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Preparation method of sorafenib tosylate

A technology of sorafenib p-toluenesulfonate and p-toluenesulfonic acid is applied in the field of preparation of sorafenib p-toluenesulfonate, can solve the problems of poor stability, cumbersome reaction operation, long reaction time and the like, and achieves the reaction step Less, safe process, simple operation effect

Active Publication Date: 2016-01-27
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Among them, the phosgene method is the most widely used, and phosgene is highly toxic, has great dangers in the process of transportation, use and storage, and cannot be accurately measured in the reaction. The later research and development of diphosgene (chloroformic acid three Although diphosgene can replace phosgene for experimental synthesis and industrial production, diphosgene, as a highly toxic and pungent-smelling liquid, still has greater danger
Triphosgene [bis(trichloromethyl)carbonate] has also been reported as a substitute for phosgene and diphosgene, which is stable at room temperature, can be accurately measured, safe and convenient to use, and convenient for transportation and storage; but there are still The preparation of compound 7 is cumbersome in operation, long in reaction time, difficult in separation and purification, very harsh on equipment and management requirements, and produces a large amount of waste gas and other unavoidable problems, and compound 7 has high reactivity, poor stability, and is difficult to store; and Compound 7 is prone to side reaction with aniline to form diaryl urea by-product
[0017] The yield of this method is low, and the raw materials -2-nitrophenyl chloroformate and phenyl chloroformate are unstable and corrosive, and have certain damage to the equipment

Method used

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  • Preparation method of sorafenib tosylate
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  • Preparation method of sorafenib tosylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: Synthesis of (4-chloro-3-trifluoromethylaniline)-propenyl formate (compound 6)

[0033] Triethylamine (42ml, 300mmol) and 4-chloro-3-trifluoromethylaniline (compound 2) (19.6g, 100mmol) were added to 500mL of dichloromethane, and the temperature during the dropping process was controlled below 5°C, and Stir at 0°C~5°C until clear; add propylene chloroformate (compound 5) (11.7ml, 110mmol) dropwise, control the temperature of the dropping process below 5°C; stir the reaction mixture at room temperature for 2 hours, and use brine for the reaction solution Washing (4×300mL), anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate to a crude product, crystallize with ethyl acetate: n-heptane (1:2) solution, filter with suction, and dry to obtain (4-chloro-3-trifluoromethylaniline)-propenyl formate (Compound 6 ) 25.6g, yield 91.6%, purity 99.3% (HPLC method).

Embodiment 2

[0034] Example 2: Synthesis of (4-chloro-3-trifluoromethylaniline)-propenyl formate (compound 6)

[0035] Add sodium hydroxide aqueous solution (100mL, 2M) and 4-chloro-3-trifluoromethylaniline (compound 2) (19.6g, 100mmol) to 500mL ethyl acetate, and control the temperature of the dropping process below 5°C, And stir at 0℃~5℃ for 30min; add propylene chloroformate (compound 5) (15ml, 140mmol) dropwise, control the temperature of the dropping process below 5℃; stir the reaction mixture at room temperature for 3 hours, then separate the mixture, The aqueous phase was extracted with ethyl acetate (4×300 mL), the organic phases were combined, washed with brine (3×400 mL), anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate to a crude product, crystallize with ethyl acetate: n-heptane (1:2) solution, filter with suction, and dry to obtain (4-chloro-3-trifluoromethylaniline)-propenyl formate (Compound 6 ) 25.2g, yield 90.3%, purity 99.2% (HPLC method).

Embodiment 3

[0036] Example 3: Synthesis of (4-chloro-3-trifluoromethylaniline)-propenyl formate (compound 6)

[0037] Add N,N-diisopropylethylamine (33ml, 200mmol) and 4-chloro-3-trifluoromethylaniline (compound 2) (19.6g, 100mmol) to 500mL ethyl acetate to control the dropping process The temperature is below 5℃, and stir at 0℃~5℃ until it is clear; propylene chloroformate (compound 5) (16ml, 150mmol) is added dropwise, and the temperature of the dripping process is controlled below 5℃; the reaction mixture is stirred at room temperature 2 Hours, the reaction solution was washed with brine (4×300mL), anhydrous Na 2 SO 4 Dry, filter, concentrate the filtrate to a crude product, crystallize with ethyl acetate: n-heptane (1:2) solution, filter with suction, and dry to obtain (4-chloro-3-trifluoromethylaniline)-propenyl formate (Compound 6 ) 25.5g, yield 91.3%, purity 99.2% (HPLC method).

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Abstract

The invention relates to a preparation method of sorafenib tosylate. The preparation method comprises the steps of reacting propylene chloroformate (5) with low cost and 4-chloro-3-trifluoromethyl phenylamine (2) with low cost to generate activated ester (6); reacting activated ester and 4-(4-aminophenoxy)-N-methyl-2-pyridine carboxamide (3) under the catalysis of N-methylpyrrolidine to obtain sorafenib with high yield; carrying out simple aftertreatment on the reaction to obtain sorafenib with relatively high purity; and then, reacting sorafenib and p-toluene sulphonic acid to generate the target product. The method is low in cost, simple in operation, few in reaction step, short in period, low in energy consumption, safe in process, free of high-toxicity reagents and suitable for industrial production, and the obtained product is high in yield and purity and free of potential safety problems.

Description

Technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a preparation method of sorafenib p-toluenesulfonate. Background technique [0002] Sorafenib p-toluenesulfonate (sorafenib), chemical name: N-[4-chloro-3-(trifluoromethyl)phenyl]-N′-[4-[2-(N-methylamine Formyl)-4-pyridyloxy]phenyl]urea p-toluenesulfonate has the chemical structure shown in formula 1. It is a new type of signal transduction inhibitor and polytoluene sulfonate jointly developed by Bayer and Onxy. Target anti-tumor drugs. Sorafenib has a dual anti-tumor effect: it can directly inhibit the proliferation of tumor cells by blocking the cell signaling pathway mediated by RAF / MEK / ERK, and it can also inhibit the formation and formation of new blood vessels by acting on VEGFR. Cut off the nutritional supply of tumor cells to achieve the purpose of curbing tumor growth. It was listed in China in 2006, and in 2008 China approved it for the treatment o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 陈雨马少红王彦锋
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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