Method for comprehensively and efficiently synthesizing anti-cancer drug regorafenib

Abstract

The invention discloses a method for comprehensively synthesizing a regorafenib anticancer drug with high efficiency and low cost, which is applied to the field of anticancer drugs and chemical industry. The preparation method comprises the following steps: carrying out amidation reaction on 2-amino-4-chloropyridine and formic acid or carrying out amidation reaction on 4-chloro-2-picolinic acid and ammonia to obtain an intermediate (1), namely 2-formamido-4-chloropyridine; then carrying out N-methylation reaction on the intermediate (1) 2-formamide-4-chloropyridine and a methyl reagent (the methyl reagent comprises dimethyl sulfate, dimethyl carbonate and methyl iodide (or alkali participates in) to obtain an intermediate (2) 4-chlorine N-methylpyridine-2-formamide, and carrying out N-methylation reaction on the intermediate (1) 2-formamide-4-chloropyridine and the methyl reagent (the methyl reagent comprises dimethyl sulfate, dimethyl carbonate and methyl iodide (or alkali participates in) to obtain an intermediate (2) 4-chlorine N-methylpyridine-2-formamide; then, enabling the intermediate (2) 4-chloro-N-methylpyridine-2-formamide to react with 4-amino-3-fluorophenol, so as to obtain an intermediate (3) 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide, and enabling the intermediate (3) 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide to react with 4-amino-3-fluorophenol; and then continuously using an intermediate (3) 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide and 4-chloro-3-trifluoromethyl phenyl isocyanate to obtain a final product 4-[4-{4-chloro-3-(trifluoromethyl) phenyl} carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-formamide (regorafenib), wherein the final product 4-[4-{4-chloro-3-(trifluoromethyl) phenyl} carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-formamide (regorafenib) is obtained from the intermediate (3) 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide and 4-chloro-3-trifluoromethyl phenyl isocyanate. Wherein the production and synthesis technologies of the bottom raw materials and the intermediate raw materials are most comprehensive and more practical, the substitution reaction is used, and the used synthesis reaction is more suitable for industrial production and is more friendly to industrial medicine production.

Description

Technical Field

[0001] Applied in the fields of medicine and chemical industry, the inventor provides a complete technology chain from the base raw materials to the final product, which is independently developed and designed by the inventor. Background Art

[0002] Since its development by Bayer, Regorafenib has been widely used to treat tumor diseases such as liver cancer, colorectal cancer, gastric cancer, and blood cancer. After years of application, it has good therapeutic effects and can be used to treat various types of cancer. Regorafenib is an oral multi-target tyrosine kinase inhibitor, which mainly acts by inhibiting a variety of key kinases involved in tumor growth, angiogenesis, and tumor microenvironment regulation. According to preclinical studies, Regorafenib can inhibit a variety of VEGF receptor tyrosine kinases that promote angiogenesis. These receptors play an important role in the formation and growth of new blood vessels in tumors. In addition to VEGFR1-3, Regorafenib can also inhibit a variety of kinases including TIE-2, RAFI, BRAF, BRAFV600E, KIT, RET, PDGFR, and FGFR, with a very wide range of inhibition. More than 90% of the Regorafenib currently taken by most patients in China is imported. The Regorafenib currently sold by online merchants and their tertiary hospitals comes from the drug with the trademark Baiwango. In view of the incomplete technology of domestic production of Regorafenib anti-cancer drug, low production efficiency and high production cost, the inventor provides a complete technology chain in the present invention to increase the production speed of Regorafenib, optimize the reaction path to increase the yield and purity, reduce costs, and simplify the synthesis of Regorafenib. At the same time, it can allow domestic patients to take drugs produced in their own country. This invention has important significance and development potential for the pharmaceutical field and the synthesis of the anti-cancer drug Regorafenib.

[0003] According to the inventor's search of existing domestic patents containing regorafenib-related keywords, it was found that more than 90% of them used regorafenib in combination with other drugs or chemicals. Few companies can achieve integrated production from the most basic raw materials to the final regorafenib. The inventor provides all the technologies from the most basic raw materials to the final synthesis.

[0004] The chemical formula and chemical name of regorafenib are C21H15CIF4N4O3, molecular weight 519.27634, 4-[4-{4-chloro-3-(trifluoromethyl)phenyl}carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide. Summary of the invention

[0005] The inventors used 2-amino-4-chloropyridine C5H5CIN2 and formic acid HCOOH for amidation reaction or used 4-chloro-2-pyridinecarboxylic acid and ammonia NH3 for amidation reaction to obtain intermediate (1) 2-formamido-4-chloropyridine CóH5CIN2O, and then used intermediate (1) 2-formamido-4-chloropyridine C6H5CIN2O and a methyl reagent (the methylation reagent includes: dimethyl sulfate (CH3O)2SO2, dimethyl carbonate (CH3O)2CO, iodomethane CH3I (or alkali) for N-methylation reaction to obtain intermediate (2) 4-chloro-N-methylpyridine-2-carboxamide C7H7CIN2O, and then used intermediate (2) 4-Chloro-N-methylpyridine-2-carboxamide C7H7CIN2O reacts with 4-amino-3-fluorophenol C6H6FNO to obtain intermediate (3) 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide C13H12FN3O2, and then intermediate (3) 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide C13H12FN3O2 is used to react with 4-chloro-3-trifluoromethylphenyl isocyanate C8H3CIF3NO to obtain the final product 4-[4-{4-chloro-3-(trifluoromethyl)phenyl}carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide. (Regorafenib C21H15F4N4O3CI).

[0006] In 0005, the synthesis of 4-amino-3-fluorophenol is as follows: 3-fluorophenol and mixed acid undergo nitration reaction C6H4FOH+HNO3→C6H3FNO2OH+H2O, and the nitration reaction obtains 3-fluoro-4-nitrophenol C6H3FNO2OH. The obtained 3-fluoro-4-nitrophenol undergoes a reduction reaction to reduce the nitro group to the amino group, and iron powder and hydrochloric acid are used as reducing agents to obtain 4-amino-3-fluorophenol. The basic reaction chemical equation is: C6H4FNO3+3Fe+6HCl→C6H6FNO+3FeCI2+2H2O.

[0007] In 0005, the basic reaction chemical equations for the reaction of 2-amino-4-chloropyridine C5H5CIN2 with formic acid HCOOH or the reaction of 4-chloro-2-pyridinecarboxylic acid C6H4CINO2 with ammonia NH3 to obtain 2-formamido-4-chloropyridine C6H5CIN2O are: C5H5CIN2+HCOOH→C6H5CIN2O+H2O and the latter is C6H4CINO2+NH3→C6H5CIN2O+H2O.

[0008] In 0005, the chemical equation for the N-methylation reaction of 2-formamido-4-chloropyridine with a methyl reagent to obtain the intermediate 4-chloro-N-methylpyridine-2-formamide is: C6H5CIN2O+CH3I→C7H7CIN2O+HI. If a base is used to participate in the reaction, the equation is: C6H5CIN2O+CH3I+NaOH→C7H7CIN2O+NaI+H2O, C6H5CIN2O+CH3I+KOH→C7H7CIN2O+KI+H2O. C6H5CIN2O+(CH3O)2CO→C7H7CIN2O+CO2↑+CH3OH, C6H5CIN2O+(CH3O)2SO2→C7H7CIN2O+CH3HSO4.

[0009] In 0005, the chemical reaction of 4-chloro-N-methylpyridine-2-carboxamide C7H7CIN20 and 4-amino-3-fluorophenol C6H6FNO gives 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide. The reaction equation is: C7H7CIN2O+C6H6FNO→C13H12FN3O2+HCI↑.

[0010] In 0005, 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide C13H12FN3O2 reacts with 4-chloro-3-trifluoromethylphenylisocyanate C8H3CIF3NO to obtain the final product 4-[4-{4-chloro-3-(trifluoromethyl)phenyl}carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide. (Regorafenib C21H15F4N4O3CI). Its basic reaction chemical equation is: C13H12FN3O2+C8H3CIF3NO→C21H15CIF4N4O3, which is a typical nucleophilic addition reaction in which -N=C=O isocyanate reacts with amino group to obtain regorafenib.

[0011] The reaction formula of 4-chloro-3-trifluoromethylphenyl isocyanate described in 0005 is: first use 3-trifluoromethylaniline and acetylating agent to protect the amino group to ensure the selective reaction in the later stage to obtain the target structure product C7H4F3NH2+CH3COCI→C7H4F3NHC(O)CH3+HCI (this is the chemical formula of acetyl chloride to protect the amino group), C7H4F3NH2+(CH3CO)2O→C7H4F3NHC(O)CH3+CH3COOH (this is the acetic anhydride used to protect the amino group). At the beginning, the inventor designed to use 3-trifluoromethylaniline to react with chlorine, but the amino group would affect the reaction and could not stably obtain the target structure product, so the amino protection strategy must be used. Using acetyl to protect the amino group is the most economical and stable method. The selectivity of chlorination can be enhanced by protecting the amino group, so that it can be precisely chlorinated at the 4-position. Direct chlorination of 3-trifluoromethylaniline can also obtain 4-position chloride, but its ortho-positions 2 and 6 will also be chlorinated, so it is impossible to accurately control the selectivity, and the product of chlorination at the 4-position becomes less, and separation is also a problem and separation is also in the cost. Only by reducing the ortho-position electron density to increase the steric hindrance to the ortho-position and stabilizing the 4-position to make it an electron-rich area can the selective 4-position chlorinated product be stably obtained. Since the amino group has a high electron donation effect of +M, it is not conducive to the reaction. It is protected by acetyl. Acetyl also has a slight electron donation effect, but in this compound, it is mainly the -I position that is most significant, and acetyl has a certain steric hindrance. According to the inventor's structural research, this hindrance has a strong restraint on the ortho-position and has little effect on the 4-position, which further suppresses the possibility of chlorination at the ortho-position. After the acetyl group protects the amino group, the electron donation effect of the amino group is weakened, thereby significantly reducing the electron density and reactivity of the ortho-position, making the reaction more selective, mainly occurring at the 4-position, reducing side reactions, and the overall analysis shows that the 4-position has the highest activity. The strong electron-donating effect of the amino group not only affects the aromatic ring, but also makes the amino group itself prone to side reactions with electrophilic reagents. This is a problem that must be considered in chemical synthesis. According to the inventor's analysis, the ortho position will be further restrained by the -I effect of the trifluoromethyl group, while the 4th position is not significantly affected. This is because it attracts electrons on the surrounding carbon atoms through the inductive effect, that is, through the σ bond, so that the electron density of the adjacent position is reduced. Since the influence of the -I effect is mainly transmitted through the σ bond, the closer the position is to the trifluoromethyl group, the more obvious the effect of reducing the electron density is. The ortho and meta positions are most significantly affected by the electron-withdrawing effect and steric hindrance of the trifluoromethyl group. The 4th position is far away from the trifluoromethyl group and is still affected by a certain electron-withdrawing effect, but this effect is much weaker than the ortho position. Therefore, the electron density of the 4th position, that is, the para position, is reduced less, and it still retains a relatively high electron density compared to the ortho position, which is the most helpful in chemical reactions. The inventor's research and development idea is to improve selectivity and controllability, enhance yield and avoid side reactions.

[0012] After protection, N-acetyl-3-trifluoromethylaniline is obtained, and then the chlorinating agent (chlorine, N-chlorosuccinimide) is used to continue chlorinating. The basic chemical equation is: C7H4F3NHC(O)CH3+CI2→C7H3F3CINHC(O)CH3+HCI. C7H4F3NH(O)CH3+C4H4NO2CI→C7H3F3CINHC(O)CH3+C4H5NO2. This is the equation for obtaining N-acetyl-4-chloro-3-trifluoromethylaniline. Then, the acetyl group is hydrolyzed to restore the amino group (including alkaline hydrolysis and acidic hydrolysis). The basic chemical equation of alkaline hydrolysis is: C7H3F3CINHC(O)CH3+NaOH→C7H3F3CINH2(4-chloro-3-trifluoromethylaniline)+CH3COONa, C7H3F3CINHC(O)CH3+KOH→C7H3F3CINH2+CH3COOK. The basic chemical formula of acidic (hydrochloric acid, sulfuric acid) hydrolysis is: C7H3F3CINHC(O)CH3+H2O→C7H3F3CINH2(4-chloro-3-trifluoromethylaniline)+CH3OOH (where the acid H+ proton plays a catalytic role). Then, 4-chloro-3-trifluoromethylaniline is reacted with phosgene, diphosgene, and triphosgene to convert the amino group into isocyanate to obtain 4-chloro-3-trifluoromethylphenyl isocyanate. The basic chemical equation of this reaction is: C7H5CIF3N+COCI2→C8H3CIF3NO+2HCI↑, C7H5CIF3N+C2CI4O2→C8H3CIF3NO+COCI2+2HCI↑, C7H5CIF3N+C3CI6O3→C8H3CIF3NO+2COCI2+2HCI↑.

[0013] The chemical reaction equation above is very complete and easy to review. Synthesis method

[0014] Add a solvent such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc. to the reactor. The reactor is in an anhydrous dry environment. Then, 1 mol of 2-amino-4-chloropyridine is added to the reaction vessel, and then 1 mol~1.1 mol of formic acid is slowly added. Stir continuously during the feeding process to ensure that the materials are evenly mixed, and pay attention to controlling the feeding rate to prevent the reaction from being too fast. Turn on the heating device to heat the reaction, and slowly heat the reaction system to a suitable reaction temperature. The reaction temperature is between 80°C~100°C. During the reaction, keep the stirring speed moderate so that the reaction is fully carried out. After the reaction is completed, turn off the heating device and allow the reaction system to cool naturally to room temperature. Then the solid product after the reaction is filtered out by a filtering device, and the solid is washed with a small amount of organic solvents such as organic solvents such as ethanol or ether to obtain a crude product 4-chloropyridine-2-formamide. The crude product is then recrystallized to obtain high-purity 4-chloropyridine-2-carboxamide, and the recrystallized purified product is then placed in a vacuum drying oven or other drying equipment, and dried at a temperature of 40°C to 80°C for 4 to 8 hours until the product quality no longer changes and is taken out.

[0015] The reactor is added with solvents such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, etc. One of the solvents is added to the reaction vessel. 1 mol of 4-chloro-2-pyridinecarboxylic acid (4-chloropyridine-2-carboxylic acid) is added to the reaction vessel and stirred to dissolve. Then use a gas conduction device to pass ammonia into the device slowly. The gas conduction device can be placed in contact with or into the reaction solution. The reaction requires 1.1 mol~1.2 mol of ammonia, which can be slightly excessive. The reaction system is heated to between 30~80°C. The reaction temperature can be raised to 90℃~100℃ in the later stage. During the reaction, a small amount of dehydrating agent can be selectively added to speed up the reaction. When it is observed that the raw materials are basically reacted, stop heating and stirring. After the reaction is completed, the reaction solution is cooled to room temperature. If the solvent used is not miscible with water, an appropriate amount of water can be added to precipitate the product from the organic phase. Then the product is separated by filtration or centrifugation. If the solvent is miscible with water, the product is separated from the reaction solution by distillation or extraction. The separated product contains some impurities, and is purified by recrystallization and other methods to improve the purity of the product and perform recrystallization. The purified product needs to be dried to remove residual solvent and moisture. The product can be placed in a vacuum drying oven at a temperature of about 40°C to 80°C and dried for 4-8 hours until the quality of the product no longer changes, and 4-chloropyridine-2-carboxamide is taken out. 0014 to 0015 are all basic synthetic methods for 4-chloropyridine-2-carboxamide.

[0016] Prepare the raw materials 1mol 4-chloropyridine-2-carboxamide and 1mol~1.1mol iodomethane. If a base is used, 1mol~1.1mol of base (such as the above 0008 chemical equation) can be added, solvent: dimethyl sulfoxide, N, N-dimethylformamide and other solvents, weighed 2-carboxamide 4-chloropyridine, base (sodium hydroxide, potassium hydroxide) are added to the reaction vessel, and then an appropriate amount of solvent is added. Stir evenly to fully dissolve or disperse the reactants in the solvent. Slowly add iodomethane to the reaction vessel, control the drop rate to avoid excessive reaction. After the dropwise addition, continue stirring for a period of time to fully mix the reactants. Turn on the heating device and raise the temperature of the reaction system to a set temperature range between 30°C and 80°C. During the heating process, pay close attention to the change of the reaction temperature to ensure that the temperature is stable within the set range. When the reaction is completed, turn off the heating device and let the reaction mixture cool naturally to room temperature. Filter the reaction mixture to remove impurities. Then, separation is performed, and after separation, the product is concentrated and then the organic phase is dried with a desiccant such as anhydrous sodium sulfate to remove the moisture therein. The desiccant is filtered out to obtain a dry organic solution. Finally, the product is purified by recrystallization to obtain high-purity 4-chloro-N-methylpyridine-2-carboxamide white crystals, and then vacuum drying or other drying equipment is prepared for drying for 4 to 8 hours at a temperature between 40° and 80°C, until the product quality no longer changes, indicating that the product is basically dried and can be prepared for removal.

[0017] Weigh 1 mol of 2-formamide-4-chloropyridine, 1:1~1:1.2 mol of iodomethane and solvents such as dimethyl sulfoxide and N. N-dimethylamide and add them to the reactor. Synthesis can be performed without the participation of alkali, but it is not as fast as using alkali and is easier to handle. The order of adding materials is to add the solvent first, then add 2-formamide-4-chloropyridine, and finally slowly add iodomethane to prevent violent reaction. Turn on the heating device to increase the temperature in the reactor. The reaction temperature is between 20°C and 100°C. During the heating process, turn on the stirring device to fully mix the reactants to improve the reaction efficiency. The by-product hydroiodic acid released during the reaction is absorbed and treated by an absorption tower or other equipment. During the reaction, monitor the reaction and adjust the pH value. If the acidity is too heavy, use dilute alkali solution to adjust the pH value to determine the progress of the reaction and whether it is completed. When the reaction is completed, turn off the heating device and let the reactor cool naturally to room temperature. The reaction liquid is then released from the reactor and processed to remove impurities. It is separated by extraction and concentrated by distillation. It is then purified by washing, recrystallization and other methods to obtain a pure product. It is then placed in a vacuum drying oven or other drying equipment, heated to between 40 and 80 degrees Celsius, and dried for about 6 to 8 hours until the product quality no longer changes, and the product is taken out.

[0018] Add a solvent such as acetonitrile, dimethyl sulfoxide, N, N-dimethylamide, etc., and add 2-formamide 4-chloropyridine and dimethyl carbonate to the reaction vessel in a molar ratio of 1:1.1 to 1:1.3. A small amount of base can be added during the reaction to catalyze and promote the reaction. Heat the reaction system to an appropriate temperature between 20°C and 70°C. At the same time, stirring can be performed during the reaction to ensure that the reaction is uniform. When the reaction is detected to be over, the reaction system is naturally cooled to room temperature. Filter the reaction mixture to remove impurities. Then, by distillation, extraction, recrystallization, the product after recrystallization or other purification is placed in a vacuum drying oven or other drying equipment for drying and heating to between 30 degrees Celsius and 60 degrees Celsius, and dried for about 4 to 8 hours until the product quality no longer changes to obtain 4-chloro-N-methylpyridine-2-formamide.

[0019] Add anhydrous dichloromethane or dimethyl sulfoxide as a solvent in the reactor. Dissolve 4-chloropyridine-2-carboxamide in the solvent in the reactor to form a uniform solution. Use a stirring device to stir to ensure uniformity and keep the system temperature between 25°C and 30°C. The speed of slowly adding dimethyl sulfate to the reactor should be controlled to be completed within 30 minutes to 40 minutes to avoid local overheating or side reactions. Continue to stir the reaction system to keep the temperature no higher than 30°C. Ensure that the N-methylation reaction is fully completed. Until 4-chloropyridine-2-carboxamide is completely converted into 4-chloro-N-methylpyridine-2-carboxamide. After the reaction is completed, you can choose to add an appropriate amount of water to the reaction system, and slowly add sodium carbonate or potassium carbonate, stirring to convert the by-product methylsulfuric acid in the system into a more soluble salt. Separate the liquid, extract the organic phase, and discard the aqueous phase. Dry the organic phase over anhydrous sodium sulfate. The dried organic phase is distilled under reduced pressure to remove the solvent to obtain a crude product. The crude product can be further purified by recrystallization or column chromatography to obtain high-purity 4-chloro-N-methylpyridine-2-carboxamide, and then placed in a vacuum drying oven or oven for drying at a temperature of 30 to 60 degrees Celsius for 4 to 8 hours. If the mass of the dried product no longer changes, it means that the drying is basically completed, and then it can be taken out.

[0020] The prepared 4-chloro-N-methylpyridine-2-carboxamide is set aside for reaction with 4-amino-3-fluorophenol. The production and synthesis of 4-amino-3-fluorophenol is firstly nitrated by 3-fluorophenol and mixed acid to obtain 3-fluoro-4-nitrophenol, and then it is used to reduce to amino to obtain 4-amino-3-fluorophenol. Prepare 3-fluorophenol raw material, nitric acid and sulfuric acid, and first modulate the two acids into a mixed acid, in which nitric acid plays the main role, and sulfuric acid only plays the role of dehydration to prevent nitric acid from being diluted and catalytic effect to enhance the nitration ability. After adding sulfuric acid with strong proton supply ability to nitric acid, the degree of nitric acid dissociation of nitroxyl cations is increased, making nitration smooth and rapid. Solvents such as dichloromethane are selected as organic solvents, and ice-salt water baths are prepared to cool the reaction system to control the reaction temperature. Saturated sodium bicarbonate solution, saturated sodium chloride solution, anhydrous magnesium sulfate, etc. are prepared for washing and drying of the product. Dissolve 3-fluorophenol in an organic solvent, and cool the reaction system to 0℃~15℃ with an ice-salt water bath under stirring. Under low temperature control, on the one hand, it is to reduce the occurrence of side reactions, and on the other hand, it is conducive to the formation of target products, because at a lower temperature, the nitration reaction can mainly occur at the 4th position. Control the internal temperature at 0℃~15°C, and slowly drip the mixed acid to ensure that the reaction proceeds smoothly and the temperature will not get out of control. After the acid is dripped, continue to stir moderately at 0℃-15℃ to allow the nitration reaction to proceed fully. In this process, the hydrogen atoms on the benzene ring in the 3-fluorobenphenol molecule are replaced by nitro groups to generate 3-fluoro-4-nitrobenzene and a small amount of by-products. When the reaction is monitored to be over, add an appropriate amount of water to the reaction bottle, and then perform steam distillation. In this process, the organic solvent is first evaporated, and then a yellow turbid liquid is distilled out. Continue distillation until no oil is distilled out, and then stop distillation. Steam distillation can remove unreacted raw materials and some impurities. Then use ether to extract the kettle liquid to separate the ether layer containing the product. Then, wash the ether layer with saturated sodium bicarbonate solution to remove residual acidic substances. Then, wash with saturated sodium chloride solution to further remove impurities. Dry the washed ether layer with anhydrous magnesium sulfate or other desiccant to remove the moisture therein. After drying, filter to remove solid impurities such as desiccant. Finally, evaporate the ether to obtain a pale yellow solid 3-fluoro-4-nitrophenol crude product, which is then recrystallized or otherwise purified for purification. After treatment, dry it and place it in a vacuum drying oven or drying oven for about 4-8 hours at a temperature of 20 to 70 degrees Celsius. If the product quality no longer changes, it means that it is almost dry, and then you can prepare to take it out.

[0021] Then the obtained 3-fluoro-4-nitrophenol is mixed with iron powder and hydrochloric acid to reduce the nitro group to amino group to obtain 4-amino-3-fluorophenol. Prepare the raw materials - 3-fluoro-4-nitrophenol, concentrated hydrochloric acid, and iron powder. The finer the fineness is, the better the reaction is. The molar ratio is 1:3:6-1:3.1:6.2. The solvent is selected from ethanol / water mixture, ethanol, isopropanol, and methanol. Add solvent (water-ethanol mixed solvent or other water-miscible solvent) to the reaction vessel. Add 3-fluoro-4-nitrophenol and stir to dissolve it under stirring. Then add iron powder to the reaction solution and continue stirring. A magnetic stirrer or a mechanical stirrer can be used. Keep the reaction temperature between 20 degrees Celsius and 40 degrees Celsius. Too high a temperature will lead to an increase in side reactions, and too low a temperature may reduce the reaction rate. Put concentrated hydrochloric acid into a dropping funnel or other dropping equipment and slowly drip it into the reaction mixture to ensure that the acid addition rate is controlled to avoid overheating of the reaction and splashing of the solution. During the addition process, the reaction will gradually release hydrogen (H2), and the generation of bubbles can be observed at this time. After the addition of hydrochloric acid is completed, the reaction solution is stirred continuously until the reaction is basically completed at 20-40°C. After the reaction is completed, the reaction mixture is cooled to room temperature. The reaction mixture is passed through a vacuum filtration device to separate the iron powder and other insolubles after the reaction. After filtration, the filtrate obtained contains the target product 4-amino-3-fluorophenol. The remaining acid in the reaction solution is neutralized with a dilute alkali solution (5% to 10% NaOH or Na2CO3 solution) until the pH value is close to neutral pH 6-7. The neutralized aqueous phase is liquid-liquid extracted with an organic solvent such as ethyl acetate or dichloromethane. The amount of each extraction is approximately equal volume of organic solvent, and the extraction is performed 3 times. The organic phase is collected in one place. The organic phase is dried with anhydrous sodium sulfate to remove moisture. Sodium sulfate is then removed by filtration. The organic solvent is evaporated off with a rotary evaporator to obtain a crude product 4-amino-3-fluorophenol. The crude product is dissolved in hot ethanol. After the solution is cooled, 4-amino-3-fluorophenol will crystallize out. The crystals are collected by vacuum filtration and then washed with a small amount of cold ethanol. The recrystallized product is placed in a vacuum drying oven and dried at 40°C to 60°C for 4 to 8 hours until the product mass is observed to no longer change, indicating that the drying is basically complete and waiting to be taken out to obtain a high-purity product.

[0022] Get 4-amino-3-fluorophenol and then take the previous 4-chloro-N-methylpyridine-2-carboxamide to react to get 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide. Accurately weigh 1mol: 1mol~1.1mol: 1.1mol of 4-chloro-N-methylpyridine-2-carboxamide and 4-amino-3-fluorophenol, use N, N-dimethylformamide, dimethyl sulfoxide, 1-methyl-2-pyrrolidone, etc. as solvents, and acid binding agent (a small amount of potassium carbonate, which can be added if the control is not good, but it can be omitted if the control is good, depending on the pH value. Adding a small amount of alkali can provide an alkaline environment to promote the reaction. It is best to use a weak base in this type of reaction. Many people use a strong base in this type of reaction, but this is an unwise choice. The inventor believes that this will lead to side reactions). In a dry reaction vessel, connect a nitrogen protection device, pass nitrogen to exhaust the air and moisture in the container, and keep the reaction system in an oxygen-free and water-free environment. This step is very important because oxygen and moisture may interfere with the reaction or cause side reactions. Add the weighed 4-amino-3-fluorophenol to the solvent and stir to fully dissolve it. Then, slowly add 4-chloro-N-methylpyridine-2-carboxamide under stirring, and continue stirring for a period of time to fully mix the two reactants. Slowly add an acid binding agent such as potassium carbonate to the reaction system. The role of the acid binding agent is to neutralize acidic substances such as hydrogen chloride produced during the reaction and promote the reaction in the positive direction. The speed of adding the acid binding agent should be moderate to avoid excessive reaction. Heat the reaction vessel and slowly heat it to a suitable reaction temperature of 40-90°C. Keep the reaction at this temperature for a period of time, stirring continuously during the period, so that the reaction is fully carried out. After the reaction is completed, cool the reaction solution to room temperature. Then, slowly pour the reaction solution into a large amount of ice water to precipitate the product. Use a Buchner funnel for suction filtration to collect the precipitated product. The product is washed with an appropriate amount of cold water to remove residual solvents, unreacted raw materials and by-products, etc. A suitable eluent is selected to separate and purify the product, and the fraction of the target product is collected, then concentrated and recrystallized, and then placed in a drying oven or a drying oven for 6-8 hours at a temperature of 60 degrees Celsius to 80 degrees Celsius, until the product quality does not change, indicating that it has been basically dried and is waiting to be taken out, and high-purity 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide can be obtained.

[0023] The obtained 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide is kept aside for the synthesis of 4-chloro-3-trifluoromethylphenyl isocyanate. However, in actual production scale, it can be produced together with the synthesis of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide. Prepare the raw material 3-trifluoromethylaniline, more widely known as m-aminotrifluorotoluene, a kind of acetic anhydride or acetyl chloride. Use acetyl to protect the amino group so that the amino group will not affect the chlorination in the subsequent chlorination. If the amino group is not protected, the chlorination position of 4-chloro-3-trifluoromethylaniline cannot be selectively obtained, which affects the yield and selectivity. This is a problem that the inventor considered when designing the reaction in the first place. Weigh 3-trifluoromethylaniline and put it into the reactor. No solvent is required. If a solvent is used, dimethyl sulfoxide, chloroform, N-dimethylformamide, dichloromethane, tetrahydrofuran, acetonitrile (use anhydrous solvents with a water content of less than 0.01%), etc., are selected. A slightly excess amount of acetic anhydride is added to the reaction at a molar ratio of 1:1.1~1:1.2 to ensure complete reaction. If the reaction rate is slow, a small amount of acid catalyst such as concentrated phosphoric acid or acetic acid can be added to promote the reaction. Heat the reaction mixture to 50-60°C and maintain the temperature for a period of time under stirring to allow the reaction to proceed fully. In this process, the amino group reacts with the acetyl group in the acetic anhydride to form an N-acetylated product. Acetic acid is a byproduct and will gradually form. After the reaction is completed, cool the reaction mixture to room temperature. If a solvent is used, water or a saturated sodium carbonate solution can be added after cooling to decompose the excess acetic anhydride. Wash the reaction mixture several times with water or a dilute alkaline solution of 5% to 10% (NaOH or Na2CO3) to remove excess acetic acid and impurities. Extract the organic phase with an organic solvent, ethyl acetate. The organic phase is further washed with saturated brine or sodium carbonate solution to remove residual acetic acid. The organic phase is dried over anhydrous sodium sulfate to remove residual moisture. The solvent is removed by distillation or rotary evaporation to obtain a crude product. The crude product is purified by recrystallization and then placed in a drying oven or a drying oven at a temperature of about 60°C to 80°C for 4-8 hours until the product quality no longer changes.

[0024] 3-trifluoromethylaniline is used to react with acetyl chloride to protect the amino group to obtain N-acetyl-3-trifluoromethylaniline, and a dry, anhydrous reactor is prepared, and the reaction system is protected by vacuumizing and filling with inert gas. An appropriate amount of organic solvent anhydrous dichloromethane, acetonitrile, etc. are added to the reaction bottle, and 1mol of 3-trifluoromethylaniline is dissolved therein, and the reaction bottle is placed in an ice-water bath, and the solution temperature is reduced to 0~5°, and the reaction rate is controlled to prevent the occurrence of side reactions. Under stirring, 1mol~1.1nol of acetyl chloride is slowly added dropwise to the solution dissolved with 3-trifluoromethylaniline through a dropping funnel. The dropping speed is controlled to keep the reaction system temperature within the low temperature range. After the dropwise addition is completed, the reaction temperature can be slowly raised to room temperature, and the stirring reaction is continued at room temperature. Samples are taken to check the degree of conversion during the reaction to ensure that the reaction is complete. The hydrogen chloride gas released during the reaction is absorbed and processed with a gas absorption device, and a small amount of acid binding agent is added to the reaction system to neutralize a small amount of acid, which is to avoid protonation causing side reactions. After the reaction is completed, water or ice water is slowly added to the reaction mixture to decompose the excess acetyl chloride, and the organic phase and the aqueous phase are separated by a separatory funnel. The organic phase contains the target product N-acetyl-3-trifluoromethylaniline. The organic phase is washed with a saturated sodium carbonate solution or saturated brine for many times to remove the residual acid. After washing, the organic phase is dried with anhydrous sodium sulfate to remove residual moisture. The dried organic solvent is removed by a rotary evaporator to obtain a crude product. The crude product can be further purified by recrystallization, and after purification, the product is placed in a drying oven to dry the product at a temperature between 30 degrees Celsius and 80 degrees Celsius, and the product can be taken out until the quality no longer changes during the drying process.

[0025] The reaction is that N-acetyl-3-trifluoromethylaniline undergoes aromatic ring chlorination reaction under the action of chlorine. This is because the trifluoromethyl electron-withdrawing effect and acetyl protection of the amino group make it easier to occur at position 4. The molar ratio of the prepared N-acetyl-3-trifluoromethylaniline and chlorine should be controlled at 1:1.1~1:1.2, with slightly more chlorine. The solvent is selected from dichloromethane, carbon tetrachloride, and dimethyl sulfoxide organic solvents, and the entire reaction system cannot have water molecules in it. The catalyst accounts for 5%-10% of the total reaction volume. The catalyst includes ferric chloride and aluminum chloride. Ice water or a cooling device is prepared to control the reaction temperature. N-acetyl-3-trifluoromethylaniline is added to the reactor, and a solvent is used to completely dissolve it. Keep the temperature within the range of low temperature to room temperature to prevent the reaction from being too violent. Use a gas conduction device to add chlorine, slowly introduce chlorine and continue stirring under stirring conditions. The flow rate of chlorine should be moderate and the introduction should be completed within 10 to 30 minutes, while avoiding too fast a rise in the reaction temperature. A small amount of ferric chloride or aluminum chloride is added as a catalyst to promote the chlorination reaction. This is because ferric chloride is used as a catalyst for the chlorination of aromatic rings. It activates chlorine to make chlorination smoother, so that the product can be obtained more selectively and the yield can be guaranteed. The reaction is carried out under low temperature and then heated up, and the reaction is constantly controlled and monitored. The pH value should be controlled at neutral to weak alkalinity. If the reaction is close to completion, slowly return the reactor temperature to room temperature and introduce a small amount of nitrogen or other inert gas to help discharge the remaining chlorine. The reaction mixture is added to a saturated sodium carbonate solution and washed to neutralize the generated hydrogen chloride and remove the reaction by-products. The washed organic phase is washed several times with distilled water until the pH value is neutral. Then continue to use anhydrous sodium sulfate to dry the organic phase to remove residual moisture. Continue to remove the solvent from the dried organic phase by a rotary evaporator or other means to obtain a crude product. Then continue to recrystallize and purify the crude product to obtain high-purity N-acetyl-4-chloro-3-trifluoromethylaniline. Then continue to put the product into a vacuum drying oven and dry it for 4 to 8 hours at 40°C ~ 80°C. If the quality of the product does not change, it means that the drying is basically completed, and then you can take it out.

[0026] N-acetyl-3-trifluoromethylaniline is chlorinated by reacting with N-chlorosuccinimide to obtain N-acetyl-4-chloro-3-trifluoromethylaniline. N-chlorosuccinimide is a mild chlorination reagent. In addition to being slightly more expensive, it has a higher selectivity. Another point is that the byproduct succinimide can be effectively recovered. The recovered succinimide can continue to synthesize N-chlorosuccinimide, which is not costly. The molar ratio of the raw materials N-acetyl-3-trifluoromethylaniline and N-chlorosuccinimide can be 1mol:1mol. If you want more complete chlorination, you can use a little excess, 1mol:1.1mol solvent dichloromethane, carbon tetrachloride, dimethyl sulfoxide. Dry the inside of the reactor and then add N-acetyl-3-trifluoromethylaniline and dissolve it with a solvent. Place the reactor in an ice bath or cooling bath to reduce the reaction temperature by 0~5°C. This is to control the reaction rate and avoid the occurrence of side reactions. Weigh N-chlorosuccinimide and slowly add it to the reactor under cooling conditions while keeping stirring. Continue to stir the reaction system in an ice bath and control the temperature at 0~5°C to reduce the possibility of side reactions before heating. Continuously monitor the reaction process, and you can detect that there are no reactants in the reaction system, indicating that the reaction is almost complete. When the reaction is completed, let it rise to room temperature. Add a small amount of saturated sodium carbonate solution to neutralize the trace acidic substances in the reaction mixture. If the pH value is not obviously acidic, it can be left alone. Although N-chlorosuccinimide is slightly more expensive, the by-product is mainly succinimide, which dissolves well in water, so it can be directly separated by washing with water. This makes the separation and purification cost relatively low, and the organic phase is washed multiple times with water or saturated sodium carbonate solution until the pH is neutral. Dry the organic phase with anhydrous sodium sulfate to remove residual moisture. Use a rotary evaporator or other evaporation means to evaporate the solvent to obtain a crude product. The crude product is then recrystallized or purified by column chromatography to obtain high-purity N-acetyl-4-chloro-3-trifluoromethylaniline. The purified product is then dried and placed in a vacuum drying oven or drying oven at a temperature between 40°C and 80°C for about 4 to 8 hours. The dried product is ready to be taken out as long as the quality does not change.

[0027] Alkaline hydrolysis of acetyl restores amino groups. Prepare raw materials N-acetyl-4-chloro-3-trifluoromethylaniline and sodium hydroxide or potassium hydroxide, and select water-ethanol mixed solvent or other water-miscible solvents as solvents. Weigh 1 mol of N-acetyl-4-chloro-3-trifluoromethylaniline and dissolve it in a water-miscible solvent. Under stirring, slowly drip sodium hydroxide solution into the solution of N-acetyl-4-chloro-3-trifluoromethylaniline. The dripping speed should be slow to avoid local overreaction or overheating of the solution. At this time, the acetyl group will be hydrolyzed to generate amino groups. Continue heating and stirring to allow the reaction to continue at 60-80°C for 2-3 hours. During this period, a pH meter is used to monitor the pH value of the solution. During the reaction, the solution should be maintained alkaline to ensure the smooth progress of the reaction. After the reaction is completed, stop heating and cool the reaction mixture to room temperature. The reaction can be terminated by adjusting the pH value to neutral. Use ice water or dilute hydrochloric acid to adjust the pH to neutral. Pour the cooled reaction mixture into a separatory funnel and extract it with an organic solvent. Extract 2-3 times continuously to ensure that all 4-chloro-3-trifluoromethylaniline is transferred to the organic phase. Combine the organic phases and wash the organic layer with water several times until the washing liquid is neutral. Use anhydrous sodium sulfate to dry the organic phase to remove residual moisture. After drying, remove the desiccant by filtering. Evaporate the dried organic phase on a rotary evaporator or other evaporation means to remove the organic solvent to obtain a crude product. Continue recrystallization or column chromatography for further purification to obtain 4-chloro-3-trifluoromethylaniline, the product is white to light yellow crystals or solids, then prepare a drying oven or drying oven to dry for 4 to 8 hours, the temperature is about 4 to 8 hours, observe that the product quality does not change and prepare to take it out.

[0028] Acid hydrolysis of acetyl restores amino groups. Prepare 1 mol of N-acetyl-4-chloro-3-trifluoromethylaniline, with a slightly excess of concentrated hydrochloric acid or sulfuric acid over the first raw material. Generally, hydrochloric acid is used, and the solvent is an alcohol-water mixed solvent. Dissolve N-acetyl-4-chloro-3-trifluoromethylaniline in the solvent. In order to enhance solubility, it is chosen to be dissolved in a mixture of ethanol and water. If other solvents are chosen, it is ensured that they are miscible with water and can dissolve the reactants well, which helps to improve the solubility of the reactants and the reaction efficiency. In the reactor, concentrated hydrochloric acid or sulfuric acid is slowly added to the solution. Depending on the amount of reactants, the amount of acid is between a molar ratio of 1:1 and 1:1.2 to ensure that there are enough protons for catalysis. In this reaction, the acid is mainly catalyzed by acid protons. Heat the reaction solution to 60-80°C while maintaining continuous stirring. This temperature range can accelerate the hydrolysis reaction while preventing the occurrence of side reactions. Monitor the progress of the reaction during the reaction to determine the completion of the hydrolysis, and sample the generation of amino groups. During the reaction, the pH value should be below 2 to ensure that the reaction is carried out under strong acid conditions. If necessary, continue to add a small amount of acid during the reaction to maintain an acidic environment. After the reaction is completed, the reaction solution is cooled to room temperature or further cooled by an ice water bath. Gradually add dilute alkali solution to adjust the pH of the reaction system to near neutrality to prevent the acidic environment from affecting subsequent steps. Pour the cooled solution into a separatory funnel and extract the organic phase with an organic solvent. Since the product 4-chloro-3-trifluoromethylaniline has good organic phase solubility, it will enter the organic layer. Repeat the extraction several times to increase the recovery rate of the product. After each extraction, collect the organic layer separately. Mix the organic layer with a desiccant such as anhydrous sodium sulfate to remove residual moisture. After filtering out the desiccant, evaporate the organic solvent using a rotary evaporator or other means to obtain a crude product. Purify by recrystallization, slowly cool the solution to obtain pure 4-chloro-3-trifluoromethylaniline crystals, then prepare a drying oven or oven, set the temperature between 40℃~80℃, and dry for about 4~8 hours, until the quality of the direct product no longer changes. If the quality of the product no longer changes, it means that the drying is basically completed and it is ready to be taken out.

[0029] Then a reaction of 4-chloro-3-trifluoromethylaniline with phosgene, diphosgene, and triphosgene converts the amine therein into an isocyanate to obtain 4-chloro-3-trifluoromethylphenyl isocyanate. If triphosgene is used for reaction, prepare raw materials 4-chloro-3-trifluoromethylaniline and triphosgene, and select anhydrous dichloromethane or anhydrous dimethyl sulfoxide as solvents to dissolve reactants and reaction media, which must be dried before use to ensure anhydrous. Before the reaction starts, it is necessary to use anhydrous nitrogen to purge the reactor to remove air and moisture therein to ensure an oxygen-free and water-free environment during the reaction. 1mol 4-chloro-3-trifluoromethylaniline is dissolved in a solvent and stirred to form a uniform solution. 1mol-1.1mol triphosgene is gradually added to the solution under low temperature conditions. This process is dissolved in the solvent by a dropping funnel or a dropper and then dripped, preferably slowly dripped into the reactor within 30 to 60 minutes. Keep the temperature below 10°C at low temperature. After the addition of trimerized phosgene, continue to stir the reaction solution and slowly heat it to room temperature or above, keep stirring at this temperature to ensure complete reaction. Phosgene and hydrogen chloride gas will be released during the reaction and absorbed and treated by an absorption device. During the entire reaction process, attention should be paid to the pH value of the reaction medium. Since the reaction will generate a small amount of hydrogen chloride, it will make the solution acidic. The ideal pH value should be maintained at 3-4, which is the optimal acid range for the reaction of phosgene and amine to generate isocyanate. Too high acidity will lead to side reactions, while too low acidity will lead to incomplete reaction. The hydrogen chloride in the reaction system can be neutralized by adding a small amount of sodium bicarbonate solution or weak base buffer solution to keep the pH value of the reaction solution stable within the weak acid range, but strong base cannot be added, and strong base will produce by-products. Samples are taken during the reaction to check the reaction degree of trimerized phosgene. After the reaction is detected to be nearly complete, the reaction system is naturally cooled to room temperature, and then most of the solvent is evaporated by a rotary evaporator or a pressure reducing device. The reaction solution is mixed with an appropriate amount of cold water or brine to clean impurities, and the water layer is separated from the organic layer using a liquid separation device. The organic phase is dried with anhydrous sodium sulfate and filtered again to remove moisture. Then, it is purified by recrystallization or vacuum distillation. The purified product is placed in a vacuum drying oven at a temperature set between 40°C and 80°C for about 4 to 8 hours, and the product quality is observed to be unchanged. If it no longer changes, it means that the drying is basically complete and it is ready to be taken out.

[0030] The reaction using diphosgene is the same as the reaction using triphosgene. Prepare the raw materials 4-chloro-3-trifluoromethylaniline and dimerized phosgene, and use anhydrous dichloromethane or dimethyl sulfoxide as the solvent to ensure that the solvent is completely anhydrous or the water content is not higher than 0.01%. It is also necessary to use nitrogen to purge the reactor before the reaction to remove the oxygen and moisture in the kettle to ensure an anhydrous and oxygen-free environment. Dissolve 1mol 4-chloro-3-trifluoromethylaniline in the solvent, use a stirrer to make the solution uniform, and try not to heat it during this period. Dissolve 1mol-1.1mol of diphosgene and then slowly add it to the solution using a dropping funnel or other dropper, and reduce the system temperature to 0°C to 5°C, preferably slowly dripping it into the reactor within 30-60 minutes. Control the uniformity of the solution while stirring, and keep it stable at low temperature. After completing the addition of diphosgene, gradually raise the temperature of the reaction system to 20°C to 30°C, and keep stirring at this temperature to ensure that the reaction is completely uniform. Hydrogen chloride will be produced during the reaction, which will reduce the pH value of the reaction system. The ideal pH value should be maintained at 3-4 to ensure smooth reaction. If the pH value of the reaction solution drops too much, a small amount of sodium bicarbonate solution or weak base buffer solution can be gradually added to control the pH value to avoid the reaction solution being too acidic. Phosgene will also be released during the reaction, and an absorption device must be prepared to treat these gases before the reaction. Taking a sample to detect the conversion situation can tell whether the reaction is over. After the reaction is over, the reaction system is cooled to room temperature and then the solution is treated. The reaction solution is transferred to a separatory funnel and an appropriate amount of cold water is added to extract impurities. The pH should be controlled at 3-5 during water washing. Continue to use sodium sulfate to dry the organic phase solution to remove residual water in the organic solvent. After drying, the solution is filtered to remove sodium sulfate and other insolubles. Use a rotary evaporator to evaporate the organic solvent to obtain a crude product of 4-chloro-3-trifluoromethylphenyl isocyanate, and continue to use recrystallization or vacuum distillation to purify it. Put the purified product into a vacuum drying oven or other drying oven. The temperature can be set within 40°C~80°C, and the time is 4 hours to 8 hours. Observe the change in product quality. If the quality does not change, it means that the drying is basically completed and it can be prepared to be taken out.

[0031] The principle of using phosgene to react with diphosgene and triphosgene is basically the same. Prepare the raw materials: 4-chloro-3-trifluoromethylaniline and phosgene, and the solvent is anhydrous dichloromethane, dimethyl sulfoxide, etc. Before the reaction, the reaction system is also kept in an anhydrous and oxygen-free environment. Before the reaction, it is necessary to purge the reactor with nitrogen to make the reaction system anhydrous and oxygen-free. Dissolve 1 mol of 4-chloro-3-trifluoromethylaniline in a solvent, stir to dissolve it, and then connect the reactor through a gas guide device to ensure the speed of phosgene introduction and ensure that the gas can fully contact the reaction liquid. Pay special attention to the air tightness and strength of the reactor and the gas guide device to ensure the safety of production work. When introducing phosgene, ensure that the reaction system is at a low temperature to avoid premature reaction. The speed of introducing phosgene is completed within 30 minutes to 60 minutes. After that, the reaction system is slowly heated to low medium temperature to medium temperature to accelerate the reaction. Hydrogen chloride will rise during the reaction. During the reaction, a tail gas treatment device needs to be used to absorb hydrogen chloride into the absorption system. Since the acid produced by the reaction system will affect the pH value of the reaction system, the pH value of the reaction system needs to be controlled at about 3~4. During the reaction, stirring is continued to ensure full reaction. During the reaction, the progress of the reaction and the physical changes in the reaction system are detected. After the reaction is completed, the reaction system is cooled to room temperature, the reaction solution is poured into cold water, and a separatory funnel or other separatory equipment is used to extract impurities. The organic phase of the reaction system is separated from the water, and then the organic phase is dried with anhydrous sodium sulfate to remove the moisture therein. After drying, it is filtered to filter the solid desiccant therein, and then the solvent is evaporated to remove most of the solvent, and then purified by recrystallization. After that, the purified product is placed in a vacuum drying oven or a drying oven for drying treatment, and the temperature is set at about 40°C-80°C. The time is about 4 to 8 hours until the quality of the product no longer changes and the product is ready to be taken out to obtain the product.

[0032] Finally, 4-chloro-3-trifluoromethylaniline isocyanate is reacted with the previous 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide to obtain regorafenib. This is an addition reaction, an addition reaction between isocyanate and amine compounds. The amino group attacks the isocyanate by nucleophilic attack to form an unstable intermediate, and then a proton transfer occurs to form a urea structure. The solvent is selected to be an inert organic solvent, dichloromethane, acetonitrile, N,N-dimethylformamide, a solvent that can dissolve the reactants and maintain stability, and is relatively stable to isocyanate and amine compounds. The molar ratio of the raw materials is 1:1 mol~1:1.2 mol, and the reaction is carried out at room temperature to a slight temperature rise of 30~40°C. Excessive temperature will cause the side reaction isocyanate to decompose or cross-linking reaction to occur. The whole reaction is controlled to be carried out under anhydrous and oxygen-free conditions to prevent isocyanate from reacting with water. Avoiding these factors can obtain high purity. 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide is dissolved in a solvent. In another container, 4-chloro-3-trifluoromethylphenyl isocyanate is also dissolved in the same solvent to control the concentration. Under stirring, the raw material solution is slowly added dropwise to the raw material solution containing 2. The speed should be controlled during the dropping process to avoid local excessive reaction. Isocyanate reacts with amino to form a urea structure. The reaction process generates a small amount of heat, so it is necessary to control the temperature at 30~40°C. The detection reaction is carried out, and sampling is taken to check the conversion of the reactants. After the reaction is basically completed, the heating and stirring are turned off and then naturally cooled to room temperature. After that, the reaction solution is continued to be poured into ice water to precipitate a solid product. The product is collected by suction filtration or centrifugation. The product is washed with cold ethanol or cold ether to remove unreacted raw materials or by-products. Recrystallize the washed crude product, then prepare a vacuum drying oven or drying oven and put it in. Heat the temperature to about 40 to 80 degrees Celsius (not too high). Dry for 4 to 8 hours until the mass of regorafenib no longer changes and you can take it out to get the product. You can then process the drug according to your needs.

[0033] The inventor has fully described the reaction equation and basic technical field of the invention in the above description to facilitate the review. The inventor intends to develop the technology of the invention. The optimization and changes made by the inventor without departing from the basic principles and basic features of the invention are within the scope of protection.

Claims

1. A comprehensive, efficient and low-cost synthesis of the anticancer drug regorafenib, which is applied to the fields of anticancer drugs and chemical industry. The inventor uses 2-amino-4-chloropyridine C5H5CIN2 and formic acid HCOOH for amidation reaction or uses 4-chloro-2-pyridinecarboxylic acid and ammonia NH3 for amidation reaction to obtain the intermediate (1) 2-formamido-4-chloropyridine CóH5CIN2O, and then uses the intermediate (1) 2-formamido-4-chloropyridine C6H5CIN2O and a methyl reagent (the methylation reagent includes: Dimethyl sulfate (CH3O)2SO2, dimethyl carbonate (CH3O)2CO, methyl iodide CH3I (or base) are reacted in N-methylation reaction to obtain intermediate (2) 4-chloro-N-methylpyridine-2-carboxamide C7H7CIN2O, and then intermediate (2) 4-chloro-N-methylpyridine-2-carboxamide C7H7CIN2O is used to react with 4-amino-3-fluorophenol C6H6FNO to obtain intermediate (3) 4-(4-amino-3-fluorophenoxy)- N-methylpyridine-2-carboxamide C13H12FN3O2, and then the intermediate (3) 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide C13H12FN3O2 is used to react with 4-chloro-3-trifluoromethylphenylisocyanate C8H3CIF3NO to obtain the final product 4-[4-{4-chloro-3-(trifluoromethyl)phenyl}carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide. (Regorafenib C21H15F4N4O3CI).

2. The synthesis characteristic of 4-amino-3-fluorophenol as described in claim 1 is that 3-fluorophenol and mixed acid are used for nitration to obtain 3-fluoro-4-nitrophenol, and its basic equation is: C6H4FOH+HNO3→C6H3FNO2OH+H2O, and then 3-fluoro-4-nitrophenol is further reduced to reduce the nitro group to the amino group by reduction reaction, and its basic equation is: C6H4FNO3+3Fe+6HCl→C6H6FNO+3FeCI2+2H2O.

3. The synthesis characteristic of 4-chloro-3-trifluoromethylphenyl isocyanate as claimed in claim 1 is that 3-trifluoromethylaniline is first reacted with an acetylating agent (the agent includes acetyl chloride and acetic anhydride) to protect the amino group so that the subsequent reaction is more selective to obtain N-acetyl-3-trifluoromethylaniline, and its basic reaction equation is: C7H4F3NH2+CH3COCI→C9H8F3NO+HCI, C7H4F3NH2+(CH3CO)2O→C9H8F3NO+CH3COOH. The obtained N-acetyl-3-trifluoromethylaniline is reacted with a chlorinating agent (the chlorinating agent includes N-chlorosuccinimide and chlorine (Lewis acid catalysis)) to obtain N-acetyl-4-chloro-3-trifluoromethylaniline, and the basic reaction equation is: C9H8F3NO+CI2→C7H3F3CINHC(O)CH3+HCl, C9H8F3NO+C4H4NO2CI→C7H3F3CINHC(O)CH3+C4H5NO2. The obtained N-acetyl-4-chloro-3-trifluoromethylaniline is hydrolyzed with alkaline (sodium hydroxide, potassium hydroxide) or acid (hydrochloric acid, sulfuric acid) to restore the amino group to obtain 4-chloro-3-trifluoromethylaniline. The basic reaction equation of its alkaline hydrolysis is: C7H3F3CINHC(O)CH3+NaOH→C7H3F3CINH2+CH3COONa, C7H3F3CINHC(O)CH3+KOH→C7H3F3CINH2+CH3COOK. The basic reaction equation of its acidic hydrolysis is: C7H3F3CINHC(O)CH3+H2O→C7H3F3CINH2+CH3COOH, where (the acid H+ plays a role in catalyzing the hydrolysis). The obtained 4-chloro-3-trifluoromethylaniline is reacted with phosgene, diphosgene, or triphosgene to convert the amino group therein into isocyanate to obtain 4-chloro-3-trifluoromethylphenyl isocyanate, and its basic reaction equation is: C7H5CIF3N+COCI2→C8H3CIF3NO+2HCl, C7H5CIF3N+C2CI4O2→C8H3CIF3NO+COCI2+2HCl, C7H5CIF3N+C3CI6O3→C8H3CIF3NO+2COCI2+2HCl.

4. The basic equation for the reaction of 2-amino-4-chloropyridine as claimed in claim 1 with formic acid or the amidation reaction of 4-chloro-2-pyridinecarboxylic acid with ammonia to obtain the intermediate 2-formamido-4-chloropyridine CóH5CIN2O is: C5H5CIN2+HCOOH→C6H5CIN2O+H2O, and the latter is C6H4CINO2+NH3→C6H5CIN2O+H2O.

5. The 2-formamido-4-chloropyridine and 2-formamide-4-chloropyridine C6H5CIN2O as claimed in claim 1 and a methyl reagent (the methyl reagent comprises: Dimethyl sulfate (CH3O)2SO2, dimethyl carbonate (CH3O)2CO, iodomethane CH3I (or base)) N-methylation reaction is carried out to obtain the intermediate (2) 4-chloro-N-methylpyridine-2-carboxamide C7H7CIN2O. The basic reaction mode is: C6H5CIN2O+CH3I C7H7CIN2O+HI. If a strong base is used to participate in the reaction, the basic chemical equation is: C6H5CIN2O+CH3I+NaOH→C7H7CIN2O+Nal+H2O, C6H5CIN2O+CH3I+KОН→C7H7CIN2O+KI+H2O, C6H5CIN2O+(CH3O)2CO→C7H7CIN2O+CO2↑+CH3OH, C6H5CIN2O+(CH3O)2SO2 C7H7CIN2O+CH3HSO4. This is a very typical N-methylation reaction.

6. The 4-chloro-N-methylpyridine-2-carboxamide as described in claim 1 is reacted with 4-amino-3-fluorophenol to synthesize the intermediate (3) 4-(4-amino-3-fluorophenoxy)N-methylpyridine-2-carboxamide C13H12FN3O2, and its basic reaction equation is: C7H7CIN2O+C6H6FNO→C13H12FN3O2+HCl↑.

7. The intermediate (3) 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide as described in claim 1 reacts with 4-chloro-3-trifluoromethylphenyl isocyanate to obtain regorafenib, 4-[4-{4-chloro-3-(trifluoromethyl)phenyl}carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide, the basic chemical reaction equation is: C13H12FN3O2+C8H3CIF3NO→C21H15F4N4O3CI, which is a typical nucleophilic addition reaction in which -N=C=O isocyanate undergoes a nucleophilic addition reaction with the amino group to finally obtain regorafenib.