CN106565733B - A kind of synthetic method of polyhydroxy substitution coumestrol class natural products - Google Patents
A kind of synthetic method of polyhydroxy substitution coumestrol class natural products Download PDFInfo
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- 229930014626 natural product Natural products 0.000 title claims abstract description 43
- 238000006467 substitution reaction Methods 0.000 title claims abstract description 36
- ZZIALNLLNHEQPJ-UHFFFAOYSA-N coumestrol Chemical class C1=C(O)C=CC2=C1OC(=O)C1=C2OC2=CC(O)=CC=C12 ZZIALNLLNHEQPJ-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000010189 synthetic method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 70
- 238000010438 heat treatment Methods 0.000 claims abstract description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- -1 aldehyde compound Chemical class 0.000 claims abstract description 9
- 240000000203 Salix gracilistyla Species 0.000 claims abstract description 7
- 238000006482 condensation reaction Methods 0.000 claims abstract description 7
- 230000000640 hydroxylating effect Effects 0.000 claims abstract description 5
- 238000005691 oxidative coupling reaction Methods 0.000 claims abstract description 5
- 239000007787 solid Substances 0.000 claims description 50
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 45
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 42
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 claims description 41
- 239000012065 filter cake Substances 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- ZLFIOJHGCKELIM-UHFFFAOYSA-N 2-bromo-2-(4-hydroxyphenyl)acetic acid Chemical class OC(=O)C(Br)C1=CC=C(O)C=C1 ZLFIOJHGCKELIM-UHFFFAOYSA-N 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 15
- 239000005457 ice water Substances 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 14
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 150000003935 benzaldehydes Chemical class 0.000 claims description 8
- 239000003446 ligand Substances 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 6
- 150000001299 aldehydes Chemical class 0.000 claims description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical group [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 3
- 239000005751 Copper oxide Substances 0.000 claims description 3
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 3
- 229920002565 Polyethylene Glycol 400 Chemical group 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 229940116318 copper carbonate Drugs 0.000 claims description 3
- 229910000431 copper oxide Inorganic materials 0.000 claims description 3
- GEZOTWYUIKXWOA-UHFFFAOYSA-L copper;carbonate Chemical compound [Cu+2].[O-]C([O-])=O GEZOTWYUIKXWOA-UHFFFAOYSA-L 0.000 claims description 3
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- BTQAJGSMXCDDAJ-UHFFFAOYSA-N 2,4,6-trihydroxybenzaldehyde Chemical class OC1=CC(O)=C(C=O)C(O)=C1 BTQAJGSMXCDDAJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000005725 8-Hydroxyquinoline Substances 0.000 claims description 2
- 241000522215 Dipteryx odorata Species 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical group [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical group [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 229960003540 oxyquinoline Drugs 0.000 claims description 2
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 claims description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019798 tripotassium phosphate Nutrition 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical class OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 claims 1
- 150000002989 phenols Chemical class 0.000 claims 1
- 239000010970 precious metal Substances 0.000 abstract description 3
- 238000010523 cascade reaction Methods 0.000 abstract description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract 2
- 229910052794 bromium Inorganic materials 0.000 abstract 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 39
- 238000002360 preparation method Methods 0.000 description 27
- 238000001556 precipitation Methods 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 6
- OZSAHRXVIHCZIQ-UHFFFAOYSA-N aureol Natural products O1C2=CC=CC=C2CC2(C)C(C)CCC3C12CCCC3(C)C OZSAHRXVIHCZIQ-UHFFFAOYSA-N 0.000 description 5
- UYLGYRGJFUJKFM-PXNLJIHASA-N aureol Chemical compound O1C2=CC=C(O)C=C2C[C@]2(C)[C@@H](C)CC[C@@H]3[C@]12CCCC3(C)C UYLGYRGJFUJKFM-PXNLJIHASA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 102100024295 Maltase-glucoamylase Human genes 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 102000011990 Sirtuin Human genes 0.000 description 2
- 108050002485 Sirtuin Proteins 0.000 description 2
- 241000219793 Trifolium Species 0.000 description 2
- 108010028144 alpha-Glucosidases Proteins 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102100038595 Estrogen receptor Human genes 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 101000663635 Homo sapiens Sphingosine kinase 1 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102100038494 Nuclear receptor subfamily 1 group I member 2 Human genes 0.000 description 1
- 241000219833 Phaseolus Species 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 108010001511 Pregnane X Receptor Proteins 0.000 description 1
- 102100039024 Sphingosine kinase 1 Human genes 0.000 description 1
- 240000004922 Vigna radiata Species 0.000 description 1
- 235000010721 Vigna radiata var radiata Nutrition 0.000 description 1
- 235000011469 Vigna radiata var sublobata Nutrition 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- PGXWDLGWMQIXDT-UHFFFAOYSA-N methylsulfinylmethane;hydrate Chemical compound O.CS(C)=O PGXWDLGWMQIXDT-UHFFFAOYSA-N 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000003075 phytoestrogen Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
Abstract
The invention discloses the synthetic methods that a kind of polyhydroxy replaces coumestrol class natural products, it is that condensation reaction occurs by the bigcatkin willow aldehyde compound of raw material and hydroxyl substitution of 2 bromine, 4 hydroxyl phenylacetic acid, obtain 3 (2 bromine, 4 hydroxy phenyl) 7 Hydroxycoumarin class compound of hydroxyl substitution, hydroxylating/oxidative coupling reaction occurs under catalyst and microwave heating condition for another step, obtains polyhydroxy substitution coumestrol class natural products.Route of the present invention is simple and direct, easy to operate, multistep cascade reaction occurs simultaneously, yield is higher, and reaction condition is mild, is not necessarily to precious metal catalyst, Atom economy is high, at low cost.
