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Method for synthesizing loteprednol etabonate

A technology of loteprednol etabonate and sodium periodate, which is applied in the field of drug preparation, can solve problems such as low yield of loteprednol etabonate, waste of manpower, material resources, complicated operation, etc., to reduce production costs, reduce The generation of waste water and the effect of simple operation of the preparation process

Inactive Publication Date: 2021-08-03
HENAN LIHUA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The steps of the above two preparation processes are cumbersome. After each step is completed, the raw materials need to be processed. The operation is complicated. At the same time, a large amount of waste water will be generated, seriously polluting the environment, and each step needs to be centrifugally discharged, which wastes manpower and material resources. The yield that causes the loteprednol etabonate of preparation is lower

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  • Method for synthesizing loteprednol etabonate
  • Method for synthesizing loteprednol etabonate
  • Method for synthesizing loteprednol etabonate

Examples

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Embodiment 1

[0035] A method for synthesizing loteprednol etabonate, comprising the following steps:

[0036] S1. Mix 30g of sodium periodate with 150mL of water, stir and dissolve at 0°C to obtain a sodium periodate solution, and set aside;

[0037] Mix 20g of prednisolone with 120mL of tetrahydrofuran, add the prepared sodium periodate solution to react for 5h at 0°C, and use TLC (dichloromethane: the mass ratio of methanol is 9:1) to detect that there is almost no raw material. Tetrahydrofuran was concentrated under pressure, filtered, and the filter residue was dried for 11 hours to obtain intermediate I. The mass of intermediate I was 18.8 g, the mass yield was 94%, the HPLC content was 99.5%, and the maximum simple impurity was 0.15%;

[0038] S2. Under the protection of nitrogen, mix 18g of intermediate I with 180mL of dichloromethane and 24mL of triethylamine, add 25mL of ethyl chloroformate dropwise at 5°C, and finish the dropwise addition within 30min. After reacting for 2 hours...

Embodiment 2

[0042] A method for synthesizing loteprednol etabonate, comprising the following steps:

[0043] S1. Mix 30g of sodium periodate with 150mL of water, stir and dissolve at 3°C ​​to obtain sodium periodate solution, set aside;

[0044] Mix 20g of prednisolone with 120mL of tetrahydrofuran, add the prepared sodium periodate solution to react for 5h at 3°C, and use TLC (dichloromethane: the mass ratio of methanol is 9:1) to detect that there is almost no raw material. Tetrahydrofuran was concentrated under pressure, filtered, and the filter residue was dried for 12 hours to obtain intermediate I. The mass of intermediate I was 18.5 g, the mass yield was 92.5%, the HPLC content was 99.5%, and the maximum simplex was 0.18%;

[0045] S2. Under the protection of nitrogen, mix 18g of intermediate I with 180mL of dichloromethane and 24mL of triethylamine, add 30mL of ethyl chloroformate dropwise at 7°C, and finish the dropwise addition within 30min. After reacting for 2 hours, using TLC ...

Embodiment 3

[0049] A method for synthesizing loteprednol etabonate, comprising the following steps:

[0050] S1. Mix 30g of sodium periodate with 150mL of water, stir and dissolve at 5°C to obtain a sodium periodate solution, set aside;

[0051] Mix 20g of prednisolone with 120mL of tetrahydrofuran, add the prepared sodium periodate solution at 5°C and react for 5h, when almost no raw materials are detected by TLC (the mass ratio of dichloromethane: methanol is 9:1), the Tetrahydrofuran was concentrated under pressure, filtered, and the filter residue was dried for 12 hours to obtain intermediate I. The mass of intermediate I was 18.6 g, the mass yield was 93%, the HPLC content was 99.55%, and the maximum simplex was 0.17%;

[0052] S2. Under the protection of nitrogen, mix 18g of intermediate I with 180mL of dichloromethane and 24mL of triethylamine, add 25mL of ethyl chloroformate dropwise at 10°C for reaction, and finish the dropwise addition within 30min. Reaction at ℃ for 2 hours, u...

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Abstract

The invention relates to the technical field of medicine preparation, in particular to a method for synthesizing loteprednol etabonate. The method comprises the following steps: preparing an intermediate I by using prednisolone and a sodium periodate solution as raw materials; mixing the intermediate I with an organic solvent and an organic base catalyst, and adding ethyl chloroformate for a reaction to obtain a reaction solution containing an intermediate II; filtering the reaction solution containing the intermediate II, adding an organic solvent and an inorganic base catalyst into the filtrate, conducting reacting, then performing standing for layering, carrying out separating to obtain an organic layer, washing the organic layer, performing standing for layering again, carrying out separating again to obtain an organic layer which is a reaction solution containing an intermediate III, adding a chloromethylation reagent, and performing reacting to obtain a crude product of loteprednol etabonate; and recrystallizing the crude product of the loteprednol etabonate to obtain the loteprednol etabonate. According to the method, acylation, hydrolysis salification and chloromethyl esterification reactions can be completed in one system, a production period is shortened, waste water is reduced, yield is increased, and production cost is reduced.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a method for synthesizing loteprednol etabonate. Background technique [0002] Loteprednol etabonate is a new type of glucocorticoid, which can be used to treat inflammations sensitive to corticosteroids such as eyelid and bulbar conjunctivitis, uveitis, cornea and anterior segment inflammation. After eye drops, it can be quickly metabolized into inactive products, reduce systemic toxicity, minimize adverse reactions of glucocorticoids, and have strong anti-inflammatory effects. The structural formula of loteprednol etabonate is as follows: [0003] [0004] Eccloteprednol is mainly prepared from prednisolone through a series of reactions. At present, there are mainly the following synthetic methods: [0005] Chen Aijun used prednisolone as a raw material in the "Synthetic Process Improvement of Loteprednol" published by the Chinese Journal of Medicinal Chemistr...

Claims

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Application Information

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IPC IPC(8): C07J3/00
CPCC07J3/005
Inventor 王海波刘娜娜李合兴王瑞玲陈玉真
Owner HENAN LIHUA PHARMA
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