KR20070068428A - Process for the de-enrichment of enantiomerically enriched substrates - Google Patents

Abstract

There is provided a process for the de-enrichment of enantiomerically enriched compositions which comprises reacting an enantiomerically enriched composition comprising at least a first enantiomer or diastereomer of a substrate comprising a carbon-heteroatom bond, wherein the carbon is a chiral centre and the heteroatom is a group VI heteroatom, in the presence of a catalyst system and optionally a reaction promoter to give a product composition comprising first and second enantiomers or diastereomers of the substrate having a carbon-heteroatom bond, the ratio of second to first enantiomer or disatereomer in the product composition being greater than the ratio of second to first enantiomer or disatereomer in the enantiomerically enriched composition. Preferred substrates include compounds of Formula (1) wherein: X represents O, S; R1, R2 each independently represents an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, an optionally substituted heterocyclyl group; or R1 & R2 are optionally linked in such a way as to form an optionally substituted ring(s); provided that R1 and R2are selected such that * is a chiral centre. In a preferred process a compound of Formula : (2) wherein: X represents O, S; R1, R2 each independently represents an optionally substituted hydrocarbyl, a perhalogenated hydrocarbyl, an optionally substituted heterocyclyl group; or R1 & R2 are optionally linked in such a way as to form an optionally substituted ring(s); provided that R1 and R2 are different, may be obtained.

Description

Process for the De-Enrichment of Enantiomerically Enriched Substrates

The present invention relates to a method for de-enrichment of enantiomerically concentrated substrates, in particular alcohols and sulfides.

According to a first aspect of the present invention, there is provided a method for deconcentrating an optically concentrated composition, comprising: at least a first optical isomer of a substrate comprising carbon-heteroatom bonds in the presence of a catalyst system and optionally a reaction promoter or Reacting the optically condensed composition comprising the diastereomer to provide a resulting composition comprising the first and second optical isomers or diastereomers of the substrate having a carbon-heteroatom bond, wherein Carbon is chiral centered and the heteroatom is a Group VI heteroatom, and the ratio of the second optical isomer or diastereomer to the first optical isomer or diastereomer in the resulting composition is the first in the optically concentrated composition. Second isomer or diastere for an isomer or diastereomer This method is larger than the ratio of Omer is provided.

Preferably, the resulting composition is a racemic mixture of first and second optical isomers of a substrate comprising a carbon-heteroatom bond, wherein the carbon is chiral centered.

Substrates that can be optically deconcentrated by the process of the present invention include alcohols at chiral secondary carbon atoms and sulfide chirals at secondary carbon atoms.

Preferably, in the process of the invention, the substrate comprises a carbon-heteroatom bond, wherein the carbon atom is a compound of formula (1) which is chiral centered.

here,

X represents O, S,

R ¹ , R ² each independently represent an optionally substituted hydrocarbyl group, a perhalogenated hydrocarbyl group, an optionally substituted heterocyclyl group, or

R ¹ and R ² are optionally linked to form an optionally substituted ring,

With the proviso that R ¹ and R ² are selected such that * is the chiral center.

Hydrocarbyl groups which may be represented by R ^1-2 independently include alkyl groups, alkenyl groups and aryl groups, and combinations thereof such as aralkyl and alkaryl, for example benzyl groups.

The alkyl group which may be represented by R ^1-2 includes linear and branched alkyl groups containing up to 20 carbon atoms, in particular 1 to 7 carbon atoms, preferably 1 to 5 carbon atoms. When an alkyl group is branched, the alkyl groups in most cases contain up to 10 branched carbon atoms, preferably up to 4 branched chain atoms. In some embodiments, an alkyl group may be cyclic, typically containing 3 to 10 carbon atoms in the largest ring and, in some circumstances, characterized by one or more bridging rings. Examples of alkyl groups which may be represented by R ^{1 -4} may include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl group, a t- butyl group and a cyclohexyl group.

Alkenyl groups which may be represented by R ^1-2 include C _2-20 , preferably C _2-6 alkenyl groups. One or more carbon-carbon double bonds may be present. Alkenyl groups may bear one or more substituents, especially phenyl substituents. Examples of alkenyl groups include vinyl groups, styryl groups and indenyl groups. When either R ¹ or R ² represents an alkenyl group, the carbon-carbon double bond is preferably located as a C-heteroatom moiety at the β-position.

The aryl group represented by R ^1-2 may have one ring or two or more condensed rings, which may include a cycloalkyl ring, an aryl ring, or a heterocycle. Examples of the aryl group which may be represented by R ^1-2 include a phenyl group, tolyl group, fluorophenyl group, chlorophenyl group, bromophenyl group, trifluoromenylphenyl group, anylyl group, naphthyl group and ferrocenyl group.

The perhalogenated hydrocarbyl group which can be represented by R ^1-2 independently includes a perhalogenated alkyl group and an aryl group, and a combination thereof such as an aralkyl group and an alkali group. Examples of perhalogenated alkyl groups which may be represented by R ^1-2 include -CF ₃ and -C ₂ F ₅ .

The heterocyclic group represented by R ^{1 -2} independently includes an aromatic saturated and partially unsaturated ring system, which may include a cycloalkyl ring, an aryl ring, or a heterocycle, or Two or more condensed rings may be formed. The heterocyclic group will have at least one heterocycle, wherein the largest ring typically contains 3 to 7 ring atoms, where at least one atom is carbon and at least one atom is N, O, S Or P. When either R ¹ or R ² represents or includes a heterocyclic group, the atom of R ¹ or R ² bonded to the C-heteroatom group is preferably a carbon atom. Examples of heterocyclic groups which may be represented by R ^1-2 include pyridyl, pyrimidyl, pyrrolyl, thiophenyl, furanyl, indolyl, quinolyl, isoquinolyl, imidazoyl and triazoyl groups do.

If any of R ^1-2 is a substituted hydrocarbyl or heterocyclyl group, the substituents should not adversely affect the rate or stereoselectivity of the reaction. Optional substituents include halogen, cyano, nitro, hydroxy, amino, thiol, acyl, hydrocarbyl, perhalogenated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydrocarbylamino groups , Hydrocarbylthio group, ester group, carbonate group, amide group, sulfonyl group, and sulfonamido group, wherein the hydrocarbyl group is as defined for R ¹ above. One or more substituents may be present.

When R ¹ and R ² are linked in such a way as to form a ring when taken together with the carbon atom and / or atom X of the compound of the formula (1), these are 5-membered rings, 6-membered rings or 7-membered rings, Is one or more cyclic heteroatoms, preferably O, S or N cyclic atoms. Examples of such compounds of formula (1) include 2-methylcyclohexanol.

In certain preferred embodiments, R ¹ and R ² are both different and are chosen to be different C _1-6 alkyl groups, both in particular when one is a phenyl group, or both are different aryl groups, or one is an aryl group, in particular a phenyl group and one is selected to be a C _{1 -6} alkyl group; Substituents may be present, especially when one or two of R ¹ and R ^{2 are} substituted phenyl groups, a substituent para may be present on the CX group.

Examples of the compound of formula (1) include 1-phenylethan-1-ol, 1- (2-naphthyl) ethan-1-ol, 1- (1-naphthyl) ethan-1-ol, 1-phenyl Ethane-1-thiol, 1-(-naphthyl) ethane-1-thiol, and 1- (1-naphthyl) ethane-1-thiol.

The catalyst system preferably comprises a transition metal catalyst and optionally a ligand.

Ligands that may be present in some circumstances include amines, alcohols and sulfides.

In the case of using a ligand, depending on the situation, the ligand and the transition metal catalyst may be premixed or precoordinated before reaction with the substrate. Examples of such pre-coordinated ligands and transition metal catalysts include the catalysts disclosed in International Patent Publications WO97 / 20789, WO98 / 42643, and WO02 / 44111, which are incorporated herein by reference.

Transition metal catalysts include transition metal halides, transition metal halide complexes and transition metal complex salts, where the transition metal is selectively synthesized by a displaceable ligand.

Substituted ligands include, for example, phosphines such as tri-hydrocarbyl phosphine such as Ph ₃ P, carbenes such as imidazole carbene, nitriles such as acetonitrile, carbon monoxide, triflate, alkenes and dienes. The transition metal of the transition metal complex salt is selectively synthesized by a substituted ligand, and the transition metal complex salt includes a complex salt of the formula M _n L _o X _p Y _r ,

here

M is a transition metal,

L is a substituted ligand,

X is a halide,

Y is a neutral optionally substituted hydrocarbyl complex, a neutral optionally substituted perhalogenated hydrocarbyl complex, or an optionally substituted cyclopentadienyl complex,

n is an integer,

o, p, and r are each zero or an integer, where o + p + r is an integer

Preferably, the transition metal catalyst is a transition metal halide or transition metal halide complex salt of the transition metal group of Group VIII of the periodic table.

More preferably, the transition metal catalyst is a transition metal halide complex salt of formula M _n X _p Y _r ,

here,

M is a transition metal,

X is a halide,

Y is a neutral optionally substituted hydrocarbyl complex, a neutral optionally substituted perhalogenated hydrocarbyl complex, or an optionally substituted cyclopentadienyl complex,

n, p and r are integers.

Although the transition metal catalyst is generally considered to be shown in the above formula, the transition metal catalyst may optionally exist as a dimer, trimer or other polymer type.

Metals that can be represented by M include those that can catalyze transfer hydrogenation. Preferred metals are transition metals, more preferably metals of group VIII of the periodic table (iron, cobalt, nickel, ruthenium, rhodium, palladium, osmium, iridium and platinum), more preferably ruthenium, rhodium or iridium, most preferably Contains iridium.

In general, the integers n, p, r are chosen such that the transition metal halide complex salt is a totally neutral species. Thus, the choice of n, p, r is directly related to the valence state of the metal and the number of halides present and the nature of the complex base Y. For example, if Y is a negatively charged cyclopentadienyl complex base, the number of negatively charged halides needed to balance the valence state of the metal will be less than if Y is a neutral hydrocarbyl complex base.

If the metal is ruthenium, it is preferably in valence II. If the metal is rhodium or iridium, it is preferably in valence I when Y is neutral optionally substituted hydrocarbyl or neutral optionally substituted perhalogenated hydrocarbyl ligand, preferably Y is optionally substituted Is a cyclopentadienyl ligand present in valence III. Particularly preferred metal is iridium.

Neutral optionally substituted hydrocarbyl or perhalogenated hydrocarbyl complex groups which may be represented by Y include optionally substituted aryl groups and alkenyl complex bases.

The optionally substituted aryl complex base represented by Y may have one ring or two or more condensed rings, which include a cycloalkyl ring, an aryl ring or a heterocyclic ring. Preferably, the complex base contains a 6-membered aromatic ring. Rings or rings of aryl complex bases are in most cases substituted with hydrocarbyl groups. Substitution patterns and the number of substituents will vary and can be affected by the number of rings present, but in most cases there are 1 to 6 substituents. The substituent includes a halogen group, cyano group, nitro group, hydroxy group, amino group, thiol group, acyl group, hydrocarbyl group, perhalogenated hydrocarbyl group, heterocyclyl group, hydrocarbyloxy group, mono or di-hydrocarbylamino group, hydrocar Bilthio groups, ester groups, carbonate groups, amide groups, sulfonyl groups and sulfonamido groups may be included, wherein the hydrocarbyl group is as defined for R ¹ above. In general, 1 to 6 substituents are each independently a hydrocarbyl group, preferably 2, 3 or 6 hydrocarbyl groups, more preferably 6 hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl, ethyl, isopropyl, menthyl, neomentyl and phenyl groups. Especially when the aryl complex base is monocyclic, the complex base is preferably benzene or substituted benzene. When the complex base is a perhalogenated hydrocarbyl, polyhalogenated benzene, such as hexachlorobenzene or hexafluorobenzene, is preferable. If the hydrocarbyl substituents have optically and / or diastereomeric centers, it is preferred to use their optically and / or diastereomericly purified forms. Benzene, p-similar, mesitylene and hexamethylbenzene are particularly preferred complex bases.

Optionally substituted alkenyl complex bases which may be represented by Y include C _2-30 , preferably C _6-12 , alkenes or cycloalkenes, preferably two or more carbon-carbon double bonds, preferably It has only two carbon-carbon double bonds. Carbon-carbon double bonds may be selectively conjugated with other unsaturated systems that may be present but are preferably conjugated to each other. Alkenes or cycloalkenes may preferably be substituted with hydrocarbyl substituents. If the alkenes have only one double bond, the optionally substituted alkenyl complex base may comprise two separate alkenes. Preferred hydrocarbyl substituents include methyl, ethyl, isopropyl and phenyl. Examples of optionally substituted alkenyl complex bases include cyclo-octa-1,5-diene and 2,5-norbornadiene. Cyclo-octa-1,5-dienes are particularly preferred.

The optionally substituted cyclopentadienyl complex base represented by Y includes a cyclopentadienyl group capable of eta-5 bonds. Cyclopentadienyl groups are in most cases substituted with 1 to 5 substituents. Examples of the substituent include a halogen group, cyano group, nitro group, hydroxy group, amino group, thiol group, acyl group, hydrocarbyl group, perhalogenated hydrocarbyl group, heterocyclyl group, hydrocarbyloxy group, mono or di-hydrocarbylamino group, hydro Carbylthio group, ester group, carbonate group, amide group, sulfonyl group and sulfonamido group may be included, wherein the hydrocarbyl group is as defined for R ¹ above. Preferably, the cyclopentadienyl group is substituted with 1 to 5 hydrocarbyl groups, more preferably 3 to 5 hydrocarbyl groups, most preferably 5 hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl, ethyl and phenyl. If the hydrocarbyl substituents have optically and / or diastereomeric centers, it may be advantageous to use their optically and / or diastereoally purified forms. Examples of the optionally substituted cyclopentadienyl complex base include a cyclopentadienyl group, a pentamethyl-cyclopentadienyl group, a pentalphenylcyclopentadienyl group, a tetraphenylcyclopentadienyl group, an ethyl tetramethylpentadienyl group, menthyl tetraphenyl Cyclopentadienyl group, neomentyl-tetraphenylcyclopentadienyl group, menthylcyclopentadienyl group, neomentylcyclopentadienyl group, tetrahydroindenyl group, menthyl tetrahydroindenyl group, and neomentyl tetrahydroindenyl group are contained. Pentamethylcyclopentadienyl group is particularly preferred.

Preferred are transition metal halide complex salts of formula M _n X _p Y _r wherein M is Rh or Ir and Y is an optionally substituted cyclopentadienyl group. Most preferred is a transition metal halide complex salt of formula M _n X _p Y _r wherein M is Ir and Y is an optionally substituted cyclopentadienyl group.

Examples of transition metal halide complex salts include Ru ₂ Cl ₄ (cymyl) ₂ , Rh ₂ Cl ₄ (Cp ^* ) ₂ , Rh ₂ Br ₄ (Cp ^* ) ₂ , Rh ₂ I ₄ (Cp ^* ) ₂ , Ir ₂ Cl ₄ (Cp ^* ) ₂ , Ru ₂ I ₄ (cymyl) ₂ , RhCl ₂ Cp ^* , RhBr ₂ Cp ^* , RhI ₂ Cp ^* , and Ir ₂ I ₄ (Cp ^* ) ₂ , where Cp ^* is penta It is a methylcyclopentadienyl group.

In certain preferred embodiments, the catalyst system is a composition which is preferably obtained by contacting a transition metal halide complex salt of formula M _n X _p Y _r with an alcohol or sulfide ligand of formula (1), wherein M is a transition metal, X Is a halide, Y is a neutral optionally substituted hydrocarbyl complex, a neutral optionally substituted perhalogenated hydrocarbyl complex, or an optionally substituted cyclopentadienyl complex, n, p and r are integers to be.

The catalyst system can be advantageously introduced at least in part in a solid support or as an encapsulated system. If a catalyst system is present on a solid carrier or as an encapsulation system, this supported catalyst system can help to carry out the separation operation that may be required, especially if repetition is expected between the steps of the material. Circulation can be facilitated. Examples of solid carrier or encapsulation techniques that can be used to support or encapsulate the catalyst system are described in WO03 / 006151 and WO05 / 016510.

