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Method for preparing posaconazole intermediate

A technology for posaconazole and intermediates, which is applied in the preparation of organic compounds, carboxylate esters, and oxygen-containing compounds, and can solve problems such as poor solubility of salts

Active Publication Date: 2016-06-22
CHONGQING SHENGHUAXI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Converting compound A into 4-(2,4-difluorophenyl)-4-oxo-butyrate (compound B) instead of preparing a salt can solve the problem of poor solubility of the salt in compound A , and compound B is prone to wittig reaction, which is very thorough, and the ester bond in compound B will not affect the reaction

Method used

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  • Method for preparing posaconazole intermediate
  • Method for preparing posaconazole intermediate
  • Method for preparing posaconazole intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] (1) Preparation of Compound B

[0027] Compound A (M=214) 200g

[0028] Ethanol 400ml 2 times

[0029] Thionyl chloride (M=119ρ=1.638) 68ml 1 times

[0030] Install a magnetic stirrer and a thermometer into a 1000ml three-neck bottle, add posaconazole d-1200g, ethanol 400ml, stir and mix, and slowly add 68ml of thionyl chloride dropwise at room temperature. After the dropwise addition, the heating mantle was heated to 60-70° C. for reflux reaction for 2 hours, and the end point of the reaction was monitored by a thin-layer plate. (TLC: chloroform: methanol = 30: 1). After the reaction was completed, the reaction solution was evaporated to dryness under reduced pressure, and after evaporation, 150ml of toluene and 150ml of water were added and stirred to separate layers. Separate the organic and aqueous layers. The organic layer was washed with water (200ml×3), the aqueous layers were combined, extracted once with 100ml toluene, and the organic layers were combined....

Embodiment 2

[0059] (1) Preparation of Compound B

[0060] Compound A (M=214) 200g

[0061] Methanol 400ml 2 times

[0062] Thionyl chloride (M=119ρ=1.638) 70ml 1 times

[0063] Install a magnetic stirrer and a thermometer into a 1000ml three-necked bottle, add posaconazole d-1200g, methanol 400ml, stir and mix, and slowly add 70ml of thionyl chloride dropwise at room temperature. After the dropwise addition, the heating mantle was heated to 60-70° C. for reflux reaction for 2 hours, and the end point of the reaction was monitored by a thin-layer plate. (TLC: chloroform: methanol = 30: 1). After the reaction was completed, the reaction solution was evaporated to dryness under reduced pressure, and after evaporation, 150ml of toluene and 150ml of water were added and stirred to separate layers. Separate the organic and aqueous layers. The organic layer was washed with water (200ml×3), the aqueous layers were combined, extracted once with 100ml toluene, and the organic layers were combi...

example

[0075]

[0076] The preparation methods refer to Example 1.

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Abstract

The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a method for preparing a posaconazole intermediate. The method comprises steps of esterification, methylenation, hydrolysis, acylation and hydroxymethylation to obtain a target compound 1. Compared with the method reported in the literature, the synthesis method of the present invention has the characteristics of simple operation, easy purification of intermediate and high yield.

Description

technical field [0001] The invention discloses a method for preparing a posaconazole intermediate, and the product of the method can be used to prepare the second-generation antifungal drug posaconazole, which belongs to the field of medicinal chemistry. Background technique [0002] Posaconazole (cas registration number 171228-49-2: cas name: 2,5-anhydro-1,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4- [[4-[4-[1-[(1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-1,5-dihydro-5-oxo-4H-1,2 ,4-triazol-4-yl]phenyl]-1-piperazinyl]phenoxy]methyl]-1-(1H-1,2,4-triazol-1-yl)-D-threo - Pentitol, the structure is as follows. [0003] Posaconazole is used in immunocompromised patients or patients who have not responded to other antifungal agents such as amphotericin B (amphotericin B), fluconazole, itraconazole, and patients who are intolerant to these antifungal agents. The antifungal spectrum includes: invasive fungal infections caused by Candida, Mucor, Aspergillus, Fusarium, and Coccidioides, pro...

Claims

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Application Information

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IPC IPC(8): C07D263/26C07C69/738C07C67/08C07C69/65C07C67/343C07C57/60C07C27/02
Inventor 和国栋丁菲苏晓琴
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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