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Method for producing miconazole nitrate on industrialized basis

A technology of miconazole nitrate and dichlorophenyl, which is applied in the field of raw material drug synthesis, can solve the problems of complicated operation of miconazole nitrate, difficult solvent recovery, and difficulty in obtaining raw materials, and achieves saving of raw materials, low cost, and easy availability of raw materials. Effect

Inactive Publication Date: 2010-10-20
湖北远成赛创科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The purpose of the present invention is to address the deficiencies in the prior art, to provide a method for the industrial production of miconazole nitrate with low cost, easy access to raw materials, mild reaction conditions and easy operation. The present invention uses methanol as a solvent The method of direct reduction with potassium borohydride under the conditions is simple in operation and high in yield, suitable for industrial operation, and solves the problems of complicated operation, difficult solvent recovery, difficult raw materials and low yield in the existing industrial production of miconazole nitrate

Method used

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  • Method for producing miconazole nitrate on industrialized basis
  • Method for producing miconazole nitrate on industrialized basis
  • Method for producing miconazole nitrate on industrialized basis

Examples

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Embodiment 1

[0026] A method for industrialized production of miconazole nitrate, the steps are as follows:

[0027] A, the preparation of intermediate 1

[0028] Mix 1 mol of chloroacetyl chloride with 1.1 mol of anhydrous AlCl 3 Mix well, then add 1.1mol m-dichlorobenzene dropwise, and react at 40°C for 5h after the dropwise addition is completed for 30-40min.

[0029] After the reaction was completed, the reaction solution was slowly added to 1.3 L of ice water, stirred, and filtered to obtain the crude intermediate 1. The crude product of intermediate 1 was recrystallized from n-hexane, and the melting point of intermediate 1 was measured at 52-54° C., and the yield was 92%.

[0030] B, the preparation of intermediate 2

[0031] Suspend 3 mol of imidazole in 1 L of dichloromethane, add 1 mol of intermediate 1 obtained in step A and stir for 30 min, then heat to reflux for 5 h. After the reaction was completed, dichloromethane was distilled off at -0.06~-0.08MPa, the residue was add...

Embodiment 2

[0037] A method for industrialized production of miconazole nitrate, the steps are as follows:

[0038] A, the preparation of intermediate 1

[0039] Mix 1 mol of chloroacetyl chloride with 2 mol of anhydrous AlCl 3 Mix well, then add 2 mol of m-dichlorobenzene dropwise, after 30-40min dropwise, react at 40°C for 3h.

[0040] After the reaction was completed, the reaction solution was slowly added to 1.3 L of ice water, stirred, and filtered to obtain the crude intermediate 1. The crude product of intermediate 1 was recrystallized from n-hexane to obtain the melting point of intermediate 1: 52-54° C., and the yield was 91%.

[0041] B, the preparation of intermediate 2

[0042] Suspend 1 mol of imidazole in 1 L of dichloromethane, add 1 mol of intermediate 1 obtained in Step A and stir for 30 min, then heat to reflux for 5 h. After the reaction was completed, dichloromethane was distilled off at -0.06~-0.08MPa, and the residue was dissolved in 1.5L of water with vigorous s...

Embodiment 3

[0048] A method for industrialized production of miconazole nitrate, the steps are as follows:

[0049] A, the preparation of intermediate 1

[0050] Mix 1 mol of chloroacetyl chloride with 1.3 mol of anhydrous AlCl 3 Mix well, then add 1.6mol m-dichlorobenzene dropwise, and react at 40°C for 4h after the dropwise addition is completed for 30-40min.

[0051] After the reaction was completed, the reaction solution was slowly added to 1.3 L of ice water, stirred, and filtered to obtain the crude intermediate 1. The crude product of intermediate 1 was recrystallized from n-hexane to obtain the melting point of intermediate 1: 52-54° C., and the yield was 93%.

[0052] B, the preparation of intermediate 2

[0053] Suspend 2 mol of imidazole in 1 L of dichloromethane, add 1 mol of intermediate 1 obtained in step A and stir for 30 min, then heat to reflux for 5 h. After the reaction was completed, dichloromethane was distilled off at -0.06~-0.08MPa, and the residue was dissolved...

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Abstract

The invention discloses a method for producing miconazole nitrate on an industrialized basis. The method comprises the following steps: A, conducting the Friedel-crafts reaction between chloroacetic chloride and m-dichlorobenzene to prepare 2-chloro-1-(2,4-dichlorophenyl)ethanone; B, conducting the N-alkylation reaction to prepare 1-(2,4-dichlorophenyl)-2-(1H-imidazolyl)ethanone; C, conducting the potassium borohydride reduction reaction to prepare 1-(2,4-dichlorophenyl)-2-(1H-imidazolyl)ethylate; and D, conducting the O-alkylation reaction to prepare the miconazole nitrate as the target product. The method of the invention has the overall advantages of industrialized application value, low cost, easily accessible materials, mild reaction conditions and easy operation; the total yield is not lower than 64%; and the purity of the miconazole nitrate product is higher than 99%.

Description

technical field [0001] The invention belongs to the field of raw material drug synthesis, and in particular relates to a method for industrialized production of miconazole nitrate. Background technique [0002] The chemical name of miconazole nitrate is 1-[2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]-1H-imidazole nitrate , whose structural formula is: [0003] [0004] This product is white or off-white crystal or crystalline powder, odorless or almost odorless. [0005] Miconazole nitrate is an imidazole derivative, which is a broad-spectrum antifungal drug, which can inhibit and kill dermatophytes, candida, yeast and other algae, ascomycetes, cryptococcus, etc. Positive cocci and bacilli also have strong antibacterial power. Its indications are: [0006] 1. Skin and nail infections caused by dermatophytes, yeasts and other fungi, such as athlete's foot, jock itch, manuum, tinea corporis, tinea versicolor, tinea capitis, tinea barbae, onychomycosis, s...

Claims

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Application Information

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IPC IPC(8): C07D233/60
Inventor 王小华叶传发
Owner 湖北远成赛创科技有限公司
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