CN103613558B - A kind of preparation method of valsartan - Google Patents
A kind of preparation method of valsartan Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of valsartan, comprising: by Valine methyl ester hydrochloride and 2-cyano group-4 '-bromomethylbiphenyl carries out the first step reaction, then carries out second step reaction with n-amyl chloride, finally carry out three-step reaction and obtain valsartan crude product; Described three-step reaction comprises: the product of second step reaction under triethylamine hydrochloride catalysis and reaction of sodium azide, hypochlorite is added after reaction, and with acid for adjusting pH to 2 ~ 5, stratification, organic layer is washed, then add alkali and regulate pH to 10 ~ 13, insulation reaction, reaction terminates rear stratification, water layer is lowered the temperature, with acid for adjusting pH to 0.5 ~ 3, filter, washing obtains valsartan crude product.The inventive method, adopts hypochlorite, can cut off the source of nitrous acid, eliminates the generation of diovan foreign matter K, and, the adjustment of other conditions is also avoided to the generation of other difficult impurity, highly purified 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 controlling the valsartan of diovan foreign matter K.
Background technology
Valsartan (chemistry is by name: N-(1-pentanoyl)-N-[4-[2-(1H-tetrazole-5-base) phenyl] benzyl]-Valine) can be used for all kinds hypertension, and has better protecting effect to heart and brain kidney.The hypertensive patients such as myocardial infarction, heart failure, proteinuria, diabetes can use as routine, can with diuretic(s) (as hydrochlorothiazide) conbined usage.The structural formula of valsartan is as follows:
Document about valsartan is quite abundant, especially concentrates in synthetic route, and such as, patent application about valsartan synthetic route has US5399578, US7199144, WO2006067216, WO2008007391, WO2004026847, CN00115355 etc.
In the Control of Impurities of valsartan, application number is 200810223659.8(publication number is CN101367772A) Chinese patent application discloses a kind of control method of diovan foreign matter, made following restriction: VLSI-A is no more than 1.0% to related substance; VLSI-B and VLSI-D respectively must not more than 0.2% with 0.1%, and other single unknown impuritie must not more than 0.1%, and total impurities (not comprising VLSI-A) is no more than 0.3%, meets the requirement of American Pharmacopeia; Application number is 200910085197.2(publication number is CN101560190A) Chinese patent application is studied diovan foreign matter E, the L-valine ester salify thing being not more than 0.23% with the content of Isoleucine ester salify thing is the starting raw material of said synthesis route, synthesizing Xieshatan, the content of its impurity VLSI-E is no more than 0.1%.Application number is 200910242972.0(publication number is CN 101735164A) Chinese patent application discloses and is studied diovan foreign matter F.
In the research of diovan compound preparation, the quality for valsartan bulk drug is had higher requirement, particularly to unknown impuritie.Therefore, be necessary very much to study the unknown impuritie in valsartan bulk drug, find Producing reason and control method.
By the research to valsartan process for purification, finding RRT(relative retention time) impurity of value about 0.6 is difficult to effectively remove by recrystallization, and analyzed by LC-MS, the molecular weight of this impurity is [M+1]
+=381.Tentatively be judged as that valsartan takes off pentanoyl nitrosifying impurity again, and by this impurity called after diovan foreign matter K, structural formula is as follows:
After this impurity of controlled syntheses, 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 to cyclization post processing mode in valsartan synthesis, control the content of impurity, prepare highly purified valsartan product.
A preparation method for valsartan, comprises the following steps:
By Valine methyl ester hydrochloride and 2-cyano group-4 '-bromomethylbiphenyl carries out the first step reaction, then carries out second step reaction with n-amyl chloride, finally carry out three-step reaction and obtain valsartan crude product;
Described three-step reaction comprises: the product of second step reaction under triethylamine hydrochloride catalysis and reaction of sodium azide, hypochlorite is added after reaction, and with acid for adjusting pH to 2 ~ 5, stratification, organic layer is washed, then add alkali and regulate pH to 10 ~ 13, insulation reaction, reaction terminates rear stratification, water layer is lowered the temperature, with acid for adjusting pH to 0.5 ~ 3, filter, washing obtains valsartan crude product.
