CN115286608B - Benzopyran compound and preparation method thereof - Google Patents
Benzopyran compound and preparation method thereof Download PDFInfo
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- CN115286608B CN115286608B CN202210881947.2A CN202210881947A CN115286608B CN 115286608 B CN115286608 B CN 115286608B CN 202210881947 A CN202210881947 A CN 202210881947A CN 115286608 B CN115286608 B CN 115286608B
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- benzopyran
- compound
- unsaturated carbonyl
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- naphthol
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- -1 Benzopyran compound Chemical class 0.000 title claims description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 150000001562 benzopyrans Chemical class 0.000 claims abstract description 23
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 9
- 150000001728 carbonyl compounds Chemical class 0.000 claims description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 17
- 239000003054 catalyst Substances 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 4
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- QJQYPZZUKLQGGT-UHFFFAOYSA-N methyl hypobromite Chemical compound COBr QJQYPZZUKLQGGT-UHFFFAOYSA-N 0.000 claims description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 239000000758 substrate Substances 0.000 abstract description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 3
- 229930014626 natural product Natural products 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000007363 ring formation reaction Methods 0.000 abstract description 3
- 238000006845 Michael addition reaction Methods 0.000 abstract description 2
- 238000010523 cascade reaction Methods 0.000 abstract description 2
- 150000004780 naphthols Chemical class 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 6
- 238000004817 gas chromatography Methods 0.000 description 6
- 229940094933 n-dodecane Drugs 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 3
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 3
- 229940035437 1,3-propanediol Drugs 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 3
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- WMIQCCDZARURRI-UHFFFAOYSA-N 1,1-dichloroethane Chemical compound CC(Cl)Cl.CC(Cl)Cl WMIQCCDZARURRI-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 150000001241 acetals Chemical group 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000002214 flavonoid derivatives Chemical class 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical group COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 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
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention belongs to the technical field of natural product synthesis, and particularly relates to benzopyran compounds and a preparation method thereof. The invention uses alpha, beta-unsaturated carbonyl and naphthol derivatives as reaction substrates, and converts raw materials into benzopyran compounds through oxa-Michael addition and cyclization tandem reaction under the action of potassium carbonate; the preparation method provided by the invention is simple to operate, mild in reaction condition, high in synthesis speed, high in preparation efficiency and high in yield, and provides an efficient and rapid method for synthesizing benzopyran compounds.
Description
Technical Field
The invention belongs to the technical field of natural product synthesis, and relates to benzopyran compounds and a preparation method thereof.
Background
Benzopyrans are compounds consisting of a benzene ring and an oxygen heteroatom six-membered ring, also known as chroman. Substituted chroman building blocks are widely found in a variety of natural products with biological activity, such as vitamin E, a variety of coumarin and flavonoid derivatives. In particular, the synthesized benzopyran and its derivatives have very abundant physiological activities. Therefore, efficient synthesis of benzopyran backbones has been of interest to synthetic chemists. The invention synthesizes benzopyran compound by using cheap and easily purchased potassium carbonate as a catalyst and naphthol and unsaturated ketone as substrates, and obtains good yield. Relates to a technology for constructing benzopyran and derivatives thereof.
Currently, the primary route to benzopyrans is to catalyze the reaction of phenols with olefins by lewis acids. Wherein the first is the reaction of phenol with a conjugated diene; the second type is the reaction of phenol with allyl alcohol or allyl esters and the like. In the above reaction scheme, an acid catalyst is mostly used. However, in drug molecules there are often active groups such as hydroxyl or amino groups, which need to be protected during the synthesis, whereas most protecting groups such as acetals, methoxymethyl ethers, t-butoxycarbonyl groups, etc. are acid sensitive, resulting in that the acid catalyzed method of constructing benzopyrans cannot be used for the synthesis of acid sensitive drug molecules.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a benzopyran compound and a preparation method thereof.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
in a first aspect, the present invention provides a benzopyran compound having the following structural general formula:
wherein R is 1 Selected from any one of methyl, cyclopropane, benzene ring, methoxy and benzene ring containing substituent.
Preferably, the substituent in the benzene ring containing the substituent is selected from any one of methoxy, bromine, chlorine and methyl.
