JP2006014636A - Method for producing acyl derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method capable of producing an acyl derivative having a high optical purity and used in various fields such as a medicine, an agrochemical, a physiologically active material, in an industrially excellent productivity and also with a low load to environment. <P>SOLUTION: This method for producing the acyl derivative from an alcohol and an acylating agent comprises a super critical continuous reaction process performing a stereo selective esterification reaction by using an enzyme in the presence of super critical carbon dioxide. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

The present invention relates to a method for producing an acylated derivative. More specifically, the present invention relates to a method for producing an acylated derivative by a kinetic resolution reaction that is useful for large-scale production of optically active compounds and is environmentally advantageous.

Optically active compounds are useful as compounds and intermediates used in various fields such as pharmaceuticals, agricultural chemicals and physiologically active substances. If a racemate or a compound with low optical purity is used in these fields, the target biological activity may be significantly reduced or it may be toxic. In the manufacturing method, a method capable of industrially manufacturing a compound having high optical purity is being studied.

With respect to a conventional method for producing an optically active ester compound, it has been disclosed that an ester synthesis reaction by an enzyme is performed in an atmosphere of carbon dioxide at a critical temperature or higher and a critical pressure or higher (see, for example, Patent Document 1). In the Examples, it is described that oleic acid and (±) -citronellol are used as substrates and the esterification reaction with lipase is continuously performed in a supercritical carbon dioxide atmosphere. Also disclosed is a method for producing a polyester in which an organic diol is reacted with either an organic diester or an organic dicarboxylic acid in the presence of a supercritical fluid and in the presence of a solid esterase enzyme (see, for example, Patent Document 2).
However, these production methods are useful in various fields such as pharmaceuticals, agricultural chemicals, physiologically active substances, and the like, and are optically active compounds having an increased optical purity that can be produced with industrially improved productivity. There was room for ingenuity.

The present invention also relates to a method for producing an optically active compound, a step of reacting an ester of (R, S) -3-hydroxytetrahydrofuran with an enzyme capable of optically hydrolyzing the compound, and the produced optically active 3-hydroxy A process for separating tetrahydrofuran and an ester of optically active 3-hydroxytetrahydrofuran (see, for example, Patent Document 3), an enzyme having an activity of synthesizing optically active glycerol α-monocarboxylic acid ester A method for producing an optically active glycerol α-monocarboxylic acid ester in which glycerol is esterified with an acyl donor in the presence (see, for example, Patent Document 4), one of 2-hydroxy fatty acid esters including R-form and S-form In an organic solvent in the presence of an enzyme capable of stereoselectively esterifying A method for producing an optically active ester that acts with an esterifying agent (for example, see Patent Document 5) is disclosed.
However, in these production methods, since the yield and yield are not sufficient, it is possible to industrially produce an optically active compound with improved optical purity while improving this point and making it a practical production method. There was room for ingenuity to make it a method.
JP-A-9-283 (page 2-3) JP-A-8-256783 (2nd page) JP 10-337197 A (page 2) Japanese Patent Laid-Open No. 11-113590 (page 2) JP 2001-128694 A (second page)

The present invention has been made in view of the above situation, and provides a production method capable of obtaining an acylated derivative having high optical purity with industrially excellent productivity and low environmental impact. It is for the purpose.

The inventors of the present invention have studied various methods for producing optically active compounds. As a result, the (R) isomer and the (S) isomer were obtained using a continuous flow reactor in the presence of an enzyme catalyst in supercritical carbon dioxide. (R) having a high optical purity by acylating only one optical isomer of alcohol with an acylating agent (stereoselective esterification) and carrying out a kinetic resolution reaction. The present inventors have found that the ester compound of the isomer or the (S) isomer can be obtained with a high space time yield, and have conceived that the above-mentioned problems can be solved brilliantly. In addition, by adopting such a form, it is possible to greatly reduce the organic raw materials and the like that must be discarded, and because it can be a non-solvent reaction, it has also been found to be excellent in productivity and environmentally advantageous, Furthermore, the remaining alcohol that is not acylated is racemized with a catalyst containing ruthenium atoms, etc. to form a racemic alcohol, which is again used as a raw material for the supercritical continuous reaction under an enzyme catalyst, and this is repeated. Since almost all of the raw material alcohol can be converted into the (R) or (S) ester compound, it has also been found that a compound with high optical purity can be obtained in a high yield, and the present invention has been achieved.

