CN111592499A - Preparation method of Favipiravir - Google Patents
Preparation method of Favipiravir Download PDFInfo
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Abstract
The invention relates to a preparation method of Favipiravir. The preparation method comprises the following steps: dissolving 6-bromo-3-hydroxypyrazine-2-formamide in a first solvent, adding a first fluorinating agent, and stirring for reaction to prepare 6-bromo-3-fluoropyrazine-2-formamide; dissolving the 6-bromo-3-fluoropyrazine-2-formamide, a second fluorinating agent and a catalyst in a second solvent, and heating for reaction to prepare 6-fluoro-3-fluoropyrazine-2-formamide; and (3) carrying out hydroxyl substitution on the 6-fluoro-3-fluoropyrazine-2-formamide to prepare the Piperavir. In the preparation method of the Lavipiravir, the reaction operation is simple, convenient and safe, the three wastes are less, the synthetic route is green and environment-friendly, and the prepared Lavipiravir is high in yield, stable and low in production cost, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of Favipiravir.
Background
Favipiravir, chemical name: the 6-fluoro-3-hydroxypyrazine-2-formamide is mainly used for treating novel or reoccurrent influenza of adults, has a good treatment effect on influenza viruses, and also has a good curative effect on bunyaviruses, yellow fever viruses, west nile viruses, arenaviruses and the like. The structural formula is as follows:
at present, in the reports of related favipiravir synthesis, the synthetic route is mainly as follows:
route one:
the above process is widely used industrially, wherein 3, 6-difluoro-2-cyanopyrazine is a key intermediate, however, the common synthetic route of 3, 6-difluoro-2-cyano is:
in the process, a large amount of phosphorus-containing wastewater and highly concentrated organic wastewater can be produced, great environmental protection pressure is brought to industrial production, and meanwhile, in the production of the 3, 6-difluoro-2-cyanopyrazine, the intermediate 3, 6-dichloro-2-cyanopyrazine has strong sensitization to human bodies and also brings great pressure to production operation.
And a second route:
the method is characterized in that 3-amino-2-pyrazinecarboxylic acid is used as a starting material and subjected to six steps of hydroxylation, esterification, amination, nitration, reduction and fluorination to prepare a target compound, the reaction steps of the method are long, the solubility of 6-nitro-3-hydroxy-2-pyrazinamide in a common organic solvent is limited, the 6-nitro-3-hydroxy-2-pyrazinamide is difficult to reduce into an amino compound, the yield is low, in addition, in the synthesis method, an expensive palladium reagent is used, the cost is high, and the corrosion of the final step by using hydrofluoric acid is strong.
And a third route:
the method takes 6-bromo-3-aminopyrazine-2-carboxylic acid as a raw material, and the Favipiravir is obtained through esterification, diazotization hydrolysis reaction, hydroxyl protection, fluorination, deprotection and ammoniation. The reaction steps of the route are longer, the Pd catalyst is used for deprotection, and the cost is higher.
In conclusion, the application of the existing synthetic route of the Favipiravir in industrial production has disadvantages and needs to be further improved.
Disclosure of Invention
Based on the above, the invention provides a preparation method of Favipiravir, the Favipiravir is prepared by adopting a new synthesis route, in the preparation method of Favipiravir, the reaction operation is simple, convenient and safe, the three wastes are less, the synthesis route is green and environment-friendly, the yield of the prepared Favipiravir is higher, and the method is stable, low in production cost and suitable for industrial production.
The technical scheme of the invention is as follows:
a preparation method of Favipiravir comprises the following steps:
dissolving 6-bromo-3-hydroxypyrazine-2-formamide in a first solvent, adding a first fluorinating agent, and stirring for reaction to prepare 6-bromo-3-fluoropyrazine-2-formamide;
dissolving the 6-bromo-3-fluoropyrazine-2-formamide, a second fluorinating agent and a catalyst in a second solvent, and heating for reaction to prepare 6-fluoro-3-fluoropyrazine-2-formamide;
and (3) carrying out hydroxyl substitution on the 6-fluoro-3-fluoropyrazine-2-formamide to prepare the Piperavir.
