CN108047152A - A kind of process for purification of Valsartan - Google Patents
A kind of process for purification of Valsartan Download PDFInfo
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- CN108047152A CN108047152A CN201711320558.8A CN201711320558A CN108047152A CN 108047152 A CN108047152 A CN 108047152A CN 201711320558 A CN201711320558 A CN 201711320558A CN 108047152 A CN108047152 A CN 108047152A
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- valsartan
- purification
- ethyl acetate
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- centrifugation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of process for purification of Valsartan, including following two steps, step 1：Valsartan crude product and ethyl acetate are placed in same reactor, dissolved by heating, is subsequently cooled to room temperature, adds in activated carbon reflux decoloration；Step 2：It filters while hot, to filtrate Temperature fall, stirring and crystallizing, after crystallization, centrifugation takes a small amount of ethyl acetate elution solid, and the precipitation after centrifugation is put into vacuum desiccator by centrifugation, takes out up to the Valsartan raw material after refined.The process for purification that the present invention uses can be effectively reduced the content of impurity in Valsartan, improve product purity (＞ 99.9), and the process for purification of the present invention is easy to operate, is suitble to large-scale industrial production.
Description
Technical field
The invention belongs to technical field of medical chemistry, and in particular to a kind of process for purification of Valsartan.
Background technology
Valsartan is angiotensin II receptor antagonist of new generation, has high selectivity and special direct effect,
Can effective antagonism ATl receptors, when half-life period is about 9 small, efficacy of antihypertensive treatment can maintain 24 it is small when more than, and have preferable paddy peak ratio
Value, possesses extensive therapeutic effect, patient's better tolerance.
Since Valsartan is chronic disease medication, it is necessary to long-term use, thus in order to prevent impurity accumulate in patient's body and
Caused side effect is badly in need of developing a kind of process for purification of Valsartan, to ensure the purity of product.
Because Valsartan easily hydrolyzes in alkaline conditions, 104402838 A of Patent No. CN disclose a kind of using acid
Property or neutral alumina adsorbing contaminant Valsartan process for purification, but the method to some positively charged impurity absorptions effects not
By force.Patent No. CN 103435567 A, CN 102391200 A disclose the process for purification of Valsartan, though both approaches
Can reach refining effect, but it is refined after Valsartan yield it is relatively low, and two kinds of solvents or two or more molten are used in technique
Agent adds dissolvent residual.
The content of the invention
The technical problems to be solved by the invention are to overcome the shortcomings of to mention in background above technology and defect, provide one
The process for purification of kind Valsartan.
In order to solve the above technical problems, technical solution proposed by the present invention is：
A kind of process for purification of Valsartan, including following two steps：
Step 1：Valsartan crude product and solvent are placed in same reactor, is dissolved by heating, is subsequently cooled to room temperature, adds
Enter decolorising agent reflux decoloration；The solvent is at least one of ethyl alcohol, water, methanol, ethyl acetate；The decolorising agent is activity
At least one of charcoal, aluminium oxide；
Step 2：It filters while hot, to filtrate Temperature fall, stirring and crystallizing, after crystallization, separation of solid and liquid takes a small amount of acetic acid second
Ester elutes solid, and the precipitation after centrifugation is put into vacuum desiccator by centrifugation, takes out the Valsartan raw material after refining；Institute
The mode of separation of solid and liquid is stated as at least one of centrifugation, filtering.
Above-mentioned method, it is preferred that the solvent in the step 1 is ethyl acetate.
Why select ethyl acetate as solvent be due to：Valsartan easily dissolves in ethanol, readily soluble in methyl alcohol,
It is slightly molten in ethyl acetate, it is almost insoluble in water.According to this property of Valsartan, ethyl alcohol is selected：Water (1:1), acetic acid second
Ester, methanol：Ethyl acetate (1:10) it is solvent, handles through activated carbon decolorizing, under the process conditions such as identical crystallization temperature, obtain
The purity of the Valsartan arrived and yield are as shown in table 1 below.
The influence that 1 different solvents of table refine Valsartan
Valsartan is practically insoluble in water, and is completely dissolved in ethanol solution.Using ethyl alcohol plus water as solvent, can make
Valsartan dissolves under heating conditions, then cooling crystallization.But the excessive concentration of ethyl alcohol, Valsartan are not easy crystallization, concentration mistake
Low, then Valsartan cannot be dissolved in ethanol water, and reduces the yield of product, therefore selects ethyl alcohol：Water (1:1).Figured silk fabrics
Sha Tan has high-temperature digestion in ethyl acetate, and the characteristic of crystallization is precipitated under low temperature, can be effectively improved using this characteristic
The purity of Valsartan.It is readily soluble in methyl alcohol because Valsartan is slightly molten in ethyl acetate, a small amount of methanol is added in into ethyl acetate
In, Valsartan is made to be easier to be dissolved in solvent, to improve the crystallization purity of Valsartan.
As can be seen from Table 1, with ethyl alcohol：Water (1:1) it is solvent, the purity of Valsartan is low, and yield is also low, and moisture exists
It is not easy to remove in Valsartan.Solvent is methanol：Ethyl acetate (1:10) it is very close with the purity of Valsartan in ethyl acetate, but second
The yield of Valsartan is higher in acetoacetic ester solvent.Ethyl acetate solvent 1- solvents 3 the results show that using ethyl acetate as solvent,
With the extension of crystallization time, the purity and yield of Valsartan are improved, when reaching 16h when the crystallization time, then extending crystallization
Between, the purity of Valsartan and varying less for yield, so, choose recrystallisation solvent of the ethyl acetate as Valsartan, crystallization
16h。
Above-mentioned method, it is preferred that the solid-liquid of Valsartan crude product and ethyl acetate proportioning is 1g in the step 1：6~
8mL。
It using ethyl acetate as solvent, is handled through activated carbon decolorizing, when the crystallization time is 16 small, crystallization temperature is 15 DEG C.No
The purity and yield for the Valsartan that same solid-to-liquid ratio obtains are as shown in table 2 below
Different solid is with the influence for comparing Valsartan purity and yield when 2 ethyl acetate of table is solvent
Table 2 the results show that with the increase of quantity of solvent, meltage of the Valsartan in ethyl acetate is more, then is precipitated
Crystallization in Valsartan purity it is higher；Conversely, with the reduction of quantity of solvent, meltage of the Valsartan in ethyl acetate is got over
Few, then the purity of Valsartan is lower in the crystallization being precipitated.But if the amount of solvent is excessive, the supersaturation of solution cannot be formed
State so as to influence crystallization, reduces the yield of product.As seen from the above table, solid-to-liquid ratio 1:The purity of product is too low in 4；Solid-liquid
Than for 1:10、1:Although the purity of product is very high in 8, the yield of product is but respectively less than 70%；Solid-to-liquid ratio is 1:Product in 6
Purity be more than 99%, and yield is also more than 90%, therefore this experiment selection 1:6 solid-to-liquid ratio as solvent.
Above-mentioned method, it is preferred that the decolorising agent in the step 1 is activated carbon.
Using ethyl acetate as solvent, decolorization is carried out through activated carbon adsorption, peroxidating aluminium column, the crystallization time is small for 16
When, crystallization temperature is 15 DEG C.The purity for the Valsartan that different decoloration treatment methods obtains and yield are as shown in table 3 below：
Influence of 3 ethyl acetate of the table decoloration treatment method different when being solvent to Valsartan purity and yield
3 data of upper table are shown, maximum without the Valsartan yield of decolorization, but impurity content is exceeded；It is oxidized
Aluminium cross column decoloration Valsartan purity, yield it is low compared with activated carbon decolorizing, and from aluminium oxide decolourize result can be seen that because of oxygen
Change aluminium dress column complex process, influence factor is more, so, there are larger with yield for the product purity after oxidized aluminium decoloration
Difference.And activated carbon decolorizing method is easy, and repeatability is preferably, therefore this experiment chooses activated carbon and Valsartan is carried out at decoloration
Reason.
Above-mentioned method, it is preferred that in the step 1 addition of activated carbon for Valsartan crude product quality 2%~
4%.
Using ethyl acetate as solvent, through activated carbon adsorption, influence of the different activities charcoal addition to Valsartan purity is studied,
The results show that when the addition of activated carbon is the 2%~4% of Valsartan crude product quality, the purity of Valsartan is optimal.Reason is
The absorption of activated carbon can reach certain saturation state, and when the amount of activated carbon is smaller, it is full that activated carbon has reached it soon
And state, activated carbon reach after the saturation state of absorption just no longer adsorbing contaminant, cause the impurity in product that can not obtain comprehensively
Removing；And when the addition of activated carbon is excessive, because contained therein water-soluble into analyzing and solution can be polluted,
It is similary to influence sample purity.Therefore the present invention is by experimental study, it is last preferred to make with the 2%~4% of Valsartan crude product quality
For the optimal addn of activated carbon.
