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Preparation method of intermediate for synthesis of micafungin and derivative thereof

A compound and ketone compound technology, applied in the field of drug synthesis, can solve the problems of expensive metal reagents, short reaction routes, and low yields

Inactive Publication Date: 2012-11-21
TIANJIN XINHUI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Disadvantages of this route: expensive and heavily polluting metal reagents (triphenylphosphorous palladium chloride) need to be used, the synthesis steps are too long, and the overall yield is not high
[0022] Although the reaction scheme three steps are shorter, its yield is lower, and the yield of step a is only 20%, and the yield of step b is only 24%
[0023] It can be seen that the three preparation methods in the prior art have their own defects. The present invention solves the deficiencies in the prior art and provides a short reaction route that can easily synthesize the intermediate required for micafungin. method, and the reaction yield is higher, which simplifies the production process and reduces the production cost

Method used

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  • Preparation method of intermediate for synthesis of micafungin and derivative thereof
  • Preparation method of intermediate for synthesis of micafungin and derivative thereof
  • Preparation method of intermediate for synthesis of micafungin and derivative thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Embodiment 1: the synthesis of compound b

[0046] Compound b synthesis consists of the following three steps:

[0047] (1) Synthesis of compound 1

[0048]

[0049] Dissolve 23g (136g / mol, 0.17mol) of p-hydroxyacetophenone, 28g (151g / mol, 0.19mol) of bromopentane, and 28g (138g / mol, 0.21mol) of anhydrous potassium carbonate in 115mL of dimethylformaldehyde Stir in amide (DMF) at an internal temperature of 65-70°C for 4 hours. The reaction solution was a white suspension. After the reaction was completed, it was cooled to room temperature, and 210 mL of petroleum ether and 210 mL of water were added in sequence, separated by shaking, and the petroleum ether layer was retained. Wash the petroleum ether layer successively with 120ml of 0.5mol / L sodium hydroxide solution and 120ml of saturated brine, add anhydrous magnesium sulfate to dry the petroleum ether for 30min, remove the magnesium sulfate by filtration and evaporate the petroleum ether to obtain a colorless oil...

Embodiment 2

[0059] Embodiment 2: the synthesis of compound a

[0060]

[0061] Compound 3 crude product 1.05g (351g / mol, 0.003mol), HOBT 0.51g (135g / mol, 0.0036mol), EDCI 1.05g (192g / mol, 0.0045mol) were dissolved in 30ml of dichloromethane, stirred at room temperature for 5 hours, The reaction starting materials gradually dissolved. After the reaction was completed, 30 ml of water was added to wash the reaction liquid, the liquid was separated, the organic phase was retained, anhydrous magnesium sulfate was added to dry the organic phase, and the organic phase was separated through a silica gel column by filtration. The eluent was dichloromethane:n-hexane:ethyl acetate=10:10:1~5:5:1 gradient elution, and 0.72g of compound a was obtained.

[0062] 1 H-NMR (400MHz, CDCl 3 )0.95(3H, t, J=6.7Hz), 1.36-1.51(4H, m), 1.80-1.87(2H, m), 4.03(2H, t, J=6.4Hz), 6.81(1H, s), 7.01 (2H, d, J = 8.4Hz), 7.45-7.60 (3H, m), 7.79 (2H, d, J = 8.3Hz), 8.11 (2H, d, J = 8.0Hz), 8.13 (1H, s ), 8.39 (2H, ...

Embodiment 3

[0063] Embodiment 3: N-hydroxy p-toluenesulfonamide (TsNHOH) is synthesized

[0064] Mixed solution A was prepared by dissolving 60 g (190 g / mol, 0.3 mol) of p-toluenesulfonyl chloride and 200 ml (101 g / mol, 1.5 mol) of triethylamine in 200 ml of deionized water. Dissolve 62 g of hydroxylamine hydrochloride (69 g / mol, 0.9 mol) in 200 ml of THF, cool in an ice bath and control the temperature at 0-5°C, and add it dropwise into the mixture A with vigorous stirring. Rising to room temperature and stirring for 2 hours, the reaction was completed, the liquid was separated, and the upper organic phase was collected. 100ml of 10% dilute hydrochloric acid was added to the organic phase, and the mixed solution was evaporated to dryness by rotary evaporation, and a large amount of white solid was precipitated. After filtration, 23g of the white solid product hydroxy-p-toluenesulfonamide was obtained, with a yield of 39%.

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Abstract

The invention provides a preparation method of an intermediate for synthesis of a side chain of micafungin and a derivative thereof. The method is realized by reaction of an alpha, beta-unsaturated ketone compound in the presence of N-hydroxy-para toluene sulfonamide and inorganic base. Defects of the prior art can be overcome, the reaction conditions are mild, no expensive reagents are needed in the whole reaction process, the reaction router is shorter, the intermediate compound for synthesis of the side chain of micafungin can be prepared conveniently, and the reaction yield is high.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of micafungin and its intermediate. Background technique [0002] Micafungin (Micafungin), also known as FK462, has a structural formula as shown below. It is a novel echinocandin antifungal drug obtained by chemical synthesis by modifying the natural product of Coleophoma empedri; it is effective against Candida such as Candida albicans , Candida glabrata, Candida tropicalis, Candida krusei and Candida parapsilosis have good inhibitory activity, and also have good inhibitory activity against Aspergillus in vitro. Micafungin was first developed by Fujisawa Corporation of Japan and launched in Japan in December 2002 under the product name Fungusrd. It passed the US FDA certification in March 2005 and is currently only approved for the treatment of esophageal candida infection, bone marrow transplantation and Prevention and treatment of neutropenia in ADS patient...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/08C07D413/12
Inventor 赵鑫
Owner TIANJIN XINHUI PHARMA
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