CN115521248B - Chiral alpha-aminomalonate compound containing N-pyridyl benzenesulfonamide, preparation method and application - Google Patents

Chiral alpha-aminomalonate compound containing N-pyridyl benzenesulfonamide, preparation method and application Download PDF

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CN115521248B
CN115521248B CN202211030549.6A CN202211030549A CN115521248B CN 115521248 B CN115521248 B CN 115521248B CN 202211030549 A CN202211030549 A CN 202211030549A CN 115521248 B CN115521248 B CN 115521248B
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pyridylbenzenesulfonamide
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张妙鹤
柏松
冯双
张文娟
朱芸莹
牟红兰
魏娴
李渺
陈丽军
罗孜
吴琴
吴蓉
周涵
罗健林
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Guizhou Institute of Technology
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Abstract

The invention discloses a chiral alpha-amino malonate compound containing N-pyridyl benzenesulfonamide, which is characterized in that: the structure of the compound is shown as (I):

Description

Chiral alpha-aminomalonate compound containing N-pyridyl benzenesulfonamide, preparation method and application
Technical Field
The invention relates to the technical field of chemistry, in particular to a preparation method of an alpha-aminomalonate compound with high optical activity of N-pyridylbenzenesulfonamide with antiviral activity and bactericidal activity and application of the alpha-aminomalonate compound in inhibiting tobacco mosaic virus, cucumber mildew virus, verticillium bacteria, citrus canker pathogen, rice bacterial leaf blight bacteria and kiwi fruit canker pathogen.
Background
Plant viral diseases, plant pathogenic bacteria and plant pathogenic fungi bring about a great loss to the global agricultural economy. For example: tobacco mosaic virus (Tobacco Mosaic Virus, TMV) can infect more than 400 plants belonging to 36 families, causing great economic loss and safety stress to agriculture. Bacterial leaf blight of rice is considered one of the most damaging bacterial diseases, and may adversely affect rice throughout the growth phase. However, the plant virus resisting agents (ningnanmycin, ribavirin and the like) and the antibacterial agents (copper-based antibacterial agents) used in the market at present have the problems of poor prevention effect, adverse effect on ecological environment and the like, so that an efficient, low-toxicity and environment-friendly antiviral agent and antibacterial agent are required to be developed to meet the agricultural development needs.
In recent years, chiral pesticides are widely applied in the field of agriculture, most natural or synthetic drugs contain chiral centers, and isomers of chiral drugs have many same physicochemical properties, but biological activity, toxicity and pharmacological effects of the chiral pesticides often have great differences, so that resolution of enantiomers of the chiral drugs has great economic value. The invention adopts the principle of active splicing, splices active structures such as pyridine, benzenesulfonamide, malonate and the like, designs and synthesizes chiral alpha-amino malonate compounds of N-pyridylbenzenesulfonamide, and researches the activity of the chiral alpha-amino malonate compounds.
In 2015, song et al (Song Baoan, zhang Guoping, hu Deyu, xue Wei, li Xiangyang, chen Meihang, pan Jianke, luo Liang) designed and synthesized a series of chiral alpha-phosphoramidate compounds containing benzothiazole heterocycle with antiviral activity, which were designed and synthesized in China, 104987350,2015, and tested cucumber mosaic virus, tobacco mosaic virus and southern rice black-streaked dwarf virus, found that compound (R) -4h was higher than commercial agents ningnanmycin in terms of treatment, protection and passivation of cucumber mosaic virus, and that compounds (R) -4h and (R) -4q had good inhibitory activity on three viruses.
In 2015, liu et al (Liu, L.X.; whang, X.Q.; zhou, B.; yang, L.J; zang, H.B.; yang, X.D. Synthesis and antitumor activity of novel N-substituted carbazole imidazolium salt derivatives [ J ]]Scientific Reports,2015, 5:13101-13120) designed a series of new derivatives of N-substituted carbazole imidazolium salts and studied their cytotoxic activity against human tumor cell lines by MST assay, wherein compound 8 had a higher selectivity for HL-60, SMMC-7721, MCF-7 and SW480 cell lines, IC 50 The value is 0.51-2.48 mu M.
In 2017 Wang et al (Wang, P.Y.; fang H.S.; shao, W.B.; zhou, J.; chen, Z; song, B.A.; yang, S.Synthesis and biological evaluation of pyridinium-functionalized carbazole derivatives as promising antibacterial agents, [ J ]]Bioorg med chem lett, 2017, 27:4294-4297) to synthesize a series of N-substituted pyridinium carbazole derivatives, and testing the activity of the target compounds on Xoo, xac and Verticillium bacteria by nephelometry, the test results show that part of the compounds have EC on three bacteria 50 0.4, 0.3 and 0.3mg/L respectively.
Disclosure of Invention
The invention aims to provide a preparation method of chiral alpha-aminomalonate compounds containing N-pyridylbenzenesulfonamide with antiviral activity and bactericidal activity.
The invention also aims to provide the application of the chiral alpha-aminomalonate compounds containing N-pyridylbenzenesulfonamide with antiviral activity and bactericidal activity to inhibiting tobacco mosaic virus, cucumber mildew virus, verticillium wilt bacteria, citrus canker bacteria, rice bacterial blight bacteria and kiwi fruit canker bacteria.
The technical scheme of the invention is as follows: the chiral alpha-aminomalonate compound containing N-pyridylbenzenesulfonamide has the structure shown in (I):
in formula (I), represents a chiral carbon atom; wherein: r is R 1 Is C1-C3 alkyl; r is R 2 Phenyl, substituted phenyl,
Furyl, cyclohexyl or pentyl.
The C1-C3 alkyl is methyl, ethyl or isopropyl.
The substituent of the substituted phenyl is halogen, methyl or methoxy.
The preparation method of the chiral alpha-amino malonate compound containing N-pyridylbenzenesulfonamide comprises the following synthetic route:
the method comprises the following specific steps:
(1) Preparation of cinchona alkaloid aromatic amide catalysts Q1 and Q2:
2-aminobenzimidazole, 3, 4-dimethoxy cyclobut-3-alkene-1, 2-diketone and quinine amine are taken as initial raw materials, absolute methanol is taken as solvent, and high-activity chiral cinchona alkaloid aromatic amide catalysts Q1 and Q2 are synthesized by a one-pot method at normal temperature;
(2) Preparation of chiral alpha-aminomalonate compound containing N-pyridylbenzenesulfonamide:
and putting 4-amino-N- (pyridine-2-yl) benzenesulfonamide, substituted aldehyde, malonate and catalyst cinchona alkaloid aromatic amide into a single-port bottle, adding paraxylene, heating to reflux, reacting for 4-6 hours, recovering paraxylene under reduced pressure, and separating by column chromatography to obtain the target product.
The column chromatographic separation conditions are petroleum ether: ethyl acetate=6:1V/V.
The chiral alpha-aminomalonate compounds containing N-pyridylbenzenesulfonamide are applied to the preparation of medicaments and medicaments for preventing and treating crop diseases.
The crop diseases comprise tobacco mosaic virus, cucumber mildew virus, verticillium wilt, citrus canker, rice bacterial leaf blight and kiwi fruit canker.
Wherein a part of the compounds have the following structural characteristics:
the invention has the beneficial effects that: the chiral alpha-aminomalonate compound containing N-pyridylbenzenesulfonamide and having activities of resisting tobacco mosaic virus, cucumber mildew virus, verticillium wilt, citrus canker, rice bacterial blight bacteria and kiwi fruit canker is synthesized. The invention has the advantages of easily obtained raw materials, simple process, mild reaction conditions and high reaction yield. And in the present invention, compound I 3 And I 5 In the aspect of preventing and controlling the activity of cucumber mosaic virus, the activity of the cucumber mosaic virus is superior to that of a commercial control medicament Ningnanmycin in treatment, protection and passivation. In addition, the invention also relates to the compound I with optimal biological activity 2 Is subjected to intensive studies and finally determines the activity-optimal compound I in the present invention 2 Is a continuous production and preparation method of the (C).
