KR20030093609A - The method of making optical active 1-phenyl ethanol and their esters in non-solvent phase - Google Patents

Abstract

PURPOSE: Provided is a method of preparing optical active 1-phenyl ethanol and their derivatives by lipase without a solvent. Without using solvent, reaction is carried out in the high concentration of reactants and in a high yield of optical purity. CONSTITUTION: The method comprises esterification of 1-phenylethanol with vinyl acetate, vinyl benzoate, vinyl propionate and vinyl butyrate without a solvent, with powder or immobilized lipase of microorganism origin or from pig pancreas extract.

Description

The method of making optical active 1-phenyl ethanol and their esters in non-solvent phase

The present invention relates to a process for preparing optically active 1-phenyl ethanol and esters thereof using an enzyme on a non-solvent, and more particularly from racemic 1-phenyl ethanol using an enzyme, in particular a lipase enzyme, under a non-solvent. A method for preparing optically active 1-phenyl ethanol and ester derivatives thereof.

Racemic 1-phenyl ethanol is present in half of (R) -1-phenyl ethanol and (S) -1-phenyl ethanol. Ester derivatives of optically active 1-phenyl ethanol can be easily converted to optically active 1-phenyl ethanol by hydrolysis. There are many methods for preparing optically active 1-phenyl ethanol, among which, many attempts have been made to prepare racemic 1-phenyl ethanol from optically active 1-phenyl ethanol using enzymes.

A method for preparing optically active 1-phenyl ethanol using an organic acid and the like on an organic solvent has been reported (Bianchi et al., J. Org. Chem. Vol. 53: 5531-5534, 1988: Gutman et al., Tetrahedron: Asymmetry vol. 4: 839-844, 1994: Guibe-Jampel et al., Tetrahedron vol. 52: 4397-4402, 1996), using a vinyl ester compound as an acyl donor in an organic solvent has been reported. Fitzpatrick and Klibanov (J. Am. Chem. Soc. Vol. 113: 3166-3171, 1991) are organic solvents using vinyl butylate as an acyl donor and subtilisin Carlsberg, a protease as a catalyst. An attempt was made to prepare optically active 1-phenyl ethanol via an ester reaction of 1-phenyl ethanol on the bed. It has been reported that the optical selectivity (enantioselectivity) is different depending on the organic solvent used.

Griebenow et al. (J. Am. Chem. Soc. Vol. 121: 8157-8163, 1999) reported that immobilization of subtilisin Carlsberg in methylbetacyclodextrin yielded twice the optical selectivity. At this time, the vinyl butyrate used has a problem in economical efficiency when commercialized at a high price compared to other vinyl ester compounds. Ferraboschi et al. (Biocatalysis vol. 10: 279-288, 1994) use vinyl acetate as acyl donor on methylene chloride and (S) -1-phenyl ethanol (96 ee%) using PFL (Flukas) enzyme as catalyst. Prepared. In addition, the use of a vinyl ester compound having a modified structure in order to increase the optical selectivity has been proposed. (Kawasaki et al., Tetrahedron Letters vol. 40: 5223-5226, 1999)

However, the reaction on the organic solvent requires a high cost to separate and recover the product from the organic solvent, so using only the liquid reactant without using the organic solvent reduces the production cost, and is a safe and easy process of separation and recovery. Establishment is possible.

In addition, the reaction can be selected while maintaining a high concentration of the reactants, and it is more economical than the organic solvent phase process by continuing to use the vinyl ester compound recovered after the reaction.

Accordingly, the present inventors have developed a method for preparing optically active 1-phenyl ethanol and its ester derivatives by reacting a reactant vinyl ester compound with racemic 1-phenyl ethanol using a lipase enzyme in a non-solvent, in an organic solvent. Completion was made based on compensating for the shortcomings in preparing optically active 1-phenylethanol.

Accordingly, an object of the present invention is to provide high optical purity of (S) -1-phenyl ethanol and (R) -1- using lipase enzyme in the presence of racemic 1-phenyl ethanol and a vinyl ester compound acting as an acyl donor. There is provided a method for preparing phenyl ethanol ester. The opposite is also true if the appropriate lipase enzyme is selected.

The production method of the present invention for achieving the above object consists of esterifying the racemic 1-phenyl ethanol and the vinyl ester compound in liquid form in a non-solvent with a lipase enzyme.

Looking at the present invention in more detail as follows.

As described above, the optically active 1-phenyl ethanol and ester derivatives thereof are prepared by reacting racemic 1-phenyl ethanol with a vinyl ester compound using a lipase enzyme under a non-solvent.

Lipases used in the present invention include enzymes or immobilized lipases, or biological cells containing lipases and immobilized biological cells, which are extracted from a microorganism-derived lipase, or a pig pancreas, and provided in powder form. In particular, the lipase may be commercially available, or may be manufactured and used as necessary.

Commercially available lipases include Novo's Novozyme 435 (Candida antarctica), Amano's lipase PS (Pseudomonas cepatia), Celite's immobilized PS (PS-C), or Sigma's Lipase PPL (porcine pancreatic) and the like, but are not limited thereto.

As the vinyl ester compound used in the present invention, vinyl acetate, vinyl propionate or vinyl butylate is used.

1-phenyl ethanol and optically active 1-phenyl ethanol and ester derivatives were analyzed using gas chromatography (Donam Instruments Co., Ltd. model DS 6200).

1-phenyl ethanol and ester derivatives are SGE's BP5 capillary column (internal diameter 0.53 mm, length 30 m), and optically active (R)-and (S) -1-phenyl ethanol are B-PM from Alltech. The analysis was performed using a capillary column (internal diameter 0.32 mm, length 30 m).

As analytical conditions for 1-phenyl ethanol and ester derivatives of 1-phenyl ethanol, the BP5 column was heated at 60 ° C. for 8 minutes, increased to 220 ° C. at 10 ° C. per minute, and held at 220 ° C. for 5 minutes. As a carrier, helium gas was flowed at a rate of 2 ml per minute, and detected using a flame ionization detector (FID) at 220 ° C. 1-phenyl ethanol was detected at 14.4 minutes.

Optically active (R)-and (S) -1-phenyl ethanol heated the B-PM column at 120 ° C. for 30 minutes, flowing helium gas at a head pressure of 4 psi with a carrier, and a flame ionization detector (FID) at 150 ° C. Detected using.

(R) -1-phenyl ethanol was detected at 12.4 minutes and (S) -1-phenyl ethanol at 12.9 minutes, respectively.

Hereinafter, the present invention will be described in more detail with reference to the following Examples, but the scope of the present invention is not limited to the following Examples.

Example 1.

Into a vial containing 2.5 ml of vinyl propionate, add 1% (v / v) of racemic 1-phenylethanol in liquid form, and then add 2% (w / v) of Novozyme 435 enzyme from Novo, at 35 ° C. The reaction was carried out. After the reaction, the supernatant of the reaction product was recovered and analyzed for optically active 1-phenyl ethanol and its ester derivatives according to the above analysis method. 99.5 ee% of (S) -1-phenyl ethanol was obtained in 2.5 hours of reaction. (55.1% conversion)

Example 2-5

The reaction was carried out using the lipase enzymes listed in Table 1 instead of the Novozyme 435 enzyme among the conditions of Example 1. The conversion and optical purity are as follows.

TABLE 1

Example 6

Instead of the lipase PS used in Example 2, 5% of 1-phenylethanol was added to the vial using a PS enzyme immobilized on diatomaceous earth (PS-D), followed by reaction.

After 6 hours of reaction, (S) -1-phenyl ethanol (99.1 ee%) was obtained.

Example 7-8

The reaction was performed using another vinyl ester compound instead of the vinyl propionate used in Example 1. The conversion and optical purity are as follows.

TABLE 2

Example 9

The reaction was carried out using vinyl benzoate instead of vinyl propionate, novzyme 435 enzyme instead of lipase PS under the conditions of Example 1. After 6 hours, 62.5 ee% of (S) -1-phenylethanol was obtained.

As can be seen in Examples 1-9, in the synthesis of (S) -1-phenyl ethanol, the reaction time can be adjusted to selectively produce chiral compounds present in excess of (S) -1-phenyl ethanol. If the appropriate lipase enzyme or vinyl ester compound is selected, 1-phenyl ethanol having high optical purity can be easily produced.

In addition, since the vinyl ester compound recovered after the reaction is easy to reuse, it has the advantage of reducing the generation of waste.

Thus, the process of the present invention can produce optically active 1-phenyl ethanol and its esters in a simple and inexpensive manner compared to organic solvent phase reactions.

Claims (3)

Method for producing optically active 1-phenyl ethanol and ester compounds thereof characterized by esterifying a 1-phenyl ethanol and a vinyl ester compound using a lipase enzyme in a non-solvent The method of claim 1, wherein the lipase enzyme is a lipase derived from powder or immobilized microorganism-derived lipase or pig pancreas. The method of claim 1, wherein the vinyl ester compound is vinyl acetate, vinyl benzoate, vinyl propionate, or vinyl butylate.