CN108467372A - The preparation method of difenidol hydrochloride - Google Patents
The preparation method of difenidol hydrochloride Download PDFInfo
- Publication number
- CN108467372A CN108467372A CN201810386040.2A CN201810386040A CN108467372A CN 108467372 A CN108467372 A CN 108467372A CN 201810386040 A CN201810386040 A CN 201810386040A CN 108467372 A CN108467372 A CN 108467372A
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- Prior art keywords
- preparation
- hydrochloric acid
- solution
- added dropwise
- piperidines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
Abstract
The present invention provides the preparation methods of sour difenidol, include the following steps, to 1, piperidines is added dropwise in 3 bromo-chloropropanes, insulation reaction 2~4 hours instills 30wt% sodium hydroxide solutions, insulation reaction 2~4 hours, stratification takes oil reservoir, it is acidified with 16wt% hydrochloric acid solutions, stratification takes oil reservoir to isolate excessive bromo-chloropropane, pH value of solution=11 are adjusted with 36wt% sodium hydroxide solutions, stratification takes oil reservoir, and uses desiccant dryness；Prepare α, 1 piperidine butanol of α diphenyl；α is added into isopropanol, α diphenyl-piperidine butanol is heated to reflux, and is subsequently cooled to 37 DEG C, and 16wt% hydrochloric acid solutions are added dropwise to adjust the pH=3 of solution, are kept for pH value half an hour constant, and crystallisation by cooling is dried using centrifuge to get difenidol hydrochloride.Disclosed preparation method can reduce the impurity content in chloropropyl piperidines, restrained effectively the generation of ene compound and impurity, improve product quality, and reduce operation difficulty.
Description
Technical field
The present invention relates to chemicals synthesis technical field more particularly to a kind of preparation methods of difenidol hydrochloride.
Background technology
Difenidol hydrochloride (Difenidol hydrochloride) can improve the artery blood supply of vertebra bottom, adjust vestibular system
Function inhibits vomiting centre, there is combating vertigo and anti-vomiting effect, be usually used in dizziness caused by preventing many reasons or disease, nausea,
Vomiting, the motion sickness as ridden, when ship, aircraft.
The Chinese invention patent application of Publication No. CN106749101A discloses a kind of preparation side of difenidol hydrochloride
Method, and include the following steps：The preparation of S1.1- (3- chloropropyls) hexahydropyridine；S2. the system of α, α-diphenyl -1- piperidine butanols
It is standby；S3. the preparation of α, α-diphenyl -1- piperidine butanol hydrochlorides；Wherein, step S3 includes following preparation process：Obtained by S2
Reactant be dissolved in organic solvent, and buffer salt solution is added, is heated to 55 ± 5 DEG C, activated carbon is added, keep the temperature 1 hour, mistake
Filter；Hydrochloric acid is added into gained filtrate, it is 5~6 to adjust PH, controls 50~60 DEG C of temperature, stirs 25~35min, is filtered, and is done
It is dry, obtain difenidol hydrochloride.
In the preparation method of the revealed difenidol hydrochloride of the prior art, the hydrochloric acid that is finally prepared ground Pfennig
The minimum recall rate of ene compound in more still reaches to 0.08%, therefore still remains certain limitation；Meanwhile in the preparation
Filter method employed in method may cause the yield of difenidol hydrochloride relatively low；Meanwhile preparing α-diphenyl -1- piperazines
It needs to coordinate buffer solution in 75% or more alcohol organic solvent using solute concentration during pyridine Kauri-butanol hydrochloric salt, therefore
There are the defect of complex process, it is unfavorable for recycling, and causes production cost excessively high；Finally, due to which the prior art needs
The pH of system is adjusted to 5~6 and maintains higher reaction temperature, therefore cannot effectively inhibit the production of ene compound and impurity
It is raw.
In view of this, it is necessary to the preparation method of difenidol hydrochloride in the prior art is improved, it is above-mentioned to solve
Problem.
Invention content
It is an object of the invention to disclose a kind of preparation method of difenidol hydrochloride, to improve difenidol hydrochloride
Yield reduces process complexity, and realizes the recycling of organic solvent, with reduction prepare the generation of difenidol hydrochloride at
This, while inhibiting the content of the impurity such as ene compound.
To achieve the above object, the present invention provides a kind of preparation method of difenidol hydrochloride, include the following steps,
S1,1- (3- chloropropyls) hexahydro piperidines is prepared：
Piperidines is added dropwise into 1,3- bromo-chloropropanes, insulation reaction 2~4 hours instills 30wt% sodium hydroxide solutions, heat preservation
Reaction 2~4 hours, stratification takes oil reservoir, is acidified with 16wt% hydrochloric acid solutions, stratification is to isolate excessive bromine chlorine
Propane takes oil reservoir, adjusts pH value of solution=11 with 36wt% sodium hydroxide solutions, stratification takes oil reservoir, and dry using drier
It is dry；
S2, α, α-diphenyl -1- piperidine butanols are prepared；
S3, α, α-diphenyl -1- piperidine butanol hydrochlorides are prepared：
α is added into isopropanol, α-diphenyl-piperidine butanol is heated to reflux, and is subsequently cooled to 37 DEG C, and 16wt% salt is added dropwise
Acid solution is kept for pH value half an hour constant to adjust the pH=3 of solution, crystallisation by cooling, to get hydrochloric acid using centrifuge drying
Pfennig is more.
As a further improvement on the present invention, in the step S1, piperidines, 1,3- bromo-chloropropanes, sodium hydroxide and hydrochloric acid
Volume ratio be：1：2.05：1.14：1.27.
As a further improvement on the present invention, in the step S1, before piperidines is added dropwise into 1,3- bromo-chloropropanes, also
Including：It is water-cooled to 20 DEG C using jacket refrigerating；
Meanwhile the temperature that solution is controlled during piperidines is added dropwise into 1,3- bromo-chloropropanes maintains 18~25 DEG C.
As a further improvement on the present invention, in the step S1, during using hydrochloric acid souring soln, solution is controlled
Temperature maintain 30 DEG C.
As a further improvement on the present invention, in the step S1, during sodium hydroxide solution is added dropwise, solution is controlled
Temperature maintain 25~35 DEG C.
As a further improvement on the present invention, in the step S3, α, α-diphenyl-piperidine butanol, isopropanol and hydrochloric acid
Volume ratio is：1：2.5：0.6.
As a further improvement on the present invention, in the step S3, during hydrochloric acid solution is added dropwise, the temperature of solution is controlled
Degree maintains 25~45 DEG C.
As a further improvement on the present invention, the step S1~S3 is with thermometer, agitating device and reflux
Enamel reaction still in execute.
Compared with prior art, the beneficial effects of the invention are as follows：
(1) in the present invention, lye is acidified by alkylation process with hydrochloric acid, and standing differentiates excessive bromine chlorine third
Alkane reduces the impurity content in chloropropyl piperidines；
(2) in the present invention, isopropanol is selected to do organic solvent in salt-forming reaction, control titration temperature is simultaneously less than 45 degree
It is titrated to pH=3, to restrained effectively the generation of ene compound and impurity, improves product quality；
(3) isopropanol is instead of the combination for using organic solvent to add buffer solution in the prior art, therefore has solvent list
One the characteristics of changing, operation difficulty is reduced, and isopropanol is recyclable applies mechanically in the reaction, reduce difenidol hydrochloride production
Cost.
Specific implementation mode
With reference to each embodiment, the present invention is described in detail, but it should explanation, these embodiments are simultaneously
Non- limitation of the present invention, those of ordinary skill in the art are according in function, method or structure made by these embodiments
Equivalent transformation or replacement, all belong to the scope of protection of the present invention within.
Present embodiment discloses a kind of preparation method of difenidol hydrochloride, and as follows.
Step S1,1- (3- chloropropyls) hexahydro piperidines is prepared.Step S1 is alkylated reaction.
Rate of charge (volume ratio) is specifically, piperidines：1,3- bromo-chloropropanes：Sodium hydroxide：Hydrochloric acid=1：2.05：1.14：
1.27。
Technical process：
1,3- bromo-chloropropanes are first put into 500L enamel reaction stills, open jacket refrigerating water cooling, slowly at 20 DEG C or so
Piperidines is added dropwise, reacting liquid temperature is controlled at 18~25 DEG C, is added dropwise, and in 20 DEG C or so insulation reactions 4 hours, is then instilled pre-
First prepared 30% sodium hydroxide solution, reaction solution are controlled at 25~35 DEG C, in 25~35 DEG C of insulation reactions 4 after being added dropwise
Hour, static layering, after putting sub-cloud lye (i.e. sodium hydroxide solution), oil reservoir is acidified to pH=3 with 16wt% hydrochloric acid solutions,
Temperature control hereinafter, static layering 1 hour, separates excessive bromo-chloropropane at 30 DEG C, then with prepared 36wt% alkali in advance
For drop to PH=11, reacting liquid temperature is maintained at 25~35 DEG C, and static layering puts sub-cloud lye (i.e. sodium hydroxide solution),
Upper layer oil reservoir is obtained, oil reservoir desiccant dryness obtains 1- (3- chloropropyls) hexahydro piperidines.In the present embodiment, which can
Select solid NuaO either silica gel or activated alumina, and preferably solid NuaO.
Step S2, α, α-diphenyl -1- piperidine butanols are prepared.
Magnesium chips is mixed with anhydrous tetrahydro furan 120ml, is added iodine and bromoethane, control solution temperature 50~65 DEG C it
Between be added 1- (3- chloropropyls) hexahydro piperidines obtained by step S1, after reaction 1 hour, anhydrous tetrahydro furan is added again
150ml and benzophenone, sustained response is after 3 hours, recycles tetrahydrofuran, is added the ammonium chloride solution of 12wt%, hydrolysis to get
α, α-diphenyl -1- piperidine butanols.
Step S3, α, α-diphenyl -1- piperidine butanol hydrochlorides are prepared.Step S3 salt-forming reactions.
Rate of charge (volume ratio) is specially：α, α-diphenyl-piperidine butanol：Isopropanol：Hydrochloric acid=1：2.5：0.6.
Technical process：
In the 500L enamel reaction stills equipped with stirring, thermometer and reflux, isopropanol is first put into, is thrown under stiring
Enter α, α-diphenyl-piperidine butanol is heated to reflux 1 hour, makes it dissolve, and is cooled to 37 DEG C or so, starts that 16wt% is slowly added dropwise
Hydrochloric acid solution, temperature control, hereinafter, when to pH=3, stop being added dropwise, be sufficiently stirred, repeatedly the pH value of test reaction liquid at 45 DEG C,
When keeping half an hour pH value constant, reaction terminates, cooling crystallization, and white powder or needle-shaped crude product are dried to obtain with centrifuge.
In the present invention, lye is acidified by alkylation process with hydrochloric acid, and standing differentiates excessive bromo-chloropropane, is dropped
Impurity content in low chloropropyl piperidines；Meanwhile in the present invention, it selects isopropanol to do organic solvent in salt-forming reaction, controls
Titration temperature processed is less than 45 degree and is titrated to pH=3, to restrained effectively the generation of ene compound and impurity, raising product
Quality；Finally, in the present invention, isopropanol is instead of the combination for using organic solvent to add buffer solution in the prior art, therefore
Have the characteristics that solvent unification, reduce operation difficulty, and isopropanol is recyclable applies mechanically in the reaction, with reducing hydrochloric acid
The more production costs of Pfennig.
The series of detailed descriptions listed above only for the present invention feasible embodiment specifically
Bright, they are all without departing from equivalent implementations made by technical spirit of the present invention not to limit the scope of the invention
Or change should all be included in the protection scope of the present invention.
It is obvious to a person skilled in the art that invention is not limited to the details of the above exemplary embodiments, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention is by appended power
Profit requires rather than above description limits, it is intended that all by what is fallen within the meaning and scope of the equivalent requirements of the claims
Variation is included within the present invention.
In addition, it should be understood that although this specification is described in terms of embodiments, but not each embodiment is only wrapped
Containing an independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should
It considers the specification as a whole, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
The other embodiment being appreciated that.
Claims (8)
1. the preparation method of difenidol hydrochloride, which is characterized in that include the following steps,
S1,1- (3- chloropropyls) hexahydro piperidines is prepared：
Piperidines is added dropwise into 1,3- bromo-chloropropanes, insulation reaction 2~4 hours instills 30wt% sodium hydroxide solutions, insulation reaction
2~4 hours, stratification took oil reservoir, with 16wt% hydrochloric acid solutions be acidified, stratification to isolate excessive bromo-chloropropane,
Oil reservoir is taken, adjusts pH value of solution=11 with 36wt% sodium hydroxide solutions, stratification takes oil reservoir, and uses desiccant dryness；
S2, α, α-diphenyl -1- piperidine butanols are prepared；
S3, α, α-diphenyl -1- piperidine butanol hydrochlorides are prepared：
α is added into isopropanol, α-diphenyl-piperidine butanol is heated to reflux, and is subsequently cooled to 37 DEG C, and it is molten that 16wt% hydrochloric acid is added dropwise
Liquid is kept for pH value half an hour constant to adjust the pH=3 of solution, crystallisation by cooling, and to get hydrochloric acid Pfennig is dried using centrifuge
It is more.
2. preparation method according to claim 1, which is characterized in that in the step S1, piperidines, 1,3- bromo-chloropropanes,
The volume ratio of sodium hydroxide and hydrochloric acid is：1：2.05：1.14：1.27.
3. preparation method according to claim 1, which is characterized in that in the step S1, into 1,3- bromo-chloropropanes
It is added dropwise before piperidines, further includes：It is water-cooled to 20 DEG C using jacket refrigerating；
Meanwhile the temperature that solution is controlled during piperidines is added dropwise into 1,3- bromo-chloropropanes maintains 18~25 DEG C.
4. preparation method according to claim 1, which is characterized in that in the step S1, use hydrochloric acid souring soln
In the process, the temperature for controlling solution maintains 30 DEG C.
5. preparation method according to claim 1, which is characterized in that in the step S1, sodium hydroxide solution is added dropwise
In the process, the temperature for controlling solution maintains 25~35 DEG C.
6. preparation method according to claim 1, which is characterized in that in the step S3, α, α-diphenyl-piperidine butanol,
The volume ratio of isopropanol and hydrochloric acid is：1：2.5：0.6.
7. preparation method according to claim 1, which is characterized in that in the step S3, the process of hydrochloric acid solution is added dropwise
In, the temperature for controlling solution maintains 25~45 DEG C.
8. preparation method according to claim 1, which is characterized in that the step S1~S3 is with thermometer, stirring
It is executed in the enamel reaction still of device and reflux.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810386040.2A CN108467372A (en) | 2018-04-26 | 2018-04-26 | The preparation method of difenidol hydrochloride |
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| CN201810386040.2A CN108467372A (en) | 2018-04-26 | 2018-04-26 | The preparation method of difenidol hydrochloride |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109265413A (en) * | 2018-10-12 | 2019-01-25 | 河南精康制药有限公司 | A kind of preparation method and refining methd of difenidol hydrochloride |
| CN110627744A (en) * | 2019-09-10 | 2019-12-31 | 株洲千金药业股份有限公司 | Preparation method of difenidol hydrochloride intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104447620A (en) * | 2014-11-28 | 2015-03-25 | 瑞阳制药有限公司 | Preparation method of 1-[3-[3-(4-chlorphenyl) propoxy] propyl]-piperidine hydrochloride |
| CN106749101A (en) * | 2016-12-30 | 2017-05-31 | 湖南千金湘江药业股份有限公司 | A kind of preparation method of difenidol hydrochloride |
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2018
- 2018-04-26 CN CN201810386040.2A patent/CN108467372A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447620A (en) * | 2014-11-28 | 2015-03-25 | 瑞阳制药有限公司 | Preparation method of 1-[3-[3-(4-chlorphenyl) propoxy] propyl]-piperidine hydrochloride |
| CN106749101A (en) * | 2016-12-30 | 2017-05-31 | 湖南千金湘江药业股份有限公司 | A kind of preparation method of difenidol hydrochloride |
Non-Patent Citations (1)
| Title |
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| WEN PAN,ET AL: "Determination of difenidol hydrochloride by capillary electrophoresis with electrochemiluminescence detection", 《J. CHROMATOGR. B》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109265413A (en) * | 2018-10-12 | 2019-01-25 | 河南精康制药有限公司 | A kind of preparation method and refining methd of difenidol hydrochloride |
| CN109265413B (en) * | 2018-10-12 | 2022-08-09 | 河南精康制药有限公司 | Preparation method and refining method of difenidol hydrochloride |
| CN110627744A (en) * | 2019-09-10 | 2019-12-31 | 株洲千金药业股份有限公司 | Preparation method of difenidol hydrochloride intermediate |
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Application publication date: 20180831 |