1_取代苯基_1_4_二氢_6__省略__3_酰肼衍生物的合成及生物活性_邹霞娟

有机化学

Chinese J ournal of Organic Chemistry

Vol.23,2003

No.1,62~65

#研究论文#

1-取代苯基-1,4-二氢-6-甲基-4-哒嗪酮-3-酰肼衍生物的合成及生物活性

邹霞娟金桂玉X

(南开大学元素有机化学研究所元素有机化学国家重点实验室天津300071)

摘要以1-取代苯基-3-羰基肼-1,4-二氢-6-甲基-4-哒嗪酮为原料,进行衍生化,合成了哒嗪酮的酰腙、酰氨基取代脲、N-乙氧基羰基羰基肼、N-氯乙酰基羰基肼等五类新型化合物,并研究其生物活性.初步生物活性测试表明目标化合物对烟草花叶病毒(TMV)、水稻纹枯病(Pellicula ria sasakii)和小麦锈病(Puccinia recondita tritici)具有一定的抑制作用.其结构经元素分析、红外光谱及1H NMR确证.

关键词哒嗪酮,酰肼,合成,生物活性

Hydrazine Derivatives of1-Ary-l1,4-dihydro-3-carboxy-6-methy-l4-pyridazone.

Synthesis and Biological Activity

ZOU,Xia-Juan JI N,Gu-i Yu X

(Institute of Elemento-Organic Chemistry,National Key Labor a tory o f Elemento-Organic Chemistry,Nankai University,T ian j in300071)

Abstract Five series of new hydrazine derivatives of1-ary-l1,4-dihydro-3-carboxy-6-methy-l4-pyridazones have been synthesized and characterized by spectral and ele mental analyses.Some of the compounds showed significant inhibition against TMV,Pellicularia sasakii and Puccinia recondita tritici.

Keywords pyridazinone,hydrazine,synthesis,bioactivity

植物病毒对寄主植物的危害,素有/植物癌症0之称.病毒侵染寄主后不仅与寄主争夺植物生长所必需的营养成份,并且破坏植物的养分输导,改变寄主植物的某些代谢平衡及一些酶的活性,植物的光合作用受到抑制,致使植物生长困难,产生畸型、黄化等症状,严重的还造成寄主植物死亡,导致作物减产和品质下降.如何控制、减轻或消灭植物病毒的危害,向人类提出了新的挑战[1].哒嗪酮类杂环化合物具有广泛的生物活性,在农药、医药研究中有着重要的应用[2,3].在我们的研究中发现,1-(取代)苯基-1,4-二氢-6-甲基-4-哒嗪酮-3-酰肼[4]和1-(取代)苯基-1,4-二氢-6-甲基-4-哒嗪酮-3-酰氨基硫脲[5]对烟草花叶病毒具有较好的抑制作用.另外,酰腙类化合物具有杀菌活性[6~8].为进一步寻找具有开发潜力的先导化合物,本工作以1-(取代)苯基-1,4-二氢-3-羰基肼-6-甲基-4-哒嗪酮为原料,进行衍生化,合成了哒嗪酮的酰腙、酰氨基取代脲、N-乙氧基羰基羰基肼、N-氯乙酰基羰基肼等五类新型化合物,并研究其生物活性.生物活性表明目标化合物对烟草花叶病毒(TMV)、水稻纹枯病(Pellicularia sasakii)和小麦锈病(Puccinia recondita tritici)具有一定的抑制作用.合成路线如Sc heme1所示.

1实验部分

1.1仪器与试剂

JEOL FX-90Q核磁共振仪(90MHz,TMS);MT-3型元素分析仪;Shimadzu IR-435型红外光谱仪,KBr压片;Yanaco熔点仪,温度计未校正;实验用的试剂均为分析纯或化学纯试剂.

1.2中间体的合成

中间体1的制备按文献[2,5]方法.

1.3目标化合物的合成

1.3.11-(取代)苯基-1,4-二氢-6-甲基-4-哒嗪酮-3-酰腙的合成

将1mmol的1-(取代)苯基-1,4-二氢-6-甲基-4-哒嗪酮-3-酰肼(1)溶于30mL的乙醇中,加入1mmol的芳醛,加热回

X E-mail:jinjie@public.tpt.tj.cn

Received M arch26,2002;revi sed May31,2002;accepted Jul y10,2002.

