WO2018169420A9 - Procédé de préparation de trazodone - Google Patents
Procédé de préparation de trazodone Download PDFInfo
- Publication number
- WO2018169420A9 WO2018169420A9 PCT/PL2018/000024 PL2018000024W WO2018169420A9 WO 2018169420 A9 WO2018169420 A9 WO 2018169420A9 PL 2018000024 W PL2018000024 W PL 2018000024W WO 2018169420 A9 WO2018169420 A9 WO 2018169420A9
- Authority
- 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
Links
Classifications
-
- 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).
Landscapes
- 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 WO2018169420A1 (fr) | 2018-09-20 |
| WO2018169420A9 true 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) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1066857B (it) | 1965-12-15 | 1985-03-12 | Acraf | Derivati della s ipiazolo 4.3 a piridina e processi per la loro preparazione |
| WO2009105604A1 (fr) | 2008-02-20 | 2009-08-27 | Auspex Pharmaceuticals, Inc. | Triazolopyridines substituées |
| IN2014MU00203A (fr) | 2014-01-21 | 2015-09-25 | Piramal Entpr Ltd |
-
2017
- 2017-03-14 PL PL420845A patent/PL234822B1/pl unknown
-
2018
- 2018-03-06 WO PCT/PL2018/000024 patent/WO2018169420A1/fr not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| PL234822B1 (pl) | 2020-04-30 |
| WO2018169420A1 (fr) | 2018-09-20 |
| PL420845A1 (pl) | 2018-09-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7455810B2 (ja) | 二級アミンを含有する化合物のアミン部分に重水素低級アルキルを導入する方法 | |
| EP3658552B1 (fr) | Procédé pour la préparation de n-(5-((4-(4-((diméthylamino)méthyl)-3-phényl-1h-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-méthoxy-2-morpholinophényl)acrylamide par réaction de l'amine correspondante avec un 3-halo-propionyl chloride | |
| CA3040720A1 (fr) | Procede de production de 5-fluoro-1h-pyrazolopyridines substituees | |
| FI92067C (fi) | Menetelmä valmistaa terapeuttisesti aktiivisia mono- tai disubstituoituja (imidatsol-4-yyli)metyylipyrido/4,3-b/indol- ja atsepino/4,3-b/indol-1-oneja | |
| DK142498B (da) | Analogifremgangsmåde til fremstilling af benzopyridoazepinderivater. | |
| WO2012078859A2 (fr) | Inhibiteurs de la protéine kinase d | |
| JP3939246B2 (ja) | インドロキナゾリノン類 | |
| JP2021119142A (ja) | キサンチンをベースとする化合物の調製方法 | |
| JP6038111B2 (ja) | 多置換７−デアザプリン誘導体合成のための２，６−ジクロロ−８−ヨード−７−デアザプリン | |
| IE57057B1 (en) | Carboxamides,process for their preparation and pharmaceutical preparations containing them | |
| US4672117A (en) | Antipsychotic gamma-carbolines | |
| WO2020089828A1 (fr) | Procédé amélioré pour la préparation de sitagliptine et de ses intermédiaires | |
| WO2018169420A9 (fr) | Procédé de préparation de trazodone | |
| EP3292112B1 (fr) | Procédé pour la préparation d' alogliptine | |
| CN101456862B (zh) | 含有吡唑并嘧啶酮的苯基胍衍生物、其药物组合物及其制备方法和用途 | |
| WO2013059572A1 (fr) | Procédé de préparation d'etravarine et produits intermédiaires utiles dans la synthèse de ce composé | |
| US10131674B2 (en) | Process for preparing Substituted Indole Compounds | |
| KR20240046742A (ko) | 소분자 sting 길항제 | |
| CZ294957B6 (cs) | Způsob přípravy substituované imidazopyridinové sloučeniny | |
| US7863276B2 (en) | Salts of modulators of PPAR and methods of treating metabolic disorders | |
| KR20020001041A (ko) | 발기부전 치료에 효과를 갖는 피라졸로피리미디논화합물의 제조방법 | |
| EP1763529A1 (fr) | Procede de preparation de risperidone | |
| RU2795581C2 (ru) | Синтез замещенных конденсированных с гетероциклом гаммакарболинов | |
| NO882085L (no) | Cyklobutenmellomprodukt. | |
| KR101346555B1 (ko) | 9-히드록시-3-(2-클로로에틸)-2-메틸-6,7,8,9-테트라히드로-4Ｈ-피리도[1,2-ａ]피리미딘-4-온의 제조방법 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 18717744 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase in: |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 18717744 Country of ref document: EP Kind code of ref document: A1 |