CN110698456A - Synthesis method of 2, 3-dihydrothiochromen-4-one and derivatives thereof - Google Patents
Synthesis method of 2, 3-dihydrothiochromen-4-one and derivatives thereof Download PDFInfo
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- CVQSWZMJOGOPAV-UHFFFAOYSA-N 2,3-dihydrothiochromen-4-one Chemical compound C1=CC=C2C(=O)CCSC2=C1 CVQSWZMJOGOPAV-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000001308 synthesis method Methods 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 22
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 18
- 125000003118 aryl group Chemical group 0.000 claims abstract description 17
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims abstract description 16
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 16
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 12
- KOODSCBKXPPKHE-UHFFFAOYSA-N propanethioic s-acid Chemical compound CCC(S)=O KOODSCBKXPPKHE-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 9
- -1 aromatic thiophenol compounds Chemical class 0.000 claims abstract description 5
- 238000005406 washing Methods 0.000 claims abstract description 5
- 230000009471 action Effects 0.000 claims abstract description 4
- 238000006798 ring closing metathesis reaction Methods 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000012044 organic layer Substances 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- WRXOZRLZDJAYDR-UHFFFAOYSA-N 3-methylbenzenethiol Chemical compound CC1=CC=CC(S)=C1 WRXOZRLZDJAYDR-UHFFFAOYSA-N 0.000 claims description 3
- VZXOZSQDJJNBRC-UHFFFAOYSA-N 4-chlorobenzenethiol Chemical compound SC1=CC=C(Cl)C=C1 VZXOZSQDJJNBRC-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- CQJDYPZUDYXHLM-UHFFFAOYSA-N 3-chlorobenzenethiol Chemical compound SC1=CC=CC(Cl)=C1 CQJDYPZUDYXHLM-UHFFFAOYSA-N 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- NBBGHADNMPMHST-UHFFFAOYSA-N 6-fluoro-2,3-dihydrothiochromen-4-one Chemical compound S1CCC(=O)C2=CC(F)=CC=C21 NBBGHADNMPMHST-UHFFFAOYSA-N 0.000 claims 1
- 238000000605 extraction Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000020477 pH reduction Effects 0.000 abstract description 2
- 238000000935 solvent evaporation Methods 0.000 abstract description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 229920000137 polyphosphoric acid Polymers 0.000 description 4
- 102000009515 Arachidonate 15-Lipoxygenase Human genes 0.000 description 3
- 108010048907 Arachidonate 15-lipoxygenase Proteins 0.000 description 3
- ZGOOPZVQMLHPFM-UHFFFAOYSA-N PD-146176 Chemical compound N1C2=CC=CC=C2C2=C1C1=CC=CC=C1SC2 ZGOOPZVQMLHPFM-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- ZXNYWOVMBYLGON-UHFFFAOYSA-N 2-chloro-2,3-dihydrothiochromen-4-one Chemical compound C1=CC=C2SC(Cl)CC(=O)C2=C1 ZXNYWOVMBYLGON-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- GAWAYYRQGQZKCR-REOHCLBHSA-N (S)-2-chloropropanoic acid Chemical compound C[C@H](Cl)C(O)=O GAWAYYRQGQZKCR-REOHCLBHSA-N 0.000 description 1
- YSYYFHVHCXBCCS-UHFFFAOYSA-N 2-methyl-2,3-dihydrothiochromen-4-one Chemical compound C1=CC=C2SC(C)CC(=O)C2=C1 YSYYFHVHCXBCCS-UHFFFAOYSA-N 0.000 description 1
- QEYMMOKECZBKAC-UHFFFAOYSA-N 3-chloropropanoic acid Chemical compound OC(=O)CCCl QEYMMOKECZBKAC-UHFFFAOYSA-N 0.000 description 1
- JZLMLFCJWFMZMC-UHFFFAOYSA-N 3-phenylpropanethioic s-acid Chemical compound SC(=O)CCC1=CC=CC=C1 JZLMLFCJWFMZMC-UHFFFAOYSA-N 0.000 description 1
- MJPVYTKZYZPIQA-UHFFFAOYSA-N 3-thiophen-2-ylpropanoic acid Chemical compound OC(=O)CCC1=CC=CS1 MJPVYTKZYZPIQA-UHFFFAOYSA-N 0.000 description 1
- OKHUUKHZUNKSQA-UHFFFAOYSA-N 6-chloro-2,3-dihydrothiochromen-4-one Chemical compound S1CCC(=O)C2=CC(Cl)=CC=C21 OKHUUKHZUNKSQA-UHFFFAOYSA-N 0.000 description 1
- LOMUZJMYCDMNFP-UHFFFAOYSA-N 7-chloro-2,3-dihydrothiochromen-4-one Chemical compound O=C1CCSC2=CC(Cl)=CC=C21 LOMUZJMYCDMNFP-UHFFFAOYSA-N 0.000 description 1
