WO2001028971A1

WO2001028971A1 - Method for preparing chiral ester

Info

Publication number: WO2001028971A1
Application number: PCT/KR2000/001171
Authority: WO
Inventors: Jai Wook Park; Mahn-Joo Kim; Jeong Hwan Koh; Hyun Min Jung
Original assignee: Samsung Fine Chemicals Co., Ltd.; Pohang University Of Science And Technology
Priority date: 1999-10-18
Filing date: 2000-10-18
Publication date: 2001-04-26
Also published as: KR100402049B1; AU1058901A; CA2387950A1; EP1226105A4; JP2003512035A; KR20010040122A; CN1379753A; EP1226105A1

Abstract

The present invention relates to a process for preparing a chiral ester expressed in formula (100) by mixing and reacting: a ketone of formula (4); a ruthenium complex selected from the group consisting of compounds (1, 2 and 3) expressed in formula (1) to (3) to activate hydrogenation of said ketone to a racemic alcohol and racemization of said racemic alcohol; a lipase to acylate selectively one of enantiomers of said racemic alcohol; a hydride donor group to supply a hydride group to said ruthenium complex; and an acyl donor group to supply acyl group to said lipase. In formula (1) wherein Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, and Y12 are independentlya hydrogen atom or C1-C5 alkyl group; and X is Br, Cl or I. In formula (2) wherein Y1, Y2, Y3, Y4, Y5, Y6 Y7, Y8, Y9, Y10, Y11, and Y12 are independently a hydrogen atom or C1-C5 alkyl group; and X is Br, Cl, or I. In formulae (3), (4), and (100) wherein R?1, R2, and R3¿ are, independently, optionally substituted alkyl, optionally substituted aryl or optionally substituted cyclyoalkyl group and R?1 and R2, R1 and R3, and R2 and R3¿ can be cyclized each other, where said substituent of alkyl, aryl and cycloalkyl is a hetero atom such as a halogen atom and a cyano group.

Description

METHOD FOR PREPARING CHIRAL ESTER

BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to a method for preparing a chiral ester and more particularly, the method for preparing an optically pure chiral ester from a ketone at a high yield by using an enzyme and a metallic catalyst.

It is one of important aims to convert a racemic mixture to an optically pure compound enantioselectively in organic synthesis. Recently, studies for using a metal or an enzyme as a catalyst have been increased in asymmetric syntheses. It has been widely known to use an enzyme as a catalyst for kinetic resolution of a racemic mixture in organic syntheses. A variety of effective methods for hydrolyses of esters and acylations of alcohols in the presence of lipase as a catalyst have been reported. Kinetic resolution is the fact that the two enantiomers react at different rates with a chiral addend. An effective kinetic resolution is the enantioselective conversion from the racemic mixture to an optically pure product (scheme 1), leaving the other enantiomer in the reaction mixture.

cheme 1

OH OH Lipase OAc OH

Acyl donor

+ . + R₁ ^/^R₂ R^ ^R₂ Rι^^R₂ RΓ ^"R₂

Conventional methods for preparing a chiral ester from a ketone such as asymmetric hydrogenation of an enol ester converted from a ketone, or esterification of a chrial alcohol prepared by asymmetric hydrogenation of a ketone require at least more than two step syntheses from a ketone to an enol ester. These methods are relatively long and complicate.

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide a simple process for preparing an optically pure chiral ester at a high yield to resolve the above problems.