In a second aspect, the present invention provides a method for preparing a benzopyran compound according to the first aspect, comprising the steps of:
under the protection of inert gas and the action of an alkaline catalyst, the alpha, beta-unsaturated carbonyl compound and naphthol react in a solvent to obtain the benzopyran compound.
Conventional processes typically require acidic catalysts to build up chroman structures. According to the invention, an alkaline catalyst is adopted, alpha, beta-unsaturated carbonyl compounds and naphthol are used as reaction substrates, and undergo the processes of oxaMichael addition and cyclization tandem connection to synthesize benzopyran compounds, so that the influence of an acid catalyst on acid sensitive groups in the reaction substrates is avoided; the invention can obtain the target product under the mild alkaline condition, and the carbonyl at the molecular tail end of the product can be further subjected to structural modification.
Preferably, the basic catalyst comprises at least one of potassium carbonate, 1, 8-diazabicyclo undec-7-ene, cesium fluoride, potassium phosphate, potassium tert-butoxide, and cesium carbonate.
Further preferably, the basic catalyst is potassium carbonate.
The invention selects potassium carbonate as catalyst, has low price and easy-to-purchase chemical raw materials, and has low price compared with noble metal catalyst used in the traditional method.
Preferably, the structural formula of the α, β -unsaturated carbonyl compound is as follows:
wherein R is 2 Any one selected from methyl, cyclopropane, benzene ring, methoxy and benzene ring containing substituent; r is R 3 Any one selected from tertiary butyl diphenyl siloxy, benzyloxy, acetoxy and dimethyl tertiary butyl silyl ether.
The inventors have found that, when the protecting group R 3 When the compound is either dimethyl tertiary butyl silyl ether or acetoxy, the yield of benzopyran compounds is high.
Preferably, the solvent includes at least one of N, N-dimethylamide, dimethylsulfoxide, tetrahydrofuran, methanol, 1, 4-dioxane, toluene, dichloroethane and ethyl acetate.
Further preferably, the solvent is at least one of methanol and N, N-dimethylamide.
The inventor finds that the type of the solvent has an important influence on the yield of the benzopyran compound, and the yield of the benzopyran compound is higher when methanol or N, N-dimethylamide is used as the solvent.
Preferably, the ratio of the total mole of the alpha, beta-unsaturated carbonyl compound and naphthol to the volume of the solvent is 1 (2-4) mmol/mL.
Preferably, the ratio of the total mole of the α, β -unsaturated carbonyl compound and naphthol to the mole of the basic catalyst is (1-2): 1.
Preferably, the molar ratio of the alpha, beta-unsaturated carbonyl compound to the naphthol is 1 (1-2).
Preferably, the inert gas includes at least one of nitrogen and argon.
Preferably, the temperature of the reaction is 60-100 ℃ and the time is 8-10 h.
In the invention, the alpha, beta-unsaturated carbonyl compound and naphthol react in the solvent under the action of the alkaline catalyst, the reaction condition is mild, the synthesis speed is high, and the preparation efficiency is high.
Preferably, the preparation method of the benzopyran compound specifically comprises the following steps: mixing alpha, beta-unsaturated carbonyl compound, naphthol and alkaline catalyst, adding solvent under nitrogen protection, stirring to react, diluting, washing, drying, concentrating and purifying to obtain benzopyran compound.
It is to be understood that the method of dilution, washing, drying, concentration, purification is not particularly limited. Optionally, the method for diluting, washing, drying, concentrating and purifying specifically comprises the following steps: adding ethyl acetate to dilute the reaction system, washing with saturated brine for 2-3 times, combining organic phases, drying, concentrating under reduced pressure, and purifying to obtain benzopyran compounds.
Compared with the prior art, the invention has the beneficial effects that:
the invention uses alpha, beta-unsaturated carbonyl and naphthol derivatives as reaction substrates, and converts raw materials into benzopyran compounds through oxa-Michael addition/cyclization tandem reaction under the action of potassium carbonate; the preparation method provided by the invention is simple to operate, mild in reaction condition, high in synthesis speed, high in preparation efficiency and high in yield, and provides an efficient and rapid method for synthesizing benzopyran compounds.
Detailed Description
For a better description of the objects, technical solutions and advantages of the present invention, the present invention will be further described with reference to the following specific examples. It will be appreciated by persons skilled in the art that the specific embodiments described herein are for purposes of illustration only and are not intended to be limiting.
The reagents, methods and apparatus employed in the present invention, unless otherwise specified, are all conventional in the art.
Examples 1 to 8
Benzopyran compound has the following structural formula:
a preparation method of benzopyran compounds comprises the following steps:
(1) Synthesis of alpha, beta-unsaturated carbonyl compounds
The synthetic route is as follows:
dissolving 26mmol of 1, 3-propanediol in 100mL of Tetrahydrofuran (THF) to obtain a tetrahydrofuran solution containing 1, 3-propanediol, adding NaH (26.5mmol,60%in mineral oil) into the tetrahydrofuran solution containing 1, 3-propanediol under the protection of nitrogen, stirring for 40 minutes at room temperature, adding 26mmol of tert-butyldimethylsilyl chloride (TBSCl) into the system, dropwise adding saturated sodium bicarbonate solution into the system for quenching after TLC monitoring reaction is complete, extracting with ethyl acetate, washing with saturated sodium chloride, merging organic phases, drying, concentrating under reduced pressure, and purifying to obtain a compound shown as a formula I;
2mmol of a compound shown in a formula I is dissolved in 10mL of dichloromethane to obtain a dichloromethane solution containing the compound shown in the formula I; 2.4mmol of pyridinium chlorochromate (PCC) and 1g of kieselguhr are added into a dichloromethane solution containing the compound shown in the formula I under the protection of nitrogen, the mixture is stirred at room temperature for 3 hours, after the reaction is monitored by TLC, saturated sodium bicarbonate solution is added dropwise into the system for quenching, diethyl ether extraction and washing are carried out, and the compound shown in the formula II is obtained after the organic phases are combined, dried, concentrated under reduced pressure and purified.
2mmol of a compound shown in a formula II is dissolved in 10mL of dichloromethane to obtain a dichloromethane solution containing the compound shown in the formula II; under the protection of nitrogen, the temperature is controlled at 0 ℃, 2.08mmol of the compound shown in the formula III is added into a dichloromethane solution containing the compound shown in the formula II, the reaction is carried out for 24 hours at room temperature, no other post-treatment is needed after the TLC monitoring reaction is completed, the vacuum concentration is directly carried out, and the crude product is purified through column chromatography, so that the alpha, beta-unsaturated carbonyl compound is obtained, and the structural formula of the alpha, beta-unsaturated carbonyl compound is shown in the formula IV.
(2) A reaction tube having a capacity of 15mL was charged with 0.2mmol of the α, β -unsaturated carbonyl compound prepared in step (1), 0.3mmol of naphthol and 0.4mmol of 1, 8-diazabicyclo undec-7-ene (DBU), 1.5mL of the solvent shown in Table 1 was added to the reaction tube under nitrogen protection, stirred at 80℃for 10 hours, and TLC monitoring gave V PE :V EA The reaction was completed by 8:1, the reaction system was diluted with 2mL of ethyl acetate, washed 2 times with saturated brine, and the organic phases were combined, dried, concentrated under reduced pressure, and purified by column chromatography (PE: ea=15:1) to give benzopyran-based compounds.
The yields of benzopyrans were measured by gas chromatography using n-dodecane as an internal standard, and the measurement results are shown in Table 1.
TABLE 1
| Examples | Solvent(s) | Yield (%) |
| 1 | Dimethyl sulfoxide | 17 |
| 2 | Tetrahydrofuran (THF) | 26 |
| 3 | Methanol | 37 |
| 4 | N, N-dimethylformamide | 41 |
| 5 | 1, 4-Dioxahexacyclic ring | 32 |
| 6 | Toluene (toluene) | 31 |
| 7 | Dichloroethane (dichloroethane) | 28 |
| 8 | Acetic acid ethyl ester | 20 |
As can be seen from Table 1, in the present invention, the yields of benzopyran compounds in examples 3 and 4 were 37% and 41% respectively, which are significantly higher than those in other examples, using methanol and N, N-dimethylformamide as solvents, respectively.
Examples 9 to 13
Examples 9 to 13 respectively provide benzopyran compounds having the following structural formula:
the preparation process differs from example 1 in that the basic catalysts used in examples 9 to 14 are shown in Table 2. The yields of benzopyrans were measured by gas chromatography using n-dodecane as an internal standard, and the measurement results are shown in Table 2.
TABLE 2
As can be seen from Table 2, in example 9 of the present invention, the yield of benzopyran compound was 91% as a basic catalyst, which is much higher than that of other examples.
Examples 14 to 16
Examples 14 to 16 respectively provide benzopyran compounds having the following structural formula:
the preparation method comprises the following steps:
(1) Taking 0.2mmol of alpha, beta-unsaturated carbonyl compound, the structural formula of the alpha, beta-unsaturated carbonyl compound is as follows:
wherein R is 2 Is methyl, R 3 As shown in table 3;
(2) To a reaction tube having a capacity of 15mL, 0.2mmol of the α, β -unsaturated carbonyl compound of step (1), 0.3mmol of naphthol and 0.4mmol of 1, 8-diazabicyclo undec-7-ene (DBU) were added, 1.5mL of toluene was added to the reaction tube under nitrogen protection, stirring was performed at 80℃for 10 hours, and as a result of TLC monitoring, VPE: VEA=8:1 was obtained, the reaction was completed, the reaction system was diluted with 2mL of ethyl acetate, washed with saturated brine, and the organic phases were combined, dried, concentrated under reduced pressure, and purified to obtain benzopyran compounds.
The yields of benzopyrans were measured by gas chromatography using n-dodecane as an internal standard, and the measurement results are shown in Table 3.
TABLE 3 Table 3
As can be seen from Table 3, the yields of benzopyrans of example 16 and example 6 of the present invention were 30% and 31% respectively, which are far higher than those of other examples, using acetoxy group and dimethyl t-butyl silyl ether as protecting groups, respectively.
Example 17
The embodiment provides a benzopyran compound, which has the following structural formula:
the preparation method comprises the following steps:
(1) Taking 0.2mmol of alpha, beta-unsaturated carbonyl compound, the structural formula of the alpha, beta-unsaturated carbonyl compound is as follows:
wherein R is 2 Is cyclopropane group, R 3 Is dimethyl tertiary butyl silyl ether;
(2) In a 15mL reaction tube, 0.2mmol of the α, β -unsaturated carbonyl compound of step (1), 0.3mmol of naphthol and 0.4mmol of potassium carbonate were added, and 1.5mL of N, N-dimethylformamide was added to the reaction tube under the protection of nitrogen gas, at 8Stirring at 0deg.C for 10h, and TLC monitoring to obtain V PE :V EA The reaction was completed, the reaction system was diluted with 2mL of ethyl acetate, washed with saturated brine, and the organic phases were combined, dried, concentrated under reduced pressure, and purified to give benzopyran-based compounds.
Example 18
The embodiment provides a benzopyran compound, which has the following structural formula:
the preparation method is different from example 17 in that the structural formula of the α, β -unsaturated carbonyl compound used in this example is as follows:
wherein R is 2 Is a benzene ring, R 3 Is dimethyl tertiary butyl silyl ether.
Example 19
The embodiment provides a benzopyran compound, which has the following structural formula:
the preparation method is different from example 17 in that the structural formula of the α, β -unsaturated carbonyl compound used in this example is as follows:
example 20
The embodiment provides a benzopyran compound, which has the following structural formula:
the preparation method is different from example 17 in that the structural formula of the α, β -unsaturated carbonyl compound used in this example is as follows:
example 21
The embodiment provides a benzopyran compound, which has the following structural formula:
the preparation method is different from example 17 in that the structural formula of the α, β -unsaturated carbonyl compound used in this example is as follows:
example 22
The embodiment provides a benzopyran compound, which has the following structural formula:
the preparation method is different from example 17 in that the structural formula of the α, β -unsaturated carbonyl compound used in this example is as follows:
example 23
The embodiment provides a benzopyran compound, which has the following structural formula:
the preparation method is different from example 17 in that the structural formula of the α, β -unsaturated carbonyl compound used in this example is as follows:
example 24
The embodiment provides a benzopyran compound, which has the following structural formula:
the preparation method is different from example 17 in that the structural formula of the α, β -unsaturated carbonyl compound used in this example is as follows:
example 25
The embodiment provides a benzopyran compound, which has the following structural formula:
the preparation method is different from example 17 in that the structural formula of the α, β -unsaturated carbonyl compound used in this example is as follows:
the yields of the benzopyrans obtained in examples 19 to 27 were measured by gas chromatography using n-dodecane as an internal standard, and the measurement results are shown in Table 4.
TABLE 4 Table 4
Example 26
This example provides a benzopyran compound, which is prepared by a method different from example 9 in that in step (2) of this example, the amount of naphthol is 0.2mmol, the amount of dimethyl sulfoxide is 1.6mL, and the temperature of stirring is 100deg.C.
The yield of benzopyran compound was 77% by gas chromatography using n-dodecane as internal standard.
Example 27
The present example provides a benzopyran compound, which is different from example 9 in that in step (2) of the present example, the amount of naphthol is 0.4mmol, the amount of potassium carbonate is 0.3mmol, the amount of dimethyl sulfoxide is 1.2mL, and the stirring temperature is 60℃for 10 hours.
The yield of benzopyran compound was determined by gas chromatography using n-dodecane as internal standard, 86%.
Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted equally without departing from the spirit and scope of the technical solution of the present invention.
Claims (6)
1. The preparation method of the benzopyran compound is characterized in that the benzopyran compound has the following structural general formula:
；
the preparation method of the benzopyran compound comprises the following steps:
under the protection of inert gas and the action of alkaline catalyst, the catalyst is preparedα, β-reacting an unsaturated carbonyl compound with naphthol in a solvent to obtain a benzopyran compound;
the alkaline catalyst is at least one selected from potassium carbonate, 1, 8-diazabicyclo undec-7-ene, cesium fluoride, potassium phosphate and cesium carbonate;
the structural general formula of the alpha, beta-unsaturated carbonyl compound is as follows:
，R 1 any one selected from methyl, cyclopropane, benzene ring, methoxy and benzene ring containing substituent; r is R 3 Any one selected from tertiary butyl diphenyl siloxy, acetoxy and dimethyl tertiary butyl silyl ether; the substituent in the benzene ring containing the substituent is selected from any one of methoxy, bromine, chlorine and methyl.
2. The process for preparing benzopyrans according to claim 1, wherein R 3 Is any one of dimethyl tertiary butyl silyl ether and acetoxy.
3. The method for producing benzopyran-based compound according to claim 1, wherein said solvent is at least one selected from the group consisting of N, N-dimethylamide, dimethylsulfoxide, tetrahydrofuran, methanol, 1, 4-dioxane, toluene, dichloroethane and ethyl acetate.
4. The method for producing benzopyran-based compounds according to claim 1, wherein the molar ratio of α, β -unsaturated carbonyl compound to naphthol is 1 (2 to 4); the ratio of the total mole of the alpha, beta-unsaturated carbonyl compound and the naphthol to the volume of the solvent is 1 (1-2) mmol/mL; the ratio of the total mole of the alpha, beta-unsaturated carbonyl compound and the naphthol to the mole of the basic catalyst is (1-2): 1.
5. The method for preparing benzopyran compound according to claim 1, wherein the reaction temperature is 60-100 ℃ and the time is 8-10 h.
6. The method for producing benzopyran-based compound according to claim 1, wherein said inert gas comprises at least one of nitrogen and argon.
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| CN1824660A (en) * | 2005-02-21 | 2006-08-30 | 中国科学院化学研究所 | Benzopyran kind compound and its preparation method |
| CN106995428A (en) * | 2017-05-18 | 2017-08-01 | 绍兴文理学院 | A kind of synthetic method of 6H benzos [C] benzopyrans compounds |
| CN112079808A (en) * | 2020-09-14 | 2020-12-15 | 五邑大学 | Method for preparing benzopyran compound based on in-situ generated alkynyl-substituted p-methylenequinone |
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| CN1824660A (en) * | 2005-02-21 | 2006-08-30 | 中国科学院化学研究所 | Benzopyran kind compound and its preparation method |
| CN106995428A (en) * | 2017-05-18 | 2017-08-01 | 绍兴文理学院 | A kind of synthetic method of 6H benzos [C] benzopyrans compounds |
| CN112079808A (en) * | 2020-09-14 | 2020-12-15 | 五邑大学 | Method for preparing benzopyran compound based on in-situ generated alkynyl-substituted p-methylenequinone |
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| The Important Role of the Byproduct Triphenylphosphine Oxide in the Magnesium(II)-Catalyzed Enantioselective Reaction of Hemiacetals and Phosphorus Ylides;Linqing Wang, et al;Angew. Chem. Int. Ed.;第57卷(第29期);9088-9092 * |
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