CN1548421A - Tilmisartan salt and its prepn - Google Patents
Tilmisartan salt and its prepn Download PDFInfo
- Publication number
- CN1548421A CN1548421A CNA031170870A CN03117087A CN1548421A CN 1548421 A CN1548421 A CN 1548421A CN A031170870 A CNA031170870 A CN A031170870A CN 03117087 A CN03117087 A CN 03117087A CN 1548421 A CN1548421 A CN 1548421A
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- China
- Prior art keywords
- salt
- telmisartan
- preparation
- amine
- tilmisartan
- Prior art date
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Abstract
The Tilmisartan salt of the present invention is salt formed with Tilmisartan and alkali metal, alkali earth metal, pharmaceutically acceptable amine, amino acid. It may be sodium salt, potassium salt, calcium salt, magnesium salt and amine salt, preferably sodium salt, potassium salt or tert-butyl amine salt. The preparation of Tilmisartan salt includes the following steps: reaction between Tilmisartan and organic alkali, inorganic alkali, arginine or lysine in organic solvent or water to produce target product, and collecting Tilmisartan salt. The Tilmisartan salt may be used to replace available Tilmisartan.
Description
Technical field
The present invention relates to telmisartan salt and preparation method thereof.
Background technology
European patent EP 502314B1 has disclosed a kind of compound, telmisartan, and general structure is disclosed, as follows:
Telmisartan and physiologically acceptable salt thereof have valuable pharmacological character.It is a kind of Angiotensin II antagonist, in view of its pharmacological property can be used for the treatment of hypertension and myocardial function is incomplete, treats ischemic peripheral circulatory diseases, myocardial ischaemia (angina).
Telmisartan bulk drug solubleness is less, after making preparation, its dissolution rate is lower, and patent CN1336920A reported once that telmisartan was dissolved in 0.1mol/L NaOH, be converted into a kind of homogeneous and complete indefiniteness particle by spraying drying, but the sample water-absorbent that makes with this method is stronger.
Summary of the invention
The technical issues that need to address of the present invention are to disclose a kind of telmisartan salt, to overcome the low and stronger shortcoming of water-absorbent of prior art dissolution rate;
Two of the technical issues that need to address of the present invention are the preparations that openly contain described telmisartan salt;
Three of the technical issues that need to address of the present invention provide the preparation method of described telmisartan salt, so that industrializing implementation.
Telmisartan salt of the present invention be a kind of telmisartan with basic metal, alkaline-earth metal, pharmaceutically acceptable amine and amino acid (routine arginine or Methionin) in a kind of salt that becomes, comprise sodium salt, sylvite, calcium salt, magnesium salts, amine salt and amino acid salts, usually adopt sodium salt, sylvite or tert-butylamine salt, its general structure is as follows:
M
+=Na
+, K
+, 1/2Ca
2+, 1/2Mg
2+, (CH
3)
3C-NH
3 +,
Or R
2-NH
3 +,
R wherein
1Be natural amino acid substituting group, R
2Be C
1-C
5Alkane.
The preparation method of telmisartan salt of the present invention comprises the steps:
A kind of with in telmisartan and organic and inorganic alkali, the amino acid (routine arginine or Methionin), organic solvent and (or) react in the water, generate target product, from reaction product, collect telmisartan salt.
Temperature of reaction-20～150 ℃ was reacted 1～30 hour;
The mol ratio of telmisartan and alkali is 1: 0.4-10;
Said organic bases is an amine, the preferred tertiary butylamine;
Said mineral alkali comprises a kind of in alkali-metal oxyhydroxide, alkaline earth metal hydroxides, pharmaceutically acceptable amine, arginine or the Methionin, comprise sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, amine, adopt sodium hydroxide, potassium hydroxide or TERTIARY BUTYL AMINE usually;
Said solvent comprises ethers, alcohols, ketone, halogenated alkane, alkane or aromatic hydrocarbons and composition thereof.
The invention still further relates to a kind of preparation, contain the described telmisartan salt and the pharmaceutically receivable carrier for the treatment of significant quantity;
Said carrier is meant the carrier of medicine and pharmacology field routine, for example, and weighting agent such as starch etc., tackiness agent such as derivatived cellulose etc., or other sweeting agents, flavouring agent etc., and adopt technology well known in the art to be prepared into oral preparations, as tablet, capsule, medicinal powder, granule and oral liquid etc.
Usage quantity of the present invention can change according to the type of route of administration, patient's age, body weight, disease and severity etc., and its per daily dose is generally 20-80mg.
Telmisartan salt dissolution rate of the present invention is higher, adopts two appendix XC second methods of Chinese Pharmacopoeia version in 2000 to test, and the result shows that telmisartan sheet dissolution rate is greater than 80%.
This shows that compound dissolution rate of the present invention is higher, preparation can substitute original telmisartan easily, has higher popularizing application prospect.
Embodiment
Embodiment 1
4 '-[(1,4 '-dimethyl-2 '-n-propyl [2,6 '-two-1 hydrogen-benzoglyoxaline]-1 '-yl) methyl]-[1,1 '-biphenyl]-2-carboxylic acid sodium salt
In the 250ml reaction flask, add telmisartan 10g (0.0195mol), NaOH0.75g (0.0189mol) and water 100ml, stir 1 hour (30 ℃), filter, the elimination insolubles is concentrated into small volume, add ethanol 30ml, concentrate, add normal hexane 30ml washing, incline, add ethanol 30ml, concentrate, repeat again once, be concentrated into driedly, promptly get the sodium salt of telmisartan 9.9g, yield 95.2%.Fusing point: 223-225 ℃.
Ultimate analysis: C
33H
29N
4O
2NaH
2O calculated value: C71.48 H5.10 N10.11
Experimental value: C71.42 H5.08 N10.22
Embodiment 2
4 '-[(1,4 '-dimethyl-2 '-n-propyl [2,6 '-two-1 hydrogen-benzoglyoxaline]-1 '-yl) methyl]-[1,1 '-biphenyl]-2-carboxylic acid sylvite
In the 250ml reaction flask, add telmisartan 10g (0.0195mol), KOH1.06g (0.0188mol) and water 100ml, stir 1 hour (30 ℃), filter, the elimination insolubles is concentrated into small volume, add ethanol 30ml, concentrate, add normal hexane 30ml washing, incline, add ethanol 30ml, concentrate, repeat again once, be concentrated into driedly, promptly get telmisartan sylvite 10.6g, yield 95.6%.Fusing point: 203-205 ℃.
Ultimate analysis: C
33H
29N
4O
2KH
2O calculated value: C69.04 H5.40 N9.76 experimental value: C69.01 H5.28 N9.88
Embodiment 3
The fine powder of raw material and auxiliary material mixed sieve, add 5% polyvinylpyrrolidone liquid and make particle, drying.Dried particles adds Magnesium Stearate and mixes behind whole grain, carry out compressing tablet.
The mg/ sheet
The sodium salt of telmisartan 20
Lactose 170
Sodium starch glycolate 10
Meglumine 8
Magnesium Stearate 2
5% polyvinylpyrrolidone liquid is an amount of
Embodiment 4
The fine powder of raw material and auxiliary material mixed sieve, add 5% polyvinylpyrrolidone liquid and make particle, drying.Dried particles adds Magnesium Stearate and mixes behind whole grain, carry out compressing tablet.
The mg/ sheet
The sodium salt of telmisartan 40
Lactose 200
Secondary calcium phosphate 140
Sodium starch glycolate 16
Magnesium Stearate 4
5% polyvinylpyrrolidone liquid is an amount of
Embodiment 5
Get this product, according to dissolution method (two appendix XC second methods of Chinese Pharmacopoeia version in 2000), with phosphate buffered saline buffer 900ml is solvent, rotating speed is that per minute 75 changes, operation in the time of 30 minutes, is got solution as need testing solution in accordance with the law, according to spectrophotometry (two appendix IVA of Chinese Pharmacopoeia version in 2000), measure optical density at 295nm wavelength place.Precision is measured the reference substance stock solution 10ml under the assay item in addition, put in the 100ml measuring bottle, be diluted to scale with phosphate buffered saline buffer, precision is measured 5ml again, puts in the 10ml measuring bottle, be diluted to scale with phosphate buffered saline buffer, shake up, measure optical density, calculate every stripping quantity with method, limit is 80% of a scalar, should be up to specification.Dissolution determination the results are shown in Table.
Table dissolution determination result
Dissolution rate (%)
The sodium salt of telmisartan 97.29 99.65 102.55 95.83 101.10 98.92 99.20 ± 2.45
Claims (10)
1. a telmisartan salt is characterized in that, is a kind of telmisartan and basic metal, alkaline-earth metal, pharmaceutically acceptable amine, a kind of salt that becomes in the amino acid, and its general structure is as follows:
M
+=Na
+, K
+, 1/2Ca
2+, 1/2Mg
2+, (CH
3)
3C-NH
3 +,
Or R
2-NH
3 +R wherein
1Be natural amino acid substituting group, R
2Be C
1-C
5Alkane.
2. telmisartan salt according to claim 1 is characterized in that the salt of being addressed comprises sodium salt, sylvite, calcium salt, magnesium salts or amine salt.
3. telmisartan salt according to claim 2 is characterized in that the salt of being addressed comprises sodium salt, sylvite or tert-butylamine salt.
4. according to the preparation method of claim 1,2 or 3 described telmisartan salt, it is characterized in that comprising the steps:
A kind of with in telmisartan and organic bases, mineral alkali, the amino acid reacts in organic solvent and/or water, generates target product, collects telmisartan salt from reaction product.
5. the preparation method of telmisartan salt according to claim 4 is characterized in that, temperature of reaction-20～150 ℃ was reacted 1～30 hour.
6. the preparation method of telmisartan salt according to claim 4 is characterized in that, the mol ratio of telmisartan and alkali is 1: 0.4-10.
7. the preparation method of telmisartan salt according to claim 4 is characterized in that, said organic bases is an amine; Said mineral alkali comprises a kind of in alkali-metal oxyhydroxide, alkaline earth metal hydroxides, pharmaceutically acceptable amine, the amino acid.
8. the preparation method of telmisartan salt according to claim 7 is characterized in that, mineral alkali comprises sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or TERTIARY BUTYL AMINE.
9. according to the preparation method of each described telmisartan salt of claim 4～8, it is characterized in that said solvent comprises ethers, alcohols, ketone, halogenated alkane, alkane or aromatic hydrocarbons and composition thereof.
10. one kind contains the described telmisartan salt of claim 1,2 or 3 described treatment significant quantities and the composition of receivable carrier pharmaceutically.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031170870A CN1548421A (en) | 2003-05-22 | 2003-05-22 | Tilmisartan salt and its prepn |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031170870A CN1548421A (en) | 2003-05-22 | 2003-05-22 | Tilmisartan salt and its prepn |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1548421A true CN1548421A (en) | 2004-11-24 |
Family
ID=34320591
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA031170870A Pending CN1548421A (en) | 2003-05-22 | 2003-05-22 | Tilmisartan salt and its prepn |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1548421A (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006050509A3 (en) * | 2004-11-03 | 2006-08-03 | Teva Pharma | Amorphous and polymorphic forms of telmisartan sodium |
| WO2007147889A2 (en) * | 2006-06-23 | 2007-12-27 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Preparation of telmisartan salts |
| CN100370984C (en) * | 2005-03-11 | 2008-02-27 | 浙江泰利森药业有限公司 | Telmisartan dispersible tablet and its preparation method |
| JP2008542435A (en) * | 2005-06-06 | 2008-11-27 | サノフイ−アベンテイス | Alkaline earth salt hydrate of irbesartan and its preparation |
| US7501448B2 (en) | 2004-10-15 | 2009-03-10 | Teva Pharmaceutical Industries, Ltd. | Process for preparing telmisartan |
| WO2010146187A2 (en) | 2009-06-19 | 2010-12-23 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for the preparation of telmisartan |
| WO2012055941A1 (en) | 2010-10-27 | 2012-05-03 | Krka,Tovarna Zdravil, D. D., Novo Mesto | Multilayer pharmaceutical composition comprising telmisartan and amlodipine |
| CN102526037A (en) * | 2012-02-10 | 2012-07-04 | 重庆康刻尔制药有限公司 | Telmisartan medicinal composition, telmisartan medicinal composition tablets and preparation method for telmisartan medicinal composition tablets |
| WO2015099111A1 (en) * | 2013-12-27 | 2015-07-02 | トーアエイヨー株式会社 | Salt of angiotensin ii receptor antagonist |
| CN109020896A (en) * | 2018-09-13 | 2018-12-18 | 湖北舒邦药业有限公司 | The sodium salt of telmisartan with and preparation method thereof |
-
2003
- 2003-05-22 CN CNA031170870A patent/CN1548421A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7501448B2 (en) | 2004-10-15 | 2009-03-10 | Teva Pharmaceutical Industries, Ltd. | Process for preparing telmisartan |
| WO2006050509A3 (en) * | 2004-11-03 | 2006-08-03 | Teva Pharma | Amorphous and polymorphic forms of telmisartan sodium |
| CN100370984C (en) * | 2005-03-11 | 2008-02-27 | 浙江泰利森药业有限公司 | Telmisartan dispersible tablet and its preparation method |
| JP2008542435A (en) * | 2005-06-06 | 2008-11-27 | サノフイ−アベンテイス | Alkaline earth salt hydrate of irbesartan and its preparation |
| WO2007147889A2 (en) * | 2006-06-23 | 2007-12-27 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Preparation of telmisartan salts |
| WO2007147889A3 (en) * | 2006-06-23 | 2008-05-08 | Krka Tovarna Zdravil D D Novo | Preparation of telmisartan salts |
| WO2010146187A2 (en) | 2009-06-19 | 2010-12-23 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for the preparation of telmisartan |
| WO2012055941A1 (en) | 2010-10-27 | 2012-05-03 | Krka,Tovarna Zdravil, D. D., Novo Mesto | Multilayer pharmaceutical composition comprising telmisartan and amlodipine |
| CN102526037A (en) * | 2012-02-10 | 2012-07-04 | 重庆康刻尔制药有限公司 | Telmisartan medicinal composition, telmisartan medicinal composition tablets and preparation method for telmisartan medicinal composition tablets |
| CN102526037B (en) * | 2012-02-10 | 2014-08-27 | 重庆康刻尔制药有限公司 | Telmisartan medicinal composition, telmisartan medicinal composition tablets and preparation method for telmisartan medicinal composition tablets |
| WO2015099111A1 (en) * | 2013-12-27 | 2015-07-02 | トーアエイヨー株式会社 | Salt of angiotensin ii receptor antagonist |
| CN109020896A (en) * | 2018-09-13 | 2018-12-18 | 湖北舒邦药业有限公司 | The sodium salt of telmisartan with and preparation method thereof |
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