CN103613558A - Preparation method of valsartan - Google Patents
Preparation method of valsartan Download PDFInfo
- Publication number
- CN103613558A CN103613558A CN201310557907.3A CN201310557907A CN103613558A CN 103613558 A CN103613558 A CN 103613558A CN 201310557907 A CN201310557907 A CN 201310557907A CN 103613558 A CN103613558 A CN 103613558A
- Authority
- CN
- China
- Prior art keywords
- valsartan
- reaction
- step reaction
- preparation
- product
- 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.)
- Granted
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of valsartan. The preparation method comprises the following steps: firstly, carrying out first-step reaction onto L-valine methyl-ester hydrochloride and 2-cyanogroup-4'-brooethyl biphenyl; then, carrying out second-step reaction with valeryl chloride; and finally, carrying out third-step reaction to obtain a valsartan crude product, wherein the third-step reaction comprises the following steps: enabling a product of the second-step reaction to react with sodium azide under catalysis of triethylamine hydrochloride, adding hypochlorite after the reaction; using acid to adjust pH to 2-5, standing and layering, washing an organic layer; and then, adding alkali to adjust pH to 10-13, preserving heat for reaction, standing and layering after the reaction is ended, cooling a water layer, using acid to adjust pH to 0.5-3, filtering and washing to obtain the valsartan crude product. According to the preparation method disclosed by the invention, a source of nitrous acid can be cut off by adopting the hypochlorite, and production of valsartan impurity K can be eliminated; and moreover, production of other impurities which are difficult to treat can be avoided by adjusting other conditions, and a high-purity valsartan product can be prepared.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, be specifically related to a kind of preparation method who controls the valsartan of diovan foreign matter K.
Background technology
Valsartan (chemistry is by name: N-(1-pentanoyl)-N-[4-[2-(1H-tetrazole-5-yl) phenyl] benzyl]-Valine) can be used for all kinds hypertension, and heart and brain kidney is had to better protecting effect.The hypertensive patients such as myocardial infarction, heart failure, proteinuria, diabetes can use as routine, can combine use with diuretic(s) (as hydrochlorothiazide).The structural formula of valsartan is as follows:
Document about valsartan is quite abundant, especially concentrates in synthetic route, such as the patent application about valsartan synthetic route, has US5399578, US7199144, WO2006067216, WO2008007391, WO2004026847, CN00115355 etc.
Aspect the Control of Impurities of valsartan, application number is that 200810223659.8(publication number is CN101367772A) Chinese patent application discloses a kind of control method of diovan foreign matter, related substance made to following restriction: VLSI-A is no more than 1.0%; VLSI-B and VLSI-D must not distinguish over 0.2% and 0.1%, and other single unknown impuritie must not surpass 0.1%, and total impurities (not comprising VLSI-A) is no more than 0.3%, meets the requirement of American Pharmacopeia; Application number is that 200910085197.2(publication number is CN101560190A) Chinese patent application is studied diovan foreign matter E, with the content of Isoleucine ester salify thing, be not more than the starting raw material that 0.23% L-valine ester salify thing is said synthesis route, synthesizing Xieshatan, the content of its impurity VLSI-E is no more than 0.1%.Application number is that 200910242972.0(publication number is CN 101735164A) Chinese patent application discloses diovan foreign matter F has been studied.
In the research of diovan compound preparation, for the quality of valsartan bulk drug, have higher requirement, particularly to unknown impuritie.Therefore, be necessary very much the unknown impuritie in valsartan bulk drug to study, find reason and the control method of generation.
By the research to valsartan process for purification, find RRT(relative retention time) impurity that is worth 0.6 left and right is difficult to effectively removal by recrystallization, by LC-MS, analyzes, and the molecular weight of this impurity is [M+1]
+=381.Tentatively be judged as the de-pentanoyl of valsartan nitrosifying impurity again, and by this impurity called after diovan foreign matter K, structural formula is as follows:
By orientation, synthesize after this impurity, through liquid phase location, confirm this impurity diovan foreign matter K really.
