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Posaconazole synthesis method

A technique for the synthesis of posaconazole, which is applied in the field of drug synthesis, can solve the problems of cumbersome post-processing, easy oxidation, and low yield, and achieve the effects of simple post-processing, shortened reaction time, and reduced pressure.

Active Publication Date: 2017-02-01
河北广祥制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this experimental method, hydrobromic acid is both the reaction solvent and the hydrogen source, which has a strong thorny taste and is not easy to store and is easily oxidized
Moreover, the post-processing is cumbersome and the yield is low, so it is not suitable for large-scale production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] For illustrating the present invention posaconazole and its synthetic method

[0042] (1) Reactor structure with built-in agitator:

[0043] The reactor has a height of 120cm and a diameter of 100L enamel reactor of 50cm. There is a stirrer and a set of baffle plates, the stirrer is standard, including a stirring shaft arranged along the axis of the reactor and two sets of stirring blades uniformly distributed along the axis of the stirring shaft Groups, each group of stirring blade groups are arranged in parallel, and each group of stirring blade groups includes two stirring blades uniformly distributed along the circumference of the stirring shaft, and the length of each stirring blade along the radial direction of the reactor is 8cm; The plate group includes a height of 60 cm, a width of 5 cm, and a thickness of 4 baffles of 1 cm. The length direction of each baffle is arranged along the axial direction parallel to the stirrer (one side is fixed on the bottom wall o...

Embodiment 2

[0047] For illustrating the present invention posaconazole and its synthetic method

[0048] (1) Built-in reactor structure of agitator: same as embodiment 1.

[0049] (2) Synthesis of posaconazole:

[0050] Add in the enamel reactor of aforementioned 100L, add 60L methyl alcohol, compound shown in 4kg formula II, 6L concentration is the sulfuric acid of 98wt%, 10% palladium carbon catalyst (water content 50%) of 400g, seal reactor, open stirrer ( Stirring speed is 400rpm). First replace the air in the kettle with nitrogen for 3 times, then replace it with hydrogen for 3 times, keep the pressure of hydrogen at 0.1 MPa (gauge pressure), raise the temperature to 55°C, monitor the reaction by HPLC, and the reaction is completed after 2 hours. Cool down, replace with nitrogen for 3 times, and filter to obtain 10% palladium carbon catalyst. Pour the filtrate into another 200L enamel reaction kettle, add ice cubes, cool down to 0-5°C, add 2mol / L NaOH solution dropwise to the filt...

Embodiment 3

[0052] For illustrating the present invention posaconazole and its synthetic method

[0053] (1) built-in reactor structure with stirrer: same as embodiment 1;

[0054] (2) Synthesis of posaconazole:

[0055] Add in the enamel reactor of aforementioned 100L, add 60L methyl alcohol, the compound shown in 4kg formula II, 4L concentration is the hydrochloric acid of 36.5wt%, the 10% palladium carbon catalyst (water content 50%) of 200g, seal reactor, open stirrer (Stirring speed is 450rpm). First replace the air in the kettle with nitrogen for 3 times, then replace it with hydrogen for 3 times, keep the pressure of hydrogen at 0.12MPa, raise the temperature to 50°C, monitor the reaction by HPLC, and the reaction is completed in 3 hours. Cool down, replace with nitrogen for 3 times, and filter to obtain 10% palladium-carbon catalyst (standby). Pour the filtrate into another 200L enamel reaction kettle, add ice cubes, cool down to 0-5°C, add 2mol / L Na to the filtrate dropwise 2...

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Abstract

The invention provides a posaconazole synthesis method which includes the steps: S1, taking a compound displayed by a following formula II as a raw material, taking hydrogen as a hydrogen source, stirring the compound displayed by the formula II, catalysts and acidic reagents in reaction solvents under the hydrogenation debenzylation reaction condition, and performing contact reaction to obtain mixed solution; S2, reducing the temperature of the mixed solution to range from 0 DEG C to 5 DEG C, dropping sodium hydroxide solution into the mixed solution until a pH (potential of hydrogen) value of the mixed solution is 10-12, stirring, filtering to obtain filter cakes, washing the filter cakes, and drying the washed filter cakes to obtain posaconazole as shown in the following formula I.

Description

technical field [0001] The invention relates to the field of drug synthesis, and relates to a method for synthesizing posaconazole. Background technique [0002] Posaconazole (Chinese chemical name: 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-hydroxypentyl- 3-yl]-1,2,4-triazol-3-one), has the structure shown in the following formula I. [0003] [0004] Posaconazole is an antifungal drug developed by Schering-Plough in Germany under the trade name "Noxafil", which was approved for marketing in the European Union and the US FDA on October 20, 2005. In September 2006, posaconazole oral suspension was once again approved by the US FDA for patients with weakened immunity after bone marrow transplantation and leukopenia caused by cancer chemotherapy to prevent infections caused by Aspergillus and Candida. Because of its high efficiency and low toxicity, wide range of clinical applica...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14
CPCC07D405/14
Inventor 殷殿书魏赛丽孙曼印杰刘玉扑胡硕武玉杰
Owner 河北广祥制药有限公司
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