CN114213430B - Preparation method of 4-aminothiophene[3,2-d]pyrimidine-7-carboxylic acid, protein kinase inhibitor intermediate - Google Patents

Abstract

The application belongs to the technical field of protein kinase inhibitors, and relates to a preparation method of 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid and a protein kinase inhibitor intermediate. In a first aspect, the present application provides a method for preparing 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid, comprising the steps of: mixing 4-methyl-3-thiophene amine, N-cyanoimino-S, S-dimethyl dithiocarbonate and a first solvent, carrying out nucleophilic addition reaction and intramolecular Friedel-crafts reaction to obtain a first intermediate; mixing the first intermediate, a reducing agent and a second solvent, and removing methylthio to obtain a second intermediate; and (3) carrying out mixing treatment and oxidation reaction on the second intermediate, an oxidant and a third solvent to obtain the 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid. The application provides a reasonable synthetic route for synthesizing 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid.

Description

Preparation method of 4-aminothiophene[3,2-d]pyrimidine-7-carboxylic acid, protein kinase inhibition agent intermediate

technical field

The application belongs to the technical field of protein kinase inhibitors, and more specifically, relates to a preparation method of 4-aminothiophene[3,2-d]pyrimidine-7-carboxylic acid and an intermediate of protein kinase inhibitors.

Background technique

Protein kinases are enzymes that play a key role in the mediation of signal transduction by phosphorylating hydroxyl groups in tyrosine, serine, or threonine residues and are thus deeply involved in the processes of cell growth, differentiation, proliferation, etc. adjust. Wherein, the structure of 4-aminothiophene[3,2-d]pyrimidine-7-carboxylic acid is shown in formula III. 4-Aminothiophene[3,2-d]pyrimidine-7-carboxylic acid is an important intermediate of various protein kinase inhibitors, including the drug Belvarafenib (GDC-5573), which is being clinically used to treat advanced solid tumors.

At present, the document Org.Process.Res.Dev.2021(25)2338-2350 published a method for the synthesis of 4-aminothiophene[3,2-d]pyrimidine-7-carboxylic acid: methyl thiopheneaminocarboxylate as substrate , first in 2-methoxyethanol solvent, carry out condensation cyclization with formamidine acetate, prepare thienopyrimidinone 1c; then, in the acetic acid solution that sodium acetate exists, obtain bromide 1d through bromine treatment; Then , treated with phosphorus oxychloride to convert the ketone to the corresponding chlorinated compound 1e; in isopropanol, use tert-butylamine at high temperature to carry out nucleophilic substitution of the chlorinated compound to amine 1f; bromoarene 2f is reacted in palladium acetate and BINAP ( Under the catalysis of 1,1'-binaphthyl-2,2'-bisdiphenylphosphine), react with carbon monoxide in triethylamine and methanol, and undergo carbonyl insertion to generate 1 g of methyl carboxylate; The tert-butyl group on the ammonium is removed, treated with potassium hydroxide and hydrolyzed to generate the final product 4-aminothiophene[3,2-d]pyrimidine-7-carboxylic acid. This process route uses high-pressure carbon monoxide, the conditions are relatively harsh, and it is very unfriendly to the environment and personnel; at the same time, the route is long, which is very unfavorable for large-scale synthesis. The abbreviated synthetic route is shown in Formula 1:

Contents of the invention

Aiming at the prior art, the purpose of this application is to provide a method for the preparation of protein kinase inhibitor intermediates, aiming to solve the problem in the prior art that the synthetic route is complex and unfavorable to production.

In order to realize the above-mentioned application purpose, the technical scheme adopted in this application is as follows:

The application provides a preparation method of 4-aminothiophene [3,2-d] pyrimidine-7-carboxylic acid, comprising the following steps:

4-methyl-3-thiopheneamine, N-cyanoimino-S, S-dimethyl dithiocarbonate and the first solvent are mixed, nucleophilic addition reaction, intramolecular Friedel-Crafts reaction, Obtain the first intermediate;

The first intermediate, the reducing agent and the second solvent are mixed and processed, and the methylthio group is removed to obtain the second intermediate;

performing mixed treatment and oxidation reaction on the second intermediate, the oxidizing agent and the third solvent to obtain 4-aminothiophene[3,2-d]pyrimidine-7-carboxylic acid;

