CN111004188B - NS3/4A protease inhibitor intermediate, and synthetic method and application thereof - Google Patents

NS3/4A protease inhibitor intermediate, and synthetic method and application thereof Download PDF

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CN111004188B
CN111004188B CN201911308644.6A CN201911308644A CN111004188B CN 111004188 B CN111004188 B CN 111004188B CN 201911308644 A CN201911308644 A CN 201911308644A CN 111004188 B CN111004188 B CN 111004188B
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quinoxaline
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高仰哲
吴法浩
李钢
王志航
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Anhui Sequoia Biomedical Technology Co ltd
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Abstract

The invention belongs to the technical field of medicines, and particularly relates to an NS3/4A protease inhibitor intermediate, a synthetic method and application thereof, wherein the synthetic method comprises the following steps: 4-methoxy o-phenylenediamine is taken as an initial raw material to carry out a plurality of reactions in sequence; drying and filtering to obtain the 2, 3-dichloro-6-methoxy quinoxaline; the NS3/4A protease inhibitor intermediate and the synthesis method and application thereof select 4-methoxy o-phenylenediamine as a raw material, combine a reactant which is added subsequently to react, and finally synthesize 2, 3-dichloro-6-methoxy quinoxaline, and the purity and yield of the product can be effectively improved by reasonably setting the component content ratio of each raw material; the purity of the final product is as high as 99%, the yield is more than 90%, and the method is favorable for industrial production.

Description

NS3/4A protease inhibitor intermediate, and synthetic method and application thereof
Technical Field
The invention relates to the technical field of medicines, and particularly relates to an NS3/4A protease inhibitor intermediate, and a synthesis method and application thereof.
Background
Viral hepatitis C, a viral hepatitis caused by Hepatitis C Virus (HCV) infection, is mainly transmitted by blood transfusion, acupuncture, drug inhalation, etc., and is epidemic worldwide, which can cause chronic inflammation necrosis and fibrosis of liver, and some patients can develop liver cirrhosis and even hepatocellular carcinoma (HCC). The mortality rate associated with HCV infection (death from liver failure and hepatocellular carcinoma) will continue to increase over the next 20 years, posing significant health and life risks to the patient and becoming a serious social and public health problem.
The Moshadong company discloses a hepatitis C drug compound Zepatier and discloses MK-5172(NS3/4A protease inhibitor) + MK-8742(NS5A inhibitor) for treating HIV and genotype 1 HCV. This drug combination was once qualified by FDA for breakthrough medication in 2013, month 10.
The product 2, 3-dichloro-6-methoxy quinoxaline related by the invention is just an intermediate of MK-5172, and the existing route is to synthesize the 2, 3-dichloro-6-methoxy quinoxaline by taking 4-methoxy o-phenylenediamine and oxalic acid as raw materials and POCl3 as a reagent, but phosphide is not easy to treat and has large environmental hazard, so that the method is not beneficial to industrial production.
Disclosure of Invention
The invention aims to provide an NS3/4A protease inhibitor intermediate, a synthetic method and application thereof.
In order to solve the technical problems, the invention provides a method for synthesizing 2, 3-dichloro-6-methoxy quinoxaline, which comprises the following steps: 4-methoxy o-phenylenediamine is taken as an initial raw material to carry out a plurality of reactions in sequence; and drying and filtering to obtain the 2, 3-dichloro-6-methoxy quinoxaline.
Further, the reaction formula of the first reaction is as follows:
Figure BDA0002323887290000021
further, the first reaction comprises:
adding 4-methoxy o-phenylenediamine and formic acid into a reaction kettle, dropwise adding acetic anhydride at normal temperature, heating to 85-90 ℃ for reaction for about 4 hours, concentrating to slurry after the reaction is finished, adding water for crystallization to obtain 4-methoxy phthalic diamide for later use.
Further, the reaction formula of the second reaction is:
Figure BDA0002323887290000022
further, the second reaction comprises:
adding the 4-methoxy phthalic diamide obtained after the first reaction into methanol, keeping the temperature below 10 ℃, adding metal sodium for multiple times, heating to 50 ℃ after the addition is finished, reacting for about 4 hours, and cooling to below 20 ℃; and
then adding hydrochloric acid, heating to 65 ℃ and reacting for about 6 hours to obtain 2, 3-dihydroxy-6-methoxy quinoxaline for later use.
Further, the reaction formula of the third reaction is:
Figure BDA0002323887290000023
further, the third reaction comprises:
adding the 2, 3-dihydroxy-6-methoxy quinoxaline obtained by the second reaction into dichloromethane, dropwise adding acetyl chloride, reacting for about 1h at 20-25 ℃ after dropwise adding, filtering, and drying to obtain the product 2, 3-dichloro-6-methoxy quinoxaline.
Furthermore, the molar ratio of the 4-methoxy o-phenylenediamine to the acetic anhydride is 1: 1.2-2.
Furthermore, the molar ratio of the 4-methoxyphthalamide to the metal sodium is 1: 2-3.
Further, the molar ratio of 2, 3-dihydroxy-6-methoxyquinoxaline to acetyl chloride is 1: 3-4.
In another aspect, the present invention also provides a 2, 3-dichloro-6-methoxyquinoxaline, wherein the structural formula of the 2, 3-dichloro-6-methoxyquinoxaline is:
Figure BDA0002323887290000031
in a third aspect, the present invention further provides a first reactant for synthesizing 2, 3-dichloro-6-methoxyquinoxaline, wherein the structural formula of the first reactant is:
Figure BDA0002323887290000032
in a fourth aspect, the present invention further provides a second reactant for synthesizing 2, 3-dichloro-6-methoxyquinoxaline, wherein the structural formula of the second reactant is:
Figure BDA0002323887290000033
in a fifth aspect, the invention also provides application of the 2, 3-dichloro-6-methoxy quinoxaline as an intermediate for synthesizing the NS3/4A protease inhibitor.
The NS3/4A protease inhibitor intermediate, the synthesis method and the application thereof have the advantages that 4-methoxy o-phenylenediamine is selected as an initial raw material, the subsequent added reactants are combined for reaction, 2, 3-dichloro-6-methoxy quinoxaline is finally synthesized, the reaction rate can be effectively improved and the reaction time can be shortened by controlling the reaction conditions (such as the reaction conditions, the addition time of the reactants, the reaction temperature and the like) of the reaction; by reasonably setting the component content proportion of each raw material, the purity and yield of the product can be effectively improved. Therefore, the synthesis method has the advantages of cheap and easily-obtained raw materials, easy treatment of byproducts, short reaction time, high chemical purity of the product, high yield and the like, particularly the purity of the final product is up to 99%, the yield is up to more than 90%, and the synthesis method is favorable for industrial production and has better industrial prospect.
Drawings
The invention is further illustrated with reference to the following figures and examples.
FIG. 1 is a process flow diagram of the synthetic method of the present invention.
Detailed Description
To make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings, and it is apparent that the described embodiments are some, but not all embodiments of the present invention. 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
As shown in fig. 1, this example 1 provides a method for synthesizing 2, 3-dichloro-6-methoxyquinoxaline, comprising: step S1, taking 4-methoxy o-phenylenediamine as an initial raw material to perform multiple reactions in sequence; and a step S2 of drying and filtering to obtain the 2, 3-dichloro-6-methoxy quinoxaline.
Specifically, in the embodiment 1, 4-methoxy o-phenylenediamine is selected as a raw material, and is combined with a reactant which is added subsequently to perform a reaction, so as to finally synthesize 2, 3-dichloro-6-methoxy quinoxaline, and the purity and the yield of the product can be effectively improved by reasonably setting the component content ratio of each raw material; the purity of the final product is as high as 99%, the yield is more than 90%, and the method is favorable for industrial production.
Further, the reaction formula of the first reaction is as follows:
Figure BDA0002323887290000051
as an alternative to the first reaction.
The first reaction comprises the following steps:
adding 4-methoxy o-phenylenediamine and formic acid into a reaction kettle, dropwise adding acetic anhydride at normal temperature, heating to 85-90 ℃ for reaction for about 4 hours, concentrating to slurry after the reaction is finished, adding water for crystallization, filtering, and drying to obtain 4-methoxy phthalic diamide for later use.
Further, the reaction formula of the second reaction is:
Figure BDA0002323887290000052
as an alternative embodiment of the second reaction.
