CN114516853A - Electrocatalytic preparation method of benzothiophene derivative containing drug molecules - Google Patents
Electrocatalytic preparation method of benzothiophene derivative containing drug molecules Download PDFInfo
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- HQALDKFFRYFTKP-UHFFFAOYSA-N 2-[4-[4-(2-benzyl-1-benzothiophen-3-yl)phenyl]-2-bromo-6-(3-methoxyphenyl)phenoxy]acetic acid Chemical compound COC1=CC=CC(C=2C(=C(Br)C=C(C=2)C=2C=CC(=CC=2)C=2C3=CC=CC=C3SC=2CC=2C=CC=CC=2)OCC(O)=O)=C1 HQALDKFFRYFTKP-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 229940079593 drug Drugs 0.000 title claims abstract description 16
- 239000003814 drug Substances 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 239000002904 solvent Substances 0.000 claims abstract description 12
- -1 phenyl pentynyl p-toluenesulfonate Chemical compound 0.000 claims abstract description 11
- 239000000047 product Substances 0.000 claims abstract description 11
- 239000012043 crude product Substances 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 10
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims abstract description 6
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003792 electrolyte Substances 0.000 claims abstract description 6
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 5
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 11
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 7
- 229960001680 ibuprofen Drugs 0.000 claims description 7
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 claims description 6
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims description 6
- 229960003627 gemfibrozil Drugs 0.000 claims description 6
- 229960000905 indomethacin Drugs 0.000 claims description 6
- QFGMXJOBTNZHEL-UHFFFAOYSA-N isoxepac Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC(CC(=O)O)=CC=C21 QFGMXJOBTNZHEL-UHFFFAOYSA-N 0.000 claims description 6
- 229950011455 isoxepac Drugs 0.000 claims description 6
- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 claims description 6
- 229960002373 loxoprofen Drugs 0.000 claims description 6
- 229960002009 naproxen Drugs 0.000 claims description 6
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 229910002804 graphite Inorganic materials 0.000 claims description 3
- 239000010439 graphite Substances 0.000 claims description 3
- XLOPRKKSAJMMEW-SFYZADRCSA-N Chrysanthemic acid Natural products CC(C)=C[C@@H]1[C@@H](C(O)=O)C1(C)C XLOPRKKSAJMMEW-SFYZADRCSA-N 0.000 claims description 2
- 238000001311 chemical methods and process Methods 0.000 claims description 2
- XLOPRKKSAJMMEW-UHFFFAOYSA-N chrysanthemic acid Chemical compound CC(C)=CC1C(C(O)=O)C1(C)C XLOPRKKSAJMMEW-UHFFFAOYSA-N 0.000 claims description 2
- 239000007772 electrode material Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- SPVZAYWHHVLPBN-WREUKLMHSA-N (1r,3r)-3-[(z)-2-chloro-3,3,3-trifluoroprop-1-enyl]-2,2-dimethylcyclopropane-1-carboxylic acid Chemical compound CC1(C)[C@@H](\C=C(/Cl)C(F)(F)F)[C@H]1C(O)=O SPVZAYWHHVLPBN-WREUKLMHSA-N 0.000 claims 1
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 abstract description 10
- 239000003054 catalyst Substances 0.000 abstract description 6
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 239000013067 intermediate product Substances 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000010183 spectrum analysis Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- RVDOYUFNRDGYGU-UHFFFAOYSA-N 1-bromo-2-ethynylbenzene Chemical group BrC1=CC=CC=C1C#C RVDOYUFNRDGYGU-UHFFFAOYSA-N 0.000 description 1
- JGMXNNSYEFOBHQ-OWOJBTEDSA-N 2-[(e)-4-morpholin-4-ylbut-2-enyl]-1,1-dioxothieno[3,2-e]thiazine-6-sulfonamide Chemical compound O=S1(=O)C=2SC(S(=O)(=O)N)=CC=2C=CN1C\C=C\CN1CCOCC1 JGMXNNSYEFOBHQ-OWOJBTEDSA-N 0.000 description 1
- OVDGUTHABMXVMI-UHFFFAOYSA-N 3-nitro-4-(propylamino)benzoic acid Chemical compound CCCNC1=CC=C(C(O)=O)C=C1[N+]([O-])=O OVDGUTHABMXVMI-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000002058 anti-hyperglycaemic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005868 electrolysis reaction Methods 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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Classifications
-
- 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
- C07D333/56—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
- C25B3/01—Products
- C25B3/05—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
- C25B3/01—Products
- C25B3/07—Oxygen containing compounds
-
- C—CHEMISTRY; METALLURGY
- C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
- C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
- C25B3/00—Electrolytic production of organic compounds
- C25B3/20—Processes
- C25B3/29—Coupling reactions
Abstract
