CN107501368B - 一种多拉菌素衍生物的合成及其杀虫应用 - Google Patents

一种多拉菌素衍生物的合成及其杀虫应用 Download PDF

Info

Publication number
CN107501368B
CN107501368B CN201710916981.8A CN201710916981A CN107501368B CN 107501368 B CN107501368 B CN 107501368B CN 201710916981 A CN201710916981 A CN 201710916981A CN 107501368 B CN107501368 B CN 107501368B
Authority
CN
China
Prior art keywords
doramectin
derivative
substituted
nmr
methyl ester
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
CN201710916981.8A
Other languages
English (en)
Other versions
CN107501368A (zh
Inventor
卢晓霞
张琪
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.)
Chengdu Institute of Biology of CAS
Original Assignee
Chengdu Institute of Biology of CAS
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 Chengdu Institute of Biology of CAS filed Critical Chengdu Institute of Biology of CAS
Priority to CN201710916981.8A priority Critical patent/CN107501368B/zh
Publication of CN107501368A publication Critical patent/CN107501368A/zh
Application granted granted Critical
Publication of CN107501368B publication Critical patent/CN107501368B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • 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
    • A01N47/18—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, directly attached to a heterocyclic or cycloaliphatic ring
    • 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
    • A01N47/20—N-Aryl derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

本发明涉及化学化工及农药领域，目的是提供一种多拉菌素衍生物及合成方法及其在杀虫方面的应用。采用的技术方案是：一种氨基甲酯类多拉菌素衍生物，化学通式为
Figure DDA0002243218010000011
式中：R为饱和烷基、不饱和烷基、芳香基、杂环芳香基的一种；所述的饱和烷基为C1～C12的直链、支链烷基；所述的不饱和烷基为C1～C12的直链、支链的烯烃、炔烃或为C3～C6的环状烷基；所述的芳香基为单环芳香基或稠环芳香基；所述的杂环芳香基为吡咯基、吡啶基、咪唑基、噻唑基、吲哚基、吡唑基、喹啉基的一种。本发明方法制备的多拉菌素衍生物，相较于传统化学农药，具有高效、低毒、对环境友好等优点，有望成为新一代绿色环保的生物农药。

Description

一种多拉菌素衍生物的合成及其杀虫应用
技术领域
本发明涉及化学化工及农药领域，具体来说是一种多拉菌素衍生物及合成方法及其在杀虫方面的应用。
背景技术
多拉菌素是以环已氨羧酸(cyclohex aneca rbox y licacid)为前体，通过基因重组的阿维链霉菌(streptomyces avermitilis)新菌株发酵而成的一种阿维菌素第3代抗生素，为20世纪90年代中期美国辉瑞公司研制，是目前世界上效果最好、最有开发潜力的抗寄生虫新药。在农业方面，研究表明其对于防治各种螨、土壤线虫效果显著，同时发现对防治小菜蛾、棉铃虫等严重危害农作物的害虫效果明显，是目前研究的一类非常热门的课题，有望成为下一代新型生物农药。其作用机制与阿维菌素相似，有如下几个特点：①通过抑制氨基丁酸(G A B A)受体，从而使神经传导受阻来达到的，因而可以防治那些对普通药剂已产生抗性的寄生虫；②有效剂量低，在0.2mg/k g体重的剂量下即显示出有效的驱虫活性；③安全性高。由于哺乳动物以G A B A作传导介质的神经只存在于中枢神经系统，而无脊椎动物以G A B A作传导介质的神经起调节周围肌肉的作用。因此多拉菌素对哺乳动物有较高的安全性。目前,对于多拉菌素的结构改造，主要集中在双键的还原与氧化，羟基的改造，糖的水解与改造。1)双键的还原与氧化。主要是C22-C23双键还原，也可以是C2-C3、C8-C9或C10-C11双键还原；2)羟基的改造。C5-OH可以改造成酯、成醚或氧化成酮；C4"-OH的改造最为频繁，可以氧化成酮，可以成醚、成酯、磺酸酯、氨基甲酯(氨基甲酸酯)等，也可以羟基变氨基成酰胺、磺酰胺、脲、磺酰脲等；3)糖环的改造。在强酸作用下，可以脱去一个或两个糖环，也可以将糖环用其它糖替代，如鼠李糖等。国内外市场对多拉菌素的需求量在不断的增长，拉动了我国的出口多拉菌素的市场空间大幅增加，而且成熟的生产工艺过程和产品的高质量将为打开国内及国际市场提供有力的保证。
氨基甲酸酯类农药是人类针对有机氯和有机磷农药的缺点而开发出的一种新型广谱杀虫、杀螨、除草剂。具有高效、残留期短的优点。目前，使用较多的有速灭威(Metolcarb)、西维因(Carbaryl)、涕灭威(Aldicarb)、克百威(Carbofuran)、叶蝉散(Isoprocarb)和抗蚜威(Pirimicarb)等。
鉴于氨基甲酸酯类农药这一优点，同时结合国务院提出要加强农业生态治理，大力推广生物有机肥、低毒低残留农药。因此，大力开发和推广高效、安全和环境友好型的生物农药产品，以绿色环保的新型生物农药替代或部分替代高毒化学农药是我国农业生产可持续性发展的迫切要求。因此，将活性好的氨基甲酸酯类与同样具有良好活性的多拉菌素通过化学技术结合起来，进行抗虫活性测试，期望获得高效、低毒、对环境友好的新型生物农药，用于替代部分传统的化学农药，不仅是我国21世纪农药发展的趋势，也是国际农药发展的趋势。
发明内容
本发明的目的是提供一种新型多拉菌素衍生物的制备方法，通过多拉菌素为母体经过一系列反应最终合成所需的目标化合物，该化合物用于杀虫。
为实现发明目的，本发明的采取的技术方案：
一种氨基甲酯类多拉菌素衍生物，化学通式为
Figure GDA0002243216000000031
化学结构式为：
Figure GDA0002243216000000032
式中：R为饱和烷基、不饱和烷基、芳香基、杂环芳香基的一种；
所述的饱和烷基为C1～C12的直链、支链烷基；
所述的不饱和烷基为C1～C12的直链、支链的烯烃、炔烃或为C3～C6的环状烷基；
所述的芳香基为单环芳香基或稠环芳香基；
所述的杂环芳香基为吡咯基、吡啶基、咪唑基、噻唑基、吲哚基、吡唑基、喹啉基的一种。
优选的，所述的芳香基为苯基、单卤代苯基、单烷基苯基、单烷氧基苯基、单硝基苯基、多取代苯基、多卤代苯基、多烷基苯基、多烷氧基苯基、多硝基苯基、萘基、单取代萘基、多取代萘基、蒽基、菲基的一种。
优选的，所述的不饱和烷基为烯丙基、1-丁烯基、2-丁烯基、2-甲基-1-丙烯基、2-甲基-1-丁烯基、3-甲基-1-丁烯基、环丙基、环戊基、环己基的一种。
优选的，所述的饱和烷基为甲基、乙基、正丙基、异丁基、丁基的一种。
优选的，所述的R为甲基、环丙基、烯丙基的一种。
相应的，当所述多拉菌素衍生物是脂肪族氨基甲酯类多拉菌素衍生物，其制备步骤如下：
(1)多拉菌素C4"-OH取代基的合成
1)以二氯甲烷作为溶剂，将多拉菌素、叔丁基二甲基氯硅烷、咪唑、4-二甲氨基吡啶按摩尔比1:3.5:10:0.1混合，在氮气保护下，常温搅拌4小时，经萃取、过滤、柱层析，得到叔丁基二甲基氯硅烷取代C5-OH的多拉菌素衍生物；
2)以二氯甲烷作为溶剂，将上述叔丁基二甲基氯硅烷取代C5-OH的多拉菌素衍生物、羰基二咪唑、4-二甲氨基吡啶按摩尔比1:3.5:2混合，在氮气保护下，常温搅拌3小时，经萃取、过滤、旋蒸，得到羰基咪唑取代C4"-OH的多拉菌素衍生物；
(2)多拉菌素衍生物的合成
1)以二氯甲烷作为溶剂，将羰基咪唑取代C4"-OH的多拉菌素衍生物、脂肪族胺、4-二甲氨基吡啶按摩尔比1.1:1:0.1混合，在氮气保护下，常温搅拌6-8小时，经萃取、过滤、旋蒸，得到C5-OH保护的脂肪族氨基甲酯类多拉菌素衍生物；
2)以甲醇作为溶剂，将上述C5-OH保护的脂肪族氨基甲酯类多拉菌素衍生物、对甲苯磺酸按摩尔比1:3.5混合，在氮气保护下，常温搅拌1-2小时，经萃取、过滤、柱层析，得到脂肪族氨基甲酯类多拉菌素衍生物。
具体合成路线如下：
Figure GDA0002243216000000051
式中R为C1～C12的直链、支链烷基、C1～C12的直链、支链的烯烃或炔烃或为C3～C6的环状烷基。其中TBSCl:叔丁基二甲基氯硅烷；Imidazole:咪唑；DMAP：4-二甲氨基吡啶；CDI：N,N'-羰基二咪唑；CH2Cl2:二氯甲烷；methanol:甲醇；p-Toluenesulfonic acid:对甲基苯磺酸。
相应的，当所述多拉菌素衍生物是芳香族氨基甲酯类多拉菌素衍生物，其制备步骤如下：
(1)多拉菌素C4"-OH取代基的合成
以二氯甲烷作为溶剂，将多拉菌素、叔丁基二甲基氯硅烷、咪唑、4-二甲氨基吡啶按摩尔比1:3.5:10:0.1混合，在氮气保护下，常温搅拌4小时，经萃取、过滤、柱层析，得到叔丁基二甲基氯硅烷取代C5-OH的多拉菌素衍生物；
(2)多拉菌素衍生物的合成
1)以二氯甲烷作为溶剂，将芳香异氰酸酯、叔丁基二甲基氯硅烷取代C5-OH的多拉菌素衍生物、4-二甲氨基吡啶按摩尔比5:1:0.1混合，在氮气保护下，常温搅拌5-10小时，经萃取、过滤、旋蒸，得到C5-OH保护的芳香族氨基甲酯类多拉菌素衍生物；
2)以甲醇作为溶剂，将上述C5-OH保护的芳香族氨基甲酯类多拉菌素衍生物、对甲苯磺酸按摩尔比1:3.5混合，在氮气保护下，常温搅拌1-2小时，经萃取、过滤、柱层析，得到芳香族氨基甲酯类多拉菌素衍生物。
优选的，所述芳香族异氰酸酯的合成步骤如下：以二氯甲烷和饱和碳酸氢钠溶液作为溶剂，将芳香胺、三光气按摩尔比1:0.33混合，在0℃反应4小时，经萃取、过滤、旋蒸，得到芳香异氰酸酯。
Figure GDA0002243216000000071
式中R为:单环芳香基、稠环芳香基、芳香基、杂环芳香基、吡咯基、吡啶基、咪唑基、噻唑基、吲哚基、吡唑基、喹啉基等。其中TBSCl:叔丁基二甲基氯硅烷；Imidazole:咪唑；DMAP：4-二甲氨基吡啶；triphosgene：三光气；CH2Cl2:二氯甲烷；methanol:甲醇；p-Toluenesulfonic acid:对甲基苯磺酸；NaHCO3：碳酸氢钠。
相应的，具有保护价值的是：所述的氨基甲酯类多拉菌素衍生物合成用的中间体：叔丁基二甲基氯硅烷取代C5-OH的多拉菌素衍生物。
本发明还保护所述氨基甲酯类多拉菌素衍生物在杀虫中的应用。优选用于杀灭黏虫、小菜蛾、玉米螟。
本发明的氨基甲酯类多拉菌素杀虫活性研究验证实验方法和结果如下：
1)称取一定量的待测样品，加入丙酮溶解，配置成浓度为1mg/mL的母液；
2)取上述母液200uL、100uL、50uL、2 5uL、12.5uL分别加入含有吐温80的蒸馏水800uL、900uL、950uL、975uL、987.5uL配成浓度为200mg/L、100mg/L、50mg/L、25mg/L、12.5mg/L的溶液
3)采用浸渍叶片法。采集新鲜无污染的玉米叶片(黏虫、玉米螟)或卷心菜叶片(小菜蛾)，浸在上述配制的溶液中5秒，以丙酮和清水作为对照。室内晾干后，放入培养皿中，然后放入大小一致的3龄(黏虫、小菜蛾、玉米螟)幼虫，每处理重复3次，每重复处理10头(黏虫、小菜蛾、玉米螟)。在养虫室内饲养，48小时后检查死虫数。其公式为：校正致死率＝(X-CK)/(1-CK)×100％，公式中X为样品致死率，CK为对照的致死率。
表一、多拉菌素衍生物抗黏虫活性测试
Figure GDA0002243216000000081
Figure GDA0002243216000000091
注:死亡率范围“0-100％”,“0”表示没有死亡；“100％”表示全部死亡。
表二、多拉菌素衍生物抗小菜蛾活性测试
R 200(mg/L) 100(mg/L) 50(mg/L) 25(mg/L) 12.5(mg/L)
多拉菌素 90.00％ 70.00％ 46.67％ 30.00％ 13.33％
4-F-Ph 0 0 0 0 0
4-Cl-Ph 0 0 0 0 0
4-Br-Ph 33.33％ 0 0 0 0
2-CH<sub>3</sub>-Ph 30.00％ 0 0 0 0
3-Cl-Ph 30.00％ 0 0 0 0
4-OCH<sub>3</sub>-Ph 46.67％ 20.00％ 0 0 0
Ph 30.00％ 0 0 0 0
4-CH<sub>3</sub>-Ph 40.00％ 10.00％ 0 0 0
2,6-二异丙基苯基 0 0 0 0 0
1-萘 0 0 0 0 0
4-CF<sub>3</sub>-Ph 10.00％ 0 0 0 0
CH<sub>3</sub> 100.00％ 80.00％ 50.00％ 30.00％ 16.67％
CH<sub>3</sub>CH<sub>2</sub> 83.33％ 46.67％ 20.00％ 16.67％ 0
CH<sub>3</sub>CH<sub>2</sub>CH<sub>2</sub> 56.67％ 50.00％ 16.67％ 0 0
n-C<sub>4</sub>H<sub>9</sub> 66.67％ 46.67％ 13.33％ 0 0
CH<sub>3</sub>(CH<sub>2</sub>)<sub>7</sub> 23.33％ 10.00％ 0 0 0
C<sub>6</sub>H<sub>11</sub> 40.00％ 10.00％ 0 0 0
C<sub>3</sub>H<sub>5</sub> 100.00％ 90.00％ 70.00％ 50.00％ 36.67％
CH<sub>2</sub>＝CHCH<sub>2</sub> 100.00％ 90.00％ 60.00％ 46.67％ 20.00％
C<sub>6</sub>H<sub>5</sub>CH<sub>2</sub> 70.00％ 36.67％ 20.00％ 0 0
4-OCH<sub>3</sub>-Ph-CH<sub>2</sub> 33.33％ 30.00％ 0 0 0
阿维菌素 90.00％ 70.00％ 50.00％ 36.67％ 20.00％
注:死亡率范围“0-100％”,“0”表示没有死亡；“100％”表示全部死亡。
表三、多拉菌素衍生物抗玉米螟活性测试
R 200mg/L 100mg/L 50mg/L 25mg/L 12.5mg/L
多拉菌素 86.67％ 66.67％ 50％ 36.67％ 13.33％
CH<sub>3</sub> 90％ 80％ 50％ 33.33％ 20％
C<sub>3</sub>H<sub>5</sub> 100％ 90％ 70％ 46.67％ 40％
CH<sub>2</sub>＝CHCH<sub>2</sub> 90％ 70％ 50％ 33.33％ 13.33％
阿维菌素 83.33％ 50％ 40％ 20％ 10％
注:死亡率范围“0-100％”,“0”表示没有死亡；“100％”表示全部死亡。
表四、多拉菌素衍生物对黏虫的毒力回归方程
Figure GDA0002243216000000092
Figure GDA0002243216000000101
表五、多拉菌素衍生物对小菜蛾的毒力回归方程
Figure GDA0002243216000000102
表六、多拉菌素衍生物对玉米螟的毒力回归方程
由上述实验结果可见：本发明方法制备的多拉菌素衍生物，相较于传统化学农药，具有高效、低毒、对环境友好等优点，其中R为:CH3、C3H5、CH2＝CHCH2时，具备良好的抗黏虫、小菜蛾、玉米螟活性，有望成为新一代绿色环保的生物农药。
附图说明
图1对三氟甲基苯氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图2 2,6-二异丙基苯氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图3对溴苯氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图4对甲基苯氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图5对甲氧基苯氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图6间氯苯氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图7苯氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图8对氟苯氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图9对氯苯氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图10 1-萘氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图11甲氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图12丙氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图13辛氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图14对甲氧基苄氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图15苄氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图16乙氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图17丁氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图18邻甲基苯氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图19环丙氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图20环己氨基甲酸酯取代多拉菌素的核磁共振氢谱；
图21烯丙氨基甲酸酯取代多拉菌素的核磁共振氢谱。
具体实施方式
以下提供本发明一种新型多拉菌素衍生物的合成的具体实施方式。
实施例1：
一种新型多拉菌素衍生物，其化学通式为
Figure GDA0002243216000000121
结构式为
Figure GDA0002243216000000122
式中：R为CH3。
化学名称：甲基氨基甲酸酯取代多拉菌素，该衍生物的制备步骤如下：
(1)多拉菌素C4"-OH取代基的合成：
1)以二氯甲烷作为溶剂，将多拉菌素、叔丁基二甲基氯硅烷、咪唑、4-二甲氨基吡啶按摩尔比1:3.5:10:0.1混合，在氮气保护下，常温搅拌4小时，加入饱和食盐水，经二氯甲烷萃取、加无水硫酸镁过滤、柱层析(V乙酸乙酯：V石油醚＝1:2)、旋蒸，得到叔丁基二甲基氯硅烷取代的C5-OH的多拉菌素衍生物；
2)以二氯甲烷作为溶剂，将会上述叔丁基二甲基氯硅烷取代的C5-OH的多拉菌素衍生物、羰基二咪唑、4-二甲氨基吡啶按摩尔比1:3.5:2混合，在氮气保护下，常温搅拌3小时，加入饱和食盐水，经二氯甲烷萃取、加无水硫酸镁过滤、旋蒸，得到羰基咪唑取代C4"-OH的多拉菌素衍生物；
(2)甲基氨基甲酯多拉菌素衍生物合成
