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Preparation method of posaconazole

A technology for posaconazole and a compound, which is applied in the field of preparation of posaconazole, can solve the problems of dangerous technical operation, unsuitability for industrialized production, and high production cost, and achieves the effect of high yield

Inactive Publication Date: 2013-01-09
NANJING CHANGAO PHARMA SCI & TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The technical problem to be solved by the present invention is that the existing technical operation is dangerous, not suitable for industrial production, and the problem of high production cost

Method used

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  • Preparation method of posaconazole
  • Preparation method of posaconazole
  • Preparation method of posaconazole

Examples

Experimental program
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Effect test

Embodiment 1

[0027] 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl) Oxolan-3-yl"methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-benzyloxypent-3-yl]-1, 2, the preparation of 4-triazol-3-ketone (IV):

[0028] Add (1S)-(2S)-2-(2-benzyloxy-1-ethyl-propyl)-4-{4-[4-(4-hydroxy-phenyl)-piperidine to a 100mL three-necked flask Oxyzin-1-yl]-phenyl]-2,4-dihydro-1,2,4-triazol-3-one (II) (4.78 g, 9.31 mmol) and DMSO (40 mL), stirred and dissolved. Then 25% aqueous NaOH (1.6 mL, 9.4 mmol) was added and the mixture was stirred for 10 min. Add (5R,3R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazole-1-methyl)tetrahydrofuran-3-methanol p-toluenesulfonate (III) (4.40g, 9.79mmol), the mixture was reacted at 30°C for about 12-14h. The liquid phase was monitored for the completion of the reaction, and the reaction solution was slowly poured into vigorously stirred water (240 mL). After the addition was complete, the mixture was stirred vigorously for 10 minutes, filtered, the filter cak...

Embodiment 2

[0032] 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl) Oxolan-3-yl"methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-benzyloxypent-3-yl]-1, 2, the preparation of 4-triazol-3-ketone (IV):

[0033] Add (1S)-(2S)-2-(2-benzyloxy-1-ethyl-propyl)-4-{4-[4-(4-hydroxy-phenyl)-piperidine to a 100mL three-necked flask Azin-1-yl]-phenyl 1-2,4-dihydro-1,2,4-triazol-3-one (II) (5.02g, 9.77mmol) and DMF (40mL), stirred and dissolved. Then 2.0 ml of 25% aqueous NaOH solution was added, and the mixture was stirred for 10 minutes. Add (5R,3R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazole-1-methyl)tetrahydrofuran-3-methanol p-toluenesulfonate (III) (6.25g, 13.91mmol), the mixture was reacted at 35°C for 12-14h. The liquid phase was monitored for the completion of the reaction, and the reaction solution was slowly poured into vigorously stirred water (240 mL). After the addition was complete, the mixture was stirred vigorously for 10 minutes, filtered, the filter cake was...

Embodiment 3

[0037] 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl) Oxolan-3-yl"methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-benzyloxypent-3-yl]-1, 2, the preparation of 4-triazol-3-ketone (IV):

[0038] Add (1S)-(2S)-2-(2-benzyloxy-1-ethyl-propyl)-4-{4-[4-(4-hydroxy-phenyl)-piperidine to a 100mL three-necked flask Oxyzin-1-yl]-phenyl]-2,4-dihydro-1,2,4-triazol-3-one (II) (5.37g, 10.46mmol) and DMF (40mL), stirred and dissolved. Then 25% aqueous NaOH (2.1 mL) was added and the mixture was stirred for 10 minutes. Add (5R,3R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazole-1-methyl)tetrahydrofuran-3-methanol p-toluenesulfonate (III) (3.76g, 0.84mmol), the mixture was reacted at 20°C for 12-14h. The liquid phase was monitored for the completion of the reaction, and the reaction solution was slowly poured into vigorously stirred water (240 mL). After the addition was complete, the mixture was stirred vigorously for 10 minutes, filtered, the filter cake was washed wi...

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Abstract

The invention belongs to the medicine pharmacy field, and relates to a preparation method of posaconazole, which comprises the following steps: adding a compound in a formula (II) in an aprotic solvent for stirring and dissolving, adding an alkaline aqueous solution, and adding a compound in a formula (III) for reacting to obtain an intermediate compound in a formula (IV); reacting a compound in a formula (IV) and hydrochloric acid to obtain a compound crude product in a formula (I); and performing recrystallization by a mixed solvent of acetone / methanol. The method of the invention has the advantages that the operation is safe, the reaction is simple, the post-treatment is convenient, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine and relates to a preparation method of posaconazole. Background technique [0002] The chemical name of posaconazole is 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4 A triazol-1-ylmethyl)oxolan-3-yl”methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentane -3-yl]-1,2,4-triazol-3-one, developed by Schering-Plough, was first launched in Germany in 2005 under the trade name of Noxafil. It was subsequently launched in Australia, the United Kingdom, the United States, the European Union and other countries for the prevention and treatment of invasive fungal infections, drug-resistant or invasive fungal infections that are ineffective by other drugs. Posaconazole is a second-generation novel triazole drug, and its structural formula is as shown in (I): [0003] [0004] Posaconazole is a new insoluble triazole antifungal drug derived from itraconazole, and its antifungal activity i...

Claims

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Application Information

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IPC IPC(8): C07D405/14
Inventor 陈义朗王伟尹建新徐辉
Owner NANJING CHANGAO PHARMA SCI & TECH CO LTD
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