CN113816993B - Synthesis method of beta-cyanophosphonate derivative - Google Patents
Synthesis method of beta-cyanophosphonate derivative Download PDFInfo
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- CN113816993B CN113816993B CN202110357640.8A CN202110357640A CN113816993B CN 113816993 B CN113816993 B CN 113816993B CN 202110357640 A CN202110357640 A CN 202110357640A CN 113816993 B CN113816993 B CN 113816993B
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- 239000003054 catalyst Substances 0.000 claims abstract description 19
- 239000002608 ionic liquid Substances 0.000 claims abstract description 19
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 238000010189 synthetic method Methods 0.000 claims abstract description 17
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 claims abstract description 14
- -1 ketene compound Chemical class 0.000 claims abstract description 13
- 230000035484 reaction time Effects 0.000 claims abstract description 12
- 150000008301 phosphite esters Chemical class 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 86
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 40
- 238000003756 stirring Methods 0.000 claims description 34
- 239000003208 petroleum Substances 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 15
- FTTATHOUSOIFOQ-UHFFFAOYSA-N 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine Chemical compound C1NCCN2CCCC21 FTTATHOUSOIFOQ-UHFFFAOYSA-N 0.000 claims description 13
- 239000003480 eluent Substances 0.000 claims description 13
- 238000004809 thin layer chromatography Methods 0.000 claims description 13
- 239000000376 reactant Substances 0.000 claims description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 238000001704 evaporation Methods 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- JLBFLZFFGYGZGN-UHFFFAOYSA-N 1,4-diazabicyclo[2.2.2]octane;hydrochloride Chemical compound Cl.C1CN2CCN1CC2 JLBFLZFFGYGZGN-UHFFFAOYSA-N 0.000 claims description 2
- WVGKARZQRBRAJO-UHFFFAOYSA-N acetic acid;1,4-diazabicyclo[2.2.2]octane Chemical group CC(O)=O.C1CN2CCN1CC2 WVGKARZQRBRAJO-UHFFFAOYSA-N 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims 1
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 abstract 1
- 150000003934 aromatic aldehydes Chemical class 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 239000012973 diazabicyclooctane Substances 0.000 abstract 1
- 125000000524 functional group Chemical group 0.000 abstract 1
- 125000004095 oxindolyl group Chemical class N1(C(CC2=CC=CC=C12)=O)* 0.000 abstract 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 42
- JLIDVCMBCGBIEY-UHFFFAOYSA-N 1-penten-3-one Chemical compound CCC(=O)C=C JLIDVCMBCGBIEY-UHFFFAOYSA-N 0.000 description 12
- PHENPABYBHPABM-UHFFFAOYSA-N acetic acid;octane Chemical compound CC(O)=O.CCCCCCCC PHENPABYBHPABM-UHFFFAOYSA-N 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000004679 31P NMR spectroscopy Methods 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 7
- 238000012544 monitoring process Methods 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- KXPRLNWTJHJCIX-UHFFFAOYSA-N 1,4-diazabicyclo[2.2.2]octane;sulfuric acid Chemical compound OS(O)(=O)=O.C1CN2CCN1CC2 KXPRLNWTJHJCIX-UHFFFAOYSA-N 0.000 description 1
- NDOPHXWIAZIXPR-UHFFFAOYSA-N 2-bromobenzaldehyde Chemical compound BrC1=CC=CC=C1C=O NDOPHXWIAZIXPR-UHFFFAOYSA-N 0.000 description 1
- ZWUSBSHBFFPRNE-UHFFFAOYSA-N 3,4-dichlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1Cl ZWUSBSHBFFPRNE-UHFFFAOYSA-N 0.000 description 1
- SUISZCALMBHJQX-UHFFFAOYSA-N 3-bromobenzaldehyde Chemical compound BrC1=CC=CC(C=O)=C1 SUISZCALMBHJQX-UHFFFAOYSA-N 0.000 description 1
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 1
- WZWIQYMTQZCSKI-UHFFFAOYSA-N 4-cyanobenzaldehyde Chemical compound O=CC1=CC=C(C#N)C=C1 WZWIQYMTQZCSKI-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- UHPDSDITGNBVDE-UHFFFAOYSA-N bromic acid octane Chemical compound Br(=O)(=O)O.CCCCCCCC UHPDSDITGNBVDE-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- ZHVULPDNOFUIML-UHFFFAOYSA-N octane;hydrochloride Chemical compound Cl.CCCCCCCC ZHVULPDNOFUIML-UHFFFAOYSA-N 0.000 description 1
- UZZYXUGECOQHPU-UHFFFAOYSA-N octyl hydrogen sulfate Chemical compound CCCCCCCCOS(O)(=O)=O UZZYXUGECOQHPU-UHFFFAOYSA-N 0.000 description 1
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4056—Esters of arylalkanephosphonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
-
- 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
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of a derivative containing beta-cyano phosphonate, which comprises the following steps: under the catalysis of DABCO-based ionic liquid, aromatic aldehyde, malononitrile, phosphite ester and ketene compound are heated and reacted mildly in a solvent to prepare the derivative containing beta-cyano phosphonate. The synthetic method disclosed by the invention has the advantages of simple steps, short reaction time, high reaction yield, low price and easiness in obtaining of the used ionic liquid catalyst, wide application range of the substrate of the synthetic method disclosed by the invention, and the most important oxindole compounds with multiple functional group phosphonate groups can be obtained by a four-component one-pot method, so that the method is a high-efficiency four-component reaction.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of derivatives containing beta-cyanophosphonate derivatives.
Background
Beta-cyanophosphonate derivatives are a very important class of compounds, which are important skeletons of many natural products and bioactive compounds, and the abundant diversity structure of the derivatives and the broad spectrum of biological activity thereof make the compounds extremely in need of efficient synthetic methods. In the synthesis system, the constructed carbon four-center is still a difficulty in the current organic synthesis chemistry, and the derivatives containing the beta-cyanophosphonate derivatives are not reported at present.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a synthetic method of derivatives containing beta-cyanophosphonate derivatives, the synthetic method is simple and convenient to operate, short in reaction time, low in production cost, less in reaction green pollution, simple in post-treatment and low in cost, and the ionic liquid catalyst used in the synthetic method is a cheap, easily-obtained and environment-friendly efficient catalyst.
The purpose of the invention is realized by the following technical scheme.
A synthetic method of a derivative containing beta-cyanophosphonate comprises the following steps: stirring a reactant, malononitrile, phosphite ester, an ketene compound, an ionic liquid catalyst and a solvent for reaction, extracting, drying, filtering, evaporating and separating by a chromatographic column to obtain the derivative containing beta-cyanophosphonate, wherein the ratio of the reactant, the malononitrile, the phosphite ester, the ketene compound and the ionic liquid catalyst is (1-1.5): (1-1.5): (1-1.5): (0.1-0.2), wherein the ionic liquid catalyst is 1, 4-diazabicyclo [2.2.2] octane acetate, 1, 4-diazabicyclo [2.2.2] octane bromate, 1, 4-diazabicyclo [2.2.2] octane hydrogen sulfate, 1, 4-diazabicyclo [2.2.2] octane hydrochloride or 1, 4-diazabicyclo [2.2.2] octane tetrafluoroborate.
In the above-mentioned technical scheme, 1, 4-diazabicyclo [2.2.2]The structural formula of octane acetate is
1, 4-diazabicyclo [2.2.2]The structural formula of octane bromate is shown in the specification
1, 4-diazabicyclo [2.2.2]The structural formula of the octyl hydrogen sulfate is shown in the specification
1, 4-diazabicyclo [2.2.2]The structural formula of octane hydrochloride is
1, 4-diazabicyclo [2.2.2]The structural formula of octane tetrafluoroborate is shown in the specification
In the technical scheme, the solvent is one or a mixture of more of toluene, ethanol, n-hexane, tetrahydrofuran and methanol.
In the technical scheme, the stirring reaction is a reaction at 20-60 ℃.
In the technical scheme, the reactant is
Wherein, R is1Is CH3CN or Br.
In the above technical scheme, the phosphite ester is
Wherein, R is2Me, Et or Ph.
In the above technical solution, the ratio of the parts by weight of the substance of the reactant to the parts by volume of the solvent is 1: (0.5-1), wherein the unit of the parts by weight of the substances is mmol, and the unit of the parts by volume is mL.
In the above technical scheme, the time for the stirring reaction to proceed is detected by thin layer chromatography.
In the technical scheme, the stirring reaction time is at least 20min, and preferably 150-210 min.
In the technical scheme, the reactant, the malononitrile, the phosphite ester, the ionic liquid catalyst and the solvent are stirred for 30-60 min at 40-50 ℃, and then the ketene compound is added for the stirring reaction.
In the technical scheme, the extraction is to add water and then add ethyl acetate for washing.
In the technical scheme, anhydrous sodium sulfate is adopted for drying.
In the technical scheme, an eluent for the chromatographic reaction is a mixture of petroleum ether and ethyl acetate, and the ratio of the petroleum ether to the ethyl acetate is (1-3): 1 in parts by volume.
The synthetic method disclosed by the invention has the advantages of simple steps, short reaction time, high reaction yield, low price and easiness in obtaining of the used ionic liquid catalyst, and in addition, the substrate application range of the synthetic method disclosed by the invention is wide, and the extremely important multifunctional group beta-cyanophosphonate derivatives can be obtained through a four-component one-pot method.
Detailed Description
The technical scheme of the invention is further explained by combining specific examples.
In the specific implementation mode of the invention, the reagents and medicines involved in the synthesis are purchased from Tianjin reagent six factories in commercial way, the purity of the medicines is analytically pure, and the reagents and the medicines are directly used without any pretreatment.
The synthesis method of the invention continuously stirs in the whole process, and the model of an electromagnetic heating stirrer used for stirring is NUOVAII (Temaran, USA); the rotary evaporator was model RE-2000A (Otsuwa instruments liability Co., Ltd., Otsu). Nuclear magnetic resonance instrument model: bruker AV-400 spectrometer, 400MHz, DMSO-d 6. In a particular embodiment of the invention, parts by weight of a substance are in mmol units and parts by volume are in ml units. Filtering through a glass sand core funnel (model: G120-30 um).
The extent of reaction progress was checked by Thin Layer Chromatography (TLC). In thin layer chromatography, silica gel plate type G254 with size of 15mm × 50mm is used; the polarity of the developing solvent is a mixture of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1: 2. The detection process uses a ZF-I type three-purpose ultraviolet analyzer (Shanghai Ching Tang), the used medicines are purchased from Tianjin reagent six factories, the purity of the medicines is analytical purity, all medicines are directly used, and no pretreatment is carried out. When the increase of the product is not found by TLC monitoring, the synthesis method of the invention is marked to be finished, and the next separation operation can be continued.
Example 1
A synthetic method of a derivative containing beta-cyanophosphonate comprises the following steps: 1.0mmol (0.120g) of p-tolualdehyde, 1.0mmol (0.066g) of malononitrile, 1.0mmol (0.138g) of diethyl phosphite and 0.2mmol of an ionic liquid catalyst 1, 4-diazabicyclo [2.2.2] in that order]Adding octane acetate into 10ml dry round bottom flask, adding 1ml THF (tetrahydrofuran) as solvent, heating at 40 deg.C and stirring for reaction for 30min, and adding 1.0mmol (0.084g) 1-pentaneAlkene-3-ketone, stirring at 40 ℃ for reaction, monitoring the stirring reaction time (2h) by TLC, adding 10ml of water after the reaction is finished, cooling, adding 10ml of ethyl acetate for extraction for 3 times, drying the organic phase by anhydrous sodium sulfate, filtering and distilling off, separating and purifying the crude product by column chromatography, adopting petroleum ether and ethyl acetate as eluent (the ratio of the petroleum ether to the ethyl acetate is 3:1 in parts by volume), distilling off the eluent and drying to obtain the pure derivative (molecular formula C) containing beta-cyanophosphonate20H27N2O4P)0.183g, purity greater than 98% and reaction yield 47%.
1H NMR(400MHz,CDCl3):δ＝1.06(t,J＝7.2Hz,3H,CH3),1.15(t,J＝7.2Hz,3H,CH3),1.34(t,J＝7.2Hz,3H,CH3),2.27-2.32(m,1H,CH2),2.36(s,3H,CH3),2.43-2.51(m,3H,CH2),2.83(t,J＝7.2Hz,2H,CH2),3.42(s,0.5H,CH),3.48(s,0.5H,CH),3.81-3.88(m,1H,CH2),4.03-4.09(m,1H,CH2),4.12-4.20(m,2H,CH2),7.22(d,J＝7.8Hz,1H,ArH),7.43(s,1H,ArH).
13C NMR(100MHz,CDCl3):δ＝7.6,16.1,21.2,31.7,36.1,38.0,39.3,48.9(d,JCP＝187.6Hz,C-P),63.1,64.1,114.1,114.2,114.4,127.1,129.9,130.2,139.5,207.4.
31P NMR(162MHz,CDCl3):δ＝18.40.
Example 2
A synthetic method of a derivative containing beta-cyanophosphonate comprises the following steps: 1.0mmol (0.131g) of p-cyanobenzaldehyde, 1.0mmol (0.066g) of malononitrile, 1.0mmol (0.138g) of diethyl phosphite and 0.2mmol of an ionic liquid catalyst 1, 4-diazabicyclo [2.2.2] in that order]Adding octane acetate into 10ml dry round-bottom flask, adding 1ml THF as solvent, heating and stirring at 40 deg.C for 30min, adding 1.0mmol (0.084g) 1-penten-3-one, stirring at 40 deg.C for reaction, and allowing reaction to pass through TLC monitors the stirring reaction time (2h), after the reaction is finished, 10ml of water is added, after cooling, 10ml of ethyl acetate is added for extraction for 3 times, the organic phase is dried by anhydrous sodium sulfate, filtered and evaporated, the crude product is separated and purified by column chromatography, petroleum ether and ethyl acetate are used as eluent (the ratio of the petroleum ether to the ethyl acetate is 3:1 according to the volume portion), and the eluent is evaporated and dried to obtain the pure derivative (the molecular formula C) containing the beta-cyanophosphonate20H24N3O4P)0.220g, purity greater than 98% and reaction yield 55%.
1H NMR(400MHz,CDCl3):δ＝0.97(t,J＝7.2Hz,3H,CH3),1.11(t,J＝6.8Hz,3H,CH3),1.24(t,J＝7.2Hz,3H,CH3),2.16-2.24(m,1H,CH2),2.39-2.44(m,2H,CH2),2.46-2.54(m,1H,CH2),2.72-2.79(m,2H,CH2),3.60(s,0.5H,CH),3.66(s,0.5H,CH),3.86-3.92(m,1H,CH2),3.98-4.14(m,3H,CH2),7.65(s,4H,ArH).
13C NMR(100MHz,CDCl3):δ＝7.6,16.0,16.1,16.2,31.6,36.1,38.0,39.0,48.7(d,JCP＝141.0Hz,C-P),63.7,64.4,113.4,113.7,113.8,113.9,118.0,131.1,132.8,136.2,207.4.
31P NMR(162MHz,CDCl3):δ＝16.84.
Example 3
A synthetic method of a derivative containing beta-cyanophosphonate comprises the following steps: 1.0mmol (0.185g) of p-bromobenzaldehyde, 1.0mmol (0.066g) of malononitrile, 1.0mmol (0.138g) of diethyl phosphite and 0.2mmol of an ionic liquid catalyst 1, 4-diazabicyclo [2.2.2] in that order]Adding octane acetate into 10ml dry round-bottom flask, adding 1ml THF as solvent, heating and stirring at 50 deg.C for reaction for 30min, adding 1.0mmol (0.084g) 1-penten-3-one, stirring at 50 deg.C for reaction, monitoring stirring reaction time by TLC (2 hr), adding 10ml water after reaction, cooling, addingExtracting with 10ml ethyl acetate for 3 times, drying the organic phase with anhydrous sodium sulfate, filtering, distilling off, separating and purifying the crude product by column chromatography, eluting with petroleum ether and ethyl acetate (the ratio of petroleum ether to ethyl acetate is 3:1) by volume, distilling off the eluent, and drying to obtain the pure derivative (molecular formula C) containing beta-cyanophosphonate19H24BrN2O4P)0.336g, purity greater than 98%, reaction yield 74%.
1H NMR(400MHz,CDCl3):δ＝1.07(t,J＝7.8Hz,3H,CH3),1.88(t,J＝7.2Hz,3H,CH3),1.35(t,J＝7.2Hz,3H,CH3),2.24-2.32(m,1H,CH2),2.47-2.52(m,3H,CH2),2.82-2.86(m,2H,CH2),3.44(s,0.5H,CH),4.00(s,0.5H,CH),3.88-3.94(m,1H,CH2),4.08-4.10(m,1H,CH2),4.15-4.21(m,2H,CH2),7.44(d,J＝6.8Hz,1H,ArH),7.57(d,J＝8.4Hz,1H,ArH).
13C NMR(100MHz,CDCl3):δ＝7.6,16.1,31.6,36.0,38.0,39.1,48.3,49.7,63.4(d,JCP＝87.6Hz,C-P),113.9,114.0,114.1,123.9,129.6,131.9,132.4,207.3.
31P NMR(162MHz,CDCl3):δ＝17.61.
Example 4
A synthetic method of a derivative containing beta-cyanophosphonate comprises the following steps: 1.0mmol (0.185g) of m-bromobenzaldehyde, 1.0mmol (0.066g) of malononitrile, 1.0mmol (0.138g) of diethyl phosphite and 0.2mmol of the ionic liquid catalyst 1, 4-diazabicyclo [2.2.2] in that order]Adding octane acetate into a 10ml dry round-bottom flask, adding 1ml THF as a solvent, heating and stirring at 40 ℃ for reaction for 30min, adding 1.0mmol (0.084g) of 1-penten-3-one, stirring at 40 ℃ for reaction, monitoring the stirring reaction time by TLC (thin layer chromatography) for 2h), adding 10ml water after the reaction is finished, cooling, adding 10ml ethyl acetate for extraction for 3 times, drying an organic phase by anhydrous sodium sulfate, and then performing stirring reaction on the organic phase for 2hFiltering, evaporating, purifying the crude product by column chromatography, eluting with petroleum ether and ethyl acetate (the ratio of petroleum ether to ethyl acetate is 3:1), evaporating, eluting, and drying to obtain pure derivative (molecular formula C) containing beta-cyanophosphonate19H24BrN2O4P)0.286g, purity greater than 98% and reaction yield 63%.
1H NMR(400MHz,CDCl3):δ＝0.98(t,J＝7.2Hz,3H,CH3),1.11(t,J＝7.2Hz,3H,CH3),1.27(t,J＝6.8Hz,3H,CH3),2.18-2.24(m,1H,CH2),2.39-2.49(m,3H,CH2),2.72-2.79(m,2H,CH2),3.43(s,0.5H,CH),3.49(s,0.5H,CH),3.83-3.90(m,1H,CH2),4.01-4.13(m,3H,CH2),7.24(t,J＝8.0Hz,1H,ArH),7.48(d,J＝7.6Hz,1H,ArH),7.61(s,1H,ArH).
13C NMR(100MHz,CDCl3):δ＝7.6,16.1,31.7,36.1,38.0,39.0,48.8(d,JCP＝141.5Hz,C-P),63.8,64.5,113.5,113.6,113.8,113.8,117.9,131.1,132.9,136.1,207.4.
31P NMR(162MHz,CDCl3):δ＝16.89.
Example 5
A synthetic method of a derivative containing beta-cyanophosphonate comprises the following steps: 1.0mmol (0.185g) of o-bromobenzaldehyde, 1.0mmol (0.066g) of malononitrile, 1.0mmol (0.138g) of diethyl phosphite and 0.2mmol of an ionic liquid catalyst 1, 4-diazabicyclo [2.2.2] in this order]Adding octane acetate into 10ml of dry round-bottom flask, adding 1ml of THF as solvent, heating and stirring at 40 ℃ for reaction for 30min, adding 1.0mmol (0.084g) of 1-penten-3-one, stirring at 40 ℃ for reaction, monitoring the stirring reaction time (2h) by TLC (thin layer chromatography), adding 10ml of water after the reaction is finished, cooling, adding 10ml of ethyl acetate for extraction for 3 times, drying an organic phase with anhydrous sodium sulfate, filtering and distilling off, separating and purifying a crude product by column chromatography, and adopting petroleum ether and acetic acidEthyl ester is used as eluent (the ratio of petroleum ether to ethyl acetate is 3:1 according to the volume portion), and pure derivative (molecular formula C) containing beta-cyano phosphonate is obtained after evaporation, eluent and drying19H24BrN2O4P)0.322g, purity greater than 98% and reaction yield 71%.
1H NMR(400MHz,CDCl3):δ＝1.07(t,J＝7.2Hz,3H,CH3),1.16(t,J＝7.2Hz,3H,CH3),1.37(t,J＝7.2Hz,3H,CH3),2.22-2.30(m,1H,CH2),2.47-2.52(m,2H,CH2),2.55-2.63(m,2H,CH2),2.80-2.92(m,1H,CH2),3.87-3.94(m,1H,CH2),4.04-4.13(m,2H,CH2),4.18-4.28(m,2H,CH2),4.38(s,0.5H,CH),4.43(s,0.5H,CH),7.27-7.31(m,1H,ArH),7.44(t,J＝8.0Hz,1H,ArH),7.69(d,J＝8.0Hz,1H,ArH),8.03(d,J＝8.0Hz,1H,ArH).
13C NMR(100MHz,CDCl3):δ＝7.5,15.9,16.1,31.4,35.9,37.7,38.9,46.1,47.5,63.4(d,JCP＝68.4Hz,C-P),113.5,113.6,114.0,126.8,128.3,130.4,130.9,133.6,207.0.
31P NMR(162MHz,CDCl3):δ＝17.40.
Example 6
A synthetic method of a derivative containing beta-cyanophosphonate comprises the following steps: 1.0mmol (0.175g) of 3, 4-dichlorobenzaldehyde, 1.0mmol (0.066g) of malononitrile, 1.0mmol (0.138g) of diethyl phosphite and 0.2mmol of an ionic liquid catalyst 1, 4-diazabicyclo [2.2.2] in that order]Adding octane acetate into a 10ml dry round-bottom flask, adding 1ml THF as a solvent, heating and stirring at 40 ℃ for reaction for 30min, adding 1.0mmol (0.084g) of 1-penten-3-one, stirring at 40 ℃ for reaction, monitoring the stirring reaction time (3h) by TLC (thin layer chromatography), adding 10ml water after the reaction is finished, cooling, adding 10ml ethyl acetate for extraction for 3 times, drying an organic phase by anhydrous sodium sulfate, filtering and distilling off, and purifying a crude product by column chromatography separationPetroleum ether and ethyl acetate are used as eluent (the ratio of the petroleum ether to the ethyl acetate is 3:1 in parts by volume), and the eluent is evaporated and dried to obtain the pure derivative (molecular formula C) containing the beta-cyano phosphonate ester19H23Cl2N2O4P)0.320g, purity greater than 98% and reaction yield 72%.
1H NMR(400MHz,CDCl3):δ＝1.08(t,J＝7.2Hz,3H,CH3),1.24(t,J＝7.2Hz,3H,CH3),1.36(t,J＝6.8Hz,3H,CH3),2.25-2.32(m,1H,CH2),2.48-2.58(m,3H,CH2),2.83-2.88(m,2H,CH2),3.45(s,0.5H,CH),3.50(s,0.5H,CH),3.96-4.03(m,1H,CH2),4.11-4.22(m,3H,CH2),7.45(d,J＝7.2Hz,1H,ArH),7.53(d,J＝8.4Hz,1H,ArH),7.64(s,1H,ArH).
13C NMR(100MHz,CDCl3):δ＝7.6,16.2,31.7,36.1,38.0,39.1,48.3(d,JCP＝141.7Hz,C-P),63.6,64.4,113.7,113.8,113.9,129.4,130.8,131.2,132.2,133.5,134.1,207.2.
31P NMR(162MHz,CDCl3):δ＝17.05.
Example 7
A synthetic method of a derivative containing beta-cyanophosphonate comprises the following steps: 1.0mmol (0.112g) of 2-thiophenecarboxaldehyde, 1.0mmol (0.066g) of malononitrile, 1.0mmol (0.138g) of diethyl phosphite, and 0.2mmol of an ionic liquid catalyst 1, 4-diazabicyclo [2.2.2] in that order]Adding octane acetate into 10ml of dry round-bottom flask, adding 1ml of THF as solvent, heating and stirring at 50 ℃ for reaction for 30min, adding 1.0mmol (0.084g) of 1-penten-3-one, stirring at 50 ℃ for reaction, monitoring the stirring reaction time (3h) by TLC, after the reaction is finished, adding 10ml of water, cooling, adding 10ml of ethyl acetate for extraction for 3 times, drying an organic phase with anhydrous sodium sulfate, filtering and distilling off, separating and purifying a crude product by column chromatography, and adopting petroleum ether and ethyl acetate as eluents (according to volume)The ratio of petroleum ether to ethyl acetate is 3:1 in parts by weight, and pure derivatives (molecular formula C) containing beta-cyanophosphonate are obtained after evaporation, eluent removal and drying17H23N2O4PS)0.275g, purity greater than 98%, reaction yield 72%.
1H NMR(400MHz,CDCl3):δ＝1.09(t,J＝7.8Hz,3H,CH3),1.22(t,J＝7.2Hz,3H,CH3),1.37(t,J＝7.2Hz,3H,CH3),2.32-2.39(m,1H,CH2),2.48-2.56(m,3H,CH2),2.85(t,J＝7.8Hz,2H,CH2),3.79(s,0.5H,CH),3.84(s,0.5H,CH),3.89-3.98(m,1H,CH2),4.11-4.26(m,3H,CH2),7.10(t,J＝4.0Hz,1H,ArH),7.40(t,J＝5.2Hz,2H,ArH).
13C NMR(100MHz,CDCl3):δ＝7.7,16.2,31.4,36.1,38.1,39.8,44.2,45.6,63.6,63.7,64.6,113.8,114.0,127.5,127.8,130.2,207.3.
31P NMR(162MHz,CDCl3):δ＝16.29.
The invention has been described in an illustrative manner, and it is to be understood that any simple variations, modifications or other equivalent changes which can be made by one skilled in the art without departing from the spirit of the invention fall within the scope of the invention.
Claims (8)
1. A synthetic method of a derivative containing beta-cyanophosphonate is characterized by comprising the following steps: stirring a reactant, malononitrile, phosphite ester, an ketene compound, an ionic liquid catalyst and a solvent for reaction, extracting, drying, filtering, evaporating and separating by a chromatographic column to obtain the derivative containing beta-cyanophosphonate, wherein the ratio of the reactant, the malononitrile, the phosphite ester, the ketene compound and the ionic liquid catalyst is (1) - (1.5): (1-1.5): (1-1.5): (0.1-0.2), wherein the ionic liquid catalyst is 1, 4-diazabicyclo [2.2.2]Octane acetate, 1, 4-diazabicyclo [2.2.2]Octane bromate, 1, 4-diazabicyclo [2.2.2]Hydrogen octanesulfate, 1, 4-diazabicyclo [2.2.2]Octane hydrochloride or 1, 4-bisAzabicyclo [2.2.2]Octane tetrafluoroborate, the reactant is
Wherein, R is1Is CH3CN or Br, the phosphite ester is
Wherein, R is2The ketene compound is 1-pentene-3-ketone, and the beta-cyano phosphonate ester derivative has the following structures:
R1is CH3CN or Br, R2Me, Et or Ph.
2. The synthesis method according to claim 1, wherein the solvent is one or more of toluene, ethanol, n-hexane, tetrahydrofuran and methanol.
3. The synthesis method according to claim 1, wherein the stirring reaction is a reaction at 20-60 ℃.
4. The synthesis process according to claim 1, characterized in that the ratio of the parts by mass of the reactants to the parts by volume of the solvent is 1: (0.5-1), wherein the unit of the parts by weight of the substances is mmol, and the unit of the parts by volume is mL.
5. The method of claim 1, wherein the time for the stirring reaction to proceed is determined by thin layer chromatography.
6. The method of claim 1, wherein the stirring is for a reaction time of at least 20 min.
7. The synthesis method according to claim 1, wherein the reactants, the malononitrile, the phosphite ester, the ionic liquid catalyst and the solvent are stirred at 40-50 ℃ for 30-60 min, and then the ketene compound is added for the stirring reaction.
8. The synthesis method of claim 1, wherein the extraction is washing by adding water and ethyl acetate; the drying adopts anhydrous sodium sulfate; an eluent of the chromatographic reaction is a mixture of petroleum ether and ethyl acetate, and the ratio of the petroleum ether to the ethyl acetate is (1-3): 1 in parts by volume.
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