CN102241582B - Synthesis technology of sodium valproate - Google Patents
Synthesis technology of sodium valproate Download PDFInfo
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- CN102241582B CN102241582B CN 201010177052 CN201010177052A CN102241582B CN 102241582 B CN102241582 B CN 102241582B CN 201010177052 CN201010177052 CN 201010177052 CN 201010177052 A CN201010177052 A CN 201010177052A CN 102241582 B CN102241582 B CN 102241582B
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Abstract
The invention belongs to the technical field of pharmaceutical synthesis and discloses a synthesis technology of sodium valproate. The synthesis technology comprises the following steps: dissolving diethyl malonate and 1-bromo-n-propane, slowly adding the obtained mixture in the ethanol solution of sodium ethoxide at 40-80 DEG C, heating to reflux for 3 hours, recycling ethanol until 120 DEG C, reducing the temperature to less than 90 DEG C, adding a defined amount of water to dissolve sodium bromide, adding a 15-20% sodium hydroxide solution after layering, hydrolyzing at 70-90 DEG C for four hours, heating to recycle ethanol until the gas temperature is 99 DEG, reducing the temperature to less than 90 DEG C, adding hydrochloric acid to neutralize, acidifying, adding crude valproic acid to dissolve dipropylmalonic acid and form a mixed acid, slowly heating the mixed acid from 140-180 DEG C to decarboxylate and prepare a crude valproic acid; rectifying and refining the crude valproic acid, adding a defined amount of sodium hydroxide solution to neutralize, adding toluene, refluxing to take away water and ensure that sodium valproate is dewatered and crystallized, filtering, washing with chloroform and drying to obtain the finished product. The technology is safe and environmentally-friendly, has good quality and low cost and is suitable for industrial production.
Description
Technical field
The invention belongs to technical field of medicine synthesis.Especially a kind of synthesis technique of medical material Sodium Valproate.
Background technology
Sodium Valproate another name depakine, English name Sodium Volproate.This product is all effective to people's various epilepsy such as various petit mal, lafora's disease, limitation outbreak, grand mal and mixed type epilepsy.Be used for the invalid various epileptic patient of other antiepileptic drug, especially take petit mal as best.Sodium Valproate is white crystalline powder or particle; It is little puckery to distinguish the flavor of; Strong water absorbability is arranged.This product is very easily dissolving in water, and is easily molten in methyl alcohol or ethanol, almost insoluble in acetone.
Past is less to the synthesis technique of Sodium Valproate report, and domestic do not have a patent application, only have the part bibliographical information, and building-up process is more original.Such as: the diethyl malonate of 1moL is dissolved in the 1-bromine n-propane back flow reaction 2～4 hours that drips 3moL in the ethanolic soln that contains the 2.1moL sodium ethylate in about 75 ℃, and cold filtration behind the Recycled ethanol is removed Sodium Bromide, and redistillation to 110 ℃ purifies ethanol.The residue alkide adds 40% potassium hydroxide of 8.5moL again and the alcohol reflux of 8moL is hydrolyzed 4 hours, adds a large amount of hydrochloric acid neutralizations and acidifying again, filters and the dry hydrolysate dipropyl propanedioic acid that gets.Hydrolysate reheats 180 ℃ and sloughs a carboxyl and become valproic acid, and the crude product valproic acid is collected the cut of 112～114 ℃/7～8mm or 128～130 ℃/20mm through underpressure distillation, gets the light yellow liquid valproic acid.With the liquid caustic soda neutralization, heating is concentrated into dried rear valproic acid, adds acetic acid ethyl dissolution again, and decrease temperature crystalline behind the heat filtering refilters dry finished product, the total recovery 50～52% of getting.
Reaction equation is as follows:
So 1-bromine n-propane proportioning is larger in the prior art---excessive 50%, after alkylation and hydrolysis, all to use filtration step in the process, cause loss larger, operation easier is large, the finished product Sodium Valproate is mainly with evaporated in vacuo, crystallization and purification in N-BUTYL ACETATE because its water absorbability is difficult for more greatly crystallization, is difficult to operation again; Have in toluene with sodium alkoxide neutralization, with washing with acetone, operate more loaded down with trivial detailsly after the dehydration crystallization, with solvent seasoning certain danger is arranged.Existing document synthesis technique total recovery is lower, only has 50～52%, and each raw material application quantity own is larger, causes cost higher, is unfavorable for popularizing and using of this medicine.
Summary of the invention
(1) goal of the invention: purpose of the present invention is exactly for a kind of more rational material proportion is provided, and does not have too many filter operation, and total recovery is higher, safety and environmental protection, the synthesis technique of the medical material Sodium Valproate of application distillation technology refined product.
(2) technical scheme: the synthesis technique of Sodium Valproate of the present invention is mutually to dissolve with diethyl malonate and 1-bromine n-propane, mixture slowly adds the ethanolic soln of sodium ethylate in the time of 40～80 ℃, rear temperature rising reflux 3 hours, Recycled ethanol to 120 ℃, cool to below 90 ℃, add quantitative water dissolution NaBr, organic layer adds 15～50% aqueous sodium hydroxide solutions after the layering, in 70～90 ℃ of hydrolysis 4 hours, rear rising temperature reclamation ethanol is to gas phase temperature to 99 ℃, cool to below 90 ℃, add hydrochloric acid neutralization and acidifying, rear adding crude product valproic acid dissolving dipropyl propanedioic acid makes the formation nitration mixture, and nitration mixture generates the crude product valproic acid in 140～180 ℃ of slow intensification decarboxylations again.The crude product valproic acid adds quantitative aqueous sodium hydroxide solution neutralization after rectified purified, adds refluxing toluene band water, makes Sodium Valproate dehydration crystallization, and rear filtration is with chloroform washing and dry finished product.
Lower mask body association reaction condition, material proportion, working method, it is as follows by following five key steps in detail technical process to be described in detail:
The first step: alkylated reaction
Under the normal pressure, a certain amount of diethyl malonate and 1-bromine n-propane are mixed, diethyl malonate: 1-bromine n-propane=1: 2.1～3.0 (preferably 1: 2.2～2.4) (mol ratio), be warmed up to 40～80 ℃ (preferably 50～70 ℃) and under this temperature, continue to add the ethanolic soln that contains sodium ethylate 16～21%, diethyl malonate: sodium ethylate=1: 2.0～2.4 (be preferably 1: 2.2～2.3) (mol ratio), after be warmed up to reflux state reaction 3 hours, rear intensification Distillation recovery ethanol to 110～120 ℃ (preferably 120 ℃).After cool to below 90 ℃ that adding purifies waste water and bromizate sodium and dissolve fully, (bromizate sodium and form 10～40% the aqueous solution) leaves standstill the water layer that minute desalts, getting oil reservoir is the dipropyl diethyl malonate.
Second step: hydrolysis reaction
Add 15%～50% aqueous sodium hydroxide solution (preferably 20%～30%) in the dipropyl diethyl malonate with the previous step gained, dipropyl diethyl malonate: sodium hydroxide=1: 2.1～3.0 (preferably 1: 2.2～2.4), be heated to 70～90 ℃ of (preferably 80～90 ℃) back hydrolysis 4 hours, then begin slow Distillation recovery ethanol, until about 109～110 ℃ of liquid phase, about 99～100 ℃ of effluents of gas phase stop distillation when almost can't detect ethanol, cool to below 90 ℃, slowly add 30% hydrochloric acid while stirring, sodium hydroxide: hydrogenchloride=1: 1.05～1.1, so that brine layer PH is at the front two batches crude product valproic acid of 1～2 rear adding, make the dipropyl propanedioic acid of separating out be dissolved in valproic acid, minute remove behind the sodium-chlor water layer to get nitration mixture, nitration mixture leaves standstill and can enter next step reaction after peace and quiet.
The 3rd step: decarboxylation
With the nitration mixture of previous step gained under continuous stirring state, slowly heating, begin decomposition reaction during approximately to 150 ℃, decompose the fastest during to 160～180 ℃, when being raised to 180 ℃, temperature kept 1 hour, make no longer include carbon dioxide and emit after, decarboxylic reaction carries out thoroughly just obtaining the crude product valproic acid.
The 4th step: rectification and purification
Change the crude product valproic acid over to rectifying still, start stirring, gas clean-up to-more than the 0.096MP, 130～155 ℃ of the control tower top temperatures that heats up gradually, control reflux ratio 2: 1～10: 1 is collected elaboration valproic acid in 1～2 ℃ of scope by high-efficient spiral-screen column behind system stability.Front-end volatiles and after cut are overlapped respectively for next batch rectifying, to improve product yield.
The 4th step: salify processing
This step purpose is with elaboration valproic acid and 20%～50% clean sodium hydroxide salify crystallization, valproic acid: sodium hydroxide=1: 1～1.02, and so that the PH of solution is 8.5～9.5, can distill out first the toluene after 5～10 times the distillation that adds the valproic acid amount behind the part moisture to 120 ℃, by condenser and water trap with refluxing toluene tape loop water, through the Sodium Valproate of strong dehydration gradually crystallization be tiny needle-like crystal.Cooling final vacuum suction filtration is with chloroform wash residual toluene.Get the Sodium Valproate finished product after the drying, drying temperature of the present invention is at 70～150 ℃.
(3) technique effect:
The invention has the advantages that, with industrial raw material diethyl malonate, 1-bromine n-propane, sodium ethylate, sodium hydroxide and the hydrochloric acid reaction that is easy to get, take toluene and not flammable solvent chloroform as solvent, by four step synthesis material medicine Sodium Valproates, the environmental protection of this process safety, the good cost of quality is low, can be used for suitability for industrialized production.Be embodied in following several respects:
1. the first step alkylation process of the present invention in 40～80 ℃ of adding sodium ethylates, has relaxed reaction conditions and catalysis intensity, and side reaction is few, has effectively improved yield.
2. after alkylated reaction of the present invention is finished, behind Recycled ethanol, be dissolved in water and wash out Sodium Bromide, the danger when organic loss when having avoided filtering, loaded down with trivial details operation and organic solvent washing.
3. the present invention adopts few excessive liquid sodium hydroxide to carry out saponification in hydrolysing step, has not only saved the raw materials cost of alkali and acid, has also improved the throughput of equipment.
4. the present invention adds crude product valproic acid dissolving dipropyl propanedioic acid after the hydrolysis neutralization, has avoided filtration step.
5. the present invention uses the rectifying tower with certain stage number in the treating process of valproic acid, namely improved valproic acid purity, reclaimed certain organic by-products and avoided again environmental pollution.
6. the present invention is directed to the extremely strong water absorbability of Sodium Valproate, in toluene, disperse after making the valproic acid salify, with toluene circulation azeotropic band water, Sodium Valproate is fully dewatered and crystallization.Behind filtering toluene, wash toluene with chloroform, removed the potential safety hazard of filter cake when oven dry.
7. advantage of the present invention also is embodied in owing to the common use to above each optimizing process, so that the synthesis technique of this Sodium Valproate is very suitable for suitability for industrialized production, and cost is very low.
Embodiment is as follows:
Under the normal temperature and pressure, use the 1000ml four-hole boiling flask, the diethyl malonate of 96g and the 1-bromine n-propane of 172.7g are mixed, be warmed up to 50 ℃ and begin to continue to add the ethanolic soln that contains sodium ethylate 19.0%, keep 50～70 ℃ of temperature, be warmed up to reflux state reaction after adding 3 hours, the Distillation recovery ethanol to 120 that heats up again ℃.After cool to below 90 ℃, adding the 200g that purifies waste water bromizates sodium and dissolves fully, leave standstill the water layer that minute desalts, oil reservoir is the dipropyl diethyl malonate, add again 96% sodium hydroxide 55g and water 300ml, be heated to 80～90 ℃ of back hydrolysis 4 hours, then begin slow Distillation recovery ethanol, until about 109～110 ℃ of liquid phase, about 99～100 ℃ of effluents of gas phase stop distillation when almost can't detect ethanol, cool to below 90 ℃, slowly add 30% hydrochloric acid 143g while stirring, so that the crude product valproic acid of brine layer PH two batches before 1～2 rear adding, make the dipropyl propanedioic acid of separating out be dissolved in valproic acid, divide and go to get nitration mixture behind the sodium-chlor water layer, nitration mixture leaves standstill and can slowly heat after peace and quiet, kept 1 hour during to 180 ℃, after no longer including carbon dioxide and emitting, the crude product valproic acid that front two batches are taken out in weighing changes rectifier unit, start stirring, gas clean-up is stabilized to-0.096MP intensification rectifying, collect the cut of 136～138 ℃ of tower top temperatures, be total to get front-end volatiles 4.5g, elaboration valproic acid 66.5g and resistates 2g.Entry 60ml and 96% sodium hydroxide 19.4g will be added among the elaboration valproic acid 66.5g, so that the PH of solution is 8.5～9.5, add 400ml toluene after elder generation's distilled water is assigned to 120 ℃, with refluxing toluene tape loop water, Sodium Valproate gradually crystallization is tiny needle-like crystal by water trap.Cooling final vacuum suction filtration is with chloroform wash residual toluene.After 90 ℃ of lower dryings, get Sodium Valproate finished product 75g, yield 75.3%.
Claims (1)
1. the synthesis technique of a Sodium Valproate, it is characterized in that mutually dissolving with diethyl malonate and 1-bromine n-propane, mixture is in 40～80 ℃ of ethanolic solns that slowly add sodium ethylate, rear temperature rising reflux 3 hours, Recycled ethanol to 120 ℃, cool to below 90 ℃, add quantitative water dissolution NaBr, organic layer adds 15～50% aqueous sodium hydroxide solutions after the layering, in 70～90 ℃ of hydrolysis 4 hours, rear rising temperature reclamation ethanol cooled to below 90 ℃ to gas phase temperature to 99 ℃, add the neutralization of 30% hydrochloric acid and acidifying, so that hydrochloric acid layer pH be at 1-2, rear adding crude product valproic acid dissolving dipropyl propanedioic acid makes the formation nitration mixture, nitration mixture generates the crude product valproic acid in 140～180 ℃ of slow intensification decarboxylations again, the crude product valproic acid adds quantitative aqueous sodium hydroxide solution neutralization after rectified purified, adds refluxing toluene band water, make Sodium Valproate dehydration crystallization, rear filtration is with the chloroform washing and at the 70-150 ℃ of dry finished product that gets; Wherein, diethyl malonate: 1-bromine n-propane: the mol ratio of sodium ethylate is 1: 2.2～2.4: 2.0～2.4; Dipropyl diethyl malonate during hydrolysis: the mol ratio of sodium hydroxide is 1: 2.1～3.0.
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Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102603510B (en) * | 2011-02-25 | 2014-04-23 | 四川科瑞德凯华制药有限公司 | Sodium valproate crystal form as well as preparation method and application thereof |
| CN103183612A (en) * | 2011-12-30 | 2013-07-03 | 北大方正集团有限公司 | Dipropylmalonic acid diester preparation method |
| CN103183602B (en) * | 2011-12-30 | 2015-08-12 | 北大方正集团有限公司 | The crystallization method of 2,2-dipropyl propanedioic acid |
| CN103183599B (en) * | 2011-12-30 | 2015-04-01 | 北大方正集团有限公司 | Method for preparing 2-valproic acid |
| CN105017007B (en) * | 2014-04-16 | 2019-04-16 | 四川科瑞德制药股份有限公司 | A kind of sodium vedproate compound |
| CN106748724A (en) * | 2015-11-25 | 2017-05-31 | 中国科学院上海高等研究院 | A kind of method for preparing Guerbet acid as raw material with malonate |
| CN111349003B (en) * | 2018-12-20 | 2023-10-03 | 四川科瑞德制药股份有限公司 | Preparation method of sodium valproate |
| CN110563572A (en) * | 2019-08-23 | 2019-12-13 | 仁和堂药业有限公司 | Production process of sodium valproate |
| CN112972449B (en) * | 2019-12-18 | 2023-03-21 | 四川科瑞德制药股份有限公司 | Pharmaceutical composition with high safety and preparation method thereof |
| CN111257440A (en) * | 2019-12-25 | 2020-06-09 | 四川健能制药有限公司 | GC-HS-based method for determining potential genotoxic impurities in sodium valproate |
| CN112047964A (en) * | 2020-09-07 | 2020-12-08 | 宋喂 | Preparation method and application of Grignard reagent |
| 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 |
| CN113200844A (en) * | 2021-03-29 | 2021-08-03 | 上海青平药业有限公司 | Preparation method of sodium valproate |
| CN115304481A (en) * | 2022-07-25 | 2022-11-08 | 九江德思光电材料有限公司 | Preparation method of dimethyl dialkyl malonate |
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