CN106349179A - Refining method of valsartan - Google Patents
Refining method of valsartan Download PDFInfo
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- CN106349179A CN106349179A CN201610731226.8A CN201610731226A CN106349179A CN 106349179 A CN106349179 A CN 106349179A CN 201610731226 A CN201610731226 A CN 201610731226A CN 106349179 A CN106349179 A CN 106349179A
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- solution
- valsartan
- acetoacetic acid
- refining
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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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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a refining method of valsartan. The method comprises the following steps: by using acetoacetic acid as a solvent, putting valsartan into the solvent, regulating the pH value of the solution to 3.0-5.0, heating the solution to 40 DEG C, quickly stirring until the solid is completely dissolved, carrying out ultrasonic dispersion on the solution, quickly filtering the solution, taking the filtrate, adding phthalate into the filtrate, quickly stirring for 5 minutes, stopping stirring, standing for 25-30 minutes, cooling to 0 DEG C or below to precipitate a crystal, filtering, heating the obtained crystal again in an acetoacetic acid solution to dissolve the crystal, stirring for 5 minutes, standing for 25-30 minutes, cooling to 0 DEG C or below to precipitate a crystal, and filtering, thereby finally obtaining the valsartan refined product. The valsartan refined product prepared by the method has the advantages of high product yield (90.1% or above) and high purity (99.86% or above).
Description
Technical field
The invention belongs to technical field of medical chemistry is and in particular to a kind of process for purification of Valsartan.
Background technology
Valsartan chemistry entitled (s)-n- valeryl-n- [4- (2- tetrazole radical) phenyl] benzyl L-Valine, is a kind of blood
Angiotensin at1Receptor antagonist, it is continue calcium ion channel blocker and angiotensin-convertion enzyme inhibitor (acei)
Another novel antihypertensive medicine afterwards.Due to its Small side effects, mechanism of action is unique, better tolerance, and taking convenience may well
Replace front two class medicines and become the choice drug of this century antihypertensive aspect.
Valsartan is chiral drug, and during synthesis, easy racemization is thus produce isomer, isomer is refined
During more difficult removing, current people are purified to Valsartan repeatedly using multiple solution, therefore in industrialized production, meeting
Produce substantial amounts of waste liquid, serious pollutes environment, and production cost also can raise.
Content of the invention
In order to solve the above problems, the invention provides a kind of simple to operate, product purity is high, low cost, to environment no
The Valsartan process for purification of the suitable industrialized production of pollution.
Valsartan process for purification of the present invention, step is as follows: it is using acetoacetic acid as solvent, and Valsartan is put
Enter in above-mentioned solvent, the ph adjusting solution is 3.0-5.0, then solution is warming up to 40 DEG C, quickly stirs completely molten to solid
Solution, then carries out ultrasonic disperse to solution, afterwards by solution fast filtering, takes filtrate, adds phthalic acid ester in filtrate,
Stop after continuing quick stirring 5 minutes, stand 25-30 minute, be cooled to less than 0 DEG C, filter after separating out crystal, then will obtain
Crystal again with acetoacetic acid solution rising temperature for dissolving, stand 25-30 minute after stirring 5 minutes, be cooled to less than 0 DEG C again,
Filter after separating out crystal, finally give Valsartan fine work.
Above-mentioned acetoacetic acid is 6-8:1 with the volume ratio of water.
Above-mentioned acetoacetic acid solution with the volume mass ratio of thick Valsartan is: 1.2-1.5:1.
The above-mentioned solution for adjusting ph is 95% acetic acid solution, and wherein 95% is volume fraction.
Above-mentioned acetoacetic acid solution is 1-2:1 with the volume ratio of phthalic acid ester.
During above-mentioned recrystallization, acetoacetic acid and the volume ratio of water are 6-8:1.
Compared with prior art, beneficial effect is the present invention:
Acetoacetic acid is adopted as lytic agent, it is less to have the high and low toxicity of dissolubility, an environmental pollution in one, the present invention, and
And recyclable reuse.