Summary of the invention
The invention provides a kind of preparation method of valsartan, by the research to diovan foreign matter in valsartan product, determine the character of diovan foreign matter K, by the change of cyclization post processing mode in synthetic to valsartan, control the content of impurity, prepare highly purified valsartan product.
A preparation method for valsartan, comprises the following steps:
Valine methyl ester hydrochloride and 2-cyano group-4 '-bromomethylbiphenyl are carried out to the first step and react, then carry out second step with n-amyl chloride and react, finally carry out three-step reaction and obtain valsartan crude product;
Described three-step reaction comprises: product and the reaction of sodium azide of second step reaction under triethylamine hydrochloride catalysis, after reaction, add hypochlorite, and with acid for adjusting pH to 2～5, stratification, organic layer is washed, then add alkali to regulate pH to 10～13, insulation reaction, reaction finishes rear stratification, water layer is lowered the temperature, with acid for adjusting pH to 0.5～3, to filter, washing obtains valsartan crude product.
The reaction synthetic route of described valsartan crude product is as follows:
Wherein, using dimethyl formamide (DMF) as reaction solvent in three-step reaction, hypochlorite is clorox, and acid is hydrochloric acid, and alkali is potassium hydroxide, take above-mentioned condition as example in reaction formula.
In the present invention, three-step reaction is improved, can effectively avoid diovan foreign matter K, because diovan foreign matter K is nitroso compound, toxicity is larger, therefore, control diovan foreign matter K for not detecting the preparation method's who is valsartan of the present invention object, simultaneously, because being valsartan, diovan foreign matter K takes off pentanoyl product and nitrite reaction generation again, the present invention adjusts cyclization post processing mode for this reason, when aftertreatment, do not use Sodium Nitrite to destroy excessive sodiumazide, use hypochlorite instead, can cut off the source of nitrous acid like this, can eliminate the generation of impurity K completely, and, other conditions have been carried out to corresponding adjustment, can also avoid the generation of other difficult impurity, according to said synthesis route, synthesize, obtain valsartan, diovan foreign matter K is not for detecting.
As preferably, described the first step reaction is usingd methylene dichloride as reaction solvent and take triethylamine as acid binding agent, and triethylamine can be dissolved in methylene dichloride preferably, thereby guarantees carrying out smoothly and can reducing side reaction to reduce the generation of impurity of reaction.
The reaction conditions of described the first step reaction is: first by Valine methyl ester hydrochloride and 2-cyano group-4 '-bromomethylbiphenyl hybrid reaction 1～4 hour, again 20 ℃～35 ℃ reactions 12～20 hours, then be warming up to 30 ℃～50 ℃ reactions 1～3 hour, temperature rising reflux reaction afterwards 0.5～2 hour.This reaction conditions is conducive to carrying out smoothly of reaction, and can reduce side reaction to reduce the generation of impurity.
As preferably, described second step reaction be take triethylamine as acid binding agent, and n-amyl chloride adds in the mode dripping, and reacts 2～5 hours at-5～10 ℃, after reaction, add methyl alcohol to destroy n-amyl chloride, through the product washing, dry, underpressure distillation obtains second step reaction.
As preferably, in described three-step reaction, the product of second step reaction reacts 24～60 hours at 90 ℃～115 ℃ with sodiumazide.Further preferably, 100 ℃～105 ℃ reactions 36～48 hours.
In described three-step reaction, it is reaction solvent that the product of second step reaction and reaction of sodium azide be take dimethyl formamide (DMF).
In described three-step reaction, after reaction, add hypochlorite, and with acid for adjusting pH to 3～4.
In described three-step reaction, add alkali to regulate pH to 10～13,15 ℃～35 ℃ insulation reaction 8～17 hours.Further preferably, add alkali to regulate pH to 11～12.
In described three-step reaction, reaction finishes rear stratification, and water layer is cooled to 0 ℃～15 ℃.
In described three-step reaction, described acid is hydrochloric acid.Further preferably, the mass percent of described hydrochloric acid is 5%～15%, and in conjunction with water layer is cooled to 0 ℃～15 ℃, is conducive to remove diovan foreign matter K.
In described three-step reaction, described hypochlorite is that clorox is or/and potassium hypochlorite.
In described three-step reaction, described alkali is that sodium hydroxide is or/and potassium hydroxide.
Above-mentioned three-step reaction is conducive to obtain target product, and can reduce as much as possible the generation of side reaction, thereby when obtaining valsartan, avoids as much as possible the generation of impurity.
As preferably, the preparation method of described valsartan, also comprise the refining of valsartan crude product, specifically comprise the steps: the valsartan crude product obtaining to be added in ethyl acetate, heating for dissolving, is cooled to 5～15 ℃ and preserves 1～3 hour, filters, filter cake washs by ethyl acetate, the dry valsartan primary crystallization product that obtains; Valsartan primary crystallization product is added in ethyl acetate, and heating for dissolving, stirs coolingly, filters, and filter cake washs by ethyl acetate, dry, obtains refining valsartan.Valsartan crude product obtains refining valsartan through refining, and its purity is higher, and its foreign matter content is extremely low.
Compared with prior art, the present invention has following beneficial effect:
The preparation method of valsartan of the present invention, focus on, improvement to three-step reaction is not used Sodium Nitrite to destroy excessive sodiumazide when aftertreatment, uses hypochlorite instead, can cut off the source of nitrous acid like this, can eliminate the generation of diovan foreign matter K completely, and, other conditions have been carried out to corresponding adjustment, can also avoid the generation of other difficult impurity, thereby be conducive to prepare highly purified valsartan product.
The preparation method of valsartan of the present invention, in preferred version, respectively the first step reaction, second step reaction and three-step reaction are further limited, by the control of reaction conditions, in synthesizing Xieshatan product, avoid the generation of other impurity as far as possible, effectively control foreign matter content, thereby prepare highly purified valsartan product, promote the quality of valsartan product, significant for the security that guarantees valsartan bulk drug.
Embodiment
Further illustrate by the following examples the present invention, but not as restriction of the present invention
Embodiment 1
One, the preparation of valsartan crude product:
N
2under protection, in reaction flask, drop into methylene dichloride 200ml, 20gL-valine methyl ester hydrochloride and 2-cyano group-4 '-bromomethylbiphenyl 34.5g, stir after 2 hours, at 10 ℃, drip triethylamine, then 25 ℃ of reactions 14 hours, then be warming up to 38 ℃ of reactions 2 hours, temperature rising reflux reaction afterwards 1 hour, reaction finishes, and obtains the reaction solution containing the product of the first step reaction;
The reaction solution of the product containing the first step reaction is directly cooled to 0 ℃, drip n-amyl chloride, within 1 hour, dropwise, be then incubated 0.5 hour.And be controlled at 0 ℃, and drip triethylamine, at this temperature, be incubated 2 hours, reaction finishes, and the second step reaction times is 3.5 hours, adds methyl alcohol 10ml, destroys n-amyl chloride, and 25 ℃ of stirrings of normal temperature 1 hour, use saturated Na
2cO
3solution washing 3 times (each 100ml), organic layer is dry with Sodium sulfate anhydrous.min(99), and underpressure distillation evaporate to dryness obtains the product of second step reaction;
At N
2protection under, with 90mlDMF, dissolve the product of 20g second step reaction, then drop into 16.8g triethylamine hydrochloride, and 16g sodiumazide (NaN
3), 100 ℃ of insulation reaction 36 hours, add 200ml toluene.Be cooled to 25 ℃, adding 50ml concentration is 1mol/l aqueous sodium hypochlorite solution, with mass percent, be 9% salt acid for adjusting pH to 3, stratification, upper strata is toluene layer, by toluene layer saturated common salt water washing, divide 3 times, each 100ml, then adds 20ml water, and add KOH to make its pH=11,25 ℃ of insulation reaction 10 hours.Reaction finishes, and layering, cools to 10 ℃ by water layer, with mass percent, is that 9% hydrochloric acid regulates pH=1, filters, and washing obtains valsartan crude product.
Two, valsartan is refining:
The valsartan crude product obtaining is added in 200ml ethyl acetate, is heated to dissolve completely; Be cooled to after 25 ℃ of room temperatures, continue to be cooled to 10 ℃ and preserve 2 hours, filter, filter cake with on a small quantity cold (5 ℃, ethyl acetate washing 20ml); Dry, obtain valsartan primary crystallization product; Valsartan primary crystallization product is added in 150ml ethyl acetate, is heated to dissolve, stir and be cooled to 25 ℃ of room temperatures, filter, a small amount of ethyl acetate for filter cake (20ml) washing, dries, and obtains valsartan secondary crystal product, i.e. refining valsartan.
By HPLC method, impurity in refining valsartan is detected, relative substance does not detect, and diovan foreign matter K does not detect, and chiral isomer does not detect.
Embodiment 2
One, the preparation of valsartan crude product:
N
2under protection, in reaction flask, drop into methylene dichloride 200ml, 20gL-valine methyl ester hydrochloride and 2-cyano group-4 '-bromomethylbiphenyl 34.5g, stir after 3 hours, at 15 ℃, drip triethylamine, then react more than 15 hours at 30 ℃, then be warming up to 39 ℃ of reactions 2 hours, temperature rising reflux reaction afterwards 1 hour, reaction finishes, and obtains the reaction solution containing the product of the first step reaction;
The reaction solution of the product containing the first step reaction is directly cooled to 5 ℃, drip n-amyl chloride, within 1 hour, dropwise, be then incubated 0.5 hour.And be controlled at 5 ℃, and drip triethylamine, at this temperature, be incubated 2 hours, reaction finishes, and adds methyl alcohol 10ml, destroys n-amyl chloride, and 25 ℃ of stirrings of normal temperature 1 hour, use saturated Na
2cO
3solution washing 3 times (each 100ml), organic layer is dry with Sodium sulfate anhydrous.min(99), and underpressure distillation evaporate to dryness obtains the product of second step reaction.
At N
2protection under, with 90mlDMF, dissolve the product of 20g second step reaction, then drop into 16.8g triethylamine hydrochloride, and 16g sodiumazide (NaN
3), 105 ℃ of insulation reaction 48 hours, add 200ml toluene.Be cooled to 20 ℃, adding 50ml concentration is 1mol/l aqueous sodium hypochlorite solution, with mass percent, be 15% salt acid for adjusting pH to 4, stratification, upper strata is toluene layer, by toluene layer saturated common salt water washing, divide 3 times, each 100ml, then adds 20ml water, and add KOH to make its pH=12,30 ℃ of insulation reaction 15 hours.Reaction finishes, and layering, cools to 15 ℃ by water layer, with mass percent, is that 15% hydrochloric acid regulates pH=2, filters, and washing obtains valsartan crude product.
Two, valsartan is refining:
The valsartan crude product obtaining is added in 200ml ethyl acetate, is heated to dissolve completely; Be cooled to after 25 ℃ of room temperatures, continue to be cooled to 10 ℃ and preserve 2 hours, filter, filter cake with on a small quantity cold (5 ℃, ethyl acetate washing 20ml); Dry, obtain valsartan primary crystallization product; Valsartan primary crystallization product is added in 150ml ethyl acetate, is heated to dissolve, stir and be cooled to 25 ℃ of room temperatures, filter, a small amount of ethyl acetate for filter cake (20ml) washing, dries, and obtains valsartan secondary crystal product, i.e. refining valsartan.
By HPLC method, impurity in refining valsartan is detected, relative substance does not detect, and diovan foreign matter K does not detect, and chiral isomer does not detect.
Comparative example 1
By 50ml concentration in embodiment 1, be that 1mol/l aqueous sodium hypochlorite solution is that 1mol/l sodium nitrite in aqueous solution replaces by 50ml concentration, other are with embodiment 1.
