CN108033969B - 一种氧化吲哚螺四氢呋喃化合物及其制备方法和用途 - Google Patents
一种氧化吲哚螺四氢呋喃化合物及其制备方法和用途 Download PDFInfo
- Publication number
- CN108033969B CN108033969B CN201711165992.3A CN201711165992A CN108033969B CN 108033969 B CN108033969 B CN 108033969B CN 201711165992 A CN201711165992 A CN 201711165992A CN 108033969 B CN108033969 B CN 108033969B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- preparation
- nmr
- ppm
- 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
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—Spiro-condensed systems
-
- 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
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种如式(Ⅰ)所示的氧化吲哚螺四氢呋喃化合物或其晶型:其中,R1选自苯环、萘环、噻吩环或肉桂基;R2选自H、F、Cl、Br、I或C1‑3的烷氧基;R3选自H、苄基或C1~C3的烷基;R4选自H、F、Cl、Br、I、C1‑3的烷氧基或C1~C3的烷基。本发明还提供了制备前述化合物的方法;本发明的化合物制备方法简便、反应温和、收率高,并且具有抗肿瘤活性,具有广阔的市场应用前景。
Description
技术领域
本发明涉及一种氧化吲哚螺四氢呋喃化合物及其制备方法和用途。
背景技术
氧化吲哚螺环化合物多含有电负强的氧和氮等杂原子,可以与其它生物大分子分之间有较大的分子间作用力,因此是一类重要的类药性骨架。
近年来,国内外学者越来越重视该领域的研究,合成了成千上万种具有氧化吲哚螺环骨架的化合物,期望可以从中筛选出了一批有药效的化合物。许多人工合成的螺环化合物(包括天然提取物中得到的螺环化合物)一般都是消旋化合物,而其中的R构型和S构型的药理和毒理是不一样的。但是从天然产物中分离出来或是通过传统方法化学合成的吲哚螺环产物几乎都是消旋体,或者立体选择性不高。
目前,常通过手性催化剂介导的有机串联反应不对称合成氧化吲哚螺环化合物,以改善氧化吲哚螺环化合物立体选择性不高的缺点。但是由于有机催化剂存在种类少、一种催化剂所能催化的反应种类单一以及构建吲哚螺环的底物范围窄等局限,目前仅合成出少部分可供筛选的氧化吲哚螺环化合物,且未见与本发明结构相似的氧化吲哚螺环化合物的报道。
发明内容
本发明的目的在于提供一种氧化吲哚螺四氢呋喃化合物及其制备方法和用途。
本发明首先提供了一种如式(Ⅰ)所示的氧化吲哚螺四氢呋喃化合物或其晶型:
其中,R1选自苯环、萘环、噻吩环或肉桂基;
R2选自H、F、Cl、Br、I或C1-3的烷氧基;
R3选自H、苄基或C1~C3的烷基;
R4选自H、F、Cl、Br、I、C1-3的烷氧基或C1~C3的烷基。
进一步地,所述化合物为如下化合物之一:
本发明还提供了一种制备上述化合物的方法,其特征在于:包括以下步骤:
(1)取1-苄基-4,5-二氧代吡咯烷-3-羧酸乙酯与甲醛类化合物,在90±3℃反应即得式(1)所示吡咯烷二酮;
(2)取式(2-3)所示化合物与NaBH4,于0±5℃下,在乙醇中反应,即得式(2)所示羟基氧化吲哚;
(3)取式(1)所示吡咯烷二酮和式(2)所示羟基氧化吲哚,以方酰胺为催化剂,在有机溶剂中反应,即得式(Ⅰ)所示化合物。
进一步地,R1为苯环、萘环、噻吩环或肉桂基;R2选自H、F、Cl、Br、I或C1-3的烷氧基;R3选自H、苄基或C1~C3的烷基;R4选自H、F、Cl、Br、I、C1-3的烷氧基或C1~C3的烷基。
进一步地,步骤(1)中,1-苄基-4,5-二氧代吡咯烷-3-羧酸乙酯与甲醛类化合物的摩尔比为1:1。
进一步地,步骤(2)中,式(2-3)所示化合物与NaBH4的摩尔比为1:1.25。
进一步地,步骤(3)中,吡咯烷二酮、羟基氧化吲哚和方酰胺的摩尔比为1:1.5:0.2。
进一步地,所述方酰胺结构如下:
进一步地,步骤(3)中,所述有机溶剂选自二氯甲烷。
本发明还提供了上述化合物在制备治疗抗肿瘤药物中的用途,所述肿瘤为乳腺癌或黑色素瘤。
本发明成功合成了一部分立体选择性高的氧化吲哚螺环化合物,且本发明化合物的制备方法简便、反应温和、收率高,并且具有抗肿瘤活性,具有广阔的市场应用前景。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
实施例1、本发明化合物的制备
原料
通用合成路线:
其中,R1为苯环、萘环、噻吩环或肉桂基;R2选自H、F、Cl、Br、I或C1-3的烷氧基;R3选自H、苄基或C1~C3的烷基;R4选自H、F、Cl、Br、I、C1-3的烷氧基或C1~C3的烷基。
