KR100832749B1 - Method for preparing chiral alpha fluoromethyl propargyl alcohol derivatives - Google Patents

Method for preparing chiral alpha fluoromethyl propargyl alcohol derivatives Download PDF

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KR100832749B1
KR100832749B1 KR1020060081510A KR20060081510A KR100832749B1 KR 100832749 B1 KR100832749 B1 KR 100832749B1 KR 1020060081510 A KR1020060081510 A KR 1020060081510A KR 20060081510 A KR20060081510 A KR 20060081510A KR 100832749 B1 KR100832749 B1 KR 100832749B1
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optically active
compound
phenyl
ester derivative
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KR20080019345A (en
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고성진
김범태
김성환
민용기
박노균
이우길
이혁
전난영
허정녕
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한국화학연구원
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Abstract

The present invention relates to a method for preparing an optically active α-fluoromethyl propargyl alcohol derivative, in the presence of a racemic α-fluoro in the presence of a lipase catalyst derived from Candida antarctica or Mucor miehei . The methyl propargyl alcohol derivative is reacted with vinyl alkanoate to perform stereoselective esterification reaction to obtain an optically active compound and ester derivative in the form of (-)-, followed by hydrolysis of the ester derivative in the form of (+)- It is characterized by obtaining the optically active substance of. According to this method of the present invention, the desired optically active α-fluoromethyl propargyl alcohol derivative can be easily obtained from the racemic raw material compound, and the obtained optically active compound has high optical purity of up to 99% ee or more.

Description

METHOD FOR PREPARING CHIRAL α-FLUOROMETHYL PROPARGYL ALCOHOL DERIVATIVES}

The present invention relates to a method for efficiently preparing a desired optically active derivative from racemic α-fluoromethyl propargyl alcohol derivatives.

Optically active propargyl alcohols include prostaglandins, steroids, carotenoids, HMG-CoA synthesis inhibitors of formula (F-244), antiobesity drug tetrahydrolipstatin (antiobesity drug tetrahydrolipstatin) , And major compounds widely used in the synthesis of natural or biologically active organic compounds such as second generation 5-lipoxygenase inhibitors of Formula 5 (A-78773) ( J. Am. Chem. Soc. 1977 , 99 , 8341; J. Org. Chem. 1976 , 41 , 3497; and Tetrahedron, Asymmetry 1996 , 7 , 729):

Figure 112006061512757-pat00001

Figure 112006061512757-pat00002

These optically active propargyl alcohols include (1) alkynylating aldehyde raw materials using various optically active ligands in the presence of metal catalysts, (2) reducing ketone raw materials using reducing agents, or (3) metal catalysts. In the presence of a racemic raw material is conventionally synthesized by stereoselective kinetic resolution to separate it into an optically active compound.

In particular, it is known that optically active propargyl alcohols containing fluorine have a great influence on molecular properties such as biological activity, metabolism, solubility, hydrophobicity, and the like. Interested in the synthesis of optically active propargyl alcohols.

As an example of the synthesis of fluorine-containing optically active α-propargyl alcohols known to date, the optically active 1-benzyloxy-2,2,2-trifluoroethyl tosylate is alkoxylized using lithium alkynyltriethyl aluminate. An optically active α-trifluoromethyl propargyl alcohol was prepared by nitrile substitution reaction to obtain trifluoromethyl-propargyl benzyl ether to maintain optical activity, followed by deprotection to remove the benzyl group from the ether. (See Chem. Lett. 1999 , 529).

In addition, a technique for synthesizing optically active α-fluoromethyl propargyl alcohol by reducing fluoromethyl propargyl ketone using an optically active reducing agent such as B -chlorodiisopinecamphor borane is introduced ( Tetrahedron, Asymmetry 1994 , 5 , 1061).