Above-mentioned method, it is preferred that the time for the decoloration that flows back in the step 1 is 30~60min.
Using ethyl acetate as solvent, through activated carbon adsorption, respectively reflux decoloration 10min, 20min, 30min, 40min,
60min, when the crystallization time is 16 small, crystallization temperature is 15 DEG C.The purity of the Valsartan obtained under different reflux bleaching times
It is as shown in table 4 below with yield：
Influence of the different reflux bleaching times of table 4 to Valsartan purity
Upper table 4 the results show that with reflux bleaching time extension, the purity of Valsartan, which has, to be obviously improved, when
After time reaches 30 minutes, Valsartan purity varies less, when reason needs to contact one section between activated carbon and adsorbing medium
Between can reach adsorption equilibrium, the results show has obviously had reached this when the bleaching time that flows back reaches 30 minutes
Kind balance, is further added by bleaching time, and the purity of Valsartan does not vary widely, therefore from raising product quality and reduces cost
Upper consideration, 30~60min of present invention selection activated carbon reflux decoloration.
Above-mentioned method, it is preferred that the temperature of the reflux decoloration is 75~85 DEG C.
Above-mentioned method, it is preferred that the speed that filtrate is stirred in the step 2 is 200~300r/min.
Using ethyl acetate as solvent, handled through activated carbon decolorizing, filter, filtrate respectively with 0r/min, 100r/min,
200r/min, 300r/min, 500r/min stirring and crystallizing, when the crystallization time is 16 small, crystallization temperature is 15 DEG C.Centrifugation, it is dry,
Valsartan raw material refine to obtain the final product after.
Influence of the different mixing speed of table 5 to Valsartan character, purity and yield
By upper table 5 as it can be seen that not agitated crystal is in irregular bulk, and color is partially yellow；Crystal color after agitated
Bleach, and shape attenuates.Reason is that crystal generation easy to stick in bottle wall in crystallization process forms bulk, and some are coloured miscellaneous
Matter, easily by the crystallisation adsorption of big grain, and makes product colour partially yellow in Crystallization Process；And it is agitated after, figured silk fabrics on the one hand can be promoted husky
Smooth dissolving removes part insoluble impurities；On the other hand the uniform crystallization of Valsartan can also be promoted during Temperature fall, from
And make the crystallization of precipitation thinner, whiter.But if mixing speed is too fast, the crystal being growing is easily by big cutting force
It smashes, generates a large amount of crystallizations fine crushing, enhance superficial attractive forces, reduce the purity of product instead.To sum up, this experiment selection exists
Stirring and crystallizing under the speed conditions of 200r/min.
Above-mentioned method, it is preferred that the solid-liquid separation method in the step 2 is centrifugation.
Precision weighs Valsartan 80g and puts in reactor, adds the ethyl acetate of 6 times of amounts, dissolves by heating, activated carbon decolorizing
30min, filtering, filtrate is with 200r/min stirring and crystallizings, and centrifugation is respectively adopted for the crystal of precipitation and the method for suction filtration carries out solid-liquid
Separation, to get the Valsartan raw material after refined after residue is vacuum dried.
Influence of the different separation methods of table 6 to Valsartan purity and yield
6 data of upper table show, the yield of the Valsartan raw material of gained after separation of solid and liquid is carried out apparently higher than pumping using centrifugation
Filter method.Reason is, containing a small amount of solvent (ethyl acetate) in the filter residue obtained by suction method, in the drying process because of the liter of temperature
Height, part Valsartan is dissolved in again in remaining ethyl acetate, and reduces yield.
Above-mentioned method, it is preferred that crystallization temperature is 10~20 DEG C in the step 2, when the crystallization time 10~16 is small.