In this way, when supercritical carbon dioxide is used as a solvent and an enzyme such as lipase (Novozyme 435) is used in a fixed bed and a stereoselective esterification reaction (acylation reaction) is continuously performed, it is about 400 times that of the batch method. Productivity and a stereoselectivity of E> 1000 can be achieved. In such a form, the (S) alcohol and the (R) acylated derivative can be obtained separately with high optical purity. Thus, what is obtained by the present invention is an optically active acylated derivative (acyl form) and an optically active unreacted alcohol. Therefore, the present invention is not only an optically active acylated derivative, but also a method for producing an optically active alcohol by optical resolution. Further, for example, by using a slight excess of vinyl acetate (vinyl acetate) as an acylating agent, it is possible to increase the acetylation conversion rate, thereby further increasing the optical purity.
By the way, supercritical carbon dioxide has been attracting attention as an environmentally friendly solvent having high reactivity. In addition, since enzymes are natural, have excellent chemical selectivity, regioselectivity, and enantioselectivity, and are reusable heterogeneous catalysts, such supercritical carbon dioxide and enzymes The reaction process combined with a catalyst is a promising synthetic means for producing an optically active compound, and is also useful in green chemistry (environmentally friendly chemistry).

That is, the present invention is a method for producing an acylated derivative from an alcohol and an acylating agent, and a supercritical continuous reaction step in which a stereoselective esterification reaction is continuously performed using an enzyme in the presence of supercritical carbon dioxide. Is a method for producing an acylated derivative.
The present invention is described in detail below.

In the present invention, an acylated derivative is produced from an alcohol and an acylating agent by continuously performing a stereoselective esterification reaction using an enzyme in the presence of supercritical carbon dioxide. In such a supercritical continuous reaction process, racemic alcohol undergoes a kinetic resolution reaction and is efficiently converted to the corresponding optically pure acylated derivative. Thus, the productivity can be improved and it is also useful as a practical means for the synthesis of optically active compounds. Thus, the use of a continuous flow reaction system for kinetic resolution not only provides a significant improvement in productivity over long reaction times, but can also be a substantially non-solvent reaction.

The stereoselective esterification reaction is a reaction for stereoselectively acylating a substrate alcohol which is a mixture of (S) alcohol and (R) alcohol, by using an acylating agent ( A form in which any one of the S) form and the (R) form is selectively acylated to produce an acylated derivative is preferred. In this case, it is preferable that either the (S) isomer or the (R) isomer that is not acylated remains as alcohol as it is. That is, the product of the supercritical continuous reaction step is a mixture containing unreacted (S) alcohol and the produced (R) acylated derivative, or unreacted (R) alcohol and produced (S ) A mixture containing an acylated derivative is preferred.
In such a product, the acylated derivative is obtained with high optical purity by dividing the acylated derivative by an ordinary method using the difference in chemical and physical properties between the acylated derivative and the unreacted alcohol. Will be able to.
In addition, not only optically active acylated derivatives but also optically active unreacted alcohols can be obtained by resolution utilizing such differences in chemical and physical properties. Therefore, the present invention has a high optical purity. It is also a preferred method when producing alcohol. That is, a method for producing an optically active acylated derivative and / or an optically active alcohol from an alcohol and an acylating agent, wherein a stereoselective esterification reaction is continuously performed using an enzyme in the presence of supercritical carbon dioxide. A method for producing an optically active acylated derivative and / or an optically active alcohol, which includes a continuous supercritical reaction step, is also one preferred embodiment of the present invention.
The acylation reaction refers to, for example, a reaction represented by the following reaction formula (1). In the formula, R _{I to} R _III are an alkyl group, an alkenyl group, an alkynyl group, an aryl group, and the like, and X is a halogen atom.

