CN116535358A - 一种含硫氰基吡唑结构的苯甲酰胺类衍生物、制备方法及其应用 - Google Patents
一种含硫氰基吡唑结构的苯甲酰胺类衍生物、制备方法及其应用 Download PDFInfo
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- CN116535358A CN116535358A CN202310451956.2A CN202310451956A CN116535358A CN 116535358 A CN116535358 A CN 116535358A CN 202310451956 A CN202310451956 A CN 202310451956A CN 116535358 A CN116535358 A CN 116535358A
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- 239000003899 bactericide agent Substances 0.000 claims abstract description 18
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 7
- 125000001246 bromo group Chemical group Br* 0.000 claims abstract description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 3
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- 238000000034 method Methods 0.000 claims description 62
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P3/00—Fungicides
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Environmental Sciences (AREA)
- Wood Science & Technology (AREA)
- Plant Pathology (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Pest Control & Pesticides (AREA)
- General Health & Medical Sciences (AREA)
- Dentistry (AREA)
- Health & Medical Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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Abstract
本发明公开了一种含硫氰基吡唑结构的苯甲酰胺类衍生物、制备方法及其应用。这种含硫氰基吡唑结构的苯甲酰胺类衍生物的结构式如下通式(I),其中,R1为三氟甲基、二氟甲基或甲基;R2为不同位置取代的氢、甲基、甲氧基、三氟甲基、三氟甲氧基、氟、氯、溴、氰基或其多取代组合。本发明制备的含硫氰基吡唑结构的苯甲酰胺类衍生物具有广谱的抗真菌和卵菌活性,尤其对于苹果腐烂病菌和辣椒疫霉病菌表现出显著的抑制活性,这为开发以含硫氰基吡唑结构的苯甲酰胺类衍生物为活性成分的新型杀菌剂提供了基础。
Description
技术领域
本发明涉及化学技术以及药物化学技术领域,具体涉及一种含硫氰基吡唑结构的苯甲酰胺类衍生物、制备方法及其应用。
背景技术
农药是粮食生产过程中重要的生产资料,对于保证农业作物高产稳产具有至关重要的作用。据统计,植物致病真菌感染导致每年全球农作物产量减少20%,且收获后再减少10%,这不仅给农民带来巨大的经济损失,而且严重威胁了全球的粮食生产安全。杀菌剂的应用是目前防治植物致病真菌最有效的措施,每年可挽回大量损失。在众多杀菌剂中,SDHIs类杀菌剂因其高效广谱的抗真菌活性被广泛应用,其作用机制为:通过作用于蛋白复合体Ⅱ影响病原菌的呼吸链电子传递系统,阻碍能量的代谢,抑制病原菌的生长,导致其死亡,从而达到防治病害的目的。
SDHIs类杀菌剂在化学结构上最为显著的特征是含有酰胺基,新研发的该类杀菌剂是在已有的基础上进行基团替代衍生而成,从1996年到2023年,已有25种SDH抑制剂上市,其中含有吡唑环的占比高达52.00%(13/25);该类杀菌剂因其广谱和高效抗真菌活性被用于许多作物上的真菌病害防治,已经成为生产上的一类重要的杀菌剂品种。然而,因其过度及不合理使用,使真菌对该类杀菌剂的耐药性日趋严峻,国际杀菌剂抗性委员会(FRAC)2009年已把SDHIs类杀菌剂归为中等至高抗性风险杀菌剂。另一方面,SDHIs杀菌剂的杀菌谱已经很广,几乎覆盖所有的真菌病害,如:灰霉病、白粉病、纹枯病、赤霉病和锈病等,但在目前已上市的品种中,均没有对黄瓜霜霉病,辣椒疫霉病等卵菌有较高防效的品种出现,这无疑是令人遗憾的。因此,开发新型杀菌剂,拓展杀菌剂防治谱及解决真菌耐药性问题对农业可持续发展具有十分重要的作用。
发明内容
本发明要解决的技术问题是:克服现有技术的不足,提供一种含硫氰基吡唑结构的苯甲酰胺类衍生物、制备方法及其应用,本发明将硫氰基引入吡唑苯甲酰胺先导结构中,合成了含硫氰基吡唑结构的苯甲酰胺类衍生物,成为具有高效广谱抑制植物病原菌活性的化合物。
本发明解决其技术问题所采用的技术方案是:一种含硫氰基吡唑结构的苯甲酰胺类衍生物,其特征在于:其结构通式(I)如下:
其中,R1为三氟甲基、二氟甲基或甲基;R2为不同位置取代的氢、甲基、甲氧基、三氟甲基、三氟甲氧基、氟、氯、溴、氰基或其多取代组合。
进一步地,该含硫氰基吡唑结构的苯甲酰胺类衍生物优选如下化合物:
一种如上述的含硫氰基吡唑结构的苯甲酰胺类衍生物的制备方法,包括如下合成路线:
进一步地,所述合成路线具体包括如下步骤:
步骤S1、以5-吡唑胺(II)为原料,一定比例的乙醇/水作为溶剂,加入适量硫氰酸铵和过硫酸铵,室温下搅拌反应,生成4-硫氰基-5-吡唑胺(III),所得产物经柱层析或重结晶提纯得到纯品;
步骤S2、以4-硫氰基-5-吡唑胺(III)为原料,与不同取代的苯甲酸或苯甲酰氯(IV)发生缩合反应获得通式(I)对应的含硫氰基吡唑结构的苯甲酰胺类衍生物,所得产物经柱层析分离得到纯品。
一种如上述的含硫氰基吡唑结构的苯甲酰胺类衍生物的应用,它在防治油菜菌核病、苹果树腐烂病、水稻纹枯病、小麦赤霉病、番茄灰霉病、辣椒疫霉病和瓜果腐霉病等真菌/卵菌病害方面的应用。
另外,这种含硫氰基吡唑结构的苯甲酰胺类衍生物可以用于制成各种防治由植物病原真菌和卵菌的引起的植物病害农药制剂。
本发明的有益效果是:本发明将硫氰基引入吡唑酰胺先导结构中,合成了一类含硫氰基吡唑结构的苯甲酰胺类衍生物,并选取常见植物真菌和卵菌,如油菜菌核病菌、苹果树腐烂病菌、水稻纹枯病菌、小麦全蚀病菌、葡萄灰霉病菌、辣椒疫霉病菌等为防治对象进行抑菌活性测定,结果表明,该类化合物对植物真菌和卵菌表现出了广谱的抑菌活性,特别是对苹果树腐烂病菌和辣椒疫霉病菌表现出优异的抑菌活性,构效关系分析表明,分子骨架吡唑环上的硫氰基取代对于该类化合物保持高广谱抑菌活性具有至关重要的作用,该类化合物结构上具有原始新颖性,合成简单,且与现有商用杀菌剂结构完全不同,有望开发成为高效、广谱的新型杀菌剂。
具体实施方式
现在结合优选实施例对本发明作进一步详细的说明,以令本领域技术人员参照说明书文字能够据以实施。
实施例1
含硫氰基-5-吡唑胺类化合物III(R1=三氟甲基)的制备方法,含硫氰基-5-吡唑胺类化合物III(R1=三氟甲基)的化学式如下:
本实施例中含硫氰基-5-吡唑胺类化合物III(R1=三氟甲基)的制备方法具体如下:室温条件下,将5-吡唑胺II(R1=三氟甲基)(1.65g,10mmol)和硫氰酸铵(3.04g,40mmol)溶于30mL乙醇和水的混合溶液(乙醇/水=2:1)中,搅拌数分钟,随后分批加入过硫酸铵(11.4g,50mmol),于室温下反应24小时左右,TLC监测直至5-吡唑胺(II)反应完全。反应完成后真空旋蒸去除大部分乙醇,随后用乙酸乙酯萃取(3×40mL),合并有机层并用饱和食盐水洗涤,最后用无水硫酸镁干燥,减压旋干溶剂后得黄色粗产物。硅胶柱层析(石油醚/乙酸乙酯=5:1→3:1)纯化得到含硫氰基-5-吡唑胺类化合物III(R1=三氟甲基)(2.02g,收率91%)。1H NMR(400MHz,DMSO-d6)δ6.71(s,2H,NH2),3.63(s,3H,N-CH3);13C NMR(101MHz,DMSO-d6)δ152.2,139.9(q,J=35.7Hz),120.7(q,J=269.5Hz),111.6,72.7,35.8.
实施例2
化合物I-1的制备,化合物I-1的化学式如下:
本实施例中化合物I-1的制备方法具体如下:将实施例1中所得含硫氰基-5-吡唑胺类化合物III(R1=三氟甲基)(222.2mg,1mmol)与三乙胺(0.55mL)溶于无水二氯甲烷(2mL)中,随后于冰浴下缓慢滴加苯甲酰氯。冰浴下反应30分钟后移至室温,继续在室温下反应3小时左右,TLC监测直至含硫氰基-5-吡唑胺(III)反应完全。乙酸乙酯萃取(3×10mL),合并有机相并用饱和食盐水洗涤,最后用无水硫酸镁干燥,过滤,减压旋干溶剂得粗产物。硅胶柱层析(石油醚/乙酸乙酯=3:1)纯化得淡黄色固体化合物I-1(254.5mg,收率78%),m.p.=126.3–127.9℃;1HNMR(500MHz,DMSO-d6)δ11.01(s,1H,CONH-H),8.05(d,J=7.2Hz,2H,Ph-H),7.70(t,J=7.4Hz,1H,Ph-H),7.61(t,J=7.6Hz,2H,Ph-H),3.87(s,3H,NCH3);13C NMR(126MHz,DMSO-d6)δ166.0,142.3,140.1(q,J=36.9Hz),132.9,132.1,128.7(2C),128.1(2C),120.3(q,J=269.8Hz),110.4,93.5,37.6.
实施例3
化合物I-2的制备,化合物I-2的化学式如下:
本实施例中化合物I-2的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为邻氟苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-2为淡黄色固体(247.9mg,收率72%),m.p.=139.1–141.5℃;1H NMR(500MHz,DMSO-d6)δ11.03(s,1H,CONH-H),7.84(m,1H,Ph-H),7.69(m,1H,Ph-H),7.42(m,2H,Ph-H),3.88(s,3H,NCH3);13C NMR(126MHz,DMSO-d6)δ163.4,159.4(d,J=251.3Hz),141.7,140.2(q,J=37.0Hz),134.1(d,J=8.6Hz),130.5(d,J=2.2Hz),124.8(d,J=3.5Hz),121.8(d,J=13.6Hz),120.3(q,J=269.8Hz),116.5(d,J=21.5Hz),110.3,93.5,37.6.
实施例4
化合物I-3的制备,化合物I-3的化学式如下:
本实施例中化合物I-3的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为间氟苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-3为淡黄色固体(303.0mg,收率88%),m.p.=122.7–124.8℃;1H NMR(500MHz,DMSO-d6)δ11.11(s,1H,CONH-H),7.89(d,J=7.7Hz,1H,Ph-H),7.84(d,J=9.3Hz,1H,Ph-H),7.68(m,1H,Ph-H),7.56(m,1H,Ph-H),3.88(s,3H,NCH3);13C NMR(126MHz,DMSO-d6)δ164.8(d,J=2.7Hz),162.0(d,J=245.2Hz),142.0,140.1(q,J=36.9Hz),134.4(d,J=7.1Hz),131.0(d,J=8.0Hz),124.4(d,J=3.0Hz),120.3(q,J=269.8Hz),119.8(d,J=21.0Hz),115.0(d,J=23.3Hz),110.4,93.6,37.6.
实施例5
化合物I-4的制备,化合物I-4的化学式如下:
本实施例中化合物I-4的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为对氟苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-4为淡黄色固体(285.8mg,收率83%),m.p.=168.8–170.5℃;1H NMR(500MHz,DMSO-d6)δ11.04(s,1H,CONH-H),8.12(m,2H,Ph-H),7.46(m,2H,Ph-H),3.87(s,3H,NCH3);13C NMR(126MHz,DMSO-d6)δ165.0,164.9(d,J=251.1Hz),142.2,140.1(q,J=37.1Hz),131.1,131.0,128.6(d,J=2.9Hz),120.4(q,J=270.0Hz),115.9,115.7,110.4,93.6,37.6.
实施例6
化合物I-5的制备,化合物I-5的化学式如下:
本实施例中化合物I-5的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为邻氯苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-5为淡黄色固体(259.7mg,收率72%),m.p.=145.6–146.9℃。1H NMR(500MHz,DMSO-d6)δ11.37(s,1H,CONH-H),7.74(d,J=7.2Hz,1H,Ph-H),7.65(d,J=7.9Hz,1H,Ph-H),7.60(m,1H,Ph-H),7.54(t,J=7.3Hz,1H,Ph-H),3.91(s,3H,NCH3);13C NMR(126MHz,DMSO-d6)δ165.7,141.5,140.3(q,J=37.1Hz),134.6,132.1,130.0,129.9,129.2,127.4,120.3(q,J=269.8Hz),110.4,93.2,37.8.
实施例7
化合物I-6的制备,化合物I-6的化学式如下:
本实施例中化合物I-6的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为间氯苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-6为淡黄色固体(299.4mg,收率83%),m.p.=153.9–155.2℃。1H NMR(500MHz,DMSO-d6)δ11.15(s,1H,CONH-H),8.08(t,J=1.9Hz,1H,Ph-H),7.98(d,J=7.8Hz,1H,Ph-H),7.78(m,1H,Ph-H),7.65(t,J=7.9Hz,1H,Ph-H),3.88(s,3H,NCH3);13C NMR(126MHz,DMSO-d6)δ164.8,142.0,140.2(q,J=37.0Hz),134.1,133.5,132.7,130.8,127.9,127.0,120.3(q,J=270.0Hz),110.4,93.6,37.7.
实施例8
化合物I-7的制备,化合物I-7的化学式如下:
本实施例中化合物I-7的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为对氯苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-7为白色固体(342.7mg,收率95%),m.p.=141.5–143.4℃;1H NMR(400MHz,DMSO-d6)δ11.12(s,1H,CONH-H),8.06(d,J=8.6Hz,2H,Ph-H),7.70(d,J=8.6Hz,2H,Ph-H),3.87(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ165.1,142.1,140.2(q,J=37.1Hz),137.9,130.9,130.1(2C),128.9(2C),120.4(q,J=269.9Hz),110.5,93.6,37.7.