In some preferred embodiments, the first fluorinating agent is selected from one or more of diethylaminosulfur trifluoride, sulfur tetrafluoride/morpholine trifluoride and [ bis (2-methoxyethyl) amine ] sulfur trifluoride.
In some preferred embodiments, the second fluorinating agent is potassium fluoride.
In some preferred embodiments, the first solvent is selected from dichloromethane.
In some preferred embodiments, the second solvent is toluene.
In some preferred embodiments, the catalyst is 18-crown-6.
In some preferred embodiments, the molar ratio of the 6-bromo-3-hydroxypyrazine-2-carboxamide to the first fluorinating agent is 1 (1-1.2).
In some preferred embodiments, the temperature of the stirring reaction is 0 ℃ to 5 ℃ and the time is 4h to 6 h.
In some preferred embodiments, the molar ratio of the 6-bromo-3-fluoropyrazine-2-carboxamide to the second fluorinating agent is 1: (1.8-2.2).
In some preferred embodiments, the heating reaction is carried out at a temperature of 100 ℃ to 110 ℃ for a time of 15h to 25 h.
In some preferred embodiments, the step of hydroxyl substitution comprises:
mixing the 6-fluoro-3-fluoropyrazine-2-formamide, the alkaline substance and the second solvent, heating to 50-60 ℃, and reacting for 7-9 h.
In some preferred embodiments, the alkaline substance is selected from one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.
In some preferred embodiments, the second solvent is methanol and water.
Compared with the prior art, the invention has the following beneficial effects:
different from the existing synthetic route, the inventor obtains a new synthetic route of the Favipiravir by long-term experience accumulation and a large number of creative experiments in the field, in the preparation method of the Favipiravir, 6-bromo-3-hydroxypyrazine-2-formamide is used as an initial raw material, 6-fluoro-3-fluoropyrazine-2-formamide is prepared through two fluoro reactions, then hydroxyl substitution is carried out on the 6-fluoro-3-fluoropyrazine-2-formamide to obtain the Favipiravir, no intermediate harmful to a human body exists, reaction conditions are mild, reaction operation is simple, convenient and safe, solvents can be recycled, three wastes are few, the synthetic route is green and environment-friendly, and a large number of experiments prove that the yield of the Favipiravir prepared by the preparation method is high, and the method is stable, low in production cost and suitable for industrial production.
Drawings
FIG. 1 is a liquid chromatogram of a control;
FIG. 2 is a liquid chromatogram of the product of example 1;
FIG. 3 is a carbon spectrum of the product of example 1;
FIG. 4 is a hydrogen spectrum of the product of example 1.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
In the compounds of the invention, when any variable (e.g. R)1，R2Etc.) more than one time in any component, then the definition at each occurrence is independent of the definitions at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds.
In the compounds of the present invention, "substituted" means that the atom in the substituent is substituted with a substituent.
In the compound of the present invention, the "number of reductants" represents the number of atoms among atoms constituting a structural compound (for example, a monocyclic compound, a fused ring compound, a crosslinked compound, a carbocyclic compound, and a heterocyclic compound) in which atoms are bonded in a ring shape. When the ring is substituted with a substituent, the atoms contained in the substituent are not included in the ring-forming atoms. The "number of ring atoms" described below is the same unless otherwise specified. For example, the number of ring atoms of the benzene ring is 6, the number of ring atoms of the naphthalene ring is 10, and the number of ring atoms of the thienyl group is 5.
At present, in the related reports of Favipiravir synthesis, a certain disadvantage still exists in the synthetic route. Unlike the existing synthetic route, the inventor of the application obtains a new synthetic route of Favipiravir through long-term experience accumulation and a large amount of creative experiments in the field.
The specific technical scheme is as follows:
a preparation method of Favipiravir comprises the following steps:
and 3, carrying out hydroxyl substitution on the 6-fluoro-3-fluoropyrazine-2-formamide to prepare the Pilarvir.
It will be appreciated that the synthetic route of the present invention is shown in the following formula:
the preparation method comprises the steps of taking 6-bromo-3-hydroxypyrazine-2-formamide as an initial raw material, preparing 6-fluoro-3-fluoropyrazine-2-formamide through two fluoro reactions, and then carrying out hydroxyl substitution on the 6-fluoro-3-fluoropyrazine-2-formamide to obtain the Favipiravir.
The step 1 is a first fluorination reaction, and the 3-hydroxy group of the pyrazine ring is substituted to obtain a compound 2a, namely 6-bromo-3-fluoropyrazine-2-formamide.
Preferably, the first fluorinating agent is selected from one or more of diethylaminosulfur trifluoride (DAST reagent), sulfur tetrafluoride/morpholine trifluoride and [ bis (2-methoxyethyl) amine ] sulfur trifluoride. More preferably, the first fluorinating agent is a DAST reagent. And (3) dropwise adding the DAST reagent into a solution containing 6-bromo-3-hydroxypyrazine-2-formamide, and stirring for reaction. In some preferred embodiments, the temperature of the stirring reaction is 0 ℃ to 5 ℃ and the time is 4h to 6 h.
Preferably, the first solvent is selected from dichloromethane.
Preferably, the molar ratio of the 6-bromo-3-hydroxypyrazine-2-carboxamide to the first fluorinating agent is 1 (1-1.2).
It is understood that when the plate layer is not developed to the point of the starting material by TLC (thin layer chromatography), the reaction may be stopped. After the reaction is stopped, the method also comprises the step of adding water into the reaction liquid for liquid separation, collecting an organic phase and concentrating to obtain the compound 2 a.
Preferably, after adding water, stirring for 0.4h to 0.6h, and then transferring the material to a separatory funnel.
The product of the fluorination reaction does not need to be purified and can be directly used for the next reaction.
The step 1 is a second fluorination reaction, in which bromine at the 6-position of the pyrazine ring is substituted to obtain a compound 3a, namely 6-fluoro-3-fluoropyrazine-2-formamide.
Preferably, the second fluorinating agent is potassium fluoride; the second solvent is toluene.
6-fluoro-3-fluoropyrazine-2-formamide is heated to react in a toluene/potassium fluoride system, preferably with 18-Crown-6 (18-Crown-6) as a catalyst. The substitution of 6-position bromine of pyrazine ring is facilitated, and in some preferred embodiments, the heating reaction is performed at 100-110 ℃ for 15-25 h.
Preferably, the molar ratio of the 6-bromo-3-fluoropyrazine-2-carboxamide to the second fluorinating agent is 1: (1.8-2.2).
It is understood that when the plate layer is not developed 2a by TLC (thin layer chromatography), the reaction can be stopped. After the reaction is stopped, the method also comprises the step of adding water into the reaction liquid for liquid separation, collecting an organic phase and concentrating to obtain the compound 3 a.
Preferably, after adding water, stirring for 0.4h to 0.6h, and then transferring the material to a separatory funnel.
The product of the fluorination reaction does not need to be purified and can be directly used for the next reaction.
In the step 3, 6-fluoro-3-fluoropyrazine-2-formamide is subjected to hydroxyl substitution, and 6-F of the pyrazine ring is substituted into hydroxyl, so that the Favipiravir is obtained.
In some preferred embodiments, the step of hydroxyl substitution comprises:
mixing the 6-fluoro-3-fluoropyrazine-2-formamide, the alkaline substance and the second solvent, heating to 50-60 ℃, and reacting for 7-9 h.
Preferably, the alkaline substance is selected from one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate, preferably sodium bicarbonate, and the second solvent is methanol and water. The hydroxyl substitution is carried out in aqueous alkali.
It is understood that when the plate layer does not develop the compound 3a as detected by TLC (thin layer chromatography), the reaction can be stopped. And after the reaction is stopped, concentrating the material at 35-55 ℃ to obtain a solvent, adding water into a concentration bottle after the concentration is finished, cooling the material to 0-10 ℃, adjusting the pH value to 3-4 by using 30% hydrochloric acid at the temperature, stirring for 2 hours while maintaining the pH value, filtering, leaching a filter cake with water, performing suction filtration until no effluent liquid exists, and drying the filter cake at 50-60 ℃ under reduced pressure for 10-14 hours to obtain the Lapirovir.
