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A kind of preparation method of fluocinolone acetate intermediate

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, improve quality and yield, the effect of reducing production costs

Active Publication Date: 2016-03-23
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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  • A kind of preparation method of fluocinolone acetate intermediate
  • A kind of preparation method of fluocinolone acetate intermediate
  • A kind of preparation method of fluocinolone acetate intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Take a three-necked reaction flask, protect it with nitrogen gas, add 300ml of 2-picoline and 100g of compound I, namely 11α-hydroxy-ADD, into the reaction flask, stir at room temperature for 10-15min, cool down to -20°C, and add to the reaction solution in batches 20g of phosphorus pentachloride, stirred for 10-15min, then 20g of sulfur dioxide was introduced into the reaction flask, the temperature was kept at -20--10°C, and the time was about 1.5-2h. , after the reaction is complete, slowly drop 2500ml of water into the reaction solution, filter, wash with a small amount of water until neutral, and dry the solid at 60°C to obtain 92g of compound II, namely 1,4,9(11)-triene androster -3,17 diketone, 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 in sequence. After stirring evenly, add 200ml of 10wt% potassium carbonate aqueous solution, and control the tem...

Embodiment 2

[0037] Take a three-necked reaction flask, pass it through nitrogen protection, add 300ml of pyridine and 100g of compound I, namely 11α-hydroxyl-ADD, into the reaction flask, stir at room temperature for 10-15min, cool down to 15°C, and add N-bromobutylene to the reaction solution 54g of imide, stirred for 10-15min, passed 20g of sulfur dioxide into the reaction flask, kept the temperature at 10-15°C, and took about 1.5-2h. Slowly drop 2500ml of water into the reaction solution, filter, wash with a small amount of water until neutral, and dry the solid at 60°C to obtain 95g of compound II, namely 1,4,9(11)-triene androst-3,17di Ketone, 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 in sequence. After stirring evenly, add 150ml of 10wt% sodium carbonate solution, control the temperature of the system at 40-50°C for 20 hours, and detect with TLC Raw material...

Embodiment 3

[0044] Take a three-necked reaction flask, protect it with nitrogen gas, add 400ml of diisopropylamine, compound I, 11α-hydroxy-ADD into the reaction flask, stir at room temperature for 10-15min, cool down to -10°C, and add N-chloro Add 50g of succinimide, stir for 10-15min, pass 20g of sulfur dioxide into the reaction flask, keep the temperature below -10-5°C, for about 1.5-2h, after the completion of the passage, keep warm for 1h, TLC Detection, after the reaction is complete, slowly drop 2500ml of water into the reaction solution, filter, wash with a small amount of water until neutral, and dry the solid at 60°C to obtain 94g of compound II, namely 1,4,9(11)-triene androgen Steroid-3,17dione, mass yield: 94%, HPLC purity: 98%.

[0045] Add 200ml of methanol, 160g of sodium cyanide, and 200.0g of compound II to a clean four-necked reaction flask in sequence. The temperature of the system is controlled at 0-10°C. After stirring evenly, 128ml of glacial acetic acid is added dr...

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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- Process for the preparation of diketones. Background technique [0002] Fluocinolone acetate, also known as fluocinolone, fluocinolone, English name FluocinoloneAcetonide, chemical name: 11β-hydroxy-16α,17-[(1-methylethylene)-bis(oxygen)]-21-(acetyloxy base)-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 to glucocorticoids, such as contact dermatitis, atopic dermatitis, seborrheic dermatitis, eczema, skin pruritus, psoriasis, neurodermatitis and other itching 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 in t...

Claims

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Application Information

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Patent Type & Authority Patents(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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