CN105753854A - New preparation method of azilsartan kamedoxomil - Google Patents
New preparation method of azilsartan kamedoxomil Download PDFInfo
- Publication number
- CN105753854A CN105753854A CN201410774050.5A CN201410774050A CN105753854A CN 105753854 A CN105753854 A CN 105753854A CN 201410774050 A CN201410774050 A CN 201410774050A CN 105753854 A CN105753854 A CN 105753854A
- Authority
- CN
- China
- Prior art keywords
- azilsartan
- salt
- potassium
- organic amine
- potassium salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention discloses a new preparation method of azilsartan kamedoxomil. The preparation method is characterized by comprising the steps: taking azilsartan medoxomil as a raw material, carrying out a reaction with an organic alkali to obtain azilsartan medoxomil organic amine salt with high solubility, and then carrying out a reaction of the azilsartan medoxomil organic amine salt with an organic kali salt to obtain the target product-azilsartan kamedoxomil. Compared with a conventional process, the method has the advantages of novel design, low impurity, high yield and the like. Moreover, the operation is safe and convenient, the problem of poor solubility of azilsartan medoxomil is solved, and the preparation method has industrialized prospect.
Description
Technical field
The present invention relates to field of medicine and chemical technology, particularly relate to a kind of new technology preparing Azilsartan potassium salt.
Background technology
Azilsartan potassium salt raw material and preparation are by the angiotensin ii receptor antagonist medicine of the treatment vascular hypertension of military field pharmacy [TakedaPharmaceuticalCompanyLimited] company exploitation, it is used for treatment vascular hypertension, is also currently the only angiotensin ii receptor antagonist (the husky smooth class) medicine being in late-stage clinical.List in the U.S. on February 22nd, 2011, be used for treating essential hypertension.Its chemistry (5-methyl-2-2 oxo-1,3-dioxole-4-base) methyl 2-ethyoxyl-1-{ [2 '-(5-oxo-4,5-dihydro-1,2,4-diazole-3-base) biphenyl-4-base] methyl }-1 by nameH-benzimidazole-7-carboxylate potassium salt.As shown in structural formula 1:
The preparation technology of current Azilsartan potassium salt has several as follows:
Military field pharmacy [TakedaPharmaceuticalCompanyLimited] company preparation method of Azilsartan potassium salt disclosed in Chinese patent CN1946717: by Azilsartan at high-temperature digestion in 18 times of acetone, then the acetone solution of cooling dropping isooctyl acid potassium.Mixture is obtained target product refrigerator is static.Route is as follows:
This synthetic route, solvent makes consumption big, and it is higher to react molten clear temperature, and impurity easily becomes big, is therefore unfavorable for industrialized production.
Shi Yao group is in Chinese patent CN102351853A, with Azilsartan for raw material.In methanol with potassium chloride on potassium reagent, obtain target product.
This route is simple, although yield is high, but Azilsartan is poorly soluble, and substantially insoluble in methanol, upper potassium salt is incomplete.It is unfavorable for industrialized production.It addition, take potassium chloride, residue on ignition easily exceeds standard.
Therefore, one the Azilsartan potassium salt technique that can really adapt to industrialized production of exploitation is of crucial importance.
Summary of the invention
The present invention provides a kind of new technology synthesizing Azilsartan potassium salt, has the features such as simple to operate, yield is higher, purity is high, and solution Azilsartan is poorly soluble, is a kind of applicable industrialized production process.
It is an object of the invention to provide the new preparation process of a kind of Azilsartan potassium salt.
In one embodiment of the present invention, the invention provides a kind of new method preparing Azilsartan potassium salt, comprise the steps:
A) Azilsartan is added in organic solvent, add organic amine, obtain the clear liquor of Azilsartan organic amine salt；
B) in the clear liquor of Azilsartan organic amine salt, the organic solvent of the same race of dropping potassium salt, stirring and crystallizing；Then isolated by filtration, obtains Azilsartan potassium salt.
In one embodiment of the present invention, the Azilsartan organic amine salt that step a) obtains, without processing, is directly used in step b).
In one embodiment of the present invention, it is preferable that organic amine described in step a) selected from triethylamine, pyridine,N,N-diisopropylethylamine, dimethylamine, ethamine, diethylamine, piperazine, ethanolamine or choline.Preferred triethylamine, pyridine, it is most preferred that triethylamine.Described Azilsartan and organic base mol ratio are 1:1 ~ 2, it is preferred to 1:1.05, reaction temperature is 0 ~ 30 DEG C, it is preferred to 10 ~ 20 DEG C.
In one embodiment of the present invention, it is preferable that potassium salt described in step b) is selected from isooctyl acid potassium, potassium acetate, potassium ascorbate, benzoic acid potassium.Most preferably isooctyl acid potassium, described Azilsartan and potassium salt mol ratio are 1:1 ~ 2, it is preferred to 1:1.1, reaction temperature is 0 ~ 30 DEG C, it is preferred to 10 ~ 20 DEG C.
In one embodiment of the present invention, step a), b) described in react at organic solvent one in methanol, ethanol, acetone, dichloromethane, ethyl acetate, chloroform, the acetonitrile or wherein any two mixture.Ethyl acetate, acetone, it is most preferred that acetone.
Compared with prior art, there is advantages that and 1. make reaction clarification homogeneous: the preparation technology of Azilsartan potassium salt provided by the invention, obtain Azilsartan triethylamine salt with Azilsartan and triethylamine and dissolve clarification in organic solvent, be conducive to reaction to carry out；Industrialization to enter clean area operation；2. yield is high: in initiation material Azilsartan, yield can reach 95%, and relatively prior art improves a lot；3. product purity is high: Azilsartan is changed into Azilsartan triethylamine salt and reacts, for clarification system, it is to avoid solid-liquid hybrid reaction, the incomplete phenomenon of upper potassium.Obtained Azilsartan potassium salt purity is up to more than 99.5%.
Specific implementation method
Specifically describe embodiment of the present invention by following example, but the present invention be not limited by the following examples:
The condition determination of Azilsartan potassium salt is as follows with method:
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica, mobile phase A: (0.01mol potassium dihydrogen phosphate is dissolved in 1000ml water 0.01mol/L potassium dihydrogen phosphate buffer salt, phosphorus acid for adjusting pH value is to 2.0), Mobile phase B: acetonitrile-water (70:30), detection wavelength is 220nm, flow velocity is 1.0mL/min, and main peak and the peak-to-peak separating degree of other impurities meet the requirements.
Assay method: take this product and be about 10mg, accurately weighed, it is placed in 50ml measuring bottle, adds acetonitrile and dissolve, become in every 1ml the solution containing about 0.2mg by dilution in acetonitrile, as need testing solution；Precision measures need testing solution 20ul, injects chromatograph of liquid, records chromatogram；Main peak purity is calculated by area normalization method.
Embodiment 1:
The preparation of complex: add Azilsartan 5g, ethyl acetate 70ml in dry reaction bottle.Stirring cooling, drips triethylamine 1g in 10 ~ 15 DEG C.Stir molten clearly, obtain the molten clear liquid of ethyl acetate of Azilsartan triethylamine salt.This intermediate, without processing, is made directly next step.
In 10 ~ 15 DEG C in the ethyl acetate clear liquor of Azilsartan triethylamine salt, the acetic acid ethyl fluid 20ml of dropping isooctyl acid potassium 1.8g.Dropwise, stir 1h, crystallize, filter, obtain Azilsartan potassium salt 5.0g, yield 94.1%, purity 99.6%.Mp:209.4 ~ 210.8 DEG C, (data in literature: 209 ~ 213 DEG C).
1HNMR(DMSO-d6) б 1.37-1.41(3H, t), 2.16(3H, s), 4.57-4.63(2H, q), 5.12(2H, s), 5.55(2H, s), 6.86-6.88(2H, d), 7.19-7.46(4H, m), 7.52-7.54(2H, m), 7.62-7.63(2H, m), 1.37-1.41(3H, m), 7.72-7.74(1H, d)
Embodiment 2:
The preparation of complex: add Azilsartan 10g, acetone 75ml in dry reaction bottle.Stirring cooling, drips pyridine 1.5g in 15 ~ 20 DEG C.Stir molten clearly, obtain the molten clear liquid of acetone of Azilsartan pyridiniujm.This intermediate, without processing, is made directly next step.
In 15 ~ 20 DEG C, by the acetone solution 20ml of isooctyl acid potassium 3.4g, it is added drop-wise in the acetone clear liquor of Azilsartan pyridiniujm, dropwises, stir 1h, crystallize, filter, obtain Azilsartan potassium salt 9.96g, yield 93.1%, purity 99.4%.Mp:208.9 ~ 210.7 DEG C.
Embodiment 3:
The preparation of complex: add Azilsartan 9.5g, acetone 75ml in dry reaction bottle.Stirring cooling, drips triethylamine 1.8g in 12 ~ 17 DEG C.Stir molten clearly, obtain the molten clear liquid of acetone of Azilsartan triethylamine salt.This intermediate, without processing, is made directly next step.
In 12 ~ 17 DEG C of acetone solution 20ml dripping isooctyl acid potassium 3.4g in the acetone clear liquor of Azilsartan triethylamine salt.Dropwise, stir 2h, crystallize, filter, obtain Azilsartan potassium salt 9.6g, yield 95.05%, purity 99.7%.Mp:208.4 ~ 210.5 DEG C.
Embodiment 4:
The preparation of complex: add Azilsartan 56.8g, acetone 450ml in dry reaction bottle.Stirring cooling, drips triethylamine 10.6g in 13 ~ 18 DEG C.Stir molten clearly, obtain the molten clear liquid of acetone of Azilsartan triethylamine salt.This intermediate, without processing, is made directly next step.
In 13 ~ 18 DEG C, in the acetone clear liquor of Azilsartan triethylamine salt, the acetone solution 110ml of dropping isooctyl acid potassium 20g.Dropwise, stir 3h, crystallize, filter, obtain Azilsartan potassium salt 58.7g, yield 96.8%, purity 99.56%.Mp:209.1 ~ 211.3 DEG C.
Claims (8)
1. the method synthesizing Azilsartan potassium salt, comprises the steps:
A) adding in organic solvent by Azilsartan, add organic amine, obtain the clear liquor of Azilsartan organic amine salt, R is organic amine here；
B) organic solvent of the same race dripping potassium salt in Azilsartan organic amine salt clear liquor reacts into salt, obtains Azilsartan potassium salt；
Method according to claim 1, wherein organic amine described in step a) be triethylamine, pyridine,N,N-diisopropylethylamine, dimethylamine, ethamine, diethylamine, piperazine, ethanolamine or choline.
2. the Azilsartan described in and organic amine mol ratio are 1:1 ~ 2, and reaction temperature is 0 ~ 30 DEG C.
3. method according to claim 2, wherein described organic amine described in step a) selects triethylamine, is 1.05:1 with Azilsartan mol ratio, and reaction temperature is 10 ~ 20 DEG C.
4. method according to claim 1, wherein in salt-forming reaction described in step b), described potassium salt is isooctyl acid potassium, potassium acetate, potassium ascorbate, benzoic acid potassium.
5. the Azilsartan described in and potassium salt mol ratio are 1:1 ~ 2, and reaction temperature is 0 ~ 30 DEG C.
6. method according to claim 4, wherein potassium salt described in step b) selects isooctyl acid potassium, is 1.1:1 with Azilsartan mol ratio, and reaction temperature is 10 ~ 20 DEG C.
7. method according to claim 1, wherein step a), b) described in react and carry out in organic solvent, described organic solvent is the one in methanol, ethanol, acetone, dichloromethane, ethyl acetate, chloroform, acetonitrile or wherein any two mixture.
8. ethyl acetate, acetone, it is most preferred that acetone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410774050.5A CN105753854A (en) | 2014-12-16 | 2014-12-16 | New preparation method of azilsartan kamedoxomil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410774050.5A CN105753854A (en) | 2014-12-16 | 2014-12-16 | New preparation method of azilsartan kamedoxomil |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105753854A true CN105753854A (en) | 2016-07-13 |
Family
ID=56336487
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410774050.5A Pending CN105753854A (en) | 2014-12-16 | 2014-12-16 | New preparation method of azilsartan kamedoxomil |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105753854A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108358907A (en) * | 2018-04-03 | 2018-08-03 | 山东科兴生物制品有限公司 | A kind of preparation method of Azilsartan sylvite hydrate |
| US20190389848A1 (en) * | 2016-05-20 | 2019-12-26 | Wuhan Ll Science And Technology Development Co., Ltd. | Compound and preparation method therefor, composition and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100503605C (en) * | 2004-02-25 | 2009-06-24 | 武田药品工业株式会社 | Benzimidazole derivative and its use as AII receptor antagonist |
| 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 |
