CN105884678A - Sodium picosulfate intermediate and sodium picosulfate preparation method - Google Patents
Sodium picosulfate intermediate and sodium picosulfate preparation method Download PDFInfo
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- CN105884678A CN105884678A CN201410821038.5A CN201410821038A CN105884678A CN 105884678 A CN105884678 A CN 105884678A CN 201410821038 A CN201410821038 A CN 201410821038A CN 105884678 A CN105884678 A CN 105884678A
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Abstract
The invention provides a sodium picosulfate intermediate preparation method. The sodium picosulfate intermediate preparation method is characterized by comprising the steps that 2-pyridylaldehyde and phenol are used as raw materials, trichloromethane is used as a solvent, and reaction liquid is formed after even mixing; acid substance is dropwise added to the reaction liquid, the solutes 2-pyridylaldehyde and phenol in the reaction liquid complete chemical reaction in an acidic environment to prepare a solution containing an intermediate; crystallization and purification are conducted on the solution to obtain a sodium picosulfate intermediate, namely 4,4'-(2- pyridine methylene)-phenol. According to the preparation method of the intermediate, the invention further provides a sodium picosulfate preparation method. Based on the methods provided by the invention, the isomer content of the intermediate in the synthesis process is reduced, the purity, conversion rate and reaction rate of the intermediate are improved, and meanwhile the yield is improved remarkably.
Description
Technical field
The present invention relates to the preparation method of a kind of medicine, particularly to the synthetic method of a kind of sodium picosulfate intermediate.
Background technology
Sodium picosulfate is the caccagogue of De Angel i company of Italy exploitation, and it is that one has unique effect mode
Special laxative, colorectal mucosa is directly acted on and produces gentle cathartic effect, it cannot be only used for various form just
Secret, it is possible to exempt the defecation pain caused because of hemorrhoid or anal fissure etc., also for difficult defecation.Sodium picosulfate oral to stomach,
Small intestinal, almost without effect, can make intestinal peristalsis hyperfunction, play mitigation discharge function.After sodium picosulfate is oral hardly
Absorb, directly arrive large intestine, resolved into active biphenol metabolite by large intestine microorganism sulfatase, its activity
Metabolite { 4,4 '-(2-pyridine methylene)-phenol } stimulates colorectal mucosa to cause enterokinesia hyperfunction, hinders moisture simultaneously
Absorption, cause under rushing down.Amount of activated metabolite is after intestinal absorption, from biliary excretion.Therefore, can sulphuric acid
Sodium is { 4,4 '-(2-pyridine methylene)-phenol } at the active ingredient of large intestine, and its structural formula is as follows:
4,4 '-(2-pyridine methylene)-phenol are still used for synthesizing the medicine intermediate of sodium picosulfate and bisacodyl,
Typically can be prepared through condensation reaction under conditions of acidic dehydration agent by 2-pyridine carboxaldehyde and phenol.Sodium picosulfate
Including Europe, Japan etc. multiple countries use for many years, abroad it is conducted in-depth research.Foreign literature report
The synthetic method in road has multiple, and the most topmost have following several:
(1) it is condensed with 2-pyridine carboxaldehyde with 2-chlorophenol, then phenolic hydroxyl group is carried out sulfonation, become salt, finally use
Raney's nickel reduction obtains sodium picosulfate, and course of reaction is as follows:
This route uses 2-chlorophenol to be raw material, make use of the meta locating effect of chlorine element, makes reaction all at 4 carbon
Carry out, decrease the generation of side reaction；But also because the introducing of chlorine element, cause after to hydrogenate, make reaction walk
Abruptly increase adds, and reacts more complicated.
(2) with 2,6-chlorophenesic acid is condensed with 2-pyridine carboxaldehyde, and then phenolic hydroxyl group carries out sulfonation, becomes salt,
Reducing sodium picosulfate with Raney's nickel afterwards, course of reaction is as follows:
This route duplicates with route one, simply introduces chlorine element at 6 further, adds orientation effect, simultaneously handle
The position that may react all occupies, and makes ortho position by-product be nearly free from.But same, because the introducing of chlorine element, lead
To hydrogenate after cause, make reactions steps increase, react more complicated, cost is higher.
