CN106749217A - A kind of Azilsartan I crystal - Google Patents
A kind of Azilsartan I crystal Download PDFInfo
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- CN106749217A CN106749217A CN201710053991.3A CN201710053991A CN106749217A CN 106749217 A CN106749217 A CN 106749217A CN 201710053991 A CN201710053991 A CN 201710053991A CN 106749217 A CN106749217 A CN 106749217A
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- azilsartan
- crystal
- alkali lye
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention relates to a kind of Azilsartan I crystal.The crystal formation shows diffraction maximum at 9.135 ± 0.2 degree, 12.72 ± 0.2 degree, 18.295 ± 0.2 degree, 19.358 ± 0.2 degree, 20.350 ± 0.2 degree, 21.477 ± 0.2 degree, 23.530 ± 0.2 degree, 25.287 ± 0.2 degree, 26.690 ± 0.2 degree and 28.811 ± 0.2 degree of following angles of diffraction.Its preparation method includes：With [[2 ' ((5 oxos 4 of 2 ethyoxyl 1,5 dihydros 1,2, the base of 4 oxadiazole 3) substitution of biphenyl 4) methyl] carboxylate methyl ester of benzimidazole 7 is in the basic conditions, add organic solvent hydrolysis, acid for adjusting pH, is incubated growing the grain, and I crystal is obtained by crystal collection, washing, drying process.This method process is simple, product purity and high income, are suitable to industrialized production, significant with clinical efficacy to Drug's control.
Description
Technical field
The present invention relates to technical field of medicine synthesis, and in particular to a kind of Azilsartan I crystal.
Background technology
Azilsartan, chemical name 2- ethyoxyls -1- [[2 '-((5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) join
Benzene -4- replaces) methyl]-benzimidazole -7- carboxylic acids, structural formula (I) is as follows：
Azilsartan is the Angiotensin Ⅱ receptor antagonist developed by Japanese Wu Tian companies.2 months 2012 U.S.'s foods
Product ratify Azilsartan and are used for hypertension therapeutic with drug administration (FDA).The medicine is that a kind of angiotensin-ii-receptor is short of money
Anti-agent, can be used alone or be used in combination with other antihypertensives, with steady step-down, will not cause the advantage of dry cough.Its
4,5- dihydro -5- oxo -1,2,4- the oxadiazole rings having in structure are tetrazoliums in Candesartan (candesartan) structure
Bioisostere, allows it to overcome the shortcomings of tetrazolium in terms of synthesis and metabolism, with oral bioavailability higher
Degree.
Chinese patent CN92105152C discloses a certain solvate of Azilsartan and preparation method：Use ethyl acetate weight
Crystallization, obtains the solvate containing 0.5 molecule ethyl acetate and 0.2 molecular water, 156~157 DEG C of fusing point.Additionally, document
(J.Med.Chem.1996,39,5228-5235) reports the fusing point of Azilsartan for 212~214 DEG C, but does not carry out crystal formation and grind
Study carefully；WO2012107814A1 discloses the preparation method of Azilsartan, but does not also illustrate crystal type or solvate；In
State patent CN102827153A discloses the crystal formation (hereinafter referred to as II type) obtained with absolute ethyl alcohol recrystallization method, the spy of PXRD
Levy peak and be expressed as 9.01 °, 12.60 °, 18.21 °, 19.21 °, 21.37 °, 24.42 °, 25.25 °, 26.58 ° with 2 θ (± 0.2 °).
Chinese patent CN102766139A also discloses that various recrystallization methods prepare Azilsartan crystal formation, but compare PXRD collection of illustrative plates and its
His data, what is obtained is also crystal formation II.
In patent CN1040755C specifications, page 60 discloses a kind of preparation method of Azilsartan, is directed to it brilliant
The separation method of type, will wash organic layer with water after product distributed in the water and chloroform, use ethyl acetate after solvent evaporated again
Recrystallization.But, Azilsartan dissolubility in ethyl acetate is poor, and the crystal formation obtained using the method is yielded poorly, purity difference, surely
It is qualitative not good, it is not suitable for the demand of industrial production and medicine preparation.
J.Med.Chem, discloses the method for formula (I) in 1996 (36) 26, while being also documented in Chinese patent
In CN92105152.2.Wherein it is briefly noted the compound recrystallization method：By Azilsartan crude product 15 times of quantity of solvent of addition
In ethanol, stir 1 hour, the fusing point for obtaining colourless prism is 212 DEG C~214 DEG C.Document (Synthesisof azilsartan
[J].Shu,Beiyan；Wu,esong；en,Junda,ZhongguoYiyaoGongyeZazhi(2010),41(12),881-
883.) preparation method of the compound is described, it is mentioned that the fusing point of the compound crystal is 190 DEG C~191 DEG C, but not
Disclose detailed crystal preparation method.Polymorph in pharmaceuticals phenomenon is one of key factor of influence drug quality and clinical efficacy,
Therefore Azilsartan is polymorphous prepares significant, needs to prepare the polymorphous additional method of Azilsartan in this area.
The polycrystal of medicine is one of the factor for influenceing drug quality, its preparation to bulk drug and pharmaceutical preparation, and
The stability of preparation, dissolution rate and bioavilability etc. have very important influence, having or even bring toxic and side effect, therefore
The crystal for studying medicine has great importance.
On the other hand, it is contemplated that crystal formation is directly prepared by intermediate would generally bring the problem that impurity is more, purity is low, existing
, when high-purity crystal formation is prepared, the method that often use first prepares refining crystallization after crude product, operating procedure is more, high cost for technology.
The content of the invention
In view of the deficiencies in the prior art, the invention provides crystal formation of a kind of Azilsartan I and preparation method thereof.The crystal formation
Preparation method directly by intermediate Azilsartan ester, eliminate crude product preparation process, saved cost, and products obtained therefrom is pure
Degree is unexpected high.
Concrete technical scheme of the present invention is：
A kind of Azilsartan crystal, fusing point is 162 DEG C.In the X-ray powder diffraction pattern of the crystal, at least following
9.37 ± 0.2 degree of the angle of diffraction, 13.08 ± 0.2 degree, 18.89 ± 0.2 degree, 19.75 ± 0.2 degree, 21.06 ± 0.2 degree, 21.94 ±
Diffraction maximum is shown at 0.2 degree, 23.54 ± 0.2 degree, 25.34 ± 0.2 degree, 27.24 ± 0.2 degree and 28.74 ± 0.2 degree, its X
Ray powder diffraction is as shown in Figure 1.
In the infrared spectrogram of crystal of the present invention, at least in following wave number 3238.35cm-1、3013.13cm-1、
1766.21cm-1、1708.44cm-1、1612.13cm-1、1548.80cm-1、1476.70cm-1、1428.89cm-1、
1345.06cm-1、1282.79cm-1、1182.36cm-1、1134.25cm-1、1033.33cm-1、935.52cm-1、764.04cm-1
And 686.82cm-1Place shows absworption peak.Its infrared absorption pattern is as shown in Figure 2.
The crystal formation crystal of Azilsartan of the present invention I is prepared and is achieved through the following technical solutions：By 2- ethyoxyls -1-
[[2 '-((5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) biphenyl -4- substitutions) methyl]-benzimidazole -7- carboxylic acid first
Ester adds alkali lye, and hydrolysis, filtering, cooling adds organic solvent A, drips acid for adjusting pH, and insulated and stirred crystallization, filtering obtains A Qi
Husky smooth I crystal crystal；
Alkali lye in above-mentioned technical proposal is one or more of NaOH, potassium hydroxide, sodium carbonate or potassium carbonate
The aqueous solution；
The mass fraction of the alkali lye in above-mentioned technical proposal is 1%~10%, more preferably 1%~5%.
In above-mentioned technical proposal alkali lye used be preferably mass fraction 1%~10% NaOH or sodium carbonate it is water-soluble
The NaOH or aqueous sodium carbonate of liquid, more preferably mass fraction 1%~5%；Concentration of lye is easy during acid adjustment beyond 10%
Caking, product purity reduction；
The preferred mole of alkali lye used is 2~10 times of Azilsartan of NaOH in above-mentioned technical proposal, or excellent
Select 1~5 times of aqueous sodium carbonate that mole is Azilsartan；More preferably mole is the hydrogen of 2~4 times of Azilsartan
Sodium oxide molybdena, or preferably mole is 1~3 times of aqueous sodium carbonate of Azilsartan；
Hydrolysis temperature is 50~80 DEG C in above-mentioned technical proposal, and more preferably hydrolysis temperature is 65~75 DEG C；
Organic solvent A used is the mixed of one or more of acetone, butanone and tetrahydrofuran in above-mentioned technical proposal
Compound；
In above-mentioned technical proposal, in terms of mass volume ratio, the consumption of organic solvent A used is the 3~15 of Azilsartan
Times, more preferably 5~10 times；
PH value in above-mentioned technical proposal during acid adjustment is controlled 1~4；
The temperature of insulated and stirred crystallization is 0~40 DEG C in above-mentioned technical proposal, and the temperature of more preferably warm stirring and crystallizing is 15
~25 DEG C, the time of warm stirring and crystallizing is 2~6 hours.
The preparation method of crystal formation disclosed by the invention I, impurity is few, and product quality is high, it is single it is miscellaneous be less than 0.02%, high income,
Yield can reach more than 88%, purity more than 99.93%.Preparation method is simple, is adapted to industrialized production.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction figure of Azilsartan crystal formation I
Fig. 2 is the infrared spectrogram of Azilsartan crystal formation I
Specific embodiment
Following examples further describe the present invention, but these embodiments are only for the explanation present invention, rather than right
Limitation of the invention.
Hereinafter starting material Azilsartan ester is published in from Shu Beiyan etc. in embodiment illustratively《Chinese Medicine work
Industry magazine》2010,41 (12) the 881-883 pages of documents《The synthesis of Azilsartan》.But empirical tests the method for the invention is same
Sample is applied to the Azilsartan ester obtained by other method, including Zhang Zhi is super is published in《Chinese pharmaceutical chemistry magazine》2011,21(4)
331-334 pages of document《Azilsartan ester (azilsartan medoxomil)》The Azilsartan ester；Jia Jingyu《Chemistry grinds
Study carefully and application》2014,26 (3) 413-417 pages of documents《The synthesising process research of Azilsartan ester》The Azilsartan ester, receives
Rate is attained by more than 88%, and purity more than 99.93% is singly miscellaneous to be less than 0.02%.
Embodiment 1
Will Azilsartan (5.0g, 10.6mmol) put into there-necked flask in, add 2% sodium hydrate aqueous solution (60ml,
30mmol), it is heated to 75 DEG C to stir 1 hour, heat filter, filtrate adds the stirring of 25ml acetone to be cooled to 0 DEG C, 3% hydrochloric acid is added dropwise molten
Liquid is adjusted to PH to 2, and 20 DEG C are stirred 4 hours, and suction filtration is vacuum dried to obtain Azilsartan off-white powder, and yield 94.84% is pure
Degree 99.97%.List is miscellaneous to be less than 0.02%.
Embodiment 2
Will Azilsartan (5.0g, 10.6mmol) put into there-necked flask in, add 1% sodium hydrate aqueous solution (120ml,
30mmol), it is heated to 65 DEG C to stir 2 hours, heat filter, filtrate adds the stirring of 25ml acetone to be cooled to 0 DEG C, 3% hydrochloric acid is added dropwise molten
Liquid is adjusted to PH to 2, and 15 DEG C are stirred 3 hours, and suction filtration is vacuum dried to obtain Azilsartan off-white powder, and yield 93.78% is pure
Degree 99.97%.List is miscellaneous to be less than 0.02%.
Embodiment 3
Will Azilsartan (5.0g, 10.6mmol) put into there-necked flask in, add 5% sodium hydrate aqueous solution (24ml,
40mmol), it is heated to 70 DEG C to stir 1 hour, heat filter, filtrate adds the stirring of 25ml acetone to be cooled to 5 DEG C, 3% hydrochloric acid is added dropwise molten
Liquid is adjusted to PH to 3, and 25 DEG C are stirred 2 hours, and suction filtration is vacuum dried to obtain Azilsartan off-white powder, and yield 92.72% is pure
Degree 99.97%.List is miscellaneous to be less than 0.02%.
Embodiment 4
Will Azilsartan (5.0g, 10.6mmol) put into there-necked flask in, add 10% sodium hydrate aqueous solution (12ml,
20mmol), it is heated to 50 DEG C to stir 1 hour, heat filter, filtrate adds the stirring of 50ml tetrahydrofurans to be cooled to 0 DEG C, and 3% salt is added dropwise
Acid solution is adjusted to PH and stirred 2 hours for 0 DEG C to Isosorbide-5-Nitrae, and suction filtration is vacuum dried to obtain Azilsartan off-white powder, yield
90.66%, purity 99.96%.List is miscellaneous to be less than 0.02%.
Embodiment 5
Will Azilsartan (5.0g, 10.6mmol) put into there-necked flask in, add 10% aqueous sodium carbonate (16ml,
15mmol), it is heated to 80 DEG C to stir 1 hour, heat filter, filtrate adds the stirring of 75ml butanone to be cooled to 2 DEG C, 3% hydrochloric acid is added dropwise molten
Liquid is adjusted to PH to 4, and 30 DEG C are stirred 2 hours, and suction filtration is vacuum dried to obtain Azilsartan off-white powder, and yield 88.96% is pure
Degree 99.97%.List is miscellaneous to be less than 0.02%.
Embodiment 6
Will Azilsartan (5.0g, 10.6mmol) put into there-necked flask in, add 10% aqueous sodium carbonate (16ml,
30mmol), it is heated to 80 DEG C to stir 1 hour, heat filter, filtrate adds the stirring of 75ml butanone to be cooled to 2 DEG C, 3% hydrochloric acid is added dropwise molten
Liquid is adjusted to PH to 4, and 30 DEG C are stirred 2 hours, and suction filtration is vacuum dried to obtain Azilsartan off-white powder, and yield 88.88% is pure
Degree 99.96%.List is miscellaneous to be less than 0.02%.
Embodiment 7
By in Azilsartan (5.0g, 10.6mmol) input there-necked flask, 10% potassium hydroxide aqueous solution is added
(16.8ml, 30mmol), is heated to 80 DEG C and stirs 2 hours, and heat filter, filtrate adds 15ml butanone and acetone mixture (butanone：Third
Ketone=1:3) stirring is cooled to 0 DEG C, 3% hydrochloric acid solution is added dropwise and adjusts to PH to 4, and 5 DEG C are stirred 6 hours, and suction filtration is vacuum dried
Azilsartan off-white powder, yield 90.08%, purity 99.94%.List is miscellaneous to be less than 0.02%.
Embodiment 8
Will Azilsartan (5.0g, 10.6mmol) put into there-necked flask in, add 13% aqueous sodium carbonate (44.9ml,
63.6mmol), it is heated to 75 DEG C to stir 1 hour, heat filter, filtrate adds the stirring of 25ml isopropanols to be cooled to 0 DEG C, and 3% salt is added dropwise
Acid solution is adjusted to PH to 5, and 20 DEG C are stirred 4 hours, and suction filtration is vacuum dried to obtain Azilsartan off-white powder, yield
83.71%, purity 97.04%.List is miscellaneous to be less than 0.12%.
Embodiment 9
Will Azilsartan (5.0g, 10.6mmol) put into there-necked flask in, add 13% aqueous sodium carbonate (44.9ml,
63.6mmol), it is heated to 75 DEG C to stir 1 hour, heat filter, filtrate adds the stirring of 10ml isopropanols to be cooled to 0 DEG C, and 3% salt is added dropwise
Acid solution is adjusted to PH to 5, and 20 DEG C are stirred 4 hours, and suction filtration is vacuum dried to obtain Azilsartan off-white powder, yield
83.75%, purity 96.22%.List is miscellaneous to be less than 0.15%.
Embodiment 10
Will Azilsartan (5.0g, 10.6mmol) put into there-necked flask in, add 13% aqueous sodium carbonate (44.9ml,
63.6mmol), it is heated to 75 DEG C to stir 1 hour, heat filter, filtrate adds the stirring of 100ml isopropanols to be cooled to 0 DEG C, and 3% salt is added dropwise
Acid solution is adjusted to PH to 5, and 20 DEG C are stirred 4 hours, and suction filtration is vacuum dried to obtain Azilsartan off-white powder, yield
80.22%, purity 97.81%.List is miscellaneous to be less than 0.07%.
Claims (10)
1. a kind of Azilsartan I crystal, in the X-ray powder diffraction pattern of its crystal, at least following angles of diffraction 9.135 ±
0.2 degree, 12.72 ± 0.2 degree, 18.295 ± 0.2 degree, 19.358 ± 0.2 degree, 20.350 ± 0.2 degree, 21.477 ± 0.2 degree,
Diffraction maximum is shown at 23.530 ± 0.2 degree, 25.287 ± 0.2 degree, 26.690 ± 0.2 degree and 28.811 ± 0.2 degree.
2. the preparation method of I crystal according to claim 1, it is characterised in that operating procedure is as follows：By 2- ethyoxyls -1-
[[2 '-((5- oxo -4,5- dihydro -1,2,4- oxadiazole -3- bases) biphenyl -4- substitutions) methyl]-benzimidazole -7- carboxylic acid first
Ester adds alkali lye, and hydrolysis, filtering, cooling adds organic solvent A, drips acid for adjusting pH, and insulated and stirred crystallization, filtering obtains A Qi
Husky smooth I crystal.
3. preparation method according to claim 2, it is characterised in that the alkali lye is selected from NaOH, potassium hydroxide, carbon
One or more in sour sodium and potassium carbonate of the aqueous solution.
4. the preparation method according to Claims 2 or 3, it is characterised in that the mass fraction of the alkali lye is 1%~
10%, more preferably 1%~5%.
5. the preparation method according to Claims 2 or 3, it is characterised in that the alkali lye is mass fraction 1%~10%
The NaOH or aqueous sodium carbonate of NaOH or aqueous sodium carbonate, more preferably mass fraction 1%~5%.
6. preparation method according to claim 2, it is characterised in that hydrolysis temperature is 50~80 DEG C, preferably 65~75
℃。
7. preparation method according to claim 2, it is characterised in that organic solvent A used is selected from acetone, butanone and tetrahydrochysene
One or more mixture in furans.
8. the preparation method according to claim 2 or 7, it is characterised in that in terms of mass volume ratio, organic solvent A used
Consumption be 3~15 times, more preferably 5~10 times of Azilsartan.
9. preparation method according to claim 2, it is characterised in that pH value during acid adjustment is controlled 1~4.
10. preparation method according to claim 2, it is characterised in that the temperature of insulated and stirred crystallization is 0~40 DEG C, excellent
Elect 15~25 DEG C as, the time of insulated and stirred crystallization is 2~6 hours.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| JP2019172635A (en) * | 2018-03-29 | 2019-10-10 | 金剛化学株式会社 | Manufacturing method of azilsartan fine crystal |
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| 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 |
| 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 |
| CN103664921A (en) * | 2013-11-27 | 2014-03-26 | 湖南千金湘江药业股份有限公司 | Azilsartan of crystal form A, and preparation method thereof |
| CN103930419A (en) * | 2011-09-30 | 2014-07-16 | 广东东阳光药业有限公司 | Crystalline forms of azilsartan and preparation and uses thereof |
| CN105949182A (en) * | 2013-10-12 | 2016-09-21 | 杭州领业医药科技有限公司 | Crystal form of azilsartan medoxomil and preparation method of crystal form |
-
2017
- 2017-01-22 CN CN201710053991.3A patent/CN106749217A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN103930419A (en) * | 2011-09-30 | 2014-07-16 | 广东东阳光药业有限公司 | Crystalline forms of azilsartan and preparation and uses 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 |
| CN105949182A (en) * | 2013-10-12 | 2016-09-21 | 杭州领业医药科技有限公司 | Crystal form of azilsartan medoxomil and preparation method of crystal form |
| CN103664921A (en) * | 2013-11-27 | 2014-03-26 | 湖南千金湘江药业股份有限公司 | Azilsartan of crystal form A, 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2019172635A (en) * | 2018-03-29 | 2019-10-10 | 金剛化学株式会社 | Manufacturing method of azilsartan fine 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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