For example, organic Process Research & Development, 24 (5), 713-723, 2020 takes benzothiophene-3-methylene bromide as raw material and reacts with carbon monoxide under pressure under the catalysis of palladium hydroxide to prepare benzothiophene-3-acetic acid with the yield of 54%.

The literature Chemical Science, 9 (21), 4873-4878, 2018, uses benzothiophene-3-formaldehyde as a starting material to react with hydrazine hydrate to form hydrazone, and then the benzothiophene-3-acetic acid is prepared by carbon dioxide reaction.

Patent WO2002016353 directly takes benzothiophene-3-acetonitrile as a raw material, and obtains benzothiophene-3-acetic acid by alkaline hydrolysis, and the yield is not mentioned.

In the method, the method (1) needs to undergo 4 steps of reaction, and has long route and complicated operation. The starting material, thiophenol, is a malodorous liquid which is very unpleasant to use.

Scheme (2), organic Process Research & Development, 24 (5), 713-723; 2020 requires the use of a noble metal based catalyst, palladium hydroxide, which is costly. High-pressure equipment is required for pressurizing carbon monoxide, and the conditions are harsh; benzothiophene-3-carbaldehyde, a raw material used in Chemical Science, 9 (21), 4873-4878; 2018, is expensive and not easily available; the patent WO2002016353 is the simplest, but does not mention the preparation of the used common raw material benzothiophene-3-acetonitrile, and the yield data of the reaction is lacked.

Disclosure of Invention

The invention aims to solve the technical problem of overcoming the defects in the prior art, and provides a synthetic method of benzothiophene-3-acetic acid, which is characterized in that on the basis of the patent WO2002016353, benzothiophene which is easily purchased in the market is adopted as an initial raw material, and the required compound benzothiophene-3-acetic acid is prepared through three steps of reactions of chloromethylation, cyano substitution and hydrolysis.

In order to solve the technical problems, the invention adopts the technical scheme that: a synthetic method of benzothiophene-3-acetic acid comprises the following steps:

the method comprises the following steps:

s1, taking a compound 1 as a raw material, dissolving the compound in a solvent, completing a chloromethylation process by using hydrochloric acid and paraformaldehyde at 15-20 ℃, and processing the obtained reaction solution after the reaction is finished to obtain a concentrated solution which is neutral and contains acompound 2;

s2, placing the concentrated solution obtained in the S1 in an aprotic polar solvent to complete cyano substitution with a cyaniding reagent, and extracting and purifying to obtain a compound 3;

s3: carrying out alkaline hydrolysis on the compound 3 obtained in the S2 to obtain a compound 4;

wherein the compound 1 is benzothiophene, the compound 3 is benzothiophene-3-acetonitrile, and the compound 4 is benzothiophene-3-acetic acid.

Further, acetic acid is selected as a solvent in the S1, and the dosage of the acetic acid is 1.2-1.5 times of the volume of the benzothiophene; the S1 also comprises a catalyst, and the dosage of the catalyst is 1.2 to 1.5 times of the molar weight of the benzothiophene.

Furthermore, the dosage of the hydrochloric acid is 7-8 times of the molar quantity of the benzothiophene, and the dosage of the paraformaldehyde is 4-5 times of the molar quantity of the benzothiophene.

Further, the processing process specifically comprises the following steps: diluting the obtained reaction liquid after the reaction is finished, standing and layering to obtain an organic phase, extracting the water phase by using a chloroalkane extractant to obtain an organic phase, combining the organic phases, washing the organic phases by using a sodium bicarbonate solution until the organic phases tend to be neutral, and drying the organic phases by using an acidic or neutral drying agent; the chloralkane extractant is any one of dichloroethane, dichloromethane and chloroform; the acidic or alkaline drying agent is any one of anhydrous sodium sulphate, magnesium sulfate and calcium chloride.

Further, the drying agent in the organic phase is filtered off and the extractant is recovered by distillation under reduced pressure to obtain a concentrated solution which tends to be neutral and contains thecompound 2.

Further, the aprotic polar solvent is any one of DMF, DMAC and DMSO, and the volume amount of the aprotic polar solvent is 1.0-1.2 times of the weight of the concentrated solution; the cyaniding reagent is any one of cuprous cyanide, sodium cyanide, potassium cyanide and cyanogen bromide; the reaction process is carried out for 2h at the temperature of 90-95 ℃.

Further, the purification process comprises suction filtration, extraction, drying and solid precipitation, wherein a fat-soluble solvent is selected as an extracting agent in the extraction process, and the fat-soluble solvent comprises ethyl acetate, toluene and xylene; and selecting a neutral drying agent in the drying process, wherein the neutral drying agent comprises anhydrous sodium sulphate and magnesium sulfate.

Compared with the prior art, the invention has the beneficial effects that: the synthetic route is short, the used raw materials are common chemicals with common prices, the equipment is simple, the reaction condition is mild, and the method is suitable for small-batch industrial synthesis.

Drawings

The disclosure of the present invention is illustrated with reference to the accompanying drawings. It is to be understood that the drawings are designed solely for the purposes of illustration and not as a definition of the limits of the invention. In the drawings, like reference numerals are used to refer to like parts. Wherein:

FIG. 1 schematically shows the nuclear magnetic hydrogen spectrum of benzothiophene-3-acetic acid obtained after alkaline hydrolysis.

Detailed Description

It is easily understood that according to the technical solution of the present invention, a person skilled in the art can propose various alternative structures and implementation ways without changing the spirit of the present invention. Therefore, the following detailed description and the accompanying drawings are merely illustrative of the technical aspects of the present invention, and should not be construed as all of the present invention or as limitations or limitations on the technical aspects of the present invention.

A synthetic method of benzothiophene-3-acetic acid comprises the following steps:

the method comprises the following steps:

The following description will be given with reference to specific examples.

Chloromethylation

250ml of hydrochloric acid and 45ml of 85% phosphoric acid are added into a 1000ml reaction bottle, the temperature of the saline is reduced to 15 ℃ after stirring, and 50g of paraformaldehyde is added. Beginning to drop solution prepared by 50g of benzothiophene and 60ml of acetic acid, wherein the acetic acid is used as a solvent, the volume consumption of the acetic acid is 1.2-1.5 times of that of the benzothiophene, and the temperature is controlled at 15-20 ℃ in the dropping process. In order to achieve the best possible chloromethylation, hydrochloric acid and paraformaldehyde have to be fed in excess. Feeding molar ratio, benzothiophene: paraformaldehyde: hydrochloric acid: phosphoric acid = 1:4-5:7-8. After the dropwise addition, the temperature was maintained overnight.

The next day, the solution was diluted with about 200ml of water at 0-5 ℃ in an ice-water bath, the amount of water used for dilution was typically 4-5 times the weight of benzothiophene, and a slight exotherm occurred during dilution. Stirring for several minutes, filtering, standing the filtrate, separating out a lower organic phase, extracting an upper aqueous phase for 2 times by using dichloroethane, or replacing by using a chlorinated alkane extracting agent such as dichloromethane or chloroform, combining the organic phases, adding a sodium bicarbonate solution, washing until the organic phase tends to be neutral (taking attention to bubbles), collecting the organic phase, drying anhydrous sodium sulphate overnight, or replacing the anhydrous sodium sulphate by using an acidic or neutral drying agent such as magnesium sulphate, calcium chloride and the like. The next day, the drying agent is filtered, and the dichloroethane is recovered by reduced pressure distillation to obtain a concentrated solution 72g (with a little solvent residue), which is not required to be purified and enters the next reaction.

Cyano substitution

72g of the concentrated solution, 42g of cuprous cyanide and 80ml of DMF are added into a 500ml reaction bottle, the cyaniding reagent can be replaced by cyaniding reagents such as sodium cyanide, potassium cyanide and cyanogen bromide, the dosage of the cyaniding reagent is generally excessive by 10-20% to ensure the complete reaction, the DMF can also be replaced by aprotic polar solvents such as DMAC and DMSO, and the volume dosage of the aprotic polar solvents is generally 1.0-1.2 times of the weight of the raw material liquid. After stirring, the temperature is raised to 90-95 ℃ in an oil bath for 2 hours of reaction. Suction filtration and rinsing of the filter cake with ethyl acetate. The filtrate and the washing liquid are combined and poured into 250ml of water to be stirred. Extracting with ethyl acetate for 3 times, wherein the ethyl acetate can be replaced by toluene, xylene and other fat-soluble solvents, combining extract liquor, washing with water, washing with saturated saline water, drying anhydrous sodium sulphate overnight, filtering out a drying agent the next day, carrying out reduced pressure distillation to recover most of ethyl acetate, standing the rest liquid, cooling, separating out a solid, carrying out suction filtration, and drying to obtain 52.3g of benzothiophene-3-acetonitrile, wherein the total yield of the two steps is 81%.

