CN118108728A - Preparation method and application of fluorine-containing condensed ring coumarin derivative - Google Patents
Preparation method and application of fluorine-containing condensed ring coumarin derivative Download PDFInfo
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- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 229910052731 fluorine Inorganic materials 0.000 title claims abstract description 20
- 239000011737 fluorine Substances 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- CFNMUZCFSDMZPQ-GHXNOFRVSA-N 7-[(z)-3-methyl-4-(4-methyl-5-oxo-2h-furan-2-yl)but-2-enoxy]chromen-2-one Chemical compound C=1C=C2C=CC(=O)OC2=CC=1OC/C=C(/C)CC1OC(=O)C(C)=C1 CFNMUZCFSDMZPQ-GHXNOFRVSA-N 0.000 title claims description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 36
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 125000001424 substituent group Chemical group 0.000 claims abstract description 12
- 239000007800 oxidant agent Substances 0.000 claims abstract description 10
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 9
- 230000001590 oxidative effect Effects 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 238000000746 purification Methods 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 108
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 73
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N benzo-alpha-pyrone Natural products C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- -1 coumarin compound Chemical class 0.000 claims description 24
- 230000002829 reductive effect Effects 0.000 claims description 24
- 229960000956 coumarin Drugs 0.000 claims description 21
- 235000001671 coumarin Nutrition 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 210000004027 cell Anatomy 0.000 claims description 17
- 239000012043 crude product Substances 0.000 claims description 14
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical group [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 14
- 239000003480 eluent Substances 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 12
- 239000012044 organic layer Substances 0.000 claims description 12
- 239000003208 petroleum Substances 0.000 claims description 12
- 238000010898 silica gel chromatography Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 210000004881 tumor cell Anatomy 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 4
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims description 4
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 4
- 229940045803 cuprous chloride Drugs 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 3
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 2
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical group I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 2
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 abstract description 3
- 230000011987 methylation Effects 0.000 abstract description 2
- 238000007069 methylation reaction Methods 0.000 abstract description 2
- 150000001893 coumarin derivatives Chemical class 0.000 abstract 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 60
- 239000000047 product Substances 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000004293 19F NMR spectroscopy Methods 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 238000003760 magnetic stirring Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- GOLORTLGFDVFDW-UHFFFAOYSA-N 3-(1h-benzimidazol-2-yl)-7-(diethylamino)chromen-2-one Chemical compound C1=CC=C2NC(C3=CC4=CC=C(C=C4OC3=O)N(CC)CC)=NC2=C1 GOLORTLGFDVFDW-UHFFFAOYSA-N 0.000 description 5
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 5
- 229960004316 cisplatin Drugs 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 150000004775 coumarins Chemical class 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 230000005918 in vitro anti-tumor Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
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- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000000385 effect on melanoma Effects 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
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- 229940068196 placebo Drugs 0.000 description 1
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- 238000010186 staining Methods 0.000 description 1
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- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a preparation method and application of fluorine-containing condensed ring coumarin derivatives, and the specific implementation mode is that 4- (N-methyl-N-acrylamide) coumarin compounds shown in a formula (I), a thio-difluoro aryl acetic acid compound shown in a formula (II), an oxidant and a catalyst are added into a reaction solvent, and stirred and reacted for 6-12h under the protection of nitrogen at 60-85 ℃, and the obtained reaction solution is subjected to necessary purification steps to obtain the fluorine-containing condensed ring coumarin derivatives of target compounds shown in a formula (III), wherein the reaction formula is as follows: When H on the benzene ring in the formula (I) is substituted or not substituted by a substituent R 1, the substituent R 1 is selected from alkyl, halogen or methoxy, and when H on the benzene ring in the formula (II) is substituted or not substituted by a substituent R 2, the substituent R 2 is selected from alkyl, methoxy or halogen. The invention realizes the synthesis of difluoro methylation/cyclized condensed ring coumarin compounds with anti-tumor activity, and has mild reaction conditions and high reaction yield.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method and application of fluorine-containing condensed ring coumarin derivatives.
Background
Coumarin (1, 2-benzopyrone and o-phthalanone) is an oxygen-containing heterocyclic compound widely existing in nature, plays an important role in resisting cancer, bacteria, inflammation, HIV, coagulation and the like, and has been widely focused on developing a direct and effective synthesis method of related compounds with potential pharmaceutical active Coumarin lead structure skeletons. Chinese patent CN102584841B discloses that quinoline coumarin compounds are synthesized by a one-pot method, and an antitumor activity test is carried out, and researches show that the novel compounds have good inhibition effect on MCF-7, A-549, and the IC 50 value of individual compounds reaches 0.52 mu M.
In addition, in the field of pharmaceutical chemistry, fluoroalkyl groups can act as bioisosteres with poor stability, scientists often replace the C-H bond in the drug molecule with a C-F bond, thereby improving selectivity, stability, lipophilicity, membrane permeability, etc. of the drug, and the presence of sulfur atoms can also improve the lipophilicity of the parent molecule. In 2010, wang Cheng synthesizes coumarin compounds or corresponding fluoro analogues thereof, takes human liver cancer cells (HepG-2) as tumor cell lines, takes 5-fluorouracil (5-Fu) as a positive control drug to examine the antitumor activity of partial products, and discovers that the antitumor activity of the fluoro compounds is also stronger than that of corresponding non-fluorocoumarins (a thesis, the synthesis and antibacterial antitumor activity research of coumarin compounds and fluoro derivatives thereof, jiangsu university, 2010.).
Disclosure of Invention
In view of the above problems, an object of the present invention is to provide a method for producing a fluorine-containing fused ring coumarin derivative and use thereof.
The specific technical scheme is as follows:
A preparation method of fluorine-containing condensed ring coumarin derivatives comprises the following steps: adding a 4- (N-methyl-N-acrylamide) coumarin compound shown in a formula (I), a thio-difluoro aryl acetic acid compound shown in a formula (II), an oxidant and a catalyst into a reaction solvent, stirring and reacting for 6-12h at 60-85 ℃ under the protection of nitrogen, and obtaining a fluorine-containing condensed ring coumarin derivative shown in a formula (III) of a target compound through necessary purification steps, wherein the reaction formula is as follows:
When H on the benzene ring in the formula (I) is substituted or not substituted by a substituent R 1, the substituent R 1 is selected from alkyl, halogen or methoxy, and when H on the benzene ring in the formula (II) is substituted or not substituted by a substituent R 2, the substituent R 2 is selected from alkyl, methoxy or halogen.
Further, the total volume of the reaction solvent is tetrahydrofuran, water=1:0.2-2, acetonitrile, water=1:0.2-2 or acetone, water=1:0.2-2, preferably acetonitrile, water=1:1.5, and the total volume of the reaction solvent is 5-15 mL/mmol, preferably 6-10mL/mmol, based on the amount of the substance of the 4- (N-methyl-N-acrylamide) coumarin compound shown in the formula (I).
Further, the oxidant is potassium persulfate, ammonium persulfate or tert-butyl hydroperoxide, preferably potassium persulfate, and the mass ratio of the oxidant to the 4- (N-methyl-N-acrylamide) coumarin compound shown in the formula (I) is 1.2-3.5:1, preferably 2.0-2.5:1.
Further, the catalyst is cuprous iodide, cuprous chloride or silver carbonate, preferably cuprous chloride, and the dosage of the catalyst is 5-30mol%, preferably 15-20mol%, of 4- (N-methyl-N-acrylamide) coumarin compound shown in the formula (I).
Further, the reaction temperature is 70-80 ℃, and the reaction time is 8-10h.
Further, the mass ratio of the 4- (N-methyl-N-acrylamide) coumarin compound shown in the formula (I) to the thiodifluoroaryl acetic acid compound shown in the formula (II) is 1:1.5-3.0, preferably 1:2-2.5.
Further, the necessary purification steps are: after the reaction is finished, recovering an organic solvent under reduced pressure, extracting with ethyl acetate, combining organic layers, drying with anhydrous Na 2SO4, recovering ethyl acetate under reduced pressure to obtain a crude product, separating and purifying the crude product by silica gel column chromatography, wherein an eluent is petroleum ether/ethyl acetate mixed solvent with the volume ratio of 6-10:1, and obtaining the fluorine-containing condensed ring coumarin derivative shown in the formula (III).
The application of the fluorine-containing condensed ring coumarin derivative prepared by the preparation method is the application of the fluorine-containing condensed ring coumarin derivative in preparing tumor cell melanoma B16-F10 and lung cancer A549 cell inhibitors.
Further, the fluorine-containing fused ring coumarin derivative is a compound represented by the formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi) or (IIIj),
The invention has the beneficial effects that:
1) The invention takes 4- (N-methyl-N-acrylamide) coumarin compound and thio-difluoro aryl acetic acid compound as raw materials, and can realize the synthesis of difluoro methylated/cyclized condensed ring coumarin compound with anti-tumor activity by low-cost metal catalysis, and the reaction condition is mild and the reaction yield is high;
2) Compared with the conventional technology, the method is simple to operate, does not need to perform pre-functionalization on the reaction substrate, has higher atomic economy, low cost and advanced process route;
3) The compound synthesized by the invention has novel structure, and preliminary pharmacological activity screening shows that most of the compounds have obvious in-vitro inhibition effect on melanoma B16-F10 cell lines and lung cancer A-549 cell lines, and part of the compounds have obvious proliferation inhibition effect, are superior to cisplatin which is a positive control drug, and have the prospect of being developed into new antitumor drugs.
Detailed Description
The invention will be further illustrated with reference to specific examples, but the scope of the invention is not limited thereto.
Example 1 6- (2, 2-difluoro-2- (phenylsulfanyl) ethyl) -4, 6-dimethylpyrano [2,3,4-ij ] isoquinoline-2, 5 (4H, 6H) -dione
To the reaction with magnetic stirring was added the compound 4- (N-methyl-N-acrylamido) coumarin (121.5 mg,0.5mmol,1.0 eq.) and the compound thiodifluoroarylacetic acid (204 mg,1.0 mmol), cuCl was 20mol% of the compound 4- (N-methyl-N-acrylamido) coumarin, potassium persulfate (270 mg,1.0 mmol), acetonitrile: water=1:1 (5.0 mL), nitrogen was substituted three times, the reaction system was stirred at 70 ℃ for 10 hours, acetonitrile was recovered under reduced pressure, the aqueous layer was extracted three times with ethyl acetate, the organic layer was combined, anhydrous Na 2SO4 was dried, ethyl acetate was recovered under reduced pressure to give a crude product, which was separated and purified by silica gel column chromatography (eluent was petroleum ether/ethyl acetate mixed solvent in a volume ratio of 8:1) to give the objective product 280.7mg, yield 70%.
1H NMR(400MHz,CDCl3)δ7.57(t,J＝8.1Hz,1H),7.37(dd,J＝14.3,7.3Hz,3H),7.32-7.19(m,4H),5.83(s,1H),3.46-3.35(m,4H),2.97-2.80(m,1H),1.67(s,3H).
13C NMR(101MHz,CDCl3)δ171.8,161.6,152.1,148.5,137.3,136.1,132.3,130.0,128.9,127.9(d,JC-F＝280.8Hz),125.7,121.52(d,JC-F＝1.7Hz),115.4,108.7,92.8,49.9(t,JC-F＝21.8Hz),43.9(d,JC-F＝2.1Hz),31.7,29.5.
19F NMR(376MHz,CDCl3)δ-65.36--73.32(m).
Examples 2 to 9: preparation of fluorine-containing fused Ring coumarin (III-a) the preparation method of each example is shown in example 1, except that certain reaction conditions (such as the type of solvent, the amounts of raw materials (I) and (II) fed, the type of catalyst, the type of oxidant, the temperature and the like) are changed to determine the optimal reaction conditions, and the specific changed conditions and corresponding reaction effects of each example are shown in tables 1-2 below.
TABLE 1 summary of reaction conditions for examples 2-5
TABLE 2 summary of reaction conditions for examples 6-9
In combination with tables 1 to 2, example 2 and example 3, the changed reaction conditions were the type of the reaction solvent and the amount of the catalyst, the reaction solvents were replaced with THF, H 2O＝1:1.5、CH3CN:H2 o=1:1.5, and the amount of the catalyst was replaced with 15mol%; in example 4 and example 5, the changed reaction conditions are the type and amount of the oxidizing agent, and (NH 4) 2S2O8, 2.0 equivalents, (NH 4) 2S2O8, 1.5 equivalents are replaced; example 6, example 7, the changed feed molar ratio of the reaction compound (I) to the compound (II) and the kind of catalyst were replaced with 1:2.5, 1:3.0 and CuI, ag 2CO3; example 8, example 9, the temperature of the modified reaction conditions was replaced with 75℃and 80℃respectively. The above results revealed that: the type and amount of the solvent, the catalyst and the oxidant, and the temperature can have certain influence on the reaction yield.
Example 10 6- (2, 2-difluoro-2- (phenylsulfanyl) ethyl) -4,6, 7-trimethylpyrano [2,3,4-ij ] isoquinoline-2, 5 (4H, 6H) -dione
To the reaction with magnetic stirring was added the compound 4- (N-methyl-N-acrylamido) -6-methylcoumarin (128.5 mg,0.5 mmol), the compound thiodifluoroarylacetic acid (204.0 mg,1.0 mmol), cuCl in an amount of 20mol% of 4- (N-methyl-N-acrylamido) -6-methylcoumarin, potassium persulfate (270 mg,1.0 mmol), acetonitrile: water=1:1 (5.0 mL), nitrogen was added to the mixture, after three substitutions of nitrogen, the reaction system was stirred at 70 ℃ for 10 hours, acetonitrile was recovered under reduced pressure, the aqueous layer was extracted with ethyl acetate three times, the organic layer was combined, anhydrous Na 2SO4 was dried, ethyl acetate was recovered under reduced pressure to give a crude product, which was separated and purified by silica gel column chromatography (eluent was petroleum ether/ethyl acetate mixed solvent in a volume ratio of 8:1) to give the objective product of 290.5mg, yield 77%.
1H NMR(400MHz,CDCl3)δ7.45-7.32(m,4H),7.34-7.25(m,2H),7.19(d,J＝8.5Hz,1H),5.79(s,1H),3.57-3.26(m,5H),2.54(s,3H),1.76(s,3H).
13C NMR(101MHz,CDCl3)δ173.1,161.5,151.2,148.8,137.1,136.1,133.9,131.6(d,JC-F＝1.5Hz),130.0,129.0,128.23(t,JC-F＝280.8Hz),125.8,116.0,109.1,92.6,46.0(t,JC-F＝21.5Hz),45.3(d,JC-F＝2.1Hz),30.0,27.8,22.1.
19F NMR(376MHz,CDCl3)δ-71.5(d,J＝205.8Hz),-72.7(d,J＝205.6Hz).
Example 11 7-bromo-6- (2, 2-difluoro-2- (phenylsulfanyl) ethyl) -4, 6-dimethylpyrano [2,3,4-ij ] isoquinoline-2, 5 (4H, 6H) -dione
To the reaction with magnetic stirring was added the compound 4- (N-methyl-N-acrylamido) -6-bromocoumarin (160.5 mg,0.5 mmol), the compound thiodifluoroaryl acetic acid (204.0 mg,1.0 mmol), cuCl in an amount of 20mol% of 4- (N-methyl-N-acrylamido) -6-bromocoumarin, potassium persulfate (270 mg,1.0 mmol), acetonitrile: water=1:1 (5.0 mL), nitrogen was added to the mixture, after three substitutions of nitrogen, the reaction system was stirred at 70 ℃ for 10 hours, acetonitrile was recovered under reduced pressure, the aqueous layer was extracted with ethyl acetate three times, the organic layer was combined, anhydrous Na 2SO4 was dried, ethyl acetate was recovered under reduced pressure to give a crude product, which was separated and purified by silica gel column chromatography (eluent was petroleum ether/ethyl acetate mixed solvent of 8:1 by volume ratio) to give the objective product 335.3mg, yield 75%.
1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.9Hz,1H),7.46-7.25(m,5H),7.16(d,J＝8.9Hz,1H),5.82(s,1H),4.15(ddd,J＝20.5,15.5,9.9Hz,1H),3.43(s,3H),3.30(ddd,J＝23.3,15.5,7.7Hz,1H),1.92(s,3H).
13C NMR(101MHz,CDCl3)δ172.1,160.6,152.0,147.8,139.2,136.2,134.5,130.0,129.0,128.49(t,JC-F＝280.8Hz),125.8(t,JC-F＝2.2Hz),117.7,116.3(d,JC-F＝1.8Hz),111.0,45.6(d,JC-F＝1.9Hz),44.5(t,JC-F＝21.2Hz),30.1,26.3.
19F NMR(376MHz,CDCl3)δ-71.4(d,J＝205.2Hz),-72.3(d,J＝205.3Hz).
Example 12 7-chloro-6- (2, 2-difluoro-2- (phenylsulfanyl) ethyl) -4, 6-dimethylpyrano [2,3,4-ij ] isoquinoline-2, 5 (4H, 6H) -dione
To the reaction with magnetic stirring was added the compound 4- (N-methyl-N-acrylamido) -6-chlorocoumarin (138.5 mg,0.5 mmol), the compound thiodifluoroaryl acetic acid (204.0 mg,1.0 mmol), cuCl in an amount of 20mol% of 4- (N-methyl-N-acrylamido) -6-chlorocoumarin, potassium persulfate (270 mg,1.0 mmol), acetonitrile: water=1:1 (5.0 mL), nitrogen was added to the mixture, after three substitutions of nitrogen, the reaction system was stirred at 70 ℃ for 10 hours, acetonitrile was recovered under reduced pressure, the aqueous layer was extracted with ethyl acetate three times, the organic layer was combined, anhydrous Na 2SO4 was dried, ethyl acetate was recovered under reduced pressure to give a crude product, which was separated and purified by silica gel column chromatography (eluent was petroleum ether/ethyl acetate mixed solvent in a volume ratio of 8:1) to give the objective product of 313.2mg, yield 72%.
1H NMR(400MHz,CDCl3)δ7.56(d,J＝8.9Hz,1H),7.45-7.25(m,6H),5.83(s,1H),3.94(ddd,J＝20.0,15.5,10.3Hz,1H),3.43(s,3H),3.34(ddd,J＝23.5,15.5,8.4Hz,1H),1.88(s,3H).
13C NMR(101MHz,CDCl3)δ172.1,160.7,151.4,147.8,136.1,135.4,133.0,130.3,129.9,128.34(t,JC-F＝281.8Hz),128.0,125.7,117.4,110.5,93.1,44.9(d,JC-F＝2.0Hz),44.6(d,JC-F＝21.3Hz),30.0,26.1.
19F NMR(376MHz,CDCl3)δ-71.66(d,J＝205.0Hz),-72.42(d,J＝205.0Hz).
Example 136- (2, 2-difluoro-2- (phenylsulfanyl) ethyl) -7-methoxy-4, 6-dimethylpyrano [2,3,4-ij ] isoquinoline-2, 5 (4H, 6H) -dione
To the reaction with magnetic stirring was added the compound 4- (N-methyl-N-acrylamido) -6-methoxycoumarin (136.5 mg,0.5 mmol), the compound thiodifluoroaryl acetic acid (204.0 mg,1.0 mmol), cuCl in an amount of 20mol% of 4- (N-methyl-N-acrylamido) -6-methoxycoumarin, potassium persulfate (270 mg,1.0 mmol), acetonitrile: water=1:1 (5.0 mL), nitrogen was added to the mixture, after three substitutions of nitrogen, the reaction system was stirred at 70 ℃ for 10 hours, acetonitrile was recovered under reduced pressure, the aqueous layer was extracted with ethyl acetate three times, the organic layer was combined, anhydrous Na 2SO4 was dried, ethyl acetate was recovered under reduced pressure to give a crude product, which was separated and purified by silica gel column chromatography (eluent was petroleum ether/ethyl acetate mixed solvent of 8:1 by volume ratio) to give the objective product 318.9mg, yield 74%.
1H NMR(400MHz,CDCl3)δ7.43-7.33(m,3H),7.31-7.24(m,3H),7.15(d,J＝9.1Hz,1H),5.79(s,1H),3.89(s,3H),3.74-3.58(m,1H),3.41(s,3H),3.27(ddd,J＝21.1,15.0,10.1Hz,1H),1.73(s,3H).
13C NMR(101MHz,CDCl3)δ173.1,161.9,153.2,148.7,146.5,136.1,129.9,129.0,128.6,(d,JC-F＝280.8Hz),126.2,123.0,116.52,115.8,109.6,93.1,56.0,45.5(t,JC-F＝21.4Hz),43.7(d,JC-F＝2.2Hz),29.8,26.9.
19F NMR(376MHz,CDCl3)δ-71.3(d,J＝204.4Hz),-72.0(d,J＝204.3Hz).
Example 14 6- (2, 2-difluoro-2- (phenylsulfanyl) ethyl) -4,6, 8-trimethylpyrano [2,3,4-ij ] isoquinoline-2, 5 (4H, 6H) -dione
To the reaction with magnetic stirring was added the compound 4- (N-methyl-N-acrylamido) -7-methylcoumarin (128.5 mg,0.5 mmol), the compound thiodifluoroarylacetic acid (204.0 mg,1.0 mmol), cuCl in an amount of 20mol% of 4- (N-methyl-N-acrylamido) -7-methylcoumarin, potassium persulfate (270 mg,1.0 mmol), acetonitrile: water=1:1 (5.0 mL), nitrogen was added to the mixture, after three substitutions of nitrogen, the reaction system was stirred at 70 ℃ for 10 hours, acetonitrile was recovered under reduced pressure, the aqueous layer was extracted with ethyl acetate three times, the organic layer was combined, anhydrous Na 2SO4 was dried, ethyl acetate was recovered under reduced pressure to give a crude product, which was separated and purified by silica gel column chromatography (eluent was petroleum ether/ethyl acetate mixed solvent in a volume ratio of 8:1) to give the objective product 311.2mg, yield 75%.
H NMR(400MHz,CDCl3)δ7.44-7.22(m,5H),7.08-6.98(m,2H),5.75(s,1H),3.46-3.30(m,4H),2.86(ddd,J＝18.7,15.1,9.9Hz,1H),2.45(s,3H),1.65(s,3H).
13C NMR(101MHz,CDCl3)δ172.0,161.9,152.2,148.6,143.5,137.0,136.1,130.0,128.9,127.9(t,JC-F＝281.8Hz),125.8,122.4(d,JC-F＝1.6Hz),115.6,106.3,91.9,49.9(t,JC-F＝21.8Hz),43.8(d,JC-F＝2.1Hz),31.7,29.5,21.9.
19F NMR(376MHz,CDCl3)δ-68.8(d,J＝205.0Hz),-70.2(d,J＝205.0Hz).
Example 15 6- (2, 2-difluoro-2- (p-toluenesulfonyl) ethyl) -4, 6-dimethylpyrano [2,3,4-ij ] isoquinoline-2, 5 (4H, 6H) -dione
To the reaction with magnetic stirring was added the compound 4- (N-methyl-N-acrylamido) coumarin (121.5 mg,0.5 mmol), the compound p-methylthio difluoroaryl acetic acid (218.1 mg,1.0 mmol), cuCl in an amount of 20mol% of 4- (N-methyl-N-acrylamido) coumarin, potassium persulfate (270 mg,1.0 mmol), acetonitrile: water=1:1 (5.0 mL), nitrogen was substituted three times, the reaction system was stirred at 70 ℃ for 10 hours, acetonitrile was recovered under reduced pressure, the aqueous layer was extracted three times with ethyl acetate, the organic layer was combined, dried over anhydrous Na 2SO4, and ethyl acetate was recovered under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluent was petroleum ether/ethyl acetate mixed solvent in a volume ratio of 8:1) to give the objective product 311.2mg, yield 76%.
1H NMR(400MHz,CDCl3)δ7.57(t,J＝8.1Hz,1H),7.34-7.16(m,4H),7.09(d,J＝7.9Hz,2H),5.80(s,1H),3.42(s,3H),3.40-3.33(m,1H),2.99-2.75(m,1H),2.31(s,3H),1.67(s,3H).
13C NMR(101MHz,CDCl3)δ171.9,161.6,152.1,148.5,140.4,137.3,136.1,132.2,129.7,127.8(t,JC-F＝280.8Hz),122.1,121.5(d,JC-F＝1.7Hz),115.3,108.7,92.7,49.9(t,JC-F＝21.8Hz),43.82(d,JC-F＝2.1Hz),31.6,29.5,21.2.
19F NMR(376MHz,CDCl3)δ-69.1(d,J＝204.7Hz),-70.9(d,J＝204.9Hz).
Example 16 6- (2, 2-difluoro-2- ((4-methoxyphenyl) thio) ethyl) -4, 6-dimethylpyrano [2,3,4-ij ] isoquinoline-2, 5 (4H, 6H) -dione
To the reaction with magnetic stirring was added the compound 4- (N-methyl-N-acrylamido) coumarin (121.5 mg,0.5 mmol), the compound p-methoxythiodifluoroaryl acetic acid (234.0 mg,1.0 mmol), cuCl in an amount of 20mol% of 4- (N-methyl-N-acrylamido) coumarin, potassium persulfate (270 mg,1.0 mmol), acetonitrile: water=1:1 (5.0 mL), nitrogen was substituted three times, the reaction system was stirred at 70 ℃ for 10 hours, acetonitrile was recovered under reduced pressure, the aqueous layer was extracted three times with ethyl acetate, the organic layer was combined, dried over anhydrous Na 2SO4, and ethyl acetate was recovered under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluent was petroleum ether/ethyl acetate mixed solvent in a volume ratio of 8:1) to give 310mg of the objective product in a yield of 72%.
1H NMR(400MHz,CDCl3)δ7.57(t,J＝8.1Hz,1H),7.34-7.26(m,2H),7.23(ddd,J＝15.4,8.1,0.9Hz,2H),6.85-6.77(m,2H),5.80(s,1H),3.77(s,3H),3.42(s,3H),3.40-3.29(m,1H),2.84(ddd,J＝19.3,15.1,9.2Hz,1H),1.67(s,3H).
13C NMR(101MHz,CDCl3)δ171.9,161.7,161.2,152.2,148.6,138.0,137.4,132.3,127.8(t,JC-F＝281.8Hz),121.6(d,JC-F＝1.8Hz),116.2(t,JC-F＝2.2Hz),115.4,114.5,108.8,92.8,55.3,49.8(t,JC-F＝21.8Hz),43.9(d,JC-F＝2.0Hz),31.7,29.6.
19F NMR(376MHz,CDCl3)δ-69.64(d,J＝204.9Hz),-71.52(d,J＝204.9Hz).
Example 17 6- (2, 2-difluoro-2- ((4-fluorophenyl) thio) ethyl) -4, 6-dimethylpyrano [2,3,4-ij ] isoquinoline-2, 5 (4H, 6H) -dione
To the reaction with magnetic stirring was added the compound 4- (N-methyl-N-acrylamido) coumarin (121.5 mg,0.5 mmol), the compound p-fluorothioaryl acetic acid (222.0 mg,1.0 mmol), cuCl in an amount of 20mol% of 4- (N-methyl-N-acrylamido) coumarin, potassium persulfate (270 mg,1.0 mmol), acetonitrile: water=1:1 (5.0 mL), nitrogen was substituted three times, the reaction system was stirred at 70 ℃ for 10 hours, acetonitrile was recovered under reduced pressure, the aqueous layer was extracted three times with ethyl acetate, the organic layer was combined, dried over anhydrous Na 2SO4, ethyl acetate was recovered under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluent was petroleum ether/ethyl acetate mixed solvent in a volume ratio of 8:1) to give the objective product 318.4mg, yield 76%.
1H NMR(400MHz,CDCl3)δ7.59(t,J＝8.1Hz,1H),7.42-7.31(m,2H),7.24(t,J＝8.8Hz,2H),6.98(t,J＝8.6Hz,2H),5.82(s,1H),3.43(s,3H),3.41-3.34(m,1H),2.99-2.76(m,1H),1.68(s,3H).
13C NMR(101MHz,CDCl3)δ171.8,165.2,162.7,161.5,152.1,148.4,138.4(d,J＝8.8Hz),137.2,132.3,127.7(t,J＝281.2Hz),121.5(d,J＝1.7Hz),120.9(d,J＝2.3Hz),116.3,116.1,115.4,108.7,92.8,49.7(t,J＝21.7Hz),43.8(d,J＝2.2Hz),31.7,29.5.
19F NMR(376MHz,CDCl3)δ-69.1(d,J＝204.3Hz),-70.9(d,J＝204.3Hz),-110.0.
Example 18 6- (2- ((4-chlorophenyl) thio) -2, 2-difluoroethyl) -4, 6-dimethylpyrano [2,3,4-ij ] isoquinoline-2, 5 (4H, 6H) -dione
To the reaction with magnetic stirring was added the compound 4- (N-methyl-N-acrylamido) coumarin (121.5 mg,0.5 mmol), the compound p-chlorothiodifluoroarylacetic acid (238.0 mg,1.0 mmol), cuCl in an amount of 20mol% of 4- (N-methyl-N-acrylamido) coumarin, potassium persulfate (270 mg,1.0 mmol), acetonitrile: water=1:1 (5.0 mL), nitrogen was substituted three times, the reaction system was stirred at 70 ℃ for 10 hours, acetonitrile was recovered under reduced pressure, the aqueous layer was extracted three times with ethyl acetate, the organic layer was combined, dried over anhydrous Na 2SO4, ethyl acetate was recovered under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluent was petroleum ether/ethyl acetate mixed solvent in a volume ratio of 8:1) to give the objective product 339.3mg, yield 78%.
1H NMR(400MHz,CDCl3)δ7.59(t,J＝8.1Hz,1H),7.39-7.13(m,6H),5.82(s,1H),3.44(s,3H),3.42-3.31(m,1H),2.97-2.80(m,1H),1.68(s,3H).
13C NMR(101MHz,CDCl3)δ171.8,161.5,152.2,148.4,137.3,137.1,136.7,132.3,129.2,124.1(d,JC-F＝2.6Hz),121.5(d,JC-F＝1.8Hz),115.5,108.7,92.9,49.8(t,JC-F＝21.7Hz),43.8(d,JC-F＝2.3Hz),31.7,29.6.
19F NMR(376MHz,CDCl3)δ-68.62(d,J＝204.3Hz),-70.39(d,J＝204.2Hz).
Example 19 antitumor Activity test:
Proliferation test activity results of the compound on melanoma B16-F10 cell line and lung cancer A549 cell line:
And (3) performing in-vitro anti-tumor activity test by adopting an SRB method. Cisplatin was used as a control. First, B16-F10 and A549 cells were inoculated into a sterile 96-well plate at 5000 cells/well, an equal volume of culture solution or PBS buffer was added to a round of wells around the periphery of the cells, and after the cells were attached overnight, the above test compound (0,1,2,4,8,16,32,64,128. Mu.M) was added per well according to the concentration gradient of experimental design, wherein B16-F10 cells were cultured for 24 hours, and A549 cells were cultured for 48 hours after administration. After the administration time, the old culture solution was discarded, 100. Mu.L of pre-chilled 10% trichloroacetic acid (TCA) solution was added to each well, and the cells were placed in a refrigerator at 4℃for more than 1 hour. And removing TCA solution in the culture plate holes, washing with deionized water for more than 5 times, and drying residual water in the plates. The 96-well plate was placed in a constant temperature oven at 60 ℃ for about 1 hour to dry. The dried 96-well plate was removed, 80. Mu.L of SRB solution prepared with 1% acetic acid was added to each well, and the plate was left to stand at room temperature for 20min for staining. The SRB dye solution in each well was discarded, slowly washed 5 times with 1% acetic acid, and excess unbound SRB dye was washed and the remaining solution in the plate was drained off. The 96-well plate was placed in a constant temperature oven at 60 ℃ for about 1 hour to dry. The dried 96-well plates were removed, 100. Mu.L of 10mM Tris-base solution at pH=10.5 was added to each well and the mixture was placed on a plate shaker for 15min to thoroughly lyse intracellular SRB. The microplate reader detects absorbance at 540 nm. The survival rate was calculated from the OD value of each well measured by the microplate reader according to the following formula:
Survival (%) = (OD dosing/OD control) ×100% and IC 50 values were calculated using GRAPHPAD PRISM 8.0.0 software.
Experimental results: the half-maximal inhibitory concentration (IC 50) of the samples on tumor cell growth was determined after 24h and 48h dosing of the test compounds, respectively, compared to the placebo group, and the specific test results are shown in Table 3.
TABLE 3 antitumor Activity of Compounds III-a to III-j
Note that: cisplatin is a control drug, aIC50: test compound concentration that inhibited 50% of cell growth.
Table 3 shows that most of the compounds have better inhibition activity on MCF-7 and A-549 tumor cell strains.
1) Of all the compounds, the compounds III-a, III-B, III-c, III-d, III-g and III-j have good inhibitory activity on melanoma B16-F10 cell lines, and the IC 50 values are 21.78 mu M, 8.57 mu M, 20.41 mu M, 18.35 mu M, 14.92 mu M and 16.02 mu M respectively, and the in vitro tumor cell inhibition activity of the compounds is greater than that of a positive control drug cisplatin (26.52 mu M), wherein the compound III-B has the best inhibitory activity.
2) Of all the compounds, the compounds III-b, III-c, III-g, III-h and III-j have good inhibitory activity on human lung cancer cells A-549, and the IC 50 values are 63.72 mu M, 55.08 mu M, 47.69 mu M, 58.44 mu M and 16.04 mu M respectively, wherein the in vitro tumor cell inhibitory activity of the compounds III-g and III-j is greater than that of cisplatin (48.28 mu M) which is a positive control drug. The inhibitory activity of the compound III-j is best.
3) Therefore, the difluoro methylation/condensed ring coumarin derivative provided by the invention has a good in-vitro anti-tumor cell effect, and has a prospect of developing an anti-tumor drug.
What has been described in this specification is merely an enumeration of possible forms of implementation for the inventive concept and may not be considered limiting of the scope of the present invention to the specific forms set forth in the examples.
Claims (9)
1. The preparation method of the fluorine-containing condensed ring coumarin derivative is characterized by comprising the following steps of: adding a 4- (N-methyl-N-acrylamide) coumarin compound shown in a formula (I), a thio-difluoro aryl acetic acid compound shown in a formula (II), an oxidant and a catalyst into a reaction solvent, stirring and reacting for 6-12h at 60-85 ℃ under the protection of nitrogen, and obtaining a fluorine-containing condensed ring coumarin derivative shown in a formula (III) of a target compound through necessary purification steps, wherein the reaction formula is as follows:
When H on the benzene ring in the formula (I) is substituted or not substituted by a substituent R 1, the substituent R 1 is selected from alkyl, halogen or methoxy, and when H on the benzene ring in the formula (II) is substituted or not substituted by a substituent R 2, the substituent R 2 is selected from alkyl, methoxy or halogen.
2. The preparation method according to claim 1, wherein the reaction solvent is tetrahydrofuran, water=1:0.2-2, acetonitrile, water=1:0.2-2 or acetone, water=1:0.2-2, preferably acetonitrile, water=1:1.5, and the total volume of the reaction solvent is 5-15 mL/mmol, preferably 6-10mL/mmol, based on the amount of the substance of the 4- (N-methyl-N-acrylamido) coumarin compound represented by formula (i).
3. The process according to claim 1, wherein the oxidizing agent is potassium persulfate, ammonium persulfate or t-butyl hydroperoxide, preferably potassium persulfate, and the ratio of the oxidizing agent to the substance of the 4- (N-methyl-N-acrylamido) coumarin compound of formula (i) is 1.2 to 3.5:1, preferably 2.0 to 2.5:1.
4. The preparation method according to claim 1, wherein the catalyst is cuprous iodide, cuprous chloride or silver carbonate, preferably cuprous chloride, and the catalyst is used in an amount of 5 to 30mol%, preferably 15 to 20mol%, of the 4- (N-methyl-N-acrylamido) coumarin compound represented by the formula (i).
5. The process according to claim 1, wherein the reaction is carried out at a temperature of 70 to 80℃for a period of 8 to 10 hours.
6. The preparation method according to claim 1, wherein the mass ratio of the 4- (N-methyl-N-acrylamido) coumarin compound represented by the formula (I) to the thio-difluoroaryl acetic acid compound represented by the formula (II) is 1:1.5-3.0, preferably 1:2-2.5.
7. The method of claim 1, wherein the necessary purification steps are: after the reaction is finished, recovering an organic solvent under reduced pressure, extracting with ethyl acetate, combining organic layers, drying with anhydrous Na 2SO4, recovering ethyl acetate under reduced pressure to obtain a crude product, separating and purifying the crude product by silica gel column chromatography, wherein an eluent is petroleum ether/ethyl acetate mixed solvent with the volume ratio of 6-10:1, and obtaining the fluorine-containing condensed ring coumarin derivative shown in the formula (III).
8. The use of the fluorine-containing fused ring coumarin derivative prepared by the preparation method of claims 1-7, which is characterized in that the use of the fluorine-containing fused ring coumarin derivative is the use of the fluorine-containing fused ring coumarin derivative in preparing tumor cell melanoma B16-F10 and lung cancer A549 cell inhibitor.
9. The use according to claim 8, wherein the fluorine-containing fused ring coumarin derivative is a compound of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi) or (IIIj),
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