CN114213430B - Preparation method of 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid and protein kinase inhibitor intermediate - Google Patents
Preparation method of 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid and protein kinase inhibitor intermediate Download PDFInfo
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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
Technical Field
The application belongs to the technical field of protein kinase inhibitors, and particularly relates to a preparation method of 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid and a protein kinase inhibitor intermediate.
Background
Protein kinase is an enzyme which plays a key role in the mediation of signal transduction by phosphorylating hydroxyl groups in tyrosine, serine or threonine residues, and thus is deeply involved in the regulation of cell growth, differentiation, proliferation, etc. Wherein the structure of the 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid is shown in a formula III. 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid is an important intermediate for a variety of protein kinase inhibitors, including the drug Belvarafenib (GDC-5573) which is undergoing clinical treatment for advanced solid tumors.
At present, the document org.process.Res.Dev.2021 (25) 2338-2350 discloses a process for the synthesis of 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid: taking thiophene amino carboxylic acid methyl ester as a substrate, firstly, carrying out condensation cyclization with formamidine acetate in a 2-methoxy ethanol solvent to prepare thiophene pyrimidinone 1c; then, bromine is treated in an acetic acid solution with sodium acetate to obtain a bromide 1d; then, using phosphorus oxychloride for treatment, converting ketone into the corresponding chloride 1e; in isopropanol, the chloro compound is subjected to nucleophilic substitution at high temperature by using tert-butylamine and is converted into amine 1f; bromo-arene 2f reacts with carbon monoxide in triethylamine and methanol under the catalysis of palladium acetate and BINAP (1, 1 '-binaphthyl-2, 2' -bis-diphenylphosphine), and methyl carboxylate 1g is generated through carbonyl insertion esterification; the tertiary butyl on amine is removed through sulfuric acid treatment in sequence, and the final product 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid is generated through potassium hydroxide treatment and hydrolysis. The process route uses high-pressure carbon monoxide, has harsh conditions and is not friendly to the environment and personnel; meanwhile, the route is long, which is very unfavorable for large-scale synthesis. The simplified synthetic route is shown in formula 1:
disclosure of Invention
The application aims at providing a preparation method of a protein kinase inhibitor intermediate in the prior art, and aims to solve the problems that the synthesis route is complex and the production is not facilitated in the prior art.
In order to achieve the purpose of the application, the technical scheme adopted by the application is as follows:
the application provides a preparation method of 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid, which comprises the following steps:
mixing 4-methyl-3-thiophene amine, N-cyanoimino-S, S-dimethyl dithiocarbonate and a first solvent, performing 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;
the application provides a reasonable synthesis route for the synthesis of 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid, the synthesis route can complete 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid only by three steps, the synthesis route is short, the synthesis time is saved, on the one hand, 4-methyl-3-thiophenylamine, N-cyanoimino-S, S-dithio-dimethyl carbonate is taken as a raw material, and continuous nucleophilic addition reaction and intramolecular Friedel-crafts reaction are carried out, the reaction speed is high, no other side products exist, the purity of the obtained first intermediate is high, on the other hand, methylthio removal reaction is carried out through the first intermediate, the reaction speed is high, no other side products exist, the purity of the obtained second intermediate is high, on the other hand, no other side products exist through the oxidation reaction of the second intermediate, the purity of the obtained 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid is high, therefore, the preparation process provided by the embodiment of the application has the advantages of high synthesis efficiency, few side products, and the synthesis cost is saved.
In a second aspect, the application provides a protein kinase inhibitor intermediate, which comprises 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;
the protein kinase inhibitor intermediates provided herein, the first intermediate and the second intermediate of the first aspect, both of which may be stable, are intermediates of 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid, wherein the first intermediate may be reduced to produce the second intermediate, and the second intermediate may be oxidized to produce 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present application more clearly apparent, the present application is further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present application and are not intended to limit the present application.
In this application, the term "and/or" describes an association relationship of associated objects, meaning that there may be three relationships, e.g., a and/or B, which may mean: a is present alone, A and B are present simultaneously, and B is present alone. Wherein A and B can be singular or plural. The character "/" generally indicates that the former and latter associated objects are in an "or" relationship.
