CN115433176A - 含硫脲结构的almazole D生物碱衍生物及其制备方法和用途 - Google Patents
含硫脲结构的almazole D生物碱衍生物及其制备方法和用途 Download PDFInfo
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- CN115433176A CN115433176A CN202211188962.5A CN202211188962A CN115433176A CN 115433176 A CN115433176 A CN 115433176A CN 202211188962 A CN202211188962 A CN 202211188962A CN 115433176 A CN115433176 A CN 115433176A
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- China
- Prior art keywords
- group
- almazole
- oxazole
- alkaloid
- indol
- Prior art date
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- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea group Chemical group NC(=S)N UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 title claims abstract description 37
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
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- 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
- A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
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- A—HUMAN NECESSITIES
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- 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
- A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
- A01N47/30—Derivatives containing the group >N—CO—N aryl or >N—CS—N—aryl
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- 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
- A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
- A01N47/32—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N< containing >N—CO—N< or >N—CS—N< groups directly attached to a cycloaliphatic ring
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Abstract
本发明为含硫脲结构的almazole D生物碱衍生物及其制备方法和用途。所述的含硫脲结构的almazole D生物碱衍生物，为具有如下通式(I)所示结构的化合物；通过对almzole D生物碱的结构修饰，引入了硫脲官能团合成系列含硫脲结构的almazole D生物碱衍生物，提高了该类化合物的抗烟草花叶病毒和植物病原菌活性。本发明化合物用作抗植物病毒剂和杀植物病原菌剂，扩大了生物碱almzole D及其衍生物作为生物农药的应用范围。
Description
技术领域
本发明含硫脲结构的almazole D生物碱衍生物及其制备方法和用途，涉及含有硫脲结构杂环化合物的杀生剂，具体地说是含硫脲结构的almazole D生物碱衍生物及其制备方法和用途。
背景技术
Almazole D生物碱是从塞内加尔海岸的红藻中分离得到的一种噁唑类化合物。从自然界提取的含有该类核心骨架的化合物有pimprinine、ws-30581 A、ws-30581 B、almazole C和almazole D、以及martefragin A等生物碱(European Journal ofMedicinalChemistry,2012,53,283-291；Folia Microbiologica,1973,18,524-526；Synthesis,2006,2006,3948-3954；Acta Pharmacologica Sinica,2004,39,37-40；Chemical andPharmaceutical Bulletin,1998,46,1527-1529.)，如结构式一所示。
1960年，Bhate等人(Experientia,1960,16,504.)从链霉菌Streptomycespimprina的培养液中提取分离得到pimprinine,但未确定化学结构。后来Koyama等人发现具有3-(5-吲哚)噁唑结构的pimprinine具有一定的抗微生物活性和药理学活性，可作为单胺氧化酶抑制剂，也具有一定的抗癫痫作用(Agricultural and Biological Chemistry,1981,45,1285-1287.)，此外，Pimprinine也能抑制有震颤素(Tremorine)引起的颤抖和痛觉缺失(Synthesis,2006,2006,3948-3954.)。先达公司的生物活性测试结果表明，pimprinine具有一定的农业杀菌活性，其在100mg/L浓度下，对出芽短梗霉菌(Aureobasidium pullulans)、葡萄灰霉菌(Botrytis cinerea)、稻瘟病菌(Magnaporthegrisea)和小麦叶枯病(Septoria tritici)等多种农作物病菌具有广谱的抑制作用。具有相似结构的ws-30581 A和ws-30581 B是从Streptoverticillium wasksmanni中分离得到,被报道具有抑制血小板聚集的作用(Phycologia,1996,35,239.)。1994年，Guella等人(Helvetica Physica Acta,1994,77,1999-2006.)从塞内加尔沿海的红藻中分离出生物碱almazole C，并确定了almazole C的结构，但并未对其进行活性测试。
1996年，N'Diaye等人(Tetrahedron Letters,1996,37,3049-3050.)从塞内加尔海岸的红藻中分离出一种新型的2,5-二取代噁唑二肽almazole D，后续证明almazole D对革兰氏阴性粘质沙雷氏菌和伤寒沙门氏菌XLD具有抗菌作用，而且没有潜在的副作用，既不具有细胞毒性，也不具有溶血或AcChE抑制作用。
Miyake等人在2010年(Tetrahedron,2010,66,4888-4893.)报道了合成了噁唑天然产物almazole D，并提出对almazole D结构的修改，见反应式一。该课题组首先以吲哚-3-羰基氰化物为原料与异氰基乙酸甲酯，进行环加成得到中间体5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯，随后经过水解得到氧代色氨酸甲酯，后者与N,N-二甲基苯丙氨酸进行偶合生成酰胺，并利用POCl3进行环化，最后进行水解可得到almazole D生物碱。
