Improved preparation method of dexamethasone sodium phosphate intermediate

A technology of dexamethasone sodium phosphate and dexamethasone phosphate, applied in the direction of steroids, organic chemistry, etc., can solve the problems of incomplete reaction of dexamethasone, reduction of product purity, increase of side reactions, etc., and achieve good industrial application Foreground, increasing organic solvent extraction, effect of increasing yield

Active Publication Date: 2014-07-23
SHANGHAI NEW HUALIAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In the above reaction, the preparation of dexamethasone phosphate is to react at a low temperature of -50°C to -60°C. Due to the slow reaction rate and short time of only 1h at ultra-low temperature, the reactant dexamethasone cannot be completely reacted, and the yield rate is too low
At the same time, the concentration temperature is 70°C to 80°C. If the temperature is too high, the side reactions will increase and the purity of the product will be reduced.

Method used

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  • Improved preparation method of dexamethasone sodium phosphate intermediate
  • Improved preparation method of dexamethasone sodium phosphate intermediate
  • Improved preparation method of dexamethasone sodium phosphate intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] (A) In a 500ml four-necked reaction flask, add 20g dexamethasone, 200ml tetrahydrofuran, and ventilate nitrogen. Under stirring, the temperature is controlled to -45℃~-55℃, 22g pyrophosphoryl chloride is added dropwise, and the temperature is increased to -35. ℃~-45℃, heat preservation reaction for 1h;

[0042] (B) Control the temperature to -30℃~-45℃, add 100ml purified water dropwise to stop the reaction, slowly add the reaction solution to a 2000ml four-necked reaction flask containing 580ml ice water; after the addition, slowly add 100g hydrogen carbonate Sodium, control the temperature to 5℃~10℃ and stir for 2h;

[0043] (C) Filter, rinse the filtered sodium bicarbonate with 200ml of purified water, combine the eluent with the filtrate, and concentrate the combined solution under reduced pressure at 40°C to 45°C until there is no tetrahydrofuran;

[0044] (D) After concentration, cool to 10℃~20℃, add 180ml ethyl acetate to extract 3 times, separate into layers, add activ...

Embodiment 2

[0048] (A) In a 250ml four-necked reaction flask, add 10g of dexamethasone, 120ml of tetrahydrofuran, and aeration of nitrogen. While stirring, the temperature is controlled to -45℃~-55℃, and 12g of pyrophosphoryl chloride is added dropwise, and the temperature is increased to -35. ℃~-45℃, heat preservation reaction for 1h;

[0049] (B) Control the temperature to -30℃~-40℃, add 50ml purified water dropwise to stop the reaction, slowly add the reaction solution to a 1000ml four-necked reaction flask containing 350ml ice water; after the addition, slowly add 60g hydrogen carbonate Sodium, control the temperature to 5℃~10℃ and stir for 2.5h;

[0050] (C) Filter, rinse the filtered sodium bicarbonate with 100ml of purified water, combine the eluent with the filtrate, and concentrate the combined solution under reduced pressure at 40°C to 45°C until there is no tetrahydrofuran;

[0051] (D) After concentrating, cool to 10℃~20℃, add 90ml ethyl acetate to extract 3 times, separate into lay...

Embodiment 3

[0055] (A) In a 1000ml four-necked reaction flask, add 40g dexamethasone, 450ml tetrahydrofuran, and ventilate nitrogen. Under stirring, the temperature is controlled to -45℃~-55℃, and 45g pyrophosphoryl chloride is added dropwise, and the temperature is increased to -35. ℃~-45℃, keep warm for 75min;

[0056] (B) Control the temperature to -30℃~-45℃ and add 400ml purified water dropwise to stop the reaction, slowly add the reaction solution to a 3000ml four-necked reaction flask containing 1200ml ice water; after the addition, slowly add 250g hydrogen carbonate Sodium, control the temperature to 5℃~10℃ and stir for 2h;

[0057] (C) Filter, rinse the filtered sodium bicarbonate with 400ml of purified water, combine the eluent with the filtrate, and concentrate the combined solution under reduced pressure at 40°C to 45°C until there is no tetrahydrofuran;

[0058] (D) After concentrating, cool to 10℃~20℃, add 360ml ethyl acetate to extract 3 times, separate into layers, add activated ...

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Abstract

The invention provides an improved preparation method of a dexamethasone sodium phosphate intermediate. The improved preparation method of the dexamethasone sodium phosphate intermediate comprises the following steps: (a) in tetrahydrofuran, with dexamethasone and pyrophosphoryl chloride as raw materials, carrying out a reaction at the temperature ranging from minus 35 DEG C to minus 45 DEG C, so that dexamethasone phosphate is obtained; (b) adding purified water, carrying out hydraulic analysis after a termination reaction is finished, and then adding sodium hydrogen carbonate for salifying; (c) filtering, and carrying out reduced pressure concentration at the temperature of 30-45 DEG C until tetrahydrofuran is not contained in filtrate; (d) adding an organic solvent for extraction; and (e) filtering, carrying out reduced pressure concentration at the temperature of 30-45 DEG C until the organic solvent is not contained in the filtrate, adding acid for acidification, stirring for 6-8 hours, filtering, and carrying out vacuum drying, so that dexamethasone phosphate is obtained. The improved preparation method of the dexamethasone sodium phosphate intermediate has the advantages that utilization rate of raw materials and purity and yield of a product are improved, so that production cost is reduced; and the improved preparation method of the dexamethasone sodium phosphate intermediate has a wide industrial application prospect.

Description

Technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to an improved preparation method of dexamethasone sodium phosphate intermediate. Background technique [0002] The chemical name of Dexamethasone sodium phosphate is: 16a-methyl-11,17a,21-trihydroxy-9a-fluoropregester-1,4-diene-3,20-dione-21 -Phosphate disodium salt, the molecular formula is C22H28FO8PNa2, and its chemical structure is shown in formula (I). [0003] Dexamethasone sodium phosphate is a kind of adrenal glucocorticoid drugs. It has stronger anti-inflammatory, anti-toxin and anti-shock effects, and has no sodium retention and potassium excretion effects. It is an indispensable emergency medicine for rescuing dying patients. It was once known as the "king of corticosteroid drugs" in the decade. Its raw materials can be made into clinical injections, oral tablets and external preparations. [0004] Structural formula of dexamethasone sodium phosphate: [0005] [0...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00
Inventor 袁文龙卿文彬吴庆安周秋火
Owner SHANGHAI NEW HUALIAN PHARMA
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