CN103936704A - Method of preparing chrysin - Google Patents
Method of preparing chrysin Download PDFInfo
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- CN103936704A CN103936704A CN201410137766.4A CN201410137766A CN103936704A CN 103936704 A CN103936704 A CN 103936704A CN 201410137766 A CN201410137766 A CN 201410137766A CN 103936704 A CN103936704 A CN 103936704A
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- Prior art keywords
- chrysin
- dimethoxy
- hydroxyl
- reaction
- solid
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- RTIXKCRFFJGDFG-UHFFFAOYSA-N chrysin Chemical compound C=1C(O)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=CC=C1 RTIXKCRFFJGDFG-UHFFFAOYSA-N 0.000 title claims abstract description 88
- NYCXYKOXLNBYID-UHFFFAOYSA-N 5,7-Dihydroxychromone Natural products O1C=CC(=O)C=2C1=CC(O)=CC=2O NYCXYKOXLNBYID-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 235000015838 chrysin Nutrition 0.000 title claims abstract description 43
- 229940043370 chrysin Drugs 0.000 title claims abstract description 43
- 238000000034 method Methods 0.000 title claims abstract description 26
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000002994 raw material Substances 0.000 claims abstract description 15
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 8
- 239000011630 iodine Substances 0.000 claims abstract description 8
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 7
- 230000001335 demethylating effect Effects 0.000 claims abstract description 3
- JRFZSUMZAUHNSL-UHFFFAOYSA-N chrysin 5,7-dimethyl ether Chemical compound C=1C(OC)=CC(OC)=C(C(C=2)=O)C=1OC=2C1=CC=CC=C1 JRFZSUMZAUHNSL-UHFFFAOYSA-N 0.000 claims description 25
- 239000007787 solid Substances 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 21
- LKUDPHPHKOZXCD-UHFFFAOYSA-N 1,3,5-trimethoxybenzene Chemical compound COC1=CC(OC)=CC(OC)=C1 LKUDPHPHKOZXCD-UHFFFAOYSA-N 0.000 claims description 20
- 239000013078 crystal Substances 0.000 claims description 18
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- IAFBOKYTDSDNHV-UHFFFAOYSA-N (2S)-(-)-5,7-dimethoxyflavanone Natural products O1C2=CC(OC)=CC(OC)=C2C(=O)CC1C1=CC=CC=C1 IAFBOKYTDSDNHV-UHFFFAOYSA-N 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 238000001953 recrystallisation Methods 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- NQBWNECTZUOWID-UHFFFAOYSA-N (E)-cinnamyl (E)-cinnamate Natural products C=1C=CC=CC=1C=CC(=O)OCC=CC1=CC=CC=C1 NQBWNECTZUOWID-UHFFFAOYSA-N 0.000 claims description 9
- NQBWNECTZUOWID-QSYVVUFSSA-N cinnamyl cinnamate Chemical compound C=1C=CC=CC=1\C=C/C(=O)OC\C=C\C1=CC=CC=C1 NQBWNECTZUOWID-QSYVVUFSSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 6
- 244000124209 Crocus sativus Species 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 5
- 229960004756 ethanol Drugs 0.000 claims description 5
- 235000019441 ethanol Nutrition 0.000 claims description 5
- 238000002386 leaching Methods 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 238000007363 ring formation reaction Methods 0.000 claims description 5
- 238000010792 warming Methods 0.000 claims description 5
- 239000012153 distilled water Substances 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 229940030010 trimethoxybenzene Drugs 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 10
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 abstract 2
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 abstract 2
- 235000005513 chalcones Nutrition 0.000 abstract 2
- 229930003944 flavone Natural products 0.000 abstract 2
- 150000002212 flavone derivatives Chemical class 0.000 abstract 2
- 235000011949 flavones Nutrition 0.000 abstract 2
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 abstract 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 abstract 1
- CPEDYIVPGWUOGI-UHFFFAOYSA-N 1,3,5-triethoxybenzene Chemical compound CCOC1=CC(OCC)=CC(OCC)=C1 CPEDYIVPGWUOGI-UHFFFAOYSA-N 0.000 abstract 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 abstract 1
- 229930016911 cinnamic acid Natural products 0.000 abstract 1
- 235000013985 cinnamic acid Nutrition 0.000 abstract 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 0 CC1=C(C*=C=O)CCC=*1 Chemical compound CC1=C(C*=C=O)CCC=*1 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- JPYHHZQJCSQRJY-UHFFFAOYSA-N Phloroglucinol Natural products CCC=CCC=CCC=CCC=CCCCCC(=O)C1=C(O)C=C(O)C=C1O JPYHHZQJCSQRJY-UHFFFAOYSA-N 0.000 description 3
- 230000017858 demethylation Effects 0.000 description 3
- 238000010520 demethylation reaction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 description 3
- 229960001553 phloroglucinol Drugs 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001236253 Pinus aristata Species 0.000 description 2
- 241000218617 Pinus monticola Species 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000010010 raising Methods 0.000 description 2
- 239000002023 wood Substances 0.000 description 2
- 241001090347 Bignoniaceae Species 0.000 description 1
- GKKZMYDNDDMXSE-UHFFFAOYSA-N Ethyl 3-oxo-3-phenylpropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=CC=C1 GKKZMYDNDDMXSE-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- 240000005790 Oroxylum indicum Species 0.000 description 1
- 235000012920 Oroxylum indicum Nutrition 0.000 description 1
- 241000233805 Phoenix Species 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 241000218641 Pinaceae Species 0.000 description 1
- KRNZFFBDDYAVCO-UHFFFAOYSA-N [Cl].CC#N Chemical compound [Cl].CC#N KRNZFFBDDYAVCO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 238000007033 dehydrochlorination reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 210000003746 feather Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
Abstract
The invention discloses a method of preparing chrysin. The method comprises the following steps: S1, synthesizing 2'-hydroxyl-4', 6'-dimethoxyl chalcone by 1, 3, 5-triethoxy benzene and cinnamic acid under catalysis of boron trifluoride diethyl etherate; S2, generating 5, 7'-dimethoxyl flavone by 2'-hydroxyl-4', 6'-dimethoxyl chalcone under catalysis of a single substance iodine; and S3, fully demethylating 5, 7'-dimethoxyl flavone to generate chrysin. The method of preparing chrysin provided by the invention improves the synthetic yield of chrysin, is few in synthetic step, low in cost, easy to control and simple to operate, and has a high industrial application prospect, and the raw materials are easily available.
Description
Technical field
The present invention relates to the synthetic field of medicine, be specifically related to a kind of method of preparing chrysin.
Background technology
Chrysin (5,7-dihydroxy-2-phenyl-4
h-chromen-4-
one), English name chrysin, the seed, the stem skin that are present in Bignoniaceae plant Semen Oroxyli [Oroxylum indicum (L.) Vent.], the heart wood of pinaceae plant western white pine (Pinus mon-ticola Dougl.), in the various plants such as heart wood of bristlecone pine (P.aristata Engelm.), its chemical structural formula is as follows.
Modern pharmacology research shows, chrysin has pharmacologically active effect widely, for example antitumor action (M. C á rdenas, et al.,
bioorg. Med. Chem., 2006,14,2966); Anti-allergic effects (F. L. Pearce, et al.,
j. Allergy Clin. Immun., 1984,73,819); Anti-inflammatory action (H. Cho, et al..
pharmacol. Res., 2004,49,37); Antivirus action (J.-H. Lee, et al.,
korean Journal of Pharmacognosy., 1999,30,34); Resisting pathogenic microbes effect (K. Suresh Babu, et al.,
bioorg. Med. Chem. Lett., 2006,16,221) and hypoglycemic activity (J.-S. Shin, et al,
med. Chem. Lett., 1999,9,869.) etc.Using chrysin as the medicine of main active ingredient in many countries and regions existing use.Take chrysin as arrive first compound carry out multiple derivative that structural modification obtains also show have than quite or more good pharmacologically active effect (F. Yang, et al,
bioorg. Med. Chem. Lett., 2013,23,5544.).
Usually, the acquisition of current chrysin is mainly to extract and obtain from plant material.But due to the finiteness of natural plant resource, and wherein chrysin content is also on the low side, makes to obtain in a large number chrysin with this method and be restricted.Yet, by chemical process, synthesize and be one and obtain in a large number the fabulous approach of chrysin successively have scholar to be studied exploitation to this method.Xiao Jinxia etc. are with 1,3,5-trimethoxy-benzene is starting raw material, by reacting and obtain intermediate 2 with Acetyl Chloride 98Min. generation good fortune gram, 4,6-trimethoxy methyl phenyl ketone, then obtains β-propanedione with methyl benzoate condensation under sodium methylate catalysis, and last demethylation closes ring and obtains chrysin (CN 102127044).But raw material Acetyl Chloride 98Min. poor stability, in operation or the Shi Yifen that is heated explain hypertoxic phosgene and hydrogen chloride gas, be unfavorable for safety in production, and last demethylation cyclization process produces a large amount of spent acid.In addition in another piece of patent documentation; Wu Yonglong etc. (CN 102010393) be take Benzoyl chloride as raw material; under condensing agent catalysis, obtain ethyl benzoylacetate with methyl aceto acetate condensation; then under high-temperature vacuum condition, obtain chrysin with Phloroglucinol mixing condensation reaction; but this reaction must be carried out in a vacuum; production unit is had relatively high expectations, and Phloroglucinol price is more expensive.Minister in ancient times phoenix tail feathers etc. (CN 1475487) have been reported and a kind ofly take Phloroglucinol as raw material, first react and obtain intermediate 2 with excess chlorine acetonitrile generation Hoesch, 4,6-trihydroxy--α-chloro-methyl phenyl ketone, it becomes after phenyl styryl ketone with benzaldehyde under alkaline environment, by cyclization under alkaline condition and dehydrochlorination, generates chrysin.But this method Hoesch long reaction time, operation has inconvenience, and needs with a large amount of HCl gas, and equipment corrosion is serious, and requires equipment higher, is unfavorable for amplifying producing.Document Med. Chem. Res.; 20; 838 – 846; in 2011, reported with 2; 4,6-trihydroxy-acetophenone is raw material, with methyl-sulfate selective protection, obtains 2-hydroxyl-4; after 6-dimethoxy-acetophenone; process becomes under ester, alkaline environment and is rearranged to β-propanedione with Benzoyl chloride again, cyclization under the catalysis of acetic acid/sulfuric acid nitration mixture, and final demethylation obtains chrysin; this method route is long; synthetic total recovery and efficiency are all not high, and the methyl-sulfate of using has strong toxicity and corrodibility, and raw material is difficult for obtaining; and price is more expensive, be unsuitable for for the production of.
Summary of the invention
The present invention is intended to provide a kind of easier, method of preparing efficiently chrysin, and the method adopts commercially available cheap raw material, by three-step reaction only, has realized the complete synthesis of chrysin, makes synthetic total recovery and all raisings greatly of efficiency.
The method of preparing chrysin of the present invention, concrete steps are as follows:
(1) with 1,3,5-trimethoxy-benzene and styracin for raw material, with the synthetic 2 '-hydroxyl-4 ' of boron trifluoride diethyl etherate catalyzed reaction, 6 '-dimethoxy phenyl styryl ketone;
(2) 2 '-hydroxyls-4 ', the cyclization under iodine/DMSO condition of 6 '-dimethoxy phenyl styryl ketone, generates 5,7-dimethoxy flavone;
(3) 5,7-dimethoxy flavones demethylating under pyridine hydrochloride is processed generates chrysin;
The chemical reaction synthetic route the present invention relates to is:
The concrete operations of the inventive method are as follows:
(1) with 1,3,5-trimethoxy-benzene and styracin, be that raw material is placed in flask, 1, the blending ratio of 3,5-trimethoxy-benzene and styracin is mol ratio 1:1 ~ 1:2, and boron trifluoride diethyl etherate is added in raw material, in temperature of reaction, be that under 80 ~ 120 ℃ of conditions, condensing reflux reacts after 3 ~ 5h, be cooled to room temperature and filter, obtain crystal, crystal is placed in to aqueous ethanolic solution reflux 2 ~ 3h, obtain safran clear liquor, add activated carbon decolorizing to filter; After cooling, separate out yellow solid, filter, washing leaching cake obtains 2 '-hydroxyl-4 ' after dry, 6 '-dimethoxy phenyl styryl ketone, wherein the addition of boron trifluoride diethyl etherate is 5 ~ 15 times of 1,3,5-trimethoxy-benzene mole number;
(2) by 2 '-hydroxyl-4 ', 6 '-dimethoxy phenyl styryl ketone is dissolved in DMSO solution, adds iodine, is warming up to 80-140 ℃ of backflow 3-6h, is cooled to room temperature, then reaction solution is poured into mass percent concentration and be 2% NaHSO
3in solution, after fully stirring, leach solid, after being dried, with dehydrated alcohol recrystallization, obtain pale yellow powder shape crystal 5,7-dimethoxy flavone, 2 '-hydroxyl-4 ' wherein, the blending ratio of 6 '-dimethoxy phenyl styryl ketone and iodine is 10:1-20:1 (mol ratio);
(3) by 5, the mol ratio of 7-dimethoxy flavone and pyridine hydrochloride is the ratio of 1:5-1:15,5,7-dimethoxy flavone is added in pyridine hydrochloride, at 180-220 ℃, after stirring reaction 4-6h, mixture is let cool to room temperature, add water, separate out solid, after fully stirring, filter, collect solid, after fully washing solid with distilled water, be dried, after ethyl alcohol recrystallization, obtain chrysin.
The present invention has obviously simplified the synthetic route of chrysin for the preparation of the method for chrysin, improved synthesis yield and the efficiency of chrysin, has raw material cheap and easy to get, and synthesis step reduces, and is easy to control, easy and simple to handle, has very high prospects for commercial application.
The compound of the final preparation of the method for the invention passes through magnetic resonance detection, prove that its structure is consistent with chrysin structure, and synthetic total recovery has been up to 62.6% left and right after testing, compared significant raising with existing synthesis yield, prepared chrysin detects through HPLC method, purity reaches more than 98%, and quality is higher.
Embodiment
The method of preparing chrysin disclosed by the invention, those skilled in the art can be easy to the operation with reference to teachings herein and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, the method of the invention is described by following instance, and related personnel obviously can realize the technology of the present invention to method as herein described in the scope that does not depart from content of the present invention, connotation.These are similarly replaced and change and also should be placed in the claim of the application's patent.
It is as follows that this prepares the concrete implementation content of chrysin:
embodiment 1:
(1) 2 '-hydroxyl-4 ', 6 '-dimethoxy phenyl styryl ketone synthetic
Take 4.2g 1,3,5-trimethoxy-benzene (0.025mol) and 3.7g styracin (0.025mol) add in dry round-bottomed flask, then add 15.0mL boron trifluoride diethyl etherate, 80 ℃ of condensing refluxes of band drying tube.After reaction 3h, stop being heated to room temperature, separate out red needle crystal, leach crystal.Crystal is added in 100mL aqueous ethanolic solution to reflux 2.5 hours, obtain safran clear liquor, add activated carbon decolorizing to filter.After cooling, wash out yellow solid, filtration, washing leaching cake obtain 5.35g 2 '-hydroxyl-4 ', 6 '-dimethoxy phenyl styryl ketone, yield 75.4% after being dried.
Structural parameter
1h NMR (400 MHz, DMSO-d
6), δ: 3.83 (s, 3H, OCH
3-4 '), 3.91 (s, 3H, OCH
3-6 '), 6.14 (d, J=1.6 Hz, 1H, H-3 '), 6.17 (d, J=1.6 Hz, 1H, H-5 '), 7.45 – 7.49 (m, 3H, H-3,4,5), 7.65 (d, 1H, J=16 Hz, H-α), 7.72 – 7.74 (m, 2H, H-2,6), 7.78 (d, J=16 Hz, 1H, H-β), 13.41 (s, 1H, OH-2 ').
Synthesizing of (2) 5,7-dimethoxy flavones
Take 5.7g(0.02 mol) 2 '-hydroxyl-4 ', synthesizing of 6 '-dimethoxy phenyl styryl ketone, after adding 30 mL DMSO to dissolve completely, adds 0.13g iodine under room temperature, be warming up to 80 ℃ of reaction 4h hour.Be chilled to room temperature, then reaction solution poured into 200mL 2% NaHSO
3solution, leaches solid after fully stirring, and after being dried, with dehydrated alcohol recrystallization, obtains pale yellow powder shape crystal 4.79g 5,7-dimethoxy flavone, yield 84.9%.
Structural parameter
1h NMR (400 MHz, DMSO-d6), δ: 3.83 (s, 3H, OCH3-7), 3.90 (s, 3H, OCH3-5), 6.50 (d, 1H, J=2.4 Hz, H-8), 6.76 (s, 1H, H-3), 6.85 (d, 1H, J=2.4 Hz, H-6), 7.56 (m, 3H, H-4 ', 5 ', 6 '), 8.03 (m, 2H, H-2 ', 3 ').
(3) chrysin is synthetic
Take 2.8g (0.01 mol) 5, synthesizing of 7-dimethoxy flavone, puts in 50mL reaction flask, adds 5.7g pyridine hydrochloride.With mixture being heated to 180 ℃ after air in nitrogen replacement bottle, after stirring reaction 4 h, mixture is let cool to room temperature, add water, separate out a large amount of solids, after fully stirring, filter, collect solid, water fully washs rear dry, and solid obtains chrysin 2.1g after ethyl alcohol recrystallization, and yield is 82.7%.
Structural parameter:
1h NMR (400 MHz, DMSO-d
6), δ: 6.23 (d, 1H, J=2.0 Hz, H-6), 6.53 (d, 1H, J=2.0 Hz, H-8), 6.97 (s, 1H, H-3), 7.55 – 7.62 (m, 3H, H-4 ', 5 ', 6 '), 8.06 (m, 2H, H-2 ', 3 '), 10.94 (s, 1H, OH-5), 12.83 (s, 1H, OH-7).
embodiment 2:
(1) 2 '-hydroxyl-4 ', 6 '-dimethoxy phenyl styryl ketone synthetic
Take 4.2g 1,3,5-trimethoxy-benzene (0.025mol) and 5.5g styracin (0.0375mol) add in dry round-bottomed flask, then add 30.0mL boron trifluoride diethyl etherate, 100 ℃ of condensing refluxes of band drying tube.After reaction 4h, stop being heated to room temperature, separate out red needle crystal, leach crystal.Crystal is added in 100mL aqueous ethanolic solution to reflux 2.5 hours, obtain safran clear liquor, add activated carbon decolorizing to filter.After cooling, wash out yellow solid, filtration, washing leaching cake obtain 5.79g 2 '-hydroxyl-4 ', 6 '-dimethoxy phenyl styryl ketone, yield 81.6% after being dried.
Synthesizing of (2) 5,7-dimethoxy flavones
Take 5.7g(0.02 mol) 2 '-hydroxyl-4 ', synthesizing of 6 '-dimethoxy phenyl styryl ketone, after adding 30 mL DMSO to dissolve completely, adds 0.17g iodine under room temperature, be warming up to 120 ℃ of reaction 5h.Be chilled to room temperature, then reaction solution poured into 200mL 2% NaHSO
3solution, leaches solid after fully stirring, and after being dried, with dehydrated alcohol recrystallization, obtains pale yellow powder shape crystal 5.0 g 5,7-dimethoxy flavone, yield 88.6%.
(3) chrysin is synthetic
Take 2.8g (0.01 mol) 5, synthesizing of 7-dimethoxy flavone, puts in 50mL reaction flask, adds 11.5g pyridine hydrochloride.With mixture being heated to 200 ℃ after air in nitrogen replacement bottle, after stirring reaction 5 h, mixture is let cool to room temperature, add water, separate out a large amount of solids, after fully stirring, filter, collect solid, water fully washs rear dry, and solid obtains chrysin 2.2g after ethyl alcohol recrystallization, and yield is 86.7%.
embodiment 3:
(1) 2 '-hydroxyl-4 ', 6 '-dimethoxy phenyl styryl ketone synthetic
Take 4.2g 1,3,5-trimethoxy-benzene (0.025mol) and 7.4g styracin (0.050mol) add in dry round-bottomed flask, then add 45.0mL boron trifluoride diethyl etherate, 120 ℃ of condensing refluxes of band drying tube.After reaction 5h, stop being heated to room temperature, separate out red needle crystal, leach crystal.Crystal is added in 100mL aqueous ethanolic solution to reflux 2.5 hours, obtain safran clear liquor, add activated carbon decolorizing to filter.After cooling, wash out yellow solid, filtration, washing leaching cake obtain 6.1g 2 '-hydroxyl-4 ', 6 '-dimethoxy phenyl styryl ketone, yield 85.9% after being dried.
Synthesizing of (2) 5,7-dimethoxy flavones
Take 5.7g(0.02 mol) 2 '-hydroxyl-4 ', synthesizing of 6 '-dimethoxy phenyl styryl ketone, after adding 30mL DMSO to dissolve completely, adds 0.25g iodine under room temperature, be warming up to 140 ℃ of reaction 6h.Be chilled to room temperature, then reaction solution poured into 200mL 2% NaHSO
3solution, leaches solid after fully stirring, and after being dried, with dehydrated alcohol recrystallization, obtains pale yellow powder shape crystal 5.1 g 5,7-dimethoxy flavone, yield 90.1%.
(3) chrysin is synthetic
Take 2.8g (0.01 mol) 5, synthesizing of 7-dimethoxy flavone, puts in 50mL reaction flask, adds 17.4g pyridine hydrochloride.With mixture being heated to 220 ℃ after air in nitrogen replacement bottle, after stirring reaction 6 h, mixture is let cool to room temperature, add water, separate out a large amount of solids, after fully stirring, filter, collect solid, water fully washs rear dry, and solid obtains chrysin 2.1g after ethyl alcohol recrystallization, and yield is 82.6%.
Claims (4)
1. a method of preparing chrysin, is characterized in that carrying out as follows:
(1) with 1,3,5-trimethoxy-benzene and styracin for raw material, with the synthetic 2 '-hydroxyl-4 ' of boron trifluoride diethyl etherate catalyzed reaction, 6 '-dimethoxy phenyl styryl ketone;
(2) 2 '-hydroxyls-4 ', the cyclization under iodine/DMSO condition of 6 '-dimethoxy phenyl styryl ketone, generates 5,7-dimethoxy flavone;
(3) 5,7-dimethoxy flavones demethylating under pyridine hydrochloride is processed generates chrysin;
Synthetic route is as follows:
。
2. prepare according to claim 1 the method for chrysin, the concrete operations that it is characterized in that step (1) are as follows: with 1,3,5-trimethoxy-benzene and styracin are that raw material is placed in flask, 1,3, the blending ratio of 5-trimethoxy-benzene and styracin is mol ratio 1:1-1:2, boron trifluoride diethyl etherate is added in raw material, is that under 80 ~ 120 ℃ of conditions, condensing reflux reacts after 3-5h in temperature of reaction, is cooled to room temperature and filters, obtain crystal, crystal is placed in to aqueous ethanolic solution reflux 2-3h, obtains safran clear liquor, add activated carbon decolorizing to filter; After cooling, separate out yellow solid, filter, washing leaching cake obtains 2 '-hydroxyl-4 ' after dry, 6 '-dimethoxy phenyl styryl ketone, wherein the addition of boron trifluoride diethyl etherate be 1,3,5-trimethoxy-benzene mole number 5-15 doubly.
3. prepare according to claim 1 the method for chrysin, the concrete operations that it is characterized in that step (2) are as follows: by 2 '-hydroxyl-4 ', 6 '-dimethoxy phenyl styryl ketone is dissolved in DMSO solution, add iodine, be warming up to 80-140 ℃ of backflow 3-6h, be cooled to room temperature, then reaction solution poured into mass percent concentration and be 2% NaHSO
3in solution, after fully stirring, leach solid, after being dried, with dehydrated alcohol recrystallization, obtain pale yellow powder shape crystal 5,7-dimethoxy flavone, 2 '-hydroxyl-4 ' wherein, the blending ratio of 6 '-dimethoxy phenyl styryl ketone and iodine is 10:1-20:1 (mol ratio).
4. prepare according to claim 1 the method for chrysin, the concrete operations that it is characterized in that step (3) are as follows: the ratio that is 1:5-1:15 by the mol ratio of 5,7-dimethoxy flavone and pyridine hydrochloride, by 5,7-dimethoxy flavone adds in pyridine hydrochloride, at 180-220 ℃, after stirring reaction 4-6 h, mixture is let cool to room temperature, add water, separate out solid, after fully stirring, filter, collect solid, with distilled water, fully wash after solid dry, after ethyl alcohol recrystallization chrysin.
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| CN105237503A (en) * | 2015-10-19 | 2016-01-13 | 昆明理工大学 | Method for preparing baicalein |
| CN107759646A (en) * | 2016-08-22 | 2018-03-06 | 昆明龙津药业股份有限公司 | A kind of synthetic method of lamp-dish flower acetic |
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| CN101918037A (en) * | 2007-11-15 | 2010-12-15 | 通用医疗公司 | Be used to reduce the method and composition of skin injury |
| CN102465158A (en) * | 2010-11-19 | 2012-05-23 | 苏州宝泽堂医药科技有限公司 | Method for preparing chrysin |
| CN102793712A (en) * | 2012-09-07 | 2012-11-28 | 天津医科大学 | Application of chrysin in preparation of medicaments for treating autoimmune and inflammatory diseases |
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| CN101918037A (en) * | 2007-11-15 | 2010-12-15 | 通用医疗公司 | Be used to reduce the method and composition of skin injury |
| CN102465158A (en) * | 2010-11-19 | 2012-05-23 | 苏州宝泽堂医药科技有限公司 | Method for preparing chrysin |
| CN102793712A (en) * | 2012-09-07 | 2012-11-28 | 天津医科大学 | Application of chrysin in preparation of medicaments for treating autoimmune and inflammatory diseases |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105237503A (en) * | 2015-10-19 | 2016-01-13 | 昆明理工大学 | Method for preparing baicalein |
| CN107759646A (en) * | 2016-08-22 | 2018-03-06 | 昆明龙津药业股份有限公司 | A kind of synthetic method of lamp-dish flower acetic |
| CN107759646B (en) * | 2016-08-22 | 2021-07-27 | 昆明龙津药业股份有限公司 | Method for synthesizing scutellarin |
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