CN-122010873-A - Synthesis method of gem-diamine compound

Abstract

The invention discloses a synthesis method of a geminal diamine compound. In an organic solvent system and in the presence of alkali, an amide N-OTs compound a reacts with an amine compound b to generate a target compound c, wherein the reaction formula is shown as follows: . The method has the advantages of simple operation, readily available raw materials, low cost, low toxicity, strong compatibility, various product structures, mild reaction conditions, easy realization of large-scale production and the like, and has important significance for the rapid synthesis and application of geminal diamine compounds.

Inventors

• DAI JIANJUN
• PAN YAN
• ZHAO MINGZHU

Assignees

• 合肥工业大学

Dates

Publication Date

20260512

Application Date

20260202

Claims (8)

1. 1. A synthesis method of geminal diamine compound is characterized in that: In an organic solvent system, in the presence of alkali, an amide N-OTs compound a reacts with an amine compound b to generate a target compound c; the reaction formula is as follows: ; Wherein: R 1 is selected from C1-C6 alkyl, substituted or unsubstituted aryl, 、 The substituent for substitution is selected from one or more of C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C2-C6 alkynyl and hetero atom; R 2 is selected from any one of hydrogen and C1-C8 alkyl; The structural fragment of R 3 、R 4 and the N atom connected with the R 3 、R 4 in the target compound c is selected from substituted or unsubstituted pyrrole ring, piperidine ring, piperazine ring, aniline, 、 、 、 、 、 、 Or R 3 and R 4 are respectively and independently selected from C1-C8 alkyl, Any one of the following.
2. 2. The synthesis method according to claim 1, wherein: R 1 is selected from C1-C6 alkyl, phenyl, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 R 5 is selected from any one of methyl, methoxy, tertiary butyl, chlorine, bromine, fluorine, cyano, trifluoromethyl, methyl formate and alkynyl; The structural fragment consisting of R 3 、R 4 and the N atom connected with the R 3 、R 4 in the target compound c is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or R 3 and R 4 are respectively selected from C1-C8 alkyl, Any one of the following.
3. 3. The synthesis method according to claim 1 or 2, characterized in that: the target compound c is selected from any one of compounds shown in the following structures: ; 。
4. 4. the synthesis method according to claim 1, wherein: the alkali is selected from any one of Et 3 N、DIPEA、DBU、tBuONa、Cs 2 CO 3 .
5. 5. The method of synthesis according to claim 4, wherein: the base was Et 3 N.
6. 6. The synthesis method according to claim 1, wherein: The solvent is selected from any one of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and acetonitrile.
7. 7. The synthesis method according to claim 1, wherein: The molar ratio of the amide N-OTs compound a to the amine compound b is 1:1-3, and the molar ratio of the amide N-OTs compound a to the alkali is 1:1-3.
8. 8. The synthesis method according to claim 1, wherein: The reaction temperature is 80-120 ℃ and the reaction time is 3-12 hours.

Description

Synthesis method of gem-diamine compound Technical Field The invention relates to a synthesis method of geminal diamine compounds, belonging to the technical field of organic synthesis. Background Geminal diamines refer to important structural units in which two amino groups or derivatives thereof are connected to the same carbon atom, and are widely present in natural products, pharmaceutically active molecules and functional materials [1]. For example, the gem-diamine compound, molafungin amide, is an important antitubercular drug, which not only has a remarkable therapeutic effect on various tuberculosis forms, but also shows antitubercular activity [2] in infected human macrophages, which is superior to that of the classical drug pyrazinamide. The geminal diamine compound shows excellent reactivity and coordination capacity, and has wide application prospect in the fields of new material development, pharmaceutical chemistry, green chemistry catalysis and the like. At present, the method for synthesizing the gem-diamine compound has larger limitation. For example, glase et al synthesized the gem-diamine benzamide derivative [3] using a two-step lead-mediated oxidation-amination strategy. The method comprises the steps of firstly, taking N- (3-methylbenzoyl) glycine as a raw material, refluxing in toluene under the catalysis of lead tetraacetate and copper acetate, generating a key intermediate [ (3-methylbenzoyl) amino ] methyl acetate through oxidative decarboxylation, and then carrying out nucleophilic substitution on the intermediate and substituted piperidine in acetonitrile and in the presence of triethylamine to construct a gem-diamine framework. The method is a traditional strategy for constructing the structure in early stage, and has the defects that a reaction system needs to use lead tetraacetate which is extremely toxic and harmful to the environment as an oxidant and does not accord with the principle of green synthesis, the operation steps are complicated, and in addition, the method needs to prepare halogenated intermediates in advance, so that the atomic economy and the step economy are poor. Subsequently Kappe and Cantillo et al developed an electrochemical decarboxylation acetylation process [4]. The process takes acetic acid as a solvent and sodium acetate as alkali, and directly realizes decarboxylation and acetylation through anodic oxidation under mild conditions. The method uses electrons as cleaning 'reagent', and byproducts are only CO 2 and H 2, so that the atomic economy is high. Compared with a lead-based method, the electrochemical process has remarkable advantages in green indexes such as atomic economy, reaction quality efficiency and the like, avoids heavy metal use, and has excellent sustainability and industrialization potential. Lian et al used an electrochemical dehydroimidization method [5] to achieve direct coupling of N-methylbenzylamine and phthalimide, and synthesized a series of phthalimide-protected gem-diamine compounds. The research shows that the reaction is carried out in a platinum electrode pair, acetonitrile/methanol mixed solvent and tetrabutylammonium perchlorate electrolyte system under the conditions of constant temperature and constant current without adding an oxidant, thus the advantages of green synthesis and high regioselectivity are reflected. The disadvantage of this strategy is that it is mainly limited to N-methyl substituted benzyl amine substrates and relies on noble metal electrodes, limiting its range of application and ease of operation. Li et al adopt a copper catalytic oxidation coupling method to realize the one-pot reaction of N-aryl glycine ethyl ester and enamide, and synchronously construct two derivatives [6] of quinoline and gem-diamine. According to the research, cu (OTf) 2 is used as a catalyst, and reacts with double bonds of enamide and an amide fragment after cleavage of the enamide respectively through the same imine intermediate in an oxygen atmosphere and an acetonitrile solvent, so that high atom economy and synthesis efficiency are reflected. The process involves multi-step cascade of amine oxidation, povarov cyclization, deamidation aromatization, nucleophilic addition of amide to imine, etc. The strategy has the defects that the reaction time is long, the oxygen atmosphere is required to be strictly controlled, the proportion of the substrate is unbalanced, and the simplicity and the universality of operation are affected to a certain extent. In summary, the conventional synthesis methods of geminal diamines have many limitations in terms of cost, safety, selectivity, operational complexity, high toxicity and environmental impact. Therefore, there is an urgent need to develop a new synthesis paradigm to construct structurally diverse gem diamines in a compact and modular manner. [ Reference ] to [1] Xu Z.; Chen Z.; Liu S.; Gao J.; Lei J.; Li M.; Zhang Y.; Gan Z.; Yu L.; Liu S.X.; Jin Y. Transition photocatal