CN111943998B - Methyl mercapto substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative and preparation method and application thereof - Google Patents
Methyl mercapto substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a methyl mercapto substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative and a preparation method and application thereof, firstly, (E) -2- (4-methyl mercapto benzylidene) -2, 3-dihydro pyrrolizine-1-ketone and acetyl arabinose triazole salicylaldoxime are synthesized, then dissolving the above 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 the filtrate to remove the methanol to obtain a light yellow solid, and carrying out column chromatography separation to obtain the spiroisoxazole-pyrrolizine derivative with the methylthio-substituted arabinose triazole structure. The methyl mercapto-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative prepared by the invention has a strong tumor cell inhibition effect, and provides a basis for further application in the medical field.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a methyl mercapto-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative, and a preparation method and application thereof.
Background
Chemical name: (E) -2- (4-methylmercaptobenzylidene) -2, 3-dihydropyrrolizin-1-one, having the following chemical structural 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 mercapto-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative, a preparation method and application thereof, and the mercapto-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 methyl mercapto-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative is characterized in that the chemical structural formula of the methyl mercapto-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative is as follows:
wherein-Glu' is an arabinosyl group represented by the formula:
a preparation method of a methylmercapto-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative comprises the following steps:
step 1, (E) -2- (4-methylmercaptobenzylidene) -2, 3-dihydropyrrolizine-1-ketone synthesis: dissolving 2, 3-dihydropyrrolizine-1-ketone and 4-methylmercaptobenzaldehyde in ethanol, adding 40% NaOH aqueous solution, stirring at 75-85 ℃ for 3-4 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-methylmercaptobenzylidene) -2, 3-dihydropyrrolizine-1-ketone;
Further, the ratio of the amount of 2, 3-dihydropyrrolizine-1-one to 4-methiobenzaldehyde material is 1:1.
Further, 2-3mL of 40% NaOH aqueous solution was added to 10mmol of 2, 3-dihydropyrrolizin-1-one and 10mmol of 4-mercaptobenzaldehyde dissolved in 20-30mL of ethanol.
Furthermore, the ratio of the amounts of the (E) -2- (4-methylmercaptobenzylidene) -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-methylthiophenyl) -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 methyl mercapto-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative in the aspect of antitumor drugs.
The invention provides a spiroisoxazole-pyrrolizine derivative with a methyl mercapto-substituted arabinose triazole structure, and a preparation method and application thereof, wherein in the preparation method, a 1, 3-dipolar cycloaddition method is used for introducing an isoxazole ring into a chemical structure of (E) -2- (4-methyl mercapto benzylidene) -2, 3-dihydro pyrrolizine-1-one, so that a novel spiroisoxazole-pyrrolizine derivative with a methyl mercapto-substituted arabinose triazole structure is finally synthesized. The methyl mercapto-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative prepared by the invention has a strong tumor cell inhibition effect, and provides a basis for further application in the medical field.
Drawings
FIG. 1 is a schematic diagram showing the chemical structure of the preparation of (E) -2- (4-methylmercaptobenzylidene) -2, 3-dihydropyrrolizin-1-one according to the present invention;
FIG. 2 is a schematic diagram of a chemical structural formula of a preparation of the methyl mercapto-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 various pharmaceutical activities exhibited by themselves. The general idea of the invention is to skillfully introduce glucoside with biological activity, 1,2, 3-triazole pharmacodynamic structure and five-membered isoxazole ring into the molecular structure of (E) -2- (4-methylmercapto benzylidene) -2, 3-dihydro pyrrolizine-1-ketone, finally prepare the spiroisoxazole-pyrrolizine derivative with the methylmercapto substituted arabinose triazole structure, and improve pharmacological activity.
The invention relates to a methyl mercapto 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 methyl mercapto-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative, which comprises the following steps:
step 1, (E) -2- (4-methylmercaptobenzylidene) -2, 3-dihydropyrrolizine-1-ketone synthesis: dissolving 2, 3-dihydropyrrolizine-1-ketone (compound 1) and 4-methylmercaptobenzaldehyde (compound 2) in ethanol, adding 40% NaOH aqueous solution, stirring at 75-85 ℃ for 3-4 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-methylmercaptobenzylidene) -2, 3-dihydropyrrolizine-1-ketone (compound 3);
as shown in fig. 1 and 2, in fig. 2, chemical formula 1 is 2, 3-dihydropyrrolizine-1-one, chemical formula 2 is 4-methylthiobenzaldehyde, and (E) -2- (4-methylthiobenzylidene) -2, 3-dihydropyrrolizine-1-one, (E) -2- (4-methylthiobenzylidene) -2, 3-dihydropyrrolizine-1-one corresponds to chemical formula 3.
The amount ratio of 2, 3-dihydropyrrolizine-1-one to 4-methiobenzaldehyde substance described herein is 1:1, and 2-3mL of 40% aqueous NaOH solution is added to 10mmol of 2, 3-dihydropyrrolizine-1-one to 10mmol of 4-methiobenzaldehyde in 20-30mL of ethanol.
One example of the present application, synthesis of (E) -2- (4-methylmercaptobenzylidene) -2, 3-dihydropyrrolizin-1-one: dissolving 10mmol of 2, 3-dihydropyrrolizine-1-one (compound 1) and 10mmol of 4-methylthiobenzaldehyde (compound 2) in 20mL of ethanol, adding 2mL of 40% NaOH aqueous solution, stirring at 75 ℃ 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-methylthio benzylidene) -2, 3-dihydropyrrolizine-1-one (compound 3).
In another example, the synthesis of (E) -2- (4-methylmercaptobenzylidene) -2, 3-dihydropyrrolizin-1-one: dissolving 10mmol of 2, 3-dihydropyrrolizine-1-one (compound 1) and 10mmol of 4-methylthiobenzaldehyde (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-methylthio benzylidene) -2, 3-dihydropyrrolizine-1-one (compound 3).
In one example of the present application, the synthesis of (E) -2- (4-methylmercaptobenzylidene) -2, 3-dihydropyrrolizin-1-one: dissolving 10mmol of 2, 3-dihydropyrrolizine-1-one (compound 1) and 10mmol of 4-methylthiobenzaldehyde (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-methylthio benzylidene) -2, 3-dihydropyrrolizine-1-one (compound 3).
The present application dissolves 2, 3-dihydropyrrolizin-1-one and 4-methiobenzaldehyde in ethanol, wherein the ethanol is 95% aqueous ethanol. Ethanol is only the reaction solvent and is present in excess. The ethanol is less than 2, 3-dihydropyrrolizine-1-ketone and 4-methylmercaptobenzaldehyde, and is not dissolved, and the molar concentration of the solution is too dilute, so 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:
suspending acetyl azide arabinose and 2-propargyloxybenzaldehyde in a mixed solvent of dichloromethane and water, heating to 40-44 ℃, and adding sodium ascorbate and CuSO in turn 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 substance of acetyl arabinose triazole salicylaldehyde to the amount of hydroxylamine hydrochloride is 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, separating liquid when the solution system of the chemical reaction is cooled to room temperature (20-30 ℃), and using CH for a water layer2C12Extracting twice (50mL multiplied by 2), combining organic phases, drying over night by anhydrous sodium sulfate, filtering, decompressing to remove solvent, and separating by flash column chromatography to obtainAcetyl 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). The arabinofuranotriazole salicylaldehyde (0.4mol) and 50mL of absolute ethanol are weighed into a 250mL conical flask under stirring, and stirred vigorously for 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 form the arabinoside triazole salicylaldoxime in this embodiment is a relatively mature technology, and is not described herein again.
And 3, dissolving (E) -2- (4-methylmercaptobenzylidene) -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 ratio of the (E) -2- (4-methylmercaptobenzylidene) -2, 3-dihydropyrrolizine-1-one, the acetyl arabinose triazole salicylaldoxime and the chloramine T substance is 1:1: 1.2.
In this example, 10mmol (E) -2- (4-methylmercaptobenzylidene) -2, 3-dihydropyrrolizin-1-one (compound 3) and 10mmol (compound 4) of acetylarabinoltriazole salicylaldoxime (compound 4) are dissolved in 30mL of absolute ethanol, 12mmol of chloramine T is added, reflux is carried out for 12 hours, 1, 3-dipolar cycloaddition reaction is carried out, arabinoltriazole and isoxazole structures are introduced, and recrystallization is carried out with methanol to obtain compound 5((2S,3R,4S,5S) -2- (4- ((2- (4- (4-methylmercaptophenyl) -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);
as shown in figure 2, the chemical structural formula 3 in the figure is (E) -2- (4-methylmercaptobenzylidene) -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: the volume ratio (chloroform: methanol ═ 20: 1) ], to obtain the methyl mercapto substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative 4- (4-methyl mercapto phenyl) -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).
As shown in fig. 2, the chemical structural formula 6 is the generated methyl mercapto-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative, i.e. compound 6.
