CN104418807A - Preparation method of 2-ethoxyl-1-[[2'-(hydroxyl amidino)-biphenylyl]-4-yl]methyl-1H-benzimidazole-7-carboxylic acid and ester derivatives thereof - Google Patents
Preparation method of 2-ethoxyl-1-[[2'-(hydroxyl amidino)-biphenylyl]-4-yl]methyl-1H-benzimidazole-7-carboxylic acid and ester derivatives thereof Download PDFInfo
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Abstract
The invention relates to a synthesis method of an azilsartan intermediate compound 2-ethoxyl-1-[[2'-(hydroxyl amidino)-biphenylyl]-4-yl]methyl-1H-benzimidazole-7-carboxylic acid and ester derivatives thereof. According to the method, 2-ethoxyl-1-[[2'-cyano-biphenylyl]-4-yl]methyl-1H-benzimidazole-7-carboxylic acid and esters thereof used as the raw materials react with hydroxylamine hydrochloride aqueous solution under the weak base condition with ethanol as the solvent. The method disclosed by the invention has the advantages of less side reaction, unnecessary purification of the product obtained according to the method and suitability for industrial production; and the method can be used for preparing high-purity azilsartan and azilsartan medoxomil.
Description
Technical field
The invention belongs to pharmaceutical technology sectors, be specifically related to the preparation method of Azilsartan intermediate 2-oxyethyl group-1-[[2`-(hydroxyl amidino groups)-xenyl]-4-base] methyl isophthalic acid H-benzoglyoxaline-7-carboxylic acid and ester (compound ii) thereof.
Background technology
The present invention relates to the preparation method of a kind of 2-oxyethyl group-1-[[2`-(hydroxyl amidino groups)-xenyl]-4-base] methyl isophthalic acid H-benzoglyoxaline-7-carboxylic acid and ester (compound ii) thereof.
Wherein R is H, or C
1-C
4alkyl, or phenmethyl, diphenyl-methyl, trityl.
Compound ii is the important intermediate preparing antihypertensive drugs Azilsartan and ester thereof.Azilsartan is a novel hypertension II receptor antagonist (ARB).Compared with other depressor, ARB class medicine has unique mechanism of action, by reducing blood pressure; reduce cardiovascular event; and play the heart, brain, kidney target organ protection function, reverse myocardial plumpness slowing down heart failure simultaneously, alleviating symptoms of heart failure by reducing Peripheral resistance.In renal function protecting, ARB class drug effect is particularly outstanding, effectively can reduce whole body and renal glomerulus localised blood pressure, reduces renal glomerulus to albumen permeability, reduces proteinuria, stop the generation of glomerular sclerosis, delay the development of ephrosis.Because step-down is steady, curative effect strong, long action time, better tolerance, compliance is high, and related reactions is few, and ARB class medicine plays an important role in cardiovascular system diseases treatment, is subject to increasing attention.Azilsartan (compound III) is in 2012 in Japan's listing, and commodity are called
azilsartan (compounds Ⅳ) is in 2011 in U.S.'s listing, and commodity are called
azilsartan is a kind of high selectivity Angiotensin Ⅱ receptor antagonist, expects that potential applicability in clinical practice is extensive by the hypotensive effect more effective and more lasting than existing ARB class medicine performance.
Current Azilsartan synthetic method has lot of documents and patent openly, and the synthetic route of most practical value is route shown in figure below:
Synthetic route take chemical compounds I as initiator.Chemical compounds I is an intermediate of candesartan Cilexetil medicine, and candesartan Cilexetil is an ARB medicine gone on the market for many years, and share of market is high, therefore chemical compounds I has stable a large amount of commercialization approach supply.In kind obtain compound ii with azanol reaction as it, after obtain the distinctive oxygen of Azilsartan for oxadiazole rings through esterification, cyclization, then through being hydrolyzed to obtain Azilsartan (compound III), also then esterification can obtain Azilsartan (compounds Ⅳ).
