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A kind of preparation method of 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: 2018-01-19
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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  • A kind of preparation method of posaconazole intermediate
  • A kind of preparation method of posaconazole intermediate
  • A kind of preparation method of 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=119 ρ=1.638) 68ml 1 times

[0030] A 1000ml three-necked flask was equipped with magnetic stirring and a thermometer, and 200g of posaconazole d-1 and 400ml of ethanol were added in sequence, and stirred and mixed well, and 68ml of thionyl chloride was slowly added dropwise at room temperature. After the dripping is completed, the heating mantle is heated to 60-70° C. and the reaction is refluxed for 2 hours, and the thin layer plate monitors the end of the reaction. (TLC: chloroform: methanol = 30:1). After the completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure, and then 150ml of toluene was poured into 150ml of clear water and then separated into layers. Separate the organic layer and the water layer. The organic layer was washed with clear water (200ml×3), the aqueous layers were combined, extracted onc...

Embodiment 2

[0059] (1) Preparation of compound B

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

[0061] Methanol 400ml 2 times

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

[0063] A 1000ml three-necked bottle was equipped with magnetic stirring and a thermometer, and 200g of posaconazole d-1 and 400ml of methanol were added in turn, stirring and mixing, and 70ml of thionyl chloride was slowly added dropwise at room temperature. After the dripping is completed, the heating mantle is heated to 60-70° C. and the reaction is refluxed for 2 hours, and the thin layer plate monitors the end of the reaction. (TLC: chloroform: methanol = 30:1). After the completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure, and then 150ml of toluene was poured into 150ml of clear water and then separated into layers. Separate the organic layer and the water layer. The organic layer was washed with clear water (200ml×3), the aqueous layers were combined, extracted once with 1...

example

[0075]

[0076] For the preparation methods, refer to Example 1.

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Abstract

The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of a posaconazole intermediate. The method comprises esterification, methylation, hydrolysis, acylation, and five steps of hydroxymethylation to obtain the target compound 1. The synthetic method of the present invention has simple operation compared with the method reported in the literature, and the intermediate Easy to purify, high yield and so on.

Description

Technical field [0001] A preparation method of posaconazole intermediate. The product of the method can be used to prepare the second generation antifungal drug posaconazole, belonging to the field of medicinal chemistry. Background technique [0002] Posaconazole (cas registration number 171228-49-2: cas name: 2,5-dehydrate-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] [0004] Posaconazole is used for immunocompromised patients or other antifungal agents such as amphotericin B (amphothericin B), fluconazole, itraconazole ineffective patients, and patients who are intolerant to these antibacterial agents. The anti-fungal spectrum includes: Candida, Mucor, Aspergillus, Fusarium, Coccidia causing invasive fungal infections, providing for the prevention and treatment of deep fu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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