实施例9
化合物I-8的制备,化合物I-8的化学式如下:
本实施例中化合物I-8的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为邻三氟甲基苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-8为淡黄色固体(315.4mg,收率80%),m.p.=172.1–174.0℃;1H NMR(400MHz,DMSO-d6)δ11.50(s,1H,CONH-H),7.92(m,3H,Ph-H),7.81(m,1H,Ph-H),3.90(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ166.5,141.4,140.4(q,J=36.9Hz),133.8(d,J=2.4Hz),132.9,131.2,129.0,126.7(q,J=4.6Hz),126.3(q,J=31.8Hz),125.0,122.0(q,J=57.6Hz),110.5,93.4,37.7.
实施例10
化合物I-9的制备,化合物I-9的化学式如下:
本实施例中化合物I-9的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为间三氟甲基苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-9为淡黄色固体(374.6mg,收率95%),m.p.=187.2–188.7℃;1H NMR(400MHz,DMSO-d6)δ11.29(s,1H,CONH-H),8.37(s,1H,Ph-H),8.33(d,J=7.9Hz,1H,Ph-H),8.08(d,J=7.8Hz,1H,Ph-H),7.87(t,J=7.8Hz,1H,Ph-H),3.89(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.8,141.9,140.2(q,J=37.1Hz),133.1,132.4,130.2,129.5(q,J=3.2Hz),129.5(q,J=32.3Hz),124.8(q,J=3.8Hz),122.1(q,J=81.0Hz),119.0,110.5,93.7,37.7.
实施例11
化合物I-10的制备,化合物I-10的化学式如下:
本实施例中化合物I-10的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为对三氟甲基苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-10为淡黄色固体(382.3mg,收率97%),m.p.=164.1–166.2℃;1H NMR(400MHz,DMSO-d6)δ11.29(s,1H,CONH-H),8.24(d,J=8.1Hz,2H,Ph-H),8.01(d,J=8.3Hz,2H,Ph-H),3.89(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ165.1,141.9,140.2(q,J=37.1Hz),135.9,132.6(q,J=32.1Hz),129.2(2C),125.8(q,J=3.8Hz),125.2,122.1(q,J=75.2Hz),119.0,110.4,93.7,37.7;HRMS(ESI)m/z[M+Na]+:calcd for C14H8F6N4NaOS,417.0215,found,417.0222.
实施例12
化合物I-11的制备,化合物I-11的化学式如下:
本实施例中化合物I-11的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为邻甲基苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-11为淡黄色固体(306.3mg,收率90%),m.p.=142.1–143.7℃;1H NMR(400MHz,DMSO-d6)δ11.05(s,1H,CONH-H),7.68(d,J=7.2Hz,1H,Ph-H),7.49(m,1H,Ph-H),7.38(t,J=6.6Hz,2H,Ph-H),3.90(s,3H,NCH3),2.49(s,3H,Ph-CH3);13C NMR(101MHz,DMSO-d6)δ168.4,142.1,140.2(q,J=37.1Hz),136.2,134.3,130.9,130.8,127.7,125.8,120.4(q,J=270.0Hz),110.4,93.2,37.7,19.5.
实施例13
化合物I-12的制备,化合物I-12的化学式如下:
本实施例中化合物I-12的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为间甲基苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-12为白色固体(313.1mg,收率92%),m.p.=159.0–159.8℃;1H NMR(400MHz,DMSO-d6)δ10.96(s,1H,CONH-H),7.84(m,2H,Ph-H),7.50(m,2H,Ph-H),3.86(s,3H,NCH3),2.43(s,3H,Ph-CH3);13C NMR(101MHz,DMSO-d6)δ166.1,142.4,140.1(q,J=37.1Hz),138.2,133.5,132.1,128.6,128.6,125.3,120.4(q,J=270.0Hz),110.4,93.5,37.6,20.9.
实施例14
化合物I-13的制备,化合物I-13的化学式如下:
本实施例中化合物I-13的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为对甲基苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-13为淡黄色固体(289.3mg,收率85%),m.p.=131.1–132.8℃;1H NMR(400MHz,DMSO-d6)δ10.91(s,1H,CONH-H),7.95(d,J=8.2Hz,2H,Ph-H),7.41(d,J=8.0Hz,2H,Ph-H),3.86(s,3H,NCH3),2.42(s,3H,Ph-CH3);13C NMR(101MHz,DMSO-d6)δ165.8,143.3,142.4,140.1(q,J=37.0Hz),129.3(2C),129.1,128.2(2C),120.4(q,J=269.7Hz),110.4,93.5,37.6,21.1.
实施例15
化合物I-14的制备,化合物I-14的化学式如下:
本实施例中化合物I-14的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为邻甲氧基苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-14为淡黄色固体(252.9mg,收率71%),m.p.=120.5–121.3℃;1H NMR(400MHz,DMSO-d6)δ10.55(s,1H,CONH-H),7.85(dd,J=7.7,1.8Hz,1H,Ph-H),7.63(m,1H,Ph-H),7.27(d,J=8.4Hz,1H,Ph-H),7.13(t,J=7.5Hz,1H,Ph-H),3.99(s,3H,Ph-OCH3),3.86(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.7,157.5,142.4,139.9(q,J=37.0Hz),134.0,130.8,120.9,120.8,120.4(q,J=269.9Hz),112.4,110.5,93.5,56.2,37.6.
实施例16
化合物I-15的制备,化合物I-15的化学式如下:
本实施例中化合物I-15的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为间甲氧基苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-15为淡黄色固体(310.0mg,收率87%),m.p.=132.5–133.7℃;1H NMR(400MHz,DMSO-d6)δ11.00(s,1H,CONH-H),7.63(d,J=7.9Hz,1H,Ph-H),7.57(dd,J=2.7,1.6Hz,1H,Ph-H),7.53(t,J=7.9Hz,1H,Ph-H),7.27(m,1H,Ph-H),3.87(s,3H,Ph-OCH3),3.86(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ165.8,159.4,142.3,140.1(q,J=37.1Hz),133.4,130.0,120.4(q,J=269.9Hz),120.4,118.7,113.4,110.5,93.6,55.5,37.6;HRMS(ESI)m/z[M+Na]+:calcd forC14H11F3N4NaO2S,379.0447,found,379.0443.
实施例17
化合物I-16的制备,化合物I-16的化学式如下:
本实施例中化合物I-16的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为对甲氧基苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-16为淡黄色固体(331.4mg,收率93%),m.p.=133.8–134.5℃;1H NMR(400MHz,DMSO-d6)δ10.82(s,1H,CONH-H),8.03(d,J=8.9Hz,2H,Ph-H),7.14(d,J=8.9Hz,2H,Ph-H),3.87(s,3H,NCH3),3.85(s,3H,Ph-OCH3);13C NMR(101MHz,DMSO-d6)δ165.3,163.0,142.6,140.1(q,J=37.0Hz),130.3(2C),124.4,120.4(q,J=269.8Hz),114.0(2C),110.5,93.4,55.6,37.6.
实施例18
化合物I-17的制备,化合物I-17的化学式如下:
本实施例中化合物I-17的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为邻溴苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-17为淡黄色固体(368.7mg,收率91%),m.p.=145.9–147.4℃;1H NMR(400MHz,DMSO-d6)δ11.41(s,1H,CONH-H),7.80(d,J=7.8Hz,1H,Ph-H),7.71(dd,J=7.5,1.8Hz,1H,Ph-H),7.59(t,J=7.3Hz,1H,Ph-H),7.51(td,J=7.8,1.6Hz,1H,Ph-H),3.93(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ166.5,141.4,140.3(q,J=37.0Hz),136.8,133.0,132.2,129.2,127.9,120.3(q,J=269.9Hz),118.8,110.5,93.2,37.9.
