 16a, 21-diacetyl oxygen group prednisolone product, which comprises the steps of adopting 17 a-dehydroxy prednisolone as a raw material, firstly, carrying out epoxidation reaction on the starting raw material 17 a-dehydroxy prednisolone and organic peroxy acid at 16,17 positions in a first organic solvent to prepare an epoxy substance; reacting the epoxy compound with glacial acetic acid in a second organic solvent under the catalysis of an acid catalyst for ring opening to prepare a target product 16a, 21-diacetyl oxygen prednisolone; and heating, refluxing, decoloring and recrystallizing the crude product of the 16a, 21-diacetyl oxygen prednisolone by using low-carbon alcohol of which the carbon number is less than 4 to obtain a 16a, 21-diacetyl oxygen prednisolone product.
In a specific embodiment, the lower alcohol is alcohol, and the ratio of the crude 16a, 21-bisacetoxyprednisolone product to the alcohol is 1 g: 3.5-6 ml.
The invention also provides a method for preparing 16 a-hydroxy prednisolone, which comprises the steps of adopting 17 a-dehydroxy prednisolone as a raw material, and firstly carrying out epoxidation reaction on the starting raw material 17 a-dehydroxy prednisolone and organic peroxy acid at 16,17 positions in a first organic solvent to prepare an epoxy substance; reacting the epoxy compound with glacial acetic acid in a second organic solvent under the catalysis of an acid catalyst for ring opening to prepare 16a, 21-diacetyl oxygen prednisolone; and then dissolving 16a, 21-diacetyl oxygen prednisolone into a third 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, before the 16a, 21-bisacetoxyprednisolone is hydrolyzed, a process of refining the 16a, 21-bisacetoxyprednisolone crude product by heating, refluxing, decoloring and recrystallizing with a lower alcohol of below C4 is further included, and then the refined 16a, 21-bisacetoxyprednisolone product is used for preparing 16 a-hydroxyprednisolone by hydrolysis.
In a specific embodiment, in the process of preparing 16 a-hydroxy prednisolone by hydrolyzing 16a, 21-diacetyl prednisolone, 16a, 21-diacetyl prednisolone is dissolved in a third organic solvent, stirring is carried out, a solid-phase alkali catalyst is added, the temperature is kept at 10-60 ℃, hydrolysis reaction is carried out for 6-12 hours, TLC confirms the reaction end point, after the reaction is finished, pressure filtration is carried out by nitrogen while hot, a filter cake is washed by the third organic solvent, and then the solid-phase alkali catalyst is recovered for reuse; and combining the filtrate and the washing liquid, concentrating under reduced pressure to recover a third organic solvent, cooling, adding water for elutriation, preferably using tap water, centrifuging, recovering the residual third organic solvent from the filtrate under reduced pressure, washing a filter cake with water, and drying to obtain a crude 16 a-hydroxyprednisolone product.
In a specific embodiment, the third organic solvent is one or more selected from the group consisting of toluene, chloroform, dichloromethane, acetone, DMF, DME, dioxane, C4 and lower alcohols, preferably toluene or chloroform; the reaction temperature is preferably 40-45 ℃; and the weight ratio in the step is 16a, 21-diacetyl oxygen prednisolone: solid phase base catalyst ═ 1: 0.5 to 1.2, preferably 1: 0.6 to 1.0; the ratio of the reactants to the solvent is 16a, 21-diacetyl oxygen prednisolone: third organic solvent ═ 1 g: 10 to 25 ml.
In a specific embodiment, the solid-phase base catalyst is prepared by the following steps: dissolving solid strong base sodium carbonate or sodium hydroxide in water, adding carrier powder, stirring and adsorbing at 10-50 ℃ for reaction for 3-4 hours, evaporating water under reduced pressure until the water is nearly dry after the reaction is finished, taking out the reaction product and drying the reaction product to obtain a solid-phase base catalyst, wherein the water content is 3-8%; the weight ratio of reactants is as follows: alkali: water 1: 0.2-0.4: 8 to 12.
