Patent Description:
L-Iditol (<NPL>) is a sugar alcohol which can be derived by conversion of certain sugars and carbohydrates. L-Iditol can serve, inter alia, as the starting point for the synthesis of pharmaceuticals, polymers and macrocyclic compounds, but is of particular commercial interest.

As L-Iditol is only found in trace amounts in nature, isolation from natural sources is not an economic option. Therefore, the hydrogenation of L-Sorbose (<NPL>) (produced as an intermediate on a large scale in the vitamin C synthesis) is of particular interest. But in the prior art, only few approaches for accessing L-Iditol from L-Sorbose have been suggested.

One way to produce L-Iditol is the reduction of L-Sorbose by fermentation with yeasts, as described by <NPL>. Unfortunately, the process provides only low yields of L-lditol with a maximum <NUM>% of the consumed L-Sorbose in the fermentation, because the yeast metabolizes most of the sugar starting material under fermentation conditions. Also isolation of the L-lditol from this mixture was only possible after peracetylation, which must be followed than by a saponification of all acetyl-protecting group, to yield the pure L-Iditol in max <NUM> % yield and resulting in significant amounts of salt-waste from the protection/deprotection sequence.

An improved fermentation of L-Sorbitol to L-Iditol using yeasts was reported by <NPL>. Using methanol and xylose as the carbon source for the metabolism increases the yield of L-Iditol with regard to the consumed L-Sorbose up to <NUM> % in the crude fermentation mixture. Unfortunately, this process requires high amounts of FeSO<NUM> (<NUM> times the amount by weight according the used sorbose) as well as strict pH-Control by using a phosphate buffer. This is a drawback, as the highly water-soluble L-Iditol must be separated from the large amount of highly water-soluble salts (which are waste) from the fermentation mixture for isolation of L-Iditol. Unfortunately no means for isolation were disclosed. Rather, only the crude fermentation mixture was analyzed by HPLC.

Principally, it should be possible to overcome the drawbacks of a fermentation by heterogeneous hydrogenation of L-Sorbose to L-Iditol. For example, <CIT> discloses the production of sugar alcohols by catalytic hydrogenation of keto sugars on copper catalysts containing finely divided metallic copper on a particulate support material. However, applying this process to the reduction of Sorbose yields mainly D-sorbitol. L-Iditol can only be obtained as the byproduct, with a maximum ratio of L-Iditol to D-Sorbitol of <NUM>:<NUM> at <NUM>% conversion of L-Sorbose.

There is a demand that the hydrogenation can be run more selectively towards the L-Iditol, the whole process would be more efficient, for example there would no longer be a need for the subsequent fermentation as the isolation of L-Iditol from the <NUM>:<NUM>-mixture with D-Sorbitol is very difficult and inefficient.

In <NPL>, the hydrogenation of L-Sorbose to L-Iditol with a selectivity towards L-Iditol ><NUM>% using asymmetric transition metal catalysts is described. This approach delivers for the first time in an nonenzymatic process the L-Iditol as the main product directly from L-Sorbose without the need for protection groups. However, for an efficient industrial process, a simple recycling of the used expensive stereoselective transition metal catalyst is necessary, which was not disclosed in this work.

A recycling of a stereoselective hydrogenation catalyst without a significiant loss of its activty as well as selectivty is usally not easy to achieve and in most asymmetric transformations, the catalyst is not reused.

Accordingly, it is an object of the invention to provide a process for the recycling and reactivation of a stereoselective ruthenium catalyst for the synthesis of L-Iditol by hydrogenating L-Sorbose. With this process, it should be possible to produce L-Iditol by the hydrogenation of L-Sorbose in a cost-efficient manner.

Surprisingly, it was found that the problem is solved by a process for the preparation of L-Iditol comprising at least the process steps:.

The invention relates to a process for the preparation of L-Iditol and recycling of the stereoselective catalyst comprising the process steps: <NUM>) a L-Sorbose comprising composition is subjected to hydrogenation with hydrogen in the presence of a hydrophobic stereoselective ruthenium catalyst complex in a homogenous solution, wherein the transition metal catalyst complex comprises at least one chiral ligand containing at least two phosphorus atoms, which are capable of coordinating to the transition metal yielding in a composition comprising L-Iditol as the main product; <NUM>) extraction of the L-Iditol and other hexoses with water; <NUM>) Reusing the catalyst in the selective hydrogenation of L-Sorbose to L-Iditol under addition of a chloride-source to reactivate the catalyst.

The compounds L-Sorbose, L-Iditol and D-Sorbitol have the following chemical structions depicted as Fischer projection.

In the context of the invention, the expression "alkyl" means straight and branched alkyl groups. Preferred are straight or branched C<NUM>-C<NUM>-alkyl groups, more preferably C<NUM>-C<NUM>-alkyl groups, even more preferably C<NUM>-C<NUM>-alkyl groups and in particular C<NUM>-C<NUM>-alkyl groups. Examples of alkyl groups are particularly methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, <NUM>-pentyl, <NUM>-methylbutyl, <NUM>-methylbutyl, <NUM>,<NUM>-dimethylpropyl, <NUM>,<NUM>-dimethylpropyl, <NUM>,<NUM>-dimethylpropyl, <NUM>-ethylpropyl, n-hexyl, <NUM>-hexyl, <NUM>-methylpentyl, <NUM>-methylpentyl, <NUM>-methylpentyl, <NUM>,<NUM>-dimethylbutyl, <NUM>,<NUM>-dimethylbutyl, <NUM>,<NUM>-dimethylbutyl, <NUM>,<NUM>-dimethylbutyl, <NUM>,<NUM>-dimethylbutyl, <NUM>,<NUM>-dimethylbutyl, <NUM>,<NUM>,<NUM>-trimethylpropyl, <NUM>,<NUM>,<NUM>-trimethylpropyl, <NUM>-ethylbutyl, <NUM>-ethylbutyl, <NUM>-ethyl-<NUM>-methylpropyl, n-heptyl, <NUM>-heptyl, <NUM>-heptyl, <NUM>-ethylpentyl, <NUM>-propylbutyl, n-octyl, <NUM>-ethylhexyl, <NUM>-propylheptyl, nonyl and decyl.

