CN109608511B - Chemical synthesis process of prednisolone valerate acetate - Google Patents
Chemical synthesis process of prednisolone valerate acetate Download PDFInfo
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- 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 belongs to the technical field of chemical synthesis, and discloses a chemical synthesis process of prednisolone valerate acetate, which takes prednisolone, p-toluenesulfonic acid, trimethyl ortho-valerate, dimethylaminopyridine, pyridine and acetic anhydride as raw materials, synthesizes prednisolone valerate acetate through fewer process steps, simplifies production procedures, obviously reduces production cost, has high yield and product purity, is suitable for large-scale production of factories, and has good industrial development value and good market application prospect.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a chemical synthesis process of prednisolone valerate acetate.
Background
Prednisolone valerate acetate, which is an adrenocortical hormone, exhibits an excellent anti-inflammatory action on the affected area, can be converted into a highly safe and low-active substance in vivo, and is widely used as a therapeutic agent for eczema, dermatitis, macula, insect bite, pruritus, miliaria, urticaria, and the like. In the existing chemical synthesis process method of prednisolone valerate acetate, the process flow is not easy to master, and the generated pure product has low purity, complex manufacturing procedure, low production efficiency and high manufacturing cost, and is not suitable for large-scale production. For this reason, it is necessary to develop a new chemical synthesis process of prednisolone valerate acetate to solve the above problems.
Disclosure of Invention
The invention aims to provide a chemical synthesis process of prednisolone valerate acetate, which overcomes the defects in the prior art.
In order to achieve the purpose, the invention adopts the following technical scheme:
the chemical synthesis process of prednisolone valerate acetate includes the following steps:
s1: dissolving prednisolone (I) with appropriate amount of dichloromethane and dimethyl sulfoxide to obtain a dissolved solution system, and starting nitrogen protection;
s2: adding p-toluenesulfonic acid (PTS) and trimethyl orthovalerate into the solution clear system obtained in the step S1, controlling the reaction temperature to be 20-30 ℃, stirring and reacting for 1-2 hours, and obtaining a reaction system containing a cyclic ester (II) after the reaction is completed; the addition amount of the p-toluenesulfonic acid is 2.5-4% of the mass of prednisolone; the volume-mass ratio of trimethyl ortho-valerate to prednisolone is 1.5-1.75 g/ml;
s3: adding a proper amount of dilute sulfuric acid and an organic cosolvent into the reaction system of the step S2, controlling the reaction temperature to be 20-30 ℃, stirring and reacting for 1-2 hours, and obtaining a mixed system containing prednisolone valerate (III) after the reaction is completed;
s4: adding a proper amount of dimethyl sulfoxide and water into the mixed system obtained in the step S3, collecting a lower organic phase layer by layer, carrying out vacuum distillation and concentration on the organic phase, adding a proper amount of dichloromethane, carrying and dehydrating to obtain a prednisolone valerate crude product;
s5: cooling the prednisolone valerate crude product obtained in the step S4 to 20-30 ℃, adding dimethylaminopyridine, pyridine and acetic anhydride, and stirring for reaction for 1-3 hours while keeping the temperature to obtain prednisolone valerate acetate (IV) crude product; the adding amount of the dimethylaminopyridine is 0.6-0.75% of the mass of prednisolone, and the volume-mass ratio of the pyridine to the prednisolone is 0.5-0.6 ml/g; the volume-mass ratio of the acetic anhydride to the prednisolone is 1.5-1.75 ml/g;
s6: adding water into the prednisolone valerate acetate crude product obtained in the step S5, stirring, standing for layering, performing cyclic operation for 1-5 times, collecting an organic phase, adding an appropriate amount of organic cosolvent into the organic phase, adding a small amount of decolorizing agent for decolorization and filtration, washing a filter cake with an appropriate amount of dichloromethane, merging filtrate, distilling the filtrate at normal pressure until the material is separated out, adding the organic cosolvent for dissolution, concentrating, cooling, stirring, performing suction filtration, washing, and drying to obtain prednisolone valerate acetate.
According to the invention, as can be easily understood by those skilled in the art, the dichloromethane and the dimethyl sulfoxide can be added into the prednisolone respectively and then mixed together, and the ratio of the total volume of the added dichloromethane and the dimethyl sulfoxide to the volume of the prednisolone is 20-25 ml/g. (ii) a It can also be mixed in advance and added in the form of a mixed solvent.
Preferably, in the step S1, the dichloromethane and the dimethyl sulfoxide are added in the form of a mixed solvent, and the volume ratio of the dichloromethane to the dimethyl sulfoxide in the mixed solvent is 8-4: 1; the volume-mass ratio of the added mixed solvent to the prednisolone is 20-25 ml/g.
According to the invention, in the step S2, the content of prednisolone as a reaction raw material in the reaction system containing the cyclic ester is detected to be less than or equal to 1 wt%, namely the reaction is complete;
in step S3, the content of cyclic ester is detected to be less than or equal to 1 wt% in the mixed system containing prednisolone valerate, that is, the reaction is complete.
In step S5, it is detected that the content of prednisolone valerate in the mixed system containing prednisolone valerate acetate is less than or equal to 0.5 wt%, i.e., the reaction is complete.
According to the invention, in the step S3, the dilute sulfuric acid is prepared by uniformly mixing 98% concentrated sulfuric acid and water according to the volume ratio of 1: 130-170; the volume-mass ratio of the dilute sulfuric acid to the prednisolone is 0.15-0.25 g/ml.
According to the invention, in the step S3, before adding the dilute sulfuric acid, the temperature of the reaction system containing the cyclic ester is reduced. Preferably, the temperature of the reaction system containing the cyclic ester is reduced to 18-20 ℃.
According to the invention, in the step S3, the organic cosolvent is selected from one or two of acetone and glacial acetic acid.
According to the invention, in the step S4, the volume-to-mass ratio of the amount of the dichloromethane used for entrainment to the prednisolone is 5-7.5 g/ml.
According to the invention, in the step S4, dichloromethane is added to carry the water content of the system to be less than 0.3 wt%.
According to the invention, in the step S4, the volume-to-mass ratio of the addition amount of the dimethyl sulfoxide to the prednisolone is 0.4-1.0 ml/g. Preferably 0.4 to 0.5 ml/g.
According to the invention, in the step S4, the volume-to-mass ratio of the added amount of the water to the prednisolone is 15-20 ml/g. Preferably 15 to 16 ml/g.
According to the invention, in the step S4, the organic phase is distilled under reduced pressure until the volume of the organic phase is 30-60% of the volume of the stock solution.
The volume of the organic phase after distillation under reduced pressure cannot be too small or too large, otherwise both affect the subsequent dichloromethane drying step and the reaction step of S5, eventually resulting in a reduction in yield and purity of the product.
According to the specific embodiment of the invention, 20g of prednisolone is used as a starting material, and in the step S4, the organic phase is distilled under reduced pressure until the volume is 190-210 ml.
According to the invention, in the step S6, the organic cosolvent is one or more of methanol, ethanol and acetone. Preferably, the organic co-solvent is methanol.
Further, in step S6, if the reaction temperature is not higher than the boiling point of the organic co-solvent during the atmospheric distillation, the organic co-solvent may be continuously added until the reaction temperature is higher than the boiling point of the organic co-solvent.
When methanol is used as the preferred organic co-solvent, it is generally set that if atmospheric distillation is used, the reaction temperature is not 64.5 ℃ above the boiling point of methanol, and the organic co-solvent can be added continuously until the reaction temperature is greater than 64.5 ℃.
The temperature value of 65 ℃ can be preset as the end point of the atmospheric distillation, and when the atmospheric distillation is carried out, the reaction temperature reaches 65 ℃, and then the atmospheric distillation is finished.
According to the invention, in the step S6, the decoloring temperature is 40 +/-2 ℃, and the decoloring time is 2-12 hours.
It is well understood by those skilled in the art that the decolorizing agent can be one or more of activated carbon, clay, adsorbent resin, molecular sieve, diatomaceous earth, neutral alumina, silicon magnesium adsorbent.
Preferably, in the step S6, the decoloring agent is activated carbon.
According to the invention, in the step S6, the concentration step takes the reaction temperature higher than the boiling point of the organic cosolvent as the concentration end point.
According to the present invention, it is easily understood by those skilled in the art that the concentration step may be atmospheric distillation or vacuum distillation. Atmospheric distillation is preferred in this step.
According to the invention, in the step S6, the temperature reduction step adopts a step-by-step temperature reduction method, the temperature is reduced to the reaction temperature of less than 40 ℃ by using a conventional method, and then the temperature is reduced to 0-5 ℃ by freezing.
According to the present invention, in the step S6, the stirring step is performed for 1 to 8 hours.
According to the present invention, in the step S6, the drying step is performed for 5 to 10 hours at 40 to 60 ℃ under vacuum.
The yield of the prednisolone valerate acetate prepared by the invention is 95.0-115.0%, and the purity of the finished product is more than or equal to 99.5%.
Further, the purity of the finished product is 99.5-99.8%.
Compared with the prior art, the invention has the following beneficial technical effects:
the chemical synthesis process of prednisolone valerate acetate takes prednisolone, p-toluenesulfonic acid, trimethyl ortho-valerate, dimethyl aminopyridine, pyridine and acetic anhydride as raw materials, synthesizes prednisolone valerate acetate through fewer process steps, simplifies production procedures, obviously reduces production cost, has high yield and product purity, is suitable for large-scale production of factories, and has good industrial development value and good market application prospect.
Drawings
FIG. 1 is a schematic diagram of the chemical synthesis process of prednisolone valerate acetate of the present invention.
Detailed Description
The present invention will be further described with reference to the following examples. It should be understood that the following examples are illustrative only and are not intended to limit the scope of the present invention.
In the following examples, all the starting materials used are commercially available.
Defining the yield as ═ 100% of (mass of prednisolone valerate acetate product obtained by final drying of S6/mass of input raw material prednisolone ] ×
The prednisolone valerate acetate prepared in the following examples has the weight of 19-23 g, the yield of 95.0% -115.0%, and the purity of the finished product is 99.5-99.8%.
And detecting the content of the sample in each step by adopting a high performance liquid chromatography.
Example 1 prednisolone valerate acetate chemical Synthesis Process
The chemical synthesis process of prednisolone valerate acetate includes the following steps:
s1: adding 20g of prednisolone into a reaction bottle, controlling the reaction temperature at 25 ℃, then adding 25ml of mixed solvent of dichloromethane and dimethyl sulfoxide with the volume ratio of 4:1, stirring until the materials are dissolved clearly to obtain a clear solution system, and starting nitrogen protection.
S2: and (3) adding 0.5g of p-toluenesulfonic acid into the solution clear system obtained in the step S1, adding 30mL of trimethyl orthovalerate, controlling the reaction temperature to be 25 ℃, stirring and reacting for 1 hour, and detecting that the content of prednisolone in the reaction system is less than or equal to 1 wt%, so that the reaction is complete, and thus obtaining the reaction system containing the cyclic ester.
S3: and (3) reducing the temperature of the reaction system in the step S2 to 20 +/-2 ℃, adding 3mL of dilute sulfuric acid solution, adding 20mL of acetone, controlling the reaction temperature at 25 ℃, stirring for reacting for 2 hours, and detecting that the content of cyclic ester in the reaction system is less than or equal to 1 wt%, namely completely reacting to obtain a prednisolone valerate mixed system. In the step, the dilute sulfuric acid is prepared by uniformly mixing 98% concentrated sulfuric acid and water according to the volume ratio of 1: 150.
S4: and adding 8mL of dimethyl sulfoxide and 300mL of water into the mixed system obtained in the step S3, stirring for 5 minutes, standing for 15 minutes, collecting organic phases in a layered mode into another reaction bottle, distilling under reduced pressure until the volume is 200mL, adding 100mL of dichloromethane for entrainment and dehydration until the water content in the reaction system is less than 0.3 wt%, and obtaining a prednisolone valerate crude product.
S5: and (3) cooling the prednisolone valerate crude product obtained in the step (S4) to 25 ℃, adding 0.12g of dimethylaminopyridine, 10mL of pyridine and 10mL of acetic anhydride into the reaction bottle, controlling the reaction temperature to be 25 ℃, keeping the temperature, stirring and reacting for 2 hours, and detecting that the content of prednisolone valerate in the reaction system is less than or equal to 0.5 wt%, namely completely reacting to obtain the prednisolone valerate acetate crude product.
S6: and (3) adding 100mL of water into the prednisolone valerate acetate crude product obtained in the step S5, stirring for 5 minutes, standing for layering, circulating for 3 times, collecting an organic phase, adding 100mL of methanol and a small amount of activated carbon, heating to 40 +/-2 ℃, stirring for decoloring for 2 hours, filtering, washing a filter cake with 20mL of dichloromethane, combining filtrates, distilling at normal pressure until a material is separated out, adding 240mL of methanol for dissolving, continuing distilling at normal pressure until the reaction temperature is higher than 64.5 ℃, and finishing concentration. And then, firstly, cooling to the reaction temperature of less than 40 ℃ by using tap water, then freezing and cooling to 0-5 ℃ by using ice water, stirring for 2 hours, then carrying out suction filtration, leaching and drying a filter cake by using 20mL of glacial methanol, collecting the filter cake, drying for 6 hours at the temperature of 60 ℃, collecting the material and weighing.
The weight of the prepared prednisolone valerate acetate finished product is 20g, the yield is 100%, and the purity of the finished product is 99.5% through HPLC detection.
Example 2 prednisolone valerate acetate chemical synthesis process
The chemical synthesis process of prednisolone valerate acetate includes the following steps:
s1: adding 20g of prednisolone into a reaction bottle, controlling the reaction temperature at 30 ℃, then adding 20ml of dichloromethane and dimethyl sulfoxide with the volume ratio of 8:1, stirring until the materials are dissolved to obtain a dissolved solution system, and starting nitrogen protection.
S2: and (3) adding 0.6g of p-toluenesulfonic acid into the solution clear system obtained in the step S1, adding 32mL of trimethyl orthovalerate, controlling the reaction temperature to be 30 ℃, and stirring for reaction for 1 hour, wherein the content of prednisolone in the reaction system is detected to be less than or equal to 1 wt%, and the reaction is completed to obtain a reaction system containing the cyclic ester (II).
S3: reducing the reaction temperature of the reaction system in the step S2 to 20 +/-2 ℃, adding 4mL of dilute sulfuric acid solution, adding 22mL of acetone, controlling the reaction temperature at 20 ℃, stirring for reacting for 2 hours, and detecting that the content of cyclic ester in the reaction system is less than or equal to 1 wt%, namely completely reacting to obtain the prednisolone valerate mixed system. In the step, the dilute sulfuric acid is prepared by uniformly mixing 98% concentrated sulfuric acid and water according to the volume ratio of 1: 150.
S4: adding 9mL of dimethyl sulfoxide and 310mL of water into the mixed system obtained in the step S3, stirring for 5 minutes, standing for 15 minutes, collecting organic phases in a layered manner into another reaction bottle, distilling under reduced pressure until the volume is 200mL, adding 150mL of dichloromethane for entrainment and dehydration until the water content in the reaction system is less than 0.3 wt%, and obtaining a prednisolone valerate crude product;
s5: and (3) cooling the prednisolone valerate crude product obtained in the step (S4) to 30 ℃, adding 0.13g of dimethylaminopyridine, 11mL of pyridine and 11mL of acetic anhydride into the reaction bottle, controlling the reaction temperature to be 30 ℃, keeping the temperature, stirring and reacting for 2 hours, and detecting that the content of prednisolone valerate in the reaction system is less than or equal to 0.5 wt%, namely completely reacting to obtain the prednisolone valerate acetate crude product.
S6: adding 100mL of water into the prednisolone valerate acetate crude product obtained in the step S5, stirring for 5 minutes, standing for layering, circulating for 3 times, collecting an organic phase, adding 100mL of methanol and a small amount of activated carbon, heating to 40 +/-2 ℃, stirring for decoloring for 6 hours, filtering, washing a filter cake with 20mL of dichloromethane, combining filtrates, distilling at normal pressure until a material is separated out, adding 240mL of methanol for dissolution, continuing distilling at normal pressure until the reaction temperature is higher than 65 ℃, and ending concentration. And then, firstly, cooling the mixture to a reaction temperature of less than 40 ℃ by using tap water, then freezing and cooling the mixture to 0-5 ℃ by using brine ice, stirring the mixture for 2 hours, then carrying out suction filtration, leaching and drying a filter cake by using 20mL of methanol ice, collecting the filter cake, drying the filter cake in vacuum at 60 ℃ for 6 hours, collecting the material and weighing the material.
The weight of the prepared prednisolone valerate acetate finished product is 23g, the yield is 115%, and the purity of the finished product is 99.6% through HPLC detection.
Example 3 prednisolone valerate acetate chemical Synthesis Process
The chemical synthesis process of prednisolone valerate acetate includes the following steps:
s1: adding 20g of prednisolone into a reaction bottle, controlling the reaction temperature at 20 ℃, then adding 22ml of dichloromethane and dimethyl sulfoxide with the volume ratio of 6:1, stirring until the materials are dissolved to obtain a dissolved solution system, and starting nitrogen protection.
S2: and (3) adding 0.8g of p-toluenesulfonic acid into the solution clear system obtained in the step S1, adding 35mL of trimethyl orthovalerate, controlling the reaction temperature to be 20 ℃, stirring and reacting for 2 hours, and detecting that the content of prednisolone in the reaction system is less than or equal to 1 wt%, so that the reaction is complete, and thus obtaining the reaction system containing the cyclic ester.
S3: reducing the reaction temperature of the reaction system in the step S2 to 20 +/-2 ℃, adding 5mL of dilute sulfuric acid solution, adding 25mL of acetone, controlling the reaction temperature at 30 ℃, stirring and reacting for 1 hour, and detecting that the content of cyclic ester in the reaction system is less than or equal to 1 wt%, namely completely reacting to obtain a mixed system containing prednisolone valerate. In the step, the dilute sulfuric acid is prepared by uniformly mixing 98% concentrated sulfuric acid and water according to the volume ratio of 1: 150.
S4: and (3) adding 10mL of dimethyl sulfoxide and 320mL of water into the mixed system obtained in the step S3, stirring for 5 minutes, standing for 15 minutes, collecting organic phases in a layered mode into another reaction bottle, distilling under reduced pressure until the volume is 200mL, adding 120mL of dichloromethane for entrainment and dehydration until the water content in the reaction system is less than 0.3 wt%, and obtaining a prednisolone valerate crude product.
S5: and (3) cooling the prednisolone valerate crude product obtained in the step (S4) to 20 ℃, adding 0.15g of dimethylaminopyridine, 12mL of pyridine and 12mL of acetic anhydride into the reaction bottle, controlling the reaction temperature to be 20 ℃, keeping the temperature, stirring and reacting for 2 hours, and detecting that the content of prednisolone valerate is less than or equal to 0.5 wt%, so that the reaction is complete, thereby obtaining the prednisolone valerate acetate crude product.
S6: adding 100mL of water into the prednisolone valerate acetate crude product obtained in the step S5, stirring for 5 minutes, standing for layering, circulating for 3 times, collecting an organic phase, adding 100mL of methanol and a small amount of activated carbon, heating to 40 +/-2 ℃, stirring for decoloring for 12 hours, filtering, washing a filter cake with 20mL of dichloromethane, combining filtrates, distilling at normal pressure until a material is separated out, adding 240mL of methanol for dissolution, continuing distilling at normal pressure until the reaction temperature is higher than 65 ℃, and ending concentration. And then, firstly, cooling to the reaction temperature of less than 40 ℃ by using tap water, then freezing and cooling to 0-5 ℃ by using ice water, stirring for 2 hours, then carrying out suction filtration, leaching and drying a filter cake by using 20mL of glacial methanol, collecting the filter cake, drying for 6 hours at the temperature of 60 ℃, collecting the material and weighing.
The weight of the prepared prednisolone valerate acetate finished product is 19g, the yield is 95%, and the purity of the finished product is 99.7% through HPLC detection.
Example 4 prednisolone valerate acetate chemical Synthesis Process
The preparation method is substantially the same as that of example 1, except that,
s5: and (3) cooling the prednisolone valerate crude product obtained in the step (S4) to 25 ℃, adding 0.12g of dimethylaminopyridine, 10mL of pyridine and 10mL of acetic anhydride into the reaction bottle, controlling the reaction temperature to be 25 ℃, keeping the temperature, stirring and reacting for 1 hour, and detecting that the content of prednisolone valerate in the reaction system is less than or equal to 0.5 wt%, namely completely reacting to obtain the prednisolone valerate acetate crude product.
S6: adding 100mL of water into the prednisolone valerate acetate crude product obtained in the step S5, stirring for 5 minutes, standing for layering, circulating for 1 time, collecting an organic phase, adding 100mL of ethanol and a small amount of diatomite, heating to 40 +/-2 ℃, stirring for decoloring for 2 hours, filtering, washing a filter cake with 20mL of dichloromethane, combining filtrates, distilling at normal pressure until a material is separated out, adding 240mL of ethanol for dissolving, continuing distilling at normal pressure until the reaction temperature is higher than 78 ℃, and ending concentration. Firstly, cooling to a reaction temperature of less than 40 ℃ by using tap water, then freezing and cooling to 0-5 ℃ by using brine ice, stirring for 2 hours, then carrying out suction filtration, leaching and drying a filter cake by using 20mL of methanol ice, collecting the filter cake, drying for 10 hours at 40 ℃ in vacuum, collecting the material, and weighing.
The weight of the prepared prednisolone valerate acetate finished product is 21g, the yield is 105%, and the purity of the finished product is 99.5% through HPLC detection.
Example 5 prednisolone valerate acetate chemical Synthesis Process
The preparation method is substantially the same as that of example 1, except that,
s5: and (3) cooling the prednisolone valerate crude product obtained in the step (S4) to 20 ℃, adding 0.12g of dimethylaminopyridine, 10mL of pyridine and 10mL of acetic anhydride into the reaction bottle, controlling the reaction temperature to be 20 ℃, keeping the temperature, stirring and reacting for 8 hours, and detecting that the content of prednisolone valerate in the reaction system is less than or equal to 0.5 wt%, namely completely reacting to obtain the prednisolone valerate acetate crude product.
S6: adding 100mL of water into the prednisolone valerate acetate crude product obtained in the step S5, stirring for 5 minutes, standing for layering, circulating for 5 times, collecting an organic phase, adding 100mL of acetone and a small amount of activated carbon, heating to 40 +/-2 ℃, stirring for decoloring for 2 hours, filtering, washing a filter cake with 20mL of dichloromethane, combining filtrates, distilling at normal pressure until a material is separated out, adding 240mL of acetone for dissolving, continuing distilling at normal pressure until the reaction temperature is higher than 58.5 ℃, and ending concentration. And then, firstly, cooling the mixture to a reaction temperature of less than 40 ℃ by using tap water, then freezing and cooling the mixture to 0-5 ℃ by using ice water, stirring the mixture for 2 hours, then carrying out suction filtration, leaching and drying a filter cake by using 20mL of glacial methanol, collecting the filter cake, drying the filter cake for 6 hours at a temperature of 60 ℃, collecting the material and weighing the material.
The weight of the prepared prednisolone valerate acetate finished product is 20g, the yield is 100%, and the purity of the finished product is 99.8% through HPLC detection.
Example 6 prednisolone valerate acetate chemical Synthesis Process
The preparation method is substantially the same as that of example 1, except that,
step S3: the dilute sulfuric acid is prepared by uniformly mixing 98% concentrated sulfuric acid and water according to the volume ratio of 1: 130.
The weight of the prepared prednisolone valerate acetate finished product is 22g, the yield is 110%, and the purity of the finished product is 99.5% through HPLC detection.
Example 7 prednisolone valerate acetate chemical Synthesis Process
The preparation method is substantially the same as that of example 1, except that,
step S3: the dilute sulfuric acid is prepared by uniformly mixing 98% concentrated sulfuric acid and water according to the volume ratio of 1: 170.
The weight of the prepared prednisolone valerate acetate finished product is 19, the yield is 95%, and the purity of the finished product is 99.5% through HPLC detection.
Example 8 prednisolone valerate acetate chemical Synthesis Process
The preparation method is substantially the same as that of example 1, except that,
step S6: in the cooling step, the reaction system after the concentration is directly cooled to 0-5 ℃.
The weight of the prepared prednisolone valerate acetate finished product is 20, the yield is 100%, and the purity of the finished product is 99.6% through HPLC detection.
Example 9 prednisolone valerate acetate chemical Synthesis Process
The preparation method is substantially the same as that of example 1, except that,
step S4: the amount of dimethyl sulfoxide added was 20ml, the amount of water added was 400ml and the organic phase was distilled under reduced pressure to a volume of 210 ml.
The weight of the prepared prednisolone valerate acetate finished product is 19g, the yield is 95%, and the purity of the finished product is 99.7% through HPLC detection.
Example 10 prednisolone valerate acetate chemical Synthesis Process
The preparation method is substantially the same as that of example 1, except that,
step S4: the organic phase was distilled under reduced pressure to a volume of 190 ml.
The weight of the prepared prednisolone valerate acetate finished product is 20g, the yield is 100%, and the purity of the finished product is 99.6% through HPLC detection.
The embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. Any equivalent modifications or alterations to this practice will occur to those skilled in the art and are intended to be within the scope of this invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.
Claims (11)
1. The chemical synthesis process of prednisolone valerate acetate is characterized by comprising the following preparation steps:
s1: dissolving prednisolone with appropriate amount of dichloromethane and dimethyl sulfoxide to obtain a dissolved solution system, and starting nitrogen protection;
s2: adding p-toluenesulfonic acid and trimethyl orthovalerate into the solution system obtained in the step S1, controlling the reaction temperature to be 20-30 ℃, stirring and reacting for 1-2 hours, and obtaining a reaction system containing cyclic ester after complete reaction; the addition amount of the p-toluenesulfonic acid is 2.5-4% of the mass of prednisolone; the volume-mass ratio of trimethyl ortho-valerate to prednisolone is 1.5-1.75 ml/g;
s3: adding a proper amount of dilute sulfuric acid and an organic cosolvent into the reaction system of the step S2, controlling the reaction temperature to be 20-30 ℃, stirring and reacting for 1-2 hours, and obtaining a mixed system containing prednisolone valerate after complete reaction;
s4: adding a proper amount of dimethyl sulfoxide and water into the mixed system obtained in the step S3, collecting a lower organic phase layer by layer, carrying out vacuum distillation and concentration on the organic phase, adding a proper amount of dichloromethane, carrying and dehydrating to obtain a prednisolone valerate crude product;
s5: cooling the prednisolone valerate crude product obtained in the step S4 to 20-30 ℃, adding dimethylaminopyridine, pyridine and acetic anhydride, keeping the temperature, stirring and reacting for 1-3 hours, and obtaining prednisolone valerate acetate crude product after complete reaction; the adding amount of the dimethylaminopyridine is 0.6-0.75% of the mass of prednisolone; the volume-mass ratio of the pyridine to the prednisolone is 0.5-0.6 ml/g; the volume-mass ratio of the acetic anhydride to the prednisolone is 1.5-1.75 ml/g;
s6: adding a proper amount of water into the prednisolone valerate acetate crude product obtained in the step S5, stirring, layering, circularly operating for 1-5 times, collecting an organic phase, adding a proper amount of organic cosolvent into the organic phase, adding a small amount of decolorizing agent for decolorization and filtration, washing a filter cake with a proper amount of dichloromethane, merging filtrate, distilling the filtrate at normal pressure until materials are separated out, adding a proper amount of organic cosolvent solute, concentrating, cooling, stirring, performing suction filtration, washing, and drying to obtain prednisolone valerate acetate;
in step S3, the organic cosolvent is acetone or glacial acetic acid; in the step S6, the organic cosolvent is one or more of methanol, ethanol, and acetone.
2. The chemical synthesis process of prednisolone valerate acetate according to claim 1, wherein in step S1, the dichloromethane and dimethyl sulfoxide are added in the form of a mixed solvent, and the volume ratio of dichloromethane to dimethyl sulfoxide in the mixed solvent is (4-8): 1; the volume-mass ratio of the added mixed solvent to the prednisolone is 20-25 ml/g.
3. The chemical synthesis process of prednisolone valerate acetate according to claim 1,
in the step S2, detecting that the content of prednisolone serving as a reaction raw material in the reaction system containing the cyclic ester is less than or equal to 1 wt%, namely the reaction is complete;
in the step S3, detecting that the content of cyclic ester is less than or equal to 1 wt% in the mixed system containing prednisolone valerate, namely the reaction is complete;
in step S5, it is detected that the content of prednisolone valerate in the mixed system containing prednisolone valerate acetate is less than or equal to 0.5 wt%, i.e., the reaction is complete.
4. The chemical synthesis process of prednisolone valerate acetate according to claim 1, wherein in step S3, the dilute sulfuric acid is prepared by uniformly mixing 98% concentrated sulfuric acid and water in a volume ratio of 1: 130-170; the volume-mass ratio of the dilute sulfuric acid to the prednisolone is 0.15-0.25 ml/g.
5. The chemical synthesis process of prednisolone valerate acetate according to claim 1, wherein in step S3, the temperature of the reaction system containing the cyclic ester is reduced before the diluted sulfuric acid is added.
6. The chemical synthesis process of prednisolone valerate acetate according to claim 1, wherein in step S4, the volume/mass ratio of the dichloromethane used for entrainment to prednisolone is 5-7.5 ml/g.
7. The chemical synthesis process of prednisolone valerate acetate according to claim 6, wherein in step S4, dichloromethane is added to entrain the water in the system to be less than 0.3 wt%.
8. The chemical synthesis process of prednisolone valerate acetate according to claim 1, wherein in step S6, the decoloring temperature is 40 ± 2 ℃ and the decoloring time is 2 to 12 hours.
9. The chemical synthesis process of prednisolone valerate acetate according to claim 1, wherein in step S6, the temperature reduction step is a stepwise temperature reduction method, and the temperature reduction step is performed by first reducing the temperature to a reaction temperature of less than 40 ℃ and then cooling the temperature to 0-5 ℃.
10. The chemical synthesis process of prednisolone valerate acetate according to claim 1, wherein in step S6, the concentration step is performed with a system temperature equal to or higher than the boiling point of the organic co-solvent as the concentration endpoint.
11. The chemical synthesis process of prednisolone valerate acetate according to claim 1, wherein in step S6, the volume-to-mass ratio of the appropriate amount of water to the starting material prednisolone is 4-6 ml/g; the volume-mass ratio of the added proper amount of organic cosolvent to the initial prednisolone is 4-6 ml/g.
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| US3147249A (en) * | 1961-06-13 | 1964-09-01 | Vismara Francesco Spa | 17alpha, 21-substituted methylenedioxy steroids and methods therefor |
| US4113680A (en) * | 1975-03-31 | 1978-09-12 | Taisho Pharmaceutical Co., Ltd. | Method for preparing 17 α-ester-21-halo pregnanes |
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| US3147249A (en) * | 1961-06-13 | 1964-09-01 | Vismara Francesco Spa | 17alpha, 21-substituted methylenedioxy steroids and methods therefor |
| US4113680A (en) * | 1975-03-31 | 1978-09-12 | Taisho Pharmaceutical Co., Ltd. | Method for preparing 17 α-ester-21-halo pregnanes |
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| A SIMPLE ROUTE TO STEROID 17a,20a,21-TRIOLS;R. Gardi,等;《Tetrahedron Letters》;19621231(第5期);189-194 * |
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