CN110437128B - Synthetic method of 3-thioether-based isoindolinone compound - Google Patents
Synthetic method of 3-thioether-based isoindolinone compound Download PDFInfo
- Publication number
- CN110437128B CN110437128B CN201910761090.9A CN201910761090A CN110437128B CN 110437128 B CN110437128 B CN 110437128B CN 201910761090 A CN201910761090 A CN 201910761090A CN 110437128 B CN110437128 B CN 110437128B
- Authority
- CN
- China
- Prior art keywords
- compound
- thioether
- isoindolinone
- reaction
- nickel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- -1 isoindolinone compound Chemical class 0.000 title claims abstract description 23
- 238000010189 synthetic method Methods 0.000 title claims description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical compound C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000001308 synthesis method Methods 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 4
- 238000010898 silica gel chromatography Methods 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 2
- LGQLOGILCSXPEA-UHFFFAOYSA-L nickel sulfate Chemical compound [Ni+2].[O-]S([O-])(=O)=O LGQLOGILCSXPEA-UHFFFAOYSA-L 0.000 claims description 2
- UQPSGBZICXWIAG-UHFFFAOYSA-L nickel(2+);dibromide;trihydrate Chemical compound O.O.O.Br[Ni]Br UQPSGBZICXWIAG-UHFFFAOYSA-L 0.000 claims description 2
- ZLQBNKOPBDZKDP-UHFFFAOYSA-L nickel(2+);diperchlorate Chemical compound [Ni+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O ZLQBNKOPBDZKDP-UHFFFAOYSA-L 0.000 claims description 2
- KVRSDIJOUNNFMZ-UHFFFAOYSA-L nickel(2+);trifluoromethanesulfonate Chemical compound [Ni+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F KVRSDIJOUNNFMZ-UHFFFAOYSA-L 0.000 claims description 2
- 229910000363 nickel(II) sulfate Inorganic materials 0.000 claims description 2
- KBJMLQFLOWQJNF-UHFFFAOYSA-N nickel(ii) nitrate Chemical compound [Ni+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O KBJMLQFLOWQJNF-UHFFFAOYSA-N 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- 239000003208 petroleum Substances 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
- 238000005406 washing Methods 0.000 claims description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 229930014626 natural product Natural products 0.000 abstract description 6
- 238000011160 research Methods 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract description 4
- 238000011065 in-situ storage Methods 0.000 abstract description 4
- 238000005935 nucleophilic addition reaction Methods 0.000 abstract description 4
- 229910052717 sulfur Inorganic materials 0.000 abstract description 4
- 239000011593 sulfur Substances 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 239000007832 Na2SO4 Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 229910003771 Gold(I) chloride Inorganic materials 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229910001914 chlorine tetroxide Inorganic materials 0.000 description 1
- 230000002153 concerted effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- MJEMIOXXNCZZFK-UHFFFAOYSA-N ethylone Chemical compound CCNC(C)C(=O)C1=CC=C2OCOC2=C1 MJEMIOXXNCZZFK-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- FDWREHZXQUYJFJ-UHFFFAOYSA-M gold monochloride Chemical compound [Cl-].[Au+] FDWREHZXQUYJFJ-UHFFFAOYSA-M 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000003951 lactams Chemical group 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a synthesis method of a 3-thioether isoindolinone compound, which is characterized in that 3-hydroxy-2-benzyl-isoindolinone-1-one compound and thiol compound are catalyzed by Ni (II) to generate imine cations in situ and generate nucleophilic addition reaction to construct the 3-thioether isoindolinone, and the product yield is 82-95%. The method is completed in one step, has simple operation, simple raw materials and reagents and higher reaction yield, avoids the defects of expensive catalyst and harsh conditions of the traditional method, has easy separation and purification of the product, has important value for the synthesis research of the 3-thioether-based isoindolinone compound, and has important significance in the synthesis of sulfur-containing natural products and drug molecules.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a 3-thioether-based isoindolinone compound.
