Process For Preparing (r Or S)-2-alkyl-3-heterocyclyl-1-propanols

Process for preparing (R or S)-2-alkyl-3-heterocvclyl-1 -propanols

FIELD OF THE INVENTION

The invention relates to a stereoselective process for preparing (R or S)-2-alkyl-3- heterocyclyl-1 -propanols and novel intermediates which are obtained in the process stages.

BACKGROUND OF THE INVENTION

WO 2005/090305 A1 describes delta-amino-gamma-hydroxy-omega-heterocyclyl- alkanecarboxamides which have renin-inhibiting properties and can be used as antihypertensives in pharmaceutical formulations. The preparation processes described there, which proceed via a coupling of a heterocyclyl-metal species to an aldehyde as the key step, are unsuitable for an industrial process especially with regard to the sometimes unsatisfactory yields.

DETAILED DESCRIPTION OF THE INVENTION

In a novel process, the starting materials are 2,7-dialkyl-8-heterocyclyl-4-octenoyl- amides whose double bond is simultaneously halogenated in the 5-position and hydroxylated with lactonization in the 4-position, the halogen is then replaced with azide, the lactone is amidated and then the azide is converted to the amine. The desired alkanecarboxamides are obtained avoiding steps unsuitable for an industrial process. The halolactonization, the azidation and the azide reduction are performed on the basis of the process described by P. Herald in Journal of Organic Chemistry, VoI . 54 (1989), pages 1178-1185.

The 2,7-dialkyl-8-heterocyclyl-4-octenoylamides may, for example, correspond to the formula A

in which Het is a bicyclic unsaturated heterocyclyl bonded to the rest of the molecule via a carbon atom, where the ring not bonded directly to the rest of the molecule is substituted by R'i and R'2, R'i and R'2 are each independently H, d-Cβ-alkyl, halogen, polyhalo-d-Cs-alkoxy, polyhalo-Ci-Cs-alkyl, d-Cs-alkoxy, Ci-Cs-alkoxy- d-Cs-alkyl or Ci-Cs-alkoxy-Ci-Cs-alkoxy, where R'i and R'2 are simultaneously not both H, R's is Ci-C8-alkyl, R4 is Ci-C8-alkyl, R'5 is Ci-C8-alkyl or Ci-C8-alkoxy, R'6 is d-Cs-alkyl, or R'5 and R'6 together are optionally Ci-C4-alkyl-, phenyl- or benzyl- substituted tetramethylene, pentamethylene, 3-oxa-1 ,5-pentylene or -CH2CH2O- C(O)-, and in which the carbon atom to which the R'3 radical is bonded has either the (R)- or (S)-configuration, preference being given to the (R)-configuration.

The compounds of the formula A are obtainable by reacting a compound of the formula B

with a compound of the formula C

R1.

in which Het and R'i to R'β are each as defined above, Y is Cl, Br or I and Z is Cl, Br or I, and in which the carbon atom to which the R'3 radical is bonded has either the (R)- or (S)-configuration, preference being given to the (R)-configuration, in the presence of an alkali metal or alkaline earth metal. Y and Z are preferably each Br or Cl and more preferably Cl. Alternatively, in a novel process, the starting materials are 2,7-dialkyl-8-heterocyclyl- 4-octenoylesters, which may first be converted to the free acid or a suitable salt thereof, whose double bond is simultaneously halogenated in the 5-position and hydroxylated with lactonization in the 4-position, the "halo-lactone" is converted to the 4,5-epoxide, the epoxide is opened with concomitant re-lactonization, the resulting hydroxyl -group is converted to a leaving group and replaced with azide, the lactone is amidated and then the azide is converted to the amine. The desired alkane- carboxamides are obtained avoiding steps unsuitable for an industrial process. The conversion of the ester to the free acid, the salt formation, the halolactonization, the epoxidation, the re-lactonization, the leaving group formation, the azidation, the amidation and the azide reduction are performed on the basis of the process described by P. Herold, S. Stutz and F. Spindler in WO02/02508 A1..

The 2,7-dialkyl-8-heterocyclyl-4-octenoylesters may, for example, correspond to the formula A'

in which Het is a bicyclic unsaturated heterocyclyl bonded to the rest of the molecule via a carbon atom, where the ring not bonded directly to the rest of the molecule is substituted by R'i and R'2, R'i and R'2 are each independently H, d-Cβ-alkyl, halogen, polyhalo-d-Cs-alkoxy, polyhalo-Ci-Cs-alkyl, d-Cs-alkoxy, Ci-Cs-alkoxy-Ci-Cs-alkyl or Ci-Cs-alkoxy-Ci-Cs-alkoxy, where R'i and R'2 are simultaneously not both H, R'3 is d-Cβ-alkyl, R'4 is d-Cβ-alkyl and R's is d-Cβ-alkyl, and in which the carbon atom to which the R'3 radical is bonded has either the (R)- or (S)-configuration, preference being given to the (R)-configuration.

The compounds of the formula A' are obtainable by reacting a compound of the formula B - A -

with a compound of the formula C

R '14.

in which Het and R'i, R'2, R'3, R 4 and R's are each as defined above, Y is Cl, Br or I and Z is Cl, Br or I, and in which the carbon atom to which the R'3 radical is bonded has either the (R)- or (S)-configuration, preference being given to the (Reconfiguration, in the presence of an alkali metal or alkaline earth metal. Y and Z are preferably each Br or Cl and more preferably Cl.

The compounds of the formula C can be prepared by amidating the corresponding carboxylic esters of formula C, carboxamides or carbonyl halides. The formation of carboxamides from carboxylic esters and amines in the presence of thalkylaluminium or dialkylaluminium halide, for example with thmethylaluminium or dimethylaluminium chloride, is described by S. M. Weinreb in Organic Syntheses, 59, pages 49-53 (1980). The carboxylic esters are obtainable by the reaction of trans-1 ,3-dihalo- propenes (for example trans-1 , 3-dichloropropene) with the corresponding carboxylic esters in the presence of strong bases, for example alkali metal amides.

The stereoselective preparation of compounds of the formula B is as yet unknown. It has now surprisingly been found that it is possible to prepare, in a highly stereoselective manner, 2-alkyl-3-heterocyclyl-1-propanols (compounds of the formula B where Y is defined as OH; referred to hereafter as a compound of the formula I) in only four or five process stages in high yields. When, analogously to the process described in WO 02/02487 A1 , suitably substituted, unsaturated heterocyclyl- aldehydes are condensed with carboxylic esters to give 2-alkyl-3-hydroxy-3-hetero- cyclylcarboxylic esters, the diastereomehc products are obtained in high yields. It has been found that, surprisingly, the resulting diastereomers, in the case of the 2-alkyl-3- hydroxy-3-heterocyclylcarboxylic esters, are advantageously not separated, since, after conversion of the hydroxyl group to a leaving group followed by base-induced elimination, (E)-3-heterocyclyl-2-alkyl-acrylic esters are formed with high stereoselectivity. The (E)-3-heterocyclyl-2-alkyl-acrylic esters are an important intermediate of the process. Proceeding from these (E)-3-heterocyclyl-2-alkyl-acrylic esters, the 2-alkyl-3-heterocyclyl-1 -propanols can be obtained by three process variants:

1 ) From the crude 3-heterocyclyl-2-alkyl-acrylic esters, after hydrolysis and crystallization, exclusively (E)-3-heterocyclyl-2-alkyl-acrylic acids are obtained in high yields. The (E)-3-heterocyclyl-2-alkyl-acrylic acids can be hydrogenated in the presence of particular catalysts to virtually enantiomerically pure 2-alkyl-3-hetero- cyclyl-1 -propionic acids, which can be converted by reduction to 2-alkyl-3-hetero- cyclyl-1-propanols of the formula I.

2) From the crude 3-heterocyclyl-2-alkyl-acrylic esters, after hydrolysis and crystallization, exclusively (E)-3-heterocyclyl-2-alkyl-acrylic acids are obtained in high yields. The (E)-3-heterocyclyl-2-alkyl-acrylic acids can be reduced to allyl alcohols. The resulting allyl alcohols in turn can be hydrogenated in the presence of particular catalysts to give virtually enantiomerically pure 2-alkyl-3-heterocyclyl-1-propanols of the formula I.

3) The (E)-3-heterocyclyl-2-alkyl-acrylic esters can be reduced to allyl alcohols. The resulting allyl alcohols in turn can be hydrogenated in the presence of particular catalysts to virtually enantiomerically pure 2-alkyl-3-heterocyclyl-1-propanols of the formula I.

In process variants 1 ) and 2), all process steps up to the (E)-3-heterocyclyl-2-alkyl- acrylic acids are advantageously performed without purification of the intermediates, which means a considerable advantage (for example cost savings) for the preparation on an industrial scale. Process variant 3) is shorter by one process stage, which is likewise advantageous for the preparation on an industrial scale. The 2-alkyl-3-heterocyclyl-1 -propanols of the formula I below obtained by these routes can then be converted by halogenation in a manner known per se, for example by the process described by J. Maibaum in Tetrahedron Letters, Vol. 41 (2000), pages 10085-10089, to the compounds of the formula B.

The invention provides a process for preparing compounds of the formula I

in which Het is a bicyclic unsaturated heterocyclyl bonded to the rest of the molecule via a carbon atom, where the ring not bonded directly to the rest of the molecule is substituted by R'i and R'2, R'i and R'2 are each independently H, Ci-C8-alkyl, halogen, polyhalo-Ci-Cs-alkoxy, polyhalo-Ci-C8-alkyl, Ci-C8-alkoxy, Ci-C8-alkoxy- d-Cs-alkyl or Ci-Cs-alkoxy-Ci-Cs-alkoxy, where R'i and R'2 are simultaneously not both H, R'3 is d-Cβ-alkyl, and in which the carbon atom to which the R'3 radical is bonded has either the (R)- or (S)-configuration, preference being given to the (R)-configuration, which is characterized in that a) a compound of the formula Il

in which Het, R'i and R'2 are each as defined above is reacted with a compound of the formula III

R'a\ /COORV

in which R'3 is as defined above to give a diastereomer mixture of the formula IV in which R'7 is Ci-Ci2-alkyl, Cs-Cs-cycloalkyl, phenyl or benzyl, b) the OH group of the diastereomer mixture of the formula IV is converted to a leaving group and the compound containing a leaving group is eliminated in the presence of a strong base to give an acrylic ester of the formula V

Process variant 1

This process variant is characterized in that

1 c) the acrylic ester of the formula V is converted by hydrolysis to a compound of the formula Vl

1d) the acid of the formula Vl is hydrogenated in the presence of hydrogen and catalytic amounts of a metal complex as an asymmetric hydrogenation catalyst, which contains metals from the group of ruthenium, rhodium or iridium, to which chiral bidentate ligands are bonded, to give a compound of the formula VII

1 e) the acid of the formula VII is reduced to a compound of the formula I. Process variant 2

This process variant is characterized in that

2c) the acrylic ester of the formula V is converted by hydrolysis to a compound of the formula Vl

2d) the acid of the formula Vl is reduced to a compound of the formula VIII

2e) the alcohol of the formula VIII is hydrogenated in the presence of hydrogen and catalytic amounts of a metal complex as an asymmetric hydrogenation catalyst, which contains metals from the group of ruthenium, rhodium or iridium, to which chiral bidentate ligands are bonded, to give a compound of the formula I.

Process variant 3

This process variant is characterized in that

3c) the acrylic ester of the formula V is reduced to a compound of the formula VIII

3d) the alcohol of the formula VIII is hydrogenated in the presence of hydrogen and catalytic amounts of a metal complex as an asymmetric hydrogenation catalyst, which contains metals from the group of ruthenium, rhodium or iridium, to which chiral bidentate ligands are bonded, to give a compound of the formula I. R'i and R'2 may, as Ci-Cs-alkyl, be linear or branched and preferably contain 1 to 4 carbon atoms. Examples are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl.

R'i and R'2 may, as polyhalo-Ci-Cs-alkyl, be linear or branched and preferably contain 1 to 4, more preferably 1 or 2, carbon atoms. Examples are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl and 2,2,2-trifluoroethyl.

R'i and R'2 may, as polyhalo-Ci-C8-alkoxy, be linear or branched and preferably contain 1 to 4, more preferably 1 or 2, carbon atoms. Examples are fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, 2-chloroethoxy and 2,2,2-thfluoroethoxy.

R'i and R'2 may, as halogen, including halogen in polyhalo-Ci-Cs-alkyl and polyhalo- d-Cs-alkoxy, be F, Cl or Br, preference being given to F and Cl.

R'i, R'2 and R'5 may, as Ci-C8-alkoxy, be linear or branched and preferably contain 1 to 4 carbon atoms. Examples are methoxy, ethoxy, n- and i-propoxy, n-, i- and t-butoxy, pentoxy and hexoxy.

R'i and R'2 may, as Ci-Cs-alkoxy-CrCs-alkyl, be linear or branched. The alkoxy group contains preferably 1 to 4 and particularly 1 or 2 carbon atoms, and the alkyl group contains preferably 1 to 4 carbon atoms. Examples are methoxymethyl, 1 -methoxyeth-2-yl, 1-methoxyprop-3-yl, 1 -methoxybut-4-yl, methoxypentyl, methoxyhexyl, ethoxymethyl, 1 -ethoxyeth-2-yl, 1 -ethoxyprop-3-yl, 1 -ethoxybut-4-yl, ethoxypentyl, ethoxyhexyl, propoxymethyl, butoxymethyl, 1 -propoxyeth-2-yl and 1 -butoxyeth-2-yl.

R'i and R'2 may, as Ci-Cs-alkoxy-Ci-Cs-alkoxy, be linear or branched. The alkoxy group contains preferably 1 to 4 and particularly 1 or 2 carbon atoms, and the alkoxy group contains preferably 1 to 4 carbon atoms. Examples are methoxymethoxy, 2-methoxyethoxy, 3-methoxypropoxy, 4-methoxybutoxy, methoxypentoxy, methoxyhexoxy, ethoxymethoxy, 2-ethoxyethoxy, 3-ethoxypropoxy, 4-ethoxybutoxy, ethoxypentoxy, ethoxyhexoxy, propoxymethoxy, butoxymethoxy, 2-propoxyethoxy and 2-butoxyethoxy.

In a preferred embodiment, R'i is methoxy- or ethoxy-Ci-C4-alkyl, and R'2 is preferably methyl, ethyl, methoxy or ethoxy. Very particular preference is given to compounds of the formula I in which R'i is 3-methoxypropyl or 4-methoxybutyl, and R'2 is methyl or methoxy.

R'3, R4, R'5j R'β and R's may, as Ci-Cs-alkyl, be linear or branched and preferably contain 1 to 4 carbon atoms. Examples are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl. In a preferred embodiment, R'3 in the compounds of the formula I is isopropyl, and the carbon atom to which the R'3 radical is bonded has (R)-configuration. In a preferred embodiment, R'8 in the compounds of the formula C is imethyl or ethyl.

