CN100556893C - A kind of method for preparing torasemide intermediate and analogue thereof - Google Patents
A kind of method for preparing torasemide intermediate and analogue thereof Download PDFInfo
- Publication number
- CN100556893C CN100556893C CNB2006100400777A CN200610040077A CN100556893C CN 100556893 C CN100556893 C CN 100556893C CN B2006100400777 A CNB2006100400777 A CN B2006100400777A CN 200610040077 A CN200610040077 A CN 200610040077A CN 100556893 C CN100556893 C CN 100556893C
- Authority
- CN
- China
- Prior art keywords
- preparation
- add
- solvent
- compound
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The present invention relates to the pharmaceutical chemistry field, be specifically related to the preparation method of torasemide intermediate and analogue thereof.By selecting appropriate solvent for use, under gentle relatively temperature, react, without copper powder, avoid purification difficult, and can obtain high yield and highly purified product, preparation method of the present invention is applicable to large-scale production process.
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 (4)
1, prepare the method for general formula X compound, comprising: with formula XI compound and the reaction of formula IV compound, reclaim solvent, add water, the isopropyl ether extraction, water layer adds activated carbon decolorizing, transfers pH6～7, crystallization,
Wherein reaction solvent is selected from methyl alcohol, ethanol, Virahol, propyl carbinol, acetonitrile, N, 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, wherein R is methyl or trifluoromethyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100400777A CN100556893C (en) | 2006-04-30 | 2006-04-30 | A kind of method for preparing torasemide intermediate and analogue thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100400777A CN100556893C (en) | 2006-04-30 | 2006-04-30 | A kind of method for preparing torasemide intermediate and analogue thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1844100A CN1844100A (en) | 2006-10-11 |
| CN100556893C true CN100556893C (en) | 2009-11-04 |
Family
ID=37063071
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006100400777A Active CN100556893C (en) | 2006-04-30 | 2006-04-30 | A kind of method for preparing torasemide intermediate and analogue thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100556893C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2006
- 2006-04-30 CN CNB2006100400777A patent/CN100556893C/en active Active
Non-Patent Citations (1)
| Title |
|---|
| 新型降压利尿药－托拉塞米的合成研究. 熊振湖等.中国药物化学杂志，第12卷第4期. 2002 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1844100A (en) | 2006-10-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102311392B (en) | Synthetic method of azoxystrobin and special intermediate for synthesis | |
| CN100418953C (en) | Process for manufacture of telmisartan | |
| CN103304512A (en) | Preparation method for febuxostat | |
| CN112679420B (en) | Preparation method of 2,5-dibromopyridine | |
| CN112707836A (en) | Preparation method of m-diamide compound | |
| CN103373989A (en) | Preparation method of intermediate of pazopanib hydrochloride | |
| CN100556893C (en) | A kind of method for preparing torasemide intermediate and analogue thereof | |
| CN101265172B (en) | Technique for synthesizing buparvaquone | |
| WO2001042240A1 (en) | Process for the preparation of a pyridinemethanol compound | |
| CN107602570A (en) | A kind of nitrogenous polynary and heterocyclic compound method of synthesis | |
| CN103772189B (en) | Synthesis method of diethylstilbestrol compound methyl pigeon pea ketonic acid A | |
| NZ582589A (en) | Process for producing toluidine compound fluazinam | |
| CN1321972C (en) | Process of preparing 4-nitro phthalic acid from the reaction mother liquor of nitrating phthalic anhydride to prepare 3-nitro phthalic acid | |
| CN102516182B (en) | Preparation method for 4-amino-6-alkoxyl pyrimidine compounds | |
| CN103539728A (en) | Synthesis method of lansoprazole drug intermediate chloromethyl pyridine derivative | |
| CN103373963A (en) | Intermediate of pazopanib hydrochloride and preparation method of intermediate of pazopanib hydrochloride | |
| CN105130972A (en) | Emtricitabine benzoate, preparation method thereof, and method of preparing emtricitabine from emtricitabine benzoate | |
| CN101516817A (en) | Process for the preparation of trifluoroethoxytoluenes | |
| CN111303047A (en) | Synthesis method of 2-amino-4, 6-dimethylpyridine | |
| CN103274998B (en) | Preparation method of flupirtine maleate | |
| CN105418507A (en) | Preparation method for 1-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine | |
| CN103804187A (en) | Synthesis method of diethylstilbestrol compound pigeon pea ketonic acid A | |
| CN115677707B (en) | Method for preparing 2,4,6, 8-tetrahydroxypyrimido [5,4-d ] pyrimidine by diaminomaleonitrile method | |
| CN102351779A (en) | Preparation method of fexofenadine intermediate | |
| CN104876830A (en) | Preparing method of agomelatine I crystal form crystals |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee |
Owner name: NANJING HICIN PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: HAICHEN PHARMACEUTICAL CO., LTD., NANJING |
|
| CP03 | Change of name, title or address |
Address after: 210046 Jiangsu city of Nanjing Province Economic and Technological Development Zone HENGFA Road No. 1 Nanjing hicin pharmaceutical Limited by Share Ltd Patentee after: Nanjing hicin pharmaceutical Limited by Share Ltd Address before: 210046 Jiangsu province Nanjing HENGFA economic and Technological Development Zone, Road No. 1 Patentee before: Haichen Pharmaceutical Co., Ltd., Nanjing |