CN105254556B - A kind of method for preparing picosulfate sodium - Google Patents
A kind of method for preparing picosulfate sodium Download PDFInfo
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
The present invention relates to a kind of method for preparing high purity sodium picosulfate, first pyridine and chlorosulfonic acid are reacted, again 4 are added dropwise into above-mentioned mixed liquor, the pyridine solution of 4 ' [(base of pyridine 2) methylene] bis-phenols is reacted, then by multiple steps such as solvent distillation, extraction, decolouring, washing, drying, picosulfate sodium is prepared.The present invention often walks the temperature of reaction by control, adjusts the reaction sequence between material, the picosulfate sodium for the high-purity being prepared, simple process, has good promotion prospect.
Description
Technical field
The invention belongs to pharmaceutical technology field, and the present invention relates to a kind of preparation method of picosulfate sodium, and in particular to one
The method that kind prepares high purity sodium picosulfate.
Background technology
Constipation (constipation) is clinical common complicated symptom, is primarily referred to as defecation frequency reduction, excrement amount subtracts
Less, excrement is dry and hard, defecation is laborious etc..Constipation is not a kind of single disease, and more long-term persistently presence, symptoms disturb people, influence to give birth to
Bioplasm amount, the cause of disease is various, most commonly seen with intestines problem.Constipation not only reduces the quality of life of patient, also with colon cancer, senilism
Property the disease such as dementia, mammary gland disease generation it is closely related, severe patient can cause cardiovascular and cerebrovascular unexpected, therefore early prevention and conjunction
Reason treatment can mitigate the serious consequence that constipation is brought.
(English name is picosulfate sodium：Sodium picosulfate, chemical name are：(pyridine -2- bases are sub- by 4,4'-
Methyl) the double sodium sulfovinates of double phenyl), a gram sodium sulphate is also, is clinically conventional laxative.This belongs to dimethylbenzene alkane derivative
Thing, hardly picked up after oral, large intestine is directly reached in the form of active compound, be hydrolyzed under the effect of large intestine micropopulation sulfatase
Active biphenol metabolin, its active metabolite produces stimulation to intestinal mucosa, while hinders the absorption of moisture,
Cause and rush down the purpose for being issued to cleaning intestine.Its Major excretion mode is excrement and urine.Rat test finds that it is largely living
Sexual element is discharged from excrement, is partly into liver, after glucuronic acid, through urine and biliary excretion.Can sulfuric acid
Sodium catharsis action temperature and promotion defecation, operation consent intestinal tube after being administered suitable for various constipations, postoperative defecation assisting, contrast agent
Content excludes, is disposed before large intestine inspection (introscope), and intestinal tube content excludes etc..Particularly picosulfate sodium is used as treatment just
Secret disease, it is listed in the use of OTC medicines, it is sufficient to prove that it treats the security and validity of constipation.In addition, can sulfuric acid in Britain
Sodium is also by most Britain surgeons as the standard of enteron aisle prepares agent before endoscopy large intestine and before elective surgery.
Picosulfate sodium is preferable to various constipation curative effects, and better tolerance, adverse reaction is less, predominantly suffers from diarrhoea, stomachache
Deng gastrointestinal reaction.Picosulfate sodium before endoscopy enteron aisle and with tolerance the effect of operation consent cleaning intestinal tract to being superior to
Deficol and phosphate enema are used in combination, polyethylene glycol electrolyte solution, and adverse reaction rate is low.Can phosphorus with
Sour sodium is compared, and this product curative effect and tolerance are slightly worse.Meanwhile polyethylene glycol electrolyte solution is used for INTESTINAL CLEANSING and needs largely to drink
Water, many patients are difficult to receive.Sodium phosphate oral medicine is used as the laxative of constipation patient, also for intestinal cleaning agentses as surgery
Operation or the Preoperative Method of colonoscopy.But easily make patient cause severe electrolyte (hypocalcemia, hypernatremia,
Hypopotassaemia and acid poisoning), also dehydration and kidney function damage if patient's oral dose is more than 45ml, can also cause tetany.
Result above proves, picosulfate sodium is used for various constipations, before endoscopy enteron aisle and operation consent cleaning intestinal tract good effect,
Tolerance is high, and adverse reaction rate is low, and is suitable for children, adult and the elderly.
Picosulfate sodium, initially developed by Italian De Angeli companies, and in list marketing in 1966.Meanwhile meaning is big
Sharp De Angeli companies respectively nineteen sixty-eight and 1970 U. S. application obtain include can sulfate Patents,
Its patent No. is respectively：US3528986, US3558643.And Boehringer Ingelheim company is as laxative, and it is subject to
Laxoberal trade name is secured permission, and aqua is started selling from May, 1980.Finally introduced by Japanese Di Ren drugmakers
Exploitation, and listing license is obtained with Laxoberon trade name in May, 1980.
The preparation method of some compounds is described in the prior art, but all inevitably introduces a large amount of impurity,
Prepared by the purification for target compound has very big difficulty：
Swiss Patent 1152199 discloses the preparation method of picosulfate sodium.4,4 '-[(pyridine -2- bases) methylene] bis-phenols
Sulfuric acid esterification is carried out in pyridine solvent with chlorosulfonic acid, is then poured into water reaction solution, neutralizes, wash, evaporated in vacuo
The solid obtained after water is extracted with absolute ethyl alcohol, and picosulfate sodium hydrate is directly obtained after being evaporated ethanol.Patent CH515902,
ES543613, DE1904322 and patent US3528986 are also to be prepared for anhydrous picosulfate sodium with identical method.
