CN102391200A - Preparation method of high purity valsartan - Google Patents
Preparation method of high purity valsartan Download PDFInfo
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- CN102391200A CN102391200A CN2011102957076A CN201110295707A CN102391200A CN 102391200 A CN102391200 A CN 102391200A CN 2011102957076 A CN2011102957076 A CN 2011102957076A CN 201110295707 A CN201110295707 A CN 201110295707A CN 102391200 A CN102391200 A CN 102391200A
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Abstract
The invention discloses a preparation method of high purity valsartan, which comprises the following steps: drying after a valsartan crude product is recrystallized through esters solvent, dissolving in inorganic base aqueous solution, then adjusting the inorganic base aqueous solution to be acidic by using hydrochloric acid, washing materials by using acid water solution after centrifugation, drying and crushing, and producing the high purity valsartan through centrifugation and drying. The method is simple to operate, the prepared valsartan is high in purity and has the quality that relevant impurities are not detected, chiral isomers are not detected, individual solution remains is smaller than 100 ppm, frequently-used reagents are used, the cost is low, the access is easy, the cost is lower, and meanwhile, the preparation method is beneficial to environmental protection and suitable for industrialized production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to a kind of preparation method of high purity valsartan.
Background technology
(chemistry is by name: N-(1-pentanoyl)-N-[4-[2-(1H-tetrazole-5-yl) phenyl] benzyl]-L-Xie Ansuan) can be used for all kinds hypertension, and the heart and brain kidney is had the better protecting effect for valsartan.Hypertensive patients such as myocardial infarction, heart failure, proteinuria, mellitus can use as routine, can unite use with diuretic(s) (like hydrochlorothiazide).The structural formula of valsartan is following:
Pertinent literature about valsartan is a lot; Especially about the document of valsartan synthetic route; For example disclose improving one's methods of a kind of synthesizing Xieshatan among the Chinese patent ZL200710038346.0, this method is participated in reaction without tin compound, with condenses N-[(2 '-cyanic acid-1; 1 '-biphenyl-4-yl) alkyl]-the L-L-valine ester is a raw material, accomplishes through valerylization and synthesizing Xieshatan two-step reaction.Improving one's methods of a kind of synthesizing Xieshatan disclosed among the Chinese patent ZL001100115355.2, the positive valerylization of mainly having improved N-[[2 '-cyanic acid (1,1 '-phenylbenzene)-4-yl]-methyl]-L-L-valine ester hydrochloride with become the tetrazole reactions step.A kind of compound method of valsartan is disclosed among the patent WO2004026847, with 2 '-(1H-tetrazolium-5-yl)-xenyl-4-formaldehyde is raw material and the ester condensation of L-Xie Ansuan benzyl, valerylization then, and hydrogenation is taken off benzyl and is got valsartan.A kind of preparation method of valsartan is disclosed among the patent WO2008007391, with 5-thiophenyl valeric acid and N-[(2 '-tetrazolium-1,1 '-biphenyl-4-yl) alkyl]-condensation of L-L-valine ester, take off thiophenyl then and get valsartan.Patent US7741507 discloses a kind of compound method; With 4-brooethyl-2 '-cyanobiphenyl is raw material and the condensation of L-valine methyl ester, valerylization again, cyclization, hydrolysis get valsartan; A kind of preparation method of valsartan is disclosed among the patent US7199144; With N-(trityl group)-5-(4 '-bromomethylbiphenyl-2-yl) tetrazole is raw material and the condensation of L-valine methyl ester, acidylate, and deprotection, hydrolysis get valsartan.Though the document about valsartan is a lot, do not see the preparing method's of relevant high purity (that is: relative substance does not detect, and chiral isomer does not detect, and is single molten residual less than 100ppm) valsartan bibliographical information.Valsartan is as bulk drug, and high purity helps increasing the curative effect of medicine and the security of medication.
For this reason, be necessary to develop a kind of preparation method of high purity valsartan, to satisfy industrial needs.
