CN105037264A - Purifying method of aripiprazole - Google Patents
Purifying method of aripiprazole Download PDFInfo
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- CN105037264A CN105037264A CN201510504835.5A CN201510504835A CN105037264A CN 105037264 A CN105037264 A CN 105037264A CN 201510504835 A CN201510504835 A CN 201510504835A CN 105037264 A CN105037264 A CN 105037264A
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- Prior art keywords
- aripiprazole
- purification process
- mixed solvent
- crude product
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
Abstract
The invention discloses a purifying method of aripiprazole. The purifying method comprises the steps of firstly, dissolving a crude product of aripiprazole by using a mixed solvent composed of dichloromethane and isopropanol, and then, adding mixed acid to separate out a crystal; and then, dissolving the separated crystal by using a mixed solvent composed of dimethylsulfoxide and water, then, regulating the alkalinity by adding strong alkaline to separate out the crystal. The purifying method is carried out under the mild condition, so that the purity of aripiprazole is increased, and the yield of aripiprazole is increased.
Description
Technical field
The present invention relates to the technical field of Aripiprazole, particularly relate to a kind of purification process of Aripiprazole.
Background technology
Aripiprazole, has another name called for 7-{4-[4-(2,3-dichlorophenyl)-l-piperazinyl] butoxy }-3,4-dihydro-2 (1H)-quinolinones.Molecular formula is C
23h
27n
3o
2cl
2, molecular weight: 448, its outward appearance is a kind of colorless crystalline powder.Its molecular structural formula is as follows:
Aripiprazole belongs to qualone derivative, is that one is used for the treatment of fear, obsession, somnopathy, sexual dysfunction, depression, anxiety or the schizoid spiritual neurologic agent such as manic and goes on the market at multiple state approval at present.
In prior art, to the report of Aripiprazole synthetic method, preparation and various crystal formation, the preparation method's ubiquity preparation process wherein related to is complicated, yield is low, product impurity is many, purity does not reach the problems such as standards of pharmacopoeia.US Patent No. 5006528 discloses a kind of purification process of Aripiprazole, adopts ethanol to carry out twice recrystallization in the method.Although the method operation is comparatively simple, the purity of yield and product is not ideal enough.
Summary of the invention
In view of this, the invention provides a kind of purification process of Aripiprazole, the higher and yield of the purity of the refined product obtained through this purification process.
A purification process for Aripiprazole, comprises the following steps:
(1) by pending Aripiprazole dissolving crude product in the mixed solvent be made up of for 1:1 ~ 3 methylene dichloride and Virahol mass ratio, then add the mix acid liquor that is made up of for 1:2 ~ 5 trifluoroacetic acid and hydrochloric acid mol ratio to crystallize out;
(2) be dissolved in institute's crystallize out in step (1) in the mixed solvent be made up of for 1:4 ~ 8 DMSO and water mass ratio, then add highly basic and regulate pH to be 8 ~ 9 with crystallize out, this crystal dry, obtains Aripiprazole sterling.
Aforementioned, in step (1), adopt mixed solvent to be preferably 50 ~ 60 DEG C to the temperature that Aripiprazole crude product dissolves.As for the consumption of mix acid liquor and mix acid liquor, in the quality of Aripiprazole crude product for 1g, the consumption of mix acid liquor is 30 ~ 60ml, and the consumption of mixed solvent is 8 ~ 16ml.
After acid solution crystallize out, suction filtration can be adopted acid solution to be separated from liquid phase.Based on easy to operate consideration, the filter cake that suction filtration obtains, without the need to drying, is directly used as follow-up process.
In abovementioned steps (2), highly basic can be in potassium hydroxide, sodium hydroxide, sodium methylate any one or two or more.Highly basic adds as an aqueous solution, and the massfraction of described strong alkali aqueous solution is 5 ~ 10wt%
Highly basic to be employed regulates alkalescence to crystallize out, obtains crystallization by suction filtration.Again crystallization is adopted and be washed with water to neutrality, then adopt known mode to carry out drying.Dry temperature is 35 ~ 45 DEG C preferably.
In purification process of the present invention, after first the mixed solvent formed with methylene dichloride and Virahol in Aripiprazole crude product being dissolved, add mixing acid with crystallize out; Then, after the mixed solvent formed with DMSO and water in crystallization dissolves, add highly basic and regulate alkalescence with crystallization.This purification process carries out in a mild condition, improves the purity of product thus, ensure that yield.
Embodiment
Technical scheme of the present invention is further illustrated below in conjunction with embodiment.
Embodiment 1
20g Aripiprazole crude product, 160ml mixed solvent (mass ratio is methylene dichloride and the Virahol of 1:1) are inserted in 2L flask, stirs, be heated to 50 ~ 60 DEG C and reflux simultaneously.After Aripiprazole crude product dissolves completely, add 1200ml mixing acid (mol ratio is 1:5 trifluoroacetic acid and hydrochloric acid), stir half an hour, crystallize out in solution, carries out suction filtration to this solution and obtains filter cake.
Above-mentioned filter cake is dissolved in mixed solvent (mass ratio is 1:8 DMSO and water), under agitation, dripping massfraction is that 5wt% sodium hydroxide regulates pH to be 8, has crystallize out in solution.Carry out suction filtration to this solution, filter cake is washed with distilled water to neutrality.Dry cake at 35 DEG C, obtains Aripiprazole sterling 17.70g, and yield is 88.5%, and testing purity through HLPC is 99.2%.
Embodiment 2
20g Aripiprazole crude product, 320ml mixed solvent (mass ratio is methylene dichloride and the Virahol of 1:3) are inserted in 2L flask, stirs, be heated to 50 ~ 60 DEG C and reflux simultaneously.After Aripiprazole crude product dissolves completely, add 600ml mixing acid (mol ratio is 1:2 trifluoroacetic acid and hydrochloric acid), stir half an hour, crystallize out in solution, carries out suction filtration to this solution and obtains filter cake.
Above-mentioned filter cake is dissolved in mixed solvent (mass ratio is 1:4 DMSO and water), under agitation, dripping massfraction is that 10wt% sodium hydroxide regulates pH to be 9, has crystallize out in solution.Carry out suction filtration to this solution, filter cake is washed with distilled water to neutrality.Dry cake at 45 DEG C, obtains Aripiprazole sterling 18.16g, and yield is 90.8%, and testing purity through HLPC is 99.4%.
Embodiment 3
20g Aripiprazole crude product, 240ml mixed solvent (mass ratio is methylene dichloride and the Virahol of 1:3) are inserted in 2L flask, stirs, be heated to 55 DEG C and reflux simultaneously.After Aripiprazole crude product dissolves completely, add 900ml mixing acid (mol ratio is 1:5 trifluoroacetic acid and hydrochloric acid), stir half an hour, crystallize out in solution, carries out suction filtration to this solution and obtains filter cake.
Above-mentioned filter cake is dissolved in mixed solvent (mass ratio is 1:8 DMSO and water), under agitation, dripping massfraction is that 10wt% sodium hydroxide regulates pH to be 9, has crystallize out in solution.Carry out suction filtration to this solution, filter cake is washed with distilled water to neutrality.Dry cake at 40 DEG C, obtains Aripiprazole sterling 18.74g, and yield is 93.7%, and testing purity through HLPC is 99.6%.
Embodiment 4
20g Aripiprazole crude product, 240ml mixed solvent (mass ratio is methylene dichloride and the Virahol of 1:2) are inserted in 2L flask, stirs, be heated to 60 DEG C and reflux simultaneously.After Aripiprazole crude product dissolves completely, add 900ml mixing acid (mol ratio is 1:2 ~ 5 trifluoroacetic acid and hydrochloric acid), stir half an hour, crystallize out in solution, carries out suction filtration to this solution and obtains filter cake.
Above-mentioned filter cake is dissolved in mixed solvent (mass ratio is 1:4 ~ 8 DMSO and water), under agitation, dripping massfraction is that 10wt% sodium hydroxide regulates pH to be 8, has crystallize out in solution.Carry out suction filtration to this solution, filter cake is washed with distilled water to neutrality.Dry cake at 40 DEG C, obtains Aripiprazole sterling 19.08g, and yield is 95.4%, and testing purity through HLPC is 99.8%.
Because the numerical range of each processing parameter involved in the present invention can not all embody in the above-described embodiments, as long as but those skilled in the art can imagine any numerical value fallen in this numerical range above-mentioned completely all can implement the present invention, certainly also comprise the arbitrary combination of occurrence in some numerical ranges.Herein, for the consideration of length, eliminate the embodiment providing occurrence in certain one or more numerical range, this should not be considered as the insufficient disclosure of technical scheme of the present invention.
Applicant states, the present invention illustrates detailed process equipment and process flow process of the present invention by above-described embodiment, but the present invention is not limited to above-mentioned detailed process equipment and process flow process.Person of ordinary skill in the field should understand, any improvement in the present invention, to equivalence replacement and the interpolation of ancillary component, the concrete way choice etc. of each raw material of product of the present invention, all drops within protection scope of the present invention and open scope.
Claims (6)
1. a purification process for Aripiprazole, is characterized in that, comprises the following steps:
(1) by pending Aripiprazole dissolving crude product in the mixed solvent be made up of for 1:1 ~ 3 methylene dichloride and Virahol mass ratio, then add the mix acid liquor that is made up of for 1:2 ~ 5 trifluoroacetic acid and hydrochloric acid mol ratio to crystallize out;
(2) be dissolved in institute's crystallize out in step (1) in the mixed solvent be made up of for 1:4 ~ 8 DMSO and water mass ratio, then add highly basic and regulate pH to be 8 ~ 9 with crystallize out, this crystal dry, obtains Aripiprazole sterling.
2. purification process according to claim 1, is characterized in that, in step (1):
The temperature of described dissolving is 50 ~ 60 DEG C.
3. purification process according to claim 1, is characterized in that, in step (1):
The consumption of described mixed solvent is 8 ~ 16ml, in the quality of Aripiprazole crude product for 1g.
4. purification process according to claim 1, is characterized in that, in step (1):
The consumption of described mix acid liquor is 30 ~ 60ml, in the quality of Aripiprazole crude product for 1g.
5. purification process according to claim 1, is characterized in that, in step (2):
Described highly basic be in potassium hydroxide, sodium hydroxide, sodium methylate any one or two or more.
6. purification process according to claim 1, is characterized in that, in step (2):
Described highly basic adds as an aqueous solution, and the massfraction of described strong alkali aqueous solution is 5 ~ 10wt%.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008001188A2 (en) * | 2006-06-29 | 2008-01-03 | Cadila Pharmaceuticals Limited | An improved process for the preparation of substantially pure aripiprazole |
WO2008146156A2 (en) * | 2007-06-01 | 2008-12-04 | Aurobindo Pharma Limited | An improved process for the preparation of aripiprazole |
CN102617461A (en) * | 2012-03-14 | 2012-08-01 | 北京德众万全医药科技有限公司 | Novel method for refining aripiprazole |
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 |
-
2015
- 2015-08-17 CN CN201510504835.5A patent/CN105037264A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008001188A2 (en) * | 2006-06-29 | 2008-01-03 | Cadila Pharmaceuticals Limited | An improved process for the preparation of substantially pure aripiprazole |
WO2008146156A2 (en) * | 2007-06-01 | 2008-12-04 | Aurobindo Pharma Limited | An improved process for the preparation of aripiprazole |
CN102617461A (en) * | 2012-03-14 | 2012-08-01 | 北京德众万全医药科技有限公司 | Novel method for refining aripiprazole |
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 |
Non-Patent Citations (1)
Title |
---|
徐建明等: "阿立哌唑的制备工艺研究", 《药学实践杂志》 * |
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Application publication date: 20151111 |