CN108727385B - Preparation method of polysubstituted dihydropyrimido indolone derivative - Google Patents
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- 150000005624 indolones Chemical class 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical class CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 9
- 239000012043 crude product Substances 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 7
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical class [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 6
- 239000000047 product Substances 0.000 claims abstract description 6
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical class [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims abstract description 6
- 229940071536 silver acetate Drugs 0.000 claims abstract description 6
- 239000001632 sodium acetate Chemical class 0.000 claims abstract description 6
- 235000017281 sodium acetate Nutrition 0.000 claims abstract description 6
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical class C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Natural products C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000003011 styrenyl group Chemical class [H]\C(*)=C(/[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 5
- ZFGGCPZSSCNZSR-UHFFFAOYSA-N n-methoxy-1h-indole-2-carboxamide Chemical class C1=CC=C2NC(C(=O)NOC)=CC2=C1 ZFGGCPZSSCNZSR-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical group FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- CZCXETFSJAOEHW-UHFFFAOYSA-N C(=O)N.CON1C=CC2=CC=CC=C12 Chemical class C(=O)N.CON1C=CC2=CC=CC=C12 CZCXETFSJAOEHW-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 238000001311 chemical methods and process Methods 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- ZBYYWKJVSFHYJL-UHFFFAOYSA-L cobalt(2+);diacetate;tetrahydrate Chemical class O.O.O.O.[Co+2].CC([O-])=O.CC([O-])=O ZBYYWKJVSFHYJL-UHFFFAOYSA-L 0.000 claims 2
- XMSZANIMCDLNKA-UHFFFAOYSA-N methyl hypofluorite Chemical compound COF XMSZANIMCDLNKA-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 238000001308 synthesis method Methods 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 229940011182 cobalt acetate Drugs 0.000 abstract description 4
- QAHREYKOYSIQPH-UHFFFAOYSA-L cobalt(II) acetate Chemical class [Co+2].CC([O-])=O.CC([O-])=O QAHREYKOYSIQPH-UHFFFAOYSA-L 0.000 abstract description 4
- 238000003756 stirring Methods 0.000 abstract description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000741 silica gel Substances 0.000 abstract description 2
- 229910002027 silica gel Inorganic materials 0.000 abstract description 2
- 229960004249 sodium acetate Drugs 0.000 abstract description 2
- 229940044603 styrene Drugs 0.000 abstract description 2
- 238000013375 chromatographic separation Methods 0.000 abstract 1
- 239000000706 filtrate Substances 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 3
- 229910052703 rhodium Inorganic materials 0.000 description 3
- 239000010948 rhodium Substances 0.000 description 3
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 238000010183 spectrum analysis Methods 0.000 description 2
- YCIPQJTZJGUXND-UHFFFAOYSA-N Aglaia odorata Alkaloid Natural products C1=CC(OC)=CC=C1C1(C(C=2C(=O)N3CCCC3=NC=22)C=3C=CC=CC=3)C2(O)C2=C(OC)C=C(OC)C=C2O1 YCIPQJTZJGUXND-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- IMACFCSSMIZSPP-UHFFFAOYSA-N phenacyl chloride Chemical compound ClCC(=O)C1=CC=CC=C1 IMACFCSSMIZSPP-UHFFFAOYSA-N 0.000 description 1
- VNYMSZNLHWOCCO-UHFFFAOYSA-N pyrrolo[2,3-f]quinazolin-2-one Chemical class C1=NC=C2C3=NC(=O)C=C3C=CC2=N1 VNYMSZNLHWOCCO-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000144 sodium(I) superoxide Inorganic materials 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a preparation method of a novel polysubstituted dihydropyrimido indolone derivative, belonging to the technical field of organic synthesis. The method comprises the following steps: adding substituted N-methoxyindole carboxamide, substituted styrene, cobalt acetate, silver acetate, sodium acetate, 4-methylpyridine and tricyclohexylphosphine into a reactor, stirring in a solvent, concentrating the filtrate by using a rotary evaporator after the reaction is finished to obtain a crude product, and performing chromatographic separation on the crude product by using a silica gel column to obtain the target compound. The synthesis method of the polysubstituted dihydropyrimido indolone derivative provided by the invention has the characteristics of scientificity, reasonability, simple synthesis method, higher yield of a target compound, easiness in purification of a product and the like. The reaction equation is as follows:
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an dihydropyrimido indolone derivative.
