CN105732344A - Synthesis method of symmetric butanedione compounds - Google Patents
Synthesis method of symmetric butanedione compounds Download PDFInfo
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- CN105732344A CN105732344A CN201610067122.1A CN201610067122A CN105732344A CN 105732344 A CN105732344 A CN 105732344A CN 201610067122 A CN201610067122 A CN 201610067122A CN 105732344 A CN105732344 A CN 105732344A
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- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical class CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 title abstract description 9
- 238000001308 synthesis method Methods 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 107
- 239000002904 solvent Substances 0.000 claims abstract description 45
- 239000003054 catalyst Substances 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 30
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 7
- 150000001340 alkali metals Chemical group 0.000 claims abstract description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 77
- 238000010189 synthetic method Methods 0.000 claims description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- 239000002253 acid Substances 0.000 claims description 28
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 23
- 239000003960 organic solvent Substances 0.000 claims description 19
- 229910052763 palladium Inorganic materials 0.000 claims description 13
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims description 12
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 12
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical group [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 claims description 12
- -1 diacetyl compound Chemical class 0.000 claims description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 8
- 238000012805 post-processing Methods 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 7
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 5
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 claims description 5
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 4
- INIOZDBICVTGEO-UHFFFAOYSA-L palladium(ii) bromide Chemical compound Br[Pd]Br INIOZDBICVTGEO-UHFFFAOYSA-L 0.000 claims description 4
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 claims description 2
- UTEFBSAVJNEPTR-RGEXLXHISA-N loprazolam Chemical compound C1CN(C)CCN1\C=C/1C(=O)N2C3=CC=C([N+]([O-])=O)C=C3C(C=3C(=CC=CC=3)Cl)=NCC2=N\1 UTEFBSAVJNEPTR-RGEXLXHISA-N 0.000 claims description 2
- 229960003019 loprazolam Drugs 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 40
- 238000003786 synthesis reaction Methods 0.000 abstract description 16
- 239000003446 ligand Substances 0.000 abstract description 9
- 230000007547 defect Effects 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 2
- 150000007513 acids Chemical class 0.000 abstract 2
- 230000002349 favourable effect Effects 0.000 abstract 1
- 230000002195 synergetic effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- 239000012044 organic layer Substances 0.000 description 40
- 238000002360 preparation method Methods 0.000 description 37
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 239000010410 layer Substances 0.000 description 20
- 238000005406 washing Methods 0.000 description 20
- 239000000047 product Substances 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 14
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 239000000376 reactant Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 239000007832 Na2SO4 Substances 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 238000001704 evaporation Methods 0.000 description 10
- 230000008020 evaporation Effects 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 238000003818 flash chromatography Methods 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 238000011835 investigation Methods 0.000 description 9
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 8
- 230000008569 process Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical group O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 240000004859 Gamochaeta purpurea Species 0.000 description 1
- 229910021605 Palladium(II) bromide Inorganic materials 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- ZPFKRQXYKULZKP-UHFFFAOYSA-N butylidene Chemical group [CH2+]CC[CH-] ZPFKRQXYKULZKP-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000003863 metallic catalyst Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a synthesis method of symmetric butanedione compounds disclosed as Formula (III). The method comprises the following steps: in a solvent, carrying out reaction on compounds disclosed as Formula (I) and compounds disclosed as Formula (II) in the presence of a catalyst, a ligand and an acidic compound; and after the reaction finishes, carrying out after-treatment, thereby obtaining the compounds disclosed as Formula (III), wherein X is an alkali metal element. Under the combined selection and synergic actions of the specific catalyst, ligand, acidic compound and solvent, the method can overcome the defect of overlow yield of butanedione compounds in the prior art, can obtain the target products at high yield, and has favorable application prospects and industrial production potential in the field of organic chemical synthesis.
Description
Technical field
The present invention relates to the synthetic method of a kind of dicarbonyl compound, particularly the synthetic method of a kind of symmetrical diacetyl compound, belongs to organic chemical synthesis field.
Background technology
In organic chemistry filed especially pharmaceutical intermediate synthesis technical field, ketone compounds is due to the existence of carbonyl, and has its good reactivity, is used widely as intermediate in multiple synthesis field of being everlasting.
And in all of ketone compounds, owing to there are two carbonyls in cyclohexadione compounds, thus expanding the popularity of its purposes further and reacting the suitability more, such as in pharmaceutical intermediate field, use cyclohexadione compounds to carry out multiple chemical reaction on carbonyl in a large number to be synthetically derived final purpose product, thus introducing the correct structure of active group or desired chemical constitution.
Just because of the so important effect of cyclohexadione compounds, its synthesis has been carried out substantial amounts of further investigation by people, and achieves many achievements, for instance the many synthetic method that relate to cyclohexadione compounds is listed below:
ChaoLiu et al. (Palladium-CatalyzedC-CBondFormationToConstruct1,4-DiketonesunderMildConditions, Angew.Chem.Int.Ed., 2011,50, p7337-7341) method of synthesis Isosorbide-5-Nitrae-cyclohexadione compounds disclosed in, the method is at alkali, ZnCl2, under palladium catalyst and part exist, reacted by following formula and obtain::
MyronM.D.Wilde et al. (Bis (amino) cyclopropenylidenesasOrganocatalystsforAcylAnionandExten dedUmpolungReactions, Angew.Chem.Int.Ed., 2013,50, p12651-12654) disclosed in a kind of 1, the method of 4-cyclohexadione compounds, its reaction equation is as follows:
JinXie et al. (Thecascadecarbo-carbonylationofunactivatedalkenescatalyz edbyanorganocatalystandatransitionmetalcatalyst:afacilea pproachtoc-diketonesandc-carbonylaldehydesfromarylalkene sunderair, Chem.Commun., 2010,46, p1947-1949) a kind of 1 is disclosed, the synthetic method of 4-cyclohexadione compounds, it adopts metallic catalyst, DMF/H2The combined systems such as O and obtain productivity, its reaction equation is as follows:
JunXuan et al. (Visible-Light-InducedC_SBondActivation:FacileAccessto1,4-Diketonesfromb-Ketosulfones, Chem.Eur.J., 2014,20, p3045-3049) disclose a kind of with Ru compound for catalyst and when there is amine and additive, synthesis diphenyl replace 1, the method of 4-cyclohexadione compounds, its reaction equation is as follows:
AkkattuT.Biju et al. (N-HeterocyclicCarbene-CatalyzedCascadeReactionInvolvingt heHydroacylationofUnactivatedAlkynes, J.AM.CHEM.SOC., 2010,132, p5970-5971) disclosing a kind of method synthesizing cyclohexadione compounds under potassium carbonate exists, its reaction equation is as follows:
ShenlinHuang et al. (CatalyticAsymmetricDearomatizingRedoxCrossCouplingofKeto neswithArylHydrazinesGiving1,4-Diketones, J.AM.CHEM.SOC., 2015,137, p3446-3449) synthetic method of a kind of cyclohexadione compounds is disclosed, described method is with phosphine compound for catalyst, under benzoic acid and water exist, being reacted by hydrazine compound and Ketohexamethylene and obtained, reaction equation is as follows:
As mentioned above, synthesis cyclohexadione compounds multiple method disclosed in prior art, but all there is certain defect in these methods, for instance and product yield is relatively low, or employ expensive reagent etc., still cannot meet the requirement at present for the extensive of dione compounds preparation method and simplicity.
nullFor these above-mentioned defects，The synthesis of cyclohexadione compounds has been carried out inventive improvements by the present inventor，And at (XingyongWang et al.，“Palladium-catalyzedadditionofpotassiumphenyltrifluoroboratetodinitriles:synthesisofdiketonecompounds”，JournalofChemicalResearch，P.470-472) following preparation method disclosed in: in palladium acetate catalyst、Ligand 1,Under 10-phenanthrene quinoline and trifluoroacetic acid exist，Following formula (II) compound and following formula (III) compound react in reaction dissolvent，Generate the dione compounds of following formula (I)，
Wherein, L can be C1-C5The connection base of alkylidene, X is alkali metal.
But surprisingly, it is under the premise of phenyl at Ar, when L is ethylidene, find that corresponding diacetyl compounds productivity is only about 57% in this reaction system, it is significantly lower than the productivity (this achievement is also partly disclosed in Chinese patent application CN201310178323.5, is no longer described in detail) for methylene (84%), propylidene (91%) or butylidene (89%) at this.
For the defect that the productivity of diacetyl compounds as indicated above is too low, the present inventor has proceeded further investigation, by the combined selection of suitable catalyst, part, acid and organic solvent etc. with collaborative, thus significantly improving products collection efficiency.
Summary of the invention
As mentioned above, for as too low in yield, the many defects such as process is loaded down with trivial details, expensive reagents is rare that solve to exist in above-mentioned prior art, the present inventor conducts in-depth research for the synthesis of symmetrical diacetyl compounds, after paying a large amount of creative work, thus completing the present invention.
It is pointed out that the present invention completes under the subsidy of state natural sciences fund (bullets: 21572162) and Zhejiang Province's Natural Science Fund In The Light (bullets: LY16B020012), express thanks at this.
The present invention relates to the synthetic method of symmetrical diacetyl compound shown in a kind of following formula (III), described method includes in a solvent, under the existence of catalyst, part and acid compound, following formula (I) compound and following formula (II) compound react, react after terminating through post processing, thus obtaining described formula (III) compound
Wherein, X is alkali metal.
In the described synthetic method of the present invention, X is alkali metal, for instance can be Li, Na or K.
In the described synthetic method of the present invention, described catalyst is palladium acetylacetonate (Pd (acac)2), acid chloride (Pd (OAc)2), diethyl cyano group Palladous chloride. (Pd (CH3CN)2Cl2), palladium trifluoroacetate (Pd (OTA)2), palladium bromide (PdBr2), Palladous chloride. (PdCl2), tetrakis triphenylphosphine palladium (Pd (PPh3)4) or double; two (dibenzalacetone) palladium (Pd (dba)2) in any one, it is most preferred that for palladium acetylacetonate (Pd (acac)2)。
In the described synthetic method of the present invention, described part is 2,2 '-bipyridyl.
In the described synthetic method of the present invention, described acid compound is any one in camphorsulfonic acid, acetic acid, trifluoroacetic acid (TFA) or p-methyl benzenesulfonic acid (TSOH), it is preferably camphorsulfonic acid, trifluoroacetic acid (TFA) or p-methyl benzenesulfonic acid (TSOH), it is most preferred that for camphorsulfonic acid.
In the described synthetic method of the present invention, described solvent is the mixture of organic solvent and water, and wherein organic solvent is 1:0.1-0.3 with the volume ratio of water, for instance can be 1:0.1,1:0.2 or 1:0.3.
Wherein, described organic solvent is any one in oxolane (THF), dimethyl sulfoxide (DMSO), DMF (DMF) or toluene, it is most preferred that for oxolane (THF).
The consumption of described solvent is not particularly limited, those skilled in the art can according to practical situation, that such as reacts is smoothed out, facilitates the concrete conditions such as post processing carry out suitable selection and determine, this is all the routine techniques knowledge of those skilled in the art, is no longer described in detail at this.
In the described synthetic method of the present invention, the mol ratio of described formula (I) compound and formula (II) compound is 1:1.5-2.5, for instance can be 1:1.5,1:2 or 1:2.5.
In the described synthetic method of the present invention, the mol ratio of described formula (I) compound and catalyst is 1:0.06-0.12, for instance can be 1:0.06,1:0.08,1:0.1 or 1:0.12.
In the described synthetic method of the present invention, the mol ratio of described formula (I) compound and part is 1:0.15-0.25, for instance can be 1:0.15,1:2 or 1:0.25.
In the described synthetic method of the present invention, the mol ratio of described formula (I) compound and acid compound is 1:1.5-2.5, for instance can be 1:1.5,1:2 or 1:2.5.
In the described synthetic method of the present invention, reaction temperature is 70-90 DEG C, for instance can be 70 DEG C, 80 DEG C or 90 DEG C.
In the described synthetic method of the present invention, response time, there is no particular limitation, such as can determine the suitable response time by the residual percentage of liquid chromatographic detection purpose product or raw material, it typically is 20-30 hour, for instance can be 20 hours, 25 hours or 30 hours.
In the described synthetic method of the present invention, reacting the post processing after terminating can be specific as follows: gained reactant mixture is naturally cooled to room temperature, then uses saturated NaHCO after terminating by reaction3Aqueous solution and saturated NaCl solution washing, isolate water layer and organic layer, is extracted by aqueous layer with ethyl acetate, merges organic layer (organic layer after namely merging washing and the organic layer being obtained by extraction), uses anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue is purified by flash column chromatography (n-hexane/ethyl acetate), thus obtaining described formula (III) compound.
In the described synthetic method of the present invention, described formula (I) compound as raw material prepares as follows, namely its synthetic method is as follows: in a solvent, under the existence of catalyst, part and acid, following formula (I-1) compound and following formula (II-1) compound react, react after terminating through post processing, thus obtaining described formula (III) compound
Wherein, X is defined as above.
Namely X is alkali metal, for instance can be Li, Na or K..
In the synthetic method of described formula (I) compound of the present invention, described catalyst is acid chloride (Pd (OAc)2), diethyl cyano group Palladous chloride. (Pd (CH3CN)2Cl2), palladium trifluoroacetate (Pd (OTA)2), palladium bromide (PdBr2), Palladous chloride. (PdCl2), palladium acetylacetonate (Pd (acac)2), triphenylphosphine palladium chloride (Pd (PPh3)2Cl2), tetrakis triphenylphosphine palladium (Pd (PPh3)4), double; two (dibenzalacetone) palladium (Pd (dba)2) or three (dibenzalacetone) two palladium (Pd2(dba)3) in any one, it is preferred to double; two (dibenzalacetone) palladium (Pd (dba)2) or three (dibenzalacetone) two palladium (Pd2(dba)3), it is most preferred that it is three (dibenzalacetone) two palladium (Pd2(dba)3)。
In the synthetic method of described formula (I) compound of the present invention, described part is any one in following formula L1-L8,
It most preferably is L1.
In the synthetic method of described formula (I) compound of the present invention, described acid is any one in p-methyl benzenesulfonic acid, trifluoroacetic acid, d-camphorsulfonic acid, acetic acid or Loprazolam, it is most preferred that for d-camphorsulfonic acid.
In the synthetic method of described formula (I) compound of the present invention, described solvent is the mixture of organic solvent and water, and wherein organic solvent is 4-6:1 with the volume ratio of water, for instance can be 4:1,5:1 or 6:1.
Wherein, described organic solvent is dimethyl sulfoxide (DMSO), N, dinethylformamide (DMF), N, N-dimethyl acetylamide (DMAC), toluene, o-Dimethylbenzene, benzene, 1, any one in 4-dioxane, oxolane (THF), ethanol, acetone, normal hexane or ether, it is most preferred that for benzene.
The consumption of described solvent is not particularly limited, those skilled in the art can according to practical situation, that such as reacts is smoothed out, facilitates the concrete conditions such as post processing carry out suitable selection and determine, this is all the routine techniques knowledge of those skilled in the art, is no longer described in detail at this.
In the synthetic method of described formula (I) compound of the present invention, the mol ratio of described formula (I-1) compound and formula (II-1) compound is 1:1.5-2.5, for instance can be 1:1.5,1:2 or 1:2.5.
In the synthetic method of described formula (I) compound of the present invention, the mol ratio of described formula (I-1) compound and catalyst is 1:0.04-0.08, for instance can be 1:0.04,1:0.05,1:0.06,1:0.07 or 1:0.08.
In the synthetic method of described formula (I) compound of the present invention, the mol ratio of described formula (I-1) compound and part is 1:0.15-0.25, for instance can be 1:0.15,1:2 or 1:0.25.
In the synthetic method of described formula (I) compound of the present invention, described formula (I-1) compound is 1:1-3 with sour mol ratio, for instance can be 1:1,1:1.5,1:2,1:2.5 or 1:3.
In the synthetic method of described formula (I) compound of the present invention, reaction temperature is 60-80 DEG C, for instance can be 60 DEG C, 70 DEG C or 80 DEG C.
In the synthetic method of described formula (I) compound of the present invention, response time, there is no particular limitation, such as can determine the suitable response time by the residual percentage of liquid chromatographic detection purpose product or raw material, it typically is 18-30 hour, for instance can be 18 hours, 22 hours, 26 hours or 30 hours.
In the synthetic method of described formula (I) compound of the present invention, reacting the post processing after terminating can be specific as follows: gained reactant mixture is poured in ethyl acetate, sequentially uses saturated NaHCO after terminating by reaction3Aqueous solution and saturated NaCl solution washing, isolate water layer and organic layer, is extracted by aqueous layer with ethyl acetate, merges organic layer (organic layer after namely merging washing and the organic layer being obtained by extraction), uses anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue is purified by flash column chromatography (n-hexane/ethyl acetate), thus obtaining described formula (I) compound.
Inventor have found that, when adopting said method to prepare starting compound (I) compound, it is possible to obtain formula (I) compound with high yield, thus the synthesis for end product and formula (III) compound provides starting compound.
In sum, the present invention, by suitable catalyst, part and acid compound and suitable dicyandiamide solution, such that it is able to high yield obtains symmetrical diacetyl compounds, and have studied the optimum synthesising method of raw material reaction thing.Thus having a good application prospect and researching value in organic chemical synthesis field, the synthesis for symmetrical diacetyl compounds provides brand-new method.
Detailed description of the invention
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary embodiments and purpose are only used for enumerating the present invention; not the real protection scope of the present invention is constituted any type of any restriction, more non-protection scope of the present invention is limited thereto.
Preparation example 1
Under room temperature, add 100mmol above formula (I-1) compound, 150mmol above formula (II-1) compound, 4mmol catalyst Pd to appropriate solvent (benzene and the mixture of water for volume ratio 5:1) is middle2(dba)3, 25mmol ligand L 1 and 100mmol d-camphorsulfonic acid, then stirring is warming up to 60 DEG C, and stirring reaction 30 hours at such a temperature；
Gained reactant mixture is poured in ethyl acetate, sequentially uses saturated NaHCO after terminating by reaction3Aqueous solution and saturated NaCl solution washing, isolate water layer and organic layer, is extracted by aqueous layer with ethyl acetate, merges organic layer (organic layer after namely merging washing and the organic layer being obtained by extraction), uses anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue is purified by flash column chromatography (n-hexane/ethyl acetate), thus obtaining above formula (I) compound, productivity is 85.7%.
Nuclear magnetic resonance, NMR:1HNMR(CDCl3, 500MHz): δ 7.957 (d, J=8.5Hz, 2H), 7.617 (dd, J=7.5Hz, 1H), 7.499 (dd, J=8Hz, 2H), 3.384 (t, J=7.5Hz, 2H), 2.778 (t, J=7.5Hz, 2H)；
13CNMR(CDCl3,125MHz):δ195.33,135.68,133.91,128.90(2C),128.04(2C),119.19,34.30,11.81。
Preparation example 2
Reaction equation is with preparation example 1, and specific operation process is as follows:
Under room temperature, add formula (II-1) compound, 6mmol catalyst Pd described in formula (I-1) compound, 200mmol described in 100mmol to appropriate solvent (benzene and the mixture of water for volume ratio 4:1) is middle2(dba)3, 15mmol ligand L 1 and 200mmol d-camphorsulfonic acid, then stirring is warming up to 70 DEG C, and stirring reaction 24 hours at such a temperature；
Gained reactant mixture is poured in ethyl acetate, sequentially uses saturated NaHCO after terminating by reaction3Aqueous solution and saturated NaCl solution washing, isolate water layer and organic layer, is extracted by aqueous layer with ethyl acetate, merges organic layer (organic layer after namely merging washing and the organic layer being obtained by extraction), uses anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue is purified by flash column chromatography (n-hexane/ethyl acetate), thus obtaining described formula (I) compound, productivity is 85.3%.Characterize data with preparation example 1.
Preparation example 3
Reaction equation is with preparation example 1, and specific operation process is as follows:
Under room temperature, add formula (II-1) compound, 8mmol catalyst Pd described in formula (I-1) compound, 250mmol described in 100mmol to appropriate solvent (benzene and the mixture of water for volume ratio 6:1) is middle2(dba)3, 20mmol ligand L 1 and 300mmol d-camphorsulfonic acid, then stirring is warming up to 80 DEG C, and stirring reaction 18 hours at such a temperature；
Gained reactant mixture is poured in ethyl acetate, sequentially uses saturated NaHCO after terminating by reaction3Aqueous solution and saturated NaCl solution washing, isolate water layer and organic layer, is extracted by aqueous layer with ethyl acetate, merges organic layer (organic layer after namely merging washing and the organic layer being obtained by extraction), uses anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue is purified by flash column chromatography (n-hexane/ethyl acetate), thus obtaining described formula (I) compound, productivity is 85.5%.Characterize data with preparation example 1.
Preparation example 4
Reaction equation is with preparation example 1, and specific operation process is as follows:
Under room temperature, add formula (II-1) compound, 5mmol catalyst Pd described in formula (I-1) compound, 170mmol described in 100mmol to appropriate solvent (benzene and the mixture of water for volume ratio 5:1) is middle2(dba)3, 22mmol ligand L 1 and 150mmol d-camphorsulfonic acid, then stirring is warming up to 65 DEG C, and stirring reaction 27 hours at such a temperature；
Gained reactant mixture is poured in ethyl acetate, sequentially uses saturated NaHCO after terminating by reaction3Aqueous solution and saturated NaCl solution washing, isolate water layer and organic layer, is extracted by aqueous layer with ethyl acetate, merges organic layer (organic layer after namely merging washing and the organic layer being obtained by extraction), uses anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue is purified by flash column chromatography (n-hexane/ethyl acetate), thus obtaining above formula (I) compound, productivity is 85.6%.Characterize data with preparation example 1.
Be can be seen that by above-mentioned preparation example 1-4, when the synthetic method adopting the present invention prepares starting compound (I) compound, (I) compound can be obtained, thus the synthesis for follow-up formula (III) compound provides and lays a good foundation with good productivity.
Preparation example 5-13: the investigation of catalyst
Pd is replaced except using following catalyst2(dba)3Outward, other operation is all constant, thus according to the same procedure of preparation example 1-4, implementing preparation example 5-13, used catalyst, preparation example corresponding relation and products collection efficiency are shown in table 1 below.
Table 1
As can be seen here, in all of catalyst, Pd (dba)2Or Pd2(dba)3There is good effect, and Pd2(dba)3Then excellent productivity.Other catalyst all causes that productivity significantly reduces, or even cannot react.
Preparation example 14-20: the investigation of part
Except using different ligands and replacing L1, other operation is all constant, thus according to the same procedure of preparation example 1-4, implementing preparation example 14-20, used part, preparation example corresponding relation and products collection efficiency are shown in table 2 below.
Table 2
As can be seen here, in all of ligand L 1-L8, L1 has best effect, it is possible to obtaining products collection efficiency excellent especially, even if L2, the L5-L6 very similar with it, productivity also has significant reduction, and especially L2 product is 0.This proves part structurally slight change, and namely may result in productivity has beyond thought greatest differences.
Preparation example 21-28: the investigation of acid
Except using different acid and replacing d-camphorsulfonic acid, other operation is all constant, thus according to the same procedure of preparation example 1-4, implementing preparation example 21-24；And in order to investigate the impact of acid further, respectively the d-camphorsulfonic acid in preparation example 1-4 is omitted, other operation is all constant, thus being repeated preparation example 1-4, sequentially obtains preparation example 25-28.
Acid, preparation example corresponding relation and products collection efficiency is used to see table 3 below.
Table 3
Note: " * " refers to and repeat preparation example 1-4 and sequentially obtain preparation example 25-28.
As can be seen here, the kind of acid has uncertain impact for final products collection efficiency, and wherein d-camphorsulfonic acid can obtain the productivity of excellence, and other acid all causes that productivity has significant reduction.And when not using d-camphorsulfonic acid, then reaction cannot be carried out, thus product cannot be obtained.
Preparation example 29-40: the investigation of solvent
Except using different organic solvents and replacing the benzene in solvent, other operation is all constant, thus according to the same procedure of preparation example 1-4, implementing preparation example 29-40 (namely still for the mixture of the organic solvent in table 4 below with water), organic solvent in the solvent used, preparation example corresponding relation and products collection efficiency are shown in table 4 below.
Table 4
Note: " * " represents that the solvent of preparation example 38 is only one-component water.
As can be seen here: 1, (preparing example 38) when simply using water as solvent, productivity has significant reduction；2, when using the organic solvent mixture with water as solvent, wherein organic solvent most preferably is benzene, even if being replaced with very similar toluene or o-Dimethylbenzene, but its productivity still has significant reduction (see preparation example 32-33).There is when thus demonstrating benzene-aqueous mixtures as solvent best beyond thought technique effect.
Example 1-40 produced above is visible, when adopting the Material synthesis method of the present invention, by the selection of unique reaction system that special catalyst, part, acidity and solvent are constituted, starting compound formula (I) compound can be obtained with good productivity, synthesis for example below Chinese style (III) compound provides the foundation and reactant (namely obtaining formula (I) compound according to above-mentioned preparation example, then carrying out the subsequent operation of example below).
Embodiment 1
Under room temperature, 100mmol above formula (I) compound, 150mmol above formula (II) compound, 6mmol catalyst Pd (acac), 15mmol part 2 is added to appropriate solvent (THF and the mixture of water for volume ratio 1:0.2) is middle, 2 '-bipyridyl and 150mmol acid compound camphorsulfonic acid, then heat to 70 DEG C, and stirring reaction 30 hours at such a temperature；
Gained reactant mixture is naturally cooled to room temperature, then uses saturated NaHCO after terminating by reaction3Aqueous solution and saturated NaCl solution washing, isolate water layer and organic layer, is extracted by aqueous layer with ethyl acetate, merges organic layer (organic layer after namely merging washing and the organic layer being obtained by extraction), uses anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue is purified by flash column chromatography (n-hexane/ethyl acetate), thus obtaining described formula (III) compound, productivity is 91.7%.
Nuclear magnetic resonance, NMR:1HNMR(DMSO-d6, 500MHz): δ 8.03 (d, J=8Hz, 4H), 7.66 (dd, J=8Hz, 2H), 7.56 (dd, J=8HZ, 4H), 3.42 (s, 4H)；
13CNMR(DMSO-d6,125MHz):δ198.58(2C),136.55(2C),133.16(2C),128.71(4C),127.87(4C),32.27(2C)。
Embodiment 2
Reaction equation is with embodiment 1, and concrete operation process is as follows:
Under room temperature, 100mmol above formula (I) compound, 200mmol above formula (II) compound, 9mmol catalyst Pd (acac), 20mmol part 2 is added to appropriate solvent (THF and the mixture of water for volume ratio 1:0.1) is middle, 2 '-bipyridyl and 200mmol acid compound camphorsulfonic acid, then heat to 80 DEG C, and stirring reaction 25 hours at such a temperature；
Gained reactant mixture is naturally cooled to room temperature, then uses saturated NaHCO after terminating by reaction3Aqueous solution and saturated NaCl solution washing, isolate water layer and organic layer, is extracted by aqueous layer with ethyl acetate, merges organic layer (organic layer after namely merging washing and the organic layer being obtained by extraction), uses anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue is purified by flash column chromatography (n-hexane/ethyl acetate), thus obtaining described formula (III) compound, productivity is 91.5%.
Nuclear magnetic data is with embodiment 1.
Embodiment 3
Reaction equation is with embodiment 1, and concrete operation process is as follows:
Under room temperature, 100mmol above formula (I) compound, 250mmol above formula (II) compound, 12mmol catalyst Pd (acac), 25mmol part 2 is added to appropriate solvent (THF and the mixture of water for volume ratio 1:0.3) is middle, 2 '-bipyridyl and 250mmol acid compound camphorsulfonic acid, then heat to 90 DEG C, and stirring reaction 20 hours at such a temperature；
Gained reactant mixture is naturally cooled to room temperature, then uses saturated NaHCO after terminating by reaction3Aqueous solution and saturated NaCl solution washing, isolate water layer and organic layer, is extracted by aqueous layer with ethyl acetate, merges organic layer (organic layer after namely merging washing and the organic layer being obtained by extraction), uses anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue is purified by flash column chromatography (n-hexane/ethyl acetate), thus obtaining described formula (III) compound, productivity is 91.8%.
Nuclear magnetic data is with embodiment 1.
Embodiment 4
Reaction equation is with embodiment 1, and concrete operation process is as follows:
Under room temperature, 100mmol above formula (I) compound, 170mmol above formula (II) compound, 10mmol catalyst Pd (acac), 23mmol part 2 is added to appropriate solvent (THF and the mixture of water for volume ratio 1:0.2) is middle, 2 '-bipyridyl and 180mmol acid compound camphorsulfonic acid, then heat to 85 DEG C, and stirring reaction 25 hours at such a temperature；
Gained reactant mixture is naturally cooled to room temperature, then uses saturated NaHCO after terminating by reaction3Aqueous solution and saturated NaCl solution washing, isolate water layer and organic layer, is extracted by aqueous layer with ethyl acetate, merges organic layer (organic layer after namely merging washing and the organic layer being obtained by extraction), uses anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue is purified by flash column chromatography (n-hexane/ethyl acetate), thus obtaining described formula (III) compound, productivity is 91.4%.
Nuclear magnetic data is with embodiment 1.
Be can be seen that by above-described embodiment 1-4, when the reaction adopting the present invention is, it is possible to obtaining symmetrical nail cyclohexadione compounds with high yield, improve about 44% with the productivity of 57% in the above-mentioned periodical of the present inventor, productivity has had significant raising and improvement.
Embodiment 5-32: the investigation of catalyst
Embodiment 5-8: remove catalyst by Pd (acac)2Replace with Pd (OAc)2Outward, other operation is all constant, thus repeating to implement embodiment 1-4, sequentially obtains embodiment 5-8.
Embodiment 9-12: remove catalyst by Pd (acac)2Replace with Pd (CH3CN)2Cl2Outward, other operation is all constant, thus repeating to implement embodiment 1-4, sequentially obtains embodiment 9-12.
Embodiment 13-16: remove catalyst by Pd (acac)2Replace with Pd (OTA)2Outward, other operation is all constant, thus repeating to implement embodiment 1-4, sequentially obtains embodiment 13-16.
Embodiment 17-20: remove catalyst by Pd (acac)2Replace with PdBr2Outward, other operation is all constant, thus repeating to implement embodiment 1-4, sequentially obtains embodiment 17-20.
Embodiment 21-24: remove catalyst by Pd (acac)2Replace with PdCl2Outward, other operation is all constant, thus repeating to implement embodiment 1-4, sequentially obtains embodiment 21-24.
Embodiment 25-28: remove catalyst by Pd (acac)2Replace with Pd (PPh3)4Outward, other operation is all constant, thus repeating to implement embodiment 1-4, sequentially obtains embodiment 25-28.
Embodiment 29-32: remove catalyst by Pd (acac)2Replace with Pd (dba)2Outward, other operation is all constant, thus repeating to implement embodiment 1-4, sequentially obtains embodiment 29-32.
Result is shown in table 5 below.
Table 5
As can be seen here, in all of catalyst, Pd (acac)2There is best catalytic effect；Other catalyst all causes that productivity is greatly lowered, and even lower than productivity of the prior art (productivity is 57% in the above-mentioned periodical literature of the present inventor), more even cannot obtain product (see embodiment 17-20,25-28).
Embodiment 33-44: the investigation of acid compound
Embodiment 33-36: except acid compound is replaced with acetic acid by camphorsulfonic acid, other operation is all constant, thus repeating to implement embodiment 1-4, sequentially obtains embodiment 33-36.
Embodiment 37-40: except acid compound is replaced with trifluoroacetic acid (TFA) by camphorsulfonic acid, other operation is all constant, thus repeating to implement embodiment 1-4, sequentially obtains embodiment 37-40.
Embodiment 41-44: except acid compound is replaced with p-methyl benzenesulfonic acid (TSOH) by camphorsulfonic acid, thus repeating to implement embodiment 1-4, sequentially obtains embodiment 41-44.
Result is shown in table 6 below.
Table 6
As can be seen here, in all of acid compound, camphorsulfonic acid, TFA and TSOH have good effect (effect of camphorsulfonic acid is the most excellent), and other acid all causes that productivity has obvious reduction, especially acetic acid, but it is also seen that, although TFA is very similar with acetic acid, but its productivity to be significantly higher than acetic acid.
Embodiment 45-56: the investigation of solvent
Embodiment 45-48: except the organic solvent in solvent is replaced with DMSO by THF, other operation is all constant, thus repeating to implement embodiment 1-4, sequentially obtains embodiment 45-48.
Embodiment 49-52: except the organic solvent in solvent is replaced with DMF by THF, other operation is all constant, thus repeating to implement embodiment 1-4, sequentially obtains embodiment 49-52.
Embodiment 53-56: except the organic solvent in solvent is replaced with toluene by THF, other operation is all constant, thus repeating to implement embodiment 1-4, sequentially obtains embodiment 53-56.
Result is shown in table 7 below.
Table 7
As can be seen here, when using the composite solvent system of THF and water, purpose product can be obtained with excellent productivity, but surprisingly, when THF therein being replaced other organic solvent such as DMSO, DMF or toluene, all will cause that productivity has certain or even significant reduction (time especially for DMF), and this demonstrate that the bi-component composite solvent system only using THF and water composition, beyond thought high products collection efficiency could be obtained.
In sum, can clearly be found out by above-mentioned all embodiments, when applying the method according to the invention, by the combined selection of special catalyst, part, acid compound and solvent with collaborative, such that it is able to overcome the defect that in prior art, the productivity of diacetyl compounds is too low, high yield can obtain purpose product, have a good application prospect and industrial production potential in organic chemical synthesis field.
Should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limit the scope of the invention.In addition; it is also contemplated that; after the technology contents having read the present invention, the present invention can be made various change, amendment and/or modification by those skilled in the art, and all these equivalent form of value falls within the application appended claims protection defined equally.
Claims (10)
1. the synthetic method of symmetrical diacetyl compound shown in a following formula (III), described method includes in a solvent, under the existence of catalyst, part and acid compound, following formula (I) compound and following formula (II) compound react, react after terminating through post processing, thus obtaining described formula (III) compound
Wherein, X is alkali metal.
2. synthetic method as claimed in claim 1, it is characterised in that: described catalyst is palladium acetylacetonate (Pd (acac)2), acid chloride (Pd (OAc)2), diethyl cyano group Palladous chloride. (Pd (CH3CN)2Cl2), palladium trifluoroacetate (Pd (OTA)2), palladium bromide (PdBr2), Palladous chloride. (PdCl2), tetrakis triphenylphosphine palladium (Pd (PPh3)4) or double; two (dibenzalacetone) palladium (Pd (dba)2) in any one, it is most preferred that for palladium acetylacetonate (Pd (acac)2)。
3. synthetic method as claimed in claim 1 or 2, it is characterised in that: described part is 2,2 '-bipyridyl.
4. the synthetic method as described in any one of claim 1-3, it is characterized in that: described acid compound is any one in camphorsulfonic acid, acetic acid, trifluoroacetic acid (TFA) or p-methyl benzenesulfonic acid (TSOH), it is preferably camphorsulfonic acid, trifluoroacetic acid (TFA) or p-methyl benzenesulfonic acid (TSOH), it is most preferred that for camphorsulfonic acid.
5. the synthetic method as described in any one of claim 1-4, it is characterised in that: described solvent is the mixture of organic solvent and water, and wherein organic solvent is 1:0.1-0.3 with the volume ratio of water.
6. the synthetic method as described in any one of claim 1-5, it is characterized in that: described formula (I) compound as raw material prepares as follows: in a solvent, under the existence of catalyst, part and acid, following formula (I-1) compound and following formula (II-1) compound react, react after terminating through post processing, thus obtaining described formula (III) compound
Wherein, X is alkali metal.
7. synthetic method as claimed in claim 6, it is characterised in that: described catalyst is acid chloride (Pd (OAc)2), diethyl cyano group Palladous chloride. (Pd (CH3CN)2Cl2), palladium trifluoroacetate (Pd (OTA)2), palladium bromide (PdBr2), Palladous chloride. (PdCl2), palladium acetylacetonate (Pd (acac)2), triphenylphosphine palladium chloride (Pd (PPh3)2Cl2), tetrakis triphenylphosphine palladium (Pd (PPh3)4), double; two (dibenzalacetone) palladium (Pd (dba)2) or three (dibenzalacetone) two palladium (Pd2(dba)3) in any one, it is preferred to double; two (dibenzalacetone) palladium (Pd (dba)2) or three (dibenzalacetone) two palladium (Pd2(dba)3), it is most preferred that it is three (dibenzalacetone) two palladium (Pd2(dba)3)。
8. synthetic method as claimed in claims 6 or 7, it is characterised in that: described part is any one in following formula L1-L8,
It most preferably is L1.
9. the synthetic method as described in any one of claim 6-8, it is characterised in that: described acid is any one in p-methyl benzenesulfonic acid, trifluoroacetic acid, camphorsulfonic acid, acetic acid or Loprazolam, it is most preferred that for camphorsulfonic acid.
10. the synthetic method as described in any one of claim 6-9, it is characterised in that: described solvent is the mixture of organic solvent and water, and wherein organic solvent is 4-6:1 with the volume ratio of water.
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