CN107663198A - Olmesartan medoxomil and its production and use - Google Patents
Olmesartan medoxomil and its production and use Download PDFInfo
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- CN107663198A CN107663198A CN201610601571.XA CN201610601571A CN107663198A CN 107663198 A CN107663198 A CN 107663198A CN 201610601571 A CN201610601571 A CN 201610601571A CN 107663198 A CN107663198 A CN 107663198A
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- China
- Prior art keywords
- olmesartan medoxomil
- hydrate
- olmesartan
- composition
- medoxomil
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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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Present invention relates particularly to the olmesartan medoxomil hydrate that olmesartan medoxomil hydrate, the present invention obtain, have the advantage that：Purity is high, and maximum contaminant is less than 1 ‰；Stability is good.The invention further relates to the application using this olmesartan medoxomil hydrate compositions treatment hypertension.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to olmesartan medoxomil hydrate and preparation method thereof, the present invention is also
It is directed to use with the application of this olmesartan medoxomil hydrate compositions treatment hypertension.
Background technology
High blood pressure is most common disease of cardiovascular system, is that one kind is increased as principal character with arterial pressure continuation
Progressive " cardiovascular syndrome ".Most of hypertension pathogenies are failed to understand, are essential hypertension, account for more than 95%；It is secondary
Property hypertension be mostly the hypertension secondary to kidney, endocrine or the nervous system disease.Conventional anti-hypertension medicine has：Calcium
Antagonism of ions agent, angiotensin converting enzyme inhibitor, Angiotensin Ⅱ receptor antagonist, diuretics etc..
Olmesartan medoxomil is a kind of pro-drug, is absorbed through intestines and stomach and is hydrolyzed to Olmesartan.Olmesartan is selectivity
AT_1 receptor (AT1) antagonist, passes through selective exclusion angiotensinⅡ and vascular smooth muscle AT1 acceptors
With reference to and block the vasoconstriction of angiotensinⅡ to act on, therefore outside its effect is independently of the route of synthesis of AT II, its
Structural formula is as follows：
Olmesartan medoxomil has side disclosed in a variety of preparation methods, such as US5616599, WO2004085428, WO2007017135 etc.
Method prepares olmesartan medoxomil.
In research process, the literature methods such as above-mentioned patent are repeated, obtained olmesartan medoxomil impurity number is more, impurity
Total amount is higher.The olmesartan medoxomil hydrate that the present invention obtains, has the advantage that：Purity is high, and maximum contaminant is less than 1 ‰；It is stable
Property is good.
The content of the invention
One object of the present invention, disclose a kind of olmesartan medoxomil hydrate.
Another object of the present invention, disclose the preparation method of olmesartan medoxomil hydrate.
A further object of the present invention, disclose the drug regimen of olmesartan medoxomil hydrate.
Thing.
The invention also discloses olmesartan medoxomil hydrate manufacture treat hypertension, light Moderate Essential Hypertension, especially
Application in secondary hypertension medicine caused by it is applicable kidney damage.
Present invention is specifically described in conjunction with the purpose of the present invention.
The invention provides a kind of olmesartan medoxomil times semihydrate（Shown in formula I）,
（Ⅰ）
Karl_Fischer method（Karl Fischer methods）Be it is a kind of determine material in moisture all kinds of chemical methodes in, it is the most special to water
First, method the most accurate, has been listed in the standard method of determination of moisture in many materials, especially organic compound, as a result
Reliably.Determined through 4 batches, the moisture that described invention compound contains is between 5.61% -5.86% (percentage by weight).
The theoretical content of olmesartan medoxomil times semihydrate reclaimed water is 5.70%, it can be assumed that invention compound contains a hypocrystalline water.
The olmesartan medoxomil times hemi-hydrate crystalline, determined using D/Max-2500.9161 types x-ray diffractometer, measure
Condition：Cu Ka targets, tube voltage 40KV, tube current 100mA.X-ray powder diffraction characteristic absorption peak（2θ）It is as follows with D values.
The measure of 2 θ values uses light source in the present invention, and precision is ± 0.2 °, therefore represents above-mentioned taken value and allow have certain conjunction
The error range of reason, its error range are ± 0.2 °.
Fusing point test：According to Pharmacopoeia of People's Republic of China（2010 editions, two）The first methods of C of annex VI determine Olmesartan
The fusing point of ester times hemi-hydrate crystalline, the fusing point measured are 181.2 DEG C -191.8 DEG C.
Another object of the present invention, the preparation method of olmesartan medoxomil times hemi-hydrate crystalline is disclosed,
Document report, olmesartan medoxomil have a variety of preparation methods, and because its process for purification is different, fusing point has relatively big difference;Impurity
Quantity and total amount are larger.The present inventor explores the matter of refining solvent and obtained Olmesartan medoxomil crystal by largely testing
Magnitude relation, by the way that olmesartan medoxomil is dissolved in acetone-acetic acid-heated in water solution, then cool stage by stage, obtain this hair
The preparation method of bright olmesartan medoxomil hydrate crystal.Astoundingly, the olmesartan medoxomil hydrate has the advantage that：Purity
Height, maximum contaminant are less than 1 ‰；Stability is good.
The preparation method is screened from substantial amounts of single or in the mixed solvent, and no method can be instructed and drawn.
The partial solvent tested has, water；Methanol, acetone, propyl alcohol, isopropanol, butanol, isobutanol, propane diols etc.；The ketones such as acetone try
Agent；The ethers reagent such as ether and diisopropyl ether；Esters, such as ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, butyric acid
Ethyl ester, methyl butyrate etc.；Acetonitrile；Dichloromethane, chloroform, hexane, heptane, toluene, tetrahydrofuran, DMF etc..Use
Their single or mixed solvent, mixed solvent can be that two kinds, three kinds or four kinds solvents mix, the various solvents of in the mixed solvent
Ratio it is different.
Specifically include the following steps：Olmesartan medoxomil adds 3-5 times（Weight or measurement (WM) ratio）Acetone-acetic acid-water=9-
10：0.5-1：In 0.5-1 mixed liquor, 50 DEG C -55 DEG C are heated to, is filtered while hot, 32 DEG C of -36 DEG C of insulation 3-4 hours of filtrate, 18
DEG C -23 DEG C, then 3-4 hours are incubated, separate out crystallization, filtering, through the above-mentioned olmesartan medoxomil times hemi-hydrate crystalline of drying to obtain.
Olmesartan medoxomil used, synthesized according to the method for the grade offers of document US 5616599, the olmesartan medoxomil of synthesis
Chemical constitution is through proton nmr spectra, elementary analysis, it was demonstrated that chemical constitution is correct.
A further object of the present invention, there is provided include olmesartan medoxomil times hemi-hydrate crystalline and one or more pharmacy
The composition of the olmesartan medoxomil hydrate of upper acceptable carrier composition.
The pharmaceutical composition of the present invention prepares as follows：Using standard and conventional technique, make the compounds of this invention and preparation
Acceptable solid or liquid-carrier combine on, and be allowed to arbitrarily with acceptable adjuvant and excipient on galenic pharmacy
With reference to being prepared into particulate or microballoon.Said composition is used to prepare oral formulations.
The active ingredient contained in pharmaceutical composition and unit dosage form（The compounds of this invention）Amount can be according to patient
The state of an illness, the situation of diagnosis be specifically applied, the amount or concentration of compound used are in a wider scope
Regulation, the amount scope of reactive compound are the 1%~50% of composition（Weight）.
Present invention also offers application of the olmesartan medoxomil times hemi-hydrate crystalline in hypertension drug is treated in manufacture.
Through animal（Male rat）Experiment, it is administered orally, olmesartan medoxomil times hemi-hydrate crystalline has and Olmesartan
The suitable good antihypertensive activity of ester, administering mode also can be identical with olmesartan medoxomil.
Stability test
Inventor is studied the chemical stability of the olmesartan medoxomil times hemi-hydrate crystalline of the present invention, and investigation condition is
High temperature（60℃±2℃）, strong illumination（4500Lx±500lx）, high humidity（92.5%,RH）Inspection target is outward appearance, content and is had
Close material (optical isomer).
Outward appearance, content is without change.
As a result：From 0-10 days under strong light, high temperature, super-humid conditions, outward appearance, optical isomer, content do not change, and say
Bright chemical stability is good, is adapted to the manufacture of pharmaceutical preparation and long-term storage.
At 40 DEG C, relative humidity（RH）Under condition 92.5%, olmesartan medoxomil and olmesartan medoxomil times hemi-hydrate crystalline
The measure of middle moisture：
| 0 day | 3 days | 5 days | |
| Olmesartan medoxomil times semihydrate | 5.83% | 5.94% | 5.99% |
| Olmesartan medoxomil | 0.19% | 1.16% | 2.05% |
As a result：At 40 DEG C, relative humidity（RH）Under condition 92.5%, olmesartan medoxomil times hemi-hydrate crystalline reclaimed water point keeps permanent
It is fixed, have good stability；Olmesartan medoxomil has moisture absorption weightening.
Embodiment：
With reference to embodiment, the present invention is described further, professional and technical personnel in the field is better understood from this hair
It is bright.Embodiment is only explanatory, is in no way intended to the scope that it limit the invention in any way.
Olmesartan medoxomil used in the present invention, is synthesized, purity 97.6% according to the method for the grade offers of document US 5616599
(HPLC normalization methods).Its chemical constitution is confirmed through proton nmr spectra, elementary analysis.
Embodiment 1
Equipped with stirring, thermometer, condenser 3000ml reaction bulbs in, add the third of 200 grams of olmesartan medoxomils and 600ml
Ketone-acetic acid-water (9：0.5：0.5) mixed liquor, stirring is started, heat temperature raising is heated to 50 DEG C -55 DEG C, filtered while hot, filtrate 32
DEG C -36 DEG C are incubated 3 hours, 18 DEG C -23 DEG C, then are incubated 3 hours, separate out crystallization, filtering, through the above-mentioned Olmesartan of drying to obtain
Ester times hemi-hydrate crystalline, 182.6 grams.Purity 99.94%, optical isomer 0.05%.
Determined through Karl_Fischer method, the moisture containing 5.73% (percentage by weight).
Embodiment 2
Equipped with stirring, thermometer, condenser 3000ml reaction bulbs in, add the third of 200 grams of olmesartan medoxomils and 1000ml
Ketone-acetic acid-water (10：1：0.5) mixed liquor, stirring is started, heat temperature raising is heated to 51 DEG C -55 DEG C, filtered while hot, filtrate 32
DEG C -35 DEG C are incubated 3 hours, 18 DEG C -23 DEG C, then are incubated 4 hours, separate out crystallization, filtering, through the above-mentioned Olmesartan of drying to obtain
Ester times hemi-hydrate crystalline, 168.2 grams.Purity 99.95%, optical isomer 0.04%.
Determined through Karl_Fischer method, the moisture containing 5.76% (percentage by weight).
Embodiment 3
Equipped with stirring, thermometer, condenser 3000ml reaction bulbs in, add the third of 200 grams of olmesartan medoxomils and 800ml
Ketone-acetic acid-water (9：0.5：1) mixed liquor, stirring being started, heat temperature raising is heated to 51 DEG C -55 DEG C, filtered while hot, 32 DEG C of filtrate -
35 DEG C are incubated 4 hours, 19 DEG C -23 DEG C, then are incubated 3 hours, separate out crystallization, filtering, through the above-mentioned olmesartan medoxomil of drying to obtain
Times hemi-hydrate crystalline, 160.9 grams.Purity 99.96%, optical isomer 0.03%.
Determined through Karl_Fischer method, the moisture containing 5.71% (percentage by weight).
Embodiment 4
Capsule containing olmesartan medoxomil hydrate
Prescription：85 grams, propane diols 3.5ml of olmesartan medoxomil hydrate, 145 grams of starch, is made 1000.
Technique：By olmesartan medoxomil hydrate, starch, soaked with 20% aqueous solution of propylene glycol, granulation of being sieved after mixing, 55
DEG C drying, whole grain, fill capsule.
Claims (6)
1. the hydrate of olmesartan medoxomil shown in formula I,
The crystal of the olmesartan medoxomil hydrate, in being determined by the use of CuKa rays as characteristic X-ray powder, under its collection of illustrative plates has
The θ angles of diffraction of row 2 and D values,
The error of the 2 θ angles of diffraction is ± 0.2.
2. the preparation method of olmesartan medoxomil hydrate crystal described in claim 1, by by olmesartan medoxomil in acetone-second
Acid-heated in water solution dissolving, then cooling obtains stage by stage.
3. the preparation method of olmesartan medoxomil hydrate crystal described in claim 2, it is characterised in that comprise the following steps：Aomei
Husky smooth ester adds 3-5 times（Weight or measurement (WM) ratio）Acetone-acetic acid-water=9-10：0.5-1：In 0.5-1 mixed liquor, it is heated to
50 DEG C -55 DEG C, filter while hot, 32 DEG C of -36 DEG C of insulation 3-4 hours of filtrate, 18 DEG C -23 DEG C, then be incubated 3-4 hours, separate out crystallization,
Filtering, through the above-mentioned olmesartan medoxomil times hemi-hydrate crystalline of drying to obtain.
4. one kind contains olmesartan medoxomil hydrate crystal described in claim 1 and one or more pharmaceutically acceptable carriers
The composition of the olmesartan medoxomil hydrate of composition.
5. the composition described in claim 4, it is characterised in that said composition is used to prepare oral formulations.
6. application of the olmesartan medoxomil hydrate described in claim 1 in hypertension drug is treated in manufacture.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610601571.XA CN107663198A (en) | 2016-07-28 | 2016-07-28 | Olmesartan medoxomil and its production and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610601571.XA CN107663198A (en) | 2016-07-28 | 2016-07-28 | Olmesartan medoxomil and its production and use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107663198A true CN107663198A (en) | 2018-02-06 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610601571.XA Pending CN107663198A (en) | 2016-07-28 | 2016-07-28 | Olmesartan medoxomil and its production and use |
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| Country | Link |
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| CN (1) | CN107663198A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112321575A (en) * | 2020-11-18 | 2021-02-05 | 福建天泉药业股份有限公司 | Olmesartan medoxomil refining method suitable for industrial production |
-
2016
- 2016-07-28 CN CN201610601571.XA patent/CN107663198A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112321575A (en) * | 2020-11-18 | 2021-02-05 | 福建天泉药业股份有限公司 | Olmesartan medoxomil refining method suitable for industrial production |
| CN112321575B (en) * | 2020-11-18 | 2023-07-21 | 福建天泉药业股份有限公司 | Olmesartan medoxomil refining method suitable for industrial production |
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Application publication date: 20180206 |