Preparation method of butoconazole nitrate intermediate suitable for industrial production

A technology for butconazole nitrate and intermediates, which is applied in the field of preparation of butconazole nitrate intermediates, can solve problems such as damage to personnel and equipment, difficult control of Grignard reaction, volatilization of ether, etc., so as to reduce side reactions and increase operability. Safety and security, the effect of increasing viability

Active Publication Date: 2014-06-25
SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
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Problems solved by technology

If some ether is used for the reaction, the Grignard reaction will also be difficult to control, especially in large-scale industrial produc

Method used

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  • Preparation method of butoconazole nitrate intermediate suitable for industrial production
  • Preparation method of butoconazole nitrate intermediate suitable for industrial production
  • Preparation method of butoconazole nitrate intermediate suitable for industrial production

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Embodiment 1

[0031] 1. Grignard reaction: In a 20L dry reaction kettle, add 504g (21mol) of magnesium powder, 6.4L of anhydrous methyl tert-butyl ether and tetrahydrofuran (volume ratio 15:1) mixed solvent and a catalytic amount of iodine in sequence at room temperature , under stirring, first drop 0.6~0.8L of anhydrous methyl tert-butyl ether solution (4L in total) containing 3.22kg (20mol) of p-chlorobenzyl chloride, and stir until the reaction is initiated (the solution becomes cloudy and the temperature rises), and the temperature Raise to about 40°C, continue to add the remaining solution, keep at 40-50°C, drop for about 1-2 hours, and keep warm for 1-2 hours.

[0032] 2. Condensation reaction: the above reaction system is lowered to room temperature, and directly dropwise add a solution of 1.85kg (20mol) of epichlorohydrin 4L of anhydrous methyl tert-butyl ether to the reaction kettle under stirring, control the rate of addition, and maintain the temperature At about 40°C, drop it fo...

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Abstract

The invention provides a method for industrial production of a butoconazole nitrate intermediate, that is 1-chloro-4-p-chlorophenyl-2-butanol (a compound in formula II). The method of the invention comprises: 1. a Grignard reaction, that is, adopting p-chlorobenzyl chloride as a raw material, and performing a Grignard reaction with magnesium powder in a mixed solvent of methyl tertiary butyl ether and tetrahydrofuran; 2. a condensation reaction, that is, continuing reaction by adding epichlorohydrin to obtain the compound II which is an important intermediate for preparing butoconazole nitrate. According to the method, the raw materials are cheap and easily available, the reaction solvent is safer, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the fields of organic chemistry and medicinal chemistry, in particular, the invention relates to a method for preparing a butoconazole nitrate intermediate (compound of formula II) suitable for industrial production. Background technique [0002] Butoconazole Nitrate (Butoconazole Nitrate, 64872-76-0), chemical name 1-[4-(4-chlorophenyl)-2-[(2,6-dichlorophenyl)thio]butyl]- 1H-imidazole nitrate, (±)-1-[4-(4-chlorophenyl)-2-[(2,6-dichlorophenyl)thio]butyl]-1H-imidazole mononitrate, is a new broad-spectrum imidazole Antifungal drugs, which mainly act on fungal cell membranes, increase the osmotic resistance and reduce fungal viability by changing the permeability of the cell membranes, and are highly effective against vaginal infections caused by Candida albicans, Candida tropicalis and other species of this genus, clinically It is mainly used for vulva and vaginal fungal infections caused by candida after diagnosis. In gynecolo...

Claims

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Application Information

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IPC IPC(8): C07C33/46C07C29/64
CPCC07C29/64C07F3/02C07C33/46
Inventor 郑德强王长斌赵国敏毋立华刘文涛孙利民任文杰李帅索栋
Owner SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
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