CN113896709A - Synthetic method of benzothiophene-3-acetic acid - Google Patents
Synthetic method of benzothiophene-3-acetic acid Download PDFInfo
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- CN113896709A CN113896709A CN202111388715.5A CN202111388715A CN113896709A CN 113896709 A CN113896709 A CN 113896709A CN 202111388715 A CN202111388715 A CN 202111388715A CN 113896709 A CN113896709 A CN 113896709A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The invention provides a synthetic method of benzothiophene-3-acetic acid, which comprises the following steps: s1, dissolving the compound 1 in a solvent, completing a chloromethylation process by 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 the compound 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: basic hydrolysis of the compound 3 obtained in 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. The method has the advantages of short synthetic route, simple equipment and mild reaction conditions, and the used raw materials are common chemicals with common prices, and are suitable for small-batch industrial synthesis.
Description
Technical Field
The invention relates to a synthetic method of benzothiophene-3-acetic acid.
Background
The compound benzothiophene-3-acetic acid was used as an important organic synthesis fragment, CAS: 1131-09-5. Is often used in chemical research and drug synthesis. Because the dosage is not large, no factory mass production exists in the market. The user often needs to compose himself. Through the research of pen workers, the preparation methods of benzothiophene-3-acetic acid reported in the literature are mainly divided into two main categories.
The scheme is that benzothiophene-3-ethyl acetate is obtained by cyclization from thiophenol, and benzothiophene-3-acetic acid (Pharma Chemica,9(19), 85-90; 2017) is prepared by alkaline hydrolysis
Scheme II, benzothiophene-3-substituent is used as raw material
Such as Organic Process Research & Development,24(5), 713-; 2020 taking benzothiophene-3-methylene bromide as a raw material, carrying out a pressure reaction with carbon monoxide under the catalysis of palladium hydroxide to obtain benzothiophene-3-acetic acid, wherein the yield is 54%.
Literature Chemical Science,9(21), 4873-; 2018, using benzothiophene-3-formaldehyde as a starting material, reacting the benzothiophene-3-formaldehyde with hydrazine hydrate to form hydrazone, and reacting the hydrazone with carbon dioxide to obtain benzothiophene-3-acetic acid.
In WO2002016353, benzothiophene-3-acetic acid is obtained by alkaline hydrolysis of benzothiophene-3-acetonitrile as a raw material, and the yield is not mentioned.
In the method, the first method needs 4 steps of reaction, the route is long, and the operation is complicated. The starting material, thiophenol, is a malodorous liquid which is very unpleasant to use.
Scheme II, Organic Process Research & Development,24(5), 713-; 2020 requires the use of palladium hydroxide as a noble metal catalyst, which is expensive. High-pressure equipment is needed for pressurizing carbon monoxide, and the conditions are harsh; chemical Science,9(21), 4873-; 2018, the used raw material benzothiophene-3-formaldehyde is high in price and is not easy to obtain; 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 overcome 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 taken as an initial raw material, and the required compound benzothiophene-3-acetic acid is prepared through three steps 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, dissolving the compound 1 in a solvent, completing a chloromethylation process by 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 the compound 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: basic hydrolysis of the compound 3 obtained in 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 S1, and the dosage of the acetic acid is 1.2-1.5 times of the volume of the benzothiophene; in S1, a catalyst is also included, the amount of catalyst used being 1.2 to 1.5 times the molar amount of 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 the compound 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.
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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:
s1, dissolving the compound 1 in a solvent, completing a chloromethylation process by 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 the compound 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: basic hydrolysis of the compound 3 obtained in 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.
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: 1.2-1.5. 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 was filtered off, and dichloroethane was recovered by vacuum distillation to obtain 72g of concentrated solution (containing a little solvent residue) which was subjected to the next reaction without purification.
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 ℃ by oil bath for reaction for 2 hours. 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 to 1-2 with hydrochloric acid, and precipitating solid. After room temperature, the mixture is filtered, washed and dried to obtain 55.7g of benzothiophene-3-acetic acid, white powder with a melting point of 110-. 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 (7)
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, dissolving the compound 1 in a solvent, completing a chloromethylation process by 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 the compound 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: basic hydrolysis of the compound 3 obtained in 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.
2. The method for synthesizing benzothiophene-3-acetic acid as claimed in claim 1, wherein the solvent in S1 is acetic acid, the amount of acetic acid is 1.2-1.5 times of the volume of benzothiophene; in S1, a catalyst is also included, the amount of catalyst used being 1.2 to 1.5 times the molar amount of benzothiophene.
3. The method for synthesizing benzothiophene-3-acetic acid according to claim 2, wherein the amount of hydrochloric acid is 7 to 8 times the molar amount of benzothiophene, and the amount of paraformaldehyde is 4 to 5 times the molar amount of benzothiophene.
4. The method for synthesizing benzothiophene-3-acetic acid according to claim 1, wherein the treatment process is specifically as follows: 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 neutral drying agent is any one of anhydrous sodium sulphate, magnesium sulfate and calcium chloride.
5. The process for the synthesis of benzothiophene-3-acetic acid according to claim 4, characterized in that the drying agent in the organic phase is filtered off and the extractant is recovered by distillation under reduced pressure to obtain a concentrate which tends to be neutral and contains compound 2.
6. The method for synthesizing benzothiophene-3-acetic acid according to claim 5, wherein the aprotic polar solvent is any one of DMF, DMAC and DMSO, and the volume amount of the aprotic polar solvent is 1.0 to 1.2 times of the weight of the reaction 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 ℃.
7. The method for synthesizing benzothiophene-3-acetic acid according to claim 6, wherein the purification process comprises suction filtration, extraction, drying and solid precipitation, and a fat-soluble solvent is selected as an extractant 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.
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2021
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