CN113045505A

CN113045505A - Favipiravir intermediate and synthesis method of favipiravir

Info

Publication number: CN113045505A
Application number: CN202110330873.9A
Authority: CN
Inventors: 张巧兰; 王有为
Original assignee: Lanzhou Kohn & Shawn Pharmatech Co ltd
Current assignee: Lanzhou Kohn & Shawn Pharmatech Co ltd
Priority date: 2020-03-26
Filing date: 2021-03-26
Publication date: 2021-06-29
Also published as: CN111471025A

Abstract

The invention discloses a Favipiravir intermediate and a synthesis method of Favipiravir, belonging to the technical field of organic chemistry, the invention uses single 2, 5-dichloropyrazine or a mixture of 2, 5-dichloropyrazine and 2-chloro-5-bromopyrazine as a raw material compound 1 to prepare the Favipiravir intermediate 3, 6-dichloro-2-cyanopyrazine, and the 3, 6-dichloro-2-cyanopyrazine is subjected to aromatic ring fluoro reaction, hydrolysis reaction and cyano hydrolysis reaction to finally obtain Favipiravir; the invention provides a new preparation method for the Favipiravir intermediate 3, 6-dichloro-2-cyanopyrazine, and the preparation method is simple and safe and is suitable for industrial popularization; particularly, when a mixture of 2, 5-dichloropyrazine and 2-chloro-5-bromopyrazine is used as a raw material compound 1 to synthesize the plalazvir intermediate, the raw material cost can be remarkably reduced, and the technical advantages of high yield and high purity are achieved.

Description

Favipiravir intermediate and synthesis method of favipiravir

Technical Field

The invention relates to the technical field of organic chemistry, in particular to a Favipiravir intermediate and a synthesis method of Favipiravir.

Background

Favipiravir (favipiravir, T-705), chemically known as 6-fluoro-3-hydroxypyrazine-2-carboxamide, was developed by Fushan chemical Co., Ltd, Japan, approved for marketing in 2014, and is a broad-spectrum antiviral drug of RNA polymerase inhibitors. Favipiravir selectively disrupts the RNA replication and transcription process of the virus in infected cells, thereby halting the infection cycle. It has obvious effect on treating common influenza, H1N1, Ebola and other viruses.

The existing domestic and foreign synthesis method of the Pilaravir mainly comprises the following two methods:

route one: patent WO 01/60834 reports that favipiravir is obtained in a 5-step synthesis from a hydroxyamide as starting material.

This route is excellent in yield, but it involves nitration reactions involving the risk of explosion (from VI to VII, and therefore requires explosion-proof equipment for industrial production, and is not suitable for inexpensive production.

And a second route: patent WO2010/087117 reports that fapirovir is obtained from aminomalonate ethyl hydrochloride as starting material by 7-step reaction.

The route has simple process, but has long synthesis route, low total yield (9%), large amount of waste water and high comprehensive cost.

From the synthetic routes, 3, 6-dichloro-2-cyanopyrazine is a key intermediate for synthesizing the piravir, and whether the synthesis process of the piravir is suitable for industrial production amplification is directly influenced by the yield, the process complexity, the production cost and the like of the 3, 6-dichloro-2-cyanopyrazine.

Disclosure of Invention

The invention aims to: the method for synthesizing the Favipiravir intermediate and the Favipiravir provides a new preparation idea for the Favipiravir intermediate 3, 6-dichloro-2-cyanopyrazine, is simple and safe, has the technical advantages of high yield, high purity and low cost, and is suitable for industrial popularization.

The technical scheme adopted by the invention is as follows:

in order to achieve the above object, the present invention provides a method for synthesizing a favipiravir intermediate, which comprises:

the synthesis steps comprise:

(1) reacting the compound 1 with formamide under the action of an oxide and a catalyst to generate a compound 2;

(2) the compound 2 reacts under the action of a dehydration chlorinating agent and an acid-binding agent to generate a compound 3;

the R is Br or Cl;

the compound 1 is single 2, 5-dichloropyrazine or a mixture of 2, 5-dichloropyrazine and 2-chloro-5-bromopyrazine;

the compound 2 is single 3, 6-dichloro-2-amide pyrazine or a mixture of 3, 6-dichloro-2-amide pyrazine and 6-bromo-3-chloro-2-amide pyrazine.

