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Method for synthesizing fenticonazole nitrate

A kind of technology of fenticonazole nitrate and fenfen nitrate, applied in directions such as organic chemistry, can solve problems such as being unsuitable for industrialized production, high chemical reaction activity, expensive solvent and the like

Inactive Publication Date: 2018-02-02
XIANGYU PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] Both method 1 and method 2 are under anhydrous and anaerobic conditions, using sodium hydride as a condensing agent to react to obtain fenticonazole, the difference is that the solvents used are different, which are hexamethylphosphoric triamide and dimethyl ethylene oxide respectively. Sulfone, although the yield is significantly improved when dimethyl sulfoxide is used, these solvents are expensive, and the chemical reactivity of the reactant sodium hydride is very high. It releases heat and hydrogen, causing combustion and explosion, and forms hydroxides when it encounters moisture and moisture. It is highly corrosive, so the required solvent must be absolutely anhydrous, and the reaction must be carried out under the protection of an inert gas, which is not suitable for industrial production.

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  • Method for synthesizing fenticonazole nitrate
  • Method for synthesizing fenticonazole nitrate
  • Method for synthesizing fenticonazole nitrate

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Embodiment 1

[0031] A method for synthesizing fenticonazole nitrate, which adopts a phase transfer catalysis method, and carries out condensation reaction in the presence of sodium hydroxide, the reagents used are cheap and easy to obtain, the synthesis cost is greatly reduced, the operation is simple and convenient, and there is no special requirement for equipment. It is more suitable for large-scale production, so it is initially planned to adopt this process, so the synthetic process of finally selected fenticonazole nitrate is shown in figure 1 , Synthetic fenticonazole nitrate laboratory test feeding and output situation are shown in Table 1:

[0032] Table 1

[0033]

Embodiment 2

[0035] Intermediate Ⅰ: Synthesis of 4-phenylmercaptobenzaldehyde

[0036] Feed according to the molar ratio of p-bromobenzaldehyde: thiophenol: cuprous iodide = 1:1.15:0.025, stir in DMF and heat up to reflux, TLC detection (n-hexane: ethyl acetate = 10:1) for about 8 hours After the reaction, filter, and concentrate the filtrate to dryness under reduced pressure (pressure 1720Pa, temperature 85°C) to obtain a viscous residue, add a certain amount of dichloromethane, wash with water three times, dry over anhydrous magnesium sulfate, filter, and concentrate the filtrate under normal pressure To dryness, the residue was dissolved in a mixed solvent of n-hexane: ethyl acetate = 1:1, frozen (0°C) for crystallization, filtered, and the filter cake was dried at 25°C under normal pressure to obtain a light yellow crystalline powder.

[0037] Considering that the optimization process should speed up the reaction rate and increase the yield, the influence of the main feed ratio (p-brom...

Embodiment 3

[0043] Intermediate Ⅱ: Synthesis of 4-Phenylmercaptobenzyl Alcohol

[0044]Put 4-phenylmercaptobenzaldehyde and methanol into the reaction flask, add sodium borohydride in batches under stirring, exotherm violently, and naturally raise the temperature to 55°C, TLC detection (n-hexane:ethyl acetate=10:1) to At the end of the reaction, the reaction was about 1 hour. Add hydrochloric acid dropwise to adjust pH=6, filter, and concentrate the filtrate to dryness under reduced pressure (pressure 1330Pa, temperature 45°C), recover methanol to obtain a viscous residue, add appropriate amount of dichloromethane, wash with water until neutral, anhydrous magnesium sulfate Dry, filter, and concentrate the filtrate under reduced pressure (pressure 1720Pa, temperature 25°C), recover dichloromethane, and cool to room temperature to obtain a yellowish solid.

[0045] Considering the optimization process, it is necessary to control the reaction rate and improve the product quality. At the sam...

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Abstract

The invention belongs to the technical field of chemical synthesis, and discloses a method for synthesizing fenticonazole nitrate. By the aid of a phase transfer catalytic method, condensation reaction is performed at the presence of sodium hydroxide. The method particularly includes the steps: 1) synthesizing 4-mercaptophenyl-benzaldehyde; 2) synthesizing 4-mercaptophenyl benzyl alcohol; 3) synthesizing 4-mercaptophenyl-benzyl chloride; 4) synthesizing fenticonazole nitrate crude products. Used reagents are low in cost and easy to obtain, synthesis cost is greatly reduced, operation is simpleand convenient, special requirements on equipment are omitted, and the method is more suitable for scale production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, in particular to a method for synthesizing fenticonazole nitrate. Background technique [0002] Fenticonazole nitrate has a wide range of uses in the field of medicine, and its overall preparation route is similar. Both intermediates: 4-phenylmercaptobenzyl chloride and intermediates: 1-(2,4- Dichlorophenyl)-2-imidazole ethanol is condensed under different conditions to obtain fenticonazole, and finally salted with nitric acid. [0003] Method 1. Use diphenyl sulfide and formaldehyde as raw materials to react under HCl conditions to generate 4-phenylmercaptobenzyl chloride; condense m-dichlorobenzene and chloroacetyl chloride to obtain 2-chloro-1-(2,4-dichlorobenzene base) ethyl ketone, and then reduced by sodium borohydride, and condensed with 1H-imidazole to obtain the intermediate 1-(2,4-dichlorophenyl)-2-imidazole ethanol. 4-Phenylmercaptobenzyl chloride and 1-(2,4-dichlorophen...

Claims

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Application Information

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IPC IPC(8): C07D233/60
CPCC07D233/60
Inventor 林凡儒吴士平周爱玲薛颖王文天
Owner XIANGYU PHARMA
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