| WO2014020381A1 (en) * | 2012-08-01 | 2014-02-06 | Alembic Pharmaceuticals Limited | Novel crystalline form of azilsartan medoxomil potassium |
| CN103588764A (en) * | 2013-11-11 | 2014-02-19 | 浙江永宁药业股份有限公司 | Synthesis method for azilsartan medoxomil or salt thereof and intermediate of azilsartan medoxomil or salt thereof |
| WO2014048404A1 (en) * | 2012-09-26 | 2014-04-03 | Zentiva, K.S. | A method of preparing a highly pure potassium salt of azilsartan medoxomil |
-
2014
- 2014-12-16 CN CN201410774050.5A patent/CN105753854A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100503605C (en) * | 2004-02-25 | 2009-06-24 | 武田药品工业株式会社 | Benzimidazole derivative and its use as AII receptor antagonist |
| 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 |
| WO2014020381A1 (en) * | 2012-08-01 | 2014-02-06 | Alembic Pharmaceuticals Limited | Novel crystalline form of azilsartan medoxomil potassium |
| WO2014048404A1 (en) * | 2012-09-26 | 2014-04-03 | Zentiva, K.S. | A method of preparing a highly pure potassium salt of azilsartan medoxomil |
| CN103588764A (en) * | 2013-11-11 | 2014-02-19 | 浙江永宁药业股份有限公司 | Synthesis method for azilsartan medoxomil or salt thereof and intermediate of azilsartan medoxomil or salt thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20190389848A1 (en) * | 2016-05-20 | 2019-12-26 | Wuhan Ll Science And Technology Development Co., Ltd. | Compound and preparation method therefor, composition and application thereof |
| US11008311B2 (en) * | 2016-05-20 | 2021-05-18 | Wuhan Ll Science And Technology Development Co., Ltd. | Potassium salt of benzimidazole compound and preparation method therefor, composition and application thereof |
| CN108358907A (en) * | 2018-04-03 | 2018-08-03 | 山东科兴生物制品有限公司 | A kind of preparation method of Azilsartan sylvite hydrate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20080281100A1 (en) | Pure paliperidone and processes for preparing thereof | |
| JPH07508028A (en) | 6-amino-substituted imidazo[4,5-b]pyridine as angiotensin 2 antagonist | |
| EP2489661B1 (en) | Impurity of lapatinib and salts thereof | |
| AU2016274961A1 (en) | Adipate forms and compositions of biaryl inhibitors of Bruton's tyrosine kinase | |
| EP1922319A2 (en) | Pure paliperidone and processes for preparing thereof | |
| CN105753854A (en) | New preparation method of azilsartan kamedoxomil | |
| BR112015030527B1 (en) | ACID ESTER COMPOUNDS 3- (5-REPLACED OXY-2,4-DINITROPHENYL) -2-OXO-PROPYLIC, PROCESS AND APPLICATIONS OF THE SAME | |
| EP3024821B1 (en) | Process for the preparation of perampanel | |
| CN103601777A (en) | Preparation method of capecitabine | |
| CN104311485B (en) | A kind of preparation method treating leukemic medicine bosutinib | |
| CN104193766A (en) | Method for preparing cefetamet acid | |
| CN105777608A (en) | Indolylcarboxylic acid compound and application thereof in preparation of antitumor drugs | |
| CN104086478B (en) | Impurity compound in tirofiban hydrochloride and preparation method | |
| CN106928186A (en) | Compound and its production and use | |
| CN104262340B (en) | A kind of preparation method of Tadalafei | |
| CN106220634B (en) | The related substances F and G of pemetrexed disodium and its preparation and detection method | |
| CN105622452A (en) | AHU-377 crystal-type free acid, preparation method and applications thereof | |
| US10059654B2 (en) | Composition containing 3-chloro-4-methoxybenzylamine hydrochloride, and method for producing same | |
| CN103664990A (en) | Preparation method of Vicagrel | |
| CN104829533A (en) | Preparation method of tolvaptan key intermediate | |
| CN104098590B (en) | Benzo [1,2-d:5,4-d`] two (azoles)-2,6-two mercaptan and preparation method thereof | |
| CN103483316A (en) | 5-acetic acid-1-(6-bromopyridine)-1 hydrogen-pyrazole-3-methyl acetate and synthesis method thereof | |
| CN104098516B (en) | A kind of intermediate for preparing esomeprazole or its sodium salt and preparation method thereof | |
| CN109153652A (en) | The preparation process of 1- (aryl methyl) quinazoline -2,4 (1H, 3H)-diketone | |
| CN102503753A (en) | Method for synthesizing 2-amino five-membered heterocyclic derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160713 |
|
| WD01 | Invention patent application deemed withdrawn after publication |