In the present application, "at least one" means one or more, "a plurality" means two or more. "at least one of the following" or similar expressions refer to any combination of these items, including any combination of the singular or plural items. For example, "at least one item(s) of a, b, or c," or "at least one item(s) of a, b, and c," may each represent: a, b, c, a-b (i.e., a and b), a-c, b-c, or a-b-c, wherein a, b, and c may be single or plural, respectively.
It should be understood that, in various embodiments of the present application, the sequence numbers of the above-mentioned processes do not imply an execution sequence, some or all steps may be executed in parallel or executed sequentially, and the execution sequence of each process should be determined by its function and inherent logic, and should not limit the implementation process of the embodiments of the present application in any way.
The terminology used in the embodiments of the present application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used in the specification of the present application and the appended claims, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.
The weight of the related components mentioned in the specification of the embodiments of the present application may not only refer to the specific content of each component, but also refer to the proportional relationship of the weight of each component, and therefore, the proportional enlargement or reduction of the content of the related components according to the specification of the embodiments of the present application is within the scope disclosed in the specification of the embodiments of the present application. Specifically, the mass described in the specification of the embodiments of the present application may be a mass unit known in the chemical industry field such as μ g, mg, g, kg, etc.
The terms first, second, etc. are used for descriptive purposes only and are used for distinguishing purposes such as substances from one another and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. For example, a first XX may also be referred to as a second XX, and similarly, a second XX may also be referred to as a first XX, without departing from the scope of regulations of this application. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature.
The embodiment of the application provides a preparation method of 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid, which comprises the following steps:
step S10: mixing 4-methyl-3-thiophene amine, N-cyanoimino-S, S-dimethyl dithiocarbonate and a first solvent, performing nucleophilic addition reaction and intramolecular Friedel-crafts reaction to obtain a first intermediate;
step S20: mixing the first intermediate, a reducing agent and a second solvent, and removing methylthio to obtain a second intermediate;
step S30: 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;
the embodiment of the application provides a reasonable synthesis route for the synthesis of 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid, the synthesis route can complete 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid only by three steps, the synthesis route is short, the synthesis time is saved, firstly, 4-methyl-3-thiophenylamine, N-cyanoimino-S, S-dimethyl dithiocarbonate are taken as raw materials, and the continuous nucleophilic addition reaction and intramolecular Friedel-crafts reaction are carried out, the reaction speed is high, no other by-products exist, the purity of the first intermediate is high, then, the methylthio reaction is removed through the first intermediate, the reaction speed is high, no other by-products exist, the purity of the second intermediate is high, and finally, the purity of the 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid is high through the oxidation reaction of the second intermediate, no other by-products exist, so the preparation process provided by the embodiment of the application has the advantages of high synthesis efficiency, few by-products, and the synthesis cost is saved. In addition, the first intermediate and the second intermediate synthesized in the embodiment can exist stably and can be used for preparing 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid.
Wherein, the synthetic route of the first intermediate in the step S10 is as follows:
in the nucleophilic addition reaction and intramolecular friedel-crafts reaction in step S10, 4-methyl-3-thiophenamine as a nucleophilic reagent substitutes a nitrogen-carbon triple bond on N-cyanoimino-S, S-dithio-dimethyl carbonate, specifically, an amino group on 4-methyl-3-thiophenamine is an active group and substitutes an active nitrogen-carbon triple bond to form a third intermediate, but the third intermediate does not exist stably and undergoes intramolecular cyclization immediately in the first solvent, i.e., intramolecular friedel-crafts reaction occurs to form the first intermediate which can exist stably and is provided in the embodiments of the present application.
In the examples, 4-methyl-3-thiophenamine and N-cyanoimino-S, S-dithio-dimethyl carbonate in step S10 can be mixed according to the molar ratio of the above reaction formula, for example, 4-methyl-3-thiophenamine and N-cyanoimino-S, S-dithio-dimethyl carbonate can be mixed according to the mass ratio of 146:113 to increase the reaction rate.
