CN1379753A - Method for preparing chiral ester - Google Patents
Method for preparing chiral ester Download PDFInfo
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- CN1379753A CN1379753A CN00814419A CN00814419A CN1379753A CN 1379753 A CN1379753 A CN 1379753A CN 00814419 A CN00814419 A CN 00814419A CN 00814419 A CN00814419 A CN 00814419A CN 1379753 A CN1379753 A CN 1379753A
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- ketone
- lipase
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
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- 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
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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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>, R<2>, and R<3> are, independently, optionally substituted alkyl, optionally substituted aryl or optionally substituted cyclyoalkyl group and R<1> and R<2>, R<1> and R<3>, and R<2> and R<3> 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
Background of invention
Invention field
The present invention relates to a kind of method for preparing chiral ester, or rather, relate to a kind of method of utilizing enzyme and metal catalyst to prepare optically pure chiral ester by the ketone high productivity.
It is a free-revving engine in the organic synthesis that racemic mixture is changed into the optically pure compound with enantio-selectivity.Recently, in asymmetric synthesis, use metal or enzyme more and more as the research of catalyzer.Utilizing enzyme as catalyzer racemic mixture to be carried out kinetic resolution in organic synthesis has been well-known.The multiple effective ways that carry out the acidylate of the hydrolysis of ester and alcohol at lipase under as the condition of catalyzer have been reported.
The fact of kinetic resolution is that two enantiomorphs react with different speed and chirality annexation.Effectively kinetic resolution is the enantio-selectivity conversion (shown in scheme 1) from racemic mixture to the optical purity product, and stays another kind of enantiomorph in reaction mixture.Scheme 1
Prepare the traditional method (for example esterification of the chiral alcohol for preparing of the asymmetric hydrogenation of the enol ester that transforms from ketone or the asymmetric hydrogenation by ketone) of chiral ester by ketone, from ketone to the enol ester, need above synthetic of at least two steps.These are relatively long and complicated methods.
Summary of the invention
Therefore, in order to address the above problem, an object of the present invention is to provide the method that a kind of high productivity prepares optically pure chiral ester.Detailed Description Of The Invention
The method that the present invention prepares chiral ester is characterised in that; with ketone, can activate described ketone be hydrogenated to the compound 1,2 of the formula that is selected from 1 to 3 expression of racemic alcohol and described racemic pure racemization and 3 ruthenium complex, can to a kind of enantiomorph of described racemic alcohol carry out selectively acylating lipase, the hydride donor of hydride group is provided and provides the acry radical donor of acyl group to mix and react to described ruthenium complex to described lipase
Y wherein
1, Y
2, Y
3, Y
4, Y
5, Y
6, Y
7, Y
8, Y
9, Y
10, Y
11And Y
12Be hydrogen atom or C independently of one another
1-C
5Alkyl; X is Br, Cl or I;
Y wherein
1, Y
2, Y
3, Y
4, Y
5, Y
6, Y
7, Y
8, Y
9, Y
10, Y
11And Y
12Be hydrogen atom or C independently of one another
1-C
5Alkyl; X is Br, Cl or I;
Described ruthenium complex is selected from the compound 5 to 10 of following formula 5 to 10 expressions.
Wherein X is Cl, Br or I, most preferably Cl.
Describe the method for preparing chiral ester by the single stage synthesis method by ketone below in detail.
The mixture that is selected from ruthenium complex, lipase, hydride donor, acry radical donor and the ketone of formula 1 to 3 under existing, the alkali shown in the scheme 2 is reacted in appropriate solvent.Reaction conditions changes along with the structure of ruthenium complex.For example, when utilizing the ruthenium complex of formula 5, react under 40～50 ℃ the temperature and carry out.When utilizing the ruthenium complex of formula 8, the temperature that reaction needed is 40～50 ℃.When utilizing the complex compound of formula 3, the temperature that reaction needed is 70～80 ℃.The ruthenium complex of formula 5 can buy, and it can transform the ruthenium complex of an accepted way of doing sth 8 under alcohol/amine alkaline condition.Therefore, the result of the ruthenium complex of formula 5 and the ruthenium complex of formula 8 almost is identical.Described ruthenium complex is with respect to the preferred 0.1～5mol% of the content of ketone.If this content is greater than 5mol%, it is expensive that cost becomes.On the other hand, if this content less than 0.1mol%, it is very low that speed of reaction becomes.Scheme 2
R wherein
1, R
2And R
3Be alkyl, the aryl of selectivity replacement or the cycloalkyl that selectivity replaces that selectivity replaces independently of one another, and R
1And R
2, R
1And R
3And R
2And R
3Cyclisation mutually, the substituting group of wherein said alkyl, aryl and cycloalkyl are the heteroatomss such as halogen atom and cyano group.
