CN103554105A - 9-hydroxyl risperidone purifying method - Google Patents
9-hydroxyl risperidone purifying method Download PDFInfo
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- CN103554105A CN103554105A CN201310533393.8A CN201310533393A CN103554105A CN 103554105 A CN103554105 A CN 103554105A CN 201310533393 A CN201310533393 A CN 201310533393A CN 103554105 A CN103554105 A CN 103554105A
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- risperidone
- hydroxy
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- carbonyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The 9-site secondary hydroxyl in 9-hydroxyl risperidone is easily oxidized under certain conditions to become 9-carbonyl risperidone, and the impurity influences the purity and appearance of a product. The invention discloses a method for reducing the content of 9-carbonyl risperidone to improve the product purity, namely, reducing 9-carbonyl risperidone to generate 9-hydroxyl risperidone again. The method greatly improves the appearance color of the product, is simple and convenient to operate, and avoids the shortcoming that other methods need multiple times of refining to meet the requirement.
Description
Technical field
The present invention relates to pharmaceutical chemistry, be specifically related to a kind of purification process of antischizophrinic thing paliperidone.
Background technology
9-hydroxy-risperidone, have another name called paliperidone, chemistry 3-[2-[4-(6-fluorobenzene is [d] isoxazole-3-base also)-piperidino by name] ethyl]-7-hydroxy-4-methyl-1,5-diazabicyclo [4.4.0] last of the ten Heavenly stems-3,5-diene-2-ketone, being a kind of novel treatment schizophrenia drug, belonging to the 5-HT antagonist of benzisoxazole derivatives class, itself is the active metabolite of risperidone.Its structural formula is
Relevant paliperidone preparation method's report is a lot, current most study be to use the fluoro-3-of 6-(4 piperidyl)-1 for the method for preparation of industrialization, 2-benzoisoxazole and 3-(2-chloroethyl)-6,7,8,9-tetrahydrochysene-9-hydroxyl 2-methyl-4H-pyrido [1,2-a]-pyrimidin-4-one is as raw material, both carry out condensation reaction under certain condition and obtain 9-hydroxy-risperidone, see following reaction formula:
By this kind of method, prepare 9-hydroxy-risperidone relatively easy and simple to handle, control condition is not harsh, and yield is higher, is the method for the most widely using at present.But due to the existence of 9 secondary hydroxyls in 9-hydroxy-risperidone structure, this hydroxyl is easily oxidized under certain conditions to make 9-hydroxy-risperidone, becomes 9-carbonyl risperidone.Generally, the content of this impurity is between 0.6-1.2%, although content is not high, due to its existence, not only affects purity and the content of product, and this impurity is deep yellow simultaneously, and the existence of a small amount of impurity all affects the color of product greatly.Reduce the content of this impurity, the appearance color that improves the purity of product and improve product has great importance.
The main method that improves at present 9-hydroxy-risperidone product purity has three classes:
The one, the 9-hydroxy-risperidone crude product that reaction is obtained is directly refined, the method adopting as ZL200880015395.5, from being selected from mixture, the acetic acid C of mixture, acetonitrile, acetonitrile and water of mixture, N-Methyl pyrrolidone, C3-6 acid amides, halo C 6-12 aromatic hydrocarbons, propylene glycol, methyl-sulphoxide, methylcarbonate, C1-4 alkyl alcohol, C1-4 alkyl alcohol and the water of C3-6 ketone, C3-6 ketone and water
2-6alkyl ester, acetic acid C
2-6the mixture of alkyl ester and water, cellosolve, methylcarbonate, polyethylene glycol monomethyl ether and C
2-8crystallization 9-hydroxy-risperidone at least one solvent of ether.
