CZ2011810A3 - Process for preparing 1-(pyridin-4-yl)piperazine and 1,1-dialkyl-1-ium derivatives thereof - Google Patents

Abstract

The present invention relates to a novel, economically and environmentally advantageous process for preparing 1- (pyridin-4-yl) piperazine and its 1,1-dialkyl-1-ium derivative, including the step of 4-chloropyridine or 4-cyanopyridine, protonated or quaternized on a nitrogen atom of pyridine with benzyl, is reacted with piperazine in water or in a lower alcohol, under nitrogen, by catalysis with a metal or cerium in a positively charged complex or in the form of compounds.

Description

The present invention relates to a novel, economically and environmentally advantageous process for the preparation of 1- (pyridin-4-yl) piperazine and 1,1-dialkyl-1-ium derivatives thereof, comprising the step of protonated or 4-chloropyridine or 4-cyanopyridine; quaternized on the pyridine nitrogen atom by botzyl, is reacted with pipaazine in water or in a lower C 1 -C 6 alcohol. after catalysis with d-metal or cerium in a positively charged complex or in the form of a compound.

CZ2011 -810 A3 i 4 · i · · ·

A process for the preparation of 1- (pyridin-4-yl) piperazine and its 1,1-dialkyl-1-ium derivatives

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Technical field:

The present invention relates to a novel process for the preparation of 1- (pyridin-4-yl) piperazine and 1,1-dialkyl-1-ium derivatives thereof.

BACKGROUND OF THE INVENTION 1- (Pyridin-4-yl) piperazine (PyPi) belongs to the group of 4-N, N-dialkylanalogues of 4-N, N-dimethylaminopyridine (DMAP). DMAP and its analogues, such as 4-pyrrolidinopyridine (PPy), are laboratory, but currently also technologically used catalysts - activators of electrophilic reagents, especially acylating agents, especially in the production of chemical and pharmaceutical specialties. Examples of their use are described in review papers (Ramiah Murugan, R., Scriven, EFV: Aldrichchimica Acta, 2003, 36 (1), 21; Berry, DJ, DiGiovanna, Ch. V., Metrick, Stephanie S., R. : ARKIVOC, 2001, 201; Goldberg, Yu .: Phase transfer catalysis - Selected problems and application Chapter 7. Gordon and Breach Science Publisher, Amsterdam, 1992, Hofle, G., Steglich, W., Vorbrueggen, H .: Angew Chem. Int. Ed. Engl. 1978, 17, 569.).

In addition, PyPi is primarily an important pharmaceutical intermediate for the manufacture of drugs, its structural motif appears in drugs or potential drugs from the group of substituted disulfonamides suppressing or suppressing pain caused by bradykinin 1 receptors (Melanie Reich, Schunk, S., Ruth Jostock, Sabina Hees, Aachen (DE); Germann, T., Engels, F.-M. (Gruenenthal, GmbH.): US 2010/0152: 158 A1.), In CXCchemokine receptor ligands in 3,4-disubstituted cyclobutene-1,2-dione (Taveras AG, Cynthia J. Aki, Bond, RW, Chao, J., Dwyer, M., Ferreira, MA, Chao, J., Yu, Y., Baldwin, JJ, Kaiser, B., Li, G. Merritt, JR, Biju, PJ, Nelson Jr, BH, Laura L.

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Rokosz (Schering Corporation): US 2004/0) 10 ^ 794 A1), as a medicament for the prophylaxis or treatment of various diseases caused by abnormal TNF-alpha production, diseases treatable by IL-10, such as acute and chronic inflammatory diseases, allergic and autoimmune diseases (Adachi,

K., Aoki, Y., Hanano, T., Morimoto, H., Hisadome, M. (Mitsubishi Pharma Corp.): US ^v

645 ^ 28 (2002)., In 2,3-dihydro-3- [4- (substituted) piperazinyl] -1H-isoindol-1-ones for the treatment of hypertension (Demerson, CA, Jirkovsky, IL (American Home Products Corp.). ): US «lit.

4355031 (1982).), For CCR5 antagonists for the treatment of HIV-1 (Liu, Y., Zhou, E., Yu, K. Zhu, J. Zhang, Y., Xie, X., Li, J., Jiang. , H .: Molecules 2008, 13, 2426.), in hybrid and isosteric analogues of 1-acetyl-4-dimethylpiperazinium iodide (ADMP) and 1-phenyl-4-dimethylpiperazinium iodide (DMPP) with effect on central nicotinic cholinergic receptors (nAChRs ) that play an important role in neurodegenerative diseases such as Parkinson's or Alzheimer's (Dina Manetti, Bartolini, A., Borea, PA, Cristina Bellucci, Silvia Dei, Carla Ghelardini, Gualtieri, F., Maria Novella Romanelli, Serena Scapecchi, Elisabetta Theodors, Katia Varani: Bioorg. Med. Chem. 1999, 7, 457.), in mu-opioid receptor agonists with a piperazine structural motif (Komoto, T., Okada, T., Sato, S., Niino, Y., Oka, T., Sakamoto, T .: Chem. Pharm. Bull. 2001, 49, 1314.), in indole compositions for the treatment of nephritis (Taniguchi, N., Shirouchi, Y. (Nippon.

Shinyaku Co.): WO 01/043 (746 (2001).), In piperazine structural compositions for dissolving blood clots in heart or stroke (Hosaka, Y.

Miyazaki, Y., Matsusue, T., Mukaihira, T .: Mochida Pharmaceutical Co.): WO 99/33805 (1999)., In 4-arylpiperazines with positive allosteric modulation of metabotropic glutamate 5 receptors (mGluR5) in the treatment of schizophrenic patients (Xiong, H., Brugel, T.

A., Balestra, M., Brown, D.G., Brush, K.A., Hightower, C., Hinkley, L., Valerie Hoesch, Kang, J., Koether, G.M., McCauley Jr., J.P., McLaren, F.M .; Laura M. Panko, Simpson, T. R., Smith, R. W., Woods, J. M., Brockel, B., Chhajlani, V., Gadient, R. A., Spear, N., Linda

Sygowski, A., Zhang, M., King, Megan, M .; Arora, J., Nathalie Breysse, Julie M. Wilson, Isaac, M., Slassi, A., Bioorganic and Medicinal Chemistry Letters 2010, vol. 20, 7381.).

In addition, the 1- (pyridin-4-yl) piperazine motif is part of the ligands used in homogeneous catalysis (Schneider, R., Hosseini, MW, Planeix, J.-M., De Cian, A., Fischer, J .: Chem. Commun. 1998, 1625.) to form supramolecular complexes.

1,1-Dimethyl-4- (pyridin-4-yl) piperazin-1-one salt has been used successfully in the depolymerization of Nylon-6 to caprolactam in ionic liquids (Yamamoto, S., Kamimura,

A .: Chemistry Letters 2009, 38, 1016.).

The introduction of a secondary dialkylamino group at the 4-position in pyridine is generally not easy (Pyramid and Its Derivatives, A. Weissberger, EC Taylor, eds.). (RA Abramovich, ed. Supplement, Part

2. Μ. M. Boudakain, Halopyridines. Part 3 CS Giam, Aminopyridines, J. Wiley & Sons, Inc., 1974; H. Vorbruggen, Advances in Amination of Nitrogen Heterocycles in Advances in Heterocyclic Chemistry (AR Katritzky, ed.), Vol. 49, Academic Press, 1990, 118-184.); «<T _(i * l · ♦ well, I> t» i. "T '| I <' t ♦« < «*« «« »··« * <* for the piperazine group, the situation is often complicated by the emergence of Therefore, a monoprotected piperazine, such as 1-benzyl-, 1-tert-butyloxycarbonyl- or 1-ethoxycarbonylpiperazine, is used very often for synthesis, whereby the protecting group is removed in the last synthetic step. However, this process is economically and environmentally disadvantageous compared to the direct reaction of unsubstituted piperazine with a 4-X-pyridine precursor.

Therefore, it cannot be considered serious that PyPi can be prepared from 4-chloropyridine by reaction with piperazine while boiling in xylene (Demerson, C.A., Jirkovsky, I.L. (American Home Products)

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Corp.): US 4B55 / 3131 (1982).), Or in dimethylformamide at 45 ° C (Liu, Y., Zhou,

E., Yu, K., Zhu, J., Zhang, Y., Xie, X., Li, J., Jiang, H.: Molecules 2008, 13, 2426.), or even by aromatic nucleophilic substitution of bromine at 4. bromopyridine (Komoto, T., Okada, T., Sato, S.,, Niino, Y., Oka, T., Sakamoto, T .: Chem. Pharm. Bull. 2001, 49, 1314; Adachi, K. ,

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Aoki, Y., Hanano, T., Morimoto, H., Hisadome, M. (Mitsubishi Pharma Corp.): US 61455 1528

Λ A (2002).

The authors (Schneider, R., Hosseini, MW, Planeix, J.-M., De Cian, A., Fischer, J .: Chem. Commun. 1998, 1625.) used the method of Kauffmann and Boettcher (Kauffmann, T., Boettcher,

F. -P .: Chem. Ber., 1962, 88, 1528.) described for secondary amines other than piperazine for the synthesis of PyPi by reacting under reflux in diethyl ether under an inert nitrogen atmosphere 1: 2 4-chloropyridine, phenyllithium and piperazine, 2: 2.5 and obtained PyPi in 22% yield in addition to the 1,4-bis- (pyridin-4-yl) piperazine product in 20% yield. The disadvantages of this procedure are obvious.

