CN117362273B - 一种吲哚吗啡烷衍生物的制备方法 - Google Patents
一种吲哚吗啡烷衍生物的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- -1 propargylamine cyclic ketone compound Chemical class 0.000 claims abstract description 34
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 239000000654 additive Substances 0.000 claims abstract description 6
- 230000000996 additive effect Effects 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 41
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 30
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 18
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 18
- 238000004440 column chromatography Methods 0.000 claims description 13
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 claims description 12
- NWJBOTGGBYFKEJ-UHFFFAOYSA-M bromorhenium;carbon monoxide Chemical compound [O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[O+]#[C-].[Re]Br NWJBOTGGBYFKEJ-UHFFFAOYSA-M 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
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- 230000008569 process Effects 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- QCCKSFHMARIKSK-UHFFFAOYSA-N 5,6-dihydro-4h-pyrrolo[3,2,1-ij]quinoline Chemical compound C1CCC2=CC=CC3=C2N1C=C3 QCCKSFHMARIKSK-UHFFFAOYSA-N 0.000 claims description 3
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- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000005362 aryl sulfone group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 24
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 13
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- 229910052757 nitrogen Inorganic materials 0.000 description 12
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- FDASSSDQTCSNEB-ZTCOLXNVSA-N (1R,9R,10R)-6-(1H-indol-2-yl)-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2,4,6-triene Chemical group C1=CC=C2NC(C3=C4C[C@H]5NCC[C@]6(C4=CC=C3)CCCC[C@H]65)=CC2=C1 FDASSSDQTCSNEB-ZTCOLXNVSA-N 0.000 description 1
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- FHOAKXBXYSJBGX-YFKPBYRVSA-N (2s)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](CO)C(O)=O FHOAKXBXYSJBGX-YFKPBYRVSA-N 0.000 description 1
