KR100846674B1 - The method of preparing optically active trans-alcohols and their esters by enzymatic method - Google Patents

Abstract

The present invention relates to a process for preparing racemic trans alcohol compounds into optically active trans alcohol compounds and ester compounds thereof by enzymatic methods. To be more specific, it is to stereoselectively esterify a racemic trans alcohol compound using a hydrolase or a strain comprising the same to prepare an optically active trans alcohol compound and an ester compound thereof in a solvent phase or a nonsolvent phase.

Lipase, ester reaction, trans cyclohexanol derivative, trans cyclopentanol derivative

Description

The method of preparing optically active trans-alcohols and their esters by enzymatic method}

The present invention relates to an optically active trans alcohol compound and a method for preparing an ester compound thereof, and more particularly, an ester reaction of a trans alcohol compound in an organic solvent or an inorganic solvent using a hydrolase, or a strain comprising the same. The present invention relates to a method of preparing an optically active trans alcohol and an ester thereof.

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Ajay the like (Tetrahedron:. Asymmetry, vol 5 , 879-888, 1993) is a racemic trans-1-acetoxy-2-bromo-cyclohexane (trans -1- acetoxy 2-bromocyclohexane) the synthesized in cyclohexene (cyclohexene) Later, lipase was used to prepare optically active trans- 2-bromocyclohexanol and its esters by hydrolysis.

Takada et al. (Bulletin of the Chemical Society of Japan, vol. 67, 1196-1197, 1994) described Pseudomonas Hydrolysis reaction with cepacia lipase separated optically active (1R, 2R) -2- trans -t-butoxycarbonylaminocyclohexanol and (1S, 2S) -2- trans -t-butoxycarbonylaminocyclohexanol, but the amount of enzyme was used and the reaction time was long. .

Faber (Tetrahedron Letters, vol. 29, 1903-1904, 1988) et al. Synthesized racemic trans- 2-azidocyclohexanoate from cyclohexene oxide and then Candida Trans 2-azidocyclohexanol having optical activity was prepared through hydrolysis using cylindraces lipase.

Honig and Seufer-Wasserthal (Synthesis, vol. 1137-1140, 1990) were trans-2-substituted-cyclohexylbutanoate having a substituent at position 2 by hydrolysis reaction with lipase at room temperature for 1-50 hours. trans- 2-substituted-cyclohexylbutanoate) produced an optically active trans- 2-substituted-cyclohexanol derivative.

On the other hand, Maestro et al. (Tetrahedron: Asymmetry, vol 8, 3153-3159, 1997) described trans- 2-aminocyclohexanol and trans 2-aminocyclo having optical activity through ester reaction using lipase. Pentanol ( trans- 2-amino cyclopentanol) was produced.

Luna et al. (Tetrahedron: Asymmetry, vol. 9, 4483-4487, 1998) reported high optical activity using lipases from racemic cis-N-benzyloxycarbonyl-2-aminocylopentanol and racemic cis-N-benzyloxycarbonyl-2-aminocylohexanol. the cis-2-amino-cyclo-pentanol (cis -2-aminocyclopentanol) and cis-2-amino-cyclo-hexanol (cis -2-aminocyclhexanol) was generated with.

 As mentioned above, studies have been made to produce an optically active 2-substituted cyclohexanol or 2-substituted cyclopentanol by hydrolysis using lipase, 2-aminocyclohexanol or 2-aminocyclopentanol. A study to increase the optical purity through the ester reaction in the derivative has been reported. However, no method of preparing an optically active alcohol and its ester by ester-reacting transcyclohexanol or trans cyclopentanol having a substituent added at the 2nd position has not been reported.

Accordingly, the present inventors selectively esterify the trans alcohol compound represented by the general formula (1) using a hydrolase, or a strain comprising the same, in an organic solvent or in an organic solvent, and thus an optically active trans alcohol and ester thereof. A method of manufacturing was devised.

The method according to the present invention has the advantage that the reaction is simpler than the conventional method and high optical purity of alcohol and its esters can be obtained.

Therefore, an object of the present invention is a general reaction with the optically active trans alcohol represented by the general formula (2) having a high yield and optical purity by ester-reacting the racemic trans compound represented by the general formula (1) in the above [Scheme 1] It is providing the method of manufacturing the ester thereof represented by Formula (3).

