CN102766138A - Preparation method of azilsartan - Google Patents
Preparation method of azilsartan Download PDFInfo
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- CN102766138A CN102766138A CN2012102544059A CN201210254405A CN102766138A CN 102766138 A CN102766138 A CN 102766138A CN 2012102544059 A CN2012102544059 A CN 2012102544059A CN 201210254405 A CN201210254405 A CN 201210254405A CN 102766138 A CN102766138 A CN 102766138A
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Abstract
The invention relates to a preparation method of azilsartan, comprising the following steps of: (1) preparing ethoxybenzimidazole-7-methyl carboxylate; (2) preparing 2-cyan-4'-bromomethyl biphenyl; (3) dissolving the ethoxybenzimidazole-7-methyl carboxylate and the 2-cyan-4'-bromomethyl biphenyl into ethanol; adding potassium carbonate to react to obtain 1-[(2'-cyan diphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-methyl carboxylate; (4) suspending the 1-[(2'-cyan diphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-methyl carboxylate in water; adding hydroxylamine hydrochloride, sodium hydroxide and tetrabutylammonium fluoride; heating and reflowing, and then cooling; adding the sodium hydroxide and ethyl chloroformate, heating and reflowing to obtain azilsartan methyl ester; and (5) hydrolyzing the azilsartan methyl ester to obtain a product. The preparation method of the azilsartan, disclosed by the invention, has the advantages of being short in process route, high in yield, and safe and reliable; and the purity of the azilsartan obtained by using the method is high.
Description
Technical field
The invention belongs to the preparation field of treatment hypertension drug, particularly the preparation method of a kind of A Qishatan.
Background technology
A Qishatan is the angiotensin ii receptor antagonist medicine of a treatment vascular hypertension, is used for treating vascular hypertension more, also is at present unique clinical angiotensin ii receptor antagonist in latter stage (husky smooth type) medicine that is in.This medicine by Japan military field drugmaker in listing in 2012, its clinical stage evident in efficacy.Prediction according to the famous Thomson Reuters Pharma of Di mechanism; This medicine annual sales amount in 2016 can be above 300,000,000 dollars; This midbody can also be used for TCV-116, medicines such as the husky smooth ester of Archie synthetic, and the increasing demand to such midbody on the market increases.Be the synthetic important intermediate that comprises multiple medicines such as HA-1077, and it is at oxidation inhibitor, whipping agent, makeup, emulsifying agent, aspects such as energetic material are widely used, and have very big market potential.
The US5583141 patent report adopted the husky smooth methyl esters of Archie as raw material in 1996, and through the final step hydrolysis, it is smooth directly to obtain Archie sand, but concrete grammar, and concrete technology before, do not announce.PCT2006015134 patent report in 2006 is a raw material with 2-carboxyl-3-nitro-methyl-formiate, through acidylate, and reduction, Guan Huansan step, synthetic intermediate 1-[(2`-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester; Technology and above chapter that this patent adopts are similar, and the thionyl chloride that in the first step, uses and used sodiumazide in second step all belongs to comparatively dangerous industrial chemicals, in use increased produce danger, be unfavorable for industrial safety.PCT2011145100 patent report in 2011 with the 3-nitrophthalic acid as starting raw material, through over-churning, acidylate; Reset alkylation, deprotection; Reduction, seven steps reaction such as Guan Huan, synthetic intermediate 1-[(2`-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester; The route that this patent relates to is longer, and process cycle is long, and raw material type is many; Synthetic cost is high, and yield is lower, particularly for the thionyl chloride that uses in second step; With the sodiumazide that uses in the 3rd step; Belong to comparatively dangerous industrial chemicals, in use increased the danger of producing, be unfavorable for the safety of industry.
Summary of the invention
Technical problem to be solved by this invention provides the preparation method of a kind of A Qishatan, and the operational path of this method is short, and is with short production cycle, and synthetic cost is low, has avoided the use of hazardous substance such as thionyl chloride and sodiumazide, and is safe and reliable; The product purity that obtains is high, is 98.0 ~ 99.5%.
