CN113072488A - 一种苯乙烯衍生物及其合成方法与应用 - Google Patents
一种苯乙烯衍生物及其合成方法与应用 Download PDFInfo
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- CN113072488A CN113072488A CN202110341421.0A CN202110341421A CN113072488A CN 113072488 A CN113072488 A CN 113072488A CN 202110341421 A CN202110341421 A CN 202110341421A CN 113072488 A CN113072488 A CN 113072488A
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Abstract
本发明涉及有机合成技术领域,尤其涉及一种苯乙烯衍生物及其合成方法与应用。本发明公开了一种具有式(Ⅰ)所示结构苯乙烯衍生物,该乙烯衍生物结构新颖、具有较好的水溶性,仅通过除去R1即可得到式(Ⅱ)所示结构的化合物,式(Ⅱ)所示结构的化合物对LPS诱导的巨噬细胞NO生成有较强的抑制作用,可应用于抗银屑病、抗特应性皮炎药物开发。
Description
技术领域
本发明涉及有机合成技术领域,尤其涉及一种苯乙烯衍生物及其合成方法与应用。
背景技术
炎症作为一种重要的病理过程在人体中十分常见,它本身是作为机体对于外来的或者异体的刺激的一种自身免疫应答。而当这种应答失调或者过分应答导致机体的自损伤时,就演变成了炎症。所以大多数的疾病都伴随着炎症的介导和发生,而炎症的介导和发生又使得疾病对于机体的损伤加重,如急性肺损伤、风湿性关节炎、糖尿病合并症、癌症、动脉粥样硬化、炎性肠病等。
长期大量使用抗炎药物易产生一系列不良反应、耐受性和副作用等。因此,为解决上述问题,寻找新的抗炎药物成为本领域的研究热点。
发明内容
有鉴于此,本发明提供了一种苯乙烯衍生物及其合成方法与应用,该苯乙烯衍生物结构新颖,抗炎效果显著。
其具体技术方案如下:
本发明提供了一种苯乙烯衍生物,具有式(Ⅰ)所示结构或其药学上可接受的盐、所述药学上可接受的盐的溶剂化合物、对映异构体、非对映异构体、互变异构体、消旋体或其组合;
其中,R1各自独立的选自烷基、芳烷基或酰基;R2选自烷基、环烷基、芳烷基或卤素;R3选自:取代或非取代的五元~六元的杂环基、取代或非取代的五元~六元的苯并杂环基。
优选地,R1选自甲基或苄基;
优选地,R2选自烷基,更优选为异丙基;
优选地,R3选自取代或非取代的吡啶基、取代或非取代的噻吩基、取代或非取代的苯并吡啶基。
更优选地,R3中取代的五元~六元的杂环基中的取代基选自甲基、甲酰基、苯基或卤素。
进一步优选地,R3选自:
本发明中,所述盐选自盐酸盐,硫酸盐,硝酸盐,磷酸盐,偏磷酸盐,甲磺酸盐,乙磺酸盐,柠檬酸盐,苯磺酸盐,对苯甲磺酸盐,苹果酸盐,酒石酸盐,琥珀酸盐,富马酸盐,乙酸盐,羟基乙酸盐,羟乙基磺酸盐,马来酸盐,乳酸盐,乳糖酸盐和三氟乙酸盐的一种或两种以上。
本发明还提供了(Ⅰ)所示结构苯乙烯衍生物的第一种制备方法,包括以下步骤:
步骤1:在有机溶剂中,将式1-1所示化合物与R2-Br在催化剂存在下进行烷基化反应,得到式1所示化合物;
步骤2:在催化剂的存在下,将式1所示化合物进行去甲基化反应,得到式2所示化合物;
步骤3:在催化剂的存在下,将式2所示化合物与R-OH进行酯化反应,得到式3所示化合物;
步骤4:在碱性条件下,将式3所示化合物与R1-X在有机溶剂中进行反应,得到式4所示化合物;
步骤5:将式4所示化合物与还原剂在有机溶剂中进行酯还原反应,得到式5a所示化合物;
步骤6:将式5a所示化合物与三溴化磷在有机溶剂中进行卤代反应,得到式6a所示化合物;
步骤7:将式6a所示化合物与亚磷酸三乙酯在催化剂的条件下进行反应,得到式7a所示化合物,再与芳香醛在有机溶剂中进行Wittig反应,得到式(Ⅰ)所示化合物;
R选自烷基或酰基,优选为甲基;R1选自烷基、芳烷基或酰基;R2选自烷基、环烷基、芳烷基或卤素;R3选自取代或非取代的五元~六元的杂环基、取代或非取代的五元~六元的苯并杂环基;X为卤素,优选为溴。
本发明步骤1中,所述有机溶剂优选为1,2-二氯乙烷;所述催化剂优选为无水三氯化铝;所述式1-1化合物与所述R2-Br的摩尔比为1:1~1:1.5,优选为20.4:22.4;所述烷基化反应的温度为90~95摄氏度,时间为4~6h,优选在90摄氏度下反应6h;所述烷基化反应在搅拌的条件下进行。
本发明步骤2中,所述催化剂优选为吡啶盐酸盐;所述化合物1与所述催化剂的摩尔比为1:5~1:10,优选为8.4:33.6;所述去甲基化反应的温度为180~200摄氏度,时间为4~6h,优选在200摄氏度下反应6h。
本发明步骤3中,所述催化剂优选为SOCl2;所述式2所示化合物与催化剂、R-OH的摩尔体积比为1:1.5:10~1:2:10,优选为1mmol:1.5mmol:10mL;所述醇优选为所述酯化反应的温度为70~90摄氏度,时间为4~6h,优选在70摄氏度下反应4h。
本发明步骤4中,所述提供碱性条件的碱性试剂优选为碳酸铯;所述有机溶剂优选为四氢呋喃;所述式3所示化合物、提供碱性条件的碱性试剂与R1-X的摩尔比为1:2:1.5~1:3:2,优选为1:2.5:2;所述反应的温度为70~90摄氏度,时间为8~12h,优选为70摄氏度下反应12h。
本发明步骤5中,所述步骤5具体为:将式4所示化合物溶于有机溶剂中,在0摄氏度搅拌状态下加入还原剂进行反应;所述有机溶剂优选为四氢呋喃;所述还原剂优选为氢化铝锂;所述式4所示化合物与所述还原剂的摩尔比为1:1~1:1.5,优选为1:1.2;所述酯还原反应的温度为室温,时间为4~6h,优选为在室温下反应6h。
本发明步骤6中,所述有机溶剂优选为二氯甲烷;式5a所示化合物与所述三溴化磷的摩尔体积比为10mmol:2mL,所述卤代反应的温度为室温,时间为4~6h,优选在室温下反应6h。
