阅读说明：本技术 2,1-苯并异噁唑衍生物及其合成方法和应用 (2, 1-benzisoxazole derivative and synthetic method and application thereof ) 是由 陈云峰 王雨微 于 2019-09-06 设计创作，主要内容包括：本发明属于有机及药物合成技术领域,具体涉及2,1-苯并异噁唑衍生物及其合成方法和应用。本发明采用简单易得的邻溴苯乙酮、醛和叠氮化钠作为起始原料,通过羟醛缩合、叠氮加成环化、芳基的叠氮化和氧化环化,可以一锅法的合成2,1-苯并异噁唑衍生物。该合成方法条件温和,操作简便,底物范围广,兼容不同取代基。合成得到的2,1-苯并异噁唑衍生物为康普瑞汀的类似物,有望在抗有丝分裂,抗肿瘤以及抗癌活性等方面表现出较高活性。(The invention belongs to the technical field of organic and pharmaceutical synthesis, and particularly relates to a 2, 1-benzisoxazole derivative and a synthesis method and application thereof. The invention adopts simple and easily obtained o-bromoacetophenone, aldehyde and sodium azide as starting materials, and can synthesize the 2, 1-benzisoxazole derivative by a one-pot method through aldol condensation, azide addition cyclization, aryl azide and oxidative cyclization. The synthesis method has the advantages of mild conditions, simple and convenient operation, wide substrate range and compatibility with different substituents. The synthesized 2, 1-benzisoxazole derivative is an analogue of combretastatin, and is expected to show higher activity in the aspects of antimitotic, antitumor, anticancer activity and the like.)

A2, 1-benzisoxazole derivative characterized by the general structural formula:

wherein R is halogen, methoxy or hydrogen; ar is aryl or heterocyclic radical.

2. 2, 1-benzisoxazole derivatives according to claim 1 characterised in that: ar is phenyl, 2-methoxyphenyl, p-tolyl, 2-fluorophenyl, 4-nitrophenyl, cyanophenyl, furan-2-yl or 4-chlorophenyl.

3. A preparation method of a 2, 1-benzisoxazole derivative is characterized by comprising the following steps:

wherein:

r is halogen, methoxy or hydrogen; ar is aryl or heterocyclic radical;

the catalyst is selected from CuI, CuBr, CuCl and Cu₂O、Cu(OTf)₂、Cu(OAc)₂、CuO、CuCl₂Or CuBr₂Any one of the above;

the base is selected from Cs₂CO₃、K₃PO₄、K₂CO₃Or NaOH;

the solvent is selected from one or more of DMSO, DMF, N-pyrrolidone, 1,4 dioxane or ethylene glycol;

the temperature is 80-130 ℃.

4. A process for the preparation of 2, 1-benzisoxazole derivatives according to claim 3 characterised in that: ar is phenyl, 2-methoxyphenyl, p-tolyl, 2-fluorophenyl, 4-nitrophenyl, cyanophenyl, furan-2-yl or 4-chlorophenyl.

5. A process for the preparation of 2, 1-benzisoxazole derivatives according to claim 4 or 3 characterised in that: the dosage of the catalyst is 0.05-0.5 times of that of o-bromoacetophenone by weight of the material.

6. Use of a 2, 1-benzisoxazole derivative according to claim 1 or 2 characterised in that: can be used for preparing anticancer drugs.

Technical Field

The invention belongs to the technical field of organic and pharmaceutical synthesis, and particularly relates to a 2, 1-benzisoxazole derivative and a synthesis method and application thereof.

Background

1,2, 3-triazoles are ubiquitous building blocks in biologically active molecules because of their good biocompatibility and their remarkable stability under hydrolytic, oxidative and reductive conditions. 4, 5-diaryl substituted 1,2, 3-triazoles are reported to have a wide range of biological activities, including antimitotic, antitumor and anticancer activities. The linkage of benzisoxazoles to 1,2, 3-triazoles not only constructs a class of diheterocycles with novel structures, but also may possess promising biological activity in terms of their structural similarity.

Currently, the synthesis of benzisoxazoles is mainly divided into two types: 1) the o-nitrobenzaldehyde compound is used as a raw material, a reduction system is usually required, and a noble metal reducing agent is generally used, so that economic waste is caused. 2) The o-azidobenzaldehyde is used as a raw material, and through denitrification gas cyclization reaction, the yield is generally low, the raw material is not easy to obtain, and the substrate range is limited. Therefore, it is necessary to develop a more convenient and wide-range method for synthesizing novel 2, 1-benzisoxazole derivatives.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention provides a 2, 1-benzisoxazole derivative, a synthetic method and application thereof. The synthesis method has the advantages of simple and easily obtained raw materials, simple and convenient operation and higher yield. The synthesized 2, 1-benzisoxazole derivative is expected to show higher activity in the aspects of antimitotic activity, antitumor activity, anticancer activity and the like.

The technical scheme provided by the invention is as follows:

the 2, 1-benzisoxazole derivative has the following structural general formula:

r is halogen, methoxy or hydrogen; ar is aryl or heterocyclic radical.

The 2, 1-benzisoxazole derivative provided by the invention is a novel compound containing a 1,2, 3-triazole structure, and is an analogue of Combretastatin. The design of the 1,2, 3-triazole ring system not only prevents cis-trans isomerization, but also improves the drug similarity of the CA-4 analogue. Meanwhile, the existence of the 2, 1-benzisoxazole structure provides space for further structural diversity. The bis-heterocyclic compound with the structure is expected to show higher activity in the aspects of antimitotic activity, antitumor activity, anticancer activity and the like.

Specifically, Ar is phenyl, 2-methoxyphenyl, p-tolyl, 2-fluorophenyl, 4-nitrophenyl, cyanophenyl, furan-2-yl, 4-chlorophenyl.

The invention also provides a preparation method of the 2, 1-benzisoxazole derivative, which comprises the following steps:

wherein:

r is halogen, methoxy or hydrogen; ar is aryl or heterocyclic radical;

the catalyst is selected from CuI, CuBr, CuCl and Cu₂O、Cu(OTf)₂、Cu(OAc)₂、CuO、CuCl₂Or CuBr₂Any one of them, preferably CuO, can achieve a high reaction yield;

the base is selected from Cs₂CO₃、K₃PO₄、K₂CO₃Or NaOH, preferably K₂CO₃The generation of byproducts can be effectively inhibited, and the reaction is ensured to be carried out stably and rapidly;

the solvent is selected from one or a mixture of more of DMSO, DMF, N-pyrrolidone, 1,4 dioxane or glycol, and DMSO is preferred, so that high reaction yield can be realized;

the temperature is 80-130 ℃, preferably 100-120 ℃, and the temperature range is suitable for the reaction of various substrates defined by the invention.

According to the technical scheme, the 2, 1-benzisoxazole derivative can be synthesized by a one-pot method by using simple and easily-obtained o-bromoacetophenone, aldehyde and sodium azide as starting raw materials through aldol condensation, azide addition cyclization, aryl azide and oxidative cyclization. The synthesis method has the advantages of mild conditions, simple and convenient operation, wide substrate range and compatibility with different substituents.

Specifically, Ar is phenyl, 2-methoxyphenyl, p-tolyl, 2-fluorophenyl, 4-nitrophenyl, cyanophenyl, furan-2-yl, 4-chlorophenyl.

Specifically, the dosage of the catalyst is 0.05-0.5 times of that of o-bromoacetophenone by mass.

The invention also provides application of the 2, 1-benzisoxazole derivative in preparing anti-cancer drugs.

In general, the synthesis method provided by the invention has the advantages of mild conditions, simple operation, wide substrate range and compatibility with different substituents, and can be used as a novel method for synthesizing the 2, 1-benzisoxazole derivative. The synthesized 2, 1-benzisoxazole derivative is expected to show higher activity in the aspects of antimitotic activity, antitumor activity, anticancer activity and the like.

Drawings

FIG. 1 is a diagram of the compound synthesized in example 1 of the present invention¹H NMR characterization spectrum.

FIG. 2 is a diagram of the compound synthesized in example 1 of the present invention¹³C NMR characterization spectrum.

FIG. 3 is a diagram of the compound synthesized in example 2 of the present invention¹H NMR characterization spectrum.

FIG. 4 is a diagram of the compound synthesized in example 2 of the present invention¹³C NMR characterization spectrum.

FIG. 5 is a diagram of the compound synthesized in example 3 of the present invention¹H NMR characterization spectrum.

FIG. 6 is a diagram of the compound synthesized in example 3 of the present invention¹³C NMR characterization spectrum.

FIG. 7 shows a compound synthesized in example 4 of the present invention¹H NMR characterization spectrum.

FIG. 8 is a diagram of the compound synthesized in example 4 of the present invention¹³C NMR characterization spectrum.

FIG. 9 is a photograph of a compound synthesized in example 5 of the present invention¹H NMR characterization spectrum.

FIG. 10 is a photograph of a compound synthesized in example 5 of the present invention¹³C NMR characterization spectrum.

FIG. 11 is a photograph of a compound synthesized in example 6 of the present invention¹H NMR characterization spectrum.

FIG. 12 is a photograph of a compound synthesized in example 6 of the present invention¹³C NMR characterization spectrum.

FIG. 13 is a photograph of a compound synthesized in example 7 of the present invention¹H NMR characterization spectrum.

FIG. 14 is a photograph of a compound synthesized in example 7 of the present invention¹³C NMR characterization spectrum.

FIG. 15 is a photograph of a compound synthesized in example 8 of the present invention¹H NMR characterization spectrum.

FIG. 16 is a photograph of a compound synthesized in example 8 of the present invention¹³C NMR characterization spectrum.

FIG. 17 is a photograph of a compound synthesized in example 9 of the present invention¹H NMR characterization spectrum.

FIG. 18 is a photograph of a compound synthesized in example 9 of the present invention¹³C NMR characterization spectrum.

Detailed Description

The principles and features of this invention are described below in conjunction with examples which are set forth to illustrate, but are not to be construed to limit the scope of the invention.