Alkaline hydrolysis

52.3g of benzothiophene-3-acetonitrile prepared in the above, 150ml of water and 16g of sodium hydroxide are added into a 250ml reaction bottle, wherein the volume consumption of the water is 2.5-3.0 times of the weight of the benzothiophene-3-acetonitrile, the sodium hydroxide can be replaced by caustic alkali such as potassium hydroxide, lithium hydroxide and the like, and the molar consumption of the sodium hydroxide is 1.2-1.3 times of the benzothiophene-3-acetonitrile, namely, the excess is 20-30%. After stirring, the oil bath was heated to reflux for 1 hour. Cooling, filtering to remove mechanical impurities, adjusting pH of the filtrate with hydrochloric acid =1-2, and precipitating solid. After room temperature, the mixture is filtered, washed and dried to obtain 55.7g of benzothiophene-3-acetic acid as white powder with the melting point of 110-111 ℃ and the hydrolysis yield of 96 percent. The nuclear magnetic hydrogen spectrum is shown in fig. 1 below.

The technical scope of the present invention is not limited to the above description, and those skilled in the art can make various changes and modifications to the above-described embodiments without departing from the technical spirit of the present invention, and such changes and modifications should fall within the protective scope of the present invention.

Claims

1. The synthetic method of benzothiophene-3-acetic acid is characterized in that the synthetic route is as follows:

the method comprises the following steps:

s1, chloromethylation

Adding 250ml of hydrochloric acid and 45ml of 85% phosphoric acid into a 1000ml reaction bottle, stirring, cooling the saline to 15 ℃, and adding 50g of paraformaldehyde; beginning to dropwise add a solution prepared from 50g of benzothiophene and 60ml of acetic acid, wherein the acetic acid is used as a solvent, and the temperature is controlled at 15-20 ℃ in the dropwise adding process; after the dropwise addition, keeping the temperature overnight;

the next day, about 200ml of water is added for dilution at 0-5 ℃ under the cooling of ice water bath, and the slight heat release condition occurs in the dilution process; stirring for several minutes, performing suction filtration, standing the filtrate, separating a lower organic phase, extracting an upper aqueous phase for 2 times by using dichloroethane, combining the organic phases, adding a sodium bicarbonate solution, washing until the organic phase is neutral, collecting the organic phase, and drying anhydrous sodium sulphate overnight; on the next day, filtering out the drying agent, and carrying out reduced pressure distillation to recover dichloroethane, wherein the concentrated solution is not required to be purified and then enters the next step of reaction;

s2, cyano substitution

Adding the 72g of concentrated solution, 42g of cuprous cyanide and 80ml of DMF into a 500ml reaction bottle; after stirring, heating in oil bath to 90-95 ℃ for reaction for 2 hours; performing suction filtration, and rinsing a filter cake by using ethyl acetate; mixing the filtrate and the washing liquid, pouring into 250ml of water and stirring; extracting with ethyl acetate for 3 times, mixing extractive solutions, washing with water, washing with saturated saline water, drying anhydrous sodium sulphate overnight, filtering to remove desiccant, distilling under reduced pressure to recover most of ethyl acetate, standing the rest liquid, cooling, precipitating solid, vacuum filtering, and oven drying to obtain benzothiophene-3-acetonitrile;

s3, alkaline hydrolysis

52.3g of benzothiophene-3-acetonitrile prepared above, 150ml of water and 16g of sodium hydroxide were added to a 250ml reaction flask; after stirring, heating in oil bath and refluxing for 1 hour; cooling, filtering to remove mechanical impurities, adjusting pH of the filtrate to =1-2 with hydrochloric acid, and separating out solids; and (4) carrying out suction filtration, washing and drying at room temperature to obtain benzothiophene-3-acetic acid.