CN111909230B - Chlorine-substituted arabinose triazole structure spiro isoxazole-pyrrolizine derivative and preparation method and application thereof - Google Patents
Chlorine-substituted arabinose triazole structure spiro isoxazole-pyrrolizine derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN111909230B CN111909230B CN202010767391.5A CN202010767391A CN111909230B CN 111909230 B CN111909230 B CN 111909230B CN 202010767391 A CN202010767391 A CN 202010767391A CN 111909230 B CN111909230 B CN 111909230B
- Authority
- CN
- China
- Prior art keywords
- pyrrolizine
- chlorine
- arabinose triazole
- spiroisoxazole
- methanol
- 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
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/056—Triazole or tetrazole radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a chlorine substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative and a preparation method and application thereof, firstly, (E) -2- (4-chlorobenzylidene) -2, 3-dihydro pyrrolizine-1-one and acetyl arabinose triazole salicylaldoxime are synthesized, then dissolving the raw materials in absolute ethyl alcohol, carrying out 1, 3-dipolar cycloaddition reaction, introducing arabinose triazole and isoxazole structures, finally suspending the intermediate compound in methanol, slowly dropwise adding a methanol solution of sodium methoxide under the protection of nitrogen, heating to room temperature for continuous reaction, washing ion exchange resin with methanol, decompressing filtrate to remove methanol to obtain light yellow solid, and separating after column chromatography to obtain the chlorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative. The prepared chlorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative has a strong tumor cell inhibition effect, and provides a basis for further application in the field of medicine.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a chlorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative, and a preparation method and application thereof.
Background
Chemical name: (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizin-1-one having the following chemical formula:
pyrrolizine is an important component of alkaloids with biological activity, and derivatives thereof are widely applied in the aspects of inflammation diminishing, pain easing, diabetes resistance, sugar anxiety resistance, tumor resistance and the like.
The triazole has aromaticity and abundant electrons in a molecular structure, can interact with enzymes and receptors in organisms by forming hydrogen bonds, and has various biological activities. Glycoside compounds widely exist in organisms and play important physiological functions, and introduction of glycoside into compound molecules can increase water solubility and guidance of the compounds and improve pharmacological properties of the compounds. Recent studies have shown that some compounds containing glycosylated triazole show better inhibition effects on carbonic anhydrase, glycosyltransferase and protein tyrosine phosphatase.
The isoxazoline skeleton is an important pharmacophore in the application of medicines and has obvious physiological and pharmacological activity. In addition, spiroisoxazolines synthesized by 1, 3-dipolar cycloaddition of nitrile oxides to exocyclic double bonds have attracted attention by pharmacologists because of exhibiting some important physiological properties.
The 1, 3-dipolar cycloaddition reaction is the most important method for synthesizing five-membered heterocyclic compounds with good regioselectivity and body selectivity, and is also a more active reaction in heterocyclic pharmaceutical chemistry research. Therefore, the heterocyclic compound has high synthetic value in terms of pharmacology and synthesis angle.
Disclosure of Invention
The invention aims to provide a chlorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative, a preparation method and application thereof, and the chlorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative is prepared.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the chlorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative is characterized in that the chemical structural formula of the chlorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative is as follows:
wherein-Glu' is an arabinosyl group represented by the formula:
the application also provides a preparation method of the chlorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative, which comprises the following steps:
Further, the ratio of the 2, 3-dihydropyrrolizine-1-ketone to the 4-chlorobenzaldehyde substance is 1:1.
Furthermore, each 10mmol of 2, 3-dihydropyrrolizine-1-ketone and 10mmol of 4-chlorobenzaldehyde are dissolved in 20-30mL of ethanol, and 2-3mL of 40% NaOH aqueous solution is added.
Furthermore, the ratio of the amounts of the (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-one, the acetyl arabinose triazole salicylaldoxime and the chloramine T substance is 1:1: 1.2.
Further, the ratio of the amount of (2S,3R,4S,5S) -2- (4- ((2- (4- (4-chlorophenyl) -1 '-oxo-1' H,3'H,4H spiro [ isoxazole-5, 2' -pyrrolizin ] -3-yl) phenoxy) methyl) -1H-1,2, 3-triazol-1-yl) tetrahydro-2H-pyran-3, 4, 5-triacetate to sodium methoxide species is 1: 2.
Further, the volume ratio of chloroform to methanol in the eluent adopted by the column chromatography separation is 20: 1.
The invention also provides application of the chlorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative in the aspect of antitumor drugs.
The invention provides a spiroisoxazole-pyrrolizine derivative with a chlorine-substituted arabinose triazole structure and a preparation method and application thereof, wherein in the preparation method, an isoxazole ring is introduced into a chemical structure of (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-one by using a 1, 3-dipolar cycloaddition method, so that a novel spiroisoxazole-pyrrolizine derivative with a chlorine-substituted arabinose triazole structure is finally synthesized. The prepared chlorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative has a strong tumor cell inhibition effect, and provides a basis for further application in the field of medicine.
Drawings
FIG. 1 is a schematic diagram of the chemical structure of the preparation of (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizin-1-one of the present invention;
FIG. 2 is a schematic diagram of a chemical structural formula of a preparation of a chloro-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative.
Detailed Description
The technical solutions of the present invention are further described in detail below with reference to the drawings and examples, which should not be construed as limiting the present invention.
Isoxazole derivatives have attracted much attention as a class of useful intermediates and as a variety of pharmaceutical activities that they themselves exhibit. The general idea of the invention is to skillfully introduce glucoside, 1,2, 3-triazole pharmacodynamic structure and five-membered isoxazole ring with biological activity into the molecular structure of (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-one, finally prepare the spiroisoxazole-pyrrolizine derivative with the chlorine-substituted arabinose triazole structure, and improve the pharmacological activity.
The invention relates to a chlorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative, which has the following chemical structural formula:
wherein-Glu' is an arabinosyl group represented by the formula:
the embodiment provides a preparation method of a chlorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative, which comprises the following steps:
as shown in fig. 1 and 2, chemical structural formula 1 in fig. 2 is 2, 3-dihydropyrrolizine-1-one, chemical structural formula 2 is 4-chlorobenzaldehyde, and (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-one, (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-one corresponds to chemical structural formula 3 is generated through reaction.
The mass ratio of 2, 3-dihydropyrrolizine-1-ketone to 4-chlorobenzaldehyde substances is 1:1, each 10mmol of 2, 3-dihydropyrrolizine-1-ketone and 10mmol of 4-chlorobenzaldehyde are dissolved in 20-30mL of ethanol, and 2-3mL of 40% NaOH aqueous solution is added.
One example of the present application, synthesis of (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizin-1-one: dissolving 10mmol of 2, 3-dihydropyrrolizine-1-ketone (compound 1) and 10mmol of 4-chlorobenzaldehyde (compound 2) in 20mL of ethanol, adding 2mL of 40% NaOH aqueous solution, stirring at 75 ℃ for 4 hours, then filtering and separating by using a Buchner funnel, washing a filter cake with water, recrystallizing and purifying by using ethanol, filtering and drying to obtain a product (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-ketone (compound 3).
In another example, the synthesis of (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizin-1-one: dissolving 10mmol of 2, 3-dihydropyrrolizine-1-ketone (compound 1) and 10mmol of 4-chlorobenzaldehyde (compound 2) in 30mL of ethanol, adding 3mL of 40% NaOH aqueous solution, stirring at 85 ℃ for 3 hours, then filtering and separating by using a Buchner funnel, washing a filter cake with water, recrystallizing and purifying by using ethanol, filtering and drying to obtain a product (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-ketone (compound 3).
In another example, synthesis of (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizin-1-one: dissolving 10mmol of 2, 3-dihydropyrrolizine-1-ketone (compound 1) and 10mmol of 4-chlorobenzaldehyde (compound 2) in 20mL of ethanol, adding 2mL of 40% NaOH aqueous solution, stirring at 80 ℃ for 3 hours, then filtering and separating by using a Buchner funnel, washing a filter cake with water, recrystallizing and purifying by using ethanol, filtering and drying to obtain a product (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-ketone (compound 3).