Patent US3528986 is disclosed：With anhydrous pyridine, lower addition, 4,4 '-[(pyridine -2- bases) methylene] bis-phenols are stirred
And chlorosulfonic acid, dissolving are complete.Control system temperature, in chlorosulfonic acid is added dropwise in half an hour.Solid can be generated during dropwise addition not allow
Thing, as the progress of stirring and reaction is slowly dissolved.Environment temperature is warmed naturally to, insulated and stirred is reacted 7 hours.By reaction solution
Pour into mixture of ice and water, add sodium hydroxide solution and adjust pH value to strong basicity, most of pyridine is extracted with ether solvent.Water
Activated carbon decolorizing filtering is added to, adds hydrochloric acid regulation pH8.Add chloroform extraction and have neither part nor lot in reaction, 4,4 '-[(pyrrole
Pyridine -2- bases) methylene] bis-phenol and chlorosulfonic acid.Be concentrated under reduced pressure into it is dry, add ether solvent mashing extraction, residue absolute ethyl alcohol
Backflow, filter, filtrate cooling crystallization, filter, filter cake produces the picosulfate sodium product of white in being dried under reduced pressure.By 4,4 '-
[(pyridine -2- bases) methylene] bis-phenol is dissolved in pyridine, then chlorosulfonic acid is added dropwise, and this feeding mode directly results in secondary in reaction solution
Product impurity content is very high, and need to carry out no less than 5 times in last handling process refined can just control picosulfate sodium product
In unknown impuritie be not more than 0.1%；And patent US3528986 is simple synthesis technique introduction, have no that be related to can sulphur
Sour sodium product physicochemical property index, such as the control of sulfate and the crystallization water；In addition, condensation reaction finishes, reaction solution is poured into ice
Terminating reaction in aqueous mixtures, there is certain limitation under large-scale production pattern.In periodical Helvetica Chimica
Acta is referred in (phase page 1164~1168 of volume 51 the 5th nineteen sixty-eight), and the preparation of 4,4 '-[(pyridine -2- bases) methylene] bis-phenols is
It is raw material by phenol or 2- chlorine (bromine) phenol or 2,6- dichloro (bromine) phenol, by carrying out condensation reaction with 2- pyridine carboxaldehydes,
Obtained product is reduced to obtain 4,4'- dihydroxyphenyls-(2- pyridines) methane in sodium hydroxide solution with nickel alumin(i)um alloy.Wen Zhong
Be mentioned to phenol or 2- chlorine (bromine) phenol and 2- pyridine carboxaldehydes condensation after inevitably form accessory substance, the accessory substance with
Product belongs to isomer, it is difficult to removed from product, thus be prepared, 4 '-[(pyridine -2- bases) methylene] bis-phenols
Purity is not high, has influence on the purity of end product picosulfate sodium.
2nd, using 2- chlorophenols as raw material
Patent US3558643 be also using 2- chlorophenols as initiation material, and 2- pyridine carboxaldehydes carry out condensation reaction after, obtain
Product reduce to obtain with nickel alumin(i)um alloy in sodium hydroxide solution, 4,4 '-[(pyridine -2- bases) methylene] bis-phenols.As this is special
Described in profit, 2- chlorophenols and 2- pyridine carboxaldehydes carry out step of condensation and obtain 69% isomer accessory substance 3,3'-
Dichloro 2,4'- (pyridine -2- methylenes) biphenol, it is difficult to be separated from product.As follows, the chemistry of specific technical process
Reaction equation represents：
In addition, also refer to, with after 2,6- chlorophenesic acids and the reaction of 2- pyridine carboxaldehydes, be prepared in patent US3558643
After 3,3', 5,5'- tetra- chloro- 4,4'- (pyridine -2- methylenes) biphenols, and chlorosulfonic acid progress Sulfation, nickel is recycled
Aluminium alloy carries out dechlorination and prepares picosulfate sodium.But when carrying out Sulfation with chlorosulfonic acid, on two ortho positions of hydroxyl all
Chlorine atom be present, due to the influence of space steric effect, reaction temperature is relatively high, reaches 75~80 DEG C, and yield compared with
It is low, only 40% or so yield.Made simultaneously in 2,6- chlorophenesic acids and 2- pyridine carboxaldehyde courses of reaction using a large amount of concentrated sulfuric acids
For catalysts and solvent, extremely sticky reactant is formed after the completion of reaction, post processing is extremely difficult.Specific reaction process
Process is represented with following chemical equation：
The content of the invention
It is an object of the present invention to provide a kind of simple preparation high purity sodium picosulfate method.
The present invention is realized by following technical scheme：
The invention provides a kind of new method for preparing picosulfate sodium, comprise the following steps：
(1) under nitrogen protection, at -30~-10 DEG C, in enclosed system, into pyridine, dropwise addition chlorosulfonic acid is reacted；
(2) system reaction temperature is adjusted to -20~0 DEG C, and a certain amount of 4 are added dropwise into the enclosed system described in step (1),
The pyridine solution of 4 '-[(pyridine -2- bases) methylene] bis-phenols is reacted, after reacting 15~60 minutes, slowly heating, and control volume
It is that temperature reaches 10 DEG C~35 DEG C, then is incubated and is reacted, obtains reactant mixture；
(3) reactant mixture obtained by step (2) is evaporated under reduced pressure after removing pyridine, after adjusting its pH value as alkalescence, then
Extracted, obtain extract and aqueous phase, water intaking is mutually evaporated under reduced pressure, obtains product of distillation, the product of distillation can be obtained after purification
Sterling picosulfate sodium.
A kind of new method for preparing picosulfate sodium of the present invention, it is further comprising the steps of：
(4) system reaction temperature is adjusted to continue to react to 0 DEG C~40 DEG C；After reaction 15~60 minutes, it is evaporated under reduced pressure
Methanol must be evaporated product to doing；
(5) a small amount of absolute ethyl alcohol washs, and filters to dry to obtain picosulfate sodium wet product；It will be dried under wet product constant temperature and pressure
Obtain sterling picosulfate sodium.Specific reaction process process is represented with following chemical equation：
Preferably, described pH is 10.0~13.0, and preferably pH is 11~12.
It is further preferred that the invention provides a kind of new method for preparing picosulfate sodium, comprise the following steps：
(1) under nitrogen protection, at -30~-10 DEG C, in enclosed system, into pyridine, dropwise addition chlorosulfonic acid is reacted,
Milky insoluble matter is generated during dropwise addition, insulated and stirred is added dropwise 15~45 minutes, it is preferred that the reaction temperature is preferred
For -20~-15 DEG C, mixing time is 30~45 minutes；
(2) -20~0 DEG C is kept, a certain amount of 4,4 '-[(pyridine -2- is added dropwise into the enclosed system described in step (1)
Base) methylene] pyridine solution of bis-phenol reacted；The temperature for controlling reaction system is -20~-10 DEG C, is reacted 15~60 minutes
Afterwards, slowly heating, control system temperature are 25 DEG C~35 DEG C, are further continued for being reacted, obtain reactant mixture；
(3) reactant mixture obtained by step (2) is evaporated under reduced pressure and removes pyridine, adjustment temperature of reaction system is to -10 DEG C
~20 DEG C, and its pH is adjusted as 11.0~12.0；Extraction 1~3 time is carried out again, is preferably extracted 3 times, is obtained extract and aqueous phase；Take
After aqueous phase heating water bath, constant temperature decompression water removal, it is dehydrated, dehydrating operations 1~3 time, preferred operations 2 times, is obtained de- using absolute ethyl alcohol
Aquatic products；The reaction condition that the constant temperature is dried under reduced pressure is vacuum -0.05MPa~-0.1MPa, and bath temperature is no more than 80
℃；More preferably vacuum -0.07MPa~-0.1MPa, hot water temperature are no more than 60 DEG C；
(4) absolute methanol is added into the dehydration product described in step (3), control system temperature 50 C~60 DEG C are simultaneously protected
Temperature stirring is reacted；After 30 minutes~45 minutes, adjustment temperature of reaction system is to 0 DEG C~40 DEG C, to reaction under constant temperature and pressure
Anhydrous sodium sulfate, activated carbon are added in system, is stirred, decolourizes, 0 DEG C~30 DEG C of whipping temp, decolouring 5.0 hours~12 are small
When, preferably 10 DEG C~20 DEG C of whipping temp, bleaching time 8.0~10 hours；It is then centrifuged for, retort rotating speed 90rpm~
120rpm, preferably 95rpm~105rpm；Methanol is evaporated under reduced pressure to dry, bath temperature be no more than 60 DEG C, vacuum-
0.05MPa~-0.1MPa, product must be evaporated；
(5) be evaporated to gained in step (4) in product and add absolute ethyl alcohol, distilled water, heating water bath to 60~90 DEG C, and
Insulated and stirred, preferably stir 2.0 hours~3.0 hours；0 DEG C~30 DEG C, preferably 20 DEG C~30 DEG C are cooled to after completion of the reaction；
Centrifugation, a small amount of absolute ethyl alcohol wash, and filter to dry to obtain picosulfate sodium wet product；Will under wet product constant temperature and pressure dry i.e. can obtain it is pure
Product picosulfate sodium, the pressure of the constant temperature and pressure is -0.05MPa~-0.1MPa, and bath temperature is 40 DEG C~70 DEG C, is dried
Time is 5.0 hours~10 hours, preferably 8.0~10.0 hours, further preferred pressure, temperature, time is respectively preferably-
0.07MPa~-0.1MPa, 50 DEG C~60 DEG C, 6.0 hours~8.0 hours；Total impurities in the sterling picosulfate sodium is not
More than 0.1%.
