CN117486776A - 一种基于n-酰基邻炔基苯胺的吲哚类化合物的制备方法 - Google Patents
一种基于n-酰基邻炔基苯胺的吲哚类化合物的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 66
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 title claims abstract description 19
- -1 indole compound Chemical class 0.000 title claims abstract description 15
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims description 23
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims description 18
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 20
- 238000004440 column chromatography Methods 0.000 claims abstract description 15
- 238000010791 quenching Methods 0.000 claims abstract description 13
- 238000005406 washing Methods 0.000 claims abstract description 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 11
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 238000001704 evaporation Methods 0.000 claims abstract description 8
- 150000002475 indoles Chemical class 0.000 claims abstract description 8
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 7
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 4
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 4
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- 239000000741 silica gel Substances 0.000 claims description 10
- 229910002027 silica gel Inorganic materials 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 4
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- 238000003756 stirring Methods 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
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- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- MXJGZAMERDEUKM-UHFFFAOYSA-N N[Li].C[Si](N[Si](C)(C)C)(C)C Chemical compound N[Li].C[Si](N[Si](C)(C)C)(C)C MXJGZAMERDEUKM-UHFFFAOYSA-N 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
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- 125000001041 indolyl group Chemical group 0.000 description 2
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
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- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
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- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- 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
- C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
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Abstract
本发明公开了一种基于N‑酰基邻炔基苯胺的吲哚类化合物的制备方法,在非质子溶剂中,将式(Ⅰ)化合物和碱按摩尔比为1:4混合反应,反应完成后加饱和氯化铵溶液淬灭,滤过,洗涤后减压蒸干,柱层析分离得到产物(Ⅲ);当N‑酰基邻炔基苯胺类化合物为式(Ⅱ)时得到产物(Ⅳ);其中,Ar1为苯基或取代苯基;Ar2为2‑萘基、取代2‑萘基、2‑噻吩基、取代2‑噻吩基、2‑苯并噻吩基的任意一种;R1为苯基、取代苯基、吡啶基、环烷基、烷基的任意一种;R2为苯基、烷基、卤素、三氟甲基、甲氧基的任意一种。本发明在无金属催化的条件下,以简单易得的N‑酰基邻炔基苯胺为原料,在碱性环境下发生串联反应,得到吲哚类化合物。
Description
技术领域
本发明涉及有机合成领域,尤其涉及一种基于N-酰基邻炔基苯胺的吲哚类化合物的制备方法。
背景技术
吲哚母核及吲哚稠环结构广泛存在于天然产物、生物活性物质以及上市药物中。邻炔基苯胺类化合物作为一种常用的合成砌块,已经在合成多官能团化吲哚的合成上有了诸多应用。通常有两种策略。一是利用邻炔基苯胺环化后形成的活性中间体与异氰酸酯、二氧化碳、一氧化碳、推-拉电子环丙烷等亲电试剂反应,从而在吲哚的C3位上引入新的基团(如下列式1所示);二是利用环化/基团迁移的串联策略,将氮上的基团迁移到吲哚C3位上,进而合成多官能团化的吲哚(如下列式2所示)。但它们通常需要在贵重的过渡金属催化剂的参与下才能顺利进行反应,难以放大反应并且操作复杂,并且过渡金属对环境不友好。
发明内容
针对现有技术的不足,本发明提出一种以N-酰基邻炔基苯胺为起始原料、工艺简单、无过渡金属催化、无氧化剂、高选择性的基于N-酰基邻炔基苯胺的吲哚类化合物的制备方法。
具体技术方案如下:
一种基于N-酰基邻炔基苯胺的吲哚类化合物的制备方法,在非质子溶剂中,将N-酰基邻炔基苯胺类化合物和碱按摩尔比为1:4混合进行反应,反应完成后加入饱和氯化铵溶液淬灭,滤过,洗涤后减压蒸干,柱层析分离得到吲哚类化合物;反应温度为80~100℃,反应时间为12~18小时;
当所述N-酰基邻炔基苯胺类化合物结构式如式(Ⅰ)所示时,得到的吲哚类化合物为产物(Ⅲ);
当所述N-酰基邻炔基苯胺类化合物结构式如式(Ⅱ)所示时,得到的吲哚类化合物为产物(Ⅳ);
其中,Ar1选自苯基、取代苯基中的任意一种;Ar2选自2-萘基、取代2-萘基、2-噻吩基、取代2-噻吩基、2-苯并噻吩基中的任意一种;R1选自苯基、取代苯基、吡啶基、环烷基、烷基中的任意一种;R2选自苯基、烷基、卤素、三氟甲基、甲氧基中的任意一种。
进一步地,所述非质子溶剂选自甲苯、乙二醇二甲醚、环戊基甲醚、二氧六环中的任意一种,有助于提高产率。
进一步地,所述碱选自六甲基二硅基氨基锂、六甲基二硅基氨基钠、六甲基二硅基氨基钾中的任意一种,有助于提高产率,其中六甲基二硅基氨基锂对产率的提高效果最好。
进一步地,在淬灭后加入硅胶粉进行滤过操作。
进一步地,用乙酸乙酯进行洗涤。
进一步地,制备产物(Ⅲ)时,所述柱层析分离中PE:EA=30:1~2:1;制备产物(Ⅳ)时,所述柱层析分离中PE:EA=30:1~10:1;在这一洗脱剂条件下分离效果最佳。
本发明的有益效果是:
本发明在无金属催化的条件下,以简单易得的N-酰基邻炔基苯胺为原料,在碱性环境下发生串联反应,得到具有代表性的吲哚类化合物。
具体实施方式
下面根据优选实施例详细描述本发明,本发明的目的和效果将变得更加明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
本发明提出的一种基于N-酰基邻炔基苯胺的吲哚类化合物的制备方法,具体如下:
在惰性气体保护下,将式(Ⅰ)所示的化合物0.1mmol溶于1mL的非质子溶剂中,在搅拌下加入0.4mmol的六甲基二硅基氨基锂,80~100℃条件下反应12-18个小时,然后加入4滴饱和氯化铵淬灭,加入少量硅胶粉滤过,用乙酸乙酯洗涤后减压蒸干,混合物用柱层析分离(PE:EA=30:1~2:1)得到产物(Ⅲ)。
在惰性气体保护下,将式(Ⅱ)所示的化合物0.1mmol溶于1mL的非质子溶剂中,在搅拌下加入0.4mmol的六甲基二硅基氨基锂,80~100℃条件下反应12-18个小时,然后加入4滴饱和氯化铵淬灭,加入少量硅胶粉滤过,用乙酸乙酯洗涤后减压蒸干,混合物用柱层析分离(PE:EA=30:1~10:1)得到产物(Ⅳ)。
其中,Ar1选自苯基、取代苯基中的任意一种,Ar2选自2-萘基、取代2-萘基、2-噻吩基、取代2-噻吩基、2-苯并噻吩基中的任意一种,R1选自苯基、取代苯基、吡啶基、环烷基、烷基中的任意一种,R2选自苯基、烷基、卤素、三氟甲基、甲氧基中的任意一种。
实施例1
化合物Ⅲ-1的制备与表征:
氮气保护下,将I-1(31.1mg,0.1mmol,1.0equiv)精确称入10mL反应管中,并加入1mL干燥的甲苯,搅拌溶解。六甲基二硅基氨基锂(1.0mol/L in THF,0.4mL,0.4mmol,4.0equiv)加入到反应管中。于80℃搅拌12小时。反应结束后,加入四滴饱和氯化铵溶液淬灭反应。加入少量硅胶粉滤过,用乙酸乙酯洗涤后减压蒸干,混合物用柱层析分离(PE:EA=30:1),得到产物Ⅲ-1,黄色固体,产率为91%;1H NMR(500MHz,CDCl3):δ8.77(s,1H),8.13-8.00(m,2H),7.59-7.50(m,2H),7.47-7.42(m,2H),7.35-7.27(m,5H),7.25-7.22(m,1H),7.15-7.11(m,1H),7.08-7.04(m,1H),6.41(s,1H),6.25(s,1H)。
实施例2
化合物Ⅲ-2的制备与表征:
氮气保护下,将I-2(32.9mg,0.1mmol,1.0equiv)精确称入10mL反应管中,并加入1mL干燥的乙二醇二甲醚(DME),搅拌溶解。六甲基二硅基氨基锂(1.0mol/L in THF,0.4mL,0.4mmol,4.0equiv)加入到反应管中。于80℃搅拌12小时。反应结束后,加入四滴饱和氯化铵溶液淬灭反应。加入少量硅胶粉滤过,用乙酸乙酯洗涤后减压蒸干,混合物用柱层析分离(PE:EA=25:1),得到产物Ⅲ-2,白色固体,产率为71%;1H NMR(500MHz,DMSO-d6)δ11.09(s,1H),8.15-8.11(m,2H),7.41-7.36(m,3H),7.33-7.27(m,5H),7.25-7.20(m,1H),7.01-6.97(m,1H),6.91-6.87(m,1H),6.44(s,1H),6.05(d,J=1.8Hz,1H)。
实施例3
化合物Ⅲ-3的制备与表征:
制备条件同实施例2,黄色固体,产率为81%;1H NMR(500MHz,DMSO-d6):δ11.08(s,1H),8.05-8.01(m,2H),7.54-7.47(m,2H),7.36(d,J=7.9Hz,3H),7.31-7.26(m,3H),7.22-7.17(m,1H),7.00-6.95(m,1H),6.89-6.84(m,1H),6.42(s,1H),6.04(d,J=1.9Hz,1H)。
实施例4
化合物Ⅲ-4的制备与表征:
制备条件同实施例1,黄色固体,产率为51%;1H NMR(500MHz,DMSO-d6):δ11.14(s,1H),8.22(d,J=8.2Hz,2H),7.84(d,J=8.3Hz,2H),7.40-7.36(m,3H),7.34-7.29(m,3H),7.26-7.22(m,1H),7.02-6.97(m,1H),6.91-6.87(m,1H),6.50(s,1H),6.05(d,J=1.8Hz,1H)。
实施例5
化合物Ⅲ-5的制备与表征:
制备条件同实施例2,黄色固体,产率为84%;1H NMR(500MHz,DMSO-d6):δ11.11(s,1H),8.21-8.16(m,2H),7.46(d,J=8.1Hz,2H),7.41-7.37(m,3H),7.34-7.29(m,3H),7.27-7.22(m,1H),7.03-6.98(m,1H),6.93-6.88(m,1H),6.47(s,1H),6.06(d,J=1.7Hz,1H)。
实施例6
化合物Ⅲ-6的制备与表征:
制备条件同实施例1,黄色固体,产率为86%;1H NMR(500MHz,DMSO-d6):δ11.08(s,1H),7.96(d,J=8.3Hz,2H),7.40-7.36(m,3H),7.32-7.20(m,6H),7.01-6.97(m,1H),6.91-6.87(m,1H),6.41(s,1H),6.06(d,J=1.9Hz,1H),2.29(s,3H)。
实施例7
化合物Ⅲ-7的制备与表征:
制备条件同实施例1,黄色固体,产率为77%;1H NMR(500MHz,DMSO-d6):δ11.12(s,1H),8.13(d,J=8.5Hz,2H),7.74(d,J=8.5Hz,2H),7.67-7.63(m,2H),7.43-7.28(m,9H),7.23-7.19(m,1H),7.01-6.96(m,1H),6.90-6.86(m,1H),6.48(s,1H),6.08(d,J=1.7Hz,1H)。
实施例8
化合物Ⅲ-8的制备与表征:
制备条件同实施例2,白色固体,产率为85%;δ11.06(s,1H),8.05-8.01(m,2H),7.39-7.35(m,3H),7.28(t,J=7.8Hz,3H),7.21-7.17(m,1H),6.99-6.94(m,3H),6.90-6.85(m,1H),6.38(s,1H),6.06(d,J=1.7Hz,1H),3.74(s,3H)。
实施例9
化合物Ⅲ-9的制备与表征:
氮气保护下,将I-2(32.9mg,0.1mmol,1.0equiv)精确称入10mL反应管中,并加入1mL干燥的乙二醇二甲醚(DME),搅拌溶解。六甲基二硅基氨基锂(1.0mol/L in THF,0.4mL,0.4mmol,4.0equiv)加入到反应管中。于100℃搅拌18小时。反应结束后,加入四滴饱和氯化铵溶液淬灭反应。加入少量硅胶粉滤过,用乙酸乙酯洗涤后减压蒸干,混合物用柱层析分离(PE:EA=2:1),得到产物Ⅲ-9,黄色固体,产率为70%;1H NMR(500MHz,DMSO-d6):δ11.18(s,1H),8.77(dd,J=4.5,1.6Hz,2H),7.91(dd,J=4.5,1.6Hz,2H),7.42(d,J=7.8Hz,3H),7.39-7.33(m,3H),7.30-7.26(m,1H),7.06-7.02(m,1H),6.96-6.92(m,1H),6.50(s,1H),6.09(d,J=1.8Hz,1H)。
实施例10
化合物Ⅲ-10的制备与表征:
制备条件同实施例1,黄色液体,产率为75%;1H NMR(500MHz,DMSO-d6):δ11.04(s,1H),7.41(d,J=7.9Hz,1H),7.34-7.28(m,5H),7.27-7.23(m,1H),7.02-6.97(m,1H),6.93-6.89(m,1H),6.14(d,J=2.0Hz,1H),5.55(s,1H),2.13-2.06(m,1H),0.95-0.83(m,4H)。
实施例11
化合物Ⅲ-11的制备与表征:
制备条件同实施例2,黄色液体,产率为85%;1H NMR(500MHz,DMSO-d6):δ11.01(s,1H),7.41(d,J=7.8Hz,1H),7.33-7.28(m,5H),7.25-7.21(m,1H),7.01-6.97(m,1H),6.92-6.88(m,1H),6.14(d,J=1.8Hz,1H),5.51(s,1H),3.07(p,J=8.0Hz,1H),1.72-1.41(m,8H)。
实施例12
化合物Ⅲ-12的制备与表征:
制备条件同实施例1,黄色固体,产率为51%;1H NMR(500MHz,DMSO-d6):δ11.01(s,1H),7.37(d,J=7.8Hz,1H),7.29-7.23(m,5H),7.22-7.18(m,1H),7.16-7.12(M,2H),7.10-7.03(m,3H),6.99-6.95(m,1H),6.90-6.86(m,1H),6.06(d,J=1.9Hz,1H),5.41(s,1H),2.92-2.81(m,2H),2.78-2.70(m,2H)。
实施例13
化合物Ⅲ-13的制备与表征:
制备条件同实施例1,黄色固体,产率为81%;1H NMR(500MHz,DMSO-d6):δ11.20(s,1H),8.08-8.01(m,2H),7.57-7.52(m,1H),7.47-7.43(m,2H),7.40-7.36(m,2H),7.32-7.25(m,3H),7.24-7.20(m,1H),7.14(dd,J=10.0,2.5Hz,1H),6.86-6.79(m,1H),6.46(s,1H),6.05(d,J=1.9Hz,1H)。
实施例14
化合物Ⅲ-14的制备与表征:
制备条件同实施例1,黄色固体,产率为81%;1H NMR(500MHz,DMSO-d6):δ11.28(s,1H),8.05-7.99(m,2H),7.53-7.49(m,1H),7.45-7.39(m,3H),7.38-7.34(m,2H),7.30-7.24(m,3H),7.20-7.16(m,1H),6.96(dd,J=8.6,2.1Hz,1H),6.45(s,1H),6.03(d,J=1.8Hz,1H)。
实施例15
化合物Ⅲ-15的制备与表征:
氮气保护下,将I-15(37.9mg,0.1mmol,1.0equiv)和18-冠-6(211mg,0.8mmol,8.0equiv)精确称入10mL反应管中,并加入1mL干燥的DME搅拌溶解。将六甲基二硅基氨基锂(1.0mol/L in THF,0.4mL,0.4mmol,4.0equiv)加入到反应管中。于80℃搅拌12小时。反应结束后,加入四滴饱和氯化铵溶液淬灭反应。加入少量硅胶粉滤过,用乙酸乙酯洗涤后减压蒸干,混合物用柱层析分离(PE:EA=25:1),得到产物Ⅲ-15,白色固体,产率为77%;1H NMR(500MHz,DMSO-d6):δ11.58(s,1H),8.10-8.04(m,2H),7.81(s,1H),7.58(t,J=7.4Hz,1H),7.48(t,J=7.8Hz,3H),7.41(d,J=7.3Hz,2H),7.35-7.28(m,3H),7.25(t,J=7.3Hz,1H),6.54(s,1H),6.22(d,J=1.5Hz,1H)。
实施例16
化合物Ⅲ-16的制备与表征:
制备条件同实施例2,黄色固体,产率为91%;1H NMR(500MHz,DMSO-d6):δ10.96(s,1H),8.07-8.03(m,2H),7.58-7.54(m,1H),7.48-7.44(m,2H),7.40-7.37(m,2H),7.33-7.29(m,2H),7.24-7.21(m,1H),7.20-7.15(m,2H),6.82(dd,J=8.2,1.3Hz,1H),6.42(s,1H),5.98(d,J=1.9Hz,1H),2.28(s,3H)。
实施例17
化合物Ⅲ-17的制备与表征:
制备条件同实施例1,白色固体,产率为80%;1H NMR(500MHz,DMSO-d6):δ11.19(s,1H),8.09-8.03(m,2H),7.65(d,J=0.8Hz,1H),7.58-7.52(m,3H),7.45(t,J=7.7Hz,2H),7.41-7.28(m,8H),7.24-7.19(m,2H),6.47(s,1H),6.12(d,J=1.4Hz,1H).
实施例18
化合物Ⅲ-18的制备与表征:
制备条件同实施例1,黄色固体,产率为91%;1H NMR(500MHz,DMSO-d6):δ10.92(s,1H),8.05-8.00(m,2H),7.54-7.50(m,1H),7.45-7.40(m,2H),7.38-7.34(m,2H),7.30-7.25(m,2H),7.21-7.16(m,2H),6.88(d,J=2.4Hz,1H),6.63(dd,J=8.7,2.5Hz,1H),6.40(s,1H),6.00(d,J=1.9Hz,1H),3.63(s,3H).
实施例19
化合物Ⅲ-19的制备与表征:
制备条件同实施例1,黄色固体,产率为85%;1H NMR(500MHz,DMSO-d6):δ11.10(s,1H),8.05-7.99(m,2H),7.53-7.48(m,1H),7.43-7.37(m,4H),7.34(d,J=7.8Hz,1H),7.27(dd,J=8.1,0.6Hz,1H),7.13-7.08(m,2H),6.98-6.93(m,1H),6.88-6.83(m,1H),6.45(s,1H),6.03(d,J=1.8Hz,1H).
实施例20
化合物Ⅲ-20的制备与表征:
制备条件同实施例2,黄色固体,产率为80%;1H NMR(500MHz,DMSO-d6):δ11.14(s,1H),8.09-8.02(m,2H),7.60-7.56(m,1H),7.48(t,J=7.7Hz,2H),7.42-7.36(m,5H),7.29(dd,J=8.1,0.7Hz,1H),7.02-6.98(m,1H),6.92-6.88(m,1H),6.49(s,1H),6.07(d,J=1.8Hz,1H).
