CN117050090A - Dihydro-levoglucosone-pyrazole fused ring compound and preparation method thereof - Google Patents
Dihydro-levoglucosone-pyrazole fused ring compound and preparation method thereof Download PDFInfo
- Publication number
- CN117050090A CN117050090A CN202310813098.1A CN202310813098A CN117050090A CN 117050090 A CN117050090 A CN 117050090A CN 202310813098 A CN202310813098 A CN 202310813098A CN 117050090 A CN117050090 A CN 117050090A
- Authority
- CN
- China
- Prior art keywords
- dihydro
- fused ring
- levoglucosone
- ring compound
- pyrazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 66
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 239000002904 solvent Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 15
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims abstract description 13
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 238000010992 reflux Methods 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 150000002081 enamines Chemical class 0.000 claims description 12
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003208 petroleum Substances 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- WHIRALQRTSITMI-UJURSFKZSA-N (1s,5r)-6,8-dioxabicyclo[3.2.1]octan-4-one Chemical compound O1[C@@]2([H])OC[C@]1([H])CCC2=O WHIRALQRTSITMI-UJURSFKZSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000002028 Biomass Substances 0.000 abstract description 2
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical class BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 abstract description 2
- 230000003287 optical effect Effects 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 29
- 238000001228 spectrum Methods 0.000 description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 11
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 11
- 238000012512 characterization method Methods 0.000 description 10
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 2
- FOLCUFKJHSQMEL-BIXPGCQOSA-N (4-butylcyclohexyl) N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CCCCC1CCC(CC1)OC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@@H]2CCNC2=O)C=O FOLCUFKJHSQMEL-BIXPGCQOSA-N 0.000 description 2
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 2
- HSWVJQBEXRKOBZ-QGZVFWFLSA-N FC1=C(OC2CCN(CC2)C=2N=C3C(=NC=2N[C@H]2COCC2)CN(CC3)C(C)=O)C=CC(=C1)F Chemical compound FC1=C(OC2CCN(CC2)C=2N=C3C(=NC=2N[C@H]2COCC2)CN(CC3)C(C)=O)C=CC(=C1)F HSWVJQBEXRKOBZ-QGZVFWFLSA-N 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- COXVPYKZDDKVRF-ULQDDVLXSA-N (4,4-difluorocyclohexyl)methyl N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C[C@@H]1CCNC1=O)C=O)NC(=O)OCC2CCC(CC2)(F)F COXVPYKZDDKVRF-ULQDDVLXSA-N 0.000 description 1
- NYUKTFZVAKBIDK-UHFFFAOYSA-N 1h-pyrazole;1,3-thiazole Chemical group C=1C=NNC=1.C1=CSC=N1 NYUKTFZVAKBIDK-UHFFFAOYSA-N 0.000 description 1
- VNTCGXMLDSKOKN-OAHLLOKOSA-N 4-[4-[[(3r)-3-methyl-4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]methyl]-1h-pyrazol-5-yl]benzonitrile Chemical class C([C@H](N(CC1)C=2N=CC(=CC=2)C(F)(F)F)C)N1CC=1C=NNC=1C1=CC=C(C#N)C=C1 VNTCGXMLDSKOKN-OAHLLOKOSA-N 0.000 description 1
- DYXJGWLSYLPWMO-UHFFFAOYSA-N 6,8-dioxabicyclo[3.2.1]octane Chemical group C1CCC2COC1O2 DYXJGWLSYLPWMO-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 239000000877 Sex Attractant Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- -1 biaryl compound Chemical class 0.000 description 1
- 150000005347 biaryls Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229940051021 yellow-fever virus Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a dihydro-levoglucosone-pyrazole fused ring compound and a preparation method thereof, the method adopts enaminoxirane, thiosemicarbazide and alpha-bromoketone to be placed in a 25ml round bottom flask according to the mol ratio of 1:1:1, then 0.2 mol equivalent of sodium dodecyl sulfate and solvent acetonitrile are added for heating reaction, and the target product is obtained through silica gel column chromatography purification, and the product is characterized by chiral novel xirane-pyrazole fused ring compound. According to the preparation method of the dihydro-levoglucosone-pyrazole fused ring compound, which is provided by the invention, the dihydro-levoglucosone serving as a biomass chemical is taken as a main raw material, the obtained fused ring product is an optical pure chiral molecule, and the chiral fused ring product with a diversity substituted structure can be rapidly obtained by changing the secondary structure of a bromoketone substrate, so that the synthesis operation is simple, the raw materials are cheap and easy to obtain, and the industrialization prospect is provided.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a dihydro-levoglucosone-pyrazole fused ring compound and a preparation method thereof.
