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Beclomethasone dipropionate intermediate and preparation method thereof

A technology of clometasone dipropionate and intermediates, applied in the direction of steroids, organic chemistry, etc., can solve the problems of difficult wastewater treatment, long separation process route, complicated operation, etc., to reduce production costs and achieve obvious competitiveness , the effect of simple operation

Inactive Publication Date: 2020-11-17
HENAN LIHUA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above-mentioned synthesis method has a long process route for the separation of intermediates, complicated operations, a wide variety of auxiliary materials, and produces a large amount of difficult-to-treat wastewater.

Method used

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  • Beclomethasone dipropionate intermediate and preparation method thereof
  • Beclomethasone dipropionate intermediate and preparation method thereof
  • Beclomethasone dipropionate intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] The preparation method of the beclomethasone dipropionate of the present embodiment, the steps are as follows:

[0045] 1. Preparation of aluminum trichloride solution

[0046] Dissolve 0.8g of anhydrous aluminum trichloride in 100mL of water to prepare an aluminum trichloride solution for later use.

[0047] 2. Macrocyclic and ring-opening reactions

[0048] Under the protection of nitrogen, add 120mL tetrahydrofuran, 20g DB11 and 20mL triethyl orthopropionate into the reaction flask, cool down to about 20°C, add 0.8g p-toluenesulfonic acid, the system dissolves, react at 20°C for 2 hours, TLC (Dichloromethane: acetone = 6: 1) There is almost no spot at Rf 0.44, and a system containing the compound of formula I is obtained.

[0049] Lower the temperature of the above system to about 10°C, add 100mL of the above-mentioned aluminum chloride aqueous solution dropwise, control the temperature at 25°C, and keep the reaction for more than 10 hours. TLC (dichloromethane:aceto...

Embodiment 2

[0056] The preparation method of the beclomethasone dipropionate of the present embodiment, the steps are as follows:

[0057] 1. Preparation of aluminum trichloride solution

[0058] Dissolve 0.8g of anhydrous aluminum trichloride into 100mL of water to prepare an aluminum trichloride solution for later use.

[0059] 2. Macrocyclic and ring-opening reactions

[0060] Under nitrogen protection, 120mL DMF, 20gDB11 and 30mL triethyl orthopropionate were added to the reaction flask, the temperature was lowered to 25°C, 1g p-toluenesulfonic acid was added, the system was dissolved and reacted at 25°C for 2 hours, TLC (2 Chloromethane: acetone = 6: 1) There is almost no spot at Rf 0.44, and a system containing the compound of formula I is obtained.

[0061] Lower the temperature of the above system to about 15°C, add 100mL of the above-mentioned aluminum chloride aqueous solution dropwise, control the temperature at 30°C, and keep the reaction for more than 10 hours. TLC (dichlor...

Embodiment 3

[0068] The preparation method of the beclomethasone dipropionate of the present embodiment, the steps are as follows:

[0069] 1. Preparation of aluminum trichloride solution

[0070] Dissolve 0.8g of anhydrous aluminum trichloride into 100mL of water to prepare aluminum trichloride solution, and set aside.

[0071] 2. Macrocyclic and ring-opening reactions

[0072] Under nitrogen protection, add 120mL of 1,4-dioxane, 20g of DB11 and 20mL of trimethyl orthopropionate into the reaction flask, cool down to 25°C, add 0.6g of p-toluenesulfonic acid, the system is dissolved, and at 25°C After reacting for 2 hours, TLC (dichloromethane: acetone = 6:1) detected almost no spots at Rf 0.44, and a system containing the compound of formula I was obtained.

[0073] Lower the temperature of the above system to about 10°C, add 100mL of the above-mentioned aluminum chloride aqueous solution dropwise, control the temperature at 25°C, and keep the reaction for more than 10 hours. TLC (dichlo...

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Abstract

The invention provides a beclomethasone dipropionate intermediate and a preparation method thereof. The preparation method of beclomethasone dipropionate comprises the following steps: A) in a first organic solvent, reacting a compound DB11, ortho-propionate and p-toluenesulfonic acid to obtain an intermediate shown as a formula I; B) dropwise adding an aluminum trichloride solution into the intermediate shown in the formula I, reacting, adding a second organic solvent after reaction, and separating an organic layer to obtain an intermediate shown in a formula II; C) adding a catalyst and a propionylation reagent into the intermediate shown in the formula II and reacting to obtain an intermediate shown in a formula III; D) dropwise adding hydrochloric acid into the intermediate shown in the formula III, reacting, and separating an organic layer after reaction to obtain a beclomethasone dipropionate crude product. The reaction route is shown in the description. The preparation method disclosed by the invention is environment-friendly, low in energy consumption and high in product purity and yield.

Description

technical field [0001] The invention relates to the technical field of pharmacy, in particular to a beclomethasone dipropionate intermediate and a preparation method. Background technique [0002] Beclomethasone dipropionate is a potent topical glucocorticoid with the chemical name 9-chloro-11,17,21-trihydroxy-16-methylpregna-1,4-diene -3,20-diketone-17,21-dipropionate, has anti-inflammatory, anti-allergic and antipruritic effects, can inhibit bronchial exudate, eliminate bronchial mucosal swelling, relieve bronchospasm, and constrict skin blood vessels The effect is far stronger than hydrocortisone, and the local anti-inflammatory effect is 5 times that of Fucaolin and Triamcinolone. Beclomethasone dipropionate has strong lipophilicity and is easy to penetrate. It will take effect 30 minutes after being applied to the affected area. [0003] The structural formula of beclomethasone dipropionate is as follows: [0004] [0005] The traditional process route starts with...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00C07J71/00
CPCC07J5/0076C07J71/0015
Inventor 王海波牛志刚王泉泉李合兴苏静
Owner HENAN LIHUA PHARMA
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