CN103880756B - The preparation method of a kind of Azilsartan intermediate - Google Patents
The preparation method of a kind of Azilsartan intermediate Download PDFInfo
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- CN103880756B CN103880756B CN201410116645.1A CN201410116645A CN103880756B CN 103880756 B CN103880756 B CN 103880756B CN 201410116645 A CN201410116645 A CN 201410116645A CN 103880756 B CN103880756 B CN 103880756B
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- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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Abstract
The present invention discloses the preparation method of a kind of Azilsartan intermediate. The preparation method of described Azilsartan intermediate, comprise the following steps: hydroxylamine hydrochloride in the ethanol that mass percent is 90%-95% through alkaline hydrolysis from after, filter, filtrate adds formula II compound, triethylamine and ethanol, back flow reaction is to after completing, cooling crystallization, filters, the title intermediate of obtained formula I. The title intermediate content height that preparation method of the present invention obtains, amide impurities content is low, usually less than 10%.
Description
Technical field
The invention belongs to the preparation of medical compounds, specifically, it relates to the preparation method of a kind of Angiotensin �� receptor antagonist Azilsartan intermediate.
Background technology
Azilsartan (Azilsartan) is by the Angiotensin �� receptor antagonist of Takede Chemical Industries Ltd of Japan research and development, can oral potent depressor. Its preparation and therepic use are described in the specification sheets of Chinese invention patent CN92105152.2. Wherein, lower formula I compound, that is, 2-oxyethyl group-1-{ [((2'-hydroxyl ammonia auxotox radical) xenyl)-4-base] methyl }-1H-benzoglyoxaline-7-carboxylic acid be synthesis Azilsartan important intermediate.
(I)
The method preparing formula I compound is at document J.Med.chem.1996.Vo39(26) the detailed description of 5528-5235 and Chinese patent CN92105152.2: get formula II compound, i.e. 1-[((2 '-cyanobiphenyls base)-4-base) methyl]-2-oxyethyl group-1H-benzoglyoxaline-7-carboxylate methyl ester, under oxammonium hydrochloride and triethylamine effect, it is prepared by solvent taking methyl-sulphoxide. This reaction all can produce the following formula III of amides impurity, and this foreign matter content is too high very big on subsequent reactions impact, extremely difficult removal. Therefore the content how reducing this impurity is the key of this class synthetic method.
(II),
(III).
In Chinese patent CN92105152, formula II compound is under oxammonium hydrochloride and 28% sodium methylate effect, prepares by solvent of dimethyl sulfoxide (DMSO) (DMSO). The method long reaction time, and a large amount of amide by-product (formula III compound) can be produced, cause receipts rate low, and need aftertreatment.
In Chinese patent CN201010245420.8, formula II compound is under aqueous hydroxylamine and triethylamine effect, is that solvent refluxing reacts preparation in 24 hours taking ethanol. The method needs 50% aqueous hydroxylamine, this 50% aqueous hydroxylamine place for some time after concentration can reduce and price more expensive, the reaction times is longer, and the growing amount of acid amides is higher and unstable.
With formula II compound and oxammonium hydrochloride and sodium hydroxide, tetrabutyl ammonium fluoride in Chinese patent CN201210254405.9, take water as solvent refluxing reaction preparation. Using catalyzer tetrabutyl ammonium fluoride price expensive, one pot synthesis causes product very assorted, is unfavorable for that next step reacts.
Summary of the invention
It is low and do not need the preparation method of the Azilsartan intermediate of aftertreatment that technical problem to be solved by this invention is to provide a kind of amide impurities content.
The present invention's technical scheme adopted that solves the problem is: the preparation method providing a kind of Azilsartan intermediate, comprises the following steps:
Hydroxylammonium salt in the ethanol that mass percent is 90%-95% through alkaline hydrolysis from after, filter, filtrate add lower formula II compound, acid binding agent and ethanol, back flow reaction to after completing, cooling crystallization, filters, the title intermediate of obtained formula I;
(I),
(II).
The preparation method of Azilsartan intermediate of the present invention, it is also possible to specifically comprise the following steps:
Hydroxylammonium salt is in the ethanol that mass percent is 90%-95%, add siccative, solid alkali, when stopping heat release to reaction system only, filter, filtrate adds lower formula II compound, acid binding agent and ethanol, back flow reaction to after completing, cooling crystallization, filter, the title intermediate of obtained formula I;
(I),
(II).
Wherein, in preparation method of the present invention, the ethanol added in back flow reaction is fresh ethanol, and the concentration of this ethanol there is no and specifies.
In preparation method of the present invention, hydroxylammonium salt through alkaline hydrolysis from after obtain azanol, azanol again with the title intermediate of the formula II compound obtained formula I of the back flow reaction when acid binding agent and ethanol, the equation of this back flow reaction is as follows:
��
Wherein, described hydroxylammonium salt is selected from oxammonium sulfate or oxammonium hydrochloride, it is preferable that oxammonium hydrochloride.
Wherein, the preferred anhydrous sodium sulphate of described siccative.
Wherein, described solid alkali is at least one in following material: sodium hydroxide, potassium hydroxide, salt of wormwood, sodium carbonate, further preferred sodium hydroxide.
Wherein, described acid binding agent is diethylamine or triethylamine, further preferred triethylamine.
Wherein, the mol ratio of described hydroxylammonium salt and solid alkali can be 1:0.7-1:0.9. Further, the preferred 1:0.7 of the mol ratio of described hydroxylammonium salt and solid alkali. The present inventor passes through test of many times, it has been found that when the mol ratio of described hydroxylammonium salt and solid alkali is 1:0.7, and the amides foreign matter content that described preparation method produces is obviously less.
Wherein, the mol ratio of described formula II compound and described acid binding agent can be 1:4-1:10, it is preferable that 1:5.
Wherein, the mol ratio of described formula II compound and described hydroxylammonium salt can be 1:4-1:10, it is preferable that 1:5.
Wherein, in the alkali dissociation process of the present invention, the addition that the mass percent added is 90%-95% ethanol is not particularly limited, those skilled in the art can according to any selection so that described hydroxylammonium salt in this ethanol can fully alkaline hydrolysis from being advisable.
Wherein, the weight of described anhydrous sodium sulphate can be 0.23-0.24 times of hydroxylammonium salt weight.
Wherein, the temperature of the back flow reaction in the method for the invention is 72-80 DEG C, it is preferable that 78 DEG C.
Wherein, the back flow reaction in the method for the invention 16 hours.
Wherein, the recrystallization temperature in the method for the invention is room temperature.
The amides impurity that preparation method of the present invention produces is few, usually less than 10%, it is more preferable to ground is less than 5%.
To sum up, the invention has the beneficial effects as follows:
1, amide impurities content is lower, product purity height, it is to increase the receipts rate of target product;
2, reacted without the need to aftertreatment, directly carried out the next step;
3, cost is low, and solvent toxicity is low and reclaims simple, and environmental influence is little;
4, continuous dosing, easy and simple to handle, it is easy to industrial production.
Embodiment
Below in conjunction with embodiment, the present invention is done detailed explanation further, but embodiments of the present invention are not limited to this.
Azilsartan intermediate of the present invention adopts following standard testing:
HPLC detects: get this product, adds acetonitrile and aqueous dissolution that volume ratio is 1:1 and is quantitatively diluted to 0.4mg/ml solution, makes need testing solution. Getting need testing solution appropriate, dilution is 4 �� g/ml, in contrast solution. Detect according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD).
Embodiment 1
Get oxammonium hydrochloride 42.4g(0.61mol), add in 85ml95% ethanol, stir, 0-20 DEG C, add anhydrous sodium sulphate 10g, slowly add sodium hydroxide 19.45g(0.49mol), filter when reaction system stops heat release, filtrate adds 25g formula II compound (0.061mol), 61.5g triethylamine (0.61mol), 125ml ethanol, 75-80 DEG C is refluxed 16 hours, it is cooled to room temperature, filters, the intermediate 15.4g of obtained formula I. Detection HPLC obtains: formula I intermediate 83.363%, acid amides 8.784%.
Embodiment 2
Get oxammonium sulfate 196.8g(1.2mol), add in 420ml90% ethanol, stir, 0-20 DEG C, add anhydrous sodium sulphate 50g, slowly add potassium hydroxide 60.5g(1.08mol), filter when reaction system stops heat release, filtrate adds 125g formula II compound (0.3mol), 87.6g diethylamine (1.2mol), 600ml ethanol, 75-80 DEG C is refluxed 16 hours, it is cooled to room temperature, filters, the intermediate 79.0g of obtained formula I. Detection HPLC obtains: formula I intermediate 85.741%, acid amides 7.518%.
Embodiment 3
Get oxammonium hydrochloride 210g(3mol), add in 420ml95% ethanol, stir, 0-20 DEG C, add anhydrous sodium sulphate 50g, slowly add sodium hydroxide 84g(2.1mol), filter when reaction system stops heat release, filtrate adds 125g formula II compound (0.3mol), 310g triethylamine (3mol), 600ml ethanol, 75-80 DEG C is refluxed 16 hours, it is cooled to room temperature, filters, the intermediate 79.0g of obtained formula I. Detection HPLC obtains: formula I intermediate 86.906%, acid amides 3.076%.
Embodiment 4
Get oxammonium hydrochloride 1056.4g(15.2mol), add in 4.2L95% ethanol, whipped state, 0-20 DEG C, add anhydrous sodium sulphate 500g, sodium hydroxide 486.4g(12.16mol), filter when reaction system stops heat release, filtrate adds 1250g formula II compound (3.04mol), 1538.2g triethylamine (15.2mol), 6L ethanol, 75-80 DEG C is refluxed 16 hours, it is cooled to room temperature, filters, the intermediate 814g of obtained formula I. Detection HPLC obtains: formula I intermediate 93.160%, acid amides 4.304%.
Embodiment 5
Get oxammonium hydrochloride 1056.4g(15.2mol), add in 4.2L95% ethanol, whipped state, 0-20 DEG C, add anhydrous sodium sulphate 500g, sodium hydroxide 486.4g(12.16mol), filter when reaction system stops heat release, after filtrate sealing being placed 5 hours, add 1250g formula II compound (3.04mol), 1538.2g triethylamine (15.2mol), 6L ethanol, 75-80 DEG C is refluxed 16 hours, is cooled to room temperature, filter, the intermediate 788g of obtained formula I. Detection HPLC obtains: formula I intermediate 93.502%, acid amides 4.711%.
Comparative example 1
Add 10g formula II compound, 8.45g oxammonium hydrochloride, 12.3g triethylamine, 60mlDMSO, 85 DEG C of oil baths, back flow reaction 24h. TLC(thin-layer chromatography) detect raw material reaction completely, the 240ml that adds water stirs, and after being cooled to room temperature, filters, and 25ml tetrahydrofuran (THF) washs, the intermediate of obtained formula I. Detection HPLC obtains: formula I intermediate 51.505%, acid amides 32.402%.
Comparative example 2
Add 10g formula II compound, 8.45g oxammonium hydrochloride, 12.3g triethylamine, 100ml ethanol, 82 DEG C of oil baths, back flow reaction 24h. It is complete that TLC detects raw material reaction, and the 100ml that adds water stirs, and after being cooled to room temperature, filters, the intermediate of obtained formula I. Detection HPLC obtains: formula I intermediate 40.525%, acid amides 49.503%.
Comparative example 3
Add 10g formula II compound, 50% aqueous hydroxylamine 17g, triethylamine 2.5g, ethanol 100ml, 82 DEG C of oil bath heating, back flow reaction 24h. Cooling, filters, and 60 DEG C of vacuum-dryings, obtain the thick product of 7.7g. Detection HPLC obtains, formula I intermediate: acid amides: raw material=77.316%:16.195%:0.32%.
Comparative example 4
Add 10g formula II compound, sealed the 50% aqueous hydroxylamine 17g that placed 5 hours, triethylamine 2.5g, ethanol 100ml, 82 DEG C of oil bath heating, back flow reaction 24h. Cooling, filters, and 60 DEG C of vacuum-dryings, obtain the thick product of 5.7g. Detection HPLC obtains, formula I intermediate: acid amides: raw material=57.254%:36.085%:0.32%.
Contrasting from above-described embodiment 1-5 and comparative example 1-4 phase, the amide impurities content height in comparative example 1-2, thick product obtained in comparative example 3-4 can not be directly used in next step, also needs to carry out aftertreatment. It may be seen that compared to the preparation method of Azilsartan intermediate in prior art, in the Azilsartan intermediate that method of the present invention is obtained, amide content is low, and does not need aftertreatment can be directly used in next step.
The amides impurity that preparation method of the present invention produces is few, usually less than 10%, it is more preferable to ground is less than 5%.
Embodiment 1 and embodiment 3 contrast, it can be seen that when the mol ratio of all the other components is constant, when the mol ratio of described hydroxylammonium salt and solid alkali is 1:0.7, and the amides foreign matter content that described preparation method produces obviously reduces.
Embodiment 1 and embodiment 4 contrast, can find out, when the mol ratio of all the other components is constant, when the mol ratio that the mol ratio of described formula II compound and described acid binding agent is 1:5 and described formula II compound and described hydroxylammonium salt is 1:5, the amides foreign matter content that described preparation method produces obviously reduces.
Contrast from embodiment 4-5 and comparative example 3-4, can find out, compared with placing the aqueous hydroxylamine after the long period, the hydroxylammonium salt in the present invention through alkaline hydrolysis from after solution place the long period after the content of formula I intermediate for preparing still stablize, and amides foreign matter content is less.
As mentioned above, it is necessary, the present invention can be realized preferably.
Claims (3)
1. a preparation method for Azilsartan intermediate, comprises the following steps:
Hydroxylammonium salt is in the ethanol that mass percent is 90%-95%, add siccative, solid alkali, when stopping heat release to reaction system only, filter, filtrate adds lower formula II compound, acid binding agent and ethanol, refluxes 16 hours at 75-80 DEG C, cooling crystallization, filter, the title intermediate of obtained formula I; The mol ratio of described formula II compound and described acid binding agent is 1:5 or 1:10; Described acid binding agent is triethylamine; Described siccative is anhydrous sodium sulphate; When the mol ratio of described formula II compound and described acid binding agent is 1:5, the mol ratio of hydroxylammonium salt and solid alkali is 1:0.8, and when the mol ratio of described formula II compound and described acid binding agent is 1:10, the mol ratio of hydroxylammonium salt and solid alkali is 1:0.7;
(I),(II).
2. the preparation method of Azilsartan intermediate according to claim 1, it is characterised in that, described hydroxylammonium salt is selected from oxammonium sulfate or oxammonium hydrochloride.
3. the preparation method of Azilsartan intermediate according to claim 1, it is characterised in that, described solid alkali is at least one in following material: sodium hydroxide, potassium hydroxide, salt of wormwood, sodium carbonate.
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| CN106478515B (en) * | 2016-10-13 | 2018-11-23 | 艾美科健（中国）生物医药有限公司 | A kind of preparation method of Azilsartan intermediate |
| CN107840827A (en) * | 2017-11-06 | 2018-03-27 | 江苏中邦制药有限公司 | A kind of synthetic method of Azilsartan intermediate |
| CN108456202B (en) * | 2017-12-15 | 2021-10-29 | 江苏联环药业股份有限公司 | Preparation method of azilsartan with low amide impurity content |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013186792A2 (en) * | 2012-06-11 | 2013-12-19 | Msn Laboratories Limited | Process for the preparation of (5-methyl-2-oxo-l,3-dioxoi-4-vl)methvl 2- ethoxv-l-{[2'-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vl)biphenyi-4-vl]methyl}- lh-benzimidazole-7-carboxyiate and its salts |
| CN103476758A (en) * | 2011-03-04 | 2013-12-25 | 赞蒂瓦有限合伙公司 | A method of manufacturing 2-ethoxy-1-((2'-((hydroxyamino) iminomethyl)biphenyl-4- yl)methyl)-1h-benzo [d] imidazole-7-carboxylic acid and its esters |
| CN103554031A (en) * | 2013-11-01 | 2014-02-05 | 深圳科兴生物工程有限公司 | Preparation method of azilsartan intermediate |
| CN103588765A (en) * | 2013-11-11 | 2014-02-19 | 浙江永宁药业股份有限公司 | Synthesis method for azilsartan medoxomil or salt thereof, intermediate of azilsartan medoxomil or salt thereof and synthesis method for intermediate |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103476758A (en) * | 2011-03-04 | 2013-12-25 | 赞蒂瓦有限合伙公司 | A method of manufacturing 2-ethoxy-1-((2'-((hydroxyamino) iminomethyl)biphenyl-4- yl)methyl)-1h-benzo [d] imidazole-7-carboxylic acid and its esters |
| WO2013186792A2 (en) * | 2012-06-11 | 2013-12-19 | Msn Laboratories Limited | Process for the preparation of (5-methyl-2-oxo-l,3-dioxoi-4-vl)methvl 2- ethoxv-l-{[2'-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vl)biphenyi-4-vl]methyl}- lh-benzimidazole-7-carboxyiate and its salts |
| CN103554031A (en) * | 2013-11-01 | 2014-02-05 | 深圳科兴生物工程有限公司 | Preparation method of azilsartan intermediate |
| CN103588765A (en) * | 2013-11-11 | 2014-02-19 | 浙江永宁药业股份有限公司 | Synthesis method for azilsartan medoxomil or salt thereof, intermediate of azilsartan medoxomil or salt thereof and synthesis method for intermediate |
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