CN106083833B - Purification method of trityl olmesartan medoxomil - Google Patents
Purification method of trityl olmesartan medoxomil Download PDFInfo
- Publication number
- CN106083833B CN106083833B CN201610533492.XA CN201610533492A CN106083833B CN 106083833 B CN106083833 B CN 106083833B CN 201610533492 A CN201610533492 A CN 201610533492A CN 106083833 B CN106083833 B CN 106083833B
- Authority
- CN
- China
- Prior art keywords
- olmesartan medoxomil
- trityl olmesartan
- crude
- purification method
- trityl
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Abstract
The invention provides a purification method of trityl olmesartan medoxomil, which is characterized in that a trityl olmesartan medoxomil crude product is dissolved in a mixed solution of a sodium carbonate solution and acetonitrile, and then the high-purity trityl olmesartan medoxomil is obtained by adopting a cooling crystallization method. The method has the characteristics of large single-batch treatment capacity, good refining effect and high yield, and is low in equipment requirement, simple and convenient to operate, environment-friendly, less in waste water generation and beneficial to industrial mass production, and the crystallization solvent is recycled and reused.
Description
Technical Field
The invention discloses a purification method of trityl Olmesartan Medoxomil, namely a purification method of an intermediate of Olmesartan Medoxomil (Olmesartan Medoxomil) which is a hypertension treatment drug, belonging to the field of medicines.
Background art:
chemical name of trityl olmesartan medoxomil: 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (2-trityltetrazol-5-yl) phenyl ] phenyl } methylimidazole-5-carboxylic acid (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl ester.
Olmesartan medoxomil is a prodrug, is absorbed by gastrointestinal tract after being taken orally, and is hydrolyzed into a bioactive product, olmesartan, which is the 7 th angiotensin II receptor antagonist approved by FDA in the United states and marketed, is successfully developed by Sankyo society in 1991, has better curative effect on various types of hypertension, and has the outstanding characteristics of long half-life period, small administration dose and quick response. And trityl olmesartan medoxomil is an important intermediate of olmesartan medoxomil.
Patent 92102075.9 published by Sankyo corporation of japan provides the following route for the synthesis of trityl olmesartan medoxomil:
the trityl olmesartan medoxomil prepared by the method has high impurity level, not only is complex to operate, but also needs column chromatography purification, can be obtained by 3 times of crystallization purification, and has serious loss of the total yield of the product, thereby being not beneficial to industrial production.
CN102206208A discloses a method for purifying trityl olmesartan medoxomil, which is to dissolve a crude trityl olmesartan medoxomil in acetone, and obtain trityl olmesartan medoxomil by cooling and crystallization.
According to the method, high-purity trityl olmesartan medoxomil can be obtained only when the content of trityl olmesartan medoxomil is low, but when the content of trityl olmesartan medoxomil is high, the purification effect is not obvious, or multiple times of purification are needed, acetone is used as a crystallization solvent, and the product yield is not high.
Therefore, the development of a purification method which can obtain high-purity trityl olmesartan medoxomil by one-time treatment under the condition that the purity of the trityl olmesartan medoxomil is not high is of great significance. The method overcomes various defects in the prior art, has mild conditions and simple operation, can remove more than 15 percent of trityl olmesartan acid by only 1 crystallization, has high yield and short production period, and simultaneously the purity of the prepared trityl olmesartan medoxomil reaches more than 99 percent, thereby being suitable for industrial production.
The invention content is as follows:
the method can effectively remove trityl olmesartan acid and other impurities brought in the production of trityl olmesartan medoxomil, and solves the problem of industrial preparation and purification of trityl olmesartan medoxomil.
In order to solve the problems, the invention adopts the following technical scheme: the method comprises the steps of dissolving a crude product of trityl olmesartan medoxomil, namely a crude product of 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (2-trityltetrazol-5-yl) phenyl ] phenyl } methylimidazole-5-carboxylic acid (5-methyl-2-oxo-1, 3-dioxole-4-yl) methyl ester in a mixed solvent of a sodium carbonate solution and acetonitrile, and then cooling and crystallizing to obtain the trityl olmesartan medoxomil.
The invention is characterized in that the mass ratio range of the trityl olmesartan medoxomil crude product to acetonitrile is 1: 2-1: 5, preferably 1: 3; the mass ratio of the crude trityl olmesartan medoxomil to water is 1: 1-1: 3, preferably 1: 2; the mass ratio of the crude trityl olmesartan medoxomil to the sodium carbonate is 15: 1-30: 1, and preferably 25: 1.
The preparation method of the mixed solvent comprises the steps of firstly dissolving sodium carbonate in water, then mixing a sodium carbonate solution with acetonitrile, and stirring for 5-15 minutes.
The stirring temperature of the crude trityl olmesartan medoxomil in the mixed solvent is 40-80 ℃, and the crude trityl olmesartan medoxomil is completely dissolved.
Dissolving the crude product of trityl olmesartan medoxomil in the mixed solvent, and stirring for 10-30 minutes.
After the dissolution and stirring are finished, a low-temperature crystallization method is adopted to obtain a product, wherein the crystallization temperature is-5-10 ℃, and preferably 0-5 ℃; the crystallization time is 0 to 10 hours, preferably 3 to 4 hours.
The purity of the methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (2-trityltetrazol-5-yl) phenyl ] phenyl } methylimidazole-5-carboxylate (5-methyl-2-oxo-1, 3-dioxol-4-yl) obtained according to the purification process of the present invention is not less than 98.5% and as high as 99.6%.
After the product is obtained by adopting a crystallization method, the mother liquor can be recycled by simple distillation, and the product quality is not influenced.
Compared with the prior art, the invention has the following advantages:
1) the operation is simplified, and the requirement on equipment is low;
2) the single batch processing capacity is large, and the productivity is improved;
3) good yield and high purity product: the purity of the crude product of trityl olmesartan medoxomil adopted by the invention is 80.2%, the purity of trityl olmesartan medoxomil is 17.0%, the purity of trityl olmesartan medoxomil is more than or equal to 98.5% and the highest purity is 99.6% after one-time treatment, and the product can meet the quality requirements of various medical intermediates.
4) The crystallization solvent can be used mechanically after simple distillation, thereby reducing the industrialization cost and reducing the environmental pressure.
Detailed Description
The following description is of the preferred embodiments of the present invention, but it is to be understood that the description is intended to further illustrate the features and advantages of the invention, and not to limit the claims.
The quality detection and analysis of olmesartan medoxomil adopts the detection and analysis method of olmesartan medoxomil specified in European pharmacopoeia EP 7.4.
Example 1:
crude trityl olmesartan medoxomil purity was 80.2% according to the route of trityl olmesartan medoxomil synthesis provided by patent CN92102075.9 published by Sankyo, japan, wherein trityl olmesartan medoxomil acid was 17.0%.
1.2g of sodium carbonate and 60g of water were put into a 500ml four-necked flask, and stirred at room temperature for 15 minutes, and after the sodium carbonate was completely dissolved, 90g of acetonitrile was added and stirred for 5 minutes. Adding 30g of crude trityl olmesartan medoxomil, slowly heating to 75 +/-5 ℃, and continuously stirring for 30 minutes. After the materials are completely dissolved, slowly cooling to 20-30 ℃, stirring and stirring for 1 hour. And continuously cooling to 0-5 ℃, stirring for crystallization for 4 hours, and performing suction filtration and drying to obtain trityl olmesartan medoxomil white solid powder 22.7g with the yield of 75.7%. HPLC analysis shows that the purity is 99.6%, the acid impurity is 0.09%, and other unknown single impurities are less than 0.1%.
Example 2:
crude trityl olmesartan medoxomil purity was 80.2% according to the route of trityl olmesartan medoxomil synthesis provided by patent CN92102075.9 published by Sankyo, japan, wherein trityl olmesartan medoxomil acid was 17.0%.
1.2g of sodium carbonate and 60g of water were put into a 500ml four-necked flask, and stirred at room temperature for 15 minutes, and 150g of acetonitrile was added thereto after the sodium carbonate was completely dissolved, and stirred for 5 minutes. Adding 30g of crude trityl olmesartan medoxomil, slowly heating to 75 +/-5 ℃, and continuously stirring for 30 minutes. After the materials are completely dissolved, slowly cooling to 20-30 ℃, stirring and stirring for 1 hour. And continuously cooling to 0-5 ℃, stirring for crystallization for 4 hours, and performing suction filtration and drying to obtain trityl olmesartan medoxomil white solid powder 25.5g with the yield of 85.0%. HPLC analysis shows that the purity is 99.6%, the acid impurity is 0.08%, and other unknown single impurities are less than 0.1%.
Example 3:
crude trityl olmesartan medoxomil purity was 80.2% according to the route of trityl olmesartan medoxomil synthesis provided by patent 92102075.9 published by Sankyo, japan, wherein trityl olmesartan medoxomil acid was 17.0%.
1.2g of sodium carbonate and 90g of water are added into a 500ml four-mouth bottle, stirred for 15 minutes at normal temperature, and after the sodium carbonate is completely dissolved, 90g of acetonitrile is added, and stirred for 5 minutes. Adding 30g of crude trityl olmesartan medoxomil, slowly heating to 75 +/-5 ℃, and continuously stirring for 30 minutes. After the materials are completely dissolved, slowly cooling to 20-30 ℃, stirring and stirring for 1 hour. And continuously cooling to 5-10 ℃, stirring for crystallization for 4 hours, and performing suction filtration and drying to obtain trityl olmesartan medoxomil white solid powder 25.8g with the yield of 86.0%. Purity 99.5%, acid impurity 0.07%, other unknown single impurity < 0.1%.
Example 4:
crude trityl olmesartan medoxomil purity was 80.2% according to the route of trityl olmesartan medoxomil synthesis provided by patent 92102075.9 published by Sankyo, japan, wherein trityl olmesartan medoxomil acid was 17.0%.
2.0g of sodium carbonate and 90g of water are added into a 500ml four-mouth bottle, stirred for 15 minutes at normal temperature, and after the sodium carbonate is completely dissolved, 90g of acetonitrile is added, and stirred for 5 minutes. Adding 30g of crude trityl olmesartan medoxomil, slowly heating to 75 +/-5 ℃, and continuously stirring for 30 minutes. After the materials are completely dissolved, slowly cooling to 20-30 ℃, stirring and stirring for 1 hour. And continuously cooling to 5-10 ℃, stirring for crystallization for 4 hours, and performing suction filtration and drying to obtain trityl olmesartan medoxomil white solid powder 25.5g with the yield of 85.0%. HPLC analysis shows that the purity is 99.4%, the acid impurity is 0.06%, and other unknown single impurities are all less than 0.1%.
Example 5:
crude trityl olmesartan medoxomil purity was 80.2% according to the route of trityl olmesartan medoxomil synthesis provided by patent 92102075.9 published by Sankyo, japan, wherein trityl olmesartan medoxomil acid was 17.0%.
1.0g of sodium carbonate and 30g of water are added into a 500ml four-mouth bottle, stirred for 15 minutes at normal temperature, and after the sodium carbonate is completely dissolved, 90g of acetonitrile is added, and stirred for 5 minutes. Adding 30g of crude trityl olmesartan medoxomil, slowly heating to 75 +/-5 ℃, and continuously stirring for 30 minutes. After the materials are completely dissolved, slowly cooling to 20-30 ℃, stirring and stirring for 1 hour. And continuously cooling to 5-10 ℃, stirring for crystallization for 4 hours, and performing suction filtration and drying to obtain trityl olmesartan medoxomil white solid powder 25.4g with the yield of 84.7%. Purity 99.4%, acid impurity 0.09%, other unknown single impurity is less than 0.1% by HPLC analysis.
Comparative example 1:
crude trityl olmesartan medoxomil purity was 80.2% according to the route of trityl olmesartan medoxomil synthesis provided by patent CN92102075.9 published by Sankyo, japan, wherein trityl olmesartan medoxomil acid was 17.0%.
150g of acetonitrile and 30g of crude trityl olmesartan medoxomil are added into a 500ml four-mouth bottle, the temperature is slowly increased to 75 +/-5 ℃, and the stirring is continued for 30 minutes. After the materials are completely dissolved, slowly cooling to 20-30 ℃, stirring and stirring for 1 hour. And continuously cooling to 0-5 ℃, stirring for crystallization for 4 hours, and performing suction filtration and drying to obtain trityl olmesartan medoxomil white solid powder of 26.3g with the yield of 87.7%. Purity by HPLC analysis was 86.2%, acid impurity 13.5%, other unknown single impurity was < 0.1%.
The comparative experiment shows that: only acetonitrile is used as a solvent, and sodium carbonate is not added, so that the product purity is low, and the acid impurity content is high.
Comparative example 2:
crude trityl olmesartan medoxomil purity was 80.2% according to the route of trityl olmesartan medoxomil synthesis provided by patent CN92102075.9 published by Sankyo, japan, wherein trityl olmesartan medoxomil acid was 17.0%.
120g of acetone and 30g of crude trityl olmesartan medoxomil are added into a 500ml four-mouth bottle, the temperature is slowly increased to 50 +/-5 ℃, and the stirring is continued for 30 minutes. After the materials are completely dissolved, slowly cooling to 20-30 ℃, stirring and stirring for 1 hour. And continuously cooling to 0-5 ℃, stirring for crystallization for 4 hours, and performing suction filtration and drying to obtain 20.9g of trityl olmesartan medoxomil white solid powder with the yield of 69.7%. Purity 90.0%, acid impurity 10.7%, other unknown single impurity < 0.1%.
The comparative experiment shows that: acetone has a certain removal effect on trityl olmesartan acid, but is not obvious. And the product yield is not high.
Claims (8)
1. A purification method of trityl olmesartan medoxomil shown in formula (I) with a chemical name of 4- (1-hydroxy-1-methylethyl) -2-propyl-1- {4- [2- (2-trityl tetrazole-5-yl) phenyl ] phenyl } methylimidazole-5-carboxylic acid (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl ester is characterized in that a crude trityl olmesartan medoxomil is dissolved in a mixed solution of sodium carbonate aqueous solution and acetonitrile, a cooling crystallization method is adopted to obtain trityl olmesartan medoxomil,
wherein the mass ratio of the crude trityl olmesartan medoxomil to the acetonitrile is 1: 2-1: 5; the mass ratio of the crude trityl olmesartan medoxomil to water is 1: 1-1: 3; the mass ratio of the crude trityl olmesartan medoxomil to the sodium carbonate is 15: 1-30: 1; dissolving a crude product of trityl olmesartan medoxomil in a mixed solution of a sodium carbonate solution and acetonitrile, and stirring at the temperature of 40-80 ℃;
wherein the crystallization temperature in the cooling crystallization is-5 to 10 ℃, and the crystallization time is 0 to 10 hours.
2. The purification method according to claim 1, wherein the sodium carbonate is dissolved in water and then mixed with acetonitrile and stirred for 5 to 15 minutes.
3. The purification method according to claim 1, wherein the trityl olmesartan medoxomil is dissolved in the mixed solution and then stirred for 10 to 30 minutes.
4. The purification method according to claim 1, wherein the mass ratio of the crude trityl olmesartan medoxomil to the acetonitrile is 1: 3.
5. The purification method according to claim 1, wherein the mass ratio of the crude trityl olmesartan medoxomil to water is 1: 2.
6. The purification method according to claim 1, wherein the mass ratio of the crude trityl olmesartan medoxomil to the sodium carbonate is 25: 1.
7. The purification method according to claim 1, wherein the crystallization temperature is 0 to 5 ℃.
8. The purification method according to claim 1, wherein the crystallization time is 3 to 4 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610533492.XA CN106083833B (en) | 2016-06-30 | 2016-06-30 | Purification method of trityl olmesartan medoxomil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610533492.XA CN106083833B (en) | 2016-06-30 | 2016-06-30 | Purification method of trityl olmesartan medoxomil |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106083833A CN106083833A (en) | 2016-11-09 |
| CN106083833B true CN106083833B (en) | 2020-12-08 |
Family
ID=57212652
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610533492.XA Active CN106083833B (en) | 2016-06-30 | 2016-06-30 | Purification method of trityl olmesartan medoxomil |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106083833B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110396084B (en) * | 2018-04-24 | 2023-01-20 | 连云港润众制药有限公司 | Method for preparing high-purity trityl olmesartan medoxomil |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011021224A2 (en) * | 2009-08-19 | 2011-02-24 | Msn Laboratories Limited | Process for (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-tetrazol-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate |
| CN103880825B (en) * | 2014-03-14 | 2019-03-05 | 浙江华海药业股份有限公司 | A kind of preparation process of high-purity trityl olmesartan medoxomil |
| CN104592213A (en) * | 2014-12-15 | 2015-05-06 | 山东新华制药股份有限公司 | Preparation method of olmesartan intermediate |
-
2016
- 2016-06-30 CN CN201610533492.XA patent/CN106083833B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN106083833A (en) | 2016-11-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106256824B (en) | Preparation method of high-purity delafloxacin meglumine salt | |
| CN103724261B (en) | A kind of industrialized process for preparing of hydroxychloroquine sulfate quinoline | |
| CN109336892B (en) | Preparation method of tofacitinib impurity | |
| CN104402838B (en) | The process for purification of valsartan | |
| CN102395591B (en) | Method for preparing prasugrel | |
| CN103664912A (en) | Synthesis process of prucalopride | |
| US10538507B2 (en) | Preparation process for high-purity dabigatran etexilate | |
| CN108341804A (en) | The preparation method of high-purity olmesartan medoxomil | |
| CN106083833B (en) | Purification method of trityl olmesartan medoxomil | |
| EP3109241B1 (en) | Method of refining valsartan comprising more than 10% d-isomers | |
| CN102206208A (en) | Preparation method for olmensartan medoxomil with low-level impurity | |
| CN103435567A (en) | Valsartan refining method | |
| CN113651798A (en) | Preparation method of Voranolan fumarate | |
| CN102633801B (en) | Method for preparing tebipenem ester | |
| CN103724288A (en) | Post-processing method for preparing 1H-tetrazole-1-acetic acid through triethyl orthoformate method | |
| CN104788429B (en) | A kind of method for preparing sartans by removing trityl-protecting group | |
| CN106883227B (en) | The method for preparing ergometrine by ergot fermentation waste | |
| CN102336721B (en) | Method for synthesizing AE-active ester by using water-containing 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid | |
| CN105440054A (en) | Process for preparing high-purity cefathiamidine | |
| CN104650048B (en) | Purification method of olmesartan medoxomil condensation compound | |
| CN115785181A (en) | Method for preparing mupirovir intermediate by one-pot method | |
| CN112898267A (en) | Refining method of alogliptin benzoate | |
| CN101857600B (en) | Method for preparing 7-phenylacetylamino-3-methylcephalosporanic acid | |
| CN112480075A (en) | Refining method of trelagliptin succinate | |
| CN110563721A (en) | Preparation method of azasetron hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |