CN115160159B - 一种Halichonine B类似物及其制备方法和在制备农用杀菌剂中的应用 - Google Patents

一种Halichonine B类似物及其制备方法和在制备农用杀菌剂中的应用 Download PDF

Info

Publication number
CN115160159B
CN115160159B CN202210274285.2A CN202210274285A CN115160159B CN 115160159 B CN115160159 B CN 115160159B CN 202210274285 A CN202210274285 A CN 202210274285A CN 115160159 B CN115160159 B CN 115160159B
Authority
CN
China
Prior art keywords
halichonin
germ
formula
analogue
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202210274285.2A
Other languages
English (en)
Other versions
CN115160159A (zh
Inventor
李圣坤
胡女丹
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guizhou University
Original Assignee
Guizhou University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guizhou University filed Critical Guizhou University
Priority to CN202210274285.2A priority Critical patent/CN115160159B/zh
Publication of CN115160159A publication Critical patent/CN115160159A/zh
Application granted granted Critical
Publication of CN115160159B publication Critical patent/CN115160159B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • 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
    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
    • A01N33/02—Amines; Quaternary ammonium compounds
    • A01N33/08—Amines; Quaternary ammonium compounds containing oxygen or sulfur
    • 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
    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
    • A01N33/16—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds containing nitrogen-to-oxygen bonds
    • A01N33/18—Nitro compounds
    • 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
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/34—Nitriles
    • 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
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
    • 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
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/12—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing a —O—CO—N< group, or a thio analogue thereof, neither directly attached to a ring nor the nitrogen atom being a member of a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
    • C07C2602/28—Hydrogenated naphthalenes
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Dentistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Plant Pathology (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明提供了一种Halichonine B类似物及其制备方法和在制备农用杀菌剂中的应用，属于农药技术领域。本发明提供的Halichonine B类似物对水稻纹枯病菌、小麦纹枯病菌、油菜菌核病菌、小麦赤霉病菌、小麦全蚀病菌、番茄灰霉病菌、马铃薯晚疫病菌、辣椒疫霉病菌、番茄早疫病菌、水稻恶苗病菌、马铃薯干腐病菌、黄瓜炭疽病菌、水稻稻瘟病菌等多种植物病原真菌均具有抑菌活性。