Summary of the invention
The invention provides a kind of preparation method of high purity valsartan of easy and simple to handle, suitable suitability for industrialized production, can make highly purified valsartan.
A kind of preparation method of high purity valsartan comprises step:
The valsartan bullion with ester solvent recrystallization after drying, is dissolved in the aqueous solution of mineral alkali again, transfers to acidity with aqueous solution of hydrochloric acid then, the material after centrifugal, dry and pulverizing washs with aqueous acid, and centrifugal, drying makes highly purified valsartan.
In order further to improve the purity of gained valsartan, preferably:
With the valsartan bullion with after the ester solvent recrystallization after drying and the quality that is dissolved in the valsartan before the aqueous solution of mineral alkali meet: relative substance does not detect, and chiral isomer does not detect, and ester solvent is residual≤25000ppm; Further be preferably ester solvent residual≤15000ppm.
Described ester solvent is selected one or more in ethyl formate, ETHYLE ACETATE, propyl acetate, the isobutyl acetate for use, further is preferably ETHYLE ACETATE.
Described mineral alkali is selected one or more in Pottasium Hydroxide, sodium hydroxide, yellow soda ash, salt of wormwood, the sodium hydrogencarbonate for use, further is preferably sodium hydroxide.
The mass percentage concentration of the aqueous solution of described mineral alkali is 2%-40%, further is preferably 5%-10%.
The mass percentage concentration of described aqueous solution of hydrochloric acid is 5%-36%, further is preferably 9%.
The mass percentage concentration of described aqueous acid is 1%-10%, further is preferably 2%.Acid in the described aqueous acid can be adopted this area acid commonly used, example hydrochloric acid, sulfuric acid etc.
The temperature of the aqueous solution dissolving valsartan of mineral alkali is controlled at 0 ℃-30 ℃, further is preferably 0 ℃-10 ℃.
The temperature that transfers to the tart process with aqueous solution of hydrochloric acid is controlled at 0 ℃-30 ℃, further is preferably 0 ℃-10 ℃.
It is 5 ℃-30 ℃ that material after the pulverizing uses the temperature of the process of aqueous acid washing, further is preferably 5 ℃-10 ℃.
Transfer to the acidity described in the acidity with aqueous solution of hydrochloric acid and refer to pH=1-2.
Described valsartan bullion can adopt existing commercially available prod or adopt the valsartan bullion of existing preparing method's preparation; Also can adopt preparing method's preparation of following valsartan bullion:
With a kind of and valsartan methyl esters in potassium hydroxide aqueous solution, aqueous sodium hydroxide solution, the lithium hydroxide aqueous solution in 25 ℃ of-35 ℃ of stirring reactions 7 hours-9 hours; Be cooled to below 15 ℃, dripping sour adjust pH is 1-2 again, adds the ester solvent extraction; The ester solvent layer uses the aqueous solution of strong base-weak acid salt to be washed till the pH value to be 6-6.9; With the saturated aqueous solution washing of inorganic salt, dry after-filtration gets the valsartan bullion after filtrating concentrates again.
Described strong base-weak acid salt is selected this area strong base-weak acid salt commonly used for use, a kind of as in sodium hydrogencarbonate, yellow soda ash, the salt of wormwood etc.
Described inorganic salt are selected this area inorganic salt commonly used for use, a kind of as in sodium-chlor, calcium chloride, Repone K or the like.
Described drying can select for use this area siccative commonly used to carry out drying, and described siccative is selected a kind of in SODIUM SULPHATE ANHYDROUS 99PCT, anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, the molecular sieve etc. for use.
Compared with prior art, the present invention has following advantage:
The inventive method is simple to operate, and the valsartan purity that makes is high, and reagent is some common agents, and is cheap and easy to get, and cost is lower, helps environmental protection simultaneously, is fit to suitability for industrialized production.
The quality of the highly purified valsartan that the present invention makes is: relative substance does not detect, and chiral isomer does not detect, and is single molten residual less than 100ppm.
Embodiment
Following examples are in order to further specify of the present invention, should it not to be regarded as limitation of the present invention.
The preparation of embodiment 1 valsartan bullion
Add 200g valsartan methyl esters in the there-necked flask of 3000ml, add the 790g mass percentage concentration again and be 10% potassium hydroxide aqueous solution, in 30 ℃ of stirring reactions 8 hours; Reaction is finished, and is cooled to below 15 ℃, and dripping mass percentage concentration and be 36% concentrated hydrochloric acid adjust pH is 1; After mixing up; Add 1000ml ethyl acetate extraction, layering, it is that 5% sodium bicarbonate aqueous solution is washed till slightly acidic (the pH value is 6.9) that ethyl acetate layer uses mass percentage concentration, uses the saturated common salt water washing more once; The anhydrous sodium sulfate drying after-filtration gets the valsartan bullion after filtrating concentrates.
The preparation of embodiment 2 valsartan bullions
Add 200g valsartan methyl esters in the there-necked flask of 3000ml, add the 790g mass percentage concentration again and be 10% potassium hydroxide aqueous solution, in 30 ℃ of stirring reactions 8 hours; Reaction is finished, and is cooled to below 15 ℃, and dripping mass percentage concentration and be 32% concentrated hydrochloric acid adjust pH is 1.5; After mixing up; Add 1000ml ethyl acetate extraction, layering, it is that 5% sodium bicarbonate aqueous solution is washed till slightly acidic (the pH value is 6.5) that ethyl acetate layer uses mass percentage concentration, uses the saturated common salt water washing more once; The anhydrous sodium sulfate drying after-filtration gets the valsartan bullion after filtrating concentrates.
Embodiment 3 valsartans heavily refining
Add 500ml ETHYLE ACETATE in the valsartan bullion that makes in the embodiment 1,, after the dissolving, be cooled to 0 ℃ of crystallization 10 hours 50 ℃ of dissolvings, centrifugal, valsartan, yield 95%, the quality of valsartan: relative substance is 0.6%, chiral isomer 0.5%.
Add the valsartan of the above-mentioned preparation of 100g in the there-necked flask of 1000ml, add 600ml ETHYLE ACETATE again 50 ℃ of dissolvings, after the dissolving; Be cooled to 0 ℃ of crystallization 20 hours, centrifugal, drying; Get the valsartan elaboration, yield 90%, quality: relative substance does not detect; Chiral isomer does not detect, and ETHYLE ACETATE is residual to be 14000ppm.
Embodiment 4 valsartans heavily refining
Add 700ml ETHYLE ACETATE in the valsartan bullion that makes in the embodiment 2,, after the dissolving, be cooled to 0 ℃ of crystallization 10 hours 50 ℃ of dissolvings, centrifugal, valsartan, yield 90%, the quality of valsartan: relative substance is 0.3%, chiral isomer 0.2%.
500ml ETHYLE ACETATE 50 ℃ of dissolvings, after the dissolving, is cooled to 0 ℃ of crystallization 10 hours, and is centrifugal, gets valsartan, yield 95%, and the quality of valsartan: relative substance is 0.6%, chiral isomer 0.5%.
Add the valsartan of the above-mentioned preparation of 100g in the there-necked flask of 1000ml, add 500ml ETHYLE ACETATE again 50 ℃ of dissolvings, after the dissolving; Be cooled to 0 ℃ of crystallization 20 hours, centrifugal, drying; Get the valsartan elaboration, yield 90%, quality: relative substance does not detect; Chiral isomer does not detect, and ETHYLE ACETATE is residual to be 15000ppm.