Detailed Description
Example 1: i 1 - (R) -dimethyl 2- (phenyl ((4- (N- (pyridin-2-yl) sulfamoyl) phenyl) amino) methyl) malonate;
in a 100mL single-port flask, 4-amino-N- (pyridin-2-yl) benzenesulfonamide (0.001 mol), benzaldehyde (0.001 mol) and dimethyl malonate (0.0015 mol) were added, chiral cinchona alkaloid aromatic amide catalyst Q2 was added, p-xylene (40 mL) was added as a solvent, the temperature was raised and refluxed, TLC was used to monitor the progress of the reaction, after 5 hours, the reaction was completed, p-xylene was recovered under reduced pressure, and the target product was obtained by column chromatography separation (petroleum ether: ethyl acetate=6:1V/V).
I 1 Physicochemical properties of- (R): white solid, m.p.285-287 ℃; 1 H NMR(400MHz,CDCl 3 )δ8.33(d, J＝5.1Hz,1H),7.58(d,J＝8.6Hz,3H),7.35(d,J＝8.7Hz,1H),7.29(t,J＝5.7Hz, 5H),6.80(t,J＝6.3Hz,1H),6.53(d,J＝8.7Hz,2H),5.95(d,J＝8.9Hz,1H),5.22 (dd,J＝8.8,5.4Hz,1H),3.92(d,J＝5.3Hz,1H),3.66(s,3H),3.62(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ168.47,167.32,153.82,149.88,143.51,140.61,138.50, 128.83,128.11,126.49,115.62,113.91,112.84,57.40,56.50,53.03,52.70；IR(KBr): ν3312,3212,1670,1463,1325,1276,1224,1032,1007,827,635,611cm -1 ；Anal. Calcd for C 23 H 23 N 3 O 6 S:C,58.84；H,4.94；N,8.95；foundC,58.83；H,4.95；N,8.96.； HRMS(ESI)m/z for C 23 H 23 N 3 O 6 S[M+H] + cacld:470.12996,found:470.12128. This product was obtained as white solid from a reaction catalyzed by Q4；yield 91％by preparative TLC(GF254 silica gel:Hexane/Ethyl ether＝4/1)；98％ee as determined by HPLC[Daicel Chiralpak IA,Hexane/IPA＝90/10,1.0mL·min -1 ,λ＝220nm,tr(major)＝8.93min,tr(minor)＝6.48min]；[α] D 25 ＝+40.2(c＝0.22, CHCl 3 )；
example 2: i 1 - (S) -dimethyl 2- (phenyl ((4- (N- (pyridin-2-yl) sulfamoyl) phenyl) amino) methyl) malonate;
in a 100mL single-port flask, 4-amino-N- (pyridin-2-yl) benzenesulfonamide (0.001 mol), benzaldehyde (0.001 mol) and dimethyl malonate (0.0015 mol) were added, chiral cinchona alkaloid aromatic amide catalyst Q1 was added, p-xylene (40 mL) was added as a solvent, the temperature was raised and refluxed, TLC was used to monitor the progress of the reaction, after 5 hours, the reaction was completed, p-xylene was recovered under reduced pressure, and the target product was obtained by column chromatography separation (petroleum ether: ethyl acetate=6:1V/V).
I 1 Physicochemical properties of- (S): white solid, m.p.285-287 c, 1 H NMR(400MHz,CDCl 3 )δ8.33(d,J＝5.1 Hz,1H),7.58(d,J＝8.6Hz,3H),7.35(d,J＝8.7Hz,1H),7.29(t,J＝5.7Hz,5H),6.80(t,J＝6.3Hz,1H),6.53(d,J＝8.7Hz,2H),5.95(d,J＝8.9Hz,1H),5.22(dd,J＝8.8,5.4Hz,1H),3.92 (d,J＝5.3Hz,1H),3.66(s,3H),3.62(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ168.47,167.32, 153.82,149.88,143.51,140.61,138.50,128.83,128.11,126.49,115.62,113.91,112.84,57.40,56.50,53.03,52.70；IR(KBr):ν3312,3212,1670,1463,1325,1276,1224,1032,1007,827,635, 611cm -1 ；Anal.Calcd for C 23 H 23 N 3 O 6 S:C,58.84；H,4.94；N,8.95；foundC,58.83；H,4.95；N, 8.96.；HRMS(ESI)m/z for C 23 H 23 N 3 O 6 S[M+H] + cacld:470.12996,found:470.12128.this product was obtained as white solid from a reaction catalyzed byQ5；yield 93％by preparative TLC(GF254 silica gel:Hexane/Ethyl ether＝4/1)；97％ee as determined by HPLC[Daicel Chiralpak IA,Hexane/IPA＝90/10,1.0mL·min -1 ,λ＝220nm,tr(major)＝6.48min,tr(minor) ＝8.94min]；[α] D 25 ＝-80.6(c＝0.46,CHCl 3 )；
example 3: i 2 - (R) diisopropyl 2- ((4-chlorophenyl) ((4- (N- (pyridin-2-yl) sulfamoyl) phenyl) amino) methyl) malonate;
in a 100mL single-port flask, 4-amino-N- (pyridin-2-yl) benzenesulfonamide (0.001 mol), 4-chlorobenzaldehyde (0.001 mol), diisopropyl malonate (0.0015 mol) and chiral cinchona alkaloid aromatic amide catalyst Q1 were added, p-xylene (40 mL) was added as a solvent, the reaction was heated to reflux, TLC was monitored for the progress of the reaction, the reaction was completed for 5 hours, and p-xylene was recovered under reduced pressure and subjected to column chromatography (petroleum ether: ethyl acetate=6:1V/V) to obtain the objective product.
I 2 Physicochemical properties of- (R): white colorSolid, m.p.271-273 c, 1 H NMR(400MHz,CDCl3)δ8.34 (d,J＝4.6Hz,1H),7.60(d,J＝8.8Hz,3H),7.35(d,J＝8.7Hz,1H),7.27(d,J＝2.5 Hz,4H),6.81(t,J＝6.4Hz,1H),6.50(d,J＝8.8Hz,2H),5.98(d,J＝8.5Hz,1H), 5.30(s,1H),5.20–5.12(m,1H),5.03–4.90(m,2H),3.79(d,J＝5.1Hz,1H),1.17(dd,J＝6.2,3.5Hz,6H),1.04(t,J＝6.7Hz,6H)； 13 C NMR(101MHz,CDCl3) δ167.51,166.32,150.01,143.04,140.98,137.25,133.79,128.98,128.37,128.08,115.97,113.93,112.51,57.65,55.84,53.45,21.59,21.50,21.42,21.39；IR(KBr): ν3301,3233,1663,1445,1320,1268,1200,1072,1011,820,631,678cm -1 ；Anal. Calcd forC 27 H 30 ClN 3 O 6 S:C,57.90；H,5.40；N,7.50；FoundC,57.91；H,5.41；N, 7.49.；HRMS(ESI)m/z for C 27 H 30 ClN 3 O 6 S[M+H] + cacld:559.22782,found: 559.22134.This product was obtained as white solid from a reaction catalyzed by Q4； yield 90％by preparative TLC(GF254 silica gel:Hexane/Ethyl ether＝4/1)；＞ 99％ee as determined by HPLC[Daicel Chiralpak IA,Hexane/IPA＝90/10,1.0 mL·min -1 ,λ＝220nm,tr(major)＝11.33min,tr(minor)＝8.78min]；[α] D 25 ＝+20.1(c ＝0.15,CHCl 3 )；
example 4: i 2 - (S) diisopropyl (S) 2- ((4-chlorophenyl) ((4- (N- (pyridin-2-yl) sulfamoyl) phenyl) amino) methyl) malonate;
in a 100mL single-port flask, 4-amino-N- (pyridin-2-yl) benzenesulfonamide (0.001 mol), 4-chlorobenzaldehyde (0.001 mol), diisopropyl malonate (0.0015 mol) and chiral cinchona alkaloid aromatic amide catalyst Q2 were added, p-xylene (40 mL) was added as a solvent, the reaction was heated to reflux, TLC was monitored for the progress of the reaction, the reaction was completed for 5 hours, and p-xylene was recovered under reduced pressure and subjected to column chromatography (petroleum ether: ethyl acetate=6:1V/V) to obtain the objective product.
