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Preparation method for fluocinolone acetonide midbody

A technology of fluocinolone acetate and intermediates, applied in the directions of steroids, organic chemistry, etc., can solve the problems of eliminating many side reactions, prone to rearrangement, and low refining yield, etc., to improve yield and quality, and improve quality. and yield, the effect of reducing production costs

Active Publication Date: 2015-01-28
江西赣亮医药原料有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This method has the higher price of starting material prednisolone, and this material is prone to rearrangement in the dissolved state, which brings great inconvenience to the reaction operation; There are many side reactions to eliminate, so that the yield of this step is difficult to achieve an ideal state; similarly, carrying out the brominated epoxy reaction in the presence of the 21-position acetate will inevitably cause the hydrolysis reaction of part of the 21-position acetate, As a result, the final refining yield is not high, resulting in the high cost of 21-acetate-9,11-epoxy-17α-hydroxypregna-1,4-diene-3,20-dione prepared by this method The high cost directly determines the high cost of fluocinonide

Method used

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  • Preparation method for fluocinolone acetonide midbody
  • Preparation method for fluocinolone acetonide midbody
  • Preparation method for fluocinolone acetonide midbody

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Take a three-necked reaction flask and let it be protected by nitrogen. Add 300ml of 2-methylpyridine and 100g of compound I (11α-hydroxy-ADD) into the reaction flask. Stir at room temperature for 10-15 minutes, cool to -20°C, and add to the reaction solution in batches Add 20g of phosphorus pentachloride, stir for 10-15min, then pass 20g of sulfur dioxide into the reaction flask, keep the temperature at -20~-10℃, for about 1.5~2h, after the introduction, keep the temperature for 1h, TLC After the reaction was completed, 2500ml of water was slowly dropped into the reaction solution, filtered, washed with a small amount of water to neutrality, and the solid was dried at 60°C to obtain 92g of compound II, namely 1,4,9(11)-triene Androsta-3,17 dione, mass yield: 92%, HPLC purity: 98%.

[0031] Add 200ml of methanol, 100ml of acetone cyanohydrin, and 200.0g of compound II to a clean four-necked reaction flask. After stirring, add 200ml of 10wt% potassium carbonate aqueous solu...

Embodiment 2

[0037] Take a three-necked reaction flask and put it under nitrogen protection. Add 300ml of pyridine and 100g of compound I (11α-hydroxy-ADD) to the reaction flask. Stir at room temperature for 10-15 minutes, cool to 15°C, and add N-bromobutyl to the reaction solution. 54g of diimide, stirring for 10-15min, inject 20g of sulfur dioxide into the reaction flask, keep the temperature at 10-15℃, for about 1.5-2h, after the introduction, keep the reaction temperature for 1h, TLC detection, after the reaction is complete , Slowly drip 2500ml of water into the reaction solution, filter, wash with a small amount of water to neutrality, and dry the solid at 60°C to obtain 95g of compound II, namely 1,4,9(11)-trienandrosta-3, 17 diketone, mass yield: 95%, HPLC purity: 98%.

[0038] Add 300ml of acetone, 120ml of acetone cyanohydrin, and 200.0g of compound II to a clean and dry four-necked reaction flask. After stirring evenly, add 150ml of 10wt% sodium carbonate solution. The temperature ...

Embodiment 3

[0044] Take a three-necked reaction flask and put it under nitrogen protection. Add 400ml of diisopropylamine, compound I, 11α-hydroxy-ADD, to the reaction flask, stir at room temperature for 10-15 minutes, and cool to -10°C. Add N-chlorine to the reaction solution. Substitute succinimide 50g, stir for 10-15min, pass 20g sulfur dioxide into the reaction flask, keep the temperature below -10~-5℃, time about 1.5~2h, after passing through, keep the temperature and react for 1h, TLC It was detected that after the reaction was completed, 2500ml of water was slowly dropped into the reaction solution, filtered, washed with a small amount of water to neutrality, and the solid was dried at 60°C to obtain 94g of compound II, namely 1,4,9(11)-triene Androsta-3,17 dione, mass yield: 94%, HPLC purity: 98%.

[0045] Add 200ml methanol, 160g sodium cyanide, and 200.0g compound II to a clean four-necked reaction flask. The temperature of the system is controlled at 0~10℃. After stirring, 128ml o...

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Abstract

The invention discloses a preparation method for a fluocinolone acetonide midbody, i.e., 21-acetate-9,11-epoxy-17-alpha-hydroxypregn-1,4-diene-3,20-diketone. A compound I, i.e., 11-alpha-hydroxy-ADD (androstadienedione), serves as a starting material; an elimination reaction, a cyano-substitution reaction, a siloxy protective reaction, an intramolecular nucleophilic substitution reaction, a bromo-epoxy reaction and a replacement reaction are carried out to obtain the fluocinolone acetonide midbody. The preparation method provided by the invention has the advantages that the starting material which is relatively cheap is used, the reactions in the steps are relatively easy to implement, and the yield is higher, so that the production is more economical and safe, and higher applicability for industrial production is achieved; through route design optimization, the preparation method avoids 9 (11)-double-bonded epoxidation with the existence of 21-acetate in the traditional technique, so as to avoid the 21-acetate hydrolysis, greatly improve the quality and yield of the fluocinolone acetonide midbody, and reduce the entire production cost.

Description

Technical field [0001] The invention relates to a chemical synthesis method of a compound, in particular to a fluocinolone acetate intermediate, namely 21-acetate-9,11-epoxy-17α-hydroxypregna-1,4-diene-3,20- Preparation method of diketone. Background technique [0002] Fluocinolone Acetate, also known as Fluocinolone Acetonide, English name Fluocinolone Acetonide, chemical name: 11β-hydroxy-16α,17-[(1-methylethylene)-bis(oxy)]-21-(acetyl (Oxy)-6α,9-difluoropregna-1,4-diene-3,20-dione, its structural formula is as follows: [0003] [0004] It is an adrenal corticosteroid drug, suitable for skin diseases that are effective for glucocorticoids, such as contact dermatitis, atopic dermatitis, seborrheic dermatitis, eczema, pruritus, psoriasis, neurodermatitis, etc. Sexual and non-infectious inflammatory skin diseases. [0005] The compound 21-acetate-9,11-epoxy-17α-hydroxypregna-1,4-diene-3,20-dione is the most important intermediate for the synthesis of fluocinolone acetate, and its ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J71/00
CPCC07J71/0015
Inventor 蒋青锋杨坤应正平蒋华容
Owner 江西赣亮医药原料有限公司
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