Detailed Description of the Invention A process for preparing a chiral ester of the present invention is characterized by mixing and reacting: a ketone; a ruthenium complex selected from the group consisting of compounds

1, 2 and 3 expressed in formulas 1 to 3 to activate hydrogenation of said ketone to a racemic alcohol and racemization of said racemic alcohol; a lipase to acylate selectively one of enantiomers of said racemic alcohol; a hydride donor group to supply a hydride group to said ruthenium complex; and an acyl donor group to supply acyl group to said lipase,

wherein Yi, Y₂, Y₃, Y , Ys, Yβ, 7, Ys, Y9, Yio, Yπ, and Y₁₂ are independently a hydrogen atom or C1-C5 alkyl group; and X is Br, Cl or I;

wherein Yi, Y₂, Y3, Y4, Ys, Yό, Y7, Ys, Y9, Yio, Y11, and Y₁₂ are independently a hydrogen atom or C1-C5 alkyl group; and X is Br, Cl or I;

Said ruthenium complex is selected from the group consisting of the compounds 5 to 10 expressed in the following formulas 5 to 10,

wherein X is Cl, Br or I, the most preferably Cl.

A method for preparing a chiral ester from a ketone through one-step synthesis is described in detail as set forth hereunder.

A mixture of a ruthenium complex selected from the group consisting of formulas 1 to 3, a lipase, a hydride donor, an acyl donor, and a ketone is reacted in an appropriate solvent in the presence of a base as shown in Scheme 2. The reaction condition can be varied with a structure of ruthenium complex. For example, when the ruthenium complex of formula 5 is used, the reaction is performed at a temperature of 40 to 50 ^°C . When the ruthenium complex of formula 8 is used, the reaction requires 40 to 50 ^°C of a reaction temperature. When the ruthenium complex of formula 3 is used, the reaction requires 70 to 80 ^°C of a reaction temperature. The ruthenium complex of formula 5 is commercially available and can be converted to the ruthenium complex of formula 8 in alcohol/ amine base condition. Therefore, results from the ruthenium complex of formula 5 and the ruthenium complex of formula 8 are almost same. A content of said ruthenium complex is preferred to use 0.1 to 5 mol%, relative to a ketone. If the content is more than 5 mol%, cost becomes expensive. On the other hand, if it is less than 0.1 mol%, the rate of the reaction becomes too slow. Scheme 2

(4) (100) wherein R¹, R² and R³ are, independently, optionally substituted alkyl, optionally substituted aryl or optionally substituted cycloalkyl group and R¹ and R², R¹ and R³, and R² and R³ can be cyclized each other, where said substituent of alkyl, aryl and cycloalkyl is a hetero atom such as halogen atom and a cyano group.

Said ruthenium complex activates hydrogenation reaction of a ketone to a racemic alcohol by acting as a catalyst to transfer a hydrogen atom and further activates racemization of obtained racemic alcohol.

Said lipase, which is esterase, acylates one enantiomer from a racemic alcohol selectively to a chiral ester. Examples of lipase are Pseudomonas cepacias lipase and Candida antarctica lipase and more particulary, Candida antarctica component B lipase supported on acrylic resin (Novozym 435, Novo company) or Pseudomonas cepacias lipase supported on ceramic particle (lipase PS-C, Amano company), the most preferably Candida antarctica component B lipase supported on acrylic resin for heat resistance, reactivity, optical purity and the like. An amount of said lipase is in the range of 10 to 60mg, preferably 30 mg, relative to 1 mmol of a ketone in Novozym 435 case, and is in the range of 40 to 240 mg, preferably 80 mg, relative to 1 mmol of ketone in lipase PS-C case.

Said ketone is generally expressed in the formula 4. It is not limited but examples of the present invention are compounds 4a, 4b, 4c, 4d, 4e, 4f or 4g,

wherein R¹ and R² are the same as defined above.

Said acyl donor supplies an acyl group to a lipase and acts to move a reaction balance to an acylated product in the presence of lipase catalyst. Preferred acyl donor is aryl ester or alkenyl acetate, the most preferably aryl ester such as p-chlorophenyl acetate having electron withdrawing group. An example of alkenyl acetate is isoprophenyl acetate. Such acyl donor compounds are preferred to use because they have an appropriate reactivity without inhibiting racemization. A preferred amount of said acyl donor compound is 2 to 4 equivalents to 1 equivalent of a ketone. If the amount is more than 4 equivalents to 1 equivalent of a ketone, it is difficult to isolate after reaction. On the other hand, if it is less than 2 equivalents to 1 equivalent of a ketone, the rate of acylation becomes too slow.

