CN103709155A - Preparation method of azilsartan - Google Patents
Preparation method of azilsartan Download PDFInfo
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- CN103709155A CN103709155A CN201310744903.6A CN201310744903A CN103709155A CN 103709155 A CN103709155 A CN 103709155A CN 201310744903 A CN201310744903 A CN 201310744903A CN 103709155 A CN103709155 A CN 103709155A
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- azilsartan
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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Abstract
The invention discloses a preparation method of azilsartan. The preparation method comprises the steps of enabling azilsartan nitrile to react with hydroxylamine hydrochloride and triethylamine in dimethylsulfoxide solution to obtain hydroxy oxime, and further processing the hydroxy oxime to obtain the azilsartan; the preparation method is characterized in that the hydroxy oxime reacts with strong alkali aqueous solution, methyl ester is hydrolyzed to obtain water-soluble carboxylate; then carbonyl ring-closing reagent is added dropwise to obtain an oxo oxadiazole ring, and the pH value is adjusted to be acidity, therefore, the target product (azilsartan) is obtained. The azilsartan is obtained through two-step reaction. The method overcomes the defects of the prior art, and has the characteristics of short route, low cost, less solvent dosage and high atom economy.
Description
Technical field
The invention belongs to the preparation field for the treatment of hypertension drug, specifically refer to a kind of chemical synthesis process of Azilsartan.
Technical background
Azilsartan (Azilsartan), commodity are called Azilva, i.e. 2-oxyethyl group-1-{[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazoles-3-yl) biphenyl-4-yl] methyl }-1H-benzo [d] imidazoles-7-carboxylic acid, structural formula is as follows:
It is the AT1 subtype angiotensin II receptor antagonist (ARB) by the exploitation of the military field of Japan (Takeda) company, on January 18th, 2012, goes through in Japan's listing, and the listing license of the U.S. now having obtained and European Union's listing.Azilsartan is as dual-use function ARBs of new generation, and not only 1 receptor of antagonizing vessel Angiotensin Converting Enzyme II (AT1 acceptor), also may reduce by number of mechanisms the risk of cardiovascular disorder and diabetes.Clinical trial proves, Azilsartan has good therapeutic effect, and adverse reaction rate is lower, the good feature of compliance.
1996, first the preparation process of Azilsartan is disclosed in patent (US5583141 and EP0520423), 1-((2'-cyanobiphenyl-4-yl) methyl)-2-oxyethyl group-1H-benzo [d] imidazoles-7-carboxylate methyl ester of take is starting raw material, generate hydroxyoxime with azanol reaction, then by esterification, Guan Huan, finally hydrolysis obtains Azilsartan.This route four-step reaction, and reflux and close ring in dimethylbenzene, step is many, and temperature is high, and impurity is on the high side.Its synthetic route as shown in Figure 1.This patent has also disclosed following route two, as shown in Figure 2, and this route three-step reaction.But starting material is without stablizing supplier.Synthetic starting raw material, need use that hydrogen chloride gas--condition is harsher.And product purity is not high.
Document (Organic Process Research & Development, 17 (1), 77-86; 2013) in, with methylcarbonate, replace chloro-formic ester, sodium methylate is made alkali, and in dimethylsulfoxide solvent, under room temperature condition, and the direct ring that closes of hydroxyoxime reaction obtains Azilsartan methyl esters.As shown in Figure 3, its route steps only has 3 steps, improves to some extent, but use methyl-sulphoxide at penultimate stride compared with other route, and residual solvent is not easy to remove.
(US20050187269) reported that a six-step process prepares the route of Azilsartan, as shown in Figure 4, this route not only step is long, and uses expensive triethyl a tetrafluoro borate and be not suitable for industrialization completely.
Summary of the invention
Variety of issue in view of above route exists, the object of this invention is to provide the variation route (see figure 5) that a two-step reaction is prepared Azilsartan, by two-step reaction, obtains Azilsartan.The shortcoming that overcomes prior art, has route short, and cost is low, and solvent load is few, the feature that Atom economy is high.
A kind of preparation method of Azilsartan, adopt Azilsartan nitrile with oxammonium hydrochloride, triethylamine, in dimethylsulfoxide solvent, react and obtains hydroxyoxime and obtain Azilsartan by further processing, it is characterized in that, gained hydroxyoxime reacts with strong alkali aqueous solution, and its methyl esters hydrolysis obtains water-soluble carboxylate; Then drip carbonyl and close cyclization reagent, obtain oxo oxadiazoles ring; Adjust PH to acid, obtain target product Azilsartan.
It is a kind of of following material that described carbonyl closes cyclization reagent: triphosgene, trichloromethylchloroformate, phosgene, methylcarbonate, diethyl carbonate and other dialkyl carbonate.
Drip in cyclization reagent (triphosgene, trichloromethylchloroformate, the phosgene) process of carbonyl pass and control temperature at 10-50 ℃; Optimum control is 20-30 ℃ and dropwises rear maintenance temperature of reaction, continues reaction 2-3 hour, reacts complete, adjusts PH to 2-3.
Carbonyl closes the reaction that cyclization reagent (triphosgene, trichloromethylchloroformate, phosgene) participates in, and is preferably dissolved in ether solvent, and such as tetrahydrofuran (THF), diisopropyl ether etc., are preferably tetrahydrofuran (THF).
Drip in cyclization reagent (methylcarbonate, diethyl carbonate, and other dialkyl carbonate) process of carbonyl pass and control temperature at 30-60 ℃; Optimum control is 45-55 ℃.
Carbonyl closes the reaction that cyclization reagent (methylcarbonate, diethyl carbonate, and other dialkyl carbonate) participates in, and is preferably dissolved in alcohols, in ether solvents, and such as methyl alcohol, ethanol, tetrahydrofuran (THF), diisopropyl ether etc., are preferably ethanol.
Dropwise rear maintenance temperature of reaction, continue reaction 2-3 hour, react complete, adjust PH to 2-3.
Adopt the inventive method: first, Azilsartan nitrile is with oxammonium hydrochloride, and triethylamine reacts in dimethylsulfoxide solvent, obtain that hydroxyoxime-this is all common in other patents; The reaction of resulting product hydroxyoxime and strong base solution, the methyl esters that dissociates, obtains the carboxylate salt of hydroxyoxime, water-soluble; Then drip carbonyl and close cyclization reagent pass ring, adjust PH to acid, obtain Azilsartan.This is invented main advantage and is: before 1) comparing, technique is used methylene dichloride, dimethylbenzene, and ethanol equal solvent, this technique has reduced kind and the consumption that uses solvent in a large number; 2) room temperature is closed ring, and technique before needs high temperature to close ring; 3) shorten reactions steps, from three steps, become two-step reaction.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of prior art synthetic route one.
Fig. 2 is the synthetic route chart of prior art synthetic route two.
Fig. 3 is the synthetic route chart of prior art synthetic route three.
Fig. 4 is the synthetic route chart of prior art synthetic route four.
Fig. 5 is synthetic route chart of the present invention.
Embodiment
The preparation of embodiment 1 Azilsartan oxime
In the mixing solutions of methyl-sulphoxide (200mL) and oxammonium hydrochloride (42.4g), add triethylamine (61.8g), separate out a large amount of solids.Filter, filter cake washs with tetrahydrofuran (THF).Filtrate is concentrated goes to add 1-[(2'-cyanobiphenyl-4-yl after tetrahydrofuran (THF)) methyl]-2-oxyethyl group-1H-benzoglyoxaline-7-methyl-formiate 50.0g, 75 ℃ are reacted 15 hours.After reaction finishes, add shrend and go out, ethyl acetate extraction.1mol/L salt acid elution for organic phase, water regulates pH to 10-11 with the aqueous sodium hydroxide solution of 1mol/L again, ethyl acetate extraction, anhydrous sodium sulfate drying, filters, concentrated, obtains Azilsartan oxime 29.7g, yield 55%.
The preparation of embodiment 2 Azilsartans
Azilsartan oxime 8.8g adds 10% sodium hydroxide solution 20ml, and 50 ℃ are stirred 3 hours, all dissolve.Control temperature at 20-30 ℃, drip triphosgene (3.0g)/tetrahydrofuran (THF) (15ml) mixing solutions.Dropwise rear maintenance temperature of reaction at 20-30 ℃, continue reaction 2-3 hour, react complete, adjust PH to 2-3, separate out white solid, dry, obtain Azilsartan 7.5g, yield 83%.
The preparation of embodiment 3 Azilsartans
Azilsartan oxime 8.8g adds 10% potassium hydroxide solution 20ml, and 50 ℃ are stirred 3 hours, all dissolve.Control temperature at 20-30 ℃, drip diethyl carbonate (2.1g)/tetrahydrofuran (THF) (10ml) mixing solutions.Dropwise rear maintenance temperature of reaction at 20-30 ℃, continue reaction 2-3 hour, react complete, adjust PH to 2-3, separate out white solid, dry, obtain Azilsartan 6.5g, yield 72%.
The preparation of embodiment 4 Azilsartans
Azilsartan oxime 8.8g adds 10% lithium hydroxide solution 20ml, and 50 ℃ are stirred 3 hours, all dissolve.Then slowly pass into phosgene (3-4g), control temperature at 20-30 ℃.Dropwise rear maintenance temperature of reaction, continue reaction 2-3 hour, react complete, adjust PH to 2-3, separate out white solid, dry, obtain Azilsartan 7.8g, yield 86%.
The preparation of embodiment 5 Azilsartans
Azilsartan oxime 10.8g adds 10% sodium hydroxide solution 25ml, and 50 ℃ are stirred 3 hours, all dissolve, and then slowly drip the mixing solutions of methylcarbonate 6.5g and methyl alcohol 10ml, controls temperature at 45-50 ℃.Dropwise rear maintenance temperature of reaction, continue reaction 2-3 hour, react complete, adjust PH to 2-3, separate out white solid, dry, obtain Azilsartan 7.2g, yield 73.9%.
The preparation of embodiment 6 Azilsartans
Azilsartan oxime 10.8g adds 10% sodium hydroxide solution 25ml, and 50 ℃ are stirred 3 hours, all dissolve, and then slowly drip the mixing solutions of diethyl carbonate 7.5g and ethanol 10ml, controls temperature at 50-55 ℃.Dropwise rear maintenance temperature of reaction, continue reaction 2-3 hour, react complete, adjust PH to 2-3, separate out white solid, dry, obtain Azilsartan 7.9g, yield 71.2%.
Claims (10)
1. the preparation method of an Azilsartan, adopt Azilsartan nitrile with oxammonium hydrochloride, triethylamine, in dimethylsulfoxide solvent, react and obtains hydroxyoxime and obtain Azilsartan by further processing, it is characterized in that, gained hydroxyoxime reacts with strong alkali aqueous solution, and its methyl esters hydrolysis obtains water-soluble carboxylate; Then drip carbonyl and close cyclization reagent, obtain oxo oxadiazoles ring; Adjust PH to acid, obtain target product Azilsartan.
2. the preparation method of Azilsartan according to claim 1, is characterized in that, it is phosgene derivative that described carbonyl closes cyclization reagent, carbonic ether.
3. the preparation method of Azilsartan according to claim 2, is characterized in that, described carbonyl closes cyclization reagent phosgene derivative and comprises phosgene, trichloromethylchloroformate, triphosgene.
4. the preparation method of Azilsartan according to claim 2, is characterized in that, described carbonyl closes cyclization reagent carbonic ether and comprises methylcarbonate, diethyl carbonate, dialkyl carbonate.
5. the preparation method of Azilsartan according to claim 1, is characterized in that, drips carbonyl and closes in cyclization reagent process and controls temperature at 10-60 ℃.
6. the preparation method of Azilsartan according to claim 3, is characterized in that, drips carbonyl and closes in cyclization reagent process and controls temperature at 20-30 ℃.
7. the preparation method of Azilsartan according to claim 4, is characterized in that, drips carbonyl and closes in cyclization reagent process and controls temperature at 45-55 ℃.
8. the preparation method of Azilsartan according to claim 1, is characterized in that, described highly basic is sodium hydroxide, potassium hydroxide, and lithium hydroxides etc., are preferably sodium hydroxide.
9. the preparation method of Azilsartan according to claim 3, is characterized in that, reaction is carried out in ether solvent, and such as tetrahydrofuran (THF), diisopropyl ether etc., are preferably tetrahydrofuran (THF).
10. the preparation method of Azilsartan according to claim 4, is characterized in that, reaction is carried out in alcohols or ether solvents, such as methyl alcohol, and ethanol, tetrahydrofuran (THF), diisopropyl ether etc., are preferably ethanol.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104119279A (en) * | 2014-05-30 | 2014-10-29 | 上海天慈生物谷生物工程有限公司 | Novel method for preparing 2-ethyoxyl-1-{[2'-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3-yl) xenyl-4-yl]methyl}-1H- benzimidazole-7-carboxylic acid |
| CN107325092A (en) * | 2017-08-07 | 2017-11-07 | 山东鲁宁药业有限公司 | A kind of new preparation process of Azilsartan |
| 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 |
|---|---|---|---|---|
| WO2012139536A1 (en) * | 2011-04-11 | 2012-10-18 | Zentiva, K.S. | A method of preparing 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl- 4-yl)methyl)-1h-benzo[d]imidazole-7-carboxylates and conversion thereof to azilsartan |
| WO2013186792A2 (en) * | 2012-06-11 | 2013-12-19 | Msn Laboratories Limited | Process for the preparation of (5-methyl-2-oxo-l,3-dioxoi-4-vl)methvl 2- ethoxv-l-{[2'-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vl)biphenyi-4-vl]methyl}- lh-benzimidazole-7-carboxyiate and its salts |
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2013
- 2013-12-30 CN CN201310744903.6A patent/CN103709155A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012139536A1 (en) * | 2011-04-11 | 2012-10-18 | Zentiva, K.S. | A method of preparing 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl- 4-yl)methyl)-1h-benzo[d]imidazole-7-carboxylates and conversion thereof to azilsartan |
| WO2013186792A2 (en) * | 2012-06-11 | 2013-12-19 | Msn Laboratories Limited | Process for the preparation of (5-methyl-2-oxo-l,3-dioxoi-4-vl)methvl 2- ethoxv-l-{[2'-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vl)biphenyi-4-vl]methyl}- lh-benzimidazole-7-carboxyiate and its salts |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104119279A (en) * | 2014-05-30 | 2014-10-29 | 上海天慈生物谷生物工程有限公司 | Novel method for preparing 2-ethyoxyl-1-{[2'-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3-yl) xenyl-4-yl]methyl}-1H- benzimidazole-7-carboxylic acid |
| CN104119279B (en) * | 2014-05-30 | 2018-01-02 | 上海天慈生物谷生物工程有限公司 | The method for preparing the carboxylic acid of 2 ethyoxyl 1 { [base of 2 ' (base of 5 carbonyl, 4,5 dihydro, 1,2,4 oxadiazole 3) xenyl 4] methyl } 1H benzimidazoles 7 |
| CN107325092A (en) * | 2017-08-07 | 2017-11-07 | 山东鲁宁药业有限公司 | A kind of new preparation process of Azilsartan |
| CN107325092B (en) * | 2017-08-07 | 2021-01-08 | 山东鲁宁药业有限公司 | Novel preparation process of azithromycin |
| 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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Application publication date: 20140409 |