CN102643211A - Preparation method of p-Nitrobenzyl 2-diazoacetoacetate - Google Patents
Preparation method of p-Nitrobenzyl 2-diazoacetoacetate Download PDFInfo
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- CN102643211A CN102643211A CN2012101024521A CN201210102452A CN102643211A CN 102643211 A CN102643211 A CN 102643211A CN 2012101024521 A CN2012101024521 A CN 2012101024521A CN 201210102452 A CN201210102452 A CN 201210102452A CN 102643211 A CN102643211 A CN 102643211A
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Abstract
The invention particularly relates to a preparation method of p-Nitrobenzyl 2-diazoacetoacetate, wherein when a compound III is prepared, aluminum trichloride is added to be taken as ester exchange catalyst, the reaction speed is accelerated, so that the ester exchange time is shortened to 4-6h from 18hours reported in the document US: 5340927, the reaction can be promoted by the evaporation mode that the methylbenzene is constantly evaporated and the equivalent methylbenzene is constantly supplemented in the ester exchange reaction, the operation mode reported in the document US: 5340927 is the constant reflow of the methylbenzene, and the reaction can be promoted by constantly changing molecular sieves. Compared with the method reported in the document US: 5340927, the method is simpler and easier to realize in the industrial production operation.
Description
Technical field
The present invention is specifically related to the preparation method of a kind of 2-diazonium etheric acid to the nitrobenzyl ester.
Background technology
2-diazonium etheric acid is one of key intermediate of synthetic rare type of microbiotic imipenum of carbon mould to the nitrobenzyl ester, and at present according to the documents and materials report, preparation 2-diazonium etheric acid mainly contains following several to the route of nitrobenzyl ester:
Article one, route is disclosed in Chemical Communications 2,006 12 1316-1318
Second is published in GB:2173801
Article three, be published in US:5340927
Article four, be published in CN:101983958
Article one, the shortcoming of operational path is: operational path is complicated, and catalyzer is expensive.
The shortcoming of second operational path is: the transesterify yield is low, and total recovery is 69.2%, diazo reagent TaN
3Be not easy to obtain.
Article three, the shortcoming of operational path is: 4A molecular sieve consumption is big, changes often; Change the molecular sieve complicated operation in the industry; The transesterification reaction time long (more than 18 hours); Back flow reaction causes the ester exchange offspring color dark for a long time; Used azide reagent is relatively more expensive, and total recovery has only 77.6%
Article four, the shortcoming of process route is: this route has used 2,2-dimethyl-1, and 3-dislikes hexamethylene-4-alkene-6-ketone, and this compound is expensive and difficult to be bought.
Summary of the invention
The objective of the invention is to customer service deficiency of the prior art and provide a kind of simple to operate, cost is low, good product quality, and the high 2-diazonium etheric acid of yield is to the preparation method of nitrobenzyl ester.
The objective of the invention is to realize like this:
A kind of 2-diazonium etheric acid is to the preparation method of nitrobenzyl ester, is to make 2-diazonium etheric acid to the nitrobenzyl ester by following two-step reaction:
The temperature of the first step reaction is 80-125 ℃, and the reaction times is 4-6h, and the mol ratio of chemical compounds I and compound ii is 1-2:1, and toluene is not only as reaction solvent but also as the azeotropic solvent of transesterification reaction generation methyl alcohol, AlCl
3As transesterification catalyst, AlCl wherein
3With the mol ratio of compound ii be 0.01-0.5:1, toluene and compound ii volume/weight ratio are 2-10:1, the weight of Calcium Chloride Powder Anhydrous is 1%～10% of toluene by weight, the compound III is without separation, directly gets into the reaction of second step.
The first step reaction is constantly mended the evaporation mode of going into through the liquid that steams after adopting a kind of reaction solution constantly to steam to handle with equivalent, and the continuous azeotropic of toluene that the methyl alcohol that transesterify is generated is steamed goes out reaction system, impels reaction constantly to go on.Steam methyl alcohol in the liquid through generating CaCl with Calcium Chloride Powder Anhydrous
2.4CH
3OH is removed, and the toluene and the chemical compounds I that steam in the liquid can be recycled, and has reduced cost.
The temperature of second step reaction is 45-55 ℃, and the reaction times is 2-4h, and acetone and water are solvent, NaN
3And CH
3SO
2Cl is as diazo reagent; Sodium hydrogencarbonate is an acid binding agent; Acetone and compound ii volume/weight ratio are 1-5:1, and water and compound ii volume/weight ratio are 1-5:1, and the mol ratio of sodium hydrogencarbonate and compound ii is 0.1-0.8:1; The mol ratio of sodiumazide and compound ii is 1-2:1, and the mol ratio of methylsulfonyl chloride and compound ii is 1-2:1.
In the second step reaction process, the mixed solution of compound III and the methylsulfonyl chloride mode through dropping joined contain NaN
3In the aqueous acetone solution of sodium hydrogencarbonate.
Second step was reacted postcooling to the 10 ℃ suction filtration that finishes, and was dry under 45 ℃ of conditions in temperature, got the compound IV.
The product gas purity that second step generated>99%, total molar yield>93%.
Wherein in the preparation of compound III, add aluminum chloride as transesterification catalyst, accelerated speed of response, make the transesterification reaction time by document US: 18 hours of 5340927 reports shorten to 4～6h.
In transesterification reaction, taked toluene constantly to steam with equivalent toluene and constantly mended the carrying out that the evaporation mode of going into impels reaction, and document US: the operating method of 5340927 reports is that toluene constantly refluxes, the carrying out of impelling reaction through continuous replacing molecular sieve.Present method and document US: 5340927 reported method are compared, and present method is in the suitability for industrialized production operation, and is simpler, more are prone to realize.
The toluene that contains chemical compounds I that steams adds the Calcium Chloride Powder Anhydrous stirring and removes methyl alcohol.After the filtration, toluene and wherein contained excessive chemical compounds I recycle have once more improved the utilization ratio of chemical compounds I and toluene, have reduced cost.
The compound III need not be separated, and directly gets into step reaction down, has both simplified operation, has improved the yield in per step again.
In the preparation process of compound IV, adopt and be added drop-wise to the feed way in the reaction solution to compound III and methylsulfonyl chloride mixed solution, solved the problem of compound IV double team compound III in going out brilliant process, improved the quality of compound IV.
In the preparation process of compound IV, use cheap sodium azide and mesyl chloride as diazo reagent, reduced cost.
In the preparation process of compound IV, use aqueous acetone solution as reaction solvent, promptly avoided the use of phase-transfer catalyst, improved the quality of product again.
Embodiment
Embodiment below in conjunction with concrete is further described the present invention.
Embodiment 1: in 300ml toluene, add 115 ℃ of 50g compound iis, 52ml chemical compounds I, 1.3g aluminum chloride, temperature control, reaction solution is evenly steamed, the reaction solution that steams adds 3% Calcium Chloride Powder Anhydrous of its weight; 45 ℃; Stir 1h, after the filtration, mend in the reaction system.After the reaction to terminal, steam desolventize the compound III, with compound III and 37.8mlCH
3SO
2The mixed solution of Cl is added drop-wise to and contains 32g NaN
3In the aqueous acetone solution of 8g sodium hydrogencarbonate, 50 ℃ of controlled temperature, reaction is cooled to 10 ℃ to terminal, suction filtration, 45 ℃ of vacuum-dryings get compound IV 80g, HPLC Chun Du>99%, yield 93%.
Embodiment 2: in 150ml toluene, add 115 ℃ of 50g compound iis, 52ml chemical compounds I, 0.5g aluminum chloride, temperature control, reaction solution is evenly steamed, the reaction solution that steams adds 3% Calcium Chloride Powder Anhydrous of its weight; 45 ℃; Stir 1h, after the filtration, mend in the reaction system.After the reaction to terminal, steam desolventize the compound III, with compound III and 32.8mlCH
3SO
2The mixed solution of Cl is added drop-wise to and contains 27.6g NaN
3In the aqueous acetone solution of 8g sodium hydrogencarbonate, 50 ℃ of controlled temperature, reaction is cooled to 10 ℃ to terminal, suction filtration, 45 ℃ of vacuum-dryings get compound IV 79g, HPLC Chun Du>99%, yield 92%.
Embodiment 3: in 200ml toluene, add 115 ℃ of 50g compound iis, 59ml chemical compounds I, 0.8g aluminum chloride, temperature control, reaction solution is evenly steamed, the reaction solution that steams adds 3% Calcium Chloride Powder Anhydrous of its weight; 45 ℃; Stir 1h, after the filtration, mend in the reaction system.After the reaction to terminal, steam desolventize the compound III, with compound III and 35.3mlCH
3SO
2The mixed solution of Cl is added drop-wise to and contains 30g NaN
3In the aqueous acetone solution of 8g sodium hydrogencarbonate, 50 ℃ of controlled temperature, reaction is cooled to 10 ℃ to terminal, suction filtration, 45 ℃ of vacuum-dryings get compound IV 80.5g, HPLC Chun Du>99%, yield 93.7%.
Owing to described the present invention with specific embodiment, to be proficient in this technological technician and can to revise and the equivalence change it, this is understood to include within scope of the present invention.
Claims (7)
1. a 2-diazonium etheric acid is characterized in that the preparation method of nitrobenzyl ester: be to make 2-diazonium etheric acid to the nitrobenzyl ester by following two-step reaction:
2. a kind of 2-diazonium etheric acid according to claim 1 is to the preparation method of nitrobenzyl ester; It is characterized in that: the temperature of the first step reaction is 80-125 ℃; Reaction times is 4-6h; The mol ratio of chemical compounds I and compound ii is 1-2:1, and toluene not only generated the azeotropic solvent of methyl alcohol, AlCl as reaction solvent but also as transesterification reaction
3As transesterification catalyst, AlCl wherein
3With the mol ratio of compound ii be 0.01-0.5:1, toluene and compound ii volume/weight ratio are 2-10:1, the compound III is without separation, directly gets into the reaction of second step.
3. a kind of 2-diazonium etheric acid according to claim 2 is characterized in that the preparation method of nitrobenzyl ester: the first step reaction is constantly mended the mode of going into and is reacted through adopting toluene after constantly steaming of toluene handled with equivalent to steam liquid.
4. a kind of 2-diazonium etheric acid according to claim 3 is characterized in that the preparation method of nitrobenzyl ester: described toluene steams methyl alcohol in the liquid through generating CaCl with an amount of Calcium Chloride Powder Anhydrous
2.4CH
3OH is removed, and toluene and chemical compounds I that toluene steams in the liquid utilize once more.
5. a kind of 2-diazonium etheric acid according to claim 2 is characterized in that the preparation method of nitrobenzyl ester: the temperature of second step reaction is 45-55 ℃, and the reaction times is 2-4h, and acetone and water are solvent, NaN
3And CH
3SO
2Cl is as diazo reagent; Sodium hydrogencarbonate is an acid binding agent; Acetone and compound ii volume/weight ratio are 1-5:1, and water and compound ii volume/weight ratio are 1-5:1, and the mol ratio of sodium hydrogencarbonate and compound ii is 0.1-0.8:1; The mol ratio of sodiumazide and compound ii is 1-2:1, and the mol ratio of methylsulfonyl chloride and compound ii is 1-2:1.
6. a kind of 2-diazonium etheric acid according to claim 5 is characterized in that the preparation method of nitrobenzyl ester: in the second step reaction process, the mixed solution of compound III and the methylsulfonyl chloride mode through dropping joined contain NaN
3In the aqueous acetone solution of sodium hydrogencarbonate.
7. a kind of 2-diazonium etheric acid according to claim 2 is characterized in that the preparation method of nitrobenzyl ester: second step was reacted postcooling to the 10 ℃ suction filtration that finishes, and was dry under 45 ℃ of conditions in temperature, got the compound IV.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105906529A (en) * | 2016-06-07 | 2016-08-31 | 江西富祥药业股份有限公司 | 4-halogenated-2-diazo-3-oxo-valeric acid(4-nitrobenzene)methyl ester and preparation method thereof |
| CN107556212A (en) * | 2017-09-14 | 2018-01-09 | 台州昌霖化工科技有限公司 | A kind of method for preparing 2 diazonium p-nitrobenzyl acetoacetates |
| CN113292436A (en) * | 2021-06-18 | 2021-08-24 | 蒲鹏 | Method for preparing 2-diazo-acetoacetic acid p-nitrobenzyl ester by using microchannel reactor |
| CN113880726A (en) * | 2021-10-14 | 2022-01-04 | 南昌大学 | Method for efficiently synthesizing diazo compound |
| CN114516820A (en) * | 2022-02-25 | 2022-05-20 | 山东艾孚特科技有限公司 | Method for preparing 2-diazo-acetoacetic acid p-nitrobenzyl ester |
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| US4683296A (en) * | 1983-03-07 | 1987-07-28 | Bristol-Myers Company | Carbapenem intermediates |
| US5340927A (en) * | 1989-07-18 | 1994-08-23 | Merck & Co., Inc. | Process for the preparation of 2-diazo-3-trisubstituted silyloxy 3-butenoates |
| CN101570537A (en) * | 2009-06-18 | 2009-11-04 | 浙江师范大学 | Preparation method of panipenem |
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2012
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Patent Citations (3)
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| US4683296A (en) * | 1983-03-07 | 1987-07-28 | Bristol-Myers Company | Carbapenem intermediates |
| US5340927A (en) * | 1989-07-18 | 1994-08-23 | Merck & Co., Inc. | Process for the preparation of 2-diazo-3-trisubstituted silyloxy 3-butenoates |
| CN101570537A (en) * | 2009-06-18 | 2009-11-04 | 浙江师范大学 | Preparation method of panipenem |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105906529A (en) * | 2016-06-07 | 2016-08-31 | 江西富祥药业股份有限公司 | 4-halogenated-2-diazo-3-oxo-valeric acid(4-nitrobenzene)methyl ester and preparation method thereof |
| CN107556212A (en) * | 2017-09-14 | 2018-01-09 | 台州昌霖化工科技有限公司 | A kind of method for preparing 2 diazonium p-nitrobenzyl acetoacetates |
| CN107556212B (en) * | 2017-09-14 | 2020-03-24 | 台州昌霖化工科技有限公司 | Method for preparing 2-diazo-acetoacetic acid p-nitrobenzyl ester |
| CN113292436A (en) * | 2021-06-18 | 2021-08-24 | 蒲鹏 | Method for preparing 2-diazo-acetoacetic acid p-nitrobenzyl ester by using microchannel reactor |
| CN113292436B (en) * | 2021-06-18 | 2023-04-18 | 蒲鹏 | Method for preparing 2-diazo-acetoacetic acid p-nitrobenzyl ester by using microchannel reactor |
| CN113880726A (en) * | 2021-10-14 | 2022-01-04 | 南昌大学 | Method for efficiently synthesizing diazo compound |
| CN114516820A (en) * | 2022-02-25 | 2022-05-20 | 山东艾孚特科技有限公司 | Method for preparing 2-diazo-acetoacetic acid p-nitrobenzyl ester |
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Inventor after: Li Lingling Inventor after: Zhou Chengkun Inventor after: Cheng Jinhua Inventor after: Guo Jinghong Inventor after: Hou Yongtao Inventor after: Li Guoqiang Inventor before: Zhou Chengkun Inventor before: Cheng Jinhua Inventor before: Guo Jinghong Inventor before: Hou Yongtao Inventor before: Li Guoqiang |
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Free format text: CORRECT: INVENTOR; FROM: ZHOU CHENGKUN CHENG JINHUA GUO JINGHONG HOU YONGTAO LI GUOQIANG TO: LI LINGLING ZHOU CHENGKUN CHENG JINHUA GUO JINGHONG HOU YONGTAO LI GUOQIANG |
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Application publication date: 20120822 |