CA2169301A1 - Lipase-catalyzed acylation of alcohols with diketenes - Google Patents
Lipase-catalyzed acylation of alcohols with diketenesInfo
- Publication number
- CA2169301A1 CA2169301A1 CA002169301A CA2169301A CA2169301A1 CA 2169301 A1 CA2169301 A1 CA 2169301A1 CA 002169301 A CA002169301 A CA 002169301A CA 2169301 A CA2169301 A CA 2169301A CA 2169301 A1 CA2169301 A1 CA 2169301A1
- Authority
- CA
- Canada
- Prior art keywords
- alcohols
- alcohol
- lipase
- diketene
- acylated
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000001298 alcohols Chemical class 0.000 title claims abstract description 41
- 230000010933 acylation Effects 0.000 title description 5
- 238000005917 acylation reaction Methods 0.000 title description 5
- 239000004367 Lipase Substances 0.000 claims abstract description 26
- 108090001060 Lipase Proteins 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 25
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 238000006555 catalytic reaction Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 4
- 238000007257 deesterification reaction Methods 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 6
- 241000589516 Pseudomonas Species 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 238000005815 base catalysis Methods 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 150000002561 ketenes Chemical class 0.000 description 2
- 229920001567 vinyl ester resin Polymers 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- GSBJXOIVIOYPOW-SNVBAGLBSA-N [(1r)-1-phenylethyl] 3-oxobutanoate Chemical compound CC(=O)CC(=O)O[C@H](C)C1=CC=CC=C1 GSBJXOIVIOYPOW-SNVBAGLBSA-N 0.000 description 1
- 241000179532 [Candida] cylindracea Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- -1 arylalkyl alcohols Chemical class 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- CRQQGFGUEAVUIL-UHFFFAOYSA-N chlorothalonil Chemical compound ClC1=C(Cl)C(C#N)=C(Cl)C(C#N)=C1Cl CRQQGFGUEAVUIL-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
- C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
- C07C29/095—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of esters of organic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/88—Separation; Purification; Use of additives, e.g. for stabilisation by treatment giving rise to a chemical modification of at least one compound
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/26—Polyhydroxylic alcohols containing only six-membered aromatic rings as cyclic part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/46—Preparation of carboxylic acid esters from ketenes or polyketenes
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Wood Science & Technology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Health & Medical Sciences (AREA)
- Biotechnology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Analytical Chemistry (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for preparing acylated alcohols from alcohols is characterised in that the alcohol is reacted with a diketene in the presence of lipase. The process is particularly suitable for the enantioselective acetoacetylation of racemic alcohols.
Description
~ 0050/44264 Lipase-catalyzed acylation of alcohols with diketenes The present invention relates to a process for preparing acylated 5 alcohols from alcohols, in particular for preparing enantioselectively acylated alcohols from racemic alcohols.
The preparation of acetoacetylated alcohols by reaction of alcohol with diketene is known. This reaction is generally 10 carried out at elevated temperatures with acid or base catalysis.
For sensitive alcohols which rearrange easily, these acetoacetylation conditions are unsuitable.
A process for the resolution of racemic alcohols using vinyl 15 esters in the presence of lipases as catalyst is known (EP 321 918). Suitable acylating agents described here are vinyl esters of the general formula I
R2 o ~ R1 I, where 25 Rl is hydrogen, alkyl, phenyl or alkoxyalkyl and R2 is hydrogen or methyl.
During the transesterification, the by-products acetaldehyde and acetone are formed from the vinyl esters I and have to be 30 separated off, as they can inactivate enzymes. Furthermore, when using vinyl acetate as the acylating agent, alcohol and ester have boiling points lying very close together, so that they can only be separated with great difficulty by distillation.
35 In a review article on enzyme-catalyzed acyl transfers (Faber and Riva, Synthesis 1992, 895-910), it was described that the acylating agent diketene is not suitable for enzymatic enantioselective acetoacetylations, as it only leads to an extremely small enantiomer excess.
The two racemic alcohols II and III were reacted with diketene in toluene at room temperature in the presence of Candida cylindracea lipase to give the correspondingly acetoacetylated compounds IIa and IIIa. This reaction, however, exhibited no 45 enantioselectivity, as can be gathered from the enantiomer excess of less than 10% (loc. cit. p. 900).
OH ~'~ " J ~ /
rac II IIa Ph Ph ~ OH ~~ J ~ /
rac III IIIa It was furthermore stated there that no specific lipase catalysis 20 with diketene took place, but a nonspecific base catalysis by protein, which was also possible with bovine serum albumin, which has no esterase activity.
It is an object of the present invention to provide a process for 25 preparing acylated alcohols from alcohols, which enables the esterification of the alcohol under conditions which are as mild as possible.
It is a further object to provide a process which permits 30 optically active alcohols to be prepared selectively from racemic alcohols without the disadvantages described above occurring.
We have found that alcohols can be reacted with a diketene to give acylated alcohols under particularly mild conditions if the 35 reaction is carried out with specific lipase catalysis.
We have further found that enantioselectively acylated alcohols can be prepared from racemic alcohols if the racemic alcohols are reacted with a diketene in the presence of lipase, ie. the 40 reaction is carried out with specific lipase catalysis.
Furthermore, we have found a process for preparing optically active alcohols from racemic alcohols, which comprises 45 a) enantioselectively acylating a racemic alcohol with a diketene in the presence of lipase, 21 6q301 b) separating the mixture of optically active alcohol and optically active acylated alcohol and thus obtaining one enantiomer of the alcohol, 5 c) if desired, obt~;n;ng the other enantiomer of the alcohol from the acylated alcohol by ester cleavage.
These processes according to the invention are particularly suitable for preparing optically active compounds.
The acylation of alcohols proceeds according to the following reaction equation:
RlOH + ~ Lipase R2 R2 The alcohols R1OH used as starting substances can be primary, secondary or tertiary alcohols. Both alkyl and arylalkyl alcohols 25 are suitable for the process.
The diketene used can be either the dimerization product of ketene CH2=C=O or a substituted ketene R2HC=C=O. The radical R2 can be an alkyl or an aryl radical.
Preferably, the diketene used is the dimer of unsubstituted ketene (R2 = hydrogen). In this case, the acylation leads to acetoacetylated alcohols.
35 When using racemic alcohols, an enantioselective acylation takes place under the conditions described. One enantiomer of the alcohol is acylated, while the other enantiomer of the alcohol remains unchanged. This selective reaction enables the resolution of racemic alcohols into their enantiomers.
gO
The diketene is generally employed in a slight molar excess, based on the alcohol to be reacted. Preferably, 1.1 mol of diketene are used per mole of alcohol. For the reaction of diketene with racemic alcohols this means that from 0.5 to 45 0.55 mol of diketene are employed per mole of racemates, as only one enantiomer reacts with diketene under the given conditions.
- 216~301 Suitable solvents are generally organic solvents. The reaction proceeds particularly well in ethers, for example in MTBE or THF, or in hydrocarbons such as hexane, cyclohexane, toluene or halogenated hydrocarbons such as methylene chloride.
Bacterial lipases have proven to be highly suitable catalysts for the process. Particularly suitable lipases are those from Pseudomonas, for example the lipase Amano P~ or the lipase from Pseudomonas spec. DSM 8246.
This lipase has proved to be particularly active, selective and resistant with respect to inactivation.
However, a number of other lipases, for example Candida 15 cylindracea lipase (CCL), are also suitable for the process according to the invention.
The lipase can also be employed bonded adsorptively or covalently to an insoluble support.
The reaction of the alcohol with the diketene is generally carried out at room temperature.
After completion of the reaction, the lipase is in general 25 filtered off, the solvent and the excess diketene are removed from the filtrate and the mixture of acylated enantiomer and unreacted enantiomer are resolved by customary methods. If the desired enantiomer was the unreacted alcohol, it is now already in pure form; if the acylated enantiomer was the desired 30 enantiomer, it must additionally be liberated from the acetoacetic ester by a customary ester cleavage.
The process according to the invention is generally carried out by initially introducing the starting compounds alcohol and 35 diketene into the solvent and starting the reaction by addition of the lipase.
If desired, the lipase can be recovered after completion of the reaction and reused for a new reaction.
The process according to the invention has the advantage that it proceeds under simple and very mild conditions. It is therefore also highly suitable for sensitive as well as SNl-active alcohols (eg. l-phenylethanol). No by-products are formed here which can 45 inhibit the lipase. Furthermore, the resulting products can be ' 0050/44264 2 1 6 9 3 0 1 readily separated by distillation on account of their different boiling points.
The following examples serve to illustrate the invention.
Example 1 General procedure for the preparation of acetoacetic esters 10 55 mmol of diketene and 50 mmol of alcohol were dissolved in 30 ml of THF. After addition of 50 mg of lipase (Pseudomonas spec., 658 U/mg), the mixture was stirred at room temperature.
After complete conversion (4 h), the solution was filtered and concentrated in vacuo (50 C, 30 mbar). The NMR-pure acetoacetic 15 ester was obtained in a yield of over 90%.
Ethanol, isopropyl alcohol and benzyl alcohol were reacted according to this procedure.
20 Example 2 Kinetic resolution of l-phenylethanol:
55 mmol of diketene and 50 mmol of phenylethanol (rac.) were 25 dissolved in 30 ml of THF. The reaction was started by addition of 100 mg of Pseudomonas spec. DSM 8246 (see Example 1). The conversion of the reaction was checked by GC. The specific rotation of the filtered reaction solution was simultaneously monitored. At a conversion of about 50% (specific rotation 30 maximum, about 5 h), the reaction was terminated by filtering off the lipase. The product mixture was concentrated and separated by chromatography on silica gel (cyclohexane: ethyl acetate = 5:1).
The following were obtained:
5.3 g of R-(+)-l-phenylethanol acetoacetate (52% yield) ee = 75% (87.5:12.5) [a]D20 = +84.5- (c = 1.078 in toluene) 0 2.1 g of S-(-)-l-phenylethanol (34% yield) ee = 97% (98.5:1.5) [a]D20 = -43.8- (c z 0,984 in toluene) The enantiomer excesses were determined by 500 MHz lH-NMR of the5 Mosher esters (JACS 95 (1973) 512):
o o O ~ OH OMTPA
5 ~ ~ ~ I ~ MTPACl ~
~Mosher ester"
MTPACl: S-(+)-a-methoxy--tri-fluoromethylphenyl-acetyl chloride gO
The preparation of acetoacetylated alcohols by reaction of alcohol with diketene is known. This reaction is generally 10 carried out at elevated temperatures with acid or base catalysis.
For sensitive alcohols which rearrange easily, these acetoacetylation conditions are unsuitable.
A process for the resolution of racemic alcohols using vinyl 15 esters in the presence of lipases as catalyst is known (EP 321 918). Suitable acylating agents described here are vinyl esters of the general formula I
R2 o ~ R1 I, where 25 Rl is hydrogen, alkyl, phenyl or alkoxyalkyl and R2 is hydrogen or methyl.
During the transesterification, the by-products acetaldehyde and acetone are formed from the vinyl esters I and have to be 30 separated off, as they can inactivate enzymes. Furthermore, when using vinyl acetate as the acylating agent, alcohol and ester have boiling points lying very close together, so that they can only be separated with great difficulty by distillation.
35 In a review article on enzyme-catalyzed acyl transfers (Faber and Riva, Synthesis 1992, 895-910), it was described that the acylating agent diketene is not suitable for enzymatic enantioselective acetoacetylations, as it only leads to an extremely small enantiomer excess.
The two racemic alcohols II and III were reacted with diketene in toluene at room temperature in the presence of Candida cylindracea lipase to give the correspondingly acetoacetylated compounds IIa and IIIa. This reaction, however, exhibited no 45 enantioselectivity, as can be gathered from the enantiomer excess of less than 10% (loc. cit. p. 900).
OH ~'~ " J ~ /
rac II IIa Ph Ph ~ OH ~~ J ~ /
rac III IIIa It was furthermore stated there that no specific lipase catalysis 20 with diketene took place, but a nonspecific base catalysis by protein, which was also possible with bovine serum albumin, which has no esterase activity.
It is an object of the present invention to provide a process for 25 preparing acylated alcohols from alcohols, which enables the esterification of the alcohol under conditions which are as mild as possible.
It is a further object to provide a process which permits 30 optically active alcohols to be prepared selectively from racemic alcohols without the disadvantages described above occurring.
We have found that alcohols can be reacted with a diketene to give acylated alcohols under particularly mild conditions if the 35 reaction is carried out with specific lipase catalysis.
We have further found that enantioselectively acylated alcohols can be prepared from racemic alcohols if the racemic alcohols are reacted with a diketene in the presence of lipase, ie. the 40 reaction is carried out with specific lipase catalysis.
Furthermore, we have found a process for preparing optically active alcohols from racemic alcohols, which comprises 45 a) enantioselectively acylating a racemic alcohol with a diketene in the presence of lipase, 21 6q301 b) separating the mixture of optically active alcohol and optically active acylated alcohol and thus obtaining one enantiomer of the alcohol, 5 c) if desired, obt~;n;ng the other enantiomer of the alcohol from the acylated alcohol by ester cleavage.
These processes according to the invention are particularly suitable for preparing optically active compounds.
The acylation of alcohols proceeds according to the following reaction equation:
RlOH + ~ Lipase R2 R2 The alcohols R1OH used as starting substances can be primary, secondary or tertiary alcohols. Both alkyl and arylalkyl alcohols 25 are suitable for the process.
The diketene used can be either the dimerization product of ketene CH2=C=O or a substituted ketene R2HC=C=O. The radical R2 can be an alkyl or an aryl radical.
Preferably, the diketene used is the dimer of unsubstituted ketene (R2 = hydrogen). In this case, the acylation leads to acetoacetylated alcohols.
35 When using racemic alcohols, an enantioselective acylation takes place under the conditions described. One enantiomer of the alcohol is acylated, while the other enantiomer of the alcohol remains unchanged. This selective reaction enables the resolution of racemic alcohols into their enantiomers.
gO
The diketene is generally employed in a slight molar excess, based on the alcohol to be reacted. Preferably, 1.1 mol of diketene are used per mole of alcohol. For the reaction of diketene with racemic alcohols this means that from 0.5 to 45 0.55 mol of diketene are employed per mole of racemates, as only one enantiomer reacts with diketene under the given conditions.
- 216~301 Suitable solvents are generally organic solvents. The reaction proceeds particularly well in ethers, for example in MTBE or THF, or in hydrocarbons such as hexane, cyclohexane, toluene or halogenated hydrocarbons such as methylene chloride.
Bacterial lipases have proven to be highly suitable catalysts for the process. Particularly suitable lipases are those from Pseudomonas, for example the lipase Amano P~ or the lipase from Pseudomonas spec. DSM 8246.
This lipase has proved to be particularly active, selective and resistant with respect to inactivation.
However, a number of other lipases, for example Candida 15 cylindracea lipase (CCL), are also suitable for the process according to the invention.
The lipase can also be employed bonded adsorptively or covalently to an insoluble support.
The reaction of the alcohol with the diketene is generally carried out at room temperature.
After completion of the reaction, the lipase is in general 25 filtered off, the solvent and the excess diketene are removed from the filtrate and the mixture of acylated enantiomer and unreacted enantiomer are resolved by customary methods. If the desired enantiomer was the unreacted alcohol, it is now already in pure form; if the acylated enantiomer was the desired 30 enantiomer, it must additionally be liberated from the acetoacetic ester by a customary ester cleavage.
The process according to the invention is generally carried out by initially introducing the starting compounds alcohol and 35 diketene into the solvent and starting the reaction by addition of the lipase.
If desired, the lipase can be recovered after completion of the reaction and reused for a new reaction.
The process according to the invention has the advantage that it proceeds under simple and very mild conditions. It is therefore also highly suitable for sensitive as well as SNl-active alcohols (eg. l-phenylethanol). No by-products are formed here which can 45 inhibit the lipase. Furthermore, the resulting products can be ' 0050/44264 2 1 6 9 3 0 1 readily separated by distillation on account of their different boiling points.
The following examples serve to illustrate the invention.
Example 1 General procedure for the preparation of acetoacetic esters 10 55 mmol of diketene and 50 mmol of alcohol were dissolved in 30 ml of THF. After addition of 50 mg of lipase (Pseudomonas spec., 658 U/mg), the mixture was stirred at room temperature.
After complete conversion (4 h), the solution was filtered and concentrated in vacuo (50 C, 30 mbar). The NMR-pure acetoacetic 15 ester was obtained in a yield of over 90%.
Ethanol, isopropyl alcohol and benzyl alcohol were reacted according to this procedure.
20 Example 2 Kinetic resolution of l-phenylethanol:
55 mmol of diketene and 50 mmol of phenylethanol (rac.) were 25 dissolved in 30 ml of THF. The reaction was started by addition of 100 mg of Pseudomonas spec. DSM 8246 (see Example 1). The conversion of the reaction was checked by GC. The specific rotation of the filtered reaction solution was simultaneously monitored. At a conversion of about 50% (specific rotation 30 maximum, about 5 h), the reaction was terminated by filtering off the lipase. The product mixture was concentrated and separated by chromatography on silica gel (cyclohexane: ethyl acetate = 5:1).
The following were obtained:
5.3 g of R-(+)-l-phenylethanol acetoacetate (52% yield) ee = 75% (87.5:12.5) [a]D20 = +84.5- (c = 1.078 in toluene) 0 2.1 g of S-(-)-l-phenylethanol (34% yield) ee = 97% (98.5:1.5) [a]D20 = -43.8- (c z 0,984 in toluene) The enantiomer excesses were determined by 500 MHz lH-NMR of the5 Mosher esters (JACS 95 (1973) 512):
o o O ~ OH OMTPA
5 ~ ~ ~ I ~ MTPACl ~
~Mosher ester"
MTPACl: S-(+)-a-methoxy--tri-fluoromethylphenyl-acetyl chloride gO
Claims (5)
1. A process for preparing acylated alcohols from alcohols, which comprises reacting the alcohol with a diketene with specific lipase catalysis.
2. A process for preparing enantioselectively acylated alcohols from racemic alcohols, which comprises reacting a racemic alcohol with a diketene with specific lipase catalysis.
3. A process for preparing optically active alcohols from racemic alcohols, which comprises a) enantioselectively acylating a racemic alcohol with a diketene with specific lipase catalysis, b) separating the mixture of optically active alcohol and optically active acylated alcohol and thus obtaining one enantiomer of the alcohol, c) if desired, obtaining the other enantiomer of the alcohol from the acylated alcohol by ester cleavage.
4. The use of a process as claimed in claim 2 or 3 in the preparation of optically active compounds.
5. A process for preparing optically active compounds, wherein at least one step comprises a process as claimed in claim 2 or 3.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4329293.3 | 1993-08-31 | ||
| DE4329293A DE4329293A1 (en) | 1993-08-31 | 1993-08-31 | Lipase-catalyzed acylation of alcohols with diketenes |
| PCT/EP1994/002757 WO1995006746A1 (en) | 1993-08-31 | 1994-08-19 | Lipase-catalysed acylation of alcohols with diketenes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2169301A1 true CA2169301A1 (en) | 1995-03-09 |
Family
ID=6496445
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002169301A Abandoned CA2169301A1 (en) | 1993-08-31 | 1994-08-19 | Lipase-catalyzed acylation of alcohols with diketenes |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0716712B1 (en) |
| JP (1) | JPH09501834A (en) |
| AT (1) | ATE173020T1 (en) |
| CA (1) | CA2169301A1 (en) |
| DE (2) | DE4329293A1 (en) |
| WO (1) | WO1995006746A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6528643B1 (en) * | 2000-05-05 | 2003-03-04 | Hercules Incorporated | Esterified polysaccharide products and B-lactone ring opened ketene dimer products containing the compositions, and process of making the same |
| NL1015313C2 (en) * | 2000-05-26 | 2001-11-27 | Dsm Nv | Process for the preparation of enantiomerically enriched esters and alcohols. |
| US6528644B1 (en) * | 2001-09-26 | 2003-03-04 | Hercules Incorporated | Acetoacetylated saccharides and process of making the same |
| DE10336270B3 (en) * | 2003-08-07 | 2005-04-14 | Consortium für elektrochemische Industrie GmbH | Process for the enantioselective preparation of secondary alcohols by lipase-catalyzed solvolysis of the corresponding acetoacetic esters |
| CN119998251A (en) | 2022-08-23 | 2025-05-13 | 拜耳公司 | Nucleic acids encoding improved lipase proteins |
| KR20250164220A (en) | 2023-03-14 | 2025-11-24 | 바이엘 악티엔게젤샤프트 | Lipases and lipase-based chiral separation methods with improved stereoselectivity |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3743824C2 (en) * | 1987-12-23 | 1997-03-06 | Hoechst Ag | Process for the enzymatic resolution of racemic alcohols with / in vinyl esters by transesterification |
| US5106750A (en) * | 1988-08-30 | 1992-04-21 | G. D. Searle & Co. | Enantio- and regioselective synthesis of organic compounds using enol esters as irreversible transacylation reagents |
| ATE141950T1 (en) * | 1990-12-24 | 1996-09-15 | Hoechst Ag | METHOD FOR ACYLATION OF ALCOHOLS USING AN IMMOBILIZED PSEUDOMONAS LIPASE |
| DE4100394A1 (en) * | 1991-01-09 | 1992-07-16 | Jeromin Guenter E Prof Dr Rer | Prepn. of optically active alcohol(s) and optically active ester(s) - by enantioselective acylation of racemic alcohol(s) with vinyl ester(s) of higher fatty acids in the presence of a lipase |
-
1993
- 1993-08-31 DE DE4329293A patent/DE4329293A1/en not_active Withdrawn
-
1994
- 1994-08-19 WO PCT/EP1994/002757 patent/WO1995006746A1/en not_active Ceased
- 1994-08-19 AT AT94926853T patent/ATE173020T1/en not_active IP Right Cessation
- 1994-08-19 JP JP7507214A patent/JPH09501834A/en active Pending
- 1994-08-19 EP EP94926853A patent/EP0716712B1/en not_active Expired - Lifetime
- 1994-08-19 DE DE59407242T patent/DE59407242D1/en not_active Expired - Lifetime
- 1994-08-19 CA CA002169301A patent/CA2169301A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO1995006746A1 (en) | 1995-03-09 |
| EP0716712A1 (en) | 1996-06-19 |
| JPH09501834A (en) | 1997-02-25 |
| EP0716712B1 (en) | 1998-11-04 |
| ATE173020T1 (en) | 1998-11-15 |
| DE59407242D1 (en) | 1998-12-10 |
| DE4329293A1 (en) | 1995-03-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100511533B1 (en) | CHIRAL INTERMEDIATE, PROCESS FOR THE PRODUCTION THEREOF, AND PROCESS FOR THE PRODUCTION OF HMG-CoA REDUCTASE INHIBITOR | |
| JP3789938B2 (en) | Racemic resolution of primary and secondary heteroatom-substituted amines by enzyme-catalyzed acylation | |
| JP2707076B2 (en) | Production method of optically active compound | |
| EP0454463B1 (en) | Process for producing epoxyalcohols of high optical purity | |
| JPH0436195A (en) | Production of optically active alpha-hydroxyesters | |
| CA2169301A1 (en) | Lipase-catalyzed acylation of alcohols with diketenes | |
| EP1587943A1 (en) | Method for preparing a (r)- or (s)- form of n-(2,6-dimethyl phenyl) alanine and a counter enantiomeric form of n-(2,6-dimethyl phenyl) alanine ester thereto using enzyme | |
| KR100402048B1 (en) | Preparing method of chiral ester | |
| EP0231089A2 (en) | Process for producing an optically active alcohol by a biochemical method | |
| JPH1057094A (en) | Enzymatic optical resolution of alcohol using ketene acetal type acylating agent | |
| US5756321A (en) | Process for enzymatic acylation of alcohols with alkoxyvinyl acetates by transesterification | |
| KR100419595B1 (en) | Racemate Separation of Primary and Secondary Heteroatom-Substituted Amine by Enzyme-Catalysed Acylation | |
| EP0451668B1 (en) | Process for the production of optically active alkyl 3-aryl-3-hydroxypropionates | |
| US6475773B2 (en) | Method for preparing chiral esters | |
| CA2145230A1 (en) | Enzymatic resolution of asymmetric alcohols by means of vinyl esters of polybasic carboxylic acids | |
| EP0783039B1 (en) | Process for producing optically active 2-alkoxycyclohexanol derivatives | |
| US6140516A (en) | Process for the preparation of trans-3-alkyloxy-4-hydroxytetrahydrofuran | |
| JP3555480B2 (en) | Production method of optically active compound | |
| JPH1175889A (en) | Production method and purification method of optically active α-trifluoromethyl lactic acid and its enantiomer ester | |
| KR100359028B1 (en) | Method for preparing chiral allyl ester | |
| US5639662A (en) | Increased enantioselectivity of lipase catalyzed transesterification of alkynols with vinyl esters | |
| Inagaki | Applications of Lipase as a Catalyst for Stereoselective Reactions in Organic Solvent | |
| JPS63123399A (en) | Production of optically active alcohol and ester | |
| JPH08113550A (en) | Production of optically active 3-hydroxyhexanoic acids | |
| Inagaki | Applications of Lipase as a Catalyst for Stereoselective |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |