CN106279140A - A kind of preparation method of Azilsartan contamination levels product - Google Patents
A kind of preparation method of Azilsartan contamination levels product Download PDFInfo
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- CN106279140A CN106279140A CN201610662625.3A CN201610662625A CN106279140A CN 106279140 A CN106279140 A CN 106279140A CN 201610662625 A CN201610662625 A CN 201610662625A CN 106279140 A CN106279140 A CN 106279140A
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- Prior art keywords
- azilsartan
- preparation
- dihydro
- oxo
- impurity
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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
Abstract
The invention discloses the preparation method of a kind of Azilsartan contamination levels product, it is with Azilsartan as raw material, crude product is prepared through mineral acid hydrolysis, crude product warp is refined and obtains 2 oxo 3 [[2'(5 oxos 4,5 dihydros 1,2,4 diazole 3 bases) double phenyl 4 bases] methyl] 2,3 dihydro 1H benzimidazole 4 carboxylic acid sterlings.The impurity preparation method cheaper starting materials that the present invention provides is easy to get, technique is simple and direct, manufacturing cycle is short, through demarcating product content more than 98.5%.The Azilsartan impurity that the present invention provides can be applied to Azilsartan raw material and the qualitative and quantitative study of preparation impurity thereof and detection as contamination levels product.
Description
One, technical field
The present invention relates to the preparation method of a kind of impurity of the drug standard substance, specifically a kind of Azilsartan contamination levels
The preparation method of product, belongs to pharmaceutical technology field.
Two, background technology
Azilsartan (Azilsartan) is a kind of angiotensin-ii receptor AT1Receptor subtype antagonist, the most right
AT on vascular smooth muscle, adrenal gland1Subtype acceptor, can block its pressor effect and reduce the effect of aldosterone, clinical research
Showing, Azilsartan reduces contraction pressure ratio other angiotensin receptor antagonists (Angiotensin receptor
Blocker, ARB) class medicine (such as: Olmesartan, valsartan, Candesartan) and Angiotensin-Converting
(Angiotensin-convertingenzyme, ACE) inhibitor (such as: ramipril) is more effective.It addition, Azilsartan and calcium
Antagonism of ions agent amlodipine (Amlodipine) share and can not only effectively reduce contraction pressure, and can reduce periphery edema
Occur, can effectively reduce contraction pressure with thiazide diuretic chlortalidone use in conjunction, the hyperpietic of complicated with diabetes is had
Prevention and treatment dual function.
Azilsartan chemistry entitled 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-diazole-3-base) double phenyl-4-
Base] methyl]-2-ethyoxyl-1H-benzimidazole-7-carboxylic acid, by the exploitation of Wu Tian company of Japan, list in Japan in May, 2012,
Trade name " Azilva ", specification is 20mg and 40mg tablet.
Azilsartan raw material and preparation thereof can produce degradation impurity in storage, transportation: 2-oxo-3-[[2'-(5-
Oxo-4,5-dihydro-1,2,4-diazole-3-base) double phenyl-4-bases] methyl]-2,3-dihydro-1H-benzimidazole-4-carboxylic
Acid, shown in its structure such as formula (I).This impurity can significantly generate during preparation produces and stability keeps sample.Japan
IF file reports that this impurity is that metabolite, patent CN201310382706.4 and CN201510926624.0 disclose it for degraded
Impurity, is major impurity in Azilsartan raw material and preparation thereof.Synthesis and content scaling method currently, with respect to this impurity have no
Report.In view of this impurity is most important to controlling Azilsartan product quality, and what it can use as those skilled in the art
Preparation method and the quality determining method of standard substance are the most not available, therefore the acquisition of these contamination levels product is to effectively controlling A Qisha
Smooth raw material and the quality of the pharmaceutical preparations thereof have great significance.
Three, summary of the invention
It is desirable to provide the preparation method of a kind of Azilsartan contamination levels product, i.e. 2-oxo-3-[[2'-(5-oxygen
Generation-4,5-dihydro-1,2,4-diazole-3-base) double phenyl-4-bases] methyl]-2,3-dihydro-1H-benzimidazole-4-carboxylic acid work
Making the preparation method of standard substance, this method has the advantage that cheaper starting materials is easy to get, technique is simple and direct, manufacturing cycle is short, proven
Product content is high.
The preparation method of Azilsartan contamination levels product of the present invention, comprises the steps:
1, hydrolysis
Azilsartan is added in ethanol and heating for dissolving, drips mineral acid, in 78～85 DEG C of return stirrings react 3～
4h, reaction is cooled to 0～10 DEG C after terminating, and filters, and solid, in 50～60 DEG C of drying under reduced pressure 2～3h, obtains impurity crude product (i.e. 2-oxygen
Generation-3-[[2'-(5-oxo-4,5-dihydro-1,2,4-diazole-3-base) double phenyl-4-bases] methyl]-2,3-dihydro-1H-benzene
And imidazoles-4-crude carboxylic acid).
The Azilsartan that the present invention uses is general commercially available commercial synthesis product, and its No. CAS is 147403-03-0.
Mineral acid described in step 1 is selected from one or both in hydrochloric acid, hydrobromic acid.
In step 1, Azilsartan is 1g:10～20ml with the mass volume ratio of ethanol；Azilsartan and mineral acid mole
Ratio is 1:4～8.
2, refined
In impurity crude product, adding organic solvent, dissolve in 80～100 DEG C of heated and stirred, filtered while hot, filtrate is cooled to-
5～0 DEG C of stirring and crystallizing 1～2h, filter, and filter cake washing with alcohol, solid, in 50～60 DEG C of drying under reduced pressure 3～5h, obtains impurity pure
Product (i.e. 2-oxo-3-[[2'-(5-oxo-4,5-dihydro-1,2,4-diazole-3-base) double phenyl-4-bases] methyl]-2,3-
Dihydro-1H-benzimidazole-4-carboxylic acid sterling), for white crystal.
Organic solvent described in step 2 is selected from one or both in N,N-dimethylformamide, dimethyl sulfoxide.
Impurity crude product described in step 2 is 1g:10～15ml with the mass volume ratio of organic solvent.
Syntheti c route of the present invention is as follows:
2-oxo-3-that the present invention prepares [[2'-(5-oxo-4,5-dihydro-1,2,4-diazole-3-base) double phenyl-
4-yl] methyl] the cubage method of-2,3-dihydro-1H-benzimidazole-4-carboxylic acid is as follows:
Content (%)=(100.0% loss on drying % residue on ignition %) × chromatographic purity
Loss on drying is used for measuring volatile impurity in sample (such as residual solvent) or low boiling impurity (such as: moisture)
Content, analyzes method as follows:
Take this product 1g, totally 2 parts, put in the constant temperature vacuum drying apparatus added with phosphorus pentoxide, according to dry weightless mensuration (in
2015 editions four general rules<0831>of state's pharmacopeia) 80 DEG C of drying under reduced pressure to constant weight, calculate less loss weight respectively and account for the hundred of sample total amount
Proportion by subtraction, takes the meansigma methods of 2 results.
Residue on ignition be used for measuring inorganic impurity in sample (such as: inorganic salt) or can not the content of carbide (such as: metal),
Analysis method is as follows:
Take this product 1g, totally 2 parts, measure according to residue on ignition algoscopy (2015 editions four general rules<0841>of Chinese Pharmacopoeia), point
Ji Suan not account for the percentage ratio of sample total amount by level of residue, take the meansigma methods of 2 results.
Chromatographic purity accounts for the ratio of detection total organic matter for analyzing main composition in sample, analyzes method as follows:
HPLC method:
Chromatographic column: Agilent C18 (250mm × 4.6mm, 5.0 μm)
Flowing phase: water-acetonitrile-acetic acid (55:45:1)
Detection wavelength: 242nm
Sample concentration: 0.3mg/ml (solvent is flowing phase)
Flow velocity: 1.0ml/min
Sample size: 10 μ l
In HPLC chromatogram, after deduction solvent peak, (main peak area accounts for Zong Feng to calculate main peak content by areas of peak normalization method
The percentage ratio of area).It is calculated as follows chromatographic purity:
Chromatographic purity=main peak content %/100%
As stated above, demarcate the present invention prepare 2-oxo-3-[[2'-(and 5-oxo-4,5-dihydro-1,2,4-bis-
Azoles-3-base) double phenyl-4-bases] methyl]-2,3-dihydro-1H-benzimidazole-4-carboxylic acid content, demarcate content and be all higher than
98.5%.
2-oxo-3-of the present invention [[2'-(5-oxo-4,5-dihydro-1,2,4-diazole-3-base) double phenyl-4-bases] first
Base]-2,3-dihydro-1H-benzimidazole-4-carboxylic acid manufacturing processes is simple and direct, synthesis cycle is short, raw materials used cheap and easy to get, synthesis
Low cost, had both been suitable for laboratory in a small amount synthesis it can also be used to large-scale production.
2-oxo-3-of the present invention [[2'-(5-oxo-4,5-dihydro-1,2,4-diazole-3-base) double phenyl-4-bases] first
Base]-2,3-dihydro-1H-benzimidazole-4-carboxylic acid content scaling method is conventional method of analysis, and appointed condition is the highest, the most in fact
Existing.
Use 2-oxo-3-[[2'-(5-oxo-4,5-dihydro-1,2,4-diazole-3-base) prepared by the inventive method
Double phenyl-4-bases] methyl]-2, the demarcation content of 3-dihydro-1H-benzimidazole-4-carboxylic acid is all higher than 98.5%, can be as miscellaneous
Matter standard substance, are applied to Azilsartan raw material and the qualitative and quantitative study of preparation impurity thereof and detection, to effectively controlling A Qisha
Smooth raw material and the quality of the pharmaceutical preparations thereof have positive progressive meaning.
Four, accompanying drawing explanation
Fig. 1 is [[2'-(5-oxo-4,5-dihydro-1,2,4-diazole-3-base) the double benzene of 2-oxo-3-in embodiment 1
Base-4-base] methyl]-2,3-dihydro-1H-benzimidazole-4-carboxylic acid purity detecting chromatogram.It will be seen from figure 1 that chromatographically pure
Degree is 0.9914.
Fig. 2 is [[2'-(5-oxo-4,5-dihydro-1,2,4-diazole-3-base) the double benzene of 2-oxo-3-in embodiment 2
Base-4-base] methyl]-2,3-dihydro-1H-benzimidazole-4-carboxylic acid purity detecting chromatogram.Figure it is seen that chromatographically pure
Degree is 0.9913.
Five, detailed description of the invention
Following preferable examples of the present invention will be described, it will be appreciated that preferred embodiment described herein is only used for
Bright and explain the present invention, be not intended to limit the present invention.
Embodiment 1:
In the present embodiment, the preparation method of Azilsartan contamination levels product is as follows:
1, Azilsartan 8g (17.52mmol) heated and stirred is dissolved in 120ml ethanol, drips 40%HBr solution 17.4g
(86mmol), reacting 0.5h in 78～85 DEG C of return stirrings after dripping off, stirring is cooled to 0～10 DEG C, filters, and solid is in 50～60
DEG C drying under reduced pressure 3h, obtains 2-oxo-3-[[2'-(5-oxo-4,5-dihydro-1,2,4-diazole-3-bases) double phenyl-4-bases]
Methyl]-2,3-dihydro-1H-benzimidazole-4-crude carboxylic acid 6.8g, yield 90.6%.
2, in 6.8g crude product, add DMF 80ml, dissolve in 80～100 DEG C of heated and stirred, mistake while hot
Filter, filtrate is cooled to-5～0 DEG C of stirring and crystallizing 1h, filters, and filter cake ethanol in proper amount is washed, and solid is in 50～60 DEG C of drying under reduced pressure
3h, obtains 2-oxo-3-[[2'-(5-oxo-4,5-dihydro-1,2,4-diazole-3-bases) double phenyl-4-bases] methyl]-2,3-
Dihydro-1H-benzimidazole-4-carboxylic acid sterling 6.2g, yield 91.2%.
Elementary analysis is C23H16N4O5
| Analysis project | C (%) | H (%) | N (%) |
| Theoretical value | 64.48 | 3.76 | 13.08 |
| Measured value | 64.32 | 3.90 | 13.11 |
TOF-MS[M+H]+: 429.1 (Exact Mass:428.11)
IR(KBr)ν(cm-1): 3572,3490,3371,3086,3033,2952,1725,1679,1624,1598,1555,
1492,1470,1386
1HNMR (DMSO-d6) δ (ppm): 13.13 (s, 1H, COOH), 12.41 (s, 1H, NH), 11.39 (s, 1H, NH),
7.64～7.68 (m, 2H, Ar-H), 7.54 (m, 1H, Ar-H), 7.47 (d, 1H, Ar-H), 7.34 (dd, 1H, Ar-H), 7.21～
7.24 (m, 3H, Ar-H), 7.11 (d, 2H, Ar-H), 7.06 (t, 1H, Ar-H), 5.45 (s, 2H, CH2)
13CNMR (DMSO-d6) δ (ppm): 167.3,159.4,158.2,154.9,140.7,137.5,137.4,131.8,
130.6,130.2,129.8,128.7 (2C), 128.0,127.7,126.7 (2C), 122.4,122.1,120.5,115.7,
112.2
Content calibration result:
Purity detecting chromatogram is shown in Fig. 1.
Embodiment 2:
In the present embodiment, the preparation method of Azilsartan contamination levels product is as follows:
1, Azilsartan 10g (21.5mmol) heated and stirred is dissolved in 100ml ethanol, drips 40%HBr solution
21.75g (107.5mmol), reacts 1h in 78～85 DEG C of return stirrings after dripping off, and stirring is cooled to 0～10 DEG C, filters, solid
In 50～60 DEG C of drying under reduced pressure 5h, obtain 2-oxo-3-[[2'-(5-oxo-4,5-dihydro-1,2,4-diazole-3-bases) double benzene
Base-4-base] methyl]-2,3-dihydro-1H-benzimidazole-4-crude carboxylic acid 8.3g, yield 88.4%.
2, adding dimethyl sulfoxide 100ml in 8g crude product, dissolve in 80～100 DEG C of heated and stirred, filtered while hot, filtrate is dropped
Temperature, to-5～0 DEG C of stirring and crystallizing 2h, filters, and filter cake ethanol in proper amount is washed, and solid, in 50～60 DEG C of drying under reduced pressure 5h, obtains 2-oxygen
Generation-3-[[2'-(5-oxo-4,5-dihydro-1,2,4-diazole-3-base) double phenyl-4-bases] methyl]-2,3-dihydro-1H-benzene
And imidazoles-4-carboxylic acid sterling 7.3g, yield 91.3%.
Content calibration result:
Purity detecting chromatogram is shown in Fig. 2.
Unless otherwise defined, all professional terms and term used in the present invention are familiar with one skilled in the art
Meaning consistent.Additionally, any method similar or impartial to described content and material all can be applicable in the inventive method.
Claims (5)
1. the preparation method of Azilsartan contamination levels product, it is characterised in that comprise the steps:
(1) hydrolysis
Azilsartan is added in ethanol and heating for dissolving, drip mineral acid, in 78～85 DEG C of return stirrings reactions 3～4h, instead
Should be cooled to 0～10 DEG C after terminating, filter, solid, in 50～60 DEG C of drying under reduced pressure 2～3h, obtains impurity crude product；
(2) refined
Adding organic solvent in impurity crude product, dissolve in 80～100 DEG C of heated and stirred, filtered while hot, filtrate is cooled to-5～0
DEG C stirring and crystallizing 1～2h, filters, filter cake washing with alcohol, and solid, in 50～60 DEG C of drying under reduced pressure 3～5h, obtains impurity sterling i.e.
2-oxo-3-[[2'-(5-oxo-4,5-dihydro-1,2,4-diazole-3-base) double phenyl-4-bases] methyl]-2,3-dihydro-
1H-benzimidazole-4-carboxylic acid sterling, for white crystal.
Preparation method the most according to claim 1, it is characterised in that:
Mineral acid described in step (1) is selected from one or both in hydrochloric acid, hydrobromic acid.
Preparation method the most according to claim 1, it is characterised in that:
In step (1), Azilsartan is 1g:10～20ml with the mass volume ratio of ethanol；Azilsartan and the mol ratio of mineral acid
For 1:4～8.
Preparation method the most according to claim 1, it is characterised in that:
Organic solvent described in step (2) is selected from one or both in N,N-dimethylformamide, dimethyl sulfoxide.
Preparation method the most according to claim 1, it is characterised in that:
Impurity crude product described in step (2) is 1g:10～15ml with the mass volume ratio of organic solvent.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113880824A (en) * | 2021-09-28 | 2022-01-04 | 山东创新药物研发有限公司 | Azilsartan photodegradation impurity compound, preparation method and application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012107814A1 (en) * | 2011-02-08 | 2012-08-16 | Jubilant Life Sciences Limited | An improved process for the preparation of azilsartan medoxomil |
| CN104072491A (en) * | 2013-03-29 | 2014-10-01 | 天津药物研究院 | Azilsartan derivative compound and preparation method and application thereof |
| CN105712984A (en) * | 2016-03-04 | 2016-06-29 | 江苏正大清江制药有限公司 | Preparation method of Azilsartan |
-
2016
- 2016-08-12 CN CN201610662625.3A patent/CN106279140A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012107814A1 (en) * | 2011-02-08 | 2012-08-16 | Jubilant Life Sciences Limited | An improved process for the preparation of azilsartan medoxomil |
| CN104072491A (en) * | 2013-03-29 | 2014-10-01 | 天津药物研究院 | Azilsartan derivative compound and preparation method and application thereof |
| CN105712984A (en) * | 2016-03-04 | 2016-06-29 | 江苏正大清江制药有限公司 | Preparation method of Azilsartan |
Non-Patent Citations (1)
| Title |
|---|
| NAOHIRO KAWAGUCHI，ET AL.: ""Absorption of TAK-491,a new angiotensin II receptor antagonist,in animals"", 《XENBIOTICA》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113880824A (en) * | 2021-09-28 | 2022-01-04 | 山东创新药物研发有限公司 | Azilsartan photodegradation impurity compound, preparation method and application |
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