制备得到了一下化合物:
1、化合物4a的制备
(1)化合物(1)的制备:
取一只150mL的圆底烧瓶,称取1-苄基-4,5-二氧代吡咯烷-3-羧酸乙酯7.7mmol,分别量取17mL的无水乙醇,10mL的20%HCl溶液,以及和底物前体等当量的苯甲醛,90℃下回流4h。回流结束后,待体系冷却至室温后,滤出固体中并加入乙酸乙酯,90℃回流至溶液澄清,移出油浴锅,冷却至室温,有淡黄色晶体析出,析出的淡黄色晶体粉末即为化合物(1)。
其中,1-苄基-4,5-二氧代吡咯烷-3-羧酸乙酯:可以通过市场购买得到,也可以采用以下方法制备得到。
取一只150mL的圆底烧瓶,分别量取30mmol量的苯甲胺,10mL的无水乙醇,及等当量的丙烯酸乙酯1-2,室温下搅拌16h。称取苯甲胺1.0倍当量的草酸二乙酯,和1.5倍当量的乙醇钠加入第一步的反应液中,并补加10mL无水乙醇,将体系移至90℃的油浴锅中回流反应1h。后处理:真空旋干反应液中的无水乙醇,冷却至室温后加入70mL去离子水,再加入浓盐酸调节体系pH=1,此时体系放热,故移至冰浴中冷却,此时有黄白色固体析出。倾倒上清液,干燥即得1-苄基-4,5-二氧代吡咯烷-3-羧酸乙酯。
(2)化合物(2)的制备:
在150mL的圆底烧瓶中,用一定量的乙醇将硼氢化钠(1.25倍1-苄基吲哚-2,3-二酮当量)超声溶解,冷却至0℃,将1-苄基吲哚-2,3-二酮用剩于量的乙醇溶解并冷却至0℃(乙醇共90mL),在冰浴下缓慢的将NaBH4加入烧瓶中,冰浴下搅拌,红色即刻消失,TLC监测反应完全后,加水淬灭反应,固体析出。洗去硼氢化钠,固体用二氯甲烷溶解并用无水硫酸钠干燥,过滤,减压浓缩后重结晶,过滤得化合物(2)。
其中,式(2-3)所示1-苄基吲哚-2,3-二酮,可以通过市场购买得到,也可以采用以下方法制备得到。
在150mL的圆底烧瓶中,称取5.0g靛红和碳酸钾(1.5倍靛红当量),溶解于100mLTHF溶剂中后加入苄溴(1.2倍靛红当量),于60℃回流36h。TLC监测反应完全后,旋干,水洗除去碳酸钾,并用石油醚洗去苄溴,即得1-苄基吲哚-2,3-二酮。
(3)化合物4a的制备
在一干净的反应管中,依次加入式(1)吡咯烷酮缺电子二烯化合物(0.05mmol),式(2)羟基氧化吲哚(0.075mmol),二氯甲烷(1mL),和方酰胺催化剂(0.01mmol),在25℃下搅拌12小时,TLC监测原料1a(R1=H)消失,反应结束后,减压除去反应溶剂,残留物上硅胶柱,石油醚:乙酸乙酯=3:1洗脱,薄层跟踪,合并洗脱液,除去溶剂,所得纯化物即得化合物4a,白色固体,其反应收率为99%,er值95:5。
HRMS(ESI):m/z calculated for C33H28N2O4Na+:539.1947,found:539.1938.
1H NMR(600MHz,CDCl3):δ(ppm):7.46(d,J=8.4Hz,1H),7.38–7.23(m,6H),7.16–7.06(m,7H),6.94(d,J=7.8Hz,2H),6.49(d,J=7.2Hz,2H),6.35(d,J=7.8Hz,1H),4.96(d,J=15.6Hz,1H),4.59(s,2H),4.29(d,J=16.2Hz,1H),3.82–3.79(m,1H),3.63–3.60(m,1H),3.48(d,J=10.8Hz,1H),2.93(d,J=10.8Hz,1H).
13C NMR(150MHz,CDCl3):δ(ppm):176.9,168.6,143.2,135.5,134.2,131.7,130.6,128.9,128.8,128.7,128.3,128.2,128.0,127.3,127.3,126.3,125.3,124.0,123.6,109.9,108.2,89.8,63.3,47.4,47.1,45.7,43.7.
2、化合物4b的制备
制备方法同化合物4a,只需将步骤(1)中的苯甲醛换成对溴苯甲醛,即得化合物4b,白色固体,反应收率为97%,er值93:7。
HRMS(ESI):m/z calculated for C33H27BrN2O4H+:595.1154,found:595.1231.
1H NMR(600MHz,CDCl3):δ(ppm):7.44(d,J=7.8Hz,1H),7.38–7.30(m,5H),7.25–7.10(m,7H),6.79(d,J=8.4Hz,2H),6.52–6.50(m,2H),6.41(d,J=7.8Hz,1H),5.32(s,1H),5.0(d,J=15.6Hz,1H),4.58(s,2H),4.28(d,J=16.2Hz,1H),3.75–3.72(m,1H),3.62–3.60(m,1H),3.41(d,J=10.8Hz,1H),2.89(d,J=10.2Hz,1H).
13C NMR(150MHz,CDCl3):δ(ppm):176.5,168.4,143.1,135.4,134.2,131.9,130.8,129.9,128.9,128.7,128.3,128.0,127.6,126.3,125.0,124.0,123.7,122.5,109.9,108.1,89.4,62.6,47.2,47.1,45.6,43.8.