1)以二氯甲烷作为溶剂，将羰基咪唑取代C4"-OH的多拉菌素衍生物、甲胺、4-二甲氨基吡啶按摩尔比1.1:1:0.1混合，在氮气保护下，常温搅拌6小时，加入饱和食盐水，经二氯甲烷萃取、加无水硫酸镁过滤、旋蒸，得到C5-OH保护的甲基氨基甲酯多拉菌素衍生物；
2)以甲醇作为溶剂，将上述C5-OH保护的甲基氨基甲酸酯取代类多拉菌素衍生物、对甲苯磺酸按摩尔比1:3.5混合，在氮气保护下，常温搅拌1小时，加入饱和食盐水，经二氯甲烷萃取、加无水硫酸镁过滤、柱层析(V乙酸乙酯：V石油醚＝1:2.5)、旋蒸，得到甲基氨基甲酸酯取代多拉菌素。
化合物甲基氨基甲酸酯取代多拉菌素核磁共振氢谱如图11，基本数据如下：
1H NMR(400MHz,CDCl3)δ5.88(d,J＝10.1Hz,1H,H9),5.80-5.68(m,3H,H10,H11,H23),5.53(dd,J＝9.8,2.5Hz,1H,H22),5.47–5.32(m,3H,H3,H19,H1"),5.04–4.96(m,1H,H15),4.78(d,J＝3.8Hz,1H,H1′),4.68(t,J＝3.3Hz,2H,H8a),4.63(s,1H,NHCOO),4.53(t,J＝9.4Hz,1H,H4"),4.29(d,J＝6.2Hz,1H,H5),4.06(s,1H,H7-OH),3.97(d,J＝6.2Hz,1H,H6),3.93(s,1H,H13),3.90-3.73(m,3H,H17,H5′,H5"),3.60(qd,J＝14.3,12.0,4.9Hz,2H,H3,H3"),3.42(s,3H,H3′-OMe),3.37(s,3H,H3"-OMe),3.33–3.19(m,3H,H2,H25,H4),2.82(d,J＝4.7Hz,3H,CH3 NH),2.59–2.45(m,1H,H12),2.27(ddt,J＝23.7,13.0,5.2Hz,6H,H5-OH,H16,H24,H2′a,H2"a),2.00(dd,J＝12.2,4.7Hz,1H,H20a),1.87(s,3H,H4a-CH3),1.79(d,J＝7.9Hz,3H,H27a,H30a,H31a),1.73–1.59(m,5H,H18a,H28a,H26,H29),1.48(d,J＝6.2Hz,4H,H14a-CH3,H20b),1.38–1.09(m,15H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3),0.92(d,J＝7.1Hz,3H,H24a-CH3),0.85(d,J＝12.1Hz,1H,H18b).13CNMR(100MHz,CDCl3)δ173.69,156.57,139.59,138.13,137.98,136.21,135.09,127.74,124.72,120.49,118.26,118.08,98.29,95.71,94.93,81.89,80.50,80.40(2-C),79.28,79.13,77.24,75.74,68.46,68.30,68.20,67.72,67.20,66.81,56.81,56.58,45.73,40.37,39.75,38.71,36.74,35.04,34.63,34.37,31.44,30.03,27.70,26.99,26.63,26.52,25.58,20.23,19.98,18.39,17.39,16.65,15.18.
HRMS(ESI)m/z calcd.for C52H77NNaO15:(M+Na)+,978.5185；found 978.5231.
其它脂肪族氨基甲酯类多拉菌素衍生物的制备方法与实施例1相同。部分脂肪族化合物的核磁数据如下：
R＝CH3CH2(化合物乙氨基甲酸酯取代多拉菌素)核磁共振氢谱如图16，基本数据如下：
1H NMR(400MHz,CDCl3)δ5.89(d,J＝10.1Hz,1H,H9),5.82–5.68(m,3H,H10,H11,H23),5.54(dd,J＝9.8,2.5Hz,1H,H22),5.48–5.33(m,3H,H3,H19,H1"),5.01(d,J＝10.5Hz,1H,H15),4.78(d,J＝3.8Hz,1H,H1′),4.75–4.59(m,3H,H8a,NHCOO),4.53(t,J＝9.4Hz,1H,H4″),4.30(t,J＝7.3Hz,1H,H5),4.06(s,1H,H7-OH),3.97(d,J＝6.2Hz,1H,H6),3.94(s,1H,H13),3.92–3.76(m,3H,H17,H5′,H5"),3.66–3.53(m,2H,H3′,H3"),3.43(s,3H,H3′-OMe),3.38(s,3H,H3"-OMe),3.34–3.18(m,5H,H2,H25,H4′,CH3 CH2 N),2.52(t,J＝7.6Hz,1H,H12),2.41-2.19(m,6H,H5-OH,H16,H24,H2′a,H2"a),2.04–1.97(m,1H,H20a),1.87(t,J＝1.9Hz,3H,H4a-CH3),1.79(d,J＝7.6Hz,3H,H27a,H30a,H31a),1.70–1.64(m,2H,H18a,H28a),1.58–1.53(m,3H,H26,H29),1.49(d,J＝5.9Hz,4H,H14a-CH3,H20b),1.36–1.10(m,18H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3,CH3 CH2N),0.92(d,J＝7.1Hz,3H,H24a-CH3),0.85(d,J＝12.1Hz,1H,H18b).13C NMR(100MHz,CDCl3)δ173.70,155.82,139.59,138.14,137.99,136.22,135.09,127.74,124.72,120.50,118.27,118.08,98.27,95.71,94.94,81.89,80.46,80.40(2-C),79.29,79.13,77.24,75.79,68.47,68.30,68.20,67.72,67.20,66.84,56.90,56.59,45.74,40.37,39.76,38.71,36.74,35.99,35.09,34.63,34.38,31.45,30.03,29.32,26.99,26.63,26.52,25.59,20.22,19.98,18.39,17.40,16.65,15.19.
HRMS(ESI)m/z calcd.for C53H79NNaO15:(M+Na)+,992.5342；found 992.5380.
R＝CH3CH2CH2(化合物丙氨基甲酸酯取代多拉菌素的核磁共振氢谱)核磁共振氢谱如图12，基本数据如下：
1H NMR(400MHz,CDCl3)δ5.89(d,J＝10.1Hz,1H,H9),5.84–5.67(m,3H,H10,H11,H23),5.54(dd,J＝9.9,2.5Hz,1H,H22),5.49–5.32(m,3H,H3,H19,H1"),5.05–4.96(m,1H,H15),4.78(d,J＝3.8Hz,1H,H1′),4.68(t,J＝3.3Hz,3H,H8a,NHCOO),4.53(t,J＝9.4Hz,1H,H4″),4.30(s,1H,H5),4.06(s,1H,H7-OH),3.97(d,J＝6.2Hz,1H,H6),3.94(s,1H,H13),3.91–3.74(m,3H,H17,H5′,H5"),3.67–3.52(m,2H,H3′,H3"),3.43(s,3H,H3′-OMe),3.38(s,3H,H3"-OMe),3.35–3.12(m,5H,H2,H25,H4′,CH3CH2 CH2 NH),2.52(t,J＝7.7Hz,1H,H12),2.40–2.17(m,6H,H5-OH,H16,H24,H2′a,H2"a),2.00(dd,J＝12.0,4.6Hz,1H,H20a),1.87(d,J＝2.4Hz,3H,H4a-CH3),1.79(d,J＝9.1Hz,3H,H27a,H30a,H31a),1.74–1.57(m,7H,H18a,H28a,H26,H29,CH3 CH2 CH2NH),1.49(d,J＝6.0Hz,4H,H14a-CH3,H20b),1.37–1.12(m,15H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3),0.93(dd,J＝7.2,1.9Hz,6H,H24a-CH3,CH3 CH2CH2NH),0.90–0.80(m,1H,H18b).13C NMR(100MHz,CDCl3)δ173.69,155.99,139.59,138.13,137.98,136.21,135.09,127.74,124.72,120.49,118.27,118.08,98.28,95.71,94.94,81.88,80.47,80.40(2-C),79.29,79.13,77.24,75.81,68.46,68.30,68.20,67.72,67.20,66.84,56.91,56.59,45.74,42.80,40.37,39.76,38.71,36.75,35.11,34.63,34.38,31.44,30.03,26.99,26.63,26.52,25.58,23.22,20.22,19.98,18.39,17.39,16.65,15.18,11.14.
HRMS(ESI)m/z calcd.for C54H81NNaO15:(M+Na)+,1006.5498；found 1006.5506.
R＝n-C4H9(化合物丁氨基甲酸酯取代多拉菌素)核磁共振氢谱如图17，基本数据如下：
.1H NMR(400MHz,CDCl3)δ5.89(d,J＝9.9Hz,1H,H9),5.82–5.68(m,3H,H10,H11,H23),5.54(dd,J＝9.9,2.5Hz,1H,H22),5.48–5.32(m,3H,H3,H19,H1"),5.01(d,J＝10.7Hz,1H,H15),4.78(d,J＝3.8Hz,1H,H1′),4.75–4.60(m,3H,H8a,NHCOO),4.52(t,J＝9.4Hz,1H,H4″),4.30(t,J＝7.2Hz,1H,H5),4.06(s,1H,H7-OH),3.97(d,J＝6.3Hz,1H,H6),3.94(s,1H,H13),3.91-3.73(m,3H,H17,H5′,H5"),3.66–3.53(m,2H,H3′,H3"),3.43(s,3H,H3′-OMe),3.38(s,3H,H3"-OMe),3.34–3.15(m,5H,H2,H25,H4′,CH3CH2CH2 CH2 N),2.53(t,J＝7.8Hz,1H,H12),2.39-2.18(m,6H,H5-OH,H16,H24,H2′a,H2"a),2.04–1.97(m,1H,H20a),1.88(t,J＝2.0Hz,3H,H4a-CH3),1.79(d,J＝8.0Hz,3H,H27a,H30a,H31a),1.68(t,J＝5.9Hz,2H,H18a,H28a),1.57–1.44(m,7H,H26,H29,H14a-CH3,H20b),1.40–1.11(m,19H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3,CH3 CH2CH2 CH2N),0.99–0.79(m,7H,H24a-CH3,H18b,CH3 CH2CH2CH2N).13C NMR(100MHz,CDCl3)δ173.70,155.95,139.59,138.13,137.99,136.21,135.09,127.74,124.72,120.50,118.27,118.08,98.28,95.71,94.94,81.89,80.45,80.40(2-C),79.29,79.13,77.23,75.81,68.47,68.30,68.20,67.73,67.20,66.84,56.91,56.58,45.74,40.83,40.37,39.76,38.71,36.75,35.10,34.63,34.38,32.06,31.45,30.03,26.99,26.63,26.52,25.59,20.22,19.98,19.84,18.39,17.40,16.65,15.18,13.73.HRMS(ESI)m/z calcd.for C55H83NNaO15:(M+Na)+,1020.5655；found 1020.5688.
R＝CH3(CH2)7(化合物辛氨基甲酸酯取代多拉菌素)核磁共振氢谱如图13，基本数据如下：
.1H NMR(400MHz,CDCl3)δ5.89(d,J＝10.4Hz,1H,H9),5.82–5.68(m,3H,H10,H11,H23),5.54(dd,J＝9.9,2.5Hz,1H,H22),5.47–5.31(m,3H,H3,H19,H1"),5.04–4.97(m,1H,H15),4.78(d,J＝3.8Hz,1H,H1′),4.74–4.61(m,3H,H8a,NHCOO),4.52(t,J＝9.4Hz,1H,H4″),4.29(d,J＝6.3Hz,1H,H5),4.06(s,1H,H7-OH),3.97(d,J＝6.2Hz,1H,H6),3.94(s,1H,H13),3.91-3.75(m,3H,H17,H5′,H5"),3.65–3.53(m,2H,H3′,H3"),3.42(s,3H,H3′-OMe),3.37(s,3H,H3"-OMe),3.33–3.14(m,5H,H2,H25,H4′,CH3(CH2)6 CH2 NH),2.57–2.47(m,1H,H12),2.38–2.18(m,6H,H5-OH,H16,H24,H2′a,H2"a),2.03–1.97(m,1H,H20a),1.87(t,J＝1.9Hz,3H,H4a-CH3),1.82–1.76(m,3H,H27a,H30a,H31a),1.73–1.60(m,5H,H18a,H28a,H26,H29),1.59–1.44(m,8H,CH3(CH2)4 (CH2)2 CH2NH,H14a-CH3,H20b),1.37–1.11(m,23H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3,CH3 (CH2)4 (CH2)2CH2NH),0.92(d,J＝7.1Hz,3H,H24a-CH3),0.86(q,J＝6.4Hz,4H,CH3 (CH2)4(CH2)2CH2NH,H18b).13C NMR(100MHz,CDCl3)δ173.69,155.94,139.59,138.13,137.98,136.21,135.08,127.74,124.72,120.49,118.27,118.07,98.28,95.71,94.94,81.89,80.47,80.40(2-C),79.29,79.13,77.24,75.81,68.46,68.30,68.20,67.72,67.20,66.85,56.91,56.58,45.73,41.13,40.37,39.76,38.71,36.74,35.10,34.62,34.38,31.77,31.44,30.03,29.98,29.23,29.20,26.99,26.68,26.63,26.52,25.58,22.63,20.22,19.98,18.39,17.39,16.64,15.18,14.08.
HRMS(ESI)m/z calcd.for C59H91NNaO15:(M+Na)+,1076.6281；found 1076.6322.
R＝C6H11(化合物环己氨基甲酸酯取代多拉菌素)核磁共振氢谱如图20，基本数据如下：
