Patent Description:
Chiral triols are versatile building blocks for the preparation of various pharmaceutically active drug substances such as for instance for statin drugs (<NPL>).

<NPL> describe a synthesis of chiral triols by way of the diastereoselective reduction of a hydroxy ketone precursor (S)-<NUM> or (R)-<NUM> with borohydride type catalysts.

The object of the present invention was to provide a process which allows the preparation of the chiral triol in a scalable manner with high enantiomeric purity and yield.

The object could be reached with the process for the preparation of the chiral triol of formula I <NUM>
<CHM>
wherein.

Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below.

The term "chiral" denotes the ability of non-superimposability with the mirror image, while the term "achiral" refers to embodiments which are superimposable with their mirror image. Chiral molecules are optically active, i.e., they have the ability to rotate the plane of plane-polarized light. Whenever a chiral center is present in a chemical structure, it is intended that all stereoisomers associated with that chiral center are encompassed by the present invention.

The term "chiral" signifies that the molecule can exist in the form of optically pure enantiomers, mixtures of enantiomers, optically pure diastereoisomers or mixtures of diastereoisomers.

In a preferred embodiment of the invention the term "chiral" denotes optically pure enantiomers or optically pure diastereoisomers.

The term "stereoisomer" denotes a compound that possesses identical molecular connectivity and bond multiplicity, but which differs in the arrangement of its atoms in space.

The term "diastereomer" denotes a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers may have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities.

The term "enantiomers" denotes two stereoisomers of a compound which are non-superimposable mirror images of one another.

In the structural formula presented herein a dashed bond (a) denotes that the substituent is below the plane of the paper and a wedged bond (b) denotes that the substituent is above the plane of the paper. a) <IMG> b) <IMG>.

The spiral bond (c) denotes both options i.e. either a dashed bond (a) or a wedged bond (b).

The term "C-<NUM>-<NUM>- alkyl" denotes a monovalent linear or branched saturated hydrocarbon group of <NUM> to <NUM> carbon atoms. Examples of C<NUM>-<NUM>-alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or pentyl, hexyl, heptyl or octyl with its isomers. Preferably the term denotes a C-<NUM>-<NUM>- alkyl group.

The term "C<NUM>-<NUM>-cycloalkyl" denotes a saturated carbocycle of <NUM> to <NUM> carbon atoms. Examples of C<NUM>-<NUM>-cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl with its isomers. Preferably the term encompasses C<NUM>-<NUM>-cycloalkyl, more preferably cyclpentyl and cyclohexyl.

The term "C-<NUM>-<NUM>- alkoxy" denotes a monovalent linear or branched saturated hydrocarbon group of <NUM> to <NUM> carbon atoms attached to an oxygen atom. Examples of C<NUM>-<NUM>-alkoxy include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, or pentoxy or hexoxy.

with its isomers. Preferably the term denotes a C-<NUM>-<NUM>- alkoxy group, more preferably the methoxy group.

The term "halogen" denotes fluoro, chloro, bromo, or iodo.

The term "C-<NUM>-<NUM>- halogenalkyl" denotes a monovalent linear or branched saturated hydrocarbon group of <NUM> to <NUM> carbon atoms which is substituted by one or more halogen atoms. Preferably the term denotes C-<NUM>-<NUM>- halogenalkyl, more preferably a methyl group which is substituted with one or more halogen atoms such as trifluoromethyl.

The ketone of formula IIa may occur in the mesomeric structures outlined in the scheme below. For the sake of clarity the formula IIa is consistently used throughout this description.

The process of the present invention can be illustrated with the scheme <NUM> below
<CHM>
and comprises the following various principal embodiments for the preparation of the chiral triol of formula I.

The embodiments a) to d) are preferred, more preferred are the embodiments a), b) and d) and embodiment d) is most preferred.

In a preferred embodiment of the present invention the chiral triol has the formula Ia
<CHM>
wherein R<NUM> is as above, but preferably stands for halogen, more preferably for chlorine.

R<NUM> can be in the ortho-, meta- or para-position of the phenyl ring, but preferably R<NUM> is in the para-position of the phenyl ring.

In a further preferred embodiment of the present invention the chiral triol has the formula Ib
<CHM>.

Scheme <NUM> illustrates a preferred embodiment of the invention. <CHM>
<CHM>.

The iridium spiro-pyridylamidophosphine catalyst (Ir-SpiroPAP catalyst) are of the formula IIIa or IIIb, or enantiomers thereof
<CHM>
wherein.

In a further preferred embodiment the iridium spiro-pyridylamidophosphine catalyst (Ir-SpiroPAP catalyst) are selected from the compounds
<CHM>
<CHM>
wherein;.

In a further preferred embodiment the iridium spiro-pyridylamidophosphine catalyst (Ir-SpiroPAP catalyst) is selected from the compound
<CHM>
wherein.

Suitable catalysts are typically commercially available e.g. from Jiuzhou Pharma in China.

The asymmetric hydrogenation can be performed in the presence of suitable organic solvent and a base at a hydrogen pressure of <NUM> bar to <NUM> bar, preferably of <NUM> bar to <NUM> bar and at a reaction temperature of <NUM> to <NUM>, preferably of <NUM> to <NUM>.

The organic solvent can be selected from aliphatic alcohols selected from methanol, ethanol, isopropanol, tert-amylalcohol, from halogen substituted alcohols like trifluoroethanol, from haloalkanes like dichloromethane, from ethers like tetrahydrofuran or dioxane or from aromatic solvents like toluene or mixtures thereof. Also suited are mixtures of aliphatic alcohols such as methanol or ethanol with water or with dioxane. The preferred solvent is methanol or ethanol, even more preferred ethanol.

Suitable bases are inorganic bases selected from alkali or earth alkali- carbonates or - hydrogen carbonates or phosphates or hydrogenphosphates or dihydrogenphosphates or acetates or formates or organic bases selected from amines, alkali alcoholates or amidines. Organic bases are usually preferred. Typical representatives of organic bases are potassium tert-butylate or <NUM>,<NUM>-Diazabicyclo[<NUM>. <NUM>]undec-<NUM>-ene (DBU), <NUM>,<NUM>-Diazabicyclo(<NUM>. <NUM>)octane (DABCO) and <NUM>-Methyl-<NUM>,<NUM>,<NUM>-triazabicyclo[<NUM>. <NUM>]dec-<NUM>-ene (MTBD), most preferred is DBU.

A substrate to catalyst ratio can expediently be chosen in a range of <NUM> to <NUM>'<NUM>, preferably in a range of <NUM> to <NUM>.

The chiral triol of formula I can be separated from the reaction mixture by evaporation of the solvent. Subsequent crystallization in a suitable solvent, typically in ketones like methyl isobutyl ketone or esters like isopropyl acetate renders the chiral triol of formula I in good yields, high purity and high enantiomeric excess.

In another embodiment the iridium spiro-pyridylamidophosphine catalyst (Ir-SpiroPAP catalyst) of formula IIIa or IIIb may be prepared in situ in the course of the asymmetric hydrogenation reaction by bringing together a suitable Iridium-pre catalyst complex with a spiro-pyridylamidophosphine ligand of the formula
<CHM>
wherein
R4a, R4b, R4c and R4d, Q<NUM> and Q<NUM> and Z have the meanings as outlined above. Suitable Iridium-pre catalyst complex compounds are commercially available e.g. from Sigma Aldrich and can be selected e.g. from [Ir(cod)<NUM>]BF<NUM>, [IrCl(COD)]<NUM>, [Ir(acac)(COD)], [Ir(OMe)(COD)]<NUM>, [Ir(cod)<NUM>]BARF, [Ir(cod)<NUM>]PF6, wherein cod or COD has the meaning of cyclooctadiene, acac the meaning of acetylacetonate, BARF the meaning of tetrakis(<NUM>,<NUM>-bis(trifluoromethyl)phenyl)borate and OMe the meaning of methoxy.

Preferred Iridium-pre catalyst complex compound is [IrCl(COD)]<NUM>.

Usually the iridium-pre catalyst complex compound and the spiro-pyridylamidophosphine ligand are typically mixed in the presence of the organic solvent and the base mentioned under embodiment a).

The substrate to Iridium ratio as a rule is adjusted between <NUM> and <NUM>, preferably between <NUM> and <NUM>. The substrate to ligand ratio as a rule is adjusted between <NUM> and <NUM>, preferably between <NUM> and <NUM>.

The asymmetric hydrogenation conditions and the isolation of the chiral triol of formula I can otherwise be chosen as for the process of embodiment a). Also the preferred embodiments outlined in embodiment a) apply likewise.

The iridium-phenylendiamine catalyst (Ir-PEN catalyst) are of the formula IVa or IVb, or enantiomers thereof
<CHM>
wherein,.

In a further preferred embodiment the iridium-phenylendiamine catalyst (Ir-PEN catalyst) are of the formula IVa, or enantiomers thereof, wherein,.

In a further preferred embodiment the iridium-phenylendiamine catalyst (Ir-PEN catalyst) are of the formula IVb, or enantiomers thereof, wherein,
R<NUM> is methylsulfonyl, trifluoromethylsulfonyl, <NUM>,<NUM>-dimethyl-<NUM>-oxobicyclo[<NUM>. <NUM>] heptane-<NUM>-yl; tolylsulfonyl or <NUM>,<NUM>,<NUM>-tri-i-propylphenyl sulfonyl.

In a further preferred embodiment the iridium-phenylendiamine catalyst (Ir-PEN catalyst) are selected from compounds of the formula IVc and IVd
<CHM>.

The asymmetric hydrogenation for the formation of the ketone of formula IIb of can be performed in the presence of suitable organic solvent at a hydrogen pressure of <NUM> bar to <NUM> bar, preferably of <NUM> bar to <NUM> bar and at a reaction temperature of <NUM> to <NUM>, preferably of <NUM> to <NUM>.

The reaction can be performed without the presence of a base.

However, bases are tolerated. Suitable bases are inorganic bases selected from alkali or earth alkali- carbonates or - hydrogen carbonates or phosphates or hydrogenphosphates or dihydrogenphosphates or acetates or formates or organic bases selected from amines, alkali alcoholates or amidines. Organic bases are usually preferred. Typical representatives of organic bases are potassium tert-butylate or <NUM>,<NUM>-Diazabicyclo[<NUM>. <NUM>]undec-<NUM>-ene (DBU), <NUM>,<NUM>-Diazabicyclo(<NUM>. <NUM>)octane (DABCO) and <NUM>-Methyl-<NUM>,<NUM>,<NUM>-triazabicyclo[<NUM>. <NUM>]dec-<NUM>-ene (MTBD), most preferred is DBU.

A substrate to catalyst ratio can expediently be chosen in a range of <NUM> to <NUM>, preferably in a range of <NUM> to <NUM>.

The ketone of formula IIb can be separated from the reaction mixture by evaporation of the solvent. Subsequent crystallization in a suitable solvent, typically in an aliphatic alcohol like i-propanol renders the ketone of formula IIb in good yields, high purity and high enantiomeric excess. Alternatively the ketone of formula IIb is not isolated and is further hydrogenated to the chiral triol of formula I in the presence of the Ir-SpiroPAP catalyst.

The subsequent asymmetric hydrogenation can take place in the same manner as described in embodiment a).

In this embodiment the asymmetric hydrogenation is performed in the presence of a mixture of the Ir-SpiroPAP catalyst and an Ir-PEN catalyst.

Typically the Ir-PEN catalyst catalyzes the first step of the reaction i.e. the transformation to the ketone of formula IIb faster and with a higher chiral selectivity than the Ir-SpiroPAP catalyst.

Therefore, regarding catalyst concentration of the two catalysts a higher Ir-PEN catalyst concentration is as a rule applied.

The substrate to Ir-PEN catalyst ratio can therefore expediently be chosen in a range of <NUM> to <NUM> preferably in a range of <NUM> to <NUM>.

The substrate to Ir-Spiro-PAP catalyst ratio can expediently be chosen in a range of <NUM> to <NUM>, preferably in a range of <NUM> to <NUM>.

The intermediates IIb, IIc or IId typically need not to be isolated and can directly be converted to the desired chiral triol of formula I.

Intermediate IIb can be prepared and isolated in accordance with embodiment c).

Also intermediate IIc or IId can in principle be isolated by interrupting the hydrogenation at the appropriate stage and individually be subjected to the asymmetric hydrogenation with either the Ir-Spiro PAP catalyst alone or in the presence of a mixture of an Ir-SpiroPAP catalyst and an Ir-PEN catalyst. The reaction conditions as described in the previous embodiments can likewise be applied.

As outlined above the embodiments a) to d) are preferred, more preferred are the embodiments a), b) and d) and embodiment d) is most preferred.

<NUM>-<NUM> and <NUM>-<NUM> were prepared according to <NPL>. All other (pre-) catalysts and ligands were commercially available e.g. from Strem, Sigma Aldrich, Jiuzhou Pharma.

In a glove box under argon atmosphere, a <NUM> autoclave was charged with <NUM> (<NUM>, <NUM> mmol), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>) and EtOH (<NUM>). The autoclave was sealed and removed from the glove box, connected to a hydrogen line, pressurized with hydrogen gas to <NUM> bar and heated to <NUM>. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of <NUM> bar. Reaction samples were taken after <NUM> (<NUM>% conversion) and <NUM> (><NUM> % conversion) to follow the progress of the reaction. After a total reaction time of <NUM>, the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (<NUM>) from the autoclave into a <NUM> round bottomed flask and the orange reaction solution rotatory evaporated at <NUM> / <NUM> mbar to constant weight to yield crude (R)-<NUM> (<NUM>) with <NUM> area-% purity and <NUM>% ee. <NUM>% of trans-<NUM> was detected as major impurity (note: trans-<NUM> demonstrated to have limited stability and converted during handling and storage gradually into trans-<NUM>).

Next, crude (R)-<NUM> (<NUM>) was dissolved in iPr<NUM>O (<NUM>) at <NUM>. The clear solution was allowed to cool to <NUM> within <NUM> and stirred at this temperature for another <NUM>. The formed white crystals were filtered, washed with <NUM> of ice cold iPr<NUM>O and dried for <NUM> at <NUM> under vacuum (<NUM> mbar) to afforded pure (R)-<NUM> (<NUM>, <NUM>% yield) with <NUM> area-% purity and <NUM>% ee.

In a glove box under argon atmosphere, a <NUM> autoclave was charged with <NUM> (<NUM>, <NUM> mmol), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>) and EtOH (<NUM>). The autoclave was sealed and removed from the glove box, connected to a hydrogen line, pressurized with hydrogen gas to <NUM> bar and heated to <NUM>. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of <NUM> bar. A reaction sample was taken after <NUM> (<NUM>% conversion) to follow the progress of the reaction. After a total reaction time of <NUM>, the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (<NUM>) from the autoclave into a <NUM> round bottomed flask and the orange reaction solution rotatory evaporated at <NUM> / <NUM> mbar to constant weight to yield crude (R)-<NUM> (<NUM>) with <NUM> area-% purity and <NUM>% ee. <NUM>% of trans-<NUM> was detected as major impurity. Next, crude (R)-<NUM> (<NUM>) was dissolved in iPr<NUM>O (<NUM>) at <NUM>. The clear solution was then allowed to cool to <NUM> within <NUM> and stirred at this temperature for another <NUM>. The formed white crystals were filtered, washed with <NUM> of ice cold iPr<NUM>O and dried for <NUM> at <NUM> under vacuum (<NUM> mbar) to afforded <NUM> of pure (R)-<NUM> (<NUM>, <NUM>% yield) with <NUM> area-% purity and <NUM>% ee.

In analogy to Example <NUM>, <NUM> (<NUM>, <NUM> mmol) was hydrogenated for <NUM> in EtOH (<NUM>) and the presence of the catalysts as listed in Table <NUM> at <NUM> and an initial hydrogen pressure of <NUM> bar H<NUM>.

In analogy to Example <NUM>, <NUM> (<NUM>, <NUM> mmol) was hydrogenated for <NUM> in EtOH (<NUM>) at <NUM> in the presence of the catalysts (S/C <NUM>'<NUM>) and initial hydrogen pressures as listed in Table <NUM>.

In analogy to Example <NUM>, <NUM> (<NUM>, <NUM> mmol) was hydrogenated for <NUM> in EtOH (<NUM>) at <NUM> and an initial hydrogen pressures of <NUM> bar in the presence of various amounts of catalysts and DBU as base as listed in Table <NUM>.

In a glove box under argon atmosphere, a <NUM> autoclave was charged with <NUM> (<NUM>, <NUM> mmol), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>), DBU (<NUM>, <NUM> mmol, S/B <NUM>) and EtOH (<NUM>). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to <NUM> bar and heated to <NUM>. Under stirring, the hydrogenation was run at a constant hydrogen pressure of <NUM> bar. After a total reaction time of <NUM> (><NUM>% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (<NUM>) from the autoclave into a <NUM> round bottomed flask and the orange reaction solution rotatory evaporated at <NUM> / <NUM> mbar to constant weight to yield crude <NUM> (<NUM>) with <NUM> area-% purity (DBU not integrated) and a trans/cis ratio of <NUM>. (R,R)-<NUM> was obtained with <NUM>% ee.

In a glove box under argon atmosphere, a <NUM> autoclave was charged with <NUM> (<NUM>, <NUM> mmol), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/Ir <NUM>'<NUM>), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/L <NUM>'<NUM>), DBU (<NUM>, <NUM> mmol, S/B <NUM>) and EtOH (<NUM>). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to <NUM> bar and heated to <NUM>. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of <NUM> bar. After a total reaction time of <NUM> (><NUM>% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (<NUM>) from the autoclave into a <NUM> round bottomed flask and the orange reaction solution rotatory evaporated at <NUM> / <NUM> mbar to constant weight to yield crude <NUM> (<NUM>) with <NUM> area-% purity (DBU not integrated) and a trans/cis ratio of <NUM>. (R,R)-<NUM> was obtained with ><NUM>% ee.

In a glove box under argon atmosphere, a <NUM> autoclave was charged with <NUM> (<NUM>, <NUM> mmol), <NUM>, <NUM>, <NUM> x <NUM>-<NUM> mol, S/Ir <NUM>'<NUM>), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/L <NUM>'<NUM>), KOtBu (<NUM>, <NUM> mmol, S/B <NUM>) and EtOH (<NUM>). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to <NUM> bar and heated to <NUM>. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of <NUM> bar. After a total reaction time of <NUM> (><NUM>% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (<NUM>) from the autoclave into a <NUM> round bottomed flask and the orange reaction solution rotatory evaporated at <NUM> / <NUM> mbar to constant weight to yield crude <NUM> (<NUM>) with <NUM> area-% purity and a trans/cis ratio of <NUM>. (R,R)-<NUM> was obtained with <NUM>% ee.

In analogy to Example <NUM>, <NUM> (<NUM>, <NUM> mmol) was hydrogenated for <NUM> in EtOH (<NUM>) at <NUM> and an initial hydrogen pressure of <NUM> bar in the presence KOtBu (<NUM> x <NUM>-<NUM> mol, S/B <NUM>) and of the catalysts (S/C <NUM>'<NUM>) as listed in Table <NUM>.

In analogy to Example <NUM>, <NUM> (<NUM>, <NUM> mmol) was hydrogenated for <NUM> in EtOH (<NUM>) at <NUM> and an initial hydrogen pressure of <NUM> bar in the presence of <NUM> (<NUM> x <NUM>-<NUM> mol, S/L <NUM>'<NUM>), the presence or absence of DBU (<NUM> x <NUM>-<NUM> mol, S/B <NUM>) and the presence of a pre-catalyst (S/Ir <NUM>'<NUM>) as listed in Table <NUM>.

In analogy to Example <NUM>, <NUM> (<NUM>, <NUM> mmol or <NUM>, <NUM> mmol) was hydrogenated for <NUM> in EtOH (<NUM> for <NUM> scale experiments, resp. <NUM> for <NUM> experiments) at <NUM> and an initial hydrogen pressure of <NUM> bar in the presence of <NUM> (<NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>), the presence of a base (S/B <NUM>) as listed in Table <NUM>.

In analogy to Example <NUM>, <NUM> (<NUM>, <NUM> mmol) was hydrogenated for <NUM> at <NUM> and an initial hydrogen pressure of <NUM> bar in the presence of <NUM> (either <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM> or <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>), the presence of KOtBu (<NUM> mmol, S/B <NUM>) and a solvent or solvent mixtures (<NUM>) as listed in Table <NUM>.

In analogy to Example <NUM>, <NUM> (<NUM>, <NUM> mmol) was hydrogenated for <NUM> in EtOH (<NUM>) the presence of <NUM> (either <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM> or <NUM> x <NUM>-<NUM> mol S/C <NUM>'<NUM>), the presence of various amounts of KOtBu, different temperatures and initial hydrogen pressures all as listed in Table <NUM>.

In a glove box under argon atmosphere, a <NUM> autoclave was charged with <NUM> (<NUM>, <NUM> mmol), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>), DBU (<NUM>, <NUM> x <NUM>-<NUM> mol, S/B <NUM>) and EtOH (<NUM>). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to <NUM> bar and heated to <NUM>. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of <NUM> bar. Reaction samples were taken at different time points (see Table <NUM>) to follow the progress of the reaction.

In a glove box under argon atmosphere, a <NUM> autoclave was charged with <NUM> (<NUM>, <NUM> mmol), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>) and EtOH (<NUM>). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to <NUM> bar and heated to <NUM>. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of <NUM> bar for <NUM>. Afterward the pressure was released to <NUM>-<NUM> bar and the autoclave returned to the glove box where under argon atmosphere it was opened and charged with <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>), DBU (<NUM>, <NUM> x <NUM>-<NUM> mol, S/B <NUM>). The autoclave was sealed again and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to <NUM> bar and heated to <NUM>. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of <NUM> bar. The reaction was continued for <NUM> at to <NUM> bar and heated to <NUM>. Reaction samples were taken at different time points (see Table <NUM>) to follow the progress of the reaction.

In a glove box under argon atmosphere, a <NUM> autoclave was charged with <NUM> (<NUM>, <NUM> mmol), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>), DBU (<NUM>, <NUM> x <NUM>-<NUM> mmol, S/B <NUM>) and EtOH (<NUM>). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to <NUM> bar and heated to <NUM>. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of <NUM> bar for <NUM>. Afterward the pressure was increased to <NUM> bar and the reaction carried out for additional <NUM>. Reaction samples were taken at different time points (see Table <NUM>) to follow the progress of the reaction.

In a glove box under argon atmosphere, a <NUM> autoclave was charged with <NUM> (<NUM>, <NUM> mmol), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>), DBU (<NUM>, <NUM> x <NUM>-<NUM> mmol, S/B <NUM>) and EtOH (<NUM>). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to <NUM> bar and heated to <NUM>. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of <NUM> bar for <NUM>. Reaction samples were taken at different time points (see Table <NUM>) to follow the progress of the reaction.

In a glove box under argon atmosphere, a <NUM> autoclave was charged with <NUM> (<NUM>, <NUM> mmol), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>), DBU (<NUM>, <NUM> x <NUM>-<NUM> mol, S/B <NUM>) and EtOH (<NUM>). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to <NUM> bar and heated to <NUM>. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of <NUM> bar for <NUM>. Reaction samples were taken at different time points (see Table <NUM>) to follow the progress of the reaction.

In a glove box under argon atmosphere, a <NUM> autoclave was charged with <NUM> (<NUM>, <NUM> mmol), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>), DBU (<NUM>, <NUM> mmol, S/B <NUM>) and EtOH (<NUM>). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to <NUM> bar and heated to <NUM>. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of <NUM> bar. Reaction samples were taken at different time points (see Table <NUM>) to follow the progress of the reaction. After a total reaction time of <NUM> (><NUM>% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (<NUM>) from the autoclave into a <NUM> round bottomed flask and the orange reaction solution rotatory evaporated at <NUM> / <NUM> mbar to constant weight to afford crude <NUM> (<NUM> - a higher yield would be achievable when omitting IPC sampling) with <NUM> area-% purity and a trans/cis ratio of <NUM>. (R,R)-<NUM> was obtained with ><NUM>% ee.

Next, crude (R,R)-<NUM> (<NUM>) was suspended in iPrOAc (<NUM>) and the slurry stirred for <NUM> at <NUM>. The suspension was cooled to <NUM> and stirred at this temperature for <NUM>, filtered and the filter cake washed with ice-cold iPrOAc (<NUM>) in <NUM> portions to afford after drying (<NUM>, <NUM> mbar) pure <NUM> (<NUM>, <NUM>% yield) with <NUM> area-% purity and a trans/cis ratio of <NUM>. (R,R)-<NUM> was obtained with ><NUM>% ee.

Subsequently, (R,R)-<NUM> (<NUM>) from above was dissolved in iPrOAc (<NUM>) at <NUM>. The colorless solution was cooled to <NUM> within <NUM> whereby the product started to crystallize. The formed suspension was kept at <NUM> for <NUM> and cooled to <NUM> within <NUM>. The crystals were filtered and washed with ice-cold iPrOAc (<NUM>) in <NUM> portions to afford after drying (<NUM>, <NUM> mbar) off-white, crystalline <NUM> (<NUM>, <NUM>% yield - a higher yield would be achievable when omitting IPC sampling during the hydrogenation run) with ><NUM> area-% purity and a trans/cis ratio of <NUM>. (R,R)-<NUM> was obtained with ><NUM>% ee.

Next, crude (R,R)-<NUM> (<NUM>) was suspended in DCM (<NUM>) and the slurry stirred for <NUM> at <NUM>. The suspension was cooled to <NUM> and stirred at this temperature for <NUM>, filtered and the filter cake washed with ice-cold DCM (<NUM>) in <NUM> portions to afford after drying (<NUM>, <NUM> mbar) pure <NUM> (<NUM>, <NUM>% yield) with <NUM> area-% purity and a trans/cis ratio of <NUM>. (R,R)-<NUM> was obtained with ><NUM>% ee.

Subsequently, (R,R)-<NUM> (<NUM>) from above was dissolved in iPrOAc (<NUM>) at <NUM>. The colorless solution was cooled to <NUM> within <NUM> whereby the product started to crystallize. The formed suspension was kept at <NUM> for <NUM> and cooled to <NUM> within <NUM>. The crystals were filtered and washed with ice-cold iPrOAc (<NUM>) in <NUM> portions to afford after drying (<NUM>, <NUM> mbar) off white, crystalline <NUM> (<NUM>, <NUM>% yield - a higher yield would be achievable when omitting IPC sampling during the hydrogenation run) with ><NUM> area-% purity and a trans/cis ratio of <NUM>. (R,R)-<NUM> was obtained with ><NUM>% ee.

In a glove box under argon atmosphere, a <NUM> autoclave was charged with <NUM> (<NUM>, <NUM> mmol), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>), DBU (<NUM>, <NUM> mmol, S/B <NUM>) and EtOH (<NUM>). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to <NUM> bar and heated to <NUM>. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of <NUM> bar. After a total reaction time of <NUM> (><NUM>% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (<NUM>) from the autoclave into a <NUM> round bottomed flask and the orange reaction solution rotatory evaporated at <NUM> / <NUM> mbar to constant weight to afford crude <NUM> (<NUM>) with <NUM> area-% purity and a trans/cis ratio of <NUM>. (R,R)-<NUM> was obtained with ><NUM>% ee.

Subsequently, (R,R)-<NUM> (<NUM>) from above was dissolved in iPrOAc (<NUM>) at <NUM>. The colorless solution was cooled to <NUM> within <NUM> whereby the product started to crystallize. The formed suspension was kept at <NUM> for <NUM> and cooled to <NUM> within <NUM>. The crystals were filtered and washed with ice-cold iPrOAc (<NUM>) in <NUM> portions to afford after drying (<NUM>, <NUM> mbar) off-white, crystalline <NUM> (<NUM>, <NUM>% yield) with ><NUM> area-% purity and a trans/cis ratio of <NUM>. (R,R)-<NUM> was obtained with ><NUM>% ee.

In a glove box under argon atmosphere, a <NUM> autoclave was charged with (R)-<NUM> (<NUM>, <NUM> mmol, quality: <NUM>% ee, <NUM> area-% purity), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>) and DBU (<NUM>, <NUM> x <NUM>-<NUM> mol, S/B <NUM>) and EtOH (<NUM>). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to <NUM> bar and heated to <NUM>. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of <NUM> bar. Reaction samples were taken at different time points (see Table <NUM>) to follow the progress of the reaction.

In analogy to Example <NUM>, <NUM> (<NUM>, <NUM> mmol) was hydrogenated in the presence of <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>) for <NUM> in EtOH (<NUM>) at <NUM> and the presence of DBU as base in amounts as listed in Table <NUM>.

In a glove box under argon atmosphere, a <NUM> autoclave was charged with (R)-<NUM> (<NUM>, <NUM> mmol, quality: <NUM>% ee, <NUM> area-% purity) <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>) and DBU (<NUM>, <NUM> x <NUM>-<NUM> mol, S/B <NUM>) and EtOH (<NUM>). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to <NUM> bar and heated to <NUM>. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of <NUM> bar. After a total reaction time of <NUM> (<NUM>% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (<NUM>) from the autoclave into a <NUM> round bottomed flask and the orange reaction solution rotatory evaporated at <NUM> / <NUM> mbar to constant weight to yield crude (R,R)-<NUM> (<NUM>) with <NUM> area-% purity and a trans/cis ratio of <NUM>. (R,R)-<NUM> was obtained with ><NUM>% ee.

Subsequently, (R,R)-<NUM> (<NUM>) from above was dissolved in iPrOAc (<NUM>) at <NUM>. The colorless solution was cooled to <NUM> within <NUM> whereby the product started to crystallize. The formed suspension was kept at <NUM> for <NUM> and cooled to <NUM> within <NUM>. The crystals were filtered and washed with ice-cold iPrOAc (<NUM>) in <NUM> portions to afford after drying (<NUM>, <NUM> mbar) off white, crystalline <NUM> (<NUM>, <NUM>% yield) with ><NUM> area-% purity and a trans/cis ratio of <NUM>. (R,R)-<NUM> was obtained with ><NUM>% ee.

In a glove box under argon atmosphere, a <NUM> autoclave was charged with (R,R)-<NUM> (<NUM>, <NUM> mmol; quality: <NUM>% ee, <NUM> area-% purity), <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>), DBU (<NUM>, <NUM> x <NUM>-<NUM> mol, S/B <NUM>) and EtOH (<NUM>). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to <NUM> bar and heated to <NUM>. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of <NUM> bar. A reaction sample was taken at different time points (see Table <NUM>) to follow the progress of the reaction.

In analogy to Example <NUM>, (R,R)-<NUM> (<NUM>, <NUM> mmol; quality: <NUM>% ee, <NUM> area-% purity) was hydrogenated in the presence of <NUM> (<NUM>, <NUM> x <NUM>-<NUM> mol, S/C <NUM>'<NUM>) and DBU (<NUM>, <NUM> x <NUM>-<NUM> mol, S/B <NUM>) in EtOH (<NUM>) to yield after <NUM> at <NUM> and an initial hydrogen pressure of <NUM> bar crude (R,R)-<NUM> with <NUM>% purity and ><NUM>% ee (<NUM>% conversion; trans/cis ratio ><NUM>).

Claim 1:
Process for the preparation of a chiral triol of formula I
<CHM>
wherein
R<NUM> is hydrogen or halogen and
<IMG> denotes either a dashed bond (a) or a wedged bond (b)
a) <IMG> b) <IMG>.
comprising the asymmetric hydrogenation of a ketone compound of formula IIa
<CHM>
wherein
R<NUM> is hydrogen or halogen and
R<NUM> is
with hydrogen in the presence of an iridium spiro-pyridylamidophosphine catalyst (Ir-SpiroPAP catalyst) of the formula IIIa or IIIb, or enantiomers thereof,
<CHM>
wherein
R4a, R4b, R4c and R4d independently of each other are hydrogen or C<NUM>-<NUM>-alkyl; the dotted ring signifies an aromatic ring when Q<NUM> is nitrogen and Q<NUM> is carbon and the dotted ring signifies a cycloalkane ring wherein Q<NUM> and Q<NUM> are sulfur;
X<NUM> is either a coordinated ligand or a counter anion selected from halogen, C<NUM>-<NUM>-alkoxy, tetrahalogeno borate, hexahalogenoborate, tetrakis(<NUM>,<NUM>-bis(trihalogeno-C<NUM>-<NUM>-alkyl)phenyl)borate, acetylacetonate, hexahalogenophosphate, p-tolylsulfonate (OTs) or trihalogeno methanesulfonate and
Z is phenyl, optionally substituted by one or more groups selected from C<NUM>-<NUM>-alkyl, C<NUM>-<NUM>-halogenalkyl or phenyl; C<NUM>-<NUM>-cycloalkyl, optionally substituted by one or more C<NUM>-<NUM>-alkyl groups or di- C<NUM>-<NUM>-alkyl phosphinyl.