Wherein, the structural formula of the first intermediate is shown in formula I, and the structural formula of the second intermediate is shown in formula II;

This application provides a reasonable synthetic route for the synthesis of 4-aminothiophene[3,2-d]pyrimidine-7-carboxylic acid. This synthetic route only needs three steps to complete 4-aminothiophene[3,2-d ] pyrimidine-7-carboxylic acid, the synthetic route is short, saves synthetic time, the first aspect is with 4-methyl-3-thienylamine, N-cyanoimino-S, S-dimethyl dithiocarbonate as The raw material undergoes continuous nucleophilic addition reaction and intramolecular Friedel-Crafts reaction, the reaction speed is fast, there are no other by-products, and the purity of the first intermediate is higher. The second aspect is to remove methylsulfide through the first intermediate base reaction, the reaction speed is fast, there are no other by-products, and the purity of the second intermediate is obtained. The third aspect is through the oxidation reaction of the second intermediate, and there are no other by-products to obtain 4-aminothiophene [3,2-d ] The purity of pyrimidine-7-carboxylic acid is relatively high. Therefore, the preparation process provided in the examples of the present application has high synthesis efficiency, less by-products, and saves synthesis cost.

The second aspect of the present application provides a protein kinase inhibitor intermediate, including a first intermediate and/or a second intermediate, the structural formula of the first intermediate is shown in formula I, and the structural formula of the second intermediate is shown in formula II shown;

The protein kinase inhibitor intermediate provided by the application, the first intermediate and the second intermediate in the first aspect, can exist stably, and the first intermediate and the second intermediate in the second aspect are 4-aminothiophene [3,2 -d] an intermediate product of pyrimidine-7-carboxylic acid, wherein the first intermediate can generate a second intermediate through a reductive desulfurization reaction, and the second intermediate can undergo an oxidation reaction to generate 4-aminothiophene[3,2-d] Pyrimidine-7-carboxylic acid.

Detailed ways

In order to make the technical problems, technical solutions and beneficial effects to be solved in the present application clearer, the present application will be further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described here are only used to explain the present application, and are not intended to limit the present application.

In this application, the term "and/or" describes the association relationship of associated objects, indicating that there may be three relationships, for example, A and/or B may mean: A exists alone, A and B exist simultaneously, and B exists alone Condition. Among them, A and B can be singular or plural. The character "/" generally indicates that the contextual objects are an "or" relationship.

In this application, "at least one" means one or more, and "multiple" means two or more. "At least one of the following" or similar expressions refer to any combination of these items, including any combination of single or plural items. For example, "a, b, or at least one item (unit) of c", or, "at least one item (unit) of a, b, and c", can mean: a, b, c, a-b( That is, a and b), a-c, b-c, or a-b-c, where a, b, and c can be single or multiple.

It should be understood that in various embodiments of the present application, the sequence numbers of the above-mentioned processes do not mean the order of execution, and some or all steps may be executed in parallel or sequentially, and the execution order of each process shall be based on its functions and The internal logic is determined, and should not constitute any limitation on the implementation process of the implementation regulations of this application.

The terms used in the embodiments of the present application are only for the purpose of describing specific implementation regulations, and are not intended to limit the present application. As used in the Regulations of this application and the appended claims, the singular forms "a", "the" and "the" are also intended to include the plural forms unless the context clearly dictates otherwise.

The weight of the relevant components mentioned in the description of the embodiments of the present application can not only refer to the specific content of each component, but also represent the proportional relationship between the weights of the various components. The scaling up or down of the content of the fraction is within the scope disclosed in the description of the embodiments of the present application. Specifically, the mass described in the description of the embodiments of the present application may be μg, mg, g, kg and other well-known mass units in the chemical industry.

The terms first and "second" are only used for descriptive purposes to distinguish objects such as substances from each other, and cannot be understood as indicating or implying relative importance or implicitly indicating the number of indicated technical features. For example, without departing from the scope of the implementation regulations of this application, the first XX can also be called the second XX, and similarly, the second XX can also be called the first XX. Thus, a feature defined as "first" and "second" may explicitly or implicitly include one or more of these features.