Description
Technical field
The present invention relates to organic synthesis field, more particularly to a kind of synthesis of polyhydroxy substitution coumestrol class natural products
Method.
Background technology
3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (Coumestrol) be clover, clover and
A kind of polyhydroxy substitution coumestrol class phytoestrogen found in soybean, has multiple biological activities, such as inhibitory activity sheath
Ammonia alcohol kinases (SPHK1) inhibits alpha-glucosidase (α-glucosidase), activation 1 antibody of Sirtuin (SIRT 1), people
The bioactivity such as pregnane X receptor antagonists and neuroprotection, and can be used as fluorescence probe and be used for the efficient of estrogen receptor
(the Steroids 2014,80,37 such as screening；Neurol.Res.2014,36,198；Mol.Endocrinol.2008,22,838；
J.Biomol.Screen.2014,19,253；J.Agric.Food Chem.2014,62,4298；Food Chem.2011,
126,1057；Bioorg.&Med.Chem.Lett.2014,24,2560；Appl.Environ.Microbiol.2012,78,
2896).Simultaneously [3,2-c] chroman -6- ketone (Aureol) is in mung bean (Phaseolus to 1,3,9- trihydroxy -6H- benzofurans
Aureus Roxb.) in detach for the first time discovery polyhydroxy substitution coumestrol class natural products (Z.Naturforsch.1983,
38c, 698), there is antimycotic and neuroprotective activity (Physiol.Mol.Plant Pathology 1986,29,95；
Planta.Med.2005,71,835), the content in nature is more rare.Therefore, invention is a kind of easy to operate, practical
Method come prepare polyhydroxy substitution coumestrol class natural products be of great significance.
The team such as Emers, Jurd, Sakamoto, Botting once complete 3,9- dihydroxy -6H- benzofurans simultaneously [3,
2-c] chroman -6- ketone (Coumestrol) synthetic work (J.Am.Chem.Soc.1958,80,4381-4383；
J.Org.Chem.1964,29,3036–3038；J.Chem.Soc.,Perkin Trans.1 2000,4339-4346；
Tetrahedron.2004,1637–1642).The above method uses precious metal palladium as catalyst more, reaction step is long, receives
Rate is relatively low.In addition, 1,3,9- trihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (Aureol) synthesis at present also not
It appears in the newspapers.
Invention content
It is an object of the invention to overcome disadvantage existing in the prior art, a kind of simple and direct, efficient, at low cost, work is provided
The simple polyhydroxy of skill replaces coumestrol class natural products 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone
(Coumestrol, structural formula 4a) and 1,3,9- trihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (Aureol, structure
Formula 4b) synthetic method.
The purpose of the invention is achieved by the following technical solution：
A kind of polyhydroxy substitution coumestrol class natural products 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -
The synthesis side of 6- ketone (Coumestrol) and 1,3,9- trihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (Aureol)
Method includes the following steps：
(1) in solvent A, in the presence of alkali A, the salicylide of the bromo- 4- hydroxyl phenylacetic acids (structural formula 1) of 2- and hydroxyl substitution
Condensation reaction occurs for class compound (structural formula 2), obtains 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone of hydroxyl substitution
Class compound (structural formula 3)；
(2) 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone class compound that hydroxyl replaces is dissolved in solvent B,
In the presence of catalyst B, ligand B, alkali B, hydroxylating/oxidative coupling reaction occurs under microwave heating condition, it is post-treated to obtain
To polyhydroxy substitution coumestrol class natural products (structural formula 4).
The bigcatkin willow aldehyde compound of hydroxyl substitution include but not limited to 2,4- 4-dihydroxy benzaldehydes (structural formula 2a) with
2,4,6- tri hydroxybenzaldehydes (structural formula 2b).
3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone class compound of the hydroxyl substitution includes but not limited to 3-
(the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (structural formula 3a) and 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxy tonka-beans
Plain (structural formula 3b).
In step (1), after condensation reaction, crude product is poured into ice water, is stirred, is filtered, filter cake is washed, filter cake is used
Sodium hydrate aqueous solution dissolves, and is washed with ethyl acetate, is acidified to pH=3~4 with hydrochloric acid, solid is precipitated, filter, wash, receive
Collect filter cake, 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone class compound (structural formula 3) of hydroxyl substitution is obtained after dry.
In step (2), after hydroxylating/oxidative coupling reaction, reaction solution is cooled to room temperature, is filtered, filtrate is through acetic acid second
PH=4~5 are acidified to hydrochloric acid after ester washing, are filtered, are washed, it is dry, it is recrystallized with ethyl acetate-light petrol, obtains polyhydroxy
Base replaces coumestrol class natural products (structural formula 4).
In step (1), the solvent A can be, but not limited to be acetic anhydride, propionic andydride, butyric anhydride, and preferred solvent A is second
Acid anhydrides；The alkali A can be, but not limited to be sodium acetate, sodium ethoxide, triethylamine, and preferably alkali A is triethylamine.
In step (1), the temperature of the condensation reaction is 100~140 DEG C, and preferable temperature is 110 DEG C；Reaction time is 5
~9 hours, preferred reaction time was 7 hours.
In step (1), the bromo- 4- hydroxyl phenylacetic acids of 2-, hydroxyl substitution bigcatkin willow aldehyde compound, alkali A molar ratio be 1：
(1.0~1.2)：The molar ratio of the bromo- 4- hydroxyl phenylacetic acids in (1~4), preferably 2-, the bigcatkin willow aldehyde compound of hydroxyl substitution, alkali A
It is 1：1：2.
In step (2), the catalyst B can be, but not limited to be copper sulphate, basic copper carbonate, copper oxide, copper acetate,
Cuprous iodide, preferred catalyst B are copper acetate；The ligand B can be, but not limited to be glycolic, glycine, the adjacent phenanthrene of 1,10-
Sieve quinoline, 8-hydroxyquinoline, tetramethylethylenediamine, preferably ligand B are 1,10- Phens.
In step (2), the alkali B can be, but not limited to be sodium hydroxide, potassium hydroxide, cesium carbonate, tripotassium phosphate, three
Ethamine, preferably alkali B are potassium hydroxide；The solvent B is distilled water, dimethyl sulfoxide, polyethylene glycol-400 (PEG-400), two
First sulfoxide-water (volume ratio 1：1), n,N-Dimethylformamide, preferred solvent B are dimethyl sulfoxide.
In step (2), the temperature of microwave heating is 100~180 DEG C, and preferable temperature is 120 DEG C；Reaction time is 2~4 small
When, preferred reaction time is 3 hours.
In step (2), hydroxyl substitution 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone class compound, catalyst B,
Ligand B, alkali B molar ratio be 1：(0.1~0.4)：(0.1~0.4)：3- (the bromo- 4- hydroxyls of 2- of (5~15), preferably hydroxyl substitution
Base phenyl)-umbelliferone class compound, catalyst B, ligand B, alkali B molar ratio be 1：0.2：0.2：10.
Chemical equation of the present invention is as follows：
It should be pointed out that the synthetic method of coumestrol class natural products of the present invention can be not limited to
3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (structural formula 4a) and 1,3,9- trihydroxies -6H-
The preparation of benzofuran simultaneously [3,2-c] chroman -6- ketone (structural formula 4b).In fact, can be closed using method of the present invention
At numerous coumestrol class natural products and derivative containing hydroxyl substitution.
The present invention has the following advantages that compared with prior art and effect：
(1) route of the present invention is simple and direct, easy to operate, multistep cascade reaction occurs simultaneously, yield is higher；Gained in the first step
To product do not need complicated purification processing, filter, it is dry after can direct plunge into and react in next step.
(2) present invention reaction condition harsh without anhydrous and oxygen-free etc. is not necessarily to precious metal catalyst, and Atom economy is high, symbol
It closes the theory of Modern Green Chemistry and there is cost advantage, be conducive to prepare with scale and industrialized implementation.
Description of the drawings
Fig. 1 is the nuclear magnetic resonance spectroscopy of 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (structural formula 4a)
(400MHz,DMSO-d6)。
Fig. 2 is the carbon-13 nmr spectra of 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (structural formula 4a)
(100MHz,DMSO-d6)。
Fig. 3 is the hydrogen nuclear magnetic resonance of 1,3,9- trihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (structural formula 4b)
Compose (400MHz, DMSO-d6)。
Fig. 4 is the nuclear magnetic resonance carbon of 1,3,9- trihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (structural formula 4b)
Compose (100MHz, DMSO-d6)。
Specific implementation mode
Further detailed description is done to the present invention with reference to embodiment, embodiments of the present invention are not limited thereto.
