CN113717135A - Synthesis method of carbonyl substituted benzodihydropyran and benzodihydropyran compound - Google Patents
Synthesis method of carbonyl substituted benzodihydropyran and benzodihydropyran compound Download PDFInfo
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 title claims description 55
- 150000001875 compounds Chemical class 0.000 title abstract description 16
- 238000001308 synthesis method Methods 0.000 title abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- -1 carbonyl-substituted chroman Chemical class 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 23
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 16
- GHWJXMOSGFPZSG-UHFFFAOYSA-N C(C)(C)C=CC1=C(C=CC=C1)O Chemical class C(C)(C)C=CC1=C(C=CC=C1)O GHWJXMOSGFPZSG-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000000746 purification Methods 0.000 claims abstract description 4
- 238000000926 separation method Methods 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 71
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 37
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical class C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 claims description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 31
- 239000012044 organic layer Substances 0.000 claims description 29
- 239000003208 petroleum Substances 0.000 claims description 15
- 238000010898 silica gel chromatography Methods 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 13
- 239000000706 filtrate Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 11
- 238000005406 washing Methods 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 5
- 229920000388 Polyphosphate Polymers 0.000 claims description 3
- 239000001205 polyphosphate Substances 0.000 claims description 3
- 235000011176 polyphosphates Nutrition 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000010828 elution Methods 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 4
- 230000035484 reaction time Effects 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 abstract 1
- 229920000137 polyphosphoric acid Polymers 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 44
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- HBEDSQVIWPRPAY-UHFFFAOYSA-N dihydro-benzofuran Natural products C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 21
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 239000002994 raw material Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 9
- INLWEXRRMUMHKB-UHFFFAOYSA-N 2-hydroxy-3-prop-2-enylbenzaldehyde Chemical compound OC1=C(CC=C)C=CC=C1C=O INLWEXRRMUMHKB-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 2
- QIRNGVVZBINFMX-UHFFFAOYSA-N 2-allylphenol Chemical group OC1=CC=CC=C1CC=C QIRNGVVZBINFMX-UHFFFAOYSA-N 0.000 description 1
- 102000004674 D-amino-acid oxidase Human genes 0.000 description 1
- 108010003989 D-amino-acid oxidase Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 229910007932 ZrCl4 Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/14—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
Abstract
本发明提供了羰基取代苯并二氢呋喃及羰基取代苯并二氢吡喃化合物的合成方法，具体为：耐压反应瓶中加入多聚磷酸PPA、溶剂N,N‑二甲基甲酰胺DMF和羰基取代邻烯丙基/羰基取代异戊烯基苯酚，加热搅拌反应2‑10h；反应结束后分离纯化，即得羰基取代苯并二氢呋喃/羰基取代苯并二氢吡喃化合物。本发明合成方法为首次公开，其反应时间短、催化剂PPA廉价易得、底物普适性好且产物产率较好，不但为羰基取代苯并二氢呋喃及羰基取代苯并二氢吡喃化合物的合成提供了一种新方法，也为产品规模化生产及提高生产效率奠定了基础。The invention provides a method for synthesizing carbonyl-substituted chroman and carbonyl-substituted chroman compounds, which comprises the following steps: adding polyphosphoric acid PPA and solvent N,N-dimethylformamide DMF into a pressure-resistant reaction flask and carbonyl-substituted o-allyl/carbonyl-substituted isopentenylphenol, heated and stirred for 2-10 h; after the reaction, separation and purification were performed to obtain a carbonyl-substituted chroman/carbonyl-substituted chroman compound. The synthesis method of the invention is disclosed for the first time, and the reaction time is short, the catalyst PPA is cheap and easy to obtain, the substrate is universal and the product yield is good, not only carbonyl-substituted chroman and carbonyl-substituted chroman The synthesis of the compound provides a new method, and also lays the foundation for the large-scale production of products and the improvement of production efficiency.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of carbonyl-substituted chroman and carbonyl-substituted chroman compounds.
Background
The chroman and chroman system exists in a large number of bioactive compounds and has remarkable biological activity, such as anti-genetic toxicity, anti-proliferation, anti-cancer, anti-inflammation and the like, and the most common reported method for preparing the chroman and chroman compounds is an intra-molecular cyclization method of o-allyl/isopentenylphenol. The carbonyl substituted chromans and chromans also have a wide range of biological activities, such as anti-cancer, anti-proliferative and inhibitory activity on D-amino acid oxidases. The synthesis method of carbonyl substituted benzodihydro furan and benzodihydropyran compounds mainly uses I2(Heterocycles.1995,41:219-223)、H2SO4(Lett Org Chem.2009,6:29-36；Synthesis.2010,21:3745-3754；Eur J Org Chem.2015,10:2297-2302)、HCl(Chem Pharm Bull.1981,29:3033-3036)、p-TsOH(Can J Chem.1970,48:680-684；RSC Adv.2018,8:41377-41388)、TFA(Molecules.2018,23:776-792)、AlCl3(Molecules.2018,23:776-792)、ZrCl4(Synth Commun.2004,34:3091-3097) and BF3/Et2O (Tetrahedron Lett.2007,48: 7628-. However, these synthetic methods have limitations such as low yield, long reaction time, and no discussion of substrate universality, and the specific limitations are shown in table 1.
Table 1 reported limitations of the synthesis method of carbonyl substituted chromans and chromans
Disclosure of Invention
The invention aims to provide a synthesis method of carbonyl-substituted chroman and a carbonyl-substituted chroman compound, which has the advantages of short reaction time, simple operation, no need of nitrogen protection, cheap and easily available catalyst PPA and good substrate universality.
In order to achieve the purpose, the invention adopts the following technical scheme:
the carbonyl substituted chroman and the carbonyl substituted chroman compound have the following structures shown as formulas II 1-11:
the synthesis method comprises the following steps:
adding PPA, N-dimethylformamide DMF and carbonyl substituted o-allyl/carbonyl substituted isopentenyl phenol into a pressure-resistant reaction bottle, and heating and stirring for reacting for 2-10 h; separating and purifying after the reaction is finished to obtain a carbonyl substituted chroman/carbonyl substituted chroman compound; the pressure-resistant reaction bottle can effectively avoid solvent volatilization;
the structures of the carbonyl-substituted o-allyl and carbonyl-substituted isopentenyl phenol are shown as the following formulas I1-11:
according to the synthesis method of the carbonyl-substituted chroman and the carbonyl-substituted chroman compound, the molar ratio of the carbonyl-substituted o-allyl/carbonyl-substituted isopentenyl phenol to the PPA polyphosphate is 1: 5 to 30.
According to the synthesis method of the carbonyl-substituted chroman and the carbonyl-substituted chroman compound, the dosage of the DMF solvent is 1.5mL/mmol of the carbonyl-substituted o-allyl/carbonyl-substituted isopentenyl phenol.
The synthesis method of the carbonyl-substituted chroman and the carbonyl-substituted chroman compound is characterized in that the heating is carried out in an oil bath at 90-160 ℃.
According to the synthesis method of the carbonyl-substituted chroman and the carbonyl-substituted chroman compound, the separation and purification process after the reaction is finished is as follows: extracting a substance obtained after the reaction is finished for 2-3 times by using ethyl acetate, taking an organic layer, washing the organic layer by using water and a saturated sodium chloride solution in sequence, drying the washed organic layer by using anhydrous sodium sulfate, and filtering; concentrating the filtrate under reduced pressure, and separating and purifying the concentrated residue by silica gel column chromatography to obtain carbonyl substituted chroman/carbonyl substituted chroman compound.
The eluent of silica gel column chromatography is petroleum ether and ethyl acetate, VPetroleum ether/VEthyl acetate＝2～5：1。
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a synthesis method of carbonyl substituted chroman and carbonyl substituted chroman compounds, and discloses a method for synthesizing carbonyl substituted chroman/carbonyl substituted chroman compounds by using PPA (PPA) polyphosphate as a catalyst to catalyze intramolecular cyclization of carbonyl substituted o-allyl/carbonyl substituted isopentenylphenol. The synthesis method disclosed by the invention has the advantages that the reaction time is short (2-10h), the catalyst PPA is cheap and easy to obtain, and the production period and the cost are greatly reduced; the reaction substrate has good universality, the average yield of the product is higher and can reach 91 percent at most, a new method is provided for the synthesis of the carbonyl substituted chroman and the carbonyl substituted chroman compound, and a foundation is laid for the large-scale production of the product and the improvement of the production efficiency.
In order to ensure that the synthesis method of the carbonyl-substituted chroman and chroman compounds is scientific and reasonable, the inventor carries out corresponding research and screening through the following tests to finally determine the technical scheme of the invention.
3-allyl-2-hydroxybenzaldehyde (I1) (0.2mmol) was used as a reaction substrate, and the reaction was carried out in an oil bath at 130 ℃ with stirring for 10 hours using a solvent amount of 0.3 mL. PPA molar equivalent and solvent category are selected as reaction factors to investigate the influence of each reaction factor on yield, and the results are shown in Table 1.
TABLE 1 Effect of various reaction factors on yield
As can be seen from Table 1, the optimum reaction conditions were PPA molar equivalent of 5 and DMF as the reaction solvent. When the reaction substrates I2-I11 are used for synthesis verification according to the optimal conditions, the yield is higher when the PPA molar equivalent is increased to 20 and 30 by a few substrates, so that the PPA molar equivalent is finally selected to be 5-30.
Carbonyl substituted chroman/carbonyl substituted chroman compounds with different substituents are synthesized by using the optimized PPA molar equivalent and the reaction solvent DMF, and are detailed in examples 1-11.
Detailed Description
To further confirm the rationality of the preparation method and the structural accuracy of the synthesized compound, the carbonyl-substituted chroman/carbonyl-substituted chroman compounds prepared in examples 1 to 11 were subjected to nuclear magnetic resonance using nuclear magnetic resonance (1H NMR and13c NMR).
Example 1: a method for synthesizing carbonyl substituted benzodihydrofuran compound comprises the following steps:
adding 1mmol of PPA and 0.3mL of DMF (dimethyl formamide) solvent into a 5mL pressure-resistant reaction bottle, adding 0.2mmol of raw material I1, and stirring in an oil bath at 130 ℃ for reaction for 10 hours; extracting with ethyl acetate for 3 times after reaction, sequentially washing organic layer with water and saturated sodium chloride solution, drying the washed organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and subjecting the residue to silica gel column chromatography (V)Petroleum ether/VEthyl acetateAnd (5) separating and purifying the obtained product to obtain the carbonyl substituted dihydrobenzofuran compound II 1 with the yield of 81%.
Nuclear magnetic resonance of the prepared carbonyl-substituted benzodihydrofuran compound (II 1) (II 1)1H NMR and13c NMR) the data were:1H NMR(600MHz,CDCl3)δ10.23(s,1H),7.59(d,J＝7.8Hz,1H),7.38(dd,J＝7.2,1.2Hz,1H),6.92(t,J＝7.5Hz,1H),5.12(ddq,J＝12.7,8.8,6.3Hz,1H),3.36(dd,J＝15.6,8.9Hz,1H),2.85(dd,J＝15.6,7.4Hz,1H),1.55(d,J＝6.3Hz,3H).13C NMR(151MHz,CDCl3)δ189.00,161.97,130.93,129.53,126.99,120.36,119.51,81.72,36.01,21.83.
example 2: a method for synthesizing carbonyl substituted benzodihydrofuran compound comprises the following steps:
adding 1mmol of PPA and 0.3mL of DMF (dimethyl formamide) solvent into a 5mL pressure-resistant reaction bottle, adding 0.2mmol of raw material I2, and stirring in an oil bath at 150 ℃ for reacting for 6 hours; extracting with ethyl acetate for 3 times after reaction, sequentially washing organic layer with water and saturated sodium chloride solution, drying the washed organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and subjecting the residue to silica gel column chromatography (V)Petroleum ether/VEthyl acetateSeparation and purification are carried out according to the ratio of 5:1), and the carbonyl substituted dihydrobenzofuran compound II 2 is obtained with the yield of 52%.
