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Preparing method of 1-triazole-2-butanol derivative

A technology of derivatives and butanol, which is applied in the field of preparation of 1-triazole-2-butanol derivative ffluconazole, can solve the problems of low product purity, low yield and many impurities, and achieves selectivity Good, high yield, complete reaction effect

Active Publication Date: 2018-03-06
SUZHOU VIGONVITA LIFE SCIENCES CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Among the above two methods, the method reported in WO1994026734 patent has the disadvantages of low yield, many impurities and the need for chromatographic column purification.
Although the method reported by CN103080100A obtained a higher yield when the raw material adopted was 4-methylene piperidine hydrobromide or 4-methylene piperidine hydroiodide, when the raw material was 4-piperidine When using pyridine hydrochloride, the yield is still on the low side, and the yield can only be obtained when the preparation scale is very small scale
In addition, if the patented method is not subjected to chromatographic column purification during post-processing, the purity of the obtained product is not high. In order to ensure product purity, chromatographic column purification must still be carried out

Method used

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  • Preparing method of 1-triazole-2-butanol derivative
  • Preparing method of 1-triazole-2-butanol derivative
  • Preparing method of 1-triazole-2-butanol derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] In a 250mL three-neck flask, equipped with a thermometer, add 4-methylene piperidine hydrochloride (25.7g, 199mmol), NaOH (8g, 199mmol), 80mL acetonitrile, and stir for 30 minutes at 25°C. Then add (2R, 3S) -2-(2,4-Difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (20g, 79.6mmol) , LiCl (8.4g, 199mmol). 85-90°C for 22-25 hours. TLC shows that the reaction is complete. Post-treatment: stop heating, cool to room temperature, filter, wash the filter cake with 50 mL of acetonitrile, wash the organic phase with 50 mL of water, separate liquids, concentrate and dry to obtain 35 g of oil. Then recrystallize from ethanol / water. The white solid obtained by drying is efluconazole: 25.7 g, yield: 93.0%, purity: 99.5%.

[0030] Obtained solid 1 H NMR(300MHz, CDCl 3 ): δ8.00(s,1H),7.75(s,1H),7.51-7.45(m,1H),6.78-6.68(m,2H),5.44(s,1H), 4.82(dd,J=18.0 ,12.0Hz,2H),4.61(s,2H),2.90-2.86(m,1H),2.69-2.66(m,2H),2.32(br,2H),2.21-2.17(m,4H),0.92( dd,J=6.0,3.0Hz,3H); 13CNMR (75M...

Embodiment 2

[0032] In a 250mL three-neck flask, equipped with a thermometer, add 4-methylene piperidine hydrochloride (25.7g, 199mmol), NaOH (8g, 199mmol), 80mL acetonitrile, and stir for 30 minutes at 25°C. Then add (2R, 3S) -2-(2,4-Difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (20g, 79.6mmol) , LiBr (17.3g, 199mmol). The reaction was conducted at 85-90°C for 5 hours. TLC indicated that the reaction was complete. Post-treatment: stop heating, cool to room temperature, filter, wash the filter cake with 50 mL of acetonitrile, wash the organic phase with 50 mL of water, separate, concentrate and dry, use ethanol 50 mL*2 twice to obtain 36 g of oil. Then recrystallize from ethanol / water. The white solid obtained by drying is efluconazole: 25.9 g, yield: 93.7%, purity: 99.6%.

Embodiment 3

[0034] In a 250mL three-neck flask, equipped with a thermometer, add 4-methylene piperidine hydrochloride (25.7g, 199mmol), NaOH (8g, 199mmol), 80mL acetonitrile, and stir for 30 minutes at 25°C. Then add (2R, 3S) -2-(2,4-Difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (20g, 79.6mmol) , LiI (26g, 199mmol), reacted at 85-90°C for 5 hours. TLC indicated that the reaction was complete. Post-treatment: stop heating, cool to room temperature, filter, wash the filter cake with 50 mL of acetonitrile, wash the organic phase with 50 mL of water, separate and concentrate to dry to obtain 38 g of oil. Then recrystallize from ethanol / water. The white solid obtained by drying is efluconazole: 26.5 g, yield: 96%, purity: 99.7%.

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Abstract

The invention relates to a preparing method of a 1-triazole-2-butanol derivative. The preparing method comprises the steps of making 4-methylpiperidine addition salt react with (2R,3S)-2-(2,4-di-fluorophenyl)-3-methyl-2-[(1H-1,2,4-traizole-1-radical)methyl]oxirane in a solvent in the presence of lithium halide and / or magnesium halide and alkaline to generate the 1-triazole-2-butanol derivative. The reaction is complete, the selectivity is high, and the product of the 1-triazole-2-butanol derivative of which the purity is larger than 99% can be obtained through simple aftertreatment. Besides, the yield is high no matter which form of 4-methylpiperidine addition salt is adopted as raw materials.

Description

Technical field [0001] The invention relates to a preparation method of 1-triazole-2-butanol derivative efluconazole. Background technique [0002] In 1994, Japan Scientific and Pharmaceutical Co., Ltd. (WO1994026734) took the lead in inventing efluconazole (chemical name: (2R, 3R)-2-(2,4-difluorophenyl)-3-(4-methylene piperidine) -1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol) compound patent, and introduced the free 4-piperidine hydrochloride in 50% NaOH solution , And then with (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl]epoxy Ethane is used as a solvent in ethanol / water, and the crude product is obtained at 85°C. The product is purified by chromatography to obtain the efluconazole product. The synthetic route is as follows: [0003] [0004] CN103080100A discloses a method for preparing efluconazole, which is in the presence of hydroxides or hydrates of alkali metals or alkaline earth metals selected from lithium, sodium, calcium and strontium in a reac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/06
CPCC07D401/06
Inventor 倪润炎钱智理吴建忠田广辉
Owner SUZHOU VIGONVITA LIFE SCIENCES CO LTD
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