The experimental data are as follows: the methyl mercapto substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative (compound 6) is light yellow powder, the yield is 30.8 percent, the melting point is m.p.142-144 ℃, and the nuclear magnetic hydrogen spectrum, the infrared spectrogram and the element analysis data are as follows:
1H NMR(DMSO-d6)δ:7.28-7.49(m,4H,Ar-H),6.80(dd, J=2.1,0.8Hz,1H),6.55(dd,J=4.1,2.3Hz,1H),6.47(s,1H,C=C-H),5.82 (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),5.57(1H,d,J=9.6H z),5.26(2H,s),5.18(s, 1H),4.36(1H,t),4.33(d,J=12.8Hz,1H),4.01(1H,dd,J=3.2,10.0 Hz),3.91(d,J=12.8Hz,1H),3.78(1H,t),3.67~3.68(1H,m),3.44 ~3.46(2H,m),2.43(s,3H,CH3)。
IR(KBr)v/cm-1 3457,3433,2916,1712,1601,1458,1242,1095, 1045,753
m/e:603(100.0%)。
Anal.calcd.for C30H29N5O7S:C,59.64;H,4.87;N,11.63。
in this example, the MTT method is used to determine the in vitro inhibitory effect of compound 6 on different tumor strains, and the results of the determination of the anti-tumor activity of the spiroisoxazole-pyrrolizine derivative with the structure of methylthio-substituted arabinoltriazole are as follows:
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 following table.
Table 1 IC of 6-methyl-mercapto-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative on six tumor cell strains50Value of
TABLE 1
In Table 1, the IC of the methylmercapto-substituted arabinose triazole 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 A549 (lung adenocarcinoma 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 methyl mercapto-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative is characterized in that the chemical structural formula of the methyl mercapto-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 methylmercapto-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative according to claim 1 is characterized by comprising the following steps:
step 1, (E) -2- (4-methylmercaptobenzylidene) -2, 3-dihydropyrrolizine-1-ketone synthesis: dissolving 2, 3-dihydropyrrolizine-1-ketone and 4-methylmercaptobenzaldehyde in ethanol, adding 40% NaOH aqueous solution, stirring at 75-85 ℃ for 3-4 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-methylmercaptobenzylidene) -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-methylmercaptobenzylidene) -2, 3-dihydropyrrolizine-1-one and acetyl arabinotriazole salicylaldoxime in absolute ethyl alcohol, adding chloramine T, refluxing for 8-12 hours, performing 1, 3-dipolar cycloaddition reaction, introducing arabinotriazole and isoxazole structures, recrystallizing with methanol to obtain (2S,3R,4S,5S) -2- (4- ((2- (4- (4-methylmercaptophenyl) -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-methylmercaptophenyl) -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 ℃, 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 room temperature, TLC is used for monitoring until the raw material point disappears, 732 strong acid styrene cation exchange resin is used for regulating the system to be neutral, and filtration is carried out, washing the ion exchange resin with methanol, decompressing the filtrate to remove the methanol to obtain a light yellow solid, and separating by column chromatography to obtain the methyl mercapto substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative 4- (4-methyl mercapto phenyl) -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.
3. The preparation method of the spiroisoxazole-pyrrolizine derivative with the methylmercapto-substituted arabinose triazole structure according to claim 2, wherein the amount ratio of the 2, 3-dihydro-pyrrolizin-1-one to the 4-methylmercaptobenzaldehyde substance is 1:1.
4. The preparation method of the spiroisoxazole-pyrrolizine derivative with the methylmercapto-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-methylmercaptobenzaldehyde are dissolved in 20-30mL of ethanol every 10mmol of 2, 3-dihydro pyrrolizin-1-one and 10mmol of 4-methylmercaptobenzaldehyde.
5. The preparation method of the spiroisoxazole-pyrrolizine derivative with the methylmercapto-substituted arabinose triazole structure according to claim 2, wherein the amount ratio of the (E) -2- (4-methylmercaptobenzylidene) -2, 3-dihydro pyrrolizine-1-one, the acetyl arabinose triazole salicylaldoxime and the chloramine T substance is 1:1: 1.2.
6. The method for preparing spiroisoxazole-pyrrolizine derivatives with methylmercapto-substituted arabinose triazole structure according to claim 2, wherein the ratio of the amount of (2S,3R,4S,5S) -2- (4- ((2- (4- (4-methylmercaptophenyl) -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 material is 1: 2.
7. The method for preparing the spiroisoxazole-pyrrolizine derivative with the methylmercapto-substituted arabinose triazole structure as claimed in claim 2, wherein the volume ratio of chloroform to methanol in eluent for column chromatography separation is 20: 1.
8. An application of the methyl mercapto-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative in the preparation of anti-lung adenocarcinoma drugs according to claim 1.
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