CN110240579B - 一种多取代γ-丁内酯类化合物、制备方法及其应用 - Google Patents

一种多取代γ-丁内酯类化合物、制备方法及其应用 Download PDF

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CN110240579B
CN110240579B CN201910498397.4A CN201910498397A CN110240579B CN 110240579 B CN110240579 B CN 110240579B CN 201910498397 A CN201910498397 A CN 201910498397A CN 110240579 B CN110240579 B CN 110240579B
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王继宇
张华�
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Abstract

本发明公开了一种多取代γ‑丁内酯类化合物的制备方法,所述化合物的反应式为：

Description

一种多取代γ-丁内酯类化合物、制备方法及其应用
技术领域
本发明涉有机合成的技术领域，具体的说，是指一种多取代γ-丁内酯类化合物、制备方法及其应用。
背景技术
γ-丁内酯是一种无色油状液体，能与水混溶，溶于甲醇、乙醇、丙酮、乙醚和苯。能随水蒸气挥发并可在热碱溶液中分解，有芳香气味。
目前，合成γ-丁内酯的方法有很多，但是现有制备多取代的γ-丁内酯的却很少，而多取代的γ-丁内酯广泛存在各种天然产物和药物分子中，具有很好的生物活性，现有制备过程复杂，且转化率较低。
发明内容
本发明提供一种多取代γ-丁内酯类化合物、制备方法及其应用，
本发明的第一个目的的在于提供一种多取代γ-丁内酯类化合物，其化学结构式如下：
Figure GDA0002149928740000011
其中，R1为芳基或芳杂基，R2与R3为烷基，R4为芳基或烷基。
R1选自对氟苯基、对氯苯基、対溴苯基、吡啶基中的一种或多种。
R4选自2-萘基、对氟苯基、对氯苯基、対溴苯基、对三氟甲基苯基中的一种或多种。
本发明所提供的化合物具有一定的生物活性和抗菌和/或抗肿瘤的功能，具体是因为化合物中的R1含有对氟苯基、对氯苯基、対溴苯基、吡啶基；或者R4为2-萘基、对氟苯基、对氯苯基、対溴苯基、对三氟甲基苯基，才使得该化合物具有一定的生物活性，从而使得该化合物可以作为潜在药物或候选药物，本化合物中因为含有三氟甲基、F、Cl、Br、氰基、萘基等，从而可以用于抗菌和/或抗肿瘤。
本发明的第二个目的的在于提供一种多取代γ-丁内酯类化合物的制备方法，该多取代γ-丁内酯类化合物的化学反应式如下：
Figure GDA0002149928740000021
具体的反应步骤为：
称取一定量的N-取代马来酰亚胺和烯丙醇加入反应瓶中，并向反应瓶中加入溶剂、催化剂和还原剂，反应一定时间后，通过分离提纯得到最终的多取代γ-丁内酯类化合物。
本发明所提供的一种多取代γ-丁内酯类化合物的制备方法，通过采用缺电子的烯烃受体(N-取代马来酰亚胺)和富电子的烯烃给体(烯丙醇)配合反应制得。
该制备过程简单，易于操作，且收率高，进而使得该制备方法更适用于工业化大规模的生产。
为了更好的实现本发明，进一步的，所述溶剂选自甲苯、乙苯、苯、二氯甲烷、乙醇、异丙醇、甲醇、正丁醇、1,2-二氯乙烷、四氢呋喃、1,4-二氧六环、乙醚、乙二醇二甲醚、乙腈、DMF、DMA、DMSO中的一种或几种。
进一步，优选溶剂为乙腈或乙腈与醚类溶剂的混合溶剂，该优选的溶剂对合成收率有着较大的影响，通过长期的实验得出，当溶剂选用乙腈或乙腈与醚类溶剂时，收率最高。
为了更好的实现本发明，进一步的，所述催化剂选自Zn(OAc)2.2H2O、CuSO4.5H2O、Cu(OTf)2、Pd(OAc)2、FeSO4、Fe(acac)3、FeCl3、Fe(ox)3.6H2O、FeBr3、Co(acac)2、Ni(acac)2、MnCl2.4H2O、La(OTf)3中的一种或几种。
为了使合成反应中收率最高，因此优选催化剂为Co(acac)2、Ni(acac)2，，除了能够提高收率外，现在镍钴催化剂相对钯催化剂较便宜，能够为企业节约生产成本。
为了更好的实现本发明，进一步的，所述还原剂选自NaBH4、NaCNBH3、HSiCl3、Et3SiH、PhSiH3、(EtO)3SiH、HCOOH、PMHS中的一种或几种。
通常还原剂与催化剂的协同作用来提高合成的收率，优选还原剂为NaBH4、NaCNBH3，主要原因是能够提高收率的同时还能够降低成本。
为了更好的实现本发明，进一步的，所述N-取代马来酰亚胺与烯丙醇的摩尔比为1:0.4～5。
在该比值范围下均能以较高的收率得到目标产物，进一步优选比例为1:4,在该条件下，收率高，成本低。
为了更好的实现本发明，进一步的，所述N-取代马来酰亚胺与催化剂的摩尔比为1:0.1～2。
在该比值范围下均能以较高的收率得到目标产物，进一步优选比例为1:1,在该条件下，收率高，成本低。
