CN108084200A - 一种卤代二氢吡喃并吡咯酮化合物及其制备方法和用途 - Google Patents
一种卤代二氢吡喃并吡咯酮化合物及其制备方法和用途 Download PDFInfo
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- CN108084200A CN108084200A CN201711296699.0A CN201711296699A CN108084200A CN 108084200 A CN108084200 A CN 108084200A CN 201711296699 A CN201711296699 A CN 201711296699A CN 108084200 A CN108084200 A CN 108084200A
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- 150000003233 pyrroles Chemical class 0.000 title 1
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- 239000000460 chlorine Chemical group 0.000 claims abstract description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 12
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 12
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 12
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Classifications
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- C—CHEMISTRY; METALLURGY
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- 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
- C07D491/02—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 two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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- 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
- C07B2200/07—Optical isomers
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Abstract
本发明提供了一种如式(Ⅰ)所示的卤代二氢吡喃并吡咯酮化合物或其晶型，其中，X为氟、氯、溴、碘；L1为无或乙烯基；环A为萘环、苯环、噻吩环；R1为苄基、C1‑C8的烷基或(CH2)n‑O‑Bn；n为1～5的整数；R2为苄基、烯丙基、对甲氧苄基；R3、R4分别独立地选自氢、氟、氯、溴、碘、C1‑C3的烷基、硝基、甲氧基。本发明还提供了上述化合物或其晶型的制备方法。本发明的化合物制备方法简便、反应温和、收率高，并且具有一定的抗肿瘤活性，具有广阔的市场应用前景。
Description
技术领域
本发明涉及一种卤代二氢吡喃并吡咯酮化合物及其制备方法和用途。
背景技术
多取代吡喃类化合物，尤其是基于吡喃并环骨架的多取代化合物广泛存在于具有生理活性的天然产物或医药中间体中，对此类化合物的取代基修饰、结构类似物的衍生化以及进一步生物学活性再评价成为了研究热点。
Huynh等(T.H.V.Huynh，I.Shim，H.Bohr，B.Abrahamsen，B.Nielsen，A.A.Jensen，L.Bunch，J.Med.Chem.2012,55,5403-5412.)报道了如下所示的一系列吡喃并环骨架的多取代化合物作为EAAT1-选择性抑制剂的用途。
CN105541853A公开了如下所示的多取代基类型的γ-吡喃并吡咯烷酮化合物，此类化合物具有良好的抗菌活性。
目前还未见报道本发明所示结构的卤代二氢吡喃并吡咯酮化合物。
发明内容
为了解决上述技术问题，本发明提供了一种卤代二氢吡喃并吡咯酮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)所示的卤代二氢吡喃并吡咯酮化合物或其晶型：
其中，X为氟、氯、溴、碘；
L1为无或乙烯基；
环A为萘环、苯环、噻吩环；
R1为苄基、C1-C8的烷基或(CH2)n-O-Bn；n为1～5的整数；
R2为苄基、烯丙基、对甲氧苄基；
R3、R4分别独立地选自氢、氟、氯、溴、碘、C1-C3的烷基、硝基、甲氧基。
进一步地，上述化合物为如下化合物之一：
本发明还提供了上述化合物或其晶型的制备方法，包括以下步骤：
(1)取式(1-1)所示化合物与式(1-2)所示丙烯酸乙酯，于25±2℃，在乙醇中反应16±2h后，加入式(1-4)所示草酸二乙酯、乙醇钠，于90±2℃反应后，即得式(1-5)所示化合物；
(2)取式(1-5)所示化合物与式(1-6)所示化合物，在90±3℃反应即得式(1)所示化合物，
(3)取式(1)所示化合物与式(2)所示化合物，以氯苯为溶剂，方酰胺为催化剂，在25±3℃下反应，即得式(Ⅰ)所示化合物。
进一步地，X为氟、氯、溴、碘；L1为无或乙烯基；环A为萘环、苯环、噻吩环；R1为苄基、C1-C8的烷基或(CH2)n-O-Bn；n为1～5的整数；R2为苄基、烯丙基、对甲氧苄基；R3、R4分别独立地选自氢、氟、氯、溴、碘、C1-C3的烷基、硝基、甲氧基。