国家自然科学基金(No.29832050)重点资助项目.Scheme1

流4~6h(TLC跟踪反应进程),放置冷却,将析出的固体物用乙醇重结晶,其物理常数、收率及分析数据如下: 2a(R1=o-Cl,R2=o-OC H3):产率78%,m.p.263~2 e;1H N MR(CDCl3+DMSO-d6,90MHz)D:2120(s,3H, CH3),3188(s,3H,CH3),6180(s,1H,Pyridazinone), 6180~8110(m,8H,2C6H4),8172(s,1H,CH),12180 (bs,1H,NH).Anal.calcd for C20H17N4O3Cl:C60153,H 4129,N14112;fo und C60134,H4114,N14102.

2b(R1=o-Cl,R2=p-OH):产率86%,m.p.>300e; 1H NMR(DMSO-d

6

,90MHz)D:2120(s,3H,CH3),6180~ 8100(m,9H,2C6H4,pyridazinone),8140(s,1H,C H), 8H,12180(bs,1H,N H);IR(KBr)M C O:1695,1609c m-1. Anal.calcd for C19H15N4O3Cl:C59161,H3192,N141;found C59157,H3163,N14143.

2c(R1=o-Cl,R2=m-NO2):产率80%,m.p.254~256 e;1H N MR(CD Cl3+D MSO-d6,90MHz)D:2120(s,3H, CH3),6180(s,1H,pyridazinone),7152~8140(m,8H, 2C6H4),8172(s,1H,C H),13152(bs,1H,N H);IR (KBr)M C O:1695,1659c m-1.Anal.calc d fo r C19H14N5O4Cl: C55141,H3140,N17101;found C55129,H3141,N17134.

2d(R1=o-Cl,R2=p-CH3):产率75%,m.p.241~243 e;1H NMR(DMSO-d6,90MHz)D:2110(s,3H,CH3), 2120(s,3H,CH3),6180(s,1H,pyridazinone),7120~8104 (m,8H,2C6H4),8148(s,1H,CH),12180(bs,1H, NH);I R(KBr)M C O:1695,1613cm-1.Anal.calcd for C20H17N4O2Cl:C63107,H4147,N14172;found C63108,H

63

No.1邹霞娟等:1-取代苯基-1,4-二氢-6-甲基-4-哒嗪酮-3-酰肼衍生物的合成及生物活性

4147,N14173.

2e(R1=H,R2=p-C H3):产率87%,m.p.248~250e; 1H N MR(DMSO-d

6

,90MHz)D:2120(s,3H,CH3),2140 (s,3H,CH3),6180(s,1H,pyridazinone),61~8104(m, 9H,C6H5,C6H4),8148(s,1H,C H),12180(bs,1H, NH).Anal.calc d fo r C20H18N4O2:C69136,H5120,N16118; found C69129,H5105,N15193.

2f(R1=2,6-Cl2,R2=p-C H3):产率96%,m.p.288~ 2e;1H NMR(D MSO-d6,90MHz)D:2120(s,3H,CH3), 2140(s,3H,CH3),6180(s,1H,pyridazinone),7120~8104 (m,7H,C6H3,C6H4),8140(s,1H,CH),13120(bs,1H, NH).Anal.calc d fo r C20H16N4O2Cl2:C57183,H3185,1H,N 13149;found C57163,H3162,N13127.

1.3.21-(取代)苯基-1,4-二氢-6-甲基-4-哒嗪酮-3-酰氨基取代脲的制备

将1mmol的1-(取代)苯基-1,4-二氢-6-甲基-4-哒嗪酮-3-酰肼(1)溶于30mL无水乙醇中,加入1mmol的异氰酸酯,加热回流4~6h(TLC跟踪反应过程),放置冷却,将析出的固体用乙醇重结晶,其物理常数、收率及分析数据如下: 3a(R1=p-Cl,R2=(C H2)3CH3):产率85%,m.p. 237~238e;1H NMR(D MSO-d6,90MHz)D:0192(t,J= 712Hz,3H,CH3),1140~1.46(m,4H,2C H2),2120(s, 3H,CH3),3112(t,J=710Hz,2H,CH2),6180(s,1H, pyridazinone),7160(s,4H,C6H4),8110(s,1H,NH),11162 (bs,2H,N H);IR(KBr)M C O:1697,1659,1613c m-1. Anal.calcd for C17H20N5O3Cl:C54105,H5132,N18154; found C54106,H5114,N18142.