Embodiment 1
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (structural formula 3a)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4- 4-dihydroxy benzaldehydes is added
(25mmol, 3.45g), triethylamine (50mmol, 5.06g), acetic anhydride (10mL), stirring, for oil bath heating to 110 DEG C, reaction 7 is small
When.After completion of the reaction, reaction solution is poured into while hot in 50mL ice water, stirs, there is solid precipitation, filtered, wash filter cake, collect filter
Cake obtains hazel-color solid after dry, is 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone, weight 7.83g, yield
94%.1H NMR(DMSO-d6, 400MHz, ppm) and δ 10.38 (s, OH), 9.94 (s, OH), 7.89 (s, 1H), 7.57 (d, J=
8.8Hz, 1H), 7.26 (d, J=8.4Hz, 1H), 7.11 (d, J=2.0Hz, 1H), 6.86 (dd, J=2.0,8.8Hz, 1H),
6.83 (dd, J=2.0,8.4Hz, 1H), 6.78 (d, J=2.0Hz, 1H)；13C NMR(DMSO-d6,100MHz,ppm)δ
161.3,159.6,158.2,155.2,143.0,132.5,129.9,126.9,123.6,123.4,118.9,114.8,
113.4,111.4,102.0
(2) preparation of 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (structural formula 4a)
In 50mL microwave reaction bottles, sequentially add 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (5mmol,
1.67g), copper acetate (1mmol, 0.18g), 1,10- Phens (1mmol, 0.19g), potassium hydroxide (50mmol, 2.81g),
Dimethyl sulfoxide (20mL), stirring, microwave heating are reacted 3 hours to 120 DEG C.It after the completion of reaction, is cooled to room temperature, with acetic acid second
Ester washs (10mL × 3), and water phase is acidified to pH=4~5 with dilute hydrochloric acid, there is solid precipitation, filters, and washes filter cake, dry, uses second
Acetoacetic ester-petroleum ether recrystallization, obtains white solid, is natural products 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -
6- ketone, weight 0.99g, yield 74%.1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),10.04(s,1H),7.85(d,
J=8.8Hz, 1H), 7.69 (d, J=8.8Hz, 1H), 7.16 (d, J=2.0Hz, 1H), 6.90-6.96 (m, 3H) is (such as Fig. 1 institutes
Show)；13C NMR(100MHz,DMSO-d6)δ161.2,159.5,157.6,157.0,155.9,154.6,122.7,120.6,
(114.6,114.0,113.7,104.2,103.0,102.0,98.7 as shown in Figure 2).
Embodiment 2
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (structural formula 3a)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4- 4-dihydroxy benzaldehydes is added
(25mmol, 3.45g), triethylamine (25mmol, 2.53g), acetic anhydride (10mL), stirring, for oil bath heating to 110 DEG C, reaction 7 is small
When.After completion of the reaction, reaction solution is poured into while hot in 50mL ice water, stirs, there is solid precipitation, filtered, wash filter cake, collect filter
Cake obtains hazel-color solid after dry, is 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone, weight 6.91g, yield
83%.
(2) preparation of 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (structural formula 4a)
In 50mL microwave reaction bottles, sequentially add 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (5mmol,
1.67g), basic copper carbonate (1mmol, 0.24g), 1,10- Phens (1mmol, 0.19g), potassium hydroxide (50mmol,
2.81g), dimethyl sulfoxide (20mL), stirring, microwave heating are reacted 3 hours to 120 DEG C.It after the completion of reaction, is cooled to room temperature,
Enter in 50mL distilled water, pH=4~5 are acidified to dilute hydrochloric acid, there is solid precipitation, filter, washes filter cake, it is dry, with acetic acid second
Ester-petroleum ether recrystallization, obtains white solid, is natural products 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6-
Ketone, weight 0.87g, yield 65%.
Embodiment 3
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (structural formula 3a)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4- 4-dihydroxy benzaldehydes is added
(25mmol, 3.45g), triethylamine (75mmol, 7.59g), acetic anhydride (10mL), stirring, for oil bath heating to 110 DEG C, reaction 7 is small
When.After completion of the reaction, reaction solution is poured into while hot in 80mL ice water, stirs, there is solid precipitation, filtered, wash filter cake, collect filter
Cake obtains hazel-color solid after dry, is 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone, weight 7.16g, yield
86%.
(2) preparation of 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (structural formula 4a)
In 50mL microwave reaction bottles, sequentially add 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (5mmol,
1.67g), copper oxide (1mmol, 0.08g), 1,10- Phens (1mmol, 0.19g), potassium hydroxide (50mmol, 2.81g),
Dimethyl sulfoxide (20mL), stirring, microwave heating are reacted 3 hours to 120 DEG C.It after the completion of reaction, is cooled to room temperature, with acetic acid second
Ester washs (10mL × 3), and water phase is acidified to pH=4~5 with dilute hydrochloric acid, there is solid precipitation, filters, and washes filter cake, dry, uses second
Acetoacetic ester-petroleum ether recrystallization, obtains white solid, is natural products 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -
6- ketone, weight 0.78g, yield 58%.