- RQKPWCBIBIMKRP-UHFFFAOYSA-N 7-methyl-2,3-dihydrothiochromen-4-one Chemical compound O=C1CCSC2=CC(C)=CC=C21 RQKPWCBIBIMKRP-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 210000001995 reticulocyte Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing 2, 3-dihydro thiochromen-4-one and derivatives thereof, which 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. The raw materials of the invention adopt acrylic acid and concentrated sulfuric acid, and are easy to obtain, low in cost and easy to feed. The post-treatment only needs to be carried out by acidification, extraction, washing and solvent evaporation, and the method has the advantages of simple post-treatment, high yield and low cost and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a synthetic method of 2, 3-dihydrothiochromene-4-ketone and derivatives thereof.
Background
2, 3-dihydrothiochromen-4-one and derivatives thereof are important medical intermediates. The 2, 3-dihydrothiochromene-4-ketone has the functions of selectively inhibiting cyclooxygenase, shows obvious anti-inflammatory activity and also shows better activity in the fields of inhibiting protease, resisting tumor ropes, resisting estrogen effect, treating heart disease and the like. For example, inhibitor PD146176(NSC168807) is a 15-lipoxygenase (15-LO) inhibitor, and has a Ki value of 197nm for inhibiting 15-LO in rabbit reticulocytes. PD146176(NS168807) had a significant effect in reducing atherosclerosis.
The current synthetic method for 2, 3-dihydrothiochromen-4-one and its derivatives is: thiophenol is used as a raw material, substituted reaction is carried out on the thiophenol and 3-chloropropionic acid, and then ring closure is carried out under the catalysis of polyphosphoric acid, and chloropropionic acid is a pipe product, so that the raw material is not easy to purchase. The polyphosphoric acid is sticky and needs a large amount of polyphosphoric acid, so that the feeding is difficult in the production and preparation process, the post-treatment is complex, the yield is not high, and the post-treatment of the polyphosphoric acid can generate a large amount of phosphorus-containing wastewater, so that the environmental pollution is large.
Disclosure of Invention
Aiming at the technical problems, the invention aims to provide a synthesis method of 2, 3-dihydrothiochromene-4-ketone and derivatives thereof, which has the advantages of easily available raw materials, low production cost, simple post-treatment and suitability for industrial production.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: 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.
The general reaction formula is as follows:
in the scheme, the specific operation steps are as follows:
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.
In the scheme, the method comprises the following steps: the organic solvent is tetrahydrofuran and dioxane.
In the scheme, the method comprises the following steps: the organic base is one of triethylamine, N-diisopropylethylamine and pyridine.
In the scheme, the method comprises the following steps: 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. Ensuring the full reaction.
In the scheme, the method comprises the following steps: 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. Reduce impurities and improve yield.
In the scheme, the method comprises the following steps: the organic layer was washed to neutrality with saturated sodium bicarbonate and water.
In the scheme, the method comprises the following steps: the concentrated sulfuric acid is 98% concentrated sulfuric acid or 80% concentrated sulfuric acid.
In the scheme, the method comprises the following steps: the substituted and unsubstituted aromatic thiophenol is selected from thiophenol, p-chlorothiophenol, 5-chlorothiophenol, and 5-methylthiophenol.
The method has the beneficial effects that substituted and unsubstituted aromatic thiophenol compounds are used as raw materials, the substituted and unsubstituted aromatic thiophenol compounds react with acrylic acid to generate corresponding aromatic thiopropionic acid, and then the corresponding aromatic thiopropionic acid is subjected to ring closing under the action of concentrated sulfuric acid to obtain a product, wherein the raw materials are acrylic acid and concentrated sulfuric acid, and are easy to obtain, low in cost and easy to feed. The post-treatment only needs to be carried out by acidification, extraction, washing and solvent evaporation, and the method has the advantages of simple post-treatment, high yield and low cost and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples:
EXAMPLE 1 Synthesis of Thiochroman-4-one
Synthesis of 3-thiophenylpropionic acid
Thiophenol (89g, 810mmol) was added to THF200mL and triethylamine (86g, 119mL, 850mmol), and 58g of acrylic acid (55mL,810mmol) was added dropwise at-5 deg.C to 5 deg.C. The reaction mixture was stirred at-5 ℃ to 5 ℃ for 1 hour then overnight, 2N hydrochloric acid was added to adjust the pH to 1 and extracted twice with 300ml of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give 137g of product in 93% yield as a white solid mp.51-54 ℃. 1H-NMR (DMSO-d6) δ:2.53(2H, t, J ═ 7.1 Hz); 3.13(2H, t, J ═ 7.2 Hz); 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 (13.54g,74mmol) was added to 50ml of 80% concentrated sulfuric acid and stirred at 110 ℃ for 4 h. After cooling to room temperature, the reaction mixture was poured into 100ml of ice water, extracted three times with 100ml of ethyl acetate each time, the organic phases were combined and the organic layer was washed with saturated NaHCO respectively3The solution (100 ml) and water (100 ml) were washed to neutrality, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to give 9.7g of thiochroman-4-one in 80% yield.
1H-NMR (DMSO-d6) δ:2.90(2H, t, J ═ 6.6 Hz); 3.32(2H, t, J ═ 6.3 Hz); 7.22(1H, dd, J ═ 8.1 and 8.1 Hz); 7.36(1H, d, J ═ 7.9 Hz); 7.47(1H, dd, J ═ 8.1 and 8.1 Hz); 7.96(1H, d, J ═ 8.1 Hz).
EXAMPLE 26 Synthesis of chlorothiochroman-4-one
P-chlorothiophenol (117g, 810mmol) was added to THF200mL and pyridine 1620mmol, and 69.6g of acrylic acid (66mL, 972mmol) was added dropwise at-5 deg.C to 5 deg.C. The reaction mixture was stirred at-5 ℃ to 5 ℃ for 2 hours then overnight, 2N hydrochloric acid was added to adjust the pH to 2 and ethyl acetate was extracted twice with 300ml each time. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 165.7g of an intermediate in 94% yield.
21g of the intermediate was added to 50ml of 98% concentrated sulfuric acid, and the mixture was stirred at 90 ℃ for 4 hours. After cooling to room temperature, the reaction mixture was poured into 120ml of ice water, extracted three times with 100ml of ethyl acetate each time, the organic phases were combined and the organic layer was washed with saturated NaHCO3The solution (100 ml) and water (100 ml) were washed to neutrality, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to give 15.6g of 6-chlorothiochroman-4-one in 82% yield. m.p.69-71 ℃ 1H NMR (CDCl)3)δ:2.95-2.97(m,2H,COCH2CH2S),3.17-3.19(m,2H,COCH2CH2S),6.97-7.01(m,1H,ArH),7.19(d,J＝8.4Hz,1H,ArH),7.60(d,J＝3.2Hz,1H,ArH)
EXAMPLE 37 Synthesis of chlorothiochroman-4-one
5-Chlorobenzothiophenol (117g, 810mmol) was added to 200mL of dioxane and 972mmol of N, N-diisopropylethylamine, and 63.8g of acrylic acid (60.5mL, 891mmol) was added dropwise at-5 ℃ to 5 ℃. The reaction mixture was stirred at-5 ℃ to 5 ℃ for 2 hours then overnight, 2N hydrochloric acid was added to adjust the pH to 1 and two extractions with 300ml of ethyl acetate were carried out. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 163.6g of an intermediate in 92.8% yield.
21g of the intermediate was added to 50ml of 98% concentrated sulfuric acid, and the mixture was stirred at 90 ℃ for 4 hours. After cooling to room temperature, the reaction mixture was poured into 120ml of ice water, extracted three times with 100ml of ethyl acetate each time, the organic phases were combined and the organic layer was washed with saturated NaHCO3The solution (100 ml) and water (100 ml) were washed to neutrality, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to give 7-chlorothiochroman-4-one as a white solid (14.3 g, 75% yield). 1HNMR (CDCl)3)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 47 Synthesis of methylthiochroman-4-one
5-Methylthiophenol (100.6g, 810mmol) was added to 200mL of THF and triethylamine (98.3g, 136mL, 972mmol), and 58g of acrylic acid (55mL,810mmol) was added dropwise at a temperature of-5 ℃ to 5 ℃. The reaction mixture was stirred at-5 ℃ to 5 ℃ for 2 hours then overnight, 2N hydrochloric acid was added to adjust the pH to 1 and two extractions with 300ml of ethyl acetate were carried out. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give an intermediate in 93.2% yield.
21g of the intermediate was added to 60ml of 80% concentrated sulfuric acid, and the mixture was stirred at 100 ℃ for 4 hours. Cooling to room temperature, pouring the reaction solution into 100ml of ice water, extracting with 100ml of ethyl acetate three times, combining organic phases, washing the organic layer with 100ml of saturated NaHCO3 solution and 100ml of water respectively to neutrality, drying the organic layer with anhydrous sodium sulfate, and removing the solvent in vacuum to obtain yellow9.5g of 7-methylthiochroman-4-one as an oil, yield 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-described embodiments, and those skilled in the art will understand that: various changes, modifications, substitutions and alterations can be made to the embodiments without departing from the principles and spirit of the invention, the scope of which is 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.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113929658A (en) * | 2021-11-05 | 2022-01-14 | 太原理工大学 | Isothiochromene derivative and preparation method thereof |
| CN114031603A (en) * | 2021-11-24 | 2022-02-11 | 深圳市芯研材料科技有限公司 | Thiochromane 4-ketone compound, preparation method thereof and UV (ultraviolet) photocuring combination system thereof |
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| US20080161352A1 (en) * | 2005-05-20 | 2008-07-03 | Gruenenthal Gmbh | Substituted Benzo-Condensed Cycloheptanone Derivatives and the Use Thereof for Medicament Production |
| CN106699726A (en) * | 2016-12-30 | 2017-05-24 | 河北大学 | Thiochromanone derivative and preparation method and application thereof |
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| CN1729191A (en) * | 2002-11-22 | 2006-02-01 | 活跃生物技术股份公司 | Pyrazoloquinolines with immunomodulating activity |
| US20080161352A1 (en) * | 2005-05-20 | 2008-07-03 | Gruenenthal Gmbh | Substituted Benzo-Condensed Cycloheptanone Derivatives and the Use Thereof for Medicament Production |
| CN106699726A (en) * | 2016-12-30 | 2017-05-24 | 河北大学 | Thiochromanone derivative and preparation method and application thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113929658A (en) * | 2021-11-05 | 2022-01-14 | 太原理工大学 | Isothiochromene derivative and preparation method thereof |
| CN114031603A (en) * | 2021-11-24 | 2022-02-11 | 深圳市芯研材料科技有限公司 | Thiochromane 4-ketone compound, preparation method thereof and UV (ultraviolet) photocuring combination system thereof |
| CN114031603B (en) * | 2021-11-24 | 2024-07-19 | 深圳市大衍创新材料科技有限公司 | Thiochroman 4-ketone compound, preparation method thereof and UV (ultraviolet) photocuring combination system thereof |
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