3b(R1=p-Cl,R2=p-CH3Ph):产率85%,m.p.278~ 279e;1H NMR(D MSO-d6,90MHz)D:2120(s,3H,CH3), 2152(s,3H,CH3),6180(s,1H,pyridazinone),6188~7160 (m,8H,2C6H4),8168(bs,1H,NH),11180(bs,1H,NH). Anal.calcd for C20H18N5O3Cl:C58132,H4137,N17101; found C58108,H4136,N16196.

3c(R1=p-Cl,R2=p-OC H3Ph):产率83%,m.p.274~ 275e;1H NMR(D MSO-d6,90MHz)D:2120(s,3H,CH3), 3178(s,3H,C H3),6180~7178(m,9H,2C6H4,pyrida-zinone),8148(bs,1H,NH),81(bs,1H,N H),11136(bs, 1H,NH).Anal.c alcd for C20H18N5O4Cl:C56112,H4121,N 15144;found C56115,H4137,N15151.

3d(R1=p-Cl,R2=p-FPh):产率83%,m.p.226~228 e;1H NMR(DMSO-d6,90MHz)D:2120(s,3H,CH3), 6180(s,1H,pyridazinone),6188~7180(m,8H,2C6H4), 8160(bs,NH),9100(bs,N H).Anal.calcd for C19H15-N5O3ClF:C54186,H3161,N16191,found C54178,H3158, N16170.

1.3.31-(4-氯代苯基)-1,4-二氢-3-氯乙羰基肼羰基-6-甲基-4-哒嗪酮(4a)的制备

将1mmol的1-对氯代苯基-1,4-二氢-6-甲基-4-哒嗪酮-3-酰肼溶于30mL二氯甲烷,加入0.3mL三乙胺,在冰水浴中慢慢地滴加0112g氯乙酰氯的3mL二氯甲烷溶液.室温搅拌,9h后反应完全.加入3mL水,继续搅拌1h,萃取出有机层,干燥,减压脱溶,固体物用DMF/乙醇重结晶,得目标产物4a,产率85%,m.p.241~242e;1H N MR(D MSO-d6, 90MHz)D:2120(s,3H,C H3),4120(s,2H,CH2),6180 (s,1H,pyridazinone),7172~7174(m,4H,C6H4),11136 (bs,NH),12120(bs,NH);IR(KBr)M C O:1708,12, 1617c m-1.Anal.calcd for C14H12N4O3Cl2:C47132,H3138,N 15184;found C47138,H3140,N15169.

用同样的方法合成了化合物4b~4c,其物理常数、收率及分析数据如下:

4b(R1=2,4-Cl2):产率77%,m.p.227~229e;1H NMR(CDCl3+D MSO-d6)D:2120(s,3H,CH3),4120(s, 2H,CH2),6196(s,1H,pyridazinone),7165~7170(m,3H, C6H3);I R(KBr)M C O:1721,1671,1612c m-1.Anal.calcd for C14H11N4O3Cl3:C43114,H2182,N14144;found C43112, H2170,N14122.

4c(R1=o-Cl):产率83%,m.p.246~247e;1H NMR (DMSO-d6)D: 2.20(s,3H,CH3),4120(s,2H,CH2),6180 (s,1H,pyridazinone),7172~7180(m,4H,C6H4),11136 (bs,NH);I R(KBr)M C O:1710,1668,1617c m-1.Anal. ca lcd for C14H12N4O3Cl2:C47132,H3138,N15184;fo und C 47140,H3135,N15160.

4d(R1=2,4,5-Cl3):产率81%,m.p.265~266e;1H NMR(D MSO-d6)D:2120(s,3H,CH3),4120(s,2H,CH2), 6196(s,1H,pyridazinone),8136(d,J=0.6Hz,2H,C6H2), 10175(bs,NH).Anal.calc d for C14H10N4O3Cl4:C39163,H 2136,N13126;found C39167,H2133,N13110.

