CN102079721A - Torasemide compound and new preparation method thereof - Google Patents
Torasemide compound and new preparation method thereof Download PDFInfo
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- CN102079721A CN102079721A CN 201110031844 CN201110031844A CN102079721A CN 102079721 A CN102079721 A CN 102079721A CN 201110031844 CN201110031844 CN 201110031844 CN 201110031844 A CN201110031844 A CN 201110031844A CN 102079721 A CN102079721 A CN 102079721A
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Abstract
The invention provides a torasemide compound and a new preparation method thereof, and the method comprises the following steps: (1) processing the torasemide raw material by alkali metals or alkaline earth metal alkane oxides with the presence of an appropriate solvent or solvent mixture under an alkaline and heating condition; (2) adjusting the pH value by an appropriate acid; (3) adsorbing the torasemide by strong basic ion exchange resin and eluting the product; (4) adjusting the pH value by an appropriate acid to obtain a three-stage purified torasemide. The preparation method of torasemide improves the product quality of the preparation, reduces the toxic and side effects, is simple and easy to operate, and is applicable to large-scale industrial production.
Description
Technical field
The present invention relates to a kind of torasemide compound and new preparation method thereof, belong to medical technical field.
Background technology
(English name: Torasemide), its chemical name is torasemide: N-(((1-methylethyl) amino) carbonyl)-4-((3-aminomethyl phenyl) amino)-3-pyridine sulfonamide, molecular formula: C
16H
20N
4O
3S, molecular weight: 348.43, structural formula is:
Torasemide is the efficient loop diuretic of a new generation, goes on the market in Germany in 1993, and next year goes on the market in the U.S., first torasemide hydro-acupuncture preparation (Te Suni) in China SFDA approval producing countries in 2004.Torasemide is a sulfonylurea pyridines hydragog(ue), and it acts on the Heng Lishi ascending thick limb of Henle's loop, suppresses Na
+/ K
+/ 2Cl
-Carrier system makes Na in the urine
+, Cl
-Increase with the drainage of water, but to glomerular filtration rate(GFR, acid base equilibrium does not make significant difference in renal plasma flow or the body.Be mainly used in diseases such as treatment congestive heart failure, hypertension, renal insufficiency, renal edema, hepatic ascites and cerebral edema clinically.
Order China pharmaceutical chemistry magazine, 2002,12 (4) phases, reported a kind of synthetic method of torasemide, with the 4-pyridone is raw material, the chlorine atom by sulfonation, chloro, Clofenamideization, No. 4 positions of pyridine ring by the 3-monomethylaniline replace, with 5 step prepared in reaction such as isopropyl isocyanate condensation torasemide.Synthetic route is:
This synthetic method cost height, yield is low, and the torasemide purity that makes is lower.
In addition, the fine or not direct relation of torasemide raw materials quality the quality of the pharmaceutical preparations of producing, and ropy torasemide raw material has influenced the yield of producing in process of production, increases cost.
The method that obtains high purity, high yield, high-load torasemide compound becomes the focus of current research.
Summary of the invention
In order to overcome the defective of above-mentioned prior art, particularly overcome the low defective of torasemide purity of prior art for preparing, the invention provides a kind of new preparation method of torasemide, it is made with extra care by torasemide, obtain the high purity torasemide with high yield, improved the quality product of preparation, reduced toxic side effect, ensure the quality of raw material, improved the production yield.
Process for purification provided by the invention at torasemide be prepared torasemide crude product of present known synthetic method or commercially available torasemide bulk drug, below be referred to as raw material torasemide or torasemide crude product that the present invention adopts.
The inventor by comprising the process for purification of following treatment step, can increase substantially the purity of raw material torasemide through discovering with keen determination:
(1) in the presence of suitable solvent or solvent mixture, under alkaline condition, under heating, handles the raw material torasemide with basic metal or alkaline-earth metal alkyl oxide;
(2) with suitable acid for adjusting pH value, the torasemide precipitation is separated out in cooling, obtains the torasemide of elementary purification;
(3) with strong basic ion exchange resin torasemide is adsorbed, wash-out is collected elutriant then, and concentrating under reduced pressure obtains the torasemide that secondary is purified;
(4) with suitable acid for adjusting pH value, carry out crystallization, with the crystal centrifuge washing of separating out, drying, the torasemide of three grades of purifications of acquisition.
