阅读说明：本技术 吡咯醛化合物的制备方法 (Process for producing pyrrole aldehyde compound ) 是由 付海燕 陈华 许可 郑学丽 袁茂林 李瑞祥 于 2020-05-29 设计创作，主要内容包括：本发明公开了吡咯醛化合物的制备方法,涉及化合物制备技术领域。将起始物料混合进行反应,起始物料包括取代吡啶季铵盐、碘源、碱以及水,取代吡啶季铵盐的结构式为：<Image he="270" wi="289" file="DDA0002516610190000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>取代基R在氮原子的邻位和/或间位,R为烷基、芳香基、杂芳基或卤素,取代基R3为烷基或苄基。该方法操作简单,原料容易得到,化学选择性良好,副产物少,底物可转化为多种其他有用的分子,相较于现有的吡咯醛化合物的制备具有很强的实用性,且产率最高可达到86％。(The invention discloses a preparation method of a pyrrole aldehyde compound, and relates to the technical field of compound preparation. Mixing starting materials for reaction, wherein the starting materials comprise substituted quaternary ammonium pyridinium salt, an iodine source, alkali and water, and the structural formula of the substituted quaternary ammonium pyridinium salt is as follows:)

1. A method for producing a pyrrole aldehyde compound, comprising:

mixing starting materials for reaction, wherein the starting materials comprise substituted quaternary ammonium pyridinium salt, an iodine source, alkali and water, and the structural formula of the substituted quaternary ammonium pyridinium salt is as follows:

the substituent R being at nitrogenOrtho and/or meta to the atom, R is alkyl, aryl, heteroaryl or halogen, and the substituent R3 is alkyl or benzyl.

2. The method for producing a pyrrole aldehyde compound according to claim 1, wherein X in the structural formula of the substituted quaternary ammonium salt of pyridine^-Is a halide ion, when X^-When the iodine source is iodide ions, the iodine source is at least one of iodine simple substance and NIS; when X is present^-When the iodine source is other halogen ions except the iodide ions, the iodine source is iodine simple substance.

3. The method for producing a pyrrole aldehyde compound according to claim 1, wherein the molar ratio of the amount of the iodine source to the amount of the substituted quaternary ammonium pyridine salt is 30% to 70%.

4. The method for producing a pyrrole aldehyde compound according to claim 1, wherein the starting material further comprises an organic solvent;

preferably, the volume ratio of the added amount of the organic solvent to the water contained in the starting material is 1-10: 1;

preferably, the organic solvent is at least one of dichloroethane and acetonitrile.

5. The method for producing a pyrrole aldehyde compound according to claim 4, wherein the concentration of the substituted quaternary ammonium pyridine salt is 0.1 to 1M after the starting materials are mixed.

6. The method for producing a pyrrole aldehyde compound according to claim 1, wherein the base is a weak base;

preferably, the base comprises K₂CO3、K₃PO₄And Na₂CO₃At least one of (1);

preferably, the molar ratio of the weak base to the substituted quaternary ammonium pyridine salt is 1-4: 1.

7. The method for producing a pyrrole aldehyde compound according to claim 1, wherein the starting material further comprises a double bond-containing additive comprising at least one of methyl methacrylate, ethyl acrylate, and methyl acrylate;

preferably, the molar ratio of the double bond-containing additive to the substituted quaternary ammonium pyridine salt is 0.5-2: 1.

8. The method for preparing a pyrrole aldehyde compound according to claim 1, wherein the reaction temperature of the mixing reaction is 20 to 100 ℃ and the reaction time is 15 to 36 hours;

preferably, the reaction temperature is 65-100 ℃;

more preferably, the reaction temperature is 75-85 ℃.

9. The method for producing a pyrrole aldehyde compound according to claim 1, wherein the mixing reaction is carried out under continuous stirring.

10. The method for preparing a pyrrole aldehyde compound according to claim 1, further comprising performing solid-liquid separation after the mixing reaction, preferably, the solid-liquid separation is filtration, and sequentially performing washing, solvent removal, extraction and column chromatography on the obtained filtrate;

preferably, the filtration is carried out by adopting a glass hourglass funnel padded with diatomite;

preferably, the filtrate is washed by dichloromethane and ethyl acetate respectively and sequentially;

preferably, the solvent is removed by distilling off the solvent from the washed filtrate under reduced pressure;

preferably, the extraction is to add water into the substance obtained after the solvent is removed, extract the substance by ethyl acetate for multiple times after mixing, and evaporate the solvent under reduced pressure after the extract liquid is dried, wherein the volume ratio of the added water to the substance obtained after the solvent is removed is 1-5: 1;

preferably, the column chromatography separation is to select petroleum ether/ethyl acetate as a mobile phase for the extracted substances, wherein the volume ratio of the petroleum ether to the ethyl acetate is 20-100: 1, purifying by flash silica gel column chromatography.

Technical Field

The invention relates to the technical field of compound preparation, in particular to a preparation method of a pyrrole aldehyde compound.

Background

The pyrrole aldehydes are widely present as important structural skeletons in general intermediates for pharmaceuticals, perfumes, fine chemicals and natural products. In the past, people all adopt a multi-component synthesis method to construct a pyrrole skeleton, the reaction conditions are harsh, and the atom economy is low.

For the synthesis method of pyrrole aldehyde compounds, a great space for improvement exists at present.

In view of this, the invention is particularly proposed.

Disclosure of Invention

The object of the present invention is to provide a process for the preparation of a pyrrole aldehyde compound, aiming at improving at least one of the problems mentioned in the background.

The invention is realized by the following steps:

the preparation method of the pyrrole aldehyde compound provided by the embodiment of the invention comprises the following steps:

mixing raw materials for reaction, wherein the raw materials comprise substituted quaternary ammonium pyridine salt, an iodine source, alkali and water substituted quaternary ammonium pyridine salt, and the structural formula of the raw materials is as follows:

the substituent R is ortho-position and/or meta-position of the nitrogen atom, R is alkyl, aryl, heteroaryl or halogen, and the substituent R3 is alkyl or benzyl.

In an alternative embodiment, X in the formula of the substituted quaternized pyridinium salt^-Is a halide ion, when X^-When the iodine source is iodine ion, the iodine source is at least one of iodine simple substance and NIS; when X is present^-When the iodine source is other halogen ions besides iodide ions, the iodine source is iodine simple substance.

In an alternative embodiment, the molar ratio of the amount of iodine source to the amount of substituted quaternized pyridinium salt is from 30% to 70%.

In an alternative embodiment, the starting material further comprises an organic solvent;

in an alternative embodiment, the volume ratio of the added amount of the organic solvent to the water in the starting material is 1-10: 1;

in an alternative embodiment, the organic solvent is at least one of dichloroethane and acetonitrile.

In an optional embodiment, after the starting materials are mixed, the concentration of the substituted quaternary ammonium pyridine salt is 0.1-1M.

In alternative embodiments, the base is a weak base;

in an alternative embodiment, the weak base comprises K₂CO₃、K₃PO₄And Na₂CO₃At least one of (1);

in an alternative embodiment, the molar ratio of the weak base to the substituted quaternary ammonium pyridine salt is 1-4: 1.

In an alternative embodiment, the starting material further comprises a double bond containing additive comprising at least one of methyl methacrylate, ethyl acrylate, and methyl acrylate;

in an alternative embodiment, the double bond-containing additive is used in a molar ratio of 0.5-2: 1 to the amount of the substituted quaternary ammonium pyridinium salt.

In an optional embodiment, the reaction temperature of the mixing reaction is 20-100 ℃, and the reaction time is 15-36 h;

in an optional embodiment, the reaction temperature is 65-100 ℃;

in an alternative embodiment, the reaction temperature is 75-85 ℃.

In an alternative embodiment, the mixing reaction is carried out with constant stirring.

In an optional embodiment, after the mixing reaction, performing solid-liquid separation, preferably, the solid-liquid separation is filtration, and sequentially performing washing, solvent removal, extraction and column chromatography on the obtained filtrate;

in an alternative embodiment, the filtration is performed using a glass funnel lined with diatomaceous earth;

in an alternative embodiment, the filtrate is washed with dichloromethane and ethyl acetate;

in an alternative embodiment, the solvent is removed by distilling off the solvent from the washed filtrate under reduced pressure;

in an optional embodiment, the extraction is to add water to the substance obtained after the solvent is removed, extract the substance for multiple times by using ethyl acetate after mixing, and evaporate the solvent under reduced pressure after the extract liquid is dried, wherein the volume ratio of the added water to the substance obtained after the solvent is removed is 1-10: 1;

in an optional implementation mode, the column chromatography separation is to select petroleum ether/ethyl acetate as a mobile phase for an extracted substance, wherein the volume ratio of the petroleum ether to the ethyl acetate is 20-100: 1, purifying by flash silica gel column chromatography.

The invention has the following beneficial effects:

the invention develops a method for preparing the pyrrole aldehyde compound by the ring opening of the quaternary ammonium salt of pyridine under the nucleophilic attack of water molecules and then the ring closing process in the molecule. The method has the advantages of mild reaction conditions, simple operation, easily obtained raw materials, good chemical selectivity, few byproducts, conversion of the substrate into various other useful molecules, strong practicability compared with the existing preparation of the pyrrole aldehyde compound, and the highest yield of the pyrrole aldehyde compound can reach 86%.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

The following is a detailed description of the preparation method of the pyrrole aldehyde compound provided in the examples of the present invention.

The invention provides a preparation method of a pyrrole aldehyde compound, which comprises the following steps:

mixing the substituted pyridine quaternary ammonium salt, an iodine source, weak base and a mixed solvent for reaction. The structural formula of the substituted pyridine quaternary ammonium salt is as follows:

the substituent R is ortho-position and/or meta-position of the nitrogen atom, R is alkyl, aryl or heteroaryl, and the substituent R3 is alkyl or benzyl.

Namely, the structure of the substituted pyridine quaternary ammonium salt is as follows:

the substituents R1 and R2 are alkyl, aryl, heteroaryl or halogen, R1 and R2 may be the same or different, and the substituent R3 is alkyl or benzyl.

The chemical reaction general formula is:

the method has the advantages that under the action of an iodine source, water attacks the adjacent carbon atoms of the quaternary ammonium salt of pyridine in an alkaline environment, the pyridine undergoes a ring opening reaction and then undergoes an intramolecular ring closing reaction to generate the pyrrole aldehyde, and the defects that the conventional method for synthesizing the substance is harsh in conditions, complicated in reaction steps, many in byproducts and the like are overcome.

Specifically, the temperature of the mixing reaction is 20-100 ℃, and the reaction time is 15-36 h. When the reaction temperature is higher or lower than the above range, the reaction may be impossible or the reaction by-products may be increased to result in a low yield. Under the conditions of the reaction temperature and the reaction time, the reaction can be ensured to be more sufficient, and the yield is higher.

Preferably, in order to ensure a high reaction rate, the reaction temperature is 65-100 ℃; further preferably, the reaction temperature is 75-85 ℃ and is usually set to 80 ℃ to ensure higher reaction rate and higher yield.

Preferably, in order to further increase the reaction rate, after the substances participating in the reaction are mixed, the mixing reaction is carried out under the condition of continuous stirring. The stirring means may be magnetic stirring.

Preferably, the substituted pyridineIn the structural formula of quaternary ammonium salt, X^-Is a halide ion, when X^-When the iodine source is iodine ion, the iodine source is at least one of iodine simple substance and NIS; when X is present^-When the iodine source is other halogen ions except the iodide ions, the iodine source is iodine simple substance for ensuring the reaction to be normally carried out.

Preferably, in order to ensure higher reaction rate, the molar ratio of the iodine source to the substituted quaternary ammonium pyridine salt is 30-70%.

Preferably, the starting material also comprises an organic solvent. In the preparation process, an organic solvent is added, and the organic solvent can dissolve the generated pyrrole aldehyde compound in the organic solvent, so that the reaction balance is shifted to the right, and the yield of the pyrrole aldehyde compound is improved.

Preferably, the volume ratio of the added amount of the organic solvent to the water is 1-10: 1. in a preferred embodiment of the invention, the volume ratio of organic solvent to water is 1: 1.

Specifically, the organic solvent is at least one of dichloroethane and acetonitrile.

Preferably, in order to ensure smooth and efficient reaction, the concentration of the substituted quaternary ammonium pyridine salt is 0.1-1M after the starting materials are mixed.

Preferably, to further reduce reaction by-products and increase reaction rate, the base used is a weak base, preferably, the weak base comprises K₂CO₃、K₃PO₄And Na₂CO₃At least one of them. Specifically, in order to ensure that the reaction is carried out more efficiently, the molar ratio of the consumption of weak base to the quantity of the substituted pyridine quaternary ammonium salt is 1-4: 1.

Preferably, in order to further improve the reaction yield, the starting material further comprises an additive containing a double bond, the additive containing a double bond comprising at least one of methyl methacrylate, ethyl acrylate and methyl acrylate. Preferably, the yield is high on the basis of avoiding raw material waste, and the molar ratio of the double bond-containing additive to the substituted quaternary ammonium pyridine salt is 0.5-2: 1. The reason why the double bond-containing additive can improve the reaction yield may be that it competes with the reaction intermediate for iodine in iodonium during the reaction, accelerating the elimination of iodine from the intermediate.

Further, filtering is carried out after the mixing reaction is finished, and the obtained filtrate is sequentially washed, subjected to solvent removal, extracted and subjected to column chromatography separation.

The method specifically comprises the following steps: filtering by using a glass hourglass funnel filled with diatomite, washing by using dichloromethane and ethyl acetate respectively, combining filtrates, distilling the solvent out under reduced pressure, adding distilled water into the substance obtained after the solvent is removed, wherein the volume ratio of the added amount of the distilled water to the substance obtained after the solvent is removed is 1-5: 1, extracting by using ethyl acetate for multiple times after the distilled water is added, drying the extract by using anhydrous magnesium sulfate, and distilling the solvent out under reduced pressure; and then, selecting petroleum ether/ethyl acetate as a mobile phase (the volume ratio is 20-100: 1) for the extracted substances, and purifying by adopting a rapid silica gel column chromatography to obtain the final product, namely the pyrrole aldehyde compound.

The features and properties of the present invention are described in further detail below with reference to examples.

Melting points of the compounds of the following examples were measured by XRC-I type micro melting point apparatus (Sichuan Dake cheian apparatus length) with thermometer uncorrected; NMR spectra were obtained from Bruker DPX-400MHz NMR spectrometer (solvent: CDCl)₃Or DMSO-d6, internal standard TMS); the high-resolution mass spectrum adopts a Water Micromass GCT mass spectrometer (ESI source); the thin layer chromatography adopts a [ HFGF254 silica gel plate](Qingdao maritime plant); the silica gel used for column chromatography is 300-400 mesh (Qingdao ocean chemical plant).

Reagents used in the following examples: all were analytically pure and were purchased directly from the market without further treatment prior to use. The substrate-substituted quaternary ammonium pyridines used in examples 1 to 37 were prepared directly from pyridine and methyl iodide in a single step according to conventional methods. The reagents used in example 38 and the following examples were all purchased from reagent companies. Other reagents were purchased directly from reagents such as Aladdin, TCI, Aldrich and Adamas without further purification.