2017年，Lade等人(ChemistrySelect,2017,2,1250-1252.)设计合成了almazoleD生物碱(反应式二)和它的异构体，并利用离体MABA测试方法对almazole D及其异构体的抗结核分枝杆菌作用进行了测试，最小抑制浓度(MIC)分别为100和12μM，almazole D生物碱及其中间体的MIC也达到了6.25、12.50、12.50、6.25和12.5μM，发现它们对结核分枝杆菌有较强的抑制作用，证实3-(5-吲哚基)噁唑骨架具有药物特性，对抗结核生物药物提供了探索机会。
2020年Mhlongo等人(Marine Drugs,2020,18,203.)对含噁唑结构的肽类分子进行了总结报道，其中包括长线型肽、环肽、双环肽等多种化合物，而almazoles A-D属于短线型肽的一种，发现大部分化合物具有一定的生物活性，这将有助于新型药物的研发。
2021年，Oberheide等人(Advanced Synthesis and Catalysis,2021,363,1132-1136.)利用交叉偶联方法合成了生物碱almazole D，首先将羧酸、咪唑三氟甲磺酸盐和三乙胺的1,2-二氯乙烷溶液分离纯化得到氨基磺酸盐，随后与受保护的1-(苯磺酰基)-3-吲哚硼酸发生交叉偶联反应，以90％的收率得到噁唑基吲哚化合物，经脱除保护基及胺甲基化，最后，在碱性条件下羧酸酯发生水解、脱除苯磺酸保护基实现almazole D生物碱的全合成，见反应式三。
Almazole D生物碱因其具有独特的3-(5-吲哚)噁唑结构，引起了广泛的关注。多个研究小组对其结构进行修饰并进行生物活性研究。缪宇平(缪宇平.海藻生物活性物质研究—1.天然海藻抗氧化剂-吲哚噁唑生物碱martefragin A衍生物的合成及其生物活性研究；2.麻痹性贝毒之膝沟藻毒素gonyautoxins的制备及其测定方法研究[D].上海:复旦大学,2003.)以具有相同骨架的生物碱martefraginA为先导化合物，在结构上保留了吲哚噁唑结构，在侧链上加以改造，如引入芳环，同时在芳环上引入不同的取代基，合成了系列衍生物并系统考察了目标化合物对β-胡萝卜素亚油酸抗氧化模型、DPPH抗氧化模型以及P-388抗肿瘤的活性测试，发现个别衍生物在β-胡萝卜素模型(IC50为0.45mmol/mL)和DPPH模型(IC50为3.86mmol/mL)中的活性比比对照物BHA(IC50为0.84mmol/mL)和维生素E(IC50为12.56mmol/mL)强，且在P-388抗肿瘤模型中表现了一定的抗肿瘤活性(浓度为10-4M时抑制率为70％左右)。
通过文献调研，由于almazole D生物碱自然界含量低，且合成收率低、成本高，研究人员对其应用研究主要集中在医药比如抗结核方面，在控制病虫害方面还鲜有报道。
发明内容
本发明的目的是提供含硫脲结构的almazole D生物碱衍生物及其制备方法和在防治植物病害方面的应用。本发明的含硫脲结构的almazole D生物碱衍生物表现出很好的抗植物病毒活性以及杀菌活性。通过对almzole D生物碱的结构修饰引入硫脲官能团提高了该类化合物的抗烟草花叶病毒活性；引入硫脲结构片段后，化合物(S)-5-(1H-吲哚-3-基)-2-(2-苯基-1-(3-(对甲苯基)硫脲基)乙基)噁唑-4-羧酸甲酯(化合物I-4b)抗TMV活性大大提高。本发明在杀菌活性测试中，almzole D生物碱在离体测试中测试浓度为50μg/L的条件下对小麦纹枯病原菌的杀菌活性达51％，同等测试条件下，含硫脲结构片段的(S)-2-(1-(3-(2-溴苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸甲酯(化合物I-4i)可达87％，引入硫脲结构片段后明显优于almzole D生物碱，且多数化合物均具有广谱的杀菌活性，扩大了生物碱almzole D及其衍生物作为生物农药的应用范围。
本发明的技术方案为：
含硫脲结构的almazole D生物碱衍生物，为具有如下通式(I)所示结构的化合物：
上述化学结构式通式Ⅰ中，R代表氢或甲基；
R1代表氢、甲基、苯基、丙基、异丙基、正丁基、正丁基、叔丁基、苄基、环戊基、二苯基、环己基、2-氟苯基、3-氟苯基、4-氟苯基、3,4-二氟苯基、2,6-二氟苯基、2,4-二氟苯基、2,3-二氟苯基、4-氟苯基、2-氯苯基、3-氯苯基、3,4-二氯苯基、2,6-二氯苯基、2,4-二氯苯基、2,3-二氯苯基、2,5-二氯苯基、4-氯苯基、5-氯-2-氟苯基、2-溴苯基、3-溴苯基、4-溴苯基、4-碘苯基、2-硝基苯基、3-硝基苯基、4-硝基苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-三氟甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、3,5-双(三氟甲基)苯基、3-甲氧基苯基、2,4-二甲氧基苯基、3,4,5-三(甲氧基)苯基、4-甲氧基苯基、2-噻吩基、2-呋喃基、2-吡啶基或4-吡啶基。
上述含硫脲结构的almazole D生物碱衍生物，优选具有如下化学结构式I-4a～I-4n和I-5a～I-5d所示的化合物：
上述含硫脲结构的almazole D生物碱衍生物的制备方法，具体步骤如下化学反应方程式所示：
通过使用容易获得的N-Boc-L-苯丙氨酸与L-色氨酸甲酯盐酸盐的偶联反应，生成如化学结构式1所示的(叔丁氧羰基)-L-苯丙氨酰色氨酸甲酯；将该中间体溶解在无水四氢呋喃溶液中，在无水条件下用二氯二氰苯醌(DDQ)对酰胺进行氧化环化便可得到如化学结构式2所示N-Boc保护的(S)-2-(1-((叔丁氧基羰基)氨基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯；随后又利用三氟乙酸(TFA)对噁唑的叔丁基羰基进行脱保护得到如化学结构式3所示手性伯胺化合物(S)-2-(1-氨基-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯；其中，通过对(S)-2-(1-氨基-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯的伯胺官能团进行修饰合成系列almazole D衍生物。具体为，以(S)-2-(1-氨基-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯与不同取代的异硫氰酸酯进行反应如化学结构式通式Ⅰ所示的含手性硫脲结构的系列almazole D生物碱衍生物；后续再进行水解反应，便可得到含羧酸及硫脲结构单元的系列almazole D生物碱衍生物。
上述含硫脲结构的almazole D生物碱衍生物，用作抗植物病毒剂，
所述植物病毒为烟草花叶病毒。
上述含硫脲结构的almazole D生物碱衍生物的用途，用作杀植物病原菌剂，
所述植物病原菌为黄瓜枯萎菌、花生褐斑菌、苹果轮纹菌、小麦纹枯菌、番茄早疫菌、水稻稻瘟菌、油菜菌核菌或辣椒疫霉菌。
本发明的有益效果是：与现有技术相比，本发明具有的突出的实质性特点和显著进步如下：
(1)生物活性性能大大提高。通过对almzole D生物碱的结构修饰引入硫脲官能团提高了该类化合物的抗烟草花叶病毒活性，在用药量为500μg/mL时，活体钝化、活体治疗和活体保护三种测试模式下almzole D生物碱抗烟草花叶病毒活性分别为为37％、34％和34％，引入硫脲结构片段后，化合物(S)-5-(1H-吲哚-3-基)-2-(2-苯基-1-(3-(对甲苯基)硫脲基)乙基)噁唑-4-羧酸甲酯(化合物I-4b)抗TMV活性大大提高(活体钝化、活体治疗和活体保护测试模式下，抑制率分别为：50％、46％和48％)；在离体杀菌测试中，比如筛选出来的化合物(S)-2-(1-(3-(3-氯苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3基)-噁唑-4-羧酸(化合物I-5a)在用药浓度为50μg/L的条件下对小麦纹枯病原菌的杀菌活性达58％，优于防效效果好的商品化品种多菌灵(52％)；同等测试条件下，化合物(S)-5-(1H-吲哚-3-基)-2-(2-苯基-1-(3-苯基硫脲基)乙基)噁唑-4-羧酸甲酯(化合物I-4a)对番茄早疫病的杀菌活性达50％，而明显高于商品化品种多菌灵(＜50％)和almazole D生物碱(36％)，多数化合物均具有广谱性，扩大了生物碱almazole D及其衍生物作为生物农药的应用范围。
(2)简化了化合物的合成。通过对比反应式三，本发明专利的化合物I-4b～I-4n不仅具有良好的抗烟草花叶病毒活性，而且与天然产物almazole D相比无需进行水解，减少了大量氢氧化钠溶液的使用，节约了资源。
具体实施方式
实施例1
化学结构式I-4a所示的制备方法如下：(S)-5-(1H-吲哚-3-基)-2-(2-苯基-1-(3-苯基硫脲基)乙基)噁唑-4-羧酸甲酯的制备方法如下：
(S)-5-(1H-吲哚-3-基)-2-(2-苯基-1-(3-苯基硫脲基)乙基)噁唑-4-羧酸甲酯的化学结构式I-4a为
其制备方法的具体步骤如下：
第一步：取100mL圆底烧瓶，将L-色氨酸甲酯盐酸盐(1.75g,8.0mmol,1.0equiv.)溶于二氯甲烷(40mL)中，加入Et3N(2.36mL,17.0mmol,2.1equiv.)、N-Boc保护的苯丙氨酸(2.12g,8.0mmol,1.0equiv.)，冰水浴下加入碳二亚胺盐酸盐(EDCl)(1.68g,8.8mmol,1.1equiv.)，加入羟基苯并三唑(HOBt)(1.16g,8.8mmol,1.1equiv.)，搅拌30min，然后在室温下搅拌6h，TLC监测，待反应完成后加水萃取，用无水硫酸镁(15.5g)干燥有机相，过滤后真空脱溶，残留液用石油醚：乙酸乙酯(2：1)重结晶，即可得到白色固体化合物1，收率为79.2％，经测定，该白色固体物质的相关参数为：1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),8.31(d,J＝7.6Hz,1H),7.49(d,J＝7.8Hz,1H),7.34(d,J＝8.0Hz,1H),7.27-7.15(m,6H),7.07(t,J＝7.5Hz,1H),6.99(t,J＝7.4Hz,1H),6.88(d,J＝8.7Hz,1H),4.60-4.49(m,1H),4.26-4.14(m,1H),3.56(s,3H),3.13(m,2H),2.92(dd,J＝13.9,4.2Hz,1H),2.75-2.62(m,1H),1.28(s,9H)；13C NMR(100MHz,DMSO-d6)δ172.2,171.8,155.1,138.0,136.0,129.2,127.9,127.0,126.1,123.7,121.0,118.4,118.0,111.4,109.1,78.0,55.5,53.0,51.8,37.4,28.1,27.0；确定该中间产物为(叔丁氧羰基)-L-苯丙氨酰色氨酸甲酯。
第二步：将二氯二氰苯醌(DDQ)(0.34g,1.5mmol,3.0equiv.)溶于四氢呋喃溶液(10mL)中，逐滴加入化合物1(0.233g,0.5mmol,1.0equiv.)的四氢呋喃溶液(15mL)，在65℃下加热回流4h，TLC监测，反应结束后真空脱去溶剂，残渣用乙酸乙酯溶解，并用饱和碳酸氢钠溶液及饱和食盐水洗涤，有机相用无水硫酸镁(10.0g)干燥，过滤后真空脱溶，粗产品经柱层析提纯即可得到白色固体化合物2，收率为45％，经测定，该白色固体物质的相关参数为：1H NMR(400MHz,CDCl3)δ8.85(s,1H),8.70(s,1H),7.76(d,J＝8.0Hz,1H),7.40(d,J＝8.1Hz,1H),7.28(s,1H),7.26-7.12(m,6H),5.33(s,1H),3.94(s,3H),3.34(d,J＝3.2Hz,2H),1.44(s,9H)；13C NMR(100MHz,CDCl3)δ163.0,159.8,154.9,135.9,135.7,129.7,129.3,128.7,127.1,125.0,123.1,122.8,121.4,121.3,111.6,103.7,100.0,80.3,52.0,50.3,40.4,28.3；确定该中间产物为(S)-2-(1-((叔丁氧基羰基)氨基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸酯。
第三步：称取化合物2(0.5g,1.0mmol,1.0equiv.)于50mL圆底烧瓶中，加入二氯甲烷(10mL)、三氟乙酸(5mL)，室温搅拌2h，TLC监测，反应完成后真空脱溶，残留物用氯仿重结晶，可得到白色固体化合物3，收率为80％；经测定，该白色固体物质的相关参数为：1H NMR(400MHz,Methanol-d4)δ8.68(s,1H),7.67(d,J＝8.1Hz,1H),7.46(d,J＝8.2Hz,1H),7.28(dt,J＝21.3,6.6Hz,6H),7.14(d,J＝7.7Hz,1H),4.99(dd,J＝9.1,6.2Hz,1H),3.92(s,3H),3.54-3.37(m,2H)；13C NMR(100MHz,Methanol-d4)δ164.1,157.6,156.6,137.7,135.4,131.8,130.4,130.2,129.1,126.2,124.0,123.6,122.4,122.0,113.0,103.5,52.4,51.2,39.5；确定该中间产物为(S)-2-(1-氨基-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯。
第四步：向化合物3(0.2g,0.42mmol,1.0equiv.)的二氯甲烷溶液(3mL)中加入苯基异硫氰酸酯(0.42mmol,1.0equiv.)及三乙胺(0.058mL,0.42mmol,1.0equiv.)，室温下反应，TLC监测，待反应完毕后，反应体系直接利用柱层析提纯即可得到黄色固体产物I-4a，产率为87.2％；经测定，该黄色固体物质的相关参数为：1H NMR(400MHz,CDCl3)δ8.74(s,1H),8.72(d,J＝2.8Hz,1H),7.91(s,1H),7.67(d,J＝8.1Hz,1H),7.42(d,J＝8.1Hz,1H),7.35(t,J＝7.6Hz,2H),7.29(d,J＝7.0Hz,1H),7.25–7.05(m,9H),6.78(s,1H),6.27(q,J＝7.1Hz,1H),3.88(s,3H),3.37(d,J＝6.8Hz,2H)；13C NMR(100MHz,CDCl3)δ180.8,162.7,159.7,155.0,136.3,135.7,135.4,129.7,129.1,128.9,127.4,127.0,125.2,124.9,123.2,122.6,121.6,121.3,111.7,103.6,53.9,51.8,39.7；HR-MS(ESI):calcd forC28H24N4O3S[M+H]+497.1642,found(ESI+)497.1640；确定该产物为5-(1H-吲哚-3-基)-2-(2-苯基-1-(3-苯基硫脲基)乙基)噁唑-4-羧酸甲酯。
实施例2
化学结构式I-2所示(S)-5-(1H-吲哚-3-基)-2-(2-苯基-1-(3-(对甲苯基)硫脲基)乙基)噁唑-4-羧酸甲酯的制备方法如下：
(S)-5-(1H-吲哚-3-基)-2-(2-苯基-1-(3-(对甲苯基)硫脲基)乙基)噁唑-4-羧酸甲酯的化学结构式I-2为
其制备方法的具体步骤如下：
第一步至第三步，同实施例1；
第四步，除用4-甲基苯基异硫氰酸酯替换苯基异硫氰酸酯之外，其他同实施例1，反应体系直接利用柱层析提纯即可得到淡黄色固体产物I-4b，收率82.6％；经测定，该淡黄色固体物质的相关参数为：1H NMR(400MHz,CDCl3)δ8.77(s,1H),8.70(d,J＝2.9Hz,1H),7.78(s,1H),7.63(d,J＝8.0Hz,1H),7.41(d,J＝8.1Hz,1H),7.27(s,0.5H),7.24–7.19(m,3.5H),7.17–7.12(m,3H),7.08(dd,J＝6.5,2.8Hz,2H),6.99(d,J＝8.0Hz,2H),6.65(s,1H),6.25(q,J＝7.1Hz,1H),3.90(s,3H),3.35(dt,J＝14.0,6.6Hz,2H),2.36(s,3H)；13CNMR(100MHz,CDCl3)δ180.9,162.8,159.5,154.9,137.4,135.7,135.4,133.3,130.5,129.6,129.2,128.8,127.3,125.6,124.9,123.1,122.8,121.5,121.3,111.6,103.6,53.9,51.8,39.8,21.1；HR-MS(ESI):calcd for C29H26N4O3S[M+H]+511.1799,found(ESI+)511.1792；确定该产物为(S)-5-(1H-吲哚-3-基)-2-(2-苯基-1-(3-(对甲苯基)硫脲基)乙基)噁唑-4-羧酸甲酯。
实施例3
化学结构式I-4c所示(S)-5-(1H-吲哚-3-基)-2-(1-(3-(4-甲氧基苯基)硫脲基)-2-苯乙基)噁唑-4-羧酸甲酯的制备方法如下：
(S)-5-(1H-吲哚-3-基)-2-(1-(3-(4-甲氧基苯基)硫脲基)-2-苯乙基)噁唑-4-羧酸甲酯的化学结构式I-4c为
其制备方法的具体步骤如下：
第一步至第三步，同实施例1；
第四步，除用4-甲氧基苯基异硫氰酸酯替换苯基异硫氰酸酯之外，其他同实施例1，反应体系直接利用柱层析提纯即可得到淡黄色固体产物I-4c，收率73.1％；经测定，该淡黄色固体物质的相关参数为：1H NMR(400MHz,CDCl3)δ9.03(s,1H),8.64(d,J＝3.0Hz,1H),7.95(s,1H),7.60(d,J＝8.0Hz,1H),7.38(d,J＝8.1Hz,1H),7.23–7.16(m,4H),7.15–7.01(m,5H),6.87–6.82(m,2H),6.65(s,1H),6.27(q,J＝7.1Hz,1H),3.83(s,3H),3.81(s,3H),3.31(d,J＝6.6Hz,2H)；13C NMR(100MHz,CDCl3)δ181.2,162.7,159.4,158.8,154.9,135.7,135.4,129.7,129.2,128.8,127.7,127.3,124.9,123.0,122.6,121.4,121.2,115.0,111.7,103.5,55.5,53.9,51.8,39.8；HR-MS(ESI):calcd for C29H26N4O4S[M+H]+527.1748,found(ESI+)527.1751；确定该产物为(S)-5-(1H-吲哚-3-基)-2-(1-(3-(4-甲氧基苯基)硫脲基)-2-苯乙基)噁唑-4-羧酸甲酯。
实施例4
化学结构式I-4d所示(S)-2-(1-(3-(2,4-二甲氧基苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯的制备方法如下：
(S)-2-(1-(3-(2,4-二甲氧基苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯的化学结构式I-4d为
第四步，除用2,4-二甲氧基苯基异硫氰酸酯替换苯基异硫氰酸酯之外，其他同实施例1，反应体系直接利用柱层析提纯即可得到黄色固体产物I-4d，收率67％；经测定，该黄色固体物质的相关参数为：1H NMR(400MHz,CDCl3)δ8.77(s,1H),8.73(d,J＝2.9Hz,1H),7.81(s,1H),7.67(d,J＝8.1Hz,1H),7.42(d,J＝8.1Hz,1H),7.26–7.09(m,6H),7.05(dd,J＝6.5,3.1Hz,2H),6.80(d,J＝8.3Hz,1H),6.72(s,1H),6.70(s,1H),6.26(d,J＝7.2Hz,1H),3.88(s,6H),3.68(s,3H),3.36(d,J＝6.9Hz,2H)；13C NMR(100MHz,CDCl3)δ181.0,162.8,159.5,156.1,155.0,149.7,148.2,135.7,135.4,129.7,129.1,128.8,127.3,124.9,123.2,122.7,121.5,121.3,118.2,111.6,111.5,109.7,103.6,56.1,56.0,53.8,51.8,39.7；HR-MS(ESI):calcd for C30H28N4O5S[M+H]+557.1853,found(ESI+)557.1855；确定该产物为(S)-2-(1-(3-(2,4-二甲氧基苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯。
实施例5
化学结构式I-4e所示(S)-2-(1-(3-(4-氟苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯的制备方法如下：
(S)-2-(1-(3-(4-氟苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯的化学结构式I-4e为
第四步，除用4-氟苯基异硫氰酸酯替换苯基异硫氰酸酯之外，其他同实施例1，反应体系直接利用柱层析提纯即可得到淡黄色固体产物I-4e，收率71％；经测定，该淡黄色固体物质的相关参数为：1H NMR(400MHz,CDCl3)δ8.85(s,1H),8.73(d,J＝3.0Hz,1H),8.22(s,1H),7.72(d,J＝7.9Hz,1H),7.44(d,J＝8.1Hz,1H),7.29(s,0.5H),7.25–6.93(m,11.5H),6.31(d,J＝7.5Hz,1H),3.77(s,3H),3.40–3.20(m,2H)；13C NMR(100MHz,CDCl3)δ181.3,162.4,155.2,135.7,135.3,129.8,129.0(d,JC-F＝9.6Hz),127.5,127.1(d,JC-F＝7.5Hz),124.8,123.3,122.4,121.7,121.2,116.2,115.9,111.7,103.5,53.6,51.7,39.6；HR-MS(ESI):calcd for C28H23FN4O3S[M+H]+515.1548,found(ESI+)515.1551；确定该产物为(S)-2-(1-(3-(4-氟苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯。
实施例6
化学结构式I-4f所示(S)-2-(1-(3-(4-氯苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯的制备方法如下：
(S)-2-(1-(3-(4-氯苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯的化学结构式I-4f为
第四步，除用4-氯苯基异硫氰酸酯替换苯基异硫氰酸酯之外，其他同实施例1，反应体系直接利用柱层析提纯即可得到淡黄色固体产物I-4f，收率65.1％；经测定，该淡黄色固体物质的相关参数为：1H NMR(400MHz,CDCl3)δ9.01(s,1H),8.74(d,J＝3.0Hz,1H),7.77(d,J＝8.1Hz,1H),7.47(d,J＝8.1Hz,1H),7.33–7.26(m,3H),7.18(m,8H),7.03(dd,J＝6.5,2.8Hz,2H),6.37(q,J＝7.1Hz,1H),3.65(s,3H),3.31(dd,J＝14.4,5.6Hz,1H),3.10(dd,J＝14.3,7.1Hz,1H)；13C NMR(100MHz,CDCl3)δ180.9,162.1,160.7,155.7,136.7,135.8,135.1,130.7,130.0,129.0,128.9,128.8,127.6,125.0,124.8,123.4,121.9,121.9,121.0,111.7,103.2,53.1,51.6,39.3；HR-MS(ESI):calcd for C28H23ClN4O3S[M+H]+531.1252,found(ESI+)531.1247；确定该产物为(S)-2-(1-(3-(4-氯苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯。