1.3.41-(2-氯代苯基)-1,4-二氢-3-乙氧基羰基肼羰基-6-甲基-4-哒嗪酮(5)的制备

将0.4g1-(2-氯代苯基)-1,4-二氢-6-甲基-4-哒嗪酮-3-酰肼溶于40mL二氯甲烷中,加入0.3mL三乙胺,在冰盐浴中,慢慢地滴加含0.16g氯甲酸乙酯的4mL二氯甲烷溶液.撤去冰盐浴,室温下反应24h,加入4mL水,继续搅拌21h,萃取出有机层,浓缩溶剂.用减压柱层析分离得到产物5[洗脱剂:石油醚(沸程60~90e)B乙酸乙酯=3B1,V B V].产率50%,m.p.182~183e;1H NMR(CD Cl3)D:1125(t,J= 712Hz,3H,CH3),2120(s,3H,CH3),4120(q,J=712Hz, 2H,CH2),6180(s,1H,pyridazinone),7104~7168(m,4H, C6H4),10120(bs,NH).Anal.calcd for C15H15N4O4Cl:C 51134,H4127,N16103;found C51115,H4100,N15175.

1.3.51-(2,6-二氯代苯基)-1,4-二氢-3-(N c,N c-二乙氧基羰基)肼羰基-6-甲基-4-哒嗪酮(6a)的制备将0.4g1-(2,6-二氯代苯基)-1,4-二氢-6-甲基-4-哒嗪酮-3-酰肼溶于40mL二氯甲烷中,加入013mL三乙胺,在冰盐水浴中,慢慢地滴加含0116g氯甲酸乙酯的4mL二氯甲烷溶液.撤去冰盐浴,室温下反应24h,加入4mL水,继续搅

有机化学Vol.23,2003拌1h,萃取出有机层,浓缩溶剂.用减压柱层析分离得到纯品6a[洗脱剂:石油醚(沸程60~90e)B乙酸乙酯=1B3, V B V].产率45%,m.p.170~171e;1H NMR(CDCl3)D: 1130(t,J=712Hz,6H,2CH3),2118(s,3H,CH3),4127 (q,J=712Hz,4H,2CH2),6180(s,1H,pyridazinone),7156 (s,4H,C6H4),11197(s,1H,N H).Anal.calcd fo r C18H18-N4O6Cl2:C47127,H3194,N12130;found C47118,H3190, N12128.

用同样的方法合成了化合物(6b),产率45%,m.p. 170~171e;1H N MR(CDCl3)D:1136(t,J=712Hz,6H, 2CH3),2120(s,3H,CH3),4120(q,J=712Hz,4H, 2CH2),6180(s,1H,pyridazinone),7180(s,3H,C6H3), 12110(s,1H,N H);IR(KBr)M C O:1771,1746,1704,1626 c m-1.Anal.calc d fo r C18H18N4O6Cl2:C47127,H3194,N 12130;found C47118,H3190,N12128.

2结果与讨论

2.1合成

化合物1与芳醛、异氰酸酯及氯乙酰氯的反应不受R1, R2取代基的影响,均能顺利进行.化合物1与氯甲酸乙酯按1B1的摩尔比反应时,当R1=o-Cl时,生成化合物5;当R1= 2,6-Cl2时,生成化合物6b,并且产率较低,在反应过程中,用TCL跟踪反应,发现原料没有反应完全,经柱层析分离后,得目标产物及化合物1.将化合物1与氯甲酸乙酯按1B2的摩尔比反应时,当R1=o-Cl时,生成一取代产物5和二取代产物6a,并且在反应过程中,用TCL跟踪反应,即使延长反应时间,发现原料没有反应完全;当R1=2,6-Cl2时,主要生成二取代产物6b,用TCL跟踪反应,即使延长反应时间,发现原料也没有反应完全.这说明该反应受取代基及反应物的影响,化合物1与氯甲酸乙酯反应时,先生成一取代产物,同时也有二取代产物生成.

2.2化合物的结构与图谱解析

此五类化合物的1H NMR特征:芳香环的化学位移在D 6.~8.40,哒嗪酮环上的甲基的化学位移为D2.20,环上的氢为D6.96或6.80.

2.3生物活性

采用半叶法测定了目标化合物对烟草花叶病毒(TMV)的抑制活性.取新鲜具有典型TMV病毒症状的珊西病叶,加入磷酸缓冲溶液(0.01mol/L,p H=7.2),在研钵中研碎,在撒有金钢砂的珊西烟叶片上接种,并用清水快速冲洗.接种1.2~2h后,将接种叶片主脉剪成两个相等半叶,一半叶片用不同化合物水溶液浸叶处理,另一半浸于清水中作对照. 72h后,统计半叶枯斑数,质量浓度为500L g/mL,测试数据列于表1中.酰腙类化合物2a~2f对烟草花叶病毒具有一定的抑制作用,尤其是化合物2a,其抑制率为60%,生物活性超过已商品化的V A(抑制率为50%).

采用水稻半叶法对化合物2a~2f进行水稻纹枯病(P.s)的生物活性测定,质量浓度为500L g/mL,其测试数据列于表3中.酰腙类化合物2a~2f对水稻纹枯病具有较高的抑制作用,尤其是化合物2b和2c,它们的抑制率分别为12%和9113%.

采用植株法对部分目标化合物进行小麦锈病(P.r.t)的生物活性测定,质量浓度为500L g/mL,其测试数据列于表3中.化合物5和6对小麦锈病具有较好的抑制作用,它们的抑制率分别为80%和70%.

表1新化合物对植物病毒和菌类的百分抑制率(%,500L g/m L)

Table1Inhibition percen tage(%)of the new compounds against phytoviral and fungi(500L g/mL)

Compd.2a2b2c2d2e2f3a3b3c3d4a4b4c4d56 TMV60450404001502822350036

P.s70.4.291.369.861.744.6

P.r.t207.1303010108070

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54A novel catalytic system Co(OAc)2/CCl3COOH/K2S2O8was developed for direct carboxyla-tion of benzene to benzoic acid with more than20%yield.

A Study on the Imm obilization of Polyphenol Oxidase w ith Sodium Alginate and Its Application in Conversion of Pyrogallol

YU,Jiang-Ping;GUO,Gang-Jun;XIAO,Yun-Peng;LIU,Xing-Kuan;GU,Lian-Quan X Chin.J.Org.Chem.2003,23(1),

57Conditions for immobilization of polyphenol ox idase from potato wi th sodium alginate and glu-taric dialdehyde and the nature of the immobilized enzyme(IPPO)were studied.The IPPO was used for transforming pyrogallol in to purpurogallin in aqueous phase.

Hydrazine Derivatives of1-Ary-l1,4-dihydro-

3-carboxy-6-methy-l4-pyridazone.Synthesis and Biological Activity

ZOU,Xia-Juan;JIN,Gu-i Yu X

Chin.J.Org.Chem.2003,23(1),

62Five series of new hydrazi ne derivatives of1-ary-l1,4-dihyd ro-3-carboxy-6-methy-l4-pyrida-zones have been synthesized and characterized by spectral and elemental analyses.Some of the compounds showed si gni ficant inhibition against TMV,Pellicularia sasa kii and Puccinia recon dita tritici.

Synthesis of the Galactoglycerolipids I.the

Synthesis of1,2-D-i O-acy-l3-O-(A-D-Galac-topyranosyl)-sn-glycerols

LI,Chun-Xia;LI,Ying-Xia X;YU,Ling-Bo; CHU,Sh-i Dong;GUAN,Hua-Shi

Chin.J.Org.Chem.2003,23(1),

66Five1,2-d-i O-acy-l3-O-(A-D-galactopyranosyl)-sn-glycerols with different acyl group were synthesized through five steps.The route of reaction included allylation of D-galactose,pro-tection of hydroxy group,oxidation of1-O-allyl,acylation with various acyl chlorides and hy-drogenolytic deprotection.The acyl groups were lauroyl,myristoyl,palmitoyl,stearoyl and hexanoyl,respecti vely.

23(1)Chinese Jou r na l o f Organ ic Chemistry

2003