MXPA06009844A

MXPA06009844A - Process for the preparation of tryptase inhibitors

Info

Publication number: MXPA06009844A
Application number: MXPA/A/2006/009844A
Authority: MX
Inventors: W Sledeski Adam; Graf Clausdieter; Tappertzhofen Christoph
Original assignee: Sanofiaventis Deutschland GMBH
Priority date: 2004-03-02
Filing date: 2006-08-30
Publication date: 2007-04-20

Abstract

This invention is directed to processes for the preparation of compounds of the formula (I) and their salts, formula (I) which are useful as tryptase inhibitors, to intermediates useful in the preparation of such compounds, to processes for the preparation of such intermediates, and to the use of such intermediates for the preparation of such compounds.

Description

PROCESS FOR THE PREPARATION OF TRIPTASE INHIBITORS This invention relates to processes for the preparation of compounds that are useful as inhibitors of tryptase, to intermediates useful in the preparation of said compounds, to processes for the preparation of said intermediates, and to the use of said intermediates for the preparation of said intermediates. compounds BACKGROUND OF THE INVENTION Inflammatory conditions mediated by mast cells, particularly asthma, are a growing concern for public health. Asthma is often characterized by the progressive development of a hyper-response of the trachea and bronchi both immunospecific rgens and generalized chemical or physical stimuli, which leads to the onset of chronic inflammation. Leukocytes containing IgE receptors, particularly mast cells and basophils, are present in the epithelium and in the smooth muscle tissue underlying the bronchi. These leukocytes are initi activated by the binding of specific inhaled antigens to the IgE receptors that then release several chemical mediators. For example, degranulation of mast cells leads to the release of proteoglycans, peroxidase, arylsulfatase B, chymase and tryptase, which produces a constriction of the bronchioles.

Tryptase is stored in mast cell secretory granules and is the main secretion protease of human mast cells. Tryptase has been implicated in a variety of biological processes, including the degradation of neuropeptides with vasodilatory and bronchorelaxing activity (Caughey et al., J. Pharmacol. Exp. Ther., 1988, 244, pages 133-137; Franconi et al., J. Pharmacol. Exp. Ther., 1988, 248, pages 947-951; and Tam et al., Am. J. Respir. Cell Mol. Biol., 1990, 3, pages 27-32) and the modulation of bronchial sensitivity to histamine (Sekizawa et al., J. Clin. Invest., 1989, 83, pages 175-179).

As a result, tryptase inhibitors are considered useful as anti-inflammatory agents (K. Rice, PA Sprengler, Current Opinion in Drug Discovery and Development, 1999, 2, pages 463-474) particularly in the treatment of chronic asthma (MQ Zhang, H Timmerman, Mediators Inflamm., 1997, 112, pages 311-317), and may also be useful in the treatment or prevention of rgic rhinitis (SJ Wilson et al., Clin. Exp. rgy, 1998, 28, pages 220 -227), inflammatory bowel disease (SC Bischoff et al., Histopathology, 1996, 28, pages 1-13), psoriasis (A. Naukkarinen et al., Arch. Dermatol. Res., 1993, 285, pages 341- 346), conjunctivitis (AAIrani et al., J. rgy Clin.Immunol., 1990, 86, pages 34-40), atopic dermatitis (A. Jarviko et al., Br. J. Dermatol., 1997, 136, pages 871-877), rheumatoid arthritis (LC Tetlow et al., Ann. Rheum. Dis., 1998, 54, pages 549-555), osteoarthritis (MG Buckiey et al., J. Pathol., 1998, 18 6, pages 67-74), gouty arthritis, rheumatoid spondylitis and cartilage destruction diseases.

In addition, tryptase has been shown to be a potent mitogen for fibroblasts, suggesting its involvement in pulmonary fibrosis in asthma and interstitial lung diseases (Ruoss et al., J. Clin. Invest., 1991, 88, pages 493- 499).

Therefore, tryptase inhibitors are considered useful in the treatment or prevention of fibrotic disorders (JA Caims, AF W, J. Clin. Invest., 1997, 99, pages 1313-1321) for example, fibrosis, scleroderma, fibrosis. pulmonary, liver cirrhosis, myocardial fibrosis, neurofibromas and hypertrophic scars.

In addition, tryptase inhibitors are considered useful in the treatment or prevention of myocardial infections, stroke, angina and other consequences of the rupture of atherosclerotic plaques (M. Jeziorska et al., J. Pathol., 1997, 182, pages 115- 122).

It has also been discovered that tryptase activates the prostomelysin which in turn activates the collagenase, thus initiating the destruction of the cartilage and the periodontal connective tissue, respectively.

Therefore, tryptase inhibitors are considered useful in the treatment or prevention of arthritis, periodontal disease, diabetic retinopathy and tumor growth (W. J. Beil et al., Exp. Hematol., 1998, 26, pages 158-169). In addition, tryptase inhibitors are considered useful in the treatment of anaphylaxis (LB Schwarz et al., J. Clin. Invest., 1995, 96, pages 2702-2710), multiple sclerosis (M. Steinhoff et al., Nat. Med. (NY), 2000, 6, pages 151-158), peptic ulcers and syncytial virus infections.

The compounds of formula I have been described as useful compounds as tryptase inhibitors, for example, in WO 01/90101 and WO 2004/060884 (international patent application PCT / US2003 / 040653). Processes for preparing compounds of formula I are also described in these documents, however, they have substantial drawbacks and risks, in particular when it is desired to prepare a compound of formula I on a large scale. The present invention provides advantageous processes that are useful in the preparation of compounds of formula I and allow to overcome the drawbacks and avoid the risks of the processes of the prior art.

SUMMARY OF THE INVENTION This invention relates to processes for the preparation of compounds of formula where R1 is H, F, CF3, OCF3, (C? -C8) alkyl, (C3-C10) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 identical or different heteroatoms in the ring selected from nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (CrC8), cycloaicoxy (C3-C10), aryloxy (C6-C14), di (C1-C8 alkyl) amino, di (cycloalkyl (C3-C) -, o)) amino or di (aryl (Ce-C14)) amino; and R2 is H, F, CF3, OCF3, (Cs C) alkyl, (C3-C10) cycloalkyl, 10-membered, 3-membered heterocycle comprising 1, 2 or 3 heteroatoms the same or different in the ring chosen from nitrogen, oxygen and sulfur, aryl (C6-C4), 5-membered, 10-membered heteroaryl comprising 1, 2 or 3 same or different heteroatoms in the ring chosen from nitrogen, oxygen and sulfur, (C8) alkoxy, cycloalkoxy (C3) -C10), (C6-C14) aryloxy, 5-membered, 10-membered heteroaryloxy comprising 1, 2 or 3 heteroatoms identical or different in the ring chosen from nitrogen, oxygen and sulfur, di (C 1 -C 8 alkyl) amino, di- (cycloalkyl (C3-C10)) amino or d (ar (C6-C1)) amino; and its salts.

This invention also relates to intermediates useful in the preparation of compounds of formula I, to processes for the preparation of said intermediates, and to the use of said intermediates for the preparation of said compounds.

Detailed description of the invention In a first aspect, the present invention provides a process for the preparation of a compound of the formula I, where R1 is H, F, CF3, OCF3, (C8) alkyl, (C3-C10) cycloalkyo, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms same or different in ring selected from nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (C? -C8), cycloalkoxy (C3-C.0), aryloxy (C6-C14), di (C8-alkyl) amino, di (C3- (C3- C10)) amino or di (aryl (C6-C14)) amino; and R2 is H, F, CF3, OCF3, (C8) alkyl, cycloalkyl (OrC-io), 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms same or different in the ring chosen from nitrogen, oxygen and sulfur, aryl (C6-C14), 5-membered heteroaryl to 10 members comprising 1, 2 or 3 heteroatoms the same or different in the ring chosen from nitrogen, oxygen and sulfur, alkoxy (C8), cycloalkoxy (C3-C) , 0), (C6-C14) aryloxy, 5-membered, 10-membered heteroaryloxy comprising 1, 2 or 3 heteroatoms either identical or different in the ring chosen from nitrogen, oxygen and sulfur, di (C8 alkyl) amino) , di- (C3-C10) cycloalkyl) amino or di (aryl (C6-C14)) amino; or its salts, comprising the steps of a) treating a phenylethylsilane compound of formula II, wherein G is trimethylsilyl, triethylsilyl, tri-isopropylsilyl, or dimethyl-tert-butylsilyl, and R2 'is R2 as defined above or is a protected derivative thereof or a precursor residue thereof, in a solvent, such as an aliphatic alcohol or a mixture of an aliphatic alcohol and an ether, for example methanol or a mixture of methanol and tetrahydrofuran, with a hydroxide, carbonate or alcohol of an alkali metal, or an alcohol of an alkaline earth metal, to form a solution of a phenyletino of formula III; and b) combining the resulting solution of the phenyletino with a compound of the formula IV, wherein X is bromine or iodine, R1 is R1 as defined above or is a protected derivative thereof or a precursor residue thereof, and Boc is tert-butoxycarbonyl, in the presence of a homogeneous palladium catalyst, a salt of copper, and a hindered amine in a solvent, such as an ether or a mixture of an ether and an aliphatic alcohol, for example tetrahydrofuran or a mixture of tetrahydrofuran and methanol, to form a protected compound of formula V, wherein Rr and R2 'are R1 and R2, respectively, as defined above or are a protected derivative thereof or a precursor thereof, and Boc is tert-butoxycarbonyl, or salts thereof.

Particular embodiments of this first aspect of the present invention are those in which G is trimethylsilyl, and / or X is bromine, and / or the homogeneous palladium catalyst is bis (triphenylphosphine) palladium (II) chloride and / or the The copper salt is copper iodide (I), and / or the hindered amine is triethylamine.

A special embodiment of this first aspect provides for the further removal of the tert-butoxycarbonyl group from the protected compound of formula V and, if possible, the removal of any other protecting group and / or the conversion of the precursor moieties that may be present in R1. and / or R2 in a compound of the formula V by conventional procedures, in a solvent, for example an aliphatic alcohol or an ether, to provide a compound of the formula I or its salts. Another special embodiment of this first aspect provides the removal of the tert-butoxycarbonyl group of the protected compound of formula V, in particular of a compound in which R1 and R2 are R1 and R2, respectively, in the presence of an acid, in particular an acid Physiologically acceptable, for example methanesulfonic acid, in a solvent, for example an aliphatic alcohol or an ether such as isopropanol, to provide a compound of the formula I or its salts.

A second aspect of the present invention provides a process for the preparation of 4- [3- (aminomethyl) phenyl] -1- [5- (2-fluorophenylethynyl) -2-furanoyl] piperidine, ie, the compound of formula , or its salts, comprising the steps of a) treating a 2-fluorophenylethylsilyl compound of formula Ia, wherein G is trimethylsilyl, triethylsilyl, tri-isopropylsilyl, or dimethyl-tert-butylsilyl, in a solvent, such as an aliphatic alcohol or a mixture of an aliphatic alcohol and an ether, for example methanol or a mixture of methanol and tetrahydrofuran , with a hydroxide, carbonate or alcohol of an alkali metal, or an alcohol of an alkaline earth metal, for example with potassium carbonate in methanol, to form a 2-fluorophenylethine solution; Y b) combining the resulting solution of 2-fluorophenylethine with a compound of the formula IVa, IVa wherein X is bromine or iodine, and Boc is tert-butoxycarbonyl, in the presence of a homogeneous palladium catalyst, a copper salt and a hindered amine in a solvent, such as an ether or a mixture of an ether and a aliphatic alcohol, for example tetrahydrofuran or a mixture of tetrahydrofuran and methanol, to form 4- [3- (tert-butoxycarbonyllaminomethyl) phenol] -1- [5- (2-fluorophenyletinyl) -2-furanoyl] piperidine, that is,. the compound of formula Va, wherein Boc is tert-butoxycarbonyl.

Particular embodiments of this second aspect of the present invention are those in which G is trimethylsilyl, and / or X is bromine, and / or the homogeneous palladium catalyst is bis (triphenylphosphine) palladium (II) chloride, and / or the copper salt is copper iodide (I), and / or the hindered amine is triethylamine.

A special embodiment of this second aspect provides for the further removal of the tert-butoxycarbonyl group from 4- [3- (tert-butoxycarbonyllaminomethyl) phenyl] -1- [5- (2-fluorophenylethynyl) -2-furanoyl] piperidine. Formula Va in a solvent to provide the compound of formula la or its salts. Another special embodiment of this second aspect provides the removal of the tert-butoxycarbonyl group from 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] -1- [5- (2-fluorophenylethynyl) -2-furanoyl] piperidine of formula Va in presence of an acid, in particular a physiologically acceptable acid, for example methanesulfonic acid, in a solvent, for example an aliphatic alcohol or an ether such as isopropanol, to provide the compound of the formula la or its salts, for example the methanesulfonic acid salt of 4- [3- (aminomethyl] I) phenyl] -1- [5- (2-fluorophenylethynyl) -2-furanoyljpiperidine.

A third aspect of the present invention provides a process for the preparation of a compound of formula IV, where R1 'is H, F, CF3, OCF3, (C8) alkyl, (C3-C-, 0) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 same or different heteroatoms in the ring selected between nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (C | -8), cycloalkoxy (C3-C10), aryloxy (C6-C? 4), di (alkyl (CrC8)) amino, di (cycloalkyl) (C3-C10)) amino or di (aryl (C6-C14)) amino, or a protected derivative thereof or a precursor thereof; and X is bromine or iodine, comprising the steps of a) activating 5-bromo-2-furoic acid or 5-iodo-2-furoic acid, for example by converting it into an activated acid derivative which can be prepared in situ or can be isolated, such as with a acid, in particular an acid chloride, an active ester or a mixed anhydride or anhydride, for example by treatment with a halogenating agent such as thionyl chloride or oxalyl chloride in a solvent, such as a hydrocarbon or a chlorinated hydrocarbon, by toluene, at a temperature from about 0 ° C to about 120 ° C, for example at the reflux temperature of the solvent, or by treatment with an alkyl chlorocarbonate such as ethyl chlorocarbonate or isobutyl chlorocarbonate and a base such as, for example, triethylamine in a solvent, for example a halogenated hydrocarbon or an ether such as tetrahydrofuran, at a temperature of about -10 ° to about 30 ° C, or by treating it with a conditioning agent. or a coupling agent as is commonly used for the preparation of amide bonds in peptide chemistry, for example, such as a carbodiimide such as dicyclohexylcarbodumide or diisopropylcarbodiimide or a carbonyldiazole such as carbonyldiimidazole or tetrafluoroborate of 0 - ((cyano) carboni) methylene) amino) -N, N, N, N, -tetramethyluronium (TOTU) or propylphosphonic anhydride, optionally in the presence of an auxiliary agent such as 1-hydroxybenzotriazole, for example, in a solvent, example a halogenated hydrocarbon or an ether or an amide such as tetrahydrofuran or dimethylformamide, at a temperature from about 0 ° C to about 30 ° C, to provide an activated form of 5-bromo-2-furoic acid or 5-iodo- 2-furoic, for example 5-bromo-2-furoyl chloride or 5-iodo-2-furoyl chloride, respectively, wherein said activated form can be obtained and subsequently used in the form of a solution, for example a solution in toluene; Y b) combining the activated form of 5-bromo-2-furoic acid or 5-iodo-2-furoic acid with a compound of the formula VI, wherein R is as defined for formula IV and Boc is tert-butoxycarbonyl, in a solvent, for example a hydrocarbon, a chlorinated hydrocarbon or an ether such as toluene or dichloromethane, optionally in the presence of a base, for example a tertiary amine such as triethylamine.

