CN112679424A - Synthesis method of regorafenib - Google Patents
Synthesis method of regorafenib Download PDFInfo
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- CN112679424A CN112679424A CN201910997733.XA CN201910997733A CN112679424A CN 112679424 A CN112679424 A CN 112679424A CN 201910997733 A CN201910997733 A CN 201910997733A CN 112679424 A CN112679424 A CN 112679424A
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Abstract
The invention provides a regorafenib synthesis method, which adopts 3-fluoro-4-nitrophenol as a raw material to replace the traditional 3-fluoro-4-aminophenol for etherification reaction, and then the 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide is obtained through catalytic hydrogenation, and the regorano has the advantages that the stability of the nitro group is higher than that of the amino group, and the catalytic hydrogenation is carried out after the 4-chloro-2-pyridineformamide is etherified, at the moment, the hydroxyl group is etherified, the stability of the product is greatly improved, the purity and yield of the product obtained after the catalytic hydrogenation are greatly improved, and the quality of the final product regorafenib is ensured. 3-fluoro-4-nitrophenol is used as a starting material to carry out an ether forming reaction with 4-chloro-2-pyridinecarboxamide, 4-methyl-2-pentanone is not needed to protect amino, and the quality of an intermediate and a final product obtained after catalytic hydrogenation is better.
Description
Technical Field
The invention belongs to the field of raw material medicines, and particularly relates to regorafenib.
Background
According to the traditional synthetic route of regorafenib, 3-fluoro-4-aminophenol and 4-chloro-2-pyridinecarboxamide are subjected to an ether forming reaction to obtain an intermediate 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide, and 3-fluoro-4-aminophenol has hydroxyl and amino groups, so that the stability is poor, the oxidation is easy, the normal state is a tan solid, many impurities exist, the yield is low, and the purification is difficult. And the purity of the final product obtained is not high.
The 3-fluoro-4-aminophenol used as the raw material in the traditional process has poor stability, is easy to oxidize and is difficult to store.
According to the traditional synthetic route, 4-methyl-2-pentanone is adopted to carry out amino protection on 3-fluoro-4-aminophenol, then the amino protection and 4-chloro-2-pyridinecarboxamide are subjected to ether forming reaction, and then a protection group is removed to obtain a corresponding intermediate 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide.
Disclosure of Invention
Aiming at the defects of the prior art, the invention adopts 3-fluoro-4-nitrophenol as a raw material to replace the traditional 3-fluoro-4-aminophenol for etherification reaction, and then the 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide is obtained by catalytic hydrogenation, and the invention has the advantages that the stability of nitro groups is higher than that of amino groups, and the catalytic hydrogenation is carried out after the 4-chloro-2-pyridineformamide is etherified, at the moment, because hydroxyl groups are etherified, the stability of the product is greatly improved, the purity and yield of the product obtained after the catalytic hydrogenation are greatly improved, and the quality of the final product regorafenib is ensured.
3-fluoro-4-nitrophenol is used as a starting material to carry out an ether forming reaction with 4-chloro-2-pyridinecarboxamide, 4-methyl-2-pentanone is not needed to protect amino, and the quality of an intermediate and a final product obtained after catalytic hydrogenation is better.
3-fluoro-4-nitrophenol is used as a starting material, the process route is simple, the intermediate 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide is easy to purify, the defects that the intermediate 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide is rich in impurities and difficult to purify in the traditional synthesis process are overcome, and high-purity regorafenib is obtained more easily.
According to one aspect of the technical scheme, the invention provides a regorafenib synthesis method, which uses 3-fluoro-4-nitrophenol as a raw material.
According to one aspect of the technical scheme, the invention provides a regorafenib synthesis method, wherein 3-fluoro-4-nitrophenol is subjected to etherification reaction and then catalytic hydrogenation to obtain 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide, namely, the 3-fluoro-4-nitrophenol is used for synthesizing the 4- (4-nitro-3-fluorophenoxy) -N-methylpyridine-2-formamide.
According to one aspect of the technical scheme of the invention, a regorafenib synthesis method is provided, which comprises the following steps:
adding 3-fluoro-4-nitrophenol, 4-chloro-2-pyridinecarboxamide, dry DMF (dimethyl formamide), potassium carbonate and nitrogen gas into a reaction vessel, heating, keeping the temperature for reaction, filtering to remove insoluble substances after the reaction is finished, concentrating the filtrate under reduced pressure, and recrystallizing the residue by using a mixed solvent of ethyl acetate and petroleum ether to obtain the 4- (4-nitro-3-fluorophenoxy) -N-methylpyridine-2-carboxamide.
According to one aspect of the technical scheme of the invention, the synthesis method of regorafenib is provided, wherein 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide is synthesized by using 4- (4-nitro-3-fluorophenoxy) -N-methylpyridine-2-formamide,
according to one aspect of the technical scheme of the invention, a regorafenib synthesis method is provided, which further comprises the following steps:
adding the 4- (4-nitro-3-fluorophenoxy) -N-methylpyridine-2-formamide, ethyl acetate and Pd/C into a reaction container, introducing hydrogen, controlling the pressure, carrying out catalytic hydrogenation reaction overnight, finishing the reaction, filtering, concentrating the filtrate under reduced pressure to obtain a brown solid, and recrystallizing with ethyl acetate/petroleum ether to obtain the solid 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide.
According to one aspect of the technical scheme of the invention, a method for synthesizing regorafenib is provided, wherein the method for synthesizing regorafenib uses 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide, and comprises the following steps:
adding 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide and dichloromethane into a reaction container, stirring, cooling, adding 4-chloro-3-trifluoromethylphenylisocyanate, keeping the temperature, stirring, reacting, heating, keeping the temperature, reacting, filtering, washing a filter cake with dichloromethane, and recrystallizing ethyl acetate/petroleum ether to obtain the solid regorafenib.
According to one aspect of the technical scheme of the invention, a regorafenib synthesis method is provided, which comprises the following steps:
adding the 3-fluoro-4-nitrophenol and 4-chloro-2-pyridinecarboxamide into a reaction container, drying to obtain DMF100ml, potassium carbonate, protecting with nitrogen, heating to 110 ℃, keeping the temperature for reaction, filtering to remove insoluble substances, concentrating the filtrate under reduced pressure, and recrystallizing the residue with a mixed solvent of ethyl acetate and petroleum ether to obtain 4- (4-nitro-3-fluorophenoxy) -N-methylpyridine-2-carboxamide.
Adding the 4- (4-nitro-3-fluorophenoxy) -N-methylpyridine-2-formamide, 500ml of ethyl acetate and 5% Pd/C into a reaction vessel, introducing hydrogen, controlling the pressure to be 0.15MPa, carrying out catalytic hydrogenation reaction overnight, finishing the reaction, filtering, concentrating the filtrate under reduced pressure to obtain a brown solid, and recrystallizing with ethyl acetate/petroleum ether to obtain the solid 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide.
Adding the 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide and dichloromethane into a reaction container, stirring, cooling to 0 ℃, adding 4-chloro-3-trifluoromethylphenylisocyanate, keeping the temperature, stirring, reacting for 1 hour, heating to 25 ℃, keeping the temperature, reacting, separating out a large amount of solids, filtering, washing a filter cake with dichloromethane, and recrystallizing ethyl acetate/petroleum ether to obtain solid regorafenib.
Drawings
FIG. 1 is a synthesis scheme of one of the synthetic methods of the present invention.
Detailed Description
The following examples are intended to further illustrate some, but not all, preferred embodiments of the present invention. Other embodiments of the invention based on the present invention, which can be made by a person skilled in the art without inventive step, belong to the scope of protection of the present invention. The invention will be further described with reference to the accompanying drawings.
The first embodiment is as follows: synthesis of 4- (4-nitro-3-fluorophenoxy) -N-methylpyridine-2-carboxamide
Adding 3-fluoro-4-nitrophenol (15.7g, 0.1mol) and 4-chloro-2-pyridinecarboxamide (17.0g, 0.1mol) into a 500ml three-neck flask, drying to obtain DMF100ml, potassium carbonate (27.6g, 0.2mol), heating to 110 ℃ under the protection of nitrogen, preserving heat for 3 hours, ending the reaction, filtering to remove insoluble substances, decompressing and concentrating the filtrate, recrystallizing the residue by using a mixed solvent of ethyl acetate and petroleum ether to obtain 20.4g of 4- (4-nitro-3-fluorophenoxy) -N-methylpyridine-2-carboxamide, wherein the yield is as follows: 70.1 percent.
Example two: synthesis of 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide
Adding 4- (4-nitro-3-fluorophenoxy) -N-methylpyridine-2-formamide (14.5g, 0.05mol), 500ml of ethyl acetate and 5% Pd/C5.0g into a 1000ml three-neck flask, introducing hydrogen, controlling the pressure to be 0.15MPa, carrying out catalytic hydrogenation reaction overnight, finishing the reaction, filtering, concentrating the filtrate under reduced pressure to obtain a brown solid, and recrystallizing with ethyl acetate/petroleum ether to obtain a white-like solid, namely 10.8g of 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide, wherein the yield is 82.7%.
Example three: synthesis of regorafenib
Adding 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide (25.0g, 0.096mol) and 200ml of dichloromethane into a 500ml single-neck flask, stirring, cooling to 0 ℃, adding 4-chloro-3-trifluoromethylphenyl isocyanate (24.4g, 0.11mol), keeping the temperature and stirring for reaction for 1 hour, heating to 25 ℃, keeping the temperature and reacting for 2 hours, precipitating a large amount of solid, filtering, washing a filter cake with dichloromethane, and recrystallizing ethyl acetate/petroleum ether to obtain 30.1g of white-like solid regorafenib, wherein the yield is 67.2%, and the liquid phase purity is HPLC: 99.8 percent.
The synthetic route is shown in FIG. 1
The foregoing examples are intended to further illustrate some preferred embodiments of the invention, not all embodiments. Other embodiments of the invention based on the present invention, which can be made by a person skilled in the art without inventive step, belong to the scope of protection of the present invention.
Claims (6)
1. The regorafenib synthesis method is characterized in that 3-fluoro-4-nitrophenol is used as a raw material, and in the method, etherification reaction is carried out on the 3-fluoro-4-nitrophenol, and then catalytic hydrogenation is carried out to obtain 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide.
2. A method of synthesizing regorafenib according to claim 1, wherein the method comprises the steps of:
adding the 3-fluoro-4-nitrophenol, 4-chloro-2-pyridinecarboxamide, dry DMF (dimethyl formamide), potassium carbonate and nitrogen protection into a reaction vessel, heating, keeping the temperature for reaction, filtering to remove insoluble substances, concentrating the filtrate under reduced pressure, and recrystallizing the residue with a mixed solvent of ethyl acetate and petroleum ether to obtain the 4- (4-nitro-3-fluorophenoxy) -N-methylpyridine-2-carboxamide.
3. A synthesis method of regorafenib according to claim 1, wherein the 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide is used in the synthesis method of regorafenib and is synthesized from 4- (4-nitro-3-fluorophenoxy) -N-methylpyridine-2-carboxamide.
4. A method of synthesizing regorafenib according to claim 3 further comprising the steps of:
adding the 4- (4-nitro-3-fluorophenoxy) -N-methylpyridine-2-formamide, ethyl acetate and Pd/C into a reaction container, introducing hydrogen, controlling the pressure, carrying out catalytic hydrogenation reaction overnight, finishing the reaction, filtering, concentrating the filtrate under reduced pressure to obtain a brown solid, and recrystallizing with ethyl acetate/petroleum ether to obtain the solid 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide.
5. The method for synthesizing regorafenib according to claim 2, wherein the 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide is used for synthesizing regorafenib, and the steps are as follows:
adding the 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide and dichloromethane into a reaction container, stirring, cooling, adding 4-chloro-3-trifluoromethylphenylisocyanate, keeping the temperature, stirring, reacting, heating, keeping the temperature, reacting, filtering, washing a filter cake with dichloromethane, and recrystallizing ethyl acetate/petroleum ether to obtain solid regorafenib.
6. A method for synthesizing regorafenib according to claim 1, wherein the steps of the method for synthesizing regorafenib are as follows:
adding the 3-fluoro-4-nitrophenol and 4-chloro-2-pyridinecarboxamide into a reaction container, drying to obtain DMF100ml, potassium carbonate, protecting with nitrogen, heating to 110 ℃, keeping the temperature for reaction, filtering to remove insoluble substances, concentrating the filtrate under reduced pressure, and recrystallizing the residue with a mixed solvent of ethyl acetate and petroleum ether to obtain 4- (4-nitro-3-fluorophenoxy) -N-methylpyridine-2-carboxamide.
Adding the 4- (4-nitro-3-fluorophenoxy) -N-methylpyridine-2-formamide, 500ml of ethyl acetate and 5% Pd/C into a reaction vessel, introducing hydrogen, controlling the pressure to be 0.15MPa, carrying out catalytic hydrogenation reaction overnight, finishing the reaction, filtering, concentrating the filtrate under reduced pressure to obtain a brown solid, and recrystallizing with ethyl acetate/petroleum ether to obtain the solid 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide.
Adding the 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-formamide and dichloromethane into a reaction container, stirring, cooling to 0 ℃, adding 4-chloro-3-trifluoromethylphenylisocyanate, keeping the temperature, stirring, reacting for 1 hour, heating to 25 ℃, keeping the temperature, reacting, separating out a large amount of solids, filtering, washing a filter cake with dichloromethane, and recrystallizing ethyl acetate/petroleum ether to obtain solid regorafenib.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113466395A (en) * | 2021-08-03 | 2021-10-01 | 杭州微源检测技术有限公司 | Method for detecting content of 4-chloro-3-trifluoromethyl phenyl isocyanate in regorafenib and intermediate drug |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108440403A (en) * | 2018-03-31 | 2018-08-24 | 山东罗欣药业集团恒欣药业有限公司 | A kind of preparation method of Rui Gefeini |
| CN108558747A (en) * | 2018-03-31 | 2018-09-21 | 山东罗欣药业集团恒欣药业有限公司 | A kind of preparation method of Rui Gefeini |
| CN110183377A (en) * | 2019-07-16 | 2019-08-30 | 浙江工业大学上虞研究院有限公司 | A kind of synthetic method of anticancer drug Rui Gefeini |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108440403A (en) * | 2018-03-31 | 2018-08-24 | 山东罗欣药业集团恒欣药业有限公司 | A kind of preparation method of Rui Gefeini |
| CN108558747A (en) * | 2018-03-31 | 2018-09-21 | 山东罗欣药业集团恒欣药业有限公司 | A kind of preparation method of Rui Gefeini |
| CN110183377A (en) * | 2019-07-16 | 2019-08-30 | 浙江工业大学上虞研究院有限公司 | A kind of synthetic method of anticancer drug Rui Gefeini |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113466395A (en) * | 2021-08-03 | 2021-10-01 | 杭州微源检测技术有限公司 | Method for detecting content of 4-chloro-3-trifluoromethyl phenyl isocyanate in regorafenib and intermediate drug |
| CN113466395B (en) * | 2021-08-03 | 2023-11-21 | 杭州微源检测技术有限公司 | Method for detecting content of 4-chloro-3-trifluoromethyl isocyanate phenyl in regorafenib and intermediate drug |
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