Synthetic method of oxidation indoles compound

A technology for the synthesis of oxindole and its synthesis method, which is applied in the field of synthesis of oxindole compounds, can solve the problems of unsatisfactory chemical yield and complex operation, and achieve good application prospects, simple treatment process, and simplified production process

Inactive Publication Date: 2013-01-16
安徽世华化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the current synthetic method of indole, there are many problems in the processing and purification of target products and intermediates, such as complicated operations and unsatisfactory chemical yields.

Method used

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  • Synthetic method of oxidation indoles compound
  • Synthetic method of oxidation indoles compound
  • Synthetic method of oxidation indoles compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020]

[0021] Under stirring at 0-5°C, a solution of 109.8 g of liquid bromine (MW=159.81,687 mmol, 1 eq.) in dichloromethane (200 mL) was added dropwise to a solution containing 3-chloro-4-fluoro 100 g of aniline (MW=145.56, 687 mmol, 1eq.), and 80.4 g of pyridine (MW=79.10, 1.02 mol, 1.5eq. ) in dichloromethane (600 mL) were placed in a 3L three-neck round bottom flask. After the dropwise addition, keep the temperature at 0-5°C and continue to stir for one hour, and follow the TLC to complete the reaction. The reaction solution was washed with water (3×200 mL) and saturated brine (1×200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a crude oily product. Recrystallized from n-heptane to obtain 60.38 g of white crystals with a yield of 39%. HPLC purity: 99.65%; 1 H NMR (400 MHz CDCl 3 ): δ 3.91(2H, br. s), 6.71(1H,d), 7.16(1H,d).

Embodiment 2

[0023]

[0024] In a 1L three-neck round bottom flask, add 2-bromo-5-chloro-4-fluoroaniline (I) 40 g (MW=224.46, 178.2 mmol, 1 eq.) and anhydrous reagent dichloromethane 300 mL. At 0°C, 44.9 g of trifluoroacetic anhydride (MW=210.03, 213.8 mmol, 1.2 eq.) was added dropwise, and the stirring was continued for 1 hour. TLC detected that the reaction was complete. Neutralize with saturated sodium bicarbonate solution, separate the organic phase, extract the aqueous phase with dichloromethane (3×100 mL), combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate to dryness to give a white solid 55.96 g, yield 98%. HPLC purity: 97.90%; 1 H NMR (400 MHz CDCl 3 ): δ 7.44(1H, d), 8.305(1H,br. s), 8.44(1H,d).

Embodiment 3

[0026]

[0027] In a 500 mL three-neck round bottom flask, N 2 Under protection, 20.0 g (MW=320.47, 62.4 mmol, 1 eq.) of 2-bromo-5-chloro-4-fluorotrifluoroacetanilide (II) was dissolved in 250 mL of anhydrous DMSO, and malonic acid was added at room temperature Diethyl ester 12.0 g (MW=160.17, 74.88mmol, 1.2eq.), cuprous iodide 2.4 g (MW=190.45, 12.4mmol, 0.2eq.), L-proline 2.88 g (MW=115.13, 24.96 mmol, 0.4eq.), 81.4 g cesium carbonate (MW=325.82, 249.6 mmol, 4eq.). Stir at 50°C for 4 hours, and follow the completion of the reaction by TLC. Saturated ammonium chloride solution was added, and the blue precipitate disappeared. Extracted with ethyl acetate (3×100 mL), combined the organic layers, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained pale yellow oily crude product was dissolved in 200 mL of methanol and 200 mL of 6N HCl aqueous solution, and reacted at 80° C. for 2 to 3 hours, and the reaction was compl...

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Abstract

The invention discloses a synthetic method of an oxidation indoles compound. The synthetic method comprises the following steps of: taking an anilines compound as a raw material to generate an adjacent bromaniline compound; getting cuprous iodide as a catalyst and getting L-proline and inorganic salt cesium carbonate as additives to conveniently achieve an arylation coupling reaction between molecules of a bromoaniline compound and a beta-dicarbonyl compound; and finally carrying out intramolecular cyclization so as to further synthesize the oxoindole compound. According to the synthetic method disclosed by the invention, selected raw materials are easy to obtain; the catalyst and ligands are cheap; a reaction condition is mild; and the most important is that a simple recrystallizing method is adopted during post-purifying processing of a product; the synthetic method has the advantages of being simple and convenient to operate, and high in chemical yield and the like, and is more suitable for industrial production, and has a good application prospect; and another new way and method are provided for synthesizing and purifying the oxoindole compound.

Description

Technical field: [0001] The invention relates to a method for synthesizing oxindole compounds, which belongs to the technical field of organic synthesis. Background technique: [0002] As an important organic heterocyclic compound, indole and indole hydroxyl structural units are found in many drugs. Therefore, their synthesis and application have received extensive attention and research. However, due to the existence of regioselectivity in the reaction process such as the classic synthetic methods such as the Larock indole synthesis method and the Ficher indole synthesis method, or the use of highly toxic and expensive heavy metal reagents, the post-treatment of the reaction and the purification process of the product are complicated. It is not suitable for industrialized production, and the problem of serious environmental pollution. In recent years, on the basis of the rapid development of the Ulluman reaction, copper-catalyzed arylation reactions have made some progres...

Claims

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Application Information

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IPC IPC(8): C07D209/34
Inventor 孔祥俊贾邦乐马家松孔令航孔晓伟
Owner 安徽世华化工有限公司
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