In addition, the reaction is carried out using succinic anhydride as an acyl donor, followed by extraction by adding a basic aqueous solution of Na ₂ CO ₃ or NaHCO ₃ dissolved, so that the transalcohol having optical activity is transferred to the solvent layer and its ester is transferred to the aqueous solution layer. Not only is easy to recover, but the aqueous layer can be hydrolyzed with NaOH or the like to obtain (1R, 2R) and (1S, 2S) -trans alcohol products having high yield and high optical activity at once.

The production method of the present invention for achieving the above object is a stereotransesterification of the racemic trans alcohol compound represented by the formula (1) in an organic solvent or a nonsolvent by adding a hydrolase or a strain comprising the same, and stereosterically esterifying It is made to make.

상기 식에서, n은 1 내지 4이고, X는 N₃, CN, F, Cl, Br, I이며, R은 치환되거나 또는 치환되지 않은 탄소수 1 내지 8의 알킬기 또는 알케닐기, 벤질기, 탄소수 3 내지 6의 싸이클로알킬기, 치환되거나 치환되지 않은 아릴알킬기, 및 치환되거나 치환되지 않은 헤테로 아릴알킬기로 이루어진 군으로부터 선택되어 진다. 이때, 아실공여체(Acyldonor)는 비닐에스테르 화합물 또는 무수산 화합물로부터 선택된다.
또한, 본 발명은 하기 [반응식 1]에서 일반식(1)로 표시되는 라세믹 알코올 화합물을 아실공여체인 무수숙신산 용매에 첨가한 후, 가수분해효소 또는 이를 포함하는 균주를 촉매로 입체선택적으로 에스테르반응시켜 일반식(2)로 표시되는 광학활성 트랜스 알코올 화합물과 일반식(3)으로 표시되는 광학활성 에스테르 화합물을 제조한다.
[반응식 1]

상기 식에서, n은 1 내지 4이고, X는 N₃, CN, F, Cl, Br, I이며, R은 치환되거나 또는 치환되지 않는 탄소수 1 내지 8의 알킬기 또는 알케닐기, 벤질기, 탄소수 3 내지 6의 싸이클로알킬기, 치환되거나 치환되지 않은 아릴알킬기, 및 치환되거나 치환되지 않은 헤테로 아릴알킬기로 이루어진 군으로부터 선택된다.
이때, 아실공여체(Acyldonor)로는 무수숙신산을 사용하며, 최종적으로 생성된 에스테르 화합물에서의 R은 CH₂CH₂COOH)이다.
본 발명을 좀 더 상세히 설명하면 다음과 같다.The present invention relates to a racemic transalcohol compound represented by the general formula (1) in the following Scheme 1 as an optically active transalcohol and its ester represented by the general formulas (2) and (3) by enzymatic methods, respectively. It relates to a manufacturing method. More specifically, the compound represented by the general formula (1) in the solvent or nonsolvent phase is subjected to stereoselective esterification using a hydrolase or a strain comprising the same, and represented by the general formulas (2) and (3). To an optically active trans alcohol and an ester thereof.

Wherein n is 1 to 4, X is N ₃ , CN, F, Cl, Br, I, and R is a substituted or unsubstituted alkyl group having 1 to 8 carbon atoms or alkenyl group, benzyl group, 3 to 3 carbon atoms 6 cycloalkyl group, substituted or unsubstituted arylalkyl group, and substituted or unsubstituted hetero arylalkyl group. At this time, the acyl donor is selected from a vinyl ester compound or an anhydride compound.
In addition, the present invention, after adding the racemic alcohol compound represented by the general formula (1) in the following [Scheme 1] to the succinic anhydride solvent, which is an acyl donor, the hydrolytic enzyme or a strain containing the same is stereoselectively esterified with a catalyst. The reaction is carried out to produce an optically active trans alcohol compound represented by the general formula (2) and an optically active ester compound represented by the general formula (3).
Scheme 1

Wherein n is 1 to 4, X is N ₃ , CN, F, Cl, Br, I, R is substituted or unsubstituted alkyl group having 1 to 8 carbon atoms or alkenyl group, benzyl group, 3 to C carbon A cycloalkyl group of 6, a substituted or unsubstituted arylalkyl group, and a substituted or unsubstituted hetero arylalkyl group.
At this time, succinic anhydride is used as the acyldonor, and R in the finally produced ester compound is CH ₂ CH ₂ COOH).
The present invention is described in more detail as follows.

As described above, in the present invention, a hydrolase or a strain containing the same is added to the racemic trans alcohol represented by the general formula (1) using only an acyl donor without an organic solvent or an organic solvent, and then the mixture is The reaction is carried out at a constant temperature to prepare an optically active trans alcohol and an ester thereof.

The hydrolase used in the present invention can be used commercially available or can be prepared and used as needed. Commercially available lipases include, but are not limited to, lipase enzymes such as PS, PS-D, AH from Amano, and CAL B from Novozymes.

After the ester reaction, each is separated into an optically active trans alcohol and its ester by a method well known in the art.

Racemic trans 2-azidocyclohexanol is a gas chromatography (Donan Instruments, Model DS 6200) equipped with a capillary column, BP-1 (SGE, 30m × 0.53mm). 10 minutes per minute up to 220 ℃ after heating for 5 minutes at 70 ℃, was maintained at 220 ℃ 10 minutes. Racemic trans 2-azidocyclohexanol had a retention time of 11.58 minutes and trans- 1-acetoxy 2-azido cyclohexane had a retention time of Trans 2-azido 1-propionoxycyclohexane was detected at 13.78 minutes, and trans 2-azido 1-succinyloxycyclohexane was detected at 13.59 minutes. trans- 2-azido 1-succinyloxy cyclohexane) was detected at retention time of 13.85 minutes.

Optically active (1R, 2R)-and (1S, 2S) -trans-2-azidocyclohexanol are HPLC (Lab Alliance, Model 201) equipped with a chiral column AD-H (Daicel) ), A mixture of hexane and 2-propanol (95: 5) was flowed at 0.7 ml / min, and the absorbance was analyzed at 220 nm. The (1R, 2R) -trans-2-azidocyclohexanol had a retention time of 14.44 minutes and the (1S, 2S) -trans-2-azidocyclohexanol had a retention time of 16.51 minutes. (1R, 2R) -trans-1-acetoxy 2-azidocyclohexane was detected at retention time 7.34 minutes, and (1S, 2S) -trans-1-acetoxy 2-azidocyclohexane was retention time 8.27 minutes Was detected in. (1R, 2R) -trans-2-azido 1-propionoxycyclohexane was detected at retention time of 6.96 minutes and (1S, 2S) -trans-2-azido 1-propionoxycyclohexane was stored at 6.10 minutes Was detected in. (1R, 2R) -trans-2-azidosuccinyloxycyclohexane was detected at retention time 20.42 minutes, and (1S, 2S) -trans-2-azidosuccinyloxycyclohexane was detected at retention time 28.30 minutes It became.

Racemic trans 2-bromocyclohexanol is a gas chromatograph equipped with capillary column BP-1 (SGE, 30m × 0.53mm) (Donan Instruments, Model DS 6200). 10 minutes per minute up to 220 ℃ after heating for 5 minutes at 70 ℃, was maintained at 220 ℃ 10 minutes. Racemic trans 2-bromocyclohexanol was detected at retention time 9.69 minutes, trans 1-acetoxi 2-bromocyclohexane was detected at retention time 13.97 minutes and trans 2-bromo-1-oxy-succinyl cyclohexane (trans -2-bromo 1-succinyloxy cyclohexane) was detected at a retention time of 14.09 minutes.

Optically active (1R, 2R)-and (1S, 2S) -trans-2-bromocyclohexanol is HPLC (Lab Alliance, Model 201) equipped with chiral column AD-H (Daicel) ), A mixture of hexane and 2-propanol (95: 5) was flowed at 0.7 ml / min, and the absorbance was analyzed at 220 nm. The (1R, 2R) -trans-2-bromocyclohexanol had a retention time of 14.38 minutes and the (1S, 2S) -trans-2-bromocyclohexanol had a retention time of 16.09 minutes. (1R, 2R) -trans-1-acetoxy 2-bromocyclohexane was detected at retention time of 6.48 minutes and (1S, 2S) -trans-1-acetoxy 2-bromocyclohexane was detected at retention time of 7.34 minutes. Detected. (1R, 2R) -trans-2-bromo 1-succinyloxycyclohexane was detected at retention time 7.23 minutes and (1S, 2S) -trans-2-bromo 1-succinyloxycyclohexane was retained. It was detected at time 8.39 minutes.

Racemic trans 2-cyanocyclohexanol is a gas chromatography (Donan Instruments, Model DS) equipped with HP-FFAPP (J & W Scientific, 30 m × 0.53 mm), a capillary column. 6200), and heated to 70 ℃ 10 minutes per minute after heating for 5 minutes at 70 ℃, it was maintained for 10 minutes at 220 ℃. Racemic trans 2-cyanocyclohexanol was detected at retention time 20.08 minutes and trans 1-acetoxy 2-cyano cyclohexanol at retention time 17.81 minutes Trans 2-cyano 1-succinyloxycyclohexane was detected at retention time of 22.82 minutes.

Optically active trans 2-cyanocyclohexanol was analyzed using gas chromatography (Donam Instruments, Model DS 6200) equipped with a capillary column, G-TA (astec, 30 m × 0.32 mm). After heating at 70 ° C. for 5 minutes, the temperature was raised to 170 ° C. by 10 ° C. per minute and maintained at 170 ° C. for 10 minutes. The retention time of (1R, 2R) -trans-2-cyanocyclohexanol was detected at 19.52 minutes and the (1S, 2S) -trans-2-cyanocyclohexanol was detected at 19.19 minutes. (1R, 2R) -trans-1-acetoxy 2-cyanocyclohexane was detected at retention time 17.98 minutes and (1S, 2S) -trans-1-acetoxy 2-cyanocyclohexane was retained at 16.88 minutes Detected. (1R, 2R) -trans-2-cyano 1-succinyloxycyclohexane was detected at retention time 20.97 minutes and (1S, 2S) -trans-2-cyano 1-succinyloxycyclohexane was retention time 20.02 Detected in minutes.

Racemic trans 2-chlorocyclohexanol is a gas chromatography (Donan Instruments, Model DS 6200) equipped with HP-FFAPP (J & W Scientific, 30m × 0.53mm), a capillary column. 10 minutes per minute up to 220 ℃ after heating for 5 minutes at 70 ℃, was maintained at 220 ℃ 10 minutes. Racemic trans 2-chlorocyclohexanol was detected at a retention time of 18.64 minutes, and racemic trans 1-acetoxy 2-chlorocyclohexnaol had a retention time. ) Was detected at 16.04 minutes.

Optically active (1R, 2R)-and (1S, 2S) -trans-2-chlorocyclohexanol were HPLC (Lab Alliance, Model 201) equipped with chiral column AD-H (Daicel) The mixture (95: 5) of hexane and 2-propanol was flowed at 0.7 ml / min, and the absorbance was analyzed at 220 nm. (1R, 2R) -trans-2-chlorocyclohexanol was detected at retention time 23.22 minutes and (1S, 2S) -trans-2-chlorocyclohexanol was detected at retention time 25.72 minutes. (1R, 2R) -trans-1-acetoxy 2-chlorocyclohexane was detected at retention time 6.96 minutes, and (1S, 2S) -trans-1-acetoxy 2-chlorocyclohexane was detected at retention time 7.71 minutes It became.

Racemic trans 2-azidocyclopentanol is a gas chromatograph equipped with capillary column BP-1 (Astec, 30m × 0.32mm) (Donan Instruments, Model DS 6200). 10 minutes per minute up to 170 ℃ after heating for 5 minutes at 70 ℃, it was maintained for 10 minutes at 170 ℃. Racemic trans 2-azidocyclopentanol was detected at 13.23 minutes of retention time. Trans-1-acetoxy-2-O map cyclopentane (trans -1-acetoxy 2-azidocyclo pentane) was detected at a retention time of 12.21 minutes trans-2-azido-1-oxy-succinyl cyclopentane (trans -2-azido 1- Succinyloxycyclopentane) was detected at retention time 11.44 minutes.