Using ethyl acetate as solvent, through activated carbon adsorption, reflux decoloration 30min is filtered while hot, respectively at 5 DEG C, 10 DEG C,
Under the conditions of 15 DEG C, 30 DEG C, when cooling crystallization 16 is small.The purity of the Valsartan obtained under different crystallization temperatures and yield such as following table
Shown in 7：
Influence of the different crystallization temperatures of table 7 to Valsartan purity and yield
For upper table 7 the results show that with the promotion of crystallization temperature, the purity of Valsartan is higher and higher, but when temperature reaches 30
DEG C when, though the purity of Valsartan is high, yield is substantially reduced.Reason is that higher temperature conditions lower part Valsartan is dissolved in solvent
In cannot be precipitated completely, so as to reduce yield；And under conditions of temperature is relatively low, crystal was not precipitated before this, followed by a large amount of
It is precipitated, and into bulk, partial impurities is caused to be adsorbed in plane of crystal, the crystal for then continuing to be precipitated again is wrapped in interior and is difficult to
Removal, so as to reduce the purity of Valsartan.Therefore the present invention, by experimental study, it is 10~20 DEG C of conditions to select in crystallization temperature
Under crystallized.
The crystallization time 10~16 is through obtained by experimental study, the crystallization time is too short when small, then incomplete, time mistake is precipitated
Long, then time consumption and energy consumption, increases cost.
Above-mentioned method, it is preferred that vacuum drying temperature is 40~60 DEG C in the step 2, and drying time 1~2 is small
When.
Compared with prior art, the advantage of the invention is that：
1. the present invention improves the purity of Valsartan using the method for activated carbon reflux decoloration, easy to operate, at low cost, it is applicable in
In industrialized production；
2. only used a kind of organic solvent in the subtractive process of the present invention, i.e., ethyl acetate is solvent, is reduced organic
The pollution of solvent；
3. the present invention carries out separation of solid and liquid using centrifugation to crystal is precipitated, hyperfiltration technique and other separation of solid and liquid skills are improved
The defects of a small amount of solvent is still remained during art is residue obtained avoids crystal in heat drying process is continued, because residual solvent exists
To low yield phenomenon caused by the dissolving of partial crystals under hot conditions；
4. process for purification using the present invention refines Valsartan, containing for impurity in Valsartan can be effectively reduced
Amount improves product purity (＞ 99.9), and the process for purification of the present invention is easy to operate, is suitble to large-scale industrial production.
Description of the drawings
It in order to illustrate more clearly about the embodiment of the present invention or technical scheme of the prior art, below will be to embodiment or existing
There is attached drawing needed in technology description to be briefly described, it should be apparent that, the accompanying drawings in the following description is the present invention
Some embodiments, for those of ordinary skill in the art, without creative efforts, can also basis
These attached drawings obtain other attached drawings.
Fig. 1 Valsartans related substance chromatogram before refining.(1- hydrolysates；2- impurity D；3- Valsartans；4- is unknown miscellaneous
Matter)
Fig. 2 Valsartans related substance chromatogram after refining.(1- hydrolysates；3- Valsartans)
Specific embodiment
For the ease of understanding the present invention, the present invention is done below in conjunction with Figure of description and preferred embodiment more complete
Face meticulously describes, but protection scope of the present invention is not limited to specific examples below.
Unless otherwise defined, all technical terms used hereinafter are generally understood meaning phase with those skilled in the art
Together.Technical term used herein is intended merely to the purpose of description specific embodiment, is not intended to the limitation present invention's
Protection domain.
Unless otherwise specified, various raw material, reagent, the instrument and equipment etc. used in the present invention can pass through city
Field is commercially available or can be prepared by existing method.
Embodiment 1
Valsartan about 80g and ethyl acetate 480mL are taken, is put in same 1000mL reactors, dissolves by heating, is cooled to room temperature
Afterwards, activated carbon 3.2g is added in, 80 DEG C of reflux are decolourized 30 minutes.It filters while hot, filtrate is stirred with the speed mechanical of 200~300r/min
It mixes, is naturally cooling to 15 DEG C or so, overnight after crystallization when small (about 16), centrifugation separately takes a small amount of ethyl acetate elution filter residue, from
Filter residue is put into vacuum desiccator by the heart, and when 50 DEG C of dryings about 2 are small, continuous treating three batches takes out the Valsartan after refining
Raw material.
The comparison of the refined front and rear Valsartan purity of table 8 and yield
The Valsartan purity that is obtained it can be seen from upper table 8 by process for refining of the present invention it is high (>99.5%), impurity is few, receives
Rate height (>90%).And three batches of continuous treating, it is reproducible.
Claims (10)
1. a kind of process for purification of Valsartan, which is characterized in that including following two steps：
Step 1：Valsartan crude product and solvent are placed in same reactor, dissolved by heating, is subsequently cooled to room temperature, is added in de-
Toner reflux decoloration；The solvent is at least one of ethyl alcohol, water, methanol, ethyl acetate；The decolorising agent for activated carbon,
At least one of aluminium oxide；
Step 2：It filters while hot, to filtrate Temperature fall, stirring and crystallizing, after crystallization, separation of solid and liquid takes a small amount of ethyl acetate to drench
Solid is washed, centrifuges, the precipitation after centrifugation is put into vacuum desiccator, takes out the Valsartan raw material after refining；It is described solid
The separated mode of liquid is at least one of centrifugation, filtering.
2. the process for purification of Valsartan according to claim 1, which is characterized in that the solvent in the step 1 is acetic acid
Ethyl ester.
3. the process for purification of Valsartan according to claim 2, which is characterized in that in the step 1 Valsartan crude product with
The solid-liquid proportioning of ethyl acetate is 1g：6~8mL.
4. the process for purification of Valsartan according to any one of claim 1-3, which is characterized in that in the step 1
Decolorising agent is activated carbon.
5. the process for purification of Valsartan according to claim 4, which is characterized in that the addition of activated carbon in the step 1
It measures as the 2%~4% of Valsartan crude product quality.
6. the process for purification of Valsartan according to claim 1, which is characterized in that the decoloration that flows back in the step 1 when
Between be 30~60min；The temperature of the reflux decoloration is 75~85 DEG C.
7. the process for purification of Valsartan according to any one of claim 1-3, which is characterized in that stirred in the step 2
The speed for mixing filtrate is 200~300r/min.
8. the process for purification of Valsartan according to any one of claim 1-3, which is characterized in that in the step 2
Solid-liquid separation method is centrifugation.
9. the process for purification of Valsartan according to any one of claim 1-3, which is characterized in that tied in the step 2
Brilliant temperature is 10~20 DEG C, when the crystallization time 10~16 is small.
10. the process for purification of Valsartan according to any one of claim 1-3, which is characterized in that in the step 2
Vacuum drying temperature is 40~60 DEG C, when drying time 1~2 is small.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111103252A (en) * | 2019-12-18 | 2020-05-05 | 上海微谱化工技术服务有限公司 | Structural characterization method of sartan drugs |
| CN111393357A (en) * | 2020-04-26 | 2020-07-10 | 上海新华联制药有限公司 | Refining method of chlorpheniramine maleate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007088558A2 (en) * | 2006-02-02 | 2007-08-09 | Alembic Limited | A process for purification of valsartan |
| WO2012056294A1 (en) * | 2010-10-29 | 2012-05-03 | Jubilant Life Sciences Ltd. | An improved process for the preparation of n-pentanoyl-n-[[2'-(1h-tetrazol-5-yi)[1,1'-biphenyl]-4-yi]methyl]-l-valine |
| CN104402838A (en) * | 2014-11-04 | 2015-03-11 | 常州康丽制药有限公司 | Valsartan refining method |
| CN105859646A (en) * | 2016-06-06 | 2016-08-17 | 浙江华海药业股份有限公司 | Refining method for valsartan |
| CN107056720A (en) * | 2016-12-30 | 2017-08-18 | 湖南千金湘江药业股份有限公司 | A kind of preparation and purification method of Valsartan |
-
2017
- 2017-12-12 CN CN201711320558.8A patent/CN108047152A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007088558A2 (en) * | 2006-02-02 | 2007-08-09 | Alembic Limited | A process for purification of valsartan |
| WO2012056294A1 (en) * | 2010-10-29 | 2012-05-03 | Jubilant Life Sciences Ltd. | An improved process for the preparation of n-pentanoyl-n-[[2'-(1h-tetrazol-5-yi)[1,1'-biphenyl]-4-yi]methyl]-l-valine |
| CN104402838A (en) * | 2014-11-04 | 2015-03-11 | 常州康丽制药有限公司 | Valsartan refining method |
| CN105859646A (en) * | 2016-06-06 | 2016-08-17 | 浙江华海药业股份有限公司 | Refining method for valsartan |
| CN107056720A (en) * | 2016-12-30 | 2017-08-18 | 湖南千金湘江药业股份有限公司 | A kind of preparation and purification method of Valsartan |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111103252A (en) * | 2019-12-18 | 2020-05-05 | 上海微谱化工技术服务有限公司 | Structural characterization method of sartan drugs |
| CN111393357A (en) * | 2020-04-26 | 2020-07-10 | 上海新华联制药有限公司 | Refining method of chlorpheniramine maleate |
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Application publication date: 20180518 |