In a preferred embodiment, the synthetic route of the invention is shown in the following formula:
in the preparation method of the Favipiravir, no intermediate harmful to human bodies exists, the reaction condition is mild, the reaction operation is simple, convenient and safe, useful solvents can be recycled, the three wastes are less, the synthetic route is green and environment-friendly, and a large number of experiments prove that the Favipiravir prepared by the preparation method has high yield, stability and low production cost, and is suitable for industrial production.
The following description will be given with reference to specific embodiments. Unless otherwise specified, the raw materials used in the following embodiments may be commercially available. The apparatus used is conventional in the art.
Example 1
The embodiment provides Favipiravir and a preparation method thereof, and the synthetic route and the specific steps are as follows:
1. preparation of Compound 2a
Adding 300ml of dichloromethane and 20g (0.0917mol) of 6-bromo-3-hydroxypyrazine-2-formamide into a 500ml three-necked bottle, cooling the material in the three-necked bottle to 0 ℃ under stirring, dropwise adding 15.5g (0.0963mol) of DAST reagent, maintaining the temperature of the reaction liquid at 0 ℃ after the dropwise adding, stirring for 5 hours, detecting by TLC (thin layer chromatography), stopping the reaction, adding 120ml of process water into the reaction liquid, stirring for 0.5 hour after the adding is finished, transferring the material into a separating funnel, standing for 1 hour, separating out an organic phase, and concentrating to obtain 18.56g of a compound 2a, wherein the mol yield is as follows: 92% and the product obtained is used directly in the next reaction without purification.
2. Preparation of Compound 3a
320ml of toluene, 18.56g (0.0844mol) of Compound 2a, 2g of 18-Crown-6, 9.8g (0.1687mol) of potassium fluoride were added to a 500ml three-necked flask, the temperature of the contents in the three-necked flask was heated to 110 ℃ with stirring and kept at this temperature for 20 hours, TLC was carried out, no Compound 2a was developed in the sheet, the reaction was stopped, 150ml of process water was added to the reaction solution, and after completion of the addition, the mixture was stirred for 0.5 hour, transferred to a separatory funnel, allowed to stand for 1 hour, the organic phase was separated and concentrated to obtain 12.6g of Compound 3a, mol yield: 93.8%, and the obtained product was used in the next reaction without purification.
3. Preparation of Favipiravir
Adding 20ml of process water, 200ml of methanol, 12.6g (0.0792mol) of the compound 3a and 10g (0.1188mol) of sodium bicarbonate into a 500ml three-necked flask, heating the material in the three-necked flask to 50 ℃ under stirring, maintaining the temperature and stirring for 8 hours, stopping the reaction when no compound 3a is developed on a plate layer, maintaining the material temperature at 55 ℃ under stirring to concentrate the methanol, adding 100ml of process water into the concentration flask after the concentration is finished, cooling the material temperature to 0 ℃, maintaining the temperature, adjusting the pH value to 3 by using 30% hydrochloric acid, maintaining the pH value and stirring for 2 hours, filtering, leaching a filter cake by using 30ml of process water, filtering the filter cake until no effluent is produced, drying the filter cake at 50 ℃ under reduced pressure for 1 hour to obtain 11.82g of the Lapirovir, and obtaining the mol yield: 95 percent.
Respectively preparing a reference solution and a sample solution to be detected by using 6-fluoro-3-hydroxypyrazine-2-formamide as a reference and the product obtained in the step 3 as a sample to be detected, and then performing liquid chromatogram characterization, wherein a liquid chromatogram of the reference is shown in figure 1, and a liquid chromatogram of the product obtained in the step 3 is shown in figure 2. And (3) performing nuclear magnetic resonance detection on the product obtained in the step (3), wherein a carbon spectrum spectrogram of the product is shown in fig. 3, and a hydrogen spectrum spectrogram of the product is shown in fig. 4. As can be seen from FIGS. 1-4, Favipiravir was successfully prepared in this example.
