CN114014749A - 一类4-羟基联苯类衍生物、制备方法及应用 - Google Patents

一类4-羟基联苯类衍生物、制备方法及应用 Download PDF

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CN114014749A
CN114014749A CN202111392490.0A CN202111392490A CN114014749A CN 114014749 A CN114014749 A CN 114014749A CN 202111392490 A CN202111392490 A CN 202111392490A CN 114014749 A CN114014749 A CN 114014749A
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宋国强
狄万慧
谈颖
夏颜
王贺成
唐龙
孔韧
冯筱晴
黄险峰
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Changzhou University
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Abstract

本发明提供了一类4‑羟基联苯类衍生物、制备方法及应用，属于药物化学领域。主要包括4‑羟基联苯、4‑羟基‑4'‑甲氧基联苯和4,4'‑二羟基联苯类衍生物32个化合物，具有较好的PDE2抑制活性，能够用于治疗中枢神经系统疾病，比如治疗记忆缺陷、认知障碍、焦虑和抑郁症等，也可用来治疗大脑的神经变性过程疾病，作为活性成分制备抑制PDE2活性的药物。另外，针对提供的化合物结构，给出了相应的合成方法，合成方法简单，后处理方法创造性的用溶剂和化合物的特性分离，省去了繁杂的柱层析，适合工业化大生产的需求。

Description

一类4-羟基联苯类衍生物、制备方法及应用
技术领域
本发明属于药物化学领域，具体涉及作为磷酸二酯酶2(PDE2)的抑制剂的新颖的4-羟基联苯类衍生物。
背景技术
尿石素类化合物是鞣花单宁的代谢产物，尿石素在抗氧化、抗炎、抗肿瘤和中枢神经系统等疾病表现出了积极的作用。
磷酸二酯酶(PDEs)具有水解细胞内第二信使(cAMP环磷酸腺苷或cGMP环磷酸鸟苷)的功能，降解细胞内cAMP或cGMP，从而终结这些第二信使所传导的生化作用。cAMP和cGMP对于细胞活动起着重要的调节作用。而其浓度的调节主要由核苷酸环化酶的合成和磷酸二酯酶(PDEs)水解作用之间的平衡决定。PDEs在人体内分布广泛，生理作用涉及多个研究领域。近年来，PDEs作为新的治疗靶点，引起了众多学者广泛的关注，成为一个新的研究热点。PDE2可以同时水解cAMP和cGMP，其在认知损伤、炎症、心绞痛、心律失常、高血压和心衰中发挥重要作用。但是，由于种种原因，目前市面上没有商品化的PDE2抑制剂，所以，仍需要研发PDE2抑制剂化合物，这些化合物应该具有对PDE2有选择性，具有良好的化学稳定性以及可透过血脑屏障到达相关脑区域。
针对尿石素类化合物靶向到PDE2小分子的研究，国内外已经开始，但是，针对尿石素类化合物的修饰和改造，目前研究较少，这就影响了尿石素类化合物药品商品化的进程。
发明内容
针对尿石素类化合物靶向到PDE2小分子的研究不足，本发明的目的是拓展尿石素类化合物，提供新颖的PDE2的抑制剂小分子化合物。
本发明的技术方案：
化合物结构如下：
Figure BDA0003369240940000021
R为氢原子、甲氧基或羟基中的一种；
R1为C2-C9烷基、甲硫基取代的C2-C9烷基、环烷基取代的C1-C9烷基、乙基酯基取代的C1-C9烷基、杂环基取代的C1-C9烷基、羟基取代的C1-C9烷基、芳香基取代的C1-C9烷基或C2-C9杂环基中的一种。
所述化合物Ⅰ选自式1a-1j、2a-2p或3a-3f所示的化合物：
Figure BDA0003369240940000022
Figure BDA0003369240940000031
4-羟基联苯类衍生物制备方法：