Nuclear magnetic resonance of the prepared carbonyl-substituted benzodihydrofuran compound (II 2) ((1H NMR and13c NMR) the data were:1H NMR(600MHz,CDCl3)δ9.82(s,1H),7.36(s,1H),7.34(s,1H),5.19–5.12(m,1H),3.96(s,3H),3.43(dd,J＝15.4,9.0Hz,1H),2.93(dd,J＝15.4,7.8Hz,1H),1.58(d,J＝6.3Hz,3H).13C NMR(151MHz,CDCl3)δ190.63,153.85,145.00,130.96,128.47,121.76,111.11,82.25,56.03,36.75,21.79.
example 3: a method for synthesizing carbonyl substituted benzodihydrofuran compound comprises the following steps:
adding 4mmol of PPA, 0.3mL of DMF solvent and 0.2mmol of the raw material I3 into a 5mL pressure-resistant reaction bottle, and stirring in an oil bath at 90 ℃ for reaction for 10 hours; extracting with ethyl acetate for 3 times after reaction, sequentially washing organic layer with water and saturated sodium chloride solution, drying the washed organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and subjecting the residue to silica gel column chromatography (V)Petroleum ether/VEthyl acetateSeparating and purifying the obtained product at a ratio of 4:1) to obtain the carbonyl substituted dihydrobenzofuran compound II 3 with the yield of 78%.
Nuclear magnetic resonance of the prepared carbonyl-substituted benzodihydrofuran compound (II 3) (II 3)1H NMR and13c NMR) the data were:1H NMR(600MHz,CDCl3)δ7.84(s,1H),7.82(d,J＝8.4,1.8Hz,1H),6.79(d,J＝8.4Hz,1H),5.05(m,J＝8.8,7.3,6.4Hz,1H),3.38(dd,J＝15.5,8.9Hz,1H),2.87(dd,J＝15.5,7.4Hz,1H),2.56(s,3H),1.51(d,J＝6.3Hz,3H).13C NMR(151MHz,CDCl3)δ196.72,163.85,130.56,130.46,127.76,125.63,108.92,81.04,36.37,26.40,21.79.
example 4: a method for synthesizing carbonyl substituted benzodihydrofuran compound comprises the following steps:
adding 4mmol of PPA and 0.3mL of DMF (dimethyl formamide) solvent into a 5mL pressure-resistant reaction bottle, adding 0.2mmol of raw material I4, and stirring in an oil bath at 90 ℃ for reaction for 10 hours; after the reaction, ethyl acetate was extracted 3 times, the organic layer was washed with water and saturated sodium chloride solution in this order, and thenThe washed organic layer was dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (V)Petroleum ether/VEthyl acetateSeparating and purifying the obtained product by the ratio of 3:1) to obtain the carbonyl substituted dihydrobenzofuran compound II 4 with the yield of 71%.
Nuclear magnetic resonance of the prepared carbonyl-substituted benzodihydrofuran compound (II 4) (II)1H NMR and13c NMR) the data were:1H NMR(600MHz,CDCl3)δ7.69(d,J＝8.7Hz,1H),6.40(d,J＝8.7Hz,1H),5.16–5.10(m,1H),3.32(dd,J＝15.2,9.0Hz,1H),2.79(dd,J＝15.2,7.2Hz,1H),2.60(s,3H),1.54(d,J＝6.3Hz,3H).13C NMR(151MHz,CDCl3)δ196.54,162.52,157.21,130.52,114.76,113.15,108.68,81.44,33.31,30.71,22.07.
example 5: a method for synthesizing carbonyl substituted benzodihydrofuran compound comprises the following steps:
adding PPA 6mmol, DMF 0.3mL and 0.2mmol of raw material I5 into a 5mL pressure-resistant reaction bottle, and stirring in an oil bath at 160 ℃ for reaction for 10 h; extracting with ethyl acetate for 2 times after reaction, sequentially washing organic layer with water and saturated sodium chloride solution, drying the washed organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and subjecting the residue to silica gel column chromatography (V)Petroleum ether/VEthyl acetateSeparating and purifying the obtained product by the ratio of 5:1) to obtain the carbonyl substituted dihydrobenzofuran compound II 5 with the yield of 90 percent.
Nuclear magnetic resonance of the prepared carbonyl-substituted benzodihydrofuran compound (II 5) (II 5)1H NMR and13c NMR) the data were:1H NMR(600MHz,CDCl3)δ12.82(s,1H),7.90(s,1H),7.79–7.77(m,2H),7.68–7.65(m,2H),7.56(td,J＝7.5,1.2Hz,2H),7.49–7.43(m,4H),5.18(dp,J＝9.2,6.4Hz,1H),3.42(dd,J＝15.6,9.3Hz,1H),2.89(dd,J＝15.6,6.7Hz,1H),1.49(d,J＝6.3Hz,3H).13C NMR(151MHz,CDCl3)δ200.35,192.81,165.50,163.27,139.19,138.08,137.81,132.53,131.95,129.68,128.97,128.43,128.03,114.59,114.34,113.82,83.41,32.89,21.96.
example 6: a method for synthesizing carbonyl substituted chroman compounds comprises the following steps:
adding 1mmol of PPA and 0.3mL of DMF (dimethyl formamide) solvent into a 5mL pressure-resistant reaction bottle, adding 0.2mmol of raw material I6, and stirring in an oil bath at 110 ℃ for reaction for 2 hours; extracting with ethyl acetate for 3 times after reaction, sequentially washing organic layer with water and saturated sodium chloride solution, drying the washed organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and subjecting the residue to silica gel column chromatography (V)Petroleum ether/VEthyl acetateSeparating and purifying the product by the ratio of 3:1) to obtain the carbonyl substituted chroman compound II 6 with the yield of 80 percent.
Nuclear magnetic resonance of the obtained carbonyl-substituted chroman compound (II 6) (II 6)1H NMR and13c NMR) the data were:1H NMR(600MHz,CDCl3)δ13.09(s,1H),7.85(d,J＝15.4Hz,1H),7.64(s,1H),7.61(d,J＝8.5Hz,2H),7.48(d,J＝15.4Hz,1H),6.91(d,J＝8.6Hz,2H),6.39(s,1H),5.38(s,1H),2.80(t,J＝6.7Hz,2H),1.87(t,J＝6.7Hz,2H),1.39(s,6H).13C NMR(151MHz,CDCl3)δ191.76,164.13,161.38,157.90,143.76,131.04,130.53,127.90,118.18,115.98,114.25,112.63,104.93,75.94,32.80,26.99,21.83.
example 7: a method for synthesizing carbonyl substituted chroman compounds comprises the following steps:
adding 1mmol of PPA, 0.3mL of DMF solvent and 0.2mmol of the raw material I7 into a 5mL pressure-resistant reaction bottle, and stirring in an oil bath at 110 ℃ for reaction for 2 h; extracting with ethyl acetate for 2 times after reaction, sequentially washing organic layer with water and saturated sodium chloride solution, drying the washed organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and subjecting the residue to silica gel column chromatography (V)Petroleum ether/VEthyl acetateSeparating and purifying the product by the ratio of 3:1) to obtain the carbonyl substituted chroman compound II 7 with the yield of 77 percent.
Nuclear magnetic resonance of the obtained carbonyl-substituted chroman compound (II 7) (II 7)1H NMR and13c NMR) the data were:1H NMR(600MHz,CDCl3)δ14.84(s,1H),7.85(d,J＝15.6Hz,1H),7.78(d,J＝15.6Hz,1H),7.53(d,J＝8.6Hz,2H),6.89(d,J＝8.6Hz,2H),5.90(s,1H),5.73(s,1H),3.90(s,3H),2.65(t,J＝6.8Hz,2H),1.83(t,J＝6.8Hz,2H),1.38(s,6H).13C NMR(151MHz,CDCl3)δ192.59,165.55,160.75,160.73,157.61,142.02,130.29,128.48,125.39,115.88,105.52,102.03,91.78,76.21,55.70,32.16,26.75,16.12.
example 8: a method for synthesizing carbonyl substituted chroman compounds comprises the following steps:
adding 1mmol of PPA and 0.3mL of DMF (dimethyl formamide) solvent into a 5mL pressure-resistant reaction bottle, adding 0.2mmol of the raw material I8, and stirring in an oil bath at 130 ℃ for reaction for 2 hours; extracting with ethyl acetate for 3 times after reaction, sequentially washing organic layer with water and saturated sodium chloride solution, drying the washed organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and subjecting the residue to silica gel column chromatography (V)Petroleum ether/VEthyl acetate2:1) to obtain the carbonyl substituted chroman compound II 8 with the yield of 81 percent.
Nuclear magnetic resonance of the obtained carbonyl-substituted chroman compound (II 8) (II 8)1H NMR and13c NMR) the data were:1H NMR(600MHz,CDCl3)δ11.51(s,1H),8.21(d,J＝8.9Hz,2H),7.06(d,J＝9.0Hz,2H),6.71(s,1H),6.28(s,1H),3.92(s,3H),2.93(t,J＝6.7Hz,2H),1.92(t,J＝6.7Hz,2H),1.41(s,6H).13C NMR(151MHz,CDCl3)δ175.18,160.99,160.37,158.38,153.91,144.97,135.78,129.16,123.65,114.14,103.54,99.83,76.12,55.43,31.71,26.65,16.25.
example 9: a method for synthesizing carbonyl substituted chroman compounds comprises the following steps:
adding 1mmol of PPA, 0.3mL of DMF solvent and 0.2mmol of raw material I9 into a 5mL pressure-resistant reaction bottle, and stirring in an oil bath at 110 ℃ for reaction for 4 hours; extracting with ethyl acetate for 3 times after reaction, sequentially washing organic layer with water and saturated sodium chloride solution, drying the washed organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and subjecting the residue to silica gel column chromatography (V)Petroleum ether/VEthyl acetateSeparating and purifying the product by the ratio of 3:1) to obtain the carbonyl substituted chroman compound II 9 with the yield of 69 percent.
Nuclear magnetic resonance of the obtained carbonyl-substituted chroman compound (II 9) (II)1H NMR and13c NMR) the data were:1H NMR(600MHz,CDCl3)δ11.80(s,1H),7.20(dd,J＝8.4,2.0Hz,1H),7.16(s,1H),6.85(d,J＝8.4Hz,1H),5.99(s,1H),5.34(dd,J＝13.3,2.8Hz,1H),3.08(dd,J＝17.0,13.3Hz,1H),2.83(t,J＝6.7Hz,2H),2.79(dd,J＝17.0,2.9Hz,1H),2.66–2.55(m,2H),1.85(t,J＝6.7Hz,2H),1.82–1.73(m,2H),1.38(s,6H),1.37(s,3H),1.35(s,3H).13C NMR(151MHz,CDCl3)δ196.12,162.99,161.45,160.04,154.47,129.72,127.47,125.41,121.12,117.56,102.64,100.81,97.41,78.99,76.12,74.58,43.19,32.66,31.91,27.16,26.94,22.57,16.36.
example 10: a method for synthesizing carbonyl substituted chroman compounds comprises the following steps:
adding 1mmol of PPA, 0.3mL of DMF solvent and 0.2mmol of raw material I10 into a 5mL pressure-resistant reaction bottle, and stirring in an oil bath at 130 ℃ for reaction for 2 h; extracting with ethyl acetate for 3 times after reaction, sequentially washing organic layer with water and saturated sodium chloride solution, drying the washed organic layer with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and subjecting the residue to silica gel column chromatography (V)Petroleum ether/VEthyl acetate2:1) to obtain carbonyl substituted chroman compound II 10 with the yield of 91%.
Nuclear magnetic resonance of the obtained carbonyl-substituted chroman compound (II 10) (II 10)1H NMR and13c NMR) the data were:1H NMR(600MHz,CDCl3)δ13.74(s,1H),6.84(s,1H),6.37(s,1H),6.25(s,1H),5.30(t,J＝6.4Hz,1H),4.12(d,J＝6.3Hz,2H),3.83(s,3H),2.73(t,J＝6.8Hz,2H),1.87–1.84(m,5H),1.71(s,3H),1.39(s,6H).13C NMR(151MHz,CDCl3)δ182.04,160.73,160.62,155.89,154.72,154.45,142.40,136.94,132.08,123.27,112.15,103.78,102.87,101.62,94.02,76.04,62.03,31.89,26.75,26.55,25.83,18.22.
example 11: a method for synthesizing carbonyl substituted chroman compounds comprises the following steps:
adding 1mmol of PPA and 0.3mL of DMF (dimethyl formamide) solvent into a 5mL pressure-resistant reaction bottle, adding 0.2mmol of raw material I11, and stirring in an oil bath at 130 ℃ for reaction for 2 hours; after the reaction, ethyl acetate was extracted 3 times, the organic layer was washed with water and a saturated sodium chloride solution in this order, and the washed organic layer was dried over anhydrous sodium sulfateThe organic layer was filtered, and the residue obtained after concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (V)Petroleum ether/VEthyl acetate2:1) to obtain the carbonyl substituted chroman compound II 11 with 89 percent of yield.
Nuclear magnetic resonance of the obtained carbonyl-substituted chroman compound (II 11) (II 11)1H NMR and13c NMR) the data were:1H NMR(600MHz,CDCl3)δ13.76(s,1H),6.82(s,1H),6.41(s,1H),6.27(s,1H),3.53(t,J＝6.8Hz,2H),2.74(t,J＝6.8Hz,2H),1.91(t,J＝6.8Hz,2H),1.86(t,J＝6.8Hz,2H),1.41(s,6H),1.39(s,6H).13C NMR(151MHz,CDCl3)δ182.67,160.51,160.44,154.93,153.27,151.54,137.79,121.33,111.22,103.53,103.03,100.50,93.99,75.94,75.51,32.89,31.92,26.77,26.49,22.37,16.08.
the structural formulas of the carbonyl substituted chroman/carbonyl substituted chroman compounds II 1-11 correspond to the following numbers:
Claims (6)
1. the carbonyl substituted chroman and the carbonyl substituted chroman compound have the following structures shown as formulas II 1-11:
the method is characterized by comprising the following steps:
adding PPA, N-dimethylformamide DMF and carbonyl substituted o-allyl/carbonyl substituted isopentenyl phenol into a pressure-resistant reaction bottle, and heating and stirring for reacting for 2-10 h; separating and purifying after the reaction is finished to obtain a carbonyl substituted chroman/carbonyl substituted chroman compound;
the structures of the carbonyl-substituted o-allyl and carbonyl-substituted isopentenyl phenol are shown as the following formulas I1-11:
2. the method for synthesizing carbonyl-substituted chroman and carbonyl-substituted chroman compounds according to claim 1, wherein: the molar ratio of the carbonyl-substituted o-allyl/carbonyl-substituted isopentenyl phenol to the PPA polyphosphate is 1: 5 to 30.
3. The method for synthesizing carbonyl-substituted chroman and carbonyl-substituted chroman compounds according to claim 1, wherein: the dosage of the solvent DMF is 1.5mL/mmol of carbonyl-substituted o-allyl/carbonyl-substituted isopentenyl phenol.
4. The method for synthesizing carbonyl-substituted chroman and carbonyl-substituted chroman compounds according to claim 1, wherein: the heating is carried out by oil bath heating at 90-160 ℃.
5. The method for synthesizing carbonyl-substituted chroman and carbonyl-substituted chroman compounds according to claim 1, wherein: the separation and purification process after the reaction is as follows: extracting a substance obtained after the reaction is finished for 2-3 times by using ethyl acetate, taking an organic layer, washing the organic layer by using water and a saturated sodium chloride solution in sequence, drying the washed organic layer by using anhydrous sodium sulfate, and filtering; concentrating the filtrate under reduced pressure, and separating and purifying the concentrated residue by silica gel column chromatography to obtain carbonyl substituted chroman/carbonyl substituted chroman compound.
6. The method for synthesizing carbonyl-substituted chroman and carbonyl-substituted chroman compounds according to claim 5, wherein: the silica gel column chromatography elution is carried outThe agent is petroleum ether and ethyl acetate, VPetroleum ether/VEthyl acetate＝2～5：1。
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| CN115160280A (en) * | 2022-06-07 | 2022-10-11 | 贵州农业职业学院 | Method for synthesizing flavanone compound |
| CN120289477A (en) * | 2025-06-13 | 2025-07-11 | 天津泰普药品科技发展有限公司 | A kind of synthetic method of glabridin |
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| WO2016156872A1 (en) * | 2015-04-01 | 2016-10-06 | Cancer Research Technology Limited | Quinoline derivatives as inhibitors of heat shock factor 1 pathway activity |
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