CN115572269B - 一种n-三氟异丙基唑类和吲哚化合物及其制备方法 - Google Patents
一种n-三氟异丙基唑类和吲哚化合物及其制备方法 Download PDFInfo
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- CN115572269B CN115572269B CN202211223084.6A CN202211223084A CN115572269B CN 115572269 B CN115572269 B CN 115572269B CN 202211223084 A CN202211223084 A CN 202211223084A CN 115572269 B CN115572269 B CN 115572269B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- 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
- A01P3/00—Fungicides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D249/18—Benzotriazoles
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明涉及医药化工领域,且公开了一种N‑三氟异丙基唑类和吲哚化合物及其制备方法,本发明通过在反应容器中加入含NH的杂环化合物、β‑三氟甲基烯基锍盐、碱和溶剂,反应混合物在室温下反应24小时,减压蒸除溶剂,然后经硅胶柱层析分离得到N‑三氟丙烯基唑类和吲哚化合物。该烯基化合物随后在钯碳催化下进行氢化反应,生成N‑三氟异丙基唑类和吲哚化合物。该方法具有以下优点:反应条件温和,操作简单方便;底物适用性广,官能团耐受性好,对一系列的N‑三氟异丙基唑类和吲哚化合物均可取得中等以上的产率;适用于唑类和吲哚化合物的直接后期N‑氟烷基化修饰。所得N‑三氟异丙基唑类和吲哚化合物具有抗菌性、杀菌等应用。
Description
技术领域
本发明涉及医药化工领域,具体为一种N-三氟异丙基唑类和吲哚化合物及其制备方法。
背景技术
含氮杂环化合物(如氮唑化合物、吲哚等)不仅广泛存在于天然产物中,在医药、农药和材料等领域都有重要应用(J.Med.Chem.2014,57,5845-5859;J.Med.Chem.2014,57,10257-10274)。例如,在农药领域,吡唑化合物具有高效、低毒、结构多样的优点,广泛用于杀虫/螨、杀菌以及作物除草(Chem.Rev.2021,121,1670-1715)。此外,三唑类杀菌剂是目前第二大杀菌剂类型,以其高效、低毒、广谱在农业和医药等领域备受青睐。另一方,三氟甲基是一类重要的含氟基团,在医药、农药开发过程中应用广泛(Science 2007,317,1881-1886)。向唑类化合物的氮上引入三氟异丙基能够改善其代谢稳定和药代动力学特性,调节其pKa和亲脂性等作用。例如,含N-三氟异丙基的化合物B相比于其N-异丙基类似物A具有更好的凋亡信号调节激酶1(ASK1)抑制活性和更低的外排率(ER)(J.Med.Chem.2021,64,15402-15419)。化合物C是表皮生长因子受体(EGFR)激酶的有效抑制剂,其氮杂苯并咪唑氮原子上的三氟丙基可以增加核糖袋内的亲脂相互作用,使药物分子与受体的结合构象更有利(J.Med.Chem.2015,58,8877-8895)。
目前关于唑类化合物N上烷基化的报道已经很多,包括烷基卤代物的亲核取代、Mitsunobu反应、过渡金属催化的烯丙基化反应、重氮插入、氧化脱氢偶联、光电催化等方法,但是构建N-三氟异丙基唑类化合物的方法仍然十分有限。由于三氟异丙基是一个位阻较大的基团,以三氟异丙基(拟)卤代物作为三氟异丙基源的经典双分子亲核取代反应(SN2)反应普遍存在反应条件苛刻(例如高温)且产率低等缺点。另一种N-三氟异丙基唑类化合物的合成方法是从三氟异丙基胺砌块出发,通过环化反应来构建,但该方法局限于合成某些特定的唑类结构(J.Med.Chem.2021,64,15402-15419;J.Med.Chem.2015,58,8877-8895)。因此,发展实用且反应条件温和的策略来实现唑类和吲哚等化合物的后期N-三氟异丙基化修饰具有重要意义。
终上所述,含N-三氟异丙基的唑类化合物在医药、农药领域有很好的应用前景。发展温和条件下唑类化合物的N-三氟异丙基化方法将推动唑类先导化合物的结构优化,进而筛选出具有高活性的唑类药物分子,为此我们提出了一种N-三氟异丙基唑类和吲哚化合物及其制备方法。
发明内容
(一)解决的技术问题
针对现有技术的不足,本发明提供了一种N-三氟异丙基唑类和吲哚化合物及其制备方法,解决了上述的问题。
(二)技术方案
为实现上述所述目的,本发明提供如下技术方案:一种N-三氟异丙基唑类和吲哚化合物,化学结构式如下式所示:
氮杂芳香环可以是取代四唑、取代吡唑、取代咪唑、苯并咪唑、嘌呤、1,2,3-三唑、取代吲哚中的一种;
R为芳基、烷基、酯基、含硫基团、胺基、卤素中的任意一种。
优选的,所述化学结构为如下所示结构中的任意一种:
一种N-三氟异丙基唑类和吲哚化合物的制备方法,包括以下步骤:
第一步:氮气保护下,向反应容器中依次加入含NH的氮杂环化合物、反式-β-三氟甲基烯基锍盐(95mg,0.22mmol)、碱和溶剂一,碱为1.0至1.1当量的三乙胺或碳酸钾,室温下搅拌反应,将反应液减压浓缩后用硅胶柱层析分离得化合物一;
第二步:在带磁力搅拌子的两口烧瓶中依次加入化合物一、溶剂二和催化剂,溶剂二为甲醇、乙醇、或乙酸乙酯,催化剂为Pd/C、Pt/C、PtO2中的至少一种;
在一个大气压氢气下室温搅拌反应,反应结束后,进行分离纯化,得到在制备抗菌药物中应用的N-三氟异丙基唑类和吲哚化合物;
反应通式如下所示:
优选的,所述第一步中的碱为1.1当量三乙胺。
优选的,所述第一步中的氮杂环化合物、β-三氟甲基烯基锍盐、碱的物质的量之比为1:1.1:1.1。
优选的,所述第一步中的溶剂一为乙酸乙酯、二氯甲烷、乙腈、四氢呋喃、氯苯、二甲苯、甲苯、乙醇、氯仿、环己烷、丁酮、丙酮、石油醚、正辛烷、环己烷、乙醚中的至少一种。
优选的,所述第二步中的溶剂二为乙酸乙酯。
优选的,所述第二步中的催化剂为Pd/C。
优选的,所述第一步以及第二步中的反应条件为室温下反应24h。
优选的,所述第二步中的分离纯化按照以下步骤进行:反应结束后,用硅藻土过滤除去催化剂,乙酸乙酯洗涤,滤液减压浓缩后用硅胶柱层析分离,得到N-三氟异丙基唑类和吲哚化合物。
优选的,所述第二步中的分离纯化按照以下步骤进行:反应结束后,将反应混合液减压蒸除溶剂,而后直接硅胶柱层析分离,以乙酸乙酯和石油醚的混合溶液为洗脱剂,分离得到N-三氟丙烯基唑类和吲哚化合物。
(三)有益效果
与现有技术相比,本发明提供了一种N-三氟异丙基唑类和吲哚化合物及其制备方法,具备以下有益效果:
1、该N-三氟异丙基唑类和吲哚化合物及其制备方法,反应条件温和,操作简单方便;底物适用性广,官能团耐受性好,对一系列的N-三氟异丙基唑类和吲哚化合物均可取得中等以上的产率;适用于对唑类和吲哚化合物的后期N-氟烷基化修饰。
2、该N-三氟异丙基唑类和吲哚化合物及其制备方法,N-三氟异丙基唑类和吲哚化合物具有抑菌活性。因此有望开发成一类新的抗菌药物。
附图说明
图1为实施例1中制备的式IV-1所示N-三氟异丙基四唑化合物的核磁氢谱。
图2为实施例1中制备的式IV-1所示N-三氟异丙基四唑化合物的核磁碳谱。
图3为实施例1中制备的式IV-1所示N-三氟异丙基四唑化合物的核磁氟谱。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
请参阅图1-3。
式I所示化合物为含NH的杂环化合物中,除式I-12按照以下文献方法合成[Jin,T.;Kamijo,S.;Yamamoto,Y.Eur.J.Org.Chem.2004,2004,3789-3791],其他式I所示化合物都可直接购买。
式II所示化合物可按照以下文献方法合成[Kasai,N.;Maeda,R.;Furuno,H.;Hanamoto,T.Synthesis 2012,44,3489-3495]。
实施例1
式IV-1所示N-三氟异丙基四唑化合物的合成:
步骤一:氮气保护下,向反应管中依次加入5-苯基四氮唑I-1(29mg,0.2mmol)、反式-β-三氟甲基烯基锍盐II(95mg,0.22mmol)、乙腈(2mL),和三乙胺(31μL,0.22mmol)。室温下搅拌反应24小时,将反应液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比0:100~5:95)],得式化合物III-1所示化合物38mg,产率80%,为白色固体。
M.p.=58-59℃.
1H NMR(400MHz,CDCl3)δ8.21-8.18(m,J=2.6Hz,2H),7.52-7.49(m,3H),6.65-6.55(m,1H),6.16(d,J=3.1Hz,1H).
13C NMR(101MHz,CDCl3)δ165.4,133.1(q,J=38.4Hz),131.2,129.1,127.3,126.3,119.3(q,J=274.7Hz),115.1(q,J=4.0Hz).
19F NMR(376MHz,CDCl3)δ-66.6.
HRMS m/z[M+H]+calculated for C10H8F3N4 +:241.0696,found:241.0700.
步骤二:在带磁力搅拌子的25mL两口烧瓶中依次加入三氟甲基烯烃III-1(48mg,0.2mmol),EtOAc(4mL),5%的钯/碳催化剂(32mg)。在一个大气压氢气(氢气球)下室温搅拌反应24h。反应结束后,用硅藻土过滤除去钯碳催化剂(乙酸乙酯洗涤),滤液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比5:95)],得到IV-1所示化合物46mg,产率96%,为无色油状液体。
1H NMR(400MHz,CDCl3)δ8.26-8.12(m,2H),7.56-7.45(m,3H),5.58-5.47(m,1H),1.98(d,J=7.2Hz,3H).
13C NMR(101MHz,CDCl3)δ165.6,130.7,129.0,127.0,126.8,123.0(q,J=282.1Hz),60.2(q,J=33.7Hz),13.4.
19F NMR(376MHz,CDCl3)δ-75.3.
HRMS m/z[M+H]+calculated for C10H10F3N4 +:243.0852,found:243.0854.
实施例2
步骤一:氮气保护下,向反应管中依次加入5-甲酸乙酯四氮唑I-2(28mg,0.2mmol)、反式-β-三氟甲基烯基锍盐II(95mg,0.22mmol)、乙腈(2mL),和三乙胺(31μL,0.22mmol)。室温下搅拌反应24小时,将反应液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比0:100~5:95)],得式化合物III-2所示化合物33mg,产率69%,为无色液体。
1H NMR(400MHz,CDCl3)δ6.68-6.66(m,1H),6.30(dt,J=3.0,0.8Hz,1H),4.54(qd,J=7.2,0.6Hz,2H),1.45(td,J=7.1,0.6Hz,3H).
13C NMR(101MHz,CDCl3)δ158.0,157.2,133.0(q,J=39.0Hz),119.0(q,J=272.7Hz),117.8(q,J=3.8Hz),63.2,14.2.
19F NMR(376MHz,CDCl3)δ-66.8.
HRMS m/z[M+Na]+calculated for C7H7F3N4NaO2 +:259.0413,found:259.0406.
步骤二:在带磁力搅拌子的25mL两口烧瓶中依次加入三氟甲基烯烃III-2(48mg,0.2mmol),EtOAc(4mL),5%的钯/碳催化剂(32mg)。在一个大气压氢气(氢气球)下室温搅拌反应24h。反应结束后,用硅藻土过滤除去钯碳催化剂(乙酸乙酯洗涤),滤液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比5:95)],得到IV-2所示化合物45mg,产率95%,为淡黄色油状液体。
1H NMR(400MHz,CDCl3)δ5.63-5.49(m,1H),4.52(qd,J=7.1,1.1Hz,2H),1.97(d,J=7.2Hz,3H),1.44(td,J=7.1,1.2Hz,3H).
13C NMR(101MHz,CDCl3)δ158.3,157.4,122.7(q,J=282.2Hz),63.0,61.1(q,J=33.9Hz),14.2,13.4.
19F NMR(376MHz,CDCl3)δ-75.2(d,J=6.1Hz).
HRMS m/z[M+Na]+calculated for C7H9F3N4NaO2 +:261.0570,found:261.0566.
实施例3
步骤一:氮气保护下,向反应管中依次加入5-苄巯基四氮唑I-3(38mg,0.2mmol)、反式-β-三氟甲基烯基锍盐II(95mg,0.22mmol)、乙腈(2mL),和三乙胺(31μL,0.22mmol)。室温下搅拌反应24小时,将反应液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比0:100~5:95)],得式化合物III-3所示化合物35mg,产率62%,为无色油状液体。
1H NMR(400MHz,CDCl3)δ7.44-7.39(m,2H),7.33-7.23(m,3H),6.47-6.45(m,1H),6.10(dt,J=2.7,0.8Hz,1H),4.45(s,2H).
13C NMR(101MHz,CDCl3)δ165.4,136.2,132.8(q,J=37.6Hz),129.2,128.7,127.9,119.2(q,J=273.2Hz),114.9(q,J=4.1Hz),36.3.
19F NMR(376MHz,CDCl3)δ-66.7.
HRMS m/z[M+Na]+calculated for C11H9F3N4NaS+:309.0392,found:309.0395.
步骤二:在带磁力搅拌子的25mL两口烧瓶中依次加入三氟甲基烯烃III-3(57mg,0.2mmol),EtOAc(4mL),5%的钯/碳催化剂(32mg)。在一个大气压氢气(氢气球)下室温搅拌反应24h。反应结束后,用硅藻土过滤除去钯碳催化剂(乙酸乙酯洗涤),滤液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比5:95)],得到IV-3所示化合物53mg,产率92%,为淡黄色油状液体。
1H NMR(400MHz,CDCl3)δ7.44-7.36(m,2H),7.33-7.23(m,3H),5.47-5.35(m,1H),4.42(s,2H),1.88(d,J=7.3Hz,3H).
13C NMR(101MHz,CDCl3)δ164.8,136.3,129.1,128.6,127.7,122.8(q,J=282.3Hz),60.3(q,J=33.7Hz),36.4,13.2.
19F NMR(376MHz,CDCl3)δ-75.3(d,J=6.3Hz).
HRMS m/z[M+Na]+calculated for C11H11F3N4NaS+:311.0549,found:311.0543.
实施例4
步骤一:氮气保护下,向反应管中依次加入4-吡唑甲酸乙酯I-4(28mg,0.2mmol)、反式-β-三氟甲基烯基锍盐II(95mg,0.22mmol)、乙腈(2mL),和三乙胺(31μL,0.22mmol)。室温下搅拌反应24小时,将反应液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比0:100~5:95)],得式化合物III-4所示化合物41mg,产率87%,为无色油状液体。
1H NMR(400MHz,CDCl3)δ8.15(d,J=1.7Hz,1H),8.04(d,J=2.2Hz,1H),6.23-6.15(m,1H),5.85(d,J=2.3Hz,1H),4.31(q,J=7.1Hz,2H),1.34(td,J=7.3,1.9Hz,3H).
13C NMR(101MHz,CDCl3)δ162.3,142.7,134.5(q,J=35.3Hz),132.2(q,J=2.4Hz),120.1(q,J=272.9Hz),117.6,112.0(q,J=4.3Hz),60.8,14.4.
19F NMR(376MHz,CDCl3)δ-66.8.
HRMS m/z[M+H]+calculated for C9H10F3N2O2 +:235.0689,found:235.0692.
步骤二:在带磁力搅拌子的25mL两口烧瓶中依次加入三氟甲基烯烃III-4(47mg,0.2mmol),EtOAc(4mL),5%的钯/碳催化剂(32mg)。在一个大气压氢气(氢气球)下室温搅拌反应24h。反应结束后,用硅藻土过滤除去钯碳催化剂(乙酸乙酯洗涤),滤液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比5:95)],得到IV-4所示化合物44mg,产率94%,为无色油状液体。
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.97(s,1H),4.92(hept,J=7.0Hz,1H),4.31(q,J=7.1Hz,2H),1.78(d,J=7.2Hz,3H),1.35(t,J=7.1Hz,3H).
13C NMR(101MHz,CDCl3)δ162.5,141.3,132.3,123.8(q,J=282.1Hz),116.5,60.4,59.1(q,J=32.2Hz),14.3,13.6.
19F NMR(376MHz,CDCl3)δ-76.4(d,J=6.8Hz).
HRMS m/z[M+H]+calculated for C9H12F3N2O2 +:237.0845,found:237.0844.
实施例5
步骤一:氮气保护下,向反应管中依次加入吡唑-3-甲酸甲酯I-5(25mg,0.2mmol)、反式-β-三氟甲基烯基锍盐II(95mg,0.22mmol)、乙腈(2mL),和三乙胺(31μL,0.22mmol)。室温下搅拌反应24小时,将反应液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比0:100~5:95)],得式化合物III-5所示化合物37mg,产率85%,为淡黄色油状液体。
1H NMR(400MHz,CDCl3)δ7.71(dq,J=2.8,1.3Hz,1H),6.94(d,J=2.6Hz,1H),6.29-6.26(m,1H),5.90(d,J=2.2Hz,1H),3.94(s,3H).
13C NMR(101MHz,CDCl3)δ162.2,145.6,134.6(q,J=35.5Hz),130.6(q,J=2.5Hz),120.2(q,J=273.1Hz),113.4(q,J=4.4Hz),110.6,52.5.
19F NMR(376MHz,CDCl3)δ-66.8.
HRMS m/z[M+Na]+calculated for C8H7F3N2NaO2 +:243.0352,found:243.0358.
步骤二:在带磁力搅拌子的25mL两口烧瓶中依次加入三氟甲基烯烃III-5(44mg,0.2mmol),EtOAc(4mL),5%的钯/碳催化剂(32mg)。在一个大气压氢气(氢气球)下室温搅拌反应24h。反应结束后,用硅藻土过滤除去钯碳催化剂(乙酸乙酯洗涤),滤液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比5:95)],得到IV-5所示化合物40mg,产率89%,为无色油状液体。
1H NMR(400MHz,CDCl3)δ7.61-7.54(m,1H),6.92(d,J=2.5Hz,1H),5.04(hept,J=7.1Hz,1H),3.94(s,3H),1.79(d,J=7.2Hz,3H).
13C NMR(101MHz,CDCl3)δ162.3,144.1,129.8,123.8(q,J=281.9Hz),110.1,59.6(q,J=32.2Hz),52.2,13.9.
19F NMR(376MHz,CDCl3)δ-76.1(d,J=6.8Hz).
HRMS m/z[M+Na]+calculated for C8H9F3N2NaO2 +:245.0508,found:245.0515.
实施例6
步骤一:氮气保护下,向反应管中依次加入3-苯基吡唑I-6(29mg,0.2mmol)、反式-β-三氟甲基烯基锍盐II(95mg,0.22mmol)、乙腈(2mL),和三乙胺(31μL,0.22mmol)。室温下搅拌反应24小时,将反应液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比0:100~5:95)],得式化合物III-6所示化合物37mg,产率78%,为无色油状液体。
1H NMR(400MHz,CDCl3)δ7.92-7.83(m,2H),7.71(s,1H),7.45-7.34(m,3H),6.73(d,J=2.6Hz,1H),6.22(q,J=2.1Hz,1H),5.72(s,1H).
13C NMR(101MHz,CDCl3)δ153.6,134.7(q,J=34.4Hz),132.3,130.2(q,J=2.6Hz),128.8,128.7,126.1,120.6(q,J=273.0Hz),108.7(q,J=4.5Hz),105.6.
19F NMR(376MHz,CDCl3)δ-66.3.
HRMS m/z[M+H]+calculated for C12H10F3N2 +:239.0791,found:239.0796.
步骤二:在带磁力搅拌子的25mL两口烧瓶中依次加入三氟甲基烯烃III-6(48mg,0.2mmol),EtOAc(4mL),5%的钯/碳催化剂(32mg)。在一个大气压氢气(氢气球)下室温搅拌反应24h。反应结束后,用硅藻土过滤除去钯碳催化剂(乙酸乙酯洗涤),滤液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比5:95)],得到IV-6所示化合物46mg,产率97%,为无色油状液体。
1H NMR(400MHz,CDCl3)δ8.27-8.08(m,2H),7.59-7.45(m,3H),5.60-5.46(m,1H),1.98(d,J=7.2Hz,3H).
13C NMR(101MHz,CDCl3)δ165.6,130.7,129.0,127.0,126.8,123.0(q,J=282.1Hz),60.2(q,J=33.7Hz),13.4.
19F NMR(376MHz,CDCl3)δ-75.3.
HRMS m/z[M+H]+calculated for C12H12F3N2 +:241.0947,found:241.0945.
实施例7
步骤一:氮气保护下,向反应管中依次加入4-硝基吡唑I-7(23mg,0.2mmol)、反式-β-三氟甲基烯基锍盐II(95mg,0.22mmol)、乙腈(2mL),和三乙胺(31μL,0.22mmol)。室温下搅拌反应24小时,将反应液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比0:100~5:95)],得式化合物III-7所示化合物33mg,产率80%,为无色油状液体。
1H NMR(400MHz,CDCl3)δ8.43(s,1H),8.24(s,1H),6.35-6.33(m,1H),6.03(d,J=2.5Hz,1H).
13C NMR(101MHz,CDCl3)δ137.2,134.0(q,J=35.7Hz),128.0(q,J=2.3Hz),119.7(q,J=273.4Hz),114.3(q,J=4.3Hz).
19F NMR(376MHz,CDCl3)δ-66.9.
HRMS m/z[M+K]+calculated for C6H4F3KN3O2 +:245.9887,found:245.9923.
步骤二:在带磁力搅拌子的25mL两口烧瓶中依次加入三氟甲基烯烃III-7(41mg,0.2mmol),EtOAc(4mL),5%的钯/碳催化剂(32mg)。在一个大气压氢气(氢气球)下室温搅拌反应24h。反应结束后,用硅藻土过滤除去钯碳催化剂(乙酸乙酯洗涤),滤液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比5:95)],得到IV-7所示化合物21mg,产率58%,为黄色油状液体。
1H NMR(400MHz,CDCl3)δ7.16(s,1H),7.02(s,1H),4.72-4.61(m,1H),2.90(s,2H),1.62(d,J=7.2Hz,3H).
13C NMR(101MHz,CDCl3)δ132.3,129.9,124.3(q,J=282.9Hz),116.9,58.8(q,J=31.7Hz),13.6.
19F NMR(376MHz,CDCl3)δ-76.4(d,J=6.9Hz).
HRMS m/z[M+H]+calculated for C6H9F3N3 +:180.0743,found:180.0741.
实施例8
步骤一:氮气保护下,向反应管中依次加入2-丙基咪唑I-8(22mg,0.2mmol)、反式-β-三氟甲基烯基锍盐II(95mg,0.22mmol)、乙腈(2mL),和三乙胺(31μL,0.22mmol)。室温下搅拌反应24小时,将反应液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比10:90~25:75)],得式化合物III-8所示化合物26mg,产率63%,为无色油状液体。
1H NMR(400MHz,CDCl3)δ7.03(s,1H),6.91(s,1H),6.24(s,1H),5.76(q,J=1.7Hz,1H),2.60(t,J=7.7Hz,2H),1.83-1.74(m,2H),0.96(dd,J=8.3,6.5Hz,3H).
13C NMR(101MHz,CDCl3)δ149.3,133.3(q,J=36.0Hz),128.2,121.9(q,J=3.5Hz),120.1(q,J=275.7Hz),119.7,28.2,21.3,13.8.
19F NMR(376MHz,CDCl3)δ-69.8.
HRMS m/z[M+H]+calculated for C9H12F3N2 +:205.0947,found:205.0942.
步骤二:在带磁力搅拌子的25mL两口烧瓶中依次加入三氟甲基烯烃III-8(41mg,0.2mmol),EtOAc(4mL),5%的钯/碳催化剂(32mg)。在一个大气压氢气(氢气球)下室温搅拌反应24h。反应结束后,用硅藻土过滤除去钯碳催化剂(乙酸乙酯洗涤),滤液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比30:70)],得到IV-8所示化合物27mg,产率65%,为无色油状液体。
1H NMR(400MHz,CDCl3)δ7.05(s,1H),7.00(s,1H),4.66(hept,J=7.1Hz,1H),2.76-2.57(m,2H),1.88-1.74(m,2H),1.67(d,J=7.1Hz,3H),1.02(t,J=7.3Hz,3H).
13C NMR(101MHz,CDCl3)δ128.2,124.3(q,J=281.8Hz),52.3(q,J=32.5Hz),28.6,21.1,14.9,13.9.
19F NMR(376MHz,CDCl3)δ-76.1(d,J=6.8Hz).
HRMS m/z[M+H]+calculated for C9H14F3N2 +:207.1104,found:207.1107.
实施例9
步骤一:氮气保护下,向反应管中依次加入2-甲基苯并咪唑I-9(26mg,0.2mmol)、反式-β-三氟甲基烯基锍盐II(95mg,0.22mmol)、乙腈(2mL),和三乙胺(31μL,0.22mmol)。室温下搅拌反应24小时,将反应液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比30:70)],得式化合物III-9所示化合物38mg,产率84%,为黄色油状液体。
1H NMR(400MHz,CDCl3)δ7.71-7.62(m,1H),7.27-7.16(m,3H),6.46(s,1H),5.89(q,J=1.7Hz,1H),2.50(s,3H).
13C NMR(101MHz,CDCl3)δ151.6,142.4,136.3,132.4(q,J=36.7Hz),125.8(q,J=3.3Hz),123.4,123.0,120.7(q,J=275.4Hz),119.2,109.9,13.7.
19F NMR(376MHz,CDCl3)δ-68.8.
HRMS m/z[M+H]+calculated for C11H10F3N2 +:227.0791,found:227.0797.
步骤二:在带磁力搅拌子的25mL两口烧瓶中依次加入三氟甲基烯烃III-9(45mg,0.2mmol),EtOAc(4mL),5%的钯/碳催化剂(32mg)。在一个大气压氢气(氢气球)下室温搅拌反应24h。反应结束后,用硅藻土过滤除去钯碳催化剂(乙酸乙酯洗涤),滤液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比30:70)],得到IV-9所示化合物37mg,产率81%,为淡黄色油状液体。
1H NMR(400MHz,CDCl3)δ7.75-7.67(m,1H),7.60-7.39(m,1H),7.25(dd,J=7.0,3.5Hz,2H),5.06-4.81(m,1H),2.65(s,3H),1.91(d,J=7.3Hz,3H).
13C NMR(101MHz,CDCl3)δ151.8,143.0,133.2,125.0(q,J=282.7Hz),122.8,122.5,119.6,112.0,53.5(q,J=31.6Hz),14.5,12.7.
19F NMR(376MHz,CDCl3)δ-74.0.
HRMS m/z[M+H]+calculated for C11H12F3N2 +:229.0947,found:229.0942.
实施例10
步骤一:氮气保护下,向反应管中依次加入6-氯嘌呤I-10(31mg,0.2mmol)、反式-β-三氟甲基烯基锍盐II(95mg,0.22mmol)、乙腈(2mL),和三乙胺(31μL,0.22mmol)。室温下搅拌反应24小时,将反应液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比5:95~25:75)],得式化合物III-10所示化合物44mg,产率88%,为白色固体。
M.p.=86-87℃.
1H NMR(400MHz,CDCl3)δ8.84(s,1H),8.28(d,J=1.2Hz,1H),6.48-6.46(m,2H).
13C NMR(101MHz,CDCl3)δ153.1,152.2,152.1,143.2(q,J=2.2Hz),131.5,128.9(q,J=37.1Hz),120.9(q,J=4.0Hz),119.9(q,J=274.7Hz).
19F NMR(377MHz,CDCl3)δ-68.4.
HRMS m/z[M+H]+calculated for C8H5ClF3N4 +:249.0149,found:249.0147.
步骤二:在带磁力搅拌子的25mL两口烧瓶中依次加入三氟甲基烯烃III-10(50mg,0.2mmol),EtOAc(4mL),5%的钯/碳催化剂(32mg)。在一个大气压氢气(氢气球)下室温搅拌反应24h。反应结束后,用硅藻土过滤除去钯碳催化剂(乙酸乙酯洗涤),滤液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比25:75)],得到IV-10所示化合物30mg,产率60%,为白色固体。
M.p.=83-84℃.
1H NMR(400MHz,CDCl3)δ8.80(s,1H),8.27(s,1H),5.44(hept,J=7.2Hz,1H),1.90(d,J=7.3Hz,3H).
13C NMR(101MHz,CDCl3)δ152.6,151.8,151.7,142.5,131.2,123.9(q,J=281.5Hz),51.5(q,J=33.3Hz),14.1.
19F NMR(376MHz,CDCl3)δ-76.1(d,J=6.9Hz).
HRMS m/z[M+H]+calculated for C8H7ClF3N4 +:251.0306,found:251.0301.
实施例11
步骤一:氮气保护下,向反应管中依次加入苯并[d][1,2,3]三唑I-11(24mg,0.2mmol)、反式-β-三氟甲基烯基锍盐II(95mg,0.22mmol)、乙腈(2mL),和三乙胺(31μL,0.22mmol)。室温下搅拌反应24小时,将反应液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比0:100~5:95)],得式化合物III-11所示化合物27mg,产率64%,为无色油状液体。
1H NMR(400MHz,CDCl3)δ8.12(d,J=8.3Hz,1H),7.58(d,J=5.4Hz,2H),7.47-7.42(m,1H),6.41(s,1H),6.13(q,J=1.9Hz,1H).
13C NMR(101MHz,CDCl3)δ145.8,133.3,133.0(q,J=37.2Hz),129.2,124.9,120.7(q,J=3.8Hz),120.6,120.2(q,J=275.7Hz),109.9(q,J=1.6Hz).
19F NMR(376MHz,CDCl3)δ-67.5.
HRMS m/z[M+H]+calculated for C9H7F3N3 +:214.0587,found:214.0585.
步骤二:在带磁力搅拌子的25mL两口烧瓶中依次加入三氟甲基烯烃III-11(43mg,0.2mmol),EtOAc(4mL),5%的钯/碳催化剂(32mg)。在一个大气压氢气(氢气球)下室温搅拌反应24h。反应结束后,用硅藻土过滤除去钯碳催化剂(乙酸乙酯洗涤),滤液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比5:95)],得到IV-11所示化合物29mg,产率67%,为无色油状液体。
1H NMR(400MHz,CDCl3)δ8.10-8.08(m,1H),7.61-7.51(m,2H),7.43-7.38(m,1H),5.51-5.38(m,1H),2.03(d,J=7.3Hz,3H).
13C NMR(101MHz,CDCl3)δ146.3,132.9,128.3,124.6,124.3(q,J=283.8Hz),120.5,109.8,56.5(q,J=33.1Hz),13.1.
19F NMR(376MHz,CDCl3)δ-74.9(d,J=7.0Hz).
HRMS(ESI-TOF)m/z[M+Na]+calcd for C9H8F3N3Na+:238.0563,found 238.0560
实施例12
步骤一:氮气保护下,向反应管中依次加入4-苯基三氮唑I-12(29mg,0.2mmol)、反式-β-三氟甲基烯基锍盐II(95mg,0.22mmol)、乙腈(2mL),和三乙胺(31μL,0.22mmol)。室温下搅拌反应24小时,将反应液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比0:100~3:97)],得式化合物III-12所示化合物26mg,产率55%,为白色固体。
1H NMR(400MHz,CDCl3)δ7.98(s,1H),7.82-7.74(m,2H),7.43-7.31(m,3H),6.32-6.30(m,1H),5.81(d,J=2.2Hz,1H).
13C NMR(101MHz,CDCl3)δ149.6,135.1(q,J=35.9Hz),133.5,129.4,129.1,129.0,126.4,119.8(q,J=272.9Hz),110.0(q,J=4.3Hz).
19F NMR(376MHz,CDCl3)δ-66.1.
HRMS m/z[M+H]+calculated for C11H9F3N3 +:240.0743,found:240.0745.
步骤二:在带磁力搅拌子的25mL两口烧瓶中依次加入三氟甲基烯烃III-12(48mg,0.2mmol),EtOAc(4mL),5%的钯/碳催化剂(32mg)。在一个大气压氢气(氢气球)下室温搅拌反应24h。反应结束后,用硅藻土过滤除去钯碳催化剂(乙酸乙酯洗涤),滤液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比5:95)],得到IV-12所示化合物44mg,产率92%,为无色油状液体。
1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.79(dt,J=6.6,1.4Hz,2H),7.47-7.40(m,2H),7.39-7.33(m,1H),5.23(hept,J=7.0Hz,1H),1.89(d,J=7.2Hz,3H).
13C NMR(101MHz,CDCl3)δ148.8,132.3,129.8,129.0,128.9,126.2,123.8(q,J=282.7Hz),61.4(q,J=32.6Hz),13.5(q,J=1.6Hz).
19F NMR(376MHz,CDCl3)δ-75.6(d,J=6.5Hz).
HRMS m/z[M+Na]+calculated for C11H10F3N3Na+:264.0719,found:264.0717.
实施例13
步骤一:氮气保护下,向反应管中依次加入吲哚-3-甲酸乙酯I-13(38mg,0.2mmol)、反式-β-三氟甲基烯基锍盐II(95mg,0.22mmol)、乙腈(2mL),和三乙胺(31μL,0.22mmol)。室温下搅拌反应24小时,将反应液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比0:100~5:95)],得式化合物III-13所示化合物43mg,产率77%,为黄色油状液体。
1H NMR(400MHz,CDCl3)δ8.22(dt,J=4.7,2.9Hz,1H),7.86(s,1H),7.39-7.29(m,3H),6.35(d,J=0.7Hz,1H),5.95-5.90(m,1H),4.40(q,J=7.1Hz,2H),1.42(t,J=7.1Hz,3H).
13C NMR(101MHz,CDCl3)δ164.5,137.7,133.5(q,J=33.4Hz),133.3,126.4,124.1,122.9,122.0,121.2(q,J=3.5Hz),120.5(q,J=275.7Hz),110.8,110.6,60.1,14.5.
19F NMR(377MHz,CDCl3)δ-68.9.
HRMS m/z[M+Na]+calculated for C14H12F3NNaO2 +:306.0712,found:306.0713.
步骤二:在带磁力搅拌子的25mL两口烧瓶中依次加入三氟甲基烯烃III-13(57mg,0.2mmol),EtOAc(4mL),5%的钯/碳催化剂(32mg)。在一个大气压氢气(氢气球)下室温搅拌反应24h。反应结束后,用硅藻土过滤除去钯碳催化剂(乙酸乙酯洗涤),滤液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比5:95)],得到IV-13所示化合物54mg,产率95%,为白色固体。
M.p.=75-76℃.
1H NMR(400MHz,CDCl3)δ8.25-8.17(m,1H),7.96(s,1H),7.41-7.28(m,3H),5.01(hept,J=7.0Hz,1H),4.40(q,J=7.1Hz,2H),1.82(d,J=7.2Hz,3H),1.43(t,J=7.1Hz,3H).
13C NMR(101MHz,CDCl3)δ164.7,137.2,130.9,126.2,124.6(q,J=283.8Hz),123.5,122.6,122.0,110.0,109.5,60.0,52.5(q,J=32.3Hz),14.6,14.2.
19F NMR(376MHz,CDCl3)δ-75.9(d,J=6.7Hz).
HRMS m/z[M+Na]+calculated for C14H14F3NNaO2 +:308.0869,found:308.0866.
实施例14
式III-1所示N-三氟丙烯基四唑化合物的合成:
氮气保护下,向反应管中依次加入5-苯基四氮唑I-1(15mg,0.1mmol)、反式-β-三氟甲基烯基锍盐II(48mg,0.11mmol)、THF(1mL),和三乙胺(15μL,0.11mmol)。室温下搅拌反应24小时,将反应液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比0:100~5:95)],得式化合物III-1所示化合物17mg,产率71%,为白色固体。
实施例15
式III-1所示N-三氟丙烯基四唑化合物的合成:
氮气保护下,向反应管中依次加入5-苯基四氮唑I-1(15mg,0.1mmol)、反式-β-三氟甲基烯基锍盐II(48mg,0.11mmol)、DMSO(1mL),和三乙胺(15μL,0.11mmol)。室温下搅拌反应24小时,将反应液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比0:100~5:95)],得式化合物III-1所示化合物16mg,产率67%,为白色固体。
实施例16
式III-1所示N-三氟丙烯基四唑化合物的合成:
氮气保护下,向反应管中依次加入5-苯基四氮唑I-1(15mg,0.1mmol)、反式-β-三氟甲基烯基锍盐II(48mg,0.11mmol)、MeCN(1mL),和K2CO3(15mg,0.11mmol)。室温下搅拌反应24小时,将反应液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比0:100~5:95)],得式化合物III-1所示化合物16mg,产率68%,为白色固体。
实施例17
式IV-1所示N-三氟异丙基四唑化合物的合成:
在带磁力搅拌子的25mL两口烧瓶中依次加入三氟甲基烯烃III-1(48mg,0.2mmol),MeOH(4mL),5%的钯/碳催化剂(32mg)。在一个大气压氢气(氢气球)下室温搅拌反应24h。反应结束后,用硅藻土过滤除去钯碳催化剂(乙酸乙酯洗涤),滤液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比5:95)],得到IV-1所示化合物44mg,产率92%,为无色油状液体。
实施例18
式IV-1所示N-三氟异丙基四唑化合物的合成:
在带磁力搅拌子的25mL两口烧瓶中依次加入三氟甲基烯烃III-1(48mg,0.2mmol),EtOAc(4mL),PtO2(4.5mg,10mol%)。在一个大气压氢气(氢气球)下室温搅拌反应24h。反应结束后,用硅藻土过滤除去Pt催化剂(乙酸乙酯洗涤),滤液减压浓缩后用硅胶柱层析分离[洗脱剂:乙酸乙酯/石油醚(体积比5:95)],得到IV-1所示化合物42mg,产率88%,为无色油状液体。
实施例19
N-三氟异丙基唑类化合物的抑菌活性测试:
采用平板计数法测试化合物对黑曲霉菌CMCC(F)98003的MIC90,即产生90%抑菌率的药物浓度。分别称取表1中化合物各3mg,以DMSO为溶剂,配制成浓度为1mg/mL的储备药液。采取48孔板微量稀释法,将配制好的储备药液用M-H液体培养基稀释至第1-12孔中,使孔中含药浓度分别为512、256、128、64、32、16、8、4、2、1、0.5、0.25μg/mL,体积为500μL。在含药的各孔中加入500μL黑曲霉菌液,使得第1-12孔最终浓度减半为:256、128、64、32、16、8、4、2、1、0.5、0.25、0.125μg/mL。空白对照组为1000μL M-H液体培养基,生长对照组为500μLM-H液体培养基加500μL黑曲霉菌液。配制完成后放置37℃的摇床中培养24h。培养结束后吸取48孔板中的溶液,以涂布平板法计算其含菌量,并根据公式(1)算出最终抑菌率,每个处理重复3次,取其平均值。最终得到各化合物针对黑曲霉的最小抑菌浓度(MIC90)。
抑菌率(%)=(对照组含菌量-各孔含菌量)/对照组含菌量×100%(1)
表1N-三氟异丙基唑类和吲哚化合物的抑制黑曲霉菌测试数据
从表1中的数据可以看出,在黑曲霉菌CMCC(F)98003的抗菌实验中,除化合物IV-13活性较低外,测试的所有的化合物均表现出一定的抗菌活性,效果最好的是化合物IV-9(MIC90=14.2μg/mL),具备进一步优化的潜力。
尽管已经示出和描述了本发明的实施例,对于本领域的普通技术人员而言,可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由所附权利要求及其等同物限定。
Claims (9)
1.如下式所示的化合物:
2.根据权利要求1所示的化合物的制备方法,其特征在于,包括以下步骤:
第一步:氮气保护下,向反应容器中依次加入含NH的氮杂环化合物、反式β-三氟甲基烯基锍盐、碱和溶剂一,所述碱为1.0至1.1当量的三乙胺或碳酸钾,室温下搅拌反应,将反应液减压浓缩后用硅胶柱层析分离得化合物一;
第二步:在带磁力搅拌子的两口烧瓶中依次加入化合物一、溶剂二和催化剂,溶剂二为甲醇、乙醇、或乙酸乙酯,催化剂为Pd/C、Pt/C、PtO2中的至少一种;
在一个大气压氢气下室温搅拌反应,反应结束后,进行分离纯化,得到在制备抗菌药物中应用的如权利要求1所示的化合物;
所述含NH的氮杂环化合物选自以下结构式的化合物:
所述反式β-三氟甲基烯基锍盐的结构式如下:
3.根据权利要求2所述的化合物的制备方法,其特征在于:所述第一步中的含NH的氮杂环化合物、反式β-三氟甲基烯基锍盐、碱的物质的量之比为1:1.1:1.1。
4.根据权利要求2所述的化合物的制备方法,其特征在于:所述第一步中的溶剂一为乙酸乙酯、二氯甲烷、乙腈、四氢呋喃、氯苯、二甲苯、甲苯、乙醇、氯仿、环己烷、丁酮、丙酮、石油醚、正辛烷、环己烷、乙醚中的至少一种。
5.根据权利要求2所述的化合物的制备方法,其特征在于:所述第二步中的溶剂二为乙酸乙酯。
6.根据权利要求2所述的化合物的制备方法,其特征在于:所述第二步中的催化剂为Pd/C。
7.根据权利要求2所述的化合物的制备方法,其特征在于:所述第一步以及第二步中的反应条件为室温下反应24h。
8.根据权利要求2所述的化合物的制备方法,其特征在于:所述第二步中的分离纯化按照以下步骤进行:反应结束后,用硅藻土过滤除去催化剂,乙酸乙酯洗涤,滤液减压浓缩后用硅胶柱层析分离,得到如权利要求1所示的化合物。
9.根据权利要求2所述的化合物的制备方法,其特征在于:所述第二步中的分离纯化按照以下步骤进行:反应结束后,将反应混合液减压蒸除溶剂,而后直接硅胶柱层析分离,以乙酸乙酯和石油醚的混合溶液为洗脱剂,分离得到如权利要求1所示的化合物。
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