室温下，将化合物Ⅰ溶于无水DMF中，加入K2CO3搅拌均匀后，加热，滴加通式为R1X的卤代物，封管加热反应，TLC跟踪反应，反应完倒入冰水混合物中，有絮状物析出，静置，抽滤，烘干，得到4-羟基联苯类衍生物粗产品。然后用溶剂溶解粗产品，往溶剂中滴加极性较小的溶剂，有絮状物析出，静置，抽滤，固体用溶剂洗涤1-2次，烘干，得到次纯目标产品。将次纯目标产品用溶剂溶解，往溶剂中滴加极性较小的溶剂，有絮状物析出，静置，抽滤，固体用溶剂洗涤1-2次，烘干，得到纯度较高的4-羟基联苯类衍生物。合成路线如下式所示：
Figure BDA0003369240940000041
其中，R为氢原子、甲氧基或羟基中的一种；X为Cl或Br；
其中，R1为C2-C9烷基、甲硫基取代的C2-C9烷基、环烷基取代的C1-C9烷基、乙基酯基取代的C1-C9烷基、杂环基取代的C1-C9烷基、羟基取代的C1-C9烷基、芳香基取代的C1-C9烷基或C2-C9杂环基中的一种；
其中，所述化合物Ⅰ、K2CO3、R1X的摩尔比为1:1-1.5:1-1.5；
其中，封管加热反应的温度为回流温度；
其中，封管加热反应的时间为2-24h；
其中，溶剂粗产物的溶剂是二氯甲烷或1,2-二氯乙烷；
其中，极性较小的溶剂是石油醚、正己烷或环己烷；
上述的4-羟基联苯类衍生物能够作为活性成分制备抑制PDE2活性的药物。
本发明的有益效果：本发明提供了新颖的PDE2的抑制剂化合物，主要包括4-羟基联苯、4-羟基-4'-甲氧基联苯和4,4'-二羟基联苯类衍生物32个化合物，具有较好的PDE2抑制活性，能够用于治疗中枢神经系统疾病，比如治疗记忆缺陷、认知障碍、焦虑和抑郁症等，也可用来治疗大脑的神经变性过程疾病，作为活性成分制备抑制PDE2活性的药物。另外，针对提供的化合物结构，给出了相应的合成方法，合成方法简单，后处理方法创造性的用溶剂和化合物的特性分离，省去了繁杂的柱层析，适合工业化大生产的需求。
具体实施方式
下面结合实施方式对本发明作进一步描述。以下实施方式仅用于更加清楚地说明本发明的技术方案，而不能以此来限制本发明的保护范围。
实施例1
化合物1a-1j制备：
将无水DMF(30mL)加入250mL圆底烧瓶中，加入原料4-羟基联苯(9.4mmol)，无水K2CO3(12.2mmol，1.7g)和R1X(12.2mmol，具体物质见表1)，并将温度控制在回流下，反应18h。通过TLC(石油谜：乙酸乙酯＝5∶1)监测反应。反应结束后，将反应溶液加至冰水混合物中，有絮状物产生，静置，抽滤，干燥，得到粗产品，然后用二氯甲烷溶解粗产品，往溶剂中滴加极性较小的石油醚溶剂，有固体析出，静置，抽滤，固体用二氯甲烷溶剂洗涤2次，烘干，得到次纯目标产品。将次纯目标产品用二氯甲烷溶剂溶解，往溶剂中滴加极性较小的石油醚溶剂，有固体析出，静置，抽滤，固体用二氯甲烷溶剂洗涤2次，烘干，得到纯度较高的4-羟基联苯类衍生物。
1a:1H NMR(400MHz,DMSO-d6)δ7.62-7.56(m,4H),7.45-7.41(m,2H),7.33-7.28(m,1H),7.02-6.99(m,2H),4.47-4.39(m,1H),1.74-1.54(m,2H),1.25(d,J＝4.0 Hz,3H),0.94(t,J＝8.0 Hz,3H).13C NMR(75 MHz,DMSO-d6)δ157.91,140.37,132.74,129.31,128.26,127.10,126.59,116.43,74.61,29.05,19.54,10.01.
1b:1H NMR(400 MHz,DMSO-d6)δ7.62-7.56(m,4H),7.45-7.40(m,2H),7.32-7.27(m,1H),7.03-6.98(m,2H),3.89(d,J＝8.0 Hz,2H),2.33(m,1H),1.79(m,2H),1.79-1.36(m,6H).13C NMR(75 MHz,DMSO-d6)δ158.94,140.34,132.85,129.32,128.18,127.13,126.60,115.37,72.14,39.02,29.48,25.43.