The expression "alkyl" comprises also substituted alkyl groups, which may carry <NUM>, <NUM>, <NUM>, <NUM> or <NUM> substituents, preferably <NUM>, <NUM> or <NUM> substituents and particularly preferably <NUM> substituent, selected from the groups cycloalkyl, aryl, hetaryl, halogen, NE<NUM>E<NUM>, NE<NUM>E<NUM>E<NUM>+, COOH, carboxylate, SO<NUM>H and sulfonate. The expression "alkyl" also comprises alkyl groups, which are interrupted by one or more non-adjacent oxygen atoms, preferably alkoxyalkyl.

The expression "alkoxy" in the context of the present invention stands for a saturated, straightchain or branched hydrocarbon radical having <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM> or <NUM> to <NUM> carbon atoms, as defined above, which is bonded via oxygen, e.g. C<NUM>-C<NUM>-alkoxy, such as methoxy, ethoxy, n-propoxy, <NUM>-methylethoxy, butoxy, <NUM>-methylpropoxy, <NUM>-methylpropoxy or <NUM>,<NUM>-dimethylethoxy; C<NUM>-C<NUM>-alkoxy: C<NUM>-C<NUM>-alkoxy, as specified above, and e.g. pentoxy, <NUM>-methylbutoxy, <NUM>-methylbutoxy, <NUM>-methylbutoxy, <NUM>,<NUM>-dimethylpropoxy, <NUM>,<NUM>-dimethylpropoxy, <NUM>,<NUM>-dimethylpropoxy, <NUM>-ethylpropoxy, hexoxy, <NUM>-methylpentoxy, <NUM>-methylpentoxy, <NUM>-methylpentoxy, <NUM>-methylpentoxy, <NUM>,<NUM>-dimethylbutoxy, <NUM>,<NUM>-dimethylbutoxy, <NUM>,<NUM>-dimethylbutoxy, <NUM>,<NUM>-dimethylbutoxy, <NUM>,<NUM>-dimethylbutoxy, <NUM>,<NUM>-dimethylbutoxy, <NUM>-ethylbutoxy, <NUM>-ethylbutoxy, <NUM>,<NUM>,<NUM>-trimethylpropoxy, <NUM>,<NUM>,<NUM>-trimethylpropoxy, <NUM>-ethyl-<NUM>-methylpropoxy or <NUM>-ethyl-<NUM>-methylpropoxy.

The expression "alkylene" in the context of the present invention stands for straight or branched alkanediyl groups having <NUM> to <NUM>, preferably <NUM> to <NUM> carbon atoms. These are -CH<NUM>-, -(CH<NUM>)<NUM>-, -(CH<NUM>)<NUM>-,-(CH<NUM>)<NUM>-, -(CH<NUM>)<NUM>-CH(CH<NUM>)-, (-CH<NUM>-CH(CH<NUM>)-), -CH<NUM>-CH(CH<NUM>)-CH<NUM>-, (CH<NUM>)<NUM>-, -(CH<NUM>)<NUM>-, -(CH<NUM>)<NUM>, -(CH<NUM>)<NUM>-, -CH(CH<NUM>)-CH<NUM>-CH<NUM>-CH(CH<NUM>)- or -CH(CH<NUM>)-CH<NUM>-CH<NUM>-CH<NUM>-CH(CH<NUM>)- etc..

The expression "cycloalkyl" in the context of the present invention stands for a monocyclic, bicyclic or tricyclic, saturated hydrocarbon group having <NUM> to <NUM>, preferably <NUM> to <NUM> or <NUM> to <NUM> carbon ring members, e.g. a monocyclic hydrocarbon group having <NUM> to <NUM> carbon ring members, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; a bicyclic hydrocarbon group having <NUM> to <NUM> carbon ring members, such as bicyclo[<NUM>. <NUM>]hept-<NUM>-yl, bicyclo[<NUM>. <NUM>]hept-<NUM>-yl, bicyclo[<NUM>. <NUM>]hept-<NUM>-yl, bicyclo[<NUM>. <NUM>]oct-<NUM>-yl, bicyclo[<NUM>. <NUM>]oct-<NUM>-yl, bicyclo[<NUM>. <NUM>]octyl and bicyclo[<NUM>. <NUM>]decyl; a tricyclic hydrocarbon group with <NUM> to <NUM> carbon ring members, such as adamantyl.

The expression "cycloalkoxy" (= cycloalkyloxy) in the context of the present invention stands for a monocyclic, bicyclic or tricyclic, saturated hydrocarbon group having <NUM> to <NUM>, preferably up to <NUM>, up to <NUM> carbon ring members, as defined above, which is bonded via an oxygen atom.

The expression "heterocycloalkyl" in the context of the present invention comprises saturated or partially unsaturated cycloaliphatic groups with preferably <NUM> to <NUM>, more preferably <NUM> or <NUM> ring atoms, in which <NUM>, <NUM>, <NUM> or <NUM> ring atoms may be substituted with heteroatoms, preferably selected from the elements oxygen, nitrogen and sulfur. The heterocycloalkyl ring is optionally substituted. If substituted, these heterocycloaliphatic groups carry preferably <NUM>, <NUM> or <NUM> substituents, more preferably <NUM> or <NUM> substituents and in particular <NUM> substituent. These substituents are preferably selected from alkyl, cycloalkyl, aryl, COOR (R = H, alkyl, cycloalkyl, aryl), COO-M+ and NE<NUM>E<NUM>, more preferably alkyl. Examples of such heterocycloaliphatic groups are pyrrolidinyl, piperidinyl, <NUM>,<NUM>,<NUM>,<NUM>-tetramethylpiperidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, morpholidinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, piperazinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl and dioxanyl.

The expression "aryl" in the context of the present invention comprises a mono- or polynuclear aromatic hydrocarbon radical having usually <NUM> to <NUM>, preferably <NUM> to <NUM> carbon atoms, such as e.g. phenyl, tolyl, xylyl, mesityl, naphthyl, indenyl, fluoroenyl, anthracenyl or phenanthrenyl. In case these aryl groups are substituted, they may carry preferably <NUM>, <NUM>, <NUM>, <NUM> or <NUM> substituents, more preferably <NUM>, <NUM> or <NUM> substituents and particularly preferred <NUM> substituent. These substituents are preferably selected from the groups alkyl, alkoxy, carboxyl, carboxylate, trifluoromethyl, -SO<NUM>H, sulfonate, NE<NUM>E<NUM>, alkylene-NE<NUM>E<NUM>, nitro, cyano and halogen. A preferred fluorinated aryl group is pentafluorophenyl.

The expression "aryloxy" in the context of the present invention stands for a mono- or polynuclear aromatic hydrocarbon radical having usually <NUM> to <NUM>, preferably <NUM> to <NUM> carbon atoms, as defined above, which is bonded via an oxygen atom.

The expression "heterocycloalkyl (= heterocyclyl) with <NUM> to <NUM> ring atoms" in the context of the present invention refers to a saturated, partially (e.g. mono-) unsaturated heterocyclic radical having <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> ring atoms, of which <NUM>, <NUM> or <NUM> are selected from N, O, S, S(O) and S(O)<NUM>, and the other ring atoms are carbon, such as e.g. <NUM>- to <NUM>-membered saturated heterocyclyl, such as oxiranyl, oxetanyl, aziranyl, piperidinyl, piperazinyl, morpholinyl, thimorpholinyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuryl, dioxolanyl, dioxanyl, hexahydroazepinyl, hexyhydrooxepinyl, and hexahydrothiepinyl; partially unsaturated <NUM>-, <NUM>-, <NUM>-, <NUM>-, <NUM>- or <NUM>-membered heterocyclyl, such as di- and tetrahydropyridinyl, pyrrolinyl, oxazolinyl, dihydrofuryl, tetrahydroazepinyl, tetrahydrooxepinyl, and tetrahydrothiepinyl.

The expression "heterocycloalkoxy (= heterocycloalkoxy) with <NUM> to <NUM> ring atoms" in the context of the invention is a saturated, partially (e.g. mono-) unsaturated heterocyclic radical having <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> ring atoms, of which <NUM>, <NUM> or <NUM> are selected from N, O, S, S(O) and S(O)<NUM>, and the other ring atoms are carbon, as defined above, which is bonded via oxygen.

The expression "hetaryl (= heteroaryl)" in the context of the invention is an aromatic, mono- or polynuclear heterocycle, which, besides carbon atoms, comprises one to four heteroatoms from the group O, N or S as ring members, such as e.g..

If these heterocycloaromatic groups are substituted, they may carry preferably <NUM>, <NUM> or <NUM> substituents selected from the groups alkyl, alkoxy, carboxyl, carboxylate, -SO<NUM>H, sulfonate, NE<NUM>E<NUM>, alkylene-NE<NUM>E<NUM>, trifluoromethyl and halogen.

Carboxylate and sulfonate in the context of the present invention preferably stand for a derivative of a carboxylic acid function or a sulfonic acid function, in particular a metal carboxylate or metal sulfonate, a carboxylic acid ester or sulfonic acid ester or a carboxylic acid amide or sulfonic acid amide. Particularly preferred are esters with C<NUM>-C<NUM>-alkanols like methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol and tert-butanol. Preferred are also the primary amides and their N-alkyl and N,N-dialkyl derivatives.

The expression "acyl" in the context of the present invention stands for alkanoyl groups or aroyl groups with preferably <NUM> to <NUM>, more preferably <NUM> to <NUM> carbon atoms, for example acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, <NUM>-ethylhexanoyl, <NUM>-propylheptanoyl, benzoyl and naphthoyl.

The groups NE<NUM>E<NUM>, NE<NUM>E<NUM> and NE<NUM>E<NUM> are preferably selected from N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, N,N-diisopropylamino, N,N-di-n-butylamino, N,N-di-tert-butylamino, N,N-dicyclohexylamino and N,N-diphenylamino.

Halogen stands for fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

Formyl ist H-C(=O)-. Carboxy is -C(=O)OH. Sulfo is -S(=O)<NUM>-OH.

