阅读说明：本技术 一种β-碘代二氟丙酮类衍生物及其制备方法 (Beta-iodo-difluoropropanone derivative and preparation method thereof ) 是由 吴范宏 张天宇 吴晶晶 段瑾 潘军 于 2019-09-24 设计创作，主要内容包括：本发明涉及一种β-碘代二氟丙酮类衍生物及其制备方法,通过将碘二氟酮类化合物原料与烯烃原料溶于溶剂中,再加入催化剂、1,10-菲罗啉及碱性助剂,在惰性气体保护下反应,所得反应液晶萃取浓缩后,即得到目的产物β-碘代二氟丙酮衍生物。与现有技术相比,本发明的制备方法简单、易于操作、产率高、经济适用性强,具有较好的工业化生产前景。(The invention relates to a beta-iododifluoroacetone derivative and a preparation method thereof, which comprises the steps of dissolving an iododifluoroketone compound raw material and an olefin raw material in a solvent, adding a catalyst, 1, 10-phenanthroline and a basic auxiliary agent, reacting under the protection of inert gas, and extracting and concentrating the obtained reaction liquid crystal to obtain the target product, namely the beta-iododifluoroacetone derivative. Compared with the prior art, the preparation method disclosed by the invention is simple, easy to operate, high in yield, strong in economic applicability and better in industrial production prospect.)

1. A preparation method of beta-iododifluoroacetone derivatives is characterized in that raw materials of iododifluoroacetone compounds and olefin raw materials are dissolved in a solvent, then a catalyst, 1, 10-phenanthroline and an alkaline auxiliary agent are added for reaction under the protection of inert gas, and the obtained reaction liquid crystal is extracted and concentrated to obtain a target product;

the structural general formula of the raw materials of the iododifluoroketone compound is as follows:

wherein R is₁Is one of phenyl, naphthyl, phenyl containing substituent, alkyl or heterocyclic group;

the structural general formula of the olefin raw material is as follows:

wherein R is₂Is one of methyl, hydroxyl, carboxyl, phenyl containing substituent groups or heterocyclic groups, and n is 0-8.

2. The method of claim 1, wherein R is the number of R₁When the substituent is a phenyl group, the corresponding substituent is one or more of a fluorine substituent, a bromine substituent, a chlorine substituent, a trifluoromethoxy group, a methoxy group, a methyl group or a phenyl group.

3. The method of claim 1, wherein the molar ratio of the iododifluoroacetone compound to the olefin is 1 (1.2-1.5).

4. The method for preparing β -iododifluoropropanone derivative according to claim 1, wherein the solvent used is cyclopentyl methyl ether;

the catalyst is nickel diacetone;

the alkaline auxiliary agent is K₂CO₃。

5. The method for preparing beta-iododifluoropropanone derivative according to claim 1, wherein the reaction conditions are as follows: the reaction temperature is 60-100 ℃, and the reaction time is 5-8 h.

6. The method of claim 5, wherein the reaction temperature is 60-100 ℃.

7. The method for preparing β -iododifluoropropanone derivative according to claim 1, wherein a molar ratio of the catalyst to the starting iododifluoroketone compound is (0.005-0.015) to 1;

the molar ratio of the catalyst to the 1, 10-phenanthroline is 1 (1-1.5).

8. The method as claimed in claim 1, wherein the extraction concentration is performed by column chromatography, and the eluent is a mixed reagent of petroleum ether and ethyl acetate at a volume ratio of (200-.

9. A β -iododifluoroacetone derivative, which is prepared by the preparation method according to any one of claims 1 to 8, and which has the general structural formula:

wherein R is₂Is a linear alkyl or alkoxy group of C3-C8; r₃Is hydrogen or carbonyl; n is 1 or 2.

Technical Field

The invention belongs to the technical field of organic synthesis, and relates to a beta-iodo-difluoropropiophenone derivative, and a preparation method and application thereof.

Background

The organic compound has physical, chemical and physiological properties (such as lipophilicity and substitution) after introducing fluorine atom or fluorine-containing group into the moleculeMetabolic stability, ability to bind to target proteins, cell membrane penetration and bioavailability) are significantly improved over their parent molecules. Beta-difluoroacetone is a very important substructure that can serve both as a building block for further fluorinated molecules and as the reactive functional group molecule itself. At the same time, beta-difluoropropiophenone derivatives are valuable in the development of new drugs in pharmaceutical chemistry, since they readily form hydrates and mimic tetrahedral intermediates involved in peptide hydrolysis. Several derivatives of β -iododifluoropropiones have been reported to be useful as pharmaceutical and biological probes, such as lubiprostone, GABA agonists and HIV-1 aspartic protease inhibitors. Despite the importance of β -iododifluoropropanone derivatives, there remains a need for more efficient and versatile synthetic methods. The conventional method is carried out by AIBN and Na₂S₂O₄The synthesis of the beta-iododifluoroacetone derivative is realized by photo-oxidation-reduction or transition metal catalysis as a free radical initiator, but the method is limited by the application range of a substrate and the restriction of reaction conditions, so that the method is lack of practical value. It is therefore desirable to find a more efficient and economically viable initiator system for the synthesis of β -iododifluoroacetone derivatives.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a beta-iododifluoroacetone derivative and a preparation method and application thereof.

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

one of the technical aspects of the invention is to provide a preparation method of a beta-iododifluoropropiophenone derivative, which comprises the steps of dissolving an iododifluoroketone compound raw material and an olefin raw material in a solvent, adding a catalyst, 1, 10-phenanthroline and an alkaline assistant, reacting under the protection of inert gas, and extracting and concentrating the obtained reaction liquid crystal to obtain a target product;

the structural general formula of the raw materials of the iododifluoroketone compound is as follows:

wherein R is₁Is one of phenyl, naphthyl, phenyl containing substituent, alkyl or heterocyclic group,

the structural general formula of the olefin raw material is as follows:

wherein R is₂Is one of methyl, hydroxyl, carboxyl, phenyl containing substituent groups or heterocyclic groups, and n is 0-8.

Further, when R is₁When the substituent is a phenyl group, the corresponding substituent is one or more of a fluorine substituent, a bromine substituent, a chlorine substituent, a trifluoromethoxy group, a methoxy group, a methyl group or a phenyl group.

Furthermore, the molar ratio of the raw material of the iododifluoroketone compound to the raw material of the olefin is 1 (1.2-1.5).

Further, the solvent used is cyclopentyl methyl ether.

Further, the catalyst used was nickel diacetone.

Further, the alkaline assistant used is K₂CO₃。

Further, the reaction conditions are specifically as follows: the reaction temperature is 60-100 ℃, and the reaction time is 5-8 h.

Further, the reaction temperature is 60-80 ℃.

Furthermore, the molar ratio of the catalyst to the raw material of the iododifluoroketone compound is (0.005-0.015) to 1.

Furthermore, the molar ratio of the catalyst to the 1, 10-phenanthroline is 1 (1-1.5).

Furthermore, column chromatography is adopted for extraction and concentration, and the eluent is a mixed reagent consisting of petroleum ether and ethyl acetate in a volume ratio of (200-.

The reaction is carried out by a free radical process, and the iododifluoroketone compound is prepared by reacting nickel diacetone, 1, 10-phenanthroline and a basic assistant K₂CO₃Under the combined action of the above-mentioned two components to form difluoroketone free radicalTrapped by the olefin and free radical addition occurs. The invention adopts the nickel catalyst with catalytic amount and the ligand, can save the production cost to a great extent, and has strong economic applicability. Because the preparation process of the iododifluoroketone compound is complex, 1.2 times of equivalent of olefin is added and the reaction temperature is higher to ensure that the reaction is fully carried out.

The second technical scheme of the invention is to provide a beta-iododifluoroacetone derivative, the structural general formula of which is as follows:

wherein R is₂Is a linear alkyl or alkoxy group of C3-C8; r₃Is hydrogen or carbonyl; n is 1 or 2.

In the invention, the raw material of the iododifluoroketone compound can be prepared by the following method:

1) mixing a methyl ketone-containing compound shown as a formula (I) with ethyl trifluoroacetate, adding the mixture into anhydrous ether or anhydrous tetrahydrofuran, adding an initiator NaH, wherein the molar ratio of the methyl ketone-containing compound shown as the formula (I), the ethyl trifluoroacetate and the initiator is (0.3-0.5): 0.3-0.8):1, reacting for 1-3h at room temperature-50 ℃, and extracting, drying and concentrating a reaction product to obtain a compound shown as a formula (II);

2) mixing the compound shown as the formula (II) with a selective fluorination reagent (Selectfluor), adding the mixture into acetonitrile, reacting for 2-5h at room temperature to 50 ℃, and extracting, drying and concentrating the reaction product to obtain a compound shown as the formula (III);

3) adding a compound shown as a formula (III) into anhydrous tetrahydrofuran, and adding LiBr and I₂、Et₃N, wherein, the compound shown as the formula (III), LiBr and I₂And Et₃The mol ratio of N is 1 (5-8) to (1-3), the reaction is carried out for 0.5-1h at the room temperature of 50 ℃, and the reaction product is extracted, dried, concentrated, separated and purified to obtain the target product of the iododifluoroketone compound raw material.

The starting materials for the iododifluoroketones can also be prepared by reference to the following references: J.P.John, D.A.Colby, J.org.chem.76(2011)9163-9168 and the like.

Compared with the prior art, the preparation method is simple, easy to operate, high in yield, strong in economic applicability and good in industrial production prospect; the beta-iododifluoroacetone derivative prepared by the invention has good physical property, chemical property and physiological property, and has good application potential in the fields of medicines and pesticides.

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, unless otherwise specified, all the starting materials used are conventional commercial materials in the art.