The second way, is 9-hydroxy-risperidone crude product and organic acid, mineral acid first to be formed to the salt of 9-hydroxy-risperidone, and the salt obtaining dissolves, adjusts alkali, extraction, mode concentrated and crystallization to obtain highly purified 9-hydroxy-risperidone in organic solvent.For example, in ZL200980151744.0, thick product 9-hydroxy-risperidone is dissolved in methyl alcohol, add the oxalic acid that is dissolved in methyl alcohol, filtering for crystallizing material, by methanol wash, obtain the 9-hydroxy-risperidone oxalate of colorless solid, by 2.0M ammonium hydroxide, process, dichloromethane extraction, uses salt water washing, use dried over sodium sulfate organic extract, and simmer down to solid residue.9-hydroxy-risperidone is optionally used acetonitrile recrystallization.
The third mode, described in US2010267954 etc., by 9-hydroxy-risperidone crude product first and the salt of organic acid, mineral acid formation 9-hydroxy-risperidone, the salt obtaining is soluble in water, after the immiscible with water solvent extraction partial impurities such as methylene dichloride or ethyl acetate, the aqueous solution of 9-hydroxy-risperidone salt adjusts alkali, extraction, mode concentrated and crystallization to obtain highly purified 9-hydroxy-risperidone again.
By above mode, all can be met the 9-hydroxy-risperidone of specification of quality, but owing to containing more 9-carbonyl risperidone, to the purifying of 9-hydroxy-risperidone, all there are some shortcomings in these methods, first kind of way need to just can be taken the qualified samples such as related substance and appearance color by crystallization repeatedly, latter two mode is by operations such as acid adjustment, tune alkali, extraction, concentrated even repeatedly crystallizations, complex operation needs to use a large amount of organic solvents simultaneously.
In sum, there is complex operation, use a large amount of solvents, be difficult for the shortcomings such as purifying in the method for the purifying paliperidone of bibliographical information at present, therefore develops a kind of method easy and simple to handle, that significantly reduce 9-carbonyl risperidone impurity in paliperidone and be necessary.
Summary of the invention
For solving above technical problem, the invention provides a kind of method of high yield, high purity, purifying paliperidone easy and simple to handle.
Goal of the invention of the present invention is achieved through the following technical solutions, the 9-carbonyl risperidone soon obtaining due to oxidative degradation in preparing 9-hydroxy-risperidone process regenerates 9-hydroxy-risperidone through reduction, by which, can greatly reduce the content of 9-carbonyl risperidone in product, improve the appearance color of product simultaneously.
Concrete step is:
1, reduction: 9-hydroxy-risperidone crude product is placed in to a certain amount of organic solvent, water and organic monoacid mixed system, form the system of 9-hydroxy-risperidone salt, heating for dissolving, in system, add alkaline ammonium hydroxide again, form buffer system, be cooled to room temperature, in system, add reductive agent, stirring reaction.
2, adjust alkali: finish after reaction, control temperature at 0-10
oc, slowly drips the aqueous solution of mineral alkali wherein under stirring, the pH of regulation system is 8-9, obtain the 9-hydroxy-risperidone of white solid state, after dropwising, in this temperature, stir 1h, filter, the solid matter obtaining washs three times with the mixed solvent of polar solvent and water, and the solid obtaining is 9-hydroxy-risperidone.
3, refining: the 9-hydroxy-risperidone that above-mentioned steps obtains is dissolved in the mixed solvent of polar organic solvent and water, and reflux to solid materials all dissolves, reflux, cooling, at this temperature, stir, obtain white solid crystal material, filter and obtain highly purified 9-hydroxy-risperidone.
Total purity of the 9-hydroxy-risperidone obtaining by aforesaid method is at least about 99%, and more preferably at least 99.5%, most preferably be at least about 99.9%.The purifying of this invention is taked reduction, alkalization and the operation such as refining, step has been improved the color outward appearance of product and the content that reduces 9-carbonyl risperidone simply, greatly, has avoided having used a large amount of organic solvents to concentrate, repeatedly refine and just can take the shortcomings such as highly purified 9-hydroxy-risperidone in previous methods simultaneously.
The organic solvent using in above-mentioned preparation method's reduction step is C
1-4alcohol, C
3-6ketone, C
2-8ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane etc., be preferably methyl alcohol, ethanol, Virahol and tetrahydrofuran (THF).
The organic acid of mentioning in above-mentioned preparation method's reduction step or mineral acid are hydrochloric acid, sulfuric acid, C
1-4acid, oxalic acid etc., be preferably formic acid and acetic acid, and 9-hydroxy-risperidone is by the salt with these acid combination formation 9-hydroxy-risperidones, in being soluble in the aqueous phase.
In above-mentioned preparation method's reduction step, reductive agent is the alkali metal borohydrides such as sodium borohydride, lithium borohydride, POTASSIUM BOROHYDRIDE, the mixture of above-mentioned alkali metal borohydride and aluminum chloride, lithium chloride, iodine etc.; And tetrahydrofuran solution of borine, borine dimethyl sulphide etc.
The alkaline solution adding in above-mentioned preparation method's alkalinization step is preferably the aqueous solution of ammoniacal liquor, sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide.While dripping basic solvent, the temperature of the hierarchy of control is at 0-10
oc, avoids under alkaline condition, producing impurity because of excess Temperature.
Polar organic solvent in above-mentioned preparation method's crystallisation step is C
1-4alcohol and C
3-6ketone, is preferably methyl alcohol, ethanol, acetone, and the ratio of organic solvent and water is preferably 0.5-20:1, and more preferably 1-10:1, most preferably is 3:1, and the cumulative volume of solvent is preferably 15-50 times of 9-hydroxy-risperidone weight.By final crystallization operation, can obtain purity up to more than 99.9% 9-hydroxy-risperidone.
This invention is with respect to the advantage of additive method:
By simple reduction reaction, can remove very efficiently the 9-carbonyl risperidone that oxidative degradation produces in reaction, in product after processing by above method, the content of 9-carbonyl risperidone is all below 0.10%, also greatly improve the appearance color of product, avoid additive method repeatedly to refine just and can meet the requirements of shortcoming.
Form is described in further detail content of the present invention more by the following examples, but should not be interpreted as in the above-mentioned subject area of the present invention at this point and only limit to following examples.Do not departing under the above-mentioned technology prerequisite of the present invention, the corresponding replacement of making according to ordinary skill knowledge and customary means or the modification of change, include within the scope of the invention
.
embodiment mono-
Accurately take 9-hydroxy-risperidone crude product (213.4 g, 0.5 mol, the 9-carbonyl risperidone containing 0.4%), Virahol 1300 mL, water 1300 mL and acetic acid (35.7 g, 0.6 mol) and, in the three-necked bottle of 5000 mL, be warming up to 50
oC, stirring and dissolving.Mixture is cooled to 30
oC, add the ammoniacal liquor (61.4 mL, 0.123 mol) of 2 M and 40 mL sodium borohydride solutions (0.53 mL Virahol+5, mL water+100, g sodium borohydride+100 droplet 10% sodium hydroxide).Mixture stirs 30 minutes under 30 degree.Then, the ammoniacal liquor of 2M (237 mL, 0.47 mol) adds, and suspension liquid stirs 1h, filters, and the mixing solutions washing of isopropanol/water, obtains 181.4 g 9-hydroxy-risperidones.
9-hydroxy-risperidone obtained above is added in the mixed solvent of 2700 mL ethanol and 900 mL water, and reflux to solid materials all dissolves, and 1 h that refluxes, is slowly chilled to 0-5
oC, at this temperature, stir 16h, obtain white solid crystal material, filter, obtain highly purified 9-hydroxy-risperidone, dry and obtain product 166.4 g.9-carbonyl risperidone does not detect.
embodiment bis-
Accurately take 9-hydroxy-risperidone crude product (100.4 g, 0.23 mol, the 9-carbonyl risperidone containing 0.7%), ethanol 500 mL, water 500 mL and formic acid (12.7 g, 0.27 mol) and, in the three-necked bottle of 3000 mL, be warming up to 60
oC, stirring and dissolving.Mixture is cooled to 25-30
oC, add the ammoniacal liquor (28.8 mL, 0.057 mol) of 2 M and POTASSIUM BOROHYDRIDE (0.30 g, 0.005 mol) mixture under 30 degree, to stir 30 minutes.Then, add sodium bicarbonate (34.0g, 0.40 mol), suspension liquid stirs 1h, filters, and the mixing solutions washing of isopropanol/water, obtains 92.0 g 9-hydroxy-risperidones.
9-hydroxy-risperidone obtained above is added in the mixed solvent of 1380mL acetone and 460 mL water, and reflux to solid materials all dissolves, and 1 h that refluxes, is slowly chilled to 0-5
oC, at this temperature, stir 16h, obtain white solid crystal material, filter, obtain highly purified 9-hydroxy-risperidone, dry and obtain product 86.3g.9-carbonyl risperidone content is 0.05%.
embodiment tri-
Accurately take 9-hydroxy-risperidone crude product (100.0 g, 0.23 mol, the 9-carbonyl risperidone containing 0.7%), tetrahydrofuran (THF) 800 mL, water 300 mL and formic acid (12.7 g, 0.27 mol) and, in the three-necked bottle of 3000 mL, be warming up to 60
oC, stirring and dissolving.Mixture is cooled to 25-30
oC, add the ammoniacal liquor (28.8 mL, 0.057 mol) of 2 M and borine tetrahydrofuran solution (1.2 mL, the 0.0012 mol) mixture of 1.0M under 30 degree, to stir 30 minutes.Then, add sodium bicarbonate (34.0g, 0.40 mol), suspension liquid stirs 1h, filters, and the mixing solutions washing of isopropanol/water, obtains 91.2g 9-hydroxy-risperidone.
9-hydroxy-risperidone obtained above is added in the mixed solvent of 130mL acetone and 450 mL water, and reflux to solid materials all dissolves, and 1 h that refluxes, is slowly chilled to 0-5
oC, at this temperature, stir 16 h, obtain white solid crystal material, filter, obtain highly purified 9-hydroxy-risperidone, dry and obtain product 85.3g.In product, 9-carbonyl risperidone content is 0.03%.
Claims (8)
1. a method that reduces 9-carbonyl risperidone content in paliperidone, concrete technical scheme realizes by following steps, and a small amount of 9-carbonyl risperidone that is about to exist in paliperidone regenerates paliperidone through reduction:
.
2. the method for purifying paliperidone according to claim 1, specifically carry out as follows:
(1) reduction: 9-hydroxy-risperidone crude product is placed in to a certain amount of organic solvent, water and organic monoacid mixed system, form the system of 9-hydroxy-risperidone salt, heating for dissolving, in system, add alkaline ammonium hydroxide again, form buffer system, be cooled to room temperature, in system, add reductive agent, stirring reaction;
(2) adjust alkali: control temperature at 0-10
oc, slowly drips the aqueous solution of mineral alkali wherein under stirring, the pH of regulation system is 8-9, obtains the 9-hydroxy-risperidone of white solid state, after dropwising, in this temperature, stirs 1h, filters, and the solid obtaining is 9-hydroxy-risperidone;
(3) refining: the 9-hydroxy-risperidone that above-mentioned steps obtains is dissolved in the mixed solvent of polar organic solvent and water, and reflux to solid materials all dissolves, reflux, cooling, at this temperature, stir, obtain white solid crystal material, filter and obtain highly purified 9-hydroxy-risperidone.
3. the organic solvent using in above-mentioned preparation method's reduction step according to claim 2 is C
1-4alcohol, C
3-6ketone, C
2-8ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane etc., be preferably methyl alcohol, ethanol, Virahol and tetrahydrofuran (THF).
4. organic acid or the mineral acid in above-mentioned preparation method's reduction step according to claim 2, mentioned are hydrochloric acid, sulfuric acid, C
1-4acid, oxalic acid etc., be preferably formic acid and acetic acid.
5. in above-mentioned preparation method's reduction step according to claim 2, reductive agent is the mixture of the alkali metal borohydrides such as sodium borohydride, lithium borohydride, POTASSIUM BOROHYDRIDE, above-mentioned alkali metal borohydride and aluminum chloride, lithium chloride, iodine etc., tetrahydrofuran solution of borine, borine dimethyl sulphide etc.
6. according to the requirement of claims 2 or 6, in above-mentioned preparation method's reduction step the consumption of reductive agent be substrate 9-carbonyl risperidone amount 1.0-10.0 doubly, be preferably 1.5-3.0 doubly.
7. the alkaline solution adding in above-mentioned preparation method's alkalinization step according to claim 2 is preferably the aqueous solution of ammoniacal liquor, sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide.
8. the polar organic solvent in above-mentioned preparation method's crystallisation step according to claim 2 is C
1-4alcohol and C
3-6ketone, is preferably methyl alcohol, ethanol, acetone, and the ratio of organic solvent and water is preferably 0.5-20:1, and more preferably 1-10:1, most preferably is 3:1, and the cumulative volume of solvent is preferably 15-50 times of 9-hydroxy-risperidone weight, and more preferably 20-30 doubly.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110256425A (en) * | 2019-07-08 | 2019-09-20 | 华裕(无锡)制药有限公司 | A kind of synthesis technology of palmitinic acid 9-hydroxy-risperidone |
| CN116678982A (en) * | 2023-08-01 | 2023-09-01 | 济南辰欣医药科技有限公司 | Detection method of paliperidone palmitate impurity SM1-G |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009118655A2 (en) * | 2008-03-27 | 2009-10-01 | Actavis Group Ptc Ehf | Highly pure paliperidone or a pharmaceutically acceptable salt thereof substantially free of keto impurity |
| WO2010004578A2 (en) * | 2008-06-16 | 2010-01-14 | Msn Laboratories Limited | Novel and improved processes for the preparation of paliperidone |
| WO2010003703A2 (en) * | 2008-07-11 | 2010-01-14 | Synthon B.V. | Paliperidone ketone |
| WO2011030224A2 (en) * | 2009-09-10 | 2011-03-17 | Actavis Group Ptc Ehf | Paliperidone or a pharmaceutically acceptable salt thereof substantially free of impurities |
-
2013
- 2013-11-04 CN CN201310533393.8A patent/CN103554105A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009118655A2 (en) * | 2008-03-27 | 2009-10-01 | Actavis Group Ptc Ehf | Highly pure paliperidone or a pharmaceutically acceptable salt thereof substantially free of keto impurity |
| WO2010004578A2 (en) * | 2008-06-16 | 2010-01-14 | Msn Laboratories Limited | Novel and improved processes for the preparation of paliperidone |
| WO2010003703A2 (en) * | 2008-07-11 | 2010-01-14 | Synthon B.V. | Paliperidone ketone |
| WO2011030224A2 (en) * | 2009-09-10 | 2011-03-17 | Actavis Group Ptc Ehf | Paliperidone or a pharmaceutically acceptable salt thereof substantially free of impurities |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110256425A (en) * | 2019-07-08 | 2019-09-20 | 华裕(无锡)制药有限公司 | A kind of synthesis technology of palmitinic acid 9-hydroxy-risperidone |
| CN116678982A (en) * | 2023-08-01 | 2023-09-01 | 济南辰欣医药科技有限公司 | Detection method of paliperidone palmitate impurity SM1-G |
| CN116678982B (en) * | 2023-08-01 | 2023-10-27 | 济南辰欣医药科技有限公司 | Detection method of paliperidone palmitate impurity SM1-G |
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Application publication date: 20140205 |