CN109081833A - A kind of preparation method of olmesartan medoxomil intermediate - Google Patents
A kind of preparation method of olmesartan medoxomil intermediate Download PDFInfo
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- CN109081833A CN109081833A CN201811113387.6A CN201811113387A CN109081833A CN 109081833 A CN109081833 A CN 109081833A CN 201811113387 A CN201811113387 A CN 201811113387A CN 109081833 A CN109081833 A CN 109081833A
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- olmesartan medoxomil
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- trityl
- acetonitrile
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- 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
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Abstract
The invention discloses a kind of preparation methods of olmesartan medoxomil intermediate, include the following steps: S1, imidazoles monoesters and tetrabromo biphenyl tetrazole (BBTT) are reacted to obtain under base catalysis compound, filtering after system cooling, concentration, crystallization obtain 4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- { 4- [2- (trityl tetrazole -5- base) phenyl) phenyl } methylimidazole -5- carboxylic acid, ethyl ester；S2, compound is hydrolyzed in ketones solvent with highly basic again and is reacted, carbonate and 4- chloromethyl -5- methyl-1 are added after fully reacting, 3- dioxole -2- ketone occurs esterification and obtains trityl olmesartan medoxomil；S3, trityl olmesartan medoxomil carry out recrystallization purifying with acetonitrile.Compared with other preparation methods, technical price is cheap, compared be solvent with DMF, more environment-friendly, cost is lower, yield is higher, technical maturity, obtain through refining standby quality significantly.
Description
Technical field
The present invention relates to technical field of medicine synthesis, more specifically more particularly to a kind of olmesartan medoxomil intermediate
Preparation method.
Background technique
Entitled 4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- { 4- [2- (tetrazolium -5- base) benzene of olmesartan medoxomil chemistry
Base) phenyl } methylimidazole-5- carboxylic acid (5- methyl-2- oxo-1,3- Dioxol-4 -yl) methyl ester, before being one kind
Medicine hydrolyzes during absorption and plays drug effect.The medicine is a kind of selective II antagonist of ATi subtype angiotensin.
It is domestic at present more to the research of olmesartan medoxomil, but can mainly be summarized as two methods.Method one is with imidazoles
Part hydrolyzes after connecting with biphenyl, then with 4- chloromethyl -5- methyl-1,3- dioxole -2- ketone ester is finally deprotected
Obtain olmesartan medoxomil.Method second is that imidazole fragment first with 4- chloromethyl -5- methyl-1,3-dioxy it is miscellaneous-cyclopentene -2- ketone ester
It connects to obtain olmesartan medoxomil then at biphenyl after obtaining intermediate.In actual production based on the synthetic method of method one.Wherein
Main synthesis patent has CN92102075.9, CN1023518490, CN105481842A.
Japanese Sankyo Co., Ltd describes the synthesis road of olmesartan medoxomil in detail in wherein state's patent 92102075.9
Line (as follows).Compound 1 and excessive compound 2 first take under sodium hydride or potassium tert-butoxide effect in the route
In generation, obtain compound 3, compound 3 obtains compound 7 through basic hydrolysis, acidification, then again with 5 methyl of 4- chloromethyl, 1,3 dioxa
One 2- ketone of cyclopentene acetifies to obtain compound 5.Condensation reaction sodium hydride and potassium tert-butoxide reaction, reaction are more acute in this method
It is strong, and raw material potassium tert-butoxide and water are susceptible to hydrolysis, it is not easy to maintain.
Patent CN102351849 (as follows), uses imidazoles monoesters and BBTT for starting material, first with sodium hydroxide into
Row condensation, be subsequently added into lithium hydrate and obtain intermediate lithium salts, the intermediate again with 4- chloromethyl -5- methyl-1,3- bis-
One 2- ketone ester of oxole obtains olmesartan medoxomil intermediate.Although being condensed, being hydrolyzed using " one pot in this method
Method ", but the amount for the sodium hydroxide being added in condensation is excessive, has a biggish impurity and generates, yield will be greatly reduced,
Solvent used in reaction is DMF, it is difficult to recycle, can generate a large amount of waste liquid.In addition, obtained lithium salts is needed using extraction
Method, it is relatively complicated in operation.Intermediate is not purified in reaction, it is difficult to which the purity for guaranteeing olmesartan medoxomil needs essence
System, total recovery≤45%.
Patent CN105481842A uses imidazoles monoesters and BBTT for starting material, in acetone first with sodium hydroxide into
Row condensation, be subsequently added into sodium hydroxide hydrolysis obtain intermediate acid, the intermediate again in DMF with 4- chloromethyl -5- methyl-1,
One 2- ketone ester of 3- dioxole obtains olmesartan medoxomil intermediate.Although being condensed, being hydrolyzed using " one in this method
Pot method ", but behind with 4- chloromethyl -5- methyl-1, when one 2- ketone ester of 3- dioxole, solvent used was DMF,
This solvent is difficult to recycle, and wastewater flow rate is big, complicated for operation, and it is larger to produce reaction kettle used in the intermediate of same batch, to increase
The big cost of man power, for this purpose, it is proposed that a kind of preparation method of olmesartan medoxomil intermediate.
Summary of the invention
The purpose of the present invention is to solve disadvantages existing in the prior art, and among a kind of olmesartan medoxomil proposed
The preparation method of body reduces the welding procedure of the more efficient multiple-printed-panel for circuit board mode and connector of product rejection rate.
To achieve the above object, the invention provides the following technical scheme: a kind of preparation method of olmesartan medoxomil intermediate,
Include the following steps:
S1, it reacts imidazoles monoesters and tetrabromo biphenyl tetrazole (BBTT) to obtain compound, system under base catalysis
It filters, be concentrated after cooling, crystallization obtains 4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- { 4- [2- (trityl tetrazole -5-
Base) phenyl) phenyl } methylimidazole -5- carboxylic acid, ethyl ester；
S2, compound is hydrolyzed in ketones solvent with highly basic again and is reacted, carbonate and 4- are added after fully reacting
Chloromethyl -5- methyl-1,3-dioxy heterocyclic pentene -2- ketone occurs esterification and obtains trityl olmesartan medoxomil；
S3, trityl olmesartan medoxomil carry out recrystallization purifying with acetonitrile.
Preferably, the temperature of condensation reaction is 50-80 DEG C, condensation reaction time 5-8h in S1, what condensation reaction used
Solvent is acetonitrile, tetrahydrofuran, acetone, butanone etc., and the ratio for hydrolyzing the highly basic used and imidazoles monoesters is 1:1-4:1, hydrolysis temperature
Degree is 30-45 DEG C, imidazoles monoesters: tetrabromo biphenyl tetrazole (BBTT): the molar ratio of highly basic is 1:1:1.2-1:1.5:1.5, water
The solvent that solution uses is the ketones reagents such as acetone, butanone, pentanone, wherein the use of acetone being preferentially solvent.
Preferably, the alkali that S1 is used is sodium carbonate, potassium carbonate, cesium carbonate, one of sodium hydroxide, Strong oxdiative potassium or several
Kind；It is sodium hydroxide, potassium hydroxide, one or more of lithium hydroxide that the highly basic used is hydrolyzed in S2.
Preferably, in S3 after fully reacting, recycling ketones solvent is concentrated under reduced pressure, acetonitrile is added in condensate residue and is analysed
Crystalline substance, centrifugation, water washing.
Preferably, trityl olmesartan vinegar obtained in S3 is purified, and purifies the solvent used as acetonitrile.
Technical effect and advantage of the invention:
1, condensation reaction is first carried out under the alkali effect of the appropriate amount in acetone or acetonitrile with imidazoles monoesters and BBTT, avoided
The excessive impurity caused by alkali is more, and solvent for use may be recovered.Hydrolysis and esterification process one pot reaction are easy to operate, molten
Agent acetone can be recycled directly, to avoid the generation of a large amount of waste liquids.
2, trityl olmesartan carboxylate and 4- chloromethyl -5- methyl-1,3-dioxy heterocyclic pentene -2- ketone acetify
To trityl olmesartan medoxomil, the esterification products are purified to can be obtained high-purity intermediate trityl olmesartan vinegar, pure
Degree >=99.7%, to avoid bringing intermediate impurities in finished product into.
3, compared with being solvent with DMF, more environment-friendly, cost is lower, and yield is higher, and the operation is more convenient.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, below in conjunction with specific embodiment, to this
Invention is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, not
For limiting the present invention.Based on the embodiments of the present invention, those of ordinary skill in the art are not before making creative work
Every other embodiment obtained is put, shall fall within the protection scope of the present invention.
Embodiment
A kind of preparation method of olmesartan medoxomil intermediate, includes the following steps:
S1, it reacts imidazoles monoesters and tetrabromo biphenyl tetrazole (BBTT) to obtain compound, system under base catalysis
It filters, be concentrated after cooling, crystallization obtains 4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- { 4- [2- (trityl tetrazole -5-
Base) phenyl) phenyl } methylimidazole -5- carboxylic acid, ethyl ester；
S2, compound is hydrolyzed in ketones solvent with highly basic again and is reacted, carbonate and 4- are added after fully reacting
Chloromethyl -5- methyl-1,3-dioxy heterocyclic pentene -2- ketone occurs esterification and obtains trityl olmesartan medoxomil；
S3, trityl olmesartan medoxomil carry out recrystallization purifying with acetonitrile.
In summary: a kind of preparation method of olmesartan medoxomil intermediate provided by the invention, with other preparation method phases
It is cheaper than, technical price, compared be solvent with DMF, more environment-friendly, cost is lower, yield is higher, technical maturity, mention significantly
The quality of preparation.
Finally, it should be noted that the foregoing is only a preferred embodiment of the present invention, it is not intended to restrict the invention,
Although the present invention is described in detail referring to the foregoing embodiments, for those skilled in the art, still may be used
To modify the technical solutions described in the foregoing embodiments or equivalent replacement of some of the technical features,
All within the spirits and principles of the present invention, any modification, equivalent replacement, improvement and so on should be included in of the invention
Within protection scope.
Claims (5)
1. a kind of preparation method of olmesartan medoxomil intermediate, characterized by the following steps:
S1, imidazoles monoesters and tetrabromo biphenyl tetrazole (BBTT) are reacted to obtain compound, system cooling under base catalysis
It filters, be concentrated afterwards, crystallization obtains 4- (1- hydroxyl -1- Methylethyl) -2- propyl -1- { 4- [2- (trityl tetrazole -5- base)
Phenyl) phenyl } methylimidazole -5- carboxylic acid, ethyl ester；
S2, compound is hydrolyzed in ketones solvent with highly basic again and is reacted, carbonate and 4- chloromethane are added after fully reacting
Base -5- methyl-1,3-dioxy heterocyclic pentene -2- ketone occurs esterification and obtains trityl olmesartan medoxomil；
S3, trityl olmesartan medoxomil carry out recrystallization purifying with acetonitrile.
2. a kind of preparation method of olmesartan medoxomil intermediate according to claim 1, it is characterised in that: be condensed in S1 anti-
The temperature answered be 50-80 DEG C, condensation reaction time 5-8h, the solvent that condensation reaction uses be acetonitrile, tetrahydrofuran, acetone,
Butanone etc., the ratio for hydrolyzing the highly basic used and imidazoles monoesters is 1:1-4:1, and hydrolysis temperature is 30-45 DEG C, imidazoles monoesters: tetrabromo
Biphenyl tetrazole (BBTT): the molar ratio of highly basic is 1:1:1.2-1:1.5:1.5, and hydrolyzing the solvent used is acetone, butanone, penta
The ketones reagent such as ketone, wherein the use of acetone being preferentially solvent.
3. a kind of preparation method of olmesartan medoxomil intermediate according to claim 1, it is characterised in that: the alkali that S1 is used
For sodium carbonate, potassium carbonate, cesium carbonate, one or more of sodium hydroxide, Strong oxdiative potassium；It is hydrogen that the highly basic used is hydrolyzed in S2
Sodium oxide molybdena, potassium hydroxide, one or more of lithium hydroxide.
4. a kind of preparation method of olmesartan medoxomil intermediate according to claim 1, it is characterised in that: reacted in S3
Recycling ketones solvent is concentrated under reduced pressure in Quan Hou, and acetonitrile is added in condensate residue and carries out crystallization, centrifugation, water washing.
5. a kind of preparation method of olmesartan medoxomil intermediate according to claim 1, it is characterised in that: obtained in S3
Trityl olmesartan vinegar is purified, and purifies the solvent used as acetonitrile.
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| CN201811113387.6A CN109081833A (en) | 2018-09-25 | 2018-09-25 | A kind of preparation method of olmesartan medoxomil intermediate |
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| CN201811113387.6A CN109081833A (en) | 2018-09-25 | 2018-09-25 | A kind of preparation method of olmesartan medoxomil intermediate |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090209603A1 (en) * | 2005-01-03 | 2009-08-20 | Lilach Hedvati | Olmesartan medoxomil with reduced levels of impurities |
| WO2011036674A1 (en) * | 2009-09-24 | 2011-03-31 | Inogent Laboratories Private Limited | A new process for the preparation of olmesartan medoxomil |
| CN105481842A (en) * | 2015-12-15 | 2016-04-13 | 江苏中邦制药有限公司 | Method for preparing olmesartan medoxomil |
| CN108341804A (en) * | 2017-12-19 | 2018-07-31 | 嘉实（湖南）医药科技有限公司 | The preparation method of high-purity olmesartan medoxomil |
-
2018
- 2018-09-25 CN CN201811113387.6A patent/CN109081833A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090209603A1 (en) * | 2005-01-03 | 2009-08-20 | Lilach Hedvati | Olmesartan medoxomil with reduced levels of impurities |
| WO2011036674A1 (en) * | 2009-09-24 | 2011-03-31 | Inogent Laboratories Private Limited | A new process for the preparation of olmesartan medoxomil |
| CN105481842A (en) * | 2015-12-15 | 2016-04-13 | 江苏中邦制药有限公司 | Method for preparing olmesartan medoxomil |
| CN108341804A (en) * | 2017-12-19 | 2018-07-31 | 嘉实（湖南）医药科技有限公司 | The preparation method of high-purity olmesartan medoxomil |
Non-Patent Citations (2)
| Title |
|---|
| 李项: ""奥美沙坦酯合成方法的改进研究"", 《中国优秀硕士学位论文全文数据库（电子期刊）》 * |
| 虞心红等: ""抗高血压新药奥美沙坦的合成"", 《华东理工大学学报(自然科学版)》 * |
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Application publication date: 20181225 |