CN102276476A - Production method of malonic acid mono-p-nitrobenzyl ester as penem medicament intermediate - Google Patents
Production method of malonic acid mono-p-nitrobenzyl ester as penem medicament intermediate Download PDFInfo
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- CN102276476A CN102276476A CN201110180498A CN201110180498A CN102276476A CN 102276476 A CN102276476 A CN 102276476A CN 201110180498 A CN201110180498 A CN 201110180498A CN 201110180498 A CN201110180498 A CN 201110180498A CN 102276476 A CN102276476 A CN 102276476A
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- propanedioic acid
- nitrobenzyl ester
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Abstract
The invention discloses a production method of malonic acid mono-p-nitrobenzyl ester as a penem medicament intermediate. The malonic acid mono-p-nitrobenzyl ester is generated through reaction in the existence of halogenated p-nitrobenzene and malonic acid or sodium salt thereof, a solvent, a catalyst and the like. The production method disclosed by the invention has the advantages of simple process, easiness for operation and high product yield.
Description
Technical field
The present invention relates to the production method of a kind of penem-like pharmaceutical intermediate propanedioic acid list to the nitrobenzyl ester.
Background technology
Existing propanedioic acid list is produced the nitrobenzyl ester, is to obtain through esterification with propanedioic acid and p-nitrophenyl methyl alcohol, and this reaction generates the two benzyl esters of propanedioic acid because of easy, and to nitrobenzyl alcohol price height, so raw materials cost is higher, does not have the market competitiveness.
Summary of the invention
The object of the present invention is to provide a kind of low-cost raw material is basic material to the nitro benzyl chloride, obtains propanedioic acid list benzyl ester by the reaction with excessive propanedioic acid, and it is both economical to change the raw materials technology cost, the yield height.
Technical solution of the present invention is:
A kind of penem-like pharmaceutical intermediate propanedioic acid list is characterized in that the production method of nitrobenzyl ester: under the condition to existence such as nitro halo benzyl and propanedioic acid or its salt, solvent and catalyzer, reaction and aftertreatment generate the propanedioic acid list to the nitrobenzyl ester, reaction formula:
Further, described nitro halo benzyl is meant to the nitro benzyl chloride or to the nitro bromobenzyl; Propanedioic acid or its salt are meant propanedioic acid, propanedioic acid list sodium salt, propanedioic acid double sodium salt, propanedioic acid monopotassium salt, the two sylvite of propanedioic acid.
Further, solvent is acetonitrile, toluene, benzene, dimethylbenzene in the described reaction system.Catalyzer is: any one in triethylamine and tosic acid and the esterifying catalyst, and two, or three mixture.
Further, described reaction is to react under reflux temperature, and temperature of reaction is the 60-200 degree, and the reaction times is 1-100 hour.
Further, describedly be: to nitro halo benzyl: propanedioic acid: solvent: catalyzer=1:1～10:1～100:0.1～10 to nitro halo benzyl and propanedioic acid and solvent, catalyst molar ratio.
The invention has the advantages that: technology of the present invention is simple, and is easy to operate, the product yield height.
Embodiment:
The invention will be further described below in conjunction with embodiment:
Embodiment 1:
Agitator is being housed, in 1000 milliliters of there-necked flasks of thermometer and reflux exchanger, add 296 gram propanedioic acid double sodium salts, 172 grams successively to nitro Benzyl Chloride, 400 milliliters of acetonitriles, 101 gram triethylamines, stirring and refluxing 10 hours, add 300 ml waters then and stir, filter, the filtrate layering, oil reservoir washs with aqueous sodium carbonate, arrives PH7 with the saturated common salt water washing again, and distillation obtains solid phase prod after concentrating, the refining oven dry of water obtains product 140 grams, content 98.5%.
Embodiment 2:
Agitator is being housed, in 1000 milliliters of there-necked flasks of thermometer and reflux exchanger, add 296 gram propanedioic acid double sodium salts, 172 grams successively to nitro Benzyl Chloride, 400 milliliters of toluene, 101 gram triethylamines, stirring and refluxing 10 hours, add 300 ml waters then and stir, filter, the filtrate layering, oil reservoir washs with aqueous sodium carbonate, arrives PH7 with the saturated common salt water washing again, and distillation obtains solid phase prod after concentrating, the refining oven dry of water obtains product 180 grams, content 98.5%.
Embodiment 3:
Agitator is being housed, in 1000 milliliters of there-necked flasks of thermometer and reflux exchanger, add 296 gram propanedioic acid double sodium salts, 172 grams successively to nitro Benzyl Chloride, 400 milliliters of toluene, 101 gram triethylamines, 10 gram tosic acid stirring and refluxing 10 hours, add 300 ml waters then and stir, filter, the filtrate layering, oil reservoir washs with aqueous sodium carbonate, arrives PH7 with the saturated common salt water washing again, and distillation obtains solid phase prod after concentrating, the refining oven dry of water obtains product 195 grams, content 98.5%.
Embodiment 4:
Agitator is being housed, in 1000 milliliters of there-necked flasks of thermometer and reflux exchanger, add 296 gram propanedioic acid double sodium salts, 218 grams successively to nitro benzyl bromide, 400 milliliters of toluene, 101 gram triethylamines, 10 gram tosic acid stirring and refluxing 10 hours, add 300 ml waters then and stir, filter, the filtrate layering, oil reservoir washs with aqueous sodium carbonate, arrives PH7 with the saturated common salt water washing again, and distillation obtains solid phase prod after concentrating, the refining oven dry of water obtains product 235 grams, content 98.5%.
Embodiment 5:
Agitator is being housed, in 1000 milliliters of there-necked flasks of thermometer and reflux exchanger, add 210 gram propanedioic acid, 172 grams successively to 400 milliliters of nitro Benzyl Chlorides, toluene, 101 gram triethylamines, 10 gram tosic acid stirring and refluxing 10 hours, add 300 ml waters then and stir, filter, the filtrate layering, oil reservoir washs with aqueous sodium carbonate, arrives PH7 with the saturated common salt water washing again, and distillation obtains solid phase prod after concentrating, the refining oven dry of water obtains product 185 grams, content 98.5%.
Embodiment 6:
Agitator is being housed, in 1000 milliliters of there-necked flasks of thermometer and reflux exchanger, add 210 gram propanedioic acid, 218 grams successively to 400 milliliters of nitro benzyl bromides, toluene, 101 gram triethylamines, 10 gram tosic acid stirring and refluxing 10 hours, add 300 ml waters then and stir, filter, the filtrate layering, oil reservoir washs with aqueous sodium carbonate, arrives PH7 with the saturated common salt water washing again, and distillation obtains solid phase prod after concentrating, the refining oven dry of water obtains product 215 grams, content 98.5%.
Claims (5)
1. a penem-like pharmaceutical intermediate propanedioic acid list is to the production method of nitrobenzyl ester, it is characterized in that: under the condition to existence such as nitro halo benzyl and propanedioic acid or its salt, solvent and catalyzer, reaction and aftertreatment generate the propanedioic acid list to the nitrobenzyl ester, reaction formula:
2. a kind of penem-like pharmaceutical intermediate propanedioic acid list according to claim 1 is characterized in that: nitro halo benzyl is meant to the nitro benzyl chloride or to the nitro bromobenzyl the production method of nitrobenzyl ester; Propanedioic acid or its salt are meant propanedioic acid, propanedioic acid list sodium salt, propanedioic acid double sodium salt, propanedioic acid monopotassium salt, the two sylvite of propanedioic acid.
3. a kind of penem-like pharmaceutical intermediate propanedioic acid list according to claim 1 and 2 is to the production method of nitrobenzyl ester, and it is characterized in that: solvent is acetonitrile, toluene, benzene, dimethylbenzene in the reaction system; Catalyzer is: any one in triethylamine and tosic acid and the esterifying catalyst, and two, or three mixture.
4. a kind of penem-like pharmaceutical intermediate propanedioic acid list according to claim 1 is to the production method of nitrobenzyl ester, and it is characterized in that: reaction is to react under reflux temperature, and temperature of reaction is the 60-200 degree, and the reaction times is 1-100 hour.
5. a kind of penem-like pharmaceutical intermediate propanedioic acid list according to claim 1 is characterized in that the production method of nitrobenzyl ester: to nitro halo benzyl and propanedioic acid and solvent, catalyst molar ratio be: to nitro halo benzyl: propanedioic acid: solvent: catalyzer=1:1～10:1～100:0.1～10.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011101804980A CN102276476B (en) | 2011-06-30 | 2011-06-30 | Production method of malonic acid mono-p-nitrobenzyl ester as penem medicament intermediate |
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| CN2011101804980A CN102276476B (en) | 2011-06-30 | 2011-06-30 | Production method of malonic acid mono-p-nitrobenzyl ester as penem medicament intermediate |
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| CN102276476B CN102276476B (en) | 2013-11-13 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103483202A (en) * | 2013-06-26 | 2014-01-01 | 华北水利水电大学 | Preparation method of magnesium mono-p-nitrobenzyl malonate |
| CN103540622A (en) * | 2013-09-29 | 2014-01-29 | 南京工业大学 | Method for enzymatic synthesis of mono-4-nitrobenzyl malonate |
| CN109467519A (en) * | 2017-09-07 | 2019-03-15 | 汪忠华 | A kind of preparation method of malonic acid single pair p-Nitrobenzyl |
| 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 |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108060186B (en) * | 2017-12-13 | 2020-08-28 | 台州学院 | Biological preparation method of p-nitrobenzyl alcohol malonic acid monoester |
-
2011
- 2011-06-30 CN CN2011101804980A patent/CN102276476B/en not_active Expired - Fee Related
Non-Patent Citations (3)
| Title |
|---|
| 张楷男 等: "6_溴青霉烷酸_1_氧化物对硝基苄酯的制备", 《精细与专用化学品》 * |
| 栾伟丽 等: "青霉素G亚砜对_硝基苄酯的合成工艺研究", 《江西化工》 * |
| 洪琳 等: "丙二酸二乙酯钠盐与对硝基苄基衍生物的反应", 《杭州大学学报》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103483202A (en) * | 2013-06-26 | 2014-01-01 | 华北水利水电大学 | Preparation method of magnesium mono-p-nitrobenzyl malonate |
| CN103483202B (en) * | 2013-06-26 | 2015-01-21 | 华北水利水电大学 | Preparation method of magnesium mono-p-nitrobenzyl malonate |
| CN103540622A (en) * | 2013-09-29 | 2014-01-29 | 南京工业大学 | Method for enzymatic synthesis of mono-4-nitrobenzyl malonate |
| CN103540622B (en) * | 2013-09-29 | 2016-04-13 | 南京工业大学 | Enzyme catalyzed synthesis is to the method for nitrobenzyl alcohol propanedioic acid list acid esters |
| CN109467519A (en) * | 2017-09-07 | 2019-03-15 | 汪忠华 | A kind of preparation method of malonic acid single pair p-Nitrobenzyl |
| 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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