阅读说明：本技术 含喹啉结构的二吡唑并七元氧杂环类化合物及其合成方法 (Dipyrazolo seven-membered oxygen heterocyclic compound containing quinoline structure and synthetic method thereof ) 是由 祝艳平 张秋伊 张新科 杨义杰 侬小湄 胡勇基 王宇飞 丁楚月 王艳晶 解镕基 于 2020-05-28 设计创作，主要内容包括：本发明涉及一种含喹啉结构的二吡唑并七元氧杂环类化合物及其合成方法。该方法包括：将取代的甲基喹啉类衍生物、3-甲基-1-苯基-2-吡唑啉-5-酮和碘单质接触反应,一锅合成含喹啉结构的二吡唑并七元氧杂环类化合物及其衍生物。本发明的制备方法采用的原料廉价易得,制备方法简单,步骤较短,收率高达83％,为工业上制备此类化合物提供了一种可行的方法。(The invention relates to a dipyrazolo seven-member oxacycle compound containing a quinoline structure and a synthesis method thereof. The method comprises the following steps: the substituted methylquinoline derivatives, 3-methyl-1-phenyl-2-pyrazoline-5-ketone and iodine simple substance are contacted and reacted to synthesize the dipyrazolo heptatomic oxacyclo compound containing quinoline structure and the derivatives thereof in one pot. The preparation method has the advantages of cheap and easily-obtained raw materials, simple preparation method, short steps and high yield up to 83 percent, and provides a feasible method for industrially preparing the compounds.)

1. A dipyrazolo seven-membered oxacyclo compound containing a quinoline structure, wherein the compound has a structure of general formula i:

wherein R is₁And R₂Each independently is hydrogen, halogen, alkyl, substituted alkyl or aryl.

2. The compound of claim 1, wherein the compound of formula i is selected from one of the following compounds i-1 to i-38:

3. the method for synthesizing a dipyrazolo seven-membered oxaclyl compound containing a quinoline structure according to claim 1, wherein the method comprises the steps of: dissolving a 2-methylquinoline derivative shown as a formula II, 3-methyl-1-phenyl-2-pyrazoline-5-ketone shown as a formula III, iodine and trifluoroacetic acid in a solvent, stirring for 6-10h at 80-140 ℃, and carrying out post-treatment on a reaction solution to obtain a dipyrazolo seven-membered oxacyclo compound containing a quinoline structure;

wherein, R is hydrogen, halogen, alkyl, substituted alkyl or aryl; r₁Is hydrogen, halogen or alkyl; r₂Is hydrogen, methyl or ethyl.

4. The method of claim 3, wherein the molar ratio of the 2-methylquinoline derivative to the 3-methyl-1-phenyl-2-pyrazolin-5-one is 1.0 (2.0-2.5).

5. The synthesis method of claim 3, wherein the molar ratio of the 2-methylquinoline derivative to iodine is 1 (0.1-0.5).

6. The method of claim 3, wherein the solvent is one of DMSO, acetonitrile, methanol, ethanol, toluene, chloroform, and THF.

7. The synthesis method of claim 3, wherein the post-treatment comprises adding 50m L water to the reaction solution, extracting the mixed solution, washing the organic layer, collecting the organic phase, drying with anhydrous sodium sulfate, concentrating under reduced pressure, vacuum drying, separating and purifying to obtain the dipyrazolo heptaoxacyclo compound containing quinoline structure.

8. The synthetic method of claim 7 wherein the extractive extractant is ethyl acetate; the washing detergent is a 10% sodium thiosulfate solution; the separation and purification comprises the following steps: and (3) performing column chromatography separation and purification by using a mixture of ethyl acetate and petroleum ether as eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1: 8.

Technical Field

The invention relates to a dipyrazolo seven-membered oxacyclo compound containing a quinoline structure and a synthesis method thereof, belonging to the technical field of organic and pharmaceutical synthesis.

Background

Quinoline compounds are important pharmaceutical intermediates, and compounds containing quinoline structural units are widely applied to the aspects of antimalarial, antibacterial, antiviral, anti-inflammatory, asthma and the like. In recent years, quinoline derivatives have also been used for the treatment of cancer, HIV virus and schizophrenia. The research on the structure-activity relationship shows that after some medicines are modified by quinoline units, the biological activity can be obviously improved, and the medicine effect can be effectively enhanced.

Methyl-1-phenyl-2-pyrazoline-5-ketone, namely edaravone, is a novel free radical scavenger, is firstly marketed in Japan in 4 months in 2001, is the only clinically used free radical scavenger at present, and is mainly used for treating ischemic stroke. With the intensive research on edaravone, it is found that the edaravone has a therapeutic effect on other diseases of the nervous system with oxidative stress participation besides treating acute cerebral ischemia. Furthermore, edaravone also has a protective effect on organs other than the nervous system.

Seven-membered heterocycles have also found wide application in medicine. Oxcarbazepine, shown in formulas 1 'and 2', is a neurological drug that can be used for localized and generalized seizures. Oxcarbazepine is mainly used for patients with anaphylactic reaction to carbamazepine clinically, and can be used as a substitute drug of carbamazepine for clinical application. Diazepam is also called diazepam, belongs to benzodiazepines drugs which are second-generation sedative hypnotics, has the characteristics of strong curative effect, low toxicity, wide safety range and the like, and has clinically substituted barbiturates which are first-generation sedative hypnotics, so that diazepam is a first-choice drug for sedation, hypnosis and antianxiety. When the administration dosage and the administration route are adjusted, the medicine also has a plurality of purposes of sedation, hypnosis, muscle spasm resistance, epilepsy resistance, pre-anesthesia administration and the like.

At present, few reports exist on the synthetic method of the pyrazolo seven-membered heterocyclic compound modified by quinoline units and having stronger pharmacological action and activity.

Disclosure of Invention

In order to solve the defects of the prior art, the invention provides a dipyrazolo seven-member oxacyclic compound containing a quinoline structure and a synthesis method thereof. The method has the advantages of low cost, simple operation, mild conditions, good safety and high yield.

A dipyrazolo seven-membered oxacyclic compound containing a quinoline structure, wherein the compound has a structure shown in a general formula I:

wherein R is hydrogen, halogen, alkyl, substituted alkyl or aryl.

Further, the compound of the general formula I is selected from one of the following compounds I-1 to I-38:

the invention also provides a synthesis method of the dipyrazolo seven-member oxacycle compound containing a quinoline structure, which comprises the following steps: dissolving a 2-methylquinoline derivative shown as a formula II, 3-methyl-1-phenyl-2-pyrazoline-5-ketone, iodine and trifluoroacetic acid in a solvent, and stirring at 80-140 ℃ for 6-10 h; after-treatment, the dipyrazolo seven-member oxacyclo compound containing quinoline structure is obtained;

wherein, R is hydrogen, halogen, alkyl, substituted alkyl or aryl.

Further, the molar ratio of the 2-methylquinoline derivative to the 3-methyl-1-phenyl-2-pyrazolin-5-one is 1.0 (2.0-2.5).

Further, the molar ratio of the 2-methylquinoline derivative to the iodine is 1 (0.1-0.5).

Further, the molar ratio of the 2-methylquinoline derivative to the trifluoroacetic acid is 1: 2.

Further, the solvent is one of DMSO, acetonitrile, methanol, ethanol, toluene, chloroform and THF.

And further, the post-treatment comprises the steps of adding 50m of L water into the reaction liquid, extracting the mixed liquid, washing an organic layer, collecting an organic phase, adding anhydrous sodium sulfate, drying, concentrating under reduced pressure, drying in vacuum, separating and purifying to obtain the dipyrazolo heptatomic oxacyclo compound containing a quinoline structure.

Further, the extractant for extraction is ethyl acetate; the washing detergent is a 10% sodium thiosulfate solution; the separation and purification comprises the following steps: and (3) performing column chromatography separation and purification by using a mixture of ethyl acetate and petroleum ether as eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1: 8.

Has the advantages that:

the invention adopts cheap and easily obtained molecular iodine and trifluoroacetic acid as catalysts, DMSO as a solvent, and adopts a one-pot method for synthesis. Compared with the existing method, the method has the advantages of mild reaction conditions, short reaction time, good safety, simple and convenient operation, high reaction efficiency and low catalyst cost, and is a method with potential application value.

Detailed Description

The invention relates to a synthesis method of a dipyrazolo seven-member oxacycle compound containing a quinoline structure, which comprises the following specific reaction steps:

adding 2-methylquinoline derivative, 3-methyl-1-phenyl-2-pyrazoline-5-ketone, I into a pressure resistant tube of 15m L₂The vial was sealed and the reaction mixture was stirred at 130 ℃ for 6-10 hours under air, after completion of the reaction (monitored by T L C), 50m L water was added to the mixture, followed by 3 extractions with EtOAc, the extract was dried over 10% sodium thiosulfate solution (w/w), over anhydrous sodium sulfate, concentrated under reduced pressure and dried in vacuo, and the residue was purified by flash column chromatography on silica gel or recrystallized to give the corresponding product.

The extraction agent used in the extraction step is ethyl acetate, the washing agent used in the organic layer washing step is a 10% sodium thiosulfate solution (w/w), the drying agent used in the drying step is anhydrous sodium sulfate, the leacheate used in the column chromatography separation and purification step is a mixture of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1: 8.

In order to better understand the present invention, the following examples are further provided to illustrate the present invention, but the present invention is not limited to the following examples.