- SZXBQTSZISFIAO-ZETCQYMHSA-N (2s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C SZXBQTSZISFIAO-ZETCQYMHSA-N 0.000 description 1
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 description 1
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 229930182821 L-proline Natural products 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- 238000006482 condensation reaction Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明公开了一种吲哚吗啡烷衍生物的制备方法,属于有机化学合成技术领域。所述制备方法的步骤包括:将吲哚化合物或5,6‑二氢‑4H‑吡咯并[3,2,1‑IJ]喹啉与炔丙基胺环酮化合物溶于有机溶剂中,加入催化剂和添加剂,反应后即得吲哚吗啡烷衍生物。经过生物活性评价,发现该类化合物对A549肺癌细胞有抑制作用,最低IC50值为23.11uM。本发明提供的合成方法成本低廉,操作简便,原子经济性高,副产物只有水,环境友好,具有良好的工业应用前景。
Description
技术领域
本发明属于有机化学合成技术领域,具体涉及一种具有抗肿瘤活性的吲哚吗啡烷衍生物的制备方法。
背景技术
近年来,德国的Waldmann教授首次提出了“拟天然产物”(pseudo-naturalproduct,PNP)概念,并以此为基础阐述了生物活性导向的化学进化策略。(Nat.Prod.Rep.2020,37,1497-1510;Nat.Chem.2018,10,1103-1111;J.Am.Chem.Soc.2022,144,8,3314-3329)该策略的核心是选取不同天然产物中的重要片段,利用偶联反应进行组合,从而获得结构新颖的拟天然产物分子。通常这些结构类群很难通过生物合成角度获取,且因其与市售药物分子的化学空间重叠性高,更接近Lipinski规则,更利于发现其片段所不具备的新生物功能。(Prog.Pharm.Sci.2023,47,287-302)其中,吲哚和吗啡烷生物碱组合的吲哚吗啡烷PNP被证实具有纳摩尔级别的糖摄入抑制活性效果。且作者在Lipinski-Ro5辅助分析中发现,有六成的吲哚吗啡烷拟天然产物在类药区域内。(Angew.Chem.Int.Ed.2019,58,17016-17025)然而,目前的报道中,用于构建吲哚吗啡烷骨架的方法和结构多样性非常有限(Org.Lett.2017,19,7,1894-1897)。因此,发展构建新的吲哚吗啡烷结构PNP的高效合成方法具有重要意义,对扩充PNP化学进化策略适用范围具有推动作用,有助于获取成药性更高的吲哚吗啡烷PNP类群。
发明内容
本发明的目的在于提供一种吲哚吗啡烷衍生物的快速制备方法,通过吲哚化合物与炔丙基胺环酮化合物的原位缩合/环化策略,构建高度官能化的新型吲哚吗啡烷骨架。该类化合物对A549肺癌细胞有抑制作用,最低IC50值为23.11uM。
为实现上述目的,本发明提供了如下技术方案:
一种吲哚吗啡烷衍生物的制备方法,包括以下步骤:
将吲哚化合物或5,6-二氢-4H-吡咯并[3,2,1-IJ]喹啉与炔丙基胺环酮化合物溶于有机溶剂中,加入催化剂和添加剂,反应后即得吲哚吗啡烷衍生物;
反应方程式如下:
上式中,R1为氢、烷氧基、烷基、双联嚬哪醇硼酸酯基或甲酸甲酯基;R2为氢、烷基或乙醇基;R3为氢或烷基;R4为芳基砜或烷基砜;
所述添加剂包括L-脯氨酸、醋酸、三氟甲磺酸、对甲苯磺酸、Boc-L-脯氨酸、Boc-L-颉氨酸、Boc-L-苯丙氨酸或Boc-L-丝氨酸。
优选地,反应后还包含分离步骤和提纯步骤。更优选地,所述分离步骤采用的是液相萃取;所述纯化步骤采用的是柱层析。
所述液相萃取采用的萃取剂为乙酸乙酯,萃取后收集上层液,用无水硫酸钠干燥,蒸去乙酸乙酯,得到粗结晶,重结晶后过200~400目的硅胶柱色谱层析,洗脱机选用乙酸乙酯和石油醚体积比1:2~10的混合溶液。
优选地,所述有机溶剂包括乙腈、四氢呋喃、N,N-二甲基甲酰胺、二氯乙烷、甲苯、三氟甲苯或二甲基亚砜。
优选地,所述催化剂包括:三氟甲磺酸铜、三氟甲磺酸银、五羰基溴化锰、五羰基溴化铼或十羰基二铼。
优选地,所述反应在惰性气体保护下进行,反应的温度为80~120℃,时间为12~24h。
更优选地,所述惰性气体为氮气和/或氩气。
优选地,所述吲哚化合物与所述炔丙基胺环酮化合物的摩尔比为1~1.5:1;所述炔丙基胺环酮化合物与所述催化剂的摩尔比为1:0.05~0.2;所述炔丙基胺环酮化合物与所述添加剂的摩尔比为1:0.1~0.3所述炔丙基胺环酮化合物与所述有机溶剂的用量比为0.2mmol:1~3mL。
