Process for preparing (R or S)-5-{1-azido-3-[6-methoxy-5-(3-methoxy-propoxy)- pyridin-3-ylmethyl]-4-methyl-pentyl}-3-alkyl-dihydro-furan-2-one

The invention relates to a stereoselective process for preparing (R or S)-5-{1 -azido-3- [6-methoxy-5-(3-methoxy-propoxy)-pyridin-3-ylmethyl]-4-nnethyl-pentyl}-3-alkyl- dihydro-furan-2-one,as well as sub-processes and to novel intermediates which are obtained in the process stages.

WO 2005/090305 A1 describes delta-amino-gamma-hydroxy-omega-pyridylalkane- carboxamides 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 pyhdyl-metal species to an aldehyde as the key step, are unsuitable for an industrial process especially with regard to the yields, some of which are unsatisfactory.

The invention relates to a novel process, whereby the double bond of 7-[6-methoxy- 5-(3-methoxypropoxy)-pyridin-3-ylmethyl]-2-alkyl-8-methylnon-4-enamides (A),

in which R'3 is isopropyl, R4 is Ci-Cs-alkyl, R'5 is Ci-Cs-alkyl or d-Cs-alkoxy, R'β is d-Cβ-alkyl, or R'5 and R'β together are optionally CrC4-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 (R) or (S) configuration, preference being given to (R) configuration, is simultaneously halogenated in the 5 position and hydroxylated with lactonisation in the 4 position to yield a compound of formula (D),

in which X' is Cl, Br or I,

then the halogen is replaced with azide to yield a compound of formula (E),

The lactone of formula (E) is then amidated, and the azide is converted to the amine group to yield the desired alkanecarboxamides. Said alkanecarboxamide products, corresponding to the general formula (I) as described in WO2005/090305, are obtained in significantly higher overall yields in this novel process. The amidation and the azide reduction are performed on the basis of the process described by P. Herald in the Journal of Organic Chemistry, Vol. 54 (1989), pages 1178-1185.

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

with a compound of the formula C

R1.

in which R'3, R4, R'5 and 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 (R) or (S) configuration, preference being given to (R) configuration, in the presence of an alkali metal or alkaline earth metal. Y and Z, independently of each other, 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, carboxamides or carbonyl halides. The formation of carboxamides from carboxylic esters and amines in the presence of thalkylaluminium or dialkyl- aluminium 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-dihalopropene (for example trans-1 ,3-dichloropropene) with corresponding carboxylic esters in the presence of strong bases, for example alkali metal amides.

The stereoselective preparation of a compound similar to the compounds of the formula B is known in principle:

The stereoselective preparation of 5-(3-iodo-2-methylpropyl)-2-methoxypyridine has been described by M. Banzinger and T. Troxler in Tetrahedron Asymmetry, 14, pages 3469-3477 (2003). The preparation methods described there include 2 different processes, both processes passing through the enantiomerically pure 3-(6- methoxypyridin-3-yl)-2-methylpropan-1-ol as an intermediate, which is converted to the iodide by substituting the alcohol function:

The preparation of enantiomerically pure 3-(6-methoxypyridin-3-yl)-2-methylpropan- 1 -ol according to M. Banzinger and T. Troxler in Tetrahedron Asymmetry, 14, pages 3469-3477 (2003) is effected either by means of a palladium-catalysed coupling of 5-bromo-2-methoxypyridine with enantiomerically pure 3-bromo-3-methylpropionic - A -

acid methyl ester in the presence of at least equimolar amounts of diethylzinc to give the enantiomerically pure 3-(6-methoxypyridin-3-yl)-2-methylpropionic acid methyl ester and subsequent reduction to the enantiomerically pure 3-(6-methoxypyridin-3- yl)-2-methylpropan-1 -ol. This preparation process is unsuitable for an industrial process especially with regard to the yields, some of which are unsatisfactory, and the use of at least equimolar amounts of diethylzinc.

Alternatively, the preparation of enantiomerically pure 3-(6-methoxypyridin-3-yl)-2- methylpropan-1 -ol according to M. Banzinger and T. Troxler in Tetrahedron Asymmetry, 14, pages 3469-3477 (2003) is effected via a Wittig-Horner olefination of 6-methoxypyridine-3-carbaldehyde to give (E)-3-(6-methoxypyridin-3-yl)-2-methyl- acrylic acid, followed by reduction to give (E)-3-(6-methoxypyridin-3-yl)-2-methylprop- 2-en-1-ol, and subsequent catalaytic asymmetric hydrogenation to give 3-(6-methoxy- pyhdin-3-yl)-2-methylpropan-1-ol. As an alternative variant of this process, the catalytic asymmetric hydrogenation of (E)-3-(6-methoxypyridin-3-yl)-2-methyl-acrylic acid is also described.

This preparation process is not applicable per se to the preparation of compounds of the formula B in which R'3 is different from methyl. For example, intermediates for the synthesis of Aliskiren [173334-57-1], where an isopropyl radical is likewise present as a substituent on the double bonds to be hydrogenated, are known to be difficult substrates for catalytic asymmetric hydrogenation (for example hydrogenation of phenyl analogues of the compound of the formula (VII): R. Paciello in Chemical Reviews, 106, pages 2928-2929 (2006)). Moreover, this preparation process, especially with regard to the enantiomeric excesses, some of which are unsatisfactory (asymmetric hydrogenation of (E)-3-(6-methoxypyridin-3-yl)-2-methyl-acrylic acid), is unsuitable for an industrial process. The preparation of (E)-3-(6-methoxy- pyridin-3-yl)-2-methylacrylic acid via a Wittig-Horner olefination is also relatively undesirable for an industrial process from an atom economy point of view.

It has now been found that, surprisingly, it is possible to stereospecifically prepare 2-[6-methoxy-5-(3-methoxypropoxy)pyridin-3-ylmethyl]-3-methylbutan-1 -ol (compounds of the formula B where Y is not halogen but OH; referred to hereinafter as the compound of the formula I) in three to six process stages in high yields and with very high enantiomeric excess (Scheme 1 ):

Scheme 1 If, analogously to the process described in WO 02/02487 A1 and WO 02/02500 A1 , the pyhdylaldehyde of the formula (III), which is prepared via two process variants in one stage in each case from the corresponding bromide of the formula (II; X = Br) by halogen-metal exchange (stage a), or the pyridyl bromides, iodides or triflates of the formula (II; X = Br, I, OTf) by carbonylation (stage f) analogously to commonly known methods, is condensed with carboxylic esters of the formula (IV) to give 2-isopropyl- 3-hydroxy-3-pyhdylcarboxylic esters of the formula (V) (stage b), the diastereomeric products are obtained in high yields.

It has been found that, surprisingly, in contrast to the process described in WO 02/02487 A1 and WO 02/02500 A1 , the resulting diastereomers, in the case of the 2-isopropyl-3-hydroxy-3-pyhdylcarboxylic esters of the formula (V) are advantageously not separated, since, after conversion of the hydroxyl group to a leaving group, followed by base-induced elimination (stage g), the (E)-3-pyridyl-2- isopropylacrylic esters of the formula (Vl) are formed with high stereoselectivity. Proceeding from these (E)-3-pyhdyl-2-isopropylacrylic esters of the formula (Vl), it is possible to obtain the (E)-3-pyhdyl-2-isopropylacrylic acid of the formula (VII) by hydrolysis (stage h). It has been found that, surprisingly, the (E)-3-pyridyl-2- isopropylacrylic acid of the formula (VII) can be prepared advantageously in a one-pot process (stage c) proceeding from the diastereomeric 2-isopropyl-3-hydroxy-3- pyhdylcarboxylic esters of the formula (V), completely avoiding complicated chromatographic purification processes and obtaining a higher yield of (E)-3-pyridyl-2- isopropylacrylic acid of the formula (VII) compared to the stepwise process. Alternatively, after the aldol addition, the pure syn-2-isopropyl-3-hydroxy-3- pyhdylcarboxylic esters of the formula (Va) can also be isolated and processed further.

Similar aldol condensations which find use to prepare 2-substituted 3-(3- pyridyl)acrylic acids or 2-substituted 3-(3-pyhdyl)acrylic esters are described in the literature only with very specific substrates and without comparable substituents on the pyridine radical. For instance, the synthesis of (E)-2-phenyl-3-pyridin-3-ylacrylic acid is described by Y. Nishikawa in the Journal of Medicinal Chemistry, 32, pages 583-593 (1989) and by F. H. Clarke et. al. in the Journal of Organic Chemistry, 27, pages 533-536 (1962), the desired stilbazole products being obtained there with unsatisfactory yields. The synthesis of ethyl 3-pyridin-3-ylacrylat.es which have a glycosylated radical in the 2 position has been published by RT. Tripathi in the Journal of Carbohydrate Research, 341 , pages 1930-1934 (2006), the products described there being obtained as E/Z mixtures in poor yields. These methods are unsuitable for a process on the industrial scale, since the yields here are unsatisfactory, even though 3-pyridin-3-ylacrylic acid derivatives which have, in the 2 position, a phenyl radical or an olefinic radical are obtained here, and easier elimination would be expected. A related process which leads to alkyl-substituted 3-pyridin-3-ylacrylaldehydes is described, for example, by Zh. A. Krasnaya et. al. in Chemistry of Heterocyclic Compounds, 33, pages 410-422 (1997). Here too, the yields are unsuitable for a process on the industrial scale. The 2-isopropyl-3-pyhdyl-1-propanol of the formula (I) can be obtained either by reduction (stage i) proceeding from the (E)-3-pyhdyl-2-isopropylacrylic esters of the formula (Vl) - via the allyl alcohol of the formula (IX) - followed by catalytic asymmetric hydrogenation (stage j); or the 2-isopropyl-3-pyhdyl-1 -propanol of the formula (I) is obtained by converting (E)-3-pyhdyl-2-isopropylacrylic acid of the formula (VII) by catalytic asymmetric hydrogenation (stage d) to virtually enantiomerically pure 2-isopropyl-3-pyhdyl-1 -propionic acid of the formula (VIII), followed by reduction (stage e).

It has surprisingly been found, that the catalytic asymmetric hydrogenation (stage j) of the allyl alcohol of the formula (IX) yields the 2-isopropyl-3-pyhdyl-1 -propanol of the formula (I) with complete conversion and virtually as a pure enantiomer (best result obtained: 100% conversion, >99.5%ee) compared to the processes described before, for example with stehcally much less demanding pyridine compounds reported by M. Banzinger and T. Troxler in Tetrahedron Asymmetry, 14, pages 3469- 3477 (2003) (best result reported: 100% conversion, 88%ee).

It was found that the 2-isopropyl-3-pyridyl-1 -propionic acid of the formula (VIII) is surprisingly obtained virtually as a pure enantiomer in very high yields by catalytic asymmetric hydrogenation (stage d) of (E)-3-pyhdyl-2-isopropylacrylic acid of the formula (VII). The enantiomeric excess is extremely high (best result obtained: 100% conversion, >99.5%ee) compared to the processes describes before, both, with stehcally much less demanding pyridine compounds reported by M. Banzinger and T. Troxler in Tetrahedron Asymmetry, 14, pages 3469-3477 (2003) (best result reported: 100% conversion 97.5%ee) as well as extensively studied aryl compounds described in WO 02/02500 A1 (best result reported: 100% conversion >95%ee), by W. Weissensteiner and F. Spindler in Advanced Synthesis and Catalysism, Vol. 345, (2003) (best result reported: 95%ee, conversion not mentioned), in WO 2006/075166 (best result reported: >98% conversion >98.5%ee) and in WO2006/075177 (best result reported: >98% conversion >98.5%ee).

Both hydrogenantion results are not to be expected and represent a considerable advantage for the preparation on the industrial scale, since an additional enrichment step after the catalytic asymmetric hydrogenantion can be avoide with such high ee values. This is especially important in the context of the intrinsic properties of the 2-isopropyl-3-pyhdyl-1-propanol of the formula (I) and the 2-isopropyl-3-pyridyl-1 - propionic acid of the formula (VIII), as well as for the halide of the formula (B) (Y = Br or Cl): these compounds proofed to be oils in our hands, even at relatively low temperatures, envisioning enantiomeric enrichment by crystallization seems thus hardly possible.

It has likewise been found that, surprisingly, the allyl alcohol of the formula (IX) can be obtained in good yields in only 2 stages proceeding from the pyridyl bromides, iodides or triflates of the formula (II, X = Br, I, OTf) via a Sonogashira coupling (stage I) to give the propargyl alcohol of the formula (X) followed by a Grignard addition (stage m). Sonogashira reactions of 3-pyhdyl bromides with propargyl alcohols are described, for example, by H. Doucet and M. Santelli in the Journal of Molecular Catalysis A: Chemical, 256, pages 75-84 (2006). The yields of Sonogashira reactions with 3-pyhdyl bromides are significantly lower compared to reactions with 2- or 4- pyridyl bromides. The yields described there are too low for a process on the industrial scale. The 2-isopropyl-3-pyridyl-1-propanol of the formula (I) can be converted to the halide of the formula (B) (stage n) analogously to commonly known methods, for example in analogy to the process reported by M. Banzinger and T. Troxler in Tetrahedron Asymmetry, 14, pages 3469-3477 (2003), by J. Maibaum in Tetrahedron Letters, 41 , pages 10085-10089 (2000), by D. A. Sandham in Tetrahedron Letters, 41 , pages 10091 -10094 (2000).

The coupling of the halide of the formula (B) with the amid of the formula (C) (stage o) can be carried out analogously to commonly known methods, for example in analogy to the process reported in WO 01/09083.

The halolactonization of the 7-[6-methoxy-5-(3-methoxypropoxy)-pyridin-3-ylmethyl]- 2-alkyl-8-methylnon-4-enamides of the formula (A) to the compound of formula (D) (stage p) and the azidation of the halide of the formula (D) to the azide of formula (E) (stage q) can be carried out analogously to commonly known methods, for example in analogy to the process reported in WO 01/09083.

The process stages shown in Scheme 1 can be combined with one another in a viable manner, as for example indicated by the arrows in said scheme, in order to obtain 2-isopropyl-3-pyridyl-1-propanol of the formula (I) as an intermediate and ultimately to obtain (R or S)-5-{1 -Azido-3-[6-methoxy-5-(3-methoxy-propoxy)-pyridin- 3-ylmethyl]-4-methyl-pentyl}-3-alkyl-dihydro-furan-2-one of formula (E).

Important intermediates in the process are the (E)-3-pyhdyl-2-isopropylacrylic ester of the formula (VII), the (E)-3-pyhdyl-2-isopropylacrylic acid of the formula (VII), the (E)- 2-iso-propyl-3-pyridylprop-2-en-1 -ol of the formula (IX), the 2-halomethyl-3-methyl- butyl-pyhdine of the formula (B), the 7-(pyridinylmethyl)-2-alkyl-8-methylnon-4- enamide of the formula (A), the 5-(1 -halo-4-methyl-3-pyhdinylmethyl-pentyl)-3-alkyl- dihydro-furan-2-one of the formula (D) and the 5-(1-azido-4-methyl-3-pyridinylmethyl- pentyl)-3-alkyl-dihydro-furan-2-one of the formula (E).

In the process variants which lead via the (E)-3-pyhdyl-2-isopropylacrylic acid of the formula (VII) as an intermediate, process steps b and c are advantageously carried out without purification of the intermediates, which means a considerable advantage (for example cost saving) for the preparation on the industrial scale. The process variant which leads via process steps I, m and j to the 2-isopropyl-3-pyridyl-1 - propanol of the formula (I) is, with 3 process steps, the shortest variant, which is likewise advantageous for the preparation on the industrial scale.

The invention provides a process for preparing compounds of the formula (E)

in which R'3 is isopropyl and R4 is Ci-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 (R) configuration, which is characterized in that the intermediate of the formula I

in which R'3 is as defined above, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration, is prepared via Process variant I:

IA) a compound of the formula Il

in which X is bromide, iodide or -Othflate is converted to a compound of the formula III (stage a or stage f, Scheme 1 )

IB) the compound of the formula III is reacted with a compound of the formula IV

R1, ,COOR1.

(IV), in which R'3 is as defined above, and R'7 is Ci-Ci2-alkyl, Cs-Cs-cycloalkyl, phenyl or benzyl, to give a diastereomer mixture of the formula V or a compound of the formula Va (stage b, Scheme 1 )

in which R'3 and R'7 are each as defined above. Process subvariant I:

This process subvariant is characterized in that

M C) the OH group of the diastereomer mixture of the formula V or the OH group of the compound of the formula Va is converted to a leaving group, and the compound which now contains a leaving group is eliminated in the presence of a strong base to give an acrylic ester of the formula Vl (stage g, Scheme 1 )

in which R'3 and R'7 are each as defined above,

11 D) the acrylic ester of the formula Vl is converted by hydrolysis to a compound of the formula VII (stage h, Scheme 1 )

in which R'3 is as defined above,

11 E) the acid of the formula VII is hydrogenated in the presence of hydrogen and catalytic amounts of a metal complex as an asymmetric hydrogenation catalyst, to whose metal centre chiral bidentate ligands are bonded, to give a compound of the formula VIII (stage d, Scheme 1 )

in which R'3 is as defined above, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration, and

M F) the acid of the formula VIII is reduced to a compound of the formula I (stage e, Scheme 1 ).

Process subvariant 2

This process subvariant is characterized in that

I2C) the OH group of the diastereomer mixture of the formula V or the OH group of the compound of the formula Va is converted to a leaving group and the compound which now contains a leaving group is eliminated in the presence of a strong base to give an acrylic ester of the formula Vl (stage g, Scheme 1 )

in which R'3 and R'7 are each as defined above,

12D) the acrylic ester of the formula Vl is reduced to a compound of the formula IX (stage i, Scheme 1 )

in which R'3 is as defined above,

12E) the alcohol of the formula IX is hydrogenated in the presence of hydrogen and catalytic amounts of a metal complex as an asymmetric hydrogenation catalyst, to whose metal centre chiral bidentate ligands are bonded, to give a compound of the formula I (stage j, Scheme 1 ).

Process subvahant 3:

This process subvariant is characterized in that

I3C) the OH group of the diastereomer mixture of the formula V or the OH group of the compound of the formula Va is converted to a leaving group, the compound which now contains a leaving group is converted in the presence of a strong base to an acrylic ester, and then, in a one-pot process, hydrolysed to a compound of the formula VII (stage c, Scheme 1 )

in which R'3 is as defined above,

13D) the acid of the formula VII is hydrogenated in the presence of hydrogen and catalytic amounts of a metal complex as an asymmetric hydrogenation catalyst, to whose metal centre chiral bidentate ligands are bonded, to give a compound of the formula VIII (stage d, Scheme 1 )

in which R'3 is as defined above, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration,

13E) the acid of the formula VIII is reduced to a compound of the formula I (stage e, Scheme 1 ).

Process variant II:

MA) a compound of the formula Il

in which X is bromide, iodide or -Othflate is converted to a compound of the formula X (stage I, Scheme 1 )

MB) the compound of the formula X is converted to a compound of the formula IX (stage m, Scheme 1 )

MC) the alcohol of the formula IX is hydrogenated in the presence of hydrogen and catalytic amounts of a metal complex as an asymmetric hydrogenation catalyst, to whose metal centre chiral bidentate ligands are bonded, to give a compound of the formula I (stage j, Scheme 1 ).

Continuing from the intermediate compound of the formula I, prepared via one of the above mentioned routes,

G) the compound of the formula I

in which R'3 is as defined above, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration, is then converted to a compound of the formula (B) (stage n, Scheme 1 )

in which R'3 is as defined above, Y is Cl, Br or I, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration,

H) the compound of the formula (B) is reacted with a compound of the formula (C)

R1.

in which R4, is as defined above, R'5 is Ci-C8-alkyl or Ci-C8-alkoxy, R'6 is Ci-C8-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 Z is Cl, Br or I, to give a compound of the formula (A) (stage o, Scheme 1 )

in which R'3, R4, R'5 and R'β are each as defined above, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration,

J) the compound of the formula (A) is then converted to a compound of the formula (D) (stage p, Scheme 1 )

in which X' is Cl, Br or I, and

K) the compound of the formula (D) is then converted to a compound of the formula (E) (stage q, Scheme 1 ).

R 4 may, as Ci-C8-alkyl, be linear ar branched and be methyl, ethyl, i- or n-propyl, n-, i- or t-butyl or hexyl.

R 4 is preferably Ci-C6-alkyl and more preferably Ci-C4-alkyl; most preferebla i- propyl.

R'5 and R'β, independently of each other, may be branched or preferably linear as alkyl and are preferably CrC4-alkyl, for example methyl or ethyl. R'5 as alkoxy may preferably be linear and is preferably Ci-C4-alkoxy, for example methoxy or ethoxy. R'5 and R'6 together are preferably tetramethylene, or -CH2CH2O-C(O)-.

R'7 may, as C3-C8-cycloalkyl, be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

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

X is preferably Br or I.

The starting compound of the formula Il (X = Br) used in process stage MA) is known from WO 2005/090305 A1. The starting compound of the formula Il (X = I) is known or can be prepared analogously to known processes. The starting compound of the formula Il (X = Otriflate) is obtainable from the corresponding alcohol analogously to known processes.

The compound of the formula III is prepared either in a manner known per se from the pyridyl bromide of the formula Il (X = Br) described in WO 2005/090305 A1 via halogen-metal exchange and subsequent reaction with N,N-dimethylformamide, or alternatively from the pyridyl compounds of the formula Il (X = Br, I, OTf) via a carbonylation.

The starting compounds of the formula IV used in process stage IB) are known or can be prepared analogously to known processes. The aldol reaction 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, and ethers, for example diethyl ether, tetrahydrofuran and dioxane are particularly suitable. Suitable strong bases are especially alkali metal alkoxides and secondary amides, for example lithium diisopropylamide.

The mixture of the two diastereomers of the formula V is obtained in virtually quantitative yield. Purification affords the pure syn diastereomer of the formula Va. Advantageously, the diastereomer mixture is used without purification in process stages M C), I2C), I3C). Particularly advantageously, the diastereomer mixture is used without purification in process stage I3C).

The conversion of the OH group to a leaving group in process stage M C), I2C and as part of process stage I3C) (stage g, schemel ; part of stage c, Scheme 1 ) is known per se. Particularly suitable reactions are those with carboxylic acids or sulphonic acids, or the acid chlorides or anhydrides thereof (acylation). Some examples of carboxylic or sulphonic acids are formic acid, acetic acid, propionic acid, benzoic acid, benzenesulphonic acid, toluenesulphonic acid, methylsulphonic acid and thfluoromethylsulphonic acid. The use of acetic anhydride in the presence of catalytic amounts of 4-dimethylaminopyridine has been found to be particularly useful. The elimination is appropriately undertaken in the presence of strong bases, and alkali metal alkoxides such as potassium tert-butoxide are 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 the above- mentioned process stages. The elimination leads to the desired E-isomers of the acrylic esters of the formula Vl.

The hydrolysis of the acrylic esters of the formula Vl in process stages M D) and as part of process stage I3C) (stage h, Scheme 1 , part of stage c, Scheme 1 ) is undertaken by addition of, for example, potassium hydroxide solution and stirring at temperatures between 800C and 100°C. The resulting acids of the formula VII are crystalline and can therefore be isolated in a simple manner without great losses by means of crystallisation and extraction. The yields are more than 90%. Surprisingly, exclusively the desired E-isomer is obtained.

The hydrolysis is advantageously undertaken directly after achievement of complete conversion in the elimination and after concentration of the solvent (process via process stage 13C)).

It has now been found that, surprisingly, the alpha, beta-unsaturated carboxylic acid of the formula VII and the alpha, beta-unsaturated alcohol of the formula IX can be converted by catalytic asymmetric hydrogenation in high yields and with good enantiomeric excesses up to complete enantiomeric control to the corresponding carboxylic acid of the formula VIII, and to the corresponding alcohol of the formula I respectively.

Asymmetric hydrogenations in analogy to process stage M E) or 13D) of alpha, beta- unsaturated carboxylic acid of the formula VII (stage d, Scheme 1 ) and to process stages I2E) or MC) of alpha, beta-unsaturated alcohol of the formula IX (stage j, Scheme 1 ) 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 bis III, Springer Verlag (1999), pages 121 -182, and by X. Zhang in Chemical Reviews, Vol. 103 (2003), pages 3029-3069. In the literature, ruthenium, rhodium and iridium catalysts are described as being particularly effective.

Asymmetric hydrogenations of process stage 11 E) or I3D) of the alpha, beta- unsaturated carboxylic acid of the formula VII (stage d, Scheme 1 ) can be carried out in analogy to known processes, as described, for example, by John M. Brown in E. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.) in Comprehensive Asymmetric Catalysis I bis 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 im Journal of the Chemical Society, Perkin Transactions 1 , (1997), pages 1869-1873.

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

Ligands with a ferrocenyl structure 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, Taniaphos and TriFer classes. Ligands of these classes are described, for example, by X. Zhang in Chemical Reviews, VoI 103 (2003), pages 3029-3069, and by P. Knochel in Chemistry, a European Journal 1 VoI. 8 (2002), pages 843-852, by H.-U. Blaser in Topics in Catalysis, VoI 19 (2002), pages 3-16, by F. Spindler in Tetrahedron: Asymmetry, Vol. 15 (2004), pages 2299-2306 and by W. Chen and P. J. McCormack in Angewandte Chemie, Vol. 119 (2007), pages 4219-4222.

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 im Advanced Synthesis and Catalysis Vol. 345 (2003), pages 33-43.

Good optical yields are achieved in the asymmetric hydrogenation of process stage 11 E) or I3D) of the alpha, beta-unsaturated carboxylic acid of the formula VII (stage d, Scheme 1 ) especially with metal complexes of the formulae Xl or XIa

[LM1X1X2] (Xl) [LM1X1' (XIa)

in which

M1 is rhodium or iridium;

X1 represents two olefins or one diene;

X2 is Cl, Br or I;

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

L is a chiral ligand from the group of the chiral ditertiary bisphosphines.

When X1 is defined as olefin, it 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 may comprise open-chain, cyclic or polycyclic dienes. The two olefin groups of the diene are preferably linked by one or two CH2 groups. Examples are 1 ,3-pentadiene, cyclo- pentadiene, 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 preferably represents 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 ".

In formula Xl where M is defined as rhodium or iridium, L is preferably ferrocene-1 ,1'- diphosphines which have, in the 1 position, a ferrocene-substituted secondary phosphine group and, in the V position, a secondary phosphine group of the formula XX; see below. The preferences mentioned above apply. In addition, L in formula Xl where M is defined as rhodium is preferably ligands of the Walphos class.

Particular preference is given to ligands of the formulae (i) or (ia),

in which

R10 may be C3-C8-cycloalkyl or aryl, and

R20 may be Cs-Cs-cycloalkyl or aryl.

Examples of R10 when defined as Cs-Cs-cycloalkyl are cyclohexyl and 2-norbornyl. Examples of R10 when defined as aryl are phenyl, or phenyl substituted once or more than once by methyl, methoxy or trifluoromethyl.

One example of R20 when defined as Cs-Cs-cycloalkyl is cyclohexyl.

Examples of R20 when defined as aryl are phenyl, or phenyl substituted once or more than once by methyl, methoxy or trifluoromethyl.

Particular preference is given to ligands of the formulae (i) or (ia) in which R10 is aryl and R20 is aryl or Cs-Cs-cycloalkyl.

Very particular preference is given to ligands of the formulae (i) or (ia) in which R10 is 3,5-bis(thfluoromethyl)phenyl and R20 is 4-methoxy-3,5-dimethylphenyl.

In addition, L in formula Xl when M is defined as rhodium is preferably ligands of the TriFer class (see below, same preferences apply).

It has been found that, surprisingly, with respect to the process described by M. Banzinger and T. Troxler in Tetrahedron Asymmetry, 14, pages 3469-3477, (2003), that extremely high enantiomeric excesses up to complete enantiomeric control are obtained for the asymmetrical hydrogenation of process stage 11 E) or I3D) of the alpha, beta-unsaturated carboxylic acid of the formula VII (stage d, Scheme 1 ). It has been found that ligands of the Walphos class and of the TriFer class (see below), and also novel ligands of the ferrocene-1 ,1 '-diphosphine type (see below) which have, in the 1 position, a ferrocene-substituted secondary phosphine group and, in the 1' position, a secondary phosphine group are preferably suitable for the asymmetric hydrogenations of process stage 11 E) or I3D) of the alpha, beta- unsaturated carboxylic acid of the formula VII (stage d, Scheme 1 ). With these ligands in the metal complexes of the formulae Xl and XIa, it is possible to achieve very high optical yields, which constitutes a considerable advantage (for example cost saving) for the preparation on the industrial scale.

Also surprising in this connection is the use of iridium-ferrocenyl complexes for the asymmetric hydrogenation of process stage M E) or I3D) of the alpha, beta- unsaturated carboxylic acid of the formula VII (stage d, Scheme 1 ), which means a further considerable advantage (for example further cost saving compared to the use, for example, of more expensive rhodium complexes) for the preparation on the industrial scale.

Asymmetric hydrogenations of process stage I2E) or MC) of the alpha, beta- unsaturated alcohol of the formula IX (stage j, Scheme 1 ) can be carried out in analogy to known processes, 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 im 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.

The ligands used for rhodium are frequently chiral ditertiary bisphosphines. Such chiral ditertiary bisphosphines are described, for example, by X. Zhang in Chemical Reviews, VoI 103 (2003), pages 3029-3069. Ligands with a ferrocenyl structure are generally particularly suitable for the asymmetric hydrogenation of alpha, beta-unsaturated alcohols. Examples are described by F. Spindler in Tetrahedron: Asymmetry, Vol. 15 (2004), pages 2299- 2306. Examples are ligands of the Walphos, Josiphos, Mandyphos, Taniaphos and TriFer classes. Ligands of these classes are described, for example, by X. Zhang in Chemical Reviews, VoI 103 (2003), pages 3029-3069, and by P. Knochel in Chemistry, a European Journal 1 VoI. 8 (2002), pages 843-852, by H.-U. Blaser in Topics in Catalysis, VoI 19 (2002), pages 3-16, by F. Spindler in Tetrahedron: Asymmetry, Vol. 15 (2004), pages 2299-2306 and by W. Chen and P. J. McCormack in Angewandte Chemie, Vol. 119 (2007), pages 4219 ^222.

Good optical yields in the asymmetric hydrogenation of process stage I2E) or MC) of the alpha, beta-unsaturated alcohol of the formula IX (stage j, Scheme 1 ) are achieved especially with metal complexes of the formula XII or XIIa

[LM2X1X2] (XII) [LM2X1~ (XIIa)

in which

M2 is rhodium; and

X1, X2, and E" each have the definitions and preferences specified above; and L has the definition specified above.

In formula XII, L preferably represents ligands of the formula XV, XVI or XVII

in which q and p are each independently 0 or 1 -4 (for XV); or are 0 or 1 or 2 (for XVI); and R11 and R12 are each hydrogen or an identical or different substituent from the group of Ci-C4-alkyl and Ci-C4-alkoxy; and X3 and X4 are each independently secondary phosphino. In the ligands of the formula XV, the substituents R11 and R12 are present preferably in the 6 position or in the 6,6' position.

As alkyl, R11 and R12 are preferably linear. Examples are methyl, ethyl, n-propyl, iso- propyl, n-butyl, isobutyl and tert-butyl. Methyl and ethyl are preferred; methyl is particularly preferred.

As alkoxy, R11 and R12 are preferably linear. Examples are methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Methoxy and ethoxy are preferred; methoxy is particularly preferred.

The X3 and X4 groups may be identical or different; X3 and X4 are preferably identical and correspond to the formula PR13R14, in which R13 and R14 are identical or different, and branched Cs-Cs-alkyl, C3-Cs-CyClOaI kyl, unsubstituted phenyl, or phenyl substituted by 1 -3 Ci-C4-alkyl, Ci-C4-alkoxy or trifluoromethyl groups.

Particular preference is given to ligands of the formula XV in which X3 and X4 are each a PR13R14 group in which R13 and R14 are each cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or phenyl substituted by 1 -2 methyl, methoxy or trifluoromethyl groups.

Likewise particularly preferred are ligands of the formulae XV, XVI and XVII in which X3 and X4 are each a PR13R14 group in which R13 and R14 are each phenyl.

Very particular preference is given to ligands of the formula XVI in which R11 and R12 are each methyl and q and p are each 2.

In addition, L in formula XII preferably represents 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, of the formula XX; see below. The preferences mentioned there apply. In addition, L in formula XII preferably represents ligands of the Josiphos class. Particular preference is given to ligands of the formulae (XIV) or (XIVa)

where

R9 is d-Cs-alkyl, C3-C8-cycloalkyl or aryl, and R8 d-Cs-alkyl, C3-C8-cycloalkyl or aryl.

When defined as Ci-Cs-alkyl, R9 is, for example, tert-butyl.

When defined as Cs-Cs-cycloalkyl, R9 is, for example, cyclohexyl.

When defined as aryl, R9 is, for example, phenyl, or phenyl substituted by 1 -2 methyl.

When defined as Ci-Cs-alkyl, R8 is, for example, ethyl or tert-butyl.

When defined as C3-C8-cycloalkyl, R8 is, for example, cyclohexyl.

When defined as aryl, R8 is, for example, phenyl, or phenyl, 2-furyl and 1 -naphthyl substituted by 1 -3 methyl, methoxy or trifluoromethyl.

Particular preference is given to ligands of the formula XIV and XIVa in which R9 is Ci-Cs-alkyl and R8 is aryl, and also ligands of the formula XIV and XIVa in which R9 is aryl and R8 is Ci-C8-alkyl.

Very particular preference is given to ligands of the formula XIV and XIVa in which R9 is phenyl and R8 is tert-butyl.

In addition, L in formula Xl preferably represents ligands of the TriFer class.

Particular preference is given to ligands of the formulae (ii) or (iia) and their diastereomers in which

R30 may be C3-C8-cycloalkyl or aryl, and R40 may be C3-C8-cycloalkyl or aryl.

Examples of R30 when defined as Cs-Cs-cycloalkyl are cyclohexyl and 2-norbornyl. Examples of R30 when defined as aryl are phenyl, or phenyl substituted once or more than once by methyl, methoxy or trifluoromethyl.

One example of R40 when defined as Cs-Cs-cycloalkyl is cyclohexyl.

Examples of R40 when defined as aryl are phenyl, or phenyl substituted once or more than once by methyl, methoxy or trifluoromethyl.

Particular preference is given to ligands of the formulae (ii) or (iia) in which R30 is aryl and R40 is aryl or Cs-Cs-cycloalkyl.

Very particular preference is given to ligands of the formulae (ii) or (iia) in which R30 is phenyl and R40 is phenyl or cyclohexyl.

With the ligands described in the metal complexes of the formulae XII and XIIa, it is possible to achieve unexpectedly high optical yields up to complete enantiomeric control, which means a considerable advantage (for example cost saving) for the preparation on the industrial scale.

In the context of the present invention are novel 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 of the formula XX in the form of enantiomerically pure diastereomers or a mixture of diastereomers

in which

Ri is the same or different at each instance and is 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.

Ferrocene-1 ,1 '-diphosphines of the formula XX are meanwhile published in WO 2007/116081. Said publication is thus incorporated by reference herein, in particular the disclosure on pages 2-15.

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

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

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

C6-alkoxy)C6H4, 4-(Ci-C6-alkoxy)C6H4, 2-(trifluoromethyl)C6H4, 3-(trifluoro- methyl)C6H4, 4-(thfluoromethyl)C6H4, 3,5-bis(trifluoromethyl)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 CrC4-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, norbonyl, 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.

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

The metal complexes used as catalysts in process stages M E), I2E), I3D) or MC) 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 ligands in the case of 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. The metal complexes are, for example, complexes of the metals ruthenium, rhodium and iridium.

Process stages 11 E), I2E), I3D) and MC) may be carried out 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 M E), 12E), 13D) and MC) 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 compound to be hydrogenated.

The preparation of the catalysts and process stages M E), I2E), I3D) and MC) and the other process stages can be performed without or in the presence of an inert solvent, it being possible to use one solvent or mixtures of solvents. 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 tetrachloro- ethane), 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 ether or monoethyl ether), ketones (acetone, methyl isobutyl ketone), carboxylic esters and lactones (ethyl 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 11 E), I2E), I3D) and MC) can be performed in the presence of cocatalysts, for example quaternary ammonium halides (tetrabutyl- ammonium iodide) and/or in the presence of protic acids, for example mineral acids.

Process stages M F) and I3E) 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, metal hydrides are appropriately used 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 MA) (stage I, Scheme 1 ) is advantageously performed at higher temperatures, for example 60 to 900C, in the presence of catalytic amounts of a palladium catalyst, for example Pd(PPh3)4, Pd(PPh3)2CI2 or Pd/C + PPh3, and optionally catalytic amounts of a copper(l) halide, for example CuI, and in the presence of at least equivalent amounts of an amine base. The reaction is also appropriately performed without solvent, but can also be performed in polar protic solvents, for example water. Suitable amine bases are, for example, pipehdine, pyrrolidine, diisopropylethylamine, triethylamine or ammonia.

The addition in process stage MB) (stage m, Scheme 1 ) is advantageously performed at lower temperatures, for example -100C to room temperature (e.g. 23°C), in the presence of catalytic amounts of a copper(l) halide, for example CuI. The alkyl-metal compound is advantageously used in excess. The reaction can optionally be performed in the presence of an additive, for example TMEDA. The reaction is also appropriately performed in a solvent, particularly suitable solvents being ethers, for example diethyl ether, tetrahydrofuran and dioxane.

Suitable chlorination, bromination and iodination agents used in the process stage G) (stage n, Scheme 1 ) are N-chloro, N-bromo and N-iodophthalimide and especially chloro, N-bromo and N-iodosuccinimide. These reagents are used together with a phosphine such as, for example, triphenylphosphine. Reagents like sulfonylchloride or phosphorylchloride in the presence of at least equimolar quantities of a suitable amine base such as, for example, pyridine or a co-solvent such N,N-dimethylamine can be used.

The coupling of Grignard reagents (for example with magnesium) derived from halides of the formula (B) with amids of the formula (C) in the process stage H) (stage o, Scheme 1 ) is best carried out in an ether such as, for example, tetrahydro- furan or dioxan as solvent in the presence of catalytic quantities of a soluble metal complex, for example an iron complex such as iron acetonyl acetate, and in the presence of catalytic quantities of a solvent stabilizing the metal complex, for example n-methylpyrrolidone. The reaction temperature may for example be -500C to 800C, preferably -20°C to 500C. It is expedient to carry out the reaction so that initially a compound of formula (B) is converted to a Grignard compound (for example with magnesium) and then adding a solution of a compound of formula (C), metal complex and N-methylpyrrolidone, or vice versa. Catalytic quantities of a soluble metal complex may for example be 0.1 to 20% by weight in relation to a compound of formula (C). Catalytic quantities of a solvent stabilizing the metal complex may for example be 1 to 10 mol percent, preferably 1 to 5 mol percent, in relation to the compounds of formulae (B) or (C).

The starting compound of the formula (C) used in process stage H) is known from WO 01/09079 A1.

Suitable chlorination, bromination and iodination agents used in the process stage J) (stage p, Scheme 1 ) are elemental bromine and iodine, in particular N-chlohne, N- bromine and N-iodocarboxamides and dicarboximides. Preferred are N-chloro, N- bromo and N-iodophthalimide and especially chloro, N-bromo and N-iodosuccinimide, as well as tertiary butyl hypochlorite and N-halogenated sulfonamides and imides, for example chloroamine T. It is of advantage to carry out the reaction in organic solvents. The reaction temperature may range for example from approximately -70°C to ambient temperature and preferably from -30°C to 100C Carboxamides are advantageously lactonized in the presence of inorganic or organic acids, at least equimolar quantities of water, and reacted in the presence of water-miscible solvents, for example tetrahydrofuran or dioxane. Suitable acids are for example fonnic acid, acetic acid, methanesulfonic acid, thfluoroacetic acid, thfluoromethanesulfonic acid, toluenesulfonic acid, H2SO4, H3PO4, hydrogen halides, acid ion exchange resins, and acids immobilized on solid carriers. Water is generally used in at least equimolar quantities. Suitable azidation agents for the azidation in process stage K) (stage q, Scheme 1 ) are for example metal azides, especially alkaline earth metal azides and alkali metal azides, as well as silyl azides. Especially preferred azidation agents are lithium azide, sodium azide and potassium azide. The reaction may be carried out in organic solvents; advanatageously in water-miscible solvents mixed with water or not, typically for example alcohols or ethers (methanol, ethanol, ethylene glycol, diethylene glycol, diethylene glycol monomethyl or ethyl ether, diethyl ether, tetrahydrofuran, dioxane) or in other polar solvents like hexamethylphosphoramide or 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyhmidinone The reaction temperature may range for example from approximately 200C. to 1500C. and preferably from 50°C to 1200C. It may be expedient to include the use of phase transfer catalysts.

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

The invention also provides the compounds (intermediates) of the formula Vl

of the formula VII

of the formula VIII

of the formula IX

in which R'3 and R'7 are each as defined above, and in which, for formula VIII, the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration.

The invention further provides the compounds (intermediates) of the formulae V and Va,

in which R'3 and R'7 are each as defined above.

For R'3 and R'7, the embodiments and preferences described above apply.

The invention further provides the compounds (intermediates) of the formula I,

of the formula (B)

of the formula (A)

of the formula (D),

in which R'3, R4, R'5, R'6, Y and X' are each as defined above, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration.

The invention further provides a process for preparing a compound of formula I comprising the process stages IA), IB), 11 C), 11 D), 11 E) and 11 F) or the process stages IA), IB), I2C), I2D) and I2E) or the process stages IA), IB), I3C), I3D) and I3E) or the process stages MA), MB) and MC); in the order as stated and each stage as described hereinbefore.

The invention further provides a process for preparing a compound of formula (A) comprising the process stages IA), IB), MC), M D), M E), M F), G) and H), or the process stages IA), IB), I2C), I2D), I2E), G) and H) or the process stages IA), IB), I3C), I3D), I3E), G) and H) or the process stages MA), MB), NC), G) and H); in the order as stated and each stage as described hereinbefore. The invention further provides a process for preparing a compound of formula (E) comprising the process stages IA), IB), MC), M D), M E), M F), G), H), J) and K) or the process stages IA), IB), 12C), 12D), 12E), G), H), J) and K) or the process stages IA), IB), 13C), 13D), 13E), G), H), J) and K) or the process stages MA), MB), MC), G), H), J) and K); in the order as stated and each stage as described hereinbefore.

The invention further provides a process for preparing a compound of formula I comprising the process stages IA), IB), 13C), 13D) and 13E),); in the order as stated and each stage as described hereinbefore; using the mixture of the two diastereomers of the formula V without purification in process stage I3C.

The invention further provides a process for preparing a compound of formula (A) comprising the process stages IA), IB), 13C), 13D), 13E), G) and H); in the order as stated and each stage as described hereinbefore; using the mixture of the two diastereomers of the formula V without purification in process stage I3C.

The invention further provides a process for preparing a compound of formula (E) comprising the process stages IA), IB), 13C), 13D), 13E), G), H), J) and K); in the order as stated and each stage as described hereinbefore; using the mixture of the two diastereomers of the formula V without purification in process stage I3C.

The examples which follow illustrate the invention in detail.

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% water75% 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 % thfluoroacetic acid

Example A)

Process for preparing (3S,5S)-5-{(1 S,3S)-1 -Azido-3-[6-methoxy-5-(3-methoxy- propoxy)-pyridin-3-ylmethyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2- one (A12).

Example A1 :

Preparation of 6-methoxy-5-(3-methoxypropoxy)pyridine-3-carbaldehyde

(A1)

via halogen-metal exchange

A solution of 6.0 g [20.4 mM] of 5-bromo-2-methoxy-3-(3-methoxypropoxy)pyridine (WO 2005/090305 A1 ) in 50 ml of tetrahydrofuran is cooled to -78°C and admixed with 2.29 ml [1.0 mM] of N-methylmorpholine. The mixture is cooled again to -78°C, and 14.03 ml [22.4 mM] 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 for a further 2 minutes. Subsequently, 3.16 ml [40.8 mM] of N1N- dimethylformamide are added dropwise at such a rate that the internal temperature does not exceed -70°C. Stirring is continued at -700C for a further 5 minutes. 50 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 colourless oil-crystal mixture; (4.09 g, 84.8%). Rf = 0.40 (1 :1 ethyl acetate-heptane); Rt = 3.26 (gradient I).

via Carbonylation

A 100 ml autoclaven is initially charged with 2.76 g [9.021 mM] of 5-bromo-2-methoxy- 3-(3-methoxypropoxy)pyridine (WO 2005/090305 A1 ), 1.40 g [20.586 mM] sodium formate, 142 mg [0.200 mM] of bis(thphenylphosphine)palladium(ll) chloride and 104 mg [0.396 mM] of triphenylphosphine in 35 ml of dimethylformamide. The autoclave is closed and purged with carbon monoxide (a pressure of 15 bar is applied and released again to 6 bar 3 times each). The autoclave is subsequently placed under a pressure of 6.4 bar with carbon monoxide and heated to 1100C. After 5 hours, the pressure is released. The reaction solution is diluted with dichloromethane, filtered through a glass fibre filter and concentrated by evaporation on a rotary evaporator. The residue is taken up in 100 ml of ethyl acetate and washed with brine (2 x 100 ml). The aqueous phase is extracted with ethyl acetate (2 x 100 ml). The combined organic phases are dried over sodium sulphate, filtered and concentrated by evaporation on a rotary evaporator. The title compound A7 is obtained as a yellow solid (1.108 g, 54%) from the residue by means of flash chromatography (SiO2 6OF, 1 :1 ethyl acetate-heptane). Rf = 0.40 (1 :1 ethyl acetate-heptane); Rt = 3.26 (gradient I).

Example A2:

Preparation of 2-{hydroxy-[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]methyl}-3- methylbutyric acid ethyl ester.

A solution of 0.904 ml [6.33 mM] of diisopropylamine and 7 ml of tetrahydrofuran is cooled to -200C, and 3.957 ml [6.33 mM] 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 0.902 ml [5.80 mM] of ethyl isovalerate in 4 ml of tetra- hydrofuran is added dropwise at -20°C over 10 minutes. After a further 5 minutes, a solution of 1.247 g [5.28 mM] of 6-methoxy-5-(3-methoxypropoxy)pyridine-3-carbal- dehyde (A1 ) in 4 ml of tetrahydrofuran is added dropwise, and the mixture is stirred at -200C over a further 30 minutes. 35 ml of saturated aqueous ammonium chloride solution are then added dropwise, and the mixture is then extracted with tert-butyl methyl ether (2 x 25 ml). The organic phases are washed successively with aqueous ammonium chloride solution (1 x 25 ml) and brine (1 x 25 ml). The combined organic phases are dried over sodium sulphate, filtered and concentrated on a rotary evaporator. The crude title compound A2 is obtained from the residue as a yellowish oil (1.88 g, 91.5%, syn:anti = 81 :19); Rt = 3.79, 3.94 (gradient I).

Example A3:

Preparation of 2-[1 -[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]meth-(E)-ylidene]-3- methylbutyric acid.

Proceeding from 2-{hydroxy-[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]methyl}-3- methylbutyric acid ethyl ester (A2).

(A2) (A3)

A solution of 1.88 g [4.83 mM] of 2-{hydroxy-[6-methoxy-5-(3-methoxypropoxy)- pyridin-3-yl]methyl}-3-methylbutyhc acid ethyl ester (A2) and 30 mg [0.24 mM] of 4- dimethylaminopyridine in 11 ml of tetrahydrofuran is cooled to 0°C. 0.504 ml [5.31 mM] of acetic anhydride is added dropwise over 5 minutes and the reaction mixture is stirred at 0°C over 1 hour. A solution of 1.68 g [14.49 mM] of potassium tert-butoxide in 12 ml of tetrahydrofuran is then added dropwise at 00C over 1 hour and then stirred at 00C for 1 hour. 5.5 ml of ice-water are added dropwise to the reaction mixture over 5 minutes, and the tetrahydrofuran is evaporated off on a rotary evaporator. The aqueous emulsion is admixed with 15 ml of ethanol and 2.4 ml of 2 M aqueous potassium hydroxide solution, and the mixture is heated to reflux for 17 hours. The ethanol is evaporated off from the reaction mixture on a rotary evaporator (35°C). The resulting aqueous solution is diluted with water (15 ml) and washed with tert-butyl methyl ether (2 x 15 ml). The aqueous phase is acidified with 25 ml of 1 M aqueous citric acid solution and extracted with tert-butyl methyl ether (2 x 25 ml). The organic phases are washed with 15 ml of brine, dried over sodium sulphate, filtered and concentrated on a rotary evaporator. The pure title compound A3 is obtained from the residue as white crystals (1.1 O g, 70.7%) by means of crystallisation from tert-butyl methyl ether-hexane mixture. Rf = 0.18 (1 :1 ethyl acetate-heptane); Rt = 3.92 (gradient I).

Example A2a:

Preparation of (S)-2-{(S)-hydroxy-[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]- methyl}-3-methylbutyric acid ethyl ester.

A solution of 1.713 ml [12.0 mM] of diisopropylamine and 14 ml of tetrahydrofuran is cooled to -200C, and 7.50 ml [12.0 mM] 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 1.709 ml [11.0 mM] of ethyl isovalerate in 8 ml of tetrahydrofuran is added dropwise at -20°C over 10 minutes. After a further 5 minutes, a solution of 2.36 g [10.0 mM] of 6-methoxy-5-(3-methoxypropoxy)pyridine-3-carbal- dehyde (A1 ) in 8 ml of tetrahydrofuran is added dropwise, and the mixture is stirred at -200C over a further 30 minutes. 20 ml of saturated aqueous ammonium chloride solutuion are then added dropwise and the mixture is then extracted with ethyl acetate (2 x 80 ml). The organic phases are washed successively with aqueous ammonium chloride solution (1 x 50 ml) and brine (1 x 50 ml). The combined organic phases are dried over sodium sulphate, filtered and concentrated on a rotary evaporator. The pure title compound A2a is obtained from the residue as white crystals (2.46 g, 69%) by means of flash chromatography (SiO2 6OF, 1 :1 ethyl acetate-heptane) and subsequent crystallisation from tert-butyl methyl ether-hexane mixture.

Example A4:

Preparation of 2-[1 -[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]meth-(E)-ylidene]-3- methylbutyric acid ethyl ester.

A solution of 2.40 g [6.48 mM] (S)-2-{(S)-hydroxy-[6-methoxy-5-(3-methoxy- propoxy)pyridin-3-yl]methyl}-3-methylbutyric acid ethyl ester (A2) and 40 mg [0.324 mM] of 4-dimethylaminopyridine in 14 ml of tetrahydrofuran is cooled to 00C. 0.676 ml [7.123 mM] of acetic anhydride is added dropwise over 5 minutes and the reaction mixture is stirred at 00C over 1 hour. A solution of 2.25 g [19.43 mM] of potassium tert-butoxide in 15 ml of tetrahydrofuran is then added dropwise at 00C over 1 hour, and then the mixture is stirred at 00C for 1 hour. The reaction mixture is poured onto 80 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 A4 is obtained from the residue as a colourless oil (1.73 g, 79%) by means of flash chromatography (SiO2 6OF, 1 :2 ethyl acetate- hexane). Rf = 0.23 (1 :3 ethyl acetate-heptane); Rt = 5.07 (gradient I).

Example A3:

Preparation of 2-[1 -[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]meth-(E)-ylidene]-3- methybutyric acid.

Proceeding from 2-[1 -[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]meth-(E)- ylidene]-3-methylbutyric acid ethyl ester (A4).

(A4)

(A3)

The mixture of 1.60 g [4.74 mM] of 2-[1 -[6-methoxy-5-(3-methoxypropoxy)pyridin-3- yl]meth-(E)-ylidene]-3-methylbutyric acid ethyl ester (A4), 18.6 ml of ethanol and 2.7 ml of 2 M aqueous potassium hydroxide solution is heated to reflux for 17 hours. The ethanol is evaporated off from the reaction mixture on a rotary evaporator (35°C). The resulting aqueous solution is diluted with water (15 ml) and washed with tert-butyl methyl ether (2 x 15 ml). The aqueous phase is acidified with 25 ml of 1 M aqueous citric acid solution and extracted with tert-butyl methyl ether (2 x 25 ml). The organic phases are washed with 15 ml of brine, dried over sodium sulphate, filtered and concentrated on a rotary evaporator. The pure title compound A3 is obtained from the residue as white crystals (1.32 g, 90%) by means of crystallisation from tert- butyl methyl ether-hexane mixture. Rf = 0.18 (1 :1 ethyl acetate-heptane); Rt = 3.92 (gradient I).

Example A5:

Preparation of 2-[1 -[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]meth-(E)-ylidene]-3- methylbutan-1-ol.

Proceeding from 2-[1 -[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]meth-(E)- ylidene]-3-methyl butyric acid ethyl ester (A4).

(A4) (A5)

A solution of 0.100 g [0.296 mM] of 2-[1 -[6-methoxy-5-(3-methoxypropoxy)pyridin-3- yl]meth-(E)-ylidene]-3-methylbutyric acid ethyl ester (A4) in 3 ml of toluene is cooled to -200C and admixed with a solution of 0.592 ml [0.888 mM] of diisobutylaluminium hydride (1.7 M in toluene), in the course of which the temperature is kept at -200C. The reaction mixture is subsequently stirred at -20°C over 1 hour and at room temperature over 1 hour. The reaction mixture is subsequently admixed slowly with 1.0 ml of methanol and 2 ml of 1 M aqueous citric acid solution, and extracted with ethyl acetate (2 x 25 ml). The organic phases are washed with 25 ml of brine, dried over sodium sulphate, filtered and concentrated on a rotary evaporator. The pure title compound A5 is obtained from the residue as a slightly yellow oil (0.062 g, 71 %) by means of flash chromatography (SiO2 6OF, 1 :1 ethyl acetate-heptane). Rf = 0.35 (2:1 ethyl acetate-heptane); Rt = 3.67 (gradient I).

Example A6:

Preparation of 3-[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]prop-2-yn-1 -ol.

(A6)

A 250 ml round-bottom flask is initially charged with 5.0 g [17.0 mM] of 5-bromo-2- methoxy-3-(3-methoxypropoxy)pyridine (WO 2005/090305 A1 ), 0.007 g [0.034 mM] of copper (I) iodide and 0.365 g [0.510 mM] of bis(triphenylphosphine) palladium (II) chloride. The apparatus is evacuated under high vacuum for 30 minutes and then sparged with argon. 45 ml of diisopropylamine and 2.03 ml [34.0 mM] of propargyl alcohol are added to the reaction vessel, and the solution is stirred at 800C over 3 hours. The reaction mixture is cooled to room temperature and poured onto 200 ml of saturated aqueous ammonium chloride solution. The mixture is extracted with ethyl acetate (2 x 250 ml). The combined organic phases are washed with brine (250 ml), dried over sodium sulphate, filtered and concentrated on a rotary evaporator. The title compound A6 is obtained from the residue as orange crystals (4.25 g, 98%) by means of flash chromatography (SiO2 6OF, 2:1 ethyl acetate-heptane). Rf = 0.33 (2:1 ethyl acetate-heptane); Rt = 3.14 (gradient I).

Example A5:

Preparation of 2-[1 -[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]meth-(E)-ylidene]-3- methylbutan-1-ol.

Proceeding from 3-[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]prop-2-yn-1 -ol (A6).

A 100 ml round-bottom flask is charged under an argon atmosphere with a solution of 3.92 g [15.4 mM] of 3-[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]prop-2-yn-1 -ol (A6) in 39 ml of tetrahydrofuran. The solution is admixed with 0.30 g [1.54 mM] of solid copper(l) iodide, and the suspension is cooled to 00C. Subsequently, 19.3 ml [38.6 mM] of an isopropylmagnesium chloride solution (2 M in diethyl ether) are added. The resulting mixture is stirred at 0°C over 1 hour. The reaction mixture is then poured onto 100 ml of saturated aqueous ammonium chloride solution at 00C and extracted with ethyl acetate (2 x 150 ml). The combined organic phases are washed with brine (150 ml), dried over sodium sulphate, filtered and concentrated on a rotary evaporator. The title compound A5 is obtained from the residue as a colourless oil (2.76 g, 60%) by means of flash chromatography (SiO2 6OF, 2:1 ethyl acetate-heptane). Rf = 0.35 (2:1 ethyl acetate-heptane); Rt = 3.67 (gradient I).

Example A7:

Preparation of (R)-2-[6-methoxy-5-(3-methoxypropoxy)pyridin-3-ylmethyl]-3-methyl- butyric acid.

The title compound is obtainable as a slightly yellowish oil by catalytic asymmetric hydrogenation of 2-[1 -[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]meth-(E)- ylidene]-3-methylbutyric acid (A3) and purification of the residue by means of flash chromatography (SiO2 6OF, 1 :1 ethyl acetate-heptane). Rf = 0.14 (1 :1 ethyl acetate- heptane); Rt = 3.63 (gradient I).

The asymmetric hydrogenations of 2-[1 -[6-methoxy-5-(3-methoxypropoxy)pyridin-3- yl]meth-(E)-ylidene]-3-methylbutyric acid (A3) are conducted in a fully automated high-throughput screening system developed by Symyx.

The reaction mixture is analysed for conversion and enantiomeric excess by means of the HPLC method specified below. To this end, 35 μl of the reaction solution are dissolved in 600 μl of methanol. The following results are achieved:

* HTS; P(H2): 20 bar; T: room temperature; Reaction time: 16 hours

** Reaction performed with 1 g of substrate; p(H2): 20 bar; T: room temperature;

Reaction time: 20 hours Ligands:

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

HPLC conditions:

Instrument Agilent Column CHIRACEL-AD-H (TFA mod), KF075

Standard solution 1 mg in 1 ml of methanol Outlet pressure 70 bar Eluent isocratic, 95:5 hexane/ethanol Flow rate 1.0 ml/min. Detection UV (220 nm) Temperature 200C Injection volume 3.0 μl loop Retention times:

- (S)-(A7) 12.2 min

- (R)-(A7) 14.7 min

- (A3) 13.3 min

Representative description of the reaction procedure on a larger scale: A 50 ml stainless steel autoclave is initially charged with 0.473 g [1.53 mM] of 2-[1 -[6- methoxy-5-(3-methoxypropoxy)pyridin-3-yl]meth-(E)-ylidene]-3-methylbutyric acid (A3). In a 10 ml Schlenk tube under an argon atmosphere, a solution of 0.012 g [0.016 mM] of the ligand (Example L1 ) and 0.00353 g [0.008 mM] of the metal precursor ([Rh(NBD)CIk) in 10 ml of degassed dry methanol is prepared, and the mixture is stirred at room temperature for 0.5 hour. The catalyst solution is transferred via a cannula to the 50 ml autoclave which had been placed under an argon atmosphere beforehand. The autoclave is closed and purged with argon (a pressure of 10 - 12 bar is applied and released again to 1 bar 3 times each). The argon is subsequently replaced by hydrogen and the autoclave is purged with hydrogen (a pressure of 20 bar is applied and released again to 1 bar 3 times each). The autoclave is subsequently placed under a pressure of 20 bar with hydrogen. After 17 hours, the pressure is released. The reaction solution (100% conversion; absolute configuration: (R) 98.1 % ee)** is concentrated on a rotary evaporator. The title compound A7 is obtained from the residue as a slightly yellowish oil (0.370 g, 77.7%) by means of flash chromatography (SiO2 6OF, 1 :1 ethyl acetate-heptane) Rf = 0.14 (1 :1 ethyl acetate-heptane); Rt = 3.63 (gradient I).

** Chiral HPLC method for determining the conversion/enantioselectivity:

Instrument: Agilent Series 1100

Column: Chiralpak OD-H, 25cm x 0.46cm

Solvent: hexane - EtOH: 95:5

Flow rate: LO ml/min

Temperature: 200C

Wavelength: 220 nm Retention times:

(S)-2-[6-nnethoxy-5-(3-nnethoxypropoxy)pyridin-3-ylnnethyl]-3-nnethylbutyπc acid: 14.7 min

(R)-2-[6-nnethoxy-5-(3-nnethoxypropoxy)pyridin-3-ylnnethyl]-3-nnethylbutyric acid (A7): 18.1 min

2-[1 -[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]meth-(E)-ylidene]-3-methylbutyric acid (A3): 18.1 min

Example A8:

Preparation of (R)-2-[6-methoxy-5-(3-methoxypropoxy)pyridin-3-ylmethyl]-3-methyl- butan-1-ol.

(A5) (A8)

The title compound is obtainable as a slightly yellowish oil by catalytic asymmetric hydrogenation of 2-[1 -[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]meth-(E)- ylidene]-3-methylbutan-1 -ol (A5) and purification of the reside by means of flash chromatography (SiO2 6OF, 1 :1 ethyl acetate-heptane). Rf = 0.11 (1 :1 ethyl acetate- heptane); Rt = 3.64 (gradient I).

The asymmetric hydrogenations of 2-[1 -[6-methoxy-5-(3-methoxypropoxy)pyridin-3- yl]meth-(E)-ylidene]-3-methylbutan-1 -ol (A5) are conducted in a fully automated high- throughput screening system developed by Symyx.

The reaction mixture is analyzed for conversion and enantiomeric excess by means of the HPLC method specified below. The following results are achieved:

HTS; P(H2): 80 bar; T: 400C; reaction time: 16 hours

Reaction carried out with 1 g of substrate; p(H2): 80 bar; T: 400C; reaction time: 20 hours

Ligands:

L1 L4

[175871-48-4] [223121-01-5] Under otherwise identical conditions, the product with the (S) configuration is obtained with the enantiomeric ligand.

HPLC conditions:

Instrument SFC Berger Instruments

Column CHIRALPAK-AD (250 mm * 0.46 cm)

Modifier methanol

Outlet pressure 100 bar

Gradient 10% MeOH 9', 90%/min 40%, V 40%, 90%/min 10%, total 17'

Flow rate 1.5 ml/min.

Detection UV (210 nm)

Temperature 400C

Sample concentration 3 mg of product in 1.0 ml of MeOH

Injection volume 5.0 μl loop

Retention times:

- (S)-(AS) 6.7 min

- (R)-(AS) 9.0 min

- (AS) 7.3 min

Representative description of the reaction procedure on a larger scale:

In a 10 ml Schlenk tube, a solution of 0.500 g [1.69 mM] of 2-[1 -[6-methoxy-5-(3- methoxypropoxy)pyridin-3-yl]meth-(E)-ylidene]-3-methylbutan-1-ol (A5) in 5 ml of degassed dry ethanol is prepared, and the mixture is stirred at room temperature for 10 minutes. In a second Schlenk tube under an argon atmosphere, a solution of 0.0126 g [0.0177 mM] of the ligand (Example L1 ) and 0.00633 g [0.0169 mM] of the metal precursor ([Rh(NBD)2]BF4) (1.05 equivalents of ligand per metal) in 5 ml of degassed dry ethanol is prepared, and the mixture is stirred at room temperature for 10 minutes. The two solutions are transferred via a cannula to a 50 ml stainless steel autoclave which had been placed under an argon atmosphere beforehand. The autoclave is closed and purged with argon (a pressure of 10 - 12 bar is applied and released again to 1 bar 4 times each). Subsequently, the argon is replaced by hydrogen and the autoclave is purged with hydrogen (a pressure of 10 - 12 bar is applied and released again to 1 bar 4 times each). The autoclave is subsequently placed under a pressure of 80 bar with hydrogen and heated to 400C. After 17 hours, the mixture is cooled to room temperature and the pressure is released. The reaction solution (100% conversion; absolute configuration: (R) 98.8% ee)*** is concentrated on a rotary evaporator. The title compound A8 is obtained from the residue as a slightly yellowish oil (0.442 g, 88%) by means of flash chromatography (SiO2 6OF, 1 :1 ethyl acetate-heptane). Rf = 0.11 (1 :1 ethyl acetate-heptane); Rt = 3.64 (gradient I).

*** Chiral HPLC method for determining the conversion/enantioselectivity:

Instrument: Agilent Series 1100

Column: Chiralpak OD-H, 25cm x 0.46cm

Solvent: Hexanes - i-PrOH: 99:1

Flow rate: 0.6 ml/min

Temperature: 200C

Wavelength: 230 nm

Retention times:

(S)-2-[6-methoxy-5-(3-methoxypropoxy)pyridin-3-ylmethyl]-3-methylbutan-1 -ol: 105.8 min

(R)-2-[6-methoxy-5-(3-methoxypropoxy)pyridin-3-ylmethyl]-3-methylbutan-1 -ol (A8): 116.4 min

2-[1 -[6-methoxy-5-(3-methoxypropoxy)pyridin-3-yl]meth-(E)-ylidene]-3-methylbutan- 1 -ol (A5): 161.1 min Example A9-1 :

Preparation of 5-((R)-2-chloromethyl-3-methyl-butyl)-2-methoxy-3-(3-nnethoxy- propoxy)-pyridine

(A8) (A9-1)

To a solution of 1.62 g [5.45 mM] of (R)-2-[6-methoxy-5-(3-methoxy-propoxy)-pyridin- 3-ylmethyl]-3-methyl-butan-1 -ol (A8) in 25 ml of toluene is added at 00C 0.839 ml [5.99 mM] of triethylamine and 0.475 ml [5.99 mM] of methanesulfonyl chloride. The reaction mixture is stirred at 00C for 30 min (conversion checked by TLC). The reaction mixture is poured into ice-cold 1 N aqueous ammonium chloride solution (50 ml) and extracted with tert-butyl methyl ether (2 x 100 ml). The combined organic layers are dried over sodium sulphate and concentrated in vacuo. To the residue is added 25 ml of dimethylformamide and 0.462 g [10.89 mM] of lithium chloride. The resulting mixture is stirred for 2h at 60° C. The reaction mixture is poured onto water (200 ml) and extracted with tert-butyl methyl ether (3 x 100 ml). The combined organic layers are washed successively with water (2 x 100 ml) and brine (50 ml), dried over sodium sulphate and concentrated in vacuo. Purification by flash chromatography (SiO2 6OF, EtOAc - n-heptane 1 :2) afforded the title compound A9-1 as slightly yellow oil (1.25 g, 73%). Rf = 0.40 (EtOAc/heptane 1 :1 ); Rt = 5.24 (gradient I).

Example A9-2:

Preparation of 5-((R)-2-bromomethyl-3-methyl-butyl)-2-nnethoxy-3-(3-nnethoxy- propoxy)-pyridine

(A8) (A9-2)

To a solution of 7.26 g [24.41 mM] of (R)-2-[6-methoxy-5-(3-methoxy-propoxy)- pyridin-3-ylmethyl]-3-methyl-butan-1 -ol (A8) in 140 ml of dichloromethane is added at 00C 8.09 g [29.29 mM] of triphenylphosphine and in portions 8.09 g [29.29 mM] of N-bromosuccinimide. The reaction mixture is stirred at room temperature over night (conversion checked by TLC). The reaction mixture is concentrated in vacuo. Purification by flash chromatography (SiO2 6OF, EtOAc - n-heptane 1 :3) afforded the title compound A9-2 as slightly yellow oil (6.49 g, 73%). Rf = 0.48 (EtOAc/heptane 1 :1 ); Rt = 5.37 (gradient I).

Example A10:

Preparation of (E)-(2S,7R)-2-lsopropyl-7-[6-methoxy-5-(3-methoxy-propoxy)-pyridin-

3-ylmethyl]-8-methyl-non-4-enoic acid dimethylamide

(A9-1) (A10)

A mixture of 0.294 g [3.0 mM] of magnesium powder and 3.0 ml of tetrahydrofuran is heated to 65°C, and 0.016 ml [mM] of 1.2-dibromoethane then added over a period of 1 minutes (visible reaction). A solution of 0.948 g [3.0 mM] of 5-((R)-2-chloro- methyl-3-methyl-butyl)-2-methoxy-3-(3-methoxy-propoxy)-pyridine (A9-1 ), 0.116 g [mM] of 1.2-dibromoethane in 9.0 ml of tetrahydrofuran is added dropwise over a period of 15 minutes at reflux temperature. The reaction mixture is stirred additional 8 hours at reflux temperature. The resulting reaction mixture is cooled to 300C, filtered under argon until clear and the resulting Ghgnard solution added dropwise over a period of 10 minutes to a solution of 0.612 g [3.0 mMol] of (E)-(S)-5-chloro-2- isopropyl-pent-4-enoic acid dimethylamide [324519-68-8], 0.022 g [0.02 mM] of ferric acetylacetonate and 0.006 ml of [mM] 1 -methyl-2-pyrrolidone in 6.2 ml of tetrahydrofuran at 00C. The reaction mixture is agitated for a further 15 minutes at 0°C, and 1 N aqueous ammonium chloride solution (25 ml) is then added. The mixture is extracted with tert-butyl methyl ether (2 x 25 ml) and the organic phases washed successively with water (25 ml) and brine (25 ml), dried over sodium sulphate and concentrated in vacuo. Purification by flash chromatography (SiO2 6OF, EtOAc - n-heptane 1 :1 ) afforded the title compound A10 as slightly yellow oil (0.385 g, 29%). Rf = 0.14 (EtOAc/heptane 1 :1 ); Rt = 22.31 (gradient II).

Example A11

Preparation of (3S,5S)-5-{(1 R,3S)-1 -Bromo-3-[6-methoxy-5-(3-methoxy-propoxy)- pyridin-3-ylmethyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2-one

(A10) (A11)

To a solution of 0.376 g (0.825 mM) of (E)-(2S,7R)-2-isopropyl-7-[6-methoxy-5-(3- methoxy-propoxy)-pyridin-3-ylmethyl]-8-methyl-non-4-enoic acid dimethylamide (A10) in 3.8 ml of tetrahydrofuran is added 0.0038 ml of water, and cooled to 00C. The 5 times 0.023 ml [0.866 mM] of 42.5 % phosphoric acid and 5 times 0.036 g [0.949 mM] of N- bromosuccinimide are added alternately every 5 minutes. The reaction mixture is stirred for another 30 minutes at 0°C and then, over a period of 2 minutes, to 10 ml of a pre- cooled (0°C) sodium hydrogen sulfite solution is introduced. The mixture is stirred for another 15 minutes at 00C and then extracted with tert-butyl methyl ether (3 x 25 ml). The organic phases are washed consecutively with 1 N aqueous ammonium chloride solution (25 ml), water (2 x 25 ml) and brine (25 ml), dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (SiO2 6OF, EtOAc - n- heptane 1 :1 ) afforded the title compound A11 as slightly yellow oil (0.273 g, 66%). Rf = 0.46 (EtOAc/heptane 1 :1 ); Rt = 23.24 (gradient II).

Example A12:

Preparation of (3S,5S)-5-{(1 S,3S)-1 -Azido-3-[6-methoxy-5-(3-methoxy-propoxy)- pyridin-3-ylmethyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2-one

<A1 1> (A12)

To the solution of 0.100 g [0.193 mM] of (3S,5S)-5-{(1 R,3S)-1 -bromo-3-[6-methoxy-5- (3-methoxy-propoxy)-pyridin-3-ylmethyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan- 2one (A11 ) in 0.60 ml of 1 ,3-dimethyl-3,4J5!6-tetrahydro~2(1 H)-pyπmidinone is added 0.063 g [0.965mM] of sodium azide and stirred for 2 hours at 800C. The reaction mixture (at room temperature) is poured onto water (25 ml) and extracted with tert- butyl methyl ether (3 x 25 ml). The organic phases are washed consecutively with water (2 x 25 ml) and brine (25 ml), dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography (SiO2 6OF, EtOAc - n-heptane 1 :2) afforded the title compound A12 as slightly yellow oil (0.040 g, 25%). Rf = 0.32 (EtOAc/heptane 1 :2); Rt = 22.89 (gradient II).

Example L:

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

1 '-bromoferrocene of the formula (B1 ) [Ph = phenyl; Me = methyl].

N MΘQ diastereomers One diastereomer a) Preparation of i -phenylchlorophosphine-i '-bromoferrocene (X1 ).

At a temperature of <-30°C, 14.5 ml (23.2 mmol) of n-butyllithium (n-Bu-Li) (1.6 M in hexane) are added dropwise to a solution of 8 g (23.2 mmol) of 1 ,1 '-dibromoferrocene in 30 ml of tetrahydrofuran (THF). The mixture is stirred at this temperature for a further 30 minutes. The mixture 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 the mixture is stirred for another hour. A suspension of the monochlorophosphine X1 is thus obtained.

b) Preparation of L (mixture of diastereomers).

At <-100C, 15.5 ml (23.2 mmol) of t-butyllithium (t-Bu-Li) (1.5 M in pentane) are added dropwise to a solution of 5.98 g (23.2 mmol) of (R)-1 -dimethylamino-1 - ferrocenylethane in 40 ml of diethyl ether (DE). 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. A solution of the compound X2 is thus obtained, which is added via a cannula to the cooled suspension of the monochlorophosphine X1 at a sufficiently slow rate that the temperature does not exceed -300C. After stirring at -30°C 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 on a rotary evaporator under reduced pressure. After chromatographic purification (silica gel 60; eluent = heptane/ethyl acetate(EA)/Nethyl3(Net3) 85:10:5), 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 step 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 recrystallised in ethanol. The compound A1 is obtained as yellow crystals and as a pure diastereomer with a yield of 59% of theory. 31P NMR (121.5 MHz, CDCI3): δ -35.3 (s). Example L1 :

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

1 '-dicyclohexylphosphinoferrocene (L1 ) of the formula

)2

At a temperature below 00C, 0.85 ml (1.1 mmol) of sec-butyllithium (S-Bu-Li) (1.3 M in cyclohexane) is added dropwise to a solution of 629 mg (1 mmol) of compound L in 5 ml of tert-butyl methyl ether (TBME). The temperature is left at 00C, the mixture is stirred for a further 1 hour, and then 0.24 ml (1.1 mmol) of chlorodicyclohexyl- phosphine is added. The temperature is allowed to rise to room temperature, and the reaction mixture is stirred for a further 2 hours and then 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 = heptane/EA/NEt.3 85:10:5) and recrystallisation in methanol, the compound L1 is obtained as orange crystals and as a pure diastereomer in a yield of 95% of theory. 31P NMR (121.5 MHz, CDCI3): δ -35.4 (s), -6.5 (s).

The ligands L2 and L3 are prepared in an analogous manner.

The preparation of ligand L4 is described (WO 2006/075166; specifically Example 1 ).

Example M1 : Preparation of a rhodium complex (NBD is norbornadiene). 11 mg ( 0.0148 mmol) of ligand L1 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 overlapping 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. The metal complexes can be prepared in situ in the reaction solution.

Claims

1 . Process, characterized in that either, according to

Process variant I:

IA) a compound of the formula Il

in which X is bromide, iodide or -Othflate is converted to a compound of the formula

IB) the compound of the formula III is reacted with a compound of the formula IV

R1, ,COOR1,

(IV), in which R'3 is isopropyl, and R'7 is Ci-Ci2-alkyl, Cs-Cs-cycloalkyl, phenyl or benzyl, to give a diastereomer mixture of the formula V or a compound of the formula Va

in which R'3 and R'7 are each as defined above; then, either according to process subvariant 1 :

M C) the OH group of the diastereomer mixture of the formula V or the OH group of the compound of the formula Va is converted to a leaving group, and the compound which now contains a leaving group is eliminated in the presence of a strong base to give an acrylic ester of the formula Vl

11 D) the acrylic ester of the formula Vl is converted by hydrolysis to a compound of the formula VII

11 E) the acid of the formula VII is hydrogenated in the presence of hydrogen and catalytic amounts of a metal complex as an asymmetric hydrogenation catalyst, to whose metal centre chiral bidentate ligands are bonded, to give a compound of the formula VIII

M F) the acid of the formula VIII is reduced to a compound of the the formula I

in which R'3 is isopropyl, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration;

or, according to process subvahant 2,

12C) the OH group of the diastereomer mixture of the formula V or the OH group of the compound of the formula Va is converted to a leaving group and the compound which now contains a leaving group is eliminated in the presence of a strong base to give an acrylic ester of the formula Vl

12D) the acrylic ester of the formula Vl is reduced to a compound of the formula IX:

12E) the alcohol of the formula IX is hydrogenated in the presence of hydrogen and catalytic amounts of a metal complex as an asymmetric hydrogenation catalyst, to whose metal centre chiral bidentate ligands are bonded, to give a compound of the the formula I

in which R'3 is isopropyl, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration;

or, according to process subvahant 3,

13C) the OH group of the diastereomer mixture of the formula V or the OH group of the compound of the formula Va is converted to a leaving group, the compound which now contains a leaving group is converted in the presence of a strong base to an acrylic ester, and then, in a one-pot process, hydrolysed to a compound of the formula VII

13D) the acid of the formula VII is hydrogenated in the presence of hydrogen and catalytic amounts of a metal complex as an asymmetric hydrogenation catalyst, to whose metal centre chiral bidentate ligands are bonded, to give a compound of the formula VIII

13E) the acid of the formula VIII is reduced to a compound of the the formula I

in which R'3 is isopropyl, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration;

or, according to

Process variant II:

MA) a compound of the formula Il

in which X is bromide, iodide or -Otriflate is converted to a compound of the formula X

MB) the compound of the formula X is converted to a compound of the formula IX

MC) the alcohol of the formula IX is hydrogenated in the presence of hydrogen and catalytic amounts of a metal complex as an asymmetric hydrogenation catalyst, to whose metal centre chiral bidentate ligands are bonded, to give a compound of the the formula I

in which R'3 is isopropyl, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration.

2. Process according to Claim 1 , characterized in that

G) the compound of the formula I thus obtained is converted to a compound of the formula B

H) this compound of the formula B is reacted with a compound of the formula C

R1. in which R'3 is isopropyl, R4 is Ci-Cs-alkyl, R'5 is Ci-Cs-alkyl or d-Cs-alkoxy, R'β 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)-, 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 (R) or (S) configuration, preference being given to (R) configuration, in the presence of an alkali metal or alkaline earth metal to give a compound of the formula A

in which R'3, R4, R'5 and R'β are as defined above, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration.

3. Process according to Claim 2, characterized in that

J) the compound of the formula (A) is then converted to a compound of the formula (D)

in which R'3 is isopropyl and R4 is Ci-Cs-alkyl, X' is Cl, Br or I, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration, and K) the compound of the formula (D) is then converted to a compound of the formula (E)

in which R'3 and R4 are as defined above, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration.

4. Process according to Claim 1 , 2 or 3, characterized in that the procedure is according to process subvariant 3 of process variant I, using a diastereomeric mixture of the formula V.

5. Process according to Claim 1 , 2 or 3, characterized in that the procedure is according to process variant II.

6. Compound of the formula Vl

in which R'3 is isopropyl and R'7 is Ci-Ci2-alkyl, C3-C8-cycloalkyl, phenyl or benzyl.

7. Compound of the formula VII

in which R'3 is isopropyl.

8. Compound of the formula VIII

in which R'3 is isopropyl, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration.

9. Compound of the formula IX

in which R'3 is isopropyl.

10. Compound of the formula V

in which R'3 is isopropyl, and R'7 is Ci-Ci2-alkyl, C3-C8-cycloalkyl, phenyl or benzyl.

11. Compound of the formula Va

in which R'3 is isopropyl, and R'7 is Ci-Ci2-alkyl, C3-C8-cycloalkyl, phenyl or benzyl.

12. Compound of the formula I

in which R'3 is isopropyl, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration.

13. Compound of the formula B

in which R'3 is isopropyl, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration.

14. Compound of the formula A

in which R'3 is isopropyl, 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 (R) or (S) configuration, preference being given to (R) configuration.

15. Compound of the formula D

in which R'3 is isopropyl, R4 is Ci-Cs-alkyl and X' is Cl, Br or I, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration.

16. Use of a compound according to any one of Claims 6 to 15 for the synthesis of a compound of formula (E) according to claim 3.

17. Use of a compound according to any one of Claims 6 to 13 for the synthesis of a compound of formula (A) according to claim 2.

18. Use of a compound according to any one of claims 6 to 11 for the synthesis of a compound of formula (I) according to claim 1.

19. Process, characterized in that IA) a compound of the formula Il

(II) in which X is bromide, iodide or -Otriflate is converted to a compound of the formula

IB) the compound of the formula III is reacted with a compound of the formula IV

R1, ,COOR1,

(IV), in which R'3 is isopropyl, and R'7 is Ci-Ci2-alkyl, C3-C8-cycloalkyl, phenyl or benzyl, to give a diastereomer mixture of the formula V or a compound of the formula Va

in which R'3 and R'7 are each as defined above.

20. Process according to Claim 19, characterized in that

I3C) the OH group of the diastereomer mixture of the formula V or the OH group of the compound of the formula Va is converted to a leaving group, the compound which now contains a leaving group is converted in the presence of a strong base to an acrylic ester, and then, in a one-pot process, hydrolysed to a compound of the formula VII

21. Process according to Claim 20, characterized in that I3D) the acid of the formula VII is hydrogenated in the presence of hydrogen and catalytic amounts of a metal complex as an asymmetric hydrogenation catalyst, to whose metal centre chiral bidentate ligands are bonded, to give a compound of the formula VIII

13E) the acid of the formula VIII is reduced to a compound of the the formula I

in which R'3 is isopropyl, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration;

22. Process, characterized in that MA) a compound of the formula Il

in which X is bromide, iodide or -Othflate is converted to a compound of the formula X

23. Process according to Claim 22, characterized in that

MB) the compound of the formula X is converted to a compound of the formula IX

MC) the alcohol of the formula IX is hydrogenated in the presence of hydrogen and catalytic amounts of a metal complex as an asymmetric hydrogenation catalyst, to whose metal centre chiral bidentate ligands are bonded, to give a compound of the the formula I

in which R'3 is isopropyl, and in which the carbon atom to which the R'3 radical is bonded has either (R) or (S) configuration, preference being given to (R) configuration.

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