Example 2
This example provides a favipiravir and a method for its preparation, which is substantially the same as example 1 except that: the stirring reaction temperature is different, and the synthetic route and the specific steps are as follows:
1. preparation of Compound 2a
Adding 300ml of dichloromethane and 20g (0.0917mol) of 6-bromo-3-hydroxypyrazine-2-formamide into a 500ml three-necked bottle, cooling the material in the three-necked bottle to 20 ℃ under stirring, dropwise adding 15.5g (0.0963mol) of DAST reagent, maintaining the temperature of the reaction liquid at 20 ℃ after the dropwise adding, stirring for 5 hours, detecting by TLC (thin layer chromatography), stopping the reaction, adding 120ml of process water into the reaction liquid, stirring for 0.5 hour after the adding is finished, transferring the material into a separating funnel, standing for 1 hour, separating out an organic phase, and concentrating to obtain 16.15g of a compound 2a, wherein the mol yield is: 80%, and the obtained product is directly used for the next reaction without purification.
2. Preparation of Compound 3a
Adding 320ml of toluene, 18.56g (0.0844mol) of the compound 2a, 2g of 18-Crown-6 and 9.8g (0.1687mol) of potassium fluoride into a 500ml three-necked flask, heating the material in the three-necked flask to 100 ℃ under stirring, maintaining the temperature and stirring for 20 hours, detecting by TLC, stopping the reaction when no compound 2a is developed on the plate layer, adding 150ml of process water into the reaction solution, stirring for 0.5 hour after the addition is finished, transferring the material into a separating funnel, standing for 1 hour, separating out an organic phase and concentrating to obtain 12.6g of the compound 3a, wherein the mol yield is as follows: 93.8%, and the obtained product was used in the next reaction without purification.
3. Preparation of Favipiravir
Adding 20ml of process water, 200ml of methanol, 12.6g (0.0792mol) of the compound 3a and 10g (0.1188mol) of sodium bicarbonate into a 500ml three-necked flask, heating the material in the three-necked flask to 50 ℃ under stirring, maintaining the temperature and stirring for 8 hours, stopping the reaction when no compound 3a is developed on a plate layer, maintaining the material temperature at 55 ℃ under stirring to concentrate the methanol, adding 100ml of process water into the concentration flask after the concentration is finished, cooling the material temperature to 0 ℃, maintaining the temperature, adjusting the pH value to 3 by using 30% hydrochloric acid, maintaining the pH value and stirring for 2 hours, filtering, leaching a filter cake by using 30ml of process water, filtering the filter cake until no effluent is produced, drying the filter cake at 50 ℃ under reduced pressure for 1 hour to obtain 11.82g of the Lapirovir, and obtaining the mol yield: 95 percent.
Example 3
This example provides a favipiravir and a method for its preparation, which is substantially the same as example 1 except that: the heating reaction temperature is different, and the synthesis route and the specific steps are as follows:
1. preparation of Compound 2a
Adding 300ml of dichloromethane and 20g (0.0917mol) of 6-bromo-3-hydroxypyrazine-2-formamide into a 500ml three-necked bottle, cooling the material in the three-necked bottle to 0 ℃ under stirring, dropwise adding 15.5g (0.0963mol) of DAST reagent, maintaining the temperature of the reaction liquid at 0 ℃ after the dropwise adding, stirring for 5 hours, detecting by TLC (thin layer chromatography), stopping the reaction, adding 120ml of process water into the reaction liquid, stirring for 0.5 hour after the adding is finished, transferring the material into a separating funnel, standing for 1 hour, separating out an organic phase, and concentrating to obtain 18.56g of a compound 2a, wherein the mol yield is as follows: 92% and the product obtained is used directly in the next reaction without purification.
2. Preparation of Compound 3a
Adding 320ml of toluene, 18.56g (0.0844mol) of the compound 2a, 2g of 18-Crown-6 and 9.8g (0.1687mol) of potassium fluoride into a 500ml three-necked flask, heating the material in the three-necked flask to 90 ℃ under stirring, maintaining the temperature and stirring for 20 hours, detecting by TLC, stopping the reaction when the compound 2a cannot be developed on the plate layer, adding 150ml of process water into the reaction solution, stirring for 0.5 hour after the addition is finished, transferring the material into a separating funnel, standing for 1 hour, separating an organic phase and concentrating to obtain 10.2g of the compound 3a, wherein the mol yield is as follows: 76%, and the obtained product is directly used for the next reaction without purification.
