阅读说明：本技术 一种由四取代脲一步合成磺酰胍的方法 (Method for synthesizing sulfonylguanidine from tetra-substituted urea in one step ) 是由 刘懋 韩建杰 于 2019-09-19 设计创作，主要内容包括：本发明公开了一种由四取代脲一步合成磺酰胍的方法。以四取代脲与磺酰异氰酸酯为原料,在回流条件下进行反应。反应结束,通过淬灭,萃取,旋干、后柱层析得到磺酰胍。本发明通过四取代脲与磺酰异氰酸酯来制备磺酰胍,此方法操作简单,可得到结构多样的磺酰胍,产率较高,产率最高可达95.9％,具有较大工业化潜力的有益效果。(The invention discloses a method for synthesizing sulfonylguanidine from tetra-substituted urea in one step. Tetra-substituted urea and sulfonyl isocyanate are used as raw materials to react under the reflux condition. After the reaction is finished, the sulfonylguanidine is obtained by quenching, extraction, spin drying and post column chromatography. The method for preparing the sulfonylguanidine through the tetra-substituted urea and the sulfonylisocyanate has the advantages of simple operation, capability of obtaining the sulfonylguanidine with various structures, high yield (the highest yield can reach 95.9 percent), and great industrial potential.)

1. A method for synthesizing sulfonylguanidine from tetra-substituted urea in one step is characterized in that: the method comprises the following steps: adding tetra-substituted urea and sulfonyl isocyanate into a container, adding a first solvent, heating and refluxing, adding water for quenching after complete reaction, extracting with a second solvent, drying an organic phase obtained after extraction with a drying agent, filtering to remove the drying agent, spin-drying, and performing column chromatography to obtain sulfonyl guanidine.

2. The method of claim 1 for the one-step synthesis of sulfonylguanidines from tetra-substituted ureas, comprising: the molar ratio of the tetra-substituted urea to the sulfonyl isocyanate is 1: 1-8.

3. The method of claim 2 for the one-step synthesis of sulfonylguanidines from tetra-substituted ureas, comprising: the molar ratio of the tetra-substituted urea to the sulfonyl isocyanate is 1: 2.

4. The method of claim 1 for the one-step synthesis of sulfonylguanidines from tetra-substituted ureas, comprising: according to the proportion, 1.25-2.5ml of first solvent is added to every 4mmol of sulfonyl isocyanate.

5. The method of claim 1 for the one-step synthesis of sulfonylguanidines from tetra-substituted ureas, comprising: the first solvent is xylene.

6. The method of claim 1 for the one-step synthesis of sulfonylguanidines from tetra-substituted ureas, comprising: heating and refluxing, and reacting for 3-48 h.

7. The method of claim 1 for the one-step synthesis of sulfonylguanidines from tetra-substituted ureas, comprising: the second solvent is one of ethyl acetate or dichloromethane.

Technical Field

The invention relates to a method for synthesizing sulfonylguanidine, in particular to a method for synthesizing sulfonylguanidine by tetra-substituted urea in one step.

Background

Guanidine is structurally present in many natural or synthetic molecules and plays a critical role in many biological activities, such as exhibiting inhibitory activity in antibacterials, anti-hypertension, anti-cancer, and the like. The sulfonylguanidine, as a general unit for constructing a plurality of inhibitors, also shows the activities of resisting tumor, cancer, HIV, hepatic fibrosis and the like, and has wide application range.

At present, the construction from urea to sulfonylguanidine is mainly to synthesize sulfonylurea first, then to react with triphosgene and PCl₅、POCl₃And the corresponding halide is formed and then reacted with an amine to give sulfonylguanidine, which is a cumbersome procedure. To use urea directlySynthesis of sulfonylguanidines N-trifluoromethylguanidines have been prepared by reaction of N-sulfinyltrifluoromethanesulfonamide with urea, but with liberation of SO₂Such toxic and harmful gases, and the range of the substrate is narrow, and only one substrate (only urea) is provided. The tetramethylurea is converted into the corresponding sulfonyl guanidine by a CuAAC/ring opening method by using sulfonyl azide and 3-butyn-2-one, but the reaction reagent and the operation are complex, and the raw materials are CuI and ArSO₃N₃3-alkynyl-2-butanone, a narrow substrate range (tetramethylurea only).

Disclosure of Invention

The invention aims to provide a method for synthesizing sulfonylguanidine from tetra-substituted urea in one step. The method for preparing the sulfonylguanidine through the tetra-substituted urea and the sulfonylisocyanate has the characteristics of simple operation, capability of obtaining the sulfonylguanidine with various structures, high yield (the highest yield can reach 95.9 percent) and great industrial potential.

