CN106518825A - Chemically selective mono-methylation method of coumarin catechol compounds - Google Patents
Chemically selective mono-methylation method of coumarin catechol compounds Download PDFInfo
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- CN106518825A CN106518825A CN201510574322.1A CN201510574322A CN106518825A CN 106518825 A CN106518825 A CN 106518825A CN 201510574322 A CN201510574322 A CN 201510574322A CN 106518825 A CN106518825 A CN 106518825A
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- Prior art keywords
- coumarin
- catechol
- monomethylation
- chemo
- pyrocatechol
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- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N benzo-alpha-pyrone Natural products C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 235000001671 coumarin Nutrition 0.000 title claims abstract description 37
- 229960000956 coumarin Drugs 0.000 title claims abstract description 34
- -1 coumarin catechol compounds Chemical class 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 title claims abstract description 17
- 238000007069 methylation reaction Methods 0.000 title claims abstract description 10
- YCIMNLLNPGFGHC-UHFFFAOYSA-N o-dihydroxy-benzene Natural products OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims abstract description 54
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- 238000006053 organic reaction Methods 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000002512 chemotherapy Methods 0.000 claims description 12
- 230000001035 methylating effect Effects 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 8
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 2
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 claims description 2
- 239000003880 polar aprotic solvent Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims 1
- AXNBHOOQHIIQFA-UHFFFAOYSA-N [S].C(F)(F)F Chemical compound [S].C(F)(F)F AXNBHOOQHIIQFA-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- INQOMBQAUSQDDS-BJUDXGSMSA-N iodomethane Chemical group I[11CH3] INQOMBQAUSQDDS-BJUDXGSMSA-N 0.000 claims 1
- 150000004702 methyl esters Chemical class 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000011987 methylation Effects 0.000 abstract 2
- 230000035484 reaction time Effects 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 8
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 7
- 239000000376 reactant Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 6
- 239000011435 rock Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 238000005292 vacuum distillation Methods 0.000 description 5
- JHEDXMVWNCTPTI-UHFFFAOYSA-N 7-hydroxy-8-methoxy-4-methylchromen-2-one Chemical compound CC1=CC(=O)OC2=C1C=CC(O)=C2OC JHEDXMVWNCTPTI-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- RODXRVNMMDRFIK-UHFFFAOYSA-N scopoletin Chemical compound C1=CC(=O)OC2=C1C=C(OC)C(O)=C2 RODXRVNMMDRFIK-UHFFFAOYSA-N 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- HAQWEMHXSIRYBE-UHFFFAOYSA-N 7-hydroxy-8-methoxycoumarin Chemical compound C1=CC(=O)OC2=C1C=CC(O)=C2OC HAQWEMHXSIRYBE-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- AZELSOYQOIUPBZ-UHFFFAOYSA-N Dalbergin Chemical compound C1=2C=C(O)C(OC)=CC=2OC(=O)C=C1C1=CC=CC=C1 AZELSOYQOIUPBZ-UHFFFAOYSA-N 0.000 description 2
- XEHFSYYAGCUKEN-UHFFFAOYSA-N Dihydroscopoletin Natural products C1CC(=O)OC2=C1C=C(OC)C(O)=C2 XEHFSYYAGCUKEN-UHFFFAOYSA-N 0.000 description 2
- 208000035126 Facies Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000019802 Sexually transmitted disease Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 238000005815 base catalysis Methods 0.000 description 2
- PZZFRNARZSDSHQ-UHFFFAOYSA-N dalbergin Natural products COc1cc2OC(=O)CC(c3ccccc3)c2cc1O PZZFRNARZSDSHQ-UHFFFAOYSA-N 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- RQSKEMWBCJHQMX-UHFFFAOYSA-N isoscopoletin Natural products COc1cc2OC(=O)CCc2cc1O RQSKEMWBCJHQMX-UHFFFAOYSA-N 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- FWYIBGHGBOVPNL-UHFFFAOYSA-N scopoletin Natural products COC=1C=C2C=CC(OC2=C(C1)O)=O FWYIBGHGBOVPNL-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 150000005206 1,2-dihydroxybenzenes Chemical class 0.000 description 1
- NWQBYMPNIJXFNQ-UHFFFAOYSA-N 7,8-dihydroxy-4-methyl-1-benzopyran-2-one Chemical compound OC1=C(O)C=CC2=C1OC(=O)C=C2C NWQBYMPNIJXFNQ-UHFFFAOYSA-N 0.000 description 1
- ATEFPOUAMCWAQS-UHFFFAOYSA-N 7,8-dihydroxycoumarin Chemical compound C1=CC(=O)OC2=C(O)C(O)=CC=C21 ATEFPOUAMCWAQS-UHFFFAOYSA-N 0.000 description 1
- 206010059245 Angiopathy Diseases 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001529246 Platymiscium Species 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- YBGKGTOOPNQOKH-UHFFFAOYSA-N daphnetin Natural products OC1=CC=CC2=C1OC(=O)C=C2O YBGKGTOOPNQOKH-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 230000002792 vascular Effects 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
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
-
- 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
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/18—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted otherwise than in position 3 or 7
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a chemically selective mono-methylation method of coumarin catechol compounds, and belongs to the field of natural drug synthesis. According to the method, catechol coumarin compounds are added into an organic reaction system in the presence of a proper amount of alkali catalyst, and high selectivity methylation reactions happen between the catechol coumarin compounds and a methylation reagent so as to obtain a mono-methylation product; wherein the mole ratio of the alkali to the catechol coumarin compounds is 1.0-5.0:1; the mole ratio of the methylation reagent to the catechol coumarin compounds is 1.0-2.0:1, the temperature of the reaction system is -20 to 10 DEG C, and the reaction time is 0.5 to 3 hours. The method has the characteristics of simple operation, mild conditions, good selectivity, and high yield, and can be used to prepare mono-methylation products of coumarin catechol compounds with different substituents.
Description
Technical field
The invention belongs to natural drug synthesis field, and in particular to a kind of chemo-selective monomethylation method of coumarin catechol.
Background technology
The pyrocatechol coumarin monomethylation products such as scopoletin (Scopolean), dalbergin (4- phenyl-Scopolean) are the important natural products of a class, with various pharmacologically actives.Scopoletin is one of the main component in Caulis Erycibess (a kind of Chinese medicine for treating rheumatism sexually transmitted disease (STD)) [Bioorgan.Med.Chem.2013,84], possesses extensive biological activity, such as：Pharmacologically active [the Eur.J.Pharmacol.2007,555,218 such as antiinflammatory, uric acid resisting, antioxidation, defying age and antitumor and suppression new vascular generation；Lett.Drug Des.Disc.2012,9,397].Yellow wingceltis platymiscium be it is a kind of treat angiopathy and inflammation and well-known Chinese herbal medicine, effective ingredient therein is dalbergin [Phytochemistry.1997,46,947].Additionally, 7-hydroxy-8-methoxycoumarin is reported can suppress hepatic fibrosis, play a part of to prevent liver cirrhosis [J.Nat.Med.2011,65,370].But content of this kind of compound in plant is relatively low, extraction process is complicated, time-consuming bothersome [Nat.Prod.Res.2015].Therefore, study that such compound is practical and efficient preparation method is developed to which and using most important.At present, mostly there is the number of drawbacks such as the experimental facilitiess that experimental raw is expensive, needs are advanced, poor selectivity low yield and experiment condition harshness in the synthetic method reported.Therefore, a kind of new and effective selective alkylation technology is developed, prepares development and utilization of the pyrocatechol coumarin monomethylation product to such compound and there is important value.
The content of the invention
The purpose of the present invention is the deficiency existed for above-mentioned prior art and research, it is i.e. different for the bond energy of pyrocatechol coumarin diverse location hydroxyl, from appropriate base catalysiss, under certain organic reaction system, there is high selectivity Monomethylation with methylating reagent, prepare monomethylation product.
A kind of chemo-selective monomethylation method of coumarin catechol of the present invention, by pyrocatechol coumarin compound, add under the organic reaction system of appropriate base catalyst, there is high selectivity methylation reaction with methylating reagent, and then obtain monomethylation product, the alkali and pyrocatechol coumarin compound and mol ratio be：1.0～5.0：1；The methylating reagent and pyrocatechol coumarin compound and mol ratio be：1.0～2.0：1, the temperature of reaction system is -20 DEG C～10 DEG C, and the response time is 0.5～3 hour；
The pyrocatechol coumarin compound structure is such as：
Wherein R is H, (C1-C6) alkyl, (C1-C6) alkoxyl, aryl, (C1-C6) replace alkyl in any one；
The monomethylation product structure formula is：
Wherein R is H, (C1-C6) alkyl, (C1-C6) alkoxyl, (C1-C6) replace alkyl, any one in aryl.
The methylating reagent is any one or more combination in iodomethane, dimethyl sulfate, Methyl triflate or methyl mesylate.
The base catalyst is any one or more combination in sodium hydroxide, potassium hydroxide, sodium hydride or hydrofining.
The organic reaction system be polar aprotic solvent, one or more in DMF, tetrahydrofuran, acetonitrile or dimethyl sulfoxide.
The alkali and pyrocatechol coumarin compound and mol ratio preferably 2.5：1.
The methylating reagent and pyrocatechol coumarin compound and mol ratio be preferably：1.1：1.
The reaction temperature is preferably -5～5 DEG C.
The response time is preferably 0.5～1 hour.
It is characteristic of the invention that with pyrocatechol coumarin (6 cheap and easy to get, 7/7,8- dihydroxycoumarins) or C4- replace pyrocatechol coumarin be raw material, for the difference of its diverse location phenolic hydroxyl group dissociation energy, from appropriate base catalysiss, under certain organic reaction system, there is high selectivity methylation reaction with methylating reagent, prepare monomethylation product.Also there is while the preparation method has high selection monomethylation characteristic process is simple, it is easy to operate, the characteristics of cheap practical.This preparation technology is not only to prepare pyrocatechol coumarin monomethylation product to provide a kind of available method conscientiously, and the also selective alkylation for other catechols provides technological guidance.
Description of the drawings
Fig. 1. the syntheti c route figure of pyrocatechol coumarin selectivity monomethylation product；
Fig. 2 .6- methoxyl groups-umbelliferone (I-aa)1H-NMR spectrum；
Fig. 3 .4- methyl-Scopolean (I-ab)1H-NMR spectrum；
Fig. 4 .4- phenyl-Scopolean (I-ac)1H-NMR spectrum；
Fig. 5's .7- hydroxyl -8- methoxy coumarins (II-aa)1H-NMR spectrum；
Fig. 6 .4- methyl -7-hydroxy-8-methoxycoumarin (II-ab)1H-NMR spectrum；
Fig. 7's .4- phenyl-7-hydroxyl -8- methoxy coumarins (II-ac)1H-NMR spectrum.
Specific embodiment
The following examples will be further described to the present invention, but not thereby limiting the invention.The syntheti c route figure of pyrocatechol coumarin chemo-selective monomethylation product is as shown in figure 1, be specifically shown in following examples.
Embodiment 1
The preparation (I-aa) of Scopolean
Weigh 6; in there-necked flask, argon protection is lower to add DMF 5mL sample dissolutions to 7- dihydroxycoumarin 500mg; bath on the rocks; make the temperature of reaction system drop to -20 DEG C, add sodium hydride 280mg, reactant liquor is in thick; after fully reaction 15min; 250 μ L of iodomethane are added dropwise over, maintain the temperature of reaction system at -15～0 DEG C, TLC monitors reaction process (VCH2Cl2：VCH3OH=50：1), after 0.5h, reaction terminates, and reactant liquor is added drop-wise in 40mL frozen water, adds salt acid for adjusting pH, when about 3, has Precipitation, filter after 30min, collect filter cake, as crude product under stirring action.15mL re-crystallizing in ethyl acetate is used, room temperature after being heated to reflux 1h, is cooled to, is filtered, filter cake ethyl acetate is washed twice, collected filter cake, obtain white solid 490mg, its1H NMR are as shown in Figure 2.
1H NMR(500MHz,DMSO-d6)δ:3.82(s,3H,OCH3), 6.22 (d, J=9.5Hz, 1H, COCH=C), 6.78 (s, 1H, Ar-H), 7.22 (s, 1H, Ar-H), 7.91 (d, J=9.5Hz, 1H, C=CH), 10.29 (d, br, 1H, Ar-OH)
Embodiment 2
The preparation of 4- methyl-Scopolean (I-ab)
Weigh 4- methyl -6; 7- dihydroxycoumarin 500mg are in there-necked flask; argon protection is lower to add DMF 5mL sample dissolutions, water-bath on the rocks; the temperature of reaction system is made to drop to less than -10 DEG C; potassium hydroxide 660mg is added, after fully reaction 15min, gradually 210 μ L of Deca iodomethane; the reaction temperature of maintenance system is at -10～0 DEG CMonitoring reaction process, reaction after 2h terminate, and reactant liquor are dropwise added drop-wise in 40mL frozen water under stirring, plus dilute hydrochloric acid adjusts pH to 3～4, has Precipitation, filters after 30min, collects filter cake, as crude product.Crude product re-crystallizing in ethyl acetate, is heated to reflux 1h, and cooled and filtered collects filter cake, and vacuum drying obtains white solid 440mg, its1H NMR are as shown in Figure 3.1H NMR(400MHz,DMSO-d6)δ:2.40(s,3H,CH3),3.85(s,3H,OCH3), 6.13 (s, 1H, COCH=C), 6.90 (s, 1H, Ar-H), 7.13 (s, 1H, Ar-H), 10.53 (s, 1H, OH).
Embodiment 3
The preparation of 4- phenyl-Scopolean (I-ac)
Weigh 4- phenyl -6; 7- dihydroxycoumarin 500mg are in there-necked flask; argon protection is lower to add DMF 5mL sample dissolutions, water-bath on the rocks; the temperature of reaction system is made to drop to 0 DEG C; sodium hydroxide 360mg is added, after fully reaction 15min, gradually 190 μ L of Deca iodomethane; the reaction temperature of maintenance system is at 0～10 DEG CMonitoring reaction process, reaction after 3h terminate, and reactant liquor are dropwise added drop-wise in 40mL frozen water under stirring, plus dilute hydrochloric acid adjusts pH to 3～4, has Precipitation, filters after 30min, collects filter cake, as crude product.Crude product recrystallizing methanol, is heated to reflux 1h, and cooled and filtered collects filter cake, and vacuum drying obtains white solid 380mg, its1H NMR are as shown in Figure 4.
1H NMR(500MHz,DMSO-d6)δ:3.67(s,3H,OCH3), 6.17 (s, 1H, COCH=C), 6.83 (s, 1H, Ar-H), 6.89 (s, 1H, Ar-H), 7.58 (s, 5H, Ar-H), 10.47 (s, br, 1H, Ar-OH).
Embodiment 4
The preparation of 7-hydroxy-8-methoxycoumarin (II-aa)
Weigh 7, 8- dihydroxycoumarin 500mg are in there-necked flask, argon protection is lower to add N, dinethylformamide 5mL, bath on the rocks makes the temperature of reaction system drop to -20 DEG C, add hydrofining 330mg, after reaction 15min, , it is added dropwise over 220 μ L of iodomethane, the temperature of reaction system is maintained at -20～-5 DEG C, TLC monitors reaction process, after 0.5h, reaction terminates, reactant liquor is added drop-wise in 100mL frozen water, salt adding acid for adjusting pH is about 3, ethyl acetate extracts (50mL × 3), combined ethyl acetate phase, saturated common salt is washed twice, organic faciess vacuum distillation removes ethyl acetate, as crude product, crude product Jing silica gel post separations, mobile phase is VPetroleum ether：VDichloromethane：VAcetone=2:1:0.15, vacuum distillation removes solvent, and vacuum drying obtains white solid 370mg, its1H NMR are as shown in Figure 5.
1H NMR(400MHz,DMSO-d6)δ:3.82(s,3H,OCH3), 6.22 (d, J=9.2Hz, 1H, COCH=C), 6.85 (d, 1H, J=8.4Hz, Ar-H), 7.26 (d, 1H, J=8.4Hz, Ar-H), 7.92 (d, J=9.2,1H, C=CH), 10.38 (s, 1H, Ar-OH).
Embodiment 5
The preparation of 4- methyl -7-hydroxy-8-methoxycoumarin (II-ab)
Weigh 4- methyl -7, 8- dihydroxycoumarin 500mg are in there-necked flask, argon protection is lower to add N, dinethylformamide 5mL dissolves substrate, bath on the rocks, the temperature of reaction system is made to drop to less than -10 DEG C, add potassium hydroxide 380mg, after reaction 20min, it is added dropwise over 280 μ L of iodomethane, the temperature of reaction system is maintained at -10～0 DEG C or so, TLC monitors reaction process, after 0.5h, reaction terminates, reactant liquor is added drop-wise in 100mL frozen water, salt adding acid for adjusting pH is about 3, ethyl acetate extracts (50mL × 3), combined ethyl acetate phase, saturated common salt is washed twice, organic faciess vacuum distillation removes ethyl acetate, as crude product, crude product Jing silica gel post separations, mobile phase is VPetroleum ether：VDichloromethane：VAcetone=2:1:0.15, vacuum distillation removes solvent, and vacuum drying obtains white solid 326mg, its1H NMR are as shown in Figure 6.
1H NMR(400MHz,DMSO-d6)δ:2.36(s,3H,CH3),3.82(s,3H,OCH3), 6.16 (s, 1H, COCH=C), 6.88 (d, J=8,1H, Ar-H), 7.35 (d, J=8,1H, Ar-H), 10.33 (s, 1H, OH).
Embodiment 6
The preparation of 4- phenyl-7-hydroxyl -8- methoxy coumarins (II-ac)
Weigh 4- phenyl -7; 8- dihydroxycoumarin 500mg are in there-necked flask; argon protection is lower to add N; dinethylformamide 5mL dissolves substrate, and bath on the rocks makes the temperature of reaction system drop to 0 DEG C; add sodium hydroxide 240mg; after reaction 25min, 250 μ L of iodomethane are added dropwise over, the thermotonuses of reaction system are maintained at 0～10 DEG C; TLC monitors reaction process; after 0.5h, reaction terminates, and reactant liquor is added drop-wise in 100mL frozen water, and salt adding acid for adjusting pH is about 3; there is Precipitation; filter after 30min, collect filter cake, as crude product.Crude product Jing silica gel post separations, mobile phase is VPetroleum ether：VEthyl acetate：VMethanol=4:1:0.1, vacuum distillation removes organic solvent, obtains white yellowish needle-like solid 280mg, its1H NMR are as shown in Figure 7.
1H NMR(500MHz,DMSO-d6)δ:3.87(s,3H,OCH3), 6.18 (s, 1H, COCH=C), 6.86 (d, J=9Hz, 1H, Ar-H), 7.02 (d, J=9Hz, 1H, Ar-H), 7.50-7.57 (m, 5H, Ar-H), 10.49 (s, br, 1H, Ar-OH).
Claims (8)
1. a kind of chemo-selective monomethylation method of coumarin catechol, it is characterised in that
Pyrocatechol coumarin compound is added under the organic reaction system of appropriate base catalyst, with the examination that methylates
There is high selectivity methylation reaction in agent, and then obtain monomethylation product, the alkali and pyrocatechol coumarin
Compound and mol ratio be：1.0～5.0：1；The methylating reagent and pyrocatechol coumarin compound
With mol ratio be：1.0～2.0：1, the temperature of reaction system is -20～10 DEG C；Response time is 0.5～3
Hour；
The pyrocatechol coumarin compound structure is：
Wherein R is H, (C1-C6) alkyl, (C1-C6) alkoxyl, aryl, (C1-C6) replace alkyl in appoint
Meaning is a kind of；
The monomethylation product structure formula is：
Wherein R is H, (C1-C6) alkyl, (C1-C6) alkoxyl, (C1-C6) replace alkyl, appointing in aryl
Meaning is a kind of.
2. a kind of chemo-selective monomethylation of coumarin catechol as claimed in claim 1
Method, it is characterised in that：The methylating reagent is iodomethane, methanol, dimethyl sulfate, fluoroform sulphur
Any one or more combination in sour methyl ester or methyl mesylate.
3. a kind of chemo-selective monomethylation of coumarin catechol as claimed in claim 1
Method, it is characterised in that：During the base catalyst is sodium hydroxide, potassium hydroxide, sodium hydride or hydrofining
Any one or more combination.
4. a kind of chemo-selective monomethylation of coumarin catechol as claimed in claim 1
Method, it is characterised in that：The organic reaction system is polar aprotic solvent, selected from N, N- dimethyl
One or more in Methanamide, tetrahydrofuran, acetonitrile or dimethyl sulfoxide.
5. a kind of chemo-selective monomethylation of coumarin catechol as claimed in claim 1
Method, it is characterised in that：Alkali and pyrocatechol coumarin compound and mol ratio preferably 2.5：1.
6. a kind of chemo-selective monomethylation of coumarin catechol as claimed in claim 1
Method, it is characterised in that：Methylating reagent and pyrocatechol coumarin compound and mol ratio be preferably 1.1：
1。
7. a kind of chemo-selective monomethylation of coumarin catechol as claimed in claim 1
Method, it is characterised in that the reaction temperature is preferably -5～5 DEG C.
8. a kind of chemo-selective monomethylation of coumarin catechol as claimed in claim 1
Method, it is characterised in that the response time is preferably 0.5～1 hour.
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| CN102702155A (en) * | 2012-06-15 | 2012-10-03 | 南京中医药大学 | Scutellarin aglycone methylate product based on in-vivo metabolic mechanism as well as preparation method and application of scutellarin aglycone methylate product |
| WO2012174488A2 (en) * | 2011-06-15 | 2012-12-20 | Nono, Inc. | Agents and methods for treating ischemic and other diseases |
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| CN102702155A (en) * | 2012-06-15 | 2012-10-03 | 南京中医药大学 | Scutellarin aglycone methylate product based on in-vivo metabolic mechanism as well as preparation method and application of scutellarin aglycone methylate product |
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