1H NMR(400MHz,CDCl3)δ5.89(d,J＝10.1Hz,1H,H9),5.83–5.68(m,3H,H10,H11,H23),5.54(dd,J＝9.9,2.5Hz,1H,H22),5.48–5.32(m,3H,H3,H19,H1"),5.01(d,J＝10.8Hz,1H,H15),4.78(d,J＝3.8Hz,1H,H1′),4.69(t,J＝3.2Hz,2H,H8a),4.60–4.45(m,2H,H4″,NHCOO),4.30(t,J＝7.3Hz,1H,H5),4.06(s,1H,H7-OH),3.97(d,J＝6.3Hz,1H,H6),3.94(s,1H,H13),3.91–3.75(m,3H,H17,H5′,H5"),3.67–3.45(m,3H,H3′,H3",1C6H11 ),3.43(s,3H,H3′-OMe),3.38(s,3H,H3"-OMe),3.34–3.18(m,3H,H2,H25,H4),2.58–2.49(m,1H,H12),2.39–2.18(m,6H,H5-OH,H16,H24,H2′a,H2"a),2.06–1.90(m,3H,H20a,2C6H11 ),1.88(t,J＝2.0Hz,3H,H4a-CH3),1.80(d,J＝8.6Hz,3H,H27a,H30a,H31a),1.74–1.64(m,4H,H18a,H28a,2C 6 H 11 ),1.57-1.51(m,3H,H26,H29),1.49(d,J＝5.6Hz,4H,H14a-CH3,H20b),1.42–1.06(m,21H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3,6C6H11 ),0.93(d,J＝7.1Hz,3H,H24a-CH3),0.89–0.82(m,1H,H18b).13C NMR(100MHz,CDCl3)δ173.69,155.09,139.58,138.13,137.98,136.21,135.08,127.73,124.72,120.49,118.26,118.07,98.27,95.71,94.93,81.88,80.40(3-C),79.29,79.13,77.24,75.80,68.47,68.30,68.20,67.73,67.21,66.87,56.95,56.59,49.86,45.74,40.37,39.76,38.71,36.75,35.14,34.63,34.38,33.40(2-C),31.45,30.03,26.99,26.63,26.52,25.59,25.51,24.76(2-C),20.22,19.99,18.39,17.42,16.65,15.19.
HRMS(ESI)m/z calcd.for C57H85NNaO15:(M+Na)+,1046.5811；found 1046.5833.
R＝C3H5(化合物环丙氨基甲酸酯取代多拉菌素)核磁共振氢谱如图19，基本数据如下：
1HNMR(400MHz,CDCl3)δ5.89(d,J＝10.0Hz,1H,H9),5.82–5.68(m,3H,H10,H11,H23),5.54(dd,J＝9.9,2.5Hz,1H,H22),5.47–5.33(m,3H,H3,H19,H1"),5.01(d,J＝10.7Hz,1H,H15),4.86(s,1H,NHCOO),4.78(d,J＝3.8Hz,1H,H1′),4.68(t,J＝3.2Hz,2H,H8a),4.54(t,J＝9.3Hz,1H,H4″),4.30(t,J＝7.0Hz,1H,H5),4.06(s,1H,H7-OH),3.97(d,J＝6.3Hz,1H,H6),3.94(s,1H,H13),3.92–3.73(m,3H,H17,H5′,H5"),3.67–3.53(m,2H,H3,H3"),3.43(s,3H,H3′-OMe),3.37(s,3H,H3"-OMe),3.34–3.18(m,3H,H2,H25,H4′),2.61(s,1H,C3H5 ),2.52(t,J＝7.5Hz,1H,H12),2.41-2.18(m,6H,H5-OH,H16,H24,H2′a,H2"a),2.00(dd,J＝12.0,4.5Hz,1H,H20a),1.88(t,J＝1.9Hz,3H,H4a-CH3),1.79(d,J＝11.9Hz,3H,H27a,H30a,H31a),1.70–1.65(m,2H,H18a,H28a),1.55(d,J＝3.5Hz,3H,H26,H29),1.49(d,J＝5.5Hz,4H,H14a-CH3,H20b),1.39–1.10(m,15H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3),0.93(d,J＝7.1Hz,3H,H24a-CH3),0.85(d,J＝11.9Hz,1H,H18b),0.73(d,J＝6.7Hz,2H,C3H5 ),0.55–0.48(m,2H,C3H5 ).13C NMR(100MHz,CDCl3)δ173.69,152.61,139.58,138.11,137.97,136.21,135.09,127.73,124.72,120.49,118.26,118.07,98.28,95.71,94.94,81.90,80.52,80.40(2-C),79.28,79.14,77.24,75.73,68.46,68.30,68.20,67.72,67.19,66.79,56.84,56.58,45.73,40.37,39.75,38.71,36.74,35.04,34.63,34.37,31.44,30.02,26.99,26.63,26.52,25.58,23.20(2-C),20.22,19.98,18.37,17.42,16.65,15.18,7.03.
HRMS(ESI)m/z calcd.for C54H79NNaO15:(M+Na)+,1004.5342；found 1004.5361.
R＝CH2＝CHCH2.(化合物烯丙氨基甲酸酯取代多拉菌素)核磁共振氢谱如图21，基本数据如下：
1HNMR(400MHz,CDCl3)δ5.91-5.80(m,2H,H9,CH2＝CH-CH2),5.75(t,J＝9.3Hz,3H,H10,H11,H23),5.54(dd,J＝9.9,2.5Hz,1H,H22),5.47–5.33(m,3H,H3,H19,H1"),5.24–5.09(m,2H,CH2 ＝CH-CH2),5.01(d,J＝10.8Hz,1H,H15),4.76(dd,J＝18.4,5.4Hz,2H,H1′,NHCOO),4.69(t,J＝3.2Hz,2H,H8a),4.54(t,J＝9.4Hz,1H,H4″),4.29(d,J＝7.1Hz,1H,H5),4.06(s,1H,H7-OH),3.97(d,J＝6.2Hz,1H,H6),3.94(s,1H,H13),3.91-3.76(m,5H,H17,H5′,H5",CH2＝CH-CH2 ),3.61(qd,J＝10.3,4.6Hz,2H,H3′,H3"),3.43(s,3H,H3′-OMe),3.38(s,3H,H3"-OMe),3.34–3.20(m,3H,H2,H25,H4′),2.53(t,J＝7.8Hz,1H,H12),2.29(ddd,J＝31.5,16.0,7.3Hz,6H,H5-OH,H16,H24,H2′a,H2"a),2.04–1.97(m,1H,H20a),1.88(d,J＝2.1Hz,3H,H4a-CH3),1.80(d,J＝9.3Hz,3H,H27a,H30a,H31a),1.71-1.61(m,5H,H18a,H28a,H26,H29),1.49(d,J＝5.7Hz,4H,H14a-CH3,H20b),1.34–1.12(m,15H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3),0.93(d,J＝7.1Hz,3H,H24a-CH3),0.89–0.82(m,1H,H18b).13C NMR(100MHz,CDCl3)δ173.70,155.84,139.60,138.13,137.99,136.21,135.09,134.53,127.74,124.73,120.50,118.27,118.08,115.89,98.29,95.71,94.93,81.89,80.49,80.41(2-C),79.29,79.13,77.23,75.80,68.47,68.30,68.20,67.73,67.19,66.78,56.90,56.58,45.74,43.49,40.37,39.76,38.71,36.75,35.08,34.63,34.38,31.45,30.03,26.99,26.63,26.52,25.59,20.23,19.98,18.40,17.40,16.65,15.19.
HRMS(ESI)m/z calcd.for C54H79NNaO15:(M+Na)+,1004.5342；found 1004.5386.
R＝C6H5CH2(化合物苄氨基甲酸酯取代多拉菌素)核磁共振氢谱如图15，基本数据如下：
.1H NMR(400MHz,CDCl3)δ7.36-7.27(m,5H,Ph),5.88(d,J＝10.1Hz,1H,H9),5.82–5.66(m,3H,H10,H11,H23),5.54(dd,J＝9.9,2.5Hz,1H,H22),5.41(d,J＝11.5Hz,3H,H3,H19,H1"),5.00(d,J＝9.2Hz,2H,H15,NHCOO),4.78(d,J＝3.8Hz,1H,H1′),4.68(dd,J＝4.4,2.4Hz,2H,H8a),4.58(t,J＝9.4Hz,1H,H4″),4.41(d,J＝6.0Hz,2H,Ph-CH2 ),4.30(t,J＝7.1Hz,1H,H5),4.06(s,1H,H7-OH),3.97(d,J＝6.2Hz,1H,H6),3.93(s,1H,H13),3.84(dq,J＝15.7,6.1,5.4Hz,3H,H17,H5′,H5"),3.66–3.53(m,2H,H3′,H3"),3.43(s,3H,H3′-OMe),3.38(s,3H,H3"-OMe),3.34–3.18(m,3H,H2,H25,H4′),2.52(t,J＝7.7Hz,1H,H12),2.39–2.18(m,6H,H5-OH,H16,H24,H2′a,H2"a),2.03–1.97(m,1H,H20a),1.87(t,J＝2.0Hz,3H,H4a-CH3),1.79(d,J＝9.9Hz,3H,H27a,H30a,H31a),1.67(d,J＝8.8Hz,2H,H18a,H28a),1.56(t,J＝5.8Hz,3H,H26,H29),1.49(d,J＝5.1Hz,4H,H14a-CH3,H20b),1.35–1.07(m,15H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3),0.93(d,J＝7.1Hz,3H,H24a-CH3),0.85(d,J＝12.0Hz,1H,H18b).13C NMR(100MHz,CDCl3)δ173.70,156.08,139.58,138.59,138.13,137.99,136.22,135.09,128.66(3-C),127.74,127.49,127.43,124.72,120.49,118.26,118.08,98.26,95.71,94.92,81.88,80.44,80.40(2-C),79.30,79.13,77.24,75.85,68.46,68.30,68.20,67.72,67.18,66.76,56.91,56.57,45.74,45.17,40.37,39.75,38.71,36.75,35.07,34.63,34.38,31.45,30.03,26.99,26.63,26.53,25.59,20.23,19.99,18.41,17.44,16.65,15.19.
HRMS(ESI)m/z calcd.for C58H81NNaO15:(M+Na)+,1054.5498；found 1054.5531.
R＝4-OCH3-C6H5CH2.(化合物对甲氧基苄氨基甲酸酯取代多拉菌素)核磁共振氢谱如图14，基本数据如下：
1H NMR(400MHz,CDCl3)δ7.21(d,J＝8.5Hz,2H,Ph),6.86(d,J＝8.6Hz,1H,Ph),5.88(d,J＝10.4Hz,1H,H9),5.83–5.66(m,3H,H10,H11,H23),5.54(dd,J＝9.9,2.5Hz,1H,H22),5.48–5.31(m,3H,H3,H19,H1"),5.00(d,J＝10.7Hz,1H,H15),4.94(t,J＝5.9Hz,1H,NHCOO),4.78(d,J＝3.8Hz,1H,H1′),4.68(dd,J＝4.6,2.4Hz,2H,H8a),4.57(t,J＝9.4Hz,1H,H4″),4.31(dd,J＝15.4,6.1Hz,3H,H5,4-CH3O-Ph-CH2 ),4.06(s,1H,H7-OH),3.97(d,J＝6.3Hz,1H,H6),3.93(s,1H,H13),3.91-3.76(s,6H,H17,H5′,H5",4-CH3 O-Ph-CH2),3.67–3.53(m,2H,H3′,H3"),3.42(s,3H,H3′-OMe),3.37(s,3H,H3"-OMe),3.33–3.18(m,3H,H2,H25,H4′),2.52(t,J＝7.3Hz,1H,H12),2.38–2.17(m,6H,H5-OH,H16,H24,H2′a,H2"a),2.04–1.97(m,1H,H20a),1.87(t,J＝2.0Hz,3H,H4a-CH3),1.83–1.75(m,3H,H27a,H30a,H31a),1.73-1.60(m,5H,H18a,H28a,H26,H29),1.48(d,J＝5.3Hz,4H,H14a-CH3,H20b),1.37–1.08(m,15H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3),0.92(d,J＝7.1Hz,3H,H24a-CH3),0.85(d,J＝12.0Hz,1H,H18b).13C NMR(100MHz,CDCl3)δ173.69,159.02,155.99,139.58,138.17,138.13,137.98,136.22,135.08,130.69,128.83,127.74,124.72,120.49,118.26,118.08,114.04(2-C),98.26,95.71,94.92,81.88,80.58,80.40(2-C),79.30,79.13,77.24,75.85,68.46,68.30,68.20,67.72,67.18,66.77,56.93,56.58,55.31,45.74,44.65,40.37,39.75,38.71,36.74,35.08,34.63,34.37,31.45,30.03,27.00,26.63,26.52,25.59,20.23,19.99,18.40,17.44,16.65,15.19.
HRMS(ESI)m/z calcd.for C59H83NNaO16:(M+Na)+,1084.5604；found 1084.5638.
实施例2
一种新型多拉菌素衍生物，其化学通式为
Figure GDA0002243216000000181
结构式为
Figure GDA0002243216000000191
式中：R为4-CH3-Ph。化学名称4-甲基苯基氨基甲酸酯取代多拉菌素衍生物的制备方法，步骤如下：
(1)多拉菌素C5-OH取代基的合成
以二氯甲烷作为溶剂，将多拉菌素、叔丁基二甲基氯硅烷、咪唑、4-二甲氨基吡啶按摩尔比1:3.5:10:0.1混合，在氮气保护下，常温搅拌4小时，加入饱和食盐水，经二氯甲烷萃取、加无水硫酸镁过滤、柱层析(V乙酸乙酯：V石油醚＝1:2)、旋蒸，得到叔丁基二甲基氯硅烷取代的C5-OH的多拉菌素衍生物；
(2)4-甲基苯异氰酸酯的合成
以二氯甲烷和饱和碳酸氢钠作为溶剂，将4-甲基苯胺、三光气按摩尔比1:0.33混合，在0℃左右反应4小时，加入饱和食盐水，经二氯甲烷萃取、无水硫酸镁过滤、旋蒸，得到4-甲基苯异氰酸酯；
(3)以二氯甲烷作为溶剂，将4-甲基苯异氰酸酯、叔丁基二甲基氯硅烷取代的C5-OH的多拉菌素衍生物、4-二甲氨基吡啶按摩尔比5:1:0.1混合，在氮气保护下，常温搅拌5小时，加入饱和食盐水，经二氯甲烷萃取、无水硫酸镁过滤、旋蒸，得到C5-OH保护的4-甲基苯氨基甲酸酯取代多拉菌素衍生物；
(4)以甲醇作为溶剂，将上述C5-OH保护的4-甲基苯氨基甲酸酯取代多拉菌素衍生物、对甲苯磺酸按摩尔比1:3.5混合，在氮气保护下，常温搅拌1小时，加入饱和食盐水，经二氯甲烷萃取、无水硫酸镁过滤、柱层析(V乙酸乙酯：V石油醚＝1:2.5)，得到4-甲基苯氨基甲酸酯取代多拉菌素。
化合物4-甲基苯氨基甲酸酯取代多拉菌素的核磁共振氢谱如图4，基本数据如下：
1H NMR(400MHz,CDCl3)δ7.29(d,J＝8.4Hz,2H,Ph),7.11(d,J＝8.2Hz,2H,Ph),6.56(s,1H,NHCOO),5.94–5.85(m,1H,H9),5.83–5.67(m,3H,H10,H11,H23),5.54(dd,J＝9.8,2.5Hz,1H,H22),5.43(q,J＝2.4Hz,3H,H3,H19,H1"),5.01(d,J＝10.5Hz,1H,H15),4.79(d,J＝3.7Hz,1H,H1′),4.69(dd,J＝4.2,2.4Hz,2H,H8a),4.62(t,J＝9.4Hz,1H,H4″),4.35–4.24(m,1H,H5),4.07(s,1H,H7-OH),3.98(d,J＝6.2Hz,1H,H6),3.95(s,1H,H13),3.86(ddd,J＝9.2,7.5,6.2Hz,3H,H17,H5′,H5"),3.64(dddd,J＝11.5,8.7,7.3,4.9Hz,2H,H3′,H3"),3.44(s,3H,H3"-OMe),3.39(s,3H,H3"-OMe),3.34–3.21(m,3H,H2,H25,H4′),2.58–2.50(m,1H,H12),2.38–2.20(m,9H,H5-OH,H16,H24,H2′a,H2"a,CH3 -Ph),2.04–1.96(m,1H,H20a),1.88(t,J＝2.1Hz,3H,H4a-CH3),1.80(d,J＝7.7Hz,3H,H27a,H30a,H31a),1.72–1.65(m,2H,H18a,H28a),1.55(d,J＝3.8Hz,3H,H26,H29),1.49(d,J＝5.6Hz,4H,H14a-CH3,H20b),1.36–1.14(m,15H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3),0.93(d,J＝7.1Hz,3H,H24a-CH3),0.89–0.82(m,1H,H18b).13C NMR(100MHz,CDCl3)δ173.70,152.89,139.60,138.12,138.00,136.22,135.24,135.09,133.05,129.54(3-C),127.74,124.74,120.50,118.66,118.27,118.08,98.27,95.72,94.93,81.90,80.53,80.41(2-C),79.30,79.14,77.24,75.70,68.47,68.31,68.21,67.73,67.18,66.70,56.83,56.57,45.74,40.37,39.76,38.71,36.76,35.01,34.63,34.38,31.45,30.03,27.00,26.63,26.53,25.59,20.75,20.25,19.99,18.42,17.49,16.65,15.20.
HRMS(ESI)m/z calcd.for C58H81NNaO15:(M+Na)+,1054.5498；found 1054.5427.
其它芳香族氨基甲酯类多拉菌素衍生物的制备方法与实施例2基本相同。部分芳香族氨基甲酯类化合物合成数据如下：
R＝4-F-Ph.(化合物对氟苯氨基甲酸酯取代多拉菌素)的核磁共振氢谱如图8，基本数据如下：
1H NMR(400MHz,CDCl3)δ7.37(dd,J＝8.8,4.8Hz,2H,Ph),7.00(t,J＝8.6Hz,2H,Ph),6.59(s,1H,NHCOO),5.89(d,J＝10.1Hz,1H,H9),5.84–5.67(m,3H,H10,H11,H23),5.54(dd,J＝9.9,2.5Hz,1H,H22),5.48–5.30(m,3H,H3,H19,H1"),5.01(d,J＝10.8Hz,1H,H15),4.82–4.77(m,1H,H1′),4.69(t,J＝3.4Hz,2H,H8a),4.62(t,J＝9.4Hz,1H,H4″),4.30(t,J＝7.2Hz,1H,H5),4.07(s,1H,H7-OH),3.98(d,J＝6.3Hz,1H,H6),3.95(s,1H,H13),3.92–3.79(m,3H,H17,H5′,H5"),3.64(dt,J＝11.9,9.2Hz,2H,H3′,H3"),3.44(s,3H,H3′-OMe),3.39(s,3H,H3"-OMe),3.35–3.21(m,3H,H2,H25,H4′),2.53(t,J＝7.4Hz,1H,H12),2.39–2.18(m,6H,H5-OH,H16,H24,H2′a,H2"a),2.05–1.97(m,1H,H20a),1.88(s,3H,H4a-CH3),1.80(d,J＝9.2Hz,3H,H27a,H30a,H31a),1.72–1.65(m,2H,H18a,H28a),1.56(d,J＝3.5Hz,3H,H26,H29),1.49(d,J＝6.3Hz,4H,H14a-CH3,H20b),1.38–1.12(m,15H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3),0.93(d,J＝7.1Hz,3H,H24a-CH3),0.86(d,J＝12.7Hz,1H,H18b).13C NMR(100MHz,CDCl3)δ173.71,157.68,152.96,139.62,138.10,137.99,136.22,135.08,133.83,127.73,124.75,120.49,118.28,118.07,115.78(2-CAr),115.56(2-CAr),98.24,95.72,94.94,81.92,80.53,80.41(2-C),79.29,79.14,77.24,75.65,68.47,68.31,68.20,67.73,67.16,66.62,56.72,56.55,45.74,40.37,39.75,38.71,36.76,34.95,34.63,34.39,31.45,30.03,27.00,26.63,26.53,25.59,20.25,19.99,18.42,17.49,16.65,15.20.
HRMS(ESI)m/z calcd.for C57H78FNNaO15:(M+Na)+,1058.5314；found 1058.5314
R＝4-Cl-Ph.(化合物对氯苯氨基甲酸酯取代多拉菌素)的核磁共振氢谱如图9，基本数据如下：
.1H NMR(400MHz,CDCl3)δ7.36(d,J＝8.5Hz,2H,Ph),7.27(d,J＝6.8Hz,2H,Ph),6.63(s,1H,NHCOO),5.89(d,J＝10.1Hz,1H,H9),5.84–5.68(m,3H,H10,H11,H23),5.54(dd,J＝9.9,2.5Hz,1H,H22),5.42(d,J＝10.5Hz,3H,H3,H19,H1"),5.01(d,J＝10.6Hz,1H,H15),4.79(d,J＝4.0Hz,1H,H1′),4.69(t,J＝3.4Hz,2H,H8a),4.62(t,J＝9.5Hz,1H,H4″),4.30(t,J＝7.2Hz,1H,H5),4.07(s,1H,H7-OH),3.98(d,J＝6.4Hz,1H,H6),3.94(s,1H,H13),3.91–3.78(m,3H,H17,H5′,H5"),3.69–3.58(m,2H,H3′,H3"),3.44(s,3H,H3′-OMe),3.38(s,3H,H3"-OMe),3.31–3.22(m,3H,H2,H25,H4’),2.53(t,J＝7.5Hz,1H,H12),2.41–2.19(m,6H,H5-OH,H16,H24,H2′a,H2"a),2.04–1.98(m,1H,H20a),1.88(s,3H,H4a-CH3),1.80(d,J＝8.7Hz,3H,H27a,H30a,H31a),1.71–1.65(m,2H,H18a,H28a),1.55(d,J＝3.5Hz,3H,H26,H29),1.49(d,J＝6.3Hz,4H,H14a-CH3,H20b),1.36–1.11(m,15H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3),0.93(d,J＝7.2Hz,3H,H24a-CH3),0.89–0.82(m,1H,H18b).13C NMR(100MHz,CDCl3)δ173.72,152.69,139.63,138.09,138.00,136.45,136.22,135.08,129.05(3-C),128.48,127.73,124.75,120.49,119.82,118.29,118.08,98.23,95.72,94.95,81.93,80.53,80.41(2-C),79.29,79.14,77.24,75.63,68.47,68.31,68.20,67.73,67.15,66.57,56.70,56.54,45.74,40.37,39.75,38.71,36.75,34.92,34.62,34.38,31.45,30.03,27.00,26.63,26.52,25.59,20.25,19.99,18.42,17.49,16.65,15.20.
HRMS(ESI)m/z calcd.for C57H78ClNNaO15:(M+Na)+,1074.4952；found1074.4988.
R＝4-Br-Ph.(化合物对溴苯氨基甲酸酯取代多拉菌素)的核磁共振氢谱如图3，基本数据如下：
1H NMR(400MHz,CDCl3)δ7.41(d,J＝8.9Hz,2H,Ph),7.31(d,J＝8.6Hz,2H,Ph),6.62(s,1H,NHCOO),5.89(d,J＝9.8Hz,1H,H9),5.84–5.66(m,3H,H10,H11,H23),5.54(dd,J＝9.9,2.6Hz,1H,H22),5.43(s,3H,H3,H19,H1"),5.01(d,J＝10.7Hz,1H,H15),4.79(d,J＝3.8Hz,1H,H1′),4.69(d,J＝1.9Hz,2H,H8a),4.62(t,J＝9.4Hz,1H,H4″),4.30(t,J＝7.4Hz,1H,H5),4.08(s,1H,H7-OH),3.98(d,J＝6.2Hz,1H,H6),3.94(s,1H,H13),3.92–3.79(m,3H,H17,H5′,H5"),3.64(ddd,J＝15.7,10.9,5.4Hz,2H,H3′,H3"),3.44(s,3H,H3′-OMe),3.38(s,3H,H3"-OMe),3.34–3.20(m,3H,H2,H25,H4′),2.52(d,J＝7.3Hz,1H,H12),2.41–2.19(m,6H,H5-OH,H16,H24,H2′a,H2"a),2.00(dd,J＝11.4,4.7Hz,1H,H20a),1.88(d,J＝2.0Hz,3H,H4a-CH3),1.80(d,J＝9.7Hz,3H,H27a,H30a,H31a),1.68(dd,J＝11.8,3.4Hz,2H,H18a,H28a),1.65–1.60(m,1H,H26),1.55(d,J＝3.4Hz,2H,H29),1.49(d,J＝5.2Hz,4H,H14a-CH3,H20b),1.35–1.14(m,15H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3),0.93(d,J＝7.2Hz,3H,H24a-CH3),0.87(d,J＝12.3Hz,1H,H18b).13CNMR(100MHz,CDCl3)δ173.72,152.63,139.63,138.10,138.01,136.97,136.23,135.08,131.99(4-C),127.73,124.75,120.49,120.14,118.29,118.08,98.23,95.72,94.94,81.93,80.53,80.41(2-C),79.29,79.13,77.23,75.62,68.48,68.31,68.20,67.73,67.15,66.57,56.70,56.54,45.74,40.37,39.75,38.71,36.76,34.92,34.63,34.38,31.45,30.03,27.00,26.63,26.52,25.58,20.24,19.99,18.42,17.49,16.65,15.20.
HRMS(ESI)m/z calcd.for C57H78BrNNaO15:(M+Na)+,1118.4447；found1118.4458.
R＝2-CH3-Ph.(化合物邻甲基苯氨基甲酸酯取代多拉菌素)的核磁共振氢谱如图18，基本数据如下：
1H NMR(400MHz,CDCl3)δ7.84(s,1H,Ph),7.24–7.13(m,2H,Ph),7.03(t,J＝7.4Hz,1H,Ph),6.42(s,1H,NHCOO),5.89(d,J＝10.3Hz,1H,H9),5.82-5.68(m,3H,H10,H11,H23),5.54(dd,J＝9.8,2.5Hz,1H,H22),5.48–5.32(m,3H,H3,H19,H1"),5.01(d,J＝10.5Hz,1H,H15),4.79(d,J＝3.8Hz,1H,H1′),4.69(t,J＝3.2Hz,2H,H8a),4.64(t,J＝9.4Hz,1H,H4″),4.30(t,J＝6.8Hz,1H,H5),4.07(s,1H,H7-OH),3.98(d,J＝6.2Hz,1H,H6),3.95(s,1H,H13),3.92-3.78(m,3H,H17,H5′,H5"),3.72–3.58(m,2H,H3′,H3"),3.44(s,3H,H3′-OMe),3.41(s,3H,H3"-OMe),3.35–3.19(m,3H,H2,H25,H4′),2.53(t,J＝7.7Hz,1H,H12),2.40–2.16(m,9H,H5-OH,H16,H24,H2′a,H2"a,2-CH3 -Ph),2.04–1.97(m,1H,H20a),1.88(t,J＝1.9Hz,3H,H4a-CH3),1.80(d,J＝8.5Hz,3H,H27a,H30a,H31a),1.68(d,J＝4.5Hz,2H,H18a,H28a),1.56(d,J＝3.4Hz,3H,H26,H29),1.49(d,J＝6.4Hz,4H,H14a-CH3,H20b),1.36–1.14(m,15H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3),0.93(d,J＝7.1Hz,3H,H24a-CH3),0.89–0.82(m,1H,H18b).13C NMR(100MHz,CDCl3)δ173.68,153.21,139.61,138.10,137.98,136.21,135.81,135.09,130.37(2-C),127.74,126.93,124.74,124.24,121.23,120.49,118.28,118.08,98.34,95.72,94.94,81.91,80.67,80.41(2-C),79.29,79.16,77.25,75.70,68.45,68.31,68.21,67.73,67.18,66.67,56.84,56.58,45.74,40.38,39.76,38.72,36.75,35.07,34.63,34.38,31.45,30.04,27.00,26.64,26.53,25.59,20.25,19.98,18.44,17.68,17.48,16.65,15.20.
HRMS(ESI)m/z calcd.for C58H81NNaO15:(M+Na)+,1054.5498；found 1054.5524.
R＝3-Cl-Ph.(化合物间氯苯氨基甲酸酯取代多拉菌素)的核磁共振氢谱如图6，基本数据如下：
1H NMR(400MHz,CDCl3)δ7.54(s,1H,Ph),7.22(d,J＝7.1Hz,2H,Ph),7.04(dt,J＝6.7,2.0Hz,1H,Ph),6.66(s,1H,NHCOO),5.92–5.86(m,1H,H9),5.83–5.68(m,3H,H10,H11,H23),5.54(dd,J＝9.9,2.5Hz,1H,H22),5.43(d,J＝2.8Hz,3H,H3,H19,H1"),5.01(d,J＝10.6Hz,1H,H15),4.79(d,J＝3.8Hz,1H,H1′),4.69(dd,J＝4.3,2.4Hz,2H,H8a),4.62(t,J＝9.4Hz,1H,H4″),4.30(t,J＝6.9Hz,1H,H5),4.07(s,1H,H7-OH),3.98(d,J＝6.2Hz,1H,H6),3.95(s,1H,H13),3.86(dq,J＝10.8,6.0Hz,3H,H17,H5′,H5"),3.66(ddd,J＝11.4,8.8,4.8Hz,2H,H3′,H3"),3.44(s,3H,H3′-OMe),3.38(s,3H,H3"-OMe),3.33–3.20(m,3H,H2,H25,H4′),2.53(t,J＝7.7Hz,1H,H12),2.30(dtd,J＝25.0,11.3,6.8Hz,6H,H5-OH,H16,H24,H2′a,H2"a),2.06–1.96(m,1H,H20a),1.88(t,J＝1.9Hz,3H,H4a-CH3),1.80(d,J＝8.9Hz,3H,H27a,H30a,H31a),1.72–1.65(m,2H,H18a,H28a),1.55(d,J＝3.6Hz,3H,H26,H29),1.49(d,J＝6.4Hz,4H,H14a-CH3,H20b),1.37–1.11(m,15H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3),0.93(d,J＝7.1Hz,3H,H24a-CH3),0.86(d,J＝12.8Hz,1H,H18b).13C NMR(100MHz,CDCl3)δ173.71,152.55,139.62,139.03,138.10,138.00,136.22,135.08,134.82,130.02,127.73,124.75,123.52,120.50,118.69,118.28,118.08,116.52,98.23,95.72,94.94,81.92,80.52,80.41(2-C),79.29,79.14,77.23,75.61,68.48,68.31,68.20,67.73,67.16,66.55,56.70,56.54,45.75,40.37,39.76,38.72,36.76,34.93,34.63,34.39,31.46,30.03,27.00,26.63,26.53,25.59,20.25,19.99,18.43,17.49,16.65,15.20.HRMS(ESI)m/z calcd.for C57H78ClNNaO15:(M+Na)+,1074.4952；found 1074.4940.
R＝4-OCH3-Ph.(化合物对甲氧基苯氨基甲酸酯取代多拉菌素)的核磁共振氢谱如图5，基本数据如下：
1H NMR(400MHz,CDCl3)δ7.30(d,J＝3.3Hz,2H,Ph),6.85(d,J＝9.0Hz,2H,Ph),6.52(s,1H,NHCOO),5.94–5.86(m,1H,H9),5.82–5.67(m,3H,H10,H11,H23),5.54(dd,J＝9.9,2.5Hz,1H,H22),5.48–5.32(m,3H,H3,H19,H1"),5.05–4.96(m,1H,H15),4.79(d,J＝3.7Hz,1H,H1′),4.69(dd,J＝4.5,2.4Hz,2H,H8a),4.62(t,J＝9.2Hz,1H,H4″),4.38–4.26(m,1H,H5),4.08(s,1H,H7-OH),3.98(d,J＝6.2Hz,1H,H6),3.94(s,1H,H13),3.85(dt,J＝9.5,6.3Hz,3H,H17,H5′,H5"),3.78(s,3H,OCH3 ),3.69–3.55(m,2H,H3′,H3"),3.44(s,3H,H3′-OMe),3.39(s,3H,H3"-OMe),3.34–3.19(m,3H,H2,H25,H4′),2.53(t,J＝8.1Hz,1H,H12),2.41–2.18(m,6H,H5-OH,H16,H24,H2′a,H2"a),2.04–1.97(m,1H,H20a),1.89(dt,J＝8.3,2.0Hz,3H,H4a-CH3),1.79(d,J＝7.4Hz,3H,H27a,H30a,H31a),1.73–1.67(m,2H,H18a,H28a),1.55(d,J＝4.1Hz,3H,H26,H29),1.49(d,J＝5.4Hz,4H,H14a-CH3,H20b),1.33–1.14(m,15H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3),0.95–0.90(m,3H,H24a-CH3),0.88–0.81(m,1H,H18b).13C NMR(100MHz,CDCl3)δ173.70,155.98,151.24,139.61,138.12,137.99,136.22,135.09,130.92,127.74,124.74,120.49,120.07,118.28,118.08,114.26(4-C),98.27,95.72,94.94,81.91,80.54,80.41(2-C),79.29,79.14,77.24,75.70,68.47,68.31,68.21,67.73,67.18,66.71,56.82,56.57,55.53,45.74,40.37,39.76,38.72,36.75,35.01,34.63,34.38,31.45,30.03,27.00,26.63,26.53,25.59,20.25,19.99,18.41,17.49,16.65,15.19.
HRMS(ESI)m/z calcd.for C58H81NNaO16:(M+Na)+,1070.5448；found 1070.5398.
R＝Ph.(化合物苯氨基甲酸酯取代多拉菌素)的核磁共振氢谱如图7，基本数据如下：
1H NMR(400MHz,CDCl3)δ7.41(d,J＝8.0Hz,2H,Ph),7.31(t,J＝7.8Hz,2H,Ph),7.06(t,J＝7.4Hz,1H,Ph),6.63(s,1H,NHCOO),5.89(d,J＝10.0Hz,1H,H9),5.84–5.67(m,3H,H10,H11,H23),5.54(dd,J＝9.9,2.5Hz,1H,H22),5.42(d,J＝4.2Hz,3H,H3,H19,H1"),5.01(d,J＝10.6Hz,1H,H15),4.79(d,J＝3.8Hz,1H,H1′),4.69(t,J＝3.2Hz,2H,H8a),4.63(t,J＝9.3Hz,1H,H4″),4.29(d,J＝7.2Hz,1H,H5),4.07(s,1H,H7-OH),3.98(d,J＝6.3Hz,1H,H6),3.95(s,1H,H13),3.86(dq,J＝10.4,5.9Hz,3H,H17,H5′,H5"),3.65(qd,J＝9.7,8.9,4.6Hz,2H,H3′,H3"),3.44(s,3H,H3′-OMe),3.39(s,3H,H3"-OMe),3.34–3.20(m,3H,H2,H25,H4′),2.53(t,J＝7.7Hz,1H,H12),2.40–2.17(m,6H,H5-OH,H16,H24,H2′a,H2"a),2.00(dd,J＝12.4,4.7Hz,1H,H20a),1.88(s,3H,H4a-CH3),1.80(d,J＝8.4Hz,3H,H27a,H30a,H31a),1.69(d,J＝12.4Hz,2H,H18a,H28a),1.55(d,J＝3.5Hz,3H,H26,H29),1.49(d,J＝6.7Hz,4H,H14a-CH3,H20b),1.38–1.13(m,15H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3),0.93(d,J＝7.1Hz,3H,H24a-CH3),0.86(d,J＝12.6Hz,1H,H18b).13CNMR(100MHz,CDCl3)δ173.71,152.77,139.61,138.12,138.01,137.83,136.22,135.09,129.07(3-C),127.74,124.74,123.49,120.50,118.59,118.28,118.08,98.26,95.72,94.94,81.91,80.53,80.41(2-C),79.30,79.14,77.23,75.68,68.48,68.31,68.21,67.73,67.18,66.66,56.81,56.57,45.75,40.37,39.76,38.72,36.76,35.00,34.63,34.38,31.45,30.03,27.00,26.63,26.52,25.59,20.24,19.99,18.42,17.49,16.65,15.20.
HRMS(ESI)m/z calcd.for C57H79NNaO15:(M+Na)+,1040.5342；found 1040.5263.
R＝2,6-di isopropylphenyl.(化合物2,6-二异丙基苯氨基甲酸酯取代多拉菌素)的核磁共振氢谱如图2，基本数据如下：
1H NMR(400MHz,CDCl3)δ7.26(s,1H,Ph),7.16(d,J＝7.7Hz,2H,Ph),5.98(s,1H,NHCOO),5.90(d,J＝10.2Hz,1H,H9),5.84–5.68(m,3H,H10,H11,H23),5.54(dd,J＝9.9,2.5Hz,1H,H22),5.42(d,J＝4.5Hz,3H,H3,H19,H1"),5.01(d,J＝11.4Hz,1H,H15),4.82–4.76(m,1H,H1′),4.69(d,J＝2.9Hz,2H,H8a),4.61(t,J＝9.4Hz,1H,H4″),4.30(t,J＝7.4Hz,1H,H5),4.08(s,1H,H7-OH),3.98(d,J＝6.2Hz,1H,H6),3.95(s,1H,H13),3.88(m,3H,H17,H5′,H5"),3.77–3.58(m,2H,H3′,H3"),3.46(s,3H,H3′-OMe),3.44(s,3H,H3"-OMe),3.35–3.27(m,2H,H2,H25),3.24(d,J＝4.4Hz,2H,CH(CH3)2),3.19–3.11(m,1H,H4′),2.54(d,J＝11.9Hz,1H,H12),2.39–2.19(m,6H,H5-OH,H16,H24,H2′a,H2"a),2.00(dd,J＝12.2,4.6Hz,1H,H20a),1.88(t,J＝2.1Hz,3H,H4a-CH3),1.80(d,J＝9.0Hz,3H,H27a,H30a,H31a),1.68(d,J＝9.6Hz,2H,H18a,H28a),1.56(s,3H,H26,H29),1.49(d,J＝6.7Hz,4H,H14a-CH3,H20b),1.33–1.12(m,27H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3,CH(CH3 )2),0.93(d,J＝7.1Hz,3H,H24a-CH3),0.86(d,J＝12.8Hz,1H,H18b).13CNMR(100MHz,CDCl3)δ173.70,154.69,146.82(2-CPh),139.61,138.14,138.00,136.22,135.08,130.71,128.38,127.74,124.74,123.49(2-CPh),120.50,118.28,118.08,98.35,95.72,94.94,81.89,80.51,80.40(2-C),79.33,79.14,77.24,75.82,68.47,68.31,68.20,67.73,67.21,66.78,56.91,56.58,45.74,40.37,39.76,38.72,36.75,34.62,34.38,31.45,30.03,29.69,28.68(2-C),26.99,26.63,26.52,25.59,23.68(2-C),23.47(2-C),20.24,19.99,18.48,17.31,16.65,15.19.
HRMS(ESI)m/z calcd.for C63H91NNaO15:(M+Na)+,1124.6281；found 1124.6257.
R＝1-naphthalene.(化合物1-萘氨基甲酸酯取代多拉菌素)的核磁共振氢谱如图10，基本数据如下：
1H NMR(400MHz,CDCl3)δ8.01–7.82(m,3H,ArH),7.67(d,J＝8.3Hz,1H,ArH),7.58–7.42(m,3H,ArH),6.99(s,1H,NHCOO),5.90(d,J＝10.2Hz,1H,H9),5.85–5.68(m,3H,H10,H11,H23),5.54(dd,J＝9.9,2.5Hz,1H,H22),5.43(d,J＝3.2Hz,3H,H3,H19,H1"),5.01(d,J＝11.1Hz,1H,H15),4.80(d,J＝3.8Hz,1H,H1′),4.75–4.62(m,3H,H8a,H4),4.30(t,J＝7.0Hz,1H,H5),4.07(s,1H,H7-OH),3.98(d,J＝6.2Hz,1H,H6),3.95(s,1H,H13),3.93–3.79(m,3H,H17,H5′,H5"),3.65(td,J＝13.4,12.2,7.2Hz,2H,H3′,H3"),3.44(d,J＝4.6Hz,6H,H3′-OMe,H3"-OMe),3.35–3.20(m,3H,H2,H25,H4′),2.54(t,J＝7.7Hz,1H,H12),2.44–2.14(m,6H,H5-OH,H16,H24,H2′a,H2"a),2.04–1.98(m,1H,H20a),1.88(s,3H,H4a-CH3),1.80(d,J＝7.7Hz,3H,H27a,H30a,H31a),1.68(d,J＝10.4Hz,2H,H18a,H28a),1.56(d,J＝3.5Hz,3H,H26,H29),1.49(d,J＝7.0Hz,4H,H14a-CH3,H20b),1.36-1.09(m,15H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3),0.93(d,J＝7.2Hz,3H,H24a-CH3),0.86(d,J＝12.5Hz,1H,H18b).13C NMR(100MHz,CDCl3)δ173.72,153.79,139.61,138.13,138.01,136.23,135.09(2-C),134.06,132.43(2-C),128.81,127.74,126.23(2-C),125.98(2-C),125.87,124.74,120.50,118.28,118.08,98.32,95.72,94.94,81.91,80.61,80.42,79.30,79.14,77.57,77.24,75.73,68.48,68.31,68.21,67.74,67.19,66.68,56.87,56.58,45.75,40.38,39.77,38.72,36.76,35.05,34.64,34.39,31.46,30.04,27.01,26.64,26.53,25.59,20.27,20.00,18.45,17.54,16.66,15.20.
HRMS(ESI)m/z calcd.for C61H81NNaO15:(M+Na)+,1090.5498；found 1090.5472.
R＝4-CF3-Ph.(化合物对三氟甲基苯氨基甲酸酯取代多拉菌素)的核磁共振氢谱如图1，基本数据如下：
1H NMR(400MHz,CDCl3)δ7.62–7.47(m,4H,Ph),6.80(s,1H,NHCOO),5.89(d,J＝10.0Hz,1H,H9),5.84–5.67(m,3H,H10,H11,H23),5.54(dd,J＝9.9,2.5Hz,1H,H22),5.49–5.30(m,3H,H3,H19,H1"),5.01(d,J＝10.7Hz,1H,H15),4.79(d,J＝3.8Hz,1H,H1′),4.69(dd,J＝4.3,2.4Hz,2H,H8a),4.63(t,J＝9.4Hz,1H,H4″),4.30(t,J＝7.3Hz,1H,H5),4.08(s,1H,H7-OH),3.98(d,J＝6.2Hz,1H,H6),3.95(s,1H,H13),3.87(m,3H,H17,H5′,H5"),3.65(qd,J＝10.6,10.2,4.8Hz,2H,H3′,H3"),3.44(s,3H,H3′-OMe),3.38(s,3H,H3"-OMe),3.34–3.21(m,3H,H2,H25,H4′),2.54(t,J＝7.6Hz,1H,H12),2.41–2.18(m,6H,H5-OH,H16,H24,H2′a,H2"a),2.00(dd,J＝11.9,4.5Hz,1H,H20a),1.88(d,J＝2.1Hz,3H,H4a-CH3),1.80(d,J＝9.9Hz,3H,H27a,H30a,H31a),1.72–1.65(m,2H,H18a,H28a),1.62(d,J＝8.9Hz,1H,H26),1.56(d,J＝3.9Hz,2H,H29),1.49(d,J＝5.9Hz,4H,H14a-CH3,H20b),1.32–1.15(m,15H,H2"b,H27b,H28b,H30b,H31b,H2′b,H5′-Me,H5"-Me,H12a-CH3),0.93(d,J＝7.2Hz,3H,H24a-CH3),0.86(d,J＝13.3Hz,1H,H18b).13CNMR(100MHz,CDCl3)δ173.72,152.48,140.97,139.64,138.09,138.01,136.23,135.07,127.73,126.37(2-C),126.34(2-C),125.49,124.76,120.49,118.29,118.06(2-C),98.21,95.72,94.95,81.94,80.53,80.41,79.29,79.14,77.56,77.23,75.60,68.47,68.31,68.20,67.73,67.14,66.51,56.66,56.53,45.75,40.37,39.75,38.71,36.76,34.89,34.63,34.39,31.46,30.03,27.00,26.63,26.53,25.59,20.25,19.99,18.42,17.49,16.65,15.20.
HRMS(ESI)m/z calcd.for C58H78F3NNaO15:(M+Na)+,1108.5216；found 1108.5266.

