CN103086957A - Method for preparing high purity sodium picosulfate - Google Patents
Method for preparing high purity sodium picosulfate Download PDFInfo
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- CN103086957A CN103086957A CN2013100549122A CN201310054912A CN103086957A CN 103086957 A CN103086957 A CN 103086957A CN 2013100549122 A CN2013100549122 A CN 2013100549122A CN 201310054912 A CN201310054912 A CN 201310054912A CN 103086957 A CN103086957 A CN 103086957A
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- sodium picosulfate
- bisacodyl
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Abstract
The invention relates to a method for preparing high purity sodium picosulfate. The method is characterized in that based on bisacodyl as the starting material, sodium picosulfate is prepared by hydrolysis reaction and sulphating reaction. The preparation method is simple in process flow, simple and convenient to operate, and suitable for industrial production. The sodium picosulfate prepared is high in purity and meets the quality standard required by European and United States Pharmacopeia.
Description
Technical field
The present invention relates to a kind of preparation method of sodium picosulfate.The preparation method who specifically relates to the high purity sodium picosulfate.
Background technology
Constipation (constipation) refers to that times of defecation reduces, and generally is less than weekly 3 times, follows difficult defecation, ight soil dry and hard.Constipation is common clinically symptom, phase sustainable existence how long, and symptom is disturbed the people, affects quality of life, and the cause of disease is various, and is the most common with intestinal tract disease.Constipation not only reduces Quality of Life, and also closely related with the generation of the diseases such as colorectal carcinoma, galactophore disease, presenile dementia, severe patient can cause cordis and cerebral accident, but so serious consequence of bringing of early prevention and rational therapy alleviate constipation.
(chemical name is: the two sodium sulfovinates of the two phenyl of 4,4'-(pyridine-2-methylene)), also be a gram sodium sulfate, be the laxative of commonly using clinically to sodium picosulfate, and the country of going on the market comprises a plurality of countries such as Italy, Germany, Japan, Australia.At first sodium picosulfate is by the exploitation of Italian De Angeli company, introduces exploitation by Japanese Supreme Being people drugmaker at last, and obtains the listing license in May, 1980 with the trade(brand)name of Laxoberon.Sodium picosulfate is the special laxative with unique effect mode, the mechanism of action is that its triarylmethane group generates diphenol after colonic is by bacteria lysis, stimulate colorectal mucosa, cause colonic peristalsis hyperfunction, reduce moisture absorption, after the latent period relevant with drug dose, sodium picosulfate can make intestinal contents emptying at the individual susceptibility of experience.Sodium picosulfate catharsis action temperature and, be applicable to promote after various constipations, postoperative defecation assisting, contrast medium administration that defecation, operation front intestinal pipe content are got rid of, the front disposal of large intestine inspection (endoscopy), intestinal tube content eliminating etc.
Swiss Patent 1152199 has disclosed the preparation method of sodium picosulfate.4,4'-dihydroxyphenyl-(2-pyridine) methane and chlorsulfonic acid carry out sulfuric acid esterification in pyridine solvent, then reaction solution is poured into water neutralization, washing, the solid dehydrated alcohol extraction that obtains after evaporated in vacuo water directly obtains the sodium picosulfate hydrate after evaporate to dryness ethanol.
Patent CH515902, ES543613, DE1904322 are also to have prepared anhydrous sodium picosulfate with identical method with patent US3528986.
1164 ~ 1168 pages of 51 the 5th phases of volume of periodical Helvetica Chimica Acta(1968) in mentioned 4, the preparation of 4'-dihydroxyphenyl-(2-pyridine) methane is by phenol or 2-chlorine (bromine) phenol or 2,6-dichloro (bromine) phenol is raw material, by carrying out condensation reaction with the 2-pyridylaldehyde, the product that obtains obtains 4,4'-dihydroxyphenyl-(2-pyridine) methane with the alumel reduction in sodium hydroxide solution.Be mentioned to form by product after phenol or 2-chlorine (bromine) phenol and the condensation of 2-pyridylaldehyde in literary composition all unavoidablely, this by product and product belong to isomers, be difficult to remove from product, thereby prepare 4,4'-dihydroxyphenyl-(2-pyridine) methane purity is not high, has influence on the purity of final product sodium picosulfate.
Technological process in this periodical represents with following chemical equation:
1, take phenol as raw material
2, take the 2-chlorophenol as raw material
Patent US3558643 is also take the 2-chlorophenol as starting raw material, and after the 2-pyridylaldehyde carried out condensation reaction, the product that obtains obtained 4,4'-dihydroxyphenyl-(2-pyridine) methane with the alumel reduction in sodium hydroxide solution.Described in this patent, 2-chlorophenol and 2-pyridylaldehyde carry out step of condensation and obtain 69% isomers by product 3,3'-dichloro 2, and 4'-(pyridine-2-methylene) biphenol is difficult to separate from product.Concrete technological process represents with following chemical equation:
Also mentioned in patent US3558643 with after 2,6-chlorophenesic acid and the reaction of 2-pyridylaldehyde, prepared 3,3', 5,5'-tetrachloro-4,4'-(pyridine-2-methylene) biphenol, and after chlorsulfonic acid carried out sulphating, the recycling alumel carried out dechlorination and prepares sodium picosulfate.But when carrying out sulphating with chlorsulfonic acid, all there is the chlorine atom in hydroxyl on two ortho positions, and due to the impact of space steric effect, temperature of reaction is relatively high, reaches 75 ~ 80 ℃, and yield is lower, only has the yield of 40% left and right.Simultaneously 2, use a large amount of vitriol oils as catalysts and solvent in 6-chlorophenesic acid and 2-pyridylaldehyde reaction process, the formation reactant of thickness very after reaction is completed, aftertreatment is very difficult.Concrete reaction process process represents with following chemical equation:
Summary of the invention
The object of the invention is to provide a kind of simple preparation high purity sodium picosulfate method.Resulting sodium picosulfate quality meets Europe, the desired quality standard of American Pharmacopeia.
The present invention realizes by following technical scheme:
1, bisacodyl is added to the water, heating hydrolysis under alkaline condition.The preferred sodium hydroxide of alkaline condition, potassium hydroxide.The temperature of reaction of bisacodyl hydrolysis reaction is 20 ~ 100 ℃, preferred 50 ~ 80 ℃.
2, hydrating solution cooling after, add acid to be neutralized to pH2 ~ 5, separate out solid 4,4'-dihydroxyphenyl-(2-pyridine) methane.Described acid is hydrochloric acid, sulfuric acid.
3, filter, the washing solid, obtain 4,4'-dihydroxyphenyl-(2-pyridine) methane vacuum-drying.
4,4 of drying, 4'-dihydroxyphenyl-(2-pyridine) methane prepares the product sodium picosulfate with reference to US Patent No. 3528986 methods.
Above-mentioned technological process can represent with following chemical equation:
The advantage that the present invention has is as follows:
(1) hydrolysis reaction of bisacodyl in technological process of the present invention, reaction mechanism is simply single, reaction thoroughly can not introduced impurity by other side reactions, can prepare highly purified 4,4'-dihydroxyphenyl-(2-pyridine) methane.Therefore adopt bisacodyl as the starting raw material of preparation sodium picosulfate, with respect to adopting phenol or 2-halogen phenol is starting raw material, avoid the 2-pyridylaldehyde to carry out condensation at the ortho position of the upper oh group of phenol (or 2-halogen phenol), formed the by product that is difficult to separate.
(2) technological process of the present invention in hydrolysis reaction, uses pure water as reaction solvent, can not cause environmental pollution, belongs to environmentally friendly green reaction, and reaction is simple, and aftertreatment is very easy to, and is simple to operate, is fit to suitability for industrialized production.And adopt 2, and the 6-dichloropyridine reacts in a large amount of sulfuric acid as raw material and 2-pyridylaldehyde, severe reaction conditions, and simultaneously, reaction solution is very sticky, is unfavorable for reaction, neutralization difficulty, aftertreatment trouble.
(3) the final product sodium picosulfate based on very high purity for preparing by the present invention.Owing to not introducing unmanageable isomers by product 2-[(pyridine-2-yl in technological process of the present invention) (4-hydroxybenzene) methylene radical] phenol, therefore the impurity 2 that forms after also can not forming when the preparation final product by by product and chlorsulfonic acid reaction, alkalizing, the two sulfuric ester sodium salts of the two phenyl of 4'-(pyridine-2-methylene), product can meet Europe, the desired quality standard of American Pharmacopeia through simple processing.Detect through high performance liquid chromatography, adopting bisacodyl according to the present invention is the standby sodium picosulfate that obtains of starting raw material, about 12 minutes, does not have the impurity peaks of the two sulfuric ester sodium salts of the two phenyl of 2,4'-(pyridine-2-methylene) to occur in retention time.
Description of drawings
The high purity sodium picosulfate HPLC figure of Fig. 1 for preparing according to the present invention.
The sodium picosulfate HPLC figure of Fig. 2 for preparing take the 2-chlorophenol as starting raw material.
Embodiment
Embodiment 1
The 81g bisacodyl is added in 300ml water become suspension solution, add again by 380ml water and 39g sodium hydroxide and be mixed with alkaline solution, during this mixture heating up to 50 ℃, bisacodyl can all dissolve, keep 50 ℃ of stirring reactions after 40 minutes, be cooled to room temperature, add 10% dilute hydrochloric acid 300ml, separate out solid.Filter, washing, 80 ℃ of decompression freeze-day with constant temperature of solid obtain 58.8g4,4'-dihydroxyphenyl-(2-pyridine) methane.
Embodiment 2
The 81g bisacodyl is added in 300ml water become suspension solution, add again by 380ml water and 39g sodium hydroxide to be mixed with alkaline solution, with this mixture heating up to 70 ℃ and keep this temperature stirring reaction after 30 minutes, be cooled to room temperature, add 10% dilute hydrochloric acid 300ml, separate out solid.Filter, washing, 80 ℃ of decompression freeze-day with constant temperature of solid obtain 57.6g4,4'-dihydroxyphenyl-(2-pyridine) methane.
Embodiment 3
The 81g bisacodyl is added in 300ml water become suspension solution, add again by 380ml water and 54.7g potassium hydroxide and be mixed with alkaline solution, during with this mixture heating up to 50 ℃, bisacodyl can all dissolve, keep 50 ℃ of stirring reactions after 40 minutes, be cooled to room temperature, add 25% dilute sulphuric acid 220ml, separate out solid.Filter, washing, 80 ℃ of decompression freeze-day with constant temperature of solid obtain 58.2g4,4'-dihydroxyphenyl-(2-pyridine) methane.
Embodiment 4
The 102g chlorsulfonic acid is added drop-wise to contains 100g 4, in the 750ml pyridine solution of 4'-dihydroxyl phenylbenzene (2-pyridyl) methane, holding temperature is between 0 ~ 5 ℃.After being added dropwise to complete, stirring at room reaction 7 hours.Reactant is poured in the 3L frozen water, and the sodium hydroxide with 30% makes it be alkalescence, and this solution is removed most of pyridine with washed with dichloromethane, and with filtering after activated carbon decolorizing, the hydrochloric acid of use is regulated pH8,40 ~ 45 ℃ of concentrating under reduced pressure of surplus solution vacuum.The dehydrated alcohol extraction of the solid boiling that obtains is removed inorganic salt, and the ethanolic soln cooling crystallization filters, and 40 ℃ of vacuum-dryings of solid obtain white solid 4, the two sodium sulfovinates (sodium picosulfate) of the two phenyl of 4'-(pyridine-2-methylene).
Claims (6)
1. method for preparing the high purity sodium picosulfate, it is characterized in that take bisacodyl as starting raw material, bisacodyl joins in solvent, be hydrolyzed under alkaline condition, add again acidifying, obtain product 4,4'-dihydroxyphenyl-(2-pyridine) methane and chlorsulfonic acid carry out sulfuric acid esterification, prepare the high purity sodium picosulfate.
2. described preparation method according to claim 1, the solvent that it is characterized in that the bisacodyl hydrolysis reaction is water.
3. described preparation method according to claim 1, is characterized in that described alkaline condition is sodium hydroxide, potassium hydroxide.
4. described preparation method according to claim 1, is characterized in that hydrolysis temperature is 20 ~ 100 ℃.
5. described preparation method according to claim 5, is characterized in that hydrolysis temperature is 50 ~ 80 ℃.
6. described preparation method according to claim 1, is characterized in that described acid is hydrochloric acid, sulfuric acid.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175316A (en) * | 2015-10-23 | 2015-12-23 | 青岛辰达生物科技有限公司 | Method for preparing laxative sodium picosulfate |
| CN105175317A (en) * | 2015-10-23 | 2015-12-23 | 青岛辰达生物科技有限公司 | Method for preparing sodium picosulfate |
| CN105254556A (en) * | 2015-11-17 | 2016-01-20 | 重庆莱美药业股份有限公司 | Method for preparing high-purity sodium picosulfate |
| CN105294544A (en) * | 2015-11-30 | 2016-02-03 | 山东罗欣药业集团股份有限公司 | Method for preparing high-purity sodium picosulfate |
| CN105884678A (en) * | 2014-12-26 | 2016-08-24 | 重庆莱美药业股份有限公司 | Sodium picosulfate intermediate and sodium picosulfate preparation method |
| CN113354574A (en) * | 2021-04-13 | 2021-09-07 | 上海高准医药有限公司 | Synthetic method of sodium picosulfate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3528986A (en) * | 1966-08-22 | 1970-09-15 | Angeli Inst Spa | Disodium 4,4'-disulphoxydiphenyl-(2-pyridyl)-methane |
| WO2012168885A2 (en) * | 2011-06-06 | 2012-12-13 | Université De Strasbourg | Bisacodyl and analogues as drugs for treating cancer |
-
2013
- 2013-02-21 CN CN2013100549122A patent/CN103086957A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3528986A (en) * | 1966-08-22 | 1970-09-15 | Angeli Inst Spa | Disodium 4,4'-disulphoxydiphenyl-(2-pyridyl)-methane |
| WO2012168885A2 (en) * | 2011-06-06 | 2012-12-13 | Université De Strasbourg | Bisacodyl and analogues as drugs for treating cancer |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105884678A (en) * | 2014-12-26 | 2016-08-24 | 重庆莱美药业股份有限公司 | Sodium picosulfate intermediate and sodium picosulfate preparation method |
| CN105175316A (en) * | 2015-10-23 | 2015-12-23 | 青岛辰达生物科技有限公司 | Method for preparing laxative sodium picosulfate |
| CN105175317A (en) * | 2015-10-23 | 2015-12-23 | 青岛辰达生物科技有限公司 | Method for preparing sodium picosulfate |
| CN105175317B (en) * | 2015-10-23 | 2017-08-04 | 河南科技大学第一附属医院 | A kind of method for preparing picosulfate sodium |
| CN105175316B (en) * | 2015-10-23 | 2017-11-14 | 欧阳征鹏 | A kind of method for preparing laxative picosulfate sodium |
| CN105254556A (en) * | 2015-11-17 | 2016-01-20 | 重庆莱美药业股份有限公司 | Method for preparing high-purity sodium picosulfate |
| CN105294544A (en) * | 2015-11-30 | 2016-02-03 | 山东罗欣药业集团股份有限公司 | Method for preparing high-purity sodium picosulfate |
| CN105294544B (en) * | 2015-11-30 | 2017-09-22 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of high purity sodium picosulfate |
| CN113354574A (en) * | 2021-04-13 | 2021-09-07 | 上海高准医药有限公司 | Synthetic method of sodium picosulfate |
| CN113354574B (en) * | 2021-04-13 | 2024-04-19 | 上海高准医药有限公司 | Synthesis method of sodium picosulfate |
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Application publication date: 20130508 |