CN102219779A - Method for synthetizing irbesartan - Google Patents
Method for synthetizing irbesartan Download PDFInfo
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- CN102219779A CN102219779A CN2011102195034A CN201110219503A CN102219779A CN 102219779 A CN102219779 A CN 102219779A CN 2011102195034 A CN2011102195034 A CN 2011102195034A CN 201110219503 A CN201110219503 A CN 201110219503A CN 102219779 A CN102219779 A CN 102219779A
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Abstract
A method for synthetizing irbesartan is characterized by comprising the steps of: under the existence of phase transfer catalyst, reacting 2-butyl-3-{[2'-cyanobiphenyl-4-yl]methyl}-1,3-diazabicyclo[4.4]nonane-1-ene-4-ketone with alkali metal azide and inorganic ammonium slat in nonpolar nonprotonic solvent, directly carrying out acid neutralization and purification to obtain irbesartan after reaction. Finished reaction liquid is adopted for acidizing so as to avoid decomposition under alkaline condition, the product is manufactured by the total yield of 88-95 percent with purity higher than 99.8 percent. During the process of preparing irbesartan, the normally used tributyl azide immersion tin and triethylamine hydrochloride in the prior art are avoided, the content of tin and triethylamine in the obtained irbesartan can be lower than 5ppm, or the tin and triethylamine is not detected. The method is simple to operate, has lower cost and is more beneficial to industrial production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to the synthetic of a kind of antihypertensive drug irbesartan and improve one's methods.
Background technology
Irbesartan (Irbesartan), chemical name are 2-butyl-3-[[2-(1H-tetrazolium-5-yl) xenyl-4-yl] methyl]-1,3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone is white crystalline powder.Irbesartan belongs to non-peptide class angiotensin II receptor antagonists, is used for the treatment of as the cardiovascular disorder of hypertension, heart failure and prevents disorder, glaucoma, diabetic retinopathy and the diabetic nephropathy of central nervous system.Irbesartan is developed jointly by Sai Nuofei and 100 o'clock Mei Shibao companies, and commodity were called An Bowei (Anprovel) first in Britain's listing in 1997.The structural formula of irbesartan is as follows:
U.S. Pat P5270317[1993. 12. 14], USP5629331[1997. 5. 13] reported the various preparation methods of irbesartan and related compound.
U.S. Pat P5270317[1993. 12. 14] reported method is to use tributyl azide tin to carry out tetrazolium reaction at last; react through trityl group chlorine; obtain irbesartan through hydrochloric acid deprotection, column chromatography separating purification again; the product productive rate is low; use cost height such as tributyl azide tin, trityl group chlorine; and deleterious tin is residual higher in the product, and tributyl azide tin should not be used for industrial production in a large number.
U.S. Pat P5629331[1997. 5. 13] method of irbesartan of record, wherein use triethylamine hydrochloride and sodiumazide to replace tributyl azide tin to carry out the tetrazolium reaction, the solvent that uses be 1-methylpyrrolidin-2-ketone, it costs an arm and a leg and is difficult for reclaiming, and therefore makes this method be unsuitable for industrial production.The process of separating irbesartan from reaction mixture is tediously long, needs the layer separation and the layer of some keys to filter, and can not obtain gratifying yield and purity.
Chinese patent CN101657442[2010. 2. 24] the disclosed improved method for preparing irbesartan, wherein use triethylamine hydrochloride and sodiumazide to carry out the tetrazolium reaction, the solvent that uses be non-polar non-protic solvent toluene or dimethylbenzene, use alkali lye to separate 2-butyl-3-[[2-(1H-tetrazolium-5-yl) xenyl-4-yl] methyl]-1, the an alkali metal salt of 3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone might cause its decomposition, influences yield.
Based on the shortcoming of prior art, still need continue to improve production technique, further reduce cost, improve the yield and the purity of product, be more conducive to industrial-scale production.
Summary of the invention
The inventor is by repeatedly experiment discovery, 2-butyl-3-[[2-(1H-tetrazolium-5-yl) xenyl-4-yl] methyl]-1,3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone (irbesartan) can be by under the existence of phase-transfer catalyst, 2-butyl-3-[[2-cyanobiphenyl base-4-yl] methyl]-1,3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone and an alkali metal azide and inorganic ammonium salt react in non-polar non-protic solvent, with high yield and prepared in high purity.
The inventor also finds, in the last handling process of irbesartan, add alkali lye and attempt to extract 2-butyl-3-[[2-(1H-tetrazolium-5-yl) xenyl-4-yl] methyl]-1, the an alkali metal salt of 3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone is gone in the process of water layer, alkali can impel 2-butyl-3-[[2-(1H-tetrazolium-5-yl) xenyl-4-yl] methyl]-1,3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone produces and decomposes, and produces impurity.The concentration of alkali lye is big more, and the treatment time is long more, and the impurity of generation is many more, causes the yield of irbesartan to reduce, and it is complicated that purification process becomes.
The purpose of this invention is to provide the synthetic of a kind of irbesartan improves one's methods, it comprises: in the presence of phase-transfer catalyst, 2-butyl-3-[[2-cyanobiphenyl base-4-yl] methyl]-1,3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone and an alkali metal azide and inorganic ammonium salt react in non-polar non-protic solvent, and directly acid neutralizes, purifying obtains irbesartan in the reaction back.This method is simple to operate, and cost is lower, is more conducive to industrial production.Reaction formula is as follows:
Reaction formula
The present invention is realized by the following technical programs: wherein said phase-transfer catalyst is tetrabutylammonium chloride or Tetrabutyl amonium bromide, an alkali metal azide is a sodiumazide, described inorganic ammonium salt is an ammonium chloride, and non-polar non-protic solvent is toluene or dimethylbenzene.
2-butyl-3-[[2-cyanobiphenyl base-4-yl] methyl]-1,3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone and sodiumazide, Tetrabutyl amonium bromide, ammonium chloride, toluene or dimethylbenzene carry out to the reflux temperature of solvent for use for 80 ℃ in temperature.
Common 2-butyl-3-[[2-cyanobiphenyl base-4-yl] methyl]-1, the ingredient proportion of 3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone and sodiumazide, Tetrabutyl amonium bromide, ammonium chloride is: 2-butyl-3-[[2-cyanobiphenyl base-4-yl] methyl]-1,3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone: sodiumazide: Tetrabutyl amonium bromide: ammonium chloride=1:2-3:0.04-0.08:2-4 (mol/mol/ mol/ mol), the usage quantity of solvent toluene or dimethylbenzene is that 3-8 times of volume doubly measured.
Resultant reaction residual liquor has reaction solvent directly by adding the pH=4-5 of diluted acid conditioned reaction liquid, and selected acid is hydrochloric acid, sulfuric acid or acetate.
Resulting suspension after the acidifying obtains the irbesartan crude product by separation method known in the art.
The irbesartan crude product that obtains uses the mixed solvent of methyl alcohol, ethanol, Virahol and water, obtains pure product irbesartan by conventional crystallization operation.
Owing to adopt the direct acidification of reaction residual liquor of the present invention, avoided the decomposition under the alkaline condition, so make product with the total recovery of 88-95%, purity is higher than 99.8%.
The present invention prepares the process of irbesartan, avoids using tributyl azide tin and triethylamine hydrochloride commonly used in the prior art, and the tin content of the irbesartan that is obtained and triethylamine content are lower than 5ppm or do not detect.
Embodiment
The present invention is further described with specific embodiment below, but the present invention is not imposed any restrictions.
Embodiment 1:2-butyl-3-[(2'-cyanobiphenyl-4-yl) methyl]-1,3-diazaspiracyclic [4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone 50g (0.13 mol), ammonium chloride 24g (0.45mol), Tetrabutyl amonium bromide 2.5g (7.7mmol) and sodiumazide 16.9g (0.26mol) 120-130 ℃ of stirring reaction 24h in 250mL dimethylbenzene, be chilled to room temperature, add 250mL water, with 4
NHydrochloric acid is regulated pH=4-5, has precipitation to produce, and stirring at room 1h filters, after the filter cake washing drying, add 500mL 95% ethanol and proper amount of active carbon, reflux 1 hour, heat filtering, filtrate is cooled to 20-25 ℃, filtration drying obtains the 49g irbesartan, yield 88.1%, purity 99.82%.
The organic volatile foreign matter content is analyzed: dimethylbenzene-20ppm, and triethylamine-do not detect, tin--do not detect.
Embodiment 2:2-butyl-3-[(2'-cyanobiphenyl-4-yl) methyl]-1,3-diazaspiracyclic [4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone 50g (0.13 mol), ammonium chloride 24g (0.45mol), Tetrabutyl amonium bromide 2.5g (7.7mmol) and sodiumazide 16.9g (0.26mol) 110 ℃ of stirring reaction 40h in 250mL toluene, be chilled to room temperature, add 250mL water, with 4
NHydrochloric acid is regulated pH=4-5, has precipitation to produce, and stirring at room 1h filters, after the filter cake washing drying, add 500mL 95% ethanol and proper amount of active carbon, reflux 1 hour, heat filtering, filtrate is cooled to 20-25 ℃, filtration drying obtains the 49.8g irbesartan, yield 90%, purity 99.80%.
The organic volatile foreign matter content is analyzed: toluene 15ppm, and triethylamine does not detect, and tin does not detect.
Embodiment 3:2-butyl-3-[(2'-cyanobiphenyl-4-yl) methyl]-1,3-diazaspiracyclic [4.4] ninth of the ten Heavenly Stems-1-alkene-4-ketone 50g (0.13 mol), ammonium chloride 24g (0.45mol), Tetrabutyl amonium bromide 2.5g (7.7mmol) and sodiumazide 16.9g (0.26mol) 110 ℃ of stirring reaction 48h in 250mL toluene, be chilled to room temperature, add 250mL water, regulate pH=4-5 with acetate, have precipitation to produce stirring at room 1h, filter, after the filter cake washing drying, add 500mL 95% ethanol and proper amount of active carbon, reflux 1 hour, heat filtering, filtrate is cooled to 20-25 ℃, and filtration drying obtains the 50.5g irbesartan, yield 91%, purity 99.81%.
The organic volatile foreign matter content is analyzed: toluene 12ppm, and triethylamine does not detect, and tin does not detect.
Claims (4)
1. the synthetic method of an irbesartan, it is characterized in that: in the presence of phase-transfer catalyst, 2-butyl-3-[[2 '-cyanobiphenyl base-4-yl] methyl]-1,3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone and an alkali metal azide and inorganic ammonium salt react in non-polar non-protic solvent, and the directly sour neutralization in reaction back is purified and obtained irbesartan.
2. the synthetic method of irbesartan according to claim 1, it is characterized in that: described phase-transfer catalyst is Tetrabutyl amonium bromide or tetrabutylammonium chloride, described an alkali metal azide is a sodiumazide, described inorganic ammonium salt is an ammonium chloride, and described non-polar non-protic solvent is toluene or dimethylbenzene.
3. the synthetic method of irbesartan according to claim 1 is characterized in that: directly add the acid neutralization after described direct acid neutralization is meant ring-closure reaction, employed acid is hydrochloric acid or sulfuric acid or acetate.
4. the synthetic method of irbesartan according to claim 1, it is characterized in that: 2-butyl-3-[[2 '-cyanobiphenyl base-4-yl] methyl]-1,3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone and sodiumazide, Tetrabutyl amonium bromide, the ingredient proportion of ammonium chloride is: 2-butyl-3-[[2 '-cyanobiphenyl base-4-yl] methyl]-1,3-diazaspiracyclic [4.4] nonane-1-alkene-4-ketone: sodiumazide: Tetrabutyl amonium bromide: ammonium chloride=1:2-3:0.04-0.08:2-4 (mol/mol/ mol/ mol), the usage quantity of solvent toluene or dimethylbenzene is that 3-8 times of volume doubly measured.
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| CN2011102195034A CN102219779A (en) | 2011-08-02 | 2011-08-02 | Method for synthetizing irbesartan |
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| CN2011102195034A CN102219779A (en) | 2011-08-02 | 2011-08-02 | Method for synthetizing irbesartan |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106674205A (en) * | 2016-12-09 | 2017-05-17 | 浙江华海药业股份有限公司 | Sartan compound discoloration method |
| CN107312011A (en) * | 2017-06-29 | 2017-11-03 | 上海药明康德新药开发有限公司 | The synthetic method of the carboxylic acid of 2,7 diaza spiro nonane of racemic 7 tert-butoxycarbonyl, 1 oxygen subunit 4 |
| CN114835689A (en) * | 2022-06-07 | 2022-08-02 | 浙江金立源药业有限公司 | Method for preparing irbesartan without solvent |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101657442A (en) * | 2007-03-06 | 2010-02-24 | 阿克塔维什集团Ptc公司 | Improved process for preparing irbesartan |
-
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- 2011-08-02 CN CN2011102195034A patent/CN102219779A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101657442A (en) * | 2007-03-06 | 2010-02-24 | 阿克塔维什集团Ptc公司 | Improved process for preparing irbesartan |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106674205A (en) * | 2016-12-09 | 2017-05-17 | 浙江华海药业股份有限公司 | Sartan compound discoloration method |
| CN107312011A (en) * | 2017-06-29 | 2017-11-03 | 上海药明康德新药开发有限公司 | The synthetic method of the carboxylic acid of 2,7 diaza spiro nonane of racemic 7 tert-butoxycarbonyl, 1 oxygen subunit 4 |
| CN114835689A (en) * | 2022-06-07 | 2022-08-02 | 浙江金立源药业有限公司 | Method for preparing irbesartan without solvent |
| CN114835689B (en) * | 2022-06-07 | 2024-01-02 | 浙江金立源药业有限公司 | Solvent-free method for preparing irbesartan |
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Application publication date: 20111019 |