实施例7
化学结构式I-4g所示(S)-2-(1-(3-(3-氯苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯的制备方法如下：
(S)-2-(1-(3-(3-氯苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯的化学结构式I-4g为
第四步，除用3-氯苯基异硫氰酸酯替换苯基异硫氰酸酯之外，其他同实施例1，反应体系直接利用柱层析提纯即可得到淡黄色固体产物I-4g，收率83.9％；经测定，该淡黄色固体物质的相关参数为：1H NMR(400MHz,CDCl3)δ8.85(s,1H),8.78(d,J＝2.9Hz,1H),8.54(s,1H),7.82(d,J＝8.1Hz,1H),7.47(d,J＝8.3Hz,3H),7.30(t,J＝7.6Hz,1H),7.25–7.03(m,9H),6.34(d,J＝7.0Hz,1H),3.71(s,3H),3.34(dd,J＝14.4,5.8Hz,1H),3.19(s,1H)；13C NMR(100MHz,CDCl3)δ180.8,162.4,160.6,155.3,135.7,135.3,129.9,129.8,128.9,127.5,125.8,124.9,123.7,123.4,122.5,121.9,121.2,111.7,103.6,53.4,51.7,39.4；HR-MS(ESI):calcd for C28H23ClN4O3S[M+H]+531.1252,found(ESI+)531.1250；确定该产物为(S)-2-(1-(3-(3-氯苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯。
实施例8
化学结构式I-4h所示(S)-2-(1-(3-(2,4-二氯苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯的制备方法如下：
(S)-2-(1-(3-(2,4-二氯苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯的化学结构式I-4h为
第四步，除用2,4-二氯苯基异硫氰酸酯替换苯基异硫氰酸酯之外，其他同实施例1，反应体系直接利用柱层析提纯即可得到黄色固体产物I-4h，收率52.4％；经测定，该黄色固体物质的相关参数为:1H NMR(400MHz,CDCl3)δ8.77(s,1H),8.74(d,J＝3.1Hz,1H),7.80(s,1H),7.66(d,J＝8.1Hz,1H),7.50–7.40(m,3H),7.31–7.27(m,1H),7.23(dd,J＝5.0,1.9Hz,4H),7.18(m,1H),7.13–7.09(m,3H),6.24(q,J＝7.0Hz,1H),3.86(s,3H),3.50–3.36(m,2H)；13CNMR(100MHz,CDCl3)δ180.9,162.7,160.4,155.3,135.8,135.3,133.4,131.5,129.9,129.5,129.1,128.9,128.5,127.5,127.4,126.6,124.9,123.3,122.4,121.7,121.2,111.8,103.3,53.9,51.9,39.8；HR-MS(ESI):calcd for C28H22Cl2N4O3S[M+H]+565.0863,found(ESI+)565.0869；确定该产物为(S)-2-(1-(3-(2,4-二氯苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯。
实施例9
化学结构式I-4i所示(S)-2-(1-(3-(2-溴苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸甲酯的制备方法如下：
(S)-2-(1-(3-(2-溴苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸甲酯的化学结构式I-4i为
第四步，除用2-溴苯基异硫氰酸酯替换苯基异硫氰酸酯之外，其他同实施例1，反应体系直接利用柱层析提纯即可得到黄色固体产物I-4i，收率75％；经测定，该黄色固体物质的相关参数为:1H NMR(400MHz,CDCl3)δ8.76(s,1H),8.71(d,J＝2.9Hz,1H),7.70–7.59(m,3H),7.42(d,J＝8.1Hz,1H),7.28(d,J＝7.8Hz,1H),7.26–7.06(m,9H),6.66(d,J＝8.0Hz,1H),6.23(d,J＝7.3Hz,1H),3.92(s,3H),3.44(m,2H)；13C NMR(100MHz,CDCl3)δ180.5,163.0,159.2,154.9,135.6,135.4,134.7,133.9,129.6,129.2,128.9,128.7,128.6,127.3,127.2,125.0,123.3,123.0,121.6,121.4,120.2,111.5,103.8,54.2,52.0,39.8；HR-MS(ESI):calcd for C28H23BrN4O3S[M+H]+575.0747,found(ESI+)575.0749；确定该产物为(S)-2-(1-(3-(2-溴苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸甲酯。
实施例10
化学结构式I-4j所示(S)-2-(1-(3-(4-溴苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸甲酯的制备方法如下：
(S)-2-(1-(3-(4-溴苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸甲酯的化学结构式I-4j为
第四步，除用4-溴苯基异硫氰酸酯替换苯基异硫氰酸酯之外，其他同实施例1，反应体系直接利用柱层析提纯即可得到淡黄色固体产物I-4j，收率75.9％；经测定，该淡黄色固体物质的相关参数为:1H NMR(400MHz,CDCl3)δ8.93(s,1H),8.77(d,J＝2.9Hz,1H),8.64(s,1H),7.79(d,J＝8.0Hz,1H),7.48(d,J＝8.1Hz,2H),7.32(t,J＝8.0Hz,3H),7.25–7.14(m,6H),7.08–7.00(m,2H),6.35(d,J＝7.1Hz,1H),3.66(s,3H),3.31(dd,J＝14.5,5.6Hz,1H),3.12(s,1H)；13C NMR(100MHz,CDCl3)δ180.8,162.2,160.7,155.6,135.8,135.2,131.8,129.9,128.9,128.9,127.6,125.2,124.8,123.4,122.1,121.9,121.1,111.7,103.4,53.2,51.6,39.3；HR-MS(ESI):calcd for C28H23BrN4O3S[M+H]+575.0747,found(ESI+)575.0750；确定该产物为(S)-2-(1-(3-(4-溴苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸甲酯。
实施例11
化学结构式I-4k所示(S)-2-(1-(3-二苯甲基硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯的制备方法如下：
(S)-2-(1-(3-二苯甲基硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯的化学结构式I-4k为
第四步，除用1,2-二苯甲基异硫氰酸酯替换苯基异硫氰酸酯之外，其他同实施例1，反应体系直接利用柱层析提纯即可得到淡黄色固体产物I-4j，收率68.3％；经测定，该淡黄色固体物质的相关参数为：1H NMR(400MHz,CDCl3)δ8.87(s,1H),8.68(d,J＝2.9Hz,1H),7.66(d,J＝8.1Hz,1H),7.42(d,J＝8.2Hz,1H),7.29(d,J＝6.0Hz,5H),7.26–7.09(m,11H),6.98(s,2H),6.77(s,1H),6.56(s,1H),6.14(s,1H),3.87(s,3H),3.41(dd,J＝13.9,5.6Hz,1H),3.30(dd,J＝13.1,6.7Hz,1H)；13C NMR(100MHz,DMSO-d6)δ182.0,163.0,160.1,154.6,142.8,142.6,137.0,136.4,130.4,129.6,128.9,128.9,127.7,127.6,127.5,127.5,127.2,125.1,123.1,122.4,121.5,121.3,112.7,102.6,61.3,55.4,53.5,51.9；确定该产物为(S)-2-(1-(3-二苯甲基硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯。
实施例12
化学结构式I-4l所示(S)-2-(1-(3-苄基硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸甲酯的制备方法如下：
(S)-2-(1-(3-苄基硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸甲酯的化学结构式I-4l为
第四步，除用苄基异硫氰酸酯替换苯基异硫氰酸酯之外，其他同实施例1，反应体系直接利用柱层析提纯即可得到淡黄色固体产物I-4l，收率69.6％；经测定，该淡黄色固体物质的相关参数为：1H NMR(400MHz,CDCl3)δ8.98(s,1H),8.72(d,J＝2.8Hz,1H),7.81(d,J＝8.0Hz,1H),7.66(s,1H),7.51(d,J＝8.0Hz,1H),7.41–7.28(m,5H),7.25–7.18(m,3H),7.15–7.07(m,3H),7.05–6.96(m,2H),6.27(d,J＝7.3Hz,1H),5.21(s,1H),4.50(d,J＝14.3Hz,1H),3.31(s,3H),3.19(dd,J＝14.1,5.7Hz,1H),3.05(s,1H)；13C NMR(100MHz,CDCl3)δ182.7,162.0,161.4,155.3,135.8,135.4,129.8,128.9,128.8,128.6,127.5,127.3,124.9,123.3,121.9,121.9,121.3,111.7,103.5,53.5,51.1,49.0,39.6；HR-MS(ESI):calcd for C29H26N4O3S[M+H]+511.1799,found(ESI+)511.1791；确定该产物为(S)-2-(1-(3-苄基硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸甲酯。
实施例13
化学结构式I-4m所示(S)-2-(1-(3-环己基硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸甲酯的制备方法如下：
(S)-2-(1-(3-环己基硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸甲酯的化学结构式I-4m为
第四步，除用环己基异硫氰酸酯替换苯基异硫氰酸酯之外，其他同实施例1，反应体系直接利用柱层析提纯即可得到淡黄色固体产物I-4m，收率58％；经测定，该淡黄色固体物质的相关参数为：1H NMR(400MHz,CDCl3)δ9.17(s,1H),8.69(d,J＝2.9Hz,1H),7.58(d,J＝8.1Hz,1H),7.49(d,J＝8.2Hz,1H),7.28(d,J＝7.3Hz,1H),7.18–7.04(m,7H),6.55(s,1H),6.28(s,1H),3.81(s,3H),3.25(s,2H),2.14–1.98(m,2H),1.67(dd,J＝45.1,12.7Hz,3H),1.44–1.10(m,6H)；13C NMR(100MHz,CDCl3)δ181.0,162.2,160.9,155.9,135.8,135.5,129.7,129.0,128.7,127.2,124.7,123.0,121.8,121.5,121.0,111.5,103.1,55.9,53.1,51.5,40.1,33.0,32.7,25.5,25.3,25.2；HR-MS(ESI):calcd for C28H30N4O3S[M+H]+503.2112,found(ESI+)503.2114；确定该产物为(S)-2-(1-(3-环己基硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸甲酯。
实施例14
化学结构式I-4n所示(S)-2-(1-(3-丁基硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸甲酯的制备方法如下：
(S)-2-(1-(3-丁基硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸甲酯的化学结构式I-4n为
第四步，除用丁基异硫氰酸酯替换苯基异硫氰酸酯之外，其他同实施例1，反应体系直接利用柱层析提纯即可得到淡黄色固体产物I-4n，收率79％；经测定，该淡黄色固体物质的相关参数为：1H NMR(400MHz,CDCl3)δ9.42(s,1H),8.71(d,J＝3.1Hz,1H),7.60(dd,J＝26.7,8.2Hz,3H),7.29(t,J＝7.6Hz,1H),7.26–6.90(m,7H),6.31(s,1H),3.67(s,3H),3.38(s,1H),3.17(d,J＝14.2Hz,1H),2.93(s,1H),1.65–1.57(m,2H),1.38(m,2H),1.25(s,1H),0.94(m,3H)；13C NMR(100MHz,CDCl3)δ182.3,162.2,155.7,135.8,135.5,129.8,128.9,128.7,127.3,124.8,123.2,121.9,121.1,111.6,103.3,53.1,51.4,39.6,31.2,29.7,20.3,13.9；HR-MS(ESI):calcd for C26H28N4O3S[M+H]+477.1955,found(ESI+)477.1957；确定该产物为(S)-2-(1-(3-丁基硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸甲酯。
实施例15
化学结构式I-5a所示(S)-2-(1-(3-(3-氯苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3基)-噁唑-4-羧酸的制备方法如下：
(S)-2-(1-(3-(3-氯苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3基)-噁唑-4-羧酸的化学结构式I-5a为
第四步，除用3-氯苯基异硫氰酸酯替换苯基异硫氰酸酯之外，其他同实施例1，得到目标化合物I-4g。
第五步：称量化合物I-4g(0.1g)于25mL圆底烧瓶中，加入2N NaOH溶液(2mL)和四氢呋喃溶液(10mL)，室温搅拌10h，通过添加2N盐酸溶液将所得混合物pH调节至4，并将沉淀的固体过滤，干燥后即可得黄色固体产物I-5a，收率为68.9％；经测定，该黄色固体物质的相关参数为：1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),10.04(s,1H),8.66(s,1H),8.63(d,J＝2.9Hz,1H),7.90(d,J＝8.0Hz,1H),7.70(s,1H),7.50(d,J＝8.2Hz,1H),7.33–7.08(m,11H),6.07(d,J＝7.6Hz,1H),3.40(d,J＝7.6Hz,2H)；13C NMR(100MHz,DMSO-d6)δ181.2,164.1,159.5,154.1,141.1,137.4,136.4,133.2,130.7,130.4,129.7,128.9,127.2,125.2,124.4,123.5,123.0,122.7,121.7,121.4,121.3,112.6,102.9,53.7,38.9；HR-MS(ESI):calcd for C27H21ClN4O3S[M+H]+517.1096,found(ESI+)517.1099；确定该产物为(S)-2-(1-(3-(3-氯苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3基)-噁唑-4-羧酸。
实施例16
化学结构式I-5b所示(S)-2-(1-(3-(2,4-二氯苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸的制备方法如下：
(S)-2-(1-(3-(2,4-二氯苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸的化学结构式I-5b为
第五，除用2,4-二氯苯基异硫氰酸酯替换苯基异硫氰酸酯之外，其他同实施例1，反应体系直接利用柱层析提纯即可得到黄色固体产物I-5b，收率75.4％；经测定，该黄色固体物质的相关参数为：1H NMR(400MHz,DMSO-d6)δ12.81(s,1H),11.86(s,1H),9.53(s,1H),8.84(d,J＝7.5Hz,1H),8.63(s,1H),7.90(d,J＝7.7Hz,1H),7.67–7.64(m,1H),7.50(d,J＝8.2Hz,1H),7.40(dd,J＝8.6,2.5Hz,1H),7.35–7.17(m,7H),7.12(t,J＝7.6Hz,1H),6.05(d,J＝8.2Hz,1H),3.39(d,J＝7.3Hz,2H)；13C NMR(100MHz,DMSO-d6)δ182.1,164.1,159.3,154.2,137.2,136.4,135.7,130.9,130.6,130.4,129.7,129.3,128.8,127.7,127.2,125.2,123.4,123.0,121.4,121.3,112.6,102.8,53.8,39.1；HR-MS(ESI):calcd forC27H20Cl2N4O3S[M+H]+551.0706,found(ESI+)551.0700；确定该产物为(S)-2-(1-(3-(2,4-二氯苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸。
实施例17
化学结构式I-5c所示(S)-2-(1-(3-(2-溴苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸的制备方法如下：
(S)-2-(1-(3-(2-溴苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸的化学结构式I-5c为
第五，除用2-溴苯基异硫氰酸酯替换苯基异硫氰酸酯之外，其他同实施例1，反应体系直接利用柱层析提纯即可得到黄色固体产物I-5c，收率72.3％；经测定，该黄色固体物质的相关参数为：1H NMR(400MHz,DMSO-d6)δ12.78(s,1H),11.87(s,1H),9.44(s,1H),8.76(d,J＝8.2Hz,1H),8.64(s,1H),7.91(d,J＝8.4Hz,1H),7.72–7.47(m,3H),7.40–7.08(m,9H),6.07(d,J＝7.9Hz,1H),3.41(s,2H)；13C NMR(100MHz,DMSO-d6)δ182.1,164.1,159.4,154.2,137.9,137.2,136.4,133.0,130.4,130.1,129.7,128.9,128.1,127.2,125.2,123.4,123.0,121.4,121.3,112.6,102.8,53.8,39.2；HR-MS(ESI):calcd forC27H21BrN4O3S[M+H]+561.0591,found(ESI+)561.0595；确定该产物为(S)-2-(1-(3-(2-溴苯基)硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸。
实施例18
化学结构式I-5d所示(S)-2-(1-(3-二苯甲基硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸的制备方法如下：
(S)-2-(1-(3-二苯甲基硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸的化学结构式I-5d为
第五，除用1,2-二苯甲基异硫氰酸酯替换苯基异硫氰酸酯之外，其他同实施例1，反应体系直接利用柱层析提纯即可得到黄色固体产物I-5d，收率78.6％；经测定，该黄色固体物质的相关参数为：1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),11.00(s,1H),10.75(s,1H),8.74(s,1H),7.54(d,J＝30.0Hz,4H),7.37(t,J＝7.5Hz,5H),7.25(t,J＝5.5Hz,7H),7.12(d,J＝24.3Hz,4H),6.98(t,J＝7.7Hz,1H),6.03(d,J＝12.2Hz,1H),3.54(d,J＝44.9Hz,2H)；13C NMR(101MHz,DMSO-d6)δ182.2,159.2,143.6,137.8,136.2,129.7,129.4,128.9,128.8,128.6,128.0,128.0,127.5,127.2,127.1,127.0,125.1,122.4,120.7,112.3,103.5,62.0,54.4,41.6；HR-MS(ESI):calcd for C34H28N4O3S[M+H]+573.1955,found(ESI+)573.1956；确定该产物为(S)-2-(1-(3-二苯甲基硫脲基)-2-苯乙基)-5-(1H-吲哚-3-基)-噁唑-4-羧酸。
实施例19
上述I-4a～I-4n和I-5a～I-5d所示的almazole D生物碱及其衍生物的个体化合物用作抗植物病毒剂：
上述I-4a～I-4n和I-5a～I-5d所示的almazole D生物碱及其衍生物的个体化合物的抗烟草花叶病毒活性的测定，测定程序如下：
第一步，烟草花叶病毒提纯及浓度测定：
病毒提纯及浓度测定参照南开大学元素所生测室编制烟草花叶病毒SOP规范执行。病毒粗提取液经二次聚乙二醇离心处理后测定浓度，测定浓度为20μg/mL，4℃冷藏备用；
第二步，上述I-4a～I-4n和I-5a～I-5d所示的almazole D生物碱及其衍生物的个体化合物药剂溶液的配制：