Description

一种Halichonine B类似物及其制备方法和在制备农用杀菌 剂中的应用
技术领域
本发明涉及农药技术领域，尤其涉及一种Halichonine B类似物及其制备方法和在制备农用杀菌剂中的应用。
背景技术
天然产物是药物先导结构的重要来源，以天然产物为模版开展优化研究，是实现农药绿色化的重要途径。随着基础科学、高新技术和有机合成化学的发展，人们对于绿色农药与生态环境的重视，天然产物作为农药活性分子先导化合物的可能性将进一步扩大。
Drimane倍半萜是一类重要的天然产物，在自然界分布广泛，且具有广泛的生物活性(Jansen B J M,Groot A D.Occurrence,biological activity and synthesis ofdrimane sesquiterpenoids[J].Cheminform,2004,21(4):449.)。倍半萜生物碱Halicholine B分离于海洋生物Halichondria okadai Kadota，对人类白血病细胞HL 60具有强的细胞毒作用(IC50＝0.60μg·mL-1)(Ohno O,Chiba T,Todoroki S,etal.Halichonines A,B,and C,novel sesquiterpene alkaloids from the marinesponge Halichondria okadai Kadota.[J].Chemical Communications,2011,47(46):12453.)。
Figure BDA0003555231010000011
发明人一直致力于Drimane类倍半萜及其衍生物作为先导化合物的农药分子设计和优化研究，前期发现含氮的手性补身烷并噁嗪酮类化合物具有较好的抑菌活性(Li D,Zhang S,Song,Z,et al.Synthesis and bio-inspired optimization of drimenal:Discovery of chiral drimane fused oxazinones as promising antifungal andantibacterial candidates[J].European Journal of Medicinal Chemistry,2018,143:558.)，Halichonine B结构中具有与含氮的手性补身烷并噁嗪酮类化合物相同的Drimanylamine骨架，且Halicholine B的十氢萘双环结构与已商品化的内吸性杀菌剂十三吗啉和环十二吗啉长链部分相似，Halichonine B中Drimanylamine经双烷基化后与十三吗啉及环十二吗啉结构相似，因此，对Halicholine B类似物进行分子优化设计，很必要且有重要的前景。
发明内容
本发明的目的在于提供一种Halichonine B类似物及其制备方法和在制备农用杀菌剂中的应用，本发明提供的Halichonine B类似物对多种植物病原真菌具有良好的抑菌活性。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了一种Halichonine B类似物，具有式1所示结构：
Figure BDA0003555231010000021
所述式1中，R为苄基、取代苄基、脂肪烃基、卤素取代脂肪烃基、氨取代脂肪烃基、杂环亚甲基或稠环亚甲基。
优选的，所述取代苄基中的取代基为卤素、甲氧基、乙氧基、甲基、硝基、三氟甲基、丁基、异丙基、氯甲基、溴甲基、苯氧基、苄氧基、4-吡啶基、2-吡啶基和叔丁氧基中的一种或多种。
优选的，所述取代苄基为
Figure BDA0003555231010000031
优选的，所述脂肪烃基为
Figure BDA0003555231010000032
所述卤素取代脂肪烃基包括卤素取代的C1～C10脂肪烃基。
优选的，所述杂环亚甲基中的杂环为喹啉、吲哚、噻吩、呋喃、吡啶或吡啶并吡咯。
优选的，所述杂环亚甲基为：
Figure BDA0003555231010000041
优选的，所述稠环亚甲基中的稠环为萘或蒽。
本发明提供了上述方案所述Halichonine B类似物的制备方法，包括以下步骤：
将具有式2所示结构的(1S,2S)-1-(氨基甲基)-2,5,5,8a-四甲基十氢化萘-2-醇、R1CHO、还原剂和有机溶剂混合，进行还原胺化反应，得到具有式1所示结构的HalichonineB类似物；
Figure BDA0003555231010000042
所述R1CHO中，R1与式1中的R取代基减去与母核相连的CH2对应。
优选的，所述还原胺化反应的温度为0～35℃，时间为12～24小时。
本发明提供了上述方案项所述Halichonine B类似物或其农药学上可接受的盐或上述方案所述制备方法制备得到的Halichonine B类似物或其药学上可接受的盐在制备农药杀菌剂中的应用。
本发明提供了一种Halichonine B类似物，具有式1所示结构：
Figure BDA0003555231010000043