The invention discloses an electrocatalytic preparation method of benzothiophene derivatives containing drug molecules, belonging to the technical field of organic synthesis. The method comprises the following steps: adding phenyl pentynyl p-toluenesulfonate and p-toluenesulfonyl hydrazide in a molar ratio of 1:3 into a reactor, adding tetraethyl ammonium hexafluorophosphate as an electrolyte, and adding a solution of 47: 3 hexafluoroisopropanol and nitromethane as solvents, and the reaction is promoted to be carried out by an electrocatalytic strategy. After the reaction is finished, concentrating by using a rotary evaporator to obtain a crude product, and separating by using silica gel column chromatography to obtain the benzothiophene derivative.Adding a benzothiophene derivative, a drug molecule and potassium carbonate in a molar ratio of 1:1:1 into a reactor, adding N, N-dimethylacetamide as a solvent, and reacting at 80 ℃ for 8 hours. After the reaction is finished, concentrating by using a rotary evaporator to obtain a crude product, and separating by using silica gel column chromatography to obtain a target product. The synthetic method of the benzothiophene derivative coupled drug molecule provided by the invention is scientific and reasonable, the synthetic route is green and environment-friendly, and a metal catalyst is not needed; the reaction condition is mild; the intermediate product can react under weak current; the synthesis method is simple and the reaction is rapid; high yield of the target compound, easy purification of the product and the like. The reaction equation is as follows:
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method for coupling drug molecules of benzothiophene derivatives through electrocatalysis.
Background
Benzothiophenes are widely found in nature, and their derivatives have a wide range of biopharmacological activities: such as anti-inflammatory, analgesic, antifungal, antidepressant, estrogen receptor modulation, enzyme inhibitor, anticancer, antitubercular, antimalarial, antihyperglycemic and insecticide. ((a) Eur.J.Med.chem.2009,44,1718-
A method for synthesizing benzothiophene derivatives is reported by the Karlsruhe Institute of Technology university Marius Kuhn, Florian C. Falk, and Jan Paradie: under the catalysis of palladium, the o-bromophenylacetylene substance and thiourea are coupled and cyclized to synthesize the benzothiophene derivative (org. Lett.2011,13, 4100-4103). The reaction formula is shown as formula I:
the above method has obvious disadvantages of using a metal catalyst, a long reaction time, additionally using a phosphorus catalyst, and the like.
Disclosure of Invention
In order to overcome the defects of the prior art for synthesizing the benzothiophene derivative, the invention provides a preparation method for preparing a benzothiophene derivative coupling drug molecule by electrocatalysis.
Electrocatalytic synthesis reactions have a number of significant advantages: the method can avoid using toxic or difficultly-treated catalysts, electrons are green reaction reagents, reaction products have high purity and are easy to separate, and the method almost has no pollution to the environment; in the electrocatalytic reaction, the electrode voltage or current can be changed to regulate and control the reaction rate so as to avoid side reaction, thereby improving the selectivity and yield of the target product.
A method for preparing a benzothiophene derivative conjugate drug molecule by electrocatalysis, wherein the benzothiophene derivative conjugate drug molecule has a structure shown in a formula II:
the R substituent group is selected from Ibuprofen (Ibuprofen), indomethacin (indomethacin), Gemfibrozil (Gemfibrozil), Loxoprofen (Loxoprofen), trifluoracetic acid (trifluoracetic acid ju), Naproxen (Naproxen), Isoxepac (Isoxepac). The method is characterized in that phenyl pentynyl p-toluenesulfonate and p-toluenesulfonyl hydrazide in a molar ratio of 1:3 are added into a reactor, tetraethylammonium hexafluorophosphate is added as an electrolyte, and the volume ratio of the reactants is 47: 3 hexafluoroisopropanol and nitromethane as solvents, and the reaction is promoted to be carried out by an electrocatalytic strategy. After the reaction is finished, concentrating by using a rotary evaporator to obtain a crude product, and separating by using silica gel column chromatography to obtain the benzothiophene derivative. Adding a benzothiophene derivative, a drug molecule and potassium carbonate in a molar ratio of 1:1:1 into a reactor, adding N, N-dimethylacetamide as a solvent, and reacting at 80 ℃ for 8 hours. After the reaction is finished, concentrating by using a rotary evaporator to obtain a crude product, and separating by silica gel column chromatography to obtain a target product, wherein the chemical process is shown in a reaction formula III:
The molar ratio of the phenyl pentynyl p-toluenesulfonate to the p-toluenesulfonylhydrazide is 1: 3, the electrolyte is tetraethylammonium hexafluorophosphate, and the solvent 1 is a mixture of hexafluoroisopropanol and nitromethane, wherein the volume ratio of the hexafluoroisopropanol to the nitromethane is 47: promoting the reaction to be carried out by an electrocatalysis strategy, wherein the current is 5mA, the electrode material is graphite felt, the reaction temperature is 1 room temperature, the reaction time is 8h, the molar ratio of the benzothiophene derivative to the drug molecule is 1:1, the alkali is potassium carbonate, the solvent 2 is N, N-dimethylacetamide, the temperature is 80 ℃, and the reaction time is 8 h.