Reaction accelerators that may be present in some circumstances include halogenated salts, for example metal halides. Preferred reaction promoters include bromide and in particular iodide salts. Potassium iodide and cesium iodide are very preferred.

Preferably, the process of the invention is carried out in the presence of a base. Examples of bases include potassium carbonate and sodium carbonate.

In another aspect of the present invention, corresponding ketones or thioketones of formula (2) derived by deprotonation of the starting alcohol or sulfide of formula (1) can be prepared.

here,

X represents O, S,

R ¹ , R ² each independently represent an optionally substituted hydrocarbyl group, a perhalogenated hydrocarbyl group, an optionally substituted heterocyclyl group, or

R ¹ and R ² are optionally linked to form an optionally substituted ring,

However, R ¹ and R ² are different from each other.

Hydrogen acceptors and / or hydrogen donors can be advantageously used if one wishes to inhibit or promote the preparation of the corresponding ketones or thioketones of formula (2) derived by the deprotonation of the starting alcohol or of sulfide of formula (1). .

Hydrogen acceptors that may be present in the process of the invention include protons, imines and iminium salts of acids, oxygen, aldehydes and ketones, easily hydrogenated hydrocarbons, dyes, clean oxidants, carbonates, bicarbonates and combinations thereof.

Both can come from convenient and compatible acids, such as formic acid, acetic acid, hydrogen carbonate, hydrogen sulfate, ammonium salt or alkyl ammonium salt. Conveniently both can be from the substrate itself.

Aldehydes and ketones which can be used as hydrogen acceptors usually contain from 1 to 20 carbon atoms, preferably from 2 to 15 carbon atoms, more preferably from 3 to 5 carbon atoms. Aldehydes and ketones include alkyl groups, aryl groups, heteroaryl aldehyde groups and ketone groups, and ketones mixed with alkyl groups, aryl groups and heteroaryl groups. Examples of aldehydes and ketones that can be represented as hydrogen acceptors include formaldehyde, acetone, methylethylketone and benzophenone. Acetone is particularly preferred when the hydrogen donor is an aldehyde or ketone.

Easily hydrogenated hydrocarbons that can be used as hydrogen acceptors include hydrocarbons that tend to accept hydrogen or hydrocarbons that tend to form reducing systems. Examples of readily hydrogenated hydrocarbons that can be used as hydrogen donors include quinones, dihydroarene and tetrahydroarene.

Clean oxidising agents, which can be represented as hydrogen acceptors, are oxidation reducing agents with high reduction potentials, in particular greater than about 0.1 eV, in most cases greater than about 0.5 eV, and preferably greater than about 1 eV. It includes having a potential. Examples of clean oxidants that can be represented as hydrogen acceptors include metal oxides and oxygen.

Dyes include Rose Bengal, Proflavin, Ethidium Bromide, Eosin and Phenolphthalein.

Carbonates and bicarbonates include carbonates and bicarbonates of alkali metals, alkaline earth metals, ammonium and quaternary amine salts.

Most preferred hydrogen acceptors are both acid, acetone, oxygen, substrate amines and carbonates and bicarbonates.

Hydrogen donors include hydrogen, primary and secondary alcohols, primary, secondary and tertiary amines, carboxylic acids and their esters and amine salts, easily dehydrogenated hydrocarbons, clean reducing agents, And combinations thereof.

Primary and secondary alcohols which can be used as hydrogen donors usually comprise 1 to 10 carbon atoms, preferably 2 to 7 carbon atoms, more preferably 3 or 4 carbon atoms. Examples of primary and secondary alcohols that can be represented as hydrogen donors include methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, butan-2-ol, cyclopentanol, cyclo Hexanol, benzyl alcohol, and menthol. If the hydrogen donor is an alcohol, secondary alcohols are preferred, especially propan-2-ol and butan-2-ol.

Primary, secondary and tertiary amines that can be used as hydrogen donors usually have 1 to 20 carbon atoms, preferably 2 to 14 carbon atoms, more preferably 3 or 8 carbon atoms. Include. Examples of primary, secondary and tertiary amines that may be represented as hydrogen donors include ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, hexylamine, diethylamine, dipropylamine, di Isopropylamine, dibutylamine, di-isobutylamine, dihexylamine, benzylamine, dibenzylamine, piperidine, (R) or (S) 6,7-dimethoxy-1-methyldihydroiso Quinoline, triethylamine. If the hydrogen donor is an amine, primary amines are preferred, especially primary amines comprising secondary alkyl groups, in particular isopropylamine and isobutylamine.

Carboxylic acids or esters or salts thereof which can be represented as hydrogen donors usually comprise 1 to 10 carbon atoms, preferably 1 to 3 carbon atoms. In some embodiments the carboxylic acid is advantageously beta-hydroxy-carboxylic acid. Esters may be derived from carboxylic acids and C _1-10 alcohols. Examples of carboxylic acids that can be represented as hydrogen donors include formic acid, lactic acid, ascorbic acid and mandelic acid. When using carboxylic acid as the hydrogen donor, at least part of the carboxylic acid is preferably present as a salt. Amine salts may be formed. The amines used to form such salts include aromatic amines and non-aromatic amines, and primary, secondary and tertiary amines, and generally comprise from 1 to 20 carbon atoms. Tertiary amines, in particular trialkylamines, are preferred. Examples of amines that can be used to form salts include trimethylamine, triethylamine, di-isopropylethylamine and pyridine. Most preferred amine is triethylamine. When at least a portion of the carboxylic acids are present as amine salts, in particular when using a mixture of formic acid and triethylamine, the molar ratio of acid to amine is usually about 5: 2. This ratio is maintained during the reaction by the addition of any component, but can usually be maintained by the addition of carboxylic acid. Other preferred salts include sodium, potassium and magnesium.

Easily dehydrogenated hydrocarbons that can be used as hydrogen donors include hydrocarbons that tend to aromatize or hydrocarbons that tend to form highly conjugated systems. Easily dehydrogenated hydrocarbons that can be used as hydrogen donors include cyclohexadiene, cyclohexene, tetralin, dihydrofuran and terpene.

Clean reducing agents that can be represented as hydrogen donors include high reducing potentials, particularly reducing agents having a reducing potential for standard hydrogen electrodes that are greater than about -0.1 eV, in most cases greater than about -0.5 eV, and preferably greater than about -1 eV. Include. Examples of clean reducing agents that can be represented as hydrogen donors include hydrazine and hydroxylamine.

Most preferred hydrogen donors are (R) or (S) 6,7-dimethoxy-1-methyldihydroisoquinoline, propan-2-ol, butan-2-ol, triethylammonium formate, sodium formate, potassium Formate and triethylammonium formate and formic acid.

Although gaseous hydrogen may be present, the method normally operates without gaseous hydrogen, because it is thought that gaseous hydrogen is not needed.

Inert gas sparging can generally be used.

Suitably the method is carried out at a temperature of -78 ° C to + 150 ° C, preferably -20 ° C to + 110 ° C, more preferably -10 ° C to + 40 ° C.

The initial concentration of the substrate, which is a compound of formula (1), is suitably in the range of 0.05 to 1.0 on a molar basis, and may be, for example, 6.0 or below, in particular 0.75 to 2.0, for larger scale convenient operation. The molar ratio of substrate to catalyst system is suitably at least 50: 1, preferably between 50000: 1, preferably between 250: 1 and 5000: 1, more preferably between 500: 1 and 2500: 1.

If present, the promoter is preferably used at a molar concentration higher than the substrate, in particular 1 to 5 times, or up to 20 times, if desired.

If a hydrogen donor and / or acceptor is present, the hydrogen donor and / or acceptor is preferably used at a molar concentration above the substrate, in particular 5 to 20 times, or up to 500 times, for example.

The reaction time is generally in the range of 1.0 minute to 24 hours, in particular 8 hours or less, conveniently about 3 hours. After the reaction, the mixture is worked up by standard procedures.

Substrate alcohols or sulfides may be present when the reaction solvent, for example dimethylformamide, acetonitrile, tetrahydrofuran, toluene, chloroform, dichloromethane, or conveniently the substrate alcohol or sulfide is liquid at the reaction temperature. Although it is usually preferable to operate in the substantially absence of water, it is not considered that water unreasonably interferes with the reaction. If the substrate amine or the reaction solvent are not miscible with water and the desired product is water soluble, it may be desirable for water to be present as the second phase. The concentration of the substrate can be selected to optimize the reaction time, yield and deconcentration of the enantiomeric excess.

