CN103992332B - Prepare the method for furans [3,2-C] coumarin compound - Google Patents

Prepare the method for furans [3,2-C] coumarin compound Download PDF

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CN103992332B
CN103992332B CN201410247448.3A CN201410247448A CN103992332B CN 103992332 B CN103992332 B CN 103992332B CN 201410247448 A CN201410247448 A CN 201410247448A CN 103992332 B CN103992332 B CN 103992332B
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coumarin
alkene
furans
palladium
compound
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CN103992332A (en
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潘英明
谭显春
王恒山
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Guangxi Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

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Abstract

The method of synthesis furans [3,2-C] coumarin compound of the present invention, with alkene and 4 hydroxy coumarin compounds for raw material, using palladium as catalyzer.Comprise the steps: A) in solvent, add alkene, coumarin kind compound, palladium; B) at 80 ~ 120 DEG C of reaction 4 ~ 8h; C) be added to the water after cool to room temperature; D) organic solvent extraction; E) dry, filter; F) remove organic solvent, obtain product through column chromatography purification.The method action required is simple, and raw material is easy to get, and reactions steps is few, and productive rate is high, and application prospect is extensive.

Description

Prepare the method for furans [3,2-C] coumarin compound
Technical field
The present invention relates to furans [3,2-C] tonka bean camphor, specifically prepare the method for furans [3,2-C] coumarin compound.
Background technology
Furocoumarin(e) is widespread in nature, and the multiple medicinal plant of China's traditional Chinese medicine root of Dahurain angelica, levisticum, the root of purple-flowered peucedanum, Radix Angelicae Sinensis, Psoralea corylifolia etc. and external report is all containing furocoumarin compound.Furans [3,2-C] tonka bean camphor is one of heterogeneous ring compound of the normal See of occurring in nature, 3,4 provide two carbon atoms to form the tonka bean camphor of furan nucleus, be widely used in clinical as medicine, one of major fields of current drug development research, and, be the important source material of the aspects such as spices, makeup, agricultural chemicals.
The people such as LauraPiccagli report the screening that furocoumarin(e) compound and derivative thereof have carried out kappa nf B (NF-jB) in the virtual screening (VS) based on compound structure, the target molecule of selection can suppress the combination of DNA transcription factor (" bioorg.Med.Chem.Lett. ", 2010,18,8341).The people such as XihongWang report furocoumarin(e) compound be of great value antitumor promotor (" pharmaceuticalBiology", 2006,44,116).The people such as GiovanniMarzaro report furocoumarin compound be the very potential drug candidate of cystic fibrosis (" j.Med.Chem.", 2013,56,830).The people such as YizhouDong report furocoumarin compound to cancer cells have good cytotoxicity (" j.Med.Chem.", 2009,52,3586).AdamsM etc. are isolated 7 furocoumarin(e)s from rutaceae TetradiumDaniellii, show through pharmacology activity research, these compounds have the active and anti-accidental mycobacterium effect of efficient anti-mycobacterium (" plantaMed", 2006,72,1132).The research such as SanchoR finds that transcription factor sp1 is the key factor that pentosalen has inhibit activities, and in the cycle of HeLa cell, pentosalen inhibits cyclin D1 genetic transcription and protein expression strongly, and makes cell stop at G 1phase; Pentosalen also have suppress the sick and 1 type HIV (human immunodeficiency virus) (HIV-1) of stomatitis herpesvirus to copy effect (" jBiolChem", 2004,279,37349).The research such as PotapenkoAY finds that the photo-oxidation product of furocoumarin(e) has immunosuppressive action, its immunosuppression mechanism and PUVA (Psoralen+UVA) therapy and photophoresis have some identical features (" biofizika", 2004,49,322).
The research of furans [3,2-C] coumarin compound new synthetic method is subject to people's attention always.A small amount of report is only had to set forth the method for synthesis furans [3,2-C] coumarin derivatives at present.The people such as GangCheng generate furans [3,2-C] coumarin derivatives (Scheme1) with acid catalysis 2-(1-alkynyl)-2-alken-1-ones initial ring oxidative addition.These class methods respond, and substrate 2-(1-alkynyl)-2-alken-1-one needs are further to be synthesized, and long reaction time, substrate expands the shortcomings such as scope is little.
Scheme1
The people such as JingxinLiu react with transition metal-catalyzed 3-halo-4 hydroxy coumarin or 3-halo-4-alkoxyl group tonka bean camphor and alkynes and generate furans [3,2-C] coumarin derivatives (Scheme2).Such reaction substrate suitability is little, reaction conditions relative complex.
Scheme2
The people such as Chia-JuiLee use 4 hydroxy coumarin, aldehyde, tributyl phosphorus to generate furans [3,2-C] coumarin derivatives (Scheme3) by generating phosphonium ion through cascade reaction.This kind of reaction phosphonium ion is unstable, and reaction process is more complicated, and solvent must be changed in midway.
Scheme3
Summary of the invention
In order to overcome above-mentioned defect, provide simple and easy to get, reaction conditions is gentle, and reaction times shorter and substrate has the new method of good universality, and the present invention proposes the method that one prepares furans [3,2-C] coumarin kind compound.
The method of synthesis furans [3,2-C] coumarin compound of the present invention, with alkene and 4 hydroxy coumarin compounds for raw material, using palladium as catalyzer.
Described alkene is as shown in the formula shown in 1:
R 1=aromatic base,
R 2=H, aromatic base.
Wherein aromatic base is selected from phenyl, alkyl phenyl, alkoxyl phenyl, halobenzene base, naphthyl.
And alkyl is selected from methyl, ethyl, alkoxyl group is selected from: methoxyl group, oxyethyl group, and halogen is selected from chlorine, bromine.
4 hydroxy coumarin compounds of the present invention is as shown in the formula shown in 2:
R 3=H, alkyl, alkoxyl group.
Wherein alkyl is selected from methyl, ethyl, and alkoxyl group is selected from: methoxyl group, oxyethyl group.
Method of the present invention, comprises the steps:
A) in solvent, alkene, coumarin kind compound, palladium is added;
B) at 80 ~ 120 DEG C of reaction 4 ~ 8h;
C) be added to the water after cool to room temperature;
D) organic solvent extraction;
E) dry, filter;
F) remove organic solvent, obtain product through column chromatography purification.
In steps A), the equivalence ratio of alkene, coumarin kind compound is: 1:1, and palladium consumption is 20% equivalent.
In step B), also comprise TLC tracking reaction process, so that whether observing response is normal and determine whether reaction is complete;
In step D) be extracted with ethyl acetate, and also comprise and use saturated common salt water washing.
In step F), use purification by silica gel column chromatography, moving phase is ethyl acetate/petroleum ether=1:10 ~ 20.
Method of the present invention, the available following general formula of its synthesis represents:
R 1=aromatic base,
R 2=H, aromatic base,
R 3=H, alkyl, alkoxyl group,
PhCI is solvent,
Formula 3 is target product of the present invention.
The invention provides the novel method of synthesis furans [3, a 2-C] coumarin compound, action required is simple, and raw material is easy to get, and reactions steps is few, and productive rate is high, and application prospect is extensive.
Embodiment
The embodiment of the method for furans of the present invention [3,2-C] coumarin compound is:
With chlorobenzene PhCI for solvent, add alkene and the 0.3mmol4-Hydroxycoumarin compounds of 0.3mmol in test tube, then add the Pd (OAc) of 20% equivalent 2catalyzer, 90 oc reacts 6h, TLC and follows the tracks of reaction.Question response completely after, cool to room temperature, pours into reactant in 10mL water, and with 3 × 10mL extraction into ethyl acetate three times, washs three times, finally use anhydrous Na with saturated aqueous common salt (3 × 10mL) 2sO 4drying, filters, and decompression removing ethyl acetate, obtains product through Flash silica column chromatography purification (ethyl acetate/petroleum ether=1:20).
Typical product characterizes as follows:
1), 2-phenyl-furans [3,2-C] tonka bean camphor
White solid. 1HNMR(500MHz,CDCl 3)δ7.97-7.95(m,1H),7.82-7.80(m,2H),7.55–7.50(m,1H),7.50-7.45(m,3H),7.41-7.36(m,2H),7.18(s,1H). 13CNMR(125MHz,CDCl 3)δ158.2,156.9,156.6,152.6,130.6,129.1,129.0,128.9,124.6,124.5,120.8,117.4,112.7,112.5,102.7。
2), 2-(4-aminomethyl phenyl)-furans [3,2-C] tonka bean camphor
White solid. 1HNMR(500MHz,CDCl 3)δ7.96-7.94(m,1H),7.70(d, J=8.1Hz,2H),7.55–7.51(m,1H),7.46(d, J=8.2Hz,1H),7.41–7.37(m,1H),7.28(d, J=7.6Hz,2H),7.11(s,1H),2.42(s,3H). 13CNMR(125MHz,CDCl 3)δ158.3,156.9,156.6,152.5,139.4,130.5,129.7,126.2,124.6,124.5,120.7,117.3,112.8,112.5,101.9,21.4。
3), 2-(4-p-methoxy-phenyl)-furans [3,2-C] tonka bean camphor
White solid. 1HNMR(500MHz,CDCl 3)δ7.94-7.92(m,1H),7.73(d, J=6.9Hz,2H),7.52–7.49(m,1H),7.44(d, J=7.8Hz,1H),7.40–7.34(m,1H),7.02(s,1H),6.99(d, J=8.9Hz,2H),3.87(s,3H). 13CNMR(125MHz,CDCl 3)δ160.4,158.4,156.8,156.4,152.4,130.3,126.1,124.5,121.8,120.6,117.3,114.4,112.8,112.6,100.9,55.4。
4), 2-(2-aminomethyl phenyl)-furans [3,2-C] tonka bean camphor
White solid. 1HNMR(500MHz,CDCl 3)δ7.95-7.93(m,1H),7.84-7.82(m,1H),7.55-7.52(m,1H),7.47-7.456(m,1H),7.40-7.38(m,1H),7.36-7.34(m,1H),7.33(t, J=3.0Hz,2H),7.08(s,1H),2.58(s,3H). 13CNMR(125MHz,CDCl 3)δ158.4,156.6,156.2,152.6,135.6,131.5,130.6,129.1,128.3,127.6,126.3,124.6,120.8,117.4,112.8,112.3,106.2,21.9。
5), 2-(4-chloro-phenyl-)-furans [3,2-C] tonka bean camphor
Yellow solid. 1HNMR(500MHz,CDCl 3)δ7.96(d, J=7.8Hz,1H),7.75(d, J=8.5Hz,2H),7.55(t, J=7.8Hz,1H),7.48-7.45(m,3H),7.39(t, J=7.5Hz,1H),7.18(s,1H). 13CNMR(125MHz,CDCl 3)δ158.1,157.1,155.5,152.7,135.1,130.9,129.4,127.5,125.8,124.7,120.8,117.5,112.6,112.5,103.2。
6), 2-naphthyl-furans [3,2-C] tonka bean camphor
1HNMR(500MHz,CDCl 3)δ8.29(s,1H),8.02(d, J=7.7Hz,1H),7.95-7.91(m,2H),7.86-7.82(m,2H),7.56-7.52(m,3H),7.47-7.44(m,1H),7.40(t, J=7.4Hz,1H),7.27(s,1H). 13CNMR(125MHz,CDCl 3)δ158.2,157.0,156.7,152.7,133.4,133.3,130.7,128.9,128.4,127.9,127.0,126.9,126.2,124.6,125.6,122.1,120.9,117.4,112.8,112.6,103.2。
7), 2,3-phenylbenzene-furans [3,2-C] tonka bean camphor
White solid. 1HNMR(500MHz,CDCl 3)δ8.01(d, J=7.8Hz,1H),7.59-7.57(m,2H),7.55-7.54(m,3H),7.50-7.46(m,4H),7.40(s,1H),7.36-7.34(m,3H). 13CNMR(125MHz,CDCl 3)δ157.4,156.4,152.6,151.3,130.7,130.2,130.1,129.2,128.8,128.5,128.5,128.4,126.6,124.4,120.8,120.8,117.2,112.7,111.2。
8), 2-phenyl-furans [3,2-C]-6-Methylcoumarin
White solid. 1HNMR(500MHz,CDCl 3)δ7.81-7.79(m,2H),7.72-7.71(m,1H),7.49-7.45(m,2H),7.40-7.38(m,1H),7.33-7.31(m,2H),7.15(s,1H),2.47(s,3H). 13CNMR(125MHz,CDCl 3)δ158.4,156.9,156.4,150.8,134.4,131.6,130.3,129.1,129.0,126.7,124.5,120.5,117.1,112.4,102.7,21.0。
9), 2-phenyl--furans [3,2-C]-ayapanin
White solid. 1HNMR(500MHz,CDCl 3)δ7.87(d, J=8.9Hz,1H),7.82-7.80(m,2H),7.49(t, J=7.6Hz,2H),7.42-7.39(m,1H),7.15(s,1H),7.00-6.97(m,2H),3.92(s,3H). 13CNMR(125MHz,CDCl 3)δ162.0,158.5,157.6,155.7,154.4,129.1,129.0,128.8,124.4,121.8,112.9,110.0,106.2,102.5,101.5,55.8。

Claims (4)

1. synthesize the method for furans [3,2-C] coumarin compound, it is characterized in that: with alkene and 4 hydroxy coumarin compounds for raw material, using palladium as catalyzer;
Alkene is as shown in the formula shown in 1, and 4 hydroxy coumarin compounds is as shown in the formula shown in 2:
R 1=aromatic base, R 2=H, aromatic base, R 3=H, alkyl, alkoxyl group;
Aromatic base is selected from phenyl, alkyl phenyl, alkoxyl phenyl, halobenzene base, naphthyl, and alkyl is selected from methyl, ethyl, and alkoxyl group is selected from: methoxyl group, oxyethyl group, and halogen is selected from chlorine, bromine;
Comprise the steps:
A) in solvent, alkene, coumarin kind compound, palladium is added;
B) at 80 ~ 120 DEG C of reaction 4 ~ 8h;
C) be added to the water after cool to room temperature;
D) organic extraction;
E) dry, filter;
F) remove organic solvent, obtain product through column chromatography purification.
2. method according to claim 1, is characterized in that: in steps A), the equivalence ratio of alkene, coumarin kind compound is: 1:1, and palladium consumption is 20% equivalent.
3. method according to claim 1, is characterized in that: in step B), also comprise TLC tracking reaction process; In step D) be extracted with ethyl acetate, and also comprise and use saturated common salt water washing.
4. method according to claim 1, is characterized in that: in step F), use purification by silica gel column chromatography, moving phase is ethyl acetate/petroleum ether=1:10 ~ 20.
CN201410247448.3A 2014-06-06 2014-06-06 Prepare the method for furans [3,2-C] coumarin compound Expired - Fee Related CN103992332B (en)

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Citations (2)

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Publication number Priority date Publication date Assignee Title
CN101613354A (en) * 2009-07-30 2009-12-30 浙江大学 A kind of method for preparing pyrans and coumarin derivatives
CN103232462A (en) * 2013-05-13 2013-08-07 湖北科技学院 Synthetic method of coumarin-pyrrole compound

Family Cites Families (1)

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Publication number Priority date Publication date Assignee Title
WO2010080414A2 (en) * 2008-12-19 2010-07-15 The University Of North Carolina At Chapel Hill Substituted fno (2-[furan-2-yl] naphthalen-1-ol) derivatives as anti-cancer agents

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
CN101613354A (en) * 2009-07-30 2009-12-30 浙江大学 A kind of method for preparing pyrans and coumarin derivatives
CN103232462A (en) * 2013-05-13 2013-08-07 湖北科技学院 Synthetic method of coumarin-pyrrole compound

Non-Patent Citations (3)

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Title
"Novel Synthesis of Substituted Furo[3,2-c]chromen-4-ones via Four-component Reaction from Substituted Nitrostyrenes, Aromatic Aldehydes, Coumarins, and Ammonium Acetate";Zhengquan Zhou等，;《ACS Comb. Sci.》;20130617;第15卷;第363-369页 *
"Palladium-Catalyzed [2+2+1] Oxidative Annulation of 4-Hydroxycoumarins with Unactivated Internal Alkynes: Accessto Spiro Cyclopentadiene-Chroman-2,4-dione Complexes";Shiyong Peng等，;《Adv. Synth. Catal.》;20140202;第356卷;第319-324页 *
"Palladium-Catalyzed Synthesis of Benzofurans and Coumarins from Phenols and Olefins";Upendra Sharma等，;《Angew. Chem.》;20131011;第125卷;第12901-12905页 *

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