CN102766138B - A kind of preparation method of Azilsartan - Google Patents
A kind of preparation method of Azilsartan Download PDFInfo
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- CN102766138B CN102766138B CN201210254405.9A CN201210254405A CN102766138B CN 102766138 B CN102766138 B CN 102766138B CN 201210254405 A CN201210254405 A CN 201210254405A CN 102766138 B CN102766138 B CN 102766138B
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Abstract
The present invention relates to a kind of preparation method of Azilsartan, including：（1）Prepare the carboxylate methyl ester of ethoxybenzoimidazole 7；（2）Prepare the bromomethylbiphenyl of 2 cyano group 4 '；（3）The above-mentioned carboxylate methyl ester of ethoxybenzoimidazole 7 and the bromomethylbiphenyl of 2 cyano group 4 ' are dissolved into ethanol, potassium carbonate is added, reaction obtains the carboxylate methyl ester of 1 [(base of 2 ' cyanobiphenyl 4) methyl] 2 ethoxybenzoimidazole 7；（4）The carboxylate methyl ester of above-mentioned 1 [(base of 2 ' cyanobiphenyl 4) methyl] 2 ethoxybenzoimidazole 7 is suspended in water, add hydroxylamine hydrochloride, sodium hydroxide and tetrabutyl ammonium fluoride, cooled down after being heated to reflux, sodium hydroxide, ethyl chloroformate are added, is heated to reflux obtaining Azilsartan methyl esters；（5）By the hydrolysis of above-mentioned Azilsartan methyl esters.The process route of the present invention is short, and high income is safe and reliable；The purity for the Azilsartan that the present invention is obtained is high.
Description
Technical field
The invention belongs to treat the preparation field of hypertension drug, more particularly to a kind of preparation method of Azilsartan.
Background technology
Azilsartan is the angiotensin II receptor antagonist medicine of a treatment vascular hypertension, is used for treating high blood
Disease is pressed, is also the currently the only angiotensin II receptor antagonist in late-stage clinical（Husky smooth class）Medicine.The medicine is by day
This Takeda Pharmaceutical Company Limited 2012 list, its clinical stage it is evident in efficacy.According to famous Di mechanism Thomson
Reuters Pharma prediction, the medicine annual sales amount of 2016 can be more than 300,000,000 dollars, and the intermediate can be also used for bank
Ground sand is smooth, and the synthesis of the medicine such as Azilsartan ester, in the market increasingly increases the demand of such intermediate.It is that synthesis includes hydrochloric acid
The important intermediate of the multi-medicaments such as Fasudil, and it is in antioxidant, foaming agent, cosmetics, emulsifying agent, energetic material etc.
Aspect is widely used, with very big market potential.
US5583141 patent reports in 1996, as raw material, are hydrolyzed, directly using Azilsartan methyl esters by final step
Obtain Azilsartan, but specific method, and its concrete technology before, do not announce.The PCT2006015134 of 2006 is special
Profit report is using 2- carboxyls -3- nitros-methyl formate as raw material, by acylation, reduction, the step of cyclization three, synthetic intermediate 1- [(2`-
Cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters；The technique that the patent is used is similar with above chapter,
The thionyl chloride used in the first step, and sodium azide has been used in second step, more dangerous industrial chemicals is belonged to,
The danger of production is added in use, is unfavorable for the safety of industry.The PCT2011145100 patent reports 3- of 2011
Nitrophthalic acid is as initiation material, through over-churning, acylated, resets, and is alkylated, and is deprotected, reduction, and seven steps such as cyclization are anti-
Should, synthetic intermediate 1- [(2`- cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters；The patent is related to
And route it is longer, process cycle is long, and raw material type is more, and synthesis cost is high, and yield is relatively low, especially for being used in second step
Thionyl chloride, and the sodium azide used in the 3rd step belongs to more dangerous industrial chemicals, production added in use
Danger, be unfavorable for industry safety.
The content of the invention
The technical problems to be solved by the invention are to provide a kind of preparation method of Azilsartan, the process route of this method
Short, with short production cycle, synthesis cost is low, it is to avoid the uses of the dangerous material such as thionyl chloride and sodium azide, safe and reliable；Obtain
Product purity it is high, be 98.0 ~ 99.5%.
