CN110156805B - Preparation method of 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid - Google Patents
Preparation method of 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid Download PDFInfo
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Abstract
The invention discloses a preparation method of 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid, which comprises the following steps: dissolving 7-bromo-2, 3-dihydro [1,4] dioxino [2,3-b ] pyridine in a solvent, adding a cyanating reagent, and reacting to obtain 2, 3-dihydro- [1,4] dioxino [2,3-b ] pyridine-7-carbonitrile; hydrolyzing the prepared 2, 3-dihydro- [1,4] dioxino [2,3-b ] pyridine-7-carbonitrile in an alkaline solution to obtain 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid. The invention synthesizes 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid for the first time, and provides a basis for the preparation and the application of a medical intermediate; the preparation method of the 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid has the advantages of short reaction steps, high yield, simple and convenient operation and suitability for large-scale production.
Description
Technical Field
The invention relates to a preparation method of 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid, belonging to the technical field of synthesis of medical intermediates.
Background
2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid (I) is an important drug intermediate, and various reported PI3K inhibitors, CDK9 kinase inhibitors, CFTR modulators and pharmaceutically active molecules with analgesic effect all contain the key structure. Therefore, the compound has important application in the research and development of tumor-targeted drugs, the treatment of cystic fibrosis diseases and the research of drugs with analgesic effect, and has very wide market prospect. However, the synthesis of 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid has not been reported in the literature at present. The development of a method which is simple and convenient to operate, short in route, high in yield and suitable for large-scale production has important significance.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of the prior art, provide a preparation method of 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid and solve the problem that no synthesis report exists for the compound.
The technical purpose of the invention is realized by the following technical scheme:
a method for preparing 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid, comprising the steps of:
(1) dissolving 7-bromo-2, 3-dihydro [1,4] dioxino [2,3-b ] pyridine in a solvent, adding a cyanating reagent, and reacting to obtain 2, 3-dihydro- [1,4] dioxino [2,3-b ] pyridine-7-carbonitrile;
(2) hydrolyzing the 2, 3-dihydro- [1,4] dioxino [2,3-b ] pyridine-7-carbonitrile prepared in step (1) in a basic solution to obtain 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid;
the reaction process is as follows:
by adopting the technical scheme, the 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid is prepared, the reaction steps are simple, and the reaction raw materials are easy to obtain.
Preferably, the solvent in the step (1) is one or a mixture of N, N-Dimethylformamide (DMF), Dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP).
By adopting the technical scheme, the reaction between the compounds is more thorough by adopting the high-boiling-point aprotic solvent.
Preferably, the cyanating reagent in step (1) may be CuCN or Zn (CN)2One kind of (1).
By adopting the technical scheme, CuCN or Zn (CN)2The reaction conditions as a cyanating reagent are mild.
Preferably, the molar ratio of the 7-bromo-2, 3-dihydro [1,4] dioxadieno [2,3-b ] pyridine to the cyanating reagent in step (1) is 1.0:0.2 to 1.0: 8.0.
By adopting the technical scheme, 7-bromo-2, 3-dihydro [1,4] dioxino [2,3-b ] pyridine and a cyaniding reagent in a certain molar ratio are adopted for reaction, so that the reaction and the post-treatment are facilitated.
Preferably, the reaction temperature in the step (1) is 80-150 ℃.
By adopting the technical scheme, the reaction is easy to occur within a certain temperature range, and the conversion rate is high.
Preferably, the base in step (2) is one or a mixture of NaOH, KOH or CsOH.
By adopting the technical scheme, the hydrolysis of the 2, 3-dihydro- [1,4] dioxino [2,3-b ] pyridine-7-carbonitrile is facilitated in a strong alkaline solution, and the improvement of the reaction efficiency is promoted.
Preferably, the solvent of the alkaline solution in the step (2) is water or a mixed solvent containing water.
Preferably, the molar ratio of 2, 3-dihydro- [1,4] dioxino [2,3-b ] pyridine-7-carbonitrile to a base in step (2) is 1.0: 0.2-1.0: 10.0.
preferably, the reaction temperature in the step (2) is 80-100 ℃.
The prior art is referred to in the art for techniques not mentioned in the present invention.
In conclusion, the invention has the following beneficial effects:
(1) the invention synthesizes 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid for the first time, and provides a basis for the preparation and the application of a medical intermediate;
(2) the preparation method of the 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid has the advantages of short reaction steps, high yield, simple and convenient operation and suitability for large-scale production.
Drawings
FIG. 1 shows the preparation of 2, 3-dihydro- [1,4] according to the invention]Dioxadieno [2,3-b]Process for preparing pyridine-7-carbonitriles1H NMR chart;
FIG. 2 is a scheme of the preparation of 2, 3-dihydro-1, 4-dioxo [2,3-b ] according to the invention]Process for preparing pyridine-7-carboxylic acids1H NMR chart.
Detailed Description
The invention is further described below with reference to the accompanying drawings. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
A method for preparing 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid, comprising the steps of:
(1) dissolving 7-bromo-2, 3-dihydro [1,4] dioxino [2,3-b ] pyridine in a solvent, adding a cyanating reagent, and reacting to obtain 2, 3-dihydro- [1,4] dioxino [2,3-b ] pyridine-7-carbonitrile;
(2) hydrolyzing the 2, 3-dihydro- [1,4] dioxino [2,3-b ] pyridine-7-carbonitrile prepared in step (1) in a basic solution to obtain 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid;
the reaction process is as follows:
wherein 7-bromo-2, 3-dihydro [1,4] dioxino [2,3-b ] pyridine is prepared according to the method of patent US2013012530a 1.
2, 3-dihydro- [1,4] prepared by the invention]Dioxadieno [2,3-b]Process for preparing pyridine-7-carbonitriles1The H NMR chart is shown in FIG. 1.
The 2, 3-dihydro-1, 4-dioxo [2,3-b ] prepared by the invention]Process for preparing pyridine-7-carboxylic acids1The H NMR chart is shown in FIG. 2.
Example 1
(1) Synthesis of 2, 3-dihydro- [1,4] dioxadieno [2,3-b ] pyridine-7-carbonitrile:
7-bromo-2, 3-dihydro [1,4] dioxino [2,3-b ] pyridine (17.76 g, 82.21 mmol, 1.0 equiv.) was dissolved in 80 ml of DMF, cuprous cyanide (8.10 g, 90.44 mmol, 1.1 equiv.) was added, reflux was carried out at 140 ℃ for 8 hours, TLC showed completion of the reaction, the system was poured into 400 ml of water, filtered, the filter cake was slurried with THF, filtered to give 16.75 g of crude yellow product, which was used directly in the next reaction.
(2) Synthesis of 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid:
the 2, 3-dihydro- [1,4] dioxino [2,3-b ] pyridine-7-carbonitrile (16.75 g, 1.0 eq.) obtained by the above preparation was dispersed in 200ml of an aqueous solution of sodium hydroxide (20.66 g, 5.0 eq.), reacted at 100 ℃ under reflux for 3 hours, cooled to room temperature, extracted with ethyl acetate to remove impurities, filtered through a pad of celite, adjusted to pH 3, filtered, and dried to give 9.23 g of a white solid.
The total yield of the two-step reaction was 62.0%.
HNMR(400 MHz, DMSO-D6) （ppm）: 13.03（s，1H）8.30（s，1H）7.63（s，1H），4.90（dd，2H， J = Hz）4.30（dd，2H，J = Hz）。
LC-MS (ESI+): m/z 182.22 (M+H)。
Example 2
(1) Synthesis of 2, 3-dihydro- [1,4] dioxadieno [2,3-b ] pyridine-7-carbonitrile:
2, 3-dihydro- [1, 4)]Dioxadieno [2,3-b]Pyridine-7-carbonitrile (10.0 g, 46.29 mmol, 1.0 equiv.) was dissolved in 50 ml of NMP, and Zn (CN) was added2 (5.98 g, 50.92 mmol, 1.1 equiv.)，N2The temperature is raised to 120 ℃ under protection, the reaction is carried out for 8 hours, and TLC shows that the reaction is complete. Cooling to room temperature, pouring the reaction solution into water, precipitating a large amount of solid, adding ethyl acetate to dissolve, filtering with diatomite to remove insoluble substances, and washing filter cake with ethyl acetate. Mixing filtrates, extracting with ethyl acetate twice, mixing organic phases, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, and performing sand column chromatography to obtain yellow solid 4.60 g which is directly used for the next reaction.
Crude nuclear magnetism:1H NMR (400M Hz, DMSO-D6) ppm 8.24 (d, J = 2.24 Hz, 1H), 7.86 (d, J = 2.28 Hz, 1H), 4.51 (m, 2H), 4.33 (m, 2H)。
LC-MS (ESI+): m/z 163.23 (M+H)。
(2) synthesis of 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid:
the 2, 3-dihydro- [1,4] dioxino [2,3-b ] pyridine-7-carbonitrile (4.60 g) obtained by the above preparation was dispersed in 50 ml of an aqueous potassium hydroxide solution (4.15 g, 74.0 mmol, 4.0 equiv.), reacted at 100 ℃ under reflux for 6 hours, TLC showed completion of the reaction, cooled to room temperature, EA extracted to remove impurities, adjusted pH of the aqueous phase to 3, filtered and dried to obtain 2.82 g of a white solid.
The total yield of the two-step reaction was 40.3%.
1H NMR(400 MHz, DMSO-D6) （ppm）: 13.05（s，1H）8.31（s，1H）7.63（d，J = 1.68 Hz, 1H），4.48（m，2H）4.30（m，2H）。
LC-MS (ESI+): m/z 182.22 (M+H)。
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and are considered to be within the scope of the invention.
Claims (7)
1. A preparation method of 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid is characterized by comprising the following steps:
(1) dissolving 7-bromo-2, 3-dihydro [1,4] dioxino [2,3-b ] pyridine in a solvent, adding a cyanating reagent, and reacting at 80-150 ℃ to obtain 2, 3-dihydro- [1,4] dioxino [2,3-b ] pyridine-7-carbonitrile;
(2) hydrolyzing the 2, 3-dihydro- [1,4] dioxino [2,3-b ] pyridine-7-carbonitrile prepared in the step (1) in an alkaline solution, and reacting at 80-100 ℃ to obtain 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid;
the reaction process is as follows:
2. the method for preparing 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid according to claim 1, wherein the solvent in step (1) is one or more of DMF, DMAC and NMP.
3. 2, 3-dihydro-1, 4-dioxo [2,3-b ] according to claim 1]A process for producing pyridine-7-carboxylic acid, characterized in that the cyanating reagent in the step (1) is CuCN or Zn (CN)2One kind of (1).
4. The process according to claim 1, wherein the molar ratio of 7-bromo-2, 3-dihydro [1,4] dioxadieno [2,3-b ] pyridine to the cyanating agent in step (1) is 1.0:0.2 to 1.0: 8.0.
5. The method for preparing 2, 3-dihydro-1, 4-dioxo [2,3-b ] pyridine-7-carboxylic acid according to claim 1, wherein the base in step (2) is one or more of NaOH, KOH, or CsOH.
6. The process according to claim 1, wherein the solvent of the basic solution in step (2) is water or a mixed solvent containing water.
7. The process according to claim 1, wherein the molar ratio of 2, 3-dihydro- [1,4] dioxadieno [2,3-b ] pyridine-7-carbonitrile to the base in step (2) is 1.0: 0.2-1.0: 10.0.
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| CN101374843A (en) * | 2005-12-21 | 2009-02-25 | 詹森药业有限公司 | Triazolopyridazines as tyrosine kinase modulators |
| US7635715B2 (en) * | 2006-12-18 | 2009-12-22 | Amgen Inc. | Naphthalenone compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof |
| CN102344359A (en) * | 2011-11-01 | 2012-02-08 | 常熟三爱富中昊化工新材料有限公司 | Method for preparing 3-butenoic acid |
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