CN104557899A - Preparation method of azilsartan I-form crystal - Google Patents
Preparation method of azilsartan I-form crystal Download PDFInfo
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- CN104557899A CN104557899A CN201410652324.3A CN201410652324A CN104557899A CN 104557899 A CN104557899 A CN 104557899A CN 201410652324 A CN201410652324 A CN 201410652324A CN 104557899 A CN104557899 A CN 104557899A
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- azilsartan
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- CXWGNXLUYZEQLR-QXMHVHEDSA-N CCOc1nc(C)c(C(C)C(O)=O)[n]1CC(C)/C=C\[IH]C(c(cccc1)c1[IH]C(NO1)=NC1=O)=C Chemical compound CCOc1nc(C)c(C(C)C(O)=O)[n]1CC(C)/C=C\[IH]C(c(cccc1)c1[IH]C(NO1)=NC1=O)=C CXWGNXLUYZEQLR-QXMHVHEDSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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Abstract
The invention discloses a new preparation method of an azilsartan I-form crystal. The preparation method comprises the following steps: dissolving an azilsartan crude product in methanol, ethanol or a methanol-ethanol mixed solvent, dropwisely adding an ether or alkane poor solvent, and cooling to crystallize, thereby obtaining the azilsartan I-form crystal. The method is simple to operate; and the product is easy for separation and drying, and has the advantages of high yield and the like.
Description
Technical field
The present invention relates to the control techniques of crystal habit, more specifically, relate to the preparation method of Azilsartan I crystal crystal.
Technical background
As described in Japanese patent application JP5271228A and US Patent No. 5583141A, Azilsartan (Azilsartan) shown in known following formula is selectivity AT1 subtype angiotensin II receptor antagonist (ARBS) class antihypertensive drug of new generation, there is steady step-down, the advantage of dry cough can not be caused, developed by Japan's military field pharmacy, in January, 2012 obtains listing in Japan first.Structural formula is as follows:
The known report of Azilsartan has multiple crystal formation, is divided into I or A, II or B, C etc., and wherein mainly I crystal is used for clinical treatment.Chinese patent CN102827153A, CN102766139A, CN103113364A disclose some methods preparing I crystal crystal, wherein CN102827153A adopts ethanol to carry out recrystallization, have employed the mixed solvent systems such as methanol/water, methanol/ethyl acetate, acetonitrile/water in CN102766139A and carry out recrystallization, adopt the dissolving of the good solvent such as methyl alcohol, ethanol to add water again in CN103113364A and carry out crystallization.The shortcomings such as it is high that the preparation method of Azilsartan I crystal crystal that Chinese patent CN102827153A, CN102766139A, CN103113364A etc. describe exists bake out temperature respectively, and solvent multiplying power is high, and product yield is unstable, the product colour difference obtained,
Summary of the invention
The object of the present invention is to provide a kind of new preparation method of Azilsartan I crystal crystal.The invention solves product yield in aforesaid method unstable, the shortcomings such as solvent multiplying power is high, and product degree of crystallinity is poor, and color class is white.
A preparation method for Azilsartan I crystal crystal, comprises the steps: that Azilsartan crude product dissolves in methyl alcohol, ethanol or both mixed solvents, adds ethers or alkanes poor solvent carries out cooling crystallization, obtains the crystal of Azilsartan I crystal.
Described ethers poor solvent is methyl tertiary butyl ether, isopropyl ether, methyl-phenoxide, and described alkanes poor solvent is hexanaphthene, normal hexane, normal heptane.
The temperature of crystallisation by cooling is at-10 ~ 10 DEG C.
Described quantity of solvent is 5 ~ 50 times (ml/g) of the quality of Azilsartan.
Described quantity of solvent is 8 ~ 15 times (ml/g) of the quality of Azilsartan.
The quantity of solvent of described poor solvent be the quality of Azilsartan be 5 ~ 50 times (ml/g).
The quantity of solvent of described poor solvent be the quality of Azilsartan be 10 ~ 20 times (ml/g).
The technical solution used in the present invention concrete operations are: Azilsartan crude product refluxes dissolving in 5 ~ 50 times of (ml/g) methyl alcohol, ethanol or both mixed solvents, drip 5 ~ 50 times of (ml/g) ethers or alkanes poor solvent, carry out cooling crystallization again, filter, filter cake, at 40 DEG C of vacuum-drying 4-6 hour, obtains the crystal of Azilsartan I crystal.
The invention provides Azilsartan I crystal crystal, its X-ray powder diffraction (XRPD) collection of illustrative plates as shown in Figure 1.The XRPD figure's of this Azilsartan crystal form A is that 9.3 ± 0.2,12.8 ± 0.2,18.2 ± 0.2,21.6 ± 0.2,23.8 ± 0.2 places have obvious absorption peak at 2 θ.
The common recrystallization method of crystal comprises decrease temperature crystalline, evaporative crystallization, dilution crystallization etc.The process for purification of the Azilsartan I crystal crystal of current report mostly adopts conventional high-temperature digestion, the method for low temperature crystallization or dilution crystallization method (poor solvent is water).And Azilsartan causes that its solubleness in alcohols or other good solvent is less and solubility curve is comparatively mild due to the singularity of its molecular radical, along with the change of temperature, Azilsartan changes in solubility is in a solvent little, which results in the solvent multiplying power that Azilsartan uses when recrystallization comparatively large, the yield of recrystallization is on the low side.Fig. 5 is the solubility curve of Azilsartan in methyl alcohol.
And Azilsartan solution stirs easily generation esterification impurity in the solution for a long time.Cause the rubicundity of product, in off-white color.
The present invention is directed to the problems referred to above, add poor solvent and carry out crystallization in the solution of Azilsartan, can effectively make the Azilsartan in solution crystallize out comparatively thoroughly, the yield of product is high; Crystallization speed, it also avoid Azilsartan and exists for a long time with solution state, and reduce the risk producing impurity, the outward appearance of product is better; Employ the lower ethers of boiling point, alkanes as poor solvent, compared with water, product drying time is shorter, and temperature is lower, and energy consumption is lower.
Beneficial effect:
(1) ethers, alkane solvents is adopted to carry out dilution crystallization as poor solvent to Azilsartan solution in the present invention, make the Crystallization Process of product faster, reduce the risk producing impurity and cause product colour poor, and the product yield obtained is higher, more easily dry.
(2) be more conducive to the shortening time in industrialized production, save energy, reduces costs.
Accompanying drawing explanation
The X-ray powder diffraction pattern (XRPD) of the Azilsartan I crystal crystal obtained in Fig. 1 embodiments of the invention 1
The means of differential scanning calorimetry figure (DSC) of the Azilsartan I crystal crystal obtained in Fig. 2 embodiments of the invention 1
The infrared absorpting light spectra (IR) of the Azilsartan I crystal crystal obtained in Fig. 3 embodiments of the invention 1
The HPLC-UV detection (HPLC) of the Azilsartan obtained in Fig. 4 embodiments of the invention 1
The solubility curve of Fig. 5 Azilsartan in methyl alcohol
Embodiment
Below in conjunction with embodiment, the present invention is further elaborated, but these examples do not form any restriction to the present invention.
The Azilsartan crude product adopted in the present embodiment is with reference to the method preparation in military field medicine company compound patent US5583141A embodiment 1.HPLC purity 97-98%.
Embodiment 1
10g Azilsartan crude product, 200g methyl alcohol are dropped into reaction flask, and reflux stirring and dissolving, dissolves complete, solution is cooled to 40 ± 5 DEG C.Lower the temperature complete, drip 50g hexanaphthene, dropwise in bottle, temperature in bottle is down to 10 DEG C, stirred crystallization 2 hours, filter, vacuum-drying obtains Azilsartan 8.5kg, yield 85.0%, HPLC purity 99.8%.The X-ray powder diffraction of Azilsartan I crystal crystal asks for an interview Fig. 1, adopt PANalytical x-ray diffractometer, means of differential scanning calorimetry figure (DSC) asks for an interview Fig. 2, infrared absorpting light spectra (IR) asks for an interview Fig. 3, adopt Fourier transformation infrared spectrometer (pellet technique), HPLC-UV detection (HPLC) asks for an interview Fig. 4, moving phase: acetonitrile: water: trifluoroacetic acid (35:65:0.1).
Embodiment 2
10g Azilsartan crude product, 50g methyl alcohol, 250g ethanol are dropped into reaction flask, and reflux stirring and dissolving, dissolves complete, solution is cooled to 30 ± 5 DEG C.Lower the temperature complete, drip 50g isopropyl ether, dropwise in bottle, temperature in bottle is down to-10 DEG C, stirred crystallization 2 hours, filter, vacuum-drying obtains Azilsartan 8.9kg, yield 89.0%, HPLC purity 99.6%.
Embodiment 3
10g Azilsartan crude product, 300g ethanol are dropped into reaction flask, and reflux stirring and dissolving, dissolves complete, solution is cooled to 30 ± 5 DEG C.Lower the temperature complete, drip 1000g methyl tertiary butyl ether, dropwise in bottle, temperature in bottle is down to 0 DEG C, stirred crystallization 2 hours, filter, vacuum-drying obtains Azilsartan 9.2kg, yield 92.0%, HPLC purity 99.8%.
Embodiment 4
10g Azilsartan crude product, 300g ethanol are dropped into reaction flask, and reflux stirring and dissolving, dissolves complete, solution is cooled to 40 ± 5 DEG C.Lower the temperature complete, drip 300g normal heptane, dropwise in bottle, temperature in bottle is down to-10 DEG C, stirred crystallization 4 hours, filter, vacuum-drying obtains Azilsartan 9.5kg, yield 95.0%, HPLC purity 99.7%.
Embodiment 5
10g Azilsartan crude product, 40g methyl alcohol, 200g ethanol are dropped into reaction flask, and reflux stirring and dissolving, dissolves complete, solution is cooled to 50 ± 5 DEG C.Lower the temperature complete, drip 300g methyl-phenoxide, dropwise in bottle, temperature in bottle is down to 0 DEG C, stirred crystallization 4 hours, filter, vacuum-drying obtains Azilsartan 9.1kg, yield 91.0%, HPLC purity 99.8%.
Claims (7)
1. a preparation method for Azilsartan I crystal crystal, comprises the steps: that Azilsartan crude product dissolves in methyl alcohol, ethanol or both mixed solvents, adds ethers or alkanes poor solvent carries out cooling crystallization, obtains the crystal of Azilsartan I crystal.
2. preparation method according to claim 1, is characterized in that: described ethers poor solvent is methyl tertiary butyl ether, isopropyl ether, methyl-phenoxide, and described alkanes poor solvent is hexanaphthene, normal hexane, normal heptane.
3. preparation method according to claim 1, is characterized in that: the temperature of crystallisation by cooling is at-10 ~ 10 DEG C.
4. preparation method according to claim 1, is characterized in that: described quantity of solvent is 5 ~ 50 times (ml/g) of the quality of Azilsartan.
5. preparation method according to claim 4, is characterized in that: described quantity of solvent is 8 ~ 15 times (ml/g) of the quality of Azilsartan.
6. preparation method according to claim 1, is characterized in that: the quantity of solvent of described poor solvent be the quality of Azilsartan be 5 ~ 50 times (ml/g).
7. preparation method according to claim 6, is characterized in that: the quantity of solvent of described poor solvent be the quality of Azilsartan be 10 ~ 20 times (ml/g).
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410652324.3A CN104557899B (en) | 2014-11-17 | 2014-11-17 | A kind of preparation method of Azilsartan I crystal crystal |
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| CN201410652324.3A CN104557899B (en) | 2014-11-17 | 2014-11-17 | A kind of preparation method of Azilsartan I crystal crystal |
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| CN104557899A true CN104557899A (en) | 2015-04-29 |
| CN104557899B CN104557899B (en) | 2018-05-22 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749216A (en) * | 2016-12-30 | 2017-05-31 | 湖南千金湘江药业股份有限公司 | A kind of process for purification of crystal formation A Azilsartans |
| CN108912109A (en) * | 2018-08-17 | 2018-11-30 | 珠海润都制药股份有限公司 | A kind of high-purity, small particle and azilsartan crude drug of low solvent residue and preparation method thereof |
| CN111699183A (en) * | 2018-02-09 | 2020-09-22 | 株式会社德山 | Method for producing azilsartan A-type crystal |
Citations (7)
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| WO2012090043A1 (en) * | 2010-12-29 | 2012-07-05 | Jubilant Life Sciences Limited | Novel solid state forms of azilsartan medoxomil and preparation thereof |
| CN102766139A (en) * | 2012-08-14 | 2012-11-07 | 江苏先声药物研究有限公司 | Azilsartan polymorphic substance and preparation method thereof |
| CN102827153A (en) * | 2011-06-14 | 2012-12-19 | 江苏豪森药业股份有限公司 | Crystal form of azilsartan and preparation method thereof |
| CN103044412A (en) * | 2012-12-26 | 2013-04-17 | 华润赛科药业有限责任公司 | Azilsartan polymorph and preparation method thereof |
| CN103113364A (en) * | 2012-08-27 | 2013-05-22 | 南京华威医药科技开发有限公司 | Preparation method of azilsartan polymorphism |
| WO2013124748A1 (en) * | 2012-02-20 | 2013-08-29 | Alembic Pharmaceuticals Limited | Novel polymorphs of azilsartan medoxomil potassium |
| CN103664922A (en) * | 2013-12-30 | 2014-03-26 | 成都天地仁和药物研究有限公司 | Novel crystal-form azilsartan and preparation method for same |
-
2014
- 2014-11-17 CN CN201410652324.3A patent/CN104557899B/en active Active
Patent Citations (7)
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| WO2012090043A1 (en) * | 2010-12-29 | 2012-07-05 | Jubilant Life Sciences Limited | Novel solid state forms of azilsartan medoxomil and preparation thereof |
| CN102827153A (en) * | 2011-06-14 | 2012-12-19 | 江苏豪森药业股份有限公司 | Crystal form of azilsartan and preparation method thereof |
| WO2013124748A1 (en) * | 2012-02-20 | 2013-08-29 | Alembic Pharmaceuticals Limited | Novel polymorphs of azilsartan medoxomil potassium |
| CN102766139A (en) * | 2012-08-14 | 2012-11-07 | 江苏先声药物研究有限公司 | Azilsartan polymorphic substance and preparation method thereof |
| CN103113364A (en) * | 2012-08-27 | 2013-05-22 | 南京华威医药科技开发有限公司 | Preparation method of azilsartan polymorphism |
| CN103044412A (en) * | 2012-12-26 | 2013-04-17 | 华润赛科药业有限责任公司 | Azilsartan polymorph and preparation method thereof |
| CN103664922A (en) * | 2013-12-30 | 2014-03-26 | 成都天地仁和药物研究有限公司 | Novel crystal-form azilsartan and preparation method for same |
Non-Patent Citations (1)
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| YASUHISA KOHARA，等: "Synthesis and Angiotensin II Receptor Antagonistic Activities of Benzimidazole Derivatives Bearing Acidic Heterocycles as Novel Tetrazole Bioisosteres", 《J. MED. CHEM.》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749216A (en) * | 2016-12-30 | 2017-05-31 | 湖南千金湘江药业股份有限公司 | A kind of process for purification of crystal formation A Azilsartans |
| CN106749216B (en) * | 2016-12-30 | 2021-05-04 | 湖南千金湘江药业股份有限公司 | Refining method of crystal form A azilsartan |
| CN111699183A (en) * | 2018-02-09 | 2020-09-22 | 株式会社德山 | Method for producing azilsartan A-type crystal |
| CN108912109A (en) * | 2018-08-17 | 2018-11-30 | 珠海润都制药股份有限公司 | A kind of high-purity, small particle and azilsartan crude drug of low solvent residue and preparation method thereof |
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| CN104557899B (en) | 2018-05-22 |
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Application publication date: 20150429 Assignee: Nanjing Red Sun Pharmaceutical Research Institute Co.,Ltd. Assignor: Jiangsu Zhongbang Pharmaceutical Co.,Ltd. Contract record no.: X2022980010825 Denomination of invention: A preparation method of azilsartan crystal form I Granted publication date: 20180522 License type: Common License Record date: 20220721 |
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