阅读说明：本技术 一种2-噻吩乙酰氯的制备方法 (Preparation method of 2-thiopheneacetyl chloride ) 是由 郭启双 刘静 张明 郭万宝 王利宝 于 2020-05-29 设计创作，主要内容包括：本发明公开了一种2-噻吩乙酰氯的制备方法,属于化工合成技术领域。所述制备方法包括：(1)将2-噻吩乙醇溶解在有机溶剂中,在固体酸催化剂、碱和氧化剂的作用下,在50～120℃下反应制得2-噻吩乙酸；所述氧化剂为氧气或双氧水；(2)将2-噻吩乙酸溶解在有机溶剂中,以碱性离子液体为催化剂,滴加氯化亚砜进行酰氯化反应,制得2-噻吩乙酰氯。本发明制备工艺路线简洁,原料易得,反应条件温和,在2-噻吩乙酸合成中采用氧气或者双氧水做氧化剂,副产物少,易于纯化分离；在进行2-噻吩乙酸的酰氯化反应时,采用了碱性离子液体作为催化剂,反应过程平稳,易于控制,产物收率高,副产物少,是一种高效绿色的合成工艺。(The invention discloses a preparation method of 2-thiophene acetyl chloride, belonging to the technical field of chemical synthesis. The preparation method comprises the following steps: (1) dissolving 2-thiophene ethanol in an organic solvent, and reacting at 50-120 ℃ under the action of a solid acid catalyst, alkali and an oxidant to prepare 2-thiophene acetic acid; the oxidant is oxygen or hydrogen peroxide; (2) dissolving 2-thiopheneacetic acid in an organic solvent, taking an alkaline ionic liquid as a catalyst, and dropwise adding thionyl chloride to carry out acyl chlorination reaction to prepare 2-thiopheneacetyl chloride. The preparation process has the advantages of simple route, easily obtained raw materials, mild reaction conditions, less by-products and easy purification and separation, and oxygen or hydrogen peroxide is used as an oxidant in the synthesis of 2-thiopheneacetic acid; in the acyl chlorination reaction of 2-thiopheneacetic acid, the alkaline ionic liquid is used as the catalyst, the reaction process is stable and easy to control, the product yield is high, the byproducts are few, and the method is an efficient green synthesis process.)

1. The preparation method of 2-thiopheneacetyl chloride is characterized by comprising the following steps:

(1) dissolving 2-thiophene ethanol in an organic solvent, and reacting at 50-120 ℃ under the action of a solid acid catalyst, a cocatalyst and an oxidant to prepare 2-thiophene acetic acid;

the cocatalyst is inorganic base or organic base;

the oxidant is oxygen or hydrogen peroxide;

(2) dissolving 2-thiopheneacetic acid in an organic solvent, taking an alkaline ionic liquid as a catalyst, and dropwise adding thionyl chloride to carry out acyl chlorination reaction to prepare 2-thiopheneacetyl chloride.

2. The method for preparing 2-thiopheneacetyl chloride of claim 1 wherein in step (1), the organic solvent is at least one of diisopropyl ether, methyl tert-butyl ether, methyl N-butyl ether, anisole, ethyl N-butyl ether, cyclopentyl methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, acetonitrile, N-dimethylformamide, dimethylsulfoxide; the addition ratio of the 2-thiophene ethanol to the organic solvent is 0.1-10 mol: 1L of the compound.

3. The method of claim 1, wherein in step (1), the solid acid catalyst is phosphotungstic acid, bentonite, alumina, zirconia, titania, SiO₂-Al₂O₃、ZrO₂-SiO₂Natural zeolite, X-type ZSM-5 or Y-type ZSM-5; the dosage of the solid acid catalyst is 1 to 10 percent of the mass of the 2-thiophene ethanol.

4. The method for preparing 2-thiopheneacetyl chloride of claim 1 wherein in step (1), the cocatalyst is sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, triethylamine, diethylamine, tetraethylammonium hydroxide, sodium hydroxide, potassium hydroxide, pyridine or quinoline; the molar ratio of the cocatalyst to the 2-thiopheneethanol is 0.2-3: 1.

5. The method for preparing 2-thiopheneacetyl chloride of claim 1 wherein in step (1), the molar ratio of the oxidizing agent to 2-thiopheneethanol is 2-3: 1.

6. The method of claim 1, wherein step (1) further comprises: after the reaction is finished, the reaction solution is purified by concentration, column chromatography, recrystallization or reduced pressure distillation.

7. The method for preparing 2-thiopheneacetyl chloride of claim 1 wherein in step (2), said basic ionic liquid is butyl-3-methylimidazole hydroxide, bis- (3-methyl-1-imidazole) ethylene hydroxide, bis N- (2-diethylamino) ethylbisimidazole hydroxide salt; the mass ratio of the alkaline ionic liquid to the 2-thiopheneacetic acid is 0.05-10%.

8. The method for preparing 2-thiopheneacetyl chloride according to claim 1, wherein in the step (2), the molar ratio of thionyl chloride to 2-thiopheneacetic acid is 1.5 to 2:1, and the time for adding thionyl chloride is controlled to be 1 to 4 hours.