所述式1中，R为取代苄基、脂肪烃基、卤素取代脂肪烃基、杂环亚甲基或稠环亚甲基。本发明提供的Halichonine B类似物对植物病原真菌具有良好的杀菌活性。
具体实施方式
本发明提供了一种Halichonine B类似物，具有式1所示结构：
Figure BDA0003555231010000051
所述式1中，R为苄基、取代苄基、脂肪烃基、卤素取代脂肪烃基、氨取代脂肪烃基、杂环亚甲基或稠环亚甲基。
在本发明中，所述取代苄基中的取代基优选为卤素、甲氧基、乙氧基、甲基、硝基、三氟甲基、丁基、异丙基、氯甲基、溴甲基、苯氧基、苄氧基、4-吡啶基、2-吡啶基和叔丁氧基中的一种或多种，更优选为
Figure BDA0003555231010000061
在本发明中，所述脂肪烃基优选为：
Figure BDA0003555231010000062
在本发明中，所述卤素取代脂肪烃基优选包括卤素取代的C1～C10脂肪烃基，更优选为
Figure BDA0003555231010000063
在本发明中，所述氨取代脂肪烃基优选包括氨基取代的C1～C10脂肪烃基，更优选为
Figure BDA0003555231010000071
Figure BDA0003555231010000072
在本发明中，所述杂环亚甲基中的杂环优选为喹啉、吲哚、噻吩、呋喃、吡啶或吡啶并吡咯。在本发明中，所述杂环亚甲基优选为：
Figure BDA0003555231010000073
在本发明中，所述稠环亚甲基中的稠环优选为萘或蒽，更优选为
Figure BDA0003555231010000074
本发明提供了上述方案所述Halichonine B类似物的制备方法，包括以下步骤：
将具有式2所示结构的(1S,2S)-1-(氨基甲基)-2,5,5,8a-四甲基十氢化萘-2-醇、R1CHO、还原剂和有机溶剂混合，进行还原胺化反应，得到具有式1所示结构的HalichonineB类似物；
Figure BDA0003555231010000081
所述R1CHO中，R1与式1中的R取代基减去与母核相连的CH2对应。
例如，当式1中R为
Figure BDA0003555231010000082
时，则R1CHO中R1为-NH2。
在本发明中，未经特殊说明，所用原料均为本领域熟知的市售商品。
在本发明中，所述具有式2所示结构的(1S,2S)-1-(氨基甲基)-2,5,5,8a-四甲基十氢化萘-2-醇(简称胺B)的制备优选以香紫苏内脂为起始原料，首先在甲醇钠催化条件下胺解得到酰胺，然后经霍夫曼重排获得氨基甲酸酯中间体A；氨基甲酸酯中间体A经碱解获得胺B，反应的流程如式3所示：
Figure BDA0003555231010000083
在本发明中，所述具有式2所示结构的(1S,2S)-1-(氨基甲基)-2,5,5,8a-四甲基十氢化萘-2-醇(简称中间体胺B)的制备方法优选包括以下步骤：
将香紫苏内酯、甲醇钠和氨甲醇溶液混合，进行氨解，得到酰胺；
将所述酰胺、醇溶剂、碱和碘试剂混合，进行霍夫曼重排，得到氨基甲酸酯中间体A；
将所述氨基甲酸酯中间体A和碱性试剂混合，进行碱解，得到中间体胺B。
本发明优选将香紫苏内酯、甲醇钠和氨甲醇溶液混合，进行胺解，得到酰胺。
在本发明中，所述氨甲醇溶液的浓度优选为7mol/L；所述香紫苏内酯和甲醇钠的摩尔比优选为1:1；所述甲醇钠做碱。在本发明中，所述胺解的温度优选为60℃，时间优选为24小时。在本发明中，所述氨甲醇溶液中氨与香紫苏内酯的摩尔比优选为7:1。
完成所述胺解后，本发明优选还包括对反应后产物体系进行减压蒸除甲醇，硅胶柱层析分离，得到酰胺。
得到酰胺后，本发明优选将所述酰胺、醇溶剂、碱和碘试剂混合，进行霍夫曼重排，得到氨基甲酸酯中间体A。
在本发明中，所述霍夫曼重排的反应温度优选为室温；反应时间优选为3～5小时；在本发明中，所述碘试剂优选为碘苯二乙酸或二(三氟乙酸)碘苯；所述碱优选为KOH或NaOH；所述溶剂优选为甲醇。在本发明中，所述酰胺、碱和碘试剂的摩尔比优选为1:2.5:1.1；所述溶剂的用量优选为使香紫苏内酯的浓度为0.1～3mol/L。
完成所述霍夫曼重排后，本发明优选对产物体系进行减压除去醇溶剂，加入饱和氯化铵水溶液，二氯甲烷萃取，水和饱和氯化钠水溶液洗，无水硫酸钠干燥后，在减压下旋干溶剂，硅胶柱层析分离，获得氨基甲酸酯中间体A。
得到氨基甲酸酯中间体A后，本发明优选将所述氨基甲酸酯中间体A和碱混合，进行碱解，得到中间体胺B。
在本发明中，所述碱性试剂优选为二乙烯三胺、三亚乙基四胺、水合肼和戊胺中的一种或多种；在本发明中，所述氨基甲酸酯中间体A和碱的摩尔比优选为1：(4～20)；在本发明中，所述碱解的温度优选为130～140℃，时间优选为2～24小时。
完成所述碱解后，本发明优选向碱解后的体系中加入水，然后用乙酸乙酯和甲醇进行萃取，有机相用饱和氯化钠洗，无水硫酸钠干燥后，在减压下旋干溶剂，硅胶柱层析分离(200～300目；洗脱剂：EtOAc/MeOH(5:1，V/V))，获得中间体胺B。
