CN105732344B - A kind of synthetic method of symmetrical diacetyl compound - Google Patents
A kind of synthetic method of symmetrical diacetyl compound Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 35
- -1 diacetyl compound Chemical class 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 93
- 239000002904 solvent Substances 0.000 claims abstract description 45
- 239000003054 catalyst Substances 0.000 claims abstract description 38
- 239000002253 acid Substances 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 239000003446 ligand Substances 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 25
- 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 Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 63
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000003960 organic solvent Substances 0.000 claims description 20
- 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 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 15
- 229910052763 palladium Inorganic materials 0.000 claims description 13
- 239000002994 raw material Substances 0.000 claims description 9
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- 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 6
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 230000007547 defect Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- 239000012044 organic layer Substances 0.000 description 39
- 238000002360 preparation method Methods 0.000 description 35
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- 239000007864 aqueous solution Substances 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 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
- 239000010410 layer Substances 0.000 description 12
- 238000005406 washing Methods 0.000 description 11
- 239000007832 Na2SO4 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
- 239000011541 reaction mixture Substances 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 238000000746 purification 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
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 238000011835 investigation Methods 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 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 description 4
- 238000012805 post-processing Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 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 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 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 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
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- AKGGYBADQZYZPD-UHFFFAOYSA-N benzylacetone Chemical compound CC(=O)CCC1=CC=CC=C1 AKGGYBADQZYZPD-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 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 description 2
- INIOZDBICVTGEO-UHFFFAOYSA-L palladium(ii) bromide Chemical compound Br[Pd]Br INIOZDBICVTGEO-UHFFFAOYSA-L 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 241001614291 Anoplistes Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- CXOJWKKOZWZNFC-IAGOWNOFSA-N C[C@@]([C@@](CCCC1)(C1=O)N)(C=Cc1ccccc11)C1=O Chemical compound C[C@@]([C@@](CCCC1)(C1=O)N)(C=Cc1ccccc11)C1=O CXOJWKKOZWZNFC-IAGOWNOFSA-N 0.000 description 1
- 238000010485 C−C bond formation reaction Methods 0.000 description 1
- 229910021605 Palladium(II) bromide Inorganic materials 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- KILYNHHCRKVDRU-UHFFFAOYSA-N [S].C1CC2(C)C(=O)CC1C2(C)C Chemical compound [S].C1CC2(C)C(=O)CC1C2(C)C KILYNHHCRKVDRU-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- VEFXTGTZJOWDOF-UHFFFAOYSA-N benzene;hydrate Chemical compound O.C1=CC=CC=C1 VEFXTGTZJOWDOF-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- ZPFKRQXYKULZKP-UHFFFAOYSA-N butylidene Chemical group [CH2+]CC[CH-] ZPFKRQXYKULZKP-UHFFFAOYSA-N 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 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 description 1
- 229960003019 loprazolam Drugs 0.000 description 1
- 239000000463 material 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
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000006250 specific catalysis Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of synthetic methods of symmetrical diacetyl compound shown in lower formula (III), the described method includes in a solvent, in the presence of catalyst, ligand and acid compound, lower formula (I) compound reacts with lower formula (II) compound, it is post-treated after reaction, so as to obtain the formula (III) compound
Description
Technical field
The present invention relates to a kind of synthetic method of dicarbonyl compound, a kind of particularly symmetrical diacetyl compound
Synthetic method belongs to organic chemical synthesis field.
Background technology
In organic chemistry filed especially pharmaceutical intermediate synthesis technical field, ketone compounds are deposited due to carbonyl
, and with its good reactivity, often it is used widely in multiple synthesis fields as intermediate.
And in all ketone compounds, cyclohexadione compounds are due to there are two carbonyls, so as to further expand
The popularity of its purposes and more reaction applicabilities, such as in pharmaceutical intermediate field, in order to synthesize to obtain final purpose product
And largely using cyclohexadione compounds to carry out a variety of chemical reactions on carbonyl, so as to introduce active group or desired chemistry
The correct structure of structure.
Just because of such important role of cyclohexadione compounds, people, which synthesize it, largely deeply grind
Study carefully, and achieve many achievements, such as many synthetic methods for being related to cyclohexadione compounds are listed below：
Chao Liu et al. people (Palladium-Catalyzed C-C Bond Formation To Construct 1,4-
Diketones under Mild Conditions, Angew.Chem.Int.Ed., 2011,50, p 7337-7341) disclosed in
The method of synthesis Isosorbide-5-Nitrae-cyclohexadione compounds, this method are in alkali, ZnCl2, in the presence of palladium catalyst and ligand, pass through following formula
It reacts and obtains：：
Myron M.D.Wilde et al. (Bis (amino) cyclopropenylidenes as Organocatalysts
For Acyl Anion and Extended Umpolung Reactions, Angew.Chem.Int.Ed., 2013,50, p
A kind of method of Isosorbide-5-Nitrae-cyclohexadione compounds is disclosed in 12651-12654), reaction equation is as follows：
Jin Xie et al. (The cascade carbo-carbonylation of unactivated alkenes
catalyzed by an organocatalyst and a transition metal catalyst:a facile
Approach to c-diketones and c-carbonyl aldehydes from arylalkenes under air,
Chem.Commun., 2010,46, p 1947-1949) a kind of synthetic method of Isosorbide-5-Nitrae-cyclohexadione compounds is disclosed, it uses
Metallic catalyst, DMF/H2The combined systems such as O and obtain yield, reaction equation is as follows：
Jun Xuan et al. (Visible-Light-Induced C_S Bond Activation:Facile Access
To Isosorbide-5-Nitrae-Diketones from b-Ketosulfones, Chem.Eur.J., 2014,20, p 3045-3049) disclose one
In the case of kind using Ru compounds as catalyst and there are amine and additive, Isosorbide-5-Nitrae-cyclohexadione compounds that synthesis diphenyl substitutes
Method, reaction equation is as follows：
Akkattu T.Biju et al. (N-Heterocyclic Carbene-Catalyzed Cascade Reaction
Involving the Hydroacylation of Unactivated Alkynes, J.AM.CHEM.SOC., 2010,132, p
A kind of method that cyclohexadione compounds are synthesized in the presence of potassium carbonate 5970-5971) is disclosed, reaction equation is as follows：
Shenlin Huang et al. (Catalytic Asymmetric Dearomatizing Redox Cross
Coupling of Ketones with Aryl Hydrazines Giving Isosorbide-5-Nitrae-Diketones, J.AM.CHEM.SOC.,
2015,137, p 3446-3449) disclose a kind of synthetic method of cyclohexadione compounds, the method is using phosphine compound to urge
Agent in the presence of benzoic acid and water, is obtained, reaction equation is as follows by hydrazine compound and hexamethylene reactive ketone：
As described above, the synthesis a variety of methods of cyclohexadione compounds are disclosed in the prior art, but there are one for these methods
The defects of determining, such as product yield is relatively low or has used expensive reagent etc., can not still meet at present for dione compounds system
The extensive and easy requirement of Preparation Method.
For these above-mentioned defects, the present inventor has carried out the synthesis of cyclohexadione compounds inventive improvements, and
(Xingyong Wang et al., " Palladium-catalyzed addition of potassium
phenyltrifluoroborate to dinitriles:Synthesis of diketone compounds ", Journal
Of Chemical Research, p.470-472 following preparation method is disclosed in)：In palladium acetate catalyst, ligand 1,
In the presence of 10- ferrosins and trifluoroacetic acid, lower formula (II) compound occurs instead with lower formula (III) compound in reaction dissolvent
Should, the dione compounds of formula (I) under generating,
Wherein, L can be C1-C5The linker of alkylidene, X are alkali metal element.
But it was unexpectedly determined that on the premise of Ar is phenyl, when L is ethylidene, finds in the reaction system
Corresponding diacetyl class compound yield is only 57% or so, is significantly lower than methylene (84%), propylidene (91%)
Or (achievement is also partly disclosed in Chinese patent application CN201310178323.5 the yield of butylidene (89%), herein
It is no longer described in detail).
For diacetyl class compound as indicated above yield it is too low the defects of, the present inventor continued deeply
Research, by the comprehensive selection of suitable catalyst, ligand, acid and organic solvent etc. with cooperateing with, so as to significantly improve product
Yield.
The content of the invention
It is as described above, above-mentioned in the prior art as yield is too low, process is cumbersome, expensive reagents are rare in order to solve
Etc. many defects, the present inventor has made intensive studies for the synthesis of symmetrical diacetyl class compound, is paying a large amount of creation
Property work after, so as to complete the present invention.
It is pointed out that the present invention is in state natural sciences fund (project number：21572162) with Zhejiang Province certainly
Right science fund (project number：LY16B020012 complete under subsidy), express thanks herein.
The present invention relates to a kind of synthetic method of symmetrical diacetyl compound shown in lower formula (III), the described method includes
In solvent, in the presence of catalyst, ligand and acid compound, lower formula (I) compound occurs anti-with lower formula (II) compound
Should, it is post-treated after reaction, so as to obtain the formula (III) compound,
Wherein, X is alkali metal element.
In the synthetic method of the present invention, X is alkali metal element, may be, for example, Li, Na or K.
In the synthetic method of the present invention, the catalyst is palladium acetylacetonate (Pd (acac)2), acid chloride (Pd
(OAc)2), diethyl cyano palladium bichloride (Pd (CH3CN)2Cl2), palladium trifluoroacetate (Pd (OTA)2), palladium bromide (PdBr2), palladium bichloride
(PdCl2), tetrakis triphenylphosphine palladium (Pd (PPh3)4) or double (dibenzalacetone) palladium (Pd (dba)2) in any one, most
Preferably palladium acetylacetonate (Pd (acac)2)。
In the synthetic method of the present invention, the ligand is 2,2 '-bipyridyl.
In the synthetic method of the present invention, the acid compound is camphorsulfonic acid, acetic acid, trifluoroacetic acid (TFA)
Or any one in p-methyl benzenesulfonic acid (TSOH), it is preferably camphorsulfonic acid, trifluoroacetic acid (TFA) or p-methyl benzenesulfonic acid
(TSOH), it is most preferably camphorsulfonic acid.
In the synthetic method of the present invention, the solvent is organic solvent and the mixture of water, wherein organic solvent
Volume ratio with water is 1:0.1-0.3 may be, for example, 1:0.1、1:0.2 or 1:0.3.
Wherein, the organic solvent is tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) (DMSO), n,N-Dimethylformamide
(DMF) any one or in toluene is most preferably tetrahydrofuran (THF).
The dosage of the solvent is not particularly limited, and those skilled in the art can be according to actual conditions, such as react
Be smoothed out, facilitate post processing etc. concrete conditions and carry out suitably select and determine, this is all those skilled in the art
Routine techniques knowledge, is no longer described in detail herein.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and formula (II) compound is 1:
1.5-2.5 it may be, for example, 1:1.5、1:2 or 1:2.5.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and catalyst is 1:0.06-
0.12, it may be, for example, 1:0.06、1:0.08、1:0.1 or 1:0.12.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and ligand is 1:0.15-0.25,
It may be, for example, 1:0.15、1:2 or 1:0.25.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and acid compound is 1:1.5-
2.5, it may be, for example, 1:1.5、1:2 or 1:2.5.
In the synthetic method of the present invention, reaction temperature is 70-90 DEG C, may be, for example, 70 DEG C, 80 DEG C or 90 DEG C.
In the synthetic method of the present invention, the reaction time, there is no particular limitation, such as can be examined by liquid chromatogram
Survey the residual percentage of purpose product or raw material and determine the suitable reaction time, it typically is 20-30 it is small when, may be, for example, 20
Hour, 25 it is small when or 30 it is small when.
In the synthetic method of the present invention, post processing after reaction can be specific as follows：After reaction, by institute
Reaction mixture cooled to room temperature is obtained, then with saturation NaHCO3Aqueous solution and the washing of saturation NaCl aqueous solutions, are isolated
Water layer and organic layer, aqueous layer with ethyl acetate is extracted, and is merged organic layer and (is merged the organic layer after washing and be obtained by extraction
Organic layer), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through flash column chromatography (n-hexane/acetic acid second
Ester) purification, so as to obtain the formula (III) compound.
In the synthetic method of the present invention, the formula (I) compound as raw material is obtained as follows
Namely its synthetic method it is as follows：In a solvent, in the presence of catalyst, ligand and acid, following formula (I-1) compound is under
Formula (II-1) compound reacts, post-treated after reaction, so as to obtain the formula (III) compound,
Wherein, X is defined as above.
Namely X is alkali metal element, may be, for example, Li, Na or K..
In the synthetic method of the formula (I) compound of the present invention, the catalyst is acid chloride (Pd (OAc)2), two
Second cyano palladium bichloride (Pd (CH3CN)2Cl2), palladium trifluoroacetate (Pd (OTA)2), palladium bromide (PdBr2), palladium bichloride (PdCl2), second
Acyl acetone palladium (Pd (acac)2), triphenylphosphine palladium chloride (Pd (PPh3)2Cl2), tetrakis triphenylphosphine palladium (Pd (PPh3)4), it is double
(dibenzalacetone) palladium (Pd (dba)2) or three (dibenzalacetone) two palladium (Pd2(dba)3) in any one, be preferably
Double (dibenzalacetone) palladium (Pd (dba)2) or three (dibenzalacetone) two palladium (Pd2(dba)3), it is most preferably three (two Asias
Benzylacetone) two palladium (Pd2(dba)3)。
In the synthetic method of the formula (I) compound of the present invention, the ligand is any one in following formula L1-L8
Kind,
Most preferably L1.
In the synthetic method of the formula (I) compound of the present invention, the acid is p-methyl benzenesulfonic acid, trifluoroacetic acid, the right side
Any one in camphorsulfonic acid, acetic acid or Loprazolam is revolved, is most preferably d-camphorsulfonic acid.
In the synthetic method of the formula (I) compound of the present invention, the solvent is the mixture of organic solvent and water,
Wherein the volume ratio of organic solvent and water is 4-6:1, it may be, for example, 4:1、5:1 or 6:1.
Wherein, the organic solvent for dimethyl sulfoxide (DMSO) (DMSO), n,N-Dimethylformamide (DMF), N, N- dimethyl
Acetamide (DMAC), toluene, ortho-xylene, benzene, 1,4- dioxane, tetrahydrofuran (THF), ethyl alcohol, acetone, n-hexane or second
Any one in ether is most preferably benzene.
The dosage of the solvent is not particularly limited, and those skilled in the art can be according to actual conditions, such as react
Be smoothed out, facilitate post processing etc. concrete conditions and carry out suitably select and determine, this is all those skilled in the art
Routine techniques knowledge, is no longer described in detail herein.
In the synthetic method of the formula (I) compound of the present invention, formula (I-1) compound and formula (II-1) chemical combination
The molar ratio of object is 1:1.5-2.5 it may be, for example, 1:1.5、1:2 or 1:2.5.
In the synthetic method of the formula (I) compound of the present invention, mole of formula (I-1) compound and catalyst
Than for 1:0.04-0.08 may be, for example, 1:0.04、1:0.05、1:0.06、1:0.07 or 1:0.08.
In the synthetic method of the formula (I) compound of the present invention, the molar ratio of formula (I-1) compound and ligand
For 1:0.15-0.25 may be, for example, 1:0.15、1:2 or 1:0.25.
In the synthetic method of the formula (I) compound of the present invention, formula (I-1) compound and the molar ratio of acid are
1:1-3 may be, for example, 1:1、1:1.5、1:2、1:2.5 or 1:3.
The present invention the formula (I) compound synthetic method in, reaction temperature be 60-80 DEG C, may be, for example, 60 DEG C,
70 DEG C or 80 DEG C.
In the synthetic method of the formula (I) compound of the present invention, the reaction time, there is no particular limitation, such as can lead to
It crosses the residual percentage of liquid chromatographic detection purpose product or raw material and determines the suitable reaction time, it is small it typically is 18-30
When, may be, for example, 18 it is small when, 22 it is small when, 26 it is small when or 30 it is small when.
In the synthetic method of the formula (I) compound of the present invention, post processing after reaction can be specific as follows：Instead
After answering, gained reaction mixture is poured into ethyl acetate, sequentially with saturation NaHCO3Aqueous solution and saturation NaCl are water-soluble
Liquid washs, and separates water-yielding stratum and organic layer, aqueous layer with ethyl acetate is extracted, and merges organic layer and (merges organic after washing
Layer and the organic layer being obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through flash column chromatography
(n-hexane/ethyl acetate) purifies, so as to obtain the formula (I) compound.
Inventor has found, when preparing raw material compound (I) compound, can be obtained when using the above method with high yield
Formula (I) compound, so as to provide raw material compound for the synthesis of final product, that is, formula (III) compound.
In conclusion it is of the invention by suitable catalyst, ligand and acid compound and suitable dicyandiamide solution, thus
Symmetrical diacetyl class compound can be obtained with high yield, and has studied the optimum synthesising method of raw material reactant.So as to organic
It has a good application prospect in the field of chemical synthesis and researching value, the synthesis for symmetrical diacetyl class compound provides entirely
New method.
Specific embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and
Purpose is only used for enumerating the present invention, not forms any type of any restriction to the real protection scope of the present invention, more non-to incite somebody to action
Protection scope of the present invention is confined to this.
Preparation example 1
At room temperature, to appropriate solvent (for volume ratio 5:1 benzene and the mixture of water) in add in 100mmol above formulas (I-1)
Compound, 150mmol above formulas (II-1) compound, 4mmol catalyst Pd2(dba)3, 25mmol ligand Ls 1 and 100mmol dextrorotation
Camphorsulfonic acid, then stirring be warming up to 60 DEG C, and be stirred to react at such a temperature 30 it is small when；
After reaction, gained reaction mixture is poured into ethyl acetate, sequentially with saturation NaHCO3Aqueous solution and full
It is washed with NaCl aqueous solutions, separates water-yielding stratum and organic layer, aqueous layer with ethyl acetate is extracted, merged organic layer and (merge and wash
Organic layer after washing and the organic layer being obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through fast
Fast column chromatography (n-hexane/ethyl acetate) purification, so as to obtain upper formula (I) compound, yield 85.7%.
Nuclear magnetic resonance：1H NMR(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)；
13C NMR(CDCl3,125MHz):δ195.33,135.68,133.91,128.90(2C),128.04(2C),
119.19,34.30,11.81。
Preparation example 2
For reaction equation with preparation example 1, specific operation process is as follows：
At room temperature, to appropriate solvent (for volume ratio 4:1 benzene and the mixture of water) in add in 100mmol described in formula (I-
1) compound, formula (II-1) compound, 6mmol catalyst Pd described in 200mmol2(dba)3, 15mmol ligand Ls 1 and 200mmol
D-camphorsulfonic acid, then stirring be warming up to 70 DEG C, and be stirred to react at such a temperature 24 it is small when；
After reaction, gained reaction mixture is poured into ethyl acetate, sequentially with saturation NaHCO3Aqueous solution and full
It is washed with NaCl aqueous solutions, separates water-yielding stratum and organic layer, aqueous layer with ethyl acetate is extracted, merged organic layer and (merge and wash
Organic layer after washing and the organic layer being obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through fast
Fast column chromatography (n-hexane/ethyl acetate) purification, so as to obtain the formula (I) compound, yield 85.3%.Characterize data is same
Preparation example 1.
Preparation example 3
For reaction equation with preparation example 1, specific operation process is as follows：
At room temperature, to appropriate solvent (for volume ratio 6:1 benzene and the mixture of water) in add in 100mmol described in formula (I-
1) compound, formula (II-1) compound, 8mmol catalyst Pd described in 250mmol2(dba)3, 20mmol ligand Ls 1 and 300mmol
D-camphorsulfonic acid, then stirring be warming up to 80 DEG C, and be stirred to react at such a temperature 18 it is small when；
After reaction, gained reaction mixture is poured into ethyl acetate, sequentially with saturation NaHCO3Aqueous solution and full
It is washed with NaCl aqueous solutions, separates water-yielding stratum and organic layer, aqueous layer with ethyl acetate is extracted, merged organic layer and (merge and wash
Organic layer after washing and the organic layer being obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through fast
Fast column chromatography (n-hexane/ethyl acetate) purification, so as to obtain the formula (I) compound, yield 85.5%.Characterize data is same
Preparation example 1.
Preparation example 4
For reaction equation with preparation example 1, specific operation process is as follows：
At room temperature, to appropriate solvent (for volume ratio 5:1 benzene and the mixture of water) in add in 100mmol described in formula (I-
1) compound, formula (II-1) compound, 5mmol catalyst Pd described in 170mmol2(dba)3, 22mmol ligand Ls 1 and 150mmol
D-camphorsulfonic acid, then stirring be warming up to 65 DEG C, and be stirred to react at such a temperature 27 it is small when；
After reaction, gained reaction mixture is poured into ethyl acetate, sequentially with saturation NaHCO3Aqueous solution and full
It is washed with NaCl aqueous solutions, separates water-yielding stratum and organic layer, aqueous layer with ethyl acetate is extracted, merged organic layer and (merge and wash
Organic layer after washing and the organic layer being obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through fast
Fast column chromatography (n-hexane/ethyl acetate) purification, so as to obtain upper formula (I) compound, yield 85.6%.Characterize data is the same as system
Standby example 1.
It can be seen that by above-mentioned preparation example 1-4, raw material compound (I) compound prepared when synthetic method using the present invention
When, (I) compound can be obtained with good yield, so as to provide and establish base for the synthesis of follow-up formula (III) compound
Plinth.
Preparation example 5-13：The investigation of catalyst
Pd is replaced except following catalyst is used2(dba)3Outside, other operations are constant, so as to according to the phase of preparation example 1-4
Same method, implements preparation example 5-13, and institute see the table below 1 using catalyst, preparation example correspondence and products collection efficiency.
Table 1
It can be seen that in all catalyst, Pd (dba)2Or Pd2(dba)3With good effect, and Pd2(dba)3
Then most excellent yield.Other catalyst cause yield to significantly reduce, and can not even react.
Preparation example 14-20：The investigation of ligand
In addition to different ligands is used to replace L1, other operations are constant, thus according to the same procedure of preparation example 1-4, it is real
Preparation example 14-20 is applied, institute see the table below 2 using ligand, preparation example correspondence and products collection efficiency.
Table 2
It can be seen that in all ligand L 1-L8, L1 has best effect, can obtain especially excellent product
Yield, even L2, L5-L6 very similar with it, yield are also significantly reduced, and especially L2 products are 0.This proof is matched somebody with somebody
Body slight change in structure, you can yield is caused to have unexpected greatest differences.
Preparation example 21-28：The investigation of acid
In addition to different acid is used to replace d-camphorsulfonic acid, other operations are constant, so as to according to the identical of preparation example 1-4
Method implements preparation example 21-24；And for the influence for further investigating acid, respectively by the gum camphor in preparation example 1-4
Sulfonic acid is omitted, and other operations are constant, so as to which preparation example 1-4 be repeated, sequentially obtain preparation example 25-28.
Institute see the table below 3 using acid, preparation example correspondence and products collection efficiency.
Table 3
Note：" * " refers to repeat preparation example 1-4 and sequentially obtain preparation example 25-28.
It can be seen that the species of acid has uncertain influence, wherein d-camphorsulfonic acid for final products collection efficiency
Excellent yield can be obtained, and other acid cause yield to be significantly reduced.And when without using d-camphorsulfonic acid, then
Reaction can not carry out, so as to obtain product.
Preparation example 29-40：The investigation of solvent
In addition to different organic solvents is used to replace the benzene in solvent, other operations are constant, so as to according to preparation example 1-4
Same procedure, implement preparation example 29-40 (being still the organic solvent and the mixture of water in the following table 4), it is used molten
Organic solvent, preparation example correspondence and products collection efficiency in agent see the table below 4.
Table 4
Note：" * " represents that the solvent of preparation example 38 is only one-component water.
It can be seen that：1st, when water is only used only as solvent (i.e. preparation example 38), yield is significantly reduced；2nd, when making
During by the use of the mixture of organic solvent and water as solvent, wherein organic solvent is most preferably benzene, is even replaced with very
Similar toluene or ortho-xylene, but its yield is still significantly reduced (see preparation example 32-33).Thus benzene-water is demonstrated
With best unexpected technique effect when mixture is as solvent.
Example 1-40 produced above as it can be seen that when Material synthesis method using the present invention, by special catalyst, ligand,
The selection for unique reaction system that acid and solvent is formed, can obtain raw material compound formula (I) compound with good yield,
It provides the foundation for the synthesis of formula (III) compound in example below and (is obtaining formula according to above-mentioned preparation example with reactant
(I) compound, then carry out the subsequent operation of example below).
Embodiment 1
At room temperature, to appropriate solvent (for volume ratio 1:0.2 THF and the mixture of water) in add in 100mmol on formula (I)
The upper formula (II) compound of compound, 150mmol, 6mmol catalyst Pd (acac), 2,2 '-bipyridyl of 15mmol ligands and
150mmol acid compound camphorsulfonic acids, then heat to 70 DEG C, and be stirred to react at such a temperature 30 it is small when；
After reaction, by gained reaction mixture cooled to room temperature, then with saturation NaHCO3Aqueous solution and full
It is washed with NaCl aqueous solutions, separates water-yielding stratum and organic layer, aqueous layer with ethyl acetate is extracted, merged organic layer and (merge and wash
Organic layer after washing and the organic layer being obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through fast
Fast column chromatography (n-hexane/ethyl acetate) purification, so as to obtain the formula (III) compound, yield 91.7%.
Nuclear magnetic resonance：1H NMR(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)；
13C NMR(DMSO-d6,125MHz):δ198.58(2C),136.55(2C),133.16(2C),128.71(4C),
127.87(4C),32.27(2C)。
Embodiment 2
For reaction equation with embodiment 1, specific operation process is as follows：
At room temperature, to appropriate solvent (for volume ratio 1:0.1 THF and the mixture of water) in add in 100mmol on formula (I)
The upper formula (II) compound of compound, 200mmol, 9mmol catalyst Pd (acac), 2,2 '-bipyridyl of 20mmol ligands and
200mmol acid compound camphorsulfonic acids, then heat to 80 DEG C, and be stirred to react at such a temperature 25 it is small when；
After reaction, by gained reaction mixture cooled to room temperature, then with saturation NaHCO3Aqueous solution and full
It is washed with NaCl aqueous solutions, separates water-yielding stratum and organic layer, aqueous layer with ethyl acetate is extracted, merged organic layer and (merge and wash
Organic layer after washing and the organic layer being obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through fast
Fast column chromatography (n-hexane/ethyl acetate) purification, so as to obtain the formula (III) compound, yield 91.5%.
Nuclear magnetic data is the same as embodiment 1.
Embodiment 3
For reaction equation with embodiment 1, specific operation process is as follows：
At room temperature, to appropriate solvent (for volume ratio 1:0.3 THF and the mixture of water) in add in 100mmol on formula (I)
The upper formula (II) compound of compound, 250mmol, 12mmol catalyst Pd (acac), 2,2 '-bipyridyl of 25mmol ligands and
250mmol acid compound camphorsulfonic acids, then heat to 90 DEG C, and be stirred to react at such a temperature 20 it is small when；
After reaction, by gained reaction mixture cooled to room temperature, then with saturation NaHCO3Aqueous solution and full
It is washed with NaCl aqueous solutions, separates water-yielding stratum and organic layer, aqueous layer with ethyl acetate is extracted, merged organic layer and (merge and wash
Organic layer after washing and the organic layer being obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through fast
Fast column chromatography (n-hexane/ethyl acetate) purification, so as to obtain the formula (III) compound, yield 91.8%.
Nuclear magnetic data is the same as embodiment 1.
Embodiment 4
For reaction equation with embodiment 1, specific operation process is as follows：
At room temperature, to appropriate solvent (for volume ratio 1:0.2 THF and the mixture of water) in add in 100mmol on formula (I)
The upper formula (II) compound of compound, 170mmol, 10mmol catalyst Pd (acac), 2,2 '-bipyridyl of 23mmol ligands and
180mmol acid compound camphorsulfonic acids, then heat to 85 DEG C, and be stirred to react at such a temperature 25 it is small when；
After reaction, by gained reaction mixture cooled to room temperature, then with saturation NaHCO3Aqueous solution and full
It is washed with NaCl aqueous solutions, separates water-yielding stratum and organic layer, aqueous layer with ethyl acetate is extracted, merged organic layer and (merge and wash
Organic layer after washing and the organic layer being obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through fast
Fast column chromatography (n-hexane/ethyl acetate) purification, so as to obtain the formula (III) compound, yield 91.4%.
Nuclear magnetic data is the same as embodiment 1.
It can be seen that by above-described embodiment 1-4, when reaction system using the present invention, symmetrically nail two can be obtained with high yield
57% yield in ketone compounds, with the above-mentioned periodical of the present inventor improves 44% or so, and yield, which has, significantly to be carried
High and improvement.
Embodiment 5-32：The investigation of catalyst
Embodiment 5-8：Except by catalyst by Pd (acac)2Replace with Pd (OAc)2Outside, other operations are constant, so as to weight
Embodiment 1-4 is implemented again, sequentially obtains embodiment 5-8.
Embodiment 9-12：Except by catalyst by Pd (acac)2Replace with Pd (CH3CN)2Cl2Outside, other operations are constant,
So as to repeat to implement embodiment 1-4, embodiment 9-12 is sequentially obtained.
Embodiment 13-16：Except by catalyst by Pd (acac)2Replace with Pd (OTA)2Outside, other operations are constant, so as to
Repetition implements embodiment 1-4, sequentially obtains embodiment 13-16.
Embodiment 17-20：Except by catalyst by Pd (acac)2Replace with PdBr2Outside, other operations are constant, so as to repeat
Embodiment 1-4 is implemented, sequentially obtains embodiment 17-20.
Embodiment 21-24：Except by catalyst by Pd (acac)2Replace with PdCl2Outside, other operations are constant, so as to repeat
Embodiment 1-4 is implemented, sequentially obtains embodiment 21-24.
Embodiment 25-28：Except by catalyst by Pd (acac)2Replace with Pd (PPh3)4Outside, other operations are constant, so as to
Repetition implements embodiment 1-4, sequentially obtains embodiment 25-28.
Embodiment 29-32：Except by catalyst by Pd (acac)2Replace with Pd (dba)2Outside, other operations are constant, so as to
Repetition implements embodiment 1-4, sequentially obtains embodiment 29-32.
The result is shown in the following table 5.
Table 5
It can be seen that in all catalyst, Pd (acac)2With best catalytic effect；Other catalyst are led
Cause yield have be greatly lowered in addition will be less than yield of the prior art (yield is in the above-mentioned periodical literature of the present inventor
57%), more even it can not obtain product (see embodiment 17-20,25-28).
Embodiment 33-44：The investigation of acid compound
Embodiment 33-36：In addition to acid compound is replaced with acetic acid by camphorsulfonic acid, other operations are constant, so as to
Repetition implements embodiment 1-4, sequentially obtains embodiment 33-36.
Embodiment 37-40：In addition to acid compound is replaced with trifluoroacetic acid (TFA) by camphorsulfonic acid, other operations are equal
It is constant, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 37-40.
Embodiment 41-44：In addition to acid compound is replaced with p-methyl benzenesulfonic acid (TSOH) by camphorsulfonic acid, so as to repeat
Embodiment 1-4 is implemented, sequentially obtains embodiment 41-44.
The result is shown in the following table 6.
Table 6
It can be seen that in all acid compounds, camphorsulfonic acid, TFA and TSOH have preferable effect (camphor sulphur
The effect of acid is the most excellent), and other acid cause yield to have apparent reduction, especially acetic acid, although it can also be seen that
TFA is very similar with acetic acid, but its yield will be significantly higher than acetic acid.
Embodiment 45-56：The investigation of solvent
Embodiment 45-48：In addition to the organic solvent in solvent is replaced with DMSO by THF, other operations are constant, so as to
Repetition implements embodiment 1-4, sequentially obtains embodiment 45-48.
Embodiment 49-52：In addition to the organic solvent in solvent is replaced with DMF by THF, other operations are constant, so as to
Repetition implements embodiment 1-4, sequentially obtains embodiment 49-52.
Embodiment 53-56：In addition to the organic solvent in solvent is replaced with toluene by THF, other operations are constant, so as to
Repetition implements embodiment 1-4, sequentially obtains embodiment 53-56.
The result is shown in the following table 7.
Table 7
It can be seen that when using the composite solvent system of THF and water, can purpose product be obtained with excellent yield, but
It was unexpectedly determined that when THF therein is replaced other organic solvent such as DMSO, DMF or toluene, will all yield be caused to have one
It is fixed it is even significant reduce when DMF (especially for), this demonstrate that the bi-component double solvents only formed using THF with water
System could obtain unexpected high product yield.
In conclusion can clearly be found out by above-mentioned all embodiments, when applying the method according to the invention, pass through specific catalysis
Agent, ligand, the comprehensive selection of acid compound and solvent are with cooperateing with, so as to overcome diacetyl class compound in the prior art
Yield it is too low the defects of, can purpose product be obtained with high yield, had a good application prospect in organic chemical synthesis field
And industrial production potential.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to the protection model of the limitation present invention
It encloses.In addition, it should also be understood that, after reading the technical contents of the present invention, those skilled in the art can make the present invention each
Kind change, modification and/or variation, all these equivalent forms equally fall within the guarantor that the application the appended claims are limited
Within the scope of shield.
Claims (2)
1. the synthetic method of symmetrical diacetyl compound shown in a kind of lower formula (III), the described method includes in a solvent, in catalysis
In the presence of agent, ligand and acid compound, lower formula (I) compound reacts with lower formula (II) compound, after reaction
It is post-treated, so as to obtain the formula (III) compound,
Wherein, X is alkali metal element；
The catalyst is palladium acetylacetonate；
The ligand is 2,2 '-bipyridyl；
The acid compound is camphorsulfonic acid；
The solvent is organic solvent and the mixture of water, and the wherein volume ratio of organic solvent and water is 1:0.1-0.3, it is described to have
Solvent is tetrahydrofuran.
2. synthetic method as described in claim 1, it is characterised in that：The formula (I) compound as raw material is according to such as
Made from the method for lower section：In a solvent, in the presence of catalyst, ligand and acid, following formula (I-1) compound is changed with following formula (II-1)
Object is closed to react, it is post-treated after reaction, so as to obtain the formula (III) compound,
Wherein, X is alkali metal element；
The catalyst is three (dibenzalacetone) two palladium；
The ligand is following formula L1,
The acid is camphorsulfonic acid；
The solvent is organic solvent and the mixture of water, and the wherein volume ratio of organic solvent and water is 4-6:1, it is described organic molten
Agent is benzene.
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| Title |
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| Palladium-Catalyzed Addition of Potassium Aryltrifluoroborates to Aliphatic Nitriles: Synthesis of Alkyl Aryl Ketones, Diketone Compounds, and 2‑Arylbenzo[b]furans;Xingyong Wang, et al;《The Journal of Organic Chemistry》;20130513;第78卷;5273-5281 * |
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