CN110963981B - 一类苯并噻唑芳基化合物衍生物及其制备方法 - Google Patents
一类苯并噻唑芳基化合物衍生物及其制备方法 Download PDFInfo
- Publication number
- CN110963981B CN110963981B CN201911194368.5A CN201911194368A CN110963981B CN 110963981 B CN110963981 B CN 110963981B CN 201911194368 A CN201911194368 A CN 201911194368A CN 110963981 B CN110963981 B CN 110963981B
- Authority
- CN
- China
- Prior art keywords
- reaction
- drying
- preparation
- benzothiazole
- finished
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
Description
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苯并噻唑芳基化合物的制备方法及生物活性。
背景技术
有机杂环分子广泛存在于医药,农药,配体,天然产物和其他功能分子中。 2-芳基苯并噻唑化合物,早在2006年左右就被报道了Phortress是治疗乳腺癌的重要的前药和结构5F-203是临床试验治疗老年痴呆的重要药物(J.Med.Chem., 2006,49,179-185),还有很多文献也报道了2-芳基苯并噻唑化合物的在生物活性方面的多种用途,当然在化学合成领域也有很多化学家对它的合成比较感兴趣,如2010、2011年报道了通过碳-碳键的构建合成2-芳基苯并噻唑化合物,其发表在国际顶级期刊(J.Am.Chem.Soc.,2010,132,3674-3675;J.Am.Chem.Soc., 2011,133,4243-4245),根据目前的报道,合成2-芳基苯并噻唑化合物都是通过过渡金属络合剂(如钯、酮等)催化合成,然而非金属催化合成的还未报道,存在挑战,在氮杂环卡宾催化领还未报道2芳基苯并噻唑化合物的合成。
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2-芳基苯并噻唑类化合物,并进一步发掘其在有机合成中选择性活化方面的用途。
本发明的技术方案:一类苯并噻唑芳基化合物衍生物,如下述通式(1)表示:
其中R1为卤素原子、甲基或甲氧基,R2为卤素原子、甲基、甲氧基、硝基、氰基、2-溴-5甲基、3-氯-4-溴基或3-氯-4-氟基,R3为卤素原子、甲基或甲氧基。
所述卤素原子为氟、氯或溴。
所述的一类苯并噻唑芳基化合物衍生物的制备方法,包括以下步骤:
(1)取代芳基γ醛与手性卡宾催化剂反应,得到Breslow中间体Ⅰ,其中间体在氧化剂的存在下被氧化为α,β-不饱和酰基唑鎓中间体Ⅱ;
(2)由步骤(1)此时所得的中间体分子α,β-不饱和酰基唑鎓中间体中γ位上的甲基氢酸性增强在磷酸钾K3PO4的条件下,发生去质子化,失去一个质子H 生成形成Dienolate中间体Ⅲ;
(3)步骤(2)亲核性Dienolate中间体Ⅲ与亲电体取代(Z)-2-(苯并[d]噻唑 -2-基)-1,3-二苯基-2-烯-1-酮发生Michael加成形成中间体Ⅳ,然后,γ位氢原子再一次去质子化形式中间体Ⅴ,发生分子内Aldol反应,卡宾离去,形成一个环己烯并四元环内脂的中间体Ⅶ,脱去一分子CO2,在氧化剂存在的条件下进一步氧化后得到目标产物。
反应通式及过程如下:
所述的反应温度为40℃,反应溶剂为甲基叔丁基醚MTBE。
所述的(Z)-2-(苯并[d]噻唑-2-基)-1,3-二苯基-2-烯-1-酮的合成路线如下:将取代的2-氯苯并噻唑S1和取代苯乙酮溶于甲苯中,在低温反应器中缓慢加入双(三甲基硅基)氨基钠,搅拌,监测反应,TLC监测反应完毕后,在冰浴中边搅拌边缓慢加入饱和氯化铵水溶液,后用乙酸乙酯萃取三次,有机相用无水硫酸钠干燥,旋干,重结晶得到白色固体S2;氮气保护,将S2溶解于N,N-二甲基甲酰胺中,加入取代苯甲醛或者烷基醛,在向其中缓慢滴加三甲基氯硅烷,反应过夜监测反应情况,反应完毕后,冷却至室温,加水超声,然后用EA萃取,有机相用无水硫酸钠干燥,旋干,重结晶得到白色固体S3。
所述的取芳基γ醛的合成路线如下:在冰浴条件下,将磷酰基乙酸三乙酯溶于四氢呋喃THF溶液中,向其中缓慢加入氢化钠,搅拌,撤掉冰浴,向其中加入取代苯乙酮,监测反应,TLC监测反应完毕后,将反应液缓慢倒入水中,用乙醚萃取,有机相用无水硫酸钠干燥,旋干,过柱得到黄色油状液体S4产物;在冰浴条件下,将产物S4溶于四氢呋喃,缓慢加入强碱氢化铝锂,加完之后撤掉冰浴,室温反应过夜,监测反应,TLC监测反应完毕后,在冰浴下,向反应液中缓慢滴加盐酸,加入水淬灭反应,然后反应液用二氯甲烷萃取,有机相用无水硫酸钠干燥,旋干,过柱得到黄色油状产物S5;将S5溶解于氯仿中加入二氧化锰,加热回流,监测反应情况,反应完毕后,抽滤,滤液旋干,过柱纯化即得黄色油状产物S6;