The preparation of embodiment 5 high purity valsartans
Add the 360g mass percentage concentration in the 1000ml there-necked flask and be 5% aqueous sodium hydroxide solution, 0 ℃ of temperature control adds the valsartan highly finished product of 80g embodiment 3 preparations wherein, and stirring and dissolving is after the dissolving; 0 ℃ of temperature control, the dropping mass percentage concentration is 9% Hydrogen chloride, transfers pH=1, after mixing up, is incubated 2 hours; Centrifugal, drying is pulverized, and the material after the pulverizing adds in the 1000ml there-necked flask, and adding 500ml massfraction is 2% Hydrogen chloride; Stirred 4 hours at 5 ℃, centrifugal, drying gets final finished; Yield 98%, quality is: relative substance does not detect, and chiral isomer does not detect, and dissolvent residual is 10ppm.
The preparation of embodiment 6 high purity valsartans
Add the 200g mass percentage concentration in the 1000ml there-necked flask and be 10% aqueous sodium hydroxide solution, 10 ℃ of temperature controls add the valsartan highly finished product of 80g embodiment 3 preparations wherein, and stirring and dissolving is after the dissolving; 10 ℃ of temperature controls, the dropping mass percentage concentration is 9% Hydrogen chloride, transfers pH=1, after mixing up, is incubated 2 hours; Centrifugal, drying is pulverized, and the material after the pulverizing adds in the 1000ml there-necked flask, and adding 500ml massfraction is 2% Hydrogen chloride; Stirred 4 hours at 10 ℃, centrifugal, drying gets final finished; Yield 98%, quality is: relative substance does not detect, and chiral isomer does not detect, and dissolvent residual is 5ppm.
The preparation of embodiment 7 high purity valsartans
Add the 280g mass percentage concentration in the 1000ml there-necked flask and be 8% aqueous sodium hydroxide solution, 5 ℃ of temperature controls add the valsartan highly finished product of 80g embodiment 3 preparations wherein, and stirring and dissolving is after the dissolving; 0 ℃ of temperature control, the dropping mass percentage concentration is 9% Hydrogen chloride, transfers pH=1, after mixing up, is incubated 2 hours; Centrifugal, drying is pulverized, and the material after the pulverizing adds in the 1000ml there-necked flask, and adding 500ml massfraction is 2% Hydrogen chloride; Stirred 4 hours at 8 ℃, centrifugal, drying gets final finished; Yield 98.2%, quality is: relative substance does not detect, and chiral isomer does not detect, and dissolvent residual is 4ppm.
The preparation of embodiment 8 high purity valsartans
Add the 100g mass percentage concentration in the 1000ml there-necked flask and be 40% aqueous sodium hydroxide solution, 30 ℃ of temperature controls add the valsartan highly finished product of 80g embodiment 3 preparations wherein, and stirring and dissolving is after the dissolving; 30 ℃ of temperature controls, the dropping mass percentage concentration is 5% Hydrogen chloride, transfers pH=1, after mixing up, is incubated 2 hours; Centrifugal, drying is pulverized, and the material after the pulverizing adds in the 1000ml there-necked flask, and adding 500ml massfraction is 1% Hydrogen chloride; Stirred 4 hours at 30 ℃, centrifugal, drying gets final finished; Yield 98%, quality is: relative substance does not detect, and chiral isomer does not detect, and dissolvent residual is 15ppm.
The preparation of embodiment 9 high purity valsartans
Add the 420g mass percentage concentration in the 1000ml there-necked flask and be 2% aqueous sodium hydroxide solution, 0 ℃ of temperature control adds the valsartan highly finished product of 80g embodiment 3 preparations wherein, and stirring and dissolving is after the dissolving; 0 ℃ of temperature control, the dropping mass percentage concentration is 36% Hydrogen chloride, transfers pH=1, after mixing up, is incubated 2 hours; Centrifugal, drying is pulverized, and the material after the pulverizing adds in the 1000ml there-necked flask, and adding 500ml massfraction is 10% Hydrogen chloride; Stirred 4 hours at 5 ℃, centrifugal, drying gets final finished; Yield 98%, quality is: relative substance does not detect, and chiral isomer does not detect, and dissolvent residual is 16ppm.
The preparation of embodiment 10 high purity valsartans
Add the 280g mass percentage concentration in the 1000ml there-necked flask and be 8% aqueous sodium hydroxide solution, 5 ℃ of temperature controls add the valsartan highly finished product of 80g embodiment 4 preparations wherein, and stirring and dissolving is after the dissolving; 0 ℃ of temperature control, the dropping mass percentage concentration is 9% Hydrogen chloride, transfers pH=2, after mixing up, is incubated 2 hours; Centrifugal, drying is pulverized, and the material after the pulverizing adds in the 1000ml there-necked flask, and adding 500ml massfraction is 2% Hydrogen chloride; Stirred 4 hours at 8 ℃, centrifugal, drying gets final finished; Yield 97.5%, quality is: relative substance does not detect, and chiral isomer does not detect, and dissolvent residual is 6ppm.
The detection method of relative substance of the present invention and chiral isomer is a prior art, i.e. HPLC method is specific as follows:
1. the chromatographic condition that detects of relative substance
Moving phase: water-acetonitrile-glacial acetic acid (500: 500: 1, volume ratio)
Chromatographic column: (L1) Nucleosil 100-5,20cm * 3.0mm, 5 μ m;
Detect wavelength: 225nm
Flow velocity: 0.6ml/min
Column temperature: 25 ℃
Sample size: 10 μ l.
2. the chromatographic condition that detects of chiral isomer
Moving phase: normal hexane-Virahol-trifluoroacetic acid (85: 15: 0.1, volume ratio)
Chromatographic column: L40, Kromasil 5-cellucoat, 250 * 4.6mm
Detect wavelength: 230nm
Flow velocity: 0.8ml/min
Column temperature: 25 ℃
Sample size: 10 μ l.
Claims (10)
1. the preparation method of a high purity valsartan comprises step:
The valsartan bullion with ester solvent recrystallization after drying, is dissolved in the aqueous solution of mineral alkali again, transfers to acidity with aqueous solution of hydrochloric acid then, the material after centrifugal, dry and pulverizing washs with aqueous acid, and centrifugal, drying makes highly purified valsartan.
2. the preparation method of high purity valsartan according to claim 1; It is characterized in that; With the valsartan bullion with after the ester solvent recrystallization after drying and the quality that is dissolved in the valsartan before the aqueous solution of mineral alkali meet: relative substance does not detect; Chiral isomer does not detect, and ester solvent is residual≤25000ppm.
3. the preparation method of high purity valsartan according to claim 2 is characterized in that, ester solvent is residual≤and 15000ppm.
4. the preparation method of high purity valsartan according to claim 1 is characterized in that, described ester solvent is one or more in ethyl formate, ETHYLE ACETATE, propyl acetate, the isobutyl acetate;
Perhaps, described mineral alkali is one or more in Pottasium Hydroxide, sodium hydroxide, yellow soda ash, salt of wormwood, the sodium hydrogencarbonate.
5. the preparation method of high purity valsartan according to claim 1 is characterized in that, the mass percentage concentration of the aqueous solution of described mineral alkali is 2%-40%.
6. the preparation method of high purity valsartan according to claim 1 is characterized in that, the mass percentage concentration of described aqueous solution of hydrochloric acid is 5%-36%;
Perhaps, the mass percentage concentration of described aqueous acid is 1%-10%.
7. the preparation method of high purity valsartan according to claim 1 is characterized in that, the temperature of the aqueous solution dissolving valsartan of mineral alkali is controlled at 0 ℃-30 ℃;
Perhaps, the temperature that transfers to the tart process with aqueous solution of hydrochloric acid is controlled at 0 ℃-30 ℃.
8. the preparation method of high purity valsartan according to claim 1 is characterized in that, it is 5 ℃-30 ℃ that the material after the pulverizing uses the temperature of the process of aqueous acid washing.
9. the preparation method of high purity valsartan according to claim 1 is characterized in that, transfers to the acidity described in the acidity with aqueous solution of hydrochloric acid and refers to pH=1-2.
10. the preparation method of high purity valsartan according to claim 1 is characterized in that, the preparation method of described valsartan bullion comprises step:
With a kind of and valsartan methyl esters in potassium hydroxide aqueous solution, aqueous sodium hydroxide solution, the lithium hydroxide aqueous solution in 25 ℃ of-35 ℃ of stirring reactions 7 hours-9 hours; Be cooled to below 15 ℃, dripping sour adjust pH is 1-2 again, adds the ester solvent extraction; The ester solvent layer uses the aqueous solution of strong base-weak acid salt to be washed till the pH value to be 6-6.9; With the saturated aqueous solution washing of inorganic salt, dry after-filtration gets the valsartan bullion after filtrating concentrates again.
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Cited By (10)
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| CN103127131A (en) * | 2012-07-27 | 2013-06-05 | 华润赛科药业有限责任公司 | Solid composition with valsartan and preparation method thereof |
| CN103554049A (en) * | 2013-11-08 | 2014-02-05 | 浙江新赛科药业有限公司 | Method for preparing valsartan |
| CN103951659A (en) * | 2014-04-11 | 2014-07-30 | 烟台万润药业有限公司 | Olmesartan Medoxomi I with low solvent residue |
| CN104030996A (en) * | 2014-05-21 | 2014-09-10 | 丽珠医药集团股份有限公司 | Synthetic method of valsartan |
| CN104496921A (en) * | 2014-12-27 | 2015-04-08 | 浙江华海药业股份有限公司 | Valsartan crude product mother liquor recovery 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 |
| CN106349179A (en) * | 2016-08-26 | 2017-01-25 | 安徽省虹升生物股份有限公司 | Refining method of valsartan |
| CN111072581A (en) * | 2018-10-22 | 2020-04-28 | 珠海润都制药股份有限公司 | Valsartan free of genotoxic impurities and preparation method thereof |
| WO2021022516A1 (en) * | 2019-08-07 | 2021-02-11 | 浙江华海药业股份有限公司 | Valsartan refinement method |
| CN113264891A (en) * | 2021-05-26 | 2021-08-17 | 珠海润都制药股份有限公司 | Method for recovering L-valsartan from valsartan mother liquor containing D-valsartan |
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| CN103127131A (en) * | 2012-07-27 | 2013-06-05 | 华润赛科药业有限责任公司 | Solid composition with valsartan and preparation method thereof |
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| CN104496921A (en) * | 2014-12-27 | 2015-04-08 | 浙江华海药业股份有限公司 | Valsartan crude product mother liquor recovery method |
| CN104496921B (en) * | 2014-12-27 | 2020-02-18 | 浙江华海药业股份有限公司 | Method for recovering valsartan crude product mother liquor |
| CN105859646A (en) * | 2016-06-06 | 2016-08-17 | 浙江华海药业股份有限公司 | Refining method for valsartan |
| CN106349179A (en) * | 2016-08-26 | 2017-01-25 | 安徽省虹升生物股份有限公司 | Refining method of valsartan |
| CN111072581A (en) * | 2018-10-22 | 2020-04-28 | 珠海润都制药股份有限公司 | Valsartan free of genotoxic impurities and preparation method thereof |
| WO2021022516A1 (en) * | 2019-08-07 | 2021-02-11 | 浙江华海药业股份有限公司 | Valsartan refinement method |
| CN113993851A (en) * | 2019-08-07 | 2022-01-28 | 浙江华海药业股份有限公司 | Valsartan refining method |
| CN113993851B (en) * | 2019-08-07 | 2024-02-09 | 浙江华海药业股份有限公司 | Valsartan refining method |
| CN113264891A (en) * | 2021-05-26 | 2021-08-17 | 珠海润都制药股份有限公司 | Method for recovering L-valsartan from valsartan mother liquor containing D-valsartan |
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