本发明的原理为:吲哚在催化剂的作用下首先与羰基发生缩合反应,生成烯基吲哚,炔基与催化剂配位并接受所生成的烯基碳的亲核进攻成环,最后经过质子化与电子迁移得到最终产物。
本发明的有益技术效果如下:
本发明提供了一种吲哚吗啡烷骨架的快速合成方法,可用于构建一类全新的吲哚吗啡烷衍生物,有助于先导化合物的发现。
本发明提供的合成方法成本低廉,操作简便,原子经济性高,副产物只有水,环境友好,具有良好的工业应用前景。
具体实施方式
现详细说明本发明的多种示例性实施方式,该详细说明不应认为是对本发明的限制,而应理解为是对本发明的某些方面、特性和实施方案的更详细的描述。应理解本发明中所述的术语仅仅是为描述特别的实施方式,并非用于限制本发明。
另外,对于本发明中的数值范围,应理解为还具体公开了该范围的上限和下限之间的每个中间值。在任何陈述值或陈述范围内的中间值,以及任何其他陈述值或在所述范围内的中间值之间的每个较小的范围也包括在本发明内。这些较小范围的上限和下限可独立地包括或排除在范围内。
除非另有说明,否则本文使用的所有技术和科学术语具有本发明所述领域的常规技术人员通常理解的相同含义。虽然本发明仅描述了优选的方法和材料,但是在本发明的实施或测试中也可以使用与本文所述相似或等同的任何方法和材料。
关于本文中所使用的“包含”、“包括”、“具有”、“含有”等等,均为开放性的用语,即意指包含但不限于。
以下实施例中所使用的炔丙基胺环酮化合物可参照文献进行合成(Angew.Chem.Int.Ed.2017,56,5834-5838)。
实施例1
向25mL史莱克管中依次加入称量好的吲哚化合物(0.24mmol)、炔丙基胺环酮化合物(0.2mmol)、五羰基溴化铼(0.02mmol)、Boc-L-颉氨酸(0.02mmol)和甲苯(1mL),置换氮气,充入氮气,置于100℃油浴下充分反应16小时,反应结束后,使用氯化铵饱和溶液淬灭反应,乙酸乙酯(15mL×3)萃取,乙酸乙酯层用氯化钠饱和水溶液洗涤,无水硫酸钠干燥,真空浓缩,通过硅胶柱柱层析分离(梯度洗脱:石油醚/乙酸乙酯=10/1-5/1),得到白色固体,产率为88%。
反应方程式如下:
所得目标产物的结构表征数据如下所示:
1H NMR(400MHz,Chloroform-d)δ7.78-7.71(m,3H),7.31-7.18(m,4H),7.13-7.08(d,1H),7.01(s,1H),6.17(s,1H),4.86(d,J=5.7Hz,2H),4.38(s,1H),4.16(d,J=13.7Hz,1H),3.91(d,J=13.7Hz,1H),3.73(s,3H),3.33(s,1H),2.62(d,J=19.8Hz,1H),2.43(s,3H),2.24(d,J=19.7Hz,1H),1.94(d,J=11.9Hz,1H),1.84(d,J=11.6Hz,1H).
13C NMR(101MHz,Chloroform-d)δ143.4,143.2,138.0,137.5,132.9,129.8,127.3,126.2,126.0,122.1,121.2,120.6,119.8,116.1,110.8,109.6,47.0,45.9,41.1,33.0,32.4,31.2,21.7.
HRMS(ESI)m/z:calcd for C25H27O2N2S+[M+H]+419.1788,found 419.1780.
经以上表征数据推断目标化合物的结构如下:
该化合物对A549肺癌细胞有抑制作用,IC50>80uM。
实施例2
向25mL史莱克管中依次加入称量好的吲哚(0.24mmol)、炔丙基胺环酮(0.2mmol)、五羰基溴化铼(0.02mmol)、Boc-L-颉氨酸(0.02mmol)和甲苯(1mL),置换氮气,充入氮气,置于100℃油浴下充分反应16小时,反应结束后,使用氯化铵饱和溶液淬灭反应,乙酸乙酯(15mL×3)萃取,乙酸乙酯层用氯化钠饱和水溶液洗涤,无水硫酸钠干燥,真空浓缩,通过硅胶柱柱层析分离(梯度洗脱:石油醚/乙酸乙酯=10/1-2/1),得到黄色液体,产率为85%。
反应方程式如下:
所得目标产物的结构表征数据如下所示:
1H NMR(400MHz,Chloroform-d)δ7.78(d,J=7.5Hz,1H),7.73(d,J=7.3Hz,2H),7.31(t,J=8.0Hz,3H),7.23-7.18(m,1H),7.16-7.09(m,2H),6.20(s,1H),4.85(d,J=9.5Hz,2H),4.38(s,1H),4.19(dd,J=23.7,8.7Hz,3H),3.92(d,J=7.5Hz,3H),3.34(s,1H),2.67-2.59(m,1H),2.44(s,3H),2.26(d,J=19.5Hz,1H),1.93(d,J=12.1Hz,1H),1.84(d,J=12.1Hz,1H),1.64(s,1H).
13C NMR(101MHz,Chloroform-d)δ143.3,143.2,137.9,136.9,132.8,129.8,127.3,126.4,125.8,122.2,121.6,120.8,120.1,116.5,110.9,109.7,61.9,48.7,47.0,45.9,41.0,32.4,31.3,21.7.
HRMS(ESI)m/z calcd for C26H29O3N2S+[M+H]+449.1893,found 449.1885.
经以上表征数据推断目标化合物的结构如下:
该化合物对A549肺癌细胞有抑制作用,IC50为40.62uM。
实施例3
向25mL史莱克管中依次加入称量好的5,6-二氢-4H-吡咯并[3,2,1-IJ]喹啉(0.24mmol)、炔丙基胺环酮(0.2mmol)、五羰基溴化铼(0.02mmol)、Boc-L-颉氨酸(0.02mmol)和甲苯(1mL),置换氮气,充入氮气,置于100℃油浴下充分反应16小时,反应结束后,使用氯化铵饱和溶液淬灭反应,乙酸乙酯(15mL×3)萃取,乙酸乙酯层用氯化钠饱和水溶液洗涤,无水硫酸钠干燥,真空浓缩,通过硅胶柱柱层析分离(梯度洗脱:石油醚/乙酸乙酯=10/1-5/1),得到橙色固体,产率为85%。
反应方程式如下:
所得目标产物的结构表征数据如下所示:
1H NMR(400MHz,Chloroform-d)δ7.73(d,J=5.7Hz,2H),7.57(d,J=7.1Hz,1H),7.32-7.25(m,2H),7.03(d,J=14.1Hz,2H),6.91(s,1H),6.21(s,1H),4.89(d,J=13.0Hz,2H),4.38(s,1H),4.19-4.08(m,3H),3.91(d,J=13.0Hz,1H),3.36(s,1H),2.96(s,2H),2.63(d,J=19.6Hz,1H),2.43(s,3H),2.23(d,J=20.2Hz,3H),1.93(d,J=11.6Hz,1H),1.84(d,J=12.3Hz,1H).
13C NMR(101MHz,Chloroform-d)δ143.6,143.2,138.0,134.9,133.3,129.8,127.4,123.5,123.4,122.1,120.4,120.3,119.2,118.3,116.0,110.9,47.1,46.0,44.3,40.7,32.5,31.2,24.8,22.8,21.7.
HRMS(ESI)m/z:calcd for C27 H29O2N2S+[M+H]+445.1944,found 445.1938.
经以上表征数据推断目标化合物的结构如下:
该化合物对A549肺癌细胞有抑制作用,IC50为45.94uM。
实施例4
向25mL史莱克管中依次加入称量好的吲哚(0.24mmol)、炔丙基胺环酮(0.2mmol)、五羰基溴化铼(0.02mmol)、Boc-L-颉氨酸(0.02mmol)和甲苯(1mL),置换氮气,充入氮气,置于100℃油浴下充分反应16小时,反应结束后,使用氯化铵饱和溶液淬灭反应,乙酸乙酯(15mL×3)萃取,乙酸乙酯层用氯化钠饱和水溶液洗涤,无水硫酸钠干燥,真空浓缩,通过硅胶柱柱层析分离(梯度洗脱:石油醚/乙酸乙酯=10/1-5/1),得到白色固体,产率为70%。
反应方程式如下:
所得目标产物的结构表征数据如下所示:
1H NMR(400MHz,Chloroform-d)δ7.72(d,J=7.3Hz,2H),7.63(d,J=7.8Hz,1H),7.29(d,J=7.1Hz,2H),7.06(s,1H),6.94(s,2H),6.15(s,1H),4.85(d,J=6.6Hz,2H),4.38(s,1H),4.15(d,J=13.8Hz,1H),3.91(d,J=13.7Hz,1H),3.69(s,3H),3.32(s,1H),2.61(d,J=19.7Hz,1H),2.45(d,J=14.6Hz,6H),2.24(d,J=19.8Hz,1H),1.93(d,J=12.2Hz,1H),1.83(d,J=12.0Hz,1H).
13C NMR(101MHz,Chloroform-d)δ143.5,143.2,138.0,137.9,133.0,132.0,129.8,127.3,125.6,123.9,121.6,120.9,120.3,116.0,110.8,109.6,47.1,45.9,41.0,32.9,32.4,31.3,21.9,21.7.
HRMS(ESI)m/z:calcd for C26H29O2N2S+[M+H]+433.1944,found 433.1935.
经以上表征数据推断目标化合物的结构如下:
该化合物对A549肺癌细胞有抑制作用,IC50>80uM。
实施例5
向25mL史莱克管中依次加入称量好的吲哚(0.24mmol)、炔丙基胺环酮(0.2mmol)、五羰基溴化铼(0.02mmol)、Boc-L-颉氨酸(0.02mmol)和甲苯(1mL),置换氮气,充入氮气,置于100℃油浴下充分反应16小时,反应结束后,使用氯化铵饱和溶液淬灭反应,乙酸乙酯(15mL×3)萃取,乙酸乙酯层用氯化钠饱和水溶液洗涤,无水硫酸钠干燥,真空浓缩,通过硅胶柱柱层析分离(梯度洗脱:石油醚/乙酸乙酯=10/1-5/1),得到白色固体,产率为80%。
反应方程式如下:
所得目标产物的结构表征数据如下所示:
1H NMR(400MHz,Chloroform-d)δ7.75(d,J=7.4Hz,2H),7.35-7.21(m,4H),7.16-7.10(d,1H),7.03-7.00(m,1H),5.68(s,1H),4.64(s,1H),4.42(d,J=18.6Hz,2H),4.18(d,J=14.1Hz,1H),4.04(d,J=13.9Hz,1H),3.63(s,3H),3.29(s,1H),2.62(d,J=19.5Hz,1H),2.43(s,3H),2.32(s,1H),2.26(s,3H),2.01(d,J=11.8Hz,1H),1.84(d,J=11.6Hz,1H).
13C NMR(101MHz,Chloroform-d)δ143.2,141.9,138.0,136.5,134.5,133.5,129.8,127.4,127.3,126.5,120.8,119.2,118.7,114.3,110.9,108.8,46.8,45.6,41.8,31.9,31.7,29.7,21.7,11.1.
HRMS(ESI)m/z:calcd for C26H29O2N2S+[M+H]+433.1944,found 433.1936.
经以上表征数据推断目标化合物的结构如下:
该化合物对A549肺癌细胞有抑制作用,IC50>80uM。
实施例6
向25mL史莱克管中依次加入称量好的吲哚(0.24mmol)、炔丙基胺环酮(0.2mmol)、五羰基溴化铼(0.02mmol)、Boc-L-颉氨酸(0.02mmol)和甲苯(1mL),置换氮气,充入氮气,置于100℃油浴下充分反应16小时,反应结束后,使用氯化铵饱和溶液淬灭反应,乙酸乙酯(15mL×3)萃取,乙酸乙酯层用氯化钠饱和水溶液洗涤,无水硫酸钠干燥,真空浓缩,通过硅胶柱柱层析分离(梯度洗脱:石油醚/乙酸乙酯=10/1-5/1),得到白色固体,产率为70%。
反应方程式如下:
结构表征数据如下所示:
1H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.73(d,J=7.2Hz,2H),7.45(s,2H),7.33(d,J=32.2Hz,6H),7.22(d,J=8.7Hz,1H),7.13(s,1H),6.92(d,J=7.8Hz,1H),6.07(s,1H),5.08(s,2H),4.82(s,2H),4.38(s,1H),4.15(d,J=13.7Hz,1H),3.90(d,J=13.7Hz,1H),3.30(s,1H),2.61(d,J=17.5Hz,1H),2.42(s,3H),2.23(d,J=19.9Hz,1H),1.92(d,J=12.2Hz,1H),1.82(d,J=11.9Hz,1H).
13C NMR(101MHz,Chloroform-d)δ153.7,143.3,143.3,137.9,137.7,133.0,132.1,129.8,128.7,128.0,127.8127.3,125.9,122.4,121.3,117.4,112.8,112.0,110.8,104.9,71.3,47.0,45.9,41.0,32.4,31.2,21.7.
HRMS(ESI)m/z:calcd for C31H31O3N2S+[M+H]+511.2050,found 511.2044.
经以上表征数据推断目标化合物的结构如下:
该化合物对A549肺癌细胞有抑制作用,IC50>80uM。
实施例7
向25mL史莱克管中依次加入称量好的吲哚(0.24mmol)、炔丙基胺环酮(0.2mmol)、五羰基溴化铼(0.02mmol)、Boc-L-颉氨酸(0.02mmol)和甲苯(1mL),置换氮气,充入氮气,置于100℃油浴下充分反应16小时,反应结束后,使用氯化铵饱和溶液淬灭反应,乙酸乙酯(15mL×3)萃取,乙酸乙酯层用氯化钠饱和水溶液洗涤,无水硫酸钠干燥,真空浓缩,通过硅胶柱柱层析分离(梯度洗脱:石油醚/乙酸乙酯=10/1-5/1),得到白色固体,产率为60%。
反应方程式如下:
结构表征数据如下所示:
1H NMR(400MHz,Chloroform-d)δ7.77(d,J=7.6Hz,3H),7.28-7.18(m,2H),7.12(d,J=8.6Hz,1H),7.02(s,1H),6.97(d,J=8.1Hz,2H),6.18(d,J=4.5Hz,1H),4.86(d,J=8.5Hz,2H),4.37(s,1H),4.15(d,J=13.5Hz,1H),3.91(d,J=13.2Hz,1H),3.87(s,3H),3.73(s,3H),3.33(s,1H),2.63(d,J=19.1Hz,1H),2.26(d,J=19.8Hz,1H),1.94(d,J=12.5Hz,1H),1.84(d,J=12.5Hz,1H).
13C NMR(101MHz,Chloroform-d)δ162.8,143.5,137.6,132.9,132.6,129.4,126.2,126.0,122.1,121.2,120.6,119.8,116.1,114.3,110.8,109.6,55.9,47.0,45.8,41.06,32.9,32.4,31.2.
HRMS(ESI)m/z calcd for C25H27O3N2S+[M+H]+435.1737,found 435.1729.
经以上表征数据推断目标化合物的结构如下:
该化合物对A549肺癌细胞有抑制作用,IC50为72.55uM。
实施例8
向25mL史莱克管中依次加入称量好的吲哚(0.24mmol)、炔丙基胺环酮(0.2mmol)、五羰基溴化铼(0.02mmol)、Boc-L-颉氨酸(0.02mmol)和甲苯(1mL),置换氮气,充入氮气,置于100℃油浴下充分反应16小时,反应结束后,使用氯化铵饱和溶液淬灭反应,乙酸乙酯(15mL×3)萃取,乙酸乙酯层用氯化钠饱和水溶液洗涤,无水硫酸钠干燥,真空浓缩,通过硅胶柱柱层析分离(梯度洗脱:石油醚/乙酸乙酯=10/1-5/1),得到淡黄色液体,产率为55%。
反应方程式如下:
结构表征数据如下所示:
1H NMR(400MHz,Chloroform-d)δ7.83(d,J=6.1Hz,1H),7.33-7.24(m,2H),7.18-7.12(m,5.9Hz,1H),7.05(s,1H),6.32(s,1H),4.94(d,J=18.4Hz,2H),4.33(s,1H),4.09(d,J=14.0Hz,1H),3.99(d,J=14.2Hz,1H),3.76(s,3H),3.72-3.67(m,2H),3.46(s,1H),3.14(s,2H),2.86(d,J=20.0Hz,1H),2.57(d,J=19.7Hz,1H),2.33-2.25(m,2H),2.09(q,J=12.3Hz,2H).
13C NMR(101MHz,Chloroform-d)δ143.7,137.5,132.9,126.2,126.1,122.1,121.3,120.6,119.9,116.1,110.9,109.60,50.1,47.2,46.0,43.2,41.2,33.2,33.1,33.0,27.0.
HRMS(ESI)m/z calcd for C21H26O2N2ClS+[M+H]+405.1398,found 405.1392.
经以上表征数据推断目标化合物的结构如下:
该化合物对A549肺癌细胞有抑制作用,IC50为23.11uM。
实施例9
向25mL史莱克管中依次加入称量好的吲哚(0.24mmol)、炔丙基胺环酮(0.2mmol)、五羰基溴化铼(0.02mmol)、Boc-L-颉氨酸(0.02mmol)和甲苯(1mL),置换氮气,充入氮气,置于100℃油浴下充分反应16小时,反应结束后,使用氯化铵饱和溶液淬灭反应,乙酸乙酯(15mL×3)萃取,乙酸乙酯层用氯化钠饱和水溶液洗涤,无水硫酸钠干燥,真空浓缩,通过硅胶柱柱层析分离(梯度洗脱:石油醚/乙酸乙酯=10/1-5/1),得到白色固体,产率为68%。
反应方程式如下:
结构表征数据如下所示:
1H NMR(400MHz,Chloroform-d)δ8.09(s,1H),7.77(d,J=7.5Hz,1H),7.75-7.70(m,2H),7.37-7.27(m,3H),7.18(s,2H),7.14-7.09(m,1H),6.21(s,1H),4.85(s,2H),4.39(s,1H),4.17(d,J=13.7Hz,1H),3.92(d,J=13.6Hz,1H),3.35(s,1H),2.63(d,J=21.7Hz,1H),2.43(s,3H),2.25(d,J=19.7Hz,1H),1.95(d,J=12.3Hz,1H),1.84(d,J=12.6Hz,1H).
13C NMR(101MHz,Chloroform-d)δ143.4,143.2,138.0,136.7,132.9,129.8,127.4,125.6,122.5,121.8,121.4,120.5,120.3,117.8,111.5,110.8,47.0,45.9,41.1,32.4,31.3,21.7.
HRMS(ESI)m/z calcd for C24H25O2N2S+[M+H]+405.1631,found 405.1625.
经以上表征数据推断目标化合物的结构如下:
该化合物对A549肺癌细胞有抑制作用,IC50为28.24uM。
实施例10
向25mL史莱克管中依次加入称量好的吲哚(0.24mmol)、炔丙基胺环酮(0.2mmol)、五羰基溴化铼(0.02mmol)、Boc-L-颉氨酸(0.02mmol)和甲苯(1mL),置换氮气,充入氮气,置于100℃油浴下充分反应16小时,反应结束后,使用氯化铵饱和溶液淬灭反应,乙酸乙酯(15mL×3)萃取,乙酸乙酯层用氯化钠饱和水溶液洗涤,无水硫酸钠干燥,真空浓缩,通过硅胶柱柱层析分离(梯度洗脱:石油醚/乙酸乙酯=10/1-5/1),得到白色固体,产率为40%。
反应方程式如下:
结构表征数据如下所示:
1H NMR(400MHz,Chloroform-d)δ8.23(s,1H),7.73(d,J=7.1Hz,2H),7.66(d,J=7.8Hz,1H),7.30-7.22(m,3H),6.99(s,1H),6.25(s,1H),4.86(d,J=5.2Hz,2H),4.39(s,1H),4.16(d,J=13.6Hz,1H),3.90(d,J=13.4Hz,1H),3.71(s,3H),3.32(s,1H),2.63(d,J=19.5Hz,1H),2.43(s,3H),2.24(d,J=19.8Hz,1H),1.93(d,J=12.2Hz,1H),1.84(d,J=11.5Hz,1H),1.36(s,12H).
13C NMR(101MHz,Chloroform-d)δ143.6,143.2,139.4,138.0,132.5,129.8,128.4,128.2,127.3,126.2,125.8,121.9,117.0,110.8,108.9,83.6,47.1,45.9,41.0,32.9,32.5,31.2,25.0,24.9,21.7.
HRMS(ESI)m/z calcd for C31H38O4N2BS+[M+H]+545.2640,found 545.2636.
经以上表征数据推断目标化合物的结构如下:
该化合物对A549肺癌细胞有抑制作用,IC50为78.81uM。
实施例11
向25mL史莱克管中依次加入称量好的吲哚(0.24mmol)、炔丙基胺环酮(0.2mmol)、五羰基溴化铼(0.02mmol)、Boc-L-颉氨酸(0.02mmol)和甲苯(1mL),置换氮气,充入氮气,置于100℃油浴下充分反应16小时,反应结束后,使用氯化铵饱和溶液淬灭反应,乙酸乙酯(15mL×3)萃取,乙酸乙酯层用氯化钠饱和水溶液洗涤,无水硫酸钠干燥,真空浓缩,通过硅胶柱柱层析分离(梯度洗脱:石油醚/乙酸乙酯=10/1-5/1),得到黄色液体,产率为54%。
反应方程式如下:
结构表征数据如下所示:
1H NMR(400MHz,Chloroform-d)δ8.64(s,1H),8.10(s,1H),7.77(s,2H),7.73(d,J=7.6Hz,2H),7.35-7.25(m,3H),6.20(s,1H),4.84(s,2H),4.39(s,1H),4.17(d,J=13.9Hz,1H),3.90(d,J=13.2Hz,4H),3.32(s,1H),2.62(d,J=19.8Hz,1H),2.43(s,3H),2.25(d,J=19.8Hz,1H),1.94(d,J=12.2Hz,1H),1.84(d,J=11.9Hz,1H).
13C NMR(101MHz,Chloroform-d)δ168.1,143.3,143.2,137.8,136.0,132.4,129.9,129.0,127.3,124.8,124.0,122.5,121.1,120.0,118.1,113.9,111.0,52.1,46.9,45.8,41.1,32.4,31.2,21.7.
HRMS(ESI)m/z calcd for C26H27O4N2S+[M+H]+463.1686,found 463.1678.
经以上表征数据推断目标化合物的结构如下:
该化合物对A549肺癌细胞有抑制作用,IC50为78.34uM。
以上所述的实施例仅是对本发明的优选方式进行描述,并非对本发明的范围进行限定,在不脱离本发明设计精神的前提下,本领域普通技术人员对本发明的技术方案做出的各种变形和改进,均应落入本发明权利要求书确定的保护范围内。
Claims (4)
1.一种吲哚吗啡烷衍生物的制备方法,其特征在于,包括以下步骤:将吲哚化合物或5,6-二氢-4H-吡咯并[3,2,1-IJ]喹啉与炔丙基胺环酮化合物溶于有机溶剂甲苯中,加入催化剂五羰基溴化铼和添加剂Boc-L-颉氨酸,反应后即得吲哚吗啡烷衍生物;
反应方程式如下:
上式中,R1为氢、烷氧基、烷基、双联频哪醇硼酸酯基或甲酸甲酯基;R2为氢、烷基或乙醇基;R3为氢或烷基;R4为芳基砜或烷基砜;
所述反应在惰性气体保护下进行,反应的温度为100℃,时间为16h。
2.根据权利要求1所述的吲哚吗啡烷衍生物的制备方法,其特征在于,反应后还包含分离步骤和提纯步骤。
3.根据权利要求2所述的吲哚吗啡烷衍生物的制备方法,其特征在于,所述分离步骤采用的是液相萃取;所述提纯步骤采用的是柱层析。
4.根据权利要求1所述的吲哚吗啡烷衍生物的制备方法,其特征在于,所述吲哚化合物与所述炔丙基胺环酮化合物的摩尔比为1~1.5:1;所述炔丙基胺环酮化合物与所述催化剂的摩尔比为1:0.05~0.2;所述炔丙基胺环酮化合物与所述添加剂的摩尔比为1:0.1~0.3;所述炔丙基胺环酮化合物与所述有机溶剂的用量比为0.2mmol:1~3mL。
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