CN108373473B - Oxidized indole spiro tetrahydrofuran fluoride and crystal thereof, and preparation method and application thereof - Google Patents
Oxidized indole spiro tetrahydrofuran fluoride and crystal thereof, and preparation method and application thereof Download PDFInfo
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- CN108373473B CN108373473B CN201711165996.1A CN201711165996A CN108373473B CN 108373473 B CN108373473 B CN 108373473B CN 201711165996 A CN201711165996 A CN 201711165996A CN 108373473 B CN108373473 B CN 108373473B
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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Abstract
The invention discloses an oxindole spiro tetrahydrofuran fluoride and a preparation method thereof, wherein the structural formula of the fluoride is shown as a formula I, and the invention also discloses a crystal form of a compound shown as the formula I: the crystal form is monoclinic system, and the cell parameter is
α is 90 °, β is 99.228(2 °), γ is 90 °, and space group is P21Z is 2 and the unit cell volume is
The invention also discloses a method for preparing the crystal form, and discloses application of the compound, or the crystal form, or the solvate, or the pharmaceutically acceptable salt thereof in preparing an anti-tumor medicament.
Description
Technical Field
The invention relates to an oxindole spiro tetrahydrofuran fluoride oxide and a crystal thereof, and a preparation method and application thereof.
Background
Fluoride refers to organic or inorganic compounds containing negative fluorine, related studies [ muller, k.; faeh, c.; diederich, F.fluorine in pharmaceuticals: viewing beyond and intuition.science 2007,317,1881-1886.] and [ Purser, S.; moore, p.r.; swallow, S.; gouverneur, v. fluorine in medical chemistry. chem. soc. rev.2008,37,320-330 ] demonstrated that the introduction of fluorine atoms into drug molecules would make them more bioavailable, have greater lipid solubility and metabolic stability, and enhance the interaction between the compound and the target protein.
Two or more different crystalline states are common for the same compound, while different crystalline forms typically exhibit different bioavailability, dissolution rates, stability, melting points, color, filterability, density, and flowability, among others. Therefore, the development of a crystal form with better solubility and stability is very important.
Disclosure of Invention
In order to solve the problems, the invention provides an oxindole spiro tetrahydrofuran fluoride and a crystal thereof, and a preparation method and application thereof.
The invention discloses an oxindole spiro tetrahydrofuran fluoride oxide, which has a structural formula shown as a formula I:
the invention provides a method for preparing a compound shown as a formula I: it comprises the following steps:
(1) adding a compound shown as a formula 1, a compound shown as a formula 2 and a chiral squarylium amide tertiary amine catalyst shown as a formula 3 into dichloromethane, stirring at 25 +/-2 ℃, removing the solvent after the reaction is finished to obtain a residue, carrying out column chromatography to obtain an eluent, and removing the solvent to obtain the oxindole spiro tetrahydrofuran shown as a formula 4.
(2) Adding oxindole spiro tetrahydrofuran into dichloromethane, adding diethylaminosulfur trifluoride at 0 +/-2 ℃, reacting at 25 +/-2 ℃, and obtaining reaction liquid after the reaction is finished; extracting, drying, removing solvent, performing column chromatography to obtain eluent, and removing solvent to obtain the compound shown in formula I.
In the step (1), the molar ratio of the compound shown in the formula 1 to the compound shown in the formula 2 to the catalyst shown in the formula 3 is 1: 1.5: 0.2; and/or the reaction time is 12 h; and/or, the column chromatography is carried out by using petroleum ether: ethyl acetate 3:1 as eluent; and/or, the eluent is prepared by thin layer chromatography, and the developing solvent is petroleum ether: ethyl acetate 2:1, Rf 0.2-0.4.
Wherein in the step (2), the mol ratio of the indole oxide spiro tetrahydrofuran to the diethylamino sulfur trifluoride is 1: 1.5; and/or the reaction time is 1 h; and/or, the extraction is sequentially extracting with water and dichloromethane; and/or, the drying is to dry the dichloromethane extract by using anhydrous sodium sulfate; and/or, the column chromatography is carried out by using petroleum ether: ethyl acetate 3:1 as eluent; and/or, the eluent is prepared by thin layer chromatography, and the developing solvent is petroleum ether: ethyl acetate 3:1, Rf 0.2-0.4.
