Synthesis method of 3, 6-dihydropyridone compounds
阅读说明：本技术 一种3，6-二氢吡啶酮化合物的合成方法 (Synthesis method of 3, 6-dihydropyridone compounds ) 是由 韩晓丹 胡居吾 王慧宾 熊伟 于 2018-12-21 设计创作，主要内容包括：本发明公开一种3,6-二氢吡啶酮化合物的合成方法,其以α-羰基酰胺化合物和烯烃类化合物为原料,以强碱为催化剂,溶于有机溶剂中,进行加热反应,得到3,6-二氢吡啶酮化合物。本发明原材料来源广泛,成本低廉,反应步骤少,操作简便,产品产率高,普适性强,工艺环保,省时高效,具有良好的市场前景。(The invention discloses a synthesis method of 3, 6-dihydropyridone compounds, which takes α -carbonyl amide compounds and olefin compounds as raw materials, takes strong base as a catalyst, is dissolved in an organic solvent, and is subjected to heating reaction to obtain the 3, 6-dihydropyridone compounds.)
The synthesis process of kinds of 3, 6-dihydropyridine ketone compounds features that α -carbonyl amide compound A and olefin compound B as material are dissolved in organic solvent in strong alkali as catalyst and heated to react to obtain 3, 6-dihydropyridine ketone compound C;
wherein R is1Is selected from C1～C5Straight or branched alkanes of (C)1～C5 kinds of halogenated alkyl and phenyl, R2、R3Each independently selected from C1～C5Is straight or branched alkane, phenyl, or R2、R3And the carbonyl ortho-carbon attached thereto to form a cycloalkane, R4Selected from the group consisting of COOMe, COOEt, COOH, CN, CHO, NO2 kinds of halogen, R5Selected from H, C1～C5 of alkyl, phenyl, COOMe, COOEt and COOH, R is H, C1～C3 of straight-chain or branched-chain alkane, halogen and alkoxy.
2. The method for synthesizing a3, 6-dihydropyridone compound according to claim 1, characterized in that: r of which1Is Me, Et, Pr, Ph or CF3。
3. The method for synthesizing a3, 6-dihydropyridone compound according to claim 1, characterized in that: r of which2、R3Each independently selected from Me, Et, Pr, Ph, or R2、R3And the ortho-carbon attached thereto form a cyclopropane, cyclopentane or cyclohexane.
4. The method for synthesizing a3, 6-dihydropyridone compound according to claim 1, characterized in that: r of which4Selected from the group consisting of COOMe, COOEt, COOH, CN, CHO, NO2Cl or Br.
5. The method for synthesizing a3, 6-dihydropyridone compound according to claim 1, characterized in that: r of which5Selected from H, Me, Et, Pr, Ph, COOMe, COOEt or COOH.
6. The method for synthesizing a3, 6-dihydropyridone compound according to claim 1, characterized in that: and R is selected from H, Me, Et, Cl, Br, OMe or OEt.
7. The method for synthesizing a3, 6-dihydropyridone compound according to claim 1, wherein the molar ratio of the α -carbonyl amide compound to the olefin compound is 1: 1 to 3, and the amount ratio of the α -carbonyl amide compound, the organic solvent and the strong base is 1 mmol: 5 to 8 mL: 1 to 2.5 mmol.
8. The process according to claim 1, wherein the strong base is types selected from potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, tert-butyllithium and methyllithium, and the organic solvent is types selected from ethanol, methanol, tetrahydrofuran, acetonitrile, 1, 4-dioxane and 1, 2-dichloroethane.
9. The method for synthesizing a3, 6-dihydropyridone compound according to claim 1, characterized in that: the heating reaction temperature is from room temperature to 80 ℃, and the reaction time is 6-10 h.
10. The method for synthesizing a3, 6-dihydropyridone compound according to claim 1, characterized in that: monitoring the reaction process by thin layer chromatography TLC, adding saturated salt solution into the reaction system after the reactants completely disappear, extracting by using an extracting agent, and combining organic phases; drying the organic phase with a drying agent, filtering, concentrating, and carrying out column chromatography to obtain the 3, 6-dihydropyridone compound.
Technical Field
The invention belongs to the technical field of compound synthesis, and particularly relates to a synthesis method of 3, 6-dihydropyridone compounds.
Background
The pyridone compound is an important structural unit commonly existing in natural products, bioactive molecules and pesticide chemicals, is an important raw material and an intermediate of chemicals such as medicines, pesticides and materials, plays a very important role in the synthesis of multifunctional compounds or the synthesis of natural products, and can develop a drug precursor with a recognition function through derivatives of the pyridone compound, for example, the phenoxy substituted pyridone compound is a key intermediate for preparing herbicides and the like, the pyridone derivative is used as coupling components and has strong coupling capacity, fuel after the pyridone is introduced is bright in color and has bright fluorescence, and the pyridone derivative is widely applied to the fields of ink-jet printing, hepatic fibrosis materials, photosensitive materials and the like in recent years, pharmacological research shows that the pyridone compound has a potential anti-tumor effect, can prevent and treat hepatic fibrosis and senile dementia and the like, for example, the dihydropyridone compound has a calcium ion channel regulating effect, 5-methyl-2 (1H) pyridone is a compound which is synthesized to have an anti-fibrosis activity, 5-methyl-1-phenyl-2 (PDGF) and is a compound which can remarkably inhibit the aggregation of fibroblast growth factor (TGF), a collagen factor (TGF-factor and the like which can be obviously expressed.
As -class important heterocyclic compounds, the existing methods for synthesizing pyridone compounds are mainly divided into two main groups, namely (1) cyclocondensation reaction and (2) cycloaddition reaction, under the catalysis of alkali, 1, 3-dicarbonyl compound and nitrilo acetamide undergo cyclocondensation to generate 3-nitrilo pyridone, the Guareschi synthesis method is the most common method for the pyridone compounds, and similarly, β -ketoaldehyde, malonaldehyde, ethynyl ketone and α -acylketone-S, S-acetal can all undergo Guareschi reaction, because the source of the 1, 3-dicarbonyl compound is low in price, the strategy for synthesizing the pyridone derivative from the 1, 3-dicarbonyl compound is widely applied to , for example, in SnCl4β -amino alkene nitrile compound and malonic ester undergo a cyclocondensation reaction to produce a dicyclo 2-pyridone amino alkene nitrile compound, Zhangyi et al utilize ethyl nitriloacetate, ethyl acetoacetate and ethylamine as raw materials to prepare N-ethyl-3-nitrile-4-methyl-6-hydroxypyridine-2-one through condensation and ring closure, Svetik et al report that 4-phenyl-6-methyl-5-ethoxycarbonyl-2-pyridone compound is synthesized by refluxing aromatic aldehyde, methyl acetoacetate, isopropylidene malonate and ammonium acetate in ethanol solution, Dong research group successfully realizes that 1, 3-dibromopropane and acetoacetyl aromatic amine produce dihydrofuran compound, and Vilsmeier reagent undergoes a ring-opening reaction to obtain polysubstituted pyridone compoundThe methods of (1) have various methods, however, reports about dihydropyridone structures and spiro compounds containing such structures are not common, and the universality is not effectively expanded because of severe constraints on the other or more components of the reaction with the 1, 3-dicarbonyl compound, the required raw materials have various types, the application range of reaction substrates is narrow, the reaction steps are long, side reactions in the reaction are increased, and the yield of the target product is reduced to degree, so that the method is not suitable for large-scale production.
Disclosure of Invention
In order to solve the above problems, the present invention aims to provide simple and efficient methods for synthesizing 3, 6-dihydropyridone compounds, and the synthesized 3, 6-dihydropyridone compounds have good economic value when applied to various industries such as medicine, chemical industry, fuel, etc.
In order to achieve the purpose, the invention adopts the following technical scheme:
A process for synthesizing 3, 6-dihydropyridone compound includes such steps as dissolving α -carbonyl amide compound A and olefin compound B in organic solvent in the presence of strong alkali as catalyst, and heating to obtain 3, 6-dihydropyridone compound C;
wherein R is1Is selected from C1～C5Straight or branched alkanes of (C)1～C5 kinds of halogenated alkyl and phenyl, R2、R3Each independently selected from C1～C5Is straight or branched alkane, phenyl, or R2、R3And the carbonyl ortho-carbon attached thereto to form a cycloalkane, R4Selected from the group consisting of COOMe, COOEt, COOH, CN, CHO, NO2 kinds of halogen, R5Selected from H, C1～C5 of alkyl, phenyl, COOMe, COOEt and COOH, R is H, C1～C3 of straight-chain or branched-chain alkane, halogen and alkoxy.
The process for synthesizing the above-mentioned 3, 6-dihydropyridone compound, R1Is Me, Et, Pr, Ph or CF3。
The process for synthesizing the above-mentioned 3, 6-dihydropyridone compound, R2、R3Each independently selected from Me, Et, Pr, Ph, or R2、R3And the ortho-carbon attached thereto form a cyclopropane, cyclopentane or cyclohexane.
The process for synthesizing the above-mentioned 3, 6-dihydropyridone compound, R4Selected from the group consisting of COOMe, COOEt, COOH, CN, CHO, NO2Cl or Br.
The process for synthesizing the above-mentioned 3, 6-dihydropyridone compound, R5Selected from H, Me, Et, Pr, Ph, COOMe, COOEt or COOH.
In the above method for synthesizing a3, 6-dihydropyridone compound, R is selected from H, Me, Et, Cl, Br, OMe and OEt.
, the molar ratio of the α -carbonyl amide compound to the olefin compound is 1: 1 to 3, and the amount ratio of the α -carbonyl amide compound, the organic solvent and the strong base is 1 mmol: 5 to 8 mL: 1 to 2.5 mmol.
the strong base is of potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, tert-butyllithium and methyllithium.
Further , when the strong base is t-butyllithium or methyllithium, the reaction system must be operated under anhydrous and oxygen-free conditions.
the organic solvent is kinds selected from ethanol, methanol, tetrahydrofuran, acetonitrile, 1, 4-dioxane, and 1, 2-dichloroethane.
, the temperature of the heating reaction is between room temperature and 80 ℃, and the reaction time is 6-10 h.
In the synthesis method of the 3, 6-dihydropyridone compound, thin layer chromatography TLC is used for monitoring the reaction process, saturated saline solution is added into the reaction system after the reactants completely disappear, extraction is carried out by using an extracting agent, and organic phases are combined; drying the organic phase with a drying agent, filtering, concentrating, and carrying out column chromatography to obtain the 3, 6-dihydropyridone compound.
the above extractant is dichloromethane, ethyl acetate, n-butanol or chloroform.
, drying the organic phase with desiccant for 10-15 hr.
Further , the drying agent is anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium chloride or molecular sieve.
Due to the adoption of the technical scheme, the invention has the following advantages:
the synthesis method of the 3, 6-dihydropyridone compound has the advantages of raw material source of , low cost, few reaction steps, few side reactions, simple and convenient operation, high product yield, strong universality, environment-friendly process, time saving, high efficiency and good market prospect.
Detailed Description
The present invention will be described in further detail in with reference to the following examples, which are, however, merely illustrative and not intended to limit the scope of the present invention.