WO2010020628A1 - Novel production method for l-piperidine-4-yl-1,3-dihydro-imidazo [4,5-b] pyridine-2-one and mono- and dihydrochlorides thereof - Google Patents

Abstract

The object of the present invention is a method for producing compounds of formula (I), in which n is defined in the description that follows, said compounds being found in CGRP antagonists as structural elements.

Description

NEW MANUFACTURING METHOD FOR 1-PIPERIDIN-4-YL-1, 3-DIHYDRO-IMIDAZO [4,5-B] PYRIDIN-2-ON AND ITS MONO AND

DI HYDROCHLORIDE

The present invention is a process for the preparation of compounds of general formula I.

(n = 0.1 or 2) which are found as a structural element in CGRP antagonists. Examples of compounds having CGRP-antagonistic properties which contain as structural element the compound of the formula I are described in the international patent applications WO 2004/092166 and WO 2004/092168. As a disadvantage of previously known methods (e.g., WO 2007/120590), the following points have been recognized.

• When using starting materials without a chromophore, analytical monitoring of the reaction using HPLC / UV detection is not readily possible. This requires an increased analytical effort (Example 8, WO 2007/120590), e.g. the discovery and use of suitable thin-layer chromatographic (DC)

Systems for the quantitative determination of the starting material contained and its detection with appropriate staining reagents.

• In the open literature (M. McLaughlin et al. Org. Lett, 2006 (8) 331 1 -3314), the positive influence of defined amounts of water on the reaction course of palladium-catalyzed cyclization of urea derivatives, analogous substance V in

Scheme 1. In a technical process, therefore, an easily and reproducibly settable water content is of particular importance. Instead of analytically determining the water content of the reaction mixture and, if appropriate, adjusting it by adding water, in the present invention a defined amount of water is previously dried azeotropically

Given reaction mixture. As a result, an increased analytical effort (eg determination of water content according to Karl Fischer) is avoided. BRIEF SUMMARY OF THE INVENTION

The present application is a process for the preparation of the compound 1-piperidin-4-yl-1,3-dihydro-imidazo [4,5-b] pyridin-2-one of the formula I. The inventive method results in a few Steps to good yields of the desired

Compound that is also obtained in high purity. The 4-step procedure is outlined in Scheme 1. As an advantage of the present synthesis, especially the following points can be considered:

• Step A: The use of the UV-active Z-protecting group allows a fast and efficient reaction control and a good detection of the starting material 4-oxo-piperidine-1-carboxylic acid benzyl ester in the product by HPLC measurement with UV detection.

• Step C: By using tert-amyl alcohol as a solvent, a significantly simplified reaction is possible. By distillation, water residues can be effectively azeotropically removed from the reaction mixture, so that the analytical

Effort through KF titration completely eliminated. The water required for the reaction can then be added selectively in the required quantity.

• Step D: The possibility of hydrogenolytic cleavage of the protecting group allows for complete and virtually byproduct-free reaction. In this case, isolation of the product either as a base or by direct precipitation in the form of a dihydrochloride from the reaction solution is possible. Both compounds are crystalline.

DESCRIPTION OF THE INVENTION

The invention relates to a process for preparing the compounds 1-piperidin-4-yl-1,3-dihydro-imidazo [4,5-b] pyridin-2-one of the formula I as base (n = 0), as appropriate Monohydrochloride (n = 1) or as dihydrochloride (n = 2).

The process shown in Scheme 1 for the preparation of the compound 1-piperidin-4-yl-1,3-dihydro-imidazo [4,5-b] pyridin-2-one of the formula I and its precursors according to the invention has proven particularly useful. As a starting material for the synthesis of compound I, 3-amino-2-chloropyridine II can be used. In a first step (A), 3-amino-2-chloropyridine II is reductively alkylated with 4-oxopiperidine-1-carboxylic acid benzyl ester III in the presence of sodium triacetoxyborohydride and trifluoroacetic acid in isopropyl acetate.

In the next stage (B), the ring-open urea V is formed by reaction of IV with chlorosulfonyl isocyanate, which is reacted under Pd catalysis to give the corresponding imidazolone VI. The catalytic hydrogenation of VI leads to elimination of the Z-protecting group to I

Scheme 1:

vi

vi

The invention is not limited to the explicitly mentioned examples and reactions. Modifications, including use of alternative reagents, solvents, reaction conditions, purification and isolation techniques, which are known to one skilled in the art but are not expressly described herein, may also be made from the reactions described.

A first subject of the present invention relates to a process for the preparation of compounds of general formula I. - A -

in which n represents one of the numbers O, 1 or 2, comprising the steps of:

(A) Coupling of a compound of general formula II

in the LG represents a leaving group, for example a fluorine, chlorine, bromine or iodine atom or the triflate (-OSO ₂ CF ₃ ), preferably a chlorine atom, with a compound of general formula III

in which Ar represents an unsubstituted or substituted phenyl group which is selected from the group consisting of phenyl, 2-chlorophenyl, 2-bromophenyl, 2,4-dichlorophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 2,4,6- Trimethylphenyl and 4-nitrophenyl, in a solvent and in the presence of an acid and a reducing agent;

(AA) optionally isolating a compound of general formula IV obtained under (A)

, (IV) in der LG eine wie oben beschriebene Abgangsgruppe bedeutet und Ar eine wie oben beschriebene Phenylgruppe darstellt;

, (IV) in LG, a leaving group as described above, and Ar represents a phenyl group as described above;

(B) reaction of a compound of general formula IV obtained under (A) or (AA) with chlorosulfonyl isocyanate, NaOCN, phosgene / NH ₃ , triphosgene / NH ₃ ,

Carbonyldiimidazole (CDI) / NH ₃ or carbonylditriazole (CDT) / NH ₃ , in a solvent;

(BB) Isolating and optionally recrystallizing a compound of general formula V obtained under (B)

in LG, represents a leaving group as described above, and Ar represents a phenyl group as described above from a solvent;

(C) cyclization of a compound of general formula V obtained under (B) or (BB) in the presence of a catalyst and a base in a solvent, optionally adding a ligand to the catalyst;

(CC) isolating and optionally recrystallizing a compound of general formula VI obtained under (C)

Ar is a phenyl group as described above, from a solvent; (D) reacting a compound of general formula VI obtained under (C) or (CC) by adding a reducing agent in a polar organic solvent; and

(DD) optionally isolating a compound of general formula I obtained under (D)

as the base (n = 0), or in the form of a hydrochloride (n = 1 or 2) by adding the appropriate amount of hydrochloric acid.

In the coupling in step (A) 1.0 equivalents of a compound of general formula II can be reacted with 1.0 to 2.0, preferably 1.1 to 1.3 equivalents, of a compound of general formula III. As the solvent, ethyl acetate, isopropyl acetate or THF may be used. In this case, the solvent in an amount of 1.5 to 3.5, preferably in an amount of 2.4 to 2.6 L / mol of the compound of formula II, are added. The acid used in step (A) may be selected from the group consisting of trifluoroacetic acid or acetic acid; preferably trifluoroacetic acid is used. The acid may be added in an amount of from 1 to 3, preferably from 1.5 to 2.5, equivalents, in each case based on the amount of compound of general formula II used. The reducing agent used in step (A) may be selected from the group consisting of Sodium triacetoxyborohydride or sodium cyanoborohydride, preferably sodium triacetoxyborohydride is used. The reducing agent may be added in an amount of 1 to 3, preferably from 1.0 to 1.5, equivalents, in each case based on the amount of compound of the general formula II used. The reaction temperature is preferably between 0 and 30 ^° C., more preferably between 10 and 20 ⁰ C, in particular between 14 and 16 ° C. In the reaction in step (B) 1.0 equivalents of a compound of general formula IV with 1.0 to 2.0, preferably 1.3 to 1.7 equivalents, of a compound selected from the group consisting of chlorosulfonyl isocyanate, NaOCN, phosgene / NH ₃ , triphosgene / NH ₃ , CDI / NH ₃ or CDT / NH ₃ , preferably chlorosulfonyl isocyanate and NaOCN; particularly preferably, chlorosulfonyl isocyanate can be reacted. When

Solvents can be used tetrahydrofuran, isopropyl acetate or a mixture of both solvents. The solvent may be added in an amount of 2 to 5, preferably in an amount of 3 to 3.5 L / mol of the compound of general formula IV used. The reaction temperature is preferably between -30 and -7 ° C, more preferably between -20 and -7 ° C, in particular between -10 and -7 ° C.

The recrystallization described in step (BB) can be carried out from a polar organic solvent, e.g. Ethyl acetate, n-butyl acetate, isopropyl acetate or mixtures of the two solvents. The solvent may be added in an amount of 0.5 to 3, preferably in an amount of 1.5 to 2.5 L / mol of the compound of general formula V used.

Before the cyclization in step (C) is 1 equivalent of the compound of general formula V with 1.5 to 4.5, preferably 2.0 to 4.0, particularly preferably 2.5 to 3.5

Equivalents of a weak base, preferably sodium bicarbonate or potassium bicarbonate; sodium hydrogen carbonate in a volume of 3.0 to 7.0, preferably 4.0 to 6.0, particularly preferably 4.5 to 5.5 L / mol of compound of the general formula V used, of a solvent selected from the group consisting of n-propanol, n-butanol, isobutanol , n-amyl alcohol, iso-amyl alcohol, tert-amyl alcohol or tert-butanol, preferably tert-amyl alcohol; heated and then distilled off a volume of 10-30%, preferably 15-25, particularly preferably 18-22% of the liquid portion. The remaining liquid volume 0.01-0.2%, preferably 0.1% water is added. Subsequently, 0.01 to 0.03, preferably 0.015 to 0.025, particularly preferably 0.02 equivalents of catalyst and 0.02 to 0.06, preferably 0.03 to 0.05, particularly preferably 0.04 equivalents of a ligand are added and the reaction mixture is heated under reflux. The catalyst used may be selected from the group consisting of palladium (II) acetate, palladium (II) chloride, tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ), bis (dibenzylideneacetone) palladium (Pd (dba) ₂ ), 1 _! 1 'bis (diphenylphosphino) ferrocenedichloropalladium (II) (Pd (DPPF)), palladium (II) trifluoroacetate and bis (acetonitrile) dichloropalladium (II); preferably palladium acetate is used. The ligand used can be selected from 1,4-bis (diphenylphosphino) butane (DPPB), 9,9-dimethylsilane-4,4-bis (diphenylphosphino) xanthene (xantphos) and 2-dicyclohexylphosphino-2 ', 4''6'-triisopropylbiphenyl(X-Phos); Preferably, 1,4-bis (diphenylphosphino) butane (DPPB) is used.

The reaction is preferably conducted overnight, which corresponds to a reaction time of 6 to 18, preferably 9 to 15, particularly preferably 11 to 13 hours. Thereafter, the reaction mixture is preferably treated with water and worked up.

The recrystallization described in step (CC) can be carried out from a polar, organic solvent. As the polar organic solvent, ethyl acetate, isopropyl acetate, or butyl acetate, preferably isopropyl acetate (IPAC) can be used. The methods known in the prior art for recrystallization are used.

In the reaction in step (D), 1.0 equivalents of a compound of general formula VI may be reacted by means of hydrogen as known in the art using a hydrogenation catalyst. As the organic solvent, methanol, ethanol, THF or ethyl acetate, preferably methanol or ethanol, more preferably methanol can be used. In this case, the solvent may be added in an amount of 1.0 to 5.0, preferably in an amount of 2.0 to 3.0 L / mol. The hydrogenation catalyst used in step (D) may be selected from the group consisting of palladium / carbon or rhodium / carbon; preferably

Palladium / carbon used. The hydrogenation catalyst may be added in an amount of 0.5 to 20% by weight, preferably 3 to 10% by weight.

Subsequently, the product can be isolated by precipitation by means of methylcyclohexane (MCH) or the crystallization described in step (DD) can be carried out by means of hydrochloric acid-containing alcohols directly from the reaction medium. Also, the product isolated by means of methylcyclohexane (MCH) can be crystallized out in hydrochloric acid-containing alcohols and thus converted into the monohydrochloride or dihydrochloride. In this case, the methods known in the prior art for solidification and recrystallization applied. The hydrochloric acid-containing alcohol used may be selected from the group consisting of methanol, ethanol, isopropanol, propanol, preferably methanol, ethanol, isopropanol; particularly preferably ethanol. The concentration of hydrochloric acid in the alcohol can be in the range from 5 to 15, preferably 7 to 13, particularly preferably 9 to 1 1 mol / L. The amount of hydrochloric acid relative to the compound of formula I (where n = 0) may here be from 2 to 6, preferably 2 to 4 equivalents.

Another object of the present invention are the compounds of general formula III

wherein Ar represents a phenyl group selected from the group consisting of phenyl, 2-chlorophenyl, 2-bromophenyl, 2,4-dichlorophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 2,4,6-trimethylphenyl and 4-nitrophenyl.

Another object of the present invention relates to the use of the above-mentioned compounds of general formula III as intermediates for the preparation of compounds of general formula I by a method described above.

Another object of the present invention are the compounds of general formula IV

wherein Ar represents a phenyl group selected from the group consisting of phenyl, 2-chlorophenyl, 2-bromophenyl, 2,4-dichlorophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 2,4,6-trimethylphenyl and 4-nitrophenyl and LG is selected from the A group consisting of a fluorine, chlorine, bromine or iodine atom or the triflate group (-OSO ₂ CF ₃ ).

Another object of the present invention relates to the use of the above-mentioned compounds of general formula IV as intermediates for the preparation of compounds of general formula I by a method described above.

Another object of the present invention are the compounds of general formula V

wherein Ar represents a phenyl group selected from the group consisting of phenyl, 2-chlorophenyl, 2-bromophenyl, 2,4-dichlorophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 2,4,6-trimethylphenyl and 4-nitrophenyl and LG is selected from the group consisting of a fluorine, chlorine, bromine or iodine atom or the triflate group (-OSO ₂ CF ₃ ).

Another object of the present invention relates to the use of the above-mentioned compounds of general formula V as intermediates for the preparation of compounds of general formula I by a method described above.

Another object of the present invention are the compounds of general formula VI

wherein Ar represents a phenyl group selected from the group consisting of phenyl, 2-chlorophenyl, 2-bromophenyl, 2,4-dichlorophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 2,4,6-trimethylphenyl and 4-nitrophenyl.

Another object of the present invention relates to the use of the above compounds of general formula VI as intermediates for the preparation of compounds of general formula I by a method described above.

USED TERMS AND DEFINITIONS

In the context of the invention, the term "optionally substituted" is understood to mean the abovementioned group which is optionally substituted by a lower-molecular radical. Low-molecular radicals are understood to be chemically meaningful groups consisting of 1-200 atoms. Preferably, such groups have no negative effect on the pharmacological activity of the compounds. For example, the groups may include: straight or branched carbon chains, possibly interrupted by

Heteroatoms, optionally substituted with rings, heteroatoms or other common functional groups.

Aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms, which in turn may be substituted with functional groups.

A plurality of aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms, which may be substituted by one or more carbon chains, optionally interrupted by heteroatoms substituted with heteroatoms or other common functional groups can be linked.

"Protecting groups" in the meaning of the present invention are to be understood as a collective term for such organic radicals with which certain functional groups of a molecule containing several active sites can be temporarily protected against the attack of reagents so that reactions take place only at the desired (unprotected) sites occur. The protecting groups should be selectively introduced under mild conditions. They must be stable for the duration of the protection under all conditions of the reactions and cleaning operations to be performed; Racemizations and epimerizations must be suppressed. Protective groups should again be cleavable under mild conditions selectively and ideally with high yield. The choice of a suitable protective group, the conditions for the reaction (solvent, temperature, duration, etc.) but also the possibilities to remove a protective group are known in the art (eg Philip Kocienski, Protecting Groups, 3rd ed. 2004, THIEME, Stuttgart, ISBN: 3131370033).

In the context of the invention, a "solvent" is understood to mean an organic, low-molecular substance which can bring other organic substances to solution by physical means. Prerequisite for the suitability as a solvent is that during the dissolution process neither the solvent nor the solute chemically change, so that the components of the solution can be recovered by physical separation processes such as distillation, crystallization, sublimation, evaporation, adsorption in its original form. For various reasons, not only the pure solvents but mixtures that combine the dissolution properties can be used. For example, called his:

Alcohols, preferably methanol, ethanol, propanol, butanol, octanol, cyclohexanol;

Glycols, preferably ethylene glycol, diethylene glycol;

Ether / glycol ethers, preferably diethyl ether, tert-butyl methyl ether, dibutyl ether, anisole, dioxane, tetrahydrofuran, mono-, di-, tri-, polyethylene glycol ethers;

Ketones, preferably acetone, butanone, cyclohexanone;

Esters, preferably acetic acid esters, glycol esters;

Amides, inter alia, nitrogen compounds, preferably dimethylformamide, pyridine, N-methylpyrrolidone, acetonitrile; Sulfur compounds, preferably carbon disulfide, dimethylsulfoxide, sulfolane;

Nitro compounds, preferably nitrobenzene;

Halogenated hydrocarbons, preferably dichloromethane, chloroform, carbon tetrachloride, trichlorethylene, tetrachloroethene, 1,2-dichloroethane, chlorofluorocarbons; Aliphatic or alicyclic hydrocarbons, preferably benzines, petroleum ethers, cyclohexane, methylcyclohexane, decalin, terpene-L; or

Aromatic hydrocarbons, preferably benzene, toluene, o-xylene, m-xylene, p-xylene; or corresponding mixtures thereof.

"Halogen" in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine, chlorine and bromine are preferred halogens.

EXPERIMENTAL PART

The following abbreviations are used:

BuAC n-butyl acetate

TLC thin layer chromatography DPPB 1, 4-bis (diphenylphosphino) butane d. Th. Of theory

Fl% area percent

Weight% by weight

IPAC isopropyl acetate i.vac. in vacuo (in vacuum)

KF Karl Fischer (water content determination)

MCH methylcyclohexane

RT room temperature

TFA trifluoroacetic acid THF tetrahydrofuran

HPLC method: column: Prontosil 120-5-C18; Solvent A: 0.2% KH ₂ PO ₄ pH 3 (adjusted with H ₃ PO ₄ ); Solvent B: acetonitrile; Gradient: 80:20 to 50:50; Temperature: 50 ^° C Example 1: 4- (2-Chloro-pyridin-3-yl-amino) -piperidine-1-carboxylic acid benzyl ester

To 930 g (3.99 mol, 1.1 eq) of V-benzyloxycarbonyl-4-piperidone and 466 g (3.63 mol, 1.0 eq) of 2-chloro-3-aminopyridine in 9.5 L (2.6 L / mol) of isopropyl acetate were added at ca. ° C 560 ml (7.25 mol, 2.0 eq) TFA was added dropwise. 922 g (4.35 mol, 1.2 eq) of sodium triacetoxyborohydride were added portionwise. It was stirred until the reaction was complete. At RT, the reaction mixture was mixed with 860 ml of sodium hydroxide solution (2 mol / L). The organic phase was separated, washed with 5 L of water and concentrated.

Yield: 1250 g (crude 100% of theory)

ESI-MS: m / z = 346 (M + H) ⁺

Purity HPLC: 98.5 fl.%; Column: Prontosil 120-5-C18

Example 2: 4- [1- (2-Chloro-pyridin-3-yl) -ureido] -piperidine-1-carboxylic acid benzyl ester

530 ml (6.1 mol, 1.5 eq) of chlorosulfonyl isocyanate were initially charged in 6 L of THF and cooled to -15 ° C. To this mixture was then added a solution of 1.25 kg (3.63 mol, 1.0 eq) 4- (2-chloro-pyridin-3-yl-amino) -piperidine-1-carboxylic acid benzyl ester in 7 L (1.7 L / mol) THF within one Hour added so that the temperature of the reaction mixture -7 ° C was not exceeded. The mixture was stirred for 90 minutes at about -8 ° C and then added dropwise 700 ml of water within 30 minutes. The mixture was stirred for 30 minutes at about 10 ⁰ C and then treated slowly with 8.1 L sodium hydroxide solution (2 mol / L). The reaction mixture was then heated to 50 ⁰ C and the Phases separated. The organic phase was washed with 2 L of water. Thereafter, 10 L of solvent were distilled off from the organic phase, added 15 L of butyl acetate to the residue and distilled off another 8 L thereof. By slow cooling to 0 ⁰ C, the product was crystallized. The precipitate was filtered off, washed with 2L butyl acetate and dried at 40 ⁰ C. Yield: 1108 g (78.8% of theory) ESI-MS: m / z = 389/391 (M + H) ⁺ Purity HPLC: 99.6 FL%; Column: Prontosil 120-5-C18

Example 3: 4- (2-Oxo-2,3-dihydro-imidazo [4,5-b] pyridin-1-yl) -piperidine-1-carboxylic acid benzyl ester

1,108 g (2.85 mol, 1.0 eq) of 4- [1- (2-chloro-pyridin-3-yl) -ureido] -piperidine-1-carboxylic acid benzyl ester were reacted with 720 g (8.57 mol, 3.0 eq) of NaHCO ₃ heated in 14.5 L tert-amyl alcohol (5.1 L / mol) under reflux. Here, 3 L of solvent were distilled off. The

Reaction mixture was cooled to 35 ° C (see above) and treated with 11 ml of water. Subsequently, 13 g (0.058 mol, 0.02 eq) of palladium acetate and 49 g (0.115 mol, 0.04 eq) of DPPB were added and heated to reflux temperature. The mixture was stirred at 100 ⁰ C until the reaction was complete, cooled to RT and 7.5 L of water was added. The organic phase was separated, washed with 5 L of water and then concentrated. The oily residue was mixed twice with 3 L IPAC and distilled off. The residue was then dissolved hot in 7 L IPAC and cooled slowly to room temperature. The crystallized solid was filtered off, washed with 2 L IPAC and TBME and dried at 50 ⁰ C. Yield: 690 g (69% of theory) ESI-MS: m / z = 353 (M + H) ⁺ HPLC grade: 95.6 FL%; Column: Prontosil 120-5-C18

Example 4: 1-Piperidin-4-yl-1,3-dihydro-imidazo [4,5-b] pyridin-2-one

690 g (1.96 mol) of 4- (2-oxo-2,3-dihydro-imidazo [4,5-o-pyridin-1-yl) -piperidine-1-carboxylic acid benzyl ester were dissolved in 5.4 L (2.8 L / mol ) Methanol and hydrogenated with complete addition of 46 g of Pd / C (10%, 6.6 wt.%) At 60 ⁰ C and a hydrogen pressure of 60 psi to the complete hydrogen uptake. The catalyst was filtered off. From the filtrate, 4 L of methanol were distilled off. 2 L of methylcyclohexane were added and a further 1.5 L of solvent were distilled off. The suspension obtained was suction filtered, the residue washed with methylcyclohexane and dried at 40 ⁰ C. Yield: 446 g (100% of theory) of ESI-MS: m / z = 219 (M + H) ⁺

Example 5: 1-Piperidin-4-yl-1,3-dihydro-imidazo [4,5-b] pyridin-2-one dihydrochloride

63.8 g (0.181 mol) of 4- (2-oxo-2,3-dihydro-imidazo [4,5-b] pyridin-1-yl) -piperidine-1-carboxylic acid benzyl ester were dissolved in 0.5 l of methanol and added of 6.3 g Pd / C

(10%, 10% by weight) hydrogenated at 60 ° C and a hydrogen pressure of 60 psi until fully hydrogen uptake. The catalyst was filtered off and washed with 50 ml of methanol. The filtrate was mixed with 45.3 ml of ethanolic hydrochloric acid (10 mol / L) and the product crystallized out. The solid was filtered off, washed with methanol and dried. Yield: 47.6 g (90% of theory) ESI-MS: m / z = 219 (M + H) ⁺

Claims

1. Process for the preparation of compounds of the formula I. O NH x n HCl HN in which n represents one of the numbers O, 1 or 2, comprising the steps of: (A) Coupling of a compound of general formula II

in LG represents a leaving group, with a compound of general formula III in which Ar represents an unsubstituted or substituted phenyl group which is selected from the group consisting of phenyl, 2-chlorophenyl, 2-bromophenyl, 2,4-dichlorophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 2,4,6- Trimethylphenyl and 4-nitrophenyl, in a solvent and in the presence of an acid and a reducing agent; (B) Reaction of a compound of general formula IV obtained under (A)

■ (iv) in the LG is a leaving group as described above and Ar represents a phenyl group as described above, with chlorosulfonyl isocyanate, NaOCN, phosgene / NH ₃ , triphosgene / NH ₃ , carbonyldiimidazole (CDI) / NH ₃ or carbonyldiazole (CDT) / NH ₃ in a solvent; (C) Cyclization of a compound of general formula V obtained under (B)

in LG is a leaving group as described above and Ar is a phenyl group as described above in the presence of a catalyst and a base in a solvent, optionally adding a ligand to the catalyst; (D) Reaction of a compound of general formula VI obtained under (C)

Ar is a phenyl group as described above, by addition of a reducing agent in a polar organic solvent; and optionally isolating a compound of the formula I obtained under (D)

, (I) as base (n = 0), or in the form of a hydrochloride (n = 1 or 2) by adding an appropriate amount of hydrochloric acid. 2. A process for the preparation of compounds of the formula I according to claim 1, wherein LG is selected from the group consisting of a fluorine, chlorine, bromine or Iodine atom or the triflate group (-OSO ₂ CF ₃ ). 3. A process for the preparation of compounds of formula I according to claim 1, wherein the catalyst in step (C) is selected from the group consisting of palladium acetate, palladium (II) chloride, tris (dibenzylideneacetone) dipalladium (Pd ₂ ( dba) ₃ ), bis (dibenzylideneacetone) palladium (Pd (dba) ₂ ), 1,1'-bis (diphenylphosphino) ferrocenedichloro-palladium (II) (Pd (DPPF)), palladium (II) trifluoroacetate and bis (acetonitrile) dichloro-palladium (II). 4. A process for the preparation of compounds of formula I according to claim 1, wherein the catalyst in step (C) is palladium acetate. 5. A process for the preparation of compounds of formula I according to claim 1, wherein the ligand in step (C) is selected from 1,4-bis (diphenylphosphino) butane (DPPB), 9,9-dimethyl-4,4-bis ( diphenylphosphino) xanthene (xantphos) and 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (x-phos). A process for the preparation of compounds of formula I according to claim 1, wherein the ligand in step (C) is 1,4-bis (diphenylphosphino) butane (DPPB). 7. A process for the preparation of compounds of the formula I according to claim 1, wherein the base in step (C) is selected from the group consisting of sodium bicarbonate or potassium bicarbonate. 8. A process for the preparation of compounds of formula I according to claim 1, wherein the solvent in step (C) is selected from the group consisting of n-propanol, n-butanol, iso-butanol, n-amyl alcohol, iso-amyl alcohol , tert-amyl alcohol and tert-butanol. 9. A process for the preparation of compounds of formula I according to claim 1, wherein the reducing agent in step (D) is selected from the group consisting of palladium / carbon and rhodium / carbon. 10. A process for the preparation of compounds of formula I according to claim 1, wherein the solvent in step (D) is selected from the group consisting of methanol, ethanol, THF and ethyl acetate. 11. A process for the preparation of compounds of the formula I according to any one of claims 1 to 10, wherein a compound obtained under (A) of the general formula IV

is isolated. 12. A process for the preparation of compounds of the formula I according to one of Claims 1 to 10, wherein a compound of the general formula V obtained under (B)

is isolated. 13. A process for the preparation of compounds of the formula I according to any one of claims 1 to 10, wherein a compound obtained under (C) of the general formula VI

is isolated. 14. The method according to any one of claims 1 to 13, wherein the cyclization in step (C) in a solvent selected from the group consisting of n-propanol, n-butanol, iso-butanol, n-amyl alcohol, iso-amyl alcohol, tert-amyl alcohol, and tert-butanol, is heated and then distilled off a volume of 10-30% of the liquid portion. 15. The method of claim 14 wherein after distilling off the remaining liquid volume 0.01-0.2% water are added. 16. Compound of the general formula III

wherein Ar represents a phenyl group selected from the group consisting of phenyl, 2-chlorophenyl, 2-bromophenyl, 2,4-dichlorophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 2,4,6-trimethylphenyl and 4-nitrophenyl. 17. Compound of the general formula IV

■ (iv) wherein Ar represents a phenyl group selected from the group consisting of phenyl, 2-chlorophenyl, 2-bromophenyl, 2,4-dichlorophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 2,4,6-trimethylphenyl and 4-nitrophenyl and LG is selected from the group consisting of a fluorine, chlorine, bromine or iodine atom and the triflate group (-OSO ₂ CF ₃ ). 18. Compound of the general formula V

wherein Ar represents a phenyl group selected from the group consisting of phenyl, 2-chlorophenyl, 2-bromophenyl, 2,4-dichlorophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 2,4,6-trimethylphenyl and 4-nitrophenyl and LG is selected from the group consisting of a fluorine, chlorine, bromine or iodine atom and the triflate group (-OSO ₂ CF ₃ ). 19. Compound of the general formula VI

wherein Ar represents a phenyl group selected from the group consisting of phenyl, 2-chlorophenyl, 2-bromophenyl, 2,4-dichlorophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 2,4,6-trimethylphenyl and 4-nitrophenyl.