CN110194733B

CN110194733B - Preparation method of 3-difluoroalkyl-3-hydroxyindolone compound

Info

Publication number: CN110194733B
Application number: CN201910555563.XA
Authority: CN
Inventors: 刘振江; 黄大康; 高宇宁; 廖爱雪; 连波; 胡晓钧
Original assignee: Shanghai Institute of Technology
Current assignee: Shanghai Institute of Technology
Priority date: 2019-06-25
Filing date: 2019-06-25
Publication date: 2022-11-15
Anticipated expiration: 2039-06-25
Also published as: CN110194733A

Abstract

The invention relates to a preparation method of a 3-difluoroalkyl-3-hydroxyindolone compound, which comprises the steps of adding an alpha, alpha-difluoro-beta-keto acid compound and isatin into an organic solvent under the protection of inert gas, heating and carrying out decarboxylation addition reaction to obtain the 3-difluoroalkyl-3-hydroxyindolone compound. Compared with the prior art, the raw materials used in the invention have low price, easy obtainment, mild reaction conditions, no need of any catalyst, easy operation of reaction, simple post-treatment and wide application range, and the invention is a novel method for preparing the 3-difluoroalkyl-3-hydroxyindolone compound and has good application prospect.

Description

Preparation method of 3-difluoroalkyl-3-hydroxyindolone compound

Technical Field

The invention belongs to the technical field of organic synthesis, and relates to a preparation method of a 3-difluoroalkyl-3-hydroxyindolone compound.

Background

2, 3-dicarbonyl indoles, commonly known as isatin, are an important natural product. Also, many natural products or biologically active molecules contain isatin or oxindole building blocks. Isatin-based compounds have multiple reactivity properties, such as electrophilic substitution on aromatic rings, nucleophilic addition of carbonyl groups, spiro cyclization, and the like (see da Silva, j.f.m.; garden, s.j.; pinto, a.c.j. Braz. Chem. Soc.2001,12, 273.). Isatin and some substituted isatins with simple structures are cheap and easily available, so that, in terms of the reaction of isatin-like compounds, both theoretical research and practical application, there has been great development in recent years (see Mohammadi, s.; heiran, r.; herrera, r.p.; marqu es-l. Lopez, e.chemcatchem 2013,5, 2131.).

In view of the fact that the carbonyl group at the 3-position of isatin has high reaction activity and can be used as a potential chiral center in synthesis, the conversion of isatin compounds into 2-oxindole compounds through nucleophilic addition or spiro cyclization reaction is a widely applied and important methodology (Klein, J.E.M.N.; taylor, R.J.K.Euro.J.org.chem.2011,2011,6821. And the like). In particular, 3-substituted 3-hydroxyindolone derivatives, many are natural products or bioactive molecules such as convolutamidines, diazolamides, leptin D, etc., which generally possess important biological activities such as antibacterial, anticancer, antiviral, etc. (see Kamano, Y.; zhang, H. -P.; ichiahara, Y.; kizu, H.; komiyama, K.; peit ttt, G.R. tetrahedron Lett.1995,36,2783, etc.).

Because fluorine atoms have stronger electron-withdrawing property, lipophilicity and smaller steric hindrance, the selective introduction of fluorine atoms into organic molecules can change certain chemical properties and physiological activities of the organic molecules, and the method and the approach are important for synthesizing drug molecules. At present, the preparation method for introducing fluorine atoms into organic molecules is less, expensive catalysts, ligands or raw materials for reaction are generally required to be difficult to prepare, and the like, such as nucleophilic addition reaction of enol silyl ether compounds of difluoroolefins and isatin compounds. (e.g., yu, J. -S.; liu, Y. -L.; tang, J.; wang, X.; zhou, J. Angew. Chem. Int. Ed.2014,53,9512. Et al). .

In the method, the preparation conditions of the difluoroenol silyl ether are harsh, and strong alkali and expensive fluorination reagents are needed, so the source of raw materials is limited to a certain extent, and the large-scale production and preparation are difficult to carry out. In addition, the reaction requires expensive and complicated organic ligands, which limits its application. Therefore, there is a need for a new process for the preparation of 3-difluoroalkyl-3-oxindole compounds.

Disclosure of Invention

The present invention aims to overcome the defects of the prior art and provide a preparation method of a 3-difluoroalkyl-3-hydroxyindolone compound.

The purpose of the invention can be realized by the following technical scheme:

a preparation method of 3-difluoroalkyl-3-hydroxyindolone compounds comprises the steps of adding phenyl-substituted alpha, alpha-difluoro-beta-keto acid compounds and isatin into an organic solvent under the protection of inert gas, and heating for decarboxylation addition reaction to obtain the 3-difluoroalkyl-3-hydroxyindolone compounds.

Further, the molar ratio of the phenyl-substituted α, α -difluoro- β -keto acid compound to isatin is (2-4): 1. if the amount of keto acid is small, for example, if the molar ratio of keto acid compound to isatin is 1. If the amount of the keto acid is too large, the raw material is wasted excessively.

Further, the molecular structural formula of the phenyl-substituted alpha, alpha-difluoro-beta-keto acid compound is as follows:

further, the inert gas is nitrogen or argon.

Further, the organic solvent is any one or a mixture of several of DMSO, DMF, NMP, toluene, dioxane and THF, and the solvent is preferably toluene.

Further, the reaction temperature is 80-120 ℃. If the temperature is lower than 80 ℃, the decarboxylation process is difficult to perform, and if the temperature is too high, the yield is lowered.

Further, the reaction time is 6-18h.

Further, after the reaction is finished, the reaction product is obtained by column chromatography separation and purification.

The reaction formula of the invention is as follows:

the method can prepare the easily obtained 3-difluoroalkyl-3-hydroxyindole compound with high yield by the decarboxylation addition reaction of the isatin reagent and the phenyl-substituted alpha, alpha-difluoro-beta-keto acid without any catalyst.

Compared with the prior art, the invention provides a method for directly, conveniently and efficiently synthesizing the 3-difluoroalkyl-3-hydroxyindolone compound, the needed raw materials are cheap and easy to obtain, the synthesis method is simple to operate, the reaction time is short, the yield of the product is higher, and the method has good application prospect.

Detailed Description

The present invention will be described in detail with reference to specific examples. The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments.

In the following examples, the molecular structure of the α, α -difluoro- β -keto acid compound used is:

it was prepared by reference to the following references (Yang, M. -H.; orsi, D.L.; altman, R.A.Angew.chem.int.Ed.2015,54, 2361.). And the rest of the raw materials or processing techniques which are not specifically described are conventional commercial raw materials or conventional processing techniques in the field.

Example 1

Isatin (30.0 mg,0.2 mmol), an α, α -difluoro- β -keto acid compound (120.1 mg,0.6 mmol) and 1ml of toluene were added to a reaction tube in one portion under nitrogen protection, and the temperature was slowly raised to 100 ℃ under stirring to react for 12 hours. After the reaction is finished, the product is transferred into an egg-shaped bottle, rotary evaporation is carried out, and column chromatography is carried out to obtain 57.9mg of a product, wherein the yield is 95.5%.

The resulting product was tested as follows:

¹ H NMR(400MHz,DMSO)δ10.64(s,1H),8.09(d,J＝7.7Hz,2H),7.74(t,J＝7.4Hz,1H),7.58(t,J＝7.8Hz,2H),7.26–7.40(m,3H),6.99(t,J＝7.6Hz,1H),6.88(d,J＝7.7Hz,1H). ¹⁹ F NMR(376MHz,DMSO)δ-108.75(d,J＝271.9Hz,1F),-109.62(d,J＝271.9Hz,1F).。

example 2

Compared to example 1, most of them are the same except that in this example: the molar ratio of the α, α -difluoro- β -keto acid compound to isatin is 2.

Example 3

Compared to example 1, most of them are the same except that in this example: the molar ratio of the alpha, alpha-difluoro-beta-keto acid compound to isatin is 4.

Example 4

Compared to example 1, most of them are the same except that in this example: the inert gas is argon.

Examples 5 to 10

Compared to example 1, most of them are the same except that in this example: the organic solvent was changed to DMSO, DMF, NMP, dioxane, THF, or a mixture of DMSO, DMF and toluene at a volume ratio of 1.

Example 11

Compared to example 1, most of them are the same except that in this example: the reaction temperature is 80 ℃, and the reaction time is 18h.

Example 12

Compared to example 1, most of them are the same except that in this example: the reaction temperature is 120 ℃, and the reaction time is 6h.

Comparative example 1

Compared to example 1, most of them are the same except that in this example: the reaction temperature was 60 ℃. After 12h of reaction, TLC observation shows almost no product and no subsequent treatment.

Comparative example 2

Compared to example 1, most of them are the same except that in this example: the reaction temperature was 140 ℃. After the reaction is finished, the product is transferred into an egg-shaped bottle, rotary evaporation is carried out, and column chromatography is carried out to obtain 31.5mg of product with the yield of 51.9%.

The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.

Claims

1. A preparation method of 3-difluoroalkyl-3-hydroxyindolone compounds is characterized in that phenyl-substituted alpha, alpha-difluoro-beta-keto acid compounds and isatin are added into an organic solvent under the protection of inert gas, and the mixture is heated to carry out decarboxylation addition reaction, so that the 3-difluoroalkyl-3-hydroxyindolone compounds are prepared;

the molar ratio of the phenyl-substituted alpha, alpha-difluoro-beta-keto acid compound to isatin is (2-4): 1;

the molecular structural formula of the phenyl-substituted alpha, alpha-difluoro-beta-keto acid compound is as follows:

the inert gas is nitrogen or argon;

the organic solvent is toluene;

the reaction temperature is 80-120 ℃, and the reaction time is 6-18h.

2. The method for preparing a 3-difluoroalkyl-3-hydroxyindolone compound according to claim 1, wherein the reaction product is obtained by column chromatography separation and purification after the reaction is completed.