CN112457363B - Potato trisaccharide oleanolic acid saponin derivative and preparation method and application thereof - Google Patents

Potato trisaccharide oleanolic acid saponin derivative and preparation method and application thereof Download PDF

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CN112457363B
CN112457363B CN202011324176.4A CN202011324176A CN112457363B CN 112457363 B CN112457363 B CN 112457363B CN 202011324176 A CN202011324176 A CN 202011324176A CN 112457363 B CN112457363 B CN 112457363B
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宋高鹏
李辉
刘志浩
刘铭健
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South China Agricultural University
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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a trisaccharide oleanolic acid saponin derivative of potatoes, and a preparation method and application thereof. Experimental research shows that the potato trisaccharide oleanolic acid saponin derivative provided by the invention has a remarkable inhibitory effect on novel coronavirus SARS-CoV-2, and can be applied to preparation of a medicament for treating novel coronavirus pneumonia; wherein part of the triose oleanolic acid saponin derivatives have inhibitory effect on novel coronavirus IC50The molecular weight of the coronavirus reaches below 10 mu M, has very good development potential, and provides more choices for treating the novel coronavirus.

Description

Potato trisaccharide oleanolic acid saponin derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry. More particularly relates to a potato trisaccharide oleanolic acid saponin derivative, a preparation method and application thereof.
Background
Coronaviruses belong to the phylogenetic group of the order of the nested viruses (Nidovirales), the family of Coronaviridae (Coronaviridae), the genus Coronaviridae (Coronavir), and only infect vertebrates, including humans, and currently known coronaviruses that infect humans and bring about a tremendous epidemic, such as SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1, can cause diseases in the respiratory, digestive, hepatic and nervous systems. Human coronaviruses have been isolated in 1965, but until now their knowledge has been rather limited, and the serotype and antigenic variability of coronaviruses has not been confirmed. Moreover, the coronavirus can be repeatedly infected, which shows that the coronavirus has a plurality of serotypes (at least 4 types are known) and antigenic variation, is difficult to immunize, and has no specific preventive and therapeutic medicine.
At present, no specific medicine for treating the new coronary pneumonia exists, and the existing treatment method is mostly from the treatment experiences of the existing SARS and MERS. As found in experimental research, azauracil (alpha zauracil) and ribavirin (ribavirin, Virazole) have obvious inhibiting effect on coronavirus (Qian, Wang Rui. coronavirus infection characteristics and prevention and treatment [ J ] J. Chinese Hospital J. infectivity, 2003, 013(011): 1097) 1100.), but the medicines are easy to cause adverse reactions such as diarrhea, anemia, dizziness, headache, weakness, hypodynamia and the like; chloroquine and hydroxychloroquine may be used for the treatment of new indications for covi-19 and have a certain positive effect, but chloroquine and hydroxychloroquine have been found to have cardiotoxicity in clinical applications (bang, zhanfan, majogen, liu, chloroquine and hydroxychloroquine have been shown to have clinical research progress in the treatment of novel coronavirus pneumonia and their cardiotoxic side effects [ J ]. journal of practical cardio-cerebral-pulmonary vascular diseases 2020,28(03): 1-5.). As can be seen, the types of the medicines for treating the novel coronavirus pneumonia at present are very few, adverse reactions with different degrees exist, and specific medicines are particularly deficient. Therefore, there is a great need to develop new drugs for treating the novel coronavirus pneumonia.
Disclosure of Invention
The invention aims to overcome the defects and shortcomings of few types of alternative drugs for treating novel coronavirus pneumonia in the prior art, and provides application of a trisaccharide oleanolic acid saponin derivative in preparation of a drug for treating novel coronavirus pneumonia. The inventor finds that the potato trisaccharide oleanolic acid saponin derivative with a specific structure has better activity of inhibiting novel coronavirus, and can be used for treating diseases of novel coronavirus pneumonia.
Therefore, the invention aims to provide a trisaccharide oleanolic acid saponin derivative of potato.
The invention also aims to provide a preparation method of the potato trisaccharide oleanolic acid saponin derivative.
The invention also aims to provide application of the potato trisaccharide oleanolic acid saponin derivative in preparing a medicine for treating coronavirus.
The above purpose of the invention is realized by the following technical scheme:
a potato trisaccharide oleanolic acid saponin derivative having the structure of formula I:
Figure BDA0002793825590000021
wherein R is hydrogen or C1～8Alkoxy radical, C1～8Cycloalkoxy, C1～8Haloalkoxy, C1～8Hydroxy-substituted alkoxy, phenoxy, halophenoxy, nitrophenoxy, C1～4Alkyl substituted phenoxy, C1～4Alkoxy substituted phenoxy, benzyloxy, halobenzyloxy, nitrobenzyloxy, C1～4Alkyl-substituted benzyloxy, C1～4Alkoxy substituted benzyloxy, C1～8Alkylamino radical, C1～8Cycloalkylamino radical, C1～8Haloalkylamino, anilino, haloanilino, nitroanilino, C1～4Alkyl-substituted anilino group, C1～4Alkoxy-substituted anilino, benzylamino, halobenzylamino, nitrobenzylamino, C1～4Alkyl-substituted benzylamine radical, C1～4Alkoxy substituted benzylamino, phenylethylamino and C1～4Alkyl substituted phenylethylamino and C1～4Alkyl substituted phenylethylamino and C1～4Alkoxy substituted phenyl ethylamino, phenyl propylamino, C1～4Alkyl substituted phenyl propylamine, C1～4Alkyl radical, C1～4Alkoxy substituted benzylamine substituted phenyl propylamine, C1～4Alkoxy substituted phenyl propylamine.
Preferably, R is anilino, benzylamino, 2-phenylethylamino, 3-phenylpropylamino, N-methyl-benzylamino, o-methoxyanilino, m-methoxyanilino, p-methoxyanilino, 2-furanmethylamino, 2-thienylmethylamino, 2-pyridinemethylamino, o-fluorobenzylamino, o-chlorobenzylamino, o-bromobenzylamino, o-methoxybenzylamino, o-chlorophenyl, 2-hydroxyethoxy or ethoxycarbonylmethoxy.
Preferably, R is benzylamino, 2-phenylethylamino, N-methyl-benzylamino, o-methoxyanilino, m-methoxyanilino, p-methoxyanilino, 2-thienylmethylamino or o-fluorobenzylamino.
More preferably, R is benzylamino, o-methoxyanilino, 2-thienylmethylamino or o-fluorobenzylamino.
In addition, the invention also provides a preparation method of the potato trisaccharide oleanolic acid saponin derivative, which comprises the following steps:
s1, taking oleanolic acid as a raw material, and carrying out substitution reaction to obtain an intermediate compound T-1:
Figure BDA0002793825590000031
s2, subjecting the compound T-1 obtained in the step S1 to glycosylation reaction to obtain an intermediate compound T-2:
Figure BDA0002793825590000032
s3, carrying out hydrolysis reaction on the intermediate compound T-2 obtained in the step S2 to obtain an intermediate compound T-3:
Figure BDA0002793825590000033
s4, selectively protecting the glucose 3 and 6-hydroxy group of the intermediate compound T-3 obtained in the step S3 through esterification reaction to obtain an intermediate compound T-4:
Figure BDA0002793825590000041
s5, subjecting the intermediate compound T-4 obtained in the step S4 to glycosylation reaction to obtain an intermediate compound T-5:
Figure BDA0002793825590000042
s6, carrying out hydrolysis reaction on the intermediate compound T-5 obtained in the step S5 to obtain an intermediate compound T-6:
Figure BDA0002793825590000043
s7, carrying out reduction reaction on the intermediate compound T-6 obtained in the step S6 to obtain an intermediate compound T-7:
Figure BDA0002793825590000051
s8, carrying out esterification reaction on the intermediate compound T-7 obtained in the step S7 to obtain an intermediate compound T-8:
Figure BDA0002793825590000052
s9, sequentially carrying out condensation reaction and hydrolysis reaction on the intermediate compound T-8 obtained in the step S8 to obtain the potato trisaccharide oleanolic acid saponin derivative compound I.
Further, in step S1, potassium carbonate may be added to catalyze the reaction.
Further, in step S2, intermediate 1 is added to perform glycosylation;
the structural formula of the intermediate 1 is as follows:
Figure BDA0002793825590000053
further, in step S2, trimethylsilyl trifluoromethanesulfonate TMSOTf may be added to catalyze the reaction at a reaction temperature of 0 ℃.
Further, in step S3, the reaction is performed under basic conditions, a basic environment is obtained by adding sodium methoxide, a dichloromethane-methanol mixed solvent (volume ratio 1:1) is used as a reaction solvent, and the reaction temperature is room temperature.
Further, in step S4, the reaction is performed under the action of pivaloyl chloride, a dichloromethane-pyridine mixed solvent (volume ratio of 1:1) is used as a reaction solvent, and the reaction temperature is room temperature.
Further, in step S5, intermediate 2 is added to perform glycosylation;
the structural formula of the intermediate 2 is as follows:
Figure BDA0002793825590000061
further, in step S5, the temperature of the reaction is 0 ℃.
Further, in step S6, the reaction is carried out under the action of sodium hydroxide at a reaction temperature of 50 ℃.
Further, in step S7, PdCl may be added2And (4) catalyzing the reaction.
Further, in step S8, the reaction is acetylated by the action of acetic anhydride, and the reaction solvent is pyridine.
Further, in step S9, after the intermediate compound T-8 reacts with oxalyl chloride to generate an acyl chloride intermediate, the acyl chloride intermediate undergoes a condensation reaction with the corresponding amine, and the reaction solvent is dichloromethane; removing acetyl from the intermediate obtained by condensation reaction under the action of sodium methoxide, wherein the reaction solvent is a dichloromethane-methanol mixed solvent.
In addition, the invention also provides application of the triose oleanolic acid saponin derivative in preparing a medicine for treating coronaviruses.
Preferably, the coronavirus is a novel coronavirus SARS-CoV-2.
Further, the medicine also comprises a pharmaceutically acceptable carrier, and is prepared into an oral preparation, an injection or an inhalant.
The invention has the following beneficial effects:
experiments prove that the invention provides a brand new potato trisaccharide oleanolic acid saponin derivative, which has obvious inhibition effect on novel coronavirus SARS-CoV-2 and can be applied to the preparation of medicaments for treating novel coronavirus pneumonia; wherein part of the triose oleanolic acid saponin derivatives have inhibitory effect on novel coronavirus IC50The molecular weight of the coronavirus reaches below 10 mu M, has very good development potential, and provides more choices for treating the novel coronavirus.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the invention in any way. The reagents, methods and apparatus employed in the present invention are conventional in the art, unless otherwise specified.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
EXAMPLE 1 preparation of a Potato trisaccharide Oleanolic acid saponin derivative Compound I-A
The synthetic route of the compound I-A of the potato trisaccharide oleanolic acid saponin derivative is as follows:
Figure BDA0002793825590000071
wherein a is allyl bromide, potassium carbonate and DMF; b is trimethylsilyl trifluoromethanesulfonate,
Figure BDA0002793825590000072
molecular sieve, dichloromethane; c is sodium methoxide, methanol-dichloromethane; d is pivaloyl chloride, pyridine-dichloromethane; e is trimethylsilyl trifluoromethanesulfonate,
Figure BDA0002793825590000073
molecular sieves, dichloromethane; f is 4N sodium hydroxide, methanol-tetrahydrofuran; g is palladium dichloride, methanol-dichloromethane; h is acetic anhydride, DMAP, pyridine; i is (1) oxalyl chloride and dichloromethane; (2) aniline, triethylamine, dichloromethane; (3) sodium methoxide, methanol-dichloromethane.
The preparation method comprises the following steps:
s1 and preparation of intermediate compound T-1
Dissolving oleanolic acid (10g, 21.90mmol) in 200mL DMF, adding potassium carbonate (6.05g, 43.80mmol), stirring at room temperature for 20min, gradually adding allyl bromide (2.27mL, 26.27mmol), heating to 80 deg.C, and refluxing overnight; adding methanol dropwise in an ice bath to quench the reaction, evaporating the solvent under reduced pressure, dissolving the residue in ethyl acetate, washing with water, saturated sodium bicarbonate solution and saturated sodium chloride solution for 3 times in sequence, drying with anhydrous sodium sulfate, and performing silica gel column chromatography (V petroleum ether/V ethyl acetate/V dichloromethane ═ 10/1/1) to obtain a white solid product (11.34g, yield 94.68%);
s2 and preparation of intermediate compound T-2
Intermediate compound T-1(3g, 5.49mmol) from step S1 was dissolved in 50mL dry dichloromethane, and intermediate 1(5.29g, 7.13mmol) and the appropriate amount of activated
Figure BDA0002793825590000081
After stirring for 20min at normal temperature, gradually dropwise adding trimethylsilyl trifluoromethanesulfonate (150 μ L and 0.83mmol) in an ice bath, reacting for 30min in the ice bath, returning to room temperature, adding triethylamine to terminate the reaction, performing diatomite assisted filtration, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography (V petroleum ether/V ethyl acetate/V dichloromethane ═ 8/1/1) to obtain a white solid product (5.73g and the yield of 92.68%);
s3 and preparation of intermediate compound T-3
Dissolving the intermediate compound T-2(5g, 4.44mmol) obtained in step S2 in 50mL (V dichloromethane/V methanol 1/1) mixed solvent, adding sodium methoxide to adjust the system pH to 10, and reacting at room temperature overnight; adding acidic cation resin to adjust the pH of the system to 7, filtering, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography (V dichloromethane/V methanol ═ 10/1) to obtain a white solid product (3.05g, yield 96.97%);
s4 and preparation of intermediate compound T-4
Intermediate compound T-3(3g, 4.23mmol) obtained in step S3 was dissolved in 30mL (V dichloromethane/V pyridine ═ 1/1) mixed solvent, pivaloyl chloride (2.60mL, 21.15mmol) was added at-12 ℃, and reaction was carried out for 12 h; adding methanol to terminate the reaction, evaporating the solvent under reduced pressure, dissolving the residue in dichloromethane, washing with 1M hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution sequentially for 3 times, drying with anhydrous sodium sulfate, and performing silica gel column chromatography (V petroleum ether/V ethyl acetate/V dichloromethane ═ 8/1/1) to obtain a white solid product (2.74g, 73.83% yield);
s5 and preparation of intermediate compound T-5
Intermediate compound T-4(2g, 2.28mmol) from step S4 was dissolved in 30mL dry dichloromethane, and intermediate 2(4.96g, 11.40mmol) and the appropriate amount of activated
Figure BDA0002793825590000082
After stirring for 20min at normal temperature, gradually dropwise adding trimethylsilyl trifluoromethanesulfonate (123 mu L and 0.68mmol) under ice bath, reacting for 30min under ice bath, returning to room temperature, adding triethylamine to terminate the reaction, performing diatomite assisted filtration, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography (V petroleum ether/V ethyl acetate/V dichloromethane ═ 3/1/1) to obtain a white solid product (3.03g and the yield of 93.54%);
s6 and preparation of intermediate compound T-6
Intermediate compound T-5(3.00g, 2.11mmol) obtained in step S5 was dissolved in a mixed solvent (V methanol/V tetrahydrofuran/V water 1/1/1), NaOH (1.67g, 42.2mmol) was added, and the mixture was reacted at room temperature overnight; adding acidic cation resin to adjust the pH of the system to 7, filtering, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography (V dichloromethane/V methanol ═ 5/1) to obtain a white solid product (2.06g, yield 97.83%);
s7 and preparation of intermediate compound T-7
The intermediate compound T-6(2.00g, 2.00mmol) obtained in step S6 was dissolved in a mixed solvent (V methanol/V dichloromethane ═ 1/1), and palladium dichloride (100mg) was added thereto and stirred at room temperature for 3 days; celite assisted filtration, the filtrate concentrated under reduced pressure and silica gel column chromatography (V dichloromethane/V methanol ═ 5/1) afforded the product as a white solid (1.67g, 91.57% yield);
s8 and preparation of intermediate compound T-8
Dissolving the intermediate compound T-7(1.5g, 1.65mmol) obtained in the step S7 in 20mL of pyridine, adding acetic anhydride (2.50mL, 26.40mmol) and DMAP (303mg, 2.48mmol) under ice bath, and returning to room temperature for reaction overnight; the reaction was terminated by adding methanol, concentrated under reduced pressure, and the residue was dissolved in dichloromethane, washed three times with 1M hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride solution in this order, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography (V petroleum ether/V ethyl acetate/V dichloromethane ═ 3/1/1) to obtain a white solid product (1.97g, yield 95.88%);
s9 preparation of Compound I-A
The intermediate compound T-8(200mg, 0.16mmol) obtained in step S8 was dissolved in 5mL of dry dichloromethane and oxalyl chloride (54. mu.L, 0.64mmol) was reacted at room temperature for 24 h; the remaining oxalyl chloride was evaporated under reduced pressure, aniline (30. mu.L, 0.32mmol) and triethylamine (89. mu.L, 0.64mmol) were added under ice bath, and the mixture was returned to room temperature for overnight reaction; concentrated under reduced pressure and chromatographed on silica gel (V petroleum ether/V ethyl acetate/V dichloromethane ═ 2/1/1) to give the intermediate product as a white solid (200mg, 94.83% yield); dissolving the obtained intermediate product in 10 mL (V methanol/V dichloromethane ═ 1/1) mixed solvent, adding sodium methoxide to adjust pH to 10, and reacting at room temperature overnight; acidic cation resin was added to adjust the system pH to 7, and the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography (V dichloromethane/V methanol ═ 6/1) to obtain the product i-a (138mg, yield 93.70%) as a white solid.
Nuclear magnetic hydrogen spectrum data of the obtained compound I-A1H NMRδ(ppm,600MHz)：1H NMR(CD3OD) δ7.46(d,2H,J＝7.7Hz),7.29(t,2H,J＝7.9Hz),7.09(t,1H,J＝7.4Hz),5.45(t, 1H,J＝3.3Hz),5.36(d,1H,J＝1.0Hz),4.42(d,1H,J＝7.7Hz),3.91(dd,1H,J＝ 9.5,6.2Hz),3.84(dd,1H,J＝2.9,1.8Hz),3.80(d,1H,J＝11.8Hz,1.4Hz),3.74(dd, 1H,J＝9.6,3.4Hz),3.66(dd,1H,J＝12.1,4.0Hz),3.63(dd,1H,J＝9.5,3.3Hz), 3.60–3.56(m,1H),3.54(t,1H,J＝9.1Hz),3.46–3.36(m,3H),3.16(dd,1H,J＝11.7, 4.2Hz),2.95(dd,1H,J＝13.0,3.3Hz),1.26(d,3H,J＝6.2Hz),1.20(d,6H,J＝6.0 Hz),1.04,0.98,0.94,0.92,0.84,0.74(each s,each 3H).