In addition to this, the fluoro's can be reduced using a baker's yeast or a biocatalyst, or a lipase derived from Candida cylindracea is used as a biocatalyst. A method for synthesizing an optically active α-trifluoromethyl propargyl alcohol by hydrolyzing an ester having a fluoromethyl propargyl group has been published ( J. Fluorine Chem. 1985 , 30 , 189) and [T J. Org.Chem. 1987 , 52 , 3211.

In addition, a method of synthesizing an optically active α-trifluoromethyl propargyl alcohol by reducing trifluoromethyl propargyl ketone using a yeast (baker's yeast) or a biocatalyst has been disclosed. In addition, a method of hydrolyzing an ester having an α-trifluoromethyl propargyl group using a lipase derived from Candida cylindracea as a biocatalyst has been disclosed, but low optical purity, that is, 67% There was a problem that products with less than enantiomeric excess (simply ee) were obtained ( J. Fluorine Chem. 1985, 30 , 189) and T. J. Org. Chem. 1987, 52 , 3211). However, the use of biocatalysts still had the advantages of being environmentally friendly, highly selective, and capable of proceeding at room temperature and atmospheric pressure.

In this regard, even in the case of optically active propargyl alcohols containing no fluorine, various racemic propargyl alcohols are subjected to the rate-fractionation reaction with vinyl acetate in the presence of lipase biocatalysts derived from Pseudomonas sp. Techniques for obtaining propargyl alcohol have been disclosed (see J. Am. Chem. Soc. 1991 , 113 , 6129), but in this case an optical purity of up to 95% ee has been achieved but usually about 78% ee. An object having an unsatisfactory optical purity of was obtained.

It is therefore an object of the present invention to provide a method for efficiently and efficiently obtaining desired optically active derivatives from racemic α-fluoromethyl propargyl alcohol derivatives using certain lipase biocatalysts.

In order to achieve the above object, the present invention

(1) In the organic solvent, in the presence of a lipase catalyst derived from Candida antarctica or Mucor miehei , a compound of formula 1 as racemate is reacted with vinyl alkanoate of formula 2 Performing a stereoselective esterification reaction to obtain a compound of formula (I) as an (-)-form optical activator and an ester derivative of formula (3); And

(2) After separating the compound of formula (1) and the ester derivative of formula (3) as the (-)-form optically active agent, the ester derivative of formula (3) is hydrolyzed to give the Obtaining Compound

Provided is a method of preparing a compound of Formula 1 as an optically active agent, including:

Figure 112006061512757-pat00003

Figure 112006061512757-pat00004

Figure 112006061512757-pat00005

Where

R 1 is CF 3 , CF 2 Br or CF 2 Cl;

R 2 is phenyl, cyclohexyl, n -hexyl, n -butyl or n -propyl;

R 3 is methyl, ethyl or n -propyl.

Hereinafter, the present invention will be described in more detail.

The preparation according to the invention is carried out by specific fractionation of lipases from Candida antarcica or muco mihei in obtaining optically active α-fluoromethyl propargyl alcohol derivatives from racemic α-fluoromethyl propargyl alcohol derivatives by rate dividing. It is characterized by using a catalyst.

The preparation method of the optically active α-fluoromethyl propargyl alcohol derivative according to the present invention is shown in Scheme 1 below.

Figure 112006061512757-pat00006

Wherein R 1 to R 3 are as defined above.

<Step (1)>

In step (1), the α-fluoromethyl propargyl alcohol derivative of formula (I) as racemate is subjected to room temperature with vinyl alkanoate of formula (2) in the presence of a lipase catalyst derived from Candida antarctica or muco mihei in organic solvent. The reaction is carried out at -60 ° C. to undergo stereosterically esterification to obtain an (-)-form optically active compound and an ester derivative of the formula (3).

Preferred examples of the α-fluoromethyl propargyl alcohol derivative of the formula (1) as the racemate used in the present invention include 1,1,1-trifluoro-4-phenyl-3-butyn-2-ol, 1-bro Parent-1,1-difluoro-4-phenyl-3-butyn-2-ol, 1-chloro-1,1-difluoro-4-phenyl-3-butyn-2-ol, 1,1, 1-trifluorohept-3-yn-2-ol, 1,1,1-trifluorooct-3-in-2-ol, 1,1,1-trifluorodec-3-yn-2 -Ols and 4-cyclohexyl-1,1,1-trifluorobut-3-yn-2-ols.

As the organic solvent used in the present invention, diethyl ether, CH 2 Cl 2 , hexane, toluene and mixtures thereof are suitable, and hexane and toluene may be particularly preferably used.

According to the present invention, the compound of Formula 1 as the racemate and the vinyl alkanoate of Formula 2 may be used in a molar ratio of 1: 0.5 to 5, and the lipase catalyst is based on 100 parts by weight of the compound of Formula 1 as the racemate. It can be used in amounts of 10 to 100 parts by weight.

<Step (2)>

In step (2), the (-)-form optically active compound obtained in step (1) and the ester derivative of Chemical Formula 3 are separated by column chromatography, and then the ester derivative of Chemical Formula 3 in an organic solvent such as methanol Is reacted with a strong acid such as sulfuric acid at room temperature to hydrolyze to obtain an optically active compound of (+)-form. Thereby, α-fluoromethyl propargyl alcohol derivatives of the formula (1) as optically active agents in (+)-and (-)-forms can be obtained.

Thus, according to the method of the present invention, the desired α-fluoromethyl propargyl alcohol derivative having optical activity can be easily obtained from the racemic raw material compound, and the obtained optically active compound has a high opticality of up to 99% ee or more. Has purity.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the scope of the present invention is not limited by the embodiment.

<Chromatographic analysis conditions according to the type of racemic compound>

● For racemic 1,1,1-trifluoro-4-phenyl-3-butyn-2-ol

Quantification was carried out using gas chromatography (Young-Lin, Model M600D) equipped with an optically active column, RT-βEDXcst (Restex, 30m × 0.25mm ID). Analytical conditions were heated at 60 ° C. for 5 minutes and increased to 130 ° C. at 5 ° C. per minute, then held at 130 ° C. for 30 minutes, and then increased to 160 ° C. at 5 ° C. per minute. Nitrogen gas was flowed as a support, and it detected using the flame ionization detector (FID) at 230 degreeC. The (+)-form was detected at 53.27 minutes and the (-)-form was detected at 53.67 minutes, and its ester derivatives were detected at 49.74 minutes without dividing the ( R ) -form and the ( S ) -form. After hydrolysis to obtain an alcohol to confirm the ee value.

Alternatively, quantification was performed using HPLC (Young Lin, Pump Model M930, Detector M720) equipped with an optically active column, OJ-H (Daicel, 0.46 cm × 25 cm). At this time, hexane and isopropanol were mixed at a ratio of 10: 1 and flowed at 0.6 ml per minute, and the UV absorbance was analyzed at 254 nm. The (-)-form was detected at 14.15 minutes and the (+)-form was detected at 14.49 minutes, and its ester derivatives were detected at 6.91 minutes without dividing the ( R ) -form and the ( S ) -form, thus yielding this ester derivative. After hydrolysis to obtain an alcohol to confirm the ee value.

● In the case of racemic 1-chloro-1,1-difluoro-4-phenyl-3-butyn-2-ol

Quantification was carried out using HPLC (Young Lin, Pump Model M930, Detector M720) equipped with an optically active column, OJ-H (Dyssel, 0.46 cm × 25 cm). At this time, hexane and isopropanol were mixed at a ratio of 10: 1 and flowed at 0.6 ml per minute, and the UV absorbance was analyzed at 254 nm. The (-)-form was detected at 16.92 minutes and the (+)-form was detected at 18.74 minutes, and its ester derivative was detected at 7.13 minutes without dividing the ( R ) -form and the ( S ) -form. After hydrolysis to obtain an alcohol to confirm the ee value.