In the method for producing the acylated derivative, an unreacted alcohol is preferably racemic and used as a raw material for a supercritical continuous reaction step. Thus, by using unreacted alcohol as a raw material and repeating this, almost all of the alcohol initially used as the raw material can be converted into an acylated derivative.
As a method for converting the unreacted alcohol into a racemate, it is preferable to use a catalyst capable of racemizing the alcohol. For example, a catalyst containing a ruthenium atom is preferable.
As the above-mentioned catalyst containing a ruthenium atom, for example, η ⁵ -C ₅ (CH ₃ ) ₅ RuCl-1,5-cyclooctadiene is suitable.
By performing the racemization reaction alternately or simultaneously with the stereoselective esterification reaction described above, the starting alcohol can be converted to an acylated derivative at a high conversion rate.
In the racemization reaction, for example, the reaction is preferably performed in a solvent such as toluene in the presence of an amino compound. As reaction temperature, 10-50 degreeC is preferable, for example, and 20-30 degreeC is more preferable.
Examples of the amino compound may be a compound which can be a ligand of a catalyst containing ruthenium atoms mentioned above, for _{example, (CH 3) 2 N (} CH 2) 2 NH 2, (C 6 H 5) 2 P _{(CH 2) 2 NH 2,} (C 6 H 5) 2 P (CH 2) 2 NHCH 3, (C 6 H 5) 2 P (CH 2) 2 N (CH 3) 2, C 6 H 5 S ( CH ₂ ) ₂ NH ₂ , (C ₆ H ₅ ) ₂ P (CH ₂ ) ₃ NH _{2 and the} like are preferable.

Performing the esterification reaction continuously is to perform the esterification reaction by continuously adding a reaction substrate so that the reaction product can be continuously taken out. A flow-through form using a fixed bed is suitable.
In such a supercritical continuous reaction step, for example, it is preferable to continuously react in a form as shown in FIG. In FIG. 1, the substrate and carbon dioxide are sent to a reactor having an enzyme by a substrate pump for feeding alcohol and an acylating agent which are racemic substrates and a CO ₂ pump for sending carbon dioxide. The pressure of carbon dioxide is controlled by a pressure regulating valve, and the temperature is controlled by a heating oven (not shown) or the like, so that it becomes a supercritical state. The chiral product produced in the reactor is recovered as an effluent from the reactor outlet together with unreacted alcohol. Since such a reaction process is performed continuously, productivity can be improved.

The supercritical carbon dioxide is carbon dioxide in a supercritical condition, and the supercritical condition is a region exceeding the critical temperature and critical pressure inherent to the substance. In carbon dioxide, the temperature is 31 ° C. or higher. Yes, the pressure is 7.3 MPa or more. Moreover, the carbon dioxide in subcritical conditions may be sufficient. The subcritical condition refers to a condition region (subcritical condition) lower than the critical pressure near the critical point, and specifically, a region where the temperature is 30 ° C. or higher and the pressure is 5 MPa or higher.
As said temperature, it is preferable that it is 30 degreeC or more. More preferably, it is 35 degreeC or more, More preferably, it is 40 degreeC or more. Moreover, it is preferable that it is 70 degrees C or less. More preferably, it is 65 degrees C or less, More preferably, it is 60 degrees C or less. The pressure is preferably 7 MPa or more. More preferably, it is 10 MPa or more. Moreover, it is preferable that it is 25 Mpa or less. More preferably, it is 20 MPa or less.

The flow rate of the carbon dioxide is preferably 1 ml / hr / ml or more, for example. More preferably, it is 5 ml / hr / ml or more, More preferably, it is 10 ml / hr / ml or more. Moreover, it is preferable that it is 500 ml / hr / ml or less. More preferably, it is 300 ml / hr / ml or less, More preferably, it is 200 ml / hr / ml or less.
The flow rate of the substrate is preferably 0.1 ml / hr / ml or more. More preferably, it is 0.2 ml / hr / ml or more, and still more preferably 0.5 ml / hr / ml or more. Moreover, it is preferable that it is 50 ml / hr / ml or less. More preferably, it is 30 ml / hr / ml or less, More preferably, it is 20 ml / hr / ml or less. The flow rate of oxygen dioxide and the substrate is represented by a velocity per unit volume of the enzyme catalyst (space velocity).
As the molar ratio of the alcohol as the substrate and the acylating agent, for example, the alcohol / acylating agent is preferably 1 / 2.0 or more. More preferably, it is 1 / 1.5 or more. Moreover, it is preferable that it is 1 / 0.4 or less. More preferably, it is 1 / 0.5 or less.
The amount of the enzyme used is preferably, for example, 1.0 g / l or more. More preferably, it is 10 g / l or more, More preferably, it is 50 g / l or more. Moreover, it is preferable that it is 250 g / l or less. More preferably, it is 200 g / l or less, More preferably, it is 150 g / l or less.

The enzyme may be any enzyme that can stereoselectively acylate alcohol, and is preferably an enzyme that selectively acylates (R) alcohol, such as lipase or esterase. Preferably there is. As such lipase and esterase, for example, microorganisms belonging to the following, and those derived from mammals such as pig pancreas and pig liver are preferable.
Klebsiella genus, Serratia genus, Candida genus, Achromobacter genus, Alcaligenes genus, Aspergillus genus, Pseudomonas genus, Bacillus genus Rhizopus genus, Penicillium genus, Geotrichum genus, Mucor genus, Rhizomucor genus, Humicola genus, Burkholderia genus, Brevibacterium ) Genus, Corynebacterium genus, Nocardia genus, Cedecea genus, Proteus genus, Methylobacterium genus and the like.

Examples of the microorganism include, for example, Klebsiella oxytoca, Serratia marcescens, Candida cylindracea, Candida rugosa, Aspergillus oryzae, Aspergillus oryzae, and Aspergillus oryzae. • Aspergillus melleus, Bacillus amyloliquefaciens, Cedecea davisae JCM1685, Brevibacterium protophomiae IFO12128, Corynebacterium aquaticum 154 Nocardia corallina IFO3338, Pseudomonas maltophila IFO12690, Pseudomonas chlororaphis IFO3523, Bacillus Ste Rosamofirasu (Bacillus stearothermophillus) IAM1035, Bacillus subtilis (Bacillus subtilis) JCM1465 ^T, Methylobacterium Radio tolerance (Methylobacterium radiotolerans) IAM12099, Proteus vulgaris (Proteus vulgaris) IAM12003 the like are suitable.

As the enzyme, for example, the following commercially available enzymes are suitable, and the use form thereof may be used in a powder form or may be used by being supported on a carrier, but is preferably used after being immobilized. . As the carrier, inorganic materials such as activated carbon, celite, zeolite, alumina, silica gel and other metal oxides; organic materials such as polystyrene and starch are suitable.

Novozyme 435 (derived from Candida antactica, manufactured by Novozyme), SNSM-87 (derived from Klebsiella oxytoca, manufactured by Nagase Seikagaku Corporation), SM enzyme (derived from Serratia marcescens, manufactured by Nagase Seikagaku Corporation), lipase OF ( Candida cylindrasse derived, manufactured by Meika Sangyo Co., Ltd., lipase AL (from Achromobacter, manufactured by Meishoku Sangyo Co., Ltd.), lipase PL-679 (derived from Alkali Genes, manufactured by Meito Sangyo Co., Ltd.), lipase AY “Amano” (Candy) Derived from Da Lugosa, manufactured by Amano Pharmaceutical Co., Ltd., D-150 (derived from Aspergillus oryzae, manufactured by Nagase Seikagaku Corporation), lipase type II (derived from porcine pancreas, manufactured by Sigma), lipase P bulk powder (derived from Pseudomonas sp) , Manufactured by Nagase Seikagaku Corporation), XP-488 (derived from Aspergillus mereus), Gase Seikagaku Co., Ltd.), crystalline bacterial alkaline protease (derived from Bacillus amyloliquefaciens, Nagase Seikagaku Co., Ltd.), Sumiteam MP (derived from Aspergillus oryzae, Shin Nippon Chemical Co., Ltd.), lipase QL (Alkaligenes sp Origin, manufactured by Meito Sangyo Co., Ltd.), Biolase AL-45 (derived from Bacillus subtilis, manufactured by Nagase Seikagaku Corporation), lipase AK (derived from Pseudomonas fluorescens), lipase D (derived from Rhizopus derema), lipase F- AP (derived from Rhizopus genus), lipase G (derived from Penicillium casbati), lipase GC-20 (derived from Geotrichum candidium), lipase PZ-6 (derived from Aspergillus genus), lipase M-AP (derived from genus Mucor, Amano Pharmaceutical Co., Ltd.), Kirazyme L-1 (Burkhoderia) Genus origin), kylazyme L-4 (derived from Pseudomonas genus), kirazyme L-6 (derived from Pseudomonas genus), kirazyme L-8 (derived from genus Humicola, manufactured by Boehringer Mannheim), lipozyme (derived from Rhizomucor Mihai, Fulka) Lipase A (derived from Aspergillus niger, Amano Pharmaceutical Co., Ltd.), lipase P (derived from Pseudomonas cepacia, Amano Pharmaceutical Co., Ltd.), lipase PS (derived from Pseudomonas cepacia, manufactured by Amano Pharmaceutical Co., Ltd.), lipase AH (Pseudomonas Sephacia origin, Amano Pharmaceutical Co., Ltd., lipase AK (Pseudomonas fluorescens origin, Amano Pharmaceutical Co., Ltd.), Lipase MY (Candida Rugosa origin, Meisho Sangyo Co., Ltd.), CRL (Candida Rugosa origin, Sigma) Manufactured), lipase L-9 (from Mucor Meihai, Made shoe Diagnostics, Inc.), MML (derived from Mucor Mihai, manufactured by Novo Nordisk), and the like.

