CN101863796B - Aliskiren compound and novel preparation method thereof - Google Patents
Aliskiren compound and novel preparation method thereof Download PDFInfo
- Publication number
- CN101863796B CN101863796B CN2010101695616A CN201010169561A CN101863796B CN 101863796 B CN101863796 B CN 101863796B CN 2010101695616 A CN2010101695616 A CN 2010101695616A CN 201010169561 A CN201010169561 A CN 201010169561A CN 101863796 B CN101863796 B CN 101863796B
- Authority
- CN
- China
- Prior art keywords
- aliskiren
- acid
- purification
- filtrate
- organic acid
- 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.)
- Expired - Fee Related
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a refining method of an aliskiren compound, which comprises the following steps that: first, salifying aliskiren and organic acid, absorbing with active carbon, separating and purifying with a chromatographic column, finally reacting with alkali to obtain the high-purity aliskiren compound. The invention greatly improves the purity and the content of the aliskiren, optimizes the preparation product quality, ensures the safety of clinical medication; and the method has the advantages of simple process, low cost and high yield, and is applicable of large-scale production.
Description
Technical field
The present invention relates to a kind of aliskiren compound and process for purification thereof, belong to medical technical field.
Background technology
Western countries' large-scale crowd investigation result according to The World Health Organization's report shows that adult's hypertension morbidity is 8%-18%, whole world hypertension morbidity about 10%.Investigation in recent years shows that China hyperpietic has 1.8 hundred million, annual newly-increased hyperpietic 3,500,000.Hypertension is the modal cardiovascular disorder of China, also is one of maximum prevailing disease.It is the morbidity height not only, and often causes the heart, brain, kidney complication, is cerebral apoplexy.One of primary hazard factor of coronary heart disease.Antihypertensive drug is of a great variety at present, is divided into diuretic(s), adrenoreceptor blocker, calcium channel blocker, angiotensin converting enzyme inhibitor, angiotensin-ii receptor antagonistic etc. by mechanism of action.
Aliskiren is a kind of novel antihypertensive medicine of Switzerland Novartis Co.,Ltd research and development, 2007 successively in the U.S. and European Union's approval listing, being a kind of orally active non-peptide class renin inhibitor that acts on renin angiotensin sterone system (RAS), is the first medicine with novel pharmacological mechanism that the hypertension therapeutic field is released.
Aliskiren, chemical being called (2S, 4S, 5S, 7S)-5-amino-N-(2-formamyl-2-methyl-propyl)-4-hydroxyl-2-sec.-propyl-7-[4-methoxyl group-3-(3-methoxy propoxy) benzyl]-8-methyl pelargonamide, molecular formula C
30H
54ClN
3O
6, molecular weight 588.22, structural formula is:
Aliskiren form with fumarate in preparation exists, and the oral organism-absorbing availability is about 2.5%, t
1/2=20-45h, oral 1-3h Plasma Concentration reaches the peak, reaches steady state plasma concentration behind the medication 7-8d.The aliskiren absorption dose 1/4 with prototype through urine excretion.Clinical study: the back patient's blood renin activity of taking medicine reduces about 50%-80%, and does not have dose-dependently.After clinical 2 weeks of independent use, patient's blood pressure of 85%-90% obviously descends.The ambulatory blood pressure monitor showing still can be well controlled at dosing interval phase blood pressure, and average blood pressure in the daytime is 0.6-0.9 with the ratio of average nocturnalism blood pressure.Aliskiren can produce lasting antihypertensive effect, and blood pressure just returns to baseline values gradually after drug withdrawal several weeks.Aliskiren and other antihypertensive drug Combined Preparation, antihypertensive effect all are better than individually dosed respectively.
The synthesis technique of aliskiren bulk drug reports that seldom the study route of present domestic report is all very complicated, and yield is very low, and the final product purity that obtains is also very low, can not be used for large-scale production.
Summary of the invention
The object of the present invention is to provide a kind of process for purification of aliskiren compound, it passes through acid-base reaction, charcoal absorption and chromatographic column absorption and purification reach the purpose of refining purifying, final product purity improves a lot than currently available products, optimize the formulation products quality, guaranteed safety of clinical administration.
The technical scheme that the present invention solves is as follows:
A kind of process for purification of aliskiren compound of structure as follows,
With aliskiren and organic acid salify, use the charcoal absorption purifying earlier, use the chromatographic column separation and purification again, last and alkali reaction obtains highly purified aliskiren compound.
Preferably, the acid described in the aforesaid method is selected from a kind of in fumaric acid, Aspartic Acid, tartrate, oxysuccinic acid, Phenylsulfonic acid, oxalic acid, Citric Acid, phenylformic acid, the Whitfield's ointment, is preferably fumaric acid.
Preferably, the chromatographic column purification condition described in the aforesaid method is: with volume ratio is that 1: 3 Virahol and acetonitrile mixed solvent is moving phase, and fixed phase stuffing is silica gel or aluminum oxide, and flow velocity is 2.8-5.2ml/min, column temperature 30-40 ℃.
Preferably, the alkali described in the aforesaid method is selected from a kind of in sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, the ammoniacal liquor, is preferably sodium bicarbonate.
As the present invention's one preferred embodiment, the preparation process of aliskiren compound of the present invention comprises:
(1) the aliskiren crude product is dissolved in the organic solvent, slowly adds organic acid soln, stirring reaction produces precipitation, filters and obtains aliskiren organic acid salt solid;
(2) the aliskiren organic acid salt is dissolved in an amount of purified water, adds the gac of overall solution volume 0.1-0.3 (g/ml), 60-70 ℃ is stirred 20-30min, filters decarburization, collects filtrate;
(3) with filtrate by the chromatographic column separation and purification, be that 1: 3 Virahol and acetonitrile is mixed solvent moving phase with volume ratio, fixed phase stuffing is silica gel or aluminum oxide, flow velocity is 2.8-5.2ml/min, column temperature 30-40 ℃, collects filtrate;
(4) add in the alkaline solution in filtrate and organic acid, 60-80 ℃ of decompression stirred, and separates out solid gradually, is incubated abundant stirring reaction 2-4h again, filter, and water washing, 50 ℃ of drying under reduced pressure obtain highly purified aliskiren.
Preferably, the organic solvent described in the aforesaid method is selected from one or more in methylene dichloride, acetonitrile, trichloromethane, Virahol, hexanaphthene, isopropyl ether, the sherwood oil, and being preferably volume ratio is 1: 3 the hexanaphthene and the mixed solvent of isopropyl ether.
The process for purification of aliskiren compound provided by the invention; by acid-base reaction, charcoal absorption and chromatographic column absorption and purification; the purity and the content of aliskiren have been improved greatly; optimized the quality product of preparation; guaranteed safety of clinical administration, and present method technology is simple, cost is low; the yield height is suitable for large-scale production.
Embodiment
Below further explain and describe content of the present invention by embodiment, but embodiment is not to be construed as limiting the scope of the invention.
Making with extra care of embodiment 1 aliskiren
(1) 100g aliskiren crude product is dissolved in the mixed solvent that the 1000ml volume ratio is 1: 3 hexanaphthene and isopropyl ether, slowly adds 5% fumaric acid solution, stirring reaction produces precipitation, filters and obtains aliskiren fumarate solid;
(2) the aliskiren fumarate is dissolved in the 2000ml purified water, adds the 2g gac, 70 ℃ are stirred 20min, filter decarburization, collect filtrate;
(3) with filtrate by the chromatographic column separation and purification, be that 1: 3 Virahol and acetonitrile is mixed solvent moving phase with volume ratio, fixed phase stuffing is silica gel or aluminum oxide, flow velocity is 2.8ml/min, 30 ℃ of column temperatures are collected filtrate;
(4) add 10% sodium hydrogen carbonate solution in filtrate, 80 ℃ of decompressions are stirred, and separate out solid gradually, are incubated abundant stirring reaction 2h again, filter, and water washing, 50 ℃ of drying under reduced pressure obtain highly purified aliskiren 87.8g, yield 87.8%.
Making with extra care of embodiment 2 aliskirens
(1) 100g aliskiren crude product is dissolved in the mixed solvent that the 1000ml volume ratio is 1: 1 trichloromethane and sherwood oil, slowly adds 10% Aspartic Acid solution, stirring reaction produces precipitation, filters and obtains aliskiren aspartate solid;
(2) the aliskiren aspartate is dissolved in the 2000ml purified water, adds the 6g gac, 60 ℃ are stirred 30min, filter decarburization, collect filtrate;
(3) with filtrate by the chromatographic column separation and purification, be that 1: 3 Virahol and acetonitrile is mixed solvent moving phase with volume ratio, fixed phase stuffing is silica gel or aluminum oxide, flow velocity is 5.2ml/min, 40 ℃ of column temperatures are collected filtrate;
(4) add 5% sodium carbonate solution in filtrate, 60 ℃ of decompressions are stirred, and separate out solid gradually, are incubated abundant stirring reaction 4h again, filter, and water washing, 50 ℃ of drying under reduced pressure obtain highly purified aliskiren 85.9g, yield 85.9%.
Making with extra care of embodiment 3 aliskirens
(1) 100g aliskiren crude product is dissolved in the mixed solvent that the 1500ml volume ratio is 2: 1 hexanaphthene and sherwood oil, slowly adds 6% tartaric acid solution, stirring reaction produces precipitation, filters and obtains aliskiren tartrate solid;
(2) the aliskiren tartrate is dissolved in the 2000ml purified water, adds the 4g gac, 65 ℃ are stirred 20min, filter decarburization, collect filtrate;
(3) with filtrate by the chromatographic column separation and purification, be that 1: 3 Virahol and acetonitrile is mixed solvent moving phase with volume ratio, fixed phase stuffing is silica gel or aluminum oxide, flow velocity is 3.9ml/min, 40 ℃ of column temperatures are collected filtrate;
(4) add 10% ammonia soln in filtrate, 70 ℃ of decompressions are stirred, and separate out solid gradually, are incubated abundant stirring reaction 3h again, filter, and water washing, 50 ℃ of drying under reduced pressure obtain highly purified aliskiren 88.4g, yield 88.4%.
Making with extra care of embodiment 4 aliskirens
(1) 100g aliskiren crude product is dissolved in the mixed solvent that the 1000ml volume ratio is 1: 4 methylene dichloride and acetonitrile, slowly adds 10% malic acid solution, stirring reaction produces precipitation, filters and obtains aliskiren malate solid;
(2) the aliskiren malate is dissolved in the 2000ml purified water, adds the 2g gac, 70 ℃ are stirred 30min, filter decarburization, collect filtrate;
(3) with filtrate by the chromatographic column separation and purification, be that 1: 3 Virahol and acetonitrile is mixed solvent moving phase with volume ratio, fixed phase stuffing is silica gel or aluminum oxide, flow velocity is 3.3ml/min, 40 ℃ of column temperatures are collected filtrate;
(4) add 4% sodium hydroxide solution in filtrate, 60 ℃ of decompressions are stirred, and separate out solid gradually, are incubated abundant stirring reaction 2h again, filter, and water washing, 50 ℃ of drying under reduced pressure obtain highly purified aliskiren 85.7g, yield 85.7%.
Making with extra care of embodiment 5 aliskirens
(1) 100g aliskiren crude product is dissolved in the mixed solvent that the 1000ml volume ratio is 1: 2 Virahol and isopropyl ether, slowly adds 8% Phenylsulfonic acid solution, stirring reaction produces precipitation, filters and obtains aliskiren benzene sulfonate solid;
(2) the aliskiren benzene sulfonate is dissolved in the 3000ml purified water, accretion 9g gac, 60 ℃ are stirred 20min, filter decarburization, collect filtrate;
(3) with filtrate by the chromatographic column separation and purification, be that 1: 3 Virahol and acetonitrile is mixed solvent moving phase with volume ratio, fixed phase stuffing is silica gel or aluminum oxide, flow velocity is 4.4ml/min, 30 ℃ of column temperatures are collected filtrate;
(4) add 5% potassium bicarbonate solution in filtrate, 80 ℃ of decompressions are stirred, and separate out solid gradually, are incubated abundant stirring reaction 4h again, filter, and water washing, 50 ℃ of drying under reduced pressure obtain highly purified aliskiren 86.1g, yield 86.1%.
Making with extra care of embodiment 6 aliskirens
(1) 100g aliskiren crude product is dissolved in the mixed solvent that the 1000ml volume ratio is 1: 3 hexanaphthene and isopropyl ether, slowly adds 5% citric acid soln, stirring reaction produces precipitation, filters and obtains aliskiren citrate solid;
(2) the aliskiren citrate is dissolved in the 2000ml purified water, adds the 3g gac, 70 ℃ are stirred 20min, filter decarburization, collect filtrate;
(3) with filtrate by the chromatographic column separation and purification, be that 1: 3 Virahol and acetonitrile is mixed solvent moving phase with volume ratio, fixed phase stuffing is silica gel or aluminum oxide, flow velocity is 4.0ml/min, 40 ℃ of column temperatures are collected filtrate;
(4) add 10% solution of potassium carbonate in filtrate, 70 ℃ of decompressions are stirred, and separate out solid gradually, are incubated abundant stirring reaction 3h again, filter, and water washing, 50 ℃ of drying under reduced pressure obtain highly purified aliskiren 85.5g, yield 85.5%.
Claims (5)
1. the process for purification of the aliskiren compound of a structure as follows,
It is characterized in that elder generation with aliskiren and organic acid salify, uses the charcoal absorption purifying, use the chromatographic column separation and purification again, last and alkali reaction obtains highly purified aliskiren compound;
Described organic acid is selected from a kind of in fumaric acid, Aspartic Acid, tartrate, oxysuccinic acid, Phenylsulfonic acid, oxalic acid, Citric Acid, phenylformic acid, the Whitfield's ointment;
Described alkali is selected from a kind of in sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, the ammoniacal liquor;
The chromatographic column purification condition is: with volume ratio is that 1: 3 Virahol and acetonitrile mixed solvent is moving phase, and fixed phase stuffing is silica gel or aluminum oxide, and flow velocity is 2.8-5.2ml/min, column temperature 30-40 ℃.
2. the process for purification of aliskiren compound according to claim 1 is characterized in that described organic acid is selected from fumaric acid, and described alkali is selected from sodium bicarbonate.
3. according to each described method of claim 1-2, it is characterized in that comprising the steps:
(1) the aliskiren crude product is dissolved in the organic solvent, slowly adds organic acid soln, stirring reaction produces precipitation, filters and obtains aliskiren organic acid salt solid;
(2) the aliskiren organic acid salt is dissolved in an amount of purified water, adds the gac of overall solution volume 0.1-0.3 (g/ml), 60-70 ℃ is stirred 20-30min, filters decarburization, collects filtrate;
(3) with filtrate by the chromatographic column separation and purification, be that 1: 3 Virahol and acetonitrile is mixed solvent moving phase with volume ratio, fixed phase stuffing is silica gel or aluminum oxide, flow velocity is 2.8-5.2ml/min, column temperature 30-40 ℃, collects filtrate;
(4) add in the alkaline solution in filtrate and organic acid, 60-80 ℃ of decompression stirred, and separates out solid gradually, is incubated abundant stirring reaction 2-4h again, filter, and water washing, 50 ℃ of drying under reduced pressure obtain highly purified aliskiren.
4. method according to claim 3 is characterized in that organic solvent is selected from one or more in methylene dichloride, acetonitrile, trichloromethane, Virahol, hexanaphthene, isopropyl ether, the sherwood oil.
5. method according to claim 4 is characterized in that organic solvent is that volume ratio is 1: 3 the hexanaphthene and the mixed solvent of isopropyl ether.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101695616A CN101863796B (en) | 2010-05-12 | 2010-05-12 | Aliskiren compound and novel preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101695616A CN101863796B (en) | 2010-05-12 | 2010-05-12 | Aliskiren compound and novel preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101863796A CN101863796A (en) | 2010-10-20 |
| CN101863796B true CN101863796B (en) | 2011-08-24 |
Family
ID=42955760
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010101695616A Expired - Fee Related CN101863796B (en) | 2010-05-12 | 2010-05-12 | Aliskiren compound and novel preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101863796B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060154926A1 (en) * | 2002-06-11 | 2006-07-13 | Elan Pharmaceuticals, Inc. | Methods of treating alzheimer's disease using aryl alkanoic acid amides |
| CN1990461A (en) * | 2005-12-27 | 2007-07-04 | 上海药明康德新药开发有限公司 | Industrial preparation method for 3-amino-2, 2-dimethyl propionamide |
| CN101016253A (en) * | 2006-02-09 | 2007-08-15 | 上海药明康德新药开发有限公司 | Practical synthesis method for feritin inhibitor aliskiren |
| CN101273012A (en) * | 2005-09-28 | 2008-09-24 | 诺瓦提斯公司 | Sythesis of renin inhibitors involving a cycloaddition reaction |
-
2010
- 2010-05-12 CN CN2010101695616A patent/CN101863796B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060154926A1 (en) * | 2002-06-11 | 2006-07-13 | Elan Pharmaceuticals, Inc. | Methods of treating alzheimer's disease using aryl alkanoic acid amides |
| CN101273012A (en) * | 2005-09-28 | 2008-09-24 | 诺瓦提斯公司 | Sythesis of renin inhibitors involving a cycloaddition reaction |
| CN1990461A (en) * | 2005-12-27 | 2007-07-04 | 上海药明康德新药开发有限公司 | Industrial preparation method for 3-amino-2, 2-dimethyl propionamide |
| CN101016253A (en) * | 2006-02-09 | 2007-08-15 | 上海药明康德新药开发有限公司 | Practical synthesis method for feritin inhibitor aliskiren |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101863796A (en) | 2010-10-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101279997B (en) | Novel preparation of budesonide | |
| CN109705013B (en) | 1- (4-methylbenzyl) -3-amino-4-methylselenylmaleimide compound and preparation method thereof | |
| CN102584677B (en) | Method for preparing gliclazide | |
| CN104086624A (en) | Preparation method for carfilzomib | |
| CN106431993A (en) | Method for preparing LCZ-696 key intermediate | |
| CN101239937B (en) | Method for preparing optical activity R-(-)-1-benzylcarbonyl-3-aminopyrrolidine and hydrochloride thereof | |
| CN107216298A (en) | A kind of preparation method of butylphenyl phthaleine | |
| CN112898307A (en) | Ketorolac impurity C and preparation method and application thereof | |
| CN101863796B (en) | Aliskiren compound and novel preparation method thereof | |
| CN107903147A (en) | A kind of synthesis technique of Crizotinib intermediate | |
| CN102010386B (en) | Method for preparing trimetazidine hydrochloride | |
| CN115340481A (en) | Method for industrially producing deuterated medical intermediate by adopting immobilized nickel catalysis | |
| CN107043385B (en) | A method of preparing darunavir intermediate | |
| CN101492413B (en) | Fine purification method for carprofen | |
| CN104262301B (en) | A kind of method of synthesis S-(+)-tetrahydro 3 furanmethanol | |
| CN106674135A (en) | Uracil synthesizing method | |
| CN102127134B (en) | Ribavirin compound and novel preparation method thereof | |
| CN102875499B (en) | The preparation method of 3-aminomethyl trimethylene oxide and organic acid salt thereof | |
| CN112225716A (en) | Synthetic method of chickpea element A | |
| CN110229111A (en) | Ambroxol impurity and the preparation method and application thereof | |
| CN111875666B (en) | Method for synthesizing Edwarden sweet | |
| CN109988174A (en) | A kind of preparation method of tropsch imatinib key intermediate | |
| CN115785057B (en) | Preparation method of ticagrelor intermediate compound and salt thereof | |
| CN101768164B (en) | Naloxone hydrochloride compound with high purity | |
| CN103304543A (en) | Preparation method of candesartan cilexetil |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110824 Termination date: 20160512 |