According to another aspect of the invention, an optically condensed enrichment comprising at least a first optical isomer or diastereomer of a substrate comprising a carbon-heteroatom bond (carbon is chiral centered and heteroatoms are Group VI heteroatoms). A composition is provided comprising a ketone or thioketone of formula (2) obtained by reacting a composition in the presence of a catalyst system, optionally wherein the promoter is contacted with a transfer hydrogenation catalyst and a hydrogen donor to form a substrate having a carbon-heteroatom bond Providing a product composition comprising the first and second optical isomers or diastereomers, wherein the ratio of the second optical isomer or diastereomer to the first optical isomer or diastereomer in the resulting composition is in the optically concentrated composition Ratio of the second optical isomer or diastereomer to the first optical isomer or diastereomer of Greater than

The hydrogen donor is as defined above.

Reduction of the compound of formula 2 is preferably accomplished using a stereoselective reduction system. Stereoselective reduction is most preferably using a chiral tuned transition metal catalyzed transfer hydrogenation process. Such processes, and catalysts, reagents and conditions used herein, include those disclosed in WO97 / 20789, WO98 / 42643, and WO02 / 44111, which are incorporated herein by reference. Preferred transfer hydrogenation catalysts used in the process of the invention have the general formula (a).

here,

R ³ represents neutral optionally substituted hydrocarbyl, neutral optionally substituted perhalogenated hydrocarbyl, or optionally substituted cyclopentadienyl ligand,

A represents optionally substituted nitrogen,

B represents optionally substituted nitrogen, oxygen, sulfur or phosphorus,

E represents a linking group,

M represents a metal capable of catalyzing transfer hydrogenation,

Y represents an anionic group, base ligand or vacant site

Provided that at least one of A or B contains a substituted nitrogen, the substituent has at least one chiral center,

Provided that at least one of A or B has a hydrogen atom when Y is not a blank.

Particularly preferred transfer hydrogenation catalysts are Ru, Rh or Ir catalysts of the type described in WO97 / 20789, WO98 / 42643 and WO02 / 44111, which include optionally substituted diamine ligands, for example optionally substituted ethylene diamine ligands. Wherein at least one nitrogen atom of the optionally substituted diamine ligand is preferably a group having a chiral center, and a neutral aromatic ligand such as p-cymene, or optionally substituted cyclopentadiene ligand, eg For example, it is substituted with pentamethylcyclopentadiene.

A very preferred transfer hydrogenation catalyst for use in the process of the invention consists of general formula (A).

Wherein R ³ represents neutral optionally substituted hydrocarbyl, neutral optionally substituted perhalogenated hydrocarbyl, or optionally substituted cyclopentadienyl ligand,

A represents -NR ^4- , -NR ^5- , -NHR ⁴ , -NR ⁴ R ⁵ or -NR ⁴ R ⁵ , where R ⁴ is H, C (O) R ⁶ , SO ₂ R ⁶ , C ( O) NR ⁶ R ¹⁰ , C (S) NR ⁶ R ¹⁰ , C (= NR ¹⁰ ) SR ¹¹ or C (= NR ¹⁰ ) OR ¹¹ , R ⁵ and R ⁶ are each optionally substituted hydrocarbyl, fur Independently represent a halogenated hydrocarbyl or optionally substituted heterocyclyl group, and R ¹⁰ and R ¹¹ are each independently a group or hydrogen as defined for R ⁶ .

B is -O-, -OH, OR ⁷ , -S-, -SH, SR ⁷ , -NR ⁷ -,-NR ^8- , -NHR ⁸ , -NR ⁷ R ⁸ , -NR ⁷ R ⁹ , -PR ⁷ -or -PR ⁷ R ⁹ , wherein R ⁸ is H, C (O) R ⁹ , SO ₂ R ⁹ , C (O) NR ⁹ R ¹² , C (S) NR ⁹ R ¹² , C (= NR ¹² ) SR ¹³ or C (= NR ¹² ) OR ¹³ , and R ⁷ and R ⁸ each independently represent an optionally substituted hydrocarbyl, perhalogenated hydrocarbyl or optionally substituted heterocyclyl group, and R ¹² and Each R ¹³ is independently hydrogen or a group as defined for R ⁹ ,

E represents a linking group,

M represents a metal capable of catalyzing transfer hydrogenation,

Y represents an anionic group, a base ligand or a free site

Provided that at least one of A or B has a hydrogen atom when Y is not a void.

Very preferred are the transfer hydrogenation catalysts of formula (A), wherein at least one of A or B comprises substituted nitrogen and the substituent has at least one chiral center.

This catalytic species is considered to be substantially the same as shown in the above formula. It may be introduced on a solid carrier.

The optionally substituted hydrocarbyl group represented by R ^5-7 or R ^9-11 includes alkyl groups, alkenyl groups, alkynyl groups and aryl groups, and combinations thereof such as aralkyl and alkaryl, such as benzyl groups. .

Alkyl groups represented by R ^5-7 or R ^9-11 include linear and branched groups containing 1 to 20 carbon atoms, in particular 1 to 7 carbon atoms, preferably 1 to 5 carbon atoms. Alkyl groups are included. In some embodiments, an alkyl group may be cyclic, typically containing 3 to 10 carbon atoms in the largest ring and, in some circumstances, characterized by one or more bridging rings. Examples of the alkyl group which may be represented by R ^5-7 or R ^9-11 include a methyl group, ethyl group, propyl group, 2-propyl group, butyl group, 2-butyl group, t-butyl group and cyclohexyl group.

Alkenyl groups which may be represented by R ^5-7 or R ^9-11 include C _2-20 , preferably C _2-6 alkenyl groups. One or more carbon-carbon double bonds may be present. Alkenyl groups may bear one or more substituents, especially phenyl substituents.

Alkynyl groups which may be represented by one or more of R ^5-7 or R ^9-11 include an alkynyl group of C _2-20 , preferably C _2-10 . One or more carbon-carbon triple bonds may be present. Alkynyl groups may have one or more substituents, especially phenyl substituents. Examples of alkynyl groups include ethynyl, propyl and phenylethynyl groups.

An aryl group which may be represented by one or more of R ^5-7 or R ^9-11 may have one ring or two or more condensed rings or a proximate exchange, which may include a cycloalkyl ring, an aryl ring or a heterocycle. have. Examples of R ^{5 -7,} or aryl which may be represented by R ^9-11 groups include phenyl group as a phenyl group, a chlorophenyl group, a bromo group, a trifluoromethyl group, a tolyl group, a fluoro, no group, naphthyl and ferrocenyl groups do.

Perhalogenated hydrocarbyl groups which can be represented by R ^5-7 or R ^9-11 include perhalogenated alkyl groups and aryl groups, and combinations thereof such as aralkyl groups and alkaryl groups. R ⁵ flops Examples of the halogenated alkyl group which may be represented by R ^{9 -7} or ^-11 include the -CF ₃ and -C ₂ F _5.

The heterocyclic group represented by R ^5-7 or R ^9-11 independently includes an aromatic saturated and partially unsaturated ring system, and includes one or two or more rings which may include a cycloalkyl ring, an aryl ring or a heterocycle. It may include a condensed ring. The heterocyclic group will have at least one heterocycle, wherein the maximum ring typically contains 3 to 7 ring atoms, where one atom is carbon and at least one atom is any of N, O, S or P . Examples of the heterocyclic group represented by R ^5-7 or R ^9-11 include pyridyl group, pyrimidyl group, pyrrolyl group, thiophenyl group, furanyl group, indolyl group, quinolyl group, isoquinolyl group, imidazolyl group and Triazolyl groups are included.

If either R ^5-7 or R ^9-11 is a substituted hydrocarbyl group or heterocyclyl group, the substituents should not adversely affect the rate or stereoselectivity of the reaction. Optional substituents include halogen, cyano, nitro, hydroxy, amino, imino, thiol, acyl, hydrocarbyl, perhalogenated hydrocarbyl, heterocyclyl, hydrocarbyloxy, mono or di-hydro there is included a hydrocarbyl amino group, a dihydro-car bilti come, an ester group, a carboxyl group, a carbonate group, an amide group, a sulfonyl group, an amido group and a sulfonamide, where dihydro car pray is as defined with respect to the R ⁵ or R ^{9 -7 -11} same. One or more substituents may be present. R ^5-7 or R ^9-11 may each have one or more chiral centers.