Preferably, when the compound 1 is single 2, 5-dichloropyrazine, the synthesis steps of the compound 1 are as follows:

(1) reacting 2-hydroxypyrazine with dichlorohydantoin under the action of N, N-dimethyl sulfoxide to generate 2-hydroxy-5-chloropyrazine;

(2) 2-hydroxy-5-chloropyrazine reacts with phosphorus oxychloride to generate 2, 5-dichloropyrazine.

Preferably, when the compound 1 is a mixture of 2, 5-dichloropyrazine and 2-chloro-5-bromopyrazine, the synthesis steps of the compound 1 are as follows:

(1) reacting the 2-hydroxypyrazine with dibromohydantoin under the action of N, N-dimethyl sulfoxide to generate 2-hydroxy-5-bromopyrazine;

(2) reacting the 2-hydroxy-5-bromopyrazine with phosphorus oxychloride to generate a mixture of 2, 5-dichloropyrazine and 2-chloro-5-bromopyrazine.

Because the raw material compound 1-2, 5-dichloropyrazine is required to be obtained from 2-hydroxy-5-chloropyrazine, but the preparation of the 2-hydroxy-5-chloropyrazine (1a) is a difficult problem, no matter which chlorination method is used, the chlorination activity is higher, and the steric hindrance of a chlorine atom relative to a bromine atom is smaller, so that the byproducts 2-hydroxy-3, 5-dichloropyrazine generated by chlorination at the 3 position simultaneously are more, and the byproducts are difficult to purify, so the yield of the 2-hydroxy-5-chloropyrazine (1a) is very low, and the preparation cost of the 2, 5-dichloropyrazine is very high. If a single 2, 5-dichloropyrazine is used as the compound 1, the cost of the whole synthetic route is high.

We have found in their studies that 2-hydroxy-5-bromopyrazine (1b) is obtained in high yields due to the significantly smaller impurities of the bromination reaction, which are relatively easier to control, and which can form a mixture of 2, 5-dichloropyrazine and 2-bromo-5-chloropyrazine in a subsequent chlorination reaction.

Furthermore, the mixture is used as a compound 1 to react to generate a compound 2, and experiments prove that although the mixture is used, a pure product of an important intermediate compound 3 of the Favipiravir can be obtained,

practice shows that when the compound 1 in the form of a mixture is used as a raw material, the raw material cost is greatly reduced due to simple preparation process, high yield and few byproducts, the raw material is easier to obtain and is more beneficial to industrialization, and meanwhile, the yield and the purity of the prepared compound 3 are not reduced, so that compared with the case of using single 2, 5-dichloropyrazine as the compound 1, the compound 1 in the form of a mixture has obvious advantages, and the important innovation of the invention is also.

Preferably, the oxide in the step (1) is selected from any one of potassium persulfate, ammonium persulfate, sodium persulfate, hydrogen peroxide and peroxyacetic acid or a mixture thereof; more preferably, the oxide is potassium persulfate, and the molar weight ratio of the compound 1 to the oxide is 1 (2-20).

Preferably, the catalyst in step (1) is selected from any one of silver nitrate, ferrous sulfate, ferrous sulfide, ferric chloride and ferrous chloride or a mixture thereof; further preferably, the catalyst is ferrous sulfide.

The reaction is catalyzed by iron salt, and other iron salts such as ferrous sulfide, ferrous sulfate and the like are used as catalysts, so that the reaction yield can be further improved, and compared with the reaction, the experimental result of the ferrous sulfide is better; as for the reaction mechanism of the ferrous sulfide, according to the experimental data results, it is inferred that the ferrous sulfide mainly plays a catalytic role in the reaction and is a heterogeneous catalytic reaction. According to literature research, ferrous sulfide can be used as a heterogeneous catalyst in a Fenton reaction to be applied to degradation of herbicide 2, 4-dichlorophenoxyacetic acid in an aqueous solution, and the pH variation range of a reaction system is 2.0-6.5. Description of appendix 2: ferrous sulfide can also play a catalytic role as a heterogeneous catalyst under the condition that the reaction system is close to neutral (the pH is 6.5).

Preferably, the solvent in step (1) is selected from any one of water, dimethylformamide, dimethyl sulfoxide and acetonitrile or a mixture thereof; further preferably, the solvent is water; the reaction temperature of the step (1) is 50-100 ℃, and preferably 80-100 ℃; the ratio of compound 1 to solvent is 1 g/1 ml to 1 g/50 ml; preferably, the solvent ratio is from 1 g/3 ml to 1 g/10 ml.

Preferably, the molar weight ratio of the compound 1, formamide and catalyst is 1: (0.8-20): (0.1-1).

Preferably, the dehydration chlorinating agent in the step (2) is selected from any one of phosphorus oxychloride, thionyl chloride and bis (trichloromethyl) carbonate; further preferably, the dehydration chlorinating agent is phosphorus oxychloride; the molar weight ratio of the dehydration chlorinating agent to the compound 2 is (2-10): 1.

preferably, the acid-binding agent in the step (2) is selected from any one of triethylamine, diisopropylethylamine, pyridine and dimethylamine; the molar weight ratio of the acid-binding agent to the compound 2 is (1-10): 1.

Preferably, the acid-binding agent is diisopropylethylamine, and the molar weight ratio of the diisopropylethylamine to the compound 2 is (2-5): 1.

Preferably, the reaction temperature in the step (2) is 0 to 150 ℃, and more preferably 20 to 80 ℃; the reaction time is 3-10 hours.

Preferably, the crude product in step (2) is purified by recrystallization, and the solvent for recrystallization is one or a mixture of dichloromethane, chloroform, ethyl acetate, isopropyl acetate, ethyl formate, ethyl acetate, toluene, methanol, ethanol, isopropanol, acetone, and water; more preferably, the recrystallization solvent is ethanol.

The invention also provides a synthesis method of Favipiravir, which comprises the following steps:

the synthesis steps comprise:

(1) obtaining a compound 3 by adopting the synthesis method of the Lavipiravir intermediate, heating the compound 3 and a fluorinating agent in dimethyl sulfoxide to 60-140 ℃ to perform aromatic ring fluorination reaction to generate a compound 4;

(2) adding the compound 4 into an aqueous solution containing sodium acetate, and carrying out hydrolysis reaction to obtain a compound 5;

(3) compound 5 undergoes a cyanohydrolysis reaction to give compound 6.

In the synthesis step of favipiravir, the fluorinating agent in the step (1) is a fluorine-containing salt, preferably potassium fluoride, sodium fluoride, ammonium fluoride, tetrabutylammonium fluoride; further preferably, the fluorinating agent is potassium fluoride; the molar weight ratio of the potassium fluoride to the compound 3 is (3-20): 1.

the solvent in the step (1) is any one or mixture of dimethylformamide, dimethyl sulfoxide and acetonitrile; further preferably dimethyl sulfoxide; the ratio of the compound 3 to the solvent in the step (1) is 1 g/3 ml-1 g/10 ml; the reaction temperature in the step (1) is 60-140 ℃.

Wherein, the compound 4 is used as a key intermediate for synthesis of the Favipiravir, the purity of the final Favipiravir is directly influenced, and the impurities generated in the step (1) are similar to the structure and similar in polarity, so that the step (1) needs to be purified and cannot be directly put into a subsequent reaction by a one-pot method; preferably, the crude product obtained by the reaction in the step (1) is purified by recrystallization, and the solvent for recrystallization is one or a mixture of more than two of dichloromethane, chloroform, ethyl acetate, isopropyl acetate, ethyl formate, ethyl acetate, toluene, methanol, ethanol, isopropanol, acetone and water; further preferably, the recrystallization solvent is acetone.

In addition, the crude compound 6 obtained in the step (3) is purified by recrystallization; the recrystallization solvent is one or a mixture of dichloromethane, chloroform, ethyl acetate, isopropyl acetate, ethyl formate, ethyl acetate, toluene, methanol, ethanol, isopropanol, acetone and water.

Specifically, the synthesis method of the Favipiravir comprises the following steps:

step 1: adding the compound 1 into water, adding potassium persulfate and a catalyst ferrous sulfide at room temperature, slowly heating to 80-100 ℃, dropwise adding formamide to perform free radical reaction, keeping the temperature for 3 hours, cooling to 20-50 ℃, keeping the temperature for 1 hour, filtering, and washing to obtain a compound 2.

Step 2: adding phosphorus oxychloride into the compound 2 at room temperature, heating to 20-80 ℃, dropwise adding diisopropylethylamine, keeping the temperature for 5 hours, cooling, adding the mixture into water with the temperature below 10 ℃, filtering, and recrystallizing by using ethanol as a solvent to obtain a compound 3.

And step 3: heating the compound 3 and potassium fluoride in dimethyl sulfoxide to 60-140 ℃, carrying out aromatic ring fluorination reaction, adding water, filtering, recrystallizing the obtained crude product with acetone, and filtering to obtain a compound 4.

And 4, step 4: and adding the compound 4 into an aqueous solution containing sodium acetate to perform hydrolysis reaction to obtain a compound 5.

And 5: and adding the compound 5 into an aqueous solution of sodium hydroxide to perform cyano hydrolysis reaction, and recrystallizing and refining the obtained crude product to obtain a compound 6, namely the Favipiravir.

In summary, due to the adoption of the technical scheme, the invention has the beneficial effects that:

1. the invention provides a novel preparation method of a pyrrosia intermediate 3, 6-dichloro-2-cyanopyrazine, which does not contain nitration reaction with explosion risk, is simple and safe, and has the intermediate yield of more than 78 percent and the purity of more than 97 percent.

2. The invention provides a method for efficiently converting 3, 6-difluoro-2-cyanopyrazine into pyrrosia faba in two steps, wherein the yield is 84%, and the method is obviously superior to the existing method.

3. The invention adopts the mixture of 2, 5-dichloropyrazine and 2-chloro-5-bromopyrazine as the compound 1, and the compound 2 is generated in the form of mixture after reaction, although the compound 2 is the mixture, the pure compound 3 can still be obtained. When the compound 1 in the form of a mixture is used as a raw material, the preparation process of the raw material is simple, the yield is high, and byproducts and impurities are few, so that the raw material cost is greatly reduced, the raw material is more easily obtained, and the industrialization is more favorably realized. Meanwhile, the yield and the purity of the compound 3 finally prepared by utilizing the compound 1 in the form of a mixture are not reduced, the yield of the intermediate compound 3 is 78-80%, the purity is 97.1%, and the method has the technical advantages of high yield, low cost and simple preparation process.

Drawings

The invention will now be described, by way of example, with reference to the accompanying drawings, in which:

FIG. 1 is an XRD powder diffractogram of Favipiravir prepared in accordance with the present invention;

FIG. 2 is a hydrogen spectrum of Favipiravir prepared in accordance with the present invention;

FIG. 3 is a HNMR spectrum of 2, 5-dichloropyrazine prepared in example 1 of the present invention;

FIG. 4 is a HNMR map of 3, 6-dichloro-2-cyanopyrazine prepared according to example 1 of the present invention;

FIG. 5 is a powder diffraction pattern of XRD of 3, 6-dichloro-2-amidopyrazine prepared in example 1 of the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be described clearly and completely with reference to the accompanying drawings, and it is to be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1

When the compound 1 is single 2, 5-dichloropyrazine, the synthesis method of the Favipiravir intermediate is as follows:

(1) compound 1: preparation of 2, 5-dichloropyrazine

Adding 12 g of 2-hydroxypyrazine into 250 ml of N, N-dimethyl sulfoxide, cooling to 0-2 ℃, adding 12.8 g of dichlorohydantoin in batches, preserving heat for 1 hour, adding 450 ml of water, adding 700 ml of isopropyl acetate for extraction, washing an organic phase (300 ml of 2), drying, carrying out spin-drying on a solvent, and carrying out column chromatography to obtain 3.59 g of yellow powder 2-hydroxy-5-chloropyrazine. The detection shows that: the ratio of 2-hydroxy-5-chloropyrazine obtained by an area normalization method in HPLC of the reaction system is 22.1 percent, a byproduct is 27.9 percent, and other impurities are 36 percent.

Adding 2-hydroxy-5-chloropyrazine into 35 g of phosphorus oxychloride, heating to 60 ℃, preserving the temperature for 2 hours, pouring the mixture into 100g of ice-water mixture, filtering, extracting 150 ml of isopropyl acetate, concentrating and distilling to obtain 2.6 g of light yellow oily 2, 5-dichloropyrazine with the purity of 98 percent and the two-step total yield of 14.3 percent, and 1H-NMR (CDCl)₃,600MHz)：δ8.39(s,2H)。

(2) Compound 2: preparation of 3, 6-dichloro-2-amidopyrazines

Adding 3 g of 2, 5-dichloropyrazine into 20 ml of water, adding 10.4 g of potassium persulfate and 0.2 g of ferrous sulfide in batches at room temperature, slowly heating to 80 ℃, dropwise adding 5 g of formamide at 80-85 ℃, preserving heat for 1 hour after adding, cooling to 30 ℃, stirring for half an hour, performing suction filtration, washing a filter cake with 10 ml of water and 5 ml of methanol, and performing vacuum drying to obtain 2.8 g of a light yellow product (yield 72%).

(3) Preparation of Compound 3

Adding 1.9 g of the product 3, 6-dichloro-2-amide pyrazine obtained in the step 1 into 9.4 ml of phosphorus oxychloride, heating to 75 ℃, dropwise adding 3.9 g of diisopropylethylamine, keeping the temperature for 1 hour, performing HPLC (high performance liquid chromatography) to show that the raw materials completely react, cooling, pouring into 50 ml of ice water, filtering, and recrystallizing with 10 ml of ethanol to obtain 1.5 g of a light yellow powder product, namely the compound 3 (yield 82%) with the purity of 97.7%. MP: 95-97 deg.C, 1H-NMR (CDCl)₃,600MHz)：δ8.60(s,1H)。

Example 2

When the compound 1 is a mixture of 2, 5-dichloropyrazine and 2-chloro-5-bromopyrazine, the synthesis method of the Favipiravir intermediate is as follows:

(1) compound 1: preparation of a mixture of 2, 5-dichloropyrazine and 2-chloro-5-bromopyrazine

Adding 50 g of 2-hydroxypyrazine into 250 ml of N, N-dimethyl sulfoxide, cooling to 10-12 ℃, adding 74 g of dibromohydantoin in batches, preserving heat for 1 hour, adding 500 ml of water, precipitating a large amount of yellow solid, filtering, and drying to obtain 80.1 g of 2-hydroxy-5-bromopyrazine; the detection shows that: the ratio of 2-hydroxy-5-bromopyrazine obtained by HPLC in the reaction system is 72.7%, the byproduct is 8.3%, and other impurities are 3.5%

Adding 2-hydroxy-5-bromopyrazine into 341 g of phosphorus oxychloride, heating to 60 ℃, preserving the temperature for 2 hours, pouring into 800 g of ice-water mixture, filtering, extracting with 350 ml of isopropyl acetate, and concentrating to obtain 72 g of dark brown oily substance, namely the mixture of 2, 5-dichloropyrazine and 2-chloro-5-bromopyrazine. The effective purity of the mixture was 98% and the overall yield in two steps was about 79%.

(2) Compound 2: preparation of a mixture of 3, 6-dichloro-2-amidopyrazine and 6-bromo-3-chloro-2-amidopyrazine

350 g of the mixture (mass ratio is about 4:3) of the 2, 5-dichloropyrazine and the 2-chloro-5-bromopyrazine obtained in the step (1), 1.5L of water is added, 950 g of potassium persulfate and 2 g of ferrous sulfide are added in batches at room temperature, the temperature is slowly raised to 80 ℃, 52 g of formamide is added dropwise, the temperature is not more than 85 ℃, the temperature is kept for about 1.5 hours, the mixture is cooled to 25 ℃ and kept for 1 hour, the mixture is filtered, 300 ml of water and 300 ml of methanol are used for washing a filter cake, and 323 g of yellow powder is obtained by vacuum drying, namely the mixture of the 3, 6-dichloro-2-amidopyrazine and the 6-bromo-3-chloro-2-amidopyrazine (yield is 72-76%).

(3) Preparation of Compound 3

At room temperature, 500 g of a mixture of 3, 6-dichloro-2-aminopyrazine and 6-bromo-3-chloro-2-aminopyrazine (the mass ratio is about 4:3) is added with 900 ml of phosphorus oxychloride in batches, the temperature is raised to 70 ℃, 904 g of diisopropylethylamine is dropwise added after 1 hour, the temperature is controlled to be 70-80 ℃, the dropwise addition is completed after 1 hour, the temperature is kept for 3 hours, HPLC (high performance liquid chromatography) shows that the raw materials are completely reacted, the mixture is slowly cooled and poured into 10 ℃ cold water (10 liters), the mixture is stirred for 1 hour, a centrifugal machine is used for drying, a crude product is recrystallized by using 3 liters of ethanol, 320 g of a light yellow powder product is obtained, namely 3, 6-dichloro-2-cyanopyrazine (compound 3), the yield is 78-80%, the purity is 97: 95-97 deg.C, 1H-NMR (CDCl)₃,600MHz)：δ8.60(s,1H)。

The synthetic route of this example is:

in this example, since the raw material used in preparing compound 3 is a mixture of 3, 6-dichloro-2-amidopyrazine and 6-bromo-3-chloro-2-amidopyrazine, impurity a, which is an intermediate product of the 6-bromo-3-chloro-2-pyrazinamide reaction, is generated in the preparation of compound 3, the reaction mechanism is as follows:

the method for measuring the impurity A comprises the following steps: after completion of the preparation of compound 3, a sample was taken from the reaction system, and then the content of impurity a in the reaction system was determined by HPLC. The inventor finds out through a plurality of experiments that: the dosage of the acid-binding agent Diisopropylethylamine (DIPEA) has important relevance to the occurrence of the impurity A, and the relationship between the molar weight ratio of the diisopropylethylamine to the compound 2 and the impurity A is shown in Table 1.

TABLE 1

Amount of DIPEA (molar ratio)	Content of impurity A
		5	0.72％
4.5	1.80％
		4	3.15％
3.5	5.23％
		2	8.11％

As can be seen from table 1, the content of impurity a decreases with the increase of the molar amount of diisopropylethylamine, and impurity a has an important influence on the time of the next fluorination reaction and the purity of compound 4, although increasing diisopropylethylamine reduces the presence of impurity a, but quaternary ammonium salt generated by excess diisopropylethylamine significantly affects the post-treatment crystallization of the product, so we need to perform process screening and optimization on the amount of diisopropylethylamine. Thus, in combination with the data in table 1, the molar ratio of diisopropylethylamine to compound 2 is preferably (2-5):1, more preferably (2.5-3.5): 1.

example 3

Preparation of Favipiravir from Compound 3

(1) At room temperature, 2 kg of 3, 6-dichloro-2-cyanopyrazine is added into 8L of DMSO, the temperature is raised to 60 ℃, 2.33 kg of potassium fluoride is added in batches, the system is slightly raised in temperature, the reaction system is raised to 90 ℃ for reaction for 12h, and the reaction solution is brown turbid solution. The reaction solution was slowly poured into 20L of water while cooling, extracted with 20L of chloroform, washed with 10L of water for 3 times, dried and filtered over anhydrous sodium sulfate to obtain 1.6kg of crude product of about 1.5L, which was dropped into 5L of cold acetone, stirred for 3 hours, and filtered to obtain 1.38 kg of yellow 3, 6-difluoro-2-cyanopyrazine (yield 85%). 1H-NMR (CDCl3, 600MHz): delta 8.35(dd, J ═ 6,1H)

(2) At room temperature, 1.38 kg of 3, 6-difluoro-2-cyanopyrazine is added into 3.96 l of DMSO, the temperature of an ice-water bath is reduced to 5 ℃, 8.2 kg of 18 percent sodium acetate aqueous solution is slowly added, the temperature is obviously increased, the temperature T of a reaction system is controlled to be less than 10 ℃, reaction liquid is light yellow clear liquid, the mixture is stirred for 1 hour, and then the mixture is heated to 45 ℃ and stirred for 3 hours. After the reaction, concentrated sulfuric acid was added dropwise to the reaction mixture, and the mixture was cooled to 5 ℃ to adjust the pH to 5, extracted with ethyl acetate 15L three times, and concentrated to obtain 1.29 kg of 6-fluoro-3-hydroxy-2-cyanopyrazine as a brown powder (yield 93%). 1H-NMR (DMSO,600 MHz): δ 8.53(d, J ═ 6, 1H).

(3)645 g of sodium hydroxide is dissolved in 9L of water, the temperature is reduced to 5 ℃, 1.29 kg of 6-fluoro-3-hydroxy-2-cyanopyrazine is added in batches, the mixture is stirred and slightly heated, the temperature of a reaction system is controlled to be 5-10 ℃, the reaction is finished after 3.5h of use, the temperature is kept for 1h, and then the reaction is carried out for 1h at 40 ℃. Adding 100g of activated carbon into the reaction solution, carrying out hot filtration, cooling the mother solution to 5 ℃, adjusting the pH value of the mother solution to 3-4 by concentrated hydrochloric acid, separating out a large amount of solid, filtering, drying to obtain a white-like powder crude product, pulping by 2.8 liters of 15% methanol aqueous solution, filtering, and drying to obtain 1.34 kg of white-like powder pyrrosia. 1H-NMR (DMSO,600 MHz): δ 13.38(s,1H),8.73(1s,1H),8.51-8.49(d, J ═ 12,2H) (yield 91%). Structural characterization of prepared favipiravir refers to fig. 1 and fig. 2, wherein fig. 1 is an XRD powder diffractogram of favipiravir prepared by the present invention. FIG. 2 is a hydrogen spectrum of Favipiravir prepared in accordance with the present invention.

Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; these modifications and substitutions do not cause the essence of the corresponding technical solution to depart from the scope of the technical solution of the embodiments of the present invention, and are intended to be covered by the claims and the specification of the present invention.

Claims

1. A synthetic method of a Favipiravir intermediate is characterized by comprising the following steps:

the synthesis steps comprise:

the R is Br or Cl;

2. The synthesis method of the favipiravir intermediate, according to claim 1, is characterized in that when the compound 1 is single 2, 5-dichloropyrazine, the synthesis method of the compound 1 is as follows:

the synthesis steps are as follows:

(1) 2-hydroxy pyrazine reacts with dichloro hydantoin in the solvent to generate 2-hydroxy-5-chloropyrazine;

3. The synthesis method of the favipiravir intermediate, according to claim 1, is characterized in that when the compound 1 is a mixture of 2, 5-dichloropyrazine and 2-chloro-5-bromopyrazine, the synthesis method of the compound 1 is as follows:

the synthesis steps are as follows:

(1) reacting 2-hydroxypyrazine with dibromohydantoin in a solvent to generate 2-hydroxy-5-bromopyrazine;

4. The synthesis method of the favipiravir intermediate, according to claim 1, is characterized in that the oxide in the step (1) is selected from any one of potassium persulfate, ammonium persulfate, sodium persulfate, hydrogen peroxide, peroxyacetic acid or a mixture thereof; the catalyst in the step (1) is any one or a mixture of silver nitrate, ferrous sulfate, ferrous sulfide, ferric chloride and ferrous chloride.

5. The synthesis method of the fapirovir intermediate as claimed in claim 1, wherein the solvent in step (1) is selected from any one of water, dimethylformamide, dimethyl sulfoxide and acetonitrile or a mixture thereof; the reaction temperature of the step (1) is 50-100 ℃.

6. The synthesis method of the fapirovir intermediate as claimed in claim 1, wherein the molar weight ratio of the compound 1, the formamide and the catalyst is 1: (0.8-20): (0.1-1).

7. The method for synthesizing the fapirovir intermediate as claimed in claim 1, wherein the dehydrochlorination agent in step (2) is selected from any one of phosphorus oxychloride, thionyl chloride and bis (trichloromethyl) carbonate; the molar weight ratio of the dehydration chlorinating agent to the compound 2 is (2-10): 1.

8. the synthesis method of the fapirovir intermediate as claimed in claim 1, wherein the acid-binding agent in step (2) is selected from any one of triethylamine, diisopropylethylamine, pyridine and dimethylamine; the molar weight ratio of the acid-binding agent to the compound 2 is (1-10): 1.

9. The synthesis method of the fapirovir intermediate according to claim 8, wherein the acid-binding agent is diisopropylethylamine, and the molar ratio of the diisopropylethylamine to the compound 2 is (2-5): 1.

10. A synthetic method of Favipiravir is characterized by comprising the following steps:

the synthesis steps comprise:

(1) the synthesis method of the Favipiravir intermediate of any one of claims 1-9 is adopted to obtain a compound 3, the compound 3 and a fluorinating agent are heated in dimethyl sulfoxide to 60-140 ℃ to perform an aromatic ring fluorination reaction to generate a compound 4;

(3) compound 5 undergoes a cyanohydrolysis reaction to give compound 6.