Method for preparing regorafenib intermediate

A technology for regorafenib and intermediates, applied in the field of preparing regorafenib intermediate I, can solve the problems of inconsistent solvent, unfavorable recovery, complicated post-processing and the like

Active Publication Date: 2014-12-31
SHANGHAI FANGNAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this process route is that the intermediates in each step need to be separated, and the solvents in each step are not uniform; from the perspective of green chemistry,

Method used

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  • Method for preparing regorafenib intermediate
  • Method for preparing regorafenib intermediate
  • Method for preparing regorafenib intermediate

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0014] Example 1 Use tetrahydrofuran as a solvent to synthesize repagliptin intermediate I without separation in each step.

[0015] method 1

[0016] Step A: Add 4-chloropyridine-2-carboxylic acid methyl ester hydrochloride (10.4g, 50mmol) and 40mL THF to a four-neck round bottom flask, cool down to 0°C, and add 2M methylamine in tetrahydrofuran dropwise to the system Solution (150mL, 300mmol), keep the temperature of the system not exceeding 10°C, after the dropwise addition is completed, the system is kept at 5-10°C for 6 hours, filtered through silica gel, rinsed with 50mL tetrahydrofuran on the silica gel, combined with the organic phase, directly used for Step C operation. Organic phase is through HPLC content analysis, obtains product compound IIX8.4g, external standard yield 98%.

[0017] HPLC ES / MS m / z:171((M+H) + )

[0018] Step B: Add 3-fluoro-4-nitrophenol (7.9g, 50mmol), 10%Pd / C (0.4g, 5wt%) and 20mL THF into the autoclave, the system is under 0.3Mpa hydrogen...

example 2

[0027] Example 2 Use toluene as a solvent to synthesize repagliptin intermediate I without separation in each step.

[0028] Step A: Add 4-chloropyridine-2-carboxylic acid methyl ester hydrochloride (10.4g, 50mmol) and 40mL THF to a four-neck round bottom flask, cool down to 0°C, and add 2M methylamine in tetrahydrofuran dropwise to the system solution (50mL, 100mmol), keep the temperature of the system not exceeding 10°C, after the dropwise addition is completed, the system is kept at 5-10°C for 6 hours, filtered through silica gel, rinsed with 50mL tetrahydrofuran on the silica gel, combined with the organic phase, directly used for Step C operation. The organic phase was analyzed by HPLC to obtain 7.5 g of the product compound IIX, with an external standard yield of 87%.

[0029] Step B: Add 3-fluoro-4-nitrophenol (7.9g, 50mmol), 20% Pd / C (0.4g, 5wt%) and 20mL toluene into the autoclave, drop two drops of formic acid, the system is at 0.2MPa Under the hydrogen pressure of...

example 3

[0032] Example 3 Use 1,4-dioxane as a solvent to synthesize repagliptin intermediate I without separation in each step.

[0033] Step A: Add 4-chloropyridine-2-carboxylic acid methyl ester hydrochloride (10.4g, 50mmol) and 40mL of 1,4-dioxane into a four-neck round bottom flask, cool down to 5°C, add dropwise 2M tetrahydrofuran solution of methylamine (150mL, 300mmol), keep the temperature of the system not exceeding 10°C, after the dropwise addition, keep the system at 5-10°C for 12h, filter through silica gel, rinse the silica gel with 50mL THF, combine organic After phase, directly used for step C operation. The organic phase was analyzed by HPLC to obtain 8.2 g of the product compound IIX, with an external standard yield of 96%.

[0034] Step B: Add 3-fluoro-4-nitrophenol (7.9g, 50mmol), 1% Pd / C (1.6g, 20wt%) and 20mL 1,4-dioxane into the autoclave, the system is at 0.1Mpa Under the hydrogen pressure of 30 DEG C, react 12h. After the reaction is completed, filter, and the...

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Abstract

The invention discloses a method for preparing a regorafenib intermediate; a compound represented by the formula II and a compound represented by the formula III are subjected to three stages of a step A, a step B and a step C, intermediates of all the stages are not separated, and thus the regorafenib intermediate I is prepared. According to the method, the intermediates of all the steps are not separated, post-treatment procedures are reduced, the process operational flow is saved, the solvent recovery and utilization efficiency is improved, pollution emissions and energy consumption are reduced, the requirements on green chemical process are met, and the method is suitable for industrialized production.

Description

technical field [0001] The invention relates to a method for preparing regorafenib intermediate I. Background technique [0002] Regorafenib is a multi-targeted tyrosine kinase inhibitor developed by Bayer Healthcare for the treatment of metastatic colorectal cancer. The intermediate structural formula for preparing regorafenib is shown in formula I below: [0003] [0004] Bayer company disclosed the preparation method of the intermediate I in the patent CN1721397A, using 3-fluoro-4 nitrophenol and 4-chloropyrimidine-2-methyl carboxylate as starting materials, through three steps of hydrogenation, ammoniation and coupling , intermediate I was obtained. The disadvantage of this process route is that the intermediates in each step need to be separated, and the solvents in each step are not uniform; from the perspective of green chemistry, the post-processing of this synthesis scheme is complicated, the separation operation is time-consuming and energy-consuming, and the ...

Claims

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Application Information

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IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 张念
Owner SHANGHAI FANGNAN PHARMA
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