The invention also provides a method for preparing the 16 a-hydroxy prednisolone product, which comprises the steps of adopting 17 a-dehydroxy prednisolone as a raw material, firstly, carrying out epoxidation reaction on the starting raw material 17 a-dehydroxy prednisolone and organic peroxy acid at 16 and 17 positions in a first organic solvent to prepare an epoxy substance; reacting the epoxy compound with glacial acetic acid in a second organic solvent under the catalysis of an acid catalyst for ring opening to prepare 16a, 21-diacetyl oxygen prednisolone; then dissolving 16a, 21-diacetyl oxygen prednisolone into a third organic solvent, and hydrolyzing acetic esters on two positions under the catalytic action of a solid-phase base catalyst to prepare 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; and finally, heating, refluxing, decoloring and recrystallizing the crude product of the 16 a-hydroxy prednisolone obtained by the catalytic hydrolysis of the solid-phase alkali by using low-carbon alcohol of which the carbon number is less than C4 to obtain the 16 a-hydroxy prednisolone product.
In a specific embodiment, the lower alcohol used for refining the crude 16 a-hydroxyprednisolone product is alcohol, and the dosage ratio of the crude 16 a-hydroxyprednisolone product to the alcohol is 1 g: 8-15 ml.
That is, the present invention aims to provide a novel synthesis method for indirectly preparing 16 a-hydroxyprednisolone by synthesizing 16a, 21-bisacetoxyprednisolone, aiming at the defects of more reaction impurities, low synthesis yield, high production cost and the like in the synthesis of 16 a-hydroxyprednisolone, namely, 17 a-dehydroxyprednisolone is used as a raw material, 16, 17-double bonds in molecules are firstly oxidized by peroxy acid to form epoxy substances, and the epoxy substances are subjected to acid catalytic ring opening in acetic acid to prepare 16a, 21-bisacetoxyprednisolone. The 16a, 21-diacetyl oxygen radical prednisolone is catalyzed and hydrolyzed by solid phase alkali to prepare the 16 a-hydroxyl prednisolone. The method avoids a plurality of difficulties of side reactions, a plurality of impurities, difficult purification of the impurities and the like caused by using potassium permanganate for oxidation in the conventional production method of the 16 a-hydroxy prednisolone, greatly improves the total synthesis yield of the 16 a-hydroxy prednisolone, and greatly reduces the production cost of the 16 a-hydroxy prednisolone.
The technical scheme of the invention is as follows: a preparation method of 16a, 21-diacetyl oxygen radical prednisolone adopts 17 a-dehydroxy prednisolone as raw material, namely: firstly, performing epoxidation reaction on a starting material 17 a-dehydroxyprednisolone and organic peroxy acid at 16 and 17 positions in a first organic solvent to prepare an epoxy substance; reacting the epoxy compound with glacial acetic acid in a second organic solvent under the catalysis of acid for ring opening to prepare a target product 16a, 21-diacetyl oxygen prednisolone;
further, the specific operation steps of the preparation method of the 16a, 21-diacetyl oxygen prednisolone are as follows:
A. preparing an epoxy material: dissolving 17 a-dehydroxyprednisolone serving as an initial raw material into a first organic solvent, dropwise adding a peracid solution prepared from organic peroxy acid and the first organic solvent within 2-2.5 hours at 10-60 ℃, continuously carrying out heat preservation reaction for 6-12 hours at 10-60 ℃ after dropwise adding, confirming a reaction end point by TLC (thin layer chromatography), neutralizing acid and excessive peroxy acid generated by a destruction reaction after the reaction is finished, then carrying out reduced pressure concentration to recover 90-95% of the organic solvent, cooling, adding tap water for elutriation, filtering, discharging filtrate into a wastewater treatment tank, washing and drying a filter cake to obtain 16,17 a-epoxy prednisolone, wherein the HPLC content is 95.0-98.0%, and the weight yield is 95-100%;
