CN102702040A - Method for preparing high-purity docusate sodium - Google Patents
Method for preparing high-purity docusate sodium Download PDFInfo
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Abstract
The invention relates to a method for preparing docusate sodium. The method comprises the step of esterification between 2-ethyl hexanol and maleic anhydride and the step of sulfonation of the obtained ester and sodium hydrogensulfite in a water solution. The method is characterized in that the method further comprises the following steps of purification of rough products: crystallizing the sulfonated rough products in an alcohol and water system to obtain a water-containing crystal, dissolving the water-containing crystal in alcohol dehydratum, performing reduced pressure distillation to remove a solvent so as to obtain anhydrous docusate sodium, wherein alcohol in the alcohol and water system is selected from a group comprising methyl alcohol, ethanol, normal propyl alcohol and isopropyl alcohol, and the alcohol dehydratum is selected from ethanol, normal propyl alcohol and isopropyl alcohol. By the method provided by the invention, the high-purity docusate sodium can be prepared.
Description
Technical field
The present invention relates to organic preparation method, be specifically related to the preparation method of high purity Docusate Sodium.
Background technology
The Docusate Sodium suffering has another name called butyl ester sodium sulfonate (Dioctyl Sodium, Sulfosuceinate); Be tensio-active agent, oral back can make water and lipoid material immerse ight soil in intestines, and short its softens; Be applicable to defecation inability such as anus, rectum patient, or postoperative patient.The synthetic two-step approach that adopts usually of Docusate Sodium, the first step is to make maleic anhydride and 2-Ethylhexyl Alcohol in the presence of mineral acid or organic acid, carry out esterification; Second step was to make the ester and the sodium sulfite anhy 96 that obtain in the aqueous solution, carry out sulfonation reaction, obtained Docusate Sodium.Although Docusate Sodium has bigger demand; But product supplied purity is not high on the market; About 95-96%; According to the disclosed document of prior art, can not get content at the product more than 99%, for example only obtain the Docusate Sodium of content about 96% according to Colloid Polym Sci 277:1051-1057 (1999) disclosed method.
Therefore, prior art need be researched and developed the preparation technology of high purity Docusate Sodium.
Summary of the invention
The object of the invention provides a kind of preparation method of high purity Docusate Sodium, can not obtain the problem that purity is higher than 99% Docusate Sodium to solve prior art.
The method that is used for preparing the high purity Docusate Sodium according to the present invention comprise 2-Ethylhexyl Alcohol and maleic anhydride esterif iotacation step, make the ester that obtains and sodium sulfite anhy 96 at the sulfonation procedure of the aqueous solution and following crude product purification step: the thick product after the sulfonation is carried out crystallization in alcohol-water system; Obtain hydrated crystal; Then said hydrated crystal is dissolved in the absolute alcohol; Underpressure distillation removes and desolvates, and obtains anhydrous Docusate Sodium, wherein; The alcohol that said alcohol-water system uses is selected from the group that is made up of methyl alcohol, ethanol, n-propyl alcohol and Virahol, and said absolute alcohol is selected from ethanol, n-propyl alcohol and Virahol.
In a kind of embodiment, alcohol is 6～10: 1 with the ratio of water by volume in the above-mentioned alcohol-water system, is preferably 8～10: 1.
In a kind of embodiment, earlier will said thick product be dissolved in 50～80 ℃ the alcohol, after dissolving fully, add the water of predetermined amount again, naturally cool to room temperature, place then under 5～-12 ℃ and leave standstill crystallization.
In a kind of embodiment, earlier will said thick product be dissolved in 50～80 ℃ the alcohol, after the dissolving, add proper amount of active carbon fully, stir, filter, the water of adding predetermined amount in filtrating naturally cools to room temperature again, places then under 5～-12 ℃ and leaves standstill crystallization.
Preferred as to above-mentioned various embodiments introduced toluene in alcohol-water system, alcohol is preferably 10-15 with the ratio by volume of toluene: 1.
The method that another kind of the present invention prepares the high purity Docusate Sodium comprises the esterif iotacation step of 2-Ethylhexyl Alcohol and maleic anhydride; And make ester and the sulfonation procedure of sodium sulfite anhy 96 in the aqueous solution that obtains, in esterif iotacation step, use strongly acidic cationic exchange resin as catalyzer.In this real-time mode, aforesaid various technical characterictics can be used as further preferred version equally.
Embodiment
Term among this paper " thick product " is meant in the aqueous solution with the reaction system behind the own ester of sodium sulfite anhy 96 sulfonation maleic acid two (2-ethyl) and is removed the product behind the water.
Cause the not high reason of Docusate Sodium purity to have two aspects in the prior art: the first, lack method of purification efficiently, by product is not fully removed.For example; In sulfonation reaction; It is excessive that sodium sulfite anhy 96 or pyrosulphite hydrogen sodium often need, thereby cause the residual of salt such as sodium sulfite anhy 96 arranged in the product, and the purifying of product generally relies on dissolving, filters, deviates from solvent in the current methods; Be that purifying depends on impurity and do not dissolve, and title product is not told from system with purified state; The second, the strongly-acid esterifying catalyst of employing causes the side reaction degree higher, and for example the part catalyst themselves is introduced in the reaction product, and because the rerum natura and the title product of these by products are comparatively approaching, thoroughly separates comparatively difficulty.
Based on aforementioned understanding, the contriver has carried out a large amount of trials, thereby accomplishes the present invention.
In first aspect of the present invention, a kind of method of the thick product of Docusate Sodium of purifying is proposed, this method comprises; At first in alcohol-water system, carry out crystallization, obtain the high purity hydrated crystal, then hydrated crystal is dissolved in the absolute alcohol; Underpressure distillation removes and desolvates, and obtains anhydrous Docusate Sodium.
In the present invention, the alcohol that above-mentioned alcohol-water system uses is selected from methyl alcohol, ethanol, n-propyl alcohol and Virahol, wherein particular methanol and ethanol.Alcohol suits 6～10 with the ratio of water by volume: 1, and the ratio of alcohol is too high then can not remove residual sodium sulfite anhy 96 fully, and it is more that the too high meeting of the ratio of water is run off product, reduces yield.In exemplary embodiment of the present invention, adopt methyl alcohol or ethanol to form alcohol-water system, alcohol-water ratio is preferably 8-10: 1.The height of alcohol-water ratio is also relevant with the excessive degree of sodium sulfite anhy 96 in the sulfonation reaction, and for aforementioned proportion, the excessive degree of sodium sulfite anhy 96 suits between 15-23%, typically between 15-20%.
Adopt the alcohol-water system of aforementioned proportion, only need thick product is carried out primary treatment, just can obtain highly purified Docusate Sodium, purity is usually more than 99%.
When embodiment of the present invention, can the alcohol-water solvent that prepare in advance be joined in the thick product in batches or continuously, stir simultaneously, solvent temperature is controlled at 50～80 ℃ scope, and the consumption of solvent just is dissolved as suitable with thick product fully.Place 5～-12 ℃ to carry out crystallization solution after the dissolving.As optimal way, earlier thick product is dissolved in 50～80 ℃ the alcohol, after the dissolving, add the water of predetermined amount more fully, naturally cool to room temperature, place then under 5～-12 ℃, preferred 0～-8 ℃ and leave standstill crystallization.This operating method can improve product gas purity, can also avoid introducing excessive alcoholic solvent in addition.Under the situation of needs, can also before adding entry, in alcoholic solution, introduce proper amount of active carbon, to adsorb a small amount of insoluble organic impurity in the thick product.
The contriver finds, when in alcohol-water system, introducing toluene, can further improve the eduction rate of Docusate Sodium.In this embodiment, alcohol is for example 10-15 with the ratio by volume of toluene: 1.Introducing toluene maybe be favourable to the present invention from two aspects: one of which, impel the sodium sulfite anhy 96 in the thick product soluble in water fully; Its two, system polarity is reduced, promote high polar Docusate Sodium from system, to separate out more fully, the sub product of unsulfonated (having lower polarity) is then separated out not too easily.