● for racemic 1-bromo-1,1-difluoro-4-phenyl-3-butyn-2-ol

Quantification was carried out using HPLC (Young Lin, Pump Model M930, Detector M720) equipped with an optically active column, OJ-H (Dyssel, 0.46 cm × 25 cm). At this time, hexane and isopropanol were mixed at a ratio of 10: 1 and flowed at 0.6 ml per minute, and the UV absorbance was analyzed at 254 nm. The (-)-form was detected at 22.84 minutes and the (+)-form was detected at 24.39 minutes, and its ester derivative was detected at 7.67 minutes without dividing the ( R ) -form and the ( S ) -form. After hydrolysis to obtain an alcohol to confirm the ee value.

For racemic 4-cyclohexyl-1,1,1-trifluorobut-3-yn-2-ol

Quantification was performed using gas chromatography (Young Lin, Model M600D) equipped with an optically active column, RT-βEDXcst (Lextex, 30 m × .25 mm ID). Analytical conditions were heated at 60 ° C. for 5 minutes, increased to 100 ° C. at 5 ° C. per minute, maintained at 100 ° C. for 30 minutes, and again increased to 200 ° C. at 5 ° C. per minute. Nitrogen gas was flowed as a carrier and detected using FID at 230 degreeC. The (-)-form was detected at 55.50 minutes and the (+)-form was detected at 55.15 minutes, and its ester derivatives were detected at 55.48 minutes without dividing the ( R ) -form and the ( S ) -form, resulting in this ester derivative. After hydrolysis to obtain an alcohol to confirm the ee value.

Racemic 1,1,1-trifluorodec-3-yn-2-ol, racemic 1,1,1-trifluorooct-3-yn-2-ol and racemic 1,1,1 For trifluorohept-3-yn-2-ol

Quantification was carried out using gas chromatography (Younglin, Model M600D) equipped with an optically active column, RT-βEDXcst (Lextex, 30 m × 0.25 mm ID). Analytical conditions were heated at 60 ° C. for 5 minutes and increased to 100 ° C. at 5 ° C. per minute, then held at 100 ° C. for 10 minutes, and again increased to 200 ° C. at 5 ° C. per minute. Nitrogen gas was flowed as a carrier and detected using FID at 230 degreeC. For 1,1,1-trifluorodec-3-yn-2-ol, the (-)-form is detected at 34.90 minutes and the (+)-form at 34.76 minutes, and its ester derivative is ( R ) -Form and ( S ) -form were detected in 35.48 minutes without division; For 1,1,1-trifluorooct-3-yn-2-ol, the (-)-form is detected at 28.56 minutes, the (+)-form at 29.25 minutes, and its ester derivative is ( R ) -Form and ( S ) -form were detected in 28.16 minutes without division; For 1,1,1-trifluorohept-3-yn-2-ol, the (-)-form is detected at 23.73 minutes and the (+)-form at 25.11 minutes and its ester derivative is ( R ) The -form and ( S ) -forms were undivided and detected at 20.86 minutes. Therefore, these ester derivatives were hydrolyzed to obtain alcohol after confirming the ee value.

Example 1

Novozym 435 (made by Novozyme), a lipase catalyst derived from Candida antarctica, was used for the rate division of racemic 1,1,1-trifluoro-4-phenyl-3-butyn-2-ol. Stereoselective esterification reaction was carried out.

Specifically, in 7 mL vials, racemic 1,1,1-trifluoro-4-phenyl-3-butyn-2-ol (rac-1a) 10 mg (0.05 mmol), vinyl butanoate (2a) 11.4 mg (0.1 mmol), 5 mg of Novozyme 435 and 1 mL of hexane as a solvent were added, and then reacted for 12 hours while shaking at 200 rpm in an incubator at 30 ° C. After completion of the reaction, the reaction solution was filtered to remove the lipase catalyst and then column chromatography to give solids in the reaction solution, that is, the remaining (-)-form optically active 1,1,1-trifluoro-4-phenyl-3- Butin-2-ol ((-)-1a) and the stereoselectively produced ester derivative (3a) were separated (see Scheme 2 below). The results are shown in Table 1 below:

Figure 112006061512757-pat00007

Example 2 and Comparative Examples 1 to 6

Except for changing the type of lipase catalyst as shown in Table 1 below, the stereo-selective esterification reaction was carried out in the same manner as in Example 1 to separate the solid in the reaction solution. At this time, only in the case of Comparative Example 1, the reaction time was 9 hours. The results are shown in Table 1 below:

Figure 112006061512757-pat00008

From Table 1, Examples 1 and 2, in which the rate-division of the racemates were performed using lipase catalysts derived from Candida antarctica and muco mihei, respectively, compared to Comparative Examples 1 to 6 using other lipase catalysts. In addition to achieving a high conversion to the compound, it can be seen that it produces an optically active material with a much higher optical purity.

Reference Example 1 Test According to Different Solvent Types

In order to confirm the test results according to the different solvent types, racemic 1,1,1-trifluoro-4-phenyl-3-butyn-2-ol (rac-1a) 10 in a total of six 7 mL vials. After adding mg (0.05 mmol), vinyl butanoate (2a), 11.4 mg (0.1 mmol), Novozyme 435 5 mg, and 1 mL of an organic solvent, the mixture was reacted for 12 hours while shaking at 200 rpm in an incubator at 30 ° C. As the solvent, one of diethyl ether, CH 2 Cl 2 , tetrahydrofuran (THF), hexane, dioxane and toluene was used. After completion of the reaction, the reaction solution was filtered to remove the lipase catalyst and then column chromatography to give solids in the reaction solution, ie, the remaining ( S ) -form optically active 1,1,1-trifluoro-4-phenyl-3- Butin-2-ol (( S ) -1a) and the stereoselectively produced ester derivative (( R ) -3a) were separated (see Scheme 3 below). The results are shown in Table 2 below:

Figure 112006061512757-pat00009

Figure 112006061512757-pat00010

Table 2 shows that diethyl ether, CH 2 Cl 2 , hexane or toluene, in particular hexane or toluene, are suitable as the organic solvent used in the method of the present invention.

Reference Example 2: Test according to the difference in temperature

In order to confirm the test results according to the temperature difference, 100 mg of racemic 1,1,1-trifluoro-4-phenyl-3-butyn-2-ol (rac-1a) was added to four 7 mL vials. (0.50 mmol), 114 mg (1.0 mmol) of vinyl butanoate (2a), 25 mg of Novozyme 435 and 1 mL of hexane as a solvent were added, followed by reaction with shaking at 200 rpm in an incubator. At this time, the temperature of the incubator was 30, 40, 50 and 60 ℃ to vary the reaction time. During the reaction, a small amount of water was ejected to check the progress of the reaction. The reaction solution was filtered to remove the lipase catalyst, followed by column chromatography (hexane: ethyl acetate = 9: 1) to obtain a solid in the reaction solution, ie, the remaining ( S ) -form optically active 1,1,1-trifluoro- 4-phenyl-3-butyn-2-ol (( S ) -1a) and the stereoselectively produced ester derivative (( R ) -3a) were separated. Next, remove the ester derivative ((R) -3a) the (R) by using sulfuric acid in methanol is hydrolyzed for 4 hours at room temperature in the form of an optically active 1,1,1-trifluoro-4-phenyl 3-Butyn-2-ol (( R ) -1a) was obtained (see Scheme 4 below). The results are shown in Table 3 below:

Figure 112006061512757-pat00011

Figure 112006061512757-pat00012

Reference Example  3: vinyl Alkanoate  Test according to kind difference

In order to confirm the test result according to the difference of the vinyl alkanoate type, racemic 1,1,1-trifluoro-4-phenyl-3-butyn-2-ol (rac- 1a) 100 mg (0.50 mmol), vinyl alkanoate (2), 25 mg of Novozyme 435 and 1 mL of hexane as a solvent were added, followed by reaction with shaking at 200 rpm in an incubator at 60 ° C. At this time, as vinyl alkanoate (2), 86 mg (1.0 mmol) of vinyl acetate, 100 mg (1.0 mmol) of vinyl propanoate, and 114 mg (1.0 mmol) of vinyl butanoate were used, respectively. The reaction time was varied. The reaction solution was filtered to remove the lipase catalyst, followed by column chromatography (hexane: ethyl acetate = 9: 1) to obtain a solid in the reaction solution, ie, the remaining ( S ) -form optically active 1,1,1-trifluoro- 4-phenyl-3-butyn-2-ol (( S ) -1a) and the stereoselectively produced ester derivative (( R ) -3b) were separated. Next, remove the ester derivative ((R) -3b) the (R) by using sulfuric acid in methanol is hydrolyzed for 4 hours at room temperature in the form of an optically active 1,1,1-trifluoro-4-phenyl 3-Butyn-2-ol (( R ) -1a) was obtained (see Scheme 5 below). The results are shown in Table 4 below:

Figure 112006061512757-pat00013

Wherein R 3 is as defined above.

Figure 112006061512757-pat00014

Reference Example  4: vinyl Butanoate  Test by difference of addition amount

In order to confirm the test results according to the difference in the amount of vinyl butanoate added, racemic 1,1,1-trifluoro-4-phenyl-3-butyn-2-ol (rac- 1a) 100 mg (0.50 mmol), vinyl butanoate (2a), 25 mg of Novozyme 435 and 1 mL of hexane as a solvent were added and reacted for 9 hours while shaking at 200 rpm in an incubator at 60 ° C. At this time, vinyl butanoate was used in amounts of 57 mg (0.5 mmol), 114 mg (1.0 mmol) and 171 mg (1.5 mmol), respectively. The reaction solution was filtered to remove the lipase catalyst, followed by column chromatography (hexane: ethyl acetate = 9: 1) to obtain a solid in the reaction solution, ie, the remaining ( S ) -form optically active 1,1,1-trifluoro- 4-phenyl-3-butyn-2-ol (( S ) -1a) and the stereoselectively produced ester derivative (( R ) -3a) were separated. Next, remove the ester derivative ((R) -3a) the (R) by using sulfuric acid in methanol is hydrolyzed for 4 hours at room temperature in the form of an optically active 1,1,1-trifluoro-4-phenyl 3-butyn-2-ol (( R ) -1a) was obtained (see Scheme 4 above). The results are shown in Table 5 below:

Figure 112006061512757-pat00015

From the separation yield results shown in Table 5, it can be seen that the reaction rate is almost not different depending on the amount of vinyl butanoate added.

Reference Example 5: Test according to racemic material (substrate) difference

In order to confirm the test results according to the difference of racemic raw materials, racemic raw materials (rac-1), vinyl butanoate (2a) 342 mg (3.0 mmol), and Novozyme 435 75 mg or 150 mg, and 1 mL of hexane as a solvent were added and then reacted with shaking at 200 rpm in an incubator at 60 ° C. At this time, the racemic raw material as shown in Table 6 was used in an amount of 1.5 mmol, and the reaction time was different for each. During the reaction, a small amount of water was ejected to check the progress of the reaction. The reaction solution was filtered to remove the lipase catalyst, followed by column chromatography (hexane: ethyl acetate = 9: 1) to obtain a solid in the reaction solution, ie, the remaining (-)-form optically active 1,1,1-trifluoro- 4-phenyl-3-butyn-2-ol ((-)-1) and the stereoselectively produced ester derivative ((+)-3c) were separated. Subsequently, the isolated ester derivative ((+)-3c) was hydrolyzed at room temperature for 4 hours using sulfuric acid in methanol solvent to obtain (+)-form optically active 1,1,1-trifluoro-4-phenyl 3-butyn-2-ol ((+)-1a) was obtained (see Scheme 6 below). The results are shown in Table 6:

Figure 112006061512757-pat00016

Wherein R 1 and R 2 are as defined above.

Figure 112006061512757-pat00017

As described above, according to the method of the present invention, the desired α-fluoromethyl propargyl alcohol derivative having optical activity can be easily obtained from the racemic raw material compound, and the obtained optically active compound is at least 99% ee or more. It has high optical purity.

Claims (6)

  1. (1) In the organic solvent, in the presence of a lipase catalyst derived from Candida antarctica or Mucor miehei , a compound of formula 1 as racemate is reacted with vinyl alkanoate of formula 2 Performing a stereoselective esterification reaction to obtain a compound of formula (I) as an (-)-form optical activator and an ester derivative of formula (3); And
    (2) After separating the compound of formula (1) and the ester derivative of formula (3) as the (-)-form optically active agent, the ester derivative of formula (3) is hydrolyzed to give the Obtaining Compound
    A method for preparing a fluorine-containing α-propargyl alcohol compound of formula (I) as an optically active substance comprising:
    Formula 1
    Figure 112007078038052-pat00018
    Formula 2
    Figure 112007078038052-pat00019
    Formula 3
    Figure 112007078038052-pat00020
    Where
    R 1 is CF 3 , CF 2 Br or CF 2 Cl;
    R 2 is phenyl, cyclohexyl, n -hexyl, n -butyl or n -propyl;
    R 3 is methyl, ethyl or n -propyl.
  2. The method of claim 1,
    Compound of formula (1) is 1,1,1-trifluoro-4-phenyl-3-butyn-2-ol, 1-bromo-1,1-difluoro-4-phenyl-3-butyne-2 -Ol, 1-chloro-1,1-difluoro-4-phenyl-3-butyn-2-ol, 1,1,1-trifluorohept-3-yn-2-ol, 1,1, 1-trifluorooct-3-yn-2-ol, 1,1,1-trifluorodec-3-yn-2-ol and 4-cyclohexyl-1,1,1-trifluorobuty- Characterized in that it is selected from the group consisting of 3-in-2-ol.
  3. The method of claim 1,
    The organic solvent of step (1) is selected from the group consisting of diethyl ether, CH 2 Cl 2 , hexane, toluene and mixtures thereof.
  4. The method of claim 1,
    In step (1), the compound of formula (1) and vinyl alkanoate of formula (2) as racemates are used in a molar ratio of 1: 0.5 to 5.
  5. The method of claim 1,
    In step (1), the lipase catalyst is used in an amount of 10 to 100 parts by weight based on 100 parts by weight of the compound of formula 1 as the racemate.
  6. The method of claim 1,
    Method characterized in that the esterification reaction of step (1) is carried out at room temperature to 60 ℃.
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JP2007009710A (en) * 2005-06-28 2007-01-18 Mazda Motor Corp Deterioration diagnostic device for linear air-fuel ratio sensor
JP2007091013A (en) * 2005-09-28 2007-04-12 Denso Corp Display device and program

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000228994A (en) * 1999-02-12 2000-08-22 Daiso Co Ltd Production of optically active compound
KR20000060898A (en) * 1999-03-20 2000-10-16 남창우 Method of preparing trans-(1S,2S)-2-bromo-1-indanyl acetate by enzymatic method
KR20010027210A (en) * 1999-09-11 2001-04-06 박호군 Lipase Catalysed Resolutions of Verapamil Intermediate and Process for Preparing (R)- and (S)-Verapamil
JP2007009710A (en) * 2005-06-28 2007-01-18 Mazda Motor Corp Deterioration diagnostic device for linear air-fuel ratio sensor
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