CN103073424B - Green preparation method for intermediate of valproic acid derivatives - Google Patents
Green preparation method for intermediate of valproic acid derivatives Download PDFInfo
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- CN103073424B CN103073424B CN201310018398.7A CN201310018398A CN103073424B CN 103073424 B CN103073424 B CN 103073424B CN 201310018398 A CN201310018398 A CN 201310018398A CN 103073424 B CN103073424 B CN 103073424B
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Abstract
The invention relates to a green preparation method for diethyl dipropylmalonate as shown in a chemical structure formula I. The green preparation method comprises the steps as follows: taking sodium bromide recovered from the production process of diethyl dipropylmalonate as a raw material, and treating sodium bromide with a cyclic process to prepare diethyl dipropylmalonate.
Description
Technical field
The present invention relates to a kind of environment-friendly preparation method thereof of key intermediate dipropyl diethyl malonate of valproic acid derivative.
Background technology
Dipropyl diethyl malonate is the key intermediate of preparing Sodium Valproate, Magnesium Valproate and valpromide, and preparation feedback is as follows:
Sodium Valproate is the antiepileptic drug of a widespread use.Its preparation method is taking diethyl malonate or ethyl cyanoacetate as raw material, makes finished product through alkylation, hydrolysis, decarboxylation, salify.Concrete grammar and synthetic route are as follows:
Adopt taking diethyl malonate and 1-N-PROPYLE BROMIDE as raw material, make Sodium Valproate [Hu'nan Inst. of Plarmaceutical Industry through alkylation, hydrolysis, decarboxylation and salify four-step reaction, the synthetic method of antiepileptic drug antiepilepsirin. Chinese Journal of Pharmaceuticals, 1978,1:34-35; Qu Di. the exploration of the synthetic Sodium Valproate condition in laboratory. Shandong chemical industry, 2012,41(3): 30-31,35].
Adopt taking methyl cyanoacetate as raw material, taking 1-N-PROPYLE BROMIDE as alkylating reagent, under the catalysis of quaternary ammonium salt, carry out dipropyl alkylation taking solid carbonic acid potassium as alkali, again through hydrolysis, decarboxylation and the preparation of salify four-step reaction can obtain Sodium Valproate/magnesium or valpromide [Li Xinyuan etc. solid-liquid phase-transfer-catalyzed reactions synthesizes valproic acid class antiepileptic drug. Chinese Journal of Pharmaceuticals, 1984,5:4-6].
Taking methyl acetoacetate as raw material through the alkylation of solid liquid phase transfer catalysis, deacylated tRNA base, hydrolysis, salify make Sodium Valproate [Zhou Qiqun etc. Synthesis of Sodium Valproate improve. Chinese Journal of Pharmaceuticals .1993,24(8): 347-348; Wang Xueqin, Tian Yongguang. Sodium Valproate new synthetic process. Chinese Journal of Pharmaceuticals .1999,30(9): 389-390]:
1-N-PROPYLE BROMIDE generally adopts the synthesis technique that under sulphuric acid catalysis, n-propyl alcohol reacts with Hydrogen bromide or Sodium Bromide (potassium), and preparation method is as follows.
Under sulphuric acid catalysis n-propyl alcohol react with Hydrogen bromide make 1-N-PROPYLE BROMIDE [Zhang Shuwen, Bai Xue, Hou Linyan etc. one kettle way synthetic bromide is for the research of toluene and 1-N-PROPYLE BROMIDE. chemistry world, 2011,52(9); 538-540,546; Grand generation. the improvement of bromine n-propane synthesis technique operation. Hunan chemical industry. 1998,28(2): 34-35]:
Adopt bromine and sulfur reaction, generate sulfur bromide, in the situation that having water to exist, hydrolysis reaction occurs, produce hydrogen bromide and sulfuric acid.Hydrogen bromide is as reaction raw materials, and sulfuric acid, as catalytic dehydrating agent, is prepared 1-N-PROPYLE BROMIDE; Its total reaction following [Liu Yaoyuan, Shen Shitang, Zhou Fuqiang etc. sulphur bromine method is synthesized 1-N-PROPYLE BROMIDE technique. sea lake salt and chemical industry, 1998,27(2): 12-13]:
Adopt the preparation method of propylene method: under peroxidation hydrogen bromide and propylene gas generation anti-Markovnikov addition make 1-N-PROPYLE BROMIDE [Tang Changsheng, additive process production 1-N-PROPYLE BROMIDE technical study. sea lake salt and chemical industry, 2004,33(5): 17-18; Liang Li. propylene " single stage method " synthesizes 1-N-PROPYLE BROMIDE. Guangdong University of Technology, 2004]:
In existing preparation 1-N-PROPYLE BROMIDE technological method, while using the vitriol oil as catalyzer, need a large amount of vitriol oils, 1-N-PROPYLE BROMIDE yield is only 80 ~ 90%,, there is the problem such as environmental pollution and the wasting of resources in the sulfuric acid waste that reaction obtains, makes the economic benefit of the method and social benefit lower; Sulphur bromine method desired raw material environmental pollution is serious; Propylene method is gas reaction, and required technical qualification harshness exists safety problem to a certain degree in superoxide or ozone catalytic agent use procedure.
Existing 1-N-PROPYLE BROMIDE production method: employing adds the vitriol oil and prepares 70% sulphur acid as catalyst in the sulfuric acid waste reclaiming.In sulfuric acid waste, can there is redox reaction in residual Hydrogen bromide and the vitriol oil:
The bromine and the sulfurous gas that in reaction, produce are poisonous, have a strong impact on the healthy of operator, the serious environmental pollution simultaneously producing again.Impurity residual in waste liquid, as 2-N-PROPYLE BROMIDE, has a strong impact on the quality of preparation 1-N-PROPYLE BROMIDE.
Summary of the invention
The invention provides the dipropyl diethyl malonate environment-friendly preparation method thereof shown in chemical structural formula I:
It is characterized in that utilizing the Sodium Bromide reclaiming in dipropyl diethyl malonate production process as raw material, prepare dipropyl diethyl malonate through following working cycle:
The invention provides by product sodium pyrosulfate and decompose the method that can obtain sodium sulfate and sulfuric acid:
The invention provides the method for the cycle for the treatment of utilization of sulfuric acid waste: in sulfuric acid waste, add organic solvent and oxygenant, the 2-N-PROPYLE BROMIDE remaining in waste reaction solution is dissolved in organic solvent, residual Hydrogen bromide is oxidized to bromine, bromine is dissolved in organic solvent, the organic solvent that contains bromine is through Distillation recovery bromine and organic solvent, organic solvent recycle; Oxygenant is selected from: hydrogen peroxide, Manganse Dioxide, tert-butyl peroxide, benzoyl hydroperoxide or Peracetic Acid; Organic solvent is selected from: chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, tetrachloroethane or benzene.
The invention provides and utilize limit coronite distillating method to produce 1-N-PROPYLE BROMIDE.The preparation feedback of 1-N-PROPYLE BROMIDE is reversible reaction, and the 1-N-PROPYLE BROMIDE that reaction is generated steams in time from system, is conducive to preparation feedback.
The present invention compared with prior art has the following advantages:
1. in the present invention, make full use of the by product Sodium Bromide reclaiming in dipropyl diethyl malonate production process as raw material, produce 1-N-PROPYLE BROMIDE with sulfuric acid and propyl alcohol, reduced the pollution of by product to environment, reduced production cost.
2. the decomposition of by product sodium pyrosulfate can obtain sodium sulfate and sulfuric acid; Decompose the sulfuric acid obtaining and can be used for preparing 1-N-PROPYLE BROMIDE; Reduce the consumption of the vitriol oil in the preparation of 1-N-PROPYLE BROMIDE; The sulfuric acid conversion consuming is sodium sulfate.
3. utilize limit coronite distillating method, reaction yield brings up to 95 ~ 97%.
4. fully effectively utilize and produce the spent acid that 1-N-PROPYLE BROMIDE process produces; Spent acid is treated to be recycled; Spent acid zero release in reaction process, has solved spent acid problem of environmental pollution, has good social benefit and economic benefit.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail.
Embodiment 1
The preparation of 1-N-PROPYLE BROMIDE
The Sodium Bromide (deriving from embodiment 8) that 1.0 ~ 1.2 mol reclaim, 1.0 mol n-propyl alcohols, stir at 56 DEG C, drip 1.89 mol 70% sulfuric acid, drip and finish, be warming up to 66 DEG C, insulation reaction 1.0 h, are warming up to 76 DEG C, reaction 1.0 ~ 1.5 h, be warming up to 86 DEG C, limit coronite distillation 1-N-PROPYLE BROMIDE, total reaction time 4.0 ~ 4.5 h.The thick 1-N-PROPYLE BROMIDE of collecting is through washing, and sodium carbonate solution is washed till pH6 ~ 7, and calcium chloride is dry, obtains clear colourless liquid 1-N-PROPYLE BROMIDE 116 g ~ 119 g, yield 95 ~ 97%, content >=97%.
Embodiment 2
The recovery of sodium pyrosulfate
In embodiment 1,1-N-PROPYLE BROMIDE is collected in distillation, and in reactor, residual reaction solution leaves standstill, and separates out sodium pyrosulfate solid, and suction filtration obtains 135 ~ 136g Sodium Bisulfate Monohydrate, and filtrate recovery obtains 165 ~ 167 g spent acid.
Embodiment 3
Sodium pyrosulfate decomposes prepares sodium sulfate
In embodiment 2, reclaim Sodium Bisulfate Monohydrate 136 g and 1.0 mol propyl alcohol, 48 ~ 50 DEG C are stirred 1.0 h, and filtered and recycled sodium sulfate is dried to obtain 70 g sodium sulfate.Reclaim the vitriolated filtrate of 108 g (~ 0.5mol sulfuric acid+~ 1.0 mol propyl alcohol) for the preparation of 1-N-PROPYLE BROMIDE (seeing embodiment 4).
Embodiment 4
The preparation of 1-N-PROPYLE BROMIDE
The Sodium Bromide that adds 1.0 ~ 1.2 mol to reclaim in embodiment 3 gained 108 g filtrates, stirs at 56 DEG C, mends and drips new 70% sulfuric acid of 1.39 mol, drip and finish, be warming up to 66 DEG C, insulation reaction 1.0 h, be warming up to 76 DEG C, 1-N-PROPYLE BROMIDE, reaction times 3.5 h are collected in coronite distillation in limit.The thick 1-N-PROPYLE BROMIDE that distillation is collected obtains clear colourless liquid 119g, content >=97%, yield 96.7% through aftertreatment.
Embodiment 5
Recycling of Waste Sulfuric Acid
In the 166 g spent acid that reclaim, add 4 ~ 6 mL 30% H in embodiment 2
2o
2with 80 ~ 120mL tetracol phenixin, stir, leave standstill separatory, the vitriolated solution (~ 159 g, ~ 0.86mol) that recovery obtains is made catalyzer and is used, and adds new 1 mol sulfuric acid (100 g, 98%) be configured to 70% sulfuric acid stand-by, for the preparation of embodiment 6 1-N-PROPYLE BROMIDEs.Organic solvent is collected recycle through distillation.
Embodiment 6
The preparation of 1-N-PROPYLE BROMIDE
Sodium Bromide and 1.0 mol n-propyl alcohols that 1.0 ~ 1.2 mol reclaim, 56 DEG C, stir, drip 70% sulfuric acid of configuration in embodiment 5, drip and finish, be warming up to 66 DEG C, insulation reaction 1.0 h, are warming up to 76 DEG C, limit coronite distillation 1-N-PROPYLE BROMIDE.Steamed, reaction residue leaves standstill, separate out sodium pyrosulfate crystal, suction filtration obtains 135 ~ 136 g Sodium Bisulfate Monohydrates, obtain 165 ~ 167 g spent acid (recovery is reused, and sees embodiment 5), the thick 1-N-PROPYLE BROMIDE that distillation is collected obtains 1-N-PROPYLE BROMIDE 116 g ~ 119 g through aftertreatment, yield 95 ~ 97%, content >=97%.
Embodiment 7
The preparation of dipropyl diethyl malonate
Press document [Hu'nan Inst. of Plarmaceutical Industry. the synthetic method of antiepileptic drug antiepilepsirin. Chinese Journal of Pharmaceuticals, 1978, (1): 34-35] working method preparation.Its operating process is as follows:
Sealed stirrer is housed, weighing apparatus is pressed in 3 liters of three-necked flasks of dropping funnel and reflux condensing tube, drop into alcohol sodium solution, under stirring, outer bath is heated to 80 DEG C of left and right, starts to drip diethyl malonate, finishes, after stirring reaction 10 minutes, drip 1-N-PROPYLE BROMIDE, within approximately 30 minutes, add, then stirring and refluxing is reacted 2 hours.Under room temperature, leave standstill 2 hours, filtered and recycled Sodium Bromide, with a small amount of absolute ethanol washing filter cake, merging filtrate and washing lotion, ethanol is reclaimed in air distillation, obtains 274 grams of oily matter dipropyl diethyl malonate crude products.After anhydrous sodium sulfate drying, carry out underpressure distillation, collect the fraction of 110 ~ 124 DEG C/7 ~ 8 mmhg, product is 263 grams of colourless oil liquids, yield 90%.
Embodiment 8
The recovery of Sodium Bromide
By document [Shi Qizeng. norfloxicin produce in bromine recycle research. Environmental science and technology, 2006,29(8): 23-24] working method reclaims Sodium Bromide.Embodiment 7 filtered and recycled Sodium Bromides, obtain Sodium Bromide solid, purify and obtain 95% Sodium Bromide, as the synthesis material (seeing embodiment 9) of 1-N-PROPYLE BROMIDE.
Embodiment 9
The preparation of 1-N-PROPYLE BROMIDE
The Sodium Bromide that adds 1.0 ~ 1.2 mol to reclaim in the vitriolated solution of approximately 159 g that the embodiment 3 gained vitriolated filtrate of approximately 108 g and embodiment 5 reclaim, at 56 DEG C, stir, mend and drip new 75% sulfuric acid of 0.5 mol, drip and finish, be warming up to 66 DEG C, insulation reaction 1.0 h, are warming up to 76 DEG C, 1-N-PROPYLE BROMIDE, reaction times 3.5 h are collected in limit coronite distillation.The thick 1-N-PROPYLE BROMIDE that distillation is collected obtains clear colourless liquid 120 g, content >=97%, yield 97% through aftertreatment.
Claims (2)
1. the environment-friendly preparation method thereof of the dipropyl diethyl malonate shown in chemical structural formula I:
It is characterized in that utilizing the Sodium Bromide reclaiming in dipropyl diethyl malonate production process as raw material, prepare dipropyl diethyl malonate through following working cycle:
It is characterized in that by product sodium pyrosulfate or Sodium Bisulfate Monohydrate decomposition can obtain sodium sulfate and sulfuric acid, decomposition reaction is as follows:
Decompose the sulphur acid as catalyst reusable edible obtaining;
It is characterized in that utilizing limit coronite distillating method to produce 1-N-PROPYLE BROMIDE; The preparation feedback of 1-N-PROPYLE BROMIDE is reversible reaction; The 1-N-PROPYLE BROMIDE that reaction generates steams in time from system, is conducive to preparation feedback:
Utilize limit coronite distillating method, the yield of 1-N-PROPYLE BROMIDE brings up to 95～97%, content >=97%.
2. preparation method claimed in claim 1, it is characterized in that the treated reusable edible of sulfuric acid waste: in sulfuric acid waste, add organic solvent and oxygenant, the 2-N-PROPYLE BROMIDE remaining in waste reaction solution is dissolved in organic solvent, residual Hydrogen bromide is oxidized to bromine, bromine is dissolved in organic solvent, the organic solvent that contains bromine is through Distillation recovery bromine and organic solvent, organic solvent recycle; Described oxygenant is selected from: hydrogen peroxide, Manganse Dioxide, tert-butyl peroxide, benzoyl hydroperoxide or Peracetic Acid; Described organic solvent is selected from: chloroform, tetracol phenixin, ethylene dichloride, trichloroethane, tetrachloroethane or benzene.
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| CN112142588B (en) * | 2020-10-22 | 2022-01-28 | 湖南省湘中制药有限公司 | Recovery of 2-propylmalonic acid and method for preparing valproic acid by using same |
| CN114763319B (en) * | 2022-05-16 | 2023-03-31 | 湖南大学 | Method for co-producing valproamide and sodium valproate |
| CN115433081B (en) * | 2022-07-22 | 2024-04-26 | 北京悦康科创医药科技股份有限公司 | Preparation method of diethyl dipropylmalonate |
Citations (2)
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| CN101798121A (en) * | 2009-12-25 | 2010-08-11 | 溧阳市永安精细化工有限公司 | Method for recovering and recycling sodium bromide from diethylbutylmalonate waste water |
| CN102774812A (en) * | 2011-05-09 | 2012-11-14 | 郭建利 | New technology for extracting bromine from waste hydrobromic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101798121A (en) * | 2009-12-25 | 2010-08-11 | 溧阳市永安精细化工有限公司 | Method for recovering and recycling sodium bromide from diethylbutylmalonate waste water |
| CN102774812A (en) * | 2011-05-09 | 2012-11-14 | 郭建利 | New technology for extracting bromine from waste hydrobromic acid |
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