Polyalkylene oxide is a radical derived from identical or different C<NUM>-<NUM>-oxyalkylene monomer building blocks, as defined above, with a degree of polymerization (number average) in the range of <NUM> to <NUM>, or <NUM> to <NUM> or <NUM> to <NUM> or <NUM> to <NUM>.

Polyalkyleneimine is a structure-analogous radical to the above polyalkylene oxide radical with the oxygen atom being replaced by an imine group.

M+ refers to a cation equivalent, which means a monovalent cation or the part of a polyvalent cation representing a positive single charge. The cation M+ is only a counter ion, which neutralizes negatively charged substituents like the COO- or the sulfonate group and which can principally be selected arbitrarily. Preferred are alkaline metal ions, in particular Na+, K+ and Li+ ions, or onium ions like ammonium ions, mono-, di-, tri-, tetraalkylammonium ions, phosphonium ions, tetraalkylphosphonium ions and tetraarylphosphonium ions.

The same applies to the anion equivalent X-, which is only a counter ion for positively charged substituents like the ammonium group and which can principally be selected arbitrarily among monovalent anions and the parts of polyvalent anions, which correspond to a single negative charge. Preferred are halogenides X-, in particular chloride and bromide. Also preferred are sulfates and sulfonates, in particular SO<NUM><NUM>-, tosylate, trifluoromethane sulfonate and methylsulfonate.

Condensed ring systems, also termed fused ring systems, are aromatic, heteroaromatic or cyclic compounds, which have fused-on rings obtained via anellation. Condensed ring systems consist of two, three or more than three rings. Depending on the type of connection, one distinguishes between ortho-anellation and peri-anellation. In case of ortho-anellation, each ring has two atoms in common with each adjacent ring. In case of peri-anellation, a carbon atom belongs to more than two rings. Preferred among the condensed ring systems are ortho-condensed ring systems.

In the context of the present invention, "chiral ligands" are ligands without an axis of symmetry. They are in particular ligands with at least one chirality center (i.e. at least one asymmetric atom, in particular at least one asymmetric P atom or C atom). In a special embodiment of the present invention, addition ligands are employed, which show axial chirality. Axial chirality occurs, for example, in biphenyls, such as BINAP, which are substituted in the ortho-positions in such a way that the free rotation of the aromatic compounds around the C-C single bond is strongly hindered. This then results in two mirror-image isomers.

In the context of the present invention, the term "chiral catalyst" comprises catalysts, which have at least one chiral ligand.

"Achiral compounds" are compounds, which are not chiral.

A "prochiral compound" is understood as meaning a compound with at least one prochiral center.

"Asymmetric synthesis" refers to a reaction in which a compound with at least one chirality center is produced from a compound with at least one prochiral center, where the stereoisomeric products are formed in unequal amounts.

"Stereoisomers" are compounds of identical constitution, but different atomic arrangement in the three-dimensional space.

"Enantiomers" are stereoisomers, which behave like image to mirror image to one another. The "enantiomeric excess" (ee) achieved during asymmetric synthesis is given here by the following formula: ee [%] = (R-S)/(R+S) x <NUM>. R and S are the descriptors of the CIP system for the two enantiomers and describe the absolute configuration on the asymmetric atom. The enantiomerically pure compound (ee = <NUM>%) is also referred to as "homochiral compound".

The process according to the invention leads to products, which are enriched with regard to a specific stereoisomer, in particular with regard to L-Iditol. The attained "enantiomer excess" (ee) is generally at least <NUM>%, preferably at least <NUM>%, in particular at least <NUM>%.

"Diastereomers" are stereoisomers, which are not enantiomeric to one another.

L-Sorbose is commercially available or can be prepared from D-Sorbitol via microbiological oxidation.

In the process of the invention, the composition comprising L-Sorbose is subjected to hydrogenation in a liquid reaction medium in the presence of a transition metal catalyst complex, which comprises at least one chiral ligand containing at least two phosphorus atoms, which are capable of coordinating to the transition metal and ruthenium as the metal center. Due to this chiral ligand the transition metal catalyst complex is stereoselective. In other words: Applying the stereoselective transition metal catalyst complex the product mixture predominately comprises the desired stereoisomer. In particular, the product mixture exclusively comprises the desired stereoisomer.

The process of the invention is carried out as a homogeneously catalyzed hydrogenation using a ruthenium catalyst complex. That means the ruthenium catalyst complex is dissolved in the liquid reaction medium under the reaction conditions. Typically, the ruthenium catalyst complex is in the same phase as the reactants, i.e. the L-Sorbose. Further, the liquid reaction medium may comprise at least one chiral ligand in excess. In this embodiment, the liquid reaction contains free chiral ligands that are not bound to the ruthenium complex. The free chiral ligands are selected from the phosphorous containing ligands defined in the following.

The ruthenium catalyst complex comprises at least one chiral ligand containing at least two phosphorus atoms, which are capable of coordinating to the transition metal. Typically, the molar ratio of the chiral ligand to the transition metal is at least <NUM>, e.g. in the range from <NUM> to <NUM>, especially <NUM> or <NUM>. The chiral ligand contains at least two phosphorus atoms, which are capable of coordinating to the transition metal and is especially a chiral bidentate ligand having two phosphorous atoms, which are capable of coordinating to the ruthenium. More particularly, the ruthenium catalyst complex has <NUM> or <NUM> chiral bidentate ligands having two phosphorous atoms, which are capable of coordinating to the transition metal, in particular <NUM> of such a bidentate chiral ligand. Especially, the ruthenium catalyst complex has <NUM> or <NUM> chiral bidentate ligands having two phosphorous atoms, which are capable of coordinating to the transition metal, in particular <NUM> of such a bidentate chiral ligand.