The embodiment of the present application provides a preparation method of 4-aminothiophene[3,2-d]pyrimidine-7-carboxylic acid, comprising the following steps:

Step S10: Mixing 4-methyl-3-thiopheneamine, N-cyanoimino-S,S-dimethyldithiocarbonate and the first solvent, nucleophilic addition reaction, intramolecular Fu- Gram reaction, obtains the first intermediate;

Step S20: Mixing the first intermediate, the reducing agent and the second solvent to remove the methylthio group to obtain the second intermediate;

Step S30: performing mixed treatment and oxidation reaction on the second intermediate, the oxidizing agent and the third solvent to obtain 4-aminothiophene[3,2-d]pyrimidine-7-carboxylic acid;

Wherein, the structural formula of the first intermediate is shown in formula I, and the structural formula of the second intermediate is shown in formula II;

The examples of this application provide a reasonable synthetic route for the synthesis of 4-aminothiophene[3,2-d]pyrimidine-7-carboxylic acid. This synthetic route only needs three steps to complete 4-aminothiophene[3,2 -d] pyrimidine-7-carboxylic acid, the synthesis route is short, and the synthesis time is saved. The raw material undergoes continuous nucleophilic addition reaction and intramolecular Friedel-Crafts reaction, the reaction speed is fast, there are no other by-products, the purity of the first intermediate is high, and then the methylthio group is removed through the first intermediate , the reaction speed is fast, there are no other by-products, and the purity of the second intermediate is higher, and finally through the oxidation reaction of the second intermediate, there are no other by-products, and 4-aminothiophene[3,2-d]pyrimidine-7 is obtained -The purity of carboxylic acid is relatively high, therefore, the preparation process provided by the embodiment of the present application has high synthesis efficiency, less by-products, and saves synthesis cost. In addition, the first intermediate and the second intermediate synthesized in the examples of the present application can exist stably and can be used for the preparation of 4-aminothiophene[3,2-d]pyrimidine-7-carboxylic acid.

Wherein, the synthesis route of the first intermediate in the above step S10 is as follows:

In the nucleophilic addition reaction and the intramolecular Friedel-Crafts reaction in step S10, the reactant 4-methyl-3-thiopheneamine is used as a nucleophile for N-cyanoimino-S, S-dithio The nitrogen-carbon triple bond on dimethyl carbonate is replaced, specifically, the amino group on 4-methyl-3-thiopheneamine is an active group, which will replace the active nitrogen-carbon triple bond to form a third intermediate, but the first The three intermediates cannot exist stably, and intramolecular ring formation will immediately occur in the first solvent, that is, an intramolecular Friedel-Crafts reaction will occur to generate the first intermediate provided by the examples of the present application that can exist stably.

In the embodiment, in step S10, 4-methyl-3-thiopheneamine and N-cyanoimino-S, S-dimethyl dithiocarbonate can be mixed according to the reaction molar dosage ratio of the above reaction chemical formula, such as In the embodiment, the mass ratio of 4-methyl-3-thiopheneamine and N-cyanoimino-S,S-dimethyldithiocarbonate can be 146:113 to increase the reaction rate.

In some embodiments, the first solvent includes acetonitrile, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1,4-dioxane, acetonitrile, diglyme At least one of , toluene and methylene chloride, the first solvent provided by the embodiments of the present application can be 4-methyl-3-thienamine and N-cyanoimido-S, S-dithiocarbonic acid dimethyl The ester reaction provides a good reaction environment, thereby promoting the formation of the first intermediate.

In some embodiments, the temperature of nucleophilic addition reaction and intramolecular Friedel-Crafts reaction is 80-300°C, and the reaction time is 15-25h, which is beneficial to increase the reaction rate, such as 150°C for 25 hours or 170°C for 15 hours. Hours, the examples of the present application are not carried out in the environment of high pressure and carbon monoxide, therefore, the preparation method provided by the examples of the present application is safer. As in the example, 250 mL of N,N-dimethylformamide, 14.6 g (100 mmol) of N-cyanoimino-S, S-dimethyldithiocarbonate, 4- 11.3 g (100 mmol) of methyl-3-thiopheneamine was reacted at 170° C. for 15 hours to obtain the first intermediate provided in the examples of this application.

In some embodiments, after the 4-methyl-3-thiopheneamine and N-cyanimino-S, S-dimethyldithiocarbonate in step S10 are completed, further comprising performing the first intermediate The steps of purification treatment, filtration treatment and drying treatment, therefore, the above step S10 specifically includes the following steps:

Step S110: Mix the first solvent, 4-methyl-3-thiopheneamine, and N-cyanoimino-S,S-dimethyldithiocarbonate, and perform nucleophilic addition reaction, intramolecular Friedel-Crafts reaction to obtain the first mixed solution to promote the full reaction of 4-methyl-3-thienylamine and N-cyanoimido-S, S-dimethyldithiocarbonate;

Step S120: add n-hexane to the solution containing the first intermediate to precipitate a solid, and the volume ratio of n-hexane to the first solvent is 5:6, filter and dry the solid to obtain the first intermediate. As in the examples, 300 ml of n-hexane was added to the first mixed liquid I, and a solid was precipitated, filtered and dried to obtain 20.3 g of off-white solid product, namely the first intermediate, with a purity of 98% and a yield of 95%.

The synthetic route of the second intermediate in the above-mentioned step S20 is as follows:

In the demethylthio reaction, the first intermediate is used as a raw material to undergo reductive demethylthio reaction to generate the second intermediate. In the embodiment of the present application, the reduction occurs in the second solvent, and the reducing agent reduces the first intermediate, and the methylthio group contained in the first intermediate will be removed to form a stable second intermediate, and There are few by-products, and the separation and purification treatment can remove the second solvent and some redundant reaction raw materials, and can further improve the purity of the second intermediate.

In the embodiment, the first intermediate and the reducing agent in step S20 can be mixed according to the reaction molar dosage ratio of the above reaction chemical formula. As in the embodiment, the first intermediate and the reducing agent can be mixed according to the mass ratio of 939:40, with Increase reaction rate.

In some embodiments, the second solvent is selected from methanol, ethanol, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1,4-dioxane, acetonitrile, diethylene glycol At least one of dimethyl ether, toluene and methylene chloride, the second solvent provided in the embodiment of the present application can provide a good reaction environment for the reaction of the first intermediate and the reducing agent, and promote the formation of the second intermediate.

In some embodiments, the temperature of the reductive demethylthio group reaction is 80-300°C, and the reaction time is 10-15 hours, such as 15 hours at 70°C or 10 hours at 80°C. Carry out under the environment of carbon monoxide, therefore, the preparation method provided in the embodiment of the present application is safer.

In some embodiments, the reducing agent includes at least one of Raney nickel and palladium carbon, Raney nickel and palladium carbon can improve the effect on the methylthio site, increase the amount of the second intermediate, and can reduce By-products that increase the rate of the reaction.

In some embodiments, after the reaction of the first intermediate and the reducing agent in step S20 is completed, the steps of purifying, filtering and drying the second intermediate are also included. Therefore, the above step S20 specifically includes the following step:

Step S210: mixing the second solvent, the reducing agent and the first intermediate, and performing a methylthio removal reaction to obtain a second mixed solution;

Step S221: removing the solid residue in the solution containing the second intermediate to obtain a mixed solution;

Step S222: Carrying out rotary evaporation under reduced pressure on the mixed solution to obtain a solid crude product;

Step S223: dissolving the crude solid product in methyl tert-butyl ether to precipitate a solid, and the volume ratio of methyl tert-butyl ether to the second solvent is 4:5;

Step S224: Filtrating and drying the solid to obtain a second intermediate. As in the examples, the solid residue was removed by filtration, and the mixed solution was rotary evaporated under reduced pressure to obtain a crude solid product. The crude solid was dissolved by heating with 200ml of methyl tert-butyl ether, the solid was precipitated by cooling, filtered, and dried to obtain 14.1g of off-white solid product, namely the second intermediate, with a purity of 95% and a yield of 90%.

The synthetic route of 4-aminothiophene [3,2-d] pyrimidine-7-carboxylic acid in the above step S30 is as follows:

In the oxidation reaction in step S30, the second intermediate is used as a raw material to perform an oxidation reaction on the second intermediate, wherein the methyl group on the second intermediate will be oxidized to generate a carboxyl group, and then generate 4-aminothiophene [3 ,2-d] pyrimidine-7-carboxylic acid.

In the embodiment, the second intermediate and the oxidant in step S310 can be mixed according to the reaction molar dosage ratio of the above reaction chemical formula. As in the embodiment, the second intermediate and the oxidant can be in a mass ratio of 133:100 to improve the reaction rate.

In some embodiments, the third solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, acetone, 1,4-dioxane, acetonitrile, diglyme, At least one of toluene and dichloromethane, the third solvent provided by the embodiment of the present application can be a good reaction environment for the second intermediate and oxidant, and promote 4-aminothiophene[3,2-d]pyrimidine-7- Formation of carboxylic acids.

In some embodiments, the temperature in the oxidation reaction treatment is 20-200° C., and the reaction time is 3 hours. The examples of the present application are not carried out under high pressure and carbon monoxide environment. Therefore, the preparation method provided in the examples of the present application is more safety.

In some embodiments, the oxidizing agent is at least one of potassium permanganate and manganese dioxide, and the oxidizing agent provided in the embodiments of the present application can promote the oxidation of the second intermediate to generate 4-aminothiophene[3,2-d]pyrimidine -7-carboxylic acid, and will increase the reaction rate.

In a specific example, the intermediate formula II (13.3 g, 79.6 mmoL), active manganese dioxide (10 g) and 200 ml of tetrahydrofuran were added into a 500 mL double port and reacted at 80° C. for 3 h.

In some embodiments, after the reaction between the second intermediate and the oxidizing agent in step S30 is completed, the 4-aminothiophene[3,2-d]pyrimidine-7-carboxylic acid is purified and dried under reduced pressure Processing steps, therefore, the above-mentioned step S30 specifically includes the following steps:

Step S310: Mixing the second intermediate, the oxidizing agent and the third solvent to obtain a third mixed liquid;

Step S321: add n-hexane to the solution containing the purity of 4-aminothiophene[3,2-d]pyrimidine-7-carboxylic acid to precipitate a solid, and the volume ratio of n-hexane to the third solvent is 1:1;

Step S322: drying the solid under reduced pressure to obtain 4-aminothiophene[3,2-d]pyrimidine-7-carboxylic acid.

In the examples of this application, the oxidation occurs in the third solvent, and the oxidizing agent oxidizes the second intermediate, and the methyl group on the second intermediate will be oxidized to form a carboxyl group, resulting in a compound containing 4-aminothiophene[3,2-d] Pyrimidine-7-carboxylic acid, with few by-products, adopts separation and purification treatment, which can remove the third solvent and some redundant reaction raw materials, and can further increase the content of 4-aminothiophene[3,2-d]pyrimidine-7-carboxylic acid purity.

As in the examples, remove the solid by filtration, add 300 mL of water to the mixed liquid, precipitate the solid, filter again, add 200 ml of n-hexane to reflux to dissolve the solid, cool and precipitate the solid, and dry under reduced pressure to obtain 13.7 g of 4-aminothiophene[3,2-d ] Pyrimidine-7-carboxylic acid with a purity of 99% and a yield of 88%.

The second aspect of the embodiment of the present application provides a protein kinase inhibitor intermediate, including a first intermediate and/or a second intermediate, the structural formula of the first intermediate is shown in formula I, and the structural formula of the second intermediate is shown in Shown in formula II;

The protein kinase inhibitor intermediates provided in the examples of the present application, the first intermediate and the second intermediate, can exist stably, and the first intermediate and the second intermediate are 4-aminothiophene [3,2-d] An intermediate product of pyrimidine-7-carboxylic acid, wherein the first intermediate can be converted into a second intermediate through reductive desulfurization, and the second intermediate can be oxidized to produce 4-aminothiophene[3,2-d]pyrimidine-7 -carboxylic acid.

In order to make the above-mentioned implementation details and operations of the present application clearly understood by those skilled in the art, and the preparation method of 4-aminothiophene [3,2-d] pyrimidine-7-carboxylic acid and protein kinase inhibitors in the examples of the present application The improved performance of the body is significantly reflected, and the above technical solutions are illustrated below through a number of embodiments.

Example 1

The embodiment of the present application is a first intermediate whose structural formula is shown in formula I.

In addition, the embodiment of the present application also provides a preparation method of the first intermediate. The synthetic route is as follows:

Specifically, 250 mL of acetonitrile, 14.6 g (100 mmol) of dimethyl N-cyanoimido-S, S-dithiocarbonate, 11.3 g of 4-methyl-3-thienylamine ( 100mmol), reacted at 150°C for 25 hours. After the reaction, 300ml of n-hexane was added to the system to precipitate a solid, which was filtered and dried to obtain 20.7g of an off-white solid product, the intermediate formula II, with a purity of 98% and a yield of 97%. The structure of the obtained product was confirmed by mass spectrometry, and the result was: MS (ESI): [M+H ⁺ ] 214.33.

Example 2

The embodiment of the present application is a first intermediate whose structural formula is shown in formula I.

In addition, the embodiment of the present application also provides a preparation method of the first intermediate.

Specifically, 250 mL of N,N-dimethylformamide, 14.6 g (100 mmol) of N-cyanoimido-S, S-dimethyldithiocarbonate, 4-methyl - 11.3 g (100 mmol) of 3-thiopheneamine was reacted at 170° C. for 15 hours. After the reaction, 300ml of n-hexane was added to the system to precipitate a solid, which was filtered and dried to obtain 20.3g of an off-white solid product, the intermediate formula II, with a purity of 98% and a yield of 95%.

Example 3

The embodiment of the present application is a second intermediate whose structural formula is shown in formula II.

In addition, the embodiment of the present application also provides a preparation method of the first intermediate. The synthetic route is as follows:

250 mL of ethanol, 20 g (93.9 mmol) of the first intermediate, and 40 g of Raney nickel were sequentially added into a 500 mL three-necked bottle, and reacted at 80° C. for 10 hours. After the reaction, the solid residue was removed by filtration, and the mixed solution was rotary evaporated under reduced pressure to obtain a crude solid product. The crude solid was dissolved by heating with 200ml of methyl tert-butyl ether, the solid was precipitated by cooling, filtered, and dried to obtain 14.1g of off-white solid product, namely the second intermediate, with a purity of 95% and a yield of 90%.

Example 4

The embodiment of the present application is a second intermediate whose structural formula is shown in formula II.

In addition, the embodiment of the present application also provides a preparation method of the first intermediate.

Specifically, 250 mL of methanol, 20 g (93.9 mmol) of the first intermediate, and 40 g of Raney nickel were sequentially added into a 500 mL three-necked bottle, and reacted at 70° C. for 15 hours. After the reaction, the solid residue was removed by filtration, and the mixed solution was rotary evaporated under reduced pressure to obtain a crude solid product. The crude solid was dissolved by heating with 200ml of methyl tert-butyl ether, the solid was precipitated by cooling, filtered, and dried to obtain 13.3g of off-white solid product, intermediate formula III, with a purity of 95% and a yield of 85%. The structure of the obtained product was confirmed by mass spectrometry, and the result was: MS (ESI): [M+H ⁺ ] 168.23.

Example 5

The embodiment of the present application also provides a preparation method of 4-aminothiophene[3,2-d]pyrimidine-7-carboxylic acid. The synthetic route is as follows:

Specifically, the second intermediate (13.3 g, 79.6 mmoL), potassium permanganate (10 g) and 200 ml of tetrahydrofuran were added into a 500 mL double port and reacted at 80° C. for 3 h. After the reaction, remove the solid by filtration, then add 300mL of water to the mixed liquid, precipitate the solid, filter again, add 200ml of n-hexane to reflux to dissolve the solid, cool and precipitate the solid, dry under reduced pressure to obtain 14.7g of 4-aminothiophene[3,2-d] Pyrimidine-7-carboxylic acid, the purity is 99%, the yield is 95%. The structure of the obtained product was confirmed by mass spectrometry and nuclear magnetic resonance, and the results were:

¹ H NMR(400MHz,DMSO-d6)δ8.92(s,1H),8.51(s,1H),7.94(s,2H). ¹³ C NMR(101MHz,DMSO-d6)δ162.2,159.2,156.3,155.2 ,142.7,126.8,115.0.HRMS(ESI ⁺ )calculated for C7H6N3O2S[M+H] ⁺ m/z 196.0175,found196.0163.

Example 6

The embodiment of the present application also provides a preparation method of 4-aminothiophene[3,2-d]pyrimidine-7-carboxylic acid.

Specifically, the second intermediate (13.3 g, 79.6 mmoL), active manganese dioxide (10 g) and 200 ml tetrahydrofuran were added into a 500 mL double port and reacted at 80° C. for 3 h. After the reaction, remove the solid by filtration, add 300mL of water to the mixed liquid, precipitate the solid, filter again, add 200ml of n-hexane to reflux to dissolve the solid, cool to precipitate the solid, dry under reduced pressure to obtain 13.7g of 4-aminothiophene [3,2-d] Pyrimidine-7-carboxylic acid, the purity is 99%, the yield is 88%.