The preparation method of a kind of A Qishatan of the present invention comprises:
(1) oxyethyl group benzo imidazoles-7-carboxylate methyl ester
1:1 ~ 1:3 is with 2 in molar ratio, and 3-diamino-methyl benzoate and tetraethyl orthocarbonate are dissolved in the acetic acid, adds tetrabutyl ammonium fluoride in 20 ~ 30 ℃; 10 ~ 16 hours postcooling of heating reflux reaction are to room temperature; Boil off solvent acetic acid then, the thick product water making beating that obtains is filtered, solid is used ethyl alcohol recrystallization; Drying obtains oxyethyl group benzo imidazoles-7-carboxylate methyl ester;
(2) 2-cyanic acid-4 '-bromomethylbiphenyl synthetic
With 2-cyanic acid-4 '-methyl diphenyl is dissolved in the methylene dichloride; Add N-bromosuccinimide in batches, stirred 4-8 hour under the room temperature, after reaction finishes; Through washing, distillation, sherwood oil making beating; Filter then, drying, obtain 2-cyanic acid-4 '-bromomethylbiphenyl, this bullion need not to be further purified;
(3) 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester is synthetic
In molar ratio 1:1 ~ 1:2 with above-mentioned oxyethyl group benzo imidazoles-7-carboxylate methyl ester and 2-cyanic acid-4 '-bromomethylbiphenyl is dissolved in the ethanol; Add salt of wormwood; Refluxed 8 ~ 16 hours; Steam ethanol then, add the water making beating, refilter, obtain 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester with ethyl alcohol recrystallization;
(4) above-mentioned 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester is suspended in water; Add oxammonium hydrochloride, sodium hydroxide and tetrabutyl ammonium fluoride; 10 ~ 16 hours postcooling of reflux add sodium hydroxide then, add Vinyl chloroformate in 20 ~ 30 ℃ again; 8 ~ 16 hours postcooling of reflux are separated out solid, filter at last, wash, drying obtains the husky smooth methyl esters of Archie;
(5) the husky smooth methyl esters of above-mentioned Archie is suspended in water, add lithium hydroxide aqueous solution, stirring at room 12-16 hour, regulating the pH value down in ice-water bath was the 2-4 after-filtration, obtains white crystal with ethyl alcohol recrystallization at last, is A Qishatan, and purity is 98 ~ 99%.
The consumption of the tetrabutyl ammonium fluoride described in the step (1) is 2,5 ~ 20% of 3-diamino-methyl benzoate molar weight.
N-bromosuccinimide described in the step (2) and 2-cyanic acid-4 '-mol ratio of methyl diphenyl is 1 ~ 2:1.
The mol ratio of the salt of wormwood described in the step (3) and oxyethyl group benzo imidazoles-7-carboxylate methyl ester is 3 ~ 5:1.
The mol ratio of oxammonium hydrochloride described in the step (4) and 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester is 4 ~ 8:1.
The mol ratio of sodium hydroxide that the reflux described in the step (4) was added before 10 ~ 16 hours and 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester is 4 ~ 8:1.
The consumption of the tetrabutyl ammonium fluoride described in the step (4) is the 5-20% of 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester molar weight.
The mol ratio of sodium hydroxide that the reflux described in the step (4) was added after 10 ~ 16 hours and 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester is 1:1; The mol ratio of Vinyl chloroformate and 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester is 1:1.
The mass concentration of the lithium hydroxide aqueous solution described in the step (5) is 20%, and the content of Lithium Hydroxide MonoHydrate is 2 ~ 5 times of the husky smooth methyl esters molar weight of Archie in the lithium hydroxide aqueous solution.
Adjusting pH value described in the step (5) is regulated for adopting Hydrogen chloride.
Synthetic route of the present invention is following:
The sign of sintetics A Qishatan of the present invention:
Pass through proton nmr spectra below, mass spectrum, methods such as high resolution gas chromatography, fusing point test characterize synthetic compound A Qishatan of the present invention.
1, the proton nmr spectra data are following:
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)。
The hydrogen of oxyethyl group on chemical shift δ=1.47 (3H) and 4.76 (2H) imidazole ring wherein; 5.77 (2H) be the hydrogen of benzyl position, 7.07-7.70 (11H) is fragrant ring hydrogen.The nuclear magnetic resonance hydrogen spectruming determining result confirms as A Qishatan.
2. the mass spectrograph determination data is following:
ESI-MS(m/z,%)457。
This compound molecular weight is 456.14, occurs 457 [M+H] in the spectrogram
+Signal.The mass spectroscopy result confirms as A Qishatan.
3, high resolution gas chromatography:
Purity is 98.0 ~ 99.5%.
4, fusing point analysis:
Fusing point is 192-194 ℃.
The above-mentioned proton nmr spectra of analysis-by-synthesis, mass spectrum, high resolution gas chromatography, fusing point test show that synthetic the finished product of the present invention are A Qishatan, and purity are qualified.Its structural formula is:
Wherein yield is 46.5 ~ 63.5%.
The present invention is with 2, the 3-diamino-methyl benzoate, and tetraethyl orthocarbonate, 2-cyanic acid-4'-methyl diphenyl is a raw material; With acetic acid, methylene dichloride, ethanol, water are solvent; Through the reaction of five steps, obtain target product A Qishatan, and carry out data characterization through liquid chromatography, nuclear magnetic spectrogram, mass spectrum.Operational path section of the present invention is short, and is with short production cycle, and synthetic cost is low; Avoid the use of hazardous substance such as thionyl chloride and sodiumazide in the previous patent, made technology gentle more, reliable, safety; The yield of product of the present invention high (being 46.5 ~ 63.5%), product purity high (being 98.0 ~ 99.5%).
Beneficial effect:
1, avoid the use of hazardous substance such as thionyl chloride and sodiumazide among the preparation method of the present invention, made technology gentle more, reliable, safety, and reduced cost; And repeatedly reclaim ethanol, the methylene dichloride equal solvent has reduced the discharging and the processing cost of toxic reagent, meets national environmental protection and calls; In addition, the present invention can realize the heavy demand of domestic and international market to this product satisfied in this product scale operation;
2, the present invention uses midbody 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester, and through one kettle way and hydrolysis, it is smooth to obtain the finished product Archie sand; Compared with prior art, can significantly reduce production costs and the cycle, practice thrift cost;
3, in production process of the present invention, midbody and the finished product purity can both reach more than 95%, all can satisfy market demands, and yield is high, is 46.5 ~ 63.5%; The husky smooth purity of the product Archie that obtains is up to 98.0 ~ 99.5%.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in the restriction scope of the present invention.Should be understood that in addition those skilled in the art can do various changes or modification to the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Embodiment 1
(1) oxyethyl group benzo imidazoles-7-carboxylate methyl ester
With 2, and the 3-diamino-methyl benzoate (166.18g, 1mol) (192.3g 1mol) is dissolved in (2L) in the acetic acid with tetraethyl orthocarbonate; In 20 ℃ add tetrabutyl ammonium fluorides (13g, 5%mol), temperature rising reflux reaction 10 hours is cooled to room temperature; Boil off solvent acetic acid, thick product water making beating is filtered, and solid is used ethyl alcohol recrystallization; Drying obtains oxyethyl group benzo imidazoles-7-carboxylate methyl ester (202.6g, yield 92%);
(2) 2-cyanic acid-4'-bromomethylbiphenyl is synthetic
(193g 1mol) is dissolved in (2L) in the methylene dichloride, and room temperature adds N-bromosuccinimide (178g in batches with 2-cyanic acid-4'-methyl diphenyl; 1mol), stirred 4 hours under the room temperature, after reaction finishes; Through washing, distillation, sherwood oil making beating, filter drying; Obtain 2-cyanic acid-4'-bromomethylbiphenyl, this bullion need not to be further purified (243.3g, yield 89.4%);
(3) 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester is synthetic
With oxyethyl group benzo imidazoles-7-carboxylate methyl ester (22g, 0.1mol) (27.2g 0.1mol) is dissolved in (300mL) in the ethanol with 2-cyanic acid-4'-bromomethylbiphenyl; (41.4g 0.3mol), refluxed 8 hours to add salt of wormwood; Steam ethanol, add the water making beating, filter; Ethyl alcohol recrystallization obtains 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (32.1g, yield 78%);
(4) with 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (20.6g, 0.05mol) suspend in water (250mL), add oxammonium hydrochloride (13.9g, 0.2mol) and sodium hydroxide (8g; 0.2mol), (0.65g 2.5mmol), refluxed 10 hours to add tetrabutyl ammonium fluoride again; Cooling, add again sodium hydroxide (2g, 0.05mol), 20 ℃ add Vinyl chloroformate (5.4g; 0.05mol), refluxing again 8 hours, cooling washes out solid, filters; Washing, drying obtain the husky smooth methyl esters (17.4g, 74%) of Archie;
(5) with the husky smooth methyl esters of Archie (10g, 21.3mmol) suspend in water (45mL), add mass concentration and be 20% lithium hydroxide aqueous solution (5.0mL, 41.6mmol), stirring at room 16 hours.Be acidified to pH=3 with Hydrogen chloride under the ice-water bath, it is smooth that filtration obtains product Archie sand, and ethyl alcohol recrystallization obtains white crystal, and purity is 98 ~ 99% (9.50g, yields 98%).
Embodiment 2
(1) oxyethyl group benzo imidazoles-7-carboxylate methyl ester
With 2, and the 3-diamino-methyl benzoate (166.18g, 1mol) (384.6g 2mol) is dissolved in (2L) in the acetic acid with tetraethyl orthocarbonate; In 20 ℃ add tetrabutyl ammonium fluorides (13g, 5%mol), temperature rising reflux reaction 10 hours is cooled to room temperature; Boil off solvent acetic acid, thick product water making beating is filtered, and solid is used ethyl alcohol recrystallization; Drying obtains oxyethyl group benzo imidazoles-7-carboxylate methyl ester (204.8g, yield 93%);
(2) 2-cyanic acid-4'-bromomethylbiphenyl is synthetic
With 2-cyanic acid-4'-methyl diphenyl (193g 1mol) is dissolved in (2L) in the methylene dichloride, room temperature add in batches N-bromosuccinimide (356g, 2mol); Stirred 4 hours under the room temperature, after reaction finishes, through washing, distillation; Drying is filtered in the sherwood oil making beating; Obtain 2-cyanic acid-4'-bromomethylbiphenyl, this bullion need not to be further purified (244.9g, yield 90%);
(3) 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester is synthetic
With oxyethyl group benzo imidazoles-7-carboxylate methyl ester (22g, 0.1mol) (27.2g 0.11mol) is dissolved in (300mL) in the ethanol with 2-cyanic acid-4'-bromomethylbiphenyl; (41.4g 0.3mol), refluxed 8 hours to add salt of wormwood; Steam ethanol, add the water making beating, filter; Ethyl alcohol recrystallization obtains 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (32.9g, yield 80%);
(4) with 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (20.6g, 0.05mol) suspend in water (250mL), add oxammonium hydrochloride (13.9g, 0.2mol) and sodium hydroxide (8g; 0.2mol), (1.3g 5mmol), refluxed 10 hours to add tetrabutyl ammonium fluoride again; Cooling, add again sodium hydroxide (2g, 0.05mol), 20 ℃ add Vinyl chloroformate (5.4g; 0.05mol), refluxing again 8 hours, cooling washes out solid, filters; Washing, drying obtain the husky smooth methyl esters (18.3g, 78%) of Archie;
(5) (the adding mass concentration is 20% lithium hydroxide aqueous solution (10mL, 83.2mmol) (the same), stirring at room 16 hours for 10g, 21.3mmol) suspend in water (45mL) with the husky smooth methyl esters of Archie.Be acidified to pH=3 with Hydrogen chloride under the ice-water bath, it is smooth that filtration obtains product Archie sand, and ethyl alcohol recrystallization obtains white crystal, and purity is 98 ~ 99% (9.56g, yields 98.6%).
Embodiment 3
(1) oxyethyl group benzo imidazoles-7-carboxylate methyl ester
With 2, and the 3-diamino-methyl benzoate (166.18g, 1mol) (384.6g 2mol) is dissolved in (2L) in the acetic acid with tetraethyl orthocarbonate; In 30 ℃ add tetrabutyl ammonium fluorides (13g, 5%mol), temperature rising reflux reaction 16 hours is cooled to room temperature; Boil off solvent acetic acid, thick product water making beating is filtered, and solid is used ethyl alcohol recrystallization; Drying obtains oxyethyl group benzo imidazoles-7-carboxylate methyl ester (211.4g, yield 96%);
(2) 2-cyanic acid-4'-bromomethylbiphenyl is synthetic
With 2-cyanic acid-4'-methyl diphenyl (193g 1mol) is dissolved in (2L) in the methylene dichloride, room temperature add in batches N-bromosuccinimide (356g, 2mol); Stirred 8 hours under the room temperature, after reaction finishes, through washing, distillation; Drying is filtered in the sherwood oil making beating; Obtain 2-cyanic acid-4'-bromomethylbiphenyl, this bullion need not to be further purified (255.8g, yield 94%);
(3) 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester is synthetic
With oxyethyl group benzo imidazoles-7-carboxylate methyl ester (22g, 0.1mol) (27.2g 0.13mol) is dissolved in (300mL) in the ethanol with 2-cyanic acid-4'-bromomethylbiphenyl; (41.4g 0.3mol), refluxed 8 hours to add salt of wormwood; Steam ethanol, add the water making beating, filter; Ethyl alcohol recrystallization obtains 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (34.5g, yield 84%);
(4) with 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (20.6g, 0.05mol) suspend in water (250mL), add oxammonium hydrochloride (27.8g, 0.4mol) and sodium hydroxide (16g; 0.4mol), (1.3g 5mmol), refluxed 10 hours to add tetrabutyl ammonium fluoride again; Cooling, add again sodium hydroxide (2g, 0.05mol), 20 ℃ add Vinyl chloroformate (5.4g; 0.05mol), refluxing again 8 hours, cooling washes out solid, filters; Washing, drying obtain the husky smooth methyl esters (19.2g, 82%) of Archie;
(5) with the husky smooth methyl esters of Archie (10g, 21.3mmol) suspend in water (45mL), add mass concentration and be 20% lithium hydroxide aqueous solution (10mL, 83.2mmol), stirring at room 16 hours.Be acidified to pH=3 with Hydrogen chloride under the ice-water bath, it is smooth that filtration obtains product Archie sand, and ethyl alcohol recrystallization obtains white crystal, and purity is 98 ~ 99% (9.56g, yields 98.6%).
Embodiment 4
(1) oxyethyl group benzo imidazoles-7-carboxylate methyl ester
With 2, and the 3-diamino-methyl benzoate (166.18g, 1mol) (384.6g 2mol) is dissolved in (2L) in the acetic acid with tetraethyl orthocarbonate; In 30 ℃ add tetrabutyl ammonium fluorides (13g, 5%mol), temperature rising reflux reaction 16 hours is cooled to room temperature; Boil off solvent acetic acid, thick product water making beating is filtered, and solid is used ethyl alcohol recrystallization; Drying obtains oxyethyl group benzo imidazoles-7-carboxylate methyl ester (211.4g, yield 96%);
(2) 2-cyanic acid-4'-bromomethylbiphenyl is synthetic
With 2-cyanic acid-4'-methyl diphenyl (193g 1mol) is dissolved in (2L) in the methylene dichloride, room temperature add in batches N-bromosuccinimide (356g, 2mol); Stirred 8 hours under the room temperature, after reaction finishes, through washing, distillation; Drying is filtered in the sherwood oil making beating; Obtain 2-cyanic acid-4'-bromomethylbiphenyl, this bullion need not to be further purified (255.8g, yield 94%);
(3) 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester is synthetic
With oxyethyl group benzo imidazoles-7-carboxylate methyl ester (22g, 0.1mol) (27.2g 0.13mol) is dissolved in (300mL) in the ethanol with 2-cyanic acid-4'-bromomethylbiphenyl; (41.4g 0.3mol), refluxed 8 hours to add salt of wormwood; Steam ethanol, add the water making beating, filter; Ethyl alcohol recrystallization obtains 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (34.5g, yield 84%);
(4) with 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (20.6g, 0.05mol) suspend in water (250mL), add oxammonium hydrochloride (27.8g, 0.4mol) and sodium hydroxide (16g; 0.4mol), (1.95g 7.5mmol), refluxed 10 hours to add tetrabutyl ammonium fluoride again; Cooling, add again sodium hydroxide (2g, 0.05mol), 20 ℃ add Vinyl chloroformate (5.4g; 0.05mol), refluxing again 16 hours, cooling washes out solid, filters; Washing, drying obtain the husky smooth methyl esters (19.9g, 85%) of Archie;
(5) with the husky smooth methyl esters of Archie (10g, 21.3mmol) suspend in water (45mL), add mass concentration and be 20% lithium hydroxide aqueous solution (10mL, 83.2mmol), stirring at room 16 hours.Be acidified to pH=3 with Hydrogen chloride under the ice-water bath, it is smooth that filtration obtains product Archie sand, and ethyl alcohol recrystallization obtains white crystal, and purity is 98 ~ 99% (9.56g, yields 98.6%).
Embodiment 5
(1) oxyethyl group benzo imidazoles-7-carboxylate methyl ester
With 2, and the 3-diamino-methyl benzoate (166.18g, 1mol) (576.9g 3mol) is dissolved in (2L) in the acetic acid with tetraethyl orthocarbonate; In 30 ℃ add tetrabutyl ammonium fluorides (13g, 5%mol), temperature rising reflux reaction 16 hours is cooled to room temperature; Boil off solvent acetic acid, thick product water making beating is filtered, and solid is used ethyl alcohol recrystallization; Drying obtains oxyethyl group benzo imidazoles-7-carboxylate methyl ester (211.4g, yield 96%);
(2) 2-cyanic acid-4'-bromomethylbiphenyl is synthetic
With 2-cyanic acid-4'-methyl diphenyl (193g 1mol) is dissolved in (2L) in the methylene dichloride, room temperature add in batches N-bromosuccinimide (356g, 2mol); Stirred 8 hours under the room temperature, after reaction finishes, through washing, distillation; Drying is filtered in the sherwood oil making beating; Obtain 2-cyanic acid-4'-bromomethylbiphenyl, this bullion need not to be further purified (255.8g, yield 94%);
(3) 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester is synthetic
With oxyethyl group benzo imidazoles-7-carboxylate methyl ester (22g, 0.1mol) (27.2g 0.2mol) is dissolved in (300mL) in the ethanol with 2-cyanic acid-4'-bromomethylbiphenyl; (69g 0.5mol), refluxed 16 hours to add salt of wormwood; Steam ethanol, add the water making beating, filter; Ethyl alcohol recrystallization obtains 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (34.5g, yield 84%);
(4) with 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (20.6g, 0.05mol) suspend in water (250mL), add oxammonium hydrochloride (27.8g, 0.4mol) and sodium hydroxide (16g; 0.4mol), (2.6g 10mmol), refluxed 10 hours to add tetrabutyl ammonium fluoride again; Cooling, add again sodium hydroxide (2g, 0.05mol), 20 ℃ add Vinyl chloroformate (5.4g; 0.05mol), refluxing again 16 hours, cooling washes out solid, filters; Washing, drying obtain the husky smooth methyl esters (19.9g, 85%) of Archie;
(5) with the husky smooth methyl esters of Archie (10g, 21.3mmol) suspend in water (45mL), add mass concentration and be 20% lithium hydroxide aqueous solution (10mL, 83.2mmol), stirring at room 16 hours.Be acidified to pH=3 with Hydrogen chloride under the ice-water bath, it is smooth that filtration obtains product Archie sand, and ethyl alcohol recrystallization obtains white crystal, and purity is 98 ~ 99% (9.56g, yields 98.6%).
Claims (10)
1. the preparation method of Yi Zhong A Qishatan comprises:
(1) in molar ratio 1:1 ~ 1:3 with 2; 3-diamino-methyl benzoate and tetraethyl orthocarbonate are dissolved in the acetic acid, and in 20 ~ 30 ℃ of adding tetrabutyl ammonium fluorides, 10 ~ 16 hours postcooling of heating reflux reaction are to room temperature; Boil off acetic acid then; The thick product water making beating that obtains is filtered, use ethyl alcohol recrystallization, drying at last, obtain oxyethyl group benzo imidazoles-7-carboxylate methyl ester;
(2) with 2-cyanic acid-4 '-methyl diphenyl is dissolved in the methylene dichloride, adds N-bromosuccinimide in batches, stirred 4-8 hour under the room temperature; After reaction finishes; Through washing, distillation, sherwood oil making beating, filter then, drying, obtain 2-cyanic acid-4 '-bromomethylbiphenyl;
(3) in molar ratio 1:1 ~ 1:2 with above-mentioned oxyethyl group benzo imidazoles-7-carboxylate methyl ester and 2-cyanic acid-4 '-bromomethylbiphenyl is dissolved in the ethanol; Add salt of wormwood; Reflux 8 ~ 16 hours; Steam ethanol then, add the water making beating, refilter, obtain 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester with ethyl alcohol recrystallization;
(4) above-mentioned 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester is suspended in water; Add oxammonium hydrochloride, sodium hydroxide and tetrabutyl ammonium fluoride; 10 ~ 16 hours postcooling of reflux add sodium hydroxide then, add Vinyl chloroformate in 20 ~ 30 ℃ again; 8 ~ 16 hours postcooling of reflux are separated out solid, filter at last, wash, drying obtains the husky smooth methyl esters of Archie;
(5) the husky smooth methyl esters of above-mentioned Archie is suspended in water, add lithium hydroxide aqueous solution, stirring at room 12-16 hour, regulating the pH value down in ice-water bath was the 2-4 after-filtration, uses ethyl alcohol recrystallization at last, obtains A Qishatan.
2. the preparation method of a kind of A Qishatan according to claim 1, it is characterized in that: the consumption of the tetrabutyl ammonium fluoride described in the step (1) is 2,5 ~ 20% of 3-diamino-methyl benzoate molar weight.
3. the preparation method of a kind of A Qishatan according to claim 1 is characterized in that: N-bromosuccinimide described in the step (2) and 2-cyanic acid-4 '-mol ratio of methyl diphenyl is 1 ~ 2:1.
4. the preparation method of a kind of A Qishatan according to claim 1, it is characterized in that: the mol ratio of the salt of wormwood described in the step (3) and oxyethyl group benzo imidazoles-7-carboxylate methyl ester is 3 ~ 5:1.
5. the preparation method of a kind of A Qishatan according to claim 1 is characterized in that: the mol ratio of oxammonium hydrochloride described in the step (4) and 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester is 4 ~ 8:1.
6. the preparation method of a kind of A Qishatan according to claim 1 is characterized in that: the mol ratio of sodium hydroxide that the reflux described in the step (4) was added before 10 ~ 16 hours and 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester is 4 ~ 8:1.
7. the preparation method of a kind of A Qishatan according to claim 1 is characterized in that: the consumption of the tetrabutyl ammonium fluoride described in the step (4) is the 5-20% of 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester molar weight.
8. the preparation method of a kind of A Qishatan according to claim 1 is characterized in that: the mol ratio of sodium hydroxide that the reflux described in the step (4) was added after 10 ~ 16 hours and 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester is 1:1; The mol ratio of Vinyl chloroformate and 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester is 1:1.
9. the preparation method of a kind of A Qishatan according to claim 1; It is characterized in that: the mass concentration of the lithium hydroxide aqueous solution described in the step (5) is 20%, and the content of Lithium Hydroxide MonoHydrate is 2 ~ 5 times of the husky smooth methyl esters molar weight of Archie in the lithium hydroxide aqueous solution.
10. the preparation method of a kind of A Qishatan according to claim 1 is characterized in that: the adjusting pH value described in the step (5) is regulated for adopting Hydrogen chloride.
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| CN103044412A (en) * | 2012-12-26 | 2013-04-17 | 华润赛科药业有限责任公司 | Azilsartan polymorph and preparation method thereof |
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