Het may, as a bicyclic unsaturated heterocyclyl bonded to the rest of the molecule via a carbon atom, include unsaturated heterocyclic radicals having a total of 8 to 16 ring atoms, preferably of which 1 to 4 are nitrogen atoms and/or 1 or 2 are sulphur or oxygen atoms, most preference being given to radicals having one or 2 nitrogen atoms. Preferred bicycles consist of in each case 5- and/or 6-membered rings. Examples of Het are benzothiazolyl, quinazolinyl, quinolyl, quinoxalinyl, isoquinolyl, benzo[b]thienyl, isobenzofuranyl, benzoimidazolyl, indolyl, dihydrobenzofuranyl, tetrahydroquinoxalinyl, 3,4-dihydro-2H-benzo[1 ,4]oxazinyl, 1 H-pyrrolizinyl, phthalazinyl, dihydro-2H-benzo[1 ,4]thiazinyl, 1 H-pyrrolo[2,3-b]pyridyl, imidazo[1 ,5- a]pyridyl, benzoxazolyl, 2,3-dihydroindolyl, indazolyl or benzofuranyl. Het is more preferably 1 H-indol-6-yl, imidazo[1 ,5-a]pyridin-6-yl or 1 H-indazol-6-yl.

Particular preference is given to compounds of the formula I, in which RV and RV substituted Het is 1 -(3-methoxypropyl)-3-methyl-1 H-indol-6-yl, 3-(3-methoxypropyl)- 1 -methyl imidazo[1 ,5-a]pyridin-6-yl or 1 -(3-methoxypropyl)-3-methyl-1 H-indazol-6-yl, and R'3 is isopropyl.

RV may, as Cs-Cs-cycloalkyl, be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

R'7 is preferably CrCβ- and more preferably Ci-C4-alkyl; some examples are methyl, ethyl, n-propyl and n-butyl.

The substituent groups mentioned above are not to be regarded as closed, but rather parts of these substituent groups may be used for the definition of the compounds in a sensible manner, for example by replacing a general by a more specific definition. The definitions are valid in accordance with general chemical principles, such as, for example, the common valences for atoms.

The starting compounds of the formulae Il and III used in process stage a) are known or can be prepared analogously to known processes. Compounds of the formula Il are prepared in a manner known per se from the bicyclic unsaturated heterocyclyl bromides described in WO 2005/090305 A1 via halogen-metal exchange and subsequent reaction with N,N-dimethylformamide. The reaction of process stage a) is advantageously performed at low temperatures, for example -40 to 00C, in the presence of at least equivalent amounts of a strong base. The reaction is also appropriately performed in a solvent, particularly suitable solvents being ethers, for example diethyl ether, tetrahydrofuran and dioxane. Suitable strong bases are especially alkali metal alkoxides and secondary amides, for example lithium diisopropylamide.

The mixture of the two diastereomers of the formula IV is obtained in virtually quantitative yield. Advantageously, the diastereomer mixture is used without purification in the next process stage.

The conversion of the OH group to a leaving group in process stage b) is known per se. Particularly suitable reactions are those with carboxylic acids or sulphonic acids, or their acid chloride or anhydrides (acylation). Some examples of carboxylic acids or sulphonic acids are formic acid, acetic acid, propionic acid, benzoic acid, benzene- sulphonic acid, toluenesulphonic acid, methylsulphonic acid and trifluoromethyl- sulphonic acid. The use of acetic anhydride in the presence of catalytic amounts of 4-dimethylaminopyridine has been found to be particularly suitable. The elimination is appropriately undertaken in the presence of strong bases, alkali metal alkoxides such as potassium tert-butoxides being particularly suitable. The presence of solvents such as ethers is appropriate. The reaction is advantageously performed at low temperatures, for example 00C to 400C. Advantageously, the elimination reaction is performed directly in the reaction mixture of process stage a). The elimination leads surprisingly selectively to the desired E-isomers of the acrylic esters of the formula V.

The hydrolysis of the acrylic esters of the formula V in process stages 1 c) or 2c) is advantageously performed directly after achievement of the complete conversion of the elimination (process stage b) and after concentration of the solvent, by adding, for example, potassium hydroxide solution and stirring at temperatures between 800C and 100°C. The resulting acids of the formula Vl are highly crystalline and can therefore be isolated in a simple manner without great losses by means of extraction and crystallization. The yields are above 60%. Surprisingly, exclusively the desired E-isomers are obtained.

Asymmetric hydrogenations of alpha, beta-unsaturated carboxylic acids of the formula Vl in analogy to process stage 1d) or of alpha, beta-unsaturated alcohols of the formula VIII in analogy to process stages 2e) or 3d) with homogeneous asymmetric hydrogenation catalysts are known per se and are described, for example, by J. M. Brown in E. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.) in Comprehensive Asymmetric Catalysis I to III, Springer Verlag, 1999, pages 121-182 and by X. Zhang in Chemical Reviews, VoI 103 (2003), pages 3029-3069. Ruthenium, rhodium and iridium catalysts are particularly effective.

Asymmetric hydrogenations of alpha, beta-unsaturated carboxylic acids of the formula Vl can generally be performed with preference using ruthenium or rhodium catalysts, as described, for example, by J. M. Brown in E. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.) in Comprehensive Asymmetric Catalysis I to III, Springer Verlag, 1999, pages 163-166, W. Weissensteiner and F. Spindler in Advanced Synthesis and Catalysis Vol. 345 (2003), pages 160-164 and by T. Yamagishi in Journal of the Chemical Society, Perkin Transactions 1 , (1997), pages 1869-1873.

The ligands used for rhodium and ruthenium are frequently chiral ditertiary bis- phosphines. Such chiral ditertiary bisphosphines are described, for example, by X. Zhang in Chemical Reviews, VoI 103 (2003), pages 3029-3069.

Ligands with a ferrocenyl skeleton are generally particularly suitable for the asymmetric hydrogenation of alpha, beta-unsaturated carboxylic acids. Examples are described by F. Spindler in Tetrahedron: Asymmetry, Vol. 15 (2004), pages 2299- 2306. Examples are ligands of the Walphos, Josiphos, Mandyphos and Taniaphos classes. Ligands of these classes are described, for example, by X. Zhang in Chemical Reviews, VoI 103 (2003), pages 3029-3069, and also by P. Knochel in Chemistry, a European Journal Vol. 8 (2002), pages 843-852, by H.-U. Blaser in Topics in Catalysis, VoI 19 (2002), pages 3-16 and by F. Spindler in Tetrahedron: Asymmetry, Vol. 15 (2004), pages 2299-2306.

The ligands used for iridium are frequently chiral phosphine-oxazoline ligands or phosphinite-oxazoline ligands. Such chiral phosphine-oxazoline ligands or phosphinite-oxazoline ligands are described, for example, by A. Pfaltz in Advanced Synthesis and Catalysis Vol. 345 (2003), pages 33-43.

Good optical yields are achieved especially with metal complexes of the formulae IX or IXa

[LM1X1X2] (IX), [LM1X1]+E" (IXa), in which

M1 is rhodium or iridium;

X1 is two olefins or one diene;

X2 is Cl, Br or I;

E" is the anion of an oxoacid or complex acid; and L is a chiral ligand from the group of the ferrocene-1 ,1 '-diphosphines which, in the 1 -position, have a ferrocene-substituted secondary phosphine group and, in the 1 '-position, a secondary phosphine group.

When X1 is defined as olefin, the olefins may be C2-Ci2-olefins, preferably C2-C6- olefins and more preferably C2-C4-olefins. Examples are propene, butene and particularly ethylene. The diene may contain 5 to 12 and preferably 5 to 8 carbon atoms, and the dienes may be open-chain, cyclic or polycyclic dienes. The two olefin groups of the diene are preferably connected by one or two CH2 groups. Examples are 1 ,3-pentadiene, cyclopentadiene, 1 ,5-hexadiene, 1 ,4-cyclohexadiene, 1 ,4- or 1 ,5- heptadiene, 1 ,4- or 1 ,5-cycloheptadiene, 1 ,4- or 1 ,5-octadiene, 1 ,4- or 1 ,5-cyclo- octadiene and norbornadiene. X1 is preferably two ethylene or 1 ,5-hexadiene, 1 ,5- cyclooctadiene or norbornadiene.

In formula IX, X2 is preferably Cl or Br. Examples of E' are CIO4 ', CF3SO3 ', CH3SO3 ', HSO4 ', BF4 ', B(phenyl)4 ', BARF (B(3,5-bis(thfluoromethyl)phenyl)4 ~, PF6 ', SbCI6 ', AsF6 ' or SbF6 '.

It has now been found that, surprisingly, ligands of the ferrocene-1 , 1 '-diphosphine type which have, in the 1 -position, a ferrocene-substituted secondary phosphine group and, in the 1 '-position, a secondary phosphine group are particularly suitable for the asymmetric hydrogenation of alpha, beta-unsaturated carboxylic acids. With these ligands in the metal complexes of the formulae IX and IXa, it is possible to achieve unprecedented, extremely high optical yields (>98%ee) under optimized conditions, on a synthetically useful scale. In a similar process described in WO02/02500A1 , using, among others, ferrocenyl based ligands, a maximum optical yield of only >95%ee was achieved. Such optical yields will, in the context of the production of an optically pure active compound used as a pharmaceutical ingredient, require at least one further recrystallization step to improve the optical purity. In contrast, such a recrystallization step becomes obsolete when the optical purity reaches a level of about 98%ee. The fact that this purification step becomes unnecessary is a considerable advantage for the preparation on an industrial scale (for example cost savings). In a direct comparison experiment the optical yields obtained when employing ligand (100) with alpha, beta-unsaturated carboxylic acids of the formula Vl are considerably higher than the optical yields obtained employing a state of the art ferrocenyl based ligand, (R)-1 -{(R)-2-[2-(diphenylphosphino)phenyl]-ferrocenyl}ethylbis[3,5-bis- (thfluoromethyl)phenyl]phosphine [387868-06-6], as described in WO02/02500A1 with the alpha, beta-unsaturated carboxylic acid substrate 2-[1 -[4-methoxy-3-(3- methoxy-propoxy)-phenyl]-meth-(E)-ylidene]-3-methyl-butyric acid [387868-07-7].

Also surprising in this connection is the possibility to use iridium complexes for the asymmetric hydrogenation of alpha, beta-unsaturated carboxylic acids, which is another considerable advantage for the preparation on an industrial scale (for example, further cost savings compared to the use, for example, of more expensive rhodium complexes). In process stages 1d), proceeding from alpha, beta-unsaturated carboxylic acids of the formula Vl, it is therefore possible to use, for example, metal complexes of the formulae IX and IXa whose ligands belong to the ferrocene- 1 ,1'- diphosphines which have, in the 1 -position, a ferrocene-substituted secondary phosphine group and, in the 1 '-position, a secondary phosphine group.

In the context of the present invention, ferrocene-1 ,1'-diphosphines which, in the 1 -position, have a ferrocene-substituted secondary phosphine group and, in the 1 '-position, a secondary phosphine group are compounds of the formula X in the form of enantiomerically pure diastereomers or a mixture of diastereomers

in which the Ri are the same or different and are each Ci-C4-alkyl; m is 0 or an integer of 1 to 3; n is 0 or an integer of 1 to 4;

R2 is a hydrocarbon radical or C-bonded heterohydrocarbon radical;

Cp is unsubstituted or Ci-C4-alkyl-substituted cyclopentadienyl;

X is a C-bonded chiral group which directs metals of metallating reagents into the ortho position; and

Phos is a P-bonded P(III) substituent.

Phos, as a P-bonded P(III) substituent, is more preferably a secondary phosphine group.

In the case of Ri as alkyl, it may, for example, be methyl, ethyl, n- or i-propyl, n-, i- or t-butyl, preference being given to methyl, m and n are preferably each 0 (and Ri is thus a hydrogen atom).

The hydrocarbon radicals R2 may be unsubstituted or substituted and/or contain heteroatoms selected from the group of O, S, -N= or N(Ci-C4-alkyl). They may contain 1 to 22, preferably 1 to 18, more preferably 1 to 12 and especially preferably 1 to 8 carbon atoms, and 1 to 4 and preferably 1 or 2 of the heteroatoms mentioned. R2 may be radicals selected from the group of linear or branched Ci-Ci2-alkyl; unsubstituted or Ci-Cβ-alkyl- or CrCβ-alkoxy-substituted C4-Ci2-cycloalkyl or C4-Ci2- cycloalkyl-CH2-; C6-Ci4-aryl; C4-Ci2-heteroaryl; C7-Ci4-aralkyl; C4-Ci2-heteroaralkyl; or halogen- (fluorine-, chlorine- or bromine-), Ci-Cβ-alkyl-, trifluoromethyl-, Ci-Cβ- alkoxy-, trifluoromethoxy-, (CeHs)3Si-, (Ci-Ci2-alkyl)3Si- or sec-amino-substituted C6-Ci4-aryl, C4-Ci2-heteroaryl, C7-Ci4-aralkyl or C4-Ci2-heteroaralkyl. Heteroaryl and heteroaralkyl preferably contain heteroatoms selected from the group of O, S and -N=.

Examples of R2 as alkyl which preferably contains 1 to 6 carbon atoms are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and the isomers of pentyl and hexyl. Examples of R2 as optionally alkyl-substituted cycloalkyl are cyclopentyl, cyclohexyl, methyl- and ethylcyclohexyl, dimethylcyclohexyl, cycloheptyl, cyclooctyl, norbornyl and adamantyl. Examples of R2 as optionally alkyl- and alkoxy-substituted C5-C12- cycloalkyl-CH2- are cyclopentylmethyl, cyclohexyl methyl, cyclooctyl methyl, methyl- cyclohexylmethyl and dimethylcyclohexylmethyl. Examples of R2 as aryl and aralkyl are phenyl, naphthyl, anthracenyl, fluorenyl, benzyl and naphthylmethyl. Examples of R2 as heteroaryl and heteroaralkyl are furyl, thiophenyl, N-methylpyrrolidinyl, pyridyl, benzofuranyl, benzothiophenyl, quinolinyl, furylmethyl, thiophenylmethyl and pyridylmethyl. Examples of R2 as substituted aryl, aralkyl, heteroaryl and heteroaralkyl are phenyl, naphthyl, benzyl, naphthylmethyl, phenylethyl, furyl, thiophenyl, benzofuryl and benzothiophenyl, which are substituted by 1 to 3 radicals selected from the group of methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, ethoxy, methoxy, trifluoromethyl, trifluoromethoxy, fluorine or chlorine. Some preferred examples are 2-, 3- or 4-methylphenyl, 2,4- or 3,5-dimethylphenyl, 3,4,5-thmethylphenyl, 4-ethylphenyl, 2- or 4-methylbenzyl, 2-, 3- or 4-methoxyphenyl, 2,4- or 3,5-dime- thoxyphenyl, 3,4,5-thmethoxyphenyl, 2-, 3- or 4-thfluoromethylphenyl, 2,4- or 3,5- di(thfluoromethyl)phenyl, tris(thfluoromethyl)phenyl, 2- or 4-thfluoromethoxyphenyl, 3,5-bis(thfluoromethoxy)phenyl, 2- or 4-fluorophenyl, 2- or 4-chlorophenyl and 3,5- dimethyl-4-methoxyphenyl.

In a particularly preferred embodiment, R2 is d-Cβ-alkyl, C5-C8-cycloalkyl, C7-C8- bicycloalkyl, o-furyl, phenyl, naphthyl, 2-(Ci-C6-alkyl)C6H4, 3-(Ci-C6-alkyl)C6H4, 4-(Ci-C6-alkyl)C6H4, 2-(Ci-C6-alkoxy)C6H4, 3-(Ci-C6-alkoxy)C6H4, 4-(CrC6- alkoxy)C6H4, 2-(thfluoromethyl)C6H4, 3-(thfluoromethyl)C6H4, 4-(trifluoromethyl)C6H4, 3,5-bis(trifluoromethyl)C6H3, -3,5-bis(Ci-C6-alkyl)2C6H3, 3,5-bis(Ci-C6-alkoxy)2C6H3 and 3,5-bis(Ci-C6-alkyl)2-4-(Ci-C6-alkoxy)C6H2.

