CN114805347B - 一种有机催化合成手性吡唑并[3,4-b]吡啶酮类化合物及应用 - Google Patents

一种有机催化合成手性吡唑并[3,4-b]吡啶酮类化合物及应用 Download PDF

Info

Publication number
CN114805347B
CN114805347B CN202210520694.6A CN202210520694A CN114805347B CN 114805347 B CN114805347 B CN 114805347B CN 202210520694 A CN202210520694 A CN 202210520694A CN 114805347 B CN114805347 B CN 114805347B
Authority
CN
China
Prior art keywords
pyrazolo
chiral
methyl
nmr
chloroform
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202210520694.6A
Other languages
English (en)
Other versions
CN114805347A (zh
Inventor
池永贵
聂桂花
金智超
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guizhou University
Original Assignee
Guizhou University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guizhou University filed Critical Guizhou University
Priority to CN202210520694.6A priority Critical patent/CN114805347B/zh
Publication of CN114805347A publication Critical patent/CN114805347A/zh
Application granted granted Critical
Publication of CN114805347B publication Critical patent/CN114805347B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

本发明一类手性化合物吡唑并[3,4‑b]吡啶酮衍生物，如下述通式(1)表示：其中标有*的碳原子为手性碳原子，R1为烷基、芳香基或取代苯基，R2为烷基、芳香基或取代苯基，R3为烷基、芳香杂环或取代苯基。本发明公开的α‑溴代肉桂醛和5‑氨基吡唑的不对称环化反应制备吡唑骨架手性化合物吡啶衍生物，其衍生物普适性好，具有良好的产率高达99％、对映选择性高达99:1和良好的衍生化反应。

Description

一种有机催化合成手性吡唑并[3,4-b]吡啶酮类化合物及 应用
技术领域
本发明涉及一种氮杂环卡宾有机小分子催化合成含吡唑并[3,4-b]吡啶酮骨架手性化合物的制备方法及衍生化研究。
背景技术
近年来，植物真菌和细菌严重影响着全球农作物的产量和质量，植物真菌病害直接造成农作物产量下降与品质降低，给农民带来了巨大的经济损失。例如，小麦赤霉病菌(Gibberellazeae.Retch)是丝状的子囊菌，是由多种镰刀菌侵染所引起的、发生在小麦上的病害。该病菌能引起小麦苗腐、茎基腐、杆腐和穗腐，它每年给小麦种植的国家带来至少10-20％的减产。此外，辣椒疫霉病菌(Phytophthora capsici)是鞭毛属亚门疫霉属的一种病原真菌。病菌孢囊梗不规则分枝或伞形分枝，它每年给国家带来至少1亿美元的损失。辣椒炭疽病菌(Colletotrichum capsicum)会导致辣椒腐烂，在全球范围内影响着辣椒的产量。在农业生产过程中，由于传统药剂的长期使用，使得植物病原菌对其产生了一定的抗性。因此，创制新型高效、低毒、安全的绿色农药具有十分重要的意义
吡唑类骨架常存在于天然产物和非天然化合物中，具有良好的生物活性。含吡唑核的各种分子在抗病毒、抗菌、抗真菌、抗癌和农药等方面得到了广泛的研究。因此，吡唑类化合物的合成受到了广泛的关注。开发高效、高立体选择性的手性吡唑衍生物的制备方法具有重要的应用价值。
发明内容
本发明的目的是为了设计合成出一类结构新颖、底物普适性好和高对映选择性的吡唑并[3,4-b]吡啶酮骨架手性化合物，并进一步应用在农业上方面的研究。
本发明的技术方案：一类手性化合物吡唑衍生物，如下述通式(1)表示：
其中标有*的碳原子为手性碳原子，R1为烷基、芳香基或取代苯基，R2为烷基、芳香基或取代苯基，R3为烷基、芳香杂环或取代苯基。
所述的取代苯基为苯环的取代基为卤素、甲基、甲氧基、三氟甲基或硝基。
所述卤原子为氟、氯或溴。
所述的手性化合物吡唑并[3,4-b]吡啶酮衍生物的制备方法，包括以下步骤：
(1)取代α-溴代肉桂醛与手性卡宾催化剂反应，得到α，β-不饱和酰基唑中间体Ⅰ；
(2)由5-氨基吡唑与中间体Ⅰ发生反应，得到中间体II，中间体II发生aza-Claisen重排得到中间体III；
(3)中间体III发生异构化得到中间体IV，最后环化脱去卡宾得到产物；
反应通式及过程如下：
将本发明的具体制备内容如下：
(1)催化合成的手性化合物吡唑并[3,4-b]吡啶酮衍生物
(2)对合成的进行衍生化研究
所述的衍生物在防治农业病虫害方面的用途。
所述农业病虫害为植物真菌性或细菌性病。
所述农业病虫害为植物疫霉菌和植物炭疽病。
所述农业病虫害为小麦赤霉病菌、马铃薯晚疫病菌、蓝莓根腐病菌、辣椒枯萎病菌、油菜菌核病菌、油菜炭疽病菌、葡萄座腔菌、水稻纹枯病菌、水稻白叶枯病菌、烟草青枯病菌、柑桔溃疡病菌、猕猴桃溃疡病菌、黄瓜白叶枯病菌、魔芋白叶枯病菌、葡萄溃疡病菌、辣椒疫霉病菌和辣椒炭疽病菌。
本发明的有益效果：以常见的α-溴代肉桂醛和修饰的5-氨基吡唑为原料，通过氮杂环卡宾(NHC)催化合成了一系列具有高立体选择性的手性吡唑并[3,4-b]吡啶酮化合物，然后利用合成的产物进行了一系列的衍生化。发现其有很好的普适性和良好的转化性。利用有机小分子催化合成这一类吡唑骨架是一种全新的、高效的手性吡唑类化合物的合成方法，在新农药创制及绿色手性农药创制方面具有潜在的应用前景，对于新结构在农药上的开发，提供了一种全新的解决方案和合成策略。
具体制备实施方式
以下介绍本发明的实施例，介绍28个制备实施例及2个衍生化研究。
总实施例
(1)制备吡唑并[3,4-b]吡啶酮衍生物的合成路线：
制备实施方法和条件如下：
分别称取0.24mmol取代α-溴代肉桂醛1、0.20mmol取代5-氨基吡唑2、0.001mmol的氮杂环卡宾催化剂，加入配有磁力搅拌子的10mL Schlenk反应管中，0.24mmol碳酸铯(Cs2CO3)和3.0mL溶剂乙酸乙酯。盖上瓶盖，置于25℃油浴中充分搅拌反应12h。TLC监测反应完毕后，旋干，少量二氯甲烷充分溶解后湿法上样，通过柱层析分离，洗脱剂极性石油醚:乙酸乙酯＝5:1得到目标化合物，称量后计算相应的产率，化合物通过熔点仪，旋光仪，核磁共振仪NMR，高分辨质谱仪HRMS和高效液相色谱仪HPLC予以表征。
(2)对合成的手性吡唑并[3,4-b]吡啶酮进行衍生化研究：
得到目标化合物，称量后计算相应的产率，化合物通过熔点仪，旋光仪，核磁共振仪NMR，高分辨质谱仪HRMS和高效液相色谱仪HPLC予以表征。
由化合物3a转化为化合物5和的制备方法
在一个配有磁力搅拌子的10.0mL干净瓶子中加入38.0mg四氢锂铝于3.0mL的四氢呋喃中，再加入60.7mg 3a 90℃回流。TLC监测反应完毕后，加水淬灭四氢锂铝，乙酸乙酯萃取三次，干燥，旋干，通过柱层析分离，洗脱剂极性石油醚:乙酸乙酯＝10:1得到目标化合物5，77％的收率。
由化合物3a转化为化合物6的制备方法
在一个配有磁力搅拌子的10mL干净瓶子中加入60.7mg 3a于DMF中，再加入60％96.0mg氢化钠和68.4mg溴化苄。反应2小时，TLC监测反应完毕后，加水淬灭氢化钠和洗掉DMF，乙酸乙酯萃取三次，干燥，旋干，过通过柱层析分离，洗脱剂极性石油醚:乙酸乙酯＝10:1得到目标化合物6，74％的收率。
对合成的化合物实验表征如下：
(R)-3-甲基-二苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
1H),3.05(dd,J＝16.0,7.2Hz,1H),2.85(dd,J＝16.0,6.4Hz,1H),1.95(s,3H).
13C NMR(101MHz,Chloroform-d)δ169.9,146.9,142.3,137.4,137.4,130.0,128.9,127.8,127.3,127.2,123.0,102.8,40.6,35.5,12.5.
HRMS(ESI,m/z):Mass calcd.for C19H18N3O+[M+H]+,304.1444；found:304.1442.
UPLC analysis:99:1 er(Daicel Chiralcel IC-U column,80:20 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝2.9min,Rt(major)＝3.3min.
(R)-(4-溴苯基)-3-甲基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
取代基R1为对溴代苯基,R2为甲基，R3为苯基制备实施方法
1H NMR(400MHz,Chloroform-d)δ8.46(s,1H),7.45–7.43(m,6H),7.36–7.30(m,1H),7.09–7.05(m,2H),4.16(t,J＝6.8Hz,1H),3.00(dd,J＝16.2,7.2Hz,1H),2.74(dd,J＝16.2,6.2Hz,1H),1.94(s,3H).
13C NMR(101MHz,Chloroform-d)δ169.8,146.7,141.4,137.6,137.4,132.1,129.8,128.9,127.8,123.0,121.1,102.2,40.5,34.9,12.5.
HRMS(ESI,m/z):Mass calcd.for C19H17BrN3O+[M+Na]+,382.0549；found:382.0545.
UPLC analysis:96:4 er(Daicel Chiralcel IC-U column,90:10 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝6.5min,Rt(major)＝6.9min.
(R)-(4-氯苯基)-3-甲基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
取代基R1为对氯代苯基,R2为甲基，R3为苯基制备实施方法
6.4Hz,1H),1.94(s,3H).
13C NMR(101MHz,Chloroform-d)δ169.9,146.7,140.9,137.6,137.4,133.0,129.8,129.1,128.6,127.8,123.1,102.3,40.5,34.8,12.5.