Background
3-thioether-based isoindolinones are very active and important intermediates, which are widely used in natural products and pharmaceutical chemistry. Because the 3-thioether isoindolinone compound is widely applied, the research on the preparation method thereof is always a focus of attention of organic synthesis experts. Many methods are available for preparing such compounds, such as noble metal catalysis, acidic, basic conditions, etc., and the reaction conditions are harsh. Most of the existing reaction methods are high in cost or are not suitable for preparing compounds containing acid-base sensitive functional groups, and after the reaction is finished, the system needs to be neutralized to be neutral, so that the post-treatment operation is complicated.
The construction of carbon-sulfur bonds has wide application in the synthesis of many sulfur-containing natural products and drug molecules. In recent years, chemists have promoted the formation of carbon-sulfur bonds mainly by noble metals, acidic and basic catalysts, such as (IMesPr) AuCl, [ LNi ]2(CH3CN)(THF)](ClO4)3,[Ru(acetone)(R,R-BIPHOP-F)Cp][SbF6],NEt3,SDS/NaHCO3Co/SBA-15. Therefore, a method for constructing a mild and efficient carbon-sulfur bond is urgently needed to be developed.
Imide ions are important electrophilic intermediates in organic synthesis, which form carbon-carbon bonds and carbon heteroatom bonds through intermolecular or intramolecular reactions, thereby synthesizing various biologically important natural products and drug molecules. Having a good leaving group in the alpha position of the amide or lactam helps to generate the N-imide ion. Chemists have developed various interesting transition metal complexes or concerted catalytic systems for the formation of N-imide ions, followed by subsequent intramolecular or intermolecular amidation reactions. For example Au (I)/Ag (I), Sn (NTf)4And Pd (II) -Ag (I) catalytic systems, but the existing synthetic methods have the limitations that the used catalysts are expensive, the catalyst structures are complex and difficult to synthesize or harsh reaction conditions are required, so that the development of a simple and efficient synthetic method for forming imide ions is urgently needed.
Based on the research background, the development of a novel method for simply and efficiently synthesizing the 3-thioether isoindolinone is of great significance.
Disclosure of Invention
The invention aims to provide a novel synthesis method of a novel 3-thioether-based isoindolinone compound. According to the preparation method, imide cations are generated in situ in the reaction, and a thiol compound and the imide cations are subjected to nucleophilic addition reaction, so that the synthesis method is mild in condition, simple and convenient to operate, less in limitation of substitution types of functional groups, and easy to separate and purify the product; has important significance for the synthesis research of 3-thioether isoindolinone.
The invention is realized by the following technical scheme, and provides a synthetic method of a 3-thioether-based isoindolinone compound, which comprises the following reaction steps:
dissolving 3-hydroxy-2-benzyl-isoindoline-1-ketone compound and thiol compound in a solvent, and adding a catalyst for reaction; the catalyst is Ni (II) compound; extracting the reacted reaction solution, combining organic layers, washing, drying, evaporating to remove the solvent, and performing silica gel column chromatography on the residue to obtain the product.
According to the invention, 3-hydroxy-2-benzyl-isoindoline-1-ketone compounds and thiol compounds are catalyzed by Ni (II) to generate imide cations in situ and generate nucleophilic addition reaction, and the product yield is 82-95%. The method has the advantages of simple operation, simple raw materials and reagents, high reaction yield, easy separation and purification of the product, and important significance for the synthesis research of 3-thioether-based isoindolinone compounds, and the synthesis of sulfur-containing natural products and drug molecules, and avoids the defects of expensive catalyst and harsh conditions in the traditional method.
The preparation method generates imine cations in situ in the reaction, and uses thiol compounds to perform nucleophilic addition reaction with the imine cations, the synthesis method has mild conditions, simple and convenient operation, less limitation on the substitution types of functional groups, and easy separation and purification of products; has important significance for the synthesis research of 3-thioether isoindolinone compounds.
Preferably, in the formula, R1 and R2 are respectively selected from any one OR any two OR three substituted combinations of H, C1-C5 alkyl, X, NO2, CN and OR 4.
Preferably, in the formula, R4 is selected from any one of alkyl groups H, C1-C5.
Preferably, in the formula, R3 is selected from any one of alkyl of C1-C10.
Preferably, the reaction conditions are that the reaction is carried out for 5 to 10 hours at a temperature of between 80 and 120 ℃ with stirring. The reaction condition is mild, and the reaction effect is good.
Preferably, the adding amount ratio of the 3-hydroxy-2-benzyl-isoindoline-1-ketone compound, the thiol compound, the catalyst and the solvent is as follows: 1 mmol: (1.5-3) mmol: (0.05-0.2) mmol: (2.5-10) ml.
Preferably, the Ni (II) compound is selected from one or more of nickel perchlorate, nickel trifluoromethanesulfonate, nickel chloride, nickel bromide, nickel nitrate and nickel sulfate.
Preferably, the solvent is one of DMF, DMSO, toluene, acetonitrile, dichloromethane, chloroform, 1, 2-dichloroethane, ethyl acetate, or tetrahydrofuran.
Preferably, the eluent of the silica gel column chromatography is the combination of ethyl acetate and one or more of petroleum ether, normal hexane and cyclohexane.
The invention has the beneficial effects that: the experiment is completed in one step, the operation is simple, the raw materials and the reagents are simple, the reaction yield is high and reaches 82% -95%, the defects of high cost and harsh conditions of the catalyst in the traditional method are avoided, and the product is easy to separate and purify; has important application value in the synthesis of natural products containing sulfur and drug molecules.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The application of the principles of the present invention will now be described in further detail with reference to specific embodiments.
Example 1:
a100 mL round-bottom flask was charged with 2.39g (10mmol) of Compound I-1, 1.24g (20mmol) of Compound II-1, 0.26g (1mmol) of solid Ni (ClO)4)2Finally, 20mL of dry 1, 2-dichloroethane were added and the resulting mixture was stirred at 80 ℃ for 10 hours. The reaction mixture was cooled to room temperature, poured into ice water, extracted with 50mL × 3 dichloromethane, the organic phases combined and washed once with saturated brine, anhydrous Na2SO4Drying, filtering, concentrating to remove solvent to obtain crude product, and separating by column chromatography to obtain pure product of compound III-1. Oily liquid, 2.60g, 92% yield.1HNMR(400MHz,CDCl3)δ:7.87(d,J＝7.5Hz,1H),7.57(s,2H),7.51–7.44(m,1H),7.30(dq,J＝13.7Hz,7.3Hz,5H),5.38(d,J＝14.7Hz,1H),5.28(s,1H),4.39(d,J＝14.7Hz,1H),1.96(dd,J＝12.3Hz,7.5Hz,1H),1.87–1.79(m,1H),0.96(t,J＝7.5Hz,3H)；13C NMR(CDCl3,100MHz)δ:167.33,143.66,136.91,132.12,131.95,128.86,128.79,128.60,127.67,123.61,123.56,62.85,42.85,20.21,14.14；HRMS(ESI)calcd for C17H18NOS[M+H]+284.1104,found 284.1104.
Example 2:
a100 mL round-bottomed flask was charged with 2.39g (10mmol) of Compound I-1, 1.52g (20mmol) of Compound II-2, 0.26g (1mmol) of solid Ni (ClO)4)2Finally, 25mL of dry DMF was added and the resulting mixture was stirred at 100 ℃ for 5 hours until the reaction was complete. The reaction mixture was cooled to room temperature, poured into water, stirred, extracted with 50mL × 3 dichloromethane, the organic phases combined and washed once with saturated brine, anhydrous Na2SO4Drying, filtering, concentrating to remove solvent to obtain crude product, and separating by column chromatography to obtain pure product of compound III-2. Oily liquid, 2.67g, yield 90%.1HNMR(400MHz,CDCl3)δ7.87(d,J＝7.5Hz,1H),7.57(d,J＝12.6Hz,2H),7.52–7.43(m,1H),7.29(ddd,J＝22.2Hz,13.8Hz,6.9Hz,5H),5.37(d,J＝14.7Hz,1H),5.27(s,1H),4.39(d,J＝14.7Hz,1H),1.90(dt,J＝12.3Hz,7.4Hz,1H),1.82–1.69(m,1H),1.28(dt,J＝14.5Hz,7.2Hz,2H),0.80(t,J＝7.3Hz,3H)；13C NMR(CDCl3,100MHz)δ:167.35,143.69,136.91,132.03,128.85,128.78,128.60,127.66,123.60,123.52,62.70,42.85,28.02,22.36,13.59；HRMS(ESI)calcd for C18H20NOS[M+H]+298.1260,found 298.1261.
Example 3:
a100 mL round-bottomed flask was charged with 2.39g (10mmol) of Compound I-1, 1.35g (15mmol) of Compound II-3, 0.09g (0.5mmol) of solid Ni (NO)3)2Finally, 50mL of dry DMSO was added and the resulting mixture was stirred vigorously at 120 ℃ for 5 hours. The reaction mixture was cooled to room temperature, poured into water, stirred, extracted with 50mL × 3 dichloromethane, the organic phases combined and washed once with saturated brine, anhydrous Na2SO4Drying, filtering, concentrating, evaporating to remove solvent to obtain crude product, and purifying by column chromatography to obtain pure product of compound III-3. Oily liquid, 2.58g, yield 87%.1HNMR(400MHz,CDCl3)δ:7.87(d,J＝7.5Hz,1H),7.60–7.51(m,2H),7.51–7.44(m,1H),7.30(ddd,J＝22.5Hz,13.9Hz,7.0Hz,5H),5.37(d,J＝14.7Hz,1H),5.28(s,1H),4.37(d,J＝14.7Hz,1H),1.80(dd,J＝12.0Hz,6.7Hz,1H),1.63(dd,J＝11.9Hz,6.9Hz,1H),1.46(dt,J＝13.3Hz,6.7Hz,1H),0.81(t,J＝6.2Hz,6H)；13C NMR(CDCl3,100MHz)δ:167.39,143.64,136.91,132.10,131.98,128.85,128.81,128.78,128.61,127.67,123.59,123.49,62.59,42.85,34.60,28.07,22.14,22.08；HRMS(ESI)calcd for C18H20NOS[M+H]+298.1260,found 298.1261.
Example 4:
a100 mL round bottom flask was charged with 2.39g (10mmol) of Compound II-1, 1.86g (15mmol) of Compound II-4, 0.13g (10mmol) of solid NiCl2Finally, 50mL of 1, 2-dichloroethane were added and the resulting mixture was stirred vigorously at 80 ℃ for 7 hours. The reaction mixture was cooled to room temperature, poured into water, stirred, extracted with 50mL × 3 dichloromethane, the organic phases combined and washed once with saturated brine, anhydrous Na2SO4Drying, filtering, concentrating to remove solvent to obtain oily residue, and purifying by column chromatography to obtain pure compound III-4. Oily liquid, 3.14g, 91% yield.1H NMR(400MHz,CDCl3)δ:7.89(d,J＝7.2Hz,1H),7.55–7.45(m,3H),7.33–7.24(m,5H),7.21–7.12(m,3H),6.95(d,J＝6.9Hz,2H),5.30(s,1H),5.22(d,J＝14.8Hz,1H),4.26(d,J＝14.8Hz,1H),3.09(d,J＝2.8Hz,2H)；13C NMR(CDCl3,100MHz)δ:167.25,143.15,137.04,136.90,132.22,132.08,129.02,128.83,128.80,128.75,128.61,128.50,127.70,127.1,123.68,123.59,63.24,42.89,31.29；HRMS(ESI)calcd for C22H20NOS[M+H]+346.1260,found 346.1261.
Example 5:
a100 mL round bottom flask was charged with 2.39g (10mmol) of Compound I-1, 2.04g (20mmol) of Compound II-5, 0.13g (1mmol) of solid NiCl2Finally, 100mL of dry DMF was added and the resulting mixture was stirred vigorously at 100 ℃ for 8 hours. The reaction mixture was cooled to room temperature, poured into water, stirred, extracted with 50mL × 3 dichloromethane, the organic phases combined and washed once with saturated brine, anhydrous Na2SO4Drying, filtering, concentrating to remove solvent to obtain oily residue, and purifying by column chromatography to obtain pure compound III-5. Oily liquid, 2.78g, yield 86%.1H NMR(400MHz,CDCl3)δ:7.88(d,J＝7.5Hz,1H),7.56(dd,J＝7.0Hz,5.5Hz,2H),7.50–7.39(m,1H),7.38–7.16(m,5H),5.39(d,J＝14.7Hz,1H),5.29(s,1H),4.42(d,J＝14.7Hz,1H),2.32(dd,J＝15.3Hz,7.8Hz,1H),1.78–1.67(m,1H),1.65–1.46(m,2H),1.43–1.23(m,4H),1.19–1.09(m,1H)；13C NMR(CDCl3,100MHz)δ:167.28,144.10,136.94,131.95,131.76,128.82,128.79,128.75,128.61,128.58,128.56,127.65,123.83,123.63,63.24,42.90,39.66,34.56,34.10,24.72,24.44；HRMS(ESI)calcd for C20H22NOS[M+H]+324.1417,found324.1418.
Example 6:
circle of 100mL2.69g (10mmol) of Compound I-2, 1.52g (20mmol) of Compound II-2, 0.22g (1mmol) of solid NiBr were added to a bottom flask2Finally 50mL of dry DMF was added and the resulting mixture was stirred at 100 ℃ for 10 h. The reaction mixture was cooled to room temperature, poured into water, stirred, extracted with 50mL × 3 dichloromethane, the organic phases combined and washed once with saturated brine, anhydrous Na2SO4Drying, filtering, concentrating to remove solvent to obtain crude product, and purifying by column chromatography to obtain pure product of compound III-6. Oily liquid, 2.88g, 88% yield.1H NMR(400MHz,CDCl3)δ:7.86(d,J＝7.5Hz,1H),7.62–7.52(m,2H),7.51–7.41(m,1H),7.28(t,J＝6.4Hz,2H),6.84(d,J＝8.6Hz,2H),5.31(d,J＝14.5Hz,1H),5.26(s,1H),4.32(d,J＝14.5Hz,1H),3.77(s,3H),1.83(ddt,J＝53.5Hz,12.2Hz,7.4Hz,2H),1.29(dt,J＝14.4Hz,7.2Hz,2H),0.81(t,J＝7.3Hz,3H)；13C NMR(CDCl3,100MHz)δ:167.27,159.13,143.69,132.04,129.97,129.00,128.81,123.55,123.47,114.13,62.56,55.28,42.23,27.97,22.35,13.57；HRMS(ESI)calcd for C19H22NO2S[M+H]+328.1366,found 328.1366.
Of course, the present invention is not limited to the above examples, and technical features of the present invention that are not described may be implemented by or using the prior art, and are not described herein again; while the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art will appreciate that various changes, modifications, additions and substitutions can be made without departing from the spirit of the invention and the scope of the invention as defined in the accompanying claims.
Claims (5)
1. A synthetic method of a 3-thioether-based isoindolinone compound comprises the following reaction steps:
dissolving 3-hydroxy-2-benzyl-isoindoline-1-ketone compound and thiol compound in a solvent, and adding a catalyst for reaction; the catalyst is Ni (II) compound; extracting the reaction solution after the reaction, combining organic layers, washing, drying, evaporating to remove the solvent, and performing silica gel column chromatography on the residue to obtain a product;
the synthesis method of the 3-thioether isoindolinone is characterized in that in the formula, R1 and R2 are respectively selected from H, C1-C5 alkyl, halogen substituent and NO2CN and OR4Any one or any two or three of the substitution combination, R3 is selected from any one of C1-C10 alkyl, R4 is selected from any one of H, C1-C5 alkyl; the Ni (II) compound is selected from one or more of nickel perchlorate, nickel trifluoromethanesulfonate, nickel chloride, nickel bromide, nickel nitrate and nickel sulfate.
2. The method for synthesizing 3-thioether-based isoindolinone according to claim 1, wherein the reaction condition is stirring reaction at 80-120 ℃ for 5-10 h.
3. The method for synthesizing 3-thioether-based isoindolinone according to claim 1, wherein the 3-hydroxy-2-benzyl-isoindoline-1-one compound, the thiol compound, the catalyst and the solvent are added in the following ratio: 1 mmol: (1.5-3) mmol: (0.05-0.2) mmol: (2.5-10) ml.
4. The method of claim 1, wherein the solvent is one of DMF, DMSO, toluene, acetonitrile, dichloromethane, chloroform, 1, 2-dichloroethane, ethyl acetate or tetrahydrofuran.
5. The method for synthesizing 3-thioether-based isoindolinone according to claim 1, wherein the eluent of the silica gel column chromatography is one or more of ethyl acetate, petroleum ether, n-hexane and cyclohexane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910761090.9A CN110437128B (en) | 2019-08-17 | 2019-08-17 | Synthetic method of 3-thioether-based isoindolinone compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910761090.9A CN110437128B (en) | 2019-08-17 | 2019-08-17 | Synthetic method of 3-thioether-based isoindolinone compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110437128A CN110437128A (en) | 2019-11-12 |
| CN110437128B true CN110437128B (en) | 2022-07-12 |
Family
ID=68436248
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910761090.9A Active CN110437128B (en) | 2019-08-17 | 2019-08-17 | Synthetic method of 3-thioether-based isoindolinone compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110437128B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111057128B (en) * | 2019-12-25 | 2023-05-16 | 哈尔滨师范大学 | Sulfur-containing isoindolone cyclic peptide derivative and preparation method thereof |
| CN114539124B (en) * | 2022-02-28 | 2023-07-21 | 大连大学 | Method for enantioselectively synthesizing N, 3-disubstituted-1-isoindolinone compound |
| CN114394926B (en) * | 2022-02-28 | 2023-06-27 | 大连大学 | High-yield synthesis method of N, 3-disubstituted-1-isoindolinone compound |
-
2019
- 2019-08-17 CN CN201910761090.9A patent/CN110437128B/en active Active
Non-Patent Citations (4)
| Title |
|---|
| A Multimetallic Piano-Stool Ir−Sn3 Catalyst for Nucleophilic Substitution Reaction of γ-Hydroxy Lactams through N-Acyliminium Ions;Arnab Kumar Maity等;《J. Org. Chem.》;20120224;第77卷;2935−2941 * |
| Josipa Suc等.Chiral Brønsted acid-catalysed enantioselective synthesis of isoindolinone-derived N(acyl),S-acetals.《ChemComm》.2015,第52卷2071-2074. * |
| Multimetallic Iridium-Tin (Ir-Sn3) Catalyst in N-Acyliminium Ion Chemistry: Synthesis of 3-Substituted Isoindolinones via Intra-and Intermolecular Amidoalkylation Reaction;Arnab Kumar Maity等;《Adv. Synth. Catal》;20140731;第356卷;2627-2642 * |
| PdII/AgI‑Catalyzed Room-Temperature Reaction of γ‑Hydroxy Lactams: Mechanism, Scope, and Antistaphylococcal Activity;Manali Dutta等;《J. Org. Chem》;20170117;第82卷;2193−2198 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110437128A (en) | 2019-11-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110437128B (en) | Synthetic method of 3-thioether-based isoindolinone compound | |
| CN110437129B (en) | Simple method for synthesizing 3-ether-based isoindolinone compound | |
| CN109651210B (en) | Preparation method of 3-sulfonyl-1, 2-dihydronaphthalene compound | |
| CN109096162B (en) | Sc-catalyzed nucleophilic addition reaction method of mercaptan to o-methylenebenzoquinone | |
| Wang et al. | Synthesis of [2.2] paracyclophane-based bidentate oxazoline–carbene ligands for the asymmetric 1, 2-silylation of N-tosylaldimines | |
| CN113527173B (en) | Method for synthesizing indole terpene analogues through Heck tandem reaction | |
| CN111662202B (en) | Synthetic method of alpha-ketoamide compound | |
| CN111170926B (en) | Method for catalyzing asymmetric synthesis of chiral beta-alkynyl-beta-aminoketone derivative | |
| CN110540516B (en) | Preparation method of 1-sulfonylmethyl-3, 4-dihydronaphthalene | |
| CN110467556B (en) | Nucleophilic reaction method for catalyzing imine ions and acetophenone by nickel | |
| JP4413507B2 (en) | Pincer metal complex, method for producing the same, and pincer metal complex catalyst | |
| CN108129348B (en) | Nitrine trifluoromethoxy compound and its synthetic method | |
| CN112939830B (en) | Nucleophilic reaction method of alkenyl thioether to o-methylene benzoquinone | |
| CN110467613B (en) | Reaction method for alkylation of imide cation intramolecular amide by nickel catalysis | |
| JP5232989B2 (en) | Optically active 2,6-bisaminomethylpyridine derivative, production method thereof and use thereof | |
| CN111499660A (en) | Chiral sulfonamide proline bifunctional catalyst and preparation method and application thereof | |
| CN101314559A (en) | Preparation of aromatic chirality secondary alcohol compounds | |
| CN113200884B (en) | Chiral carboxylic acid compound and synthesis method and application thereof | |
| CN115093413B (en) | Dihydropyridino spiro [3,4' ] indole and tetrahydropyridofuran [2,3-b ] indol-5-one skeletons and preparation thereof | |
| TWI222970B (en) | Improved process for asymmetric hydrogenation | |
| CN110467558B (en) | Reaction method for synthesizing 3-aminoisoindolinone under catalysis of nickel | |
| CN116478052B (en) | Method for synthesizing 1-naphthylamine derivative by copper catalysis | |
| CN114436922B (en) | Compound containing C-S bond, and preparation method and application thereof | |
| CN116375602B (en) | Method for photochemically synthesizing benzonitrile by using arylthianthrene salt | |
| CN113999207B (en) | Pyridyl-containing chiral NNN tridentate ligand, asymmetric catalytic hydrogenation synthesis thereof and application of pyridyl-containing chiral NNN tridentate ligand in asymmetric catalytic reaction |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20221215 Address after: Room 3115, No. 135, Ward Avenue, Ping'an Street, Changqing District, Jinan, Shandong 250300 Patentee after: Shandong Jiqing Technology Service Co.,Ltd. Address before: 250353 University Road, Changqing District, Ji'nan, Shandong Province, No. 3501 Patentee before: Qilu University of Technology |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20240717 Address after: 250353 University Road, Changqing District, Ji'nan, Shandong Province, No. 3501 Patentee after: Qilu University of Technology (Shandong Academy of Sciences) Country or region after: China Address before: 250306 Room 3115, No. 135, Ward Avenue, Ping'an Street, Changqing District, Jinan City, Shandong Province Patentee before: Shandong Jiqing Technology Service Co.,Ltd. Country or region before: China |