在本发明中，所述乙酸乙酯和甲醇的体积比优选为10:1。
本发明采用3步法即可制备得到中间体胺B，相比文献报道需要7步才能合成(Barrero A F,Alvarez-Manzaneda EJ,Chahboun R,et al.New Routes Toward Drimanesand nor-Drimanes from(-)-Sclareol[J].Synlett,2000,2000(11):1561-1564.)，步骤大大简化，降低了生产成本，能够经济型合成Halichonine B类似物。
得到(1S,2S)-1-(氨基甲基)-2,5,5,8a-四甲基十氢化萘-2-醇后，本发明将(1S,2S)-1-(氨基甲基)-2,5,5,8a-四甲基十氢化萘-2-醇、R1CHO、还原剂和有机溶剂混合，进行还原胺化反应，得到具有式1所示结构的Halichonine B类似物。
在本发明中，所述(1S,2S)-1-(氨基甲基)-2,5,5,8a-四甲基十氢化萘-2-醇和R1CHO的摩尔比优选为1:1；所述还原剂优选为硼氢化钠、三乙酰氧基硼氢化钠或氰基硼氢化钠；所述有机溶剂优选为四氢呋喃、1,2-二氯乙烷、二氯甲烷或甲醇。在本发明中，所述还原剂与(1S,2S)-1-(氨基甲基)-2,5,5,8a-四甲基十氢化萘-2-醇的摩尔比优选为4:1；所述(1S,2S)-1-(氨基甲基)-2,5,5,8a-四甲基十氢化萘-2-醇与有机溶剂的用量比优选为1mmol：1mL。
本发明对所述混合的过程没有特殊要求，能够将各物料混合均匀即可。
在本发明中，所述还原胺化反应的温度优选为0～35℃，时间优选为12～24小时。在本发明中，所述还原胺化反应优选在氮气保护下进行。
在本发明中，所述还原胺化反应的方程式如式4所示：
Figure BDA0003555231010000101
本发明在所述还原胺化过程中，R1CHO中的醛基被还原为CH2。
完成所述还原胺化反应后，本发明优选还包括向反应体系中滴加NaHCO3溶液淬灭反应，二氯甲烷萃取，有机相依次用水、饱和氯化钠溶液洗，无水硫酸钠干燥，硅胶柱层析分离，得到具有式1所示结构的Halichonine B类似物。
本发明提供了上述方案所述Halichonine B类似物或其农药学上可接受的盐或上述方案所述制备方法制备得到的Halichonine B类似物或其药学上可接受的盐在制备农药杀菌剂中的应用。
本发明对所述农药杀菌剂的制备方法和剂型没有特殊要求，本领域熟知的制备方法和剂型均可。
本发明提供的Halichonine B类似物对多种植物病原真菌具有抑菌活性，所述植物病原真菌优选包括水稻纹枯病菌(Rhizoctonia solani)、小麦纹枯病菌(Rhizoctoniacerealis)、油菜菌核病菌(Sclerotinia scleotiorum)、小麦赤霉病菌(Fusariumgraminearum)、小麦全蚀病菌(Gaeumanomyce graminis)、番茄灰霉病菌(Botrytiscinerea)、马铃薯晚疫病菌(Phytophthora infestans)、辣椒疫霉病菌(Phytophthoracapsici)、番茄早疫病菌(Alternaria solani)、水稻恶苗病菌(Fusarium fujikuroi)、马铃薯干腐病菌(Fusarium sulphureum)、黄瓜炭疽病菌(Colletotrichum lagenarium)和水稻稻瘟病菌(Phyricularia cerealis)中的一种或多种。
下面结合实施例对本发明提供的Halichonine B类似物及其制备方法和在制备农用杀菌剂中的应用进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。
实施例1
(1)(1S,2S)-1-(氨基甲基)-2,5,5,8a-四甲基十氢化萘-2-醇的合成(中间体胺B)
Figure BDA0003555231010000111
称取香紫苏内脂(10g,39.9mmol)于茄形瓶中，加入7M氨甲醇溶液(40.0mL,280mmol)，室温下再加入甲醇钠(2.16g,39.9mmol)，60℃搅拌24小时，减压蒸除溶剂，硅胶柱层析分离(200～300目，MeOH/EtOAc＝1:20)，获得酰胺(白色固体，9.0g，84％)。
称取上述酰胺(5.6g,21.0mmol)于茄形瓶中，加入60mL甲醇溶液，再加入KOH(3g,52.5mmol)，冷却至0℃，加入碘苯二乙酸(7.5g,23.1mmol)，室温搅拌3小时(TLC监测反应完全)，减压蒸除溶剂，二氯甲烷萃取，饱和氯化铵水溶液，水，氯化钠水溶液依次洗，无水硫酸钠干燥，硅胶柱层析分离(200～300目，石油醚/乙酸乙酯＝1:1)，获得氨基甲酸酯中间体A(白色固体，3.6g，67％)。
称取化合物A(2.4.g,9.04mmol)于茄形瓶中，加入二乙烯三胺(20mL,180mmol)，140℃搅拌12小时(TLC监测反应完全)，向其中缓慢加入30mL水，乙酸乙酯和甲醇(20mL×2,10:1,v/v)萃取，有机相用饱和氯化钠洗，无水硫酸钠干燥后，在减压下旋干溶剂，硅胶柱层析分离(200～300目，EtOAc/MeOH＝5:1)，获得中间体胺B(白色固体，1.1g，产率49％)。