According to the invention, the ligand containing at least two phosphorus atoms, which are capable of coordinating to the transition metal, is chiral, i.e. it bears at least one group that is asymmetric. Chirality of the ligand may be caused, e.g. because at least one of the P atoms is asymmetric, and/or the ligand has axial chirality. In particular, the chiral ligand bears a group, which causes axial chirality.

Preferably, the chiral ligand is selected from compounds of formula (I)
<CHM>
wherein.

In formula (I), the variables RA, RB, RC, RD, X<NUM>, X<NUM>, X<NUM>, X<NUM>, X<NUM>, X<NUM>, X<NUM>, X<NUM>, X<NUM>, a, b, c, d, e and f, individually or in particular in combination, have preferably the following meanings, provided that formula (I) has at least one chiral group, e.g. because at least one of the P atoms is asymmetric, and/or the ligand of formula (I) has axial chirality:.

In particular, the chiral ligand is selected from organo phosphines, in particular from compounds of the formula (I), wherein a, b, c, d, e and f are <NUM>, or wherein X<NUM>, X<NUM>, X<NUM>, X<NUM>, X<NUM>, X<NUM>, X<NUM>, X<NUM> and X<NUM> are, at each occurrence, a group CRxRy. In particular, the integers a, b, c, d, e and f in formula (I) are <NUM>.

In formula (I), the variables RA, RB, RC, RD have in particular the following meanings:.

More particularly, the variables RA, RB, RC, RD have in particular the following meanings:
Organo phosphines are derived from phosphines (also called phosphanes), wherein one or more hydrogens are replaced by an organic substituent.

In particular, the chiral ligand is selected from compounds of formulae (II) or (III)
<CHM>
<CHM>
wherein,.

More particularly, the chiral ligand is selected from compounds of formulae (II) or (III)
<CHM>
<CHM>
wherein.

In formula (IV), the radicals Re1 Re2, Re3, Re4, Re5, Re6, Re7 and Re8 are preferably independently from each other selected from the group consisting of hydrogen, halogen in each case unsubstituted or substituted C<NUM>-C<NUM>-alkyl, C<NUM>-C<NUM>-alkoxy, C<NUM>-C<NUM>-aryl, hetaryl with <NUM> to <NUM> atoms, or two adjacent radicals Re1 to Re8 together with the carbon atoms of the benzene ring to which they are bound may also be a condensed ring system with one further ring, and
in formula (IV) the radical A' is in particular a single bond, O or S.

In a very preferred group of embodiments, the transition metal catalyst complex comprises at least one chiral ligand selected from compounds of formulae (I) or (II), wherein.

Even more preferably, the transition metal catalyst complex comprises at least one chiral ligand selected from compounds of formulae (I) or (II), wherein.

Especially, the transition metal catalyst complex comprises at least one ligand selected from compounds of formulae (I) or (II), wherein.

As mentioned above, the chiral ligand either contains at least one chirality center or exhibit axial chirality.

In a preferred embodiment, the chiral ligand exhibits axial chirality. Especially, the ligands of formulae (I), (II) and (III) have axial chirality. Especially, axial chirality is caused by the bridging group Y.

Preferably, the divalent bridging group Y in formulae (I), (II) and (III) is selected from groups of the formulae (V) or (VI):
<CHM>
<CHM>
wherein.

More preferably, the divalent bridging group Y has one of the meanings of formulae (V) or (VI)
<CHM>
<CHM>
wherein.

Especially, the radicals RI, RI', RII, RII', RIII, RIII', RIV, RIV', RV, RV', RVI, RVI', RVII, RVII', RVIII', RVIII, RIX, RX, RXI and RXII are each, independently from each other, hydrogen, C<NUM>-C<NUM>-alkyl, C<NUM>-C<NUM>-aryl, hetaryl with <NUM> to <NUM> atoms,.

Especially, the divalent bridging group Y has one of the meanings of formulae (V), wherein RI, RI', RII, RII', RIII, RIII', RIV and RIV' are each, independently from each other, hydrogen, C<NUM>-C<NUM>-alkyl, C<NUM>-C<NUM>-aryl, hetaryl with <NUM> to <NUM> atoms,.

The ligand is selected in a manner, that a catalyst is formed, which has a low solubility in water. Preferably it is selected in way, that in the process step <NUM> the amount of ruthenium in the aqueous phase after the extraction is below <NUM> part per million. The below given ligands A-H will result in a ruthenium catalyst, which provides the required low solubility of the ruthenium catalyst in water.

In especially preferred embodiments, the ruthenium catalyst complex comprises at least one ligand selected from the formulae A to H and mixtures thereof
<CHM>
<CHM>
<CHM>.

The ruthenium catalyst according to the invention can be employed in the form of a preformed complex, which comprises the ruthenium compound and one or more ligands. Alternatively, the ruthnium catalyst is formed in situ in the reaction medium by combining a metal compound, herein also termed pre-catalyst, with one or more suitable ligands to form a catalytically ruthenium complex in the reaction medium. It is also possible that the ruthenium catalyst is formed in situ in the presence of an auxiliary ligand by combining a metal compound, herein also termed pre-catalyst, with one or more auxiliary ligands to form a catalytically ruthenium complex in the reaction medium. Suitable pre-catalysts are selected from neutral ruthenium complexes, oxides and salts of ruthenium.