Next, the Docusate Sodium water-containing crystal that obtains is dissolved in the absolute alcohol, reclaim under reduced pressure alcohol obtains anhydrous product again.Alcohol used herein can be ethanol, n-propyl alcohol or Virahol, and these alcohol all can form azeotrope with water.In application examples, ethanol is preferred.The present invention has got rid of the real-time mode of using methyl alcohol, and the contriver finds, uses methyl alcohol can not realize the object of the invention as absolute alcohol.
In second aspect of the present invention, a kind of improved method that is used for synthetic Docusate Sodium is provided.Present method is esterifying catalyst with the strongly acidic cationic exchange resin, carries out the esterification of maleic anhydride.The contriver has compared the ion exchange resin of a large amount of different matrix; For example; Polystyrene, vinylformic acid (ester) are, phenolic aldehyde is (fp), epoxy system (epa), vinylpyridine system (vp), urea aldehyde system (ua) etc.; Find the most suitable of the present invention be to have sulfonic vinylbenzene-divinyl benzene series strongly acidic cationic exchange resin; Operable example comprises 001x7 (732) type, 734 types, DH type, D001 type, D002 type, D061 type, D072 type, JK008 type etc., or their compsn, most preferably is 001x7 (732) type ion exchange resin.
The contriver finds that the ion exchange resin that adopts the present invention to select can obviously improve product yield, also obtains highly purified target product easily.Be not wishing to be bound by theory; Have several kinds of reasons and can explain the advantage of present technique scheme: one of which; Adopt the selected solid acid catalyst of the present invention, catalyst themselves can not add in the two keys of C-C of toxilic acid (possibly be because too high sterically hindered), and catalyzer can not be consumed; Therefore catalyzer can be kept high catalytic activity, has also reduced side reaction.They are two years old; Even when stopping esterification, have the part sulfonic group to add in the toxilic acid, but because this sulfonic group is bonded on the vinylbenzene matrix simultaneously, the addition by product is fixed on the catalyzer; Can not get into next step reaction system; And this by product is the running balance that is in addition-elimination in follow-up reaction process, and part can revert to the ethylene linkage structure, thereby shows as on the whole and do not have side reaction.The 3rd, the catalyzer that adopts the present invention to select, high temperature esterification method that can abandoning tradition, and with temperature by being reduced to 80～100 ℃ more than 120 ℃, this possibly also can reduce the by product that Yin Gaowen causes.
Embodiment 1
In the there-necked flask of a 500mL that water trap, reflux condensing tube and TM be housed, add MALEIC ANHYDRIDE 50g (0.5mol), 2-Ethylhexyl Alcohol 230mL (1.50mol), tosic acid 1.0g (5mmol), toluene 50mL; Shake up, oil bath is heated to backflow, and temperature is at 125～140 ℃ in the control; React about 1.5hr, divide water outlet 9mL (the theoretical water yield 9mL that generates) in the water trap, stopped reaction; Cool off faint yellow reaction solution, successively use isopyknic washing, 10% NaHCO
3Solution (100ml) is washed, and (2 * 100mL) wash water, and toluene and 2-Ethylhexyl Alcohol are reclaimed in underpressure distillation, obtain the own ester 163.4g of faint yellow oily maleic acid two (2-ethyl), yield 96.0% again.
With maleic acid two (2-ethyl) own ester 340g (1.0mol), NaHSO
3125g (1.2mol), water 300mL are added in the 1000mL autoclave; Airtight, in 105～110 ℃ of stirring reaction 8hr, obtain thickness water white transparency liquid; Pour out reaction solution while hot; Cooling disperses translucent paste, in 100 ℃ of drying under vacuum overnight (about 14 hours), obtains faint yellow translucent rubber shape Docusate Sodium bullion 410g.
Docusate Sodium bullion 410g is dissolved in the 850mL anhydrous methanol, and a small amount of insolubles is arranged, and adds 4～5g gac, filters, and filtrating adds 90mL water, is cooled to-5 ℃, separates out crystal, and crystallization is spent the night, and suction filtration gets 335g Docusate Sodium crystal (containing 1.5 crystal water).This crystal is dissolved in the 1500mL absolute ethyl alcohol, and decompression recycling ethanol gets the Powdered Docusate Sodium of 302g, the whole yield 68.0% of sulfonation, purity 99.5%.
Embodiment 2
The operation step is with embodiment 1, and purification step is pressed following operation: Docusate Sodium bullion 410g is dissolved in the 900mL absolute ethyl alcohol; A small amount of insolubles is arranged, add 4～5g gac, filter; Filtrating adds 90mL water and 90mL toluene, is cooled to-5 ℃, separates out crystal; Crystallization is spent the night, and suction filtration gets the 348g hydrated crystal.This crystallisate is dissolved in the 1500mL absolute ethyl alcohol, and decompression recycling ethanol gets the Powdered Docusate Sodium of 314g, sulphonation recovery 70.7%, purity 99.5%.
Embodiment 3
In the there-necked flask of a 1000mL that water trap, reflux condensing tube and TM be housed, add MALEIC ANHYDRIDE 50g (0.5mol), 2-Ethylhexyl Alcohol 230mL (1.50mol), 25g 001x7 (732) Zeo-karb, toluene 100mL; Shake up, oil bath is heated to backflow, and temperature is at 100 ℃ in the control; React about 3hr, divide water outlet 9mL (the theoretical water yield 9mL that generates) in the water trap, stopped reaction; Cool off faint yellow reaction solution, remove by filter exchange resin, resin is with twice of 50mL washing; Toluene and 2-Ethylhexyl Alcohol are reclaimed in underpressure distillation, obtain the own ester 163.4g of faint yellow oily maleic acid two (2-ethyl), yield 96.0%.
With maleic acid two (2-ethyl) own ester 340g (1.0mol), NaHSO
3125g (1.2mol), water 300mL are added in the 1000mL autoclave; Airtight, in 105～110 ℃ of stirring reaction 8hr, obtain thickness water white transparency liquid; Pour out reaction solution while hot; Cooling disperses translucent paste, in 100 ℃ of drying under vacuum overnight (about 14 hours), obtains colourless translucent rubber shape Docusate Sodium bullion 410g.
Docusate Sodium bullion 410g is dissolved in the 900mL anhydrous methanol, does not have obvious insolubles, adds the 3g gac, filters, and filtrating adds 90mL water, is cooled to-5 ℃, separates out crystal, and crystallization is spent the night, and suction filtration gets the 364g product.This crystallisate is dissolved in the 1500mL absolute ethyl alcohol, and decompression recycling ethanol gets the Powdered Docusate Sodium of 327g, sulphonation recovery 73.6%, purity 99.5%.
Embodiment 4
The operation step is with embodiment 3, and purification step is pressed following operation: Docusate Sodium bullion 410g is dissolved in the 900mL absolute ethyl alcohol; A small amount of insolubles is arranged, add the 3g gac, filter; Filtrating adds 90mL water and 90mL toluene, is cooled to-5 ℃, separates out crystal; Crystallization is spent the night, and suction filtration gets the 372g hydrated crystal.This crystallisate is dissolved in the 1500mL absolute ethyl alcohol, and decompression recycling ethanol gets the Powdered Docusate Sodium of 333g, sulphonation recovery 75.0%, purity 99.9%.
More than combine specific embodiment that technical scheme of the present invention is set forth, these embodiment can not be understood that limitation of the present invention.Those skilled in the art can do various changes and variation to it.Protection scope of the present invention should be exceeded with claim and equivalents thereof.
Claims (10)
1. be used to prepare the method for high purity Docusate Sodium, comprise the esterif iotacation step of 2-Ethylhexyl Alcohol and maleic anhydride, and make ester and the sulfonation procedure of sodium sulfite anhy 96 in the aqueous solution that obtains; It is characterized in that, also comprise following crude product purification step: the thick product after the sulfonation is carried out crystallization in alcohol-water system, obtain hydrated crystal; Then said hydrated crystal is dissolved in the absolute alcohol; Underpressure distillation removes and desolvates, and obtains anhydrous Docusate Sodium, wherein; The alcohol that said alcohol-water system uses is selected from the group that is made up of methyl alcohol, ethanol, n-propyl alcohol and Virahol, and said absolute alcohol is selected from ethanol, n-propyl alcohol and Virahol.
2. method according to claim 1 is characterized in that, the excessive degree of sodium sulfite anhy 96 suits between 15-23%, and in the said alcohol-water system, alcohol is 6～10: 1 with the ratio of water by volume.
3. method according to claim 2 is characterized in that, in the said alcohol-water system, alcohol is 8～10: 1 with the ratio of water by volume.
4. according to claim 2 or 3 described methods, it is characterized in that, earlier will said thick product be dissolved in 50～80 ℃ the alcohol, after dissolving fully, add the water of predetermined amount again, naturally cool to room temperature, place then under 5～-12 ℃ and leave standstill crystallization.
5. according to claim 2 or 3 described methods, it is characterized in that, earlier said thick product is dissolved in 50～80 ℃ the alcohol; After the dissolving, add proper amount of active carbon fully, stir, filter; In filtrating, add the water of predetermined amount again, naturally cool to room temperature, place then under 5～-12 ℃ and leave standstill crystallization.
6. method according to claim 4 is characterized in that, in alcohol-water system, introduces toluene.
7. method according to claim 6 is characterized in that, alcohol is 10-15 with the ratio by volume of toluene: 1.
8. be used to prepare the method for high purity Docusate Sodium; The esterif iotacation step that comprises 2-Ethylhexyl Alcohol and maleic anhydride; And make ester and the sulfonation procedure of sodium sulfite anhy 96 in the aqueous solution that obtains, and it is characterized in that, in esterif iotacation step, use strongly acidic cationic exchange resin as catalyzer.
9. method according to claim 7 is characterized in that, said strongly acidic cationic exchange resin is to have sulfonic vinylbenzene-divinyl benzene series strongly acidic cationic exchange resin.
10. method according to claim 9 is characterized in that, said strongly acidic cationic exchange resin is a 001x7 type resin.
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| CN104940165A (en) * | 2015-07-23 | 2015-09-30 | 北京康远制药有限公司 | Capsule comprising docusate sodium and dantron and preparation method of capsule |
| CN116082198A (en) * | 2023-02-07 | 2023-05-09 | 河北新启元能源技术开发股份有限公司 | Synthesis method of diisooctyl succinate sodium sulfonate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104940165A (en) * | 2015-07-23 | 2015-09-30 | 北京康远制药有限公司 | Capsule comprising docusate sodium and dantron and preparation method of capsule |
| CN104940165B (en) * | 2015-07-23 | 2018-01-16 | 哈尔滨瀚钧药业有限公司 | A kind of capsule containing docusate sodium and danthron and preparation method thereof |
| CN116082198A (en) * | 2023-02-07 | 2023-05-09 | 河北新启元能源技术开发股份有限公司 | Synthesis method of diisooctyl succinate sodium sulfonate |
| CN116082198B (en) * | 2023-02-07 | 2024-04-26 | 河北新启元能源技术开发股份有限公司 | Synthesis method of diisooctyl succinate sodium sulfonate |
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Address after: 410331 Liuyang biological medicine Park, Hunan Province Patentee after: HUNAN WARRANT PHARMACEUTICAL CO., LTD. Address before: 410331 Liuyang biological medicine Park, Hunan Province Patentee before: Hunan Warrant Pharmaceutical Co., Ltd. |