1c:1H NMR(300 MHz,CDCl3)δ7.61-7.53(m,4H),7.43-7.38(m,2H),7.31-7.24(m,1H),7.01-6.98(m,2H),4.30(t,J＝4.5 Hz,1H),4.04-3.81(m,4H),2.14-1.75(m,4H).13CNMR(75 MHz,CDCl3)δ158.51,140.83,133.91,128.73,128.12,126.75,126.68,114.90,70.57,68.66,28.33,25.75.
1d:1H NMR(300 MHz,CDCl3)δ7.53-7.24(m,8H),7.04-6.98(m,2H),6.34(d,J＝3.0,1H),5.07(s,2H),3.93(s,3H).13C NMR(75 MHz,CDCl3)δ163.26,145.02,137.83,134.08,132.99,131.93,131.38,120.08,106.42,69.50,68.78,38.56.
1e:1H NMR(400 MHz,DMSO-d6)δ7.64-7.62(m,4H),7.43-7.38(m,2H),7.34-7.33(m,1H),7.15-7.13(m,2H),6.18(s,1H),5.16(s,2H),3.77(s,3H),2.14(s,3H).13C NMR(75MHz,DMSO-d6)δ157.98,146.04,140.22,138.44,133.59,129.34,128.24,127.27,126.71,115.79,106.94,60.53,36.56,13.64.
1f:1H NMR(400 MHz,DMSO-d6)δ7.63-7.58(m,4H),7.45-7.41(m,2H),7.33-7.29(m,1H),7.04-7.02(m,2H),3.91-3.87(m,4H),3.37(d,J＝2.1 Hz,1H),3.37(d,J＝4.0 Hz,1H),2.05-2.00(m,1H),1.72-1.68(m,2H),1.40-1.27(m,2H).13CNMR(75 MHz,CDCl3)δ158.60,140.83,133.81,128.74,128.18,126.75,114.75,72.67,67.68,35.17,29.79.
1g:1H NMR(300 MHz,DMSO-d6)δ7.63-7.57(m,4H),7.45-7.40(m,2H),7.33-7.28(m,1H),7.11-7.06(m,2H),6.62(d,J＝3.0 Hz,2H),6.45(t,J＝3.0 Hz,1H),5.09(s,2H),3.75(s,6H).13C NMR(75 MHz,CDCl3)δ161.05,160.78,158.30,140.79,139.42,134.09,128.74,128.19,126.76,126.72,115.17,105.22,99.91,70.08,55.40.
1h:1H NMR(400 MHz,DMSO-d6)δ8.68(d,J＝8.0 Hz,2H),7.74-7.69(m,4H),7.51-7.47(m,2H),7.41-7.37(m,1H),7.32-7.29(m,3H).13C NMR(75 MHz,CDCl3)δ165.46,159.81,152.31,140.49,138.64,128.80,128.45,127.17,121.94,116.27.
1i:1H NMR(300 MHz,DMSO-d6)δ7.57-7.52(m,5H),7.44-7.39(m,2H),7.33-7.28(m,2H),7.20-7.04(m,4H),5.19(s,2H).13C NMR(75 MHz,DMSO-d6)δ162.49,159.25,158.29,140.22,133.46,131.18,130.93,130.82,129.34,128.29,127.25,126.69,125.05,115.63,64.06.
1j:1H NMR(300 MHz,DMSO-d6)δ7.62-7.58(m,4H),7.45-7.40(m,4H),7.35-7.28(m,3H),7.10-7.07(m,2H),5.19(t,J＝4.5 Hz,1H),5.14(s,2H),4.50(d,J＝3.0Hz,2H).13CNMR(75MHz,DMSO-d6)δ158.45,142.70,140.27,135.83,133.18,129.33,128.22,127.98,127.20,126.98,126.66,115.75,69.62,63.13.
实施例2
化合物2a-2p的制备：
将无水DMF(30mL)加入250mL圆底烧瓶中，加入原料4-羟基-4'-甲氧基联苯(9.4mmol)，无水K2CO3(12.2mmol，1.7g)和R1X(12.2mmol，具体物质见表2)，并将温度控制在回流下，反应18h。通过TLC(石油谜：乙酸乙酯＝5∶1)监测反应。反应结束后，将反应溶液加至冰水混合物中，有絮状物产生，静置，抽滤，干燥，得到粗产品，然后用1,2-二氯乙烷溶解粗产品，往溶剂中滴加极性较小的正己烷溶剂，有固体析出，静置，抽滤，固体用1,2-二氯乙烷溶剂洗涤2次，烘干，得到次纯目标产品。将次纯目标产品用1,2-二氯乙烷溶剂溶解，往溶剂中滴加极性较小的正己烷溶剂，有固体析出，静置，抽滤，固体用1,2-二氯乙烷溶剂洗涤2次，烘干，得到纯度较高的4'-甲氧基联苯类衍生物。
2a:1H NMR(300MHz,CDCl3)δ7.50-7.43(m,4H),6.97-6.91(m,4H),4.37-4.27(m,1H),3.84(s,3H),1.84-1.61(m,2H),1.32(d,J＝6.0Hz,3H),0.99(t,J＝7.5Hz,3H).13C NMR(75MHz,CDCl3)δ158.65,157.38,133.60,133.23,127.75,127.72,116.14,114.15,75.18,55.35,29.25,19.35,9.87.
2b:1H NMR(300MHz,DMSO-d6)δ7.56-7.52(m,4H),7.02-6.98(m,4H),4.18(t,J＝7.5Hz,2H),3.78(s,3H),2.86(t,J＝6.0Hz,2H),2.17(s,3H).13C NMR(75MHz,CDCl3)δ158.75,157.63,133.82,133.40,127.79,127.75,114.87,114.19,67.56,55.37,33.11,16.25.
2c:1H NMR(300 MHz,CDCl3)δ7.48-7.45(m,4H),6.97-6.93(m,4H),4.65(s,2H),4.28(q,J＝7.5 Hz,2H),3.84(s,3H),1.31(t,J＝7.5 Hz,3H).13C NMR(75MHz,CDCl3)δ169.00,158.83,156.95,134.57,133.23,127.84,127.81,114.96,114.19,65.59,61.43,55.36,14.20.
2d:1H NMR(300 MHz,DMSO-d6)δ7.54-7.50(m,4H),7.00-6.96(m,4H),3.86(d,J＝6.0 Hz,2H),3.78(s,3H),2.36-2.26(m,1H),1.81-1.73(m,2H),1.64-1.49(m,4H),1.37-1.28(m,2H).13C NMR(75 MHz,CDCl3)δ158.65,158.44,133.60,133.24,127.72,127.68,114.81,114.15,72.38,55.36,39.12,29.52,25.45.
2e:1H NMR(300 MHz,CDCl3)δ7.48-7.44(m,4H),6.99-6.93(m,4H),4.33-4.25(m,1H),4.07-3.92(m,4H),3.84(s,3H),2.14-1.72(m,4H).13C NMR(75 MHz,CDCl3)δ158.70,158.05,133.61,133.48,127.74,127.68,114.86,114.16,70.55,68.61,55.36,28.31,25.72.
2f:1H NMR(300 MHz,CDCl3)δ7.49-7.44(m,4H),7.01-6.94(m,4H),5.31(t,J＝4.0Hz,1H),4.09-3.95(m,6H),3.84(s,3H).13C NMR(75 MHz,CDCl3)δ158.75,157.67,133.98,133.38,127.76,127.73,114.91,114.17,102.01,68.90,65.33,55.36.
2g:1H NMR(300 MHz,CDCl3)δ7.49-7.43(m,4H),6.98-6.94(m,4H),5.11(t,J＝4.5Hz,1H),4.16(t,J＝7.5 Hz,2H),4.03-3.88(m,4H),3.84(s,3H),2.21-2.15(m,2H).13C NMR(75 MHz,CDCl3)δ158.69,157.96,133.53,133.51,127.74,127.72,114.80,114.17,102.09,64.96,63.71,55.36,33.87.
2h:1H NMR(300 MHz,CDCl3)δ7.49-7.43(m,4H),6.97-6.91(m,4H),3.83(s,3H),3.78(d,J＝6.0 Hz,2H),1.90-1.75(m,6H),1.38-1.17(m,3H),1.13-0.99(m,2H).13C NMR(75 MHz,CDCl3)δ158.65,158.48,133.61,133.19,127.72,127.69,114.77,114.16,73.62,55.36,37.74,29.96,26.57,25.85.
2i:1H NMR(300 MHz,CDCl3)δ7.49-7.45(m,4H),6.98-6.92(m,4H),4.03(dd,J＝12.0,3.0 Hz,2H),3.85-3.83(m,5H),3.45(td,J＝12.0,2.1 Hz,2H),2.16-2.01(m,1H),1.78(dd,J＝12.0,2.0 Hz,2H),1.54-1.40(m,2H).13C NMR(75 MHz,CDCl3)δ158.71,158.15,133.51,133.48,127.74,114.73,114.18,72.68,67.68,55.36,35.17,29.79.
2j:1H NMR(300 MHz,DMSO-d6)δ7.80(dd,J＝3.0,0.7 Hz,1H),7.54-7.50(m,4H),7.47(dd,J＝1.8,0.7 Hz,1H),7.00-6.95(m,4H),6.25(t,J＝3.0 Hz,1H),4.51(t,J＝4.5Hz,2H),4.36(t,J＝6.0 Hz,2H),3.78(s,3H).13C NMR(75 MHz,DMSO-d6)δ158.87,157.64,139.31,133.17,132.66,131.00,127.72,115.41,114.76,105.63,67.08,55.59,51.12.
2k:1H NMR(300 MHz,DMSO-d6)δ7.56-7.53(m,4H),7.11-7.07(m,2H),7.02-6.97(m,2H),6.16(s,1H),5.13(s,2H),3.78(s,3H),3.75(s,3H),2.12(s,3H).13C NMR(75 MHz,DMSO)δ158.90,157.42,146.02,138.50,133.37,132.67,127.76,127.71,115.74,114.76,106.91,60.51,55.60,36.55,13.63.
2l:1H NMR(400 MHz,DMSO-d6)δ7.55-7.53(d,J＝6.0 Hz,4H),7.48-7.32(m,5H),7.08-6.98(m,4H),5.15(s,2H),3.79(s,3H).13C NMR(75 MHz,CDCl3)δ158.74,157.94,137.07,133.76,133.45,128.63,128.00,127.77,127.51,115.14,114.19,70.12,55.37.
2m:1H NMR(300 MHz,DMSO-d6)δ8.66(d,J＝3.0 Hz,2H),7.69-7.60(m,4H),7.30-7.23(m,3H),7.07-7.02(m,2H),3.81(s,3H).13C NMR(75 MHz,DMSO-d6)δ165.28,160.53,159.33,152.26,137.44,132.39,128.23,127.89,122.54,117.42,114.87,55.64.
2n:1H NMR(300 MHz,DMSO-d6)δ7.55-7.51(m,4H),7.43-7.30(m,4H),7.08-6.96(m,4H),5.20-5.12(m,3H),4.50(d,J＝3.0 Hz,2H),3.78(s,3H).13C NMR(75 MHz,DMSO-d6)δ158.84,157.90,142.67,135.89,132.97,132.74,127.96,127.72,127.69,126.98,115.69,114.75,69.59,63.13,55.59.
2o:1H NMR(300 MHz,DMSO-d6)δ7.61-7.53(m,5H),7.45-7.40(m,1H),7.30-7.25(m,2H),7.11-7.02(m,2H),7.02-6.97(m,2H),5.18(s,2H),3.78(s,3H).13C NMR(75 MHz,DMSO-d6)δ158.88,157.74,133.25,132.67,131.17,131.11,130.91,130.80,127.75,125.04,124.99,124.43,124.24,116.01,115.74,115.58,114.76,64.06,64.01,55.59.
2p:1H NMR(300MHz,DMSO-d6)δ7.55-7.52(m,4H),7.07-6.97(m,4H),6.63(d,J＝3.0Hz,2H),6.46(t,J＝3.0Hz,1H),5.08(s,2H),3.78(s,3H),3.75(s,6H).13C NMR(75MHz,DMSO-d6)δ161.03,158.85,157.82,140.03,133.03,132.71,127.72,127.70,115.68,114.75,105.80,99.82,69.55,55.65,55.58.