The step of whole synthetic route most critical is the first step reaction.Namely compound ii is prepared by chemical compounds I.There are many sections of patents and paper to relate to this step reaction for this reason.Reaction conditions disclosed in CN92105152.2 is that the dimethyl sulphoxide solution of oxammonium hydrochloride adds sodium methylate, reacts to obtain compound ii after preparing hydroxylamine solution with chemical compounds I in dimethyl sulphoxide solution.The method of document J.Med.Chem.1996,39,5228-5235 report is the dimethyl sulphoxide solution using triethylamine alkalization oxammonium hydrochloride, and the dimethyl sulphoxide solution and the chemical compounds I that obtain azanol react.WO2012119573A1 discloses a kind of condition of directly reacting in dimethyl sulfoxide solvent with the aqueous solution of azanol and chemical compounds I.The synthesis of document Azilsartan, 881-883,2010,41(12) Chinese Journal of Pharmaceuticals reports and directly uses aqueous hydroxylamine and triethylamine, the condition that chemical compounds I reacts in ethanol.The improvement in synthesis of document 5-oxo-1,2,4-oxadiazole compound, 646-647,2004,35(11) Chinese Journal of Pharmaceuticals reports chemical compounds I and is dissolved in dimethyl sulfoxide (DMSO), adds the condition of oxammonium hydrochloride and triethylamine reaction.
These reaction conditionss are roughly divided into two classes, a class be chemical compounds I directly and azanol reaction, another kind of is chemical compounds I and oxammonium hydrochloride, adds stronger alkali (such as triethylamine), and reacts in the DMSO solution with certain alkalescence.Contriver draws through a large amount of comparative experimental research, and prior art condition owing to using azanol direct reaction, or uses the solvent of stronger alkali and alkalescence, causes reaction conditions excessively strong, produces a large amount of side reaction product (compound V).In the compound ii product that contriver uses prior art condition to draw, generally all do not contain by-product impurities (compound V) 10%-40% not etc.If purifying can not have a strong impact on the quality of subsequent reactions and the finished product.Purifying can increase reactions steps again, causes output to reduce and cost increase.
Summary of the invention:
The object of the present invention is to provide a kind of New Terms method being prepared compound ii by chemical compounds I.The side reaction that the method produces is extremely low, the amount of compound V impurity in product can be controlled within 2%, and can realize commercial scale production.
Figure below is reaction formula of the present invention:
Wherein R is H, or C
1-C
4alkyl, or phenmethyl, diphenyl-methyl, trityl.
In view of above-mentioned background illustrates, the present inventor, by the research realizing above-mentioned reaction prior art condition, finds that prior art condition can produce larger side reaction.In the compound ii product that the present inventor uses prior art condition to draw, generally all do not contain by-product impurities (compound V) 10%-40% not etc.Pass through column chromatography for separation, the present inventor has successfully isolated pure by-product impurities from compound ii product, by analysis means such as high resolution mass spectrum (HRMS), proton nmr spectra (1H-NMR), carbon-13 nmr spectras (13C-NMR), confirm the structure (in figure below compound V) of this by-product impurities.Study by analysis, the present inventor thinks that this impurity is produced by following side reaction.
Think that the generation of this impurity is caused by reaction conditions is crossed by force through researching and analysing the present inventor.So through a large amount of research trial, by rationally reducing response intensity condition, the present inventor achieves the object significantly reducing this step side reaction.Make this step reaction product compound ii, without any purification process, HPLC purity can reach more than 97%, and the content of impurity (compound V) is lower than 2%.
Concrete method is: use the stable oxammonium hydrochloride be easy to get to be reactant, by its water-soluble aqueous solution; The oxammonium hydrochloride aqueous solution is added in the alcoholic solution of chemical compounds I; Then weak base solid is added; Start heating, stirring reaction is to complete.
In aforesaid method, (weight ratio) concentration of the oxammonium hydrochloride aqueous solution is 35%-60%, preferred 40-45%.
In aforesaid method, weak base solid reagent is carbonate and supercarbonate.Being in particular carbonate is sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus.More preferably sodium bicarbonate.
Adding weak base amount ratio (mol ratio) in aforesaid method is: supercarbonate is 2-8 than chemical compounds I; Supercarbonate is 1.1-1.5 than oxammonium hydrochloride.Add weak base amount ratio (mol ratio) more preferably: supercarbonate is 4-6 than chemical compounds I; Sodium bicarbonate is 1.2-1.3 than oxammonium hydrochloride.
In aforesaid method, alcohol is methyl alcohol, ethanol, propyl alcohol, Virahol, butanols.Preferred alcohol, methyl alcohol.
In aforesaid method, reacting by heating temperature is 50-100 DEG C, preferred 75-85 DEG C.
The time of heated and stirred reaction in aforesaid method, rely on tlc detection reaction liquid (TLC), developping agent is developping agent methylene dichloride: acetone=7:3, and the time that reacting completely needs is 30-50 hour.
Technological method of the present invention, effectively can reduce and prepare by 2-oxyethyl group-1-[[2`-cyano-biphenyl base]-4-base] methyl isophthalic acid H-benzoglyoxaline-7-carboxylic acid and ester (chemical compounds I) thereof the by product that 2-oxyethyl group-1-[[2`-(hydroxyl amidino groups)-xenyl]-4-base] methyl isophthalic acid H-benzoglyoxaline-7-carboxylic acid and ester (compound ii) thereof produce.Make the amount of compound V impurity in product be reduced within 2% from the 10-40% of prior art, this step yield can reach more than 70%, is substantially equal to prior art yield.Due to the reduction of by product, make the intermediate (compound ii) obtained not need purifying, directly can carry out next step reaction, simplify the technical process preparing Azilsartan, make whole production technique be more suitable for suitability for industrialized production.The raising of key intermediate (compound ii) quality, make the quality of reacting final product Azilsartan have large increase, Azilsartan crude product quality prepared by the present invention can reach HPLC purity more than 99%.This technological method is significant for raising Azilsartan medicine quality standard.
Specific embodiment
In following examples, 2-oxyethyl group-1-[[2`-cyano-biphenyl base]-4-base] methyl isophthalic acid H-benzoglyoxaline-7-carboxylic acid, ethyl ester (code name C-5) is buied by commercialization approach, also can prepare according to CN200510131970.6 method.Other reagent is commercialization approach and buys.
Embodiment 1:
Products therefrom 2-oxyethyl group-1-of the present invention [[2`-(hydroxyl amidino groups)-xenyl]-4-base] methyl isophthalic acid H-benzoglyoxaline-7-carboxylic acid, ethyl ester (compound ii) HPLC analytical procedure is:
Be weighting agent with octadecylsilane chemically bonded silica, with water-Glacial acetic acid (1000:1) for mobile phase A, acetonitrile is Mobile phase B, and according to the form below carries out gradient elution; Determined wavelength is 254nm; Flow velocity is per minute 1ml; Column temperature 25 DEG C; Sample bin temperature 20 DEG C.
Precision takes sample and is about 10mg, puts in 25ml measuring bottle, adds acetonitrile to scale, shakes up, as need testing solution.Get mobile phase A, each 20 μ l of acetonitrile injection liquid chromatography respectively, record color atlas, as a setting collection of illustrative plates, according to determining that background cutting edge of a knife or a sword position is deducted when sample calculates.Get need testing solution 20 μ L, injection liquid chromatography, record color atlas.Calculate by area normalization, the main peak of about 12.8 minutes is the normalization method purity of product 2-oxyethyl group-1-[[2`-(hydroxyl amidino groups)-xenyl]-4-base] methyl isophthalic acid H-benzoglyoxaline-7-carboxylic acid, ethyl ester.Within about 16.1 minutes, impurity peaks is the foreign matter content of by product (compound V).
Embodiment 2:
Add oxammonium hydrochloride 8.42 grams in 250 milliliters of three mouthfuls of glass flask, add dimethyl sulfoxide (DMSO) (DMSO) 50 milliliters in reaction flask, after stirring and dissolving, add the sodium methoxide solution (concentrations by weight) 23.3 grams of 28%, mixture room temperature 25 DEG C stirs 20 minutes.40 milliliters of DMSO solution of 2-oxyethyl group-1-[[2`-cyano-biphenyl base]-4-base] methyl isophthalic acid H-benzoglyoxaline-7-carboxylic acid, ethyl ester (code name C-5) 10 grams are added in reaction solution.Be heated with stirring to 100 DEG C, react 1.5 hours.Be cooled to room temperature, add water and ethyl acetate under stirring, after organic layer washing and drying, evaporated under reduced pressure solvent obtains product as white solid 5.8 grams, yield 53.8%.HPLC detects product purity 59.3%, by-product impurities content 35.6%.
Embodiment 3:
Add oxammonium hydrochloride 8.48 grams in 100 milliliters of single port flasks, add DMSO40 milliliter, stir.20 DEG C, in reaction flask, add triethylamine 12.36 grams, produce a large amount of white solid.20 DEG C are stirred filtration after 15 minutes.Solid 100 milliliters of tetrahydrofuran (THF)s wash, merging filtrate, pressure reducing and steaming tetrahydrofuran (THF).Obtain colourless transparent solution.In solution, add 2-oxyethyl group-1-[[2`-cyano-biphenyl base]-4-base] methyl isophthalic acid H-benzoglyoxaline-7-carboxylic acid, ethyl ester (code name C-5) 10 grams, be heated to 75 DEG C, stirring reaction 15 hours.
Reaction solution is down to room temperature, adds large water gaging, separates out solid, filters, obtains white solid 6 grams.Yield 55.7%.HPLC detects, product purity 55.7%, by-product impurities content 39.9%.
Embodiment 4:
C-5(10 gram is added in 250 milliliters of there-necked flasks), DMSO(150 milliliter) stir, add oxammonium hydrochloride (16 grams) and triethylamine (23.5 grams), obtain turbid liquid.Be warming up to 85-90 DEG C.Stirring reaction 22 hours.TLC detection reaction terminates, reactionless object point, but product point has two.
Cooling adds water, and ethyl acetate is extracted, and extracts after point water-yielding stratum by ethyl acetate.Merge ester layer dry.Evaporated under reduced pressure solvent, obtains light yellow solid 5 grams, yield 46%.HPLC detects, product purity 54.5%, by-product impurities content 38.9%.
Embodiment 5:
17 grams of oxammonium hydrochlorides add 10 milliliters, water, add triethylamine 25 grams, produce solid.Filter, 8 milliliters of washing solids.Merging filtrate obtains aqueous hydroxylamine.By C-5(10 gram), triethylamine 2.5 grams, aqueous hydroxylamine adds in 100 milliliters of ethanol.Be heated to reflux temperature about 80 DEG C, stirring and refluxing reacts 24 hours.
Be cooled to room temperature, filter to obtain white solid 10.7 grams, productive rate 100%.HPLC detects, product purity 40.7%, by-product impurities content 57.4%.
Embodiment 6:
By embodiment 5 products obtained therefrom by column chromatography for separation (eluent petroleum ether: ethyl acetate=3:1 volume ratio), obtain white solid 3.2 grams.It is 96.82% that HPLC detects purity.
HR-MS(m/z M+H
+):444.1921。
1HNMR(400MHz,DMSO-d
6)(δ,ppm),1.14-1.18(t,J=7.0Hz,3H),1.39-1.43(t,J=7.0Hz,3H),4.17-4.22(m,J=7.0Hz,2H),4.58-4.64(m,J1=7.0Hz,2H),5.53(s,2H),6.92-6.94(d,J=8.4Hz,2H),7.16-7.20(m,2H),7.26-7.32(m,3H),7.35-7.46(m,4H),7.59(s,2H),7.67-7.69(d,J=8.0Hz,1H)。
13CNMR(100MHz,DMSO-d
6)(δ,ppm),13.87(1C),14.35(1C),46.20(1C),61.00(1C),66.58(1C),115.88(1C),120.73(1C),121.42(1C),122.79(1C),125.92(2C),126.92(1C),127.42(1C),128.47(2C),129.0 7(1C),129.72(1C),130.76(1C),135.84(1C),137.23(1C),138.24(1C),139.37(1C),141.58(1C),158.25(2C),165.70(1C),170.94(1C)。
Embodiment 7:
C-5(30 gram is added in 500 milliliters of four-hole boiling flasks), ethanol 300 milliliters.Oxammonium hydrochloride 20 grams is dissolved in 45 ml waters, obtains the oxammonium hydrochloride aqueous solution and adds in reaction flask.Room temperature 20 DEG C is added dropwise to triethylamine 35 grams in white turbid liquid in reaction flask.20 minutes used times added, and were warming up to reflux temperature 80 DEG C.Back flow reaction 24 hours.
Be cooled to room temperature, add 400 milliliters, water in reaction solution, separate out a large amount of white solid.Filter, obtain off-white color solid 23 grams, yield 71.1%.HPLC detects, product purity 75.0%, by-product impurities content 15.5%.
Embodiment 8:
45 grams of oxammonium hydrochlorides are dissolved in 100 ml waters, and the aqueous solution is added to C-5(50 gram) 500 milliliters of ethanolic solns in, add sodium bicarbonate 70 grams.Be warming up to reflux temperature 80 DEG C, back flow reaction.Reaction, to reactionless object point in TLC detection reaction liquid, stops heating, altogether stirring reaction 36 hours.
Reaction solution is down to room temperature, adds 1.2 liters, water, stirring and crystallizing.Filter, obtain white solid 40.5 grams, yield 75.2%.HPLC detects, product purity 86.87%, by-product impurities content 9.35%.
Embodiment 9:
17 grams of oxammonium hydrochlorides are dissolved in 40 ml waters, and the aqueous solution is added to C-5(50 gram) 500 milliliters of ethanolic solns in, add sodium bicarbonate 25 grams.Be warming up to reflux temperature 80 DEG C, back flow reaction.Reaction, to reactionless object point in TLC detection reaction liquid, stops heating, altogether stirring reaction 50 hours.
Reaction solution is down to room temperature, adds 1.2 liters, water, stirring and crystallizing.Filter, obtain white solid 29 grams, yield 53.8%.HPLC detects, product purity 82.9%, by-product impurities content 3.1%, unreacted raw material (C-5) 8.33%.
Embodiment 10:
33 grams of oxammonium hydrochlorides are dissolved in 75 ml waters, and the aqueous solution is added to C-5(50 gram) 500 milliliters of ethanolic solns in, add sodium bicarbonate 50 grams.Oil bath is heated, and oil bath temperature is set as 90 DEG C, the backflow of reaction solution fierceness.Reaction, to reactionless object point in TLC detection reaction liquid, stops heating, altogether stirring reaction 30 hours.
Reaction solution is down to room temperature, adds 1.2 liters, water, stirring and crystallizing.Filter, obtain white solid 30 grams, yield 55.7%.HPLC detects, product purity 86.43%, by-product impurities content 8.15%.
Embodiment 11:
33 grams of oxammonium hydrochlorides are dissolved in 80 ml waters, and the aqueous solution is added to C-5(50 gram) 500 ml methanol solution in, add sodium bicarbonate 50 grams.Be warming up to reflux temperature 75 DEG C, back flow reaction.Reaction, to reactionless object point in TLC detection reaction liquid, stops heating, altogether stirring reaction 46 hours.
Reaction solution is down to room temperature, adds 1.2 liters, water, stirring and crystallizing.Filter, obtain white solid 41 grams, yield 76.1%.HPLC detects, product purity 91.4%, by-product impurities content 3.17%, unreacted raw material (C-5) 2.63%.
Embodiment 12:
33 grams of oxammonium hydrochlorides are dissolved in 75 ml waters, and the aqueous solution is added to C-5(50 gram) 500 milliliters of ethanolic solns in, add sodium bicarbonate 50 grams.Be warming up to 50 DEG C, react reactionless object point to TLC detection reaction liquid, stop heating, altogether stirring reaction 50 hours.
Reaction solution is down to room temperature, adds 1.2 liters, water, stirring and crystallizing.Filter, obtain white solid 30 grams, yield 55.7%.HPLC detects, product purity 86.43%, by-product impurities content 8.15%.
Embodiment 13:
32.7 grams of oxammonium hydrochlorides are dissolved in 75 ml waters, and the aqueous solution is added to C-5(50 gram) 500 milliliters of ethanolic solns in, add 41 grams, salt of wormwood.Be warming up to reflux temperature 80 DEG C, back flow reaction.Reaction, to reactionless object point in TLC detection reaction liquid, stops heating, altogether stirring reaction 34 hours.
Reaction solution is down to room temperature, adds 1.2 liters, water, stirring and crystallizing.Filter, obtain white solid 38.4 grams, yield 71.3%.HPLC detects, product purity 85.7%, by-product impurities content 9.1%.
Embodiment 14:
32.5 grams of oxammonium hydrochlorides are dissolved in 75 ml waters, and the aqueous solution is added to C-5(50 gram) 500 milliliters of ethanolic solns in, add 32 grams, sodium carbonate.Be warming up to reflux temperature 80 DEG C, back flow reaction.Reaction, to reactionless object point in TLC detection reaction liquid, stops heating, altogether stirring reaction 38 hours.
Reaction solution is down to room temperature, adds 1.2 liters, water, stirring and crystallizing.Filter, obtain white solid 42 grams, yield 77.9%.HPLC detects, product purity 89.8%, by-product impurities content 3.81%.
Embodiment 15:
28 grams of oxammonium hydrochlorides are dissolved in 80 ml waters, and the aqueous solution is added to C-5(50 gram) 500 milliliters of ethanolic solns in, add saleratus 52 grams.Be warming up to reflux temperature 80 DEG C, back flow reaction.Reaction, to reactionless object point in TLC detection reaction liquid, stops heating, altogether stirring reaction 45 hours.
Reaction solution is down to room temperature, adds 1.2 liters, water, stirring and crystallizing.Filter, obtain white solid 28.5 grams, yield 52.9%.HPLC detects, product purity 93.2%, by-product impurities content 3.78%.
Embodiment 16
C-5(14 kilogram is added in 200 liters of reactors), ethanol 110 kilograms, stirring at room temperature.Oxammonium hydrochloride 9.20 kilograms adds 22 kg water and dissolves, in sucting reaction still.Stir.Add anhydrous sodium bicarbonate 14.5 kilograms of solids.
Reactor is warming up to reflux temperature, keeps 80 DEG C of back flow reaction, TLC detection reaction terminal.Stirring reaction 40 hours.Reaction solution adds the dilution of 200 kilograms, water.Stirring and crystallizing.Centrifugal drying material, washes with water, dry.Obtain white solid 12.1 kilograms.Yield 80.7%.HPLC detects, product purity 97.30%, by-product impurities content 1.24%.
HR-MS(m/z M+H
+):459.2032.
1HNMR(400MHz,CDCl
3)(δ,ppm),1.24-1.27(t,J=7.2Hz,3H),1.45-1.49(t,J=7.2Hz,3H),4.20-4.25(q,J=7.2Hz,2H),4.63-4.68(q,J=7.2Hz,2H),5.64(s,2H),6.98-6.99(d,J=8.0Hz,2H),7.13-7.17(t,J=7.8Hz,1H),7.24-7.35(m,4H),7.39-7.41(t,J=7.6Hz,1H),7.51-7.54(m,2H),7.69-7.72(d,J=7.6Hz,1H)。
13CNMR(400MHz,DMSO-d
6)(δ,ppm),14.03(1C),14.49(1C),46.34(1C),61.22(1C),66.80(1C),116.04(1C),120.95(1C),121.57(1C),123.00(1C),126.04(2C),127.06(1C),128.66(2C),129.03(1C),129.95(1C),130.12(1C),130.85(1C),133.21(1C),135.67(1C),139.87(1C),141.65(1C),152.16(2C),158.40(1C),165.91(1C)。
Embodiment 17
C-5(14 kilogram is added in 200 liters of reactors), ethanol 110 kilograms, stirring at room temperature.Oxammonium hydrochloride 9.17 kilograms adds 21 kg water and dissolves, in sucting reaction still.Stir.Add anhydrous sodium bicarbonate 14 kilograms of solids.
Reactor is warming up to reflux temperature, keeps 80 DEG C of back flow reaction, TLC detection reaction terminal.Stirring reaction 40 hours.Reaction solution adds the dilution of 200 kilograms, water.Stirring and crystallizing.Centrifugal drying material, washes with water, dry.Obtain white solid 12.3 kilograms.Yield 82.0%.HPLC detects, product purity 97.52%, by-product impurities content 1.14%.
Embodiment 18
The preparation of Azilsartan
Product embodiment 15 obtained 12.3 kilograms is dissolved in methylene dichloride 90 kilograms, adds triethylamine 4.3 kilograms, slowly drips methylene dichloride 50 kilogram solution containing Vinyl chloroformate 3.6 kilograms under room temperature.Dropwise room temperature reaction 6 hours.With water double centner washing third-order reaction liquid.Dry after separating reaction solution, evaporated under reduced pressure solvent obtains white solid 10.2 kilograms.
Above-mentioned gained solid 10.2 kilograms is added in ethanol 36 kilograms and reflux 20 hours.Cooled and filtered obtains white solid 7.4 kilograms.Gained solid is dissolved in methyl alcohol 60 kilograms, adds 10% aqueous sodium hydroxide solution 22 kilograms, be heated to 75 DEG C of stirring reactions 1 hour.Add 1mol/L hydrochloric acid (about 36 kilograms) under stirring and adjust PH to 3.Filter, obtain white Azilsartan crude product 6.6 kilograms.HPLC detects normalization method purity 99.21%.Azilsartan crude product recrystallizing methanol is refined, and obtains Azilsartan 4.1 kilograms.HPLC detects normalization method purity 99.77%.
Claims (10)
1. the preparation method of 2-oxyethyl group-1-[[2`-(hydroxyl amidino groups)-xenyl]-4-base] methyl isophthalic acid H-benzoglyoxaline-7-carboxylic acid and ester thereof, it is characterized in that with 2-oxyethyl group-1-[[2`-cyano-biphenyl base]-4-base] methyl isophthalic acid H-benzoglyoxaline-7-carboxylic acid and ester (I) thereof for raw material, under weak base reagent exists, compound ii is obtained with oxammonium hydrochloride reactant aqueous solution
Wherein R is H, C
1-C
4alkyl, phenmethyl, diphenyl-methyl, trityl.
2. the weak base reagent described in claim 1 is carbonate and supercarbonate.
3. the weak base reagent described in claim 2 is sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus.
4. the preferred sodium bicarbonate of the weak base reagent according to any one of claims 1 to 3.
5. the sodium bicarbonate described in claim 4 is in the reaction conditions of claim 1, and the mol ratio of sodium bicarbonate and chemical compounds I is 2-8; The mol ratio of sodium bicarbonate and oxammonium hydrochloride is 1.1-1.5.
6. sodium bicarbonate described in claim 5 is in the reaction conditions of claim 1, and the mol ratio of sodium bicarbonate and chemical compounds I is 4-6; The mol ratio of sodium bicarbonate and oxammonium hydrochloride is 1.2-1.3.
7. be reaction solvent with alcohol in claim 1, wherein alcohol is methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, particular methanol, ethanol.
8. the aqueous solution weight concentration of oxammonium hydrochloride described in claim 1 is 40-45%.
9. react described in claim 1, its temperature of reaction is 50-100 DEG C.
10. described in claim 9, temperature of reaction is preferably 75-85 DEG C.
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| CN105712984A (en) * | 2016-03-04 | 2016-06-29 | 江苏正大清江制药有限公司 | Preparation method of Azilsartan |
| WO2018008219A1 (en) * | 2016-07-05 | 2018-01-11 | 株式会社トクヤマ | Azilsartan intermediate, azilsartan, method for producing azilsartan intermediate, and method for producing azilsartan |
| JP2018008889A (en) * | 2016-07-13 | 2018-01-18 | 株式会社トクヤマ | Method for producing azilsartan alkyl ester, and method for producing azilsartan |
| 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 |
| JP2018076258A (en) * | 2016-11-09 | 2018-05-17 | 株式会社トクヤマ | Azilsartan alkyl ester, method for producing azilsartan methyl ester, and method for producing azilsartan |
| JP2018087178A (en) * | 2016-11-30 | 2018-06-07 | 株式会社トクヤマ | Method for producing azilsartan |
| JP2021059607A (en) * | 2021-01-21 | 2021-04-15 | 株式会社トクヤマ | Azilsartan alkyl ester, method for producing azilsartan methyl ester, and method for producing azilsartan |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105712984A (en) * | 2016-03-04 | 2016-06-29 | 江苏正大清江制药有限公司 | Preparation method of Azilsartan |
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| JP2018008889A (en) * | 2016-07-13 | 2018-01-18 | 株式会社トクヤマ | Method for producing azilsartan alkyl ester, and method for producing azilsartan |
| JP2018076258A (en) * | 2016-11-09 | 2018-05-17 | 株式会社トクヤマ | Azilsartan alkyl ester, method for producing azilsartan methyl ester, and method for producing azilsartan |
| JP2018087178A (en) * | 2016-11-30 | 2018-06-07 | 株式会社トクヤマ | Method for producing azilsartan |
| 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 |
| JP2021059607A (en) * | 2021-01-21 | 2021-04-15 | 株式会社トクヤマ | Azilsartan alkyl ester, method for producing azilsartan methyl ester, and method for producing azilsartan |
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