进一步地，步骤(1)中，式(1-1)所示化合物、丙烯酸乙酯、草酸二乙酯和乙醇钠的摩尔比为1：1：1：1.5。
进一步地，步骤(2)中，式(1-5)所示化合物与式(1-6)所示化合物的摩尔比为1:1。
进一步地，步骤(3)中，式(1)所示化合物与式(2)所示化合物以及方酰胺的摩尔比为10:30:1。
进一步地，步骤(3)中，所述方酰胺结构如下：
本发明还提供了上述化合物或其晶型在制备抗肿瘤药物中的用途。
进一步地，所述肿瘤为乳腺癌、黑色素瘤。
实验结果表明：本发明制备得到了一系列的卤代二氢吡喃并吡咯酮化合物，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。
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
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
C1-C3的烷基是指甲基、乙基、丙基。
化合物结构式中的Et表示乙基，Me表示甲基，Bn表示苄基；PMB表示对甲氧基苄基。
实施例1、本发明化合物的制备
原料
奎宁定方酰胺催化剂：结构为购自大赛璐药物手性技术(上海)有限公司
通用合成路线：
其中，X为氟、氯、溴、碘；L1为无或乙烯基；环A为萘环、苯环、噻吩环；R1为苄基、C1-C8的烷基或(CH2)n-O-Bn；n为1～5的整数；R2为苄基、烯丙基、对甲氧苄基；R3、R4分别独立地选自氢、氟、氯、溴、碘、C1-C3的烷基、硝基、甲氧基。
制备得到了以下化合物：
1、化合物4a的制备
①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，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，干燥即得式1-5所示化合物。
②将36mmol的式1-5所示化合物、36mmol量的苯甲醛、112.5ml的20％HCl溶液加入到55ml无水乙醇中，90℃下反应4h，降温至25±2℃，过滤得残余物，加入乙酸乙酯，90℃下放置至溶液澄清，冷却至25±2℃，析出得式(1)所示化合物。
③以α-氯代苯丙醛(0.3mmol)和式(1)所示化合物(0.1mmol)为原料，依次加入反应试管，加入1ml氯苯做溶剂以及奎宁定方酰胺催化剂(0.01mmol)。在室温下反应16h，使用薄层色谱监测反应，待反应完成后，浓缩溶剂，得到的粗产品使用柱层析纯化，使用石油醚：二氯甲烷：乙酸乙酯＝4：4：1分离，即得化合物4a，白色固体，产率95％，dr值90：10，ee值99％。
1H NMR(400MHz,CDCl3)δ(ppm):7.69(s,1H),7.46–7.05(m,15H),5.30(d,J＝2.8Hz,1H),4.71(d,J＝14.8Hz,1H),4.43(d,J＝14.8Hz,1H),4.24(s,1H),3.64(d,J＝18.4Hz,1H),3.41(d,J＝18.4Hz,1H),3.32(d,J＝13.6Hz,1H),2.69(d,J＝13.6Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.8,142.5,136.5,134.7,134.4,131.4,128.8,128.3,128.1,128.0,127.8,127.1,122.1,96.1,70.1,48.1,46.8,46.5,43.2.
HRMS(ESI):m/z calculated for C27H24ClNO3+Na+:468.1337,found:468.1340.
2、化合物4b的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为对甲苯甲醛，即得化合物4b，白色固体，产率95％，dr值87：13，ee值99％。
1H NMR(400MHz,CDCl3)δ(ppm):7.70(s,1H),7.38–7.07(m,14H),5.36(s,1H),4.77(d,J＝14.8Hz,1H),4.50(d,J＝14.8Hz,1H),4.27(s,1H),3.71(d,J＝18.4Hz,1H),3.47(d,J＝18.4Hz,1H),3.37(d,J＝13.6Hz,1H),2.77(d,J＝13.6Hz,1H),2.36(s,3H).
13C NMR(100MHz,CDCl3)δ(ppm):166.8,142.4,137.9,136.5,134.5,131.6,131.4,128.8,128.3,128.0,127.8,127.0,122.3,96.1,70.2,48.1,46.8,46.1,43.1,21.1.
HRMS(ESI):m/z calculated for C28H26ClNO3+Na+:482.1493,found:482.1499.
3、化合物4c的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为对氟苯甲醛，即得化合物4c，白色固体，产率99％，dr值88：12，ee值99％。
1H NMR(400MHz,CDCl3)δ(ppm):7.77(s,1H),7.44–7.17(m,12H),7.14–6.95(m,2H),5.36(s,1H),4.77(d,J＝14.8Hz,1H),4.51(d,J＝14.8Hz,1H),4.30(s,1H),3.66(d,J＝18.4Hz,1H),3.48(d,J＝18.4,1H),3.37(d,J＝13.6Hz,1H),2.72(d,J＝13.6Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.7,142.6,136.4,134.2,131.4,128.9,128.3,128.1,127.9,127.1,121.7,96.1,70.0,48.0,46.8,45.8,43.1.
HRMS(ESI):m/z calculated for C27H23ClFNO3+H+:464.1423,found:464.1428.
4、化合物4d的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为对氯苯甲醛，即得化合物4d，白色固体，产率98％，dr值87：13，ee值99％。
1H NMR(400MHz,CDCl3)δ(ppm):7.80(s,1H),7.43–7.12(m,14H),5.36(s,1H),4.76(d,J＝14.8Hz,1H),4.51(d,J＝14.8Hz,1H),4.28(s,1H),3.65(d,J＝18.4Hz,1H),3.46(d,J＝18.4Hz,1H),3.37(d,J＝13.6Hz,1H),2.72(d,J＝13.6Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.7,142.7,136.4,134.2,134.1,133.2,131.4,128.9,128.4,128.3,128.1,127.9,127.2,121.4,96.0,69.9,47.9,46.8,46.0,43.1.
HRMS(ESI):m/z calculated for C27H23Cl2NO3+Na+:502.0947,found:502.0955.
5、化合物4e的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为对溴苯甲醛，即得化合物4e，白色固体，产率96％，dr值90：10，ee值97％。
1H NMR(400MHz,CDCl3)δ(ppm):7.90(s,1H),7.48(d,J＝8.4Hz,2H),7.37–7.12(m,12H),5.36(d,J＝3.2Hz,1H),4.76(d,J＝14.8Hz,1H),4.51(d,J＝14.8Hz,1H),4.27(s,1H),3.65(d,J＝18.8Hz,1H),3.46(d,J＝18.8Hz,1H),3.37(d,J＝13.6Hz,1H),2.72(d,J＝13.6Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.7,142.7,136.3,134.1,133.8,131.4,128.9,128.3,128.1,127.9,127.2,122.4,121.3,96.0,69.8,47.9,46.9,46.1,43.1.
HRMS(ESI):m/z calculated for C27H23BrClNO3+Na+:546.0442,found:546.0447.
6、化合物4f的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为对硝基苯甲醛，即得化合物4f，白色固体，产率99％，dr值91：9，ee值99％。
1H NMR(400MHz,CDCl3)δ(ppm):7.91(s,1H),7.48–7.14(m,14H),5.37(d,J＝4.0Hz,1H),4.81(s,1H),4.49(d,J＝14.8Hz,1H),4.28(s,1H),3.68(d,J＝18.4Hz,1H),3.48(d,J＝18.4Hz,1H),3.38(d,J＝13.6Hz,1H),2.74(d,J＝13.6Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.7,142.7,136.9,136.4,134.1,131.4,129.4,128.9,128.4,128.3,128.1,127.9,127.2,121.1,96.1,69.7,47.9,46.8,46.3,43.2.
HRMS(ESI):m/z calculated for C27H23ClN2O5+Na+:513.1188,found:513.1193.
7、化合物4g的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为邻氯苯甲醛，即得化合物4g，白色固体，产率99％，dr值96：4，ee值95％。
1H NMR(400MHz,CDCl3)δ(ppm):7.88(s,1H),7.57–7.50(m,1H),7.47–7.38(m,1H),7.37–7.14(m,12H),5.42(d,J＝2.4Hz,1H),5.15(s,1H),4.78(d,J＝14.8Hz,1H),4.49(d,J＝14.8Hz,1H),3.70(d,J＝14.0Hz,1H),3.58(d,J＝18.8Hz,1H),3.46(d,J＝18.8Hz,1H),2.69(d,J＝14.0Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.8,142.8,136.4,136.3,134.5,131.5,129.8,129.4,128.9,128.3,128.0,127.9,127.0,126.3,121.8,96.3,71.6,48.0,46.8,42.8,41.6.
HRMS(ESI):m/z calculated for C27H23Cl2NO3+Na+:502.0947,found:502.0952.
8、化合物4h的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为间甲苯甲醛，即得化合物4h，白色固体，产率90％，dr值91：9，ee值99％。
1H NMR(400MHz,CDCl3)δ(ppm):7.77(s,1H),7.39–7.12(m,14H),5.37(s,1H),4.79(d,J＝14.8Hz,1H),4.50(d,J＝14.8Hz,1H),4.27(s,1H),3.70(d,J＝18.8Hz,1H),3.47(d,J＝18.8Hz,1H),3.39(d,J＝13.6Hz,1H),2.78(d,J＝13.6Hz,1H),2.34(s,3H).
13C NMR(100MHz,CDCl3)δ(ppm):166.9,142.4,137.7,136.5,134.7,134.5,131.4,128.8,128.3,128.0,127.9,127.8,127.0,122.2,96.1,70.1,48.1,46.8,46.5,43.2,21.5.
HRMS(ESI):m/z calculated for C28H26ClNO3+Na+:482.1493,found:482.1501.
9、化合物4i的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为间甲氧苯甲醛，即得化合物4i，白色固体，产率76％，dr值85：15，ee值99％。
1H NMR(400MHz,CDCl3)δ(ppm):7.85(s,1H),7.40–7.09(m,11H),7.08–6.74(m,3H),5.27(s,1H),4.74(d,J＝14.8Hz,1H),4.51(d,J＝14.8Hz,1H),4.28(s,1H),3.84–3.68(m,4H),3.48(d,J＝18.8Hz,1H),3.35(d,J＝14.0Hz,1H),2.80(d,J＝14.0Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):165.7,158.2,141.4,135.5,135.1,133.4,130.3,128.0,127.8,127.2,127.0,126.8,126.0,121.0,95.1,68.9,54.2,47.0,45.7,42.2,28.7.
HRMS(ESI):m/z calculated for C28H26ClNO4+Na+:498.1443,found:498.1450.
10、化合物4j的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为间氯苯甲醛，即得化合物4j，白色固体，产率99％，dr值88：12，ee值98％。
1H NMR(400MHz,CDCl3)δ(ppm):7.89(s,1H),7.51–7.05(m,14H),5.36(s,1H),4.82(s,1H),4.49(d,J＝14.8Hz,1H),4.28(s,1H),3.68(d,J＝18.8Hz,1H),3.48(d,J＝18.8Hz,1H),3.38(d,J＝13.6Hz,1H),2.74(d,J＝13.6Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.7,142.7,136.9,136.3,134.1,131.4,129.4,128.9,128.4,128.3,128.1,127.9,127.2,121.1,96.1,69.7,47.9,46.8,46.3,43.2.
HRMS(ESI):m/z calculated for C27H23Cl2NO3+Na+:502.0947,found:502.0955.
11、化合物4k的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为间溴苯甲醛，即得化合物4k，白色固体，产率98％，dr值87：13，ee值99％。
1H NMR(400MHz,CDCl3)δ(ppm):7.70(s,1H),7.58–7.39(m,2H),7.39–7.14(m,12H),5.35(s,1H),4.81(s,1H),4.49(d,J＝14.8Hz,1H),4.26(s,1H),3.67(d,J＝18.8Hz,1H),3.48(d,J＝18.8Hz,1H),3.37(d,J＝13.6Hz,1H),2.74(d,J＝13.6Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.6,142.7,137.1,136.4,134.0,131.3,129.6,128.9,128.3,128.1,127.9,127.2,121.1,96.0,69.7,47.9,46.8,46.3,43.2.
HRMS(ESI):m/z calculated for C27H23BrClNO3+Na+:546.0442,found:546.0446.
12、化合物4l的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为2，4-二氯苯甲醛，即得化合物4l，白色固体，产率99％，dr值96：4，ee值99％。
1H NMR(400MHz,CDCl3)δ(ppm):7.94(s,1H),7.53–7.42(m,2H),7.39–7.14(m,12H),5.40(s,1H),5.08(s,1H),4.76(d,J＝14.8Hz,1H),4.51(d,J＝14.8Hz,1H),3.66(d,J＝14.0Hz,1H),3.53(d,J＝18.4Hz,1H),3.46(d,J＝18.4Hz,1H),2.65(d,J＝14.0Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.6,143.0,136.9,136.3,134.7,134.2,134.1,131.5,129.6,129.0,128.9,128.3,128.0,127.9,127.1,126.8,121.1,96.3,71.4,47.8,46.9,42.8,41.2.
HRMS(ESI):m/z calculated for C27H22Cl3NO3+Na+:536.0557,found:536.0567.
13、化合物4m的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为2-萘甲醛，即得化合物4m，白色固体，产率90％，dr值90：10，ee值99％。
1H NMR(400MHz,CDCl3)δ(ppm):7.97–7.79(m,3H),7.79–7.55(m,2H),7.54–7.46(m,2H),7.38–7.13(m,10H),5.42(s,1H),4.80(d,J＝12.4Hz,1H),4.56–4.32(m,2H),3.72(d,J＝14.8Hz,1H),3.55–3.42(m,2H),2.84(d,J＝11.2Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):166.8,142.6,136.5,134.4,133.1,131.4,128.9,128.4,128.1,127.9,127.7,127.2,126.4,96.3,68.3,48.2,46.9,43.3,41.4.
HRMS(ESI):m/z calculated for C31H26ClNO3+Na+:518.1493,found:518.1498.
14、化合物4n的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为噻吩甲醛，即得化合物4n，白色固体，产率98％，dr值85：，e15e值99％。
1H NMR(400MHz,CDCl3)δ(ppm):7.92(s,1H),7.37–7.16(m,11H),7.10–6.97(m,2H),5.38(d,J＝2.4Hz,1H),4.81(d,J＝14.8Hz,1H),4.70(s,1H),4.45(d,J＝14.8Hz,1H),3.70(d,J＝18.8Hz,1H),3.52(d,J＝18.8Hz,1H),3.34(d,J＝14.0Hz,1H),2.88(d,J＝14.0Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.7,141.8,136.4,136.3,134.4,131.3,129.7,128.8,128.3,128.1,127.8,127.1,126.5,126.4,121.8,96.0,69.9,48.2,46.8,43.1,42.6.
HRMS(ESI):m/z calculated for C25H22ClNO3S+Na+:474.0901,found:474.0907.
15、化合物4o的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为1-萘甲醛，即得化合物4o，白色固体，产率92％，dr值93：7，ee值99％。
1H NMR(400MHz,CDCl3)δ(ppm):8.27(s,1H),8.07(s,1H),7.91–7.82(m,2H),7.69(d,J＝6.0Hz,1H),7.56–7.42(m,3H),7.33–7.12(m,10H),5.53(s,1H),5.48(s,1H),4.82(d,J＝14.8Hz,1H),4.50(d,J＝14.8Hz,1H),3.73(d,J＝18.4Hz,1H),3.60(d,J＝13.6Hz,1H),3.43(d,J＝18.4Hz,1H),2.49(d,J＝13.6Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.9,143.0,136.4,134.5,133.8,133.5,131.4,130.4,129.2,128.8,128.3,128.0,127.8,127.0,126.6,125.7,124.8,123.3,123.1,96.4,71.9,48.2,46.8,43.6,39.4.
HRMS(ESI):m/z calculated for C31H26ClNO3+Na+:518.1493,found:518.1495.
16、化合物4p的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为肉桂醛，即得化合物4p，白色固体，产率99％，dr值88：12，ee值98％。
1H NMR(400MHz,CDCl3)δ(ppm):7.53(s,1H),7.46–7.17(m,15H),6.65(d,J＝15.6Hz,1H),6.34(dd,J＝15.6,9.2Hz,1H),5.34(s,1H),4.71(d,J＝14.8Hz,1H),4.56(d,J＝14.8Hz,1H),3.77(d,J＝9.2Hz,1H),3.66(s,2H),3.32(d,J＝14.0Hz,1H),3.12(d,J＝14.0Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.8,141.0,136.6,136.5,136.2,134.6,131.4,128.9,128.7,128.4,128.2,128.1,127.8,127.1,126.6,123.7,121.5,95.7,70.2,48.3,46.8,44.6,43.3.
HRMS(ESI):m/z calculated for C29H26ClNO3+Na+:494.1493,found:494.1496.
17、化合物4q的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为肉桂醛，即得化合物4q，白色固体，产率98％，dr值86：14，ee值99％。
1H NMR(400MHz,CDCl3)δ(ppm):8.19(d,J＝8.5Hz,2H),7.73(s,1H),7.51(d,J＝8.6Hz,2H),7.43–7.17(m,11H),6.70(d,J＝16.0Hz,1H),6.51(dd,J＝16.0,9.2Hz,1H),5.37(s,1H),4.70(d,J＝14.8Hz,1H),4.57(d,J＝14.8Hz,1H),3.84(d,J＝9.2Hz,1H),3.66(s,2H),3.34(d,J＝14.0Hz,1H),3.10(d,J＝14.0Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.7,147.3,142.4,141.3,136.4,134.3,131.4,129.2,129.0,128.9,128.3,128.1,127.9,127.3,127.2,124.1,120.5,95.8,69.9,48.2,46.8,44.7,43.5.
HRMS(ESI):m/z calculated for C29H25ClN2O5+Na+:539.1344,found:539.1353.
18、化合物4r的制备
制备方法同化合物4a，只需将步骤①中的苯甲胺置换为对甲氧基苄基胺，步骤②中的苯甲醛置换为苯丙醛，即得化合物4r，白色固体，产率95％，dr值88：12，ee值99％。
1H NMR(600MHz,CDCl3)δ(ppm):7.86(s,1H),7.52–7.28(m,7H),7.26–7.14(m,5H),6.90–6.81(m,2H),5.36(d,J＝2.2Hz,1H),4.73(d,J＝14.8Hz,1H),4.44(d,J＝14.8Hz,1H),4.32(d,J＝13.6Hz,1H),3.79(s,3H),3.68(d,J＝18.6Hz,1H),3.45(d,J＝18.6Hz,1H),3.39(d,J＝13.8Hz,1H),2.75(d,J＝13.8Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):166.8,159.3,142.6,134.8,134.5,131.5,129.8,128.6,128.2,128.1,127.1,122.0,114.2,96.1,70.1,55.4,48.0,46.6,46.3,43.2.
HRMS(ESI):m/z calculated for C28H26ClNO4+Na+:498.1443,found:498.1448.
19、化合物4s的制备
制备方法同化合物4a，只需将步骤①中的苯甲胺置换为烯丙胺，即得化合物4s，白色固体，产率92％，dr值90：10，ee值99％。
1H NMR(600MHz,CDCl3)δ(ppm):7.81(s,1H),7.54–7.32(m,5H),7.32–7.27(m,1H),7.26–7.14(m,4H),5.83–5.70(m,1H),5.33(s,1H),5.21–5.12(m,2H),4.34(s,1H),4.14(dd,J＝15.3,6.0Hz,1H),4.00(dd,J＝15.3,6.6Hz,1H),3.76(d,J＝18.6Hz,1H),3.57(d,J＝18.6Hz,1H),3.39(d,J＝13.8Hz,1H),2.76(d,J＝13.8Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):166.7,142.6,134.8,134.4,132.9,131.4,128.2,128.1,127.1,122.2,118.8,96.1,70.1,48.1,46.6,45.6,43.2.
HRMS(ESI):m/z calculated for C23H22ClNO3+Na+:418.1180,found:418.1183.
20、化合物4t的制备
制备方法同化合物4a，只需将步骤③中的α-氯代苯丙醛置换为2-氯己醛，即得化合物4t，白色固体，产率93％，dr值95：5，ee值99％。
1H NMR(400MHz,CDCl3)δ(ppm):7.76(s,1H),7.37–7.16(m,10H),5.88(s,1H),4.73(d,J＝14.8Hz,1H),4.48(d,J＝14.8Hz,1H),4.17(s,1H),3.69(d,J＝18.4Hz,1H),3.45(d,J＝18.4,1H),2.13–2.01(m,1H),1.63–1.42(m,3H),1.38–1.27(m,1H),1.22–1.09(m,1H),0.87(t,J＝7.2Hz,3H).
13C NMR(150MHz,CDCl3)δ(ppm):167.0,142.1,136.5,135.0,128.9,128.3,128.1,128.0,127.9,122.4,96.8,71.2,48.2,46.8,46.6,38.1,25.4,23.0,14.1.
HRMS(ESI):m/z calculated for C24H26ClNO3+Na+:434.1493,found:434.1501.
21、化合物4u的制备
制备方法同化合物4a，只需将步骤③中的α-氯代苯丙醛置换为2-氯庚醛，即得化合物4u，白色固体，产率93％，dr值95：5，ee值99％。
1H NMR(400MHz,CDCl3)δ(ppm):7.78(s,1H),7.39–7.16(m,10H),5.87(s,1H),4.72(d,J＝14.8Hz,1H),4.48(d,J＝14.8Hz,1H),4.17(s,1H),3.69(d,J＝18.8Hz,1H),3.45(d,J＝18.8Hz,1H),2.14–1.99(m,1H),1.62–1.45(m,3H),1.38–1.19(m,3H),1.19–1.04(m,1H),0.85(t,J＝7.2Hz,3H).
13C NMR(150MHz,CDCl3)δ(ppm):167.0,142.0,136.5,134.9,128.9,128.3,128.0,127.9,122.4,96.8,71.2,48.2,46.8,46.6,38.3,32.1,23.0,22.7,14.2.
HRMS(ESI):m/z calculated for C25H28ClNO3+Na+:448.1650,found:448.1658.
22、化合物4v的制备
制备方法同化合物4a，只需将步骤③中的α-氯代苯丙醛置换为氯代苄氧丁醛，即得化合物4v，白色固体，产率96％，dr值95：5，ee值99％。
1H NMR(400MHz,CDCl3)δ(ppm):7.79–7.45(br,1H),7.36–7.22(m,13H),7.18(d,J＝6.4Hz,2H),5.99(s,1H),4.70(d,J＝14.8Hz,1H),4.51–4.41(m,3H),4.20(s,1H),3.86(dd,J＝16.4,8.0Hz,1H),3.74–3.59(m,2H),3.45(d,J＝18.8Hz,1H),2.58–2.45(m,1H),1.94–1.81(m,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.7,142.0,138.1,136.5,134.6,128.8,128.4,128.2,128.1,127.9,127.8,127.5,121.8,96.9,73.3,70.0,66.3,48.1,46.7,46.3,37.3.
HRMS(ESI):m/z calculated for C29H28ClNO4+Na+:512.1599,found:512.1606.