Described ruthenium complex can be used as catalyzer transfer hydrogen atom and activates the hydrogenation that ketone is changed into racemic alcohol, and can activate the racemization of the racemic alcohol that is generated.
Described lipase is esterase, its optionally acidylate come from a kind of enantiomorph of racemic alcohol and generate chiral ester.The example of lipase is pseudomonas cepacia lipase and arctic candiyeast (Candida antarctica) lipase, or rather, be to be carried on acrylic resin (Novozym 435, Novo company) arctic candiyeast B component lipase on or be carried on ceramic particle (lipase PS-C, Amano company) the pseudomonas cepacia lipase on, based on reasons such as thermotolerance, reactivity, optical purities, most preferably be carried on the arctic candiyeast B component lipase on the acrylic resin.In the situation of Novozym 435, described lipase is 10～60mg with respect to the amount of 1mmol ketone, preferred 30mg, and in the situation of lipase PS-C, described lipase is 40～240mg with respect to the amount of 1mmol ketone, preferred 80mg.
Described ketone is the compound of formula 4 expressions normally.But be not limited to compound 4a, 4b, 4c, 4d, 4e, 4f or the 4g of the embodiment of the invention,
R wherein
1And R
2Definition as mentioned above.
In the presence of lipase-catalyzed dose, described acry radical donor provides acyl group and molecular balance is moved to generating acylate to lipase.Preferred acry radical donor is aryl ester or alkenyl acetic ester, most preferably has the aryl ester such as the rubigan acetic ester of drawing electron group.The example of alkenyl acetic ester is different propylene acetic ester.Because this kind acry radical donor compound has suitable reactivity and does not suppress racemization, so such acry radical donor compound preferably uses.Described acry radical donor compound is 2～4 equivalents with respect to the preferred amounts of 1 equivalent ketone.If greater than 4 equivalents, this acry radical donor compound is difficult to separate after the reaction so with respect to the amount of 1 equivalent ketone.On the other hand, if with respect to the amount of 1 equivalent ketone less than 2 equivalents, acidylate speed becomes very low so.
The hydride donor provides hydride to ruthenium complex.The example of described hydride donor is 2,6-dimethyl-g-4-alcohol, hydrogen and formic acid.Described hydride donor is 1～2 equivalent with respect to the preferred amounts of 1 equivalent ketone.If content departs from this scope, it will suppress racemization.
Need alkali to remove the acid that produces in the reaction process simultaneously.Described alkali comprises triethylamine or diisopropylethylamine, and its preferred usage quantity with respect to 1 equivalent ketone is 1～2 equivalent.
Reaction solvent is unrestricted, but owing to solvent in the catalyzed reaction of enzyme influences the product productive rate usually, so preferably use methylene dichloride, toluene, benzene or hexane.The amount of described solvent is 0.2～0.3M concentration of ketone normally.
There are the chiral ester that reacts the formula that can obtain 100 expressions down in ketone, ruthenium complex, lipase and acry radical donor compound in the hydride donor,
R wherein
1, R
2And R
3Be alkyl, the aryl of selectivity replacement or the cycloalkyl that selectivity replaces that selectivity replaces independently of one another, and R
1And R
2, R
1And R
3And R
2And R
3Cyclisation mutually, the substituting group of wherein said alkyl, aryl and cycloalkyl are the heteroatomss such as halogen atom and cyano group.
The chiral ester of formula 100 of the present invention can be as the synthetic intermediate of preparation various chipal compounds, chirality medicament or chirality agrochemicals, or rather, can be as the essential intermediate as the Agenerase of the L-carnitine of food and medicated premix and formula 103 essential intermediates expression, the AIDS medicine of the medicine Atorvastatin that can be used for treating hyperlipidemia of preparation formula 101 expression, formula 102 expressions.
Particularly, the chipal compounds of formula 100a is wherein a kind of compound of the present invention, and it is that preparation is recorded in US 5,908, the key intermediate of the Atorvastatin of the molecular formula 101 in 953.
Wherein R is a low alkyl group.
The method for preparing the chiral ester of formula 100 of the present invention provide at most less than 5% minimum by product (for example unreacted pure resistates) productive rate and up to 100% have 99% or the maximum product productive rate of higher high-optical-purity.Because optical purity is the important factor that preparation is used for the chipal compounds of food and medicine, therefore chiral ester of the present invention can be as the useful raw material of various fields, particularly field of fine chemical.
The following examples are to be used to illustrate the present invention, should not be interpreted as the restriction to the defined scope of appended claims of the present invention.
Embodiment 1
With the ruthenium complex (0.0130mmol) (wherein X is Cl), 2 of the ketone (0.25mmol) of formula 4a, triethylamine (0.75mmol), formula 5, the lipase PS-C (Amano company) of 6-dimethyl-g-4-alcohol (0.38mmol) and 20mg joins in the methylene dichloride of 2.0ml.This reaction mixture in stirring at room 5 minutes, is added rubigan acetic ester (0.75mmol) then and generates the suspension of dark red in this reaction mixture.
After under vacuum condition, removing oxygen, in reaction suspension, feed argon gas, then this suspension was heated 78 hours in 50 ℃.
Embodiment 2 to 5
Same step according to embodiment 1 prepares the product chiral ester, and different is the ketone that replaces formula 4a with the ketone of formula 4b-4e.Embodiment 6
Same step according to embodiment 1 prepares the product chiral ester, and different is the ruthenium complex (wherein X is Cl) of ruthenium complex (wherein X is Cl) the replacement formula 5 with formula 8.
Embodiment 7 to 10
Same step according to embodiment 6 prepares the product chiral ester, and different is the ketone that replaces formula 4a with the ketone of formula 4b-4e.
Embodiment 11
With the ketone (0.25mmol) of formula 4a, the ruthenium complex (0.050mmol), 2 of formula 3, the Nozyme 435 of 6-dimethyl-g-4-alcohol (0.38mmol), 7.5mg and rubigan acetic ester (0.75mmol) join in the toluene of 0.8ml and generate yellow suspension.
After under vacuum condition, removing oxygen, in reaction suspension, feed argon gas, then this suspension was heated 44 hours in 70 ℃.
Embodiment 12 to 17
Same step according to embodiment 11 prepares the product chiral ester, and different is the ketone of using the ketone substituted molecule formula 4a of formula 4b-4g.
In the preparation of the chiral ester of embodiment 1 to 5 and embodiment 11 to 17, will as the productive rate of the rate of formation of the alcohol of by product, chirality acetic ester and optical purity be measured and will the results are shown in Table 1.The described productive rate of pure and mild chirality acetic ester is analyzed with gas-chromatography, with the described optical purity of high-performance liquid chromatogram determination.The described gas-chromatography of utilizing is HewlettPackard 5890 Series II, and the described high performance liquid chromatography of utilization is SpectraSystemP2000.
Table 1
| Part | The rate of formation (%) of alcohol | Productive rate (%) | Optical purity (e.e.%) |
| Embodiment 1 | ????1 | ????93 | ????97 |
| Embodiment 2 | ????0 | ????81 | ????99 |
| Embodiment 3 | ????2 | ????92 | ????99 |
| Embodiment 4 | ????0 | ????73 | ????99 |
| Embodiment 5 | ????5 | ????86 | ????99 |
| Embodiment 11 | ????2 | ????96 | ????98 |
| Embodiment 12 | ????2 | ????94 | ????99 |
| Embodiment 13 | ????2 | ????98 | ????99 |
| Embodiment 14 | ????0 | ????94 | ????97 |
| Embodiment 15 | ????0 | ????100 | ????99 |
| Embodiment 16 | ????0 | ????98 | ????99 |
| Embodiment 17 | ????0 | ????95 | ????95 |
As shown in table 1, embodiment 1 to 5 and embodiment 11 to 17 confirm the invention provides the single stage synthesis method that is prepared optically pure chiral ester by ketone, and this method activates racemization and hydrogen transference and lipase activation esterification by the control ruthenium complex and realizes.And, the invention provides the product chiral ester of high yield, the amount of unreacted alcohol is less than 5%.
Claims (9)
1. a method for preparing the chiral ester of formula 100 expressions of the present invention is characterized in that following material is mixed and reaction
The ketone of formula 4 expressions;
Described ketone be can activate and the compound 1,2 that is selected from molecular formula 1 to 3 expression of racemic alcohol and described racemic pure racemization and 3 ruthenium complex are hydrogenated to;
Can carry out the lipase of selectively acylating to a kind of enantiomorph of described racemic alcohol;
The hydride donor of hydride group is provided to described ruthenium complex; With
Provide the acry radical donor of acyl group to described lipase,
Y wherein
1, Y
2, Y
3, Y
4, Y
5, Y
6, Y
7, Y
8, Y
9, Y
10, Y
11And Y
12Be hydrogen atom or C independently of one another
1-C
5Alkyl; X is Br, Cl or I;
Y wherein
1, Y
2, Y
3, Y
4, Y
5, Y
6, Y
7, Y
8, Y
9, Y
10, Y
11And Y
12Be hydrogen atom or C independently of one another
1-C
5Alkyl; X is Br, Cl or I;
R wherein
1, R
2And R
3Be alkyl, the aryl of selectivity replacement or the cycloalkyl that selectivity replaces that selectivity replaces independently of one another, and R
1And R
2, R
1And R
3And R
2And R
3Cyclisation mutually, the substituting group of wherein said alkyl, aryl and cycloalkyl are the heteroatomss such as halogen atom and cyano group.
2. the method for preparing chiral ester according to claim 1, wherein said ketone are selected from compound 4a, 4b, 4c, 4d, 4e, 4f and the 4g of formula 4a to 4g.
3. the method for preparing chiral ester according to claim 1, wherein said ruthenium complex are selected from compound 5,6,7,8,9 and 10, and wherein X is Cl, Br or I.
4. according to claim 1 to 3 any one described method for preparing chiral ester wherein, wherein X is Cl.
5. the method for preparing chiral ester according to claim 1, wherein said lipase are selected from pseudomonas cepacia lipase and arctic candiyeast B component lipase.
6. the method for preparing chiral ester according to claim 1, wherein said acry radical donor compound is an aryl ester.
7. the method for preparing chiral ester according to claim 6, wherein said aryl ester are selected from rubigan acetic ester and alkenyl acetic ester.
8. the method for preparing chiral ester according to claim 1, wherein said hydride compound donator is selected from 2,6-dimethyl-g-4-alcohol, hydrogen and formic acid.
9. the method for preparing chiral ester according to claim 1, wherein said ruthenium complex is 0.1～5mol% with respect to the content of described ketone.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1999/45041 | 1999-10-18 | ||
| KR19990045041 | 1999-10-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1379753A true CN1379753A (en) | 2002-11-13 |
Family
ID=19615712
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00814419A Pending CN1379753A (en) | 1999-10-18 | 2000-10-18 | Method for preparing chiral ester |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1226105A4 (en) |
| JP (1) | JP2003512035A (en) |
| KR (1) | KR100402049B1 (en) |
| CN (1) | CN1379753A (en) |
| AU (1) | AU1058901A (en) |
| CA (1) | CA2387950A1 (en) |
| WO (1) | WO2001028971A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004110943A2 (en) | 2003-06-19 | 2004-12-23 | Elop Electro-Optics Industries Ltd. | Glass ceramics for laser systems |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0641445B2 (en) * | 1988-12-22 | 1994-06-01 | 高砂香料工業株式会社 | Process for producing optically active carnitine ester |
| DE19845517A1 (en) * | 1998-10-02 | 2000-04-06 | Basf Ag | Process for the asymmetric hydrogenation of beta-keto esters |
-
2000
- 2000-10-18 CA CA002387950A patent/CA2387950A1/en not_active Abandoned
- 2000-10-18 EP EP00971840A patent/EP1226105A4/en not_active Withdrawn
- 2000-10-18 CN CN00814419A patent/CN1379753A/en active Pending
- 2000-10-18 KR KR10-2000-0061351A patent/KR100402049B1/en not_active IP Right Cessation
- 2000-10-18 AU AU10589/01A patent/AU1058901A/en not_active Abandoned
- 2000-10-18 JP JP2001531776A patent/JP2003512035A/en active Pending
- 2000-10-18 WO PCT/KR2000/001171 patent/WO2001028971A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| CA2387950A1 (en) | 2001-04-26 |
| EP1226105A1 (en) | 2002-07-31 |
| KR100402049B1 (en) | 2003-10-17 |
| AU1058901A (en) | 2001-04-30 |
| EP1226105A4 (en) | 2004-11-03 |
| KR20010040122A (en) | 2001-05-15 |
| JP2003512035A (en) | 2003-04-02 |
| WO2001028971A1 (en) | 2001-04-26 |
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Owner name: LEGAL PERSON OF THE SCHOOL POHANG UNIVERSITY OF S Free format text: FORMER OWNER: SAMSUNG FINE CHEMICALS CO., LTD. Free format text: FORMER OWNER: LEGAL PERSON OF THE SCHOOL POHANG UNIVERSITY OF SCIENCE AND TEC Effective date: 20040702 |
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Effective date of registration: 20040702 Address after: Pohang City, South Korea Applicant after: Pohang Polytechnic School Address before: Ulsan, South Korea Applicant before: Samsung Fine Chemicals Co., Ltd. Co-applicant before: Pohang Polytechnic School |
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