B. preparation of 16a, 21-bisacetoxyprednisolone: dissolving the epoxy prepared in the step A into a second organic solvent, adding glacial acetic acid and a proper amount of acid catalyst at room temperature, reacting for 2-3 hours at the temperature of 10-80 ℃, confirming the reaction end point by TLC, neutralizing excessive acetic acid and catalytic acid after the reaction is finished, then decompressing, concentrating and recovering 90% of organic solvent, cooling again, adding tap water for elutriation, filtering, discharging filtrate into a wastewater treatment tank, washing and drying filter cakes; combining the filtrate and the washing liquid, concentrating under reduced pressure to recover 90-95% of organic solvent, cooling, adding tap water for elutriation, centrifuging, recovering residual organic solvent from the filtrate under reduced pressure, then discharging the residual organic solvent into a wastewater treatment tank, washing and drying a filter cake to obtain a crude product of 16a, 21-diacetyl oxygen prednisolone;
m, decoloring and recrystallizing the crude product by using lower carbon alcohol of below C4 to obtain a 16a, 21-diacetyl oxygen prednisolone product.
HPLC content is above 99.0%.
The invention has the beneficial effects that: the method adopts 17 a-dehydroxy prednisolone as a raw material, and firstly, the 17 a-dehydroxy prednisolone and organic peroxy acid undergo epoxidation reaction at 16 and 17 positions in a first organic solvent to prepare an epoxy substance; reacting the epoxy compound with glacial acetic acid in a second organic solvent under the catalysis of an acid catalyst for ring opening, and preparing a target product 16a, 21-diacetyl oxygen prednisolone through two-step reaction; the 16a, 21-diacetyl oxygen group prednisolone produced by the method is used in a third organic solvent, and a solid phase alkali catalytic hydrolysis method is used to produce the 16 a-hydroxy prednisolone, so that the production operation is simple and convenient, the production process is economic and environment-friendly, and most importantly, the difficulties of more side reactions, more impurities, difficult purification of impurities and the like caused by the oxidation of potassium permanganate in the traditional 16 a-hydroxy prednisolone production method are avoided, thereby greatly improving the total synthesis yield. Compared with the preparation method of 16 a-hydroxy prednisolone in the traditional production method, the preparation cost of the method of the invention is reduced by 10-15%. In addition, the solvent used in the production of the method can be recycled, and the method is easy to implement industrial production.
In conclusion, the 16 alpha-hydroxy prednisolone and the intermediate 16a, 21-diacetyl oxygen prednisolone thereof are prepared by an efficient, environment-friendly and flat method.
Drawings
FIG. 1 is a flow chart of the structures of 16a, 21-bisacetoxyprednisolone and 16 a-hydroxyprednisolone prepared in the present invention.
Detailed Description
In order to more conveniently explain the gist and spirit of the present invention, the following examples are given:
example 1
Step A- -preparation of the epoxy:
adding 100g of starting material 17 a-dehydroxyprednisolone and 1000ml of ethyl acetate into a 3000ml three-neck bottle, stirring at room temperature to completely dissolve solids, dropwise adding a peracid solution prepared from 40g of o-peroxy benzoic acid and 500ml of ethyl acetate at 25-30 ℃, completing dropwise within 2-2.5 hours, continuing heat preservation reaction at 25-30 ℃ for 6-12 hours after completing dropwise addition, confirming the reaction end by TLC, adding a mixed solution prepared from 400ml of 5% sodium hydroxide and 100ml of 10% sodium sulfite after the reaction is completed, neutralizing acid generated by the destruction reaction and excessive peroxy acid, then decompressing and concentrating at 50 ℃ to recover 90-95% ethyl acetate, cooling to room temperature, adding 500ml of tap water, stirring and precipitating for 3-4 hours, filtering, discharging filtrate into a waste water treatment pool, washing filter cakes with water, drying at 60 ℃, 99.3g of 16,17 a-epoxy prednisolone is obtained, the HPLC content is 97.8 percent, and the weight yield is 99.3 percent.
Step B- - -preparation of 16a, 21-diacetyloxyprednisolone:
and (2) adding 100g of the epoxy prepared in the step A and 500ml of dichloromethane into a 1000ml three-neck flask, stirring at room temperature to completely dissolve the epoxy, adding 100g of glacial acetic acid and 6g of p-toluenesulfonic acid catalyst, reacting at 40-45 ℃ for 2-3 hours under heat preservation, confirming the reaction end point by TLC, after the reaction is finished, slowly dropwise adding 200ml of 10% sodium bicarbonate solution, neutralizing excessive acetic acid and catalytic acid to ensure that the pH of the system is about 6-7, then concentrating under reduced pressure at the temperature of below 35 ℃ to recover 90-95% of solvent dichloromethane, cooling to 5-10 ℃, adding 500ml of tap water, stirring and precipitating for 3-4 hours, filtering, discharging filtrate into a wastewater treatment tank, washing filter cakes with water, and drying at the temperature of below 70 ℃ to obtain 127.8g of crude 16a, 21-bisacetoxyprednisolone.
Step M- - -16a, 21-bisacetoxyprednisolone product preparation:
adding the crude product obtained in the step B into 500ml of alcohol, decoloring, adding 5g of activated carbon, heating, refluxing for 1.0-1.5 hours, press-filtering while hot, soaking and washing a filter cake with 100ml of alcohol twice, then sending the filter cake to a manufacturer for recycling, merging filtrate and washing liquor, concentrating under reduced pressure, recycling 85-90% of alcohol, cooling to-5-0 ℃, stirring, crystallizing for 2-3 hours, filtering, recycling the alcohol from the filtrate, and sleeving the alcohol and a mother liquor material into the next refining process; rinsing the filter cake with 5ml of cold alcohol, and drying to obtain 103.3g of 16a, 21-diacetyl oxygen prednisolone refined product, the HPLC content is 99.6 percent, and the weight yield is 103.3 percent.
Step C, synthesizing 16 a-hydroxy prednisolone
Adding 100g of 16a, 21-diacetyl oxygen prednisolone prepared in the step M into a 2000ml three-necked bottle as a raw material, 1500ml of toluene, stirring to completely dissolve the toluene, adding 60g of a self-prepared solid-phase base catalyst, keeping the temperature, stirring and hydrolyzing at 40-45 ℃ for 6-8 hours, confirming the reaction end point by TLC (thin layer chromatography), performing pressure filtration while hot nitrogen is used after the reaction is finished, soaking and washing a filter cake twice by using 500ml of toluene, and recovering the solid-phase base catalyst for reuse; combining the filtrate and the washing liquid, concentrating under reduced pressure to recover 95% of toluene, then cooling, adding tap water for elutriation, centrifuging, firstly recovering residual toluene from the filtrate under reduced pressure, then discharging the residual toluene into a wastewater treatment tank, washing and drying a filter cake to obtain 80.1g of a 16 a-hydroxy prednisolone crude product, wherein the HPLC content is 98.5%, and the weight yield is 80.1%; dissolving the crude 16 a-hydroxyprednisolone product in 800ml of alcohol, adding 5g of activated carbon, heating and refluxing for 1.0-1.5 hours, press-filtering while hot, soaking and washing the filter cake with 100ml of alcohol twice, then sending the filter cake to a manufacturer for recovery, merging the filtrate and the washing liquid, concentrating under reduced pressure to recover 95% alcohol, cooling to-5-0 ℃, stirring for crystallization for 2-3 hours, filtering, rinsing the filter cake with 5ml of cold alcohol, and drying to obtain 70.5g of refined 16 a-hydroxyprednisolone product, wherein the HPLC content is 99.6%, the refined weight yield is 88.0%, and the total preparation weight yield is 70.5%; the recovered alcohol of the filtrate and the mother liquor are used for the next refining process.
