WO2023201802A1

WO2023201802A1 - Synthesis method for ensitrelvir

Info

Publication number: WO2023201802A1
Application number: PCT/CN2022/093012
Authority: WO
Inventors: 王鹏; 陈正树; 田湘寅; 刘国杰; 钱刚
Original assignee: 杭州国瑞生物科技有限公司
Priority date: 2022-04-20
Filing date: 2022-05-16
Publication date: 2023-10-26
Also published as: CN114805314B; CN114805314A

Abstract

The present invention particularly relates to the technical field of synthesis of compounds. Disclosed is a synthesis method for ensitrelvir. The synthesis method is as follows: cyanuric chloride (SM) serving as a starting material reacts to obtain an intermediate C-1; the intermediate C-1 reacts with (1-methyl-1H-1,2,4-triazol-3-yl)methanol to obtain an intermediate C-2; the intermediate C-2 reacts to obtain an intermediate C-3; and then the intermediate C-3 reacts to obtain a product C-4, namely the ensitrelvir. The synthesis method disclosed in the present invention simplifies the synthesis steps, reduces the cost of starting materials, and has a high yield, thus being suitable for industrial production.

Description

A kind of synthesis method of ensetvir

Technical field

The present invention relates to the technical field of compound synthesis, and specifically relates to a method for synthesizing ensetivir.

Background technique

Currently, the novel coronavirus is spreading around the world, and the number of infections is also rising. People infected with the virus will have varying degrees of symptoms, some will just have a fever or a mild cough, some will develop into pneumonia, and some will be more serious or even death. Therefore, developing a targeted and effective drug is an issue of great concern to everyone.

Ensitrelvir is a small molecule drug jointly developed by Japan's Shionogi Company and Hokkaido University to target the new coronavirus. This is a 3CL protease inhibitor, mainly used to inhibit the activity of the new coronavirus and various mutant strains, thereby achieving the purpose of treating the new coronavirus. Unlike Pfizer Paxlovid (PF-07321332), ensetvir can get rid of dependence on P450 enzyme inhibitors (such as ritonavir) and achieve single-drug treatment of COVID-19 without worrying about other drugs that need to be taken at the same time due to P450 enzyme inhibitory effects. and produce pharmacological reactions.

Its structural formula is:

Currently, only the article "Discovery of S-217622, a Non-Covalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19" in the BioRxiv database reports the synthesis method of ensetvir. The synthesis route is as follows:

In the article, thiourea and ethyl bromide are used as raw materials to produce intermediate A-1 through a substitution reaction. A-1 undergoes ring closure and tert-butyl protection to obtain intermediate A-2. A-2 undergoes a substitution reaction to obtain intermediate A-3, which is then deprotected to obtain intermediate A-4. Finally, after two steps of substitution reaction, intermediate A-5 and the final product A-6 (i.e. ensetvir) are obtained respectively. The overall yield is approximately 5.1%. This route is long, the reagents are expensive, the yield is low, and the production cost is high. The smell of raw materials is unpleasant, and the use of trifluoroacetic acid to deprotect the group is highly corrosive to the equipment and is not conducive to industrial production.

Contents of the invention

In view of the shortcomings of the existing technical solutions, the present invention aims to provide a synthesis method of ensetvir small molecule drug with simplified synthesis steps, low raw material prices, high yield, and suitable for industrial production.

In order to achieve the above object, the present invention provides a synthesis method of ensetvir, and the synthesis method is:

Hydrolysis reaction using cyanuric chloride (SM) as raw material yields intermediate C-1; intermediate C-1 reacts with (1-methyl-1H-1,2,4-triazol-3-yl)methanol to yield intermediate Body C-2; Intermediate C-2 reacts to obtain Intermediate C-3; Intermediate C-3 reacts to obtain Product C-4, which is ensetvir. The reaction equation is as follows: Formula (1):

The hydrolysis reaction from SM to C-1 described in the above synthesis method is carried out in an alkaline or acidic environment; the base is selected from one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide; The acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, and acetic acid; preferably it is one of sodium hydroxide or sulfuric acid.