本发明的积极效果是:具有简单结构单元的反应物分子取代(Z)-2-(苯并[d] 噻唑-2-基)-1,3-二苯基-2-烯-1-酮能有效在氮杂环卡宾的催化作用下,高效的制备了2-(5'-芳基-[1,1':3',1”-3芳基]-2'-基)苯并[d]噻唑,衍生物并具有衍生物具有优异的产率,并以2-(5'-芳基-[1,1':3',1”-3芳基]-2'-基)苯并[d]噻唑为导向基团选择性合成了2'-(苯并[d]噻唑-2-基)-5'-芳基-[1,1':3',1”-3芳基]-2-基醋酸酯类化合物。
具体制备实施方式
以下介绍本发明的实施例,介绍33个制备实施例。
总实施例
底物取代(Z)-2-(苯并[d]噻唑-2-基)-1,3-二苯基-2-烯-1-酮的合成路线如下:将取代的2-氯苯并噻唑S1和取代苯乙酮溶于甲苯中,在低温反应器中(0℃)缓慢加入双(三甲基硅基)氨基钠,0℃搅拌5h,然后室温搅拌16h,监测反应,TLC 监测反应完毕后,在冰浴中边搅拌边缓慢加入饱和氯化铵水溶液用来猝灭反应液中的强碱双(三甲基硅基)氨基钠,猝灭结束后用乙酸乙酯萃取三次,有机相用无水硫酸钠干燥,旋干,重结晶得到白色固体S2;在油浴温度为40℃的条件下,氮气保护,将S2溶解于适量的N,N-二甲基甲酰胺(DMF)中,加入取代苯甲醛 (或者烷基醛),在向其中缓慢滴加三甲基氯硅烷(TMSCl),反应过夜(2~24h) 监测反应情况,反应完毕后,撤掉加热,冷却至室温,加适量水超声1h,然后用EA萃取,有机相用无水硫酸钠干燥,旋干,重结晶得到白色固体S3;
反应底物取代芳基或烷基γ醛的合成路线如下:在冰浴0℃条件下,将磷酰基乙酸三乙酯溶于四氢呋喃溶液中,向其中缓慢加入氢化钠,加完之后搅拌反应30 分钟,撤掉冰浴,向其中加入取代苯乙酮,反应12h,监测反应,TLC监测反应完毕后,将反应液缓慢倒入水中,搅拌30分钟,用乙醚萃取,有机相用无水硫酸钠干燥,旋干,过柱得到黄色油状液体S4产物进行下一步反应;在冰浴0℃条件下,将产物S4用于四氢呋喃,缓慢加入强碱氢化铝锂,加完之后撤掉冰浴,室温反应过夜,监测反应,TLC监测反应完毕后,在冰浴下,向反应液中缓慢滴加适量的1M盐酸,加入适量的水淬灭反应,然后反应液用二氯甲烷萃取,有机相用无水硫酸钠干燥,旋干,过柱得到黄色油状产物S5直接进行下一步;将 S5溶解于适量氯仿中加入适量二氧化锰,加热回流,监测反应情况,反应完毕后,抽滤,滤液旋干,过柱纯化即得黄色油状产物S6。
制备2-(5'-芳基-[1,1':3',1”-3芳基]-2'-基)苯并[d]噻唑衍生物的合成路线(I):
制备实施方法和条件如下:
分别称取0.25mmol取代芳基γ醛、0.1mmol取代(Z)-2-(苯并[d]噻唑-2- 基)-1,3-二苯基-2-烯-1-酮、0.02mmol的氮杂环卡宾催化剂D、0.20mmol K3PO4和0.30mmol氧化剂DQ加入配有磁力搅拌子的10mL Schlenk反应管中,加入 1.5mL溶剂甲基叔丁基醚MTBE,轻轻晃动反应壁,使其充分混匀。盖上瓶盖,置于40℃的油浴中充分搅拌反应24h。TLC监测反应完毕后,旋干,通过柱层析分离,洗脱剂极性石油醚:乙酸乙酯=20:1得到目标化合物I,称量后计算相应的产率,化合物通过熔点仪,核磁共振仪NMR,高分辨质谱仪HRMS予以表征。
制备实施例1
取代基R1为H,R2为H,R3为Br,CH3,OCH3.
分别称取0.25mmol(40ul)取代芳基γ醛、0.1mmol(34.14mg)(Z)-2-(苯并[d] 噻唑-2-基)-1,3-二苯基-2-烯-1-酮、0.02mmol(6.4mg)的氮杂环卡宾催化剂D、 0.2mmol(44mg)K3PO4和0.3mmol(120mg)氧化剂DQ加入配有磁力搅拌子的10mL Schlenk反应管中,加入1.5mL溶剂甲基叔丁基醚MTBE,置于40℃的油浴中充分搅拌反应24h。TLC监测反应完毕后,旋干,通过柱层析分离,洗脱剂极性石油醚:乙酸乙酯=20:1得到目标化合物I1,称量后计算相应的产率,表征方法同总实施例I。
2-(5'-苯基-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I1):
13C NMR(101MHz,CDCl3)δ166.8,152.8,143.6,142.53,140.8,140.1,136.7,130.6,129.4,129.1,128.3,128.1,128.1,127.4,127.2 125.7,124.9,123.4,121.4;
HRMS(ESI,m/z):Mass calcd.for C31H22NS[M+H]+,440.1457;found 440.1459.
制备实施例2
取代基R1为H,R2为H,R3为4-CH3制备实施方法和条件同实施例I;
2-(5'-(4-甲基)-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I2):
140.9,138.1,137.1,136.7,130.3,129.8,129.5,128.1,128.1,127.2,127.1,125.7,124.9,123.4,121.4,21.3;
HRMS(ESI,m/z):Mass calcd.for C32H24NS[M+H]+,454.1624;found 454.1620.
制备实施例3
取代基R1为H,R2为H,R3为4-OCH3制备实施方法和条件同实施例I;
2-(5'-(4-甲氧基)-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I3):
13C NMR(101MHz,CDCl3)δ167.0,159.9,152.8,143.6,142.1,141.0,136.7,132.5,130.0,129.5,128.5,128.1,127.8,127.1,125.7,124.9,123.4,121.3,114.5,55.5;
HRMS(ESI,m/z):Mass calcd.for C32H24NOS[M+H]+,470.1573;found 470.1564.
制备实施例4
取代基R1为H,R2为H,R3为4-Br制备实施方法和条件同实施例I;
2-(5'-(4-溴)-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I4):
140.6,139.0,136.7,132.2,131.0,129.4,129.0,128.1,128.1,127.3,125.7,125.0,123.4,122.5,121.4;
HRMS(ESI,m/z):Mass calcd.for C31H21BrNS[M+H]+,517.0494;found 517.0494.
制备实施例5
取代基R1为H,R2为H,R3为3-CH3制备实施方法和条件同实施例I;
2-(5'-(3-甲基)-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I5):
白色固体,产率64%;熔点:184-186℃;
13C NMR(101MHz,CDCl3)δ166.9,152.8,143.5,142.6,140.9,140.3,140.0,138.8,136.7,136.0,130.5,129.5,129.0,128.9,128.4,128.2,128.1,127.2,125.7,124.9,124.5,123.4,121.4,21.7;
HRMS(ESI,m/z):Mass calcd.for C32H24NS[M+H]+,454.1624;found 454.1615.
制备实施例6
取代基R1为H,R2为H,R3为3-OCH3制备实施方法和条件同实施例I;
2-(5'-(3-甲氧基)-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I6):
13C NMR(101MHz,CDCl3)δ166.8,161.3,160.2,152.8,143.6,142.4,141.6,140.8,136.7,130.7,130.1,129.5,128.4,128.1,127.2,125.7,124.9,123.4,121.4,119.9,113.7,113.0,55.5;
HRMS(ESI,m/z):Mass calcd.for C32H24NOS[M+H]+,470.1573;found 470.1574.
制备实施例7
取代基R1为H,R2为H,R3为2-CH3制备实施方法和条件同实施例I;
2-(5'-(2-甲基)-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I7):
140.7,136.7,135.5,130.7,130.5,130.1,129.9,129.5,128.1,127.9,127.1,126.1,125.7,124.9,123.4,121.4,20.8;
HRMS(ESI,m/z):Mass calcd.for C32H24NS[M+H]+,454.1624 found 454.1619.
制备实施例8
取代基R1为H,R2为H,R3为2-OCH3制备实施方法和条件同实施例I;
2-(5'-(2-甲氧基)-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I8):
13C NMR(101MHz,CDCl3)δ167.1,156.7,152.8,142.7,141.0,136.7,131.1,130.8,129.6,129.4,128.0,127.0,125.6,124.8,123.4,121.4,121.1,111.4,55.8;
HRMS(ESI,m/z):Mass calcd.for C32H24NOS[M+H]+,470.1573;found 470.1565.
制备实施例9
取代基R1为H,R2为H,R3为2-Br制备实施方法和条件同实施例I;
2-(5'-(2-溴)-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I9):
Hz,1H),7.25–7.20(m,1H),7.19–7.14(m,6H);
13C NMR(101MHz,CDCl3)δ166.8,152.7,142.8,142.4,141.5,140.6,136.6,133.5,131.4,130.8,130.7,129.5,129.4,128.1,127.7,127.2,125.7,124.9,123.4,122.6,121.4;
HRMS(ESI,m/z):Mass calcd.for C31H21BrNS[M+H]+,517.0494;found 517.0496.
制备实施例10
取代基R1为H,R2为H,R3为2,5-二甲基制备实施方法和条件同实施例I;
2-(5'-(2,5-二甲基)-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I10):
13C NMR(101MHz,CDCl3)δ167.1,152.8,143.7,142.9,140.8,140.7,136.7,135.6,132.4,130.6,130.5,129.5,128.6,128.1,127.1,125.7,124.9,123.4,121.4,21.1,20.2;
HRMS(ESI,m/z):Mass calcd.for C33H26NS[M+H]+,468.1780;found 468.1771.
制备实施例11
取代基R1为H,R2为H,R3为4-萘基制备实施方法和条件同实施例I;
2-(5'-(4-萘基)-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I11):
13CNMR(101MHz,CDCl3)δ166.8,152.8,143.7,142.4,140.9,137.3,136.7,133.8,133.1,130.7,129.5,128.8,128.6,128.5,128.1,127.8,127.2,126.6,126.5,126.4,125.7,125.4,124.9,123.4,121.4;
HRMS(ESI,m/z):Mass calcd.for C35H24NS[M+H]+,490.1624;found 490.1613.
制备实施例12
取代基R1为H,R2为H,R3为噻吩制备实施方法和条件同实施例I;
2-(5'-(2-噻吩基)-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I12):
白色固体,产率84%;熔点:149-151℃;
141.4,140.6,139.3,136.7,136.3,135.7,130.6,129.4,128.4, 128.1,127.3,126.8,126.0,125.7,124.9,124.4,123.4,121.4;
HRMS(ESI,m/z):Mass calcd.for C30H20NS2[M+H]+,446.1032;found 446.1021.
制备实施例13
取代基R1为H,R2为H,R3为环丙基制备实施方法和条件同实施例I;
2-(5'-环丙基-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I13):
13C NMR(101MHz,CDCl3)δ167.2,152.8,146.1,143.0,141.1,136.7,129.4,128.8,128.0,127.0,126.9,125.6,124.7,123.3,121.3,15.6,10.0;
HRMS(ESI,m/z):Mass calcd.for C28H22NS[M+H]+,404.1467;found 404.1461.
制备实施例14
取代基R1为H,R2为4-CH3,R3为H制备实施方法和条件同实施例I;
2-(4-甲基-5'-苯基-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I14):
7.21(m,2H),7.20–7.16(m,3H),7.02–6.99(m,2H),2.26(s,3H);
13C NMR(101MHz,CDCl3)δ167.0,152.8,143.6,143.5,142.5,140.9,140.1,137.9,136.9,136.7,129.4,129.3,129.1,128.9,128.4,128.2,128.1,128.0,127.4,127.1,125.65,124.8,123.4,121.4,21.2;
HRMS(ESI,m/z):Mass calcd.for C32H23NS[M+H]+,453.1548;found 453.1537.
制备实施例15
取代基R1为H,R2为4-F,R3为H制备实施方法和条件同实施例I;
2-(4-氟-5'-苯基-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I15):
13C NMR(101MHz,CDCl3)δ166.6,162.1(d,J=247.4Hz),152.7,143.7,142.5(d, J=4.0Hz),140.7,140.0,136.8(d,J=4.0Hz),136.6,136.5,131.0(d,J=8.1Hz), 130.7,129.4,129.1,128.5,128.4,128.2(d,J=5.1Hz),127.4,127.3,125.8,125.0, 123.4,121.4,115.0(d,J=22.2Hz);
19F NMR(471MHz,CDCl3)δ-115.12;
HRMS(ESI,m/z):Mass calcd.for C31H21NFS[M+H]+,458.1373;found 458.1366.
制备实施例16
取代基R1为H,R2为4-Cl,R3为H制备实施方法和条件同实施例I;
2-(4-氯-5'-苯基-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I16):
7.15(m,2H);
13C NMR(101MHz,CDCl3)δ166.6,152.9,143.9,142.8,142.5,140.7,140.0,139.5,136.7,133.5,130.9,130.7,129.6,129.2,128.8,128.4,128.4,128.3,128.3,127.5,127.4,126.0,125.2,123.6,121.5;
HRMS(ESI,m/z):Mass calcd.for C31H19NClS[M+H]+,472.0921;found 472.0873.
制备实施例17
取代基R1为H,R2为4-Br,R3为H制备实施方法和条件同实施例I;
2-(4-溴-5'-苯基-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I17):
140.6,139.9,139.8,136.6,131.2,131.1,130.5,129.4,129.1,128.7,128.3,128.1,127.4,127.3,125.9,125.1,123.5,121.6,121.4;
HRMS(ESI,m/z):Mass calcd.for C31H21NBrS[M+H]+,518.0573;found 518.0565.
制备实施例18
取代基R1为H,R2为4-NO2,R3为H制备实施方法和条件同实施例I;
2-(4-硝基-5'-苯基-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I18):
1H NMR(500MHz,CDCl3)δ8.07–8.04(m,2H),7.84–7.81(m,1H),7.79(d,J= 1.9Hz,1H),7.73–7.70(m,2H),7.69(d,J=1.9Hz,1H),7.68–7.66(m,1H),7.52 –7.47(m,4H),7.43(ddd,J=7.4,3.9,1.2Hz,1H),7.40–7.37(m,1H),7.33–7.28 (m,3H),7.23–7.20(m,3H);
13C NMR(101MHz,CDCl3)δ165.8,152.7,147.9,146.9,144.0,143.0,141.4,140.2,139.6,136.5,130.5,130.3,129.5,129.2,128.5,128.3,128.0,127.6,127.4,126.1,125.4,123.5,123.3,121.5;
HRMS(ESI,m/z):Mass calcd.for C31H34N2O2S[M+H]+,485.1318;found 485.1309.
制备实施例19
取代基R1为H,R2为3-F,R3为H制备实施方法和条件同实施例I;
2-(3”-氟-5'-苯基-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I19):
7.15–7.05(m,3H),6.88(ddd,J=8.7,4.8,1.1Hz,1H);
13C NMR(101MHz,CDCl3)δ166.2,162.3.(d,J=246.4Hz),152.7,143.6,142.9(d,J=7.1Hz),142.6,142.2(d,J=2.0Hz),140.5,139.8,136.5,130.5,129.4,129.3, 129.0,128.6,128.2,128.0,127.3,127.2,125.7,125.1(d,J=3.0Hz),124.9,123.3, 121.3,116.5,116.3,114.0(d,J=21.2Hz);
19FNMR(471MHz,CDCl3)δ-113.31;
HRMS(ESI,m/z):Mass calcd.for C31H21NFS[M+H]+,458.1373;found 458.1365.
制备实施例20
取代基R1为H,R2为3-F,R3为H制备实施方法和条件同实施例I;
2-(3”-氯-5'-苯基-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I20):
13C NMR(101MHz,CDCl3)δ166.3,152.7,143.7,142.7,142.6,142.2,140.6,139.8,136.6,134.0,130.6,129.6,129.5,129.2,129.1,128.7,128.3,128.1,128.1,127.6,127.4,127.3,125.9,125.1,123.4,121.34;
HRMS(ESI,m/z):Mass calcd.for C31H21NClS[M+H]+,474.1077;found 474.1070.
制备实施例21
取代基R1为H,R2为3-Cl-4-F,R3为H制备实施方法和条件同实施例I;
2-(3”-氯-4”-氟-5'-苯基-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I21):
1H NMR(500MHz,CDCl3)δ7.89–7.85(m,1H),7.74(d,J=1.9Hz,1H),7.73– 7.70(m,2H),7.68(dd,J=8.0,0.4Hz,1H),7.66(d,J=1.9Hz,1H),7.51–7.46(m, 3H),7.42(dd,J=8.9,2.8Hz,1H),7.39(dd,J=4.6,3.6Hz,1H),7.33–7.28(m,3H), 7.22–7.18(m,3H),7.10(ddd,J=8.5,4.6,2.3Hz,1H),6.89(t,J=8.7Hz,1H);
13C NMR(101MHz,CDCl3)δ166.1,157.4(d,J=249.5Hz),152.7,143.8,142.8,141.3,140.5,139.8,137.9(d,J=4.1Hz),136.6,131.7,130.7,129.5,129.3,129.2,129.1,128.8,128.3,128.2,128.1,127.4,126.0,125.2,123.5,121.4,120.6(d,J=17.8Hz),116.1(d,J=21.2Hz);
19F NMR(377MHz,CDCl3)δ-117.68;
HRMS(ESI,m/z):Mass calcd.for C31H20ClFNS[M+H]+,492.0984;found 492.1129.
制备实施例22
取代基R1为H,R2为3-Cl-4-Br,R3为H制备实施方法和条件同实施例I;
2-(3”-氯-4”-溴-5'-苯基-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I22):
13C NMR(101MHz,CDCl3)δ166.0,152.7,143.9,142.9,141.5,141.1,140.4,139.7,136.6,134.2,133.2,131.3,130.5,129.4,129.2,129.0,128.9,128.4,128.2,128.0,127.4,126.0,125.2,123.5,121.4;
HRMS(ESI,m/z):Mass calcd.for C31H20NBrClS[M+H]+,552.0183;found552.0182.
制备实施例23
取代基R1为H,R2为2-F-5-Br,R3为H制备实施方法和条件同实施例I;
2-(5”-溴-2”-氟-5'-苯基-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I23):
3.3,1.6Hz,3H),6.78(t,J=8.9Hz,1H);
13C NMR(126MHz,CDCl3)δ165.8,158.8(d,J=248.2Hz),152.7,143.6,142.6,140.5,139.7,136.6,136.2,134.7(d,J=3.8Hz),132.2(d,J=8.8Hz),131.4,130.4 (d,J=17.8Hz),129.6,129.5,129.1,128.6,128.3,128.2,127.5,127.4,125.8,125.1, 123.4,121.4,117.1(d,J=23.9Hz),116.1(d,J=3.1Hz);
19F NMR(471MHz,CDCl3)δ-116.13;
HRMS(ESI,m/z):Mass calcd.for C31H20FBrNS[M+H]+,536.0478;found 536.0478.
制备实施例24
取代基R1为H,R2为3噻吩基,R3为H制备实施方法和条件同实施例I;
2-(5'-(噻吩-3-基)-[1,1':3',1”-三联苯]-4'-基)苯并[d]噻唑(I24):
13C NMR(101MHz,CDCl3)δ166.9,152.8,143.7,142.7,141.0,140.7,140.1,138.3,136.7,130.4,129.4,129.1,128.8,128.3,128.2,128.1,127.9,127.4,127.2,125.8,125.2,125.1,123.9,123.5,121.5;
HRMS(ESI,m/z):Mass calcd.for C29H20NS2[M+H]+,446.1032;found 446.1031.
制备实施例25
取代基R1为H,R2为3吡啶基,R3为H制备实施方法和条件同实施例I;
2-(5'-(吡啶-3-基)-[1,1':3',1”-三联苯]-4'-基)苯并[d]噻唑(I25):
13C NMR(101MHz,CDCl3)δ166.0,152.7,149.8,148.3,143.9,142.9,140.4,140.0,139.7,136.8,136.7,136.6,130.9,129.5,129.2,129.1,128.4,128.3,128.2,127.4,126.0,125.2,123.5,122.9,121.4;
HRMS(ESI,m/z):Mass calcd.for C30H21N2S[M+H]+,441.1420;found 441.1414.
制备实施例26
取代基R1为4-Br,R2为H,R3为H制备实施方法和条件同实施例I;
2-(4-溴-5'-苯基-[1,1':3',1”-三联苯]-4'-基)苯并[d]噻唑(I26):
142.3,140.6,139.9,139.8,136.6,131.2,131.1,129.4,129.1,128.7,128.3,128.1,127.4,127.3,125.9,125.1,123.5,121.6,121.4;
HRMS(ESI,m/z):Mass calcd.for C31H21BrNS[M+H]+,518.0572;found.518.0566.
制备实施例27
取代基R1为4-F,R2为H,R3为H制备实施方法和条件同实施例I;
2-(4-氟-5'-苯基-[1,1':3',1”-三联苯]-4'-基)苯并[d]噻唑(I27)
1H NMR(500MHz,CDCl3)δ7.86–7.83(m,1H),7.73–7.70(m,3H),7.69(d,J= 1.9Hz,1H),7.68–7.66(m,1H),7.50–7.46(m,2H),7.43–7.39(m,1H),7.37(ddd, J=8.3,7.2,1.3Hz,1H),7.33–7.29(m,3H),7.29–7.26(m,2H),7.19(tdd,J=2.3, 1.9,0.8Hz,3H),6.90–6.85(m,2H);
13C NMR(101MHz,CDCl3)δ166.6,163.2(d,J=247.4Hz),152.8,143.7,142.6(d, J=3.0Hz),140.7,140.0,136.8(d,J=4.0Hz),136.6,131.1(d,J=8.1Hz),130.7, 129.4,129.1,128.5,128.2(d,J=5.0Hz),128.1,127.4,127.3,125.8,125.0,123.4, 121.4,115.1(d,J=21.2Hz);
19F NMR(471MHz,CDCl3)δ-115.16;
HRMS(ESI,m/z):Mass calcd.for C31H21FNS[M+H]+,458.1373;found 458.1373.
制备实施例28
取代基R1为4-CH3,R2为4-CN,R3为H制备实施方法和条件同实施例I;
2'-(苯并[d]噻唑-2-基)-4”-甲基-5'-苯基-[1,1':3',1”-三联苯]-4-甲腈(I28):
141.8,139.7,137.3,137.3,136.5,131.8,130.4,130.1,129.3,129.2,129.0,128.4,127.7,127.4,126.0,125.3,123.5,121.5,118.9,110.9,21.2;
HRMS(ESI,m/z):Mass calcd.for C33H23N2S[M+H]+,479.1576;found 479.1576.
制备实施例29
取代基R1为4-Br,R2为3-Cl,R3为H制备实施方法和条件同实施例I;
2-(4-溴-3-氯-5'-苯基-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I29)
白色固体,产率99%;熔点:180-182℃;
142.3,139.6,139.5,136.5,134.0,131.3,131.1,130.4,129.6, 129.2,129.2 128.5,128.4,128.4,127.6,127.4,126.0,125.3,123.5,121.8,121.5;
HRMS(ESI,m/z):Mass calcd.for C31H20NBrClS[M+H]+,552.0183;found552.0169.
制备实施例30
取代基R1为4-CH3,R2为3-Cl,R3为H制备实施方法和条件同实施例I;
2-(3-氯-4”-甲基-5'-苯基-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I30):
1H NMR(400MHz,CDCl3)δ7.87(d,J=8.1Hz,1H),7.72(dd,J=3.0,1.7Hz,2H),7.67(dd,J=10.5,3.7Hz,3H),7.47(t,J=7.4Hz,2H),7.42–7.39(m,2H),7.36(dd, J=8.2,1.1Hz,1H),7.28(dd,J=11.1,4.1Hz,1H),7.21(d,J=8.1Hz,2H),7.15– 7.10(m,2H),7.04(d,J=7.8Hz,1H),7.00(d,J=8.0Hz,2H),2.25(s,3H);
13C NMR(101MHz,CDCl3)δ166.5,152.8,143.6,142.7,142.2,139.9,137.6,137.1,136.6,133.9,130.5,129.6,129.3,129.1,129.1,128.9,128.8,128.2,127.9,127.6,127.4,127.3,125.8,125.0,123.5,121.4,21.2;
HRMS(ESI,m/z):Mass calcd.for C32H22ClNS[M+H]+,488.1234;found 488.1227.
制备实施例31
取代基R1为4-F,R2为3-Cl,R3为H制备实施方法和条件同实施例I;
2-(3-氯-4”-氟-5'-苯基-[1,1':3',1”-三联苯]-2'-基)苯并[d]噻唑(I31)
134.0,131.1(d,J=8.1Hz),130.7,129.6,129.2,129.1,128.7,128.3(d,J=11.1Hz),127.6,127.4,126.0,125.2,123.5,121.4,115.1(d,J=21.2Hz);
19F NMR(377MHz,CDCl3)δ-114.99;
HRMS(ESI,m/z):Mass calcd.for C31H20NClFS[M+H]+,492.0983;found 492.0982.
制备实施例32
取代基R1为4-F,R2为3-Cl,R3为H制备实施方法和条件同实施例I;
2'-(苯并[d]噻唑-2-基)-5'-苯基-[1,1':3',1”-三联苯]-2-基醋酸酯(I32):
Hz,3H),7.07(td,J=7.6,0.9Hz,1H),7.04(d,J=8.1Hz,1H),2.10(s, 3H,-OCOCH3);
13C NMR(101MHz,CDCl3)δ169.5,166.0,152.8,148.3,143.5,141.9,140.8,139.7,138.8,136.6,133.4,131.8,131.3,129.5,129.1,128.8,128.7,128.3,128.2, 128.1,127.3,127.2,125.7,125.6,124.8,123.3,122.4,121.3,21.1;
HRMS(ESI,m/z):Mass calcd.for C33H24O2NS[M+H]+,498.1522;found 498.1510.
制备实施例33
取代基R1为4-F,R2为3-Cl,R3为H制备实施方法和条件同实施例I;
6'-(苯并[d]噻唑-2-基)-4”-甲基-5'-苯基-[1,1':3',1”-三联苯]-2-基醋酸酯(I33):
1.2Hz,1H),7.03(dd,J=8.1,1.1Hz,1H),2.41(s,3H,Ar-CH3),2.09(s,3H, -OCOCH3);
13C NMR(101MHz,CDCl3)δ169.6,166.1,152.8,148.3,143.4,141.8,140.9,138.8,138.1,136.8,136.7,133.5,131.8,131.0,129.9,129.5,128.8,128.5,128.1,128.0,127.2,127.1,125.7,125.6,124.8,123.3,122.4,121.3,21.3,21.1;
HRMS(ESI,m/z):Mass calcd.for C34H26O2NS[M+H]+,512.1679;found 512.1674.
综合如上所述,仅是本发明的较佳实施例而已,并非对本发明作任何形式上的限制,任何未脱离本发明技术方案内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均仍属于本发明技术方案的范围内。
Claims (5)
2.根据权利要求1所述的一类苯并噻唑芳基化合物衍生物的制备方法,其特征在于:所述卤素原子为氟、氯或溴。
3.根据权利要求1所述的一类苯并噻唑芳基化合物衍生物的制备方法,其特征在于:R2为2-溴-5甲基、3-氯-4-溴或3-氯-4-氟。
4.根据权利要求1所述的一类苯并噻唑芳基化合物衍生物的制备方法,其特征在于:所述的(Z)-2-(苯并[d]噻唑-2-基)-1,3-二苯基-2-烯-1-酮的合成路线如下:将2-氯苯并噻唑S1和取代苯乙酮溶于甲苯中,在低温反应器中缓慢加入双(三甲基硅基)氨基钠,搅拌,监测反应,TLC监测反应完毕后,在冰浴中边搅拌边缓慢加入饱和氯化铵水溶液,后用乙酸乙酯萃取三次,有机相用无水硫酸钠干燥,旋干,重结晶得到白色固体S2;氮气保护,将S2溶解于N,N-二甲基甲酰胺中,加入取代苯甲醛,在向其中缓慢滴加三甲基氯硅烷,反应过夜监测反应情况,反应完毕后,冷却至室温,加水超声,然后用EA萃取,有机相用无水硫酸钠干燥,旋干,重结晶得到白色固体S3;
5.根据权利要求1所述的一类苯并噻唑芳基化合物衍生物的制备方法,其特征在于:其反应底物取芳基γ醛的合成路线如下:在冰浴条件下,将磷酰基乙酸三乙酯溶于四氢呋喃THF溶液中,向其中缓慢加入氢化钠,搅拌,撤掉冰浴,向其中加入取代苯乙酮,监测反应,TLC监测反应完毕后,将反应液缓慢倒入水中,用乙醚萃取,有机相用无水硫酸钠干燥,旋干,过柱得到黄色油状液体S4产物;在冰浴条件下,将产物S4溶于四氢呋喃,缓慢加入强碱氢化铝锂,加完之后撤掉冰浴,室温反应过夜,监测反应,TLC监测反应完毕后,在冰浴下,向反应液中缓慢滴加盐酸,加入水淬灭反应,然后反应液用二氯甲烷萃取,有机相用无水硫酸钠干燥,旋干,过柱得到黄色油状产物S5;将S5溶解于氯仿中加入二氧化锰,加热回流,监测反应情况,反应完毕后,抽滤,滤液旋干,过柱纯化即得黄色油状产物S6;
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911194368.5A CN110963981B (zh) | 2019-11-28 | 2019-11-28 | 一类苯并噻唑芳基化合物衍生物及其制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911194368.5A CN110963981B (zh) | 2019-11-28 | 2019-11-28 | 一类苯并噻唑芳基化合物衍生物及其制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110963981A CN110963981A (zh) | 2020-04-07 |
CN110963981B true CN110963981B (zh) | 2023-04-07 |
Family
ID=70032130
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911194368.5A Active CN110963981B (zh) | 2019-11-28 | 2019-11-28 | 一类苯并噻唑芳基化合物衍生物及其制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110963981B (zh) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109053625A (zh) * | 2018-08-22 | 2018-12-21 | 浙江工业大学 | 一种取代苯并噻唑c2烷基化衍生物的制备方法 |
CN110256383A (zh) * | 2019-06-25 | 2019-09-20 | 浙江大学城市学院 | 二苯并呋喃丙烯酸酯类化合物及其制备方法 |
-
2019
- 2019-11-28 CN CN201911194368.5A patent/CN110963981B/zh active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109053625A (zh) * | 2018-08-22 | 2018-12-21 | 浙江工业大学 | 一种取代苯并噻唑c2烷基化衍生物的制备方法 |
CN110256383A (zh) * | 2019-06-25 | 2019-09-20 | 浙江大学城市学院 | 二苯并呋喃丙烯酸酯类化合物及其制备方法 |
Non-Patent Citations (2)
Title |
---|
New methodology for the conversion of pyrylium salts into pyridinium derivatives;Pyschev, Alexander I.,et al.;《Mendeleev Communications》;19961231(第3期);第99-101页 * |
Ring transformations of heterocyclic compounds. XIV. Ring transformations of pyrylium and thiopyrylium salts with anhydrobases derived from 1H-benzimidazolium and benzothioazolium salts: an easy access to 2-(2,4,6-triarylphenyl)-1H-benzimidazolium and -ben;Zimmermann, Thomas,et al.;《Journal of Heterocyclic Chemistry》;19971231;第33卷(第6期);第1717-1721页 * |
Also Published As
Publication number | Publication date |
---|---|
CN110963981A (zh) | 2020-04-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110183378B (zh) | 一种烟酰胺的衍生物及其催化合成方法 | |
CN106967003A (zh) | 一种合成1,3‑苯并噁嗪‑4‑酮化合物的方法 | |
CN113861137B (zh) | 酮与alpha氯代酮一步反应合成呋喃类化合物的方法 | |
CN105541834B (zh) | 一种2‑苯基咪唑并[1,2‑a]吡啶类化合物的合成方法 | |
CN110963981B (zh) | 一类苯并噻唑芳基化合物衍生物及其制备方法 | |
CN115286594B (zh) | 一种以s8为原料合成醌并噻唑类化合物的方法 | |
CN102276616B (zh) | 一种呋喃[3,2-c]吡啶-4(5H)-酮类化合物合成方法 | |
CN108191735B (zh) | 单质碘促进的烯胺酮环化合成多取代吲哚的方法 | |
CN105820174A (zh) | 一种多取代噻吩并吲哚衍生物的制备方法 | |
CN107382858B (zh) | 系列1,2,3,4-四氢异喹啉-4-酮化合物及其合成方法与应用 | |
CN112574225B (zh) | 一种四氢呋喃并二氢喹啉类化合物及其制备方法和应用 | |
CN113511986B (zh) | 一种芳基乙腈类衍生物的制备方法 | |
JP2019085385A (ja) | インデノイソキノリン派生物の調製方法 | |
CN111592509B (zh) | 一种铜催化合成芳基(3-砜基苯并呋喃-2-基)甲酮化合物的方法 | |
CN107163036A (zh) | 一种含噻唑环5,6‑二取代吡啶‑2‑酮化合物及其制备方法 | |
CN110240572B (zh) | 一种反式-1,1-环丙烷二羧酸酯的合成方法 | |
CN109251192B (zh) | 3位或4位三氟甲基取代异香豆素的制备方法 | |
CN109265409B (zh) | 一种2-取代的苯并噁唑和2-取代的苯并噻唑及其衍生物的合成方法 | |
Cliff et al. | Asymmetric synthesis of (1R, 2S, 3R)-2-acetyl-4 (5)-(1, 2, 3, 4-tetrahydroxybutyl) imidazole | |
CN106957251B (zh) | 一种制备烷基硫甲基酯类化合物的方法 | |
CN110698422A (zh) | 一种芳巯基二唑类衍生物的合成方法 | |
CN107417688B (zh) | 一种苯并[f]吡啶[1,2-a]吲哚-6,11-二酮衍生物及其制备方法 | |
CN111592486B (zh) | 一种芳基乙烯与n,n-二甲基甲酰胺通过环化反应构建3,5-二取代吡啶的方法 | |
CN110372718B (zh) | 一种二氟甲硫化色酮并噻吩化合物及其制备方法 | |
CN114230526B (zh) | 一种4-3(h)喹唑啉酮及其衍生物的合成方法 |
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 |