CN104987318A - Synthesis method for naphthalene-vinyl-substituted ketone compounds - Google Patents
Synthesis method for naphthalene-vinyl-substituted ketone compounds Download PDFInfo
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- CN104987318A CN104987318A CN201510401729.4A CN201510401729A CN104987318A CN 104987318 A CN104987318 A CN 104987318A CN 201510401729 A CN201510401729 A CN 201510401729A CN 104987318 A CN104987318 A CN 104987318A
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- -1 naphthalene-vinyl-substituted ketone compounds Chemical class 0.000 title claims abstract description 24
- 238000001308 synthesis method Methods 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- 239000003513 alkali Substances 0.000 claims abstract description 23
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 230000003213 activating effect Effects 0.000 claims abstract description 19
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- 238000010189 synthetic method Methods 0.000 claims description 34
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 18
- 239000002131 composite material Substances 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 15
- OMAWWKIPXLIPDE-UHFFFAOYSA-N (ethyldiselanyl)ethane Chemical compound CC[Se][Se]CC OMAWWKIPXLIPDE-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 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 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000009413 insulation Methods 0.000 claims description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 5
- 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 5
- 229920002554 vinyl polymer Polymers 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 claims description 4
- 229940043276 diisopropanolamine Drugs 0.000 claims description 4
- 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 claims 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 claims description 4
- 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 claims description 3
- 101150003085 Pdcl gene Proteins 0.000 claims description 3
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 2
- 229940043237 diethanolamine Drugs 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims 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 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229940086542 triethylamine Drugs 0.000 claims description 2
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 13
- 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 3
- 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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 9
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 8
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 7
- 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- 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
- 238000005516 engineering process Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 150000002941 palladium compounds Chemical class 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- XUXNAKZDHHEHPC-UHFFFAOYSA-M sodium bromate Chemical compound [Na+].[O-]Br(=O)=O XUXNAKZDHHEHPC-UHFFFAOYSA-M 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 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
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 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
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 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
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 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
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 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
- 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
- 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002994 raw material Substances 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
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 239000000126 substance Substances 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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 of fused rings compounds, relate more particularly to the synthetic method of the cyclic ketones compounds that a kind of naphthalene vinyl replaces, belong to organic intermediate synthesis field.
Background technology
Fused rings ketone compounds is in organic synthesis, especially pharmaceutical intermediate synthesis technical field has important effect and purposes, owing to wherein containing fused rings, and be easy to the carbonyl that reaction further occurs, be therefore the common structure fragment being usually used for building synthetic drugs, natural product and material molecule.Also just because of the important potentiality of such structural compounds, therefore, develop fused rings ketone compounds new and effective synthetic method day by day become the key issue of scientific research.
But another aspect, in modern synthesising chemical technology, directly constructing C-O key is that organic synthesis field has challenging problem, and this is because the low-oxidation-state of c h bond in organic molecule, chemo-selective and regioselectivity are restive, thus is difficult to directly form C-O key.
In recent years, in organic catalysis chemistry, the construction technology relating to the C-O key of fused rings ketone compounds has achieved significant progress and development, also reports multiple synthetic method in prior art, such as:
Safdar Hayat etc. (" An improved method for the synthesis ofg-lactones using sodium bromate and sodium hydrogen sulfite ", Tetrahedron Letters, 2001,42,1647-1649) report a kind of with sodium bromate and sodium bisulfite be catalyzer, the ethyl acetate method being prepared cyclisation product by adjacent alkylbenzoic acid that is solvent, its reaction formula is as follows:
Ji Min Lee etc. (" Pt-Catalyzed sp3C – H bond activation of o-alkylsubstituted aromatic carboxylic acid derivatives for the formation of aryllactones ", Tetrahedron Letters, 2006,47,1375-1379) disclose a kind of employing palladium or platinum catalyst, with ortho-alkyl aromatic carboxylic acid for raw material builds the method for aryl rings lactone, its reaction formula is as follows:
As mentioned above, although disclose the method for some synthesis fused rings ketone compounds in prior art, but for the synthetic method that it is novel, still there is the necessity continuing research, this is also one of study hotspot and emphasis in this field, also just the power place that is accomplished of the present invention and basis lean on.
Summary of the invention
In order to develop the method for new synthesis fused rings ketone compounds, present inventor has performed deep research and exploration, after having paid enough creative works, thus completing the present invention.