The above is only a preferred embodiment of the present invention, and it should be pointed out that for those skilled in the art, without departing from the technical principle of the present invention, it is possible to realize various modifications to these embodiments, and These modifications should also be regarded as the protection scope of the present invention.

It is easy for those skilled in the art to understand that the above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements and improvements made within the spirit and principles of the present invention, All should be included within the protection scope of the present invention.

Claims (10)

1. A method for preparing 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid, which is characterized by comprising the following steps:

mixing 4-methyl-3-thiophene amine, N-cyanoimino-S, S-dimethyl dithiocarbonate and a first solvent, and carrying out nucleophilic addition reaction and intramolecular Friedel-crafts reaction to obtain a first intermediate;

mixing the first intermediate, a reducing agent and a second solvent, and removing methylthio to obtain a second intermediate;

mixing the second intermediate, an oxidant and a third solvent, and carrying out oxidation reaction to obtain 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid;

wherein the structural formula of the first intermediate is shown as formula I, and the structural formula of the second intermediate is shown as formula II:

2. the method according to claim 1, wherein the mixing mass ratio of the 4-methyl-3-thiophenamine and the dimethyl-N-cyanoimino-S, S-dithiocarbonate in the first solvent is 146:113;

or/and the first solvent comprises at least one of acetonitrile, N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1, 4-dioxane, acetonitrile, diethylene glycol dimethyl ether, toluene and dichloromethane;

or/and the temperature of the nucleophilic addition reaction and the intramolecular Friedel-crafts reaction is 80-300 ℃, and the reaction time is 15-25 h.

3. The method according to claim 1, wherein the second solvent is at least one selected from the group consisting of methanol, ethanol, N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1, 4-dioxane, acetonitrile, diglyme, toluene, and dichloromethane;

or/and the temperature of the reduction and methylthio removal reaction is 80-300 ℃, and the reaction time is 10-15 h;

or/and the reducing agent comprises at least one of Raney nickel and palladium carbon;

or/and the mass ratio of the first intermediate to the reducing agent is 939.

4. The method according to claim 1, wherein the third solvent is at least one selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, acetone, 1, 4-dioxane, acetonitrile, diglyme, toluene and dichloromethane;

or/and the temperature in the oxidation reaction treatment is 20-200 ℃, and the reaction time is 3h;

or/and the oxidant comprises at least one of potassium permanganate and manganese dioxide;

or/and the mass ratio of the second intermediate to the oxidant is 133:100.

5. the process for producing 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid according to any one of claims 1-4, further comprising the steps of subjecting the first intermediate to a purification treatment, a filtration treatment and a drying treatment;

or/and further comprises the steps of carrying out purification treatment, filtration treatment and drying treatment on the second intermediate;

or/and further comprises the steps of carrying out purification treatment and decompression drying treatment on the 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid.

6. The preparation method according to claim 5, wherein the purification treatment of the first intermediate comprises the following steps:

adding n-hexane into the solution containing the first intermediate to precipitate a solid, wherein the volume ratio of the n-hexane to the first solvent is 5.

7. The preparation method according to claim 5, wherein the purification treatment of the second intermediate comprises the following steps:

removing solid residues in the solution containing the second intermediate to obtain a mixed solution;

carrying out reduced pressure rotary evaporation treatment on the mixed solution to obtain a solid crude product;

dissolving the crude solid in methyl tert-butyl ether to precipitate a solid, wherein the volume ratio of the methyl tert-butyl ether to the second solvent is 4.

8. The method according to claim 5, wherein the purification treatment of 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid comprises the steps of:

adding n-hexane into the solution containing the 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid to precipitate a solid, wherein the volume ratio of the n-hexane to the third solvent is 1.

9. The process according to claim 8, wherein the 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid has a purity of not less than 99% and a yield of not less than 88%.

10. The protein kinase inhibitor intermediate is characterized by comprising a first intermediate and/or a second intermediate, wherein the structural formula of the first intermediate is shown as a formula I, and the structural formula of the second intermediate is shown as a formula II;