CN103664922A - Novel crystal-form azilsartan and preparation method for same - Google Patents
Novel crystal-form azilsartan and preparation method for same Download PDFInfo
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Abstract
The invention discloses novel crystal-form azilsartan and a preparation method for the same. Characteristic peaks of a PXRD (power X ray diffraction) chart of a polycrystalline form-B azilsartan target are positioned at 2Theta (+/-0.2 degrees, 2Theta) of 7.489, 8.482, 9.384, 13.524, 18.892, 21.147, 23.129 and 25.405, and the melting point is 188 to 190 DEG C. The preparation method comprises the following steps of dissolving azilsartan in methanol, and performing heating reflux until solids are completely dissolved; adding tetrahydrofuran, performing stirring, and performing crystallization at room temperature to obtain the polycrystalline form-B azilsartan target, wherein the using amount of the methanol is about 30 to 70 times the mass of the azilsartan, and the addition of the tetrahydrofuran is about 10 to 30 times the mass of the azilsartan.
Description
Technical field
The present invention relates to medical compounds preparation, especially new polymorphic form of Azilsartan and preparation method thereof.
Background technology
Azilsartan (Azilsartan), commodity are called Azilva, i.e. 2-oxyethyl group-1-{[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazoles-3-yl) biphenyl-4-yl] methyl }-1H-benzo [d] imidazoles-7-carboxylic acid, structural formula is as follows:
It is the AT1 subtype angiotensin II receptor antagonist (ARB) by the exploitation of the military field of Japan (Takeda) company, on January 18th, 2012, goes through in Japan's listing, and the listing license of the U.S. now having obtained and European Union's listing.Azilsartan is as dual-use function ARBs of new generation, and not only 1 receptor of antagonizing vessel Angiotensin Converting Enzyme II (AT1 acceptor), also may reduce by number of mechanisms the risk of cardiovascular disorder and diabetes.Clinical trial proves, Azilsartan has good therapeutic effect, and adverse reaction rate is lower, the good feature of compliance.
Chinese patent CN92105152C(right of priority patent JP1991157194) embodiment 1 discloses the preparation method of Azilsartan.The saponification in methyl alcohol/LiOH of Azilsartan methyl esters, obtains Azilsartan crude product after acid treatment, then recrystallization in ethyl acetate, obtain colourless rhomboidan, gained compound is solvate, and containing 0.5 molecule ethyl acetate and 0.2 molecular water, fusing point is 156-157 ℃.
Chinese patent CN102766139 and CN102827153 successively disclose the polymorphic of Azilsartan in 2012, the characteristic peak crystal formation parameter of the polymorphic form of its requirement is all identical: there is peak at the 2 θ places such as value 9.01 ± 0.2,12.60 ± 0.2,18.21 ± 0.2,19.21 ± 0.2,20.3 ± 0.2,21.37 ± 0.2,23.5 ± 0.2,25.25 ± 0.2,26.58 ± 0.2 degree.
Summary of the invention
The object of this invention is to provide a kind of new polymorph b of Azilsartan, and this polymorphous preparation method is provided, and it is easy to make it to have preparation method, is easy to the advantage of industrial application.
New crystal Azilsartan of the present invention, has following structure,
The characteristic peak of the PXRD figure of Azilsartan polymorph b of the present invention represents to be positioned at 7.489,8.482,9.384,13.524,18.892,21.147,23.129,25.405 with 2 θ (± 0.2 °, 2 θ).The present invention is doing fusing point analysis to this crystal formation, and the fusing point of finding this crystal formation is 188-190 ℃; And the fusing point about Azilsartan is 190 ℃ in Japanese Orange Book.
Azilsartan, be 2-oxyethyl group-1-{[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazoles-3-yl) biphenyl-4-yl] methyl }-1H-benzo [d] imidazoles-7-carboxylic acid, can be by for example document J.Med.Chem.1996,39 (26): the public technology that 5228-5235 provides, take 2-oxyethyl group-1-[(2'-cyano group-biphenyl-4-yl) methyl]-1H-benzo [d] imidazoles-7-carboxylate methyl ester is starting raw material, by becoming oxime with oxammonium hydrochloride, then Vinyl chloroformate esterification, closes ring, and hydrolysis makes.Its reaction process is as follows:
The standby Azilsartan of this legal system is crystal form A.
Investigated ethanol, the product of recrystallization in Virahol, crystal formation is A.And in document, at DMF/ water, methanol/water, the solid of separating out in the various conditions such as methanol/ethyl acetate, is crystal form A.
The invention provides the preparation method of above-mentioned crystal form B.It is starting raw material that the method be take self-control Azilsartan, and by dissolving, the method for crystallization is prepared crystal form B.That is:
New crystal Azilsartan preparation method, comprises and is prepared as follows step:
Azilsartan is dissolved in to methyl alcohol, and reflux, until solid dissolves completely; Add tetrahydrofuran (THF), stir, room temperature crystallization, obtains the crystal form B of target compound Azilsartan.
Azilsartan polymorph b preparation method provided by the invention is easy, is easy to industrial application, and can be used on the polymorphous method of strict control in Qi Shatan bulk drug preparation process.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction figure of Azilsartan crystal form A.
Fig. 2 is the X-ray powder diffraction figure of Azilsartan crystal form B
Fig. 3 is the 1H-NMR spectrogram of Azilsartan 400MHz.
Fig. 4 is Azilsartan 400MHz
13c-NMR spectrogram.
Embodiment
Embodiment 1
2-oxyethyl group-1-{[2'-(N-hydroxy formamidine base)-biphenyl-4-yl] methyl } preparation of-1H-benzo [d] imidazoles-7-carboxylate methyl ester:
In the mixing solutions of methyl-sulphoxide (200mL) and oxammonium hydrochloride (42.4g), add triethylamine (61.8g), separate out a large amount of solids.Filter, filter cake washs with tetrahydrofuran (THF).Filtrate is concentrated goes to add 2-oxyethyl group-1-[(2'-cyano group-biphenyl-4-yl after tetrahydrofuran (THF)) methyl]-1H-benzo [d] imidazoles-7-carboxylate methyl ester 50.0g, 75 ℃ are reacted 15 hours.After reaction finishes, add shrend and go out, ethyl acetate extraction.1N salt acid elution for organic phase, water regulates pH to 10-11 with the aqueous sodium hydroxide solution of 1N again, ethyl acetate extraction, anhydrous sodium sulfate drying, filter, concentrated, obtain 2-oxyethyl group-1-{[2'-(N-hydroxy formamidine base)-biphenyl-4-yl] methyl }-1H-benzo [d] imidazoles-7-carboxylate methyl ester 29.7g.
2-oxyethyl group-1-{[2'-[(N-ethoxycarbonyl-oxygen base amidino)-biphenyl-4-yl] methyl } preparation of-1H-benzo [d] imidazoles-7-carboxylate methyl ester:
17.0g2-oxyethyl group-1-{[2'-(N-hydroxy formamidine base)-biphenyl-4-yl] methyl }-1H-benzo [d] imidazoles-7-carboxylate methyl ester is dissolved in methylene dichloride (100mL), add triethylamine (6.0g, 59mmol), under room temperature, slowly drip containing Vinyl chloroformate (5g, methylene dichloride 47.2mmol) (100mL) solution, drips complete room temperature reaction 0.5h.Water (150mL*2) washing, anhydrous sodium sulfate drying, filtrate decompression evaporate to dryness, isopropyl ether-methyl alcohol for residue (10:1) recrystallization, obtains white solid 2-oxyethyl group-1-{[2'-[(N-ethoxycarbonyl-oxygen base amidino)-biphenyl-4-yl] methyl }-1H-benzo [d] imidazoles-7-carboxylate methyl ester 18.0g.
Embodiment 3
2-oxyethyl group-1-{[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazoles-3-yl)-biphenyl-4-yl] methyl } preparation of-1H-benzo [d] imidazoles-7-carboxylate methyl ester:
2-oxyethyl group-1-{[2'-[(N-ethoxycarbonyl-oxygen base amidino)-biphenyl-4-yl] methyl }-1H-benzo [d] imidazoles-7-carboxylate methyl ester 15g adds in 100ml dimethylbenzene, after back flow reaction 2 hours, concentrated desolventizing, adds chloroform-ethyl acetate (3:1) 200mL stirring at room to separate out solid.Solid methanol wash, dries, and obtains 2-oxyethyl group-1-{[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazoles-3-yl)-biphenyl-4-yl] methyl }-1H-benzo [d] imidazoles-7-carboxylate methyl ester 10.5g.
Embodiment 4
2-oxyethyl group-1-{[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazoles-3-yl) biphenyl-4-yl] methyl } preparation of-1H-benzo [d] imidazoles-7-carboxylic acid (Azilsartan)
2-oxyethyl group-1-{[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazoles-3-yl)-biphenyl-4-yl] methyl }-1H-benzo [d] imidazoles-7-carboxylate methyl ester (12g, 25.5mmol) add in methyl alcohol, add 10% aqueous sodium hydroxide solution (30mL, 75mmol), be heated to 75 ℃ of stirring reactions 1 hour.Under stirring, add 1mol/L hydrochloric acid (about 50mL) to be adjusted to pH3.Filter, obtain product Azilsartan 7.5g.By X powder diffraction, product is analyzed, be defined as A crystal formation.
The Azilsartan of using in subsequent technique is all according to above method preparation
Embodiment 5
The preparation of Azilsartan crystal form A
Take Azilsartan 10g, add in reaction flask, then add ethanol 600ml, reflux, until solid dissolves completely.Stir, be naturally cooled to room temperature, separate out solid.Filter, 40-50 ℃ is dried to constant weight, obtains the Azilsartan 7.5g of crystal form A, fusing point 188-189.5 ℃.
The preparation of Azilsartan crystal form A
Take Azilsartan 10g, add in reaction flask, then add Virahol 500ml, reflux, until solid dissolves completely.Stir, be naturally cooled to room temperature, separate out solid.Filter, 40-50 ℃ is dried to constant weight, obtains the Azilsartan 8.9g of crystal form A, fusing point 188.5-190 ℃.
The preparation of Azilsartan crystal form B
Take Azilsartan 10g, add in reaction flask, then add methyl alcohol 450ml, reflux, until solid dissolves completely.Then add tetrahydrofuran (THF) 220ml, stir, be naturally cooled to room temperature, separate out solid.Filter, 40-50 ℃ is dried to constant weight, obtains the Azilsartan 8.6g of crystal form B, fusing point 188-190.2 ℃.
The preparation of Azilsartan crystal form B
Take Azilsartan 10g, add in reaction flask, then add methyl alcohol 650ml, reflux, until solid dissolves completely.Then add tetrahydrofuran (THF) 280ml, stir, be naturally cooled to room temperature, separate out solid.Filter, 40-50 ℃ is dried to constant weight, obtains the Azilsartan 8.1g of crystal form B, fusing point 188.5-189.3 ℃.
Embodiment 9
The preparation of Azilsartan crystal form B
Take Azilsartan 10g, add in reaction flask, then add methyl alcohol 350ml, reflux, until solid dissolves completely.Then add tetrahydrofuran (THF) 200ml, stir, be naturally cooled to room temperature, separate out solid.Filter, 40-50 ℃ is dried to constant weight, obtains the Azilsartan 7.9g of crystal form B, fusing point 188.3-190 ℃.
The preparation of Azilsartan crystal form B
Take Azilsartan 10g, add in reaction flask, then add methyl alcohol 480ml, reflux, until solid dissolves completely.Then add tetrahydrofuran (THF) 220ml, stir, be naturally cooled to room temperature, separate out solid.Filter, 40-50 ℃ is dried to constant weight, obtains the Azilsartan 8.7g of crystal form B, fusing point 188.9-189.3 ℃.
In conjunction with Fig. 3, Fig. 4 can determine that this white solid is Azilsartan.
The X-ray powder diffraction figure of comparison diagram 1 crystal form A, the powder diffraction spectrum contrast of the crystal form B that we prepare, can find that the crystal formation of invention is a kind of new crystal formation.
Claims (4)
1. new crystal Azilsartan, has following structure,
It is characterized in that, the characteristic peak of the PXRD figure of Azilsartan polymorph b represents to be positioned at 7.489,8.482,9.384,13.524,18.892,21.147,23.129,25.405 with 2 θ (± 0.2 °, 2 θ).
2. new crystal Azilsartan preparation method: comprise and be prepared as follows step: Azilsartan is dissolved in to methyl alcohol, and reflux, until solid dissolves completely; Add tetrahydrofuran (THF), stir, room temperature crystallization, obtains the crystal form B of target compound Azilsartan; The consumption of methyl alcohol is about the quality of 30-70 times of Azilsartan; Add tetrahydrofuran (THF) consumption to be about the quality of 10-30 times of Azilsartan.
3. new crystal Azilsartan preparation method as claimed in claim 2, the consumption of described methyl alcohol is the quality of 60 times of Azilsartans; Adding tetrahydrofuran (THF) consumption is the quality of 20 times of Azilsartans.
4. contain and treat the Azilsartan crystal formation as claimed in claim 1 of significant quantity as the pharmaceutical composition of effective constituent and pharmaceutically acceptable carrier, it is characterized in that described Azilsartan crystal formation or the purposes of its pharmaceutical composition in preparing antihypertensive drug.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104119279A (en) * | 2014-05-30 | 2014-10-29 | 上海天慈生物谷生物工程有限公司 | Novel method for preparing 2-ethyoxyl-1-{[2'-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3-yl) xenyl-4-yl]methyl}-1H- benzimidazole-7-carboxylic acid |
| CN104230910A (en) * | 2014-09-16 | 2014-12-24 | 常州大学 | Preparation methods of crystal form and crystal of azilsartan intermediate |
| CN104262334A (en) * | 2014-09-16 | 2015-01-07 | 常州大学 | Azilsartan crystal and preparation method thereof |
| CN104557899A (en) * | 2014-11-17 | 2015-04-29 | 江苏中邦制药有限公司 | Preparation method of azilsartan I-form crystal |
| CN106749217A (en) * | 2017-01-22 | 2017-05-31 | 鲁南制药集团股份有限公司 | A kind of Azilsartan I crystal |
| CN108774217A (en) * | 2018-09-07 | 2018-11-09 | 浙江宏元药业股份有限公司 | A kind of preparation process of Azilsartan powder material medicine |
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| WO2013044816A1 (en) * | 2011-09-30 | 2013-04-04 | Sunshine Lake Pharma Co., Ltd. | Crystalline forms of azilsartan and preparation and uses 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 |
| CN103360381A (en) * | 2013-07-30 | 2013-10-23 | 山东新华制药股份有限公司 | New crystal form of Azilsartan, and preparation method and application thereof |
| WO2013186792A2 (en) * | 2012-06-11 | 2013-12-19 | Msn Laboratories Limited | Process for the preparation of (5-methyl-2-oxo-l,3-dioxoi-4-vl)methvl 2- ethoxv-l-{[2'-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vl)biphenyi-4-vl]methyl}- lh-benzimidazole-7-carboxyiate and its salts |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2013044816A1 (en) * | 2011-09-30 | 2013-04-04 | Sunshine Lake Pharma Co., Ltd. | Crystalline forms of azilsartan and preparation and uses thereof |
| WO2013186792A2 (en) * | 2012-06-11 | 2013-12-19 | Msn Laboratories Limited | Process for the preparation of (5-methyl-2-oxo-l,3-dioxoi-4-vl)methvl 2- ethoxv-l-{[2'-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vl)biphenyi-4-vl]methyl}- lh-benzimidazole-7-carboxyiate and its salts |
| 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 |
| CN103360381A (en) * | 2013-07-30 | 2013-10-23 | 山东新华制药股份有限公司 | New crystal form of Azilsartan, and preparation method and application thereof |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104119279A (en) * | 2014-05-30 | 2014-10-29 | 上海天慈生物谷生物工程有限公司 | Novel method for preparing 2-ethyoxyl-1-{[2'-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3-yl) xenyl-4-yl]methyl}-1H- benzimidazole-7-carboxylic acid |
| CN104119279B (en) * | 2014-05-30 | 2018-01-02 | 上海天慈生物谷生物工程有限公司 | The method for preparing the carboxylic acid of 2 ethyoxyl 1 { [base of 2 ' (base of 5 carbonyl, 4,5 dihydro, 1,2,4 oxadiazole 3) xenyl 4] methyl } 1H benzimidazoles 7 |
| CN104230910A (en) * | 2014-09-16 | 2014-12-24 | 常州大学 | Preparation methods of crystal form and crystal of azilsartan intermediate |
| CN104262334A (en) * | 2014-09-16 | 2015-01-07 | 常州大学 | Azilsartan crystal and preparation method thereof |
| CN104557899A (en) * | 2014-11-17 | 2015-04-29 | 江苏中邦制药有限公司 | Preparation method of azilsartan I-form crystal |
| CN104557899B (en) * | 2014-11-17 | 2018-05-22 | 江苏中邦制药有限公司 | A kind of preparation method of Azilsartan I crystal crystal |
| CN106749217A (en) * | 2017-01-22 | 2017-05-31 | 鲁南制药集团股份有限公司 | A kind of Azilsartan I crystal |
| CN108774217A (en) * | 2018-09-07 | 2018-11-09 | 浙江宏元药业股份有限公司 | A kind of preparation process of Azilsartan powder material medicine |
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Application publication date: 20140326 |