The second reaction comprises the following steps:
adding the 4-methoxy phthalic diamide obtained after the first reaction into methanol, keeping the temperature below 10 ℃, adding metal sodium for multiple times, heating to 50 ℃ after the addition is finished, reacting for about 4 hours, and cooling to below 20 ℃; and
and then adding hydrochloric acid, heating to 65 ℃ for reaction for about 6 hours, concentrating to be dry after the reaction is finished, adding water for crystallization, and filtering to obtain 2, 3-dihydroxy-6-methoxy quinoxaline for later use.
Further, the reaction formula of the third reaction is:
Figure BDA0002323887290000053
as an alternative embodiment of the third reaction.
The third reaction comprises: adding the 2, 3-dihydroxy-6-methoxy quinoxaline obtained by the second reaction into dichloromethane, dropwise adding acetyl chloride, reacting for about 1h at 20-25 ℃ after dropwise adding, filtering, and drying to obtain the product 2, 3-dichloro-6-methoxy quinoxaline.
Furthermore, the molar ratio of the 4-methoxy o-phenylenediamine to the acetic anhydride is 1: 1.2-2.
Furthermore, the molar ratio of the 4-methoxyphthalamide to the metal sodium is 1: 2-3.
Further, the molar ratio of 2, 3-dihydroxy-6-methoxyquinoxaline to acetyl chloride is 1: 3-4.
Example 2
On the basis of example 1, this example 2 provides a 2, 3-dichloro-6-methoxyquinoxaline, and the structural formula of the 2, 3-dichloro-6-methoxyquinoxaline is:
Figure BDA0002323887290000061
specifically, for the content of the 2, 3-dichloro-6-methoxyquinoxaline and the specific implementation process, reference is made to the relevant discussion of example 1, and further description is omitted here.
Example 3
On the basis of example 1, this example 3 provides a first reactant for synthesizing 2, 3-dichloro-6-methoxyquinoxaline, wherein the structural formula of the first reactant is as follows:
Figure BDA0002323887290000062
specifically, the first reactant is 4-methoxyphthalamide.
Specifically, for the content of the 4-methoxyphthalamide and the specific implementation process, reference is made to the relevant discussion of example 1, and further description is omitted here.
Example 4
On the basis of example 1, this example 4 provides a second reactant for synthesizing 2, 3-dichloro-6-methoxyquinoxaline, wherein the structural formula of the second reactant is as follows:
Figure BDA0002323887290000071
specifically, the second reactant is 2, 3-dihydroxy-6-methoxy quinoxaline.
Specifically, for the content of the 2, 3-dihydroxy-6-methoxy quinoxaline and the specific implementation process, refer to the related discussion of example 1, and are not repeated herein.
Example 5
Based on example 1, this example 5 provides the use of 2, 3-dichloro-6-methoxyquinoxaline as an intermediate in the synthesis of NS3/4A protease inhibitor.
Specifically, for the content of the 2, 3-dichloro-6-methoxyquinoxaline and the specific implementation process, reference is made to the relevant discussion of example 1, and further description is omitted here.
Example 6
Example 6 exemplifies four experiments, and studies were made on the influence of the purity and yield of 2, 3-dichloro-6-methoxyquinoxaline, a product synthesized by the four experiments, as shown in table 1.
TABLE 1 component content and product yield
Figure BDA0002323887290000072
Group 1
(1) Taking 100g of 4-methoxy o-phenylenediamine, adding 500g of formic acid, keeping the temperature at 20-25 ℃, dropwise adding 88.5g of acetic anhydride, ending dropwise adding, heating to 85-90 ℃, reacting for 4 hours, controlling by HPLC (high performance liquid chromatography), concentrating the raw material to be less than 1% into slurry, adding 500 ml of water, crystallizing, filtering, and drying at 60 ℃ to obtain 131g of 4-methoxy phthalic diamide, wherein the purity is 99.1%, and the yield is 93.5%.
(2) Adding the 4-methoxy phthalic diamide obtained in the step (1) into 560g of methanol, adding 31g of metal sodium in portions, controlling the temperature within 10 ℃, connecting with a gas guide pipe, and leading out the tail gas. After the addition of the metallic sodium, the reaction was carried out at 50 ℃ for 4 hours. Cooling to 20 ℃, adding 100 ml of hydrochloric acid, heating to 65 ℃ and reacting for 6 hours. After the reaction is finished, the mixture is concentrated to be dry, 600 ml of water is added for crystallization, filtration and drying to obtain 122.5g of 2.3-dihydroxy-6-methoxy quinoxaline, the purity is 99.2 percent, and the yield is 94.5 percent.