In the step (1), the compound shown in the formula 1 is prepared by the following method:
(a) adding benzylamine and ethyl acrylate into absolute ethyl alcohol A, stirring at 25 +/-2 ℃ for 16 +/-2 h, adding diethyl oxalate, sodium ethoxide and absolute ethyl alcohol B, heating to 90 ℃, reacting for 1h, concentrating, dissolving, precipitating, and drying to obtain a compound shown in a formula 1-5;
(b) adding a compound shown in a formula 1-5, benzaldehyde and a 20% HCl solution into absolute ethyl alcohol, reacting for 4 hours at 90 ℃, cooling to 25 +/-2 ℃, filtering to obtain a residue, adding ethyl acetate, standing at 90 ℃ until the solution is clear, cooling to 25 +/-2 ℃, and separating out the compound shown in the formula 1.
In the step (a), the molar ratio of the benzylamine to the ethyl acrylate to the diethyl oxalate to the sodium ethoxide is 1: 1: 1: 1.5; and/or the feeding amount ratio of the benzylamine to the absolute ethyl alcohol A to the absolute ethyl alcohol B is 3:1:1 mmol/mL/mL; and/or the dissolving is deionized water dissolving; and/or, the precipitation is the addition of concentrated hydrochloric acid to a pH of 1.
Wherein, in the step (b), the molar ratio of the compound shown in the formula 1-5 to the benzaldehyde is 1: 1; and/or the feeding amount ratio of the compound shown in the formula 1-5, the 20% HCl solution and the absolute ethyl alcohol is 0.77: 1.7: 1 mmol/mL/mL.
In the step (1), the compound shown in the formula 2 is prepared by the following method:
adding a compound shown as a formula 2-1, benzyl bromide and potassium carbonate into THF, reacting for 36 hours at the temperature of 60 +/-2 ℃, concentrating and washing to obtain a compound shown as a formula 2-3;
② at 0 ℃, dissolving sodium borohydride and the compound shown in the formula 2-3 in ethanol, stirring for 0.33h, quenching reaction, separating out solid, filtering to obtain solid, and purifying to obtain the compound shown in the formula 2.
In the step (i), the molar ratio of the compound shown in the formula 2-1, benzyl bromide and potassium carbonate is 1: 1.2: 1.5; and/or the molar volume ratio of the compound shown in the formula 2-1 to THF is 1: 2.94 mmol/mL; and/or, the washing is with water and petroleum ether, respectively.
In the step II, the molar ratio of the sodium borohydride to the compound shown in the formula 2-3 is 1: 0.8; and/or the molar ratio volume of the compound shown in the formula 2-3 to ethanol is 1: 1.2 mmol/mL; and/or, the quenching reaction is quenched with water; and/or, the purification is carried out by dissolving with dichloromethane, drying by anhydrous sodium sulfate, filtering, concentrating and recrystallizing.
The invention also provides a crystal form of the compound shown as the formula I, wherein the crystal form is a monoclinic system, and the unit cell parameter is
α＝90°，β＝99.228(2)°，γ＝90°。
Further, the space group of the crystal form is P21Z is 2 and the unit cell volume is
Further, the ee value of the crystalline form is > 99%.
Further, the melting point of the crystal form is 135-136 ℃.
The invention provides a method for preparing the crystal form, which comprises the following steps:
(1) according to the preparation method, the compound shown in the formula I is obtained;
(2) and (2) crystallizing the compound shown in the formula I in the step (1) in an ethyl acetate/petroleum ether mixed solvent to obtain the crystal form of the compound shown in the formula I.
Wherein in the step (2), the volume ratio of the ethyl acetate to the petroleum ether is 2: 4-9, preferably 2: 5.
The compound shown in the formula I, or a crystal form, a solvate or a pharmaceutically acceptable salt thereof can be used for preparing the antitumor drug.
Preferably, the tumor is breast cancer or melanoma.
The invention provides a pharmaceutical composition, which is prepared into a commonly used pharmaceutical preparation by taking a compound shown as the formula I, or a crystal form, or a solvate, or a pharmaceutically acceptable salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
The room temperature of the invention is 25 +/-2 ℃.
