CN104557915A - Method for preparing high-purity paliperidone II crystal form - Google Patents
Method for preparing high-purity paliperidone II crystal form Download PDFInfo
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- CN104557915A CN104557915A CN201410718481.XA CN201410718481A CN104557915A CN 104557915 A CN104557915 A CN 104557915A CN 201410718481 A CN201410718481 A CN 201410718481A CN 104557915 A CN104557915 A CN 104557915A
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- hydroxy
- risperidone
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- PMXMIIMHBWHSKN-UHFFFAOYSA-N CC(N=C1N2CCCC1O)=C(CCN(CC1)CCC1c1n[o]c3c1ccc(F)c3)C2=O Chemical compound CC(N=C1N2CCCC1O)=C(CCN(CC1)CCC1c1n[o]c3c1ccc(F)c3)C2=O PMXMIIMHBWHSKN-UHFFFAOYSA-N 0.000 description 1
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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
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a method for preparing a high-purity paliperidone II crystal form. The method comprises the following steps: re-crystallizing a paliperidone crude product by adopting a mixed solvent of tetrahydrofuran and water to obtain a high-purity paliperidone mixed crystal product; stirring the high-purity paliperidone mixed crystal product in hot water, then filtering, and drying to obtain a high-purity paliperidone II crystal form product. According to the method disclosed by the method, impurities particularly oxide impurities in the paliperidone crude product can be effectively removed, and the purity of the obtained paliperidone is more than 99.5%.
Description
Technical field
The present invention relates to the preparation method of compound, particularly relate to a kind of method preparing high purity 9-hydroxy-risperidone II crystal formation
Background technology
9-hydroxy-risperidone, chemical name: (9RS)-3-[2-[4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-)-piperidino]-ethyl]-6,7,8,9-tetrahydrochysene-9-hydroxy-2-methyl-4H-pyrido [1,2-α] pyrimidin-4-one is the schizoid medicine for the treatment of of Johnson Co.'s research and development, go on the market in December, 2006 in the U.S., commodity are called " Invega ", and in September, 2008, " Rui Da " of Xi'an Janssen Pharmaceutica pharmaceutical Co. Ltd is in Discussion on Chinese Listed.Its molecular formula: C
23h
27fN
4o
3, molecular weight: 426.48, structural formula is shown below:
9-hydroxy-risperidone II crystal formation is the one of 9-hydroxy-risperidone crystal, and feature diffract spectral line diffraction angle 2 θ of its II crystal formation 9-hydroxy-risperidone is (± 0.2 °): 8.1,10.3,13.1,13.7,14.6,14.9,16.2,18.6,19.2,20.0,20.6,22.0,24.6,25.0,27.9,31.2.
The method of the existing II of preparation crystal formation 9-hydroxy-risperidone is obtain with solvent recrystallization substantially, especially in the majority with alcoholic solvent, but, the existing method yield preparing II crystal formation 9-hydroxy-risperidone is on the low side, finished product impurity is larger, particularly oxidation impurities is comparatively large, because of similar, there is the problem being difficult to remove.
Summary of the invention
The object of the invention is: a kind of method preparing high purity 9-hydroxy-risperidone I I crystal is provided.The present invention effectively can remove the impurity in 9-hydroxy-risperidone crude product, especially oxidation impurities, and the 9-hydroxy-risperidone purity obtained is greater than 99.5%; Also there is green, safety, environmental protection, the feature that pollution-free, yield is high simultaneously.
Object of the present invention realizes by following technical proposal: a kind of method preparing high purity 9-hydroxy-risperidone II crystal formation, and the method comprises the following steps;
(1) 9-hydroxy-risperidone crude product is adopted the mixed solvent recrystallization of tetrahydrofuran (THF) and water, the weight ratio of 9-hydroxy-risperidone crude product and mixed solvent is 1:5 ~ 20, and the weight ratio of tetrahydrofuran (THF) and water is 1 ~ 5:1, obtains highly purified Pa Lipai ketone mixed crystal product;
(2) by highly purified Pa Lipai ketone mixed crystal product, stir 2 ~ 10 hours in the hot water of 50 ~ 100 DEG C, the weight ratio of highly purified Pa Lipai ketone mixed crystal product and water is 1:5 ~ 20, and filtration, drying, obtain finished product.
Above-mentioned prepares in the method for high purity 9-hydroxy-risperidone II crystal formation, in step (1), 9-hydroxy-risperidone crude product is adopted the mixed solvent recrystallization of tetrahydrofuran (THF) and water, be that the mixed solvent of 9-hydroxy-risperidone crude product with tetrahydrofuran (THF) and water is mixed, be heated to 60 ~ 70 DEG C, after solution is clarified completely, be cooled to 0 ~ 50 DEG C of crystallization, filter, dry, obtain highly purified Pa Lipai ketone mixed crystal product.
