阅读说明：本技术 4-亚苄基-2-芳基异噁唑烷-3,5-二酮及其制备方法 (4-benzylidene-2-aryl isoxazolidine-3, 5-diketone and preparation method thereof ) 是由 马军安 李军宽 张发光 于 2019-11-25 设计创作，主要内容包括：本发明提供一种4-亚苄基-2-芳基异噁唑烷-3,5-二酮及其制备方法,此类分子具有式(I)结构,式中Ar<Sup>1</Sup>与Ar<Sup>2</Sup>为相同或不同的芳香基团。本发明提供两种合成4-亚苄基-2-芳基异噁唑烷-3,5-二酮的方法,如反应方程式1)与2)所示：其中1)是芳基羟胺与丙二酰氯在二氯甲烷溶液中混合,首先制得2-芳基异噁唑烷-3,5-二酮,然后2-芳基异噁唑烷-3,5-二酮在加热条件下与芳基醛反应,得到目标化合物；方法2)是通过一步法合成,即芳基羟胺在丙二酰氯的氯仿溶液中滴加溶有芳基羟胺氯仿溶液,反应一段时间后加热至50℃除去氯化氢,然后直接滴加芳基醛的氯仿溶液,从而得到目标产物。(The invention provides a 4-benzylidene-2-aryl isoxazolidine-3, 5-diketone and a preparation method thereof, wherein the molecules have a structure shown in a formula (I), wherein Ar is 1 And Ar 2 Are identical or different aromatic radicals. The present invention provides two methods for synthesizing 4-benzylidene-2-aryl isoxazolidine-3, 5-dione, as shown in reaction equations 1) and 2): wherein 1) aryl hydroxylamine and malonyl chloride are mixed in a dichloromethane solution to prepare 2-aryl isoxazolidine-3, 5-diketone, and then the 2-aryl isoxazolidine-3, 5-diketone reacts with aryl aldehyde under the heating condition to obtain a target compound; the method 2) is synthesized by a one-step method, namely, the aryl hydroxylamine is dropwise added into chloroform solution of malonyl chloride, the chloroform solution in which the aryl hydroxylamine is dissolved is heated to 50 ℃ after reacting for a period of time to remove hydrogen chloride, and then the chloroform solution of aryl aldehyde is directly dropwise added, so that the target product is obtained.)

1. A synthetic method for preparing 4-benzylidene-2-aryl isoxazolidine-3, 5-diketone has a structure shown in formula (I), wherein Ar is¹And Ar²Are the same or different aromatic groups, and comprise the following two routes:

1) aryl hydroxylamine and malonyl chloride are mixed in a dichloromethane solution, then 2-aryl isoxazolidine-3, 5-diketone is prepared by adjusting pH and performing a reverse extraction method, then aryl aldehyde is added into the 2-aryl isoxazolidine-3, 5-diketone under the heating condition for reaction, and the mixture is cooled, filtered and thermally crystallized;

2) is synthesized by a one-step method: dripping aryl hydroxylamine in chloroform solution of malonyl chloride, after the reaction, detecting by TLC to complete the reaction, heating to 50 ℃ to remove hydrogen chloride, then directly dripping chloroform solution of aryl aldehyde, cooling, filtering, and thermally crystallizing;

1)

2)

2. the synthesis method for preparing 4-benzylidene-2-aryl isoxazolidine-3, 5-dione as claimed in claim 1, wherein the starting materials are aryl hydroxylamine, malonyl chloride and aryl aldehyde, and the molar ratio is 1/1/1.1.

3. The synthesis method for preparing 4-benzylidene-2-aryl isoxazolidine-3, 5-dione as claimed in claim 1, wherein the pH-adjusted back extraction method comprises adding saturated sodium bicarbonate solution in batches, extracting with dichloromethane, adjusting pH of inorganic phase to 1-2 with 6N hydrochloric acid, back extracting with dichloromethane, and combining organic phases.

4. The synthetic method for preparing 4-benzylidene-2-aryl isoxazolidine-3, 5-dione as claimed in claim 1, wherein the thermal crystallization solvent is ethyl acetate and petroleum ether.

5. The synthetic method for preparing 4-benzylidene-2-aryl isoxazolidine-3, 5-dione as claimed in claim 1, wherein the organic solvent is dichloromethane, absolute ethanol, chloroform, ethyl acetate, petroleum ether.

6. The 4-benzylidene-2-aryl isoxazolidine-3, 5-dione compound prepared according to the method of claims 1 to 5, characterized in that it has one of the following structures:

Technical Field

The invention belongs to the field of organic synthesis and pharmaceutical chemistry, and relates to two 4-benzylidene-2-aryl isoxazolidine-3, 5-diketone and preparation methods of derivatives thereof, in particular to a series of 4-benzylidene-2-aryl isoxazolidine-3, 5-diketone and two efficient synthesis methods thereof, wherein the compound contains a 4-benzylidene-2-aryl isoxazolidine-3, 5-diketone heterocyclic structure, and can be used as a medicament or a core structural unit for medicament synthesis and used for medicament activity screening.

Background

Isoxazolidine-3, 5-diketone and derivatives thereof are important heterocyclic compounds, and as early as 1986, 12 isoxazolidine-3, 5-diketone are obtained by taking aryl hydroxylamine as a raw material through two-step reaction at a low yield by Klausrehse and Joachim Meder, and are subjected to anticoagulation analysis, so that the series of compounds have good anticoagulation. (Arch.pharm.1986,319, 133-140). However, this reaction has certain disadvantages: large amount of ether extraction, relatively complicated post-treatment, long reaction time and the like. Therefore, the development of a new synthesis method for preparing the 2-aryl isoxazolidine-3, 5-diketone and the derivatives thereof has important significance in the fields of organic synthesis and pharmaceutical chemistry.

Disclosure of Invention

In view of the above, the technical problem to be solved by the present invention is to provide a new method for efficiently and rapidly preparing isoxazolidine-3, 5-dione and its derivatives, which has the structure of formula (I), wherein Ar is¹And Ar²Are identical or different aromatic radicals. The following reaction equations 1) and 2) provide two methods for synthesizing isoxazolidine-3, 5-dione and its derivatives, wherein 1) aryl hydroxylamine and malonyl chloride are mixed in dichloromethane solution, and then 2-aryl isoxazolidine-3, 5-dione is prepared by adjusting pH and performing reverse extraction, and then 2-aryl isoxazolidine-3, 5-dione is added with a certain amount of aryl aldehyde under heating condition, reacted for a period of time, cooled, filtered, and thermally crystallized. The method 2) is synthesized by a one-step method: the aryl hydroxylamine is added with chloroform solution dissolved with aryl hydroxylamine in chloroform solution of malonyl chloride dropwise, after a period of reaction, TLC detection reaction is completed, and then heated to 50 ℃ to remove hydrogen chloride, then directly added with chloroform solution of aryl aldehyde dropwise, cooled, filtered and thermally crystallized.

1)

2)

The molar ratio of the aryl hydroxylamine, the malonyl chloride and the aryl aldehyde is 1/1/1.1.

The pH-adjusted reverse extraction method is characterized in that saturated sodium bicarbonate solution is added in batches, dichloromethane is used for extraction, the pH of an inorganic phase is adjusted to be 1-2 by 6N hydrochloric acid, dichloromethane is used for reverse extraction, and organic phases are combined.

The thermal crystallization solvent is ethyl acetate and petroleum ether.

The organic solvent comprises dichloromethane, absolute ethyl alcohol, chloroform, ethyl acetate and petroleum ether.

In the present invention, the isoxazolidine-3, 5-dione represented by the formula (I) and a derivative thereof, most preferably one of the following structures:

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The aryl hydroxylamines can be prepared according to published procedures such as (Org Lett.2017,19(8), 2194-2196). To further illustrate the present invention, the isoxazolidine-3, 5-dione and its derivatives provided by the present invention and the preparation method thereof are described in detail below with reference to examples. All chemicals and reagents in the following examples were purchased from commercial suppliers and used without further purification treatment unless otherwise specified. All parts and percentages are parts by mass and percentages by mass, and the temperatures indicated are in degrees centigrade unless otherwise specified; 200-mesh 300-mesh standard silica gel for Qingdao ocean chemical engineering for rapid column chromatography; a Qingdao ocean chemical industry 0.20mm standard plate for thin-layer chromatography; nuclear magnetic resonance spectroscopy data (NMR) were obtained using Bruker (Bruker)400 or 600 million nuclear magnetic resonance spectroscopy measurements with tetramethylsilane as an internal standard and deuterated chloroform or deuterated dimethyl sulfoxide or deuterated methanol as a solvent (s represents a single peak, d represents a doublet, t represents a triplet, q represents a quadruplet, m represents a multiplet, br represents a broad peak); mass spectral data were obtained using a MicroTOF-QII or Waters Micromass GCT Premier instrument.