I 2 Physicochemical properties of- (S): m.p.271-273 c, 1 H NMR(400MHz,CDCl3)δ8.34(d,J＝4.6 Hz,1H),7.60(d,J＝8.8Hz,3H),7.35(d,J＝8.7Hz,1H),7.27(d,J＝2.5Hz,4H),6.81(t,J＝6.4Hz,1H),6.50(d,J＝8.8Hz,2H),5.98(d,J＝8.5Hz,1H),5.30(s,1H), 5.20–5.12(m,1H),5.03–4.90(m,2H),3.79(d,J＝5.1Hz,1H),1.17(dd,J＝6.2,3.5Hz,6H),1.04(t,J＝6.7Hz,6H)； 13 C NMR(101MHz,CDCl3)δ167.51,166.32, 150.01,143.04,140.98,137.25,133.79,128.98,128.37,128.08,115.97,113.93,112.51,57.65,55.84,53.45,21.59,21.50,21.42,21.39；IR(KBr):ν3301,3233,1663, 1445,1320,1268,1200,1072,1011,820,631,678cm -1 ；Anal.Calcd forC 27 H 30 ClN 3 O 6 S:C,57.90；H,5.40；N,7.50；FoundC,57.91；H,5.41；N,7.49.； HRMS(ESI)m/z for C 27 H 30 ClN 3 O 6 S[M+H] + cacld:559.22782,found:559.22134. This product was obtained as white solid from a reaction catalyzed by Q5；yield 94％by preparative TLC(GF254 silica gel:Hexane/Ethyl ether＝4/1)；＞99％eeee as determined by HPLC[Daicel Chiralpak IA,Hexane/IPA＝90/10,1.0mL·min -1 ,λ＝220nm,tr(major)＝8.75min,tr(minor)＝11.41min]；[α] D 25 ＝-63.1(c＝0.48, CHCl 3 )；
example 5: i 3 - (R): -dimethyl 2- ((((4- (N- (pyridin-2-yl) sulfamoyl) phenyl) amino) dimethyl) (p-tolyl) methyl) malonate;
in a 100mL single-port flask, 4-amino-N- (pyridin-2-yl) benzenesulfonamide (0.001 mol), 4-methylbenzaldehyde (0.001 mol) and dimethyl malonate (0.0015 mol) were added, chiral cinchona alkaloid aromatic amide catalyst Q1 was added, p-xylene (40 mL) was used as a solvent, the reaction was heated to reflux, TLC was monitored for the progress of the reaction, the reaction was completed for 4 hours, and p-xylene was recovered under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate=6:1V/V) to obtain the objective product.
I 3 Physicochemical properties of- (R): white solid, m.p.268-270 c, 1 H NMR(400MHz,DMSO)δ8.04 (d,J＝4.4Hz,1H),7.63(t,J＝7.6Hz,1H),7.51(d,J＝8.5Hz,2H),7.30(d,J＝7.8 Hz,2H),7.09–6.98(m,3H),6.90–6.82(m,1H),6.65(d,J＝8.6Hz,2H),5.03(t,J ＝9.8Hz,1H),3.96(d,J＝10.4Hz,1H),3.63(s,3H),3.39(s,3H),2.21(s,3H)； 13 C NMR(101MHz,DMSO)δ167.59,166.88,152.81,150.92,139.46,137.38,136.73,129.35,128.95,127.76,117.37,112.83,112.62,58.63,56.02,53.08,52.84,21.14；IR (KBr):ν3413,3362,1720,1472,1349,1224,1187,1056,994,862,654cm -1 ；Anal. Calcd for C 24 H 25 N 3 O 6 S:C,59.62；H,5.21；N,8.69；foundC,59.61；H,5.20；N,8.70.； HRMS(ESI)m/z for C 24 H 25 N 3 O 6 S[M+H] + cacld:483.14368,found: 483.14123.This product was obtained as white solid from a reaction catalyzed by Q4；yield 92％by preparative TLC(GF254 silica gel:Hexane/Ethyl ether＝4/1)；＞ 99％eeas determined by HPLC[Daicel Chiralpak IA,Hexane/IPA＝90/10,1.0 mL·min -1 ,λ＝220nm,tr(major)＝9.62min,tr(minor)＝7.30min]；[α] D 25 ＝+20.6(c ＝0.21,CHCl 3 )；
example 6: i 3 - (S) -2- ((((4- (N- (pyridin-2-yl) sulfamoyl) phenyl) amino) dimethyl) (p-tolyl) methyl) malonate dimethyl ester;
in a 100mL single-port flask, 4-amino-N- (pyridin-2-yl) benzenesulfonamide (0.001 mol), 4-methylbenzaldehyde (0.001 mol) and dimethyl malonate (0.0015 mol) were added, chiral cinchona alkaloid aromatic amide catalyst Q2 was added, p-xylene (40 mL) was used as a solvent, the reaction was heated to reflux, TLC was monitored for the progress of the reaction, the reaction was completed for 4 hours, and p-xylene was recovered under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate=6:1V/V) to obtain the objective product.
I 3 Physicochemical properties of- (S): white solid, m.p.268-270 c, 1 H NMR(400MHz,DMSO)δ8.04(d, J＝4.4Hz,1H),7.63(t,J＝7.6Hz,1H),7.51(d,J＝8.5Hz,2H),7.30(d,J＝7.8Hz, 2H),7.09–6.98(m,3H),6.90–6.82(m,1H),6.65(d,J＝8.6Hz,2H),5.03(t,J＝ 9.8Hz,1H),3.96(d,J＝10.4Hz,1H),3.63(s,3H),3.39(s,3H),2.21(s,3H)； 13 C NMR(101MHz,DMSO)δ167.59,166.88,152.81,150.92,139.46,137.38,136.73,129.35,128.95,127.76,117.37,112.83,112.62,58.63,56.02,53.08,52.84,21.14；IR (KBr):ν3413,3362,1720,1472,1349,1224,1187,1056,994,862,654cm -1 ；Anal. Calcd for C 24 H 25 N 3 O 6 S:C,59.62；H,5.21；N,8.69；foundC,59.61；H,5.20；N,8.70.； HRMS(ESI)m/z for C 24 H 25 N 3 O 6 S[M+H] + cacld:483.14368,found: 483.14123.This product was obtained as white solid from a reaction catalyzed by Q5； yield 90％by preparative TLC(GF254 silica gel:Hexane/Ethyl ether＝4/1)；＞ 99％eeas determined by HPLC[Daicel Chiralpak IA,Hexane/IPA＝90/10,1.0 mL·min -1 ,λ＝220nm,tr(major)＝7.33min,tr(minor)＝9.59min]；[α] D 25 ＝-43.0(c ＝0.41,CHCl 3 )；
example 7: i 4 - (R) -2- ((4-methoxyphenyl) ((4- (N- (pyridin-2-yl) sulfamoyl) phenyl) amino) methyl) malonic acid diethyl ester;
in a 100mL single-port flask, 4-amino-N- (pyridin-2-yl) benzenesulfonamide (0.001 mol), 4-methoxybenzaldehyde (0.001 mol) and diethyl malonate (0.0015 mol) were added, chiral cinchona alkaloid aromatic amide catalyst Q1 was added, p-xylene (40 mL) was used as a solvent, the reaction was heated to reflux, TLC was monitored for the course of the reaction, the reaction was completed for 6 hours, p-xylene was recovered under reduced pressure, and the target product was obtained by column chromatography separation (petroleum ether: ethyl acetate=6:1V/V).
I 4 Physicochemical properties of- (R): white solid, m.p.220-222 c, 1 H NMR(400MHz,CDCl 3 )δ8.32(d, J＝5.1Hz,1H),7.59(d,J＝8.7Hz,3H),7.37(d,J＝8.7Hz,1H),7.22(d,J＝8.6Hz, 2H),6.82(d,J＝8.7Hz,3H),6.52(d,J＝8.7Hz,2H),5.93(s,1H),5.16(s,1H),4.19 –4.02(m,4H),3.85(d,J＝5.4Hz,1H),3.76(s,3H),1.12(td,J＝7.1,2.3Hz,6H)； 13 C NMR(101MHz,CDCl 3 )δ168.16,166.97,159.22,153.47,150.15,143.65, 140.59,130.48,128.84,128.30,127.74,115.90,114.19,113.80,112.69,62.05,61.77,57.80,55.96,55.26,13.93,13.90；IR(KBr):ν3316,3253,1682,1412,1301,1245, 1210,1003,954,893,701cm -1 ；Anal.Calcd forC 26 H 29 N 3 O 7 S:C,59.19；H,5.54；N, 7.96；foundC,59.18；H,5.53；N,7.97.；HRMS(ESI)m/z for C 26 H 29 N 3 O 7 S[M+H] + cacld:527.21469,found:527.22223.This product was obtained as white solid from areaction catalyzed by Q4；yield 90％by preparative TLC(GF254 silica gel:Hexane/ Ethyl ether＝4/1)；97％ee as determined by HPLC[Daicel Chiralpak IA,Hexane/IPA＝90/10,1.0mL·min -1 ,λ＝220nm,tr(major)＝8.53min,tr(minor)＝6.36min]； [α] D 25 ＝+36.1(c＝0.33,CHCl 3 )；
example 8: i 4 - (S) -2- ((4-methoxyphenyl) ((4- (N- (pyridin-2-yl) sulfamoyl) phenyl) amino) methyl) malonic acid diethyl ester;
in a 100mL single-port flask, 4-amino-N- (pyridin-2-yl) benzenesulfonamide (0.001 mol), 4-methoxybenzaldehyde (0.001 mol) and diethyl malonate (0.0015 mol) were added, chiral cinchona alkaloid aromatic amide catalyst Q2 was added, p-xylene (40 mL) was used as a solvent, the reaction was heated to reflux, TLC was monitored for the course of the reaction, the reaction was completed for 6 hours, p-xylene was recovered under reduced pressure, and the target product was obtained by column chromatography separation (petroleum ether: ethyl acetate=6:1V/V).
I 4 Physicochemical properties of- (S): white solid, m.p.220-222 c, 1 H NMR(400MHz,CDCl 3 )δ8.32(d, J＝5.1Hz,1H),7.59(d,J＝8.7Hz,3H),7.37(d,J＝8.7Hz,1H),7.22(d,J＝8.6Hz, 2H),6.82(d,J＝8.7Hz,3H),6.52(d,J＝8.7Hz,2H),5.93(s,1H),5.16(s,1H),4.19 –4.02(m,4H),3.85(d,J＝5.4Hz,1H),3.76(s,3H),1.12(td,J＝7.1,2.3Hz,6H)； 13 C NMR(101MHz,CDCl 3 )δ168.16,166.97,159.22,153.47,150.15,143.65, 140.59,130.48,128.84,128.30,127.74,115.90,114.19,113.80,112.69,62.05,61.77,57.80,55.96,55.26,13.93,13.90；IR(KBr):ν3316,3253,1682,1412,1301,1245, 1210,1003,954,893,701cm -1 ；Anal.Calcd forC 26 H 29 N 3 O 7 S:C,59.19；H,5.54；N, 7.96；foundC,59.18；H,5.53；N,7.97.；HRMS(ESI)m/z for C 26 H 29 N 3 O 7 S[M+H] + cacld:527.21469,found:527.22223.This product was obtained as white solid from areaction catalyzed by Q5；yield 92％by preparative TLC(GF254 silica gel:Hexane/ Ethyl ether＝4/1)；98％ee as determined by HPLC[Daicel Chiralpak IA,Hexane/IPA＝90/10,1.0mL·min -1 ,λ＝220nm,tr(major)＝6.36min,tr(minor)＝8.52min]； [α] D 25 ＝-73.6(c＝0.69,CHCl 3 )；
example 9: i 5 - (R) -diethyl 2- (furan-2-yl ((4- (N- (pyridin-2-yl) sulfamoyl) phenyl) amino) methyl) malonate;
in a 100mL single-port flask, 4-amino-N- (pyridin-2-yl) benzenesulfonamide (0.001 mol), 2-furaldehyde (0.001 mol) and diethyl malonate (0.0015 mol) were added, chiral cinchona alkaloid aromatic amide catalyst Q1 was added, p-xylene (40 mL) was used as a solvent, the reaction was heated and refluxed, TLC was monitored for 6 hours to complete the reaction, and p-xylene was recovered under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate=6:1V/V) to obtain the objective product.
I 5 Physicochemical properties of- (R): white solid, m.p.243-245 c, 1 H NMR(400MHz,CDCl 3 )δ8.32(d, J＝5.3Hz,1H),7.64(t,J＝9.1Hz,3H),7.41(d,J＝8.7Hz,1H),7.31(s,1H),6.85(t, J＝6.3Hz,1H),6.63(d,J＝8.6Hz,2H),6.26(s,1H),6.16(d,J＝2.9Hz,1H),5.61(d,J＝7.8Hz,1H),5.33(s,1H),4.23–4.07(m,4H),4.04(d,J＝5.5Hz,1H),1.15 (dt,J＝23.8,7.1Hz,6H)； 13 C NMR(101MHz,DMSO)δ163.12,161.90,149.09, 147.10,145.19,138.75,137.59,135.95,124.50,124.09,110.94,109.20,105.76,102.82,57.36,57.10,50.26,46.27,9.16；IR(KBr):ν3393,3201,1604,1455,1369, 1251,1184,1099,932,840,721cm -1 ；Anal.Calcd for C 23 H 25 N 3 O 7 S:C,55.64；H, 5.28；N,8.46；found C,55.65；H,5.29；N,8.47.；HRMS(ESI)m/z for C 23 H 25 N 3 O 7 S [M+H] + cacld:487.14193,found:470.14999.This product was obtained as white solid from a reaction catalyzed by Q4；yield 94％by preparative TLC(GF254 silica gel:Hexane/Ethyl ether＝4/1)；99％ee as determined by HPLC[Daicel Chiralpak IA,Hexane/IPA＝90/10,1.0mL·min -1 ,λ＝220nm,tr(major)＝8.99min,tr(minor) ＝6.62min]；[α] D 25 ＝+26.9(c＝0.30,CHCl 3 )；
example 10: i 5 - (S) -diethyl 2- (furan-2-yl ((4- (N- (pyridin-2-yl) sulfamoyl) phenyl) amino) methyl) malonate;
in a 100mL single-port flask, 4-amino-N- (pyridin-2-yl) benzenesulfonamide (0.001 mol), 2-furaldehyde (0.001 mol) and diethyl malonate (0.0015 mol) were added, chiral cinchona alkaloid aromatic amide catalyst Q2 was added, p-xylene (40 mL) was used as a solvent, the reaction was heated and refluxed, TLC was monitored for 6 hours to complete the reaction, and p-xylene was recovered under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate=6:1V/V) to obtain the objective product.
I 5 Physicochemical properties of- (S): white solid, m.p.243-245 c, 1 H NMR(400MHz,CDCl 3 )δ8.32(d, J＝5.3Hz,1H),7.64(t,J＝9.1Hz,3H),7.41(d,J＝8.7Hz,1H),7.31(s,1H),6.85(t, J＝6.3Hz,1H),6.63(d,J＝8.6Hz,2H),6.26(s,1H),6.16(d,J＝2.9Hz,1H),5.61(d,J＝7.8Hz,1H),5.33(s,1H),4.23–4.07(m,4H),4.04(d,J＝5.5Hz,1H),1.15 (dt,J＝23.8,7.1Hz,6H)； 13 C NMR(101MHz,DMSO)δ163.12,161.90,149.09, 147.10,145.19,138.75,137.59,135.95,124.50,124.09,110.94,109.20,105.76,102.82,57.36,57.10,50.26,46.27,9.16；IR(KBr):ν3393,3201,1604,1455,1369, 1251,1184,1099,932,840,721cm -1 ；Anal.Calcd for C 23 H 25 N 3 O 7 S:C,55.64；H, 5.28；N,8.46；found C,55.65；H,5.29；N,8.47.；HRMS(ESI)m/z for C 23 H 25 N 3 O 7 S [M+H] + cacld:487.14193,found:470.14999.This product was obtained as white solid from a reaction catalyzed by Q5；yield 93％by preparative TLC(GF254 silica gel:Hexane/Ethyl ether＝4/1)；＞99％ee as determined by HPLC[Daicel Chiralpak IA,Hexane/IPA＝90/10,1.0mL·min -1 ,λ＝220nm,tr(major)＝6.62 min,tr(minor)＝8.96min]；[α] D 25 ＝-58.3(c＝0.65,CHCl 3 )；
example 11: i 6 - (R) -2- (cyclohexyl ((4- (N- (pyridin-2-yl) sulfamoyl) phenyl) amino) methyl) malonate dimethyl;
in a 100mL single-port flask, 4-amino-N- (pyridin-2-yl) benzenesulfonamide (0.001 mol), cyclohexylformaldehyde (0.001 mol) and dimethyl malonate (0.0015 mol) were added, chiral cinchona alkaloid aromatic amide catalyst Q1 was added, p-xylene (40 mL) was used as a solvent, the reaction was monitored by TLC under reflux at a temperature elevated for 6 hours, the reaction was completed, and p-xylene was recovered under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate=6:1V/V) to obtain the objective product.
I 6 Physicochemical properties of- (R): white solid, m.p.264-266 c, 1 H NMR(400MHz,CDCl 3 )δ8.42(d, J＝4.9Hz,1H),7.67–7.56(m,3H),7.42(d,J＝8.7Hz,1H),6.89–6.80(m,1H), 6.55(d,J＝8.9Hz,2H),5.35–5.24(m,1H),5.07(d,J＝10.8Hz,1H),3.96(dd,J＝16.1,7.7Hz,1H),3.77(d,J＝4.7Hz,1H),3.70(s,3H),3.42(s,3H),1.85–1.47(m, 6H),1.21–0.87(m,5H)； 13 C NMR(101MHz,CDCl 3 )δ169.09,168.53,153.06, 151.68,144.02,140.53,129.05,126.87,116.43,113.62,111.99,58.02,52.94,52.63,52.56,42.12,30.36,29.86,26.03,25.97,25.85；IR(KBr):ν3374,3211,1637,1412, 1385,1294,1206,1143,1052,923,886cm -1 ；Anal.Calcd for C 23 H 29 N 3 O 6 S:C,58.09； H,6.15；N,8.84；foundC,58.10；H,6.15；N,8.83.；HRMS(ESI)m/z for C 23 H 29 N 3 O 6 S [M+H] + cacld:475.28211,found:475.28329.This product was obtained as white solid from a reaction catalyzed by Q4；yield 90％by preparative TLC(GF254 silica gel:Hexane/Ethyl ether＝4/1)；99％ee as determined by HPLC[Daicel Chiralpak IA,Hexane/IPA＝90/10,1.0mL·min -1 ,λ＝220nm,tr(major)＝9.03min,tr(minor) ＝6.62min]；[α] D 25 ＝+33.6(c＝0.40,CHCl 3 )；
example 12: i 6 - (S) -2- (cyclohexyl ((4- (N- (pyridin-2-yl) sulfamoyl) phenyl) amino) methyl) malonate dimethyl;
in a 100mL single-port flask, 4-amino-N- (pyridin-2-yl) benzenesulfonamide (0.001 mol), cyclohexylformaldehyde (0.001 mol) and dimethyl malonate (0.0015 mol) were added, chiral cinchona alkaloid aromatic amide catalyst Q2 was added, p-xylene (40 mL) was used as a solvent, the temperature was raised and the reaction progress was monitored by TLC, the reaction was terminated for 6 hours, and p-xylene was recovered under reduced pressure and subjected to column chromatography (petroleum ether: ethyl acetate=6:1V/V) to obtain the objective product.
I 6 Physicochemical properties of- (S): white solid, m.p.264-266 c, 1 H NMR(400MHz,CDCl 3 )δ 8.42(d,J＝4.9Hz,1H),7.67–7.56(m,3H),7.42(d,J＝8.7Hz,1H),6.8 9–6.80(m,1H),6.55(d,J＝8.9Hz,2H),5.35–5.24(m,1H),5.07(d,J ＝10.8Hz,1H),3.96(dd,J＝16.1,7.7Hz,1H),3.77(d,J＝4.7Hz,1H),3.70(s,3H),3.42(s,3H),1.85–1.47(m,6H),1.21–0.87(m,5H)； 13 C N MR(101MHz,CDCl 3 )δ169.09,168.53,153.06,151.68,144.02,140.53,129. 05,126.87,116.43,113.62,111.99,58.02,52.94,52.63,52.56,42.12,30.36,29.86,26.03,25.97,25.85；IR(KBr):ν3374,3211,1637,1412,1385,1294,1206, 1143,1052,923,886cm -1 ；Anal.Calcd for C 23 H 29 N 3 O 6 S:C,58.09；H,6.15； N,8.84；foundC,58.10；H,6.15；N,8.83.；HRMS(ESI)m/z for C 23 H 29 N 3 O 6 S [M+H] + cacld:475.28211,found:475.28329.This product was obtained as whi te solid from a reaction catalyzed by Q5；yield 90％by preparative TLC(GF254silica gel:Hexane/Ethyl ether＝4/1)；＞99％ee as determined by HP LC[Daicel Chiralpak IA,Hexane/IPA＝90/10,1.0mL·min -1 ,λ＝220n m,tr(major)＝6.83min,tr(minor)＝9.00min]；[α] D 25 ＝-65.9(c＝0.83,CH Cl 3 )；
example 13: i 7 - (R) -2- (1- ((4- (N- (pyridin-2-yl) sulfamoyl) phenyl) amino) hexyl) malonic acid diethyl ester;
in a 100mL single-port flask, 4-amino-N- (pyridin-2-yl) benzenesulfonamide (0.001 mol), hexanal (0.001 mol) and diethyl malonate (0.0015 mol) were added, chiral cinchona alkaloid aromatic amide catalyst Q1 was added, p-xylene (40 mL) was used as a solvent, the reaction was monitored by TLC under reflux at a temperature elevated for 6 hours, and the reaction was completed, and p-xylene was recovered under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate=6:1V/V) to obtain the objective product.
I 7 Physicochemical properties of- (R): white solid, m.p.290-292 deg.c, 1 H NMR(400MHz,CDCl 3 )δ8.41(d, J＝6.6Hz,1H),7.62(d,J＝8.8Hz,3H),7.42(d,J＝8.7Hz,1H),6.85(t,J＝6.4Hz, 1H),6.55(d,J＝8.9Hz,2H),4.99(d,J＝10.1Hz,1H),4.21–4.09(m,3H),4.01(q, J＝7.1Hz,2H),3.61(d,J＝4.8Hz,1H),1.65–1.52(m,2H),1.28(ddd,J＝24.8,22.3,13.0Hz,10H),1.07(t,J＝7.1Hz,3H),0.83(t,J＝6.8Hz,3H)； 13 C NMR(101 MHz,CDCl 3 )δ168.42,167.75,153.45,150.92,144.35,140.28,129.01,127.51, 116.18,113.54,112.08,61.74,61.58,55.26,52.83,33.91,31.47,26.03,22.42,14.00,13.91,13.87；IR(KBr):ν3366,3245,1692,1489,1343,1237,1197,1023,1048,887, 632cm -1 ；Anal.Calcd for C 24 H 33 N 3 O 6 S:C,58.64；H,6.77；N,8.55；foundC,58.65；H, 6.78；N,8.56.；HRMS(ESI)m/z for C 24 H 33 N 3 O 6 S[M+H] + cacld:491.25691,found: 491.25584.This product was obtained as white solid from a reaction catalyzed by Q4； yield 91％by preparative TLC(GF254 silica gel:Hexane/Ethyl ether＝4/1)；＞ 99％ee as determined by HPLC[Daicel Chiralpak IA,Hexane/IPA＝90/10,1.0 mL·min -1 ,λ＝220nm,tr(major)＝8.18min,tr(minor)＝6.15min]；[α] D 25 ＝+16.9(c ＝0.35,CHCl 3 )；
example 14: i 7 - (S) -2- (1- ((4- (N- (pyridin-2-yl) sulfamoyl) phenyl) amino) hexyl) malonic acid diethyl ester;
in a 100mL single-port flask, 4-amino-N- (pyridin-2-yl) benzenesulfonamide (0.001 mol), hexanal (0.001 mol) and diethyl malonate (0.0015 mol) were added, chiral cinchona alkaloid aromatic amide catalyst Q2 was added, p-xylene (40 mL) was used as a solvent, the reaction was monitored by TLC under reflux at a temperature elevated for 6 hours, and the reaction was completed, and p-xylene was recovered under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate=6:1V/V) to obtain the objective product.
I 7 Physicochemical properties of- (S): white solid, m.p.290-292 deg.c, 1 H NMR(400MHz,CDCl 3 )δ8.41(d, J＝6.6Hz,1H),7.62(d,J＝8.8Hz,3H),7.42(d,J＝8.7Hz,1H),6.85(t,J＝6.4Hz, 1H),6.55(d,J＝8.9Hz,2H),4.99(d,J＝10.1Hz,1H),4.21–4.09(m,3H),4.01(q, J＝7.1Hz,2H),3.61(d,J＝4.8Hz,1H),1.65–1.52(m,2H),1.28(ddd,J＝24.8,22.3,13.0Hz,10H),1.07(t,J＝7.1Hz,3H),0.83(t,J＝6.8Hz,3H)； 13 C NMR(101 MHz,CDCl 3 )δ168.42,167.75,153.45,150.92,144.35,140.28,129.01,127.51, 116.18,113.54,112.08,61.74,61.58,55.26,52.83,33.91,31.47,26.03,22.42,14.00,13.91,13.87；IR(KBr):ν3366,3245,1692,1489,1343,1237,1197,1023,1048,887, 632cm -1 ；Anal.Calcd for C 24 H 33 N 3 O 6 S:C,58.64；H,6.77；N,8.55；foundC,58.65；H, 6.78；N,8.56.；HRMS(ESI)m/z for C 24 H 33 N 3 O 6 S[M+H] + cacld:491.25691,found: 491.25584.This product was obtained as white solid from a reaction catalyzed by Q5； yield 91％by preparative TLC(GF254 silica gel:Hexane/Ethyl ether＝4/1)；＞ 99％ee ee as determined by HPLC[Daicel Chiralpak IA,Hexane/IPA＝90/10,1.0 mL·min -1 ,λ＝220nm,tr(major)＝6.28min,tr(minor)＝8.16min]；[α] D 25 ＝-34.8(c＝ 0.72,CHCl 3 )；
example 15: cinchona alkaloid aromatic amide Q1:3- (((1H-benzo [ d ] imidazol-2-yl ] amino) -4- (((1S) - (6-methoxyquinolin-4-yl) (((1S, 4S,5 r) -5-vinylquinolin-2-yl) methyl) amino) cyclobut-3-ene-1, 2-dione;
2-aminobenzimidazole (0.001 mol) and 3, 4-dimethoxy cyclobut-3-ene-1, 2-dione (0.001 mol) are added into absolute methanol (40 mL) as a solvent, and after stirring for 48 hours at normal temperature, 9S-amino-9-deoxyquinine (0.001 mol) is dissolved into absolute methanol (5 mL), and slowly dripped into a reaction system, after continuing stirring for 12 hours, the reaction is finished, and the absolute methanol is recovered under reduced pressure to obtain a product cinchona alkaloid aromatic amide catalyst Q1.
Physicochemical properties of Q1: white solid, 80.2%, 1 H NMR(400MHz,CDCl 3 ):δ. 13 C NMR(100 MHz,CDCl 3 ):δ.HRMS(ESI)m/z for C 31 H 30 N 6 O 3 [M+H] + cacld:535.247856, found:535.24138.
example 16: cinchona alkaloid aromatic amide Q2:3- (((1H-benzo [ d ] imidazol-2-yl ] amino) -4- (((1R) - (6-methoxyquinolin-4-yl) (((1S, 4S, 5R) -5-vinylquinolin-2-yl) methyl) amino) cyclobut-3-ene-1, 2-dione;
2-aminobenzimidazole (0.001 mol) and 3, 4-dimethoxy cyclobut-3-ene-1, 2-dione (0.001 mol) are added into absolute methanol (40 mL) as a solvent, and after stirring for 48 hours at normal temperature, 9R-amino-9-deoxyquinine (0.001 mol) is dissolved into absolute methanol (5 mL), and slowly dripped into a reaction system, after stirring for 12 hours, the reaction is finished, and the absolute methanol is recovered under reduced pressure to obtain a product cinchona alkaloid aromatic amide catalyst Q2.
Physicochemical properties of Q2: pale yellow solid, 80.2%, yield 77%. [ alpha ]] D 25 ＝-118.2(c＝0.5,CHCl 3 ). 1 H NMR(400MHz,DMSO-d6)δ8.75(d,J＝4.5Hz,1H),7.99–7.84(m,2H),7.67 (d,J＝4.5Hz,1H),7.36(ddd,J＝9.0,7.5,2.8Hz,3H),7.11(dd,J＝7.5,4.9Hz,2H),6.21–5.45(m,2H),5.19–4.83(m,2H),3.89(s,3H),3.62–3.31(m,2H),3.27– 3.11(m,1H),2.93–2.54(m,2H),2.27(s,1H),1.53(dd,J＝41.8,16.1Hz,4H),0.83–0.51(m,1H). 13 C-NMR(100MHz,DMSO-d6):δ(ppm)184.7,180.2,168.4,162.5, 157.6,147.6,144.1,142.7,142.2,140.9,131.9,131.1,127.3,123.0,121.8,118.2,117.1,114.8,114.2,101.4,58.4,55.6,40.1,39.9,27.1,25.9.IR(KBr,cm -1 ):ν3210, 3082,2928,2874,1675,1642,1575,1467,1359,1271,1188,1122,1043,892,714.Anal.Calcd for C 31 H 30 N 6 O 3 :C,69.65；H,5.66；N,15.72；Found:C,69.67；H, 5.62；N,15.73.HRMS(ESI)m/z for C 31 H 30 N 6 O 3 [M+H] + cacld:535.247856,found: 535.24138.
Example 17: therapeutic, inactivating and protective activities of target compounds against tobacco mosaic virus
(1) Test method
A. Virus purification
Adopting a good method (good; et al 1967), selecting upper leaves of a plant infected by a TMV system host heart leaf smoke (Nicotiana glutinosa L.) after inoculation for more than 3 weeks, homogenizing in a phosphoric acid buffer solution, filtering with double-layer gauze, centrifuging at 1000rpm, treating with polyethylene glycol for 2 times, centrifuging, and suspending the precipitate with the phosphoric acid buffer solution to obtain a TMV crude extract. The whole experiment was carried out at 4 ℃. The absorbance at 260nm was measured with an ultraviolet spectrophotometer, and the virus concentration was calculated according to the formula.
Virus concentration (mg/mL) = (A260×dilution)/E0.1% 1cm 260nm
Wherein E represents the extinction coefficient, i.e. the value of the light absorption (optical density) at an optical path length of lcm for a suspension having a concentration of 0.1% (1 mg/mL) at a wavelength of 260 nm. E0.1% of TMV was 3.1 at 260 cm.
B. Active therapeutic effects of agents on TMV infection: selecting a leaf tobacco with consistent growth vigor, dipping a writing brush in virus juice, inoculating the virus to the whole leaf, and flushing with clear water after inoculation. After the leaves were dried, the right half She Tushi of the dose and the left half She Tushi of the corresponding dose of solvent were used as controls. Subsequently, the culture was kept under humidity in an illumination incubator at a temperature of 23.+ -. 1 ℃ for 10000Lux under illumination for 3-4d, and the number of generated spots was observed and recorded. 3 plants are arranged for each medicament treatment, and 3 to 4 leaves are arranged for each plant. The inhibition was calculated as follows by repeating the above method 3 times per agent.
C. In vivo protection of TMV infection by agents
Living protection lease of agent against TMV infection: selecting leaf tobacco with consistent growth vigor, firstly using a writing brush to prepare She Tushi medicament on the right half and a solvent with a dosage corresponding to She Tushi on the left half as a control, dipping the leaf by the pen after the leaf is dried, inoculating the virus on the whole leaf, and flushing with clear water after inoculation. Subsequently, the culture was kept under humidity in an illumination incubator at a temperature of 23.+ -. 1 ℃ for 10000Lux under illumination for 3-4d, and the number of generated spots was observed and recorded. 3 plants are arranged for each medicament treatment, and 3 to 4 leaves are arranged for each plant. The inhibition was calculated as follows by repeating the above method 3 times per agent.
D. In vivo inactivation of TMV infection by agents
The in-vivo deactivation of the medicament on TMV infection comprises selecting leaf tobacco with consistent growth vigor, scattering carborundum on whole leaves, mixing and deactivating the compound with an equal volume of virus juice for 30 minutes, manually rubbing and inoculating the compound with a gang pen to right half leaf of Portulaca oleracea scattered with carborundum, mixing and inoculating a solvent with the virus juice with a corresponding dose to left half leaf of Portulaca oleracea scattered with carborundum, observing and recording the number of generated dead spots after 3-4 d. 3 plants are arranged for each medicament treatment, and 3 to 4 leaves are arranged for each plant. The inhibition was calculated as follows by repeating the above method 3 times per agent.
Y＝(C-A)/C×100％
Wherein: y is the inhibition rate of the compound on tobacco mosaic virus; c is the number of the dead spots in the control group (left half leaf), and A is the number of the dead spots in the control group (right half leaf).
(2) Biological test results
TABLE 1 treatment, protection and inactivation Activity of target Compounds against tobacco mosaic Virus
The anti-TMV activity of the target compound is tested by adopting a half-leaf spot-drying method with the concentration of 500 mug/mL and using Ningnanmycin as a control medicament, and the biological activity determination result in table 1 shows that the chiral alpha-amino malonate compound containing N-pyridylbenzenesulfonamide has medium to excellent inhibitory activity on TMV, wherein I 3 (R) and I 5 (R) is superior to the control medicament Ningnanmycin in treatment, protection and passivation.
In order to further study the anti-TMV activity of chiral alpha-aminomalonate compounds containing N-pyridylbenzenesulfonamide, we determined I in the compounds 3 (R) and I 5 Treatment of (R) EC 50 Values, results are shown in Table 2.
TABLE 2 part of the therapeutic Activity of target Compounds against TMV EC 50 Value of
As can be seen from the results, I in the compounds 3 (R) and I 5 (R) EC for therapeutic Activity on TMV 50 189.4 mug/mL and 210.3 mug/mL respectively, which are superior to the control medicament Ningnanmycin221.1μg/mL。
Example 18: therapeutic, inactivating and protective activities of target compounds against cucumber mosaic virus
(1) Test method
A. Virus purification
Adopting a method of Chen (Chen, J.; et al 2017), selecting and inoculating for more than 3 weeks, infecting upper leaves of a host Nicotiana tabacum.L plant by a CMV system, homogenizing in a phosphate buffer, filtering by double-layer gauze, centrifuging at 8000g, treating by polyethylene glycol for 2 times, centrifuging again, and suspending the precipitate by the phosphate buffer to obtain the CMV refined extract. The whole experiment was performed at 4℃and the absorbance at 260nm was measured with an ultraviolet spectrophotometer, and the virus concentration was calculated according to the formula.
Virus concentration (mg/mL) = (A260×dilution)/E0.1% 1cm 260nm
Wherein E represents the extinction coefficient, i.e.the value of the light absorption (optical density) at an optical path length of l cm, of a suspension having a concentration of 0.1% (1 mg/mL) at a wavelength of 260 nm. E0.1% of CMV 1cm 260nm is 5.0.
B. Active therapeutic effects of agents on CMV infection: selecting purslane in 5-6 leaf period with growing vigor, topping, spreading silicon carbide uniformly on whole leaves, dipping virus juice (6×10-3 mg/mL) on whole leaves with a gang pen, inoculating virus, naturally airing, and washing with clear water. After the leaves are dried, the left half She Qing is lightly coated with a writing brush Shi Yaoji, the right half She Tushi is used as a control, the number of dead spots is recorded after 6-7 days, and the inhibition rate is calculated according to the following formula.
C. In vivo protection of CMV infection by agents
In vivo protection of CMV infection by agents: selecting purslane in 5-6 leaf period with consistent growth vigor, lightly coating Shi Yaoji on the left half She Qing by using a writing brush, using solvent with corresponding concentration on the right half She Tushi as a control, scattering silicon carbide evenly on the whole leaves after 24 hours, dipping virus juice (6X 10-3 mg/mL) of the whole leaf inoculated virus by using a gang pen, flushing by using clear water, recording the number of dead spots after 6-7 days, and calculating the inhibition rate according to the following formula.
D. In vivo inactivation of CMV infection by agents
The in-vivo deactivation of CMV infection by the agent comprises topping purslane in 5-6 leaf period with consistent growth vigour, sprinkling carborundum on whole leaves, and adding phosphoric acid buffer solution to the CMV; diluting the virus to 6X 10-3mg/mL, mixing the compound with an equal volume of virus juice, inactivating for 30 minutes, manually rubbing and inoculating the compound to the left half of Portulaca oleracea with silicon carbide scattered, mixing a solvent with the virus juice at a corresponding dosage, inoculating the compound to the right half of Portulaca oleracea with silicon carbide scattered, recording the number of dead spots after 6-7 days, and calculating the inhibition rate according to the following formula.
X％＝(CK－T)/CK×100
X is the relative inhibition rate (%),
CK average number of dead spots of half leaves without applied agent
T average number of dead spots of half leaf coated with Shi Yaoji
Wherein CK and T are the average of three replicates of each group
(2) Biological test results
TABLE 3 treatment, protection and inactivation Activity of target Compounds against cucumber mosaic Virus
The CMV activity of the target compound is tested by adopting a half-leaf spot-drying method with the concentration of 500 mug/mL and Ningnanmycin as a control medicament, and the biological activity measurement result of the table 1 shows that the chiral alpha-aminomalonate compound containing N-pyridylbenzenesulfonamide has medium to excellent inhibitory activity on CMV, wherein I 3 (R)、I 5 (R) is superior to the control medicament Ningnanmycin in treatment, protection and passivation.
In order to further study the CMV-resistant activity of chiral alpha-aminomalonates of N-pyridylbenzenesulfonamide, we determined I in this class of compounds 3 (R)、I 5 Treatment of (R) EC 50 Values, results are shown in Table 4.
TABLE 4 part of the therapeutic Activity of target Compounds against CMV EC 50 Value of
As can be seen from the results, I in the compounds 3 (R) and I 5 (R) EC for CMV therapeutic Activity 50 210.3 mug/mL and 190.4 mug/mL respectively, which are superior to the control medicament ningnanmycin 218.8 mug/mL.
Example 19: inhibitory Activity of target Compounds against Verticillium bacteria, peronospora crassa
(1) Test method
The bacteriostatic activity of the compounds was determined using the ex vivo growth rate method (Tarun, k.c.; et al, 2006). Potato dextrose agar medium (PDA medium: potato 200g, agar 20g, glucose 20g, distilled water 1000 mL) is heated to a molten state (40-60 ℃), 10mL of the liquid medicine (10 times of the final concentration of the liquid medicine) is poured into 90mL of PDA medium, fully and uniformly shaken, uniformly poured into a culture dish with the diameter of 9cm, horizontally placed, and cooled and solidified. The 4mm diameter bacterial dish is picked up by a puncher at the edge of the fresh pathogenic bacteria colony which has been cultivated for 4d, the bacterial dish is placed in the center of a reagent-containing PDA flat plate in an inverted mode, then the bacterial dish is placed in a 27 ℃ constant temperature and humidity incubator for inverted cultivation, observation is started when a blank control colony grows to be close to two thirds of the flat plate, the colony diameter is measured by a crisscross method, and the average value is obtained (Song Suqin, et al, 2004). The blank was not dosed, but contained the same concentration of solvent and 0.5% tween 20, and each treatment was repeated three times. The inhibition of hyphal growth by the agent was calculated by the following formula:
I(％)＝(C-T)/(C-0.4)×100％
where I is inhibition, C is blank diameter (cm), and T is treatment diameter (cm).
(2) Biological test results
TABLE 5 inhibitory Activity of target Compounds against Peronospora Cucumidis
Activity measurements from Table 5The test results show that most of the compounds have higher inhibition activity on the cucumber mildew bacteria and the verticillium bacteria. Wherein I in the compound 3 (R)、I 5 The inhibition rate of the (R) on the cucumber mildew and the verticillium bacteria is higher than that of the commercial control medicament hymexazol on the cucumber mildew and the verticillium bacteria.
Example 20: inhibitory Activity of target Compounds against Umbelliferae citruses, rhizoctonia solani, actinidia deliciosa
(1) Test method
The bactericidal activity of the compounds was determined using nephelometry (Yang l.; et al, 2017). The test compound was prepared at a concentration of 100. Mu.g/mL. NB medium (3.0 g beef extract, 5.0g peptone, 1.0g yeast powder, 10.0g glucose, 1000mL distilled water, pH 7.0-7.2) was prepared, a small piece of medium containing citrus canker, rice bacterial leaf blight bacteria and kiwi fruit canker was inoculated and placed into two NB media, plugs were plugged, and shaking culture was carried out at a constant temperature of 28℃and 180rpm until the growth log phase (OD=0.6-0.8) was reached for use. mu.L of the bacterial liquid, 4mL of water-Tween (1% Tween 20) and 1mL of the prepared compound solution were taken, and the test tube was incubated at 28.+ -. 1 ℃ and continuously shaken at 180rpm for 1-3 days. Bacterial growth was monitored by measuring optical density at 595nm (OD 595), but with the same concentration of solvent and 0.1% tween 20 as a blank, copper thiabendazole as a control agent, and each treatment was repeated three times. The inhibition of bacteria by the agent was calculated by the following formula:
I＝(Ctur-Ttur)/Ctur×100％
where I is the inhibition rate, ctur represents the corrected turbidity value of bacterial growth in the non-drug treated tube (blank), ttur represents the corrected turbidity value of bacterial growth in the compound treated tube.
(2) Biological test results
Table 6 inhibition Activity of target Compounds against Pyricularia citri, rhizoctonia solani, actinidia deliciosa
As can be seen from the biological activity test results of Table 6, most of the compounds show higher inhibition activities on citrus canker, rice bacterial blight and kiwi fruit canker at the concentration of 100 mug/mL. Wherein I in the compound 5 (R) and I 7 The inhibition rate of (R) on the citrus canker, the rice bacterial leaf blight bacteria and the kiwi fruit canker is higher than 90 percent, which is equivalent to that of a commercial control medicament hymexazol.
The embodiment of the invention is assisted with the technical scheme of the invention. The invention has the advantages of simple synthetic route and higher yield, and obtains a novel and efficient novel medicament with inhibition effect on tobacco mosaic virus, cucumber mildew bacteria, verticillium wilt, citrus canker bacteria, rice bacterial leaf blight bacteria and kiwi fruit canker bacteria.

Claims (7)

1. A chiral alpha-aminomalonate compound containing N-pyridylbenzenesulfonamide is characterized in that: the structure of the compound is shown as (I):
in formula (I), represents a chiral carbon atom; wherein: r is R 1 Is C1-C3 alkyl; r is R 2 Phenyl, substituted phenyl, cyclohexyl or pentyl; the substituent of the substituted phenyl is halogen, methyl or methoxy.
2. The chiral alpha-aminomalonate compounds containing N-pyridylbenzenesulfonamide according to claim 1, which are characterized in that: the C1-C3 alkyl is methyl, ethyl or isopropyl.
3. The method for preparing chiral alpha-aminomalonate compounds containing N-pyridylbenzenesulfonamide according to claim 1, which is characterized by comprising the following steps: the synthetic route is as follows:
4. the method for preparing chiral alpha-aminomalonate compounds containing N-pyridylbenzenesulfonamide according to claim 3, which is characterized in that: the method comprises the following specific steps:
(1) Preparation of cinchona alkaloid aromatic amide catalysts Q1 and Q2:
2-aminobenzimidazole, 3, 4-dimethoxy cyclobut-3-alkene-1, 2-diketone and quinine amine are taken as initial raw materials, absolute methanol is taken as solvent, and high-activity chiral cinchona alkaloid aromatic amide catalysts Q1 and Q2 are synthesized by a one-pot method at normal temperature;
(2) Preparation of chiral alpha-aminomalonate compound containing N-pyridylbenzenesulfonamide:
and putting 4-amino-N- (pyridine-2-yl) benzenesulfonamide, substituted aldehyde, malonate and catalyst cinchona alkaloid aromatic amide into a single-port bottle, adding paraxylene, heating to reflux, reacting for 4-6 hours, recovering paraxylene under reduced pressure, and separating by column chromatography to obtain the target product.
5. The method for preparing chiral alpha-aminomalonate compounds containing N-pyridylbenzenesulfonamide according to claim 4, which is characterized in that: the conditions for the column chromatography separation are petroleum ether: ethyl acetate=6:1V/V.
6. The use of a class of chiral alpha-aminomalonates containing N-pyridylbenzenesulfonamide according to one of claims 1 to 2 for the preparation of a medicament for the control of crop diseases.
7. The use according to claim 6, characterized in that: the crop diseases comprise tobacco mosaic virus, cucumber mildew virus, verticillium wilt, citrus canker, rice bacterial leaf blight and kiwi fruit canker.
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