CN114409662A - Method for synthesizing spiro [ pyrrolidine-3, 2' -oxindole ] skeleton compound - Google Patents
Method for synthesizing spiro [ pyrrolidine-3, 2' -oxindole ] skeleton compound Download PDFInfo
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- CN114409662A CN114409662A CN202210226824.5A CN202210226824A CN114409662A CN 114409662 A CN114409662 A CN 114409662A CN 202210226824 A CN202210226824 A CN 202210226824A CN 114409662 A CN114409662 A CN 114409662A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 49
- 125000003003 spiro group Chemical group 0.000 title claims abstract description 31
- 238000000034 method Methods 0.000 title claims abstract description 24
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 239000000758 substrate Substances 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 6
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 3
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- -1 (2,2, 2-trifluoroethyl) imino Chemical group 0.000 abstract description 5
- 150000001299 aldehydes Chemical class 0.000 abstract description 5
- 230000003197 catalytic effect Effects 0.000 abstract description 5
- 239000000376 reactant Substances 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000011734 sodium Substances 0.000 description 12
- 239000012043 crude product Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 description 5
- 229940117916 cinnamic aldehyde Drugs 0.000 description 5
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 4
- XKGOAMJBNGNKSS-UHFFFAOYSA-N FC(C\N=C/1\C(NC2=CC=CC=C\12)=O)(F)F Chemical class FC(C\N=C/1\C(NC2=CC=CC=C\12)=O)(F)F XKGOAMJBNGNKSS-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- KVXVLARNFDFDEK-UHFFFAOYSA-N 1-methyl-3-(2,2,2-trifluoroethylimino)indol-2-one Chemical compound CN1C2=CC=CC=C2C(=NCC(F)(F)F)C1=O KVXVLARNFDFDEK-UHFFFAOYSA-N 0.000 description 2
- 229910014263 BrF3 Inorganic materials 0.000 description 2
- 229910020323 ClF3 Inorganic materials 0.000 description 2
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 150000005623 oxindoles Chemical class 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- HONRSHHPFBMLBT-OWOJBTEDSA-N (e)-3-(4-chlorophenyl)prop-2-enal Chemical compound ClC1=CC=C(\C=C\C=O)C=C1 HONRSHHPFBMLBT-OWOJBTEDSA-N 0.000 description 1
- ZLVBDEOINCJRRV-UHFFFAOYSA-N 1-benzyl-3-(2,2,2-trifluoroethylimino)indol-2-one Chemical compound C(C1=CC=CC=C1)N1C(C(C2=CC=CC=C12)=NCC(F)(F)F)=O ZLVBDEOINCJRRV-UHFFFAOYSA-N 0.000 description 1
- KIPSRYDSZQRPEA-UHFFFAOYSA-N 2,2,2-trifluoroethanamine Chemical compound NCC(F)(F)F KIPSRYDSZQRPEA-UHFFFAOYSA-N 0.000 description 1
- NXTVAYZXNKQSRK-UHFFFAOYSA-N 2-aminoindol-3-one Chemical compound C1=CC=C2C(=O)C(=N)NC2=C1 NXTVAYZXNKQSRK-UHFFFAOYSA-N 0.000 description 1
- XYRAWLRFGKLUMW-UHFFFAOYSA-N 3-(4-bromophenyl)prop-2-enal Chemical compound BrC1=CC=C(C=CC=O)C=C1 XYRAWLRFGKLUMW-UHFFFAOYSA-N 0.000 description 1
- IGXUUWYVUGBMFT-UHFFFAOYSA-N 3-methyleneoxindole Chemical compound C1=CC=C2C(=C)C(=O)NC2=C1 IGXUUWYVUGBMFT-UHFFFAOYSA-N 0.000 description 1
- XKYGPXHTXPZYFV-UHFFFAOYSA-N CN(C(C(C1=NCC(F)(F)F)=C2)=CC=C2Cl)C1=O Chemical compound CN(C(C(C1=NCC(F)(F)F)=C2)=CC=C2Cl)C1=O XKYGPXHTXPZYFV-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a method for synthesizing spiro [ pyrrolidine-3, 2' -oxindole ] skeleton compounds, belongs to the technical field of chemical synthesis, and solves the problems of long route, expensive raw materials, environmental friendliness, high cost and the like of the skeleton compounds in the synthesis process. The method comprises the step of synthesizing a compound with a spiro [ pyrrolidine-3, 2' -oxindole ] structure with an unsaturated aldehyde or a derivative thereof under the catalytic action of alkali by using a compound shown as a formula I as a substrate. The invention efficiently prepares the (3R,3' S,4' R,5' S) -1-aryl-2-oxo-4 ' -phenyl-5 ' - (trifluoromethyl) spiro [ indoline-3, 2' -pyrrolidine ] -3' -formaldehyde derivative by substituting a reactant molecule with a simple structure unit for 3- ((2,2, 2-trifluoroethyl) imino) -1H-indol-2-ketone and unsaturated aldehyde under the catalytic action of alkali, effectively reduces the reaction cost, and has the advantages of simple reaction condition, good universality of the derivative, excellent yield, simple operation and the like.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing a spiro [ pyrrolidine-3, 2' -oxindole ] skeleton compound.