为了更好的实现本发明，进一步的，所述N-取代马来酰亚胺与还原剂的摩尔比为1:0.5～6。
在该比值范围下均能以较高的收率得到目标产物，进一步优选比例为1:1,在该条件下，收率高，成本低。
为了更好的实现本发明，进一步的，所述N-取代马来酰亚胺与溶剂的比例为N-取代马来酰亚胺浓度为0.1-2mol/L,其最优浓度为1mol/L。
为了更好的实现本发明，进一步的，所述反应时间为1～24h。
设置反应时间为1～24h，可以使反应更加充分，并且杂质少，当超过24小时，反应体现杂质增多。
为了更好的实现本发明，进一步的，所述该反应的反应温度为室温～100℃,最优温度为40℃。反应对压力没有要求。
本发明的第三个目的在于提供一种多取代γ-丁内酯类化合物在抗菌和/或抗肿瘤药物中的应用。
在抗心脏病药物喜巴辛、Ixocarpalactone提取于墨西哥粘果酸浆、杯苋甾酮是川牛膝的有效成分中均含有γ-丁内酯，其中杯苋甾酮具有祛风除湿的疗效，Ixocarpalactone具有抗结肠癌的活性。
Figure GDA0002149928740000041
合成机理：
Figure GDA0002149928740000051
本发明实施例的有益效果是：本发明通过N-取代马来酰亚胺与烯丙醇在溶剂、催化剂和还原剂制得多取代γ-丁内酯类化合物，该化合物具有生物活性，可以应用在抗菌、抗肿瘤等药物中；
本发明通过N-取代马来酰亚胺与烯丙醇一步合成，原料易得，操作简单，合成方便、快捷，可以应用于工业生产；
本发明所提供的制备方法采用的原料价格低廉，对环境友好，且中间产物少，同时最终得到的多取代γ-丁内酯收率高。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将结合本发明实施例，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。
一种多取代γ-丁内酯的制备方法，包括以下反应式：
Figure GDA0002149928740000052
具体制备步骤如下：
反应瓶中依次加入N-对氯苯基马来酰亚胺、烯丙烯、催化剂、还原剂和混合溶剂，室温反应1～24h，加水淬灭，乙酸乙酯萃取，重结晶得最终目标产物白色固体。
实施例1：
原料是：1.7g N-苯基马来酰亚胺；1.5g 1-苯基-2-甲基烯丙醇
还原剂是：2.0g苯硅烷
催化剂是：2.1g乙酰丙酮钴
溶剂是：6ml DMF与THF的混合溶剂
目标产物如下：
Figure GDA0002149928740000061
白色固体,熔点.196-198℃；1H NMR(400MHz,DMSO-d6)δ9.79(s,1H),7.27(d,J＝7.8Hz,2H),7.05(dd,J＝14.3,7.0Hz,3H),7.01–6.91(m,4H),6.71(t,J＝7.4Hz,1H),5.05(s,1H),3.06(s,1H),2.28(dd,J＝15.5,7.4Hz,1H),2.21–2.14(m,1H),0.79(s,3H),0.16(s,3H).13C NMR(101MHz,DMSO-d6)δ177.49,169.32,139.58,135.13,129.18,128.65,128.62,126.53,123.65,119.51,87.29,48.59,44.45,32.07,22.91,17.51.HRMS:[M+Na]+calcd.For C20H21NNaO3 +:346.1414；found:346.1416。
实施例2：
原料是：1.7g N-苯基马来酰亚胺；1.6g 1-(4-氟-苯基)-2-甲基烯丙醇
还原剂是：2.0g苯硅烷
催化剂是：2.1g乙酰丙酮钴
溶剂是：6ml乙腈
目标产物如下：
Figure GDA0002149928740000071
白色固体,熔点.176-177℃；1H NMR(300MHz,DMSO-d6)δ10.13(s,1H),7.61(d,J＝7.8Hz,2H),7.39–7.19(m,6H),7.04(t,J＝7.6Hz,1H),5.40(s,1H),3.37-3.40(d,J＝9Hz,1H),2.70–2.51(m,2H),1.11(s,3H),0.50(s,3H).1H NMR(300MHz,DMSO-d6)δ10.13(s,1H),7.57(d,J＝7.4Hz,2H),7.37–7.20(m,6H),7.03(t,J＝7.4Hz,1H),5.34(s,1H),3.05(t,J＝6.8Hz,1H),2.60(dd,J＝6.8,4.6Hz,2H),1.16(s,3H),0.66(s,3H).13C NMR(101MHz,DMSO-d6)δ177.33,169.27,163.57,139.58,131.29,129.18,128.73,128.65,123.64,119.51,115.67,115.46,86.68,48.52,44.45,32.05,22.82,17.43.19F NMR(376MHz,DMSO-d6)δ-114.16.HRMS:[M+Na]+calcd.For C20H20NFNaO3 +:364.1319；found:364.1322.
实施例3：
原料是：1.7g N-苯基马来酰亚胺；1.8g 1-(4-氯-苯基)-2-甲基烯丙醇
还原剂是：1.2g三乙基硅烷
催化剂是：2.0g醋酸铜
溶剂是：10ml甲醇与DMF的混合溶剂
目标产物如下：
Figure GDA0002149928740000081
白色固体,熔点.207-208℃；1H NMR(300MHz,DMSO-d6)δ10.13(s,1H),7.61(d,J＝8.0Hz,2H),7.48(d,J＝8.2Hz,2H),7.30(t,J＝7.6Hz,4H),7.03(d,J＝7.7Hz,1H),5.40(s,1H),3.39-3.41(d,J＝6Hz,1H),2.62(dd,J＝15.6,7.3Hz,1H),2.48(d,J＝6.4Hz,1H),1.13(s,3H),0.50(s,3H).1H NMR(300MHz,DMSO-d6)δ10.13(s,1H),7.57(d,J＝8.0Hz,2H),7.50(d,J＝8.2Hz,2H),7.29(dd,J＝8.1,5.3Hz,4H),7.04(t,J＝7.3Hz,1H),5.34(s,1H),3.04(t,J＝6.7Hz,1H),2.71–2.53(m,2H),1.16(s,3H),0.67(s,3H).13C NMR(101MHz,DMSO-d6)δ177.27,169.25,139.57,134.18,133.26,129.18,128.73,128.43,123.65,119.52,86.53,48.50,44.49,32.02,22.81,17.43.HRMS:[M+Na]+calcd.For C20H20NClNaO3 +:380.1024；found:380.1028.
实施例4：
原料是：1.7g N-苯基马来酰亚胺；2.3g 1-(4-溴-苯基)-2-甲基烯丙醇
还原剂是：1.2g三乙基硅烷
催化剂是：2.0g醋酸铜
溶剂是：10ml甲醇与DMF的混合溶剂
目标产物如下：
Figure GDA0002149928740000091
白色固体,熔点.118-120℃；1H NMR(300MHz,DMSO-d6)δ10.13(s,1H),7.62(d,J＝8.6Hz,4H),7.37–7.21(m,4H),7.04(t,J＝7.3Hz,1H),5.39(s,1H),3.40(d,J＝6.8Hz,1H),2.62(dd,J＝15.5,7.3Hz,1H),2.47(s,1H),1.13(s,3H),0.50(s,3H).1H NMR(300MHz,DMSO-d6)δ10.12(s,1H),7.63(d,J＝8.4Hz,2H),7.57(d,J＝7.9Hz,3H),7.35–7.19(m,4H),7.04(t,J＝7.3Hz,1H),5.32(s,1H),3.04(t,J＝6.7Hz,1H),2.68–2.53(m,2H),1.16(s,3H),0.67(s,3H).13C NMR(101MHz,DMSO-d6)δ177.27,169.25,139.57,134.62,131.64,129.18,128.74,123.66,121.81,119.52,86.56,48.49,44.45,32.02,22.81,17.44.HRMS:[M+Na]+calcd.For C20H20NBrNaO3 +:424.0519；found:424.0521.
实施例5：
原料是：1.7g N-苯基马来酰亚胺；2.2g 1-(4-三氟甲基-苯基)-2-甲基烯丙醇
还原剂是：1.2g三乙基硅烷
催化剂是：1.6g三氯化铁
溶剂是：10ml甲醇与DMF的混合溶剂
目标产物如下：
Figure GDA0002149928740000101
白色固体,熔点.222-224℃；1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),7.52(d,J＝8.1Hz,2H),7.40–7.32(m,2H),7.27(d,J＝8.0Hz,2H),7.08–7.00(m,2H),6.82–6.74(m,1H),5.25(s,1H),3.21–3.15(m,1H),2.41–2.34(m,1H),2.26(dd,J＝14.1,4.9Hz,1H),0.91(s,3H),0.23(s,3H).1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),7.56(d,J＝6.1Hz,2H),7.36–7.28(m,2H),7.25(d,J＝7.7Hz,2H),7.08–6.98(m,2H),6.82–6.73(m,1H),5.20(s,1H),2.83–2.75(m,1H),2.40(d,J＝15.7Hz,1H),2.24(t,J＝3.6Hz,1H),0.93(s,3H),0.41(s,3H).13C NMR(101MHz,DMSO-d6)δ177.16,169.22,140.02,139.57,129.33,129.17,129.02,127.34,125.94,125.62,125.58,123.66,123.23,119.53,86.40,48.47,44.58,31.97,22.82,17.47.19F NMR(376MHz,DMSO-d6)δ-61.11.HRMS:[M+Na]+calcd.For C21H20NF3NaO3 +:414.1287；found:414.1290.
实施例6：
原料是：1.7g N-苯基马来酰亚胺；1.8g 1-(4-氰基-苯基)-2-甲基烯丙醇
还原剂是：1.2g三乙基硅烷
催化剂是：1.7g草酸铁
溶剂是：10ml甲醇
目标产物如下：
Figure GDA0002149928740000111
白色固体,熔点.194-196℃；1H NMR(300MHz,DMSO-d6)δ10.14(s,1H),7.61(d,J＝7.2Hz,2H),7.45(d,J＝6.4Hz,2H),7.29(dd,J＝15.3,7.4Hz,4H),7.04(t,J＝7.4Hz,1H),5.41(s,1H),3.39(s,1H),2.62(dd,J＝15.6,7.3Hz,1H),2.53(d,J＝6.3Hz,1H),1.14(s,3H),0.51(s,3H).1H NMR(300MHz,DMSO-d6)δ10.13(s,1H),7.57(d,J＝7.3Hz,2H),7.51–7.40(m,2H),7.39–7.19(m,4H),7.04(t,J＝7.4Hz,1H),5.35(s,1H),3.05(t,J＝6.7Hz,1H),2.71–2.51(m,2H),1.17(s,3H),0.69(s,3H).13C NMR(101MHz,DMSO-d6)δ177.15,169.22,139.57,137.74,133.54,130.67,129.18,128.66,126.24,125.33,123.65,119.51,86.34,48.47,44.50,31.98,22.88,17.48.HRMS:[M+Na]+calcd.For C21H20N2NaO3 +:371.1366；found:371.1369.
实施例7：
原料是：1.7g N-苯基马来酰亚胺；1.9g 1-(2-氯-苯基)-2-甲基烯丙醇
还原剂是：0.5g硼氢化钠
催化剂是：2.0g醋酸钯
溶剂是：10ml1，2-二氯乙烷
目标产物如下：
Figure GDA0002149928740000121
白色固体,熔点.150-152℃；1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),7.61(d,J＝8.0Hz,2H),7.56–7.48(m,1H),7.47–7.36(m,3H),7.31(t,J＝7.8Hz,2H),7.04(t,J＝7.5Hz,1H),5.85(d,J＝2.9Hz,1H),3.51(t,J＝6.8Hz,1H),2.63(dd,J＝15.6,7.4Hz,1H),2.56–2.50(m,1H),1.19(s,3H),0.64(s,3H).1H NMR(300MHz,DMSO-d6)δ10.16(s,1H),7.63–7.51(m,3H),7.50–7.40(m,2H),7.35–7.22(m,3H),7.10–6.98(m,1H),5.64(s,1H),3.15(t,J＝6.7Hz,1H),2.70–2.53(m,2H),1.23(s,4H),0.80(s,3H).13C NMR(101MHz,DMSO-d6)δ177.39,169.25,139.58,132.84,132.30,130.54,130.24,129.71,129.18,127.40,123.64,119.52,83.47,48.59,45.60,32.01,24.35,18.20.HRMS:[M+Na]+calcd.For C20H20NClNaO3 +:380.1024；found:380.1029.
实施例8：
原料是：1.7g N-苯基马来酰亚胺；1.6g 1-(3-氯-苯基)-2-甲基烯丙醇
还原剂是：2.0g苯硅烷
催化剂是：2.1g乙酰丙酮钴
溶剂是：8ml乙腈
目标产物如下：
Figure GDA0002149928740000131
白色固体,熔点.185-187℃；1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),7.58(d,J＝7.3Hz,2H),7.46–7.39(m,2H),7.33–7.21(m,4H),7.06–6.98(m,1H),5.39(s,1H),3.39–3.34(m,1H),2.59(dd,J＝15.6,7.4Hz,1H),2.51(d,J＝6.3Hz,1H),1.12(s,3H),0.49(s,3H).1H NMR(300MHz,DMSO-d6)δ10.11(s,1H),7.57(d,J＝8.0Hz,2H),7.47(d,J＝6.4Hz,2H),7.28(td,J＝15.4,13.9,8.0Hz,4H),7.04(t,J＝7.3Hz,1H),5.35(s,1H),3.05(t,J＝6.7Hz,1H),2.61(t,J＝6.3Hz,2H),1.17(s,3H),0.70(s,3H).13C NMR(101MHz,DMSO-d6)δ177.15,169.22,139.57,137.74,133.54,130.68,129.18,128.67,126.24,125.33,123.65,119.52,86.35,48.47,44.51,31.98,22.88,17.48.HRMS:[MH+]calcd.For C20H21NClO3:358.1204；found:358.1207.
实施例9：
原料是：1.7g N-苯基马来酰亚胺；2.6g 1-(3，4-二氯-苯基)-2-甲基烯丙醇
还原剂是：2.0g苯硅烷
催化剂是：2.6g乙酰丙酮镍
溶剂是：8ml乙腈
目标产物如下：
Figure GDA0002149928740000141
白色固体,熔点.165-168℃；1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),7.70(d,J＝8.3Hz,1H),7.65–7.56(m,2H),7.55(d,J＝2.0Hz,1H),7.36–7.26(m,3H),7.10–7.01(m,1H),5.43(s,1H),3.42–3.37(m,1H),2.65–2.59(m,1H),2.54(d,J＝6.3Hz,1H),1.15(s,3H),0.53(s,3H).1H NMR(300MHz,DMSO-d6)δ10.12(s,1H),7.70(d,J＝8.3Hz,1H),7.57(dd,J＝4.9,2.6Hz,3H),7.35–7.22(m,3H),7.04(t,J＝7.4Hz,1H),5.36(s,1H),3.04(t,J＝6.7Hz,1H),2.72–2.52(m,2H),1.17(s,3H),0.71(s,3H).13C NMR(101MHz,DMSO-d6)δ177.01,169.18,139.56,136.39,131.62,131.34,131.02,129.18,128.46,127.00,123.66,119.52,85.76,48.41,44.55,31.95,22.83,17.42.HRMS:[M+Na]+calcd.For C20H19NCl2NaO3 +:414.0634；found:414.0638.
实施例10：
原料是：1.7g N-苯基马来酰亚胺；1.6g 1-(4-甲基-苯基)-2-甲基烯丙醇
还原剂是：1.3g三乙基硅烷
催化剂是：2.6g乙酰丙酮镍
溶剂是：8ml乙腈
目标产物如下：
Figure GDA0002149928740000151
白色固体,熔点.194-195℃；1H NMR(300MHz,DMSO-d6)δ10.13(s,1H),7.62(d,J＝8.7Hz,2H),7.31(dd,J＝8.5,7.3Hz,2H),7.19(q,J＝8.1Hz,4H),7.04(t,J＝7.4Hz,1H),5.34(s,1H),3.41–3.36(m,1H),2.62(dd,J＝15.5,7.4Hz,1H),2.53(s,1H),2.32(s,3H),1.11(s,3H),0.50(s,3H).13C NMR(101MHz,DMSO-d6)δ177.54,169.33,139.60,137.86,132.08,129.20,129.17,126.52,123.63,119.50,87.36,48.61,44.45,32.11,22.90,21.17,17.48.HRMS:[MH+]calcd.For C21H24NO3:338.1751；Found:338.1749.
实施例11：
原料是：1.7g N-苯基马来酰亚胺；1.8g 1-(4-乙基-苯基)-2-甲基烯丙醇
还原剂是：0.8g硼氢化钠
催化剂是：2.6g乙酰丙酮镍
溶剂是：8ml乙腈
目标产物如下：
Figure GDA0002149928740000152
白色固体,熔点.152-155℃；1H NMR(300MHz,DMSO-d6)δ10.12(s,1H),7.61(d,J＝7.4Hz,2H),7.37–7.15(m,6H),7.10–6.99(m,1H),5.35(s,1H),3.44–3.36(m,1H),2.62(q,J＝7.4Hz,3H),2.53(s,1H),1.19(t,J＝7.6Hz,3H),1.11(s,3H),0.50(s,3H).13C NMR(101MHz,DMSO-d6)δ177.55,169.33,144.11,139.60,132.35,129.17,127.99,126.58,123.63,119.50,87.37,48.61,44.46,32.11,28.27,22.91,17.52,15.85.HRMS:[MH+]calcd.For C22H26NO3:352.1907；Found:352.1909.
实施例12：
原料是：1.7g N-苯基马来酰亚胺；3.2g 1-(4-甲氧基-苯基)-2-甲基烯丙醇
还原剂是：0.8g硼氢化钠
催化剂是：2.6g乙酰丙酮镍
溶剂是：8ml乙腈
Figure GDA0002149928740000161
目标产物如下：
白色固体,熔点.147-149℃；1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),7.58(d,J＝8.6Hz,2H),7.33–7.23(m,2H),7.18(d,J＝6.8Hz,2H),7.06–6.97(m,1H),6.94(d,J＝6.6Hz,2H),5.29(s,1H),3.74(s,3H),3.30(s,1H),2.59(dd,J＝15.5,7.4Hz,1H),2.45(d,J＝6.4Hz,1H),1.06(s,3H),0.49(s,3H).13C NMR(101MHz,DMSO-d6)δ177.55,169.34,159.56,139.59,129.17,127.96,126.83,123.63,119.51,114.04,87.28,55.52,48.61,44.49,32.13,22.88,17.47.HRMS:[M+Na]+calcd.For C21H23NNaO4 +:376.1519；found:376.1525.
实施例13：
原料是：1.7g N-苯基马来酰亚胺；2.8g 1-(2-萘基)-2-甲基烯丙醇
还原剂是：0.8g硼氢化钠
催化剂是：2.6g乙酰丙酮镍
溶剂是：8ml乙腈
目标产物如下：
Figure GDA0002149928740000171
无色液体；1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),7.93(q,J＝5.6Hz,3H),7.82(s,1H),7.59(d,J＝8.0Hz,2H),7.55–7.47(m,2H),7.43–7.38(m,1H),7.28(t,J＝7.8Hz,2H),7.02(t,J＝7.5Hz,1H),5.55(s,1H),3.44(s,1H),2.66–2.51(m,2H),1.17(s,3H),0.51(s,3H).1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),7.94(t,J＝9.3Hz,3H),7.76(s,1H),7.60–7.47(m,4H),7.39(d,J＝8.7Hz,1H),7.26(t,J＝7.9Hz,2H),7.01(t,J＝7.6Hz,1H),5.47(s,1H),3.16–3.10(m,1H),2.62(dp,J＝16.0,9.2,7.9Hz,2H),1.20(s,3H),0.67(s,3H).13CNMR(101MHz,DMSO-d6)δ178.26,169.22,139.47,134.59,133.05,132.91,129.19,128.44,128.35,128.05,127.03,126.84,124.98,124.66,123.71,119.49,88.23,45.15,42.77,32.41,23.70,23.63.HRMS:[M+Na]+calcd.For C24H23NNaO3 +:396.1570；found:396.1569.
实施例14：
原料是：1.7g N-苯基马来酰亚胺；1.3g 1-丙基-2-甲基烯丙醇
还原剂是：0.8g硼氢化钠
催化剂是：2.6g乙酰丙酮镍
溶剂是：8ml乙腈
目标产物如下：
Figure GDA0002149928740000181
白色固体,熔点.51-53℃；1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),7.59(d,J＝7.4Hz,2H),7.30(t,J＝7.1Hz,2H),7.10–7.00(m,1H),3.29(dd,J＝7.6,6.2Hz,1H),2.54(d,J＝7.6Hz,1H),2.42(dd,J＝15.4,6.1Hz,1H),1.91(d,J＝10.7Hz,1H),1.64(d,J＝11.4Hz,2H),1.44(qd,J＝10.1,3.6Hz,3H),1.27–1.13(m,2H),1.00(s,3H),0.84(s,3H).13CNMR(101MHz,DMSO-d6)δ176.99,169.53,139.60,129.15,123.60,119.48,88.00,46.19,44.03,32.25,31.27,25.15,22.72,21.38,19.42.HRMS:[M+Na]+calcd.For C17H23NNaO3 +:290.1751；found:290.1757.
实施例15：
原料是：1.7g N-苯基马来酰亚胺；1.7g 1-环己基-2-甲基烯丙醇
还原剂是：0.8g硼氢化钠
催化剂是：2.6g乙酰丙酮镍
溶剂是：10ml乙腈
目标产物如下：
Figure GDA0002149928740000191
白色固体,熔点.118-120℃；1H NMR(300MHz,DMSO-d6)δ10.08(s,1H),7.65–7.55(m,2H),7.30(t,J＝7.8Hz,2H),7.03(t,J＝7.4Hz,1H),3.91(d,J＝9.6Hz,1H),3.14–3.06(m,1H),2.49–2.37(m,2H),1.90(d,J＝12.7Hz,1H),1.64(dq,J＝32.8,12.8,10.6Hz,5H),1.21(d,J＝9.8Hz,3H),1.13(s,3H),1.03(t,J＝11.5Hz,2H),0.85(s,3H).1H NMR(300MHz,DMSO-d6)δ10.06(s,1H),7.57(d,J＝6.5Hz,2H),7.31(d,J＝7.7Hz,2H),7.04(t,J＝7.3Hz,1H),3.89(d,J＝5.0Hz,1H),2.98(t,J＝6.8Hz,1H),2.53(s,1H),1.66(d,J＝14.5Hz,6H),1.20(d,J＝22.1Hz,5H),1.10(s,3H),1.02(s,3H).13C NMR(101MHz,DMSO-d6)δ177.19,169.49,139.63,129.15,123.57,119.45,90.44,49.26,42.63,38.21,31.39,31.12,30.60,28.72,26.14,25.46,24.33,16.16.HRMS:[M+Na]+calcd.For C20H27NNaO3 +:352.1883；found:352.1886.
实施例16：
原料是：1.7g N-苯基马来酰亚胺；1.8g 1-(4-苯基乙基)-2-甲基烯丙醇
还原剂是：0.8g硼氢化钠
催化剂是：2.6g乙酰丙酮镍
溶剂是：10ml乙腈
目标产物如下：
Figure GDA0002149928740000201
无色液体；1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),7.60–7.43(m,2H),7.36–7.13(m,7H),7.06–6.95(m,1H),4.45(dd,J＝9.7,3.2Hz,1H),3.17–3.08(m,1H),2.96(q,J＝8.2,7.6Hz,1H),2.57–2.50(m,1H),2.41(td,J＝14.4,13.7,5.3Hz,1H),1.30–1.17(m,3H),0.88(s,3H),0.66(s,3H).13C NMR(101MHz,DMSO-d6)δ177.71,176.97,169.20,144.37,139.48,129.15,129.12,128.94,128.78,128.68,128.55,128.15,127.84,127.00,126.69,123.68,119.57,119.53,119.46,90.88,90.21,89.72,49.24,47.45,46.99,42.82,41.75,41.63,32.98,24.32,24.27,23.38,23.14,22.11,21.16,20.88,19.46.HRMS:[MH+]calcd.For C22H26NO3:352.1907；found:352.1910.
实施例17：
原料是：1.7g N-苯基马来酰亚胺；1.8g 1-(丙烯基)环己-1-醇
还原剂是：0.8g硼氢化钠
催化剂是：2.6g乙酰丙酮镍
溶剂是：8ml乙腈
目标产物如下：
Figure GDA0002149928740000211
白色固体,熔点.50-51℃；1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),7.57(d,J＝7.2Hz,2H),7.28(d,J＝7.4Hz,2H),7.05–6.97(m,1H),3.26(dd,J＝7.7,6.2Hz,1H),2.54–2.47(m,1H),2.39(dd,J＝15.4,6.1Hz,1H),1.87(d,J＝10.6Hz,1H),1.71–1.56(m,4H),1.41(ddt,J＝19.5,13.0,9.2Hz,4H),1.20–1.13(m,1H),0.97(s,3H),0.81(s,3H).13C NMR(101MHz,DMSO-d6)δ176.98,169.52,139.61,129.15,123.58,119.47,87.99,46.19,44.02,32.26,31.27,29.69,25.15,22.72,22.12,21.38,19.42.HRMS:[MH+]calcd.For C19H26NO3:316.1907；found:316.1904.
实施例18：
原料是：1.7g N-苯基马来酰亚胺；1.6g环戊烯甲醇
还原剂是：0.8g硼氢化钠
催化剂是：2.6g乙酰丙酮镍
溶剂是：10ml乙腈
目标产物如下：
Figure GDA0002149928740000212
白色固体,熔点.145-147℃；1H NMR(400MHz,Chloroform-d)δ8.62(s,1H),7.53(d,J＝7.9Hz,2H),7.31(t,J＝7.7Hz,2H),7.10(t,J＝7.5Hz,1H),4.12(d,J＝8.7Hz,1H),3.99(d,J＝8.7Hz,1H),3.13(dd,J＝9.0,3.8Hz,1H),2.73(dd,J＝14.9,8.8Hz,1H),2.40(dd,J＝15.0,4.0Hz,1H),1.92–1.67(m,3H),1.50(dd,J＝17.6,8.3Hz,2H),1.26(m,3H).13CNMR(101MHz,cdcl3)δ179.76,168.84,137.94,128.95,124.27,119.82,78.33,51.27,44.66,33.87,33.68,29.69,24.30,24.06.HRMS:[MH+]calcd.For C16H20NO3:274.1438；found:274.1435.
实施例19：
原料是：1.7g N-苯基马来酰亚胺；2.2g 1-苯基-2-甲酸甲酯烯丙醇
还原剂是：0.8g硼氢化钠
催化剂是：2.6g乙酰丙酮镍
溶剂是：10ml乙腈
目标产物如下：
Figure GDA0002149928740000221
白色固体,熔点.175-176℃；1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),7.56(d,J＝7.9Hz,2H),7.39(dd,J＝11.7,7.2Hz,3H),7.30(t,J＝7.9Hz,2H),7.21(d,J＝7.2Hz,2H),7.04(t,J＝7.6Hz,1H),5.95(s,1H),4.01(t,J＝7.0Hz,1H),3.65(s,3H),2.82(dd,J＝16.2,5.4Hz,1H),2.59(dd,J＝16.2,9.0Hz,1H),0.78(s,3H).13C NMR(101MHz,cdcl3)δ180.21,177.23,173.22,144.19,139.50,133.94,133.69,130.96,128.43,124.19,88.02,58.74,57.81,51.85,37.23,17.78.HRMS:[MH+]calcd.For C21H22NO5:368.1492；Found:368.1498.
实施例20：
原料是：1.7g N-苯基马来酰亚胺；0.9g 3，3-二甲基烯丙醇
还原剂是：1.1g氰基硼氢化钠
催化剂是：2.6g乙酰丙酮镍
溶剂是：8ml乙腈
目标产物如下：
Figure GDA0002149928740000231
白色固体,熔点.150-151℃；1H NMR(300MHz,DMSO-d6)δ8.12(s,1H),7.50(d,J＝8.0Hz,2H),7.30(d,J＝7.5Hz,3H),7.07(t,J＝7.3Hz,1H),4.43–4.27(m,2H),2.95(dd,J＝9.8,2.1Hz,1H),2.75(dd,J＝14.1,9.9Hz,1H),2.49–2.37(m,1H),1.91(dt,J＝14.4,5.1Hz,1H),1.84–1.68(m,1H),1.21(s,3H),0.95(s,3H).13C NMR(101MHz,cdcl3)δ175.32,170.08,138.00,129.21,128.88,126.46,124.10,119.71,65.42,48.10,38.43,34.00,33.24,28.94,24.57.HRMS:[MH+]calcd.For C15H20NO3 262.1438；Found:262.1436.
实施例21：
原料是：1.9g N-4-甲基苯基马来酰亚胺；1.4g 2-甲基烯丙醇
还原剂是：1.1g氰基硼氢化钠
催化剂是：2.6g乙酰丙酮镍
溶剂是：10ml乙腈
目标产物如下：
Figure GDA0002149928740000241
白色固体,熔点.134-135℃；1H NMR(300MHz,Chloroform-d)δ8.46(s,1H),7.40(d,J＝8.4Hz,2H),7.11(d,J＝8.2Hz,2H),4.06–3.95(m,2H),2.90(dd,J＝8.7,4.3Hz,1H),2.67(dd,J＝14.8,8.7Hz,1H),2.39–2.32(m,1H),2.30(s,3H),1.21(s,3H),1.03(s,3H).13CNMR(101MHz,cdcl3)δ179.56,168.63,135.35,133.90,129.43,119.90,78.83,62.84,47.78,40.37,33.13,23.69,20.86.HRMS:[MH+]calcd.For C15H20NO3:262.1438；Found:262.1439.
实施例22：
原料是：2.8g N-4-苄氧基苯基马来酰亚胺；1.4g 2-甲基烯丙醇
还原剂是：1.1g氰基硼氢化钠
催化剂是：1.9g乙酰丙酮钴
溶剂是：10ml乙醇
目标产物如下：
Figure GDA0002149928740000242
白色固体,熔点.178-180℃；1H NMR(300MHz,Chloroform-d)δ8.40(s,1H),7.47–7.28(m,7H),6.92(d,J＝8.9Hz,2H),5.04(s,2H),4.08–3.94(m,2H),2.89(dd,J＝8.8,4.1Hz,1H),2.66(dd,J＝14.8,8.7Hz,1H),2.35(dd,J＝14.8,4.2Hz,1H),1.21(s,3H),1.03(s,3H).13C NMR(101MHz,cdcl3)δ179.55,168.54,155.53,136.94,131.31,128.56,127.94,127.45,121.60,115.15,78.83,70.24,47.83,40.38,33.03,23.69,21.05.HRMS:[MH+]calcd.For C21H24NO4:354.1699；Found:354.1700.
实施例23：
原料是：2.1g N-4-氯苯基马来酰亚胺；1.4g 2-甲基烯丙醇
还原剂是：1.1g氰基硼氢化钠
催化剂是：2.6g乙酰丙酮镍
溶剂是：10ml甲醇
目标产物如下：
Figure GDA0002149928740000251
白色固体,熔点.154-155℃；1H NMR(300MHz,DMSO-d6)δ10.24(s,1H),7.63(d,J＝8.9Hz,2H),7.36(d,J＝8.9Hz,2H),3.98(q,J＝8.5Hz,2H),3.03(t,J＝6.9Hz,1H),2.56(d,J＝7.2Hz,2H),1.09(s,3H),0.96(s,3H).13C NMR(101MHz,DMSO-d6)δ178.52,169.59,138.52,129.10,127.14,120.99,77.96,46.77,32.01,31.14,23.65,21.44.HRMS:[MH+]calcd.For C14H17NO3Cl:282.0891；Found:282.0891.
实施例24：
原料是：2.1g N-3-氯苯基马来酰亚胺；1.4g 2-甲基烯丙醇
还原剂是：1.1g氰基硼氢化钠
催化剂是：2.6g乙酰丙酮镍
溶剂是：10ml甲醇
目标产物如下：
Figure GDA0002149928740000261
白色固体,熔点.145-148℃；1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),7.83(t,J＝2.1Hz,1H),7.44(ddd,J＝8.3,2.0,1.0Hz,1H),7.33(t,J＝8.1Hz,1H),7.09(ddd,J＝8.0,2.1,1.0Hz,1H),4.03–3.94(m,2H),3.04(t,J＝6.9Hz,1H),2.49(tt,J＝15.6,7.5Hz,2H),1.09(s,3H),0.95(s,3H).13C NMR(101MHz,DMSO-d6)δ178.48,169.85,140.97,133.53,130.88,123.33,118.94,117.83,77.99,46.78,39.61,32.07,23.68,21.43.HRMS:[MH+]calcd.For C14H17NO3Cl:282.0891；Found:282.0892.
实施例25：
原料是：2.5g N-3-氯-4-甲基苯基马来酰亚胺；1.4g 2-甲基烯丙醇
还原剂是：2.1g苯硅烷
催化剂是：2.6g乙酰丙酮镍
溶剂是：10ml乙腈
目标产物如下：
Figure GDA0002149928740000262
白色固体,熔点.146-147℃；1H NMR(300MHz,Chloroform-d)δ8.65(s,1H),7.63(d,J＝2.2Hz,1H),7.24(d,J＝2.2Hz,1H),7.12(d,J＝8.2Hz,1H),4.08–3.98(m,2H),2.90–2.86(m,1H),2.65(dd,J＝14.8,9.1Hz,1H),2.39–2.33(m,1H),2.31(s,3H),1.21(s,3H),1.02(s,3H).13C NMR(101MHz,cdcl3)δ179.70,168.76,136.72,134.35,131.74,130.88,120.35,118.04,78.92,47.78,40.39,33.08,23.62,21.03,19.43.HRMS:[MH+]calcd.ForC15H19NO3Cl:296.1048；Found:296.1047.
实施例26：
原料是：2.1g N-5-(2-氯吡啶基)马来酰亚胺；1.4g 2-甲基烯丙醇
还原剂是：2.1g苯硅烷
催化剂是：2.6g乙酰丙酮镍
溶剂是：10ml乙腈
目标产物如下：
Figure GDA0002149928740000271
淡黄色固体,熔点.142-144℃；1H NMR(300MHz,Chloroform-d)δ9.13(s,1H),8.43(d,J＝2.8Hz,1H),8.08(dd,J＝8.7,2.8Hz,1H),7.27(s,1H),4.09–4.02(m,2H),2.91(dd,J＝9.5,3.5Hz,1H),2.67(dd,J＝14.9,9.5Hz,1H),2.40(dd,J＝14.9,3.6Hz,1H),1.22(s,3H),1.02(s,3H).13C NMR(101MHz,cdcl3)δ179.91,169.33,145.66,140.61,134.08,129.89,124.19,79.07,47.73,40.44,32.88,23.55,21.06.HRMS:[MH+]calcd.ForC13H16N2O3Cl:283.0844；Found:283.0843.
尽管已经示出和描述了本发明的实施例，本领域的普通技术人员可以理解为：在不脱离本发明的原理和宗旨下可以对这些实施例进行多种变化、修改、替换和变型，本发明的范围由权利要求及其等同物限定。

Claims (5)

1.一种多取代γ-丁内酯类化合物的制备方法，其特征在于：化学结构式如下：
Figure 745109DEST_PATH_IMAGE001
；
其中，R1选自芳基或芳杂基，R2与R3均选自烷基，R4选自芳基或烷基；
所述化合物的反应式为：
Figure 770834DEST_PATH_IMAGE002
合成步骤如下：
将N-取代马来酰亚胺与
Figure 506709DEST_PATH_IMAGE003
加入反应瓶中，向反应瓶中加入溶剂、催化剂和还原 剂，反应一定时间后，分离提纯；
所述溶剂选自1,2-二氯乙烷、四氢呋喃、乙腈、DMF中的一种或几种；
所述催化剂Pd(OAc)2、FeCl3、Fe(ox)3.6H2O、Co(acac)2、Ni(acac)2中的一种或几种；
所述还原剂选自NaBH4、NaCNBH3、Et3SiH、PhSiH3中的一种或几种。
2.根据权利要求1所述的多取代γ-丁内酯类化合物的制备方法，其特征在于：所述N- 取代马来酰亚胺与
Figure 971188DEST_PATH_IMAGE003
的摩尔比为1:0.4～5。
3.根据权利要求1所述的多取代γ-丁内酯类化合物的制备方法，其特征在于：所述N-取代马来酰亚胺与催化剂的摩尔比为1:0.1～2。
4.根据权利要求1所述的多取代γ-丁内酯类化合物的制备方法，其特征在于：所述N-取代马来酰亚胺与还原剂的摩尔比为1:0.5～6。
5.根据权利要求1所述的多取代γ-丁内酯类化合物的制备方法，其特征在于：所述反应时间为1～24h。
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