WO2004039998A1 - Method for the preparation of chiral hydroxy esters by enzyme/metal multi-catalysis - Google Patents

Method for the preparation of chiral hydroxy esters by enzyme/metal multi-catalysis Download PDF

Info

Publication number
WO2004039998A1
WO2004039998A1 PCT/KR2003/001437 KR0301437W WO2004039998A1 WO 2004039998 A1 WO2004039998 A1 WO 2004039998A1 KR 0301437 W KR0301437 W KR 0301437W WO 2004039998 A1 WO2004039998 A1 WO 2004039998A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
substituted
unsubstituted
formula
ketone
Prior art date
Application number
PCT/KR2003/001437
Other languages
French (fr)
Inventor
Mahn-Joo Kim
Jai-Wook Park
Min-Young Han
Min-Young Choi
Yoon-Kyung Choi
Jae-Kwan Lee
Original Assignee
Postech Foundation
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Postech Foundation filed Critical Postech Foundation
Publication of WO2004039998A1 publication Critical patent/WO2004039998A1/en

Links

Classifications

    • 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
    • C12P7/62—Carboxylic acid esters
    • 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
    • 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
    • C12P41/005—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 carboxylic acid groups in the enantiomers or the inverse reaction

Definitions

  • the invention relates to a method for preparing chiral hydroxy esters, particularly, to a process for preparing chiral hydroxy esters with high optical purities by combining an enzyme and a metal catalyst in a single reaction chamber and inducing multi-step catalytic reactions.
  • the kinetic resolution has some advantages - high optical purity of the end product, low unit cost of the enzyme catalyst, and simple reaction condition - and one apparent disadvantage that the yield is less than 50%.
  • the asymmetric synthesis leads high optical purity and yield, but causes the increase of production cost due to the use of expensive chiral reagents. Also, the reaction conditions are complicated.
  • an enzyme as an enantioselective acylation catalyst is used with a metal catalyst as a racemization catalyst to produce single enantiomer from a racemic mixture.
  • the yields of the products by this method are higher than those by optical resolution that uses enzyme catalysts only. Furthermore, this method is cost effective compared to the asymmetric synthesis that uses expensive chiral reagents.
  • ketones were successfully transformed to optically pure esters by the combination of an enzyme and a metal catalyst.
  • a metal catalyst Jung, H. M.; Koh, J. H.; Kim, M.-J.; Park, J., Org. Lett. 2000, 2, 409; Jung, H. M.; Koh, J. EL; Kim, M.-J.; Park, J., Org. Zett. 2000, 2, 2487.
  • an excessive amount of acyl donor is used to increase yields.
  • the excessive use of acyl donor increases the production cost and makes the separation of required product difficult because the acyl donor remains unreacted in a large portion and has similar polarity with that of product.
  • the invention provides a process for synthesizing chiral hydroxy esters with high optical purity and high yield from ketones by the combination of an enzyme catalyst and a metal catalyst without additional acyl donors, thereby resolving the problem caused by the use of excessive acyl donors.
  • the invention provides a process for preparing chiral hydroxy esters by reacting a compound having both a ketone group and an acyloxy group in a molecule; a hydrogen donor which reduces the ketone into a hydroxy group; a metal complex, which catalyzes both the reduction of the ketone group and racemization of produced hydroxy group; and an enzyme, which catalyzes enantioselective acyl transfer in a suitable organic solvent.
  • Formula 1 represents the chiral hydroxy ester.
  • Formula 2 represents the substrate compound having both a ketone and an acyloxy group.
  • Ri and R 3 independently represent substituted or unsubstituted C ⁇ - ⁇ 5 alkyl group, substituted or unsubstituted C ⁇ - ⁇ 5 akenyl group, substituted or unsubstituted C ⁇ - ⁇ 5 alkynyl group, substituted or unsubstituted C 6 - ⁇ 5 aryl group, substituted or unsubstituted Ci-1 5 heteroaryl group, substituted or unsubstituted C 4 - ⁇ 5 cycloalkyl group, substituted or unsubstituted C - ⁇ 5 heterocycloalkyl group or substituted or unsubstituted C 2 - ⁇ 5 heteroarylalkyl group.
  • R 2 represents substituted or unsubstituted C 1 - 15 alkylene group, substituted or unsubstituted C 6 - ⁇ 5 arylene group, substituted or unsubstituted C - ⁇ 5 heteroarylene group, substituted or unsubstituted C - ⁇ 5 cycloalkylene group, substituted or unsubstituted C - ⁇ 5 heterocycloalkylene group, or substituted or unsubstituted C 2 - ⁇ 5 heteroarylalkylene group.
  • Ri and R , R 2 and R , R ⁇ and R 3 may be linked to each other.
  • the metal complex is a ruthenium complex represented by Formula 3.
  • Yi, Y , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 each independently represent substituted or unsubstituted C ⁇ - 10 alkyl group, substituted or unsubstituted C 6 - ⁇ 5 aryl group, substituted or unsubstituted CM S heteroaryl group.
  • a chiral hydroxy ester is prepared by multi-step catalytic reactions in which an enzyme and a metal complex are used to induce asymmetrical reduction and transformation reaction.
  • a substrate having both ketone group and acyloxy group as represented by Formula 2 a substrate having both ketone group and acyloxy group as represented by Formula 2; a ruthenium complex as represented by Formula 3, which reduces the ketone group and catalyzes the racemization of hydroxyl group; a hydrogen donor to reduce the ketone group; and an enzyme that catalyzes enantioselective acylation of one enantiomer of the racemic alcohols obtained by the racemization of hydroxyl group.
  • Ri and R 3 are independently selected from the group consisting of substituted or unsubstituted C 1 - 15 alkyl group, substituted or unsubstituted C 1 - 15 akenyl group, substituted or unsubstituted C ⁇ - ⁇ 5 alkynyl group, substituted or unsubstituted C 6 - ⁇ 5 aryl group, substituted or unsubstituted C - ⁇ 5 heteroaryl group, substituted or unsubstituted
  • R 2 is selected from the group consisting of substituted or unsubstituted C ⁇ - ⁇ 5 alkylene group, substituted or unsubstituted C 6 - ⁇ 5 arylene group, substituted or unsubstituted C 1 - 15 heteroarylene group, substituted or unsubstituted C - ⁇ 5 cycloalkylene group, substituted or unsubstituted C 4 - ⁇ 5 heterocycloalkylene group, and substituted or unsubstituted C 1 - 15 heteroarylalkylene group.
  • Ri and R , R and R 3 , and Ri and R 3 may be linked to each other.
  • Examples of linking formation are substituted or unsubstituted fused ring of 7-20 carbon atoms or substituted or unsubstituted hetero fused ring of 5-20 carbon atoms.
  • the chemical compound of Formula 2 has both ketone and acyloxy groups and is preferably represented by Formulas 4 or 5.
  • R 4 represents an Ci-10 alkyl group or an alkyl group with substituted heteroatoms
  • R 5 represents C 1 . 5 alkyl group, C 2 - 5 alkenyl group, or C 2 - 5 alkynyl group
  • m represents an integer between 1 to 6
  • X represents halogen atom, C 1 - 5 alkyl group, C 2 - 5 alkenyl group, C 1 - 5 alkoxy group, nitro group, amide group, sulfonyl group or more
  • thioalkoxy group represents C 6 - ⁇ o aryl group or Ci- 10 heteroaryl group.
  • Formulas 4 and 5 include Formulas 4a through 4d or Formulas 5 a through 5d. [Formula 4a]
  • Examples of unsubstituted C ⁇ - ⁇ 5 alkyl group include methyl, ethyl, propyl, isobutyl, sec-butyl, pentyl, iso-amil and hexyl. More than one hydrogen atom in such alkyl group may be substituted with halogen atom, halide, hydroxy group, nitro group, cyano group, amino group, amidino group, hydrazine, hydrazone, carboxyl group, sulfonic acid group, phosphoric acid group, lower alkyl group with 1 to 15 carbon atoms, and lower alkoxy group with 1 to 15 carbon atoms.
  • the unsubstituted C 1 -1 5 alkenyl or unsubstituted Ci-is alkynyl group refers to an alkyl group containing double or triple carbon bonding in the middle or at the end of the chain. Examples thereof include ethylene, propylene, butylene, hexylene and acetylene. More than one hydrogen atom in such alkenyl or alkynyl groups may be substituted with the same substituents as listed for the C 1 - 15 alkyl group.
  • Examples of the unsubstituted C 1 - 15 alkylene group include methylene, ethylene, propylene, isobutylene, sec-butylene, pentylene, iso-amilene and hexylene. More than one hydrogen atom in the alkylene group may be substituted with the same substituents as listed for the C ⁇ - ⁇ alkyl group.
  • the aryl group refers to C 6 - 3 o carbocycle aromatic system in one or more ring structure, which may be used solely or in a combination. These rings may be held together by pendant method or fused together. Examples of aryl include phenyl, naphtyl, tetrahydronaphtyl, indenyl and biphenyl. More than one hydrogen atom in these aryl groups may be substituted with the same substituents as listed for the C ⁇ - ⁇ 5 alkyl group.
  • the arylalkyl group is formed when one or more of the hydrogen atoms of the aryl group are substituted with lower alkyl radicals, such as methyl, ethyl or propyl radicals. Examples include benzil and phenylethyl. More than one hydrogen atom in the arylalkyl group may be substituted with the same substituents as listed for the d- ⁇ 5 alkyl group.
  • the heteroaryl group refers to a mono- or bicyclic aromatic group which includes 1, 2, 3 or 4 heteroatoms chosen from N, O, P and S. Also, the heteroaryl group refers to a mono- or bicyclic aromatic group in which heteroatom is oxidized or alkylated to form an oxide such as N-oxide or a quaternary amine salt.
  • Examples thereof include thienyl, benzothienyl, pyridyl, pyrazinyl, pyramidmyl, pyridazinyl, quinolinyl, quinoxalinyl, imidazolyl, furanyl, benzofuranyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pirazolyl, pyrolyl, indolyl, 2-pyridonyl, 4- pyridonyl, N-alkyl-2-pyridonyl, pyrazinonyl, pyridazinonyl, pyrimidinonyl, oxazolonyl, corresponding N-oxides (for example, pyridyl N-oxide and quinolinyl N-oxide) and quaternary salts thereof but are not limited only to the ones specified. More than one hydrogen atom in the heteroaryl group may be substituted
  • the heteroarylalkyl group refers to a heteroaryl group in which hydrogen atoms are partially substituted with alkyl groups. More than one hydrogen atom in the heteroarylalkyl group may be substituted with the same substituents as listed for the d- is alkyl group.
  • the cycloalkyl group refers to a monocyclic group including 4 to 15 carbon atoms. More than one hydrogen atom in the cycloalkyl group may be substituted with the same substituents as listed for the C1-15 alkyl group.
  • the heterocycloalkyl group refers to a monocyclic aromatic group, which includes 1, 2, 3 or 4 heteroatoms chosen from N, O, P or S. More than one hydrogen atom in the heterocycloalkyl group may be substituted with the same substituents as listed for the C 1 - 15 alkyl group.
  • the ruthenium complex of the Formula 3 reduces ketone group of the Formula 2 and simultaneously catalyzes the racemization reaction of hydroxyl obtained from the reduction.
  • the complex preferably has a phenyl group or a methyl group in all Yi to Y 8 groups.
  • the amount of the ruthenium complex per 1 mole of the compound of Formula 2 is preferably 0.01 to 0.05 mol. More preferably 0.02 to 0.04 mol. When the amount is less than 0.01 mol, the reaction is excessively slow, and when the amount is greater than 0.05 mol, the production cost of chiral ester is high.
  • Lipase is an enzyme that hydrolizes ester, and selectively acylates one of the enantiomers of the racemic alcohol to produce chiral ester with high optical purity.
  • lipase Pseudomonas cepacia lipase(LPS), Candida antarctica lipase(CAL) and Candida rugosa lipase(CRL).
  • Immobilized LPS and immobilized CAL B are preferable.
  • the amount of the immobilized lipase is 0.5 to 20 mg per 1 mmol of the substrate, but preferably 1 to 10 mg.
  • Hydrogen donor reduces the ketone group of Formula 2 to hydroxyl group in the presence of the catalyst of the ruthenium complex of Formula 3.
  • One or more of such hydrogen donor is selected from the group consisting of hydrogen, formic acid, and alcohol of Formula 6.
  • the alcohol of Formula 6 has alkyl side-chain not to be affected by enzyme. Examples thereof are 2,4-dimethyl-3- ⁇ entanol and 2,6-dimethyl-4-he ⁇ tanol.
  • hydrogen under the atmospheric pressure is used as the hydrogen donor because of easiness in removal after reaction.
  • the amount of hydrogen donor is preferably 1 to 50 mol per 1 mol of the compound of Formula 2.
  • apro tonic solvent such as benzene, toluene, hexane, tetrahydrofuran, dioxan, C 2 - ⁇ o dialkyl ether (e.g., diethyl ether), C 3 - ⁇ o alkylacetate (e.g., ethyl acetate), acetonitrile, acetone, dicloromethane, cloroform, and carbon tetrachloride.
  • benzene, toluene, hexane, tetrahydrofuran, dioxan C 2 - ⁇ o dialkyl ether (e.g., diethyl ether), C 3 - ⁇ o alkylacetate (e.g., ethyl acetate), acetonitrile, acetone, dicloromethane, cloroform, and carbon tetrachloride.
  • the suitable amount of the solvent is controlled between 0.2 to 0.4 M based on the substrate used.
  • appropriate temperature of the reaction varies depending on the ruthenium catalyst, preferably, the temperature is 50 to 100° C and more preferably 70 to 80° C. At temperature below 50° C, the racemization reaction is slow, but at temperature above 100° C, the enzyme rapidly loses its activity.
  • Equation 1 illustrates the multi-step reaction of one of the representative examples.
  • Equation 1 The product of the above Equation 1 is useful as an intermediate for chiral medicines such as rivastigmine.
  • Table 1 shows the yield and optical purity of chiral esters prepared according to Experiments 1 to 8. The yield was determined by H-NMR and the optical purity was analyzed by High Performance Liquid Chromatography (HPLC) equipped with chiral column.
  • HPLC High Performance Liquid Chromatography
  • chiral hydroxy esters are obtained with high optical purities and yields from substrates with various structures, all having both ketone and acyloxy groups in a molecule.
  • the invention demonstrates that the synthesis of chiral compound by enzyme/metal catalyzed multi-step reaction can be executed in single reaction chamber.
  • the chiral hydroxy ester prepared by the invention is useful as an intermediate compound in production of agricultural chemicals, medicines and natural chemical compounds.
  • the chiral hydroxy ester of Formula la prepared by the method according to the invention, is exceptionally useful as an intermediate compound in preparing a medicine such as rivastigmine.

Abstract

The invention provides a process for preparing a chiral hydroxy ester by reacting a compound having botha ketone group and an acyloxy group in a molecule with a hydrogen donor which reduces the ketone group into an hydroxyl group; a metal complex, which catalyzes both the reduction of the ketone and racemization reaction of produced hydroxy group; and an enzyme, which catalyzes enantioselective acyl transfer in anorganic solvent.

Description

METHOD FOR THE PREPARATION OF CHIRAL HYDROXY ESTERS BY
ENZYME/METAL MULTI-CATALYSIS
Technical Field The invention relates to a method for preparing chiral hydroxy esters, particularly, to a process for preparing chiral hydroxy esters with high optical purities by combining an enzyme and a metal catalyst in a single reaction chamber and inducing multi-step catalytic reactions.
Background Art
Much effort was focused on the developing new methods for stereoselective synthesis of optically active compounds with high optical purities. Among them, two methods are well studied and applied; one is kinetic resolution, utilizing an enzyme catalyst and the other is asymmetric synthesis, utilizing, a metal catalyst. (Wong, C. H.; Whitesides, G. M. Enzymes in Synthetic Organic Chemistry; Pergamon: Oxford, U. K., 1994; Noyori, R., Asymmetric Catalysts in Organic Synthesis; Wiley: New York, 1994).
The kinetic resolution has some advantages - high optical purity of the end product, low unit cost of the enzyme catalyst, and simple reaction condition - and one apparent disadvantage that the yield is less than 50%. On the other hand, the asymmetric synthesis leads high optical purity and yield, but causes the increase of production cost due to the use of expensive chiral reagents. Also, the reaction conditions are complicated.
Recently, a new method that combines an enzyme catalyst and a metal catalyst, has been introduced. (Persson, B. A.; Larsson, A. L. E.; Ray, M. L.; Backvall, J.-E. J. Am. Chem. Soc. 1999, 121, 1645.; Lee, D. EL; Huh, E. A.; Kim, M. -J.; Jung, H. M.; Koh, J. EL; Park, J., Org. Lett. 2000, 2, 2377) for the dynamic kinetic resolution of racemic alcohols. According to dynamic kinetic resolution, an enzyme, as an enantioselective acylation catalyst is used with a metal catalyst as a racemization catalyst to produce single enantiomer from a racemic mixture. The yields of the products by this method are higher than those by optical resolution that uses enzyme catalysts only. Furthermore, this method is cost effective compared to the asymmetric synthesis that uses expensive chiral reagents.
It was also reported that ketones were successfully transformed to optically pure esters by the combination of an enzyme and a metal catalyst. (Jung, H. M.; Koh, J. H.; Kim, M.-J.; Park, J., Org. Lett. 2000, 2, 409; Jung, H. M.; Koh, J. EL; Kim, M.-J.; Park, J., Org. Zett. 2000, 2, 2487). h this reaction, an excessive amount of acyl donor is used to increase yields. However, the excessive use of acyl donor increases the production cost and makes the separation of required product difficult because the acyl donor remains unreacted in a large portion and has similar polarity with that of product.
Disclosure of Invention
The invention provides a process for synthesizing chiral hydroxy esters with high optical purity and high yield from ketones by the combination of an enzyme catalyst and a metal catalyst without additional acyl donors, thereby resolving the problem caused by the use of excessive acyl donors.
In detail, the invention provides a process for preparing chiral hydroxy esters by reacting a compound having both a ketone group and an acyloxy group in a molecule; a hydrogen donor which reduces the ketone into a hydroxy group; a metal complex, which catalyzes both the reduction of the ketone group and racemization of produced hydroxy group; and an enzyme, which catalyzes enantioselective acyl transfer in a suitable organic solvent.
Formula 1 represents the chiral hydroxy ester. Formula 2 represents the substrate compound having both a ketone and an acyloxy group.
[Formula 1]
Figure imgf000003_0001
[Formula 2]
Figure imgf000003_0002
wherein Ri and R3 independently represent substituted or unsubstituted Cι-ι5 alkyl group, substituted or unsubstituted Cι-ι5 akenyl group, substituted or unsubstituted Cι-ι5 alkynyl group, substituted or unsubstituted C6-ι5 aryl group, substituted or unsubstituted Ci-15 heteroaryl group, substituted or unsubstituted C4-ι5 cycloalkyl group, substituted or unsubstituted C -ι5 heterocycloalkyl group or substituted or unsubstituted C2-ι5 heteroarylalkyl group.
R2 represents substituted or unsubstituted C1-15 alkylene group, substituted or unsubstituted C6-ι5 arylene group, substituted or unsubstituted C -ι5 heteroarylene group, substituted or unsubstituted C -ι5 cycloalkylene group, substituted or unsubstituted C -ι5 heterocycloalkylene group, or substituted or unsubstituted C2-ι5 heteroarylalkylene group. Ri and R , R2 and R , R\ and R3 may be linked to each other.
In one embodiment, the metal complex is a ruthenium complex represented by Formula 3.
[Formula 3]
Figure imgf000004_0001
wherein Yi, Y , Y3, Y4, Y5, Y6, Y7 and Y8 each independently represent substituted or unsubstituted Cι-10 alkyl group, substituted or unsubstituted C6-ι5 aryl group, substituted or unsubstituted CMS heteroaryl group.
Best mode for carrying out the Invention
The above and other features and advantages of the present invention will become more apparent by describing in detail exemplary embodiments thereof.
In the present invention, a chiral hydroxy ester is prepared by multi-step catalytic reactions in which an enzyme and a metal complex are used to induce asymmetrical reduction and transformation reaction.
Specifically, the following are mixed to form a substrate: a substrate having both ketone group and acyloxy group as represented by Formula 2; a ruthenium complex as represented by Formula 3, which reduces the ketone group and catalyzes the racemization of hydroxyl group; a hydrogen donor to reduce the ketone group; and an enzyme that catalyzes enantioselective acylation of one enantiomer of the racemic alcohols obtained by the racemization of hydroxyl group.
Then, the mixture is soaked in a solvent, deoxygenated by purging with inert gas, and agitated at 0 to 100° C to complete the reaction. The reacted mixture is worked-up and purification process provides optically pure hydroxy ester of Formula 1. [Formula 1]
Figure imgf000005_0001
[Formula 2]
Figure imgf000005_0002
wherein Ri and R3 are independently selected from the group consisting of substituted or unsubstituted C1-15 alkyl group, substituted or unsubstituted C1-15 akenyl group, substituted or unsubstituted Cι-ι5 alkynyl group, substituted or unsubstituted C6-ι5 aryl group, substituted or unsubstituted C -ι5 heteroaryl group, substituted or unsubstituted
C -ι5 cycloalkyl group, substituted or unsubstituted C -ι5 heterocycloalkyl group and substituted or unsubstituted C2-ι5 heteroarylalkyl group.
R2 is selected from the group consisting of substituted or unsubstituted Cι-ι5 alkylene group, substituted or unsubstituted C6-ι5 arylene group, substituted or unsubstituted C1-15 heteroarylene group, substituted or unsubstituted C -ι5 cycloalkylene group, substituted or unsubstituted C4-ι5 heterocycloalkylene group, and substituted or unsubstituted C1-15 heteroarylalkylene group.
Ri and R , R and R3, and Ri and R3 may be linked to each other. Examples of linking formation are substituted or unsubstituted fused ring of 7-20 carbon atoms or substituted or unsubstituted hetero fused ring of 5-20 carbon atoms.
[Formula 3]
Figure imgf000006_0001
wherein Yi, Y , Y3, Y4, Y5, Y6, Y7 and Y8 each independently represent substituted or unsubstituted alkyl group with 1 to 10 carbon atoms, substituted or unsubstituted C6-ι5 aryl group, substituted or unsubstituted C1-15 heteroaryl group.
The chemical compound of Formula 2 has both ketone and acyloxy groups and is preferably represented by Formulas 4 or 5.
[Formula 4]
Figure imgf000006_0002
[Formula 5]
Figure imgf000006_0003
wherein R4 represents an Ci-10 alkyl group or an alkyl group with substituted heteroatoms, R5 represents C1.5 alkyl group, C2-5 alkenyl group, or C2-5 alkynyl group, m represents an integer between 1 to 6, X represents halogen atom, C1-5 alkyl group, C2- 5 alkenyl group, C1-5 alkoxy group, nitro group, amide group, sulfonyl group or more
than one thioalkoxy group. Further,
Figure imgf000006_0004
represents C6-ιo aryl group or Ci-10 heteroaryl group.
Examples of Formulas 4 and 5 include Formulas 4a through 4d or Formulas 5 a through 5d. [Formula 4a]
Figure imgf000007_0001
[Formula 4b]
Figure imgf000007_0002
[Formula 4c]
Figure imgf000007_0003
[Formula 4d]
Figure imgf000007_0004
[Formula 5 a]
Figure imgf000007_0005
[Formula 5b]
Figure imgf000008_0001
[Formula 5 c]
Figure imgf000008_0002
[Formula 5d]
Figure imgf000008_0003
The definitions and examples of the terminology used in this invention are described herein below:
Examples of unsubstituted Cι-ι5 alkyl group include methyl, ethyl, propyl, isobutyl, sec-butyl, pentyl, iso-amil and hexyl. More than one hydrogen atom in such alkyl group may be substituted with halogen atom, halide, hydroxy group, nitro group, cyano group, amino group, amidino group, hydrazine, hydrazone, carboxyl group, sulfonic acid group, phosphoric acid group, lower alkyl group with 1 to 15 carbon atoms, and lower alkoxy group with 1 to 15 carbon atoms. The unsubstituted C1-15 alkenyl or unsubstituted Ci-is alkynyl group refers to an alkyl group containing double or triple carbon bonding in the middle or at the end of the chain. Examples thereof include ethylene, propylene, butylene, hexylene and acetylene. More than one hydrogen atom in such alkenyl or alkynyl groups may be substituted with the same substituents as listed for the C1-15 alkyl group.
Examples of the unsubstituted C1-15 alkylene group include methylene, ethylene, propylene, isobutylene, sec-butylene, pentylene, iso-amilene and hexylene. More than one hydrogen atom in the alkylene group may be substituted with the same substituents as listed for the Cι-ι alkyl group. The aryl group refers to C6-3o carbocycle aromatic system in one or more ring structure, which may be used solely or in a combination. These rings may be held together by pendant method or fused together. Examples of aryl include phenyl, naphtyl, tetrahydronaphtyl, indenyl and biphenyl. More than one hydrogen atom in these aryl groups may be substituted with the same substituents as listed for the Cι-ι5 alkyl group.
The arylalkyl group is formed when one or more of the hydrogen atoms of the aryl group are substituted with lower alkyl radicals, such as methyl, ethyl or propyl radicals. Examples include benzil and phenylethyl. More than one hydrogen atom in the arylalkyl group may be substituted with the same substituents as listed for the d-ι5 alkyl group.
The heteroaryl group refers to a mono- or bicyclic aromatic group which includes 1, 2, 3 or 4 heteroatoms chosen from N, O, P and S. Also, the heteroaryl group refers to a mono- or bicyclic aromatic group in which heteroatom is oxidized or alkylated to form an oxide such as N-oxide or a quaternary amine salt. Examples thereof include thienyl, benzothienyl, pyridyl, pyrazinyl, pyramidmyl, pyridazinyl, quinolinyl, quinoxalinyl, imidazolyl, furanyl, benzofuranyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pirazolyl, pyrolyl, indolyl, 2-pyridonyl, 4- pyridonyl, N-alkyl-2-pyridonyl, pyrazinonyl, pyridazinonyl, pyrimidinonyl, oxazolonyl, corresponding N-oxides (for example, pyridyl N-oxide and quinolinyl N-oxide) and quaternary salts thereof but are not limited only to the ones specified. More than one hydrogen atom in the heteroaryl group may be substituted with the same substituents as listed for the CM5 alkyl group.
The heteroarylalkyl group refers to a heteroaryl group in which hydrogen atoms are partially substituted with alkyl groups. More than one hydrogen atom in the heteroarylalkyl group may be substituted with the same substituents as listed for the d- is alkyl group.
The cycloalkyl group refers to a monocyclic group including 4 to 15 carbon atoms. More than one hydrogen atom in the cycloalkyl group may be substituted with the same substituents as listed for the C1-15 alkyl group.
The heterocycloalkyl group refers to a monocyclic aromatic group, which includes 1, 2, 3 or 4 heteroatoms chosen from N, O, P or S. More than one hydrogen atom in the heterocycloalkyl group may be substituted with the same substituents as listed for the C1-15 alkyl group. Preferably, the ruthenium complex of the Formula 3 reduces ketone group of the Formula 2 and simultaneously catalyzes the racemization reaction of hydroxyl obtained from the reduction. The complex preferably has a phenyl group or a methyl group in all Yi to Y8 groups. Also, the amount of the ruthenium complex per 1 mole of the compound of Formula 2 is preferably 0.01 to 0.05 mol. More preferably 0.02 to 0.04 mol. When the amount is less than 0.01 mol, the reaction is excessively slow, and when the amount is greater than 0.05 mol, the production cost of chiral ester is high.
A enzyme, which catalyzes the acyl transfer reaction, is used, and more specifically, lipase is used. Lipase is an enzyme that hydrolizes ester, and selectively acylates one of the enantiomers of the racemic alcohol to produce chiral ester with high optical purity. Examples of such lipase are Pseudomonas cepacia lipase(LPS), Candida antarctica lipase(CAL) and Candida rugosa lipase(CRL). Immobilized LPS and immobilized CAL B are preferable. The amount of the immobilized lipase is 0.5 to 20 mg per 1 mmol of the substrate, but preferably 1 to 10 mg.
Hydrogen donor reduces the ketone group of Formula 2 to hydroxyl group in the presence of the catalyst of the ruthenium complex of Formula 3. One or more of such hydrogen donor is selected from the group consisting of hydrogen, formic acid, and alcohol of Formula 6.
[Formula 6]
H
R' C R"
OH wherein R' and R"each independently represent straight-chained, or branched CMO alkyl group, C6-i5 aryl group, or C1-15 heteroaryl group.
Preferably, the alcohol of Formula 6 has alkyl side-chain not to be affected by enzyme. Examples thereof are 2,4-dimethyl-3-ρentanol and 2,6-dimethyl-4-heρtanol. Preferably, hydrogen under the atmospheric pressure is used as the hydrogen donor because of easiness in removal after reaction. The amount of hydrogen donor is preferably 1 to 50 mol per 1 mol of the compound of Formula 2.
It is not necessary to use a particular type of solvent. However, because the yield and enatioselectivity of the product are affected in lipase-catalyzed reaction by solvent, it is preferable to use apro tonic solvent such as benzene, toluene, hexane, tetrahydrofuran, dioxan, C2-ιo dialkyl ether (e.g., diethyl ether), C3-ιo alkylacetate (e.g., ethyl acetate), acetonitrile, acetone, dicloromethane, cloroform, and carbon tetrachloride. The suitable amount of the solvent is controlled between 0.2 to 0.4 M based on the substrate used. Although appropriate temperature of the reaction varies depending on the ruthenium catalyst, preferably, the temperature is 50 to 100° C and more preferably 70 to 80° C. At temperature below 50° C, the racemization reaction is slow, but at temperature above 100° C, the enzyme rapidly loses its activity.
Equation 1 illustrates the multi-step reaction of one of the representative examples.
[Equation 1]
Figure imgf000012_0001
The product of the above Equation 1 is useful as an intermediate for chiral medicines such as rivastigmine.
EXAMPLES
The following examples are intended to exemplify the claimed invention, and should not be construed as limiting the scope of the claimed invention.
[Example 1]
6mmol of compound of Formula 4, 0.012 mmol of ruthenium complex of Formula 3 (Both Yi and Y are phenyl), and 5 mg of immobilized lipase were mixed with 1.5 ml of toluene. The reaction vessel was deoxygenated and filled with hydrogen gas at atmospheric pressure. The resulting mixture was agitated for 72 hours at room temperature. After the complete reaction, optically pure hydroxy ester of Formula la was obtained by column chromatography.
[Formula la]
Figure imgf000013_0001
[Examples 2 to 8]
Using the same method as Example 1, but instead of using the compound of Formula 4, the compounds of Formula 4b to 4d and 5a to 5d, were used to obtain chiral hydroxy esters of Formulas lb to lh below, respectively.
[Formula lb]
Figure imgf000013_0002
[Formula lc]
Figure imgf000013_0003
[Formula Id]
Figure imgf000013_0004
[Formula le]
Figure imgf000014_0001
[Formula If]
Figure imgf000014_0002
[Formula lg]
Figure imgf000014_0003
[Formula lh]
Figure imgf000014_0004
Table 1 shows the yield and optical purity of chiral esters prepared according to Experiments 1 to 8. The yield was determined by H-NMR and the optical purity was analyzed by High Performance Liquid Chromatography (HPLC) equipped with chiral column.
[Table 1]
Figure imgf000015_0001
According to Examples 1 through 8, as Table 1 depicts, the compounds having both ketone and acyloxy groups in a molecule were successfully transformed to optically pure hydroxyl esters in the presence of a ruthenium complex as a reduction and racemization catalyst, lipase as an acyl transfer catalyst, hydrogen gas as a hydrogen donor by multi-step catalytic reactions.
Industrial Applicability
According to the invention, chiral hydroxy esters are obtained with high optical purities and yields from substrates with various structures, all having both ketone and acyloxy groups in a molecule. The invention demonstrates that the synthesis of chiral compound by enzyme/metal catalyzed multi-step reaction can be executed in single reaction chamber. The chiral hydroxy ester prepared by the invention is useful as an intermediate compound in production of agricultural chemicals, medicines and natural chemical compounds. In particular, the chiral hydroxy ester of Formula la, prepared by the method according to the invention, is exceptionally useful as an intermediate compound in preparing a medicine such as rivastigmine.

Claims

What is claimed is:
1. A process for preparing a chiral hydroxy ester comprising:
mixing a substrate compound having both a ketone group and an acyloxy group in a molecule with a hydrogen donor which reduces the ketone group into an hydroxy group, a metal complex ? which catalyzes both the reduction of the ketone into the hydroxy group and the racemization of produced hydroxy group, and an enzyme which catalyzes enantioselective acyl transfer in an organic solvent; and
reacting the mixture.
2. The process of claim 1, wherein the chemical compound having both the ketone and the acyloxy group is represented by Formula 2 and the chiral hydroxy ester is represented by Formula 1
[Formula 1]
Figure imgf000016_0001
[Formula 2]
Figure imgf000016_0002
wherein Ri and R3 independently represent substituted or unsubstituted C S alkyl group, substituted or unsubstituted C1-15 akenyl group, substituted or unsubstituted C1-15 alkynyl group, substituted or unsubstituted C6-i5 aryl group, substituted or unsubstituted Ci-15 heteroaryl group, substituted or unsubstituted C4_i5 cycloalkyl group, substituted or unsubstituted C -ιs heterocycloalkyl group, or substituted or unsubstituted C -ιs heteroarylalkyl group;
R represents substituted or unsubstituted Ci-15 alkylene group, substituted or unsubstituted C6-ι5 arylene group, substituted or unsubstituted .15 heteroarylene group, substituted or unsubstituted C -ι5 cycloalkylene group, substituted or unsubstituted C -ιs heterocycloalkylene group, or substituted or unsubstituted C2-ι5 heteroarylalkylene group; and
Ri and R , R2 and R3, Ri and R3 may be linked to each other.
3. The process of claim of 2, wherein the compound of the Chemical Formula 2 is represented by Formula 4 or 5
[Formula 4]
Figure imgf000017_0001
[Formula 5]
Figure imgf000017_0002
wherein R4 represents an Ci-io alkyl group or an alkyl group substituted with heteroatoms;
R5 represents C1-5 alkyl group, C2-5 alkenyl group, C2-5 alkynyl group;
m represents an integer between 1 to 6;
X represents halogen atom, C1-5 alkyl group, C2-5 alkenyl group, C1-5 alkoxy group, nitro group, amide group, sulfonyl group or more than one thioalkoxy group; and
Figure imgf000018_0001
represents C6-ιo aryl group or Ci-io heteroaryl group.
4. The process of claim 1, wherein the metal complex is a ruthenium complex as represented by Formula 3. [Formula 3]
Figure imgf000018_0002
wherein Yi, Y2, Y3, Y , Y5, Y6, Y7 and Y8 each independently represent substituted or unsubstituted Ci-io alkyl group, substituted or unsubstituted C6-ιs aryl group, substituted or unsubstituted -15 heteroaryl group.
5. The process of claim 4, wherein Yi to Y8 of the ruthenium complex are all phenyl or methyl group.
6. The process of claim 1, wherein the amount of the metal complex represented by the Formula 3 is 0.01 to 0.05 mol per 1 mol of the substrate used.
7. The process of claim 1, wherein the reaction of the mixture is carried out at a temperature of 0 to 100°. .
8. The process claim of 1, wherein the hydrogen donor is selected from the group consisting of hydrogen, formic acid and alcohol of Formula 6 [Formula 6]
H
R' c R"
OH wherein R' and R" each independently represent straight-chamed, or branched Ci-10 alkyl group, C6-ι5 aryl group, or C 1-15 heteroaryl group.
9. The process of claim 8, wherein the hydrogen donor is supplied at atmospheric pressure.
10. The process of claim 1, wherein the enzyme is a lipase selected from the group consisting of Pseudomonas cepacia lipase (LPS), Candida antarctica lipase (CAL) and Candida rugosa lipase (CRL).
PCT/KR2003/001437 2002-10-31 2003-07-21 Method for the preparation of chiral hydroxy esters by enzyme/metal multi-catalysis WO2004039998A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2002-0067058A KR100462473B1 (en) 2002-10-31 2002-10-31 Method for the preparation of chiral hydroxy esters by enzyme-metal multi-catalysis
KR10-2002-0067058 2002-10-31

Publications (1)

Publication Number Publication Date
WO2004039998A1 true WO2004039998A1 (en) 2004-05-13

Family

ID=32226220

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2003/001437 WO2004039998A1 (en) 2002-10-31 2003-07-21 Method for the preparation of chiral hydroxy esters by enzyme/metal multi-catalysis

Country Status (2)

Country Link
KR (1) KR100462473B1 (en)
WO (1) WO2004039998A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5216015A (en) * 1991-02-05 1993-06-01 Rhone-Poulenc Rorer Pharmaceuticals Inc. Compounds having hypocholesterolemic properties
US5625030A (en) * 1994-01-06 1997-04-29 Metabolix, Inc. Methods for synthesizing oligomers containing hydroxy acid units
US5886213A (en) * 1997-08-22 1999-03-23 Gilead Sciences, Inc. Preparation of carbocyclic compounds
US20020156300A1 (en) * 1996-08-23 2002-10-24 Gilead Sciences, Inc. Preparation of cyclohexene carboxylate derivatives

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1057094A (en) * 1996-06-14 1998-03-03 Yasuyuki Kita Enzymatic optical resolution of alcohol using ketene acetal type acylating agent
CN1390189A (en) * 1999-12-02 2003-01-08 三星精密化学株式会社 Method for preparing chiral ester

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5216015A (en) * 1991-02-05 1993-06-01 Rhone-Poulenc Rorer Pharmaceuticals Inc. Compounds having hypocholesterolemic properties
US5625030A (en) * 1994-01-06 1997-04-29 Metabolix, Inc. Methods for synthesizing oligomers containing hydroxy acid units
US20020156300A1 (en) * 1996-08-23 2002-10-24 Gilead Sciences, Inc. Preparation of cyclohexene carboxylate derivatives
US5886213A (en) * 1997-08-22 1999-03-23 Gilead Sciences, Inc. Preparation of carbocyclic compounds

Also Published As

Publication number Publication date
KR100462473B1 (en) 2004-12-17
KR20040038176A (en) 2004-05-08

Similar Documents

Publication Publication Date Title
JP3789938B2 (en) Racemic resolution of primary and secondary heteroatom-substituted amines by enzyme-catalyzed acylation
JPS63273499A (en) Production of optically active compound
JPH03228694A (en) Production of optically active hydroxylactones
Bora et al. First example of hydrolytic kinetic resolution of acrylate of secondary alcohols by lipase Amano AK
US6753443B1 (en) Preparing method of chiral ester
WO2004039998A1 (en) Method for the preparation of chiral hydroxy esters by enzyme/metal multi-catalysis
US7582469B2 (en) Method for enantioselectively opening oxetan-2-ones
US8546114B2 (en) Processes for the preparation of optically active cyclopentenones and cyclopentenones prepared therefrom
WO2007078176A1 (en) The method of making optically active 2-chloromandelic acid esters and 2-chloromandelic acids by enzymatic method
KR0150592B1 (en) Separation method of racemic (r,s)-1,2-phenylethandiol by using enzymes
WO2006008170A1 (en) Process for the preparation of (2r, 3r)-2-hydroxy-3-amino-3-aryl-propionamide and (2r, 3r)-2-hydroxy-3-amino-3-aryl-propionic acid alkyl ester
KR100651338B1 (en) Method for preparing optically active R-2-chloromandelic acid and its ester derivatives using Baker's Yeast
KR100359028B1 (en) Method for preparing chiral allyl ester
JP3555480B2 (en) Production method of optically active compound
EP0239122A2 (en) Process for the enzymatic resolution of racemic 2-amino-1-alkanols
EP2218788A1 (en) Process for the preparation of optically active cyclopentenones
KR20070076549A (en) Processes for the preparations of optically active cyclopentenones and cyclopentenones prepared therefrom
KR100545472B1 (en) The method of preparing optically active cis-1-Ramino-2-indanol and their esters by enzymatic method
US6140516A (en) Process for the preparation of trans-3-alkyloxy-4-hydroxytetrahydrofuran
JP5167699B2 (en) N-glucono-glutamic acid ester, method for producing the same, and intermediate thereof
JP2005506091A (en) Process for the production of (R)-and (S) -8-chloro-6-hydroxy-octanoic acid alkyl esters by enzymatic reduction
KR100688905B1 (en) Process for preparing r-2-acyloxy-1-arylpropanone and s-2-hydroxy-1-arylpropanone derivative from 2-hydroxy-1-arylpropanone by using lipase
KR20010037656A (en) Method for preparing chiral allyl alcohol
JP4106079B2 (en) Method for producing optically active epoxy alcohol
WO2001040157A1 (en) Method for preparing chiral esters

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA CN IN JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP