CN105753772A - Method for synthesizing aromatic ketone through addition oxidation by utilizing organozinc reagent - Google Patents
Method for synthesizing aromatic ketone through addition oxidation by utilizing organozinc reagent Download PDFInfo
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- CN105753772A CN105753772A CN201610208750.7A CN201610208750A CN105753772A CN 105753772 A CN105753772 A CN 105753772A CN 201610208750 A CN201610208750 A CN 201610208750A CN 105753772 A CN105753772 A CN 105753772A
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- aromatic ketone
- zinc reagent
- organic zinc
- aromatic
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- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 40
- 150000008365 aromatic ketones Chemical class 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims abstract description 24
- 238000007254 oxidation reaction Methods 0.000 title claims abstract description 9
- 230000002194 synthesizing effect Effects 0.000 title abstract description 5
- 230000003647 oxidation Effects 0.000 title abstract 2
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 31
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 28
- 150000003934 aromatic aldehydes Chemical class 0.000 claims abstract description 12
- 239000007800 oxidant agent Substances 0.000 claims abstract description 5
- 239000000758 substrate Substances 0.000 claims abstract description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 30
- 239000011701 zinc Substances 0.000 claims description 30
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 27
- 230000001590 oxidative effect Effects 0.000 claims description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- -1 aryl zinc halide Chemical class 0.000 claims description 13
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N pentanal Chemical compound CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 4
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- HUMNYLRZRPPJDN-KWCOIAHCSA-N benzaldehyde Chemical group O=[11CH]C1=CC=CC=C1 HUMNYLRZRPPJDN-KWCOIAHCSA-N 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000012036 alkyl zinc reagent Substances 0.000 claims 1
- 125000005002 aryl methyl group Chemical group 0.000 claims 1
- 125000001033 ether group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 19
- 239000002994 raw material Substances 0.000 abstract description 7
- MDKGKXOCJGEUJW-VIFPVBQESA-N (2s)-2-[4-(thiophene-2-carbonyl)phenyl]propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-VIFPVBQESA-N 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 4
- 229960004492 suprofen Drugs 0.000 abstract description 4
- GUHPRPJDBZHYCJ-SECBINFHSA-N (2s)-2-(5-benzoylthiophen-2-yl)propanoic acid Chemical compound S1C([C@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CC=C1 GUHPRPJDBZHYCJ-SECBINFHSA-N 0.000 abstract description 3
- 125000000524 functional group Chemical group 0.000 abstract description 3
- 229960001312 tiaprofenic acid Drugs 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract 2
- 239000012434 nucleophilic reagent Substances 0.000 abstract 2
- FJJYHTVHBVXEEQ-UHFFFAOYSA-N 2,2-dimethylpropanal Chemical compound CC(C)(C)C=O FJJYHTVHBVXEEQ-UHFFFAOYSA-N 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 40
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 10
- 208000035126 Facies Diseases 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 230000006837 decompression Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000004611 spectroscopical analysis Methods 0.000 description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- 239000012965 benzophenone Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000012450 pharmaceutical intermediate Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- MFPZQZZWAMAHOY-UHFFFAOYSA-N 2-Propanoylthiophene Chemical compound CCC(=O)C1=CC=CS1 MFPZQZZWAMAHOY-UHFFFAOYSA-N 0.000 description 2
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- UAYWVJHJZHQCIE-UHFFFAOYSA-L Zinc iodide Inorganic materials I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 2
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 2
- 229940102001 zinc bromide Drugs 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- SWFHGTMLYIBPPA-UHFFFAOYSA-N (4-methoxyphenyl)-phenylmethanone Chemical compound C1=CC(OC)=CC=C1C(=O)C1=CC=CC=C1 SWFHGTMLYIBPPA-UHFFFAOYSA-N 0.000 description 1
- TUCRZHGAIRVWTI-UHFFFAOYSA-N 2-bromothiophene Chemical compound BrC1=CC=CS1 TUCRZHGAIRVWTI-UHFFFAOYSA-N 0.000 description 1
- XONKJZDHGCMRRF-UHFFFAOYSA-N 7-fluoro-1h-indole Chemical compound FC1=CC=CC2=C1NC=C2 XONKJZDHGCMRRF-UHFFFAOYSA-N 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- YCBJOQUNPLTBGG-UHFFFAOYSA-N ethyl 4-iodobenzoate Chemical class CCOC(=O)C1=CC=C(I)C=C1 YCBJOQUNPLTBGG-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- UFOAYTOVTNNRKJ-UHFFFAOYSA-N methyl 2-acetylbenzoate Chemical compound COC(=O)C1=CC=CC=C1C(C)=O UFOAYTOVTNNRKJ-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 125000001979 organolithium group Chemical group 0.000 description 1
- 125000002734 organomagnesium group Chemical group 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a new method for synthesizing aromatic ketone and belongs to the fields of organic synthesis and drug intermediates. The new method provided by the invention takes aromatic aldehyde as a substrate, pivaldehyde as an oxidizing agent and an organozinc reagent as a nucleophilic reagent, and addition oxidation reaction is carried out at room temperature, so that the aromatic ketone is obtained. The organozinc reagent is adopted as the nucleophilic reagent, and the compatibility of a functional group of the organozinc reagent is relatively high, so that the yield and efficiency for synthesizing the aromatic ketone through addition oxidation are obviously improved; products can not be synthesized by adopting other methods also can be synthesized. The new method provided by the invention has the advantages of cheap and available raw materials, high reaction efficiency and simple and easy operation and is an efficient and convenient method for synthesizing the aromatic ketone, and a novel and effective synthesis method is also provided for synthesis of the drug intermediates such as suprofen and tiaprofenic acid.
Description
Technical field
The invention belongs to organic synthesis and pharmaceutical intermediate field, relate to a kind of suprofen and the synthetic method of the plug pharmaceutical intermediate aromatic ketones such as ketoprofen acid, particularly relate to and a kind of utilize organic zinc reagent as the method for nucleophilic preparation addition oxidative synthesis aromatic ketone.
Background technology
Aromatic ketone is the synthetic intermediate of a kind of important natural product and medicine, such as pharmaceutical intermediates such as suprofen and plug ketoprofen acids.The structure of aromatic ketone compound is as follows:
Wherein, R1For 2-CH3Ph, 4-OMePh, 4-ClPh, 4-CO2CH3Ph, 2-pyridine, 4-NO2
R2For Ph, PhCH2, Et, 4-CO2EtPh, 2-thiophen, 3-thiophen
The synthetic method of existing a lot of diaryl ketones in document, such as friedel-crafts acylation (organic chemistry, 2011; 31; 1188), and the oxidizing process of aryl alcohol (J.Am.Chem.Soc., 2004; 126; 4112), and the carbonylation method of halogenated hydrocarbons (Chem.Eur.J.2008,14; 3645), the addition oxidation reaction etc. of metal reagent and aromatic aldehyde.In numerous synthetic methods, it is very important synthesizing mean (Chem.Eur.J.2007,13,215) that the addition of aromatic aldehyde is aoxidized by metal reagent.
The organometallic reagent that literature method uses, such as Grignard reagent, organolithium reagent isoreactivity is too strong so that the selectivity of reaction site is poor, make himself to carry active function groups, thus largely limiting the application in organic synthesis of this kind of metal reagent.And organic zinc reagent reactivity is more weak, it is possible to carry highly active functional group, and reaction condition is gentle, stereo selectivity is also fine, and productivity is also of a relatively high, and therefore organic zinc reagent is often applied in the synthesis of the compounds such as ketone.
Summary of the invention
It is an object of the invention to the problem low for existing synthesis aromatic ketone productivity, it is provided that a kind of method utilizing organic zinc reagent high yield addition oxidative synthesis aromatic ketone.
The present invention synthesizes the method for aromatic ketone, is in organic solvent, and with aromatic aldehyde for substrate, special valeral is oxidant, and organic zinc reagent is nucleopilic reagent, at room temperature carries out addition oxidation reaction；Reaction is extracted with ethyl acetate after terminating, and organic facies anhydrous sodium sulfate dries, and filters, and decompression is distilled off column chromatography for separation after solvent, obtains target product aromatic ketone.
Described organic solvent can be ether, oxolane or Isosorbide-5-Nitrae-dioxane, it is preferable that oxolane.
The benzaldehyde that described aromatic aldehyde is benzaldehyde or ortho position, a position or para-position are replaced by halogen, nitro, alkoxyl, ester group or alkyl, and heterocycle aromatic aldehyde (such as furtural, pyridine carboxaldehyde, thiophenecarboxaldehyde etc.).Its structural formula is as follows:
The structural formula of special valeral is: (CH3)3CCOH。
Described organic zinc reagent is by halogenated hydrocarbons in the presence of anhydrous Lithium chloride, the organomagnesium reagent being obtained by reacting with magnesium metal and anhydrous zinc chloride converted in-situ and obtain.Mainly there are phenyl zinc bromide, 2-thiophene zinc bromide, 3-thiophene zinc bromide, diethyl zinc, 4-ethyl acetate phenyl zinc iodide, 3-trifluoromethyl zinc iodide etc..Its structural formula is as follows:
The mol ratio of aromatic aldehyde and oxidant spy's valeral is 1:1 ~ 1:2；
The mol ratio of aromatic aldehyde and organic zinc reagent is 1:1 ~ 1:2；
The response time of described addition oxidation reaction is 0.5 ~ 2h；
The reaction equation of above-mentioned addition oxidation reaction is as follows:
Wherein, R1For Ph, PhCH2, Et, 4-CO2EtPh, 2-thiophen, 3-thiophen；
R2For 2-CH3Ph, 4-OMePh, 4-ClPh, 4-CO2CH3Ph, 4-NO2。
The product nuclear magnetic resonance data of present invention synthesis shows, its structure is consistent with the structure of aromatic ketone, it was shown that aromatic ketone compound synthesizes successfully.
The present invention adopts organic zinc reagent to be nucleopilic reagent, and the compatibility of its functional group is higher so that productivity and the efficiency of addition oxidative synthesis aromatic ketone are all significantly improved；The product that other method cannot synthesize can also be synthesized, such as the synthesis of 4-ethylcarbonyl group-(4 ＇-methyl carbonyl)-benzophenone simultaneously.After testing, the present invention synthesizes the productivity of aromatic ketone up to 94%, and whole reaction can complete reaction in 2h.
Detailed description of the invention
Below by specific embodiment, the present invention synthesized the method for aromatic ketone and productivity is described further.
Embodiment 1,4-methoxy benzophenone synthesis
Magnesium chips (0.31g, 13mmol) and lithium chloride (0.43g, 10mmol) are put in there-necked flask, loads onto constant pressure funnel, good seal device, evacuate and change nitrogen 5 times.In there-necked flask, inject 4ml oxolane with syringe, be then turned on agitating heating.Then at N2Under protection, extraction bromobenzene (1.57g, 10mmol) adds constant pressure funnel and is slowly added dropwise, and is subsequently adding the ZnCl of equivalent2(1.36g, 10mmol), reacts 30min, synthesizes organic zinc reagent.
Then weigh P-methoxybenzal-dehyde (0.27,5mmol) with syringe and special valeral (0.86g, 10mmol) injects there-necked flask.Then TLC analyzes.After raw material reaction is complete, with saturated ammonium chloride solution cancellation reaction, separating organic facies, dry with anhydrous sodium sulfate, filter after being extracted with ethyl acetate, decompression is distilled off column chromatography (silica gel: 300-400 order after solvent；Mobile phase: petroleum ether and ethyl acetate) separate obtain sterling, productivity is 92%.
Spectroscopic data:1HNMR(400MHz,CDCl3)δ(ppm):3.89(s,3H),6.96(d,J=8.0Hz,2H),7.48(t,J=7.2Hz,2H),7.57(t,J=7.2Hz,1H),7.76(d,J=8.0Hz,2H),7.83(d,J=8.0Hz,2H)。
Embodiment 2,4-fluorine benzophenone synthesis
The synthesis of organic zinc reagent is with embodiment 1.
Weigh 4-fluorobenzaldehyde (0.63,5mmol) with syringe after synthesis organic zinc reagent and special valeral (0.86g, 10mmol) injects there-necked flask.Then TLC analyzes.After raw material reaction is complete, with saturated ammonium chloride solution cancellation reaction, separating organic facies, dry with anhydrous sodium sulfate, filter after being extracted with ethyl acetate, decompression is distilled off column chromatography (silica gel: 300-400 order after solvent；Mobile phase: petroleum ether and ethyl acetate) separate obtain sterling, productivity is 90%.
Spectroscopic data:1HNMR(400MHz,CDCl3)δ(ppm):7.16(t,J=8.4Hz,2H),7.49(t,J=8.0Hz,2H),7.60(t,J=7.6Hz,1H),7.77(ttd,J=6.8,1.6,0.4Hz,2H),7.82-7.87(m,2H)。
Embodiment 3,2-pyridine benzophenone synthesis
The synthesis of organic zinc reagent is with embodiment 1.
Weigh 2-pyridine carboxaldehyde (0.54,5mmol) with syringe after synthesis organic zinc reagent and special valeral (0.86g, 10mmol) injects there-necked flask.Then TLC analyzes.After raw material reaction is complete, with saturated ammonium chloride solution cancellation reaction, separating organic facies, dry with anhydrous sodium sulfate, filter after being extracted with ethyl acetate, decompression is distilled off column chromatography (silica gel: 300-400 order after solvent；Mobile phase: petroleum ether and ethyl acetate) separate obtain sterling, productivity is 84%.
Spectroscopic data: 1HNMR (600MHz, CDCl3) δ (ppm): 9.00 (s, 1H), 8.82 (d, J=4.8Hz, 1H), 8.17 8.11 (m, 1H), 7.82 (d, J=7.7Hz, 2H), 7.64 (t, J=7.3Hz, 1H), 7.52 (t, J=7.4Hz, 2H), 7.47 (dd, J=7.3,5.3Hz, 1H).
Embodiment 4,2-thiophene-4-fluoro benzophenone synthesis
Will be equipped with magneton there-necked flask and constant pressure funnel heat is forced heat and ensured that this device is dry.After bottle temperature drop to room temperature, magnesium chips (0.31g, 13mmol) and lithium chloride (0.43g, 10mmol) are put in there-necked flask, load onto constant pressure funnel, good seal device, evacuate and change N25 times.In there-necked flask, inject 4ml oxolane with syringe, be then turned on agitating heating.Then at N2Under protection, extraction 2-bromothiophene (1.63g, 10mmol) adds constant pressure funnel and is slowly added dropwise, and is subsequently adding the ZnCl of equivalent2(1.36g, 10mmol), reacts the 30min time, synthesizes organic zinc reagent.
Then weigh 4-fluorobenzaldehyde (0.62g, 5mmol) with syringe and special valeral (0.86g, 10mmol) injects there-necked flask.Then TLC analyzes.After raw material reaction is complete, with saturated ammonium chloride solution cancellation reaction, separating organic facies, dry with anhydrous sodium sulfate, filter after being extracted with ethyl acetate, decompression is distilled off column chromatography (silica gel: 300-400 order after solvent；Mobile phase: petroleum ether and ethyl acetate) separate obtain sterling, productivity is 78%.
Spectroscopic data:1HNMR(600MHz,CDCl3)δ(ppm):7.91(dd,J=8.5,5.5Hz,1H),7.73(d,J=4.1Hz,1H),7.63(d,J=2.9Hz,1H),7.18(dd,J=10.3,6.7Hz,2H)。
2-thiophene-4-fluoro benzophenone can be converted into suprofen (Japan Kokai 82-28709 (CA, 1982,97:21582k)) with document known method.
Embodiment 5,2-propionyl thiophene synthesis
Will be equipped with magneton there-necked flask and constant pressure funnel heat is forced heat and ensured that this device is dry.After bottle temperature drop to room temperature, magnesium bromide (1.85g, 10mmol) and lithium chloride (0.43g, 10mmol) are put in there-necked flask, load onto constant pressure funnel, good seal device, evacuate and change N25 times.In there-necked flask, inject 4ml oxolane with syringe, be then turned on agitating heating.Then at N2Under protection, extraction diethyl zinc (10ml, 10mmol) adds constant pressure funnel and is slowly added dropwise.
Then weigh 2-thiophene benzaldehyde (0.55g, 5mmol) with syringe and special valeral (0.86g, 10mmol) injects there-necked flask.Then TLC analyzes.After raw material reaction is complete, with saturated ammonium chloride solution cancellation reaction, separating organic facies, dry with anhydrous sodium sulfate, filter after being extracted with ethyl acetate, decompression is distilled off column chromatography (silica gel: 300-400 order after solvent；Mobile phase: petroleum ether and ethyl acetate) separate obtain sterling, productivity is 80%.
Spectroscopic data:1HNMR(400MHz,CDCl3)δ(ppm):7.72–7.68(m,1H),7.60(d,J=4.9Hz,1H),7.11(t,J=4.3Hz,1H),2.93(dt,J=7.3,6.1Hz,2H),1.22(dd,J=7.3,4.8Hz,3H).
2-propionyl thiophene is the key intermediate of synthesis tiaprofenic acid, and it can obtain tiaprofenic acid (Chinese Journal of Pharmaceuticals, 2006,796) then through several steps are derivative.
The synthesis of embodiment 6,4-ethylcarbonyl group-(4 ＇-methyl carbonyl)-benzophenone
Will be equipped with magneton there-necked flask and constant pressure funnel heat is forced heat and ensured that this device is dry.After bottle temperature drop to room temperature, magnesium chips (0.31g, 13mmol) and lithium chloride (0.43g, 10mmol) are put in there-necked flask, load onto constant pressure funnel, good seal device, evacuate and change N25 times.In there-necked flask, inject 4ml oxolane with syringe, be then turned on agitating heating.Then at N2Under protection, extraction 2 cbloropropane isopropyl chloride (0.78g, 10mmol) adds constant pressure funnel and is slowly added dropwise, and then adds ZnCl after-40 DEG C of 4-Iodobenzoic acid ethyl esters (2.76g, 10mmol) adding equivalent react 5min2(1.36g, 10mmol), reacts the 30min time, synthesizes organic zinc reagent.
Then weigh with syringe and acetylbenzoic acid methyl ester (0.90g, 5mmol) and special valeral (0.86g, 10mmol) are injected there-necked flask.Then TLC analyzes.After raw material reaction is complete, with saturated ammonium chloride solution cancellation reaction, separating organic facies, dry with anhydrous sodium sulfate, filter after being extracted with ethyl acetate, decompression is distilled off column chromatography (silica gel: 300-400 order after solvent；Mobile phase: petroleum ether and ethyl acetate) separate obtain sterling, productivity is 75%.
Spectroscopic data:1HNMR(600MHz,CDCl3)δ(ppm):8.19(d,J=8.3Hz,2H),8.19(d,J=8.3Hz,2H),8.07(s,1H),7.98(d,J=7.8Hz,1H),7.88(d,J=7.8Hz,1H),7.85(d,J=8.3Hz,2H),7.65(t,J=7.8Hz,1H),4.07(s,3H)。
Claims (8)
1. utilizing the addition oxidizing process synthesis aromatic ketone of organic zinc reagent and aromatic aldehyde, be in organic solvent, with aromatic aldehyde for substrate, special valeral is oxidant, and organic zinc reagent is nucleopilic reagent, at room temperature carries out addition oxidation reaction and obtains target product aromatic ketone.
2. the method utilizing organic zinc reagent addition oxidative synthesis aromatic ketone as claimed in claim 1, it is characterised in that: described organic zinc reagent is aryl zinc halide, arylmethyl base zinc halide, heteroaromatic zinc halide or alkyl zinc reagent.
3. the method utilizing organic zinc reagent addition oxidative synthesis aromatic ketone as claimed in claim 1, it is characterised in that: described organic solvent is ether, oxolane or Isosorbide-5-Nitrae-dioxane.
4. the method utilizing organic zinc reagent addition oxidative synthesis aromatic ketone as claimed in claim 1, it is characterised in that: described aromatic aldehyde is benzaldehyde and ortho position, a position or para-position are replaced by halogen, nitro, alkoxyl, ester group or alkyl aromatic aldehyde and heterocycle aromatic aldehyde.
5. the method utilizing organic zinc reagent addition oxidative synthesis aromatic ketone as claimed in claim 4, it is characterised in that: described heterocycle aromatic aldehyde is furtural, pyridine carboxaldehyde or thiophenecarboxaldehyde.
6. the method utilizing organic zinc reagent addition oxidative synthesis aromatic ketone as claimed in claim 1, it is characterised in that: the mol ratio of aromatic aldehyde and oxidant spy's valeral is 1:1 ~ 1:2.
7. the method utilizing organic zinc reagent addition oxidative synthesis aromatic ketone as claimed in claim 1, it is characterised in that: the mol ratio of aromatic aldehyde and organic zinc reagent is 1:1 ~ 1:2.
8. the method utilizing organic zinc reagent addition oxidative synthesis aromatic ketone as claimed in claim 1, it is characterised in that: the response time of described addition oxidation reaction is 0.5 ~ 2h.
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| Title |
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| RALF J. KLOETZING，等: "The Mg-Oppenauer Oxidation asa Mild Method for the Synthesisof Aryl and Metallocenyl Ketones", 《CHEM. EUR. J.》 * |
| TAKASHI OOI，等: "Practical Oppenauer (OPP) Oxidation of Alcohols with a Modified Aluminum Catalyst", 《ORG. LETT.》 * |
| YOSHIHIRO OGAWA，等: "Nucleophilic Additions of Arylzinc Compounds to Aldehydes Mediated by CrCl3: Efficient and Facile Synthesis of Functionalized Benzhydrols, 1(3H)-Isobenzofuranones, Benzyl Alcohols, or Diaryl Ketones", 《J. ORG. CHEM.》 * |
| 赵胜芳，等: "芳香醛的类格氏反应研究", 《武汉理工大学学报》 * |
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