3. Preparation of Favipiravir
Adding 20ml of process water, 200ml of methanol, 12.6g (0.0792mol) of the compound 3a and 10g (0.1188mol) of sodium bicarbonate into a 500ml three-necked flask, heating the material in the three-necked flask to 50 ℃ under stirring, maintaining the temperature and stirring for 8 hours, stopping the reaction when no compound 3a is developed on a plate layer, maintaining the material temperature at 55 ℃ under stirring to concentrate the methanol, adding 100ml of process water into the concentration flask after the concentration is finished, cooling the material temperature to 0 ℃, maintaining the temperature, adjusting the pH value to 3 by using 30% hydrochloric acid, maintaining the pH value and stirring for 2 hours, filtering, leaching a filter cake by using 30ml of process water, filtering the filter cake until no effluent is produced, drying the filter cake at 50 ℃ under reduced pressure for 1 hour to obtain 11.82g of the Lapirovir, and obtaining the mol yield: 95 percent.
Example 4
This example provides a favipiravir and a method for its preparation, which is substantially the same as example 1 except that: the molar ratio of 6-bromo-3-hydroxypyrazine-2-formamide to DAST is different, and the synthetic route and the specific steps are as follows:
1. preparation of Compound 2a
Adding 300ml of dichloromethane and 20g (0.0917mol) of 6-bromo-3-hydroxypyrazine-2-formamide into a 500ml three-necked bottle, cooling the materials in the three-necked bottle to 0 ℃ under stirring, dropwise adding 14.8g (0.0917mol) of DAST reagent, maintaining the temperature of the reaction solution at 0 ℃ and stirring for 5 hours after the dropwise adding is finished, detecting by TLC (thin layer chromatography), stopping the reaction, adding 120ml of process water into the reaction solution, stirring for 0.5 hour after the adding is finished, transferring the materials into a separating funnel, standing for 1 hour, separating out an organic phase and concentrating to obtain 16.3g of a compound 2a, the mol yield: 80.3%, and the obtained product is directly used for the next reaction without purification.
2. Preparation of Compound 3a
Adding 320ml of toluene, 18.56g (0.0844mol) of the compound 2a, 2g of 18-Crown-6 and 9.8g (0.1687mol) of potassium fluoride into a 500ml three-necked flask, heating the material in the three-necked flask to 100 ℃ with stirring, maintaining the temperature and stirring for 20 hours, detecting by TLC, stopping the reaction when the compound 2a cannot be developed on the plate layer, adding 150ml of process water into the reaction solution, stirring for 0.5 hour after the addition is finished, transferring the material into a separating funnel, standing for 1 hour, separating an organic phase and concentrating to obtain 12.6g of the compound 3a, wherein the mol yield is as follows: 93.8%, and the obtained product was used in the next reaction without purification.
3. Preparation of Favipiravir
Adding 20ml of process water, 200ml of methanol, 12.6g (0.0792mol) of the compound 3a and 10g (0.1188mol) of sodium bicarbonate into a 500ml three-necked flask, heating the material in the three-necked flask to 50 ℃ under stirring, maintaining the temperature and stirring for 8 hours, stopping the reaction when no compound 3a is developed on a plate layer, maintaining the material temperature at 55 ℃ under stirring to concentrate the methanol, adding 100ml of process water into the concentration flask after the concentration is finished, cooling the material temperature to 0 ℃, maintaining the temperature, adjusting the pH value to 3 by using 30% hydrochloric acid, maintaining the pH value and stirring for 2 hours, filtering, leaching a filter cake by using 30ml of process water, filtering the filter cake until no effluent is produced, drying the filter cake at 50 ℃ under reduced pressure for 1 hour to obtain 11.82g of the Lapirovir, and obtaining the mol yield: 95 percent.
Example 5
This example provides a favipiravir and a method for its preparation, which is substantially the same as example 1 except that: the first fluorinating agent is different, and the synthesis route and the specific steps are as follows:
1. preparation of Compound 2a
Adding 300ml of dichloromethane and 20g (0.0917mol) of 6-bromo-3-hydroxypyrazine-2-formamide into a 500ml three-necked bottle, cooling the materials in the three-necked bottle to 0 ℃ under stirring, dropwise adding 10.4g (0.0963mol) of sulfur tetrafluoride/sulfur trifluoride morpholine, maintaining the temperature of the reaction solution at 0 ℃ after the dropwise adding, stirring for 5 hours, detecting by TLC (thin layer chromatography), stopping the reaction, adding 120ml of process water into the reaction solution, stirring for 0.5 hour after the adding is finished, transferring the materials into a separating funnel, standing for 1 hour, separating out an organic phase, and concentrating to obtain 12g of a compound 2a, wherein the mol yield is: 59.48%, and the obtained product is directly used for the next reaction without purification.
2. Preparation of Compound 3a
Adding 320ml of toluene, 18.56g (0.0844mol) of the compound 2a, 2g of 18-Crown-6 and 9.8g (0.1687mol) of potassium fluoride into a 500ml three-necked flask, heating the material in the three-necked flask to 100 ℃ with stirring, maintaining the temperature and stirring for 20 hours, detecting by TLC, stopping the reaction when the compound 2a cannot be developed on the plate layer, adding 150ml of process water into the reaction solution, stirring for 0.5 hour after the addition is finished, transferring the material into a separating funnel, standing for 1 hour, separating an organic phase and concentrating to obtain 12.6g of the compound 3a, wherein the mol yield is as follows: 93.8%, and the obtained product was used in the next reaction without purification.
3. Preparation of Favipiravir
Adding 20ml of process water, 200ml of methanol, 12.6g (0.0792mol) of the compound 3a and 10g (0.1188mol) of sodium bicarbonate into a 500ml three-necked flask, heating the material in the three-necked flask to 50 ℃ under stirring, maintaining the temperature and stirring for 8 hours, stopping the reaction when no compound 3a is developed on a plate layer, maintaining the material temperature at 55 ℃ under stirring to concentrate the methanol, adding 100ml of process water into the concentration flask after the concentration is finished, cooling the material temperature to 0 ℃, maintaining the temperature, adjusting the pH value to 3 by using 30% hydrochloric acid, maintaining the pH value and stirring for 2 hours, filtering, leaching a filter cake by using 30ml of process water, filtering the filter cake until no effluent is produced, drying the filter cake at 50 ℃ under reduced pressure for 1 hour to obtain 11.82g of the Lapirovir, and obtaining the mol yield: 95 percent.
Example 6
This example provides a favipiravir and a method for its preparation, which is substantially the same as example 1 except that: the first fluorinating agent is different, and the synthesis route and the specific steps are as follows:
1. preparation of Compound 2a
Adding 300ml of dichloromethane and 20g (0.0917mol) of 6-bromo-3-hydroxypyrazine-2-formamide into a 500ml three-necked flask, cooling the material in the three-necked flask to 0 ℃ under stirring, dropwise adding 21.3g (0.0963mol) of [ bis (2-methoxyethyl) amine ] sulfur trifluoride, maintaining the temperature of the reaction solution at 0 ℃ after the dropwise addition is finished, stirring for 5 hours, detecting by TLC, stopping the reaction after the plate layer does not develop a raw material point, adding 120ml of process water into the reaction solution, stirring for 0.5 hour after the addition is finished, transferring the material into a separating funnel, standing for 1 hour, separating an organic phase, and concentrating to obtain 10.5g of compound 2a, wherein the mol yield is as follows: 52% and the product obtained was used in the next reaction without purification.
2. Preparation of Compound 3a
Adding 320ml of toluene, 18.56g (0.0844mol) of the compound 2a, 2g of 18-Crown-6 and 9.8g (0.1687mol) of potassium fluoride into a 500ml three-necked flask, heating the material in the three-necked flask to 100 ℃ with stirring, maintaining the temperature and stirring for 20 hours, detecting by TLC, stopping the reaction when the compound 2a cannot be developed on the plate layer, adding 150ml of process water into the reaction solution, stirring for 0.5 hour after the addition is finished, transferring the material into a separating funnel, standing for 1 hour, separating an organic phase and concentrating to obtain 12.6g of the compound 3a, wherein the mol yield is as follows: 93.8%, and the obtained product was used in the next reaction without purification.