It is further preferred that the mass ratio of pyridine and chlorosulfonic acid is 6~4 in step (1):1, preferably 5:1；
It is further preferred that the matter of pyridine and 4,4 '-[(pyridine -2- bases) methylene] bis-phenols in step (2) in step (1)
It is (5~8) to measure ratio:1, preferably 6:1；
It is further preferred that the pyridine in step (2) and 4,4 '-[(pyridine -2- bases) methylene] bis-phenols in step (2)
Mass ratio is (12~8)：1, preferably 10:1；
It is further preferred that 4,4 '-[(pyridine -2- bases) methylene] bis-phenol in step (2) with it is organic molten in step (3)
The mass ratio of agent is 1：(4~6), preferably 1:5；
It is further preferred that 4,4 '-[(pyridine -2- bases) methylene] bis-phenol in step (2) and the anhydrous sulphur in step (4)
The mass ratio of sour sodium is 1：(2~3), preferably 1:2；
It is further preferred that the alkali in step (3) is sodium hydroxide；
It is further preferred that the extractant in step (3) is ethyl acetate.
On the one hand, the preparation method of picosulfate sodium provided by the invention possesses advantages below：
(1) under nitrogen protection, first by pyridine and chlorosulfonic acid reaction generation pyridine. sulfur trioxide complex compound, then with 4,4 '-
[(pyridine -2- bases) methylene] bis-phenol reacts, and the content of accessory substance is no more than 0.1% in reaction solution, in picosulfate sodium product not
Above-mentioned accessory substance is detected, compared with prior art, the order that inventor is successively reacted by adjusting reactant, first by pyridine and chlorine
Sulfonic acid is reacted, then with 4, the reaction of 4 '-[(pyridine -2- bases) methylene] bis-phenols, greatly reduces accessory substance in target product
Content；
(2) this method, which controls, is added dropwise chlorosulfonic acid temperature, can effectively control product colour as white or off-white color；
(3) anhydrous sodium sulfate decolouring drying temperature is controlled, can effectively control the sulfate in product to be not more than
400ppm, greatly reduce the content of other sulfate impurities in product；
(4) it is that can effectively control product to contain an one's share of expenses for a joint undertaking crystallization water to control and be dried under reduced pressure temperature, obtains physicochemical property
Stable target product.On the other hand, the picosulfate sodium prepared using the inventive method possesses following beneficial effect：
Picosulfate sodium belongs to diphenylmethane derivatives, and this product has the characteristics that compared with other similar drugs：
(1) medication is easy, without especially preparing gut purge solution；
(2) repeatedly a small amount of clear water takes this product, avoids disposably drinking the pain that big quantity of fluid is brought；
(3) without bad mouthfeel, without enduring the bitter, puckery etc. of other gut purge solution；
(4) there is strict quality standard and usage and dosage, take and trust；
(5) cleaning intestinal tract is thorough, it is ensured that diagnoses accurate and surgical quality；
(6) gastrointestinal side effect is small, mitigates patient's Nausea and vomiting, stomachache sense；
(7) it is few without special care, postoperative complications；
(8) this product is low dose, dysphagia caused by overcoming tablet excessive.
Brief description of the drawings
Fig. 1 is the structural formula of picosulfate sodium；
Fig. 2 is that the purity for the picosulfate sodium prepared using comparative example verifies HPLC collection of illustrative plates；
Fig. 3 is that the purity for the picosulfate sodium prepared using embodiment 1 verifies HPLC collection of illustrative plates, and RRT values represent relative and protected
Stay the time；
Fig. 4 is that the purity for the picosulfate sodium prepared using embodiment 2 verifies HPLC collection of illustrative plates, and RRT values represent relative and protected
Stay the time；
Fig. 5 is that the purity for the picosulfate sodium prepared using embodiment 3 verifies HPLC collection of illustrative plates, and RRT values represent relative and protected
Stay the time；
The purity checking HPLC collection of illustrative plates for the picosulfate sodium that Fig. 6 is prepared using embodiment 4, RRT values represent relative and retained
Time.
Embodiment
Comparative example：
Preparation technology：750ml anhydrous pyridines are added in 2000ml there-necked flasks, stir 4,4 '-[(pyridine -2- of lower addition
Base) methylene] 100 grams of bis-phenol, dissolving is completely.0~5 DEG C of control system temperature, in 102 grams of chlorosulfonic acid of dropwise addition in half an hour.It is added dropwise
During can generate solid not tolerant, with stirring and reaction progress slowly dissolve.Environment temperature is warmed naturally to, insulation is stirred
Mix reaction 7 hours.
Reaction solution is poured into 3L mixture of ice and water, the sodium hydroxide solution for adding 30% adjusts pH value to strong basicity, uses
Ether solvent extracts most of pyridine.Aqueous phase adds activated carbon decolorizing filtering, adds hydrochloric acid regulation ph8.Add chloroform
Extraction has neither part nor lot in 4,4 '-[(pyridine -2- bases) methylene] bis-phenols of reaction.It is concentrated under reduced pressure at 40~45 degree dry, adds 3.4L
Ether solvent mashing extraction, the backflow of residue absolute ethyl alcohol, is filtered, and filtrate cooling crystallization, is filtered, filter cake is dried under reduced pressure in 40 degree
Produce the picosulfate sodium product of white.
Fig. 2 is according to the process route of comparative example record, after the crude product for synthesizing target compound picosulfate sodium, is used
High performance liquid chromatography (hereinafter referred to as HPLC methods) carries out purity analysis to it, finds crude product in tR=7min or so appearance, not
Know impurity peaks in tR=13min or so appearance, RRT values represent relative retention time, should test result indicates that, impurity tR=13 contain
Measure larger and be difficult to remove.
Embodiment 1:
Under nitrogen protection, pyridine 30kg, frozen cooling, adjusting body are added in the 100L glass-lined reactors of clean dried
It is extremely -30~-10 DEG C of temperature, chlorosulfonic acid 6.0kg is added dropwise, a large amount of milky insoluble matters are generated during dropwise addition.Guarantor is added dropwise
Temperature stirring 30~45 minutes.- 20~-10 DEG C of control system temperature, the pyridine of 4,4 '-[(pyridine -2- bases) methylene] bis-phenols is added dropwise
Solution, the solution are formed by 4,4 '-[(pyridine -2- bases) methylene] bis-phenol 5.0kg and pyridine 50kg mixed preparings；It is added dropwise
Insulated and stirred 2.0 hours.Slowly heating, 25 DEG C~35 DEG C of control system temperature, insulation reaction 10 hours~12 hours.React
Finish control hot water temperature and be no more than 55 DEG C, vacuum -0.07MPa, be evaporated under reduced pressure pyridine to dry.System is cooled to 0 DEG C~10 DEG C,
0 DEG C~10 DEG C of control system temperature, sodium hydroxide solution, regulation pH11.0 (in terms of actual amount), the sodium hydroxide is added dropwise
Solution is formed using purified water 52.5kg and sodium hydroxide 10.0kg mixed preparings；Add 25.0kg/ extraction of ethyl acetate
Three times.Vacuum -0.07MPa~-0.1MPa is controlled, hot water temperature is no more than 70 DEG C, is evaporated under reduced pressure aqueous phase to dry.Add anhydrous
Ethanol 10.0kg/ sub-band water twice, is evaporated under reduced pressure to dry.Absolute methanol 60.0kg, control system temperature 50 are added in residue
DEG C~60 DEG C, insulated and stirred 30 minutes~45 minutes, it is cooled to 10 DEG C~40 DEG C.Anhydrous sodium sulfate is added into retort
10.0kg, activated carbon 0.50kg.10 DEG C~20 DEG C, retort rotating speed 95rpm of control system temperature, it is small that insulation decolouring dries 8.0
When.Centrifugation, vacuum -0.07MPa is controlled, hot water temperature is no more than 60 DEG C, is evaporated under reduced pressure methanol to dry.Added into retort
Absolute ethyl alcohol 30kg, purified water 1kg, warming-in-water is to 75 DEG C, insulated and stirred 2.0 hours.20 DEG C are cooled to, is centrifuged, anhydrous second
Alcohol 10.0kg washings, rejection filter to obtain picosulfate sodium wet product to dry.Vacuum -0.07MPa, 50 DEG C of hot water temperature are controlled, decompression is done
Dry 6.0 hours.Drying finishes, and receipts, which are dried, produces high purity sodium picosulfate, and total impurities is no more than 0.1%.
Fig. 3 is according to the process route of the record of embodiment 1, after the crude product for synthesizing target compound picosulfate sodium, is adopted
Purity analysis is carried out to it with high performance liquid chromatography (hereinafter referred to as HPLC methods), finds crude product in tR=7min or so appearance,
And do not detect unknown impuritie peak.
Embodiment 2:
Under nitrogen protection, pyridine 30kg, frozen cooling to system temperature -15 are added in the 100L reactors of clean dried
~-10 DEG C, -15~-10 DEG C of control system temperature, chlorosulfonic acid 6.0kg is added dropwise, it is insoluble that a large amount of milkys are generated during dropwise addition
Thing.Insulated and stirred is added dropwise 45 minutes.It is double that 4,4 '-[(pyridine -2- bases) methylene] is added dropwise in -15~-10 DEG C of control system temperature
The pyridine solution of phenol, the solution are formed by 4,4 '-[(pyridine -2- bases) methylene] bis-phenol 5.0kg and pyridine 50kg mixed preparings；Drop
Add complete insulated and stirred 3.0 hours.Slowly heating, 30 DEG C~35 DEG C of control system temperature, insulation reaction 12 hours.Reaction finishes
Control hot water temperature to be no more than 55 DEG C, vacuum -0.1MPa, be evaporated under reduced pressure pyridine to dry.System is cooled to -10 DEG C~0 DEG C.Control
Sodium hydroxide solution is added dropwise in -10 DEG C of system temperature~0 DEG C processed, adjusts pH11.0 (in terms of actual amount), and the sodium hydroxide is molten
Liquid is formed using purified water 52.5kg and sodium hydroxide 10.0kg mixed preparings；Add 25.0kg/ extraction three of ethyl acetate
It is secondary.Vacuum -0.1MPa is controlled, hot water temperature is no more than 70 DEG C, is evaporated under reduced pressure aqueous phase to dry.Add absolute ethyl alcohol 10.0kg/
Sub-band water twice, is evaporated under reduced pressure to dry.Absolute methanol 60.0kg, control system temperature 60 C, insulated and stirred are added in residue
45 minutes, it is cooled to 30 DEG C~40 DEG C.Anhydrous sodium sulfate 10.0kg, activated carbon 0.50kg are added into retort.Control system
10 DEG C~20 DEG C, retort rotating speed 105rpm of temperature, insulation decolourize to dry 10 hours.Centrifugation, control vacuum -0.1MPa, heat
Coolant-temperature gage is no more than 60 DEG C, is evaporated under reduced pressure methanol to dry.Absolute ethyl alcohol 30kg, purified water 1kg, water-bath liter are added into retort
Warm to 85 DEG C, insulated and stirred 3.0 hours.Be cooled to 30 DEG C, centrifugation, absolute ethyl alcohol 10.0kg washings, rejection filter to dry can sulphur
Sour sodium wet product.Vacuum -0.1MPa is controlled, 60 DEG C of hot water temperature, is dried under reduced pressure 8.0 hours.Drying finish, receipts dry produce it is high-purity
Picosulfate sodium is spent, total impurities is no more than 0.1%.
Fig. 4 is according to the process route of the record of embodiment 2, after the crude product for synthesizing target compound picosulfate sodium, is adopted
Purity analysis is carried out to it with high performance liquid chromatography (hereinafter referred to as HPLC methods), finds crude product in tR=7min or so appearances,
And do not detect unknown impuritie peak.
Embodiment 3：
Under nitrogen protection, pyridine 32kg, frozen cooling to system are added in the 100L glass-lined reactors of clean dried
- 16 DEG C of temperature, -16 DEG C of dropwise addition chlorosulfonic acid 7.0kg of control system temperature, generates a large amount of milky insoluble matters during dropwise addition.Drop
Add complete insulated and stirred 35 minutes.The pyridine of -16 DEG C of 4,4 '-[(pyridine -2- bases) methylene] bis-phenols of dropwise addition of control system temperature is molten
Liquid, the solution are formed by 4,4 '-[(pyridine -2- bases) methylene] bis-phenol 5.0kg and pyridine 50kg mixed preparings；Insulation is added dropwise
Stirring 2.5 hours.Slowly heating, 30 DEG C of control system temperature, insulation reaction 12 hours.Reaction finishes control hot water temperature and not surpassed
Cross 55 DEG C, vacuum -0.08MPa, be evaporated under reduced pressure pyridine to dry.System is cooled to 0 DEG C.0 DEG C of dropwise addition hydrogen-oxygen of control system temperature
Change sodium solution, regulation pH12.0 (in terms of actual amount), the sodium hydroxide solution uses purified water 52.5kg and sodium hydroxide
10.0kg mixed preparing forms；Add 25.0kg/ extraction of ethyl acetate three times.Control vacuum -0.08MPa, hot water temperature
Degree is no more than 70 DEG C, is evaporated under reduced pressure aqueous phase to dry.Add absolute ethyl alcohol 10.0kg/ sub-band water twice, be evaporated under reduced pressure to dry.It is remaining
Absolute methanol 65.0kg is added in thing, 55 DEG C of control system temperature, insulated and stirred 35 minutes, is cooled to 25 DEG C.Into retort
Add anhydrous sodium sulfate 10.0kg, activated carbon 0.50kg.15 DEG C of control system temperature, retort rotating speed 100rpm, insulation are decolourized
Dry 9 hours.Centrifugation, vacuum -0.08MPa is controlled, hot water temperature is no more than 60 DEG C, is evaporated under reduced pressure methanol to dry.To reaction
Absolute ethyl alcohol 30kg is added in tank, purified water 1.2kg, warming-in-water is to 80 DEG C, insulated and stirred 2.5 hours.25 DEG C are cooled to, from
The heart, absolute ethyl alcohol 10.0kg are washed, and rejection filter to obtain picosulfate sodium wet product to dry.Vacuum -0.08MPa is controlled, hot water temperature 55
DEG C, it is dried under reduced pressure 7 hours.Drying finishes, and receipts, which are dried, produces high purity sodium picosulfate, and total impurities is no more than 0.1%.
Fig. 5 is according to the process route of the record of embodiment 3, after the crude product for synthesizing target compound picosulfate sodium, is adopted
Purity analysis is carried out to it with high performance liquid chromatography (hereinafter referred to as HPLC methods), finds crude product in tR=7min or so appearances,
And do not detect unknown impuritie peak.
Embodiment 4
Under nitrogen protection, pyridine 25kg, frozen cooling to system temperature -16 are added in the 100L reactors of clean dried
DEG C, -16 DEG C of dropwise addition chlorosulfonic acid 5.0kg of control system temperature, a large amount of milky insoluble matters are generated during dropwise addition.Guarantor is added dropwise
Temperature stirring 35 minutes.The pyridine solution of -15 DEG C of 4,4 '-[(pyridine -2- bases) methylene] bis-phenols of dropwise addition of control system temperature, the solution
Formed by 4,4 '-[(pyridine -2- bases) methylene] bis-phenol 5.0kg and pyridine 50kg mixed preparings；Insulated and stirred 2.5 is added dropwise
Hour.Slowly heating, 30 DEG C of control system temperature, insulation reaction 12 hours.Reaction finishes control hot water temperature and is no more than 55 DEG C,
Vacuum -0.08MPa, pyridine is evaporated under reduced pressure to dry.System is cooled to 0 DEG C.It is molten that sodium hydroxide is added dropwise in 0 DEG C of control system temperature
Liquid, regulation pH11.0 (in terms of actual amount), the sodium hydroxide solution use purified water 52.5kg and sodium hydroxide 10.0kg
Mixed preparing forms；Add 21.0kg/ extraction of ethyl acetate three times.Vacuum -0.08MPa is controlled, hot water temperature does not surpass
Cross 70 DEG C, be evaporated under reduced pressure aqueous phase to dry.Add absolute ethyl alcohol 8.3kg/ sub-band water twice, be evaporated under reduced pressure to dry.Add in residue
Enter absolute methanol 50.0kg, 55 DEG C of control system temperature, insulated and stirred 35 minutes, be cooled to 25 DEG C.Nothing is added into retort
Aqueous sodium persulfate 8.3kg, activated carbon 0.50kg.15 DEG C of control system temperature, retort rotating speed 100rpm, insulation decolourize to dry 8.0
Hour~10 hours.Centrifugation, vacuum -0.08MPa is controlled, hot water temperature is no more than 60 DEG C, is evaporated under reduced pressure methanol to dry.To anti-
Answer in tank addition absolute ethyl alcohol 25kg, purified water 1kg, warming-in-water is to 80 DEG C, insulated and stirred 2.5 hours.25 DEG C are cooled to, from
The heart, absolute ethyl alcohol 10.0kg are washed, and rejection filter to obtain picosulfate sodium wet product to dry.Vacuum -0.08MPa is controlled, hot water temperature 55
DEG C, be dried under reduced pressure 7.0 hours it is dry finish, receipts are dried and produce high purity sodium picosulfate, and total impurities is no more than 0.1%.
Fig. 6 is according to the process route of the record of embodiment 4, after the crude product for synthesizing target compound picosulfate sodium, is adopted
Purity analysis is carried out to it with high performance liquid chromatography (hereinafter referred to as HPLC methods), finds crude product in tR=7min or so appearances,
And do not detect unknown impuritie peak.
Embodiments of the invention are described in detail above, but the content is only presently preferred embodiments of the present invention,
It is not intended to limit the invention.All all any modification, equivalent and improvement done in the application range of the present invention etc., all should
Within protection scope of the present invention.
Claims (18)
- A kind of 1. method for preparing picosulfate sodium, it is characterised in that comprise the following steps：(1) under nitrogen protection, at -30~-10 DEG C, in enclosed system, into pyridine, dropwise addition chlorosulfonic acid is reacted；(2) system reaction temperature is adjusted to -20~0 DEG C, it is added dropwise a certain amount of 4,4 ' into the enclosed system described in step (1) - The pyridine solution of [(pyridine -2- bases) methylene] bis-phenol is reacted, after reacting 15~60 minutes, slowly heating, and control system temperature Degree reaches 10 DEG C~35 DEG C, then is incubated and is reacted, and obtains reactant mixture；(3) reactant mixture obtained by step (2) is evaporated under reduced pressure after removing pyridine, after adjusting its pH value as alkalescence, then carried out Extraction, obtains extract and aqueous phase, and water intaking is mutually evaporated under reduced pressure, obtains product of distillation, the product of distillation can be obtained into sterling after purification Picosulfate sodium.
- 2. according to the method for claim 1, it is characterised in that the pH value in the step (3) is 10.0~13.0.
- 3. according to the method for claim 2, it is characterised in that the pH value in the step (3) is 11~12.
- 4. according to the method for claim 1, it is characterised in that further comprising the steps of：(4) absolute methanol is added into described product of distillation, 40 DEG C~80 DEG C of control system temperature is reacted；15~60 points Zhong Hou, it is cooled to 0 DEG C~40 DEG C and continues to react；After reaction 15~60 minutes, methanol is evaporated under reduced pressure to doing, must be evaporated production Thing；(5) to gained be evaporated in product add absolute ethyl alcohol, distilled water, heating water bath stirring, after completion of the reaction cooling, from The heart, a small amount of absolute ethyl alcohol wash, and filter to dry to obtain picosulfate sodium wet product；Sterling is can obtain by being dried under wet product constant temperature and pressure Picosulfate sodium.
- 5. according to the method for claim 4, it is characterised in that comprise the following steps：(1) under nitrogen protection, at -30~-10 DEG C, in enclosed system, into pyridine, dropwise addition chlorosulfonic acid is reacted, and is added dropwise During generate milky insoluble matter, insulated and stirred is added dropwise 15~45 minutes, mixing time be 30~45 minutes；(2) system temperature is adjusted to -20~0 DEG C, a certain amount of 4 is added dropwise into the enclosed system described in step (1), 4 '-[(pyrrole Pyridine -2- bases) methylene] pyridine solution of bis-phenol reacted；The temperature for controlling reaction system is -20~-10 DEG C, reaction 15~60 After minute, slowly heating, control system temperature is 25 DEG C~35 DEG C, is further continued for being reacted, obtains reactant mixture；(3) reactant mixture obtained by step (2) is evaporated under reduced pressure and removes pyridine, adjustment temperature of reaction system to -10 DEG C~20 DEG C, and its pH is adjusted as 11.0~12.0；Extraction 1~3 time is carried out again, obtains extract and aqueous phase；Phase of fetching water heating water bath, constant temperature After decompression water removal, it is dehydrated using absolute ethyl alcohol, dehydrating operations 1~3 time, obtains dehydration product；The reaction that the constant temperature is dried under reduced pressure Condition is vacuum -0.05MPa~-0.1MPa, and bath temperature is no more than 80 DEG C；(4) absolute methanol is added into the dehydration product described in step (3), control system temperature 50 C~60 DEG C and being incubated are stirred Mix and reacted；After 30 minutes~45 minutes, adjustment system reaction temperature is to 0 DEG C~40 DEG C, to reaction system under constant temperature and pressure Middle addition anhydrous sodium sulfate, activated carbon, are stirred, decolourize, 0 DEG C~30 DEG C of whipping temp, decolourize 5.0 hours~12 hours； It is then centrifuged for, retort rotating speed 90rpm~120rpm；Methanol is evaporated under reduced pressure to dry, bath temperature be no more than 60 DEG C, vacuum- 0.05MPa~-0.1MPa, product must be evaporated；(5) into step (4), gained is evaporated in product and adds absolute ethyl alcohol, distilled water, and heating water bath is incubated to 60~90 DEG C Stirring；0 DEG C~30 DEG C are cooled to after completion of the reaction；Centrifugation, a small amount of absolute ethyl alcohol washing, is filtered to dry that picosulfate sodium is wet Product；To be dried under wet product constant temperature and pressure and can obtain sterling picosulfate sodium, the pressure of the constant temperature and pressure for -0.05MPa~- 0.1MPa, bath temperature are 40 DEG C~70 DEG C, and drying time is 5.0 hours~10 hours；In the sterling picosulfate sodium Total impurities is no more than 0.1%.
- 6. according to the method for claim 5, it is characterised in thatReaction temperature in the step (1) is -20~-15 DEG C；In the step (3) extraction times be 3 times, dehydrating operations 2 times, the reaction condition that constant temperature is dried under reduced pressure be vacuum- 0.07MPa~-0.1MPa, hot water temperature are no more than 60 DEG C；In the step (4), 10 DEG C~20 DEG C of whipping temp, bleaching time 8.0~10 hours, retort rotating speed be 95rpm~ 105rpm；OrIn the step (5), the insulated and stirred time is 2.0 hours~3.0 hours, is cooled to 20 DEG C~30 DEG C after completion of the reaction, When being dried under wet product constant temperature and pressure, pressure, temperature, the time respectively -0.07MPa~-0.1MPa, 50 DEG C~60 DEG C, 6.0 hours ~8.0 hours.
- 7. according to any described methods of claim 1-6, it is characterised in that the matter of pyridine and chlorosulfonic acid in the step (1) Amount is than being 6~4:1.
- 8. according to the method for claim 7, it is characterised in that the mass ratio of pyridine and chlorosulfonic acid is in the step (1) 5:1。
- 9. according to any described methods of claim 1-6, it is characterised in that in the step (1) in pyridine and step (2) The mass ratio of 4,4 '-[(pyridine -2- bases) methylene] bis-phenols is (5~8):1.
- 10. according to the method for claim 9, it is characterised in that in the step (1) in pyridine and step (2) 4,4 '- The mass ratio of [(pyridine -2- bases) methylene] bis-phenol is 6:1.
- 11. according to any described methods of claim 1-6, it is characterised in that pyridine and step (2) in the step (2) In the mass ratioes of 4,4 '-[(pyridine -2- bases) methylene] bis-phenols be (12~8)：1.
- 12. according to the method for claim 11, it is characterised in that the pyridine in the step (2) and 4 in step (2), The mass ratio of 4 '-[(pyridine -2- bases) methylene] bis-phenols is 10:1.
- 13. according to any described methods of claim 1-6, it is characterised in that 4,4 '-[(pyridine -2- in the step (2) Base) methylene] mass ratio of organic solvent in bis-phenol and step (3) is 1：(4~6).
- 14. according to the method for claim 13, it is characterised in that 4,4 '-[(pyridine -2- bases) first in the step (2) Support] mass ratio of organic solvent in bis-phenol and step (3) is 1:5.
- 15. according to any described methods of claim 1-6, it is characterised in that 4,4 '-[(pyridine -2- in the step (2) Base) methylene] mass ratio of anhydrous sodium sulfate in bis-phenol and step (4) is 1：(2~3).
- 16. according to the method for claim 15, it is characterised in that 4,4 '-[(pyridine -2- bases) first in the step (2) Support] mass ratio of anhydrous sodium sulfate in bis-phenol and step (4) is 1:2.
- 17. according to any described methods of claim 1-6, it is characterised in that the alkali in the step (3) is sodium hydroxide.
- 18. according to any described methods of claim 1-6, it is characterised in that the extractant in described step (3) is second Acetoacetic ester.
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| US3686189A (en) * | 1966-12-14 | 1972-08-22 | Angeli Inst Spa | 3-halogenated 4,4'-disulfoxy-diphenyl-(2-pyridyl)-methane |
| US3882131A (en) * | 1971-09-17 | 1975-05-06 | Prodotti Antibiotics S P A Spa | Process for preparing 4,4-disulphoxy-diphenyl-(2-pryidyl)-methane derivatives |
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