The invention has the beneficial effects that: the synthetic method for coupling benzothiophene and drug molecules provided by the invention is scientific and reasonable, provides a new way for synthesizing benzothiophene coupled drug molecules, obtains a product with various drug molecules and benzothiophene coupled products by the method, and is characterized in that: the synthetic route is green and environment-friendly, and a metal catalyst is not needed; the intermediate can be obtained by reaction under weak current; no additional phosphorus catalyst is needed; the synthetic method is simple; the yield of the target compound is high, and the product is easy to purify.
Drawings
FIG. 1 is an NMR spectrum of Compound 5a prepared in example 1;
FIG. 2 is an NMR spectrum of compound 5c prepared in example 3;
FIG. 3 is an NMR spectrum of compound 5e prepared in example 5.
Detailed Description
The invention is described in further detail below with reference to the following figures and specific examples:
the test methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
Example 1
Preparation of benzothiophene derivative 5a containing Ibuprofen (Ibuprofen):
to a 10mL diaphragm-free electrolytic cell, 5-phenylpent-4-ynyl 4-methylbenzenesulfonate 1 (0.2mmol,68.2mg), p-toluenesulfonylhydrazide 2(0.6mmol,111.7mg), tetraethylammonium hexafluorophosphate (0.2mmol, 55.0mg) was added, and graphite felt electrodes (1 cm. times.1 cm. times.0.5 cm) were used as the cathode and anode. The system was purged with nitrogen and hexafluoroisopropanol (4.7mL) and nitromethane (0.3mL) were added. The electrolysis was carried out at room temperature under a constant current of 5mA, and the reaction was carried out for 8 hours. After the reaction is finished, the solvent is removed by using a rotary evaporator to obtain a crude product, the crude product is separated by column chromatography (200-mesh silica gel 300 meshes, and petroleum ether/ethyl acetate 20/1), and the solvent is removed by using the rotary evaporator to obtain the target product benzothiophene derivative 3 with the yield of 55%. A10 mL thick-walled pressure-resistant tube was charged with benzothiophene derivative 3(0.1mmol,46.8mg), ibuprofen 4a (0.1mmol, 20.6mg), potassium carbonate (0.1mmol,13.8mg), and N, N-dimethylacetamide (1 mL). The reaction was carried out at 80 ℃ for 8 h. After the reaction is finished, the solvent is removed by using a rotary evaporator to obtain a crude product, the crude product is separated by column chromatography (200-mesh silica gel with 300 meshes, and petroleum ether/ethyl acetate is 2/1), and the solvent is removed by using the rotary evaporator to obtain the target product 5a, wherein the yield is 80%.
Spectrogram analysis data 5a:
1H NMR(CDCl3,500MHz):δ7.57(s,1H),7.53–7.45(m,3H), 7.33–7.24(m,3H),7.09(d,J＝7.8Hz,2H),7.03(d,J＝7.9Hz,2H), 6.98(d,J＝7.8Hz,1H),4.03(ddt,J＝39.6,11.5,6.1Hz,2H),3.54(q,J ＝7.1Hz,1H),2.56(t,J＝8.3Hz,2H),2.46–2.39(m,5H),2.03(dh,J＝ 13.5,7.0Hz,2H),1.87–1.76(m,J＝6.8Hz,1H),1.39(d,J＝7.2Hz, 3H),0.87(s,3H),0.86(s,3H)；13C NMR(CDCl3,125MHz):δ174.52, 140.46,139.23,137.64,137.22,136.41,133.90,130.74,130.68,129.44, 129.29,129.12,128.41,127.13,123.45,121.91,99.99,63.60,45.03, 30.16,27.00,22.41,21.35,20.27,18.40.
example 2
Preparation of indomethacin (indomethacin) -containing benzothiophene derivative 5b:
4a in example 1 is replaced by 4b, the other conditions are the same as example 1, and the experimental results are shown in Table 1.
Spectrum analysis data 5b:
1H NMR(500MHz,CDCl3):δ7.72(d,J＝7.9Hz,1H),7.64(d,J＝ 8.2Hz,2H),7.58(s,1H),7.54–7.47(m,3H),7.45(d,J＝8.3Hz,2H), 7.36–7.27(m,4H),7.00(d,J＝7.8Hz,1H),6.91(d,J＝2.5Hz,1H), 6.88(d,J＝9.0Hz,1H),6.65(dd,J＝9.1,2.6Hz,1H),4.08(t,J＝6.2Hz, 2H),3.81(s,3H),3.55(s,2H),2.64(t,J＝7.7Hz,2H),2.60(d,J＝5.3 Hz,1H),2.43(s,3H),2.30(s,3H),2.07(dd,J＝6.8,2.2Hz,2H)；13C NMR(125MHz,CDCl3)δ170.70,168.27,156.07,140.58,139.39, 139.17,136.96,136.32,135.88,133.97,131.19,130.63,129.69,129.51, 129.18,129.10,128.38,127.26,123.48,121.92,114.97,112.49,111.73, 101.20,63.94,55.72,30.14,26.87,21.35,20.22,13.35.
example 3
Preparation of Gemfibrozil (Gemfibrozil) -containing benzothiophene derivative 5c:
4a in example 1 was replaced by 4c, and the experimental results were shown in Table 1, under the same conditions as in example 1.
Spectrogram analysis data 5c:
1H NMR(500MHz CDCl3):δ7.58(s,1H),7.48(dtd,J＝12.7,6.9, 1.6Hz,3H),7.34–7.28(m,2H),7.28–7.22(m,1H),6.98(dt,J＝8.0, 1.8Hz,2H),6.64(d,J＝7.5Hz,1H),6.59(s,1H),4.05(td,J＝6.1,1.5 Hz,2H),3.86(dt,J＝6.7,3.4Hz,2H),2.64(dd,J＝9.1,6.8Hz,2H), 2.42(s,3H),2.29(s,3H),2.15(s,3H),2.07(dt,J＝10.5,3.8Hz,2H), 1.73–1.58(m,4H),1.11(s,6H)；13C NMR(125MHz,CDCl3):δ177.57, 156.95,140.51,139.26,137.24,136.44,136.41,133.93,130.73,130.66, 130.30,129.46,129.19,128.40,123.55,123.47,121.92,120.69,111.97, 67.89,63.36,42.05,37.01,27.26,25.13,25.08,21.44,21.36,20.47, 15.81.
example 4
Preparation of Loxoprofen (Loxoprofen) -containing benzothiophene derivative 5d:
4a in example 1 is replaced by 4d, other conditions are the same as in example 1, and the experimental results are shown in Table 1.
Spectrogram analysis data 5d:
1H NMR(500MHz,CDCl3):δ7.59(s,1H),7.55–7.48(m,3H), 7.34–7.28(m,3H),7.14–7.04(m,4H),7.00(d,J＝7.8Hz,1H),4.04 (ddt,J＝34.5,11.5,6.2Hz,2H),3.56(q,J＝7.1Hz,1H),3.11(dd,J＝ 13.9,4.2Hz,1H),2.63(dd,J＝5.5,1.2Hz,1H),2.57(t,J＝7.9Hz,2H), 2.44(s,3H),2.36–2.28(m,2H),2.06–2.00(m,4H),1.97–1.89(m, 1H),1.77–1.65(m,1H),1.60–1.47(m,1H),1.40(dd,J＝7.3,1.3Hz, 3H)；13C NMR(125MHz,CDCl3):δ174.40,140.52,139.26,138.81, 138.23,137.12,136.34,133.93,130.69,130.64,129.70,129.46,129.13, 129.08,128.39,127.49,127.27,123.47,121.90,63.66,50.98,44.99, 38.18,35.18,29.22,26.99,21.35,20.52,20.25,18.34.
example 5
Preparation of benzothiophene derivative 5e containing chrysanthemic acid (trifluoracetic acid ju):
4e is used to replace 4a in example 1, the other conditions are the same as example 1, and the experimental results are shown in Table 1.
Spectrogram analysis data 5e:
1H NMR(CDCl3,500MHz):δ7.59(s,1H),7.51(q,J＝7.5,7.1 Hz,3H),7.35–7.31(m,2H),7.29(s,1H),7.01(d,J＝7.8Hz,1H),6.90 (d,J＝9.4Hz,1H),4.04(qt,J＝11.4,6.0Hz,2H),2.68(t,J＝7.7Hz, 2H),2.44(s,3H),2.14–2.01(m,3H),1.81(d,J＝8.3Hz,1H),1.26(s, 3H),1.23(s,3H)；13C NMR(CDCl3,125MHz):δ170.07,140.54, 139.41,137.02,136.35,133.94,130.69,130.64,130.19(q,J＝4.5Hz), 129.42,129.10,128.40,123.47,121.91,63.44,32.74,30.82,28.63,28.32, 26.86,21.33,20.23,14.84.
example 6
Preparation of a benzothiophene derivative 5f containing Naproxen (Naproxen):
4a in example 1 was replaced by 4f, and the experimental results were shown in Table 1, under the same conditions as in example 1.
Spectrum analysis data 5f:
1H NMR(CDCl3,500MHz):δ7.66(t,J＝8.5Hz,2H),7.58(t,J＝ 2.2Hz,2H),7.52–7.44(m,3H),7.29(ddd,J＝16.8,6.9,2.8Hz,4H), 7.18–7.08(m,2H),6.98(d,J＝7.9Hz,1H),4.05(ddt,J＝45.4,11.6, 6.2Hz,2H),3.90(s,3H),3.71(q,J＝7.2Hz,1H),2.58(ddd,J＝8.7,6.9, 2.1Hz,2H),2.43(s,3H),2.08–2.00(m,2H),1.49(d,J＝7.1Hz,3H)；13C NMR(CDCl3,125MHz):δ174.45,157.59,140.47,139.26,137.10, 136.33,135.55,133.89,133.64,130.70,130.60,129.39,129.26,129.07, 128.87,128.35,127.10,126.22,125.86,123.43,121.88,118.92,105.57, 63.69,55.29,45.31,26.95,21.33,20.24,18.44.
example 7
Preparation of 5g of a benzothiophene derivative containing Isoxepac (Isoxepac):
4g was used instead of 4a in example 1, and the experimental results were shown in Table 1, except that the conditions were the same as in example 1.
Spectrogram analysis data 5g:
1H NMR(CDCl3,500MHz):δ8.04(d,J＝2.4Hz,1H),7.90– 7.85(m,1H),7.59–7.58(m,1H),7.57–7.50(m,4H),7.48–7.44(m, 1H),7.38–7.32(m,4H),7.28(d,J＝7.8Hz,1H),7.00(t,J＝8.1Hz, 2H),5.17(s,2H),4.08(t,J＝6.0Hz,2H),3.48(s,2H),2.66(dd,J＝8.6, 6.7Hz,2H),2.43(s,3H),2.07(p,J＝6.8Hz,2H)；13C NMR(CDCl3, 125MHz):δ190.69,171.14,170.60,160.40,140.48,140.36,139.41, 136.89,136.30,135.56,133.92,132.75,132.34,130.61,130.54,129.48, 129.38,129.18,129.13,128.36,127.81,127.62,125.02,123.45,121.81, 121.02,73.55,63.66,39.86,26.76,21.29,20.07.
TABLE 1
Claims (2)
1. An electrocatalytic preparation method of a benzothiophene derivative containing a drug molecule, said benzothiophene derivative molecule having a structure represented by formula I:
the R substituent group is selected from Ibuprofen (Ibuprofen), indomethacin (Indometacin), Gemfibrozil (Gemfibrozil), Loxoprofen (Loxoprofen), chrysanthemic acid (lambdacyhalothric acid), Naproxen (Naproxen), Isoxepac (Isoxepac). The method is characterized in that phenyl pentynyl p-toluenesulfonate, p-toluenesulfonyl hydrazide and electrolyte in a molar ratio of 1:3:1 are added into a reactor, and the volume ratio of the phenyl pentynyl p-toluenesulfonate to the p-toluenesulfonyl hydrazide and the electrolyte is 47: 3 hexafluoroisopropanol and nitromethane as solvents, and the reaction is promoted to be carried out by an electrocatalytic strategy. After the reaction is finished, concentrating by using a rotary evaporator to obtain a crude product, and separating by using silica gel column chromatography to obtain the benzothiophene derivative. Then, adding the benzothiophene derivative, the drug molecule and the alkali in a molar ratio of 1:1:1 into a reactor, and adding N, N-dimethylacetamide as a solvent. After the reaction is finished, concentrating by using a rotary evaporator to obtain a crude product, and separating by silica gel column chromatography to obtain a target product, wherein the chemical process of the target product is shown in a reaction formula II:
2. The method of claim 1, wherein: the electrode material is graphite felt, the current is 5mA, the electrolyte is tetraethylammonium hexafluorophosphate, and the alkali is potassium carbonate. The reaction temperature 1 is room temperature, the reaction time 1 is 8h, the reaction temperature 2 is 80 ℃, and the reaction time 2 is 8h.
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