Background
The spiro [ pyrrolidine-3, 2' -oxindole ] skeleton compound is a skeleton commonly used in natural product chemistry and pharmaceutical chemistry, and the compound containing the skeleton has wide biological activities of anti-inflammation, anti-tumor, anti-bacteria and the like.
In the prior art, the synthesis method of spiro [ pyrrolidine-3, 2' -oxindole ] skeleton compounds mainly comprises the following three methods: (1) constructing a spiro [ pyrrolidine-3, 2' -oxindole ] skeleton by an addition-cyclization reaction of an unsaturated oxindole derivative as a starting substrate, such as isatin, methyleneoxindole or isatin imine, with a reactant having a nucleophilic site and a electrophilic site; (2) coupling 3-substituted oxindole with a reactant, and constructing a spiro [ pyrrolidine-3, 2' -oxindole ] skeleton through an addition-cyclization process; (3) the spiro [ pyrrolidine-3, 2' -oxindole ] skeleton is constructed by coupling oxindole with double nucleophilic sites at C3 position with two other reaction substrates or a single reactant with two electrophilic sites.
However, the above methods have respective disadvantages, such as complicated preparation of the substrate, expensive reagents used, environmental pollution and non-recoverability of the catalyst, and harsh reaction conditions. Therefore, the method for preparing the spiro [ pyrrolidine-3, 2' -oxindole ] skeleton, which is simple to operate, mild in reaction conditions, high in yield and low in cost, has important significance.
Disclosure of Invention
The invention aims to provide a method for synthesizing spiro [ pyrrolidine-3, 2 '-oxindole ] skeleton compounds, which takes cheap and easily available commodities as raw materials, can obtain the spiro [ pyrrolidine-3, 2' -oxindole ] skeleton compounds only by reaction at normal temperature under the action of base catalysis, and solves the problems of long route, expensive raw materials, environmental friendliness, high cost and the like in the synthesis process of the skeleton compounds.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention provides a method for synthesizing spiro [ pyrrolidine-3, 2 '-oxindole ] skeleton compounds, which comprises the following steps of taking a compound shown as a formula I as a substrate, and synthesizing a compound with a spiro [ pyrrolidine-3, 2' -oxindole ] structure with unsaturated aldehyde or derivatives thereof under the catalytic action of alkali, wherein the general formula of the chemical reaction is as follows:
wherein: r1Is halogen atom, methyl, methoxyl, nitryl, 4, 6-difluoro or 5, 6-difluoro;
R2is methyl, substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl or thienyl;
R3is substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl or thienyl.
In some embodiments of the invention, R3Is phenyl or phenyl substituted by halogen.
In some embodiments of the invention, the halogen is selected from bromine or chlorine.
In some embodiments of the invention, the base comprises at least one of triethylamine, DIPEA, potassium carbonate, potassium bicarbonate; triethylamine is preferred.
In some embodiments of the invention, the molar ratio of the compound of formula I to the compound of formula II is from 0.8 to 1.2: 0.8 to 1.2.
In some embodiments of the invention, the molar ratio of the compound of formula I to the compound of formula II is preferably 1:
1.1 to 1.3; more preferably 1: 1.2.
in some embodiments of the invention, the molar ratio of the compound of formula I to the base is 1: 4-6, preferably 1: 4.5-5.5, more preferably 1: 4.9 to 5.1.
In some embodiments of the invention, the reaction solvent comprises at least one of dichloromethane, acetonitrile, 2-methyltetrahydrofuran, 1, 2-dichloroethane, and toluene.
In some embodiments of the invention, the reaction temperature is room temperature.
In some embodiments of the invention, 1.0 molar equivalent of substituted 3- ((2,2, 2-trifluoroethyl) imino) -1H-indol-2-one and 1.2 molar equivalents of cinnamaldehyde are subjected to [3+2] cyclization reaction under the catalysis of triethylamine, the reaction temperature is 10-30 ℃, and the reaction solvent is dichloromethane. The reaction process is as follows:
in the present invention, the reaction substrate, the compound of formula I, is prepared as follows:
compared with the prior art, the invention has the following beneficial effects:
the method has scientific design and skillful conception, and the (3R,3' S,4' R,5' S) -1-aryl-2-oxo-4 ' -phenyl-5 ' - (trifluoromethyl) spiro [ indoline-3, 2' -pyrrolidine ] -3' -formaldehyde derivative is efficiently prepared by substituting reactant molecules with simple structural units for 3- ((2,2, 2-trifluoroethyl) imino) -1H-indol-2-one and unsaturated aldehyde under the catalytic action of alkali. The method effectively reduces the reaction cost, and has the advantages of simple reaction conditions, good derivative universality, excellent yield, simple operation and the like.
Drawings
FIG. 1 is a hydrogen spectrum of compound III-1 obtained in example 1;
FIG. 2 is a carbon spectrum of the compound III-1 obtained in example 1;
FIG. 3 is a mass spectrum of the compound III-1 obtained in example 1.
Detailed Description
The advantages and the preparation of the present invention will be better understood in connection with the following examples, which are intended to illustrate, but not to limit the scope of the invention. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
A method for synthesizing spiro [ pyrrolidine-3, 2 '-oxindole ] skeleton compounds comprises the steps of taking a compound shown in formula I as a substrate, and synthesizing a compound with a spiro [ pyrrolidine-3, 2' -oxindole ] structure with unsaturated aldehyde or derivatives thereof under the catalytic action of alkali, wherein the chemical reaction general formula is shown as follows:
wherein: r1Is halogen atom, methyl, methoxyl, nitryl, 4, 6-difluoro or 5, 6-difluoro;
R2is methyl, substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl or thienyl;
R3is substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl or thienyl.
Preferably, R3Is phenyl or phenyl substituted by halogen.
Preferably, the halogen is selected from bromine or chlorine.
Preferably, the base comprises at least one of triethylamine, DIPEA, potassium carbonate, potassium bicarbonate; more preferably triethylamine.
Preferably, the molar ratio of the compound of formula I to the compound of formula II is 0.8-1.2: 0.8 to 1.2.
Preferably, the molar ratio of compound of formula I to compound of formula II is preferably 1: 1.1 to 1.3; more preferably 1: 1.2.
preferably, the molar ratio of the compound of formula I to the base is 1: 4-6, preferably 1: 4.5-5.5, more preferably 1: 4.9 to 5.1.
Preferably, the reaction solvent includes at least one of dichloromethane, acetonitrile, 2-methyltetrahydrofuran, 1, 2-dichloroethane, and toluene.
Preferably, the reaction temperature is room temperature.
The reaction substrates in the examples of the invention are compounds of formula I: the synthetic route for substituted 3- ((2,2, 2-trifluoroethyl) imino) -1H-indol-2-ones is as follows:
the substituted isatin S1, the corresponding benzyl bromide or methyl iodide and potassium carbonate are reacted by heating in acetonitrile. After completion of the reaction monitored by TLC, the solvent was distilled off under reduced pressure, and the product was extracted with ethyl acetate and aqueous liquid. Drying the organic layer with anhydrous sodium sulfate, concentrating to obtain crude product, and separating and purifying by silica gel column chromatography (eluent: petroleum ether/ethyl acetate, volume ratio 5:1) to obtain S2; dissolving S2 in toluene, adding 2,2, 2-trifluoroethylamine and p-toluenesulfonic acid hydrate, reacting at room temperature, monitoring the reaction completion by TLC, cooling the reaction mixture to room temperature, stirring with saturated sodium bicarbonate aqueous solution for 10 minutes, and extracting with ethyl acetate. And (3) combining organic phases, drying the organic phases by anhydrous sodium sulfate, decompressing and spin-drying the organic phases, and separating and purifying a crude product by silica gel column chromatography (eluent: petroleum ether/ethyl acetate in a volume ratio of 5:1) to obtain a compound shown in the formula I.
Example 1
This example discloses spiro [ pyrrolidine-3, 2' -oxindole ] backbone compounds of the present invention of formula III-1: the preparation method of (3R,3' S,4' S, 5' S) -1-methyl-2-oxo-4 ' -phenyl-5 ' - (trifluoromethyl) spiro [ indoline-3, 2' -pyrrolidine ] -3' -formaldehyde comprises the following steps:
to a dry 10mL reaction tube were added 50mg of 1-methyl-3- ((2,2, 2-trifluoroethyl) imino) -1H-indol-2-one (0.21mmol), 32.76mg of cinnamaldehyde (0.25mmol) and 104.50mg of Et respectively3N (1.03mmol), then adding 5.0mL of dichloromethane, reacting at room temperature, monitoring the reaction by TLC, concentrating the solvent, separating the obtained crude product by column chromatography, and washing and dehydrating the crude product with polar petroleum ether and ethyl acetate of 3:1 to obtain the target product III-1 with the yield of 89%.
1H NMR(600MHz,CDCl3)δ9.09(d,J＝1.6Hz,1H),7.50–7.46(m,2H),7.41–7.31(m,4H),7.29–7.26(m,1H),7.14(t,J＝7.6Hz,1H),6.87(d,J＝7.8Hz,1H),4.52(dq,J＝11.9,5.8Hz,1H),4.22(t,J＝10.2Hz,1H),3.64(dd,J＝10.9,1.7Hz,1H),3.31–3.24(m,3H),2.74(d,J＝6.8Hz,1H).13C NMR(151MHz,CDCl3)δ196.54,178.57,142.86,137.31,130.09,129.02,128.21,128.07,127.88,125.43(q,J＝279.5Hz),125.40,123.78,108.86,67.75,66.13,65.37(q,J＝29.4Hz),45.51,26.74.HRMS(ESI)calculated[M+Na]+for C20H17F3N2O2Na:397.1140,found:397.1133.
Example 2
This example discloses spiro [ pyrrolidine-3, 2' -oxindole ] backbone compounds of the present invention of formula iii-2: the preparation method of (3R,3' S,4' R,5' S) -1, 7-dimethyl-2-oxo-4 ' -phenyl-5 ' - (trifluoromethyl) spiro [ indoline-3, 2' -pyrrolidine ] -3' -formaldehyde comprises the following steps:
to a dry 10mL reaction tube were added 50mg of 1, 7-dimethyl-3- ((2,2, 2-trifluoroethyl) imino) -1H-indol-2-one (0.20mmol), 30.97mg of cinnamaldehyde (0.23mmol) and 98.79mg of Et, respectively3N (0.98mmol), then adding 5.0mL of dichloromethane, reacting at room temperature, monitoring the reaction by TLC, concentrating the solvent, separating the obtained crude product by column chromatography, and washing and dehydrating to obtain the target product III-2 with the yield of 80 percent, wherein the ethyl acetate is 3: 1.
1H NMR(600MHz,CDCl3)δ9.06(d,J＝1.7Hz,1H),7.50–7.45(m,2H),7.40–7.31(m,2H),7.29–7.26(m,1H),7.19(dd,J＝7.4,1.4Hz,1H),7.06(d,J＝8.1Hz,1H),7.01(t,J＝7.5Hz,1H),4.53(dq,J＝10.8,5.5Hz,1H),4.20(t,J＝10.2Hz,1H),3.60(dd,J＝10.6,1.7Hz,1H),3.54(s,3H),2.69(dd,J＝10.3,5.1Hz,1H),2.57(s,3H).13C NMR(151MHz,CDCl3)δ196.71,179.55,140.50,137.38,133.81,128.99,128.73,128.23,127.83,125.40(q,J＝279.6Hz),123.68,123.35,120.57,67.11,66.27,65.29(q,J＝29.5Hz),45.35,30.17,19.02.HRMS(ESI)calculated[M+Na]+for C21H19F3N2O2Na:411.1297,found:411.1291.
Example 3
This example discloses spiro [ pyrrolidine-3, 2' -oxindole ] backbone compounds of the present invention of formula iii-3: the preparation method of (3R,3' S,4' R,5' S) -5-chloro-1-methyl-2-oxo-4 ' -phenyl-5 ' - (trifluoromethyl) spiro [ indoline-3, 2' -pyrrolidine ] -3' -formaldehyde comprises the following specific steps:
to a dry 10mL reaction tube were added 50mg of 5-chloro-1-methyl-3- ((2,2, 2-trifluoroethyl) imino) -1H-indol-2-one (0.18mmol), 28.73mg of cinnamaldehyde (0.22mmol) and 91.65mg of Et, respectively3N (0.91mmol), adding 4.5mL of dichloromethane, reacting at room temperature, monitoring the reaction by TLC, concentrating the solvent, separating the obtained crude product by column chromatography, and washing and dehydrating the crude product with polar petroleum ether and ethyl acetate of 3:1 to obtain the target product III-3 with the yield of 85%.
1H NMR(600MHz,CDCl3)δ9.13(d,J＝1.6Hz,1H),7.49–7.45(m,2H),7.39–7.26(m,5H),6.80(d,J＝8.2Hz,1H),4.50(dq,J＝11.9,6.0Hz,1H),4.18(t,J＝10.4Hz,1H),3.63(dd,J＝10.9,1.6Hz,1H),3.25(s,3H),2.78(d,J＝12.6Hz,1H).13C NMR(151MHz,CDCl3)δ196.25,178.10,141.37,136.79,130.04,130.00,129.30,129.11,128.16,128.05,125.74,125.29(q,J＝279.4Hz),109.85,67.72,66.17,65.35(q,J＝29.6Hz),45.54,26.89.HRMS(ESI)calculated[M+Na]+for C20H16ClF3N2O2Na:431.0750,found:431.0744.
Example 4
This example discloses spiro [ pyrrolidine-3, 2' -oxindole ] backbone compounds of the present invention of formula III-4: the preparation method of (3R,3' S,4' S, 5' S) -4' - (4-chlorphenyl) -1-methyl-2-oxo-5 ' - (trifluoromethyl) spiro [ indoline-3, 2' -pyrrolidine ] -3' -formaldehyde comprises the following steps:
to a dry 10mL reaction tube were added 50mg of 1-methyl-3- ((2,2, 2-trifluoroethyl) imino) -1H-indol-2-one (0.21mmol), 41.29mg of p-chlorocinnamaldehyde (0.25mmol) and 104.50mg of Et respectively3N (1.03mmol), then adding 5.0mL of dichloromethane, reacting at room temperature, monitoring the reaction by TLC, concentrating the solvent, separating the obtained crude product by column chromatography, and washing and dehydrating to obtain the target product III-4 with the yield of 81 percent, wherein the polar petroleum ether is ethyl acetate which is 4: 1.
1H NMR(600MHz,CDCl3)δ9.08(d,J＝1.4Hz,1H),7.46–7.41(m,2H),7.38–7.29(m,4H),7.13(td,J＝7.6,1.0Hz,1H),6.88(d,J＝7.8Hz,1H),4.51(dq,J＝10.9,5.7Hz,1H),4.20(t,J＝10.0Hz,1H),3.57(dd,J＝10.3,1.5Hz,1H),3.27(s,3H),2.70(d,J＝6.5Hz,1H).13C NMR(151MHz,CDCl3)δ196.24,178.67,142.88,136.13,133.67,130.24,129.65,129.20,127.58,125.48,125.27(q,J＝279.6Hz),123.85,108.93,67.52,65.82,65.10(q,J＝29.5Hz),44.53,26.73.HRMS(ESI)calculated[M+Na]+for C20H16ClF3N2O2Na:431.0750,found:431.0747.
Example 5
This example discloses spiro [ pyrrolidine-3, 2' -oxindole ] backbone compounds of the present invention of formula iii-5: the preparation method of (3R,3' S,4' R,5' S) -1-benzyl-4 ' - (4-bromophenyl) -2-oxo-5 ' - (trifluoromethyl) spiro [ indoline-3, 2' -pyrrolidine ] -3' -formaldehyde comprises the following steps:
to a dry 10mL reaction tube were added 50mg of 1-benzyl-3- ((2,2, 2-trifluoroethyl) imino) -1H-indol-2-one (0.16mmol), 39.81mg of p-bromocinnamaldehyde (0.19mmol) and 79.53mg of Et respectively3N (0.79mmol), 4.0mL of bisChloromethane reacts at room temperature, TLC monitors that the reaction is complete, the solvent is concentrated, the obtained crude product is separated by column chromatography, and the polar petroleum ether and ethyl acetate which are washed and removed are 3:1, so that the target product III-5 is obtained, and the yield is 82%.
1H NMR(600MHz,CDCl3)δ9.06(d,J＝1.4Hz,1H),7.49(d,J＝8.4Hz,2H),7.38(d,J＝8.5Hz,2H),7.36–7.28(m,6H),7.26(s,0H),7.23(td,J＝7.8,1.3Hz,1H),7.09(t,J＝7.5Hz,1H),6.78(d,J＝7.8Hz,1H),5.04(d,J＝15.6Hz,1H),4.85(d,J＝15.6Hz,1H),4.51(dq,J＝11.6,6.0Hz,1H),3.65(dd,J＝10.6,1.5Hz,1H),2.79(s,1H).13C NMR(151MHz,CDCl3)δ195.99,178.71,141.94,136.47,134.97,132.18,130.12,129.96,129.03,128.06,127.83,127.21,125.44,125.29(q,J＝279.4Hz),123.88,121.86,109.96,67.67,66.20,65.20(q,J＝29.5Hz),44.75,44.29.HRMS(ESI)calculated[M+Na]+for C26H20BrF3N2O2Na:551.0558,found:551.0551.
Example 6
This example discloses spiro [ pyrrolidine-3, 2' -oxindole ] backbone compounds of the present invention of formula III-6: the preparation method of (3R,3' S,4' R,5' S) -1-allyl-4 ' - (4-bromophenyl) -2-oxo-5 ' - (trifluoromethyl) spiro [ indoline-3, 2' -pyrrolidine ] -3' -formaldehyde comprises the following steps:
to a dry 10mL reaction tube were added 50mg of 1-allyl-3- ((2,2, 2-trifluoroethyl) imino) -1H-indol-2-one (0.19mmol), 47.24mg of cinnamaldehyde (0.22mmol) and 94.34mg of Et respectively3N (0.93mmol), adding 4.5mL of dichloromethane, reacting at room temperature, monitoring the reaction by TLC, concentrating the solvent, separating the obtained crude product by column chromatography, and washing and dehydrating to obtain the target product III-6 with the yield of 87 percent, wherein the polar petroleum ether is ethyl acetate which is 3: 1.
1H NMR(600MHz,CDCl3)δ9.08(d,J＝1.4Hz,1H),7.54–7.46(m,2H),7.40–7.35(m,2H),7.35–7.27(m,2H),7.12(td,J＝7.6,1.0Hz,1H),6.87(d,J＝7.8Hz,1H),5.85(ddt,J＝17.1,10.6,5.4Hz,1H),5.33–5.23(m,2H),4.54–4.41(m,2H),4.31(ddt,J＝16.4,5.4,1.6Hz,1H),4.19(t,J＝10.1Hz,1H),3.59(dd,J＝10.6,1.5Hz,1H),2.74(s,1H).13C NMR(151MHz,CDCl3)δ196.09,178.35,142.02,136.50,132.17,130.58,130.12,129.96,127.70,125.45,125.27(q,J＝279.4Hz),123.81,121.84,118.32,109.83,67.57,65.96,65.13(q,J＝29.5Hz),44.71,42.80.HRMS(ESI)calculated[M+Na]+for C22H18BrF3N2O2Na:501.0402,found:501.0399.