1H NMR(500MHz,CDCl3)δ4.37(br,3H),3.18(dd,J＝12.7,2.5Hz,1H),2.97–2.91(m,1H),1.87(dt,J＝12.6,3.2Hz,1H),1.77–1.69(m,1H),1.66–1.60(m,1H),1.60–1.51(m,2H),1.49(dd,J＝10.9,2.5Hz,1H),1.46–1.40(m,1H),1.38–1.33(m,1H),1.31(s,3H),1.26–1.12(m,2H),1.05(td,J＝12.9,4.0Hz,1H),0.98(dd,J＝12.2,2.2Hz,1H),0.86(s,3H),0.77(s,3H),0.76(s,3H).
13C NMR(126MHz,CDCl3)δ74.31,59.09,55.96,43.82,41.78,39.92,38.25,37.77,33.63,33.43,24.80,21.71,20.08,18.71,15.88.证明为中间体胺B。
(2)Halichonine B类似物化合物1的合成：
Figure BDA0003555231010000121
称取化合物B(119mg,0.5mmol)和三乙酰氧基硼氢化钠(424mg,2mmol)于史莱克管中，抽真空，充氮气置换三次，使反应体系在氮气环境中，加入4-叔丁基苯甲醛(84μL,0.5mmol)和5mL无水1,2-二氯乙烷，室温搅拌过夜，向体系中滴加NaHCO3溶液淬灭反应，二氯甲烷萃取，有机相依次用水、饱和氯化钠溶液洗，无水硫酸钠干燥，硅胶柱层析分离(200～300m，EtOAc)，获得N-苄基取代产物(化合物228，无色油状，193mg，产率80％)。熔点：(258.2～258.6℃)。
实施例2～21
参照实施例1的方法通过将步骤(2)中的4-叔丁基苯甲醛替换为其他醛，制备了其他Halichonine B类似物。
表1 Halichonine B及其类似物的物理性、产率及洗脱条件
Figure BDA0003555231010000131
/>
Figure BDA0003555231010000141
/>
Figure BDA0003555231010000151
/>
Figure BDA0003555231010000161
应用例
采用平板抑制菌丝生长速率法对Halichonine B类似物进行离体抑菌活性评价，选取测试菌株于PDA平板进行活化，包括农业上常见的5种病原菌，小麦赤霉病菌(Fusariumgraminearum)、油菜菌核病菌(Sclerotinia sclerotiorum)、水稻纹枯病菌(Rhizoctoniasolani)、番茄灰霉病菌(Botrytis cinerea)、水稻稻瘟病菌(Phyricularia cerealis)进行将化合物配置成系列梯度浓度的PDA含药平板，将测试菌株制成5mm直径菌饼置于含药培养皿中央，25℃恒温培养至空白对照皿的测试菌株长至接近培养皿边缘时，用十字交叉法测量各含药平板的菌落直径，计算化合物对菌丝生长的抑制率，对病害的抑制率按照如下公式(1)计算：
Figure BDA0003555231010000171
在150μmol/L的浓度条件下，Halichonine B及类似物抑菌活性测试结果如表2所示。
表2 Halichonine B类似物对病原菌的抑制率(150μmol/L,％)
Figure BDA0003555231010000172
/>
Figure BDA0003555231010000181
/>
Figure BDA0003555231010000191
/>
Figure BDA0003555231010000201
表3 Halichonine B类似物的抑菌活性(EC50值，单位:μmol/L)
Figure BDA0003555231010000202
/>
Figure BDA0003555231010000211
/>
Figure BDA0003555231010000221
/>
Figure BDA0003555231010000231
从表2和表3可以看出，合成的Halichonine B类似物对油菜菌核病原菌、水稻纹枯病原菌、番茄灰霉病原菌和稻瘟病病原菌均表现出一定的抑菌活性，具有广谱杀菌性。从表2可以看出，相比饱和脂肪链取代化合物，苄基取代类化合物对植物真菌抑制活性明显提高。
从表3可以看出，增加取代基数量可提高生物活性(HND-15>HND-14)，通过改变取代基位置可以提高活性(HND-13>HND-14)。苯环的4位含空间位阻较大基团脂肪取代基的HND-17、HND-18对水稻纹枯病原菌表现较好活性，EC50值分别是5.81μmol/L和8.90μmol/L。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (4)