Aforesaidly prepare in the method for high purity 9-hydroxy-risperidone II crystal formation, in step (1), described 9-hydroxy-risperidone crude product and the weight ratio of mixed solvent are 1:10.
Aforesaidly prepare in the method for high purity 9-hydroxy-risperidone II crystal formation, in step (1), the part by weight of tetrahydrofuran (THF) and water is 3:1.
Aforesaidly prepare in the method for high purity 9-hydroxy-risperidone II crystal formation, in step (1), be cooled to 20 ~ 30 DEG C of crystallizations.
Aforesaidly prepare in the method for high purity 9-hydroxy-risperidone II crystal formation, in step (2), stir after 2 ~ 10 hours in the hot water of 50 ~ 100 DEG C, treat that solution is cooled to 20 ~ 90 DEG C and filters.
Aforesaidly prepare in the method for high purity 9-hydroxy-risperidone II crystal formation, in step (2), stir after 2 ~ 10 hours in the hot water of 50 ~ 100 DEG C, treat that solution is cooled to 50 ~ 60 DEG C and filters.
Aforesaidly prepare in the method for high purity 9-hydroxy-risperidone II crystal formation, in step (2), stir 2 ~ 10 hours in the hot water of 60 ~ 80 DEG C.
Compared with prior art, present invention improves over preparation section and the parameter of 9-hydroxy-risperidone II crystal formation, many factors synergy, make the present invention effectively can remove impurity in 9-hydroxy-risperidone crude product, especially oxidation impurities, improves the purity of finished product greatly; Meanwhile, the crystalline substance that turns of 9-hydroxy-risperidone uses water as solvent, and completely not with an organic solvent, green, safety, environmental protection, pollution-free, yield is high, and can realize suitability for industrialized production.According to applicant's test, the II crystal formation 9-hydroxy-risperidone purity obtained by the present invention can reach more than 99.5%.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction of 9-hydroxy-risperidone II crystal formation;
Fig. 2 is 9-hydroxy-risperidone II crystal formation infared spectrum;
Fig. 3 is the X-ray powder diffraction of 9-hydroxy-risperidone mixed crystal;
Fig. 4 is 9-hydroxy-risperidone mixed crystal infared spectrum.
Embodiment
The preparation of highly purified Pa Lipai ketone mixed crystal product (as shown in Figure 3, its infared spectrum is as shown in Figure 4 for its X-ray powder diffraction):
Embodiment 1: by 100g 9-hydroxy-risperidone crude product (content about 97%, lower same) be placed in reaction flask, add 750g tetrahydrofuran (THF) and 250g water, be heated to 60 ~ 70 degree, completely after clarification, be cooled to 20 ~ 30 degree, filter, gained solid drying obtains 9-hydroxy-risperidone mixed crystal product 72g, and purity is greater than 99.8%, wherein oxidation impurities 0.05%.
Embodiment 2: 100g 9-hydroxy-risperidone crude product is placed in reaction flask, add 750g tetrahydrofuran (THF) and 250g water, be heated to 60 ~ 70 degree, completely after clarification, be cooled to 10 ~ 20 degree, filter, gained solid drying obtains 9-hydroxy-risperidone mixed crystal product 75g, purity is greater than 99.5%, wherein oxidation impurities 0.06%.
Embodiment 3: 100g 9-hydroxy-risperidone crude product is placed in reaction flask, add 750g tetrahydrofuran (THF) and 250g water, be heated to 60 ~ 70 degree, completely after clarification, be cooled to 0 ~ 10 degree, filter, gained solid drying obtains 9-hydroxy-risperidone mixed crystal product 83g, purity is greater than 99.5%, wherein oxidation impurities 0.08%.
Embodiment 4: 100g 9-hydroxy-risperidone crude product is placed in reaction flask, add 667g tetrahydrofuran (THF) and 333g water, be heated to 60 ~ 70 degree, completely after clarification, be cooled to 20 ~ 30 degree, filter, gained solid drying obtains 9-hydroxy-risperidone mixed crystal product 76g, purity is greater than 99.6%, wherein oxidation impurities 0.07%.
Embodiment 5: 100g 9-hydroxy-risperidone crude product is placed in reaction flask, add 500g tetrahydrofuran (THF) and 500g water, be heated to 60 ~ 70 degree, completely after clarification, be cooled to 20 ~ 30 degree, filter, gained solid drying obtains 9-hydroxy-risperidone mixed crystal product 81g, purity is greater than 99.5%, wherein oxidation impurities 0.09%.
(, as shown in accompanying drawing 1, infared spectrum as shown in Figure 2 for its X-ray powder diffraction for high purity 9-hydroxy-risperidone II crystal formation.) preparation:
Embodiment 6: (purity is greater than 99.8% by 20g 9-hydroxy-risperidone mixed crystal, oxidation impurities 0.05%, down together) product is placed in reaction flask, adds 100g water, is warming up to 50 degree, stir 4 hours, filtered while hot, a small amount of water rinse, gained solid drying obtains II crystal formation 9-hydroxy-risperidone 19.7g, purity is greater than 99.8%, wherein oxidation impurities 0.05%.
Embodiment 7: 20g 9-hydroxy-risperidone mixed crystal product is placed in reaction flask, adds 200g water, be warming up to 50 degree, stir 4 hours, filtered while hot, a small amount of water rinse, gained solid drying obtains II crystal formation 9-hydroxy-risperidone 19.5g, and purity is greater than 99.8%, wherein oxidation impurities 0.05%.
Embodiment 8: 20g 9-hydroxy-risperidone mixed crystal product is placed in reaction flask, adds 400g water, be warming up to 50 degree, stir 4 hours, filtered while hot, a small amount of water rinse, gained solid drying obtains II crystal formation 9-hydroxy-risperidone 19.0g, and purity is greater than 99.8%, wherein oxidation impurities 0.05%.
Embodiment 9: 20g 9-hydroxy-risperidone mixed crystal product is placed in reaction flask, adds 200g water, be warming up to 60 degree, stir 3 hours, filtered while hot, a small amount of water rinse, gained solid drying obtains II crystal formation 9-hydroxy-risperidone 19.5g, and purity is greater than 99.8%, wherein oxidation impurities 0.05%.
Embodiment 10: 20g 9-hydroxy-risperidone mixed crystal product is placed in reaction flask, adds 200g water, be warming up to 80 degree, stir 3 hours, be cooled to 50 ~ 60 and spend filter, a small amount of water rinse, gained solid drying obtains II crystal formation 9-hydroxy-risperidone 19.4g, and purity is greater than 99.8%, wherein oxidation impurities 0.05%.
Embodiment 11: 20g 9-hydroxy-risperidone mixed crystal product is placed in reaction flask, adds 200g water, be warming up to 100 degree, stir 2 hours, be cooled to 50 ~ 60 and spend filter, a small amount of water rinse, gained solid drying obtains II crystal formation 9-hydroxy-risperidone 19.5g, and purity is greater than 99.8%, wherein oxidation impurities 0.05%.
Embodiment 12: 100g 9-hydroxy-risperidone mixed crystal product is placed in reaction flask, adds 1000g water, be warming up to 60 degree, stir 5 hours, filtered while hot, a small amount of water rinse, gained solid drying obtains II crystal formation 9-hydroxy-risperidone 97g, and purity is greater than 99.8%, wherein oxidation impurities 0.05%.
Embodiment 13: 4kg 9-hydroxy-risperidone mixed crystal product is placed in reactor, adds 40kg water, be warming up to 60 degree, stir 10 hours, filtered while hot, a small amount of water rinse, gained solid drying obtains II crystal formation 9-hydroxy-risperidone 3.97g, and purity is greater than 99.8%, wherein oxidation impurities 0.05%.
Claims (8)
1. prepare the method for high purity 9-hydroxy-risperidone II crystal formation, it is characterized in that: the method comprises the following steps;
(1) 9-hydroxy-risperidone crude product is adopted the mixed solvent recrystallization of tetrahydrofuran (THF) and water, the weight ratio of 9-hydroxy-risperidone crude product and mixed solvent is 1:5 ~ 20, and the weight ratio of tetrahydrofuran (THF) and water is 1 ~ 5:1, obtains highly purified Pa Lipai ketone mixed crystal product;
(2) by highly purified Pa Lipai ketone mixed crystal product, stir 2 ~ 10 hours in the hot water of 50 ~ 100 DEG C, the weight ratio of highly purified Pa Lipai ketone mixed crystal product and water is 1:5 ~ 20, and filtration, drying, obtain finished product.
2. the method preparing high purity 9-hydroxy-risperidone II crystal formation according to claim 1, it is characterized in that: in step (1), 9-hydroxy-risperidone crude product is adopted the mixed solvent recrystallization of tetrahydrofuran (THF) and water, be that the mixed solvent of 9-hydroxy-risperidone crude product with tetrahydrofuran (THF) and water is mixed, be heated to 60 ~ 70 DEG C, after solution is clarified completely, be cooled to 0 ~ 50 DEG C of crystallization, filter, dry, obtain highly purified Pa Lipai ketone mixed crystal product.
3. the method preparing high purity 9-hydroxy-risperidone II crystal formation according to claim 1, is characterized in that: in step (1), described 9-hydroxy-risperidone crude product and the weight ratio of mixed solvent are 1:10.
4. the method preparing high purity 9-hydroxy-risperidone II crystal formation according to claim 1, is characterized in that: in step (1), the part by weight of tetrahydrofuran (THF) and water is 3:1.
5. the method preparing high purity 9-hydroxy-risperidone II crystal formation according to claim 2, is characterized in that: in step (1), is cooled to 20 ~ 30 DEG C of crystallizations.
6. the method preparing high purity 9-hydroxy-risperidone II crystal formation according to claim 1, is characterized in that: in step (2), stirs after 2 ~ 10 hours, treat that solution is cooled to 20 ~ 90 DEG C and filters in the hot water of 50 ~ 100 DEG C.
7. the method preparing high purity 9-hydroxy-risperidone II crystal formation according to claim 1, is characterized in that: in step (2), stirs after 2 ~ 10 hours, treat that solution is cooled to 50 ~ 60 DEG C and filters in the hot water of 50 ~ 100 DEG C.
8. the method preparing high purity 9-hydroxy-risperidone II crystal formation according to any one of claim 1,6 or 7, is characterized in that: in step (2), stirs 2 ~ 10 hours in the hot water of 60 ~ 80 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410718481.XA CN104557915B (en) | 2014-12-01 | 2014-12-01 | Method for preparing high-purity paliperidone II crystal form |
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| CN201410718481.XA CN104557915B (en) | 2014-12-01 | 2014-12-01 | Method for preparing high-purity paliperidone II crystal form |
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| CN104557915A true CN104557915A (en) | 2015-04-29 |
| CN104557915B CN104557915B (en) | 2017-01-11 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105481854A (en) * | 2015-12-08 | 2016-04-13 | 天津市亨必达化学合成物有限公司 | Preparation method of risperidone III type crystal |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009016653A1 (en) * | 2007-07-31 | 2009-02-05 | Natco Pharma Limited | Stable polymorphic form of paliperidone and process for its preparation |
| WO2011030224A2 (en) * | 2009-09-10 | 2011-03-17 | Actavis Group Ptc Ehf | Paliperidone or a pharmaceutically acceptable salt thereof substantially free of impurities |
| WO2011073997A2 (en) * | 2009-12-14 | 2011-06-23 | Cadila Healthcare Limited | Process for preparing paliperidone and pharmaceutically acceptable salts thereof |
| CN102584818A (en) * | 2012-01-11 | 2012-07-18 | 吉林三善恩科技开发有限公司 | Novel paliperidone medicinal eutectic and preparation method thereof |
-
2014
- 2014-12-01 CN CN201410718481.XA patent/CN104557915B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009016653A1 (en) * | 2007-07-31 | 2009-02-05 | Natco Pharma Limited | Stable polymorphic form of paliperidone and process for its preparation |
| WO2011030224A2 (en) * | 2009-09-10 | 2011-03-17 | Actavis Group Ptc Ehf | Paliperidone or a pharmaceutically acceptable salt thereof substantially free of impurities |
| WO2011073997A2 (en) * | 2009-12-14 | 2011-06-23 | Cadila Healthcare Limited | Process for preparing paliperidone and pharmaceutically acceptable salts thereof |
| CN102584818A (en) * | 2012-01-11 | 2012-07-18 | 吉林三善恩科技开发有限公司 | Novel paliperidone medicinal eutectic and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| PAVANKUMAR V. SOLANKI ETAL: "An Improved and Efficient Process for the Production of Highly Pure Paliperidone, a Psychotropic Agent, via DBU Catalyzed N‑Alkylation", 《ACS SUSTAINABLE CHEMISTRY & ENGINEERING》, vol. 1, 31 December 2012 (2012-12-31) * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105481854A (en) * | 2015-12-08 | 2016-04-13 | 天津市亨必达化学合成物有限公司 | Preparation method of risperidone III type crystal |
| CN105481854B (en) * | 2015-12-08 | 2017-11-10 | 天津市亨必达化学合成物有限公司 | A kind of preparation method of the brilliant III type material of Risperidone |
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| CN104557915B (en) | 2017-01-11 |
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