The reaction from C-1 to C-2 needs to be carried out under conditions containing a reaction reagent, and the reaction reagent is selected from diethyl azodicarboxylate or diisopropyl azodicarboxylate.

Preferably, the reaction reagent is diisopropyl azodicarboxylate.

The reaction of intermediates C-2 to C-3 described in the above synthesis method is the reaction of intermediate C-2 and 2,4,5-trifluorobenzyl bromide under the action of a base; the base is selected from potassium carbonate , one or more of sodium carbonate, cesium carbonate, potassium phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, triethylamine and pyridine; preferably potassium carbonate or Sodium methoxide.

Intermediate C-3 described in the above synthesis method is reacted to obtain product C-4, which is the reaction of intermediate C-3 and 6-chloro-2-methyl-2H-indazole-5-amine under the action of alkali; so Described base is selected from potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium bistrimethylsilylamide, bistrimethylsilylamide One or more of sodium bistrimethylsilylamide and potassium bistrimethylsilylamide; preferably lithium bistrimethylsilylamide or potassium carbonate.

A synthesis method of ensetvir, the synthesis method specifically includes the following steps:

(1) Preparation of intermediate C-1: Add cyanuric chloride to water or alcohol and heat for reaction. After the reaction is completed, intermediate C-1 is obtained. The reaction equation is as follows (2):

(2) Preparation of intermediate C-2:

Add intermediate C-1, triphenylphosphine and (1-methyl-1H-1,2,4-triazol-3-yl)methanol obtained in step (1) to solvent 1, and add reaction reagents , after the reaction is completed, a crystallization solvent is added to obtain intermediate C-2. The reaction equation is as shown in the following formula (3):

(3) Preparation of intermediate C-3:

Add intermediate C-2 obtained in step (2), 2,4,5-trifluorobenzyl bromide and alkali to solvent 2, react under heating conditions, add crystallization solvent after the reaction to obtain intermediate C-3, The reaction equation is shown in the following formula (4):

(4) Preparation of ensetvir (intermediate C-4): Intermediate C-3 and 6-chloro-2-methyl-2H-indazole-5-amine obtained in step (3) are added to the solvent In 3, a base is added, and after the reaction is completed, ensetvir (C-4) is obtained. The reaction equation is as shown in the following formula (5):

The heating reaction described in step (1) is carried out under alkaline or acidic conditions, and the alkali is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; preferably sodium hydroxide; The acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid and acetic acid; preferably sulfuric acid.

The reaction reagent described in step (2) is diethyl azodicarboxylate or diisopropyl azodicarboxylate.

Preferably, the reaction reagent described in step (2) is diisopropyl azodicarboxylate.

The solvent 1 described in step (2) is one or more of tetrahydrofuran, diethyl ether, ethyl acetate, acetonitrile, N,N-dimethylformamide, dichloromethane and toluene.

The crystallization solvent described in step (2) and step (3) is one or more of methyl tert-butyl ether, diethyl ether, ethyl acetate, n-heptane, petroleum ether, acetonitrile, dichloromethane and toluene.

Preferably, the crystallization solvent described in step (2) and step (3) is one or more of ethyl acetate, methyl tert-butyl ether and toluene.

The alkali described in step (3) is potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, triethylamine and pyridine one or more.

Preferably, the base described in step (3) is potassium carbonate or/and sodium methoxide.

The base described in step (4) includes potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, and lithium bistrimethylsilylamide. , one or more of sodium bistrimethylsilylamide and potassium bistrimethylsilylamide.

Preferably, the base described in step (4) is lithium bistrimethylsilylamide or/and potassium carbonate.

beneficial effects

This application has the following beneficial effects:

First, use cheap and easily available cyanuric chloride (SM) as raw material to avoid the cumbersome steps of closing the triazine ring in the original synthesis route;

Second, the reaction of intermediate C-1 with (1-methyl-1H-1,2,4-triazol-3-yl)methanol selectively reacts with the nitrogen at position 6 to avoid the use in the original research route. It is a cumbersome step to protect the nitrogen at position 2 or 4 with tert-butyl group and then remove the protecting group.