A further embodiment of this third aspect provides a process for the preparation of a compound of formula IV wherein X is bromine, ie a compound of formula IVb, where R1 'is H, F, CF3, OCF3, (C8) alkyl, (C3-C10) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms same or different in the ring selected from among nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (C8), cycloalkoxy (C3-C10), (C6-C14) aryloxy, di (C8-alkyl) amino, di (C3-C10) cycloalkyl) amino or (aryl (C6-C? 4)) amino, or a derivative protected from it or a precursor residue thereof; and Boc is tert-butoxycarbonyl, or comprising the steps of a) activating 5-bromo-2-furoic acid to provide an activated form of 5-bromo-2-furoic acid; Y b) combining the activated form of 5-bromo-2-furoic acid with a compound of the formula VI in a solvent, optionally in the presence of a base, where all the explanations mentioned above in the third aspect of the present invention also apply to this additional embodiment. For example, 5-bromo-2-furoic acid can be activated by treatment with thionyl chloride in toluene at the reflux temperature to provide a solution of 5-bromo-2-furoyl chloride in toluene which is then reacted with a compound of the formula VI in the presence of a base such as a tertiary amine in toluene or dichloromethane.

A fourth aspect of the present invention provides a process for the preparation of a compound of the formula IV wherein R 1 is hydrogen, ie a compound of the formula IVa, wherein X is bromine or iodine; and Boc is tert-butoxycarbonyl, comprising the steps of a) activating 5-bromo-2-furoic acid or 5-iodo-2-furoic acid, for example by converting it into an activated acid derivative which can be prepared in situ or can be isolated, such as an acid halide , in particular an acid chloride, an active ester or a mixed anhydride or anhydride, for example by treatment with a halogenating agent such as thionyl chloride or oxalyl chloride in a solvent, such as a hydrocarbon or a chlorinated hydrocarbon, for example toluene, at a temperature from about 0 ° C to about 120 ° C, for example at about the reflux temperature of the solvent, or by treatment with an alkyl chlorocarbonate such as ethyl chlorocarbonate or sobutyl chlorocarbonate and a base such as , for example, triethylamine in a solvent, for example a halogenated hydrocarbon or an ether such as tetrahydrofuran, at a temperature of about -10 ° to about 30 ° C, or by treating it with a condensation agent or a coupling agent as is commonly used for the formation of amide bonds in peptide chemistry, for example, such as a carbodiimide such as dicyclohexylcarbodiimide or düsopropylcarbodiimide or a carbonyldiazole such as carbonyldiimidazole or tetrafluoroborate of 0 - ((c) an (ethoxycarbonyl) methylene) amino) -N, N, N ', N, -tetramethyluronium (TOTU) or propylphosphonic anhydride, optionally in the presence of an auxiliary agent such as 1-hydroxybenzotriazole, for example, in a solvent, for example a halogenated hydrocarbon or an ether or an amide such as tetrahydrofuran or dimethylformamide, at a temperature from about 0 ° C to about 30 ° C, to provide an activated form of 5-bromo-2-furoic acid or acid 5-iodo-2-furoic acid, for example 5-bromo-2-furoyl chloride or 5-iodo-2-furoyl chloride, respectively, wherein said activated form can be obtained and subsequently used in the form of a solution, per. example a solution in toluene; Y b) combining the activated form of 5-bromo-2-furoic acid or 5-iodo-2-furoic acid with a compound of the formula Via, wherein Boc is tert-butoxycarbonyl, in a solvent, for example a hydrocarbon, a chlorinated hydrocarbon or an ether such as toluene or dichloromethane, optionally in the presence of a base, for example a tertiary amine such as triethylamine.

A special embodiment of this fourth aspect provides a process for the preparation of a compound of the formula IVa wherein X is bromine, ie the compound of formula IVc, wherein Boc is tert-butoxycarbonyl, comprising the steps of a) activating 5-bromo-2-furoic acid to provide an activated form of 5-bromo-furoic acid, and b) combining the activated form of 5-bromo-2-furoic acid with a compound of the formula Via wherein Boc is tert-butoxycarbonyl, in a solvent, optionally in the presence of a base, where all the explanations mentioned above in the fourth aspect of the present invention also apply to this special embodiment. For example, 5-bromo-2-furoic acid can be activated by treatment with thionyl chloride in toluene at the reflux temperature to provide 5-bromo-2-furoyl chloride, preferably in the form of a solution in toluene, which is then it reacts with the compound of formula Via in the presence of a base such as a tertiary amine in toluene or dichloromethane.

A fifth aspect of the present invention provides a process for the preparation of a compound of the formula VI wherein R is H, F, CF3, OCF3, alkyl (C? -Ca), cycloalkyl (C3-C10), heterocycloalkyl of 3 members to 10 members comprising 1, 2 or 3 heteroatoms the same or different in the ring chosen between nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (C8), cycloalkoxy (C3-C | o), aryloxy (C6-C14), di (alkyl (C8)) amino, di ( (C3-C10) cycloalkyl) amino or di (aryl (C6-C14)) amino, or a protected derivative thereof or a precursor residue thereof; and Boc is tert-butoxycarbonyl, or its salts, comprising the steps of a) treating a salt of a 3-halobenzylamine of formula VII, with 1,2-bis (chlorodimethylsilyl) ethane in a solvent, for example a halogenated hydrocarbon such as dichloromethane, in the presence of a base, for example a tertiary amine tai such as triethylamine, to provide a 1- (3-halobenzyl) -2 , 2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane of formula Vlll; b) treating 1- (3-halobenzyl) -2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane of formula Vlll in a solvent, such as an ether, for example tetrahydrofuran, with an alkyllithium compound, for example n-butyllithium, and 1-benzyl-4-piperidone at a temperature from about -80 ° C to about -40 ° C to provide an alcohol of formula IX; c) treating the alcohol of formula IX with an acid, for example an inorganic acid such as phosphoric acid, in a solvent, for example a halogenated hydrocarbon such as dichloromethane, to provide a hydroxypiperidinylbenzylamine of formula X in the form of the acid salt; d) treating the hydroxypiperidinylbenzylamine of formula X or its salts with a concentrated, non-oxidizing acid at a temperature of about 70 ° C to about 150 ° C, followed by alkalization to provide an olefin of formula XI; e) treating the olefin of formula XI with di-tert-butyl dicarbonate in a solvent, for example an aliphatic alcohol such as methanol, ethyl acetate, an ether such as tetrahydrofuran, a halogenated hydrocarbon such as dichloromethane, a mixture of two or more of said solvents or a mixture of one or more of said solvents with water, in the presence of a base, for example a hydroxide, carbonate or alcohol of an alkali metal, or a tertiary amine, such as sodium hydroxide or triethylamine, preferably at a temperature from about 0 ° C to about 40 ° C, to provide a protected amine of formula XII where Boc is tert-butoxycarbonyl, and where Ph in the formulas IX, X, XI and XII is phenyl, and where X 'in the formulas VII and Vlll is bromine or iodine, and where R1' in the formulas VII, VII, IX , X, XI and XII is as defined above for formula VI.

A special embodiment of this fifth aspect is that in which X 'is bromine.

Another special embodiment of this fifth aspect provides further treating the protected amine of formula XII, wherein Boc is tert-butoxycarbonyl, Ph is phenyl and R1 is as defined above for formula VI, with hydrogen at a pressure of about 200 kPa to about 3000 kPa in a solvent, for example an aliphatic alcohol or ethyl, in the presence of a palladium catalyst, in the presence of an organic or inorganic acid, for example acetic acid, to provide a compound of the formula VI, wherein R1 'is as defined above for formula VI and Boc is tert-butoxycarbonyl, in the form of its salts or, if desired, in the form of the free compound of formula VI.

A sixth aspect of the present invention provides a process for the preparation of a compound of the formula VI, wherein R1 'is H, F, CF3, OCF3, (C8) alkyl, (C3-C10) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 same or different heteroatoms in the ring selected from nitrogen, oxygen and sulfur, aryl (C6-C), alkoxy (CrC8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (C8 alkyl) amino, di (C3-C10 cycloalkyl) amino or di (aryl (C6-C-,)) amino, or a protected derivative thereof or a precursor residue thereof; and Boc is tert-butoxycarbonyl, or its salts, comprising the steps of a) treating a 3- (4-pyridyl) benzaldehyde of formula Xlll, with hydroxylamine or a hydroxylamine salt in a solvent, for example an aliphatic alcohol, optionally in the presence of a base, at a temperature from about 0 ° C to about 40 ° C to provide an oxime of formula XIV or its salts; b) treating the oxime of formula XIV or its salts with hydrogen at a pressure of about 300 kPa to about 1500 kPa in a solvent, for example a polar organic solvent such as an aliphatic alcohol, for example methanol, in the presence of a palladium, at a temperature of about 20 ° C to about 50 ° C to provide a 3- (4-pyridyl) benzylamine of formula XV or its salts; c) treating the 3- (4-pyridyl) benzylamine of formula XV or its salts with di-tert-butyl dicarbonate in a solvent, for example an aliphatic alcohol such as methanol, ethyl acetate, an ether such as tetrahydrofuran, an halogenated hydrocarbon such as dichloromethane, a mixture of two or more of said solvents or a mixture of one or more of said solvents with water, in the presence of a base, for example a hydroxide, carbonate or alcohol of an alkali metal, or an amine tertiary, such as sodium hydroxide or triethylamine, preferably at a temperature from about 0 ° C to about 40 ° C, to provide a Boc-protected 3- (4-pyridyl) benzylamine of formula XVI, wherein Boc is tert-butoxycarbonyl; Y d) treating the Boc-protected 3- (4-pyridyl) benzylamine of formula XVI with hydrogen in a solvent, for example an aliphatic alcohol such as ethanol, at a pressure of about 2000 kPa to about 6000 kPa, in the presence of a catalyst of palladium, in the presence of an acid such as, for example, hydrogen chloride or sulfuric acid, to provide a compound of formula VI or its salts; where R1 'in the formulas Xlll, XIV, XV and XVI is as previously defined for the formula VI.

A particular embodiment of this sixth aspect provides a process for the preparation of a compound of the formula VI, where R1 'is H, F, CF3, OCF3l (C8) alkyl, (C3-C10) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms the same or different in the ring chosen from nitrogen, oxygen and sulfur, aryl (C6-C, 4), alkoxy (C8), cycloalkoxy (C3-C0), (C6-C14) aryloxy, di (C1-C8) alkyl) amino, di (cycloalkyl (C3-C? 0)) amino or di (aryl (C6-C14)) amino, or a protected derivative thereof or a precursor residue thereof; and Boc is tert-butoxycarbonyl, or its salts, comprising the steps of a) treating a 3- (4-pyridyl) benzaldehyde of formula Xlll with hydroxylamine hydrochloride in a solvent, for example an aliphatic alcohol such as methanol, at a temperature from about 0 ° C to about 40 ° C to provide an oxime hydrochloride of formula XlVa; b) treating the oxime hydrochloride of formula XlVa with hydrogen at a pressure of about 300 kPa to about 1500 kPa in a solvent, for example a polar organic solvent such as an aliphatic alcohol, for example methanol, in the presence of a palladium catalyst , at a temperature from about 20 ° C to about 50 ° C to provide a 3- (4-pyridyl) benzylamine hydrochloride of formula XVa; c) treating the 3- (4-pyridyl) benzylamine hydrochloride of formula XVa with di-tert-butyl dicarbonate in a solvent, for example an aliphatic alcohol such as methanol, ethyl acetate, an ether such as tetrahydrofuran, a hydrocarbon halogenated such as dichloromethane, a mixture of two or more of said solvents or a mixture of one or more of said solvents with water, in the presence of a base, for example a hydroxide, carbonate or alcohol of an alkali metal, or a tertiary amine , such as sodium hydroxide or triethylamine, preferably at a temperature from about 0 ° C to about 40 ° C, to provide a Boc-protected 3- (4-pyridyl) benzylamine of formula XVI, wherein Boc is tert-butoxycarbonyl; Y d) treating the Boc-protected 3- (4-pyridyl) benzylamine of formula XVI with hydrogen in a solvent, for example an aliphatic alcohol such as ethanol, at a pressure of about 2000 kPa to about 6000 kPa, in the presence of a catalyst of palladium, in the presence of hydrogen chloride or sulfuric acid, to provide a compound of formula VI or its salts; where R1 'in the formulas Xlll, XlVa, XVa and XVI is as defined above for the formula VI.

A seventh aspect of the present invention provides a process for the preparation of a compound of the formula VI wherein R1 'is H, F, CF3, OCF3, (C? -C8) alkyl, (C3-C10) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 same or different heteroatoms in the ring chosen from nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (C ^ Cs), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (C8 alkyl) amino, di (cycloalkyl) C3-C- | 0)) amino or di (aryl (C6-C14)) amino, or a protected derivative thereof or a precursor residue thereof; and Boc is tert-butoxycarbonyl, or its salts, comprising the steps of a) treating 3- (4-pyridyl) benzonitrile of formula XVII, XVII with hydrogen in the presence of a palladium catalyst at a pressure of about 2000 kPa to about 6000 kPa in the presence of an acid, for example hydrogen chloride, or with a complex hydride such as lithium aluminum hydride, lithium borohydride or borohydride sodium, optionally in the presence of an auxiliary agent such as an acid or chlorotrimethylsilane, in a solvent, for example an aliphatic alcohol or an ether such as tetrahydrofuran, to provide a 3- (4-pyridyl) benzylamine of formula XV or its salts; b) treating the 3- (4-pyridyl) benzylamine of formula XV or its salts with di-tert-butyl dicarbonate in a solvent, for example an aliphatic alcohol such as methanol, ethyl acetate, an ether such as tetrahydrofuran , a halogenated hydrocarbon such as dichloromethane, a mixture of two or more of said solvents or a mixture of one or more of said solvents with water, in the presence of a base, for example a hydroxide, carbonate or alcohol of an alkali metal, or a tertiary amine, such as sodium hydroxide or triethylamine, preferably at a temperature from about 0 ° C to about 40 ° C, to provide a Boc-protected 3- (4-pyridyl) benzylamine of formula XVI, XVI wherein Boc is tert-butoxycarbonyl; Y c) treating the Boc-protected 3- (4-pyridyl) benzylamine of formula XVI with hydrogen in a solvent, for example an aliphatic alcohol such as ethanol, at a pressure of about 2000 kPa to about 6000 kPa, in the presence of a catalyst of palladium, in the presence of an acid such as hydrogen chloride or sulfuric acid, to provide a compound of formula VI or its salts; where R1 'in formulas XV, XVI and XVI i is as defined above for formula VI.

An eighth aspect of the present invention provides a process for the preparation of 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] piperidine or its salts, comprising the steps of a) treating 3-bromobenzylamine hydrochloride or 3-iodobenzylamine hydrochloride with 1,2-bis (chlorodimethylsilyl) ethane in a halogenated aliphatic hydrocarbon in the presence of a tertiary amine to provide 1- (3-halobenzyl) Corresponding 2,2,2,5-tetramethyl-1-aza-2,5-disilacyclopentane, where halo is bromine or iodine; b) treating 1- (3-halobenzyl) -2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane in an ether with an alkyl lithium compound and 1-benzyl-4-piperidone at a temperature from about -80 ° C to about -40 ° C to provide 1- [3- (1-benzyl-4-hydroxypiperidin-4-yl) benzyl] -2,2,5,5-tetramethyl-1-aza-2 , 5-disilacyclopentane; c) treating 1- [3- (1-benzyl-4-hydroxypiperidin-4-yl) benzyl-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane with an acid inorganic in a halogenated hydrocarbon, to provide 3- (1-benzyl-4-hydroxypiperidin-4-yl) benzamine in the form of the inorganic acid salt; d) treating 3- (1-benzyl-4-hydroxypiperidin-4-yl) benzylamine with a concentrated, non-oxidizing acid at a temperature of about 70 ° C to about 150 ° C, followed by alkalization to provide 3- (1 -benzyl-1,2,3,6-tetrahydropyridin-4-yl) benzylamine; Y e) treating 3- (1-benzyl-1, 2,3,6-tetrahydropyridin-4-yl) benzylamine with di-tert-butyl dicarbonate in an aliphatic alcohol such as methanol, ethyl acetate, an ether such as tetrahydrofuran, a halogenated hydrocarbon such as dichloromethane, a mixture of two or more of said solvents or a mixture of one or more of said solvents with water, in the presence of a hydroxide, carbonate or alcohol of an alkali metal, or a tertiary amine, such as sodium hydroxide or triethylamine, preferably at a temperature from about 0 ° C to about 40 ° C, to provide 3- (1-benzyl-1, 2,3,6-tetrahydropyridin-4-yl) tert-butyl ester. ) benzylcarbamic A special embodiment of this eighth aspect provides a process for the preparation of 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] piperidine or its salts, comprising the steps of a) treating 3-bromobenzylamine hydrochloride with 1,2-bis (chlorodimethylsilyl) ethane in a halogenated aliphatic hydrocarbon, in the presence of a tertiary amine to provide 1- (3-bromobenzyl) -2,2,5 , 5-tetramethyl-1-aza-2,5-disilacyclopentane; b) treating 1- (3-bromobenzyl) -2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane in an ether, with an alkyllithium compound and 1-benzyl-4-piperidone at a temperature from about -80 ° C to about -40 ° C to provide 1- [3- (1-benzyl-4-hydroxypiperidin-4-yl) benzyl] -2,2,5,5-tetramethyl-1-aza- 2,5-disilacyclopentane; c) treating 1- [3- (1-benzyl-4-hydroxypiperidin-4-yl) benzyl] -2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane with an inorganic acid in a halogenated aliphatic hydrocarbon, to provide 3- (1-benzyl-4-hydroxypiperidin-4-yl) benzylamine in the form of the inorganic acid salt; d) treating 3- (1-benzyl-4-hydroxypiperidin-4-yl) benzylamine with a concentrated, non-oxidizing acid at a temperature of about 70 ° C to about 150 ° C, followed by alkalization to provide 3- (1 -benzyl-1,2,3,6-tetrahydropyridin-4-yl) benzylamine; Y e) treating 3- (1-benzyl-1, 2,3,6-tetrahydropyridin-4-yl) benzylamine with di-tert-butyl dicarbonate in an aliphatic alcohol such as methanol, ethyl acetate, an ether such as tetrahydrofuran, a halogenated hydrocarbon such as dichloromethane, a mixture of two or more of said solvents or a mixture of one or more of said solvents with water, in the presence of a hydroxide, carbonate or alcohol of an alkali metal, or a tertiary amine, such as sodium hydroxide or triethylamine, preferably at a temperature from about 0 ° C to about 40 ° C, to provide 3- (1-benzyl-1, 2,3,6-tetrahydropyridin-4-yl) tert-butyl ester. ) benzylcarbamic Another special embodiment of this eighth aspect further provides to treat 3- (1-benzyl-1, 2,3,6-tetrahydropyridin-4-yl) benzylcarbamic acid tert-butyl ester with hydrogen at a pressure of about 200 kPa to about 3000 kPa in an aliphatic alcohol or ethyl acetate, in the presence of a palladium catalyst, in the presence of an organic or inorganic acid, to provide 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] piperidine in the form of the acid salt organic or inorganic.

A ninth aspect of the present invention provides a process for the preparation of 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] piperidine or its salts, comprising the steps of a) treating 3- (4-pyridyl) benzaldehyde with hydroxylamine or a salt thereof in an aliphatic alcohol, optionally in the presence of a base, at a temperature of from about 0 ° C to about 40 ° C to provide 3- (4-pyridyl) benzaldehyde oxime or its salts; b) treating the 3- (4-pyridyl) benzaldehyde oxime or its salts with hydrogen at a pressure of about 300 kPa to about 1500 kPa in an aliphatic alcohol, in the presence of a palladium catalyst, at a temperature of about 20 ° C at about 50 ° C to provide 3- (4-pyridyl) benzylamine or its salts; c) treating the 3- (4-pyridyl) benzamine or its salts with di-tert-butyl dicarbonate in an aliphatic alcohol such as methanol, ethyl acetate, an ether such as tetrahydrofuran, a halogenated hydrocarbon such as dichloromethane, a mixture of two or more of said solvents or a mixture of one or more of said solvents with water, in the presence of a hydroxide, carbonate or alcohol of an alkali metal, or a tertiary amine, such as sodium hydroxide or triethylamine, preferably at a temperature from about 0 ° C to about 40 ° C, to provide 3- (4-pyridyl) benzylcarbamic acid tert-butyl ester; Y d) treating the 3- (4-pyridyl) benzylcarbamic acid tert-butyl ester with hydrogen in an aliphatic alcohol, at a pressure of about 2000 kPa to about 6000 kPa, in the presence of a palladium catalyst, in the presence of an acid such as hydrogen chloride or sulfuric acid.

A special embodiment of this ninth aspect provides a process for the preparation of 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] piperidine or its salts, comprising the steps of a) treating 3- (4-pyridyl) benzaldehyde with hydroxylamine hydrochloride in an aliphatic alcohol, at a temperature from about 0 ° C to about 40 ° C to provide 3- (4-pyridyl) benzaldehyde hydrochloride oxime; b) treating the 3- (4-pyridyl) benzaldehyde oxime hydrochloride oxime with hydrogen at a pressure of about 300 kPa to about 1500 kPa in an aliphatic alcohol, in the presence of a palladium catalyst, at a temperature of about 20 ° C at about 50 ° C to provide 3- (4-pyridyl) benzylamino hydrochloride; c) treating the 3- (4-pyridyl) benzylamine hydrochloride, with di-tert-butyl dicarbonate in an aliphatic alcohol such as methanol, ethyl acetate, an ether such as tetrahydrofuran, a halogenated hydrocarbon such as dichloromethane, a mixture of two or more of said solvents or a mixture of one or more of said solvents with water, in the presence of hydroxide, carbonate or alcohol of an alkali metal, or a tertiary amine, such as sodium hydroxide or triethylamine, preferably at a temperature from about 0 ° C to about 40 ° C, to provide 3- (4-pyridyl) benzylcarbamic acid tert-butyl ester; Y d) treating 3- (4-pyridyl) benzylcarbamic acid tert-butyl ester with hydrogen in an aliphatic alcohol, at a pressure of about 2000 kPa to about 6000 kPa, in the presence of a palladium catalyst, in the presence of an acid such as hydrogen chloride or sulfuric acid.

A tenth aspect of the present invention provides a process for the preparation of 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] piperidine or its salts, comprising the steps of a) treating 3- (4-pyridyl) benzonitrile with hydrogen in the presence of a palladium catalyst at a pressure of about 2000 kPa to about 6000 kPa in an aliphatic alcohol or a mixture of an aliphatic alcohol and water, or with a complex hydride such as lithium aluminum hydride, lithium borohydride or sodium borohydride, in an aliphatic alcohol or an ether such as methanol or tetrahydrofuran, at a temperature from about 0 ° C to about 50 ° C, to provide - (4-pyridyl) benzylamine or its salts; b) treating the 3- (4-pyridyl) benzylamine or its salts with di-tert-butyl dicarbonate in an aliphatic alcohol such as methanol, ethyl acetate, an ether such as tetrahydrofuran, a halogenated hydrocarbon such as dichloromethane, a mixture of two or more of said solvents or a mixture of one or more of said solvents with water, in the presence of a hydroxide, carbonate or alcohol of an alkali metal, or a tertiary amine, such as sodium hydroxide or triethylamine, preferably at a temperature from about 0 ° C to about 40 ° C, to provide 3- (4-pyridyl) benzylcarbamic acid tert-butyl ester; Y c) treating the 3- (4-pyridyl) benzylcarbamic acid tert-butyl ester with hydrogen in an aliphatic alcohol, at a pressure of about 2000 kPa to about 6000 kPa, in the presence of a palladium catalyst, in the presence of an acid such as hydrogen chloride or sulfuric acid.

The present invention also provides novel intermediates useful in the processes of the present invention for the preparation of a compound of the formula I, where R1 is H, F, CF3, OCF3, (C, -C8) alkyl, (C3-C0) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen between nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (C8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (C8 alkyl) amino, di (cycloalkyl (C3-) C10)) amino or di (aryl (C6-C14)) amino; and R2 is H, F, CF3, OCF3, (C8) alkyl, (C3-C10) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms the same or different in the ring selected from nitrogen, oxygen and sulfur, aryl (C6-Cu), 5-membered heteroaryl to 10 members comprising 1, 2 or 3 heteroatoms same or different in the ring chosen from nitrogen, oxygen and sulfur, alkoxy (CrC8), cycloalkoxy (C3-C10) , aryloxy (Ce-Cu), 5-membered heteroaryloxy to 10 members comprising 1, 2 or 3 heteroatoms same or different in the ring chosen from nitrogen, oxygen and sulfur, di (C 8 alkyl) amino, di- ( (C3-C10) cycloalkyl) amino or di (aryl (C6-C14)) amino; or its salts, including: a compound of the formula Vlll, wherein R1 'is H, F, CF3, OCF3, alkyl (C.-C8), cycloalkyl (C3-C10), heterocyclic alkyl of 3 members to 10 members comprising 1, 2 or 3 heteroatoms the same or different in the ring chosen from nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (C8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (C1-C3) alkyl) amino, di (cycloalkyl) C3-C 0)) amino or di (aryl (C6-C14)) amino, or a protected derivative thereof or a precursor residue thereof; X 'is bromine or iodine; excluding the compound 1- (3-bromobenzyl) -2,2,5,5-tetramethi-1-aza-2,5-disilacyclopentane; a compound of formula IX, wherein R1 'is H, F, CF3, OCF3, (C8) alkyl, (C3-C-? 0) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms the same or different in the ring chosen from nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (C8), cycloalkoxy (C3-C10), aryloxy (C6-Cu), di (alkyl (CrCs)) amino, di (cycloalkyl (C3) -C10)) amino or di (aryl (C6-C14)) amino, or a protected derivative thereof or a precursor residue thereof; and Ph is phenyl; a compound of the formula X, wherein R1 'is H, F, CF3, OCF3, (Cs) alkyl, (C3-C10) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen between nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (C -, - C8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (alkyl (C-C8)) amino, di ( (C3-C10) cycloalkyl) amino or di (aryl (C6-Cu)) amino, or a protected derivative thereof or a precursor thereof; and Ph is phenyl, or its salts; a compound of formula XI, wherein R 'is H, F, CF3, OCF3, (C8) alkyl, (C3-C10) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 identical or different ring heteroatoms chosen between nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (C8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (C1-C8 alkyl) amino, di (cycloalkyl) (C3-C10)) amino or di (aryl (C6-Cu)) amino, or a protected derivative thereof or a precursor thereof; and Ph is phenyl, or its salts; a compound of formula XII, wherein R1 'is H, F, CF3, OCF3, alkyl (CrC8), cycloalkyl (C3-C0), heterocycloalkyl of 3 members to 10 members comprising 1, 2 or 3 heteroatoms the same or different in the ring chosen from nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (C8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (alkyl (CrC8)) amino, di (cycloalkyl (C3-C10) amino or di (aryl (C6-C14)) amino, or a protected derivative thereof or a precursor residue thereof; Boc is tert-butoxycarbonyl; and Ph is phenyl, or its salts; a compound of the formula XIV, wherein R1 'is H, F, CF3, OCF3, alkyl (CrC8), cycloalkyl (C3-C.0), heterocyclic alkyl of 3 members to 10 members comprising 1, 2 or 3 heteroatoms or equal or different in the ring chosen from nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (C8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (C8 alkyl) amino, d (cycloalkyl) C3-C10)) amino or di (aryl (C6-Cu)) amino, or a protected derivative thereof or a precursor thereof, or its salts; a compound of the formula XV, wherein R1 'is H, F, CF3, OCF3, alkyl (CrC8), cycloalkyl (C3-C10), heterocycloalkyl of 3 members to 10 members comprising 1, 2 or 3 heteroatoms the same or different in the ring chosen from among nitrogen , oxygen and sulfur, aryl (C6-C14), alkoxy (CrC8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (C8 alkyl) amino, di (cycloalkyl (C3-C10)) amino or di (aryl (C6-Cu)) amino, or a protected derivative thereof or a precursor residue thereof, or its salts; a compound of formula XVI, wherein R1 'is H, F, CF3, OCF3, (C8) alkyl, (C3-C10) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 same or different heteroatoms in the ring selected from nitrogen, oxygen and sulfur, aryl (C6-C4), alkoxy (C8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (alkyl (CrC8)) amino, di (cycloalkyl (C3-C10) )) amino or di (aryl (C6-C14)) amino, or a protected derivative thereof or a precursor residue thereof; and Boc is tert-butoxycarbonyl, or its salts; Y a compound of the formula IVb, wherein R is H, F, CF3, OCF3, (C8) alkyl, (C3-C10) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms same or different in ring selected from nitrogen , oxygen and sulfur, aryl (C6-C14), alkoxy (CrC8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (alkyl (CrC8)) amino, di (cycloalkyl (C3-C? 0) amino or di (aryl (C6-C?)) amino, or a protected derivative thereof or a precursor residue thereof; and Boc is tert-butoxycarbonyl, or its salts; and, in another aspect of the present invention, the use of each of these compounds as an intermediate, in particular as an intermediate for the preparation of a compound of the formula I, wherein R1 and R2 are as defined above, or salts thereof.

