CN101643413B - One pot method for preparing aryl-alpha-keto ester based on arylethyl ketone - Google Patents
One pot method for preparing aryl-alpha-keto ester based on arylethyl ketone Download PDFInfo
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Abstract
The invention provides a one pot method for preparing aryl-alpha-keto ester based on arylethyl ketone, belonging to the technical field of organic chemical engineering. The method comprises the following steps: using arylethyl ketone as raw material to place in a reaction container, adding pyridine, piperidine or triethylamine used as solvent in the reaction container in turn, adding selenium dioxide to perform oxidation reaction and obtain aryl-keto acid, adding methanol and a defined amount of molecular sieve, placing the reaction container in ice bath, then dropwise adding thionyl chloride in the reaction container to perform esterification reaction, adding strong acid in the reaction container to perform hydrolysis reaction, then performing neutralization reaction and finally obtaining aryl-alpha-keto ester by washing, drying and filtrating. Compared with the prior art, the invention can greatly reduce the cost and simplify the operation while maintaining the yield; the raw materials can be obtained easily, the reaction yield is high, the synthesis cost is low and the yield can reach 80%.
Description
Technical field
That the present invention relates to is a kind of preparation method of field of chemical technology, specifically a kind of one-pot preparation thereof of the aryl alpha-keto ester based on aryl methyl ketone.
Background technology
In the chemical industry technical field of organic synthesis, the aryl alpha-keto ester is synthetic plurality of enzymes inhibitor and alkaloidal important intermediate.Such as the synthetic intermediate as fat, carbohydrate, ribose, porphyrin, amino acid and protein, as enzyme inhibitors or zymolyte etc.Simultaneously, the aryl alpha-keto ester also is applied to the synthetic of the multiple compounds such as angiotonin transferase inhibitor, serpin, Deoxyharringtonine, HDHT in recent years, and respectively the treatment of hypertension, cancer etc. is had certain curative effect by the medicine that these compounds synthesized.Because its significance in organic synthesis, enzyme inhibitors and drug development, aryl alpha-ketoacid ester synthesis receives people's concern always.
Find by prior art documents, aryl alpha-ketoacid ester synthesis mostly is step synthesis, prepare the aryl alpha-keto ester such as the early stage Grignard reagent that passes through, name of document is: A General, One-Step Synthesis of α-Keto Esters (a kind of general single stage method prepares alpha-keto ester), Leonard M.Weinstock, Robert B.Currie, AlfredV.Lovel, Synthetic Communications (synthesising communication), 1981,11 volumes, the 943-946 page or leaf, under cold condition, to prepare alpha-keto ester by Grignard reagent and oxalic acid diethyl ester, although be single stage method, as Grignard reagent and the not only difficult preparation of oxalic acid diethyl ester of reaction raw materials, reaction conditions is also harsh, does not have versatility; The higher method of another kind of productive rate is to prepare keto ester by the Terminal Acetylenes hydrocarbon, name of document is: An efficient methodfor synthesis of α-keto acid esters from terminal alkynes (efficiently preparing keto ester by the Terminal Acetylenes hydrocarbon), Lian-Sheng Li and Yu-Lin Wu, Tetrahedron Letters (tetrahedron wall bulletin), 2002,43 volumes, the 2427-2430 page or leaf, mainly by bromine on end position then oxidation make product.Although this method reaction conditions is gentle, because Terminal Acetylenes hydrocarbon source is not extensive, the quantity of prepared product just is restricted.One kettle way only has an example text to offer report, and namely take aryl acetate as raw material, by diazo transfer, the one kettle way of dimethyldioxirane oxidation has synthesized the aryl alpha-keto ester.Name of document is: An efficient synthesis of aryl α-keto esters (aryl α keto ester high-efficient synthesis method), Ming Ma, Changkun Li, Lingling Peng, Fang Xie, Xiu Zhangand Jianbo Wang, Tetrahedron Letters (tetrahedron wall bulletin), 2005,46 volumes, the 3927-3929 page or leaf.Although the method also is one kettle way, but used raw material, aryl acetate is not easy to obtain, and the reagent that relates to is such as the 4-kharophen Phenylsulfonic acid diazonium of using during diazo transfer in the reaction, dimethyldioxirane required during oxidation all is easy to get and easily preparation not as raw material and the reagent that this patent is mentioned, not only operation is difficult, and synthetic cost is also higher.
Summary of the invention
The present invention is directed to the prior art above shortcomings, a kind of one-pot preparation thereof of the aryl alpha-keto ester based on aryl methyl ketone is provided, its raw material and agents useful for same cheaply are easy to get, reaction conditions is gentle, easy to operate, overall yield is also higher, for the suitability for industrialized production of this compound provides reliable foundation.
The present invention is achieved by the following technical solutions, the present invention includes following steps:
The first step, place reaction vessel take aryl methyl ketone as raw material, in reaction vessel, add successively pyridine, piperidines or triethylamine as solvent, and add and carry out oxidizing reaction behind the tin anhydride and generate the aryl ketone acid;
Described reaction vessel is the encloses container with nitrogen protection environment.
Described aryl methyl ketone refers to: methyl phenyl ketone, p-methyl aceto phenone, p-methoxy-acetophenone, a kind of in fluoro acetophenone, parachloroacetophenone, o-chloroacetophenone, m chloroacetophenone, parabromoacetophenone, β-acetonaphthone and β-furans ethyl ketone.
The temperature of reaction of described oxidizing reaction is 20 ~ 120 ℃, and the reaction times is 1 ~ 48 hour, reaction vessel is kept stirring in described oxidation reaction process.
The consumption of described tin anhydride is 0.5 ~ 5 equivalent of aryl methyl ketone.
Second step, add methyl alcohol and quantitative molecular sieve in the reaction vessel, and reaction vessel is placed under the ice bath environment, then splash into thionyl chloride in the reaction vessel and carry out esterification;
The consumption of described molecular sieve is 0.1 ~ 2 times of aryl methyl ketone weight.
The consumption of described methyl alcohol is 1 ~ 50 equivalent of aryl methyl ketone.
The consumption of described thionyl chloride is 1 ~ 16 equivalent of aryl methyl ketone.
The temperature of reaction of described esterification is 0 ~ 65 ℃, and the reaction times is 1 ~ 48 hour.
The 3rd step, add the strong acid reaction that is hydrolyzed in the reaction vessel, then carry out neutralization reaction and acquisition aryl alpha-keto ester after the washing dry filter is processed.
Described strong acid refers to: a kind of or its combination in concentrated hydrochloric acid, the vitriol oil, Hydrogen bromide, perchloric acid, hyperbromic acid or the Periodic acid, the consumption of this strong acid is 1.5 ~ 10 equivalents of aryl methyl ketone.
Described neutralization reaction refers to: add gradually saturated sodium bicarbonate to remove unnecessary strong acid, until no longer include bubble formation in the reaction vessel in reaction vessel.
Described washing dry filter is processed and referred to: adopt saturated common salt water washing 1 time, behind the anhydrous magnesium sulfate drying 0.5h, solids removed by filtration is revolved and is boiled off solvent, obtains the aryl alpha-keto ester of oily or solid state.
The present invention compared with prior art when keeping yield, greatly reduces cost, has simplified operation; Raw material sources are convenient, reaction yield is high, synthetic cost is low, the preparation productive rate reaches 80%.
Description of drawings
Fig. 1 schematic flow sheet of the present invention.
Embodiment
The below elaborates to embodiments of the invention, and present embodiment is implemented under take technical solution of the present invention as prerequisite, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Embodiment 1
As shown in Figure 1, the present embodiment preparation method may further comprise the steps:
Under nitrogen protection, with methyl phenyl ketone (0.48g, 4.0mmol), tin anhydride (0.66g, 6.0mmol), pyridine (2.0mL, 25mmol) joins in two mouthfuls of flasks of 25mL, oil bath slowly is heated to 100 ℃, and behind the return stirring 12h, TLC detects raw material point 1 and disappears;
In ice water bath environment, in two mouthfuls of flasks, add 0.24g molecular sieve and methyl alcohol (2.9mL, 72mmol), after the agitation as appropriate, slowly splash into thionyl chloride (1.5mL, 20mmol), about 1h removes ice bath after all dripping off, stirring at normal temperature 16h;
The perchloric acid (1.6mL, 20mmol) of adding 70 ~ 72% is behind acetonitrile (32mL) and deionized water (3.2mL) the stirring reaction 0.5h, add gradually saturated sodium bicarbonate and remove unnecessary acid, treat to no longer include bubble formation in two mouthfuls of flasks, stop to stir, remove by filter insolubles, deionized water wash 3 times of gained organic phase, saturated common salt water washing 1 time, behind the anhydrous magnesium sulfate drying 0.5h, solids removed by filtration, revolve and boil off solvent, obtain oily aryl alpha-keto ester.
Obtain pure product through silica gel column chromatography [V (ethyl acetate): V (sherwood oil)=1: 10] separation, productive rate is 77%.
Comparative Examples:
Comparative Examples adopts the step identical with embodiment 1, chooses different aryl methyl ketones and carries out implementation, and result of implementation is as follows:
Claims (10)
1. the one-pot preparation thereof based on the aryl alpha-keto ester of aryl methyl ketone is characterized in that, may further comprise the steps:
The first step, take aryl methyl ketone or β-furans ethyl ketone as raw material places reaction vessel, in reaction vessel, add successively pyridine, piperidines or triethylamine as solvent, and add and carry out oxidizing reaction behind the tin anhydride and generate the aryl ketone acid;
Second step, add methyl alcohol and quantitative molecular sieve in the reaction vessel, and reaction vessel is placed under the ice bath environment, then splash into the dichloro Asia in the reaction vessel and sough and carry out esterification;
The 3rd step, add the strong acid reaction that is hydrolyzed in the reaction vessel, then carry out neutralization reaction and acquisition aryl alpha-keto ester after the washing dry filter is processed.
2. the one-pot preparation thereof of the aryl alpha-keto ester based on aryl methyl ketone according to claim 1, it is characterized in that the aryl methyl ketone described in the first step refers to: methyl phenyl ketone, p-methyl aceto phenone, p-methoxy-acetophenone, a kind of in fluoro acetophenone, parachloroacetophenone, o-chloroacetophenone, m chloroacetophenone, parabromoacetophenone and the β-acetonaphthone.
3. the one-pot preparation thereof of the aryl alpha-keto ester based on aryl methyl ketone according to claim 1 is characterized in that the temperature of reaction of the oxidizing reaction described in the first step is 20～120 ℃, and the reaction times is 1～48 hour.
4. the one-pot preparation thereof of the aryl alpha-keto ester based on aryl methyl ketone according to claim 1 is characterized in that the consumption of the tin anhydride described in the first step is 0.5～5 equivalent of aryl methyl ketone.
5. the one-pot preparation thereof of the aryl alpha-keto ester based on aryl methyl ketone according to claim 1 is characterized in that the consumption of the molecular sieve described in the second step is 0.1～2 times of aryl methyl ketone weight.
6. the one-pot preparation thereof of the aryl alpha-keto ester based on aryl methyl ketone according to claim 1 is characterized in that the consumption of the methyl alcohol described in the second step is 1～50 equivalent of aryl methyl ketone.
7. the one-pot preparation thereof of the aryl alpha-keto ester based on aryl methyl ketone according to claim 1 is characterized in that the consumption of the thionyl chloride described in the second step is 1～16 equivalent of aryl methyl ketone.
8. the one-pot preparation thereof of the aryl alpha-keto ester based on aryl methyl ketone according to claim 1 is characterized in that, the temperature of reaction of the esterification described in the second step is O～65 ℃, and the reaction times is 1～48 hour.
9. the one-pot preparation thereof of the aryl alpha-keto ester based on aryl methyl ketone according to claim 1, it is characterized in that, strong acid described in the 3rd step refers to: a kind of or its combination in concentrated hydrochloric acid, the vitriol oil, Hydrogen bromide, perchloric acid, hyperbromic acid or the Periodic acid, the consumption of this strong acid is 1.5～10 equivalents of aryl methyl ketone.
10. the one-pot preparation thereof of the aryl alpha-keto ester based on aryl methyl ketone according to claim 1, it is characterized in that, washing dry filter described in the 3rd step is processed and is referred to: adopt saturated common salt water washing 1 time, behind the anhydrous magnesium sulfate drying 0.5h, solids removed by filtration, revolve and boil off solvent, obtain the aryl alpha-keto ester of oily.
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| CN110590535A (en) * | 2019-10-12 | 2019-12-20 | 重庆医药高等专科学校 | Method for preparing aromatic glyoxylic acid by oxidizing acetophenone with selenium dioxide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1745896A (en) * | 2005-08-09 | 2006-03-15 | 华东理工大学 | Synthesis of ferro-niobium ellestadite aluminium molecular sieve from pyruvic acid |
| JP2007197339A (en) * | 2006-01-24 | 2007-08-09 | Fujifilm Finechemicals Co Ltd | Method for producing 2,3'-bipyridyl-6'-one |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1745896A (en) * | 2005-08-09 | 2006-03-15 | 华东理工大学 | Synthesis of ferro-niobium ellestadite aluminium molecular sieve from pyruvic acid |
| JP2007197339A (en) * | 2006-01-24 | 2007-08-09 | Fujifilm Finechemicals Co Ltd | Method for producing 2,3'-bipyridyl-6'-one |
Non-Patent Citations (2)
| Title |
|---|
| COOPER A J L,GNOS.J,.SYNTHESIS AND PROPERTIES OF THE KETO ACIDS.《chem.rev》.1983,第83卷(第3期),321-358. * |
| MING MA,CHANGKUN LI.AN EFFICIENT SYNTHESIS OF ARYL α-KETO ESTERS.《TETRAHEDRON LETTERS》.2005,第46卷3927-3929. * |
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