CN105949152B - A kind of benzofuran derivative and preparation method thereof - Google Patents
A kind of benzofuran derivative and preparation method thereof Download PDFInfo
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- 150000001907 coumarones Chemical class 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 60
- 150000001875 compounds Chemical class 0.000 claims description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 12
- 238000000926 separation method Methods 0.000 claims description 11
- 239000003208 petroleum Substances 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000012043 crude product Substances 0.000 claims description 9
- -1 diester malonate class compound Chemical class 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 7
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 claims description 7
- BPVHWNVBBDHIQU-UHFFFAOYSA-N 2-bromoethynylbenzene Chemical group BrC#CC1=CC=CC=C1 BPVHWNVBBDHIQU-UHFFFAOYSA-N 0.000 claims description 6
- HCIBTBXNLVOFER-UHFFFAOYSA-N diphenylcyclopropenone Chemical compound O=C1C(C=2C=CC=CC=2)=C1C1=CC=CC=C1 HCIBTBXNLVOFER-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 5
- 238000007445 Chromatographic isolation Methods 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 238000011097 chromatography purification Methods 0.000 claims description 4
- 238000002955 isolation Methods 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 238000003809 water extraction Methods 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 2
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 claims 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 claims 1
- 238000010828 elution Methods 0.000 claims 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 abstract description 9
- 239000000758 substrate Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000013459 approach Methods 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000010523 cascade reaction Methods 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 230000001681 protective effect Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 150000001345 alkine derivatives Chemical class 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000012265 solid product Substances 0.000 description 8
- 230000006837 decompression Effects 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- AZQCFLDDJHERFZ-UHFFFAOYSA-N Br.C#Cc1ccccc1 Chemical class Br.C#Cc1ccccc1 AZQCFLDDJHERFZ-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 241001597008 Nomeidae Species 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 102000000543 Histamine Receptors Human genes 0.000 description 2
- 108010002059 Histamine Receptors Proteins 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QRVSDVDFJFKYKA-UHFFFAOYSA-N dipropan-2-yl propanedioate Chemical class CC(C)OC(=O)CC(=O)OC(C)C QRVSDVDFJFKYKA-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 101150007969 ADORA1 gene Proteins 0.000 description 1
- 0 COC(CCc(cc1*)cc2c1[o]c(-c1ccc3OCOc3c1)c2)=* Chemical compound COC(CCc(cc1*)cc2c1[o]c(-c1ccc3OCOc3c1)c2)=* 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical class CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 244000028419 Styrax benzoin Species 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Furan Compounds (AREA)
Abstract
The invention discloses a kind of benzofuran derivatives and preparation method thereof, benzofuran compounds are constructed by cascade reaction with different multiple alkynes substrates, it is long that the reaction overcomes route in previous reaction, substrate and reaction condition require harsh, the shortcomings of replacing functional group's extension limited, not only substrate synthesis is simple, reagent is relatively cheap for the reaction, and with high atom economy, it is environmentally protective obtain target molecule, provide a kind of of great value approach to the industrialized production of benzofuran.
Description
Technical field
The invention belongs to organic compound fields, and in particular to a kind of benzofuran derivative and preparation method thereof.
Background technology
Benzofuran compounds have very strong bioactivity, can be sent out in a large amount of natural and unnatural products
The trace of such existing compound.Just because of benzofuran compounds and its extensive pharmacological activity of derivative and in nature
Generally existing in boundary, such compound cause the close attention of people.
Natural benzofuran compound 1 is demonstrated by good because of its this kind of structural framework of benzofuran with the substitution of 2- aryl
Good bioactivity is for example with protection ischemic tissue Reperfu- sion, should the effects that inhibition thrombosis and anti-platelet aggregation
Compound will occupy a tiny space in terms of the treatment of the diseases such as angiocarpy.Scammells etc. is using it as lead compound, design
A series of analog 2-4 have been synthesized, and have been confirmed after testing, wherein most compound has the apparent robust and sturdy anti-work of gland former times A1 receptor
Property.
Many novel and with obvious biological activity natural benzofuran compound is constantly found and reports,
It is expected to be applied to field of medicaments in future.Hak-Ju Lee in 2008 et al. separate and extract novel have no from styrax plant
The native compound 5 of report has potential antibacterial and antifungal activity.
2009, Ramsden etc. reported a kind of benzofuran derivative with sulfo group, such compound, which has, to be adjusted
Histamine receptor prevents and treats panimmunity and inflammatory reaction caused by histamine receptor mediates, and treats such as allergy, asthma and oneself
Body immunological diseases etc..The structure following 6 of the analog derivative.
Good bioactivity is shown just because of many natural benzofuran compounds, but in natural products
Ben Bing Misaki containing multiple substituent groups mutter, and kind compound content is less, and the limited amount of separation and Extraction, yield can not meet at all
The demand of people.Therefore, the artificial synthesized benzofuran compounds containing multiple substituent groups are even more and are particularly important.
Invention content
In order to solve the above technical problems, the present invention provides a kind of benzofuran derivative, there is polycyclic presence, structure
It is more complicated, have broad application prospects.
The present invention also provides a kind of preparation method of benzofuran derivative, easy, green, high atom economy.
The technical solution that the present invention takes is：
The general structure of a kind of benzofuran derivative, the benzofuran derivative is as follows：
Wherein, R is straight chained alkyl, branched alkyl, saturated hydrocarbons, unsaturated hydro carbons or arene group；
R1For halogen, straight chained alkyl, branched alkyl, ester group, alkoxy and its corresponding derivative；R1It can be at phenyl ring
Any position.
Further, R is preferably isopropyl or ethyl；R1 is preferably chlorine, methyl or ethyl.
The present invention also provides a kind of preparation method of benzofuran derivative, the preparation method includes following step
Suddenly：
(1) it using sodium hydride as catalyst, by malonate and propargyl bromide in anhydrous acetonitrile solvent, is reacted in ice-water bath
5~8 hours, compound a is obtained after isolating and purifying；
The general formula of the malonate is：
(2) under the conditions of anhydrous and oxygen-free, the substituent of compound a and phenyl bromoacetylene that step (1) obtains is being catalyzed
Under the action of agent and organic base, is reacted 10~14 hours for 20~35 DEG C in anhydrous acetonitrile solvent, after isolating and purifying, obtain chemical combination
Object b；
The chemical structural formula of the substituent of the phenyl bromoacetylene is：
(3) under oxygen protection, the compound b that step (2) is obtained is with diphenyl cyclopropenone in anhydrous acetonitrile solvent
In, 95-100 DEG C is reacted 12~16 hours, can be prepared by benzofuran derivative after isolating and purifying.
In the step (1), the ratio between amount of substance between malonate, propargyl bromide and sodium hydride is 1：2.2~
3.2：4~5, a concentration of 0.8~1.5mol/L of the malonate in anhydrous acetonitrile.
In the step (2), catalyst is Pd (PPh3)2Cl2With the mixture of CuI, organic base is triethylamine.Pd
(PPh3)2Cl2The ratio between amount of substance between CuI is 3：1.
In the step (2), the amount of the substance between compound a, the substituent of phenyl bromoacetylene, catalyst and organic base
The ratio between be 1：2.2~3.2：0.03~0.05：4~5, a concentration of 0.5~0.8mol/L of the compound a in anhydrous acetonitrile.Institute
Stating the isolation and purification method that step (2) is taken is：By crude product ethyl acetate and water extraction and separation, after concentration, volume ratio is used
It is 1：40~60 ethyl acetate：Petroleum ether is that eluant, eluent carries out column chromatographic isolation and purification.
In the step (3), the ratio between amount of substance between compound b and diphenyl cyclopropenone is 1.0~1.5：1；
A concentration of 0.1~0.3mol/Ls of the compound b in anhydrous acetonitrile.The isolation and purification method that the step (3) is taken is：It will be thick
Product ethyl acetate and water extraction and separation are 1 with volume ratio after concentration：20~40 ethyl acetate：Petroleum ether is eluant, eluent
Carry out column chromatographic isolation and purification.
Compared with prior art, the present invention provides a series of new benzofuran derivatives.With different multiple alkynes
Hydrocarbon substrate constructs benzofuran compounds by cascade reaction, and it is long which overcomes route in previous reaction, substrate and
Reaction condition requires harsh, the shortcomings of extension of substitution functional group is limited, and not only substrate synthesis is simple, reagent compares just for the reaction
Preferably, and with high atom economy, it is environmentally protective obtain target molecule, provide one to the industrialized production of benzofuran
The of great value approach of kind.
Relative to common benzofuran derivative, benzofuran derivative prepared by the present invention has polycyclic presence,
Its structure is more complicated various, and more wide purposes foreground will be also shown in Chemical Manufacture, clinical medicine.Also, this
It is easy, efficient to invent the preparation method provided, the reaction time is short, efficient.
Description of the drawings
Fig. 1 is the general structure of benzofuran derivative；
Fig. 2 is the synthetic route chart of benzofuran derivative；
Fig. 3 is the synthetic route chart of benzofuran derivative c-1 prepared by embodiment 1；
Fig. 4 is the nuclear magnetic resonance spectroscopy of benzofuran derivative c-1 prepared by embodiment 1；
Fig. 5 is the carbon-13 nmr spectra of benzofurans ether derivant c-1 prepared by embodiment 1；
Fig. 6 is the XRD single crystal diffraction figures of benzofuran derivative c-1 prepared by embodiment 1；
Fig. 7 is the synthetic route chart of benzofuran derivative c-2 prepared by embodiment 2；
Fig. 8 is the nuclear magnetic resonance spectroscopy of benzofuran derivative c-2 prepared by embodiment 2；
Fig. 9 is the carbon-13 nmr spectra of benzofurans ether derivant c-2 prepared by embodiment 2；
Figure 10 is the synthetic route chart of benzofuran derivative c-3 prepared by embodiment 3；
Figure 11 is the nuclear magnetic resonance spectroscopy of benzofuran derivative c-3 prepared by embodiment 3；
Figure 12 is the carbon-13 nmr spectra of benzofurans ether derivant c-3 prepared by embodiment 3.
Specific implementation mode
Embodiment 1
A kind of benzofurans analog derivative, the benzofuran derivatives structural formula are：
A kind of preparation method of benzofuran derivative, the preparation method include the following steps：
(1) using 830mmol sodium hydrides as catalyst, 200mmol Diisopropyl malonates and 440mmol propargyl bromides are added
Entering the ice-water bath into 210mL anhydrous acetonitriles, is stirred to react 8 hours, product adds water washing, is extracted with ethyl acetate, and decompression is spin-dried for,
Obtain brown solid product, i.e. compound a -1；
(2) 80mmol compound as -1 and 200mmol phenylacetylene bromides are blended in Pd (PPh3)2Cl2The anhydrous nothing of/CuI
In oxygen catalyst system and catalyzing (2.56mmol/0.85mmol), molar ratio Pd (PPh3)2Cl2：CuI=3：1, made with 336mmol triethylamines
Alkali, using 150mL anhydrous acetonitriles as solvent, 20 DEG C are stirred to react 12 hours, and product is washed with water, and is extracted with ethyl acetate, decompression
It is spin-dried for, is 1 with volume ratio：40 ethyl acetate：Petroleum ether column chromatography for separation obtains greenish yellow solid product, i.e. compound b-
1。
(3) under conditions of 95 DEG C, 1.2mmol compounds b-1 prepared by step (2) in 12mL anhydrous acetonitriles solvent and
It is reacted 16 hours with 1.0mmol diphenyl cyclopropenones in oxygen atmosphere, obtains compound c-1, is i.e. benzofuran derivative
Crude product；The crude product with water of the benzofuran derivative of preparation is washed, ethyl acetate extraction, decompression is spin-dried for, and uses volume
Compare ethyl acetate：Petroleum ether=1：20 column chromatography for separation obtain white solid product, i.e. benzofuran derivative c-1, column layer
Division rate is about 70%.
Product structure passes through1H NMR、13C NMR are measured, as a result as follows：
1H NMR (300MHz, CDCl3) δ 7.77-7.75 (m, 2H), 7.40-7.34 (m, 6H), 7.23-7.18 (m, 4H),
7.06 (d, 2H), 6.99-6.89 (m, 4H), 5.16-5.11 (m, 2H), 3.99 (s, 2H), 3.88 (s, 2H), 1.33-1.30 (m,
12H)。
13C NMR (126MHz, CDCl3) δ 193.53,171.35,154.91,149.70,141.92,137.74,
136.51,136.35,134.51,133.61,132.80,131.81,129.99,129.52,129.13,128.98,128.35,
127.99,127.77,127.51,122.48,122.04,117.19,114.83,94.67,87.81,70.02,60.43,
41.70,38.12,21.99.
Embodiment 2
A kind of benzofurans analog derivative, the benzofuran derivatives structural formula are：
A kind of preparation method of benzofuran derivative, the preparation method include the following steps：
(1) using 960mmol sodium hydrides as catalyst, 200mmol diethyl malonates and 600mmol propargyl bromides are added
To ice-water bath in 140mL anhydrous acetonitriles, it is stirred to react 5 hours, product adds water washing, is extracted with ethyl acetate, and decompression is spin-dried for, and obtains
To brown solid product, i.e. compound a -2；
(2) 80mmol compound as -2 and 240mmol phenylacetylene bromides are blended in Pd (PPh3)2Cl2The anhydrous nothing of/CuI
In oxygen catalyst system and catalyzing (1.92mmol/0.64mmol), molar ratio Pd (PPh3)2Cl2：CuI=3：1, made with 384mmol triethylamines
Alkali is stirred to react 14 hours, product is washed with water, and is extracted with ethyl acetate, and subtracts using 100mL anhydrous acetonitriles as solvent at 25 DEG C
Pressure is spin-dried for, and is 1 with volume ratio：50 ethyl acetate：Petroleum ether column chromatography for separation obtains brown solid, i.e. compound b-
2。
(3) under conditions of 95 DEG C, 1.5mmol compounds b-2 prepared by step (2) in 5mL anhydrous acetonitriles solvent and
It is reacted 14 hours with 1.0mmol diphenyl cyclopropenones in oxygen atmosphere, obtains compound c-2, is i.e. benzofuran derivative
Crude product；The crude product with water of the benzofuran derivative of preparation is washed, ethyl acetate extraction, decompression is spin-dried for, and uses volume
Compare ethyl acetate：Petroleum ether=1：30 column chromatography for separation obtain white solid product, i.e. benzofuran derivative c-2, column layer
Division rate is about 63%.
Product structure passes through1H NMR、13C NMR are measured, as a result as follows：
1H NMR (300MHz, CDCl3) δ 7.93-7.79 (m, 4H), 7.54-7.12 (m, 14H), 4.21-4.14 (m, 4H),
3.83 (t, 2H), 3.46 (t, 2H), 2.82-2.74 (m, 2H), 2.68-2.60 (m, 2H), 1.62-1.53 (m, 3H), 1.38-
1.17 (m, 11H).
13C NMR (75MHz, CDCl3) δ 193.11,172.02,157.14,145.07,144.37,139.64,137.97,
134.06,132.09,131.89,130.85,130.44,129.58,128.85,128.24,127.82,126.87,121.10,
116.44,96.92,87.37,62.15,60.07,41.29,40.43,29.26,29.20,15.92,15.79,14.40.
Embodiment 3
A kind of benzofurans analog derivative, the benzofuran derivatives structural formula are：
A kind of preparation method of benzofuran derivative, the preparation method include the following steps：
(1) using 900mmol sodium hydrides as catalyst, 200mmol Diisopropyl malonates and 500mmol propargyl bromides are added
Enter the ice-water bath into 160mL anhydrous acetonitriles, be stirred to react 7.5 hours, product adds water washing, is extracted with ethyl acetate, decompression rotation
It is dry, obtain brown solid product, i.e. compound a -3；
(2) 80mmol compound as -3 and 224mmol phenylacetylene bromides are blended in Pd (PPh3)2Cl2The anhydrous nothing of/CuI
In oxygen catalyst system and catalyzing (3.84mmol/1.28mmol), molar ratio Pd (PPh3)2Cl2：CuI=3：1, made with 360mmol triethylamines
Alkali is stirred to react 10 hours, product is washed with water, and is extracted with ethyl acetate, and subtracts at room temperature using 135mL anhydrous acetonitriles as solvent
Pressure is spin-dried for, and is 1 with volume ratio：60 ethyl acetate：Petroleum ether column chromatography for separation obtains white solid product, i.e. compound b-
3。
(3) under conditions of 100 DEG C, 1.5mmol compounds b-3 prepared by step (2) in 5mL anhydrous acetonitriles solvent and
It is reacted 16 hours with 1.0mmol diphenyl cyclopropenones in oxygen atmosphere, obtains compound c-3, is i.e. benzofuran derivative
Crude product；The crude product with water of the benzofuran derivative of preparation is washed, ethyl acetate extraction, decompression is spin-dried for, and uses volume
Compare ethyl acetate：Petroleum ether=1：40 column chromatography for separation obtain white solid product, i.e. benzofuran derivative c-3, column layer
Division rate is about 68%.
Product structure passes through1H NMR、13C NMR are measured, as a result as follows：
1H NMR (300MHz, CDCl3) δ 7.78-7.76 (m, 2H), 7.36-7.33 (m, 6H), 7.17-6.99 (m, 9H),
6.77 (s, 1H), 5.18-5.10 (m, 2H), 3.99 (s, 2H), 3.91 (s, 2H), 2.26 (dd, 2H), 2.08 (dd, 2H),
1.33-1.30 (m, 12H).
13C NMR (126MHz, CDCl3) δ 193.21,172.08,154.18,149.26,141.46,137.75,
137.50,137.23,136.76,132.66,131.87,130.93,128.63,128.29,128.05,128.01,127.89,
127.43,127.20,127.14123.32,121.41,117.11,114.67,95.27,86.60,69.51,60.07,
41.41,37.73,21.60,21.14.
The above-mentioned detailed description carried out to benzofuran derivative and preparation method thereof with reference to embodiment, is illustrative
Without being restrictive, several embodiments can be enumerated according to limited range, therefore do not departing from present general inventive concept
Under change and modification, should belong within protection scope of the present invention.
Claims (9)
1. a kind of benzofuran derivative, which is characterized in that the general structure of the benzofuran derivative is as follows：
Wherein, R is isopropyl or ethyl；
R1For chlorine, methyl or ethyl；R1It can be at any position of phenyl ring.
2. the preparation method of benzofuran derivative according to claim 1, which is characterized in that the preparation method packet
Include following steps：
(1) using sodium hydride as catalyst, by diester malonate class compound and propargyl bromide in anhydrous acetonitrile solvent, ice-water bath
Middle reaction 5~8 hours, compound a is obtained after isolating and purifying；
The structural formula of the compound a is：
The general formula of the diester malonate class compound is：
Wherein, R is isopropyl or ethyl；
(2) under the conditions of anhydrous and oxygen-free, the substituent of compound a that step (1) is obtained and phenyl bromoacetylene in catalyst and
Under the action of organic base, is reacted 10~14 hours for 20~35 DEG C in anhydrous acetonitrile solvent, after isolating and purifying, obtain compound b；
The structural formula of the compound b is：
The chemical structural formula of the substituent of the phenyl bromoacetylene is：
Wherein, R1For chlorine, methyl or ethyl；R1It can be at any position of phenyl ring；
(3) under oxygen protection, compound b that step (2) is obtained with diphenyl cyclopropenone in anhydrous acetonitrile solvent,
95-100 DEG C is reacted 12~16 hours, can be prepared by benzofuran derivative after isolating and purifying.
3. preparation method according to claim 2, which is characterized in that in the step (1), diester malonate class chemical combination
The ratio between amount of substance between object, propargyl bromide and sodium hydride is 1：2.2~3.2：4~5, diester malonate class compound is in nothing
A concentration of 0.8~1.5mol/L in water-acetonitrile.
4. preparation method according to claim 2, which is characterized in that in the step (2), catalyst is Pd (PPh3)2Cl2With the mixture of CuI, organic base is triethylamine.
5. preparation method according to claim 4, which is characterized in that Pd (PPh3)2Cl2The amount of substance between CuI it
Than being 3：1.
6. according to the preparation method described in claim 2-5 any one, which is characterized in that in the step (2), compound a,
The ratio between amount of substance between the substituent of phenyl bromoacetylene, catalyst and organic base is 1：2.2~3.2：0.03~0.05：4
~5, a concentration of 0.5~0.8mol/L of the compound a in anhydrous acetonitrile.
7. preparation method according to claim 2, which is characterized in that in the step (3), compound b and hexichol basic ring
The ratio between amount of substance between propenone is 1.0~1.5:1；A concentration of 0.1~0.3mol/s of the compound b in anhydrous acetonitrile
L。
8. the preparation method described in claim 2, which is characterized in that the isolation and purification method that the step (2) is taken is：It will
Crude product ethyl acetate and water extraction and separation are 1 with volume ratio after concentration：40~60 ethyl acetate：Petroleum ether is elution
Agent carries out column chromatographic isolation and purification.
9. preparation method according to claim 2, which is characterized in that the isolation and purification method that the step (3) is taken is：
It is 1 with volume ratio after concentration by crude product ethyl acetate and water extraction and separation：20~40 ethyl acetate：Petroleum ether is to wash
De- agent carries out column chromatographic isolation and purification.
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