HRMS(ESI,m/z):Mass calcd.for C19H17ClN3O+[M+H]+,338.1055；found:338.1049.
UPLC analysis:98:2 er(Daicel Chiralcel IC-U column,80:20 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝2.7min,Rt(major)＝2.9min.
(R)-(4-硝基苯基)-3-甲基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
7.34(m，1H)，3.16-3.08(m，1H)，2.92-2.74(m，1H)，1.97(s，3H).
13C NMR(101MHz,Chloroform-d)δ168.8,149.8,147.3,146.6,137.6,137.2,123.0,128.1,128.1,124.4,123.0,101.2,40.1,35.3,12.5.
HRMS(ESI,m/z):Mass calcd.for C16H17N4O3 +[M+H]+,349.1295；found:349.1290.
UPLC analysis:98:2 er(Daicel Chiralcel ID column,80:20 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝6.9min,Rt(major)＝8.4min,
(R)-(4-三氟甲基苯基)-3-甲基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
1H NMR(400MHz,Chloroform-d)δ8.36(s,1H),7.59(d,J＝8.4Hz,2H),7.47–7.46(m,4H),7.37–7.32(m,3H),4.28(t,J＝8.0Hz,1H),3.19–3.00(m,1H),2.83–2.76(m,1H),1.96(s,3H).
13C NMR(101MHz,Chloroform-d)δ169.4,146.7,146.4,137.6,137.3,129.85,129.30(q,J＝23.23Hz),127.90,127.56,126.0(q,J＝4.0Hz),124.6(q,J＝272.7Hz),123.0,101.81,40.29,35.25,12.49.
19F NMR(377MHz,Chloroform-d)δ-62.47.
HRMS(ESI,m/z):Mass calcd.for C20H17F3N3O+[M+H]+,372.1318；found:372.1309.
UPLC analysis:99:1 er(Daicel Chiralcel IC-U column,90:10 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝3.8min,Rt(major)＝4.9min.
(R)-(4-甲基苯基)-3-甲基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
(t,J＝6.8Hz,1H),3.00(dd,J＝16.2,7.4Hz,1H),2.80(dd,J＝16.2,6.4Hz,1H),2.33(s,3H),1.95(s,3H)
13C NMR(101MHz,Chloroform-d)δ169.9,146.9,139.2,137.4,137.3,136.9,129.9,129.6,127.8,127.0,122.9,103.0,40.7,35.1,21.1,12.5.
HRMS(ESI,m/z):Mass calcd.for C20H20N3O+[M+H]+,318.1600；found:318.1599.
UPLC analysis:98:2 er(Daicel Chiralcel IC-U column,80:20 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝2.9min,Rt(major)＝3.5min.
(R)-(4-甲氧基苯基)-3-甲基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
(m,2H),4.16(t,J＝6.8Hz,1H),3.79(s,3H),2.99(dd,J＝16.2,7.2Hz,1H),2.79(dd,J＝16.2,6.6Hz,1H),1.95(s,3H).
13C NMR(101MHz,Chloroform-d)δ170.2,158.7,146.9,137.5,137.4,134.3,129.8,128.2,127.7,123.0,114.3,103.1,55.30,40.85,34.66,12.51
HRMS(ESI,m/z):Mass calcd.for C20H20N3O2 +[M+H]+,334.1550；found:334.1546.
UPLC analysis:>99:1 er(Daicel Chiralcel IC-U column,90:10 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝8.7min,Rt(major)＝9.1min.
(R)-4-((4-甲基胺)苯基)-3-甲基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
(d,J＝8.8Hz,2H),4.13(t,J＝6.8Hz,1H),3.04–2.97(m,1H),2.93(s,6H),2.82(dd,J＝16.2,6.8Hz,1H),1.97(s,3H).
13C NMR(101MHz,Chloroform-d)δ170.3,149.8,147.0,137.5,137.2,129.9,129.8,127.8,127.7,122.9,112.9,103.6,40.9,40.7,34.5,12.6.
HRMS(ESI,m/z):Mass calcd.for C21H23N4O+[M+H]+,347.1866；found:347.1863.
UPLC analysis:99:1 er(Daicel Chiralcel IC-U column,90:10 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝17.7min,Rt(major)＝14.4min.
(R)-4-(3-溴苯基)-3-甲基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
7.4Hz,1H),2.79(dd,J＝16.4,6.2Hz,1H),1.98(s,3H).
13C NMR(101MHz,Chloroform-d)δ169.42,146.76,144.68,137.57,137.32,130.60,130.50,130.27,129.88,127.90,125.84,123.04,101.89,40.44,35.12,12.53.
HRMS(ESI,m/z):Mass calcd.for C19H17ClN3O+[M+H]+,382.0549；found:382.0547.
UPLC analysis:97:3 er(Daicel Chiralcel IA-U column,95:5 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝11.3min,Rt(major)＝12.9min.
(R)-4-(3-氯苯基)-3-甲基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
13C NMR(101MHz,Chloroform-d)δ169.6,146.7,144.5,137.7,137.4,134.8,130.3,129.8,127.8,127.5,127.4,125.4,123.1,101.9,40.4,35.1,12.5.
HRMS(ESI,m/z):Mass calcd.for C19H17ClN3O+[M+H]+,338.1055；found:338.152.
UPLC analysis:99:1 er(Daicel Chiralcel IC-U column,90:10 hexanes/i-PrOH,0.8mL/min,λ＝254nm),Rt(minor)＝4.9min,Rt(major)＝5.4min.
(R)-4-(3-氟苯基)-3-甲基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
取代基R1为间氟代苯基,R2为甲基，R3为苯基制备实施方法和条件同实施例I；白色固体,62％产率,40mg,熔点80-82℃.
130.6,130.5,129.8,127.9,123.1,122.8(d,J＝2.9Hz),114.3(d,J＝12.3Hz),114.1(d,J＝13.0Hz),102.1,40.41,35.14,12.43.
19F NMR(377MHz,Chloroform-d)δ-112.19.
HRMS(ESI,m/z):Mass calcd.for C19H17FN3O+[M+H]+,322.1350；found:322.1347.
UPLC analysis:99:1 er(Daicel Chiralcel IC-U column,90:10 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝4.9min,Rt(major)＝5.4min.
(S)-4-(2-溴苯基)-3-甲基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
取代基R1为邻溴代苯基,R2为甲基，R3为苯基制备实施方法和条件同实施例I；白色固体,89％产率,68.1mg,熔点90-92℃.
138.1,137.4,133.4,129.9,128.9,128.6,128.1,127.9,123.8,123.0,101.7,38.9,34.3,12.4.
HRMS(ESI,m/z):Mass calcd.for C19H16BrN3ONa+[M+Na]+,404.0549；found:404.0360.
UPLC analysis:97:3 er(Daicel Chiralcel IC-U column,92:8 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝4.5min,Rt(major)＝6.8min.
(S)-4-(2-氯苯基)-3-甲基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
(m,1H),4.64(dd,J＝7.8,5.2Hz,1H),2.97(dd,J＝16.4,8.0Hz,1H),2.71(dd,J＝16.4,5.2Hz,1H),1.87(s,3H).
13C NMR(101MHz,Chloroform-d)δ169.9,146.8,139.2,138.3,137.4,133.3,130.1,129.8,128.6,128.5,127.8,127.4,123.1,101.5,38.7,31.6,12.3.
HRMS(ESI,m/z):Mass calcd.for C19H17ClN3O+[M+H]+,338.1055；found:338.1050.
UPLC analysis:97:3 er(Daicel Chiralcel IC-U column,95:5 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝6.8min,Rt(major)＝10.9min.
(S)-4-(2-氟苯基)-3-甲基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
(m,3H),4.53(dd,J＝8.0,4.8Hz,1H),3.05(dd,J＝16.4,7.6,1H),2.82(dd,J＝16.4,4.4,1H),1.99(s,3H).
13C NMR(101MHz,Chloroform-d)δ168.5,159.1(d,J＝246.4Hz),145.3,136.3(d,J＝53.7Hz),128.4,127.6,127.5,127.14(d,J＝4.1Hz),126.3,123.1(d,J＝3.5Hz),121.6,114.4(d,J＝22.3Hz),99.7,37.4,27.1,10.8.
19F NMR(377MHz,Chloroform-d)δ-118.19.
HRMS(ESI,m/z):Mass calcd.for C19H17FN3O+[M+H]+,322.1350；found:322.1348.
UPLC analysis:97:3 er(Daicel Chiralcel IC-U column,92:8 hexanes/i-PrOH,0.8mL/min,λ＝254nm),Rt(minor)＝4.1min,Rt(major)＝5.5min.
(S)-4-(2-硝基苯基)-3-甲基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
2.83(dd,J＝16.8,5.2Hz,1H),1.90(s,3H).
13C NMR(101MHz,Chloroform-d)δ169.2,145.0,146.7,138.4,137.2,137.0,133.6,129.9,129.5,128.3,128.0,125.0,123.1,101.1,39.7,30.3,12.3.
HRMS(ESI,m/z):Mass calcd.for C19H17N4O3 +[M+H]+,349.1295；found:349.1294.
UPLC analysis:97:3 er(Daicel Chiralcel IC-U column,80:20 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝4.9min,Rt(major)＝5.5min.
[3,4-b]吡啶-6-酮
取代基R1为邻甲氧基代苯基,R2为甲基，R3为苯基制备实施方法和条件同实施例I；白色固体,91％产率,61mg,熔点90-92℃.
[α]26D＝74.2(c 1.0 CHCl3).
1H NMR(400MHz,Chloroform-d)δ7.81(s,1H),7.64–7.13(m,6H),7.10–6.64(m,3H),4.65–4.37(m,1H),3.83(s,3H),3.26–2.69(m,2H),2.02(s,3H).
13C NMR(101MHz,Chloroform-d)δ170.4,156.9,147.1,137.9,137.6,130.1,129.9,128.4,123.0,127.7,122.9,120.6,110.7,101.9,55.1,38.4,29.7,12.3.
HRMS(ESI,m/z):Mass calcd.for C20H20N3O2 +[M+H]+,334.1550；found:334.1549.
UPLC analysis:97:3 er(Daicel Chiralcel IC-U column,92:8 hexanes/i-PrOH,0.8mL/min,λ＝254nm),Rt(minor)＝5.9min,Rt(major)＝8.9min.
(S)-4-(2-呋喃)-3-甲基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
＝5.8Hz,2H),2.09(s,3H).
13C NMR(101MHz,Chloroform-d)δ169.6,154.6,146.8,142.2,137.4,137.3,129.8,127.8,123.0,110.3,105.7,100.8,36.9,28.9,11.9.
HRMS(ESI,m/z):Mass calcd.for C17H16 N3O2 +[M+H]+,294.1237；found:294.1236.
UPLC analysis:99:1 er(Daicel Chiralcel IC-U column,95:5 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝11.6min,Rt(major)＝12.5min,
(R)-(4-萘基)-3-甲基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
取代基R1为萘基,R2为甲基，R3为苯基制备实施方法和条件同实施例I；白色固体,
13C NMR(101MHz,Chloroform-d)δ169.7,147.1,138.2,137.5,137.2,134.4,130.8,129.9,129.4,128.1,127.8,126.5,125.8,125.6,124.6,123.0,122.7,102.1,39.8,30.9,12.4.
HRMS(ESI,m/z):Mass calcd.for C23H20N3O+[M+H]+,354.1601；found:354.1592.
UPLC analysis:97:3 er(Daicel Chiralcel ID column,90:10 hexanes/i-PrOH,0.8mL/min,λ＝254nm),Rt(minor)＝7.0min,Rt(major)＝12.9min.
(R)-3-(叔丁基)-1,4-二苯基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
7.6Hz,1H),2.74(dd,J＝15.8,1.6Hz,1H),1.21(s,9H).
13C NMR(101MHz,Chloroform-d)δ169.2,157.8,142.8,138.2,137.7,129.9,128.9,127.7,127.1,126.9,123.2,100.8,41.4,36.2,33.4,29.8.
HRMS(ESI,m/z):Mass calcd.for C22H24N3O+[M+H]+,346.1914；found:346.1910.
UPLC analysis:>99:1 er(Daicel Chiralcel IC-U column,95:5 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝4.4min,Rt(major)＝5.4min.
(R)-3-丁基-1,4-二苯基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
取代基R1为对苯基,R2为丁基，R3为苯氢制备实施方法和条件同实施例I；白色固体,71％产率,48.8mg,熔点130-132℃.
/>
13C NMR(101MHz,Chloroform-d)δ170.0,151.2,142.5,137.5,137.5,129.8,128.9,127.7,127.3,127.2,123.1,102.3,40.8,35.5,30.9,27.0,22.5,13.7.
HRMS(ESI,m/z):Mass calcd.for C22H24N3O+[M+H]+,346.1914；found:346.1907.
HPLC analysis:>99:1 er(Daicel Chiralcel IC-U column,90:10 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝4.1min,Rt(major)＝4.6min.
(R)-3-乙基-1,4-二苯基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
取代基R1为对苯基,R2为乙基，R3为苯氢制备实施方法和条件同实施例I；白色固
13C NMR(101MHz,Chloroform-d)δ169.8,152.2,142.6,137.5,137.5,129.9,128.9,127.8,127.3,127.1,123.1,102.0,40.8,35.4,20.6,13.0.
HRMS(ESI,m/z):Mass calcd.for C20H20N3O+[M+H]+,318.1601；found:318.1597.
UPLC analysis:99:1 er(Daicel Chiralcel IC-U column,90:10 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝4.2min,Rt(major)＝4.8min.
(R)-1,3,4-三苯基-一苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
实施例I；白色固体,99％产率,72.7mg,熔点99-101℃.
[α]26D＝30.1(c 1.0 CHCl3)
1H NMR(400MHz,Chloroform-d)δ8.75–8.50(m,1H),7.58–7.54(m,4H),7.48–7.44(m,2H),7.40–7.34(m,1H),7.32–7.14(m,8H),4.46(dd,J＝7.6,2.4Hz,1H),3.12(dd,J＝16.0,7.6Hz,1H),2.80(dd,J＝16.0,2.4Hz,1H).
13C NMR(101MHz,Chloroform-d)δ170.1,148.8,142.2,138.9,138.8,137.5,132.7,129.8,129.1,128.6,128.2,127.3,127.1,127.0,123.5,101.9,41.0,35.38.
HRMS(ESI,m/z):Mass calcd.for C24H20N3O+[M+H]+,366.1601；found:366.1593.
UPLC analysis:>99:1 er(Daicel Chiralcel IB-U column,80:20 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝4.6min,Rt(major)＝2.9min.
(R)-1-(4-溴苯基)-3-甲基-4-苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
12.5.
HRMS(ESI,m/z):Mass calcd.for C19H17BrN3O+[M+H]+,382.0549；found:382.0541.
UPLC analysis:99:1 er(Daicel Chiralcel IC-U column,95:5 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝12.7min,Rt(major)＝10.8min.
(R)-1-(4-氯苯基)-3-甲基-4-苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
取代基R1为对苯基,R2为甲基，R3为对氯代苯基制备实施方法和条件同实施例I；
白色固体,91％产率,61.5mg,熔点110-112℃.
UPLC analysis:99:1 er(Daicel Chiralcel OD-3 column,90:10 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝11.2min,Rt(major)＝9.9min.
法和条件同实施例I；白色固体,98％产率,62.4mg,熔点72-74℃.
[α]26D＝50.0(c 1.0 CHCl3)
1H NMR(400MHz,Chloroform-d)δ8.01(s,1H),7.41–7.18(m,9H),4.21(t,J＝6.8Hz,1H),3.03(dd,J＝16.2,7.2Hz,1H),2.83(dd,J＝16.2,6.4Hz,1H),2.39(s,3H),1.94(s,3H).
13C NMR(101MHz,Chloroform-d)δ169.9,146.6,142.4,137.9,137.4,134.9,130.4,129.0,127.3,127.2,123.0,102.5,40.7,35.5,21.1,12.5.
HRMS(ESI,m/z):Mass calcd.for C20H20N3O+[M+H]+,318.1601；found:318.1599.
UPLC analysis:>99:1 er(Daicel Chiralcel IC-U column,80:20 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝3.7min,Rt(major)＝4.6min.
(R)-1-(2-甲基苯基)-3-甲基-4-苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
取代基R1为对苯基,R2为甲基，R3为邻甲基代苯基制备实施方法和条件同实施例I；白色固体,98％产率,62.7mg,熔点92-94℃.
318.1601；found:318.1596.
UPLC analysis:>99:1 er(Daicel Chiralcel IA-U column,96:4 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝7.3min,Rt(major)＝8.9min.
(R)-1,3-甲基-4-苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
13C NMR(101MHz,Chloroform-d)δ172.4,144.7,142.6,138.5,128.9,127.2,101.0,40.7,35.3,34.6,12.3.
HRMS(ESI,m/z):Mass calcd.for C14H16N3O+[M+H]+,242.1288；found:242.1286.
UPLC analysis:95:5 er(Daicel Chiralcel OD-3 column,80:20 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝5.5min,Rt(major)＝4.4min.
(R)-3-甲基-4-苯基-4,7-二氢异恶唑并[5,4-b]吡啶-6(5H)-酮
7.14(m,2H),4.11(t,J＝7.2Hz,1H),3.08(dd,J＝16.8,8.0Hz,1H),2.84(dd,J＝16.8,6.8Hz,1H),1.89(s,3H)./>
13C NMR(101MHz,Chloroform-d)δ169.5,160.9,159.0,141.1,129.2,127.7,127.0,94.7,40.4,34.1,10.5.
HRMS(ESI,m/z):Mass calcd.for C13H13N2O2 +[M+H]+,229.0972；found:229.0966.
UPLC analysis:98:2 er(Daicel Chiralcel ID-3 column,90:10 hexanes/i-PrOH,0.8mL/min,λ＝254nm),Rt(minor)＝16.4min,Rt(major)＝17.7min.
(R)-1,4-二苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
取代基R1为对苯基,R2为氢，R3苯基制备实施方法和条件同实施例I；白色固体,36％产率,21mg,熔点161-163℃.
HRMS(ESI,m/z):Mass calcd.for C18H16N3O+[M+H]+,290.1288；found:290.1285.
UPLC analysis:99:1 er(Daicel Chiralcel IC-U column,90:10 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝13.6min,Rt(major)＝14.6min.
(R)-3-甲基-1,4-二苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
J＝16.0,4.8Hz,1H),2.98(dd,J＝16.0,6.0Hz,1H),2.34(s,3H),2.18(s,3H).
13C NMR(101MHz,Chloroform-d)δ170.1,144.6,143.9,139.5,138.4,134.3,133.3,128.1,128.1,127.8,127.7,126.4,126.0,125.9,122.4,110.8,41.4,32.6,20.5,11.2.
HRMS(ESI,m/z):Mass calcd.for C26H24N3O3S+[M+H]+,458.1533；found:1520.
HPLC analysis:85:15 er(Daicel Chiralcel AD-H column,80:20 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝30.5min,Rt(major)＝33.7min.
(R)-3-甲基-1,4-二苯基-1,4,5,7-四氢-6H-吡唑并[3,4-b]吡啶-6-酮
取代基R1为对苯基,R2为氢，R3苯基制备实施方法和条件同实施例I；白色固体,36％产率,21mg,熔点121-123℃；
3.04(m,2H),2.25–2.17(m,1H),1.97–1.90(m,1H),1.86(s,3H).
13C NMR(101MHz,Chloroform-d)δ148.1,145.5,144.8,139.2,129.4,128.4,128.0,126.3,126.0,121.9,101.0,40.3,36.6,33.0,12.6.
HRMS(ESI,m/z):Mass calcd.for C19H20N3 +[M+H]+,290.1652；found:290.1657.
UPLC analysis:99:1 er(Daicel Chiralcel IA-U column,95:5 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝5.4min,Rt(major)＝4.7min.
(R)-3-甲基-1,4-二苯基-1,4,5,7-四氢-1H-吡唑并[3,4-b]吡啶-6-酮
取代基R1为对苯基,R2为甲基，R3苯基制备实施方法和条件同实施例I；白色固体,
3H).
13C NMR(101MHz,Chloroform-d)δ170.5,146.5,140.9,140.4,139.5,135.7,131.4,130.2,129.3,128.7,128.5,128.3,127.9,127.5,127.4,127.0,125.5,107.3,45.50,41.64,34.13,12.26.
HRMS(ESI,m/z):Mass calcd.for C26H24N3O+[M+H]+,394.1914；found:394.1905.
UPLC analysis:99:1 er(Daicel Chiralcel IC-U column,90:10 hexanes/i-PrOH,0.5mL/min,λ＝254nm),Rt(minor)＝10.7min,Rt(major)＝8.7min.
药理实施例1:吡唑并[3,4-b]吡啶酮类化合物的抗致病病原真菌应用，用于辣椒疫霉病菌(P.capsica)、辣椒炭疽病菌(C.capsicum)试验方法。
从表中可以看出，以甲霜灵(Metalaxyl)、多菌灵(Carbendazim)为对照药剂，选用了辣椒疫霉菌和辣椒炭疽病菌致病病原真菌为供试对象，采用生长速率法对部分化合物进行了生物活性测试，测试结果表明，该系列化合物极好的抗真菌活性，化合物3i-rac和3j-rac对辣椒疫霉菌具有良好的抑制活性，抑制率分别达到65.39％，65.32％；化合物3i-rac，3j-rac和3p-rac对辣椒炭疽病菌相比于其他化合物具有较好抑制活性，抑制率达到51.25％，52.36和55.15％。
表一：目标化合物的消旋样对辣椒疫霉菌和辣椒炭疽菌的抑制率
表二：3i,3j,3p不同构型对辣椒疫霉菌和辣椒炭疽菌的抑制率
基于化合物3i-rac，3j-rac和3p-rac对辣椒疫霉病菌和辣椒炭疽病菌具有较好的抑制率，所以还研究了这三个化合物的R,S,rac构型产物对辣椒疫霉病菌和辣椒炭疽病菌活性差异，测试结果发现这三个化合物的R构型的活性明显高于S构型的产物，rac构型的活性在两者之间。
表三：3i,3j,3p的R构型对辣椒疫霉菌和辣椒炭疽菌的EC50
其中3i，3j和3pR构型的对辣椒病菌的活性80优于S构型的，所以继续测试了相应化合物的EC50，对应的EC50值分别为3.54±0.21、5.53±0.75、5.23±0.46μg/mL。

Claims (3)

1.一类手性化合物吡唑并[3,4-b]吡啶酮衍生物的制备方法，其特征在于：所述的衍生物如下述通式(1)表示：
其中标有*的碳原子为手性碳原子，R1为取代苯基，R2为烷基，R3为烷基、芳香杂环或取代苯基；其制备方法如下：包括以下步骤：
(1)取代α-溴代肉桂醛与手性卡宾催化剂反应，得到α,β-不饱和酰基唑中间体Ⅰ；
(2)由5-氨基吡唑化合物2与中间体Ⅰ发生反应，得到中间体II，中间体II发生aza-Claisen重排得到中间体III；
(3)中间体III发生异构化得到中间体IV，最后环化脱去卡宾得到产物；
反应过程如下：
2.根据权利要求1所述的一类手性化合物吡唑并[3,4-b]吡啶酮衍生物的制备方法，其特征在于：所述的取代苯基为苯环的取代基为卤素、甲基、甲氧基、三氟甲基或硝基。
3.根据权利要求2所述的一类手性化合物吡唑并[3,4-b]吡啶酮衍生物的制备方法，其特征在于：所述卤素为氟、氯或溴。
CN202210520694.6A 2022-05-12 2022-05-12 一种有机催化合成手性吡唑并[3,4-b]吡啶酮类化合物及应用 Active CN114805347B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210520694.6A CN114805347B (zh) 2022-05-12 2022-05-12 一种有机催化合成手性吡唑并[3,4-b]吡啶酮类化合物及应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210520694.6A CN114805347B (zh) 2022-05-12 2022-05-12 一种有机催化合成手性吡唑并[3,4-b]吡啶酮类化合物及应用

Publications (2)

Publication Number Publication Date
CN114805347A CN114805347A (zh) 2022-07-29
CN114805347B true CN114805347B (zh) 2023-10-20

Family

ID=82515517

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210520694.6A Active CN114805347B (zh) 2022-05-12 2022-05-12 一种有机催化合成手性吡唑并[3,4-b]吡啶酮类化合物及应用

Country Status (1)

Country Link
CN (1) CN114805347B (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115594691B (zh) * 2022-10-14 2024-03-26 五邑大学 一种异噁唑并[4,5-b]吡啶-6-酮类化合物的合成方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003048160A1 (en) * 2001-12-04 2003-06-12 F. Hoffmann-La Roche Ag Ring fused pyrazole derivatives
CN104513239A (zh) * 2014-12-10 2015-04-15 沈阳药科大学 吡唑并[3,4-c]吡啶-7-酮类化合物及其应用
CN110551136A (zh) * 2019-09-16 2019-12-10 贵州大学 一种氮杂环卡宾催化的含吲哚骨架手性螺环化合物的制备方法及用途
CN111072561A (zh) * 2019-11-28 2020-04-28 贵州大学 一种有机催化合成手性喹啉类化合物及其衍生化的方法
WO2020257790A1 (en) * 2019-06-20 2020-12-24 University Of Kentucky Research Foundation Pharmaceutically active pyrazolo-pyridone modulators of dcn1/2-mediated cullin neddylation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003048160A1 (en) * 2001-12-04 2003-06-12 F. Hoffmann-La Roche Ag Ring fused pyrazole derivatives
CN104513239A (zh) * 2014-12-10 2015-04-15 沈阳药科大学 吡唑并[3,4-c]吡啶-7-酮类化合物及其应用
WO2020257790A1 (en) * 2019-06-20 2020-12-24 University Of Kentucky Research Foundation Pharmaceutically active pyrazolo-pyridone modulators of dcn1/2-mediated cullin neddylation
CN110551136A (zh) * 2019-09-16 2019-12-10 贵州大学 一种氮杂环卡宾催化的含吲哚骨架手性螺环化合物的制备方法及用途
CN111072561A (zh) * 2019-11-28 2020-04-28 贵州大学 一种有机催化合成手性喹啉类化合物及其衍生化的方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Synthesis and biological evaluation of some functionalized 1H-1,2,3-triazole tethered pyrazolo[3,4-b]pyridin-6(7H)-ones as antimicrobial and apoptosis inducing agents";Jayant Sindhu et al.;《Med Chem Res》;第25卷;第1813-1830页 *
"Synthesis and fungicidal activities of some 4-aryl-1-aroyl-5-cyano-3-methylpyrazolo[4,5-b]-4,5,7-trihydropyridin-6-ones derivatives";Praveen Tripathi et al.;《Asian Journal of Chemistry》;第18卷(第4期);第3120-3122页 *
Manouchehr Mamaghani et al.."A green, efficient and recyclable Fe+3@K10 catalyst for the synthesis of bioactive pyrazolo[3,4-b]pyridin-6(7H)-ones under "on water" conditions".《Journal of Molecular Structure》.2013,第1051卷第169-176页. *

Also Published As

Publication number Publication date
CN114805347A (zh) 2022-07-29

Similar Documents

Publication Publication Date Title
Togni Asymmetric hetero Diels-Alder reactions catalyzed by novel chiral vanadium (IV) bis (1, 3-diketonato) complexes
SU1255048A3 (ru) Способ получени циклопропанкарбоксилатов
Pedras et al. Unprecedented chemical structure and biomimetic synthesis of erucalexin, a phytoalexin from the wild crucifer Erucastrum gallicum
CN114805347B (zh) 一种有机催化合成手性吡唑并[3,4-b]吡啶酮类化合物及应用
Lu et al. Total Synthesis of (−)-Chanoclavine I and an Oxygen-Substituted Ergoline Derivative
CN114591344A (zh) 一种手性螺环四氢呋喃-吡唑啉酮化合物的合成方法
CN114516881B (zh) 一种氮杂环卡宾催化的含吡唑并吡喃骨架手性化合物及制备方法
Norinder et al. Dynamic Processes in the Copper‐Catalyzed Substitution of Chiral Allylic Acetates Leading to Loss of Chiral Information
CN108383771A (zh) 手性3,3-二取代异吲哚啉-1-酮衍生物及其合成方法和应用
DE3935910A1 (de) Verfahren zur herstellung von optisch reinen 1,2,3,4-tetrahydro-3-carboxyisochinolinen
CN106518817A (zh) 对孟‑3‑烯‑1‑胺席夫碱衍生物及其制备方法与除草活性应用
Jachak et al. Stereocontrolled synthesis of pseurotin A2
Mohapatra et al. A Unified Synthetic Strategy for Dendrodolides E, F, G, I, J, and L
US4343935A (en) Chiral compounds
CN117865871A (zh) 一种光与有机共催化合成α-(2或3-吲哚)酮衍生物及应用
Zanatta et al. Highly Chemoselective Synthesis of 6‐Alkoxy‐1‐alkyl (aryl)‐3‐trifluoroacetyl‐1, 4, 5, 6‐tetrahydropyridines and 1‐Alkyl (aryl)‐6‐amino‐3‐trifluoroacetyl‐1, 4, 5, 6‐tetrahydropyridines
CN112824411B (zh) 一类桥环异吲哚啉酮衍生物及其制备方法和用途
CN112939939B (zh) 2-(4-氯苯基)吡啶类化合物及其在农药中的应用
CN113004263B (zh) 4-噻吩环取代的吡啶衍生物及其在农药中的用途
CN114716451B (zh) 一种Frutinone类化合物及其制备方法和应用
CN112979620B (zh) 6-甲氧基吡啶衍生物及其在农药中的应用
CN112939938B (zh) 2,4,6-三取代吡啶类化合物及其在农药中的用途
CN112745275B (zh) 1,3,4-恶二唑杂环化合物的合成方法
CN110256349B (zh) 多取代吡唑及其制备方法
CN111777582B (zh) 一种2-氟烷基-3-炔基取代萘并呋喃化合物及其制备方法

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant