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Preparation method of high-purity micafungin intermediate

A technology of micafungin and body formula, which is applied in the preparation of 4-[5-isoxazol-3-yl]benzoic acid and the field of preparation of high-purity micafungin intermediates, can solve the problem of low product purity and reagent Expensive, many waste solvents and other problems, to achieve the effect of high product purity and simple operation

Inactive Publication Date: 2020-05-08
NANJING CHICO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These methods have defects, the reagents used are all more expensive, and more waste solvents are produced, and the product purity is lower

Method used

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  • Preparation method of high-purity micafungin intermediate
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  • Preparation method of high-purity micafungin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1 Preparation of Compound A-1

[0025] Add 5 g of p-hydroxyacetophenone (compound of formula B), 7.9 g of iodopentane (compound of formula A), and 6 g of anhydrous potassium carbonate into 50 mL of DMF, stir at 60°C for 4 hours. Detect the reaction. After the reaction is completed, cool to room temperature, add petroleum ether (50 mL) and water (50 mL) in sequence, and keep the petroleum ether layer. The petroleum ether layer was washed successively with 0.5 mol / L sodium hydroxide solution and saturated brine, dried by adding anhydrous magnesium sulfate, filtered and concentrated to obtain 7 g of compound A-1 with a yield of 93% and a purity of 95% by HPLC.

Embodiment 2

[0026] Example 2 Preparation of Compound A-3

[0027] Compound A-1 (4g), p-aldehyde benzoic acid (4.1g, compound of formula A-2), and 1.3g of sodium hydroxide were sequentially added to water (20ml) and ethanol (8ml), and stirred at 40°C for 4 hours. After the reaction was completed, the reaction solution was cooled in an ice bath, 10% dilute hydrochloric acid was added to adjust the pH to 2, and the solid was collected by filtration. The solid was stirred in 45 ml of ethanol at room temperature, and compound A-3 (5.5 g) was obtained after filtration, with a yield of 85% and a purity of 95.7% by HPLC.

Embodiment 3

[0028] Example 3 Preparation of Compound A-4

[0029] Compound A-3 (2.7 g), TsNHOH (N-p-toluenesulfonyl hydroxylamine, 11 g), sodium hydroxide (2.5 g) were dissolved in 50 ml of a mixed solution of methanol and water (volume ratio 4:1). Stir at 43°C for 35 hours. After the reaction is completed, add 10% dilute hydrochloric acid to the reaction solution under ice water cooling to adjust the pH to 2, and filter. Add 80ml of ethanol to the obtained solid, stir and beat at room temperature, wash the filter cake, and filter to obtain compound A-4, further add the compound to 60ml of ethanol, beat at room temperature, filter and dry to obtain compound A-4 (2.2g), yield 80%. The HPLC content is 98.5%, the maximum single hetero HPLC content is <0.8%, and the isomer impurity is <0.1%.

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PUM

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Abstract

The invention belongs to the field of drug synthesis, relates to a preparation method of a high-purity micafungin intermediate, and concretely relates to a preparation method of a micafungin intermediate compound represented by formula A-4. The synthesis method is simple to operate and high in yield, and can meet the requirements of industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and relates to a preparation method of a high-purity micafungin intermediate, in particular to 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoic acid method of preparation. Background technique [0002] Micafungin (Micafungin) is a novel echinocandin antifungal drug obtained by chemical synthesis by transforming the natural product of Coleophoma empetri; Candida krusei and Candida parapsilosis have good inhibitory activity, and also have good inhibitory activity against Aspergillus in vitro, but have no inhibitory activity against Cryptococcus neoformans, Fusarium, Zygomycetes and Trichosporon albajiri. Micafungin was developed by Fujisawa Corporation of Japan and launched in Japan in December 2002 under the product name Fungusrd. It passed FDA certification in 2005 and is currently approved for the treatment of esophageal candida infection, bone marrow transplantation and ADS patients Preve...

Claims

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Application Information

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IPC IPC(8): C07D261/08
CPCC07D261/08
Inventor 杨博海威
Owner NANJING CHICO PHARMA CO LTD
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