3、化合物4c的制备
制备方法同化合物4a,只需将步骤(1)中的苯甲醛换成对氟苯甲醛,即得化合物4c,白色固体,反应收率为96%,er值99:1。
HRMS(ESI):m/z calculated for C33H27FN2O4H+:535.1955,found:535.2033.
1H NMR(600MHz,CDCl3):δ(ppm):7.44(d,J=6.6Hz,1H),7.38–7.30(m,5H),7.18–7.10(m,5H),6.90–6.88(m,2H),6.81–6.78(m,2H),6.51(d,J=6.6Hz,2H),6.41(d,J=8.4Hz,1H),5.36(s,1H),4.96(d,J=15.6Hz,1H),4.58(s,2H),3.76–3.72(m,1H),3.62–3.59(m,1H),3.44(d,J=10.8Hz,1H),2.90(d,J=11.4Hz,1H).
13C NMR(150MHz,CDCl3):δ(ppm):176.6,168.5,163.5,161.8,143.1,135.4,134.2,130.7,129.9,129.8,128.9,128.6,128.3,128.0,127.5,126.3,125.1,124.0,123.6,115.7,115.6,109.8,108.1,89.6,62.4,47.2,47.1,45.8,43.7.
4、化合物4d的制备
制备方法同化合物4a,只需将步骤(1)中的苯甲醛换成对氯苯甲醛,即得化合物4d,白色固体,反应收率为95%,er为93:7。
HRMS(ESI):m/z calculated for C33H27ClN2O4H+:551.1659,found:551.1738.
1H NMR(600MHz,CDCl3):δ(ppm):7.44(d,J=7.8Hz,1H),7.38–7.30(m,5H),7.20–7.07(m,7H),6.85(d,J=9.0Hz,2H),6.50(d,J=9.0Hz,2H),6.41(d,J=7.8Hz,1H),5.36(s,1H),4.99(d,J=16.8Hz,1H),4.58(s,2H),4.27(d,J=15.6Hz,1H),3.76–3.73(m,1H),3.62–3.59(m,1H),3.43(d,J=11.4Hz,1H),2.90(d,J=10.8Hz,1H).
13C NMR(150MHz,CDCl3):δ(ppm):176.5,168.5,143.1,135.4,134.4,134.2,130.8,130.2,129.5,128.9,128.8,128.6,128.3,128.0,127.5,126.3,125.0,124.0,123.7,109.9,108.1,89.5,62.5,47.2,47.1,45.6,43.8.
5、化合物4e的制备
制备方法同化合物4a,只需将步骤(1)中的苯甲醛换成邻氯苯甲醛,即得化合物4e,白色固体,反应收率为99%,er为90:10。
HRMS(ESI):m/z calculated for C33H27ClN2O4H+:551.1659,found:551.1738.
1H NMR(600MHz,CDCl3):δ(ppm):7.61(d,J=9.0Hz,1H),7.50(d,J=7.8Hz,1H),7.38–7.29(m,5H),7.17–7.06(m,8H),6.72(d,J=8.4Hz,1H),6.39(d,J=8.4Hz,1H),4.98(d,J=16.8Hz,1H),4.77(d,J=14.4Hz,1H),4.45–4.42(m,2H),4.38(d,J=10.8Hz,1H),3.62–3.60(m,1H),3.53–3.50(m,1H),2.95(d,J=11.4Hz,1H).
13C NMR(150MHz,DMSO-d6):δ(ppm):174.1,169.8,142.6,136.4,135.4,134.7,130.5,130.3,130.1,129.7,129.6,128.9,128.6,128.2,127.7,127.6,127.2,126.6,125.6,125.1,122.7,109.4,107.2,87.6,53.7,46.9,45.7,45.0,42.5.
6、化合物4f的制备
制备方法同化合物4a,只需将步骤(1)中的苯甲醛换成2,4-二氯苯甲醛,即得化合物4f,白色固体,反应收率为96%,er为91:9。
HRMS(ESI):m/z calculated for C33H26Cl2N2O4H+:585.1270,found:585.1346.
1H NMR(600MHz,DMSO-d6):δ(ppm):7.62–7.60(m,2H),7.36–7.27(m,7H),7.18–7.13(m,2H),7.10–7.05(m,1H),6.40(d,J=7.8Hz,2H),6.57(d,J=7.8Hz,1H),4.87(d,J=15.6Hz,1H),4.76(d,J=14.4Hz,1H),4.42(d,J=15.6Hz,1H),4.13(d,J=14.4Hz,1H),4.02(d,J=11.4Hz,1H),3.59–3.56(m,1H),3.47–3.44(m,1H),2.66–2.64(d,J=10.8Hz,1H).
13C NMR(150MHz,DMSO-d6):δ(ppm):173.9,169.8,142.5,136.4,135.6,135.5,133.6,131.8,130.6,129.3,129.0,128.9,128.4,128.2,127.8,127.7,127.3,126.7,125.5,125.1,122.8,109.4,107.2,87.4,53.4,46.8,45.7,45.0,42.5.
7、化合物4g的制备
制备方法同化合物4a,只需将步骤(1)中的苯甲醛换成对甲氧基苯甲醛,即得化合物4g,白色固体,反应收率为77%,er为96:4。
HRMS(ESI):m/z calculated for C34H30N2O5H+:547.2155,found:547.2233.
1H NMR(600MHz,CDCl3):δ(ppm):7.45(d,J=7.8Hz,1H),7.37–7.35(m,2H),7.31–7.29(m,3H),7.16–7.09(m,3H),7.08–7.06(m,2H),6.84(d,J=9.0Hz,2H),6.64(d,J=9.0Hz,2H),6.46(d,J=6.8Hz,2H),6.37(d,J=17.8Hz,1H),5.40(s,1H),5.05(d,J=16.2Hz,1H),4.58(s,2H),4.26(d,J=15.6Hz,1H),3.75–3.74(m,1H),3.71(s,3H),3.61–3.58(m,1H),3.43(d,J=10.8Hz,1H),2.91(d,J=11.4Hz,1H).
13C NMR(150MHz,CDCl3):δ(ppm):176.9,168.7,159.6,143.1,135.5,134.2,130.5,129.2,128.8,128.4,128.3,127.9,127.3,126.3,125.4,123.9,123.5,123.4,114.0,109.8,108.0,89.7,62.6,55.1,47.3,47.1,45.7,43.6.
8、化合物4h的制备
制备方法同化合物4a,只需将步骤(1)中的苯甲醛换成间甲氧基苯甲醛,即得化合物4h,白色固体,反应收率为97%,er为94:6。
HRMS(ESI):m/z calculated for C34H30N2O5H+:547.2155,found:547.2233.
1H NMR(600MHz,CDCl3):δ(ppm):7.60(d,J=6.6Hz,1H),7.37–7.35(m,2H),7.32–7.29(m,3H),7.15–7.08(m,5H),7.05(t,J=7.8Hz,1H),6.78(dd,J=8.4Hz,J=2.4Hz,1H),6.56(d,J=7.8Hz,1H),6.53(d,J=7.2Hz,2H),6.39–6.37(m,2H),5.36(s,1H),4.99(d,J=16.2Hz,1H),4.59(s,2H),4.29(d,J=16.8Hz,1H),3.80–3.76(m,1H),3.62–3.60(m,1H),3.47–3.45(m,1H),3.46(s,3H),2.94(d,J=10.8Hz,1H).
13C NMR(150MHz,CDCl3):δ(ppm):176.8,168.6,159.6,143.3,135.5,134.2,133.2,130.6,129.7,128.9,128.6,128.3,128.0,127.3,126.2,125.4,124.0,123.6,120.2,114.3,113.3,109.8,108.1,89.6,63.1,54.9,47.3,47.1,45.6,43.7.
9、化合物4i的制备
制备方法同化合物4a,只需将步骤(1)中的苯甲醛换成邻甲氧基苯甲醛,即得化合物4i,白色固体,反应收率为93%,er为95:5。
HRMS(ESI):m/z calculated for C34H30N2O5H+:547.2155,found:547.2233.
1H NMR(600MHz,CDCl3):δ(ppm):7.48–7.45(m,2H),7.37–7.34(m,2H),7.32–7.28(m,3H),7.20–7.13(m,2H),7.10–7.04(m,2H),6.85–6.82(m,2H),6.60(d,J=7.8Hz,1H),6.60(d,J=7.2Hz,2H),6.32–6.30(m,1H),5.45(s,1H),5.00(d,J=15.6Hz,1H),4.6(d,J=1.8Hz,2H),4.34(d,J=11.4Hz,1H),4.30(d,J=15.6Hz,1H),3.74–3.69(m,1H),3.54–3.51(m,1H),3.20(s,3H),2.91(d,J=10.8Hz,1H).
13C NMR(150MHz,CDCl3):δ(ppm):177.4,168.9,157.9,142.8,135.5,134.4,129.9,129.0,128.8,128.6,128.3,128.2,127.8,127.2,126.3,125.6,125.1,122.8,120.8,120.4,110.6,109.3,108.2,89.5,54.8,53.5,47.4,47.0,46.5,43.6.
10、化合物4j的制备
制备方法同化合物4a,只需将步骤(1)中的苯甲醛换成3,4-二甲氧基苯甲醛,即得化合物4j,白色固体,反应收率为99%,er为96:4。
HRMS(ESI):m/z calculated for C35H32N2O6H+:577.2260,found:577.2399.
1H NMR(600MHz,CDCl3):δ(ppm):7.47(d,J=8.4Hz,1H),7.38–7.35(m,2H),7.32–7.30(m,3H),7.14–7.08(m,5H),6.62(d,J=9.0Hz,1H),6.57(dd,J=8.4Hz,J=2.4Hz,1H),6.49(d,J=7.8Hz,2H),6.40(d,J=7.2Hz,1H),6.20(d,J=1.8Hz,1H),5.33(s,1H),4.99(d,J=3.6Hz,1H),4.63(d,J=14.4Hz,1H),4.55(d,J=14.4Hz,1H),4.29(d,J=15.6Hz,1H),3.80(s,3H),3.76–3.74(m,1H),3.65(m,1H),3.43(d,J=10.8Hz,1H),3.60(s,3H),2.93(d,J=10.2Hz,1H).
13C NMR(150MHz,CDCl3):δ(ppm):176.9,168.6,149.0,148.7,143.4,135.5,134.2,130.5,128.9,128.6,128.4,128.0,127.5,126.2,125.6,124.0,123.9,123.5,119.8,111.0,110.8,109.8,108.1,89.6,62.8,55.7,55.4,47.3,47.1,45.3,43.7.
11、化合物4k的制备
制备方法同化合物4a,只需将步骤(1)中的苯甲醛换成对甲基苯甲醛,即得化合物4k,白色固体,反应收率为99%,er为97:3。
HRMS(ESI):m/z calculated for C34H30N2O4H+:531.2206,found:531.2283.
1H NMR(600MHz,CDCl3):δ(ppm):7.45(d,J=8.4Hz,1H),7.37–7.35(m,2H),7.31–7.29(m,3H),7.16–7.09(m,3H),7.06(t,J=15Hz,2H),6.93(d,J=7.2Hz,2H),6.82(d,J=8.4Hz,2H),6.50(d,J=7.2Hz,2H),6.36(d,J=7.8Hz,1H),5.38(s,1H),5.00(d,J=16.8Hz,1H),4.60(d,J=15.0Hz,1H),4.56(d,J=14.4Hz,1H),4.27(d,J=14.4Hz,1H),3.79–3.76(m,1H),3.61–3.58(m,1H),2.91(d,J=9.6Hz,1H),2.28(s,3H).
13C NMR(150MHz,CDCl3):δ(ppm):176.9,168.7,143.1,138.0,135.4,134.3,130.5,129.4,128.8,128.6,128.5,128.3,128.1,127.9,127.3,126.4,125.4,124.0,123.5,109.8,108.1,89.7,62.9,47.3,47.1,45.7,43.7,21.1.
12、化合物4l的制备
制备方法同化合物4a,只需将步骤(1)中的苯甲醛换成间甲基苯甲醛,即得化合物4l,白色固体,反应收率为99%,er为90:10。
HRMS(ESI):m/z calculated for C34H30N2O4H+:531.2206,found:531.2284.
1H NMR(600MHz,CDCl3):δ(ppm):7.46(d,J=7.8Hz,1H),7.37–7.35(m,2H),7.32–7.29(m,3H),7.15–7.09(m,3H),7.07–7.05(m,3H),7.00(t,J=15.0Hz,1H),6.75(s,1H),6.69(d,J=7.8Hz,1H),6.45(d,J=6.6Hz,2H),6.36(d,J=8.4Hz,1H),5.42(s,1H),5.01(d,J=16.2Hz,1H),4.59(s,2H),4.25(d,J=16.2Hz,1H),3.81–3.78(m,1H),3.62–3.59(m,1H),3.45(d,J=11.4Hz,1H),2.92(d,J=12.0Hz,1H),2.10(s,3H).
13C NMR(150MHz,CDCl3):δ(ppm):176.9,168.7,143.2,138.4,135.4,134.3,131.6,130.5,129.0,128.8,128.6,127.5,128.3,127.9,127.3,126.1,125.4,124.0,123.5,109.7,108.1,89.7,63.1,47.3,47.1,45.5,43.7,21.2.
13、化合物4m的制备
制备方法同化合物4a,只需将步骤(1)中的苯甲醛换成1-萘甲醛,即得化合物4m,白色固体,反应收率为99%,er为96:4。
HRMS(ESI):m/z calculated for C37H30N2O4Na+:589.2103,found:589.2101.
1H NMR(600MHz,CDCl3):δ(ppm):7.81(d,J=7.2Hz,1H),7.72–7.72(m,2H),7.57(d,J=7.8Hz,1H),7.40–7.32(m,7H),7.30(t,J=15.0Hz,1H),7.13–7.08(m,2H),7.05–6.99(m,3H),6.96(t,J=17.4Hz,1H),6.40(d,J=4.2Hz,2H),6.14(d,J=8.4Hz,1H),5.53(s,1H),4.92(d,J=15.6Hz,1H),4.79(d,J=14.4Hz,1H),4.46(d,J=10.8Hz,1H),4.42(d,J=14.4Hz,1H),4.26(d,J=16.2Hz,1H),3.88–3.85(m,1H),3.58–3.55(m,1H),2.90–2.89(m,1H).
13C NMR(150MHz,CDCl3):δ(ppm):177.3,168.8,142.9,135.7,134.1,133.7,132.2,130.5,128.9,128.8,128.6,128.5,128.4,128.2,128.0,127.3,126.2,126.0,125.7,125.6,125.4,125.3,124.2,123.2 122.1,109.8,108.1,89.9,56.0,48.7,47.2,47.0,43.6.
14、化合物4n的制备
制备方法同化合物4a,只需将步骤(1)中的苯甲醛换成2-萘甲醛,即得化合物4n,白色固体,反应收率为99%,er为96:4。
HRMS(ESI):m/z calculated for C37H30N2O4H+:567.2206,found:567.2284.
1H NMR(600MHz,CDCl3):δ(ppm):7.76(d,J=7.8Hz,1H),7.64(d,J=8.4Hz,1H),7.55–7.47(m,4H),7.43(t,J=15.0Hz,1H),7.38–7.36(m,2H),7.33–7.30(m,3H),7.17–7.13(m,2H),6.91–6.88(m,2H),6.51(t,J=15.0Hz,2H),6.32–6.30(m,1H),6.21(d,J=7.8Hz,2H),5.46(s,1H),4.96(d,J=16.2Hz,1H),4.61(s,2H),4.17(d,J=15.6Hz,1H),3.99–3.96(m,1H),3.67–3.64(m,2H),2.97(d,J=9.6Hz,1H).
13C NMR(150MHz,CDCl3):δ(ppm):176.8,168.7,143.1,135.4,133.9,1331,133.0,130.7,129.2,129.9,128.4,128.3,128.2,128.0,127.9,127.5,127.2,127.1,126.5,126.4,126.0,125.9,125.3,124.1,123.6,109.8,108.2,89.8,63.3,47.3,47.1,45.7,43.7.
15、化合物4o的制备
制备方法同化合物4a,只需将步骤(1)中的苯甲醛换成肉桂醛,即得化合物4o,白色固体,反应收率为94%,er为92:8。
HRMS(ESI):m/z calculated for C35H30N2O4Na+:565.2206,found:565.2104.
1H NMR(600MHz,CDCl3):δ(ppm):7.40–7.32(m,6H),7.25–7.22(m,2H),7.18(t,J=15.6Hz,1H),7.12–7.07(m,6H),6.94–6.92(m,2H),6.55(d,J=7.8Hz,1H),6.12(d,J=15.6Hz,1H),5.95–5.91(m,1H),5.21(s,1H),5.15(d,J=16.2Hz,1H),4.63(d,J=14.4Hz,1H),4.56–4.52(m,2H),3.64–3.61(m,1H),3.35–3.32(m,1H),3.02–2.97(m,2H).
13C NMR(150MHz,CDCl3):δ(ppm):177.1,167.6,143.2,135.5,135.3,134.5,130.5,128.9,128.8,128.6,128.3,128.2,128.0,127.5,126.6,126.5,125.3,124.0,123.7,121.6,109.8,108.6,88.8,62.2,47.3,47.1,47.0,43.9.
16、化合物4p的制备
制备方法同化合物4a,只需将步骤(1)中的苯甲醛换成2-噻吩甲醛,即得化合物4p,白色固体,反应收率为92%,er为96:4。
HRMS(ESI):m/z calculated for C31H26N2O4SH+:523.1613,found:523.1694.
1H NMR(600MHz,CDCl3):δ(ppm):7.43(d,J=6.0Hz,1H),7.38–7.35(m,2H),7.32–7.30(m,3H),7.22–7.12(m,5H),7.08(d,J=6.6Hz,1H),6.83(t,J=7.8Hz,1H),6.64–6.30(m,3H),6.48(d,J=7.2Hz,1H),5.37(s,1H),4.99(d,J=15.0Hz,1H),4.63(d,J=14.4Hz,1H),4.54(d,J=14.4Hz,1H),4.36(d,J=16.2Hz,1H),3.76–3.66(m,3H),3.01(d,J=10.2Hz,1H).
13C NMR(150MHz,CDCl3):δ(ppm):176.6,168.3,143.6,135.3,134.6,134.3,130.9,128.9,128.7,128.3,128.0,127.4,127.2,126.5,126.0,125.3,124.9,124.1,123.7,109.9,107.9,89.1,58.2,47.5,47.1,47.1,43.8.
17、化合物4q的制备
制备方法同化合物4a,只需将步骤(2)中的靛红换成5-氟靛红,即得化合物4q,白色固体,反应收率为92%,er为96:4。
HRMS(ESI):m/z calculated for C33H27FN2O4H+:535.1955,found:535.2033.
1H NMR(600MHz,CDCl3):δ(ppm):7.38–7.36(m,2H),7.33–7.25(m,4H),7.21(dd,J=7.2Hz,J=2.4Hz,1H),7.17–7.13(m,3H),7.09–7.06(m,2H),6.97(d,J=7.8Hz,2H),6.84(td,J=9.0Hz,J=2.4Hz,1H),6.45(d,J=8.4Hz,2H),6.27(dd,J=8.4Hz,J=3.6Hz,1H),5.28(d,J=9.6Hz,1H),4.95(d,J=16.8Hz,1H),4.59(s,2H),4.27(d,J=16.2Hz,1H),3.81–3.78(m,1H),3.63–3.60(m,1H),3.42(d,J=10.8Hz,1H),2.93(d,J=10.8Hz,1H).
13C NMR(150MHz,CDCl3):δ(ppm):176.6,168.4,160.3,158.7,139.0,135.4,133.9,131.4,128.9,128.9,128.7,128.5,128.3,128.2,128.1,127.5,126.3,117.1,117.0,112.2,112.1,110.8,110.7,108.3,89.6,63.5,47.3,47.1,45.7,43.8.
18、化合物4r的制备
制备方法同化合物4a,只需将步骤(2)中的靛红换成5-溴靛红,即得化合物4r,白色固体,反应收率为92%,er为97:3。
HRMS(ESI):m/z calculated for C33H27BrN2O4H+:595.1154,found:595.1232.
1H NMR(600MHz,CDCl3):δ(ppm):7.56(d,J=1.8Hz,1H),7.39–7.24(m,7H),7.17–7.13(m,3H),7.06(m,2H),6.96(d,J=7.8Hz,2H),6.43(d,J=7.8Hz,2H),6.21(d,J=7.8Hz,1H),5.27(s,1H),4.94(d,J=15.6Hz,1H),4.58(s,2H),4.24(d,J=16.2Hz,1H),3.80–3.77(m,1H),3.63–3.60(m,1H),3.41(d,J=7.8Hz,1H),2.92(d,J=7.8Hz,1H).
