Method for preparation of Efinaconazole

A compound and iodide technology, applied in the field of preparation of efluconazole, can solve the problems of consuming manpower and material resources, increasing operating procedures, and long reaction time, and achieve the effects of promoting technological progress, simplifying process operation, and easy handling

Inactive Publication Date: 2017-04-19
WATERSTONE PHARMA WUHAN
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Yet in the prior art, we find that when using the hydrochloride of amine, need to use a large amount of excess amine (the amine mentioned in this application is the free base of the compound shown in formula 3), and the reaction time is long
Therefore when adopting the hydrochloride of amine as raw material, the disadvantage of its production method is: the by-product of the obtained product is many, and excessive amine needs to be reclaimed, has increased operating procedure, consumes manpower and material resources cost; From an economic point of view, due to Amines are expensive, making this method of preparation costly
[0005] Therefore, the current method for preparing the compound shown in formula 1 still needs to be improved

Method used

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  • Method for preparation of Efinaconazole
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  • Method for preparation of Efinaconazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Embodiment 1 prepares 4-methylene piperidine hydrochloride

[0039]

[0040] Add 600g (3.03mol) of N-Boc-4-methylenepiperidine and 3L methanol into a 5L reaction flask, add 768g (7.56mmol) of concentrated hydrochloric acid with a content of 36%, the reaction is complete, and after concentration under reduced pressure, Add 2L of ethyl acetate for slurry filtration, and dry under reduced pressure at room temperature to obtain 338.4 g of 4-methylene piperidine hydrochloride (91.0% yield, 99.9% purity), which 1 H-NMR spectrum such as figure 1 as shown,

[0041] 1 H-NMR (400MHz, CDCl 3 ): δ: 2.55 (4H, t, J = 6.09Hz), 3.19 (4H, t, J = 6.09Hz), 4.85 (2H, s), 9.64 (2H, br).

Embodiment 2

[0042] Embodiment 2 prepares efluconazole

[0043] 4-methylenepiperidine hydrochloride, 3.2g (134.0mmol) lithium hydroxide and 14.8g (89.3mmol) potassium iodide obtained in 17.9g (134.0mmol) embodiment 1 were added in 67.2g acetonitrile, after stirring , add 22.4g (89.3mmol) of the compound shown in formula 2, heat and reflux in an oil bath (external temperature 100°C) for 8 hours, after the reaction is over, add 44ml of ethanol and 100ml of water to the reaction solution, stir for 1 hour and then filter , dried under reduced pressure at 50°C to obtain 27.3g white solid (87.8% yield, 99.6% purity as detected by HPLC), which 1 H-NMR spectrum such as figure 2 as shown,

[0044] 1 H-NMR (400MHz, CDCl 3 ): δ:0.97(3H,dd,J=2.6,7.0Hz),2.21-2.25(4H,m),2.30(2H,br),2.68~2.72(2H,m),2.92-2.93(1H,m ),4.65(2H,s),4.86(1H,d,J=14.8Hz),4.87(1H,dd,J=14.4Hz),5.47(1H,s),6.75-6.80(2H,m),7.49 ~7.54 (1H, m), 7.79 (1H, s), 8.03 (1H, s).

Embodiment 3

[0045] Embodiment 3 prepares efluconazole

[0046] 17.9g (134.0mmol) of 4-methylenepiperidine hydrochloride obtained in Example 1, 3.2g (134.0mmol) lithium hydroxide and 1.48g (8.93mmol) potassium iodide were added to 67.2g cyclopentyl methyl ether After stirring, add 22.4g (89.3mmol) of the compound shown in formula 2, and heat to reflux in an oil bath (external temperature 100°C) for 10 hours. After the reaction is completed, add 44ml of ethanol and 100ml of water to the reaction solution, and stir After 1 hour, it was filtered and dried under reduced pressure at 50° C. to obtain 26.5 g of white solid (85.2% yield, 99.1% purity by HPLC).

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Abstract

The invention provides a method for preparation of Efinaconazole. The method comprises the following step: in the presence of iodide or its hydrate, in a reaction solvent and alkali, a compound as shown in the formula 2 is contacted with a compound as shown in the formula 3, so as to obtain a compound as shown in the formula 1. By the method, Efinaconazole can be effectively prepared. In addition, the method has advantages of few steps, simple synthesis process and mild reaction conditions. Meanwhile, excessive use of expensive amine can be avoided; yield and purity of the product are high; there are few by-products; production cost is low; corrosion to the reaction vessel during the production process is little; and industrial "three wastes (waste gas, waste water and industrial residue)" are easy to treat. The method is safe and environment-friendly, and is beneficial to industrial production of Efinaconazole.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular, the invention relates to a method for preparing efluconazole. Background technique [0002] The first topical triazole antifungal drug, Efinaconazole (compound represented by Formula 1), was developed for the treatment of local distal lateral subungual fungus (DLSO). DLSO is the most common onychomycosis. The pathogenic bacteria first invade the distal subungual nail bed, and the subungual horniness hyperplasia and thickening, the nail plate can become white, brown to taupe, the surface is uneven, tarnished, the nail plate missing, crunchy. Studies have found that efluconazole is effective against fungal diseases in both humans and animals. [0003] The preparation of amino alcohols usually adopts the ring-opening addition reaction of amines to epoxides. Generally speaking, amines exist in the form of salts to facilitate storage, transportation and feeding. Usually the correspon...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/06
CPCC07D401/06
Inventor 胡名龙王大鹏付美玲钱丽娜崔健
Owner WATERSTONE PHARMA WUHAN
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