1.一种Halichonine B类似物，其特征在于，具有式1所示结构：
Figure QLYQS_1
式1；
所述式1中，R为
Figure QLYQS_2
、/>
Figure QLYQS_3
、-CH2CH3、/>
Figure QLYQS_4
、/>
Figure QLYQS_5
、
Figure QLYQS_15
、/>
Figure QLYQS_8
、/>
Figure QLYQS_11
、/>
Figure QLYQS_9
、/>
Figure QLYQS_12
、/>
Figure QLYQS_16
、/>
Figure QLYQS_20
、/>
Figure QLYQS_14
、
Figure QLYQS_18
、/>
Figure QLYQS_7
、/>
Figure QLYQS_10
、/>
Figure QLYQS_13
、/>
Figure QLYQS_17
、/>
Figure QLYQS_19
、/>
Figure QLYQS_21
或/>
Figure QLYQS_6
。
2.权利要求1所述Halichonine B类似物的制备方法，包括以下步骤：
将具有式2所示结构的(1S,2S)-1-(氨基甲基)-2,5,5,8a-四甲基十氢化萘-2-醇、R1CHO、还原剂和有机溶剂混合，进行还原胺化反应，得到具有式1所示结构的HalichonineB类似物；
Figure QLYQS_22
式2；
所述R1CHO中，R1与式1中的R取代基减去与母核相连的CH2对应。
3.根据权利要求2所述的制备方法，其特征在于，所述还原胺化反应的温度为0~35℃，时间为12~24小时。
4.权利要求1所述Halichonine B类似物或其农药学上可接受的盐或权利要求2~3任一项所述制备方法制备得到的Halichonine B类似物或其药学上可接受的盐在制备农药杀菌剂中的应用。
CN202210274285.2A 2022-03-21 2022-03-21 一种Halichonine B类似物及其制备方法和在制备农用杀菌剂中的应用 Active CN115160159B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210274285.2A CN115160159B (zh) 2022-03-21 2022-03-21 一种Halichonine B类似物及其制备方法和在制备农用杀菌剂中的应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210274285.2A CN115160159B (zh) 2022-03-21 2022-03-21 一种Halichonine B类似物及其制备方法和在制备农用杀菌剂中的应用

Publications (2)

Publication Number Publication Date
CN115160159A CN115160159A (zh) 2022-10-11
CN115160159B true CN115160159B (zh) 2023-06-16

Family

ID=83483529

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210274285.2A Active CN115160159B (zh) 2022-03-21 2022-03-21 一种Halichonine B类似物及其制备方法和在制备农用杀菌剂中的应用

Country Status (1)

Country Link
CN (1) CN115160159B (zh)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011246447A (ja) * 2010-04-26 2011-12-08 National Institute Of Agrobiological Sciences 植物病害防除剤および植物病害防除方法
CN105541632A (zh) * 2015-12-03 2016-05-04 北京工商大学 一种降龙涎橙花酯杀菌剂

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001106660A (ja) * 1999-10-08 2001-04-17 Toagosei Co Ltd ヒドロナフチルアルキルアミン
CN106397254B (zh) * 2016-08-29 2017-12-29 南京农业大学 手性8‑羟基升补身烷倍半萜酰胺类化合物及作为农用杀菌剂的用途
CN107721945B (zh) * 2017-09-08 2020-10-13 南京农业大学 手性补身烷并噁嗪酮类化合物及其作为杀菌剂的用途
CN107602496B (zh) * 2017-09-08 2020-10-13 南京农业大学 手性补身烷基杂环类化合物及其作为杀菌剂的用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011246447A (ja) * 2010-04-26 2011-12-08 National Institute Of Agrobiological Sciences 植物病害防除剤および植物病害防除方法
CN105541632A (zh) * 2015-12-03 2016-05-04 北京工商大学 一种降龙涎橙花酯杀菌剂

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
香紫苏醇衍生物的合成及其杀菌活性初步研究;白红进 等;西北农业学报;第14卷(第2期);64-68、73 *

Also Published As

Publication number Publication date
CN115160159A (zh) 2022-10-11

Similar Documents

Publication Publication Date Title
Ramalingan et al. Synthesis and study of antibacterial and antifungal activities of novel 1-[2-(benzoxazol-2-yl) ethoxy]-2, 6-diarylpiperidin-4-ones
Sumangala et al. Synthesis and antimicrobial activity of 1, 2, 3-triazoles containing quinoline moiety
Gupta Efficient synthesis of antifungal active 9-substituted-3-aryl-5H, 13aH-quinolino [3, 2-f][1, 2, 4] triazolo [4, 3-b][1, 2, 4] triazepines in ionic liquids
CN103804386B (zh) 4,5-二羟基-3-h-螺[呋喃-2,3’-吲哚]-2’-酮衍生物及其合成方法和应用
CN106699766A (zh) 一种具有抗菌活性的螺靛红硫脲衍生物及其合成方法和应用
CN115160159B (zh) 一种Halichonine B类似物及其制备方法和在制备农用杀菌剂中的应用
CN107459490B (zh) 吩嗪-1-甲酰胺类化合物及其应用
CN109369608B (zh) 一种制备苯并-1,3-氧硫杂环己二烯-4-亚基胺的方法
CN104086525B (zh) 一种具有抗菌活性的螺[萘满酮-四氢噻吩]衍生物及合成方法和应用
CN103626816A (zh) 乙酰氨基葡萄糖基咪唑-2,4,5-三酮的合成方法与抑菌用途
Ma et al. Synthesis and antifungal activities of drimane-amide derivatives from sclareol
CN106967086B (zh) 一种具有抗菌活性的喹啉并硫吡喃衍生物及其合成方法和应用
CN114957113B (zh) 2-氯喹啉-3-甲醛肟-o-(n-对氟苯基)氨基甲酸酯及其制备方法与应用
CN106431977B (zh) 一种不饱和肟醚类化合物及其用途
CN109897052B (zh) 一种n-嘧啶基-1,3-氧氮杂桥环化合物及其制备方法和应用
CN112194667B (zh) 取代1,4-苯并噁嗪并二氮卓类化合物及其制备方法和用途
JP4616981B2 (ja) 新規活性物質、その製造法および用途
Hu et al. Modular Synthesis and First Antimicrobial Investigation of Mycoleptodiscin A and Simplified Indolosesquiterpenoids
CN105777773B (zh) 噻吩[2,3‑b]喹啉衍生物及其合成方法和应用
CN109400588B (zh) 一种含氟三唑喹喔啉类杀菌剂、制备方法及其应用
CN114539241B (zh) 一种含噻唑-吡啶甲基芳杂环季铵盐侧链的截短侧耳素衍生物及其制备方法与应用
CN115557855B (zh) 多取代2-羟基二苯甲酮类化合物及其制备方法与应用
CN114957112B (zh) (2-氯喹啉-3-基)甲基(n-对氟苯基)氨基甲酸酯及其制备方法与应用
CN113461632B (zh) 3-((4-氟苯基)磺酰基)-4-羟基-2-甲基噻唑烷-2-羧酸甲酯的制备方法
CN109400589B (zh) 一种喹喔啉类杀菌剂、制备方法及其应用

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant