CN102093297A - Telmisartan compound and new preparation method thereof - Google Patents
Telmisartan compound and new preparation method thereof Download PDFInfo
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- CN102093297A CN102093297A CN 201110032275 CN201110032275A CN102093297A CN 102093297 A CN102093297 A CN 102093297A CN 201110032275 CN201110032275 CN 201110032275 CN 201110032275 A CN201110032275 A CN 201110032275A CN 102093297 A CN102093297 A CN 102093297A
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- RMMXLENWKUUMAY-UHFFFAOYSA-N CCCc1nc(c(C)cc(-c2nc3ccccc3[n]2C)c2)c2[n]1Cc(cc1)ccc1-c(cccc1)c1C(O)=O Chemical compound CCCc1nc(c(C)cc(-c2nc3ccccc3[n]2C)c2)c2[n]1Cc(cc1)ccc1-c(cccc1)c1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a Telmisartan compound and a new preparation method thereof. The method comprises the following steps: carrying out acid-base conversion, adsorbing with activated carbon, and separating and purifying with neutral aluminum oxide preparative chromatographic columns to achieve the goals of refinement and purification, thereby finally obtaining the high-purity Telmisartan compound. The invention enhances the product quality of the preparation, reduces the toxic and side effects, and ensures the safety when the Telmisartan is used for preparing hypotensive medicaments.
Description
Technical field
The present invention relates to a kind of telmisartan compound and new preparation method thereof, belong to medical technical field.
Background technology
Telmisartan (Telmisartan), chemical name is: 4 '-[4-methyl-6-(1-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-2-propyl group-1H-benzoglyoxaline ylmethyl] xenyl-2-carboxylic acid; Molecular formula C
33H
30N
4O
2, molecular weight 514.63, structural formula is:
Belong to Altace Ramipril, by the development of German BoehringerIngelheim drugmaker, got permission German Patent EP502314 in 1991, at first ratify listing in November, 1998, then have in states such as Germany, Philippines, Australia, Belgium, Britain and go on the market in the U.S..Telmisartan is a specific specificity angiotensin II receptor antagonists, combines with angiotensin I receptor subtype (known Angiotensin II action site) high-affinity by substituting angiotensin-ii receptor, and plays hypotensive effect.
About the synthetic method of telmisartan and refining; (1-methyl-benzimidazolyl-2 radicals-yl)-benzoglyoxaline is a starting raw material, obtains telmisartan after reactions such as acidylate, nitration, reduction, cyclization, condensation, hydrolysis with 2-n-propyl-4-methyl-6-mostly in research both at home and abroad.A lot of patents are WO2009006860 for example, CN101100458, CN101550107A, WO2006136916, US20060211866, WO2006044648, and document OPRD (2007) 11 (1), 81-85 has report, early stage common synthetic method is through the hydrolysis of the telmisartan tert-butyl ester, this process contaminants is many, and yield is low, is unsuitable for industrial production; Later stage is more commonly through telmisartan methyl esters, ethyl ester or its hydrochloride hydrolysis.These class methods mainly are, at first synthetic preparation telmisartan methyl esters or ethyl ester crude product, and the not purified telmisartan that directly synthesizes obtains refinement treatment behind the product.In this method, the solvent that refinement treatment is used mostly is high boiling solvent, and is easily residual.
WO2006044754 in document or the patent such as OPRD (2007) 11 (1), 81-85, has adopted first refining telmisartan methyl esters, the method for posthydrolysis, and its shortcoming is: some uses salt forming method, and technical process is long; Some treating process is loaded down with trivial details, and yield is lower.
CN101838243A discloses a kind of method for refining telmisartan, and its operational path is: the reaction in the mixed solvent A of water, organic solvent or organic solvent and water composition of I. telmisartan crude product and alkali obtains the crude product of telmisartan salt; II. with crude product recrystallization in the mixed solvent B of organic solvent or organic solvent and water composition of telmisartan salt, obtain refining telmisartan salt; III. the refining telmisartan salt hydrolysis that obtains, crystallization promptly obtains colourless refining telmisartan crystallization to white.In order to reduce the foreign pigment in the telmisartan of refining back, improve the purity of product simultaneously, can in the step I-III of above-mentioned process for purification, increase the operation of activated carbon decolorizing, can only reach 89.2% but productive rate is the highest.
The telmisartan of method for preparing, generally (crude product does not have required purity to need after carrying out series of processing steps, unless carry out recrystallize twice), just can obtain gratifying quality, and when separating this material, need very long centrifugal and time of drying.Carry out technical scale synthetic telmisartan, its product need be carried out second crystallization reaction to finish purifying.In indispensable described crystallisation step, the form of the purpose product that crystallization goes out can cause unexpected problem.Be the sedimentary product of minute hand form and be difficult to be filtered, washing also separates, and owing to contain solvent, so also need very long time of drying, and when carrying out described drying means, can form very hard big block.These blocks grind and can produce dried powder, are easy to produce static, therefore in fact are difficult to use.
The above-mentioned undesirable property of these products has been proved to be the major obstacle of mass preparation compound, because the reproducibility preparation in large quantities of these products, and be difficult to obtain high-purity product.
The purity of the telmisartan of method for preparing is lower, does not reach the limit of standard preparation requirement, is difficult to prepare qualified preparation.
In addition, deposit improper or shelf-time when long in telmisartan compound, can cause active constituents of medicine content to reduce, color and luster is strengthened, and its related substances raises.In some cases, because controlling of production process is improper, cause pharmaceutical purity also undesirable.Therefore be necessary underproof product is further carried out purifying, provide highly purified telmisartan compound with high yield.
The technical issues that need to address of the present invention are to overcome the deficiencies in the prior art, and a kind of new refining purification process of telmisartan is provided, and this method is simple, telmisartan purity height, and the yield height is easy to suitability for industrialized production.
Summary of the invention
On the pharmaceutical chemistry, the technician that this area has a universal experience knows clearly and is facing all difficulties aspect the compound that obtains the high purity high yield, all these just can be expected according to the theory of existing general separation and purification absolutely not solution need overcome many difficult problems.
The applicant is on the basis of a large amount of existing documents, experiment by a large amount of screenings, find above-mentioned document and general method for purifying and separating for example method such as crystallization be difficult to obtain the compound of high purity high yield, and various separation purification method and multiple conditional parameter exist the possibility and the unpredictability of varied combination.The inventor is through long-term conscientious research, and after screening applied in any combination specific method and parameters optimization, accident has been found a kind of refining purification process of telmisartan compound, obtains the highly purified product of high yield astoundingly.
The objective of the invention is to overcome the defective that prior art exists, a kind of refining purification process of telmisartan compound is provided, method by soda acid conversion, charcoal absorption and preparative chromatography column separating purification, can reach the purpose of refining purifying, finally obtain highly purified telmisartan compound, improve the quality product of preparation, reduced toxic side effect, ensured safety of clinical administration.
The applicant has screened every investigation points such as soda acid, organic solvent, chromatographic condition, temperature of reaction, time and pH value scope through long-term conscientious big quantity research, finally obtains optimized technology.
In one aspect of the invention, the separation and the purification process of medicine comprise adsorption method, as using gac.Unfortunately, except removing color and other unwanted material, gac also irreversibly adsorbs interested medicine, and this causes productive rate obviously to reduce.The usage quantity that it is suitable that the present invention confirms gac is the 0.05-4% (g/ml) of overall solution volume, is preferably 0.1-2% (g/ml), is preferably 0.2-0.4% (g/ml) especially.
In one aspect of the invention, the diameter of chromatographic column is about 1 to about 200cm, is preferably 5cm at least.The chromatogram column length scope is preferably about 10 centimetres to about 100 centimetres.
