A method for preparing 2,5-dioxopyridine derivatives

Abstract

The invention provides a preparation method of 2,5-dioxopyridine derivatives. The method for directly synthesizing 2,5-dimethoxypyridine and 2,5-diethoxypyridine by a one-pot method has the advantages of low cost, simple process, high raw material utilization rate and less three wastes.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for preparing a 2,5-dioxopyridine derivative. Background Art

[0002] The 2,5-dioxopyridine derivative refers to a pyridine ring in which the carbon atoms 2 and 5 are connected to the oxygen atoms on the substituent, respectively, including but not limited to 2,5-dimethoxypyridine, 2,5-diethoxypyridine and 2,5-diphenoxypyridine.

[0003] At present, the method for preparing 2,5-dimethoxypyridine is to use 2,5-dibromopyridine as the raw material, first replace the bromine atom on carbon No. 2 or carbon No. 5, and then replace the remaining bromine atoms. As reported: After the bromine atom on carbon No. 2 is converted into a methoxy group under alkaline conditions, the bromine atom on carbon No. 5 is converted into boric acid or boric ester using a lithium reagent or a palladium catalyst at ultra-low temperature, and the boric acid or boric ester group is oxidized into a hydroxyl group using a peroxide, and finally the hydrogen on the hydroxyl group is replaced by a methyl group to obtain the final product 2,5-dimethoxypyridine. Or using 2,5-dibromopyridine as the raw material, first the bromine atom at position 5 is converted into boric acid using a lithium reagent at ultra-low temperature or into a boric ester using a palladium catalyst at a higher temperature, and then the boric acid or boric ester group is further oxidized into a hydroxyl group using a peroxide, and then the bromine atom at position 2 is converted into a methoxy group under alkaline conditions, and finally the hydrogen on the hydroxyl group at position 5 is replaced by a methyl group to obtain the final product 2,5-dimethoxypyridine. There is also a report on CN108863917A - a method for preparing 2,5-dimethoxypyridine: using a methoxy anion reagent in a non-protonic solvent with a catalyst, first replacing the bromine atom at carbon No. 2 with a methoxy group, separating and purifying the product, and then using a methoxy anion reagent again in an alcohol solvent to replace the bromine atom at carbon No. 5, and then obtaining the final product 2,5-dimethoxypyridine.

[0004] Among the above three methods for preparing 2,5-dimethoxypyridine, method 1 and method 2 have high cost, complicated process and low raw material utilization rate. Method 3 overcomes some disadvantages of method 1 and method 2, but still needs to be reacted in two steps. Whether it is raw material utilization rate, three wastes or production cycle, there is room for improvement.

[0005] In summary, the preparation of 2,5-diethoxypyridine is basically the same as that of 2,5-dibromomethoxypyridine. The nucleophilic reagent (ethoxy anion) reacts with the bromine atom on 2,5-dibromopyridine twice, and finally the ethoxy replaces the bromine atom on carbon No. 2 and the bromine atom on carbon No. 5 to synthesize 2,5-diethoxypyridine. The whole reaction is still carried out in two parts. At present, there is no report on the preparation method of 2,5-diphenoxypyridine. The existing preparation method has many and cumbersome reaction steps, low raw material utilization rate, and large amount of three wastes; on the other hand, the preparation process of some 2,5-dioxopyridine products requires the use of palladium catalysts, lithium reagents or boric acid reagents, which are costly and risky, and are not conducive to industrialization. Summary of the invention

[0006] In view of this, the present invention aims to overcome the defects in the prior art and proposes a method for preparing 2,5-dioxopyridine derivatives.

[0007] To achieve the above object, the technical solution created by the present invention is implemented as follows:

[0008] A method for preparing a 2,5-dioxopyridine derivative, wherein the 2,5-dioxopyridine derivative has a structure as shown in Formula 1:

[0009]

[0010] Among them, R 1 is methyl, ethyl or phenyl;

[0011] The synthetic route of the compound of formula 1 is shown in the following synthetic route (1) or synthetic route (2) or synthetic route (3):

[0012] Synthesis route (1):

[0013] When the substituent R of the compound of formula 1 1 When it is methyl:

[0014]

[0015] The synthesis steps are as follows: the compound of formula A and the catalyst are dissolved in an organic solvent, and after nitrogen replacement, a sodium methoxide solution is added, the temperature is raised to 90-130° C. and the reaction is performed for 48-72 hours, and post-treatment and purification are performed to obtain a compound of formula 1;

[0016] Synthesis route (2):

[0017] When the substituent R of the compound of formula 1 1 When it is ethyl:

[0018]

[0019] The synthesis steps are: dissolving the compound of formula A and the catalyst in an organic solvent, adding sodium ethoxide solution after nitrogen replacement, heating to 90-130° C. and reacting for 48-72 hours, post-treating and purifying to obtain the compound of formula 1;

[0020] Synthesis route (3):

[0021] When the substituent R of the compound of formula 1 1 When it is phenyl:

[0022]

[0023] The synthesis steps are: dissolving the compound of formula A, a catalyst and phenol in an organic solvent, adding cesium carbonate after nitrogen replacement, heating to 90-130° C. and reacting for 48-72 hours, post-treating and purifying to obtain the compound of formula 1.

[0024] Preferably, the catalyst is a cuprous ion catalyst, including one of cuprous bromide, cuprous chloride, and cuprous iodide; more preferably cuprous iodide.

[0025] Preferably, the weight ratio of the compound of formula A to the catalyst is 1.24:1 to 5.7:1.

[0026] Preferably, the organic solvent is an aprotic solvent, more preferably, the aprotic solvent is selected from DMF and DMSO; further preferably, it is DMF.

[0027] Preferably, the solvents in the sodium methoxide solution in the synthesis route (1) and the sodium ethoxide solution in the synthesis route (2) are both alcohol solvents.

[0028] Preferably, the alcohol solvent is methanol or ethanol.

[0029] Preferably, the weight ratio of the aprotic solvent to the alcohol solvent is 1:1 to 1:2; more preferably 1:1 to 1:1.2;

[0030] Preferably, the weight ratio of the sodium methoxide solution to the compound of formula A in the synthetic route (1) is 2.28:1 to 3.8:1.

[0031] Preferably, the weight ratio of the sodium ethoxide solution to the compound of formula A in the synthetic route (2) is 4.33:1 to 7.22:1.

[0032] Preferably, the weight ratio of phenol to the compound of formula A in the synthetic route (3) is 1.59:1 to 2.39:1.

[0033] Preferably, the weight ratio of cesium carbonate to the compound of formula A in the synthetic route (3) is 5.5:1 to 7.3:1.

[0034] Preferably, the specific steps of the synthetic route (1) are:

[0035] In the presence of DMF solvent, a material having a weight ratio of 1.24:1 to 5.7:1 of a compound of formula A to a catalyst is dissolved, and after nitrogen replacement, a sodium methoxide-methanol solution having a mass percentage concentration of 30% is added to an aprotic solvent, wherein the weight ratio of the 30% sodium methoxide-methanol solution to the compound of formula A is 2.28:1 to 3.8:1, and the reaction solution is stirred at a reaction temperature of 90-100° C. for 48-72 hours; after suction filtration, the filtrate is subjected to reduced pressure rotary evaporation until no distillate is produced, water is added to the remaining mother liquor, and the mixture is extracted twice with ethyl acetate, and the organic phases are combined, and the organic phases are washed with saturated brine for several times, and then purified by reduced pressure rotary evaporation to obtain a compound of formula 1.

[0036] Preferably, the specific steps of the synthetic route (2) are:

[0037] In the presence of DMF solvent, a material having a weight ratio of 1.24:1 to 5.7:1 of the compound of formula A to the catalyst is dissolved, and after nitrogen replacement, a sodium ethoxide-ethanol solution having a mass percentage concentration of 20% is added to the DMF solution, wherein the weight ratio of the 20% sodium ethoxide-ethanol solution to the compound of formula A is 4.33:1 to 7.22:1, and the reaction solution is stirred at a reaction temperature of 90-100°C for 48-72 hours; after suction filtration, the filtrate is subjected to reduced pressure rotary evaporation until no distillate is produced, water is added to the remaining mother liquor, and the mixture is extracted twice with ethyl acetate, and the organic phases are combined, and the organic phases are washed with saturated brine for several times, and then purified by reduced pressure rotary evaporation to obtain the compound of formula 1.

[0038] Preferably, the specific steps of the synthetic route (3) are:

[0039] In the presence of DMF solvent, a material in which the weight ratio of the compound of formula A to the catalyst is 1.24:1-5.7:1 and the weight ratio of the compound of formula A to phenol is 1.59:1-2.39:1 is dissolved, and after nitrogen replacement, cesium carbonate is added to the DMF solution, wherein the weight ratio of cesium carbonate to the compound of formula A is 5.5:1-7.3:1, and the reaction solution is stirred at a reaction temperature of 120-130°C for 48-72 hours; after suction filtration, the filtrate is subjected to reduced pressure rotary evaporation until no distillate is produced, water is added to the remaining mother liquor, and then extracted with ethyl acetate for several times, the organic phases are combined, the organic phases are washed with saturated brine for several times, and then subjected to reduced pressure rotary evaporation, and the obtained crude product is purified by column chromatography to obtain the compound of formula 1, wherein the developing solvent used is ethyl acetate:n-hexane=1:8.

[0040] Compared with the prior art, the present invention has the following advantages:

[0041] The present invention provides a method for directly preparing 2,5-dioxopyridine derivatives by a one-pot process, wherein the 2,5-dioxopyridine derivatives include 2,5-dimethoxypyridine, 2,5-diethoxypyridine and 2,5-diphenoxypyridine. Compared with the existing preparation methods of 2,5-dimethoxypyridine and 2,5-diethoxypyridine, the method for directly synthesizing 2,5-dimethoxypyridine and 2,5-diethoxypyridine by a one-pot process of the present invention has the advantages of low cost, simple process, high raw material utilization rate and low amount of three wastes; in addition, the present invention also provides a method for preparing 2,5-diphenoxypyridine. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 2,5-dimethoxypyridine according to Example 1 of the present invention 1 H-NMR spectrum;

[0043] Figure 2 The LC-MS spectrum of 2,5-dimethoxypyridine described in Example 1 of the present invention;

[0044] Figure 3 The IPC spectrum of 2,5-dimethoxypyridine described in Example 1 of the present invention;

[0045] Figure 4 2,5-diethoxypyridine as described in Example 1 of the present invention 1 H-NMR spectrum;

[0046] Figure 5 The LC-MS spectrum of 2,5-diethoxypyridine described in Example 1 of the present invention;

[0047] Figure 6 The IPC spectrum of 2,5-diethoxypyridine described in Example 1 of the present invention;

[0048] Figure 7 The 2,5-diphenoxypyridine described in Example 1 of the present invention 1 H-NMR spectrum;

[0049] Figure 8 The LC-MS spectrum of 2,5-diphenoxypyridine described in Example 1 of the present invention;

[0050] Fig. 9 This is the IPC spectrum of 2,5-diphenoxypyridine described in Example 1 of the present invention. DETAILED DESCRIPTION

[0051] Unless otherwise defined, the technical terms used in the following examples have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods, unless otherwise specified, are all conventional methods.

[0052] The present invention is described in detail below in conjunction with embodiments.

[0053] Example 1 Preparation of 2,5-dimethoxypyridine

[0054] The synthetic route is as follows:

[0055]

[0056] Take 8 ml of DMF and add it to a 50 ml three-necked flask. Start stirring, then add compound A (2.0 g) and CuI (0.35 g). After nitrogen replacement 4 times, add 30% sodium methoxide-methanol solution (4.56 g). Set the external temperature to 97°C and start heating. After the internal temperature stabilizes at 95°C, continue stirring for 72 hours.

[0057] After the reaction solution was cooled to room temperature, solid impurities were filtered out, and the filtrate was extracted with water and ethyl acetate. The organic phase was collected and washed with saturated brine, and then purified by vacuum rotary evaporation to obtain the product compound of formula 1. The final product mass was 0.98 g, the purity was 98.6%, and the reaction yield was 84.3%.

[0058] The compound of formula 1 obtained in Example 1 was analyzed by HNMR, LC-MS and IPC respectively. Figure 1-3 .

[0059] Example 2 Preparation of 2,5-diethoxypyridine

[0060] The synthetic route is as follows:

[0061]

[0062] Take 8 ml of DMF and add it to a 50 ml three-necked flask. Start stirring and then add the compound of formula A (2.0 g) and CuI (0.35 g). After nitrogen replacement 4 times, add a 20% sodium ethoxide-ethanol solution (8.65 g). Set the external temperature to 97°C and continue stirring for 72 hours after the internal temperature stabilizes at 95°C.

[0063] After the reaction solution was cooled to room temperature, solid impurities were filtered out, and the filtrate was extracted with water and ethyl acetate. The organic phase was collected and washed with saturated brine, and then purified by vacuum rotary evaporation to obtain the product compound of formula 2. The final product mass was 0.93 g, the purity was 98.3%, and the reaction yield was 67.2%.

[0064] The compound of formula 2 obtained in Example 2 was analyzed by HNMR, LC-MS and IPC respectively. Figure 4-6 .

[0065] Example 3 Preparation of 2,5-diphenoxypyridine

[0066] The synthetic route is as follows:

[0067]

[0068] Take 16 ml of DMF and add it to a 50 ml three-necked flask. After starting to stir, add the compound of formula A (2.0 g), CuI (0.35 g), and phenol (3.18 g). After nitrogen replacement 4 times, add cesium carbonate (11.0 g). Set the external temperature to 130°C. After the internal temperature stabilizes at 125-130°C, continue stirring for 72 hours.

[0069] After the reaction solution was cooled to room temperature, solid impurities were filtered out, and the filtrate was added with water and ethyl acetate for extraction. The organic phase was collected and washed with saturated brine. The organic phase was subjected to reduced pressure rotary evaporation, and the crude product was purified by column chromatography to obtain the compound of formula 3. The final product mass was 0.92 g, the purity was 99.1%, the reaction yield was 46.3%, and the developing solvent used was ethyl acetate:n-hexane = 1:8.

[0070] The compound of formula 3 obtained in Example 3 was analyzed by HNMR, LC-MS and IPC respectively. Figure 7-9 .

[0071] Example 4

[0072] 500g of 2,5-dimethoxypyridine was prepared. The synthetic route was the same as in Example 1. The specific preparation method was as follows: 2,5-dibromopyridine (1000g), DMF (4725g) and a methanol solution of sodium methoxide (mass percentage concentration 30%, 2300g) were added to a reaction vessel, vacuumed and replaced with argon, CuI (20g) was added, and the reaction solution was stirred and heated to about 95°C and continued to stir for 24 hours. After the reaction solution was cooled to room temperature, solid impurities were filtered out, and the filtrate was extracted with water and ethyl acetate. The organic phase was collected and washed with saturated brine, and then purified by vacuum rotary evaporation to obtain the product formula 1 compound (500g, yield 85.12%, purity 95.76%).

[0073] Comparative Example

[0074] 500g of 2,5-dimethoxypyridine was prepared by the existing process. The specific preparation method is as follows: 2,5-dibromopyridine (1372g) and a methanol solution of sodium methoxide (30% by mass, 3046g) were added to a reaction vessel, and the reaction solution was stirred and heated to 70°C and continued to stir for 20 hours. After the reaction was completed, the reaction solution was cooled to room temperature and the solvent was removed, ethyl acetate and water were added for extraction, the organic phase was dried, filtered, the filtrate was free of solvent, and 2-methoxy-5-bromopyridine (933g) was obtained by vacuum distillation and purification. 2-methoxy-5-bromopyridine (933g) was added, DMF (2706g) and a methanol solution of sodium methoxide (30% by mass, 1549g) were added to a reaction vessel, vacuumed and replaced with argon, CuI (23.33g) was added, the reaction solution was stirred and heated to about 110°C and continued to stir for 6 hours. After the reaction solution was cooled to room temperature, solid impurities were removed by filtration, and the filtrate was added with water and ethyl acetate, and the organic phase was extracted and collected, washed with water, dried, and filtered. The solvent was removed from the filtrate, and the product formula 1 compound was obtained by vacuum distillation and purification. (500 g, yield 62.04%, purity 97.5%)

[0075] Table 1 Comparison between the process of the present invention and the process of the comparative example

[0076]

[0077] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a 2,5-dioxopyridine derivative, characterized in that: The 2,5-dioxopyridine derivative has a structure as shown in Formula 1 below: ； 1 Among them, R 1 The synthesis route of the compound of formula 1 is as follows: ； The synthesis steps are: dissolving the compound of formula A, a catalyst and phenol in an organic solvent, adding cesium carbonate after nitrogen replacement, heating to 90-130° C. and reacting for 48-72 hours, post-treating and purifying to obtain a compound of formula 1; The weight ratio of the compound of formula A to the catalyst is 1.24:1 to 5.7:1, the weight ratio of the phenol to the compound of formula A is 1.59:1 to 2.39:1, and the weight ratio of the cesium carbonate to the compound of formula A is 5.5:1 to 7.3:1; The catalyst is a cuprous ion catalyst, including one of cuprous bromide, cuprous chloride and cuprous iodide.

2. The method for preparing a 2,5-dioxopyridine derivative according to claim 1, characterized in that: The catalyst is cuprous iodide.

3. The method for preparing a 2,5-dioxopyridine derivative according to claim 1, characterized in that: The organic solvent is an aprotic solvent.

4. The method for preparing a 2,5-dioxopyridine derivative according to claim 1, characterized in that: The aprotic solvent is selected from DMF and DMSO.

5. The method for preparing a 2,5-dioxopyridine derivative according to claim 1, characterized in that: The aprotic solvent is DMF.

6. The method for preparing a 2,5-dioxopyridine derivative according to claim 1, characterized in that: The specific steps of the synthetic route are: In the presence of DMF solvent, a material having a weight ratio of 1.24:1 to 5.7:1 for the compound A and a weight ratio of 1.59:1 to 2.39:1 for the compound A and a phenol is dissolved, and after nitrogen substitution, cesium carbonate is added to the DMF solution, wherein the weight ratio of cesium carbonate to the compound A is 5.5:1 to 7.3:1, and the reaction solution is stirred at a reaction temperature of 120-130°C for 48-72 hours; after suction filtration, the filtrate is subjected to reduced pressure rotary evaporation until no distillate is produced, water is added to the remaining mother liquor, and then the mixture is extracted with ethyl acetate for several times, the organic phases are combined, the organic phases are washed with saturated brine for several times, and then the reduced pressure rotary evaporation is performed, and the obtained crude product is purified by column chromatography to obtain the compound of formula 1, wherein the developing solvent used is ethyl acetate:n-hexane=1:8.

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