WO2018169420A9

WO2018169420A9 - Method for the preparation of trazodone

Info

Publication number: WO2018169420A9
Application number: PCT/PL2018/000024
Authority: WO
Inventors: Jolanta JAŚKOWSKA
Original assignee: Politechnika Krakowska
Current assignee: Politechnika Krakowska
Priority date: 2017-03-14
Filing date: 2018-03-06
Publication date: 2018-11-08
Anticipated expiration: 2019-09-14
Also published as: PL234822B1; WO2018169420A1; PL420845A1

Abstract

A method for the preparation of trazodone of formula III, in the reaction of 2-(3- halogenopropyl)[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one of formula la or formula lb with l-(3-chlorophenyl)piperazine hydrochloride of formula II consists in, that the reaction of 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 μηι, 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. After the synthesis is completed, to the reaction mixture water is added and stirred and then the liquid phase is separated from the containing trazodone solid phase.

Description

METHOD FOR THE PREPARATION OF TRAZODONE

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-HT₂ receptor antagonist, the activation of which usually leads to insomnia, anxiety, psychomotor agitation and disorders of the sexual sphere.

In the methods of trazodone preparation described so far in literature, the reaction of 2-(3-halogenopropylo)[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one and l-(3-chlorophenyl)- piperazine hydrochloride in toluene in the presence of triethylamine is carried out for about 3 hours [Patent US3381009; NR Pai, D A Pusalkar, An efficient synthesis of neuroleptic drugs under microwave irradiation , J. Chem. Pharm. Res ., 2010, 2, 506- 517].

According to another solution, known from the patent application US20090209550, 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.

There are also known processes for the preparation of trazodone in the reaction of 1 -(3 -bromopropyl)-4-(3 -chloropheny l)piperazine and [ 1 ,2,4]triazolo [4, 3 -a] pyridin- 3(2H)-one. The reaction is carried out in two stages in dioxane and the total reaction time is about 21 hours [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, 2013, 54, 5332 - 5334], or in isopropyl alcohol in the presence of TBAB (tetrabutylammonium bromide) and sodium carbonate [patent application WO2015110883].

Other known methods involve the use of 3-(3-oxo-[l,2,4]triazolo[4,3-a]pyridine- 2(3H)-yl)propyl methanesulfonate as a substrate in the reaction with l-(3- chlorophenyl)piperazine, which allows to obtain the expected product within 16 hours of heating in acetonitrile in the presence of potassium carbonate [ US20090209550 ].

Known methods require such solvents as acetonitrile, toluene, dioxane or isopropyl alcohol, which are toxic and expensive, and the time of the synthesis of the product varies from several to several dozen hours.

So far, no literature on the method of the trazodone synthesis in solvent-free conditions has been found.

It has surprisingly been found that 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 (K₂C0₃) 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.

According to the invention, 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 μηι, 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.

After the synthesis is completed, to the post-reaction mixture water is added and stirred and then the liquid phase is separated, in a known manner, from the solid phase containing trazodone having the purity of 96 - 99%.

Preferably, in order to reduce the duration of the synthesis, 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.

Preferably, the ratio of the substrates in the synthesis of trazodone is 1 : 1.1.

Preferably, as the PTC catalyst TBAB (tetrabutylammonium bromide) is used, in the amount of 2.2% by weight of the mixture.

Preferably, 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 -

99% with 91 - 97% of yield.

Experiments carried out showed that the reaction to obtain trazodone lasts less than 10 minutes, whereas in the presence of DMF in the reaction environment, within 1-3 minutes. The highest efficiency of the reaction is when the amount of DMF is 10% by weight, which enables to obtain the product with efficiency of 97% within 1 min. Increase in the amount of DMF to 20% by weight causes a slight decrease in product performance. In addition, it was found that replacing the PTC catalyst TBAB with TEAC or DABCO allows the product to be obtained with a lower yield and in a longer reaction time.

The solution according to the invention is illustrated by the following examples, which do not limit the scope of protection.

EXAMPLE 1

A conical flask was charged with 0.01 mol (2.96 g) of 2-(3- chloropropyl)[l,2,4]triazolo[4,3-a]pyridine-3(2H)-one (la), 0.011 mol (2.56 g) of l-(3- chlorophenyl)piperazine hydrochloride, 0.03 mol (4.14 g) of K₂C0₃ and 0.001 mol (0.32 g) of TBAB, previously triturated in a mortar. 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 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 90 % of yield. The purity was of 97.2% (determined with HPLC method).

EXAMPLE 2

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 K₂C0₃ and 0.001 mol (0.32 g) of TBAB, previously triturated in a mortar. 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 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 K₂C0₃ 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. 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 was completed. The reaction mixture was introduced into 50 ml of water. After dissolving inorganic salts, trazodone was filtrated, washed with water and dried in the air. The product was obtained with 91% of yield. The purity of crude product was 98.9% (HPLC). EXAMPLE 4

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).

EXAMPLE 5

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 K₂C0₃ 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 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 91% of yield. The purity of the crude product was 97.1% (HPLC). EXAMPLE 6

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 K₂C0₃ and 0.001 mol (0.17 g) of TEAC, 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 irradiation 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).

EXAMPLE 7

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 K₂C0₃ 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).

Claims

PATENT CLAIMS

1. A 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 phase transfer catalyst, characterized in that the reaction of the trazodone synthesis is carried out under solvent-free conditions in the presence of microwave radiation, in addition, the molar ratio of 2-(3-halogenopropyl)[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one to l -(3-chlorophenyl)piperazine hydrochloride is from 1 : 1 to 1.2, furthermore, said potassium carbonate has the graining of 20 - 900 μιπ and its amount in the reaction mixture is from 35 to 45 % by weight of the mixture, moreover, said phase transfer catalyst is selected from tetraethylammonium chloride, tetrabutylammonium bromide, l,4-diazabicyclo[2.2.2]octane, and its amount in the reaction mixture is from 1 to 4% by weight of the mixture, and after the synthesis is completed, into the post-reaction mixture is added water and stirred, then the liquid phase is separated, preferably by filtration or decantation, from the containing trazodone solid phase.

2. The method according to claim 1 , characterized in that into the reaction mixture dimethylformamide is introduced in an amount of 0.2 to 20% by weight of the mixture, preferably in the amount of 10% by weight of the mixture.

3. The method according to claim 1 , characterized in that the molar ratio of the substrates in the reaction of trazodone synthesis is 1 : 1.1.

4. The method according to claim 1, characterized in that as the phase transfer catalyst tetrabutylammonium bromide is used in the amount of 2.2% by weight of the mixture.

5. The method according to claim 1 , characterized in that the trazodone synthesis is carried out in a field of microwave radiation having the power of 300 W.