New process for synthesizing favipiravir

Abstract

Provided is a new process for synthesizing favipiravir, which comprises: step one: dissolving compound I, adjusting the pH of the solution, adding aqueous ammonia, and stirring the mixture for reaction to obtain compound II; step two: dissolving compound II, adjusting the pH of the solution, adding aqueous ammonia, and heating the mixture for reaction to obtain compound III; and step three: dissolving compound III in an organic solvent, adding an alkali reagent, adding compound IV, stirring the mixture for reaction at room temperature for conversion into compound V, adding silver chloride as a catalyst to the solution after compound III is completely consumed as detected by HPLC, continuing to stir the mixture for reaction at room temperature for 6-8 h, and upon completion of the reaction, separating the product to obtain compound VI. Favipiravir is prepared by means of reactions using simple and easily available reagents, which effectively reduces production costs. The reaction route is simple, with high yield, good selectivity in each step, few side reactions and simple product post-processing. With simple steps and ease of operation, the process is suitable for industrial scale-up production.

Description

New process for synthesizing favipiravir TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine synthesis, in particular to a new process for synthesizing favipiravir. BACKGROUND

[0002] Favipiravir (AVIGAN) is an RNA-dependent RNA polymerase (RdRp) inhibitor developed by Japan Fukuyama Chemical Co., Ltd. It has important practical significance for human response to possible severe viral infectious diseases and possible biological terrorist attacks.

[0003] Favipiravir (T705), also known as 6-fluoro-3-hydroxypyrazine-2-carboxamide, is an RNA polymerase inhibitor developed by Japan Fukuyama Chemical Co., Ltd. and approved for marketing in 2014. It is a broad-spectrum antiviral drug. Favipiravir selectively destroys the RNA replication and transcription process of viruses in infected cells, thereby stopping the infection cycle. It has obvious effect on the treatment of common influenza, H1N1, Ebola and other viruses.

[0004] Currently, there are mainly the following routes for synthesizing favipiravir at home and abroad:

[0005] Patent WO2010 / 087117 reports that favipiravir is obtained from amino malonic acid ethyl ester hydrochloride as a starting material through 7-step reaction, and the key intermediate 3,6-dichloro-2-cyanopyrazine is obtained through four-step reaction, and the total yield of the four steps is about 19.5%. The reaction route is as follows:

[0006] Route 1

[0007]

[0008] Patent WO01 / 60834 reports that favipiravir is obtained from hydroxyl amide as a starting material through 5-step synthesis, but the raw material 3-hydroxypyrazine-2-amide also needs to be prepared through two-step reaction, so the key intermediate 3,6-dichloro-2-cyanopyrazine also needs to be obtained through four-step reaction, and the total yield of the four steps is about 20.33%. The reaction route is as follows:

[0009] Route 2

[0010]

[0011] Patent CN106866553 reports that 3-amino pyrazine-2-carboxylic acid is used as a starting material, and favipiravir is obtained through 6-step reaction

[0012] The fapiavir is obtained, and 3,6-dichloro-2-cyanopyrazine is obtained through five reactions with a total yield of about 39.88%, and the reaction route is as follows:

[0013] Route three

[0014]

[0015] The above synthesis routes have more steps, complex operation, more by-products, low yield and high production cost, and are difficult to meet the needs of industrial production. SUMMARY

[0016] In view of the above problems, the present application is realized through the following technical scheme.

[0017] A new process for synthesizing fapiavir, characterized by comprising the following steps:

[0018] In the first step, compound I is dissolved in an ethanol aqueous solution, phosphoric acid monohydrate is added to adjust the pH of the solution, ammonia water is slowly added to the acidic solution, and the reaction is stirred at 35-40 DEG C, and the reaction is monitored by HPLC; after the reaction is completed, the product is separated to obtain compound II;

[0019] In the second step, compound II obtained in the previous step is dissolved in an organic solvent, benzoic acid is added to adjust the pH of the solution, ammonia water is slowly added to the acidic solution, and the reaction is heated at 50-60 DEG C, and the reaction is monitored by HPLC; after the reaction is completed, the product is separated to obtain compound III;

[0020] In the third step, compound III is dissolved in an organic solvent, a base reagent is added, compound IV is added, the reaction is stirred at room temperature, and compound V is obtained; HPLC detection shows that compound III is completely consumed, a catalyst, silver chloride, is added to the solution, and the reaction is continuously stirred at room temperature for 6-8 h; after the reaction is completed, the product is separated to obtain compound VI,

[0021] The specific reaction route is shown as follows:

[0022]

[0023] Further, the solvent in the first step is an ethanol aqueous solution with a concentration of 60-80 wt%.