EXAMPLE 2 preparation of Potato trisaccharide Oleanolic acid saponin derivative Compounds I-B
The compound I-B of the triose oleanolic acid saponin derivative of potato replaces the substituent R in the compound I-A with a benzylamine group from an anilino group, and the rest operation and parameters are referred to the example 1, so that a white solid product I-B (the total yield is 47.17%) is obtained.
Figure BDA0002793825590000101
Nuclear magnetic hydrogen spectrum data of the obtained compound I-B1H NMRδ(ppm,600MHz)：1H NMR(CD3OD) δ7.70(s,1H,J＝5.8Hz),7.30–7.27(m,4H),7.25–7.20(m,1H),5.37(s,1H),5.32 (s,1H),4.85(s,1H),4.42(d,1H,J＝7.7Hz),4.38(dd,1H,J＝14.7,5.9Hz),4.27 (dd,1H,J＝14.7,5.7Hz),4.01–3.95(m,2H),3.94–3.88(m,1H),3.85–3.83(m, 1H),3.80(d,1H,J＝10.6Hz),3.75(dd,1H,J＝9.6,3.3Hz),3.66(dd,1H,J＝12.0, 3.9Hz),3.63(dd,1H,J＝9.4,3.2Hz),3.58(t,1H,J＝8.7Hz),3.54(t,1H,J＝9.1 Hz),3.47–3.36(m,3H),3.15(dd,1H,J＝11.7,4.1Hz),2.82(dd,1H,J＝13.2,3.5 Hz),1.27(d,3H,J＝6.2Hz),1.22(d,3H,J＝6.2Hz),1.16,1.05,0.95,0.91,0.90, 0.86,0.59(each s,each 3H).
EXAMPLE 3 preparation of Potato trisaccharide Oleanolic acid saponin derivative Compounds I-C
The compound I-C of the triose oleanolic acid saponin derivative of potato has the R substituent in I-A replaced by an anilino group with a 2-phenylethylamino group, and the rest of the operation and parameters are referred to example 1 to obtain a white solid product I-C (total yield 46.98%).
Figure BDA0002793825590000111
Nuclear magnetic hydrogen spectrum data of the obtained compound I-C1H NMRδ(ppm,600MHz)：1H NMR(CD3OD) δ7.34–7.26(m,2H),7.26–7.18(m,3H),6.94–6.87(t-like,1H),5.36(s,1H),5.13 (t-like,1H),4.42(d,1H,J＝7.7Hz),4.02–3.95(m,2H),3.95–3.86(m,1H),3.86– 3.82(m,1H),3.82–3.77(m,1H),3.74(dd,1H,J＝9.5,3.1Hz),3.70–3.60(m,2H), 3.60–3.53(m,2H),3.48–3.35(m,3H),3.26–3.18(m,1H),3.15(dd,1H,J＝11.7, 3.8Hz),2.88–2.69(m,3H),2.59(dd,1H,J＝12.6,3.6Hz),1.27(d,3H,J＝6.2Hz), 1.21(d,3H,J＝6.2Hz),1.13,1.04,0.92,0.91,0.90,0.86,0.65(each s,each 3H).
EXAMPLE 4 preparation of Potato trisaccharide Oleanolic acid saponin derivative Compounds I-D
The compound I-D of the triose oleanolic acid saponin derivative of potato has the R substituent in I-A replaced by an anilino group with a 3-phenylpropylamino group, and the rest of the operation and parameters refer to example 1, to obtain the product I-D as a white solid (total yield 47.52%).
Figure BDA0002793825590000112
Nuclear magnetic hydrogen spectrum data of the obtained compound I-D1H NMRδ(ppm,600MHz)：1H NMR(CD3OD) δ7.34–7.26(m,2H),7.26–7.18(m,3H),6.94–6.87(t-like,1H),5.36(s,1H),5.13 (t-like,1H),4.42(d,1H,J＝7.7Hz),4.02–3.95(m,2H),3.95–3.86(m,1H),3.86– 3.82(m,1H),3.82–3.77(m,1H),3.74(dd,1H,J＝9.5,3.1Hz),3.70–3.60(m,2H), 3.60–3.53(m,2H),3.48–3.35(m,3H),3.26–3.18(m,1H),3.15(dd,1H,J＝11.7, 3.8Hz),2.88–2.69(m,3H),2.59(dd,1H,J＝12.6,3.6Hz),1.27(d,3H,J＝6.2Hz), 1.21(d,3H,J＝6.2Hz),1.13,1.04,0.92,0.91,0.90,0.86,0.65(each s,each 3H).
EXAMPLE 5 preparation of Potato trisaccharide Oleanolic acid saponin derivative Compounds I-E
The potato trisaccharide oleanolic acid saponin derivative compound I-E replaced the R substituent in I-a from an anilino group to an N-methyl-benzylamino group, and the rest of the procedure and parameters were referenced in example 1 to give the product I-E as a white solid (total yield 47.43%).
Figure BDA0002793825590000121
Nuclear magnetic hydrogen spectrum data of the obtained compound I-E1H NMRδ(ppm,600MHz)：1H NMR(CD3OD) δ7.35–7.28(m,2H,Ar-H),7.28–7.19(m,3H,Ar-H),5.37(s,1H),5.21(t-like,1H), 4.43(d,1H,J＝7.7Hz),4.01–3.96(m,2H),3.94–3.88(m,1H),3.84(dd,1H,J＝ 3.0,1.7Hz),3.80(d,1H,J＝10.7Hz),3.76(dd,1H,J＝9.6,3.3Hz),3.66(dd,1H,J ＝13.9,3.4Hz),3.63(dd,2H,J＝9.5,3.1Hz),3.60–3.53(m,2H),3.48–3.36(m, 3H),3.16(dd,1H,J＝11.7,3.9Hz),3.06(s,3H),1.27(d,3H,J＝6.2Hz),1.22(d, 3H,J＝6.2Hz),1.17,1.06,0.97,0.96,0.92,0.87,0.78(each s,each 3H).
EXAMPLE 6 preparation of Potato trisaccharide Oleanolic acid saponin derivative Compounds I-F
The compound I-F of the triose oleanolic acid saponin derivative of potato replaces the substituent R in the compound I-A from an anilino group to an o-methoxyanilino group, and the rest operation and parameters are referred to example 1, so that white solid products I-F (the total yield is 47.77%) are obtained.
Figure BDA0002793825590000131
Nuclear magnetic hydrogen spectrum data of the obtained compound I-F1H NMRδ(ppm,600MHz)：1H NMR(CD3OD) δ8.26(d,1H,J＝8.0Hz),7.05(t,1H,J＝7.2Hz),6.99(d,1H,J＝7.9Hz),6.90(t, 1H,J＝7.7Hz),5.54(t-like,1H),5.36(s,1H),4.42(d,1H,J＝7.7Hz),3.90(s,3H), 3.80(d,1H,J＝11.1Hz),3.74(dd,1H,J＝9.5,3.2Hz),3.66(dd,1H,J＝12.0,3.8 Hz),3.63(dd,1H,J＝9.4,3.1Hz),3.59(t,1H,J＝8.7Hz),3.54(t,1H,J＝9.1Hz), 3.47–3.36(m,3H),2.74(d,1H,J＝12.1Hz),1.27(d,3H,J＝6.1Hz),1.20(d,6H,J ＝8.4Hz),1.04,0.96,0.94,0.89,0.83,0.62(each s,each 3H).
EXAMPLE 7 preparation of Potato trisaccharide Oleanolic acid saponin derivative Compounds I-G
The compound I-G of the triose oleanolic acid saponin derivative of potato replaces the substituent R in I-A with m-methoxyanilino from anilino, and the rest of the operation and parameters refer to example 1, and a white solid product I-G is obtained (total yield 46.23%).
Figure BDA0002793825590000132
Nuclear magnetic hydrogen spectrum data of the obtained compound I-G1H NMRδ(ppm,600MHz)：1H NMR(CD3OD) δ7.20(t,1H,J＝2.0Hz),7.18(t,1H,J＝8.2Hz),7.01–6.98(m,1H),6.66(dd,1H,J ＝8.3,2.3Hz),5.44(t-like,1H),5.36(s,1H),4.42(d,1H,J＝7.7Hz),3.91(dd,1H,J ＝9.5,6.3Hz),3.77(s,3H),3.74(dd,1H,J＝9.6,3.4Hz),3.66(dd,1H,J＝12.0,3.9 Hz),3.63(dd,1H,J＝9.5,3.3Hz),3.59(t,1H,J＝8.7Hz),3.54(t,1H,J＝9.0Hz), 3.46–3.36(m,3H),2.94(dd,1H,J＝13.2,3.2Hz),1.26(d,3H,J＝6.2Hz),1.21(d, 3H,J＝6.3Hz),1.20,1.04,0.98,0.94,0.92,0.84,0.74(each s,each 3H).
EXAMPLE 8 preparation of Potato trisaccharide Oleanolic acid saponin derivative Compounds I-H
The compound I-H of the triose oleanolic acid saponin derivative of potato replaces the substituent R in I-A from an anilino group to a p-methoxyanilino group, and the rest of the operation and parameters refer to example 1, so that the product I-H of white solid is obtained (total yield 47.46%).
Figure BDA0002793825590000141
Nuclear magnetic hydrogen spectrum data of the obtained compound I-H1H NMRδ(ppm,600MHz)：1H NMR(CD3OD) δ7.33(d,2H,J＝9.0Hz),6.86(d,2H,J＝9.0Hz),5.43(t-like,1H),5.36(s,1H), 4.42(d,1H,J＝7.7Hz),3.91(dd,1H,J＝9.4,6.2Hz),3.80(d,1H,J＝10.6Hz), 3.76(s,3H),3.66(dd,1H,J＝12.0,4.0Hz),3.63(dd,1H,J＝9.4,3.0Hz),3.59(t, 1H,J＝8.7Hz),3.54(t,1H,J＝9.1Hz),3.46–3.36(m,3H),3.15(dd,1H,J＝11.7, 4.2Hz),2.93(dd,1H,J＝13.0,3.3Hz),1.26(d,3H,J＝6.2Hz),1.21(d,3H,J＝6.2 Hz),1.20,1.04,0.98,0.93,0.92,0.84,0.76(each s,each 3H).
EXAMPLE 9 preparation of Potato trisaccharide Oleanolic acid saponin derivative Compounds I-I
The compound I-I of the triose oleanolic acid saponin derivative of potato replaces the substituent R in I-A from an anilino group to a 2-furanmethylamino group, and the rest of the operation and parameters refer to example 1 to obtain a white solid product I-I (the total yield is 47.38%).
Figure BDA0002793825590000151
Nuclear magnetic hydrogen spectrum data of the obtained compound I-I1H NMRδ(ppm,600MHz)：1H NMR(CD3OD) δ7.38(d,1H,J＝0.9Hz),6.32(dd,1H,J＝2.9,1.9Hz),6.20(d,1H,J＝3.1Hz), 5.36(s,1H),5.32(t-like,1H),4.42(d,1H,J＝7.7Hz),4.34(d,1H,J＝15.4Hz), 4.28(d,1H,J＝15.4Hz),3.91(dd,1H,J＝9.4,6.2Hz),3.80(d,1H,J＝10.7Hz), 3.75(dd,1H,J＝9.6,3.3Hz),3.66(dd,1H,J＝12.1,4.0Hz),3.63(dd,1H,J＝9.5, 3.2Hz),3.58(t,1H,J＝8.7Hz),3.54(t,1H,J＝9.0Hz),3.47–3.36(m,3H),3.15(dd, 1H,J＝11.7,4.1Hz),2.78(dd,1H,J＝13.1,3.4Hz),1.26(d,3H,J＝6.2Hz),1.21 (d,3H,J＝6.2Hz),1.15,1.04,0.94,0.91,0.91,0.85,0.61(each s,each 3H).
EXAMPLE 10 preparation of Potato trisaccharide Oleanolic acid saponin derivative Compounds I-J
The compound I-J of the triose oleanolic acid saponin derivative of potato replaces the R substituent in I-A with an anilino group by a 2-thienylmethylamino group, and the rest of the operation and parameters refer to example 1 to obtain the product I-J as a white solid (total yield 47.44%).
Figure BDA0002793825590000152
Nuclear magnetic hydrogen spectrum data of the obtained compound I-J1H NMRδ(ppm,600MHz)：1H NMR(CD3OD) δ7.25(d,1H,J＝5.1Hz),6.96(d,1H,J＝3.4Hz),6.91(dd,1H,J＝5.0,3.5Hz), 5.36(s,1H),5.32(t,1H,J＝3.4Hz),4.85(d,1H,J＝1.1Hz),4.54(d,1H,J＝15.1 Hz),4.44(d,1H,J＝14.9Hz),4.42(d,1H,J＝7.7Hz),3.91(dd,1H,J＝9.5,6.2Hz), 3.84(dd,1H,J＝2.7,1.9Hz),3.79(dd,J＝11.9,1.4Hz,1H),3.74(dd,1H,J＝9.6, 3.4Hz),3.66(dd,1H,J＝12.1,4.1Hz),3.63(dd,1H,J＝9.5,3.3Hz),3.58(t,1H,J ＝8.7Hz),3.54(t,1H,J＝9.1Hz),3.46–3.37(m,3H),3.15(dd,1H,J＝11.8,4.2Hz), 2.78(dd,1H,J＝13.1,3.8Hz),1.26(d,3H,J＝6.2Hz),1.21(d,3H,J＝6.2Hz), 1.15,1.04,0.94,0.91,0.90,0.85,0.61(each s,each 3H).
EXAMPLE 11 preparation of Potato trisaccharide Oleanolic acid saponin derivative Compounds I-K
The compound I-K of the triose oleanolic acid saponin derivative of potato replaces the substituent R in I-A from anilino to 2-picolylamine, and the rest of the operation and parameters are referred to example 1, and a white solid product I-K is obtained (the total yield is 47.63%).
Figure BDA0002793825590000161
The obtained I-K nuclear magnetic hydrogen spectrum data of the compound1H NMRδ(ppm,600MHz)：1H NMR(CD3OD) δ8.49(d,1H,J＝4.5Hz),7.80–7.76(m,1H),7.36(d,1H,J＝7.9Hz),7.30(dd,1H, J＝7.2,5.2Hz),5.39(t-like,1H),5.36(s,1H),4.85(s,1H),4.46(d,1H,J＝15.8Hz), 4.42(d,1H,J＝7.6Hz),4.41(d,1H,J＝15.9Hz),3.91(dd,1H,J＝9.5,6.2Hz), 3.84(dd,1H,J＝2.8,1.8Hz),3.80(d,1H,J＝10.6Hz),3.75(dd,1H,J＝9.6,3.4 Hz),3.66(dd,1H,J＝12.1,4.0Hz),3.63(dd,1H,J＝9.5,3.3Hz),3.60–3.56(m,1H), 3.54(t,1H,J＝9.1Hz),3.46–3.42(m,1H),3.42–3.37(m,2H),3.15(dd,1H,J＝11.7, 4.2Hz),2.82(dd,1H,J＝13.1,3.5Hz),1.26(d,3H,J＝6.2Hz),1.21(d,3H,J＝6.2 Hz),1.17,1.04,0.96,0.92,0.86,0.84,0.54(each s,each 3H).
EXAMPLE 12 preparation of Potato trisaccharide Oleanolic acid saponin derivative Compounds I-L
The compound I-L of the triose oleanolic acid saponin derivative of potato replaces the R substituent in I-A with an anilino group to an o-fluorobenzylamine group, and the rest of the operation and parameters refer to example 1 to obtain a white solid product I-L (the total yield is 47.47%).
Figure BDA0002793825590000171
Nuclear magnetic hydrogen spectrum data of the obtained compound I-L1H NMRδ(ppm,600MHz)：1H NMR(CD3OD) δ7.36–7.31(m,1H),7.30–7.23(m,1H),7.13–7.08(m,1H),7.08–7.01(m,1H), 5.37(s,1H),5.32(t-like,1H),4.85(s,1H),4.46–4.32(m,3H),3.91(dd,1H,J＝9.3, 6.2Hz),3.86–3.82(m,1H),3.79(d,1H,J＝11.0Hz),3.75(dd,1H,J＝9.5,3.2Hz), 3.69–3.60(m,2H),3.60–3.50(m,2H),3.47–3.35(m,3H),3.15(dd,1H,J＝11.5, 3.6Hz),2.80(dd,1H,J＝13.3,2.7Hz),1.27(d,3H,J＝6.2Hz),1.21(d,3H,J＝6.1 Hz),1.15,1.04,0.95,0.91,0.90,0.85,0.55(each s,each 3H).
EXAMPLE 13 preparation of a Potato trisaccharide Oleanolic acid saponin derivative Compounds I-N
The compound I-N of the triose oleanolic acid saponin derivative of potato replaces the substituent R in the compound I-A with an anilino group to an o-chlorobenzylamine group, and the rest of the operation and parameters refer to example 1 to obtain a white solid product I-N (the total yield is 47.12%).
Figure BDA0002793825590000172
The obtained I-N nuclear magnetic hydrogen spectrum data of the compound1H NMRδ(ppm,600MHz)：1H NMR(CD3OD) δ7.61(t-like,1H),7.40–7.32(m,2H),7.29–7.21(m,2H),5.36(s,1H),5.34(s,1H), 4.50–4.36(m,3H),4.03–3.95(m,2H),3.94–3.86(m,1H),3.84(s,1H),3.80(d, 1H,J＝11.4Hz),3.75(dd,1H,J＝9.6,3.2Hz),3.70–3.60(m,2H),3.60–3.53(m, 2H),3.42(dt,3H,J＝18.9,8.9Hz),3.15(dd,1H,J＝11.5,3.8Hz),2.79(dd,1H,J＝13.3,3.5Hz),1.27(d,3H,J＝6.2Hz),1.22(d,3H,J＝6.1Hz),1.16,1.04,0.96,0.92, 0.90,0.85,0.54(each s,each 3H).
EXAMPLE 14 preparation of a Potato trisaccharide Oleanolic acid saponin derivative Compounds I-M
The compound I-M of the triose oleanolic acid saponin derivative of potato replaces the R substituent in I-A with an anilino group to an o-bromobenzyl group, and the rest of the operation and parameters refer to example 1 to obtain a white solid product I-M (total yield 46.75%).
Figure BDA0002793825590000181
Nuclear magnetic hydrogen spectrum data of the obtained compound I-M1H NMRδ(ppm,600MHz)：1H NMR(CD3OD) δ7.62–7.52(m,2H),7.39–7.27(m,3H),7.17(t,1H,J＝7.4Hz),5.39–5.30(m, 2H),4.48–4.35(m,3H),4.01–3.94(m,2H),3.94–3.86(m,1H),3.86–3.83(m, 1H),3.80(d,1H,J＝11.4Hz),3.75(dd,1H,J＝9.5,3.0Hz),3.70–3.60(m,2H), 3.60–3.50(m,2H),3.48–3.36(m,3H),3.15(dd,1H,J＝11.5,3.6Hz),2.78(dd, 1H,J＝12.6,3.0Hz),1.27(d,3H,J＝6.1Hz),1.22(d,3H,J＝6.2Hz),1.16,1.05, 0.96,0.92,0.90,0.85,0.55(each s,each 3H).
EXAMPLE 15 preparation of a Potato trisaccharide Oleanolic acid saponin derivative Compounds I-O
The compound I-O of the triose oleanolic acid saponin derivative of potato replaces the R substituent in the I-A by an anilino group to an O-methoxybenzylamine group, and the rest of the operation and parameters are referred to example 1, so that a white solid product I-O (the total yield is 47.59%) is obtained.
Figure BDA0002793825590000191
Nuclear magnetic hydrogen spectrum data of the obtained compound I-O1H NMRδ(ppm,600MHz)：1H NMR(CD3OD) δ7.25(t,2H,J＝6.1Hz),7.19(d,1H,J＝7.0Hz),6.95(d,1H,J＝8.3Hz),6.88(t, 1H,J＝7.4Hz),5.36(s,1H),5.31(s,1H),4.42(d,1H,J＝7.6Hz),4.35(d,2H,J＝ 5.3Hz),4.00–3.95(m,2H),3.94–3.90(m,1H),3.88(s,3H),3.84(s,1H),3.80(d, 1H,J＝11.6Hz),3.75(dd,1H,J＝9.6,3.1Hz),3.69–3.60(m,2H),3.59–3.53(m, 2H),3.47–3.36(m,3H),3.14(dd,1H,J＝11.3,3.7Hz),2.67(dd,1H,J＝12.9,2.5 Hz),1.27(d,3H,J＝6.4Hz),1.22(d,3H,J＝5.8Hz),1.04,0.94,0.91,0.87,0.85, 0.46(each s,each 3H).
EXAMPLE 16 preparation of a Potato trisaccharide Oleanolic acid saponin derivative Compounds I-P
The compound I-P of the triose oleanolic acid saponin derivative of potato replaces the substituent R in the compound I-A from an anilino group to an o-chlorophenyl group, and the rest operation and parameters are referred to example 1, so that a white solid product I-P (the total yield is 47.11%) is obtained.
Figure BDA0002793825590000192
The obtained I-P nuclear magnetic hydrogen spectrum data of the compound1H NMRδ(ppm,600MHz)：1H NMR(CD3OD) δ8.26(d,1H,J＝8.0Hz),7.05(t,1H,J＝7.2Hz),6.99(d,1H,J＝7.9Hz),6.90(t, 1H,J＝7.7Hz),5.54(t-like,1H),5.36(s,1H),4.42(d,1H,J＝7.7Hz),3.90(s,3H), 3.80(d,1H,J＝11.1Hz),3.74(dd,1H,J＝9.5,3.2Hz),3.66(dd,1H,J＝12.0,3.8 Hz),3.63(dd,1H,J＝9.4,3.1Hz),3.59(t,1H,J＝8.7Hz),3.54(t,1H,J＝9.1Hz), 3.47–3.36(m,3H),2.74(d,1H,J＝12.1Hz),1.27(d,3H,J＝6.1Hz),1.20(d,6H,J ＝8.4Hz),1.04,0.96,0.94,0.89,0.83,0.62(each s,each 3H).
EXAMPLE 17 preparation of Potato trisaccharide Oleanolic acid saponin derivative Compounds I-Q
The potato trisaccharide oleanolic acid saponin derivative compounds I-Q were prepared by replacing the R substituent in I-A with an anilino group by a 2-hydroxyethoxy group, and the rest of the procedure and parameters were as in example 1 to obtain white solid products I-Q (total yield 47.52%).
Figure BDA0002793825590000201
Nuclear magnetic hydrogen spectrum data of the obtained compound I-Q1H NMRδ(ppm,600MHz)：1H NMR(CD3OD) δ5.34(s,1H),5.25(s,1H),4.57(brs,1H),4.41(d,1H,J＝7.7Hz),4.13–4.00(m, 2H),3.98–3.93(m,2H),3.92–3.85(m,1H),3.82(s,1H),3.78(d,1H,J＝11.3Hz), 3.75–3.64(m,4H),3.64–3.61(m,1H),3.59(dd,1H,J＝9.5,3.3Hz),3.56–3.50 (m,2H),3.46–3.33(m,3H),3.14(dd,1H,J＝11.6,3.7Hz),2.87(dd,1H,J＝12.5, 2.3Hz),1.25(d,3H,J＝6.2Hz),1.19(d,3H,J＝6.2Hz),1.14,1.03,0.93,0.92,0.90, 0.84,0.74(each s,each 3H).
EXAMPLE 18 preparation of Potato trisaccharide Oleanolic acid saponin derivative Compounds I-R
The compound I-R of the triose oleanolic acid saponin derivative of the potato replaces the substituent R in the compound I-A from an anilino group to an ethoxycarbonylmethoxy group, and the rest of the operation and parameters are referred to the example 1, so that the white solid product I-R is obtained (the total yield is 47.41%).
Figure BDA0002793825590000211
The obtained I-R nuclear magnetic hydrogen spectrum data of the compound1HNMRδ(ppm,600MHz)：1H NMR(CD3OD) δ5.37(s,1H),5.25(s,1H),4.67–4.47(m,4H),4.43(d,1H,J＝7.6Hz),4.19(q,2H, J＝6.9Hz),4.02–3.94(m,2H),3.94–3.86(m,1H),3.84(s,1H),3.80(d,1H,J＝ 11.2Hz),3.77–3.71(m,2H),3.70–3.60(m,3H),3.60–3.50(m,2H),3.48–3.35 (m,3H),3.16(dd,1H,J＝11.2,3.5Hz),2.88(dd,1H,J＝12.6,2.4Hz),1.28–1.24 (m,4H),1.21(d,3H,J＝6.2Hz),1.16,1.05,0.95,0.93,0.92,0.86,0.75(each s,each 3H).
Experimental example 1 inhibitory Activity of Potato trisaccharide Oleanolic acid saponin derivative against New coronavirus
1. Experimental materials: the compounds I-A to I-R prepared in the embodiments 1 to 18 of the invention; virus: SARS-CoV-2S pseudovirus (new coronavirus S protein as membrane protein, AIDS virus as pseudovirus of kernel, new coronavirus possesses infection mechanism similar to that of true virus, and can be used in drug screening); cell: 293T cells; positive control: and (3) chloroquine.
2. The experimental method comprises the following steps:
293T cells overexpressing ACE2 by 2 x 104One/well was plated evenly in 96-well cell plates and cultured at 37 ℃ for 24 h. Before administration, gradient dilution is carried out on each compound with different concentrations by adopting a DMEM medium containing 10% fetal calf serum, and a virus control group (without medicine), a solvent control group and a positive control group are arranged. The drug was incubated with 60. mu.L of pseudovirus at ambient temperature for 30 minutes, 100. mu.L/well was added to ACE2/293T cells, and incubated at 37 ℃ for 48 hours. Discard the medium per well. Add 40. mu.L of 1 Xlysis buffer and shake lysis for 15 min at room temperature. Transferring 30 mu L/hole cracking supernatant to a 96-hole white enzyme label plate, adding the luciferase substrate diluted by the same volume, immediately carrying out enzyme label instrument to detect the fluorescence value, and calculating the IC of each compound50。
3. The experimental results are as follows: see table 1.
TABLE 1 inhibitory Activity of Potato trisaccharide Oleanolic saponin derivatives with New Coronavirus (. mu.M)
Compound (I) IC50 Compound (I) IC50
I-A 18.12 I-J 5.89
I-B 4.37 I-K ＞20.00
I-C 7.37 I-L 5.68
I-D 13.06 I-M ＞20.00
I-E 7.76 I-N 11.75
I-F 5.54 I-O 16.75
I-G 8.33 I-P ＞20.00
I-H 9.97 Ⅰ-Q ＞20.00
I-I ＞20.00 Ⅰ-R ＞20.00
Chloroquine 0.38
As can be seen from Table 1, the compound of trisaccharide oleanolic acid saponin derivative of the present invention, formula I, has generally better inhibitory activity against novel coronaviruses, especially compound I-B, I-C, I-E, I-F, I-G, I-H, I-J, I-L, which has IC inhibitory activity against novel coronaviruses50All below 10. mu.M, more preferred are compounds I-B, I-F, I-J, I-L, whose inhibitory IC for novel coronaviruses50Are all lower than 6 mu M; therefore, the compound has obvious inhibition effect on the novel coronavirus, can be prepared into a novel coronavirus resistant medicament for application, and has good application prospect in preventing and treating the novel coronavirus infection.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, and simplifications are intended to be included in the scope of the present invention.

Claims (6)

1. A potato trisaccharide oleanolic acid saponin derivative, wherein said potato trisaccharide oleanolic acid saponin derivative has the structure of formula I:
Figure FDA0003294634880000011
wherein R is anilino, benzylamino, 2-phenylethylamino, 3-phenylpropylamino, N-methyl-benzylamino, o-methoxyanilino, m-methoxyanilino, p-methoxyanilino, 2-thienylmethylamino, o-fluorobenzylamino, o-chlorobenzylamino and o-methoxybenzylamino.
2. The triose oleanolic acid saponin derivative of potato as claimed in claim 1, wherein said R is benzylamino group, 2-phenylethylamino group, N-methyl-benzylamino group, o-methoxyanilino group, m-methoxyanilino group, p-methoxyanilino group, 2-thienylmethylamino group or o-fluorobenzylamine group.
3. The triose oleanolic acid saponin derivative of potato as claimed in claim 2, wherein said R is benzylamino group, o-methoxyanilino group, 2-thienylmethylamino group or o-fluorobenzylamino group.
4. The method for preparing a trisaccharide oleanolic acid saponin derivative of potato as claimed in any one of claims 1 to 3, which comprises the steps of:
s1, taking oleanolic acid as a raw material and potassium carbonate as a catalyst, and carrying out substitution reaction to obtain an intermediate compound T-1:
Figure FDA0003294634880000012
s2, carrying out glycosylation reaction on the compound T-1 obtained in the step S1 and the intermediate 1 under the catalysis of trimethylsilyl trifluoromethanesulfonate TMSOTf to obtain an intermediate compound T-2:
Figure FDA0003294634880000021
s3, hydrolyzing the intermediate compound T-2 obtained in the step S2 in a dichloromethane-methanol mixed solvent with a volume ratio of 1:1 under a sodium methoxide alkaline environment to obtain an intermediate compound T-3:
Figure FDA0003294634880000022
s4, under the action of pivaloyl chloride, selectively protecting hydroxyl groups at 3-position and 6-position of glucose by esterification reaction of the intermediate compound T-3 obtained in the step S3 and a dichloromethane-pyridine mixed solvent with a volume ratio of 1:1 to obtain an intermediate compound T-4:
Figure FDA0003294634880000023
s5, carrying out glycosylation reaction on the intermediate compound T-4 obtained in the step S4 and the intermediate 2 to obtain an intermediate compound T-5:
Figure FDA0003294634880000031
s6, carrying out hydrolysis reaction on the intermediate compound T-5 obtained in the step S5 under the action of sodium hydroxide to obtain an intermediate compound T-6:
Figure FDA0003294634880000032
s7, putting the intermediate compound T-6 obtained in the step S6 in PdCl2Under the catalytic action, an intermediate compound T-7 is obtained through reduction reaction:
Figure FDA0003294634880000033
s8, under the action of acetic anhydride, pyridine is used as a solvent for the intermediate compound T-7 obtained in the step S7, and an esterification reaction is carried out to obtain an intermediate compound T-8:
Figure FDA0003294634880000041
s9, reacting the intermediate compound T-8 obtained in the step S8 with oxalyl chloride in sequence to generate an acyl chloride intermediate, and then performing condensation reaction with corresponding amine, wherein a reaction solvent is dichloromethane; removing acetyl from an intermediate obtained by condensation reaction under the action of sodium methoxide, wherein a reaction solvent is a dichloromethane-methanol mixed solvent; obtaining the potato trisaccharide oleanolic acid saponin derivative compound I.
5. Use of a triose oleanolic acid saponin derivative of potato as claimed in any one of claims 1 to 3 for the manufacture of a medicament for the treatment of coronavirus.
6. The use according to claim 5, wherein the coronavirus is the novel coronavirus SARS-CoV-2.
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