In the said reaction, it is good also as a form which carries out the stereoselective esterification reaction which used the enzyme as a catalyst by using the culture | cultivation body of the above-mentioned microorganisms, a microbial cell, or a microbial cell processed material.
Examples of the microorganism culture include a form in which a culture obtained by culturing a microorganism in a medium is used as it is. Examples of the cells include cells obtained from the culture by a collection operation such as centrifugation. Examples of treated cells include freeze-dried cells, crushed cells, cell-free extracts, and crude or purified enzymes obtained from cell-free extracts by gel filtration, ion exchange chromatography, and the like. . These can be used after being immobilized by a conventional method.

The alcohol may be an alcohol having an asymmetric carbon atom to which a hydroxyl group is bonded. For example, the following general formula (1);

^(Wherein, R 1 to R ³ are different from each other, a hydrogen atom, an alkyl group having 1 to 30 carbon atoms, an alkenyl group, an alkynyl group, ^.R 1 to R ³ representing an aryl group having 6 to 30 carbon atoms , Each of which may have a substituent or may be bonded to each other. The alkyl group, alkenyl group, and alkynyl group preferably have 3 to 20 carbon atoms, and more preferably 5 to 15 carbon atoms. The aryl group preferably has 6 to 18 carbon atoms, more preferably 6 to 12 carbon atoms.
Examples of the alcohol include 1-phenylethanol, 1-phenylpropanol, 1-phenyl-2-propanol, 1-phenylbutanol, 1-phenyl-2-butanol, 1-phenylpentanol, 2-butanol, 2- Pentanol, 2-hexanol, 2-heptanol, 2-octanol, 2-nonanol, 2-decanol, 2-undecanol, 2-dodecanol, 2-tridecanol, 1,2,3,4-tetrahydro-1-naphthol, etc. Is preferred. Among these, 1-phenylethanol, 2-undecanol, and 1,2,3,4-tetrahydro-1-naphthol are preferable.

As the acylating agent, organic acid esters, organic acid anhydrides and the like can be used. For example, vinyl acetate, vinyl propionate, vinyl butyrate, vinyl pivalate, vinyl caproate, vinyl laurate, vinyl myristate, Vinyl palmitate, vinyl stearate, vinyl monochloroacetate, vinyl acrylate, vinyl methacrylate, vinyl crotonate, vinyl benzoate, vinyl 2-chlorobenzoate, vinyl 4-nitrobenzoate, vinyl 2,4-dinitrobenzoate , Vinyl esters such as vinyl 3,5-dinitrobenzoate, vinyl cinnamate, vinyl 4-t-butylbenzoate, vinyl 2-furancarboxylate, vinyl 3-furancarboxylate; propenyl acetate, isopropenyl acetate, propenyl butyrate , Propenyl esters such as propenyl benzoate; vinegar anhydrous , Propionic anhydride, butyric anhydride, valeric anhydride, maleic anhydride, phthalic anhydride, oxalic anhydride, malonic anhydride, succinic anhydride, phthalic anhydride, benzoic anhydride, etc .; 1-ethoxyvinyl acetate, 1-ethoxyvinyl benzoate, 1-ethoxyvinyl 2-furancarboxylic acid, 1-ethoxyvinyl 3-furancarboxylic acid, 1-ethoxyvinyl picolinate, 1-ethoxyvinyl nicotinate, 1-ethoxyvinyl isonicotinate, 2 1-ethoxyvinyl ester such as 1-ethoxyvinyl thiophenecarboxylic acid, 1-ethoxyvinyl 3-thiophenecarboxylic acid; methyl benzoate; 2,2,2-trifluoroethyl ester such as acetic acid, butyric acid, acrylic acid, 2 2,2-trichloroethyl ester, phenyl ester and the like are preferred. Among these, organic acid vinyl ester, particularly vinyl acetate is preferable.

In the stereoselective esterification reaction of the present invention, for example, racemic-1-phenylethanol and an acylating agent vinyl acetate (vinyl acetate) are used as raw materials, and Novozyme 435 (manufactured by Novozyme) is used as an enzyme. When an acylated derivative is produced in supercritical carbon dioxide, as shown in the following reaction formula (2), the (R) -form alcohol is acylated to become an acylated derivative, and the (S) -form alcohol is unreacted. Will remain. Further, when the (S) alcohol is racemized with a catalyst containing a ruthenium atom, the racemic alcohol obtained by the racemization is used again as a raw material for the stereoselective esterification reaction. Further, when racemic-2-undecanol or racemic-tetrahydronaphthol is used as the alcohol, it reacts as shown in the following reaction formulas (3) and (4).

The optical purity of the acylated derivative obtained in the present invention is preferably 98.5% ee or more. More preferably, it is 99.0% ee or more, More preferably, it is 99.5% ee or more. The E value is preferably 500 or more. More preferably, it is 1000 or more, More preferably, it is 1500 or more.
Further, the optical purity of the remaining alcohol is preferably 85% ee or more. More preferably, it is 90% ee or more, More preferably, it is 95% ee or more.
The method for producing an acylated derivative of the present invention is a method that can be suitably applied as a method for producing compounds and intermediates used in various fields such as pharmaceuticals, agricultural chemicals and physiologically active substances.

The method for producing an acylated derivative of the present invention has the above-described configuration, and can provide an acylated derivative having high optical purity with industrially excellent productivity and low environmental impact.

The present invention will be described in more detail with reference to the following examples. However, the present invention is not limited to these examples. Unless otherwise specified, “part” means “part by weight” and “%” means “mass%”.

<Analysis and reagents>
GC analysis was performed using an optically active column (Chrompack, Chirazil-DEX CB: 25 m; He 2 ml / min) equipped with Shimazu GC-14B (C-R7A plus).
LC analysis was performed using an optically active column OJ-H (hexene / 2-propanol = 95/5, 0.4 ml / min, 254 nm, 35 ° C.).
¹ H-NMR analysis was performed with a Brucker DPX400 at 400 MHz.
The vinyl acetate was used after dried with molecular sieves and distilled. As other reagents, those commercially available from Nacalai, Wako Pure Chemical Industries, Tokyo Kasei, Aldrich, or ACROS were used as they were. Lipase (Novozym 435) was purchased from Novozymes. Moreover, the enzyme protein content in Novozym 435 is 1 to 10%.
<Flow reactor>
An enzyme continuous flow reaction was carried out using an apparatus as shown in FIG.
Carbon dioxide is fed by an HPLC pump (trade name: Intelligent HPLC pump PU-1580, manufactured by JASCO Corporation), and a substrate is fed by an HPLC pump (trade name: intelligent HPLC pump PU-2080, JASCO Corporation). Made).
The pressure of carbon dioxide was measured upstream and downstream of the reactor and controlled by a fully automatic pressure regulating valve (SCF-Bpg, manufactured by JASCO Corporation).
The temperature was controlled by measuring at the top and bottom and outside of the reactor using a heating oven (GC oven, GC14B, manufactured by Shimadzu Corporation) or a sand bath (manufactured by Matsuki Kagaku) as a reaction furnace. The following devices were used as other devices.
Head cooling jacket: JASCO pressure relief valve: NUPRO model R3A
Purge valve: JASCO Corporation SCF-Get stop valve SV-500
Tubular reactor: 1/2 inch diameter stainless steel reaction tube (with VCR fitting) manufactured by Swagelock
Pressure gauge: Digital pressure gauge manufactured by GL Science (with upper / lower limiter contact signal terminal block)
Power interrupter: GL Sciences

Example 1 Phenylethanol reaction lipase (Novozyme 435) 5 ml (1.89 g) was filled in a 1/2 inch φ reaction tube (inner diameter 10 mm) and incorporated into a reaction apparatus. Add molecular sieves to 1-phenylethanol (48.8 g) and vinyl acetate (17.2 g) (1-phenylethanol: vinyl acetate = 1: 0.5 (mol / mol)) to form a substrate solution. Was replaced. The oven temperature was raised to 42 ° C. The pressure of carbon dioxide was increased to 13.0 MPa, and the flow rate was set to 18 ml / hr / ml (1.5 ml / min). The flow rate of the substrate solution was set to 0.84 ml / hr / ml (0.07 ml / min) to start the reaction. After about 1.2 hours, when the apparatus was stabilized, the effluent was collected from the reactor outlet, and subjected to GC analysis, LC analysis and NMR analysis. The configuration was determined by comparing the retention times of the standard and GC. The results are shown in Tables 1 to 3.
Also, after 3.6 hours from the start of the reaction, the flow rate of carbon dioxide was changed to 6 ml / hr / ml (0.5 ml / min), and the flow rate of the substrate solution was changed to 0.28 ml / hr / ml (0.023 ml / min). did. After 5.2 hours, sampling of the effluent was resumed from the reactor outlet, and GC analysis, LC analysis, and NMR analysis were performed. The results are shown in 4 to 7 of Table 1. Moreover, the NMR spectrum of the extract | collected in Table 1 of 3 (it does not refine | purify) is shown in FIG. Furthermore, the pressure and the molar ratio of vinyl acetate were examined by the same experiment. The results are shown in Table 2.

From Table 2, the desired (R) acetic acid ester of 99.7% ee was obtained in a yield of 47%. The E value was over 1800. Also, the chemical yield increased from 47% to 50% by using a slight excess of vinyl acetate. In addition, a yield is the molar yield of (R) body acetate based on the initial amount of 1-phenylethanol which is a raw material.
Furthermore, even when vinyl acetate is used in a large amount, excess reaction of (S) alcohol hardly proceeds under the same conditions, and (R) acetic acid ester of 99% ee or more and unreacted. It was found that a quantitative mixture of (S) -form alcohols of the reaction was supplied, and even if the carbon dioxide pressure was changed in the range of 8.9 to 20 MPa, there was no significant change in the reaction results.
From the NMR spectrum of the reaction mixture in FIG. 3 (collected in 3 in Table 1), it was found that no side reaction occurred.

The% ee is an enantiomeric excess indicating optical purity, and can be obtained from the following formula (1). In addition, R and S are the ratio of the R body and S body which occupy in a product.

The E value is a value indicating stereoselectivity, and can be obtained from the following formula (2). C is the yield, and ee is the enantiomeric excess.

<Example 2> Phenylethanol continuous reaction lipase for 3 days (Novozyme 435) 5 ml (1.73 g) was filled in a 1/2 inch φ reaction tube (inner diameter 10 mm) and incorporated in the reaction apparatus. Molecular sieves were added to 1-phenylethanol (293 g) and vinyl acetate (124 g) (1-phenylethanol: vinyl acetate = 1: 0.6 (mol / mol)) to form a substrate solution, and the inside of the pump was replaced. The oven temperature was raised to 42 ° C. The pressure of carbon dioxide was increased to 13.0 MPa, and the flow rate was set to 18 ml / hr / ml (1.5 ml / min). The flow rate of the substrate solution was set to 0.84 ml / hr / ml (0.07 ml / min) to start the reaction. After about 1 hour, the apparatus was stabilized, and the effluent was collected from the outlet of the reactor, followed by GC analysis, LC analysis and NMR analysis.
The flow rates of carbon dioxide and substrate solution were kept constant for 3 days to convert a total of 221 g of racemic 1-phenylethanol into optically pure (S) alcohol and (R) acetate. The results are shown in FIG. In addition, a yield is the molar yield of (R) body acetate based on the initial amount of 1-phenylethanol which is a raw material. The maximum molar yield of optically active acylated derivative from racemic alcohol is 50%.
As shown in FIG. 4, such a biocatalyst maintains a catalytic action both in terms of reactivity and selectivity in a reaction for 3 days under supercritical conditions (12.9 to 13 MPa, 42 ° C.). Using a 5.0 ml reactor, (R / S) -1-phenylethanol (221 g) was quantitatively converted into 99% ee (S) alcohol and 99% ee (R) acetate ester. Converted.