23、化合物4w的制备
制备方法同化合物4a，只需将步骤③中的α-氯代苯丙醛置换为α-溴代苯丙醛，即得化合物4w，白色固体，产率93％，dr值94：6，ee值98％。
1H NMR(400MHz,CDCl3)δ(ppm):7.55–7.16(m,16H),5.49(s,1H),4.80(d,J＝14.8Hz,1H),4.50(d,J＝14.8Hz,1H),4.31(s,1H),3.76(d,J＝18.8Hz,1H),3.56–3.41(m,2H),2.88(d,J＝14.0Hz,1H).
13C NMR(100MHz,CDCl3)δ(ppm):166.7,142.4,136.5,134.8,131.5,128.8,128.3,128.2,128.0,127.9,127.8,127.1,122.4,96.4,68.4,48.0,46.9,46.8,43.8.
HRMS(ESI):m/z calculated for C27H24BrNO3+Na+:512.0832,found:512.0836.
24、化合物4x的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为对甲基苯丙醛，步骤③中的α-氯代苯丙醛置换为α-溴代苯丙醛，即得化合物4x，白色固体，产率89％，dr值96：4，ee值99％。
1H NMR(600MHz,CDCl3)δ(ppm):7.38–7.27(m,7H),7.26–7.11(m,8H),5.48(d,J＝3.6Hz,1H),4.80(d,J＝15.0Hz,1H),4.49(d,J＝15.0Hz,1H),4.28(s,1H),3.76(d,J＝18.6Hz,1H),3.51–3.41(m,2H),2.88(d,J＝14.1Hz,1H),2.37(s,3H).
13C NMR(150MHz,CDCl3)δ(ppm):166.8,142.4,138.0,136.6,134.9,131.5,128.9,128.8,128.4,128.0,127.9,127.1,122.8,96.4,68.7,48.1,46.9,46.5,43.9,21.3.
HRMS(ESI):m/z calculated for C28H26BrNO3+Na+:526.0988,found:526.0988.
25、化合物4y的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为对溴苯丙醛，步骤③中的α-氯代苯丙醛置换为α-溴代苯丙醛，即得化合物4y，白色固体，产率90％，dr值95：5，ee值98％。
1H NMR(600MHz,CDCl3)δ(ppm):7.67(s,1H),7.48(d,J＝6.2Hz,2H),7.38–7.27(m,6H),7.26–7.17(m,6H),5.48(s,1H),4.78(d,J＝15.0Hz,1H),4.51(d,J＝15.0Hz,1H),4.27(s,1H),3.70(d,J＝18.6Hz,1H),3.51–3.40(m,2H),2.82(d,J＝14.1Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):166.7,142.6,136.4,134.6,131.5,131.3,129.0,128.4,128.1,128.0,127.3,122.6,121.7,96.4,68.1,48.0,46.9,46.4,43.8.
HRMS(ESI):m/z calculated for C27H23Br2NO3+Na+:589.9937,found:589.9938.
26、化合物4z的制备
制备方法同化合物4a，只需将步骤②中的苯甲醛置换为2，4-二氯苯甲醛，步骤③中的α-氯代苯丙醛置换为α-溴代苯丙醛，即得化合物4z，白色固体，产率99％，dr值96：4，ee值98％。
1H NMR(600MHz,CDCl3)δ(ppm):7.71(s,1H),7.57(d,J＝7.8Hz,1H),7.45(s,1H),7.39–7.25(m,7H),7.24–7.15(m,4H),5.52(s,1H),5.07(s,1H),4.80(d,J＝15.0Hz,1H),4.48(d,J＝15.0Hz,1H),3.75(d,J＝14.1Hz,1H),3.57(d,J＝18.6Hz,1H),3.46(d,J＝18.6Hz,1H),2.73(d,J＝14.1Hz,1H).
13C NMR(150MHz,CDCl3)δ(ppm):166.7,142.9,137.0,136.3,134.8,134.7,131.6,129.6,129.0,128.4,128.0,127.2,126.7,121.6,96.6,70.0,47.9,46.9,43.5,41.5.
HRMS(ESI):m/z calculated for C27H22BrCl2NO3+Na+:580.0052,found:580.0055.
27、化合物6a的制备
制备方法同化合物4a，只需将步骤③中的α-氯代苯丙醛换成3-苯丙醛，即得化合物6a，白色固体，产率80％，dr值90：10，ee值97％。
1H NMR(600MHz,CDCl3):δ(ppm):7.35–7.31(m,2H),7.30–7.23(m,4H),7.21–7.16(m,6H),7.13(t,J＝7.5Hz,1H),7.05(d,J＝7.2Hz,2H),6.48(s,1H),5.44(s,1H),4.73(d,J＝15.0Hz,1H),4.39(d,J＝15.0Hz,1H),3.64(d,J＝10.8Hz,1H),3.48(d,J＝18.4Hz,1H),3.34(d,J＝18.4Hz,1H),2.73(dd,J＝13.6,11.4Hz,1H),2.56(dd,J＝13.6,3.6Hz,1H),2.29–2.22(m,1H).
13C NMR(150MHz,CDCl3):δ(ppm):166.9,142.6,140.5,139.6,136.8,129.1,128.8,128.5,128.2,127.7,127.5,126.2,124.1,94.2,48.0,46.8,46.7,40.8,34.7.
HRMS(ESI):m/z calculated for C27H25NO3+Na+:434.1727,found:434.1737.
28、化合物6b的制备
制备方法同化合物4a，只需将步骤③中的α-氯代苯丙醛换成苄氧丁醛，即得化合物6b，白色固体，产率82％，dr值88：12，ee值98％。
1H NMR(600MHz,CDCl3):δ(ppm):7.33–7.26(m,7H),7.24–7.21(m,4H),7.18–7.10(m,4H),6.37(s,1H),5.85(s,1H),4.70(d,J＝15.0Hz,1H),4.40(d,J＝15.0Hz,1H),4.32(d,J＝0.9Hz,2H),3.58(d,J＝10.8Hz,1H),3.49–3.42(m,2H),3.37–3.30(m,2H),2.30–2.21(m,1H),1.91–1.80(m,1H),1.66–1.57(m,1H).
13C NMR(150MHz,CDCl3):δ(ppm):166.9,142.4,140.5,138.4,136.9,128.9,128.8,128.4,128.3,128.2,127.7,127.6,127.4,124.2,95.1,72.7,68.1,48.1,46.6,41.7,41.0,28.9.
HRMS(ESI):m/z calculated for C29H29NO4+Na+:478.1989,found:478.1993.
以下通过试验例来具体说明本发明的有益效果。
试验例1、抗肿瘤研究
1、实验肿瘤细胞株
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
4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本发明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，其中，化合物25的抗肿瘤效果最好。
综上所述，本发明制备得到了一系列的卤代二氢吡喃并吡咯酮化合物，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。
Claims (10)
1.一种如式(Ⅰ)所示的卤代二氢吡喃并吡咯酮化合物或其晶型：
其中，X为氟、氯、溴、碘；
L1为无或乙烯基；
环A为萘环、苯环、噻吩环；
R1为苄基、C1-C8的烷基或(CH2)n-O-Bn；n为1～5的整数；
R2为苄基、烯丙基、对甲氧苄基；
R3、R4分别独立地选自氢、氟、氯、溴、碘、C1-C3的烷基、硝基、甲氧基。
2.根据权利要求1所述的化合物或其晶型，所述化合物为如下化合物之一：
3.权利要求1或2所述化合物或其晶型的制备方法，其特征在于：包括以下步骤：
(1)取式(1-1)所示化合物与式(1-2)所示丙烯酸乙酯，于25±2℃，在乙醇中反应16±2h后，加入式(1-4)所示草酸二乙酯、乙醇钠，于90±2℃反应后，即得式(1-5)所示化合物；
(2)取式(1-5)所示化合物与式(1-6)所示化合物，在90±3℃反应即得式(1)所示化合物，
(3)取式(1)所示化合物与式(2)所示化合物，以氯苯为溶剂，方酰胺为催化剂，在25±3℃下反应，即得式(Ⅰ)所示化合物。
4.根据权利要求3所述的制备方法，其特征在于：X为氟、氯、溴、碘；L1为无或乙烯基；环A为萘环、苯环、噻吩环；R1为苄基、C1-C8的烷基或(CH2)n-O-Bn；n为1～5的整数；R2为苄基、烯丙基、对甲氧苄基；R3、R4分别独立地选自氢、氟、氯、溴、碘、C1-C3的烷基、硝基、甲氧基。
5.根据权利要求3或4所述的方法，其特征在于：步骤(1)中，式(1-1)所示化合物、丙烯酸乙酯、草酸二乙酯和乙醇钠的摩尔比为1：1：1：1.5。
6.根据权利要求3-5任一项所述的方法，其特征在于：步骤(2)中，式(1-5)所示化合物与式(1-6)所示化合物的摩尔比为1:1。
7.根据权利要求3-6任一项所述的制备方法，其特征在于：步骤(3)中，式(1)所示化合物与式(2)所示化合物以及方酰胺的摩尔比为10:30:1。
8.根据权利要求3-7任一项所述的方法，其特征在于：步骤(3)中，所述方酰胺结构如下：
9.权利要求1或2所述化合物或其晶型在制备抗肿瘤药物中的用途。
10.根据权利要求9所述的用途，其特征在于：所述肿瘤为乳腺癌、黑色素瘤。
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