CN110698456A - Synthesis method of 2, 3-dihydrothiochromen-4-one and derivatives thereof - Google Patents

Abstract

The invention discloses a method for synthesizing 2,3-dihydrothiochromene-4-ketone and derivatives thereof, which is characterized in that: substituted and unsubstituted aromatic thiophenol compounds are used as raw materials, and acrylic acid reacts to generate corresponding Aromatic thiopropionic acid, and then ring-closed under the action of concentrated sulfuric acid to obtain the corresponding 2,3 dihydrothiochromene-4-ketone and its derivatives. The raw materials of the invention adopt acrylic acid and concentrated sulfuric acid, the raw materials are easy to obtain, the cost is low, and the feeding is easy. The post-processing only needs to go through acidification, extraction, washing, and evaporation of the solvent. The post-processing is simple, the yield is high, the cost is low, and it is suitable for industrial production.

Description

A kind of synthetic method of 2,3-dihydrothiochromen-4-one and derivatives thereof

technical field

The invention belongs to the technical field of medicine, and in particular relates to a method for synthesizing 2,3-dihydrothiochromene-4-one and derivatives thereof.

Background technique

2,3-Dihydrothiochromen-4-one and its derivatives are important pharmaceutical intermediates. 2,3-Dihydrothiochromen-4-one selectively inhibits cyclooxygenase and shows significant anti-inflammatory activity. also showed better activity. For example, the inhibitor PD146176 (NSC168807) is a 15-lipoxygenase (15-LO) inhibitor that inhibits 15-LO in rabbit reticulocytes with a Ki value of 197 nm. PD146176 (NS168807) has a significant effect in reducing atherosclerosis.

The current synthesis method of 2,3-dihydrothiochromen-4-one and its derivatives is as follows: taking thiophenol as raw material, substituted reaction with 3-chloropropionic acid, and then closing the ring under the catalysis of polyphosphoric acid. Propionic acid is a tube product, and the raw materials are not easy to buy. Polyphosphoric acid is viscous and requires a large amount, which makes feeding difficult in the production and preparation process, complicated post-treatment, and low yield. Moreover, post-treatment of polyphosphoric acid will generate a large amount of phosphorus-containing wastewater, which will cause great environmental pollution.

SUMMARY OF THE INVENTION

In view of the above-mentioned technical problems, the object of the present invention is to provide a synthetic method of 2,3-dihydrothiochromene-4-one and its derivatives, the raw materials are easily available, the production cost is low, the post-processing is simple, and it is suitable for industrial production .

In order to achieve the above purpose, the technical scheme adopted in the present invention is: a method for synthesizing 2,3-dihydrothiochromene-4-one and derivatives thereof, characterized in that: using substituted and unsubstituted aromatic thiophenols The compound is used as a raw material, reacts with acrylic acid to generate corresponding aromatic thiopropionic acid, and then closes the ring under the action of concentrated sulfuric acid to obtain corresponding 2,3-dihydrothiochromen-4-one and its derivatives.

The general reaction formula is:

In the above scheme, the specific operation steps are:

Dissolve the substituted and unsubstituted aromatic thiophenols in an organic solvent, add an organic base, control the temperature at -5°C to 5°C, add acrylic acid dropwise, complete the stirring reaction, add hydrochloric acid after the reaction to adjust to pH 1-2, and ethyl acetate. Ester extraction, the organic phase is dried and distilled under reduced pressure to obtain aromatic thiopropionic acid;

Add aromatic thiopropionic acid to concentrated sulfuric acid, stir the reaction at 90℃-110℃, cool to room temperature after the reaction, add ice water, extract with ethyl acetate, wash the organic layer until neutral, then dry and vacuum to remove the solvent get product.

In the above scheme: the organic solvent is tetrahydrofuran and dioxane.

In the above scheme: the organic base is one of triethylamine, N,N-diisopropylethylamine and pyridine.

In the above scheme: the molar ratio of the substituted and unsubstituted aromatic thiophenol to triethylamine is 1:1-2, and the molar ratio of the substituted and unsubstituted aromatic thiophenol to acrylic acid is 1:1-1.2. Ensure adequate response.

In the above scheme: after the dropwise addition of acrylic acid, the reaction is first stirred at -5°C to 5°C for 1-2 hours, and then stirred at room temperature until the reaction is complete. Reduce impurities and improve yield.

In the above scheme: the organic layer was washed to neutrality with saturated sodium bicarbonate and water.

In the above scheme: the concentrated sulfuric acid is the concentrated sulfuric acid with a mass concentration of 98% or a concentrated sulfuric acid with a mass concentration of 80%.

In the above scheme: the substituted and unsubstituted aromatic thiophenols are selected from thiophenol, p-chlorothiophenol, 5-chlorothiophenol, and 5-methylthiophenol.

Beneficial effects, the present invention uses substituted and non-substituted aromatic thiophenol compounds as raw materials, reacts with acrylic acid to generate corresponding aromatic thiopropionic acid, and then closes the ring under the action of concentrated sulfuric acid to obtain the product, the raw materials are acrylic acid and concentrated sulfuric acid, and the raw materials are easy to obtain. , low cost and easy feeding. The post-processing only needs to go through acidification, extraction, washing, and evaporation of the solvent. The post-processing is simple, the yield is high, the cost is low, and it is suitable for industrial production.

Detailed ways

Below by embodiment, the present invention is further described:

The synthesis of embodiment 1 thiochroman-4-one

Synthesis of 3-Phenylthiopropionic Acid

Thiophenol (89 g, 810 mmol) was added to 200 mL of THF and triethylamine (86 g, 119 mL, 850 mmol), and 58 g of acrylic acid (55 mL, 810 mmol) was added dropwise at a temperature of -5 °C to 5 °C. The reaction mixture was stirred at -5°C to 5°C for 1 hour, then overnight, adjusted to pH 1 by adding 2N hydrochloric acid, and extracted twice with 300 ml of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 137 g of the product with a yield of 93%, which was a white solid Mp.51-54°C. 1H-NMR(DMSO-d6)δ:2.53(2H,t,J=7.1Hz);3.13(2H,t,J=7.2Hz);7.18-7.23(1H,m);7.30-7.36(4H,m) ); 12.31(1H,br s).

Synthesis of 2,3-Dihydrothiochromen-4-one

3-Phenylthiopropionic acid (13.54 g, 74 mmol) was added to 50 ml of 80% concentrated sulfuric acid, and the mixture was stirred at 110° C. for 4 h. After cooling to room temperature, the reaction solution was poured into 100 ml of ice water, extracted _three times with 100 ml of ethyl acetate each time, and the organic phases were combined. It was dried with sodium sulfate, and the solvent was removed in vacuo to obtain 9.7 g of thiochroman-4-one with a yield of 80%.

1H-NMR (DMSO-d6) δ: 2.90 (2H, t, J=6.6Hz); 3.32 (2H, t, J=6.3Hz); 7.22 (1H, dd, J=8.1 and 8.1Hz); 7.36 ( 1H, d, J = 7.9 Hz); 7.47 (1 H, dd, J = 8.1 and 8.1 Hz); 7.96 (1 H, d, J = 8.1 Hz).

Example 2 Synthesis of 6-chlorothiochroman-4-one

p-Chlorothiophenol (117 g, 810 mmol) was added to 200 mL of THF and 1620 mmol of pyridine, and 69.6 g of acrylic acid (66 mL, 972 mmol) was added dropwise at a temperature of -5°C to 5°C. The reaction mixture was stirred at -5°C to 5°C for 2 hours, then overnight, adjusted to pH 2 by addition of 2N hydrochloric acid, and extracted twice with 300 ml of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 165.7 g of the intermediate with a yield of 94%.

21 g of the above intermediate was added to 50 ml of 98% concentrated sulfuric acid, and the mixture was stirred at 90° C. for 4 h. After cooling to room temperature, the reaction solution was poured into 120 ml of ice water, extracted _three times with 100 ml of ethyl acetate each time, and the organic phases were combined. Dry over sodium sulfate, and remove the solvent in vacuo to obtain 15.6 g of 6-chlorothiochroman-4-one with a yield of 82%. mp69-71°C 1H NMR (CDCl ₃ )δ: 2.95-2.97 (m, 2H, COCH ₂ CH ₂ S), 3.17-3.19 (m, 2H, COCH ₂ CH ₂ S), 6.97-7.01 (m, 1H, ArH),7.19(d,J=8.4Hz,1H,ArH),7.60(d,J=3.2Hz,1H,ArH)

Example 3 Synthesis of 7-chlorothiochroman-4-one

5-Chlorothiophenol (117 g, 810 mmol) was added to 200 mL of dioxane and 972 mmol of N,N-diisopropylethylamine, and 63.8 g of acrylic acid (60.5 mL) was added dropwise at a temperature of -5 °C to 5 °C. , 891 mmol). The reaction mixture was stirred at -5°C to 5°C for 2 hours, then overnight, adjusted to pH 1 by adding 2N hydrochloric acid, and extracted twice with 300 ml of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 163.6 g of the intermediate with a yield of 92.8%.

21 g of the above intermediate was added to 50 ml of 98% concentrated sulfuric acid, and the mixture was stirred at 90° C. for 4 h. After cooling to room temperature, the reaction solution was poured into 120 ml of ice water, extracted _three times with 100 ml of ethyl acetate each time, and the organic phases were combined. Dry over sodium sulfate, and remove the solvent in vacuo to obtain 14.3 g of 7-chlorothiochroman-4-one as a white solid with a yield of 75%. 1HNMR( _CDCl3 )δ: 8.2(IH,d,J=9Hz),7.3(1H,d,J=3Hz),7.15(1H,dd,J=9and 3Hz),3.25(2H,t,J=9Hz) ), 2.98 (2H,t,J=9Hz).

Example 4 Synthesis of 7-methylthiochroman-4-one

5-Methylthiophenol (100.6 g, 810 mmol) was added to 200 mL of THF and triethylamine (98.3 g, 136 mL, 972 mmol), and 58 g of acrylic acid (55 mL, 810 mmol) was added dropwise at a temperature of -5 °C to 5 °C. . The reaction mixture was stirred at -5°C to 5°C for 2 hours, then overnight, adjusted to pH 1 by adding 2N hydrochloric acid, and extracted twice with 300 ml of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain an intermediate with a yield of 93.2%.

21 g of the above intermediate was added to 60 ml of 80% concentrated sulfuric acid, and the mixture was stirred at 100° C. for 4 h. After cooling to room temperature, the reaction solution was poured into 100 ml of ice water, extracted three times with 100 ml of ethyl acetate each time, and the organic phases were combined. It was dried over sodium sulfate, and the solvent was removed in vacuo to obtain 9.5 g of 7-methylthiochroman-4-one as a yellow oil with a yield of 50%. 1HNMR(CDCl ₃ )δ:7.97(d,J=8.1Hz,1H)7.06(s,1H)6.97(d,J=7.7Hz,1H)3.17(m,2H)2.95(m,2H)2.31(s , 3H).

The present invention is not limited to the above-mentioned embodiments, and those of ordinary skill in the art can understand that various changes, modifications, replacements and modifications can be made to these embodiments without departing from the principle and purpose of the present invention. The scope of the present invention Defined by the claims and their equivalents.

Claims (10)

1. A method for synthesizing 2, 3-dihydro thiochromen-4-one and derivatives thereof is characterized by comprising the following steps: substituted and unsubstituted aromatic thiophenol compounds are used as raw materials, and react with acrylic acid to generate corresponding aromatic thiopropionic acid, and then the corresponding 2, 3-dihydro thiochromen-4-one and derivatives thereof are obtained by ring closure under the action of concentrated sulfuric acid.

2. The method for synthesizing 6-fluoro-2, 3-dihydrothiochromen-4-one and its derivatives according to claim 1, characterized by comprising the following steps:

dissolving substituted and unsubstituted aromatic thiophenol in an organic solvent, adding organic base, controlling the temperature at-5 ℃, dropwise adding acrylic acid, stirring for reaction after dropwise adding, adding hydrochloric acid to adjust the pH to 1-2 after the reaction is finished, extracting with ethyl acetate, and drying and distilling an organic phase under reduced pressure to obtain aromatic thiopropionic acid;

adding aromatic thiopropionic acid into concentrated sulfuric acid, stirring at 90-110 ℃ for reaction, cooling to room temperature after the reaction is finished, adding ice water, extracting with ethyl acetate, washing an organic layer to be neutral, and drying under vacuum to remove a solvent to obtain the product.

3. The method of synthesizing 2, 3-dihydrothiochromen-4-one and its derivatives as claimed in claim 2, wherein: the organic solvent is tetrahydrofuran and dioxane.

4. A method of synthesizing 2, 3-dihydrothiochromen-4-one and its derivatives as claimed in claim 3, characterized in that: the organic base is one of triethylamine, N-diisopropylethylamine and pyridine.

5. The method of synthesizing 2, 3-dihydrothiochromen-4-one and its derivatives as claimed in claim 4, wherein: the molar ratio of the substituted and unsubstituted aromatic thiophenols to the organic base is 1: 1-2.

6. The method of synthesizing 2, 3-dihydrothiochromen-4-one and its derivatives as claimed in claim 5, wherein: the molar ratio of the substituted and unsubstituted aromatic thiophenols to acrylic acid is 1: 1-1.2.

7. A method of synthesizing 2, 3-dihydrothiochromen-4-one and its derivatives as claimed in any one of claims 2-6, characterized in that: after the acrylic acid is added dropwise, the mixture is stirred and reacted for 1 to 2 hours at the temperature of between 5 ℃ below zero and 5 ℃, and then stirred and reacted at room temperature until the reaction is complete.

8. The method of synthesizing 2, 3-dihydrothiochromen-4-one and its derivatives as claimed in claim 7, wherein: the organic layer was washed to neutrality with saturated sodium bicarbonate and water.

9. The method of synthesizing 2, 3-dihydrothiochromen-4-one and its derivatives as claimed in claim 8, wherein: the concentrated sulfuric acid is 98% concentrated sulfuric acid or 80% concentrated sulfuric acid.

10. The method of synthesizing 2, 3-dihydrothiochromen-4-one and its derivatives as claimed in claim 9, wherein: the substituted and unsubstituted aromatic thiophenol is selected from thiophenol, p-chlorothiophenol, 5-chlorothiophenol, and 5-methylthiophenol.