Third, it is simple to operate, less corrosive to equipment, and has high product yield, which is suitable for industrial production.

Embodiments of the invention

Hereinafter, the present invention will be described based on specific embodiments. However, the present invention is not limited to this description, and various changes, corrections, and improvements can be made based on the knowledge of those skilled in the art without departing from the scope of the present invention.

Example 1 Synthesis method of intermediate C-1

Specifically, it includes the following steps:

Add 184g of cyanuric chloride to 1000g of water, heat to 40°C, add 25% sodium hydroxide aqueous solution with stirring until the pH value of the solution is maintained at 12-13, and continue stirring for 2 hours. At the end of the reaction, add hydrochloric acid dropwise to adjust the pH to 6-7, cool the solution to 5-10°C, continue stirring for 0.5 hours, filter, rinse with water, and dry to obtain 130.9g of intermediate C-1 as a white solid with HPLC purity of 99.3%. The yield is 88.7%.

Example 2 Synthesis method of intermediate C-1

Specifically, it includes the following steps:

Add 184g of cyanuric chloride to 1000g of water, heat to 50°C, add 25% dilute sulfuric acid with stirring until the pH value of the solution is maintained at 1, and continue stirring for 1 hour. At the end of the reaction, add sodium bicarbonate aqueous solution dropwise to adjust the pH to 6-7, cool the solution to 5-10°C, continue stirring for 0.5 hours, filter, rinse with water, and dry to obtain 119.6g of intermediate C-1 as a white solid, HPLC purity 96.5%, yield 81.1%.

Example 3 Synthesis method of intermediate C-1

Specifically, it includes the following steps:

Add 184g of cyanuric chloride to 1000g of water, heat to 25°C, add 25% lithium hydroxide aqueous solution with stirring until the pH value of the solution is maintained at 12-13, and continue stirring for 15 hours. At the end of the reaction, add hydrochloric acid dropwise to adjust the pH to 6-7, cool the solution to 5-10°C, continue stirring for 0.5 hours, filter, rinse with water, and dry to obtain 115.5g of intermediate C-1 as a white solid with HPLC purity of 97.7%. The yield is 78.3%.

1-H NMR(400MHz,DMSO-d6)δ11.95(2H,br).

Example 4 Synthesis method of intermediate C-2

Specifically, it includes the following steps:

Intermediate C-1 (29.6g, 0.2mol), triphenylphosphine (62.8g, 0.24mol) and (1-methyl-1H-1,2,4-triazole-3- (base) methanol (22.6g, 0.2mol) was added to 500mL tetrahydrofuran, protected by nitrogen replacement, cooled in an ice-water bath, and diisopropyl azodicarboxylate (48.4g, 0.24mol) was slowly added dropwise under stirring. After the dropwise addition is completed, it rises to room temperature and continues stirring for 3 hours. TLC shows that the raw material reaction is complete. The reaction solution is concentrated to dryness. Add 600 mL of ethyl acetate, wash the organic phase with 200 mL of water, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain a solid. Add 200 mL of ethyl acetate, stir for 1 hour, filter, rinse with a small amount of ethyl acetate, and dry the solid to obtain 35.6 g of intermediate C-2, with HPLC purity of 94.3% and yield of 73.3%.

Example 5 Synthesis method of intermediate C-2

Specifically, it includes the following steps:

Intermediate C-1 (14.8g, 0.1mol), triphenylphosphine (31.4g, 0.12mol) and (1-methyl-1H-1,2,4-triazole-3- (base) methanol (11.3g, 0.1mol) was added to 250mL of diethyl ether, protected by nitrogen replacement, cooled in an ice-water bath, and diethyl azodicarboxylate (20.9g, 0.12mol) was slowly added dropwise under stirring. After the dropwise addition, the mixture was raised to room temperature and continued to stir for 3 hours. TLC showed that the reaction of the raw materials was complete. The reaction solution was concentrated to dryness. Add 300 mL of ethyl acetate, wash the organic phase with 100 mL of water, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain a solid. Add 100 mL of methyl tert-butyl ether, stir for 1 hour, filter, rinse with a small amount of ethyl acetate, and dry the solid to obtain 14.9 g of intermediate C-2, with HPLC purity of 92.7% and yield of 61.3%.

1-H NMR(400MHz,DMSO-d6)δ3.88(3H,s),5.09(2H,s),6.71(1H,s),10.66(1H,br).

Example 6 Synthesis method of intermediate C-3

Specifically, it includes the following steps:

Intermediate C-2 (24.3g, 0.1mol), 2,4,5-trifluorobenzyl bromide (23.6g, 1.05mol) and potassium carbonate (20.7g, 0.15mol) obtained in Example 4 were added to 250 mL of toluene medium, raised to room temperature 85°C, and stirred for 3 hours. TLC showed that the reaction of the raw materials was complete. The reaction solution was diluted with 100 mL of toluene, and the organic phase was washed with 150 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a solid. Add 50 mL of ethyl acetate, stir for 1 hour, filter, and dry the solid to obtain 36.7 g of intermediate C-3. HPLC The purity is 95.1% and the yield is 94.8%.

Example 7 Synthesis method of intermediate C-3

Specifically, it includes the following steps:

Intermediate C-2 (2.4g, 10mmol), 2,4,5-trifluorobenzyl bromide (2.4g, 10.5mmol) and sodium methoxide (4.9g, 15mmol) obtained in Example 4 were added to 50mL of toluene, Raise to room temperature 100°C and stir for 1 hour. TLC shows that the reaction of the raw materials is complete. The reaction solution was diluted with 50 mL of toluene, and the organic phase was washed with 50 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a solid. Add 15 mL of toluene, stir for 1 hour, filter, and dry the solid to obtain 3.4 g of intermediate C-3, HPLC purity 93.3 %, yield 88.3%.

1-H NMR(400MHz, CDCl3)δ3.87(3H,s),5.13(2H,s),5.22(2H,s),6.67(1H,s),6.91-6.97(1H,m),7.12- 7.19(1H,m).

Example 8 Synthetic method of ensetvir

Specifically, it includes the following steps:

Intermediate C-3 (3.8g, 0.01mol) and 6-chloro-2-methyl-2H-indazole-5-amine (2.0g, 0.011mol) obtained in Example 7 were added to 50mL of anhydrous tetrahydrofuran, Nitrogen replacement protection, cooling to 0℃. Slowly add 1 mol/L lithium bistrimethylsilylamide (15 mL, 0.015 mol) dropwise while stirring. Complete the dropwise addition in about 1 hour. Continue stirring at 0°C for 1 hour, then raise to room temperature and stir for 1 hour. The reaction solution was added to 60 mL of saturated ammonium chloride solution to quench, and extracted twice with 30 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by silica gel column chromatography (methanol: dichloromethane). =5%~15%), 4.7g of ensetvir (C-4) solid was obtained, with HPLC purity of 98.9% and yield of 88.1%.

Example 9 Synthetic method of ensetvir

Specifically, it includes the following steps:

Intermediate C-3 (3.8g, 0.01mol) and 6-chloro-2-methyl-2H-indazole-5-amine (2.0g, 0.011mol) obtained in Example 7 were added to 50mL of anhydrous tetrahydrofuran, Nitrogen replacement protection, cooling to 0℃. Slowly add 1 mol/L potassium carbonate (15 mL, 0.015 mol) dropwise while stirring. Complete the dropwise addition in about 1 hour. Continue stirring at 0°C for 1 hour, then raise to room temperature and stir for 1 hour. The reaction solution was added to 60 mL of saturated ammonium chloride solution to quench, and extracted twice with 30 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by silica gel column chromatography (methanol: dichloromethane). =5%-15%), 1.9g of ensetvir (C-4) was obtained as a light brown solid, with HPLC purity of 98.7% and yield of 34.8%.

Example 10 Synthetic method of ensetvir

Specifically, it includes the following steps:

Intermediate C-3 (3.8g, 0.01mol) and 6-chloro-2-methyl-2H-indazole-5-amine (2.0g, 0.011mol) obtained in Example 7 were added to 50mL of anhydrous tetrahydrofuran, Nitrogen replacement protection, cooling to 0℃. Slowly add 1 mol/L potassium bistrimethylsilylamide (15 mL, 0.015 mol) dropwise while stirring. Complete the dropwise addition in about 1 hour. Continue stirring at 0°C for 1 hour, then raise to room temperature and stir for 1 hour. The reaction solution was added to 60 mL of saturated ammonium chloride solution to quench, and extracted twice with 30 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by silica gel column chromatography (methanol: dichloromethane). =5%-15%), 3.0g of ensetvir (C-4) solid was obtained, with HPLC purity of 96.7% and yield of 55.8%.

1-H NMR(400MHz,pyridine-d5)δ3.89(3H,s),4.13(3H,s),5.06(2H,s),5.28(2H,s),7.47(1H,m),7.53- 7.67(2H,m),7.75(1H,s),8.43(1H,s),9.34(1H,s).

Claims

A synthesis method of ensetvir, characterized in that: the synthesis method is as follows:

Intermediate C-1 is obtained by reacting with cyanuric chloride as raw material; intermediate C-1 is reacted with (1-methyl-1H-1,2,4-triazol-3-yl)methanol to obtain intermediate C-2 ; Intermediate C-2 reacts to obtain intermediate C-3; intermediate C-3 reacts to obtain product C-4, which is ensetvir. The reaction equation is as follows: Formula (1):
A method for synthesizing ensetvir according to claim 1, characterized in that: it specifically includes the following steps:

(1) Preparation of intermediate C-1: Add cyanuric chloride to water or alcohol and heat for reaction. After the reaction is completed, intermediate C-1 is obtained. The reaction equation is as follows (2):

(2) Preparation of intermediate C-2: Intermediate C-1 obtained in step (1), triphenylphosphine and (1-methyl-1H-1,2,4-triazol-3-yl) Methanol is added to solvent 1, and reaction reagents are added. After the reaction is completed, crystallization solvent is added to obtain intermediate C-2. The reaction equation is as follows (3):

(3) Preparation of intermediate C-3: Intermediate C-2 obtained in step (2), 2,4,5-trifluorobenzyl bromide and alkali are added to solvent 2, react under heating conditions, and the reaction is completed Add a crystallization solvent to obtain intermediate C-3, and the reaction equation is as shown in the following formula (4):

(4) Preparation of ensetvir, i.e. C-4: Intermediate C-3 and 6-chloro-2-methyl-2H-indazole-5-amine obtained in step (3) are added to solvent 3, Add a base, and after the reaction is completed, ensetvir (C-4) is obtained. The reaction equation is as shown in the following formula (5):
The synthesis method of ensetvir according to claim 2, characterized in that the heating reaction described in step (1) is performed under alkaline or acidic conditions.
A method for synthesizing ensetvir according to claim 3, characterized in that the base is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.
The method for synthesizing ensetvir according to claim 3, wherein the acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid and acetic acid.
The synthesis method of ensetivir according to claim 2, characterized in that the reaction reagent in step (2) is diethyl azodicarboxylate or diisopropyl azodicarboxylate.
The synthesis method of ensetivir according to claim 2, characterized in that the solvent 1 described in step (2) is tetrahydrofuran, diethyl ether, ethyl acetate, acetonitrile, N, N-dimethylform Amide, one or more of dichloromethane or toluene.
The synthesis method of ensetvir according to claim 2, characterized in that the crystallization solvent described in step (2) and step (3) is methyl tert-butyl ether, diethyl ether, ethyl acetate, One or more of n-heptane, acetonitrile, methylene chloride or toluene.
The synthesis method of ensetvir according to claim 2, characterized in that the alkali described in step (3) is potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium methoxide, sodium ethoxide, tert. One or more of sodium butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, triethylamine and pyridine.
The synthesis method of ensetvir according to claim 2, characterized in that the base described in step (4) includes potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide, One or more of sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide and potassium bistrimethylsilylamide.