A kind of preparation method of Azilsartan of the present invention, including：
（1）Ethoxybenzoimidazole -7- carboxylate methyl esters
In molar ratio 1:1~1:3 are dissolved into 2,3- diamino-methyl benzoates and tetraethyl orthocarbonate in acetic acid, in 20 ~
30 DEG C of addition tetrabutyl ammonium fluorides, heating reflux reaction is cooled to room temperature, then boils off solvent acetic acid after 10 ~ 16 hours, will
The crude product arrived is beaten with water and filtered, solid ethyl alcohol recrystallization, is dried, is obtained ethoxybenzoimidazole -7- carboxylate methyl esters；
（2）The synthesis of 2- cyano group -4 '-bromomethylbiphenyl
2- cyano group -4 '-methyl biphenyl is dissolved in dichloromethane, N-bromosuccinimide is added portionwise, stirs at room temperature
Mix 4-8 hours, after reaction terminates, be beaten through washing, distillation, petroleum ether, then filter, dry, obtain 2- cyano group -4 '-bromine first
Base biphenyl, the crude product is without being further purified；
（3）The synthesis of 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters
In molar ratio 1:1~1:2 by above-mentioned ethoxybenzoimidazole -7- carboxylate methyl esters and 2- cyano group -4 '-bromomethylbiphenyl
It is dissolved into ethanol, adds potassium carbonate, flows back 8 ~ 16 hours, then evaporate ethanol, add water mashing, refilter, tied again with ethanol
Crystalline substance obtains 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters；
（4）Above-mentioned 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters are suspended in
In water, hydroxylamine hydrochloride, sodium hydroxide and tetrabutyl ammonium fluoride are added, is heated to reflux cooling down after 10 ~ 16 hours, then adds hydrogen-oxygen
Change sodium, then at 20 ~ 30 DEG C of addition ethyl chloroformates, be heated to reflux cooling after 8 ~ 16 hours and separate out solid, finally filter, wash,
It is dried to obtain Azilsartan methyl esters；
（5）Above-mentioned Azilsartan methyl esters is suspended in water, lithium hydroxide aqueous solution is added, is stirred at room temperature 12-16 hours,
Filtered in being adjusted under ice-water bath after pH value is 2-4, white crystal, as Azilsartan, purity are finally obtained with ethyl alcohol recrystallization
For 98 ~ 99%.
Step（1）Described in tetrabutyl ammonium fluoride consumption be 2,3- diamino-methyl benzoate moles 5 ~ 20%.
Step（2）Described in the mol ratio of N-bromosuccinimide and 2- cyano group -4 '-methyl biphenyl be 1 ~ 2:1.
Step（3）Described in the mol ratio of potassium carbonate and ethoxybenzoimidazole -7- carboxylate methyl esters be 3 ~ 5:1.
Step（4）Described in hydroxylamine hydrochloride and 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazoles -
The mol ratio of 7- carboxylate methyl esters is 4 ~ 8:1.
Step（4）Described in the sodium hydroxide for being heated to reflux being added before 10 ~ 16 hours and 1- [(2 '-cyanobiphenyl-
4- yls) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters mol ratio be 4 ~ 8:1.
Step（4）Described in tetrabutyl ammonium fluoride consumption be 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxies
The 5-20% of base benzimidazole -7- carboxylate methyl ester moles.
Step（4）Described in the sodium hydroxide for being heated to reflux being added after 10 ~ 16 hours and 1- [(2 '-cyanobiphenyl-
4- yls) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters mol ratio be 1:1；[(2 '-cyano group joins ethyl chloroformate with 1-
Benzene -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters mol ratio be 1:1.
Step（5）Described in the mass concentration of lithium hydroxide aqueous solution be 20%, lithium hydroxide in lithium hydroxide aqueous solution
Content be 2 ~ 5 times of Azilsartan methyl esters mole.
Step（5）Described in regulation pH value be using watery hydrochloric acid regulation.
The synthetic route of the present invention is as follows：
The sign of the sintetics Azilsartan of the present invention：
Below by proton nmr spectra, mass spectrum, the change that the method such as high resolution gas chromatography, fusing point test is synthesized to the present invention
Compound Azilsartan is characterized.
1st, hydrogen nuclear magnetic resonance modal data is as follows：
H-NMR(400MHz,DMSO-d6):δ1.47(3H,t,J=7.0),4.67(2H,q,J=7.0),5.77(2H,s),
7.07-7.70(11H,m)。
Wherein chemical shift δ=1.47 (3H) and 4.76（2H）The hydrogen of ethyoxyl on imidazole ring；5.77（2H）It is benzyl position
Hydrogen, 7.07-7.70（11H）It is fragrant ring hydrogen.Nuclear magnetic resonance hydrogen spectruming determining result is defined as Azilsartan.
2. mass spectrograph determination data is as follows：
ESI-MS(m/z,%)457。
The compound molecular weight is 457 [M+H] of appearance in 456.14, spectrogram+Signal.Mass spectroscopy result be defined as Ah
Qi Shatan.
3rd, high resolution gas chromatography：
Purity is 98.0 ~ 99.5%.
4th, melting point analysis：
Fusing point is 192-194 DEG C.
The above-mentioned proton nmr spectra of comprehensive analysis, mass spectrum, high resolution gas chromatography, fusing point test show that the present invention synthesizes
Final products are Azilsartan, and purity is qualified.Its structural formula is：
Wherein yield is 46.5 ~ 63.5%.
The present invention is with 2,3- diamino-methyl benzoates, and tetraethyl orthocarbonate, 2- cyano group -4'- methyl biphenyls are raw material, with
Acetic acid, dichloromethane, ethanol, water is solvent, is reacted by five steps, obtains target product Azilsartan, and through liquid chromatogram, core
Magnetic spectrum figure, mass spectrum carry out data characterization.Present invention process route segment is short, with short production cycle, and synthesis cost is low；Avoid in the past specially
The use of the dangerous material such as thionyl chloride and sodium azide in profit so that technique is gentleer, reliably, safety；Product of the present invention
High income（For 46.5 ~ 63.5%）, product purity height（For 98.0 ~ 99.5%）.
Beneficial effect：
1st, the use of the dangerous material such as thionyl chloride and sodium azide is avoided in preparation method of the invention so that technique is more
Heat and reliably, safely, and reduce cost；And ethanol is repeatedly reclaimed, dichloromethane equal solvent reduces toxic reagent
Discharge and processing cost, meet national green environmental protection call；The product is mass produced in addition, the present invention can be realized, it is full
Wilderness demand of the sufficient domestic and international market to the product；
2nd, the present invention uses intermediate 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylic acids
Methyl esters, by one kettle way and hydrolysis, obtains final products Azilsartan；Compared with prior art, production cost can be greatly reduced
And the cycle, save cost；
3rd, in the production process of the present invention, intermediate and final products purity are attained by more than 95%, can meet city
Field is required, and high income, is 46.5 ~ 63.5%；Obtained product Azilsartan high purity 98.0 ~ 99.5%.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.In addition, it is to be understood that after the content of the invention lectured has been read, people in the art
Member can make various changes or modifications to the present invention, and these equivalent form of values equally fall within the application appended claims and limited
Scope.
Embodiment 1
（1）Ethoxybenzoimidazole -7- carboxylate methyl esters
By 2,3- diamino-methyl benzoates（166.18g,1mol）It is dissolved in tetraethyl orthocarbonate (192.3g, 1mol)
In acetic acid (2L), tetrabutyl ammonium fluoride (13g, 5%mol) is added in 20 DEG C, temperature rising reflux reacts 10 hours, is cooled to room temperature, steams
Solvent acetic acid is removed, crude product is beaten with water and filtered, solid ethyl alcohol recrystallization is dried, obtains ethoxybenzoimidazole -7- carboxylic acids
Methyl esters (202.6g, yield 92%)；
（2）The synthesis of 2- cyano group -4'- bromomethylbiphenyls
2- cyano group -4'- methyl biphenyls (193g, 1mol) are dissolved in dichloromethane (2L), N- bromos are added portionwise in room temperature
Succinimide (178g, 1mol), is stirred 4 hours at room temperature, after reaction terminates, and is beaten through washing, distillation, petroleum ether, filtering,
Dry, obtain 2- cyano group -4'- bromomethylbiphenyls, the crude product is without being further purified (243.3g, yield 89.4%)；
（3）The synthesis of 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters
By ethoxybenzoimidazole -7- carboxylate methyl esters（22g,0.1mol）With 2- cyano group -4'- bromomethylbiphenyls (27.2g,
0.1mol) dissolving in ethanol (300mL), adds potassium carbonate (41.4g, 0.3mol), flows back 8 hours, evaporates ethanol, adds water and beats
Slurry, filtering, ethyl alcohol recrystallization obtains 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters
(32.1g, yield 78%)；
（4）By 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters（20.6g,
0.05mol）Suspend in water (250mL), adds hydroxylamine hydrochloride (13.9g, 0.2mol) and sodium hydroxide (8g, 0.2mol), then
Add tetrabutyl ammonium fluoride（0.65g,2.5mmol）, flow back 10 hours, cooling adds sodium hydroxide (2g, 0.05mol), 20
DEG C add ethyl chloroformate (5.4g, 0.05mol), then flow back 8 hours, cooling washes out solid, filter, washing, be dried to obtain Ah
Qi Shatan methyl esters (17.4g, 74%)；
（5）Azilsartan methyl esters (10g, 21.3mmol) is suspended in water (45mL), the hydrogen that mass concentration is 20% is added
The lithia aqueous solution (5.0mL, 41.6mmol), is stirred at room temperature 16 hours.PH=3 are acidified to watery hydrochloric acid under ice-water bath, are filtered
To product Azilsartan, ethyl alcohol recrystallization obtains white crystal, and purity is 98 ~ 99% (9.50g, yields 98%).
Embodiment 2
（1）Ethoxybenzoimidazole -7- carboxylate methyl esters
By 2,3- diamino-methyl benzoates（166.18g,1mol）It is dissolved in tetraethyl orthocarbonate (384.6g, 2mol)
In acetic acid (2L), tetrabutyl ammonium fluoride (13g, 5%mol) is added in 20 DEG C, temperature rising reflux reacts 10 hours, is cooled to room temperature, steams
Solvent acetic acid is removed, crude product is beaten with water and filtered, solid ethyl alcohol recrystallization is dried, obtains ethoxybenzoimidazole -7- carboxylic acids
Methyl esters (204.8g, yield 93%)；
（2）The synthesis of 2- cyano group -4'- bromomethylbiphenyls
2- cyano group -4'- methyl biphenyls (193g, 1mol) are dissolved in dichloromethane (2L), N- bromos are added portionwise in room temperature
Succinimide (356g, 2mol), is stirred 4 hours at room temperature, after reaction terminates, through washing, distillation, and petroleum ether is beaten, filtering,
Dry, obtain 2- cyano group -4'- bromomethylbiphenyls, the crude product is without being further purified (244.9g, yield 90%)；
（3）The synthesis of 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters
By ethoxybenzoimidazole -7- carboxylate methyl esters（22g,0.1mol）With 2- cyano group -4'- bromomethylbiphenyls (27.2g,
0.11mol) dissolving in ethanol (300mL), adds potassium carbonate (41.4g, 0.3mol), flows back 8 hours, evaporates ethanol, add water
Mashing, filtering, ethyl alcohol recrystallization obtains 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylic acid first
Ester (32.9g, yield 80%)；
（4）By 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters（20.6g,
0.05mol）Suspend in water (250mL), adds hydroxylamine hydrochloride (13.9g, 0.2mol) and sodium hydroxide (8g, 0.2mol), then
Add tetrabutyl ammonium fluoride（1.3g,5mmol）, flow back 10 hours, cooling adds sodium hydroxide (2g, 0.05mol), 20 DEG C
Ethyl chloroformate (5.4g, 0.05mol) is added, then is flowed back 8 hours, cooling washes out solid, is filtered, washing is dried to obtain Archie
Husky smooth methyl esters (18.3g, 78%)；
（5）Azilsartan methyl esters (10g, 21.3mmol) is suspended in water (45mL), the hydrogen that mass concentration is 20% is added
The lithia aqueous solution (10mL, 83.2mmol)（Ibid）, it is stirred at room temperature 16 hours.PH=3 are acidified to watery hydrochloric acid under ice-water bath,
Product Azilsartan is filtrated to get, ethyl alcohol recrystallization obtains white crystal, and purity is 98 ~ 99% (9.56g, yields 98.6%).
Embodiment 3
（1）Ethoxybenzoimidazole -7- carboxylate methyl esters
By 2,3- diamino-methyl benzoates（166.18g,1mol）It is dissolved in tetraethyl orthocarbonate (384.6g, 2mol)
In acetic acid (2L), tetrabutyl ammonium fluoride (13g, 5%mol) is added in 30 DEG C, temperature rising reflux reacts 16 hours, is cooled to room temperature, steams
Solvent acetic acid is removed, crude product is beaten with water and filtered, solid ethyl alcohol recrystallization is dried, obtains ethoxybenzoimidazole -7- carboxylic acids
Methyl esters (211.4g, yield 96%)；
（2）The synthesis of 2- cyano group -4'- bromomethylbiphenyls
2- cyano group -4'- methyl biphenyls (193g, 1mol) are dissolved in dichloromethane (2L), N- bromos are added portionwise in room temperature
Succinimide (356g, 2mol), is stirred 8 hours at room temperature, after reaction terminates, through washing, distillation, and petroleum ether is beaten, filtering,
Dry, obtain 2- cyano group -4'- bromomethylbiphenyls, the crude product is without being further purified (255.8g, yield 94%)；
（3）The synthesis of 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters
By ethoxybenzoimidazole -7- carboxylate methyl esters（22g,0.1mol）With 2- cyano group -4'- bromomethylbiphenyls (27.2g,
0.13mol) dissolving in ethanol (300mL), adds potassium carbonate (41.4g, 0.3mol), flows back 8 hours, evaporates ethanol, add water
Mashing, filtering, ethyl alcohol recrystallization obtains 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylic acid first
Ester (34.5g, yield 84%)；
（4）By 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters（20.6g,
0.05mol）Suspend in water (250mL), adds hydroxylamine hydrochloride (27.8g, 0.4mol) and sodium hydroxide (16g, 0.4mol), then
Add tetrabutyl ammonium fluoride（1.3g,5mmol）, flow back 10 hours, cooling adds sodium hydroxide (2g, 0.05mol), 20 DEG C
Ethyl chloroformate (5.4g, 0.05mol) is added, then is flowed back 8 hours, cooling washes out solid, is filtered, washing is dried to obtain Archie
Husky smooth methyl esters (19.2g, 82%)；
（5）Azilsartan methyl esters (10g, 21.3mmol) is suspended in water (45mL), the hydrogen that mass concentration is 20% is added
The lithia aqueous solution (10mL, 83.2mmol), is stirred at room temperature 16 hours.PH=3 are acidified to watery hydrochloric acid under ice-water bath, are filtered
To product Azilsartan, ethyl alcohol recrystallization obtains white crystal, and purity is 98 ~ 99% (9.56g, yields 98.6%).
Embodiment 4
（1）Ethoxybenzoimidazole -7- carboxylate methyl esters
By 2,3- diamino-methyl benzoates（166.18g,1mol）It is dissolved in tetraethyl orthocarbonate (384.6g, 2mol)
In acetic acid (2L), tetrabutyl ammonium fluoride (13g, 5%mol) is added in 30 DEG C, temperature rising reflux reacts 16 hours, is cooled to room temperature, steams
Solvent acetic acid is removed, crude product is beaten with water and filtered, solid ethyl alcohol recrystallization is dried, obtains ethoxybenzoimidazole -7- carboxylic acids
Methyl esters (211.4g, yield 96%)；
（2）The synthesis of 2- cyano group -4'- bromomethylbiphenyls
2- cyano group -4'- methyl biphenyls (193g, 1mol) are dissolved in dichloromethane (2L), N- bromos are added portionwise in room temperature
Succinimide (356g, 2mol), is stirred 8 hours at room temperature, after reaction terminates, through washing, distillation, and petroleum ether is beaten, filtering,
Dry, obtain 2- cyano group -4'- bromomethylbiphenyls, the crude product is without being further purified (255.8g, yield 94%)；
（3）The synthesis of 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters
By ethoxybenzoimidazole -7- carboxylate methyl esters（22g,0.1mol）With 2- cyano group -4'- bromomethylbiphenyls (27.2g,
0.13mol) dissolving in ethanol (300mL), adds potassium carbonate (41.4g, 0.3mol), flows back 8 hours, evaporates ethanol, add water
Mashing, filtering, ethyl alcohol recrystallization obtains 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylic acid first
Ester (34.5g, yield 84%)；
（4）By 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters（20.6g,
0.05mol）Suspend in water (250mL), adds hydroxylamine hydrochloride (27.8g, 0.4mol) and sodium hydroxide (16g, 0.4mol), then
Add tetrabutyl ammonium fluoride（1.95g,7.5mmol）, flow back 10 hours, cooling adds sodium hydroxide (2g, 0.05mol), 20
DEG C add ethyl chloroformate (5.4g, 0.05mol), then flow back 16 hours, cooling washes out solid, filter, washing, be dried to obtain Ah
Qi Shatan methyl esters (19.9g, 85%)；
（5）Azilsartan methyl esters (10g, 21.3mmol) is suspended in water (45mL), the hydrogen that mass concentration is 20% is added
The lithia aqueous solution (10mL, 83.2mmol), is stirred at room temperature 16 hours.PH=3 are acidified to watery hydrochloric acid under ice-water bath, are filtered
To product Azilsartan, ethyl alcohol recrystallization obtains white crystal, and purity is 98 ~ 99% (9.56g, yields 98.6%).
Embodiment 5
（1）Ethoxybenzoimidazole -7- carboxylate methyl esters
By 2,3- diamino-methyl benzoates（166.18g,1mol）It is dissolved in tetraethyl orthocarbonate (576.9g, 3mol)
In acetic acid (2L), tetrabutyl ammonium fluoride (13g, 5%mol) is added in 30 DEG C, temperature rising reflux reacts 16 hours, is cooled to room temperature, steams
Solvent acetic acid is removed, crude product is beaten with water and filtered, solid ethyl alcohol recrystallization is dried, obtains ethoxybenzoimidazole -7- carboxylic acids
Methyl esters (211.4g, yield 96%)；
（2）The synthesis of 2- cyano group -4'- bromomethylbiphenyls
2- cyano group -4'- methyl biphenyls (193g, 1mol) are dissolved in dichloromethane (2L), N- bromos are added portionwise in room temperature
Succinimide (356g, 2mol), is stirred 8 hours at room temperature, after reaction terminates, through washing, distillation, and petroleum ether is beaten, filtering,
Dry, obtain 2- cyano group -4'- bromomethylbiphenyls, the crude product is without being further purified (255.8g, yield 94%)；
（3）The synthesis of 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters
By ethoxybenzoimidazole -7- carboxylate methyl esters（22g,0.1mol）With 2- cyano group -4'- bromomethylbiphenyls (27.2g,
0.2mol) dissolving in ethanol (300mL), adds potassium carbonate (69g, 0.5mol), flows back 16 hours, evaporates ethanol, adds water and beats
Slurry, filtering, ethyl alcohol recrystallization obtains 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters
(34.5g, yield 84%)；
（4）By 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters（20.6g,
0.05mol）Suspend in water (250mL), adds hydroxylamine hydrochloride (27.8g, 0.4mol) and sodium hydroxide (16g, 0.4mol), then
Add tetrabutyl ammonium fluoride（2.6g,10mmol）, flow back 10 hours, cooling adds sodium hydroxide (2g, 0.05mol), 20 DEG C
Ethyl chloroformate (5.4g, 0.05mol) is added, then is flowed back 16 hours, cooling washes out solid, is filtered, washing is dried to obtain Archie
Husky smooth methyl esters (19.9g, 85%)；
（5）Azilsartan methyl esters (10g, 21.3mmol) is suspended in water (45mL), the hydrogen that mass concentration is 20% is added
The lithia aqueous solution (10mL, 83.2mmol), is stirred at room temperature 16 hours.PH=3 are acidified to watery hydrochloric acid under ice-water bath, are filtered
To product Azilsartan, ethyl alcohol recrystallization obtains white crystal, and purity is 98 ~ 99% (9.56g, yields 98.6%).
Claims (10)
1. a kind of preparation method of Azilsartan, including：
（1）In molar ratio 1:1~1:3 are dissolved into 2,3- diamino-methyl benzoates and tetraethyl orthocarbonate in acetic acid, in 20 ~
30 DEG C of addition tetrabutyl ammonium fluorides, heating reflux reaction is cooled to room temperature, then boils off acetic acid after 10 ~ 16 hours, by what is obtained
Crude product is beaten with water and filtered, and finally with ethyl alcohol recrystallization, drying, obtains ethoxybenzoimidazole -7- carboxylate methyl esters；
（2）2- cyano group -4 '-methyl biphenyl is dissolved in dichloromethane, N-bromosuccinimide is added portionwise, stirs at room temperature
4-8 hours, after reaction terminates, it is beaten through washing, distillation, petroleum ether, then filters, dries, obtain 2- cyano group -4 '-bromomethyl
Biphenyl；
（3）In molar ratio 1:1~1:2 is molten by above-mentioned ethoxybenzoimidazole -7- carboxylate methyl esters and 2- cyano group -4 '-bromomethylbiphenyl
Solution adds potassium carbonate, is heated to reflux 8 ~ 16 hours, then evaporates ethanol, add water mashing, refilter, use ethanol weight into ethanol
Crystallization obtains 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters；
（4）Above-mentioned 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters are suspended in water
In, hydroxylamine hydrochloride, sodium hydroxide and tetrabutyl ammonium fluoride are added, is heated to reflux cooling down after 10 ~ 16 hours, then adds hydroxide
Sodium, ethyl chloroformates are added then at 20 ~ 30 DEG C, are heated to reflux cooling after 8 ~ 16 hours and are separated out solid, finally filter, wash, do
It is dry to obtain Azilsartan methyl esters；
（5）Above-mentioned Azilsartan methyl esters is suspended in water, lithium hydroxide aqueous solution is added, 12-16 hours, Yu Bing is stirred at room temperature
It is filtering after 2-4 that pH value is adjusted under water-bath, finally with ethyl alcohol recrystallization, obtains Azilsartan.
2. a kind of preparation method of Azilsartan according to claim 1, it is characterised in that：Step（1）Described in four
The consumption of butyl ammonium fluoride is the 5 ~ 20% of 2,3- diamino-methyl benzoate moles.
3. a kind of preparation method of Azilsartan according to claim 1, it is characterised in that：Step（2）Described in N-
The mol ratio of NBS and 2- cyano group -4 '-methyl biphenyl is 1 ~ 2:1.
4. a kind of preparation method of Azilsartan according to claim 1, it is characterised in that：Step（3）Described in carbon
The mol ratio of sour potassium and ethoxybenzoimidazole -7- carboxylate methyl esters is 3 ~ 5:1.
5. a kind of preparation method of Azilsartan according to claim 1, it is characterised in that：Step（4）Described in salt
The mol ratio of sour azanol and 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters is 4 ~ 8:
1。
6. a kind of preparation method of Azilsartan according to claim 1, it is characterised in that：Step（4）Described in plus
Sodium hydroxide and 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethyoxyl benzo miaows that heat backflow was added before 10 ~ 16 hours
The mol ratio of azoles -7- carboxylate methyl esters is 4 ~ 8:1.
7. a kind of preparation method of Azilsartan according to claim 1, it is characterised in that：Step（4）Described in four
The consumption of butyl ammonium fluoride is 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzoimidazole -7- carboxylate methyl esters mole
The 5-20% of amount.
8. a kind of preparation method of Azilsartan according to claim 1, it is characterised in that：Step（4）Described in plus
Sodium hydroxide and 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethyoxyl benzo miaows that heat backflow is added after 10 ~ 16 hours
The mol ratio of azoles -7- carboxylate methyl esters is 1:1；Ethyl chloroformate and 1- [(2 '-cyanobiphenyl -4- bases) methyl] -2- ethoxybenzenes
And the mol ratio of imidazoles -7- carboxylate methyl esters is 1:1.
9. a kind of preparation method of Azilsartan according to claim 1, it is characterised in that：Step（5）Described in hydrogen
The mass concentration of the lithia aqueous solution is that the content of lithium hydroxide in 20%, lithium hydroxide aqueous solution is Azilsartan methyl esters mole
2 ~ 5 times of amount.
10. a kind of preparation method of Azilsartan according to claim 1, it is characterised in that：Step（5）Described in tune
It is using watery hydrochloric acid regulation to save pH value.
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| CN103709154B (en) * | 2012-09-28 | 2016-06-15 | 武汉朗来科技发展有限公司 | Benzimidizole derivatives and preparation method thereof and medical usage |
| CN103044412B (en) * | 2012-12-26 | 2016-04-06 | 华润赛科药业有限责任公司 | Polymorphic of a kind of Azilsartan and preparation method thereof |
| CN103880830B (en) * | 2013-03-22 | 2017-01-18 | 江西同和药业股份有限公司 | Synthesis method of azilsartan |
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| CN104230909B (en) * | 2014-08-30 | 2018-01-09 | 中国人民解放军第二三○医院 | A kind of preparation method of Azilsartan |
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| CN107089972B (en) * | 2017-06-23 | 2021-05-18 | 浙江华海药业股份有限公司 | Preparation method of candesartan cilexetil |
| CN107325092B (en) * | 2017-08-07 | 2021-01-08 | 山东鲁宁药业有限公司 | Novel preparation process of azithromycin |
| 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 |
| CN108947993B (en) * | 2018-07-27 | 2020-04-28 | 常州大学 | Method for green and efficient synthesis of azilsartan in water phase |
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