Therefore, most of the processes described are based on the above-mentioned mono-protected piperazine and 4-halopyridine, wherein the halogen exchange process is catalyzed by d-metal or a complex thereof in the reaction medium (homogeneous catalysis conditions). Manetti and collaborator. (Dina Manetti, Bartolini, A., Borea, PA, Cristina Bellucci, Silvia Dei, Carla Ghelardini, Gualtieri, F., Maria Novella Romanelli, Serena Scapecchi, Elisabetta Theodors, Katia Varani: Bioorg. Med. Chem. 1999, 7, 457.) started from 4-bromopyridine, which was reacted in water with 1-benzylpiperazine in the presence of copper sulfate at 140 ° C. In the same way they prepared 1-methyl-4- (pyridin-4-yl) piperazine, by reacting 1-methylpiperazine with 4-bromopyridine. The benzyl protecting group was then removed from the intermediate 1-benzyl-4- (pyridin-4-yl) piperazine, obtained in 98% yield, by hydrogenation using ammonium formate as 1.

hydrogen source in the presence of 10% palladium on activated carbon in methanol, the yield of 1- (pyridin-4-yl) -piperazine is 67%. Another described method of debenzylation of 1-benzyl-4- (pyridin-4-yl) -piperazine uses in addition the presence of benzylamine (Taveras, AG). , Jianhua, C., Biju, PJ, Yu, Y., Fine,

JS, Hipkin, W., Aki, CJ, Merritt, JR, Li, G., Baldwin, JJ, Lai, G., Wu, Mi., Hecker, EA (Pharmacopeia Inc., Schering Corp.): WO 2004 / Or hydrogen was used as the hydrogenation agent (Bergbreiter, DE, Osburn, PL Li, C .: Organic Letters 2002, 4, 737). These authors reported that 1-benzyl-4- (pyridin-4-yl) piperazine was prepared by reacting 1-benzylpiperazine with 4-chloropyridine 18fh by boiling in xylene with a total yield of 30%.

1-tert-Butyloxycarbonylpiperazine was retained by the authors (Xiong, H., Brugel, T. A., Balestra, M., Brown, D. G., Brush, K. A., Hightower, C., Hinkley, L., Valerie Hoesch, Kang, J., Koether,

G.M., McCauley Jr., J.P., McLaren, F.M .; Laura M. Panko, Simpson, TR, Smith, RW, Woods, JM, Brockel, B., Chhajlani, V., Gadient, RA, Spear, N., Linda A. Sygowski, Zhang, M., King, Megan M. .; Arora, J., Nathalie Breysse, Julie M. Wilson, Isaac, M., Slassi, A .: Bioorganic and Medicinal Chemistry Letters 2010, vol. 20, 7381.) to react under conditions of cross-Buchwald-Hartwig coupling with 4-bromo- or 4-iodopyridine in the presence of Pd (PPh 3) 2 Cl 2 catalyst, reaction time, temperature and product yield are not shown.

The 1- tert -butyloxycarbonyl-4- (pyridin-4-yl) piperazine was then deprotected of the 1-tert-butyloxycarbonyl group by reaction with hydrogen chloride in dioxane. The reaction time, temperature and yield of PyPi are also not shown.

Cross-Buchwald-Hartwig coupling was used to synthesize 1-methyl-4- (pyridin-4-yl) piperazine in 97% yield, when 1-methylpiperazine was reacted with 4-bromopyridine in dimethoxyethane in the presence of a catalytic amount of palladium acetate and ligand 2- (2,4 , 6-i-Pr3 (6H2) -C6H4-PCy2 and sodium tert-butyl alcohol as a base (Yamamoto, S., Kamimura, A., Chemistry Letters 2009, 38, 1016.).

1-Methyl-4- (pyridin-4-yl) piperazine was also prepared by a two-step synthesis by first reacting

-methylpiperazine with n-butyl lithium under inert atmosphere in n-hexane-tetrahydrofuran at 0-20 ° C for 15 min followed by 4-cyanopyridine in the presence of cesium fluoride as Lewis acid at 65 ° C for 90 min min, the product yield in the reaction mixture determined by chromatography was 44% (Penney, JM: Tetrahedron Letters 2004, 45, 2667).

Other methods for introducing primary or secondary amines at the 4-position of pyridine are known in the literature, but none have been used to synthesize PyPi. These are reactions of 1,4'-bipyridinium dichloride with secondary amines or formamides of these secondary amines at temperatures above 150 ° C, optionally under high pressure (Scriven, E.F.V., Huckstep, L.M.

* * «C <<

(Reilly Tar & Chem Corp.): EP0074837 (1983); Lin, J. (Anhui Kelian Ind.): CN 101033212 No. · i / (2007); Vorbruggen, H. (Schering AG): US 4'440853 (1979).), Reaction from 4-chloropyridine Noxide under milder conditions (Katritzky, A. R., J. Chem. Soc. 1956, 2404; Liveris, M.

Miller, J. Chem. Soc. 1963, 3486; Essery, J. M., Schofield, K .: J. Chem. Soc. 1960, 4953.), a procedure from 1- (3-amino-3-oxopropyl) -4-cyanopyridinium chloride (Nummy, L.J. (Nepera).

Chemical Co.): US 4,672,121 (1987), a process starting from 1- [2- (2-pyridyl) ethyl] -4-cyanopyridinium chloride hydrochloride (Bailey, T.D., McGill, Ch.K. (Reilly Tar & Chem).

or from 4-cyano-1- (3-methoxy-3-xopropyl) -pyridinium chloride (Nummy, L.J. (Nepera).

Chemical Co.): US 4672 (121) (1987); Hopper, Ch.R., Murugan, R., Huckstep, ML, Balasubramanian, M., Calvin, JR, Scriven, EF (Reilly Industry Inc): EPIV422P22 ( 2004);

Hopper, Ch.R., Murugan, R., Huckstep, M.L., Scriven, E.F. (Reilly Industry Inc.):

(2004). The activating group on the pyridine nitrogen atom is then removed reductively (1-oxide), or by elimination with a strong base in the case of 1- (3-amino-3-oxopropyl), 1- (3-methoxy-3-oxopropyl) or 1 - [2- (2-pyridyl) ethyl] groups. This puts a strain on the economy and increases the environmental impact of these processes.

1,1-di-Methyl-4- (pyridin-4-yl) piperazinium salt was prepared by quaternizing 1-methyl-4 (pyridin-4-yl) piperazine with methyl iodide in dichloromethane in a yield of only 18%, apparently alongside products quaternized to the nitrogen atom of the pyridine moiety, which is not reported by the authors (Yamamoto, S., Kamimura, A .: Chemistry Letters 2009, 38, 1016.).

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of 1- (pyridin-4-yl) piperazine and its 1,1-dialkyl-1-ium derivatives of formula I

(I) wherein R ¹ and R ² are the same and are selected from the group consisting of hydrogen and C 1 -C 4 n-alkyl, or R ² is absent and R ¹ is hydrogen,

R is selected from the group consisting of benzyl and hydrogen, or R is absent and, when R ² is present, carries the nitrogen to which it is attached, positively charged, and when R ³ is present carries the nitrogen to which it is bound, a positive charge, the essence of which comprises the step in which

4-chloropyridine or 4-cyanopyridine, protonated or quaternized on the pyridine nitrogen atom with benzyl, is reacted with spiperazine in water or a lower C 1 -C 3 alcohol, under catalysis with a metal selected from the group consisting of d-metals and cerium in a positively charged complex; in the form of a compound.

Preferably, the reaction of piperazine with 4-chloropyridine or _4-t cyanopyridine at the nitrogen atom of pyridine quaternized with benzyl. More preferably, 1-benzyl-4-cyanopyridin-1-ium is used in the reaction with piperazine in the form of chloride, bromide, iodide, benzenesulfonate, or 4-tosylate, preferably chloride.

Suitable d-metals and suitable ligands for positively charged complexes are described in PV 2011-799 ((Pazdera, P., Zberovska, B., Nemeckova, D., Datinska, V., Simbera, J. (Masaryk University): Catalyst) for chemical syntheses based on d-metal complex and method of its preparation, filing date 8.12.2011).

Preferably the metal is gold Au (I), rhodium Rh (I), iron Fe (III) or Fe (II), nickel Ni (II), cobalt Co (II) or Co (III), copper Cu (II) or Cu (I), or cerium Ce (III).

Preferably, the catalysis is carried out with cuprous iodide, cuprous bromide, cuprous cyanide, or cuprous thiocyanate.

In a preferred embodiment of the invention, the metal in the positively charged complex is immobilized on a weakly acidic polyacrylate cation exchange resin as described in PV 2011-799.

In a further reaction step, it is then possible, if desired, to further quartemise the product formed on the nitrogen atom of the N-1 piperazine (i.e., the nitrogen atom to which the pyridine is not attached), i.e. introduce the groups R and R. This quaternization can advantageously be carried out by quaternizing the 1-benzyl-4- (piperazin-1-yl) pyridinium salt, preferably chloride, at the nitrogen atom N1 of the piperazine moiety with an agent selected from the group consisting of C1-C4-n-alkyl a halide, C 1 -C 4 -alkyl benzenesulfonate, and C 1 -C 4 -alkyl 4-tosylate, in a solvent selected from the group consisting of methanol, ethanol, acetonitrile, nitro methane, and binary mixtures thereof, at temperatures from 30 ° C to temperatures boiling of the solvent used.

Mil

In the next reaction step, it is also possible, if the product is quaternized on the pyridine nitrogen atom and, if desired, to remove the R ³ group.

In one preferred embodiment, R ³ , which is benzyl, can be removed from 1-benzyl-4- (piperazin-1-yl) pyridin-1-one or 4- (1-benzylpyridinium-4-yl) -1,1- dialkylpiperazin-1-one

Λ salts by hydrogenolysis on 5 to 20 wt% palladium catalyst on activated carbon, optionally in the presence of benzylamine or dibenzylamine in aqueous, methanol, aqueous methanol solution, or in ethyl acetate or acetic acid solution.

In another preferred embodiment, the R ³ group, which is benzyl, can be removed by hydrogenolysis with an agent selected from hydrogen at 1 to 10 atm, hydrazine, ammonium formate, and formamide, at 20 to 70 ° C.

In another preferred embodiment, R ³ , which is benzyl, can be removed from 1-benzyl-4- (piperazin-1-yl) pyridin-1-one or 4- (1-benzylpyridinium-4-yl) -1,1- dialkylpiperazine-1-ions salts by oxidation in basic medium. This oxidation is preferably carried out in an aqueous, methanolic or aqueous methanolic solution with an agent selected from the group consisting of sodium hypochlorite, sodium chlorite, and sodium peroxide, or in an environment of 10 to 40% by weight aqueous, methanolic or aqueous methanolic sodium hydroxide solution; Potassium hydroxide An agent selected from the group consisting of hydrogen peroxide, air and oxygen.

Said further reaction steps may be carried out and combined depending on the final product of formula (I) desired.

When the product of formula (I) carries a positive charge, it is preferably also a counterion thereof selected from the group consisting of chloride, bromide, iodide, benzenesulfonate, or 4-tosylate anion.

The present invention provides a novel, economically and environmentally advantageous process for the preparation of 1- (pyridin-4-yl) piperazine and its 1,1-dialkyl-1-ium derivatives, in particular 1,1-dialkyl-4- (pyridin-4-yl) piperazine -1-salt, wherein the alkyl is two of the same group of methyl, ethyl, n-propyl, n-and n-propyl;

or n-butyl. In contrast to known methods, the 1- (pyrid-4-yl) piperazine according to the invention is prepared on the one hand by Buchwald-Hartwig CN coupling between C-4 carbon in 4-chloropyridine molecule and piperazine nitrogen in lower alcohol solution (methanol, ethanol, propanol, isopropyl alcohol) ) boiling, whereby a low-cost copper compound, iodide, bromide, cyanide and the like, or preferably recycling a Cu (I) complex mobilized on a weakly acidic polyacrylate cation exchanger, according to PV 2011-799, is preferably used as the catalyst.

The invention further provides a novel process for the preparation of 1- (pyrid-4-yl) piperazine by aromatic nucleophilic substitution of an activated cyano group in the 1-benzyl-4-cyanopyridin-1-one salt (chloride, bromide, iodide, benzenesulfonate, or tosylate) molecule with piperazine. in an aqueous solution or in a solution of a lower alcohol (methanol, ethanol, propanol, isopropyl alcohol) at a temperature of 20 to 80 ° C, when the d-metal from the group of gold Au (I), rhodium Rh (I), iron Fe ( III) or Fe (II), nickel Ni (II), cobalt Co (II) or Co (III), copper Cu (II) or Cu (I), or cerium Ce (III), immobilized on a weakly acidic polyacrylate cation exchanger, according to PV 2011-799.

The intermediate 1-benzyl-4- (piperazin-1-yl) pyridinium salt can then be converted to the target 1-il (pyrid-4-yl) piperazine by, for example, hydrogenolysis on a 5-20% palladium catalyst on charcoal, optionally in the presence of benzylamine or dibenzylamine in an aqueous, methanolic, aqueous methanolic solution, or in a solution of ethyl acetate or in a solution in acetic acid. Hydrogenolysis can also be carried out with hydrogen at a pressure of 1 to 10 atm, or hydrazine, ammonium formate, or formamide, at a temperature of 20 to 70 ° C.

Alternatively, the benzyl group of the 1-benzyl-4- (piperazin-1-yl) pyridinium salt can be removed by oxidation in a basic medium in aqueous, methanolic or aqueous methanolic solution, with sodium hypochlorite, sodium chlorite, or sodium peroxide reagents, or medium of 10 to 40% aqueous, methanolic or aqueous methanolic sodium hydroxide or potassium hydroxide solution with hydrogen peroxide reagents, air, or oxygen at 20 to 60 ° C.

1,1-Dialkyl-4- (pyridin-4-yl) piperazin-1-one salts according to the invention can be prepared from the intermediate 1-benzyl-4- (piperazin-1-yl) pyridinium salt by quaternization with an alkylating agent on a N 1 nitrogen atom a piperazine skeleton, either with an alkyl halide, an alkyl or benzenesulfonate, or an alkyl 4-tosylate, wherein the alkyl is either methyl, ethyl, n-propyl, or n-butyl, in the middle; methanol, ethanol, acetonitrile, or nitromethane, or in binary mixtures thereof, at temperatures from 30 ° C to the boiling points of the solvent used.

The benzyl group of the prepared 4- (1-benzylpyridinium-4-yl) -1,1-dialkylpiperazin-1-one salt is removed by hydrogenolysis, or oxidatively, as described above.

An advantage of the solution according to the invention is a new economically advantageous method of producing 1- (pyrid-4-yl) piperazine and 1,1-dialkyl-4- (pyridin-4-yl) piperazin-1-one salts in high yield and low environmental burden. An advantage of the process starting from 1-benzyl-4-cyanopyridinium chloride is its order of magnitude lower compared to the starting 4-halopyridinium chloride, where the halogen is bromine or iodine, used in the Buchwald-Hartwig C-N coupling. The solution according to the invention fulfills the criteria of the so-called "green" resp. sustainable chemistry.

The invention is illustrated by the following examples without limiting the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

4-Chloropyridin-1-ium chloride (150 g, 1 mol) is dissolved in hot in 1000 ml of isopropyl alcohol at 60 ° C, 215 g (2.5 mol) of piperazine are added, and the catalyst is added. It was prepared according to the application of the invention PV 2011-799 so that the weakly acidic polyacrylate cation exchanger of the macroporous type in ionized Na ⁺ form, with a minimum total capacity of 4.5 mol / liter and a bulk density of 750 g / liter, was in an amount of 7.5 g was stirred in 30 ml of water to which 5.0 g (25 mmol) of copper acetate monohydrate was added, for 30 min.

Λ

Then the aqueous phase was decanted and the solid was washed twice with 30 ml of water. The resin was then stirred for 30 min in a solution of 25 mL of water containing 3.0 g (43 mmol) of hydroxylammonium chloride at 50 ° C until the blue color of the resin turned white. Then the solution was discarded, the solid residue was washed twice with 25 ml of water, twice with 25 ml of methanol and used in the reaction.

The reaction mixture was refluxed for 13 h, the progress of the reaction was followed by thin layer chromatography on silica gel plates, developing plates with methanol, spotting with ninhydrin. After reaction and cooling of the reaction mixture to 5-10 ° C, the precipitated piperazine-1,4-diium dichloride was filtered off together with the catalyst, filtrate

It was filtered with the addition of activated carbon, and the solvent was distilled off in vacuo to dryness.

The crude 1- (pyrid-4-yl) -piperazine residue was recrystallized from 1 liter of n-heptane with the addition of silica gel. The yield of the reaction was 115 g (70%) of 1- (pyrid-4-yl) -piperazine, mp 139.5440.0 ° C, literature (Ratouis, R., Boissier, JR, Dumont, C .: J. Med. Chem 1965,

8, 104.) 140 ° C (heptane), literature (Komoto, T., Okada, T., Sato, S., Niino, Y., Oka, T.,

Sakamoto, T .: Chem. Pharm. Bull. 2001, 49, 1314.) 138-139 ° C (solvent not shown).

The purity of the product by gas chromatography was 99.1%.

The residues undissolved in n-heptane upon recrystallization of the crude product were boiled in crystallizing n-heptane mother liquor, filtered, and the filtrate was concentrated to 1/3 of the original volume and left to crystallize at 540 ° C overnight. An additional g (15.3%) of 1- (pyrid-4-yl) -piperazine was obtained, m.p. 137.5-139.0 ° C, the purity determined by gas chromatography was 97.8%.

1 H-NMR spectrum (300 MHz, CDCl ₃ ) δ / ppm: 8.10-8.08 (2H, m, Py-H), 6.52-6.50 (2H, m, Py-H), 3.15 to 3.12 (4H, m, _CH2), 2.85-2.82 (4H, m, _CH2), 2.69 (NH).

Example 2

1-Benzyl-4-cyanopyridinium chloride (23.0 g, 0.10 mol) was stirred for 10 min in 150 mL methanol together with spiperazine (10 g, 0.12 mol) and catalyst at room temperature. The catalyst was prepared according to the application PV 2011-799 such that the weakly acidic = polyacrylate cation exchanger of the macroporous type in ionized Na ⁺ form, with a minimum total capacity of 4.5 mol / liter and a bulk density of 750 g / liter, was 7.5 g was stirred in 30 ml of water to which 9.3 g (25 mmol) of cerium chloride heptahydrate was added, for 30 min. and

The aqueous phase was decanted and the solid was washed twice with 30 ml of water, twice with 30 ml of methanol and ⁷ times with the reaction. After completion of the reaction, the catalyst was filtered off, the methanol filtrate was acidified to about pH 1 * 2 with methanolic 2M hydrogen chloride solution, 1 g of activated carbon was stirred in the solution, cooled to 5 * 10 ° C and filtered after 10 minutes. The methanol solution was concentrated to 80 ml in vacuo and heated to boiling. Acetone (60 ml) was added to the boiling solution and the solution was allowed to crystallize at 10 ° C overnight. The white crystals were aspirated, washed with methanol acetone (1: 1) and dried under vacuum to constant weight. 4- (1-Benzylpyridinium-4-yl) piperazin-1-ium dichloride was obtained in a yield of 26.1 g (80%), mp 292.5493 ° C.

Example 3 j Μ

4- (1-Benzylpyridinium-4-yl) piperazin-1-ium dichloride (3.26 g, 10 mmol) was dissolved at boiling point in methanol (25 mL) and after dissolution anhydrous potassium carbonate (2.10 π) was added.

g, 15 mmol) and the suspension was stirred under reflux for 15 min, after which methyl iodide (4.26 g, 30 mmol) and nitromethane (25 mL) were added. The suspension was stirred for 5 h, then filtered, the solid residue was boiled with 30 ml of methanol and filtered again. The filtrates were combined, a 2.0 M methanolic hydrogen chloride solution (20 mL) was added and the volume of the methanol / nitromethane mixture was reduced to 50 mL under vacuum and allowed to crystallize at 5 * 10 ° C overnight. 2.9 g (82%) of 4- (1-benzylpyridin-1-ium-4-yl) -1,1-dimethylpiperazin-1-ium were prepared.

Λ dichloride. White crystalline solid, m.p. 280/281 ° C.

1 H-NMR spectrum (300 MHz, D ₂ O) δ / ppm: 8.29-8.27 (m, 2H, Py-H), 7.40-7.38 (m, 5H, ArH), 7 , 20-7,24 (m, 2H, Py-H), 5.38 (s, 2H, _CH2 -N ^+), 3.76-3.74 (m, 4H, 2x CH ₂₎ 3, 64-3,62 (m, 4H, 2 _CH2), 3.32 (s, 6H, 2 _CH3).

Example 4

4- (1-Benzylpyridinium-4-yl) piperazin-1-ium dichloride (3.26 g, 10 mmol) was reacted in the same procedure as described in Example 3 except that n-butyl bromide was used instead of methyl iodide. ((4.11 g, 30 mmol), which was reacted for 10 h, further work-up and work-up of the reaction mixture were as described in Example 4.

It was prepared 2.9 g (82%) of 4- _{(l-Benzyl-pyridin:} ium-4-yl) -l, l-di-n-butyl-piperazine-l-ium

...

of dichloride. White crystalline solid, m.p. 272 DEG-273 DEG.

1 H-NMR spectrum (300 MHz, D ₂ O) δ / ppm: 8.28-8.27 (m, 2H, Py-H), 7.39-7.37 (m, 5H, ArH), 7 , 24-7,20 (m, 2H, Py-H), 5.36 (s, 2H, _CH2 -N ^+), 3.76-3.74 (m, 4H, 2 CH2), 3.64 -3.62 (m, 4H, 2 * CH2), 3.25 (t, 4H, CH2 --N ⁺ , J = 7.1 Hz), 1.57-1.14 (m, 8H, 4 * CH2) 0.94 (t, 6H, 2x CH _3, J = 7.12 Hz).

Example 5

4- (1-Benzylpyridinium-4-yl) piperazin-1-ium dichloride (3.26 g, 10 mmol), ammonium formate

and. (1.26 g, 20 mmol) and 250 mg of 10% palladium on charcoal were refluxed in 25 mL of methanol for 3 h. After that the solution was filtered, sodium hydroxide (0.40 g, 10 mmol) was added, After cooling to room temperature, the sodium chloride was suctioned off, the methanol was evaporated to dryness in vacuo and the residue was recrystallized from hexane.

liti «« S t

1- (pyrid-4-yl) piperazine was prepared as a white crystalline solid in a yield of 1.39 g (85%), m.p. 140 ° C.

Example 6

(Pyrid-4-yl) piperazine was prepared as described in Example 5 except that 80% hydrazine hydrate (2 mL) was used in excess at reflux under hydrogen instead of ammonium formate. The reaction mixture was worked up as in Example 6. 1- (pyrid-4-yl) piperazine was prepared as a white crystalline solid in a yield of 1.31 g (80%), mp 139.5 * 140 ° C.

Example 7

4- (1-Benzylpyridin-1-ium-4-yl) -1,1-dimethylpiperazin-1-ium dichloride (3.54 g, 10 mmol) was dissolved in 25 mL water, a 15% solution was added dropwise. sodium hypochlorite (10.0 g, 20 mmol) at 40 * 50 ° C for 1 h and then stirred for an additional 1 h. Polta was filtered with charcoal and the water evaporated to dryness in vacuo. The solid residue was boiled with 15 ml of methanol, insoluble materials were filtered off, 10 ml of ethyl acetate were added to the filtrate at boiling and the product was left to crystallize at 5 * 10 ° C overnight. 1.96 g (86%) of 1,1-dimethyl-4- (pyridin-4-yl) piperazin-1-ium chloride, white crystalline solid, m.p. 276 DEG-277 DEG C. were prepared.

1 H-NMR spectrum (300 MHz, D ₂ O) δ / ppm: 7.97-7.94 (m, 2H, Py-H), 6.94-6.91 (m, 2H, PyH), 3 , 46-3,44 (m, 4H, 2x CH _2), 3.28 to 3.26 (m, 4H, 2 _CH2), 3.30 (s, 6H, 2 _CH3).

Example 8

4- (1-Benzylpyridin-1-ium-4-yl) -1,1-dimethylpiperazin-1-ium dichloride (3.54 g, 10 mmol) was dissolved in 25 mL of a 30% aqueous sodium hydroxide solution and a solution of while stirring at 30 ° C, a stream of air (10 mL / min) was bubbled through for 24 h, methanol was continuously charged to maintain a reaction volume of between 20 and 30 mL. After the solution was shaken three times with 10 ml of diethyl ether, then filtered with activated carbon, a 5% aqueous hydrogen chloride solution was added so that the pH of the mixture was between 1-2 and the water was then evaporated to dryness in vacuo. The solid residue was boiled with 15 ml of methanol, the insoluble matter was filtered off, 10 ml of isopropanol were added to the filtrate at boiling and the product was left to crystallize at 5-10 ° C overnight.

''! tt> t I>, i ^; iti *: í »« I5 í «í í» i '!

s * · I i r s <<, tt

1.96 g (74%) of 1,1-dimethyl-4- (pyridin-1-ium-4-yl) piperazin-1-ium dichloride were obtained, white crystalline solid, m.p. 291 * 293 ° C.

1 H-NMR spectrum (300 MHz, D ₂ O) δ / ppm: 8.15-7.12 (m, 2H, Py-H), 7.16-6.7.14 (m, 2H, Py- H), 3.66-3.64 (m, 4H, 2 _CH2), 3.48-3.44 (m, 4H, 2 _CH2), 3.29 (s, 6H, 2 _CH3).

Industrial applicability

The invention is contemplated in small-scale industrial processes for the preparation of 1- (pyridin-4-yl) piperazine and its 1,1-dialkyl-1-ium derivatives, which can be used as catalyst activators of electrophilic reagents, in particular acylating agents, in particular production of chemical and pharmaceutical specialties in other chemical synthetic processes, and 1- (pyridin-4-yl) piperazine, in particular as an important pharmaceutical intermediate.

Hft

Have

PATENT CLAIMS

Claims (8)

A process for the preparation of 1- (pyridin-4-yl) piperazine derivatives of the general formula I wherein R ¹ and R ² are the same and are selected from hydrogen and C 1 -C 4 n-alkyl, or R ² is absent and R ¹ is hydrogen, R is selected from the group consisting of benzyl and hydrogen, or R is absent and, when R is present, carries the nitrogen to which it is bound, positively charged, and when R ³ is present carries the nitrogen to which it is bound, positive a charge characterized in that it comprises a step in which The 4-chloropyridine or 4-cyanopyridine, protonated or quaternized on the pyridine nitrogen atom with benzyl, is reacted with spiperazine in water or a VC1-C3 alcohol, catalysed by a metal selected from the group consisting of d-metals and cerium, in a positively charged complex or compounds. Process according to claim 1, characterized in that 4-chloropyridine or 4-cyanopyridine protonated or quaternized with benzyl is used for the reaction with piperazine, preferably 1-benzyl-4-ol is used for the reaction with piperazine. cyanopyridin-1-ium in the form of chloride, bromide, iodide, benzenesulfonate, or 4-tosylate. Method according to claim 1 or 2, characterized in that it is carried out under catalysis with a metal selected from the group comprising gold Au (I), rhodium Rh (I), iron Fe (III) or Fe (II), nickel Ni (II) , cobalt Co (II) or Co (III), copper Cu (II) or Cu (I), cerium Ce (III), in the form of a positively charged complex or compound. The method according to any one of claims 1 to 3, characterized in that the d-metal or cerium in the positively charged complex is immobilized on a weakly acidic polyacrylate cation exchanger. Process according to any one of claims 1 to 4, characterized in that the resulting product is quartemised on the nitrogen atom N1 of the piperazine, preferably 1-benzyl-4-15 (piperazin-1-yl) pyridinium salt on the nitrogen atom N1 of the piperazine is quaternized portions of the molecule with an agent selected from the group consisting of C1-C4-n-alkyl halide, C1-C4-n-alkyl benzenesulfonate, and C1-C4-n-alkyl 4-tosylate, in a solvent selected from methanol, ethanol, acetonitrile, nitromethane, and binary mixtures thereof, at temperatures from 30 ° C to the boiling points of the solvent used. The method according to any one of claims 1 to 5, characterized in that the method comprises ^: product Quaternized on the pyridine nitrogen atom removes the R group, which is benzyl. 7. The method of claim 6 wherein the R &lt; ³ &gt; group which is benzyl is removed from 1-benzyl-4- (piperazin-1-yl) pyridin-1-one or 4- (1-benzylpyridinium-4-yl). ) -1,1— l -dialkylpiperazines-l-ium salt hydrogenolysis on 5-20 _J y ^ _j Jimotn palladium catalyst on charcoal, optionally in the presence of benzylamine or dibenzylamine, in a solvent selected from the group comprising water, methanol, a mixture of water and methanol, and acetic acid ethyhacetát. A process according to claim 6, wherein the R ³ group, which is benzyl, is removed by hydrogenolysis with an agent selected from the group consisting of hydrogen at a pressure of 101325 to 1013250 Pa, hydrazine, ammonium formate, and formamide, at 20 to 70 ° C. .