实施例19
化合物I-18的制备,化合物I-18的化学式如下:
本实施例中化合物I-18的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为间溴苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-18为淡黄色固体(320.1mg,收率79%),m.p.=172.8–174.9℃;1H NMR(400MHz,DMSO-d6)δ11.15(s,1H,CONH-H),8.22(s,1H,Ph-H),8.02(d,J=7.9Hz,1H,Ph-H),7.91(d,J=8.1Hz,1H,Ph-H),7.58(t,J=7.9Hz,1H,Ph-H),3.88(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.7,141.9,140.1(q,J=37.0Hz),135.6,134.3,131.0,130.7,127.3,121.9,120.3(q,J=269.9Hz),110.4,93.6,37.7.
实施例20
化合物I-19的制备,化合物I-19的化学式如下:
本实施例中化合物I-19的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为对溴苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-19为淡黄色固体(324.2mg,收率80%),m.p.=174.3–176.5℃;1H NMR(400MHz,DMSO-d6)δ11.10(s,1H,CONH-H),7.98(d,J=8.5Hz,2H,Ph-H),7.84(d,J=8.6Hz,2H,Ph-H),3.87(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ165.2,142.0,140.11(q,J=37.0Hz),131.8(2C),131.2,130.2(2C),126.9,120.33(q,J=269.9Hz),110.4,93.6,37.6;HRMS(ESI)m/z[M+Na]+:calcd forC13H8BrF3N4NaOS,426.9446,found,426.9451.
实施例21
化合物I-20的制备,化合物I-20的化学式如下:
本实施例中化合物I-20的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为间氰基苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-20为淡黄色固体(326.7mg,收率93%),m.p.=163.6–164.8℃;1H NMR(400MHz,DMSO-d6)δ11.25(s,1H,CONH-H),8.48(s,1H,Ph-H),8.31(d,J=8.0Hz,1H,Ph-H),8.18(d,J=7.8Hz,1H,Ph-H),7.84(t,J=7.9Hz,1H,Ph-H),3.89(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.4,141.8,140.2(q,J=37.1Hz),136.2,133.3,132.9,131.8,130.2,120.3(q,J=269.8Hz),118.0,111.9,110.4,93.6,37.7.
实施例22
化合物I-21的制备,化合物I-21的化学式如下:
本实施例中化合物I-21的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为对氰基苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-21为淡黄色固体(267.0mg,收率76%),m.p.=186.5–188.5℃;1H NMR(400MHz,DMSO-d6)δ11.30(s,1H,CONH-H),8.19(d,J=8.3Hz,2H,Ph-H),8.11(d,J=8.3Hz,2H,Ph-H),3.89(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.9,141.8,140.2(q,J=37.1Hz),136.1,132.8(2C),129.0(2C),120.3(q,J=269.8Hz),118.1,115.1,110.4,93.7,37.7.
实施例23
化合物I-22的制备,化合物I-22的化学式如下:
本实施例中化合物I-22的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为邻三氟甲氧基苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-22为淡黄色固体(393.9mg,收率96%),m.p.=152.0–153.4℃;1H NMR(400MHz,DMSO-d6)δ11.35(s,1H,CONH-H),7.87(dd,J=7.6,1.4Hz,1H,Ph-H),7.76(td,J=8.0,1.6Hz,1H,Ph-H),7.61(m,2H,Ph-H),3.88(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.2,145.0,141.5,140.3(q,J=34.1Hz),133.1,130.1,128.7,127.9,122.0,121.5(q,J=37.1Hz),118.9(q,J=21.7Hz),110.3,93.3,37.6.
实施例24
化合物I-23的制备,化合物I-23的化学式如下:
本实施例中化合物I-23的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为间三氟甲氧基苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-23为淡黄色固体(377.5mg,收率92%),m.p.=159.8–161.7℃;1H NMR(400MHz,DMSO-d6)δ11.20(s,1H,CONH-H),8.09(d,J=7.5Hz,1H,Ph-H),7.98(s,1H,Ph-H),7.78(t,J=7.9Hz,1H,Ph-H),7.73(d,J=8.4Hz,1H,Ph-H),3.89(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.6,148.4,141.9,140.2(q,J=37.0Hz),134.3,131.1,127.3,125.4,121.5(q,J=21.1Hz),120.7,118.9(q,J=21.1Hz),110.5,93.7,37.7;HRMS(ESI)m/z[M+Na]+:calcd forC14H8F6N4NaO2S,433.0164,found,433.0166.
实施例25
化合物I-24的制备,化合物I-24的化学式如下:
本实施例中化合物I-24的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为对三氟甲氧基苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-24为淡黄色固体(381.6mg,收率93%),m.p.=153.6–154.7℃;1H NMR(400MHz,DMSO-d6)δ11.15(s,1H,CONH-H),8.18(d,J=8.7Hz,2H,Ph-H),7.62(d,J=8.5Hz,2H,Ph-H),3.88(s,3H,NCH3);13CNMR(101MHz,DMSO-d6)δ164.9,151.4,142.1,140.2(q,J=37.1Hz),131.2,130.7(2C),121.5(q,J=45.0Hz),121.0(2C),118.8(q,J=32.7Hz),110.5,93.6,37.7;HRMS(ESI)m/z[M+Na]+:calcd for C14H8F6N4NaO2S,433.0164,found,433.0171.
实施例26
化合物I-25的制备,化合物I-25的化学式如下:
本实施例中化合物I-25的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为2,4-二氯苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-25为淡黄色固体(355.7mg,收率90%),m.p.=142.9–145.3℃;1H NMR(400MHz,DMSO-d6)δ11.44(s,1H,CONH-H),7.86(d,J=1.9Hz,1H,Ph-H),7.78(d,J=8.3Hz,1H,Ph-H),7.66(dd,J=8.3,1.9Hz,1H,Ph-H),3.91(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.9,141.3,140.3(q,J=37.0Hz),136.0,133.4,131.4,130.7,129.6,127.7,120.3(q,J=269.8Hz),110.5,93.3,37.9.
实施例27
化合物I-26的制备,化合物I-26的化学式如下:
本实施例中化合物I-26的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为3,4-二氯苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-26为淡黄色固体(343.8mg,收率87%),m.p.=160.3–161.8℃;1H NMR(400MHz,DMSO-d6)δ11.22(s,1H,CONH-H),8.28(d,J=2.0Hz,1H,Ph-H),7.99(dd,J=8.4,2.1Hz,1H,Ph-H),7.91(d,J=8.4Hz,1H,Ph-H),3.88(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.0,141.8,140.2(q,J=37.0Hz),135.8,132.5,131.7,131.2,130.1,128.5,120.3(q,J=269.9Hz),110.4,93.6,37.7;HRMS(ESI)m/z[M+Na]+:calcd for C13H7Cl2F3N4NaOS,416.9562,found,416.9565.
实施例28
化合物I-27的制备,化合物I-27的化学式如下:
本实施例中化合物I-27的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为3,5-二氯苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-27为淡黄色固体(351.7mg,收率89%),m.p.=174.5–175.8℃;1H NMR(400MHz,DMSO-d6)δ11.26(s,1H,CONH-H),8.04(d,J=1.8Hz,2H,Ph-H),7.99(q,J=2.0Hz,1H,Ph-H),3.88(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ163.6,141.6,140.2(q,J=37.0Hz),135.4,134.6(2C),132.2,127.0(2C),120.3(q,J=269.9Hz),110.5,93.6,37.8;HRMS(ESI)m/z[M+Na]+:calcd forC13H7Cl2F3N4NaOS,416.9562,found,416.9557.
