CN115611959A - 一种阿维菌素B2a衍生物及其制备方法与应用 - Google Patents
一种阿维菌素B2a衍生物及其制备方法与应用 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000005660 Abamectin Substances 0.000 title claims description 47
- 229950008167 abamectin Drugs 0.000 title claims description 34
- IBSREHMXUMOFBB-JFUDTMANSA-N 5u8924t11h Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O3)C=C[C@H](C)[C@@H](C(C)C)O4)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 IBSREHMXUMOFBB-JFUDTMANSA-N 0.000 title claims description 30
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- 241000196324 Embryophyta Species 0.000 claims abstract description 17
- CWGATOJEFAKFBK-PDVFGPFMSA-N 5-o-demethyl-22,23-dihydro-23-hydroxy-(13r,23s)-avermectin a1a Chemical compound C1[C@H](O)[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 CWGATOJEFAKFBK-PDVFGPFMSA-N 0.000 claims abstract description 13
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- 239000000126 substance Substances 0.000 claims abstract description 4
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- RRZXIRBKKLTSOM-XPNPUAGNSA-N avermectin B1a Chemical compound C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 RRZXIRBKKLTSOM-XPNPUAGNSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
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- 238000001816 cooling Methods 0.000 claims description 10
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 9
- 238000005906 dihydroxylation reaction Methods 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
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- -1 sodium triacetoxyborohydride Chemical compound 0.000 claims description 7
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- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 6
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- 230000002194 synthesizing effect Effects 0.000 claims description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
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- 125000006239 protecting group Chemical group 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- DDFHBQSCUXNBSA-UHFFFAOYSA-N 5-(5-carboxythiophen-2-yl)thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC=C1C1=CC=C(C(O)=O)S1 DDFHBQSCUXNBSA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
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- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 2
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- 238000012360 testing method Methods 0.000 description 8
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 6
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
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- 238000001914 filtration Methods 0.000 description 4
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 239000005783 Fluopyram Substances 0.000 description 3
- 239000005959 Fosthiazate Substances 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- KVDJTXBXMWJJEF-UHFFFAOYSA-N fluopyram Chemical compound ClC1=CC(C(F)(F)F)=CN=C1CCNC(=O)C1=CC=CC=C1C(F)(F)F KVDJTXBXMWJJEF-UHFFFAOYSA-N 0.000 description 3
- DUFVKSUJRWYZQP-UHFFFAOYSA-N fosthiazate Chemical compound CCC(C)SP(=O)(OCC)N1CCSC1=O DUFVKSUJRWYZQP-UHFFFAOYSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- VOSQLWCTKGQTAY-UHFFFAOYSA-N 3,3,3-trifluoropropanoyl chloride Chemical group FC(F)(F)CC(Cl)=O VOSQLWCTKGQTAY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 241001465754 Metazoa Species 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
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- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
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- 241000134843 Aphelenchoides besseyi Species 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
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- 244000061456 Solanum tuberosum Species 0.000 description 1
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- 230000000895 acaricidal effect Effects 0.000 description 1
- 239000000642 acaricide Substances 0.000 description 1
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 1
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- 238000004166 bioassay Methods 0.000 description 1
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- 238000004364 calculation method Methods 0.000 description 1
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- 235000013305 food Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
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- 235000019713 millet Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- ZSMNRKGGHXLZEC-UHFFFAOYSA-N n,n-bis(trimethylsilyl)methanamine Chemical compound C[Si](C)(C)N(C)[Si](C)(C)C ZSMNRKGGHXLZEC-UHFFFAOYSA-N 0.000 description 1
- 239000005645 nematicide Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
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- 239000004246 zinc acetate Substances 0.000 description 1
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Classifications
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- 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
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P5/00—Nematocides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Environmental Sciences (AREA)
- Wood Science & Technology (AREA)
- Agronomy & Crop Science (AREA)
- Dentistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
Description
技术领域
本发明涉及一种阿维菌素B2a衍生物及其制备方法与应用,属于农作物杀虫剂技术领域。
背景技术
线虫又称蠕虫,是一类低等的无脊椎动物,现属于动物界中的线虫门。全世界每年因线虫危害给粮食和纤维作物造成的损失大约为12%,其中危害较大的有:甜菜孢囊线虫、马铃薯金线虫、根结线虫、大豆孢囊线虫、甘薯茎线虫、粟线虫和水稻干尖线虫等。
阿维菌素是一种被广泛使用的农用或兽用杀菌、杀虫、杀螨剂,阿维菌素 B2a作为阿维菌素的一种,对土壤地下线虫和动物体表害虫有着特殊的效果,但随着用药时间的延长,虫体的抗药性明显增强。因此,为了解决抗药性问题,对阿维菌素B2a系列衍生物的开发逐步增强。目前,对阿维菌素B2a的探索主要集中在阿维菌素B2a的1位酯键变酰胺键、合成阿维菌素B2a螺缩酮裂解的衍生物等。继续寻找新的优化位点,开发比阿维菌素B2a具有更高生物活性的化合物具有重要的经济和社会意义。
发明内容
本发明的目的是提供一种阿维菌素B2a衍生物及其制备方法与应用,可有效提高化合物对植物线虫尤其是植物根结线虫的杀虫活性,能够有效解决害虫对现有农药产生抗性的问题。
为了实现上述目的,本发明采用的技术方案是:
一种阿维菌素B2a衍生物,具有如式(Ⅰ)所示的化学结构通式,
其中,R1为氢或甲基;R2为氢、甲基、乙基或卤代C1-C2烷基。
一种阿维菌素B2a衍生物的制备方法,当R1为甲基时,包括以下步骤:
步骤a,以阿维菌素B2a为原料,合成式(Ⅱ)所示的化合物;
步骤c,将式(III)所示的化合物进行脱羟基保护基R3反应,得式(Ⅰ) 所示的化合物粗品;
步骤d,将得到的式(Ⅰ)所示的化合物粗品溶于异丙醇和环己烷的混合溶液中,降温结晶,得式(Ⅰ)所示的化合物产品。
一种阿维菌素B2a衍生物的制备方法,当R1为氢时,包括以下步骤:
步骤a,以阿维菌素B2a为原料,合成式(IV)所示的化合物;
步骤c,将得到的式(Ⅰ)所示的化合物粗品溶于异丙醇和环己烷的混合溶液中,降温结晶,得式(Ⅰ)所示的化合物产品。
本发明技术方案的进一步改进在于:所述惰性溶剂为二氯甲烷、二氯乙烷、乙酸仲丁酯和乙酸乙酯中至少一种,所述惰性溶剂的加入量为式(Ⅱ)或式(IV) 所示的化合物质量的3~10倍;所述有机碱为四甲基乙二胺、三乙胺、二异丙基胺基锂、叔丁醇钾和吡啶中至少一种,所述有机碱与式(Ⅱ)或式(IV)所示的化合物的摩尔比为1.0~2.5:1。
本发明技术方案的进一步改进在于:当R1为甲基时,所述步骤a具体包括如下步骤:有机碱条件下,以阿维菌素B2a为原料,依次进行5位羟基保护、4〞位羟基氧化、4〞位胺化还原得到式(Ⅱ)所示的化合物。
本发明技术方案的进一步改进在于:所述脱羟基保护反应的催化剂为 PdCl2、Pd(OAc)2和Pd(PPH3)4中至少一种,所述脱羟基保护反应催化剂的加入量为式(Ⅱ)所示的化合物的摩尔数的0.01%~0.1%;所述脱羟基保护反应的脱保护试剂为甲醇、乙醇、硼氢化钠、三乙酰氧基硼氢化钠、氟化铵和四丁基氟化铵中至少一种,所述脱羟基保护试剂的加入量为(Ⅱ)所示的化合物的摩尔数的0.5~10倍。
本发明技术方案的进一步改进在于:所述R3为烯丙氧羰基、三甲基硅烷基或叔丁基二甲基硅基。
本发明技术方案的进一步改进在于:当R1为氢时,所述步骤a具体包括如下步骤:有机碱条件下,以阿维菌素B2a为原料,依次进行5位羟基保护、4〞位羟基氧化、4〞位胺化还原、脱除5位羟基保护基得式(IV)所示的化合物。
本发明技术方案的进一步改进在于:所述异丙醇和环己烷的混合溶液中异丙醇和环己烷的质量比为1:1~1:3;所述异丙醇和环己烷的混合溶液与式(Ⅰ) 所示的化合物粗品的质量比为4:1~8:1。
本发明技术方案的进一步改进在于:所述结晶温度为-5℃~0℃。
一种阿维菌素B2a衍生物的应用,所述阿维菌素B2a衍生物用于防治植物线虫病害。
本发明技术方案的进一步改进在于:所述植物线虫病害为植物根结线虫病害。
由于采用了上述技术方案,本发明取得的技术效果有:
本发明通过对阿维菌素B2a的4〞位进行结构优化得到了一类阿维菌素B2a衍生物,所述衍生物具有更好的持效性和稳定性,有效提高了化合物对植物线虫尤其是植物根结线虫的杀虫活性,解决了害虫对现有农药产生抗性的问题。
本发明制备的阿维菌素B2a衍生物在大田施用时使用的浓度较低,能够节约防治成本,对人畜毒害性低,减少了对土壤和作物的化学污染,更加安全环保,也更有助于减少或延迟虫体产生抗药性。
具体实施方式
下面结合具体实施例对本发明做进一步详细说明:
以下实施例中所用阿维菌素B2a原料中的阿维菌素B2a的含量大于96%。
核磁共振谱用Bruker ARX-500测定,质谱用Agilent 1100 LC/MSD测定;所用试剂均为分析纯或化学纯。
实施例1
实施例1a式(II)所示的化合物4〞-甲胺基-5-烯丙氧羰基阿维菌素B2a的制备:
将91.85g(0.1mol)阿维菌素B2a(含量97%)溶于300g二氯甲烷中,降温至-25℃,缓慢滴加入13.2g(0.11mol)氯甲酸烯丙酯和12.7g(0.11mol)四甲基乙二胺,反应2小时。升温至-10℃再加入12.1g(0.12mol)三乙胺、31.2g(0.4mol) 二甲基亚砜,缓慢滴入用50g二氯甲烷溶解的20.7g(0.07mol)固体光气,保温反应1小时。先用1%磷酸溶液调pH值到2~3然后再用10%氢氧化钠溶液调 pH值至7~8,分层,有机层用硫酸镁干燥后40℃下减压浓缩得到氧化物。
将氧化物用500g醋酸仲丁酯溶解,然后依次加入21.0g(0.12mol)七甲基二硅氮烷、1.0g醋酸锌,65~75℃保温7小时后降温至0~5℃,加入40g甲醇,然后分批缓慢加入1.5g(0.04mol)硼氢化钠,保持1小时后反应完毕用10%的磷酸溶液终止反应,调节PH=2~3,再用10%碳酸钠溶液调节PH=7~8,分层。水相用20g乙酸仲丁酯萃取两次,合并有机相,得到甲胺基阿维菌素B2a乙酸仲丁酯溶液,减压浓缩得到下式化合物90.3g,含量82%。
实施例1b式(IV)所示的化合物4〞--氨基-5-烯丙氧羰基阿维菌素B2a的制备方法:
将91.85g(0.1mol)阿维菌素B2a(含量97%)溶于300g二氯甲烷中,降温至-25℃,缓慢滴加入13.2g(0.11mol)氯甲酸烯丙酯和12.7g(0.11mol)四甲基乙二胺,反应2小时。升温至-10℃再加入12.1g(0.12mol)三乙胺、31.2g(0.4mol) 二甲基亚砜,缓慢滴入用50g二氯甲烷溶解的20.7g(0.07mol)固体光气,保温反应1小时。先用1%磷酸溶液调pH值到2~3然后再用10%氢氧化钠溶液调 pH值至7~8,分层,用硫酸镁干燥有机相,40℃下减压浓缩得到氧化物。
将氧化物用500g醋酸异丙酯溶解,然后依次加入19.4g(0.12mol)六甲基二硅氮烷、1.0g氯化锌,90~100℃保温8小时后降温至0~5℃后加入40g甲醇,然后分批缓慢加入1.5g(0.04mol)硼氢化钠,保持1小时,加入0.0088g PdCl2 (0.05mmol),然后分批加入0.76g(20.2mmol)硼氢化钠,约2h加完,再用10%的磷酸溶液终止反应,调节PH=2~3,然后用10%碳酸钠溶液调节PH=7~8,分层。水相用20g乙酸仲丁酯萃取两次,合并有机相,得到甲胺基阿维菌素B2a 乙酸仲丁酯溶液。减压浓缩得到下式化合物92.5g,含量80%。
实施例2
4〞-乙酰氨基-5-烯丙氧羰基阿维菌素B2a的制备:
步骤一、将49.7g(40.8mmol)化合物IV(含量80%)加入到120g二氯甲烷中,将反应液降温至0℃,加入4.7g(40.8mmol)四甲基乙二胺,氮气保护下,缓慢加入3.2g乙酰氯(40.8mmol),滴加结束后0℃反应2h,得含4〞-乙酰氨基 -5-O-烯丙氧甲酰基阿维菌素B2a的反应液;反应完毕后,用5wt%磷酸溶液调节 pH为6~7,然后再用5wt%氢氧化钠溶液调节pH至7,分相,有机相中用无水硫酸钠干燥,加入5g活性炭,搅拌20min,过滤,母液浓缩,得棕黄色固体44.2g, HPLC含量79%,收率92%;
步骤二、将步骤一所得棕黄色固体用88.4g异丙醇溶液溶解后,缓慢滴加 88.4g环己烷,滴加结束后,缓慢降温至0℃,保温30min,过滤,滤饼干燥,得30.0g类白色固体,HPLC含量99.1%,结晶收率85%,结构如下所示。
将上述白色固体进行结构验证:
MS[M+H+](m/z):933.15。
1H NMR(500MHz,CDCl3)δ6.83(s,1H),5.72–5.91(m,2H),5.43(t,J=7.6Hz,1H),4.99–5.21(m,2H), 4.94(t,J=9.7Hz,2H),4.50(d,J=20.1,2H),4.00–4.40(m,5H),3.77–3.96(m,2H),3.53–3.70(m,4H),3.46(s, 3H),3.40(s,3H),3.35(t,J=9.0Hz,1H),3.16(dd,J=13.2,9.0Hz,1H),2.99(s,1H),2.60–2.85(m,2H), 2.47–2.50(m,2H),2.02–2.23(m,2H),2.00(ddd,J=14.3,12.4,6.1Hz,2H),1.99(s,3H),1.96–1.60(m,7H), 1.40–1.50(m,7H),1.30–1.32(m,2H),1.20–1.29(m,4H),1.10(dd,J=15.2,7.3Hz,6H),0.99–0.85(m,9H)。
13C NMR(500MHz,CDCl3)δ173.7,170.5,139.7,138.3,138.1,135.5,124.8,121.4,118.1,117.7,114.5, 106.4,103.3,86.5,85.5,82.0,81.5,81.3,79.1,74.4,73.6,72.7,72.3,71.7,71.1,67.9,67.1,63.2,57.4,57.1,45.9, 41.6,41.1,39.9,36.5,35.4,35.1,34.9,34.7,36.1,25.2,23.6,20.3,18.5,18.1,17.3,13.2,12.0,11.9,11.8。
实施例3
一种阿维菌素B2a衍生物的制备方法,包括以下步骤:
步骤一、将60.2g含量82%(0.05mol)化合物II加入到600g甲苯中,将反应液降温至-5℃,加入5.8g四甲基乙二胺(0.05mol),然后缓慢滴入三氟乙酸酐 10.5g(0.05mol),取样经高效液相色谱检测原料反应完毕,得反应液;
步骤二、向含4〞-乙酰氨基-5-O-烯丙氧甲酰基阿维菌素B2a的反应液中加入0.65g甲醇(20.3mmol),然后降温至-5℃,加入0.05g(0.04mmol)Pd(PPh3)4,然后分批加入0.76g(20.2mmol)硼氢化钠,反应完毕后用5wt%磷酸溶液调节 pH为6,然后再用5wt%氢氧化钠溶液调节pH至7,分相,有机相用无水硫酸钠干燥,加入2g活性炭,搅拌20min,过滤,母液浓缩,得棕黄色固体62.2g;
步骤三、将步骤二所得棕黄色固体用124.4g溶解后缓慢滴加373.2g环己烷,滴加结束后,缓慢降温至0℃,保温30min,过滤,滤饼干燥,得38.9g白色固体,HPLC含量92.5%,收率80%,结构如下所示。
将上述棕黄色固体进行结构验证:
MS[M+H+](m/z):1001.14。
1H NMR(500MHz,CDCl3)δ6.2(m,1H),5.81–5.70(m,2H),5.22(t,J=7.2Hz,1H),5.16(tt,J=6.8,1.0 Hz,1H),5.00(dt,J=8.0,1.0Hz,1H),4.95–4.87(m,2H),4.61(dt,J=13.7,6.9Hz,2H),4.33–4.08(m,2H), 4.00–3.90(m,3H),3.8(s,3H),3.70–3.60(m,3H),3.50(t,J=7.0Hz,1H),3.46(s,3H),3.30(s,3H),3.20(t,J =7.0Hz,1H),3.15–3.00(m,2H),2.90(s,1H),2.60–2.30(m,2H),2.25–2.05(m,2H),2.00(dd,J=13.2,7.0 Hz,1H),1.90–1.70(m,6H),1.60(s,3H),1.59–1.52(m,4H),1.50–1.46(m,4H),1.38(dt,J=14.0,7.0Hz, 1H),1.30–1.29(m,6H),1.20–1.10(m,4H),1.00(d,J=6.7Hz,3H),0.92–0.83(m,9H)。
13C NMR(500MHz,CDCl3)δ170.1,168.5,140.6,139.1,138.5,136.7,126.6,125.3,120.0,119.7,116.5, 109.3,105.5,89.6,86.4,83.0,82.5,81.6,80.8,76.4,74.6,73.3,72.0,71.9,71.0,68.0,67.0,66.6,57.5,55.1,46.6, 44.6,43.2,40.0,38.5,36.5,36.1,35.4,34.9,34.1,33.3,28.0,26.3,23.3,20.5,19.1,18.0,14.5,13.0,12.3,11.6。
实施例4
与实施例2的区别为:所述乙酰氯替换为三氟乙酸酐,加入量为4.65g。
实施例5
与实施例2的区别为:所述乙酰氯替换为三氟丙酰氯,加入量为6.0g。
实施例6
与实施例3的区别为:所述三氟乙酸酐替换为乙酸酐,加入量为5.1g。
实施例7
与实施例3的区别为:所述三氟乙酸酐替换为三氟丙酰氯,加入量为7.3g。
实施例8
与实施例2的区别为:所述乙酰氯替换为甲乙酸酐,加入量为3.6g。
实施例4~8得到的产品结构如下:
分别对上述产品进行结构验证,结果如下:
中间产物及最终产物的HPLC条件为:
色谱柱:C18,4.6mm×150mm×5μm;
流动相:乙腈:水(0.1%TFA)=84:16;
流速:1.4mL/min;
检测波长:245nm;
进样量:20μL。
药效实验
试验参照NY/T 1833.1-2009《农药室内生物测定试验准则杀线虫剂》第1 部分:抑制植物病原线虫试验浸虫法进行。
1试材准备
将试验用的南方根结线虫在番茄上培养,待卵期备用。
2供试药剂及初筛浓度
供试药剂:阿维菌素B2a衍生物共6个化合物均由河北威远生物化工有限公司提供;
对照药剂阿维菌素、氟吡菌酰胺、噻唑磷。
实验设置浓度为1.0mg/L、0.5mg/L、0.2mg/L。
3线虫悬浮液准备
将侵染根结线虫的新鲜植物根洗净,剪成1cm长小段,放入组织捣碎机中加3倍量的水捣碎30s,转入200目(孔径75μm)和500目(孔径26μm)组合标准筛,用自来水冲洗筛中植物组织,收集500目标准筛内的线虫卵,用质量分数为0.5%的NaClO溶液表面消毒3min,无菌水冲洗5次后放入自制贝曼漏斗中,于25℃培养箱中黑暗培养,间隔24h收集一次南方根结线虫J2,备用。
4药剂处理
按照试验设计,用0.1%曲拉通水溶液梯度稀释试验药剂,以0.1%曲拉通水溶液作对照,将收集的24h内孵化的根结线虫J2用清水配成悬浮液(200条左右/mL),用移液器移取0.5mL药液和0.5mL的J2悬浮液放于24孔板中,重复 3次,用细玻棒混匀后置于25℃恒温培养箱中黑暗培养,于24h、48h、72h后检查J2总虫数量和死虫数量,计算死亡率和校正死亡率。
5结果检查
在体视显微镜下采用针刺法判断线虫是否死亡,统计线虫死虫数,并计算线虫死亡率和校正死亡率,计算公式如下:
死亡率(%)=死亡线虫数/处理线虫数×100%
校正死亡率(%)=(处理死亡率-对照死亡率)/(100-对照死亡率)×100%若对照死亡率小于5%,无需校正;若对照死亡率在5%~15%之间,应按照公式计算校正死亡率;对照死亡率大于15%,试验需要重做。
实验数据:
由上表可知:(1)在高浓度下,化合物均表现出较高的杀虫活性。(2)在低浓度下实施例2所示化合物对根结线虫活性好,活性高于对照药剂阿维菌素、氟吡菌酰胺和噻唑膦,可以进一步进行实验。(3)实施例4、实施例5、实施例 6、实施例7所示化合物对根结线虫活性与对照药剂阿维菌素接近,与氟吡菌酰胺和噻唑膦相比活性较差。
Claims (9)
4.根据权利要求2或3所述的一种阿维菌素B2a衍生物的制备方法,其特征在于:所述惰性溶剂为二氯甲烷、二氯乙烷、乙酸仲丁酯和乙酸乙酯中至少一种;所述有机碱为四甲基乙二胺、三乙胺、二异丙基胺基锂、叔丁醇钾和吡啶中至少一种。
5.根据权利要求2所述的一种阿维菌素B2a衍生物的制备方法,其特征在于:所述步骤a具体包括如下步骤:有机碱条件下,以阿维菌素B2a为原料,依次进行5位羟基保护、4〞位羟基氧化、4〞位胺化还原得到式(Ⅱ)所示的化合物。
6.根据权利要求2所述的一种阿维菌素B2a衍生物的制备方法,其特征在于:所述脱羟基保护反应的催化剂为PdCl2、Pd(OAc)2和Pd(PPH3)4中至少一种;所述脱羟基保护反应的脱保护试剂为甲醇、乙醇、硼氢化钠、三乙酰氧基硼氢化钠、氟化铵和四丁基氟化铵中至少一种。
7.根据权利要求3所述的一种阿维菌素B2a衍生物的制备方法,其特征在于:所述步骤a具体包括如下步骤:有机碱条件下,以阿维菌素B2a为原料,依次进行5位羟基保护、4〞位羟基氧化、4〞位胺化还原、脱除5位羟基保护基得式(IV)所示的化合物。
8.一种权利要求1所述的阿维菌素B2a衍生物的应用,其特征在于:所述阿维菌素B2a衍生物用于防治植物线虫病害。
9.根据权利要求8所述的一种阿维菌素B2a衍生物的应用,其特征在于:所述植物线虫病害为植物根结线虫病害。
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