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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- lipase
- ketone
- chiral ester
- alkyl
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- 150000002148 esters Chemical class 0.000 title claims abstract description 31
- 238000000034 method Methods 0.000 title claims abstract description 22
- 150000002576 ketones Chemical class 0.000 claims abstract description 36
- 108090001060 Lipase Proteins 0.000 claims abstract description 26
- 239000004367 Lipase Substances 0.000 claims abstract description 26
- 102000004882 Lipase Human genes 0.000 claims abstract description 26
- 235000019421 lipase Nutrition 0.000 claims abstract description 26
- 239000012327 Ruthenium complex Substances 0.000 claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- -1 hydride group Chemical group 0.000 claims abstract description 10
- 150000004678 hydrides Chemical class 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 8
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
- 125000002252 acyl group Chemical group 0.000 claims abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- 125000005843 halogen group Chemical group 0.000 claims abstract description 4
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 235000019439 ethyl acetate Nutrition 0.000 claims description 10
- 230000014509 gene expression Effects 0.000 claims description 10
- 230000006340 racemization Effects 0.000 claims description 6
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims description 4
- 150000007860 aryl ester derivatives Chemical class 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 241000589513 Burkholderia cepacia Species 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- PNHBRYIAJCYNDA-VQCQRNETSA-N (4r)-6-[2-[2-ethyl-4-(4-fluorophenyl)-6-phenylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(CC)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 PNHBRYIAJCYNDA-VQCQRNETSA-N 0.000 claims description 2
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 claims description 2
- QOLHWXNSCZGWHK-BWBORTOCSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecylcarbamoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)NCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QOLHWXNSCZGWHK-BWBORTOCSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 claims description 2
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 claims description 2
- AKBHYCHPWZPGAH-UHFFFAOYSA-N 2-[3-[(3-chloro-4-methylphenyl)methoxy]azetidine-1-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one Chemical compound CC1=C(Cl)C=C(COC2CN(C2)C(=O)C2CC3(C2)COC(=O)N3)C=C1 AKBHYCHPWZPGAH-UHFFFAOYSA-N 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 6
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 abstract description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 abstract 2
- 150000001298 alcohols Chemical class 0.000 abstract 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 abstract 1
- 229910052707 ruthenium Inorganic materials 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 1
- 125000003107 substituted aryl group Chemical group 0.000 abstract 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 abstract 1
- 239000000047 product Substances 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000004925 Acrylic resin Substances 0.000 description 2
- 229920000178 Acrylic resin Polymers 0.000 description 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 2
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 108010084311 Novozyme 435 Proteins 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229960005370 atorvastatin Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 1
- YLLRPQWLASQXSI-UHFFFAOYSA-N 3-(4b,8a,9,9a-tetrahydro-4aH-pyrido[2,3-b]indol-4-ylamino)phenol Chemical compound Oc1cccc(NC2=CC=NC3NC4C=CC=CC4C23)c1 YLLRPQWLASQXSI-UHFFFAOYSA-N 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 241001661345 Moesziomyces antarcticus Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 1
- 229960001830 amprenavir Drugs 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of 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
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/62—Carboxylic acid esters
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- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Wood Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及一种制备分子式100表示的手性酯的方法,该方法将分子式4表示的酮、可以激活所述的酮氢化成外消旋的醇以及所述外消旋的醇外消旋化的选自分子式1至3表示的化合物1、2和3的钌络合物、可以对所述外消旋的醇的一种对映体进行选择性酰化的脂肪酶、向所述的钌络合物提供氢化物基团的氢化物供体和向所述的脂肪酶提供酰基的酰基供体进行混合和反应,式(1)中,Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、Y9、Y10、Y11和Y12彼此独立地是氢原子或C1－C5烷基;X是Br、Cl或I;式(2)中,Y1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、Y9、Y10、Y11和Y12彼此独立地是氢原子或C1－C5烷基;X是Br、Cl或I;式(3),(4)和(100)中,其中R1、R2和R3彼此独立地是选择性取代的烷基、选择性取代的芳基或选择性取代的环烷基,并且R1和R2、R1和R3以及R2和R3可以相互环化,其中所述的烷基、芳基和环烷基的取代基是诸如卤素原子和氰基的杂原子。
The present invention relates to a method for the preparation of chiral esters represented by molecular formula 100, which method hydrogenates ketones represented by molecular formula 4, can activate said ketones to racemic alcohols and racemizes said racemic alcohols A ruthenium complex selected from compounds 1, 2 and 3 represented by molecular formulas 1 to 3, a lipase that can selectively acylate an enantiomer of said racemic alcohol, and said ruthenium The complex provides the hydride donor of the hydride group and the acyl donor that provides the acyl group to the lipase to mix and react. In formula (1), Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 and Y 12 are independently hydrogen atoms or C 1 -C 5 alkyl groups; X is Br, Cl or I; in formula (2) , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 and Y 12 are independently hydrogen atoms or C 1 -C 5 alkyl groups X is Br, Cl or I; In formula (3), (4) and (100), wherein R 1 , R 2 and R 3 are independently of each other optionally substituted alkyl, optionally substituted aryl or Optionally substituted cycloalkyl, and R 1 and R 2 , R 1 and R 3 and R 2 and R 3 can be cyclized to each other, wherein the substituents of the alkyl, aryl and cycloalkyl are such as halogen atoms and heteroatoms of cyano groups.
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 EP EP00971840A patent/EP1226105A4/en not_active Withdrawn
- 2000-10-18 WO PCT/KR2000/001171 patent/WO2001028971A1/en not_active Application Discontinuation
- 2000-10-18 CA CA002387950A patent/CA2387950A1/en not_active Abandoned
- 2000-10-18 JP JP2001531776A patent/JP2003512035A/en active Pending
- 2000-10-18 AU AU10589/01A patent/AU1058901A/en not_active Abandoned
- 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
Also Published As
| Publication number | Publication date |
|---|---|
| EP1226105A4 (en) | 2004-11-03 |
| CA2387950A1 (en) | 2001-04-26 |
| KR20010040122A (en) | 2001-05-15 |
| EP1226105A1 (en) | 2002-07-31 |
| WO2001028971A1 (en) | 2001-04-26 |
| JP2003512035A (en) | 2003-04-02 |
| KR100402049B1 (en) | 2003-10-17 |
| AU1058901A (en) | 2001-04-30 |
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