CN111471025A

CN111471025A - Favipiravir intermediate and synthesis method of favipiravir

Info

Publication number: CN111471025A
Application number: CN202010222140.9A
Authority: CN
Inventors: 张巧兰
Original assignee: Lanzhou Kohn & Shawn Pharmatech Co ltd
Current assignee: Lanzhou Kohn & Shawn Pharmatech Co ltd
Priority date: 2020-03-26
Filing date: 2020-03-26
Publication date: 2020-07-31
Also published as: CN113045505A

Abstract

The invention discloses a Favipiravir intermediate and a synthesis method of Favipiravir, wherein the method comprises the following steps: 2, 5-dihalo pyrazine is adopted as a starting material, and the 2, 5-dihalo pyrazine and formamide react under the action of an oxide and a catalyst to generate 6-halogeno-3-chloro-2-amide pyrazine; the 6-halogenated-3-chloro-2-pyrazine-amide reacts under the action of a dehydration chlorinating agent and an acid-binding agent to generate a P-Lavir intermediate 3, 6-dichloro-3-cyano pyrazine. The obtained Favipiravir intermediate and potassium fluoride are subjected to aromatic ring fluoro reaction in dimethyl sulfoxide to generate 3, 6-difluoro-3-cyano pyrazine; then adding the mixture into an aqueous solution containing sodium acetate to perform hydrolysis reaction to obtain 6-fluoro-3-hydroxy-2-cyanopyrazine; finally, the cyano hydrolysis reaction is carried out, and the Favipiravir is obtained. The synthesis method of the piravir intermediate adopts the mixture of the 2, 5-dichloropyrazine and the 2-chloro-5-bromopyrazine as the raw material, so that the raw material cost can be obviously reduced, and the synthesis method of the piravir has the technical advantage of high yield and low cost.

Description

Favipiravir intermediate and synthesis method of favipiravir

Technical Field

The invention belongs to the technical field of chemical synthesis, and particularly relates 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.

The present route is excellent in yield, but it involves nitration reactions (from VII to VIII) involving the risk of explosion, 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, long steps, low total yield, large amount of waste water and high comprehensive cost.

In conclusion, the existing process route of the Favipiravir has more technical problems, and is not suitable for industrial production amplification.

Disclosure of Invention

The invention aims to provide a Favipiravir intermediate and a synthesis method of Favipiravir. Mainly solves the technical problems of complex process, harsh reaction conditions, low yield and high cost in the prior art.

The technical scheme adopted by the invention for solving the problems is as follows:

a method for synthesizing a Favipiravir intermediate comprises the following steps:

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;

and R is Br or Cl.

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

Preferably, the catalyst in step (1) is selected from silver nitrate, ferrous sulfate, ferrous sulfide, ferric chloride, ferrous chloride; further preferably, the catalyst is ferrous sulfide.

Preferably, the solvent of step (1) is selected from one of water, dimethylformamide, dimethyl sulfoxide, acetonitrile or a mixture thereof; further preferably, the solvent is water; the reaction temperature in step (1) is 50 to 100 ℃, preferably 80 to 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 phosphorus oxychloride, thionyl chloride, bis (trichloromethyl) carbonate; 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 triethylamine, diisopropylethylamine, pyridine, 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 step (2) is 0 to 150 ℃, further 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. Further preferably, the recrystallization solvent is ethanol.

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

the synthesis steps comprise:

(3) 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;

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

(5) performing cyano hydrolysis reaction on the compound 5 to obtain a compound 6;

and R is Br or Cl.

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

preferably, the solvent in the step (3) is one of or a mixture of dimethylformamide, dimethyl sulfoxide and acetonitrile; further preferred is dimethyl sulfoxide.

Preferably, the ratio of compound 3 to solvent in step (3) is 1 g/3 ml to 1 g/10 ml.

Preferably, the reaction temperature in the step (3) is 60 to 140 ℃.

The purity of the compound 4 serving as a key intermediate of the route directly influences the purity of the final method plavir, and impurities generated in the step (3) are similar to the structure and similar in polarity, so that the step (3) needs to be purified, and the product cannot be directly put into a subsequent reaction by a one-pot method. Preferably, the crude product obtained by the reaction in the step (3) is purified by recrystallization, wherein the solvent for recrystallization is one or more 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.

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

Compared with the prior art, the invention has the following beneficial effects:

1, provides a synthesis method of 3, 6-dichloro-2-cyanopyrazine with higher yield. The yield is 78-80%, which is obviously superior to the prior method.

2, the method for efficiently converting 3, 6-difluoro-2-cyanopyrazine into the pyrrosia fabiana by two steps is provided, the yield is 84 percent, and the method is obviously superior to the existing method.

3, the synthesis method of the Pilatavir with higher yield is provided, the total yield is 40.1-43%, and the yield is obviously improved compared with the existing method. In addition, the synthesis method adopts the mixture of 2, 5-dichloropyrazine and 2-chloro-5-bromopyrazine as the raw material to synthesize the intermediate of the piravir, so that the raw material cost can be obviously reduced, and the yield is not reduced, so that the technological method for synthesizing the piravir has the technical advantage of high yield and low cost.

Drawings

Fig. 1 is an XRD powder diffractogram of fapirovir 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 XRD powder diffraction pattern of 3, 6-dichloro-2-amide pyrazine prepared by the invention.

Detailed Description

The technical solution of the present invention will be described in detail with reference to examples. The reagents used below are all commercial products unless otherwise specified.

Example 1: synthesis of compound 3 from 2, 5-dichloropyrazine

(1) 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%). Referring to fig. 3, the XRD powder diffractogram of the prepared 3, 6-dichloro-2-amidopyrazine is shown.

(2) 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, ensuring that HP L C shows 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 a compound 3 (yield 82%), MP: 95-97 ℃, 1H-NMR (CDCl3, 600MHz): 8.60(s, 1H).

In step (2), the inventors found through a plurality of experiments that: the dosage of the acid-binding agent diisopropylethylamine has important relevance with the occurrence of the impurity A. The relationship between the molar ratio of diisopropylethylamine to compound 2 and 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 the impurity A has important influence on the time of the next fluorination reaction and the purity of the compound 4. However, the addition of diisopropylethylamine increases the corresponding by-products, which leads to a decrease in the crystallization effect in the working-up. Optimally, the molar weight ratio of the acid-binding agent is (2-5):1, more preferably (2.5-3.5): 1.

example 2: synthesis of compound 3 from mixture of 2, 5-dichloropyrazine and 2-chloro-5-bromopyrazine

(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. 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 overall yield of the two steps is about 79%.

(2) Preparation of a mixture of 3, 6-dichloro-2-amidopyrazine and 6-bromo-3-chloro-2-amidopyrazine

350 g of a mixture of 2, 5-dichloropyrazine and 2-chloro-5-bromopyrazine (the mass ratio is about 4:3), 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 increased to 80 ℃, 52 g of formamide is dropwise added, the dropwise addition is carried out for about 15 minutes, the temperature is not more than 85 ℃, the temperature is kept for about 1.5 hours, the mixture is cooled to 25 ℃, the temperature is kept for 1 hour, the mixture is subjected to suction filtration, 300 ml of water and 300 ml of methanol are used for washing a filter cake, and the mixture is dried in vacuum to obtain 323 g of yellow powder, namely the mixture of 3, 6-dichloro-2-amidopyrazine and 6-bromo-3-chloro-2-amidopyrazine (the.

(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 added dropwise after 1 hour, the temperature is controlled to 70-80 ℃, the dropwise addition is completed after 1 hour, the temperature is kept for 3 hours, HP L C shows that the raw materials are completely reacted, the temperature is reduced and slowly poured into 10 ℃ cold water (10 liters), the mixture is stirred for 1 hour, a centrifugal machine is used for drying, the crude product is recrystallized by using 3 liters of ethanol to obtain 320 g of light yellow powder product, namely 3, 6-dichloro-2-cyanopyrazine (compound 3), the yield is 78-80%, and MP is 95-97 ℃, 1H-NMR (CDCl3,600MHz) is 8.60(s, 1H).

Example 3: preparation of Favipiravir from Compound 3

(1) Adding 2 kg of 3, 6-dichloro-2-cyanopyrazine into 8L of DMSO (dimethylsulfoxide) at room temperature, heating to 60 ℃, adding 2.33 kg of potassium fluoride in batches, slightly heating the system, heating the reaction system to 90 ℃, reacting for 12H, wherein the reaction solution is brown turbid solution, cooling the reaction solution, slowly pouring the reaction solution into 20L water, extracting with 20L of chloroform, washing with 10L of water for 3 times, drying and filtering with anhydrous sodium sulfate, concentrating to obtain 1.6kg of crude product of about 1.5L, adding into 5L of cold acetone, stirring for 3H, filtering to obtain 1.38 kg of yellow 3, 6-difluoro-2-cyanopyrazine (yield 85%). 1H-NMR (CDCl)₃,600MHz)：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% sodium acetate aqueous solution is slowly added, the temperature is obviously raised, the temperature T of a reaction system is controlled to be less than 10 ℃, a reaction solution is light yellow clear solution, the temperature is raised to 45 ℃ after stirring for 3 hours, after the reaction is finished, concentrated sulfuric acid is added to the temperature of 5 ℃ to adjust the pH value to be 5, ethyl acetate 15L is extracted for three times, and concentration is carried out, so that 1.29 kg of brown powder 6-fluoro-3-hydroxy-2-cyanopyrazine (yield is 93%) is obtained, and 1H-NMR (DMSO,600MHz) is 8.53(d, J is 6, 1.

(3)645 g of sodium hydroxide is dissolved in 9L 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 system is used for 3.5H after adding, the temperature is kept for 1H, then the temperature is raised to 40 ℃ for reaction for 1H, 100g of activated carbon is added into a reaction solution, the heat filtration is carried out, a mother solution is cooled to 5 ℃, the pH value is adjusted to 3-4 by concentrated hydrochloric acid, a large amount of solid is separated out, the filtration and the drying are carried out to obtain a white powder crude product, the white powder crude product is pulped by 2.8L of 15% methanol water solution, the filtration and the drying are carried out to obtain 1.34 kg of white powder Lalavir.1H-NMR (DMSO,600MHz) 13.38(s,1H),8.73(1s,1H),8.51-8.49(d, J-12, 2H) (yield 91%), the structural representation of the Lalavor the invention powder is shown in figure 1 and figure 2.

The above description is only a part of the preferred embodiments of the present invention, and the present invention is not limited to the contents of the embodiments. It will be apparent to those skilled in the art that various changes and modifications can be made within the spirit of the invention, and any changes and modifications made are within the scope of the invention.

Claims

1. A method for synthesizing a Favipiravir intermediate comprises the following steps:

the synthesis steps comprise:

and R is Br or Cl.

2. The process for the synthesis of favipiravir intermediate as claimed in claim 1, wherein: the oxide in the step (1) is selected from one or a mixture of potassium persulfate, ammonium persulfate, sodium persulfate, hydrogen peroxide and peroxyacetic acid; preferably, the oxide is potassium persulfate; the catalyst in the step (1) is selected from silver nitrate, ferrous sulfate, ferrous sulfide, ferric chloride and ferrous chloride; preferably, the catalyst is ferrous sulfide.

3. The process for the synthesis of favipiravir intermediate as claimed in claim 1, wherein: the solvent in the step (1) is selected from one of water, dimethylformamide, dimethyl sulfoxide and acetonitrile or a mixture thereof; preferably, the solvent is water; the reaction temperature in step (1) is 50 to 100 ℃, preferably 80 to 100 ℃.

4. The process for the synthesis of favipiravir intermediate as claimed in claim 1, wherein: the molar weight ratio of the compound 1 to formamide to the catalyst is 1: (0.8-20): (0.1-1).

5. The process for the synthesis of favipiravir intermediate as claimed in claim 1, wherein: the dehydration chlorinating agent in the step (2) is selected from phosphorus oxychloride, thionyl chloride and bis (trichloromethyl) carbonate; preferably, the dehydration chlorinating agent is phosphorus oxychloride.

6. The process for the synthesis of favipiravir intermediate as claimed in claim 1, wherein: the acid-binding agent in the step (2) is selected from triethylamine, diisopropylethylamine, pyridine and dimethylamine; the molar weight ratio of the acid-binding agent to the compound 2 is (1-10): 1.

7. The process for the synthesis of favipiravir intermediate as claimed in claim 6, wherein: the acid-binding agent is diisopropylethylamine, the molar weight ratio of the diisopropylethylamine to the compound 2 is (2-5) to 1, preferably (2.5-3.5): 1.

8. the process for the synthesis of favipiravir intermediate as claimed in claim 1, wherein: purifying the crude product in the step (2) by adopting a recrystallization method, wherein a 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; preferably, the recrystallization solvent is ethanol.

9. A method for synthesizing Favipiravir comprises the following steps:

the synthesis steps comprise:

and R is Br or Cl.

10. The process for the synthesis of favipiravir according to claim 9, wherein: purifying the crude product obtained by the reaction in the step (3) by adopting recrystallization, wherein 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; preferably, the recrystallization solvent is acetone.