Optically active (1R, 2R)-and (1S, 2S) -trans-2-azidocyclopentanol were HPLC (Lab Alliance, Model 201) equipped with AS-H (Daicel), a chiral column. The mixture of hexane and 2-propanol (90:10) was flowed at 0.7 ml / min, and the absorbance was analyzed at 220 nm. (1R, 2R) -trans-2-azidocyclopentanol was detected at retention time of 9.12 minutes and (1S, 2S) -trans-2-azidocyclopentanol was detected at retention time of 9.83 minutes. (1R, 2R) -trans-1-acetoxy 2-azidocyclohexane was detected at retention time 5.95 minutes and (1R, 2R) -trans-1-acetoxy 2-azidocyclohexane was detected at retention time 7.70 minutes. Detected. (1R, 2R) -trans-2-azido 1-succinyloxycyclopentane was detected at retention time 10.65 min and (1S, 2S) -trans-2-azido 1-succinyloxycyclopentane was retention time 20.22 Detected in minutes.

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

Example 1

Racemic trans 2-azidocyclohexanol was dissolved in 5 g of cyclohexene oxide in an 80% aqueous ethanol solution and then slowly added dropwise to 3.81 g of NH ₄ Cl and 4.3 g of NaN ₃ for 4 hours at 60 ° C. Reaction was synthesized. The synthesized racemic trans 2-azidocyclohexanol was extracted with ethyl acetate and recovered.

The production of trans 2-azidocyclohexanol was confirmed by FT-NMR (Bruker DRX 300), and the analysis results are as follows.

1 H-NMR δ = 3.3-3.5 (br, 1H), 3.1-3.2 (m, 1H), 2.2 (t, 1H), 2.0-2.1 (t, 3H), 1.7-1.8 (br, 2H), 1.2- 1.4 (m, 4H)

Example 2

To 5 g of cyclohexene oxide, 21 ml of 30% bromic acid / acetic acid was added dropwise, followed by reaction at room temperature. After completion of the reaction, the mixture was extracted with ethyl acetate and purified to prepare racemic trans 1-acetoxy 2-bromocyclohexane.

The racemic trans 2-bromocyclohexanol was synthesized by hydrolysis at room temperature by adding HCl to 3 g of the trans 1-acetoxy 2-bromocyclohexane prepared above. After completion of the reaction, the mixture was neutralized and extracted with ethyl acetate.

The production of trans 2-bromocyclohexanol was confirmed by FT-NMR (Bruker DRX 300), and the analysis results are as follows.

1 H-NMR δ = 3.6-3.7 (br, 1H), 3.3-3.4 (m, 1H), 2.3 (br, 1H), 2.0-1.9 (t, 2H), 1.6-1.7 (br, 2H), 1.2- 1.3 (m, 4H)

Example 3

Racemic trans 2-cyanocyclohexanol was synthesized by dissolving 10 g of KCN in distilled water, adding 65% sulfuric acid to adjust pH 8, and slowly adding dropwise 10.05 g of cyclohexene oxide. After completion of the reaction, the mixture was extracted with ethyl acetate and recovered.

The production of trans 2-cyanocyclohexanol was confirmed by FT-NMR (Bruker DRX 300), and the analysis results are as follows.

1H-NMR δ = 3.73 (m, 1H), 2.43 (m, 2H), 2.10 (m, 2H), 1.71 (m, 2H), 1.61 (m, 1H), 1.30 (m, 3H)

Example 4

Racemic trans 2-chlorocyclohexanol was synthesized by dissolving 10 g of cyclohexene oxide in distilled water and then adding 20 ml of hydrochloric acid (HCl, 35%) dropwise. After completion of the reaction, the mixture was neutralized and extracted with ethyl acetate.

The production of trans 2-chlorocyclohexanol was confirmed by FT-NMR (Bruker DRX 300), the analysis results are as follows.

1H-NMR δ = 3.4-3.5 (t 1H), 1.7-1.6 (s, 2H), 3.3-3.2 (q, 1H), 2.1-1.9 (d, 2H), 1.7-1.6 (s, 2H), 1.4 -1.2 (t, 4H)

Example 5

Racemic trans 2-azidocyclopentanol was dissolved in 2 g of cyclopentene oxide in an aqueous 80% ethanol solution and then slowly added dropwise to 1.55 g of NH ₄ Cl and 1.64 g of NaN ₃ for 7 hours at 70 ° C. Reaction was synthesized. The synthesized racemic trans 2-azidocyclopentanol was recovered by extraction with ethyl acetate.

The production of 2-azidocyclopentanol was confirmed by FT-NMR (Bruker DRX 300), and the analysis results are as follows.

1H-NMR δ = 4.0-4.2 (br q, 1H), 3.6-3.8 (br q, 1H), 2.1-1.9 (m, 2H) 1.5-1.8 (m, 4H)

Example 6

0.05 g of racemic trans 2-azidocyclohexanol is dissolved in a vial containing 4.9 ml of tert-butylmethylether and 50 µl of vinyl acetate, followed by lipase PS-D of 0.05. g was added and the reaction was carried out at 30 ° C. The analysis results of the reactants are shown in Table 1 below.

Example 7

Instead of lipase PS-D Novozym435 (Novozymes) was carried out in the same manner as in Example 6, the analysis results of the reactants are shown in Table 1 below.

Example 8

Instead of lipase PS-D, lipase AH (manufactured by Amano) was used in the same manner as in Example 6, and the analysis results of the reactants are shown in Table 1 below.

Example Lipase Response time (hr) % Conversion product ee (%) 6 PS-D 5 51.2 (1S, 2S) -trans-2-azidocyclohexanol 99 (1R, 2R) -trans-1-acetoxy 2-cyclohexane 99 7 Novozym435 16 61.3 (1S, 2S) -trans-2-azidocyclohexanol 99 (1R, 2R) -trans-1-acetoxy 2-cyclohexane 99 8 AH 46 49.7 (1S, 2S) -trans-2-azidocyclohexanol 99 (1R, 2R) -trans-1-acetoxy 2-cyclohexane 99

Example 9

Vinyl propionate (vinyl propionate) was carried out in the same manner as in Example 6 instead of vinyl acetate, and the analysis results of the reactants are shown in Table 2 below.

Example 10

Succinic anhydride was performed in the same manner as in Example 6 instead of vinyl acetate, and the analysis results of the reactants are shown in Table 2 below.

Example 11

Butyric anhydride was carried out in the same manner as in Example 6 instead of vinyl acetate, and the analysis results of the reactants are shown in Table 2 below.

Example Acyl donor Response time (hr) % Conversion product e.e (%) 9 Vinyl propionate 23 47.1 (1S, 2S) -trans-2-azidocyclohexanol 99 (1R, 2R) -trans-2-azido 1-propionoxycyclohexane 99 10 Succinic anhydride 48 51.4 (1S, 2S) -trans-2-azidocyclohexanol 99 (1R, 2R) -trans-2-azido 1-succinyloxycyclohexane 99 11 Butyric anhydride 2.5 53.0 (1S, 2S) -trans-2-azidocyclopentanol 99 (1R, 2R) -trans-2-azido 1-butyloxycyclohexane 92

Example 12

Instead of racemic trans 2-azidocyclohexanol, racemic trans 2-cyanocyclohexanol was carried out in the same manner as in Example 6, and the analysis results of the reactants are shown in Table 3 below.

Example 13

Instead of racemic trans 2-azidocyclohexanol, racemic trans 2-chlorocyclohexanol was carried out in the same manner as in Example 6, and the analysis results of the reactants are shown in Table 3 below.

Example 14

Instead of racemic trans 2-azidocyclohexanol, racemic trans 2-bromocyclohexanol was carried out in the same manner as in Example 6, and the analysis results of the reactants are shown in Table 3 below.

Example 15

Instead of racemic trans 2-azidocyclohexanol, racemic trans 2-azidocyclopentanol was carried out in the same manner as in Example 6, and the analysis results of the reactants are shown in Table 3 below.

Example Reactant % Conversion product e.e (%) 12  Racemic Trans 2-Cyanocyclohexanol 49.5 (1S, 2S) -trans-2-cyanocyclohexanol 99 (1R, 2R) -trans-1-acetoxy 2-cyanocyclohexane 99 13  Racemic Trans 2-Chlorocyclohexanol 51.0 (1S, 2S) -trans-2-chlorocyclohexanol 99 (1R, 2R) -trans-1-acetoxy 2-chlorocyclohexane 99 14 Racemic Trans 2-Bromocyclohexanol 50.0 (1S, 2S) -trans-2-bromocyclohexanol 99 (1R, 2R) -trans-1-acetoxy 2-bromocyclohexane 99 15 Racemic Trans 2-azidocyclopentanol 52.5 (1S, 2S) -trans-2-azidocyclopentanol 99 (1R, 2R) trans--1-acetoxy 2-azidocyclopentane 99

Example 16

Instead of the solvent t-butyl methyl ether, only 4.95ml of acyl donor vinyl acetate was added thereto, and the same procedure as in Example 6 was carried out. The analysis results of the reactants are shown in Table 4 below.

Example Response time (hr) % Conversion product ee (%) 16 5 51.2 (1S, 2S) -trans-2-azidocyclohexanol 99 (1R, 2R) -trans-1-acetoxy 2-azidocyclohexane 99

Example 17

As a reaction, racemic trans 2-azidocyclohexanol was carried out in the same manner as in Example 6 using acyl donor instead of vinyl acetate as acyl donor. -Succinyloxycyclohexane was extracted by adding an aqueous solution containing a certain amount of Na ₂ CO ₃ and then hydrolyzed with NaOH to obtain (1R, 2R) -trans-2-azidocyclohexanol. The analysis results of (1S, 2S)-and (1R, 2R) -trans-azidocyclohexanol after the reaction are shown in Table 5 below.

Example 18

The reaction was carried out in the same manner as in Example 17 using racemic trans 2-bromocyclohexanol, the analysis results of the reactants are shown in Table 5 below.

Example 19

The reaction was carried out in the same manner as in Example 17 using racemic trans 2-cyanocyclohexanol, the analysis results of the reactants are shown in Table 5 below.

Example 20

The reaction was carried out in the same manner as in Example 17 using racemic trans 2-azidocyclopentanol, and the analysis results of the reactants are shown in Table 5 below.

Example Reactant % Conversion product e.e (%) 17  Racemic Trans 2-azidocyclohexanol 49.4 (1S, 2S) -trans-2-azidocyclohexanol 99 (1R, 2R) -trans-2-azidocyclohexanol 98 18  Racemic Trans 2-Bromocyclohexanol 53.6 (1S, 2S) -trans-2-bromocyclohexanol 99 (1R, 2R) -trans-2-bromocyclohexanol 97 19  Racemic Trans 2-Cyanocyclohexanol 52.1 (1S, 2S) -trans-2-cyanocyclohexanol 99 (1R, 2R) -trans-2-cyanocyclohexanol 98 20  Racemic Trans 2-azidocyclopentanol 49.4 (1S, 2S) -trans-2-azidocyclopentanol 99 (1R, 2R) -trans-2-azidocyclopentanol 98

As can be seen through Examples 6 to 20, in the method for producing an optically active trans alcohol and ester thereof, the production method according to the present invention is a high optical reaction by using a hydrolase or a strain comprising the same In addition to obtaining cycloalcohol derivatives and esters thereof with purity, the recovery of the product after the reaction is easy and easy to apply to actual processes. In addition, the biocatalyst used in the reaction is very useful in industry because it can be easily recovered and reused.

Claims (4)

In the following Scheme 1, the racemic trans alcohol compound of Formula (1) is subjected to stereoselective esterification of a hydrolase or a strain containing the same in a solvent or non-solvent phase with a catalyst to optically convert trans of Formula (2). A process for producing an alcohol compound and an optically active ester compound of the general formula (3). Scheme 1

Wherein n is 1 to 4, X is N ₃ , CN, F, Cl, Br, I, and R is substituted or unsubstituted alkyl group having 1 to 8 carbon atoms or alkenyl group, benzyl group, 3 carbon atoms To a cycloalkyl group of 6 to 6, a substituted or unsubstituted arylalkyl group, and a substituted or unsubstituted hetero arylalkyl group, and an acyldonor is selected from a vinyl ester compound or an anhydride compound.). In the following [Scheme 1], the racemic alcohol compound of the general formula (1) is added to the succinic anhydride solvent, which is the acyl donor, and then subjected to stereoselective esterification of a hydrolase or a strain containing the same by a catalyst to the general formula (2) The optically active trans alcohol compound and the optically active ester compound of General formula (3) are manufactured. Scheme 1

Wherein n is 1 to 4, X is N ₃ , CN, F, Cl, Br, I, and R is substituted or unsubstituted alkyl group having 1 to 8 carbon atoms or alkenyl group, benzyl group, 3 carbon atoms To a cycloalkyl group, a substituted or unsubstituted arylalkyl group, and a substituted or unsubstituted hetero arylalkyl group, wherein R in the ester compound is CH ₂ CH ₂ COOH). delete delete