阅读说明：本技术 一种单胺氧化酶a抑制剂 (Monoamine oxidase A inhibitor ) 是由 王宇光 刘贝 李静 于 2019-08-30 设计创作，主要内容包括：本发明公开了一种单胺氧化酶A抑制剂,所述的单胺氧化酶A抑制剂通过在室温下使用廉价的钌碳作为催化剂催化硫醚合成得到,具体为：以式(III)所示化合物为反应原料,Ru/C为催化剂,NaIO<Sub>4</Sub>为氧化剂,水为溶剂,于室温下进行反应,反应结束后,反应液经后处理,得到式(IV)所示砜类化合物。本发明所述的方法以水做溶剂,用高碘酸钠氧化廉价的钌碳生成四氧化钌,从而进一步氧化硫醚化合物合成得到目标产物,制备方法更加高效、快捷、环保、温和。制备得到的单胺氧化酶A抑制剂具有良好的单胺氧化酶A抑制活性,可用于制备抑制单胺氧化酶A活性的药物,它在药物开发中具有广阔的应用前景,以期为相关疾病的治疗提供了更加有效的途径。(The invention discloses a monoamine oxidase A inhibitor, which is obtained by catalyzing thioether synthesis at room temperature by using cheap ruthenium carbon as a catalyst, and specifically comprises the following steps: the compound shown as the formula (III) is used as a reaction raw material, Ru/C is used as a catalyst, and NaIO is added 4 The method is characterized in that the method is carried out at room temperature by taking water as a solvent as an oxidant, and after the reaction is finished, the reaction solution is subjected to post-treatment to obtain the sulfone compound shown in the formula (IV). According to the method, water is used as a solvent, and cheap ruthenium carbon is oxidized by sodium periodate to generate ruthenium tetroxide, so that a target product is further synthesized by oxidizing a thioether compound, and the preparation method is more efficient, quicker, environment-friendly and mild. The prepared monoamine oxidase A inhibitor has good monoamine oxidase A inhibition activity, can be used for preparing medicines for inhibiting the monoamine oxidase A activity, has wide application prospect in medicine development, and provides a more effective way for treating related diseases.)

1. A monoamine oxidase a inhibitor of formula (IV) wherein: the monoamine oxidase A inhibitor is synthesized according to the following method:

the compound shown as the formula (III) is used as a reaction raw material, Ru/C is used as a catalyst, and NaIO is added₄The method comprises the following steps of (1) reacting at room temperature by using water as a solvent as an oxidant, and after the reaction is finished, carrying out post-treatment on a reaction solution to obtain a sulfone compound shown as a formula (IV); the dosage of the Ru/C is 0.5-2% of the dosage of the compound shown in the formula (III) in terms of the dosage of the Ru; the NaIO₄The amount of the substance (B) is 50 to 150% of the amount of the substance of the compound represented by the formula (III);

2. the monoamine oxidase a inhibitor of claim 1 wherein: the amount of Ru/C is 1% of the amount of substance of the compound represented by the formula (III) based on the amount of substance of Ru.

3. The monoamine oxidase a inhibitor of claim 1 wherein: the NaIO₄The amount of substance (b) is 110% of the amount of substance of the compound represented by the formula (III).

4. The monoamine oxidase a inhibitor of claim 1 wherein: the volume usage amount of the water is 3-5 mL/mmol based on the amount of the compound shown in the formula (III).

5. The monoamine oxidase a inhibitor of claim 1 wherein: the post-treatment method of the reaction solution comprises the following steps: after the reaction is finished, the reaction solution is filtered, washed by dichloromethane, the filtrate and the washing solution are combined, washed twice by saturated sodium chloride solution, and dehydrated by anhydrous sodium sulfate, the solvent is removed by evaporation and dried, and the target product shown in the formula (IV) is obtained.

6. Use of a monoamine oxidase A inhibitor according to claim 1 for the preparation of a medicament for inhibiting monoamine oxidase A activity.

(I) technical field

The invention relates to a monoamine oxidase A inhibitor, a synthesis method and application thereof.

(II) background of the invention

The sulfone compound is a very important organic synthesis intermediate, has very wide application in the aspects of medicinal chemistry, material science and wide bioactivity. For example, bicalutamide (structure a) is an anti-androgen drug, and is suitable for treating advanced prostate cancer; laropilan (structure b) is a commonly used cardiovascular drug for the treatment of lipodystrophy; rofecoxib (structure c) is a cyclooxygenase selective inhibitor, can be used for treating arthritis and relieving pain, has good patient tolerance, and also has potential clinical value and therapeutic effect in preventing carcinoma of large intestine and esophageal cancer, and treating head and neck cancer, breast cancer, bladder cancer and cervical cancer; has certain bacteriostasis effect than dapsone (structure d) and is often used for treating leprosy. Meanwhile, the sulfone compound also plays a very important role in agricultural chemicals, for example, mesotrione (structure f) is a common herbicide, and has the advantages of no influence on the environment, no influence on the pesticide effect due to rainfall and the like. Meanwhile, sulfide oxidation is the basis of catalytic oxidative desulfurization of crude oil, wherein sulfur compounds are removed, which is also one of the most common difficulties.

Ruthenium tetroxide has been widely used in oxidation reactions since Djerassi reported in 1953 as an oxidant for use in chemical reactions. However, ruthenium tetroxide has the disadvantages of unstable property, high toxicity, high price and the like, which has certain limitations on chemical research. Therefore, it becomes crucial to find a more green, inexpensive, versatile, highly selective process. The method uses sodium periodate to oxidize cheap ruthenium carbon to generate ruthenium tetroxide, thereby further oxidizing the thioether compound to synthesize the sulfone compound.

Monoamine oxidase is a main enzyme participating in monoamine substance metabolism in vivo, monoamine oxidase is divided into A type and B type, metabolic substrates of monoamine oxidase are different, monoamine oxidase activity has a certain relation with body aging and Parkinson's disease, and monoamine oxidase inhibitor is used for treating various diseases which have proved to have obvious effects, such as depression, Parkinson's disease, senile dementia and the like.

Disclosure of the invention

The present invention provides a monoamine oxidase A inhibitor obtained by catalyzing thioether synthesis at room temperature using inexpensive ruthenium carbon as a catalyst. The monoamine oxidase A inhibitor has extremely strong monoamine oxidase A inhibition effect, and is applied to preparation of drugs for inhibiting monoamine oxidase A activity.

The technical scheme of the invention is as follows:

a monoamine oxidase A inhibitor of formula (IV) synthesized as follows:

the compound shown as the formula (III) is used as a reaction raw material, Ru/C is used as a catalyst, and NaIO is added₄The method comprises the following steps of (1) reacting at room temperature (20-30 ℃) by taking water as a solvent as an oxidant, and after the reaction is finished, carrying out post-treatment on a reaction solution to obtain a sulfone compound shown as a formula (IV); the amount of the Ru/C is 0.5-2%, preferably 1%, of the amount of the substance of the compound shown in the formula (III) in terms of the amount of the substance of Ru; the NaIO₄The amount of the substance(s) is 50 to 150%, preferably 110% of the amount of the substance of the compound represented by the formula (III).

Further, the volume usage amount of the water is 3-5 mL/mmol based on the amount of the compound shown in the formula (III).

The progress of the reaction of the present invention can be monitored by a conventional method, for example, TLC is used to monitor the completion of the reaction of the starting compound represented by formula (III) to determine the time point of the completion of the reaction; the reaction time is usually 2-3 h.

Further, the post-treatment method of the reaction solution comprises the following steps: after the reaction is finished, the reaction solution is filtered, washed by dichloromethane, the filtrate and the washing solution are combined, washed twice by saturated sodium chloride solution, and dehydrated by anhydrous sodium sulfate, the solvent is removed by evaporation and dried, and the target product shown in the formula (IV) is obtained.

Compared with the prior art, the invention has the beneficial effects that:

(1) the invention provides a monoamine oxidase A inhibitor, which has the advantages of simple preparation process and operation process, nearly 99% yield and simple subsequent treatment, and can obtain a pure product without complicated separation and purification.

(2) Compared with the traditional method, the method takes water as a solvent, uses sodium periodate to oxidize cheap ruthenium carbon to generate ruthenium tetroxide, further oxidizes the thioether compound to synthesize a target product, and is more efficient, quicker, more environment-friendly and milder.

(3) The monoamine oxidase A inhibitor has good monoamine oxidase A inhibition activity, can be used for preparing drugs for inhibiting the monoamine oxidase A activity, has wide application prospect in drug development, and is expected to provide a more effective way for treating related diseases.

(IV) detailed description of the preferred embodiments

The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.