阅读说明：本技术 一种羟甲基取代芳杂环类化合物的制备方法 (Preparation method of hydroxymethyl substituted aromatic heterocyclic compound ) 是由 李展 罗波 孙文海 孙喜玲 宁芳贤 于 2020-05-20 设计创作，主要内容包括：本发明提供一种羟甲基取代芳杂环类化合物的制备方法,包括：在保护气体存在下,将芳杂羧酸溶于非质子性溶剂,冰浴下加入还原剂,升温至室温,反应得到所述羟甲基取代芳杂环类化合物。本发明的羟甲基取代芳杂环类化合物的产率在93％以上,该方法不仅原料便宜易得,而且简单、高效、反应条件温和,可避免常规合成方法中硼氢化钠等易制爆危险化学品的使用的缺点。(The invention provides a preparation method of hydroxymethyl substituted aromatic heterocyclic compounds, which comprises the following steps: in the presence of protective gas, dissolving aromatic heterocyclic carboxylic acid in an aprotic solvent, adding a reducing agent in ice bath, heating to room temperature, and reacting to obtain the hydroxymethyl substituted aromatic heterocyclic compound. The yield of the hydroxymethyl substituted aromatic heterocyclic compound is more than 93 percent, the method has cheap and easily obtained raw materials, is simple and efficient, has mild reaction conditions, and can avoid the defect of using explosive hazardous chemicals such as sodium borohydride and the like in the conventional synthetic method.)

1. A preparation method of hydroxymethyl substituted aromatic heterocyclic compounds is characterized by comprising the following steps: in the presence of protective gas, dissolving aromatic heterocyclic carboxylic acid in an aprotic solvent, adding a reducing agent in ice bath, heating to room temperature, and reacting to obtain the hydroxymethyl substituted aromatic heterocyclic compound.

2. The method of claim 1, wherein: the aromatic heterocyclic carboxylic acid is shown as a formula (1) or (2):

wherein R is₁Is hydroxyl, nitryl, chlorine, bromine or iodine, and n is 0, 1, 2 or 3.

3. The method of claim 1, wherein: the aprotic solvent is at least one selected from tetrahydrofuran and dimethyl sulfide.

4. The method of claim 1, wherein: the reducing agent is at least one of borane tetrahydrofuran and borane dimethyl sulfide.

5. The method of claim 1, wherein: the molar ratio of the reducing agent to the heteroaromatic carboxylic acid is (2-3): 1.

6. the process according to claim 1, wherein the aromatic/heteroaromatic carboxylic acid and the aprotic organic solvent are used in a ratio of 1mol to (1 to 2) L.

7. The method of claim 1, wherein: and (4) heating to room temperature, and adding a quenching agent after the reaction is finished.

8. The method of claim 7, wherein: the quenching agent is selected from at least one of methanol, ethanol, propanol and water.

9. The method of claim 7, wherein: and after quenching, extracting by using an extractant, washing an organic phase obtained by extraction, drying, filtering and purifying to obtain the hydroxymethyl substituted aromatic heterocyclic compound.

10. The method of claim 9, wherein: the extractant is selected from at least one of ethyl acetate, chloroform and dichloromethane;

and/or, when washing, the adopted washing agent is at least one selected from weak alkaline aqueous solution, saturated saline solution and water, preferably, the weak alkaline aqueous solution is selected from saturated sodium bicarbonate aqueous solution;

and/or, when drying, the adopted drying agent is at least one of anhydrous sodium sulfate and anhydrous magnesium sulfate.

Technical Field

The invention relates to the fields of medicinal chemistry, synthetic chemistry, photoelectricity and organic semiconductor material science, and provides a simple and efficient preparation method for preparing hydroxymethyl substituted aromatic heterocyclic compounds by one-step reaction of aromatic heterocyclic carboxylic acids. The method is simple and efficient, can avoid the use of explosive hazardous chemicals such as sodium borohydride and the like, the nitro group in the substrate is not reduced into amino, and meanwhile, the synthetic product can fill the blank of domestic reagents and the like and break through the price or technical monopoly of foreign or imported products.

Background

Heteroaromatic compounds (Heterocyclic compounds) are organic compounds containing an aromatic Heterocyclic structure in the molecule. The atoms constituting the aromatic heterocyclic ring contain at least one hetero atom in addition to carbon atoms. Is the most numerous group of organic compounds, the most common heteroatoms being nitrogen, sulfur, oxygen atoms. Heteroaromatic compounds are ubiquitous in the structure of drug molecules and have been widely used in recent years in the organic photoelectric and semiconductor industries.

The raw materials of the aromatic heterocyclic carboxylic acid are generally easy to directly obtain or directly purchase, but the aromatic heterocyclic ring substituted by hydroxymethyl is difficult to directly obtain, the aromatic heterocyclic ring substituted by hydroxymethyl can be generally obtained by reducing the aromatic heterocyclic carboxylic acid by reducing agents such as sodium borohydride or potassium borohydride, or hydrochloric acid is needed in the post-treatment process, but the reducing agents or the hydrochloric acid used in the post-treatment process belong to the control range of easily explosive dangerous chemicals or easily toxic chemicals, the purchase and storage procedures are complicated, and the risk coefficient is high in the use process.

Disclosure of Invention

In view of the above disadvantages of the prior art, the present invention aims to provide a method for preparing a hydroxymethyl substituted aromatic heterocyclic molecular building block, which is used to solve the problems that in the prior art, a dangerous chemical which is easy to explode needs to be used when the hydroxymethyl substituted aromatic heterocyclic is prepared.

In order to achieve the above objects and other related objects, the present invention provides a method for preparing hydroxymethyl-substituted aromatic heterocyclic compounds, comprising: in the presence of protective gas, dissolving aromatic heterocyclic carboxylic acid in an aprotic solvent, adding a reducing agent in ice bath, heating to room temperature, and reacting to obtain the hydroxymethyl substituted aromatic heterocyclic compound.

Alternatively, the heteroaromatic carboxylic acid is represented by formula (1) or (2):

wherein R is₁Is hydroxyl, nitryl, chlorine, bromine or iodine, and n is 0, 1, 2 or 3.

(R₁) n is a substituent R on a carbon atom in the five-membered heterocycle of the formula (1) or (2)₁The number of (a) may be 0, 1, 2 or 3, that is, 4 carbon atoms in the five-membered heterocyclic ring, any one of which is attached to-COOH and the remaining three of which are each attached to a H. Or at least one of the 3H is substituted by R₁Specifically, 1, 2 or 3 of H may be substituted.

Optionally, the aprotic solvent is selected from at least one of tetrahydrofuran, dimethyl sulfide.

Optionally, the reducing agent is selected from at least one of borane tetrahydrofuran and borane dimethylsulfide.

The reduction using a tetrahydrofuran solution of borane tetrahydrofuran is superior to a dimethyl sulfide solution using borane dimethyl sulfide because the reduction reaction solution using a borane tetrahydrofuran solution is clear and has no odor of sulfide and easy post-treatment.

Optionally, the molar ratio of the reducing agent to the heteroaromatic carboxylic acid is (2-3): 1, including but not limited to 2:1, 2.5:1, 3:1, etc.

Optionally, the aromatic heterocyclic carboxylic acid and the aprotic organic solvent are used in a ratio of 1mol to (1-2) L, including but not limited to 1mol to 1L, 1mol to 1.5L, 1mol to 2L, and the like.

Optionally, after the reaction is complete, a quencher is added.

Alternatively, the quenching agent may be a protic solvent, and specifically may be selected from at least one of methanol, ethanol, propanol, and water.

Optionally, the protective gas is at least one selected from nitrogen and inert gas, preferably nitrogen.

The inert gas is at least one selected from helium (He), neon (Ne), argon (Ar), krypton (Kr), and xenon (Xe).

Optionally, after quenching, extracting with an extractant, washing an organic phase obtained by extraction, drying, filtering, and purifying to obtain the hydroxymethyl substituted aromatic heterocyclic compound.

Optionally, the extractant is selected from at least one of ethyl acetate, chloroform, and dichloromethane.

Optionally, in washing, the detergent used is at least one selected from the group consisting of a weakly alkaline aqueous solution, a saturated saline solution, and water.

Preferably, the weakly alkaline aqueous solution is selected from saturated aqueous sodium bicarbonate solutions.

Alternatively, the washing was carried out by washing with a saturated aqueous sodium bicarbonate solution, water and a saturated brine in this order.

Optionally, when drying, the drying agent is selected from at least one of anhydrous sodium sulfate and anhydrous magnesium sulfate.

As described above, the method for preparing hydroxymethyl substituted aromatic heterocyclic compounds according to the present invention has the following advantageous effects:

the yield of the hydroxymethyl substituted aromatic heterocyclic compound is more than 93 percent, the method is simple and efficient, and the use of sodium borohydride, hydrochloric acid and other easily explosive hazardous chemicals and easily toxic chemicals can be avoided.

Drawings

FIG. 1 shows a nuclear magnetic spectrum of 2-hydroxymethyl-5-nitrothiophene obtained in example 1 of the present invention.

FIG. 2 shows a nuclear magnetic spectrum of 2-hydroxymethyl-5-nitrofuran obtained in example 2 of the present invention.

FIG. 3 shows a nuclear magnetic spectrum of 2-hydroxymethyl-3, 5-dibromothiophene obtained in example 3 of the present invention.

FIG. 4 shows a nuclear magnetic spectrum of 2-hydroxymethyl-4, 5-dibromofuran obtained in example 4 of the present invention.

FIG. 5 shows a nuclear magnetic spectrum of 2-hydroxymethyl-3-bromothiophene obtained in example 5 of the present invention.

Detailed Description

The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.

The invention provides a simple and efficient preparation method for preparing hydroxymethyl substituted aromatic heterocyclic compounds by one-step reaction of aromatic heterocyclic carboxylic acid. In some embodiments, the method comprises: (1) adding the aromatic heterocyclic carboxylic acid into dry tetrahydrofuran under the protection of nitrogen, slowly dropwise adding a 1.0M borane tetrahydrofuran solution under an ice bath, and after dropwise adding, heating to room temperature under the protection of nitrogen and stirring for 16 hours. (2) After the reaction is finished, adding methanol under ice bath to quench the reaction; (3) the combined organic phases were washed with saturated sodium bicarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered and purified. The yield is usually above 93%. The method is simple and efficient, and can effectively avoid the use of explosive hazardous chemicals such as sodium borohydride and the like.