Neutral optionally substituted hydrocarbyl or perhalogenated hydrocarbyl ligands, which may be represented by R ³ , include optionally substituted aryl and alkenyl ligands.

The optionally substituted aryl ligand which may be represented by R ³ may have one ring or two or more condensed rings including a cycloalkyl ring, an aryl ring or a heterocyclyl ring. Preferably, the ligand contains a 6 membered aromatic ring. Rings or rings of aryl ligands are in most cases substituted with hydrocarbyl groups. The substitution pattern and number of substituents may vary and be affected by the number of rings present, but in most cases 1 to 6 hydrocarbyl substituents, preferably 2, 3 or 6 hydrocarbyl groups, more preferably There are 6 hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl, ethyl, isopropyl, menthyl, neomentyl and phenyl. Especially when the aryl ligand is a single ring, the ligand is preferably benzene or substituted benzene. When the ligand is a perhalogenated hydrocarbyl, it is preferably a polyhalogenated benzene such as hexachlorobenzene or hexafluorobenzene. If the hydrocarbyl substituents have optically and / or diastereomeric centers, it is preferred to use their optically and / or diastereoally purified forms. Benzene, p-similar, mesitylene and hexamethylbenzene are particularly preferred ligands.

The optionally substituted alkenyl ligand which may be represented by R ³ preferably is C _2-30 , preferably C ₆ having at least two carbon-carbon double bonds, preferably only two carbon-carbon double bonds. _-12 is included. The carbon-carbon double bonds can be conjugated depending on the situation and other unsaturated systems that may be present, but are preferably conjugated to each other. Alkenes or cycloalkenes may preferably be substituted with hydrocarbyl substituents. If the alkenes have only one double bond, the optionally substituted alkenyl ligand may comprise two separate alkenes. Preferred hydrocarbyl substituents include methyl, ethyl, iso-propyl and phenyl. Examples of optionally substituted alkenyl ligands include cyclo-octa-1,5-diem and 2,5-norbornadiene. Cyclo-octa-1,5-dienes are particularly preferred.

The optionally substituted cyclopentadienyl group represented by R ³ includes a cyclopentadienyl group capable of an eta-5 bond. Cyclopentadienyl groups are in most cases substituted with 1 to 5 hydrocarbyl groups, preferably 3 to 5 hydrocarbyl groups, more preferably 5 hydrocarbyl groups. Preferred hydrocarbyl substituents include methyl, ethyl and phenyl. If the hydrocarbyl substituents have optically and / or diastereocentric centers, it is preferred to use their optically and / or diastereoly purified forms. Examples of the optionally substituted cyclopentadienyl group include cyclopentadienyl group, pentamethylcyclopentadienyl group, pentaphenylcyclopentadienyl group, tetraphenylcyclopentadienyl group, ethyltetramethylpentadienyl group, menthyltetraphenylcyclopentadiene And a methyl group, neomentyl tetraphenylcyclopentadienyl group, menthylcyclopentadienyl group, neomentylcyclopentadienyl group, tetrahydroindenyl group, menthyltetrahydroindenyl group and neomentyltetrahydroindenyl group. Pentamethylcyclopentadienyl is particularly preferred.

When A or B is an amide group represented by -NR ^4- , -NHR ⁴ , NR ⁴ R ⁵ , -NR ^8- , -NHR ⁸ or NR ⁷ R ⁸ (R ⁵ and R ⁷ are as defined above and R ⁴ or R ⁸ is an acyl group represented by -C (O) R ⁶ or -C (O) R ⁹ ), R ⁶ and R ⁹ are independently in most cases linear or branched C _1-7 alkyl, C _1-8 cycloalkyl or aryl, for example phenyl. Examples of the acyl group which may be represented by R ⁶ or R ¹⁰ include benzoyl group, acetyl group and halogen noacetyl group, especially trifluoroacetyl group.

When A or B is present as a sulfonamide group represented by -NR ^4- , -NHR ⁴ , NR ⁴ R ⁴ , -NR ^8- , -NHR ⁸ or NR ⁷ R ⁸ , wherein R ⁵ and R ⁷ are As defined and R ⁴ or R ⁸ is a sulfonyl group represented by -S (O) ₂ R ⁶ or -S (O) ₂ R ⁹ ), R ⁶ and R ⁹ are independently in most cases linear or branched C _1-12 alkyl, C _1-12 cycloalkyl or aryl, for example phenyl. Preferred sulfonyl groups include methanesulfonyl groups, trifluoromethanesulfonyl groups, more preferably p-toluenesulfonyl groups and naphthylsulfonyl groups, especially camphorsulfonyl groups.

When A or B is present as a group represented by -NR ^4- , -NHR ⁴ , NR ⁴ R ⁵ , -NR ^8- , -NHR ⁸ or NR ⁷ R ⁸ , wherein R ⁵ and R ⁷ are defined as R ⁴ or R ⁸ is C (O) NR ⁶ R ¹⁰ , C (S) NR ⁶ R ¹⁰ , C (= NR ¹⁰ ) SR ¹¹ , C (= NR ¹⁰ ) OR ¹¹ , C (O) NR ⁹ R ¹² , C (S) NR ⁹ R ¹² , C (= NR ¹² ) SR ¹³ or C (= NR ¹² ) OR ¹³ ), R ⁶ and R ⁹ are independently in most cases linear or minutes of methyl branched, ethyl, isopropyl, C _1-8 cycloalkyl C _1, such as alkyl or _aryl-alkyl, and _8, for example, a phenyl group, R ¹⁰ is ^-13 in most cases each independently hydrogen, or methyl, ethyl, iso propyl, C _{1 -} C _{8 1} a linear or branched, such as cycloalkyl or _aryl-8 alkyl, for example phenyl groups.

When B is present as a group represented by -OR ⁷ , -SR ⁷ , -PR ⁷ -or -PR ⁷ R ⁹ , R ⁷ and R ⁹ are independently in most cases methyl, ethyl, isopropyl, C _1- Linear or branched C _1-8 alkyl such as ₈ cycloalkyl or aryl, for example phenyl.

It will be appreciated that the exact nature of A and B depends on whether A and / or B formally binds to the metal or coordinates to the metal via a pair of electrons.

The A and B groups are connected by the connector E. The linker E obtains the proper conformation of A and B to allow A and B to bind or coordinate to the metal M. A and B are usually connected via two, three or four atoms. Atoms at E connecting A and B may have one or more substituents. The atoms alpha at E, in particular to A or B, can be linked to A and B in such a way as to form a heterocyclic ring, preferably saturated and preferably a 5-, 6- or 7-membered ring. have. In most cases the atoms connecting A and B can be carbon atoms. Preferably, at least one of the carbon atoms connecting A and B will have a substituent in addition to A or B. Substituents include those capable of substituting R ^5-7 or R ^9-11 as defined above. Advantageously, any substituent that is a group that does not coordinate with the metal M can be selected. Preferred substituents include halogen, cyano, nitro, sulfonyl, hydrocarbyl, perhalogenated hydrocarbyl and heterocycle groups as described above. Most preferred substituents are C _1-6 alkyl groups and phenyl groups. Most preferably, A and B are linked by two carbon atoms, in particular optionally substituted ethyl moieties. When A and B are linked by two carbon atoms, the two carbon atoms linking A and B may comprise an aromatic or aliphatic cyclic group, in particular part of a 5-, 6- or 7-membered ring. have. Such rings may be fused to one or more other rings of the same kind. Particularly preferred are cyclopentane rings or cyclo in which E represents a two-carbon atom separation and one or two of the carbon atoms have an optionally substituted aryl group as described above, or E is fused to a phenyl ring depending on the circumstances. It is an Example showing 2 carbon atom separation containing a hexane ring.

E preferably comprises a portion of a compound having at least one stereospecific center. At least one of the stereospecific centers when any or all of the two, three or four atoms connecting A and B are substituted to form at least one stereospecific center at one or more of these atoms It is preferable that one is located at an atom adjacent to the A group or the B group. When at least one such stereospecific center is present, it is advantageously present in an optically purified state.

When B represents -O- or -OH and the adjacent atoms in E are carbon, it is preferable that B does not form part of the carboxyl group.

Compounds which may be represented by AEB or which may provide AEB by deprotonation are in most cases 4-aminoalkan-1-ol, 1-aminoalkan-4-ol, 3-aminoalkan-1-ol, 1- Aminoalkan-3-ols, and in particular 2-aminoalkan-1-ols, 1-aminoalkan-2-ols, 3-aminoalkan-2-ols and 2-aminoalkan-3-ols, and especially 2-amino Aminoalcohols such as ethanol or 3-aminopropanol or amines such as 1,4-diaminoalkanes, 1,3-diaminoalkanes, in particular 1,2- or 2,3-diaminoalkanes and especially ethylenediamine . Further aminoalcohols which can be represented by AEB are preferably 2-aminocyclopentanol and 2-aminocyclohexanol fused to a phenyl ring. Another diamine that can be represented by AEB is preferably 1,2-diaminocyclopentane and 1,2-diaminocyclohexane fused to a phenyl ring. Amino groups can advantageously be N-tosylated. When the diamine is represented by AEB, preferably at least one amino group may be N-tosylated. Aminoalcohols or diamines are advantageously C _{1 -} is substituted on the particular linking group E by at least one alkyl group, and specifically a methyl group or at least one aryl group, particularly phenyl group such as _4-alkyl.

Specific examples of the compound represented by A-E-B and the protonated equivalents from which they are derived are as follows.

Preferably, their optically and / or diastereomericly purified forms are used. Examples include (1S, 2R)-(+)-norephedrine, (1R, 2S)-(+)-cis-1-amino-2-indanol, (1S, 2R) -2-amino-1,2- Diphenylethanol, (1S, 2R)-(-)-cis-1-amino-2-indanol, (1R, 2S)-(-)-norephedrine, (S)-(+)-2-amino- 1-phenylethanol, (1R, 2S) -2-amino-1,2-diphenylethanol, N-tosyl- (1R, 2R) -1,2-diphenylethylenediamine, N-tosyl- (1S, 2S ) -1,2-diphenylethylenediamine, (1R, 2S) -cis-1,2-indandiamine, (1S, 2R) -cis-1,2-indandiamine, (R)-(-)-2 -Pyrrolidinemethanol and (S)-(+)-2-pyrrolidinemethanol.

Metals that can be represented by M include metals capable of catalyzing transfer hydrogenation. Preferred metals include transition metals, more preferably metals of group VIII of the periodic table, in particular ruthenium, rhodium or iridium. If the metal is ruthenium, it is preferably present in valence II. When the metal is rhodium or iridium, when R ³ is a neutral optionally substituted hydrocarbyl or a neutral optionally substituted perhalogenated hydrocarbyl ligand, it is preferably present in valence state I, and R ³ is optionally substituted When it is a cyclopentadienyl ligand, it is preferable to exist in valence III.

It is preferred that M, ie the metal, is rhodium in valence III and R ³ is an optionally substituted cyclopentadienyl ligand.

Anionic groups which may be represented by Y include hydride groups, hydroxyl groups, hydrocarbyloxy groups, hydrocarbylamino groups and halogen groups. Preferably, when halogen is represented by Y, halogen is chloride. If a hydrocarbyloxy group or hydrocarbylamino group is represented by Y, this group may be derived by deprotonation of the hydrogen donor used in this reaction.

Roneun basic ligand (basic ligand) which may be represented by Y of water, C _{1 -} include a hydrogen-donor present in the ₄ alcohols, C _{1 -8 1} amine or a secondary amine, or the reaction system. Preferred basic ligands represented by Y are water.

Most preferably, AEB, R ³ and Y are chosen such that the catalyst is chiral. In this case, it is preferred to use optically and / or diastereoscopically purified forms. These catalysts are most advantageously used in asymmetric transfer hydrogenation processes. In many embodiments, the chirality of the catalyst is derived from the nature of the AEB.

Especially preferred are catalysts of formula B (i-iv)

The transfer hydrogenation catalyst comprises a ligand, preferably a chiral bidentate nitrogen ligand, with a metal complex, for example, a neutral optionally substituted hydrocarbyl complex group, a neutral optionally substituted perhalogenated hydrocarbyl complex. Groups, or optionally substituted cyclopentadienyl complex bases, can be combined to prepare in advance or in-situ. Preferably the solvent is present in this operation. The solvent used may be anything that does not adversely affect the formation of the catalyst. These solvents include acetonitrile, ethyl acetate, toluene, methanol, tetrahydrofuran and ethylmethyl ketone. Preferably this solvent is methanol.

Advantageously, the process of the present invention can be applied for the regeneration of unwanted isomers obtained in chiral processes such as chiral separation, chemical and enzymatic chiral splitting. In general, in chiral separation or chiral separation, the racemic mixture is subjected to physical, chemical or biochemical treatment to separate the desired optical isomers or optical isomers, while in most cases leaving unreacted or unwanted optical isomers or optical isomer by-products. do. The method of the present invention provides a method for converting unreacted optical isomers into usable feedstocks having the desired optical isomers.

The invention is illustrated by the following examples.

Example  One

step

Reaction 1: Standard condition + 0.5eq 2,4-dimethyl-3-pentanol

(S) -1-phenylethanol (246.8 mg 99%, 244.3 mg, 2.0 mmol), pentamethylcyclopentadienyliridium (III) chloride dimer (16.6 mg 96%, 15.9 mg, 0.02 mmol) in a 10 ml round bottom flask ), Tridecane (372.4 mg 99%, 368.7 mg, 2.0 mmol), calcium iodide (335.4 mg 99%, 332.0 mg, 2.0 mmol), 2,4-dimethyl-3-pentanol (117.4 mg 99%, 116.2 mg, 1.0 mmol), potassium carbonate (279.2 mg 99%, 276.4 mg, 2.0 mmol) and toluene (4 ml) were added to form a pale orange solution. A water condeser was attached and the reaction vessel was placed in an oil bath at 80 ° C and the timer started. Within 1 minute in the oil bath, the reaction solution became dark orange and gradually darkened. After 2 hours the color became dark brown and the color continued to be maintained. Samples were taken at regular intervals (˜100 μl), quenched in dichloromethane (2 ml) and 0.5 M sodium hydroxide solution (2 ml), the organic layer was separated, dried over sodium sulfate and filtered to give achiral gas chromatography and chiral Analysis by gas chromatography.

Reaction 2: Standard condition + 1.0eq 2,4-dimethyl-3-pentanol

(S) -1-phenylethanol (246.8 mg 99%, 244.3 mg, 2.0 mmol), pentamethylcyclopentadienyliridium (III) chloride dimer (16.6 mg 96%, 15.9 mg, 0.02 mmol) in a 10 ml round bottom flask ), Tridecane (372.4 mg 99%, 368.7 mg, 2.0 mmol), potassium iodide (335.4 mg 99%, 332.0 mg, 2.0 mmol), 2,4-dimethyl-3-pentanol (234.7 mg 99%, 232.4 mg) , 2.0 mmol), potassium carbonate (279.2 mg 99%, 276.4 mg, 2.0 mmol) and toluene (4 ml) were added to form a pale orange solution. A water condenser was attached and the reaction vessel was placed in an oil bath at 80 ° C. The timer was started. Within 1 minute, the reaction solution became dark orange and gradually darkened, becoming dark brown after 2 hours. Maintained. Samples were taken at regular intervals (˜100 μl), immersed in dichloromethane (2 ml) and 0.5 M sodium hydroxide solution (2 ml), the organic layer was separated, dried over sodium sulfate, filtered and subjected to achiral gas chromatography and chiral gas chromatography. Analyzed.

analysis

Achiral Gas Chromatography

Chrompac 7680 CP SIL 5CB column, length = 25.0 m, diameter 320 μm, film thickness = 5.0 μm

Pressure = 8.0psi

Flow rate = 1.1 ml / min

Ramp = 20 ° C./min for 22.5 minutes at 250 ° C. and up to 300 ° C.

1-phenylethanol = 13.1 minutes

Acetophenone = 13.7 minutes

Tridecane = 27.5 minutes

2,4-dimethyl-3-pentanol = 5.7 min

Chiral Gas Chromatography

CP-Chirasil-Dex-CB column, length = 25.0 m, diameter = 250 μm, film thickness = 0.25 μm

Pressure = 10.0psi

Flow rate = 0.7 ml / min

Temperature = held at 110 ° C. for 40 minutes and at 190 ° C. at a rate of 20 ° C./min and for 5 minutes

(R) -1-phenylethanol = 23.7 min

(S) -1-phenylethanol = 26.0 min

Acetophenone = 10.0 minutes

Tridecane = 21.0 minutes

2,4-dimethyl-3-pentanol = 4.6 min

In toluene at 80 ° C [ IrCp ^* Cl ₂ ] ₂ Of KI  + 1 eq K ₂ CO ₃ 1- using Phenylethanol  Race

Reaction 1 + 0.5 eq  2,4- Dimethylpentane -3-ol

time Area alcohol Area of ketone Area Tridecane Standard % Alcohol % Ketone % Standard (R) area (S) area % ee 0 100 0 0 100.0 0.0 0.0 0 100 100.0 10 1163.67 23.761 2237.92 98.0 2.0 65.3 1.298 391.097 99.3 30 1019.62 24.127 2014.6 97.7 2.3 65.9 1.124 343.047 99.3 60 944.357 31.175 1832.72 96.8 3.2 65.3 2.436 317.466 98.5 120 1028.81 93.275 2110.7 91.7 8.3 65.3 24.911 296.958 84.5 185 957.324 239.739 2282.01 80.0 20.0 65.6 47.163 233.936 66.4 240 733.704 298.108 1955.44 71.1 28.9 65.5 49.046 171.742 55.6 305 518.397 353.609 1641.57 59.4 40.6 65.3 49.494 117.522 40.7 365 586.707 663.707 2378.319 46.9 53.1 65.5 64.354 111.557 26.8 425 465.977 771.361 2361.16 37.7 62.3 65.6 70.318 98.47 16.7 1440 371.226 928.745 2467.85 28.6 71.4 65.5 49.098 60.26 10.2

Reaction 2 + 1.0 eq  2,4- Dimethylpentane -3-ol

time Area alcohol Area of ketone Area Tridecane Standard % Alcohol % Ketone % Standard (R) area (S) area % ee 0 100 0 0 100.0 0.0 0.0 0 100 100.0 10 1149.75 24.886 2200.81 97.9 2.1 65.2 1.641 421.902 99.2 30 926.296 23.157 1812.66 97.6 2.4 65.6 1.351 312.695 99.1 60 892.692 28.24 1727.72 96.9 3.1 65.2 1.986 347.031 98.9 120 1030.14 93.317 2110.7 91.7 8.3 65.3 24.279 296.685 84.9 185 952.602 182.593 2156.04 83.9 16.1 65.5 60.163 279.616 64.6 240 739.385 243.95 1888.64 75.2 24.8 65.8 56.662 180.176 52.2 305 397.693 223.874 1197.56 64.0 36.0 65.8 35.522 85.438 41.3 365 371.698 321.486 1326.93 53.6 46.4 65.7 44.073 79.6 28.7 425 404.798 551.429 1834.782 42.3 57.7 65.7 60.164 82.946 15.9 1440 317.004 898.786 2365.34 26.1 73.9 66.1 47.624 53.189 5.5

Example  2

step

Reaction 2: + Potassium Carbonate

(S) -1-phenylethanol (246.8 mg 99%, 244.3 mg, 2.0 mmol), pentamethylcyclopentadienyliridium (III) chloride dimer (16.6 mg 96%, 15.9 mg, 0.02 mmol) in a 10 ml round bottom flask ), Tridecane (372.4 mg 99%, 368.7 mg, 2.0 mmol), potassium iodide (335.4 mg 99%, 332.0 mg, 2.0 mmol), potassium carbonate (279.2 mg 99%, 276.4 mg, 2.0 mmol) and toluene (4 ml) ) Was added to give a pale orange solution. A water condenser was attached and the reaction vessel was placed in an oil bath at 80 ° C. The timer was started. Within 1 minute, the reaction solution became dark orange and gradually darkened, becoming dark brown after 2 hours. Maintained. Samples were taken at regular intervals (˜100 μl), immersed in dichloromethane (2 ml) and 0.5 M sodium hydroxide solution (2 ml), the organic layer was separated, dried over sodium sulfate and filtered to give achiral gas chromatography and chiral gas chromatography. Analyzed.

analysis

Achiral Gas Chromatography

Chrompac 7680 CP SIL 5CB column, length = 25.0 m, diameter 320 μm, film thickness = 5.0 μm

Pressure = 8.0psi

Flow rate = 1.1 ml / min

Temperature = 20 ° C / min rate at 250 ° C for 22.5 minutes and up to 300 ° C

1-phenylethanol = 13.1 minutes

Acetophenone = 13.7 minutes

Tridecane = 27.5 minutes

Chiral Gas Chromatography

CP-Chirasil-Dex-CB column, length = 25.0 m, diameter = 250 μm, film thickness = 0.25 μm

Pressure = 10.0psi

Flow rate = 0.7 ml / min

Temperature = held at 110 ° C. for 40 minutes and at 190 ° C. at a rate of 20 ° C./min and for 5 minutes

(R) -1-phenylethanol = 23.7 min

(S) -1-phenylethanol = 26.0 min

Acetophenone = 10.0 minutes

Tridecane = 21.0 minutes

Reaction 2 Normal + 1 eq K ₂ CO ₃

time Area alcohol Area of ketone Area Tridecane Standard % Alcohol % Ketone % Standard (R) area (S) area % ee 0 100 0 0 100.0 0.0 0.0 0.000 324.281 100.0 12 1385.06 48.979 2681.29 96.6 3.4 65.2 2.096 396.069 98.9 30 1076.38 42.302 2104.06 96.2 3.8 65.3 1.662 334.271 99.0 60 1505.995 76.598 2992.3 95.2 4.8 65.4 3.767 393.765 98.1 122 1052.644 102.146 2206.188 91.2 8.8 65.6 13.431 199.745 87.4 180 1002.368 142.23 2156 87.6 12.4 65.3 68.342 366.146 68.5 240 1032.22 273.729 2434.783 79.0 21.0 65.1 77.619 243.057 51.6 300 918.881 409.19 2521.09 69.2 30.8 65.5 82.965 189.190 39.0 375 479.918 471.136 1804.79 50.5 49.5 65.5 55.711 95.038 26.1 1380 0 1178.13 2215.49 0.0 100.0 65.3 0

Example  3

Preparation of Catalyst and Reduction of Acetophenone

Reactant Weight Molar weight Molar ratio [Rh (Cp ^* ) Cl ₂ ] ₂ ^** 0.0254 g 618.08 1.0 41.2μmol (1S, 2R)-(+)-norephedrine 0.0209 g 151.21 3.36 138.2 μmol 2-propanol (anhydrous) 100 ml 60.10 31677 1.305mol KOH 0.1M in 2-propanol 3.3ml 56.11 4.01 0.33 mmol Acetophenone 2.06g 120.15 209 17mmol

Note: ** Purchased from STREM Chemicals

The solvent was degassed before the reaction:

100 ml of unhydros 2-propanol was added by syringe to a sealed, clean dried round bottom flask and degassed at 20 ° C. for 30 minutes in vacuum.

(a) preparation of catalyst

The (+)-norephedrine and rhodium compounds were weighed and placed in a clean dry Schlenk flask. The flask was closed with 'Suba-seal' (RTM). After the contents were emptied, the mixture was purged by exchanging nitrogen 15 times at room temperature. Then, 2-propanol (20 ml) was added by cannula. The tab of the flask was closed and swirled until the starting solid dissolved. The result is an orange supernatant and a dark solid. The flask tab was opened again, the nitrogen stream was introduced and the flask contents were heated at 60 ° C. for 2 hours 5 minutes. The catalyst was checked at 30 minute intervals. At each interval the catalyst was a dark brown solution with a black solid at the bottom.

(b) hydrogenation

Acetophenone was dissolved in 2-propanol (80 ml) and degassed for 40 minutes. This solution was added to the catalyst flask by cannula and then 0.1 M solution of KOH in degassed 2-propanol was added by syringe. The mixture was left at room temperature, samples were taken at regular intervals and examined by gas chromatography. In this small scale operation, the reaction mixture was not sparged with nitrogen, but sparging would be used in large scale production. After 1 hour, (R) -1-phenylethanol was obtained at a conversion rate of 92% and an optical isomer excess of 84%.

Example  4

Reactant Weight Molar weight Molar ratio [Rh (Cp ^* ) Cl ₂ ] ₂ 6.3 mg 618.08 1.0 10.2μmol (1S, 2R)-(-)-cis-1-amino-2-indanol 3.1mg 149.19 2.0 20.8μmol Acetophenone 1.29 g 120.15 1039 10.6mmol 2-propanol 63857

(a) preparation of catalyst

The rhodium compound was suspended in 50 ml of 2-propanol and degassed in three cycles of vacuum and nitrogen flush. The mixture was heated to gentle reflux until the solids dissolved and then cooled to room temperature. (1S, 2R)-(-)-cis-1-amino-2-indanol was added to this solution while stirring. The mixture was degassed with a cycle of vacuum and nitrogen flush and warmed at 30 ° C. for 30 minutes. The orange red solution of the resulting catalyst was transferred to the next step but could be stored under argon or nitrogen.

(b) hydrogenation

Acetophenone was added to the catalyst solution. The mixture was stirred at rt for 1 h. Sodium 2-propoxide (0.25 ml of a 0.1 M solution in fresh 2-propanol) was added. The mixture was sampled by stirring for 2 hours, ie 57% of acetophenone was reacted to give (R) -1-phenylethanol with 79% optical isomer excess.

Example  5

Reactant Weight Molar weight Molar ratio [Ir (Cp ^* ) Cl ₂ ] ₂ 32.8mg 796.67 1.0 41.2μmol (1S, 2R)-(+)-norephedrine 20mg 151.21 3.2 132μmol Acetophenone 2ml 120.15 413 17mmol 2-propanol 100 ml

(a) preparation of catalyst

Iridium compound and (+)-norephedrine were suspended in degassed 2-propanol (20 ml) under nitrogen and the reaction was purged with nitrogen for 30 minutes. The mixture was heated at 60 ° C. for 90 minutes and then cooled to room temperature. The resulting catalyst solution was transferred to the next step but could be stored under argon or nitrogen.

(b) hydrogenation

Acetophenone (2 ml, 17 mmol) was dissolved in 2-propanol (80 ml) and purged with nitrogen. The catalyst solution was then added followed by potassium hydroxide solution (3.3 ml of a 0.1 M solution in 2-propanol). The mixture was stirred at room temperature under nitrogen for 10 hours. The result was 1-phenylethanol. Yield 68%, optical isomer excess 49%.

Claims (18)

CLAIMS 1. A method for deconcentrating an optically concentrated composition, comprising: an optically concentrated composition comprising at least a first optical isomer or a diastereomer of a substrate comprising a carbon-heteroatom bond in the presence of a catalyst system and optionally a reaction promoter Reacting to provide a product composition comprising the first and second optical isomers or diastereomers of the substrate having carbon-heteroatom bonds, wherein the carbon is chiral and the heteroatoms are Group VI heteroatoms. And the ratio of the second optical isomer or diastereomer to the first optical isomer or diastereomer in the product composition is the second optical isomer or dia to the first optical isomer or diastereomer in the optically concentrated composition. Characterized by greater than the proportion of the stereomer Law. The method of claim 1, wherein the substrate comprises a carbon-heteroatom bond, wherein the carbon atom is a compound of formula (1) which is chiral centered.

here, X represents O, S, R ¹ , R ² each independently represent an optionally substituted hydrocarbyl group, a perhalogenated hydrocarbyl group, an optionally substituted heterocyclyl group, or R ¹ and R ² are optionally linked to form an optionally substituted ring, With the proviso that R ¹ and R ² are selected such that * is chiral The method of claim 1 or 2, wherein the catalyst system comprises a transition metal catalyst and optionally a ligand. The method of claim 3, wherein the transition metal catalyst is a transition metal halide complex salt of formula M _n X _p Y _r . here, M is a transition metal, X is a halogen compound, Y is a neutral, optionally substituted hydrocarbyl complexing group, a neutral, optionally substituted perhalogenated hydrocarbyl complex, or an optionally substituted cyclopentadienyl complex, n, p and r are integers 5. The method of claim 4 wherein M is Rh or Ir and Y is an optionally substituted cyclopentadienyl group. 6. A process according to claim 5, wherein M is Ir, X is I, and Y is an optionally substituted cyclopentadienyl group, preferably pentamethylcyclopentadienyl group. 7. The transition metal catalyst according to claim 6, wherein the transition metal catalyst is a transition metal halide complex salt of formula M ₂ X ₄ Y ₂ , wherein M is Ir, X is I, and Y is an optionally substituted cyclopentadienyl group, preferably Is a pentamethylcyclopentaenyl group. 8. Process according to one of the preceding claims, characterized in that the reaction promoter is present. 10. The method of claim 8, wherein the reaction accelerator is a halogenated salt. 10. The method of claim 9, wherein the halide salt is a metal halide. The method of claim 10 wherein the metal halide is potassium iodide or cesium iodide. Process according to one of the preceding claims, characterized in that a base, preferably potassium carbonate or sodium carbonate, is present. 13. Process according to any one of the preceding claims, wherein the compound of formula (2) is obtained.

here, X represents O, S, R ¹ , R ² each independently represent an optionally substituted hydrocarbyl group, a perhalogenated hydrocarbyl group, an optionally substituted heterocyclyl group, or R ¹ and R ² are optionally linked to form an optionally substituted ring, Provided that R ¹ and R ² are different 14. The catalyst system of claim 13, wherein the optically concentrated composition comprises at least a first optical isomer or diastereomer of a substrate comprising a carbon-heteroatom bond (carbon is a chiral center and the heteroatom is a Group VI heteroatom). Ketones or thioketones of formula (2) obtained by reaction in the presence of a reaction promoter in contact with a transfer hydrogenation catalyst and a hydrogen donor having a carbon-heteroatomic bond or a first and second optical isomers or diastereo Providing a product composition comprising a mer, wherein the ratio of the second optical isomer or diastereomer to the first optical isomer or diastereomer in the resulting composition is equal to the first optical isomer or diastereomer in the optically concentrated composition. And greater than the ratio of the second optical isomer or diastereomer to the. The method of claim 14, wherein the transfer hydrogenation catalyst is a catalyst of the general formula (a).

here, R ³ represents neutral optionally substituted hydrocarbyl, neutral optionally substituted perhalogenated hydrocarbyl, or optionally substituted cyclopentadienyl ligand, A represents optionally substituted nitrogen, B represents optionally substituted nitrogen, oxygen, sulfur or phosphorus, E represents a linking group, M represents a metal capable of catalyzing transfer hydrogenation, Y represents an anionic group, base ligand or vacant site Provided that at least one of A or B comprises substituted nitrogen and the substituent has at least one chiral center, and Provided that at least one of A or B has a hydrogen atom if Y is not free 16. The optically concentrated composition of any one of claims 1 to 15 comprising a first optical isomer or a diastereomer of a substrate comprising a carbon-heteroatom bond is a chiral separation, or a chemical or enzymatic chiral. Unreacted optical isomer or byproduct obtained from the cleavage. A composition obtainable by contacting a transition metal halide complex salt of formula M _n X _p Y _r with an alcohol or sulfide ligand of formula (1), wherein M is a transition metal, X is a halide, and Y is a neutral, optionally substituted Hydrocarbyl complex base, neutral optionally substituted perhalogenated hydrocarbyl complex base, or optionally substituted cyclopentadienyl complex base, wherein n, p and r are integers.

here, X represents O, S, R ¹ , R ² each independently represent an optionally substituted hydrocarbyl group, a perhalogenated hydrocarbyl group, an optionally substituted heterocyclyl group, or R ¹ and R ² are optionally linked to form an optionally substituted ring, With the proviso that R ¹ and R ² are selected such that * is a chiral center and optionally a base 18. The composition of claim 17, wherein a base is used, wherein the base is potassium carbonate or sodium carbonate.