CN101948426A - New method for preparing aripiprazole crystal form B - Google Patents
New method for preparing aripiprazole crystal form B Download PDFInfo
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- CN101948426A CN101948426A CN2010102879049A CN201010287904A CN101948426A CN 101948426 A CN101948426 A CN 101948426A CN 2010102879049 A CN2010102879049 A CN 2010102879049A CN 201010287904 A CN201010287904 A CN 201010287904A CN 101948426 A CN101948426 A CN 101948426A
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- aripiprazole
- crystal form
- acetone
- butanone
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Abstract
The invention provides a new method for preparing an aripiprazole crystal form B. The method is characterized by comprising the following steps of: dissolving aripiprazole in a mixed solvent consisting of butanone and acetone; cooling and performing crystallization; and filtering and drying to obtain the aripiprazole crystal form B, wherein the volume ratio of the butanone to the acetone is 8.8:1-1,000:1. The method provided by the invention has the advantages of capability of obtaining a product with high crystal form uniqueness, simple operation, time and energy saving and contribution to industrialized production.
Description
Technical field
The present invention relates to prepare the preparation method of a kind of dihydro quinoline ketone antipsychotic drug aripiprazole crystal form B.
Background technology
Aripiprazole (aripiprazole), it is a kind of dihydro quinoline ketone antipsychotic drug, be used for the treatment of various acute and chronic schizophrenia and schizoaffective disorders, chemistry 7-[4-[4-(2 by name, the 3-dichlorophenyl) piperazine-1-yl] butoxy-3,4-dihydro-1H-quinoline-4-ketones, structural formula is suc as formula shown in (I):
WO03026659 (CN1463191) discloses A, B, C, D, E, F, six kinds of anhydrous aripiprazole crystal formations of G and preparation method thereof.Wherein crystal form B is a kind of preferred crystalline form, has good stability, advantage that water absorbability is low.Crystal form B has characteristic peak in 2 θ=11.0 °, 16.6 °, 19.3 °, 20.3 °, X-ray diffraction spectrum and IR (KBr) with 22.1 °, described in this specification sheets that the Aripiprazole crude product is obtained the Aripiprazole monohydrate crystal form A with the ethyl alcohol recrystallization that contains 20% water, 100 ℃ of dryings 18 hours, obtained aripiprazole crystal form B in 3 hours 120 ℃ of heating then again.Because this method will be changeed crystal formation after wanting earlier water to be dried fully again by preparing aqueous crystal form A earlier, and is not only consuming time but also consume energy, and is not suitable for industrialized production.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of aripiprazole crystal form B simple to operate.
Method provided by the invention is as follows: in the mixed solvent of being made up of butanone and acetone, cooling crystallization filters, drying obtains aripiprazole crystal form B with the Aripiprazole dissolving crude product, and the volume ratio of wherein said butanone and acetone is 8.8: 1～1000: 1.
Wherein the Aripiprazole crude product can be pure product or crude product according to Chinese patent CN1028104C or Chinese invention patent application CN1504461A preparation; Also can be various crystal formations, as A, B, C, D, E, F, G or their mixture etc. of being set forth among the WO03026659.
The employed mixed solvent of crystallization wherein, the volume ratio of butanone and acetone more preferably 9: 1～25: 1.
Every gram Aripiprazole crude product is preferably dissolved in 4～50 milliliters of above-mentioned mixed solvents, and further preferred 5～20 milliliters of above-mentioned mixed solvents most preferably are 6～10 milliliters of above-mentioned mixed solvents.
Generally, be heated to the reflux temperature of mixed solvent, make the Aripiprazole dissolving crude product complete.
In cooling crystallization process of the present invention, rate of temperature fall and stirring there are not strict especially requirement, rate of temperature fall can be that per minute descends 1～60 ℃, stir speed (S.S.) can be elected 10～900 rev/mins of per minutes as, perhaps adopts the mode that leaves standstill crystallization.
Drying process is preferably carried out under vacuum, and drying temperature is controlled in 40～50 ℃ of scopes and gets final product, and is about 3～5 hours time of drying.
Method provided by the invention, products obtained therefrom crystal formation unicity is good, and simple to operate, and the province's energy that saves time is very beneficial for suitability for industrialized production.
Description of drawings
Fig. 1 is the X-ray powder diffraction of aripiprazole crystal form B provided by the invention;
Fig. 2 is the IR collection of illustrative plates of aripiprazole crystal form B provided by the invention;
Fig. 3 is the DSC collection of illustrative plates of aripiprazole crystal form B provided by the invention;
Write down the X-ray powder diffraction by following condition:
Detecting instrument: rotating anode target 12KW X ray polycrystalline diffracted ray D/max-2500pc.
Detect foundation: JY/T009-1996.
Sense environmental conditions: 20 ℃ of room temps; Relative humidity＜60%.
Light source: Cu K α line,
Slit: DS:1 °, SS:1 °, R
s: 0.15mm, Rsm:0.8mm.
Sweep limit 2 θ (°): 3.0 °～50.0 °.
Scan mode: stepping.
Scanning step: 0.02 °.
Cumulative time: 0.5s/step.
Pipe is pressed: 40kv.
Pipe stream: 250mA.
Rear-mounted graphite monochromator, data processing Jade 7.0 software packages.
Write down the IR collection of illustrative plates by following condition:
Detecting instrument: Nicolet 380
Detection method: pellet technique
Write down the DSC collection of illustrative plates by following condition:
Detecting instrument: METTLER DSC 822
Detection method: use the aluminium crucible, under nitrogen purging,, scan 250 ℃ from 50 ℃ with the temperature rise rate of 10 ℃/min.
Embodiment
Reference example: the preparation of Aripiprazole crude product
Add 3 to reaction flask, 4-dihydro-7-(4-chlorine butoxy)-2 (1H)-quinolinone 40g, 1-(2, the 3-dichlorophenyl) piperazine hydrochloride 46.4g, salt of wormwood 24g, acetonitrile 400ml, sodium iodide 9.6g reflux, TLC follows the tracks of, and stops heating after reacting completely, and steams solvent.Add 400ml water in residuum, stir 1 hour after-filtration, filter cake washs with suitable quantity of water.Filter cake is transferred in the another one reaction flask, adds dehydrated alcohol 400ml, gac 3.2g, reflux 30 minutes, filtered while hot, filtrate are cooled to 0～5 ℃, filter, and it is clear to add thermosol with 400ml ethanol again, be cooled to 0～5 ℃, filter, oven dry obtains the Aripiprazole crude product.
Embodiment 1: the preparation of aripiprazole crystal form B
Get Aripiprazole crude product 36 gram, add butanone 220ml, acetone 22.5ml is heated to and refluxes molten clearly, is cooled to 0～5 ℃, filters, and 40～50 ℃ of following vacuum-dryings 3～5 hours, collects and obtains aripiprazole crystal form B 32.6 grams, yield 90.6%.
The crystal form B that obtains according to the inventive method has following physico-chemical property:
Melting range is 136.5～140.5 ℃.
Differential thermal analysis (DSC) collection of illustrative plates near 137.0 ℃, have an endotherm(ic)peak (heating rate be 10 ℃/min).
Infared spectrum 2946,2811,1677,1627,1595,, 1490,1382,1241,1198,1173,960,857,778cm
-1Strong absorption peak is arranged.
It is 11.0 ± 0.2 °, 16.6 ± 0.2 °, 19.3 ± 0.2 °, 20.3 ± 0.2 °, 22.1 ± 0.2 ° that powder x-ray diffraction is composed 2 θ corner characteristics peaks.
Embodiment 2: the preparation of aripiprazole crystal form B
Get Aripiprazole crude product 36 gram, add butanone 250ml, acetone 10ml is heated to and refluxes molten clearly, is cooled to 0～5 ℃, filters, and 40～50 ℃ of following vacuum-dryings 3～5 hours, collects and obtains aripiprazole crystal form B 32.0 grams, yield 88.9%.
Claims (5)
1. method for preparing aripiprazole crystal form B, it is characterized in that: with the Aripiprazole dissolving crude product in the mixed solvent of forming by butanone and acetone, cooling crystallization, filtration, drying obtain aripiprazole crystal form B, and the volume ratio of wherein said butanone and acetone is 8.8: 1～1000: 1.
2. method according to claim 1, wherein the volume ratio of butanone and acetone be preferably 9: 1～25: 1.
3. method according to claim 1 is in 5～20 milliliters of described mixed solvents of wherein every gram Aripiprazole crude product preferred dissolution.
4. method according to claim 3 is in 6～10 milliliters of described mixed solvents of wherein every gram Aripiprazole crude product preferred dissolution.
5. method according to claim 1, wherein drying process is preferably carried out under vacuum, and drying temperature is at 40～50 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102879049A CN101948426A (en) | 2010-09-13 | 2010-09-13 | New method for preparing aripiprazole crystal form B |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102879049A CN101948426A (en) | 2010-09-13 | 2010-09-13 | New method for preparing aripiprazole crystal form B |
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| CN101948426A true CN101948426A (en) | 2011-01-19 |
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| CN2010102879049A Pending CN101948426A (en) | 2010-09-13 | 2010-09-13 | New method for preparing aripiprazole crystal form B |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670533A (en) * | 2012-05-17 | 2012-09-19 | 浙江华海药业股份有限公司 | Stable aripiprazole orally-disintegrating tablets and preparation method thereof |
| CN104072416A (en) * | 2013-03-26 | 2014-10-01 | 江苏恩华药业股份有限公司 | Method of preparing B-type aripiprazole crystal |
| CN104230799A (en) * | 2013-06-21 | 2014-12-24 | 江苏豪森药业股份有限公司 | Method for preparing aripiprazole crystal |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003026659A1 (en) * | 2001-09-25 | 2003-04-03 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
| CN1618791A (en) * | 2003-11-21 | 2005-05-25 | 上海特化医药科技有限公司 | New synthesis method of alipirazole |
| WO2005058835A2 (en) * | 2003-12-16 | 2005-06-30 | Teva Pharmaceutical Industries Ltd. | Methods of preparing aripiprazole crystalline forms |
| CN1676517A (en) * | 2004-04-02 | 2005-10-05 | 北京德众万全药物技术开发有限公司 | Aripiprazole crystal form |
| CN101333189A (en) * | 2007-06-29 | 2008-12-31 | 成都康弘药业集团股份有限公司 | Aripiprazole crystal form suitable for pharmaceutical use, preparation method and pharmaceutical compositions |
-
2010
- 2010-09-13 CN CN2010102879049A patent/CN101948426A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003026659A1 (en) * | 2001-09-25 | 2003-04-03 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
| CN1618791A (en) * | 2003-11-21 | 2005-05-25 | 上海特化医药科技有限公司 | New synthesis method of alipirazole |
| WO2005058835A2 (en) * | 2003-12-16 | 2005-06-30 | Teva Pharmaceutical Industries Ltd. | Methods of preparing aripiprazole crystalline forms |
| CN1676517A (en) * | 2004-04-02 | 2005-10-05 | 北京德众万全药物技术开发有限公司 | Aripiprazole crystal form |
| CN101333189A (en) * | 2007-06-29 | 2008-12-31 | 成都康弘药业集团股份有限公司 | Aripiprazole crystal form suitable for pharmaceutical use, preparation method and pharmaceutical compositions |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102670533A (en) * | 2012-05-17 | 2012-09-19 | 浙江华海药业股份有限公司 | Stable aripiprazole orally-disintegrating tablets and preparation method thereof |
| CN102670533B (en) * | 2012-05-17 | 2017-06-16 | 浙江华海药业股份有限公司 | Aripiprazole orally disintegrating tablet of stabilization and preparation method thereof |
| CN104072416A (en) * | 2013-03-26 | 2014-10-01 | 江苏恩华药业股份有限公司 | Method of preparing B-type aripiprazole crystal |
| CN104072416B (en) * | 2013-03-26 | 2017-06-20 | 江苏恩华药业股份有限公司 | A kind of method for preparing aripiprazole crystals B |
| CN104230799A (en) * | 2013-06-21 | 2014-12-24 | 江苏豪森药业股份有限公司 | Method for preparing aripiprazole crystal |
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Application publication date: 20110119 |