CN105636445B - 制备杀虫化合物的方法 - Google Patents
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Abstract
本申请提供制备杀虫化合物的方法以及既可用作杀虫剂又可用于制备杀虫化合物的化合物。
Description
相关申请的交叉引用
本申请要求以下美国临时申请的权益:2014年8月26日提交的序列号62/041,943;2014年5月22日提交的序列号62/001,923;和2013年10月17日提交的序列号61/892,113,这些申请的整个公开内容通过参考明确并入本申请。
技术领域
本申请涉及制备杀虫硫醚和杀虫亚砜的有效且经济的合成化学法。进一步,本申请涉及对于它们的合成而言所必需的某些新型化合物。将为有利的是,从商业可得的起始原料有效地和以高收率地制备杀虫硫醚和杀虫亚砜。
具体实施方式
除非在特定情况中限定,否则以下定义适用于说明书通篇使用的的术语。
本申请使用的术语"烷基"表示支化或非支化的烃链。
除非另有指示,否则在本申请单独使用的术语"环烷基"是饱和环状烃基团,例如环丙基,环丁基,环戊基,环己基。
本申请作为另一个基团的一部分使用的术语"硫基"是指用作两个基团之间的连接基的硫原子。
本申请使用的术语"卤素"或本申请单独使用或作为另一个基团的一部分使用的"卤代"是指氯,溴,氟,和碘。
本申请的化合物和方法在以下详细描述。
方案1
在方案1的步骤a中,将4-硝基吡唑卤化和还原,得到3-氯-1H-吡唑-4-胺盐酸盐(1a)。通过使用浓(37wt%)盐酸(HCl)在3-碳发生卤化反应。使用三乙基硅烷(Et3SiH)和钯氧化铝(Pd/Al2O3,优选约1至10wt%钯氧化铝,更优选约5wt%)发生还原反应。该反应在约0℃至约40℃、优选约10℃至约20℃的温度进行。该反应可以在极性质子溶剂例如甲醇(MeOH)或乙醇(EtOH)、优选乙醇中进行。出乎意料地发现,通过在该步骤中使用约1当量至约4当量的三乙基硅烷、优选约2.5当量至约3.5当量的三乙基硅烷,同时使反应在约10℃至约20℃进行,可得到所需卤化产物3-氯-1H-吡唑-4-胺盐酸盐(1a)与不期望产物的摩尔比为约10:1
其中不期望的产物为
在方案1的步骤b中,用乙酸酐(Ac2O)在碱、优选为无机碱例如碳酸氢钠(NaHCO3)存在下在约0℃至约10℃、优选约5℃将3-氯-1H-吡唑-4-胺盐酸盐(1a)酰化,得到N-(3-氯-1H-吡唑-4-基)乙酰胺(1b)。已经出乎意料地发现,为了使该反应进行完全以及为了避免过度酰化,氯取代基必须存在于3位。本申请也描述了在3位没有卤素的对比实施例,其得到双酰化的产物(参见“CE-1”)。此外,在3位具有溴基团的对比实施例所得到的产物具有出乎意料低的收率,与具有氯基团所得到的产物相比(参见“CE-2”)。
在方案1的步骤c中,N-(3-氯-1H-吡唑-4-基)乙酰胺(1b)与卤代吡啶例如3-溴吡啶或3-碘吡啶在铜盐(例如氯化亚铜(I)(CuCl),氯化铜(II)(CuCl2),和碘化亚铜(I)(CuI))、无机碱例如磷酸钾(K3PO4)、和胺例如N,N’-二甲基乙烷-1,2-二胺存在下反应,得到N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)乙酰胺(1c)。该方法可以在极性溶剂例如乙腈(MeCN)、二氧杂环己烷、或N,N-二甲基甲酰胺中在约50℃至约110℃的温度进行。出乎意料地发现,在该步骤的后处理过程中加入水可使收率最大化。此外,与已知的杂芳基化方法相比,该合成方法比较简单并且降低起始原料的成本。
在方案1的步骤d中,N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)乙酰胺(1c)在氢化物源(优选为硼氢化钠(NaBH4))和酸源例如酸或Lewis酸(优选Lewis酸,优选为三氟化硼醚化物(BF3 .Et2O))存在下还原,得到3-氯-N-乙基-1-(吡啶-3-基)-1H-吡唑胺(1d)。已经出乎意料地发现,反应的收率极大地受三氟化硼醚化物(购自不同的供应商,此处优选Sigma Aldrich产品编号175501)的品质的影响。
在方案1的步骤e中,3-氯-N-乙基-1-(吡啶-3-基)-1H-吡唑胺(1d)与表示为ClC(=O)C1-C4-烷基-S-R1的酰氯反应,制得杀虫硫醚(1e)。R1选自C1-C4-卤代烷基和C1-C4-烷基-C3-C6-卤代环烷基,优选地,R1选自CH2CH2CF3或CH2(2,2-二氟-环丙基)。反应可以在极性非质子溶剂例如乙酸乙酯(EtOAc)中进行。反应可以任选地在碱例如NaHCO3存在下进行,得到杀虫硫醚(1e)。
在方案1的步骤f中,用氧化剂例如过氧化氢(H2O2)将硫醚(1e)氧化,得到杀虫亚砜(1f)。氧化反应在极性质子溶剂例如伯C1-C4醇中、尤其是在甲醇中进行。
或者,N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)乙酰胺(1c)可以通过方案2中公开的N-(3-氯-1H-吡唑-4-基)乙酰胺(1b)的杂芳基化反应制备,从而进一步节省该方法的成本。
方案2
另外,如方案3中公开,杀虫硫醚(1e)可以可替换地如下制备:使3-氯-N-乙基-1-(吡啶-3-基)-1H-吡唑胺(1d)与表示为X1C(=O)C1-C4-烷基-S-R1的活化羰基硫醚反应,以制备杀虫硫醚(1e)。R1选自C1-C4-卤代烷基和C1-C4-烷基-C3-C6-卤代环烷基,优选地,R1选自CH2CH2CF3或CH2(2,2-二氟-环丙基)。当X1是OC(=O)C1-C4烷基时,反应可以在碱(优选为碳酸氢钠)存在下进行,以得到杀虫硫醚(1e)。或者,当X1形成由下述试剂活化的活化碳酸时,反应可以在约0℃至约80℃进行,所述试剂例如为2,4,6-三丙基-三氧杂三磷杂环己烷-2,4-三氧化物(T3P),羰基二咪唑(CDI),二环己基碳二亚胺(DCC)或1-乙基-3-(3-二甲基-氨基丙基)碳二亚胺(EDC),优选为2,4,6-三丙基-三氧杂三磷杂环己烷-2,4-三氧化物和羰基二咪唑;该反应也可以使用或活化基团例如O-(7-氮杂苯并***-1-基)-N,N,N′,N′-四甲基六氟磷酸盐(HATU)或苯并***-1-基-氧基三吡咯烷基-六氟磷酸盐(PyBOP)在胺碱例如二异丙基乙胺(DIPEA)或三乙胺(TEA)存在下在极性非质子溶剂例如N,N-二甲基甲酰胺(DMF)、四氢呋喃(THF)、或二氯甲烷(CH2Cl2)中在约-10℃至约30℃的温度促成,以形成杀虫硫醚(1e)。活化羰基硫醚可以由X1C(=O)C1-C4-烷基-S-R1(其中X1是OH)制备,所述X1C(=O)C1-C4-烷基-S-R1(其中X1是OH)可以通过使表示为X1C(=O)C1-C4-烷基-S-R1(其中X1是OC1-C4-烷基)的相应酯硫醚与金属氢氧化物例如氢氧化锂在极性溶剂例如MeOH或THF中反应来制备。或者,X1C(=O)C1-C4-烷基-S-R1(其中X1是OH或OC1-C4-烷基)可以通过3-巯基丙酸及其酯与3,3,3-三氟丙烯在2,2-二甲氧基-2-苯基苯乙酮引发剂和长波长UV光存在下在惰性有机溶剂中的光化学自由基偶联来制备。另外,X1C(=O)C1-C4-烷基-S-R1(其中X1是OH或OC1-C4-烷基)也可以通过3-巯基丙酸及其酯与3,3,3-三氟丙烯在2,2'-偶氮二(4-甲氧基-2,4-二甲基)戊腈(V-70)引发剂存在下在约-50℃至约40℃的温度在惰性有机溶剂中的低温自由基引发的偶联来制备。
方案3
另外,如在方案4中公开,3-氯-1H-吡唑-4-胺盐酸盐(1a)可以由4-硝基吡唑制备。在用钯氧化铝和氢(H2)进行还原的过程中通过使用浓盐酸在约10℃至约20℃,可将4-硝基吡唑在3-碳位卤化,从而得到所需产物(1a)。
方案4
通过方案5中公开的反应途径顺序,可以制备3-氯-N-乙基-1-(吡啶-3-基)-1H-吡唑胺(1d)。在步骤d1中,N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)乙酰胺(1c)可以用溴乙烷(EtBr)在碱例如氢化钠(NaH)、叔丁醇钠(NaOt-Bu)、叔丁醇钾(KOt-Bu)、或叔戊醇钾存在下在极性非质子溶剂例如四氢呋喃中在约20℃至约40℃的温度历时约60小时至约168小时的时间段烷基化,从而得到N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)-N-乙基乙酰胺(1c′)。已经发现,使用添加剂例如碘化钾(KI)或四丁基碘化铵(TBAI)可将反应完成所需的时间降至约24小时。也发现,在约50℃至约70℃在密封反应器中(防治溴乙烷损失)加热反应可将反应时间降至约24小时。在步骤d2中,可以用浓盐酸在水中在约70℃至约90℃的温度处理N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)-N-乙基乙酰胺(1c′),得到3-氯-N-乙基-1-(吡啶-3-基)-1H-吡唑胺(1d)。也可以进行方案5中公开的反应途径顺序,而无需分离N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)-N-乙基乙酰胺(1c′)。
方案5
实施例
展示以下实施例以更好说明本申请的方法。
化合物实施例
实施例1:3-氯-1H-吡唑-4-胺盐酸盐(1a):
向装配有机械搅拌器、温度探针和氮气(N2)入口的1000-mL多颈圆筒夹套反应器中装入4-硝基吡唑(50.0g,429mmol)和钯氧化铝(5wt%,2.5g)。加入乙醇(150mL),然后缓慢添加浓盐酸(37wt%,180mL)。将反应冷却至15℃,历时1小时经由添加漏斗缓慢加入三乙基硅烷(171mL,1072mmol),同时保持内部温度在15℃。将反应在15℃搅拌72小时,其后将反应混合物过滤通过垫,将垫用温乙醇(40℃,2×100mL)冲洗。将合并的滤液分离,将水层(下层)浓缩至~100mL。添加乙腈(200mL),将所得悬浮液浓缩至~100mL。第二次添加乙腈(200mL),将所得悬浮液浓缩至~100mL。第三次添加乙腈(200mL),将所得悬浮液在20℃搅拌1小时并过滤。将滤饼用乙腈(2×100mL)冲洗,并在真空下在20℃干燥,得到白色固体(1a和1H-吡唑-4-胺的~10:1混合物,65.5g,99%):1H NMR(400MHz,DMSO-d6)δ10.52(bs,3H),8.03(s,1H);EIMS m/z 117([M]+)。
实施例2:N-(3-氯-1H-吡唑-4-基)乙酰胺(1b):
向100-mL的3颈圆底烧瓶中装入3-氯-1H-吡唑-4-胺盐酸盐(5.00g,32.5mmol)和水(25mL)。历时10分钟(在添加过程中排放气体)缓慢加入碳酸氢钠(10.9g,130mmol),然后加入四氢呋喃(25mL)。将混合物冷却至5℃,历时30分钟添加乙酸酐(3.48g,34.1mmol)同时保持内部温度在<10℃。将反应在5℃搅拌1小时,此时的薄层色谱(TLC)分析[洗脱液:乙酸乙酯]表明起始原料已经小时,唯一形成主产物。将反应混合物用乙酸乙酯(25mL)和水(25mL)稀释。使各层分离,将水层用乙酸乙酯(3×25mL)萃取。将合并的有机层浓缩,得到灰白色固体,使其悬浮在甲基叔丁基醚(20mL)中,搅拌1小时,并过滤。将固体用甲基叔丁基醚(20mL)冲洗,并进一步在真空下在室温(约22℃)干燥4小时,得到白色固体(4.28g,83%):mp 162-164℃;1H NMR(400MHz,DMSO-d6)δ12.90(bs,1H),9.49(s,1H),7.97(s,1H),2.02(s,3H);13C NMR(101MHz,DMSO-d6)δ167.81,130.07,123.72,116.73,22.58;EIMS m/z 159([M]+)。
实施例3:N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)乙酰胺(1c):
向250mL的3颈圆底烧瓶中装入N-(3-氯-1H-吡唑-4-基)乙酰胺(4.8g,30.1mmol)、氯化铜(II)(0.404g,3.01mmol)、3-碘吡啶(7.40g,36.1mmol)、磷酸钾(7.66g,36.1mmol)和乙腈(100mL)。添加N,N’-二甲基乙烷-1,2-二胺(1.33g,15.0mmol),将混合物在80℃加热18小时,此时的薄层色谱分析[洗脱液:乙酸乙酯]表明仍有痕量的起始原料并形成主产物。将其过滤通过垫,将垫用乙腈(50mL)冲洗。将水(300mL)加入到滤液中,将所得悬浮液搅拌2小时并过滤。将所得固体用水(2×20mL)冲洗并在真空下在室温干燥,得到白色固体(4.60g,65%):mp 169-172℃;1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),9.05(dd,J=2.8,0.8Hz,1H),8.82(s,1H),8.54(dd,J=4.7,1.4Hz,1H),8.20(ddd,J=8.4,2.8,1.4Hz,1H),7.54,(ddd,J=8.3,4.7,0.8Hz,1H),2.11(s,3H);13C NMR(101MHz,DMSO-d6)δ168.12,147.46,139.42,135.46,133.60,125.47,124.21,122.21,120.16,22.62;EIMS m/z236([M]+)。
实施例3的替代合成路线:N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)乙酰胺:
向100-mL的3颈圆底烧瓶中装入氯化亚铜(I)(59.6mg,0.602mmol)和乙腈(10mL),添加N,N’-二甲基乙烷-1,2-二胺(106mg,1.203mmol),将混合物在氮气下搅拌,得到溶液。添加N-(3-氯-1H-吡唑-4-基)乙酰胺(480mg,3.01mmol)和碳酸钾(831mg,6.02mmol),然后添加3-溴吡啶(570mg,3.61mmol)。将混合物用氮气吹洗三次并在80℃加热18小时。薄层色谱分析[洗脱液:乙酸乙酯,SM Rf=0.5,产物Rf=0.3]表明仍有痕量的起始原料并形成主产物。将其过滤通过垫,将垫用乙腈(10mL)冲洗。将合并的滤液浓缩至约5mL,将水(10mL)添加到所得悬浮液中。将悬浮液搅拌1小时并过滤。将固体用水(2×5mL)冲洗并在真空下在室温干燥,得到白色固体(458mg,64%)。表征通过之前方法制备的相对应样品。
实施例3的替代合成路线:N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)乙酰胺:
向4颈圆底烧瓶中装入N,N’-二甲基甲酰胺(250mL),然后脱气2-3次。在25-30℃添加碘化亚铜(I)(17.9g,94.0mmol),然后添加N,N’-二甲基乙烷-1,2-二胺(16.2g,188mmol)。将混合物用氮气吹洗30分钟。在25-30℃添加3-溴吡啶(59.4g,376mmol),然后添加N-(3-氯-1H-吡唑-4-基)乙酰胺(50.0g,313mmol)和碳酸钾(87.0g,188mmol)。将反应混合物用氮气吹洗30分钟并在95-100℃加热3小时,此时的HPLC分析表明反应完全。将其冷却至25-30℃,历时30-45分钟添加水(1L)。将所得悬浮液在25-30℃搅拌30分钟并冷却至0-10℃。将其在0-10℃搅拌12小时,然后过滤。将滤饼用水(2×250mL)洗涤并干燥,得到灰白色固体(55g,74%)。表征通过之前方法制备的相对应样品。
实施例4:3-氯-N-乙基-1-(吡啶-3-基)-1H-吡唑胺(1d):
向100mL的3颈圆底烧瓶中装入N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)乙酰胺(475mg,2.01mmol)和四氢呋喃(10mL)。添加三氟化硼醚化物(0.63mL,5.02mmol),将混合物搅拌15分钟,得到悬浮液。添加硼氢化钠(228mg,6.02mmol),将反应在60℃搅拌4小时,此时的薄层色谱分析[洗脱液:乙酸乙酯,通过将反应混合物用盐酸处理,然后用碳酸氢钠碱化并用乙酸乙酯萃取来制备样品]表明反应完全。添加水(10mL)和浓盐酸(1mL),将反应在60℃搅拌1小时。将反应混合物冷却至室温并蒸馏以除去四氢呋喃。将反应混合物用饱和碳酸氢钠溶液中和至pH 8,得到悬浮液,将其搅拌1小时并过滤。将滤饼用水(10mL)冲洗并在真空下干燥,得到白色固体(352mg,79%):mp 93-96℃;1H NMR(400MHz,DMSO-d6)δ8.99(d,J=2.7Hz,1H),8.44(dd,J=4.6,1.4Hz,1H),8.10(ddd,J=8.4,2.7,1.4Hz,1H),8.06(s,1H),7.50(dd,J=.4,4.7Hz,1H),4.63(t,J=6.0Hz,1H),3.06-2.92(m,2H),1.18(t,J=7.1Hz,3H);13C NMR(101MHz,DMSO-d6)δ146.17,138.31,135.81,132.82,130.84,124.10,123.96,112.23,40.51,14.28;EIMS m/z 222([M+])。
实施例4的替代合成路线:3-氯-N-乙基-1-(吡啶-3-基)-1H-吡唑-胺:
步骤1.N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)-N-乙基乙酰胺(1c′):
向100-mL的3颈圆底烧瓶中装入N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)乙酰胺(5.00g,21.1mmol)和四氢呋喃(50mL)。添加叔丁醇钠(3.05g,31.7mmol)(导致温度从22℃升至27.9℃),然后添加溴乙烷(4.70mL,63.4mmol)。将反应在35℃搅拌168小时,此时的HPLC分析表明仅留有2.9%(曲线下面积,AUC)的起始原料。将反应混合物浓缩,得到棕色残余物,将其用乙酸乙酯(50mL)和水(50mL)稀释。将水层用乙酸乙酯(4×50mL)萃取,将合并的有机物浓缩,得到棕色残余物。将残余物溶解于二氯甲烷(2×10mL),通过使用60-100%乙酸乙酯/己烷作为洗脱液的快速柱色谱纯化。将包含纯产物的级分合并并浓缩,得到作为黄色固体的标题产物(4.20g,74%):1H NMR(400MHz,CDCl3)δ8.98(d,J=2.7,0.8Hz,1H),8.62(dd,J=4.8,1.4Hz,1H),8.06(ddd,J=8.3,2.7,1.4Hz,1H),8.00(s,1H),7.47(dd,J=8.3,4.7Hz,1H),3.71(q,J=7.1Hz,2H),1.97(s,3H),1.16(t,J=7.2Hz,3H);13C NMR(101MHz,CDCl3)δ170.69,148.56,140.89,139.95,135.64,126.22,126.08,124.86,124.09,43.77,22.27,13.15;mp:87-91℃;ESIMS m/z 265([M+H]+)。
步骤1.N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)-N-乙基乙酰胺(1c′):
向100-mL的3颈圆底烧瓶中装入N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)乙酰胺(1.66g,7.0mmol)和四氢呋喃(16mL)。添加叔丁醇钠(0.843g,8.77mmol,1.25eq)和溴乙烷(0.78mL,10.52mmol,1.5eq),将反应器用隔片盖帽。将反应在58℃搅拌24小时,此时的HPLC分析表明仅留有1.97%起始原料。将混合物浓缩,得到棕色残余物,将其溶解于水(20mL)和乙酸乙酯(20mL)。将水层用乙酸乙酯(2×20mL)萃取,将合并的有机物浓缩至干燥。使残余物穿过硅胶塞(40g硅胶)并用乙酸乙酯(200mL)洗脱。将滤液浓缩至干燥并在真空下在20℃进一步干燥,得到黄色固体(1.68g,89%)。表征通过之前方法制备的相对应样品。
步骤1.N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)-N-乙基乙酰胺(1c′):
向125mL的3颈圆底烧瓶中添加N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)乙酰胺(2.57g,9.44mmol)、四氢呋喃(55mL)、和叔丁醇钠(1.81g,18.9mmol)。将悬浮液搅拌5分钟,然后添加溴乙烷(1.41mL,18.9mmol)和四丁基碘化铵(67mg,0.2mmol)。然后将所得灰色悬浮液加热至38℃。在3小时后分析反应,发现其已经完成81%,在24小时后发现反应完全。将反应混合物冷却至环境温度并用氢氧化铵(NH4OH)/甲酸(HCO2H)缓冲液(10mL)淬灭。然后将混合物用四氢呋喃(40mL)、乙酸乙酯(120mL)、和饱和碳酸氢钠(30mL)稀释。使各层分离,将水层用乙酸乙酯(2×30mL)萃取。将有机层合并,加入硅胶(37g)。真空移除溶剂,将得到的固体使用半自动化硅胶色谱(RediSep Silica 220g柱;己烷(0.2%三乙胺)/乙酸乙酯,40/60至0/100梯度洗脱***,流速150mL/分钟)纯化,浓缩后得到橙色固体(2.19g,88%)。
步骤2.3-氯-N-乙基-1-(吡啶-3-基)-1H-吡唑胺(1d):
将N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)-N-乙基乙酰胺(1.8g,6.80mmol)在盐酸(1N,34mL)中的溶液在80℃加热18小时,此时的HPLC分析表明仅留有1.1%起始原料。将反应混合物冷却至20℃并用氢氧化钠(50重量%,NaOH)碱化至pH>9。将所得悬浮液在20℃搅拌2小时并过滤。将滤饼用水(2×5mL)冲洗,调理30分钟,并空气干燥,得到灰白色固体(1.48g,95%):1H NMR(400MHz,DMSO-d6)δ9.00(dd,J=2.8,0.8Hz,1H),8.45(dd,J=4.7,1.4Hz,1H),8.11(ddd,J=8.4,2.8,1.4Hz,1H),8.06(d,J=0.6Hz,1H),7.49(ddd,J=8.4,4.7,0.8Hz,1H),4.63(t,J=6.0Hz,1H),3.00(qd,J=7.1,5.8Hz,2H),1.19(t,J=7.1Hz,3H);13C NMR(101MHz,DMSO-d6)δ146.18,138.31,135.78,132.82,130.84,124.08,123.97,112.23,40.51,14.28;ESIMS m/z 223([M+H]+)。
实施例4的替代合成路线:3-氯-N-乙基-1-(吡啶-3-基)-1H-吡唑-胺:
向100-mL的3颈圆底烧瓶中装入N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)乙酰胺(5g,21.13mmol)和四氢呋喃(50mL)。添加叔丁醇钠(4.06g,42.3mmol)(导致温度从22℃升至27.6℃),然后添加溴乙烷(6.26mL,85mmol)。将反应在35℃搅拌144小时,此时仅留有3.2%(AUC)的起始原料。将反应混合物浓缩得到棕色残余物,将其溶解于盐酸(1N,106mL,106mmol)并在80℃加热24小时,此时的HPLC分析表明起始原料已经消耗。将反应冷却至20℃并用氢氧化钠(50wt%)碱化至pH>9。将所得悬浮液在20℃搅拌1小时并过滤,将滤饼用水(25mL)冲洗,得到棕色固体(5.18g)。将所得粗产物溶解于乙酸乙酯,使用乙酸乙酯(500mL)作为洗脱液使其穿过硅胶塞(50g)。将滤液浓缩至干燥,得到白色固体(3.8g,80%)。
实施例5:N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)-N-乙基-3-((3,3,3-三氟丙基)硫基)丙酰胺(化合物5.1):
向100-mL的3颈圆底烧瓶中装入3-氯-N-乙基-1-(吡啶-3-基)-1H-吡唑胺(5.00g,22.5mmol)和乙酸乙酯(50mL)。添加碳酸氢钠(4.72g,56.1mmol),然后在<20℃历时2小时逐滴添加3-((3,3,3-三氟丙基)硫基)丙酰氯(5.95g,26.9mmol),此时的HPLC分析表明反应完全。将反应用水(50mL)(脱气)稀释,各层分离。将水层用乙酸乙酯(20mL)萃取,将合并的有机层浓缩至干燥,得到淡棕色固体(10.1g,定量)。将粗产物的少量样品通过使用乙酸乙酯作为洗脱液的快速柱色谱纯化,得到分析用参照样品:mp 79-81℃;1H NMR(400MHz,DMSO-d6)δ9.11(d,J=2.7Hz,1H),8.97(s,1H),8.60(dd,J=4.8,1.4Hz,1H),8.24(ddd,J=8.4,2.8,1.4Hz,1H),7.60(ddd,J=8.4,4.7,0.8Hz,1H),3.62(q,J=7.2Hz,2H),2.75(t,J=7.0Hz,2H),2.66-2.57(m,2H),2.57-2.44(m,2H),2.41(t,J=7.0Hz,2H),1.08(t,J=7.1Hz,3H);ESIMS m/z 407([M+H]+)。
N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)-N-乙基-3-((3,3,3-三氟丙基)硫基)丙酰胺的替代合成路线:
向20-mL小瓶中装入3-((3,3,3-三氟丙基)硫基)丙酸(0.999g,4.94mmol)和乙腈(5mL)。添加羰基二咪唑(0.947g,5.84mmol)(脱气)和1H-咪唑盐酸盐(0.563g,5.39mmol),将反应在20℃搅拌4小时。添加3-氯-N-乙基-1-(吡啶-3-基)-1H-吡唑胺(1g,4.49mmol),将反应在75℃搅拌42小时,此时的HPLC分析表明转化率为96%。将反应冷却至20℃并浓缩至干燥。将残余物通过使用80%乙酸乙酯/己烷作为洗脱液的快速柱色谱纯化。将纯级分合并,浓缩,得到淡黄色固体(1.58g,86%)。表征通过之前方法制备的相对应样品。
N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)-N-乙基-3-((3,3,3-三氟丙基)硫基)丙酰胺的替代合成路线:
将3-((3,3,3-三氟丙基)硫基)丙酸(2.18g,10.78mmol)和3-氯-N-乙基-1-(吡啶-3-基)-1H-吡唑胺(2.00g,8.98mmol)的溶液冷却至5℃。在0-5℃历时30min逐滴添加二异丙基乙胺(5.15mL,29.6mmol),然后在0-5℃历时30分钟添加2,4,6-三丙基-三氧杂三磷杂环己烷-2,4-三氧化物(4.00g,12.6mmol)。将反应加热至25-30℃并搅拌2小时。反应完成之后,将反应混合物冷却至0-5℃并用水(12mL)淬灭。使各层分离,将水层用乙酸乙酯(30mL)萃取。将合并的有机层浓缩,得到作为油状物的所需产物(3.4g,94%)。表征通过之前方法制备的相对应样品。
N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)-N-乙基-3-((3,3,3-三氟丙基)硫基)丙酰胺的替代纯化条件:
使粗制N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)-N-乙基-3-((3,3,3-三氟丙基)硫基)丙酰胺(64g)悬浮在甲醇(90mL)中,将其加热,得到澄清的棕色溶液。添加水(30mL),将溶液冷却至20℃,用N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)-N-乙基-3-((3,3,3-三氟丙基)硫基)丙酰胺固体的样品(50mg)结种(seed)。将所得悬浮液在20℃搅拌18小时。将悬浮液过滤,将滤饼用3:1甲醇/水(2×40mL)冲洗并干燥,得到白色固体(49g,77%)。表征通过之前方法制备的相对应样品。
N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)-N-乙基-3-((3,3,3-三氟丙基)硫基)丙酰胺的替代纯化条件:
使粗制N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)-N-乙基-3-((3,3,3-三氟丙基)硫基)丙酰胺(5.0g)悬浮于甲基叔丁基醚(15mL)中并加热,得到澄清的棕色溶液。将其冷却至20℃,用N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)-N-乙基-3-((3,3,3-三氟丙基)硫基)丙酰胺固体的样品(20mg)结种。将所得悬浮液在20℃搅拌18小时。添加庚烷(10mL),固体保持为自由流动的悬浮液。将其在20℃搅拌2小时并过滤。将滤饼用庚烷(2×10mL)冲洗并干燥,得到白色固体(3.9g,78%)。表征通过之前方法制备的相对应样品。
实施例6:3-((3,3,3-三氟丙基)硫基)丙酸:
向100-mL的3颈圆底烧瓶中装入3-溴丙酸(500mg,3.27mmol)和甲醇(10mL),添加氢氧化钾(KOH,403mg,7.19mmol),然后添加3,3,3-三氟丙烷-1-硫醇(468mg,3.60mmol)。将混合物在50℃加热4小时,其后将其用盐酸(2N)酸化并用甲基叔丁基醚(2×10mL)萃取。将有机层浓缩至干燥,得到淡黄色油状物(580mg,88%):1H NMR(400MHz,CDCl3)δ2.83(td,J=7.1,0.9Hz,2H),2.78-2.64(m,4H),2.48-2.32(m,2H)。
3-((3,3,3-三氟丙基)硫基)丙酸的替代合成路线:
向100-mL不锈钢Parr反应器中装入偶氮二异丁腈(AIBN,0.231g,1.41mmol)、甲苯(45mL)、3-巯基丙酸(3.40g,32.0mmol)、和苯辛酮(526.2mg)作为内标物,将其用氮气吹洗、检测压力。将反应器用干冰冷却,将冷凝的3,3,3-三氟丙烯(3.1g,32.3mmol)装入反应器。移走冰浴,将反应器加热至60℃并搅拌27小时。通过使用苯辛酮作为内标物,反应器的内部收率确定为80%。释放压力,将粗制混合物从反应器中取出。将混合物通过旋转蒸发浓缩,添加氢氧化钠(10%,50mL)。将溶液用甲基叔丁基醚(50mL)洗涤,然后用盐酸(6N)酸化至pH~1。将产物用甲基叔丁基醚(100mL)萃取,用硫酸镁(MgSO4)干燥,过滤,浓缩,得到作为油状物的粗制标题化合物(5.34g,83%):1H NMR(400MHz,CDCl3)δ2.83(td,J=7.1,0.9Hz,2H),2.76–2.64(m,4H),2.47–2.30(m,2H);13C NMR(101MHz,CDCl3)δ177.68,125.91(q,J=277.1Hz),34.58(q,J=28.8Hz),34.39,26.63,24.09(q,J=3.3Hz);19F NMR(376MHz,CDCl3)δ-66.49。
3-((3,3,3-三氟丙基)硫基)丙酸的替代合成路线:
向250mL的3颈圆底烧瓶中装入甲苯(81mL)并用干冰/丙酮浴冷却至<-50℃。将3,3,3-三氟丙烯(10.28g,107.0mmol)鼓泡到溶剂中,移走冰浴。添加3-巯基丙酸(9.200g,86.70mmol)和2,2-二甲氧基-2-苯基苯乙酮(1.070g,4.170mmol),打开长波灯(366nm,4瓦UVP灯)(起始温度:-24℃)。由于灯的热量,反应达到27.5℃的高温。在红外灯下将反应搅拌4小时。在4小时后,关掉红外灯,将反应通过旋转蒸发(41℃,6mm Hg)浓缩,得到浅黄色油状物(18.09g,51:1线型异构体:支化异构体,90wt%线型异构体,通过GC内标法测定,16.26g活性成分,93%)。将粗制物料溶解于氢氧化钠w/w(10%,37.35g),并用甲苯(30mL)洗涤,以除去非极性杂质。将水层用盐酸(2N,47.81g)酸化至pH~2-3,并用甲苯(50mL)萃取。将有机层用水(40mL)洗涤,用硫酸镁干燥,过滤,通过旋转蒸发浓缩,得到浅黄色油状物(14.15g,34:1线型异构体:支化异构体,94wt%线型异构体,通过GC内标法测定,13.26g活性成分,76%)。
3-((3,3,3-三氟丙基)硫基)丙酸的替代合成路线:
向100mL不锈钢Parr反应器中装入3-巯基丙酸(3.67g,34.6mmol)、甲苯(30.26g)、和2,2'-偶氮二(4-甲氧基-2,4-二甲基)戊腈(V-70,0.543g,1.76mmol),将反应器用干冰/丙酮浴冷却,用氮气吹洗、检测压力。用递送滚筒(transfer cylinder)添加3,3,3-三氟丙烯(3.20g,33.3mmol),将反应加热至20℃。在24小时之后,将反应加热至50℃并保持1小时,以分解任何剩余的V-70引发剂。将反应冷却至室温。将溶液通过旋转蒸发浓缩,得到标题化合物(6.80g,通过GC内标法测定77.5wt%线型异构体,5.27g活性成分,76%,通过GC内标法测定200:1线型异构体:支化异构体,通过氟NMR测定40:1线型异构体:支化异构体)。
实施例7:3-((3,3,3-三氟丙基)硫基)丙酸甲酯(化合物7.1):
向100-mL不锈钢Parr反应器中装入偶氮二异丁腈(0.465g,2.83mmol)、甲苯(60mL)和3-巯基丙酸甲酯(7.40g,61.6mmol),用氮气吹洗、检测压力。将反应器用干冰冷却,将冷凝的3,3,3-三氟丙烯(5.7g,59.3mmol)装入反应器。移走冰浴,将反应器加热至60℃并搅拌24小时。关掉热量,将反应在室温搅拌过夜。将混合物从反应器中取出,浓缩,得到黄色液体。将液体通过真空蒸馏法(2托,85℃)蒸馏,收集到三个级分:级分1(1.3g,6.01mmol,10%,70.9面积%,通过GC测定),级分2(3.7g,17.1mmol,29%,87面积%,通过GC测定),和级分3(4.9g,22.7mmol,38%,90.6面积%,通过GC测定):1H NMR(400MHz,CDCl3)δ3.71(s,3H),2.82,(td,J=7.3,0.7Hz,2H),2.75-2.68(m,2H),2.63(td,J=7.2,0.6Hz,2H),2.47-2.31(m,2H);13C NMR(101MHz,CDCl3)δ172.04,125.93(q,J=277.2Hz),51.86,34.68(q,J=28.6Hz),34.39,27.06,24.11(q,J=3.3Hz);19F NMR(376MHz,CDCl3)δ-66.53。
3-((3,3,3-三氟丙基)硫基)丙酸甲酯的替代合成路线:
向500mL的3颈圆底烧瓶中装入甲苯(200mL)并用干冰/丙酮浴将其冷却至<-50℃。通过将气体鼓泡通过***剂而将3,3,3-三氟丙烯(21.8g,227mmol)冷凝到反应中,移走冰浴。添加3-巯基丙酸甲酯(26.8g,223mmol)和2,2-二甲氧基-2-苯基苯乙酮(2.72g,10.61mmol),将置于玻璃壁内并离玻璃壁2厘米的UVP灯(4瓦)打开调至长波功能(366纳米)。由于灯的热量,反应达到35℃。在4小时之后,所有的三氟丙烯或者消耗、或者被煮出反应。关掉光,将反应在室温搅拌过夜。在22小时之后,在室温将更多的三氟丙烯(3.1g)鼓泡通过混合物,将灯打开另外2小时。反应已经转化93%,因此不再添加三氟丙烯。将光关掉,将混合物在旋转蒸发仪(40℃,20托)上浓缩,得到黄色液体(45.7g,21.3:1线型异构体:支化异构体,通过GC内标法测定75wt%纯线型异构体,34.3g活性成分,71%一锅收率)。
3-((3,3,3-三氟丙基)硫基)丙酸甲酯的替代合成路线:
向100mL不锈钢Parr反应器中装入3-巯基丙酸甲酯(4.15g,34.5mmol)、甲苯(30.3g)、和2,2'-偶氮二(4-甲氧基-2,4-二甲基)戊腈(V-70,0.531g,1.72mmol),将反应器用干冰/丙酮浴冷却,用氮气吹洗、检测压力。用递送滚筒添加3,3,3-三氟丙烯(3.40g,35.4mmol),将反应加热至20℃。在23小时之后,将反应加热至50℃并保持1小时,以分解任何剩余的V-70引发剂。将反应冷却至室温。将溶液浓缩,得到标题化合物(7.01g,66%,通过GC内标法测定70.3wt%线型异构体,4.93g活性成分,66%,通过GC内标法测定24:1线型异构体:支化异构体,通过氟NMR测定18:1线型异构体:支化异构体)。
实施例8:N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)-N-乙基-3-((3,3,3-三氟丙基)亚砜)丙酰胺(化合物8.1):
将N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)-N-乙基-3-((3,3,3-三氟丙基)硫基)丙酰胺(57.4g,141mmol)在甲醇(180mL)中搅拌。使用注射器向所得溶液中逐滴添加过氧化氢(43.2mL,423mmol)。将溶液在室温搅拌6小时,此时的LCMS分析表明起始原料消耗。将混合物倒入二氯甲烷(360mL)中,用碳酸钠(Na2CO3)水溶液洗涤。将有机层用硫酸钠干燥并浓缩,得到浓稠黄色油状物。将粗产物通过使用0-10%甲醇/乙酸乙酯作为洗脱液的快速柱色谱纯化,将纯级分合并、浓缩,得到作为油状物的所需产物(42.6g,68%):1H NMR(400MHz,DMSO-d6)δ9.09(dd,J=2.8,0.7Hz,1H),8.98(s,1H),8.60(dd,J=4.7,1.4Hz,1H),8.24(ddd,J=8.4,2.7,1.4Hz,1H),7.60(ddd,J=8.4,4.7,0.8Hz,1H),3.61(q,J=7.4,7.0Hz,2H),3.20–2.97(m,2H),2.95–2.78(m,2H),2.76–2.57(m,2H),2.58–2.45(m,2H),1.09(t,J=7.1Hz,3H);ESIMS m/z 423([M+H]+)。
实施例9:3-((3,3,3-三氟丙基)硫基)丙酰氯:
向装备有磁力搅拌器、氮气入口、回流冷凝器、和温度计的干燥5L圆底烧瓶中装入3-((3,3,3-三氟丙基)硫基)丙酸(188g,883mmol)在二氯甲烷(3L)中的溶液。然后历时50分钟逐滴添加氯化亚砜(525g,321mL,4.42mol)。将反应混合物加热至回流(约36℃)并保持2小时,然后冷却至室温。在旋转蒸发仪上真空浓缩,然后蒸馏(40托,从123-127℃收集的产物),得到作为澄清无色液体的标题化合物(177.3g,86%):1H NMR(400MHz,CDCl3)δ3.20(t,J=7.1Hz,2H),2.86(t,J=7.1Hz,2H),2.78–2.67(m,2H),2.48–2.31(m,2H);19F NMR(376MHz,CDCl3)δ-66.42,-66.43,-66.44,-66.44。
实施例10:3-(((2,2-二氟环丙基)甲基)硫基)丙酸:
在室温将粉末状氢氧化钾(423mg,7.54mmol)和2-(溴甲基)-1,1-二氟环丙烷(657mg,3.84mmol)先后添加到3-巯基丙酸(400mg,3.77mmol)在甲醇(2mL)的搅拌溶液中。将所得白色悬浮液在65℃搅拌3小时,用盐酸水溶液(1N)淬灭,用乙酸乙酯稀释。分离有机相,将水相用乙酸乙酯(2x 50mL)萃取。将合并的有机萃取物用硫酸镁干燥,过滤,真空浓缩,得到作为无色油状物的标题分子(652mg,84%):IR(薄膜)3025,2927,2665,2569,1696cm-1;1H NMR(400MHz,CDCl3)δ2.85(t,J=7.0Hz,2H),2.82-2.56(m,4H),1.88-1.72(m,1H),1.53(dddd,J=12.3,11.2,7.8,4.5Hz,1H),1.09(dtd,J=13.1,7.6,3.7Hz,1H);ESIMSm/z 195([M-H]-)。
实施例11:3-(((2,2-二氟环丙基)甲基)硫基)丙酰氯:
在装备有悬空搅拌器、温度探针、添加漏斗、和氮气入口的3L的3颈圆底烧瓶中装入3-(((2,2-二氟环丙基)甲基)硫基)丙酸(90.0g,459mmol),将其在搅拌下立即溶解于二氯甲烷(140mL)。在室温,在搅拌下逐滴添加氯化亚砜(170mL,2293mmol)在二氯甲烷(100mL)中的溶液。将反应混合物加热至40℃并加热2小时。通过1H NMR确定反应完全(取出等分的反应混合物,用旋转蒸发仪浓缩至极干)。将反应冷却至室温,将混合物转移至干燥的3L圆底烧瓶并用旋转蒸发仪浓缩。这得到95g蜜色油状物。将内容物经重力过滤通过滤纸,将滤纸用***(10mL)冲洗。将冲洗液加入到烧瓶中。这得到澄清的黄色液体。将液体置于旋转蒸发仪来移除醚。这得到92.4g黄色油状物。将油状物进行Kugelrohr蒸馏(bp 100-110℃/0.8-0.9mm Hg),得到作为无色油状物的标题化合物(81.4g,81%):1H NMR(400MHz,CDCl3)δ3.27–3.12(m,2H),2.89(t,J=7.1Hz,2H),2.67(ddd,J=6.8,2.6,1.0Hz,2H),1.78(ddq,J=13.0,11.3,7.4Hz,1H),1.64–1.46(m,1H),1.09(dtd,J=13.2,7.7,3.7Hz,1H)。
生物学实施例
实施例A桃蚜(Green Peach Aphid,“GPA”)(Myzus persicae)(桃蚜(MYZUPE))的生物测定。
GPA是桃树的最重要的蚜虫害虫,导致减少的生长、叶子的干皱和各种组织的死亡。它也是危险的,因为它充当植物病毒运输的传病媒介,例如马铃薯Y病毒和马铃薯卷叶病毒(对于龙葵/马铃薯家族茄科的成员),和各种花叶病病毒(对于许多其它粮食作物)。GPA攻击诸如以下的植物:绿花椰菜、牛蒡、白菜、胡萝卜、花椰菜、萝卜(daikon)、茄子、菜豆、莴苣、澳大利亚坚果、番木瓜、胡椒、蕃薯、番茄、水田芥菜和西葫芦等。GPA也攻击许多观赏作物如康乃馨、菊花、开花白菜(flowering white cabbage)、猩猩木和玫瑰。GPA已经形成了对许多杀虫剂的耐药性。
使用以下描述的操作,针对GPA测试本文中公开的某些分子。
将在3英寸罐(pot)中生长的卷心菜幼苗(具有2-3片小的(3-5cm)真叶(trueleaf))用作试验底物。用20-50个桃蚜(无翅成虫和若虫阶段)对所述幼苗进行侵害1天,然后进行化学施用。每种处理使用具有各株幼苗的四个罐。将试验化合物(2mg)溶于2mL丙酮/MeOH(1:1)溶剂中,形成浓度为1000ppm试验化合物的储备溶液。储备溶液用0.025%吐温20在水中的溶液稀释5倍以得到浓度为200ppm的测试化合物溶液。使用手持抽吸器型喷雾器将溶液喷雾到卷心菜叶子的两面直到形成径流(runoff)。对照植物(溶剂检测)用仅含20体积%丙酮/MeOH(1:1)溶剂的稀释剂喷雾。将经处理的植物在保育室中在约25℃和环境相对湿度(RH)的条件下保持三天,然后评级。评价通过在显微镜下计数每株植物上的活蚜虫数目来进行。百分比防治通过使用Abbott校正公式(W.S.Abbott,“A Method ofComputing the Effectiveness of an Insecticide”J.Econ.Entomol.18(1925),pp.265-267)如下测量。
经校正的百分比防治=100*(X-Y)/X
其中
X=溶剂检测植物上的活蚜虫数目,以及
Y=经处理的植物上的活蚜虫数目
结果显示在题目为“表1:GPA(桃蚜)和甘薯粉虱(sweetpotato whitefly-crawler)(BEMITA)评级表”的表中。
实施例B对甘薯粉虱(烟粉虱(Bemisia tabaci))(甘薯粉虱(BEMITA))进行的生物测定
自19世纪末以来,美国已经报告了甘薯粉虱(烟粉虱(Bemisia tabaci))(粉虱)。在1986年的弗罗里达州,甘薯粉虱变为极度影响经济的害虫。烟粉虱通常以它们的宿主植物叶片的下表面为食。卵孵化后是短暂的爬虫(crawler)阶段,在该阶段粉虱在叶片上爬来爬去,直到其将微小的线状口器***叶子以通过从韧皮部吸吮树液来进食。成虫和幼虫分泌甘汁(大部分为来自在韧皮部进食的植物糖分),这是一种粘性的粘滞液体,其中可生长暗色烟霉。成虫及其后代的严重侵害可以导致秧苗死亡、或强健性下降以及较年长植物的产量,仅仅是由于树液的移除。甘汁可将皮棉粘在一起,使其更难轧棉去籽,由此降低其价值。甘汁覆盖的底物上的暗色烟霉,掩盖叶子并减少其光合作用,并降低果实质量等级。其运输从未侵袭过耕种作物的植物病原病毒并诱导植物生理疾病,例如番茄不规则成熟和西葫芦银叶病。烟粉虱对许多之前有效的杀虫剂具有耐药性。
将在3英寸罐中生长的棉花植物(具有1片小的(3-5cm)真叶)用作试验底物。将植物置于具有粉虱成虫的场所中。允许成虫产卵2-3天。在2-3天的产卵期后,将植物从成虫粉虱场所取出。使用手持式Devilbiss喷雾器(23psi)将成虫从叶片吹掉。将具有卵感染的植物(每株植物100-300个卵)在储存室中在82°F和50%RH放置5-6天,进行卵孵化和爬虫阶段发育。对于每一处理,使用四株棉花植物。将化合物(2mg)溶解在1mL丙酮溶剂中,形成2000ppm的储备溶液。将储备溶液用0.025%Tween 20在水中的溶液稀释10倍,得到200ppm的试验溶液。使用手持式Devilbiss喷雾器将溶液喷至棉花叶片的两侧,直到径流(runoff)。参照植物(溶剂检测)仅用稀释剂喷雾。将经处理的植物在储存室中在约82°F和50%RH储存8-9天,然后分级。评价通过在显微镜下计数每株植物上的活若虫数目来进行。杀虫活性通过使用Abbott校正公式(参见上文)测量,并在表1中提供。
表1:GPA(桃蚜)和甘薯粉虱(BEMITA)评级表
实施例化合物 | BEMITA | MYZUPE |
1a | B | B |
1b | B | B |
1c | B | B |
1d | B | B |
化合物5.1 | A | A |
化合物7.1 | C | C |
化合物8.1 | A | A |
对比实施例
实施例CE-1:N-(1-乙酰基-1H-吡唑-4-基)乙酰胺:
向250-mL的3颈烧瓶中装入1H-吡唑-4-胺(5g,60.2mmol)和二氯甲烷(50mL)。将所得悬浮液冷却至5℃并加入三乙胺(9.13g,90.0mmol),然后在<20℃加入乙酸酐(7.37g,72.2mmol)。将反应在室温搅拌18小时,此时的薄层色谱[洗脱液:乙酸乙酯]分析表明反应完全。添加另外的三乙胺(4.57g,45.0mmol)和乙酸酐(3.70g,36.0mmol),将反应在30℃加热另外3小时,得到深色溶液,此时的薄层色谱分析表明仅留有痕量的起始原料。将反应混合物通过使用乙酸乙酯作为洗脱液的快速柱色谱纯化。将包含纯产物的级分合并,浓缩至干燥,得到灰白色固体。将固体在真空下在室温干燥18小时(5.55g,55%):1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.39(d,J=0.7Hz,1H),7.83(d,J=0.7Hz,1H),2.60(s,3H),2.03(s,3H);EIMS m/z 167([M]+)。
实施例CE-2:N-(3-溴-1H-吡唑-4-基)乙酰胺:
向250mL的3颈圆底烧瓶中装入1H-吡唑-4-胺·氢溴酸盐(4.00g,24.7mmol)和水(23mL)。历时10分钟向混合物中缓慢加入碳酸氢钠(8.30g,99.0mmol),然后加入四氢呋喃(23mL)。将混合物冷却至5℃,历时30分钟加入乙酸酐(2.60g,25.4mmol),同时保持内部温度在<10℃。将反应混合物在~5℃搅拌20分钟,此时的1H NMR和UPLC分析表明起始原料消耗,且形成所需产物以及双乙酰化副产物。将反应用乙酸乙酯萃取三次,将合并的有机层用硫酸镁干燥,过滤,并浓缩。将粗制混合物用甲基叔丁基醚研磨,从而除去双乙酰化产物,从而得到~1.24g白色固体。1H NMR分析显示其为所需产物与不期望的双乙酰化产物的1:1.1混合物。将固体通过使用50-100%乙酸乙酯/己烷作为洗脱液的快速柱色谱纯化,得到作为白色固体的所需产物(380mg,7.5%)和作为白色固体的双乙酰化产物(~800mg):1H NMR(400MHz,DMSO-d6)δ13.01(s,1H),9.36(s,1H),7.92(s,1H),2.03(s,3H);13C NMR(101MHz,DMSO)δ167.94,123.93,119.19,119.11,22.63;ESIMSm/z 204([M+H]+)。
应该理解,尽管本文已经就详细记载的具体实施方式描述了本发明,但是这些实施方式的展示是为了说明本发明的一般原理,并不能认为本发明必须限于这些实施方式。在不背离本发明的实质精神和范围的情况,本领域技术人员容易想到任何所给材料、方法步骤或化学式的某些修改和变型,而所有这些修改和变型都应认为落入所附权利要求的范围内。
Claims (4)
1.具有下式的分子
N-(3-氯-1H-吡唑-4-基)乙酰胺。
2.具有下式的分子
N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)乙酰胺。
3.选择性单酰化3-氯-1H-吡唑-4-胺盐酸盐(1a)的方法
所述方法包括:在碱存在下用乙酸酐将胺(1a)酰化,得到酰胺(1b)
4.制备N-(3-氯-1-(吡啶-3-基)-1H-吡唑-4-基)乙酰胺(1c)的方法
所述方法包括:使N-(3-氯-1H-吡唑-4-基)乙酰胺(1b)与适当的卤代吡啶在铜盐、胺和碱存在下反应
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US20160152594A1 (en) | 2016-06-02 |
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CA2925953C (en) | 2021-11-02 |
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BR112016008070B8 (pt) | 2022-08-23 |
KR20160074543A (ko) | 2016-06-28 |
US9988356B2 (en) | 2018-06-05 |
WO2015058024A1 (en) | 2015-04-23 |
EP3057425A1 (en) | 2016-08-24 |
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US9796682B2 (en) | 2017-10-24 |
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