Embodiment 4
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (structural formula 3a)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4- 4-dihydroxy benzaldehydes is added
(27.5mmol, 3.80g), triethylamine (50mmol, 5.06g), acetic anhydride (10mL), stirring, oil bath heating is to 110 DEG C, reaction 7
Hour.After completion of the reaction, reaction solution is poured into while hot in 50mL ice water, stirs, there is solid precipitation, filtered, wash filter cake, collected
Filter cake obtains hazel-color solid after dry, is 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone, weight 7.08g, yield
85%.
(2) preparation of 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (structural formula 4a)
In 50mL microwave reaction bottles, sequentially add 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (5mmol,
1.67g), copper acetate (1mmol, 0.18g), 1,10- o-phenanthrolins (1mmol, 0.19g), sodium hydroxide (50mmol, 20g), two
First sulfoxide (20mL), stirring, microwave heating are reacted 3 hours to 120 DEG C.It after the completion of reaction, is cooled to room temperature, pours into 50mL water
In, pH=4~5 are acidified to dilute hydrochloric acid, ethyl acetate extracts (20mL × 3), washes, dry, concentration, with ethyl acetate-stone
Oily ether recrystallization, obtains white solid, is natural products 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone, weight
0.91g, yield 68%.
Embodiment 5
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (structural formula 3a)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4- 4-dihydroxy benzaldehydes is added
(25mmol, 3.45g), triethylamine (50mmol, 5.06g), acetic anhydride (10mL), stirring, for oil bath heating to 110 DEG C, reaction 9 is small
When.After completion of the reaction, reaction solution is poured into while hot in 50mL ice water, stirs, there is solid precipitation, filtered, wash filter cake, collect filter
Cake obtains hazel-color solid after dry, is 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone, weight 7.49g, yield
90%.
(2) preparation of natural products 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (structural formula 4a)
In 50mL microwave reaction bottles, sequentially add 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (5mmol,
1.67g), copper acetate (1mmol, 0.18g), tetramethylethylenediamine (1mmol, 0.12g), potassium hydroxide (50mmol, 2.81g),
Dimethyl sulfoxide (20mL), stirring, microwave heating are reacted 3 hours to 120 DEG C.It after the completion of reaction, is cooled to room temperature, pours into 50mL
In water, pH=4~5 are acidified to dilute hydrochloric acid, are extracted with ethyl acetate (20mL × 3), are washed, dry, concentration, with acetic acid second
Ester-petroleum ether recrystallization, obtains white solid, is natural products 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6-
Ketone, weight 0.72g, yield 54%.
Embodiment 6
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (structural formula 3a)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4- 4-dihydroxy benzaldehydes is added
(25mmol, 3.45g), triethylamine (50mmol, 5.06g), acetic anhydride (10mL), stirring, for oil bath heating to 110 DEG C, reaction 5 is small
When.After completion of the reaction, reaction solution is poured into while hot in 50mL ice water, stirs, there is solid precipitation, filtered, wash filter cake, collect filter
Cake obtains hazel-color solid after dry, is 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone, weight 7.66g, yield
92%.
(2) preparation of natural products 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (structural formula 4a)
In 50mL microwave reaction bottles, sequentially add 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (5mmol,
1.67g), copper acetate (1mmol, 0.18g), 1,10- o-phenanthrolins (1mmol, 0.19g), potassium hydroxide (50mmol, 2.81g),
Dimethyl sulfoxide-water (volume ratio 1：1,20mL) it, stirs, microwave heating is reacted 3 hours to 120 DEG C.It is cooling after the completion of reaction
To room temperature, (10mL × 3) are washed with ethyl acetate, water phase is acidified to pH=4~5 with dilute hydrochloric acid, there is solid precipitation, filters, water
Filter wash cake, it is dry, it is recrystallized with ethyl acetate-light petrol, obtains white solid, be natural products 3,9- dihydroxy -6H- benzo furans
It mutters simultaneously [3,2-c] chroman -6- ketone, weight 0.97g, yield 72%.
Embodiment 7
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins (structural formula 3b)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4,6- trihydroxy benzene first are added
Aldehyde (25mmol, 3.85g), triethylamine (50mmol, 5.06g), acetic anhydride (10mL), stirring, oil bath heating is to 110 DEG C, reaction 7
Hour.After completion of the reaction, reaction solution is poured into while hot in 50mL ice water, stirs, there is solid precipitation, filtered, wash filter cake, collected
Filter cake obtains hazel-color solid after dry, is 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins, and weight 7.68g is received
Rate 88%.1H NMR(DMSO-d6,400MHz,ppm)δ10.75(s,OH),10.46(s,OH),10.05(s,OH),7.78(s,
1H), 7.24 (d, J=8.4Hz, 1H), 7.08 (d, J=2.4Hz, 1H), 6.83 (dd, J=2.4,8.4Hz, 1H), 6.29 (d, J
=2.0Hz, 1H), 6.24 (d, J=2.0Hz, 1H)；13C NMR(DMSO-d6,100MHz,ppm)δ162.1,159.8,158.1,
156.1,156.1,137.9,132.5,127.2,123.6,120.7,118.9,114.8,101.6,98.4,93.9
(2) preparation of natural products 1,3,9- trihydroxies -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (structural formula 4b)
In 50mL microwave reaction bottles, 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins are sequentially added
(5mmol, 1.75g), copper acetate (1mmol, 0.18g), 1,10- Phens (1mmol, 0.19g), potassium hydroxide (50mmol,
2.81g), dimethyl sulfoxide (20mL), stirring, microwave heating are reacted 3 hours to 120 DEG C.It after the completion of reaction, is cooled to room temperature, uses
Ethyl acetate washs (10mL × 3), and water phase is acidified to pH=4~5 with dilute hydrochloric acid, there is solid precipitation, filters, and washes filter cake, does
It is dry, recrystallized with ethyl acetate-light petrol, obtain white solid, be 1,3,9- trihydroxy -6H- benzofurans of natural products simultaneously [3,
2-c] chroman -6- ketone (Aureol), weight 0.91g, yield 64%.1H NMR(DMSO-d6,400MHz,ppm)δ10.92(s,
), OH 10.50 (s, OH), 9.96 (s, OH), 7.67 (d, J=8.4Hz, 1H), 7.14 (d, J=1.6Hz, 1H), 6.93 (dd, J
=2.0,8.4Hz, 1H), 6.41 (d, J=2.0Hz, 1H), 6.38 (d, J=2.0Hz, 1H) (as shown in Figure 3)；13C NMR
(DMSO-d6,100MHz,ppm)δ161.4,159.8,157.7,156.6,155.8,155.6,155.2,120.2,114.4,
(113.8,100.7,99.1,98.6,95.2,94.9 as shown in Figure 4).
Embodiment 8
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins (structural formula 3b)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4,6- trihydroxy benzene first are added
Aldehyde (25mmol, 3.85g), triethylamine (50mmol, 5.06g), acetic anhydride (10mL), stirring, oil bath heating is to 100 DEG C, reaction 7
Hour.After completion of the reaction, reaction solution is poured into while hot in 50mL ice water, stirs, there is solid precipitation, filtered, wash filter cake, collected
Filter cake obtains hazel-color solid after dry, is 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins, and weight 6.81g is received
Rate 78%.
(2) preparation of natural products 1,3,9- trihydroxies -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (structural formula 4b)
In 50mL microwave reaction bottles, 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins are sequentially added
(5mmol, 1.75g), copper acetate (1mmol, 0.18g), 1,10- Phens (1mmol, 0.19g), potassium hydroxide (50mmol,
2.81g), n,N-Dimethylformamide (20mL), stirring, microwave heating are reacted 3 hours to 120 DEG C.It is cooling after the completion of reaction
It to room temperature, pours into 50mL distilled water, pH=4~5 is acidified to dilute hydrochloric acid, there is solid precipitation, filter, wash filter cake, it is dry,
It is recrystallized with ethyl acetate-light petrol, obtains white solid, be 1,3,9- trihydroxy -6H- benzofurans of natural products simultaneously [3,2-
C] chroman -6- ketone, weight 0.88g, yield 62%.
Embodiment 9
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins (structural formula 3b)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4,6- trihydroxy benzene first are added
Aldehyde (25mmol, 3.85g), triethylamine (50mmol, 5.06g), acetic anhydride (10mL), stirring, oil bath heating is to 140 DEG C, reaction 7
Hour.After completion of the reaction, reaction solution is poured into while hot in 80mL ice water, stirs, there is solid precipitation, filtered, wash filter cake, collected
Filter cake obtains hazel-color solid after dry, is 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins, and weight 6.89g is received
Rate 79%.
(2) preparation of natural products 1,3,9- trihydroxies -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (structural formula 4b)
In 50mL microwave reaction bottles, 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins are sequentially added
(5mmol, 1.75g), copper acetate (1mmol, 0.18g), 1,10- Phens (1mmol, 0.19g), potassium hydroxide (50mmol,
2.81g), dimethyl sulfoxide (20mL), stirring, microwave heating are reacted 3 hours to 100 DEG C.It after the completion of reaction, is cooled to room temperature, uses
Ethyl acetate washs (10mL × 3), and water phase is acidified to pH=4~5 with dilute hydrochloric acid, there is solid precipitation, filters, and washes filter cake, does
It is dry, recrystallized with ethyl acetate-light petrol, obtain white solid, be 1,3,9- trihydroxy -6H- benzofurans of natural products simultaneously [3,
2-c] chroman -6- ketone, weight 0.71g, yield 50%.
