EP1406853A1 - Process for the racemization of alcohols - Google Patents

Process for the racemization of alcohols

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Publication number
EP1406853A1
EP1406853A1 EP02758335A EP02758335A EP1406853A1 EP 1406853 A1 EP1406853 A1 EP 1406853A1 EP 02758335 A EP02758335 A EP 02758335A EP 02758335 A EP02758335 A EP 02758335A EP 1406853 A1 EP1406853 A1 EP 1406853A1
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EP
European Patent Office
Prior art keywords
alkyl
aryl
ruthenium
phenyl
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP02758335A
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German (de)
French (fr)
Inventor
Thomas Riermeier
Peter Gross
Manfred Hoff
Axel Monsees
Uwe Dingerdissen
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Evonik Operations GmbH
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Degussa GmbH
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Publication of EP1406853A1 publication Critical patent/EP1406853A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/56—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by isomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B55/00—Racemisation; Complete or partial inversion
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/32—Preparation of ethers by isomerisation
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12C—BEER; PREPARATION OF BEER BY FERMENTATION; PREPARATION OF MALT FOR MAKING BEER; PREPARATION OF HOPS FOR MAKING BEER
    • C12C11/00—Fermentation processes for beer
    • C12C11/02—Pitching yeast
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
    • C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention relates to a process for the racemization of alcohols and its use in dynamic kinetic resolution of racemates.
  • Enantiomerically pure alcohols are of tremendous importance in the pharmaceutical and agrochemical sectors. However, the preparation of enantiomerically pure alcohols is frequently very difficult, particularly when the processes for their preparation are to be suitable for a large-scale industrial reaction. Direct asymmetric synthesis is frequently possible only with considerable difficulty, if at all.
  • An alternative route to enantiomerically pure alcohols is offered by resolution of racemates, which is classically carried out by crystallization of diastereomers or by means of kinetic racemate resolution.
  • the great disadvantage of resolution of racemates is the fact that the yield is limited to a maximum of 50%.
  • the crystallization method requires stoichiometric amounts of a chiral crystallization reagent to form the diastereomers.
  • a further disadvantage of these processes is that the racemate resolution reagent usually has to be covalently bound to the alcohol, which makes such processes very complicated.
  • the dynamic kinetic resolution of racemates which comprises a kinetic racemate resolution coupled with in-situ racemization (e.g. U. T. Strauss, U. Felfer, K. Faber, Tetrahedron: Asymmetry 1999 (10) 107), enables enantiomerically pure products to be obtained in yields above 50%.
  • the enantiomers are in this case separated by means of a kinetic racemate resolution step, so that the direct synthesis of the enantiomeric product can also be dispensed with here.
  • this object can be achieved by means of a mixture of ruthenium complexes with chelating N-donor ligands.
  • the present invention accordingly provides a process for the racemization of alcohols with addition of at least one ruthenium precursor and at least one chelating N-donor ligand.
  • the ruthenium precursor can have been admixed beforehand with the chelating N-donor ligand to produce the catalytically active complex prior to the racemization.
  • the catalytically active complex can also be formed in the racemization mixture in the presence of the alcohol, so that the racemization can be carried out in a single-vessel reaction.
  • chelating N-donor ligands use can be made of amines such as hydroxyamine or alkoxyamine compounds or diamines. Preference is given to ligands which form five- to twelve-membered chelate rings with the ruthenium; such a chelating ligand can be based on a C 2 -C ⁇ o-alkyl, C 3 -C ⁇ 0 -cycloalkyl, C 2 -C 10 -alkenyl or -alkynyl, Cs-C ⁇ - cycloalkenyl, phenyl, naphthyl, fluorenyl or C 5 -C 14 -aryl skeleton, in each of which one or two carbon atoms may be replaced by heteroatoms from the group consisting of N, O and S.
  • the basic skeleton may bear, in addition to hydrogen, further substituents selected from the group consisting of C-i-Cio-alkyl, C 2 -C ⁇ o-alkenyl and -alkynyl, Cs-C-w-aryl, C ⁇ -C ⁇ o-alkoxy, CrCio-haloalkyl, C 3 -C 8 -cycloalkyl, Cs-Cs-cycloalkenyl, C 6 -C 8 -aryI, phenyl, naphthyl, fluorenyl, C 2 -Cg-heteroalkyl, C-i-Cg-heteroalkenyl, C 2 -C 6 -heteroaryl, where the number of heteroatoms from the group consisting of N, O and S can be from 1 to 4, d-Cg-trihalomethylalkyl, O-aryl-(C 6 -C 10 ), OCO-alkyl-(C 1 -C 8
  • n can be an integer from 2 to 9 and each of the up to 18 substituents R in formula (I) can be, independently of one another, hydrogen, (C ⁇ -C- ⁇ o)-alkyl or (C 5 -C ⁇ 0 )-aryl and
  • R 1 to R 4 are each, independently of one another, substituents selected from the group consisting of hydrogen, (Ci-Cio)-alkyl and (C 5 -C- ⁇ o)-aryI.
  • n is two, three or four.
  • R is particularly preferably hydrogen and R 1 to R 4 are each, independently of one another, particularly preferably a (C ⁇ -C 4 )-alkyl radical, in particular a methyl radical.
  • ligands selected from the group consisting of N,N,N ⁇ N'-tetraethylethylenediamine, N,N,N',N'-tetraethyI-1 ,3-propanediamine, N,N,N',N'-tetraethyldiethylenetriamine, N,N,N',N'-tetramethyl-1 ,3-butanediamine, N,N,N',N',N"-pentamethyldiethylenetriamine, N,N,N'-trimethyl-1 ,3-propanediamine, N,N,N',N'-tetramethyl-1 ,6-hexanediamine, N,N,N ⁇ N'-tetramethyl-1 ,4-butanediamine, N,N,N ⁇ N :etramethyl-1 ,3-propanediamine, N,N,N ⁇ N'-tetraisopropylethylenediamine, N,N,N',N'-tetrais
  • Suitable hydroxyamine compounds are 2-methoxybenzylamine and 4-hydroxy-4-phenylpiperidine.
  • ligands which together with the ruthenium form a chelate ring which contains one or two further heteroatoms from the group consisting of N, O and S is N,N,N',N'-tetramethyldipropylenetriamine.
  • the efficiency of the racemization increases with increasing amounts of ligand used, based on the substrate.
  • the molar ratio of ligand to ruthenium precursor is advantageously from 1 :1 to 200:1 , with the optimum molar ratio for each ligand, in particular in combination with the respective ruthenium precursor and the respective substrate, being able to be determined in a simple manner.
  • a molar ratio to the di- ⁇ - chlorobis[p-cymene]chlororuthenium(ll) precursor of 10:1 is sufficient to achieve virtually complete racemization of (+)-1-phenylethanol in a short time.
  • ruthenium precursor it is possible to use, for example, carbonyl- tris(triphenylphosphine)dihydridoruthenium(ll), ruthenium(ll) acetylacetonate, dodecacarbonyltriruthenium, ruthenium(ll) chloride hydrate, chloro(cyclopentadienyl)bis(triphenylphosphine)ruthenium, dichlorodicarbonylbis(triphenylphosphine)ruthenium(ll), tris(triphenylphosphine)ruthenium(ll) chloride, ruthenium on activated carbon, chloro(indenyl)bis(triphenylphosphine)ruthenium(ll), cis-dichlorobis(2,2 - bipyridine)ruthenium(ll) dihydrate or dichloro[(S)-(-)-2,2 x -bis(diphenylphosphino)- 2,2 ⁇ -bina
  • Organic solvents are suitable as solvents.
  • esters, ethers, tertiary alcohols or aliphatic or aromatic hydrocarbons allow good racemization to be achieved.
  • N,N-Dimethylacetamide, ethylene glycol, 1 ,4-dioxane, 1-methyl-2-pyrrolidone and dimethylformamide likewise give high yields, but the racemization is less successful.
  • further additives can be added to the reaction mixture.
  • the most important additives which come into question are bases, acids and/or ketones.
  • a preferred additive is the ketone corresponding to the alcohol to be racemized.
  • Suitable substrates are, for example, secondary alcohols of the formula R -CHOH- R", where the radicals R' and R" can each be, independently of one another, an alkyl-(C- ⁇ -C2o), cycloalkyl-(C3-C 20 ), heterocycloalkyl-(C3-C 2 o), alkenyl-(C 2 -C 2 o), alkynyl-(C 2 -C 2 o), aryl-(C 5 - 2 o), heteroaryl-(C 3 -2o), cycloalkenyl-(C 5 -C 2 o), phenyl, naphthyl or fluorenyl group, where the number of heteroatoms selected from the group consisting of N, O and S can be from 1 to 4, and the radicals R' and R" may bear further substituents selected from the group consisting of C ⁇ -C ⁇ o-alkyl, C 2 -C 10 - alkenyl and -alkyny
  • Preferred alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl and alkynyl groups contain up to 10 carbon atoms, particularly preferably up to 3 carbon atoms.
  • Preferred aryl and heteroaryl groups contain up to 10 carbon atoms, particularly preferably from 5 to 7 carbon atoms. In the groups containing heteroatoms, preference is given to one or two carbon atoms being replaced by one or two nitrogen atoms or one carbon atom being replaced by an oxygen or sulfur atom.
  • Particularly preferred alcohol substrates are secondary alcohols of the formulae (C 5 - C 10 )-aryl-CHOH-alkyl-(C 1 -C 10 ), phenyl-CHOH-R " and naphthyl-CHOH-R " .
  • the present invention further provides a process for dynamic kinetic resolution of racemates which comprises a racemization step according to the invention.