实施例3
化合物3a-3f的制备：
将无水DMF(30mL)加入250mL圆底烧瓶中，加入原料4,4'-二羟基联苯(9.4mmol)，无水K2CO3(12.2mmol，1.7g)和R1X(12.2mmol，具体物质见表3)，并将温度控制在回流温度下，反应18h。通过TLC(石油谜：乙酸乙酯＝3∶1)监测反应。反应结束后，将反应溶液加至冰水混合物中，有絮状物产生，静置，抽滤，干燥，得到粗产品，然后用二氯甲烷溶解粗产品，往溶剂中滴加极性较小的石油醚溶剂，有固体析出，静置，抽滤，固体用二氯甲烷溶剂洗涤2次，烘干，得到次纯目标产品。将次纯目标产品用二氯甲烷溶剂溶解，往溶剂中滴加极性较小的环己烷溶剂，有固体析出，静置，抽滤，固体用二氯甲烷溶剂洗涤2次，烘干，得到纯度较高的4,4'-二羟基联苯类衍生物。
3a:1H NMR(300MHz,DMSO-d6)δ9.45(s,1H),7.51-7.39(m,4H),7.00-6.95(m,2H),6.84-6.79(m,2H),4.16(t,J＝6.0Hz,2H),2.85(t,J＝7.5Hz,2H),2.16(s,3H).13C NMR(75MHz,DMSO-d6)δ157.53,156.99,133.39,131.13,127.68,127.48,116.09,115.30,67.48,32.72,15.72.
3b:1H NMR(300MHz,DMSO-d6)δ9.45(s,1H),7.49-7.38(m,4H),6.97-6.92(m,2H),6.84-6.79(m,2H),3.78(d,J＝6.0 Hz,2H),1.83-0.97(m,11H).13CNMR(75 MHz,DMSO-d6)δ158.12,156.93,133.03,131.21,127.63,127.42,116.08,115.21,73.20,37.56,29.74,26.53,25.75.
3c:1H NMR(300 MHz,DMSO-d6)δ9.44(s,1H),7.49-7.44(m,2H),7.44-7.38(m,2H),6.98-6.92(m,2H),6.84-6.77(m,2H),3.82(d,J＝6.0 Hz,2H),0.97-0.81(m,1H),0.61-0.53(m,2H),0.36-0.26(m,2H).13C NMR(75 MHz,DMSO-d6)δ157.96,156.95,133.05,131.21,127.65,127.42,116.09,115.23,72.49,10.67,3.58.
3d:1H NMR(300 MHz,DMSO-d6)δ9.59(s,1H),8.65(d,J＝4.8 Hz,2H),7.64-7.59(m,2H),7.52-7.47(m,2H),7.28-7.20(m,3H),6.89-6.84(m,2H).13CNMR(75 MHz,DMSO-d6)δ165.29,160.52,157.53,151.98,137.84,130.80,128.21,127.64,122.47,117.38,116.22.
3e:1H NMR(300 MHz,DMSO-d6)δ9.46(s,1H),7.60-7.50(m,3H),7.49-7.39(m,3H),7.29-7.22(m,2H),7.09-7.04(m,2H),6.84-6.79(m,2H),5.16(s,2H).13C NMR(75 MHz,DMSO-d6)δ157.48,157.03,133.67,130.85,127.74,127.52,125.02,124.36,116.06,115.73,115.52,63.99.
3f:1H NMR(300 MHz,DMSO-d6)δ9.48(s,1H),7.49-7.39(m,4H),6.96-6.93(m,2H),6.85-6.80(m,2H),4.00(t,J＝7.5 Hz,2H),3.57(t,J＝6,0 Hz,4H),2.44-2.36(m,6H),1.91-1.82(m,2H).13C NMR(75 MHz,DMSO-d6)δ157.92,156.97,133.12,131.17,127.64,127.43,116.09,115.21,66.67,66.22,55.34,53.85,26.38.
