阅读说明：本技术 1,3,4-恶二唑杂环化合物的合成方法 (Synthesis method of 1,3, 4-oxadiazole heterocyclic compound ) 是由 李剑 陆雪陈 刘莉 于 2020-04-28 设计创作，主要内容包括：本发明属于有机合成及药物技术领域,具体涉及一种1,3,4-恶二唑杂环化合物的合成方法。本发明是以酮酸衍生物和三价碘试剂作为原料,加入溶剂和光催化剂,在光照条件下,室温发生反应,得到1,3,4-恶二唑杂环化合物。使用本发明提出的方法,在室温条件下,反应5-10小时,一步法即可得到1,3,4-恶二唑杂环衍生物,产率为75～96％。本反应用简单易得的原料,在光照条件下,一步简便快速地合成了1,3,4-恶二唑杂环类衍生物,为合成1,3,4-恶二唑杂环类衍生物提供了一条简单高效,温和的合成新方法。(The invention belongs to the technical field of organic synthesis and medicines, and particularly relates to a synthesis method of a 1,3, 4-oxadiazole heterocyclic compound. The invention takes keto acid derivatives and trivalent iodine reagent as raw materials, adds solvent and photocatalyst, and reacts at room temperature under the condition of illumination to obtain the 1,3, 4-oxadiazole heterocyclic compound. By using the method provided by the invention, the 1,3, 4-oxadiazole heterocyclic derivative can be obtained by a one-step method at room temperature for 5-10 hours, and the yield is 75-96%. The reaction uses simple and easily obtained raw materials, and under the condition of illumination, the 1,3, 4-oxadiazole heterocyclic derivative is simply, conveniently and quickly synthesized in one step, so that a simple, high-efficiency and mild new synthesis method is provided for synthesizing the 1,3, 4-oxadiazole heterocyclic derivative.)

1. A synthesis method of a 1,3, 4-oxadiazole heterocyclic compound is characterized in that a keto acid derivative and a trivalent iodine reagent are used as raw materials, a solvent and a photocatalyst are added, and the mixture is stirred and reacts for 5-10 hours at room temperature under the illumination condition to generate the 1,3, 4-oxadiazole heterocyclic derivative.

2. The method for synthesizing a 1,3, 4-oxadiazole heterocyclic compound according to claim 1, wherein the solvent is dichloromethane, chloroform, acetonitrile or methanol.

3. The method for synthesizing a 1,3, 4-oxadiazole heterocyclic compound of claim 1, wherein the photocatalyst is selected from the group consisting of

4. The method for synthesizing the 1,3, 4-oxadiazole heterocyclic compound according to claim 3, wherein the photocatalyst of formula 1 is synthesized by slowly adding NaH into carbazole-dissolved THF under nitrogen protection, stirring for 30 minutes, adding 3,4,5, 6-tetrafluorophthalonitrile, stirring the reaction solution at room temperature for 12 hours, performing plate-tracking reaction at T L C, adding 2m L of water to quench excessive NaH, spin-drying the filtrate, adding ethanol to precipitate a crude product, and further separating and purifying the crude product by silica gel column chromatography to obtain the target photocatalyst 1.

5. The method for synthesizing a 1,3, 4-oxadiazole heterocyclic compound of claim 1, wherein the molar ratio of the keto acid derivative to the trivalent iodine reagent is 1:1 to 1: 1.5.

6. The method for synthesizing a 1,3, 4-oxadiazole heterocyclic compound according to claim 1, wherein the amount of the photocatalyst added is 10% mmol.

7. The method for synthesizing a 1,3, 4-oxadiazole heterocyclic compound according to claim 1, wherein the structural formula of the keto acid derivative is as follows

Wherein R is¹The radical being R¹＝H,4-F,4-Cl,4-Br,4-OCH₃,4-CF₃,3-CH₃3-Cl,2-Cl, 2, 4-dimethoxy, 3, 4-difluoro.

8. The method for synthesizing the 1,3, 4-oxadiazole heterocyclic compound of claim 7, wherein the trivalent iodine has the structural formula shown below,

wherein R is²The radical being R²＝COOEt,COOCH₂Ph,SO₃Et。

Technical Field

The invention belongs to the technical field of organic synthesis and drug synthesis, and particularly relates to a synthesis method of a 1,3, 4-oxadiazole heterocyclic compound.

Background

1,3, 4-oxadiazole heterocycles are present in natural products, drugs and biologically active compounds, have been widely used in organic synthesis, and have been of interest and research by numerous scientists [ (a) Sharma, s.; sharma, p.k.; kumar, n.; dudhee, r.pharma.chemica.,2010,2,253.(b) Khalilullah, h.; ahsan, m.j.; hedaitullah, m.; khan, s.; ahmed, b.mini-rev.med.chem.,2012,12,789 ]. The polycyclic compound with 1,3, 4-oxadiazole as a mother nucleus has good biological activity in the aspects of pain relieving, anticonvulsant efficacy, antifungal, insecticidal and the like, and a plurality of medicaments sold in the market, including an anti-AIDS medicament, namely Latiravir, an antihypertensive medicament, namely Nexadil and docetaxel with an anti-cancer effect, all contain the 1,3, 4-oxadiazole heterocyclic mother nucleus.

The current methods for synthesizing 1,3, 4-oxadiazole heterocycles mainly include cyclization of hydrazide [ (a) Chu, W.J.; Yang, Y.; Chen, C.F.Org. L et t.2010,12,3156; (b) Dolman, S.J; Gosselin F, O' Shea, P.D.; Davies, I.E.J.Org.Chem.2006; 71:9548.], C-H cross-oxidation of N-phenylhydrazide [ Zhang, L.; Zhao, X.; jin, X.; Zhang, X.; Lü, S.; L uo, L.; Jia, X.Tehetran L et t.2016,57,5669] and tandem cyclization of hydrazide and nitroalkane under acid catalysis (Ak, A.V.; Khamravov, V.; Ak N.3584 et t.2016,57,5669.) as well as a new and more efficient method for synthesizing the hydrazide and more particularly the method of Ak A, K, Ak A.9, K.; the method for synthesizing the above mentioned patent application, A.9, A, K.

Disclosure of Invention

The invention solves the technical problem of providing a simple method for synthesizing the 1,3, 4-oxadiazole derivative by taking α -keto acid derivative and a trivalent iodine reagent as raw materials, performing one-step reaction, and having simple operation, high efficiency and high speed in order to reduce reaction steps, use an environment-friendly solvent and improve the reaction yield.

The invention provides a method for synthesizing 1,3, 4-oxadiazole derivatives, which comprises the steps of taking α -keto acid derivatives and a trivalent iodine reagent as raw materials, adding a solvent and a photocatalyst, and reacting under the illumination condition to generate the 1,3, 4-oxadiazole heterocyclic derivatives, wherein the reaction condition is that the reaction is carried out at room temperature under the illumination condition, and the reaction time is 5-10 hours.

The raw materials have a molar ratio of α -ketonic acid to trivalence iodine reagent of 1:1-1: 1.5.

The solvent is dichloromethane, trichloromethane, acetonitrile or methanol.

The photocatalyst is prepared from (A) a photocatalyst,

the amount used was 10% mmol equivalents.

The synthesis route of the photocatalyst 1 is as follows:

under the protection of nitrogen, NaH (0.60g, 15mmol) was slowly added to THF (40m L) in which carbazole (1.67g,10.0mmol) was dissolved, and after stirring for 30 minutes, 3,4,5, 6-tetrafluorophthalonitrile (0.40g,2.0mmol) was added, the reaction solution was stirred at room temperature for 12 hours, followed by reaction at a point T L C, 2m L water was added to quench excess NaH, the filtrate was spin-dried, ethanol was added to precipitate a crude product, and the crude product was further separated and purified by silica gel column chromatography (developing solvent: dichloromethane: petroleum ether ═ 1:3) to obtain the objective photocatalyst 1.

Photocatalyst 2 (CAS: 60804-74-2) and photocatalyst 3 (CAS: 34426-19-3) are both commercially available products.

The structural formula of the raw material α -keto acid is shown as the following formula,

wherein R is¹The radical being R¹＝H,4-F,4-Cl,4-Br,4-OCH₃,4-CF₃,3-CH₃3-Cl,2-Cl, 2, 4-dimethoxy, 3, 4-difluoro.

α -keto acid is synthesized by the following steps:

adding acetophenone (1.0mmol), tin dioxide (0.167g,1.5mmol) and dried pyridine solution (10M L) into a reaction flask, heating to 90 deg.C, reacting for 4 hr, filtering the reaction solution containing residual tin dioxide, pouring the filtrate into 1M diluted hydrochloric acid, extracting with ethyl acetate, and collecting the organic layer with anhydrous MgSO₄Drying for 3 hours, filtering, spin-drying the filtrate, and further separating and purifying the crude product by silica gel column chromatography (developing solvent: ethyl acetate: petroleum ether: 9:1) to obtain 2-oxo-phenylacetic acid. Other derivatives were prepared according to this method.

The structural formula of the raw material trivalent iodine is shown as the following formula,

wherein R is²The radical being R²＝COOEt,SO₃Et,COOCH₂Ph can smoothly react to obtain the corresponding 1,3, 4-oxadiazole heterocyclic derivative.

Wherein the content of the first and second substances,

the trivalent iodine reagent is carried out according to the following steps:

1-methoxy-1, 2-benziodoxyl 3- (1H) -one (CAS: 1829-25-0, commercially available) (4.0g,14.4mmol,1equiv), trimethylsilyl trifluoromethanesulfonate (2.6m L, 14.4mmol,1equiv) and dichloromethane (25m L) were added to a 100m L round-bottomed flask at room temperature, after stirring at room temperature for 30 minutes, ethyl diazoacetate (31.8mmol,2.2equiv) was slowly added, stirring was carried out for 3 hours, after the reaction was completed, the filtrate was dried by spinning, and the crude product was recrystallized from diethyl ether/dichloromethane (5:1) under a cryopump to give pure trivalent diazonium iodine reagent, which was stored at low temperature.

Preparation of 1,3, 4-oxadiazole derivative, namely, under the illumination condition, stirring the obtained α -keto acid (1equiv) and a diazo trivalent iodine reagent (1-1.5equiv) for 5-10 hours at room temperature under a photocatalyst (10% mmol), performing plate tracking reaction at a temperature of T L C, then, drying the filtrate in a rotary manner, and further separating and purifying the crude product by silica gel column chromatography to obtain the 1,3, 4-oxadiazole.

The post-reaction treatment is simple and convenient, and the pure substituted 1,3, 4-oxadiazole derivative can be obtained by using a mixed solvent of petroleum ether and ethyl acetate as an eluent by a simple column chromatography separation method.

The method uses α -keto acid and diazo trivalent iodine reagent derivatives as raw materials for the first time, and the 1,3, 4-oxadiazole heterocyclic parent nucleus is constructed at room temperature under the condition of no catalysis of a metal photocatalyst under the illumination condition, and the yield reaches 65-85%.

Detailed Description

The reaction process and the structural formula of the obtained product are shown in the specification