The concentrated hydrochloric acid is generally specified in the specification of common reagents, and the content of the concentrated hydrochloric acid is 30-37.5% and 12 mol/L.
The invention has the beneficial effects that: the invention provides a compound shown in formula I and a preparation method thereof, and also provides a crystal form of the compound, the crystal form has high yield and purity, the crystal form of the compound with high purity can be easily obtained, the operation is simple and convenient, the cost is low, and the quality control of the compound shown in formula I is very facilitated.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a perspective view of a crystalline form of a compound of formula I according to the present invention;
FIG. 2 is a TOF-MS analysis of the flight mass spectrum of a compound of formula I of the present invention;
FIG. 3 shows the NMR spectra of the compounds of formula I according to the invention1H NMR Spectrum:
FIG. 4Nuclear magnetic resonance carbon spectrum of the compound of formula I13C NMR spectrum.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
Chiral squaramide tertiary amine catalyst: purchased from Daiiol drug chiral technology (Shanghai) Co., Ltd.
EXAMPLE 1 preparation of Compounds of formula I
(1) Preparation of Compound 1
(a) A150 mL round-bottom flask was taken, and 30mmol of benzylamine 1-1, 10mL of absolute ethanol, and 30mmol of ethyl acrylate 1-2 were weighed and stirred at room temperature for 16 h. Weighing 1-4 mmol of diethyl oxalate and 45mmol of sodium ethoxide, adding into the reaction solution in the first step, adding 10mL of absolute ethyl alcohol, and moving the system to an oil bath kettle at 90 ℃ for reflux reaction for 1 h.
And (3) post-treatment: and (3) carrying out vacuum spin-drying on absolute ethyl alcohol in the reaction solution, cooling to room temperature, adding 70mL of deionized water, adding concentrated hydrochloric acid to adjust the pH value of the system to 1, and transferring the system to an ice bath for cooling, wherein a yellow-white solid is separated out. The supernatant was poured off and the resulting solid was dried to give compound 1-5.
(b) A150 mL round bottom flask was taken, 7.7mmol of the product 1-5 were weighed, 17mL of absolute ethanol, 10mL of 20% HCl solution, and 7.7mmol of benzaldehyde 1-6 were weighed, and the mixture was refluxed at 90 ℃ for 4 hours. And after the reflux is finished, after the system is cooled to the room temperature, filtering out the solid, adding ethyl acetate, refluxing at 90 ℃ until the solution is clear, removing the solution out of the oil bath pot, cooling to the room temperature, separating out light yellow crystals, and obtaining the separated light yellow crystal powder which is the compound 1.
(2) Preparation of Compound 2
In a 150mL round-bottom flask, 33.98mmol of isatin 2-1 and 50.97mmol of potassium carbonate were weighed, dissolved in 100mL of THF solvent, and 40.78mmol of benzyl bromide 2-2 was added, followed by reflux at 60 ℃ for 36 hours. After TLC monitoring reaction is completed, spin-drying, washing with water to remove potassium carbonate, and washing with petroleum ether to remove benzyl bromide 2-2 to obtain N-benzyl indole quinone 2-3.
In a 150mL round bottom flask, 59.77mmol of sodium borohydride was ultrasonically dissolved in 30mL of ethanol, cooled to 0 ℃, 47.8mmol of N-benzylindole quinone 2-3 was dissolved in the remaining amount of ethanol and cooled to 0 ℃ (90 mL in ethanol), and NaBH was slowly added in ice bath4Adding into a flask, stirring in ice bath, instantly disappearing red, adding water to quench the reaction after TLC monitoring reaction is complete, and precipitating solid. Washing with a large amount of water to remove sodium borohydride, dissolving the solid with dichloromethane, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to precipitate a solid, and filtering to obtain the compound (2).
(3) Preparation of Compounds of formula I
In a clean reaction tube, pyrrolidone electron deficient diene compound 1(0.05mmol), indole oxyhydroxide 2(0.075mmol), and dichloromethane (1mL), and chiral squaramide tertiary amine catalyst (3) (0.01mmol) were added in this order, stirred at 25 ℃ for 12 hours, TLC monitored the disappearance of starting material 1, after the reaction was completed, the reaction solvent was removed under reduced pressure, and the residue was subjected to silica gel column, petroleum ether: ethyl acetate 3:1, using thin layer chromatography with a developing solvent of petroleum ether: and (3) combining the eluent with Rf of 0.2-0.4 at a ratio of ethyl acetate to 2:1, and removing the solvent to obtain a purified product, namely the oxindole spiro tetrahydrofuran (4).
Adding 28.5mg of oxindole spiro tetrahydrofuran (4) into a reaction tube, adding 1mL of dichloromethane, after the reaction is cooled to 0 ℃, adding 35.1mg of DAST (diethylaminosulfur trifluoride) reagent, then moving the reaction to room temperature for reaction for 1 hour, monitoring the reaction by using a TCL method, extracting with water and dichloromethane after the reaction is completed, combining dichloromethane, drying with anhydrous sodium sulfate, removing the reaction solvent under reduced pressure, separating and purifying by using a silica gel column, and adding petroleum ether: ethyl acetate 3:1 elution, thin layer tracing, developing solvent petroleum ether: ethyl acetate ═ 3:1, combining the eluates with Rf of 0.2-0.4, and removing the solvent to obtain a purified product, namely the compound of the formula I.
The prepared compound was characterized to obtain its high resolution data, hydrogen spectrum and carbon spectrum, as shown in fig. 2, 3 and 4, respectively.
Example 2 preparation of form I of the invention
35.1mg of the compound of the formula I prepared in example 1 are taken in petroleum ether: ethyl acetate 85: 15(v/v) at normal temperature to obtain a single crystal of formula I, wherein the content of ee is more than 99%, the yield is 99%, the crystal form is diffracted by the single crystal, the crystal structure data is shown in table 1, and the projection of the three-dimensional structure is shown in fig. 1.
TABLE 1 Crystal Structure data in Single Crystal diffraction
Experimental example 1: in vitro anti-tumor study
1. Experimental tumor cell strain
The human breast cancer MB468 cell line, the human breast cancer SKBR3 cell line, the human breast cancer MB231 cell line and the mouse melanoma A375 cell line are all provided by the national key laboratory of biological treatment of Sichuan university, and the tumor cells are all frozen and stored in the national key laboratory of biological treatment of Sichuan university.
2. Experimental methods
2.1 preparation and treatment of cells
4 kinds of swellingThe tumor cells are cultured in RPMI-1640 culture medium containing 10% inactivated newborn calf serum at 37 deg.C and 5% CO2Growing in incubator until 80% cell fusion, digesting with 0.1% pancreatin solution to obtain single cell suspension, adjusting cell concentration to 5 × 104/mL, uniformly inoculating into 96-well microplate, each group having 3 multiple wells and 100 μ l/well, placing at 37 deg.C saturation humidity and 5% CO2After culturing in an incubator for 24h, adding culture solution with the same amount into a normal control group; a concentration gradient of test drug (100, 50, 25, 12.5, 6.25. mu.g/mL) was added, 3 replicates per concentration and experiments were performed in 2 replicates. After the drug and the cells act for 24 hours, 10 mu L of MTT solution (5mg/mL) is added into each hole, after the culture is continued for 4 hours, 100 mu L of DMSO is added into each hole, the mixture is shaken and uniformly mixed to ensure that the crystal is fully dissolved, the absorbance value (A value) is measured at the 490nm wavelength of an enzyme-labeling instrument, and the average value of each concentration group is taken.
2.2 measurement of cell proliferation inhibition Rate
The cell proliferation inhibition rate was calculated according to the following formula: the cell growth inhibition ratio (%) × 100% (1-test group a value/control group a value). All experimental data were statistically analyzed using SPSS 13.0. Experimental results adopt Probit to obtain IC50The value is obtained.
2.3 results of the experiment
TABLE 2 inhibition of growth of test cells by form I of the present invention
| MB468 | A375 | SKBR3 | MB231 | |
| IC50(μg/mL) | 55.21 | 76.52 | 81.23 | 53.66 |
The experimental results show that the crystal form I compound provided by the invention has antitumor activity.
In conclusion, the invention provides the compound shown in the formula I and the preparation method thereof, and also provides the crystal form of the compound, the yield and the purity of the crystal form are high, the crystal form of the compound with high purity can be easily obtained, the operation is simple and convenient, the cost is low, and the quality control of the compound shown in the formula I is very favorable.
Claims (14)
1. An oxindole spiro tetrahydrofuran fluoride oxide characterized by: it has a structural formula shown in formula I:
2. a process for preparing a compound of formula I: the method is characterized in that: it comprises the following steps:
1
2
(1) adding a compound shown as a formula 1, a compound shown as a formula 2 and a chiral squarylium amide tertiary amine catalyst shown as a formula 3 into dichloromethane, stirring and reacting at 25 +/-2 ℃ for 12 hours, removing a solvent after the reaction is finished to obtain a residue, carrying out column chromatography to obtain an eluent, and removing the solvent to obtain the oxindole spiro tetrahydrofuran shown as a formula 4;
(2) adding oxindole spiro tetrahydrofuran into dichloromethane, adding diethylaminosulfur trifluoride at 0 +/-2 ℃, reacting at 25 +/-2 ℃, and obtaining reaction liquid after the reaction is finished; extracting, drying, removing solvent, performing column chromatography to obtain eluent, and removing solvent to obtain the compound shown in formula I.
3. The method of claim 2, wherein: in the step (1), the molar ratio of the compound shown in the formula 1 to the compound shown in the formula 2 to the catalyst shown in the formula 3 is 1: 1.5: 0.2; and/or, the column chromatography is carried out by using petroleum ether: ethyl acetate 3:1 as eluent; and/or, the eluent is prepared by thin layer chromatography, and the developing solvent is petroleum ether: ethyl acetate is 2:1, Rf is 0.2-0.4 elution part; and/or in the step (2), the molar ratio of the oxindole spiro-tetrahydrofuran to the diethylaminosulfur trifluoride is 1: 1.5; and/or the reaction time is 1 h; and/or, the extraction is sequentially extracting with water and dichloromethane; and/or, the drying is to dry the dichloromethane extract by using anhydrous sodium sulfate; and/or, the column chromatography is carried out by using petroleum ether: ethyl acetate 3:1 as eluent; and/or, the eluent is prepared by thin layer chromatography, and the developing solvent is petroleum ether: ethyl acetate 3:1, Rf 0.2-0.4.
4. The method of claim 2, wherein: in the step (1), the compound shown in the formula 1 is prepared by the following method:
(a)
(b)
(a) adding benzylamine and ethyl acrylate into absolute ethyl alcohol A, stirring at 25 +/-2 ℃ for 16 +/-2 h, adding diethyl oxalate, sodium ethoxide and absolute ethyl alcohol B, heating to 90 ℃, reacting for 1h, concentrating, dissolving, precipitating, and drying to obtain a compound shown in a formula 1-5;
(b) adding a compound shown in a formula 1-5, benzaldehyde and a 20% HCl solution into absolute ethyl alcohol, reacting for 4 hours at 90 ℃, cooling to 25 +/-2 ℃, filtering to obtain a residue, adding ethyl acetate, standing at 90 ℃ until the solution is clear, cooling to 25 +/-2 ℃, and separating out the compound shown in the formula 1.
5. The method of claim 4, wherein:
in the step (a), the molar ratio of the phenylmethylamine to the ethyl acrylate to the diethyl oxalate to the sodium ethoxide is 1: 1: 1: 1.5; and/or the feeding amount ratio of the benzylamine to the absolute ethyl alcohol A to the absolute ethyl alcohol B is 3:1:1 mmol/mL/mL; and/or the dissolving is deionized water dissolving; and/or, the precipitation is to add concentrated hydrochloric acid until the pH value is 1; and/or, in the step (b), the molar ratio of the compound shown in the formula 1-5 to the benzaldehyde is 1: 1; and/or the feeding amount ratio of the compound shown in the formula 1-5, the 20% HCl solution and the absolute ethyl alcohol is 0.77: 1.7: 1 mmol/mL/mL.
6. The method of claim 2, wherein: in the step (1), the compound shown in the formula 2 is prepared by the following method:
adding a compound shown as a formula 2-1, benzyl bromide and potassium carbonate into THF, reacting for 36 hours at the temperature of 60 +/-2 ℃, concentrating and washing to obtain a compound shown as a formula 2-3;
② at 0 ℃, dissolving sodium borohydride and the compound shown in the formula 2-3 in ethanol, stirring for 0.33h, quenching reaction, separating out solid, filtering to obtain solid, and purifying to obtain the compound shown in the formula 2.
7. The method of claim 6, wherein: in the step I, the molar ratio of the compound shown as the formula 2-1, benzyl bromide and potassium carbonate is 1: 1.2: 1.5; and/or the molar volume ratio of the compound shown in the formula 2-1 to THF is 1: 2.94 mmol/mL; and/or, the washing is washing with water and petroleum ether, respectively; and/or, in the step (II), the molar ratio of the sodium borohydride to the compound shown in the formula 2-3 is 1: 0.8; and/or the molar ratio volume of the compound shown in the formula 2-3 to ethanol is 1: 1.2 mmol/mL; and/or, the quenching reaction is quenched with water; and/or, the purification is carried out by dissolving with dichloromethane, drying by anhydrous sodium sulfate, filtering, concentrating and recrystallizing.
8. A crystalline form of a compound of formula i, characterized in that: the crystal form is monoclinic system, and the cell parameter is
α＝90°，β＝99.228(2)°，γ＝90°；
The structural formula of the compound shown in the formula I is shown as follows:
9. the crystalline form of claim 8, characterized in that: the space group of the crystal form is P21Z is 2 and the unit cell volume is
And/or the ee value of said crystalline form>99 percent; and/or the melting point of the crystalline form is 135-136 ℃.
10. A process for preparing the crystalline form of claim 8 or 9, characterized in that: it comprises the following steps:
(1) the preparation method according to any one of claims 2 to 5, wherein the compound shown as the formula I is obtained;
(2) and (2) crystallizing the compound shown in the formula I in the step (1) in an ethyl acetate/petroleum ether mixed solvent to obtain the crystal form of the compound shown in the formula I.
11. The method of claim 10, wherein: in the step (2), the volume ratio of the ethyl acetate to the petroleum ether is 2: 4 to 9.
12. The method of claim 11, wherein: in the step (2), the volume ratio of the ethyl acetate to the petroleum ether is 2: 5.
13. The use of a compound of formula i as defined in claim 1, or a crystalline form thereof, or a pharmaceutically acceptable salt thereof, in the preparation of an anti-tumor medicament; the crystalline form of claim 8 or 9, wherein the tumor is breast cancer or melanoma.
14. A pharmaceutical combination characterized by: the compound of formula I as shown in claim 1, or a crystal form thereof, or a pharmaceutically acceptable salt thereof is used as an active ingredient, and is added with pharmaceutically acceptable auxiliary materials to prepare a pharmaceutically common preparation; the crystalline form is as claimed in claim 8 or 9.
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| WO2012038307A1 (en) * | 2010-09-20 | 2012-03-29 | F. Hoffmann-La Roche Ag | Spiro substituted pyrrolo[1,2-c]imidazole derivatives useful as mdm2 inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012038307A1 (en) * | 2010-09-20 | 2012-03-29 | F. Hoffmann-La Roche Ag | Spiro substituted pyrrolo[1,2-c]imidazole derivatives useful as mdm2 inhibitors |
Non-Patent Citations (2)
| Title |
|---|
| Chiral squaramide-catalysed enantioselective Michael/cyclization cascade reaction of 3-hydroxyoxindoles with α,β-unsaturatedN-acylated succinimides;Sheng Ming et al.;《Organic & Biomolecular Chemistry》;20170703(第15期);第6205-6213页 * |
| Organocatalytic Asymmetric Michael/Cyclization Cascade Reactions of 3‑Hydroxyoxindoles/3-Aminooxindoles with α,β-Unsaturated Acyl Phosphonates for the Construction of Spirocyclic Oxindole-γ-lactones/lactams;Lin Chen et al.;《The Journal of Organic Chemistry》;20151109(第80期);第12668-12675页 * |
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