The application dissolves 2, 3-dihydropyrrolizine-1-one and 4-chlorobenzaldehyde in ethanol, wherein the ethanol is 95% hydrous ethanol. Ethanol is only the reaction solvent and is present in excess. The ethanol is less than 2, 3-dihydropyrrolizine-1-ketone and 4-chlorobenzaldehyde, and the ethanol is not dissolved and is more than the 2, 3-dihydropyrrolizine-1-ketone and the 4-chlorobenzaldehyde, so the molar concentration of the solution is too dilute, and the reaction is slow.
And 2, carrying out dehydration reaction on the acetyl arabinose triazole salicylaldehyde and hydroxylamine hydrochloride to generate the acetyl arabinose triazole salicylaldoxime.
In the embodiment, the preparation of the acetaarabinotriazole salicylaldoxime by the dehydration reaction of the acetaarabinotriazole salicylaldehyde and hydroxylamine hydrochloride comprises the following steps:
acetyl azide arabinose and 2-propargylSuspending oxy benzaldehyde in mixed solvent of dichloromethane and water, heating to 40-44 deg.C, adding sodium ascorbate and CuSO under vigorous stirring4·5H2And O, continuously carrying out reflux reaction for 4-5 hours, stopping the reaction, separating liquid when the solution system of the chemical reaction is cooled to room temperature, and using CH for a water layer2C12Extracting twice, combining organic phases, drying over night by using anhydrous sodium sulfate, carrying out suction filtration, removing the solvent by pressure reduction, and then carrying out flash column chromatography separation to obtain the acetyl arabinose triazole salicylaldehyde;
adding hydroxylamine hydrochloride and water into a reaction bottle, magnetically stirring until the hydroxylamine hydrochloride is dissolved, adding the acetyl arabinose triazole salicylaldehyde and the absolute ethyl alcohol under stirring, violently stirring for 2-3 hours, and adding 20% Na after the reaction is finished2CO3And (3) regulating the pH value of the reaction solution to be neutral, standing and cooling to room temperature to generate a large amount of white precipitate, putting the white precipitate into a refrigerator for a night, filtering under reduced pressure, and drying at room temperature to obtain granular white crystal acetyl arabinose triazole salicylaldoxime.
In this example, the ratio of the amount of the acetyl arabinose triazole salicylaldehyde to the amount of the hydroxylamine hydrochloride species was 4: 5.
For example:
12mmol of acetyl azidoarabinose, 1.60g (10 mmol 1) of 2-propargyloxybenzaldehyde were suspended in 100mL (dichloromethane): (water) ═ 1:1, heating to 40-44 ℃, and adding 0.2mmol of sodium ascorbate and 0.1mmol of CuSO in sequence under vigorous stirring4·5H2And O, continuously carrying out reflux reaction for 4-5 hours, stopping the reaction, when the solution system of the chemical reaction is cooled to room temperature (20-30 ℃), separating the solution, and using CH for a water layer2C12Extracting twice (50mL multiplied by 2), combining organic phases, drying over night by anhydrous sodium sulfate, filtering, decompressing, removing a solvent, and separating by fast column chromatography to obtain the acetyl arabinose triazole salicylaldehyde.
Into a 250mL Erlenmeyer flask, 35.6g (0.5mol) of hydroxylamine hydrochloride and 90mL of H were added2And O, magnetically stirring until the hydroxylamine hydrochloride is dissolved (usually stirring by a magnetic stirrer). Weighing (0.4mol) acetyl arabinose triazole salicylaldehyde and 50mL of absolute ethyl alcohol into a 250mL conical flask under stirring, and vigorously stirringFor 3 hours. After the reaction is finished, 20% Na is used2CO3And (3) adjusting the pH value of the reaction solution to be neutral, standing and cooling to room temperature to generate a large amount of white precipitate, putting the white precipitate into a refrigerator for overnight, filtering under reduced pressure, and drying at room temperature to obtain granular white crystal, namely the acetyl arabinose triazole salicylaldoxime.
It should be noted that, the dehydration reaction of the arabinoside triazole salicylaldehyde and hydroxylamine hydrochloride to generate the arabinoside triazole salicylaldoxime in this embodiment is already a relatively mature technology, and is not described herein again.
And 3, dissolving (E) -2- (4-chlorobenzylidene) -2, 3-dihydro pyrrolizine-1-one (compound 3) and acetyl arabinose triazole salicylaldoxime (compound 4) in absolute ethyl alcohol, adding chloramine T, refluxing for 8-12 hours, carrying out 1, 3-dipolar cycloaddition reaction, introducing arabinose triazole and isoxazole structures, recrystallizing with methanol, and drying in vacuum to obtain an intermediate compound 5.
The mass ratio of the (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-one, the acetyl arabinose triazole salicylaldoxime and the chloramine T substance is 1:1: 1.2.
In one example of the present application, 10mmol (e) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizin-1-one (compound 3) and 10mmol (compound 4) of arabinofuranotriazole salicylaldoxime (compound 4) are dissolved in 30mL of absolute ethanol, 12mmol of chloramine T is added, reflux is performed for 12 hours, 1, 3-dipolar cycloaddition reaction is performed, arabinotriazole and isoxazole structures are introduced, recrystallization is performed with methanol, and compound 5((2S,3R,4S,5S) -2- (4- ((2- (4- (4-chlorophenyl) -1 '-oxo-1' H,3'H,4H spiro [ isoxazole-5, 2' -pyrrolizine ] -3-yl) phenoxy) methyl) -1H-1 is obtained, 2, 3-triazol-1-yl) tetrahydro-2H-pyran-3, 4, 5-triacetate).
As shown in figure 2, the chemical structural formula 3 in the figure is (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-one, the chemical structural formula 4 is acetyl arabinose triazole salicylaldoxime, and the chemical structural formula 5 is a generated intermediate compound 5.
The ratio of the amount of compound 5 to the amount of sodium methoxide material in the column chromatography separation is 1:2, and the volume ratio of chloroform to methanol in the eluent used for the column chromatography separation is 20: 1. In this example, 5mmol of compound 5 is suspended in 20mL of methanol, cooled to 0 ℃ with ice water, slowly added dropwise with 0.6mL of a methanol solution of sodium methoxide at a concentration of 1.0mol/L under the protection of nitrogen, reacted at room temperature for 4 hours, monitored by TLC until the starting material point disappears, the system is adjusted to neutral with 732 strong acid styrene cation exchange resin, filtered, the ion exchange resin is washed with methanol, and the filtrate is decompressed to remove methanol to obtain a pale yellow solid, which is separated by column chromatography [ eluent: and obtaining the spiroisoxazole-pyrrolizine derivative 4- (4-chlorphenyl) -3- (2- ((1- ((2S,3R,4S,5S) -3,4, 5-trihydroxy tetrahydro-2H-pyran-2-yl) -1H-1,2, 3-triazole-4-yl) methoxyl) phenyl) -1'H,3' H,4H spiro [ isoxazole-5, 2 '-pyrrolizine ] -1' -ketone (compound 6) with a chlorine substituted arabinose triazole structure according to the volume ratio (chloroform: methanol ═ 20: 1) ].
As shown in fig. 2, the chemical structural formula 6 is the generated spiro isoxazole-pyrrolizine derivative with the chlorine-substituted arabinose triazole structure, i.e. compound 6.
The experimental data are as follows: the chlorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative (compound 6) is light yellow powder, the yield is 66.5%, the melting point is m.p.171-173 ℃, and the nuclear magnetic hydrogen spectrum, infrared spectrogram and element analysis data are as follows:
1H NMR(DMSO-d6)δ:7.29-7.49(m,4H,Ar-H),6.80(dd, J＝2.1,0.8Hz,1H),6.56(dd,J＝4.1,2.3Hz,1H),6.47(s,1H,C＝C-H),5.83 (d,J＝10.0Hz,1H),5.34(d,J＝10.0Hz,1H),8.40(1H,s),7.62 (1H,d,J＝6.4H z),7.52～7.53(1H,m),7.35～7.37(1H,m),7.01 ～7.20(1H,m),5.56(1H,d,J＝9.6H z),5.26(2H,s),5.20(s, 1H),4.36(1H,t),4.34(d,J＝12.8Hz,1H),4.01(1H,dd,J＝3.2,10.0 Hz),3.87(d,J＝12.8Hz,1H),3.78(1H,t),3.67～3.68(1H,m),3.44 ～3.46(2H,m)
IR(KBr)v/cm-1 3447,3430,2916,1705,1603,1458,1242,1096, 1048,757
m/e:591(100.0％)。
Anal.calcd.for C29H26ClN5O7：C,58.89；H,4.46；N,11.81。
in the embodiment, the MTT method is adopted to determine the in-vitro inhibition effect of the compound 6 on different tumor strains, and the determination result of the anti-tumor activity of the chlorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative is as follows:
compound 6 was diluted with DMSO, and tumor cells HepG2 (liver cancer cells), A375 (melanoma cells), SW620 (human colorectal adenocarcinoma cells), A549 (lung adenocarcinoma cells), SGC7901 (stomach cancer cells), SKOV3 (ovarian cancer cells) were seeded in 4000/200. mu.L/well in 96-well plates, 2. mu.L of compound was added to each well to a final concentration of 12.0. mu.M, 6.0. mu.M, 3.0. mu.M, 1.5. mu.M, together at 37 ℃ with 5% CO2The cells were incubated in an incubator for 72 hours, with DMSO (1%) as a blank control. After 72 hours, MTT was added to a final concentration of 0.25mg/mL and the mixture was left at 37 ℃ with 5% CO2After 4 hours in the cell incubator, the solvent was blotted, 100. mu.l DMSO was added to each well, absorbance (OD value) was measured at 570nm with an enzyme-linked immunosorbent assay, and the data obtained was used to calculate IC50The value is obtained. Selecting compounds with high inhibitory activity, and determining the influence of different action times of the compounds at different concentrations on the human tumor cell cycle and apoptosis.
The test compounds of different concentrations were coarse-screened in 96-well plates and IC was calculated from the resulting inhibition50Values, results are given in the table below.
Table 1 shows that the compound 6 chloro-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative has IC (integrated Circuit) effect on six tumor cell strains50Value of
TABLE 1
In Table 1, the IC of the chloro-substituted arabinoltriazole structure spiroisoxazole-pyrrolizine derivative (compound 6) on six tumor cell lines is shown50The value shows that the compound 6 has stronger tumor cell inhibition effect on HepG2 (liver cancer cells) and A375 (melanoma cells), and provides a foundation for further application in the medical field.
The above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and those skilled in the art can make various corresponding changes and modifications according to the present invention without departing from the spirit and the essence of the present invention, but these corresponding changes and modifications should fall within the protection scope of the appended claims.
Claims (8)
1. The chlorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative is characterized in that the chemical structural formula of the chlorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative is as follows:
wherein-Glu' is an arabinosyl group represented by the formula:
2. a preparation method of the chlorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative according to claim 1, which is characterized by comprising the following steps:
step 1, (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-one synthesis: dissolving 2, 3-dihydropyrrolizine-1-ketone and 4-chlorobenzaldehyde in ethanol, adding 40% NaOH aqueous solution, stirring for 3-4 hours at 75-85 ℃, then filtering and separating by using a Buchner funnel, washing a filter cake with water, recrystallizing and purifying by using ethanol, filtering and drying to obtain a product (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-ketone;
step 2, carrying out dehydration reaction on the acetyl arabinose triazole salicylaldehyde and hydroxylamine hydrochloride to generate the acetyl arabinose triazole salicylaldoxime, wherein the chemical structural formula of the acetyl arabinose triazole salicylaldoxime is as follows:
step 3, dissolving (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-one and acetyl arabinoltriazole salicylaldoxime in absolute ethyl alcohol, adding chloramine T, refluxing for 8-12 hours, performing 1, 3-dipolar cycloaddition reaction, introducing arabinoltriazole and isoxazole structures, recrystallizing with methanol to obtain (2S,3R,4S,5S) -2- (4- ((2- (4- (4-chlorophenyl) -1 '-oxy-1' H,3'H,4H spiro [ isoxazole-5, 2' -pyrrolizine ] -3-yl) phenoxy) methyl) -1H-1,2, 3-triazol-1-yl) tetrahydro-2H-pyran-3, 4, 5-triacetate;
step 4, (2S,3R,4S,5S) -2- (4- ((2- (4- (4-chlorphenyl) -1 '-oxygen-1' H,3'H,4H spiro [ isoxazole-5, 2' -pyrrolizine ] -3-yl) phenoxy) methyl) -1H-1,2, 3-triazole-1-yl) tetrahydro-2H-pyran-3, 4, 5-triacetate is suspended in methanol, ice water is cooled to-5 ℃ -0 ℃, a methanol solution of sodium methoxide is slowly dripped under the protection of nitrogen, the reaction is continued for 3-4 hours after the temperature is increased to the room temperature, TLC is used for monitoring until the raw material point disappears, 732 strong acid styrene cation exchange resin is used for adjusting the system to be neutral, filtration is carried out, methanol is used for washing the ion exchange resin, and removing methanol from the filtrate under reduced pressure to obtain a light yellow solid, and separating by column chromatography to obtain a chlorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative 4- (4-chlorphenyl) -3- (2- ((1- ((2S,3R,4S,5S) -3,4, 5-trihydroxy tetrahydro-2H-pyran-2-yl) -1H-1,2, 3-triazole-4-yl) methoxyl) phenyl) -1'H,3' H,4H spiro [ isoxazole-5, 2 '-pyrrolizine ] -1' -one.
3. The preparation method of the spiroisoxazole-pyrrolizine derivative with the chlorine-substituted arabinose triazole structure as claimed in claim 2, wherein the ratio of the 2, 3-dihydro-pyrrolizine-1-one to the 4-chlorobenzaldehyde is 1:1.
4. The preparation method of the spiroisoxazole-pyrrolizine derivative with the chlorine-substituted arabinose triazole structure as claimed in claim 3, wherein 2-3mL of 40% NaOH aqueous solution is added after 2, 3-dihydro-pyrrolizin-1-one and 10mmol of 4-chlorobenzaldehyde are dissolved in 20-30mL of ethanol every 10mmol of 2, 3-dihydro-pyrrolizin-1-one and 10mmol of 4-chlorobenzaldehyde.
5. The preparation method of the spiroisoxazole-pyrrolizine derivative with the chlorine-substituted arabinose triazole structure according to claim 2, wherein the amount ratio of the (E) -2- (4-chlorobenzylidene) -2, 3-dihydropyrrolizine-1-one, the acetyl arabinose triazole salicylaldoxime and the chloramine T is 1:1: 1.2.
6. The method for preparing the spiro isoxazole-pyrrolizine derivative with the chloro-substituted arabinose triazole structure according to claim 2, wherein the ratio of the amount of the (2S,3R,4S,5S) -2- (4- ((2- (4- (4-chlorophenyl) -1 '-oxo-1' H,3'H,4H spiro [ isoxazole-5, 2' -pyrrolizine ] -3-yl) phenoxy) methyl) -1H-1,2, 3-triazol-1-yl) tetrahydro-2H-pyran-3, 4, 5-triacetate to the amount of sodium methoxide substance is 1: 2.
7. The method for preparing the spiroisoxazole-pyrrolizine derivative with the chlorine-substituted arabinose triazole structure as claimed in claim 2, wherein the volume ratio of chloroform to methanol in an eluent for column chromatography separation is 20: 1.
8. An application of the chlorine-substituted arabinose triazole structure spiro isoxazole-pyrrolizine derivative in the preparation of anti-liver cancer or melanoma drugs according to claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010767391.5A CN111909230B (en) | 2020-08-03 | 2020-08-03 | Chlorine-substituted arabinose triazole structure spiro isoxazole-pyrrolizine derivative and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010767391.5A CN111909230B (en) | 2020-08-03 | 2020-08-03 | Chlorine-substituted arabinose triazole structure spiro isoxazole-pyrrolizine derivative and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111909230A CN111909230A (en) | 2020-11-10 |
| CN111909230B true CN111909230B (en) | 2022-05-06 |
Family
ID=73286993
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010767391.5A Active CN111909230B (en) | 2020-08-03 | 2020-08-03 | Chlorine-substituted arabinose triazole structure spiro isoxazole-pyrrolizine derivative and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111909230B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101289481A (en) * | 2008-06-06 | 2008-10-22 | 四川大学 | Synthesis of N-aryl-3-(4-beta-D-allopyranoside phenyl)-5-formyl isoxazole-4-methane amide |
| CN102276673B (en) * | 2011-06-21 | 2014-12-24 | 中国科学院成都生物研究所 | Preparation method of 2-deoxy-beta-D-glucopyranosyl triazole compound |
| CN108570086B (en) * | 2018-04-23 | 2019-08-20 | 绍兴文理学院元培学院 | Maleimide derivatives of the triazole structure containing arabinose and the preparation method and application thereof |
-
2020
- 2020-08-03 CN CN202010767391.5A patent/CN111909230B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN111909230A (en) | 2020-11-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108570086B (en) | Maleimide derivatives of the triazole structure containing arabinose and the preparation method and application thereof | |
| CN112062799B (en) | Methoxy-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative and preparation method and application thereof | |
| CN111943998B (en) | Methyl mercapto substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative and preparation method and application thereof | |
| CN111909230B (en) | Chlorine-substituted arabinose triazole structure spiro isoxazole-pyrrolizine derivative and preparation method and application thereof | |
| CN111961100B (en) | Fluorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative and preparation method and application thereof | |
| CN111961099B (en) | Methyl-substituted arabinose triazole structure spiro isoxazole-pyrrolizine derivative and preparation method and application thereof | |
| CN111961101B (en) | Spiroisoxazole-pyrrolizine derivative with arabinose triazole structure as well as preparation method and application thereof | |
| CN112028955B (en) | Trimethoxylated arabinose triazole structure spiroisoxazole-pyrrolizine derivative and preparation method and application thereof | |
| CN110642864B (en) | Spiro [ indazole-pyrazoline ] derivative containing pyrazole structure and preparation method and application thereof | |
| CN110183467B (en) | P-methoxyphenyl substituted chromone structure-containing spiro [ indazole-isoxazole ] derivative, and preparation method and application thereof | |
| CN112645957A (en) | Pyridazinone structure-containing spiropyrazole-pyrrolizine derivative and preparation method and application thereof | |
| CN108558968B (en) | Maleimide derivatives of the triazole structure containing glucose and the preparation method and application thereof | |
| CN110759920A (en) | P-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing pyrazole structure and preparation method and application thereof | |
| CN110655522B (en) | O-chlorophenyl substituted spiro [ indazole-pyrazoline ] derivative containing pyrazole structure and preparation method and application thereof | |
| CN110790769B (en) | P-methylphenyl substituted spiro [ indazole-pyrazoline ] derivative containing pyrazole structure and preparation method and application thereof | |
| CN110724148B (en) | P-chlorophenyl substituted spiro [ indazole-pyrazoline ] derivative containing pyrazole structure and preparation method and application thereof | |
| CN110128445B (en) | P-chlorophenyl substituted chromone structure-containing spiro [ indazole-isoxazole ] derivative, and preparation method and application thereof | |
| CN110746431B (en) | P-methylmercapto phenyl substituted spiro [ indazole-pyrazoline ] derivative containing pyrazole structure and preparation method and application thereof | |
| CN110143971B (en) | Methylthiophenyl substituted chromone structure-containing spiro [ indazole-isoxazole ] derivative, and preparation method and application thereof | |
| CN110256462B (en) | Para-fluorophenyl substituted chromone structure-containing spiro [ indazole-isoxazole ] derivative, and preparation method and application thereof | |
| CN110734442B (en) | 3,4, 5-trimethoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing pyrazole structure, and preparation method and application thereof | |
| CN108570087B (en) | Maleimide derivatives of the triazole structure containing galactolipin and the preparation method and application thereof | |
| CN110128447B (en) | P-methylphenyl substituted chromone structure-containing spiro [ indazole-isoxazole ] derivative, and preparation method and application thereof | |
| CN110156812B (en) | Spiro [ indazole-isoxazole ] derivative containing chromone structure, and preparation method and application thereof | |
| CN113429445A (en) | Isoxazole derivative containing arabinose triazole structure and preparation method and application thereof |
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 |