阅读说明：本技术 一种苯并硫杂环戊二烯新合成方法 (Novel synthesis method of benzothiepiene ) 是由 刘碧见 于 2020-04-30 设计创作，主要内容包括：本发明公开了一种苯并硫杂环戊二烯的新合成方法,属于合成技术领域。该方法步骤为：在碱性条件下,氯乙醛与苯硫酚发生威廉姆逊(williamson)缩合反应得到苯硫基乙醛,苯硫基乙醛在酸性条件下,由脱水剂进行环合和脱水反应后,加水,分层,取有机层,减压蒸馏得目标产物苯并硫杂环戊二烯；本发明方法操作简单,反应温和,极易实现工业化,且产物收率高。(The invention discloses a new synthesis method of benzothiophene, belonging to the technical field of synthesis. The method comprises the following steps: under the alkaline condition, chloroacetaldehyde and thiophenol are subjected to Williamson condensation reaction to obtain thiophenyl acetaldehyde, under the acidic condition, the thiophenyl acetaldehyde is subjected to cyclization and dehydration reaction by a dehydrating agent, water is added, layering is carried out, an organic layer is taken, and reduced pressure distillation is carried out to obtain a target product, namely benzothiophene; the method has the advantages of simple operation, mild reaction, easy realization of industrialization and high product yield.)

1. A new method for synthesizing benzothiophene is characterized by comprising the following steps:

(1) adding alkali into a solvent, then controlling the temperature to be 0-30 ℃, adding chloroacetaldehyde, neutralizing excessive hydrochloric acid in chloroacetaldehyde, and directly using for the next step of synthesis without treatment after the neutralization reaction is finished;

(2) controlling the temperature to be 20-25 ℃, adding thiophenol with a general formula II into the reaction liquid in the last step, and then heating to 60-70 ℃ to carry out Williamson condensation reaction to obtain thiophenyl acetaldehyde;

(3) adding an acid catalyst and a dehydrating agent into a solvent, heating to 100-200 ℃, dropwise adding the synthesized phenylthioacetaldehyde, carrying out cyclization and dehydration reaction, cooling to 40-60 ℃, adding water into the reaction liquid, layering, taking an organic layer, and carrying out reduced pressure distillation to obtain the target product, namely the benzothiepiene.

In the formula (I), R₁Is H, C₁～C₄Any one of alkyl, alkoxy, chlorine, bromine, fluorine and iodine.

2. The new synthesis method of benzothiepipentadiene as claimed in claim 1, wherein the solvent in step (1) is any one of toluene, ethylbenzene, cumene, chlorobenzene, xylene, diethylbenzene and 4-methylchlorobenzene.

3. The new synthesis method of benzothiepipentadiene as claimed in claim 1, wherein the base in step (1) is any one or more of sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate and calcium bicarbonate.

4. The new synthesis method of benzothiepipentadiene as claimed in claim 1, wherein the neutralization reaction temperature in step (1) is 15-25 ℃.

5. The new method for synthesizing benzothiepipentadiene according to claim 1, wherein the concentration of chloroacetaldehyde in step (1) is 10-40%.

6. The new method for synthesizing benzothiepipentadiene according to claim 5, wherein the concentration of chloroacetaldehyde in step (1) is 10-20%.

7. The new synthesis method of benzothiepipentadiene as claimed in claim 1, wherein the molar ratio of thiophenol to chloroacetaldehyde in step (2) is 1 (1.1-2).

8. The new synthesis method of benzothiepipentadiene as claimed in claim 7, wherein the molar ratio of thiophenol to chloroacetaldehyde in step (2) is 1 (1.2-1.4).

9. The new method for synthesizing benzothiepienes according to claim 1, wherein the acidic catalyst in step (3) is any one or a mixture of acetic acid, 4-methylbenzenesulfonic acid, methanesulfonic acid, polyphosphoric acid and trifluoromethyl acetic acid.

10. The novel process for the synthesis of benzothiepienes according to claim 1, wherein in step (3) the dehydrating agent is phosphorus pentoxide or DCC (dicyclohexyldiimine).

11. The new synthesis method of benzothiepipentadiene as claimed in claim 1, wherein the temperature of the cyclization and dehydration reaction in step (3) is 120-140 ℃.

12. The new synthesis method of benzothiepienes according to claim 1, wherein the molar ratio of thiophenol to dehydrating agent in step (3) is 1 (0.6-3).

13. The new synthesis method of benzothiepienes according to claim 12, wherein the molar ratio of thiophenol to dehydrating agent in step (3) is 1 (0.8-1.5).

Technical Field

The invention relates to a new synthesis method of benzothiophene, belonging to the technical field of organic synthesis.

Background

This patent relates to the field of medicinal chemistry and provides methods for the synthesis of benzothiophenes and substituted benzothiophene compounds.

At present, few methods for synthesizing benzothiepidine at home and abroad are reported, and industrial production is mostly difficult to realize, for example, JACSVO L69 (2008) -2009) provides a method for synthesizing benzothiepidine by using iron sulfide and aluminum oxide as catalysts and using hydrogen sulfide and styrene at 600 ℃, wherein the conversion rate is 60%, the method can be used for synthesizing target products, but the reaction conditions are harsh and difficult to industrialize, CN103717587A provides a method for synthesizing substituted benzothiepidine by using substituted benzaldehyde and methyl thioglycolate as raw materials, but the method has the defects of high reaction temperature during cyclization and difficult post-treatment and is difficult to industrialize, and CN105294785A discloses C-benzo five-membered heteroaromatic ring aryl glucoside derivatives and a preparation method and application thereof, and provides a method for synthesizing benzothiepidine by using thiophenol and bromoacetaldehyde diethyl acetal, wherein the bromoacetaldehyde diethyl acetal is expensive and low in yield and is not suitable for industrial production.

Therefore, a new method for synthesizing benzothiophene, which is simple to operate, mild in reaction conditions and easy to industrialize, is needed.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides a novel synthesis method of benzothiophene, which has mild reaction conditions, simple operation and easy realization of industrialization.

The structural formula of the synthesized benzothiophene is shown as the formula (I)

In the formula (I), R₁Is H, C₁～C₄Any one of alkyl, alkoxy, chlorine, bromine, fluorine and iodine.

In order to achieve the technical purpose, the technical scheme of the invention is as follows:

a new method for synthesizing benzothiophene comprises the following steps:

(1) adding alkali into a solvent, then controlling the temperature to be 0-30 ℃, adding chloroacetaldehyde, neutralizing excessive hydrochloric acid in chloroacetaldehyde, and directly using for the next step of synthesis without treatment after the neutralization reaction is finished;

(2) controlling the temperature to be 20-25 ℃, adding thiophenol into the reaction liquid in the last step, and then heating to 60-70 ℃ to carry out Williamson condensation reaction to obtain thiophenyl acetaldehyde;

(3) adding an acid catalyst and a dehydrating agent into a solvent, heating to 100-200 ℃, dropwise adding the synthesized phenylthioacetaldehyde, carrying out cyclization and dehydration reaction, cooling to 40-60 ℃, adding water into the reaction liquid, layering, taking an organic layer, and carrying out reduced pressure distillation to obtain the target product, namely the benzothiepiene.

In the formula (I), R₁Is H, C₁～C₄Any one of alkyl, alkoxy, chlorine, bromine, fluorine and iodine.

The synthesis reaction related by the invention is shown as formula III:

preferably, the solvent in step (1) is any one of toluene, ethylbenzene, cumene, chlorobenzene, xylene, diethylbenzene and 4-methyl chlorobenzene.

Preferably, the alkali in the step (1) is any one or a mixture of any several of sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate and calcium bicarbonate.

Preferably, the neutralization reaction temperature in the step (1) is 15-25 ℃.

Preferably, the concentration of the chloroacetaldehyde in the step (1) is 10-40%.

Further preferably, the concentration of chloroacetaldehyde in step (1) is 10% to 20%.

Preferably, the molar ratio of the thiophenol to the chloroacetaldehyde in the step (2) is 1 (1.1-2).

Preferably, the molar ratio of the thiophenol to the chloroacetaldehyde in the step (2) is 1 (1.2-1.4).

Preferably, the acidic catalyst in step (3) is any one or a mixture of any more of acetic acid, 4-methyl benzenesulfonic acid, methanesulfonic acid, polyphosphoric acid and trifluoromethyl acetic acid.

Preferably, the dehydrating agent in step (3) is phosphorus pentoxide or DCC (dicyclohexyldiimine).

Preferably, the temperature of the cyclization and dehydration reaction in the step (3) is 120-140 ℃.

Preferably, the molar ratio of the thiophenol to the dehydrating agent in the step (3) is 1 (0.6-3).

Further preferably, the molar ratio of the thiophenol to the dehydrating agent in the step (3) is 1 (0.8-1.5).

As can be seen from the above description, the present invention has the following advantageous effects:

1. the method has the advantages of wide sources of the adopted reaction raw materials, low price, mild reaction conditions, simple operation, easy realization of industrialization and high product yield.

2. The alkali adopted by the method has the effect of neutralizing chloroacetaldehyde and hydrogen chloride generated in the williamson condensation reaction, so that the yield and the content of the product are improved.

Detailed Description

The features of the invention will be further elucidated by the following examples, without limiting the claims of the invention in any way.