The Reactive Synthesis 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, for above-mentioned condition 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, controlling diovan foreign matter K is the object not detecting the preparation method being valsartan of the present invention, simultaneously, again because diovan foreign matter K is that valsartan takes off pentanoyl product and nitrite reaction produces, the present invention adjusts cyclization post processing mode for this reason, namely do not use Sodium Nitrite to destroy excessive sodiumazide when aftertreatment, use hypochlorite instead, the source of nitrous acid can be cut off like this, the generation of impurity K can be eliminated completely, and, corresponding adjustment has been carried out to other conditions, the generation of other difficult impurity can also be avoided, synthesize according to said synthesis route, obtain valsartan, diovan foreign matter K is not for detect.
As preferably, described the first step reaction using methylene dichloride as reaction solvent and with triethylamine for acid binding agent, triethylamine can be dissolved in methylene dichloride preferably, thus ensures 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 DEG C ~ 35 DEG C reactions 12 ~ 20 hours, then 30 DEG C ~ 50 DEG C reactions 1 ~ 3 hour is warming up to, 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 is acid binding agent with triethylamine, and n-amyl chloride adds in the mode dripped, and reacts 2 ~ 5 hours at-5 ~ 10 DEG C, add methyl alcohol after reaction and destroy n-amyl chloride, obtain through washing, drying, underpressure distillation the product that second step reacts.
As preferably, in described three-step reaction, product and the sodiumazide of second step reaction react 24 ~ 60 hours at 90 DEG C ~ 115 DEG C.Further preferably, 100 DEG C ~ 105 DEG C reactions 36 ~ 48 hours.
In described three-step reaction, second step reaction product and reaction of sodium azide with dimethyl formamide (DMF) for reaction solvent.
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 and regulate pH to 10 ~ 13,15 DEG C ~ 35 DEG C insulation reaction 8 ~ 17 hours.Further preferably, add alkali and regulate pH to 11 ~ 12.
In described three-step reaction, reaction terminates rear stratification, water layer is cooled to 0 DEG C ~ 15 DEG C.
In described three-step reaction, described acid is hydrochloric acid.Further preferably, the mass percent of described hydrochloric acid is 5% ~ 15%, and water layer is cooled to 0 DEG C ~ 15 DEG C by combination, is conducive to removing 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 obtaining target product, and can reduce the generation of side reaction as much as possible, thus while obtaining valsartan, avoids the generation of impurity as much as possible.
As preferably, the preparation method of described valsartan, also comprise the refining of valsartan crude product, the valsartan crude product obtained specifically is comprised the steps: to be added in ethyl acetate, heating for dissolving, is cooled to 5 ~ 15 DEG C and preserves 1 ~ 3 hour, filter, filter cake ethyl acetate is washed, and drying obtains valsartan primary crystallization product; Be added in ethyl acetate by valsartan primary crystallization product, heating for dissolving, stir cooling, filter, filter cake ethyl acetate is washed, dry, obtains the valsartan refined.Valsartan crude product is through the refining valsartan obtaining 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, to the improvement of three-step reaction, do not use when aftertreatment Sodium Nitrite to destroy excessive sodiumazide, use hypochlorite instead, the source of nitrous acid can be cut off like this, the generation of diovan foreign matter K can be eliminated completely, and, corresponding adjustment has been carried out to other conditions, the generation of other difficult impurity can also be avoided, thus be conducive to preparing 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 limited further, by the control of reaction conditions, while synthesizing Xieshatan product, avoid the generation of other impurity as far as possible, effective control foreign matter content, thus prepare highly purified valsartan product, promote the quality of valsartan product, for ensureing that the security of valsartan bulk drug is significant.
Embodiment
Further illustrate the present invention by the following examples, but not as restriction of the present invention
Embodiment 1
One, the preparation of valsartan crude product:
N
2under protection, methylene dichloride 200ml is dropped in reaction flask, 20gL-valine methyl ester hydrochloride and 2-cyano group-4 '-bromomethylbiphenyl 34.5g, stir after 2 hours, drip triethylamine at 10 DEG C, then 25 DEG C of reactions 14 hours, then 38 DEG C of reactions 2 hours are warming up to, temperature rising reflux reacts 1 hour afterwards, and reaction terminates, and obtains the reaction solution of the product containing the first step reaction;
The reaction solution of the product containing the first step reaction is directly cooled to 0 DEG C, drips n-amyl chloride, within 1 hour, dropwise, be then incubated 0.5 hour.And control at 0 DEG C, drip triethylamine, be incubated 2 hours at this temperature, reaction terminates, and namely the second step reaction times is 3.5 hours, adds methyl alcohol 10ml, destroys n-amyl chloride, and normal temperature 25 DEG C stirs 1 hour, uses 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, dissolve the product of 20g second step reaction with 90mlDMF, then drop into 16.8g triethylamine hydrochloride, and 16g sodiumazide (NaN
3), 100 DEG C of insulation reaction 36 hours, add 200ml toluene.Be cooled to 25 DEG C, adding 50ml concentration is 1mol/l aqueous sodium hypochlorite solution, be 9% salt acid for adjusting pH to 3 with mass percent, stratification, upper strata is toluene layer, toluene layer is used saturated common salt water washing, divide 3 times, each 100ml, then adds 20ml water, and add KOH and make its pH=11,25 DEG C of insulation reaction 10 hours.Reaction terminates, and layering, cools to 10 DEG C by water layer, and be that 9% hydrochloric acid regulates pH=1 with mass percent, filter, washing obtains valsartan crude product.
Two, valsartan is refining:
The valsartan crude product obtained is added in 200ml ethyl acetate, is heated to dissolve completely; After being cooled to room temperature 25 DEG C, continuing to be cooled to 10 DEG C and preserve 2 hours, filter, the filter cake ethyl acetate washing of cold (5 DEG C, 20ml) on a small quantity; Dry, obtain valsartan primary crystallization product; Be added in 150ml ethyl acetate by valsartan primary crystallization product, be heated to dissolve, stir and be cooled to room temperature 25 DEG C, filter, filter cake a small amount of ethyl acetate (20ml) washing, dries, obtains valsartan secondary crystal product, namely refining valsartan.
Detected impurity in refining valsartan by HPLC method, 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, methylene dichloride 200ml is dropped in reaction flask, 20gL-valine methyl ester hydrochloride and 2-cyano group-4 '-bromomethylbiphenyl 34.5g, stir after 3 hours, drip triethylamine at 15 DEG C, then 30 DEG C of reactions more than 15 hours, then 39 DEG C of reactions 2 hours are warming up to, temperature rising reflux reacts 1 hour afterwards, and reaction terminates, and obtains the reaction solution of the product containing the first step reaction;
The reaction solution of the product containing the first step reaction is directly cooled to 5 DEG C, drips n-amyl chloride, within 1 hour, dropwise, be then incubated 0.5 hour.And control at 5 DEG C, drip triethylamine, be incubated 2 hours at this temperature, reaction terminates, and adds methyl alcohol 10ml, destroys n-amyl chloride, and normal temperature 25 DEG C stirs 1 hour, uses 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, dissolve the product of 20g second step reaction with 90mlDMF, then drop into 16.8g triethylamine hydrochloride, and 16g sodiumazide (NaN
3), 105 DEG C of insulation reaction 48 hours, add 200ml toluene.Be cooled to 20 DEG C, adding 50ml concentration is 1mol/l aqueous sodium hypochlorite solution, be 15% salt acid for adjusting pH to 4 with mass percent, stratification, upper strata is toluene layer, toluene layer is used saturated common salt water washing, divide 3 times, each 100ml, then adds 20ml water, and add KOH and make its pH=12,30 DEG C of insulation reaction 15 hours.Reaction terminates, and layering, cools to 15 DEG C by water layer, and be that 15% hydrochloric acid regulates pH=2 with mass percent, filter, washing obtains valsartan crude product.
Two, valsartan is refining:
The valsartan crude product obtained is added in 200ml ethyl acetate, is heated to dissolve completely; After being cooled to room temperature 25 DEG C, continuing to be cooled to 10 DEG C and preserve 2 hours, filter, the filter cake ethyl acetate washing of cold (5 DEG C, 20ml) on a small quantity; Dry, obtain valsartan primary crystallization product; Be added in 150ml ethyl acetate by valsartan primary crystallization product, be heated to dissolve, stir and be cooled to room temperature 25 DEG C, filter, filter cake a small amount of ethyl acetate (20ml) washing, dries, obtains valsartan secondary crystal product, namely refining valsartan.
Detected impurity in refining valsartan by HPLC method, relative substance does not detect, and diovan foreign matter K does not detect, and chiral isomer does not detect.
Comparative example 1
To be 1mol/l aqueous sodium hypochlorite solution 50ml concentration by 50ml concentration in embodiment 1 be, and 1mol/l sodium nitrite in aqueous solution replaces, and other are with embodiment 1.
Comparative example 2
To be 1mol/l aqueous sodium hypochlorite solution 50ml concentration by 50ml concentration in embodiment 1 be, and 1mol/l sodium nitrite in aqueous solution replaces, and be 9% hydrochloric acid mass percent is that 20% hydrochloric acid substitutes by mass percent in embodiment 1, and water layer is cooled to 20 DEG C.
The preparation of diovan foreign matter K
Getting valsartan 500g joins in reaction flask, drips the hydrochloric acid 225mL that mass percent is 24%, drips Bi Huiliu 4h, cooling, suction filtration.Joined by filter cake 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, dry diovan foreign matter K.
In valsartan cyclization last handling process, add and do not add Sodium Nitrite, the concentration of acid, post-processing temperature on diovan foreign matter K to affect test-results data as shown in table 1 below.
Table 1
Can be found out by data in table 1, by adjusting cyclization post processing mode, not using when aftertreatment Sodium Nitrite to destroy excessive sodiumazide, using hypochlorite instead, the source of nitrous acid can be cut off like this, the generation of impurity K can be eliminated completely, and, corresponding adjustment has been carried out to other conditions, the generation of other difficult impurity can also be avoided, synthesize according to said synthesis route, obtain valsartan, diovan foreign matter K is not for detect.Meanwhile, the mass percent of hydrochloric acid controls, at 5% ~ 15% and combination, water layer is cooled to 0 DEG C ~ 15 DEG C, is conducive to removing diovan foreign matter K.The valsartan purity that the present invention is refined is high, and foreign matter content is extremely low, cannot be detected by HPLC method, 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 of relative substance detection
Moving phase: water-acetonitrile-glacial acetic acid (500:500:1, volume ratio)
Chromatographic column: (L1) Nucleosil100-5,20cm × 3.0mm, 5 μm;
Determined wavelength: 225nm
Flow velocity: 0.6ml/min
Column temperature: 25 DEG C
Sample size: 10 μ l.
2. the chromatographic condition of chiral isomer detection
Moving phase: normal hexane-Virahol-trifluoroacetic acid (85:15:0.1, volume ratio)
Chromatographic column: L40, Kromasil5-cellucoat, 250 × 4.6mm
Determined wavelength: 230nm
Flow velocity: 0.8ml/min
Column temperature: 25 DEG C
Sample size: 10 μ l.
Claims (6)
1. a preparation method for valsartan, comprises the following steps:
By Valine methyl ester hydrochloride and 2-cyano group-4 '-bromomethylbiphenyl carries out the first step reaction, then carries out second step reaction with n-amyl chloride, finally carry out three-step reaction and obtain valsartan crude product;
It is characterized in that, the reaction of the described the first step using methylene dichloride as reaction solvent and with triethylamine for acid binding agent;
It is acid binding agent that described second step reacts with triethylamine, and n-amyl chloride adds in the mode of dropping, reacts 2 ~ 5 hours at-5 ~ 10 DEG C, adds methyl alcohol and destroy n-amyl chloride after reaction, obtains through washing, drying, underpressure distillation the product that second step reacts;
Described three-step reaction comprises: the product of second step reaction under triethylamine hydrochloride catalysis and reaction of sodium azide, product and the sodiumazide of second step reaction react 24 ~ 60 hours at 90 DEG C ~ 115 DEG C, hypochlorite is added after reaction, and with acid for adjusting pH to 2 ~ 5, stratification, organic layer is washed, then add alkali and regulate pH to 10 ~ 13,15 DEG C ~ 35 DEG C insulation reaction 8 ~ 17 hours, reaction terminates rear stratification, water layer is cooled to 0 DEG C ~ 20 DEG C, 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, it is characterized in that, 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 DEG C ~ 35 DEG C reactions 12 ~ 20 hours, then 30 DEG C ~ 50 DEG C reactions 1 ~ 3 hour is warming up to, temperature rising reflux reaction afterwards 0.5 ~ 2 hour.
3. 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%.
4. 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.
5. 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.
6. 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 obtained to be added in ethyl acetate, heating for dissolving, be cooled to 5 ~ 15 DEG C to preserve 1 ~ 3 hour, filter, filter cake ethyl acetate is washed, and drying obtains valsartan primary crystallization product; Be added in ethyl acetate by valsartan primary crystallization product, heating for dissolving, stir cooling, filter, filter cake ethyl acetate is washed, dry, obtains the valsartan refined.
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Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| EP3822259A4 (en) * | 2018-07-13 | 2021-08-25 | 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 |
| CN109761924B (en) * | 2019-02-26 | 2020-09-01 | 安徽美诺华药物化学有限公司 | Improved post-treatment method of valsartan reaction mixed liquid |
| 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 |
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| 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 |
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| 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 |
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