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Preparation method of budesonide

An intermediate and diketone technology, which is applied in the field of preparation of budesonide, can solve the problems of slow reaction speed of intermediate preparation, unfavorable industrial production, and high industrial cost, so as to achieve easy control of reaction conditions, low production cost and guaranteed quality Effect

Active Publication Date: 2010-10-20
HUBEI GEDIAN HUMANWELL PHARMACEUTICAL CO LTD
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  • Abstract
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Problems solved by technology

[0005] However, due to the selection of reactants and the setting of reaction conditions, the preparation reaction speed of some intermediates in this preparation method is slow and the product yield is low, resulting in a final product molar yield of only about 12%, and the preparation method has The high cost of industrialization and the large environmental pollution are not conducive to industrialized production

Method used

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  • Preparation method of budesonide
  • Preparation method of budesonide

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Experimental program
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Effect test

Embodiment 1

[0028] 1) Add 100g of prednisolone (equivalent to 0.277mol), 400ml of dimethylformamide, 220ml of acetic anhydride, and 2g of 4-methylaminopyridine into the reactor, stir to raise the temperature and control the temperature at 80°C to react, TLC to track the reaction of raw materials It takes about 2.5 hours to complete, and then the reaction solution is cooled to room temperature. Pour the reaction solution into 6L of ice water, let it stand for 2 hours, filter with suction, wash with water, and dry to obtain shallow intermediate I (11,17,21-triacetoxy-1 , 4-pregnadiene-3,20-dione) yellow solid 124.8g (equivalent to 0.257mol). The molar yield of this step reaction is 92.8%.

[0029]2) Add 124.8g of intermediate I, 487ml of dimethylformamide, and 62.5g of potassium acetate into the reactor, stir and heat up to 100°C, keep warm for the reaction, TLC will take about 4 hours for the raw materials to react completely, and the reaction solution will drop to room temperature. The r...

Embodiment 2

[0036] 1) Add 80g of prednisolone (equivalent to 0.222mol), 300ml of dimethylformamide, 170ml of acetic anhydride, and 2g of 4-methylaminopyridine into the reactor, stir to raise the temperature, control the temperature at 100°C, and track the raw materials by TLC It takes about 2 hours for the reaction to complete, and the reaction solution is cooled to room temperature. The reaction solution is poured into 5L of ice water, allowed to stand for 1.6 hours, filtered with suction, washed with water, and dried to obtain shallow intermediate I (11,17,21-triacetoxy-1 , 4-pregnadiene-3,20-dione) yellow solid 99.7g (equivalent to 0.205mol), the molar yield yield of this step reaction is 92.3%.

[0037] 2) Add 99.7g of intermediate I, 400ml of dimethylformamide, and 45g of sodium acetate into the reactor, stir and raise the temperature to 120°C, keep warm for the reaction, TLC will take about 3 hours for the raw materials to react completely, and the reaction solution will drop to room...

Embodiment 3

[0044] 1) Add 150g of prednisolone (equivalent to 0.416mol), 600ml of dimethylformamide, 350ml of acetic anhydride, and 3g of 4-methylaminopyridine into the reactor, stir and raise the temperature, control the temperature at 100°C, and track the raw materials by TLC It takes about 3 hours for the reaction to complete, and the reaction solution is cooled to room temperature. The reaction solution is poured into 8L of ice water, allowed to stand for 2 hours, filtered with suction, washed with water, and dried to obtain shallow intermediate I (11,17,21-triacetoxy-1, 4-pregnadiene-3,20-dione) yellow solid 187.2g (equivalent to 0.385mol), the molar yield of this step reaction is 92.5%.

[0045] 2) Add 187.2g of intermediate I, 700ml of dimethylformamide, and 95g of potassium hydroxide into the reactor, stir and heat up to 110°C, keep warm for the reaction, TLC will take about 5 hours for the raw materials to react completely, and the reaction solution will drop to room temperature. ...

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Abstract

The invention discloses a preparation method of budesonide. The budesonide is prepared sequentially through the following steps of: carrying out an esterification reaction on a starting material and acetic anhydride, wherein the starting material is prednisolone; carrying out a degreasing reaction in the presence of a catalyst which can be alkali or an alkali metal salt ; carrying out an oxidizing reaction with potassium permanganate in acid environment; carrying out an ester exchange reaction with alcohol in alkaline environment; carrying out a condensation reaction with n-butanal, and the like. In the preparation method, appropriate catalysts are added in the reactions, and reaction conditions are appropriately controlled so as to achieve the purposes of increasing the reaction rates inall the steps and improving the yield of intermediate products, and the product quality conforms to the standard of the European Pharmacopoeia. Meanwhile, all the steps have moderate reaction condition and easy control, low energy consumption, high product yield, small pollution, easy reaction raw material obtaining and low production cost.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and specifically refers to a preparation method of budesonide. Background technique [0002] Budesonide is a non-halogenated glucocorticoid with high-efficiency local anti-inflammatory effect. It is mainly used for the treatment of asthma or allergic rhinitis. Clinical experiments have proved that budesonide has anti-inflammatory activity 1000 times that of hydrocortisone, but rarely produces systemic side effects of corticosteroids. What stands out is that it can be applied to children, which is a rare and excellent quality among corticosteroids, and thus becomes the first choice for clinical treatment of severe asthma and allergic rhinitis. Budesonide has two configurations, R and S. The anti-inflammatory effect of the R configuration is two to three times higher than that of the S configuration, and other pharmacokinetic properties are better than that of the S configuration. The ...

Claims

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Application Information

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IPC IPC(8): C07J71/00
Inventor 殷超秦贵友
Owner HUBEI GEDIAN HUMANWELL PHARMACEUTICAL CO LTD
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