Claims (3)

1.一种氨基甲酯类多拉菌素衍生物在治理玉米螟或黏虫中的应用，其特征在于：
所述多拉菌素衍生物为环丙氨基甲酸酯取代多拉菌素，其化学结构式为：
Figure FDA0002243215990000011
式中：R为环丙基。
2.如权利要求1所述的氨基甲酯类多拉菌素衍生物在治理玉米螟或黏虫中的应用，其特征在于：所述多拉菌素衍生物制备步骤如下：
(1)多拉菌素C4"-OH取代基的合成
1)以二氯甲烷作为溶剂，将多拉菌素、叔丁基二甲基氯硅烷、咪唑、4-二甲氨基吡啶按摩尔比1:3.5:10:0.1混合，在氮气保护下，常温搅拌4小时，经萃取、过滤、柱层析，得到叔丁基二甲基氯硅烷取代C5-OH的多拉菌素衍生物；
2)以二氯甲烷作为溶剂，将上述叔丁基二甲基氯硅烷取代C5-OH的多拉菌素衍生物、羰基二咪唑、4-二甲氨基吡啶按摩尔比1:3.5:2混合，在氮气保护下，常温搅拌3小时，经萃取、过滤、旋蒸，得到羰基咪唑取代C4"-OH的多拉菌素衍生物；
(2)多拉菌素衍生物的合成
1)以二氯甲烷作为溶剂，将羰基咪唑取代C4"-OH的多拉菌素衍生物、脂肪族胺、4-二甲氨基吡啶按摩尔比1.1:1:0.1混合，在氮气保护下，常温搅拌6-8小时，经萃取、过滤、旋蒸，得到C5-OH保护的脂肪族氨基甲酯类多拉菌素衍生物；
2)以甲醇作为溶剂，将上述C5-OH保护的脂肪族氨基甲酯类多拉菌素衍生物、对甲苯磺酸按摩尔比1:3.5混合，在氮气保护下，常温搅拌1-2小时，经萃取、过滤、柱层析，得到脂肪族氨基甲酯类多拉菌素衍生物。
3.如权利要求1所述的氨基甲酯类多拉菌素衍生物在治理玉米螟或黏虫中的应用，其特征在于：所述应用中，所述氨基甲酯类多拉菌素衍生物的用量为12.5mg/L或50mg/L或100mg/L或200mg/L。
CN201710916981.8A 2017-09-30 2017-09-30 一种多拉菌素衍生物的合成及其杀虫应用 Active CN107501368B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710916981.8A CN107501368B (zh) 2017-09-30 2017-09-30 一种多拉菌素衍生物的合成及其杀虫应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710916981.8A CN107501368B (zh) 2017-09-30 2017-09-30 一种多拉菌素衍生物的合成及其杀虫应用

Publications (2)

Publication Number Publication Date
CN107501368A CN107501368A (zh) 2017-12-22
CN107501368B true CN107501368B (zh) 2020-02-21

Family

ID=60700357

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710916981.8A Active CN107501368B (zh) 2017-09-30 2017-09-30 一种多拉菌素衍生物的合成及其杀虫应用

Country Status (1)

Country Link
CN (1) CN107501368B (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110818756B (zh) * 2019-12-27 2022-12-13 中国科学院成都生物研究所 一种多拉菌素结构衍生物及其合成方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1302805A (zh) * 2000-12-06 2001-07-11 南开大学 5－阿(依)维菌素B1a酯的合成及生物活性
WO2005021569A1 (en) * 2003-08-28 2005-03-10 Syngenta Participations Ag Avermectins and avermectin monosaccharides substituted in the 4’- and 4” position having pesticidal properties
CN1738828A (zh) * 2002-12-20 2006-02-22 辛根塔参与股份公司 在4"－或4′－位上有烷氧基甲基取代基的阿维菌素b1和阿维菌素b1单糖衍生物
CN1751049A (zh) * 2003-01-31 2006-03-22 辛根塔参与股份公司 具有农药活性的阿维菌素单糖衍生物

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1733742A (zh) * 2005-07-12 2006-02-15 浙江大学 苯并三嗪衍生物的制备及用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1302805A (zh) * 2000-12-06 2001-07-11 南开大学 5－阿(依)维菌素B1a酯的合成及生物活性
CN1738828A (zh) * 2002-12-20 2006-02-22 辛根塔参与股份公司 在4"－或4′－位上有烷氧基甲基取代基的阿维菌素b1和阿维菌素b1单糖衍生物
CN1751049A (zh) * 2003-01-31 2006-03-22 辛根塔参与股份公司 具有农药活性的阿维菌素单糖衍生物
WO2005021569A1 (en) * 2003-08-28 2005-03-10 Syngenta Participations Ag Avermectins and avermectin monosaccharides substituted in the 4’- and 4” position having pesticidal properties

Also Published As

Publication number Publication date
CN107501368A (zh) 2017-12-22

Similar Documents

Publication Publication Date Title
CA2783504C (en) Divalent and oxabridged heterocyclic nicotine related compounds and preparation methods thereof
TW200936047A (en) Novel systemic pesticide
CN112457288B (zh) 一种胡椒酸衍生物及其应用
CN102892290A (zh) 有害生物防除剂
JP6300207B2 (ja) 新規環状デプシペプチド誘導体およびそれを含んでなる有害生物防除剤
CN110407828B (zh) 一种含噁唑结构的吡唑-5-酰胺类衍生物及其制备方法和用途
US10717756B2 (en) Spinosyn derivatives as insecticides
EP3075729A1 (en) Pyrazole amide compound and application thereof
CN107501368B (zh) 一种多拉菌素衍生物的合成及其杀虫应用
CN108341808B (zh) 一种噁二唑连吡唑类化合物及其用途
CN104231022B (zh) 一种大环内酯类化合物的制备及应用
CN102977166B (zh) 13-硫醚取代多杀菌素衍生物及其制备方法
CN111269281B (zh) 阿维菌素B2a衍生物及其制备方法与应用
CN109422744A (zh) 苦参碱衍生物及其合成和在防治植物病虫害方面的应用
Li et al. Antifeedant activity of camptothecin and its semisynthetic derivatives against Spodoptera litura (Fabricius)(Lepidoptera: Noctuidae) larvae
CN110183434B (zh) 一种噁二唑类化合物及其制备方法和应用
CN110818756B (zh) 一种多拉菌素结构衍生物及其合成方法
CN103570672A (zh) 一种含噻吩环苯甲酰肼类化合物及其制备方法和应用
CN110903336B (zh) 阿维菌素B2a肟醚类衍生物及其在农药上的应用
CN111620837B (zh) 香柏酮噻唑酰胺类化合物、及其制备方法和应用
CN114478667B (zh) 4”,23-氧醚基取代的阿维菌素B2a/B2b衍生物及其制备方法和应用
AU2021245263B2 (en) Aziridine spinosyn derivatives and methods of making
CN110754474B (zh) 奎尼定或奎尼定类衍生物的应用、植物源杀虫剂、奎尼定类衍生物及其制备方法
EP1138666B1 (en) A preparation method for 4-(P-methoxyphenyl)-2-amino-butane and an insecticidal composition comprising it
CN113150053A (zh) 偶氮苯类阿维菌素衍生物及其制备方法和应用

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