A Simplified Protocol for Routine Chemoselective

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A Simplified Protocol for Routine Chemoselective Syntheses of Piperazines Substituted in the 1-Position by an Electron Withdrawing Group Dana Nmeková-Herová and Pavel Pazdera* 1 Centre for syntheses at sustainable conditions and their management, Chemistry Department, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic

Abstract: We report a simplified protocol for the routine direct chemoselective preparation of various piperazines substituted in the 1position by an electron withdrawing group. These syntheses are based on the reaction of piperazine-1-ium cation with different electrophilic reagents such as acyl chlorides, anhydrides, sulfonyl chlorides, carbamoyl chlorides, and nitrourea as well. Piperazine-1-ium cation was chosen because the reactions of piperazine with electrophilic reagents in different solvents at usual temperatures are not chemoselective and provide mixtures comprising 1-substituted, 1,4-disubstituted and unsubstituted piperazine as well. Simultaneously, the monoprotonation of piperazine is the simplest synthetic method for its protection/deprotection in comparison with the currently used monobenzylation, mono-Boc-protection, etc. Computer modeling of acid-base equilibria for piperazine and model 1-acetylpiperazine was used as the basis for the prediction of reaction conditions suitable for the synthesis. It was found that for in situ generating of starting piperazine-1-ium cation from piperazine the application of acetic acid as reaction medium or the chemisorption of piperazine on weakly acidic cation-exchanger resin were highly acceptable in terms of both reaction times and yields. The using of resin supported piperazine1-ium cation in reaction with carboxylic anhydrides or nitrourea is an example of the solid phase synthesis with ionically bonded substrate. Furthermore, syntheses in acetic acid medium were effectively catalyzed by Cu+, Cu2+ or Al3+ ions supported on weakly acidic cation-exchanger resin as well. Finally, it was observed that application of the solid support metal catalysis afforded target products in shortened reaction times and in 82-95% yields.

Keywords: 1-monosubstituted piperazine, ionically-bound substrate, metal catalysis, piperazine, piperazine-1-ium cation, resin supported metal ion, solid phase synthesis. INTRODUCTION Piperazine and piperazine structural motives are connected with many of medicinal drugs. Piperazine is a potent anthelmintic used in the therapy of ascariasis (roundworm) and oxyuriasis (threadworm) infestations. The piperazines were originally named because of their chemical similarity with piperidine, a constituent of piperine in the black pepper plant. Piperazine owes its anthelmintic activity to its ability to induce flaccid paralysis of the muscles of the parasite [1]. Piperazines were reported in gene transfer reactions as well [2] and quaternary piperazinium salts showed spasmolytic, anthelmintic and germicidal activity. Some piperazine derivatives possess high biological activity for multidrug resistance in cancer and malaria treatment [3]. Piperazines are a broad class of chemicals which are included in several stimulants (1-benzylpiperazine - BZP, 3-trifluoromethylphenylpiperazine monohydrochloride - TFMPP, etc.) as well as in anti-vertigo agents (1-diphenylmethyl-4-methylpiperazine - Cyclizine, 1-(m-chloro-alpha-phenylbenzyl)-4-(m-methylbenzyl)-piperazine dihydrochloride monohydrate - Meclizine). Commonly known Sildenafil citrate, 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3propyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl)phenylsulfonyl]-4-methylpiperazine sold as Viagra, Revatio and under various other trade names, is the first drug used to treat erectile dysfunction and pulmonary arterial hypertension (PAH). Analogous to Sildenafil, the drug Vardenafil, 4-[2-ethoxy-5-(4-ethylpiperazine-1-yl)sulfonylphenyl]-9-methyl-7-propyl-3,5,6,8-tetraza-bicyclo[4.3.0]nona-3,7,9trien-2-one, is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the trade names Levitra and Staxin. *Address correspondence to this author at the Centre for syntheses at sustainable conditions and their management, Chemistry Department, Masaryk University, Kamenice 5, Brno, 625 00, Czech Republic; Tel: +420 608 209 346; E-mails: [email protected], and [email protected] 1570-1794/14 $58.00+.00

Piperazine structural motive appears in chemical structure of a lot of pharmaceuticals or in chemical structure of potential pharmaceuticals from group of substituted disulfonamides. These pharmaceuticals are widely used for pain moderation or for suppressing of pain, which is evoked from bradykinin receptors 1 [4]. Structural motive of piperazine also appears in chemical structure of CXCchemokine receptor ligands and in chemical structure of 3,4disubstituted cyclobuten-1,2-diones [5]. These pharmaceuticals are used for treatment of prophylaxis or for treatment of various diseases evoked by abnormal TNF- production and diseases treatable by IL-10 such as acute and chronic inflammatory diseases, allergic and autoimmune diseases [6]. Other type of drugs containing structural motive of piperazine are 2,3-dihydro-3-[4-(substituted)piperazinyl]-1H-isoindol-1-ones which are used for treatment of hypertension [7], further CCR5 antagonists, which are used for treatment of HIV-1 [8] and hybrid and isosteric analogues of 1-acetyl-4dimethylpiperazinium iodide (ADMP) and 1-fenyl-4-dimethylpiperazinium iodide (DMPP). These pharmaceuticals are effective for central nicotinic acetylcholine receptors (nAChRs), which play main role in neurodegenerative diseases, for example Parkinson and Alzheimer disease [9]. Structural motive of 1-(pyrid-4-yl)piperazine also appears in μopioid receptors (MOR) antagonists [10], in indole compositions for treatment of nephritis [11], in piperazine structural compositions which are used for dissolving of blood clots during heart or brain strokes [12] and in 4-arylpiperazines with positive allosteric modulation of metabotropic glutamate receptors 5 (mGluR5) which are used for treatment of schizophrenic patients [13]. An introduction of a piperazine structural motive into the drug molecule is usually realized via the 1-monosubstituted piperazine. Preparation of these 1-monosubstituted piperazine derivatives is in general very complicated by formation of symmetrical 1,4-disub© 2014 Bentham Science Publishers

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Current Organic Synthesis, 2014, Vol. 11, No. 6

Nmeková-Herová and Pazdera

E

O H N

O

H N

O +

O

N H

Cl

N

N

+

H2O pH = 3

E N+

N+

HN

H

H

H

H

Scheme 2. General preparation of various 1-monosubstituted piperazines by direct method based on the reaction of piperazine-1-ium cation with electrophilic agents.

Scheme 1. Direct introduction of methoxycarbonyl functional group on piperazine in acidified water.

stituted piperazines while a part of piperazine remains unreacted in the reaction mixture. For this reason, synthetic process, where one nitrogen atom is protected [14] (mainly by Boc, alkoxycarbonyl, acyl or benzyl groups), are used for the preparation of 1-monosubstituted piperazine derivatives. Desired substituent is bound on the other nitrogen atom and deprotection of an intermediary product follows. The introduction of protecting groups usually does not give satisfactory yields. Those 1-monosubstituted piperazines are very precious building blocks because they are not included in the portfolio of all chemical suppliers. For example 4-(methoxycarbonyl) piperazine-1-ium chloride sells for 208 USD/g (Santa Cruz Biotechnology, Inc., USA) or 4-(N,N-diethylkarbamoyl)piperazine-1ium chloride sells for 114 USD/250 mg (Enamine Ltd., Ukraine).

tion into fundamental as well as practical pharmaceutical research and development. The new simplified protocol for the routine direct chemoselective preparation of these and similar piperazine derivatives could help detect this problem. RESULTS AND DISCUSSION We decided to prepare various 1-EWG-monosubstituted piperazines by direct method based on the reaction of piperazine-1ium cation, because protonation of amines is the simplest method of their protection and subsequent deprotection as well. Electrophilic agents for 1-monosubstitution reaction on piperazine-1-ium were chosen either from the family of acyl and similar reagents such as acyl chlorides, anhydrides, sulfonyl chlorides, carbamoyl chlorides or nitrourea was used (Scheme 2).

From the literature some direct 1-monosubstitution reaction of piperazine are known, for example direct introduction of methoxycarbonyl functional group on piperazine in water at pH = 3 (Scheme 1) in very poor yield about 30 % [15]. Main problems of these syntheses are their low yields generally and very frequent use of environmentally inappropriate chlorinated solvents (e.g. 1-Bocpiperazine prepared in dichloromethane, price 100 USD/5 g (VWR International, LLC)).

Furthermore, the clue of our solution was based on the premiss that nucleophilicity of piperazine is greater than the nucleophilicity of the monosubstituted piperazine if the correlation between the basicity and nucleophilicity [16] for unsubstituted and monosubstituted piperazine is applied. Comparison of acid-base constants, expressed as pKA/pKB values [17], for piperazine, 1-acetylpiperazine, and 1-(4-toluensulfonyl)piperazine is demonstrated in (Table 1).

Finally, piperazines substituted in the 1-position by a broad spectrum of electron withdrawing groups (EWGs) could be very interesting building blocks for development of novel drugs. However, their poor accessibility and high price prevents their introduc-

(Fig. 1) shows a distribution of piperazine-1,4-diium, piperazine-1-ium cations and piperazine, respectively, in the dependence on pH values in water solution. Distribution diagram

Table 1. Comparison of acid-base constants of piperazine, 1-acetylpiperazine, and 1-(4-toluensulfonyl)piperazine.

pKA1

pKA2

pKB1

pKB2

Piperazine

5.68

9.82

4.18

8.32

1-Acetyl

7.94

-

6.06

-

1-(4-Toluensulfonyl)

7.39

-

6.61

-

Fig. (1). Distribution of piperazine-1,4-diium, piperazine-1-ium cations and piperazine in the dependence on pH value in water solution.

Direct Preparation of 1-EWG-Substituted Piperazines 13

C NMR (75 MHz, D2O) /ppm: 165.0 (C=O); 135.2 (CAr); 129.2 (CHAr); 128.5 (CHAr); 126.9 (CHAr); 49.7 (CH2N+); 43.3 (CH2N); 38.1 (CH2N). Purity (acid-base potentiometric titration) min. 99.6 % Calcd for C11H15N2O: 191.250; Found: 191.245. 4-(N,N-Diethylcarbamoyl)piperazine-1-ium Chloride (4) State: white crystalline solid M.p.: 184.1-185.2 °C [methanol : acetone (3:2)], lit.: 150-152 °C [23] 1 H NMR (300 MHz, D2O) /ppm: 3.70-3.92 (4H, m, CH2); 3.293.54 (4H, m, CH2); 3.18 (4H, q, NCH2, J = 7.1 Hz); 1.14 (6H, t, CH3, J = 7.1 Hz). 13 C NMR (75 MHz, D2O) /ppm: 163.5 (C=O); 47.1 (CH2); 41.0 (2*CH2N); 35.6 (CH2); 35.0 (2*CH2N+); 14.1 (2*CH3). Purity (acid-base potentiometric titration) min. 98.9 % Calcd for C9H20N3O: 186.275; Found: 186.262 4-(Dodecanoyl)-piperazine-1-ium Chloride (5) State: white crystalline solid M.p.: 172.0-173.7 °C (isopropylalcohol) 1 H NMR (300 MHz, D2O) /ppm: 3.72-3.90 (4H, m, CH2); 3.313.49 (4H, m, CH2); 2.25 (2H, t, CH2, J = 7.2 Hz); 1.13-1.61 (18H, m, CH2); 0.87 (3H, s, CH3). 13 C NMR (75 MHz, D2O) /ppm: 174.6 (C=O); 44.1 (2*CH2N); 35.9 (2*CH2N+); 35.6 (CH2); 33.4 (CH2); 32.0 (CH2); 28.6-31.0 (7*CH2); 24.0 (CH2); 23.1 (CH2); 14.7 (CH3). Purity (acid-base potentiometric titration) min. 98.9 % Calcd for C17H35N2O: 283.423; Found: 283.414. 4-(Methylsulfonyl)piperazine-1-ium Chloride (6) State: white crystalline solid M.p.: 192.4-193.7 °C [methanol : acetone (3:2)]; lit.: 216-219 °C [24], 185-187 °C [25] 1 H NMR (300 MHz, D2O) /ppm: 3.79-3.91 (4H, m, CH2); 3.303.50 (4H, m, CH2); 2.86 (3H, s, CH3). 13 C NMR (75 MHz, D2O) /ppm: 44.2 (2*CH2N); 36.3 (CH3); 35.8 (2*CH2N+). Purity (acid-base potentiometric titration) min. 98.8 % Calcd for C5H13N2O2S: 165.235; Found: 165.229. 4-(Benzenesulfonyl)piperazine-1-ium Chloride (7) State: white crystalline solid M.p.: 176.4-177.7 °C [methanol : acetone (3:2)] 1 H NMR (300 MHz, D2O) /ppm: 7.59-7.70 (5H, m, Ar-H); 3.743.92 (4H, m, CH2); 3.33-3.50 (4H, m, CH2). 13 C NMR (75 MHz, D2O) /ppm: 140.6 (CAr); 133.0 (CHAr); 128.6129.2 (4*CHAr); 44.1 (2*CH2N); 33.8 (2*CH2N+). Purity (acid-base potentiometric titration) min. 98.1 % Calcd for C10H15N2O2S: 227.304; Found: 227.295. General Protocol Utilizing Ionically-Bound Solid Supported Piperazine-1-ium (Compounds 2, 8-13) Purolite C 104 Plus (50 g) was suspended in 200 ml of water and saturated aqueous potassium carbonate solution was added under the stirring until pH value of the solution remained between 8 and 9 after 10 minutes after the last addition. Aqueous solution was then decanted; the resin beads were washed 3 times by 200 ml of water and 2 times with 150 ml of methanol. Piperazine (8.61 g, 100 mmol) was dissolved in 100 ml of methanol, and the piperazine-1,4-diium dichloride monohydrate (17.7 g, 100 mmol) was added and the solution was stirred at 50 °C. Then, resin modified according to the above described procedure was suspended in the prepared solution of piperazine-1-ium chloride and mixture was stirred for three hour. The methanolic solution containing potassium chloride in the form of microsuspension was decanted, the potassium chloride was removed by suction and the


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filtrate was acidified with 20 ml of methanolic hydrogen chloride (conc. 4 mmol/ml) and then evaporated in vacuo to dryness. 10.17 g (64 mmol) piperazine-1,4-diium dichloride was obtained. The resin beads were washed 3 times by 200 ml of methanol and 2 times with 150 ml of acetone and dried on air to constant weight (62.8 g). Prepared resin containing piperazine-1-ium (8 g of resin, 17.3 mmol of piperazine) was suspended in 50 ml of acetone solution containing 13 mmol of corresponding carboxylic anhydride and the mixture was stirred for 4-6 hrs. at 40 °C until consumption of the starting anhydride (TLC in methanol, detecting spots by UV light and/or iodine vapors). Reaction with nitrourea was carried out as described above in ethanol under reflux for 6 hrs. After the reaction was completed, the acetone solution or suspension containing the microcrystalline product was decanted and the resin was washed twice with acetone (40 mL). The acetone parts were combined and the acetone was evaporated. The solid residue was recrystallized, in the case of acetyl derivative and urea product the oily residue was mixed with 10 ml of ethanolic hydrogen chloride (2 mmol/ml) and concentrated to crystallization by evaporation in vacuo. Synthetic details are demonstrated in (Table 4, 5) below and (Scheme 5) shows general reaction of ionicallybound solid supported piperazine-1-ium with carboxylic anhydrides. R2 H

C

H N+

Anhydride or nítrourea

N H

O

N

N H

Scheme 5. General reaction of ionically-bound solid supported piperazine1-ium with carboxylic anhydrides or nitrourea.

Product Characterization 4-Acetylpiperazine-1-ium Chloride (2) State: white crystalline solid Yield: 1.65 g (77 % based on acetic anhydride). M.p.: 190.9-191.5 °C (water-isopropylalcohol), lit.: 161-163 °C [21] 1 H NMR (300 MHz, D2O) /ppm: 3.45-4.51 (2H, m, CH2NCOCH3); 4.06-4.11 (2H, m, CH2NCOCH3); 3.28-3.41 (4H, m, CH2NHCH2); 2.04 (3H, s, COCH3). 13 C NMR (75 MHz, D2O) /ppm: 169.4 (C = O); 50.6 (CH2N+); 44.3 (CH2N); 38.8 (CH2N); 21.4 (CH3). Purity (acid-base potentiometric titration) min. 99.5 % Calcd for C6H13N2O: 129.180; Found: 129.175. 4-Formylpiperazine-1-ium Chloride (8) State: white crystalline solid. Yield 1.60 g (76 % based on acetic formic anhydride). M.p.: 267.5-269.1 °C (water-ethanol). 1 H NMR (300 MHz, D2O) /ppm: 8.48 (s, 1H, HC=O); 3.42-4.55 (2H, m, CH2); 4.04-4.10 (2H, m, CH2); 3.26-3.40 (4H, m, 2*CH2). 13 C NMR (75 MHz, D2O) /ppm: 162.4 (C=O); 50.8 (CH2N+); 44.5 (CH2N); 40.8 (CH2N). Purity (acid-base potentiometric titration) min. 99.4 % Calcd for C5H11N2O: 115.154; Found: 115.149. 1-Benzoylpiperazine (9) State: white crystalline solid Yield: 1.94 g (78 % based on benzoic anhydride). M.p.: 74.7-75.1 °C (water); lit.: 73.0-75.0 °C [26]

Direct Preparation of 1-EWG-Substituted Piperazines


ACKNOWLEDGEMENTS This project was supported by a grant from the Ministry of Industry and Trade of the Czech Republic (2A-1TP1/090). [14]

REFERENCES [1] [2]

[3]

[4]

[5]

[6]

[7] [8]

[9]

[10]

[11] [12] [13]

Satoskar, K.; Bhandarkar, B. Pharmacology and Pharmacotherapeutics, 5th ed.; Bombay Popular Prakashan Pvt. Ltd., Bombay, 1985. Cecchetti, V.; Fravolini, A.; Palumbo, M.; Sissi, C.; Tabarrini, O.; Terni, P.; Xin, T. Potent 6-Desfluoro-8-methylquinolones as New Lead Compounds in Antibacterial Chemotherapy. J. Med. Chem. 1996, 39 (25), 4952-4957 Osa, Y.; Kobayashi, S.; Sato, Y.; Suzuki, Y.; Takino, K.; Takeuchi, T.; Miyata, Y.; Sakaguchi, M.; Takayanagi, H. Structural properties of dibenzosuberanylpiperazine derivatives for efficient reversal of chloroquine resistance in plasmodium chabaudi. J. Med. Chem. 2003, 46 (10), 19481956. Reich, M.; Schunk, S.; Jostock, R.; Hees, S.; Aachen, D.E.; Germann, T.; Engels, F.M. Substituted disulfonamide compounds. U.S. Patent 20100152158 A1, June 17, 2010. Taveras, A.G.; Aki, C.J.; Bond, R.W.; Chao, J.; Dwyer, M.; Ferreira, M.A.; Chao, J.; Yu, Y.; Baldwin, J.J.; Kaiser, B.; Li, G.; Merritt, J.R.; Biju, P.J.; Nelson Jr. K.H.; Rokosz L.L. 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands. U.S. Patent 20040106794 A1, June 3, 2004. Adachi, K.; Aoki, Y.; Hanano, T.; Morimoto, H.; Hisadome, M. Tumor necrosis factor antagonist and/or interleukin promoter; antiallergens, antiinflammatory agents; autoimmune disease treatment. U.S. Patent 6455528 B1, September 24, 2002. Demerson, C.A.; Jirkovsky, I.L. 2,3-Dihydro-3-[4-(substituted)-1piperazinyl]-1H-isoindol-1-ones. U.S. Patent 4355031 A, October 19, 1982. Liu, Y.; Zhou, E.; Yu, K.; Zhu, J.; Zhang, Y.; Xie, X.; Li, J.; Jiang, H. Discovery of a novel CCR5 antagonist lead compound through fragment assembly. Molecules 13, 2426, 2008. Manetti, D.; Bartolini, A.; Borea, P.A.; Bellucci C.; Dei S.; Ghelardini C.; Gualtieri, F.; Romanelli M.N.; Scapecchi S.; Teodori E.; Varani K. Hybridized and isosteric analogues of N1-acetyl-N4-dimethyl-piperazinium iodide (ADMP) and N1-phenyl-N4-dimethyl-piperazinium iodide (DMPP) with central nicotinic action. Bioorg. Med. Chem. 1999, 7 (3), 457-465. Komoto, T.; Okada, T.; Sato, S.; Niino, Y.; Oka, T.; Sakamoto, T. New muopioid receptor agonists with piperazine moiety. Chem. Pharm. Bull. 2001, 49 (10), 1314-20. Taniguchi, N.; Shirouchi, Y. Medicinal composition. WO 2001043746 A1, July 21, 2001. Hosaka, Y.; Miyazaki, Y.; Matsusue, T.; Mukaihira, T. Aromatic compounds having cyclic amino or salts thereof. WO 1999033805 A1, July 8, 1999. Xiong, H.; Brugel, T.A.; Balestra, M.; Brown, D.G.; Brush, K.A.; Hightower, C.; Hinkley, L.; Hoesch V.; Kang, J.; Koether, G.M.; McCauley Jr.

Received: July 04, 2014

[15]

[16] [17] [18]

[19]

[20] [21]

[22]

[23] [24]

[25] [26] [27] [28] [29]

Revised: September 25, 2014

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J.P.; McLaren, F.M.; Panko L.M.; Simpson, T.R.; Smith, R.W.; Woods, J.M.; Brockel, B.; Chhajlani, V.; Gadient, R.A.; Spear, N.; Sygowski L.A.; Zhang, M.; King, M.M.; Arora, J.; Breysse N.; Wilson J.M.; Isaac, M.; Slassi, A. 4-Aryl piperazine and piperidine amides as novel mGluR5 positive allosteric modulators. Bioorg. Med. Chem. Lett. 2010, 20 (24), 7381-7384. Wuts, P.G.M.; Greene, T.W. Greene´s Protective Groups in Organic Synthesis, 4th ed.; Wiley-Interscience, 2007. Stewart, H.W.; Turner, R.J.; Denton, J.J.; Kushner, S.; Brancone, L.M.; McEwen, W.L.; Hewitt, R.I.; Subbarow, Y. Experimental chemotherapy of filariasis. iv. The preparation of derivatives of piperazine1. J. Org. Chem. 1948, 13 (1), 134-143. Hall, Jr. H.K.; Bates, R.B. Correlation of alkylamine nucleophilicities with their basicities. Tetrahedron Lett. 2012, 53 (14), 1830-1832. Perrin, D.D. Dissociation Constants of Organic Bases in Aqueous Solution. Butterworths: London, 1965. Pazdera, P.; Zberovska, B.; Nemeckova, D.; Datinska, V; Simbera, J. Catalyst based on metal complex for chemical syntheses and process for preparing thereof. CZ Patent 20110799 A3, June 19, 2013. Sladkova, K.; Houska, J.; Havel, J. Laser desorption ionization of red phosphorus clusters and their use for mass calibration in time-of-flight mass spectrometry. Rapid Commun. Mass Spectrom. 2009, 23 (19), 3114-8. School of chemical science and engineering. Chemical equilibrium diagrams. http://www.kth.se/che/medusa (Accessed September 15, 2014). Jilek, J.; Pomykacek J.; Prosek Z.; Holubek J.; Svatek E.; Metysová J.; Dlabac A.; Protiva M. 8-Chloro and 8-methylthio derivatives of 10piperazino-10,11-dihydrodibenzo[b,f]thiepins; New compounds and new procedures. Collect. Czech. Chem. Commun. 1983, 48 (3), 906-927. Dhawan, B.; Southwick, P.L. A convenient preparation of monoaroylpiperazine hydrochlorides. Org. Prep. Proced. Int. 1975, 7 (2), pp. 85-88. Verderame, M. Synthesis of 1,4-disubstituted piperazines. II. J. Med. Chem. 1968, 11 (5), 1090-1092. Fun, H.K.; Yeap, C.S.; Chidan Kumar, C.S.; Yathirajan, H.S.; Narayana, B. 4-(Methylsulfonyl)piperazin-1-ium chloride. Acta Crystallogr., Sect. E: Struct. Rep. Online. 2010, 66 (2), 361-362. Regnier, G.; Laubie, M.; Duhault, J. Procede de preparation de nouveaux derives de la piperazine. FR Patent 1313095, December 28, 1962. Desai, M.; Watthey, J.W.H.; Zuckerman M. A convenient preparation of 1aroylpiperazines. Org. Prep. Proced. Int. 1976, 8 (2), 85-86. Husain, M.I.; Misra S.N.; Shukla S.C. J. Indian Chem. Soc. 1979, 56, 171172. Henderson, E.; Henderson, K. Mono-o-phthalyl piperazine and monopiperazine mono-phthalate di-salts. US Patent 3824243 A, July 16, 1974. Abeywardane, A.; Brunette, S.R.; Burke, M.J.; Kapadia, S.R.; Kirrane, T.M.; Netherton, M.R.; Razavi, H.; Rodriguez, S.; Saha, A.; Sibley, R.; Smith, K.L.L.; Takahashi, H.; Turner, M.R.; Wu, J.P.; Young, E.R.R.; Zhang, Q.; Zindell, R.M. Benzodioxanes for inhibiting leukotriene production, Boehringer WO 2013134226 A1, September 12, 2013.

Accepted: September 30, 2014