In addition, the specific process for preparing the solid phase base catalyst in step C of this example is as follows: adding a solution prepared from 50g of solid alumina, 300ml of tap water, 200ml of tap water and 15g of sodium carbonate into a 1000ml three-necked bottle, stirring and adsorbing at 25-30 ℃ for 3-4 hours, evaporating water under reduced pressure until the water is nearly dry after the reaction is finished, taking out and drying to obtain 50.1g of solid-phase alkali catalyst, wherein the water content is 5.6 percent, and the weight yield is 102 percent.
Example 2
Step A: preparation of epoxy:
adding 100g of starting material 17 a-dehydroxyprednisolone and 1000ml of chloroform into a 3000ml three-mouth bottle, stirring at room temperature to completely dissolve solids, dropwise adding a peracid solution prepared from 40g of m-chloroperoxybenzoic acid and 500ml of ethyl acetate at the temperature of 25-30 ℃, completing dropwise addition within about 2-2.5 hours, continuing heat preservation reaction at 25-30 ℃ for 6-12 hours after completing dropwise addition, confirming the reaction end by TLC, adding a mixed solution prepared from 400ml of 5% sodium hydroxide and 100ml of 10% sodium sulfite after the reaction is completed to neutralize acid generated by the destruction reaction and excessive peroxy acid, then decompressing and concentrating at the temperature of below 50 ℃ to recover 90-95% mixed solvent of chloroform and ethyl acetate, cooling to room temperature, adding 500ml of tap water, stirring and carrying out water precipitation for 3-4 hours, filtering, discharging filtrate into a waste water treatment tank, washing filter cakes, drying at the temperature of below 60 ℃ to obtain 98.2g of 16,17 a-epoxy prednisolone, the HPLC content is 98.1 percent, and the weight yield is 98.2 percent;
and B: preparation of 16a, 21-diacetylprednisolone:
and (2) adding 100g of the epoxy prepared in the step A and 500ml of ethyl acetate into a 1000ml three-neck flask, stirring at room temperature to completely dissolve the epoxy and 500ml of ethyl acetate, then adding 100g of glacial acetic acid and 6g of concentrated sulfuric acid catalyst, reacting at 40-45 ℃ for 2-3 hours under heat preservation, confirming the reaction end point by TLC, after the reaction is finished, slowly dropwise adding 200ml of 10% sodium bicarbonate solution, neutralizing excessive acetic acid and catalytic acid to ensure that the pH of the system is about 6-7, then concentrating under reduced pressure at the temperature of 45 ℃ to recover 90-95% of solvent ethyl acetate, cooling to 5-10 ℃, adding 500ml of tap water, stirring and carrying out water precipitation for 3-4 hours, filtering, discharging filtrate into a wastewater treatment tank, washing filter cakes with water, and drying at the temperature of 70 ℃ to obtain 125.4g of a 16a 21-bisacetoxyprednisolone crude.
Step M- - -16a, 21-bisacetoxyprednisolone product preparation:
recrystallizing the crude product obtained in the step B according to the method in the step M of the embodiment 1 to obtain 101.2g of a refined 16a, 21-diacetylprednisolone product with the HPLC content of 99.5 percent and the weight yield of 101.2 percent.
Step C, synthesizing 16 a-hydroxy prednisolone
Adding 100g of 16a, 21-diacetyl oxygen prednisolone prepared in the step M into a 2000ml three-necked bottle as a raw material, 1500ml of alcohol, stirring to completely dissolve the raw material, adding 60g of a self-prepared solid-phase alkali catalyst, keeping the temperature at 40-45 ℃, stirring, hydrolyzing for 6-8 hours, confirming the reaction end point by TLC (thin layer chromatography), performing filter pressing on the mixture with hot nitrogen after the reaction is finished, soaking and washing the filter cake twice by using 500ml of alcohol, and recovering the solid-phase alkali catalyst for reuse; combining the filtrate and the washing liquid, concentrating under reduced pressure to recover 95% alcohol, cooling, adding tap water for elutriation, centrifuging, firstly recovering residual alcohol from the filtrate under reduced pressure, then discharging into a wastewater treatment tank, washing and drying a filter cake to obtain 79.5g of a 16 a-hydroxy prednisolone crude product, wherein the HPLC content is 98.6%, and the weight yield is 79.5%; recrystallizing the crude 16 a-hydroxyprednisolone product according to the method in the step C in the example 1 to obtain 68.9g of a refined 16 a-hydroxyprednisolone product, wherein the HPLC content is 99.3%, the refined weight yield is 86.7%, and the total preparation weight yield is 68.9%; the recovered alcohol of the filtrate and the mother liquor are used in the next refining process.
In addition, the specific process for preparing the solid phase base catalyst in step C of this example is as follows: 49.8g of a solid base catalyst having a water content of 6.8% on a silica gel carrier was prepared by following the procedure of the step C of example 1 except that the silica gel was used in place of the alumina.
Example 3
Step A- -preparation of the epoxy:
adding 100g of starting raw material 17 a-dehydroxyprednisolone and 1000ml of DME into a 3000ml three-neck flask, stirring at room temperature to completely dissolve solids, dropwise adding a peracid solution prepared from 40g of peracetic acid and 500ml of DME at a temperature of 25-30 ℃, completing dropwise within 2-2.5 hours, continuing to perform heat preservation reaction at 25-30 ℃ for 6-12 hours after completing dropwise addition, confirming the reaction end by TLC, adding 400ml of a mixed solution prepared from 5% sodium hydroxide and 100ml of 10% sodium sulfite after completing the reaction, neutralizing and destroying the generated acid and excessive peroxy acid, then decompressing and concentrating at 50 ℃ to recover 90-95% DME solvent, cooling to room temperature, adding 500ml of tap water, stirring and performing water precipitation for 3-4 hours, filtering, discharging filtrate into a waste water treatment tank, washing filter cake, drying at the temperature of below 60 ℃ to obtain 98.2g of 16,17 a-epoxy prednisolone, HPLC content 97.2%, weight yield 98.2%;
step B- - -preparation of 16a, 21-diacetyloxyprednisolone:
and (2) adding 100g of the epoxy prepared in the step A and 500ml of THF into a 1000ml three-neck flask, stirring at room temperature to completely dissolve the epoxy, adding 100g of glacial acetic acid and 6g of phosphoric acid catalyst, reacting at 40-45 ℃ for 2-3 hours under heat preservation, confirming the reaction end point by TLC, after the reaction is finished, slowly dropwise adding 200ml of 10% sodium bicarbonate solution, neutralizing excessive acetic acid and catalytic acid to ensure that the pH of the system is about 6-7, then concentrating under reduced pressure at 45 ℃ to recover 90-95% of solvent THF, cooling to 5-10 ℃, adding 500ml of tap water, stirring and precipitating for 3-4 hours, filtering, discharging filtrate into a wastewater treatment tank, washing filter cakes with water, and drying at 70 ℃ to obtain 128.9g of crude 16a, 21-bisacetoxyprednisolone dragon product.
Step M- - -16a, 21-bisacetoxyprednisolone product preparation:
recrystallizing the crude product obtained in the step B according to the method in the step M of the example 1 to obtain 104.5g of 16a, 21-diacetyl oxygen prednisolone refined product, the HPLC content is 99.7 percent, and the weight yield is 104.5 percent.
Step C, synthesizing 16 a-hydroxy prednisolone
Adding 100g of 16a, 21-diacetyl oxygen prednisolone prepared in the step M into a 2000ml three-necked bottle as a raw material, 1500ml of chloroform, stirring to completely dissolve the chloroform, adding 60g of a self-prepared basic calcium carbonate solid-phase alkali catalyst, keeping the temperature at 40-45 ℃, stirring, hydrolyzing for 6-8 hours, confirming the reaction end point by TLC, performing pressure filtration with hot nitrogen after the reaction is finished, soaking and washing a filter cake twice by using 500ml of chloroform, and recovering the solid-phase alkali catalyst for use; combining the filtrate and the washing liquid, concentrating under reduced pressure to recover 95% chloroform, cooling, adding tap water for elutriation, centrifuging, recovering residual chloroform from the filtrate under reduced pressure, discharging into a wastewater treatment tank, washing and drying a filter cake to obtain 79.8g of a 16 a-hydroxy prednisolone crude product, wherein the HPLC content is 98.7%, and the weight yield is 79.8%; recrystallizing the crude 16 a-hydroxyprednisolone product by the method described in the step C of the embodiment 1 to obtain 70.3g of a refined 16 a-hydroxyprednisolone product, wherein the HPLC content is 99.5%, the refined weight yield is 88.1%, and the total preparation weight yield is 70.3%; the recovered alcohol of the filtrate and the mother liquor are used in the next refining process.
In addition, the specific process for preparing the solid phase base catalyst in step C of this example is as follows: 49.6g of solid base catalyst having calcium carbonate as a carrier and 4.8% of water was prepared by following the procedure of step C of example 1 except that the alumina was replaced with calcium carbonate and the sodium carbonate was replaced with sodium hydroxide.
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 (4)
1. A method for preparing 16a, 21-diacetyl oxygen group prednisolone is characterized in that 17 a-dehydroxy prednisolone is adopted as a raw material, and the initial raw material 17 a-dehydroxy prednisolone is firstly put in a first organic solvent and undergoes epoxidation reaction with organic peroxy acid at 16,17 sites to prepare epoxy; reacting the epoxy compound with glacial acetic acid in a second organic solvent under the catalysis of an acid catalyst for ring opening to prepare a target product 16a, 21-diacetyl oxygen prednisolone; the first organic solvent is ethyl acetate, the organic peroxy acid is o-peroxy benzoic acid, and the epoxidation reaction temperature is 10-60 ℃; 17 a-dehydroxyprednisolone: organic peroxy acid ═ 1 g: 0.1-0.8 g, 17 a-dehydroxyprednisolone: first organic solvent ═ 1 g: 10-25 ml; the second organic solvent is one or more of dichloromethane, glacial acetic acid, chloroform, ethyl acetate, DME, THF, C4 and the following low-carbon alcohols, the acid catalyst is one or more of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and trifluoroacetic acid, the ring-opening reaction temperature is 10-80 ℃, and the epoxy compound in the ring-opening step: acid catalyst: glacial acetic acid ═ 1 g: 0.02-0.20 g: 0.2 to 1.6g, and epoxy: second organic solvent ═ 1 g: 2-15 ml.
2. The method according to claim 1, wherein the epoxidation reaction temperature is 25 to 30 ℃; 17 a-dehydroxyprednisolone: organic peroxy acid ═ 1 g: 0.3-0.5 g, 17 a-dehydroxyprednisolone: first organic solvent ═ 1 g: 13-17 ml.
3. The method of claim 1, wherein the second organic solvent is dichloromethane and the acid catalyst is p-toluenesulfonic acid.
4. The method according to claim 1, wherein the ring-opening reaction temperature is 40-45 ℃, and the epoxy compound in the ring-opening step: acid catalyst: glacial acetic acid ═ 1 g: 0.04-0.08 g: 0.8 to 1.2g, and epoxy: second organic solvent ═ 1 g: 4-6 ml.
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