本发明步骤7中,所述催化剂为四丁基溴化铵;式6a所示化合物与亚磷酸三乙酯、催化剂的用量比为(0.21-0.47)mmol:5mL:0.047mmol;所述反应优选在氮气或惰性气体的氛围下进行;所述反应的温度为130~150摄氏度,时间为6~8h,优选在130摄氏度下反应6h;
所述有机溶剂优选为四氢呋喃;所述Wittig反应的碱试剂优选为氢化钠;式6a所示化合物与芳香醛、氢化钠的摩尔比1:0.88:5~1:1:5,优选为1:0.88:5;所述Wittig反应优选在氮气或惰性气体的氛围下进行;所述Wittig反应的温度为室温,时间为8~12h,所述反应优选在室温下反应12h。
本发明还提供了式(Ⅰ)所示苯乙烯衍生物的第二种制备方法,包括以下步骤:
步骤1:在有机溶剂中,将式1-1所示化合物与R2-Br在催化剂存在下进行烷基化反应,得到式1所示化合物;
步骤2:将式1所示化合物与还原剂在有机溶剂中进行酯还原反应,得到式5b所示化合物;
步骤3:将式5b所示化合物与三溴化磷在有机溶剂中进行卤代反应,得到式6b所示化合物;
步骤4:将式6b所示化合物与亚磷酸三乙酯进行反应,得到式7b所示化合物,再与芳香醛在有机溶剂中进行Wittig反应,得到式(Ⅰ)所示化合物;
R1选自烷基、芳烷基或酰基;R2选自烷基、环烷基、芳烷基或卤素;R3选自取代或非取代的五元~六元的杂环基、取代或非取代的五元~六元的苯并杂环基。
本发明步骤1中,所述有机溶剂优选为1,2-二氯乙烷;所述催化剂优选为无水三氯化铝;所述式1-1化合物与R2-Br的摩尔比为1:1~1:1.5,优选为20.4:22.4;所述烷基化反应的温度为90~95摄氏度,时间为4~6h,优选在90摄氏度下反应6h;所述烷基化反应在搅拌的条件下进行。
本发明步骤2中,所述步骤5具体为:将式1所示化合物溶于有机溶剂中,在0摄氏度搅拌状态下加入还原剂进行反应;所述有机溶剂优选为四氢呋喃;所述还原剂优选为氢化铝锂;所述式1所示化合物与所述还原剂的摩尔比为1:1~1:2,优选为1:1.2;所述酯还原反应的温度为室温,时间为4~6h,优选在室温下反应6h。
本发明步骤3中,所述有机溶剂优选为二氯甲烷;式5b所示化合物与所述三溴化磷的摩尔体积比为10mmol:2mL,优选为所述卤代反应的温度为室温,时间为4~6h,优选在室温下反应6h。
本发明步骤4中,式6b所示化合物与亚磷酸三乙酯、四丁基溴化铵的摩尔体积比为(0.63-1.09)mmol:5mL:0.073mmol;所述反应优选在氮气或惰性气体的氛围下进行;所述反应的温度为130~150摄氏度,时间为6~8h,优选在130摄氏度下反应6h;
所述有机溶剂优选为四氢呋喃;所述Wittig反应的碱试剂优选为氢化钠;式7b所示化合物与芳香醛、氢化钠的摩尔比1:0.88~1:1.5,优选为1:0.88:(3-5);所述Wittig反应优选在氮气或惰性气体的氛围下进行;所述Wittig反应的温度为室温,时间为8~12h,所述反应优选在室温下反应12h。
需要说明的是,本发明中,当R1为芳烷基,R3为取代或非取代的五元杂环基、取代或非取代的五元苯并杂环基,更优选当R1为苄基,R3为 时,优选采用式(Ⅰ)所示化合物第一种制备方法;当R1为烷基或酰基,R3为取代或非取代的六元杂环基、取代或非取代的六元苯并杂环基,更优选为甲基,R3为 时,优选采用式(Ⅰ)所示化合物的第二种制备方法。
本发明还提供了一种具有式(Ⅱ)所示结构的苯乙烯衍生物或其药学上可接受的盐、所述药学上可接受的盐的溶剂化合物、对映异构体、非对映异构体、互变异构体、消旋体或其组合;
所述式(Ⅱ)所示结构由式(Ⅰ)所示化合物去R1基团得到。
本发明中,所述式(Ⅰ)所示结构的苯乙烯衍生物优选包括(E)-3-[3,5-双-(苄氧基)-4-异丙基苯乙烯基]吡啶、(E)-2-异丙基-5-[2-(吡啶-3-基)乙烯基]苯-1,3-二醇、(E)-4-[3,5-双-(苄氧基)-4-异丙基苯乙烯基]吡啶、(E)-2-异丙基-5-[2-(吡啶-4-基)乙烯基]苯-1,3-二醇、(E)-2-[3,5-双-(苄氧基)-4-异丙基苯乙烯基]-6-甲基吡啶、(E)-2-异丙基-5-[2-(6-甲基吡啶-2-基)乙烯基]苯-1,3-二醇、(E)-2-[3,5-双-(苄氧基)-4-异丙基苯乙烯基]-6-甲氧基吡啶、(E)-2-异丙基-5-[2-(6-甲氧基吡啶-2-基)乙烯基]苯-1,3-二醇、(E)-2-[3,5-双-(苄氧基)-4-异丙基苯乙烯基]喹啉、(E)-2-异丙基-5-[2-(2-喹啉-2-基)乙烯基]苯-1,3-二醇、(E)-2-[3,5-(二甲氧基苯基)-4-异丙基苯乙烯基]-5-甲基噻吩、(E)-2-异丙基-5-[2-(5-甲基噻吩-2-基)乙烯基]-苯-1,3-二醇、(E)-2-[3,5-(二甲氧基苯基)-4-异丙基苯乙烯基]-4-溴噻吩、(E)-2-异丙基-5-[2-(4-溴噻吩-2-基)乙烯基]-苯-1,3-二醇、(E)-2-[3,5-(二甲氧基苯基)-4-异丙基苯乙烯基]噻吩、(E)-2-异丙基-5-[2-(噻吩-3-基)乙烯基]-苯-1,3-二醇、(E)-2-[3,5-(二甲氧基苯基)-4-异丙基苯乙烯基]-5-苯基噻吩、(E)-2-异丙基-5-[2-(5-苯基噻吩-2-基)乙烯基]-苯-1,3-二醇、(E)-2-[3,5-(二甲氧基苯基)-4-异丙基苯乙烯基]-4-苯基噻吩和(E)-2-异丙基-5-[2-(4-苯基噻吩-2-基)乙烯基]-苯-1,3-二醇中的一种或两种以上。
本发明中,式(Ⅱ)所示结构的化合物的第一种制备方法包括以下步骤:
将式(Ⅰ)所示结构的化合物与三溴化硼在有机溶剂中进行反应,得到式(Ⅱ)所示结构的化合物。
式(Ⅱ)所示结构的化合物的第一种制备方法中,式(Ⅰ)所示结构的化合物与三溴化硼反应脱去R1基团,得到式(Ⅱ)所示结构的化合物。所述有机溶剂优选为二氯甲烷;式(Ⅰ)所示化合物与三溴化硼的摩尔体积比为为(0.11~0.27)mmol:1mL;所述反应的温度为室温,时间为4~6h,优选在室温下反应6h。
本发明中,式(Ⅱ)所示结构的化合物的第二种制备方法包括以下步骤:
将式(Ⅰ)所示结构的化合物与吡啶盐酸盐在有机溶剂中进行反应,得到式(Ⅱ)所示结构的化合物。
式(Ⅱ)所示结构的化合物的第一种制备方法中,式(Ⅰ)所示结构的化合物与三溴化硼反应脱去R1基团,得到式(Ⅱ)所示结构的化合物。
式(Ⅰ)所示化合物与吡啶盐酸盐的摩尔比为1:5,所述去反应的温度为180~200摄氏度,时间为4~6h,优选在200摄氏度下反应6h。
需要说明的是,本发明中,当R1为芳烷基,R3为取代或非取代的五元杂环基、取代或非取代的五元苯并杂环基时,优选采用式(Ⅱ)所示结构的化合物的第一种制备方法;当R1为烷基或酰基,R3为取代或非取代的六元杂环基、取代或非取代的六元苯并杂环基时,优选采用式(Ⅱ)所示结构的化合物的第二种制备方法。
本发明发现本发明提供的式(Ⅰ)所示结构的苯乙烯衍生物对LPS诱导的巨噬细胞NO生成有较强的抑制作用,抗炎效果显著。因此,本发明还提供了上述苯乙烯衍生物在制备治疗炎症性疾病药物中的应用。
本发明中,所述炎症性疾病为银屑病或特应性皮炎。
从以上技术方案可以看出,本发明具有以下优点:
本发明提供了一种具有式(Ⅰ)所示结构苯乙烯衍生物,该乙烯衍生物结构新颖、仅通过除去R1即可得到式(Ⅱ)所示结构的化合物,式(Ⅱ)所示结构的化合物对LPS诱导的巨噬细胞NO生成有较强的抑制作用,可应用于抗银屑病、抗特应性皮炎药物开发。
具体实施方式
为使得本发明的发明目的、特征、优点能够更加的明显和易懂,下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,下面所描述的实施例仅仅是本发明一部分实施例,而非全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其它实施例,都属于本发明保护的范围。
实施例1中间体式6a所示化合物的制备
式6a所示化合物的合成路线如下:
(1)3,5-二甲氧基-4-异丙基苯甲酸甲酯(1)的制备
称取3,5-二甲氧基-苯甲酸甲酯(4g,20.4mmol,1eq)和2-溴丙烷(2.76g,22.4mmol,1.1eq)溶于1,2-二氯乙烷(20mL)中,在搅拌状态下,加入无水三氯化铝(2.98g,22.4mmol,1.1eq),加热至90摄氏度下搅拌6h,TLC监测反应结束后,倒入500mL烧杯中,加入200mL饱和碳酸氢钠溶液,过滤,滤液用乙酸乙酯萃取,有机溶液用硫酸镁干燥后,减压浓缩,经硅胶柱分离得到产物1(2.91g),淡黄色固体,熔点:106℃,收率60%。1H NMR(400MHz,CDCl3)δ7.22(s,2H),3.90(s,3H),3.85(s,6H),3.63(hep,1H),1.27(d,J=7.2Hz,6H);GC-MS=238.
(2)3,5-二羟基基-4-异丙基苯甲酸(2)的制备
称取化合物1(2g,8.4mmol,1eq)和吡啶盐酸盐(3.88g,33.6mmol,4eq)置于50mL圆底烧瓶中,200摄氏度下反应6h,TLC监测反应结束后,缓慢加入10mL冰水,冷却后反应液用乙酸乙酯萃取,有机相硫酸镁干燥后,减压浓缩,经硅胶柱分离得到产物2(1.28g),淡黄色固体,熔点:183℃,收率78%。1H NMR(400MHz,DMSO)δ12.41(s,1H),9.31(s,2H),6.89(s,2H),3.47(hep,1H),1.24(d,J=7.2Hz,6H);GC-MS=196.
(3)3,5-二羟基-4-异丙基苯甲酸甲酯(3)的制备
称取化合物2(1.96g,10mmol,1eq)溶于甲醇(10mL)溶液中,滴加二氯亚砜(1.78g,15mmol,1.5eq),加热至70摄氏度,反应4h,TLC监测反应结束后,减压浓缩,经硅胶柱分离得到产物3(1.78g),淡黄色固体,熔点:151℃,收率85%。1H NMR(400MHz,CDCl3)δ7.08(s,2H),5.29(s,2H),3.89(s,3H),3.51(hep,1H),1.28(d,J=7.9Hz,6H);GC-MS=210.
(4)3,5-二苄氧基-4-异丙基苯甲酸甲酯(4)的制备
称取化合物3(2.1g,10mmol,1eq)和溴化苄(3.4g,20mmol,2eq)溶于四氢呋喃溶液中15mL,加入碳酸铯(8g,25mmol,2.5eq),70摄氏度下反应12h,TLC监测反应结束后,减压蒸出溶剂,残留物溶于乙酸乙酯溶液,并用水洗涤,将有机相用硫酸镁干燥,减压浓缩,经硅胶柱分离得到产物4(3.47g),淡黄色固体,熔点:127℃,收率89%。1H NMR(400MHz,DMSO)δ7.47(d,J=7.2Hz,4H),7.43(t,J=7.2Hz,4H),7.34(t,J=7.2Hz,2H),7.30(s,2H),5.17(s,4H),3.84(s,3H),3.66(hep,1H),1.24(d,J=7.2Hz,6H);GC-MS=390.
(5)3,5-二苄氧基-4-异丙基苯甲醇(5a)的制备
称取化合物4(3.71g,10.2mmol,1eq)溶于无水四氢呋喃(10mL)溶液中,在0摄氏度搅拌状态下,加入氢化铝锂(0.49g,12.24mmol,1.2eq),随后在室温下反应6h,TLC监测反应结束后,减压蒸出溶剂,残留物溶于二氯甲烷溶液,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,经硅胶柱分离得到产物5a(2.96g),淡黄色固体,熔点:87℃,收率80.4%。1H NMR(400MHz,DMSO)δ7.48(d,J=7.8Hz,4H),7.41(t,J=7.8Hz,4H),7.33(t,J=7.8Hz,2H),6.70(s,2H),5.07(s,4H),4.42(d,J=3.6Hz,2H),3.61(hep,1H),1.22(d,J=7.2Hz,6H);GC-MS=362.
(6)3,5-二苄氧基-4-异丙基卞溴(6a)的制备
称取化合物5a(3.62g,10mmol,1eq)溶于10mL二氯甲烷溶液中,在0摄氏度下加入三溴化磷(2mL),加热至室温下反应6h,TLC监测反应结束后,反应液用NaHCO3饱和水溶液洗涤,有机相用硫酸镁干燥,减压浓缩,经硅胶柱分离得到产物6a(3.32g),淡黄色固体,熔点:74℃,收率78.4%。1H NMR(400MHz,CDCl3)δ7.44(d,J=7.1Hz,4H),7.39(t,J=7.4Hz,4H),7.34(t,J=7.2Hz,2H),6.66(s,2H),5.07(s,4H),4.44(s,2H),3.70(hep,1H),1.29(d,J=7.1Hz,6H);GC-MS=424.
实施例2中间体式6b所示化合物的制备
式6b所示化合物的合成路线如下:
(1)3,5-二甲氧基-4-异丙基苯甲醇(5b)的制备
称取实施例1制得的化合物1(1g,4.2mmol,1eq)溶于无水四氢呋喃(10mL)溶液中,在0摄氏度搅拌状态下,加入氢化铝锂(0.19g,5mmol,1.2eq),加热至室温,反应6h,TLC监测反应结束后,减压蒸出溶剂,残留物溶于二氯甲烷溶液,并用水洗涤,将有机相硫酸镁干燥,减压浓缩,经硅胶柱分离得到产物5b(0.74g),淡黄色固体,熔点:95℃,收率84%,1H NMR(400MHz,CDCl3)δ6.56(s,2H),4.64(d,J=3.6Hz,2H),3.81(s,6H),3.58(hep,1H),1.27(d,J=7.2Hz,6H);GC-MS=210.
(2)3,5-二甲氧基-4-异丙基卞溴(6b)的制备
称取化合物5b(2.1g,10mmol,1eq)溶于10mL二氯甲烷溶液中,0摄氏度下加入三溴化磷(2mL),加热至室温,反应6h,TLC监测反应结束后,反应液用NaHCO3饱和水溶液洗涤,有机相用硫酸镁干燥,减压浓缩,经硅胶柱分离得到产物6b(2.23g),淡黄色固体,熔点:56℃,收率82%。1H NMR(400MHz,CDCl3)δ6.56(s,2H),4.46(s,2H),3.80(s,6H),3.56(hep,1H),1.25(d,J=7.2Hz,6H);GC-MS=272.
实施例3式(Ⅱ)所示化合物(8a)和式(Ⅰ)所示化合物(9a)的制备
式(Ⅰ)所示化合物的合成路线如下:
(1)(E)-3-[3,5-双-(苄氧基)-4-异丙基苯乙烯基]吡啶(8a)的制备
称取化合物6a(200mg,0.47mmol,1eq)加入25mL圆底烧瓶中,加入亚磷酸三乙酯(5mL),搅拌状态下加入四丁基溴化铵(15mg,0.047mmol,0.1eq),加热至130摄氏度,在氮气保护下反应6h,在80°加热下,通过减压除去过量的亚磷酸三乙酯,得到粗产物7a。
将上述粗产物7a溶于四氢呋喃(5mL),加入3-吡啶甲醛(38.5mg,0.36mol,0.88eq)和氢化钠(49.2mg,2.05mmol,5eq),在氮气保护下,反应液在室温下反应12h,TLC监测反应结束后,减压蒸出溶剂,残留物溶于乙酸乙酯,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,经硅胶柱分离得到产物8a(149mg),淡黄色固体,熔点:132℃,收率82.1%。1H NMR(400MHz,CDCl3)δ8.65(d,J=4.0Hz,1H),8.40(dd,J=8.4,4.0Hz,1H),7.75(d,J=8.4Hz,1H),7.45–7.29(m,11H),7.0(d,J=16.4Hz,1H),6.88(d,J=16.4Hz,1H),6.74(s,2H),5.18(s,4H),3.64(hep,1H),1.24(d,J=7.2Hz,6H);GC-MS=435.
(2)(E)-2-异丙基-5-[2-(吡啶-3-基)乙烯基]苯-1,3-二醇(9a)的制备
称取化合物8a(70mg,0.16mmol)溶于二氯甲烷(5mL)中,在0摄氏度下加入三溴化硼(1mL),之后,加热至室温下反应6h,TLC监测反应结束后,减压蒸出溶剂,残留物用重结晶,得到化合物9a(21mg),淡黄色固体,熔点:310℃,收率51.1%。1H NMR(400MHz,DMSO)δ9.20(s,2H),9.08(d,J=3.4Hz,2H),8.23(m,2H),8.72(d,J=16.4Hz,1H),7.92(d,J=16.4Hz,1H),6.64(s,2H),3.47(hep,1H),1.25(d,J=7.2Hz,6H);GC-MS=255.
实施例4式(Ⅱ)所示化合物(8b)和式(Ⅰ)所示化合物(9b)的制备
式(Ⅰ)所示化合物的合成路线如下:
(1)(E)-4-[3,5-双-(苄氧基)-4-异丙基苯乙烯基]吡啶(8b)的制备
称取化合物6a(100mg,0.21mmol,1eq)加入25mL圆底烧瓶中,加入亚磷酸三乙酯(5mL),搅拌状态下加入四丁基溴化铵(15mg,0.047mmol,0.1eq),加热至130摄氏度,在氮气保护下反应6h,在80°加热下,通过减压除去过量的亚磷酸三乙酯,得到粗产物7a。
将上述粗产物7a溶于四氢呋喃(5mL),加入吡啶-4-甲醛(19.5mg,0.18mol,0.88eq)和氢化钠(25.2mg,1.05mmol,5eq)氮气保护,室温下反应12h,TLC监测反应结束后,减压蒸出溶剂,残留物溶于乙酸乙酯,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,经硅胶柱分离得到产物8b(64mg),熔点:142℃,收率71%。1H NMR(400MHz,CDCl3)δ8.56(d,J=7.6Hz,2H),7.46–7.35(m,12H),7.16(d,J=16.4Hz,1H),6.83(d,J=16.4Hz,1H),6.75(s,2H),5.18(s,4H),3.65(hep,1H),1.24(d,J=7.2Hz,6H);GC-MS=435.
(2)(E)-2-异丙基-5-[2-(吡啶-4-基)乙烯基]苯-1,3-二醇9b的制备称取化合物8b(60mg,0.11mmol)溶于二氯甲烷(5mL)中,在0摄氏度下加入三溴化硼(1mL),加热至室温下反应6h,TLC监测反应结束后,减压蒸出溶剂,残留物用重结晶,得到化合物(9b)(30mg),淡黄色固体,熔点:305℃,收率85.2%。1H NMR(400MHz,DMSO)δ9.34(s,2H),8.79(d,J=8.0Hz,2H),8.22(d,J=8.0Hz,2H),7.75(d,J=16.4Hz,1H),7.12(d,J=16.4Hz,1H),6.64(s,2H),3.44(hep,1H),1.25(d,J=7.2Hz,6H);GC-MS=255.
实施例5式(Ⅱ)所示化合物(8c)和式(Ⅰ)所示化合物(9c)的制备
式(Ⅰ)所示化合物的合成路线如下:
(1)(E)-2-[3,5-双-(苄氧基)-4-异丙基苯乙烯基]-6-甲基吡啶(8c)的制备
称取化合物6a(200mg,0.47mmol,1eq)加入25mL圆底烧瓶中,加入亚磷酸三乙酯(5mL),搅拌状态下加入四丁基溴化铵(15mg,0.047mmol,0.1eq),加热至130摄氏度,在氮气保护下反应6h,在80°加热下,通过减压除去过量的亚磷酸三乙酯,得到粗产物7a。
将上述粗产物7a溶于四氢呋喃(5mL),加入6-甲基-2-吡啶甲醛(43.6mg,0.36mol,0.88eq)和氢化钠(49.2mg,2.05mmol,5eq),在氮气保护下,在室温反应12h,TLC监测反应结束后,减压蒸出溶剂,残留物溶于乙酸乙酯,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,经硅胶柱分离得到产物8c(121mg),淡黄色固体,熔点:168℃,收率64.9%。1H NMR(400MHz,CDCl3)δ7.55-7.29(m,12H),7.05(m,2H),6.95(d,J=7.6Hz,1H),6.82(s,2H),5.08(s,4H),3.68(hep,1H),2.58(s,3H),1.33(d,J=7.2Hz,6H);GC-MS=449.
(2)(E)-2-异丙基-5-[2-(6-甲基吡啶-2-基)乙烯基]苯-1,3-二醇(9c)的制备
称取化合物8c(121mg,0.27mmol)溶于二氯甲烷(5mL)中,在0摄氏度下加入三溴化硼(1mL),加热至室温下反应6h,TLC监测反应结束后,减压蒸出溶剂,残留物溶于乙酸乙酯,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,重结晶得化合物9c(32mg),淡黄色固体,熔点:295℃,收率44.1%。1H NMR(400MHz,DMSO)δ9.39(s,2H),8.31(m,2H),7.74(d,J=16.4Hz,1H),7.65(d,J=3.4Hz,2H),7.09(d,J=16.4Hz,1H),6.59(s,2H),3.48(hep,1H),2.55(s,3H),1.25(hep,6H);GC-MS=269.
实施例6式(Ⅱ)所示化合物(8d)和式(Ⅰ)所示化合物(9d)的制备
式(Ⅰ)所示化合物的合成路线如下:
(1)(E)-2-[3,5-双-(苄氧基)-4-异丙基苯乙烯基]-6-甲氧基吡啶(8d)的制备
称取化合物6a(200mg,0.47mmol,1eq)加入25mL圆底烧瓶中,加入亚磷酸三乙酯(5mL),搅拌状态下加入四丁基溴化铵(15mg,0.047mmol,0.1eq),加热至130摄氏度,在氮气保护下反应6h,在80°加热下,通过减压除去过量的亚磷酸三乙酯,得到粗产物7a。
将上述粗产物7a溶于四氢呋喃(5mL),加入6-甲氧基-2-吡啶甲醛(49.32mg,0.36mol,0.88eq)和氢化钠(49.2mg,2.05mmol,5eq),在氮气保护下,在室温反应12h,TLC监测反应结束后,减压蒸出溶剂,残留物溶于乙酸乙酯,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,经硅胶柱分离得到产物8d(105mg),淡黄色固体,熔点:181℃,收率54.5%。1HNMR(400MHz,CDCl3)δ7.55-7.29(m,11H),6.90(d,J=16.5Hz,1H),6.82(d,J=7.6Hz,1H),6.79(s,2H),6.55(d,J=7.6Hz,1H),5.13(s,4H),3.98(s,3H),3.73(hep,1H),1.32(d,J=7.6Hz,6H);GC-MS=465.
(2)(E)-2-异丙基-5-[2-(6-甲氧基吡啶-2-基)乙烯基]苯-1,3-二醇(9d)的制备
称取化合物8d(102mg,0.22mmol)溶于二氯甲烷(5mL)中,在0摄氏度下加入三溴化硼(1mL),加热至室温下反应6h,TLC监测反应结束后,减压蒸出溶剂,残留物溶于乙酸乙酯,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,重结晶得化合物9d(49mg),淡黄色固体,熔点:205℃,收率78.5%。1H NMR(400MHz,DMSO)δ9.10(s,2H),7.68(t,J=8.2Hz,1H),7.38(d,J=15.6Hz,1H),7.11(d,J=8.2Hz,1H),6.87(d,J=16.0Hz,1H),6.68(d,J=8.4Hz,1H),6.50(s,2H),3.92(s,3H),3.43(hep,1H),1.24(d,J=7.2Hz,6H);GC-MS=285.
实施例7式(Ⅱ)所示化合物(8e)和式(Ⅰ)所示化合物(9e)的制备
式(Ⅰ)所示化合物的合成路线如下:
(1)(E)-2-[3,5-双-(苄氧基)-4-异丙基苯乙烯基]喹啉(8e)的制备
称取化合物6a(200mg,0.47mmol,1eq)加入25mL圆底烧瓶中,加入亚磷酸三乙酯(5mL),搅拌状态下加入四丁基溴化铵(15mg,0.047mmol,0.1eq),加热至130摄氏度,在氮气保护下反应6h,在80°加热下,通过减压除去过量的亚磷酸三乙酯,得到粗产物7a。
将上述粗产物7a溶于四氢呋喃(5mL),加入2-喹啉甲醛(56.5mg,0.36mol,0.88eq)和氢化钠(49.2mg,2.05mmol,5eq),在氮气保护下,在室温反应12h,TLC监测反应结束后,减压蒸出溶剂,残留物溶于乙酸乙酯,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,经硅胶柱分离得到产物8e(48mg),熔点:172℃,收率23.8%。1H NMR(400MHz,CDCl3)δ8.11(d,J=7.8Hz,1H),8.07(d,J=7.8Hz,1H),7.77(d,J=7.8Hz,1H),7.68(m,2H),7.57(d,J=16.4Hz,1H),7.52–7.24(m,12H),6.92(s,2H),5.14(s,4H),3.78(hep,1H),1.34(d,J=7.2Hz,6H);GC-MS=485.
(2)(E)-2-异丙基-5-[2-(2-喹啉-2-基)乙烯基]苯-1,3-二醇(9e)的制备
称取化合物8e(68mg,0.14mmol)溶于二氯甲烷(5mL)中,在0摄氏度下加入三溴化硼(1mL),加热至室温下反应6h,TLC监测反应结束后,减压蒸出溶剂,残留物溶于乙酸乙酯,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,重结晶得化合物9e(19mg),淡黄色固体,熔点:211℃,收率44.5%。1H NMR(400MHz,DMSO)δ9.41(s,2H),8.82(d,J=8.4Hz,1H),8.39(d,J=8.4Hz,1H),8.18(d,J=8.4Hz,1H),8.11(d,J=8.4Hz,1H),7.97(m,2H),7.78(t,J=7.9Hz,1H),7.24(d,J=16.0Hz,1H),6.67(s,2H),3.48(m,1H),1.26(d,J=8.2Hz,,6H);GC-MS=305.
实施例8式(Ⅱ)所示化合物(8f)和式(Ⅰ)所示化合物(9f)的制备
式(Ⅰ)所示化合物的合成路线如下:
(1)(E)-2-[3,5-(二甲氧基苯基)-4-异丙基苯乙烯基]-5-甲基噻吩(8f)制备
称取化合物6b(200mg,0.73mmol,1eq)加入25mL圆底烧瓶中,加入亚磷酸三乙酯(5mL),搅拌状态下加入四丁基溴化铵(23.5mg,0.073mmol,0.1eq),加热至130摄氏度,在氮气保护下反应6h,在80°加热下,通过减压除去过量的亚磷酸三乙酯,得到粗产物7b。
将上述粗产物7b溶于四氢呋喃(5mL),加入5-甲基-2-噻吩甲醛(80.6mg,0.64mol,0.88eq)和氢化钠(87mg,3.65mmol,5eq),在氮气保护下,在室温反应12h,TLC监测反应结束后,减压蒸出溶剂,残留物溶于乙酸乙酯,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,经硅胶柱分离得到产物8f(98.6mg),黄色油状液体,收率44.4%。1H NMR(400MHz,CDCl3)δ7.09(d,J=16.0Hz,1H),6.84(d,J=3.2Hz,1H),6.73(d,J=16.0Hz,1H),6.64(m,1H),6.62(s,2H),3.83(s,6H),3.57(hep,1H),2.48(s,3H),1.27(d,J=7.2Hz,6H);GC-MS=302.
(2)(E)-2-异丙基-5-[2-(5-甲基噻吩-2-基)乙烯基]-苯-1,3-二醇(9f)的制备
称取化合物8f(90mg,0.30mmol),吡啶盐酸盐(450mg)于烧瓶中,200摄氏度下反应6h,TLC监测反应结束后,反应液溶于乙酸乙酯,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,经硅胶柱分离得到产物9f(28.9mg),黄色固体,熔点:146℃,收率35.5%。1H NMR(400MHz,CDCl3)δ7.01(d,J=16.0Hz,1H),6.81(d,J=3.4Hz,1H),6.64(d,J=3.4Hz,1H),6.61(d,J=16.0Hz,2H),6.42(s,2H),4.73(s,2H),3.44(hep,1H),2.47(s,3H),1.36(d,J=7.2Hz,6H);GC-MS=274.
实施例9式(Ⅲ)所示化合物(8g)和式(Ⅰ)所示化合物(9g)的制备
式(Ⅰ)所示化合物的合成路线如下:
(1)(E)-2-[3,5-(二甲氧基苯基)-4-异丙基苯乙烯基]-4-溴噻吩(9g)的制备
称取化合物6b(300mg,1.09mmol,1eq)加入25mL圆底烧瓶中,加入亚磷酸三乙酯(5mL),搅拌状态下加入四丁基溴化铵(23.5mg,0.073mmol,0.1eq),加热至130摄氏度,在氮气保护下反应6h,在80°加热下,通过减压除去过量的亚磷酸三乙酯,得到粗产物7b。
将上述粗产物7b溶于四氢呋喃(5mL),加入4溴-2-噻吩甲醛(208mg,1.09mmol,1eq)和氢化钠(130mg,5.45mmol,5eq),在氮气保护下,在室温反应12h,TLC监测反应结束后,减压蒸出溶剂,残留物溶于乙酸乙酯,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,经硅胶柱分离得到产物8g(188mg),黄色油状液体,收率56.8%。1H NMR(400MHz,CDCl3)δ7.01(s,1H),7.02(d,J=16.4Hz,1H),6.91(s,1H),6.80(d,J=16.4Hz,1H),6.55(s,2H),3.84(s,6H),3.59(hep,1H),1.27(d,J=7.2Hz,6H);GC-MS=366.
(2)(E)-2-异丙基-5-[2-(4-溴噻吩-2-基)乙烯基]-苯-1,3-二醇(9g)的制备
称取化合物8g(51mg,0.14mmol),吡啶盐酸盐(255mg)于烧瓶中,在200摄氏度下反应6h,TLC监测反应结束后,反应液溶于乙酸乙酯,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,经硅胶柱分离得到产物9g(29mg)黄色固体,熔点:86℃,收率61.5%。1H NMR(400MHz,CDCl3)δ6.98(d,J=16.0Hz,1H),6.95(s,1H),6.90(s,1H),6.72(d,J=16.0Hz,1H),6.44(s,2H),4.84(s,2H),3.45(hep,1H),1.37(d,J=7.2Hz,6H);GC-MS=338.
实施例10式(Ⅲ)所示化合物(8h)和式(Ⅰ)所示化合物(9h)的制备
式(Ⅰ)所示化合物的合成路线如下:
(1)(E)-2-[3,5-(二甲氧基苯基)-4-异丙基苯乙烯基]噻吩(9h)的制备
称取化合物6b(128mg,0.47mmol,1eq)加入25mL圆底烧瓶中,加入亚磷酸三乙酯(5mL),搅拌状态下加入四丁基溴化铵(23.5mg,0.073mmol,0.1eq),加热至130摄氏度,在氮气保护下反应6h,在80℃加热下,通过减压除去过量的亚磷酸三乙酯,得到粗产物7b。
将上述粗产物7b溶于四氢呋喃(5mL),加入3-噻吩甲醛(78.7mg,0.7mmol,1.5eq)和氢化钠(56.4mg,2.35mmol,5eq),在氮气保护下,在室温反应12h,TLC监测反应结束后,反应液溶于乙酸乙酯,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,经硅胶柱分离得到产物8h(118mg),黄色油状液体,收率87%。1H NMR(400MHz,CDCl3)δ7.36–7.31(m,2H),7.26(t,J=2.0Hz,1H),7.07(d,J=16.4Hz,1H),6.90(d,J=16.4Hz,1H),6.66(s,2H),3.85(s,6H),3.57(hep,1H),1.28(d,J=7.2Hz,6H);GC-MS=288.
(2)(E)-2-异丙基-5-[2-(噻吩-3-基)乙烯基]-苯-1,3-二醇(9h)的制备
称取化合物8h(118mg,0.41mmol),吡啶盐酸盐(590mg)于烧瓶中,200摄氏度下反应6h,TLC监测反应结束后,溶于乙酸乙酯,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,经硅胶柱分离得到产物9h(64.9mg),黄色固体,熔点:76℃,收率61.0%。1H NMR(400MHz,CDCl3)δ7.30(m,2H),7.23(t,J=2.0Hz,1H),6.99(d,J=16.4Hz,1H),6.75(d,J=16.4Hz,1H),6.46(s,2H),4.84(s,3H),3.43(hep,1H),1.37(d,J=2.8Hz,6H);GC-MS=260.
实施例11式(Ⅲ)所示化合物(8i)和式(Ⅰ)所示化合物(9i)的制备
式(Ⅰ)所示化合物的合成路线如下:
(1)(E)-2-[3,5-(二甲氧基苯基)-4-异丙基苯乙烯基]-5-苯基噻吩(8i)的制备
称取化合物6b(200mg,0.63mmol,1eq)加入25mL圆底烧瓶中,加入亚磷酸三乙酯(5mL),搅拌状态下加入四丁基溴化铵(23.5mg,0.073mmol,0.1eq),加热至130摄氏度,在氮气保护下反应6h,在80°加热下,通过减压除去过量的亚磷酸三乙酯,得到粗产物7b。
将上述粗产物7b溶于四氢呋喃(5mL),加入5-苯基-2-噻吩甲醛(118.6mg,0.63mmol,1eq)和氢化钠(45.4mg,1.89mmol,3eq),在氮气保护下,在室温反应12h,TLC监测反应结束后,反应液溶于乙酸乙酯,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,经硅胶柱分离得到产物8i(107mg),黄色油状液体,收率48.4%。1H NMR(400MHz,CDCl3)δ7.55(d,J=7.6Hz,2H),7.38(t,J=7.6Hz,2H),7.29(t,J=7.6Hz,1H),7.21(d,J=3.6Hz,1H),7.15(d,J=16.0Hz,1H),7.03(d,J=3.6Hz,1H),6.88(d,J=16.0Hz,1H),6.65(s,2H),3.85(s,6H),3.57(hep,1H),1.30(d,J=7.2Hz,6H);GC-MS=364.
(2)(E)-2-异丙基-5-[2-(5-苯基噻吩-2-基)乙烯基]-苯-1,3-二醇(9i)的制备
称取化合物8i(100mg,0.27mmol),吡啶盐酸盐(500mg)于烧瓶中,200摄氏度下反应6h,TLC监测反应结束后,溶于乙酸乙酯,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,经硅胶柱分离得到产物9i(59mg),黄色固体,熔点:76℃,收率60.2%。1H NMR(400MHz,CDCl3)δ7.60(d,J=7.6Hz,2H),7.38(t,J=7.6Hz,2H),7.29(t,J=7.6Hz,1H),7.21(d,J=3.6Hz,1H),7.07(d,J=16.0Hz,1H),7.00(d,J=3.6Hz,1H),6.73(d,J=16.0Hz,1H),6.46(s,2H),4.76(s,2H),3.43(hep,1H),1.37(d,J=7.2Hz,6H);GC-MS=336.
实施例12式(Ⅲ)所示化合物(8j)和式(Ⅰ)所示化合物(9j)的制备
式(Ⅰ)所示化合物的合成路线如下:
(1)(E)-2-[3,5-(二甲氧基苯基)-4-异丙基苯乙烯基]-4-苯基噻吩(8j)的制备
称取化合物6b(200mg,0.63mmol,1eq)加入25mL圆底烧瓶中,加入亚磷酸三乙酯(5mL),搅拌状态下加入四丁基溴化铵(23.5mg,0.073mmol,0.1eq),加热至130摄氏度,在氮气保护下反应6h,在80°加热下,通过减压除去过量的亚磷酸三乙酯,得到粗产物7b。
将上述粗产物7b溶于四氢呋喃(5mL),加入5-苯基-2-噻吩甲醛(118.6mg,0.63mmol,1eq)和氢化钠(45.4mg,1.89mmol,3eq)在氮气保护下,在室温反应12h,TLC监测反应结束后,反应液溶于乙酸乙酯,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,经硅胶柱分离得到产物8j(107mg),黄色固体,熔点:86℃,收率42.1%。1H NMR(400MHz,CDCl3)δ7.60(d,J=7.8Hz,2H),7.40(t,J=7.8Hz,2H),7.35(s,1H),7.31(s,1H),7.30(t,J=7.8Hz,1H),7.20(d,J=16.0Hz,1H),6.90(d,J=16.0Hz,1H),3.85(s,6H),3.58(hep,1H),1.29(d,J=7.2Hz,6H);GC-MS=364.
(2)(E)-2-异丙基-5-[2-(4-苯基噻吩-2-基)乙烯基]-苯-1,3-二醇(9j)的制备
称取化合物8j(200mg,0.55mmol),吡啶盐酸盐(1g)于烧瓶中,200摄氏度下反应6h,TLC监测反应结束后,溶于乙酸乙酯,并用水洗涤,将有机相在MgSO4上干燥,减压浓缩,经硅胶柱分离得到产物9j(71mg),黄色固体,熔点:108℃,收率38.2%。1H NMR(400MHz,CDCl3)δ7.60(d,J=7.8Hz,2H),7.39(t,J=7.8Hz,2H),7.31-7.29(m,3H),7.11(d,J=16.0Hz,1H),6.75(d,J=16.0Hz,1H),6.47(s,2H),4.82(s,2H),3.45(hep,1H),1.37(d,J=7.8Hz,6H);GC-MS=336.
试验例
本实施例对实施例2-12制备得到的苯乙烯衍生物进行对小鼠巨噬细胞(RAW264.7)的毒性测试以及对脂多糖(LPS)诱导的巨噬细胞一氧化氮(NO)生成的抑制作用的测试,评价其抗炎作用。(测试方法参照Zhou W.et al.Biomed Pharmacother.2020,131:110696.)。
(1)巨噬细胞的毒性测试采用MTT方法:
取小鼠巨噬细胞(RAW264.7),以3×104/mL浓度接种在96孔板中(100 L),在37℃,5%CO2的培养箱中培养18h,待细胞贴壁后,弃去上清液,加入不同浓度的化合物,继续培养48h,加入0.5mg/mL的MTT,继续培养4h后,每孔再加入150μL的DMSO,然后在摇床上震荡10min,用酶标仪测定570nm处的吸光度(OD值),用Prism软件算IC50,结果如表1所示。
(2)抑制LPS诱导的巨噬细胞NO生成活性测试(测试方法参照于BiomedPharmacother.2020Nov;131:110696):
取小鼠巨噬细胞(RAW264.7),以5×105/mL浓度接种在96孔板中(100 L),在37℃,5%CO2的培养箱中培养18h。之后,将化合物(最终浓度:10 M)于LPS(最终浓度:5g/mL)一齐加入细胞培养液中,在37℃下培养24h,然后取细胞培养液上清液,按每孔50L置于新的96孔板中,再加入碧云天NO试剂盒的A液和B液各50L,在37℃培养箱中培养10min后,测试540nm处的吸光度(OD值),结果如表1所示。
从表1可知,相比于已知的药物苯烯莫德(Benvitimod,一款已用于临床的,可治疗银屑病的药物),我们合成的化合物对巨噬细胞的毒性较小,除了化合物9f和9j之外。其中一些化合物对一氧化氮的抑制活性相对苯烯莫德都具较高,显示这些化合物可能对抗银屑病、抗特应性皮炎具有更好的作用。
表1实施例2-11制备得到的苯乙烯衍生物活性测试结果
以上所述,以上实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。
Claims (10)
2.根据权利要求1所述的苯乙烯衍生物,其特征在于,R3中五元~六元的杂环基选自吡啶或噻吩。
3.根据权利要求1所述的苯乙烯衍生物,其特征在于,R3中取代的五元~六元的杂环基中的取代基选自甲基、甲酰基、苯基或卤素。
5.一种苯乙烯衍生物的制备方法,其特征在于,包括以下步骤:
步骤1:在有机溶剂中,将式1-1所示化合物与R2-Br在催化剂存在下进行烷基化反应,得到式1所示化合物;
步骤2:在催化剂的存在下,将式1所示化合物进行去甲基化反应,得到式2所示化合物;
步骤3:在催化剂的存在下,将式2所示化合物与R-OH进行酯化反应,得到式3所示化合物;
步骤4:将式3所示化合物与R1-X在有机溶剂中进行反应,得到式4所示化合物;
步骤5:将式4所示化合物与还原剂在有机溶剂中进行酯还原反应,得到式5a所示化合物;
步骤6:将式5a所示化合物与三溴化磷在有机溶剂中进行卤代反应,得到式6a所示化合物;
步骤7:将式6a所示化合物与亚磷酸三乙酯进行反应,得到式7a所示化合物,再与芳香醛在有机溶剂中进行Wittig反应,得到式(Ⅰ)所示结构化合物;
R选自烷基或酰基;R1选自烷基、芳烷基或酰基;R2选自烷基、环烷基、芳烷基或卤素;R3选自取代或非取代的五元~六元的杂环基、取代或非取代的五元~六元的苯并杂环基;X为卤素。
6.一种苯乙烯衍生物的制备方法,其特征在于,包括以下步骤:
步骤1:在有机溶剂中,将式1-1所示化合物与式R2-Br在催化剂存在下进行烷基化反应,得到式1所示化合物;
步骤2:将式1所示化合物与还原剂在有机溶剂中进行酯还原反应,得到式5b所示化合物;
步骤3:将式5b所示化合物与三溴化磷在有机溶剂中进行卤代反应,得到式6b所示化合物;
步骤4:将式6b所示化合物与亚磷酸三乙酯进行反应,得到式7b所示化合物,再与芳香醛在有机溶剂中进行Wittig反应,得到式(Ⅰ)所示化合物;
R1选自烷基、芳烷基或酰基;R2选自烷基、环烷基、芳烷基或卤素;R3选自取代或非取代的五元~六元的杂环基、取代或非取代的五元~六元的苯并杂环基。
8.根据权利要求7所述的苯乙烯衍生物,其特征在于,所述式(Ⅰ)所示结构的苯乙烯衍生物包括(E)-3-[3,5-双-(苄氧基)-4-异丙基苯乙烯基]吡啶、(E)-2-异丙基-5-[2-(吡啶-3-基)乙烯基]苯-1,3-二醇、(E)-4-[3,5-双-(苄氧基)-4-异丙基苯乙烯基]吡啶、(E)-2-异丙基-5-[2-(吡啶-4-基)乙烯基]苯-1,3-二醇、(E)-2-[3,5-双-(苄氧基)-4-异丙基苯乙烯基]-6-甲基吡啶、(E)-2-异丙基-5-[2-(6-甲基吡啶-2-基)乙烯基]苯-1,3-二醇、(E)-2-[3,5-双-(苄氧基)-4-异丙基苯乙烯基]-6-甲氧基吡啶、(E)-2-异丙基-5-[2-(6-甲氧基吡啶-2-基)乙烯基]苯-1,3-二醇、(E)-2-[3,5-双-(苄氧基)-4-异丙基苯乙烯基]喹啉、(E)-2-异丙基-5-[2-(2-喹啉-2-基)乙烯基]苯-1,3-二醇、(E)-2-[3,5-(二甲氧基苯基)-4-异丙基苯乙烯基]-5-甲基噻吩、(E)-2-异丙基-5-[2-(5-甲基噻吩-2-基)乙烯基]-苯-1,3-二醇、(E)-2-[3,5-(二甲氧基苯基)-4-异丙基苯乙烯基]-4-溴噻吩、(E)-2-异丙基-5-[2-(4-溴噻吩-2-基)乙烯基]-苯-1,3-二醇、(E)-2-[3,5-(二甲氧基苯基)-4-异丙基苯乙烯基]噻吩、(E)-2-异丙基-5-[2-(噻吩-3-基)乙烯基]-苯-1,3-二醇、(E)-2-[3,5-(二甲氧基苯基)-4-异丙基苯乙烯基]-5-苯基噻吩、(E)-2-异丙基-5-[2-(5-苯基噻吩-2-基)乙烯基]-苯-1,3-二醇、(E)-2-[3,5-(二甲氧基苯基)-4-异丙基苯乙烯基]-4-苯基噻吩和(E)-2-异丙基-5-[2-(4-苯基噻吩-2-基)乙烯基]-苯-1,3-二醇。
9.权利要求1至4任意一项所述的苯乙烯衍生物、权利要求5或6所述的制备方法制得的苯乙烯衍生物或权利要求7所述的苯乙烯衍生物在制备治疗炎症疾病药物中的应用。
10.根据权利要求9所述的应用,其特征在于,所述炎症疾病为银屑病或抗特应性皮炎。
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