In the ortho-directing chiral X group, the chiral atom is preferably bonded in the 1-, 2- or 3-position to the cyclopentadienyl-X bond. The X group may be open-chain radicals or cyclic radicals, where the atoms are selected from the group of H, C, O, S and N.

The X group may, for example, correspond to the formula -HC*R5R6 (* indicates the asymmetric atom) in which R5 is Ci-C8-alkyl, C5-C8-cycloalkyl (cyclohexyl), C6-Ci0- aryl (phenyl), C7-Ci2-aralkyl (benzyl) or C7-Ci2-alkaralkyl (methylbenzyl), R6 is -OR7 or -NR8Rg, R7 is Ci-C8-alkyl, C5-C8-cycloalkyl, phenyl or benzyl, and R8 and R9 are the same or different and are each Ci-C8-alkyl, C5-C8-cycloalkyl, phenyl or benzyl, or Rs and Rg, together with the nitrogen atom, form a five- to eight-membered ring. R5 is preferably Ci-C4-alkyl, for example methyl, ethyl, n-propyl and phenyl. R7 is preferably Ci-C4-alkyl, for example methyl, ethyl, n-propyl and n- or i-butyl. R8 and Rg are preferably identical radicals and are preferably each Ci-C4-alkyl, for example methyl, ethyl, n-propyl, i-propyl and n- or i-butyl, and together are tetramethylene, pentamethylene or 3-oxa-1 ,5-pentylene. Particularly preferred groups of the formula -HCR5R6 are 1 -methoxyeth-1 -yl, 1-dimethylaminoeth-1 -yl and i -(dimethylamino)- 1 -phenylmethyl.

X is more preferably a -CHR5-NR8Rg group in which R5 is CrC4-alkyl, C5-C6- cycloalkyl, phenyl, Ci-C4-alkylphenyl or Ci-C4-alkylbenzyl, and R8 and Rg are the same and are each Ci-C4-alkyl and preferably methyl or ethyl.

Phos may, as a P-bonded P(III) substituent, be a secondary phosphine group which contains identical or different hydrocarbon radicals, or in which the hydrocarbon radical, together with the phosphorus atom, forms a 4- to 8-membered ring. The secondary phosphine group preferably contains identical hydrocarbon radicals. The hydrocarbon radicals R2 may be unsubstituted or substituted and/or contain heteroatoms selected from the group of O, S, -N= or N(Ci-C4-alkyl). They may contain 1 to 22, preferably 1 to 18, more preferably 1 to 12 and especially preferably 1 to 8 carbon atoms, and 1 to 4 and preferably 1 or 2 of the heteroatoms mentioned. R2 may be radicals selected from the group of linear or branched Ci-Ci2-alkyl; unsubstituted or Ci-C6-alkyl- or Ci-C6-alkoxy-substituted C5-Ci2-cycloalkyl or C5-Ci2- cycloalkyl-CH2-; C6-Ci4-aryl; C4-Ci2-heteroaryl; C7-Ci4-aralkyl; C4-Ci2-heteroaralkyl; or halogen- (fluorine-, chlorine- or bromine-), Ci-C6-alkyl-, thfluoromethyl-, CrC6- alkoxy-, trifluoromethoxy-, (C6Hs)3Si-, (Ci-Ci2-alkyl)3Si- or sec-amino-substituted C6- Ci4-aryl, C4-Ci2-heteroaryl, C7-Ci4-aralkyl or C4-Ci2-heteroaralkyl. Heteroaryl and heteroaralkyl preferably contain heteroatoms selected from the group of O, S and -N=.

Examples of hydrocarbon radicals as alkyl which preferably contains 1 to 6 carbon atoms are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and the isomers of pentyl and hexyl. Examples of hydrocarbon radicals as optionally alkyl-substituted cycloalkyl are cyclopentyl, cyclohexyl, methyl- and ethylcyclohexyl, dimethylcyclo- hexyl, cycloheptyl, cyclooctyl, norbornyl and adamantyl. Examples of R2 as optionally alkyl- and alkoxy-substituted C5-Ci2-cycloalkyl-CH2- are cyclopentyl methyl, cyclo- hexylmethyl, cyclooctylmethyl, methylcyclohexyl methyl and dimethylcyclohexyl- methyl. Examples of R2 as aryl and aralkyl are phenyl, naphthyl, anthracenyl, fluorenyl, benzyl and naphthylmethyl. Examples of R2 as heteroaryl and heteroaralkyl are furyl, thiophenyl, N-methylpyrrolidinyl, pyridyl, benzofuranyl, benzothiophenyl, quinolinyl, furylmethyl, thiophenylmethyl and pyridylmethyl. Examples of R2 as substituted aryl, aralkyl, heteroaryl and heteroaralkyl are phenyl, naphthyl, benzyl, naphthylmethyl, phenylethyl, furyl, thiophenyl, benzofuryl and benzothiophenyl, which are substituted by 1 to 3 radicals selected from the group of methyl, ethyl, n- and i- propyl, n-, i- and t-butyl, ethoxy, methoxy, trifluoromethyl, trifluoromethoxy, fluorine or chlorine. Some preferred examples are 2-, 3- or 4-methylphenyl, 2,4- or 3,5- dimethylphenyl, 3,4,5-thmethylphenyl, 4-ethylphenyl, 2- or 4-methylbenzyl, 2-, 3- or 4-methoxyphenyl, 2,4- or 3,5-dimethoxyphenyl, 3,4,5-thmethoxyphenyl, 2-, 3- or 4- thfluoromethylphenyl, 2,4- or 3,5-di(trifluoromethyl)phenyl, ths(thfluoromethyl)phenyl, 2- or 4-thfluoromethoxyphenyl, 3,5-bis(thfluoromethoxy)phenyl, 2- or 4-fluorophenyl, 2- or 4-chlorophenyl and 3,5-dimethyl-4-methoxyphenyl.

In a particularly preferred embodiment, the hydrocarbon radical is Ci-C6-alkyl, C5-C8- cycloalkyl, C7-C8-bicycloalkyl, o-furyl, phenyl, naphthyl, 2-(Ci-C6-alkyl)C6H4, 3-(d-C6- alkyl)C6H4, 4-(Ci-C6-alkyl)C6H4, 2-(Ci-C6-alkoxy)C6H4, 3-(Ci-C6-alkoxy)C6H4, 4-(d- C6-alkoxy)C6H4, 2-(trifluoromethyl)C6H4, 3-(trifluoromethyl)C6H4, 4-(trifluoro- methyl)C6H4, 3,5-bis(thfluoromethyl)C6H3, -3,5-bis(Ci-C6-alkyl)2C6H3, 3,5-bis(Ci-C6- alkoxy)2C6H3, and 3,5-bis(Ci-C6-alkyl)2-4-(Ci-C6-alkoxy)C6H2.

The secondary phosphino group preferably corresponds to the formula -PRsR4 in which R3 and R4 are each independently a hydrocarbon radical which has 1 to 18 carbon atoms and is unsubstituted or substituted by Ci-Cβ-alkyl, trifluoromethyl, d-Ce-alkoxy, trifluoromethoxy, (Ci-C4-alkyl)2amino, (C6H5)3Si, (Ci-Ci2-alkyl)3Si, halogen and/or contains O heteroatoms. R3 and R4 are preferably each radicals selected from the group of linear or branched d-Cβ-alkyl, cyclopentyl or cyclohexyl which are unsubstituted or substituted by one to three Ci-C4-alkyl or Ci-C4-alkoxy, furyl, benzyl which is unsubstituted or substituted by one to three Ci-C4-alkyl or Ci-C4-alkoxy, and especially phenyl or naphthyl which are unsubstituted or substituted by one to three F, Cl, CrC4-alkyl, CrC4- alkoxy, Ci-C4-fluoroalkyl or Ci-C4-fluoroalkoxy.

R3 and R4 are more preferably radicals selected from the group of Cs-Cs-alkyl, cyclopentyl, cyclohexyl, furyl, naphthyl and phenyl which is unsubstituted or substituted by one to three F, Cl, CrC4-alkyl, Ci-C4-alkoxy and/or Ci-C4-fluoroalkyl.

The secondary phosphine group Phos may be cyclic secondary phosphino, for example those of the formulae

which are unsubstituted or mono- or polysubstituted by d-Cβ-alkyl, C4-C8-cycloalkyl, d-Ce-alkoxy, Ci-C4-alkoxy-Ci-C4-alkyl, phenyl, Ci-C4-alkyl- or Ci-C4-alkoxyphenyl, benzyl, Ci-C4-alkyl- or Ci-C4-alkoxybenzyl, benzyloxy, Ci-C4-alkyl- or Ci-C4-alkoxy- benzyloxy, or Ci-C4-alkylidenedioxy.

The substituents may be bonded in one or both alpha-positions to the phosphorus atom in order to introduce chiral carbon atoms. The substituents in one or both alpha-positions are preferably Ci-C4-alkyl or benzyl, for example methyl, ethyl, n- or i-propyl, benzyl or -CH2-O-Ci-C4-alkyl or -CH2-O-C6-Ci0-aryl.

Substituents in the beta,gamma-positions may, for example, be Ci-C4-alkyl, CrC4- alkoxy, benzyloxy, or -0-CH2-O-, -O-CH(Ci-C4-alkyl)-O-, and -O-C(Ci-C4-alkyl)2-O-. Some examples are methyl, ethyl, methoxy, ethoxy, -O-CH(methyl)-O- and -O-C(methyl)2-O-. According to the type of substitution and number of substituents, the cyclic phosphine radicals may be C-chiral, P-chiral or C- and P-chiral.

An aliphatic 5- or 6-membered ring or benzene may be fused onto two adjacent carbon atoms in the radicals of the above formulae.

The cyclic secondary phosphino may, for example, correspond to the formulae (only one of the possible diastereomers specified)

in which the R' and R" radicals are each Ci-C4-alkyl, for example methyl, ethyl, n- or i-propyl, benzyl, or -CH2-O-Ci-C4-alkyl or -CH2-O-C6-Cio-aryl, and R' and R" are the same or different.

In the compounds of the formulae X, Phos as secondary phosphino is preferably non-cyclic secondary phosphine selected from the group of -P(Ci-C6-alkyl)2, -P(C5- C8-cycloalkyl)2, -P(C7-C8-bicycloalkyl)2, -P(o-furyl)2, -P(C6Hs)2, -P[2-(Ci-C6- alkyl)C6H4]2, -P[3-(Ci-C6-alkyl)C6H4]2, -P[4-(Ci-C6-alkyl)C6H4]2, -P[2-(Ci-C6- alkoxy)C6H4]2, -P[3-(Ci-C6-alkoxy)C6H4]2, -P[4-(Ci-C6-alkoxy)C6H4]2, -P[2- (trifluoromethyl)C6H4]2, -P[3-(trifluoromethyl)C6H4]2, -P[4-(thfluoromethyl)C6H4]2, -P[3,5-bis(trifluoromethyl)C6H3]2j -P[3,5-bis(Ci-C6-alkyl)2C6H3]2j -P[3,5-bis(Ci-C6- alkoxy)2C6H3]2, and -P[3,5-bis(Ci-C6-alkyl)2-4-(Ci-C6-alkoxy)C6H2]2, or a cyclic phosphine selected from the group of

which are unsubstituted or mono- or polysubstituted by Ci-C4-alkyl, CrC4-alkoxy, Ci-C4-alkoxy-Ci-C2-alkyl, phenyl, benzyl, benzyloxy or Ci-C4-alkylidenedioxy.

Some specific examples are -P(CH3)2, -P(i-C3H7)2, -P(n-C4H9)2, -P(i-C4H9)2, -P(t-C4H9)2, -P(C5H9), -P(C6Hn)2, -P(norbornyl)2, -P(o-furyl)2> -P(C6H5)2, P[2-(methyl)C6H4]2, P[3-(methyl)C6H4]2, -P[4-(methyl)C6H4]2, -P[2-(methoxy)C6H4]2, -P[3-(methoxy)C6H4]2, -P[4-(methoxy)C6H4]2, -P[3-(thfluoromethyl)C6H4]2, -P[4-(thfluoromethyl)C6H4]2, -P[3,5-bis(trifluoromethyl)C6H3]2, -P[3,5- bis(methyl)2C6H3]2, -P[3,5-bis(methoxy)2C6H3]2, and -P[3,5-bis(methyl)2-4- (methoxy)C6H2]2, and those of the formulae

alkyl alkyl

in which

R' is methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, methoxy methyl, ethoxy- methyl or benzyloxymethyl, and R" is independently as defined for R' but is different from R'. The compounds of the formula X can be prepared in a simple and modular manner in high yields even as enantiomerically pure disastereomers. Intermediates are also obtainable as enantiomerically pure diastereomers, which facilitates the preparation of pure diastereomehc end products. Appropriately, the starting material is 1 ,1'- dihaloferrocene, which is commercially available, for example 1 ,1 '-dibromoferrocene, and in which a halogen can be substituted selectively by a metal with metallating reagents, for example Li-alkyl.

In a first variant, the R2HaIP- group is then introduced by reaction with R2-P(HaI)2. The reaction with ortho-metallated and with Y-substituted ferrocenes leads to a central intermediate of the formula VIII which is obtainable as a pure diastereomer by means of heating and recrystallization:

(XVIII) where Hal is halogen (Cl, Br or I, preferably Br). In the compounds of the formula VIII, after another metallation (substitution of Hal) a desired Phos group can be introduced with halophosphines of the formula Phos-Hal.

In another variant, the Phos group is first introduced by reaction with Phos-Hal, and then the R2HaIP- group by means of metallation and subsequent reaction with R2- P(HaI)2. This affords intermediates of the formula XX

which are reacted in a last stage with ortho-metallated and with X-substituted ferrocenes to give compounds of the formula X. The resulting mixtures of diastereomers can be converted by heating and recrystallization to a pure diastereomer.

One process for preparing compounds of the formula X comprises, for example, the steps of: a) metallating a 1 ,1'-dihaloferrocene to give a 1 -metal-1 '-haloferrocene and subsequent reaction with a compound of the formula R2-P(HaI)2 in which Hal is chlorine, bromine or iodine to give a compound of the formula XVI

in which Ri, R2 and n are each as defined above, and Hal is chlorine, bromine or iodine,

b) reacting a compound of the formula XVI with a compound of the formula XVII

in which X, Cp, Ri and m are each as defined above and M is Li or MgHaI where Hal is chlorine, bromine or iodine to give a compound of the formula XVIII

(XVIII), and

C) reacting a compound of the formula XVIII with lithium alkyl and then with a halophosphine of the formula Phos-Hal in which Hal is chlorine, bromine or iodine to give a compound of the formula X. In process stage b), mixtures of diastereomers of the P-chiral compounds of the formula XVIII are obtained. Mixtures of diastereomers of the compounds of the formula XVIII according to process stage b) can be separated by means of known methods, for example chromatography, into their different stereoisomers.

These mixtures may, though, also be converted to pure diastereomers in a surprisingly simple manner by mere thermal treatment and optionally a subsequent recrystallization. A thermal treatment and optional recrystallization are advisable before performing process stage c) to avoid purification steps such as separations on chiral columns after process stage c) to prepare pure diastereomers. Thermal treatment may, for example, mean taking up the reaction product in an inert solvent and heating to 40 to 1500C and preferably 60 to 1200C for a period of minutes to hours, for example 10 minutes to 10 hours. Suitable solvents are mentioned later.

The dihaloferrocenes and dihalophosphines used in process stage a) are known and some of them are commercially available or they can be prepared by analogous processes. Compounds of the formula XVIII are known or are preparable by known or analogous processes. The starting materials are known X-substituted ferrocenes which are metallated in the ortho-position. Metallation with lithium alkyl or else magnesium Grignard compounds of ferrocenes are known reactions which are described, for example, by T. Hayashi et al., Bull. Chem. Soc. Jpn. 53 (1980), pages 1138 to 1151 or in Jonathan Clayden Organolithiums: Selectivity for Synthesis (Tetrahedron Organic Chemistry Series), Pergamon Press (2002). The alkyl in lithium alkyl may, for example, contain 1 to 6 carbon atoms and preferably 1 to 4 carbon atoms. Frequently, lithium methyl, lithium s-butyl, lithium n-butyl and lithium t-butyl are used. Magnesium Grignard compounds are preferably those of the formula (Ci-C4-alkyl)MgX0 in which X0 is Cl, Br or I.

The reactions in process stages a), b) and c) are appropriately performed at low temperatures, for example 20 to -100°C, preferably 0 to -800C. After adding reagents, the temperature can also be increased, for example to room temperature. The reactions are advantageously performed under inert protective gases, for example nitrogen or noble gases, for example helium or argon.

Preferred ligands correspond to the formula X in which m is 0; n is O;

R2 is d-Ce-alkyl, C5-C8-cycloalkyl, C7-C8-bicycloalkyl, o-furyl, phenyl, naphthyl,

2-(Ci-C6-alkyl)C6H4j 3-(Ci-C6-alkyl)C6H4j 4-(Ci-C6-alkyl)C6H4j 2-(Ci-C6-alkoxy)C6H4j

3-(Ci-C6-alkoxy)C6H4, 4-(Ci-C6-alkoxy)C6H4, 2-(thfluoromethyl)C6H4, 3-(trifluoro- methyl)C6H4, 4-(trifluoromethyl)C6H4, 3,5-bis(thfluoromethyl)C6H3, 3,5-bis(Ci-C6- alkyl)2C6H3, 3,5-bis(Ci-C6-alkoxy)2C6H3 or 3,5-bis(Ci-C6-alkyl)2-4-(Ci-C6-alkoxy)C6H2;

Cp is unsubstituted cyclopentadienyl;

X is a -CHR5-NR8Rg group in which R5 is Ci-C4-alkyl, C5-C6-cycloalkyl, phenyl, CrC4- alkylphenyl or Ci-C4-alkylbenzyl, and R8 and R9 are the same and are each CrC4- alkyl and preferably methyl or ethyl; and

Phos is a P-bonded P(III) substituent of the formula -PRsR4 in which R3 and R4 are each independently a radical selected from the group of C3-C8-alkyl, cyclopentyl, cyclohexyl, furyl, naphthyl, and phenyl which is unsubstituted or substituted by one to three F, Cl, CrC4-alkyl, Ci-C4-alkoxy and/or CrC4-fluoroalkyl.

Very particular preference is given to the ligands of the formulae:

Asymmetric hydrogenations of process stage 2e) or 3d) of alpha, beta-unsaturated alcohols of the formula VIII can generally and preferably be performed using ruthenium, iridium and rhodium catalysts, as described, for example, by M. Banziger and T. Troxler in Tetrahedron: Asymmetry, Vol. 14 (2003) pages 3469-3477, R. Gilbertson in Tetrahedron Letters, Vol. 44 (2003) pages 953-955, P. G. Andersson in Journal of the American Chemical Society, Vol. 126 (2004), pages 14308-14309, A. Pfaltz in Organic Letters, Vol. 6 (2004), pages 2023-2026, and F. Spindler in Tetrahedron: Asymmetry, Vol. 15 (2004), pages 2299-2306.

Ligands with a ferrocenyl skeleton are generally suitable for the asymmetric hydrogenation of alpha, beta-unsaturated alcohols as ligands for rhodium, and are described, for example, by F. Spindler in Tetrahedron: Asymmetry, Vol. 15 (2004), pages 2299-2306. Examples are ligands of the Walphos, Josiphos, Mandyphos and Taniaphos classes. Ligands of these classes are described, for example, by X. Zhang in Chemical Reviews, Vol. 103 (2003), pages 3029-3069 and by T. J. Colacot in Chemical Reviews, Vol. 103 (2003), pages 3101 -3118.

It has now been found that, surprisingly, metal complexes of the formula Xl with ligands of the ferrocene-1 ,1 '-diphosphine type which have, in the 1 -position, a ferrocene-substituted secondary phosphine group and, in the 1 '-position, a secondary phosphine group are particularly suitable for the asymmetric hydrogenation of alpha, beta-unsaturated alcohols. Good optical yields are achieved with metal complexes of the formulae Xl or XIa

[LM2X1X2] (Xl), [LM2X1~ (XIa), in which

M2 is rhodium;

X1 is two olefins or one diene;

X2 is Cl, Br or I;

E" is the anion of an oxoacid or complex acid; and

L is a chiral ligand from the group of the ferrocene-1 ,1 '-diphosphines which, in the

1 -position, have a ferrocene-substituted secondary phosphine group and, in the

1 '-position, a secondary phosphine group.

Where X1 is defined as olefin, it may be C2-Ci2-, preferably C2-C6- and more preferably C2-C4-olefins. Examples are propene, butene and particularly ethylene. The diene may contain 5 to 12 and preferably 5 to 8 carbon atoms, and the dienes may be open-chain, cyclic or polycyclic dienes. The two olefin groups of the diene are preferably connected by one or two CH2 groups. Examples are 1 ,3-pentadiene, cyclopentadiene, 1 ,5-hexadiene, 1 ,4-cyclohexadiene, 1 ,4- or 1 ,5-heptadiene, 1 ,4- or 1 ,5-cycloheptadiene, 1 ,4- or 1 ,5-octadiene, 1 ,4- or 1 ,5-cyclooctadiene and norbornadiene. X1 is preferably two ethylene or 1 ,5-hexadiene, 1 ,5-cyclooctadiene or norbornadiene.

In formula Xl, X2 is preferably Cl or Br. Examples of E' are CIO4 ', CF3SO3 ', CH3SO3 ', HSO4 ', BF4 ', B(phenyl)4 ', BARF (B(3,5-bis(trifluoromethyl)phenyl)4 ~, PF6 ', SbCI6 ', AsF6 " or SbF6 ".

With the ligands described below in the metal complexes of the formulae Xl and XIa, it is possible to achieve unprecedented, extremely high optical yields (>97.8%ee) under optimized conditions, on a synthetically useful scale. In a similar process described in WO02/02487A1 , using a different ligand class, an optical yield of only >96.3%ee was achieved. Such optical yields will, in the context of the production of an optically pure active compound used as a pharmaceutical ingredient, require at least one further recrystallization step to improve the optical purity. In contrast, such a recrystallization step becomes obsolete when the optical purity reaches a level of about 98%ee. The fact that this purification step becomes unnecessary is a considerable advantage (for example cost savings) for the preparation on an industrial scale.

In a direct compaihson experiment the optical yields obtained when employing ligand (100) with the alpha, beta-unsaturated alcohols of the formula VIII are considerably higher than the optical yields obtained employing a state of the art ferrocenyl based ligand, (R)-1 -{(f?)-2-[2-(diphenylphosphino)phenyl]-ferrocenyl}ethylbis[3,5-bis- (thfluoromethyl)phenyl]phosphine [387868-06-6], as described in WO02/02500 A1 with the alpha, beta-unsaturated alcohol substrate 2-[1-[4-methoxy-3-(3-methoxy- propoxy)-phenyl]-meth-(E)-ylidene]-3-methyl-butan-1-ol [387356-95-8].

In process stages 2e) or 3d), proceeding from alpha, beta-unsaturated alcohols of the formula VIII, it is therefore possible, for example, to use metal complexes of the formulae Xl and XIa whose ligands belong to the classes of the ferrocene-1 ,1 '- diphosphines which, in the 1 -position, have a ferrocene-substituted secondary phosphine group and, in the 1 '-position, a secondary phosphine group.

In the context of the present invention, ferrocene-1 ,1 '-diphosphines which, in the 1 - position, have a ferrocene-substituted secondary phosphine group and, in the 1 '- position, a secondary phosphine group are compounds of the formula X in the form of enantiomerically pure diastereomers or a mixture of diastereomers

in which the Ri are the same or different and are each Ci-C4-alkyl; m is 0 or an integer of 1 to 3; n is 0 or an integer of 1 to 4;

R2 is a hydrocarbon radical or C-bonded heterohydrocarbon radical;

Cp is unsubstituted or Ci-C4-alkyl-substituted cyclopentadienyl;

X is a C-bonded chiral group which directs metals of metallating reagents into the ortho position; and

Phos is a P-bonded P(III) substituent.

Phos, as a P-bonded P(III) substituent, is more preferably a secondary phosphine group.

In the case of Ri as alkyl, it may, for example, be methyl, ethyl, n- or i-propyl, n-, i- or t-butyl, preference being given to methyl, m and n are preferably each 0 (and Ri is thus a hydrogen atom).

The hydrocarbon radicals R2 may be unsubstituted or substituted and/or contain heteroatoms selected from the group of O, S, -N= or N(Ci-C4-alkyl). They may contain 1 to 22, preferably 1 to 18, more preferably 1 to 12 and especially preferably 1 to 8 carbon atoms, and 1 to 4 and preferably 1 or 2 of the heteroatoms mentioned. R2 may be radicals selected from the group of linear or branched Ci-Ci2-alkyl; unsub- stituted or Ci-Cβ-alkyl- or CrCβ-alkoxy-substituted C4-Ci2-cycloalkyl or C4-Ci2- cycloalkyl-CH2-; C6-Ci4-aryl; C4-Ci2-heteroaryl; C7-Ci4-aralkyl; C4-Ci2-heteroaralkyl; or halogen- (fluorine-, chlorine- or bromine-), Ci-Cβ-alkyl-, thfluoromethyl-, Ci-Cβ- alkoxy-, trifluoromethoxy-, (C6H5)3Si-, (Ci-Ci2-alkyl)3Si- or sec-amino-substituted C6-Ci4-aryl, C4-Ci2-heteroaryl, C7-Ci4-aralkyl or C4-Ci2-heteroaralkyl. Heteroaryl and heteroaralkyl preferably contain heteroatoms selected from the group of O, S and -N=.

Examples of R2 as alkyl which preferably contains 1 to 6 carbon atoms are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and the isomers of pentyl and hexyl. Examples of R2 as optionally alkyl-substituted cycloalkyl are cyclopentyl, cyclohexyl, methyl- and ethylcyclohexyl, dimethylcyclohexyl, cycloheptyl, cyclooctyl, norbornyl and adamantyl. Examples of R2 as optionally alkyl- and alkoxy-substituted C5-C12- cycloalkyl-CH2- are cyclopentylmethyl, cyclohexyl methyl, cyclooctyl methyl, methylcyclohexylmethyl and dimethylcyclohexylmethyl. Examples of R2 as aryl and aralkyl are phenyl, naphthyl, anthracenyl, fluorenyl, benzyl and naphthylmethyl. Examples of R2 as heteroaryl and heteroaralkyl are furyl, thiophenyl, N-methyl- pyrrolidinyl, pyridyl, benzofuranyl, benzothiophenyl, quinolinyl, furylmethyl, thiophenylmethyl and pyridylmethyl. Examples of R2 as substituted aryl, aralkyl, heteroaryl and heteroaralkyl are phenyl, naphthyl, benzyl, naphthylmethyl, phenyl- ethyl, furyl, thiophenyl, benzofuryl and benzothiophenyl, which are substituted by 1 to 3 radicals selected from the group of methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, ethoxy, methoxy, trifluoromethyl, trifluoromethoxy, fluorine or chlorine. Some preferred examples are 2-, 3- or 4-methylphenyl, 2,4- or 3,5-dimethylphenyl, 3,4,5-thmethylphenyl, 4-ethylphenyl, 2- or 4-methylbenzyl, 2-, 3- or 4-methoxyphenyl, 2,4- or 3,5-dimethoxyphenyl, 3,4,5-thmethoxyphenyl, 2-, 3- or 4-thfluoromethylphenyl, 2,4- or 3,5-di(trifluoromethyl)phenyl, ths(trifluoromethyl)phenyl, 2- or 4-trifluoro- methoxyphenyl, 3,5-bis(thfluoromethoxy)phenyl, 2- or 4-fluorophenyl, 2- or 4-chloro- phenyl and 3,5-dimethyl-4-methoxyphenyl.

In a particularly preferred embodiment, R2 is Ci-C6-alkyl, C5-C8-cycloalkyl, C7-C8- bicycloalkyl, o-furyl, phenyl, naphthyl, 2-(Ci-C6-alkyl)C6H4, 3-(Ci-C6-alkyl)C6H4, 4-(Ci-C6-alkyl)C6H4j 2-(Ci-C6-alkoxy)C6H4j 3-(Ci-C6-alkoxy)C6H4j 4-(Ci-C6- alkoxy)C6H4, 2-(trifluoromethyl)C6H4, 3-(trifluoromethyl)C6H4, 4-(thfluoromethyl)C6H4, 3,5-bis(trifluoromethyl)C6H3, -3,5-bis(Ci-C6-alkyl)2C6H3, 3,5-bis(Ci-C6-alkoxy)2C6H3, and 3,5-bis(Ci-C6-alkyl)2-4-(Ci-C6-alkoxy)C6H2.

In the ortho-directing chiral X group, the chiral atom is preferably bonded in the 1-, 2- or 3-position to the cyclopentadienyl-X bond. The X group may be open-chain radicals or cyclic radicals, where the atoms are selected from the group of H, C, O, S and N.

The X group may, for example, correspond to the formula -HC*R5R6 (* indicates the asymmetric atom) in which R5 is Ci-C8-alkyl, C5-C8-cycloalkyl (cyclohexyl), C6-Ci0- aryl (phenyl), C7-Ci2-aralkyl (benzyl) or C7-Ci2-alkaralkyl (methylbenzyl), R6 is -OR7 or -NR8R9, R7 is Ci-C8-alkyl, C5-C8-cycloalkyl, phenyl or benzyl, and R8 and Rg are the same or different and are each Ci-C8-alkyl, C5-C8-cycloalkyl, phenyl or benzyl, or R8 and Rg, together with the nitrogen atom, form a five- to eight-membered ring. R5 is preferably CrC4-alkyl, for example methyl, ethyl, n-propyl and phenyl. R7 is preferably Ci-C4-alkyl, for example methyl, ethyl, n-propyl and n- or i-butyl. R8 and Rg are preferably identical radicals and are preferably each Ci-C4-alkyl, for example methyl, ethyl, n-propyl, i-propyl and n- or i-butyl, and together are tetramethylene, pentamethylene or 3-oxa-1 ,5-pentylene. Particularly preferred groups of the formula -HCR5R6 are 1 -methoxyeth-1 -yl, 1-dimethylaminoeth-1 -yl and i -(dimethylamino)- 1 -phenylmethyl.

X is more preferably a -CHR5-NR8Rg group in which R5 is Ci-C4-alkyl, C5-C6- cycloalkyl, phenyl, Ci-C4-alkylphenyl or Ci-C4-alkylbenzyl, and R8 and Rg are the same and are each Ci-C4-alkyl and preferably methyl or ethyl.

Phos may, as a P-bonded P(III) substituent, be a secondary phosphine group which contains identical or different hydrocarbon radicals, or in which the hydrocarbon radical, together with the phosphorus atom, forms a 4- to 8-membered ring. The secondary phosphine group preferably contains identical hydrocarbon radicals. The hydrocarbon radicals R2 may be unsubstituted or substituted and/or contain heteroatoms selected from the group of O, S, -N= or N(Ci-C4-alkyl). They may contain 1 to 22, preferably 1 to 18, more preferably 1 to 12 and especially preferably 1 to 8 carbon atoms, and 1 to 4 and preferably 1 or 2 of the heteroatoms mentioned. R2 may be radicals selected from the group of linear or branched Ci-Ci2-alkyl; unsubstituted or d-Ce-alkyl- or Ci-C6-alkoxy-substituted C5-Ci2-cycloalkyl or C5-Ci2-cycloalkyl-CH2-; C6-Ci4-aryl; C4-Ci2-heteroaryl; C7-Ci4-aralkyl; C4-Ci2-heteroaralkyl; or halogen- fluorine-, chlorine- or bromine-), Ci-Cβ-alkyl-, thfluoromethyl-, d-Cβ-alkoxy-, trifluoro- methoxy-, (CeHs)3Si-, (Ci-Ci2-alkyl)3Si- or sec-amino-substituted C6-Ci4-aryl, C4-Ci2- heteroaryl, C7-Ci4-aralkyl or C4-Ci2-heteroaralkyl. Heteroaryl and heteroaralkyl preferably contain heteroatoms selected from the group of O, S and -N=.

Examples of hydrocarbon radicals as alkyl which preferably contains 1 to 6 carbon atoms are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and the isomers of pentyl and hexyl. Examples of hydrocarbon radicals as optionally alkyl-substituted cycloalkyl are cyclopentyl, cyclohexyl, methyl- and ethylcyclohexyl, dimethylcyclo- hexyl, cycloheptyl, cyclooctyl, norbornyl and adamantyl. Examples of R2 as optionally alkyl- and alkoxy-substituted C5-Ci2-cycloalkyl-CH2- are cyclopentyl methyl, cyclo- hexylmethyl, cyclooctyl methyl, methylcyclohexylmethyl and dimethylcyclohexyl- methyl. Examples of R2 as aryl and aralkyl are phenyl, naphthyl, anthracenyl, fluorenyl, benzyl and naphthylmethyl. Examples of R2 as heteroaryl and heteroaralkyl are furyl, thiophenyl, N-methylpyrrolidinyl, pyridyl, benzofuranyl, benzothiophenyl, quinolinyl, furylmethyl, thiophenylmethyl and pyhdylmethyl. Examples of R2 as substituted aryl, aralkyl, heteroaryl and heteroaralkyl are phenyl, naphthyl, benzyl, naphthylmethyl, phenylethyl, furyl, thiophenyl, benzofuryl and benzothiophenyl, which are substituted by 1 to 3 radicals selected from the group of methyl, ethyl, n- and i- propyl, n-, i- and t-butyl, ethoxy, methoxy, trifluoromethyl, trifluoromethoxy, fluorine or chlorine. Some preferred examples are 2-, 3- or 4-methylphenyl, 2,4- or 3,5-dimethyl- phenyl, 3,4,5-thmethylphenyl, 4-ethylphenyl, 2- or 4-methylbenzyl, 2-, 3- or 4- methoxyphenyl, 2,4- or 3,5-dimethoxyphenyl, 3,4,5-thmethoxyphenyl, 2-, 3- or 4- trifluoromethylphenyl, 2,4- or 3,5-di(trifluoromethyl)phenyl, tris(trifluoromethyl)phenyl, 2- or 4-trifluoronnethoxyphenyl, 3,5-bis(trifluoromethoxy)phenyl, 2- or 4-fluorophenyl, 2- or 4-chlorophenyl and 3,5-dimethyl-4-methoxyphenyl.

In a particularly preferred embodiment, the hydrocarbon radical is Ci-C6-alkyl, C5-C8- cycloalkyl, C7-C8-bicycloalkyl, o-furyl, phenyl, naphthyl, 2-(Ci-C6-alkyl)C6H4, 3-(Ci-C6- alkyl)C6H4, 4-(Ci-C6-alkyl)C6H4j 2-(Ci-C6-alkoxy)C6H4j 3-(Ci-C6-alkoxy)C6H4j 4-(d- C6-alkoxy)C6H4, 2-(trifluoromethyl)C6H4, 3-(thfluoromethyl)C6H4, 4-(trifluoro- methyl)C6H4, 3,5-bis(thfluoromethyl)C6H3, -3,5-bis(Ci-C6-alkyl)2C6H3, 3,5-bis(d-C6- alkoxy)2C6H3, and 3,5-bis(Ci-C6-alkyl)2-4-(Ci-C6-alkoxy)C6H2.

The secondary phosphino group preferably corresponds to the formula -PRsR4 in which R3 and R4 are each independently a hydrocarbon radical which has 1 to 18 carbon atoms and is unsubstituted or substituted by Ci-Cβ-alkyl, trifluoromethyl, d-Ce-alkoxy, thfluoromethoxy, (Ci-C4-alkyl)2amino, (C6H5)3Si, (Ci-Ci2-alkyl)3Si, halogen and/or contains O heteroatoms.

R3 and R4 are preferably each radicals selected from the group of linear or branched d-Cβ-alkyl, cyclopentyl or cyclohexyl which are unsubstituted or substituted by one to three Ci-C4-alkyl or Ci-C4-alkoxy, furyl, benzyl which is unsubstituted or substituted by one to three Ci-C4-alkyl or Ci-C4-alkoxy, and especially phenyl or naphthyl which are unsubstituted or substituted by one to three F, Cl, Ci-C4-alkyl, CrC4- alkoxy, Ci-C4-fluoroalkyl or Ci-C4-fluoroalkoxy.

R3 and R4 are more preferably radicals selected from the group of C3-C8-alkyl, cyclopentyl, cyclohexyl, furyl, naphthyl and phenyl which is unsubstituted or substituted by one to three F, Cl, Ci-C4-alkyl, Ci-C4-alkoxy and/or Ci-C4-fluoroalkyl.

The secondary phosphine group Phos may be cyclic secondary phosphino, for example those of the formulae

which are unsubstituted or mono- or polysubstituted by d-Cs-alkyl, C4-C8-cycloalkyl, d-Cβ-alkoxy, Ci-C4-alkoxy-Ci-C4-alkyl, phenyl, Ci-C4-alkyl- or Ci-C4-alkoxyphenyl, benzyl, Ci-C4-alkyl- or CrC4-alkoxybenzyl, benzyloxy, Ci-C4-alkyl- or CrC4- alkoxybenzyloxy, or Ci-C4-alkylidenedioxy.

The substituents may be bonded in one or both alpha-positions to the phosphorus atom in order to introduce chiral carbon atoms. The substituents in one or both alpha-positions are preferably Ci-C4-alkyl or benzyl, for example methyl, ethyl, n- or i-propyl, benzyl or -CH2-O-Ci-C4-alkyl or -CH2-O-C6-Ci0-aryl.

Substituents in the beta,gamma-positions may, for example, be Ci-C4-alkyl, CrC4- alkoxy, benzyloxy, or -0-CH2-O-, -O-CH(Ci-C4-alkyl)-O-, and -O-C(Ci-C4-alkyl)2-O-. Some examples are methyl, ethyl, methoxy, ethoxy, -O-CH(methyl)-O- and -O-C(methyl)2-O-.

According to the type of substitution and number of substituents, the cyclic phosphine radicals may be C-chiral, P-chiral or C- and P-chiral.

An aliphatic 5- or 6-membered ring or benzene may be fused onto two adjacent carbon atoms in the radicals of the above formulae.

The cyclic secondary phosphino may, for example, correspond to the formulae (only one of the possible diastereomers specified) C-C.-alkyl c.-c.-alkyl

in which the R' and R" radicals are each Ci-C4-alkyl, for example methyl, ethyl, n- or i-propyl, benzyl, or -CH2-O-Ci-C4-alkyl or -Chb-O-Ce-Cio-aryl, and R' and R" are the same or different.

In the compounds of the formulae X, Phos as secondary phosphino is preferably non-cyclic secondary phosphine selected from the group of -P(Ci-C6-alkyl)2, -P(C5- C8-cycloalkyl)2, -P(C7-C8-bicycloalkyl)2, -P(o-furyl)2, -P(C6Hs)2, -P[2-(Ci-C6- alkyl)C6H4]2, -P[3-(Ci-C6-alkyl)C6H4]2j -P[4-(Ci-C6-alkyl)C6H4]2j -P[2-(Ci-C6- alkoxy)C6H4]2, -P[3-(Ci-C6-alkoxy)C6H4]2j -P[4-(Ci-C6-alkoxy)C6H4]2j -P[2- (thfluoromethyl)C6H4]2, -P[3-(trifluoromethyl)C6H4]2, -P[4-(trifluoromethyl)C6H4]2, -P[3,5-bis(trifluoromethyl)C6H3]2, -P[3,5-bis(Ci-C6-alkyl)2C6H3]2, -P[3,5-bis(Ci-C6- alkoxy)2C6H3]2, and -P[3,5-bis(Ci-C6-alkyl)2-4-(Ci-C6-alkoxy)C6H2]2, or a cyclic phosphine selected from the group of

which are unsubstituted or mono- or polysubstituted by CrC4-alkyl, Ci-C4-alkoxy, Ci-C4-alkoxy-Ci-C2-alkyl, phenyl, benzyl, benzyloxy or Ci-C4-alkylidenedioxy. Some specific examples are -P(CH3)2, -P(i-C3H7)2, -P(n-C4H9)2, -P(i-C4H9)2, -P(t-C4H9)2, -P(C5H9), -P(C6Hn)2, -P(norbornyl)2, -P(o-furyl)2, -P(C6Hs)2, P[2-(methyl)C6H4]2, P[3-(methyl)C6H4]2, -P[4-(methyl)C6H4]2, -P[2-(methoxy)C6H4]2, -P[3-(methoxy)C6H4]2, -P[4-(methoxy)C6H4]2, -P[3-(trifluoromethyl)C6H4]2, -P[4-(trifluoromethyl)C6H4]2, -P[3,5-bis(trifluoromethyl)C6H3]2, -P[3,5- bis(methyl)2C6H3]2, -P[3,5-bis(methoxy)2C6H3]2, and -P[3,5-bis(methyl)2-4- (methoxy)C6H2]2, and those of the formulae

in which

R' is methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, methoxymethyl, ethoxy- methyl or benzyloxymethyl, and R" is independently as defined for R' but is different from R'.

The compounds of the formula X can be prepared in a simple and modular manner in high yields even as enantiomerically pure disastereomers. Intermediates are also obtainable as enantiomerically pure diastereomers, which facilitates the preparation of pure diastereomehc end products. Appropriately, the starting material is 1 ,1 '-dihaloferrocene, which is commercially available, for example 1 ,1'-dibromo- ferrocene, and in which a halogen can be substituted selectively by a metal with metallating reagents, for example Li-alkyl. In a first variant, the R2HaIP- group is then introduced by reaction with R2-P(HaI)2. The reaction with ortho-metallated and with Y-substituted ferrocenes leads to a central intermediate of the formula VIII which is obtainable as a pure diastereomer by means of heating and recrystallization:

(XVIII) where Hal is halogen (Cl, Br or I, preferably Br). In the compounds of the formula VIII, after another metallation (substitution of Hal) a desired Phos group can be introduced with halophosphines of the formula Phos-Hal.

In another variant, the Phos group is first introduced by reaction with Phos-Hal, and then the R2HaIP- group by means of metallation and subsequent reaction with R2-P(HaI)2. This affords intermediates of the formula XX

which are reacted in a last stage with ortho-metallated and with X-substituted ferrocenes to give compounds of the formula X. The resulting mixtures of diastereomers can be converted by heating and recrystallization to a pure diastereomer.

One process for preparing compounds of the formula X comprises, for example, the steps of: a) metallating a 1 ,1 '-dihaloferrocene to give a 1 -metal-1 '-haloferrocene and subsequent reaction with a compound of the formula R2-P(HaI)2 in which Hal is chlorine, bromine or iodine to give a compound of the formula XVI in which Ri, R2 and n are each as defined above, and Hal is chlorine, bromine or iodine,

b) reacting a compound of the formula XVI with a compound of the formula XVII

in which X, Cp, Ri and m are each as defined above and M is Li or MgHaI where Hal is chlorine, bromine or iodine to give a compound of the formula XVIII

(XVIII), and c) reacting a compound of the formula XVIII with lithium alkyl and then with a halophosphine of the formula Phos-Hal in which Hal is chlorine, bromine or iodine to give a compound of the formula X.

In process stage b), mixtures of diastereomers of the P-chiral compounds of the formula XVIII are obtained. Mixtures of diastereomers of the compouds of the formula XVIII according to process stage b) can be separated by means of known methods, for example chromatography, into their different stereoisomers.

These mixtures may, though, also be converted to pure diastereomers in a surprisingly simple manner by mere thermal treatment and optionally a subsequent recrystallization. A thermal treatment and optional recrystallization are advisable before performing process stage c) to avoid purification steps such as separations on chiral columns after process stage c) to prepare pure diastereomers. Thermal treatment may, for example, mean taking up the reaction product in an inert solvent and heating to 40 to 1500C and preferably 60 to 1200C for a period of minutes to hours, for example 10 minutes to 10 hours. Suitable solvents are mentioned later.

The dihaloferrocenes and dihalophosphines used in process stage a) are known and some of them are commercially available or they can be prepared by analogous processes. Compounds of the formula XVIII are known or are preparable by known or analogous processes. The starting materials are known X-substituted ferrocenes which are metallated in the ortho-position. Metallation with lithium alkyl or else magnesium Grignard compounds of ferrocenes are known reactions which are described, for example, by T. Hayashi et al., Bull. Chem. Soc. Jpn. 53 (1980), pages 1138 to 1151 or in Jonathan Clayden Organolithiums: Selectivity for Synthesis (Tetrahedron Organic Chemistry Series), Pergamon Press (2002). The alkyl in lithium alkyl may, for example, contain 1 to 6 carbon atoms and preferably 1 to 4 carbon atoms. Frequently, lithium methyl, lithium s-butyl, lithium n-butyl and lithium t-butyl are used. Magnesium Grignard compounds are preferably those of the formula (d- C4-alkyl)MgX0 in which X0 is Cl, Br or I.

The reactions in process stages a), b) and c) are appropriately performed at low temperatures, for example 20 to -100°C, preferably 0 to -800C. After adding reagents, the temperature can also be increased, for example to room temperature. The reactions are advantageously performed under inert protective gases, for example nitrogen or noble gases, for example helium or argon.

Preferred ligands correspond to the formula X in which m is 0; n is 0;

R2 is d-Ce-alkyl, C5-C8-cycloalkyl, C7-C8-bicycloalkyl, o-furyl, phenyl, naphthyl, 2-(Ci-

C6-alkyl)C6H4, 3-(Ci-C6-alkyl)C6H4, 4-(Ci-C6-alkyl)C6H4, 2-(Ci-C6-alkoxy)C6H4, 3-(d-

C6-alkoxy)C6H4, 4-(Ci-C6-alkoxy)C6H4, 2-(trifluoromethyl)C6H4, 3-(trifluoro- methyl)C6H4, 4-(trifluoromethyl)C6H4, 3,5-bis(trifluoromethyl)C6H3, 3,5-bis(Ci-C6- alkyl)2C6H3, 3,5-OiS(Ci-C6-SIkOXy)2C6H3 or 3,5-bis(Ci-C6-alkyl)2-4-(Ci-C6-alkoxy)C6H2;

Cp is unsubstituted cyclopentadienyl;

X is a -CHR5-NR8Rg group in which R5 is CrC4-alkyl, C5-C6-cycloalkyl, phenyl, CrC4- alkylphenyl or Ci-C4-alkylbenzyl, and Rs and Rg are the same and are each CrC4- alkyl and preferably methyl or ethyl; and

Phos is a P-bonded P(III) substituent of the formula -PRsR4 in which R3 and R4 are each independently a radical selected from the group of C3-C8-alkyl, cyclopentyl, cyclohexyl, furyl, naphthyl, and phenyl which is unsubstituted or substituted by one to three F, Cl, CrC4-alkyl, Ci-C4-alkoxy and/or CrC4-fluoroalkyl.

Very particular preference is given to the ligands of the formulae:

The metal complexes used as catalysts in process stages 1d), 2e) or 3d) may be added as separately prepared isolated compounds, or else be formed in situ before the reaction and then mixed with the substrate to be hydrogenated. It may be advantageous to additionally add ligands in the reaction using isolated metal complexes, or to use an excess of the ligands in the in situ preparation. The excess may, for example, be up to 10 mol and preferably 0.001 to 5 mol, based on the metal compound used for the preparation.

Process stages 1d), 2e) or 3d) may be performed at standard pressure or preferably at elevated pressure. The pressure may, for example, be 105 to 2x107 Pa (Pascal).

Catalysts which are used for the hydrogenation in process stages 1d), 2e) or 3d) are preferably used in amounts of 0.0001 to 10 mol%, more preferably 0.001 to 10 mol% and especially preferably 0.01 to 5 mol%, based on the compounds to be hydrogenated. The preparation of the catalysts and process stages 1d), 2e) or 3d) and the other process stages may be performed without or in the presence of an inert solvent, and one solvent or mixtures of solvents may be used. Suitable solvents are, for example, aliphatic, cycloaliphatic and aromatic hydrocarbons (pentane, hexane, petroleum ether, cyclohexane, methylcyclohexane, benzene, toluene, xylene), aliphatic halohydrocarbons (methylene chloride, chloroform, di- and tetrachlorethane), nitriles (acetonitrile, propionitrile, benzonitrile), ethers (diethyl ether, dibutyl ether, t-butyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, dioxane, diethylene glycol monomethyl or monoethyl ether), ketones (acetone, methyl isobutyl ketone), carboxylic esters and lactones (ethyl acetate or methyl acetate, valerolactone), N-substituted lactams (N- methylpyrrolidone), carboxamides, dimethylamide, dimethylformamide, acyclic ureas (dimethylimidazoline), and sulphoxides and sulphones (dimethyl sulphoxide, dimethyl sulphone, tetramethylene sulphoxide, tetramethylene sulphone) and alcohols (methanol, ethanol, propanol, butanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether) and water. The solvents may be used alone or in a mixture of at least two solvents.

The reaction of process stages 1d), 2e) or 3d) can be performed in the presence of cocatalysts, for example quaternary ammonium halides (tetrabutylammonium iodide) and/or in the presence of protic acids, for example mineral acids.

Process stages 1 e) and 2d) are preferably performed at low temperatures, for example -400C to 00C, and advantageously in a solvent. Suitable solvents are, for example, ethers (tetrahydrofuran or dioxane). For the reduction, it is appropriate to use metal hydrides in at least equimolar amounts, for example BH3 »S(CH3)2, LiAIH4, NaBH4 + TiCI4, NaBH4 + AICI3, NaBH4 + BF3-Et2O, LiAIH(OMe)3, AIH3, and also alkyl- metal hydrides such as diisobutylaluminium hydride.

Process stage 3c) is preferably performed at low temperatures, for example -40°C to 00C, and advantageously in a solvent. Suitable solvents are, for example, hydrocarbons (pentane, cyclohexane, methylcyclohexane, benzene, toluene and xylene). For the reduction, it is appropriate to use metal hydrides in at least equimolar amounts, for example NaBH4, LiAIH4, AIH3, and also alkyl-metal hydrides, for example diisobutylaluminium hydride and tributyltin hydride.

It is possible by the inventive regiospecific or regioselective and enantioselective process to prepare the intermediates for preparing the compound of the formula (B) in high yields over all process stages. The high overall yields make the process suitable for industrial use.

The examples which follow provide further illustration of the invention.

EXAMPLES

HPLC gradient on Hypersil BDS C-18 (5 μm); column: 4 x 125 mm

(I) 90% water*/10% acetonitrile* to 0% water*/100% acetonitrile* in 5 minutes + 2.5 minutes(1.5 ml/min)

(II) 95% water*/5% acetonitrile* to 0% water7100% acetonitrile* in 40 minutes (0.8 ml/min)

HPLC gradient on Synergi Polar-RP 80A(Phenomenex) (4 μm); column: 4.60 x 100 mm

(III) 90% water*/10% acetonitrile* to 0% water*/100% acetonitrile* in 5 minutes + 2.5 minutes (1.5 ml/min)

(IV) 95% water*/5% acetonitrile* to 0% water*/100% acetonitrile* in 40 minutes (0.8 ml/min)

* contains 0.1 % trifluoroacetic acid

Example A)

Process for preparing (R)-2-[1 -(3-methoxypropyl)-3-methyl-1 H-indazol-6-ylmethyl]-3- methylbutan-1-ol (A6)

Example A1 :

Preparation of 1-(3-methoxypropyl)-3-methyl-1 H-indazole-6-carbaldehyde

A solution of 10.0 g of 6-bromo-1 -(3-methoxypropyl)-3-methyl-1 H-indazole (WO 2005/090305 A1 ) in 70 ml of tetrahydrofuran is cooled to -78°C and admixed with 3.76 ml of N-methylmorpholine. The mixture is cooled again to -78°C, and 23 ml of n-butyllithium (1.6 M in hexane) are added dropwise at such a rate that the internal temperature does not exceed -700C. The mixture is stirred at -700C over a further 2 minutes. Subsequently, 5.18 ml of N,N-dimethylformamide are added dropwise at such a rate that the internal temperature does not exceed -70°C. The mixture is stirred at -700C over a further 5 minutes. 70 ml of 1 M aqueous ammonium chloride solution are added to the reaction mixture, and the reaction mixture is warmed to room temperature. The reaction mixture is diluted with 50 ml of water and then extracted with tert-butyl methyl ether (2 x 100 ml). The organic phases are washed with brine (1 x 100 ml). The combined organic phases are dried over sodium sulphate, filtered and concentrated by evaporation on a rotary evaporator. The crude title compound A1 is obtained from the residue as a yellow oil. Content (NMR): 90% (contains 10% 1 -(3-methoxypropyl)-3-methyl-1 H-indazole). (7.80 g, 90.4 %). Rf = 0.27 (1 :1 ethyl acetate-heptane); Rt = 3.67 (Gradient I).

Example A2:

Preparation of ethyl 2-{hydroxy-[1 -(3-methoxypropyl)-3-methyl-1 H-indazol-6-yl]- methyl}-3-methylbutyrate

A solution of 2.628 ml of diisopropylamine and 20 ml of tetrahydrofuran is cooled to -200C, and 11.508 ml of n-butyllithium (1.6 M in hexane) are added dropwise over 7 minutes. The mixture is stirred at -200C for a further 10 minutes. Subsequently, a solution of 2.62 ml of ethyl isovalerate in 15 ml of tetrahydrofuran is added dropwise at -20°C over 10 minutes. After a further 5 minutes, a solution of 3.60 g of 1 -(3- methoxypropyl)-3-methyl-1 H-indazole-6-carbaldehyde (A1 ) in 15 ml of tetrahydrofuran is added dropwise, and the mixture is stirred at -200C over a further 30 minutes. 30 ml of saturated aqueous ammonium chloride solution are then added dropwise and then the mixture is extracted with tert-butyl methyl ether (2 x 100 ml). The organic phases are washed successively with 0.5 N hydrochloric acid (1 x 100 ml) and brine (1 x 50 ml). The combined organic phases are dried over sodium sulphate, filtered and concentrated by evaporation on a rotary evaporator. The crude title compound A2 is obtained from the residue as a white solid (4.98 g, 89.6%, syn:anti = 67:33). Rf = 0.08 (1 :2 ethyl acetate-heptane); Rt = 15.96, 16.75 (Gradient II).

Example A3:

Preparation of ethyl 2-[1-[1 -(3-methoxypropyl)-3-methyl-1 H-indazol-6-yl]meth-(E)- ylidene]-3-methylbutyrate

A solution of 2.80 g of ethyl 2-{hydroxy-[1 -(3-methoxypropyl)-3-methyl-1 H-indazol-6- yl]methyl}-3-methylbutyrate (A2) and 47 mg of 4-dimethylaminopyhdine in 20 ml of tetrahydrofuran is cooled to 00C. 0.79 ml of acetic anhydride is added dropwise over 2 minutes and the reaction mixture is stirred at 00C over 1 hour. A solution of 2.63 g of potassium tert-butoxide in 20 ml of tetrahydrofuran is then added dropwise at 00C over 1 hour, and the mixture is then stirred at 00C for 1 hour. The reaction mixture is poured onto 100 ml of ice-water and extracted with tert-butyl methyl ether (2 x 80 ml). The organic phases are washed successively with 80 ml of water and 80 ml of brine, dried over sodium sulphate, filtered and concentrated by evaporation on a rotary evaporator. The pure title compound A3 is obtained from the residue by means of flash chromatography (SiO2 6OF, 1 :6 ethyl acetate-hexane) as a slightly yellowish oil (1.83 g, 70%). Rf = 0.28 (1 :2 ethyl acetate-heptane); Rt = 22.42 (Gradient II).

Example A4:

Preparation of 2-[1 -[1 -(3-methoxypropyl)-3-methyl-1 H-indazol-6-yl]meth-(E)-ylidene]-

3-methyl butyric acid

A solution of 2.80 g of ethyl 2-{hydroxy-[1 -(3-methoxypropyl)-3-methyl-1 H-indazol-6- yl]methyl}-3-methylbutyrate (A2) and 47 mg of 4-dimethylaminopyridine in 20 ml of tetrahydrofuran is cooled to 00C. 0.79 ml of acetic anhydride is added dropwise over 2 minutes and the reaction mixture is stirred at 00C over 1 hour. A solution of 2.63 g of potassium tert-butoxide in 20 ml of tetrahydrofuran is then added dropwise at 00C over 1 hour, and the mixture is then stirred at 00C for 1 hour. 10 ml of ice-water is added dropwise to the reaction mixture over 1 minute and the tetrahydrofuran is evaporated off on a rotary evaporator. The aqueous emulsion is admixed with 28 ml of ethanol and 3.8 ml of 2M aqueous potassium hydroxide solution and heated to reflux for 13.5 hours. The ethanol is evaporated out of the reaction mixture on a rotary evaporator (35°C). The resulting aqueous solution is washed with tert-butyl methyl ether (2 x 15 ml). The aqueous phase is acidified with 10 ml of 2M aqueous hydrochloric acid solution and extracted with tert-butyl methyl ether (2 x 30 ml). The organic phases are washed successively with 15 ml of water and 15 ml of brine, dried over sodium sulphate, filtered and concentrated by evaporation on a rotary evaporator. The pure title compound A4 is obtained as white crystals from the residue by means of crystallization from a hot ethyl acetate-heptane mixture (1.44 g.

60.1 %). Rf = 0.27 (3:1 ethyl acetate-heptane); Rt = 16.41 (Gradient II).

(A5)

Example A5:

(R)-2-[1 -(3-Methoxypropyl)-3-methyl-1 H-indazol-6-ylmethyl]-3-nnethylbutyric acid

The title compound is obtainable by catalytic asymmetric hydrogenation of 2-[1 -[1 -(3- methoxypropyl)-3-methyl-1 H-indazol-6-yl]meth-(E)-ylidene]-3-methylbutyric acid (A4).

The asymmetric hydrogenations of 2-[1 -[1 -(3-methoxypropyl)-3-methyl-1 H-indazol-6- yl]meth-(E)-ylidene]-3-methylbutyric acid (A4) are performed in a fully automated high-throughput screening system which has been developed by Symyx in order to find valuable conditions.

The reaction mixture is analysed for conversion and enantiomeric excess by means of the HPLC method specified below. To this end, 80 μl of the reaction solution are dissolved in 1000 μl of ethanol. The following promising results are achieved:

Conditions: 41.66 μmol of 2-[1 -[1 -(3-methoxypropyl)-3-nnethyl-1 H-indazol-6-yl]meth- (E)-ylidene]-3-methyl butyric acid (A4); 500 μl of solvent; 1.2 equivalents of ligand per metal; p(H2): 20 bar; T: room temperature; reaction time: 16 hours

Under otherwise identical conditions, the product with the (S)-configuration is obtained with the enantiomeric ligand.

SFC conditions:

Instrument SFC Berger Instruments

Column CHIRALPAK-AD (250 mm * 0.46 cm)

Modifier ethanol

Outlet pressure 100 bar

Gradient 15% EtOH 8 min, 60%/min 40%, 2 min 40%, 60%/min

15%, 15% 6 min, total 17 min

Flow 1.5 ml/min.

Detection UV (210 nm)

Temperature 400C

Sample concentration 2 mg of product in 1.0 ml of MeOH

Injection volume 5.0 μl loop

Run time 12 min.

Retention times:

- (S)-(A5) 4.7 min

- (R)-(A5) 5.8 min

(A4) 8.5 min Representative description of the reaction procedure on a larger, synthetically useful scale:

A 50 ml stainless steel autoclave is initially charged with 3.161 mmol of 2-[1 -[1-(3- methoxypropyl)-3-methyl-1 H-indazol-6-yl]meth-(E)-ylidene]-3-methylbutyric acid (A4). In a 20 ml Schlenk tube under an argon atmosphere, a solution of 0.016 mmol of the ligand (100) and 0.08 mmol of the metal precursor ([Rh(NBD)CI]2) in 15 ml of degassed dry methanol is prepared, and the mixture is stirred at room temperature for 1.5 hours. The catalyst solution is transferred by means of a cannula into the 50 ml autoclave which had been placed under argon atmosphere beforehand. The autoclave is closed and purged with argon (a pressure of 10 - 12 bar is applied 3 times and released again to 1 bar each time). Subsequently, the argon is replaced by hydrogen and the autoclave is purged with hydrogen (a pressure of 20 bar is applied 3 times and released again to 1 bar each time). The autoclave is subsequently placed under a pressure of 20 bar with hydrogen. After 19 hours, the pressure is released. The reaction solution is concentrated by evaporation on a rotary evaporator. Purification of the residue by means of flash chromatography (SiO2 6OF, ethyl acetate) provides the title compound A5 in the form of white crystals (yield 2.93 mmol). Rf = 0.32 (2:1 ethyl acetate-heptane); Rt = 4.03 (Gradient I).

The reaction mixture is analysed for conversion and enantiomeric excess by means of the HPLC method specified above. To this end, 80 μl of the reaction solution are dissolved in 1000 μl of ethanol. The following results are achieved:

Conversion: 100% ee% (absolute configuration): 98.9 (R)

Comparison Experiment

Example A6:

(R)-2-[1 -(3-Methoxypropyl)-3-methyl-1 H-indazol-6-ylmethyl]-3-methylbutan-1 -ol

a) Preparation proceeding from (R)-2-[1 -(3-methoxypropyl)-3-methyl-1 H-indazol-6- ylmethyl]-3-methylbutyhc acid (A5)

A solution of 8.55 g of (R)-2-[1-(3-methoxypropyl)-3-methyl-1 H-indazol-6-ylmethyl]-3- methyl butyric acid (A5) in 85 ml of tetrahydrofuran is cooled to 00C and admixed with 81.4 ml of borane-tetrahydrofuran complex (1 M in tetrahydrofuran). The reaction mixture is stirred at room temperature over 17 hours. The reaction mixture is cooled to 00C and then admixed slowly with 100 ml of methanol. The mixture is concentrated by evaporation on a rotary evaporator and dried under high vacuum. The pure title compound A6 is obtained from the residue by means of flash chromatography (SiO26OF, 2:1 ethyl acetate-hexane) as a colourless oil (8.05 g, 98%). Rf = 0.28 (2:1 ethyl acetate-heptane); Rt = 4.13 (Gradient I).

Example A6:

(R)-2-[1 -(3-Methoxypropyl)-3-methyl-1 H-indazol-6-ylmethyl]-3-methylbutan-1 -ol

b) Preparation proceeding from 2-[1 -[1 -(3-methoxypropyl)-3-methyl-1 H-indazol-6-yl]- meth-(E)-ylidene]-3-methylbutan-1 -ol (A7)

The title compound is obtainable by catalytic asymmetric hydrogenation of 2-[1 -[1 -(3- methoxypropyl)-3-methyl-1 H-indazol-6-yl]meth-(E)-ylidene]-3-methylbutan-1 -ol (A7) and purification of the residue by means of flash chromatography (SiO2 6OF, ethyl acetate) as a pale pink oil. Rf = 0.32 (2:1 ethyl acetate-heptane); Rt = 4.13 (Gradient I).

The asymmetric hydrogenations of 2-[1 -[1 -(3-methoxypropyl)-3-methyl-1 H-indazol-6- yl]meth-(E)-ylidene]-3-methylbutan-1 -ol (A7) are performed in a fully automated high- throughput screening system which was developed by Symyx in order to find valuable conditions.

The reaction mixture is analysed for conversion and enantiomeric excess by means of the HPLC method specified below. To this end, 80 μl of the reaction solution are dissolved in 1000 μl of ethanol. The following promising results are achieved:

Conditions: 41.66 μmol of 2-[1 -[1 -(3-methoxypropyl)-3-methyl-1 H-indazol-6-yl]meth- (E)-ylidene]-3-methylbutan-1 -ol (A7); 500 μl of solvent; 1.2 equivalents of ligand per metal; p(H2): 80 bar; T: 400C; reaction time: 14 hours

Under otherwise identical conditions, the product with the (S)-configuration is obtained with the enantiomeric ligand.

SFC conditions:

Instrument SFC Berger Instruments

Column CHIRALPAK-AD (250 mm * 0.46 cm)

Modifier Ethanol

Outlet pressure 100 bar

Gradient 15% EtOH 8 min, 60%/min 40%, 2 min 40%, 60%/min

15%, 15% 6 min, total 17 min

Flow 1.5 ml/min.

Detection UV (210 nm)

Temperature 400C

Sample concentration 2 mg of product in 1.0 ml of MeOH

Injection volume 5.0 μl loop

Run time 12 min.

Retention times:

- (S)-(A6) 6.1 min

- (R)-(A6) 7.5 min

(A7) 8.2 min

Representative description of the reaction procedure on a larger, synthetically useful scale: In a Schlenk tube, a solution of 1.65 mmol of 2-[1 -[1 -(3-methoxypropyl)-3-methyl-1 H- indazol-6-yl]meth-(E)-ylidene]-3-nnethylbutan-1 -ol (A7) in 4 ml of degassed dry ethanol is prepared and stirred at room temperature for 10 minutes. In a second Schlenk tube under an argon atmosphere, a solution of the appropriate amount of the ligand (100) and of the metal precursor ([Rh(NBD)2]BF4) (1.05 equivalents of ligand per metal) in 4 ml of degassed dry ethanol is prepared, and the mixture is stirred at room temperature for 10 minutes. Both solutions are transferred via a cannula into a 50 ml stainless steel autoclave which had been placed under argon atmosphere beforehand. The autoclave is closed and purged with argon (a pressure of 10 - 12 bar is applied 4 times and released again to 1 bar each time). Subsequently, the argon is replaced by hydrogen and the autoclave is purged with hydrogen (a pressure of 10 - 12 bar is applied 4 times and released again to 1 bar each time). The autoclave is subsequently placed under a pressure of 80 bar with hydrogen and heated to 400C. After 20 hours, the mixture is cooled to room temperature and the pressure is released. The reaction solution is concentrated by evaporation on a rotary evaporator. Purification of the residue by means of flash chromatography (SiO2 6OF, ethyl acetate) provides the title compound A6 as a pale pink oil (yield 1.29 mmol). Rf = 0.32 (2:1 ethyl acetate- heptane); Rt = 4.13 (Gradient I).

The reaction mixture is analysed for conversion and enantiomeric excess by means of the above-mentioned HPLC method. To this end, 80 μl of the reaction solution are dissolved in 1000 μl of ethanol. The following results are achieved:

Conversion: 100% ee% (Absolute Configuration): 97.8 (R)

Alternatively, the title compound (A6) can be obtained by reducing 2-[1 -[1-(3- methoxypropyl)-3-methyl-1 H-indazol-6-yl]meth-(E)-ylidene]-3-methylbutyric acid (A4) to 2-[1 -[1 -(3-methoxypropyl)-3-methyl-1 H-indazol-6-yl]meth-(E)-ylidene]-3-methyl- butan-1-ol (A7), and subsequent catalytic asymmetric hydrogenation.

Example A7:

2-[1 -[1 -(3-Methoxypropyl)-3-methyl-1 H-indazol-6-yl]meth-(E)-ylidene]-3-methylbutan-

1 -ol

a) Preparation proceeding from 2-[1 -[1 -(3-methoxypropyl)-3-methyl-1 H-indazol-6-yl]- meth-(E)-ylidene]-3-methyl butyric acid (A4)

A solution of 470 mg of (2-[1 -[1 -(3-methoxypropyl)-3-methyl-1 H-indazol-6-yl]meth- (E)-ylidene]-3-methyl butyric acid (A4) in 2 ml of tetrahydrofuran is cooled to 00C and admixed with a solution of 56.4 mg of lithium aluminium hydride in 2.5 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature over 19 hours. Subsequently, 50.0 mg of solid lithium aluminium hydride are added at room temperature and the reaction mixture is stirred at room temperature over 2 hours. The reaction mixture is admixed slowly with 3 ml of glacial acetic acid. The mixture is washed with sodium potassium tartrate solution, the aqueous phase is extracted with tert-butyl methyl ether and the combined organic phases are dried over sodium sulphate, filtered, concentrated by evaporation on a rotary evaporator and dried under high vacuum. The pure title compound A7 is obtained from the residue by means of flash chromatography (SiO2 6OF, 2:1 ethyl acetate-hexane) as a yellow solid (252.7 mg, 56%). Rf = 0.29 (2:1 ethyl acetate-heptane); Rt = 3.96 (Gradient I).

Alternatively, the title compound (A6) can be obtained by catalytic reduction of ethyl 2- [1 -[1 -(3-methoxypropyl)-3-methyl-1 H-indazol-6-yl]meth-(E)-ylidene]-3-methyl-butyrate (A3) to 2-[1 -[1 -(3-methoxypropyl)-3-methyl-1 H-indazol-6-yl]meth-(E)-ylidene]-3- methylbutan-1-ol (A7), and subsequent catalytic asymmetric hydrogenation.

Example A7:

2-[1 -[1 -(3-Methoxypropyl)-3-methyl-1 H-indazol-6-yl]meth-(E)-ylidene]-3-methylbutan-

1 -ol

b) Preparation proceeding from ethyl 2-[1 -[1-(3-methoxypropyl)-3-methyl-1 H-indazol- 6-yl]meth-(E)-ylidene]-3-methylbutyrate (A3)

A solution of 19.68 g of ethyl 2-[1 -[1 -(3-methoxypropyl)-3-methyl-1 H-indazol-6-yl]- meth-(E)-ylidene]-3-methylbutyrate (A3) in 433 ml of toluene is cooled to -200C and admixed with a solution of 115.2 ml of diisobutylaluminium hydride (1.7 M in toluene), in the course of which the temperature is kept at -200C. The reaction mixture is subsequently warmed to room temperature and stirred at room temperature over 1 hour. The reaction mixture is subsequently admixed slowly with 1 I of 1 M HCI, in the course of which the temperature is kept below 30°C. The phases are separated and the aqueous phase is extracted with diethyl ether (1 X 11, 2 X 300 ml). The combined organic phases are washed successively in each case with 1 I of water, of saturated aqueous sodium carbonate solution and of brine, dried over sodium sulphate, filtered and concentrated by evaporation on a rotary evaporator and dried under high vacuum. The pure title compound A7 is obtained from the residue by means of flash chromatography (SiO2 6OF, 200:5:1 dichloromethane-methanol-conc. ammonia) as a yellow oil (14.24 g, 82%). Rf = 0.29 (200:5:1 dichloromethane- methanol-conc. ammonia); Rt = 3.96 (Gradient I). It is possible by the process described in Example A to prepare the following compounds in an analogous manner:

B) (R)-2-f3-(3-Methoxypropyl)-1 -methylimidazof1.5-aipyridin-6-ylmethvn-3- methyl-butan-1 -ol

Mixture of pale yellowish oil and crystals; Rf = 0.15 (95:5 ethyl acetate-methanol); Rt = 3.29 (Gradient IV).

C) (R)-2-[1 -(3-Methoxypropyl)-3-methyl-1 H-indol-6-ylmethyl1-3-methylbutan-1 -ol Yellowish oil, Rf = 0.29 (1 :1 ethyl acetate-heptane); Rt = 4.96 (Gradient I). Hydrogenation Comparison Experiments on a Synthetically useful scale:

S/C = Substrate/ catalyst ratio

Conditions: p(H2): 50 bar; T: 25°C; reaction time: 16 hours

SFC conditions (entries 1 -5):

Instrument SFC Berger Instruments Column CHIRALPAK-AD-H (250 mm * 0.46 cm)

Modifier Ethanol

Outlet pressure 100 bar

Gradient 15% EtOH 8 min, 60%/min 40%, 2 min 40%, 60%/min

15%, 15% 6 i min, total 17 min

Flow 1.5 ml/min.

Detection UV (210 nm)

Temperature 400C

Sample concentration 0.5 mg of product in 1.0 ml of MeOH

Injection volume 5.0 μl loop

Retention times:

(A5) Enantiomer 1 5.50 min

Enantiomer 2 6.86 min

(C5) Enantiomer 1 5.85 min

Enantiomer 2 6.97 min

[172900-71 -9] Enantiomer 1 5.27 min

Enantiomer 2 6.08 min

(A6) Enantiomer 1 7.08 min

Enantiomer 2 8.78 min

(C6) Enantiomer 1 7.03 min

Enantiomer 2 8.36 min

HPLC conditions (entry 6):

Column Daicel chiral column OD-H (250 mm * 0.46 cm)

Solvent Hexane/lsopropanol

Flow 0.6 ml/min.

Detection UV (210 nm)

Temperature 200C [172900-70-8] Enantiomer 1 22.8 min

Enantiomer 2 25 min

Entrv 1

1.18 mg (0.0032 mmol) of [Rh(nbd)2]BF4 and 2.59 mg (0.0035 mmol, 1.1 eq) of Ligand (100) are placed in a 10 ml Schlenk flask that is previously set under an atmosphere of argon. Then, 4 ml of freshly distilled methanol are added and the mixture is stirred for 10 min. In another 10 ml Schlenk flask, a solution of 100 mg (0.32 mmol) of starting material (A4) in 4 ml of dry methanol is prepared and stirred for 10 min. The substrate and the catalyst solution alike are transferred via cannula into a 50 ml stainless steel autoclave that is previously set under an argon atmosphere. The reactor is sealed, purged with argon, then replaced by hydrogen (3 cycles 20 bar/1 bar). The reactor pressure is set at 50 bar hydrogen and stirred at room temperature. After 16h, the pressure in the reactor is released. The reaction mixture is a yellow solution. This crude product is analysed using the SFC method described above. The enantioselectivity is 98%.

Entrv 2

1.18 mg (0.0032 mmol) of [Rh(nbd)2]BF4 and 2.60 mg (0.0035 mmol, 1.1 eq) of Ligand (100) are placed in a 10 ml Schlenk flask that is previously set under an atmosphere of argon. Then, 4 ml of freshly distilled methanol are added and the mixture is stirred for 10 min. In another 10 ml Schlenk flask, a solution of 100 mg (0.32 mmol) of starting material (C4) in 4 ml of dry methanol is prepared and stirred for 10 min. The substrate and the catalyst solution alike are transferred via cannula into a 50 ml stainless steel autoclave that is previously set under an argon atmosphere. The reactor is sealed, purged with argon, then replaced by hydrogen (3 cycles 20 bar/1 bar). The reactor pressure is set at 50 bar hydrogen and stirred at room temperature. After 16h, the pressure in the reactor is released. The reaction mixture is a yellow solution. This crude product is analysed using the SFC method described above. The enantioselectivity is 98%. Entrv 3

1.21 mg (0.0032 mmol) of [Rh(nbd)2]BF4 and 3.32 mg (0.0036 mmol, l.leq) of Ligand [387868-06-6] are placed in a 10 ml Schlenk flask that is previously set under an atmosphere of argon. Then, 4 ml of freshly distilled methanol are added and the mixture is stirred for 10 min. In another 10 ml Schlenk flask, a solution of 100 mg (0.32 mmol) of starting material [387868-07-7] in 4 ml of dry methanol is prepared and stirred for 10 min. The substrate and the catalyst solution alike are transferred via cannula into a 50 ml stainless steel autoclave that is previously set under an argon atmosphere. The reactor is sealed, purged with argon, then replaced by hydrogen (3 cycles 20 bar/1 bar). The reactor pressure is set at 50 bar hydrogen and stirred at room temperature. After 16h, the pressure in the reactor is released. The reaction mixture is a yellow solution. This crude product is analysed using the SFC method described above. The enantioselectivity is 93%.

Entry 4

1.23 mg (0.0033 mmol) of [Rh(nbd)2]BF4 and 2.71 mg (0.0036 mmol, 1.1 eq) of Ligand (100) are placed in a 10 ml Schlenk flask that is previously set under an atmosphere of argon. Then, 4 ml of freshly distilled ethanol are added and the mixture is stirred for 10 min. In another 10 ml Schlenk flask, a solution of 100 mg (0.33 mmol) of starting material (A7) in 4 ml of dry ethanol is prepared and stirred for 10 min. The substrate and the catalyst solution alike are transferred via canula into a 50 ml stainless steel autoclave that is previously set under an argon atmosphere. The reactor is sealed, purged with argon, then replaced by hydrogen (3 cycles 20 bar/1 bar). The reactor pressure is set at 50 bar hydrogen and stirred at room temperature. After 16h, the pressure in the reactor is released. The reaction mixture is a yellow solution. This crude product is analysed using the SFC method described above. The enantioselectivity is 98%.

Entry 5

1.24 mg (0.0033 mmol) of [Rh(nbd)2]BF4 and 2.72 mg (0.0036 mmol, 1.1 eq) of Ligand (100) are placed in a 10 ml Schlenk flask that is previously set under an atmosphere of argon. Then, 4 ml of freshly distilled ethanol are added and the mixture is stirred for 10 min. In another 10 ml Schlenk flask, a solution of 100 mg (0.32 mmol) of starting material (C7) in 4 ml of dry ethanol is prepared and stirred for 10 min. The substrate and the catalyst solution alike are transferred via canula into a 50 ml stainless steel autoclave that is previously set under an argon atmosphere. The reactor is sealed, purged with argon, then replaced by hydrogen (3 cycles 20 bar/1 bar). The reactor pressure is set at 50 bar hydrogen and stirred at room temperature. After 16h, the pressure in the reactor is released. The reaction mixture is a yellow solution. This crude product is analysed using the SFC method described above. The enantioselectivity is >99%.

Entry 6

1.27 mg (0.0034 mmol) of [Rh(nbd)2]BF4 and 3.47 mg (0.0037 mmol, 1.1 eq) of Ligand [387868-06-6] are placed in a 10 ml Schlenk flask that is previously set under an atmosphere of argon. Then, 4 ml of freshly distilled ethanol are added and the mixture is stirred for 10 min. In another 10 ml Schlenk flask, a solution of 100 mg (0.34 mmol) of starting material [387356-95-8] in 4 ml of dry ethanol is prepared and stirred for 10 min. The substrate and the catalyst solution alike are transferred via canula into a 50 ml stainless steel autoclave that is previously set under an argon atmosphere. The reactor is sealed, purged with argon, then replaced by hydrogen (3 cycles 20 bar/1 bar). The reactor pressure is set at 50 bar hydrogen and stirred at room temperature. After 16h, the pressure in the reactor is released. The reaction mixture is a yellow solution. This crude product is analysed using the HPLC method described above. The enantioselectivity is 77%.

Example L:

Preparation of (RC,SFC,SP)-1 -[2-(1 -dimethylaminoethyl)ferrocen-1 -yl]phenylphosphino-

1 '-bromoferrocenes of the formula (A1 ) [Ph = phenyl; Me = methyl]

a) Preparation of i -phenylchlorophosphine-i '-bromoferrocene (X1 )

To a solution of 8 g (23.2 mmol) of 1 ,1'-dibromoferrocene in 30 ml of tetrahydrofuran (THF) are added dropwise, at a temperature of < -300C, 14.5 ml (23.2 mmol) of n-butyllithium (n-BuLi) (1.6 M in hexane). The mixture is stirred further at this temperature for 30 minutes. It is then cooled to -78°C, and 3.15 ml (23.2 mmol) of phenyldichlorophosphine are added dropwise at a sufficiently slow rate that the temperature does not rise above -600C. After stirring at -78°C for a further 10 minutes, the temperature is allowed to rise to room temperature and stirring is continued for another hour. This affords a suspension of the monochlorophosphine X1.

b) Preparation of L (mixture of diastereomers)

To a solution of 5.98 g (23.2 mmol) of (R)-1-dimethylamino-1 -ferrocenylethane in 40 ml of diethyl ether (DE) are added dropwise, at <-10°C, 15.5 ml (23.2 mmol) of t-butyllithium (t-BuLi) (1.5 M in pentane). After stirring at the same temperature for 10 minutes, the temperature is allowed to rise to room temperature and the mixture is stirred for another 1.5 hours. This affords a solution of compound X2 which is added via a cannula to the cooled suspension of the monochlorophosphine X1 at a sufficiently slow rate that the temperature does not rise above -300C. After stirring at -300C for a further 10 minutes, the temperature is allowed to rise to 0°C and the mixture is stirred at this temperature for another 2 hours. The reaction mixture is admixed with 20 ml of water. The organic phase is removed and dried over sodium sulphate, and the solvent is distilled off under reduced pressure on a rotary evaporator. After chromatographic purification (silica gel 60; eluent = 85:10:5 heptane/ethyl acetate/thethylamine), 11.39 g of the desired product are obtained as a mixture of 2 diastereomers.

c) Preparation of L (one diastereomer)

The product obtained in process stage b) is dissolved in 50 ml of toluene and heated at reflux over 4 hours. After the toluene has been distilled off, the residue is recrystallized in ethanol. Compound A1 is obtained as yellow crystals and as a pure diastereomer with a yield of 59%.

31P NMR (121.5 MHz), CDCI3: δ -35.3 (s). Example 100:

Preparation of (RC,SFC,SP)-1 -[2-(1 -dimethylaminoethyl)ferrocen-1 -yl]phenylphosphino-

1 '-dicyclohexylphosphinoferrocene (100) of the formula

To a solution of 629 mg (1 mmol) of compound L in 5 ml of tert-butyl methyl ether (TBME) are added dropwise, whereby the temperature is below 0°C, 0.85 ml (1.1 mmol) of sec-butyllithium (s-BuLi) (1.3 M in cyclohexane). At a temperature of 00C, the mixture is stirred further for 1 hour and then 0.24 ml (1.1 mmol) of chlor- odicyclohexylphosphine is added. The temperature is allowed to rise to room temperature, the mixture is stirred further for 2 hours and then the reaction mixture is admixed with 5 ml of a saturated aqueous NaHCO3 solution. The organic phase is removed and dried over sodium sulphate, and the solvent is distilled off under reduced pressure on a rotary evaporator. After chromatographic purification (silica gel 60; eluent = 85:10:5 heptane/ethyl acetate/triethylamine) and recrystallization in methanol, the compound 100 is obtained as orange crystals and as a pure diastereomer in a yield of 95%. 31P NMR (121.5 MHz, CDCI3): δ -35.4 (s), -6.5 (s).

Example M1 : Preparation of a rhodium complex (NBD is norbornadiene) 11 mg ( 0.0148 mmol) of ligand 100 and 5.4 mg (0.0144 mmol) of [Rh(NBD)2]BF4 are dissolved in 0.8 ml Of CD3OD and stirred over 10 minutes. The solution is transferred to an NMR tube for analysis. 31P NMR (121.5 MHz, CD3OD): Two superimposed doublets. Possible assignment: δ 26.60 (d, JRh-P = 163 Hz), 26.30 (d, JRh-P = 157 Hz).

The remaining metal complexes are prepared in an analogous manner.

CLAIMS

1. Process for preparing a compound of the formula I

in which Het is a bicyclic unsaturated heterocyclyl bonded to the rest of the molecule via a carbon atom, where the ring not bonded directly to the rest of the molecule is substituted by R'i and R'2, R'i and R'2 are each independently H, d-Cβ-alkyl, halogen, polyhalo-d-Cs-alkoxy, polyhalo-Ci-Cs-alkyl, d-Cs-alkoxy, Ci-Cs-alkoxy- d-Cs-alkyl or Ci-Cs-alkoxy-Ci-Cs-alkoxy, where R'i and R'2 are simultaneously not both H, R'3 is d-Cs-alkyl, and in which the carbon atom to which the R'3 radical is bonded has either (R)- or (S)-configuration, preference being given to (Reconfiguration, which is characterized in that a) a compound of the formula Il

in which Het, R'i and R'2 are each as defined above is reacted with a compound of the formula III

in which R'3 is as defined above to give a diastereomer mixture of the formula IV

in which R'7 is Ci-Ci2-alkyl, Cs-Cs-cycloalkyl, phenyl or benzyl, b) the OH group of the diastereomer mixture of the formula IV is converted to a leaving group and the compound containing a leaving group is eliminated in the presence of a strong base to give an acrylic ester of the formula V

then either, according to process variant 1 ,

1 c) the acrylic ester of the formula V is converted by hydrolysis to a compound of the formula Vl

1d) the acid of the formula Vl is hydrogenated in the presence of hydrogen and catalytic amounts of a metal complex as an asymmetric hydrogenation catalyst, which contains metals from the group of ruthenium, rhodium or iridium, to which chiral bidentate ligands of the ferrocene-1 ,1 '-diphosphine type which have, in the 1 -position, a ferrocene-substituted secondary phosphine group and, in the 1 '-position, a secondary phosphine group are bonded, to give a compound of the formula VII

1 e) the acid of the formula VII is reduced to a compound of the formula I;

or, according to process variant 2,

2c) the acrylic ester of the formula V is converted by hydrolysis to a compound of the formula Vl

2d) the acid of the formula Vl is reduced to a compound of the formula VIII

2e) the alcohol of the formula VIII is hydrogenated in the presence of hydrogen and catalytic amounts of a metal complex as an asymmetric hydrogenation catalyst, which contains metals from the group of ruthenium, rhodium or iridium, to which chiral bidentate ligands of the ferrocene-1 ,1 '- diphosphine type which have, in the 1 -position, a ferrocene-substituted secondary phosphine group and, in the 1 '-position, a secondary phosphine group are bonded, to give a compound of the formula I;

or, according to process variant 3,

3c) the acrylic ester of the formula V is reduced to a compound of the formula VIII

3d) the alcohol of the formula VIII is hydrogenated in the presence of hydrogen and catalytic amounts of a metal complex as an asymmetric hydrogenation catalyst, which contains metals from the group of ruthenium, rhodium or iridium, to which chiral bidentate ligands of the ferrocene-1 ,1 '-diphosphine type which, in the 1 -position, have a ferrocene- substituted secondary phosphine group and, in the 1 '-position, a secondary phosphine group are bonded, to give a compound of the formula I.

2. Process according to Claim 1 for preparing a compound of the formula I, wherein R'i is methoxy-or ethoxy-Ci-C4-alkyl, and R'2 is methyl, ethyl, methoxy or ethoxy.

3. Process according to either of Claims 1 and 2 for preparing a compound of the formula I, wherein Het is a bicyclic unsaturated heterocyclic radical having 1 to 4 nitrogen atoms and/or 1 or 2 sulphur or oxygen atoms, consisting of in each case 5- and/or 6-membered rings.

4. Process according to one of Claims 1 to 3 for preparing a compound of the formula I, wherein R'i and R'2 substituted Het is 1 -(3-methoxypropyl)-3-methyl-1 H-indol-6-yl, 3-(3-methoxypropyl)-1-methylimidazo[1 ,5-a]pyhdin-6-yl or 1-(3-methoxypropyl)-3- methyl-1 H-indazol-6-yl, and R'3 is isopropyl.

5. Process according to one of Claims 1 to 3 for preparing a compound of the formula I, wherein the metal complexes used in step 1d are metal complexes of the formulae IX or IXa are

[LM1X1X2] (IX), [LM1X1]+E" (IXa), in which

M1 is rhodium or iridium;

X1 is two olefins or one diene;

X2 is Cl, Br or I;

E" is the anion of an oxoacid or complex acid; and

L is a chiral ligand from the group of the ferrocene-1 ,1'-diphosphines which, in the 1- position, have a ferrocene-substituted secondary phosphine group and, in the 1'- position, a secondary phosphine group.

6. Process according to Claim 5 for preparing a compound of the formula I, wherein the ligand L used is a compound of the formula X in the form of enantiomerically pure diastereomers or a mixture of diastereomers in which the Ri are the same or different and are each Ci-C4-alkyl; m is 0 or an integer of 1 to 3; n is 0 or an integer of 1 to 4;

R2 is a hydrocarbon radical or C-bonded heterohydrocarbon radical;

Cp is unsubstituted or Ci-C4-alkyl-substituted cyclopentadienyl;

X is a C-bonded chiral group which directs metals of metallating reagents into the ortho position; and

Phos is a P-bonded P(III) substituent.

7. Process according to one of Claims 1 to 3 for preparing a compound of the formula I, wherein the metal complexes used in step 2e or 3d are metal complexes of the formulae Xl or XIa

[LM2X1X2] (Xl)1 [LM2X1I+E (XIa), in which

M2 is rhodium;

X1 is two olefins or one diene;

X2 is Cl, Br or I;

E" is the anion of an oxoacid or complex acid; and

L is a chiral ligand from the group of the ferrocene-1 ,1'-diphosphines which, in the

1 -position, have a ferrocene-substituted secondary phosphine group and, in the 1 '-

-position, a secondary phosphine group.

8. Process according to Claim 7 for preparing a compound of the formula I, wherein the ligand L used is a compound of the formula X in the form of enantiomehcally pure diastereomers or a mixture of diastereomers

in which the Ri are the same or different and are each Ci-C4-alkyl; m is 0 or an integer of 1 to 3; n is 0 or an integer of 1 to 4;

R2 is a hydrocarbon radical or C-bonded heterohydrocarbon radical;

Cp is unsubstituted or Ci-C4-alkyl-substituted cyclopentadienyl;

X is a C-bonded chiral group which directs metals of metallating reagents into the ortho position; and

Phos is a P-bonded P(III) substituent.

9. Process according to Claim 6 or 8 for preparing a compound of the formula I, wherein the ligand L used is a compound of the formula

10. Process according to Claim 1 , wherein the compound of the formula (I) prepared according to Claim 1 is converted by halogenation to a compound of the formula B

in which Het is a bicyclic unsaturated heterocyclyl bonded to the rest of the molecule via a carbon atom, where the ring not bonded directly to the rest of the molecule is substituted by R'i and R'2, R'i and R'2 are each independently H, d-Cβ-alkyl, halogen, polyhalo-d-Cs-alkoxy, polyhalo-Ci-Cs-alkyl, d-Cs-alkoxy, Ci-Cs-alkoxy-Ci- Cs-alkyl or Ci-Cs-alkoxy-Ci-Cs-alkoxy, where R'i and R'2 are simultaneously not both H, R's is d-Cs-alkyl and where Y is Cl, Br or I;

and the compound of the formula B is reacted with a compound of the formula C

R1.

in which R4 is Ci-C8-alkyl, R'5 is Ci-C8-alkyl or Ci-C8-alkoxy, R'6 is Ci-C8-alkyl, or R'5 and R'e together are optionally Ci-C4-alkyl-, phenyl- or benzyl-substituted tetramethylene, pentamethylene, 3-oxa-1 ,5-pentylene or -CH2CH2O-C(O)-, and Z is Cl, Br or I, in the presence of an alkali metal or alkaline earth metal, to give a compound of the formula A

11. Process according to Claim 1 , wherein the compound of the formula (I) prepared according to Claim 1 is converted by halogenation to a compound of the formula B

in which Het is a bicyclic unsaturated heterocyclyl bonded to the rest of the molecule via a carbon atom, where the ring not bonded directly to the rest of the molecule is substituted by R'i and R'2, R'i and R'2 are each independently H, Ci-C8-alkyl, halogen, polyhalo-Ci-Cs-alkoxy, polyhalo-Ci-Cs-alkyl, d-Cs-alkoxy, Ci-Cs-alkoxy- d-Cs-alkyl or d-Cs-alkoxy-Ci-Cs-alkoxy, where R'i and R'2 are simultaneously not both H, R'3 is Ci-Cs-alkyl and where Y is Cl, Br or I;

and the compound of the formula B is reacted with a compound of the formula C

R1.

in which R4 is Ci-Cs-alkyl, R'8 is Ci-Cs-alkyl and Z is Cl, Br or I, in the presence of an alkali metal or alkaline earth metal, to give a compound of the formula A'

(A')

Download Citation


Sign in to the Lens

Feedback