Example 3 1 ml (0.347 g) of 2-undecanol reaction lipase (Novozyme 435) was charged into a 1/2 inch φ reaction tube (inner diameter 10 mm) and incorporated into the reaction apparatus. Add molecular sieves to 2-undecanol (43.1 g) and vinyl acetate (12.91 g) (2-undecanol: vinyl acetate = 1: 0.6 (mol / mol)) to make a substrate solution, and replace the inside of the pump did. The oven temperature was raised to 42 ° C. The pressure of carbon dioxide was increased to 13.0 MPa, and the flow rate was set to 180 ml / hr / ml (3 ml / min). The flow rate of the substrate solution was set to 7.56 ml / hr / ml (0.126 ml / min) to start the reaction. After the apparatus was stabilized after about 0.5 hours, the effluent was collected from the reactor outlet, and GC analysis, LC analysis and NMR analysis were performed. The configuration was determined by comparing the retention times of the standard and GC. The yield was 48-50%, and the E value was 112-137. In addition, a yield is the molar yield of (R) isomer acetate based on the initial amount of 2-undecanol which is a raw material.

Example 4 Reaction of Tetrahydronaphthol Lipase (Novozyme 435) 5 ml (1.98 g), 1,2,3,4-tetrahydro-1-naphthol: vinyl acetate = 1: 0.6 (mol / mol), substrate Solution flow rate 0.84 ml / hr / ml (0.07 ml / min), supercritical carbon dioxide flow rate 18 ml / hr / ml (1.5 ml / min) or 36 ml / hr / ml (3 ml / min), pressure 13 The reaction was performed in the same manner as in Example 3 except that the pressure was set to 0.0 MPa.
The E value was 1500 or more.

<Example 5> Racemization reaction of products obtained by lipase reaction in a dynamic kinetic resolution reaction flow system of 1-phenylethanol (sample 3 in Table 1 in Example 1, NMR chart in FIG. 3) Went. As a result of the racemization reaction using the Ru catalyst, racemization progressed by about 60%.

Comparative Example 1 Batch Reaction Racemic-1-phenylethanol (0.83 mmol) and vinyl acetate (5.4 mmol) were reacted in the presence of an enzyme (Novozyme 435) in the presence of carbon dioxide at 40 ° C. and 9 MPa. . At 48% conversion, a 1: 1 mixture of 99.8% ee optically active (R) acetate and 90.6% ee unreacted (S) alcohol was obtained. Similarly, the reaction was performed by changing the carbon dioxide pressure in the range of 9 to 13 MPa. The results are shown in FIG.
The substrate (R) alcohol reacted faster than the (S) alcohol, and the reaction stopped after about 7 hours. Thus, since the reactivity of enantiomers is quite different, it is considered that the (R) alcohol was consumed and the reaction was stopped. In the reaction at a carbon dioxide pressure of 9 to 13 MPa, the yield was 48% and the E value was 100 or more.

In Table 1, the reaction time is the time after reaching a stable reaction time. Table 3 shows the amount of enzyme used, the flow rate of oxygen dioxide and the substrate solution (alcohol + vinyl acetate), and the space velocity in the examples.
In a batch reaction using a 10 ml reactor, 0.83 mmol of optically active acetate 3 is produced during a reaction of 7 hours. By using a continuous flow reactor (5 ml), 25 mmol / h (3 ml / h ) At the rate of product.
Furthermore, by using a slight excess of vinyl acetate, the reaction proceeded smoothly, and the desired product could be supplied with excellent purity while minimizing waste during the reaction.
This synthetic process is particularly useful for large scale production of optically active alcohols.

FIG. 1 is a conceptual diagram showing the supercritical continuous reaction process of the present invention. FIG. 2 is a conceptual diagram of the reaction apparatus used in the examples. FIG. 3 is an NMR spectrum of the reaction product in the example. FIG. 4 is a graph showing the results of 3-day continuous operation reaction of phenylethanol in Examples. FIG. 5 is a graph showing the results when a batch reaction is performed.

Claims (3)

A method for producing an acylated derivative from an alcohol and an acylating agent,
A method for producing an acylated derivative, comprising a supercritical continuous reaction step in which a stereoselective esterification reaction is continuously performed using an enzyme in the presence of supercritical carbon dioxide. The product of the supercritical continuous reaction step is a mixture containing an unreacted (S) -form alcohol and a produced (R) -form acylated derivative, or an unreacted (R) -form alcohol and produced (S). The method for producing an acylated derivative according to claim 1, wherein the mixture is a mixture containing an acylated derivative. The method for producing an acylated derivative according to claim 2, wherein an unreacted alcohol is racemic and used as a raw material for a supercritical continuous reaction step.

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