CN1844100A - Process for preparing Torasemide intermediate and its analogue - Google Patents
Process for preparing Torasemide intermediate and its analogue Download PDFInfo
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- CN1844100A CN1844100A CN 200610040077 CN200610040077A CN1844100A CN 1844100 A CN1844100 A CN 1844100A CN 200610040077 CN200610040077 CN 200610040077 CN 200610040077 A CN200610040077 A CN 200610040077A CN 1844100 A CN1844100 A CN 1844100A
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Abstract
The invention relates to a process for preparing torasemide intermediate compound or the like, which comprises selecting right solvent, and carrying reaction at relative mild temperature. The process requires no copper powder, thus the difficulty of purification can be avoided, and large scale production process can be realized.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to the preparation method of torasemide intermediate and analogue thereof.
Background technology
Torasemide is a kind of new quick-acting, potent, long-acting medullary loop hydragog(ue), and is disclosed as toluino between 1-sec.-propyl-3-[(-3-pyridyl at DE2516025 (embodiment 71)) alkylsulfonyl] urea.Except the diuresis function, it also has antihypertensive effect.
The synthetic of torasemide, torasemide intermediate and torasemide derivative is set forth in below with reference in the document: DE2516025; Delarge, J.Ann Pharm.Fr.31,467-474 (1973); Delarge, Mem.Acad.R.Med.Belg.47 (3), 131-210 (1974); Delarge, J.Ann Pharm.Fr.36,369-380 (1978); Iyakuhin Kenkyu, 25 (9), 734-750 (1994); EP618209; US2516025; US6674794; US4244950 all has report.The general preparation method who adopts is as follows:
CN01806834.0 discloses the method that is prepared IV by III; CN200410078738.6 discloses the method that is prepared VI by V.Intermediate V is the important intermediate of preparation torasemide, can make by (3-sulphonamide-4-chlorine) pyridine (IV) and a phenylmethylamine reaction, in existing bibliographical information, this step reaction is reacted with Ullmann usually, copper powder is made catalyzer, reacted the back wet distillation reclaim unnecessary between phenylmethylamine, filter then, pH is transferred in decolouring.Bigger with the wet distillation power consumption, and waste time and energy.The product of gained tends to contain a spot of cupric ion, need repeatedly the soda acid purifying just can obtain the ideal product, and total recovery is lower, is about 30～60%.
Summary of the invention
The invention discloses a kind of method for preparing compounds X and analogue thereof, select appropriate solvent for use, under gentle relatively temperature, react, without copper powder, avoid purification difficult, and can obtain high yield and highly purified product, this method is applicable to large-scale production process.
Preparation method of the present invention is as follows:
The method for preparing the general formula X compound comprises formula XI compound and the reaction of formula IV compound,
It is characterized in that: reaction solvent is selected from methyl alcohol, ethanol, Virahol, propyl carbinol, acetonitrile, dinethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide (DMSO)
Wherein R is alkyl or the trifluoromethyl of C1～C4.
Above-mentioned preparation method, wherein reaction solvent is selected from ethanol, acetonitrile or N, dinethylformamide.
Above-mentioned preparation method wherein is reflected under 50 ℃～150 ℃ and carries out.Preferred 75 ℃～120 ℃.
Above-mentioned preparation method also comprises: reclaims solvent, adds water, and organic solvent extraction, water layer adds activated carbon decolorizing, transfers pH6～7, crystallization with acid.
The organic solvent of extraction usefulness is preferably from ether, isopropyl ether, t-butyl methyl ether, methylene dichloride, chloroform or ethyl acetate.More preferably isopropyl ether or chloroform.
Wherein the amount that adds of water is 5～30 times of compound IV weight, preferred 15～25 times.More preferably 8～12 times.
Reaction times is 2～10 hours, preferred 4～8 hours.
Preparation method of the present invention, wherein R preferable methyl or trifluoromethyl.
According to method of the present invention, be respectively that the alkyl of C1～C4, the compound and a phenylmethylamine (IV) of trifluoromethyl mix back adding appropriate organic solvent with R.Preferably, R is a methyl, trifluoromethyl.Suitable have and solvent comprises methyl alcohol, ethanol, Virahol, propyl carbinol, N, dinethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide (DMSO).When R was methyl, preferred solvent was ethanol, acetonitrile, N, dinethylformamide.The preferred weight of solvent that adds is 8～12 times of compound (XI) weight.Stirring heating is finished up to reaction then.Preferred temperature of reaction is 75 ℃～120 ℃, and the reaction times is 4～8 hours.Can (developping agent be an ethyl acetate: methyl alcohol: Glacial acetic acid=90: 5: 5) detect to judge whether reaction is finished by TLC.After reaction is finished, decompression and solvent recovery.Adding entry then stirs.The amount that preferably adds entry is 15～25 times of compound (IV) weight.Add NaOH solution again and transfer pH11～12.Add organic solvent extraction, suitable have and solvent comprises ether, isopropyl ether, t-butyl methyl ether, methylene dichloride, chloroform and ethyl acetate.Preferred extraction solvent is isopropyl ether or chloroform.Water layer is transferred pH6～7, crystallization with acid after adding activated carbon decolorizing.Available acid is hydrochloric acid and sulfuric acid.Preferred acid is 2%～38% hydrochloric acid.Preferred acid is 10% hydrochloric acid.Filter, washing, oven dry can obtain 3-sulphonamide-4-(3 '-aminomethyl phenyl) aminopyridine and the analogue thereof of content more than 95%, and yield is more than 85%.Acid-alkali refining can obtain the product of content more than 98% again.
Preparation method of the present invention is simple to operate, reaction conditions gentleness, good product purity, yield height.
Embodiment
Embodiment 1
Synthesizing of 3-sulphonamide-4-(3 '-aminomethyl phenyl) aminopyridine
In a 1000mL three-necked bottle that mechanical stirrer, condenser, thermometer be housed, add (3-sulphonamide-4-chlorine) pyridine 20g (0.104mol), phenylmethylamine 27.8g (0.26mol) and propyl carbinol 400g, stir, add 95～105 ℃ of reactions of temperature 5h in the thermal control.Decompression and solvent recovery.Stir and add entry down while hot.Be cooled to 30 ℃ and add 8% sodium hydroxide down, make it molten clear (pH12).Be cooled to 20 ℃ and extract layering with the 120g isopropyl ether, water layer uses 60g * 2 time to extract again.Water layer adds activated carbon decolorizing filtration in 15 minutes, and filter cake merges washing filtrate with a small amount of washing, is cooled to 5～10 ℃ with 10% hydrochloric acid soln adjusting pH to 7, stirs 30 minutes.Filter, filter cake is with frozen water washing 3 times, 80 ℃ dry off-white color solid 24.3g, yield 88.7%.
Embodiment 2
Synthesizing of 3-sulphonamide-4-(3 '-aminomethyl phenyl) aminopyridine
In a 1000mL three-necked bottle that mechanical stirrer, condenser, thermometer be housed, add (3-sulphonamide-4-chlorine) pyridine 20g (0.104mol), phenylmethylamine 27.8g (0.26mol) and N, dinethylformamide 400g stirs, and adds 95～105 ℃ of reactions of temperature 5h in the thermal control.Decompression and solvent recovery.Stir and add entry down while hot.Be cooled to 30 ℃ and add 8% sodium hydroxide down, make it molten clear (pH12).Be cooled to 20 ℃ and extract layering with the 120g isopropyl ether, water layer uses 60g * 2 time to extract again.Water layer adds activated carbon decolorizing filtration in 15 minutes, and filter cake merges washing filtrate with a small amount of washing, is cooled to 5～10 ℃ with 10% hydrochloric acid soln adjusting pH to 7, stirs 30 minutes.Filter, filter cake is with frozen water washing 3 times, 80 ℃ dry off-white color solid 23.9g, yield 87.2%.
Embodiment 3
Synthesizing of 3-sulphonamide-4-(3 '-trifluoromethyl) aminopyridine
In a 1000mL three-necked bottle that mechanical stirrer, condenser, thermometer be housed, add (3-sulphonamide-4-chlorine) pyridine 20g (0.104mol), mamino-trifluoromethyl benzene 41.9g (0.26mol) and DMSO 400g, stir, add 95～105 ℃ of reactions of temperature 7h in the thermal control.Decompression and solvent recovery.Stir and add entry down while hot.Be cooled to 30 ℃ and add 8% sodium hydroxide down, make it molten clear (pH12).Be cooled to 20 ℃ and extract layering with the 120g isopropyl ether, water layer uses 60g * 2 time to extract again.Water layer adds activated carbon decolorizing filtration in 15 minutes, and filter cake merges washing filtrate with a small amount of washing, is cooled to 5～10 ℃ with 10% hydrochloric acid soln adjusting pH to 7, stirs 30 minutes.Filter, filter cake is with frozen water washing 3 times, 80 ℃ dry off-white color solid 29.2g, yield 88.4%.
Embodiment 4
Synthesizing of 3-sulphonamide-4-(3 '-trifluoromethyl) aminopyridine
In a 1000mL three-necked bottle that mechanical stirrer, condenser, thermometer be housed, add (3-sulphonamide-4-chlorine) pyridine 20g (0.104mol), mamino-trifluoromethyl benzene 41.9g (0.26mol) and propyl carbinol 400g, stir, add 95～105 ℃ of reactions of temperature 7h in the thermal control.Decompression and solvent recovery.Stir and add entry down while hot.Be cooled to 30 ℃ and add 8% sodium hydroxide down, make it molten clear (pH12).Be cooled to 20 ℃ and extract layering with the 120g isopropyl ether, water layer uses 60g * 2 time to extract again.Water layer adds activated carbon decolorizing filtration in 15 minutes, and filter cake merges washing filtrate with a small amount of washing, is cooled to 5～10 ℃ with 10% hydrochloric acid soln adjusting pH to 7, stirs 30 minutes.Filter, filter cake is with frozen water washing 3 times, 80 ℃ dry off-white color solid 30.2g, yield 91.5%.
Embodiment 5
Synthesizing of 3-sulphonamide-4-(3 '-trifluoromethyl) aminopyridine
In a 1000mL three-necked bottle that mechanical stirrer, condenser, thermometer be housed, add (3-sulphonamide-4-chlorine) pyridine 20g (0.104mol), mamino-trifluoromethyl benzene 41.9g (0.26mol) and N, dinethylformamide 400g stirs, and adds 95～105 ℃ of reactions of temperature 7h in the thermal control.Decompression and solvent recovery.Stir and add entry down while hot.Be cooled to 30 ℃ and add 8% sodium hydroxide down, make it molten clear (pH12).Be cooled to 20 ℃ and extract layering with the 120g isopropyl ether, water layer uses 60g * 2 time to extract again.Water layer adds activated carbon decolorizing filtration in 15 minutes, and filter cake merges washing filtrate with a small amount of washing, is cooled to 5～10 ℃ with 10% hydrochloric acid soln adjusting pH to 7, stirs 30 minutes.Filter, filter cake is with frozen water washing 3 times, 80 ℃ dry off-white color solid 28.7g, yield 86.9%.
Claims (6)
1, the method for preparing the general formula X compound comprises formula XI compound and the reaction of formula IV compound,
It is characterized in that: reaction solvent is selected from methyl alcohol, ethanol, Virahol, propyl carbinol, acetonitrile, dinethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide (DMSO)
Wherein R is alkyl or the trifluoromethyl of C1～C4.
2, the preparation method of claim 1, wherein reaction solvent is selected from ethanol, acetonitrile or N, dinethylformamide.
3, the preparation method of claim 1 wherein is reflected under 50 ℃～150 ℃ and carries out.
4, the preparation method of claim 1 also comprises: reclaims solvent, adds water, and organic solvent extraction, water layer adds activated carbon decolorizing, transfers pH6～7, crystallization.
5, the preparation method of claim 4, the organic solvent that wherein extracts usefulness is selected from ether, isopropyl ether, t-butyl methyl ether, methylene dichloride, chloroform or ethyl acetate.
6, the preparation method of claim 1, wherein R is methyl or trifluoromethyl.
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| CNB2006100400777A CN100556893C (en) | 2006-04-30 | 2006-04-30 | A kind of method for preparing torasemide intermediate and analogue thereof |
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| CNB2006100400777A CN100556893C (en) | 2006-04-30 | 2006-04-30 | A kind of method for preparing torasemide intermediate and analogue thereof |
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| CN1844100A true CN1844100A (en) | 2006-10-11 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114456104A (en) * | 2022-01-26 | 2022-05-10 | 南京正科医药股份有限公司 | Synthetic method of torasemide key intermediate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114456104A (en) * | 2022-01-26 | 2022-05-10 | 南京正科医药股份有限公司 | Synthetic method of torasemide key intermediate |
| CN114456104B (en) * | 2022-01-26 | 2023-08-25 | 南京正科医药股份有限公司 | Synthesis method of torasemide key intermediate |
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| CN100556893C (en) | 2009-11-04 |
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