CN102344415B - The preparation method of Azilsartan intermediate - Google Patents
The preparation method of Azilsartan intermediate Download PDFInfo
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- CN102344415B CN102344415B CN201010245420.8A CN201010245420A CN102344415B CN 102344415 B CN102344415 B CN 102344415B CN 201010245420 A CN201010245420 A CN 201010245420A CN 102344415 B CN102344415 B CN 102344415B
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Abstract
The present invention relates to preparation method's technical field of Azilsartan intermediate.Compound 1-[(2 '-cyanobiphenyl-4-base) methyl]-2-ethoxybenzoimidazole-7-carboxylate methyl ester and aqueous hydroxylamine react by the preparation method of Azilsartan intermediate of the present invention.Preparation method of the present invention greatly reduces the amide impurities suitable with product amount produced in prior art, improves yield; Reaction times also still had a small amount of raw material unreacted to react completely by 24 hours completely from original 48 hours, improve efficiency; Aftertreatment does not need acid to carry the free tedious steps of alkali, and reaction terminates rear cooling and directly can separate out target product.
Description
Technical field
The present invention relates to preparation method's technical field of intermediate 2-oxyethyl group-1-[(((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-base) the methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester of Azilsartan.
Background technology
Azilsartan is a kind of selectivity angiotensin II receptor antagonists, has hypotensive effect and nervus centralis effect.The preparation of Azilsartan and therepic use, be described in the specification sheets of Chinese patent CN92105152.The synthesis of Azilsartan is described in above-mentioned patent specification, wherein following formula (I) compound, namely 2-oxyethyl group-1-[(((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-base) methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester is the important intermediate of synthesis Azilsartan.
The method of preparation formula (I) compound is described in publication J.Med.Chem, 1996, Vo39 (26), in 5528-5235, is also documented in the specification sheets of Chinese patent CN92105152 simultaneously.Method disclosed in J.Med.Chem is by following formula (II) compound, namely 1-[(2 '-cyanobiphenyl-4-base) methyl]-2-ethoxybenzoimidazole-7-carboxylate methyl ester is under oxammonium hydrochloride and triethylamine effect, obtained formula (I) compound of reaction in methyl-sulphoxide.But, not only long reaction time with this understanding, and can produce and the formula of target product a great deal of (III) compound and other impurity, cause actual recovery very low, aftertreatment is not easily.In Chinese patent CN92105152 be oxammonium hydrochloride and 28% sodium methylate effect under react in methyl-sulphoxide, same produce the amide impurities with target product a great deal of.Although document yield can reach 90%, reality obviously cannot be accomplished, yield is very low.
Consider the market outlook of Azilsartan, it is necessary for improving the preparation method of its important intermediate formula (I) compound.
Summary of the invention
Object of the present invention is exactly the above-mentioned defect overcoming prior art, provides a kind of easier and method of preparation formula (I) compound that yield is higher.
The present invention is in the process of Research-type (I) compounds process for production thereof, find that directly replacing oxammonium hydrochloride and formula (II) compound to react with aqueous hydroxylamine just can obtain formula (I) compound easily, and we are surprised to find the amide impurities suitable with product amount that the method can also avoid disclosed method generation in patent CN92105152! Yield is greatly improved, and aftertreatment is also simple.
The technical scheme that the present invention takes is as follows:
The preparation method of 2-oxyethyl group-1-[(((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-base) methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester, the method is reacted at formula (II) compound 1-[(2 '-cyanobiphenyl-4-base) methyl]-2-ethoxybenzoimidazole-7-carboxylate methyl ester and aqueous hydroxylamine, and cooling crystallization obtains target product.
The preparation method of above-mentioned 2-oxyethyl group-1-[(((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-base) methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester, can also add alkali.Alkali used comprises triethylamine, diisopropylethylamine, diethylamine, Trimethylamine 99, pyridine, the organic basess such as piperidines, preferred triethylamine.When using triethylamine, every mole of formula (II) compound preferably uses the triethylamine of catalytic amount, the most preferably triethylamine of 1 mole.
Reaction of the present invention is carried out in organic solvent, and selected organic solvent comprises ethanol, methyl alcohol and Virahol, and preferred organic solvent is ethanol.
The preparation method of above-mentioned 2-oxyethyl group-1-[(((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-base) methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester, preferred mass concentration is the aqueous hydroxylamine of 20%-70%.Every mole of formula (II) compound preferably uses the azanol of 5-15 mole, most preferably uses 10 moles.
Temperature of reaction be room temperature to reflux temperature, preferable temperature is reflux temperature.
Beneficial effect of the present invention:
Preparation method of the present invention greatly reduces the amide impurities suitable with product amount produced in prior art, improves yield; Reaction times also still had a small amount of raw material unreacted to react completely by 24 hours completely from original 48 hours, improve efficiency; Aftertreatment does not need acid to carry the free tedious steps of alkali, and reaction terminates rear cooling and directly can separate out target product.
Embodiment
Embodiment 1
1-[(2 '-cyanobiphenyl-4-base) methyl]-2-ethoxybenzoimidazole-7-carboxylate methyl ester (0.4g, 0.97mmol), 50% aqueous hydroxylamine (0.33g, 4.9mmol), triethylamine (0.1g, 0.97mmol) is backflow 48h in ethanol (10ml), cooling crystallization, filtration obtains title compound 0.2g, yield 46.3%.Reaction solution liquid data display after reaction 48h, amide impurities: product (chromatograms area ratio): raw material=37.37: 54.52: 0.42.
Embodiment 2
1-[(2 '-cyanobiphenyl-4-base) methyl]-2-ethoxybenzoimidazole-7-carboxylate methyl ester (2g, 4.9mmol), 50% aqueous hydroxylamine (3.43g, 49mmol), triethylamine (0.5g, 4.9mmol) is backflow 24h in ethanol (20ml), cooling crystallization, filtration obtains title compound 1.52g, yield 70.4%.Reaction solution liquid data display after reaction 24h, amide impurities: product (chromatograms area ratio): raw material=5.04: 79.66: 0.
Embodiment 3
1-[(2 '-cyanobiphenyl-4-base) methyl]-2-ethoxybenzoimidazole-7-carboxylate methyl ester (0.4g, 0.97mmol), 50% aqueous hydroxylamine (1.0g, 14.5mmol), triethylamine (0.1g, 0.97mmol) is backflow 20h in ethanol (10ml), cooling crystallization, filtration obtains title compound 0.31g, yield 71.7%.Reaction solution liquid data display after reaction 20h, amide impurities: product (chromatograms area ratio): raw material=7.17: 78.2: 0.
Embodiment 4
1-[(2 '-cyanobiphenyl-4-base) methyl]-2-ethoxybenzoimidazole-7-carboxylate methyl ester (0.4g, 0.97mmol), 50% aqueous hydroxylamine (0.66g, 9.7mmol), triethylamine (0.1g, 0.97mmol) is backflow 40h in methyl alcohol (10ml), cooling crystallization, filtration obtains title compound 0.19g, yield 44%.Reaction solution liquid data display after reaction 40h, amide impurities: product (chromatograms area ratio): raw material=15.60: 54.28: 0.
Embodiment 5
1-[(2 '-cyanobiphenyl-4-base) methyl]-2-ethoxybenzoimidazole-7-carboxylate methyl ester (0.4g, 0.97mmol), 50% aqueous hydroxylamine (0.66g, 9.7mmol), triethylamine (0.1g, 0.97mmol) is backflow 24h in Virahol (10ml), cooling crystallization, filtration obtains title compound 0.25g, yield 57.8%.Reaction solution liquid data display after reaction 24h, amide impurities: product (chromatograms area ratio): raw material=25.62: 67.43: 0.25.
Embodiment 6
1-[(2 '-cyanobiphenyl-4-base) methyl]-2-ethoxybenzoimidazole-7-carboxylate methyl ester (0.4g, 0.97mmol), 50% aqueous hydroxylamine (0.66g, 9.7mmol) backflow 24h in ethanol (10ml), cooling crystallization, filtration obtains title compound 0.28g, yield 64.7%.Solution reaction liquid liquid data display after reaction 24h, amide impurities: product (chromatograms area ratio): raw material=17.71: 74.09: 0.
Embodiment 7
1-[(2 '-cyanobiphenyl-4-base) methyl]-2-ethoxybenzoimidazole-7-carboxylate methyl ester (0.4g, 0.97mmol), 50% aqueous hydroxylamine (0.66g, 9.7mmol), triethylamine (0.2g, 1.9mmol) is backflow 24h in Virahol (10ml), cooling crystallization, filtration obtains title compound 0.22g, yield 50.9%.Reaction solution liquid data display after reaction 24h, amide impurities: product (chromatograms area ratio): raw material=29.30: 58.65: 0.
Contrast experiment's example 1
Under room temperature, while stirring toward oxammonium hydrochloride (0.34g, NaOMe (the 0.26g of 28% is added in DMSO 4.9mmol), methyl alcohol (1ml) solution 4.9mmol), 1-[(2 '-cyanobiphenyl-4-base) methyl]-2-ethoxybenzoimidazole-7-carboxylate methyl ester (0.4g is added after 10 minutes, 0.97mmol), stir 4 hours at 90 DEG C.Reaction solution liquid data display after reaction 4h, amide impurities: product (chromatograms area ratio): raw material=26.59: 21.33: 48.96.
Contrast experiment's example 2
According to the method in J.Med.Chem, toward oxammonium hydrochloride (0.34g, triethylamine (0.5g is added in DMSO 4.9mmol), 4.9mmol), elimination insolubles is also washed with tetrahydrofuran (THF), and filtrate decompression is steamed except tetrahydrofuran (THF), adds 1-[(2 '-cyanobiphenyl-4-base) methyl]-2-ethoxybenzoimidazole-7-carboxylate methyl ester (0.4g, 0.97mmol), stir 15 hours at 75 DEG C.Reaction solution liquid data display after reaction 15h, amide impurities: product (chromatograms area ratio): raw material=24.22: 15.08: 58.29.Reaction solution liquid data display after reaction 60h, amide impurities: product (chromatograms area ratio): raw material=32.02: 33.95: 4.08.
Claims (4)
- The preparation method of 1.2-oxyethyl group-1-[(((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-base) methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester, the method is reacted under organic bases condition at compound 1-[(2 '-cyanobiphenyl-4-base) methyl]-2-ethoxybenzoimidazole-7-carboxylate methyl ester and aqueous hydroxylamine, the mass concentration of described aqueous hydroxylamine is 20%-70%, in aqueous hydroxylamine, azanol consumption is 5-15 times of 1-[(2 '-cyanobiphenyl-4-base) methyl]-2-ethoxybenzoimidazole-7-carboxylate methyl ester molar weight, described organic bases is triethylamine, described reaction is carried out in organic solvent ethanol, methyl alcohol or Virahol.
- 2. the preparation method of 2-oxyethyl group-1-[(((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-base) methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester as claimed in claim 1, is characterized in that: the solvent that reaction uses is ethanol.
- 3. the preparation method of 2-oxyethyl group-1-[(((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-base) methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester as claimed in claim 1, is characterized in that: in aqueous hydroxylamine, azanol consumption is 10 times of 1-[(2 '-cyanobiphenyl-4-base) methyl]-2-ethoxybenzoimidazole-7-carboxylate methyl ester molar weight.
- 4. the preparation method of 2-oxyethyl group-1-[(((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-base) methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester as claimed in claim 1, is characterized in that: the consumption of triethylamine is the equimolar amount of 1-[(2 '-cyanobiphenyl-4-base) methyl]-2-ethoxybenzoimidazole-7-carboxylate methyl ester.
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| CN102344415B true CN102344415B (en) | 2016-04-13 |
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Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ306650B6 (en) * | 2011-03-04 | 2017-04-19 | Zentiva, K.S. | A method of manufacturing of 2-ethoxy-1-((2'-((hydroxyamino)iminomethyl) biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylic acid and its esters, key intermediates of azilsartan synthesis |
| CN102731408A (en) * | 2012-07-20 | 2012-10-17 | 江苏先声药物研究有限公司 | Azilsartan intermediate and preparation method thereof |
| CN103664920B (en) * | 2012-09-24 | 2016-03-09 | 上海医药工业研究院 | Azilsartan intermediate and the preparation method with Azilsartan thereof |
| CN103664792B (en) * | 2012-09-24 | 2016-03-30 | 上海医药工业研究院 | Azilsartan intermediate and preparation method thereof |
| CN104072491A (en) * | 2013-03-29 | 2014-10-01 | 天津药物研究院 | Azilsartan derivative compound and preparation method and application thereof |
| CN104418807A (en) * | 2013-09-09 | 2015-03-18 | 天津药物研究院 | Preparation method of 2-ethoxyl-1-[[2'-(hydroxyl amidino)-biphenylyl]-4-yl]methyl-1H-benzimidazole-7-carboxylic acid and ester derivatives thereof |
| CN103601723B (en) * | 2013-11-19 | 2016-04-27 | 合肥远志医药科技开发有限公司 | A kind of industrialized preparing process of Azilsartan |
| JP6676487B2 (en) * | 2016-07-05 | 2020-04-08 | 株式会社トクヤマ | Method for producing amidoxime compound as intermediate of azilsartan, and method for producing 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 |
| 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 |
| CN108358849A (en) * | 2018-03-22 | 2018-08-03 | 成都诺维尔生物医药有限公司 | A kind of synthetic method of Azilsartan process contaminants D |
| CN110746415A (en) * | 2019-11-18 | 2020-02-04 | 南京恒通医药开发有限公司 | Synthesis process for continuously preparing azilsartan under microchannel reactor |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1079966A (en) * | 1991-06-27 | 1993-12-29 | 武田药品工业株式会社 | Heterogeneous ring compound, its preparation and application |
| US5583141A (en) * | 1991-06-27 | 1996-12-10 | Takeda Chemical Industries, Ltd. | Heterocyclic compounds and their use as angiotensin antagonists |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1079966A (en) * | 1991-06-27 | 1993-12-29 | 武田药品工业株式会社 | Heterogeneous ring compound, its preparation and application |
| US5583141A (en) * | 1991-06-27 | 1996-12-10 | Takeda Chemical Industries, Ltd. | Heterocyclic compounds and their use as angiotensin antagonists |
Non-Patent Citations (1)
| Title |
|---|
| 5-氧代-1,2,4-噁二唑化合物的合成工艺改进;王建国等;《中国医药工业杂志》;20041231;第35卷(第11期);第646-647页 * |
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