PL239445B1 - Method of producing long-chain arylpiperazines - Google Patents

Description

The subject of the invention is a process for the preparation of pharmacologically active compounds of the general formula III from the group of long-chain aryl piperazines, such as Aripiprazole of the formula III, Flibanserin of the formula IIIb or Trazodone of the formula Hic by the N -alkylation reaction of the arylpiperazine of the general formula II with an alkylating agent of the formula III. general I, shown in diagram 1.

Formula

Formula II

where:

• For Aripiprazole, the substituents in formulas I, II, III are as follows:

Patterns: R ': X: R ² : n:

la \ Ę lila ^Br 2,3-diCl 4 • For Flibanserin the substituents in formulas I, II, III are as follows:

patterns: la lla ula

X: R ² :

^Br 3-CF ₃ n:

• For Trazodone, the substituents in formulas I, II, III are as follows:

R ² :

3-CI n:

The mentioned bioactive compounds belong to the group of substances that affect the central nervous system by activating or blocking selected seroton, new and dopamine receptors.

Aripiprazole of formula IIIa (7- [4- [4- (2,3-dichlorophenyl) piperazin-1-yl] butoxy] -3,4-dihydro-1H-quinolin-2-one) has antipsychotic activity. because it is a partial agonist of the dopamine D2 and serotonin 5HTia receptor and an antagonist of the serotonin 5HT2A receptor.

Flibanserin of formula IIIb (1,3-Dihydro-1- [2- [4- [3- (trifluoromethyl) phenyl] -1-piperazinyl] ethyl] -2H-benzimidazol-2-one) is a potent agonist of the receptor 5-HTia and a weak 5-HT2A receptor antagonist and a very weak partial antagonist of the D4 receptor. It also has an affinity for 5-HT2B and 5-HT2C receptors. Flibanserin of formula IIIb is responsible for the balance between neurotransmitters such as dopamine, norepinephrine and serotonin.

Trazodone (Hic) (2- {3- [4- (m-chlorophenyl) -1-piperazinyl] propyl} -1,2,4-triazolo [4,3-a] pyridin-3 (2H) -on) is a well-known and widely used antidepressant substance, the effect of which is due to the fact that it is a serotonin reuptake inhibitor and an antagonist of 5-HT2 receptors.

Methods for the preparation of aripiprazole of the formula lila (7- [4- [4- (2,3-dichlorophenyl) piperazin-1-yl] butoxy] -3,4-dihydro-1H-quinolin-2- described so far in the literature. onu) can be accomplished by the N -alkylation of piperazine. This is a fairly popular path of Aripiprazole synthesis, most often it was carried out by reaction in the presence of triethylamine, pyridine, sodium or potassium hydroxide, sodium and cesium carbonate, and in solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), dioxane, tetrahydrofuran (THF), benzene, toluene, xylene and alcohols. There are also known reactions carried out in the presence of microwave radiation, both in a solvent and without its use

PL 239 445 B1

[Jaśkowska Jolanta, Drabczyk Anna Karolina, Kułaga Damian, Przemysław Zaręba, Majka Zbigniew, Solvent-free microwave-assisted synthesis of aripiprazole, Current Chemistry Letters 7 (2018) 81-86].

The synthesis of Flibanserin of formula IIIb (1,3-dihydro-1- [2- [4- [3- (trifluoromethyl) phenyl] -1-piperazinyl] ethyl] -2H-benzimidazol-2-one), so far described in the literature, on the N-alkylation reaction of 2-trifluoromethylarylpiperazine is carried out in the presence of potassium carbonate and sodium iodide, the process is carried out for 12-18 hours in water, DMF or acetonitrile [Organic Process Research and Development, 2016, vol. 20, 9, p. 1576- 1580; CN106749038, 2017]. There is also a known process using ethanol as a solvent [CN109384680, 2019, A].

Synthesis of Trazodone of formula IIIc (2- {3- [4- (3-chlorophenyl) piperazin-1-yl] propyl} -1,2,4-triazolo [4,3-a] pyridin-3-one) by the alkylation of an aryl piperazine relates, for example, to the reaction in toluene in the presence of triethylamine, [US Pat. No. 3,381,009; N.R. Pai, D.A. Pusalkar, An efficient synthesis of neuroleptic drugs under microwave irradiation, J. Chem. Pharm. Res., 2010, 2, 506-517] or in acetonitrile in the presence of potassium carbonate [patent application US20090209550]. The method of synthesis in solvent-free conditions in the presence of microwave radiation is also known [P.420845].

So far, no literature reports have been found on the method of a relatively fast synthesis of Aripiprazole of the formula III, Flibanserin of the formula IIIb or Trazodone of the formula IIIc by N-alkylation of piperazine in the presence of ultrasound, phase transfer catalysts (PTC), potassium carbonate or other salts alkalizing the environment. reactions in organic solvents or water, and the known and so far described synthesis reactions of these compounds are carried out by several or several-hour processes with the use of often toxic reagents.

It is known that sonochemical methods for the synthesis of organic compounds, i.e. those in which ultrasound is used for chemical reactions, are based on a mechanism based on the phenomenon of acoustic cavitation. By using ultrasound during chemical reactions, an increase in the reaction rate, an increase in the reaction yield, a more efficient use of energy, an improvement in the efficiency of phase transfer catalysts, and even in some cases it is possible to eliminate the catalysts is observed.

Ultrasound-assisted reactions have been known for many years in organic synthesis. Most often, these methods are used in the synthesis of heterocyclic systems such as coumarins [L. S. da Silveira Pinto, M. V. N. de Souza, Synthesis, 2017, 49, 2555-2561], pyrimidinols [M. Vidal, M. Garcia-Arriagada, M. C. Rezende, M. Dominguez, Synthesis, 2016, 48, 4246-4252], or triazines [S. Jaita, W. Phakhodee, M. Pattarawarapan, Synlett, 2015, 26, 2006-2008].

It has surprisingly been found that long chain aryl piperazines such as A ripiprazole of formula III, Flibanserin of formula IIIb or Trazodone of formula IIIc can be obtained in less than 10 minutes by reacting an alkylating agent of formula Ia, Ib or ic and the corresponding arylpiperazine of formula iia. iib or iic, carried out in the presence of a three-fold molar excess of potassium carbonate (K2CO3), PTC (Phase Transfer Catalyst) and dimethylformamide (DMF), acetonitrile (ACN) or water, if the synthesis is carried out in the presence of ultrasound, at a temperature of 40-50 ° C (reactor working conditions: P = 50-100 W, A = 60-80%, in pulse mode with a pulse duration of 60 s and a pause of 12 s).

According to the invention, a process for the preparation of long-chain aryl piperazines such as Aripiprazole of the formula III, Flibanserin of the formula IIIb, Trazodone of the formula IIIc, by N-alkylation of a substrate of the formula iia, iib, and c, respectively, with an alkylating agent of the formula Ia, ib, and c, respectively. carried out in the presence of potassium carbonate and a PTC catalyst in a solvent, the synthesis reaction is carried out at a temperature of 40-50 ° C in the presence of ultrasound, in dimethylformamide, acetonitrile or water as a solvent, using tetrabutylammonium bromide as a PTC catalyst, with a ratio of molar substrate of formula iia, ib, and c to alkylating agent of formula Ia, ib, and c respectively is 1: 1-1: 1.1. At least 0.05 moles of PTC catalyst are used in the reaction per mole of the substrate iia, i and b, i and c. On the other hand, potassium carbonate is used in a threefold molar excess with respect to the substrate of the formula iia, ib, i and c.

After the synthesis in acetonitrile or dimethylformamide has been completed, water is added to the reaction mixture to separate the reaction product, mixed, cooled, and the liquid phase is separated from the solid in a known manner, preferably by decantation or filtration under reduced pressure.

In the case of the aqueous synthesis, no additional addition of water is necessary and the reaction mixture is cooled and filtered, preferably under reduced pressure, separating the liquid phase from the solid phase.

PL 239 445 B1

After separation, the solid phase obtained is converted into the hydrochloride in a known manner to give the expected product of the formula III, IIIb, IIIc, respectively.

Preferably, the reaction is carried out using an equimolar amount of the alkylating agent of formula Ia, Ib or Ic with respect to the starting material iia, iib, IIc, respectively.

Preferably, TBAB (tetrabutylammonium bromide) is used as PTC catalyst in an amount of 0.1 mol per mol of substrate of formula iia, iib, IIc.

Preferably, the process is carried out in the presence of ultrasound under the reactor operating conditions: A = 6080%, power P = 50-100 W in pulse mode with a pulse duration of 60 s and a break of 12 s. In particular, the amplitude A = 80% is used for the synthesis of Aripiprazole and 60% for the synthesis of Flibanserin and Trazodone.

By the process of the invention, long-chain aryl piperazines of the formula III, IIIb, IIIc, respectively, can be obtained in a yield of 71-87%.

The practical tests of the implementation of the invention have shown that the reaction to obtain long-chain aryl piperazines of the formula III, IIIb, IIIc takes place in less than 10 minutes. The greatest yield is obtained with the equimolar ratio of the starting material of formula iia, ib or IIc to the alkylating agent of formula Ia, Ib or ic, respectively.

The solution according to the invention is presented in the following examples, however, not limiting its scope of protection.

The progress of all reactions for the preparation of long-chain aryl piperazines was monitored by TLC (Thin Layer Chromatography) (eluent chloroform-methanol 95: 5 or 90:10) and by HPLC (High-Performance Liquid Chromatography) (Perkin Elmer Series 200 chromatograph, XTerra RP C column) -18, 3.5 μm, 4.6 x 150 mm, mobile phase - methanol: 0.1% formic acid in H2O in a ratio of 6: 4). In the case of Aripiprazole, a standard was used, while in the case of Flibanserin and Trazodone, the progress of the reaction was monitored by observing the disappearance of the substrate iib or IIc, respectively. Moreover, for Flibanserin and Trazodone, the result obtained from infrared spectroscopy (IR) was assessed by comparing it with literature data.

P R Z Y K Ł A D I Synthesis of aripiprazole of formula lila

Step 1 - Synthesis of the alkylating agent of formula Ia (7- (4-bromobutoxy) -3,4-dihydrocarbostyril) Description of the synthesis: 0.5 g (0.0031 mol) of 7-hydroxy-3,4-dihydro was placed in a three-necked flask. (1H) -quinolinone, 1.095 cm ^{3 of} 1,4-dibromobutane, 0.37 g of sodium hydroxide and 0.1 g of TBAB. ^{25 cm 3 of} ACN was added to the flask. The reaction was carried out in the presence of ultrasound (Temperature 50 ° C, Amplitude 80%, Power 100 W, in pulse mode with a pulse duration of 60 s and an interval of 12 s) for 10 minutes. The progress of the reaction was monitored by thin layer chromatography, TLC plate and HPLC. After 5 minutes of reaction, analysis of HPLC results confirmed the presence of 87% of the compound of formula Ia, the next 5 minutes of reaction did not increase the amount of product in the reaction mixture. Water was added to the reaction mixture to isolate the compound of formula Ia, and then the resulting precipitate was filtered off under reduced pressure to give Ia in a yield of 60%.

Step 2 - Synthesis of Aripiprazole of Formula IIa (7- [4- [4- (2,3-dichlorophenyl) piperazin-1-yl] butoxy] -3,4-dihydro-1H-quinolin-2-one)

Description of the synthesis: In five 100 cm ³ three-necked flasks 1.00 g (3.5 mmol) of the alkylating agent of formula Ia (7- (4-bromobutoxy) -3,4-dihydrocarbostyril), 0.95 g ( 3.5 mmol) of a substrate of formula iia (1- (2,3-dichlorophenyl) piperazine hydrochloride), 1.39 g (10 mmol) of potassium carbonate and 0.1 g (0.3 mmol) of TBAB. To the first flask was added DMF (50 cm ^3), the second and third ACN (50 cm ^3), fourth and fifth water (50 cm ^3). The contents of the flasks were mixed and the synthesis started. The reaction was carried out at 40 ° C in the presence of ultrasound with a power of 50 W and an amplitude of 60% or alternatively with a power of 100 W and an amplitude of 80% (summarized in Table 1). The progress of the reaction was monitored by TLC (eluent chloroform methanol 9: 1) and HPLC. Running the reaction in DMF, after 10 minutes of reaction, Aripiprazole was obtained in the form of base with an efficiency of 18% (Temperature 40 ° C, Amplitude 60%, Power = 50 W, work in pulse mode with a pulse duration of 60 s and a break of 12 s) (Table 1 , No. 1). In the case of the ACN solvent, the same reactor operating conditions resulted in a threefold reduction in efficiency to 6% (Table 1, No. 2), but by changing the amplitude to 80% and the power to 100 W, it was possible to obtain Aripiprazole in the form of a base with an efficiency of 79% (Table 1 , no.3). In the case of using water as a solvent, aripiprazole base was obtained in a yield of 61% (Table 1, No. 4) and 77% (Table 1, No. 5). After the reaction, water was added to the reaction mixture and the resulting product was filtered off. The obtained aripiprazole base, after drying, was dissolved in acetone and acidified with 4M HCl to give aripiprazole hydrochloride of formula lila.

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Table 1. Synthesis of aripiprazole base by reaction of a substrate of formula Ha with an alkylating agent of formula Ia.

No Conditions Solvent Time [min] Performance [%] Amplitude [%] Power [W] 1 60 50 DMF 10 18 2 60 50 ACN 10 6 3 80 100 10 79 4 60 50 Water 10 61 5 80 100 10 77

EXAMPLE II Synthesis of Flibanserin of formula IIIb

Step 1 - synthesis of the alkylating agent of formula Ib (1- (2-bromoethyl) -3- (prop-1-en-2-yl) -1H-benzo [b] imidazol-2 (3H) -one)

Description of Synthesis: In a beaker with a capacity of 100 cm ³ provided 1.00 g (5.74 mmol) of 1 -izopropenylo1,3-dihydro-2H-benzimidazol-2-one, 3.26 g (17.3 mmol) of 1.2 -dibromoetanu, 2.39 g (17.3 mmol) of potassium carbonate and 0.2 g (0.6 mmol) of TBAB and 50 cm ³ AON. The reaction was carried out in the presence of ultrasound (Temperature 50 ° C, Amplitude 60%, Power = 50 W, in pulse mode with a pulse duration of 60 s and an interval of 12 s). The progress of the reaction was monitored by TLC (eluent chloroform methanol 95: 5) and HPLC. After 10 minutes of reaction, 50% (HPLC) of the product was observed in the reaction mixture. After the reaction, ACN was distilled off, and water was added to the reaction mixture and the product formed was filtered off (W = 77%).

Step 2 - synthesis of Flibanserin of formula IIIb

Description of Synthesis: In a beaker with a capacity of 100 cm ³ provided 0.5 g (1.8 mmol) of the alkylating agent Ib (1- (2-bromoethyl) -3- (prop-1-en-2-yl) -1H-benzo [b] imidazol-2 (3H) -one), 0.47 g (1.8 mmol) of substrate IIb (1- [3- (trifluoromethyl) phenyl] piperazine), 0.74 g (5.4 mmol) carbonate potassium and 0.06 g (0.2 mmol) TBAB and 50 cm ³ acetonitrile. The reaction was carried out in the presence of ultrasound (Temperature 45 ° C, Amplitude 60%, Power = 50 W, in pulse mode with a pulse duration of 60 s and an interval of 12 s). The progress of the reaction was monitored by TLC (eluent chloroform methanol 95: 5) and HPLC. After the reaction, water was added to the reaction mixture and the resulting reaction product was filtered off, giving a yield of 46% (purity 85%). The product obtained 1- (prop-1-en-2-yl) -3- (2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethyl) -1H-benzo [d] imidazol-2 The (3H) -one was then converted to Flibanserin hydrochloride IIIb (i.e., 1- (2- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) ethyl) -1H-benzo [d] imidazole- hydrochloride 2 (3H) -one) by the same method as in Example 1

Flibanserin was obtained in the form of the hydrochloride salt of formula IIIb in a yield of 87% (purity 96%).

EXAMPLE III Synthesis of Trazodone of formula Hic

Step 1 - Synthesis of the alkylating agent of formula la (2- (3-chloropropyl) -1,2,4-triazolo [4,3-a] pyridin-3- (2H) -one)

PL 239 445 B1

Description of the synthesis: 1.35 g (0.01 mol) 1,2,4-triazolo [4,3-a] pyridin-3- (2H) -one, 2.5 cm ³ (0.026 mol) were placed in a three-necked flask. 1-bromo-3-chloropropane, 0.32 g (0.01 mol) of TBAB, 4.14 g (0.03 mol) of K2CO3, and a suitable amount of ACN (50 cm ^3). The reactions were carried out in the presence of ultrasound (Temperature 50 ° C, Amplitude 60%, Power = 50 W, in pulse mode with a pulse duration of 60 s and an interval of 12 s). The progress of the reaction was monitored by TLC (eluent chloroform-methanol 9: 1) and HPLC. After the reaction, water was added and the resulting product was filtered off. 2- (3-chloropropyl) -1,2,4-triazolo [4,3-a] pyridin-3- (2H) -one (Ic) was obtained in a yield of 66% (100% purity).

Step 2 - Synthesis of Trazodone (IIIc)

Description of the synthesis: 2.1 g (0.01 mol) of the alkylating agent Ic (2- (3-chloropropyl) -1,2,4-triazolo [4,3-a] pyridin-3- (2H) were placed in a three-necked flask. -one), 2.3 g (0.01 mol) of the substrate Ic (1- (3-chlorophenyl) piperazine hydrochloride), 0.32 g (0.01 mol) TBAB, 4.14 g (0.03 mol) K2CO3 and 50 cm ³ ACN. The reaction was carried out in the presence of ultrasound (Temperature 50 ° C, Amplitude 60%, Power = 50 W, in pulse mode with a pulse duration of 60 s and an interval of 12 s). The progress of the reaction was monitored by TLC (eluent chloroform - methanol 9: 1). After 20 minutes of reaction, water was added and the resulting reaction product was filtered off in a yield of 76% (purity 95%). After drying, a solution of 4M HCl in dioxane was added to a solution of Trazodone base in acetone until it was acidic, then the resulting precipitate was filtered and dried to give Trazodone hydrochloride IIIc in 71% yield.

Claims (6)

1. A method for the preparation of long-chain aryl piperazines such as Aripiprazole of the formula IIIa, Flibanserin of the formula IIIb, Trazodone of the formula IIIc by N-alkylation of aryl piperazines of the formula Iia, iib, and c, respectively, carried out with an alkylating agent of the formula Ia, Ib, and c, respectively. in the presence of potassium carbonate and a PTC catalyst in a solvent, characterized in that the synthesis reaction is carried out at a temperature of 40-50 ° C in the presence of ultrasound, in dimethylformamide, acetonitrile or water as a solvent, using tetrabutylammonium bromide as a PTC catalyst, at the molar ratio of the substrate of formula iia, ib, i and c, respectively, to the alkylating agent of formula Ia, Ib, and c, respectively, of 1: 1 - 1: 1.1, wherein at least 0.05 moles of PTC catalyst are used per 1 mole of substrate of formula iia, iib, i and c, while potassium carbonate is used in a threefold molar excess to the substrate of formula iia, iib, iic, and after the synthesis with mi After the reaction, the solid phase is separated and converted to the hydrochloride to give Aripiprazole of the formula III, Flibanserin of the formula IIIb or Trazodone of the formula IIIc. The process according to claim 1, characterized in that an equimolar amount of the alkylating agent of formula Ia, ib, and c is used with respect to the substrate iia, ib, and c, respectively. The method according to claim 1, characterized in that tetrabutylammonium bromide is used in the synthesis reaction in an amount of 0.1 mole per 1 mole of the substrate of the formula iia, i and b or iic, respectively. 4. The method according to claim 1, characterized in that the process is carried out in the presence of ultrasound in the reactor operating conditions, power P = 50-100 W in pulse mode with a pulse duration of 60 s and a break of 12 s, amplitude A = 60-80%, in particular A = 80% for the synthesis of Aripiprazole and 60% for the synthesis of Flibanserin and Trazodone. 5. The method according to claim 1, characterized in that, after the end of the synthesis, for the separation of the product in the reaction carried out in acetonitrile or dimethylformamide, water is added to the reaction mixture, stirred and cooled, and then the precipitate formed is filtered off, preferably under reduced pressure, after which converts to the hydrochloride. 6. The method according to claim 1, characterized in that, after the synthesis has been completed for the separation of the product in a reaction carried out in water, the reaction mixture is cooled and filtered, preferably under reduced pressure, separating the resulting precipitate which is converted into the hydrochloride.