CN104987318B - Synthesis method for naphthalene-vinyl-substituted ketone compounds - Google Patents
Synthesis method for naphthalene-vinyl-substituted ketone compounds Download PDFInfo
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- -1 naphthalene-vinyl-substituted ketone compounds Chemical class 0.000 title claims abstract description 21
- 238000001308 synthesis method Methods 0.000 title abstract 3
- 239000003054 catalyst Substances 0.000 claims abstract description 36
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 239000003513 alkali Substances 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 230000003213 activating effect Effects 0.000 claims abstract description 19
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- 238000010189 synthetic method Methods 0.000 claims description 30
- 239000002131 composite material Substances 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 12
- OMAWWKIPXLIPDE-UHFFFAOYSA-N (ethyldiselanyl)ethane Chemical compound CC[Se][Se]CC OMAWWKIPXLIPDE-UHFFFAOYSA-N 0.000 claims description 10
- VLXBWPOEOIIREY-UHFFFAOYSA-N dimethyl diselenide Chemical compound C[Se][Se]C VLXBWPOEOIIREY-UHFFFAOYSA-N 0.000 claims description 8
- ZYWUVGFIXPNBDL-UHFFFAOYSA-N n,n-diisopropylaminoethanol Chemical compound CC(C)N(C(C)C)CCO ZYWUVGFIXPNBDL-UHFFFAOYSA-N 0.000 claims description 7
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 5
- 229920002554 vinyl polymer Polymers 0.000 claims description 5
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical group [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 4
- 238000009413 insulation Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 14
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 230000003197 catalytic effect Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 238000004321 preservation Methods 0.000 abstract 1
- 230000002195 synergetic effect Effects 0.000 abstract 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 229940113115 polyethylene glycol 200 Drugs 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000012046 mixed solvent Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 208000035126 Facies Diseases 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 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
- 238000005406 washing Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical group CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [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 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 description 2
- 229940043276 diisopropanolamine Drugs 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 150000002941 palladium compounds Chemical class 0.000 description 2
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 description 2
- 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 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- XUXNAKZDHHEHPC-UHFFFAOYSA-M sodium bromate Chemical compound [Na+].[O-]Br(=O)=O XUXNAKZDHHEHPC-UHFFFAOYSA-M 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
Abstract
The invention relates to a synthesis method for naphthalene-vinyl-substituted ketone compounds (please see the formula in the specification). The method includes the steps of making a compound of the follow formula (I) and a compound of the following formula (II) react for 2 hours to 3 hours under the temperature of 50 DEG C to 80 DEG C in solvent under the condition that catalysts, catalytic addictives and compound activating agents exist, then adding alkali, and continuing to conduct the heat preservation reaction for 3 hours to 5 hours to obtain the compound (please see the formula in the specification) of the formula (III), wherein H, halogen, C1-C6 alkyl groups or C1-C6 alkoxy are independently selected for R1 and R2, and X is halogen. According to the method, by selecting types and components of the specific catalysts, the specific catalytic addictives, the specific activating agents, the specific alkali, the specific solvent and the like and selecting the appropriate alkali adding opportunity, the unique synergistic effect is brought into full play between the components, the target product can be obtained with high yield, and the synthesis method has good application prospects and wide industrial production potential in the field of organic synthesis especially the technical field of intermediate synthesis.
Description
Technical field
The present invention relates to a kind of synthetic method for condensing cyclics, relates more particularly to what a kind of naphthalene vinyl replaced
The synthetic method of ring ketone compounds, belongs to organic intermediate synthesis field.
Background technology
Fused rings ketone compounds have important effect in organic synthesiss, especially pharmaceutical intermediate synthesis technical field
And purposes, due to wherein containing fused rings, and it is easy to the carbonyl of further reaction, therefore be to be usually used to build close
Into the common structure fragment of medicine, natural product and material molecule.Also just because of the important potentiality of such structural compounds,
Therefore, develop the new and effective synthetic method of fused rings ketone compounds has day by day become the key issue of scientific research.
But on the other hand, in modern synthesising chemical technology, it is the great challenge of organic synthesis field directly to construct C-O keys
The problem of property, this be because the low-oxidation-state of c h bond, chemo-selective and regioselectivity are difficult to control in organic molecule,
So as to be difficult to directly form C-O keys.
In recent years, in organic catalysis chemistry, the construction technology for being related to the C-O keys of fused rings ketone compounds has been achieved with
Significant progress and development, also report various synthetic methods, for example in prior art：
(" the An improved method for the synthesis of g-lactones such as Safdar Hayat
using sodium bromate and sodium hydrogen sulfite”,Tetrahedron Letters,2001,
42,1647-1649) report it is a kind of with sodium bromate and sodium sulfite as catalyst, ethyl acetate as solvent by adjacent alkyl
The method that benzoic acid prepares cyclisation product, its reaction equation is as follows：
(" Pt-Catalyzed sp3C-H bond activation of the o-alkyl such as Ji Min Lee
substituted aromatic carboxylic acid derivatives for the formation of aryl
Lactones ", Tetrahedron Letters, 2006,47,1375-1379) disclose a kind of using palladium or platinum catalyst, with
The method that ortho-alkyl aromatic carboxylic acid builds aryl cyclic lactone for raw material, its reaction equation is as follows：
Although as described above, disclose in prior art some synthesis fused rings ketone compounds methods, for it
New synthetic method, still suffers from the necessity for continuing to study, and this is also one of study hotspot and emphasis in the field, also exactly
The power that the present invention is accomplished is located and basis is leaned on.
The content of the invention
Method in order to develop new synthesis fused rings ketone compounds, present inventor has performed in-depth study and spy
Rope, after enough creative works have been paid, so as to complete the present invention.
Specifically, technical scheme and content are related to a kind of ring of the replacement of naphthalene vinyl shown in lower formula (III)
The synthetic method of ketone compounds,
Methods described includes：In a solvent, in the presence of catalyst, catalyst aid and composite activating agent, lower formula (I) chemical combination
Thing and lower formula (II) compound react 2-3 hours at 50-80 DEG C, are subsequently adding alkali, continue insulation reaction 3-5 hour, so as to
Described (III) compound is obtained,
Wherein, R1、R2It is each independently selected from H, halogen, C1-C6Alkyl or C1-C6Alkoxyl；
X is halogen.
In the synthetic method of the present invention, the implication of the halogen refers to halogen, for example can be non-exclusively
F, Cl, Br or I.
In the synthetic method of the present invention, the C1-C6The implication of alkyl refers to the straight chain with 1-6 carbon atom
Or branched alkyl, for example can be in non-limiting manner methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, uncle
Butyl, n-pentyl, isopentyl or n-hexyl etc..
In the synthetic method of the present invention, the C1-C6The implication of alkoxyl refers to C defined above1-C6Alkyl
The group obtained after being connected with oxygen atom.
In the synthetic method of the present invention, the catalyst is acid chloride (Pd (OAc)2), palladium trifluoroacetate (Pd
(TFA)2), palladium acetylacetonate (Pd (acac)2), tetrakis triphenylphosphine palladium (Pd (PPh3)4), two (triphenylphosphine) Palladous chloride .s
(PdCl2(PPh3)2Any one of), most preferably palladium trifluoroacetate (Pd (TFA)2)。
In the synthetic method of the present invention, the catalyst aid is dimethyl diselenide ether or diethyl diselenide, excellent
Elect diethyl diselenide as.
In the synthetic method of the present invention, the composite activating agent is the double benzsulfamides (NFSI) of N- fluoro and trifluoro
Change the mixture of borate ether, both mol ratios are 1:2-3.
In the synthetic method of the present invention, the alkali is NaOH, KOH, sodium carbonate, Feldalat NM, potassium tert-butoxide, three second
Amine, diethanolamine, diisopropanolamine (DIPA), diisopropyl ethanolamine, 1,4- diazabicylos [2.2.2] octane (DABCO), tetramethyl
Any one of ethylenediamine etc., most preferably diisopropyl ethanolamine.
The present invention the synthetic method in, the solvent be 1- normal-butyl -2,3- methylimidazole tetrafluoroborates
With selected from DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), ethanol, benzene, the toluene, (PEG- of Polyethylene Glycol -200
Any one of 200) mixture, wherein, 1- normal-butyl -2,3- methylimidazoles tetrafluoroborate be selected from DMF (N, N-
Dimethylformamide), DMSO (dimethyl sulfoxide), ethanol, benzene, toluene, any one of Polyethylene Glycol -200 (PEG-200)
Volume ratio be 1:8.
Wherein, most preferably volume ratio is 1:8 1- normal-butyls -2,3- methylimidazoles tetrafluoroborate and poly- second two
The mixture of alcohol -200 (PEG-200).
The consumption of the solvent does not have strict restriction, and those skilled in the art can be suitably selected its consumption
Select, for example can according to causing post processing to be easy to carry out, react the amount being smoothed out carry out it is appropriately selected.
In the synthetic method of the present invention, formula (I) compound is 1 with the mol ratio of formula (II) compound:
1.4-2, for example, can be 1:1.4、1:1.6、1:1.8 or 1:2.
In the synthetic method of the present invention, formula (I) compound is 1 with the mol ratio of catalyst:0.04-
0.07, for example can be 1:0.04、1:0.05、1:0.06 or 1:0.07.
In the synthetic method of the present invention, formula (I) compound is 1 with the mol ratio of catalyst aid:0.1-
0.2, for example can be 1:0.1、1:0.15 or 1:0.2.
In the synthetic method of the present invention, formula (I) compound is 1 with the mol ratio of composite activating agent:0.07-
0.15, i.e., mole dosage and the total moles consumption of two kinds of components of the composition composite activating agent of described formula (I) compound
Than for 1:0.07-0.15, for example, can be 1:0.07、1:0.09、1:0.11、1:0.13 or 1:0.15.
In the synthetic method of the present invention, formula (I) compound is 1 with the mol ratio of alkali:1-1.5, for example may be used
For 1:1、1:1.2、1:1.4 or 1:1.5.
In the synthetic method of the present invention, the post processing after reaction terminates is specific as follows：After the completion of reaction, mistake while hot
Filter, the pH value for adjusting filtrate is neutrality, is then fully washed 2-3 time with saturated sodium bicarbonate aqueous solution, separates organic faciess, decompression
Concentration, residue crosses 200-300 mesh silica gel column chromatographies, with volume ratio as 1:3 normal hexane and the mixed solvent of acetone are used as washing
De- liquid, so as to obtain the formula (III) compound.
As described above, the invention provides a kind of synthetic method of fused rings ketone compounds, the method is by selecting spy
The species and component of fixed catalyst, catalyst aid, composite activating agent, alkali and solvent etc., and to select suitable alkali to add fashionable
Machine, and cause to have played the synergism of uniqueness each other, purpose product can be obtained with high yield, it is outstanding in organic synthesis field
It is that intermediate synthesis technical field has a good application prospect and extensive industrial production potential.
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 constitutes 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.
Wherein, in following all embodiments, its reaction equation is as follows：
And, below in all embodiments, the characterize data of all products is as follows：
1H NMR(C6D6,400MHz):δ 5.44 (d, J=7.9Hz, 1H), 5.83 (dd, J=15.7,7.9Hz, 1H),
6.62 (d, J=15.7Hz, 1H), 6.76-6.87 (m, 1H), 6.96 (t, J=7.4Hz, 1H), 7.03 (td, J=7.5Hz, J=
1.2Hz, 1H), 7.18-7.31 (m, 3H), 7.38-7.43 (m, 1H), 7.52 (d, J=8.6Hz, 1H), 7.56-7.69 (m,
2H), 7.78 (d, J=7.6Hz, 1H).
HRMS(ESI)([M+H]+):286.098。
Embodiment 1
Specific operation process is as follows：
At room temperature, it is 1 to appropriate volume ratio:8 1- normal-butyls -2,3- methylimidazoles tetrafluoroborate and poly- second two
In the mixed solvent of alcohol -200 (PEG-200), add 100mmol on formula (I) compound, the upper formula (II) compounds of 150mmol,
5mmol catalyst Pd (TFA)2, 10mmol catalyst aid diethyl diselenides and 7mmol composite activating agents (be 2mmol N- fluorine
The mixture of generation double benzsulfamides (NFSI) and 5mmol boron trifluoride diethyl etherate), 80 DEG C are then heated to, and it is anti-at such a temperature
Answer 2 hours, 100mmol alkali diisopropyl ethanolamines are subsequently added in reaction system, and continue to be incubated instead at such a temperature
Answer 3 hours；
After the completion of reaction, filtered while hot, the pH value for adjusting filtrate is neutrality, then abundant with saturated sodium bicarbonate aqueous solution
Washing 2-3 time, separates organic faciess, and concentrating under reduced pressure, residue crosses 200-300 mesh silica gel column chromatographies, with volume ratio as 1:3 just oneself
Used as eluent, so as to obtain above-mentioned formula (III) compound, yield is 95.4% to the mixed solvent of alkane and acetone.
Embodiment 2
Specific operation process is as follows：
At room temperature, it is 1 to appropriate volume ratio:8 1- normal-butyls -2,3- methylimidazoles tetrafluoroborate and poly- second two
In the mixed solvent of alcohol -200 (PEG-200), add 100mmol on formula (I) compound, the upper formula (II) compounds of 200mmol,
7mmol catalyst Pd (TFA)2, 15mmol catalyst aid diethyl diselenides and 10mmol composite activating agents (be 2.5mmol N-
The mixture of the double benzsulfamides (NFSI) of fluoro and 7.5mmol boron trifluoride diethyl etherate), 50 DEG C are then heated to, and in the temperature
Lower reaction 3 hours, subsequently adds 130mmol alkali diisopropyl ethanolamines in reaction system, and continues to protect at such a temperature
Temperature reaction 4 hours；
After the completion of reaction, filtered while hot, the pH value for adjusting filtrate is neutrality, then abundant with saturated sodium bicarbonate aqueous solution
Washing 2-3 time, separates organic faciess, and concentrating under reduced pressure, residue crosses 200-300 mesh silica gel column chromatographies, with volume ratio as 1:3 just oneself
Used as eluent, so as to obtain above-mentioned formula (III) compound, yield is 95.1% to the mixed solvent of alkane and acetone.
Embodiment 3
Specific operation process is as follows：
At room temperature, it is 1 to appropriate volume ratio:8 1- normal-butyls -2,3- methylimidazoles tetrafluoroborate and poly- second two
In the mixed solvent of alcohol -200 (PEG-200), add 100mmol on formula (I) compound, the upper formula (II) compounds of 170mmol,
4mmol catalyst Pd (TFA)2, 20mmol catalyst aid diethyl diselenides and 15mmol composite activating agents (be 5mmol N- fluorine
The mixture of generation double benzsulfamides (NFSI) and 10mmol boron trifluoride diethyl etherate), 60 DEG C are then heated to, and it is anti-at such a temperature
Answer 2.5 hours, 150mmol alkali diisopropyl ethanolamines are subsequently added in reaction system, and continue to be incubated at such a temperature
Reaction 3 hours；
After the completion of reaction, filtered while hot, the pH value for adjusting filtrate is neutrality, then abundant with saturated sodium bicarbonate aqueous solution
Washing 2-3 time, separates organic faciess, and concentrating under reduced pressure, residue crosses 200-300 mesh silica gel column chromatographies, with volume ratio as 1:3 just oneself
Used as eluent, so as to obtain above-mentioned formula (III) compound, yield is 95.5% to the mixed solvent of alkane and acetone.
Embodiment 4-15
Embodiment 4-6：Except respectively catalyst therein being replaced with into Pd (OAc)2Outward, other operations are constant, so as to divide
Do not repeat to implement embodiment 1-3, sequentially obtain 4-6.
Embodiment 7-9：Except respectively catalyst therein being replaced with into Pd (acac)2Outward, other operations are constant, so as to divide
Do not repeat to implement embodiment 1-3, sequentially obtain 7-9.
Embodiment 10-12：Except respectively catalyst therein being replaced with into Pd (PPh3)4Outward, other operations are constant, so as to
Repeat respectively to implement embodiment 1-3, sequentially obtain 10-12.
Embodiment 13-15：Except respectively catalyst therein being replaced with into PdCl2(PPh3)2Outward, other operations are constant, from
And repeat to implement embodiment 1-3 respectively, sequentially obtain 13-15.
As a result see the table below 1：
Table 1
As can be seen here, not all of palladium compound can significantly promote the reaction of the present invention, wherein palladium trifluoroacetate
(Pd(TFA)2) there is best catalytic effect, even similar with its height acid chloride (Pd (OAc)2), its yield also has
It is significant to reduce, and other palladium compounds then reduce becoming apparent from.
Embodiment 16-21
Embodiment 16-18：In addition to catalyst aid therein is dispensed, other operations are constant, so as to repeatedly implement respectively
Embodiment 1-3, sequentially obtains 16-18.
Embodiment 19-21：In addition to catalyst aid therein is replaced with into dimethyl diselenide ether by diethyl diselenide, other
Operation is constant, so as to repeat to implement embodiment 1-3 respectively, sequentially obtains 19-21.
As a result 2 be see the table below：
Table 2
As can be seen here, when there is no catalyst aid, then products collection efficiency has substantially reduction；And when using dimethyl diselenide ether
During as catalyst aid, although having increased when yield is not than using catalyst aid, when being still significantly lower than diethyl diselenide
Effect, this prove diethyl diselenide there is optimal co-catalysis synergism.
Embodiment 22-30
Embodiment 22-24：In addition to composite activating agent therein is dispensed, other operations are constant, so as to repeat reality respectively
Embodiment 1-3 has been applied, 22-24 has sequentially been obtained.
Embodiment 25-27：Except by composite activating agent therein by the double benzsulfamide (NFSI) of N- fluoro and boron trifluoride second
The mixture of ether replaces with the double benzsulfamides (NFSI) of one-component N- fluoro of both total consumptions original outward, and other operations are not
Become, so as to repeat to implement embodiment 1-3 respectively, sequentially obtain 25-27.
Embodiment 28-30：Except by composite activating agent therein by the double benzsulfamide (NFSI) of N- fluoro and boron trifluoride second
The mixture of ether is replaced with outside the one-component boron trifluoride diethyl etherate of both total consumptions original, and other operations are constant, so as to divide
Do not repeat to implement embodiment 1-3, sequentially obtain 28-30.
As a result 3 be see the table below：
Table 3
As can be seen here, when there is no composite activating agent, then products collection efficiency has substantially reduction.But, it is surprising that work as
When simply using the double benzsulfamides of N- fluoro or boron trifluoride diethyl etherate as one-component activator, its yield is further on the contrary
Less than yield when not using any composite activating agent, this proves that only both use simultaneously, competence exertion synergism, and then
Obtain the excellent effect of the present invention.
Embodiment 31-40
In addition to using following alkali, other operations are constant, so as to the same way respectively according to embodiment 1-3 is carried out
Embodiment 31-40, the alkali for being used, corresponding relation and products collection efficiency see the table below 4：
Table 4
As can be seen here, in all of alkali, diisopropyl ethanolamine has best effect, and other alkali cause yield to have
To a certain degree even significantly reduce.
Embodiment 41-45
In addition to PEG-200 therein is replaced with into following solvent composition, other operations are constant (i.e. using the positive fourths of 1-
Base -2, the mixture of 3- methylimidazoles tetrafluoroborate and following solvent composition is used as solvent), so as to respectively according to embodiment
The same way of 1-3 is carried out a 41-45, and solvent composition, corresponding relation and the products collection efficiency for being used see the table below 5：
Table 5
As can be seen here, in the synthetic method of the present invention, when using 1- normal-butyl -2,3- methylimidazole tetrafluoro boron
When the mixture of hydrochlorate and Polyethylene Glycol -200 (PEG-200) is as solvent, best technique effect can be obtained, and be worked as it
In PEG-200 when replacing with other solvent compositions, will all cause products collection efficiency to decrease.
Embodiment 46-49
Except (all of reaction mass is added at room temperature) in addition to alkali is added at the very start, other operations are constant, from
And respectively a 46-49 being carried out according to the same way of embodiment 1-3, the yield for as a result finding final product is 80.2-
82.6%.
As can be seen here, the addition opportunity of alkali is extremely important, and after reaction a period of time alkali is added, then can obtain the present invention
Excellent yield.
Summary, the present invention creatively proposes a kind of synthesis side of the ring ketone compounds that naphthalene vinyl replaces
Method.Species and component that the method passes through the specific catalyst of selection, catalyst aid, composite activating agent, alkali and solvent etc., and
Select suitable alkali to add opportunity, and cause to have played the synergism of uniqueness each other, purpose can be obtained with high yield and be produced
Thing, in organic synthesis field, especially intermediate synthesis technical field has a good application prospect and extensive industrialized production
Potentiality.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limit the protection model of the present invention
Enclose.Additionally, it will also be appreciated that after the technology contents for having read the present invention, those skilled in the art can make each to the present invention
Plant and change, change and/or modification, all these equivalent form of value equally falls within the guarantor that the application appended claims are limited
Within the scope of shield.
Claims (7)
1. naphthalene vinyl shown in a kind of lower formula (III) replace ring ketone compounds synthetic method,
Methods described includes：In a solvent, in the presence of catalyst, catalyst aid and composite activating agent, lower formula (I) compound and
Lower formula (II) compound reacts 2-3 hours at 50-80 DEG C, is subsequently adding alkali, continues insulation reaction 3-5 hour, so as to obtain
(III) compound,
Wherein, R1、R2It is each independently selected from H, halogen, C1-C6Alkyl or C1-C6Alkoxyl；
X is halogen；
The catalyst is palladium trifluoroacetate；
The catalyst aid is dimethyl diselenide ether or diethyl diselenide；
The composite activating agent is the mixture of the double benzsulfamides of N- fluoro and boron trifluoride diethyl etherate, and both mol ratios are 1:2-3；
The alkali is diisopropyl ethanolamine.
2. synthetic method as claimed in claim 1, it is characterised in that：The catalyst aid is diethyl diselenide.
3. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound rubs with formula (II) compound
You are than being 1:1.4-2.
4. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound is with the mol ratio of catalyst
1:0.04-0.07。
5. synthetic method as claimed in claim 1, it is characterised in that：The mol ratio of formula (I) compound and catalyst aid
For 1:0.1-0.2.
6. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound and composite activating agent mole
Than for 1:0.07-0.15.
7. the synthetic method as described in any one of claim 1-6, it is characterised in that：Formula (I) compound and alkali mole
Than for 1:1-1.5.
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