Background
Among the biaryl structural molecules, many pharmaceutical molecules containing thiazole-pyrazole structural skeletons have various biological properties such as anti-inflammatory, antibacterial, antitubercular, antiviral, antidepressant, anticancer, antihypertensive and antipyretic properties. For example, anti-yellow fever virus active molecules, antifungal active molecules, diclofenac sodium-like analgesic molecules. The 6, 8-dioxa-bicyclo- [3.2.1] -octane structure contained in xirane is a potential Functional Carbohydrate Pharmacophore (FCP) and is widely found in natural products and drug molecules, such as the anticancer active natural product (+) atenol B, the insect sex pheromone multistrin, the calcium ion activated natural product pinnatixin a, and the like.
Therefore, how to realize the synthesis of fusing the 6, 8-dioxanone-bicyclo- [3.2.1] -octane structure in dihydro-levoglucosone to the biaryl compound, widens the path of synthesizing the heterocyclic compound with application value by enaminoxirane, is expected to obtain a novel pyrazole fused ring compound with chirality, and has important significance in developing a high-efficiency and economic synthesis method, particularly a synthesis method with a chiral center in a molecule.
Disclosure of Invention
The invention aims to solve the defects of the prior art and provides a dihydro-levoglucosone-pyrazole fused ring compound and a preparation method thereof:
in one aspect, the invention provides a method for preparing a dihydro-levoglucosone-pyrazole fused ring compound, which is used for preparing the dihydro-levoglucosone-pyrazole fused ring compound, and comprises the following steps:
dihydro-l-glucosone and N, N-dimethylformamide dimethyl acetal were prepared according to 1:1-1:2, adding a solvent toluene into a container according to the molar ratio, and carrying out reflux reaction in an oil bath pot to synthesize enamine dihydro-L-glucosone;
placing enamine dihydro-levoglucosone, thiosemicarbazide and alpha-bromoketone into another container according to the molar ratio of (1+/-0.05) to (1+/-0.05), adding sodium dodecyl sulfate and solvent acetonitrile, carrying out reflux reaction in an oil bath pot, and purifying by silica gel column chromatography after the reaction to obtain the dihydro-levoglucosone-pyrazole fused ring compound.
In some embodiments of the invention, the dihydro-l-glucosone and N, N-dimethylformamide dimethyl acetal are prepared according to 1:1-1:2 into a container; comprising the following steps:
the molar ratio of the dihydro-levoglucosenone to the N, N-dimethylformamide dimethyl acetal is 2:3.
in some embodiments of the invention, toluene is added as a solvent and the reflux reaction is performed in an oil bath; comprising the following steps:
the heating temperature of the oil bath pot is 90-110 ℃.
In some embodiments of the invention, the enamine dihydro-l-glucosone, thiosemicarbazide and alpha-bromoketone are placed in another container according to the molar ratio of (1+/-0.05): 1+/-0.05; comprising the following steps:
the molar ratio of enamine dihydro-L-glucosone, thiosemicarbazide and alpha-bromoketone is 1:1:1.
in some embodiments of the invention, sodium dodecyl sulfate and solvent acetonitrile are added, and reflux reaction is carried out in an oil bath; comprising the following steps:
the amount of sodium dodecyl sulfate added was 0.2 molar equivalents and the amount of solvent acetonitrile added was 2-3m l.
In some embodiments of the invention, sodium dodecyl sulfate and solvent acetonitrile are added, and reflux reaction is carried out in an oil bath; further comprises:
the reflux reaction time is 2.5-3.5h.
In some embodiments of the invention, the dihydro-levoglucosone-pyrazole fused ring compound is obtained after the reaction and purified by silica gel column chromatography; comprising the following steps:
after the reaction is completed, cooling to room temperature, decompressing and removing the solvent, purifying the obtained residue by column chromatography, and purifying by silica gel column chromatography by taking mixed petroleum ether and ethyl acetate as mobile phases to obtain the dihydro-levoglucosone-pyrazole fused ring compound.
In some embodiments of the invention, the mixing ratio of petroleum ether to ethyl acetate is 8:1 by volume.
Another object of the present invention is to provide a dihydro-levoglucosone-pyrazole fused ring compound having the structural formula of any one of formulae one to ten:
in some alternative embodiments of the invention, any of formulas one through ten is an optically pure chiral molecule.
The beneficial effects of the invention are as follows: the novel enaminone enaminoxini, thiosemicarbazide and alpha-bromoketone are adopted as initial raw materials, and a simple heating mode is adopted, so that the dihydro-levoglucosone-pyrazole condensed ring compound is synthesized through one-step series reaction; the method is suitable for synthesizing dihydro-levoglucosone-pyrazole condensed ring compounds containing different substituted structures, the operation is that alpha-bromoketone containing different substituted structures is adopted to react in the presence of sodium dodecyl sulfate, the raw materials are simple and easy to obtain, the method is simple and convenient to operate, and the pyrazole derivative with chiral polycyclic structure can be synthesized in one step through simple reaction, thus having important guiding function on discovering derivative compounds, medicaments and chiral reagents based on the heterocyclic skeleton. In addition, the biomass chemical dihydro-levoglucosone is taken as a main raw material, and the obtained condensed ring product is an optical pure chiral molecule; in addition, the chiral fused heterocyclic product with various substituted structures can be rapidly obtained by changing the secondary structure of the bromoketone substrate; in addition, the invention has simple synthesis operation, low-cost and easily obtained raw materials and industrialization prospect.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
FIG. 1 is a hydrogen nuclear magnetic resonance spectrum of a compound 3 of the invention;
FIG. 2 is a chart of the nuclear magnetic resonance carbon spectrum of the compound 3 of the invention;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of the compound 6a of the present invention;
FIG. 4 is a chart of the nuclear magnetic resonance carbon spectrum of the compound 6a of the invention;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of the compound 6b of the present invention;
FIG. 6 is a chart of a nuclear magnetic resonance carbon spectrum of the compound 6b of the present invention;
FIG. 7 is a hydrogen nuclear magnetic resonance spectrum of compound 6c of the present invention;
FIG. 8 is a nuclear magnetic resonance carbon spectrum of the compound 6c of the present invention;
FIG. 9 is a 6d NMR hydrogen spectrum of the compound of the present invention;
FIG. 10 is a chart of 6d NMR of a compound of the present invention;
FIG. 11 is a 6d NMR fluorine spectrum of the compound of the invention;
FIG. 12 is a nuclear magnetic resonance hydrogen spectrum of compound 6e of the present invention;
FIG. 13 is a nuclear magnetic resonance carbon spectrum of compound 6e of the present invention;
FIG. 14 is a 6f NMR hydrogen spectrum of the compound of the present invention;
FIG. 15 is a chart of 6f NMR of the compound of the present invention;
FIG. 16 is a hydrogen nuclear magnetic resonance spectrum of 6g of a compound of the present invention;
FIG. 17 is a chart of 6g NMR spectra of a compound of the invention;
FIG. 18 is a 6h NMR hydrogen spectrum of a compound of the invention;
FIG. 19 is a 6h NMR chart of a compound of the invention;
FIG. 20 is a nuclear magnetic resonance hydrogen spectrum of compound 6i of the present invention;
FIG. 21 is a nuclear magnetic resonance carbon spectrum of compound 6i of the present invention;
FIG. 22 is a hydrogen nuclear magnetic resonance spectrum of compound 6j of the present invention;
FIG. 23 is a chart of a 6j NMR chart of a compound of the invention;
FIG. 24 is a single crystal structure of Compound 6a of the present invention.
The invention will be further described in the following detailed description in conjunction with the above-described figures.
Detailed Description
In order that the invention may be readily understood, a more complete description of the invention will be rendered by reference to the appended drawings. Several embodiments of the invention are presented in the figures. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
The invention provides a preparation method of a dihydro-levoglucosone-pyrazole fused ring compound, which comprises the steps of S01 and S02, wherein:
step S01: dihydro-l-glucosone and N, N-dimethylformamide dimethyl acetal were prepared according to 1:1-1:2, adding a solvent toluene into a container according to the molar ratio, and carrying out reflux reaction in an oil bath pot to synthesize enamine dihydro-L-glucosone;
in some alternative embodiments of the invention, the molar ratio of the dihydrol-glucosone to the N, N-dimethylformamide dimethyl acetal may be 1:1. 2:3. 1:2, etc., preferably 2:3.
in some alternative embodiments of the invention, the amount of toluene added is dependent on the amount of dihydrol-glucosone and N, N-dimethylformamide dimethyl acetal added, while the heating temperature of the oil bath is 90-110 ℃; illustratively, the heating temperature of the oil bath in step S01 may be 90 ℃, 100 ℃, 110 ℃, preferably 100 ℃.
By way of example, and not limitation, such as: dihydrol-glucose ketone 1 (2.0 mmol), N, N-dimethylformamide dimethyl acetal 2 (3.0 mmol) were placed in a 1:1.5 molar ratio in a 50mL round bottom flask, toluene (3 mL) was added as a solvent, and the mixture was refluxed in an oil bath at 100℃for 4 hours, and petroleum ether (50 mL) was added before cooling to room temperature after the completion of the reaction. The precipitate was filtered and washed with petroleum ether to give pure product 3. The specific reaction formula is as follows:
the yield of enamine dihydro-l-glucosone was 89%. The structure of the compound is characterized as follows: yellow solid with a melting point of 168-170 ℃; 1 H NMR(400MHz,CDCl 3 )δ7.53(s,1H),5.17(s,1H),4.77(t,J＝5.4Hz,1H),3.90(t,J＝6.0Hz,1H),3.78(d,J＝7.0Hz,1H),3.25(dd,J＝14.6,5.1Hz,1H),3.11(s,6H),2.63(d,J＝14.4Hz,1H)； 13 CNMR(100MHz,CDCl 3 )δ188.5,151.9,101.3,93.9,72.3,68.1,43.0,30.9；HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 9 H 14 NO 3 + 184.0968；Found 184.0975。
step S02: placing enamine dihydro-levoglucosone, thiosemicarbazide and alpha-bromoketone into another container according to the molar ratio of (1+/-0.05) to (1+/-0.05), adding sodium dodecyl sulfate and solvent acetonitrile, carrying out reflux reaction in an oil bath pot, and purifying by silica gel column chromatography after the reaction to obtain the dihydro-levoglucosone-pyrazole fused ring compound.
In some alternative embodiments of the invention, the molar ratio of enamine dihydro-l-glucosone, thiosemicarbazide, a-bromoketone may be 1:0.95: 1. 0.95:1: 1. 1:1:0.95, preferably 1:1:1.
in some alternative embodiments of the present invention, the reflux reaction time in step S02 is 2.5-3.5 hours, and illustratively, the reflux reaction time may be 2.5 hours, 3 hours, or 3.5 hours, etc., after adding sodium dodecyl sulfate and solvent acetonitrile.
By way of example, and not limitation, such as: enaminoxirane 3 (0.3 mmol), thiosemicarbazide 4 (0.3 mmol), alpha-brominePolyketone 5 (0.3 mmol), sodium dodecyl sulfate (20 mol%) and acetonitrile (2 mL) were added to a 25mL round bottom flask, refluxed with heating in an oil bath and stirred for 3 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was purified by column chromatography to give a mixture of petroleum ether/ethyl acetate (V PE /V EA =8:1) as mobile phase by silica gel column chromatography to give the desired product 6. The product structure is confirmed to be correct through nuclear magnetic resonance, high-resolution mass spectrum, single crystal diffraction test of representative products and the like.
The reaction general formula is as follows:
the structural formula of the product dihydro-levoglucosone (xiraney) -pyrazole fused ring compound is any one of the formulas from one to ten:
the structures of the dihydro-levoglucosone-pyrazole fused ring compounds of the present invention are further illustrated in the following examples:
example 1
According to the preparation method of the dihydro-levoglucosone-pyrazole fused ring compound in the embodiment, the compound shown in the formula 6a is prepared.
Yield of this example71%. The structural characterization is as follows: white solid with a melting point of 176-178 ℃; 1 HNMR(400MHz,DMSO-d 6 )δ7.97(d,J＝7.2Hz,2H),7.90(s,1H),7.70(s,1H),7.48(t,J＝7.6Hz,2H),7.38(t,J＝7.3Hz,1H),7.08(s,1H),5.01–4.95(m,1H),4.02(t,J＝7.1Hz,1H),3.63(dd,J＝7.9,2.3Hz,1H),3.10(dd,J＝16.0,3.3Hz,1H),2.59(d,J＝16.2Hz,1H)； 13 C NMR(100MHz,DMSO-d 6 )δ160.8,151.8,141.5,139.3,133.9,129.3,128.8,126.3,115.7,111.0,94.5,72.1,68.0,27.9；HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 16 H 14 N 3 O 2 S + 312.0801；Found 312.0817。
example 2
In this example, according to the preparation method of the dihydro-levoglucosone-pyrazole fused ring compound, a compound shown in formula 6b is prepared.
The yield of this example was 73%. The structural characterization is as follows: white solid with a melting point of 136-138 ℃; 1 HNMR(400MHz,CDCl 3 )δ7.76(d,J＝7.7Hz,2H),7.47(s,1H),7.24–7.17(m,3H),7.15(s,1H),4.98–4.87(m,1H),4.12(t,J＝7.2Hz,1H),3.69(dd,J＝7.8,2.5Hz,1H),3.23(dd,J＝15.9,4.0Hz,1H),2.49(d,J＝16.0Hz,1H),2.37(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ152.8,140.2,139.0,138.2,131.2,129.4,126.0,114.5,107.8,95.1,72.1,68.0,28.2,21.3；HRMS(ESI-TOF)m/z:[M+H] + Calcd forC 17 H 16 N 3 O 2 S + 326.0958；Found326.0966.
example 3
In this example, according to the preparation method of the dihydro-levoglucosone-pyrazole fused ring compound, a compound shown in formula 6c is prepared.
The product of this exampleThe rate was 75%. The structural characterization is as follows: white solid with a melting point of 156-158 ℃; 1 HNMR(400MHz,CDCl 3 )δ7.81(dt,J＝8.7,3.3Hz,2H),7.47(s,1H),7.21(s,1H),7.08(s,1H),6.96–6.93(m,2H),4.96–4.89(m,1H),4.13(t,J＝7.4Hz,1H),3.84(s,3H),3.70(dd,J＝7.7,2.3Hz,1H),3.24(dd,J＝15.9,3.7Hz,1H),2.50(d,J＝16.0Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ159.8,152.5,140.2,139.0,127.4,125.4,114.4,114.1,106.8,95.1,72.1,68.0,55.4,28.2；HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 17 H 16 N 3 O 3 S + 342.0907；Found 342.0906.
example 4
In this example, according to the preparation method of the dihydro-levoglucosone-pyrazole fused ring compound, a compound shown in formula 6d is prepared.
The yield of this example was 70%. The structural characterization is as follows: white solid with melting point of 120-122 ℃; 1 HNMR(400MHz,CDCl 3 )δ7.89–7.81(m,2H),7.48(s,1H),7.18(s,1H),7.15(s,1H),7.14–7.07(m,2H),4.98–4.90(m,1H),4.16–4.10(m,1H),3.70(dd,J＝7.8,2.3Hz,1H),3.24(ddd,J＝16.0,4.1,1.4Hz,1H),2.51(d,J＝16.0Hz,1H)； 13 CNMR(100MHz,CDCl 3 )δ161.0,151.7,140.3,139.0,130.1,127.8,127.8,115.8,115.6,114.6,108.2,95.0,72.1,68.0,28.2； 19 FNMR(376MHz,CDCl 3 )δ-113.3；HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 16 H 13 FN 3 O 2 S + 330.0707；Found 330.0705.
example 5
In this example, according to the preparation method of the dihydro-levoglucosone-pyrazole fused ring compound, a compound shown in formula 6e is prepared.
The yield of this example was 65%. The structural characterization is as follows: white solid with a melting point of 154-156 ℃; 1 HNMR(400MHz,CDCl 3 )δ7.84–7.78(m,2H),7.49(s,1H),7.42–7.35(m,2H),7.21(s,1H),7.18(s,1H),4.97–4.92(m,1H),4.18–4.10(m,1H),3.71(dd,J＝7.7,2.3Hz,1H),3.25(dd,J＝16.0,4.0Hz,1H),2.52(d,J＝16.0Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ151.6,140.4,139.0,134.1,132.3,129.0,127.3,114.7,109.0,95.0,72.1,68.1,28.2；HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 16 H 13 ClN 3 O 2 S + 346.0412；Found 346.0431.
example 6
In this example, according to the preparation method of the dihydro-levoglucosone-pyrazole fused ring compound, a compound shown in formula 6f is prepared.
The yield of this example was 75%. The structural characterization is as follows: white solid with melting point of 172-174 ℃; 1 HNMR(400MHz,CDCl 3 )δ7.75–7.68(m,2H),7.55–7.49(m,2H),7.47(s,1H),7.19(s,1H),7.15(s,1H),4.97–4.89(m,1H),4.12(t,J＝6.5Hz,1H),3.69(dd,J＝7.8,2.3Hz,1H),3.22(dd,J＝16.0,3.2Hz,1H),2.49(d,J＝16.0Hz,1H)； 13 CNMR(100MHz,CDCl 3 )δ161.0,151.5,140.4,139.0,132.7,131.9,127.5,122.3,114.7,109.1,94.9,72.1,68.0,28.2；HRMS(ESI-TOF)m/z:[M+H] + CalcdforC 16 H 13 BrN 3 O 2 S + 389.9906；Found389.9907.
example 7
In this example, according to the above-mentioned method for preparing a dihydro-levoglucosone-pyrazole fused ring compound, a compound represented by formula 6g was prepared.
The yield of this example was 47%. The structural characterization is as follows: brown liquid; 1 HNMR(400MHz,CDCl 3 )δ7.69(d,J＝8.2Hz,2H),7.48(s,1H),7.31(t,J＝7.5Hz,1H),7.23(s,1H),7.20(s,1H),7.16(d,J＝7.6Hz,1H),4.96–4.91(m,1H),4.16–4.10(m,1H),3.70(dd,J＝7.7,2.3Hz,1H),3.24(ddd,J＝15.9,4.1,1.4Hz,1H),2.51(d,J＝16.0Hz,1H),2.41(s,3H)； 13 C NMR(100MHz,CDCl 3 )δ152.9,140.2,139.0,138.3,133.8,129.2,128.7,126.6,123.3,114.5,108.5,95.1,72.2,68.0,28.2,21.6；HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 17 H 16 N 3 O 2 S + 326.0958；Found 326.0976.
example 8
According to the preparation method of the dihydro-levoglucosone-pyrazole fused ring compound in the embodiment, the compound shown in the formula 6h is prepared.
The yield of this example was 72%. The structural characterization is as follows: white solid with a melting point of 166-168 ℃; 1 HNMR(400MHz,CDCl 3 )δ7.47(d,J＝8.3Hz,2H),7.43(t,J＝2.1Hz,1H),7.34(t,J＝7.9Hz,1H),7.22(s,1H),7.20(s,1H),6.95–6.85(m,1H),4.97–4.89(m,1H),4.16–4.09(m,1H),3.87(s,3H),3.70(dd,J＝7.8,2.3Hz,1H),3.24(ddd,J＝16.0,4.2,1.5Hz,1H),2.51(d,J＝16.0Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ159.9,152.5,140.3,139.1,135.2,129.8,118.6,114.6,113.9,111.8,109.0,95.0,72.1,68.0,55.3,28.2；HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 17 H 16 N 3 O 3 S + 342.0907；Found342.0925.
example 9
According to the preparation method of the dihydro-levoglucosone-pyrazole fused ring compound in the embodiment, the compound shown in the formula 6i is prepared.
The yield of this example was 59%. The structural characterization is as follows: yellow solid with melting point of 150-152 ℃; 1 HNMR(400MHz,CDCl 3 )δ7.73–7.63(m,2H),7.43(t,3H),7.34(t,J＝7.4Hz,1H),7.14(s,1H),4.93–4.85(m,1H),4.08(t,J＝7.0Hz,1H),3.67(dd,J＝7.7,2.0Hz,1H),3.21(dd,J＝16.0,4.0Hz,1H),2.56(s,3H),2.48(d,J＝16.0Hz,1H)； 13 C NMR(100MHz,CDCl 3 )δ156.8,139.9,138.8,134.6,128.4,128.3,127.7,124.3,114.2,95.0,72.1,68.0,28.2,12.6；HRMS(ESI-TOF)m/z:[M+H] + Calcd for C 17 H 16 N 3 O 2 S + 326.0958；Found326.0978.
example 10
In this example, according to the method for preparing the dihydro-levoglucosone-pyrazole fused ring compound described above, a compound represented by formula 6j was prepared.
The yield of this example was 39%. The structural characterization is as follows: a red liquid; 1 H NMR(400MHz,CDCl 3 )δ7.42(s,1H),7.04(s,1H),4.94–4.86(m,1H),4.12–4.05(m,1H),3.67(dd,J＝7.7,2.3Hz,1H),3.21(ddd,J＝16.0,4.1,1.4Hz,1H),2.79–2.64(m,4H),2.47(d,J＝16.0Hz,1H),1.93–1.80(m,4H)； 13 C NMR(100MHz,CDCl 3 )δ157.8,147.9,139.6,138.6,125.1,113.9,94.9,72.1,67.9,28.2,26.8,23.2,23.2,22.8；HRMS(ESI-TOF)m/z:[M+H] + CalcdforC 14 H 16 N 3 O 2 S + 290.0958；Found 290.0964。
in the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiments or examples. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (10)
1. The dihydro-levoglucosone-pyrazole fused ring compound is characterized in that the structural formula of the dihydro-levoglucosone-pyrazole fused ring compound is any one of the formulas one to ten:
2. the dihydrol-glucosone-pyrazole fused ring compound according to claim 1, wherein any one of formulae one to ten is an optically pure chiral molecule.
3. A process for preparing a dihydro-levoglucosone-pyrazole fused ring compound according to any one of claims 1 to 2, characterized in that the process comprises:
dihydro-l-glucosone and N, N-dimethylformamide dimethyl acetal were prepared according to 1:1-1:2, adding a solvent toluene into a container according to the molar ratio, and carrying out reflux reaction in an oil bath pot to synthesize enamine dihydro-L-glucosone;
placing enamine dihydro-levoglucosone, thiosemicarbazide and alpha-bromoketone into another container according to the molar ratio of (1+/-0.05) to (1+/-0.05), adding sodium dodecyl sulfate and solvent acetonitrile, carrying out reflux reaction in an oil bath pot, and purifying by silica gel column chromatography after the reaction to obtain the dihydro-levoglucosone-pyrazole fused ring compound.
4. A process for the preparation of a dihydrol-glucosone-pyrazole fused ring compound according to claim 3, wherein the process comprises reacting dihydrol-glucosone with N, N-dimethylformamide dimethyl acetal according to 1:1-1:2 into a container; comprising the following steps:
the molar ratio of the dihydro-levoglucosenone to the N, N-dimethylformamide dimethyl acetal is 2:3.
5. the method for preparing a dihydro-l-glucosone-pyrazole fused ring compound according to claim 3, wherein toluene is added as a solvent, and reflux reaction is carried out in an oil bath; comprising the following steps:
the heating temperature of the oil bath pot is 90-110 ℃.
6. The method for preparing the dihydro-levoglucosone-pyrazole fused ring compound according to claim 3, wherein enamine dihydro-levoglucosone, thiosemicarbazide and alpha-bromoketone are placed in another container according to the molar ratio of (1+/-0.05): 1+/-0.05; comprising the following steps:
the molar ratio of enamine dihydro-L-glucosone, thiosemicarbazide and alpha-bromoketone is 1:1:1.
7. the method for preparing a dihydro-l-glucosone-pyrazole fused ring compound according to claim 3, wherein sodium dodecyl sulfate and acetonitrile solvent are added, and reflux reaction is carried out in an oil bath; comprising the following steps:
the amount of sodium dodecyl sulfate added was 0.2 molar equivalents and the amount of acetonitrile solvent added was 2-3ml.
8. The method for preparing a dihydro-l-glucosone-pyrazole fused ring compound according to claim 3, wherein sodium dodecyl sulfate and acetonitrile solvent are added, and reflux reaction is carried out in an oil bath; further comprises:
the reflux reaction time is 2.5-3.5h.
9. The method for preparing a dihydro-levoglucosone-pyrazole fused ring compound according to claim 3, wherein the dihydro-levoglucosone-pyrazole fused ring compound is obtained after the reaction and is purified by silica gel column chromatography; comprising the following steps:
after the reaction is completed, cooling to room temperature, decompressing and removing the solvent, purifying the obtained residue by column chromatography, and purifying by silica gel column chromatography by taking mixed petroleum ether and ethyl acetate as mobile phases to obtain the dihydro-levoglucosone-pyrazole fused ring compound.
10. The method for preparing a dihydro-levoglucosone-pyrazole fused ring compound according to claim 9, wherein the volume mixing ratio of petroleum ether and ethyl acetate is 8:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310813098.1A CN117050090A (en) | 2023-07-04 | 2023-07-04 | Dihydro-levoglucosone-pyrazole fused ring compound and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310813098.1A CN117050090A (en) | 2023-07-04 | 2023-07-04 | Dihydro-levoglucosone-pyrazole fused ring compound and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117050090A true CN117050090A (en) | 2023-11-14 |
Family
ID=88656149
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310813098.1A Pending CN117050090A (en) | 2023-07-04 | 2023-07-04 | Dihydro-levoglucosone-pyrazole fused ring compound and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117050090A (en) |
-
2023
- 2023-07-04 CN CN202310813098.1A patent/CN117050090A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109180653B (en) | Method for preparing benzofuran-pyrrole compound under catalysis of copper | |
| JPS6263587A (en) | Manufacture of spiro(indoline) type photochromic compound | |
| CN110240568B (en) | Trisubstituted pyridazine derivative and preparation method thereof | |
| CN111675662A (en) | Preparation method of 2-trifluoromethyl substituted quinazolinone compound | |
| CN111875612B (en) | Chromanone spliced pyrrole spiro-oxoindole skeleton and trifluoromethyl compound and preparation method and application thereof | |
| JP2020518661A5 (en) | ||
| JP2020518661A (en) | Benzimidazole compound and method for producing the same | |
| CN108503552A (en) | A kind of preparation method of trifluoromethyl aromatic amine | |
| CN110105285B (en) | Trisubstituted pyrazole derivative and preparation method thereof | |
| CN106866563B (en) | Method for preparing 2, 4-disubstituted-1, 3,5 triazine derivative | |
| CN115197261B (en) | Synthesis method of oxadiazine boron derivative | |
| CN117050090A (en) | Dihydro-levoglucosone-pyrazole fused ring compound and preparation method thereof | |
| CN111138419B (en) | 4-tetrazolyl substituted-benzoxazine derivative and synthesis method thereof | |
| CN112500419A (en) | Epoxy fused 2-methylene pyrrolidine compound and preparation method thereof | |
| CN111560022A (en) | Tetrahydrobenzofuran [3,2-d ] pyrimidine derivative and preparation method and application thereof | |
| CN111732552A (en) | Method for synthesizing 1, 3-oxazole-2-thioketone by palladium catalysis | |
| CN113461624B (en) | Preparation method of selective mono-deuterated marker of mono-1-substituted 1,2, 3-triazole | |
| CN113461700B (en) | Application of oxygen-promoted dearomatization reaction in construction of spiro-dienone skeleton | |
| CN109232424A (en) | 1- nitro -3- trinitro- methylpyrazole compound | |
| CN115286637B (en) | Triazabridged ring compounds, intermediate compounds thereof, preparation method and application | |
| CN109096225A (en) | It is the hydrocarbon activation halogenating reaction method of aryl for being oriented to base with 2,1,3- diazosulfide | |
| CN113200980B (en) | Method for synthesizing indolizine compound under catalysis of silver | |
| CN112125843B (en) | Preparation method of 3-hydroxymethyl-4-phenyl-3, 4-dihydroquinolinone compound | |
| KR102147971B1 (en) | Method for preparing chemoselective triazole derivatives through miscibility with reaction solvent | |
| CN114181182A (en) | Synthesis method of polysubstituted 4H-pyran compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |