CN102617461A - Novel method for refining aripiprazole - Google Patents
Novel method for refining aripiprazole Download PDFInfo
- Publication number
- CN102617461A CN102617461A CN 201210066586 CN201210066586A CN102617461A CN 102617461 A CN102617461 A CN 102617461A CN 201210066586 CN201210066586 CN 201210066586 CN 201210066586 A CN201210066586 A CN 201210066586A CN 102617461 A CN102617461 A CN 102617461A
- Authority
- CN
- China
- Prior art keywords
- aripiprazole
- dissolving
- organic solvent
- salt
- suction filtration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a method for refining aripiprazole. By using the salifying and recrystallization combined technique, the method can be used for preparing the high-purity aripiprazole product in a simple and efficient way.
Description
Technical field
The present invention provides a kind of method of refining Aripiprazole.This method is separated salt and recrystallization coupling technique through using salify, can obtain the high Aripiprazole product of purity more succinctly, efficiently.
Background technology
Aripiprazole, chemistry 7-[4-[4-(2, the 3-dichlorophenyl)-1-piperazinyl] butoxy]-3 by name, the 4-dihydro-quinolinone, its chemical structural formula is:
Aripiprazole belongs to Carbostyril derivative, is a kind ofly to be used for treatment fear, obsession, somnopathy, sexual dysfunction, depression, anxiety or schizoid spiritual neurologic agent (US5006528, US4734416) such as manic goes on the market at a plurality of state approvals at present.
About synthesizing of Aripiprazole, in the many pieces of patents (EP367141, US5006528, CN1028104C, CN1042537A) following compound method has been described.
This reaction scheme is shorter, and raw material sources are convenient, and it is higher that each goes on foot yield, the synthetic route preferably of can yet be regarded as.
But this route weak point is that reactive behavior point is more, is easy to produce more by product, as:
We find through experiment; The growing amount of this dimer impurity II A is very high, no matter is adjustment order of addition(of ingredients) or material ratio, all can't effectively reduce the growing amount of dimer impurity II A; Impurity II A remains in the finished product Aripiprazole, through using the solvent recrystallization effect also undesirable.
So, how effectively reduce or eliminate impurity II A, important for the refining speech ten minutes of finished product.If in the first step, make with extra care, among the patent US20100130744, process for purification is provided; Use methylbenzene-silicon colloid system to make with extra care, we verify demonstration, and this method can effectively reduce the content of impurity II A; But refining yield is lower, greatly reduces the effective rate of utilization of product.Simultaneously, because midbody
IISolubleness in toluene is not high, causes refining solvent for use liquid-solid ratio to surpass 40:1, and the solvent usage quantity is big, and post-processing difficulty is big, is inappropriate for the industrialization operation.
Therefore, need seek the purity of the Aripiprazole of process for purification lifting efficiently according to the particular case of reaction and the character characteristics of bonded products.
Summary of the invention
The objective of the invention is to constructional feature, utilize the Aripiprazole can salify and impurity can't salifiable characteristics, in proper solvent system, product is separated the salt operation through salify, prepare highly purified Aripiprazole product according to compound.That this method has is simple to operate, yield is high, the characteristics of good product purity.
Method of the present invention is that the bullion Aripiprazole is dissolved into a kind of in organic solvent methyl alcohol, ethanol, acetone, methylene dichloride, ETHYLE ACETATE, the THF or wherein in several kinds the mixed solvent, after treating to dissolve fully, slowly adds hydrochloric acid or oxalic acid salify; Product is separated out, and suction filtration joins organic solvent N with the aripiprazole salts that obtains; Dinethylformamide, N; N-N,N-DIMETHYLACETAMIDE, water a kind of or wherein in several kinds the mixed solvent after treating to dissolve fully, stirs down; Slowly splash into 0.5%～10% strong alkali aqueous solution, regulation system pH is 8.5～9.Separate out a large amount of Aripiprazole products, suction filtration, filter cake washing.40 ℃ of dryings obtain white Aripiprazole highly finished product.
In the said method of this programme, separating the employed alkali of salt can be a kind of or its mixture in sodium hydroxide, Pottasium Hydroxide, yellow soda ash, the salt of wormwood.
The invention has the beneficial effects as follows, can under the condition of milder, obtain all higher product of productive rate and purity.
The practical implementation instance
Following embodiment is used for further illustrating the embodiment of claim, does not limit the present invention.
Embodiment 1
In 250 mL there-necked flasks, add bullion Aripiprazole 20 grams, acetone 120 mL stir, and are heated to backflow.Add 20 mL concentrated hydrochloric acids, stir half a hour, suction filtration.Filter cake is dissolved in 300 mL N, and in the dinethylformamide, temperature control stirs, and the NaOH aqueous solution of Dropwise 5 % gradually, control pH=8.5～9, and suction filtration, filter cake is washed with distilled water to neutrality, and 40 ℃ of dryings obtain white aripiprazole crystals 16 g, productive rate 80 %.
Embodiment 2
In 250 mL there-necked flasks, add bullion Aripiprazole 20 grams, THF 120 mL stir, and are heated to backflow.Add 20 mL concentrated hydrochloric acids, stir half a hour, suction filtration.Filter cake is dissolved in 300 mL N, and in the dinethylformamide, constant temperature stirs, and drips the KOH aqueous solution of 1 % gradually, control pH=8.5～9, and suction filtration, filter cake is washed with distilled water to neutrality, and 40 ℃ of dryings obtain white aripiprazole crystals 17.5g, productive rate 87.5%.
Embodiment 3
In 500 mL there-necked flasks, add bullion Aripiprazole 40.0 g, ethanol 350 mL stir, and are heated to backflow.Slowly add 16.0 g oxalic acid, stir half a hour, cooling, suction filtration.Filter cake is dissolved in 500 mL N, and in the dinethylformamide, constant temperature stirs, and the NaOH aqueous solution of Dropwise 5 % gradually; Drip to pH=8.5～9, suction filtration, filter cake is washed with distilled water to neutrality; 40 ℃ of dryings obtain white aripiprazole crystals 32.8 g, productive rate 82 %.
Embodiment 4
In 500 mL there-necked flasks, add bullion Aripiprazole 40.0 g, THF 250 mL stir, and are heated to backflow.Add 16.0 g oxalic acid, white solid is separated out, and stirs half a hour, cooling, suction filtration.Filter cake is dissolved in the 420 mL DMAC N,Ns, and 60 ℃ of constant temperature stir, and drip saturated K gradually
2CO
3The aqueous solution, control pH=8.5～9, suction filtration, filter cake is washed with distilled water to neutrality, and 40 ℃ of dryings obtain white aripiprazole crystals 31.2 g, productive rate 78 %.
Claims (5)
1. the present invention relates to a kind of novel method of refining Aripiprazole, the characteristic of this method is that the bullion Aripiprazole is joined organic solvent
IIn, after the dissolving, slowly add sour salify, suction filtration, the aripiprazole salts that obtains joins organic solvent with the gained aripiprazole salts
IIIn, after the dissolving, stirring down, the alkali aqueous solution of adding 0.5%～10% is separated salt, and regulation system pH is 8.5～9, suction filtration, the filter cake washing, 40 ℃ of dryings obtain the Aripiprazole highly finished product.
2. method according to claim 1 is characterized in that dissolving the organic solvent of Aripiprazole
IBe a kind of in methyl alcohol, ethanol, acetone, methylene dichloride, ETHYLE ACETATE, the THF or several kinds mixed solvent wherein.
3. method according to claim 1 is characterized in that the employed acid of salify is hydrochloric acid or oxalic acid.
4. method according to claim 1 is characterized in that dissolving the organic solvent of aripiprazole salts
IIBe N, dinethylformamide, DMAC N,N, water a kind of or several kinds mixed solvent wherein.
5. method according to claim 1 is separated the used alkali of salt and is in sodium hydroxide, Pottasium Hydroxide, yellow soda ash, the salt of wormwood one or more.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201210066586 CN102617461A (en) | 2012-03-14 | 2012-03-14 | Novel method for refining aripiprazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201210066586 CN102617461A (en) | 2012-03-14 | 2012-03-14 | Novel method for refining aripiprazole |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102617461A true CN102617461A (en) | 2012-08-01 |
Family
ID=46557725
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201210066586 Pending CN102617461A (en) | 2012-03-14 | 2012-03-14 | Novel method for refining aripiprazole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102617461A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102863377A (en) * | 2012-08-17 | 2013-01-09 | 南京正大天晴制药有限公司 | Method for preparing high-purity aripiprazole |
| CN105037264A (en) * | 2015-08-17 | 2015-11-11 | 苏州统华药品有限公司 | Purifying method of aripiprazole |
| CN107056787A (en) * | 2016-12-29 | 2017-08-18 | 大桐制药（中国）有限责任公司 | The synthesis technique of trapidil |
| CN108069900A (en) * | 2016-11-08 | 2018-05-25 | 齐鲁制药有限公司 | The preparation method and purposes of Aripiprazole hydrochloride |
-
2012
- 2012-03-14 CN CN 201210066586 patent/CN102617461A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102863377A (en) * | 2012-08-17 | 2013-01-09 | 南京正大天晴制药有限公司 | Method for preparing high-purity aripiprazole |
| CN105037264A (en) * | 2015-08-17 | 2015-11-11 | 苏州统华药品有限公司 | Purifying method of aripiprazole |
| CN108069900A (en) * | 2016-11-08 | 2018-05-25 | 齐鲁制药有限公司 | The preparation method and purposes of Aripiprazole hydrochloride |
| CN108069900B (en) * | 2016-11-08 | 2022-09-23 | 齐鲁制药有限公司 | Preparation method and application of aripiprazole hydrochloride |
| CN107056787A (en) * | 2016-12-29 | 2017-08-18 | 大桐制药（中国）有限责任公司 | The synthesis technique of trapidil |
| CN107056787B (en) * | 2016-12-29 | 2019-02-05 | 大桐制药（中国）有限责任公司 | The synthesis technology of trapidil |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106256824B (en) | Preparation method of high-purity delafloxacin meglumine salt | |
| CN102336647A (en) | Application of AK sugar crystal mother liquor and method for preparing sylvite by crystal mother liquor | |
| CN102617461A (en) | Novel method for refining aripiprazole | |
| CN105254544A (en) | Preparing method for bisphenol S | |
| CN102060860B (en) | Preparation method of Marbofloxacin | |
| CN101704766B (en) | Preparation method of arginine aspirin and powder-injection of arginine aspirin | |
| CN102887885B (en) | Preparation method of esomeprazole sodium | |
| CN102351778A (en) | Preparation method of arbidol hydrochloride | |
| CN103087017B (en) | Refinement method of crude potassium sodium dehydroandroan drographolide succinate product | |
| CN102146052B (en) | Method for preparing tryptophan | |
| CN102093263B (en) | Recycling method of levorotation camphorsulfonic acid serving as clopidogrel resolving agent | |
| CN103910659B (en) | Process for purification and the intermediate thereof of 2-nitro-4-methyl sulfonylbenzoic acid | |
| CN102485723A (en) | Semi-synthesis of vinpocetine through one kettle way and preparation of water-soluble vinpocetine salt | |
| CN101906032A (en) | Method for recycling L-(+)-tartaric acid | |
| CN102863426A (en) | Improved method for preparing (-)-pantoprazole sodium through Sharpless asymmetric epoxidation reaction | |
| CN102199073A (en) | Method for preparing 4,4'-dihydroxydiphenylmethane | |
| CN103922925B (en) | A kind of production technique of Fenofibric Acid | |
| CN103113294A (en) | Synthesizing method of rebamipide | |
| CN103664779A (en) | Preparation method of pefloxacin mesylate | |
| CN103113408B (en) | A kind of novel method preparing phosphonomycin fosfomycin phenylethylamine calt | |
| CN102146022B (en) | Method for preparing 3-chlorine-5-bromophenol | |
| CN104151275B (en) | The preparation method of Andrographolide compound | |
| CN102108049A (en) | Preparation method of 9-carboxyfluorene | |
| CN101823986A (en) | Preparation method for tert-butyl carbazate | |
| CN103044361B (en) | Preparation method of (2R,3S)-epoxidation amino-benzene butane |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120801 |