3. Preparation of Favipiravir
Adding 20ml of process water, 200ml of methanol, 12.6g (0.0792mol) of the compound 3a and 10g (0.1188mol) of sodium bicarbonate into a 500ml three-necked flask, heating the material in the three-necked flask to 50 ℃ under stirring, maintaining the temperature and stirring for 8 hours, stopping the reaction when no compound 3a is developed on a plate layer, maintaining the material temperature at 55 ℃ under stirring to concentrate the methanol, adding 100ml of process water into the concentration flask after the concentration is finished, cooling the material temperature to 0 ℃, maintaining the temperature, adjusting the pH value to 3 by using 30% hydrochloric acid, maintaining the pH value and stirring for 2 hours, filtering, leaching a filter cake by using 30ml of process water, filtering the filter cake until no effluent is produced, drying the filter cake at 50 ℃ under reduced pressure for 1 hour to obtain 11.82g of the Lapirovir, and obtaining the mol yield: 95 percent.
Comparative example 1
This comparative example provides favipiravir and a process for its preparation, essentially the same as example 1, except that: adopting fluorinating agent to directly substitute Br for F, the synthetic route and the specific steps are as follows:
1. preparation of Compound 2A
Adding 320ml of toluene, 18.4g (0.0844mol) of 6-bromo-3-hydroxypyrazine-2-formamide, 2g of 18-Crown-6 and 9.8g (0.1687mol) of potassium fluoride into a 500ml three-necked flask, heating the material in the three-necked flask to 100 ℃ under stirring, maintaining the temperature and stirring for 20 hours, detecting by TLC, stopping the reaction when no compound 2A is developed on a plate layer, adding 150ml of process water into the reaction liquid, stirring for 0.5 hour after the addition is finished, transferring the material into a separating funnel, standing for 1 hour, separating an organic phase and concentrating to obtain 2.3g of compound 2A, wherein the mol yield is as follows: 15.96 percent.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. The preparation method of Favipiravir is characterized by comprising the following steps:
dissolving 6-bromo-3-hydroxypyrazine-2-formamide in a first solvent, adding a first fluorinating agent, and stirring for reaction to prepare 6-bromo-3-fluoropyrazine-2-formamide;
dissolving the 6-bromo-3-fluoropyrazine-2-formamide, a second fluorinating agent and a catalyst in a second solvent, and heating for reaction to prepare 6-fluoro-3-fluoropyrazine-2-formamide;
and (3) carrying out hydroxyl substitution on the 6-fluoro-3-fluoropyrazine-2-formamide to prepare the Piperavir.
2. The method for preparing fapirovir according to claim 1, wherein the first fluorinating agent is one or more selected from the group consisting of diethylaminosulfur trifluoride, sulfur tetrafluoride/morpholine trifluoride and [ bis (2-methoxyethyl) amine ] sulfur trifluoride.
3. The process for preparing fapirovir according to claim 1, wherein the second fluorinating agent is potassium fluoride.
4. The process for preparing fapirovir according to claim 1, wherein the first solvent is dichloromethane.
5. The process for preparing fapirovir according to claim 1, wherein the second solvent is toluene.
6. The process for preparing fapirovir according to claim 1 wherein the catalyst is 18-crown-6.
7. The process for preparing fapirovir according to any of claims 1 to 6, wherein the molar ratio of the 6-bromo-3-hydroxypyrazine-2-carboxamide to the first fluorinating agent is 1 (1-1.2); and/or the presence of a catalyst in the reaction mixture,
the molar ratio of the 6-bromo-3-fluoropyrazine-2-carboxamide to the second fluorinating agent is 1: (1.8-2.2).
8. The preparation method of favipiravir according to claim 7, wherein the temperature of the stirring reaction is 0 ℃ to 50 ℃ and the time is 4h to 6 h; and/or the presence of a catalyst in the reaction mixture,
the heating reaction is carried out at the temperature of 100-110 ℃ for 15-25 h.
9. The process for preparing fapirovir according to any of claims 1 to 6 wherein the step of hydroxy substitution comprises:
mixing the 6-fluoro-3-fluoropyrazine-2-formamide, the alkaline substance and the third solvent, heating to 50-60 ℃, and reacting for 7-9 h.
10. The preparation method of fapirovir according to claim 9, wherein the alkaline substance is selected from one or more of sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate; and/or the presence of a catalyst in the reaction mixture,
the third solvent is methanol and water.
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