[0024] Further, the concentration of ammonia water in the first step is 5-8 mol / L, and the concentration of ammonia water in the second step is 15-18 mol%.

[0025] Further, the solvent in the second step is methanol with a concentration of 50-60 wt%.

[0026] Further, the pH of the first reaction solution is adjusted to 4-5, and the pH of the second reaction solution is adjusted to 3.5-4.5.

[0027] Further, the solvent in the third reaction is dichloromethane.

[0028] Further, the base reagent in the third reaction is sodium carbonate, the amount of the base reagent is 5-8 mol% of compound III, and the amount of the used catalyst silver chloride is 3-5 wt% of compound III.

[0029] Further, the molar ratio of ammonia water to compound I in the first reaction is 1.0:1.0-1.1.

[0030] Further, the molar ratio of compound II to ammonia water in the second reaction is 1:1-1.5, preferably 1:1.2.

[0031] Further, the molar ratio of compound IV to compound III in the third reaction is 1:1.

[0032] The present application has the following advantages: 1. The present application uses simple and easily available reagents to prepare favipiravir, which effectively reduces the production cost; 2. The reaction route of the present application is simple, the yield is high, the selectivity of each step is good, the side reaction is less, the product post-treatment is simple, the step is simple and easy to operate, and it is suitable for industrialized large-scale production; 3. The present application provides a new synthesis research idea for the synthesis of favipiravir by using a new process. BRIEF DESCRIPTION OF DRAWINGS

[0033] Fig. 1 is a schematic diagram of the reaction process of route one of the present application;

[0034] Fig. 2 is a schematic diagram of the reaction process of route two of the present application;

[0035] Fig. 3 is a schematic diagram of the reaction process of route three of the present application;

[0036] Fig. 4 is a schematic diagram of the reaction process of the present application. DETAILED DESCRIPTION

[0037] The technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application. Example 1

[0038] The first step reaction, 17.4g (0.1mol) of compound I is dissolved in 200ml of ethanol aqueous solution (60wt%), the solution is adjusted to pH 4-5 by adding phosphoric acid monohydrate, 0.1mol of ammonia water (5mol / L) is slowly added into the acidic solution, the reaction is stirred at 35-40°C, the reaction progress is monitored by HPLC, after the reaction is completed, the reaction is neutralized by adding saturated sodium bicarbonate solution, the solvent is evaporated, 100ml of chloroform and 100ml of saturated sodium chloride solution are added for extraction, the organic phase is separated, the organic phase is washed by 100ml of saturated brine for 2-3 times, the solvent is evaporated, the product is recrystallized by 50ml of toluene, 16.3g of compound II is obtained, the yield is 94.0%, the purity is 98.2%;

[0039] The second step reaction, 17.3g (0.1mol) of compound II is dissolved in 200ml of methanol aqueous solution (50wt%), the solution is adjusted to pH 3.5-4.5 by adding benzoic acid, 0.12mol of ammonia water (15mol / L) is slowly added into the acidic solution, the reaction is heated at 50-60°C, the reaction progress is monitored by HPLC, after the reaction is completed, the reaction is neutralized by adding saturated sodium bicarbonate solution, the solvent is evaporated, 100ml of dichloromethane and 100ml of saturated brine are added for extraction, the organic phase is separated, the organic phase is washed by 100ml of saturated brine for 2-3 times, the solvent is evaporated, the product is recrystallized by 50ml of toluene, 11.0g of compound III is obtained, the yield is 95.7%, the purity is 97.5%;

[0040] The third step reaction, 11.5g (0.1mol) of compound III is dissolved in 200ml of dichloromethane, 0.005mol of sodium carbonate is added as a base reagent, 0.1mol of compound IV is added, the reaction is stirred at room temperature, the conversion of compound III to compound V is detected by HPLC, 0.35g of silver chloride is added as a catalyst, the reaction is continuously stirred at room temperature for 6-8h, after the reaction is completed, the solution is neutralized by adding dilute hydrochloric acid, the solution is washed by saturated brine for 2-3 times, the organic phase is separated, the solvent is evaporated, the product is recrystallized by 60ml of toluene, 14.9g of compound VI is obtained, the yield is 94.9%, the purity is 98.6%; Example 2

[0041] The first step reaction, 17.4g (0.1mol) of compound I is dissolved in 200ml of ethanol aqueous solution (60wt%), phosphoric acid monohydrate is added to adjust the pH of the solution to 4-5, 0.1mol of ammonia water (8mol / L) is slowly added into the acidic solution, the reaction is stirred at 35-40°C, the reaction process is monitored by HPLC, after the reaction is completed, saturated sodium bicarbonate solution is added to neutralize the reaction to neutral, the solvent is evaporated, 100ml of chloroform and 100ml of saturated sodium chloride solution are added for extraction, the organic phase is separated, the organic phase is washed with 100ml of saturated brine for 2-3 times, the solvent is evaporated, the product is recrystallized with 50ml of toluene, 16.3g of compound II is obtained, the yield is 93.5%, and the purity is 97.8%; Example 3

[0042] The first step reaction, 17.4g (0.1mol) of compound I is dissolved in 200ml of ethanol aqueous solution (60wt%), phosphoric acid monohydrate is added to adjust the pH of the solution to 4-5, 0.1mol of ammonia water (8mol / L) is slowly added into the acidic solution, the reaction is stirred at 35-40°C, the reaction process is monitored by HPLC, after the reaction is completed, saturated sodium bicarbonate solution is added to neutralize the reaction to neutral, the solvent is evaporated, 100ml of chloroform and 100ml of saturated sodium chloride solution are added for extraction, the organic phase is separated, the organic phase is washed with 100ml of saturated brine for 2-3 times, the solvent is evaporated, the product is recrystallized with 50ml of toluene, 16.3g of compound II is obtained, the yield is 93.5%, and the purity is 97.8%; Example 4

[0043] The second step reaction, 17.3g (0.1mol) of compound II is dissolved in 200ml of methanol aqueous solution (60wt%), benzoic acid is added to adjust the pH of the solution to 3.5-4.5, 0.12mol of ammonia water (15mol / L) is slowly added into the acidic solution, the reaction is heated at 50-60°C, the reaction process is monitored by HPLC, after the reaction is completed, saturated sodium bicarbonate solution is added to neutralize the reaction to neutral, the solvent is evaporated, 100ml of dichloromethane and 100ml of saturated brine are added for extraction, the organic phase is separated, the organic phase is washed with 100ml of saturated brine for 2-3 times, the solvent is evaporated, the product is recrystallized with 50ml of toluene, 10.9g of compound III is obtained, the yield is 94.8%, and the purity is 97.9%; Example 5

[0044] In the second step, 17.3 g (0.1 mol) of compound II was dissolved in 200 ml of methanol aqueous solution (50 wt%). Benzoic acid was added to adjust the pH of the solution to 3.5–4.5. 0.10 mol of ammonia (15 mol / L) was slowly added to the acidic solution. The reaction was heated at 50–60 °C, and the reaction was monitored by HPLC. After the reaction was completed, saturated sodium bicarbonate solution was added to neutralize the reaction until neutral. The solvent was evaporated, and 100 ml of dichloromethane and 100 ml of saturated brine were added. The organic phase was separated and washed 2–3 times with 100 ml of saturated brine. The solvent was evaporated again, and the product was recrystallized from 50 ml of xylene to obtain 10.8 g of compound III, with a yield of 93.9% and a purity of 97.8%. Example 6

[0045] In the second step, 17.3 g (0.1 mol) of compound II was dissolved in 200 ml of methanol aqueous solution (50 wt%). Benzoic acid was added to adjust the pH of the solution to 3.5–4.5. 0.15 mol of ammonia (15 mol / L) was slowly added to the acidic solution. The reaction was heated at 50–60 °C, and the reaction was monitored by HPLC. After the reaction was completed, saturated sodium bicarbonate solution was added to neutralize the reaction until neutral. The solvent was evaporated, and 100 ml of dichloromethane and 100 ml of saturated brine were added. The organic phase was separated and washed 2–3 times with 100 ml of saturated brine. The solvent was evaporated again, and the product was recrystallized from 50 ml of xylene to obtain 11.0 g of compound III, with a yield of 95.7% and a purity of 98.1%. Example 7

[0046] In the second step, 17.3 g (0.1 mol) of compound II was dissolved in 200 ml of methanol aqueous solution (50 wt%). Benzoic acid was added to adjust the pH of the solution to 3.5–4.5. 0.12 mol of ammonia (18 mol / L) was slowly added to the acidic solution. The reaction was heated at 50–60 °C, and the reaction was monitored by HPLC. After the reaction was completed, saturated sodium bicarbonate solution was added to neutralize the reaction until neutral. The solvent was evaporated, and 100 ml of dichloromethane and 100 ml of saturated brine were added. The organic phase was separated and washed 2–3 times with 100 ml of saturated brine. The solvent was evaporated again, and the product was recrystallized from 50 ml of xylene to obtain 10.8 g of compound III, with a yield of 93.9% and a purity of 97.7%. Example 8

[0047] In the third step, 17.3 g (0.1 mol) of compound III was dissolved in 200 ml of dichloromethane, an organic solvent. 0.008 mol of sodium carbonate and 0.1 mol of compound IV were added. The mixture was stirred at room temperature to convert to the preceding product, compound V. HPLC analysis showed that compound III was completely consumed. 0.35 g of silver chloride catalyst was added to the solution, and the mixture was stirred at room temperature for 6–8 h. After the reaction was complete, dilute hydrochloric acid was added to neutralize the solution. The solution was washed 2–3 times with saturated brine to separate the organic phase. The solvent was evaporated, and the product was recrystallized from 60 ml of toluene to give 14.8 g of compound VI, with a yield of 94.3% and a purity of 98.1%. Example 9

[0048] In the third step, 17.3 g (0.1 mol) of compound III was dissolved in 200 ml of dichloromethane, an organic solvent. 0.005 mol of sodium carbonate and 0.1 mol of compound IV were added. The mixture was stirred at room temperature to convert to the preceding product, compound V. HPLC analysis showed that compound III was completely consumed. 0.58 g of silver chloride catalyst was added to the solution, and the mixture was stirred at room temperature for 6–8 h. After the reaction was complete, dilute hydrochloric acid was added to neutralize the solution. The solution was washed 2–3 times with saturated brine to separate the organic phase. The solvent was evaporated, and the product was recrystallized from 60 ml of toluene to give 14.6 g of compound VI, with a yield of 93.0% and a purity of 97.8%.

[0049] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.

[0050] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A novel process for the synthesis of favipiravir, characterized in that The method comprises the following steps: In the first step, compound I is dissolved in an aqueous solution of ethanol, and the pH of the solution is adjusted by adding phosphoric acid monohydrate. Ammonia is slowly added to the acidic solution, and the reaction is stirred at 35-40°C. The reaction is monitored by HPLC. After the reaction is completed, the product is separated to obtain compound II. In the second step, compound II obtained in the previous step is dissolved in an organic solvent, and the pH of the solution is adjusted by adding benzoic acid. Ammonia is slowly added to the acidic solution, and the reaction is heated at 50-60°C. The reaction is monitored by HPLC. After the reaction is completed, the product is separated to obtain compound III. In the third step, compound III is dissolved in an organic solvent, and a base reagent is added. Compound IV is added, and the reaction is stirred at room temperature to convert to intermediate product compound V. HPLC detection shows that compound III is completely consumed. A catalyst, silver chloride, is added to the solution, and the reaction is continued to stir at room temperature for 6-8 hours. After the reaction is completed, the product is separated to obtain compound VI. The specific reaction route is shown below: 。 2. The process for synthesis of favipiravir according to claim 1, wherein: In the first step, the solvent is an aqueous solution of 60-80 wt% ethanol.

3. The process for synthesis of favipiravir according to claim 1, wherein: In the first step, the concentration of ammonia is 5-8 mol / L, and in the second step, the concentration of ammonia is 15-18 mol%.

4. The process for synthesis of favipiravir according to claim 1, wherein: In the second step, the solvent is an aqueous solution of methanol with a concentration of 50-60 wt%.

5. The process as claimed in claim 1, wherein, In the first step, the pH of the solution is adjusted to 4-5, and in the second step, the pH of the solution is adjusted to 3.5-4.

5.

6. The process as claimed in claim 1, wherein the process for synthesis of favipiravir is characterized by: In the third step, the solvent is dichloromethane.

7. The process as claimed in claim 1, wherein the process for synthesis of favipiravir is characterized by: In the third step, the base reagent is sodium carbonate, and the amount of base reagent used is 5-8 mol% of compound III. The amount of catalyst, silver chloride, used is 3-5 wt% of compound III.

8. The process as claimed in claim 1, wherein: In the first step, the molar ratio of ammonia to compound I is 1:

1.

9. The process as claimed in claim 1, wherein the process for synthesis of favipiravir is characterized by: In the second step, the molar ratio of compound II to ammonia is 1:1-1.

5.

10. The process as claimed in claim 1, wherein the process for synthesis of favipiravir is characterized by: In the third step, the molar ratio of compound IV to compound III is 1:1.

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