实施例21
化合物Ⅲ-21的制备与表征:
制备条件同实施例1,白色固体,产率为77%;1H NMR(500MHz,DMSO-d6)δ11.17(s,1H),8.13-8.04(m,2H),7.62-7.58(m,1H),7.54-7.47(m,4H),7.41(d,J=7.8Hz,1H),7.37-7.27(m,3H),7.05-6.99(m,1H),6.94-6.90(m,1H),6.56(s,1H),6.12(d,J=1.8Hz,1H).
实施例22
化合物Ⅲ-22的制备与表征:
制备条件同实施例1,黄色固体,产率为78%;1H NMR(500MHz,DMSO-d6):δ11.04(s,1H),8.04-7.98(m,2H),7.53-7.47(m,1H),7.41(dd,J=10.6,4.7Hz,2H),7.34(d,J=7.9Hz,1H),7.29-7.23(m,3H),7.07(d,J=7.9Hz,2H),6.98-6.93(m,1H),6.88-6.83(m,1H),6.36(s,1H),6.00(d,J=1.8Hz,1H),2.17(s,3H).
实施例23
化合物Ⅲ-23的制备与表征:
制备条件同实施例1,黄色固体,产率为78%;1H NMR(500MHz,DMSO-d6):δ11.15(s,1H),8.19-8.06(m,2H),7.65-7.58(m,5H),7.53-7.48(m,4H),7.45-7.41(m,3H),7.35-7.30(m,2H),7.05-6.99(m,1H),6.94-6.88(m,1H),6.54(s,1H),6.14(d,J=1.7Hz,1H).
实施例24
化合物Ⅲ-24的制备与表征:
制备条件同实施例2,黄色固体,产率为77%;1H NMR(500MHz,DMSO-d6):δ11.10(s,1H),8.09-8.01(m,2H),7.56(t,J=7.4Hz,1H),7.46(t,J=7.7Hz,2H),7.43-7.35(m,5H),7.29(d,J=7.8Hz,1H),7.01-6.97(m,1H),6.91-6.86(m,1H),6.66(dd,J=17.6,11.0Hz,1H),6.44(s,1H),6.05(d,J=1.6Hz,1H),5.80-5.73(m,1H),5.20(d,J=11.5Hz,1H).
实施例25
化合物Ⅳ-1的制备与表征:
制备条件同实施例1,白色固体,产率为90%;1H NMR(500MHz,CDCl3):δ8.57(dd,J=8.2,0.7Hz,1H),7.39(d,J=7.6Hz,1H),7.36-7.32(m,1H),7.28-7.22(m,4H),7.14-6.86(m,4H),6.82-6.77(m,1H),6.74(dd,J=9.4,3.3Hz,1H),6.24(d,J=7.5Hz,1H),6.00-5.93(m,2H),4.35(dd,J=11.5,1.6Hz,1H),4.04(dt,J=6.0,3.0Hz,1H),3.51(ddd,J=11.5,6.2,0.8Hz,1H).
实施例26
化合物Ⅳ-2的制备与表征:
氮气保护下,将Ⅱ-2(36.1mg,0.1mmol,1.0equiv)精确称入10mL反应管中,并加入1mL干燥的环戊基甲醚,搅拌溶解。六甲基二硅基氨基锂(1.0mol/L in THF,0.4mL,0.4mmol,4.0equiv)加入到反应管中。于80℃搅拌12小时。反应结束后,加入四滴饱和氯化铵溶液淬灭反应。加入少量硅胶粉滤过,用乙酸乙酯洗涤后减压蒸干,混合物用柱层析分离(PE:EA=30:1),得到产物Ⅳ-2,白色固体,产率为58%;1H NMR(500MHz,CDCl3):δ8.56(d,J=7.7Hz,1H),7.39(d,J=7.6Hz,1H),7.36-7.29(m,1H),7.30-7.21(m,4H),7.02(s,2H),6.73-6.65(m,2H),6.34(dd,J=8.3,2.6Hz,1H),6.15(d,J=8.3Hz,1H),6.03-5.89(m,2H),4.30(dd,J=11.4,1.5Hz,1H),4.00(dt,J=6.0,2.9Hz,1H),3.73(s,3H),3.46(dd,J=11.4,6.2Hz,1H).
实施例27
化合物Ⅳ-3的制备与表征:
制备条件同实施例1,白色固体,产率为60%;1H NMR(500MHz,CDCl3):δ8.56(d,J=8.1Hz,1H),7.40(d,J=7.6Hz,1H),7.36-7.32(m,1H),7.30-7.24(m,5H),7.10-6.86(m,3H),6.68(dd,J=9.5,3.3Hz,1H),6.10(d,J=8.1Hz,1H),6.03(dd,J=9.4,1.5Hz,1H),5.98(d,J=1.6Hz,1H),4.30(dd,J=11.6,1.5Hz,1H),4.02(dt,J=6.0,2.9Hz,1H),3.49(dd,J=11.5,6.2Hz,1H).
实施例28
化合物Ⅳ-4的制备与表征:
制备条件同实施例1,白色固体,产率为84%;1H NMR(500MHz,DMSO-d6):δ8.28(d,J=8.2Hz,1H),7.47(d,J=7.5Hz,1H),7.42-7.33(m,5H),7.28(td,J=7.9,1.3Hz,1H),7.22(td,J=7.5,1.1Hz,1H),6.52-6.47(m,1H),5.86(d,J=1.3Hz,1H),5.37(dd,J=6.1,3.0Hz,1H),4.97(d,J=8.0Hz,1H),4.21(dd,J=10.5,1.5Hz,1H),3.90-3.84(m,1H).
实施例29
化合物Ⅳ-5的制备与表征:
制备条件同实施例1,白色固体,产率为67%;1H NMR(500MHz,DMSO-d6):δ8.25(d,J=8.3Hz,1H),7.50(d,J=7.3Hz,1H),7.44-7.35(m,5H),7.32-7.28(m,1H),7.25(td,J=7.5,1.2Hz,1H),5.92(d,J=1.2Hz,1H),5.53(d,J=3.3Hz,1H),5.42(d,J=7.9Hz,1H),4.43(dd,J=10.3,1.5Hz,1H),4.01-3.96(m,1H).
实施例30
化合物Ⅳ-6的制备与表征:
制备条件同实施例2,白色固体,产率为56%;1H NMR(500MHz,DMSO-d6):δ8.26(d,J=8.1Hz,1H),7.51(d,J=7.5Hz,1H),7.44-7.35(m,5H),7.33-7.29(m,1H),7.26(dt,J=7.3,3.7Hz,1H),5.93(d,J=1.2Hz,1H),5.65(d,J=3.2Hz,1H),5.40(d,J=7.9Hz,1H),4.42(d,J=9.3Hz,1H),3.95-3.90(m,1H).
实施例31
化合物Ⅳ-7的制备与表征:
氮气保护下,将Ⅱ-7(36.1mg,0.1mmol,1.0equiv)精确称入10mL反应管中,并加入1mL干燥的1,4-二氧六环,搅拌溶解。六甲基二硅基氨基锂(1.0mol/L in THF,0.4mL,0.4mmol,4.0equiv)加入到反应管中。于80℃搅拌12小时。反应结束后,加入四滴饱和氯化铵溶液淬灭反应。加入少量硅胶粉滤过,用乙酸乙酯洗涤后减压蒸干,混合物用柱层析分离(PE:EA=10:1),得到产物Ⅳ-7,白色固体,产率为86%;1H NMR(500MHz,DMSO-d6):δ8.29(d,J=8.1Hz,1H),7.50(d,J=7.6Hz,1H),7.45-7.35(m,5H),7.31(t,J=7.7Hz,1H),7.25(t,J=7.4Hz,1H),5.89(s,1H),5.13(s,1H),5.09(d,J=7.8Hz,1H),4.29(d,J=10.3Hz,1H),3.86(t,J=9.1Hz,1H),1.91(s,3H).
实施例32
化合物Ⅳ-8的制备与表征:
制备条件同实施例2,白色固体,产率为66%;1H NMR(500MHz,DMSO-d6):δ8.32(d,J=8.1Hz,1H),7.52(d,J=7.5Hz,1H),7.44-7.36(m,3H),7.36-7.25(m,5H),7.18-7.13(m,1H),6.85(t,J=7.5Hz,1H),6.39(d,J=7.5Hz,1H),5.98(d,J=1.2Hz,1H),5.21(d,J=6.8Hz,1H),4.51-4.43(m,1H),4.41-4.33(m,1H).
下面基于上述实施例的产物进行Hela细胞增殖抑制实验:
用CCK-8试剂盒对本发明实施例1~实施例32合成的化合物Ⅲ-1~Ⅲ-24、Ⅳ-1~Ⅳ-8进行人宫颈癌Hela细胞增殖抑制活性筛选。首先在96孔板培养细胞(10万细胞/孔),孵化24小时后,这些细胞与备选化合物共同孵化48小时,然后加入10μL的CCK-8溶液并在37℃再培养一个小时,然后在450nm使用SpectraMax iD5多功能微孔读板机测定光密度值;IC50值通过GraphPad Prism 8.0确定。通过对32个化合物活性筛选,发现合成的化合物Ⅲ-4、Ⅲ-14、Ⅲ-23具有较好的Hela细胞增殖抑制活性,根据实验结果,化合物Ⅲ-4的半数抑制浓度为10.3μM,化合物Ⅲ-14的半数抑制浓度为5.3μM,化合物Ⅲ-23的半数抑制浓度为6.7μM。
本领域普通技术人员可以理解,以上所述仅为发明的优选实例而已,并不用于限制发明,尽管参照前述实例对发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实例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。凡在发明的精神和原则之内,所做的修改、等同替换等均应包含在发明的保护范围之内。
Claims (6)
1.一种基于N-酰基邻炔基苯胺的吲哚类化合物的制备方法,其特征在于,在非质子溶剂中,将N-酰基邻炔基苯胺类化合物和碱按摩尔比为1∶4混合进行反应,反应完成后加入饱和氯化铵溶液淬灭,滤过,洗涤后减压蒸干,柱层析分离,得到吲哚类化合物;反应温度为80~100℃,反应时间为12~18小时;
当所述N-酰基邻炔基苯胺类化合物结构式如式(I)所示时,得到的吲哚类化合物为产物(III);
当所述N-酰基邻炔基苯胺类化合物结构式如式(II)所示时,得到的吲哚类化合物为产物(IV);
1)
2)
其中,Ar1选自苯基、取代苯基中的任意一种;Ar2选自2-萘基、取代2-萘基、2-噻吩基、取代2-噻吩基、2-苯并噻吩基中的任意一种;R1选自苯基、取代苯基、吡啶基、环烷基、烷基中的任意一种;R2选自苯基、烷基、卤素、三氟甲基、甲氧基中的任意一种。
2.根据权利要求1所述的基于N-酰基邻炔基苯胺的吲哚类化合物的制备方法,其特征在于,所述非质子溶剂选自甲苯、乙二醇二甲醚、环戊基甲醚、二氧六环中的任意一种。
3.根据权利要求1所述的基于N-酰基邻炔基苯胺的吲哚类化合物的制备方法,其特征在于,所述碱选自六甲基二硅基氨基锂、六甲基二硅基氨基钠、六甲基二硅基氨基钾中的任意一种。
4.根据权利要求1所述的基于N-酰基邻炔基苯胺的吲哚类化合物的制备方法,其特征在于,在淬灭后加入硅胶粉进行滤过操作。
5.根据权利要求1所述的基于N-酰基邻炔基苯胺的吲哚类化合物的制备方法,其特征在于,用乙酸乙酯进行洗涤。
6.根据权利要求1所述的基于N-酰基邻炔基苯胺的吲哚类化合物的制备方法,其特征在于,制备产物(Ⅲ)时,所述柱层析分离中PE:EA=30:1~2:1;制备产物(Ⅳ)时,所述柱层析分离中PE:EA=30:1~10:1。
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