CN105753772B - Utilize the method for organic zinc reagent addition oxidative synthesis aromatic ketone - Google Patents
Utilize the method for organic zinc reagent addition oxidative synthesis aromatic ketone Download PDFInfo
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- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 36
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 33
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 30
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 229910052725 zinc Inorganic materials 0.000 title claims abstract description 27
- 239000011701 zinc Substances 0.000 title claims abstract description 27
- 150000008365 aromatic ketones Chemical class 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims abstract description 20
- 230000001590 oxidative effect Effects 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N pentanal Chemical compound CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000003934 aromatic aldehydes Chemical class 0.000 claims abstract description 11
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 9
- 239000007800 oxidant agent Substances 0.000 claims abstract description 5
- 239000000758 substrate Substances 0.000 claims abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 229930192474 thiophene Natural products 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- 125000001033 ether group Chemical group 0.000 claims 1
- 150000002240 furans Chemical class 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 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
- 229960004492 suprofen Drugs 0.000 abstract description 4
- 125000000524 functional group Chemical group 0.000 abstract description 3
- 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 abstract description 3
- 229960000991 ketoprofen Drugs 0.000 abstract description 3
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- 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
- -1 aromatic ketone compound Chemical class 0.000 description 8
- 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
- 239000012074 organic phase Substances 0.000 description 7
- 238000005292 vacuum distillation Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000012071 phase 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
- 239000012965 benzophenone Substances 0.000 description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 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 description 2
- MFPZQZZWAMAHOY-UHFFFAOYSA-N 2-Propanoylthiophene Chemical compound CCC(=O)C1=CC=CS1 MFPZQZZWAMAHOY-UHFFFAOYSA-N 0.000 description 2
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 2
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical class 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
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 229960001312 tiaprofenic acid Drugs 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- TUCRZHGAIRVWTI-UHFFFAOYSA-N 2-bromothiophene Chemical class 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
- VNDYJBBGRKZCSX-UHFFFAOYSA-L Zinc bromide Inorganic materials Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- YCBJOQUNPLTBGG-UHFFFAOYSA-N ethyl 4-iodobenzoate Chemical compound CCOC(=O)C1=CC=C(I)C=C1 YCBJOQUNPLTBGG-UHFFFAOYSA-N 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens 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
- 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
- 229910052752 metalloid Inorganic materials 0.000 description 1
- 150000002738 metalloids Chemical class 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
- 125000002524 organometallic group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 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
- 239000000126 substance Substances 0.000 description 1
- 229940102001 zinc bromide Drugs 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 present invention provides a kind of new methods for synthesizing aromatic ketone, belong to organic synthesis and pharmaceutical intermediate field.The present invention is using aromatic aldehyde as substrate, and special valeral is oxidant, and organic zinc reagent is nucleopilic reagent, carries out addition oxidation reaction at room temperature and obtains aromatic ketone.Due to using organic zinc reagent as nucleopilic reagent, the compatibility of functional group is higher so that the yield and efficiency of addition oxidative synthesis aromatic ketone are all significantly improved；The product that other methods can not synthesize can also be synthesized simultaneously.Raw material of the present invention is cheap and easy to get, and reaction efficiency is high, it is easy to operation the advantages that, be synthesis aromatic ketone effectively and easily method, be also suprofen, the synthesis of the pharmaceutical intermediates such as plug ketoprofen acid provides novel and effective synthetic method.
Description
Technical field
The invention belongs to organic synthesis and pharmaceutical intermediate fields, are related among the drugs such as a kind of suprofen and plug ketoprofen acid
The synthetic method of body --- aromatic ketone more particularly to it is a kind of by the use of organic zinc reagent as nucleophilic preparation addition oxidative synthesis fragrance
The method of ketone.
Background technology
Aromatic ketone is the synthetic intermediate of a kind of important natural products and drug, such as suprofen and plug ketoprofen acid drug
Intermediate.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- thiophene, 3- thiophene
Have the synthetic method of many diaryl ketones, such as friedel-crafts acylation in document（Organic chemistry, 2011,
31, 1188）, the oxidizing process of aryl alcohol（J. Am. Chem. Soc., 2004, 126, 4112）, the carbonylation method of halogenated hydrocarbons
（Chem. Eur. J. 2008, 14, 3645）, the addition oxidation reaction of metal reagent and aromatic aldehyde etc..In numerous synthesis
In method, metal reagent is very important synthesizing mean to the addition oxidation of aromatic aldehyde（Chem. Eur. J. 2007, 13,
215）.
Organometallic reagent used in literature method, such as Grignard Reagent, organolithium reagent isoreactivity are too strong so that reaction
The selectivity in site is poor, makes its own that can not carry active function groups, so as to largely limit the examination of this metalloid
Application of the agent in organic synthesis.And organic zinc reagent reactivity is weaker, can carry the functional group of high activity, and react
Mild condition, stereoselectivity is also fine, and yield is also relatively high, therefore organic zinc reagent is often applied to the chemical combination such as ketone
In the synthesis of object.
The content of the invention
The problem of the purpose of the present invention is being directed to existing synthesis aromatic ketone low yield, provides a kind of high using organic zinc reagent
The method of yield addition oxidative synthesis aromatic ketone.
The method of present invention synthesis aromatic ketone is that in organic solvent, using aromatic aldehyde as substrate, special valeral is oxidant,
Organic zinc reagent is nucleopilic reagent, carries out addition oxidation reaction at room temperature；It is extracted with ethyl acetate after reaction, organic phase
It is dried, filtered with anhydrous sodium sulfate, vacuum distillation removes column chromatography for separation after solvent, obtains target product aromatic ketone.
The organic solvent can be ether, tetrahydrofuran or Isosorbide-5-Nitrae-dioxane, preferably tetrahydrofuran.
The aromatic aldehyde is substituted for benzaldehyde or ortho position, meta or para position by halogen, nitro, alkoxy, ester group or alkyl
Benzaldehyde 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。
The organic zinc reagent is by halogenated hydrocarbons in the presence of anhydrous lithium chloride, with magnesium metal organic-magnesium obtained by the reaction
Reagent and anhydrous zinc chloride converted in-situ and obtain.Mainly there are phenyl zinc bromide, 2- thiophene zinc bromide, 3- thiophene zinc bromide, diethyl
Base zinc, 4- ethyl acetate phenyl zinc iodide, 3- trifluoromethyl zinc iodides etc..Its structural formula is as follows：
The molar ratio of aromatic aldehyde and oxidant spy's valeral is 1:1~1:2；
The molar ratio of aromatic aldehyde and organic zinc reagent is 1:1~1:2；
The reaction time of the 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- thiophene, 3- thiophene
R2For 2-CH3Ph, 4-OMePh, 4-ClPh, 4-CO2CH3Ph, 4-NO2
The product nuclear magnetic resonance data that the present invention synthesizes shows that its structure is consistent with the structure of aromatic ketone, shows aromatic ketone
Compound synthesis success.
The present invention uses organic zinc reagent as nucleopilic reagent, and the compatibility of functional group is higher so that addition oxidative synthesis
The yield and efficiency of aromatic ketone are all significantly improved；The product that other methods can not synthesize, such as 4- can also be synthesized simultaneously
Ethylcarbonyl group-（4 ＇-methyl carbonyl）The synthesis of-benzophenone.After testing, the yield of present invention synthesis aromatic ketone is whole up to 94%
A reaction can complete reaction in 2h.
Specific embodiment
The method and yield of present invention synthesis aromatic ketone are described further below by specific embodiment.
The synthesis of embodiment 1,4- methoxy benzophenones
By magnesium chips（0.31g, 13mmol）And lithium chloride（0.43 g, 10mmol）It is put into there-necked flask, loads onto constant pressure drop
Liquid funnel, good seal device, evacuation change nitrogen 5 times.4ml tetrahydrofurans are injected into there-necked flask with syringe, are then turned on stirring
Mix heating.Then in N2Under protection, extract bromobenzene (1.57g, 10mmol) addition constant pressure funnel and be slowly added dropwise, then add in etc.
The ZnCl of amount2(1.36g, 10mmol) reacts 30min, synthesizes organic zinc reagent.
Then P-methoxybenzal-dehyde is weighed with syringe（0.27,5mmol）It is injected with special valeral (0.86g, 10mmol)
There-necked flask.Then TLC is analyzed.After raw material has reacted, reaction is quenched with the ammonium chloride solution of saturation, after being extracted with ethyl acetate
Organic phase is separated, is dried with anhydrous sodium sulfate, is filtered, vacuum distillation removes column chromatography after solvent（Silica gel：300-400 mesh；Flowing
Phase：Petroleum ether and ethyl acetate）Isolated sterling, yield 92%.
Spectroscopic data：1H NMR (400 MHz, CDCl3) δ (ppm): 3.89 (s, 3H), 6.96 (d, J =
8.0 Hz, 2H), 7.48 (t, J = 7.2 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.76 (d, J =
8.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H)。
The synthesis of embodiment 2,4- fluorine benzophenone
The synthesis of organic zinc reagent is the same as embodiment 1.
After synthesis organic zinc reagent 4- fluorobenzaldehydes are weighed with syringe（0.63,5mmol）With special valeral (0.86g,
10mmol) inject there-necked flask.Then TLC is analyzed.After raw material has reacted, reaction is quenched with the ammonium chloride solution of saturation, uses second
Organic phase is separated after acetoacetic ester extraction, is dried with anhydrous sodium sulfate, is filtered, vacuum distillation removes column chromatography after solvent（Silica gel：
300-400 mesh；Mobile phase：Petroleum ether and ethyl acetate）Isolated sterling, yield 90%.
Spectroscopic data：1H NMR (400 MHz, CDCl3) δ (ppm): 7.16 (t, J = 8.4 Hz, 2H),
7.49 (t, J = 8.0 Hz, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.77 (ttd, J = 6.8, 1.6,
0.4 Hz, 2H), 7.82-7.87 (m, 2H)。
The synthesis of embodiment 3,2- pyridine Benzophenones
The synthesis of organic zinc reagent is the same as embodiment 1.
After synthesis organic zinc reagent 2- pyridine carboxaldehydes are weighed with syringe（0.54,5mmol）With special valeral (0.86g,
10mmol) inject there-necked flask.Then TLC is analyzed.After raw material has reacted, reaction is quenched with the ammonium chloride solution of saturation, uses second
Organic phase is separated after acetoacetic ester extraction, is dried with anhydrous sodium sulfate, is filtered, vacuum distillation removes column chromatography after solvent（Silica gel：
300-400 mesh；Mobile phase：Petroleum ether and ethyl acetate）Isolated sterling, yield 84%.
Spectroscopic data：1H NMR (600 MHz, CDCl3) δ (ppm): 9.00 (s, 1H), 8.82 (d, J =
4.8 Hz, 1H), 8.17 – 8.11 (m, 1H), 7.82 (d, J = 7.7 Hz, 2H), 7.64 (t, J = 7.3
Hz, 1H), 7.52 (t, J = 7.4 Hz, 2H), 7.47 (dd, J = 7.3, 5.3 Hz, 1H)。
The synthesis of embodiment 4,2- thiophene -4- fluoro benzophenones
Ensure that this device is dry by heat is forced with heat equipped with magneton there-necked flask and constant pressure funnel.Treat a bottle temperature drop
To after room temperature, by magnesium chips（0.31 g,13mmol）And lithium chloride（0.43 g, 10mmol）It is put into there-necked flask, loads onto constant pressure drop
N is changed in liquid funnel, good seal device, evacuation25 times.4ml tetrahydrofurans are injected into there-necked flask with syringe, are then turned on stirring
Heating.Then in N2Under protection, extract 2- bromothiophenes (1.63g, 10mmol) addition constant pressure funnel and be slowly added dropwise, then add in etc.
The ZnCl of amount2(1.36 g, 10mmol) react the 30min times, synthesize organic zinc reagent.
Then 4- fluorobenzaldehydes are weighed with syringe（0.62 g, 5mmol）It is injected with special valeral (0.86 g, 10mmol)
There-necked flask.Then TLC is analyzed.After raw material has reacted, reaction is quenched with the ammonium chloride solution of saturation, after being extracted with ethyl acetate
Organic phase is separated, is dried with anhydrous sodium sulfate, is filtered, vacuum distillation removes column chromatography after solvent（Silica gel：300-400 mesh；Flowing
Phase：Petroleum ether and ethyl acetate）Isolated sterling, yield 78%.
Spectroscopic data：1H NMR (600 MHz, CDCl3) δ(ppm): 7.91 (dd, J = 8.5, 5.5 Hz,
1H), 7.73 (d, J = 4.1 Hz, 1H), 7.63 (d, J = 2.9 Hz, 1H), 7.18 (dd, J = 10.3,
6.7 Hz, 2H)。
2- thiophene -4- fluoro benzophenones can be converted into suprofen with document known method（Japan Kokai 82-28709
(CA, 1982, 97:21582k)）.
The synthesis of embodiment 5,2- propionyl thiophene
Ensure that this device is dry by heat is forced with heat equipped with magneton there-necked flask and constant pressure funnel.Treat a bottle temperature drop
To after room temperature, by magnesium bromide（1.85 g,10mmol）And lithium chloride（0.43 g, 10mmol）It is put into there-necked flask, loads onto constant pressure
N is changed in dropping funel, good seal device, evacuation25 times.4ml tetrahydrofurans are injected into there-necked flask with syringe, are then turned on stirring
Mix heating.Then in N2Under protection, extract diethyl zinc (10 ml, 10mmol) addition constant pressure funnel and be slowly added dropwise.
Then 2- thiophene benzaldehydes are weighed with syringe（0.55 g, 5mmol）It is noted with special valeral (0.86 g, 10mmol)
Enter there-necked flask.Then TLC is analyzed.After raw material has reacted, reaction is quenched with the ammonium chloride solution of saturation, is extracted with ethyl acetate
After separate organic phase, dried with anhydrous sodium sulfate, filter, vacuum distillation remove solvent after column chromatography（Silica gel：300-400 mesh；Stream
Dynamic phase：Petroleum ether and ethyl acetate）Isolated sterling, yield 80%.
Spectroscopic data：1H NMR (400 MHz, CDCl3) δ(ppm): 7.72 – 7.68 (m, 1H), 7.60 (d,J = 4.9 Hz, 1H), 7.11 (t, J = 4.3 Hz, 1H), 2.93 (dt, J = 7.3, 6.1 Hz, 2H),
1.22 (dd, J = 7.3, 4.8 Hz, 3H).
2- propionyl thiophene is the key intermediate for synthesizing Tiaprofenic Acid, it can derive to obtain Tiaprofenic Acid through several steps again（In
State's medical industry magazine, 2006,796）.
Embodiment 6,4- ethylcarbonyl groups-（4 ＇-methyl carbonyl）The synthesis of-benzophenone
Ensure that this device is dry by heat is forced with heat equipped with magneton there-necked flask and constant pressure funnel.Treat a bottle temperature drop
To after room temperature, by magnesium chips（0.31g,13mmol）And lithium chloride（0.43 g, 10mmol）It is put into there-necked flask, loads onto constant pressure drop
N is changed in liquid funnel, good seal device, evacuation25 times.4ml tetrahydrofurans are injected into there-necked flask with syringe, are then turned on stirring
Heating.Then in N2Under protection, extract 2 cbloropropane isopropyl chloride (0.78 g, 10mmol) add in constant pressure funnel be slowly added dropwise, then-
The 4-Iodobenzoic acid ethyl ester of 40 DEG C of addition equivalent（2.76 g, 10 mmol）ZnCl is added in after reaction 5min2(1.36g,10
Mmol), the 30min times are reacted, synthesize organic zinc reagent.
Then weighed with syringe to acetylbenzoic acid methyl esters（0.90 g, 5mmol）With special valeral (0.86g,
10mmol) inject there-necked flask.Then TLC is analyzed.After raw material has reacted, reaction is quenched with the ammonium chloride solution of saturation, uses second
Organic phase is separated after acetoacetic ester extraction, is dried with anhydrous sodium sulfate, is filtered, vacuum distillation removes column chromatography after solvent（Silica gel：
300-400 mesh；Mobile phase：Petroleum ether and ethyl acetate）Isolated sterling, yield 75%.
Spectroscopic data：1H NMR (600 MHz, CDCl3) δ (ppm): 8.19 (d, J = 8.3 Hz, 2H),
8.19 (d, J = 8.3 Hz, 2H), 8.07 (s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.88 (d, J
= 7.8 Hz, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.65 (t, J = 7.8 Hz, 1H), 4.07 (s,
3H)。
Claims (5)
1. synthesize aromatic ketone with the addition oxidizing process of aromatic aldehyde using organic zinc reagent, be in organic solvent, using aromatic aldehyde as
Substrate, special valeral are oxidant, and organic zinc reagent is nucleopilic reagent, carry out addition oxidation reaction at room temperature and obtain target product
Aromatic ketone；The reaction equation of the addition oxidation reaction is as follows：
Wherein, R1For Ph, PhCH2, Et, 4-CO2EtPh, 2- thiophene, 3- thiophene；
R2For 2-CH3Ph, 4-OMePh, 4-ClPh, 4-CO2CH3Ph, furans, pyridine, thiophene.
2. the method for organic zinc reagent addition oxidative synthesis aromatic ketone is utilized as described in claim 1, it is characterised in that：It is described to have
Solvent is ether, tetrahydrofuran or 1,4- dioxane.
3. the method for organic zinc reagent addition oxidative synthesis aromatic ketone is utilized as described in claim 1, it is characterised in that：Aromatic aldehyde
Molar ratio with oxidant spy's valeral is 1:1~1:2.
4. the method for organic zinc reagent addition oxidative synthesis aromatic ketone is utilized as described in claim 1, it is characterised in that：Aromatic aldehyde
Molar ratio with organic zinc reagent is 1:1~1:2.
5. the method for organic zinc reagent addition oxidative synthesis aromatic ketone is utilized as described in claim 1, it is characterised in that：It is described to add
Reaction time into oxidation reaction is 0.5 ~ 2h.
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Non-Patent Citations (4)
| Title |
|---|
| 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;Yoshihiro Ogawa，等;《J. Org. Chem.》;20020203;第65卷;第1031-1036页 * |
| Practical Oppenauer (OPP) Oxidation of Alcohols with a Modified Aluminum Catalyst;Takashi Ooi，等;《Org. Lett.》;20020709;第4卷;第2669-2672页 * |
| The Mg-Oppenauer Oxidation asa Mild Method for the Synthesisof Aryl and Metallocenyl Ketones;Ralf J. Kloetzing，等;《Chem. Eur. J.》;20061006;第13卷;第215-227页 * |
| 芳香醛的类格氏反应研究;赵胜芳，等;《武汉理工大学学报》;20091231;第31卷(第24期);第167-169页 * |
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