WO2018169420A1 - Procédé de préparation de trazodone - Google Patents
Procédé de préparation de trazodone Download PDFInfo
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- WO2018169420A1 WO2018169420A1 PCT/PL2018/000024 PL2018000024W WO2018169420A1 WO 2018169420 A1 WO2018169420 A1 WO 2018169420A1 PL 2018000024 W PL2018000024 W PL 2018000024W WO 2018169420 A1 WO2018169420 A1 WO 2018169420A1
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- WO
- WIPO (PCT)
- Prior art keywords
- mixture
- trazodone
- reaction
- formula
- weight
- 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.)
- Ceased
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the subject of the invention is a method for the preparation of trazodone of formula III by the reaction of 2-(3-halogenopropylo)[ 1 ,2,4]triazolo[4,3-a]pyridin-3(2H)- one of formula la or lb with l-(3-chlorophenyl)piperazine hydrochloride of formula II.
- Trazodone is an antidepressant. Its pharmacological effects are due to the fact, that it is a serotonin reuptake inhibitor (SRI) and 5-HT 2 receptor antagonist, the activation of which usually leads to insomnia, anxiety, psychomotor agitation and disorders of the sexual sphere.
- SRI serotonin reuptake inhibitor
- 5-HT 2 receptor antagonist the activation of which usually leads to insomnia, anxiety, psychomotor agitation and disorders of the sexual sphere.
- trazodone is obtained by reacting 2-(3-halogenopropylo)[l,2,4]triazolo[4,3-a]pyridin- 3(2H)-one with l-(3-chlorophenyl)piperazine hydrochloride in acetonitrile in the presence of potassium carbonate, carried out for 24 hours.
- trazodone (formula III) can be obtained under solvent-free conditions by reaction of 2-(3-halogenopropyl)[l,2,4]triazolo[4,3- a]pyridin-3(2H)-one (formula la or lb) and l-(3-chlorophenyl)piperazine hydrochloride (formula II), carried out in the presence of potassium carbonate (K 2 C0 3 ) as the reactants-carrier, a PTC catalyst (phase transfer catalyst) and preferably DMF (dimethylformamide ), provided that the synthesis is carried out in a microwave field.
- K 2 C0 3 potassium carbonate
- PTC catalyst phase transfer catalyst
- DMF dimethylformamide
- the method for the preparation of trazodone of the formula III by reacting 2-(3-halogenopropyl)[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one of the formula la or formula lb with l-(3-chlorophenyl)piperazine hydrochloride of formula II, carried out in the presence of potassium carbonate and a PTC catalyst, consists in that the reaction of the trazodone synthesis is carried out under solvent-free conditions, in the presence of microwave radiation.
- the reaction is carried out at the molar ratio of 2-(3-halogenopropyl)[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one to l-(3- chlorophenyl)piperazine hydrochloride of from 1 : 1 to 1.2, and using potassium carbonate having the graining of 20 - 900 ⁇ , which amount in the reaction mixture is from 35 to 45 % by weight of the mixture, and using a PTC catalyst selected from TBAB (tetrabutylammonium bromide), TEAC (tetraethylammonium chloride), DABCO (l,4-diazabicyclo[2.2.2]octane), in an amount of 1 to 4 % by weight of the mixture.
- TBAB tetrabutylammonium bromide
- TEAC tetraethylammonium chloride
- DABCO l,4-diazabicyclo[2.2.2]
- dimethylformamide in an amount of 0.2 to 20% by weight of the mixture is added to the reaction mixture, the most preferably in the amount of 10% by weight of the mixture.
- the ratio of the substrates in the synthesis of trazodone is 1 : 1.1.
- the PTC catalyst TBAB tetrabutylammonium bromide
- the process is carried out in a field of microwave radiation having the power of 300 W.
- the main advantage of the developed method in addition to the reducing of the duration of the process, is the elimination of toxic organic solvents and the ease of isolation of the product from the reaction mixture with water.
- the method of the invention enables to obtain trazodone having the purity of 96 -
- the progress of the reaction was monitored at intervals of 20 seconds with thin-layer liquid chromatography (TLC), using chloroform : methanol mixture having the volume ratio of 9 : 1. After 5 minutes, the TLC analysis showed that the reaction was completed.
- the reaction mixture was moved into a beaker, which contained 50 ml of water. After dissolving inorganic salts, trazodone was filtrated, washed with water and dried in the air. The crude product was obtained with 82 % of yield. The purity was of 97.6% (HPLC).
- EXAMPLE 3 A conical flask was charged with 0.01 mol (2.56 g) of 2-(3- bromopropyl)[l,2,4]triazolo[4,3-a]pyridine-3(2H)-one (lb), 0.011 mol (2.56 g) of l-(3- chlorophenyl)piperazine hydrochloride, 0.03 mol (4.14 g) of K 2 C0 3 and 0.001 mol (0.32 g) of TBAB, previously triturated in a mortar. 2% by mass (0.22 ml) of DMF was added to the mixture and then the mixture was subjected to microwave radiation with the power of 300 W.
- a conical flask was charged with 0.01 mol (2.56 g) of 2-(3- bromopropyl)[l,2,4]triazolo[4,3-a]pyridine-3(2H)-one (lb), 0.011 mol (2.56 g) of l-(3- chlorophenyl)piperazine hydrochloride, 0.03 mol (4.14 g) of K2CO3 and 0.001 mol (0.32 g) of TBAB, previously triturated in a mortar. 10 % by mass (2.08 ml) of DMF was added to the mixture and then the mixture was subjected to microwave radiation with the power of 300 W.
- the progress of the reaction was monitored at intervals of 20 seconds with thin-layer liquid chromatography (TLC), using chloroform : methanol mixture having the volume ratio of 9 : 1. After 60 seconds, the reaction of the substrates was completed. The reaction mixture was introduced into 50 ml of water. After dissolving inorganic salts, trazodone was filtrated. The precipitated product was washed with water and dried in the air. The product was obtained with the 97.8% of yield. The purity of the crude product was 99.1% (HPLC).
- a conical flask was charged with 0.01 mol (2.56 g) of 2-(3- bromopropyl)[l,2,4]triazolo[4,3-a]pyridine-3(2H)-one (lb), 0.01 1 mol (2.56 g) of l-(3- chlorophenyl)piperazine hydrochloride, 0.03 mol (4.14 g) of K 2 C0 3 and 0.001 mol (0.32 g) of TBAB, previously triturated in a mortar. 20% by mass (2.08 ml) of DMF was added to the mixture and the mixture was subjected to microwave radiation with the power of 300 W.
- the progress of the reaction was monitored at intervals of 20 seconds with thin-layer liquid chromatography (TLC), using chloroform : methanol mixture having the volume ratio of 9 : 1. After 2 minutes, the reaction of the substrates was completed. The reaction mixture was introduced into 50 ml of water. After dissolving inorganic salts, trazodone was filtrated. The precipitated product was washed with water and dried in the air. The product was obtained with 90% of yield. The purity of the crude product was 97.9 %. (HPLC).
- a conical flask was charged with 0.01 mol (2.56 g) of 2-(3- bromopropyl)[l,2,4]triazolo[4,3-a]pyridine-3(2H)-one (lb), 0.011 mol (2.56 g) of l-(3- chlorophenyl)piperazine hydrochloride, 0.03 mol (4.14 g) of K 2 C0 3 and 0.001 mol (0.12 g) of DABCO, previously triturated in a mortar. 10 % by mass (2.08 ml) of DMF was added to the mixture and the mixture was subjected to microwave radiation with the power of 300 W.
- the progress of the reaction was monitored at intervals of 20 seconds with thin-layer liquid chromatography (TLC), using chloroform : methanol mixture having the volume ratio of 9: 1. After 2 minutes, the reaction of the substrates was completed. The reaction mixture was introduced into 50 ml of water. After dissolving inorganic salts, trazodone was filtrated. The precipitated product was washed with water and dried in air. The product was obtained with 83% of yield. The purity of the crude product was 96.1 % (HPLC).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invention concerne un procédé de préparation de trazodone représenté par la formule III, dans la réaction de 2-(3-halogénopropyl)[l,2,4]triazolo[4,3-a]pyridin-3 (2H)-one de formule la ou de formule lb avec de l'hydrochlorure de l-(3-chlorophényl)pipérazine de formule II. Ledit procédé consiste en ce que la réaction de synthèse de trazodone est effectuée dans des conditions exemptes de solvant, en présence de rayonnement micro-onde. La réaction est effectuée à un rapport molaire de 2-(3-halogénopropyl)[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one à l'hydrochlorure de l-(3-chlorophényl)pipérazine de 1 : 1 à 1,2, et en utilisant du carbonate de potassium ayant un grainage de 20-900 μηι, laquelle quantité dans le mélange réactionnel étant de 35 à 45 % en poids du mélange, et par l'utilisation d'un catalyseur PTC choisi parmi le TBAB (bromure de tétrabutylammonium), TEAC (chlorure de tétraéthylammonium), DABCO (l,4-diazabicyclo[2.2.2]octane), en une quantité de 1 à 4 % en poids du mélange. Selon l'invention, et après la fin de la synthèse, l'eau du mélange réactionnel est ajoutée et agitée, puis la phase liquide est séparée de la phase solide contenant de la trazodone.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL420845A PL234822B1 (pl) | 2017-03-14 | 2017-03-14 | Sposób otrzymywania trazodonu |
| PLP.420845 | 2017-03-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2018169420A1 true WO2018169420A1 (fr) | 2018-09-20 |
| WO2018169420A9 WO2018169420A9 (fr) | 2018-11-08 |
Family
ID=61972190
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/PL2018/000024 Ceased WO2018169420A1 (fr) | 2017-03-14 | 2018-03-06 | Procédé de préparation de trazodone |
Country Status (2)
| Country | Link |
|---|---|
| PL (1) | PL234822B1 (fr) |
| WO (1) | WO2018169420A1 (fr) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3381009A (en) | 1965-12-15 | 1968-04-30 | Acraf | Triazole-(4,3-a)-pyridines |
| US20090209550A1 (en) | 2008-02-20 | 2009-08-20 | Auspex Pharmaceuticals, Inc. | Substituted triazolopyridines |
| WO2015110883A1 (fr) | 2014-01-21 | 2015-07-30 | Piramal Enterprises Limited | Procédé amélioré pour la préparation de trazodone et son sel de chlorhydrate |
-
2017
- 2017-03-14 PL PL420845A patent/PL234822B1/pl unknown
-
2018
- 2018-03-06 WO PCT/PL2018/000024 patent/WO2018169420A1/fr not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3381009A (en) | 1965-12-15 | 1968-04-30 | Acraf | Triazole-(4,3-a)-pyridines |
| US20090209550A1 (en) | 2008-02-20 | 2009-08-20 | Auspex Pharmaceuticals, Inc. | Substituted triazolopyridines |
| WO2015110883A1 (fr) | 2014-01-21 | 2015-07-30 | Piramal Enterprises Limited | Procédé amélioré pour la préparation de trazodone et son sel de chlorhydrate |
Non-Patent Citations (5)
| Title |
|---|
| JOLANTA JASKOWSKA ET AL: "N -Alkylation of imides using phase transfer catalysts under solvent-free conditions", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 45, no. 5, 1 September 2008 (2008-09-01), US, pages 1371 - 1375, XP055474376, ISSN: 0022-152X, DOI: 10.1002/jhet.5570450519 * |
| JOLANTA JASKOWSKA: "A new solvent-free method for the synthesis of olanzapine and its derivatives Nowa bezrozpuszczalnikowa metoda syntezy olanzapiny i jej pochodnych", PRZEMYSL CHEMICZNY, vol. 1, no. 10, 5 October 2016 (2016-10-05), PL, pages 64 - 66, XP055474358, ISSN: 0033-2496, DOI: 10.15199/62.2016.10.12 * |
| NANDINI R PAI ET AL: "An efficient synthesis of neuroleptic drugs under microwave irradiation", JOURNAL OF CHEMICAL AND PHARMACEUTICAL RESEARCH, vol. 2, no. 5, 1 January 2010 (2010-01-01), pages 506 - 517, XP055355821 * |
| NR PAI; D.A. PUSALKAR: "An efficient synthesis of neuroleptic drugs under microwave irradiation", J. CHEM. PHARM. RES ., vol. 2, 2010, pages 506 - 517, XP055355821 |
| YONG, FUI-FONG ET AL.: "Efficient copper-catalyzed cross-coupling of 1-Boc-piperazine with aryl iodides and its application in the synthesis of trazodone", TETRAHEDRON LETTERS, vol. 54, 2013, pages 5332 - 5334, XP028696438, DOI: doi:10.1016/j.tetlet.2013.07.104 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2018169420A9 (fr) | 2018-11-08 |
| PL420845A1 (pl) | 2018-09-24 |
| PL234822B1 (pl) | 2020-04-30 |
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