Comparative example 2
By 50ml concentration in embodiment 1, be that 1mol/l aqueous sodium hypochlorite solution is that 1mol/l sodium nitrite in aqueous solution replaces by 50ml concentration, by mass percent in embodiment 1, be that 9% hydrochloric acid mass percent is that 20% hydrochloric acid substitutes, and water layer is cooled to 20 ℃.
The preparation of diovan foreign matter K
Get valsartan 500g and join in reaction flask, the hydrochloric acid 225mL that dropping mass percent is 24%, drips Bi Huiliu 4h, cooling, suction filtration.Filter cake is joined in reaction flask, add the sodium nitrite in aqueous solution of 1000ml, with hydrochloric acid adjust pH to 2.5, stir 16 hours, suction filtration, filter cake is washed with water to neutrality, is dried to obtain diovan foreign matter K.
In valsartan cyclization last handling process, add and do not add Sodium Nitrite, the concentration, post-processing temperature of acid on diovan foreign matter K to affect test-results data as shown in table 1 below.
Table 1
By data in table 1, can find out, by cyclization post processing mode is adjusted, when aftertreatment, do not use Sodium Nitrite to destroy excessive sodiumazide, use hypochlorite instead, can cut off the source of nitrous acid like this, can eliminate the generation of impurity K completely, and, other conditions have been carried out to corresponding adjustment, can also avoid the generation of other difficult impurity, according to said synthesis route, synthesize, obtain valsartan, diovan foreign matter K is not for detecting.Meanwhile, the mass percent of hydrochloric acid is controlled at 5%～15% and in conjunction with water layer is cooled to 0 ℃～15 ℃, is conducive to remove diovan foreign matter K.Make the refining valsartan purity of the present invention high, foreign matter content is extremely low, by HPLC method, cannot detect, and can eliminate the generation of impurity K completely.
The detection method of relative substance of the present invention and chiral isomer is prior art, i.e. HPLC method is specific as follows:
1. the chromatographic condition that relative substance detects
Moving phase: water-acetonitrile-glacial acetic acid (500:500:1, volume ratio)
Chromatographic column: (L1) Nucleosil100-5,20cm * 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 chiral isomer detects
Moving phase: normal hexane-Virahol-trifluoroacetic acid (85:15:0.1, volume ratio)
Chromatographic column: L40, Kromasil5-cellucoat, 250 * 4.6mm
Detect wavelength: 230nm
Flow velocity: 0.8ml/min
Column temperature: 25 ℃
Sample size: 10 μ l.
Claims (10)
1. a preparation method for valsartan, comprises the following steps:
Valine methyl ester hydrochloride and 2-cyano group-4 '-bromomethylbiphenyl are carried out to the first step and react, then carry out second step with n-amyl chloride and react, finally carry out three-step reaction and obtain valsartan crude product;
It is characterized in that, described three-step reaction comprises: product and the reaction of sodium azide of second step reaction under triethylamine hydrochloride catalysis, add hypochlorite after reaction, and with acid for adjusting pH to 2～5, stratification, by organic layer washing, then adds alkali to regulate pH to 10～13, insulation reaction, reaction finishes rear stratification, by water layer cooling, with acid for adjusting pH to 0.5～3, filter, washing obtains valsartan crude product.
2. the preparation method of valsartan according to claim 1, is characterized in that, described the first step reaction is usingd methylene dichloride as reaction solvent and take triethylamine as acid binding agent;
The reaction conditions of described the first step reaction is: first by Valine methyl ester hydrochloride and 2-cyano group-4 '-bromomethylbiphenyl hybrid reaction 1～4 hour, again 20 ℃～35 ℃ reactions 12～20 hours, then be warming up to 30 ℃～50 ℃ reactions 1～3 hour, temperature rising reflux reaction afterwards 0.5～2 hour.
3. the preparation method of valsartan according to claim 1, it is characterized in that, described second step reaction be take triethylamine as acid binding agent, n-amyl chloride adds in the mode dripping, at-5～10 ℃, react 2～5 hours, after reaction, add methyl alcohol to destroy n-amyl chloride, through the product washing, dry, underpressure distillation obtains second step reaction.
4. the preparation method of valsartan according to claim 1, is characterized in that, in described three-step reaction, the product of second step reaction reacts 24～60 hours at 90 ℃～115 ℃ with sodiumazide.
5. the preparation method of valsartan according to claim 1, is characterized in that, in described three-step reaction, adds alkali to regulate pH to 10～13,15 ℃～35 ℃ insulation reaction 8～17 hours.
6. the preparation method of valsartan according to claim 1, is characterized in that, in described three-step reaction, reaction finishes rear stratification, and water layer is cooled to 0 ℃～20 ℃.
7. the preparation method of valsartan according to claim 1, is characterized in that, in described three-step reaction, described acid is hydrochloric acid, and the mass percent of described hydrochloric acid is 5%～15%.
8. the preparation method of valsartan according to claim 1, is characterized in that, in described three-step reaction, described hypochlorite is that clorox is or/and potassium hypochlorite.
9. the preparation method of valsartan according to claim 1, is characterized in that, in described three-step reaction, described alkali is that sodium hydroxide is or/and potassium hydroxide.
10. the preparation method of valsartan according to claim 1, it is characterized in that, the preparation method of described valsartan, also comprise the refining of valsartan crude product, specifically comprise the steps: the valsartan crude product obtaining to be added in ethyl acetate heating for dissolving, being cooled to 5～15 ℃ preserves 1～3 hour, filter, filter cake washs by ethyl acetate, the dry valsartan primary crystallization product that obtains; Valsartan primary crystallization product is added in ethyl acetate, and heating for dissolving, stirs coolingly, filters, and filter cake washs by ethyl acetate, dry, obtains refining valsartan.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310557907.3A CN103613558B (en) | 2013-11-08 | 2013-11-08 | A kind of preparation method of valsartan |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310557907.3A CN103613558B (en) | 2013-11-08 | 2013-11-08 | A kind of preparation method of valsartan |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103613558A true CN103613558A (en) | 2014-03-05 |
| CN103613558B CN103613558B (en) | 2015-10-21 |
Family
ID=50164288
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310557907.3A Active CN103613558B (en) | 2013-11-08 | 2013-11-08 | A kind of preparation method of valsartan |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103613558B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103923028A (en) * | 2014-05-04 | 2014-07-16 | 青岛雪洁助剂有限公司 | Preparation method of valsartan |
| CN108610269A (en) * | 2018-06-07 | 2018-10-02 | 河南华商药业有限公司 | A kind of synthetic method of Valsartan hydrocarbonylation object impurity |
| CN109574943A (en) * | 2018-12-24 | 2019-04-05 | 浙江工业大学上虞研究院有限公司 | The preparation method of Valsartan nitrous clout |
| CN109761924A (en) * | 2019-02-26 | 2019-05-17 | 安徽美诺华药物化学有限公司 | A kind of post-processing approach of improved Valsartan reaction mixture |
| CN110028426A (en) * | 2019-05-20 | 2019-07-19 | 浙江华海致诚药业有限公司 | A kind of diovan foreign matter and preparation method thereof |
| WO2020010643A1 (en) | 2018-07-13 | 2020-01-16 | 浙江华海药业股份有限公司 | Method for synthesizing 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 |
| CN112778159A (en) * | 2021-02-19 | 2021-05-11 | 安徽云帆药业有限公司 | Synthesis method of valsartan intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101270096A (en) * | 2007-03-22 | 2008-09-24 | 浙江华海药业股份有限公司 | Method for synthesizing diovan |
| CN101362728A (en) * | 2008-08-22 | 2009-02-11 | 北京赛科药业有限责任公司 | Valsartan synthesis method |
-
2013
- 2013-11-08 CN CN201310557907.3A patent/CN103613558B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101270096A (en) * | 2007-03-22 | 2008-09-24 | 浙江华海药业股份有限公司 | Method for synthesizing diovan |
| CN101362728A (en) * | 2008-08-22 | 2009-02-11 | 北京赛科药业有限责任公司 | Valsartan synthesis method |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103923028A (en) * | 2014-05-04 | 2014-07-16 | 青岛雪洁助剂有限公司 | Preparation method of valsartan |
| CN103923028B (en) * | 2014-05-04 | 2017-05-24 | 青岛雪洁助剂有限公司 | Preparation method of valsartan methyl ester |
| CN108610269A (en) * | 2018-06-07 | 2018-10-02 | 河南华商药业有限公司 | A kind of synthetic method of Valsartan hydrocarbonylation object impurity |
| WO2020010643A1 (en) | 2018-07-13 | 2020-01-16 | 浙江华海药业股份有限公司 | Method for synthesizing valsartan |
| EP3822259A4 (en) * | 2018-07-13 | 2021-08-25 | Zhejiang Huahai Pharmaceutical Co., Ltd. | Method for synthesizing valsartan |
| US11434210B2 (en) | 2018-07-13 | 2022-09-06 | Zhejiang Huahai Pharmaceutical Co., Ltd | Method for synthesizing 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 |
| CN109574943A (en) * | 2018-12-24 | 2019-04-05 | 浙江工业大学上虞研究院有限公司 | The preparation method of Valsartan nitrous clout |
| CN109761924A (en) * | 2019-02-26 | 2019-05-17 | 安徽美诺华药物化学有限公司 | A kind of post-processing approach of improved Valsartan reaction mixture |
| CN110028426A (en) * | 2019-05-20 | 2019-07-19 | 浙江华海致诚药业有限公司 | A kind of diovan foreign matter and preparation method thereof |
| CN112778159A (en) * | 2021-02-19 | 2021-05-11 | 安徽云帆药业有限公司 | Synthesis method of valsartan intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103613558B (en) | 2015-10-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103613558B (en) | A kind of preparation method of valsartan | |
| CN104860894B (en) | Method for preparing cardiotonic drug LCZ696 | |
| CN102985416B (en) | Process of preparing a thrombin specific inhibitor | |
| CN102391200B (en) | Preparation method of high purity valsartan | |
| CN102766139B (en) | Azilsartan polymorphic substance and preparation method thereof | |
| CN103113364B (en) | The polymorphous preparation method of Azilsartan | |
| CN104402838B (en) | The process for purification of valsartan | |
| CN103554049B (en) | A kind of method preparing valsartan | |
| CN102351847B (en) | Industrial method for refining esomeprazole sodium salt | |
| CN103554031B (en) | Preparation method of azilsartan intermediate | |
| KR101275092B1 (en) | Manufacturing Method Of Azilsartan | |
| CN103396406B (en) | Preparation method of candesartan cilexetil | |
| CN105481856A (en) | Preparation method of palipefidone | |
| CN103554099B (en) | Preparation method of Dasatinib | |
| CN103880829B (en) | A kind of Azilsartan crystal and its production and use | |
| WO2014020381A1 (en) | Novel crystalline form of azilsartan medoxomil potassium | |
| CN104710437B (en) | Improved method for preparing d-biotin from bisbenzyl biotin by debenzylation | |
| CN106749217A (en) | A kind of Azilsartan I crystal | |
| JP5383123B2 (en) | Method for producing pioglitazone hydrochloride | |
| CN106397400A (en) | Preparation method for dabigatran etexilate | |
| CN104230887B (en) | Dabigatran etcxilate new intermediate and preparation method thereof | |
| CN109280050B (en) | Preparation method of medical compound avanafil | |
| CN104496921B (en) | Method for recovering valsartan crude product mother liquor | |
| CN110396084B (en) | Method for preparing high-purity trityl olmesartan medoxomil | |
| CN104119326B (en) | Method for preparing azilsartan |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | 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 |