(3) Adding 122.5g of 2, 3-dihydroxy-6-methoxy quinoxaline obtained in the step (2) into 700 ml of dichloromethane, dropwise adding 150g of acetyl chloride, reacting for 1 hour at room temperature, and filtering to obtain 142.8g of product 2, 3-dichloro-6-methoxy quinoxaline, wherein the purity is 99.1 percent, and the yield is 97.8 percent.
Group 2
(1) 100g of 4-methoxy o-phenylenediamine is taken, 500g of formic acid is added, 110.7g of acetic anhydride is dropwise added at the temperature of 20-25 ℃, the temperature is raised to 85-90 ℃ for reaction for 4 hours after the dropwise addition is finished, the HPLC is controlled, the raw material is less than 1 percent, the raw material is concentrated into slurry, 500 ml of water is added, the crystallization and filtration are carried out, and the drying is carried out at the temperature of 60 ℃ to obtain 135.6g of 4-methoxy phthalic diamide, the purity is 99.2 percent, and the yield is 91.8 percent.
(2) Adding 135.6g of 4-methoxy phthalic diamide obtained in the step (1) into 560g of methanol, adding 40g of metal sodium in portions, controlling the temperature within 10 ℃, connecting a gas guide pipe, and leading out tail gas. After the addition of the metallic sodium, the reaction was carried out at 50 ℃ for 4 hours. Cooling to 20 ℃, adding 100 ml of hydrochloric acid, heating to 65 ℃ and reacting for 6 hours. After the reaction is finished, the mixture is concentrated to be dry, 600 ml of water is added for crystallization, filtration and drying to obtain 130.1g of 2.3-dihydroxy-6-methoxy quinoxaline, the purity is 99.2 percent, and the yield is 97 percent.
(3) Adding 130.1g of 2, 3-dihydroxy-6-methoxy quinoxaline obtained in the step (2) into 700 ml of dichloromethane, dropwise adding 180.6g of acetyl chloride, reacting for 1 hour at room temperature, and filtering to obtain 149.6g of a product, namely 2, 3-dichloro-6-methoxy quinoxaline, with the purity of 99.2 percent and the yield of 96.5 percent.
Group 3
(1) 100g of 4-methoxy o-phenylenediamine is taken, 500g of formic acid is added, 125.5g of acetic anhydride is dropwise added at the temperature of 20-25 ℃, the temperature is raised to 85-90 ℃ for reaction for 4 hours after the dropwise addition is finished, the HPLC is controlled, the raw material is less than 1 percent, the raw material is concentrated into slurry, 450 ml of water is added, crystals are filtered, and the raw material is dried at 60 ℃ to obtain 137g of 4-methoxy phthalic diamide, the purity is 99.1 percent, and the yield is 97.5 percent.
(2) Adding 137g of 4-methoxy phthalic diamide obtained in the step (1) into 500g of methanol, adding 25g of metal sodium for multiple times, controlling the temperature within 10 ℃, connecting with a gas guide pipe, and leading out tail gas. After the addition of the metallic sodium, the reaction was carried out at 50 ℃ for 4 hours. Cooling to within 20 ℃, adding 90 ml of hydrochloric acid, heating to 65 ℃ and reacting for 6 hours. After the reaction is finished, the mixture is concentrated to be dry, 600 ml of water is added for crystallization, filtration and drying to obtain 130.8g of 2.3-dihydroxy-6-methoxy quinoxaline, the purity is 99.5 percent, and the yield is 96.5 percent.
(3) 130.8g of 2, 3-dihydroxy-6-methoxy quinoxaline obtained in the step (2) is added into 600 ml of dichloromethane, 197.6g of acetyl chloride is dripped, the reaction is carried out for 1 hour at room temperature, and 153.6g of 2, 3-dichloro-6-methoxy quinoxaline with the purity of 99.6 percent and the yield of 98.5 percent is obtained by filtration.
Group 4
(1) 100g of 4-methoxy o-phenylenediamine is taken, 500g of formic acid is added, 147.6g of acetic anhydride is dropwise added at the temperature of 20-25 ℃, the temperature is raised to 85-90 ℃ for reaction for 4 hours after the dropwise addition is finished, the HPLC is controlled, the raw material is less than 1 percent, the raw material is concentrated into slurry, 450 ml of water is added, crystals are filtered, and the raw material is dried at 60 ℃ to obtain 137g of 4-methoxy phthalic diamide, the purity is 99.4 percent, and the yield is 97.5 percent.
(2) Adding 137g of 4-methoxy phthalic diamide obtained in the step (1) into 500g of methanol, adding 25g of metal sodium for multiple times, controlling the temperature within 10 ℃, connecting with a gas guide pipe, and leading out tail gas. After the addition of the metallic sodium, the reaction was carried out at 50 ℃ for 4 hours. Cooling to within 20 ℃, adding 90 ml of hydrochloric acid, heating to 65 ℃ and reacting for 6 hours. After the reaction is finished, the reaction solution is concentrated to be dry, 600 ml of water is added for crystallization, filtration and drying to obtain 132.1g of 2.3-dihydroxy-6-methoxy quinoxaline, the purity is 99.5 percent, and the yield is 97.5 percent.
(3) Adding 132.1g of 2, 3-dihydroxy-6-methoxy quinoxaline obtained in the step (2) into 600 ml of dichloromethane, dropwise adding 215.8g of acetyl chloride, reacting for 1 hour at room temperature, and filtering to obtain 154.3g of 2, 3-dichloro-6-methoxy quinoxaline with the purity of 99.5 percent and the yield of 98 percent.
In conclusion, the NS3/4A protease inhibitor intermediate, the synthesis method and the application thereof select 4-methoxy o-phenylenediamine as an initial raw material, combine a reactant which is added subsequently to react to finally synthesize the 2, 3-dichloro-6-methoxy quinoxaline, and can effectively improve the reaction rate and shorten the reaction time by controlling the reaction conditions (such as reaction conditions, the addition time of the reactant, the reaction temperature and the like) of the reaction; by reasonably setting the component content proportion of each raw material, the purity and yield of the product can be effectively improved. Therefore, the synthesis method has the advantages of cheap and easily-obtained raw materials, easy treatment of byproducts, short reaction time, high chemical purity of the product, high yield and the like, particularly the purity of the final product is up to 99%, the yield is up to more than 90%, and the synthesis method is favorable for industrial production and has better industrial prospect.
In light of the foregoing description of the preferred embodiment of the present invention, many modifications and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.

Claims (5)

1. A method for synthesizing 2, 3-dichloro-6-methoxy quinoxaline is characterized by comprising the following steps:
4-methoxy o-phenylenediamine is taken as an initial raw material to carry out three reactions in sequence; and
drying and filtering to obtain the 2, 3-dichloro-6-methoxy quinoxaline;
the reaction formula of the first reaction is as follows:
Figure FDA0002947524190000011
the reaction formula of the second reaction is as follows:
Figure FDA0002947524190000012
the reaction formula of the third reaction is as follows:
Figure FDA0002947524190000013
the first reaction comprises the following steps:
adding 4-methoxy o-phenylenediamine and formic acid into a reaction kettle, dropwise adding acetic anhydride at normal temperature, heating to 85-90 ℃ for reaction for 4 hours, concentrating to slurry after the reaction is finished, adding water for crystallization to obtain 4-methoxy phthalic diamide for later use;
the second reaction comprises the following steps:
adding the 4-methoxy phthalic diamide obtained after the first reaction into methanol, keeping the temperature below 10 ℃, adding metal sodium for multiple times, heating to 50 ℃ after the addition is finished, reacting for 4 hours, and cooling to below 20 ℃; and
then adding hydrochloric acid, heating to 65 ℃ and reacting for 6h to obtain 2, 3-dihydroxy-6-methoxy quinoxaline for later use.
2. The method of synthesis according to claim 1,
the third reaction comprises:
adding the 2, 3-dihydroxy-6-methoxy quinoxaline obtained by the second reaction into dichloromethane, dropwise adding acetyl chloride, reacting for 1h at 20-25 ℃ after dropwise adding, filtering, and drying to obtain the product 2, 3-dichloro-6-methoxy quinoxaline.
3. The method of synthesis according to claim 2,
the molar ratio of the 4-methoxy o-phenylenediamine to the acetic anhydride is 1: 1.2-2.
4. The method of synthesis according to claim 3,
the molar ratio of the 4-methoxyphthalamide to the metal sodium is 1: 2-3.
5. The method of synthesis according to claim 4,
2.3-dihydroxy-6-methoxy-quinoxaline and acetyl chloride in a molar ratio of 1: 3-4.
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