Embodiment 10
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins (structural formula 3b)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4,6- trihydroxy benzene first are added
Aldehyde (25mmol, 3.85g), sodium acetate (50mmol, 4.10g), acetic anhydride (10mL), stirring, oil bath heating is to 110 DEG C, reaction 7
Hour.After completion of the reaction, reaction solution is poured into while hot in 50mL ice water, stirs, there is solid precipitation, filtered, wash filter cake, collected
Filter cake obtains hazel-color solid after dry, is 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins, and weight 7.33g is received
Rate 84%.
(2) preparation of natural products 1,3,9- trihydroxies -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (structural formula 4b)
In 50mL microwave reaction bottles, 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins are sequentially added
(5mmol, 1.75g), copper acetate (1mmol, 0.18g), 1,10- Phens (1mmol, 0.19g), potassium hydroxide (50mmol,
2.81g), dimethyl sulfoxide (20mL), stirring, microwave heating are reacted 3 hours to 160 DEG C.It after the completion of reaction, is cooled to room temperature,
Enter in 50mL water, pH=4~5 are acidified to dilute hydrochloric acid, ethyl acetate extracts (20mL × 3), washes, dry, and acetic acid is used in concentration
Ethyl ester-petroleum ether recrystallization, obtains white solid, is 1,3,9- trihydroxy -6H- benzofurans of natural products simultaneously [3,2-c] chroman -
6- ketone, weight 0.74g, yield 52%.
Embodiment 11
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins (structural formula 3b)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4,6- tri- oxybenzene formaldehyde are added
(25mmol, 3.85g), sodium ethoxide (50mmol, 3.40g), acetic anhydride (10mL), stirring, for oil bath heating to 110 DEG C, reaction 7 is small
When.After completion of the reaction, reaction solution is poured into while hot in 50mL ice water, stirs, there is solid precipitation, filtered, wash filter cake, collect filter
Cake obtains hazel-color solid after dry, is 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins, weight 7.24g, yield
83%.
(2) preparation of natural products 1,3,9- trihydroxies -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (structural formula 4b)
In 50mL microwave reaction bottles, 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins are sequentially added
(5mmol, 1.75g), copper acetate (1mmol, 0.18g), 1,10- Phens (1mmol, 0.19g), potassium hydroxide (50mmol,
2.81g), dimethyl sulfoxide (20mL), stirring, microwave heating are reacted 2 hours to 120 DEG C.It after the completion of reaction, is cooled to room temperature,
Enter in 50mL water, pH=4~5 are acidified to dilute hydrochloric acid, be extracted with ethyl acetate (20mL × 3), wash, dry, second is used in concentration
Acetoacetic ester-petroleum ether recrystallization, obtains white solid, is 1,3,9- trihydroxy -6H- benzofurans of natural products simultaneously [3,2-c] color
Full -6- ketone, weight 0.80g, yield 56%.
Embodiment 12
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins (structural formula 3b)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4,6- tri- oxybenzene formaldehyde are added
(25mmol, 3.85g), triethylamine (50mmol, 5.06g), butyric anhydride (10mL), stirring, for oil bath heating to 110 DEG C, reaction 7 is small
When.After completion of the reaction, reaction solution is poured into while hot in 50mL ice water, stirs, there is solid precipitation, filtered, wash filter cake, collect filter
Cake obtains hazel-color solid after dry, is 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins, weight 6.55g, yield
75%.
(2) preparation of natural products 1,3,9- trihydroxies -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (structural formula 4b)
In 50mL microwave reaction bottles, 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins are sequentially added
(5mmol, 1.75g), copper acetate (1mmol, 0.18g), 1,10- Phens (1mmol, 0.19g), potassium hydroxide (50mmol,
2.81g), dimethyl sulfoxide (20mL), stirring, microwave heating are reacted 4 hours to 120 DEG C.It after the completion of reaction, is cooled to room temperature, uses
Ethyl acetate washs (10mL × 3), and water phase is acidified to pH=4~5 with dilute hydrochloric acid, there is solid precipitation, filters, and washes filter cake, does
It is dry, recrystallized with ethyl acetate-light petrol, obtain white solid, be 1,3,9- trihydroxy -6H- benzofurans of natural products simultaneously [3,
2-c] chroman -6- ketone, weight 0.82g, yield 58%.
Embodiment 13
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins (structural formula 3b)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4,6- tri- oxybenzene formaldehyde are added
(25mmol, 3.85g), triethylamine (50mmol, 5.06g), acetic anhydride (10mL), stirring, for oil bath heating to 110 DEG C, reaction 7 is small
When.After completion of the reaction, reaction solution is poured into while hot in 50mL ice water, stirs, there is solid precipitation, filtered, wash filter cake, collect filter
Cake obtains hazel-color solid after dry, is 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins, weight 7.68g, yield
88%..
(2) preparation of natural products 1,3,9- trihydroxies -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone (structural formula 4b)
In 50mL microwave reaction bottles, 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins are sequentially added
(5mmol, 1.75g), copper acetate (0.5mmol, 0.09g), 1,10- Phens (0.5mmol, 0.095g), potassium hydroxide
(50mmol, 2.81g), dimethyl sulfoxide (20mL), stirring, microwave heating are reacted 3 hours to 120 DEG C.It is cooling after the completion of reaction
To room temperature, (10mL × 3) are washed with ethyl acetate, water phase is acidified to pH=4~5 with dilute hydrochloric acid, there is solid precipitation, filters, water
Filter wash cake, it is dry, it is recrystallized with ethyl acetate-light petrol, obtains white solid, be 1,3,9- trihydroxy -6H- benzos of natural products
Furans simultaneously [3,2-c] chroman -6- ketone, weight 0.68g, yield 48%.
Claims (6)
1. a kind of synthetic method of polyhydroxy substitution coumestrol class natural products, it is characterised in that include the following steps：
(1) in solvent A, in the presence of alkali A, the bromo- 4- hydroxyl phenylacetic acids of 2- and the bigcatkin willow aldehyde compound of hydroxyl substitution occur
Condensation reaction obtains 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone class compound of hydroxyl substitution；The solvent A is
Acetic anhydride, propionic andydride or butyric anhydride；The alkali A is sodium acetate, sodium ethoxide or triethylamine；The bigcatkin willow aldehydes of the hydroxyl substitution
Compound is 2,4- 4-dihydroxy benzaldehydes or 2,4,6- tri hydroxybenzaldehydes；3- (the bromo- 4- hydroxy benzenes of 2- of the hydroxyl substitution
Base)-umbelliferone class compound be 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferones or 3- (the bromo- 4- hydroxy benzenes of 2-
Base) -5,7- dihydroxycoumarins；
(2) 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone class compound that hydroxyl replaces is dissolved in solvent B, is being catalyzed
In the presence of agent B, ligand B, alkali B, under microwave heating condition occur hydroxylating/oxidative coupling reaction, it is post-treated obtain it is more
Hydroxyl replaces coumestrol class natural products；The solvent B is distilled water, dimethyl sulfoxide, polyethylene glycol-400, diformazan Asia
Sulfone-water or N,N-dimethylformamide；The catalyst B is copper sulphate, basic copper carbonate, copper oxide, copper acetate or iodate
It is cuprous；The ligand B is glycolic, glycine, 1,10- Phens, 8-hydroxyquinoline or tetramethylethylenediamine；Described
Alkali B is sodium hydroxide, potassium hydroxide, cesium carbonate, tripotassium phosphate or triethylamine；The polyhydroxy substitution coumestrol class is naturally produced
Object is 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chroman -6- ketone or 1,3,9- trihydroxy -6H- benzofurans simultaneously [3,2-
C] chroman -6- ketone.
2. the synthetic method of polyhydroxy substitution coumestrol class natural products according to claim 1, it is characterised in that：Step
Suddenly in (1), after condensation reaction, crude product is poured into ice water, is stirred, is filtered, filter cake, filter cake sodium hydroxide water are washed
Solution dissolves, and is washed with ethyl acetate, is acidified to pH=3~4 with hydrochloric acid, solid is precipitated, filter, and filter cake is collected in washing, dry
3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone class compound of hydroxyl substitution is obtained afterwards.
3. the synthetic method of polyhydroxy substitution coumestrol class natural products according to claim 1, it is characterised in that：Step
Suddenly in (2), after hydroxylating/oxidative coupling reaction, reaction solution is cooled to room temperature, is filtered, filtrate is used after ethyl acetate washs
Hydrochloric acid is acidified to pH=4~5, filters, and washes, dry, is recrystallized with ethyl acetate-light petrol, obtains polyhydroxy substitution tonka-bean
Female phenols natural products.
4. the synthetic method of polyhydroxy substitution coumestrol class natural products according to claim 1, it is characterised in that：Step
Suddenly in (1), the bromo- 4- hydroxyl phenylacetic acids of 2-, hydroxyl substitution bigcatkin willow aldehyde compound, alkali A molar ratio be 1：(1.0~1.2)：
(1~4).
5. the synthetic method of polyhydroxy substitution coumestrol class natural products according to claim 1, it is characterised in that：Step
Suddenly in (1), the temperature of the condensation reaction is 100~140 DEG C, and the reaction time is 5~9 hours；In step (2), microwave heating
Temperature be 100~180 DEG C, the reaction time be 2~4 hours.
6. the synthetic method of polyhydroxy substitution coumestrol class natural products according to claim 1, it is characterised in that：Step
Suddenly in (2), 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone class compound of hydroxyl substitution, catalyst B, ligand B, alkali B
Molar ratio be 1：(0.1~0.4)：(0.1~0.4)：(5~15).
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