表14-羟基联苯衍生物(R＝H)
Figure BDA0003369240940000141
表24-羟基-4'-甲氧基联苯衍生物(R＝OMe)
Figure BDA0003369240940000151
Figure BDA0003369240940000161
表34,4'-二羟基联苯衍生物(R＝OH)
Figure BDA0003369240940000162
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来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变形，这些改进和变形也应视为本发明的保护范围。

Claims (8)

1.一类4-羟基联苯类衍生物的制备方法，其特征在于，步骤如下：室温下，将化合物Ⅰ溶于无水DMF中，加入K2CO3搅拌均匀后，加热，滴加通式为R1X的卤代物，封管加热反应，TLC跟踪反应，反应完倒入冰水混合物中，有絮状物析出，静置，抽滤，烘干，得到4-羟基联苯类衍生物粗产品；然后用溶剂溶解粗产品，往溶剂中滴加极性较小的溶剂，有絮状物析出，静置，抽滤，固体用溶剂洗涤，烘干，得到次纯目标产品；将次纯目标产品用溶剂溶解，往溶剂中滴加极性较小的溶剂，有絮状物析出，静置，抽滤，固体用溶剂洗涤，烘干，得到纯度较高的4-羟基联苯类衍生物；合成路线如下式所示：
Figure FDA0003369240930000011
其中，R为氢原子、甲氧基或羟基中的一种；X为Cl或Br；
其中，R1为C2-C9烷基、甲硫基取代的C2-C9烷基、环烷基取代的C1-C9烷基、乙基酯基取代的C1-C9烷基、杂环基取代的C1-C9烷基、羟基取代的C1-C9烷基、芳香基取代的C1-C9烷基或C2-C9杂环基中的一种。
2.根据权利要求1所述的一类4-羟基联苯类衍生物的制备方法，其特征在于，所述化合物Ⅰ、K2CO3、R1X的摩尔比为1:1-1.5:1-1.5。
3.根据权利要求1所述的一类4-羟基联苯类衍生物的制备方法，其特征在于，所述封管加热反应的温度为回流温度。
4.根据权利要求1所述的一类4-羟基联苯类衍生物的制备方法，其特征在于，所述封管加热反应的时间为2-24h。
5.根据权利要求1所述的一类4-羟基联苯类衍生物的制备方法，其特征在于，所述溶剂粗产物的溶剂是二氯甲烷或1,2-二氯乙烷。
6.根据权利要求1所述的一类4-羟基联苯类衍生物的制备方法，其特征在于，所述极性较小的溶剂是石油醚、正己烷或环己烷。
7.一类4-羟基联苯类衍生物，其特征在于，是由权利要求1-6任一所述的制备方法制得的，4-羟基联苯类衍生物的化合物结构如下：
Figure FDA0003369240930000021
其中，R为氢原子、甲氧基或羟基中的一种；R1为C2-C9烷基、甲硫基取代的C2-C9烷基、环烷基取代的C1-C9烷基、乙基酯基取代的C1-C9烷基、杂环基取代的C1-C9烷基、羟基取代的C1-C9烷基、芳香基取代的C1-C9烷基或C2-C9杂环基中的一种。
8.权利要求1-6任一所述的制备方法制得的一类4-羟基联苯类衍生物的应用，其特征在于，所述的4-羟基联苯类衍生物能够作为活性成分制备抑制PDE2活性的药物。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114890897A (zh) * 2022-05-31 2022-08-12 常州大学 一种pde2抑制剂内酯类衍生物及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014010732A1 (ja) * 2012-07-13 2014-01-16 武田薬品工業株式会社 複素環化合物
CN108884391A (zh) * 2016-02-10 2018-11-23 日产化学株式会社 液晶组合物和单层涂布型水平取向膜

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014010732A1 (ja) * 2012-07-13 2014-01-16 武田薬品工業株式会社 複素環化合物
CN108884391A (zh) * 2016-02-10 2018-11-23 日产化学株式会社 液晶组合物和单层涂布型水平取向膜

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
REGISTRY: "1395036-25-5", STN COLUMN, pages 1 - 4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114890897A (zh) * 2022-05-31 2022-08-12 常州大学 一种pde2抑制剂内酯类衍生物及其制备方法

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