阅读说明：本技术 一种含吡咯环的单环或多环化合物的制备方法 (Preparation method of pyrrole ring-containing monocyclic or polycyclic compound ) 是由 程寒松 刘开 李晨光 文家武 于 2019-11-14 设计创作，主要内容包括：本发明公开了一种含吡咯环的单环或多环化合物的制备方法。以烯胺类化合物为原料,连续经过重氮化、还原和与含羰基类化合物环化合成,所得反应混合物经过滤、洗涤、干燥后即得所述含吡咯环的单环或多环化合物。本发明公开的合成方法,原料廉价易得,操作简单,反应条件温和,经济效益高,易于工业化连续生产含吡咯环的单环或多环化合物,该方法具有普遍适用性。(The invention discloses a preparation method of a pyrrole ring-containing monocyclic or polycyclic compound. Taking enamine compounds as raw materials, continuously carrying out diazotization, reduction and cyclization synthesis with carbonyl-containing compounds, filtering, washing and drying the obtained reaction mixture to obtain the pyrrole ring-containing monocyclic or polycyclic compound. The synthesis method disclosed by the invention has the advantages of cheap and easily-obtained raw materials, simple operation, mild reaction conditions, high economic benefit, easiness for industrial continuous production of the pyrrole ring-containing monocyclic or polycyclic compound and universal applicability.)

1. A preparation method of a pyrrole ring-containing monocyclic or polycyclic compound is characterized in that: the preparation method takes enamine compound 1a and carbonyl-containing compound 4a as raw materials, and the reaction formula is shown as follows:

wherein R is₁Is H, -C_nH_2n+1、-OC_nH_2n+1or-C_nH_2n-；R₂Is H, -C_nH_2n+1、-OC_nH_2n+1、X、-NO₂or-C_nH_2n-；R₃is-C_nH_n-、-NC_nH_2n+1or-OC_nH_2nO-；R₄is-C_nH_n-、-NC_nH_2n+1or-OC_nH_2nO-; x is F, Cl, Br or I.

2. The method for preparing a monocyclic or polycyclic compound containing a pyrrole ring according to claim 1, characterized by comprising the steps of:

(1) reacting enamine compound 1a with diazo reagent at low temperature and in acid solution to prepare diazonium salt 2 a;

(2) the diazonium salt 2a is reduced by the reducing agent to the corresponding hydrazonium salt 3 a;

(3) hydrazine salt 3a reacts with carbonyl-containing compound 4a, and pyrrole ring-containing monocyclic or polycyclic compound 5a is prepared by Borsche cyclization.

3. The method for producing a monocyclic or polycyclic compound containing a pyrrole ring according to claim 1, wherein: the reaction medium in the steps (1), (2) and (3) is one or a mixture of more than two of n-hexane, water, dichloromethane, ethyl acetate, ethanol, methanol, tetrahydrofuran and toluene.

4. The method for producing a monocyclic or polycyclic compound containing a pyrrole ring according to claim 1, wherein: the acid in the step (1) is one or a mixture of more than two of hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, benzenesulfonic acid, propionic acid and acetic acid.

5. The method for producing a monocyclic or polycyclic compound containing a pyrrole ring according to claim 1, wherein: the diazotization reagent in the step (1) is one or a mixture of more than two of sodium nitrite, nitrosyl chloride and nitrosyl sulfuric acid, the molar ratio of the enamine compound to the diazotization reagent is 1: 1-1: 2, and the conversion rate of diazotization reaction is 80-100%.

6. The method for producing a monocyclic or polycyclic compound containing a pyrrole ring according to claim 1, wherein: the reaction temperature in the step (1) is-30 ℃.

7. The method for producing a monocyclic or polycyclic compound containing a pyrrole ring according to claim 1, wherein: the reducing agent in the step (2) is SnCl₂、Pd/C、Pd/Al₂O₃Sodium bisulfite, ferrous chloride, ammonium sulfite, ammonium bisulfite, sodium metabisulfite, sodium hydroxide, ferrous sulfate, sodium sulfiteThe molar ratio of the diazonium salt to the reducing agent is 1: 0.1-1: 4.

8. The method for producing a monocyclic or polycyclic compound containing a pyrrole ring according to claim 1, wherein: the reduction reaction temperature in the step (2) is 0-130 ℃.

9. The method for producing a monocyclic or polycyclic compound containing a pyrrole ring according to claim 1, wherein: and (3) the temperature of the ring closing reaction in the step (3) is 20-200 ℃.

10. The method for producing a monocyclic or polycyclic compound containing a pyrrole ring according to claim 1, wherein: the molar ratio of the hydrazine salt to the carbonyl-containing compound in the step (3) is 1: 0.9-1: 3.

Technical Field

The invention belongs to the technical field of fine chemical engineering, and particularly relates to a method suitable for industrial production of a pyrrole ring-containing monocyclic or polycyclic compound.

Background

The pyrrole ring-containing monocyclic or polycyclic compounds are important nitrogen-containing heterocyclic compounds, widely exist in nature, mostly have a plurality of unique physicochemical properties and biological activities, and are widely applied to the fields of medicines, dyes, pesticides, foods, materials and the like. With the continuous expansion of the application field of monocyclic or polycyclic compounds containing pyrrole rings, researchers have more and more researches on the synthesis methods of the compounds, and in the last 50 th century, researchers of RonaldGrigg, Bartolo Gabrile, Yong-Jiang Bian and other chemists all use the classical lipoamine reaction and then synthesize pyrrole derivatives through the catalysis of palladium catalysts. Matthew l.crawley utilizes Sonogashira to synthesize pyrrole derivatives by coupling reaction and palladium-catalyzed alkynylene alkenylation. Danlene Q.Tan et al synthesized pyrrole derivatives using cycloaddition of imines and anhydride reactions. Fischer synthesis, Hantzsch pyrrole synthesis, oxidative cyclization synthesis, and the like. Among these methods, the palladium metal catalytic synthesis method and the coupling reaction synthesis method have low yield and high cost. The Fischer synthesis has been considered to be the most economical and convenient means for its widespread use in the synthesis of mono-or polycyclic compounds containing a pyrrole ring. However, concentrated sulfuric acid and Lewis acid are mostly used as catalysts in the traditional Fischer synthesis method, and the catalysts have the factors of strong corrosivity, low yield and the like. In addition, most of the conventional Fischer synthesis methods use the irritant and volatile organic solvents acetic acid and toluene, which are not only harmful to the environment but also toxic. Therefore, the synthesis method of the pyrrole ring-containing monocyclic or polycyclic compound, which is simple to operate, environment-friendly, economical and efficient, is particularly important.

Disclosure of Invention

The invention aims to provide a method for synthesizing a pyrrole ring-containing monocyclic or polycyclic compound in an aqueous medium without adding a catalyst, aiming at a series of problems of large catalyst dosage used in the synthesis of the pyrrole ring-containing monocyclic or polycyclic compound, strong toxicity of a solvent, strong corrosion of equipment, complex operation, environmental pollution and the like.

In order to achieve the purpose, the invention adopts the following technical scheme: a preparation method of a pyrrole ring-containing monocyclic or polycyclic compound takes an enamine compound 1a and a carbonyl compound 4a as raw materials, and the reaction formula is shown as follows:wherein R is₁Is H, -C_nH_2n+1、-℃_nH_2n+1or-C_nH_2n-；R₂Is H, -C_nH_2n+1、-℃_nH_2n+1、X、-NO₂or-C_nH_2n-；R₃is-C_nH_n-、-NC_nH_2n+1or-C_nH_2nO-；R₄is-C_nH_n-、-NC_nH_2n+1or-C_nH_2nO-; x is F, Cl, Br or I.

Further, the method specifically comprises the following steps:

(1) reacting enamine compound 1a with diazo reagent at low temperature and in acid solution to prepare diazonium salt 2 a;

(2) the diazonium salt 2a is reduced by the reducing agent to the corresponding hydrazonium salt 3 a;

(3) hydrazine salt 3a reacts with carbonyl-containing compound 4a, and pyrrole ring-containing monocyclic or polycyclic compound 5a is prepared by Borsche cyclization.

Further, the reaction medium in the steps (1), (2) and (3) is one or a mixture of more than two of n-hexane, water, dichloromethane, ethyl acetate, ethanol, methanol, tetrahydrofuran and toluene.

Further, the acid in the step (1) is one or a mixture of more than two of hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, benzenesulfonic acid, propionic acid and acetic acid.

Further, the diazotization reagent in the step (1) is one or a mixture of more than two of sodium nitrite, nitryl nitrite, nitrosyl chloride and nitrosyl sulfuric acid, the molar ratio of the enamine compound to the diazotization reagent is 1: 1-1: 2, and the conversion rate of diazotization reaction is 80-100%.

Further, the reaction temperature in the step (1) is-30 ℃.

Further, the reducing agent in the step (2) is SnCl₂、Pd/C、Pd/Al₂O₃One or a mixture of more than two of sodium bisulfite, ferrous chloride, ammonium sulfite, ammonium bisulfite, sodium metabisulfite, sodium hydroxide, ferrous sulfate and sodium sulfite, wherein the molar ratio of the diazonium salt to the reducing agent is 1: 0.1-1: 4.

Further, the reduction reaction temperature in the step (2) is 0-130 ℃.

Further, the temperature of the ring closing reaction in the step (3) is 20-200 ℃.

Further, the molar ratio of the hydrazine salt to the carbonyl-containing compound in the step (3) is 1: 0.9-1: 3.

The invention advocates a green and efficient synthesis concept, uses cheap and easily-obtained amine compounds as raw materials, has the characteristics of milder reaction conditions, simpler operation, environment-friendly synthesis process, easy product separation, high yield and purity, short reaction time, universality and the like.

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

(1) all raw materials used in the continuous reaction are cheap and easy to obtain, have low toxicity and are convenient to transport and store.

(2) The reaction in water medium can reduce cost and environmental pollution.

(3) Short reaction time, simple operation, high yield and high product purity.

In conclusion, the synthesis method of the pyrrole ring-containing monocyclic or polycyclic compound is an economic and efficient green synthesis method, and is suitable for industrial production.

Detailed Description

In order to make the technical solutions of the present application better understood by those skilled in the art, the technical solutions in the embodiments of the present application will be clearly and completely described below in conjunction with the embodiments of the present application, and it is obvious that the described embodiments are only some embodiments of the present application, but not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.

It should be noted that the terms "comprises" and "comprising," and any variations thereof, in the description and claims of this application, are intended to cover a non-exclusive inclusion, such that a process, method, system, article, or apparatus that comprises a list of steps or elements is not necessarily limited to those steps or elements expressly listed, but may include other steps or elements not expressly listed or inherent to such process, method, article, or apparatus.

Example 1

Adding 70mL of hydrochloric acid into a 250mL two-mouth bottle, stirring at 0 ℃, adding 2-butenylamine (20g, 280mmol), stirring for 10min, slowly dropwise adding 40mL of prepared sodium nitrite solution, and keeping the temperature for reaction for 30min to obtain light yellow liquid diazonium salt; reducing the prepared diazonium solution by using sodium bisulfite (58.5g, 562.4mmol), heating to 60 ℃ for reaction for 2h, dropwise adding 2-butanone (20.1g, 280mmol) into the reaction solution, reacting for 2h, filtering to obtain a crude product, washing the crude product by using an aqueous solution to be neutral, and drying to obtain a product of a formula 1, wherein the yield is 30.6g and 88.3%.

Example 2

Adding 27mL of dilute hydrochloric acid into a 250mL two-mouth bottle, stirring at 0 ℃, adding aniline (6g, 64.5mmol), stirring for 10min, slowly dropwise adding 12mL of prepared sodium nitrite solution, and reacting for 30min under heat preservation to obtain light yellow liquid diazonium salt; reducing the prepared diazonium solution by using sodium bisulfite (23.5g, 225.8mmol), heating to 60 ℃ for reaction for 2h, dropwise adding 2-indanone (9.4g, 71mmol) into the reaction solution, reacting for 2h, filtering to obtain a crude product, washing the crude product to be neutral by using an aqueous solution, and drying to obtain a product of a formula 2, wherein the yield is 11.2g and 85%.

Example 3

Adding 88mL (20%) of concentrated hydrochloric acid into a 250mL two-mouth bottle, stirring at 0 ℃, adding aniline (20g), stirring for 10min, slowly dropwise adding a prepared sodium nitrite solution (40mL), and reacting for 30min under heat preservation to obtain light yellow liquid diazonium salt; reacting the prepared diazonium solution with sodium bisulfite (20g) at 80 ℃ for 2h, adding 1, 4-cyclohexanedione (12g) into the reaction solution, reacting for 2h, filtering to obtain a crude product, washing the crude product to be neutral by aqueous solution, washing by petroleum ether, and drying to obtain a product of a formula 3, wherein the yield is 23.1g and 85%.

The present invention is illustrated in detail by the above examples, but the present invention is not limited to the above methods, that is, it is not meant to imply that the present invention must be carried out depending on the above reaction conditions. It will be apparent to those skilled in the art that any modifications to the present invention, equivalent substitutions of reaction solvent catalysts and changes in the specific reaction conditions, etc., are within the scope and disclosure of the present invention.