Background
Nitrogen-containing heterocycles are widely found in natural products as well as in molecules with biological and pharmaceutical activity. Among these heterocyclic compounds, pyrimidinones and indoles are two important classes of parent nuclei. Pyrimidinone compounds have good application prospects in many fields, such as anticancer and antibacterial activities. (J.Med.chem.1987,30,1256-1261.) indoles also play an essential role in drug design and synthesis of natural products. For example, indole-based compounds are used in the treatment of hypertension and as antibacterial agents, respectively. ((a) Hypertension.1997,29, 651-658, (b) J.Antichronob.Chemother.2004, 54,549-552.)
As a combination of two nitrogen-containing heterocycles, pyrimidinone and indole, dihydropyrimidinoindolone derivatives are likely to have the advantages of both compounds. In view of the wide biological activity and application value of the dihydropyrimidoindolinone derivatives, it is of great significance to develop a new method for the practical and efficient synthesis of the dihydropyrimidoindolinone derivatives.
The process for preparing dihydropyrimidoindolone derivatives comprises:
1) in 2014, Sunliang Cui topic group reported that pyrimidoindolone derivatives were synthesized from N-pivaloyloxyindoxylcarboxamides and alkynes or alkenes under rhodium catalysis. (J.org.chem.2014,79,6490-6500.)
2) In 2016, the Zhi-Zhen Huang project group reported the synthesis of dihydropyrimidoindolone derivatives from N-methoxyindole carboxamides and α -chloroacetophenone under rhodium catalysis. (Eur.J.org.chem.2016, 5399-5404.)
The above-described process for preparing dihydropyrimidoindolinone derivatives has the significant disadvantage that: noble metal rhodium is used.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a preparation method of a low-cost cobalt-catalyzed polysubstituted dihydropyrimido indolone derivative as a supplement to the prior synthesis method of the dihydropyrimido indolone derivative.
A process for the preparation of a polysubstituted dihydropyrimido indolone derivative having the structure shown in formula I:
R1the substituent group is selected from fluorine, chlorine, bromine, methoxy and methyl; r2Selected from methoxy, fluoro, chloro, bromo; the method is characterized in that substituted N-methoxy indole formamide, substituted styrene, cobalt acetate, silver acetate, sodium acetate, 4-methylpyridine and tricyclohexyl phosphine are added into a reactor. After the stirring reaction in the solvent is finished, concentrating by using a rotary evaporator to obtain a crude product, and separating the crude product by using silica gel column chromatography to obtain a target product, wherein the chemical process is shown as a reaction formula II:
the molar ratio of the substituted N-methoxyindole formamide, the substituted styrene, the cobalt acetate, the tricyclohexylphosphine, the silver acetate, the sodium acetate and the 4-methylpyridine is 1: 2: 0.1: 0.2: 2: 2: 4. the solvent is hexafluoroisopropanol, the reaction temperature is 120 ℃, and the reaction time is 3 h.
The invention has the beneficial effects that: the synthesis method of the dihydropyrimido-indolone derivative provided by the invention is scientific and reasonable, provides a new way for synthesizing polysubstituted dihydropyrimido-indolone, and the dihydropyrimido-indolone derivative with various substituent groups is obtained by the method, and is characterized in that: the synthesis method is simple, the yield of the target compound is high, and the product is easy to purify.
Drawings
FIG. 1 is an NMR spectrum of compound 3aa prepared in example 1;
FIG. 2 is an NMR spectrum of compound 3ca prepared in example 3;
FIG. 3 is an NMR spectrum of compound 3ab prepared in example 7.
Detailed Description
The invention is described in further detail below with reference to the following figures and specific examples:
the test methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
Example 1
1) Preparation of dihydropyrimidoindolinone derivatives 3aa
To a 15mL thick-walled pressure-resistant tube were added N-methoxyindole carboxamide 1a (0.2mmol, 38.0mg), 2a (0.4mmol,41.7mg) and cobalt acetate (0.02mmol,5.0mg), silver acetate (0.4mmol, 66.8mg), sodium acetate (0.4mmol, 54.4mg) and tricyclohexylphosphine (0.04mmol, 11.2mg), and hexafluoroisopropanol (2mL) was added, followed by stirring in an oil bath at 120 ℃ for 3 hours. After the reaction is finished, the solvent is removed by using a rotary evaporator to obtain a crude product, the crude product is separated by column chromatography (200-mesh silica gel 300) (petroleum ether/ethyl acetate: 8/1), and the solvent is removed by using the rotary evaporator to obtain the target product, namely the unsubstituted dihydropyrimidinoindolinone 3aa, wherein the yield is 95%.
Spectrum analysis data 3aa:
1H NMR(500MHz,CDCl3)8.45(d,J＝8.3Hz,1H),7.46–7.29 (m,7H),7.22(t,J＝7.5Hz,1H),6.07(s,1H),4.57(dd,J＝9.8,5.4Hz, 1H),3.98–3.85(m,2H),3.85(s,3H).13CNMR(125MHz,CDCl3) 152.5,138.3,137.2,135.5,129.5,128.2,128.0,124.3,123.1,120.2, 115.5,105.2,62.7,54.6,40.9.HRMS(ESI)m/z calcd for C18H16N2NaO2 +[M+Na]+315.1104,found 315.1113.
example 2
1a in example 1 is replaced by 1b, other conditions are the same as example 1, and the experimental results are shown in Table 1.
Spectrogram analysis data 3ba:
1H NMR(500MHz,CDCl3)8.39(dd,J＝9.0,4.7Hz,1H),7.40 (dt,J＝11.6,6.7Hz,3H),7.33(d,J＝6.8Hz,2H),7.08(dd,J＝8.8,2.3 Hz,1H),7.04(td,J＝9.2,2.4Hz,1H),6.03(s,1H),4.57(dd,J＝9.6, 5.5Hz,1H),3.98–3.87(m,2H),3.85(s,3H).13C NMR(125MHz, CDCl3)160.4,158.5,152.3,138.9,138.0,131.8,130.4,130.4,129.0,1228.2,116.4,116.4,112.1,111.9,105.9,105.7,104.9,62.8,54.6,40.9.
example 3
1a in example 1 is replaced by 1c, other conditions are the same as in example 1, and the experimental results are shown in Table 1.
Spectrogram analysis data 3ca:
1H NMR(500MHz,CDCl3)8.36(d,J＝8.8Hz,1H),7.46–7.33 (m,5H),7.34–7.30(m,3H),7.29–7.23(m,2H),6.00(s,5H),4.56(dd, J＝9.1,5.6Hz,1H),3.98–3.85(m,2H),3.85(s,3H).13C NMR(125 MHz,CDCl3)152.1,138.7,137.9,133.8,130.7,129.0,128.7,128.2,124.4,119.8,116.4,104.4,62.8,54.5,40.9.
example 4
1a in example 1 is replaced by 1d, other conditions are the same as in example 1, and the experimental results are shown in Table 1.
Spectrogram analysis data 3da:
1H NMR(500MHz,CDCl3)8.31(d,J＝8.8Hz,1H),7.55(s,1H), 7.43–7.35(m,4H),7.31(d,J＝6.9Hz,2H),6.00(s,1H),4.56(dd,J＝ 9.8,5.6Hz,1H),3.97–3.86(m,2H),3.84(s,3H).13C NMR(125MHz, CDCl3)156.2,152.5,138.4,137.9,130.4,130.1,128.9,128.2,128.0, 116.1 112.7,105.0,103.1,62.7,55.6,54.8,40.9.
example 5
1a in example 1 is replaced by 1e, other conditions are the same as in example 1, and the experimental results are shown in Table 1.
Spectrogram analysis data 3ea:
1H NMR(500MHz,CDCl3)8.32(d,J＝9.0Hz,1H),7.42–7.30 (m,5H),6.93(dd,J＝9.0,2.4Hz,1H),6.90(d,J＝2.2Hz,1H),5.99(s, 1H),4.55(dd,J＝9.8,5.4Hz,1H),3.95–3.85(m,2H),3.84(s,3H), 3.82(s,3H).13C NMR(125MHz,CDCl3)156.2,152.5,138.4,137.9, 130.4,130.1,128.9,128.2,128.02,116.2,112.7,105.0,103.1,62.8,55.6,54.8,40.9.
example 6
1f is used instead of 1a in example 1, the conditions are the same as in example 1, and the experimental results are shown in Table 1.
Spectrogram analysis data 3fa:
1H NMR(500MHz,CDCl3)8.30(d,J＝8.4Hz,1H),7.38(m, 3H),7.34–7.30(m,2H),7.22(s,1H),7.14(d,J＝8.4Hz,1H),5.99(s, 1H),4.55(dd,J＝9.2,5.5Hz,1H),3.96–3.84(m,2H),3.84(s,3H), 2.42(s,3H).13C NMR(125MHz,CDCl3)152.6,138.5,137.2,133.6,132.6,129.7,128.9,128.2,128.0,125.6,120.2,115.1,104.9,62.7,54.7, 40.9,21.4.
example 7
2a in example 1 is replaced by 2b, other conditions are the same as in example 1, and the experimental results are shown in Table 1.
Spectrum analysis data 3ab:
1H NMR(500MHz,CDCl3)8.44(d,J＝8.3Hz,1H),7.43(d,J＝ 7.7Hz,1H),7.31(t,J＝7.8Hz,1H),7.26–7.18(m,3H),6.92(d,J＝8.6 Hz,2H),6.05(s,1H),4.52(dd,J＝10.1,5.5Hz,1H),3.91–3.83(m, 5H),3.83(s,3H).13C NMR(125MHz,CDCl3)159.3,152.5,137.7,135.5,130.2,129.5,124.2,123.1,120.2,115.5,114.3,105.0,62.7,55.3, 54.8,40.2.HRMS(ESI)m/z calcd for C19H19N2O3 +[M+H]+323.1390, found 323.1398.
example 8
2a in example 1 was replaced by 2c, and the experimental results are shown in Table 1, except that the conditions were the same as in example 1.
Spectrogram analysis data 3ac:
1H NMR(500MHz,CDCl3)8.44(d,J＝8.3Hz,1H),7.44(d,J＝ 7.7Hz,1H),7.36–7.28(m,3H),7.23(t,J＝7.5Hz,1H),7.09(t,J＝8.6 Hz,2H),6.06(s,1H),4.57(dd,J＝9.4,4.9Hz,1H),3.92(dd,J＝10.8, 5.4Hz,1H),3.85(s,3H),3.82(d,J＝10.5Hz,1H).13CNMR(125MHz, CDCl3)163.3,161.4,152.4,137.0,135.5,134.1,129.8,129.4,124.4,123.2,120.3,116.0,115.8,115.5,105.2,62.8,54.7,40.2.HRMS(ESI) m/z calcd forC18H16FN2O2 +[M+H]+311.1190,found 311.1197.
example 9
2a in example 1 is replaced by 2d, other conditions are the same as in example 1, and the experimental results are shown in Table 1.
Spectrogram analysis data 3ad:
1H NMR(500MHz,CDCl3)8.44(d,J＝8.3Hz,1H),7.44(d,J＝ 7.7Hz,1H),7.39–7.30(m,3H),7.25(m,3H),6.06(s,1H),4.55(dd,J ＝9.5,5.3Hz,1H),3.92(dd,J＝10.8,5.3Hz,1H),3.85(s,3H),3.81(d,J ＝10.4Hz,1H).13C NMR(125MHz,CDCl3)152.4,136.9,136.6, 135.5,133.9,129.6,129.4,129.1,124.4,123.3,120.3,115.5,105.3,62.8,54.5,40.3.HRMS(ESI)m/z calcd for C18H16ClN2O2 +[M+H]+327.0895, found 327.0903.
example 10
2a in example 1 is replaced by 2e, other conditions are the same as in example 1, and the experimental results are shown in Table 1.
Spectrogram analysis data 3ae:
1H NMR(500MHz,CDCl3)8.43(d,J＝8.2Hz,1H),7.52(d,J＝ 8.2Hz,2H),7.44(d,J＝7.7Hz,1H),7.33(t,J＝7.7Hz,1H),7.22(m, 3H),6.06(s,1H),4.54(dd,J＝9.3,5.3Hz,1H),3.92(dd,J＝10.7,5.3 Hz,1H),3.84(s,3H),3.81(d,J＝10.3Hz,1H).13C NMR(125MHz,CDCl3)152.4,137.4,136.5,135.5,132.1,129.9,129.4,124.4,123.3, 122.0,120.3,115.5,105.3,62.8,54.5,40.3.HRMS(ESI)m/z calcd for C18H16BrN2O2 +[M+H]+371.0390,found 371.0394.
TABLE 1
Claims (3)
1. A process for the preparation of a polysubstituted dihydropyrimido indolone derivative having the structure shown in formula i:
in the formula I, R1The substituent group is selected from fluorine, chlorine, bromine, methoxy and methyl; r2The substituent group is selected from methoxy, fluorine, chlorine and bromine; the method is characterized in that substituted N-methoxyindole carboxamide, substituted styrene, cobalt acetate tetrahydrate, silver acetate, sodium acetate, 4-methylpyridine and tricyclohexylphosphine are added into a reactor, the mixture is stirred in a solvent, after the reaction is finished, a rotary evaporator is used for concentrating to obtain a crude product, the crude product is separated by silica gel column chromatography to obtain a target product, and the chemical process of the target product is shown in a reaction formula II:
2. the method of claim 1, wherein: the molar ratio of substituted N-methoxyindole formamide, substituted styrene, cobalt acetate tetrahydrate, tricyclohexylphosphine, silver acetate, sodium acetate and 4-methylpyridine is 1: 2: 0.1: 0.2: 2: 2: 4.
3. the method of claim 1, wherein: the solvent is hexafluoroisopropanol, the reaction temperature is 120 ℃, and the reaction time is 3 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201810772736.9A CN108727385B (en) | 2018-07-14 | 2018-07-14 | Preparation method of polysubstituted dihydropyrimido indolone derivative |
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| CN103755708A (en) * | 2013-12-31 | 2014-04-30 | 浙江大学 | Preparation method of indole or pyrrolopyrimidine derivative |
| CN105481865A (en) * | 2015-12-21 | 2016-04-13 | 广东工业大学 | Preparation method of pyrimidine [1,6-a] indole heterocyclic derivative |
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| CN103755708A (en) * | 2013-12-31 | 2014-04-30 | 浙江大学 | Preparation method of indole or pyrrolopyrimidine derivative |
| CN105481865A (en) * | 2015-12-21 | 2016-04-13 | 广东工业大学 | Preparation method of pyrimidine [1,6-a] indole heterocyclic derivative |
Non-Patent Citations (2)
| Title |
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| A Cascade C–H-Func tionalization/Cyclization Reaction of Indoles with α-Halo or α-Sulfonyloxy Ketones for the Synthesis of Dihydropyrimidoindolone Derivatives;Zi-Jun Wu等;《Eur. J. Org. Chem.》;20161018;第5399-5404页 * |
| Rh(III)-Catalyzed C-H Activation/Cyclization of Indoles and Pyrroles:Divergent Synthesis of Heterocycles;Yan Zhang 等;《J. Org. Chem.》;20140620;第79卷;第6490-6500页 * |
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