Unlock instant, AI-driven research and patent intelligence for your innovation.

Preparation method of posaconazole

A preparation process technology for posaconazole, which is applied in the field of preparation of organic compounds, can solve the problems of high production cost, low reaction yield, unfavorable large-scale production, etc., and achieve good product quality, high yield, and short route Effect

Inactive Publication Date: 2017-05-10
甘肃皓天科技股份有限公司
View PDF6 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] Although this route is relatively short, the reaction yield of one-step condensation and cyclization is low, only 29.7%, so the production cost is very high, which is not conducive to large-scale production

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of posaconazole
  • Preparation method of posaconazole
  • Preparation method of posaconazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Method 1 of the present invention prepares posaconazole, and its preparation reaction is shown in formula 11,

[0036]

[0037] In the preparation process of this embodiment:

[0038] Preparation of compound 2a:

[0039] Dissolve compound 1 in DMF, lower the temperature to 0-10°C under the protection of argon, and add di-tert-butyl dicarbonate dropwise for 1-2 hours. After the dropwise addition was completed, the mixture was raised to room temperature and stirred for 30 hours. Add about 1 L of water to quench the reaction, stir until solid precipitates, continue stirring for 1 h, filter, and wash the filter cake with water. Add isopropanol to the filter cake, reflux for about 1 h, and cool and filter to obtain off-white solid product 2a with a yield of 86% and a purity of 97% by HPLC.

[0040] Preparation of compound 4a:

[0041] Dissolve 4 g of compound 3 in dichloromethane, add 1.2 g of triethylamine to it while stirring, and slowly drop 2 g of benzenesulfonyl ...

Embodiment 2

[0049] Method 2 of the present invention prepares posaconazole, and its preparation reaction is shown in formula 12,

[0050]

[0051] In the preparation process of this embodiment:

[0052] Preparation of Compound 8a:

[0053] Add 5g of compound 2a and 3.8g of compound 6a into dioxane, raise the temperature to 85°C under the protection of argon, add 1.5g of triethylamine dropwise, and continue to reflux for about 35 hours after the dropwise addition. The solvent was recovered under reduced pressure, extracted with dichloromethane, concentrated to obtain a residue that was recrystallized from methanol, and filtered to obtain a beige solid with a yield of 61% and a purity of 95.6% by HPLC.

[0054] Preparation of compound 7a:

[0055]Compound 8a was added to a mixture of KOH (33%) solution and DMSO, and stirred at room temperature for 45 min; compound 4a was added to the above reaction system, and stirred at 50±5°C for 5 h. Add 40 mL of water to the reaction system to que...

Embodiment 3

[0059] Method 1 of the present invention prepares posaconazole, and its preparation reaction is shown in formula 13,

[0060]

[0061]

[0062] In the preparation process of this embodiment:

[0063] Preparation of compound 2b:

[0064] Dissolve compound 1 in N,N-dimethylformamide, lower the temperature to 0-10°C under the protection of argon, and add p-nitrophenyl chloroformate dropwise for 1-2 hours. After the dropwise addition was completed, the mixture was raised to room temperature and stirred for 30 hours. Add about 1 L of water to quench the reaction, stir until solid precipitates, continue stirring for 1 h, filter, and wash the filter cake with water. Add isopropanol to the filter cake, reflux for about 1 h, and cool and filter to obtain off-white solid product 2b with a yield of 81% and a purity of 97% by HPLC.

[0065] Preparation of compound 4b:

[0066] Dissolve 4g of compound 3 in dichloromethane, add 1.2g of pyridine to it with stirring, and slowly drop...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
purityaaaaaaaaaa
Login to View More

Abstract

The invention discloses preparation methods of antifungal drug posaconazole shown in the formula as shown in the specification. A first preparation method comprises the following steps: by taking a compound 1 as a raw material, performing amino protection so as to obtain a compound 2, performing reaction on alcohol 3 with a sulfonylation reagent in the presence of alkali to protect hydroxyl so as to obtain a compound 4, performing reaction on an intermediate 2 with triazole under a strong alkali condition so as to obtain an intermediate 5, performing condensation and cyclization with a formylhydrazine derivative 6 under an organic alkali condition so as to obtain a posaconazole key intermediate compound 7, and removing a protection group R2, thereby obtaining posaconazole; a second preparation method comprises the following steps: performing cyclization reaction on the compound 2 with the compound 6 in the presence of organic alkali so as to obtain a compound 8, performing nucleophilic substitution reaction on the compound 8 and the compound 4 under the action of strong alkali so as to obtain a compound 7, and removing the protection group R2, thereby obtaining posaconazole.

Description

technical field [0001] The present invention relates to a method for preparing an organic compound, specifically as shown in formula 1, which can be used as an antifungal drug posaconazole (Posaconazole). [0002] Background technique [0003] Posaconazole is a new antifungal drug developed by Schering-Plough. It is mainly used in patients with weakened immunity and low white blood cell count after bone marrow transplantation to prevent infections caused by certain molds and yeast-like fungi. These patients' bodies struggle to fight off these infections after cancer chemotherapy. Approved by the US FDA on September 18, 2006. [0004] The English chemical name of posaconazole is: 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-hydroxype ntan-3-yl]-1,2,4-triazol- 3-one; Chinese chemical name: 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-three Azol-1-ylmethyl)oxolan-3-yl]meth...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14
CPCC07D405/14Y02P20/55
Inventor 冯伟伟张虹锐王仕祥王世娇魏鹏飞达世俊
Owner 甘肃皓天科技股份有限公司