  • the racemization described is combined with an enzymatic racemate resolution, e.g. by addition of a hydrolase in the presence of an acyl donor.
  • enantiomeric alcohols having an enantiomeric excess (ee) of over 90% can be prepared in good yields in a "single-vessel" reaction without recourse having to be made to a technically complicated process or catalysts which are complicated to prepare.
  • the present invention further provides for the use of ruthenium complexes comprising at least one chelating N-donor ligand or a mixture comprising at least one ruthenium precursor and at least one chelating N-donor ligand for the racemization or dynamic kinetic racemate resolution of secondary alcohols.
  • a metal precursor (table 4) are suspended in 2.5 ml of dry toluene at room temperature under protective gas and admixed with 0.25 mmol of N,N,N'N'-tetramethylethylenediamine.

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Abstract

A process for the racemization of alcohols using a mixture of ruthenium complexes with chelating N-donor ligands as catalyst precursor and its use in dynamic kinetic resolution of racemates are described.

Description

Process for the racemization of alcohols
Description
The present invention relates to a process for the racemization of alcohols and its use in dynamic kinetic resolution of racemates.
Enantiomerically pure alcohols are of tremendous importance in the pharmaceutical and agrochemical sectors. However, the preparation of enantiomerically pure alcohols is frequently very difficult, particularly when the processes for their preparation are to be suitable for a large-scale industrial reaction. Direct asymmetric synthesis is frequently possible only with considerable difficulty, if at all. An alternative route to enantiomerically pure alcohols is offered by resolution of racemates, which is classically carried out by crystallization of diastereomers or by means of kinetic racemate resolution. The great disadvantage of resolution of racemates is the fact that the yield is limited to a maximum of 50%. In addition, the crystallization method requires stoichiometric amounts of a chiral crystallization reagent to form the diastereomers. A further disadvantage of these processes is that the racemate resolution reagent usually has to be covalently bound to the alcohol, which makes such processes very complicated.
The dynamic kinetic resolution of racemates, which comprises a kinetic racemate resolution coupled with in-situ racemization (e.g. U. T. Strauss, U. Felfer, K. Faber, Tetrahedron: Asymmetry 1999 (10) 107), enables enantiomerically pure products to be obtained in yields above 50%. The enantiomers are in this case separated by means of a kinetic racemate resolution step, so that the direct synthesis of the enantiomeric product can also be dispensed with here.
In the preparation of enantiomerically pure alcohols, kinetic racemate resolution by enzymatic acylation is prior art; a review of this technique is given in R. Azerad et al. Curr. Opinion Biotechnol. 2000 (11) 565. A critical aspect of the dynamic kinetic resolution of racemic alcohols described there is appropriate choice of reaction conditions, since, in particular, the rapid racemization must not adversely affect the kinetic racemate resolution. Customary racemization methods for alcohols make use of strong bases or strong acids at elevated temperatures (E. J. Ebbers et al. Tetrahedron 1997 (53) 9417). Under these conditions, racemate resolution in the presence of enzymes, for example, is not possible since mild reaction conditions are required for this.
A solution to this problem is offered by racemization of alcohols by means of homogeneous transition metal catalysts. A review of methods known for this purpose is given, for example, in R. Stϋrmer, Angew. Chem. Int. Ed. Engl. 1997 (36) 1173. A transition metal-catalyzed racemization of secondary alcohols is described, for example, in P. M. Dinh et al. Tetrahedron Lett. 1996 (42) 7623. In this process, various metals and additives are tested, and a few examples of enzymatic resolution of racemates are also described. However, the processes described give low yields and display low selectivities. An alternative process is described in J. H. Koh et al. Tetrahedron Lett. 1998 (39) 5545, who carry out the dynamic kinetic resolution of racemates using commercially available ruthenium complexes and catalytic amounts of a strong base. This process likewise gives only low yields of enantiomerically pure alcohols. The same type of catalyst system is employed by J. H. Koh et al., Tetrahedron Letters 1999 (40) 6281 , but using milder bases. This makes the use of enzymes in the syntheses described possible. However, this process requires stoichiometric amounts of oxygen. As a result, this process cannot be employed in industry, since a small amount of oxygen has to be metered in precisely under protective gas. In Angew. Chem. 1997 (109) 1256, and J. Am. Chem. Soc. 1999 (121) 1645, Backvall, J.-E. et al. describe an enzymatic dynamic kinetic resolution of racemic alcohols using ruthenium catalysts for the racemization. This enables enantiomeric alcohols to be obtained in high yields and with high selectivity. The critical disadvantage of this process is the high air-sensitivity of the catalyst. The ruthenium catalysts used have to be synthesized in a plurality of steps under protective gas, which rules them out for use on a large industrial scale. It is therefore an object of the present invention to provide a process which allows alcohols to be racemized under mild conditions, so that combination of this with racemate resolution enables enantiomeric alcohols to be obtained with high selectivity and in a high yield.
Surprisingly, this object can be achieved by means of a mixture of ruthenium complexes with chelating N-donor ligands.
The present invention accordingly provides a process for the racemization of alcohols with addition of at least one ruthenium precursor and at least one chelating N-donor ligand. In this process, the ruthenium precursor can have been admixed beforehand with the chelating N-donor ligand to produce the catalytically active complex prior to the racemization. However, the catalytically active complex can also be formed in the racemization mixture in the presence of the alcohol, so that the racemization can be carried out in a single-vessel reaction.
As chelating N-donor ligands, use can be made of amines such as hydroxyamine or alkoxyamine compounds or diamines. Preference is given to ligands which form five- to twelve-membered chelate rings with the ruthenium; such a chelating ligand can be based on a C2-Cιo-alkyl, C3-Cι0-cycloalkyl, C2-C10-alkenyl or -alkynyl, Cs-Cβ- cycloalkenyl, phenyl, naphthyl, fluorenyl or C5-C14-aryl skeleton, in each of which one or two carbon atoms may be replaced by heteroatoms from the group consisting of N, O and S.
The basic skeleton may bear, in addition to hydrogen, further substituents selected from the group consisting of C-i-Cio-alkyl, C2-Cιo-alkenyl and -alkynyl, Cs-C-w-aryl, Cι-Cιo-alkoxy, CrCio-haloalkyl, C3-C8-cycloalkyl, Cs-Cs-cycloalkenyl, C6-C8-aryI, phenyl, naphthyl, fluorenyl, C2-Cg-heteroalkyl, C-i-Cg-heteroalkenyl, C2-C6-heteroaryl, where the number of heteroatoms from the group consisting of N, O and S can be from 1 to 4, d-Cg-trihalomethylalkyl, O-aryl-(C6-C10), OCO-alkyl-(C1-C8), OCO-aryl- (Cβ-Cio), O-phenyl, OH, N02, COOH, S03H, NH-alkyl-(C1-C8), NH-aryl, N-alkyl2-(Cr C8), N-aryl2, Sθ2-alkyl-(CrC6), SO2-aryl-(C6-C10), SO-alkyl-(Cι-C6), NHCO-alkyl-(C1- C4), COO-alkyl-(C C8), COOaryl-(C6-C10), CONH2, CO-alkyl-(C1-C8), CO-aryl, NHCOH, NHCOO-alkyl-(C1-C4), CO-phenyl, COO-phenyl, CHCH-C02-aIkyl-(C1-C8), PO-phenyl2, POalkyl2-(C1-C4), P03H2, PO(0-alkyl-(C1-C6))2, S03-alkyl-(CrC4), trifluoromethyl, trichloromethyl, fluoro, chloro, bromo, iodo, cyano and tri-(Cι-Ce)- alkylsilyl.
Preference is given to chelating diamine ligands of the formula (I),
R1R2N-(CR2)n-NR3R4 Formula (I)
where n can be an integer from 2 to 9 and each of the up to 18 substituents R in formula (I) can be, independently of one another, hydrogen, (Cι-C-ιo)-alkyl or (C5-Cι0)-aryl and
R1 to R4 are each, independently of one another, substituents selected from the group consisting of hydrogen, (Ci-Cio)-alkyl and (C5-C-ιo)-aryI.
In a preferred embodiment, n is two, three or four. R is particularly preferably hydrogen and R1 to R4 are each, independently of one another, particularly preferably a (Cι-C4)-alkyl radical, in particular a methyl radical.
Particular preference is given to ligands selected from the group consisting of N,N,N\N'-tetraethylethylenediamine, N,N,N',N'-tetraethyI-1 ,3-propanediamine, N,N,N',N'-tetraethyldiethylenetriamine, N,N,N',N'-tetramethyl-1 ,3-butanediamine, N,N,N',N',N"-pentamethyldiethylenetriamine, N,N,N'-trimethyl-1 ,3-propanediamine, N,N,N',N'-tetramethyl-1 ,6-hexanediamine, N,N,N\N'-tetramethyl-1 ,4-butanediamine, N,N,N\N :etramethyl-1 ,3-propanediamine, N,N,N\N'-tetraisopropylethylenediamine, N,N,N',N'-tetraisopropylethylenediamine and N,N,N',N'-tetrabutyl-1 ,6- hexanediamine. Very particular preference is given to using N,N,N',N'- tetramethylethylenediamine or N.N.N'.N'-tetramethyl-I .S-propanediamine as ligand for the process of the invention.
Examples of suitable hydroxyamine compounds are 2-methoxybenzylamine and 4-hydroxy-4-phenylpiperidine. However, it is also possible to use ligands which together with the ruthenium form a chelate ring which contains one or two further heteroatoms from the group consisting of N, O and S. An example of such a ligand is N,N,N',N'-tetramethyldipropylenetriamine.
The efficiency of the racemization increases with increasing amounts of ligand used, based on the substrate. The molar ratio of ligand to ruthenium precursor is advantageously from 1 :1 to 200:1 , with the optimum molar ratio for each ligand, in particular in combination with the respective ruthenium precursor and the respective substrate, being able to be determined in a simple manner. Thus, for example, when N,N,N',N'-tetramethyl-1 ,3-propanediamine is used as ligand, a molar ratio to the di-μ- chlorobis[p-cymene]chlororuthenium(ll) precursor of 10:1 is sufficient to achieve virtually complete racemization of (+)-1-phenylethanol in a short time.
As ruthenium precursor, it is possible to use, for example, carbonyl- tris(triphenylphosphine)dihydridoruthenium(ll), ruthenium(ll) acetylacetonate, dodecacarbonyltriruthenium, ruthenium(ll) chloride hydrate, chloro(cyclopentadienyl)bis(triphenylphosphine)ruthenium, dichlorodicarbonylbis(triphenylphosphine)ruthenium(ll), tris(triphenylphosphine)ruthenium(ll) chloride, ruthenium on activated carbon, chloro(indenyl)bis(triphenylphosphine)ruthenium(ll), cis-dichlorobis(2,2 - bipyridine)ruthenium(ll) dihydrate or dichloro[(S)-(-)-2,2x-bis(diphenylphosphino)- 2,2Λ-binaphthyl]ruthenium(ll).
Particular preference is given to using di-μ-chlorobis[p-cymene]chlororuthenium(ll) or benzeneruthenium(ll) chloride dimer.
Organic solvents are suitable as solvents. Thus, for example, esters, ethers, tertiary alcohols or aliphatic or aromatic hydrocarbons allow good racemization to be achieved. Diethylene glycol dimethyl ether, xylene and toluene, in particular, also give very good yields. N,N-Dimethylacetamide, ethylene glycol, 1 ,4-dioxane, 1-methyl-2-pyrrolidone and dimethylformamide likewise give high yields, but the racemization is less successful. In addition, further additives can be added to the reaction mixture. The most important additives which come into question are bases, acids and/or ketones. A preferred additive is the ketone corresponding to the alcohol to be racemized.
The racemization of alcohols using chelating N-donor ligands is not subject to any restrictions in respect of the alcohol substrate.
Suitable substrates are, for example, secondary alcohols of the formula R -CHOH- R", where the radicals R' and R" can each be, independently of one another, an alkyl-(C-ι-C2o), cycloalkyl-(C3-C20), heterocycloalkyl-(C3-C2o), alkenyl-(C2-C2o), alkynyl-(C2-C2o), aryl-(C5-2o), heteroaryl-(C3-2o), cycloalkenyl-(C5-C2o), phenyl, naphthyl or fluorenyl group, where the number of heteroatoms selected from the group consisting of N, O and S can be from 1 to 4, and the radicals R' and R" may bear further substituents selected from the group consisting of Cι-Cιo-alkyl, C2-C10- alkenyl and -alkynyl, C5-C-|4-aryl, C-i-C-io-alkoxy, CrC-io-haloalkyl, C3-C8-cycloalkyl, C3-C8-cycloalkenyl, Cδ-Cs-aryl, phenyl, naphthyl, fluorenyl, C2-Cg-heteroalkyl, C-i-Cg- heteroalkenyl and C2-C6-heteroaryl, where the number of heteroatoms from the group consisting of N, O and S can be from one to four, Ci-Cg-trihalomethylalkyl, O- aryl-(C6-Cιo), OCO-alkyI-(CrC8), OCO-aryl-(C6-Cι0), O-phenyl, OH, N02, COOH, SO3H, NH-alkyl-(CrC8), NH-aryl, N-alkyI2-(C1-C8), N-aryl2, SOs-alkyKC Ce), S02- aryl-(Ce-Cιo), SO-alkyl-(C1-C6), NHCO-alkyl-(C1-C4), COO-alkyl-(CrC8), COOaryl- (Cβ-Cιo), CONH2, CO-alkyl-(CrC8), CO-aryl, NHCOH, NHCOO-alkyl-(C1-C4), CO- phenyl, COO-phenyl, CHCH-C02-alkyl-(C1-C8), PO-phenyl2, POalkyl2-(CrC4), PO3H2, PO(0-alkyl-(Cι-C6))2, S03-alkyI-(C1-C4), trifluoromethyl, trichloromethyl, fluoro, chloro, bromo, iodo, cyano and tri-(Cι-C6)-alkylsilyl.
Preferred alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl and alkynyl groups contain up to 10 carbon atoms, particularly preferably up to 3 carbon atoms. Preferred aryl and heteroaryl groups contain up to 10 carbon atoms, particularly preferably from 5 to 7 carbon atoms. In the groups containing heteroatoms, preference is given to one or two carbon atoms being replaced by one or two nitrogen atoms or one carbon atom being replaced by an oxygen or sulfur atom. Particularly preferred alcohol substrates are secondary alcohols of the formulae (C5- C10)-aryl-CHOH-alkyl-(C1-C10), phenyl-CHOH-R" and naphthyl-CHOH-R".
The present invention further provides a process for dynamic kinetic resolution of racemates which comprises a racemization step according to the invention. In particular, the racemization described is combined with an enzymatic racemate resolution, e.g. by addition of a hydrolase in the presence of an acyl donor.
In this process, enantiomeric alcohols having an enantiomeric excess (ee) of over 90% can be prepared in good yields in a "single-vessel" reaction without recourse having to be made to a technically complicated process or catalysts which are complicated to prepare.
The present invention further provides for the use of ruthenium complexes comprising at least one chelating N-donor ligand or a mixture comprising at least one ruthenium precursor and at least one chelating N-donor ligand for the racemization or dynamic kinetic racemate resolution of secondary alcohols.
Examples:
Examples 1 to 23: Racemization of (+)-1-phenyIethanol with variation of the ligand and the ligand concentration
In a Schlenk tube, 15 mg (0.025 mmol) of di-μ-chIorobis[(p-cymene)chloro- ruthenium(ll)] are suspended in 2.5 ml of dry toluene at room temperature under protective gas and admixed with various ligands (see table 1) and different amounts of ligand (see table 2).
After about 10 minutes, 0.8 mmol of (+)-1-phenylethanol is added and the mixture is stirred at 80°C for 5 hours. The yields and enantiomeric excesses (ee) are determined by means of gas-chromatographic analysis (internal standard: 100 μl of hexadecane).
Table 1 : Variation of the ligand
Table 2: Variation of the amount of ligand
Examples 24 and 25: Racemization of (+)-1-phenylethanol with addition of acetophenone
The reactions were carried out in a manner analogous to examples 1 to 23 with addition of 0.4 mmol of acetophenone as additive.
Table 3: Reactions with additional acetophenone
Examples 26 to 37: Racemization of (+)-1-phenylethanol
In a Schlenk tube, 15 mg of a metal precursor (table 4) are suspended in 2.5 ml of dry toluene at room temperature under protective gas and admixed with 0.25 mmol of N,N,N'N'-tetramethylethylenediamine.
After about 10 minutes, 0.8 mmol of (+)-1-phenylethanol is added and the mixture is stirred at 80°C for 5 hours. The yields and enantiomeric excesses (ee) are determined by means of gas-chromatographic analysis (internal standard: 100 μl of hexadecane).
Table 4: Variation of the metal precursors used
Examples 38 to 49: Racemization of (+)-1-phenylethanol
In a Schlenk tube, 15 mg (0.025 mmol) of di-μ-chlorobis[(p-cymene)chloro- ruthenium(ll)] are suspended in 2.5 ml of dry solvent (table 5) at room temperature under protective gas and admixed with 0.25 mmol of N,N,N',N'-tetramethyl-1 ,3- propanediamine.
After about 10 minutes, 0.8 mmol of (+)-1-phenylethanol is added and the mixture is stirred at 80°C for 5 hours. The yields and enantiomeric excesses (ee) are determined by means of gas-chromatographic analysis (internal standard: 100 μl of hexadecane).
Table 5: Variation of the solvent used
Examples 50 to 59: Racemization of (+)-1-phenylethanol
In a Schlenk tube, 15 mg (0.025 mmol) of di-μ-chlorobis[(p-cymene)chloro- ruthenium(ll)] are suspended in 2.5 ml of dry toluene at room temperature under protective gas and admixed with 0.25 mmol of N,N,N',N'- tetramethylethylenediamine.
After about 10 minutes, 0.8 mmol of (+)-1-phenylethanol and an additive (table 6) are added and the mixture is stirred at 80°C for 5 hours. The yields and enantiomeric excesses (ee) are determined by means of gas-chromatographic analysis (internal standard: 100 μl of hexadecane).
Table 6: Variation of the additives
Examples 60 to 65: Racemization of various secondary alcohols with addition of N,N,N',N'-tetramethyl-1 ,3-propanediamine
In a Schlenk tube, 15 mg (0.025 mmol) of di-μ-chlorobis[(p-cymene)chIoro- ruthenium(ll)] are suspended in 2.5 ml of dry toluene at room temperature under protective gas and admixed with 0.25 mmol of N,N,N',N'-tetramethyl-1 ,3- propanediamine.
After about 10 minutes, 0.8 mmol of an enantiomerically pure secondary alcohol
(table 7) is added and the mixture is stirred at 80°C for 5 hours. The yields and enantiomeric excesses (ee) are determined by means of gas-chromatographic analysis (internal standard: 100 μl of hexadecane).
Table 7: Racemization of various secondary alcohols
Examples 66 to 71 : Racemization of various secondary alcohols with addition of N,N,N',N'-tetramethyl-1 ,2-ethylenediamine
In a Schlenk tube, 15 mg (0.025 mmol) of di-μ-chlorobis[(p-cymene)chloro- ruthenium(ll)] are suspended in 2.5 ml of dry toluene at room temperature under protective gas and admixed with 0.25 mmol of N,N,N',N'-tetramethyI-1 ,2- ethylenediamine.
After about 10 minutes, 0.8 mmol of an enantiomerically pure secondary alcohol (table 8) is added and the mixture is stirred at 80°C for 5 hours. The yields and enantiomeric excesses (ee) are determined by means of gas-chromatographic analysis (internal standard: 100 μl of hexadecane). Table 8: Racemization of further secondary alcohols
Examples 72 to 79: Dynamic kinetic racemate resolution of secondary alcohols
In a Schlenk tube, 15 mg (0.025 mmol) of di-μ-chIorobis[(p-cymene)chloro- ruthenium(ll)] are suspended in 2.5 ml of dry toluene at room temperature under protective gas and admixed with 0.25 mmol of N,N,N',N'-tetramethyl-1 ,3- propanediamine.
After about 10 minutes, 0.8 mmol of a racemic secondary alcohol (table 9), if applicable 0.4 mmol of an additive (table 9), 1.8 mmol of p-chlorophenyl acetate and 60 mg of Chirazym I-2, c-f, lyo are added and the mixture is stirred at 80°C for 45 hours. The yields and enantiomeric excesses (ee) are determined by means of gas- chromatographic analysis (internal standard: 100 μl of hexadecane).
Table 9: Dynamic kinetic racemate resolution of secondary alcohols

Claims

Claims
1. A process for the racemization of secondary alcohols, wherein the racemization is carried out with addition of at least one ruthenium precursor and at least one chelating N-donor ligand or a complex comprising ruthenium and at least one chelating N-donor ligand.
2. The process as claimed in claim 1 , wherein amines, hydroxyamines, alkoxyamines or diamines are used as chelating N-donor ligands.
3. The process as claimed in either of the preceding claims, wherein the ligands which together with ruthenium form five- to twelve-membered chelate rings are used.
4. The process as claimed in any of the preceding claims, wherein the chelating ligands are based on a C2-Cι0-alkyl, C3-Cιo-cycloalkyl, C2-Cι0-alkenyl or -alkynyl, Cs-Cβ-cycloalkenyl, phenyl, naphthyl, fluorenyl or Cs-C^-aryl skeleton, where one or two carbon atoms may be replaced by heteroatoms from the group consisting of N, O and S and the basic skeleton may bear, in addition to hydrogen, further substituents selected from the group consisting of Ci-C-io-alkyl, C2-Cιo-alkenyl and alkinyl, C5-Cι -aryl, Cι-Cιo-alkoxy, C-i-C-io- haloalkyl, Cs-Cs-cycloalkyl, C3-C8-cycloalkenyl, Ce-Cs-ar l, phenyl, naphthyl, fluorenyl, C2-Cg-heteroalkyl, Ci-Cg-heteroalkenyl, C2-C6-heteroaryl, where the number of heteroatoms from the group consisting of N, O and S can be from 1 to 4, CrCg-trihalomethylalkyl, O-aryl-(C6-C10), OCO-alkyl-(CrC8), OCO-aryl- (Cβ-Cio), O-phenyl, OH, N02, COOH, S03H, NH-alkyl-^-C8), NH-aryl, N- aIkyl2-(CrC8), N-aryl2, S02-alkyl-(CrC6), SO2-aryl-(C6-Cι0), SO-alkyKd-Ce), NHCO-alkyl-(CrC4), COO-alkyl-^-C8), COOaryl-(C6-C10), CONH2, CO-alkyl- (CrC8), CO-aryl, NHCOH, NHCOO-alkyl-(C1-C4), CO-phenyl, COO-phenyl, CHCH-C02-alkyl-(C1-C8), PO-phenyl2, POalkyl2-(CrC4), P03H2, PO(0-alkyl- (C C6))2, S03-alkyl-(C1-C4)> trifluoromethyl, trichloromethyl, fluoro, chloro, bromo, iodo, cyano and tri-(Cι-C6)-alkyIsilyl.
5. The process as claimed in any of the preceding claims, wherein chelating diamine ligands of the formula (I),
R1R2N-(CR2)n-NR3R4 Formula (I)
where n can be an integer from 2 to 9 and each of the up to 18 substituents R in formula (I) can be, independently of one another, hydrogen, (Cι-C-ιo)-alkyl or (C5-Cιo)-aryl and
R1 to R4 are each, independently of one another, substituents selected from the group consisting of hydrogen, (C Cιo)-alkyl and (C5-Cιo)-aryl, are used.
6. The process as claimed in any of the preceding claims, wherein at least one ligand from the group consisting of N,N,N',N'-tetraethyIethylenediamine, N,N,N',N'-tetraethyl-1 ,3-propanediamine, N,N,N',N'- tetraethyldiethylenetriamine, N,N,N',N'-tetramethyl-1 ,3-butanediamine, N,N,N',N',N"-pentamethyldiethylenetriamine, N,N,N'-trimethyl-1 ,3- propanediamine, N,N,N',N'-tetramethyl-1 ,6-hexanediamine, N,N,N',N'- tetramethyl-1 ,4-butanediamine, N,N,N',N'-tetramethyl-1 ,3-propanediamine, N,N,N',N'-tetraisopropylethylenediamine, N,N,N',N'- tetraisopropylethylenediamine and N,N,N',N'-tetrabutyl-1 ,6-hexanediamine, very particularly preferably N,N,N',N'-tetramethylethylenediamine or N,N,N',N'-tetramethyl-1 ,3-propanediamine, is used.
7. The process as claimed in any of the preceding claims, wherein carbonyltris(triphenylphosphine)dihydridoruthenium(ll), ruthenium(ll) acetylacetonate, dodecacarbonyltriruthenium, ruthenium(II) chloride hydrate, chloro(cyclopentadienyl)bis(triphenylphosphine)ruthenium, dichlorodicarbonylbis(triphenylphosphine)ruthenium(ll), tris(triphenylphosphine)ruthenium(ll) chloride, ruthenium on activated carbon, chIoro(indenyl)bis(triphenylphosphine)ruthenium(ll), cis-dichlorobis(2,2'- bipyridine)ruthenium(ll) dihydrate or dichloro[(S)-(-)-2,2'- bis(diphenylphosphine)-2,2'-binaphthyl]ruthenium(ll) is used as ruthenium precursor.
8. The process as claimed in any of the preceding claims, wherein additives selected from the group consisting of bases, acids and/or ketones are added.
9. The process as claimed in any of the preceding claims, wherein secondary alcohols of the formula R -CHOH-R"\ where the radicals
RΛ and R" can each be, independently of one another, an alkyl-(Cι-C2o), cycloalkyl-(C3-C2o), heterocycloalkyl-(C3-C20), alkenyl-(C2-C2o), alkynyl-(C2- C2o), aryl-(C5-2o), heteroaryl-(C3-2o), cycloalkenyl-(C5-C2o), phenyl, naphthyl or fluorenyl group, where the number of heteroatoms selected from the group consisting of N, O and S can be from 1 to 4, and the radicals R' and R" may bear further substituents selected from the group consisting of C-i-Cio-alkyl, C2-Cιo-aIkenyl and -alkynyl, d-Cu-aryl, Ci-C-io-alkoxy, C-i-C-io-haloalkyl, C3- Cs-cycloalkyl, C3-C8-cycloalkenyl, Ce-Cs-aryl, phenyl, naphthyl, fluorenyl, C2- Cg-heteroalkyl, d-Cg-heteroalkenyl and C2-C6-heteroaryl, where the number of heteroatoms from the group consisting of N, O and S can be from one to four, d-C -trihalomethylalkyl, O-aryl-(C6-Cι0), OCO-alkyl-(C C8), OCO-aryl- (C6-do), O-phenyl, OH, N02, COOH, S03H, NH-alkyl-(CrC8), NH-aryl, N- N-aryl2, S02-alkyl-(d-C6), SO2-aryl-(C6-C10), SO-alkyl-(d-C6), NHCO-alkyl-(CrC4), COO-alkyl-(C1-C8), COOaryl-(C6-C10), CONH2, CO-alkyl- (C1-C8), CO-aryl, NHCOH, NHCOO-alkyl-(C1-C4), CO-phenyl, COO-phenyl, CHCH-C02-alkyl-(C1-C8), PO-phenyl2, P03H2, PO(0-alkyl- (Cι-C6))2, SOg-alkyKC,-^), trifluoromethyl, trichloromethyl, fluoro, chloro, bromo, iodo, cyano and tri-(Cι-C6)-alkylsilyl, are racemized.
10. The process as claimed in any of the preceding claims, wherein secondary alcohols of the formula (C5-10)-aryl-CHOH-alkyl-(Cι-C10), phenyl-CHOH-R"or naphthyl-CHOH-R" are racemized.
11. A process for dynamic kinetic resolution of racemates comprising a racemization step as claimed in any of claims 1 to 10.
12. The process as claimed in claim 11 , wherein the racemization step is coupled with an enzymatic racemate resolution.
13. The process as claimed in claim 12, wherein the racemate resolution is carried out using a hydrolase in the presence of an acyl donor.
14. The process as claimed in any of claims 11 to 13, wherein the dynamic kinetic racemate resolution is carried out in a single-vessel reaction.
15. The use of ruthenium complexes comprising at least one chelating N-donor ligand or a mixture comprising at least one ruthenium precursor and at least one chelating N-donor ligand for the racemization or the dynamic kinetic racemate resolution of secondary alcohols.
EP02758335A 2001-07-16 2002-07-11 Process for the racemization of alcohols Withdrawn EP1406853A1 (en)

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