Production method of 5-chloro-3-hydroxy-3-difluoroalkyl-indoline-2-ketone compound
A technology of difluoroalkyl and ketone compounds, applied in the direction of organic chemistry, can solve the problems of difficult large-scale production and preparation, complex difluoroenol silyl ether, expensive and complex organic ligands, etc., and achieve direct and Simple operation, convenient and efficient preparation process
Active Publication Date: 2019-08-16
SHANGHAI APPLIED TECHNOLOGIES COLLEGE
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Problems solved by technology
[0005] In this type of existing preparation method, the preparation of difluoroenol silyl ether is relatively complicated, the conditions are relatively harsh, and a strong base and a relatively expensive fluorinating reagent are required. Therefore, the source of raw materials is limited to a certain extent, and it is difficult to carry out Large-scale production and preparation, the reaction requires expensive and complex organic ligands, which also limits its application
Method used
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Embodiment 1
[0027] Under nitrogen protection, 5-chloroisatin (37.1mg, 0.2mmol), α,α-difluoro-β-ketoacid compound (120.1mg, 0.6mmol), 1ml of toluene were added to the reaction tube once, and stirred Under the conditions, the temperature was slowly raised to 100°C, and the reaction was carried out for 10 hours. After the reaction is over, it is transferred to an egg-shaped bottle, rotary evaporated, and the product is obtained by column chromatography 70.0mg, yield 99.9%.
[0028] 1 H NMR (400 MHz, DMSO) δ10.82 (s, 1H), 8.10 (d, J = 8.0 Hz, 2H), 7.75 (t, J = 7.4 Hz, 1H), 7.59 (dd, J = 15.4, 7.7 Hz, 3H), 7.30–7.44(m, 2H), 6.92(d, J=8.4 Hz, 1H). 19 F NMR (376 MHz, DMSO) δ-108.56(d, J=275.2 Hz, 1F), -109.48(d, J=275.6Hz, 1F).
Embodiment 2
[0030] Compared with Example 1, most of them are the same, except that in this example: the molar ratio of α,α-difluoro-β-ketoacid compound to 5-chloroisatin is 2:1.
Embodiment 3
[0032] Compared with Example 1, most of them are the same, except that in this example: the molar ratio of the α,α-difluoro-β-ketoacid compound to 5-chloroisatin is 4:1.
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The invention relates to a production method of a 5-chloro-3-hydroxy-3-difluoroalkyl-indoline-2-ketone compound. The production method of the 5-chloro-3-hydroxy-3-difluoroalkyl-indoline-2-ketone compound comprises the steps of under protection of inert gas, adding an isatin compound and an alpha,alpha-difluoro-beta-keto acid compound into an organic solvent, conducting heating for decarboxylationaddition reaction, and separating and purifying an obtained reaction product to obtain the 5-chloro-3-hydroxy-3-difluoroalkyl-indoline-2-ketone compound. Compared with the prior art, the production method of the 5-chloro-3-hydroxy-3-difluoroalkyl-indoline-2-ketone compound has the advantages that the required raw materials are cheap and easy to obtain, the synthesis method is simple to operate, reaction time is short, and the yield of the product is high, so that the production method of the 5-chloro-3-hydroxy-3-difluoroalkyl-indoline-2-ketone compound has excellent application prospects.
Description
technical field [0001] The invention belongs to the technical field of organic synthesis, and relates to a preparation method of 5-chloro-3-hydroxyl-3-difluoroalkyl-indoline-2-one compound. Background technique [0002] Hydroxyl groups can significantly change the hydrophilicity of insoluble drug molecules to human body fluids. In addition, the introduction of polyhydroxyl groups can also slow down the oxidation process of easily oxidized drugs, so many drug molecules contain hydroxyl groups. Obtaining hydroxyl groups by carbonyl reduction or nucleophilic addition is a very common method. For example, isatins and substituted isatins can obtain derivatives of 3-hydroxyindolin-2-ones under the action of different nucleophiles (see Mohammadi, S.; Heiran, R.; Herrera, R.P.; Marqués-López, E. Chem Cat Chem 2013, 5, 2131. et al.). 3-Hydroxyindolin-2-one structures, as well as aryl-substituted 3-hydroxyindolin-2-one structures, are also widely found in natural products and bioacti...
Claims
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CPCC07D209/38
Inventor 刘振江高宇宁黄大康高永红费逸凡
Owner SHANGHAI APPLIED TECHNOLOGIES COLLEGE