WO2008074858A1

WO2008074858A1 - Intermediates and process for the production of 5-substituted tricyclic benzimidazoles

Info

Publication number: WO2008074858A1
Application number: PCT/EP2007/064292
Authority: WO
Inventors: Andreas Palmer; Matthias Webel; Christian Scheufler; Bernd Müller; Dieter Haag; Christof Brehm; Maria Vittoria Chiesa; Peter Jan Zimmermann; Wilm Buhr
Original assignee: Nycomed GmbH
Current assignee: Takeda GmbH
Priority date: 2006-12-21
Filing date: 2007-12-20
Publication date: 2008-06-26
Anticipated expiration: 2009-06-21

Abstract

The invention relates to compoun ds of the formula 1-a and 1-b, in which R1, R2, R3, Ar and PG have the meanings as indicated in the description. These compounds are valuable intermediates for the preparation of pharmaceutically active compounds.

Description

INTERMEDIATES AND PROCESSES FOR THE PRODUCTION OF 5-SUBSTITUTED TRICYCLIC BENZIMIDAZOLES

Technical field

The invention relates to compounds, which are valuable intermediates for the preparation of active compounds, a process for the production of these intermediates, to the use of certain catalysts in that process and the use of the intermediates for the production of pharmacologically active compounds.

Background Art

(a) Use of benzimidazole derivatives for the treatment of gastrointestinal disorders:

In the European patent application EP 0266326 (which corresponds to US Patent 5,106,862), benzimidazole derivatives having a broad variety of substituents are disclosed which are said to be active as anti-ulcer agents. In the international patent application WO 97/47603 (which corresponds to the US Patent 6,465,505), benzimidazole derivatives having a very specific substitution pattern are disclosed, which are said to be suitable for inhibition of gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases.

In the International Patent Application WO 04/054984, benzimidazole derivatives with a variety of substituents are disclosed, which are said to be active as anti-ulcer agents.

The international patent application WO 04/087701 describes cyclic benzimidazoles, which inhibit gastric acid secretion and possess excellent gastric and intestinal protective properties. Enantiopure pharmaceutically active compounds of that type are produced from enantiopure precursors, which can be obtained by an asymmetric hydrogenation of prochiral starting materials using a chiral hydrogenation catalyst.

The international patent applications WO 05/058893, WO 05/103057, WO 05/121 139, WO 06/037748, WO 06/037759 and WO 06/100255 describe tricyclic benzimidazole derivatives having different substitution patterns at the heterocyclic core structure, which compounds likewise inhibit gastric acid secretion and possess excellent gastric and intestinal protective properties.

The international patent application WO 05/058325 describes tricyclic imidazopyridine derivatives, which inhibit gastric acid secretion and possess excellent gastric and intestinal protective properties. Enantiopure compounds of that type are produced from enantiopure precursors, which can be obtained by an asymmetric hydrogenation of prochiral starting materials using a chiral hydrogenation catalyst. The international patent application WO 05/058894 describes the synthesis of enantiopure hydroxy intermediates which can be further transformed into pharmaceutically active imidazopyridine derivatives, for example those from described in WO 05/058325. The enantiopure hydroxy intermediates are obtained from prochiral ketone precursors by an asymmetric catalytic hydrogenation reaction using chiral hydrogenation catalysts.

(b) Asymmetric reduction of carbonyl compounds to alcohols in the presence of homogenous hydrogenation catalysts:

The European patent application EP 0718265 discloses a method for the reduction of carbonyl compounds to alcohols in the presence of a homogeneous hydrogenation catalyst, a base, and a nitrogen-containing organic compound. More specifically, a system consisting of a transition metal complex of a Vlll-group metal (preferably Rh, Ru, Ir, Pd, Pt), a hydroxide of an alkali metal or an alkali earth metal or a quarternary ammonium salt, and an amine is employed for this transformation. The reduction of carbonyl compounds can be conducted in an asymmetric manner when optically active bis(diarylphosphane) and diamine ligands are used. Specific examples for suitable ligands comprise BINAP (2,2'-bis(diphenylphosphanyl)-1 ,V- binaphthyl), ToIBINAP (2,2'-bis(di-4-tolylphosphanyl)-1 ,1'-binaphthyl), H₈BINAP (2,2'- bis(diphenylphosphanyl)-5,6,7,8,5',6',7',8'-octahydro-[1 ,1 ']-binaphthyl), CHIRAPHOS (2,3- bis(diphenylphosphanyl)butane), DPEN (1 ,2-diphenylethylenediamine), 1 ,2-dicyclohexylethylenediamine, DAMEN (1 ,1-di(4-anisyl)-2-methyl-1 ,2-ethylenediamine), DAIBEN (1 , 1-di(4-anisyl)-2-isobutyl-1 , 2- ethylenediamine) and DAIPEN (1 ,1-di(4-anisyl)-2-isopropyl-1 ,2-ethylenediamine). In the following description, ligands belonging to the structural classes of bis(diarylphosphanes) and diamines are represented by the generic formula PP and NN, respectively.

In a typical experimental procedure, the carbonyl derivative is dissolved in isopropanol and hydrogenated (4-50 atm hydrogen pressure, 28 ⁰C, 1-16 hours) in the presence of potassium hydroxide and a homogenous hydrogenation catalyst, which might be formed in situ, for example from (S,S)-DPEN and RuCI₂[( S)-BINAP] (DMF)_n. The method is described in more detail in J. Am. Chem. Soc. 1995, 117, 2675- 2676 (T. Ohkuma, H. Ooka, S. Hashiguchi, T. Ikariya, R. Noyori), J. Am. Chem. Soc. 1995, 117, 10417- 10418 (T. Ohkuma, H. Ooka, S. Hashiguchi, T. Ikariya, R. Noyori), J. Am. Chem. Soc. 1998, 120, 1086-1087 (T. Ohkuma, H. Doucet, T. Pham, K. Mikami, T. Korenaga, M. Terada, R. Noyori) and in the patent applications JP 10273456 and EP 901997.

In a modification of this procedure, the ternary system described above is replaced by a pure ruthenium complex of the generic formula RuXY[PP][NN], where X and Y represent anionic ligands, like e. g. halogen or hydride, and [PP] / [NN] stands for a bis(diarylphosphane) / diamine ligand. The complex RuCI₂[(S)- BINAP] [(S)-DPEN] represents a specific example for a hydrogenation pre-catalyst. The use of preformed catalyst complexes offers several advantages, like increased reaction rates, higher productivity, and increased stability against air and moisture. The synthesis and the use of these complexes are described - inter alia - in Angew. Chem. 1998, 110, 1792-1796 (H. Doucet, T. Ohkuma, K. Murata, T. Yokazawa, M. Kozawa, E. Katayama, A. F. England, T. Ikariya, R. Noyori) and in the patent application JP 1189600.

The scope of the catalyst system RuXY[PP][NN] has been investigated thoroughly. In one aspect, these efforts resulted in the discovery of immobilized hydrogenation catalysts, which allow catalyst recycling and an easier work-up of the reaction (see e. g. WO 02/062809, WO 04/084834, US 2004192543). In another aspect, catalysts were found which permit an (asymmetric) reduction of carbonyl compounds in the absence of a base. These catalysts (X = H, Y = BH₄) can be prepared easily by reduction of the corresponding pre- catalysts (X = Y = Cl) with sodium borohydride and are suitable for the preparation of alcohols containing acid-labile groups, like e. g. ester functions. The synthesis and the use of these complexes are described in the patent applications US 6720439, JP 2003104993, and JP 2004238306.

Hydrogenation catalysts of the structural class RuCI₂[PP][NN], where [PP] is an optically pure (substituted) BINAP derivative and [NN] is an optically active 1 ,2-diamine have been used for the asymmetric reduction of ketones and imines bearing a large variety of functional groups. Nevertheless, considerable efforts have been devoted to identify hydrogenation catalysts with structurally different ligands [PP] and / or [NN] (for a representative list of ligands see e. g. R. Noyori, T. Ohkuma Angew. Chem. 2001 , 113, 40-75, H.-U. Blaser, C. Malan, B. Pugin, F. Spindler, H. Steiner, M. Studer Adv. Synth. Catal. 2003, 345, 103-151 , and WO 05/007662). The synthesis of a family of ligands [PP], which has been found to be particularly suitable for the asymmetric reduction of carbonyl compounds, has been disclosed in Tetrahedron Lett. 2002, 43, 1539-1543 (J. Wu, H. Chen, W. H. Kwok, K. H. Lam, Z. Y. Zhou, C. H. Yeung, A. S. C. Chan). The preparation of hydrogenation catalysts RuCI₂[PP][NN] containing these new ligands [P-Phos (2,2',6,6'-tetramethoxy-4,4'- bis(diphenylphosphino)-3,3'-bipyridinyl), Tol-P-Phos (2,2',6,6'-tetramethoxy-4,4'-bis[di(p-tolyl)phosphino]- 3,3 -bipyridinyl), Xyl-P-Phos (2,2',6,6'-tetramethoxy-4,4'-bis[di(3,5-dimethylphenyl)phosphino]-3,3'- bipyridinyl)] in combination with a 1 ,2-diamine is described in J. Org. Chem. 2002, 67, 7908-7910 (J. Wu, H. Chen, W. Kwok, R. Guo, Z. Zhou, C. Yeung, A. S. C. Chan) and in Chem. Eur. J. 2003, 9, 2963-2968 (J. Wu, J. -X. Ji, R. Guo, C-H. Yeung, A. S. C. Chan). Furthermore, it has been demonstrated that a wide variety of aromatic and heteroaromatic ketones can be hydrogenated with excellent enantioselectivities. Typically, these reactions are performed in isopropanol in the presence of potassium ferf-butoxide using substrate to catalyst ratios (S/C-ratios) up to 100.000:1 and a hydrogen pressure of 1 bar to 400 psi. The new catalysts, like e. g. frans-RuCy^-Xyl-P-Phos^fi^-DPEN], are said to possess favourable properties.

(c) Asymmetric reduction of carbonyl compounds to alcohols by transfer hydrogenation in the presence of chiral amino alcohols:

The asymmetric reduction of carbonyl compounds by transfer hydrogenation is a well-established method for the synthesis of chiral alcohols and has been reviewed in literature (e. g. M. J. Palmer, M. Wills Tetrahedron: Asymmetry 1999, 10, 2045-2061 ; C. Malan, B. Pugin, F. Spindler, H. Steiner, M. Studer Adv. Synth. Catal. 2003, 345, 103-151 ). The transfer hydrogenation reaction is characterized by its procedural simplicity, the avoidance of hazardous reagents, and a distinct reactivity and chemo- and enantioselectivity. In the presence of transition metal complexes, the transfer hydrogenation reaction generally proceeds in a stepwise manner by way of a putative metal hydride, which then undergoes hydride transfer with a coordinated ketone (see R. Noyori, S. Hashiguchi Ace. Chem. Res. 1997, 30, 97-102). In 1991 , Backvall performed the [RuCI₂(PPh₃)₃]-catalyzed transfer hydrogenation of ketones in the presence of catalytic amounts of sodium hydroxide and discovered that the added base dramatically increased the activity of the catalyst (R. L. Chowdhury, J.-E. Backvall J. Chem. Soc, Chem. Commun. 1991 , 1063-1064). 2-Propanol (generally used with sodium or potassium hydroxide as a base) and formic acid (generally used as an azeotrope with triethylamine) constitute the hydrogen donors that are most commonly used in transfer hydrogenation reactions. In recent years, the asymmetric transfer hydrogenation in water using the formate anion as hydrogen donor and base, has emerged (see X. Wu, J. Xiao Chem. Commun. 2007, 2449-2466). Many ligands, which are generally used with rhodium, iridium, or ruthenium metals, have been reported for the enantioselective transfer hydrogenation of ketones (see e. g. M. J. Palmer, M. Wills Tetrahedron: Asymmetry 1999, 10, 2045-2061 ; X. Wu, J. Xiao Chem. Commun. 2007, 2449-2466). R. Noyori and coworkers first described the use of chiral amino alcohols as ligands for ruthenium-catalyzed asymmetric transfer hydrogenations (J. Takehara, S. Hashiguchi, A. Fujii, S. Inoue, T. Ikariya, R. Noyori Chem. Commun. 1996, 233-234). An extensive study of chiral amino alcohols as ligands for this type of reaction was conducted by J.-F. Carpentier et al. (K. Everaere, A. Mortreux, M. Bulliard, J. Brussee, A. v. d. Gen, G. Nowogrocki, J.-F. Carpentier Eur. J. Org. Chem. 2001 , 275-291 ). There are no literature precedents with regard to the use of 2-substituted 2-amino-1 ,1-diarylethanols as chiral ligands for ruthenium-catalyzed asymmetric transfer hydrogenations.

Disclosure of Invention

Technical problem

The technical problem underlying the present invention is to provide a process for the preparation of intermediates, which are useful for the preparation of enantiomers of 5-substituted tricyclic benzimidazole derivatives, which can be used in therapy.

Technical solution

It has now been found that 4-hydroxy-5-[(3f?)-3-aryl-3-hydroxy-propyl)-1 /-/-benzimidazole derivatives can be prepared by an asymmetric catalytic hydrogenation reaction from the corresponding prochiral ketones, in which the phenolic hydroxy group is protected by a suitable protective group by using a reaction sequence which comprises

(a) an asymmetric catalytic hydrogenation reaction of 4-hydroxyprotected derivatives of 5-[3-aryl-3- oxopropyl]-1 /-/-benzimidazoles using RuCI₂[(S)-Xyl-P-Phos][( S)-DAIPEN] as hydrogenation catalyst and

(b) cleavage of the protective group. Furthermore, it has been found that 4-hydroxy-5-[(3S)-3-aryl-3-hydroxy-propyl)-1 /-/-benzimidazole derivatives can be prepared by an asymmetric catalytic hydrogenation reaction from the corresponding prochiral ketones, in which the phenolic hydroxy group is protected by a suitable protective group by using a sequence which comprises

(a) an asymmetric catalytic hydrogenation reaction of 4-hydroxyprotected derivatives of 5-[3-aryl-3- oxopropyl]-1 H-benzimidazoles using RuCI₂[( fl)-Xyl-P-Phos][( R)-DAIPEN] as hydrogenation catalyst and

(b) cleavage of the protective group.

Furthermore it has been found that 4-hydroxy-5-[(3R)-3-aryl-3-hydroxy-propyl)-1 /-/-benzimidazole derivatives can be prepared by an asymmetric catalytic transfer hydrogenation reaction from the corresponding prochiral ketones, in which the phenolic hydroxy group is protected by a suitable protective group by using a sequence which comprises a) an asymmetric catalytic hydrogenation reaction of 4-hydroxyprotected derivatives of 5-[3-aryl-3- oxopropyl]-1 /-/-benzimidazoles using a catalyst system comprising a RuCI₂[η⁶-arene]₂ precatalyst and an aminoalcohol of the formula A

H₂N_. OH

H«' ^■7/ ( 1 ^■■"• iRb (A) Ra Rb wherein arene is benzene or benzene substituted by one or two substituents from the group consisting of 1-4C-alkoxy and 1-4C-alkyl Ra is 1-7C-alkyl

Rb is phenyl or phenyl substituted by a 1-4C-alkoxy or 1-4C-alkyl group b) cleavage of the protective group.

Furthermore it has been found that 4-hydroxy-5-[(3S)-3-aryl-3-hydroxy-propyl)-1 H-benzimidazole derivatives can be prepared by an asymmetric catalytic transfer hydrogenation reaction from the corresponding prochiral ketones, in which the phenolic hydroxy group is protected by a suitable protective group by using a sequence which comprises a) an asymmetric catalytic hydrogenation reaction of 4-hydroxyprotected derivatives of 5-[3-aryl-3- oxopropyl]-1 /-/-benzimidazoles using a catalyst system comprising a RuCI₂[η⁶-arene]₂ precatalyst and an aminoalcohol of the formula B

wherein arene is benzene or benzene substituted by one or two substituents from the group consisting of 1-4C-alkoxy and 1-4C-alkyl Ra is 1-7C-alkyl Rb is phenyl or phenyl substituted by a 1-4C-alkoxy or 1-4C-alkyl group b) cleavage of the protective group.

The invention therefore relates in a first aspect (aspect a) to compounds of the formula 1-a

where in a first group of compounds R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl or mono- or di-1-4C-alkylamino, R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-

4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, fluoro-1-4C-alkyl, I^C-alkoxy-I^C-alkoxy-I^C- alkyl, 1-4C-alkoxy-1-4C-alkyl wherein the 1-4C-alkoxy is substituted by a SiR8R9R10 radical, 1-4C- alkylcarbonyl, aryl-CH₂-oxycarbonyl, R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C- alkoxy-1-4C-alkyl, I^C-alkoxy-I^C-alkoxy-I^C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-

4C-alkoxy, 1-4C-alkylcarbonylamino, 1-4C-alkylcarbonyl-N-1-4C-alkylamino, 1-4C-alkoxy-1-4C- alkylcarbonylamino or the group -CO-NR31 R32, where

R31 is hydrogen, hydroxy, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 1-4C-alkoxy and

R32 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where

R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxy-pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, 1 ,2,3-triazolyl, indolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl or pyrimidinyl, wherein

R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, aryloxy-1-4C- alkyl, halogen, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C- alkoxycarbonylamino or aryl-1-4C-alkoxy-1-4C-alkyl,

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl,

R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, or where in a second group of compounds

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkyl-1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkyl-1-4C-alkyl,

R3 is either a group -CO-NR31 R32, where

R31 is 3-7C-cycloalkyl substituted by one or more substituents S1 , 3-7C-cycloalkyl-1-4C-alkyl optionally substituted by one or more substituents S1 , 1-4C-alkoxy, aryl, 1-(tetrahydrofuran-2-ylmethyl), (tetrahydro-2H-pyran-2-ylmethyl), (1-4C-alkylthio)-1-4C-alkyl, oxo-1-4C-alkyl or 2-4C-alkynyl, wherein aryl is an aromatic residue substituted by R4, which is selected from the group consisting of phenyl and thienyl and wherein R4 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or halogen, or where R31 is a residue selected from the group consisting of

and

R32 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl or where

R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, which bear each one or more substituent(s) S1 , with the proviso that if R31 and R32 together including the nitrogen atom to which both are bonded represent a pyrrolidino group, monosubstitution with S1 = hydroxy is excluded, or R3 is a residue selected from the group consisting of

whereby

51 is 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, hydroxyl or halogen and

52 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

Ar is an aromatic residue substituted by R5 and R6, which is selected from the group consisting of phenyl and thienyl wherein

R5 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or halogen, and

R6 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or halogen. and where in the first group of compounds and in the second group of compounds

PG is 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxy-1-4C-alkyl wherein the 1-4C-alkoxy is substituted by a SiR8R9R10 radical; tetrahydropyran, tetrahydrofuran, aryl-1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkylcarbonyl, aryl-carbonyl, 1-

4C-alkoxycarbonyl, aryl-1-4C-alkylcarbonyl, aryl-1-4C-alkoxycarbonyl, a radical SiR8R9R10 or a radical SO₂-R11 wherein

R8, R9, R10 are independently from each other 1-7C-alkyl, aryl or aryl-1-4C-alkyl,

R11 is 1-4C-alkyl or aryl and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, halogen, trifluoromethyl and nitro.

One subgroup of compounds according to aspect a relates to the first group of compounds, that is to compounds of the formula 1-a, in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl or mono- or di-1-4C-alkylamino, R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-

R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, aryloxy-1-4C- alkyl, halogen, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, "MC-alkoxycarbonylamino, 1-4C-alkoxy-1-4C- alkoxycarbonylamino or aryl-1-4C-alkoxy-1-4C-alkyl,

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl,

R6 is hydrogen, 1-4C-alkyl or halogen and

R7 is hydrogen, 1-4C-alkyl or halogen, and

PG is 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxy-1-4C-alkyl wherein the 1-4C-alkoxy is substituted by a SiR8R9R10 radical; tetrahydropyran, tetrahydrofuran, aryl-1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkylcarbonyl, aryl-carbonyl, 1-4C- alkoxycarbonyl, aryl-1-4C-alkylcarbonyl, aryl-1-4C-alkoxycarbonyl, a radical SiR8R9R10 or a radical SO₂- R1 1 wherein

A subgroup of the first group of compounds of aspect a are compounds of the formula 1-a, in which R31 is hydrogen, hydroxy, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and the other substituents are as defined above.

Another subgroup of compounds according to aspect a relates to the second group of compounds. R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkyl-1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkyl-1-4C-alkyl,

R3 is either a group -CO-NR31 R32, where

and

whereby

52 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

R5 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or halogen, and

R6 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or halogen and

PG is 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxy-1-4C-alkyl wherein the 1-4C-alkoxy is substituted by a SiR8R9R10 radical; tetrahydropyran, tetrahydrofuran, aryl-1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkylcarbonyl, aryl-carbonyl, 1- 4C-alkoxycarbonyl, aryl-1-4C-alkylcarbonyl, aryl-1-4C-alkoxycarbonyl, a radical SiR8R9R10 or a radical SO₂-R11 wherein

R8, R9, R10 are independently from each other 1-7C-alkyl, aryl or aryl-1-4C-alkyl, R11 is 1-4C-alkyl or aryl and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, halogen, trifluoromethyl and nitro.

A subgroup of the second group of compounds of aspect a to be mentioned are compounds of the formula 1- a,

R1 is 1-4C-alkyl,

R2 is 1-4C-alkyl,

R3 is the group -CO-NR31 R32, where

R31 is 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-(tetrahydrofuran-2-ylmethyl), (tetrahydro-2H-pyran-2- ylmethyl), (1-4C-alkylthio)-1-4C-alkyl or 2-4C-alkynyl, or where R31 is the residue \\ // ^%

N-N and

R32 is hydrogen or 1-4C-alkyl, or where

R31 and R32 together, including the nitrogen atom to which both are bonded, are an azetidino group, which bears one substituent S1 in 3-position of the azetidino ring, whereby

51 is 1-4C-alkoxy or halogen,

52 is 1-4C-alkyl,

Ar is a phenyl residue substituted by R5 and R6, wherein

R5 is in 2- or 4-position of the phenyl ring and is 1-4C-alkyl or halogen and

R6 is hydrogen.

The invention therefore relates in a second aspect (aspect b) to compounds of the formula 1-b

where in a first group of compounds

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl or mono- or di-1-4C-alkylamino, R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-

4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, fluoro-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxy-1-4C-alkyl wherein the 1-4C-alkoxy is substituted by a SiR8R9R10 radical, 1-4C- alkylcarbonyl, aryl-CH₂-oxycarbonyl, R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-

R32 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxy-pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, 1 ,2,3-triazolyl, indolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl or pyrimidinyl, wherein

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl,

R6 is hydrogen, 1-4C-alkyl or halogen and

R7 is hydrogen, 1-4C-alkyl or halogen, or where in a second group of compounds

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkyl-1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkyl-1-4C-alkyl,

R3 is either a group -CO-NR31 R32, where

and

whereby

52 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

R5 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or halogen, and

R6 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or halogen, and where in the first group of compounds and in the second group of compounds PG is 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxy-1-4C-alkyl wherein the 1-4C-alkoxy is substituted by a SiR8R9R10 radical; tetrahydropyran, tetrahydrofuran, aryl-1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkylcarbonyl, aryl-carbonyl, 1-

One subgroup of compounds according to aspect b relates to the first group of compounds, that is to compounds of the formula 1-b, in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl or mono- or di-1-4C-alkylamino, R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-

4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, fluoro-1-4C-alkyl, I^C-alkoxy-I^C-alkoxy-I^C- alkyl, 1-4C-alkoxy-1-4C-alkyl wherein the 1-4C-alkoxy is substituted by a SiR8R9R10 radical, 1-4C- alkylcarbonyl, aryl-CH₂-oxycarbonyl, R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-

4C-alkoxy, 1-4C-alkylcarbonylamino, 1-4C-alkylcarbonyl-N-1-4C-alkylamino, 1-4C-alkoxy-1-4C- alkylcarbonylamino or the group -CO-NR31 R32, where R31 is hydrogen, hydroxy, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 1-4C-alkoxy and

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl,

R6 is hydrogen, 1-4C-alkyl or halogen and

R7 is hydrogen, 1-4C-alkyl or halogen, and

PG is 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, I^C-alkoxy-I^C-alkoxy-I^C- alkyl, 1-4C-alkoxy-1-4C-alkyl wherein the 1-4C-alkoxy is substituted by a SiR8R9R10 radical; tetrahydropyran, tetrahydrofuran, aryl-1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkylcarbonyl, aryl-carbonyl, 1-4C- alkoxycarbonyl, aryl-1-4C-alkylcarbonyl, aryl-1-4C-alkoxycarbonyl, a radical SiR8R9R10 or a radical SO₂- R1 1 wherein

A subgroup of the first group of compounds of aspect b are compounds of the formula 1-a, in which R31 is hydrogen, hydroxy, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and the other substituents are as defined above.

Another subgroup of compounds according to aspect b relates to the second group of compounds. R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkyl-1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkyl-1-4C-alkyl,

R3 is either a group -CO-NR31 R32, where R31 is 3-7C-cycloalkyl substituted by one or more substituents S1 , 3-7C-cycloalkyl-1-4C-alkyl optionally substituted by one or more substituents S1 , 1-4C-alkoxy, aryl, 1-(tetrahydrofuran-2-ylmethyl), (tetrahydro-2H-pyran-2-ylmethyl), (1-4C-alkylthio)-1-4C-alkyl, oxo-1-4C-alkyl or 2-4C-alkynyl, wherein aryl is an aromatic residue substituted by R4, which is selected from the group consisting of phenyl and thienyl and wherein R4 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or halogen, or where R31 is a residue selected from the group consisting of

and

whereby

52 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

R5 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or halogen, and

R6 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or halogen and

A subgroup of the second group of compounds of aspect b to be mentioned are compounds of the formula 1- b,

R1 is 1-4C-alkyl,

R2 is 1-4C-alkyl,

R3 is the group -CO-NR31 R32, where

R31 is 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-(tetrahydrofuran-2-ylmethyl), (tetrahydro-2H-pyran-2- ylmethyl), (1-4C-alkylthio)-1-4C-alkyl or 2-4C-alkynyl, or where R31 is the residue

\\ // ^% N-N and

R32 is hydrogen or 1-4C-alkyl, or where

51 is 1-4C-alkoxy or halogen,

52 is 1-4C-alkyl,

Ar is a phenyl residue substituted by R5 and R6, wherein

R5 is in 2- or 4-position of the phenyl ring and is 1-4C-alkyl or halogen and

R6 is hydrogen.

Halogen within the meaning of the invention is bromo, chloro and fluoro.

1-4C-Alkyl represents a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group.

3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred. 3-7C-Cycloalkyl-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl groups. Examples which may be mentioned are the cyclo- propylmethyl, the cyclohexylmethyl and the cyclohexylethyl group.

1-4C-Alkoxy represents a group, which in addition to the oxygen atom contains one of the aforementioned 1- 4C-alkyl groups. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy group.

1-4C-Alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned 1-4C-alkoxy groups. Examples which may be mentioned are the methoxymethyl, the methoxyethyl group and the butoxyethyl group.

1-4C-Alkoxycarbonyl (1-4C-alkoxy-CO-) represents a carbonyl group, to which one of the aforementioned 1-4C-alkoxy groups is bonded. Examples which may be mentioned are the methoxycarbonyl (CH₃O-C(O)-), ethoxycarbonyl group (CH₃CH₂O-C(O)-) and the ferf-butoxycarbonyl group.

2-4C-Alkenyl represents a straight-chain or branched alkenyl group having 2 to 4 carbon atoms. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl and the 2-propenyl group (allyl group).

2-4C-Alkynyl represents a straight-chain or branched alkynyl group having 2 to 4 carbon atoms. Examples which may be mentioned are the 2-butynyl, 3-butynyl, and preferably the 2-propynyl, group (propargyl group).

Fluoro-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one or more fluorine atoms. An example which may be mentioned are the trifluoromethyl group, the difluoromethyl, the 2-fluoroethyl, the 2,2-difluoroethyl or the 2,2,2-trifluoroethyl group.

Hydroxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by a hydroxy group. Examples which may be mentioned are the hydroxy methyl, the 2-hydroxyethyl and the 3-hydroxypropyl group. Hydroxy-1-4C-alkyl within the scope of the invention is understood to include 1-4C- alkyl groups with two or more hydroxy groups. Examples which may be mentioned are the 3,4-dihydroxybutyl and in particular the 2,3-dihydroxypropyl group.

Mono- or di-1-4C-alkylamino represents an amino group, which is substituted by one or by two - identical or different - groups from the aforementioned 1-4C-alkyl groups. Examples which may be mentioned are the dimethylamino, the diethylamino and the diisopropylamino group.

Mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl represents a 1-4C-alkylcarbonyl group, which is substituted by a mono- or di-1-4C-alkylamino groups. Examples, which may be mentioned, are the dimethylamino- methylcarbonyl and the dimethylamino-ethylcarbonyl group. 1-4C-Alkoxy-1-4C-alkyl wherein the 1-4C-alkoxy is substituted by a SiR8R9R10 radical represents an 1-4C- alkoxy-1-4C-alkyl group in which the alkoxy-group is substituted by a silyl group. A silyl group in this regard is a Si atom to which are attached three identical or different substiutents selected from 1-4C-alkyl or aryl groups. Examples which may be mentioned are the 2-(trimethylsilyl)-ethoxymethyl, the (phenyldimethylsilyl)methoxymethyl or the 1-[2-(trimethylsilyl)ethoxy]ethyl groups.

Aryl-CH₂-oxycarbonyl represents an CH₂-oxycarbonyl group (CH₂-O-C(O)) which is substituted by an above mentioned aryl group. An example which may be mentioned is the benzyloxycarbonyl group.

1-4C-Alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by a further 1-4C-alkoxy group. Examples which may be mentioned are the groups 2-(methoxy)ethoxy (CH₃-O-CH₂-CH₂-O-) and 2-(ethoxy)ethoxy (CH₃-CH₂-O-CH₂-CH₂-O-).

1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkoxy-1-4C-alkyl groups, which is substituted by one of the aforementioned 1-4C-alkoxy groups. An example which may be mentioned is the group 2-(methoxy)ethoxymethyl (CH₃-O-CH₂-CH₂-O-CH₂-).

Fluoro-1-4C-alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by a fluoro-1-4C-alkoxy group. Fluoro-1-4C-alkoxy in this case represents one of the aforementioned 1-4C- alkoxy groups, which substituted by one or more fluorine atoms. Examples of fluoro-substituted 1-4C-alkoxy groups which may be mentioned are the 2-fluoro-ethoxy, 1 ,1 ,1 ,3,3,3-hexafluoro-2-propoxy, the 2- trifluoromethyl-2-propoxy, the 1 ,1 ,1-trifluoro-2-propoxy, the perfluoro-tert-butoxy, the 2,2,3,3,4,4,4- heptafluoro-1-butoxy, the 4,4,4-trifluoro-1-butoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1 ,2,2-trifluoroethoxy, in particular the 1 ,1 ,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy group. Examples of fluoro-1-4C-alkoxy-1-4C-alkyl radicals which may be mentioned are, 1 ,1 ,2,2-tetrafluoroethoxymethyl, the 2,2,2-trifluoroethoxymethyl, the trifluoromethoxymethyl, 2-fluoroethoxyethyl, the 1 ,1 ,2,2-tetrafluoroethoxyethyl, the 2,2,2-trifluoroethoxyethyl, the trifluoromethoxyethyl and preferably the difluoromethoxymethyl and the difluoromethoxyethyl radicals.

1-4C-Alkylcarbonylamino represents an amino group to which a 1-4C-alkylcarbonyl group is bonded. Examples which may be mentioned are the propionylamino (C₃H₇C(O)NH-) and the acetylamino group (acetamido group) (CH₃C(O)NH-).

1-4C-Alkylcarbonyl-N-1-4C-alkylamino represents an 1-4C-alkylamino group to which a 1-4C-alkylcarbonyl group is bonded. Examples which may be mentioned are the propionyl-N-methylamino (C₃H₇C(O)NCH₃-) and the acetyl-N-methylamino group (CH₃C(O)NCH₃-) . 'MC-Alkoxy-'MC-alkylcarbonylamino represents a 1-4C-alkylcarbonylamino group to which a 1-4C-alkoxy group is bonded. Examples which may be mentioned are the methoxy-propionylamino (CH₃O-C₃H₆C(O)NH-) and the methoxy-acetylamino group (CH₃O-CH₂C(O)NH-).

Hydroxy-pyrrolidino represents a pyrrolidino group, which is substituted by a hydroxy group. Examples, which may be mentioned, are the 2-hydroxypyrrolidino and the 3-hydroxypyrrolidino groups.

N-1-4C-alkylpiperazino represents a piperazino group, in which one of the piperazino nitrogen atoms is substituted by one of the aforementioned 1-4-C-alkyl groups. Examples, which may be mentioned, are the A- methylpiperazino, the 4-ethylpiperazino and the 4-iso-propylpiperazino groups.

1-7C-Alkyl represents a straight-chain or branched alkyl group having 1 to 7 carbon atoms. Examples which may be mentioned are the heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group.

Groups Ar which may be mentioned are, for example, the following substituents: 4-acetoxyphenyl, 4-acetamidophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-benzyloxyphenyl, 4-benzyl- oxyphenyl, 3-benzyloxy-4-methoxyphenyl, 4-benzyloxy-3-methoxyphenyl, 3,5-bis(trifluoromethyl)phenyl, A- butoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-chloro-6-fluorophenyl, 3-chloro-4-fluoro- phenyl, 2-chloro-5-nitrophenyl, 4-chloro-3-nitrophenyl, 3-(4-chlorophenoxy)phenyl, 2,4-dichlorophenyl, 3,4- difluorophenyl, 2,4-dihydroxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxy-5-hydroxyphenyl, 2,5- dimethylphenyl, 3-ethoxy-4-hydroxyphenyl, 2-fluorophenyl, 4-fluorophenyl, 4-hydroxy phenyl, 2-hydroxy-5- nitrophenyl, 3-methoxy-2-nitrophenyl, 3-nitrophenyl, 2,3,5-trichlorophenyl, 2,4,6-trihydroxyphenyl, 2,3,4- trimethoxyphenyl, 2-hydroxy-1-naphthyl, 2-methoxy-1-naphthyl, 4-methoxy-1-naphthyl, 1-methyl-2-pyrrolyl, 2-pyrrolyl, 3-methyl-2-pyrrolyl, 3,4-dimethyl-2-pyrrolyl, 4-(2-methoxycarbonylethyl)-3-methyl-2-pyrrolyl, 5- ethoxycarbonyl-2,4-dimethyl-3-pyrrolyl, 3,4-dibromo-5-methyl-2-pyrrolyl, 2,5-dimethyl-1-phenyl-3-pyrrolyl, 5- carboxy-3-ethyl-4-methyl-2-pyrrolyl, 3,5-dimethyl-2-pyrrolyl, 2,5-dimethyl-1-(4-trifluoromethylphenyl)-3- pyrrolyl, 1-(2,6-dichloro-4-trifluoromethylphenyl)-2-pyrrolyl, 1-(2-nitrobenzyl)-2-pyrrolyl, 1-(2-fluorophenyl)-2- pyrrolyl, 1-(4-trifluoromethoxyphenyl)-2-pyrrolyl, 1-(2-nitrobenzyl)-2-pyrrolyl, 1-(4-ethoxycarbonyl)-2,5- dimethyl-3-pyrrolyl, 5-chloro-1 ,3-dimethyl-4-pyrazolyl, 5-chloro-1-methyl-3-trifluoromethyl-4-pyrazolyl, 1-(4- chlorobenzyl)-5-pyrazolyl, 1 ,3-dimethyl-5-(4-chlorphenoxy)-4-pyrazolyl, 1-methyl-3-trifluomethyl-5-(3- trifluoromethylphenoxy)-4-pyrazolyl, 4-methoxycarbonyl-1-(2,6-dichlorophenyl)-5-pyrazolyl, 5-allyloxy-1- methyl-3-trifluoromethyl-4-pyrazolyl, 5-chloro-1-phenyl-3-trifluoromethyl-4-pyrazolyl, 3,5-dimethyl-1-phenyl-4- imidazolyl, 4-bromo-1-methyl-5-imidazolyl, 2-butylimidazolyl, 1-phenyl-1 ,2,3-triazol-4-yl, 3-indolyl, 4-indolyl, 7-indolyl, 5-methoxy-3-indolyl, 5-benzyloxy-3-indolyl, 1-benzyl-3-indolyl, 2-(4-chlorophenyl)-3-indolyl, 7- benzyloxy-3-indolyl, 6-benzyloxy-3-indolyl, 2-methyl-5-nitro-3-indolyl, 4,5,6,7-tetrafluoro-3-indolyl, 1-(3,5- difluorobenzyl)-3-indolyl, 1-methyl-2-(4-trifluorophenoxy)-3-indolyl, 1-methyl-2-benzimidazolyl, 5-nitro-2-furyl, 5-hydroxymethyl-2-furyl, 2-furyl, 3-furyl, 5-(2-nitro-4-trifluoromethylphenyl)-2-furyl, 4-ethoxycarbonyl-5- methyl-2-furyl, 5-(2-trifluoromethoxyphenyl)-2-furyl, 5-(4-methoxy-2-nitrophenyl)-2-furyl, 4-bromo-2-furyl, 5- dimethylamino-2-furyl, 5-bromo-2-furyl, 5-sulfo-2-furyl, 2-benzofuryl, 2-thienyl, 3-thienyl, 3-methyl-2-thienyl, 4-bromo-2-thienyl, 5-bromo-2-thienyl, 5-nitro-2-thienyl, 5-methyl-2-thienyl, 5-(4-methoxyphenyl)-2-thienyl, A- methyl-2-thienyl, 3-phenoxy-2-thienyl, 5-carboxy-2-thienyl, 2,5-dichloro-3-thienyl, 3-methoxy-2-thienyl, 2- benzothienyl, 3-methyl-2-benzothienyl, 2-bromo-5-chloro-3-benzothienyl, 2-thiazolyl, 2-amino-4-chloro-5- thiazolyl, 2,4-dichloro-5-thiazolyl, 2-diethylamino-5-thiazolyl, 3-methyl-4-nitro-5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-methyl-2-pyridyl, 3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridyl, 2,6-dichloro-4-pyridyl, 3-chloro- 5-trifluoromethyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 4-(4-chlorophenyl)-3-pyridyl, 2-chloro-5-methoxycarbonyl- 6-methyl-4-phenyl-3-pyridyl, 2-chloro-3-pyridyl, 6-(3-trifluoromethylphenoxy)-3-pyridyl, 2-(4-chlorophenoxy)- 3-pyridyl, 2,4-dimethoxy-5-pyrimidinyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 2-chloro-3-quinolinyl, 2-chloro- 6-methoxy-3-quinolinyl, 8-hydroxy-2-quinolinyl and 4-isoquinolinyl.

1-4C-Alkylcarbonyl represents a group, which in addition to the carbonyl group contains one of the abovementioned 1-4C-alkyl groups. Examples which may be mentioned are the acetyl and the pivaloyl group.

In the definintion of the aryl radical, which is phenyl or substituted phenyl with one, two or three same or different substituents can be attached to the following positions of the phenyl ring. If one subsituent is present, this substituent is in ortho-, meta or para-position. If two substituents are present, these two substituents are in ortho-meta, ortho-para, ortho-ortho^', meta-para or meta-meta^' position. If three substituents are present, these three substituents are in ortho-meta-para, ortho-meta-meta^', ortho-meta- ortho^', ortho-para-meta^', ortho-para-ortho^'or in meta-para-meta^'position.

Aryloxy represents an oxygen atom to which an aryl group is bonded. An example which may be mentioned is the phenoxy radical.

Aryloxy-1-4C-alkyl represents an 1-4C-alkyl group which is substituted by one of the above mentioned aryloxy groups. An example which may be mentioned is the phenyloxy-methyl group.

Aryl-1 -4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the abovementioned aryl groups. An exemplary preferred aryl-1 -4C-alkyl group is the benzyl group.

Aryl-1 -4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the abovementioned aryl groups. An exemplary preferred aryl-1 -4C-alkoxy group is the benzyloxy group.

1-4C-Alkylcarbonylamino represents an amino group to which a 1-4C-alkylcarbonyl group is bonded. Examples which may be mentioned are the propionylamino (C₃H₇C(O)NH-) and the acetylamino group (acetamido group) (CH₃C(O)NH-) . 1-4C-Alkoxycarbonylamino represents an amino group, which is substituted by one of the aforementioned 1-4C-alkoxycarbonyl groups. Examples, which may be mentioned, are the ethoxycarbonylamino and the methoxycarbonylamino group.

1-4C-Alkoxy-1-4C-alkoxycarbonyl represents a carbonyl group, to which one of the aforementioned 1-4C- alkoxy-1-4C-alkoxy groups is bonded. Examples which may be mentioned are the 2-(methoxy)ethoxy- carbonyl (CH₃-O-CH₂CH₂-O-CO-) and the 2-(ethoxy)ethoxycarbonyl group (CH₃CH₂-O-CH₂CH₂-O-CO-).

1-4C-Alkoxy-1-4C-alkoxycarbonylamino represents an amino group, which is substituted by one of the aforementioned 1-4C-alkoxy-1-4C-alkoxycarbonyl groups. Examples which may be mentioned are the 2- (methoxy)ethoxycarbonylamino and the 2-(ethoxy)ethoxycarbonylamino group.

Aryl-1-4C-alkoxy-1-4C-alkyl denotes one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the abovementioned aryl-1-4C-alkoxy radicals. Examples which may be mentioned are the benzyloxymethyl, the p-methoxybenzyloxymethyl, p-nitrobenzyloxymethyl and the o-nitrobenzyloxymethyl radical.

Aryl-1-4C-alkylcarbonyl denotes a carbonyl group to which one of the abovementioned aryl-1-4C-alkyl radicals is attached. An example, which may be mentioned, is the benzylcarbonyl radical.

Aryl-1-4C-alkoxycarbonyl denotes a carbonyl group to which one of the abovementioned aryl-1-4C- alkoxy radicals is attached. An example, which may be mentioned, is the benzyloxycarbonyl radical.

In a first embodiment (embodiment 1 ) of the invention RuCI₂[(S)-Xyl-P-Phos][( S)-DAIPEN] is used as hydrogenation catalyst for the synthesis of 4-hydroxy-5-[(3/^:?)-3-aryl-3-hydroxy-propyl)-1 H-benzimidazole derivatives.

In a second embodiment (embodiment 2) of the invention RuCI₂KR)-XyI-P-PhOSn(R)-DAIPEN] is used as hydrogenation catalyst for the synthesis of 4-hydroxy-5-[(3S)-3-aryl-3-hydroxy-propyl)-1 H-benzimidazole derivatives.

Particular emphasis is given to embodiment 1 according to the invention.

Preferred are those compounds of the formula 1-a according to aspect a and those compounds of the formula 1-b according to aspect b, where

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, fluoro-1-

4C-alkyl, or hydroxy-1-4C-alkyl, R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, hydroxy-

1-4C-alkyl, 1-4C-alkoxycarbonyl, fluoro-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy- 1-4C-alkyl wherein the 1-4C-alkoxy is substituted by a SiR8R9R10 radical, 1-4C-alkylcarbonyl or aryl-

CH₂-oxycarbonyl, R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-

R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxy-pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, Ar is a phenyl, naphthyl, pyrrolyl, thienyl or benzothienyl substituted by R4, R5, R6 and R7, wherein

R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, aryloxy-1-4C- alkyl, halogen, trifluoromethyl, 1-4C-alkylcarbonylamino or aryl-1-4C-alkoxy-1-4C-alkyl,

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen, or trifluoromethyl,

R6 is hydrogen, 1-4C-alkyl or halogen and

R7 is hydrogen, 1-4C-alkyl or halogen, PG is 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxy-1-4C-alkyl wherein the 1-4C-alkoxy is substituted by a SiR8R9R10 radical, tetrahydropyran, tetrahydrofuran, aryl-1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkylcarbonyl, aryl-carbonyl, 1-

Preferred are also those compounds of the formula 1-a according to aspect a and those compounds of the formula 1-b according to aspect b, where

R31 is hydrogen, hydroxy, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alky or 1-4C-alkoxy-1-4C-alkyl and

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen, or trifluoromethyl,

R6 is hydrogen, 1-4C-alkyl or halogen and

Particularly preferred are those compounds of the formula 1-a according to aspect a and those compounds of the formula 1-b according to aspect b, in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or hydroxy-1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl wherein the 1-4C-alkoxy is substituted by a SiR8R9R10 radical, 1-4C-alkylcarbonyl or aryl-CH₂-oxycarbonyl, R3 is carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C- alkoxy-1-4C-alkyl, or the group -CO-NR31 R32, where

R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, aryloxy-1-4C- alkyl, halogen, or aryl-1-4C-alkoxy-1-4C-alkyl,

R5 is hydrogen, 1-4C-alkyl, or halogen,

R6 is hydrogen, 1-4C-alkyl or halogen and

R7 is hydrogen, 1-4C-alkyl or halogen. PG is 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxy-1-4C-alkyl wherein the 1-4C-alkoxy is substituted by a SiR8R9R10 radical, tetrahydropyran, tetrahydrofuran, aryl-1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkylcarbonyl, aryl-carbonyl, 1-

R11 is 1-4C-alkyl or aryl and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents selected from the group consisting of 1-4C-alkyl, 1-4C-alkoxy, halogen, trifluoromethyl, and nitro.

Particularly preferred are also those compounds of the formula 1-a according to aspect a and those compounds of the formula 1-b according to aspect b, in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or hydroxy-1-4C-alkyl,

R31 is hydrogen, hydroxy, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and R32 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where

R5 is hydrogen, 1-4C-alkyl, or halogen,

R6 is hydrogen, 1-4C-alkyl or halogen and

Particular mention is given to those compounds of the formula 1-a according to aspect a and those compounds of the formula 1-b according to aspect b, in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or hydroxy-1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl wherein the 1-4C-alkoxy is substituted by a SiR8R9R10 radical, 1-4C-alkylcarbonyl or aryl-CH₂-oxycarbonyl, R3 is hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, or the group -CO-

NR31 R32, where

R31 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 1-4C- alkoxy and

R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxy-pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, Ar is selected from one of the following groups

R4

wherein

R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, aryloxy-1-4C- alkyl, halogen or aryl-1-4C-alkoxy-1-4C-alkyl, and R5 is hydrogen, 1-4C-alkyl, or halogen, R6 is hydrogen, 1-4C-alkyl, or halogen

PG is 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxy-1-4C-alkyl wherein the 1-4C-alkoxy is substituted by a SiR8R9R10 radical, tetrahydropyran, tetrahydrofuran, aryl-1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkylcarbonyl, aryl-carbonyl, 1- 4C-alkoxycarbonyl, aryl-1-4C-alkylcarbonyl, aryl-1-4C-alkoxycarbonyl, a radical SiR8R9R10 or a radical SO₂-R11 wherein

Particular mention is also given to those compounds of the formula 1-a according to aspect a and those compounds of the formula 1-b according to aspect b, in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or hydroxy-1-4C-alkyl,

NR31 R32, where

R31 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and

R32 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxy-pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,

Ar is selected from one of the following groups

R4

wherein

Emphasis is given to those compounds of the formula 1-a according to aspect a and those compounds of the formula 1-b according to aspect b, in which

R1 is 1-4C-alkyl or 3-7C-cycloalkyl,

R2 is 1-4C-alkyl,

R3 is the group -CO-NR31 R32 where

R31 is 1-7C-alkyl or 1-4C-alkoxy,

R32 is 1-7C-alkyl, or where

R31 and R32 together, including the nitrogen atom to which both are bonded, are a azetidino group, Ar is a group

wherein

R4 is 1-4C-alkyl, R5 is hydrogen, R6 is hydrogen or 1-4C-alkyl

PG is 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxy-1-4C-alkyl substituted by a SiR8R9R10 radical, tetrahydropyran, tetrahydrofuran, aryl-1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkylcarbonyl, aryl-carbonyl, 1-4C-alkoxycarbonyl, aryl-1-4C- alkylcarbonyl, aryl-1-4C-alkoxycarbonyl, a radical SiR8R9R10 or a radical SO₂-R11 wherein

Emphasis is also given to those compounds of the formula 1-a according to aspect a and those compounds of the formula 1-b according to aspect b, in which

R1 is 1-4C-alkyl,

R2 is 1-4C-alkyl,

R3 is the group -CO-NR31 R32 where

R31 is 1-7C-alkyl,

R32 is 1-7C-alkyl, or where

R31 and R32 together, including the nitrogen atom to which both are bonded, are an azetidino group, Ar is a group

wherein

R4 is 1-4C-alkyl, R5 is hydrogen, R6 is hydrogen

Particular emphasis is given to those compounds of the formula 1-a according to aspect a and those compounds of the formula 1-b according to aspect b, in which

R1 is 1-4C-alkyl or 3-7C-cycloalkyl,

R2 is 1-4C-alkyl,

R3 is the group -CO-NR31 R32 where

R31 is 1-7C-alkyl or 1-4C-alkoxy,

R32 is 1-7C-alkyl, or where

wherein

R4 is 1-4C-alkyl, R5 is hydrogen, R6 is hydrogen or 1-4C-alkyl PG is benzyl or 1-4C-alkyl.

Particular emphasis is also given to those compounds of the formula 1-a according to aspect a and those compounds of the formula 1-b according to aspect b, in which

R1 is 1-4C-alkyl,

R2 is 1-4C-alkyl,

R3 is the group -CO-NR31 R32 where

R31 is 1-7C-alkyl,

R32 is 1-7C-alkyl, or where

wherein

R4 is 1-4C-alkyl, R5 is hydrogen, R6 is hydrogen PG is benzyl.

The compounds of the formula 1-a and 1-b according to the invention can be synthesized from corresponding starting compounds, for example according to the reaction schemes given below. The synthesis is carried out in a manner known to the expert, for example as described in more detail in the examples, which follow the schemes.

The compounds of the formula 1-a and 1-b are prepared as outlined in the following scheme 1.1 or 1.2 respectively.

Scheme 1.1 RuCI₂I(S)-XyI-P-PhOs] [(S)-DAIPEN]

RuCI₂I(R)-XyI-P-PhOS] [(R)-DAIPEN]

Prochiral ketones of the formula 2 are reduced to optically pure diols of the formula 1-a by homogenous catalytic hydrogenation using RuCI₂[(S)-Xyl-P-Phos][(S)-DAIPEN].

Prochiral ketones of the formula 2 are reduced to optically pure diols of the formula 1-b by homogenous catalytic hydrogenation using RuCb^^-Xyl-P-Phosj^^-DAIPEN].

Scheme 1.2

Prochiral ketones of the formula 2 are reduced to optically pure diols of the formula 1-a by catalytic transfer hydrogenation in the presence of RuCI₂[η⁶-arene]₂ and an aminoalcohol of the formula A.

Prochiral ketones of the formula 2 are reduced to optically pure diols of the formula 1-b by catalytic transfer hydrogenation in the presence of RuCI₂[η⁶-arene]₂ and an aminoalcohol of the formula B.

The invention therefore further relates in a third aspect (aspect c) to a process of preparing a compound of the formula 1-a comprising a catalytic hydrogenation of a compound of the formula 2 in the presence of RuCI₂[(S)-Xyl-P-Phos][( S)-DAIPEN],

wherein R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-a.

The invention therefore further relates in a fourth aspect (aspect d) to a process of preparing a compound of the formula 1-b comprising a catalytic hydrogenation of a compound of the formula 2 in the presence of RuCI₂[(R)-Xyl-P-Phos][(R)-DAIPEN].,

wherein R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-b.

The invention further relates to the use of RuCI₂[(S)-Xyl-P-Phos][( S)-DAIPEN] as the hydrogenation catalyst in a process according to the present invention for the preparation of compounds of the formula 1-a from compounds of the formula 2, wherein R1 , R2, R3 and Ar have the meanings as indicated in the outset.

The invention further relates to the use of RuCI₂[(f?)-Xyl-P-Phos][(f?)-DAIPEN] as the hydrogenation catalyst in a process according to the present invention for the preparation of compounds of the formula 1-b from compounds of the formula 2, wherein R1 , R2, R3 and Ar have the meanings as indicated in the outset. The asymmetric hydrogenation according to the present invention is performed in a manner known to the expert (see e.g. the documents mentioned in the outset of the present application and the studies described by C. A. Sandoval, T. Ohkuma, K. Muήiz, and R. Noyori in J. Am. Chem. Soc. 2003, 125, 13490-13503). More specifically, the conditions discussed below or in the experimental section are preferably applied. However, it has to be emphasized that the asymmetric hydrogenation of ketones of the formula 2 according to the present invention is not limited to these conditions. Due to his expert knowledge, a person skilled in the art is able to identify reaction conditions suitable for optimal performance of the asymmetric catalytic hydrogenation reaction described in the present invention.

The asymmetric catalytic hydrogenation reaction according to the present invention is advantageously carried out in a suitable organic solvent. Solvents that are to be mentioned are inter alia aliphatic alcohols like for example methanol, ethanol or preferably isopropanol or ferf-butanol. Preferred solvent systems are also mixtures of one, two or three of the aliphatic alcohols mentioned before in any mixing ratio, whereby a mixture of isopropanol and ferf-butanol in any mixing ratio between 0 : 100 vol-% and 100 : 0 vol-% is to be particularly mentioned.

A solvent or a solvent system essentially comprises a specific solvent or a mixture of specific solvents if it contains at least 50 %, in particular at least 70 % of said specific solvent or said mixture of specific solvents. The other components the solvent or the solvent system are further additives such as for example other organic solvents or water.

The presence of other solvents or additives, such as for example toluene, might be beneficial for the course of the reaction. Due to his expert knowledge, these additives and their ratio in comparison to the solvent or the solvent system can be identified by a person skilled in the art.

The asymmetric catalytic hydrogenation reaction according to the present invention is advantageously carried out at temperatures between 0 and 80 ⁰C, preferably between 20 and 80 ⁰C. Below 20 ⁰C, the reaction rate might be low, which might result in long reaction times. Above 80 ⁰C, the reaction might proceed with concomitant decomposition of the hydrogenation catalyst. This might result in incomplete turnover and / or reduced enantioselectivities.

The reaction time depends on many parameters, like e. g. structure of the substrate, substrate to catalyst ratio (S/C-ratio), amount of base, temperature, hydrogen pressure, solvent, hydrogenation apparatus and the like. In general, complete transformation is achieved within a time range of 1 hour to 7 days. Typically, the hydrogenation reaction is conducted over a period of 17-20 hours. A person skilled in the art is able to identify the optimum reaction time for each set of reaction conditions.

The asymmetric catalytic hydrogenation reaction according to the present invention is advantageously carried out at hydrogen pressures between 1 and 200 bars, preferably between 10 and 80 bars. As a general rule, the higher the hydrogen pressure the higher is the reaction rate whereby an increase of the hydrogen pressure does not lead to an erosion of enantioselectivity.

The asymmetric catalytic hydrogenation reaction according to the present invention is carried out in the presence of a base in order to generate the active hydrogenation catalyst and in order to increase the turnover number.

The reaction mixture therefore comprises between 0.0001 and 5, preferably between 0.0005 and 1.1 and particularly between 0.0005 and 0.15 equivalents of an inorganic or organic base (relating to the substrate of the formula 2). Suitable inorganic bases are for example hydroxides, alkoxides or carbonates of alkali metals (caesium, rubidium, potassium, sodium, lithium) or earth alkali metals (magnesium, calcium). Suitable organic bases are for example tertiary amines (e.g. triethylamine) and strong nitrogen bases (e.g phosphazene bases, like e. g. P4-t-Bu, CAS 1 1 1324-04-0). Preferred bases are inorganic bases, such as for example the hydroxides, alkoxides or carbonates of the alkali or earth alkali metals mentioned above. Particular mention may be made of the inorganic bases KOMe, KO¹Pr, LiOH, LiOMe, LiO¹Pr, LiO'Bu, NaOH, NaOMe, NaO¹Pr, and NaO⁴Bu, and especially KOH, KO¹Bu, K₂C0₃ and Cs₂CO₃. The use of the bases KO¹Bu and KOH is particularly preferred.

Preferably, a solution of the corresponding base in one or more of the solvents employed for the hydrogenation reaction - rather than the solid base - is added to the reaction mixture. Specific examples comprise a solution of potassium ferf-butoxide in ferf-butanol or a solution of potassium hydroxide in water.

The asymmetric catalytic hydrogenation reaction according to the present invention is carried out in concentrations of 0.001 to 10 M, preferably 0.01 to 10 M and especially 0.1 to 1 M solutions of the substrate of the formula 2 in the solvent. A high substrate concentration is beneficial for the reaction rate and the person skilled in the art is able to identify the optimum concentration for each substrate of the formula 2 in each solvent system

The molar ratio of the substrate of the formula 2 compared to the catalyst (S/C-ratio) depends inter aha on the structure of the ketone of the formula 2. The S/C-ratio applicable according to the present invention is between 5 : 1 to 100000 : 1 , preferably between 10 : 1 and 50000 : 1 and in particular between 100 : 1 and 10000 : 1. The person skilled in the art is able to identify the optimum S/C-ratio for each substrate of the formula 2.

The sample preparation according to the present invention might be performed as described in the following examples without being limited to these procedures: Under inert atmosphere, a solution of the corresponding base and additional solvent is added to a mixture the ketone of the formula 2 and the hydrogenation pre- catalyst. The reaction solution is purged with hydrogen, hydrogen pressure is applied and the mixture is heated to the corresponding temperature. Alternatively, a suspension of the ketone of the formula 2 in degassed solvent is treated with base. Subsequently, the hydrogenation catalyst is added, followed by application of hydrogen pressure and heating as described above.

The invention particularly relates to a process for the preparation of compounds of the formula 1-a and of the formula 1-b by asymmetric hydrogenation according to the present invention, which is performed in the presence of a base which is selected from KOH, KO¹Bu, K₂CO₃ and Cs₂CO₃, in which the solvent essentially comprises isopropanol or fert-butanol or a mixture of isopropanol and terf-butanol in any mixing ratio between 0 : 100 vol-% and 100 : 0 vol-%, and which is carried out in a homogenous solution containing the ketone of the formula 2 in concentrations between 0.1 and 1 M.

The invention further relates in a fifth aspect (aspect e) to a process of preparing a compound of the formula 1-a comprising a catalytic transfer hydrogenation of a compound of the formula 2

wherein R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-a, in the presence of a RuCI₂[η⁶-arene]₂ precatalyst and an aminoalcohol of the formula A

H₂N OH

_H,..) (...

Rb (A)

Ra Rb wherein arene is benzene or benzene substituted by one or two substituents from the group consisting of 1-4C-alkoxy and 1-4C-alkyl Ra is 1-7C-alkyl

Rb is phenyl or phenyl substituted by a 1-4C-alkoxy or 1-4C-alkyl group

The invention therefore further relates in a sixth aspect (aspect f) to a process of preparing a compound of the formula 1-b comprising a catalytic transfer hydrogenation of a compound of the formula 2

wherein R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-b in the presence of a RuCI₂[η⁶-arene]₂ precatalyst and an aminoalcohol of the formula B

wherein arene is benzene or benzene substituted by one or two substituents from the group consisting of 1-4C-alkoxy and 1-4C-alkyl Ra is 1-7C-alkyl

Rb is phenyl or phenyl substituted by a 1-4C-alkoxy or 1-4C-alkyl group

The invention further relates to the use of the catalyst system described in aspect e as the transfer hydrogenation catalyst in a process according to the present invention for the preparation of compounds of the formula 1-a from compounds of the formula 2, wherein R1 , R2, R3 and Ar have the meanings as indicated in the outset.

The invention further relates to the use of the catalyst system described in aspect f as the transfer hydrogenation catalyst in a process according to the present invention for the preparation of compounds of the formula 1-b from compounds of the formula 2, wherein R1 , R2, R3 and Ar have the meanings as indicated in the outset.

Preferred catalysts for aspect e and aspect f according to the invention are those, wherein arene is benzene or 1-isopropyl-4-methyl-benzene

Ra is isobutyl or isopropyl

Rb is phenyl or 4-methoxyphenyl

In particular the following catalyst systems for aspect e are to be emphasized:

[RuCI₂(benzene)₂]₂ [RuCI₂(I -isopropyl-4-methyl-benzene)₂]₂

[RuCI₂(benzene)₂]₂ [RuCI₂(I -isopropyl-4-methyl-benzene)₂]₂

+

[RuCI₂(benzene)₂]₂ [RuCI₂(I -isopropyl-4-methyl-benzene)₂]₂ +

[RuCI₂(benzene)₂]₂ [RuCI₂(I -isopropyl-4-methyl-benzene)₂]₂ +

For aspect f of the present invention, aminoalcohols of the formula B are to be used. Catalyst systems for aspect f, which are to be emphasized, are those, which correspond to catalyst systems emphasized for aspect e, however with inverse stereochemistry with regard to the substituent Ra of the aminoalcohol to be used.

The asymmetric transfer hydrogenation according to the present invention is performed in a manner known to the expert (see e.g. the documents mentioned in the outset of the present application). More specifically, the conditions discussed below or in the experimental section are preferably applied. However, it has to be emphasized that the asymmetric transfer hydrogenation of ketones of the formula 2 according to the present invention is not limited to these conditions. Due to his expert knowledge, a person skilled in the art is able to identify reaction conditions suitable for optimal performance of the asymmetric transfer hydrogenation reaction described in the present invention. The asymmetric catalytic transfer hydrogenation reaction according to the present invention is advantageously carried out in a suitable organic solvent that might also serve as a hydrogen source. Solvents that are to be mentioned are aliphatic alcohols, like for example 2-propanol, and mixtures of formic acid with a suitable base, like for example the azeotropic mixture of formic acid and triethylamine. The transfer hydrogenation reaction can also be conducted in aqueous solution, using the formate anion, e. g. sodium formate, as a hydrogen source. In the latter case the use of a surfactant, like e. g. SDS (sodium dodecyl sulfate), SDBS (sodium dodecyclbenzenesulfonate), Tween 60, or PEG-1000 is beneficial. Alternatively, a phase transfer catalyst, like e. g. CATB (cetyltrimethylammonium bromide), TEAB (tetraethylammonium bromide), or TBAB (tetrabutylammonium bromide) can be employed. It is also possible to perform the transfer hydrogenation reaction in mixtures of organic solvents or in mixtures of an organic solvent / organic solvents with water. Suitable co-solvents that might be mentioned are e. g. dichloromethane, toluene, and dimethylformamide. Due to his expert knowledge, the most favourable solvent / solvent system can be readily identified by a person skilled in the art.

The asymmetric catalytic transfer hydrogenation reaction according to the present invention is advantageously carried out at temperatures between -40 and 120 ⁰C, preferably between 20 and 80 ⁰C. Below 20 ⁰C, the reaction rate might be low, which might result in long reaction times. Above 80 ⁰C, the reaction might proceed with concomitant decomposition of the hydrogenation catalyst. This might result in incomplete turnover and / or reduced enantioselectivities.

The reaction time depends on many parameters, like e. g. structure of the substrate, substrate to catalyst ratio (S/C-ratio), amount and type of base, temperature, hydrogen source, solvent, and the like. In general, complete transformation is achieved within a time range of 1 hour to 7 days. Typically, the transfer hydrogenation reaction is conducted over a period of 17-20 hours. A person skilled in the art is able to identify the optimum reaction time for each set of reaction conditions.

The asymmetric catalytic transfer hydrogenation reaction according to the present invention is carried out in the presence of a base in order to increase the turnover number.

The reaction mixture therefore comprises between 0.0001 and 5, preferably between 0.0005 and 1.1 and particularly between 0.0005 and 0.15 equivalents of an inorganic or organic base (relating to the substrate of the formula 2). Suitable inorganic bases are for example hydroxides, alkoxides, formates or carbonates of alkali metals (caesium, rubidium, potassium, sodium, lithium) or earth alkali metals (magnesium, calcium). Suitable organic bases are for example tertiary amines (e.g. triethylamine), pyridine and substituted pyridines, and strong nitrogen bases (e.g. phosphazene bases, like e. g. P4-t-Bu, CAS 11 1324-04-0). Preferred bases are inorganic bases, such as for example the hydroxides, alkoxides, formates or carbonates of the alkali or earth alkali metals mentioned above. Particular mention may be made of the inorganic bases K₂CO₃, Cs₂CO₃, potassium formate, KOMe, KO¹Pr, lithium formate, LiOH, LiOMe, LiO¹Pr, LiO'Bu, NaOMe, NaO¹Pr, NaO'Bu and especially KOH, NaOH, KO'Bu, and sodium formate, and of the organic base triethylamine. Depending on the solvent system used for the transfer hydrogenation reaction, the use of the bases NaOH, KO'Bu, KOH, triethylamine, or sodium formate is particularly preferred.

The asymmetric catalytic transfer hydrogenation reaction according to the present invention is carried out in concentrations of 0.001 to 10 M, preferably 0.01 to 5 M and especially 0.05 to 1 M solutions of the substrate of the formula 2 in the solvent. A high substrate concentration is beneficial for the reaction rate and the person skilled in the art is able to identify the optimum concentration for each substrate of the formula 2 in each solvent system.

The molar ratio of the substrate of the formula 2 compared to the catalyst (S/C-ratio) depends inter alia on the structure of the ketone of the formula 2. The S/C-ratio applicable according to the present invention is between 5 : 1 to 100000 : 1 , preferably between 10 : 1 and 50000 : 1 and in particular between 100 : 1 and 10000 : 1. The person skilled in the art is able to identify the optimum S/C-ratio for each substrate of the formula 2.

The sample preparation according to the present invention might be performed as described in the following examples without being limited to these procedure: Under inert atmosphere, a solution of the corresponding base is added to a mixture the ketone of the formula 2 and the ligand (chiral aminoalcohol). The reaction solution is purged with nitrogen, heated to the corresponding temperature, and the pre-catalyst (ruthenium complex) is added. After completion of the reaction, preferably, the reaction mixture is neutralized by addition of an organic or inorganic acid, like e. g. acetic acid or hydrochloric acid. The product is isolated and purified by standard methods known to the person skilled in the art, like e. g. extraction, chromatography, and crystallization.

The invention particularly relates to a process for the preparation of compounds of the formula 1-a and of the formula 1-b by transfer hydrogenation according to the present invention, which is performed in the presence of a ruthenium precursor, a chiral aminoalcohol of the general formula A or B, and a base which is selected from KOH, NaOH and KO'Bu, in which the solvent essentially comprises isopropanol, and which is carried out in a suspension or homogenous solution containing the ketone of the formula 2 in concentrations between 0.05 and 1 M. Transformation of derivatives of the formula 1-a into pharmacologically active enantiopure (8S)-8-aryl- 3,6,7,8-tetrahydro-chromeno[7,8-c(|imidazole derivatives of the formula 3-a can be accomplished by methods which proceed under S_N2 conditions, like for example those methods that are disclosed in WO 04/087701 (Scheme 2).

For this purpose, the hydroxy group in alpha-position to the Ar radical of derivatives of the formula 1-a can be transformed into a suitable leaving group LG, e. g. by esterification with acid halides or sulfonyl chlorides, furnishing intermediates of the formula 4-a. After cleavage of the protective group, e. g. applying conditions described in T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis (3^rd edition), Wiley, New York, 1999, alcohols of the formula 5-a are obtained. Cyclization to pharmacologically active derivatives of the formula 3-a occurs under conditions that are suitable for intramolecular nucleophilic substitution reactions, e.g. heating in a dipolar aprotic solvent like dimethyl sulfoxide or dimethylformamide.

Alternatively, the protective group of derivatives of the formula 1-a can be cleaved first, e.g. applying conditions described in T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis (3^rd edition), Wiley, New York, 1999, and cyclization of the diols of the formula 6-a can be accomplished under Mitsunobu conditions, e. g. using diisopropyl azodicarboxylate and triphenylphosphine in analogy to the process described in WO 04/087701.

Benzimidazoles of the formula 3-a can also be obtained from compounds of the formula 1-b (Scheme 3), e.g. by nucleophilic substitution of the benzylic hydroxy group under S_N2 conditions (inversion of the stereogenic center) using suitable nucleophiles Nu (e. g. halogen, especially chlorine) and S_N2 reaction conditions, which are known to a person skilled in the art, furnishing intermediates of the formula 8-a. After removal of the protective group, the obtained intermediates of the formula 7-a can be transformed into benzimidazoles of the formula 3-a by intramolecular nucleophilic substitution, e. g. heating in a dipolar aprotic solvent like dimethyl sulfoxide or dimethylformamide. The reaction order (a) nucleophilic substitution of the benzylic hydroxy group and (b) removal of the protective group can also be reversed.

In the same manner, compounds of the formula 1-a or 1-b or derivatives thereof (according to scheme 2 and 3) can be transformed into enantiopure (8f?)-8-aryl-3,6,7,8-tetrahydro-chromeno[7,8-d]imidazole derivatives of the formula 3-b (Scheme 4). Scheme 2:

Scheme 3

Scheme 4

The invention therefore further relates to a process of preparing a compound of the formula 6-a comprising a deprotection reaction of a compound of the formula 1-a, in which R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-a.

The invention therefore further relates to the use of compounds of the formula 1-a for the preparation of compounds of the formula 6-a, in which R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-a.

The invention therefore further relates to the use of compounds of the formula 1-a for the preparation of compounds of the formula 3-a, in which R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-a.

The invention therefore further relates to a process of preparing a compound of the formula 6-b comprising a deprotection reaction of a compound of the formula 1-b, in which R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-b.

The invention therefore further relates to the use of compounds of the formula 1-b for the preparation of compounds of the formula 6-b, in which R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-b.

The invention therefore further relates to the use of compounds of the formula 1-b for the preparation of compounds of the formula 3-b, in which R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-b.

The invention therefore further relates to a process for the preparation of compounds of the formula 3-a, which comprises transformation of a compound of the formula 1-a into a compound of the formula 4-a, further transformation of a compound of the formula 4-a into a compound of the formula 5-a and cyclization of a compound of the formula 5-a to the compound of the formula 3-a in which R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-a.

The invention therefore further relates to a process for the preparation of compounds of the formula 3-a, which comprises deprotection of a compound of the formula 1-a into a compound of the formula 6-a and cyclization of a compound of the formula 6-a to the compound of the formula 3-a in which R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-a. The invention therefore further relates to a process for the preparation of compounds of the formula 3-a, which comprises transformation of a compound of the formula 1-b into a compound of the formula 6-b, further transformation of a compound of the formula 6-b into a compound of the formula 7-a and cyclization of a compound of the formula 7-a to the compound of the formula 3-a in which R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-b and Nu is a suitable nucleophile, for example halogen, especially chlorine.

The invention therefore further relates to a process for the preparation of compounds of the formula 3-a, which comprises transformation of a compound of the formula 1-b into a compound of the formula 8-a, further transformation of a compound of the formula 8-a into a compound of the formula 7-a and cyclization of a compound of the formula 7-a to the compound of the formula 3-a in which R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-b and Nu is a suitable nucleophile, for example halogen, especially chlorine.

The invention therefore further relates to a process for the preparation of compounds of the formula 3-b, which comprises transformation of a compound of the formula 1-b into a compound of the formula 4-b, further transformation of a compound of the formula 4-b into a compound of the formula 5-b and cyclization of a compound of the formula 5-b to the compound of the formula 3-b in which R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-b.

The invention therefore further relates to a process for the preparation of compounds of the formula 3-b, which comprises deprotection of a compound of the formula 1-b into a compound of the formula 6-b and cyclization of a compound of the formula 6-b to the compound of the formula 3-b in which R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-b.

The invention therefore further relates to a process for the preparation of compounds of the formula 3-b, which comprises transformation of a compound of the formula 1-a into a compound of the formula 6-a, further transformation of a compound of the formula 6-a into a compound of the formula 7-b and cyclization of a compound of the formula 7-b to the compound of the formula 3-b in which R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-a and Nu is a suitable nucleophile, for example halogen, especially chlorine.

The invention therefore further relates to a process for the preparation of compounds of the formula 3-b, which comprises transformation of a compound of the formula 1-a into a compound of the formula 8-b, further transformation of a compound of the formula 8-b into a compound of the formula 7-b and cyclization of a compound of the formula 7-b to the compound of the formula 3-b in which R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-a and Nu is a suitable nucleophile, for example halogen, especially chlorine.

The invention therefore further relates to the use of compounds of the formula 1-b for the preparation of compounds of the formula 3-a, in which R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-b.

The invention therefore further relates to the use of compounds of the formula 1-a for the preparation of compounds of the formula 3-b, in which R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-a.

Compounds of the formula 2 can be prepared from ketones of the formula 9 (Scheme 5). Protection of the phenolic hydroxy group present in compounds of the formula 2 can be accomplished by standard procedures, which are described for example in T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis (3^rd edition), Wiley, New York, 1999. Suitable protective groups PG that are to be mentioned are for example ether, ester, sulfonate and silyl ether groups. Examples of protection groups PG which are to be mentioned are methyl, methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, o- nitrobenzyloxymethyl, p-nitrobenzyloxymethyl, ethoxyethyl, t-butoxymethyl, methoxyethoxymethyl, 2- (trimethylsilyl)-ethoxymethyl, tetrahydropyranyl, tetrahydrofuranyl, t-butyl, benzyl, p-methoxybenzyl, o- nitrobenzyl, p-nitrobenzyl, 2,6-dimethylbenzyl, cyclohexyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, pivaloate, benzoate, mesitoate, t-butyl carbonate, methanesulfonate or toluenesulfonate radicals.

Scheme 5

The invention therefore further relates to compounds of the formula 2

in which R1 , R2, R3, Ar and PG have the meanings as indicated in the outset for the compounds of the formula 1-a, and its salts.

Ketones of the formula 9 are known for example from WO 04/087701 , or they can be prepared in a known manner, analogously to known compounds. Alternatively, ketones of the formula 9 can be obtained from 5- [(dimethylamino)methyl]-4-hydroxy-1 /-/-benzimidazoles of the formula 10 as shown in Scheme 6 (process B). The base-catalyzed alkylation of Mannich bases of the formula 10 or suitable salts thereof, like for example salts with HCI, HBr or HI, with readily available β-ketoesters of the formula 11 is the preferred synthetic method (process B). The intermediates of the formula 12 can either be isolated or directly transformed further to ketones of the formula 9 by saponification and decarboxylation. In comparison to process A disclosed in the prior art (WO 2004/087701 and WO 2006/136552), process B is characterized by a consequent design for feasibility on technical scale.

Scheme 6

methyl or ethyl, or benzyl

Although in both processes A and B, the title compounds of the formula 9 are obtained in comparable yields, only process B allows the production of the title compound in a large scale. In particular, process A has several disadvantages, like for example availability, synthesis and stability of the compounds of the formula 13, and difficult and laborious isolation and / or purification of the final compounds of the formula 9. All these issues render process A inapplicable for large scale synthesis of ketones of the formula 9. In process B, all these disadvantages of process A are overcome. In all stages of process B, the products can easily be isolated, for example by simple filtration. The ketones of the formula 9 can be purified for example by salt formation, e.g. with citric acid, and are obtained in solid form and high purity after treatment with a base.

The overall process B is robust and tolerant with regard to several parameters. The following description serves as an exemplary guideline. Based on the given information, the person skilled in art will be able to identify the critical process parameters and to conduct the reaction in a successful manner. The successful implementation of process B is not limited to the parameters outlined in the following section.

The optimum reaction time and temperature depends on the character of the substrate. Typically, the reaction is performed at temperatures between 20 and 150⁰C, preferably between 60 and 110 ⁰C. The optimum reaction period can easily be determined by a person skilled in the art and is preferably between 1 h and 1 day, in particular between 6 and 10 hours, although shorter or longer reaction times are also possible. Either inorganic or organic bases can be used for the process. Examples of preferred inorganic bases are alkali metal hydroxides, like e. g. lithium hydroxide, sodium hydroxide, potassium hydroxide, or cesium hydroxide, or alkali metal carbonates, like e. g. lithium carbonates, sodium carbonates, potassium carbonates, or cesium carbonates. Alkali metal alkoxides, like e. g. alkali metal methylates, ethylates, isopropylates, ferf-butylates, or ferf-pentylates, or amine bases like dialkyl amines or trialkyl amines constitute examples of preferred organic bases. The optimum amount of base depends on the starting material (e.g. whether the Mannich bases of the formula 10 are used as free base or as salts, such as for example the HCI, HBr or HI salts), as well as of the character of the base, however, the use of at least stoichiometric amounts is recommended, typically, 1 - 10, preferably 1.0 - 2.5 equivalents. Typically, 1 - 10, preferably 1.5 - 2.5 equivalents of the corresponding alkyl 3-(2-aryl)-3-oxopropanoate of the formula 11 are used, although the optimum stoichiometry depends on the character of the starting material. The reaction is performed in a common organic solvent, such as for example aromatic hydrocarbons, like e. g. benzene, toluene or mesitylene, ethereal solvents, like e. g. tetrahydrofuran, dimethoxyethane or glycol ethers, alcohols, like e. g. ethanol, propanol or butanol, or dimethylformamide, or in a mixture of these solvents, eventually also in mixtures of these solvents with water or in pure water. Preferred solvents are mixtures of toluene and water (biphasic reaction) or mixtures of toluene and DMF (homogenous reaction). The use of a solvent or a mixture of solvents, from which the title compounds of the formula 9 precipitates easily, is preferred, such as e. g. mixtures of toluene and water (biphasic reaction). In a preferred reaction procedure, a mixture of the starting material (Mannich base of the formula 10) and base is added to a hot solution of the alkyl 3-(2-aryl)-3-oxopropanoate of the formula 1 1 in the solvent to be used. Other addition orders, e.g. reverse addition or addition of base to a hot solution of compounds of the formulae 10 and 11 , are also possible. The optimum amount of solvent results from a compromise between possible stirring problems (in the presence of too little solvent) and difficulties in precipitation of the corresponding ketone of the formula 9 (in the presence of too much solvent), which needs to be found for each substrate in an individual manner. A person skilled in the art can easily determine the optimum amount of solvent needed in this regard.

Depending on the reaction conditions applied (temperature, time, amount and type of base, solvent etc.) intermediates of the formula 12 or compounds of the formula 9 are isolated from the reaction mixture. Preferably, the ketones of the formula 9 are isolated from the reaction mixture by precipitation. Further purification of the title compounds of the formula 9 is accomplished by crystallization in the presence of an organic or inorganic acid, such as for example citric acid, fumaric acid and toluenesulfonic acid. A specific example for a suitable acid that might be mentioned is citric acid. Alternatively, intermediates of the formula 12 are isolated from the reaction mixture and transformed into ketones of the formula 9 in a subsequent reaction step. On this account, solutions of intermediates of the formula 12 in a suitable solvent or mixture of solvents, such as for example ethanol and water, are heated in the presence of a suitable base, e. g. an alkali metal carbonate. Under these conditions, saponification and decarboxylation of compounds of the formula 12 proceeds smoothly and the corresponding ketones of the formula 9 are isolated in good yields. Alternatively, other reaction conditions suitable for the saponification of carboxylic esters can be applied to transform intermediates of the formula 12 into ketones of the formula 9. If desired, the obtained ketones of the formula 9 can be purified further by crystallization from a suitable organic solvent, e. g. acetone.

The invention therefore further relates to all the aspects of process B outlined above. In particular, the invention further relates to a process for the preparation of compounds of the formula 9, which comprises reaction of a compound of the formula 10 with a compound of the formula 1 1

in which R1 , R2, R3 and Ar have the meanings as indicated in the outset for the compounds of the formula 1-a, and wherein R is a suitable radical, like for example a 1-7C-alkyl radical, in particular methyl or ethyl, or benzyl.

The invention further relates to a process for the preparation of compounds of the formula 12, which comprises reaction of a compound of the formula 10 with a compound of the formula 1 1

The invention further relates to a process for the preparation of compounds of the formula 9, which comprises conversion of a compound of the formula 12 to a compound of the formula 9

in which R1 , R2, R3 and Ar have the meanings as indicated in the outset for the compounds of the formula 1-a, and wherein R is a suitable radical, like for example a 1-7C-alkyl radical, in particular methyl or ethyl, or benzyl. In particular, the invention further relates to a process for the preparation of compounds of the formula 9, which comprises reaction of a compound of the formula 10 with a compound of the formula 1 1 to compounds of the formula 12

and further conversion of a compound of the formula 12 to a compound of the formula 9

The invention further relates to compounds of the formula 12

in which R1 , R2, R3 and Ar have the meanings as indicated in the outset for the compounds of the formula 1-a, and wherein R is a suitable radical, like for example a 1-7C-alkyl radical, in particular methyl or ethyl, or benzyl, and its salts. A convenient method to transform compounds of the formula 9 into other compounds of the formula 9 bearing a different substituent R3 is shown in Scheme 7 and might be illustrated by the following examples: Esters of the formula 14, wherein R33 is for example a 1-4C-alkyl radical, can be transformed into acetals of the formula 15, for example by reaction with 2,2-dimethoxypropane in the presence of acids. Cleavage of the ester function, e. g. by saponification with sodium hydroxide, furnishes the corresponding carboxylic acids of the formula 16, which are then treated with a suitable coupling reagent, e. g. TBTU, followed by addition of the coupling partner, e. g. an amine, yielding derivatives of the formula 17. Alternatively, esters of the formula 15 can be reduced to the corresponding primary alcohol, e. g. using lithium aluminium hydride, and the hydroxy group can be activated for example by conversion into a halide or a sulfonate using e. g. thionyl chloride or methanesulfonyl chloride. Interconversion of the substituent R3 can then be accomplished by nucleophilic displacement reactions using nucleophiles like e. g. alkoxides. Finally, ketones of the formula 9 are obtained by cleavage of acetals of the formula 17, e. g. in the presence of acids like hydrochloric acid.

Scheme 7

Compared to the processes known from the prior art for the synthesis of compounds of the formula 6-a, for example those processes mentioned in the International Patent Application WO 04/087701 , the process for the preparation of compounds of the formula 6-a according to the present invention relies on the use of RuCI₂[(S)-Xyl-P-Phos][( S)-DAIPEN] as hydrogenation catalyst or alternatively on a catalyst system comprising a RuCI₂[η⁶-arene]₂ precatalyst and an aminoalcohol of the formula A and in particular on the protection of the phenolic hydroxy group with a suitable protective group. The presence of the protective group is beneficial with respect to the performance of the hydrogenation reaction. More specifically, the hydrogenation processes according to the present invention are unexpectedly distinguished from the processes known from the prior art inter alia by the following advantages:

1. increased isolated yield and/or enantiomeric excess

2. easier purification of the product, easier removal of metal residues, and high economy due to full conversion even at very high substrate to catalyst ratios

3. cleaner conversion and formation of less / no by-products due to the possibility to use catalytic amounts of the base with respect to the substrate.

4. smooth transformation of prochiral ketones of the formula 2 bearing a variety of functional groups and substitution patterns.

The same arguments as outlined in the paragraph above apply in a corresponding manner for the synthesis of the compounds of the formula 6-b.

Mode(s) for Carrying Out the Invention

The examples below serve to illustrate the invention in more detail without limiting it. Further compounds of the formula 1-a or 1-b whose preparation is not described explicitly can likewise be prepared in an analogous manner or in a manner known per se to the person skilled in the art, using customary process techniques. The abbreviation ee stands for enantiomeric excess, RT for retention time, MT for migration time, S/C for substrate to catalyst ratio, v for volume. For the assignment of NMR signals, the following abbreviations are used: s (singlet), d (duplet), t (triplet), q (quartet), m (multiplet), b (broad). The following units are used: ml (millilitre), I (litre), nm (nanometer), mm (millimeter), mg (milligramme), g (gramme), mmol (millimol), N (normal), M (molar), min (minute), h (hour/s), d (day/s), MHz (megahertz).

Furthermore the following abbreviations are used for the chemical substances indicated:

(S)-DAIPEN (2S)-(+)-1 ,1-bis(4-methoxyphenyl)-3-methyl-1 ,2-butanediamine

(R)-DAIPEN (2f?)-(-)-1 ,1-bis(4-methoxyphenyl)-3-methyl-1 ,2-butanediamine

DIAD diisopropyl azodicarboxylate

DIPEA diisopropylethylamine

DMSO dimethylsulfoxide

THF tetrahydrofuran

DME 1 ,2-dimethoxyethane

DMF dimethylformamide

TBTU O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate

If NMR (nuclear magnetic resonance) chemical shifts are given without integration, overlay of the signal of the corresponding proton of the compound with signals of the solvent, water, or impurities was observed.

Preparation of the catalyst RuCIJ(S)-XvI-P-PhOSlK S)-DAIPENl:

(Benzene)dichlororuthenium dimer (CAS 37366-09-9, 1 equivalent) and ( S)-Xy I-P-Phos (CAS 443347-10-2, commercially available from Strem Chemicals and Alfa Aesar, 1.03 equivalents) were placed in a Schlenk flask that was evacuated and filled with argon. Anhydrous, degassed DMF (2 ml per mmol) was added and the flask was placed in an oil bath pre-heated to 105 ⁰C. The reaction was stirred at 105 ⁰C for 1.5 hours. (S)-DAIPEN (CAS 148369-91-9, commercially available from Strem Chemicals, 1.1 equivalents) was added and the reaction was stirred at room temperature for 3 hours. At this stage, a sample of the reaction mixture was diluted in chloroform-d and analysed by ³¹P-NMR spectroscopy. Only the two doublets of the desired complex + the small excess of free ligand were visible. The DMF was evaporated under vacuum (heating necessary) and the residue was dissolved in anhydrous degassed dichloromethane (5-10 ml per mmol) and placed on top of a silica gel column in a Schlenk filter under argon. The product was eluted with dichloromethane / methyl ferf-butyl ether = 1 :1 (v/v). The clear yellow solution was collected in a Schlenk flask and the solvent was evaporated to give a yellow/green solid that was further dried under vacuum overnight. The isolated yield was 90% (Adaptation of a general procedure described by R. Noyori in Angew. Chem. 1998, 110, 1792-1796, see section background art).

Asymmetric reduction of prochiral ketones of the formula 2:

1. 4-Benzyloxy-5-[(3fl)-3-hydroxy-3-(2-methylphenyl)propyl]-Λ/,Λ/,1 ,2-tetramethyl-1 H- benzimidazole-6-carboxamide

SYNTHESIS BY ASYMMETRIC HYDROGENATION:

Screen of reaction conditions, 100 ml autoclave : In a 100 ml autoclave filled with argon, 4-benzyloxy- Λ/,Λ/,1 ,2-tetramethyl-5-[3-(2-methylphenyl)-3-oxopropyl]-1 /-/-benzimidazole-6-carboxamide (example d, 10.0 g, 21.3 mmol) was suspended in degassed isopropanol (20 ml {entry 1-3}, 40 ml {entry 4-13}) and tert- butanol (20 ml {entry 2-3}, 0 ml {entry 1 , 4-13}. Potassium tert-butylate solution (1 M in tert-butanol, 23.4 ml {entry 1}, 2.0 ml {entry 2-13}) and the hydrogenation catalyst RuCI₂[(S)-Xyl-P-Phos][( S)-DAIPEN] was added. The autoclave was purged with hydrogen (3 x) and the reaction mixture was hydrogenated at 70° C and 80 bar pressure {entry 1-11} / 10 bar pressure {entry 12-13}, respectively, for 17-20 h. After cooling to room temperature and releasing of the hydrogen pressure, the white suspension was transferred into a flask with the help of methanol (80 ml). The reaction mixture was poured onto a stirred mixture of saturated ammonium chloride solution (200 ml) and dichloromethane (300 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 50 ml). The combined organic phases were washed with water (2 x 70 ml), dried over sodium sulfate, and concentrated under reduced pressure. The enantiomeric purity of the crude product was determined (first value reported for optical purity in table 1 ).

In most cases, the residue (a yellowish foam) was dissolved in hot acetone (approximately 20 ml). Upon cooling to room temperature, crystallization started. After a period of 17 h at room temperature, the precipitate was isolated by filtration, washed with acetone (5 ml) and diethyl ether (15 ml), and dried in vacuo. The title compound was isolated in the form of a colourless solid (yield and optical purity reported in table 1 , m.p. 160-162 ⁰C).

In some cases, the crude product was subjected to the next reaction step (removal of the benzyl protective group, see example A) without further purification.

In other cases, the crude product was purified by column chromatography [silica gel, eluant: dichloromethane / methanol = 50:1 to 20:1 (v/v)]. Evaporation of the corresponding fractions afforded the title compound in the form of a beige foam (yield and optical purity reported in table 1 ).

Determination of the optical purity by HPLC (column: CHIRALCEL OD-H 250 x 4.6 mm, 5 μm. - eluant: ethanol / n-heptane = 10:90 (v/v). - flow rate: 1 ml/min. - temperature: 40 ⁰C): RT [(3F?)-enantiomer] = 18.7 min; RT [(3S)-enantiomer] = 21.6 min.

Table 1 S/C base H₂ / temp. / t cone. purification yield / optical purity

1 100:1 1.1 KOtBu 100 bar, 70 ⁰C, 17 h 0.5 M chromatography 68 % (- / 99.5 % ee)

2 100:1 0.1 KOtBu 100 bar, 70 ⁰C, 17 h 0.5 M chromatography 72 % (- / 98.8 % ee)

3 250:1 0.1 KOtBu 100 bar, 70 ⁰C, 17 h 0.5 M chromatography 59 % (- / 98.8 % ee)

4 350:1 0.1 KOtBu 80 bar, 65 ⁰C, 20 h 0.5 M crystallization 75 % (98.5 / 100 % ee)

5 500:1 0.1 KOtBu 80 bar, 65 ⁰C, 20 h 0.5 M crystallization 72 % (98.7 / 99.2 % ee)

6 700:1 0.1 KOtBu 80 bar, 70 ⁰C, 18 h 0.5 M crystallization) 75 % (97.7 / 99.7 % ee)

7 1000:1 0.1 KOtBu 80 bar, 70 ⁰C, 18 h 0.5 M crude product 95 % (98.6 % / - % ee)

8 1500:1 0.1 KOtBu 80 bar, 70 ⁰C, 18 h 0.5 M crystallization 70 % (98.2 / 98.9 % ee)

9 2500:1 0.1 KOtBu 80 bar, 70 ⁰C, 18 h 0.5 M crude product 100 % (98.2 / - % ee)

10 3500:1 0.1 KOtBu 80 bar, 70 ⁰C, 18 h 0.5 M crystallization 66 % (96.3 / 98.7 % ee)

11 5000:1 0.1 KOtBu 80 bar, 70 ⁰C, 18 h 0.5 M crystallization 70 % (96.6 / 99.2 % ee)

12 2000:1 0.1 KOtBu 10 bar, 70 ⁰C, 18 h 0.5 M crystallization 73 % (96.7 / 98.2 % ee)

13 3500:1 0.1 KOtBu 10 bar, 70 ⁰C, 18 h 0.5 M crystallization 74 % (96.3 / 99.2 % ee)

Asymmetric catalytic hydrogenation at S/C=500:1, 2000 ml autoclave: In a 2 I autoclave equipped with a glass inlay and filled with argon, 4-benzyloxy-Λ/,Λ/,1 ,2-tetramethyl-5-[3-(2-methylphenyl)-3-oxopropyl]-1 /-/- benzimidazole-6-carboxamide (example d, 32.0 g, 68.1 mmol) was suspended in dry isopropanol (380 ml). Potassium tert-butylate solution (1 M in tert-butanol, 7.0 ml) and the hydrogenation catalyst RuCI₂[( S)-XyI-P- Phos][( S)-DAIPEN] (170 mg, 0.14 mmol) was added. The autoclave was purged with hydrogen (3 x) and the reaction mixture was hydrogenated at 70° C and 80 bar pressure for 20 h. After cooling to room temperature and releasing of the hydrogen pressure, the reaction mixture (a brown solution) was poured onto a stirred mixture of saturated ammonium chloride solution (250 ml) and dichloromethane (500 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 80 ml). The combined organic phases were washed with water (2 x 100 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue (33 g of a colourless foam, 97.4 % ee) was dissolved in hot acetone (60 ml). Upon cooling to room temperature, crystallization started. After a period of 17 h at room temperature, the precipitate was isolated by filtration, washed with acetone (15 ml) and diethyl ether (30 ml), and dried in vacuo. The title compound was isolated in the form of a colourless solid (25.5 g, 79 % yield, 99.5 % ee). - m.p. 160-161 ⁰C.

Determination of the optical purity by HPLC (column: CHIRALCEL OD-H 250 x 4.6 mm, 5 μm. - eluant: ethanol / n-heptane = 10:90 (v/v). - flow rate: 1 ml/min. - temperature: 40 ⁰C): RT [(3F?)-enantiomer] = 18.4 min / 99.67 area-%; RT [(3S)-enantiomer] = 21.3 min / 0.25 area-%; 99.5 % ee.

¹H-NMR (DMSO-d₆, 400 MHz): δ = 1.60 (m_c, 1 H), 1.80 (m_c, 1 H), 2.16 (s, 3 H), 2.54 (s, m_c, 4 H), 2.67 (s, 3 H), 2.94 (s, m_c, 4 H), 3.68 (s, 3 H), 4.67 (bs, 1 H), 5.00 (bs, 1 H), 5.71 (s, 2 H), 6.96 (s, 1 H), 7.11 (m_c, 3 H), 7.34 (m_c, 4 H), 7.44 (m_c, 2 H). Asymmetric catalytic hydrogenation at S/C=1000:1 and 2500:1, 10 1 autoclave: In a 10 I autoclave equipped with a glass inlay and filled with argon, 4-benzyloxy-Λ/,Λ/,1 ,2-tetramethyl-5-[3-(2-methylphenyl)-3-oxopropyl]- 1 H-benzimidazole-6-carboxamide (example d) was suspended in dry isopropanol (entry 1-5: 4000 ml; entry 6: 3500 ml). Potassium tert-butylate solution (1 M in tert-butanol) and the hydrogenation catalyst RuCI₂[(S)- Xyl-P-Phos][( S)-DAIPEN] was added (for quantities see Table 2). The autoclave was purged with hydrogen (3 x) and the reaction mixture was hydrogenated at 70° C and 80-100 bar pressure for 20 h.

Table 2

Ketone KOtBu (1 M solution) Catalyst Yield

1 1000 g / 2.13 mol 213 ml / 0.21 mol 2.65 g (S/C = 1000:1 ) 946 g / 94 %

2 1000 g / 2.13 mol 213 ml / 0.21 mol 1.06 g (S/C = 2500:1 )

1711 g / 85 %

3 100O g / 2.13 mol 213 ml / 0.21 mol 1.06 g (S/C = 2500:1 ) _

4 1000 g / 2.13 mol 213 ml / 0.21 mol 1.06 g (S/C = 2500:1 )

5 1000 g / 2.13 mol 213 ml / 0.21 mol 1.06 g (S/C = 2500:1 ) 2543 g / 90 %

_6 818 g / 1.74 mol 174 ml / 0.17 mol 0.90 g (S/C = 2500:1 )

Work-up sample 1: The reaction mixture was cooled to 35 ⁰C, transferred into a glass vessel, neutralized with acetic acid (12.2 ml, addition at a temperature of 65 ⁰C), and diluted with water (8 I, addition over a period of 0.25 h). The solution was cooled to 15-20 ⁰C and precipitate was formed. The title compound was isolated by pressure filtration and dried in vacuo at a temperature of 50 ⁰C (682 g of a colourless solid, 68 % yield). The filtrate was concentrated (removal of 2.5 I of isopropanol / water). The warm solution was transferred into a glass vessel and gradually cooled to 10 ⁰C. Further 264 g of the title compound (26 % yield) were isolated by pressure filtration.

Work-up samples 2 and 3: In the autoclave, the reaction mixtures were neutralized by addition of acetic acid (12.2 ml each) and transferred into a 60 I vessel. At a temperature of 50-55 ⁰C, 24 I of water were added over a period of 1 h. Stirring was continued for 1 h and the mixture was gradually cooled to 15-20 ⁰C. The title compound was isolated by pressure filtration and dried in vacuo at a temperature of 50 ⁰C (1711 g of a colourless solid, 85 % yield).

Work-up samples 4 to 6: Samples 4 to 6 were purified as described above for samples 2 and 3.

The three batches listed in Table 2 were combined and suspended in acetone (20 I). The suspension was stirred for 4.5 h at 50 ⁰C, for 17 h at room temperature, and for 1.5 h at 10 ⁰C. The title compound was isolated by filtration and dried in vacuo (50 ⁰C): 4236 g of a colourless solid, 73 % yield. The mother liquor was concentrated to 25 % of its original volume and stirred for 17 h at room temperature. Another batch of the title compound was obtained by filtration: 455 g of a colourless solid, 8 % yield. - m.p. 160-163 ⁰C, optical purity: 98.5 % ee ¹H-NMR (DMSO-Cl₆, 400 MHz): δ = 1.60 (m_c, 1 H), 1.80 (m_c, 1 H), 2.16 (s, 3 H), 2.54 (s, m_c, 4 H), 2.67 (s, 3 H), 2.94 (s, m_c, 4 H), 3.68 (s, 3 H), 4.67 (bs, 1 H), 5.00 (bs, 1 H), 5.71 (s, 2 H), 6.96 (s, 1 H), 7.11 (m_c, 3 H), 7.34 (m_c, 4 H), 7.44 (m_c, 2 H).

SYNTHESIS BY ASYMMETRIC TRANSFER HYDROGENATION:

Screen of reaction conditions: To a slurry of 4-benzyloxy-Λ/,Λ/,1 ,2-tetramethyl-5-[3-(2-methylphenyl)-3- oxopropyl]-1 /-/-benzimidazole-6-carboxamide (example d, 4.00 g, 8.52 mmol) in 2-propanol (80-120 ml) were added ligand (0.005-0.030 equivalents) and 50% aqueous potassium hydroxide solution (0.025-0.080 equivalents). The pressure was reduced until gentle boiling was observed (100-150 mbar) and maintained for about 30 seconds prior to repressurizing with nitrogen. This inertization cycle was repeated 5 times, before the mixture was heated to the reaction temperature (30-65 ⁰C). Then, the precatalyst

arene)]₂ (0.002-0.015 equivalents) was added, inertization was repeated twice more and the reaction mixture was stirred at the given temperature until TLC (usually after 1 , 4 and 17-20 h) indicated that either conversion had stalled or no more than 5% of starting material were left. Acetic acid (51 mg, 0.85 mmol) was added and the reaction mixture was concentrated under reduced pressure. The resulting residue was partitioned between dichloromethane (50 ml) and brine (15 ml). The crude title compound was obtained by evaporating the organic phase to dryness and analyzed by chiral HPLC.

Table 3 ligand [RuCI₂(?/⁶-arene)]2 KOH cone. T / t. conv.^a)

_^ e. -r. ^b)

Ra Rb equiv. arene equiv. equiv. (mol/l) (⁰C / h) (%)

Ph Ph 0.030 4-iPrC₆H₄Me 0.015 0.050 0.069 40 / 20 -20 43:57

Bn Ph 0.011 4-iPrC₆H₄Me 0.005 0.050 0.069 40 / 20 -40 81 :19

Me Ph 0.010 4-iPrC₆H₄Me 0.005 0.025 0.069 40 / 20 -35 85:15 iBu Ph 0.022 4-iPrC₆H₄Me 0.010 0.080 0.069 35 / 20 >99 96:4 iBu Ph 0.022 C₆H₆ 0.010 0.080 0.069 37 / 20 >99 98:2 iBu Ph 0.014 C₆H₆ 0.006 0.060 0.069 37 / 18 -95 98:2 iPr Ph 0.025 4-iPrC₆H₄Me 0.012 0.050 0.069 30 / 44 -60 97:3 iPr Ph 0.025 4-iPrC₆H₄Me 0.010 0.060 0.104 50 / 18 >95 81 :19 iPr Ph 0.025 4-iPrC₆H₄Me 0.010 0.060 0.104 65 / 18 -85 87:13 iPr Ph 0.025 C₆Me₆ 0.010 0.060 0.069 40 / 20 +25 58:42 iPr Ph 0.011 C₆H₆ 0.005 0.040 0.069 37 / 20 -99 98:2 iPr 4-MeOC₆H₄ 0.005 C₆H₆ 0.002 0.040 0.082 40 / 20 -95 95:5 iPr 4-MeOC₆H₄ 0.0055 C₆H₆ 0.0025 0.040 0.082 38 / 20 -99 96:4 a) Determined by semiquantitative TLC; b) Determined by chiral HPLC.

Optimized procedure: To a slurry of 4-benzyloxy-Λ/,Λ/,1 ,2-tetramethyl-5-[3-(2-methylphenyl)-3-oxopropyl]-1 H- benzimidazole-6-carboxamide (example d, 24.0 g, 51.1 mmol) in 2-propanol (600 ml) were added (R)-2- amino-1 ,1-di-(4-methoxyphenyl)-3-methyl-1-butanol (89 mg, 0.281 mmol) and 50% aqueous potassium hydroxide solution (152 μ\, 2.04 mmol). Under stirring, the pressure was reduced until gentle boiling was observed (100-150 mbar) and maintained for about 30 seconds prior to repressurizing with nitrogen. This inertization cycle was repeated 5 times, before the mixture was heated to 36-40 ⁰C. Then, a solution of the precatalyst [RuCI₂(?/⁶-benzene)]₂ (64 mg, 0.128 mmol) in acetonitrile (1.0 ml) was added, inertization was repeated twice more and the reaction mixture was stirred at 36-40 ⁰C for 20 h. TLC of the reaction mixture indicated that no more than 1 % of starting material were left. Acetic acid (253 μ\, 3.06 mmol) was added and the reaction mixture was concentrated under reduced pressure at 40-60 ⁰C until about 500 ml of 2-propanol had distilled off. After cooling to 35-40 ⁰C, water (300 ml) was added within 1-1.5 h. During addition, the crude product started to precipitate. Finally, the mixture was cooled to 0-5 ⁰C within 2-2.5 h, filtered, and rinsed with cold water (2 x 50 ml). This afforded the crude title compound (34.0 g, Karl Fischer titration: 33.1 % of water, 94% crude yield, 97:3 e.r.) as a greenish gray solid.

The crude product was dissolved in ethyl acetate (600 ml) and, in order to remove water, about 300 ml of solvent was distilled off at 70-80 ⁰C. After cooling to 55-60 ⁰C, 2-propanol (40 ml) and silica gel (12 g) were added. Stirring was continued for about 0.5 h at 55-60 ⁰C. Then, the dark gray-brown solids were filtered off and washed with 2 portions of warm ethyl acetate / 2-propanol [6:1 (v/v), 50 ml each, 50-60 ⁰C]. The combined filtrate was concentrated at 70-80 ⁰C, until about 340 ml of distillate had been collected. To the resulting slurry, methylcyclohexane (300 ml) was added over a period of 1.5 h at 70-80 ⁰C. Finally, the mixture was cooled to 0-5 ⁰C over at least 3 h. The solids were filtered off, washed with methyl cyclohexane / ethyl acetate [6:1 (v/v), 50 ml] and dried under vacuum at 50 ⁰C to furnish the title compound (19.7 g, 87 % yield, 99:1 e.r.) as a colorless, crystalline solid.

2. 5-[(3R)-3-Hydroxy-3-(2-methylphenyl)propyl]-4-methoxy-Λ/,Λ/,1 ,2-tetramethyl-1 W-benzimidazole- 6-carboxamide

In a 100 ml autoclave filled with argon, 4-methoxy-Λ/,Λ/,1 ,2-tetramethyl-5-[3-(2-methylphenyl)-3-oxopropyl]- 1 /-/-benzimidazole-6-carboxamide (example e, 8.5 g, 21.6mmol) was suspended in degassed isopropanol (40 ml). Potassium tert-butylate solution (1 M in tert-butanol, 2.0 ml) and the hydrogenation catalyst RuCI₂[(S)-Xyl-P-Phos][( S)-DAIPEN] (27 mg, 21.7 μmol) was added. The autoclave was purged with hydrogen (3 x) and the reaction mixture was hydrogenated at 70° C and 80 bar pressure for 17 h. After cooling to room temperature and releasing of the hydrogen pressure, the green solution was poured onto a stirred mixture of saturated ammonium chloride solution (80 ml) and dichloromethane (140 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 20 ml). The combined organic phases were washed with water (2 x 30 ml), dried over sodium sulfate, and concentrated under reduced pressure. The enantiomeric purity of the crude product (7.6 g of a green foam) was assessed by HPLC (99.0 % ee). The residue was dissolved in hot acetone (20 ml). Upon cooling to room temperature, crystallization started. After a period of 5 d at room temperature, the precipitate was isolated by filtration, washed with acetone, and dried in vacuo. The title compound was isolated in the form of a colourless solid (4.8 g, 56 % yield, 99.0 % ee, m.p. 148-150 ⁰C). The mother liquor was evaporated and the residue was purified by column chromatography [100 g of silica gel, eluant: dichloromethane / methanol = 20:1 (v/v)] and subsequent crystallization from acetone (8 ml). After a period of 1 h at room temperature, a second batch of the title compound was isolated by filtration, washed with cold acetone (5 ml) and diethyl ether (10 ml), and dried in vacuo (1.5 g of a colorless solid, 18 % yield, 99.0 % ee).

Determination of the optical purity by HPLC (column: CHIRALPAK AD-H 250 x 4.6 mm, 5 μm. - eluant: ethanol / n-heptane = 20:80 (v/v). - flow rate: 1 ml/min. - temperature: 25 ⁰C): RT [(3F?)-enantiomer] = 13.0 min; RT [(3S)-enantiomer] = 16.1 min.

¹H-NMR (DMSOd₆, 300 MHz): δ = 1.65, 1.80 (2 m_c, 2 H), 2.24, 2.30 (s, m_c, 4 H), 2.50, 2.53 (s, m_c), 2.69 (s, 3 H), 2.93 (s, 3 H), 3.65 (s, 3 H), 4.22 (s, 3 H), 4.71 (bs, 1 H), 5.01 (bs, 1 H), 6.92 (s, 1 H), 7.14 (m_c, 3 H), 7.42 (m_c, 1 H).

3. (I RJ-S-tθ-tAzetidin-i-ylcarbonylH-tbenzyloxyJ-i ^-dimethyl-I H-benzimidazol-S-yll-i^- methylphenyl)propan-1 -ol

Asymmetric hydrogenation at S/C = 100:1 In a 100 ml autoclave filled with argon, 3-[6-(azetidin-1- ylcarbonyl)-4-(benzyloxy)-1 ,2-dimethyl-1 H-benzimidazol-5-yl]-1-(2-methylphenyl)propan-1-one (example k, 5.0 g, 10.4 mmol) was suspended in isopropanol (35 ml). Potassium tert-butylate solution (1 M in tert- butanol, 1.0 ml, 1 mmol) and the hydrogenation catalyst RuCI₂[(S)-Xyl-P-Phos][( S)-DAIPEN] (120 mg, 96.5 μmol) was added. The autoclave was purged with hydrogen (3 x) and the reaction mixture was hydrogenated at 70° C and 80 bar pressure for 17 h. After cooling to room temperature and releasing of the hydrogen pressure, the reddish solution was poured onto a stirred mixture of saturated ammonium chloride solution (150 ml) and dichloromethane (250 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 100 ml). The combined organic phases were washed with water (2 x 50 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetone and diethyl ether was added. After a period of 3 d at room temperature, the precipitate was isolated by filtration and washed with diethyl ether. The title compound was obtained in the form of a slightly green solid (82 % yield, 99.5 % ee, m.p. 151-152 ⁰C).

The optical purity was determined after cleavage of the benzyl protective group (example C).

Asymmetric hydrogenation at S/C = 2000:1: In a 100 ml autoclave filled with argon, 3-[6-(azetidin-1- ylcarbonyl)-4-(benzyloxy)-1 ,2-dimethyl-1 H-benzimidazol-5-yl]-1-(2-methylphenyl)propan-1-one (example k, 5.0 g, 10.4 mmol) was suspended in isopropanol (35 ml). Potassium tert-butylate solution (1 M in tert- butanol, 1.0 ml, 1 mmol) and the hydrogenation catalyst RuCI₂[(S)-Xyl-P-Phos][( S)-DAIPEN] (6 mg, 4.8 μmol) was added. The autoclave was purged with hydrogen (3 x) and the reaction mixture was hydrogenated at 70° C and 80 bar pressure for 17 h. After cooling to room temperature and releasing of the hydrogen pressure, the solution was poured onto a stirred mixture of saturated ammonium chloride solution and dichloromethane (100 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (3 x 50 ml). The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in acetone. After a period of 3 d at 8 ⁰C, the precipitate was isolated by filtration and washed with acetone. The title compound was obtained in the form of a slightly green solid (2.14 g, 43 % yield, m.p. 154-156 ⁰C). The mother liquor was concentrated and the residue was purified by column chromatography [200 g of silica gel, eluant: dichloromethane / methanol = 13:1 (Wv)] . Evaporation of the corresponding fractions and crystallization of the obtained solid from acetone / diethyl ether afforded another batch of the title compound (2.03 g of a slightly green solid, 40 % yield).

The optical purity of the combined batches of the title compound was determined after cleavage of the benzyl protective group (in analogy to example C): 99.7 % ee.

¹H-NMR (DMSOd₆, 300 MHz): δ = 1.72 (m_c, 2 H), 2.15, 2.17 (m_c, s, 5 H), 2.54 (s, 3 H), 2.64 (m_c, 1 H), 2.85 (m_c, 1 H), 3.69 (s, 3 H), 3.75 (t, 2 H), 3.97 (t, 2 H), 4.68 (m_c, 1 H), 5.06 (d, 1 H), 5.69 (s, 2 H), 7.12 (m_c, 4 H), 7.37 (m_c, 6 H).

4. 4-(Benzyloxy)-5-[(3fi)-3-hydroxy-3-(2-methylphenyl)propyl]-Λ/-methoxy-Λ/,1 ,2-trimethyl-1 H- benzimidazole-6-carboxamide

In a 100 ml autoclave filled with argon, (4-benzyloxy)-Λ/-methoxy-Λ/,1 ,2-trimethyl-5-[3-(2-methylphenyl)-3- oxopropyl]-1 /-/-benzimidazole-6-carboxamide (example n, 2.0 g, 4.1 mmol) was suspended in isopropanol (35 ml). Potassium tert-butylate solution (1 M in tert-butanol, 1.64 ml, 1.6 mmol) and the hydrogenation catalyst RuCI₂[(S)-Xyl-P-Phos][( S)-DAIPEN] (105 mg, 84.4 μmol) was added. The autoclave was purged with hydrogen (3 x) and the reaction mixture was hydrogenated at 70° C and 80 bar pressure for 17 h. After cooling to room temperature and releasing of the hydrogen pressure, the suspension was poured onto a stirred mixture of saturated ammonium chloride solution (150 ml) and dichloromethane (200 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 100 ml). The combined organic phases were washed with water (150 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified twice by column chromatography [first column: 200 g of silica gel, eluant: ethyl acetate / triethylamine = 8:2 (v/v), then dichloromethane / methanol = 13:1 (v/v); second column: 250 g of silica gel, eluant: dichloromethane / methanol = 13:1 (v/v)]. Evaporation of the corresponding fractions afforded the title compound in 49 % yield (0.98 g of a colourless solid, 98.2 % ee, m. p. 105-107 ⁰C).

The optical purity was determined after cleavage of the benzyl protective group.

¹H-NMR (DMSOd₆, 300 MHz): δ = 1.74 (m_c, 2 H), 2.17 (s, 3 H), 2.54 (s, m_c), 2.75 (m_c, 1 H), 3.1 1 (s, 3 H), 3.48 (bs, 3 H), 3.69 (s, 3 H), 4.70 (m_c, 1 H), 4.97 (d, 1 H), 5.70 (s, 2 H), 7.08, 7.11 (s, m_c, 4 H), 7.37 (m_c, 6 H).

5. 4-Benzyloxy-2-cyclopropyl-5-[(3fi)-3-hydroxy-3-(2-methylphenyl)propyl]-Λ/,Λ/,1-trimethyl-1 W- benzimidazole-6-carboxamide

In a 100 ml autoclave filled with argon, 4-(benzyloxy)-2-cyclopropyl-Λ/,Λ/,1-trimethyl-5-[3-(2-methylphenyl)-3- oxopropyl]-1 /-/-benzimidazole-6-carboxamide (example q, 3.0 g, 6.1 mmol) was suspended in degassed isopropanol (40 ml). Potassium tert-butylate solution (1 M in tert-butanol, 0.6 ml) and the hydrogenation catalyst RuCI₂[(S)-Xyl-P-Phos][( S)-DAIPEN] (8 mg, 6.4 μmol) was added. The autoclave was purged with hydrogen (3 x) and the reaction mixture was hydrogenated at 70° C and 80 bar pressure for 17 h. After cooling to room temperature and releasing of the hydrogen pressure, the yellow solution was poured onto a stirred mixture of saturated ammonium chloride solution (70 ml) and dichloromethane (130 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 20 ml). The combined organic phases were washed with water (2 x 30 ml), dried over sodium sulfate, and concentrated under reduced pressure. The enantiomeric purity of the crude product (3.1 g of a green foam) was assessed by HPLC (95.0 % ee). The residue was purified by column chromatography [100 g of silica gel, eluant: dichloromethane / methanol = 100:2 (v/v)]. This afforded the title compound in 92 % yield (2.8 g of a colourless foam, 95.4 % ee). An analytical sample was crystallized from diethyl ether: m. p. 109-111 ⁰C.

Determination of the optical purity by HPLC (column: CHIRALCEL OD-H 250 x 4.6 mm, 5 μm. - eluant: ethanol / n-heptane = 10:90 (v/v). - flow rate: 1 ml/min. - temperature: 40 ⁰C): RT [(3F?)-enantiomer] = 12.4 min; RT [(3S)-enantiomer] = 14.0 min.

¹H-NMR (DMSOd₆, 400 MHz): δ = 1.08 (m_c, 4 H), 1.60, 1.79 (2 m_c, 2 H), 2.18 (s, 3 H), 2.24 (m_c, 1 H), 2.50 (m_c), 2.66 (s, 3 H), 2.89, 2.93 (m_c, s, 4 H), 3.78 (s, 3 H), 4.68 (bs, 1 H), 4.97 (bs, 1 H), 5.67 (s, 2 H), 6.93 (s, 1 H), 7.12 (m_c, 3 H), 7.34 (m_c, 6 H). Conversion of enantiomericallv pure alcohols of the formula 1-a into tricyclic benzimidazoles of the formula 3-a

A. 4-Hydroxy-5-[(3R)-3-hydroxy-3-(2-methylphenyl)propyl]-Λ/,Λ/,1 ,2-tetramethyl-1 H-benzimidazole- 6-carboxamide

prepared by cleavage of the benzyl protective group by catalytic hydrogenation using pure starting material : A hydrogen pressure of 1 bar was applied to a suspension of pure 4-benzyloxy-5-[(3/^:?)-3-hydroxy-3-(2- methylphenyl)propyl]-Λ/,Λ/,1 ,2-tetramethyl-1 /-/-benzimidazole-6-carboxamide (example 1 , 34.0 g, 72.1 mmol) and palladium on charcoal (10 weight-%, 1.7 g) in dry ethanol (750 ml). After a period of 18 hours at room temperature, dichloromethane (600 ml) was added to the grey suspension. After a period of 5 minutes, a solution was obtained. The catalyst was removed by filtration and the filtrate was concentrated. A colourless solid remained which was dried in vacuo. The title compound was obtained in 95 % yield (26.1 g, m.p. 230- 232 ⁰C).

prepared by cleavage of the benzyl protective group by catalytic hydrogenation using crude starting material: A hydrogen pressure of 1 bar was applied to a suspension of crude 4-benzyloxy-5-[(3f?)-3-hydroxy-3-(2- methylphenyl)propyl]-Λ/,Λ/,1 ,2-tetramethyl-1 /-/-benzimidazole-6-carboxamide (example 1 , 9.5 g, 20.1 mmol) and palladium on charcoal (10 weight-%, 0.5 g) in dry ethanol (300 ml). After a period of 3.5 hours at room temperature, the catalyst was removed by filtration and the filtrate was concentrated. The residue (8.8 g of an off-white solid) was dissolved in hot acetone (25 ml). The solution was allowed to come to room temperature and stirring was continued for 17 hours. The precipitate was isolated by filtration and washed with acetone (10 ml) and diethyl ether (20 ml). After drying in vacuo, 6.8 g of the title compound was isolated (89 % yield, m. p. 238-240 ⁰C).

prepared by cleavage of the benzyl protective group by catalytic transfer hydrogenation: 1.4-Cyclohexadiene (10.0 ml, 8.5 g, 106.0 mmol) was added to a solution of 4-benzyloxy-5-[(3f?)-3-hydroxy-3-(2- methylphenyl)propyl]-Λ/,Λ/,1 ,2-tetramethyl-1 /-/-benzimidazole-6-carboxamide (example 1 , 7.0 g, 14.8 mmol) in ethanol (140 ml). After addition of palladium on charcoal (10 weight-%, 110 mg), the reaction mixture was stirred for 2 hours at room temperature and for 2 hours at 55 °C. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue (7 g of a colourless foam) was dissolved in hot acetone (20 ml). The solution was allowed to come to room temperature and stirring was continued for 1 hour. The precipitate was isolated by filtration and washed with acetone (3 ml) and diethyl ether (15 ml). After drying in vacuo, 5.2 g of the title compound was isolated (92 % yield, m. p. 233-235 ⁰C).

prepared by cleavage of the methyl protective group: In a flame-dried flask filled with argon, a suspension of 2-(diethylamino)ethanethiol hydrochloride (1.20 g, 7.1 mmol) in dry DMF (40 ml) was stirred at room temperature for several minutes. At a temperature of 0 ⁰C, potassium tert-butylate (1.60 g, 14.3 mmol) was added and stirring was continued for 5 min at 0 ⁰C and for 0.5 h at room temperature. After addition of 5- [(S^-S-hydroxy-S^-methylphenyOpropyll^-methoxy-Λ/.Λ/J ^-tetramethyl-I H-benzimidazole-θ-carboxamide (2.00 g, 5.1 mmol), the reaction mixture was heated for 1 day at 155 ⁰C. The brown solution was cooled and poured on a mixture of saturated ammonium chloride solution (50 ml) and ethyl acetate (80 ml). A pH-value of 7 was adjusted by addition of 6 N hydrochloric acid. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 15 ml). The combined organic phases were washed with water (2 x 20 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue (5 g of a brown oil) was purified by column chromatography [100 g of silica gel, eluant: dichloromethane / methanol / acetic acid = 100:5:3 (v/v/v)]. Evaporation of the corresponding fractions afforded a brown solid (1.55 g), which was characterized by ¹H NMR spectroscopy [mixture of the title compound (73 weight-%) and acetic acid (27 weight-%), 58 % corrected yield].

¹H-NMR (DMSOd₆, 400 MHz): δ = 1.79 (bs, 2 H), 2.22 (s, 3 H), 2.49 (s, bs), 2.70 (s, 3 H), 2.93 (s, bs, 4 H), 3.65 (s, 3 H), 4.69 (bt, 1 H), 5.03 (bs, 1 H), 6.71 (s, 1 H), 7.13 (m_c, 3 H), 7.41 (m_c, 1 H), 9.85 (bs, 1 H).

B. (8S)-Λ/,Λ/,2,3-Tetramethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydrochromeno[7,8-c/]imidazole-5- carboxamide

Method A: To a suspension of 4-hydroxy-5-[(3R)-3-hydroxy-3-(2-methylphenyl)propyl]-Λ/,Λ/,1 ,2-tetramethyl- 1 /-/-benzimidazole-6-carboxamide (example A, 26.0 g, 68.1 mmol) and triphenylphosphine (23.0 g, 87.7 mmol) in dry tetrahydrofuran (500 ml), DIAD (18.5 ml, 18.0 g, 89.0 mmol) was added over a period of 15 min. A greenish solution was obtained, which was stirred for 20 min at room temperature and poured onto a stirred mixture of ice water (300 ml) and ethyl acetate (500 ml). A pH value of 2 was adjusted by addition of 6 N hydrochloric acid and stirring was continued for several minutes. The phases were separated and the aqueous phase was extracted with ethyl acetate (1 x 100 ml). The combined organic phases were discarded. The aqueous phase was diluted with ethyl acetate (500 ml) and a pH value of 8 was adjusted by addition of 6 N sodium hydroxide solution. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 80 ml). The combined organic phases were washed with water (2 x 150 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue (28 g of a brown oil) was dissolved in hot isopropyl acetate (25 ml). The solution was allowed to cool to room temperature and stirring was continued for 17 h. The precipitate was isolated by filtration, washed with isopropyl acetate (5 ml) and diethyl ether (15 ml), and dried in vacuo. This afforded the title compound (15.4 g of a colourless solid, 62 % yield, 98.5 % ee, m. p. 180-182 ⁰C). The mother liquor was concentrated and the residue (9 g of a brown oil) was purified by column chromatography [150 g of silica gel, eluant: ethyl acetate / methanol = 100:3 (v/v)]. Evaporation of the corresponding fractions furnished another 4.1 g of the title compound (colourless foam, 17 % yield, 94.0 % ee).

HPLC analytical method: column: Daicel Chiralpak AD-H, 250 x 4.6 mm, 5 μm - eluant: n-heptane / ethanol: 80 / 20, flow rate: 1 ml/ min, detection wavelength: 218 nm - first eluting enantiomer: 10.1 min / 0.74 (3.01 ) area-%, second eluting enantiomer: 13.7 min / 99.3 (97.0) area-%, 98.5 (94.0) % ee. ¹H-NMR (DMSO-Cl₆, 300 MHz): δ = 1.99 (m_c, 1 H), 2.22 (m_c, 1 H), 2.38 (s, 3 H), 2.47 (s), 2.65 (m_c, 1 H), 2.81 , 2.85 (s, m_c, 4 H), 3.02 (s, 3 H), 3.68 (s, 3 H), 5.32 (dd, 1 H), 6.92 (s, 1 H), 7.24 (m_c, 3 H), 7.47 (m_c, 1 H).

Method B: To a suspension of 4-hydroxy-5-[(3R)-3-hydroxy-3-(2-methylphenyl)propyl]-Λ/,Λ/,1 ,2-tetramethyl- 1 /-/-benzimidazole-6-carboxamide (example A, 565 g, 1.48 mol) and triphenylphosphine (505 g, 1.93 mol) in toluene (14 I), DIAD (380 ml, 1.93 mmol) was added dropwise. The temperature was maintained below 25 ⁰C in the course of the addition. An auburn solution was obtained, which was extracted with hydrochloric acid (1 N, 2 x 2.5 I). The aqueous phase was washed with methylisobutyl ketone (3 x 1 I). The combined organic phases were discarded. The pH value of the aqueous phase was adjusted to 10-12 by addition of 25 % aqueous ammonia solution and extracted with methylisobutyl ketone (2 x 2 I). The combined organic phases were concentrated under reduced pressure yielding the crude title compound (750 g).

Salt formation with succinic acid : The crude product (750 g) was dissolved in methylisobutyl ketone (2.2 I). Succinic acid (96 g, 0.815 mol) was added and the mixture heated to 80 ⁰C for several minutes. The suspension was allowed to cool to room temperature and stirring was continued for 17 h. The precipitate was isolated by filtration and dried in vacuo. This afforded the title compound as succinate salt (525 g of a colourless solid, 83 % yield, 90 % ee, m. p. 192-194 ⁰C, HPLC purity >97 %, stoichiometric ratio with respect to succinic acid: 1 : 0.53).

¹H-NMR (DMSOd₆, 400 MHz): δ = 1.99 (m_c, 1 H), 2.22 (m_c, 1 H), 2.38 (s, 3 H), 2.42 (s, 4 H), 2.47 (s, 3 H), 2.65 (m_c, 1 H), 2.81 , 2.91 (s, m_c, 4 H), 3.02 (s, 3 H), 3.68 (s, 3 H), 5.32 (dd, 1 H), 6.92 (s, 1 H), 7.24 (m_c, 3 H), 7.47 (m_c, 1 H).

Salt formation with glucuronic acid: (8S)-Λ/,Λ/,2,3-Tetramethyl-8-(2-methylphenyl)-3, 6,7,8- tetrahydrochromeno[7,8-<^imidazole-5-carboxamide (3.0 g, 8.25 mmol) was dissolved in isopropyl acetate (50 ml). The solution was heated to 55 ⁰C and glucuronic acid (2.0 g, 9.90 mmol) was added. The suspension was stirred for 5 h at 55 ⁰C and allowed to cool overnight to room temperature. The product was isolated by filtration and dried in vacuo at 50 ⁰C yielding the title compound as glucuronate salt (4.0 g, 75 % yield, m.p. 148-153 ⁰C, stoichiometric ratio with respect to glucuronic acid: 1 :1.48).

¹H-NMR (DMSOd₆, 300 MHz): δ = 1.99, 2.22 (2 m_c, 2 H), 2.38 (s, 3 H), 2.47 (s, 3 H), 2.65, 2.92 (2 m_c, 2 H), 2.94, 3.20 (2 m_c, 1 H), 2.81 , 3.02 (2 s, 6 H), 3.14, 3.42 (2 m_c, 1 H), 3.31 (m_c, 1 H), 3.59, 4.00 (2 d, 1 H), 3.68 (s, 3 H), 4.34 (d, 1 H), 4.5-5.0 (3 m_c, 3 H), 5.32 (dd, 1 H), 6.41 (m_c, 1 H), 6.74 (m_c, 1 H), 6.92 (s, 1 H), 7.24 (m_c, 3 H), 7.47 (m_c, 1 H).

Preparation of the title compound from its acid salts: The salt of the title compound with succinic acid (876 g, 2.05 mol) was suspended in dichloromethane (2.0 I) and water was added (0.5 I). To this suspension 25 % aqueous ammonia solution (0.4 I) was added under stirring. The mixture was stirred for further 0.5 h, the organic phase separated, and the aqueous phase was extracted with dichloromethane (3 x 0.5 I). The combined organic phases were washed with water (0.2 I), coevaporated with isobutylmethyl ketone (2 x 1.0 I), and the residue dissolved in isopropyl acetate (1.0 I) at 80 ⁰C. The solution was allowed to cool to room temperature over 3 h while product precipitated. The precipitate was isolated by filtration and dried in vacuo. This afforded the title compound (682 g of a colourless solid, 92 % yield, >92 % ee, m. p. 179-181 ⁰C, HPLC purity >99 %).

C. (1 fi)-3-[6-(Azetidin-1-ylcarbonyl)-4-hydroxy-1 ,2-dimethyl-1 W-benzimidazol-5-yl]-1-(2- methylphenyl)propan-1 -ol

A hydrogen pressure of 1 bar was applied to a suspension of (1 f?)-3-[6-(azetidin-1-ylcarbonyl)-4-(benzyloxy)- 1 ,2-dimethyl-1 /-/-benzimidazol-5-yl]-1-(2-methylphenyl)propan-1-ol (example 3, 4.0 g, 8.3 mmol) and palladium on charcoal (10 weight-%, 0.4 g) in methanol (100 ml). After a period of 3 hours at room temperature, the reaction mixture was filtered over a pad of diatomaceous earth. The pad was washed with a mixture of dichloromethane and methanol and the combined filtrates were concentrated. The residue was crystallized from acetone. The title compound was isolated in 69 % yield (2.23 g of an off-white solid, 99.5 % ee, m. p. 204-205 ⁰C).

Determination of the optical purity by capillary electrophoresis (capillary: Agilent barefused silica bubble, 56.0 / 64.5 cm x 50 μm. - buffer: 50 mM sodium phosphate (pH 2.5). - chiral selector: 40 mM heptakis(2,3,6- tri-O-methyl)-β-cyclodextrin. - voltage: 30 kV. - temperature: 20 ⁰C. - detection: diode array 219 nm): MT [(I S)-enantiomer] = 21.6 min / 0.22 area-%; MT [(1 F?)-enantiomer] = 22.3 min / 99.78 area-%, 99.5 % ee.

¹H-NMR (DMSOd₆, 400 MHz): δ = 1.70 (m_c, 1 H), 1.85 (m_c, 1 H), 2.16, 2.21 (m_c, s, 5 H), 2.51 (s), 2.64 (m_c, 1 H), 2.86 (m_c, 1 H), 3.66 (s, 3 H), 3.81 (m_c, 2 H), 3.96 (m_c, 2 H), 4.69 (m_c, 1 H), 5.15 (bs, 1 H), 6.83 (s, 1 H), 7.09 (m_c, 2 H), 7.16 (m_c, 1 H), 7.44 (d, 1 H), 9.76 (bs, 1 H).

D. (8S)-5-(Azetidin-1-ylcarbonyl)-2,3-dimethyl-δ-(2-methylphenyl)-3,6,7,δ-tetrahydrochromeno[7,δ- (^imidazole

To a suspension of (1 f?)-3-[6-(azetidin-1-ylcarbonyl)-4-hydroxy-1 ,2-dimethyl-1 /-/-benzimidazol-5-yl]-1-(2- methylphenyl)propan-1-ol (example C, 2.23 g, 5.7 mmol) and triphenylphosphine (1.9 g, 7.2 mmol) in dry tetrahydrofuran (40 ml), DIAD (1.5 ml, 1.54 g, 7.6 mmol) was added slowly. A greenish solution was obtained, which was stirred for 30 min at room temperature and poured onto a stirred mixture of ice water and ethyl acetate. A pH value of 2-3 was adjusted by addition of 2 N hydrochloric acid and stirring was continued for 10 min. The phases were separated and the organic phase was discarded. The aqueous phase was diluted with ethyl acetate (100 ml) and a pH value of 8 was adjusted by addition of 6 N sodium hydroxide solution. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 50 ml). The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The residue (a yellow foam) was purified by column chromatography [200 g of silica gel, eluant: ethyl acetate / triethylamine = 9:1 (v/v)]. Evaporation of the corresponding fractions and crystallization of the obtained residue from acetone / diethyl ether afforded the title compound (1.25 g of a colourless solid, 59 % yield, 99.2 % ee, m. p. 177-178 ⁰C).

HPLC analytical method: column: Daicel Chiralpak AD-H, 250 x 4.6 mm, 5 μm - eluant: n-heptane / ethanol: 80 / 20, flow rate: 1 ml/ min, detection wavelength: 218 nm - first eluting enantiomer: 12.5 min / 0.4 area-%, second eluting enantiomer: 21.3 min / 99.6 area-%, 99.2 % ee.

¹H-NMR (DMSOd₆, 300 MHz): δ = 1.95 (m_c, 1 H), 2.22 (m_c, 3 H), 2.38 (s, 3 H), 2.47 (s, 3 H), 2.82 (m_c, 1 H), 3.04 (m_c, 1 H), 3.69 (s, 3 H), 3.88 (m_c, 1 H), 4.05 (m_c, 3 H), 5.31 (dd, 1 H), 7.05 (s, 1 H), 7.26 (m_c, 3 H), 7.47 (m_c, 1 H).

E. 4-Hydroxy-5-[(3R)-3-hydroxy-3-(2-methylphenyl)propyl]-W-methoxy-Λ/,1 ,2-trimethyl-1 H- benzimidazole-6-carboxamide

A hydrogen pressure of 1 bar was applied to a suspension of 4-(benzyloxy)-5-[(3f?)-3-hydroxy-3-(2- methylphenyl)propyl]-Λ/-methoxy-Λ/,1 ,2-trimethyl-1 /-/-benzimidazole-6-carboxamide (example 4, 1.0 g, 2.1 mmol) and palladium on charcoal (10 weight-%, 0.1 g) in methanol (25 ml). After a period of 17 hours at room temperature, the reaction mixture was filtered over a pad of diatomaceous earth. The pad was washed with a mixture of dichloromethane and methanol (200 ml) and the combined filtrates were concentrated. The title compound was isolated in 82 % yield (670 mg of a brown foam, 98.2 % ee).

Determination of the optical purity by HPLC (column: CHIRALPAK AD-H 250 x 4.6 mm, 5 μm. - eluant: ethanol / n-heptane = 20:80 (v/v). - flow rate: 1 ml/min. - temperature: 25 ⁰C): RT [(3F?)-enantiomer] = 20.9 min; RT [(3S)-enantiomer] = 26.4 min.

¹H-NMR (DMSOd₆, 400 MHz): δ = 1.76 (m_c, 2 H), 2.23 (s, 3 H), 2.50 (s, m_c), 2.77 (m_c, 1 H), 3.10 (s, 3 H), 3.49 (bs, 3 H), 3.66 (s, 3 H), 4.71 (m_c, 1 H), 5.01 (bs, 1 H), 6.82 (s, 1 H), 7.07 (m_c, 2 H), 7.14 (m_c, 1 H), 7.41 (m_c, 1 H), 9.80 (bs, 1 H).

F. (8S)-Λ/-Methoxy-Λ/,2,3-trimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydrochromeno[7,8-c/]imidazole- 5-carboxamide

To a suspension of 4-hydroxy-5-[(3R)-3-hydroxy-3-(2-methylphenyl)propyl]-Λ/-methoxy-Λ/,1 ,2-trimethyl-1 H- benzimidazole-6-carboxamide (example E, 650 mg, 1.64 mmol) and triphenylphosphine (0.56 g, 2.1 mmol) in dry tetrahydrofuran (15 ml), DIAD (0.42 ml, 0.43 g, 2.1 mmol) was added slowly. The reaction mixture was stirred for 1 h at room temperature and was poured onto ice water (100 ml). Ethyl acetate (100 ml) was added and a pH value of 2-3 was adjusted by addition of 2 N hydrochloric acid. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 20 ml). The combined organic phases were discarded. The aqueous phase was diluted with ethyl acetate (100 ml) and a pH value of 7-8 was adjusted by addition of 6 N sodium hydroxide solution. The phases were separated and the aqueous phase was extracted with ethyl acetate (3 x 20 ml). The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The residue (a yellow oil) was purified twice by column chromatography [first column: 50 g of silica gel, eluant: dichloromethane / methanol = 13:1 (v/v), second column: 30 g of silica gel, eluant: ethyl acetate / triethylamine = 8:2 (v/v)]. Evaporation of the corresponding fractions and crystallization of the obtained residue from diethyl ether afforded the title compound (290 mg of a colourless solid, 47 % yield, 97.0 % ee, m.p. 178-180 ⁰C).

HPLC analytical method: column: Daicel Chiralpak AD-H, 250 x 4.6 mm, 5 μm - eluant: n-heptane / ethanol: 85 / 15, flow rate: 1 ml/ min, detection wavelength: 218 nm - first eluting enantiomer: 14.7 min / 1.5 area-%, second eluting enantiomer: 18.8 min / 98.5 area-%, 97.0 % ee.

¹H NMR (DMSOd₆, 400 MHz): δ = 1.98 (m_c, 1 H), 2.23 (m_c, 1 H), 2.38 (s, 3 H), 2.47 (s, 3 H), 2.68 (m_c, 1 H), 2.97 (m_c, 1 H), 3.22 (s, 3 H), 3.55 (s, 3 H), 3.69 (s, 3 H), 5.31 (dd, 1 H), 7.04 (s, 1 H), 7.25 (m_c, 3 H), 7.47 (m_c, 1 H).

G. 2-Cyclopropyl-4-hydroxy-5-[(3fi)-3-hydroxy-3-(2-methylphenyl)propyl]-Λ/,Λ/,1-trimethyl-1 W- benzimidazole-6-carboxamide

A hydrogen pressure of 1 bar was applied to a solution of (4-benzyloxy-2-cyclopropyl-5-[(3/^:?)-3-hydroxy-3-(2- methylphenyl)propyl]-Λ/,Λ/,1-trimethyl-1 /-/-benzimidazole-6-carboxamide (example 5, 2.7 g, 5.4 mmol) and palladium on charcoal (10 weight-%, 0.3 g) in ethanol (80 ml). After a period of 18 hours at room temperature, the hydrogenation catalyst was removed by filtration and washed with dichloromethane. The combined filtrates were evaporated to dryness. The title compound was obtained in 95 % yield (2.1 g of a colourless foam, 95.9 % ee). An analytical sample was crystallized from diethyl ether: m. p. 148-150 ⁰C.

Determination of the optical purity by HPLC (column: CHIRALPAK AD-H 250 x 4.6 mm, 5 μm. - eluant: ethanol / n-heptane = 15:85 (v/v). - flow rate: 1 ml/min. - temperature: 25 ⁰C): RT [(3F?)-enantiomer] = 17.7 min; RT [(3S)-enantiomer] = 21.3 min.

¹H-NMR (DMSOd₆, 300 MHz): δ = 1.06 (m_c, 4 H), 1.75 (m_c, 2 H), 2.19, 2.22 (m_c, s, 4 H), 2.55 (m_c), 2.69 (s, 3 H), 2.83, 2.92 (m_c, s, 4 H), 3.76 (s, 3 H), 4.69 (bs, 1 H), 5.03 (bs, 1 H), 6.71 (s, 1 H), 7.11 (m_c, 3 H), 7.43 (m_c, 1 H), 9.43 (bs, 1 H).

H. (8S)-2-Cyclopropyl-Λ/,Λ/,3-trimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydrochromeno[7,8- d]\m idazole-5-carboxam ide succi nate

To a suspension of 2-cyclopropyl-4-hydroxy-5-[(3R)-3-hydroxy-3-(2-methylphenyl)propyl]-Λ/,Λ/,1-trimethyl-1 H- benzimidazole-6-carboxamide (example G, 1.9 g, 4.7 mmol) and triphenylphosphine (1.6 g, 6.1 mmol) in dry tetrahydrofuran (40 ml), DIAD (1.18 ml, 1.21 g, 6.0 mmol) was added slowly. A greenish solution was obtained, which was stirred for 30 min at room temperature and poured onto a stirred mixture of saturated ammonium chloride solution (30 ml) and ethyl acetate (60 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 15 ml). The combined organic phases were washed with water (2 x 20 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue (5 g of a green oil) was purified twice by column chromatography [first column: 100 g of silica gel, eluant: ethyl acetate / methanol = 20:1 (v/v), second column: 50 g of silica gel, eluant: ethyl acetate / methanol = 100:1 (v/v)]. A solution of the free base of the title compound (1.25 g of a colourless foam) in methyl isobutyl ketone (10 ml) was treated with succinic acid (480 mg, 4.1 mmol). The resulting suspension was stirred for 50 minutes at 80 ⁰C and for 17 h at room temperature. The title compound was isolated by filtration, washed with methyl isobutyl ketone (3 ml), and dried in vacuo: 1.2 g of a colourless solid (95.6 % ee, 50 % yield, m. p. 146-148 ⁰C).

Determination of the optical purity by HPLC (column: CHIRALPAK AD-H 250 x 4.6 mm, 5 μm. - eluant: ethanol / n-heptane = 20:80 (v/v). - flow rate: 1 ml/min. - temperature: 25 ⁰C): RT [(3F?)-enantiomer] = 9.8 min; RT [(3S)-enantiomer] = 12.8 min.

¹H-NMR (DMSOd₆, 300 MHz, free base of the title compound): δ = 0.99 (m_c, 4 H), 2.00 (m_c, 1 H), 2.21 (m_c, 2 H), 2.37 (s, 3 H), 2.59 (m_c, 1 H), 2.80, 2.85 (s, m_c, 4 H), 3.01 (s, 3 H), 3.79 (s, 3 H), 5.30 (d, 1 H), 6.92 (s, 1 H), 7.25 (m_c, 3 H), 7.44 (m_c, 1 H).

¹H-NMR (DMSOd₆, 300 MHz, title compound): δ = 0.99 (m_c, 4 H), 2.00 (m_c, 1 H), 2.18 (m_c, 2 H), 2.37 (s, 3 H), 2.42 (s, succinic acid), 2.61 (m_c, 1 H), 2.80, 2.87 (s, m_c, 4 H), 3.79 (s, 3 H), 5.30 (dd, 1 H), 6.92 (s, 1 H), 7.25 (m_c, 3 H), 7.44 (m_c, 1 H), 12.12 (bs, succinic acid).

Synthesis of prochiral ketones of the formula 9

a. 5-[(Dimethylamino)methyl]-4-hydroxy-Λ/,Λ/,1 ,2-tetramethyl-1 H-benzimidazole-6-carboxamide hydroiodide

4-Hydroxy-Λ/,Λ/,1 ,2-tetramethyl-1 H-benzimidazole-6-carboxamide (see WO 2004/054984, 1500 g, 6.43 mmol) was suspended in a mixture of triethylamine (220 ml, 1.58 mol) and 2-propanol (12.0 I). Eschenmoser's salt (dimethylmethylideneammonium iodide; 1550 g, 8.36 mol) was added and the suspension stirred for 16 h at room temperature. The precipitate was isolated by filtration, and dried in vacuo (50 ⁰C) yielding 2800 g of the title compound (quantitative yield). This transformation is also feasible using dimethylmethylideneammonium chloride as reagent.

b. 5-[(Dimethylamino)methyl]-4-hydroxy-Λ/,Λ/,1 ,2-tetramethyl-1 H-benzimidazole-6-carboxamide hydrochloride

Method B: A mixture of 4-hydroxy-Λ/,Λ/,1 ,2-tetramethyl-1 /-/-benzimidazole-6-carboxamide (see WO 2004/054984, 5000 g, 21.43 mol) and dimethylammonium chloride (2300 g, 28.20 mol) in triethylamine (0.65 kg, 6.42 mol) and 2-propanol (35.0 I) was heated to 35-45 ⁰C and formaldehyde (37 % in water, 2300 g, 28.34 mol) was added over a period of 1-3 h at this temperature. While adding the formaldehyde, the reaction mixture was inoculated with several grams of product. After complete addition of the formaldehyde, the mixture was stirred further 1-3 h at 35-45 ⁰C. lsobutylmethyl ketone (35.0 I) was added and 15 I of distillate was removed at 35-60 ⁰C in vacuo. The reaction mixture was cooled to 10-20 ⁰C and stirred for a minimum of 1 h at this temperature. The precipitate was isolated by filtration and dried in vacuo (50 ⁰C) yielding 7000 g of the title compound (quantitative yield).

c. 4-Hydroxy-Λ/,Λ/,1 ,2-tetramethyl-5-[3-(2-methylphenyl)-3-oxopropyl]-1 H-benzimidazole-6- carboxamide

Method A. 5-[(Dimethylamino)methyl]-4-hydroxy-Λ/,Λ/,1 ,2-tetramethyl-1 /-/-benzimidazole-6-carboxamide (11.3 g, 32.8 mmol) was suspended in toluene (350 ml) and treated with 1-[1-(2-methylphenyl)-vinyl]-pyrrolidine (CAS 156004-72-7, 11.4 g, 60.8 mmol). The reaction mixture was refluxed for 4 h. After cooling to room temperature, the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel [dichloromethane / methanol = 10:1 (Wv)] and then dissolved in acetone (70 ml). Fumaric acid (3 g) was added and the solution was stirred overnight at room temperature. The precipitate was isolated by filtration, dissolved in dichloromethane and washed with aqueous saturated sodium hydrogen carbonate solution. The phases were separated, the organic layer was dried over magnesium sulfate and concentrated in vacuo. This afforded 6.7 g (55 % yield) of the title compound as a brown foam. Method B: 5-[(Dimethylamino)methyl]-4-hydroxy-Λ/,Λ/,1 ,2-tetramethyl-1 H-benzimidazole-θ-carboxamide hydrochloride (example b, 800 g, 2.34 mol) was dissolved in 2 N sodium hydroxide solution (2.3 I) and water (2.0 I) and added over a period of 1 h to a refluxing solution of ethyl 3-(2-methylphenyl)-3-oxopropanoate (669 g, 3.24 mol) in water (4.0 I) and toluene (4.0 I). The reaction mixture was stirred for 8 h at reflux. At room temperature, the precipitate was isolated by filtration and dried in vacuo (50 ⁰C) yielding 902 g of the crude title compound.

Over a period of 1 h, an aqueous solution of citric acid (1.3 M, 4.4 I) was added to a suspension of the crude product (902 g, 2.38 mol) in n-butanol (5.0 I). The suspension was stirred for 60 h at room temperature. The salt of the title compound with citric acid was isolated by filtration and dried in vacuo (50 ⁰C): 778 g (1.26 mol) of a colourless solid, 53 % yield (stoichiometric ratio with respect to citric acid: 1 :1.75).

¹H-NMR (DMSOd₆, 400 MHz): δ = 2.42 (s, 3 H), 2.52 (s, 3 H), 2.80 (s, 3 H), 3.00, 3.07 (s, bm_c, 7 H), 3.67 (s, 3 H), 6.78 (s, 1 H), 7.30 (m_c, 2 H), 7.42 (m_c, 1 H), 7.70 (m_c, 1 H), 10.00 (bs, 1 H).

A suspension of the salt of the title compound with citric acid (1020 g) in dichloromethane (6.0 I) and water (4.0 I) was neutralized with 25 % aqueous ammonia solution (~400 ml, pH 8-9). The phases were separated and the aqueous phase was extracted with dichloromethane (4.0 I). The combined organic phases were washed with water (1.0 I) and the solvent was evaporated. The residue was suspended in hot acetone (1.2 I), the suspension cooled down, the product isolated by filtration, and dried in vacuo (50 ⁰C). The pure title compound was obtained in 82 % yield (553 g, purity HPLC >96 %).

¹H-NMR (DMSOd₆, 200 MHz): δ = 2.42 (s, 3 H), 2.48 (s), 2.77, 2.80, 3.00, 3.05 (s, bm_c, s, bm_c, 10 H), 3.67 (s, 3 H), 6.78 (s, 1 H), 7.30 (m_c, 2 H), 7.42 (m_c, 1 H), 7.70 (m_c, 1 H), 10.00 (bs, 1 H).

d. 4-Benzyloxy-Λ/,Λ/,1 ,2-tetramethyl-5-[3-(2-methylphenyl)-3-oxopropyl]-1 H-benzimidazole-6- carboxamide

Benzyl bromide (15.4 g, 90.0 mmol) was slowly added to a suspension of 4-hydroxy-Λ/,Λ/,1 ,2-tetramethyl-5- [3-(2-methylphenyl)-3-oxopropyl]-1 /-/-benzimidazole-6-carboxamide (example c, 30.0 g, 79.1 mmol) and potassium carbonate (12.5 g, 90.4 mmol) in dry DMF (450 ml). The reaction mixture was stirred for 5 h at room temperature and poured on a stirred mixture of ammonium chloride solution (450 ml) and ethyl acetate (600 ml). Stirring was continued for several minutes. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 100 ml). The combined organic phases were washed with water (2 x), dried over sodium sulfate, and concentrated under reduced pressure. The residue (55 g of a colourless solid) was suspended in diethyl ether (100 ml). After a period of 1 hour at room temperature, the title compound was isolated by filtration, washed with diethyl ether (100 ml) and dried in vacuo (31.0 g of a colourless solid, 83 % yield, m. p. 146-148 ⁰C).

¹H-NMR (DMSOd₆, 400 MHz): δ = 2.36 (s, 3 H), 2.56 (s, m_c, 4 H), 2.74 (s, 3 H), 2.95, 2.99 (bs, s, 6 H), 3.71 (s, 3 H), 5.80 (s, 2 H), 7.03 (s, 1 H), 7.27 (m_c, 5 H), 7.40 (m_c, 3 H), 7.52 (m_c, 1 H). e. 4-Methoxy-Λ/,Λ/,1 ,2-tetramethyl-5-[3-(2-methylphenyl)-3-oxopropyl]-1 H-benzimidazole-6- carboxamide

Methyl iodide (3.5 ml, 8.0 g, 56.3 mmol) was slowly added to a suspension of 4-hydroxy-Λ/,Λ/,1 ,2-tetramethyl- 5-[3-(2-methylphenyl)-3-oxopropyl]-1 /-/-benzimidazole-6-carboxamide (example c, 15.0 g, 39.5 mmol) and potassium carbonate (8.0 g, 57.9 mmol) in dry DMF (180 ml). The reaction mixture was stirred for 17 h at room temperature and poured on a stirred mixture of ammonium chloride solution (400 ml) and ethyl acetate (600 ml). Stirring was continued for several minutes. The phases were separated and the aqueous phase was extracted with ethyl acetate (3 x 80 ml). The combined organic phases were washed with water (2 x 100 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue (13 g of a colourless oil) was crystallized from diethyl ether (50 ml). After a period of 1 hour at room temperature, the title compound was isolated by filtration, washed with diethyl ether (20 ml) and dried in vacuo (8.9 g of a colourless solid, 57 % yield, m. p. 125-127 ⁰C).

¹H-NMR (DMSOd₆, 300 MHz): δ = 2.42 (s, 3 H), 2.50 (s), 2.77, 2.77, 3.00, 3.05 (s, bs, s, bs, 10 H), 3.68 (s, 3 H), 4.29 (s, 3 H), 7.00 (s, 1 H), 7.31 (m_c, 2 H), 7.43 (m_c, 1 H), 7.72 (m_c, 1 H).

f. Ethyl 4-hydroxy-1 ,2-dimethyl-5-[3-(2-methylphenyl)-3-oxopropyl]-1 H-benzimidazole-6- carboxylate

A suspension of ethyl 5-[(dimethylamino)methyl-4-hydroxy-1 ,2-dimethyl-1 /-/-benzimidazole-6-carboxylate (45.0 g, 0.15 mol) in DME (600 ml) was heated to 85 ⁰C and a solution of 1-[1-(2-methylphenyl)-vinyl]- pyrrolidine (46.0 g, 0.25 mol) in DME (100 ml) was added drop-wise. The red reaction mixture was stirred for 4 h at 85 ⁰C and was concentrated under reduced pressure in the presence of silica gel. A column filled with 1 kg of silica gel was charged with the solid residue and the title compound was eluted with a mixture of dichloromethane and methanol [30:1 (v/v)]. Evaporation of the corresponding fractions furnished two batches of the title compound, which were slurried in hot isopropanol. Filtration of the first batch afforded 16.0 g of a colourless solid (pure title compound, 27 % yield, m. p. 183 ⁰C). The precipitate isolated by filtration of the second batch was treated with another portion of hot isopropanol. After filtration, 14.7 g of a pink solid was obtained (mixture of the title compound and ethyl 4-hydroxy-1 ,2-dimethyl-1 /-/-benzimidazole-6-carboxylate, (molar ratio 85:15, 23 % corrected yield).

g. Ethyl 8-methoxy-2,3-dimethyl-8-(2-methylphenyl)-3,6,7,8-tetrahydrochromeno[7,8-c/]imidazole- 5-carboxylate

2,2-Dimethoxypropane (135.7 ml, 1097 mmol) was added to a solution of ethyl 4-hydroxy-1 ,2-dimethyl-5-[3- (2-methylphenyl)-3-oxopropyl]-1 /-/-benzimidazole-6-carboxylate (example f, 28.0 g, 73.6 mmol) in dichloromethane (350 ml). After slow addition of methanesulfonic acid (6.2 ml, 95.5 mmol), the mixture was refluxed for 3 d. After cooling to room temperature, the reaction mixture was poured onto saturated sodium hydrogencarbonate solution. The biphasic mixture was stirred for 10 min. The phases were separated and the aqueous layer was extracted with dichloromethane (2 x). The collected organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from diisopropyl ether to afford 27.8 g (96 % yield) of the title compound as a beige solid. - m.p. 198 ° C.

h. δ-Methoxy-2,3-dimethyl-δ-(2-methylphenyl)-3,6,7,δ-tetrahydrochromeno[7,δ-c/]imidazole-5- carboxylic acid

To a suspension of ethyl δ-methoxy-2,3-dimethyl-δ-(2-methylphenyl)-3,6,7,δ-tetrahydrochromeno[7,δ- c(]imidazole-5-carboxylate (example g, 27.7 g, 70.2 mmol) in methanol (300 ml) and 1 ,4-dioxane (300 ml) was added a 2 M solution of sodium hydroxide in water (140 ml) and the mixture was heated to reflux for 2 h. After cooling to room temperature, the reaction mixture was poured into water and a pH value of 5-6 was adjusted by addition of concentrated hydrochloric acid. A precipitate was formed, which was isolated by filtration and dried in vacuo to afford 22.45 g (87 % yield) of the title compound as a beige solid. The mother liquor was concentrated and the pH value was re-adjusted to 5-6. Isolation of the precipitate afforded another batch of the title compound (3.2 g of a beige solid, 12 % yield) - m.p. 304-309° C.

i. 5-(Azetidin-1-ylcarbonyl)-δ-methoxy-2,3-dimethyl-δ-(2-methylphenyl)-3,6,7,δ- tetrahydrochromeno[7, 8- (^imidazole

A suspension of δ-methoxy^.S-dimethyl-δ^-methylpheny^-S.ΘJ.δ-tetrahydrochromeno^.δ-cdimidazole-S- carboxylic acid (example h, 12. δO g, 34.9 mmol) in DMF (400 ml) was treated with DIPEA (13.69 ml, 10.31 g, 79. δ mmol) and TBTU (15.4 g, 4δ.O mmol). The brown solution was stirred for 1 h at 40 °C and azetidine (4.25 ml, 3.60 g, 63.0 mmol) was added. Stirring was continued for 1 h at room temperature. The reaction mixture was concentrated and the residue was treated with water (100 ml) and dichloromethane (200 ml). The aqueous phase was extracted with dichloromethane (3 x 50 ml). The combined organic phases were washed with water (2 x 20 ml), dried over magnesium sulfate, and evaporated to dryness. A brown oil was obtained, which was purified by column chromatography [500 g of silica gel, eluant: ethyl acetate / triethylamine = δ:2 (v/v)] and subsequent washing with diethyl ether. This afforded the title compound in δ5 % yield (12.02 g of a colourless solid). - m. p. 220-221 °C.

j. 3-[6-(Azetidin-1-ylcarbonyl)-4-hydroxy-1 ,2-dimethyl-1 W-benzimidazol-5-yl]-1-(2- methylphenyl)propan-1 -one

Hydrochloric acid (135 ml of a 1 M solution in water, 135 mmol) was added to a suspension of 5-(azetidin-1 - ylcarbony^-δ-methoxy^.S-dimethyl-δ^-methylpheny^-S.ΘJ.δ-tetrahydrochromeno^.δ-cdimidazole (example i, 12.0 g, 29.6 mmol) in THF (300 ml). A solution was obtained, which was stirred at 50 ⁰C. After a period of 17 h the reaction mixture was concentrated, poured onto ice water (1000 ml), and neutralized by addition of aqueous sodium hydroxide solution (2 N). After a period of 30 min, dichloromethane was added (400 ml), and the phases were separated. The aqueous phase was extracted with dichloromethane (2 x 200 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The solid residue was slurried in diethyl ether. The title compound was isolated by filtration, washed with diethyl ether, and dried in vacuo (1 1.19 g of colourless crystals, 97 % yield). - m.p. 237-238 ⁰C.

¹H NMR (DMSOd₆, 400 MHz): δ = 2.19 (m_c, 2 H), 2.47 (s, 3 H), 2.52 (s), 2.95 (m_c, 2 H), 3.12 (m_c, 2 H), 3.68 (s, 3 H), 3.91 (t, 2 H), 4.01 (t, 2 H), 6.90 (s, 1 H), 7.31 (m_c, 2 H), 7.42 (m_c, 1 H), 7.74 (d, 1 H), 10.02 (bs, 1 H).

k. 3-[6-(Azetidin-1-ylcarbonyl)-4-(benzyloxy)-1 ,2-dimethyl-1 H-benzimidazol-5-yl]-1-(2- methylphenyl)propan-1 -one

Benzyl bromide (5.0 g, 29.5 mmol) was slowly added to a suspension of 3-[6-(azetidin-1-ylcarbonyl)-4- hydroxy-1 ,2-dimethyl-1 /-/-benzimidazol-5-yl]-1-(2-methylphenyl)propan-1-one (example j, 11.0 g, 28.1 mmol) and potassium carbonate (4.0 g, 29.0 mmol) in dry DMF (140 ml). The reaction mixture was stirred for 17 h at 65 ⁰C. More benzyl bromide (1.93 g, 11.3 mmol) and potassium carbonate (1.55 g, 11.2 mmol) was added and the reaction was continued for 1 h. The reaction mixture was poured on a stirred mixture of ammonium chloride solution (200 ml) and dichloromethane (300 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (3 x 150 ml). The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography [300 g of silica gel, eluant: ethyl acetate / triethylamine = 9:1 (Wv)] . Evaporation of the corresponding fractions afforded a colourless solid, which was suspended in diethyl ether. After a period of 17 hours at room temperature, the title compound was isolated by filtration, washed with diethyl ether, and dried in vacuo (10.9 g of a colourless solid, 81 % yield, m. p. 141-142 ⁰C).

¹H NMR (DMSOd₆, 300 MHz): δ = 2.20 (m_c, 2 H), 2.36 (s, 3 H), 2.56 (s, 3 H), 2.97 (m_c, 4 H), 3.72 (s, 3 H), 3.90 (m_c, 2 H), 4.01 (m_c, 2 H), 5.77 (s, 2 H), 7.13 (s, 1 H), 7.27 (m_c, 5 H), 7.40 (m_c, 3 H), 7.57 (d, 1 H).

I. Λ/,δ-Dimethoxy-Λ/,2,3-trimethyl-δ-(2-methylphenyl)-3,6,7,δ-tetrahydrochromeno[7,δ-d]imidazole- 5-carboxamide

A suspension of δ-methoxy^.S-dimethyl-δ^-methylpheny^-S.ΘJ.δ-tetrahydrochromeno^.δ-cdimidazole-S- carboxylic acid (example h, 5.00 g, 12.4 mmol) in DMF (160 ml) was treated with DIPEA (5.2 ml, 3.9 g, 30.3 mmol) and TBTU (6.0 g, 1δ.7 mmol). The brown solution was stirred for 45 minutes at 40 ⁰C and N, O- dimethylhydroxylamine hydrochloride (2.45 g, 25.1 mmol) was added at room temperature. Stirring was continued for 17 h at room temperature. The reaction mixture was concentrated and the residue was treated with water and dichloromethane. The organic phase was washed with water (2 x) and saturated sodium bicarbonate solution (1 x). The aqueous phase was extracted with dichloromethane (2 x). The combined organic phases were dried over magnesium sulfate and evaporated to dryness. The residue was purified by column chromatography [150 g of silica gel, eluant: ethyl acetate / triethylamine = 8:2 (v/v)]. This afforded the title compound in 85 % yield (4.37 g of a colourless solid). - m. p. 240-241 ⁰C.

¹H NMR (DMSOd₆, 300 MHz): δ = 1.88 (m_c, 1 H), 2.39 (m_c, 1 H), 2.48 (s, 3 H), 2.53, 2.55 (s, m_c, 4 H), 2.96, 3.02 (m_c, s, 4 H), 3.21 (s, 3 H), 3.54 (s, 3 H), 3.72 (s, 3 H), 7.1 1 (s, 1 H), 7.28 (m_c, 3 H), 7.70 (m_c, 1 H).

m. 4-Hydroxy-W-methoxy-Λ/,1 ,2-trimethyl-5-[3-(2-methylphenyl)-3-oxopropyl]-1 W-benzimidazole-6- carboxamide

Hydrochloric acid (48 ml of a 1 M solution in water, 48 mmol) was added to a suspension of Λ/,8-dimethoxy- Λ/^.S-trimethyl-δ^-methylpheny^-S.ΘJ.δ-tetrahydrochromeno^.δ-dlimidazole-S-carboxamide (example I, 4.30 g, 10.5 mmol) in THF (1 10 ml). A solution was obtained, which was stirred at 50 ⁰C. After a period of 17 h, the reaction mixture was concentrated, poured onto ice water (250 ml), and neutralized by addition of aqueous sodium hydroxide solution (2 N). Dichloromethane was added and the phases were separated. The aqueous phase was extracted with dichloromethane (3 x 100 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The solid residue was slurried in a mixture of diethyl ether and acetone. The title compound was isolated by filtration, washed with diethyl ether, and dried in vacuo (3.82 g of colourless crystals, 92 % yield, m.p. 190-192 ⁰C).

¹H NMR (DMSOd₆, 300 MHz): δ = 2.41 (s, 3 H), 2.53 (s, 3 H), 2.84 (m_c, 2 H), 3.09 (m_c, 2 H), 3.18 (s, 3 H), 3.53 (bs, 3 H), 3.68 (s, 3 H), 6.90 (s, 1 H), 7.30 (m_c, 2 H), 7.42 (m_c, 1 H), 7.69 (m_c, 1 H), 10.02 (bs, 1 H).

n. (4-Benzyloxy)-Λ/-methoxy-Λ/,1 ,2-trimethyl-5-[3-(2-methylphenyl)-3-oxopropyl]-1 H-benzimidazole- 6-carboxamide

Benzyl bromide (1.2 ml, 1.73 g, 10.1 mmol) was slowly added to a suspension of 4-hydroxy-Λ/-methoxy- Λ/,1 ,2-trimethyl-5-[3-(2-methylphenyl)-3-oxopropyl]-1 /-/-benzimidazole-6-carboxamide (example m, 3.80 g, 9.6 mmol) and potassium carbonate (1.4 g, 10.1 mmol) in dry DMF (50 ml). The reaction mixture was stirred for 4 h at 65 ⁰C. The reaction mixture was poured on ice water (200 ml). Saturated sodium bicarbonate solution and dichloromethane (150 ml) was added. The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 100 ml). The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The residue was slurried in diethyl ether. After a period of 30 minutes at room temperature, the title compound was isolated by filtration, washed with diethyl ether, and dried in vacuo (4.2 g of a colourless solid, 90 % yield, m.p. 120-122 ⁰C).

¹H NMR (DMSOd₆, 300 MHz): δ = 2.36 (s, 3 H), 2.57 (s, 3 H), 2.83 (m_c, 2 H), 2.93 (m_c, 2 H), 3.18 (s, 3 H), 3.51 (bs, 3 H), 3.72 (s, 3 H), 5.80 (s, 2 H), 7.14 (s, 1 H), 7.26 (m_c, 5 H), 7.39 (m_c, 3 H), 7.51 (m_c, 1 H). o. Ethyl 2-{[2-cyclopropyl-6-(dimethylcarbamoyl)-4-hydroxy-1 -methyl-1 H-benzimidazol-5- yl]methyl}-3-(2-methylphenyl)-3-oxopropanoate

A suspension of 2-cyclopropyl-5-[(dimethylamino)methyl]-4-hydroxy-Λ/,Λ/,1-trimethyl-1 /-/-benzimidazole-6- carboxamide iodide (14.0 g, 32.8 mmol) and ethyl 3-(2-methylphenyl)-3-oxopropanoate (8.0 g, 38.8 mmol) in dry toluene (120 ml) was heated to 60 ⁰C and a mixture of potassium tert-pentylate (solution in toluene, 25 weight-%, 42 ml) and DMF (22 ml) was added over a period of 40 minutes. The reaction mixture was stirred for 5 h at 60 ⁰C, cooled, and poured on a mixture of saturated ammonium chloride solution (160 ml) and ethyl acetate (350 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (40 ml). The combined organic phases were washed with water (2 x 40 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography [220 g of silica gel, eluant: dichloromethane, then dichloromethane / methanol = 100:2 (v/v)]. Evaporation of the corresponding fractions afforded the title compound (6.5 g of a yellow-brown foam, 43 % yield), which was used without further purification for the hydrolysis / decarboxylation described in example p.

¹H NMR (DMSOd₆, 300 MHz): δ = 0.92 (m_c, 3 H), 1.04 (m_c, 4 H), 2.20 (m_c, 1 H), 2.35 (s, 3 H), 2.73 (s, 3 H), 2.98 (s, 3 H), 3.20 (bs), 3.77 (s, 3 H), 3.91 (m_c, 2 H), 4.66 (t, 3 H), 6.79 (s, 1 H), 7.15-7.41 (m), 9.70 (bs, 1 H).

p. 2-Cyclopropyl-4-hydroxy-Λ/,Λ/,1-trimethyl-5-[3-(2-methylphenyl)-3-oxopropyl]-1 W-benzimidazole- 6-carboxamide

A flask containing a solution of ethyl 2-{[2-cyclopropyl-6-(dimethylcarbamoyl)-4-hydroxy-1-methyl-1 H- benzimidazol-5-yl]methyl}-3-(2-methylphenyl)-3-oxopropanoate (example o, 6.2 g, 13.0 mmol) in methanol (100 ml) was put into an oil-bath, which had been pre-heated to 85 ⁰C. A solution of cesium carbonate (21.0 g, 64.5 mmol) in water (30 ml) was added and the brown solution was stirred for 4 h at 85 ⁰C. The reaction mixture was cooled and poured on a stirred mixture of saturated ammonium chloride solution (100 ml) and dichloromethane (250 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (30 ml). The combined organic phases were washed with water (40 ml), dried over sodium sulfate, and concentrated under reduced pressure. This afforded the crude title compound in 89 % yield (4.7 g of a yellow foam), which was used without further purification for the benzylation reaction described in example q.

¹H NMR (DMSOd₆, 300 MHz): δ = 1.06 (m_c, 4 H), 2.21 (m_c, 1 H), 2.41 (s, 3 H), 2.77, 2.77, 2.99, 3.02 (bs, s, s, bs, 10 H), 3.78 (s, 3 H), 6.78 (s, 1 H), 7.30 (m_c, 2 H), 7.41 (m_c, 1 H), 7.70 (m_c, 1 H), 9.63 (bs, 1 H).

q. 4-(Benzyloxy)-2-cyclopropyl-Λ/,Λ/,1-trimethyl-5-[3-(2-methylphenyl)-3-oxopropyl]-1 W- benzimidazole-6-carboxamide Benzyl bromide (2.45 g, 14.3 mmol) was slowly added to a suspension of 2-cyclopropyl-4-hydroxy-Λ/,Λ/,1- trimethyl-5-[3-(2-methylphenyl)-3-oxopropyl]-1 /-/-benzimidazole-6-carboxamide (example p, 4.5 g, 11.1 mmol) and potassium carbonate (2.0 g, 14.5 mmol) in dry DMF (70 ml). The reaction mixture was stirred for 4 h at 55 ⁰C, cooled, and poured on a stirred mixture of saturated ammonium chloride solution (70 ml) and ethyl acetate (180 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 20 ml). The combined organic phases were washed with water (2 x 30 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue (5.7 g of a brown foam) was purified by column chromatography [200 g of silica gel, eluant: dichloromethane, then dichloromethane / methanol = 100:1 (v/v)]. Evaporation of the corresponding fractions afforded a yellow oil (4.3 g), which was dissolved in hot diethyl ether (30 ml). After a period of 18 h, the precipitate was isolated by filtration, washed with diethyl ether (15 ml), and dried. This afforded the title compound in 51 % yield (2.8 g of a colourless solid, m.p. 122- 124 ⁰C).

¹H-NMR (DMSOd₆, 300 MHz): δ = 1.09 (m_c, 4 H), 2.24 (m_c, 1 H), 2.37 (s, 3 H), 2.73, 2.73, 2.91 , 2.99 (s, bs, bs, s, 10 H), 3.81 (s, 3 H), 5.75 (s, 2 H), 7.00 (s, 1 H), 7.32 (m_c, 8 H), 7.54 (m_c, 1 H).

r. Ethyl 2-{[1 ,2-dimethyl-6-(dimethylcarbamoyl)-4-hydroxy-1 H-benzimidazol-5-yl]methyl}-3-(2,6- dimethylphenyl)-3-oxopropanoate

A suspension of 5-[(dimethylamino)methyl]-4-hydroxy-Λ/,Λ/,1 ,2-tetramethyl-1 /-/-benzimidazole-6-carboxamide iodide (23.3 g, 56 mmol) and ethyl 3-(2,6-dimethylphenyl)-3-oxopropanoate (17.0 g, 77 mmol) in dry toluene (300 ml) was heated to 75 ⁰C and a mixture of potassium tert-pentylate (1.7 M solution in toluene, 80.0 ml, 136 mmol) and DMF (100 ml) was added over a period of 40 minutes. The reaction mixture was stirred for 17 h at 75 ⁰C, cooled, and poured on a mixture of saturated ammonium chloride solution (400 ml) and ethyl acetate (600 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 100 ml). The combined organic phases were concentrated under reduced pressure and a yellow solid (20 g) was isolated. The aqueous phase was neutralized and extracted with dichloromethane (3 x 150 ml). The dichloromethane phases were washed with water (100 ml) and dried over sodium sulfate. The solvent was evaporated in vacuo and a yellow solid (23 g) remained. The combined crude product (43 g) was purified by column chromatography [450 g of silica gel, eluant: dichloromethane / methanol = 100:4 (v/v)] and crystallization from acetone (80 ml). The title compound was isolated by filtration, washed with acetone (20 ml) and diethyl ether (50 ml), and dried in vacuo (11.2 g of a colourless solid, 43 % yield, m. p. 240-242 ⁰C).

¹H-NMR (DMSOd₆, 300 MHz, 383 K): δ = 0.90 (t, 3 H), 2.18 (s, m_c, 7 H), 2.50 (s), 2.87 (bs, 6 H), 3.64 (s, 3 H), 3.82 (q, 2 H), 4.36 (bs, 1 H), 6.72 (s, 1 H), 7.02 (m_c, 2 H), 7.15 (m_c, 1 H).

s. 4-Hydroxy-Λ/,Λ/,1 ,2-tetramethyl-5-[3-(2,6-dimethylphenyl)-3-oxopropyl]-1 H-benzimidazole-6- carboxamide Method A: At a temperature of 85 ⁰C, a solution of 5-[(dimethylamino)methyl]-4-hydroxy-Λ/,Λ/,1 ,2-tetramethyl- 1 /-/-benzimidazole-6-carboxamide iodide (22.6 g, 54 mmol) in water (60 ml) and 2 N sodium hydroxide solution (65 ml) was slowly added to a solution of ethyl 3-(2,6-dimethylphenyl)-3-oxopropanoate (15.0 g, 68.1 mmol) in toluene (150 ml) and water (80 ml). The yellow biphasic mixture was stirred for 7 h at 85 ⁰C, cooled to room temperature, and poured on a mixture of saturated ammoniujm chloride solution (200 ml) and ethyl acetate (300 ml). The aqueous phase was treated with 2 N hydrochloric acid until a pH value of 8 was obtained. The organic phase, which contained solid title compound, was separated. The aqueous phase was extracted with ethyl acetate (100 ml). The combined organic phases were washed with water (2 x 150 ml) and the solvent was evaporated. The yellow residue was suspended in acetone (50 ml). After a period of 2 h at room temperature, the precipitate was isolated by filtration and washed with acetone (20 ml) and diethyl ether (50 ml). The title compound was dried in vacuo (8.1 g, 38 % yield, m.p. 233-235 ⁰C). The mother liquor was concentrated and the residue was purified by column chromatography [200 g of silica gel, eluant: ethyl acetate / methanol = 20:1 (v/v)] and subsequently washed with acetone (10 ml). This afforded a second batch of the title compound (2.9 g of a colourless solid, 14 % yield).

¹H-NMR (DMSOd₆, 300 MHz): δ = 2.16 (s, 6 H), 2.50 (s), 2.76, 2.88, 2.98 (s, bs, s, 10 H), 3.65 (s, 3 H), 6.75 (s, 1 H), 7.05 (m_c, 2 H), 7.17 (m_c, 1 H), 10.01 (bs, 1 H).

Method B: A suspension of ethyl 2-{[1 ,2-dimethyl-6-(dimethylcarbamoyl)-4-hydroxy-1 /-/-benzimidazol-5- yl]methyl}-3-(2,6-dimethylphenyl)-3-oxopropanoate (example r, 4.50 g, 9.7 mmol) in isopropanol (80 ml) was heated to 90 ⁰C. An aqueous solution of cesium carbonate (15.8 g, 48.6 mmol in 30 ml of water) was added slowly. After a reaction time of 22 h, the brown reaction mixture was cooled and poured on a mixture of saturated ammonium chloride solution (120 ml) and dichloromethane (250 ml). A pH value of 8 was adjusted by addition of 6 N hydrochloric acid. The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 30 ml). The combined organic phases were washed with water (2 x 40 ml), dried over sodium sulfate, and the solvent was evaporated. The title compound was dried in vacuo (4.1 g of an off-white solid containing 13 weight-% of 2-propanol, 93 % yield).

t. 4-(Benzyloxy)-Λ/,Λ/,1 ,2-tetramethyl-5-[3-(2,6-dimethylphenyl)-3-oxopropyl]-1 H-benzimidazole-6- carboxamide

Benzyl bromide (3.6 ml, 5.2 g, 30 mmol) was slowly added to a suspension of 4-hydroxy-Λ/,Λ/,1 ,2- tetramethyl-5-[3-(2,6-dimethylphenyl)-3-oxopropyl]-1 /-/-benzimidazole-6-carboxamide (example s, 10.5 g, 27 mmol) and potassium carbonate (4.2 g, 30 mmol) in dry DMF (150 ml). The reaction mixture was stirred for 4 h at 80 ⁰C, cooled, and poured on a stirred mixture of saturated ammonium chloride solution (200 ml) and ethyl acetate (400 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 50 ml). The combined organic phases were washed with water (2 x 100 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residue (20 g of a brown oil) was purified by column chromatography [200 g of silica gel, eluant: ethyl acetate / methanol = 100:4 (v/v)] and was washed with acetone (50 ml). The precipitate was isolated by filtration, washed with acetone (10 ml) and diethyl ether (30 ml), and dried. This afforded the title compound in 51 % yield (6.6 g of a colourless solid, m.p. 200-202 ⁰C).

¹H-NMR (DMSOd₆, 300 MHz): δ = 2.04 (s, 6 H), 2.55 (s, 3 H), 2.74, 2.75, 2.99 (s, bs, s, 10 H), 3.69 (s, 3 H), 5.78 (s, 2 H), 7.03 (m_c, 3 H), 7.15 (m_c, 1 H), 7.32 (m_c, 3 H), 7.41 (m_c, 2 H).

1-[1-(2-Methylphenyl)-vinyl]-pyrrolidine is a known compound and was synthesized following procedures analogous to those described in Synthesis 2004, 4, 521-524 (J. Palecek, O. Paleta).

Industrial applicability

The compounds of the formula 1-a and of the formula 1-b are valuable intermediates for the preparation of enantiomerically pure 8-aryl-3,6,7,8-tetrahydro-chromeno[7,8-c(|imidazoles derivatives of the formula 3-a or 3-b respectively. These 8-aryl-3,6,7,8-tetrahydro-chromeno[7,8-c(]imidazoles derivatives are compounds with valuable pharmacological properties, which make them commercially utilizable, as it was described for example in WO 04/087701.

Claims

1. A compound of the formula 1-a or 1-b

HO

where in a first group of compounds

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C- alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl or mono- or di-1-4C-alkylamino,

R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1- 4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, fluoro-1-4C-alkyl, 'MC-alkoxy-'MC-alkoxy-'MC- alkyl, 1-4C-alkoxy-1-4C-alkyl wherein the 1-4C-alkoxy is substituted by a SiR8R9R10 radical, 1-4C- alkylcarbonyl, aryl-CH₂-oxycarbonyl, R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C- alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-

R31 is hydrogen, hydroxy, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or

1-4C-alkoxy and

R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, hydroxy-pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group,

Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is selected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, 1 ,2,3-triazolyl, indolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxazolyl or pyrimidinyl, wherein

R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, or where in a second group of compounds

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkyl-1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkyl-1-4C-alkyl,

R3 is either a group -CO-NR31 R32, where

and

whereby

52 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

R5 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or halogen, and

R6 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or halogen, and where in the first group of compounds and in the second group of compounds PG is 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, I^C-alkoxy-I^C-alkoxy-I^C- alkyl, 1-4C-alkoxy-1-4C-alkyl wherein the 1-4C-alkoxy is substituted by a SiR8R9R10 radical; tetrahydropyran, tetrahydrofuran, aryl-1-4C-alkyl, 3-7C-cycloalkyl, 1-4C-alkylcarbonyl, aryl-carbonyl, 1- 4C-alkoxycarbonyl, aryl-1-4C-alkylcarbonyl, aryl-1-4C-alkoxycarbonyl, a radical SiR8R9R10 or a radical SO₂-R11 wherein

2. A compound of the formula 1-a or 1-b as claimed in claim 1 where

R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, aryloxy-1-4C- alkyl, halogen, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, "MC-alkoxycarbonylamino, 1-4C-alkoxy-1-4C- alkoxycarbonylamino or aryl-1-4C-alkoxy-1-4C-alkyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen,

3. A compound of the formula 1-a or 1-b as claimed in claim 1 where

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkyl-1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkyl-1-4C-alkyl,

R3 is either a group -CO-NR31 R32, where

and

R32 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino, aziridino, azetidino, piperidino, piperazino, N-1-4C-alkylpiperazino or morpholino group, which bear each one or more substituent(s) S1 , with the proviso that if R31 and R32 together including the nitrogen atom to which both are bonded represent a pyrrolidino group, monosubstitution with S1 = hydroxy is excluded, or R3 is a residue selected from the group consisting of

whereby

52 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,

R5 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or halogen, and

R6 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or halogen and

4. A compound of the formula 1-a or 1-b as claimed in claim 1 , in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or hydroxy-1-4C-alkyl,

R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl wherein the 1-4C-alkoxy is substituted by a SiR8R9R10 radical, 1-4C-alkylcarbonyl or aryl-CH₂-oxycarbonyl, R3 is carboxyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C- alkoxy-1-4C-alkyl, or the group -CO-NR31 R32, where R31 is hydrogen, hydroxy, 1-7C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 1-4C-alkoxy and

R5 is hydrogen, 1-4C-alkyl, or halogen,

R6 is hydrogen, 1-4C-alkyl or halogen and

5. A compound of the formula 1-a or 1-b as claimed in claim 1 , in which

R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or hydroxy-1-4C-alkyl,

NR31 R32, where

Ar is selected from one of the following groups

R4

wherein

6. A compound of the formula 1-a or 1-b as claimed in claim 1 , in which

R1 is 1-4C-alkyl or 3-7C-cycloalkyl,

R2 is 1-4C-alkyl,

R3 is the group -CO-NR31 R32 where

R31 is 1-7C-alkyl or 1-4C-alkoxy,

R32 is 1-7C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are an azetidino group, Ar is a group

wherein

R4 is 1-4C-alkyl, R5 is hydrogen, R6 is hydrogen or 1-4C-alkyl

7. A compound of the formula 1-a or 1-b as claimed in claim 1 , in which

R1 is 1-4C-alkyl or 3-7C-cycloalkyl,

R2 is 1-4C-alkyl,

R3 is the group -CO-NR31 R32 where

R31 is 1-7C-alkyl or 1-4C-alkoxy,

R32 is 1-7C-alkyl, or where

wherein

R4 is 1-4C-alkyl,

R5 is hydrogen, R6 is hydrogen or 1-4C-alkyl PG is benzyl or 1-4C-alkyl.

8. A process of preparing a compound of the formula 1-a comprising a catalytic hydrogenation of a compound of the formula 2 in the presence of RuCI₂[(S)-Xyl-P-Phos][( S)-DAIPEN],

in which R1 , R2, R3, Ar and PG have the meanings as indicated in any of claims 1 to 7.

9. A process of preparing a compound of the formula 1-b comprising a catalytic hydrogenation of a compound of the formula 2 in the presence of RuCI₂[( fl)-Xyl-P-Phos][( RJ-DAIPEN],

10. The use of RuCI₂[(S)-Xyl-P-Phos][( S)-DAIPEN] as the hydrogenation catalyst in a process according to claim 8 for the preparation of compounds of the formula 1-a from compounds of the formula 2, in which R1 , R2, R3, Ar and PG have the meanings as indicated in any of claims 1 to 7.

11. The use of RuCI₂[( fl)-Xyl-P-Phos][( R)-DAIPEN] as the hydrogenation catalyst in a process according to claim 9 for the preparation of compounds of the formula 1-b from compounds of the formula 2, in which R1 , R2, R3, Ar and PG have the meanings as indicated in any of claims 1 to 7.

12. A process of preparing a compound of the formula 6-a comprising a deprotection reaction of a compound of the formula 1-a,

13. A process of preparing a compound of the formula 6-b comprising a deprotection reaction of a compound of the formula 1-b,

14. The use of compounds of the formula 1-a, in which R1 , R2, R3, Ar and PG have the meanings as indicated in claim 1 or claim 2 or claim 3 or claim 4 or claim 5, for the preparation of compounds of the formula 6-a,

in which R1 , R2, R3 and Ar have the meanings as indicated in any of claims 1 to 7.

15. The use of compounds of the formula 1-b, in which R1 , R2, R3, Ar and PG have the meanings as indicated in any of claims 1 to 7, for the preparation of compounds of the formula 6-b,

16. The use of compounds of the formula 1-a, in which R1 , R2, R3, Ar and PG have the meanings as indicated in any of claims 1 to 7, for the preparation of compounds of the formula 3-a and their salts,

Ar (3-a) in which R1 , R2, R3 and Ar have the meanings as indicated in any of claims 1 to 7.

17. The use of compounds of the formula 1-b, in which R1 , R2, R3, Ar and PG have the meanings as indicated in any of claims 1 to 7, for the preparation of compounds of the formula 3-b and their salts,

18. The use of compounds of the formula 1-b, in which R1 , R2, R3, Ar and PG have the meanings as indicated in any of claims 1 to 7, for the preparation of compounds of the formula 3-a and their salts,

19. The use of compounds of the formula 1-a, in which R1 , R2, R3, Ar and PG have the meanings as indicated in any of claims 1 to 7, for the preparation of compounds of the formula 3-b and their salts,

18. A process of preparing a compound of the formula 1-a comprising a catalytic transfer hydrogenation of a compound of the formula 2

wherein R1 , R2, R3, Ar and PG have the meanings as indicated in any of claims 1 to 7for the compounds of the formula 1-a, in the presence of a RuCI₂[η⁶-arene]₂ precatalyst and an aminoalcohol of the formula A

Rb is phenyl or phenyl substituted by a 1-4C-alkoxy or 1-4C-alkyl group.

19. A process of preparing a compound of the formula 1-b comprising a catalytic transfer hydrogenation of a compound of the formula 2

wherein R1 , R2, R3, Ar and PG have the meanings as indicated in any of claims 1 to 7 for the compounds of the formula 1-b in the presence of a RuCI₂[η⁶-arene]₂ precatalyst and an aminoalcohol of the formula B H₂N OH

Ra -W^'" Rb ^(β) H Rb wherein arene is benzene or benzene substituted by one or two substituents from the group consisting of 1-4C-alkoxy and 1-4C-alkyl

Ra is 1-7C-alkyl Rb is phenyl or phenyl substituted by a 1-4C-alkoxy or 1-4C-alkyl group.

20. A compound of the formula 2,

in which R1 , R2, R3, Ar and PG have the meanings as indicated in any of claims 1 to 7 for the compounds of the formula 1-a, and its salts.

21 . A process for the preparation of compounds of the formula 9, which comprises - reaction of a compound of the formula 10 with a compound of the formula 11

in which R1 , R2, R3 and Ar have the meanings as indicated in any of claims 1 to 7 for the compounds of the formula 1-a, and wherein R is a suitable radical.

22. A process for the preparation of compounds of the formula 12, which comprises - reaction of a compound of the formula 10 with a compound of the formula 11

23. A process for the preparation of compounds of the formula 9, which comprises - conversion of a compound of the formula 12 to a compound of the formula 9

24. A process for the preparation of compounds of the formula 9, which comprises

- reaction of a compound of the formula 10 with a compound of the formula 11 to compounds of the formula 12

- and further conversion of a compound of the formula 12 to a compound of the formula 9

25. A compound of the formula 12

in which R1 , R2, R3 and Ar have the meanings as indicated in any of claims 1 to 7 for the compounds of the formula 1-a, and wherein R is a suitable radical, and its salts.