CN110229109B - 一种4-亚甲基喹唑啉(硫)酮类化合物的制备方法 - Google Patents
一种4-亚甲基喹唑啉(硫)酮类化合物的制备方法 Download PDFInfo
- Publication number
- CN110229109B CN110229109B CN201910453343.6A CN201910453343A CN110229109B CN 110229109 B CN110229109 B CN 110229109B CN 201910453343 A CN201910453343 A CN 201910453343A CN 110229109 B CN110229109 B CN 110229109B
- Authority
- CN
- China
- Prior art keywords
- dmso
- nmr
- quinazoline
- catalyst
- methylene
- 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
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
- C07D239/82—Oxygen atoms with an aryl radical attached in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种4‑亚甲基喹唑啉(硫)酮类化合物的制备方法将不同取代基2‑氨基苯乙酮衍生物和异(硫)氰酸苯酯衍生物溶于有机溶剂中,在催化剂(或无催化剂)的作用下,进行多组分反应,一锅法制得如式(I)所示的4‑亚甲基喹唑啉‑2(1H)‑(硫)酮类化合物(I),多数产物收率在70%以上。与现有技术相比,本发明方法中使用的催化剂(或无催化剂),从源头上避免了金属催化剂的使用,且原料易得、结构多样,还具有原子经济性高、耐水份和空气、操作简便、底物适用性广、环境友好等特点,具有较好的应用价值和潜在的经济社会效益。
Description
技术领域
本发明属于医药化工中间体合成技术领域,具体涉及4-亚甲基喹唑啉(硫)酮类化合物的制备方法。
背景技术
含氮杂环母核结构在药物分子和天然产物的核心骨架中扮演着举足轻重的地位,其中含氮六元杂环的喹唑啉酮类化合物更是在医药、化工、材料等领域起着更加重要的角色。其中多取代喹唑啉(硫)酮化合物是一类重要的杂环类化合物,是许多生物活性化合物的重要结构骨架,在生物和医药领域有着广泛的应用,喹唑啉酮及其衍生物最早来源于高等植物,微生物和动物体内分离得到,其母核结构是150多种生物碱重要组成部分,具有对风湿病、炎症、脓肿等治疗功效;色胺酮抗癌、杀菌和消炎等活性,如图1所示。
近年来,研究表明喹唑啉酮类母核结构具备抗肿瘤、抗菌、抑制DNA、非甾体抗炎及镇静镇痛等作用。研究发现喹唑啉-2(1H)-酮母核结构6(图2中6)具有强心作用。中间体经过改造后的喹唑啉-2(1H)-酮化合物7(图2中7),具有拮抗血小板活化因子的作用。2000年,Fliri团队(US6521630-B1,2013)研究发现了喹唑啉-2(1H)-酮改造的氮杂双环烷衍生物可以抑制5-羟色胺再摄取,可以在中枢神经系统疾病中起到了关键作用。
同时喹唑硫酮在材料和、化学、药物等方面同样有着不可缺少的作用。喹唑啉硫酮类化合物与喹唑啉酮化合物的区别在于分子中的官能团由脲基变成了硫脲基团。研究发现,含有硫脲基团的化合物具有抗甲亢作用,但同时当分子中的脲基变为硫脲基团时,分子的毒性大大增加,为此,科学家们一直致力于研究出毒性小,能够发挥出硫脲基团性质的化合物。1961年,Orth等(J.Pharm.Sci.1961,50,866-868)研究发现当硫脲基团并入某些带有硝基的环中,所合成的化合物的毒性大大降低,为此开始了制备一些具有活性的、无毒的含活性硫脲的杂环类衍生物8(图2中8)。1980年,Grosso等(J.Med.Chem.1980,23,1261-1264)为了研发具备抗高血压功效结构的胍基结构,从底物2-氨基苯甲酰胺出发,合成了喹唑啉-2(1H)-硫酮中间体,发现其具有活化血管活性。1990年,Leistner等(Arch.Pharm.1990,323,857-862)利用Dimroth-重排原理合成了新型喹唑啉硫酮9(图2中9),其活性在2008年被Smits等(J.Med.Chem.2008,51,7855-7865)证实了其对人类组胺H4受体具有亲和性,属于组胺H4受体反向激动剂。2018年,Mina等(J.Med.Chem.2019,83,161-169),通过设计并合成了具有抗糖尿病功效的新型化合物10(图2中10),其结构是引入了喹唑啉硫酮母核和三唑杂环结构,这两个母核都具有抗糖尿病功效,因此10衍生物(图2中10)具备了良好的体外α-葡萄糖苷酶抑制、动力学等特性。Gregoryl等(Int.J.Parasitol.-Drugs DrugResist.2018,8,137-144)通过高通量筛选到了化合物11(图2中11)具有抑制结节性囊虫生长的作用,对棘丛寄生虫等有抑制作用,可以起到保护神经作用。
由此看出喹唑啉酮结构在药物化学结构领域有着举足轻重的地位,但是限于种类和数量,从自然界中分离得到的喹唑啉(硫)酮结构无法满足生物及医药领域的应用,同时对喹唑啉(硫)酮结构的改造及其药理性质趋于缓慢,其原因在于合成工艺的繁琐,以及高成本的投入。因此,寻找简单快捷的合成工艺路线,增加喹唑啉酮类化合物的种类并扩大其在生物及医药领域的应用,成为了当今研究的热门。
目前关于常见的喹唑啉-2(1H)-酮的合成方法如图3所示:
第一类为以2-乙胺基苯胺类化合物为底物合成喹唑啉酮类化合物(图4),邻乙胺基苯胺类化合物与二氯亚砜(Journal fuer Praktische Chemie(Leipzig),1895,2,126)或S,S′-二硫代碳酸二甲酯(J.Org.Chem.2010,27)或碳酸二乙酯(J.Org.Chem.2010,75,3037-3046)或二氧化碳(Eur.J.Org.Chem.2012,43,6261-6268)或一氧化碳(Eur.J.Med.Chem.2015,90,788-796)或2-(三氯甲基)碳酸酯(Tetrahedron Lett.2018,59,1614-1618),进行反应得到喹唑啉酮-2(1H)-酮。
第二类为通过特定底物水解水解再分子内亲核反应并行合成喹唑啉酮类化合物(图5),如2-(1-氧代-1,2,3,4-四氢异喹啉-2-甲酰胺基)苄基氨基甲酸叔丁酯在三氟乙酸(Org.Biomol.Chem.2011,9,656-658)或N,N-二甲基甲酰胺(Angew.Chem.-Int.Ed.2018,57,9744-9748)作用下水解为断裂酰胺键,然后进行亲核反应得到最终的产物。
第三类为异氰酸酯作为羰基来源,如利用异氰酸酯(Sci.China-Chem.2014,57,1117-1125),与邻乙胺基苯胺在稀有金属镧(III)催化作用下制备得到目标产物喹唑啉-2(1H)-酮(图6)。
第四类为利用六羰基钼作为羰基来源,如六羰基钼可以作为羰基来源与邻乙胺基苯胺,利用醋酸铜和醋酸钯催化得到产物喹唑啉-2(1H)-酮(图7)。
目前关于常见的喹唑啉-2(1H)-硫酮的合成方法如图8所示:
第一类是以2-乙胺基苯胺类化合物与底物二硫化碳(Arch.Pharm.1983,316,379-381)或1,1-硫代羰基二咪唑(Med.Chem.Lett.2014,24,5576-5580)或异硫氰酸苯酯(Sci.China-Chem.2014,57,1117-1125)或三氯甲烷及硫(Org.Lett.2017,19,2166-2169)共同作用下合成喹唑啉-2(1H)-硫酮类化合物(图9)。
第二类为通过对特定底物还原后再生成喹唑啉-2(1H)-硫酮类化合物,如2-氨基苯腈(Arch.Pharm.1983,316:379-381)或2-氨基苯甲酰胺(J.Pharm.Sci.1987,76,633-634)在四氢锂铝还原为2-乙胺基苯胺后再与硫光气反应制备目标产物(图10),但由于其产率较低。
第三类以硫氰酸钾,亚磺酰胺基卞氯为底物合成喹唑啉-2(1H)-硫酮,如利用硫氰酸钾,亚磺酰胺基卞氯(Cheminform.1981,12)反应可以制备出目标产物(图11)。
以上方法虽然可以制备喹唑啉-2(1H)-(硫)酮,但均存在着有一些不足之处,比如高度依赖金属催化剂、原料需多步合成等。随着人们对药物中的重金属残留问题的不断重视,开发一种非金属催化、原料易得的喹唑啉(硫)酮类化合物的制备方法意义重大。
发明内容
本发明提供一种非金属催化、原料易得的4-亚甲基喹唑啉(硫)酮类化合物的制备方法,以不同取代基的2-氨基苯乙酮及异(硫)氰酸苯酯为原料,高效地制备4-亚甲基喹唑啉(硫)酮类类化合物。
一种4-亚甲基喹唑啉(硫)酮类化合物的制备方法,包括如下步骤:
将如式(II)所示的不同取代基2-氨基苯乙酮衍生物、如式(III)所示的异(硫)氰酸苯酯衍生物溶于有机溶剂中,进行多组分反应,一锅法制得如式(I)所示的4-亚甲基喹唑啉-2(1H)-(硫)酮类化合物;当X为O时,在催化剂作用下进行多组分反应,所述催化剂为无机碱或有机碱中的一种;
式中R1为氢及吸电子或给电子取代基团中的一种;R2为芳香基或脂肪基基团。
不同取代基(R1和R2)来源于2-氨基苯乙酮衍生物(II)和异(硫)氰酸酯衍生物(III)。
本发明工艺路线避开了以往合成喹唑啉(硫)酮原料昂贵、操作复杂、产率差的缺点,达到了良好的工艺效果。
将2-氨基苯乙酮类化合物(II)、异(硫)氰酸苯酯类化合物(III)、碱催化剂加入有机溶剂中,在85℃下反应10~180分钟制得如式(I)所示的4-亚甲基喹唑啉-2(1H)-(硫)酮类类化合物。反应式如下:
优选地,所述无机碱为氢氧化钠、碳酸钠、碳酸氢钠、氢氧化钾、碳酸钾或碳酸氢钾;有机碱为三乙胺、吡啶或哌啶。进一步优选氢氧化钠。
优选地,多组分反应的反应温度为20-150℃,进一步优选85℃;反应时间为0.5-3小时,进一步优选为1小时。
R1即可在4位取代也可在5位取代,优选地,所述R1为氢、甲基或氯。甲基在4位取代,氯在5位取代。
优选地,所述R2为氢、甲基、甲氧基、氟、氯、三氟甲基或硝基取代的苯或苄基、丙基,环己基。
优选地,所述不同取代基2-氨基苯乙酮衍生物、异(硫)氰酸苯酯衍生物和催化剂的摩尔比为1:1.1:0.1~0.2。
优选地,所述的有机溶剂为DMF、DMSO、CH3CN、DCE中的一种。
与现有技术相比,本发明具有如下有益效果:
1)本方法采用非金属催化剂,从源头上杜绝金属催化剂的使用,可避免医药化学品中重金属污染;
2)催化剂耐水分和空气,具有潜在的工业化前景;
3)反应原子经济性高,可在空气下进行,且不需要额外氧化剂或添加剂,副产物为水,符合绿色化学理念;
4)所用原料廉价易得、结构多样;
5)底物适用性广,对于含有不同官能团的2-氨基苯乙酮衍生物(II)如式异(硫)氰酸苯酯衍生物(III),均有较佳的收率(最高可达98%),具有较好的应用价值和潜在的社会经济效益。
附图说明
图1为天然产物中喹唑啉酮(常山碱、色胺酮、异常山碱、骆驼宁碱A)化合物结构。
图2为喹唑啉硫酮类化合物研究进展。
图3为现有喹唑啉酮类化合物的合成路线图。
图4为邻乙胺基苯胺和不同酯类化合物反应路线图。
图5为底物水解再分子内亲核反应并行合成喹唑啉酮类化合物路线图。
图6为异氰酸酯作为羰基来源合成喹唑啉酮路线图。
图7为六羰基钼作为羰基来源合成喹唑啉酮路线图。
图8为喹唑啉-2(1H)-硫酮合成路线汇总图。
图9为以2-乙胺基苯胺类化合物为底物合成喹唑啉-2(1H)-硫酮类化合物路线图。
图10为经过还原后再反应生成喹唑啉-2(1H)-硫酮类化合物路线图。
图11为硫氰酸钾,亚磺酰胺基卞氯为合成喹唑啉硫酮路线图。
具体实施方式
以下实施例将有助于理解本发明,但不限于本发明的内容:
实施例(Ia~Il):4-亚甲基-喹唑啉-2(1H)-硫酮(Ia~Il)的制备
将2-氨基苯乙酮(10mmol)、异硫氰酸苯酯(10mmol)的乙腈溶液(10mL)在85℃下搅拌反应90分钟。TLC板进行检测反应,待反应进行完全后,减压蒸馏除去溶剂,并用乙酸乙酯和石油醚(2:1)进行重结晶,得到不同4-亚甲基-喹唑啉-2(1H)-硫酮类似物产物,如表1。
表1
实施例序号 | R<sub>1</sub> | R<sub>2</sub> | 状态 | 收率(%) | 熔点(℃) |
Ia | H | Ph | 黄色粉末 | 98% | 217~218℃ |
Ib | H | 2-CH<sub>3</sub>C<sub>6</sub>H<sub>4</sub> | 棕色粉末 | 58% | 214~215℃ |
Ic | H | 3-OCH<sub>3</sub>C<sub>6</sub>H<sub>4</sub> | 黄色粉末 | 41% | 221~225℃ |
Id | H | 4-OCH<sub>3</sub>C<sub>6</sub>H<sub>4</sub> | 白色粉末 | 53% | 212~214℃ |
Ie | H | 2-ClC<sub>6</sub>H<sub>4</sub> | 黄色粉末 | 65% | 203~205℃ |
If | H | 3-ClC<sub>6</sub>H<sub>4</sub> | 白色粉末 | 75% | 234~236℃ |
Ig | H | 4-ClC<sub>6</sub>H<sub>4</sub> | 白色粉末 | 78% | 240~245℃ |
Ih | H | 2-OCH<sub>3</sub>-5-CH<sub>3</sub>C<sub>6</sub>H<sub>3</sub> | 黄色粉末 | 42% | 236~237℃ |
Ii | H | 3,4-2-ClC<sub>6</sub>H<sub>3</sub> | 白色粉末 | 90% | 236~237℃ |
Ij | H | CH<sub>2</sub>C<sub>6</sub>H<sub>4</sub> | 白色粉末 | 90% | 241~242℃ |
Ik | H | CH<sub>2</sub>CH<sub>2</sub>CH<sub>3</sub> | 白色粉末 | 20% | 168~169℃ |
Il | H | 4-NCSC<sub>6</sub>H<sub>4</sub> | 黄色粉末 | 76% | 236~239℃ |
Ia结构式为:
1H NMR(400MHz,Chloroform-d)δ9.98(s,1H),7.56(dd,J=8.3,6.8Hz,2H),7.52–7.45(m,2H),7.31–7.26(m,3H),7.24(d,J=1.3Hz,1H),7.07(td,J=7.7,1.2Hz,1H),6.91(dd,J=8.0,1.1Hz,1H),4.82(d,J=2.6Hz,1H),3.69(d,J=2.6Hz,1H).13C NMR(101MHz,Chloroform-d)δ174.18,141.83,141.66,133.23,130.65,130.07,128.94,128.67,124.40,123.83,118.26,114.84,90.14.HRMS(ESI)m/z:calc.for C15H13N2S+:253.0794,found253.2068.
Ib结构式为:
1H NMR(500MHz,DMSO-d6)δ11.64(s,1H),7.68(d,J=8.4Hz,1H),7.40–7.36(m,2H),7.36–7.32(m,2H),7.16–7.11(m,2H),7.09(dd,J=7.9,1.2Hz,1H),4.89(d,J=2.1Hz,1H),3.38(d,J=2.2Hz,1H),2.13(s,3H).13C NMR(126MHz,DMSO-d6)δ173.38,140.67,140.62,135.83,134.15,131.68,131.29,129.36,128.86,128.10,124.49,124.42,117.65,115.58,88.04,17.16.HRMS(ESI)m/z:calc.for C16H15N2S+:267.0950,found 257.0933.
Ic结构式为:
1H NMR(500MHz,DMSO-d6)δ11.63(s,1H),7.66(dd,J=8.1,1.3Hz,1H),7.47–7.41(m,1H),7.37(ddd,J=8.4,7.3,1.3Hz,1H),7.14(dd,J=8.1,1.2Hz,1H),7.09(ddd,J=8.3,7.3,1.2Hz,1H),7.03–6.97(m,1H),6.83–6.79(m,2H),4.92(d,J=2.2Hz,1H),3.77(s,3H),3.51(d,J=2.2Hz,1H).13C NMR(126MHz,DMSO-d6)δ173.95,160.93,143.12,141.84,134.13,131.20,130.93,124.40,124.36,121.71,118.04,115.51,115.30,114.15,89.25,55.81.HRMS(ESI)m/z:calc.for C16H15N2OS+:283.0900,found 283.0864.
Id结构式为:
1H NMR(400MHz,Chloroform-d)δ9.19(s,1H),7.54(d,J=8.0Hz,1H),7.33(t,J=7.9Hz,1H),7.22(d,J=8.5Hz,2H),7.16–7.04(m,3H),6.87(s,1H),4.85(d,J=2.1Hz,1H),3.89(s,3H),3.80(d,J=2.1Hz,1H).13C NMR(126MHz,DMSO-d6)δ174.47,159.01,142.36,134.93,134.14,131.18,130.57,124.44,124.34,118.05,115.50,115.39,89.18,55.76.HRMS(ESI)m/z:calc.for C16H15N2OS+:283.0900,found 283.0912.
Ie结构式为:
1H NMR(500MHz,DMSO-d6)δ11.76(s,1H),7.70(d,J=8.0Hz,1H),7.65(dd,J=7.8,1.8Hz,1H),7.55–7.45(m,2H),7.44–7.36(m,2H),7.17–7.08(m,2H),4.93(d,J=2.6Hz,1H),3.38(d,J=2.6Hz,1H).13C NMR(126MHz,DMSO-d6)δ173.56,140.37,138.85,133.99,132.29,132.00,131.38,130.96,130.54,129.24,124.56,124.52,117.66,115.68,88.17.HRMS(ESI)m/z:calc.for C15H12ClN2S+:287.0404,found 287.0389.
If结构式为:
1H NMR(400MHz,DMSO-d6)δ11.79(d,J=2.5Hz,1H),7.69(t,J=7.7Hz,1H),7.59(,J=7.9,2.6Hz,1H),7.56–7.49(m,1H),7.46–7.35(m,2H),7.27(dt,J=7.8,1.6Hz,1H),7.21–7.16(m,1H),7.12(dd,J=9.8,5.6Hz,1H),4.96(d,J=4.1,2.2Hz,1H),3.46(d,J=2.5Hz,1H).13C NMR(101MHz,DMSO-d6)δ173.93,143.32,141.91,134.21,134.06,131.86,131.30,129.90,128.81,128.77,124.49,124.42,118.03,115.64,89.35.HRMS(ESI)m/z:calc.for C15H12ClN2S+:287.0404,found 287.0423.
Ig结构式为:
1H NMR(500MHz,DMSO-d6)δ11.72(s,1H),7.68(dd,J=8.2,1.4Hz,1H),7.61–7.57(m,2H),7.38(ddd,J=8.4,7.2,1.3Hz,1H),7.31–7.26(m,2H),7.15(dd,J=8.1,1.2Hz,1H),7.10(ddd,J=8.3,7.3,1.3Hz,1H),4.94(d,J=2.4Hz,1H),3.45(d,J=2.5Hz,1H).13CNMR(126MHz,DMSO-d6)δ174.01,141.96,141.00,134.06,133.08,131.74,131.30,130.43,124.49,124.45,118.00,115.61,89.33.HRMS(ESI)m/z:calc.for C15H12ClN2S+:287.0404,found 287.0367.
Ih结构式为:
1H NMR(500MHz,DMSO-d6)δ11.54(s,1H),7.64(dd,J=8.1,1.3Hz,1H),7.35(ddd,J=8.4,7.3,1.3Hz,1H),7.23–7.19(m,1H),7.12(dd,J=8.2,1.2Hz,1H),7.10–7.05(m,2H),6.95(dd,J=2.2,0.8Hz,1H),4.82(d,J=2.1Hz,1H),3.71(s,3H),3.50(d,J=2.1Hz,1H),2.28(s,3H).13C NMR(126MHz,DMSO-d6)δ174.12,152.82,140.82,134.17,131.13,130.83,130.60,130.52,129.80,124.42,124.30,117.86,115.47,113.43,87.98,56.21,20.42.HRMS(ESI)m/z:calc.for C17H17N2OS+:297.1056,found 297.1023.
Ii结构式为:
1H NMR(500MHz,DMSO-d6)δ11.82(s,1H),7.85(d,J=2.3Hz,1H),7.71(dd,J=8.1,1.3Hz,1H),7.60(dd,J=8.5,2.4Hz,1H),7.48(d,J=8.5Hz,1H),7.39(ddd,J=8.4,7.2,1.3Hz,1H),7.18–7.13(m,1H),7.11(dd,J=8.1,1.1Hz,1H),4.96(d,J=2.7Hz,1H),3.45(d,J=2.8Hz,1H).13C NMR(126MHz,DMSO-d6)δ173.48,140.17,138.00,134.16,133.91,133.65,133.46,131.44,130.64,129.54,124.66,124.55,117.61,115.75,88.33.HRMS(ESI)m/z:calc.for C15H11Cl2N2S+:321.0015,found 321.0023.
Ij结构式为:
1H NMR(500MHz,DMSO-d6)δ11.65(s,1H),7.60(dd,J=8.1,1.3Hz,1H),7.37–7.27(m,5H),7.27–7.21(m,1H),7.14(dd,J=8.1,1.2Hz,1H),7.07(ddd,J=8.3,7.3,1.2Hz,1H),5.68(s,2H),4.98(d,J=2.9Hz,1H),4.31(d,J=2.9Hz,1H).13C NMR(126MHz,DMSO-d6)δ174.87,138.11,136.39,133.73,131.01,128.93,127.28,126.59,124.59,124.27,118.02,115.42,89.39,52.81.HRMS(ESI)m/z:calc.for C16H15N2S+:267.0950,found267.0932.
Ik结构式为:
1H NMR(500MHz,DMSO-d6)δ11.35(s,1H),7.65(dd,J=8.3,1.3Hz,1H),7.33–7.28(m,1H),7.08–7.04(m,2H),5.05(d,J=2.9Hz,1H),4.52(d,J=2.9Hz,1H),4.25(s,2H),1.78–1.68(m,2H),0.92(t,J=7.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ173.70,138.33,133.85,130.88,124.37,124.34,118.06,115.18,87.82,50.78,18.16,11.31.HRMS(ESI)m/z:(M+H+);calc.for C12H15N2S+:219.0950,found 219.0938.
ll结构式为:
1H NMR(500MHz,DMSO-d6)δ11.74(s,1H),7.68(dd,J=8.1,1.3Hz,1H),7.61–7.56(m,2H),7.38(ddd,J=9.5,6.7,1.4Hz,1H),7.35–7.32(m,2H),7.15(dd,J=8.1,1.2Hz,1H),7.10(ddd,J=8.3,7.2,1.2Hz,1H),4.94(d,J=2.4Hz,1H),3.43(d,J=2.5Hz,1H).13CNMR(126MHz,DMSO-d6)δ173.92,141.93,141.31,134.70,134.05,131.51,131.32,130.13,128.00,124.50,124.45,118.00,115.63,89.35.HRMS(ESI)m/z:calc.for C16H13N3S2 +:310.0467,found 310.0421.
实施例IAa~IAs:4-亚甲基-喹唑啉-2(1H)-酮(IAa~IAs)的制备
将2-氨基苯乙酮(10mmol)、异氰酸酯(10mmol)、催化剂(10%mmol)的乙腈溶液(10mL)在85℃下搅拌反应60分钟。TLC板进行检测反应,待反应进行完全后,减压蒸馏除去溶剂,并用乙酸乙酯和石油醚(2:1)进行重结晶,得到不同4-亚甲基-喹唑啉-2(1H)-酮类似物产物,如表2。
表2
IAa结构式为:
1H NMR(400MHz,Chloroform-d)δ8.18(s,1H),7.59–7.49(m,3H),7.47–7.40(m,1H),7.35–7.28(m,2H),7.24(dd,J=7.9,1.3Hz,1H),7.06–6.96(m,1H),6.72(dd,J=8.1,1.2Hz,1H),4.74(d,J=2.2Hz,1H),3.68(d,J=2.2Hz,1H).13C NMR(101MHz,Chloroform-d)δ150.88,143.31,138.42,135.16,130.27,129.94,129.19,128.34,123.94,122.73,117.03,115.09,87.43,.HRMS(ESI)m/z:calc.for C15H13N2O+:237.1022,found 237.1908.
IAb结构式为:
1H NMR(500MHz,DMSO-d6)δ10.30(s,1H),7.68(dd,J=8.1,1.3Hz,1H),7.42–7.37(m,1H),7.37–7.30(m,3H),7.19–7.15(m,1H),7.01(td,J=7.8,1.2Hz,1H),6.96(dd,J=8.1,1.2Hz,1H),4.75(d,J=1.8Hz,1H),3.33(d,J=1.8Hz,1H),2.11(s,3H).13C NMR(126MHz,DMSO-d6)δ149.27,142.44,137.75,136.56,136.42,131.50,130.90,129.77,128.77,127.89,124.63,122.61,116.29,115.29,85.21,17.19.HRMS(ESI)m/z:calc.forC16H15N2O+:251.1179,found 251.1121.
IAc结构式为:
1H NMR(500MHz,DMSO-d6)δ10.27(s,1H),7.65(dd,J=8.0,1.3Hz,1H),7.40(t,J=7.7Hz,1H),7.31(ddd,J=8.4,6.0,1.4Hz,1H),7.25–7.22(m,1H),7.09–7.03(m,2H),6.99(ddd,J=8.3,7.2,1.2Hz,1H),6.95(dd,J=8.1,1.2Hz,1H),4.76(d,J=1.8Hz,1H),3.43(d,J=1.8Hz,1H),2.35(s,3H).13C NMR(126MHz,DMSO-d6)δ149.71,143.72,139.63,139.04,136.37,130.82,130.16,129.92,129.07,126.71,124.53,122.57,116.59,115.22,86.38,21.24.HRMS(ESI)m/z:calc.for C16H15N2O+:251.1179,found 251.1098.
IAd结构式为:
1H NMR(500MHz,DMSO-d6)δ10.26(s,1H),7.66(dd,J=8.1,1.3Hz,1H),7.36(d,J=8.4Hz,1H),7.31(td,J=8.0Hz,1.2Hz,1H),7.15–7.11(m,2H),7.05(d,J=8.3Hz,1H),7.00(td,J=8.1Hz,1.2Hz,1H),6.94(d,J=7.9Hz,1H),4.76(d,J=1.8Hz,1H),3.43(d,J=1.8Hz,1H),2.37(s,3H).13C NMR(126MHz,DMSO-d6)δ149.77,143.81,138.18,137.74,136.49,136.36,130.83,130.65,129.49,124.56,122.56,118.61,116.58,115.20,86.25,21.21.HRMS(ESI)m/z:calc.for C16H15N2O+:251.1179,found 251.1093.
IAe结构式为:
1H NMR(500MHz,DMSO-d6)δ10.42(s,1H),7.69(dd,J=8.1,1.3Hz,1H),7.55–7.48(m,1H),7.46–7.39(m,2H),7.39–7.31(m,2H),7.03(ddd,J=8.3,7.3,1.2Hz,1H),6.97(dd,J=8.1,1.3Hz,1H),4.82(d,J=2.2Hz,1H),3.48(dd,J=2.2,0.8Hz,1H).13C NMR(126MHz,DMSO-d6)δ158.65(d,J=248Hz),149.25,142.67,136.14,132.07,131.07,130.98(d,J=7.6Hz),126.12(d,J=12.6Hz),125.97(d,J=3.8Hz),124.66,122.85,117.15(d,J=18.9Hz),116.21,115.41,85.80.HRMS(ESI)m/z:calc.for C15H12FN2O+:255.0928,found255.0876.
IAf结构式为:
1H NMR(600MHz,DMSO-d6)δ10.37(s,1H),7.68(dd,J=8.1,1.3Hz,1H),7.60–7.54(m,1H),7.35–7.27(m,2H),7.24(dt,J=9.7,2.2Hz,1H),7.15(dd,J=7.8,1.0Hz,1H),7.01(ddd,J=8.3,7.4,1.2Hz,1H),6.95(dd,J=8.1,1.2Hz,1H),4.81(d,J=2.1Hz,1H),3.44(d,J=2.1Hz,1H).13C NMR(151MHz,DMSO-d6)δ163.18(d,J=245Hz),149.52,143.48,140.70(d,J=9.1Hz),136.23,131.64(d,J=9.1Hz),130.93,126.23(d,J=3.0Hz),124.57,122.67,117.32(d,J=22.7Hz),116.51,115.56(d,J=21Hz),115.28,86.47.HRMS(ESI)m/z:calc.for C15H12FN2O+:255.0928,found 255.0885.
IAg结构式为:
1H NMR(500MHz,DMSO-d6)δ10.33(s,1H),7.67(dd,J=8.1,1.3Hz,1H),7.36–7.30(m,5H),7.01(ddd,J=8.2,7.3,1.2Hz,1H),6.95(dd,J=8.1,1.2Hz,1H),4.79(d,J=2.0Hz,1H),3.42(d,J=2.0Hz,1H).13C NMR(126MHz,DMSO-d6)δ161.80(d,J=246Hz),149.74,143.82,136.29,135.31(d,J=2.5Hz),131.97(d,J=8.8Hz),130.90,124.58,122.63,117.02(d,J=22.7Hz),116.54,115.27,86.38.HRMS(ESI)m/z:calc.for C15H12FN2O+:255.0928,found 255.0943.
IAh结构式为:
1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),7.71(ddd,J=9.3,7.2,1.9Hz,2H),7.58–7.44(m,3H),7.36(ddd,J=8.3,7.4,1.3Hz,1H),7.09–6.98(m,2H),4.82(d,J=2.2Hz,1H),3.35(d,J=2.2Hz,1H).13C NMR(101MHz,DMSO-d6)δ149.10,142.19,136.30,136.22,133.08,132.16,131.00,130.84,130.55,129.17,124.64,122.75,116.26,115.47,85.50.HRMS(ESI)m/z:calc.for C15H12ClN2O+:271.0633,found 271.0598.
IAi结构式为:
1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),7.70(dd,J=8.1,1.3Hz,1H),7.63–7.51(m,2H),7.46(t,J=2.0Hz,1H),7.39–7.29(m,2H),7.08–6.95(m,2H),4.84(d,J=2.1Hz,1H),3.44(d,J=2.1Hz,1H).13C NMR(101MHz,DMSO-d6)δ149.57,143.58,140.56,136.28,134.12,131.75,130.95,130.12,128.91,128.67,124.58,122.69,116.54,115.36,86.54.HRMS(ESI)m/z:271.0569(M+H+);calc.for C15H12ClN2O+:271.0633,found271.0569.
IAj结构式为:
1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),7.70(dd,J=8.1,1.3Hz,1H),7.64–7.57(m,2H),7.40–7.31(m,3H),7.08–6.96(m,2H),4.83(d,J=2.1Hz,1H),3.45(d,J=2.1Hz,1H).13C NMR(101MHz,DMSO-d6)δ149.61,143.63,138.05,136.29,133.00,131.90,130.93,130.27,124.58,122.67,116.54,115.33,86.49.HRMS(ESI)m/z:calc.for C15H12ClN2O+:271.0633,found 271.0896.
IAk结构式为:
1H NMR(500MHz,DMSO-d6)δ10.42(s,1H),7.91(dd,J=7.9,1.5Hz,1H),7.86(td,J=7.8,1.5Hz,1H),7.70(td,J=8.5,1.4Hz,2H),7.53(d,J=7.8Hz,1H),7.34(ddd,J=7.8,7.3,1.3Hz,1H),7.02(ddd,J=7.8,7.4,1.3Hz,1H),6.97(dd,J=8.1,1.3Hz,1H),4.84(d,J=2.3Hz,1H),3.26(d,J=2.4Hz,1H).13C NMR(126MHz,DMSO-d6)δ149.53,143.52,136.70,136.12,134.73,133.11,130.98,129.79,128.16(m),127.83,124.87,124.53,122.76,116.34,115.40,86.66.HRMS(ESI)m/z:calc.for C16H13F3N2O+:305.0896,found 305.0822.
IAl结构式为:
1H NMR(500MHz,DMSO-d6)δ10.31(s,1H),7.69(dd,J=8.1,1.3Hz,1H),7.32(ddd,J=8.3,7.3,1.3Hz,1H),7.00(d,J=4.7Hz,3H),6.99–6.95(m,1H),4.70(d,J=1.7Hz,1H),3.37(d,J=1.6Hz,1H),2.29(s,3H),2.04(s,6H).13C NMR(126MHz,DMSO-d6)δ148.95,141.08,137.57,136.51,135.94,133.93,130.90,129.66,124.71,122.59,116.03,115.32,83.80,21.07,17.37.HRMS(ESI)m/z:calc.for C18H19N2O+:279.1492,found 279.1421.
IAm结构式为:
1H NMR(500MHz,DMSO-d6)δ10.33(s,1H),7.69(dd,J=8.2,1.3Hz,1H),7.39–7.29(m,2H),7.25(d,J=7.6Hz,2H),7.01(ddd,J=8.3,7.3,1.2Hz,1H),6.97(dd,J=8.1,1.2Hz,1H),4.74(d,J=1.7Hz,1H),3.31(d,J=1.8Hz,1H),2.42(q,J=7.5Hz,4H),1.12(t,J=7.6Hz,6H).13C NMR(126MHz,DMSO-d6)δ149.43,142.12,141.77,136.44,135.36,132.56,130.97,128.88,127.15,124.68,122.66,120.86,116.00,115.32,84.83,24.84,23.79,15.07,14.50.HRMS(ESI)m/z:calc.for C19H21N2O+:293.1648,found 293.1606.
IAn结构式为:
1H NMR(500MHz,DMSO-d6)δ10.46(s,1H),7.70(dd,J=8.0,1.3Hz,1H),7.55–7.47(m,2H),7.34(ddd,J=8.4,7.3,1.3Hz,1H),7.28–7.22(m,1H),7.03(ddd,J=8.2,7.3,1.2Hz,1H),6.97(dd,J=8.1,1.2Hz,1H),4.84(d,J=2.4Hz,1H),3.52(d,J=2.3Hz,1H).13CNMR(126MHz,DMSO-d6)δ162.30(dd,J=247.5,11.8Hz),158.86(dd,J=251.1,13.2Hz),149.26,142.64,136.08,133.28(dd,J=9.9,2.1Hz),131.11,124.69,122.89,122.70(dd,J=13.4,4.0Hz),116.18,115.44,113.07(dd,J=22.5,3.6Hz),105.78(dd,J=27.1,24.1Hz),85.90.HRMS(ESI)m/z:(M+H+);calc.forC15H11F2N2O+:273.0834,found 273.0789.
IAo结构式为:
1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),7.82(dd,J=8.5,1.2Hz,1H),7.76–7.67(m,2H),7.41–7.31(m,2H),7.09–7.00(m,1H),6.98(dd,J=8.1,1.2Hz,1H),4.85(d,J=2.3Hz,1H),3.49(d,J=2.3Hz,1H).13C NMR(101MHz,DMSO-d6)δ149.53,143.45,139.15,136.28,132.36,132.08,131.33,130.97,130.67,124.59,122.71,116.53,115.41,86.71.HRMS(ESI)m/z:calc.for C15H11Cl2N2O+:305.0243,found 305.0185.
IAp结构式为:
1H NMR(500MHz,DMSO-d6)δ10.28(s,1H),7.62(d,J=8.1Hz,1H),7.36–7.19(m,6H),7.00–6.92(m,2H),5.01(s,2H),4.82(d,J=2.4Hz,1H),4.12(d,J=2.5Hz,1H).13C NMR(126MHz,DMSO-d6)δ150.60,140.23,137.50,136.08,130.65,128.92,127.21,126.81,124.40,122.62,116.46,115.12,85.70,46.30.HRMS(ESI)m/z:calc.for C16H15N2O+:251.1179,found 251.1085.
IAq结构式为:
1H NMR(500MHz,DMSO-d6)δ10.06(s,1H),7.65(dd,J=8.2,1.3Hz,1H),7.26(ddd,J=8.4,7.2,1.3Hz,1H),6.96(ddd,J=8.2,7.3,1.3Hz,1H),6.87(dd,J=8.1,1.2Hz,1H),4.87(d,J=2.3Hz,1H),4.28(d,J=2.4Hz,1H),3.70(t,J=7.6Hz,2H),1.65–1.55(m,2H),0.89(t,J=7.4Hz,3H).13C NMR(126MHz,DMSO-d6)δ150.07,140.25,136.15,130.51,124.45,122.41,116.51,114.90,84.02,44.26,18.91,11.57.HRMS(ESI)m/z:calc.forC12H15N2S+:203.1179,found 203.1089.
IAr结构式为:
1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),7.58(dd,J=8.0,1.3Hz,1H),7.25(td,J=7.6,1.3Hz,1H),7.01–6.89(m,1H),6.87(dd,J=8.1,1.2Hz,1H),4.89(d,J=2.4Hz,1H),4.53(d,J=2.4Hz,1H),3.84(tt,J=12.0,3.6Hz,1H),2.39(qd,J=12.5,3.6Hz,2H),1.82–1.62(m,4H),1.45–1.01(m,4H).13C NMR(101MHz,DMSO-d6)δ150.56,142.08,136.27,130.15,124.40,122.27,118.46,114.34,88.15,58.37,29.02,26.42,25.70.HRMS(ESI)m/z:calc.for C15H19N2O+:243.1492,found 243.1464.
IAs结构式为:
1H NMR(500MHz,DMSO-d6)δ11.75(s,1H),7.69(dd,J=8.1,1.4Hz,1H),7.57(t,J=7.9Hz,1H),7.53–7.49(m,1H),7.43–7.34(m,2H),7.28–7.22(m,1H),7.15(dd,J=8.1,1.3Hz,1H),7.13–7.08(m,1H),4.95(d,J=2.5Hz,1H),3.44(d,J=2.5Hz,1H).13C NMR(126MHz,DMSO-d6)δ173.93,143.32,141.91,134.18,134.05,131.85,131.30,129.90,128.81,128.79,124.49,124.43,118.03,115.63,89.34.HRMS(ESI)m/z:calc.forC16H12N3O2 +:278.0924,found 278.0882.
实施例IBa~IBe:4-亚甲基-喹唑啉-2(1H)-酮(IBa~IBe)的制备
将2-氨基-5-氯-苯乙酮(10mmol)、异氰酸苯酯(IIIBa~IIIBe)(10mmol)、氢氧化钠(10%mmol)的乙腈溶液(10mL)在85℃下搅拌反应60分钟。TLC板进行检测反应,待反应进行完全后,减压蒸馏除去溶剂,并用乙酸乙酯和石油醚(2:1)进行重结晶,得到不同4-亚甲基-喹唑啉-2(1H)-酮类似物产物(表3)。
表3
实施例序号 | R<sub>1</sub> | R<sub>2</sub> | 状态 | 收率(%) | 熔点(℃) |
IBa | 5-Cl | 2-F | 白色粉末 | 98% | 258.9~261.3℃ |
IBb | 5-Cl | 3-Cl | 白色粉末 | 80% | 245.6~247.2℃ |
IBc | 5-Cl | 3-CH<sub>3</sub> | 白色粉末 | 91% | 201.7~202.4℃ |
IBd | 5-Cl | 2-CH<sub>3</sub> | 白色粉末 | 40% | 221.2~222.9℃ |
IBe | 5-Cl | CH<sub>2</sub>C<sub>6</sub>H<sub>5</sub> | 白色粉末 | 92% | 214.8~215.9℃ |
IBa结构式为:
1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),7.80(d,J=2.3Hz,1H),7.56–7.48(m,1H),7.47–7.32(m,4H),6.99(dd,J=8.7,1.9Hz,1H),4.94(d,J=2.4Hz,1H),3.52(d,J=2.5Hz,1H).13C NMR(101MHz,DMSO-d6)δ158.58(d,J=249.0Hz),149.05,141.55,135.32,132.01,131.08(d,J=8.0Hz),130.87,126.79,126.01(d,J=3.9Hz),125.86,124.15,117.97,117.32(d,J=9.7Hz),117.08,87.28.HRMS(ESI)m/z:calc.for C16H14FN2O+:289.0538,found 289.0552.
IBb结构式为:
1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),7.78(d,J=2.3Hz,1H),7.61–7.48(m,2H),7.45(t,J=1.9Hz,1H),7.38(dd,J=8.6,2.3Hz,1H),7.29(dt,J=7.6,1.7Hz,1H),6.96(d,J=8.6Hz,1H),4.94(d,J=2.4Hz,1H),3.47(d,J=2.5Hz,1H).13C NMR(101MHz,DMSO-d6)δ149.28,142.39,140.29,135.23,134.14,131.78,130.75,130.04,128.82,128.76,126.69,124.10,118.31,117.10,88.14.HRMS(ESI)m/z:calc.for C15H11Cl2N2O+:305.0243,found 305.0229.
IBc结构式为:
1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),7.74(d,J=2.3Hz,1H),7.45–7.32(m,2H),7.24(d,J=7.7Hz,1H),7.11–7.02(m,2H),6.96(d,J=8.6Hz,1H),4.88(d,J=2.2Hz,1H),3.49(d,J=2.2Hz,1H),2.35(s,3H).13C NMR(101MHz,DMSO-d6)δ149.44,142.53,139.70,138.79,135.35,130.63,130.08,129.97,129.17,126.63,126.57,124.03,118.34,117.02,87.93,21.23.HRMS(ESI)m/z:calc.for C16H14ClN2O+:287.0795,found 287.0802.
IBd结构式为:
1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),7.79(d,J=2.3Hz,1H),7.42–7.32(m,5H),7.20–7.15(m,1H),6.96(d,J=8.6Hz,1H),4.88(d,J=2.1Hz,1H),3.36(d,J=2.2Hz,2H),2.10(s,3H).13C NMR(101MHz,DMSO-d6)δ148.99,141.27,137.48,136.50,135.39,131.55,130.75,129.71,128.89,127.95,126.65,124.17,118.06,117.10,86.86,17.15.HRMS(ESI)m/z:calc.for C16H14FN2O+:285.0789,found 285.0762.
IBe结构式为:
1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),7.71(d,J=2.2Hz,1H),7.33(dd,J=8.8,6.8Hz,3H),7.27–7.21(m,3H),6.95(d,J=8.6Hz,1H),4.99(s,2H),4.93(d,J=2.8Hz,1H),4.17(d,J=2.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ150.34,139.05,137.27,135.09,130.48,128.95,127.27,126.82,126.62,123.93,118.24,116.97,87.35,46.33.HRMS(ESI)m/z:calc.for C16H14ClN2O+:285.0789,found 285.0776.
实施例Ica~ICd:4-亚甲基-喹唑啉-2(1H)-酮(ICa~ICd)的制备
将2-氨基-4-甲基-苯乙酮(10mmol)、异氰酸苯酯(IIICa~IIICd)(10mmol)、氢氧化钠(10%mmol)的乙腈溶液(10mL)在85℃下搅拌反应60分钟。TLC板进行检测反应,待反应进行完全后,减压蒸馏除去溶剂,并用乙酸乙酯和石油醚(2:1)进行重结晶,得到不同4-亚甲基-喹唑啉-2(1H)-酮类似物产物(表4)。
表4
实施例序号 | R<sub>1</sub> | R<sub>2</sub> | 状态 | 收率(%) | 熔点(℃) |
ICa | 4-CH<sub>3</sub> | 3-Cl | 白色粉末 | 68% | 214.8~215.9℃ |
ICb | 4-CH<sub>3</sub> | 2-F | 白色粉末 | 93% | 224.3~224.9℃ |
ICc | 4-CH<sub>3</sub> | 3-CH<sub>3</sub> | 墨绿色粉末 | 55% | 161.3~163.6℃ |
ICd | 4-CH<sub>3</sub> | CH<sub>2</sub>C<sub>6</sub>H<sub>5</sub> | 白色粉末 | 52% | 236.8~238.4℃ |
ICa结构式为:
1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),7.60–7.48(m,3H),7.45–7.39(m,1H),7.27(dt,J=7.7,1.7Hz,1H),6.84(dd,J=8.2,1.7Hz,1H),6.75(s,1H),4.74(d,J=2.0Hz,1H),3.35(d,J=2.0Hz,1H),2.28(s,3H).13C NMR(101MHz,DMSO-d6)δ149.66,143.54,140.75,140.54,136.14,134.08,131.70,130.11,128.90,128.63,124.53,123.75,115.28,114.02,85.57,21.38.HRMS(ESI)m/z:calc.for C16H14ClN2O+:285.0789,found 285.0762.
ICb结构式为:
1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),7.57(d,J=8.1Hz,1H),7.55–7.48(m,1H),7.45–7.39(m,2H),7.35(ddd,J=7.9,7.2,1.4Hz,1H),4.75(d,J=2.1Hz,1H),3.43(d,J=2.1Hz,1H),2.08(s,2H).13C NMR(101MHz,DMSO-d6)δ156.56(d,J=247Hz),147.29,140.58,138.80,133.98,129.98,128.81(d,J=8.0Hz),124.08(d,J=13.3Hz),123.80(d,J=3.5Hz),122.48,121.78,115.02(d,J=19.7Hz),113.29,111.62,82.67,19.26.HRMS(ESI)m/z:calc.for C16H14FN2O+:269.1085,found 269.1062.
ICc结构式为:
1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),7.54(d,J=8.1Hz,1H),7.40(t,J=7.7Hz,1H),7.23(d,J=7.7Hz,1H),7.09–7.01(m,2H),6.82(dd,J=8.2,1.7Hz,1H),6.74(s,1H),4.69(d,J=1.7Hz,1H),3.36(d,J=1.7Hz,1H),2.35(s,3H),2.28(s,3H).13C NMR(101MHz,DMSO-d6)δ149.82,143.69,140.61,139.60,139.05,136.26,130.18,129.89,129.04,126.73,124.48,123.64,115.19,114.07,85.39,21.37,21.22.HRMS(ESI)m/z:calc.for C17H17N2O+:265.1335,found 265.1358.
ICd结构式为:
1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),7.50(d,J=8.2Hz,1H),7.32(t,J=7.5Hz,2H),7.28–7.19(m,3H),6.79(dd,J=8.2,1.7Hz,1H),6.75(s,1H),4.99(s,2H),4.74(d,J=2.3Hz,1H),4.06(d,J=2.4Hz,1H),2.26(s,3H).13C NMR(101MHz,DMSO-d6)δ150.72,140.41,140.22,137.58,135.99,128.91,127.18,126.78,124.36,123.68,115.12,113.94,84.68,46.23,21.33.HRMS(ESI)m/z:calc.for C17H17N2O+:265.1335,found 265.1326.
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员,在不脱离本发明构思的前提下,还可以做出若干改进和润色,这些改进和润色也应视为本发明的保护范围内。
Claims (3)
1.一种4-亚甲基喹唑啉(硫)酮类化合物的制备方法,其特征在于,包括如下步骤:
将如式(II)所示的不同取代基2-氨基苯乙酮衍生物、如式(III)所示的异(硫)氰酸苯酯衍生物溶于有机溶剂中,进行多组分反应,一锅法制得如式(I)所示的4-亚甲基喹唑啉-2(1H)-(硫)酮类化合物;当X为O时,在催化剂作用下进行多组分反应,所述催化剂为无机碱或有机碱中的一种;多组分反应的反应温度为20-150℃,反应时间为0.5-30小时;
式中R1为氢、甲基或氯;R2为苯基、取代基取代的苯基或苄基,所述的取代基为甲基、甲氧基、氟、氯、三氟甲基或硝基;
所述无机碱为氢氧化钠、碳酸钠、碳酸氢钠、氢氧化钾、碳酸钾或碳酸氢钾;有机碱为三乙胺、吡啶或哌啶。
2.根据权利要求1所述制备方法,其特征在于,所述不同取代基2-氨基苯乙酮衍生物、异(硫)氰酸苯酯衍生物和催化剂的摩尔比为1:1.1:0.1~0.2。
3.根据权利要求1所述制备方法,其特征在于,所述的有机溶剂为DMF、DMSO、CH3CN、DCE中的一种。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910453343.6A CN110229109B (zh) | 2019-05-28 | 2019-05-28 | 一种4-亚甲基喹唑啉(硫)酮类化合物的制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910453343.6A CN110229109B (zh) | 2019-05-28 | 2019-05-28 | 一种4-亚甲基喹唑啉(硫)酮类化合物的制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110229109A CN110229109A (zh) | 2019-09-13 |
CN110229109B true CN110229109B (zh) | 2020-10-16 |
Family
ID=67858731
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910453343.6A Active CN110229109B (zh) | 2019-05-28 | 2019-05-28 | 一种4-亚甲基喹唑啉(硫)酮类化合物的制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110229109B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112624984B (zh) * | 2020-12-24 | 2022-06-10 | 内蒙古工业大学 | 一种4-硫代喹唑啉二酮类衍生物及制备方法 |
-
2019
- 2019-05-28 CN CN201910453343.6A patent/CN110229109B/zh active Active
Also Published As
Publication number | Publication date |
---|---|
CN110229109A (zh) | 2019-09-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Faidallah et al. | Synthesis and biological evaluation of new barbituric and thiobarbituric acid fluoro analogs of benzenesulfonamides as antidiabetic and antibacterial agents | |
DE69913047T2 (de) | Verfahren zur Herstellung von Benzamid-Derivaten | |
JPS6236370A (ja) | チアジアジニル誘導体及びその製法 | |
CN103965120A (zh) | 喹啉及喹唑啉衍生物、制备方法、中间体、组合物及应用 | |
FR2900404A1 (fr) | Nouveaux derives d'imidazoles, leur preparation et leur utilisation en tant que medicament | |
Badawey et al. | Benzimidazole condensed ring systems. XI. Synthesis of some substituted cycloalkyl pyrido [1, 2-a] benzimidazoles with anticipated antineoplastic activity | |
Shi et al. | An efficient synthesis of quinazoline-2, 4-dione derivatives with the aid of a low-valent titanium reagent | |
CN111269197A (zh) | 苯并噻嗪酮化合物及其制备方法与作为抗结核药物的应用 | |
CN110229109B (zh) | 一种4-亚甲基喹唑啉(硫)酮类化合物的制备方法 | |
CN111303075A (zh) | 苯并噻嗪酮衍生物及其制备方法与作为抗结核药物的应用 | |
Maged et al. | Synthesis and spectroscopic characterization of new heterocyclic compounds derivatied from 1-(4-aminophenyl) ethan-1-oneoxime as a starting material with evaluate their biological activity | |
Jarallah et al. | Synthesis, characterization of heterocyclic compounds and preliminary evaluation of their antibacterial activity and antioxidant agents | |
Mohamadpour | Pectin as a natural biopolymer catalyst promoted green synthesis of dihydropyrano [2, 3-c] pyrazole derivatives in aqueous ethanol media | |
Mohammad et al. | Synthesis and characterization of some new (1, 3-Oxazepine) derivative from 6-methyl 2-thiouracil and study their biological activity | |
CN109912520A (zh) | 一种1,5-苯并二氮杂卓化合物及其制备方法 | |
Li et al. | Synthesis and bioactivity of a novel series of 3, 6-disubstituted 1, 2, 4-triazolo [3, 4-b]-1, 3, 4-thiadiazoles | |
Liu et al. | Environmentally friendly approach to convergent synthesis of highly functionalized indanone fused multicyclic pyrrolines | |
Wang et al. | One-pot synthesis of 2, 3-dihydro-2-thioxoquinazolin-4 (1H)-ones from nitro-compounds with the aid of tin (II) chloride. | |
CN103265497B (zh) | 一种替尼类抗肿瘤药合成所需中间体4-氯-6-氨基-7-羟基喹唑啉及其制备方法 | |
Paronikyan et al. | Synthesis and Biological Activity of Partially Hydrogenated 1-Aminopyrimido [4, 5-c] isoquinoline Derivatives | |
Pittalà et al. | 3-Arylpiperazinylethyl-1H-pyrrolo [2, 3-d] pyrimidine-2, 4 (3H, 7H)-dione derivatives as novel, high-affinity and selective α1-adrenoceptor ligands | |
Megahed et al. | Synthesis and Antimicrobial Activity of Methyl 2‐(2‐(2‐Arylquinazolin‐4‐yl) sulfanyl) acetylamino Alkanoates | |
Amer | Antibacterial Activity of New Synthesized Derivatives 3-Substituted Imidazo Benzothiazole from 2-amino-benzothiazole | |
Srivastava et al. | Synthesis and characterization of new thiazole involving isatin for studying their antimicrobial activity | |
BRPI0613693A2 (pt) | aminas 8-alcóxi-4-metil-3,4-diidro-quinazolin-2-ila e seus usos como ligantes do receptor da 5-ht5a |
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 | ||
TR01 | Transfer of patent right |
Effective date of registration: 20220706 Address after: 318000 room 1913-2, building 2, East Tengda center, Baiyun Street, Taizhou City, Zhejiang Province Patentee after: Taizhou Tongxu Biotechnology Co.,Ltd. Address before: 318000 No. 1139, Shifu Road, Jiaojiang District, Taizhou, Zhejiang. Patentee before: TAIZHOU University |
|
TR01 | Transfer of patent right |