By aforesaid method, can obtain highly purified torasemide with high yield from the torasemide crude product.
Embodiment
Describe the present invention below in conjunction with embodiment.Characteristics of the present invention and advantage can become more clear along with these descriptions.
Step (1)
In the step (1) of the process for purification of torasemide compound provided by the invention, in the presence of suitable solvent or solvent mixture, under alkaline condition, under heating, handle the raw material torasemide with basic metal or alkaline-earth metal alkyl oxide, use suitable acid for adjusting pH value then, the torasemide precipitation is separated out in cooling, obtains the torasemide of elementary purification.
In this step (1), optionally solvent or solvent mixture can be the solvents that can dissolve torasemide, also can be the torasemide solvents of suspendible therein.
In this step (1), to handle the raw material torasemide with basic metal or alkaline-earth metal alkyl oxide and under alkaline condition, carry out, preferred pH value is the alkaline condition more than 10, more preferably pH value is the alkaline condition of 11-13.
For the alkalescence of the system of readjusting prices, can use sodium hydroxide solution or potassium hydroxide solution.
In this step (1), described solvent is selected from the lower alcohol that can make the reaction mixture homogenizing.Described lower alcohol solvent comprises primary alconol, secondary alcohol or the tertiary alcohol with 1 to 6 carbon atom, particular methanol, ethanol or its mixture.Also can use the mixture of two or more lower alcohols.
As preferred version, use and basic metal or the identical solvent of alkaline-earth metal alkyl oxide anionicsite are as alcoholic solvent, as methyl alcohol, ethanol, propyl alcohol or butanols.
Can use any basic metal or alkaline-earth metal alkyl oxide (being alcoholate) in principle, preferred as alkali alkoxide, the more preferably alkoxide of sodium or potassium, for example sodium methylate, sodium ethylate, potassium methylate or potassium ethylate.
Basic metal or alkaline-earth metal alkyl oxide generally at first are dissolved in the alcoholic solvent, preferably are dissolved in the solvent identical with its anionicsite.For example sodium methylate or potassium methylate are dissolved in the methyl alcohol, and sodium ethylate or potassium ethylate are dissolved in the ethanol.
Basic metal or alkaline-earth metal alkyl oxide can carry out in preferred 89-95 ℃ of scope at 80-98 ℃ the processing of torasemide.
Be not subjected to the constraint of any principle, step of the present invention (1) adopts basic metal or alkaline-earth metal alkyl oxide that torasemide is handled the effect that why can reach purification, may be based on following reason:
Under alkaline condition, in the presence of the such alkaline matter of basic metal or alkaline-earth metal alkyl oxide, help Ester hydrolysis as impurity, effectively reduced impurity, in addition, some impurity materials also can be dissolved in the alcoholic solvent at basic metal or alkaline-earth metal alkyl oxide place, thereby separate with torasemide.
Step (2)
In the step (2) of the process for purification of torasemide compound provided by the invention, with suitable acid for adjusting pH value, the torasemide precipitation is separated out in cooling, obtains the torasemide of elementary purification;
After the processing of above-mentioned steps (1),,, separate out the torasemide precipitation along with temperature reduces with suitable acid for adjusting pH.
According to the present invention, the suitable acid that can adopt in this step is one or more in hydrochloric acid, citric acid, nitric acid, acetate, acetic acid, boric acid, the phosphoric acid, preferred hydrochloric acid, phosphoric acid or acetic acid.
According to the present invention, in this step, the pH value is adjusted to 6.0～10 with acid, be preferably 6.0～8.0, most preferably be 6.0.
Step (3)
In the step (3) of the process for purification of torasemide compound provided by the invention, with strong basic ion exchange resin torasemide is adsorbed, wash-out is collected elutriant then, and concentrating under reduced pressure obtains the torasemide that secondary is purified.
In step (3), use the water dissolution torasemide, adsorb with strong basic ion exchange resin again.
To be that the ion exchange resin of cation exchange groups is called strong basic ion exchange resin generally, show alkalescence by dissociateing hydroxide ion with the quaternary amine base.Strong basic ion exchange resin commonly used is to get through chloromethylation and tertiary amineization with vinylbenzene-divinylbenzene copolymerization spherolite.When with the Trimethylamine 99 amination, obtain I type strongly basic anionic resin; During with the dimethylethanolamine amination, obtain II type strongly basic anionic resin.
Generally speaking, also contain the solvent of introducing in the preparation process, various raw material and intermediate product in the raw material torasemide, owing to drawing the moist moisture of bringing into, bacterial endotoxin, and various inorganics and heavy metal etc.These materials exist with the impurity form, influence the purity of raw material torasemide.Basic resin used in the present invention has the general utility functions of ion exchange resin.When contacting with the solution that contains torasemide, except playing ion exchange, also have the function of absorption nonelectrolyte class material from solution, therefore can adsorb above-mentioned remaining impurity material; In addition, itself has decolorization resin, can remove the impurity of colour developing, and its effect is better than gac.
Itself is again macroreticular ion exchange resin for a basic resin used in the present invention, has similar gac, zeolite sample physical holes structure, and the aperture ratio intermolecular distance of macropore is much bigger, the aperture also at tens of dusts to dusts up to ten thousand.Macropore is not the part of the high-molecular gel form of resin, and its existence makes high-molecular gel be two phase structure, i.e. macropore and high-molecular gel skeleton, and macropore occupies certain space in the resin spheroid.And gel skeleton also has the existence of gel pore.This constructional feature of macroreticular ion exchange resin is the physical basis of its performance above-mentioned functions.
The present invention can use common macroporous type strong basic ion exchange resin, the polystyrene I type strongly basic anionic resin of Amberlite IRA-900 and IRA-904 for example, the II type strongly basic anionic resin of IRA-911, D201 macroporous strong basic styrene series anionite-exchange resin, the macroporous type strongly basic anionic resin of D-235, the strongly basic anion exchange resin of 201X7, or the like.Above-mentioned these strongly basic anionic resins all are commercial prods, can certainly use the macroporous type strong basic ion exchange resin of other trade names.
According to the present invention, the solution that contains torasemide can adopt the technology of continous way or discontinuous formula by strongly basic anionic resin.Particularly, comprise batch process, fixed-bed process and continuous process.
Batch operation is to carry out in retort, the exchange solution enter the jar from the bottom, then feed gas continuously and make the resin fluidization or add stirring with speeding-up ion exchange equilibrium process, reach balance after exchange process just stop, emitting solution from the bottom then.
Fixed-bed process is ion exchange resin to be filled out to be placed on form resin bed in the exchange column, feeds solution then and handles.Solution usually is that from the top down concurrent is carried out in the fixed bed operation, also can be opposite with the flow direction of exchange solution, and the counter-current regeneration mode of Tong Ruing can also adopt the convection reflux type in addition from bottom to top.
After reaching balance, by adopting alkali metal hydroxide (regeneration of resin), the torasemide that adsorbs is eluted, preferably use the aqueous solution of potassium hydroxide or sodium hydroxide.Collect elutriant, concentrating under reduced pressure forms the wash-out mother liquor.
Step (4)
In the step (4) of the process for purification of torasemide compound provided by the invention, with suitable acid for adjusting pH value, carry out crystallization, with the crystal centrifuge washing of separating out, drying obtains the torasemide of three grades of purifications.
According to the present invention, the suitable acid that can adopt in this step in this step is one or more in hydrochloric acid, citric acid, nitric acid, acetate, acetic acid, boric acid, the phosphoric acid, preferred hydrochloric acid, phosphoric acid or acetic acid.
According to the present invention, the pH value is adjusted to 6.0～10 in this step, is preferably 6.0～8.0, most preferably is 6.0.
For the torasemide that makes by process for purification of the present invention, its purity is very high, and yield is also higher.The purity of the torasemide that obtains by the inventive method can be up to more than 99.8%, and yield surpasses 90%.
The purity of torasemide is obvious to the influence of its powder flowbility, intrinsic dissolution rate, Pickering and the preparation quality prepared, the torasemide that purity is improved also correspondingly improves in these areas, thereby improve the quality product of preparation, reduce toxic side effect, ensured safety of clinical administration.Present method can ensure the quality of product, and simple, easy handling is suitable for large-scale industrial production.
In this article, if not explanation especially, content or consumption are all in weight part, the device that is adopted, instrument, raw material, material, consumption, method, time, appropriateness and other conditions all be well-known in the art, or those skilled in the art can obtain in conjunction with prior art according to the description of application.
Embodiment
Further specify the present invention by the following examples, but the present invention is not limited to the preparation method of these embodiment and use.And those skilled in the art can be equal to replacement, combination, improvement or modification to the present invention according to description of the invention, but these all will comprise within the scope of the invention.
The D201 macroporous strong basic styrene series anionite-exchange resin that uses in following examples,
IRA-900 anionite-exchange resin be the resin of industrial extensive employing, can buy by commercially available.
Making with extra care of embodiment 1 torasemide
100g crude product torasemide crude product is scattered in the 1000ml water forms water dispersion, dripping 0.5mol/L sodium hydroxide solution to pH value then in water dispersion is 11,95 ℃ of heated and stirred add the ethanolic soln 200ml of 1mol/L sodium ethylate then to clarification, stir down and handle 2 hours.
Regulating the pH value with the hydrochloric acid soln of 1mol/L then is 6.0, separates out solid, filters.
Precipitation is dissolved in the 800ml water, and adding is filled with in the fixed bed of D201 macroporous strong basic styrene series anionite-exchange resin, continues exchange 2.5 hours, uses 1.0mol/L sodium hydroxide solution wash-out then, collects elutriant, concentrating under reduced pressure.
Regulating pH value with the acetum of 0.5mol/L is 6.0, separates out solid, filters, wash with water 3 times, dry 6 hours of 50 ℃ of reduced vacuum, highly purified torasemide 93.2g, yield 93.2%, HPLC method detection purity is 99.91%.
Making with extra care of embodiment 2 torasemides
100g crude product torasemide crude product is scattered in the 1000ml water forms water dispersion, dripping 0.2mol/L sodium hydroxide solution to pH value then in water dispersion is 13,89 ℃ of heated and stirred add the ethanolic soln 200ml of 1mol/L sodium ethylate then to clarification, stir down and handle 2 hours.
Regulating the pH value with the hydrochloric acid soln of 1mol/L then is 6.0, separates out solid, filters.
Precipitation is dissolved in the 800ml water, and adding is filled with in the fixed bed of D201 macroporous strong basic styrene series anionite-exchange resin, continues exchange 2.5 hours, uses 1.0mol/L sodium hydroxide solution wash-out then, collects elutriant, concentrating under reduced pressure.
Regulating pH value with the phosphoric acid solution of 0.5mol/L is 6.0, separates out solid, filters, wash with water 3 times, dry 10 hours of 45 ℃ of reduced vacuum, highly purified torasemide 92.7g, yield 92.7%, HPLC method detection purity is 99.93%.
Making with extra care of embodiment 3 torasemides
100g crude product torasemide crude product is scattered in the 2000ml water forms water dispersion, dripping 1mol/L sodium hydroxide solution to pH value then in water dispersion is 12,90 ℃ of heated and stirred add the ethanolic soln 200ml of 1mol/L sodium ethylate then to clarification, stir down and handle 2 hours.
Regulating the pH value with the hydrochloric acid soln of 0.5mol/L then is 6.0, separates out solid, filters.
Precipitation is dissolved in the 800ml water, and adding is filled with in the fixed bed of D201 macroporous strong basic styrene series anionite-exchange resin, continues exchange 2.5 hours, uses 1.0mol/L sodium hydroxide solution wash-out then, collects elutriant, concentrating under reduced pressure.
Regulating pH value with the hydrochloric acid soln of 0.5mol/L is 6.0, separates out solid, filters, wash with water 3 times, dry 8 hours of 50 ℃ of reduced vacuum, highly purified torasemide 93.4g, yield 93.4%, HPLC method detection purity is 99.97%.
Making with extra care of embodiment 4 torasemides
100g crude product torasemide crude product is scattered in the 2000ml water forms water dispersion, dripping 1mol/L sodium hydroxide solution to pH value then in water dispersion is 11.5,98 ℃ of heated and stirred add the ethanolic soln 200ml of 1mol/L sodium ethylate then to clarification, stir down and handle 2 hours.
Regulating the pH value with the acetum of 0.5mol/L then is 6.0, separates out solid, filters.
Precipitation is dissolved in the 800ml water, and adding is filled with in the fixed bed of D201 macroporous strong basic styrene series anionite-exchange resin, continues exchange 2.5 hours, uses 1.0mol/L sodium hydroxide solution wash-out then, collects elutriant, concentrating under reduced pressure.
Regulating pH value with the hydrochloric acid soln of 0.5mol/L is 6.0, separates out solid, filters, wash with water 3 times, dry 6 hours of 50 ℃ of reduced vacuum, highly purified torasemide 92.4g, yield 92.4%, HPLC method detection purity is 99.92%.
Making with extra care of embodiment 5 torasemides
100g crude product torasemide crude product is scattered in the 1000ml water forms water dispersion, dripping 0.6mol/L sodium hydroxide solution to pH value then in water dispersion is 11,98 ℃ of heated and stirred add the ethanolic soln 200ml of 1mol/L sodium ethylate then to clarification, stir down and handle 2 hours.
Regulating the pH value with the boric acid solution of 0.5mol/L then is 6.0, separates out solid, filters.
Precipitation is dissolved in the 800ml water, and adding is filled with in the fixed bed of D201 macroporous strong basic styrene series anionite-exchange resin, continues exchange 2.5 hours, uses 1.0mol/L sodium hydroxide solution wash-out then, collects elutriant, concentrating under reduced pressure.
Regulating pH value with the hydrochloric acid soln of 0.5mol/L is 6.0, separates out solid, filters, wash with water 3 times,, dry 6 hours of 55 ℃ of reduced vacuum, highly purified torasemide 91.9g, yield 91.9%, HPLC method detection purity is 99.91%.
Claims (10)
1. the torasemide compound of structure shown in the formula (I),
Its method for making comprises the steps:
(1) in the presence of suitable solvent or solvent mixture, under alkaline condition, under heating, handles the raw material torasemide with basic metal or alkaline-earth metal alkyl oxide;
(2) with suitable acid for adjusting pH value, the torasemide precipitation is separated out in cooling, obtains the torasemide of elementary purification;
(3) with strong basic ion exchange resin torasemide is adsorbed, wash-out is collected elutriant then, and concentrating under reduced pressure obtains the torasemide that secondary is purified;
(4) with suitable acid for adjusting pH value, carry out crystallization, with the crystal centrifuge washing of separating out, drying, the torasemide of three grades of purifications of acquisition.
2. method for making according to claim 1, wherein, in step (1), described solvent or solvent mixture are selected from a kind of or its mixture in primary alconol, secondary alcohol or the tertiary alcohol with 1 to 6 carbon atom, particular methanol, ethanol or its mixture.
3. method for making according to claim 1, wherein, in step (1), described alkaline condition is that pH value is the alkaline condition more than 10, more preferably pH value is the alkaline condition of 11-13.
4. method for making according to claim 1 wherein, in step (1), at 80-98 ℃, under the temperature in the preferred 89-95 ℃ of scope, is handled the raw material torasemide with basic metal or alkaline-earth metal alkyl oxide.
5. method for making according to claim 1, wherein, in step (1), described alkali metal alkoxide is the alkoxide of sodium or potassium, for example sodium methylate, sodium ethylate, potassium methylate or potassium ethylate.
6. method for making according to claim 1, wherein, in step (2), described acid is one or more in hydrochloric acid, citric acid, nitric acid, acetate, acetic acid, boric acid, the phosphoric acid, preferred hydrochloric acid, phosphoric acid or acetic acid.
7. method for making according to claim 1 wherein, in step (2), is adjusted to 6.0～10 with acid with the pH value, is preferably 6.0～8.0, most preferably is 6.0.
8. method for making according to claim 1, wherein, in step (3), described strong basic ion exchange resin is a D201 macroporous strong basic styrene series anionite-exchange resin fire
IRA-900 anionite-exchange resin.
9. method for making according to claim 1, wherein, in step (4), described acid is one or more in hydrochloric acid, citric acid, nitric acid, acetate, acetic acid, boric acid, the phosphoric acid, preferred hydrochloric acid, phosphoric acid or acetic acid.
10. method for making according to claim 1 wherein, in step (4), is adjusted to 6.0～10 with acid with the pH value, is preferably 6.0～8.0, most preferably is 6.0.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102432532A (en) * | 2011-11-10 | 2012-05-02 | 天津市汉康医药生物技术有限公司 | High purity torasemide compounds |
| CN104370805A (en) * | 2013-08-13 | 2015-02-25 | 天津汉瑞药业有限公司 | Torasemide compound |
| CN114989077A (en) * | 2022-06-22 | 2022-09-02 | 南京正科医药股份有限公司 | New impurity reference substance of torasemide and synthetic method thereof |
| CN115010659A (en) * | 2022-06-22 | 2022-09-06 | 南京正科医药股份有限公司 | New impurity reference substance of torasemide and preparation method thereof |
| CN115417810A (en) * | 2022-09-22 | 2022-12-02 | 南京正科医药股份有限公司 | Refining method of torasemide crystal form I |
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| CA2424644A1 (en) * | 2003-04-07 | 2004-10-07 | David John Mckenzie | Preparation of torasemide |
| CN101717365A (en) * | 2009-10-09 | 2010-06-02 | 天茂实业集团股份有限公司 | Method for purification of torasemide and preparation of big crystal form |
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2011
- 2011-01-28 CN CN2011100318449A patent/CN102079721B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2424644A1 (en) * | 2003-04-07 | 2004-10-07 | David John Mckenzie | Preparation of torasemide |
| CN101717365A (en) * | 2009-10-09 | 2010-06-02 | 天茂实业集团股份有限公司 | Method for purification of torasemide and preparation of big crystal form |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102432532A (en) * | 2011-11-10 | 2012-05-02 | 天津市汉康医药生物技术有限公司 | High purity torasemide compounds |
| CN102432532B (en) * | 2011-11-10 | 2014-06-18 | 天津市汉康医药生物技术有限公司 | High-purity torasemide compound |
| CN104370805A (en) * | 2013-08-13 | 2015-02-25 | 天津汉瑞药业有限公司 | Torasemide compound |
| CN114989077A (en) * | 2022-06-22 | 2022-09-02 | 南京正科医药股份有限公司 | New impurity reference substance of torasemide and synthetic method thereof |
| CN115010659A (en) * | 2022-06-22 | 2022-09-06 | 南京正科医药股份有限公司 | New impurity reference substance of torasemide and preparation method thereof |
| CN115417810A (en) * | 2022-09-22 | 2022-12-02 | 南京正科医药股份有限公司 | Refining method of torasemide crystal form I |
| CN115417810B (en) * | 2022-09-22 | 2023-10-10 | 南京正科医药股份有限公司 | Refining method of torsemide crystal form I |
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