分别称量上述I-4a～I-4n和I-5a～I-5d所示的almazole D生物碱及其衍生物的个体化合物40mg作为原药，然后分别在该各种原药中加入DMF 0.4mL进行溶解，制得1×105μg/mL母液，再用质量百分比浓度为1‰的吐温80水溶液稀释至测试浓度为500μg/mL，由此分别配制得上述I-4a～I-4n和I-5a～I-5d所示的almazole D生物碱及其衍生物的个体化合物药剂溶液，另外取宁南霉素制剂直接兑水稀释作为对比物；
第三步，活体保护作用：
分别选长势均匀一致的3–5叶期珊西烟，每单科全株珊西烟分别喷雾施上述第二步配制得的上述I-4a～I-4n和I-5a～I-5d所示的almazole D生物碱及其衍生物的个体化合物药剂溶液，每处理3次重复，并设置质量百分比浓度为1‰的吐温80水溶液对照，24h后，叶面撒布500目金刚砂，用毛笔蘸取病毒液，在全叶面沿支脉方向轻擦2次，叶片下方用手掌支撑，病毒浓度10μg/mL，接种后用流水冲洗，3天后记录病斑数，计算防效；
第四步，活体治疗作用：
分别选长势均匀一致的3–5叶期珊西烟，分别用毛笔全叶接种病毒，病毒浓度为10μg/mL，接种后用流水冲洗，叶面收干后，二十三棵珊西烟分别全株喷雾施上述第二步配制得的上述I-4a～I-4n和I-5a～I-5d所示的almazole D生物碱及其衍生物的个体化合物药剂溶液，每处理3次重复，并设置质量百分比浓度为1‰的吐温80水溶液对照，3天后记录病斑数，计算防效；
第五步，活体钝化作用：
分别选长势均匀一致的3–5叶期珊西烟，将上述第二步配制得的上述I-4a～I-4n和I-5a～I-5d所示的almazole D生物碱及其衍生物的个体化合物药剂溶液分别与等体积的病毒汁液混合钝化30min后，分别摩擦接种，病毒浓度为20μg/mL，接种后即用流水冲洗，重复3次，设置质量百分比浓度为1‰的吐温80水溶液对照，3天后数病斑数，计算结果；
上述I-4a～I-4n和I-5a～I-5d这18种化学结构式所示的almazole D生物碱及其衍生物的个体化合物的抗烟草花叶病毒活性的测定结果见表1。
抑制率(％)＝[(对照枯斑数-处理枯斑数)/对照枯斑数]×100％
表1.上述I-4a～I-4n和I-5a～I-5d所示的almazole D生物碱及其衍生物的个体化合物的抗烟草花叶病毒活性的测定结果
从表1中可见本发明中的天然产物almazole D及其衍生物的个体化合物表现出很好的抗烟草花叶病毒(TMV)活性，以商品化品种病毒唑和宁南霉素作为对照。所有化合物在浓度为500μg/mL时均表现出一定的抗病毒活性，其中天然产物almazole D的抗病毒活性略低；而化合物I-4c和I-4j表现出与对照药病毒唑相当水平的抗病毒活性；化合物I-4a、I-4b、I-4g、I-4l、I-4n表现出比植物杀病毒剂病毒唑更高的抗病毒活性，具备极大的开发价值。
实施例20
上述I-4a～I-4n和I-5a～I-5d所示的almazole D生物碱及其衍生物的个体化合物用作杀植物病原真菌剂，
A.离体杀菌测试，菌体生长速率测定法(平皿法)：
上述I-4a～I-4n和I-5a～I-5d所示的almazole D生物碱及其衍生物的个体化合物的抗菌活性测试，离体杀菌测试，测定程序如下：
菌体生长速率测定法即平皿法：分别将上述I-4a～I-4n和I-5a～I-5d所示的almazole D生物碱及其衍生物的个体化合物各3mg溶解在0.03mL丙酮内，用含有0.1％TW-80的水溶液稀释至500μg/mL。向每个培养皿中添加1mL待测化合物溶液，再分别加入9mL培养基，摇匀后使待测化合物浓度为50μg/mL，以添加1mL含0.1％TW-80的蒸馏水和9mL培养基的培养皿做空白对照。用直径4mm的打孔器沿菌丝外缘切取菌盘，并将菌丝移至含有待测化合物的培养皿中，每个测定重复3次，随后将培养皿放在24±1℃恒温培养箱内培养。48小时后测量菌丝生长的直径，求平均值，与空白对照比较计算相对抑菌率。
上述I-4a～I-4n和I-5a～I-5d所示的almazole D生物碱及其衍生物的个体化合物的离体杀真菌活性的结果见表2。
表2.上述I-4a～I-4n和I-5a～I-5d所示的almazole D生物碱及其衍生物的个体化合物的离体杀菌活性的结果
由表2中数据可以看出，上述I-4a～I-4n和I-5a～I-5d所示的almazole D生物碱及其衍生物的个体化合物的表现出广谱的杀菌活性。化合物I-4g和I-5a在用药量为50μg/mL对花生褐斑病病原菌的杀菌活性高于商用杀菌剂多菌灵(52％)；化合物I-4a在用药量为50μg/mL对番茄早疫病病原菌的杀菌活性优于商用杀菌剂百菌清和多菌灵，抑菌率达50％以上。
上述实施例中的百分比均为质量百分比。
上述实施例中所涉及的原料和试剂均由商购获得，操作方法是本领域技术人员所能掌握的。本发明未尽事宜为公知技术。
Claims (6)
1.含硫脲结构的almazole D生物碱衍生物，其特征为具有如下通式(I)所示结构的化合物：
上述化学结构式通式Ⅰ中，R代表氢或甲基；
R1代表氢、甲基、苯基、丙基、异丙基、正丁基、正丁基、叔丁基、苄基、环戊基、二苯基、环己基、2-氟苯基、3-氟苯基、4-氟苯基、3,4-二氟苯基、2,6-二氟苯基、2,4-二氟苯基、2,3-二氟苯基、4-氟苯基、2-氯苯基、3-氯苯基、3,4-二氯苯基、2,6-二氯苯基、2,4-二氯苯基、2,3-二氯苯基、2,5-二氯苯基、4-氯苯基、5-氯-2-氟苯基、2-溴苯基、3-溴苯基、4-溴苯基、4-碘苯基、2-硝基苯基、3-硝基苯基、4-硝基苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-三氟甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、3,5-双(三氟甲基)苯基、3-甲氧基苯基、2,4-二甲氧基苯基、3,4,5-三(甲氧基)苯基、4-甲氧基苯基、2-噻吩基、2-呋喃基、2-吡啶基或4-吡啶基。
2.如权利要求1所述的含硫脲结构的almazole D生物碱衍生物，其特征为，优选具有如下化学结构式I-4a～I-4n和I-5a～I-5d所示的化合物：
3.如权利要求1所述的含硫脲结构的almazole D生物碱衍生物的制备方法，其特征为具体步骤如下化学反应方程式所示：
通过使用容易获得的N-Boc-L-苯丙氨酸与L-色氨酸甲酯盐酸盐的偶联反应，生成如化学结构式1所示的(叔丁氧羰基)-L-苯丙氨酰色氨酸甲酯；将该中间体溶解在无水四氢呋喃溶液中，在无水条件下用二氯二氰苯醌(DDQ)对酰胺进行氧化环化便可得到如化学结构式2所示N-Boc保护的(S)-2-(1-((叔丁氧基羰基)氨基)-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯；随后又利用三氟乙酸(TFA)对噁唑的叔丁基羰基进行脱保护得到如化学结构式3所示手性伯胺化合物(S)-2-(1-氨基-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯；其中，通过对(S)-2-(1-氨基-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯的伯胺官能团进行修饰合成系列almazole D衍生物。具体为，以(S)-2-(1-氨基-2-苯乙基)-5-(1H-吲哚-3-基)噁唑-4-羧酸甲酯与不同取代的异硫氰酸酯进行反应如化学结构式通式Ⅰ所示的含手性硫脲结构的系列almazole D生物碱衍生物；后续再进行水解反应，便可得到含羧酸及硫脲结构单元的系列almazole D生物碱衍生物。
4.如权利要求1所述的含硫脲结构的almazole D生物碱衍生物的应用，其特征为用作抗植物病毒剂或用作杀植物病原菌剂。
5.如权利要求4所述的含硫脲结构的almazole D生物碱衍生物的应用，其特征为所述植物病毒为烟草花叶病毒。
6.如权利要求4所述的含硫脲结构的almazole D生物碱衍生物的应用，其特征为所述植物病原菌为黄瓜枯萎菌、花生褐斑菌、苹果轮纹菌、小麦纹枯菌、番茄早疫菌、水稻稻瘟菌、油菜菌核菌或辣椒疫霉菌。
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