Specifically, technical scheme of the present invention and content relate to the synthetic method of the cyclic ketones compounds that naphthalene vinyl replaces shown in a kind of following formula (III),
Described method comprises: in a solvent, under catalyzer, catalyst aid and composite activating agent exist, following formula (I) compound and following formula (II) compound react 2-3 hour at 50-80 DEG C, then alkali is added, continue insulation reaction 3-5 hour, thus obtain described (III) compound
Wherein, R
1, R
2be selected from H, halogen, C independently of one another
1-C
6alkyl or C
1-C
6alkoxyl group;
X is halogen.
In described synthetic method of the present invention, the implication of described halogen refers to haloid element, non-exclusively such as can be F, Cl, Br or I.
In described synthetic method of the present invention, described C
1-C
6the implication of alkyl refers to the straight or branched alkyl with 1-6 carbon atom, such as can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl or n-hexyl etc. in non-limiting manner.
In described synthetic method of the present invention, described C
1-C
6the implication of alkoxyl group refers to C defined above
1-C
6the group obtained after alkyl is connected with Sauerstoffatom.
In described synthetic method of the present invention, described catalyzer is acid chloride (Pd (OAc)
2), palladium trifluoroacetate (Pd (TFA)
2), palladium acetylacetonate (Pd (acac)
2), tetrakis triphenylphosphine palladium (Pd (PPh
3)
4), two (triphenylphosphine) Palladous chloride (PdCl
2(PPh
3)
2) in any one, most preferably be palladium trifluoroacetate (Pd (TFA)
2).
In described synthetic method of the present invention, described catalyst aid is dimethyl diselenide ether or diethyl diselenide, is preferably diethyl diselenide.
In described synthetic method of the present invention, described composite activating agent is the mixture of the two benzsulfamide (NFSI) of N-fluoro and boron trifluoride diethyl etherate, and both mol ratios are 1:2-3.
In described synthetic method of the present invention, described alkali is NaOH, KOH, sodium carbonate, sodium methylate, potassium tert.-butoxide, triethylamine, diethanolamine, diisopropanolamine (DIPA), diisopropyl ethanolamine, 1, any one in 4-diazabicylo [2.2.2] octane (DABCO), Tetramethyl Ethylene Diamine etc., most preferably is diisopropyl ethanolamine.
In described synthetic method of the present invention, described solvent is 1-normal-butyl-2, 3-methylimidazole a tetrafluoro borate be selected from DMF (N, dinethylformamide), DMSO (dimethyl sulfoxide (DMSO)), ethanol, benzene, toluene, the mixture of any one in polyoxyethylene glycol-200 (PEG-200), wherein, 1-normal-butyl-2, 3-methylimidazole a tetrafluoro borate be selected from DMF (N, dinethylformamide), DMSO (dimethyl sulfoxide (DMSO)), ethanol, benzene, toluene, any one in polyoxyethylene glycol-200 (PEG-200) volume ratio be 1:8.
Wherein, most preferably being volume ratio is 1-normal-butyl-2, the 3-methylimidazole a tetrafluoro borate of 1:8 and the mixture of polyoxyethylene glycol-200 (PEG-200).
The restriction that the consumption of described solvent is strict, those skilled in the art can carry out suitable selection to its consumption, such as, can carry out according to making aftertreatment be easy to, reacting the amount of carrying out smoothly and carry out suitable selection.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and formula (II) compound is 1:1.4-2, such as, can be 1:1.4,1:1.6,1:1.8 or 1:2.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and catalyzer is 1:0.04-0.07, such as, can be 1:0.04,1:0.05,1:0.06 or 1:0.07.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and catalyst aid is 1:0.1-0.2, such as, can be 1:0.1,1:0.15 or 1:0.2.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and composite activating agent is 1:0.07-0.15, namely the mole dosage of described formula (I) compound is 1:0.07-0.15 with the ratio of total mole dosage of two kinds of components of the described composite activating agent of formation, such as, can be 1:0.07,1:0.09,1:0.11,1:0.13 or 1:0.15.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and alkali is 1:1-1.5, such as, can be 1:1,1:1.2,1:1.4 or 1:1.5.
In described synthetic method of the present invention, aftertreatment after reaction terminates is specific as follows: after having reacted, filtered while hot, regulate the pH value of filtrate to be neutral, then fully wash 2-3 time with saturated sodium bicarbonate aqueous solution, be separated organic phase, concentrating under reduced pressure, residue crosses 200-300 order silica gel column chromatography, with volume ratio be the mixed solvent of the normal hexane of 1:3 and acetone as elutriant, thus obtain described formula (III) compound.
As mentioned above, the invention provides a kind of synthetic method of fused rings ketone compounds, the method is by selecting kind and the component of specific catalyzer, catalyst aid, composite activating agent, alkali and solvent etc., and select suitable alkali to add opportunity, and make to have played unique synergy each other, high yield can obtain object product, in organic synthesis field, especially intermediate synthesis technical field has a good application prospect and industrial production potential widely.
Embodiment
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary embodiments and object are only used for exemplifying the present invention; not any type of any restriction is formed to real protection scope of the present invention, more non-protection scope of the present invention is confined to this.
Wherein, in following all embodiments, its reaction formula is all as follows:
And below in all embodiments, the characterization data of all products is as follows:
1H NMR(C
6D
6,400MHz):δ5.44(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, to appropriate volume than the 1-normal-butyl-2 for 1:8, in the mixed solvent of 3-methylimidazole a tetrafluoro borate and polyoxyethylene glycol-200 (PEG-200), add 100mmol above formula (I) compound, 150mmol above formula (II) compound, 5mmol catalyst P d (TFA)
2, 10mmol catalyst aid diethyl diselenide and 7mmol composite activating agent (for the two benzsulfamide (NFSI) of 2mmol N-fluoro and the mixture of 5mmol boron trifluoride diethyl etherate), then 80 DEG C are warming up to, and react 2 hours at such a temperature, subsequently in reaction system, add 100mmol alkali diisopropyl ethanolamine, and continue insulation reaction 3 hours at such a temperature;
After having reacted, filtered while hot, the pH value of filtrate is regulated to be neutral, then fully wash 2-3 time with saturated sodium bicarbonate aqueous solution, be separated organic phase, concentrating under reduced pressure, residue crosses 200-300 order silica gel column chromatography, with volume ratio be the mixed solvent of the normal hexane of 1:3 and acetone as elutriant, thus obtain above-mentioned formula (III) compound, productive rate is 95.4%.
Embodiment 2
Specific operation process is as follows:
At room temperature, to appropriate volume than the 1-normal-butyl-2 for 1:8, in the mixed solvent of 3-methylimidazole a tetrafluoro borate and polyoxyethylene glycol-200 (PEG-200), add 100mmol above formula (I) compound, 200mmol above formula (II) compound, 7mmol catalyst P d (TFA)
2, 15mmol catalyst aid diethyl diselenide and 10mmol composite activating agent (for the two benzsulfamide (NFSI) of 2.5mmol N-fluoro and the mixture of 7.5mmol boron trifluoride diethyl etherate), then 50 DEG C are warming up to, and react 3 hours at such a temperature, subsequently in reaction system, add 130mmol alkali diisopropyl ethanolamine, and continue insulation reaction 4 hours at such a temperature;
After having reacted, filtered while hot, the pH value of filtrate is regulated to be neutral, then fully wash 2-3 time with saturated sodium bicarbonate aqueous solution, be separated organic phase, concentrating under reduced pressure, residue crosses 200-300 order silica gel column chromatography, with volume ratio be the mixed solvent of the normal hexane of 1:3 and acetone as elutriant, thus obtain above-mentioned formula (III) compound, productive rate is 95.1%.
Embodiment 3
Specific operation process is as follows:
At room temperature, to appropriate volume than the 1-normal-butyl-2 for 1:8, in the mixed solvent of 3-methylimidazole a tetrafluoro borate and polyoxyethylene glycol-200 (PEG-200), add 100mmol above formula (I) compound, 170mmol above formula (II) compound, 4mmol catalyst P d (TFA)
2, 20mmol catalyst aid diethyl diselenide and 15mmol composite activating agent (for the two benzsulfamide (NFSI) of 5mmol N-fluoro and the mixture of 10mmol boron trifluoride diethyl etherate), then 60 DEG C are warming up to, and react 2.5 hours at such a temperature, subsequently in reaction system, add 150mmol alkali diisopropyl ethanolamine, and continue insulation reaction 3 hours at such a temperature;
After having reacted, filtered while hot, the pH value of filtrate is regulated to be neutral, then fully wash 2-3 time with saturated sodium bicarbonate aqueous solution, be separated organic phase, concentrating under reduced pressure, residue crosses 200-300 order silica gel column chromatography, with volume ratio be the mixed solvent of the normal hexane of 1:3 and acetone as elutriant, thus obtain above-mentioned formula (III) compound, productive rate is 95.5%.
Embodiment 4-15
Embodiment 4-6: except respectively catalyzer wherein being replaced with Pd (OAc)
2outward, other operation is all constant, thus repeats respectively to implement embodiment 1-3, obtains 4-6 in turn.
Embodiment 7-9: except respectively catalyzer wherein being replaced with Pd (acac)
2outward, other operation is all constant, thus repeats respectively to implement embodiment 1-3, obtains 7-9 in turn.
Embodiment 10-12: except respectively catalyzer wherein being replaced with Pd (PPh
3)
4outward, other operation is all constant, thus repeats respectively to implement embodiment 1-3, obtains 10-12 in turn.
Embodiment 13-15: except respectively catalyzer wherein being replaced with PdCl
2(PPh
3)
2outward, other operation is all constant, thus repeats respectively to implement embodiment 1-3, obtains 13-15 in turn.
The results are shown in following table 1:
Table 1
As can be seen here, and the palladium compound of not all can promote reaction of the present invention significantly, wherein palladium trifluoroacetate (Pd (TFA)
2) there is best catalytic effect, even if with its highly similar acid chloride (Pd (OAc)
2), its productive rate also has significant reduction, and other palladium compound then reduces more obvious.
Embodiment 16-21
Embodiment 16-18: except the catalyst aid dispensed wherein, other operation is all constant, thus repeats respectively to implement embodiment 1-3, obtains 16-18 in turn.
Embodiment 19-21: except replacing with except dimethyl diselenide ether by catalyst aid wherein by diethyl diselenide, other operation is all constant, thus repeats respectively to implement embodiment 1-3, obtains 19-21 in turn.
The results are shown in following table 2:
Table 2
As can be seen here, when there is not catalyst aid, then products collection efficiency has obvious reduction; And when using dimethyl diselenide ether as catalyst aid, although productive rate increases to some extent than not using during catalyst aid, but still significantly lower than effect during diethyl diselenide, this proves that diethyl diselenide has best co catalysis synergy.
Embodiment 22-30
Embodiment 22-24: except the composite activating agent dispensed wherein, other operation is all constant, thus repeats respectively to implement embodiment 1-3, obtains 22-24 in turn.
Embodiment 25-27: except composite activating agent is wherein replaced with except the two benzsulfamide (NFSI) of one-component N-fluoro of both total consumptions original by the two benzsulfamide (NFSI) of N-fluoro and the mixture of boron trifluoride diethyl etherate, other operation is all constant, thus repeat respectively to implement embodiment 1-3, obtain 25-27 in turn.
Embodiment 28-30: replaced with by the two benzsulfamide (NFSI) of N-fluoro and the mixture of boron trifluoride diethyl etherate except the one-component boron trifluoride diethyl etherate of both total consumptions original except by composite activating agent wherein, other operation is all constant, thus repeat respectively to implement embodiment 1-3, obtain 28-30 in turn.
The results are shown in following table 3:
Table 3
As can be seen here, when there is not composite activating agent, then products collection efficiency has obvious reduction.But surprisingly, when only using the two benzsulfamide of N-fluoro or boron trifluoride diethyl etherate as one-component activator, its productive rate on the contrary will further lower than productive rate when not using any composite activating agent, this proves to only have both to use simultaneously, competence exertion acts synergistically, and then obtains excellent effect of the present invention.
Embodiment 31-40
Except using following alkali, other operation is all constant, thus has carried out embodiment 31-40 according to the same way of embodiment 1-3 respectively, and the alkali used, corresponding relation and products collection efficiency see the following form 4:
Table 4
As can be seen here, in all alkali, diisopropyl ethanolamine has best effect, and other alkali all causes productive rate to have to a certain degree or even significantly reducing.
Embodiment 41-45
Replace with except following solvent composition except by PEG-200 wherein, other operation is all constant (namely uses 1-normal-butyl-2, the mixture of 3-methylimidazole a tetrafluoro borate and following solvent composition is as solvent), thus carried out embodiment 41-45 according to the same way of embodiment 1-3 respectively, the solvent composition used, corresponding relation and products collection efficiency see the following form 5:
Table 5
As can be seen here, in described synthetic method of the present invention, when use 1-normal-butyl-2, when the mixture of 3-methylimidazole a tetrafluoro borate and polyoxyethylene glycol-200 (PEG-200) is as solvent, best technique effect can be obtained, and when PEG-200 is wherein replaced with other solvent composition, products collection efficiency all will be caused to decrease.
Embodiment 46-49
(namely all reaction masses are at room temperature added) except adding except alkali at the very start, other operation is all constant, thus carried out embodiment 46-49 according to the same way of embodiment 1-3 respectively, found that the productive rate of final product is 80.2-82.6%.
As can be seen here, alkali to add opportunity extremely important, after reaction for some time, add alkali again, then can obtain excellent productive rate of the present invention.
Comprehensively above-mentioned, the present invention creatively proposes the synthetic method of the cyclic ketones compounds that a kind of naphthalene vinyl replaces.The method is by selecting kind and the component of specific catalyzer, catalyst aid, composite activating agent, alkali and solvent etc., and select suitable alkali to add opportunity, and make to have played unique synergy each other, high yield can obtain object product, in organic synthesis field, especially intermediate synthesis technical field has a good application prospect and industrial production potential widely.
Should be appreciated that the purposes of these embodiments is only not intended to for illustration of the present invention limit the scope of the invention.In addition; also should understand; after having read technology contents of the present invention, those skilled in the art can make various change, amendment and/or modification to the present invention, and these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.
Claims (10)
1. a synthetic method for the cyclic ketones compounds of the replacement of naphthalene vinyl shown in following formula (III),
Described method comprises: in a solvent, under catalyzer, catalyst aid and composite activating agent exist, following formula (I) compound and following formula (II) compound react 2-3 hour at 50-80 DEG C, then alkali is added, continue insulation reaction 3-5 hour, thus obtain described (III) compound
Wherein, R
1, R
2be selected from H, halogen, C independently of one another
1-C
6alkyl or C
1-C
6alkoxyl group;
X is halogen.
2. synthetic method as claimed in claim 1, is characterized in that: described catalyzer is acid chloride (Pd (OAc)
2), palladium trifluoroacetate (Pd (TFA)
2), palladium acetylacetonate (Pd (acac)
2), tetrakis triphenylphosphine palladium (Pd (PPh
3)
4), two (triphenylphosphine) Palladous chloride (PdCl
2(PPh
3)
2) in any one, most preferably be palladium trifluoroacetate (Pd (TFA)
2).
3. synthetic method as claimed in claim 1 or 2, is characterized in that: described catalyst aid is dimethyl diselenide ether or diethyl diselenide, is preferably diethyl diselenide.
4. the synthetic method as described in any one of claim 1-3, is characterized in that: described composite activating agent is the mixture of the two benzsulfamide (NFSI) of N-fluoro and boron trifluoride diethyl etherate, and both mol ratios are 1:2-3.
5. the synthetic method as described in any one of claim 1-4, it is characterized in that: described alkali is NaOH, KOH, sodium carbonate, sodium methylate, potassium tert.-butoxide, triethylamine, diethanolamine, diisopropanolamine (DIPA), diisopropyl ethanolamine, 1, any one in 4-diazabicylo [2.2.2] octane (DABCO), Tetramethyl Ethylene Diamine etc., most preferably is diisopropyl ethanolamine.
6. the synthetic method as described in any one of claim 1-5, is characterized in that: the mol ratio of described formula (I) compound and formula (II) compound is 1:1.4-2.
7. the synthetic method as described in any one of claim 1-6, is characterized in that: the mol ratio of described formula (I) compound and catalyzer is 1:0.04-0.07.
8. the synthetic method as described in any one of claim 1-7, is characterized in that: the mol ratio of described formula (I) compound and catalyst aid is 1:0.1-0.2.
9. the synthetic method as described in any one of claim 1-8, is characterized in that: the mol ratio of described formula (I) compound and composite activating agent is 1:0.07-0.15.
10. the synthetic method as described in any one of claim 1-9, is characterized in that: the mol ratio of described formula (I) compound and alkali is 1:1-1.5.
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Non-Patent Citations (5)
| Title |
|---|
| FELIX KRTZSCHMAR等: "Selenium-Catalyzed C(sp3)-H Acyloxylation:Application in the Expedient Synthesis of Isobenzofuranones", 《CHEMISTRY-A EUROPEAN JOURNAL》 * |
| GREGORY DANOUN等: "One-Pot Synthesis of 3-Alkylidenephthalides from Benzoic Acids by a Rhodium-Catalyzed ortho-C H Acylation Process", 《CHEMISTRY--A EUROPEAN JOURNAL》 * |
| PRITHIBA MITRA等: "Deleterious effect of 7-methyl group on glycosylation of 2-naphthols", 《TETRAHEDRON》 * |
| STEPHANIE DYNCZUKI NAVARRO等: "A new synthetic resorcinolic lipid 3-Heptyl-3,4,6-trimethoxy-3H-isobenzofuran-1-one: Evaluation of toxicology and ability to potentiate the mutagenic and apoptotic effects of cyclophosphamide", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| ZHONGMIAO XU等: "A mild and efficient carboxylate-directed C–H arylation of aryl carboxylic acids with iodobenzenes in water", 《TETRAHEDRON LETTERS》 * |
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