The technical scheme of the invention is as follows: a method for synthesizing sulfonylguanidine from tetra-substituted urea in one step comprises the following steps: adding tetra-substituted urea and sulfonyl isocyanate into a container, adding a first solvent, heating and refluxing, adding water for quenching after complete reaction, extracting with a second solvent, drying an organic phase obtained after extraction with a drying agent, filtering to remove the drying agent, spin-drying, and performing column chromatography to obtain sulfonyl guanidine.

In the method for synthesizing sulfonyl guanidine from tetra-substituted urea in one step, the molar ratio of the tetra-substituted urea to the sulfonyl isocyanate is 1: 1-8.

In the aforementioned one-step synthesis method of sulfonylguanidine from tetra-substituted urea, the molar ratio of the tetra-substituted urea to the sulfonyl isocyanate is 1: 2.

In the previous method for synthesizing sulfonyl guanidine from tetra-substituted urea in one step, 1.25-2.5ml of the first solvent is added to 4mmol of sulfonyl isocyanate according to the proportion.

In the aforementioned one-step synthesis method of sulfonylguanidine from tetra-substituted urea, the first solvent is xylene. The first solvent of the present invention may also be one of toluene, carbon tetrachloride, tetrachloroethane, or dioxane.

In the aforementioned method for synthesizing sulfonylguanidine from tetra-substituted urea in one step, the temperature of the heating reflux is determined by the boiling point of the first solvent.

In the method for synthesizing the sulfonylguanidine from the tetra-substituted urea in one step, the heating reflux is carried out, and the reaction lasts for 3-48 h.

In the aforementioned one-step synthesis method of sulfonylguanidine from tetra-substituted urea, the second solvent is one of ethyl acetate and dichloromethane.

In the aforementioned one-step synthesis method of sulfonylguanidine from tetra-substituted urea, the tetra-substituted urea is one of 1, 3-dimethyl-2-imidazolidinone, 1, 3-dimethyloctahydro-2H-benzol [ d ] imidozol-2-one, tetramethylurea, tetra-N-propylurea, 1' -carbonyldipyrrole, 1, 3-dimethyl-1, 3-diphenylurea, N-methyl-N-phenyl-1-pyrrolidinecarboxamide, N-methyl-N-phenyl-N ', N ' -di-N-propylurea, or 1, 3-dimethyl-2-imidazolidinone.

In the aforementioned one-step synthesis method of sulfonylguanidine from tetra-substituted urea, the sulfonylisocyanate is one of toluene sulfonic acid isocyanate, benzene sulfonyl isocyanate or 4-chlorobenzene sulfonyl isocyanate.

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

1. the invention aims to provide an effective method for preparing sulfonylguanidine by direct amination of tetra-substituted urea and sulfonyl isocyanate, which is simple to operate, can obtain sulfonylguanidine with various structures and has high yield. The reaction equation is as follows:

note: in the invention, R and R¹,R²,R³,R⁴May be an aromatic group, an alkyl group, or the like.

2. The invention respectively calculates the yield of the products prepared in the examples 1 to 10, and the formula of the yield calculation is the amount of the substance of the product sulfonyl guanidine: the content of tetra-substituted urea substances and the structure of the product are analyzed and confirmed, and specific results are shown in examples 1-10, so that the yield of the invention is 80.4% -95.9%, the yield is high, and the product structure is various. The prior art isThe method comprises the following steps: preparation of N-trifluoromethylguanidine by reaction of N-sulfinyl trifluoromethanesulfonamide with Urea, but with liberation of SO₂Such noxious gases, and the range of substrates is narrow, only one example of the substrate (urea only, with a yield of 95%) is the starting material for N-sulfinyl trifluoromethanesulfonamide, which is not commercialized, and is not easily prepared. Conversion of tetramethylurea to the corresponding sulfonylguanidine by CuAAC/Ring opening Using sulfonyl azide and 3-butyn-2-one starting from CuI, ArSO₃N₃3-alkynyl-2-butanone, tetramethylurea as a substrate, narrow substrate range, complex reaction reagents and operation, and 64-76% of yield. The method has the advantages of wide reaction substrates, strong applicability, commercialization of various sulfonyl isocyanates, easily available raw materials and high reaction yield.

In conclusion, the method for preparing the sulfonylguanidine through the tetra-substituted urea and the sulfonyl isocyanate has the advantages of simple operation, capability of obtaining the sulfonylguanidine with various structures, high yield of 95.9 percent and great industrial potential.

Detailed Description

The present invention is further illustrated by the following examples, which are not to be construed as limiting the invention.