The embodiments described above are some, but not all embodiments of the invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Claims (9)
1. A method for synthesizing spiro [ pyrrolidine-3, 2 '-oxindole ] skeleton compounds is characterized by taking a compound shown in formula I as a substrate, and synthesizing a compound with a spiro [ pyrrolidine-3, 2' -oxindole ] structure with unsaturated aldehyde or derivatives thereof under the catalysis of alkali, wherein the chemical reaction general formula is shown as follows:
wherein: r1Is halogen atom, methyl, methoxyl, nitryl, 4, 6-difluoro or 5, 6-difluoro;
R2is methyl, substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl or thienyl;
R3is substituted or unsubstituted phenyl, naphthyl, indenyl, furyl, pyrimidinyl, indolyl, thiazolyl or thienyl.
2. A synthetic spiro [ pyrrolidine-3, 2' -oxindole according to claim 1]Process for preparing a framework compound, characterized in that R3Is phenyl or phenyl substituted by halogen.
3. A method for synthesizing a spiro [ pyrrolidine-3, 2' -oxindole ] skeleton compound according to claim 1 or 2, wherein the halogen is selected from bromine or chlorine.
4. A process for the synthesis of a spiro [ pyrrolidine-3, 2' -oxindole ] skeleton compound according to claim 1, wherein the base comprises at least one of triethylamine, DIPEA, potassium carbonate, potassium bicarbonate; triethylamine is preferred.
5. The method for synthesizing spiro [ pyrrolidine-3, 2' -oxindole ] skeleton compounds according to any one of claims 1 to 4, wherein the molar ratio of the compound of formula I to the compound of formula II is 0.8 to 1.2: 0.8 to 1.2.
6. The process according to claim 5, wherein the molar ratio of the compound of formula I to the compound of formula II is preferably 1: 1.1 to 1.3; more preferably 1: 1.2.
7. the method of claim 5, wherein the compound of formula I is present in a molar ratio of 1: 4-6, preferably 1: 4.5-5.5, more preferably 1: 4.9 to 5.1.
8. A process for the synthesis of a spiro [ pyrrolidine-3, 2' -oxindole ] skeleton compound according to claim 5, wherein the reaction solvent comprises at least one of dichloromethane, acetonitrile, 2-methyltetrahydrofuran, 1, 2-dichloroethane and toluene.
9. The method for synthesizing a spiro [ pyrrolidine-3, 2' -oxindole ] skeleton compound according to claim 5, wherein the reaction temperature is room temperature.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115010714A (en) * | 2022-07-05 | 2022-09-06 | 河北医科大学 | Azepine [4,5-b ] indole alkaloid skeleton compound and preparation method thereof |
| CN115093413A (en) * | 2022-07-05 | 2022-09-23 | 河北医科大学 | Dihydropyridine spiro [3,4' ] indole and tetrahydropyridofuran [2,3-b ] indol-5-one skeletons and preparation |
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| MA MINGXIA: "The asymmetric synthesis of CF3-containing spiro[pyrrolidin-3,2"-oxindole] through the organocatalytic 1,3-dipolar cycloaddition reaction", 《CHEMICAL COMMUNICATIONS》 * |
| SOLEYMANI MOUSA: "Regio-, diastereo- and enantioselectivity in the synthesis of CF3-containing spiro[pyrrolidin-3,2"-oxindole] through the organocatalytic [3 + 2] cycloaddition reaction A molecular electron density theory study", 《JOURNAL OF FLUORINE CHEMISTRY》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115010714A (en) * | 2022-07-05 | 2022-09-06 | 河北医科大学 | Azepine [4,5-b ] indole alkaloid skeleton compound and preparation method thereof |
| CN115093413A (en) * | 2022-07-05 | 2022-09-23 | 河北医科大学 | Dihydropyridine spiro [3,4' ] indole and tetrahydropyridofuran [2,3-b ] indol-5-one skeletons and preparation |
| CN115010714B (en) * | 2022-07-05 | 2023-06-02 | 河北医科大学 | Azepino [4,5-b ] indole alkaloid skeleton compound and preparation method thereof |
| CN115093413B (en) * | 2022-07-05 | 2023-06-02 | 河北医科大学 | Dihydropyridino spiro [3,4' ] indole and tetrahydropyridofuran [2,3-b ] indol-5-one skeletons and preparation thereof |
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