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The preparation method of betamethasone

A technology of betamethasone and organic solvents, applied in the field of preparation of betamethasone, can solve the problems of excessive waste water and waste gas, complex chemical reactions, low utilization rate of raw materials, etc., and achieve the effect of reducing process waste water and simple process

Active Publication Date: 2022-06-24
HUNAN NORCHEM PHARMACEUTICAL CO LTD
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Problems solved by technology

At present, the process route for the production of synthetic betamethasone fluorine is very complicated and technically difficult
This is determined by the complex structure of betamethasone. The chemical structure of betamethasone is composed of three six-membered rings and one five-membered ring fused together to form a special molecular structure composed of 21 carbon atoms. It has the steric effect of special molecular configuration and the steric hindrance of steric barriers. The functional groups on its structure interfere with each other, making the chemical reaction very complicated. Too large, long production cycle, many side reactions, more solvents used in the reaction process, more waste water and waste gas generated, etc.
[0003] The most widely used betamethasone preparation process includes the following steps: fluoride the betamethasone epoxide, precipitate it with water, adjust the base, and centrifuge to obtain the crude product, and the crude product can only be obtained after recrystallization and water washing processes. Betamethasone boutique, although this process can obtain betamethasone with high purity, but there are still various problems in the process such as complicated steps, many solvents used, and more waste water

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  • The preparation method of betamethasone
  • The preparation method of betamethasone
  • The preparation method of betamethasone

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preparation example Construction

[0037] One embodiment of the present invention provides a preparation method of betamethasone, comprising the following steps S10-S30.

[0038] S10, subjecting betamethasone epoxide and hydrofluoric acid to a ring-opening fluorine reaction to obtain a mixture containing betamethasone;

[0039] The structure of betamethasone epoxide is shown in formula (1):

[0040]

[0041] In some of these embodiments, the conditions for the above ring-opening fluorine reaction are: react at -50°C to 0°C for 2h to 5h.

[0042] The ring-opening fluorine reaction is an exothermic reaction, and it is beneficial to reduce side reactions by controlling the reaction at a lower temperature, thereby increasing the yield and purity of betamethasone. Further, the reaction temperature of the above ring-opening fluorine reaction is -35°C to -15°C,

[0043]In some of these embodiments, in the ring-opening fluorine reaction in step S10, hydrofluoric acid is added in the form of hydrofluoric acid aqueo...

Embodiment 1

[0079] 1) Start the reactor to stir, put 5mL ethyl acetate, 1.0g 9β,11β-epoxy-16β-methylpregna-1,4-diene-17α,21-diol-3,20-dione, stir Mix evenly and cool the system down to -35°C, slowly add 0.75mL hydrofluoric acid solution with a mass concentration of 70%, control the adding speed of the hydrofluoric acid solution during stirring, and keep the temperature of the system at -15°C~ -10°C, after the addition is complete, keep the reaction at -15°C to -10°C for 1.5h, and use high performance liquid chromatography (HPLC) to track the raw materials (9β,11β-epoxy-16β-methylpregna-1,4 -diene-17α,21-diol-3,20-dione) <0.1%, the reaction is complete.

[0080] 2) Slowly add the reaction mixture after the reaction in step 1) into the quenching solution, which includes 3 mL of ethyl acetate, 4 mL of methanol and 1.5 mL of water, at a temperature of -5°C, and control the reaction rate by controlling the addition rate of the mixture. The temperature of the system is in the range of -10°C to...

Embodiment 2

[0084] 1) Start the reactor to stir, put 5mL ethyl acetate, 1.0g 9β,11β-epoxy-16β-methylpregna-1,4-diene-17α,21-diol-3,20-dione, stir Mix evenly and cool the system down to -35°C, slowly add 0.75mL hydrofluoric acid solution with a mass concentration of 70%, control the adding speed of the hydrofluoric acid solution during stirring, and keep the temperature of the system at -15°C~ -10°C, after the addition is complete, keep the reaction at -15°C to -10°C for 2 hours, and use high-performance liquid chromatography (HPLC) to track the raw material (9β,11β-epoxy-16β-methylpregna-1,4- Diene-17α,21-diol-3,20-dione) <0.1%, the reaction is complete.

[0085]2) Slowly add the reaction mixture after the reaction in step 1) into the quenching solution, which includes 2.5mL of dichloromethane, 4.5mL of 95% ethanol and 1.5mL of water at a temperature of -5°C. By controlling the mixture The adding speed controls the temperature of the system in the range of -10°C to 5°C. Then slowly add ...

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Abstract

The present invention relates to a preparation method of betamethasone; in the preparation method, 9β,11β-epoxy-16β-methylpregna-1,4-diene-17α,21-diol-3, 20‑diketone and hydrofluoric acid undergo a ring-opening fluorine reaction to obtain a mixture containing betamethasone; then, below 5°C, mix the mixture containing betamethasone and the quenching solution until clarification to obtain a solution; Add water dropwise to the solution for water analysis, then add lye, and centrifuge to obtain refined betamethasone; wherein, the quenching solution includes the first organic solvent, the second organic solvent and water, the first organic solvent, the second organic solvent The volume ratio of the second organic solvent and the water is (2.5~4.5):(2.5~5.5):(1~3); the first organic solvent is selected from at least one of butyl acetate, chloroform, dichloromethane and tetrahydrofuran The second organic solvent is a small molecule organic alcohol. The preparation method has high yield, high product purity and simple process steps.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of betamethasone. Background technique [0002] Betamethasone is a high-efficiency halogen-containing corticosteroid drug, which can act on the glucose metabolism process of the human body, thereby alleviating the pathological changes that occur when the body tissue responds to damaging stimuli. It has high curative effect and small side effects. It can treat lupus erythematosus, Rheumatoid arthritis, asthma and other serious diseases are widely used in international clinics. When betamethasone is used clinically, the product quality requirements of betamethasone are strict. At present, the process route for producing synthetic betamethasone fluorine is very complex and technically difficult. This is determined by the complex structure of betamethasone. The chemical structure of betamethasone is composed of three six-membered rings and one five-membe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J5/00
CPCC07J5/0076
Inventor 吴亚克曾春玲靳志忠刘喜荣刘家贝谢承哲
Owner HUNAN NORCHEM PHARMACEUTICAL CO LTD
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