9. The method for preparing 2-thiopheneacetyl chloride of claim 1 wherein in step (2), the temperature of the acylchlorination reaction is 0 to 60 ℃ and the time is 2 to 8 hours.

10. The method for preparing 2-thiopheneacetyl chloride as claimed in claim 1 or 9, wherein in the step (2), after the completion of the acylation reaction, the reaction solution is purified by distillation under reduced pressure, and the fraction at 120 ℃ under 10mmHg is collected as 2-thiopheneacetyl chloride.

Technical Field

The invention relates to the technical field of organic synthesis of pharmaceutical and chemical intermediates, in particular to a high-efficiency green synthesis method of 2-thiopheneacetyl chloride.

Background

Thiophene derivatives are widely used in synthetic medicines, pesticides, dyes, chemical reagents, polymer auxiliaries and the like. The antibiotic with thiophene ring has better curative effect than phenyl homologue, and some new anti-inflammatory analgesic drugs, such as more than 10 anti-inflammatory analgesic drugs with obvious curative effect, such as p-hydroxyephedrine, sulindac, tiaprofenic acid, pizotifen, sufentanil and the like, are thiophene derivatives. The thiophene derivative can also be used for synthesizing hundreds of medicaments such as spasmolytic drug of tiquinaldium bromide, anthelmintic of ethidium pyridine, anticholinergic drug of cyclohexylcarbinol, diuretic drug of azlotimide, chlorine pyrrole, anticholinergic drug of thiapiprazole, and the like.

2-thiopheneacetic acid and 2-thiopheneacetyl chloride are mainly used for synthesizing more than 20 antibiotics such as cephalosporin I, cephalosporin II, cefoxitin, cephalotriazole, cefditoren and the like, and also used for synthesizing various medical products such as cardiovascular drugs, hypolipidemic drugs, antiulcer drugs, platelet aggregation inhibitors, cardiovascular relaxants, 5-lipoxygenase inhibitors and the like.

The 2-thiopheneacetic acid and 2-thiopheneacetyl chloride are important intermediates for synthesizing cephalothin and cefoxitin, and the synthesis reaction is generally carried out by 3 steps, namely ① acetylation of thiophene by acetic anhydride, ② amidation by ammonia water, ③ hydrolysis by acid to obtain product 2-thiopheneacetic acid, which is the most classical and commonly used method for preparing 2-thiopheneacetic acid₃/Et₂O、I₂/HI、85％H₃PO₄Molten ZnCl₂And AlCl₃And the like. Although the catalysts have high activity, the selectivity is not ideal, the content of 3-position isomer reaches 0.5-2.0 percent and cannot meet the requirements of users, and the catalysts have strong corrosivity and toxicity and can cause a series of problems of equipment corrosion, difficult product aftertreatment, environmental pollution and the like.

Most of the existing processes of 2-thiopheneacetic acid have the problems of high production cost and serious pollution, so that a new production process is necessary to be searched. For this reason, researchers have made improvements to the synthetic route, or to the catalyst performance. Although the rearrangement production process is greatly improved compared with the prior rearrangement production process, the complicated synthesis route, the use of noble metal catalysts and highly toxic cyanide increase the production cost and limit the large-scale production of the 2-thiopheneacetic acid. It is necessary to seek new processes with lower cost and cleaner production process in today with increasingly competitive.

The 2-thiopheneacetic acid can be directly used for synthesizing cephalothin, the amidation reaction of carboxylic acid and primary amine is utilized, the process has strict requirements, the requirements on a solvent, a catalyst and temperature are high, more byproducts are generated, and the separation is difficult. Compared with the prior art, the 2-thiophene acetyl chloride has better activity, can realize high-efficiency reaction with primary amine at lower temperature, has high reaction speed and high yield, and is a more effective intermediate.

The oxidation method for oxidizing 2-thiopheneethanol is a simple and convenient and rapid method for preparing 2-thiopheneacetic acid, when the 2-thiopheneacetic acid is oxidized to obtain the 2-thiopheneacetic acid, 3-thiopheneacetic acid isomer impurities are not generated, the product purity is high, and after subsequent acyl chlorination, the 3-thiopheneacetyl chloride impurities are not contained. In the prior report, strong oxidants such as sodium hypochlorite and sodium chlorite are directly adopted to oxidize 2-thiophene ethanol, but the 2-thiophene ethanol is easily degraded; weaker oxidants such as hydrogen peroxide and oxygen are directly adopted, and the target product yield is low.

For the 2-thiophene acetic acid acyl chlorination reaction, the literature mostly uses thionyl chloride as an acyl chlorinating agent, and uses organic or inorganic base as a catalyst to synthesize 2-thiophene acetyl chloride, and because the reaction process is fast and difficult to control, impurities are easy to generate.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a simple, green and efficient synthesis method of 2-thiophene acetyl chloride, which is suitable for industrial production.

The technical scheme of the invention is as follows:

a preparation method of 2-thiopheneacetyl chloride comprises the following steps:

(1) dissolving 2-thiophene ethanol in an organic solvent, and reacting at 50-120 ℃ under the action of a solid acid catalyst, a cocatalyst and an oxidant to prepare 2-thiophene acetic acid;

the cocatalyst is inorganic base or organic base;

the oxidant is oxygen or hydrogen peroxide;

(2) dissolving 2-thiopheneacetic acid in an organic solvent, taking an alkaline ionic liquid as a catalyst, and dropwise adding thionyl chloride to carry out acyl chlorination reaction to prepare 2-thiopheneacetyl chloride.

In the step (1), oxygen or hydrogen peroxide with weak oxidizability is used as an oxidant for the 2-thiophene ethanol oxidation reaction, the reaction condition is mild, and the yield of the target product of the oxidation reaction is obviously improved under the combined action of a solid acid catalyst and an alkali compound.

Specifically, 2-thiopheneethanol is dissolved in an organic solvent, stirred and heated to the reaction temperature, then a solid acid catalyst, a cocatalyst and an oxidant are added, and oxidation reaction is carried out under the stirring condition.

In the step (1), the organic solvent is at least one of diisopropyl ether, methyl tert-butyl ether, methyl N-butyl ether, anisole, ethyl N-butyl ether, cyclopentyl methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, acetonitrile, N-dimethylformamide and dimethyl sulfoxide. The addition ratio of the 2-thiophene ethanol to the organic solvent is 0.1-10 mol: 1L, preferably, the addition ratio is 0.2mol to 6 mol: 1L of the compound.

Preferably, the solid acid catalyst is phosphotungstic acid, bentonite, alumina, zirconia, titania, SiO₂-Al₂O₃、ZrO₂-SiO₂Natural zeolite, X-type ZSM-5 or Y-type ZSM-5. The dosage of the solid acid catalyst is 1 to 10 percent of the mass of the 2-thiophene ethanol.

Preferably, the cocatalyst is sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, triethylamine, diethylamine, tetraethylammonium hydroxide, sodium hydroxide, potassium hydroxide, pyridine or quinoline. The molar ratio of the cocatalyst to the 2-thiopheneethanol is 0.2-3: 1. Preferably, the molar ratio of the cocatalyst to the 2-thiopheneethanol is 0.5-2: 1.

The molar ratio of the oxidant to the 2-thiopheneethanol is 2-3: 1. When oxygen is used as an oxidant, dry oxygen is continuously introduced into the reaction system, and the reaction is carried out while stirring, wherein the introducing time is controlled to be 5-6 hours. Air can also be directly introduced.

Preferably, the oxidation reaction conditions are: reacting for 8-12 h at 60-100 ℃.

In the step (1), after the oxidation reaction is finished, the reaction solution is subjected to concentration, column chromatography, recrystallization or reduced pressure distillation purification.

In the step (2), the 2-thiopheneacetic acid prepared in the step (1) is dissolved in an organic solvent, thionyl chloride is dripped to carry out acyl chlorination reaction, and the alkaline ionic liquid adopted by the invention is used as a catalyst of the 2-thiopheneacetic acid acyl chlorination reaction, so that the reaction rate can be effectively controlled, the selectivity of the product is improved, and byproducts are reduced.

The organic solvent is dichloromethane, trichloromethane, tetrachloromethane or tetrachloroethylene. The addition ratio of the 2-thiopheneacetic acid to the organic solvent is 0.1 mol-10 mol: 1L, preferably, the addition ratio is 0.5mol to 5 mol: 1L of the compound.

Preferably, the basic ionic liquid is butyl-3-methylimidazole hydroxide, bis- (3-methyl-1-imidazole) ethylene hydroxide, bis N- (2-diethylamino) ethylbisimidazole hydroxide salt. The mass ratio of the alkaline ionic liquid to the 2-thiopheneacetic acid is 0.05-10%, preferably 0.05-2%.

In the step (2), thionyl chloride is dropwise added under the stirring condition, the molar ratio of the thionyl chloride to the 2-thiopheneacetic acid is 1.5-2: 1, and the dropwise adding time of the thionyl chloride is controlled to be 1-4 hours.

The acyl chlorination reaction temperature is 0-60 ℃, and the time is 2-8 h. Preferably, the reaction temperature is 0-10 ℃.

After the acylation and chlorination reaction is finished, the reaction solution is purified by reduced pressure distillation, and the fraction at the temperature of 116 ℃ and 120 ℃ under the condition of 10mmHg is collected, namely the 2-thiopheneacetyl chloride.

The invention has the following beneficial effects:

the preparation process has the advantages of simple route, easily obtained raw materials, mild reaction conditions, avoidance of using a strong oxidant in the synthesis of 2-thiopheneacetic acid, direct use of oxygen or hydrogen peroxide in the air as the oxidant, few by-products in the product, easy purification and separation, and suitability for industrial production; in the acyl chlorination reaction of 2-thiopheneacetic acid, the alkaline ionic liquid is used as the catalyst, the reaction process is stable and easy to control, the product yield is high, the byproducts are few, and the method is an efficient green synthesis process.

Detailed Description

The invention is further illustrated by the following specific examples, which do not limit the scope of the invention.

In the following examples, each raw material was purchased from the market.