CN102391128B - Production method of antibiotic pharmaceutical intermediate mono-p-nitro benzyl malonate - Google Patents
Production method of antibiotic pharmaceutical intermediate mono-p-nitro benzyl malonate Download PDFInfo
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- CN102391128B CN102391128B CN2011102824290A CN201110282429A CN102391128B CN 102391128 B CN102391128 B CN 102391128B CN 2011102824290 A CN2011102824290 A CN 2011102824290A CN 201110282429 A CN201110282429 A CN 201110282429A CN 102391128 B CN102391128 B CN 102391128B
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- propanedioic acid
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- nitro benzyl
- pharmaceutical intermediate
- benzyl malonate
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Abstract
The invention discloses a production method of antibiotic pharmaceutical intermediate mono-p-nitro benzyl malonate, wherein the mono-p-nitro benzyl malonate is produced through reaction under the presence of nitrobenzyl alcohol, malonate ring (sub) isopropyl ester and a solvent and the like. The production method has a simple process, easiness for operating and high product yield, and is applicable to industrialized production.
Description
Technical field
The present invention relates to take p-nitrophenyl methyl alcohol: propanedioic acid ring (Asia) isopropyl ester is raw material, high yield, and a kind of antibiotic pharmaceutical intermediate mono-p-nitro benzyl malonate of highly purified acquisition, the simpler and technique of synthetic method is suitable for industrialized production.
Background technology
The propanedioic acid list is the essential industry raw material for preparing antibiotic medicine to p-Nitrobenzyl.
The propanedioic acid list can and be in harmonious proportion the step such as refining to nitrobenzyl alcohol through the acid of over-churning, alkali by propanedioic acid to p-Nitrobenzyl and make (referring to US5087734); Also can react and make (referring to US5516934) under the catalyzer existence condition by two (the 4-oil of mirbane methyl) esters of propanedioic acid and propanedioic acid.
Yet, disclosed method in these documents, yield low (easily generate by product propanedioic acid two benzyl esters), and product purity and post-treating method all still need to improve.Therefore still need a kind of method of propanedioic acid list to p-Nitrobenzyl that better prepare.
The present invention concentrates on studies to the method for p-Nitrobenzyl to producing the propanedioic acid list, found that, employing is raw material via propanedioic acid ring (Asia) isopropyl ester, p-nitrophenyl methyl alcohol and suitable solvent, and provide certain processing condition, can high yield (side reaction is few), purity and convenient post-treatment ground obtains the propanedioic acid list to p-Nitrobenzyl, and be applicable to very much suitability for industrialized production, completed thus the present invention.
Summary of the invention
The object of the present invention is to provide the synthetic method of a kind of new propanedioic acid list to p-Nitrobenzyl, reaction yield, product purity is high and be suitable for the synthetic method of suitability for industrialized production.
Technical solution of the present invention is:
Specifically, the invention provides that a kind of to take p-nitrophenyl methyl alcohol, propanedioic acid ring (Asia) isopropyl ester and solvent be raw material, finally obtain the method for propanedioic acid list to p-Nitrobenzyl, the method comprises the steps, reaction formula:
Further, in described reaction system, solvent is acetonitrile, toluene, benzene, dimethylbenzene.
Further, described reaction is to react under reflux temperature, and temperature of reaction is 60-160 ℃, and the reaction times is 2～20 hours.
Further, described p-nitrophenyl methyl alcohol, propanedioic acid ring (Asia) isopropyl ester and solvent mol ratio are: p-nitrophenyl methyl alcohol: propanedioic acid ring (Asia) isopropyl ester: solvent=1:1～2:1～100.
Further, the propanedioic acid list that prepared by the inventive method can adopt conventional method to carry out to the aftertreatment of p-Nitrobenzyl: washing, underpressure distillation, recrystallization etc.
The invention has the advantages that: technique of the present invention is simple, easy to operate, and conversion rate of products and yield are high.
Embodiment
Hereinafter, the present invention will make more detailed non-limiting description by the mode of embodiment:
Embodiment 1:
Agitator is being housed, in 1000 milliliters of there-necked flasks of thermometer and reflux exchanger, is adding successively 400 milliliters of 96 gram p-nitrophenyl methyl alcohol 0.63mol, 96 gram propanedioic acid ring (Asia) isopropyl ester 0.66mol, acetonitriles.Reinforced complete, stir and be warming up to backflow, temperature is controlled at 85～90 ℃, stirring and refluxing 16 hours.Solvent is by vacuum-concentrcted, and the residue obtained adds the water of 200ml and stirs 30mins, then the saleratus 200ml that is 10% by mass concentration processing, and after vacuum filtration, the hcl acidifying with 10% is to pH=3.Filter under vacuum state, use cold water washing, drain.Dry to obtain product 120.5g, yield 80%; 99～100 ℃ of fusing points, content 99%.
Embodiment 2:
Agitator is being housed, in 1000 milliliters of there-necked flasks of thermometer and reflux exchanger, add successively 400 milliliters of 96 gram p-nitrophenyl methyl alcohol 0.63mol, 96 gram propanedioic acid ring (Asia) isopropyl ester 0.66mol, toluene, reinforced complete, stirring is warming up to backflow, temperature is controlled at 110～111 ℃, stirring and refluxing 10 hours.Be cooled to after room temperature the purified water that directly adds 200ml, reaction system uses 10% saleratus (200ml) to process again, filters layering.Organic phase is recyclable applies mechanically.The water of getting to pH=3, has solid to separate out with 10% hcl acidifying, under vacuum state, filters, and uses cold water washing, drains.Dry to obtain product 128.1g, yield 85%; 99～100 ℃ of fusing points, content 99%.
Embodiment 3:
Agitator is being housed, in 1000 milliliters of there-necked flasks of thermometer and reflux exchanger, is adding successively 400 milliliters of 96 gram p-nitrophenyl methyl alcohol 0.63mol, 108.96 gram propanedioic acid ring (Asia) isopropyl ester 0.756mol, dimethylbenzene.Reinforced complete, stir and be warming up to backflow, temperature is controlled at 140 ℃, stirring and refluxing 10 hours.Be down to 60 ℃ of left and right, filter out insolubles, the rear purified water that directly adds 200ml, reaction system is processed with 10% saleratus 200ml again, filters, layering, organic phase is recyclable applies mechanically.The water of getting to pH=3, has solid to separate out with 10% hcl acidifying, under vacuum state, filters, and uses cold water washing, drains.Dry to obtain product 135.6g, yield 90%; 99～100 ℃ of fusing points, content 99%.
Embodiment 4:
Agitator is being housed, in 1000 milliliters of there-necked flasks of thermometer and reflux exchanger, is adding successively 400 milliliters of 96 gram p-nitrophenyl methyl alcohol 0.63mol, 96 gram propanedioic acid ring (Asia) isopropyl ester 0.66mol, benzene.Reinforced complete, stir and be warming up to backflow, temperature is controlled at 80 ℃, stirring and refluxing 15 hours.Solvent is by vacuum-concentrcted, and the residue obtained adds the methylene dichloride of 500ml,, be evaporated to system liquid 250ml, reaction solution is cooled to 0-5 ℃, has solid to separate out.Vacuum filtration, cold dichloromethane for filter cake, drain, and dries to obtain product 107g, yield 71% fusing point 97-99 ℃, content 99%.
Claims (3)
1. the production method of an antibiotic pharmaceutical intermediate mono-p-nitro benzyl malonate, it is characterized in that: under the condition that p-nitrophenyl methyl alcohol, propanedioic acid ring (Asia) isopropyl ester and solvent acetonitrile or dimethylbenzene exist, reaction and aftertreatment make the propanedioic acid list to p-Nitrobenzyl, reaction formula:
2. the production method of a kind of antibiotic pharmaceutical intermediate mono-p-nitro benzyl malonate according to claim 1, it is characterized in that: temperature of reaction is preferably between 60-160 ℃, and the reaction times is 2～20 hours.
3. the production method of a kind of antibiotic pharmaceutical intermediate mono-p-nitro benzyl malonate according to claim 1, it is characterized in that: p-nitrophenyl methyl alcohol, propanedioic acid ring (Asia) isopropyl ester and solvent mol ratio are: p-nitrophenyl methyl alcohol: propanedioic acid ring (Asia) isopropyl ester: solvent=1:1～2:1～100.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011102824290A CN102391128B (en) | 2011-09-22 | 2011-09-22 | Production method of antibiotic pharmaceutical intermediate mono-p-nitro benzyl malonate |
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| CN2011102824290A CN102391128B (en) | 2011-09-22 | 2011-09-22 | Production method of antibiotic pharmaceutical intermediate mono-p-nitro benzyl malonate |
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| CN102391128A CN102391128A (en) | 2012-03-28 |
| CN102391128B true CN102391128B (en) | 2013-12-11 |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103483202B (en) * | 2013-06-26 | 2015-01-21 | 华北水利水电大学 | Preparation method of magnesium mono-p-nitrobenzyl malonate |
| CN108060186B (en) * | 2017-12-13 | 2020-08-28 | 台州学院 | Biological preparation method of p-nitrobenzyl alcohol malonic acid monoester |
| CN108892618B (en) * | 2018-07-30 | 2021-03-16 | 山东沾化永浩医药科技有限公司 | Preparation method and application of p-nitrobenzyl alcohol |
| CN111019980B (en) * | 2019-12-16 | 2021-07-13 | 牡丹江医学院 | Biosynthesis method of mono-p-nitrobenzyl malonate |
| CN114773205A (en) * | 2022-05-25 | 2022-07-22 | 浙江华洲药业有限公司 | Process for producing mono-p-nitrobenzyl malonate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5516934A (en) * | 1994-08-05 | 1996-05-14 | Nippon Kayaku Kabushiki Kaisha | Process for producing mono-P-nitrobenzyl malonate |
| CN1730460A (en) * | 2005-07-21 | 2006-02-08 | 浙江工业大学 | A kind of one kettle way prepares the method for caffeic acid ester derivants |
| CN100999473A (en) * | 2006-12-19 | 2007-07-18 | 浙江工业大学 | 5-nitro coffeic acid phenylglycollic ester and its preparation and use |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP3166950B2 (en) * | 1993-04-08 | 2001-05-14 | 日本化薬株式会社 | Method for producing mono-p-nitrobenzylmalonate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5516934A (en) * | 1994-08-05 | 1996-05-14 | Nippon Kayaku Kabushiki Kaisha | Process for producing mono-P-nitrobenzyl malonate |
| CN1730460A (en) * | 2005-07-21 | 2006-02-08 | 浙江工业大学 | A kind of one kettle way prepares the method for caffeic acid ester derivants |
| CN100999473A (en) * | 2006-12-19 | 2007-07-18 | 浙江工业大学 | 5-nitro coffeic acid phenylglycollic ester and its preparation and use |
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