Ruthenium compounds that are useful as pre-catalyst are, for example, [Ru(methylallyl)<NUM>COD], [Ru(p-cymene)Cl<NUM>]<NUM>, [Ru(benzene)Cl<NUM>]n, [Ru(CO)<NUM>Cl<NUM>]n, [Ru(CO)<NUM>Cl<NUM>]<NUM>, [Ru(COD)(allyl)], [RuCl<NUM>·H<NUM>O], [Ru(acetylacetonate)<NUM>], [Ru(DMSO)<NUM>Cl<NUM>], [Ru(PPh<NUM>)<NUM>(CO)(H)Cl], [Ru(PPh<NUM>)<NUM>(CO)Cl<NUM>], [Ru(PPh<NUM>)<NUM>(CO)(H)<NUM>], [Ru(PPh<NUM>)<NUM>Cl<NUM>], [Ru(Cp)(PPh<NUM>)<NUM>Cl], [Ru(Cp) (CO)<NUM>Cl], [Ru(Cp)(CO)<NUM>H], [Ru(Cp)(CO)<NUM>]<NUM>, [Ru(Cp*)(CO)<NUM>Cl], [Ru(Cp*)(CO)<NUM>H], [Ru(Cp*)(CO)<NUM>]<NUM>, [Ru(indenyl)(CO)<NUM>Cl], [Ru(indenyl)(CO)<NUM>H], [Ru(indenyl)(CO)<NUM>]<NUM>, ruthenocen, [Ru(binap)(Cl)<NUM>], [Ru(<NUM>,<NUM>'-bipyridin)<NUM>(Cl)<NUM>-H<NUM>O], [Ru(COD)(Cl)<NUM>H]<NUM>, [Ru(Cp*)(COD)Cl], [Ru<NUM>(CO)<NUM>], [Ru(tetraphenylhydroxycyclopentadienyl)(CO)<NUM>H], [Ru(PMe<NUM>)<NUM>(H)<NUM>], [Ru(PEt<NUM>)<NUM>(H)<NUM>], [Ru(Pn-Pr<NUM>)<NUM>(H)<NUM>], [Ru(Pn-Bu<NUM>)<NUM>(H)<NUM>], [Ru(Pn-octyl<NUM>)<NUM>(H)<NUM>], of which [Ru(methylallyl)<NUM>COD], Ru(COD)Cl<NUM>]<NUM>, [Ru(Pn-Bu<NUM>)<NUM>(H)<NUM>], [Ru(Pn-octyl<NUM>)<NUM>(H)<NUM>], [Ru(PPh<NUM>)<NUM>(CO)(H)Cl] and [Ru(PPh<NUM>)<NUM>(CO)(H)<NUM>] are preferred, in particular [Ru(methylallyl)<NUM>COD].

In the aforementioned compound, names "COD" denotes <NUM>,<NUM>-cyclooctadiene; "Cp" denotes cyclopentadienyl; "Cp*" denotes pentamethylcycopentadienyl; and "binap" denotes <NUM>,<NUM>'-bis(diphenylphosphino)-<NUM>,<NUM>'-binaphthyl.

In the process of the invention, a sub-stoichiometric amount of the catalyst is generally used with the amount of catalyst typically being not more than <NUM> mol%, frequently not more than <NUM> mol% and in particular not more than <NUM> mol% or not more than <NUM> mol%, based on the amount of L-Sorbose in the L-Sorbose comprising composition. An amount of catalyst of from <NUM> to <NUM> mol%, frequently from <NUM> mol% to <NUM> mol% and in particular from <NUM> to <NUM> mol%, based on the amount of L-Sorbose in the L-Sorbose comprising composition, is generally used in the process of the invention. Preference is given to using an amount of catalyst of from <NUM> to <NUM> mol% and particularly preferably from <NUM> mol% to <NUM> mol%. All amounts of catalysts indicated are calculated as ruthenium metal and based on the amount of L-Sorbose in the L-Sorbose comprising composition.

Typically, the amount of the chiral ligand present in the process of the invention is at least <NUM> mol, in particular at least <NUM> mol, especially at least <NUM> mol per <NUM> mol of ruthenium metal, e.g. in the range of <NUM> to <NUM> mol, in particular in the range of <NUM> to <NUM> mol and especially in the range from <NUM> to <NUM> mol per <NUM> mol of the transition metal.

The process of the invention can be carried out in the presence of a solvent. Suitable solvents are selected from aliphatic hydrocarbons, aromatic hydrocarbons, amides, ureas, nitriles, sulfoxides, sulfones, alcohols, esters, carbonates, ethers and mixtures thereof. Preferred solvents are.

If desired, mixtures of two or more of the aforementioned solvents can also be used.

In a preferred embodiment, preferred solvent are alcohols, in particular C<NUM>-C<NUM>-alkanols, such as methanol, ethanol, propanol, isopropanol, <NUM>-butanol, iso-butanol, <NUM>-propanol, iso-propanol, <NUM>-hexanol or mixtures thereof.

The hydrogenation can principally be performed according to all processes known to a person skilled in the art, which are suitable for the hydrogenation of a L-Sorbose comprising composition.

The hydrogen used for the hydrogenation can be used in pure form or, if desired, also in the form of mixtures with other, preferably inert gases, such as nitrogen or argon. Preference is given to using hydrogen in undiluted form.

The hydrogenation is typically carried out at a hydrogen pressure in the range from <NUM> to <NUM> bar, preferably in the range from <NUM> to <NUM> bar, more preferably in the range from <NUM> to <NUM> bar.

The hydrogenation is typically carried out at a temperature in the range from -<NUM> to <NUM>. The hydrogenation is preferably carried out at a temperature of at least <NUM>, in particular at least <NUM>. Preferably, the temperature will not exceed <NUM>, in particular <NUM>. The hydrogenation is in particular carried out at a temperature in the range of <NUM> to <NUM> and particularly preferably in the range from <NUM> to <NUM>. Temperatures of at most <NUM>, e.g. in the range from <NUM> to <NUM>, in particular in the range from <NUM> to <NUM>, are particularly advantageous.

The hydrogenation can principally be performed in all reactors known by a person in the art for this type of reaction, and, therefore, will select the reactors accordingly. Suitable reactors are described for example in "<NPL>. Suitable pressure-resistant reactors are also known to a person skilled in the art and are described, for example, in "<NPL>ff. Preferably, for the hydrogenation an autoclave is employed, which may have an internal stirrer and an internal lining.

In a preferred embodiment according to the invention, the obtained composition comprises L-Iditol as the main product and D-Sorbitol as the minor compound. The obtained composition is enriched in L-Iditol and depleted in L-Sorbose, D-Mannitol and D-Sorbitol. The ratio of D-Sorbitol to L-Iditol is in the range of <NUM>:<NUM> to <NUM>:<NUM>, preferably in the range of <NUM>:<NUM> to <NUM>:<NUM>. Besides L-Iditol and other hexitols, the reaction mixture also contains the solvent and the stereoselective ruthenium catalyst in the form of its resting state.

From the reaction mixture obtained in step i), the L-Iditol as the main product as well as the other hexoses were separated from the catalyst system. This separation is preferably performed as an extraction with water. The amount of water used is in a range of <NUM> to <NUM> mass equivalents according the L-Iditol present in the residue obtained in step ii), preferably <NUM> to <NUM> mass equivalents according the L-Iditol present in the residue obtained in step ii). If a solvent was used in the hydrogenation reaction (step i)) providing a mixing gap with water, the L-Iditol can be directly extracted from the reaction mixture. The extraction can be carried out in any state-of-the art extraction apparatus like mixer-settler. Another way to extract the products can be selective membranes, where only the hexitols can permeate and not the ruthenium catalyst. By this extraction, the L-Iditol as the main product and the other hexoses as minor products will be dissolved in the water, whereas the resting state of the ruthenium catalyst with a ligand as defined above will remain in the non-polar phase with a ruthenium concentration in the aqueous phase of not more than <NUM> ppm.

If the solvent used in step i) provides no mixing gap with water, like methanol, the products can also be extracted by first removing the solvent by distillation or in vacuo leaving a residue, from which the L-Iditol as the main product as well as the other hexoses were extracted with water. This extraction can be performed in any setting used in the state of the art for extraction, like a stirred reactor, stirred tank, Soxhlet or filtration unit. In this step, the L-Iditol as the main product and the other hexoses as minor products will be dissolved in the water, whereas the resting state of the ruthenium catalyst with a ligand as defined above will remain as insoluble solid with a ruthenium concentration in the aqueous phase of not more than <NUM> ppm. the remaining solid ruthenium catalyst in the form of its resting state is separated from the aqueous by any setting used in the state of the art for the separation of a liquid and solid like filtration, decanting or centrifugation.

From the separated water phase, the L-Iditol as the main product and the other hexoses as minor product can be obtained by evaporating of the water and used as obtained or further purified by state-of-the-art methods, if necessary.

The separated catalyst in the form of its resting state obtained in step ii) is reactivated by adding a chloride source to the catalyst.

The chloride source can be HCl or a chloride salt or anion-exchange resins in a Cl-form. Preferred chloride salts are LiCl, NaCl, KCI, CaCl<NUM>, MgCl<NUM>, AlCl<NUM>, FeCl<NUM>. Preference is given to HCl as a methanolic solution or as HCl gas.

The amount of chloride used is in the range of <NUM> to <NUM> molar equivalent according the amount of ruthenium in the recycled catalyst, preferable in a range of <NUM> to <NUM> equivalents chloride according the ruthenium.

After the reactivation of the catalyst according to step iii) the catalyst can be reused in the hydrogenation reaction (step i)), either immediately after step iii) or after a storage period. All process steps can either be run in a continuous- or in a discontinuous manner.

Without adding a chloride source, the activity and selectivity of the recycled catalyst is low (see comparative example).

Furthermore the use of a transition metal complex, defined by a hydrophobic stereoselective ruthenium catalyst complex comprising at least one chiral ligand containing at least two phosphorus atoms, which are capable of coordinating to the ruthenium, represented by formula (I), wherein Y in formula (I) is a divalent bridging group, which contains carbon atoms, and Y being preferably selected from groups of formulae (V) or (VI), as hydrogenation catalyst for the hydrogenation of compositions comprising L-sorbose or mixtures thereof, was found, characterized in that.

The invention is described in more detail in the following examples.

All chemicals and solvents were purchased from Sigma-Aldrich, Merck or ABCR and were used without further purification.

Analytics of the reaction mixture after hydrogenation:
Samples of carbohydrates, e.g. hexoses, pentoses and, after a suitable hydrogenation, the corresponding sugar alcohols, were diluted in water to obtain a mass concentration of approximately <NUM>/ml prior to high-performance liquid chromatographic (HPLC) separation. Compositional analysis of the said samples was performed by the means of ion-moderated partition chromatography using refractive index detection. Known signals were quantified by external standard quantification. Separation was achieved using two serially coupled <NUM> x <NUM> Aminex HPX-87P columns (Bio-Rad Laboratories). Separation took place after injecting an aliquot of the sample into the HPLC system using deionized water as mobile phase at a column temperature of <NUM>.

First Hydrogenation: In an argon-filled glovebox, a <NUM> Premex stainless steel autoclave fitted with a Teflon insert was charged with L-sorbose (<NUM>, <NUM> mmol), [RuCl<NUM>(benzene)]<NUM> (<NUM>, <NUM> mmol), Ligand E (<NUM>, <NUM> mmol), MeOH (<NUM>), and a stir bar. After the autoclave was closed, the reaction vessel was removed from the glovebox. The system was purged twice with hydrogen (<NUM> bar) and then pressurized with hydrogen (<NUM> bar, ca. <NUM>) and placed into a preheated heating block (<NUM>) over a magnetic stirring plate. While stirring overnight the pressure reached ca. <NUM> bar at the reaction temperature. After <NUM>, the autoclave was then placed in a cold water bath, and after it was cooled to room temperature, it was depressurized.

The golden-yellow solution was transferred to a round-bottom flask. The solution was evaporated and dried in vacuo to yield a yellow-brown sticky residue.

The rest of the residue was mixed with distilled water (<NUM>) and the light brown suspension was filtered over a fritted filter (∅ <NUM>, pore size <NUM>) and then over a pad of celite (∅ <NUM>, <NUM>-<NUM> high) sitting on a fritted filter (∅ <NUM>, pore size <NUM>). A sample (<NUM>) of the lime-like colored solution was submitted to ICP-MS analysis. The ruthenium-content in this solution was <NUM>/kg as determined by ICP/MS.

The brown filter cake was washed with distilled water (<NUM> × <NUM>) and dried in vacuo to yield <NUM> of the ruthenium catalyst in its resting state. These two combined aqueous fractions were filtered over a pad of celite (∅ <NUM>, <NUM>-<NUM> high) sitting on a fritted filter (∅ <NUM>, pore size <NUM>) and added to the above-mentioned aqueous fraction. The solution was dried using the cryovap method (OPRD <NUM>, <NUM>, <NUM>) followed by drying on the high vacuum over the weekend resulting in a highly viscous lime-colored liquid (<NUM>). According HPLC analysis of this viscous lime-colored liquid, the conversion of L-Sorbose was <NUM>% and the overall selectivity towards L-Iditol and D-Sorbitol was <NUM>%. The ratio between L-Iditol to D-Sorbitol was <NUM> to <NUM>, according a L-Iditol yield of <NUM> % after the first hydrogenation.

Second Hydrogenation with recycled catalyst and HCl addition:
In an argon-filled glovebox, a <NUM> Premex stainless steel autoclave fitted with a Teflon insert was charged with L-Sorbose (<NUM>, <NUM> mmol), the catalyst obtained after the product extraction from the first hydrogenation (<NUM>), MeOH (<NUM>), <NUM> methanolic HCl (<NUM>, <NUM>. 08mmol), and a stir bar. After it was closed, the reaction vessel was removed from the glovebox and placed into a preheated heating block (<NUM>) over a magnetic stirring plate. After <NUM>, the autoclave was then placed in a cold water bath, and after it was cooled to room temperature, it was depressurized.

The volatiles of a sample (<NUM>) of the brown solution were evaporated to dryness. The residue was dissolved in distilled water (<NUM>). The suspension was filtered over a pad of celite and subsequently through a PTFE syringe filter (<NUM>) and submitted to HPLC analysis. According HPLC, the conversion of L-Sorbose was <NUM>% and the overall selectivity towards L-Iditol and D-Sorbitol was <NUM>%. The ratio between L-Iditol to D-Sorbitol was <NUM> to <NUM>, according a L-Iditol yield of <NUM> % after the first hydrogenation.

Second Hydrogenation with recycled catalyst but without HCl addition:
In an argon-filled glovebox, a <NUM> Premex stainless steel autoclave fitted with a Teflon insert was charged with L-Sorbose (<NUM>, <NUM> mmol), the catalyst after the product extraction from the first hydrogenation of example <NUM> (<NUM>), MeOH (<NUM>), and a stir bar (<NUM>:<NUM>). After it was closed, the reaction vessel was removed from the glovebox and placed into a preheated heating block (<NUM>) over a magnetic stirring plate. After <NUM>, the autoclave was then placed in a cold water bath, and after it was cooled to room temperature, it was depressurized.

Claim 1:
A process for the preparation of L-Iditol comprising at least the process steps:
i) a L-Sorbose comprising composition is subjected to hydrogenation with hydrogen in the presence of a hydrophobic stereoselective ruthenium catalyst complex in a homogeneous solution, wherein the ruthenium catalyst complex comprises at least one chiral ligand containing at least two phosphorus atom, which are capable of coordinating to the ruthenium yielding in a composition comprising L-Iditol as the main product;
ii) separation of the reaction products produced in step i) from the ruthenium catalyst complex ;
iii) reactivating the separated ruthenium catalyst complex of step ii) by adding a chloride source and reusing the reactivated ruthenium catalyst complex in step i).