Two, the present invention, after Valsartan dissolving, carries out supersound process to solution, can play good dispersion soln grain
The effect of son, is conducive to preferably forming crystal in crystallization and re-crystallization step.
Three, I, through many experiments, using different types of chiral resolving agent, finds the effect of phthalic acid ester
Preferably, it is easier to combine to form diastereomer with the isomer of Valsartan, thus changing the physicochemical property of isomer,
By two-step crystallization, can effectively remove the isomer of Valsartan.
The four, method that the present invention adopts, step is simple, suitable industrialized production.
Specific embodiment
Embodiment 1
Thick for 100g Valsartan is put in the acetoacetic acid solution of 120ml, wherein acetoacetic acid and the volume ratio of water are 6:1, use
Volume fraction is 95% acetic acid, adjusts the ph to 3.5 of solution, solution is warming up to 40 DEG C, quickly stirs completely molten to solid
Solution, then carries out ultrasonic disperse to solution, afterwards by solution fast filtering, takes filtrate, adds 120ml O-phthalic in filtrate
Acid esters, stops after continuing quick stirring 5 minutes, stands 25-30 minute, be cooled to 0 DEG C, filters, crystal is claimed after separating out crystal
After weight, again with acetoacetic acid solution rising temperature for dissolving, the volume ratio of wherein acetoacetic acid and water is 6:1, acetoacetic acid solution with
The volume mass of crystal ratio for 1.2:1, stands 25 minutes after stirring 5 minutes, is cooled to 0 DEG C again, filters, after separating out crystal
Obtain Valsartan fine work eventually, using the method yield up to 91.1%, purity reaches 99.90%.
Embodiment 2
Thick for 100g Valsartan is put in the acetoacetic acid solution of 130ml, wherein acetoacetic acid and the volume ratio of water are 7:1, use
Volume fraction is 95% acetic acid, adjusts the ph to 4.0 of solution, solution is warming up to 40 DEG C, quickly stirs completely molten to solid
Solution, then carries out ultrasonic disperse to solution, afterwards by solution fast filtering, takes filtrate, adds 65ml O-phthalic in filtrate
Acid esters, stops after continuing quick stirring 5 minutes, stands 25-30 minute, be cooled to -4 DEG C, filters, crystal is claimed after separating out crystal
After weight, again with acetoacetic acid solution rising temperature for dissolving, the volume ratio of wherein acetoacetic acid and water is 7:1, acetoacetic acid solution with
The volume mass of crystal ratio for 1.3:1, stands 25 minutes after stirring 5 minutes, is cooled to -4 DEG C again, filters after separating out crystal,
Finally give Valsartan fine work, using the method yield up to 92.1%, purity reaches 99.93%.
Embodiment 3
Thick for 100g Valsartan is put in the acetoacetic acid solution of 150ml, wherein acetoacetic acid and the volume ratio of water are 8:1, use
Volume fraction is 95% acetic acid, adjusts the ph to 5.0 of solution, solution is warming up to 40 DEG C, quickly stirs completely molten to solid
Solution, then carries out ultrasonic disperse to solution, afterwards by solution fast filtering, takes filtrate, adds 80ml O-phthalic in filtrate
Acid esters, stops after continuing quick stirring 5 minutes, stands 25-30 minute, be cooled to -5 DEG C, filters, crystal is claimed after separating out crystal
After weight, again with acetoacetic acid solution rising temperature for dissolving, the volume ratio of wherein acetoacetic acid and water is 8:1, acetoacetic acid solution with
The volume mass of crystal ratio for 1.5:1, stands 25 minutes after stirring 5 minutes, is cooled to -5 DEG C again, filters after separating out crystal,
Finally give Valsartan fine work, using the method yield up to 91.0%, purity reaches 99.97%.
Claims (6)
1. a kind of method of refining of Valsartan it is characterised in that: it is using acetoacetic acid as solvent, Valsartan is put into above-mentioned
In solvent, the ph adjusting solution is 3.0-5.0, then solution is warming up to 40 DEG C, quickly stirs and be completely dissolved to solid, then
Ultrasonic disperse is carried out to solution, afterwards by solution fast filtering, takes filtrate, in filtrate, add phthalic acid ester, continue fast
Speed stirring stopped after 5 minutes, stands 25-30 minute, is cooled to less than 0 DEG C, filtered, then by the crystal obtaining after separating out crystal
Again with acetoacetic acid solution rising temperature for dissolving, stirring stood 25-30 minute after 5 minutes, was cooled to less than 0 DEG C again, separated out brilliant
Filter after body, finally give Valsartan fine work.
2. a kind of Valsartan according to claim 1 method of refining it is characterised in that: the volume of acetoacetic acid and water
Than for 6-8:1.
3. a kind of Valsartan according to claim 1 method of refining it is characterised in that: acetoacetic acid solution and thick figured silk fabrics
The volume mass ratio of Sha Tan is: 1.2-1.5:1.
4. a kind of Valsartan according to claim 1 method of refining it is characterised in that: adjust ph solution be 95%
Acetic acid solution, wherein 95% is volume fraction.
5. a kind of Valsartan according to claim 1 method of refining it is characterised in that: acetoacetic acid solution and adjacent benzene
The volume ratio of dicarboxylic acid esters is 1-2:1.
6. a kind of Valsartan according to claim 1 method of refining it is characterised in that: during recrystallization acetoacetic acid with
The volume ratio of water is 6-8:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610731226.8A CN106349179A (en) | 2016-08-26 | 2016-08-26 | Refining method of valsartan |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610731226.8A CN106349179A (en) | 2016-08-26 | 2016-08-26 | Refining method of valsartan |
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| CN106349179A true CN106349179A (en) | 2017-01-25 |
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| CN201610731226.8A Pending CN106349179A (en) | 2016-08-26 | 2016-08-26 | Refining method of valsartan |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321038A (en) * | 2011-07-11 | 2012-01-18 | 安徽省虹升生物科技有限公司 | Improved valsartan preparation method |
| CN102391200A (en) * | 2011-09-30 | 2012-03-28 | 浙江新赛科药业有限公司 | Preparation method of high purity valsartan |
| CN102617497A (en) * | 2012-02-27 | 2012-08-01 | 浙江新赛科药业有限公司 | Process for refining valsartan |
| CN103086993A (en) * | 2013-02-06 | 2013-05-08 | 浙江新赛科药业有限公司 | Method for crystallizing valsartan |
| CN103435567A (en) * | 2013-09-09 | 2013-12-11 | 山东新华制药股份有限公司 | Valsartan refining method |
| 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 |
-
2016
- 2016-08-26 CN CN201610731226.8A patent/CN106349179A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102321038A (en) * | 2011-07-11 | 2012-01-18 | 安徽省虹升生物科技有限公司 | Improved valsartan preparation method |
| CN102391200A (en) * | 2011-09-30 | 2012-03-28 | 浙江新赛科药业有限公司 | Preparation method of high purity valsartan |
| CN102617497A (en) * | 2012-02-27 | 2012-08-01 | 浙江新赛科药业有限公司 | Process for refining valsartan |
| CN103086993A (en) * | 2013-02-06 | 2013-05-08 | 浙江新赛科药业有限公司 | Method for crystallizing valsartan |
| CN103435567A (en) * | 2013-09-09 | 2013-12-11 | 山东新华制药股份有限公司 | Valsartan refining method |
| 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 |
Non-Patent Citations (4)
| Title |
|---|
| 中山医学院药学系化学教研组编: "《化学》", 31 August 1977 * |
| 周年琛等: "《有机化学》", 31 January 2014 * |
| 朱洪法: "《环境保护辞典》", 30 June 2009 * |
| 简明化学试剂手册编写组: "《简明化学试剂手册》", 31 January 1991 * |
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Application publication date: 20170125 |