CN102344415A - Preparation method of azilsartan intermediate - Google Patents
Preparation method of azilsartan intermediate Download PDFInfo
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- CN102344415A CN102344415A CN2010102454208A CN201010245420A CN102344415A CN 102344415 A CN102344415 A CN 102344415A CN 2010102454208 A CN2010102454208 A CN 2010102454208A CN 201010245420 A CN201010245420 A CN 201010245420A CN 102344415 A CN102344415 A CN 102344415A
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- oxyethyl group
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- OQJREYQHKLULTR-UHFFFAOYSA-N CCOc1nc2cccc(C(OC)=O)c2[n]1Cc(cc1)ccc1-c(cccc1)c1/C(/N)=N/O Chemical compound CCOc1nc2cccc(C(OC)=O)c2[n]1Cc(cc1)ccc1-c(cccc1)c1/C(/N)=N/O OQJREYQHKLULTR-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to the technical field of azilsartan intermediate preparation method. According to the invention, a compound 1-[(2'-cyanobiphenyl-4-group)methyl]-2-ethoxy benzimidazole-7-methyl carboxylate is subject to a reaction with an aqueous solution of hydroxylamine, such that the intermediate is prepared. In prior arts, amide impurities with an amount equal to that of the products are generated. With the method provided by the invention, the impurities are greatly reduced, such that the yield is increased. In prior arts, the reaction time is 48 hours, and yet a small amount of raw materials is not reacted. With the method provided by the invention, the reaction time is 24 hours, and the reaction is sufficiently carried out, such that the efficiency is improved. In a post-processing process, complicated steps of acid extraction and alkali ionization are not required. When the reaction id finished, the materials are cooled, and the target product can be precipitated directly.
Description
Technical field
The present invention relates to husky smooth intermediate 2-oxyethyl group-1-[(((2 '-hydroxyl ammonia auxotox radical) the xenyl)-4-yl) methyl of Archie]-preparing method's technical field of 1H-benzoglyoxaline-7-carboxylate methyl ester.
Background technology
Archie sand is smooth to be a kind of selectivity angiotensin II receptor antagonists, has hypotensive effect and nervus centralis effect.Archie husky smooth preparation and therepic use are described in the specification sheets of Chinese patent CN92105152.Husky smooth the synthesizing of Archie described in above-mentioned patent specification; Wherein following formula (I) compound, i.e. 2-oxyethyl group-1-[(((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-yl) methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester is the husky smooth important intermediate of synthetic Archie.
The method for preparing formula (I) compound is described in publication J.Med.Chem, and 1996, Vo39 (26) among the 5528-5235, also is documented in the specification sheets of Chinese patent CN92105152 simultaneously.Disclosed method is with following formula (II) compound among the J.Med.Chem, i.e. 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester is under oxammonium hydrochloride and triethylamine effect, and reaction makes formula (I) compound in methyl-sulphoxide.Yet, long reaction time not only with this understanding, and can produce formula (III) compound and other impurity with the target product a great deal of, cause actual recovery very low, aftertreatment is difficult for.Be under the sodium methylate effect of oxammonium hydrochloride and 28%, in methyl-sulphoxide, to react among the Chinese patent CN92105152, the amide impurities of same generation and target product a great deal of.Though the document yield can reach 90%, reality can't accomplish that obviously yield is very low.
Consider the husky smooth market outlook of Archie, it is necessary that the preparation method of its important intermediate formula (I) compound is improved.
Summary of the invention
The object of the invention is exactly the above-mentioned defective that overcomes prior art, and a kind of easier and method for preparing formula (I) compound that yield is higher is provided.
The present invention is in the process of research formula (I) compounds process for production thereof; Find directly to replace oxammonium hydrochloride and the reaction of formula (II) compound just can make formula (I) compound easily, and we are surprised to find the amide impurities suitable with the product amount that this method can also be avoided disclosed method generation among the patent CN92105152 with aqueous hydroxylamine! Yield is greatly improved, and aftertreatment is also simple.
The technical scheme that the present invention takes is following:
2-oxyethyl group-1-[(((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-yl) methyl]-preparation method of 1H-benzoglyoxaline-7-carboxylate methyl ester; This method is with formula (II) compound 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester and aqueous hydroxylamine reaction, cooling crystallization gets target product.
Above-mentioned 2-oxyethyl group-1-[(((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-yl) methyl]-preparation method of 1H-benzoglyoxaline-7-carboxylate methyl ester, can also add alkali.Used alkali comprises triethylamine, diisopropylethylamine, diethylamine, Trimethylamine 99, pyridine, organic basess such as piperidines, preferred triethylamine.When using triethylamine, every mole of formula (II) compound preferably uses the triethylamine of catalytic amount, most preferably 1 mole triethylamine.
Of the present invention being reflected in the organic solvent carried out, and selected organic solvent comprises ethanol, methyl alcohol and Virahol, and preferred organic is an ethanol.
Above-mentioned 2-oxyethyl group-1-[(((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-yl) methyl]-preparation method of 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, preferred temperature is a reflux temperature.
Beneficial effect of the present invention:
Preparing method of the present invention has significantly reduced the amide impurities suitable with the product amount that produces in the prior art, has improved yield; Reaction times also still had the small number of materials unreacted to react completely by 24 hours fully from original 48 hours, had improved efficient; Aftertreatment does not need acid to put forward the loaded down with trivial details step of alkali free, and reaction finishes postcooling can directly separate out target product.
Embodiment
Embodiment 1
1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (0.4g; 0.97mmol); 50% aqueous hydroxylamine (0.33g; 4.9mmol); Triethylamine (0.1g, 0.97mmol) backflow 48h in ethanol (10ml), cooling crystallization; Filtration obtains title compound 0.2g, yield 46.3%.Reaction 48h afterreaction liquid liquid phase data presentation, amide impurities: product (liquid phase figure area under spectrum ratio): raw material=37.37: 54.52: 0.42.
Embodiment 2
1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (2g; 4.9mmol); 50% aqueous hydroxylamine (3.43g; 49mmol); Triethylamine (0.5g, 4.9mmol) backflow 24h in ethanol (20ml), cooling crystallization; Filtration obtains title compound 1.52g, yield 70.4%.Reaction 24h afterreaction liquid liquid phase data presentation, amide impurities: product (liquid phase figure area under spectrum ratio): raw material=5.04: 79.66: 0.
Embodiment 3
1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (0.4g; 0.97mmol); 50% aqueous hydroxylamine (1.0g; 14.5mmol); Triethylamine (0.1g, 0.97mmol) backflow 20h in ethanol (10ml), cooling crystallization; Filtration obtains title compound 0.31g, yield 71.7%.Reaction 20h afterreaction liquid liquid phase data presentation, amide impurities: product (liquid phase figure area under spectrum ratio): raw material=7.17: 78.2: 0.
Embodiment 4
1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (0.4g; 0.97mmol); 50% aqueous hydroxylamine (0.66g; 9.7mmol); Triethylamine (0.1g, 0.97mmol) backflow 40h in methyl alcohol (10ml), cooling crystallization; Filtration obtains title compound 0.19g, yield 44%.Reaction 40h afterreaction liquid liquid phase data presentation, amide impurities: product (liquid phase figure area under spectrum ratio): raw material=15.60: 54.28: 0.
Embodiment 5
1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (0.4g; 0.97mmol); 50% aqueous hydroxylamine (0.66g; 9.7mmol); Triethylamine (0.1g, 0.97mmol) backflow 24h in Virahol (10ml), cooling crystallization; Filtration obtains title compound 0.25g, yield 57.8%.Reaction 24h afterreaction liquid liquid phase data presentation, amide impurities: product (liquid phase figure area under spectrum ratio): raw material=25.62: 67.43: 0.25.
Embodiment 6
1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (0.4g, 0.97mmol), 50% aqueous hydroxylamine (0.66g; 9.7mmol) backflow 24h in ethanol (10ml); Cooling crystallization filters and obtains title compound 0.28g, yield 64.7%.Solution reaction liquid liquid phase data presentation behind the reaction 24h, amide impurities: product (liquid phase figure area under spectrum ratio): raw material=17.71: 74.09: 0.
Embodiment 7
1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (0.4g; 0.97mmol); 50% aqueous hydroxylamine (0.66g; 9.7mmol); Triethylamine (0.2g, 1.9mmol) backflow 24h in Virahol (10ml), cooling crystallization; Filtration obtains title compound 0.22g, yield 50.9%.Reaction 24h afterreaction liquid liquid phase data presentation, amide impurities: product (liquid phase figure area under spectrum ratio): raw material=29.30: 58.65: 0.
Contrast experiment's example 1
Under the room temperature; While stirring toward oxammonium hydrochloride (0.34g; 4.9mmol) DMSO in add 28% NaOMe (0.26g; 4.9mmol) methyl alcohol (1ml) solution; Add 1-[(2 '-cyanobiphenyl-4-yl) methyl after 10 minutes]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (0.4g; 0.97mmol), stirred 4 hours down in 90 ℃.Reaction 4h afterreaction liquid liquid phase data presentation, amide impurities: product (liquid phase figure area under spectrum ratio): raw material=26.59: 21.33: 48.96.
Contrast experiment's example 2
According to the method among the J.Med.Chem; Toward oxammonium hydrochloride (0.34g; 4.9mmol) DMSO in add triethylamine (0.5g; 4.9mmol); The elimination insolubles is also washed with tetrahydrofuran (THF), and filtrate decompression is steamed and removed tetrahydrofuran (THF), adds 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester (0.4g; 0.97mmol), stirred 15 hours down in 75 ℃.Reaction 15h afterreaction liquid liquid phase data presentation, amide impurities: product (liquid phase figure area under spectrum ratio): raw material=24.22: 15.08: 58.29.Reaction 60h afterreaction liquid liquid phase data presentation, amide impurities: product (liquid phase figure area under spectrum ratio): raw material=32.02: 33.95: 4.08.
Claims (10)
1.2-oxyethyl group-1-[(((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-yl) methyl]-preparation method of 1H-benzoglyoxaline-7-carboxylate methyl ester, this method is with compound 1-[(2 '-cyanobiphenyl-4-yl) methyl]-2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester and aqueous hydroxylamine reaction.
2. 2-oxyethyl group-1-[as claimed in claim 1 (((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-yl) methyl]-preparation method of 1H-benzoglyoxaline-7-carboxylate methyl ester, it is characterized in that: add organic bases during reaction.
3. 2-oxyethyl group-1-[as claimed in claim 2 (((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-yl) methyl]-preparation method of 1H-benzoglyoxaline-7-carboxylate methyl ester, it is characterized in that: said organic bases is a triethylamine, diisopropylethylamine; Diethylamine; Trimethylamine 99, pyridine, piperidines.
4. 2-oxyethyl group-1-[as claimed in claim 1 (((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-yl) methyl]-preparation method of 1H-benzoglyoxaline-7-carboxylate methyl ester, it is characterized in that: be reflected in organic solvent ethanol, methyl alcohol or the Virahol and carry out.
5. 2-oxyethyl group-1-[as claimed in claim 4 (((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-yl) methyl]-preparation method of 1H-benzoglyoxaline-7-carboxylate methyl ester, it is characterized in that: the solvent that reaction is used is ethanol.
6. 2-oxyethyl group-1-[as claimed in claim 1 (((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-yl) methyl]-preparation method of 1H-benzoglyoxaline-7-carboxylate methyl ester, it is characterized in that: the mass concentration of aqueous hydroxylamine is 20%-70%.
7. 2-oxyethyl group-1-[as claimed in claim 1 (((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-yl) methyl]-preparation method of 1H-benzoglyoxaline-7-carboxylate methyl ester, it is characterized in that: the azanol consumption is 1-[(a 2 ' cyanobiphenyl-4-yl) methyl in the aqueous hydroxylamine]-5-15 of 2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester molar weight is doubly.
8. 2-oxyethyl group-1-[as claimed in claim 7 (((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-yl) methyl]-preparation method of 1H-benzoglyoxaline-7-carboxylate methyl ester, it is characterized in that: the azanol consumption is 1-[(2 '-cyanobiphenyl-4-yl) methyl in the aqueous hydroxylamine]-10 times of 2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester molar weight.
9. 2-oxyethyl group-1-[as claimed in claim 3 (((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-yl) methyl]-preparation method of 1H-benzoglyoxaline-7-carboxylate methyl ester, it is characterized in that: said organic bases is a triethylamine.
10. 2-oxyethyl group-1-[as claimed in claim 9 (((2 '-hydroxyl ammonia auxotox radical) xenyl)-4-yl) methyl]-preparation method of 1H-benzoglyoxaline-7-carboxylate methyl ester, it is characterized in that: the consumption of triethylamine is 1-[(2 '-cyanobiphenyl-4-yl) methyl]-equimolar amount of 2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester.
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012119573A1 (en) * | 2011-03-04 | 2012-09-13 | Zentiva, K.S. | A method of manufacturing 2-ethoxy-1-((2'-((hydroxyamino) iminomethyl)biphenyl-4- yl)methyl)-1h-benzo [d] imidazole-7-carboxylic acid and its esters |
| 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 |
| CN103601723A (en) * | 2013-11-19 | 2014-02-26 | 合肥远志医药科技开发有限公司 | Industrial production method of azilsartan |
| CN103664792A (en) * | 2012-09-24 | 2014-03-26 | 上海医药工业研究院 | Azilsartan intermediate and preparation method thereof |
| CN103664920A (en) * | 2012-09-24 | 2014-03-26 | 上海医药工业研究院 | Preparation method of azilsartan intermediate and azilsartan |
| 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 |
| JP2018002672A (en) * | 2016-07-05 | 2018-01-11 | 株式会社トクヤマ | Manufacturing method of amidoxime compound which become intermediate of azilsartan, and manufacturing 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 |
| 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 |
| CN108456202A (en) * | 2017-12-15 | 2018-08-28 | 江苏联环药业股份有限公司 | A kind of Azilsartan preparation method of low amide impurities content |
| 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 |
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Cited By (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012119573A1 (en) * | 2011-03-04 | 2012-09-13 | Zentiva, K.S. | A method of manufacturing 2-ethoxy-1-((2'-((hydroxyamino) iminomethyl)biphenyl-4- yl)methyl)-1h-benzo [d] imidazole-7-carboxylic acid and its esters |
| CN103476758A (en) * | 2011-03-04 | 2013-12-25 | 赞蒂瓦有限合伙公司 | A method of manufacturing 2-ethoxy-1-((2'-((hydroxyamino) iminomethyl)biphenyl-4- yl)methyl)-1h-benzo [d] imidazole-7-carboxylic acid and its esters |
| KR20140008371A (en) * | 2011-03-04 | 2014-01-21 | 젠티바, 케이.에스. | A method of manufacturing 2-ethoxy-1-((2'-hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)-1h-benzo[d]imidazole-7-carboxylic acid and its esters |
| CN103476758B (en) * | 2011-03-04 | 2016-06-08 | 赞蒂瓦有限合伙公司 | One prepares the method for 2-ethyoxyl-1-((2 '-((hydroxylamino) iminomethyl) xenyl-4-base) methyl)-1H-benzo [d] imidazoles-7-carboxylic acid and ester thereof |
| EA023029B1 (en) * | 2011-03-04 | 2016-04-29 | Зентива К.С. | METHOD OF MANUFACTURING 2-ETHOXY-1-((2'-((HYDROXYAMINO)IMINOMETHYL)BIPHENYL-4-YL)METHYL)-1H-BENZO[d]IMIDAZOLE-7-CARBOXYLIC ACID AND ITS ESTERS |
| 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 |
| CN103664792B (en) * | 2012-09-24 | 2016-03-30 | 上海医药工业研究院 | Azilsartan intermediate and preparation method thereof |
| CN103664792A (en) * | 2012-09-24 | 2014-03-26 | 上海医药工业研究院 | 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 |
| CN103664920A (en) * | 2012-09-24 | 2014-03-26 | 上海医药工业研究院 | Preparation method of azilsartan intermediate and azilsartan |
| 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 |
| CN103601723A (en) * | 2013-11-19 | 2014-02-26 | 合肥远志医药科技开发有限公司 | Industrial production method of azilsartan |
| 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 |
| JP2018002672A (en) * | 2016-07-05 | 2018-01-11 | 株式会社トクヤマ | Manufacturing method of amidoxime compound which become intermediate of azilsartan, and manufacturing 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 |
| CN108456202A (en) * | 2017-12-15 | 2018-08-28 | 江苏联环药业股份有限公司 | A kind of Azilsartan preparation method of low amide impurities content |
| 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 |
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