实施例29
化合物I-28的制备,化合物I-28的化学式如下:
本实施例中化合物I-28的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为2-氟-4-氯-苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-28为淡黄色固体(329.5mg,收率87%),m.p.=156.0–156.7℃;1H NMR(400MHz,DMSO-d6)δ11.39(s,1H,CONH-H),7.84(dd,J=8.4,6.2Hz,1H,Ph-H),7.68(dd,J=9.0,2.3Hz,1H,Ph-H),7.45(td,J=8.5,2.4Hz,1H,Ph-H),3.91(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ165.0,162.9(d,J=251.4Hz),141.4,140.3(q,J=37.0Hz),131.2(d,J=3.5Hz),131.3(d,J=9.6Hz),131.2(d,J=3.5Hz),120.3(q,J=270.0Hz),117.6(d,J=25.5Hz),114.8(d,J=21.6Hz),110.5,93.3,37.8.
实施例30
化合物I-29的制备,化合物I-29的化学式如下:
本实施例中化合物I-29的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为3-氟-4-氯-苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-29为淡黄色固体(310.5mg,收率82%),m.p.=154.8–155.9℃;1H NMR(400MHz,DMSO-d6)δ11.19(s,1H,CONH-H),8.04(dd,J=10.0,1.8Hz,1H,Ph-H),7.89(m,2H,Ph-H),3.88(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.0,157.1(d,J=248.0Hz),141.8,140.2(q,J=37.1Hz),132.9(d,J=6.4Hz),131.3,125.5(d,J=3.6Hz),124.5,120.3(q,J=269.8Hz),116.6(d,J=22.8Hz),110.5,93.7,37.7;HRMS(ESI)m/z[M+Na]+:calcd for C13H7ClF4N4NaOS,400.9857,found,400.9858.
实施例31
化合物I-30的制备,化合物I-30的化学式如下:
本实施例中化合物I-30的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为2-三氟甲基-4-氯-苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-30为淡黄色固体(390.1mg,收率91%),m.p.=169.2–172.6℃;1H NMR(400MHz,DMSO-d6)δ11.55(s,1H,CONH-H),8.06(s,1H,Ph-H),8.03(d,J=8.4Hz,1H,Ph-H),7.96(d,J=8.2Hz,1H,Ph-H),3.89(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ165.5,141.2,140.3(q,J=37.3Hz),135.9,132.8,132.5,131.1,128.2(q,J=34.3Hz),126.8(q,J=4.9Hz),122.7(q,J=274.4Hz),120.3(q,J=269.9Hz),110.5,93.4,37.7.
实施例32
化合物I-31的制备,化合物I-31的化学式如下:
本实施例中化合物I-31的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为3-三氟甲基-4-氯-苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-31为淡黄色固体(411.5mg,收率96%),m.p.=160.2–162.5℃;1H NMR(400MHz,DMSO-d6)δ11.34(s,1H,CONH-H),8.46(d,J=2.1Hz,1H,Ph-H),8.31(dd,J=8.4,2.1Hz,1H,Ph-H),8.01(d,J=8.4Hz,1H,Ph-H),3.89(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.0,141.7,140.2(q,J=37.1Hz),135.3,133.9,132.4,131.5,127.6(q,J=5.3Hz),127.0(q,J=31.3Hz),120.33(q,J=269.9Hz),122.54(q,J=273.4Hz),110.5,93.7,37.8;HRMS(ESI)m/z[M+Na]+:calcdfor C14H7ClF6N4NaOS,450.9825,found,450.9823.
实施例33
化合物I-32的制备,化合物I-32的化学式如下:
本实施例中化合物I-32的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为2-氟-4-三氟甲基-苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-32为淡黄色固体(346.3mg,收率84%),m.p.=132.6–133.9℃;1H NMR(400MHz,DMSO-d6)δ11.34(s,1H,CONH-H),8.04(t,J=7.4Hz,1H,Ph-H),7.99(d,J=10.0Hz,1H,Ph-H),7.82(d,J=8.0Hz,1H,Ph-H),3.90(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ162.4,159.1(d,J=253.7Hz),141.3,140.2(q,J=37.0Hz),133.5(qd,J=32.9,7.7Hz),131.8(d,J=2.6Hz),126.1(d,J=13.8Hz),121.8(q,J=3.6Hz),120.3(d,J=269.9Hz),114.4(d,J=3.6Hz),114.2(d,J=3.7Hz),110.4,93.6,37.7.
实施例34
化合物I-33的制备,化合物I-33的化学式如下:
本实施例中化合物I-33的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为3-氟-4-三氟甲基-苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-33为淡黄色固体(329.8mg,收率80%),m.p.=172.1–173.5℃;1H NMR(400MHz,DMSO-d6)δ11.36(s,1H,CONH-H),8.09(m,3H,Ph-H),3.90(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ163.8,158.7(d,J=252.8Hz),141.6,140.2(q,J=37.0Hz),138.6(d,J=7.2Hz),128.3(d,J=4.7Hz),124.8(d,J=3.7Hz),122.2(q,J=272.0Hz),120.3(q,J=269.9Hz),120.1(qd,J=32.9,11.6Hz),116.9(d,J=22.5Hz),110.4,93.8,37.8;HRMS(ESI)m/z[M+Na]+:calcd forC14H7F7N4NaOS,435.0121,found,435.0126.
实施例35
化合物I-34的制备,化合物I-34的化学式如下:
本实施例中化合物I-34的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为2-氯-4-三氟甲基-苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-34为淡黄色固体(390.1mg,收率91%),m.p.=155.2–156.9℃;1H NMR(400MHz,DMSO-d6)δ11.58(s,1H,CONH-H),8.12(s,1H,Ph-H),7.98(m,2H,Ph-H),3.93(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.7,141.1,140.3(q,J=37.1Hz),138.6,132.1(q,J=32.8Hz),131.1,130.3,126.9(d,J=3.8Hz),125.7(q,J=273.1Hz),124.6(d,J=3.8Hz),120.3(q,J=270.2Hz),110.5,93.4,37.9.
实施例36
化合物I-35的制备,化合物I-35的化学式如下:
本实施例中化合物I-35的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为2,4-二三氟甲基-苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-35为淡黄色固体(379.1mg,收率82%),m.p.=168.4–170.1℃;1H NMR(400MHz,DMSO-d6)δ11.68(s,1H,CONH-H),8.35(d,J=8.1Hz,1H,Ph-H),8.30(s,1H,Ph-H),8.18(d,J=8.0Hz,1H,Ph-H),3.91(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ165.3,141.0,140.4(q,J=37.0Hz),137.6,131.3(q,J=33.2Hz),130.5,130.1,127.3(q,J=33.3Hz),123.8,123.0(q,J=272.9Hz),122.8(q,J=274.1Hz),120.3(q,J=270.1Hz),110.5,93.4,37.8.
实施例37
化合物I-36的制备,化合物I-36的化学式如下:
本实施例中化合物I-36的制备方法具体如下:采用实施例2中所述方法,将苯甲酰氯替换为3,5-二三氟甲基-苯甲酰氯,其他步骤与实施例2中相同。所得化合物I-36为淡黄色固体(328.2mg,收率71%),m.p.=182.1–183.3℃;1H NMR(400MHz,DMSO-d6)δ11.51(s,1H,CONH-H),8.65(s,2H,Ph-H),8.50(s,1H,Ph-H),3.91(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ163.6,141.6,140.3(q,J=37.2Hz),134.6,130.8(q,J=33.5Hz)(2C),129.1(2C),126.5,123.1(q,J=272.9Hz)(2C),120.4(q,J=273.1Hz),110.6,93.8,37.9;HRMS(ESI)m/z[M+Na]+:calcd for C15H7F9N4NaOS,485.0089,found,485.0092.
实施例38
含硫氰基-5-吡唑胺类化合物III(R1=二氟甲基)的制备方法,含硫氰基-5-吡唑胺类化合物III(R1=二氟甲基)的化学式如下:
本实施例中含硫氰基-5-吡唑胺类化合物III(R1=二氟甲基)的制备方法具体如下:室温条件下,将5-吡唑胺II(R1=二氟甲基)(1.47g,10mmol)和硫氰酸铵(3.04g,40mmol)溶于30mL乙醇和水的混合溶液(乙醇/水=2:1)中,搅拌数分钟,随后分批加入过硫酸铵(11.4g,50mmol),于室温下反应24小时左右,TLC监测直至5-吡唑胺(II)反应完全。反应完成后真空旋蒸去除大部分乙醇,随后用乙酸乙酯萃取(3×40mL),合并有机层并用饱和食盐水洗涤,最后用无水硫酸镁干燥,减压旋干溶剂后得黄色粗产物。硅胶柱层析(石油醚/乙酸乙酯=5:1→3:1)纯化得到含硫氰基-5-吡唑胺类化合物III(R1=二氟甲基)(1.76g,收率86%)。1H NMR(400MHz,DMSO-d6)δ6.85(t,J=53.2Hz,1H,CHF2),6.56(s,2H,NH2),3.59(s,3H,N-CH3);13C NMR(101MHz,DMSO-d6)δ151.9,144.7(t,J=27.2Hz),111.9,111.5(t,J=232.5Hz),71.6,35.4.
实施例39
化合物I-37的制备,化合物I-37的化学式如下:
本实施例中化合物I-37的制备方法具体如下:将实施例38中所得含硫氰基-5-吡唑胺类化合物(R1=二氟甲基)(204.2mg,1mmol)与三乙胺(0.55mL)溶于无水二氯甲烷(2mL),随后于冰浴下缓慢滴加邻氯苯甲酰氯。冰浴下反应30分钟后移至室温,继续在室温下反应3小时左右,TLC监测直至含硫氰基-5-吡唑胺(III)反应完全。乙酸乙酯萃取(3×10mL),合并有机相并用饱和食盐水洗涤,最后用无水硫酸镁干燥,过滤,减压旋干溶剂得粗产物。硅胶柱层析(石油醚/乙酸乙酯=3:1)纯化得淡黄色固体化合物I-37(209.0mg,收率61%),m.p.=141.6–144.0℃;1H NMR(400MHz,DMSO-d6)δ11.27(s,1H,CONH-H),7.73(d,J=7.4Hz,1H,Ph-H),7.65(d,J=7.8Hz,1H,Ph-H),7.59(m,1H,Ph-H),7.54(t,J=7.2Hz,1H,Ph-H),7.14(t,J=53.0Hz,1H,CHF2),3.86(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ165.8,145.1(t,J=27.7Hz),140.9,134.8,132.1,130.1,130.0,129.3,127.5,110.9(t,J=233.7Hz),110.9,92.1,37.4.
实施例40
化合物I-38的制备,化合物I-38的化学式如下:
本实施例中化合物I-38的制备方法具体如下:采用实施例39中所述方法,将邻氯苯甲酰氯替换为间氯苯甲酰氯,其他步骤与实施例39中相同。所得化合物I-38为淡黄色固体(253.6mg,收率74%),m.p.=150.7–151.6℃;1H NMR(400MHz,DMSO-d6)δ11.05(s,1H,CONH-H),8.08(s,1H,Ph-H),7.98(d,J=7.8Hz,1H,Ph-H),7.78(d,J=8.1Hz,1H,Ph-H),7.65(t,J=7.9Hz,1H,Ph-H),7.14(t,J=53.0Hz,1H,CHF2),3.82(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.8,145.0(t,J=27.7Hz),141.3,134.3,133.6,132.7,130.9,127.9,127.0,111.0(t,J=233.6Hz),110.8,92.5,37.3;HRMS(ESI)m/z[M+Na]+:calcd forC13H9ClF2N4NaOS,365.0046,found,365.0044.
实施例41
化合物I-39的制备,化合物I-39的化学式如下:
本实施例中化合物I-39的制备方法具体如下:采用实施例39中所述方法,将邻氯苯甲酰氯替换为对氯苯甲酰氯,其他步骤与实施例39中相同。所得化合物I-39为淡黄色固体(267.3mg,收率78%),m.p.=170.4–171.8℃;1H NMR(400MHz,DMSO-d6)δ11.00(s,1H,CONH-H),8.05(d,J=8.3Hz,2H,Ph-H),7.70(d,J=8.2Hz,2H,Ph-H),7.14(t,J=53.0Hz,1H,CHF2),3.81(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ165.0,145.0(t,J=27.6Hz),141.4,137.8,131.0,130.1(2C),128.9(2C),111.0(t,J=233.8Hz),110.8,92.5,37.3;HRMS(ESI)m/z[M+Na]+:calcd for C13H9ClF2N4NaOS,365.0046,found,365.0045.
实施例42
化合物I-40的制备,化合物I-40的化学式如下:
本实施例中化合物I-40的制备方法具体如下:采用实施例39中所述方法,将邻氯苯甲酰氯替换为邻三氟甲基苯甲酰氯,其他步骤与实施例39中相同。所得化合物I-40为淡黄色固体(312.3mg,收率83%),m.p.=163.0–164.1℃;1H NMR(400MHz,DMSO-d6)δ11.37(s,1H,CONH-H),7.94(d,J=7.9Hz,1H,Ph-H),7.90(d,J=5.9Hz,2H,Ph-H),7.81(t,J=6.7Hz,1H,Ph-H),7.15(t,J=53.0Hz,1H,CHF2),3.85(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ166.5,145.2(t,J=27.6Hz),140.8,133.9,132.9,131.2,129.0,126.7,126.2(q,J=31.8Hz),123.6(q,J=273.8Hz),110.9(t,J=233.7Hz),110.8,92.2,37.3.
实施例43
化合物I-41的制备,化合物I-41的化学式如下:
本实施例中化合物I-41的制备方法具体如下:采用实施例39中所述方法,将邻氯苯甲酰氯替换为间三氟甲基苯甲酰氯,其他步骤与实施例39中相同。所得化合物I-41为淡黄色固体(361.2mg,收率96%),m.p.=185.4-186.1℃;1H NMR(400MHz,DMSO-d6)δ11.18(s,1H,CONH-H),8.37(s,1H,Ph-H),8.33(d,J=7.9Hz,1H,Ph-H),8.08(d,J=7.8Hz,1H,Ph-H),7.87(t,J=7.8Hz,1H,Ph-H),7.15(t,J=53.0Hz,1H,Ph-H),3.84(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.8,145.0(t,J=27.7Hz),141.3,133.3,132.4,130.2,129.5(q,J=32.3Hz),129.4(q,J=3.0Hz),124.8(q,J=3.8Hz),123.9(q,J=272.4Hz),110.8,111.0(t,J=233.7Hz),92.5,37.3.
实施例44
化合物I-42的制备,化合物I-42的化学式如下:
本实施例中化合物I-42的制备方法具体如下:采用实施例39中所述方法,将邻氯苯甲酰氯替换为对三氟甲基苯甲酰氯,其他步骤与实施例39中相同。所得化合物I-42为淡黄色固体(334.9mg,收率89%),m.p.=184.0-185.1℃;1H NMR(400MHz,DMSO-d6)δ11.18(s,1H,CONH-H),8.23(d,J=8.1Hz,2H,Ph-H),8.01(d,J=8.2Hz,2H,Ph-H),7.15(t,J=53.0Hz,1H,CHF2),3.83(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ165.0,145.0(t,J=27.6Hz),141.2,136.1,132.5(q,J=32.0Hz),129.1(2C),125.8(2C),123.8(q,J=272.6Hz),110.9(t,J=233.7Hz),110.7,92.5,37.3;HRMS(ESI)m/z[M+Na]+:calcd forC14H9F5N4NaOS,399.0309,found,399.0318.
实施例45
化合物I-43的制备,化合物I-43的化学式如下:
本实施例中化合物I-43的制备方法具体如下:采用实施例39中所述方法,将邻氯苯甲酰氯替换为邻三氟甲氧基苯甲酰氯,其他步骤与实施例39中相同。所得化合物I-43为淡黄色固体(251.1mg,收率64%),m.p.=137.6–138.4℃;1H NMR(400MHz,DMSO-d6)δ11.24(s,1H,CONH-H),7.86(d,J=7.5Hz,1H,Ph-H),7.75(t,J=7.8Hz,1H,Ph-H),7.61(m,2H,Ph-H),7.15(t,J=53.0Hz,1H,CHF2),3.83(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.2,145.1(t,J=27.7Hz),145.0,140.9,133.1,130.1,128.9,128.0,122.1,120.1(q,J=257.5Hz),110.9(t,J=233.8Hz),110.7,92.2,37.2.
实施例46
化合物I-44的制备,化合物I-44的化学式如下:
本实施例中化合物I-44的制备方法具体如下:采用实施例39中所述方法,将邻氯苯甲酰氯替换为间三氟甲氧基苯甲酰氯,其他步骤与实施例39中相同。所得化合物I-44为淡黄色固体(282.5mg,收率72%),m.p.=150.6–151.6℃;1H NMR(400MHz,DMSO-d6)δ11.10(s,1H,CONH-H),8.09(d,J=7.4Hz,1H,Ph-H),7.97(s,1H,Ph-H),7.77(t,J=7.9Hz,1H,Ph-H),7.73(d,J=8.3Hz,1H,Ph-H),7.15(t,J=53.0Hz,1H,CHF2),3.83(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.6,148.5,145.0(t,J=27.6Hz),141.2,134.5,131.2,127.3,125.4,120.1(q,J=257.3Hz),120.7,110.9(t,J=233.7Hz),110.8,92.6,37.3;HRMS(ESI)m/z[M+Na]+:calcd for C14H9F5N4NaO2S,415.0259,found,415.0262.
实施例47
化合物I-45的制备,化合物I-45的化学式如下:
本实施例中化合物I-45的制备方法具体如下:采用实施例39中所述方法,将邻氯苯甲酰氯替换为对三氟甲氧基苯甲酰氯,其他步骤与实施例39中相同。所得化合物I-45为淡黄色固体(372.7mg,收率95%),m.p.=135.8–136.9℃;1H NMR(400MHz,DMSO-d6)δ11.05(s,1H,CONH-H),8.17(d,J=8.5Hz,2H,Ph-H),7.62(d,J=8.4Hz,2H,Ph-H),7.14(t,J=53.0Hz,1H,CHF2),3.82(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.9,151.4,145.0(t,J=27.7Hz),141.4,131.4,130.7(2C),121.1(2C),120.0(q,J=257.6Hz),111.0(t,J=233.7Hz),110.8,92.5,37.3;HRMS(ESI)m/z[M+Na]+:calcd for C14H9F5N4NaO2S,415.0259,found,415.0264.
实施例48
化合物I-46的制备,化合物I-46的化学式如下:
本实施例中化合物I-46的制备方法具体如下:采用实施例39中所述方法,将邻氯苯甲酰氯替换为3,4-二氯苯甲酰氯,其他步骤与实施例39中相同。所得化合物I-46为淡黄色固体(271.6mg,收率72%),m.p.=182.6–184.2℃;400MHz,DMSO-d6)δ11.13(s,1H,CONH-H),8.27(d,J=2.0Hz,1H,Ph-H),7.99(dd,J=8.4,2.0Hz,1H,Ph-H),7.90(d,J=8.4Hz,1H,Ph-H),7.14(t,J=53.0Hz,1H,CHF2),3.82(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.0,145.0(t,J=27.7Hz),141.2,135.7,132.6,131.7,131.2,130.1,128.4,110.9(t,J=233.8Hz)110.7,92.4,37.3.
实施例49
化合物I-47的制备,化合物I-47的化学式如下:
本实施例中化合物I-47的制备方法具体如下:采用实施例39中所述方法,将邻氯苯甲酰氯替换为3,5-二氯苯甲酰氯,其他步骤与实施例39中相同。所得化合物I-47为淡黄色固体(256.5mg,收率68%),m.p.=151.6–154.1℃;H NMR(400MHz,DMSO-d6)δ11.17(s,1H,CONH-H),8.03(d,J=1.8Hz,2H,Ph-H),7.99(t,J=1.9Hz,1H,Ph-H),7.14(t,J=53.0Hz,1H,CHF2),3.83(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ163.6,145.0(t,J=27.7Hz),141.0,135.6,134.7(2C),132.1,127.0(2C),110.9(t,J=233.8Hz),110.8,92.4,37.3.
实施例50
化合物I-48的制备,化合物I-48的化学式如下:
本实施例中化合物I-48的制备方法具体如下:采用实施例39中所述方法,将邻氯苯甲酰氯替换为3-三氟甲基-4-氯苯甲酰氯,其他步骤与实施例39中相同。所得化合物I-48为淡黄色固体(308.0mg,收率75%),m.p.=137.1–139.9℃;1H NMR(400MHz,DMSO-d6)δ11.25(s,1H,CONH-H),8.46(s,1H,Ph-H),8.31(dd,J=8.4,1.6Hz,2H,Ph-H),8.01(d,J=8.4Hz,1H,Ph-H),7.14(t,J=53.0Hz,1H,CHF2),3.83(s,3H,NCH3);13C NMR(101MHz,DMSO-d6)δ164.0,145.0(t,J=27.7Hz),141.1,135.2,133.8,132.4,131.7,127.5(q,J=5.2Hz),127.0(d,J=31.5Hz),122.6(d,J=273.3Hz),110.9(t,J=233.8Hz),110.7,92.5,37.3.
实施例51
化合物I-49的制备,化合物I-49的化学式如下:
本实施例中化合物I-49的制备方法具体如下:将含硫氰基-5-吡唑胺类化合物(R1=甲基)(168.2mg,1mmol)与三乙胺(0.55mL)溶于无水二氯甲烷(2mL),随后于冰浴下缓慢滴加对三氟甲基苯甲酰氯。冰浴下反应30分钟后移至室温,继续在室温下反应3小时左右,TLC监测直至含硫氰基-5-吡唑胺(III)反应完全。乙酸乙酯萃取(3×10mL),合并有机相并用饱和食盐水洗涤,最后用无水硫酸镁干燥,过滤,减压旋干溶剂得粗产物。硅胶柱层析(石油醚/乙酸乙酯=2:1)纯化得淡黄色固体化合物I-49(238.2mg,收率70%),m.p.=187.0–189.6℃;1H NMR(400MHz,DMSO-d6)δ10.98(s,1H,CONH-H),8.22(d,J=8.1Hz,2H,Ph-H),7.99(d,J=8.1Hz,2H,Ph-H),3.70(s,3H,NCH3),2.29(s,3H,CH3);13C NMR(101MHz,DMSO-d6)δ164.8,149.1,139.3,136.3,132.3(q,J=31.9Hz),130.1,129.0(2C),125.8(q,J=3.6Hz),123.8(q,J=272.6Hz),111.2,91.7,36.4,12.1.
实施例52
化合物I-50的制备,化合物I-50的化学式如下:
本实施例中化合物I-50的制备方法具体如下:采用实施例51中所述方法,将对三氟甲基苯甲酰氯替换为3,5-二氯苯甲酰氯,其他步骤与实施例51中相同。所得化合物I-50为淡黄色固体(242.3mg,收率71%),m.p.=212.4–214.8℃;1H NMR(400MHz,DMSO-d6)δ10.95(s,1H,CONH-H),8.02(s,2H,Ph-H),7.97(s,1H,Ph-H),3.69(s,3H,NCH3),2.28(s,3H,CH3);13C NMR(101MHz,DMSO-d6)δ163.4,149.1,139.0,135.7,134.6(2C),132.0,126.9(2C),111.2,91.6,36.5,12.1.
实施例53
化合物I-51的制备,化合物I-51的化学式如下:
本实施例中化合物I-51的制备方法具体如下:采用实施例51中所述方法,将对三氟甲基苯甲酰氯替换为3-三氟甲基-4-氯苯甲酰氯,其他步骤与实施例51中相同。所得化合物I-51为淡黄色固体(236.1mg,收率63%),m.p.=188.8–191.1℃;1H NMR(400MHz,DMSO-d6)δ11.04(s,1H,CONH-H),8.44(s,1H,Ph-H),8.30(d,J=8.3Hz,1H,Ph-H),7.99(d,J=8.4Hz,1H,Ph-H),3.70(s,3H,NCH3),2.28(s,3H,CH3);13CNMR(101MHz,DMSO-d6)δ163.7,149.1,139.1,135.0,133.7,132.3,131.8,127.4(q,J=5.3Hz),127.0(q,J=31.3Hz),122.6(q,J=273.3Hz),111.2,91.6,36.4,12.1.
实施例54
实施例1–53中合成的含硫氰基吡唑结构的苯甲酰胺类衍生物(化合物编号I-1到I-51)对供试植物病原真菌和卵菌的抑制作用。
1.实验对象
实施例I-1到I-51合成的含硫氰基吡唑结构的苯甲酰胺类衍生物
2.实验方法
采用菌丝线性生长速率法,测定了化合物1–51在20mg/L浓度下对供试植物病原真菌和卵菌的体外抑制活性。所选真菌与卵菌由西北农林科技大学农药学研究所提供。
以20mg/L的氟唑菌酰胺溶液为阳性对照,以5%的DMSO水溶液作为空白对照,将已准确称量的待测化合物完全溶于5%的DMSO(v/v)水溶液中,将10mL待测液或对照液与90mL无菌PDA培养基在50℃快速混匀,得到质量浓度为20mg/L的含药液;将其趁热倒入已灭菌的培养皿内,每皿10mL,冷却备用。把供试植物病原菌(菌饼直径5mm)接种到上述培养皿中,每个测试组设3个平行;将其置于25℃的恒温培养箱中培养72h后,采用十字交叉法测量菌落直径(mm),按式(1)计算菌丝生长抑制率(IR):IR(%)=[(dc-d0)-(ds-d0)]/(dc-d0)×100(1);
式中:d0为菌饼直径(5mm),dc为空白对照组菌落平均直径(mm),ds为样品组菌落平均直径(mm)。
3.实验结果如表1所示
表1实施例1~53中合成的含硫氰基吡唑结构的苯甲酰胺类衍生物的体外抑菌活性a(抑制率,%)(20mg/L)
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a表中数据为三次数据的平均值;V.m.b V.mali;B.c.c B cinerea;R.sdR.solani;S.se S.sclerotiorum;G.gf G.graminis;p.cg.P.capsica
由表1可以看出,大部分化合物对6种病菌均有抑制作用,其中以化合物I-26,I-27对油菜菌核病菌的活性最为优异,其抑制率为100%;化合物I-7,I-10对苹果腐烂病菌的活性最为优异,其抑制率高达100%;化合物I-48对小麦全蚀病菌的活性最为优异,其抑制率为85.14%;化合物I-26对水稻纹枯病菌的活性最为优异,其抑制率达到90.01%;化合物I-42,I-49对辣椒疫霉病菌的活性最为优异,其抑制率为100%;化合物I-7对葡萄灰霉病菌的活性最佳,抑制率为95.65%。
综合上述,本申请经化学合成制备的51种含硫氰基吡唑酰胺类化合物均具有显著的抗真菌及抗卵菌活性,尤其对于苹果腐烂病菌和辣椒疫霉病菌表现出突出的抑制活性,这为开发以含硫氰基吡唑结构的苯甲酰胺类衍生物为活性成分的新型杀菌剂提供了基础。
以上说明书中描述的只是本发明的具体实施方式,各种举例说明不对本发明的实质内容构成限制,所属技术领域的普通技术人员在阅读了说明书后可以对以前所述的具体实施方式做修改或变形,而不背离发明的实质和范围。
Claims (5)
1.一种含硫氰基吡唑结构的苯甲酰胺类衍生物,其特征在于,其结构通式(I)如下:
其中,R1为三氟甲基、二氟甲基或甲基;R2为不同位置取代的氢、甲基、甲氧基、三氟甲基、三氟甲氧基、氟、氯、溴、氰基或其多取代组合。
2.根据权利要求1所述的含硫氰基吡唑结构的苯甲酰胺类衍生物,其特征在于:所述含硫氰基吡唑结构的苯甲酰胺类衍生物优选如下化合物:
3.一种如权利要求1~2任一项所述的含硫氰基吡唑结构的苯甲酰胺类衍生物的制备方法,其特征在于:所述制备方法包括如下合成路线:
4.根据权利要求3所述的含硫氰基吡唑结构的苯甲酰胺类衍生物的制备方法,其特征在于:所述制备方法具体包括如下步骤:
步骤S1、以5-吡唑胺(II)为原料,乙醇/水作为溶剂,加入硫氰酸铵和过硫酸铵,室温下搅拌反应,生成4-硫氰基-5-吡唑胺(III),所得产物经柱层析或重结晶提纯得到纯品;
步骤S2、以4-硫氰基-5-吡唑胺(III)为原料,与苯甲酸或苯甲酰氯(IV)发生缩合反应获得通式(I)对应的含硫氰基吡唑结构的苯甲酰胺类衍生物,所得产物经柱层析分离得到纯品。
5.一种如权利要求1~2任一项所述的含硫氰基吡唑结构的苯甲酰胺类衍生物的应用,其特征在于:将所述含硫氰基吡唑结构的苯甲酰胺类衍生物应用于农用杀菌剂。
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