CN104557898A - Azilsartan tetrahydrofuran solvate and preparation method thereof - Google Patents
Azilsartan tetrahydrofuran solvate and preparation method thereof Download PDFInfo
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- CN104557898A CN104557898A CN201310511915.4A CN201310511915A CN104557898A CN 104557898 A CN104557898 A CN 104557898A CN 201310511915 A CN201310511915 A CN 201310511915A CN 104557898 A CN104557898 A CN 104557898A
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- azilsartan
- solvate
- tetrahydrofuran
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- tetrahydrofuran solvate
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- KGSXMPPBFPAXLY-UHFFFAOYSA-N CCOc1nc(cccc2C(O)=O)c2[n]1Cc(cc1)ccc1-c(cccc1)c1C(N1)=NOC1=O Chemical compound CCOc1nc(cccc2C(O)=O)c2[n]1Cc(cc1)ccc1-c(cccc1)c1C(N1)=NOC1=O KGSXMPPBFPAXLY-UHFFFAOYSA-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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- Plural Heterocyclic Compounds (AREA)
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Abstract
The invention provides an azilsartan solvate and a preparation method thereof. The azilsartan solvate is suitable to be used as a drug or used as an intermediate preparing the drug azilsartan ester for treating hypertension. The X-ray powder diffractogram of the azilsartan solvate has characteristic peaks at 7.5+/-0.2, 18.9+/-0.2, 21.2+/-0.2, 22.1+/-0.2, 22.7+/-0.2, 23.2+/-0.2 and 25.0+/-0.2. The preparation method of the solvate comprises the following steps: mixing azilsartan and tetrahydrofuran, and heating to completely or partially dissolve the azilsartan; and cooling to crystallize, and filtering to recover the precipitate, thereby obtaining the target product. The azilsartan solvate has the characteristics of high separation tendency, high stability, no hydroscopic property and the like, and is solvate. The preparation method is simple and convenient, and is suitable for industrial production.
Description
Technical field
The present invention relates to 2-oxyethyl group-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazoles-3-base) biphenyl-4-base] methyl] solvate of benzoglyoxaline-7-carboxylic acid (Azilsartan), and prepare the method for this solvate, belong to field of medicaments.
Background technology
Azilsartan, and 2-oxyethyl group-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazoles-3-base) biphenyl-4-base] methyl] benzoglyoxaline-7-carboxylic acid, structure is such as formula shown in I.This medicine is that Japanese Takeda Pharmaceutical Company Limited takes listing certification in 2012, and this medicine is a kind of angiotensin II receptor antagonists, can be used alone or use [3] together with other Altace Ramipril, being considered the next-generation of candesartan Cilexetil.Thomson Reuters society (Thomson Reuters) predicts that this medicine is smoothly by certification, should reach and year sell 700,010,330 dollars 2014 time.
The theme of the embodiment 1 of Chinese patent CN92105152C discloses the preparation method of chemistry examination I: by 2-oxyethyl group-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazoles-3-base) biphenyl-4-base] methyl] benzoglyoxaline-7-carboxylate methyl ester with after lithium hydroxide saponification, adjusts pH to 3 with 2mol/L hydrochloric acid, solvent evaporated in methyl alcohol, add water and chloroform, retain organic phase and drying, by re-crystallizing in ethyl acetate after evaporate to dryness organic phase, Formula I by the time.Priority Patent JP1991157194 and Chinese patent CN92105152C does not illustrate that Formula I is crystal type; In addition, whether these patents all do not disclose described compound other crystal formations or solvate.
Therefore, in view of the market outlook of Azilsartan, research is carried out to the form of Azilsartan polytropism or solvate and is very important.
Summary of the invention
The invention discloses a kind of novel Azilsartan tetrahydrofuran solvent compound.
The invention provides a kind of novel Azilsartan tetrahydrofuran solvent compound, it is characterized in that DSC collection of illustrative plates comprises transformation peaks 176 ~ 178 DEG C, fusing decomposition peak 266 ~ 268 DEG C;
Azilsartan tetrahydrofuran solvent compound of the present invention has X-ray powder diffraction as shown in Figure 1.Concrete θ angle, Prague 2, spacing d, intensity and relative intensity (representing with the percentage ratio of the strongest diffracted ray) are in table 1.
Table 1
This XRPD test set and method are:
X-ray diffractometer: X ' Pert Pro MPD (Multi-Purpose Diffractometer)
Light pipe type: Empyrean XRD tube Cu LFF HR
Electric current and voltage: 45kV, 40mA
The vertical goniometer of goniometer: PW3050/60, radius 240mm
Slit: DS=2 °, SS=1/2 °, mask=15mm, RS=5.0mm
The super detector of detector: X ' Celerator
Scan pattern: continuous sweep
Sweep limit (2 θ): 3.0-50.0 °
Step-length (2 θ): 0.0167 °
Often walk gate time: 50s
Scanning total time: 20min
DSC-TGA test set and method:
Unit type: plum Teller-Tuo benefit DSC1
Heating schedule: 30 ~ 300 DEG C, 10 DEG C/min
The invention also discloses the preparation method of Azilsartan tetrahydrofuran solvent compound, specifically comprise the steps:
(1) Azilsartan is added in tetrahydrofuran (THF)
(2) heating system is clarified or long-time stirring system still muddy
(3) suitable temp is cooled to
(4) filter to obtain solid, dry, obtain Azilsartan tetrahydrofuran solvent compound
In step of the present invention (1), the Azilsartan used can be any one crystal habit or without crystal formation form or the mixture without crystal formation form and crystal habit
In step of the present invention (1), 1 ~ 100 times that the volumetric usage of the tetrahydrofuran (THF) of use is Azilsartan quality consumption; In step of the present invention (2), heating makes system become clarification, does not have too large restriction, only need this system to clarify to the temperature range of heating;
In step of the present invention (2), the tetrahydrofuran solution system of Azilsartan also can be selected in the still muddy state of long-time stirring system, and this process temperature, below 30 DEG C, stirs the time used and temperature not requirement for a long time;
In step of the present invention (3), cooling makes the temperature of system at-30 ~ 30 DEG C, and preferably at room temperature (or other temperature ranges) obtain;
The method that the present invention prepares Azilsartan tetrahydrofuran solvent compound is reproducible, easy and simple to handle, and product yield is high, and purity is high, is applicable to suitability for industrialized production.
Thermostability experiment shows, this crystal formation has higher thermostability, as follows with former thermostability comparative data of grinding crystal formation:
Trial-product, under 50 DEG C of vacuum, detects the purity under its differing temps:
Accompanying drawing illustrates:
Fig. 1 is X-ray powder diffraction (XRPD) collection of illustrative plates of the Azilsartan tetrahydrofuran solvent compound of embodiment 1 gained.
Fig. 2 is the DSC-TGA thermal analyses collection of illustrative plates of the Azilsartan tetrahydrofuran solvent compound of embodiment 3 gained.
Fig. 3 is the H-NMR collection of illustrative plates of the Azilsartan tetrahydrofuran solvent compound of embodiment 5 gained.
Specific embodiment
Embodiment 1:
Take in Azilsartan 30g and reaction flask, then add tetrahydrofuran (THF) 600ml, be heated to backflow, after solid all dissolves, be slowly down to room temperature again, filter, at 40 DEG C, vacuum is to constant weight, obtains Azilsartan tetrahydrofuran solvate 25g.
Embodiment 2:
Take in Azilsartan 30g and reaction flask, then add tetrahydrofuran (THF) 400ml, water 200ml, be heated to slowly be down to room temperature again after solid all dissolves, filter, at 40 DEG C, vacuum is to constant weight, obtains Azilsartan tetrahydrofuran solvate 23g.
Embodiment 3:
Take in Azilsartan 30g and reaction flask, then add tetrahydrofuran (THF) 900ml, be stirred to after solid all dissolves and be slowly down to 10 DEG C again, filter, at 40 DEG C, vacuum is to constant weight, obtains Azilsartan tetrahydrofuran solvate 22g.
Embodiment 4:
Take in Azilsartan 30g and reaction flask, after adding tetrahydrofuran (THF) 3000ml, system muddiness, stirring at room temperature were filtered after 24 ~ 36 hours, and filter at-30 DEG C, at 40 DEG C, vacuum is to constant weight, obtains Azilsartan tetrahydrofuran solvate 20g.
Embodiment 5:
Take in Azilsartan 30g and reaction flask, then after adding tetrahydrofuran (THF) 30ml, system muddiness, stirring at room temperature were filtered after 36 ~ 48 hours, filtered at room temperature, at 40 DEG C, vacuum is to constant weight, obtains Azilsartan tetrahydrofuran solvate 27g.
Claims (8)
1. an Azilsartan tetrahydrofuran solvate, it is characterized in that, its X-ray powder diffraction figure is 7.5 ± 0.2, 8.5 ± 0.2, 8.9 ± 0.2, 9.5 ± 0.2, 11.0 ± 0.2, 12.4 ± 0.2, 13.1 ± 0.2, 13.5 ± 0.2, 14.2 ± 0.2, 15.0 ± 0.2, 15.5 ± 0.2, 16.2 ± 0.2, 17.1 ± 0.2, 18.4 ± 0.2, 18.9 ± 0.2, 19.9 ± 0.2, 21.2 ± 0.2, 22.1 ± 0.2, 22.7 ± 0.2, 23.2 ± 0.2, 23.5 ± 0.2, 24.1 ± 0.2, 25.0 ± 0.2, 25.5 ± 0.2, 25.8 ± 0.2, 27.4 ± 0.2, 28.6 ± 0.2, 28.9 ± 0.2, 29.3 ± 0.2, 30.3 ± 0.2, 31.4 ± 0.2, 32.4 ± 0.2, 33.9 ± 0.2, 36.0 ± 0.2, 37.7 ± 0.2 and 38.5 ± 0.2 degree of 2 θ place is containing peak.
2. Azilsartan tetrahydrofuran solvate according to claim 1, is characterized in that, when using DSC-TGA to analyze, under the rate of heating of 10K/ minute, occurring endotherm(ic)peak at 177 ± 4 DEG C, having the weightlessness of 5.5% at 140 ~ 177 DEG C.
3. Azilsartan tetrahydrofuran solvate according to claim 1, is characterized in that, when using DSC-TGA to analyze, under the rate of heating of 10K/ minute, has the weightlessness of 5.5% ± 2% at 140 ~ 177 DEG C.
4. Azilsartan tetrahydrofuran solvate according to claim 1, is characterized in that, when using H-NMR to analyze, under deuterated dimethyl sulfoxide dissolves, chemical shift is 1.7 ± 0.2, and there is H peak at 3.6 ± 0.2 places.
5. prepare a method for Azilsartan tetrahydrofuran solvate as claimed in claim 1, comprising:
(1) by Azilsartan and tetrahydrofuran (THF) mixing, heat all or part of for Azilsartan dissolving;
(2) cooling crystallization, filtered and recycled precipitates, and obtains target product.
6. preparation method according to claim 5, is characterized in that, 1 ~ 100 times that the volumetric usage of the tetrahydrofuran (THF) that step (1) uses is Azilsartan quality.
7. preparation method according to claim 5, is characterized in that, the temperature range of the described cooling crystallization of step (2) is :-30 DEG C ~ 30 DEG C.
8. preparation method according to claim 7, is characterized in that, the temperature of the described cooling crystallization of step (2) is room temperature.
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| CN201310511915.4A CN104557898A (en) | 2013-10-24 | 2013-10-24 | Azilsartan tetrahydrofuran solvate and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013044816A1 (en) * | 2011-09-30 | 2013-04-04 | Sunshine Lake Pharma Co., Ltd. | 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 |
| 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 |
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- 2013-10-24 CN CN201310511915.4A patent/CN104557898A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013044816A1 (en) * | 2011-09-30 | 2013-04-04 | Sunshine Lake Pharma Co., Ltd. | 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 |
| 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 |
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Inventor after: Liao Wenjing Inventor after: Guo Xiaowen Inventor after: Huang Luning Inventor after: Gu Hong Inventor before: Liao Wenjing Inventor before: Guo Xiaowen Inventor before: Huang Luning Inventor before: Zhang Xini |
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Application publication date: 20150429 |