CN113201040A - Method for synthesizing loteprednol etabonate - Google Patents
Method for synthesizing loteprednol etabonate Download PDFInfo
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Abstract
The invention relates to the technical field of medicine preparation, in particular to a method for synthesizing loteprednol etabonate, which comprises the following steps: preparing an intermediate I by taking prednisolone and sodium periodate solution as raw materials; mixing the intermediate I with an organic solvent and an organic base catalyst, and adding ethyl chloroformate to react to obtain a reaction solution containing an intermediate II; filtering the reaction liquid containing the intermediate II, adding an organic solvent and an inorganic base catalyst into the filtrate for reaction, standing for layering, separating to obtain an organic layer, washing the organic layer, standing for layering again, separating again to obtain the organic layer which is the reaction liquid containing the intermediate III, and adding a chloromethylation reagent for reaction to obtain a loteprednol etabonate crude product; recrystallizing the loteprednol etabonate crude product to obtain the loteprednol etabonate. The invention can realize that acylation, hydrolysis salification and chloromethyl esterification are all completed in one system, thereby shortening the production period, reducing the generation of waste water, improving the yield and reducing the production cost.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a method for synthesizing loteprednol etabonate.
Background
Loteprednol etabonate is a novel glucocorticoid, can be used for treating corticosteroid-sensitive inflammations such as eyelid and bulbar conjunctivitis, uveitis, inflammation of cornea and anterior segment of eye, can be rapidly metabolized into inactive products after being dropped into eye, reduces system toxicity, minimizes adverse reaction of glucocorticoid, and has strong anti-inflammatory effect. The formula of loteprednol etabonate is as follows:
loteprednol etabonate is mainly prepared by taking prednisolone as a raw material through a series of reactions, and the current method mainly comprises the following steps:
the technique for synthesizing loteprednol etabonate is characterized in that prednisolone is adopted as a raw material by Chenaijun in the improvement of loteprednol etabonate synthesis technique published by the Chinese journal of pharmaceutical chemistry, and the loteprednol etabonate is prepared by oxidation, acylation, hydrolysis to form salt and chloromethylation to form ester, wherein the total yield is 45 percent.
Chinese patent CN103183714A discloses a synthetic method of loteprednol etabonate, which takes prednisolone as raw material, and prepares loteprednol etabonate through oxidation, condensation, aminolysis, chloromethylesterification and other reactions, the total yield reaches more than 80%, and the technological process for synthesizing loteprednol etabonate is as follows.
The two preparation processes are complicated in steps, raw materials are required to be treated after each step is finished, the operation is complex, a large amount of waste water is generated, the environment is seriously polluted, in addition, centrifugal discharging is required in each step, the labor and the material resources are wasted, and the prepared loteprednol etabonate has low yield.
Disclosure of Invention
The invention provides a method for synthesizing loteprednol etabonate, which can shorten the production period, reduce the generation of waste water, improve the yield and reduce the production cost.
The invention provides a method for synthesizing loteprednol etabonate, which comprises the following steps:
s1, preparing an intermediate I by using prednisolone and sodium periodate solution as raw materials;
s2, mixing the intermediate I with an organic solvent and an organic base catalyst, and adding ethyl chloroformate to react to obtain reaction liquid containing an intermediate II;
s3, filtering the reaction liquid containing the intermediate II, adding an organic solvent and an inorganic base catalyst into the filtrate for reaction, standing and layering, separating a water layer and an organic layer, washing the organic layer, standing and layering, separating again to obtain an organic layer which is the reaction liquid containing the intermediate III, adding a chloromethylation reagent into the reaction liquid containing the intermediate III for reaction to obtain a loteprednol etabonate crude product;
s4, recrystallizing the loteprednol etabonate crude product to obtain loteprednol etabonate;
the reaction equation is as follows:
further, in step S3, after adding an organic solvent to the filtrate and mixing uniformly, adding an inorganic base catalyst at a temperature of 10-20 ℃ and reacting at 10-20 ℃.
The conventional reaction temperature of the one-pot method is too high, so that the raw materials cannot react fully, more impurities are generated in the preparation process, and the yield and purity of the prepared product are lower.
Further, step S3 is: filtering the reaction liquid containing the intermediate II, adding an organic solvent into the filtrate, uniformly mixing, controlling the temperature to be 10-20 ℃, adding an inorganic base catalyst, reacting at 10-20 ℃, and standing and layering to obtain a water layer and an organic layer I when no intermediate II is detected;
extracting an aqueous layer by adopting halogenated hydrocarbon to obtain an organic layer II, combining the organic layer I and the organic layer II to obtain an organic layer III, washing the organic layer III by using water, standing and layering the washed organic layer III, separating again to obtain an organic layer which is a reaction liquid containing an intermediate III, cooling the reaction liquid containing the intermediate III to-10 to-5 ℃, dropwise adding a chloromethylation reagent to react at the temperature of-5 to 5 ℃, and when detecting that no intermediate III exists, concentrating under reduced pressure, filtering and drying to obtain a loteprednol etabonate crude product.
The method comprises the steps of standing for layering to obtain an organic layer, extracting residual organic layers in an aqueous layer, combining, washing with water to remove impurities, standing again to separate out the organic layer, and standing and washing to improve the purity of the product.
Further, in step S3, the organic solvent is methanol, ethanol, propanol or acetone; the inorganic base catalyst is sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate. The organic solvent is preferably methanol, and the inorganic base catalyst is preferably sodium carbonate.
Further, step S2 is: under the protection of nitrogen, mixing the intermediate I with an organic solvent and an organic base catalyst, dropwise adding ethyl chloroformate at 5-10 ℃ for reaction, and detecting that no intermediate I exists, so as to obtain a reaction solution containing an intermediate II.
Further, in step S2, the organic solvent is a halogenated hydrocarbon having less than 6 carbon atoms; the organic base catalyst is triethylamine, diethylamine, pyridine or pyran. The organic solvent is preferably dichloromethane, and the organic base catalyst is preferably triethylamine.
Further, the ratio of the intermediate I, the organic base catalyst, the ethyl chloroformate, the inorganic base catalyst and the chloromethylation reagent is 1: (0.5-2): (0.5-3): (0.3-1): (0.5-1.5), wherein the intermediate I and the inorganic base catalyst are measured in g, and the organic base catalyst, the ethyl chloroformate and the chloromethylation reagent are measured in mL.
Further, step S1 is: mixing prednisolone and tetrahydrofuran, adding a sodium periodate solution at 0-5 ℃ for reaction, carrying out reduced pressure concentration to obtain tetrahydrofuran when no raw material exists, filtering, and drying to obtain an intermediate I; the sodium periodate solution is obtained by stirring and mixing sodium periodate and water at 0-5 DEG C
Further, in step S1, the mass ratio of prednisolone to sodium periodate in the sodium periodate solution is 1: 1-3.
Further, step S4 is: mixing the loteprednol etabonate crude product with ethanol to obtain a mixed solution, heating until the mixed solution is clear, adding activated carbon into the mixed solution for decolorization, filtering, concentrating and crystallizing the filtrate, cooling to 0-10 ℃, filtering, and drying to obtain loteprednol etabonate. And further processing the loteprednol etabonate crude product, decoloring and recrystallizing in a solvent system to obtain the loteprednol etabonate.
The invention has the beneficial effects that:
(1) the preparation process disclosed by the invention is simple to operate, and can shorten the production period, reduce the generation of wastewater, improve the yield and reduce the production cost.
(2) The invention adopts proper preparation process and conditions, can realize that the acylation, hydrolysis to form salt and chloromethyl esterification reaction processes are all completed in one system, improves the quality and yield of the loteprednol etabonate, and ensures that the HPLC content of the prepared loteprednol etabonate is more than 99.4 percent and the total mass yield is more than 92 percent.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms also include the plural forms unless the context clearly dictates otherwise, and further, it is understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of the stated features, steps, operations, devices, components, and/or combinations thereof.
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments, and it should be understood that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
A method for synthesizing loteprednol etabonate, comprising the steps of:
s1, mixing 30g of sodium periodate with 150mL of water, and stirring and dissolving at 0 ℃ to obtain a sodium periodate solution for later use;
mixing 20g of prednisolone with 120mL of tetrahydrofuran, adding the prepared sodium periodate solution at 0 ℃ for reaction for 5h, detecting by TLC (the mass ratio of dichloromethane to methanol is 9:1) that almost no raw material exists, concentrating the tetrahydrofuran under reduced pressure, filtering, and drying the filter residue for 11h to obtain an intermediate I, wherein the mass of the intermediate I is 18.8g, the mass yield is 94%, the HPLC content is 99.5%, and the maximum single impurity is 0.15%;
s2, under the protection of nitrogen, mixing 18g of the intermediate I with 180mL of dichloromethane and 24mL of triethylamine, dropwise adding 25mL of ethyl chloroformate at 5 ℃, completing dropwise adding within 30min, reacting at 5 ℃ for 2h after completing dropwise adding, and detecting by adopting TLC (the mass ratio of dichloromethane to methanol is 9:1) that almost no intermediate I exists to obtain a reaction solution containing an intermediate II;
s3, filtering the reaction liquid containing the intermediate II, adding 36mL of methanol into the filtrate, uniformly mixing, adding a prepared sodium carbonate solution (9g of sodium carbonate is dissolved in 54mL of water) at 10 ℃ to react for 2h, detecting that the intermediate II is almost not generated by TLC (dichloromethane: methanol mass ratio of 9:1), standing for 30min, separating an aqueous layer and an organic layer I, extracting the aqueous layer by 36mL of dichloromethane to obtain an organic layer II, combining the organic layer I and the organic layer II to obtain an organic layer III, washing the organic layer III for 2 times by 20mL of water, standing the washed organic layer III for demixing again, separating the obtained organic layer III again to obtain the reaction liquid containing the intermediate III, cooling the reaction liquid containing the intermediate III to-10 ℃, dropwise adding 20mL of iodoform into the reaction liquid within 10min for reacting for 8h at-5 ℃, detecting that the intermediate III is almost not generated by TLC (dichloromethane: methanol mass ratio of 9:1), concentrating under reduced pressure, filtering, and drying the filter residue for 11h to obtain a loteprednol etabonate crude product, wherein the mass of the loteprednol etabonate crude product is 20.16g, the mass yield is 112%, the HPLC content is 97.8%, and the maximum single impurity content is 0.48%;
s3, mixing 20g of loteprednol etabonate crude product with 200mL of ethanol to obtain a mixed solution, heating to 55 ℃ to dissolve the mixed solution, adding 1g of activated carbon to decolor for 30min, filtering, concentrating the filtrate under reduced pressure to crystallize in a large amount, cooling to 0 ℃, filtering, and drying the filter residue for 11h to obtain loteprednol etabonate, wherein the loteprednol etabonate has the mass of 18.10g, the mass yield of 90.5%, the HPLC content of 99.56% and the maximum single impurity of 0.12%.
Example 2
A method for synthesizing loteprednol etabonate, comprising the steps of:
s1, mixing 30g of sodium periodate with 150mL of water, and stirring and dissolving at 3 ℃ to obtain a sodium periodate solution for later use;
mixing 20g of prednisolone with 120mL of tetrahydrofuran, adding the prepared sodium periodate solution at 3 ℃ for reaction for 5h, detecting by TLC (the mass ratio of dichloromethane to methanol is 9:1) that almost no raw material exists, concentrating the tetrahydrofuran under reduced pressure, filtering, and drying the filter residue for 12h to obtain an intermediate I, wherein the mass of the intermediate I is 18.5g, the mass yield is 92.5%, the HPLC content is 99.5%, and the maximum single impurity is 0.18%;
s2, under the protection of nitrogen, mixing 18g of the intermediate I with 180mL of dichloromethane and 24mL of triethylamine, dropwise adding 30mL of ethyl chloroformate at 7 ℃, completing dropwise adding within 30min, reacting for 2h at 7 ℃ after completing dropwise adding, and detecting by adopting TLC (the mass ratio of dichloromethane to methanol is 9:1) that almost no intermediate I exists, so as to obtain a reaction solution containing an intermediate II;
s3, filtering the reaction liquid containing the intermediate II, adding 36mL of methanol into the filtrate, adding a prepared sodium carbonate solution (9g of sodium carbonate is dissolved in 54mL of water) at 15 ℃ for reaction for 2h, detecting almost no intermediate II by adopting TLC (the mass ratio of dichloromethane to methanol is 9:1), standing for 30min, separating a water layer from an organic layer I, extracting the water layer by adopting 36mL of dichloromethane to obtain an organic layer II, combining the organic layer I and the organic layer II to obtain an organic layer III, washing the organic layer III by adopting 20mL of water for 2 times, standing and layering the organic layer III after washing, separating the obtained organic layer again to obtain the reaction liquid containing the intermediate III, cooling the reaction liquid containing the intermediate III to-7 ℃, dropwise adding 25mL of chloroiodomethane into the reaction liquid containing the intermediate III within 10min for reaction for 8h at 0 ℃, detecting almost no intermediate III by adopting TLC (the mass ratio of dichloromethane to methanol is 9:1), concentrating under reduced pressure, filtering, and drying the filter residue for 12h to obtain crude loteprednol etabonate with the mass of 19.87g, the mass yield of 110.4%, the HPLC content of 98.0% and the maximum single impurity of 0.43%;
s3, mixing 19g of loteprednol etabonate crude product with 190mL of ethanol to obtain a mixed solution, heating to 57 ℃ to dissolve the mixed solution, adding 1g of activated carbon to decolor for 30min, filtering, concentrating the filtrate under reduced pressure to crystallize in a large amount, cooling to 7 ℃, filtering, and drying the filter residue for 12h to obtain loteprednol etabonate, wherein the loteprednol etabonate has the mass of 17.20g, the mass yield of 90.5%, the HPLC content of 99.63% and the maximum single impurity of 0.12%.
Example 3
A method for synthesizing loteprednol etabonate, comprising the steps of:
s1, mixing 30g of sodium periodate with 150mL of water, and stirring and dissolving at 5 ℃ to obtain a sodium periodate solution for later use;
mixing 20g of prednisolone with 120mL of tetrahydrofuran, adding a prepared sodium periodate solution at 5 ℃ for reaction for 5h, detecting by TLC (the mass ratio of dichloromethane to methanol is 9:1) that almost no raw material exists, concentrating the tetrahydrofuran under reduced pressure, filtering, and drying filter residues for 12h to obtain an intermediate I, wherein the mass of the intermediate I is 18.6g, the mass yield is 93%, the HPLC content is 99.55%, and the maximum single impurity is 0.17%;
s2, under the protection of nitrogen, mixing 18g of the intermediate I with 180mL of dichloromethane and 24mL of triethylamine, dropwise adding 25mL of ethyl chloroformate at 10 ℃ for reaction, completing dropwise adding within 30min, reacting at 10 ℃ for 2h after completing dropwise adding, and detecting by adopting TLC (mass ratio of dichloromethane to methanol is 9:1) that almost no intermediate I exists, so as to obtain a reaction solution containing an intermediate II;
s3, filtering the reaction liquid containing the intermediate II, adding 36mL of methanol into the filtrate, adding a prepared sodium carbonate solution (10g of sodium carbonate is dissolved in 54mL of water) at 20 ℃ to react for 2h, standing for 30min when almost no intermediate II is detected by TLC (dichloromethane: methanol mass ratio is 9:1), obtaining a water layer and an organic layer I, extracting the water layer by 36mL of trichloromethane to obtain an organic layer II, combining the organic layer I and the organic layer II to obtain an organic layer III, washing the organic layer III for 2 times by 20mL of water, standing and layering the organic layer III after washing by water, separating the obtained organic layer to obtain the reaction liquid containing the intermediate III again, cooling the reaction liquid containing the intermediate III to-5 ℃, dropwise adding 20mL of chloroiodomethane within 10min to react for 8h at 5 ℃, and detecting almost no intermediate III by TLC (dichloromethane: methanol mass ratio is 9:1), concentrating the filtrate under reduced pressure to obtain a solvent, filtering, and drying the filter residue for 12h to obtain a crude loteprednol etabonate product, wherein the mass of the crude loteprednol etabonate product is 20.10g, the mass yield is 111.7%, the HPLC content is 97.5%, and the maximum single impurity content is 0.52%;
s3, mixing 20g of loteprednol etabonate crude product with 200mL of ethanol to obtain a mixed solution, heating to 60 ℃ to dissolve the mixed solution, adding 1g of activated carbon to decolor for 30min, filtering, concentrating the filtrate under reduced pressure to crystallize in a large amount, cooling to 10 ℃, filtering, and drying the filter residue for 12h to obtain loteprednol etabonate, wherein the loteprednol etabonate has the mass of 18.0g, the mass yield of 90.0%, the HPLC content of 99.45% and the maximum single impurity of 0.13%.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. A method for synthesizing loteprednol etabonate, which is characterized by comprising the following steps:
s1, preparing an intermediate I by using prednisolone and sodium periodate solution as raw materials;
s2, mixing the intermediate I with an organic solvent and an organic base catalyst, and adding ethyl chloroformate to react to obtain reaction liquid containing an intermediate II;
s3, filtering the reaction liquid containing the intermediate II, adding an organic solvent and an inorganic base catalyst into the filtrate for reaction, standing and layering, separating a water layer and an organic layer, washing the organic layer, standing and layering, separating again to obtain an organic layer which is the reaction liquid containing the intermediate III, adding a chloromethylation reagent into the reaction liquid containing the intermediate III for reaction to obtain a loteprednol etabonate crude product;
s4, recrystallizing the loteprednol etabonate crude product to obtain loteprednol etabonate;
the reaction equation is as follows:
2. the method for synthesizing loteprednol etabonate as claimed in claim 1, wherein in step S3, the organic solvent is added to the filtrate and mixed uniformly, the temperature is controlled at 10-20 ℃, the inorganic base catalyst is added, and the reaction is carried out at 10-20 ℃.
3. The method for synthesizing loteprednol etabonate as claimed in claim 2, wherein the step S3 is: filtering the reaction liquid containing the intermediate II, adding an organic solvent into the filtrate, uniformly mixing, controlling the temperature to be 10-20 ℃, adding an inorganic base catalyst, reacting at 10-20 ℃, standing for layering when no intermediate II is detected, and separating a water layer and an organic layer I;
extracting an aqueous layer by adopting halogenated hydrocarbon to obtain an organic layer II, combining the organic layer I and the organic layer II to obtain an organic layer III, washing the organic layer III by using water, standing and layering the washed organic layer III, separating again to obtain an organic layer which is a reaction liquid containing an intermediate III, cooling the reaction liquid containing the intermediate III to-10 to-5 ℃, dropwise adding a chloromethylation reagent to react at the temperature of-5 to 5 ℃, and when detecting that no intermediate III exists, concentrating under reduced pressure, filtering and drying to obtain a loteprednol etabonate crude product.
4. The method for synthesizing loteprednol etabonate as claimed in claim 3, wherein in step S3, the organic solvent is methanol, ethanol, propanol or acetone; the inorganic base catalyst is sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
5. The method for synthesizing loteprednol etabonate according to claim 1, wherein the step S2 is: under the protection of nitrogen, mixing the intermediate I with an organic solvent and an organic base catalyst, dropwise adding ethyl chloroformate at 5-10 ℃ for reaction, and detecting that no intermediate I exists, so as to obtain a reaction solution containing an intermediate II.
6. The method for synthesizing loteprednol etabonate as claimed in claim 5, wherein in step S2, the organic solvent is a halogenated hydrocarbon with less than 6 carbon atoms; the organic base catalyst is triethylamine, diethylamine, pyridine or pyran.
7. The method for synthesizing loteprednol etabonate as claimed in claim 1, wherein the ratio of the intermediate I, the organic base catalyst, the ethyl chloroformate, the inorganic base catalyst and the chloromethylation reagent is 1: (0.5-2): (0.5-3): (0.3-1): (0.5-1.5), wherein: the intermediate I and the inorganic base catalyst are measured in g, and the organic base catalyst, the ethyl chloroformate and the chloromethylation reagent are measured in mL.
8. The method for synthesizing loteprednol etabonate according to claim 1, wherein the step S1 is: mixing prednisolone and tetrahydrofuran, adding a sodium periodate solution at 0-5 ℃ for reaction, carrying out reduced pressure concentration to obtain tetrahydrofuran when no raw material exists, filtering, and drying to obtain an intermediate I; the sodium periodate solution is obtained by stirring and mixing sodium periodate and water at 0-5 ℃.
9. The method for synthesizing loteprednol etabonate as claimed in claim 8, wherein in step S1: the mass ratio of the prednisolone to the sodium periodate in the sodium periodate solution is 1: 1-3.
10. The method for synthesizing loteprednol etabonate according to claim 1, wherein the step S4 is: mixing the loteprednol etabonate crude product with ethanol to obtain a mixed solution, heating until the mixed solution is clear, adding activated carbon into the mixed solution for decolorization, filtering, concentrating and crystallizing the filtrate, cooling to 0-10 ℃, filtering, and drying to obtain loteprednol etabonate.
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| US4996335A (en) * | 1980-07-10 | 1991-02-26 | Nicholas S. Bodor | Soft steroids having anti-inflammatory activity |
| CN106554383A (en) * | 2016-05-22 | 2017-04-05 | 上海清松制药有限公司 | A kind of a kind of method and synthetic method of intermediate of synthesis Loteprednol |
| CN111377991A (en) * | 2018-12-28 | 2020-07-07 | 天津药业研究院有限公司 | Preparation method of loteprednol etabonate |
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2021
- 2021-04-28 CN CN202110465783.0A patent/CN113201040A/en active Pending
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| US4996335A (en) * | 1980-07-10 | 1991-02-26 | Nicholas S. Bodor | Soft steroids having anti-inflammatory activity |
| CN106554383A (en) * | 2016-05-22 | 2017-04-05 | 上海清松制药有限公司 | A kind of a kind of method and synthetic method of intermediate of synthesis Loteprednol |
| CN111377991A (en) * | 2018-12-28 | 2020-07-07 | 天津药业研究院有限公司 | Preparation method of loteprednol etabonate |
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Application publication date: 20210803 |