(3) being condensed with 2-pyridine carboxaldehyde with phenol, then phenolic hydroxyl group carry out sulfonation, becoming salt to become salt to obtain can sulfur
Acid sodium.
But, in said process, all use pyridine carboxaldehyde to carry out under solvent-free environment with phenol or phenol derivatives
Inhomogeneous reaction, is to be added directly in reaction vessel by the phenol of solidification, operates cumbersome, especially scale metaplasia
Produce, if using pyroreaction, although but raw material has liquefied easily produced isomer impurities and difficulty owing to reaction temperature is high
Effectively to remove isomer impurities by means such as crystallization and purification；
If using low-temp reaction system, raw material thing will abnormal thickness, stirring inconvenience, production equipment is proposed the highest
Requirement.
It addition, preparing the course of reaction of sodium picosulfate and intermediate at present, it is inhomogeneous reaction, dense
Under the catalysis of sulphuric acid, local response temperature can be the highest, thus causes isomer impurities to increase, and needs the most multiple
Miscellaneous subsequent purification technique improves product purity, and this just directly results in the reduction of product yield and production efficiency, significantly
Improve production cost.
Summary of the invention
For preparing the problems referred to above present in sodium picosulfate intermediate technique at present, we have proposed a kind of can sulphuric acid
The preparation method of sodium intermediate, described preparation method is with 2-pyridine carboxaldehyde and phenol as raw material, using chloroform as molten
Matchmaker, forms reactant liquor after mix homogeneously；
Acidic materials, solute 2-pyridine carboxaldehyde in described reactant liquor and phenol is dripped at sour environment in described reactant liquor
In complete chemical reaction, form the solution comprising described intermediate；
Described solution is carried out crystal refining, it is thus achieved that described sodium picosulfate intermediate, i.e. 4,4 '-(2-pyridine methylene)-
Phenol.
Method as above, it is characterised in that:
Described crystal refining, comprises the steps:
Alkali is added to regulate the pH value of described solution in described solution；
Then alcoholic solution is used to carry out dispersed crystalline and recrystallization to purify described sodium picosulfate intermediate.
Method as above, it is characterised in that:
Described alkali is NaOH or sodium carbonate；
Regulate the pH value of described solution to 6.0-8；
Described alcoholic solution is methanol solution or ethanol solution.
Method as above, it is characterised in that:
Described dispersed crystalline uses methanol, and its consumption with the weight ratio of 2-pyridine carboxaldehyde in described reactant liquor is:
2-pyridine carboxaldehyde: methanol=1: 2-10；
Described recrystallization uses methanol solution or ethanol solution, and its concentration, i.e. methanol/ethanol with the volume ratio of water are
5∶1-1∶2。
Method as above, it is characterised in that: described acidic materials be concentrated sulphuric acid, phosphoric acid, hydrochloric acid, zinc chloride, four
Any one in stannic chloride, phosphorus Halides, aluminum chloride.
Arbitrary described method, it is characterised in that:
The weight ratio of 2-pyridine carboxaldehyde, phenol and chloroform in described reactant liquor is 2-pyridine carboxaldehyde: phenol: three chloromethanes
Alkane=1: 2-6: 2-10；
Described mixing is under inert gas shielding, and 2-pyridine carboxaldehyde, phenol are dissolved in chloroform.
Method as above, it is characterised in that:
Described acidic materials are concentrated sulphuric acids, drip described concentrated sulphuric acid amount and the 2-pyrrole in described reactant liquor in described reactant liquor
The weight ratio of pyridine formaldehyde is 2-pyridine carboxaldehyde: concentrated sulphuric acid=1: 1-3.
Method as above, it is characterised in that:
The dropping temperature of described concentrated sulphuric acid is-20-40 degree Celsius.
Method as above, it is characterised in that:
The deadline of described chemical reaction is 2-8 hour.
The invention allows for the preparation method of a kind of sodium picosulfate, it is characterised in that:
Preparation method including arbitrary described sodium picosulfate intermediate；
Phenolic hydroxyl group to described sodium picosulfate intermediate carries out sulfonation process the most again, becomes salt, i.e. obtains sodium picosulfate.
According to the preparation method of sodium picosulfate intermediate proposed by the invention, owing to have employed chloroform as solvent,
Change the inhomogeneous reaction in traditional preparation technology so that raw material is dissolved in chloroform formation homogeneous reaction, thus
Overcome prior art preparative-scale metaplasia produce that operability is the best, yield is low, product purity is difficult to control to, cost is high,
The defect that production efficiency is low.
Specific implementation method
Below preparation method proposed by the invention is specifically described.
First, at noble gas, such as He, Ne, N2Deng gas shield under, preferably nitrogen protection under, by 2-
Pyridine carboxaldehyde and phenol join in chloroform, form 2-pyridine carboxaldehyde and the chloroform soln of phenol, as preparation
The reactant liquor of the intermediate of sodium picosulfate.
In reactant liquor, phenol, the weight ratio of chloroform three can be 1: 2-6: 2-10, preferably 1: 3: 5, are configured to
Reactant liquor.
Under the conditions of uniform temperature, interpolation acidic materials, such as sulphuric acid in reactant liquor, phosphoric acid, hydrochloric acid, zinc chloride,
Butter of tin, phosphorus Halides, the one in aluminum chloride, as catalyst.The acidic materials selected are different, and reaction is required
The optimum temperature wanted is the most different, the reaction temperature of the preparation technology of the intermediate of this and the most widely used sodium picosulfate
Selection with acidic materials is the same, does not do illustrating one by one at this.
In the present invention, acidic materials preferably concentration is the concentrated sulphuric acid of 98%, when adding concentrated sulphuric acid in reactant liquor, instead
The temperature answering container is maintained at subzero 20 to 40 degrees Celsius, the most subzero 10 degree to 20 degrees Celsius, and more preferably zero
Degree is to 5 degrees Celsius.The temperature of reaction vessel is kept generally by cryosel bath.
Wherein, the addition of concentrated sulphuric acid, in visual response liquid depending on the amount of 2-pyridine carboxaldehyde, the weight of usually 2-pyridine carboxaldehyde
1-3 times, preferably 2.76 times.
After adding acidic materials, 2-pyridine carboxaldehyde and phenol reactant in question response liquid are complete, this response time one
As need 2-8 hour, preferably 3-6 hour, or 3-4 hour.
Specifically, feeding intake and course of reaction during said process is described intermediate preparation technology flow process.As wherein one
Feeding intake and operation step of individual optimization, we have selected following condition:
Feed intake:
Under nitrogen protection, in there-necked flask, add chloroform 100ml, start stirring.Add the phenol 150g of hot melt, molten
After solving completely, cooling processes.Control system temperature-10 DEG C～0 DEG C dropping 2-pyridine carboxaldehyde 50g.Control system temperature-10 DEG C～
0 DEG C of dropping concentrated sulphuric acid 138g, drips complete insulated and stirred 30 minutes～45 minutes.
Reaction:
Drip-10 DEG C～10 DEG C insulated and stirred of complete control volume system temperature 3.0 hours～4.0 hours.
After completion of the reaction, the solution in reaction vessel i.e. includes our sodium picosulfate intermediate to be prepared, passes through
Refined purifying technique obtains described intermediate.
In refined purifying technique, it is initially charged alkali liquor and is usually to the acid solution neutralizing in reaction vessel, the alkali liquor used
Sodium hydroxide or sodium carbonate, to be neutralized to the pH value scope at 6-8, preferably by the acid solution in reaction vessel
6.0～6.5.
During neutralizing acid solution, continue to keep system temperature at-10 DEG C～10 DEG C, drip 16% sodium hydroxide molten
Liquid regulates its pH value.
After being neutralized by the solution in reaction vessel, i.e. to using alcohol, the most conventional is methanol, ethanol or isopropanol
Carry out dispersed crystalline, hot wash, then be refining to obtain sodium picosulfate intermediate with methanol-water mixing.
Chemical reaction process in this method is as follows:
At dispersed crystalline, i.e. during crystallize, the consumption of methanol is 4～10 times of the 2-pyridine carboxaldehyde weight in reactant liquor,
Preferably 5 times.
In the recrystallization process as backflow remove impurity, for the concentration of the refined methanol solution purified, i.e. methanol: water
Volume mixture ratio is 5: 1～1: 2, preferably 2: 1.
In described backflow dedoping step, insulation backflow temperature be 30～80 DEG C, preferably 40～70 DEG C, more preferably 60～
75℃。
Described baking temperature is 30～80 DEG C, preferably 40～70 DEG C, more preferably 60～70 DEG C.
Specifically, the crystallization in said process, purifying technique link, the operating procedure optimized as one of them, I
Selected following condition:
Methanol crystallize: to there-necked flask add methanol 400ml, control 20 DEG C～30 DEG C stirring and crystallizing of system temperature 4.0 hours～
5.0 hour.Sucking filtration, washs filter cake three times 400ml/ time with 50 DEG C～60 DEG C of hot purified water, and sucking filtration is to dry.
Backflow remove impurity: filter cake adds methanol aqueous solution, and described methanol aqueous solution is with methanol 240ml and purified water 100ml
Formulated, insulation backflow 2.0 hours～3.0 hours at a temperature of 60～75 DEG C.Material is cooled to 20 DEG C～30 DEG C, takes out
Filter, dehydrated alcohol 200ml washs filter cake, and sucking filtration, to dry, obtains sodium picosulfate intermediate wet product.
Drying under reduced pressure: sodium picosulfate intermediate wet product is loaded drip pan.Control vacuum-0.07MPa～-0.1MPa, dry
Case temperature 60 C～70 DEG C, drying under reduced pressure 6.0 hours～8.0 hours.It is dried and terminates, close baking oven for heating and vacuum system,
Material is cooled to 10 DEG C～40 DEG C.Discharging is weighed, and seals that rear chamber is gentle puts.
It should be understood that it is above only in order to illustrative not limiting technical scheme, although with reference to above-described embodiment
The present invention is described in detail, it will be understood by those within the art that: still the present invention can have been repaiied
Change or equivalent, any modification or partial replacement without departing from the spirit and scope of the present invention, all should contain at this
In the middle of the right of invention.
Claims (10)
1. the preparation method of a sodium picosulfate intermediate, it is characterised in that:
With 2-pyridine carboxaldehyde and phenol as raw material, using chloroform as solvent, after mix homogeneously, form reactant liquor；
Acidic materials, solute 2-pyridine carboxaldehyde in described reactant liquor and phenol is dripped at sour environment in described reactant liquor
In complete chemical reaction, form the solution comprising described intermediate；
Described solution is carried out crystal refining, it is thus achieved that described sodium picosulfate intermediate, i.e. 4,4 '-(2-pyridine methylene)-
Phenol.
2. the method for claim 1, it is characterised in that:
Described crystal refining, comprises the steps:
Alkali is added to regulate the pH value of described solution in described solution；
Then alcohol is used to carry out dispersed crystalline and recrystallization to purify described sodium picosulfate intermediate.
3. method as claimed in claim 2, it is characterised in that:
Described alkali is NaOH or sodium carbonate；
Regulate the pH value of described solution to 6-8；
Described alcohol is methanol or ethanol or isopropanol.
4. method as claimed in claim 3, it is characterised in that:
Described dispersed crystalline uses methanol, and its consumption with the weight ratio of 2-pyridine carboxaldehyde in described reactant liquor is:
2-pyridine carboxaldehyde: methanol=1: 2-10；
Described recrystallization uses methanol solution or ethanol solution, and its concentration, i.e. methanol/ethanol with the volume ratio of water are
5∶1-1∶2。
5. the method for claim 1, it is characterised in that: described acidic materials be concentrated sulphuric acid, phosphoric acid, hydrochloric acid,
Any one in zinc chloride, butter of tin, phosphorus Halides, aluminum chloride.
6. the method as described in claim 1-5 is arbitrary, it is characterised in that:
The weight ratio of 2-pyridine carboxaldehyde, phenol and chloroform in described reactant liquor is 2-pyridine carboxaldehyde: phenol: three chloromethanes
Alkane=1: 2-6: 2-10；
Described mixing is under inert gas shielding, and 2-pyridine carboxaldehyde, phenol are dissolved in chloroform.
7. method as claimed in claim 6, it is characterised in that:
Described acidic materials are concentrated sulphuric acids, drip described concentrated sulphuric acid amount and the 2-pyrrole in described reactant liquor in described reactant liquor
The weight ratio of pyridine formaldehyde is 2-pyridine carboxaldehyde: concentrated sulphuric acid=1: 1-3.
8. method as claimed in claim 7, it is characterised in that:
The dropping temperature of described concentrated sulphuric acid is-20-40 degree Celsius.
9. method as claimed in claim 8, it is characterised in that:
The deadline of described chemical reaction is 2-8 hour.
10. the preparation method of a sodium picosulfate, it is characterised in that:
Preparation method including the sodium picosulfate intermediate as described in claim 1-9 is arbitrary；
Phenolic hydroxyl group to described sodium picosulfate intermediate carries out sulfonation process the most again, becomes salt, i.e. obtains sodium picosulfate.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108707108A (en) * | 2018-08-20 | 2018-10-26 | 黄石法姆药业股份有限公司 | A kind of 4,4`-（2- pyridine methylenes）Biphenol diacetate synthetic method |
| CN114436946A (en) * | 2022-02-25 | 2022-05-06 | 海南鑫开源医药科技有限公司 | Impurity in sodium picosulfate intermediate and preparation method thereof |
| CN115557885A (en) * | 2022-10-27 | 2023-01-03 | 扬州市三药制药有限公司 | Preparation method of sodium picosulfate |
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|---|---|---|---|---|
| US3528986A (en) * | 1966-08-22 | 1970-09-15 | Angeli Inst Spa | Disodium 4,4'-disulphoxydiphenyl-(2-pyridyl)-methane |
| US3873551A (en) * | 1970-06-16 | 1975-03-25 | Prodotti Antibiotici Spa | 4-acetoxy-4{40 -sulfoxydiphenyl-(2-pyridyl)methane and sodium salt thereof |
| CN101973932A (en) * | 2010-10-12 | 2011-02-16 | 河北康泰药业有限公司 | Preparation method of bisacodyl |
| WO2012168885A2 (en) * | 2011-06-06 | 2012-12-13 | Université De Strasbourg | Bisacodyl and analogues as drugs for treating cancer |
| CN103086957A (en) * | 2013-02-21 | 2013-05-08 | 山东省医药工业研究所 | Method for preparing high purity sodium picosulfate |
-
2014
- 2014-12-26 CN CN201410821038.5A patent/CN105884678A/en active Pending
Patent Citations (5)
| 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 |
| US3873551A (en) * | 1970-06-16 | 1975-03-25 | Prodotti Antibiotici Spa | 4-acetoxy-4{40 -sulfoxydiphenyl-(2-pyridyl)methane and sodium salt thereof |
| CN101973932A (en) * | 2010-10-12 | 2011-02-16 | 河北康泰药业有限公司 | Preparation method of bisacodyl |
| WO2012168885A2 (en) * | 2011-06-06 | 2012-12-13 | Université De Strasbourg | Bisacodyl and analogues as drugs for treating cancer |
| CN103086957A (en) * | 2013-02-21 | 2013-05-08 | 山东省医药工业研究所 | Method for preparing high purity sodium picosulfate |
Non-Patent Citations (1)
| Title |
|---|
| 张军辉，等: "比沙可啶的合成工艺研究", 《精细化工中间体》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108707108A (en) * | 2018-08-20 | 2018-10-26 | 黄石法姆药业股份有限公司 | A kind of 4,4`-（2- pyridine methylenes）Biphenol diacetate synthetic method |
| CN114436946A (en) * | 2022-02-25 | 2022-05-06 | 海南鑫开源医药科技有限公司 | Impurity in sodium picosulfate intermediate and preparation method thereof |
| CN115557885A (en) * | 2022-10-27 | 2023-01-03 | 扬州市三药制药有限公司 | Preparation method of sodium picosulfate |
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Application publication date: 20160824 |