13C NMR(150MHz,CDCl3):δ(ppm):176.1,168.5,142.1,135.4,133.7,133.4,131.3,128.9,128.9,128.8,128.7,128.5,128.3,128.3,128.1,127.5,127.2,126.2,116.2,111.4,108.3,89.2,63.2,47.2,47.1,45.6,43.7.
19、化合物4s的制备
制备方法同化合物4a,只需将步骤(2)中的苄溴换成碘甲烷,即得化合物4s,白色固体,反应收率为91%,er为86:14。
HRMS(ESI):m/z calculated for C27H24N2O4H+:441.1814,found:441.1814.
1H NMR(600MHz,CDCl3):δ(ppm):7.43(d,J=7.8Hz,1H),7.37–7.34(m,2H),7.31–7.25(m,5H),7.15–7.12(m,2H),7.10–7.07(m,2H),6.87(d,J=7.2Hz,2H),6.70(d,J=7.2Hz,1H),5.45(s,1H),4.57(s,2H),3.71–3.68(m,1H),3.59–3.55(m,1H),3.36(d,J=10.2Hz,1H),2.90(d,J=11.4Hz,1H),2.83(s,3H).
13C NMR(150MHz,CDCl3):δ(ppm):176.8,168.6,143.7,135.5,171.7,130.6,128.9,128.4,128.3,128.2,128.0,128.9,125.3,123.8,123.5,108.5,108.2,89.9,67.8,47.2,47.1,45.9,25.9.
以下通过试验例的方式来说明本发明的有益效果。
试验例1、抗肿瘤研究
1、实验细胞株
人乳腺癌BT474细胞株、人乳腺癌MB468细胞株、人乳腺癌SKBR3细胞株、人乳腺癌MB231细胞株、小鼠黑色素瘤B16细胞株、小鼠黑色素瘤A375细胞株均由四川大学生物治疗国家重点实验室提供,以上肿瘤细胞均冻存于四川大学生物治疗国家重点实验室。
2、实验方法
2.1细胞的准备及处理
6种肿瘤细胞均培养于含10%灭活新生小牛血清的RPMI-1640培养液,37℃、5%CO2培养箱中生长至80%细胞融合,用0.1%胰酶溶液消化,制成单细胞悬液,调整细胞浓度为5×104个/mL,均匀接种于96孔微量培养板中,每组3个复孔,100μl/孔,置37℃饱和湿度、5%CO2孵箱内培养24h后,正常对照组加入含等量的培养液;加入浓度梯度的受试药物(100、50、25、12.5、6.25μg/mL),每个浓度设3个复孔,实验平行2次。待药物与细胞作用24h后,每孔加入10μL MTT溶液(5mg/mL),继续培养4h后每孔加入100μL DMSO,振荡混匀,使结晶物充分溶解,在酶标仪490nm波长处测其吸光度值(A值),各个浓度组取其平均值。
2.2肿瘤细胞增殖抑制率的测定
按下列公式计算细胞增殖抑制率:细胞增殖抑制率(%)=(1-试验组A值/对照组A值)×100%。所有实验数据采用SPSS 13.0进行统计分析。实验结果采用Probit求得IC50值。
3、实验结果
表1不同化合物对受试细胞生长的抑制情况
实验结果表明,本发明化合物具有抗肿瘤效果。
综上所述,本发明成功合成了一部分立体选择性高的氧化吲哚螺环化合物,且本发明化合物的制备方法简便、反应温和、收率高,并且具有抗肿瘤活性,具有广阔的市场应用前景。
Claims (9)
4.根据权利要求3所述的方法,其特征在于:R1为苯基、萘基、噻吩基;R2选自H、F、Cl、Br、I;R3选自苄基或C1~C3的烷基;R4选自H、F、Cl、Br、I、C1-3的烷氧基或C1~C3的烷基。
5.根据权利要求3所述的方法,其特征在于:步骤(1)中,1-苄基-4,5-二氧代吡咯烷-3-羧酸乙酯与甲醛类化合物的摩尔比为1:1。
6.根据权利要求3所述的方法,其特征在于:步骤(2)中,式(2-3)所示化合物与NaBH4的摩尔比为1:1.25。
7.根据权利要求3所述的方法,其特征在于:步骤(3)中,吡咯烷二酮、羟基氧化吲哚和方酰胺的摩尔比为1:1.5:0.2。
8.根据权利要求3-7任一项所述的方法,其特征在于:所述有机溶剂选自二氯甲烷。
9.权利要求1或2所述的化合物在制备治疗抗肿瘤药物中的用途,所述肿瘤为乳腺癌或黑色素瘤。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711165992.3A CN108033969B (zh) | 2017-11-21 | 2017-11-21 | 一种氧化吲哚螺四氢呋喃化合物及其制备方法和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711165992.3A CN108033969B (zh) | 2017-11-21 | 2017-11-21 | 一种氧化吲哚螺四氢呋喃化合物及其制备方法和用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN108033969A CN108033969A (zh) | 2018-05-15 |
CN108033969B true CN108033969B (zh) | 2020-04-10 |
Family
ID=62092924
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201711165992.3A Active CN108033969B (zh) | 2017-11-21 | 2017-11-21 | 一种氧化吲哚螺四氢呋喃化合物及其制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108033969B (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012038307A1 (en) * | 2010-09-20 | 2012-03-29 | F. Hoffmann-La Roche Ag | Spiro substituted pyrrolo[1,2-c]imidazole derivatives useful as mdm2 inhibitors |
CN104098507A (zh) * | 2014-07-21 | 2014-10-15 | 太原理工大学 | 一种羟吲哚螺环丙烷衍生物及其合成方法 |
CN106986815A (zh) * | 2017-04-12 | 2017-07-28 | 西华师范大学 | 光学活性吲哚螺环戊烯酮及其衍生物和制备方法 |
-
2017
- 2017-11-21 CN CN201711165992.3A patent/CN108033969B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012038307A1 (en) * | 2010-09-20 | 2012-03-29 | F. Hoffmann-La Roche Ag | Spiro substituted pyrrolo[1,2-c]imidazole derivatives useful as mdm2 inhibitors |
CN104098507A (zh) * | 2014-07-21 | 2014-10-15 | 太原理工大学 | 一种羟吲哚螺环丙烷衍生物及其合成方法 |
CN106986815A (zh) * | 2017-04-12 | 2017-07-28 | 西华师范大学 | 光学活性吲哚螺环戊烯酮及其衍生物和制备方法 |
Non-Patent Citations (2)
Title |
---|
HDAC抑制剂Belinostat类似物的研究以及氧化吲哚螺四氢呋喃环衍生物的合成;张皆欢;《江苏师范大学硕士学位论文》;20171015;参见全文 * |
方酰胺衍生物及其在离子识别中的应用;钱小红等;《化学进展》;20141231;第26卷(第10期);第1701-1711页,参见全文 * |
Also Published As
Publication number | Publication date |
---|---|
CN108033969A (zh) | 2018-05-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108117507B (zh) | 一种氮杂螺环己二烯酮的合成方法和用途 | |
CN110437236B (zh) | 一种吲哚-1,2-并1,4-苯并二氮杂卓类化合物及其合成方法 | |
CN102491931B (zh) | 一种3-取代吲哚酮衍生物及其制备方法和应用 | |
Liu et al. | A highly efficient and eco-friendly method for the synthesis of 1, 3-indandione ring-fused 3-oxindoles bearing two contiguous quaternary stereocenters via an aldol reaction in aqueous media | |
CN108033969B (zh) | 一种氧化吲哚螺四氢呋喃化合物及其制备方法和用途 | |
Zhu et al. | One-pot three-component tandem reaction of diazo compounds with anilines and unsaturated ketoesters: a novel synthesis of 2, 3-dihydropyrrole derivatives | |
CN107868087B (zh) | 一种制备吡咯并吲哚类衍生物的方法 | |
CN107235887B (zh) | 一种多取代二吲哚甲烷衍生物及其制备方法 | |
CN110878099A (zh) | 一种吡咯[1,2,α]吲哚生物碱衍生物的制备方法 | |
CN105820174A (zh) | 一种多取代噻吩并吲哚衍生物的制备方法 | |
CN107586272B (zh) | 一种多取代苯并双环[2.2.2]辛烷衍生物及其制备方法 | |
CN113372352B (zh) | 吲哚3,4位并九元中环化合物及其制备方法 | |
CN102531995B (zh) | 一种3,3'-二取代-3-羟基双吲哚酮衍生物及其制备方法和应用 | |
CN111423437B (zh) | 一种帕博西尼中间体的制备方法 | |
CN110317170B (zh) | 一种3-菲啶基甲酸丙酯类化合物的绿色合成方法 | |
Du et al. | Iodine-Mediated Synthesis of 2-Acylquinoline from Acetophenone and 2-(Arylvinyl) aniline | |
CN108329249B (zh) | 一种合成吲哚-3-甲醛类化合物的方法 | |
CN108084200B (zh) | 一种卤代二氢吡喃并吡咯酮化合物及其制备方法和用途 | |
CN107759619B (zh) | 一种二氢吡喃并噻唑环化合物及其制备方法和用途 | |
CN111100085A (zh) | 一种3-芳基-2H-苯并[β][1,4]苯并恶嗪-2-酮化合物的制备方法 | |
CN116813525B (zh) | 一种多乙酰基取代的氧化吲哚类化合物的合成方法 | |
CN113943299B (zh) | 一种吲哚并[2,3-b]咔唑类化合物的合成方法 | |
CN114773354B (zh) | 一种Trisphaeridine的简易合成方法 | |
CN108084201B (zh) | 一种氧化吲哚螺四氢呋喃骨架物及其晶体和其制备方法 | |
CN111943939B (zh) | 色满酮类化合物的合成方法及其农用生物活性 |
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: 20210416 Address after: Outside the East Shiling Town of Longquanyi District of Chengdu city of Sichuan province in 610100 Patentee after: CHENGDU University Address before: 610000 Sichuan city of Chengdu province Chenghua District two East 3rd Ring Rd section of Longtan Industrial Park Patentee before: SICHUAN INDUSTRIAL INSTITUTE OF ANTIBIOTICS, CHINA NATIONAL PHARMACEUTICAL Group Corp. |
|
TR01 | Transfer of patent right |