In a particular embodiment, the present invention also provides novel intermediates useful in the processes of the present invention for the preparation of 4- [3- (aminomethyl) phenyl] -1- [5- (2-fluorophenylethyl) -2-furanoyl] piperidine or its salts, including: 1- (3-iodobenzyl) -2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane; 1- [3- (1-benzyl-4-hydroxypiperidin-4-yl) benzyl] -2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane; 3- (1-benzyl-4-hydroxypiperidin-4-yl) benzylamine or its salts; 3- (1-benzyl-1, 2,3,6-tetrahydropyridin-4-yl) benzylamine or its salts; 3- (1-benzyl-1, 2,3,6-tetrahydropyridin-4-yl) benzylcarbamic acid tert-butyl ester or its salts; 3- (4-pyridyl) benzaldehyde oxime or its salts; 3- (4-pyridyl) benzylamine or its salts; 3- (4-pyridyl) benzylcarbamic acid tert-butyl ester or its salts; Y 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] -1- [5-bromo-2-furanoyl] plperidine; and, in another particular embodiment of the present invention, the use of each of these compounds as an intermediate for the preparation of 4- [3- (aminomethyl) phenyl] -1- [5- (2-fluorophenylethynyl) -2-furanoyl ] piperidine or its salts.

As used in this document, and unless otherwise specified, it is understood that the following terms have the following meanings.

The term "alkyl" refers to a residue of an aliphatic saturated hydrocarbon group which may be linear or branched and having from about 1 to about 8 carbon atoms, for example 1, 2, 3, 4, 5, 6, 7 u 8 carbon atoms. Preferred alkyl moieties are those having from about 1 to about 6 carbon atoms, in particular from about 1 to about 4 carbon atoms. Exemplary alkyl moieties include methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl and octyl.

The term "cycloalkyl" refers to a moiety of a saturated monocyclic or bicyclic ring system containing from about 3 to about 10 carbon atoms in the ring, for example 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Preferred cycloalkyl moieties are those having from about 3 to about 7 carbon atoms. Exemplary cycloalkyl moieties include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term "heterocycloalkyl" refers to a moiety of a heterocyclic, saturated, monocyclic or multicyclic ring system, of about 3 members to about 10 members, for example of 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10 members, comprising 1, 2 or 3 heteroatoms the same or different per ring chosen from nitrogen, oxygen and sulfur, which can be attached by any carbon atom of the ring or by any ring nitrogen atom and whose Nitrogen atoms, independently of each other, may have a moiety selected from hydrogen, alkyl (C C 8), aryl (Ce-Cu) and aryl (C 6 -C 14) -alkyl (C C 4) -. The term "heterocycloalkyl" includes, for example, (i) a cycloalkyl group of about 3 to about 7 members in the ring of which 1, 2 or 3 are ring heteroatoms chosen from nitrogen, oxygen and sulfur, that is, a heterocyclic, monocyclic, saturated group, and (i) a residue of a heterocyclic, bicyclic or tricyclic group of about 6 to about 10 members in the ring of which 1, 2 or 3 are heteroatoms of the ring chosen from nitrogen, oxygen and sulfur, where a heterocyclic, monocyclic, saturated group is condensed with one or more, for example one or two, cycloalkyl groups and / or heterocyclic, monocyclic, saturated groups, to form a cyclic multicyclic structure .

Exemplary heterocycloalkyl groups include piperidinyl, pyrrolidinyl, morpholinyl, tetrahydropyranyl or tetrahydrothienyl.

The term "aryl" as a group or as part of a group refers to a moiety of a monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms per ring, for example 6, 8, 9, 10 , 12, 13 or 14 carbon atoms per ring. The term "aryl" includes: (i) a carbocyclic, aromatic, monocyclic or multicyclic, eg bicyclic or tricyclic, moiety of from about 6 to about 14 carbon atoms per ring, wherein all rings are aromatic, such as phenyl or naphthyl; or (ii) a carbocyclic, aromatic, partially saturated, multicyclic, for example bicyclic or tricyclic moiety, in which an aryl group and a cycloalkyl group are condensed together to form a cyclic structure, such as a tetrahydronaphthyl or indanyl moiety .

The term "heteroaryl" refers to a residue of a system of heteroaromatic rings of about 5 members to about 10 members, for example of 5-, 6-, 8-, 9- or 10 members, comprising 1, 2 or 3 heteroatoms the same or different in the ring chosen from nitrogen, oxygen and sulfur, which can be attached by any suitable carbon atom of the ring or by any ring nitrogen atom and whose nitrogen atoms, independently of each other, can have a residue selected from hydrogen, (C8) alkyl, (C6-C14) aryl, and (C6-C1) aryl- (C4) alkyl-. The term "heteroaryl" includes: (i) a residue of a heterocyclic, aromatic, monocyclic or bicyclic group where all rings are aromatic, including, for example, moieties such as benzimidazolyl, benzothiazolyl, benzoxazolyl, benzothienyl, furyl, imidazolyl, indolyl, indolizinyl , isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinollyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl or triazolyl, or (ii) a residue of a heteroaromatic group, bicyclic, partially saturated in which a heteroaryl group and a cycloalkyl group or an aryl group and a heterocycloalkyl group or a heteroaryl group and a heterocycloalkyl group are condensed together to form a cyclic structure, for example a pyrazinyl moiety.

The term "alkoxy" refers to an alkyl-O- moiety in which the alkyl group is as described herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and heptoxy.

The term "cycloalkoxy" refers to a cycloalkyl-O- moiety, wherein the cycloalkyl group is as described herein.

The term "aryloxy" refers to an aryl-O- moiety, wherein the aryl group is as described herein.

The term "heteroaryloxy" refers to a heteroaryl-O- moiety, wherein the heteroaryl group is as described herein.

The term "dialkylamino" refers to a -N (alkyl) (alkyl) moiety where the alkyl groups may be the same or different and are as described herein.

The term "dicycloalkylamino" refers to a -N (cycloalkyl) (cycloalkyl) moiety wherein the cycloalkyl groups may be the same or different and are as described herein.

The term "diarylamino" refers to a -N (aryl) (aryl) moiety wherein the aryl groups may be the same or different and are as described herein.

In the processes and compounds according to the invention, the groups R, R1, R2 and R2, which bind to the benzene rings represented in the formulas herein, may be present one or more times independently from each other, for example one, two or three times. Preferably, they are present once or twice independently of each other. More preferably, a group R1 or R1 is present and a group R2 or R2 'is present. When more than one of any of the R1 groups is present, R1, R2 and R2 can independently have the meanings indicated in this document and can be the same or different. The positions of the benzene rings represented in the formulas of this document that do not have a group R1, R1, R2 or R2 or another group represented in the formulas, have hydrogen atoms. That is, in a compound of the formula I in which a group R1 and a group R2 are present, the benzene ring having R1 has three hydrogen atoms in addition to the group R1 and the group -CH2NH2, and the benzene ring which has R2 has four hydrogen atoms in addition to the R2 group. In a compound of the formula i in which two R2 groups are present, the benzene ring having R2 has three hydrogen atoms in addition to the R2 group. The groups R1, R1, R2 and R2 may be present in any desired position. For example, in a compound of the formula I in which a group R2 is present which is other than hydrogen, R2 may be present in the 2, 3 and 4 positions with respect to the ethyne moiety which, by definition, is present in the position 1. If two R2 groups which are other than hydrogen are present, they can be present in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5 positions. Similarly, if a group R1 that is other than hydrogen is present, it may be present in positions 2, 3, 4 and 6 with respect to the position of the piperidine moiety that is present in position 1, if the group position -CH2NH2 in a compound of formula I or the group derived from it in the other compounds of the invention is designated as position 5 (if the position of the group -CH2-NH2 is designated as position 3, the group R1 may be present in position 2, 4, 5 and 6).

The salts of a compound according to or related to the present invention, that is, any compound that is used in a process or that is obtained by a process or that appears as an intermediate in a process described herein, including any compound that is an object of the present invention per se, which contains one or more basic groups, ie protonatable groups such as amino groups, piperidinyl groups, pyridinyl groups and / or other basic heterocyclic groups, are in particular acid addition salts formed by the respective compound and inorganic or organic acids, including mineral acids, organic carboxylic acids and sulfonic acids. Examples of acids which can form said salts are hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, citric acid, acid. trifluoroacetic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Compounds containing two or more basic groups can form acid addition salts with one equivalent of acid or with two or more equivalents of acid. In particular, in the case of compounds of the formulas I and that which are intended to be used in the production of pharmaceutical compositions or for use as pharmacologically active ingredients, the preferred salts are physiologically acceptable salts or pharmaceutically acceptable salts which are non-toxic and show a profile of suitable properties for the desired use. However, the present invention also includes salts which, because of low physiological compatibility, are not directly suitable for use in pharmaceutical compositions but which can be used, for example, as intermediates for chemical reactions or for the preparation of physiologically acceptable salts, for example, through ion exchange procedures. Salts can be obtained by any process as described herein or by conventional methods known to those skilled in the art such as, for example, by contacting a basic compound with an acid in a solvent, or by ion exchange. from another salt. Similarly, by applying conventional methods such as contacting a salt with a base in a solvent, a salt can be converted to the free base if desired, for example if an intermediate that has been isolated in the form of a free base is needed. a salt in a subsequent reaction stage.

In the processes and compounds according to the present invention, and in particular for various values of R1 and R2, it may be advantageous or necessary to protect reactive functional groups, where these are desired in the final product, or to have them initially present in the form of precursor residues which are then converted into the desired group, in order to avoid their unwanted participation in reactions according to processes of the present invention. The conventional protecting groups and the precursor moieties and processes for their introduction and removal or conversion into the desired groups can be used in accordance with conventional practice known to one skilled in the art, for example as described in TW Greene and PGM Wuts in " Protective Groups in Organic Chemistry, "John Wiley and Sons, 1991.

In the processes and compounds according to the present invention R1 and R1 are preferably H, F, CF3, OCF3, (C4) alkyl, (C3-C7) cycloalkyl, phenyl, alkoxy (CrC4), phenoxy or di (alkyl ( CrC)) amino, more preferably H, F, CF3, OCF3, (C4) alkyl, (C4) alkoxy or di (alkyl (CrC4)) amino, particularly and preferably H, F, CF3, OCF3, alkyl (CC ) or (C C4) alkoxy, more particularly and preferably H, F, CF3, OCF3, CH3 or OCH3, especially and preferably H or F, even more preferably H. In the case where a radical R1 or R1 is present, be F, the fluorine atom is preferably present in the 2-position with respect to the position of the piperidine moiety which is present in the 1-position, if the position of the group -CH 2 -NH 2 in a compound of the formula I, or of the group derived from the group same in the other compounds of the invention, it is designated as position 5. Preferably, R2 and R2 'are H, F, CF3, OCF3, alkyl (C4), cycloalkyl (C3-C7), phenyl, alkoxy (CC), phenoxy or di (alkyl (CC)) amino, more preferably H, F, CF3, OCF3, alkyl (C4), alkoxy (C4) or di (alI (CrC4)) amino, particularly preferably H, F , CF3, OCF3, (d-C4) alkyl or (C4) alkoxy, more particularly and preferably H, F, CF3, OCF3, CH3 or OCH3, especially and preferably H or F. In the case where it is present a radical R2 or R2, in a still more preferred embodiment of the present invention, R2 or R2 is F, in particular a fluorine atom in the ortho position with respect to the ethylene moiety.

The processes according to the present invention are usually carried out in the presence of a solvent (or diluent) but, depending on the individual case, they can also be carried out without the addition of a solvent. The solvents that can be used include organic solvents, for example water, and organic solvents. Examples of organic solvents are hydrocarbons, including aliphatic and aromatic hydrocarbons, for example pentane, hexane, heptane, petroleum ether, ligroin, cyclohexane, methylcyclohexane, benzene, toluene or xylene, halogenated hydrocarbons, including aliphatic hydrocarbons and halogenated aromatics, for example dichloromethane. , trichloromethane, carbon tetrachloride, dichloroethane, trichloroethane, chlorobenzene or dichlorobenzene, ethers, including aliphatic ethers and cyclic ethers, for example diethyl ether, di-n-propyl ether, di-isopropyl ether, dibutyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether , tetrahydrofuran or dioxane, esters, for example ethyl acetate, butyl acetate or dimethyl carbonate, amides, for example dimethylformamide, dimethylacetamide or N-methylpyrrolidone, alcohols including aliphatic alcohols, for example methanol, ethanol, propanol including n-propanol and isopropanol, butanol including n-butanol and i sobutanol, or ethylene glycol, acids including aliphatic acids, for example formic acid, acetic acid or trifluoroacetic acid, and others, for example acetone, butanone, dimethisulfoxide or acetonitrile. The term "solvent", as used herein, in addition to a single solvent also includes a mixture of two or more solvents that can be miscible or partially miscible or immiscible and can form two or more phases. Therefore, the term "solvent" includes, for example, mixtures of two or more organic solvents, such as mixtures of an ether and an alcohol or mixtures of an ether and a hydrocarbon, and mixtures of one, two or more organic solvents. , for example methanol, tetrahydrofuran or dichloromethane, with water. The choice of a suitable solvent that is advantageously used in a specific preparation process will be carried out by a person skilled in the art in view of the characteristics of the reaction, the compounds that are used and are obtained, and technical aspects and other aspects. In general, inert solvents are used that do not experience undesired reactions with the compounds and agents used and / or with the obtained compounds. Depending on the individual case, it may be preferable to use a solvent that dissolves the compounds and agents used and / or the compounds obtained, or a solvent that dissolves the compounds and agents used and / or the compounds obtained to a certain degree, or a solvent that only dissolves slightly to the compounds and agents used and / or to the obtained compounds. Examples of suitable solvents have been given above and are given below in the explanations of the processes according to the invention.

In various processes according to the present invention, a base is employed, for example, to produce a chemical conversion or to deprotonate a compound or release a basic starting compound from its salts or to remove an acid formed during a reaction. The bases that can be used include organic bases, for example amines including tertiary amines such as triethylamine, tributylamine, ethyldiisopropylamine or N-methylmorpholine, and inorganic bases. Normally, the inorganic bases are basic compounds of the alkali metals lithium, sodium and potassium and of the alkaline earth metals magnesium and calcium and include hydroxides, for example lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide, carbonates and hydrogencarbonates, for example sodium carbonate, sodium hydrogencarbonate or potassium carbonate, alcoholates, for example sodium methanolate, sodium ethanolate, sodium terebutanolate, potassium methanolate, potassium ethanolate, potassium tert-butanolate, magnesium methanolate, magnesium ethanolate, calcium methanolate or calcium ethanolate, and others, for example sodium hydride, sodium amide, lithium diisopropyamide, Na2HP04, Na3P04 or sodium acetate. In addition to a single base, mixtures of two or more bases can also be used. The choice of a suitable base that is advantageously used in a specific preparation process will be carried out by a person skilled in the art in view of the characteristics of the reaction, of the compounds that are used and that are obtained, of technical aspects and of others aspects. Examples of suitable bases have been given above and are given below in the explanations of the processes according to the invention.

Further explanations are given below of the processes according to the present invention. In the Schemes shown below, groups such as R1, R2, R1 and R2 are as defined above, Boc is tert-butoxycarbonyl, Ph is phenyl and nBu is n-butyl.

The compounds of formula I are prepared by processes according to the present invention as shown in Scheme 1.

Scheme 1 The phenylethylsilyl compound of formula II, wherein G is trimethylsilyl, triethylsilyl, tri-isopropylsilyl or dimethyl-tert-butylsilyl, is treated with a hydroxide, carbonate or alcohol of an alkali metal, for example the respective sodium or potassium compound, or an alcohol of an alkaline earth metal, for example a magnesium or calcium alcohol, preferably with potassium carbonate, in a solvent, such as an aliphatic alcohol or a mixture of an aliphatic alcohol and an ether, for example methanol or ethanol or a mixture of methanol and tetrahydrofuran, at a temperature from about 0 ° C to about 50 ° C, preferably from about 10 ° C to about 30 ° C, to give a solution of the corresponding phenylethynyl compound of formula III wherein said phenylethynyl compound is not isolates, thus avoiding the risks that are associated with the handling of the unstable phenylethynyl compound. The base that can be employed in a catalytic amount, for example in an amount of from about 0.02 to about 0.05 moles per mole of the compound of formula II, or in a larger amount up to an approximately equivalent amount, for example an amount of about 0.02 to about 1.1 mole of a monovalent base per mole of the compound of formula II.

The solution of the phenylethynyl compound is combined with the amide of the formula IV in a solvent, such as an ether, for example tetrahydrofuran, dioxane or 1,2-dimethoxyethane, or dimethyl carbonate, or a mixture of an ether with an alcohol aliphatic such as methanol or ethanol, and reacted in the presence of a homogeneous palladium catalyst, for example Pd (PPh3) 2Cl2, a copper salt, for example copper iodide (I), copper (I) bromide, chloride copper (I) or copper trifluoromethanesulfonate (I), where the copper salt can also be formed in situ from a copper salt, for example copper (II) acetate, and a hindered amine, for example triethylamine, tributylamine , ethyldiisopropylamine, diethylamine, pyrrolidine or piperidine, at a temperature of about 30 ° C to about 70 ° C. The compound of formula III or II, respectively, is preferably employed in a slight excess, for example in an amount of about 1 to about 1.5 moles per mole of the compound of formula IV. Each of the amounts employed of the palladium catalyst and the copper salt is preferably from about 0.005 to about 0.2, more preferably from about 0.005 to about 0.05 moles per mole of the compound of formula IV, and the amount of the hindered amine is preferably from about 1 to about 10, more preferably from about 1 to about 5 moles per mole of the compound of formula II.

The treatment of the reaction mixture can be carried out by conventional procedures, as applied to all the processes of the present invention, including treatment of the organic phase with brine, dilute hydrochloric acid and aqueous sodium carbonate, to provide the Boc-protected compound of formula V. In a surprising aspect of the present invention, the reagents present in the solution produced by the treatment of the phenylethylsilyl compound of formula II do not interfere with the subsequent coupling reaction with the compound of formula IV.

The Boc-protected compound of formula V can be used, for example, as a storage form of the compound of formula I. If it is desired to prepare the compound of formula I itself or its salts, the compound of formula V is subsequently deprotected by removal by division of the Boc group and, if possible, removal of other protecting groups and / or conversion of the precursor moieties which may be present in R1 and / or R2. Preferably, the compound of formula V is deprotected under acidic conditions, in particular from a compound in which R1 'and R2' are R1 and R2, advantageously by means of a physiologically acceptable acid such as methanesulfonic acid, for example, in a solvent such as isopropanol, for example, at a temperature of about 10 ° C to about 80 ° C, to produce the compound of the formula or its salts, preferably the salt with the acid employed in the de-deprotection step.

The compound of formula IV can be prepared as illustrated in Scheme 2. When starting from 5-bromo-2-furoic acid or 5-iodo-2-furoic acid of formula XVIII, wherein X is bromine or iodine, the acid is first activated as indicated above to give an activated acid derivative of formula XIX in which X is bromine or iodine and A is a leaving group, for example chlorine or bromine, or formula XIX represents the adduct obtained from the acid and a condensing agent such as a carbodiimide, or the mixed anhydride obtained from the acid and an alkyl chlorocarbonate. Preferably, the acid of formula XVI ii is treated with thionyl chloride in toluene at the reflux temperature until the evolution of gas ceases to provide a solution of the acid chloride of formula XIX wherein A is chlorine, where such a solution can used, if desired, in the later stage without isolation of the acid chloride. The activated acid derivative of formula XIX is combined with 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] piperidine of formula VI in a solvent, optionally in the presence of a base, for example a tertiary amine such as triethylamine, to provide the corresponding amide of formula IV, generally at a temperature of from about -10 ° C to about 40 ° C, preferably from about 10 ° C to about 30 ° C. The 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] piperidine of formula VI can be liberated from a salt of a compound of formula VI, for example a salt with p-toluenesulfonic acid, by treatment with a base, for example a hydroxide or alcohol of an alkali metal, such as sodium hydroxide, and extracting the compound of formula VI in a solvent such as, for example, toluene or dichloromethane, followed by drying the solution.

SAW Scheme 2 The processes previously described for the preparation of compounds of formula I include the processes for the preparation of the specific compound 4- [3- (aminomethyl) phenyl] -1- [5- (2-fluorophenylethynyl) -2-furanoyl] salt] piperidine methanesulfonic which is described in WO 2004/060884 (international patent application PCT / US2003 / 040653) and which is shown in Scheme 3.

XX XXI Scheme 3 According to the previously described process, 2-fluorophenylethyne of formula Illa is coupled with methyl 5-bromo-2-furoate of formula XX by a palladium-mediated process. Treatment and chromatography yield methyl 5- (2-fluorophenylethynyl) -2-furoate of formula XXI, which is saponified and recrystallized to give the respective acid of formula XXII. The conversion of the acid to the acid chloride of formula XXII! It is done with oxalyl chloride. The acylation of 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] piperidine of formula Via which, according to the above process, is prepared in a tedious process using expensive reagents as indicated below, with the acid chloride, gives 4- [3- (Aminomethyl) phenyl] -1- [5- (2-fluorophenylethynyl) -2-furanoyl] piperidine protected with N-Boc of formula Va. The crude product is purified by flash chromatography followed by trituration with diethyl ether / pentane or, alternatively, recrystallization. By treatment with methanesulfonic acid, the Boc group is removed and 4- [3- (aminomethyl) phenyl] -1- [5- (2-fluorophenylethynyl) -2-furanoyljpiperidine-methanesulfonic acid methanesulfonic acid of formula Ib is obtained.

A substantial disadvantage of the process described above is the use of phenylethines as starting materials known to be unstable. For example, 2-fluorophenylene is violently decomposed at about 120 ° C. Therefore, the use of phenylephthines poses a security risk, particularly in large-scale productions. The present invention provides advantageous processes which are useful in the preparation of compounds of formula I and are distinguished by the generation of phenyletino from the in situ silyl compound without the need for isolation of phenyletino, thus allowing to avoid the manipulation of dangerous compounds.

The 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] piperidines of formula VI useful as intermediates in the processes of the present invention can be prepared by processes of the present invention, for example, as shown in Scheme 4.

SAW Scheme 4 Accordingly, a 3-iodobenzylamine or 3-bromobenzylamine of formula VII in the form of its salts, for example the hydrochloride salt, in a solvent, for example a halogenated aliphatic hydrocarbon such as dichloromethane, is treated with an approximately equimolar amount of 1, 2-bis (chlorodimethylsilyl) ethane in the presence of a base, for example a tertiary amine such as triethylamine, preferably at a temperature of about 10 ° C to about 30 ° C. The treatment of the reaction mixture can be carried out by filtration, evaporation of the filtrate and treatment of the residue with an aliphatic or aromatic hydrocarbon, for example pentane, to remove any residual amine salt, to provide the corresponding 3-halobenzyl compound of formula Vlll , that is, the corresponding 1- (3-bromobenzyl) -2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane or 1- (3-iodobenzyl) -2,2,5,5- tetramethyl-1-aza-2,5-disilacyclopentane.

Then, the compound of formula Vlll is treated with an aikillithium compound, for example n-butyl lithium, sec-butyl lithium, t-butyl lithium or hexyl lithium, in a solvent, for example an ether such as diethyl ether or tetrahydrofuran, and subsequently with 1 -benzyl-4-piperidone at a reduced temperature, such as at a temperature from about -80 ° C to about -40 ° C, for example at about -60 ° C, to provide the corresponding alcohol of formula IX, which can be used then, if desired, without further purification. The alkyllithium compound and 1-benzyl-4-piperidone are usually employed in an amount of about 1 to about 1, 2 and about 1 to about 1.1 moles, respectively, per mole of the compound of formula Vlll.

The alcohol of formula IX is then treated with an inorganic acid, for example sulfuric acid, hydrochloric acid or phosphoric acid, preferably phosphoric acid, which may be diluted or concentrated, in a solvent, for example a halogenated aliphatic hydrocarbon such as dichloromethane, in the presence of water, at a temperature of about 10 ° C to about 30 ° C, to provide the corresponding benzylamine of formula X in the form of its salts with the acid employed, which may then be used, if desired, without further purification .

Then, the salt of the benzylamine of formula X is dehydrated with a strong, concentrated and non-oxidizing acid, for example phosphoric acid, sulfuric acid, trifluoroacetic acid or toluenesulfonic acid, preferably phosphoric acid, at an elevated temperature, for example at a temperature from about 70 ° C to about 150 ° C, preferably at about 100 ° C, followed by alkalization with a base such as a hydroxide, carbonate or alcohol) of an alkali metal, for example sodium hydroxide, to provide the corresponding olefin of formula XI, which can be used next, if desired, without further purification.

Then, the compound of formula XI is treated with di-tert-butyl dicarbonate (Boc20), which is generally employed in a slight excess of about 1 to about 1.2 molar equivalents, in a solvent, for example an aliphatic alcohol such such as methanol, ethyl acetate, an ether such as tetrahydrofuran, a halogenated hydrocarbon such as dichloromethane, a mixture of two or more of said solvents or a mixture of one or more of said solvents with water, in the presence of a base, for example a hydroxide, carbonate or alcohol of an alkali metal, or a tertiary amine, such as sodium hydroxide or triethylamine, preferably at a temperature of from about 0 ° C to about 40 ° C, preferably at a temperature from about 10 ° C to about 30 ° C to provide the Boc protected amine of formula XII.

Advantageously, by achieving the simultaneous reduction of the olefinic double bond and the removal of the benzyl group, the Boc protected amine of formula XII can then be treated with hydrogen at a pressure of about 200 kPa to about 3000 kPa, in a solvent, for example an alcohol aliphatic such as methanol, ethanol or isopropanol, or ethyl acetate, in the presence of a palladium catalyst, for example palladium on carbon or palladium hydroxide on carbon, for example Pearlman's catalyst, and an organic or inorganic acid, for example acid acetic acid, at a temperature of about 10 ° C to about 40 ° C, to provide the corresponding piperidine of formula VI in the form of its salts with the acid employed. If desired, the salt can then be converted to 4- [3- (tert-butoxycarbonylamnomethyl) phenyl] piperidine of formula VI by treatment with a base, for example a hydroxide, carbonate or alcohol of an alkali metal.

As indicated above, in the process for the preparation of the compounds of formulas XII and VI according to the present invention, many intermediates may be advantageously taken for the next reaction step, if desired, without a separate purification step. nor intermediate isolation.

The 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] pyridines useful as intermediates in the processes of the present invention can also be prepared by processes of the present invention, for example, as shown in Scheme 5.

XVI VI Scheme 5 Accordingly, a 3- (4-pyridyl) benzaldehyde of formula Xlll is treated with hydroxylamine or a hydroxylamine salt, for example hydroxylammonium chloride, sulfate or phosphate, in a solvent, for example an aliphatic alcohol such as methanol, ethanol or isopropanol, optionally in the presence of a base, for example a tertiary amine such as triethylamine, an alkali metal carbonate such as sodium carbonate, or an alkali metal hydrogen carbonate such as sodium hydrogencarbonate, at a temperature of from about 0 ° C to about 40 ° C, preferably at a temperature of about 10 ° C to about 30 ° C, to provide the corresponding oxime of formula XIV, or its salts. The solution of the oxime can then be used in the next step, if desired, without further purification.

Then, the oxime of formula XIV or its salts, in a solvent, for example a polar organic solvent such as an aliphatic alcohol or a carboxylic acid, for example methanol, ethanol, isopropanol or acetic acid, is treated with hydrogen at a pressure of about 300 kPa at about 1500 kPa, for example at about 500 kPa, in the presence of a palladium catalyst, for example palladium on carbon or palladium hydroxide, at a temperature of from about 20 ° C to about 50 ° C, for example about 35 ° C, to provide the corresponding benzylamine of formula XV, or its salts. After filtration to remove the catalyst, the solution can be used, if desired, without further purification in the next step.

Then, the benzylamine of formula XV or its salts is treated with di-tert-butyl dicarbonate (Boc20), which is generally used in a slight excess of about 1 to about 1.2 molar equivalents, in a solvent, for example a aliphatic alcohol such as methanol, ethyl acetate, an ether such as tetrahydrofuran, a halogenated hydrocarbon such as dichloromethane, a mixture of two or more of said solvents or a mixture of one or more of said solvents with water, in the presence of a base , for example an alkali metal hydroxide, carbonate or alcoholate, or a tertiary amine, such as sodium hydroxide or triethylamine, preferably at a temperature of from about 0 ° C to about 40 ° C, preferably at a temperature of about 10 ° C at about 30 ° C, to provide the corresponding Boc-protected amine of formula XVI, which may be used, if desired, without further purification for the next step.

Then, the tert-butyl ester of 3- (4-pyridyl) benzylcarbamic acid of formula XVI in a solvent, for example an aliphatic alcohol such as ethanol or isopropanol, is treated with hydrogen at a pressure of about 2000 kPa to about 6000 kPa in the presence of a platinum catalyst, for example platinum on carbon or a platinum oxide, for example in the presence of 5% platinum on carbon, at a temperature of about 20 ° C to about 80 ° C, for example about 50 ° C, in the presence of an acid, for example a mineral acid such as hydrogen chloride or sulfuric acid. In a surprising aspect of the present invention, the Boc-protected group survives the presence of acid in the reduction mixture. When hydrogen uptake is complete, the solvent for treatment can be removed under vacuum, followed by treatment of the mixture with an aqueous base, for example aqueous sodium hydroxide, and extraction in an organic solvent, for example dichloromethane or toluene. Then, the residue produced after evaporation of the solvent, if desired, can be treated with an acid, for example p-toluenesulfonic acid, to provide the desired piperidine of formula VI in the form of its salts, for example the salt with p-acid. -toluenesulfóníco.

As indicated above, instead of starting from a pyridylbenzaldehyde of formula Xlll, converting it to the oxime and hydrogenating the oxime function, the amine of formula XV or its salts can be further prepared from a pyridylbenzonitrile of formula XVII by reducing the nitrile function , for example by catalytic hydrogenation in the presence of a palladium catalyst such as palladium on carbon or by means of a complex hydride reducing agent. The catalytic hydrogenation of the nitrile function is preferably carried out in a solvent, for example an aliphatic alcohol such as methanol or a mixture of an aliphatic alcohol and water, at a temperature of about 10 ° C to about 40 ° C, at a pressure of hydrogen from about 2000 kPa to about 6000 kPa, in the presence of an acid, for example a mineral acid such as hydrochloric acid. The reduction of the nitrile function by means of a complex hydride is preferably carried out in a solvent, such as a protic solvent, for example an aliphatic alcohol such as methanol or ethanol, when a complex hydride such as sodium borohydride, or a solvent is used aprotic, for example an ether such as tetrahydrofuran, when a complex hydride such as lithium aluminum hydride is used, at a temperature of from about 0 ° C to about 50 ° C. The amine of formula XV or its salts can be used, if desired, without further purification for the next step in which it is treated with di-tert-butyl dicarbonate as explained above. The starting compounds of formulas Xlll and XVII are commercially available or can be prepared by or analogously to processes described in the literature, for example in WO 98/21210, Z.Y. Wang et al., Chin. Chem. Lett. 2003, 14, pages 13-16, or M. A. Massa et al., Bioorg. Med. Chem. Lett. 2001, 11, pages 1625-1628.

As indicated above, in the processes for the preparation of a compound of the formula VI from a compound of the formula Xlll or XVII according to the present invention, the intermediates can advantageously be used in the next reaction step, if is desired, without a separate purification step and without intermediate isolation.

According to the processes of the present invention, the 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] plperidines of formula VI can be prepared in a considerably simpler manner and with the use of cheaper reagents than those used in accordance with the processes previously described. The processes previously described for the preparation of 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] piperidines include that shown in Scheme 6, described in WO 2004/060884 (International patent application PCT / US2003 / 040653) .

XXIV XXV XXIX Scheme 6 The first stage of the process described above, protection of the 4-piperidone derivative of formula XXIV in the form of the N-Teoc derivative (2- (trimethylsilyl) ethoxycarbonyl) of formula XXV, using in situ generation of the carbamate formed from of 1, 1 '-carbonyldiimidazole (CDl) and 2- (trimethylsilyl) ethanol, requires a high vacuum distillation of the product at 156-160 ° C, as well as the use of expensive 2- (trimethylsilyl) ethanol reagent. The enolization of the ketone of formula XXV requires, at a temperature of -78 ° C, reaction with lithium bis (trimethylsilyl) amide in tetrahydrofuran, followed by inactivation of the enolate with N-phenyl-bis (trifluoromethanesulfonyl), another reagent very expensive, to give the vinyl triflate of formula XXVI. The triflate of formula XXVI is used in a Suzuki coupling with the expensive reagent 3-cyanophenylboronic acid in the presence of the expensive tetrakistriphenylphosphine palladium (0) catalyst to give the nitrile of formula XXVII which should be purified by chromatography. The hydrogenation of the nitrile function and the double bond using Pd / C in the presence of hydrogen chloride gives a mixture of the desired amine hydrochloride of formula XXVIII and the partially reduced nitrile of formula XXIX. The amine should be washed without the nitrile and then converted to the Boc-protected derivative of formula XXX in the presence of di-tert-butyl dicarbonate (Boc20). The residual nitrile of formula XXIX 'can be converted to the desired amine and protected in the form of the Boc derivative of formula XXX in the presence of NiCl2, a toxic reagent, Boc20 and NaBH4. The Boc derivative of formula XXX should be further isolated and purified by trituration with pentane, or alternatively recrystallized from cyclohexane / hexane. Removal of the N-Teoc group with tetra-n-butylammonium fluoride at 50 ° C gives, after trituration with diethyl ether / pentane, the desired piperidine of formula Via, ie the compound of formula VI in which R 1 It is hydrogen.

The prior art process for preparing the piperidine of the formula Via requires low temperature reaction conditions for a step, several steps of chromatography and purification, isolation of intermediates, and the use of toxic and expensive reagents. The processes of the present invention, as described herein, provide the compounds of formula VI using less toxic and expensive reagents, isolating fewer intermediates, and requiring fewer intermediate purification steps, these processes being therefore more suitable for the production of commercial quantities of said compounds in terms of economic and technical aspects.

The invention is further explained and illustrated by the following exemplary procedures. However, these examples should not be construed in any way as limitations on the scope of the invention.

Example 1 4- [3- (tert-Butoxycarbonylaminomethyl) phenyl] piperidine a) 1- (3-Bromobenzyl) -2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane To a stirred suspension of 3-bromobenzylamine hydrochloride (310 g, 1.39 mol) in dichloromethane (2 I) is added triethylamine (437 g, 4.32 mol), followed by a solution of 1,2-bis ( chlorodimethylsilyl) ethane (300 g, 1.39 mol) in dichloromethane (700 ml). The resulting suspension is stirred for 30 min and then filtered. The filtrate is concentrated in vacuo and pentane is added. After filtration, the solvent is removed under vacuum to yield the title compound (435 g, 95%) as a colorless oil. 1 H NMR (CDCl 3) d = 7.4-7.1 (m, 4 H), 4.0 (s, 2 H), 0.8 (t, 4 H), 0.2 (s, 12 H) . b) 3- (1-Benzyl-1, 2,3,6-tetrahydropyridin-4-yl) benzylcarbamic acid tert-butyl ester To a solution of 1- (3-bromobenzyl) -2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (435 g, 1.33 mol) in tetrahydrofuran (4 L) is added a 2.5 M solution of n-butyllithium (n-BuLi) (609 ml, 1.52 mol) at -60 ° C. After 30 min, a solution of 1-benzyl-4-piperidone (276 g, 1.46 mol) in tetrahydrofuran is added at that temperature. After stirring for a further 30 min, the reaction is stopped by the addition of methanol and allowed to warm to room temperature. The solution is concentrated in vacuo to produce the crude alcohol in the form of a sticky brown oil.

The crude residue from the previous step is dissolved in dichloromethane (1.5 I). To this solution is added concentrated phosphoric acid (H3P04) (1 equiv.) And the mixture is concentrated in vacuo. The yellowish phosphate is solidified by the addition of heptane and isolated by filtration.

The desired solid from the previous step is added to concentrated H3P04 (1.5 I) and the resulting mixture is heated at 100 ° C for two hours. After cooling to room temperature, the solution is diluted with water and extracted with ether. Then, the aqueous layer is basified with sodium hydroxide. The precipitate is isolated by filtration and used in the next step without drying.

The solid from the previous step is suspended in a mixture of methanol (4 I) and water (2 I) containing sodium hydroxide (10.0 g, 0.25 mol). Boc20 (290 g, 1.33 mole) is added and the mixture is stirred overnight at room temperature. The solid is isolated by filtration and then dried under vacuum to yield the title compound (390 g, 76%) as a light yellow solid. 1 H NMR (CDCl 3) d = 7.1-7.4 (m, 9 H), 6.03 (m, 1 H), 4.90 (m, 1 H), 4.25 (d, 2 H) , 3.68 (s, 2 H), 3.18 (m, 2 H), 2.69 (m, 2 H), 2.57 (m, 2 H), 1.42 (s, 9 H) . MS m / z 379 (M + H), 380 (M + 2H). c) 4- [3- (tert-Butoxycarbonylaminomethyl) phenyl] piperidine-acetic acid salt A mixture of 3- (1-benzyl-1, 2,3,6-tetrahydropyridin-4-yl) benzylcarbamic acid tert-butyl ester (190 g, 0.50 mol), Pearlman's catalyst (Pd (OH) 2 / C) (9.5 g) and acetic acid (60.2 g, 1.0 mol) in methanol is hydrogenated overnight at room temperature, at a hydrogen pressure of 345 kPa. After filtration and evaporation, the obtained oil is dissolved in diisopropyl ether, which causes the precipitation of the reaction product. After drying in vacuo, the pure title compound (159 g, 90%) is isolated as a yellowish solid. 1 H NMR (300 MHz, CDCl 3) d = 7.1-7.4 (m, 4 H), 4.89 (m, 1 H), 4.29 (d, 2 H), 3.42 (m, 2 H), 2.86 (m, 2 H), 2.69 (m, 1 H), 2.05 (s, 3 H), 1, 97 (m, 4 H), 1.45 (s, 9 H). MS m / z 291 (M + H), 292 (M + 2H). d) 4- [3- (tert-Butoxycarbonylaminomethyl) phenyl] piperidine Dissolves 4- [3- (tert-butoxycarbonylaminomethyl) phenyljpiperidine-acetic acid salt (147 g, 0.42 mol) in dilute hydrochloric acid and the solution extracted with ether. The aqueous phase is basified with sodium hydroxide and extracted with ether. The organic phase is concentrated in vacuo and the product is precipitated from pentane / ether, yielding the title compound (105 g, 86%) as an off-white solid. 1 H NMR (300 MHz, CDCl 3) d = 7.25 (m, 1 H), 7.07-7.13 (m, 3 H), 5.12 (m, 1 H), 4.29 (d, 2 H), 3.17 (m, 3 H), 2.72 (m, 2 H), 2.60 (m, 1 H), 1.81 (m, 2 H), 1, 55-1, 70 (m, 2 H), 1.46 (s, 9 H). MS (ESI) m / z 291 (M + + 1, 100).

Example 2 4- [3- (tert-Butoxycarbonylaminomethyl) phenyljpiperidine-p-toluenesulfonic acid salt a) 3- (4-Pyridyl) benzaldehyde oxime hydrochloride Dissolve 3- (4-pyridyl) benzaldehyde (100 g, 546 mmol) in methanol (500 mL) and then add to a solution of hydroxylamine hydrochloride (40.2 g, 573 mmol) in methanol (260 mL). After the conversion is completed, a small sample of the reaction mixture is concentrated in vacuo. MS (DCI) m / z 181.1, 199.1, 200.2. 1 H NMR (400 MHz, DMSO-d 6) d = 7.56 (t, J = 7.7 Hz, 1 H), 7.70-7.75 (m, 3 H), 7.79-7.83 (m, 1 H), 7.97-7.99 (m, 1 H), 8.25 (s, 1 H), 8.65-8.67 (m, 2 H), 11, 4 (s) , 1 HOUR). b) 3- (4-pyridyl) benzyl amine hydrochloride The methanolic solution of 3- (4-pyridyl) benzaldehyde oxime hydroxide of the previous step is added to palladium on carbon (13.1 g, 5% Pd / C). The mixture is stirred at 35 ° C and at a hydrogen pressure of 500 kPa until the consumption of hydrogen ceases. The catalyst is removed by filtration. The HPLC shows the complete conversion. A small sample of the reaction solution is concentrated in vacuo. MS (DCI) m / z 185.2, 186.2. 1 H NMR (400 MHz, DMSO-d 6) d = 4.10 (s, 2 H), 7.54-7.61 (m, 2 H), 7.74-7.77 (m, 2 H), 7.83 (dt, J = 2.1, 6.6 Hz, 1 H), 8.02-8.05 (m, 1 H), 8.53 (sa, 2 H), 8.67-8 70 (m, 2 H). c) 3- (4-pyridyl) benzylcarbamic acid tert-butyl ester The methanolic solution of 3- (4-pyridyl) bencllamine hydrochloride from the previous step is added to NaHCO 3 (109 g, 1.30 mol). The mixture is stirred until the evolution of gas ceases. A solution of di-tert-butyl dicarbonate (139 g, 623 mmol) in methanol (450 mL) is added. The mixture is stirred at room temperature until the HPLC shows complete conversion. Three quarts of the methanol are removed by distillation in vacuo. Water (500 ml) is added and the remaining methanol is removed by vacuum distillation. The aqueous layer is extracted with dichloromethane. The solvent is removed under vacuum and the residue is dissolved in ethanol (100 ml). A small sample of the reaction solution is concentrated in vacuo. MS (DCI) m / z 229.3, 285.4, 286.4, 287.4. 1 H NMR (400 MHz, CDCl 3) d = 1.48 (s, 9 H), 4.37-4.44 (m, 2 H), 4.95 (br s, 1 H), 7.34-7, 39 (m, 1 H), 7.42-7.48 (m, 1 H), 7.48-7.51 (m, 2 H), 7.52-7.56 (m, 2 H), 8.64-8.67 (m, 2 H). d) 4- [3- (tert-Butoxycarbonylaminomethyl) phenyl] piperidine-p-toluenesulfonic acid salt Charcoal (17 g) is added to half of the above ethanolic solution of 3- (4-pyridyl) benzylcarbamic acid tert-butyl ester from the previous step. The mixture is stirred at room temperature, filtered and the filter washed with additional ethanol (260 ml). The obtained solution is added to platinum on carbon (44.7 g, 5% Pt / C). A mixture of concentrated hydrochloric acid is added. (31 g) and ethanol (250 ml). "The reaction mixture is diluted with ethanol (500 ml) and then hydrogenated at 50 ° C and at a hydrogen pressure of 3000 kPa until the consumption of hydrogen ceases. it is removed by filtration, HPLC shows complete conversion, three quarts of the ethanol is removed in vacuo, a mixture of water (310 ml) and sodium hydroxide solution (33%, 33 g) is added before the rest The aqueous solution is extracted with dichloromethane, the solvent is removed in vacuo and the residue is dissolved in isopropanol (65 ml) and diisopropyl ether (2.8 l), the solution is cooled to 0 ° C. and then a solution of p-toluenesulfonic acid (57.5 g) in isopropanol (260 ml) is added.The mixture is subsequently stirred at 0 ° C. for 1 h.The precipitate is removed by filtration, washed with diisopropyl ether and dried in vacuo to give 94.5 g of the title compound as a white solid (yield total in 4 stages: 77%) MS (ESI) m / z 291.26, 292.28, 293.28. 1 H NMR (400 MHz, DMSO-d 6) d = 1.39 (s, 9 H), 1, 70-1, 95 (m, 4 H), 2.29 (s, 3 H), 2.76- 2.85 (m, 1 H), 2.96-3.05 (m, 2 H), 3.25-3.40 (m, 1 H), 4.08-4.13 (m, 2 H) ), 7.05-7.14 (m, 4 H), 7.23-7.30 (m, 1 H), 7.36-7.40 (m, 1 H), 7.46-7.56 (m, 2 H), 8.37 ( sa, 2 H).

Example 3 3- (4-pyridyl) benzylamine dihydrochloride Hydrochloric acid (34.0 g, 30% w / w) and palladium on carbon (12.0 g, 10% Pd / C) are added to a solution of 3- (4-pyridyl) benzonitrile (25.0 g, 139 mmol) in methanol / water (1: 1, 250 ml). The mixture is stirred at room temperature and at a hydrogen pressure of 3000 kPa until the consumption of hydrogen ceases. The catalyst is removed by filtration. The HPLC shows the complete conversion. A sample of the reaction solution is concentrated in vacuo. MS (DCI) m / z 185.3. H NMR (400 MHz, DMSO-d6) d = 4.15 (s, 2 H), 7.62-7.66 (m, 1 H), 7.72 (d, J = 7.6 Hz, 1 H), 7.99 (d, J = 7.8 Hz, 1 H), 8.20 (s, 1 H), 8.41 (d, J = 6.5 Hz, 2 H), 8.92 (d, J = 6.5 Hz, 2 H).

Example 4 4- [3- (tert-Butoxycarbonylaminomethyl) phenyl] -1- [5-bromo-2-furanoyl] p-peridine To a salt suspension of 4- [3- (tert-butoxycarbonylamnomethyl) phenyl] piperidine-p-toluenesulfonic acid (185 g, 0.40 mol) in toluene is added aqueous sodium hydroxide (1.1 equiv.) And the The mixture is stirred at room temperature for 30 min. The phases are separated and the toluene layer is washed with water. Dry azeotropically by distilling off part of the toluene. To this solution is added triethylamine (72 ml, 0.52 mol).

This mixture is used directly in the next stage.

To a slurry at the reflux temperature of 5-bromo-2-furoic acid (80.8 g, 0.44 mol) in toluene (400 ml) is added thionyl chloride (37 ml, 0.52 mol). The mixture is refluxed for a further 30 min and then concentrated by distilling off some of the solvent. The obtained solution is cooled to room temperature and added to the amine solution of the previous step. After stirring for one hour, water is added and the organic layer is separated and diluted with heptane. The solid is removed by filtration and dried in vacuo. Recrystallization of the crude product from isopropanol / water yields the pure title compound (143 g, 77%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) d = 7.34 (m, 1 H), 7.24 (t, J = 7.6 Hz, 1 H), 7.12 (m, 2 H), 7.06 (m, 1 H), 7.02 (d, J = 3.4 Hz, 1 H), 6.75 (d, J = 3.4 Hz, 1 H), 4.40 (sa, 2 H) , 4.10 (d, J = 6.1 Hz, 2 H), 3.25-2.90 (sa, 2 H), 2.87-2.79 (m, 1 H), 1.83 ( m, 2 H), 1, 63-1.53 (m, 2 H), 1, 39 (s, 9 H). MS (ESI) m / z 363 (M + - 100, 100).

Example 5 4- [3- (tert-Butoxycarbonylamnomethyl) phenyl] -1- [5- (2-fluorophenylenyl] -2-furanoyl] piperidine A solution of (2-fluorophenylethynyl) trimethylsilane (68.0 g, 0.35 mol) in methanol (40 ml) is added to a suspension of K2CO3 (0.76 g, 5.51 mmol) in methanol (40 ml). . The solution is stirred for 30 min at room temperature and then added to a mixture of 4- [3- (tert-butoxycarbonyllaminomethyl) phenyl] -1- [5-bromo-2-furanoyl] piperidine (126 g. 0.27 mol), Pd (PPh3) 2Cl2 (3.90 g, 5.56 mmol), Cul (1.0 g, 5.25 mmol) and triethylamine (94 mL) in tetrahydrofuran (550 mL). The reaction mixture is heated to reflux for one hour. An aqueous solution of the trisodium salt of trimercaptotriazine (0.2 equiv.) Is introduced and the mixture is heated at reflux for an additional hour. After cooling to room temperature and adding brine, the organic phase is separated and washed successively with a solution of dilute hydrochloric acid and sodium carbonate. The organic phase is refluxed with charcoal for 30 min, filtered and concentrated in vacuo. The resulting brown oil is dissolved in dichloromethane (400 ml) and stirred overnight at room temperature with Deloxan® THP II (135 g). After filtration, the solvent is evaporated and the product is crystallized from isopropanol / diisopropyl ether to yield the title compound (74.6 g, 55%) as a yellow powder. 1 H NMR (300 MHz, CDCl 3) d = 7.53 (td, 1 H), 7.41-7.28 (m, 2 H), 7.18-7.08 (m, 5 H), 7, 04 (d, 1 H, J = 3.6 Hz), 6.76 (d, 1 H, J = 3.6 Hz), 4.83 (sa, 1 H), 4.72 (ma, 2 H) ), 4.31 (d, 2 H, J = 5.6 Hz), 3.1 (sa, 1 H), 2.82 (m, 2 H), 1.96 (m, 2 H), 1.79 (td, 2 H, J = 12.8, 4.0 Hz), 1.46 (s, 9 H). MS (ESI) m / z 503 (M + + 1, 100).

EXAMPLE 6 4- [3- (Aminomethyl) pheny!] - 1- [5- (2-fluorophenylethynyl) -2-furanoyl] piperidine-methanesulfonic acid salt To a solution of 4- [3- (tert-butoxycarbonylaminomethyl) phenylj-1- [5- (2-fluorophenylethynyl) -2-furanoyljpiperidine (67.4 g, 0.13 mol) in isopropanol (350 ml) is added methanesulfonic acid (13.5 g, 0.14 mol) at 70 ° C. The mixture is stirred at that temperature for three hours and then cooled slowly to room temperature. The precipitate is removed by filtration, washed with acetone and dried in vacuo. Recrystallization of the crude product from aqueous isopropanol / diisopropyl ether yields the analytically pure title compound (56.5 g, 84%). 1 H NMR (300 MHz, DMSO-d 6) d = 8.12 (br s, 3 H), 7.67 (tm, 1 H, J = 7.5 Hz), 7.54 (cm, 1 H, J = 7.0 Hz), 7.42-7.26 (m, 6 H), 7.10 (m, 2 H), 4.34 (sa, 2 H), 4.02 (c, 2 H, J = 5.5 Hz), 3.5-2.7 (sa, 2 H), 2.89 (m, 1 H), 2.34 (s, 3 H), 1.87 (m, 2 H) , 1.65 (m, 2 H). MS (ESI) m / z 403 (M + + 1, 100).

Example 7 4- [5- (tert-Butoxycarbonylaminomethyl) -2-fluorophenyl] piperidine The title compound is prepared analogously to the preparation of the 4- [3- (tert-butoxycarbonylaminomethyl) phen] piperidine described in Example 1. In summary, in step a), 3-bromo-4-fluorobenzyl amine hydrochloride is converted into 1 ~ (3-bromo-4-fiuorobenzyl) -2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane . In step b), the latter compound is reacted with n-BuLi and 1-benzyl-4-piperidone from -75 ° C to -70 ° C to give 1- [3- (1-benzyl-4-hydroxypiperidin- 4-yl) -4-fluorobenzyl] -2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane which, by treatment with phosphoric acid, is converted to 3- (1-benzyl-4) -hydroxypiperidin-4-yl) -4-fluorobenzylamine (in the form of the phosphoric acid salt) and subsequently in 3- (1-benzyl-1, 2,3,6-tetrahydropyridin-4-yl) -4- fluorobenzylamine. Then, the reaction with Boc20 gives 3- (1-benzyl-1, 2,3,6-tetrahydropyridin-4-yl) -4-fluorobenzylcarbamic acid tert -butyl ester. In step c), the latter compound is hydrogenated to give 4- [5- (tert-butoxycarbonylaminomethyl) -2-fluorophenyl] piperidine-acetic acid salt which is purified by trituration with tert-butyl methyl ether. In step d), said acetic acid salt is converted to 4- [5- (tert-butoxycarbonylaminomethyl) -2-fluorophenyl] piperidine which is precipitated from pentane as a white solid. 1 H NMR (300 MHz, CDCl 3) d = 7.10 (m, 2 H), 6.95 (m, 1 H), 4.84 (br s, 1 H), 4.26 (d, 2 H, J = 5.6 Hz), 3.18 (d, 2 H, J = 12.0 Hz), 2.95 (m, 1 H), 2.77 (m, 2 H), 1, 81-1, 48 (m, 5 H), 1, 46 (s, 9 H). MS (ESI) m / z 309 (M + H).

Claims

1. A process for the preparation of a compound of the formula where R1 is H, F, CF3, OCF3, (C8) alkyl, (C3-C10) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms same or different in ring selected from nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (C] -C8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (alkyl (C3)) amino, di (C3-C10 cycloalkyl) amino or di (aryl (C6-Cu)) amino; and R2 is H, F, CF3, OCF3, (C8) alkyl, (C3-C10) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms the same or different in the ring chosen from nitrogen, oxygen and sulfur, aryl (C6-C14), 5-membered heteroaryl to 10 members comprising 1, 2 or 3 heteroatoms the same or different in the ring chosen from nitrogen, oxygen and sulfur, alkoxy (CrC8), cycloalkoxy (C3-C10) , aryloxy (Ce-Cu), 5-membered heteroaryloxy to 10 members comprising 1, 2 or 3 heteroatoms same or different in the ring chosen from nitrogen, oxygen and sulfur, di (C 8 alkyl) amino, di- ( cycloalkull (C3-C10)) amino or di (aryl (C6-C14)) amino; or its salts, comprising: a) treating a phenylethylsilane compound of formula II, where G is trimethylsilyl, triethylsilyl, tri-isopropylsilyl or dimethyl-tert-butylsilyl, and R2 'is R2 as defined above or is a protected derivative thereof or a precursor residue thereof, in a solvent with a hydroxide, carbonate or alcohol of an alkali metal, or an alcohol of an alkaline earth metal, to form a solution of a phenyletino of formula III; b) combining the resulting solution of phenyletino with a compound of the formula IV, where X is bromine or iodine, R1 'is R1 as defined above or is a protected derivative thereof or a precursor residue thereof, and Boc is tert-butoxycarbonyl, in the presence of a homogeneous palladium catalyst, a copper salt , and a hindered amine in a solvent to form a protected compound of formula V, wherein R and R are R > 1 y. , R n2, respectively, as defined above or are a protected derivative thereof or a precursor residue thereof, and Boc is tert-butoxycarbonyl, or salts thereof.

2. A process according to claim 1 for the preparation of 4- [3- (aminomethyl) phenyl] -1- [5- (2-fluorophenylethynyl) -2-furanoyl] piperidine of formula la, or its salts, comprising: 'a) treating a (2-fluorophenylenetinyl) silyl compound of formula lal, where G is trimethylsilyl, triethylsilyl, tri-isopropylsilyl or dimethyl-tert-butylsilyl, in a solvent with a hydroxide, carbonate or alcohol of an alkali metal, or an alcohol of an alkaline earth metal to form a solution of 2-fluorophenylethynyl; Y b) combining the resulting solution of 2-fluorophenylethine with a compound of the formula IVa, where X is bromine or iodine, and Boc is tert-butoxycarbonyl, in the presence of a homogeneous palladium catalyst, a copper salt, and a hindered amine in a solvent to form 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] - 1- [5- (2-fluorophenylethynyl) -2-furanoirjpiperidine of formula Va, where Boc is tert-butoxycarbonyl.

3. A process according to claim 1 or 2, wherein G is trimethylsilyl.

4. A process according to any one of claims 1 to 3, wherein X is bromine.

5. A process according to any one of claims 1 to 4, further comprising removing the tert-butoxycarbonyl group and other protecting groups and / or converting precursor moieties present in a compound of the formula V or Va to provide a compound of the formula I or the one or its salts.

6. A process according to any one of claims 1 to 5, further comprising removing the tert-butoxycarbonyl group from a compound of the formula V or Va in the presence of an acid to provide a compound of the formula I or the or you go out.

7. A process according to any one of claims 1 to 6, further comprising removing the tert-butoxycarbonyl group from 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] -1- [5- (2-fluorophenylethynyl) -2 -furanoyl] piperidine in the presence of methanesulfonic acid to provide the methanesulfonic acid salt of 4- [3- (aminomethyl) phenyl] -1- [5- (2-fluorophenylethynyl) -2-furanoyl] piperidine.

8. A process for the preparation of a compound of formula IV, where R1 'is H, F, CF3, OCF3, alkyl (CrC8), cycloalkyl (C3-C10), heterocycloalkyl of 3 members to 10 members comprising 1, 2 or 3 heteroatoms the same or different in the ring chosen from nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (CrC8), cycloalkoxy (C3-C? o), aryloxy (C6-C14), di (alkyl (CrC8)) amino, di (C3-C10 cycloalkyl)) amino or di (aryl (C6-Cu)) amino, or a protected derivative thereof or a precursor residue thereof; and X is bromine or iodine, comprising: a) activating 5-bromo-2-furoic acid or 5-iodo-2-furoic acid to provide an activated form of 5-bromo-2-furoic acid or 5-iodo-2-furoic acid; Y b) combining the activated form of 5-bromo-2-furoic acid or 5-iodo-2-furoic acid with a compound of the formula VI, wherein R1 'is as defined for formula IV and Boc is tert-butoxycarbonyl, in a solvent.

9. A process according to claim 8 wherein R1 is hydrogen.

10. A process according to claim 8 or 9 for the preparation of the compound of formula IVc, where Boc is tert-butoxycarbonyl, comprising: a) treating 5-bromo-2-furoic acid with thionyl chloride to provide 5-bromo-2-furoyl chloride, and b) combining the 5-bromo-2-furoyl chloride with the compound of the formula Via where Boc is tert-butoxycarbonyl, in a solvent in the presence of a base.

11. A process for the preparation of a compound of the formula VI wherein R1 'is H, F, CF3, OCF3, alkyl (CrC8), cycloalkyl (C3-C10), heterocycloalkyl of 3 members to 10 members comprising 1, 2 or 3 identical heteroatoms or ring differentials chosen from among nitrogen , oxygen and sulfur, aryl (C6-C14), alkoxy (C8), cycloalkoxy (C3-C? o), aryloxy (C6-C1), di (alkyl (CrC8)) amino, di (cycloalkyl (C3-C10) )) amino or di (aryl (C6-C14)) amino, or a protected derivative thereof or a precursor residue thereof; and Boc is tert-butoxycarbonyl, or its salts, comprising: a) treating a salt of a 3-halobenzylamine of formula VII, with 1,2-bis (chlorodimethylsilyl) ethane in a solvent in the presence of a base to provide a 1- (3-halobenzyl) -2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane of the formula Vlll; b) treating 1- (3-halobenzyl) -2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane of formula Vlll in a solvent with an alkyllithium compound and 1-benzyl-4-piperidone at a temperature from about -80 ° C to about -40 ° C to provide an alcohol of formula IX; c) treating the alcohol of formula IX with an acid in a solvent to provide hydroxypiperidinylbenzylamine of formula X in the form of the acid salt; d) treating the hydroxypiperidinylbenzylamine of formula X or its salts with a concentrated, non-oxidizing acid at a temperature of about 70 ° C to about 150 ° C, followed by alkalization to provide an olefin of formula XI; e) treating the olefin of formula XI with di-tert-butyl dicarbonate in a solvent in the presence of a base to provide a protected amine of formula XII where Boc is tert-butoxycarbonyl, and where Ph in the formulas IX, X, XI and XII is phenyl, X 'in the formulas Vll and Vlll is bromine or iodine, and R1' in the formulas Vll, Vlll, IX, X, XI and XII is as defined for formula VI.

12. A process according to claim 11 for the preparation of 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] piperidine or its salts, comprising: a) treating 3-bromobenzylamine hydrochloride or 3-iodobenzylamine hydrochloride with 1,2-bis (chlorodimethylsilyl) ethane in a halogenated aliphatic hydrocarbon in the presence of a tertiary amine to provide 1- (3-halobenzyl) -2 , Corresponding 2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane, where halo is bromo or iodo; b) treating 1- (3-halobenzyl) -2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane in an ether with an alkyl lithium compound and 1-benzyl-4-piperidone at a temperature from about -80 ° C to about -40 ° C to provide 1- [3- (1-benzyl-4-hydroxypiperidin-4-yl) benzyl] -2,2,5,5-tetramethyl-1-aza-2 , 5-disilacyclopentane; c) treating 1- [3- (1-benzyl-4-hydroxypiperidin-4-yl) benzyl] -2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane with an inorganic acid in a halogenated hydrocarbon to provide 3- (1-benzyl-4-hydroxypiperidin-4-yl) benzylamine in the form of the inorganic acid salt; d) treating 3- (1-benzyl-4-hydroxypiperidin-4-yl) benzylamine with a concentrated, non-oxidizing acid at a temperature of about 70 ° C to about 150 ° C, followed by alkalization to provide 3- (1-benzyl-1, 2,3,6-tetrahydropyridin-4-yl) benzylamine; Y e) treating 3- (1-benzyl-1, 2,3,6-tetrahydropyridin-4-yl) benzylamine with di-tert-butyl dicarbonate in an aliphatic alcohol, ethyl acetate, an ether, a halogenated hydrocarbon, a mixture of two or more of said solvents or a mixture of one or more of said solvents with water, in the presence of a hydroxide, carbonate or alcohol of an alkali metal, or a tertiary amine to provide 3- tert-butyl ester (1-Benzyl-1, 2,3,6-tetrahydropyridin-4-yl) benzylcarbamic acid.

13. A process according to claims 11 or 12, further comprising treating the amine of formula Xil with hydrogen in a solvent in the presence of a palladium catalyst and in the presence of an acid to provide a compound of formula VI or its salts.

14. A process for the preparation of a compound of formula VI, wherein R1 'is H, F, CF3, OCF3, (C8) alkyl, (C3-C10) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms same or different in ring selected from nitrogen, oxygen and sulfur, aryl (C6-C), alkoxy (CrC8), cycloalkoxy (C3-C1Q), aryloxy (C6-C14), di (alkyl (CrC8)) amino, di (cycloalkull (C3-C10)) amino or di (aryl (C6-Cu)) amino, or a protected derivative thereof or a precursor residue thereof; and Boc is tert-butoxycarbonyl, or its salts, comprising: a) treating a 3- (4-pyridyl) benzaldehyde of formula Xlll, with hydroxylamine or a hydroxylamine salt in a solvent to provide an oxime of formula XIV or its salts; b) treating the oxime of formula XIV or its salts with hydrogen in a solvent in the presence of a palladium catalyst to provide 3- (4-pyridyl) benzylamine of formula XV or its salts; XV c) treating the 3- (4-pyridyl) benzylamine of formula XV or its salts with di-tert-butyl dicarbonate in a solvent in the presence of a base to provide a 3- (4-pyridyl) benzylamine protected with Boc of Formula XVI, where Boc is tert-butoxycarbonyl; Y d) treating the Boc-protected 3- (4-pyridyl) benzylamine of formula XVI with hydrogen in a solvent in the presence of a palladium catalyst and in the presence of an acid to provide a compound of the formula VI or its salts; where R1 'in the formulas Xlll, XIV, XV and XVI is as previously defined for the formula VI.

15. A process according to claim 14 for the preparation of 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] piperidine or its salts, comprising: a) treating 3- (4-pyridyl) benzaldehyde with hydroxylamine or a salt thereof in an aliphatic alcohol at a temperature from about 0 ° C to about 40 ° C to provide 3- (4-pyridyl) benzaldehyde oxime or its salts; b) treating the 3- (4-pyridyl) benzaldehyde oxime or its salts with hydrogen at a pressure of about 300 kPa to about 1500 kPa in an aliphatic alcohol in the presence of a palladium catalyst at a temperature of about 20 ° C to about 50 ° C to provide 3- (4-pyridyl) benzylamino or its salts; c) treating 3- (4-pyridyl) benzylamine or its salts with di-tert-butyl dicarbonate in an aliphatic alcohol, ethyl acetate, an ether, a halogenated hydrocarbon, a mixture of two or more of said solvents or a mixture of one or more of said solvents with water, in the presence of a hydroxide, carbonate or alcohol of an alkali metal, or a tertiary amine to provide 3- (4-pyridyl) benzylcarbamic acid tert-butyl ester; Y d) treating the 3- (4-pyridyl) benzylcarbamic acid tert-butyl ester with hydrogen in an aliphatic alcohol at a pressure of about 2000 kPa to about 6000 kPa in the presence of a palladium catalyst and in the presence of an acid.

16. A process for the preparation of a compound of the formula VI wherein R1 'is H, F, CF3, OCF3, aikyl (C C8), cycloalkyl (C3-C10), 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms same or different in ring selected from nitrogen, oxygen and sulfur, aryl (C6-C1), alkoxy (C8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (alkyl (CrC8)) amino, di (cycloalkyl (C3-C10) amino or di (aryl (C6-Cu)) amino, or a protected derivative thereof or a precursor residue thereof; and Boc is tert-butoxycarbonyl, or its salts, comprising: a) treating a 3- (4-pyridyl) benzonitrile of formula XVII, with hydrogen in the presence of a palladium catalyst and in the presence of an acid, or with a complex hydride, in a solvent to provide a 3- (4-pyridyl) benzylamine of formula XV or its salts; b) treating the 3- (4-pyridyl) benzylamine of formula XV or its salts with di-tert-butyl dicarbonate in a solvent in the presence of a base to provide a Boc-protected 3- (4-pyridyl) benzylamine of formula XVI, where Boc is tert-butoxycarbonyl; Y c) treating the Boc-protected 3- (4-pyridyl) benzylamine of formula XVI with hydrogen in a solvent in the presence of a palladium catalyst and in the presence of an acid to provide a compound of formula VI or its salts; where R1 'in formula XV, XVI and XVII is as defined above for formula VI.

17. A process according to claim 16 for the preparation of 4- [3- (tert-butoxycarbonylamnomethyl) phenyl] piperidine or its salts, comprising: a) treating 3- (4-pyridyl) benzonitrile with hydrogen in the presence of a palladium catalyst at a pressure of about 2000 kPa to about 6000 kPa in an aliphatic alcohol or a mixture of an aliphatic alcohol and water, or with a complex hydride in an aliphatic alcohol or an ether, at a temperature from about 0 ° C to about 50 ° C, to provide 3- (4-pyridyl) benzylamine or its salts; b) treating the 3- (4-pyridyl) benzylamine or its salts with di-tert-butyl dicarbonate in an aliphatic alcohol, ethyl acetate, an ether, a halogenated hydrocarbon, a mixture of two or more of said solvents or a mixing one or more of said solvents with water, in the presence of a hydroxide, carbonate or alcohol of an alkali metal, or a tertiary amine, to provide 3- (4-pyridyl) benzylcarbamic acid tert-butyl ester; Y c) treating the 3- (4-pyridyl) benzylcarbamic acid tert-butyl ester with hydrogen in an aliphatic alcohol at a pressure of about 2000 kPa to about 6000 kPa in the presence of a palladium catalyst and in the presence of an acid.

18. A compound of formula Vlll, Vlll in which R1 'is H, F, CF3, OCF3, alkyl (CrC8), cycloalkyl (C3-C10), heterocycloalkyl of 3 members to 10 members comprising 1, 2 or 3 heteroatoms equal or different in the ring chosen from nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (C | ~ C8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (alkyl (C Ca)) amino, di (cycloalkyl (C3) -C10)) amino or di (aryl (C6-C14)) amino, or a protected derivative thereof or a precursor residue thereof; and X 'is bromine or iodine; excluding the compound 1- (3-bromobenzyl) -2,2,5,5-tetramethyl-1-aza-2,5-disilacidopentane.

19. A compound according to claim 18, which is 1- (3-iodobenzyl) -2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane.

20. A compound of formula IX, wherein R1 'is H, F, CF3, OCF3, (Cs) alkyl, (C3-C10) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 same or different heteroatoms in the ring selected from nitrogen, oxygen and sulfur, aryl (Ce-Cu), alkoxy (CrC8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (C8 alkyl) amino, di (C3-C10 cycloalkyl) amino or di (aryl (C6-Cu)) amino, or a protected derivative thereof or a precursor residue thereof; and Ph is phenyl.

21. A compound - according to claim 20 which is 1- [3- (1-benzyl-4-hydroxypiperidin-4-yl) benzyl] -2,2,5,5-tetramethyl-1-aza-2, 5-disilacyclopentane.

22. A compound of formula X, wherein R1 'is H, F, CF3, OCF3, alkyl (CrC8), cycloalkyl (C3-C10), heterocyclic acrylate of 3 members to 10 members comprising 1, 2 or 3 heteroatoms the same or different in the ring chosen from among nitrogen , oxygen and sulfur, aryl (C6-C14), alkoxy (CrC8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (alkyl (CrC8)) amino, di (C3-C10) cycloalkyl) amino or di (aryl (C6-Cu)) amino, or a protected derivative thereof or a precursor residue thereof; and Ph is phenyl, or its salts.

23. A compound according to claim 22, which is 3- (1-benzyl-4-hydroxypiperidin-4-yl) benzylamine or its salts.

24. A compound of formula XI, wherein R1 'is H, F, CF3, OCF3, (C8) alkyl, (C3-C10) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 same or different heteroatoms in the ring selected from nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (CrC8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (alkyl (CrC8)) amino, di (cycloalkyl (C3-C10)) amino or di (aryl (C6-C14)) amino, or a protected derivative thereof or a precursor residue thereof; and Ph is phenyl, or its salts.

25. A compound according to claim 24, which is 3- (1-benzyl-1, 2,3,6-tetrahydropyridin-4-yl) benzylamine or its salts.

26. A compound of formula XII, wherein R1 'is H, F, CF3, OCF3, (C8) alkyl, (C3-C0) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 same or different heteroatoms in the ring selected between nitrogen, oxygen and sulfur, aryl (C6-C1), alkoxy (C8), cycloalkoxy (C3-C10), aryloxy (C6-C14). di (C 8 alkyl) amino, di (C 3 -C 10) cycloalkyl amino or di (C 6 -C 14) aryl amino, or a protected derivative thereof or a precursor thereof; Boc is tert-butoxycarbonyl; and Ph is phenyl, or its salts.

27. A compound according to claim 26, which is 3- (1-benzyl-1, 2,3,6-tetrahydropyridin-4-yl) benzylcarbamic acid tert-butyl ester or its salts.

28. A compound of formula XIV, wherein R is H, F, CF3, OCF3, (C8) alkyl, (C3-C10) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms same or different in ring selected from nitrogen , oxygen and sulfur, ary (C6-C14), alkoxy (CrC8), cycloalkoxy (C3-C0), aryloxy (C6-C14), di (alkyl (CrC8)) amlno, di (cycloalkyl (C3-C10)) amino or di (aryl (C6-C14)) amino, or a protected derivative thereof or a precursor residue thereof, or its salts.

29. A compound according to claim 28, which is 3- (4-pyridyl) benzaldehyde oxime or its salts.

30. A compound of formula XV, wherein R1 is H, F, CF3, OCF3, alkyl (CrC8), cycloalkyl (C3-C10), heterocycloalkyl of 3 members to 10 members comprising 1, 2 or 3 heteroatoms the same or different in the ring chosen from among nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (C | -C8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (alkyl (C1tC8)) amino, di (C3-C10 cycloalkyl) amino or di (aryl (C6-C14)) amino, or a protected derivative thereof or a precursor residue thereof, or its salts.

31. A compound according to claim 30, which is 3- (4-pyridyl) benzylamine or its salts.

32. A compound of formula XVI, wherein R1 'is H, F, CF3, OCF3, alkyl (CrC8), cycloalkyl (C3-C10), heterocycloalkyl of 3 members to 10 members comprising 1, 2 or 3 heteroatoms equal or different in the ring chosen from among nitrogen , oxygen and sulfur, aryl (C6-C14), alkoxy (CrC8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (alkyl (Cs)) amino, di (cycloalkyl (C3-C10)) amino or di (aryl (C6-Cu)) amino, or a protected derivative thereof or a precursor residue thereof; and Boc is tert-butoxycarbonyl, or its salts.

33. A compound according to claim 32, which is tert-butyl ester of 3- (4-pyridyl) benzylcarbamic acid or its salts.

34. A compound of formula IVb, wherein R is H, F, CF3, OCF3, alkyl (CrC8), cycloalkyl (C3-C10), heterocycloalkyl of 3 members to 10 members comprising 1, 2 or 3 heteroatoms the same or different in the ring chosen from among nitrogen, oxygen and sulfur, aryl (C6-Cu), alkoxy (CrC8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (alkyl (Cs)) amino, di (cycloalkyl (C3-C10)) amino or di (aryl (C6-Cu)) amino, or a protected derivative thereof or a precursor residue thereof; and Boc is tert-butoxycarbonyl, or its salts.

35. A compound according to claim 34, which is 4- [3- (tert-butoxycarbonylaminomethyl) phenyl] -1- [5-bromo-2-furanoyl] piperidine.

36. The use of a compound according to any one of claims 18 to 35 as an intermediate for the preparation of a compound of the formula I, where R1 is H, F, CF3, OCF3, alkyl (CrC8), cycloalkyl (C3-C10), heterocycloalkyl of 3 members to 10 members comprising 1, 2 or 3 heteroatoms the same or different in the ring chosen from nitrogen, oxygen and sulfur, aryl (C6-C14), alkoxy (CrC8), cycloalkoxy (C3-C10), aryloxy (C6-C14), di (C8-alkyl) amino, di (C3-C10) cycloalkyl) amino or di (aryl (C6-C14)) amino; and R2 is H, F, CF3, OCF3, alkyl (CrC8), (C3-C10) cycloalkyl, 10-membered, 3-membered heterocycloalkyl comprising 1, 2 or 3 heteroatoms the same or different in the ring chosen from nitrogen, oxygen and sulfur, aryl (C6-C14), 5-membered heteroaryl to 10 members comprising 1, 2 or 3 heteroatoms same or different in the ring chosen from nitrogen, oxygen and sulfur, alkoxy (CrC8), cycloalkoxy (C3-C10), aryloxy (Ce-Cu), 10-membered 5-membered heteroaryloxy comprising 1, 2 or 3 heteroatoms the same or different in the ring chosen from nitrogen, oxygen and sulfur, di (alkyl (d-C8)) amino, di- ( (C3-C10) cycloalkyl) amino or di (aryl (C6-Cu)) amino; or its salts.