A hydride donor supplies a hydride to ruthenium complex. Examples of said hydride donor are 2,6-dimethylheptan-4-ol, hydrogen, and formic acid.

Preferred amount of said hydride donor is 1 to 2 equivalents to 1 equivalent of ketone. If the content deviates from the range, it inhibits racemization reaction.

A base is also required to remove acid generated during the reaction.

Said base includes triethylamine or diisopropylethyl amine and preferred amount to use is in the range of 1 to 2 equivalents to 1 equivalent to ketone.

Reaction solvent is not limited but it is preferred to use methylene chloride, toluene, benzene, or hexane because a solvent commonly affects production yield in enzymatic catalysis reaction. An amount of said solvent is used to be 0.2 to 0.3 M concentration of a ketone. A chiral ester expressed in formula 100 is obtained by reacting a ketone, a ruthenium complex, a lipase, and an acyl donor compound in the presence of hydride donor,

wherein R¹, R² and R³ are, independently, optionally substituted alkyl, optionally substituted aryl or optionally substituted cycloalkyl group and R¹ and R², R¹ and R³, and R² and R³ can be cyclized each other, where said substituent of alkyl, aryl and cycloalkyl is a hetero atom such as a halogen atom and a cyano group.

The chiral ester of formula 100 of the present invention can be used as a synthetic intermediate for preparing various chiral compounds, chiral pharmaceutical drugs or chiral agrochemicals and more particularly, used as an essential intermediate for preparing Atorvastatin expressed in formula 101 which is a useful drug for treatment for hyperlipemia, L-Carnitine expressed in formula 102 which is as an additive used in food and drugs, and Agenerase expressed in formula 103 which is an essential intermediate of AIDS drug.

Especially, a chiral compound of formula 100a which is one of the compounds of the present invention is a key intermediate for preparing Atorvastatin of formula 101 disclosed in US Patent No. 5,908,953,

wherein R is a low alkyl group.

The process for preparing a chiral ester of formula 100 of the present invention provides minimum production of by-products such as unreacted alcohol residue up to less than 5% and maximum production of product up to 100% having a high optical purity of 99% or more. Because optical purity is the most important factor in preparing chiral compounds for food and pharmaceutical drugs, the chiral ester of the present invention can be used as a useful starting material in various fields, especially fine chemical field. The following examples are intended to be illustrative of the present invention and should not be construed as limiting the scope of this invention defined by the appended claims.

Example 1 A ketone of formula 4a(0.25mmol), triethylamine(0.75mmol), ruthenium complex of formula 5(0.0130mmol), where X is Cl, 2,6-dimethylheptan-4- ol(0.38mmol), and 20mg of lipase PS-C(Amano Company) were added to 2.0ml of methylene chloride. The reaction mixture was stirred for 5 min at room temperature and p-chlorophenyl acetate(0.75mmol) was added thereto to give a dark redish suspension.

Argon gas was purged into the reaction suspension, after removing an oxygen under the vacuum condition and then the suspension was heated at 50 ^°C for 78 hours.

Examples 2 to 5

The product, a chiral ester, was prepared by the same procedure of Example 1 except to use ketone of formulas 4b-4e instead of a ketone of formula 4a.

Example 6

The product, a chiral ester, was prepared by the same procedure of Example 1 except to use ruthenium complex of formula 8, where X is Cl, instead of the ruthenium complex of formula 5, where X is Cl.

Examples 7 to 10

The product, a chiral ester, was prepared by the same procedure of Example 6 except to use ketone of formulas 4b-4e instead of a ketone of formula 4a.

Example 11

A ketone of formula 4a(0.25mmol), ruthenium complex of formula 3(0.050mmol), 2,6-dimethylheptan-4-ol(0.38mmol), 7.5mg of Nozyme 435 and p- chlorophenyl acetate(0.75mmol) were added to 0.8ml of toluene to give a yellow suspension. Argon gas was purged into the reaction suspension, after removing an oxygen under the vacuum condition and then the suspension was heated at 70 ^°C for 44 hours.

Examples 12 to 17

The product, a chiral ester, was prepared by the same procedure of Example 11 except to use ketone of formulas 4b-4g instead of a ketone of formula 4a.

In examples 1 to 5 and examples 11 to 17 to prepare chiral esters, formation of an alcohol as a by-product, yield of chiral acetates, and optical purity were determined and tabled in Table 1. Said yields of an alcohol and chiral acetate were analyzed by gas chromatography, and said optical purity was determined by high performance liquid chromatography. Said gas chromatography used was Hewlett Packard 5890 Series II and said high performance liquid chromatography was SpectraSystem P2000.

Table 1

As shown in Table 1, examples 1 to 5 and examples 11 to 17 proved that the present invention provides one-step synthesis for preparing an optically pure chiral ester form a ketone by controlling ruthenium complex to activate racemization and hydrogen transfer and lipase to activate esterification. Further, it provides high formation of the product, chiral ester, having less than 5% of unreacted alcohols.

Claims

CLAIMS What is claimed is:

1. A process for preparing a chiral ester expressed in formula 100 of the present invention is characterized by mixing and reacting: a ketone expressed in formula 4; a ruthenium complex selected from the group consisting of compounds 1, 2 and 3 expressed in formulas 1 to 3 to activate hydrogenation of said ketone to a racemic alcohol and racemization of said racemic alcohol; a lipase to acylate selectively one of enantiomers of said racemic alcohol; a hydride donor group to supply hydride group to said ruthenium complex; and an acyl donor group to supply acyl group to said lipase,_.

wherein Yi, Y₂, Y₃, Y , Ys, Yό, Υγ, Ys, Y9, Yio, Y11, and Y12 are independently a hydrogen atom or C1-C5 alkyl group; and X is Br, Cl or I;

wherein Yi, Y_2/ Y3, Y , Ys, Yό, Y7, Ys, Y9, Yio, Yπ, and Y₁₂ are independently a hydrogen atom or C1-C5 alkyl group; and X is Br, Cl or I;

(4)

wherein R¹, R² and R³ are, independently, optionally substituted alkyl, optionally substituted aryl or optionally substituted cycloalkyl group and R¹ and R², R¹ and R\ and R² and R³ can be cyclized each other, where said substituent of alkyl, aryl and cycloalkyl is a hetero atom such as a halogen atom and a cyano group.

2. The process for preparing a chiral ester according to claim 1, wherein said ketone is selected from the group consisting of the compounds 4a, 4b, 4c, 4d, 4e, 4f and 4g of formulas 4a to 4g.

3. The process for preparing a chiral ester according to claim 1, wherein said ruthenium complex is selected from the group consisting of compounds 5, 6, 7, 8, 9, and 10,

wherein X is Cl, Br or I.

4. The process for preparing a chiral ester according to any one of claim 1 to claim 3, wherein X is Cl.

5. The process for preparing a chiral ester according to claim 1, wherein said lipase is selected from the group consisting of Pseudomonas cepacias lipase and Candida antarctica component B lipase.

6. The process for preparing a chiral ester according to claim 1, wherein said acyl donor compound is aryl ester.

7. The process for preparing a chiral ester according to claim 6, wherein said aryl ester is selected from the group consisting of p-chlorophenyl acetate and alkenyl acetate.

8. The process for preparing a chiral ester according to claim 1, wherein said hydride donor compound is selected from the group consisting of 2,6- dimethylhepthan-4-ol, hydrogen and formic acid.

9. The process for preparing a chiral ester according to claim 1, wherein a content of said ruthenium complex is in the range of 0.1 to 5 mol%, relative to said ketone.