In some embodiments, 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 methylene chloride, and the first solvent provided in the examples herein can provide a good reaction environment for the reaction of 4-methyl-3-thiophenamine and N-cyanoimino-S, S-dimethyldithiocarbonate, thereby promoting the formation of the first intermediate.
In some embodiments, the temperature of the nucleophilic addition reaction, intramolecular friedel-crafts reaction is 80-300 ℃, the reaction time is 15-25 h, which is beneficial to increase the reaction rate, for example, 150 ℃ reaction for 25h or 170 ℃ reaction for 15h, the embodiments of the present application are not performed under high pressure and carbon monoxide environment, and therefore, the preparation method provided by the embodiments of the present application is safer. As in the example, N-dimethylformamide 250mL, N-cyanoimino-S, S-dithiocarbonic acid dimethyl ester 14.6g (100 mmol), 4-methyl-3-thiophene amine 11.3g (100 mmol) were sequentially added to a 500mL three-necked flask, and reacted at 170 ℃ for 15 hours to obtain the first intermediate provided in the example of the present application.
In some embodiments, after the 4-methyl-3-thiophenamine and the N-cyanoimino-S, S-dithiocarbonic acid dimethyl ester in step S10 are finished, the method further comprises the steps of purifying, filtering and drying the first intermediate, and therefore, step S10 specifically comprises the following steps:
step S110: mixing a first solvent, 4-methyl-3-thiophene amine, N-cyanoimino-S, S-dithio dimethyl carbonate, and carrying out nucleophilic addition reaction and intramolecular Friedel-crafts reaction to obtain a first mixed solution so as to promote the full reaction of the 4-methyl-3-thiophene amine and the N-cyanoimino-S, S-dithio dimethyl carbonate;
step S120: 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. In the example, 300ml of n-hexane was added to the first mixed solution to precipitate a solid, which was then filtered and dried to obtain 20.3g of an off-white solid product, i.e., a first intermediate, having a purity of 98% and a yield of 95%.
The synthetic route of the second intermediate in the step S20 is as follows:
in the reaction of removing the methylthio group, the first intermediate is used as a raw material, reduction reaction for removing the methylthio group is carried out, and a second intermediate is generated. In the embodiment of the application, the reduction is carried out in the second solvent, the reducing agent reduces the first intermediate, the methylthio contained in the first intermediate can be removed, the second intermediate which can exist stably is generated, few byproducts are generated, the second solvent and some redundant reaction raw materials can be removed by adopting separation and purification treatment, and the purity of the second intermediate can be further improved.
In an embodiment, the first intermediate and the reducing agent in step S20 may be mixed according to a molar reaction ratio of the reaction formula, for example, in an embodiment, the mass ratio of the first intermediate to the reducing agent may be 939.
In some embodiments, the second solvent is selected from at least one of methanol, ethanol, N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1, 4-dioxane, acetonitrile, diethylene glycol dimethyl ether, toluene, and methylene chloride, and the second solvent provided in the embodiments 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 reduction and removal of methylthio groups is 80-300 ℃, the reaction time is 10-15 h, for example, 70 ℃ for 15h or 80 ℃ for 10 h, the embodiments of the present application are not carried out under high pressure and carbon monoxide, and therefore, the preparation method provided by the embodiments of the present application is safer.
In some embodiments, the reducing agent comprises at least one of raney nickel and palladium carbon, which can improve the effect on methylthio sites, increase the production of the second intermediate, reduce byproducts, and increase the reaction rate.
In some embodiments, after the reaction between the first intermediate and the reducing agent in step S20 is finished, the method further includes the steps of performing a purification process, a filtration process, and a drying process on the second intermediate, and therefore, step S20 specifically includes the following steps:
step S210: mixing a second solvent, a reducing agent and a first intermediate, and performing methylthio removal reaction to obtain a second mixed solution;
step S221: removing solid residues in the solution containing the second intermediate to obtain a mixed solution;
step S222: carrying out reduced pressure rotary evaporation treatment on the mixed solution to obtain a solid crude product;
step S223: dissolving the crude solid in methyl tert-butyl ether to precipitate solid, wherein the volume ratio of the methyl tert-butyl ether to the second solvent is 4;
step S224: and filtering and drying the solid to obtain a second intermediate. In the examples, the solid residue was removed by filtration and the mixture was rotary evaporated under reduced pressure to give crude solid. The crude solid was dissolved in 200ml of methyl tert-butyl ether under heating, cooled to precipitate a solid, filtered and dried to give 14.1g of an off-white solid product, i.e. a second intermediate, having a purity of 95% and a yield of 90%.
The synthetic route of 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid in step S30 above is as follows:
in the oxidation reaction in step S30, the second intermediate is used as a raw material, and the second intermediate is subjected to an oxidation reaction, wherein a methyl group on the second intermediate is oxidized to generate a carboxyl group, and further generate 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid.
In an embodiment, the second intermediate and the oxidant in step S310 may be mixed according to a molar ratio of the reaction formula, for example, in an embodiment, the second intermediate and the oxidant may be mixed according to a mass ratio of 133.
In some embodiments, 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, and the third solvent provided in the embodiments herein can be a good reaction environment for the second intermediate and the oxidant, promoting the formation of 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid.
In some embodiments, the temperature in the oxidation reaction treatment is 20-200 ℃, the reaction time is 3h, and the preparation method provided by the embodiment of the application is safer because the embodiment of the application is not carried out under the environment of high pressure and carbon monoxide.
In some embodiments, the oxidizing agent is at least one of potassium permanganate and manganese dioxide, and the oxidizing agent provided in the embodiments can promote the oxidation of the second intermediate to produce 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid, and can increase the reaction rate.
In a specific example, intermediate formula II (13.3 g,79.6 mmoL), activated manganese dioxide (10 g) and 200mL of tetrahydrofuran were added to 500mL of a double-port vessel and reacted at 80 ℃ for 3 hours.
In some embodiments, after the reaction between the second intermediate and the oxidant in step S30 is finished, the method further comprises a step of performing a purification treatment and a reduced pressure drying treatment on the 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid, and therefore, the step S30 specifically comprises the following steps:
step S310: mixing the second intermediate, an oxidant and a third solvent to obtain a third mixed solution;
step S321: adding n-hexane into a solution containing 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid purity to precipitate a solid, wherein the volume ratio of the n-hexane to a third solvent is 1;
step S322: drying the solid under reduced pressure to obtain 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid.
In the embodiment of the application, the oxidation is carried out in the third solvent, the oxidizing agent oxidizes the second intermediate, the methyl on the second intermediate can be oxidized to generate carboxyl, the 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid is generated, the by-products are few, the third solvent and some redundant reaction raw materials can be removed by adopting separation and purification treatment, and the purity of the 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid can be further improved.
In the same manner as in example, the solid was removed by filtration, 300mL of water was added to the mixture to precipitate a solid, which was again filtered, and the solid was dissolved in 200mL of n-hexane under reflux, cooled to precipitate a solid, and dried under reduced pressure to obtain 13.7g of 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid, which had a purity of 99% and a yield of 88%.
The second aspect of the embodiments of the present application provides a protein kinase inhibitor intermediate, which includes a first intermediate and/or a second intermediate, 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;
the protein kinase inhibitor intermediates, the first intermediate and the second intermediate, provided in the examples herein, can each be present in a stable form, and the first intermediate and the second intermediate are intermediates of 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid, wherein the first intermediate can be reduced to form the second intermediate, and the second intermediate can be oxidized to form 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid.
In order to make the above-mentioned details and operations of the present application clearly understood by those skilled in the art and to make the progress of the preparation method of 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid and the intermediate of protein kinase inhibitor in the present application remarkably apparent, the above-mentioned technical solutions are exemplified by a plurality of examples below.
Example 1
The structural formula of the first intermediate is shown as formula I.
In addition, the embodiment of the application also provides a preparation method of the first intermediate. The synthetic route is shown as follows:
specifically, 250mL of acetonitrile, 14.6g (100 mmol) of N-cyanoimino-S, S-dithiocarbonic acid dimethyl ester and 11.3g (100 mmol) of 4-methyl-3-thiophenamine were sequentially added to a 500mL three-necked flask, and reacted at 150 ℃ for 25 hours. After the reaction is finished, 300ml of normal hexane is added into the system, solid is separated out, filtered and dried to obtain 20.7g of a white-like solid product, namely the intermediate compound II, the purity is 98 percent, and the yield is 97 percent. The structure of the obtained product was confirmed by mass spectrometry, and the results were: MS (ESI) < M + H + ]214.33。
Example 2
The structural formula of the first intermediate is shown as formula I.
In addition, the embodiment of the application also provides a preparation method of the first intermediate.
Specifically, 250mL of N, N-dimethylformamide, 14.6g (100 mmol) of N-cyanoimino-S, S-dimethyl dithiocarbonate and 11.3g (100 mmol) of 4-methyl-3-thiophenamine were sequentially added to a 500mL three-necked flask, and reacted at 170 ℃ for 15 hours. After the reaction is finished, 300ml of normal hexane is added into the system, solid is separated out, filtered and dried to obtain 20.3g of a white-like solid product, namely an intermediate product II with the purity of 98% and the yield of 95%.
Example 3
The structural formula of the second intermediate is shown as formula II.
In addition, the embodiment of the application also provides a preparation method of the first intermediate. The synthetic route is as follows:
250mL of ethanol, 20g (93.9 mmol) of the first intermediate and 40g of Raney nickel were sequentially added to a 500mL three-necked flask, and reacted at 80 ℃ for 10 hours. After the reaction is finished, filtering to remove solid residues, and carrying out reduced pressure rotary evaporation on the mixed solution to obtain a solid crude product. The crude solid was dissolved in 200ml of methyl tert-butyl ether under heating, cooled to precipitate a solid, filtered and dried to give 14.1g of an off-white solid product, i.e. a second intermediate, having a purity of 95% and a yield of 90%.
Example 4
The structural formula of the second intermediate is shown as a formula II.
In addition, the embodiment of the application also provides a preparation method of the first intermediate.
Specifically, 250mL of methanol, 20g (93.9 mmol) of the first intermediate, and 40g of Raney nickel were sequentially added to a 500mL three-necked flask, and reacted at 70 ℃ for 15 hours. After the reaction is finished, filtering to remove solid residues, and carrying out reduced pressure rotary evaporation on the mixed solution to obtain a solid crude product. The crude solid product was dissolved in 200ml of methyl tert-butyl ether by heating, cooled to precipitate a solid, filtered and dried to obtain 13.3g of an off-white solid product, i.e. 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 results were: MS (ESI): [ M + H + ]168.23.
Example 5
The embodiment of the application also provides a preparation method of the 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 200mL tetrahydrofuran were added to 500mL of a two-port reaction vessel and reacted at 80 ℃ for 3 hours. After the reaction, the solid was removed by filtration, 300mL of water was added to the mixture to precipitate a solid, which was filtered again, and the solid was dissolved by refluxing with 200mL of n-hexane, cooled to precipitate a solid, and dried under reduced pressure to obtain 14.7g of 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid with a purity of 99% and a yield of 95%. The structure of the obtained product is confirmed by mass spectrum and nuclear magnetic resonance, and the result is as follows:
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 application also provides a preparation method of the 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 200mL of tetrahydrofuran were added to 500mL of a double-port and reacted at 80 ℃ for 3 hours. After the reaction, the solid was removed by filtration, 300mL of water was added to the mixed solution to precipitate a solid, which was filtered again, and the solid was dissolved by refluxing in 200mL of n-hexane, cooled to precipitate a solid, and dried under reduced pressure to obtain 13.7g of 4-aminothiophene [3,2-d ] pyrimidine-7-carboxylic acid, the purity was 99%, and the yield was 88%.
The above description is only a preferred embodiment of the present invention, and it should be noted that various modifications to the embodiments can be implemented by those skilled in the art without departing from the technical principle of the present invention, and these modifications should also be construed as the scope of the present invention to be protected.
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the 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;
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