Generally speaking, in the separation and purification process, chromatographic column filler can be silica gel, aluminum oxide or macroporous resin etc., and the particle diameter of used silica gel can be 45-250 μ m, the aperture is 80-100
Kiselgel A; Used aluminum oxide can be neutral alumina, and used neutral alumina can be 100～200 orders or 200～300 orders; Used macroporous resin model can be Amberlite XAD-6, Amberlite XAD-7, Amberlite XAD-8, Diaion HP2MG, GDX-501, HPD400, HPD450, HPD750, Hz841, Amberlite XAD-9, Amberlite XAD-10, GDX-401, GDX-601, NKA-II, NKA-9, HPD500/600, the unexpected application macroporous resin of finding of the inventor does not have clear improvement to the purity of product, silica gel is also undesirable, and neutral alumina not only can fully adsorb composition impurity and other pigment in the upper prop thing, also this product purifying there is original effect, and cost is relatively low, operates simpler and easy.
In one aspect of the invention, fixed phase stuffing of the present invention is preferably alumina column.Used aluminum oxide most preferably is neutral alumina, and used neutral alumina can be 100～200 orders or 200～300 orders.
The inventor carries out a large amount of optimization experiment on the basis of the above, screening has obtained suitable moving phase, therefore in one aspect of the invention, preferably, chromatographic column purification condition described in the above-mentioned process for purification is: with volume ratio is 1: Virahol (1-6) and acetonitrile mixed solvent are moving phase, fixed phase stuffing is selected from neutral alumina, and flow velocity is 1.7-5.5ml/min, column temperature 20-40 ℃.
In one aspect of the invention, as preferably, the quality of each purifying medicine is 1 with the ratio of the quality of chromatographic column filler: 10-200, the preferred mass ratio is 1: 15-100.The consumption of moving phase is as long as satisfy the complete basically wash-out of medicine, flow point Fractional Collections behind the wash-out, the content difference of the flow point Chinese traditional medicine of different sections, in order to obtain highly purified medicine (purity is greater than 99.5%), need medicament contg is merged greater than 85% flow point, preferably medicament contg is merged greater than 90% flow point.
In one embodiment of the invention, method for refining telmisartan provided by the invention comprises the steps:
(1) the telmisartan crude product is scattered in the water, slowly adds alkali or strong base-weak acid salt then, to the pH value of solution value be 7.5-9.5, generate telmisartan salt, use overall solution volume 0.2-0.8% (g/ml) charcoal absorption then, 40-50 ℃ is stirred 20-30min, filter decarburization, collect filtrate;
(2) with above-mentioned filtrate and acid-respons, generate the telmisartan precipitation, filter, with less water washing, drying;
(3) precipitation in the step (2) is carried out separation and purification with preparation type neutral alumina chromatographic column, collect elutriant, concentrating under reduced pressure, vacuum-drying obtains the pure product of telmisartan.
As the present invention's one preferred embodiment, be preferably 8-9 with alkali reaction to pH value of solution value in it.
As the present invention's one preferred embodiment, wherein step (1) adds the gac of solvent cumulative volume 0.2-0.5% (g/ml), whip attachment 20-30min.
As the present invention's one preferred embodiment, wherein said alkali is selected from one or more in sodium hydroxide, potassium hydroxide, yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, sodium acetate, the potassium acetate, is preferably sodium bicarbonate or saleratus.
As the present invention's one preferred embodiment, in it and acid-respons to pH value of solution value be 4-6, preferred 4.7-5.5.
As the present invention's one preferred embodiment, wherein said acid is selected from a kind of in hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, Hydrogen bromide, the acetate, preferred hydrochloric acid.
As the present invention's one preferred embodiment, wherein the condition of chromatographic column is: with volume ratio is 1: Virahol (1-6) and acetonitrile mixed solvent are moving phase, and fixed phase stuffing is selected from neutral alumina, and flow velocity is 1.7-5.5ml/min, column temperature 20-40 ℃.
As the present invention's one preferred embodiment, wherein moving phase is that volume ratio is 1: the Virahol (2-3) and the mixing solutions of acetonitrile, flow velocity are 2.1-3.0ml/min.
The application of telmisartan compound in the preparation Altace Ramipril of the inventive method preparation is provided in one aspect of the invention.
The refining purification process of telmisartan compound provided by the invention, method by soda acid conversion, charcoal absorption and preparative chromatography column separating purification, finally obtain highly purified telmisartan compound, improved the quality product of preparation, reduce toxic side effect, ensured safety of clinical administration.And compared with prior art, present method technology is simple and easy to do, the reaction conditions gentleness, and cost is low, the yield height, the product purity height is suitable for suitability for industrialized production.
About some macroporous resins is the chromatography column of weighting agent or the purification process of ion exchange resin exchange column, because the macroporous resin rigidity is strong, easily synthesis material such as fragmentation and pore-creating agent or removal of solvents are unclean and residual, easily flow into soup and cause secondary pollution, its pre-treatment, regeneration purifying process are lacked compliance index, using the ion exchange resin exchange column then is that cost is too high, also needs the regeneration activating of pillar, comparatively complicated, and can introduce a large amount of sodium ions, purity does not have clear improvement.The inventor finds that in screening experiment neutral alumina column method of the present invention significantly is better than these purification process.
Embodiment
Below further explain and describe content of the present invention by embodiment, but embodiment is not to be construed as limiting the scope of the invention.
Embodiment 1 telmisartan is refining
(1) 100g telmisartan crude product (purity is 98.2%) is scattered in about 1000ml water, slowly add in the sodium hydrogen carbonate solution of 1% (g/ml) then, pH value to solution is 8.0, stirring reaction 30 minutes, the gac that adds 5g then, 50 ℃ of insulated and stirred 20 minutes are filtered, and collect filtrate;
(2) hydrochloric acid soln that drips 2mol/L in above-mentioned filtrate is to be 5.5 to the pH value of solution, and precipitation is separated out in stirring at room reaction 60 minutes, filters, and washs 45 ℃ of vacuum-dryings with less water;
(3) precipitation in the step (2) is dissolved with a small amount of moving phase, adding the 100g neutral alumina again stirs, be added on the chromatographic column of preparation after flinging to solvent, utilize the preparative scale chromatography post to carry out separation and purification, wherein used moving phase is that volume ratio is 1: 2 the Virahol and the mixed solvent of acetonitrile, stationary phase is the neutral alumina post, flow velocity is 2.1ml/min, 20 ℃ of column temperatures, wavelength 298nm, collect elutriant, concentrating under reduced pressure, vacuum-drying gets telmisartan 93.4g, yield is 95.1%, and purity is 99.8%.
Embodiment 2 telmisartans are refining
(1) 100g telmisartan crude product (purity is 98.2%) is scattered in about 1000ml water, slowly adds then in the potassium bicarbonate solution of 1% (g/ml), to the pH value of solution be 9, stirring reaction 30 minutes adds the gac of 5g then, 50 ℃ of insulated and stirred 20 minutes, filter, collect filtrate;
(2) acetic acid solution that drips 1mol/L in filtrate is to be 4.7 to the pH value of solution, and precipitation is separated out in stirring at room reaction 60 minutes, filters, and washs 45 ℃ of vacuum-dryings with less water;
(3) precipitation in the step (2) is dissolved with moving phase, adding the 100g neutral alumina again stirs, be added on the chromatographic column of preparation after flinging to solvent, utilize the preparative scale chromatography post to carry out separation and purification, wherein used moving phase is that volume ratio is 1: 3 the Virahol and the mixed solvent of acetonitrile, stationary phase is the neutral alumina post, flow velocity is 3.0ml/min, 40 ℃ of column temperatures, wavelength 298nm, collect elutriant, concentrating under reduced pressure, vacuum-drying gets telmisartan 92.8g, yield is 94.5%, and purity is 99.7%.
Embodiment 3 telmisartans are refining
(1) 50g telmisartan crude product (purity is 98.2%) is scattered in about 500ml water, slowly adds then in the sodium acetate solution of 1% (g/ml), to the pH value of solution be 8.5, stirring reaction 30 minutes adds the gac of 2g then, 50 ℃ of insulated and stirred 20 minutes, filter, collect filtrate;
(2) hydrochloric acid soln that drips 1mol/L in filtrate is to be 5.0 to the pH value of solution, and precipitation is separated out in stirring at room reaction 60 minutes, filters, and washs 45 ℃ of vacuum-dryings with less water;
(3) precipitation in the step (2) is dissolved with moving phase, adding the 50g neutral alumina again stirs, be added on the chromatographic column of preparation after flinging to solvent, utilize the preparative scale chromatography post to carry out separation and purification, wherein used moving phase is that volume ratio is 1: 3 the Virahol and the mixed solvent of acetonitrile, stationary phase is the neutral alumina post, flow velocity is 2.5ml/min, 30 ℃ of column temperatures, wavelength 298nm, collect elutriant, concentrating under reduced pressure, vacuum-drying gets telmisartan 91.5g, yield is 93.2%, and purity is 99.6%.
Embodiment 4 telmisartans are refining
(1) 100g telmisartan crude product (purity is 98.2%) is scattered in about 1500ml water, slowly adds then in the sodium acetate solution of 1% (g/ml), to the pH value of solution be 8.0, stirring reaction 30 minutes adds the gac of 6g then, 50 ℃ of insulated and stirred 20 minutes, filter, collect filtrate;
(2) acetic acid solution that drips 1mol/L in filtrate is to be 5.5 to the pH value of solution, and precipitation is separated out in stirring at room reaction 60 minutes, filters, and washs 45 ℃ of vacuum-dryings with less water;
(3) precipitation in the step (2) is dissolved with moving phase, adding the 100g neutral alumina again stirs, be added on the chromatographic column of preparation after flinging to solvent, utilize the preparative scale chromatography post to carry out separation and purification, wherein used moving phase is that volume ratio is 1: 3 the Virahol and the mixed solvent of acetonitrile, stationary phase is the neutral alumina post, flow velocity is 2.5ml/min, 30 ℃ of column temperatures, wavelength 298nm, collect elutriant, concentrating under reduced pressure, vacuum-drying gets telmisartan 93.3g, yield is 95.0%, and purity is 99.7%.
Embodiment 5 telmisartans are refining
(1) 100g telmisartan crude product (purity is 98.2%) is scattered in about 1000ml water, slowly adds then in the sodium hydrogen carbonate solution of 1% (g/ml), to the pH value of solution be 9, stirring reaction 30 minutes adds the gac of 3g then, 50 ℃ of insulated and stirred 20 minutes, filter, collect filtrate;
(2) hydrochloric acid soln that drips 1mol/L in filtrate is to be 6.0 to the pH value of solution, and precipitation is separated out in stirring at room reaction 60 minutes, filters, and washs 45 ℃ of vacuum-dryings with less water;
(3) precipitation in the step (2) is dissolved with a small amount of moving phase, adding the 100g neutral alumina again stirs, be added on the chromatographic column of preparation after flinging to solvent, utilize the preparative scale chromatography post to carry out separation and purification, wherein used moving phase is that volume ratio is 1: 2.5 the Virahol and the mixed solvent of acetonitrile, stationary phase is the neutral alumina post, flow velocity is 2.5ml/min, 30 ℃ of column temperatures, wavelength 298nm, collect elutriant, concentrating under reduced pressure, vacuum-drying gets telmisartan 94.5g, yield is 92.8%, and purity is 99.6%.
Enumerate the part comparative example of prior art similar approach or screening process of the present invention below, so that technique effect of the present invention to be described.
The comparative example 1
According among the CN101838243A the embodiment 2 of high yield repeat to test as follows:
1) preparation telmisartan sylvite crude product
Drop into Virahol 500ml, telmisartan 65g (content 98.2%), potassium hydroxide 8.0g (0.143mol) stirring in the 1000ml four-hole bottle successively, intensification 75-80 ℃ molten clear, add the 6.5g gac, and under this temperature, decoloured 1 hour, filter, filtrate is cooled to 0 ℃ of crystallization 8 hours, filters, 60 ℃ of decompression oven dry of filter cake 8 hours get 65g telmisartan sylvite crude product.
2) telmisartan sylvite is refining
Drop into Virahol 350ml in the 500ml four-hole bottle, telmisartan sylvite crude product 65g, intensification 75-80 ℃ is molten clear, add gac 5g decolouring 1 hour, filter, filtrate is cooled to 0 ℃ of crystallization 8 hours, filter, 60 ℃ of decompression oven dry of filter cake 8 hours get the refining telmisartan sylvite of 61g
3) hydrolysis of telmisartan sylvite obtains refining telmisartan
Drop into methyl alcohol 390ml in the 1000ml four-hole bottle, water 130ml, 65-70 ℃ of refining telmisartan sylvite 61g intensification is molten clear, adds gac 3g, reflux decolour 1 hour filters, and filtrate is stirred 65-70 ℃ of intensification, formic acid with 50% transfers PH=4-6 to stir repetition measurement, PH=4-6 0.5 hour.Cool off 5-10 ℃, filter, the drip washing of filter cake 500ml purified water, 60 ℃ of decompression oven dry got white crystals telmisartan 57g in 12 hours.Yield is 89.3%, and purity is 99.1%.
Comparative Examples 2 is used the refining telmisartan of silicagel column
(1) 100g telmisartan crude product (purity is 98.2%) is scattered in about 1000ml water, slowly add in the sodium hydrogen carbonate solution of 1% (g/ml) then, pH value to solution is 8.0, stirring reaction 30 minutes, the gac that adds 5g then, 50 ℃ of insulated and stirred 20 minutes are filtered, and collect filtrate;
(2) hydrochloric acid soln that drips 2mol/L in above-mentioned filtrate is to be 5.5 to the pH value of solution, and precipitation is separated out in stirring at room reaction 60 minutes, filters, and washs 45 ℃ of vacuum-dryings with less water;
(3) precipitation in the step (2) is dissolved with a small amount of moving phase, add 100g silica gel again and stir, fling to the chromatographic column upper end that is added to preparation behind the solvent, utilize the preparative scale chromatography post to carry out separation and purification, wherein used moving phase is that volume ratio is 1: 2 the Virahol and the mixed solvent of acetonitrile, and stationary phase is a silicagel column, flow velocity is 2.1ml/min, 20 ℃ of column temperatures, wavelength 298nm, collect elutriant, concentrating under reduced pressure, vacuum-drying gets telmisartan 89.4g, yield is 91.0%, and purity is 99.3%.
Comparative example 3 uses the refining telmisartan of Amberlite XAD-6 macroporous resin chromatography
(1) 100g telmisartan crude product (purity is 98.2%) is scattered in about 1000ml water, slowly adds then in the potassium bicarbonate solution of 1% (g/ml), to the pH value of solution be 9, stirring reaction 30 minutes adds the gac of 5g then, 50 ℃ of insulated and stirred 20 minutes, filter, collect filtrate;
(2) acetic acid solution that drips 1mol/L in filtrate is to be 4.7 to the pH value of solution, and precipitation is separated out in stirring at room reaction 60 minutes, filters, and washs 45 ℃ of vacuum-dryings with less water;
(3) precipitation in the step (2) is dissolved with moving phase, adding 100g AmberliteXAD-6 resin again stirs, be added on the chromatographic column of preparation after flinging to solvent, utilize preparation type macroporous resin chromatography to carry out separation and purification, wherein used moving phase is that volume ratio is 1: 3 the Virahol and the mixed solvent of acetonitrile, stationary phase is an Amberlite XAD-6 post, flow velocity is 3.0ml/min, 40 ℃ of column temperatures, wavelength 298nm, collect elutriant, concentrating under reduced pressure, vacuum-drying gets telmisartan 88.3g, yield is 89.9%, and purity is 98.9%.
The comparative example 4: crude product telmisartan directly refining
50g telmisartan crude product (purity is 98.2%) is dissolved with moving phase, adding the 50g neutral alumina again stirs, be added on the chromatographic column of preparation after flinging to solvent, utilize the preparative scale chromatography post to carry out separation and purification, wherein used moving phase is that volume ratio is 1: 3 the Virahol and the mixed solvent of acetonitrile, stationary phase is the neutral alumina post, flow velocity is 2.5ml/min, 30 ℃ of column temperatures, wavelength 298nm, collect elutriant, concentrating under reduced pressure, vacuum-drying gets telmisartan 90.5g, yield is 92.2%, and purity is 99.0%.
The comparative example 5～6: use silicagel column and Amberlite XAD-6 macroporous resin chromatography according to the method described above and replace the neutral alumina post that the crude product telmisartan is carried out directly making with extra care respectively, purity after it separates and productive rate illustrate and directly use the refining effect that can not obtain satisfaction of chromatographic column all not as comparative example 4.
The foregoing description and Comparative Examples have proved absolutely the superiority of particular combinations method of the present invention from different aspects, especially comprise the chromatographic condition and the optimum parameters of neutral alumina post, have brought beyond thought effect, are in theory can't rational expectation.Bound by theory not, what may be various purification process to different impurities in the medicine removes the effect difference, characteristics and obvious improvement that process for purification provided by the invention has essence have obtained beyond thought technique effect, have obtained the highly purified product of high yield.
Foregoing description of the present invention is intended to explaining, rather than restriction.Concerning the art technology people, can carry out multiple variation or modification in the embodiment described herein.Do not depart from the scope of the present invention or spirit in can obtain these variations.Each reference that the application quoted is incorporated herein by reference in full at this.
Claims (8)
1. the telmisartan compound shown in the formula (I) comprises the steps:
(1) the telmisartan crude product is scattered in the water, slowly adds alkali or strong base-weak acid salt then, to the pH value of solution value be 7.5-9.5, generate telmisartan salt, use overall solution volume 0.2-0.8% (g/ml) charcoal absorption then, 40-50 ℃ is stirred 20-30min, filter decarburization, collect filtrate;
(2) with above-mentioned filtrate and acid-respons, generate the telmisartan precipitation, filter, with less water washing, drying;
(3) precipitation in the step (2) is carried out separation and purification with preparation type neutral alumina chromatographic column, collect elutriant, concentrating under reduced pressure, vacuum-drying obtains the pure product of telmisartan.
2. process for purification according to claim 1 is characterized in that described pH value of solution value is 8-9.
3. according to the described process for purification of claim 1-2, it is characterized in that described alkali or strong base-weak acid salt are selected from one or more in sodium hydroxide, potassium hydroxide, yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, sodium acetate, the potassium acetate, are preferably sodium bicarbonate or saleratus.
4. according to the described process for purification of claim 1-3, it is characterized in that with acid-respons to pH value of solution value be 4-6, preferred 4.7-5.5.
5. process for purification according to claim 4 is characterized in that wherein said acid is selected from one or more in hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, Hydrogen bromide, the acetate, preferred hydrochloric acid.
6. according to the described process for purification of claim 1-5, the condition that it is characterized in that chromatographic column is: with volume ratio is 1: Virahol (1-6) and acetonitrile mixed solvent are moving phase, fixed phase stuffing is selected from neutral alumina, and flow velocity is 1.7-5.5ml/min, column temperature 20-40 ℃.
7. process for purification according to claim 6, it is characterized in that moving phase is that volume ratio is 1: the Virahol (2-3) and the mixing solutions of acetonitrile, flow velocity are 2.1-3.0ml/min.
8. the application of telmisartan compound in the preparation Altace Ramipril for preparing according to the described method of claim 1-7.
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| CN102267997A (en) * | 2011-07-15 | 2011-12-07 | 海南美兰史克制药有限公司 | Meropenem compound and preparation method thereof |
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| WO2006044754A2 (en) * | 2004-10-18 | 2006-04-27 | Dr. Reddy's Laboratories Ltd. | Process for preparing telmisartan |
| CN101838243A (en) * | 2010-05-25 | 2010-09-22 | 江西同和药业有限责任公司 | Method for refining telmisartan |
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|---|---|---|---|---|
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