KR20030042373A - A method for preparing of chiral 2,2-dimethylcyclopropanecarboxyl derivatives - Google Patents

Abstract

PURPOSE: A process for preparing chiral 2,2-dimethyl cyclopropane carboxyl derivatives is provided, high purity of chiral 2,2-dimethyl cyclopropane carboxyl derivatives can be easily mass-produced by using a chiral hetero ring compound of formula 3 as a beam splitter. CONSTITUTION: The process for preparing chiral 2,2-dimethyl cyclopropane carboxyl derivatives of the formula(1) comprises the steps of: reacting (RS)-2,2-dimethyl cyclopropane carbonic acid(2) with a beam splitter to prepare a partial stereoisomer; and separating the partial stereoisomer by using crystallization or chromatography to prepare (R)-2,2-dimethyl cyclopropane carboxyl derivatives(1a) and (S)-2,2-dimethyl cyclopropane carboxyl derivatives(1b), wherein the beam splitter is the chiral hetero ring compound of formula(3); X is O or S; Y is O, S or N-R5; R5 is C1-C6 alkyl, or C1-C6 alkoxy or halogen substituted or unsubstituted aryl; R1, R2, R3 and R4 are independently H, C1-C6 alkyl, C1-C6 alkoxy or halogen substituted or unsubstituted aryl, or R6-O-CH2; and R6 is C1-C6 alkyl, or C1-C6 alkoxy or halogen substituted or unsubstituted aryl.

Description

A method for preparing a derivative of chiral 2,2-dimethylcyclopropanecarboxyl {A METHOD FOR PREPARING OF CHIRAL 2,2-DIMETHYLCYCLOPROPANECARBOXYL DERIVATIVES}

The present invention relates to a method for producing a derivative of chiral 2,2-dimethylcyclopropanecarboxyl represented by the following formula (1), and more specifically to (RS) -2,2-dimethylcyclopropanecarboxylic acid (2) React with the agent to obtain the diastereomer, and the obtained diastereomer is separated from the diastereomer using crystallization or chromatography to obtain optically pure (R) -2,2-dimethylcyclopropanecarboxyl derivatives (1a) and ( S) -2,2-dimethylcyclopropanecarboxyl derivative (1b), wherein the light splitting agent is a chiral heterocyclic compound having the formula (3), characterized in that chiral 2,2-dimethylcyclopropanecarboxyl It relates to a process for the preparation of derivatives.

Formula 1

Wherein X is O; or S,

Y is O; S; NR ⁵ ,

Wherein R ⁵ is a C ₁ to C ₆ alkyl group; C ₁ -C ₆ alkyl group; An aryl group unsubstituted or substituted with a C ₁ to C ₆ alkoxy group or halogen;

R ¹ , R ² , R ³ , R ⁴ are, independently from each other, H; C ₁ -C ₆ alkyl group; An aryl group unsubstituted or substituted with a C ₁ to C ₆ alkoxy group or halogen; Or a R ⁶ -O-CH ₂ -group, wherein R ⁶ is a C ₁ to C ₆ alkyl group; C ₁ -C ₆ alkyl group; A C ₁ to C ₆ alkoxy group or an aryl group unsubstituted or substituted with halogen; R <^1> or R <^3> couple | bonds with each other and contains the 4-8 cyclic carbocyclic compound or the heterocyclic compound containing O, N, and S. Except that R ¹ , R ² , R ³ , and R ⁴ are all hydrogen.)

Optically active 2,2-dimethylcyclopropanecarboxylic acid is used in the manufacture of pyresteroidal insecticides that are extremely toxic to mammals (UK Patent No. 1,260,847) and sila that prevents carbapenem antibiotics from being degraded in the kidneys. It is used as a key intermediate of statins (European Patent No. 48,301, European Patent No. 48,025) and is applied to pesticides and medicines.

Research is actively conducted to prepare 2,2-dimethylcyclopropanecarboxylic acid having high yield and high purity optical activity. In preparing the above-mentioned 2,2-dimethylcyclopropanecarboxylic acid, a derivative of chiral 2,2-dimethylcyclopropanecarboxyl, which is primarily an intermediate of 2,2-dimethylcyclopropanecarboxylic acid synthesis, is easily synthesized and has high purity. It should have optical activity of.

A chiral amine, which is typically used as a light splitting agent, reacts with an acid base with (RS) -2,2-dimethylcyclopropanecarboxylic acid to form a salt, and crystallizes the formed salt to crystallize the diastereomer to give a chiral 2,2-dimethylcyclopropane. It is separated into a derivative of carboxyl and hydrolyzed to prepare 2,2-dimethylcyclopropanecarboxylic acid having optical activity. Specifically used chiral amines include (S) -1-phenylethylamine (UK Patent No. 1,260,847), quinine (US Pat. No. 4,539,208), and 2-diphenylethylamine (US Pat. No. 4,542,235). . However, the crystallization is performed several times to obtain high optical purity, and the yield is low. 2-diphenylethylamine can be produced with high optical purity and good yield, but the chiral 2-diphenylethylamine, a light splitting agent, is a natural product. It is impossible to manufacture from and has a very expensive disadvantage.

In another method, chiral alcohol is used as a light splitting agent, and the chiral alcohol reacts with (RS) -2,2-dimethylcyclopropanecarboxylic acid to produce a chiral ester and crystallizes it to produce a diastereomer, chiral 2,2-. It is separated into derivatives of dimethylcyclopropanecarboxyl and hydrolyzed to produce 2,2-dimethylcyclopropanecarboxylic acid having optical activity. The chiral alcohols reported use for L-menthol (US Pat. No. 4,487,956), methyl (S) -mandelate (US Pat. No. 5,243,070), and LN-methylephedrine (Japanese Patent No. 60-56,942). It is. However, in order to obtain high optical purity, the crystallization is performed several times, and the yield is low or the chiral alcohol used is expensive.

Therefore, in order to minimize the above problems, a new light splitting agent that is easy to synthesize itself is needed to obtain a chiral 2,2-dimethylcyclopropanecarboxyl derivative having high yield and high purity optical purity. The present invention introduces a chiral heterocyclic compound of formula (3) according to the above requirements, the chiral heterocyclic compound can be easily prepared through a variety of methods and used in various asymmetric conversion reaction. (Ager, DJ, Prakash, I., Schaad D. Chem. Rev. 1996, 96 , 846-859; Ager, DJ, Prakash, I., Aldrichimica Acta, 1997, 30 , 3; Nicolas, E., Russel, KC, Hruby, VJ J. Org. Chem. 1993, 58 , 766; Pridgen, LN, Prol, J. J. Org. Chem. 1989, 54 , 3231; Hsiao, CL, Liu, L., Miller, J. , J. Org.Chem. , 1987, 52 , 2201; Cardillo, G., Damico, A., Orena, M., Sandri, S., J. Org.Chem . , 1988, 53 , 2354; Orena, M , Porzi, Z., Samdri, S., Tetrahedron Lett ., 1992, 33 , 3797; Coppola, GM, Schuster, HF, A symmetric Synthesis: Construction of Chiral Molecules Using Aminoacids , Wiley, New York, 1987; Seyden- Penne, J., Chiral Auxiliaries and Ligands in Asymmetric Synthesis , Wiley Interscience, 1995). However, the examples used to prepare high purity optically active chiral 2,2-dimethylcyclopropanecarboxyl derivatives have not been reported previously.

Accordingly, the present inventors have endeavored to prepare a 2,2-dimethylcyclopropanecarboxyl derivative having high purity optical activity. As a result, the present inventors introduced a chiral heterocyclic compound of the formula (3) as a light splitting agent (RS) -2,2-dimethyl Reaction with cyclopropanecarboxylic acid (2) to give diastereomers, the diastereomers obtained are separated by crystallization or chromatography to optically pure (R) -2,2-dimethylcyclopropanecar The present invention was completed by confirming that the derivatives (1a) and (S) -2,2-dimethylcyclopropanecarboxyl derivatives (1b) were produced and confirmed that the derivatives had high yield and high purity optical activity.

It is an object of the present invention to provide a process for the preparation of (R) or (S) -2,2-dimethylcyclopropanecarboxyl derivative represented by formula (1).

Another object of the present invention is to provide a (R) or (S) -2,2-dimethylcyclopropanecarboxyl derivative represented by the formula (1).

The present invention provides a process for the preparation of (R) or (S) -2,2-dimethylcyclopropanecarboxyl derivative represented by the following general formula (1). Specifically, (RS) -2,2-dimethylcyclopropanecarboxylic acid (2) is reacted with a light splitting agent to obtain diastereomers, and the diastereomers obtained are separated by crystallization or chromatography to separate the diastereomers. In the method for producing optically pure (R) -2,2-dimethylcyclopropanecarboxyl derivative (1a) and (S) -2,2-dimethylcyclopropanecarboxyl derivative (1b), Provided is a method for preparing a derivative of chiral 2,2-dimethylcyclopropanecarboxyl, which is a chiral heterocyclic compound having formula (3).

Formula 1

Wherein X is O; or S,

Y is O; S; NR ⁵ ,

Wherein R ⁵ is a C ₁ to C ₆ alkyl group; C ₁ -C ₆ alkyl group; An aryl group unsubstituted or substituted with a C ₁ to C ₆ alkoxy group or halogen;

R ¹ , R ² , R ³ , R ⁴ are, independently from each other, H; C ₁ -C ₆ alkyl group; An aryl group unsubstituted or substituted with a C ₁ to C ₆ alkoxy group or halogen; Or a R ⁶ -O-CH ₂ -group, wherein R ⁶ is a C ₁ to C ₆ alkyl group; C ₁ -C ₆ alkyl group; A C ₁ to C ₆ alkoxy group or an aryl group unsubstituted or substituted with halogen; R <^1> or R <^3> couple | bonds with each other and contains the 4-8 cyclic carbocyclic compound or the heterocyclic compound containing O, N, and S. Except that R ¹ , R ² , R ³ , and R ⁴ are all hydrogen.)

More specifically, the method

1) reacting (RS) -2,2-dimethylcyclopropanecarboxylic acid (2) with a light splitting agent of a chiral heterocyclic compound of Formula 3 to obtain diastereomers,

2) The diastereomers thus obtained were separated by crystallization or chromatographic methods to separate the diastereomers and thereby optically pure (R) -2,2-dimethylcyclopropanecarboxyl derivatives (1a) and (S) -2,2- Preparing a dimethylcyclopropanecarboxyl derivative (1b).

Reaction of step 1, namely, (RS) -2,2-dimethylcyclopropanecarboxylic acid (2) with a photo splitting agent of a chiral heterocyclic compound of Formula 3 to obtain diastereomers is well known in the art. Can be achieved. For example, various activators can be used to increase the reactivity of (RS) -2,2-dimethylcyclopropanecarboxylic acid (2), phosgene, phosphorus tribromide, phosphorus trichloride. ), Phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride or thionyl chloride to form acyl halides, ethyl chloroformate, React with methyl chloroformate, isobutyl chloroformate or methanesulphonyl chloride to form anhydride, or N, N'-dicyclohexylcarbodiimide (N Or N, -dicyclohexylcarbodiimide (DCC) or a known coupling agent to form carbodiimides or N, N'-carbonyldiimidazole (N, N'- carbonyldiimidazole), 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline (2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline; EEDQ) or triphenylphosphine / carbon chloride and activated by reacting with carbon tetrachloride).

In the exemplary embodiment of the present invention, as the halogen compound, thionyl chloride (SOCl ₂ ) or oxaryl chloride (ClCOCOCl) is used to convert (RS) -2,2-dimethylcyclopropanecarboxylic acid (2) to (RS) -2, A method of converting to 2-dimethylcyclopropanecarbonyl chloride is used, wherein the amine used in the amidation reaction is silver tri-C _1-4 alkyl amine, specifically triethyl amine, tripropyl amine, triiso It is selected from the group consisting of propylethyl amine and tributyl amine, More preferably, triethyl amine is used.

Part of (RS) -2,2-dimethylcyclopropanecarboxyl derivative by reacting the activated (RS) -2,2-dimethylcyclopropanecarbonyl chloride obtained in the step with a chiral heterocyclic compound of formula Obtain stereoisomers. The chiral heterocyclic compound of Formula 3, which is a light splitting agent, is selected from the compounds represented by the following Formulas 3a and 3b.

Wherein X, Y, R ¹ , R ² , R ³ , and R ⁴ are as defined above.

Specifically, X and Y are 1,3-oxazolidin-2-one (1,3-oxazolidin-2-one) derivatives in which X = O and Y = O, 1 in which X = O and Y = S, 3-oxazolidine-2-thione (1,3-oxazolidine-2-thione) derivative, 1,3-thiazolidinethione derivative with X = S, Y = S, and X = A 1,3-imidazolidin-2-one derivative with O, Y = NR ⁵ is used, preferably 1,3-oxazolidin-2-one ( 1,3-oxazolidin-2-one) derivative is used.

More specifically, when the chiral heterocyclic compound of Formula 3a is used,

Any one of R ¹ or R ² is a C ₁ to C ₆ alkyl group; An aryl group unsubstituted or substituted with a C ₁ to C ₆ alkyl group, a C ₁ to C ₆ alkoxy group, or halogen; Or a R ⁶ -O-CH ₂ -group, wherein R ⁶ is a C ₁ to C ₆ alkyl group; C ₁ -C ₆ alkyl group; A C ₁ to C ₆ alkoxy group or an aryl group unsubstituted or substituted with halogen, and the other one contains hydrogen.

Preferably, X is O and Y is O and any one of R ¹ or R ² is an alkyl group including a methyl group, isopropyl group, t -butyl group, and cyclohexyl group; Benzyl groups including benzyl groups, 4-methoxybenzyl groups, and 4-chlorobenzyl groups; An aryl group comprising a phenyl group and a 4-methoxyphenyl group, the other being hydrogen, wherein R ³ and R ⁴ are hydrogen

More preferably, X is O and Y is O and either R ¹ or R ² is a benzyl group or a phenyl group, the other is hydrogen, and R ³ and R ⁴ are hydrogen

In addition, when the chiral heterocyclic compound of Formula 3b is used,

R ¹ or R ² and R ³ or R ⁴ are independently of each other a C ₁ -C ₆ alkyl group; C ₁ -C ₆ alkyl group; An aryl group unsubstituted or substituted with a C ₁ to C ₆ alkoxy group or halogen; Or a R ⁶ -O-CH ₂ -group, wherein R ⁶ is a C ₁ to C ₆ alkyl group; C ₁ -C ₆ alkyl group; An aryl group unsubstituted or substituted with a C ₁ to C ₆ alkoxy group or halogen; In this case, R ¹ or R ² and R ³ or R ⁴ are bonded to each other to include 4 to 8 carbon ring compounds or heterocyclic compounds containing O, N, and S.

Preferably X is O, Y is O, R ¹ and R ³ are independently of each other a methyl group and a phenyl group and R ² and R ⁴ are hydrogen.

The resulting diastereomers are optically pure (R) -2,2-dimethylcyclopropanecarboxyl derivatives (1a) and (S) -2,2-dimethylcyclopropanecarboxyl derivatives (1b) by crystallization or chromatography. Can be separated. Chromatography uses two diastereoisomers with different affinity to the column's stationary phase, and the conditions of the column (developing solvent, stationary phase, rate to column) are appropriately selected by those of ordinary skill in the art. Could be. According to an embodiment of the present invention, the diastereomers obtained were more easily separated than when using other light splitting agents.

Recrystallization is where the two diastereomers take advantage of the difference in solubility depending on the solvent. The choice of the solvent is not particularly limited, but according to the embodiment of the present invention, alcohols such as methanol, ethanol, isopropanol; A single solvent or two or more mixed solvents selected from the group consisting of hydrocarbons such as hexane, heptane, cyclopropane, and the like provided a desirable result. More preferably, methanol, isopropanol, hexane and dichloromethane or a mixed solvent of hexane and ethyl acetate are used. Crystallization using the solvent, either (R) or (S) -2,2-dimethylcyclopropanecarboxyl derivative was selectively isolated from (RS) -2,2-dimethylcyclopropanecarboxyl derivative, crystallization method Only one repeated run resulted in more selective and highly optical (R) or (S) -2,2-dimethylcyclopropanecarboxyl derivatives.

As shown in Scheme 1 below, the following examples are intended to illustrate the present invention in more detail. First, the carboxyl group of (RS) -2,2-dimethylcyclopropanecarboxylic acid (2) is activated using an activator. Thereafter, the chiral heterocyclic compound (3), which is a light splitting agent, is reacted in the presence of a base to obtain a diastereomer, and the obtained diastereomer is purified using crystallization or chromatography to obtain pure (R) -2,2-dimethylcyclopropanecar. The steps of preparing the compound derivative (1a) and (S) -2,2-dimethylcyclopropanecarboxyl derivative (1b) were performed.

(Wherein, X, Y, R ¹ , R ² , R ³ , and R ⁴ , as described above.)

In addition, the pure (R) -2,2-dimethylcyclopropanecarboxyl derivatives (1a) and (S) -2,2-dimethylcyclopropanecarboxyl derivatives (1b) obtained in the above production process were hydrolyzed to (R). -2,2-dimethylcyclopropanecarboxylic acid and (S) -2,2-dimethylcyclopropanecarboxylic acid can be obtained, if necessary, (R) -2,2-dimethylcyclopropanecarboxylic derivative (1a) and The (S) -2,2-dimethylcyclopropanecarboxyl derivative (1b) can act directly as an intermediate to synthesize useful products by reacting directly with other compounds.

The present invention provides (R) or (S) -2,2-dimethylcyclopropanecarboxyl derivative represented by formula (1).

Formula 1

(Wherein, X, Y, R ¹ , R ² , R ³ , and R ⁴ are as described above.)

Specific examples of the (R) or (S) 2,2-dimethylcyclopropanecarboxyl derivative of the formula (1) is X = O and Y = O, any one of R ¹ or R ² is a methyl group, isopropyl group, t An alkyl group including a butyl group and a cyclohexyl group; Benzyl groups including benzyl groups, 4-methoxybenzyl groups, and 4-chlorobenzyl groups; An aryl group comprising a phenyl group and a 4-methoxyphenyl group and the other is hydrogen, wherein R ³ and R ⁴ are hydrogen

More preferably, it is a compound of Formula 4a, Formula 4b, and Formula 4c.

Hereinafter, the present invention will be described in more detail with reference to Examples.

However, the following examples are merely to exemplify the contents of the present invention and are not limited to the examples of the present invention.

Step 1: carboxyl activation of (RS) -2,2-dimethylcyclopropanecarboxylic acid

Example 1 Preparation of (RS) -2,2-dimethylcyclopropanecarboxylic acid chloride

Two drops of 12.0 g of (RS) -2,2-dimethylcyclopropanecarboxylic acid (105 mmol), 12.0 g of hexane, and dimethylacetamide were added to a 100 mL reaction flask, and the temperature was raised to 70 ° C. 23.8 g of thionylchloride (200 mmol) and 50 g of hexane were slowly added dropwise with stirring. The mixture was further stirred at 70 ° C. for 4 hours, after which only hexane and excess thionyl chloride were removed under reduced pressure, and the remaining solution was distilled off to obtain pure (RS) -2,2-dimethylcyclopropanecarboxylic acid chloride (12.6 g). , 91%).

¹ H NMR (CDCl ₃ ): δ 1.18 (m, 1H), 1.28 (s, 6H), 1.37 (m, 1H), 2.15 (dd, 1H)

Step 2: preparing a (RS) -2,2-dimethylcyclopropanecarboxyl derivative

Example 2 Preparation of 3-((RS) -2 ′, 2′-dimethylcyclopropanecarboxyl)-(S) -4-benzyl-1,3-oxazolidin-2-one

1.06 g of (S) -4-benzyl-1,3-oxazolidin-2-one (5.99 mmol) in 5 ml of tetrahydrofuran while maintaining a temperature of 0 ° C. and 1.03 g prepared in Example 1 above. (RS) -2,2-dimethylcyclopropanecarboxylic acid chloride (7.77 mmol), 0.28 g of lithium chloride (6.60 mmol), and triethylamine (0.90 g, 8.91 mmol) were added thereto, and the temperature was raised to room temperature. It stirred at the temperature for 6 hours. After the solvent was removed under reduced pressure, 10 mL of ethyl acetate was dissolved in the filtrate, washed with 1N NaOH aqueous solution, dried over magnesium sulfate, and filtered. After the filtration, the filtrate was concentrated under reduced pressure and subjected to column chromatography with a mixed solvent of hexane and ethyl acetate to 3-((RS) -2 ', 2'-dimethylcyclopropanecarboxyl)-(S) -4 -Benzyl-1,3-oxazolidin-2-one was obtained (1.54 g, 94%)

¹ H NMR (CDCl ₃ ): δ 0.96 (m, 1H), 1.16 (s, 1.5H), 1.20 (s, 1.5H), 1.27 (s, 1.5H), 1.30 (s, 1.5H), 1.35 (m, 1H), 2.80 (m, 2H), 3.30 (m, 1H), 4.14 (m, 2H), 4.65 (m, 1H), 7.29 (m 5H)

Example 3 Preparation of 3-((RS) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one

Prepared in Example 1 above with 1.00 g of (R) -4-benzyl-1,3-oxazolidin-2-one (5.65 mmol) in 5 ml of tetrahydrofuran while maintaining a temperature of 0 ° C. ) -2,2-dimethylcyclopropanecarboxylic acid chloride (0.97 g, 7.32 mmol), 0.26 g of lithium chloride (6.10 mmol), and 0.85 g of triethylamine (8.41 mmol) were added thereto, and the temperature was raised to room temperature. Stir at temperature for 5 hours. After the solvent was removed under reduced pressure, 10 mL of ethyl acetate was dissolved in the filtrate, washed with 1N NaOH aqueous solution, dried over magnesium sulfate, and filtered. After filtration, the filtrate was concentrated under reduced pressure and subjected to column chromatography with a mixed solvent of hexane and ethyl acetate to give 3-((RS) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4 -Benzyl-1,3-oxazolidin-2-one was obtained (1.43 g, 93%)

¹ H NMR (CDCl ₃ ): δ 0.96 (m, 1H), 1.16 (s, 1.5H), 1.20 (s, 1.5H), 1.27 (s, 1.5H), 1.30 (s, 1.5H), 1.35 (m, 1H), 2.80 (m, 2H), 3.30 (m, 1H), 4.14 (m, 2H), 4.65 (m, 1H), 7.29 (m 5H)

Example 4 Preparation of 3-((RS) -2 ', 2'-dimethylcyclopropanecarboxyl)-(S) -4-phenyl-1,3-oxazolidin-2-one

1.00 g of (S) -4-phenyl-1,3-oxazolidin-2-one (6.13 mmol) in 5 ml of tetrahydrofuran while maintaining a temperature of 0 ° C. (RS ) -2,2-dimethylcyclopropanecarboxylic acid chloride (1.05 g, 7.92 mmol), 0.28 g of lithium chloride (6.60 mmol), 0.93 g of triethylamine (9.21 mmol) were added thereto, and the temperature was raised to room temperature. It was stirred for 7 hours. After the solvent was removed under reduced pressure, 10 mL of ethyl acetate was dissolved in the filtrate, washed with 1N NaOH aqueous solution, dried over magnesium sulfate, and filtered. After the filtration, the filtrate was concentrated under reduced pressure and subjected to column chromatography with a mixed solvent of hexane and ethyl acetate to 3-((RS) -2 ', 2'-dimethylcyclopropanecarboxyl)-(S) -4 -Phenyl-1,3-oxazolidin-2-one was obtained (1.45 g, 91%).

¹ H NMR (CDCl ₃ ): δ 0.90 (m, 1H), 0.90 (s, 1.5H), 1.15 (s, 1.5H), 1.24 (m, 1H), 1.29 (s, 1.5H), 1.30 ( s, 1.5H), 2.82 (m, 1H), 4.27 (m, 1H), 4.70 (m, 1H), 5.48 (m, 1H), 7.35 (m, 5H)

Example 5 3-((RS) -2 ', 2'-dimethylcyclopropanecarboxyl)-(4S, 5R) -4-methyl-5-phenyl-1,3-oxazolidin-2-one Manufacture

Example 1 above with 1.06 g (4S, 5R) -4-methyl-5-phenyl-1,3-oxazolidin-2-one (5.99 mmol) in 5 ml tetrahydrofuran while maintaining a temperature of 0 ° C (RS) -2,2-dimethylcyclopropanecarboxylic acid chloride (1.03 g, 7.77 mmol) prepared in 1, 0.28 g of lithium chloride (6.60 mmol) and 0.90 g of triethylamine (8.91 mmol) were added thereto. After raising the temperature, the mixture was stirred at the same temperature for 5 hours. After the solvent was removed under reduced pressure, 10 mL of ethyl acetate was dissolved in the filtrate, washed with 1N NaOH aqueous solution, dried over magnesium sulfate, and filtered. After filtration, the filtrate was concentrated under reduced pressure and subjected to column chromatography with a mixed solvent of hexane and ethyl acetate to give 3-((RS) -2 ', 2'-dimethylcyclopropanecarboxyl)-(4S, 5R). Obtained 4-methyl-5-phenyl-1,3-oxazolidin-2-one (1.56 g, 95%)

¹ H NMR (CDCl ₃ ): δ 0.99 (dd, 3H), 0.93 (m, 1H), 1.12 (s, 1.5H), 1.16 (s, 1.5H), 1.27 (s, 1.5H), 1.30 ( m, 1H), 1.32 (s, 1.5H), 2.75 (dd, 0.5H), 2.94 (dd, 0.5H), 4.80 (m, 1H), 5.66 (d, 1H), 7.37 (m, 5H)

Step 3: light splitting of (RS) -2,2-dimethylcyclopropanecarboxyl derivative

<Example 6> Light powder by the crystallization method of 3-((RS) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one To do 1

3-((RS) -2 ′, 2′-Dimethylylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one prepared in Example 3 (2.00 g, 7.32 mmol) was added to 35.0 mL of hexane and 4.00 mL of ethyl acetate to reflux to dissolve, and then cooled slowly to room temperature to crystallize. The precipitated crystals were filtered (0.62 g, 31.0%). The obtained crystals were analyzed by HPLC and found to be 3-((S) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-2-oxazolidinone and 3-((R)- The ratio of 2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one was 98.5: 1.5 (column: Kromasil, developing solvent: ethyl acetate / Hexane = 1:10)

¹ H NMR (CDCl ₃ ): δ 0.92 (m, 1H), 1.20 (s, 3H), 1.29 (s, 3H), 1.35 (m, 1H), 2.71 (dd, 1H), 2.79 (dd, 1H ), 3.28 (dd, 1H), 4.15 (m, 2H), 4.65 (m, 1H), 7.31 (m, 5H)

<Example 7> Light fraction by the crystallization method of 3-((RS) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one Do 2

3-((RS) -2 ′, 2′-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one prepared in Example 3 (4.00 g, 14.7 mmol) was added to 12.0 mL of isopropanol and refluxed to dissolve, followed by cooling slowly to room temperature to crystallize. The precipitated crystals were filtered (1.60 g, 40.0%). The obtained crystals were analyzed by HPLC. 3-((S) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one and 3 The ratio of-((R) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one was 97.5: 2.5 (column: Kromasil, Developing solvent: ethyl acetate / hexane = 1: 10)

¹ H NMR (CDCl ₃ ): δ 0.92 (m, 1H), 1.20 (s, 3H), 1.29 (s, 3H), 1.35 (m, 1H), 2.71 (dd, 1H), 2.79 (dd, 1H ), 3.28 (dd, 1H), 4.15 (m, 2H), 4.65 (m, 1H), 7.31 (m, 5H)

Example 8 Light fraction by the crystallization method of 3-((RS) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one 3 to do

3-((S) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one and 3-((R) -2', 2.00 g of a mixture of 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one in a ratio of 91.0: 9.0 was placed in 10.0 ml of isopropanol and refluxed. The solution was dissolved and then slowly cooled to room temperature to crystallize. The precipitated crystals were filtered (1.40 g, 70.0%). The obtained crystals were analyzed by HPLC to find 3-((S) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one and The ratio of 3-((R) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one is 99.9: 0.1, once in the crystallization step Repeatedly improved selective light splitting results (column: Kromasil, developing solvent: ethyl acetate / hexane = 1: 10)

¹ H NMR (CDCl ₃ ): δ 0.92 (m, 1H), 1.20 (s, 3H), 1.29 (s, 3H), 1.35 (m, 1H), 2.71 (dd, 1H), 2.79 (dd, 1H ), 3.28 (dd, 1H), 4.15 (m, 2H), 4.65 (m, 1H), 7.31 (m, 5H)

Example 9 Light fraction by crystallization of 3-((RS) -2 ', 2'-dimethylcyclopropanecarboxyl)-(S) -4-benzyl-1,3-oxazolidin-2-one which

2.00 g of 3-((RS) -2 ', 2'-dimethylcyclopropanecarboxyl)-(S) -4-benzyl-1,3-oxazolidin-2-one prepared in Example 2 was prepared. It was added to 10.0 ml of methanol to reflux to dissolve, and then cooled slowly to room temperature to crystallize. The precipitated crystals were filtered out (0.74 g, 37.0%), and the obtained crystals were analyzed by HPLC. The result was 3-((S) -2 ', 2'-dimethylcyclopropanecarboxyl)-(S) -4- Benzyl-1,3-oxazolidin-2-one and 3-((R) -2 ', 2'-dimethylcyclopropanecarboxyl)-(S) -4-benzyl-1,3-oxazolidine- The ratio of 2-one was 5.0: 95.0 (column: Kromasil, developing solvent: ethyl acetate / hexane = 1: 10)

¹ H NMR (CDCl ₃ ), δ 0.92 (m, 1H), 1.20 (s, 3H), 1.29 (s, 3H), 1.35 (m, 1H), 2.71 (dd, 1H), 2.79 (dd, 1H ), 3.28 (dd, 1H), 4.15 (m, 2H), 4.65 (m, 1H), 7.31 (m, 5H)

Example 10 Light fraction by the crystallization method of 3-((RS) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-phenyl-1,3-oxazolidin-2-one To do 1

2.0 g of 3-((RS) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-phenyl-1,3-oxazolidin-2-one prepared in Example 4 was prepared. The mixture was dissolved in 20.0 mL of hexane and 6.00 mL of ethyl acetate, refluxed to dissolve, and then cooled slowly to room temperature to crystallize. The precipitated crystals were obtained by filtration (0.50 g, 25%). The obtained crystals were analyzed by HPLC, and the result of 3-((S) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4- Phenyl-1,3-oxazolidin-2-one and 3-((R) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-phenyl-1,3-oxazolidine- The ratio of 2-one was 6.0: 94.0 (column: Kromasil, developing solvent: ethyl acetate / hexane = 1: 4)

¹ H NMR (CDCl ₃ ): δ 0.90 (m, 1H), 1.15 (s, 3H), 1.25 (m, 1H), 1.29 (s, 3H), 2.82 (dd, 1H), 4.27 (m, 1H ), 4.70 (m, 1H), 5.48 (m, 1H), 7.35 (m, 5H)

Example 11 Light Powder by Crystallization Method of 3-((RS) -2 ', 2'-Dimethylcyclopropanecarboxyl)-(R) -4-phenyl-1,3-oxazolidin-2-one Do 2

3-((S) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-phenyl-1,3-oxazolidin-2-one and 3-((R) -2', 2.00 g of a mixture of 2'-dimethylcyclopropanecarboxyl)-(R) -4-phenyl-1,3-oxazolidin-2-one in an amount of 82.0: 18.0 was added to 30.0 mL of isopropanol and refluxed. After dissolving, the mixture was slowly cooled to room temperature and crystallized. The precipitated crystals were obtained by filtration (0.64 g, 32%). The obtained crystals were analyzed by HPLC, and the result of 3-((S) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4- Phenyl-1,3-oxazolidin-2-one and 3-((R) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-phenyl-1,3-oxazolidine- The ratio of 2-one was 99.0: 1.0, which resulted in a more selective light splitting result in one repetition of the crystallization step (column: Kromasil, developing solvent: ethyl acetate / hexane = 1: 4)

¹ H NMR (CDCl ₃ ): δ 0.99 (m, 1H), 0.90 (s, 3H), 1.23 (m, 1H), 1.29 (s, 3H), 2.87 (dd, 1H), 4.26 (m, 1H) ), 4.70 (m, 1H), 5.44 (m, 1H), 7.35 (m, 5H)

Example 12 By Chromatography of 3-((RS) -2 ', 2'-Dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one Light split

1.00 g of 3-((RS) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one prepared in Example 3 was prepared. 0.45 g of 3-((S) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidine- separated by column chromatography

2-one (1.65 mmol) and 0.46 g of 3-((R) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one (1.68 mmol) was obtained (separation conditions: SiO ₂ 230-400 mesh, developing solvent: ethyl acetate / hexane = 1/7)

3-((S) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one; ¹ H NMR (CDCl ₃ ): δ 0.93 (m, 1H), 1.20 (s, 3H), 1.30 (s, 3H), 1.35 (m, 1H), 2.75 (m, 2H), 3.30 (m, 1H ), 4.14 (m, 2H), 4.64 (m, 1H), 7.29 (m 5H)

3-((R) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one; ¹ H NMR (CDCl ₃ ): δ 0.97 (m, 1H), 1.16 (s, 3H), 1.27 (s, 3H), 1.35 (m, 1H), 2.85 (m, 2H), 3.30 (m, 1H) ), 4.14 (m, 2H), 4.66 (m, 1H), 7.29 (m 5H)

Example 13 By Chromatography of 3-((RS) -2 ', 2'-Dimethylcyclopropanecarboxyl)-(S) -4-phenyl-1,3-oxazolidin-2-one Light split

0.50 g of 3-((RS) -2 ', 2'-dimethylcyclopropanecarboxyl)-(S) -4-phenyl-1,3-oxazolidin-2-one isolated by column chromatography to give 0.21 g g of 3-((S) -2 ', 2'-dimethylcyclopropanecarboxyl)-(S) -4-phenyl-1,3-oxazolidin-2-one (0.81 mmol) and 0.22 g of 3 -((R) -2 ', 2'-dimethylcyclopropanecarboxyl)-(S) -4-phenyl-1,3-oxazolidin-2-one (0.85 mmol) was obtained (separation condition: SiO ₂ 230-400 mesh, developing solvent: ethyl acetate / hexane = 1/4)

3-((S) -2 ', 2'-dimethylcyclopropanecarboxyl)-(S) -4-phenyl-1,3-oxazolidin-2-one; ¹ H NMR (CDCl ₃ ): δ 0.90 (m, 1H), 1.15 (s, 3H), 1.25 (m, 1H), 1.29 (s, 3H), 2.82 (dd, 1H), 4.27 (m, 1H ), 4.70 (m, 1H), 5.48 (m, 1H), 7.35 (m, 5H)

3-((R) -2 ', 2'-dimethylcyclopropanecarboxyl)-(S) -4-phenyl-1,3-oxazolidin-2-one; ¹ H NMR (CDCl ₃ ), δ 0.99 (m, 1H), 0.90 (s, 3H), 1.23 (m, 1H), 1.29 (s, 3H), 2.87 (dd, 1H), 4.26 (m, 1H ), 4.70 (m, 1H), 5.44 (m, 1H), 7.35 (m, 5H)

Example 14 3-((RS) -2 ', 2'-dimethylcyclopropanecarboxyl)-(4S, 5R) -4-methyl-5-phenyl-1,3-oxazolidin-2-one Of light by chromatographic method

1.0 g of 3-((RS) -2 ', 2'-dimethylcyclopropanecarboxyl)-(4S, 5R) -4-methyl-5-phenyl-1,3-oxazolidin-2-one column Chromatography to separate 0.43 g of 3-((S) -2 ', 2'-dimethylcyclopropanecarboxyl)-(4S, 5R) -4-methyl-5-phenyl-1,3-oxazolidine- 2-one (1.58 mmol) and 0.44 g of 3-((R) -2 ', 2'-dimethylcyclopropanecarboxyl)-(4S, 5R) -4-methyl-5-phenyl-1,3-oxa Zolidin-2-one (1.61 mmol) was obtained (separation conditions: SiO ₂ 230-400 mesh, developing solvent: ethyl acetate / hexane = 1/6)

3-((S) -2 ', 2'-dimethylcyclopropanecarboxyl)-(4S, 5R) -4-methyl-5-phenyl-1,3-oxazolidin-2-one; ¹ H NMR (CDCl ₃ ): δ 0.99 (d, 3H), 0.93 (m, 1H), 1.16 (s, 3H), 1.27 (s, 3H), 1.28 (m, 1H), 2.94 (dd, 1H) ), 4.80 (m, 1H), 5.65 (d, 1H), 7.37 (m, 5H)

3-((R) -2 ', 2'-dimethylcyclopropanecarboxyl)-(4S, 5R) -4-methyl-5-phenyl-1,3-oxazolidin-2-one; ¹ H NMR (CDCl ₃ ): δ 0.98 (d, 3H), 0.92 (m, 1H), 1.12 (s, 3H), 1.32 (s, 3H), 1.33 (m, 1H), 2.75 (dd, 1H) ), 4.74 (m, 1H), 5.67 (d, 1H), 7.37 (m, 5H)

Step 4: hydrolysis of (R) or (S) 2,2-dimethylcyclopropanecarboxyl derivative

Example 15 Preparation of (S) -2,2-dimethylcyclopropanecarboxylic acid by hydrolysis

3-((S) -2 ', 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one and 3-((R) -2', 20 ml of a 2.00 g mixture (32 mmol) in which the ratio of 2'-dimethylcyclopropanecarboxyl)-(R) -4-benzyl-1,3-oxazolidin-2-one was mixed to 99.9: 0.1 After dissolving in THF and 6 ml of H ₂ O, cooling to 0 ° C., 2.8 g of 30% H ₂ O ₂ (29 mmol) and 0.9 g of 10% LiOH (16.9 mmol) aqueous solution were added dropwise. After stirring the reaction solution for 4 hours, 3.90 g of 30.0% sodium sulfite aqueous solution was added to remove excess H ₂ O _2, and concentrated under reduced pressure to remove THF. The remaining aqueous solution was extracted with dichloromethane to recover (4R) -4-benzyl-1,3-oxazolidin-2-one, acidified with 2N aqueous hydrochloric acid solution, extracted with ethyl acetate, and the extract was extracted with magnesium sulfate. Dried and filtered. The filtrate was concentrated and distilled under reduced pressure to give pure (S) -2,2-dimethylcyclopropanecarboxylic acid (749 mg, 90%, [α] _D ²⁰ = 147 (c = 1, CHCl ₃ )

¹ H NMR (CDCl ₃ ): δ 0.92 (m, 1H), 1.12 (m, 1H), 1.17 (s, 3H), 1.24 (s, 3H), 1.50 (m, 1H)

As described above, the present invention is activated (RS) -2,2-dimethylcyclopropane using a chiral heterocyclic compound of the formula (3) as a novel light splitting agent which can be easily synthesized and obtain high optical purity. Reaction with carbonyl chloride and diastereoisomers obtained gave pure (R) or (S) -2,2-dimethylcyclopropanecarboxyl derivatives (1a, 1b) using crystallization or chromatography. In the production method of the present invention, by using a chiral heterocyclic compound of Formula 3 as a light splitting agent, a high purity 2,2-dimethylcyclopropanecarboxyl derivative which can be easily synthesized and industrially mass-produced was synthesized. Hydrolysis may yield (R) or (S) -2,2-dimethylcyclopropanecarboxylic acid.

Claims (15)

(RS) -2,2-dimethylcyclopropanecarboxylic acid (2) is reacted with a light splitting agent to obtain diastereomers, and the resulting diastereomers are separated optically by crystallization or chromatography to optically separate the diastereomers. In the method for preparing pure (R) -2,2-dimethylcyclopropanecarboxyl derivative (1a) and (S) -2,2-dimethylcyclopropanecarboxyl derivative (1b), the light splitting agent is represented by Method characterized by the chiral heterocyclic compound represented. Scheme 1 Wherein X is O; or S, Y is O; S; NR ⁵ , Wherein R ⁵ is a C ₁ to C ₆ alkyl group; C ₁ -C ₆ alkyl group; An aryl group unsubstituted or substituted with a C ₁ to C ₆ alkoxy group or halogen; R ¹ , R ² , R ³ , R ⁴ are, independently from each other, H; C ₁ -C ₆ alkyl group; An aryl group unsubstituted or substituted with a C ₁ to C ₆ alkoxy group or halogen; Or a R ⁶ -O-CH ₂ -group, wherein R ⁶ is a C ₁ to C ₆ alkyl group; C ₁ -C ₆ alkyl group; A C ₁ to C ₆ alkoxy group or an aryl group unsubstituted or substituted with halogen; R <^1> or R <^3> couple | bonds with each other and contains the 4-8 cyclic carbocyclic compound or the heterocyclic compound containing O, N, and S. Except that R ¹ , R ² , R ³ , and R ⁴ are all hydrogen.) The process according to claim 1, wherein the method hydrolyzes pure (R) -2,2-dimethylcyclopropanecarboxyl derivative (1a) and (S) -2,2-dimethylcyclopropanecarboxyl derivative (1b) ( R) -2,2-dimethylcyclopropanecarboxylic acid and (S) -2,2-dimethylcyclopropanecarboxylic acid. The method according to claim 1, wherein the chiral heterocyclic compound of formula 3, which is a light splitting agent, is selected from compounds represented by the following Chemical Formulas 3a and 3b. Formula 3a Formula 3b (Wherein R ¹ , R ² , R ³ , and R ⁴ are as defined in claim 1). The method according to claim 1, wherein the chiral heterocyclic compound of formula 3, which is a light splitting agent, is X is O and Y is O. According to claim 4, wherein the chiral heterocyclic compound of Formula 3 is any one of R ¹ and R ² is an alkyl group comprising a methyl group, isopropyl group and t- butyl group; Benzyl groups including benzyl groups, 4-methoxybenzyl groups and 4-chlorobenzyl groups; An aryl group comprising a phenyl group and a 4-methoxyphenyl group, the other is hydrogen, and R ³ and R ⁴ are hydrogen. The method of claim 4, wherein the chiral heterocyclic compound of Formula 3 is any one of R ¹ and R ² is a methyl group, benzyl group, or a phenyl group and the other is hydrogen, R ³ and R ⁴ is hydrogen Manufacturing method. The method according to claim 4, wherein the chiral heterocyclic compound of Formula 3 is R ¹ and R ³ are each independently a methyl group or a phenyl group, R ² and R ⁴ is hydrogen. The method of claim 1, wherein the crystallization is alcohols including methanol, ethanol and isopropanol; A process for producing a single solvent or a mixture of two or more selected from the group consisting of hydrocarbons including hexane, heptane and cyclopropane. The method of claim 8, wherein the crystallization is performed in methanol, isopropanol, hexane and dichloromethane, or hexane and ethyl acetate. (R) or (S) 2,2-dimethylcyclopropanecarboxyl derivative represented by the following formula (1). Formula 1 (Wherein X, Y, R ¹ , R ² , R ³ , and R ⁴ are as defined in claim 1). The derivative of claim 10 wherein the derivative is X is O and Y is O. 12. The compound of claim 11, wherein the derivative is X is O and Y is O, and any one of R ¹ and R ² is an alkyl group comprising methyl, isopropyl, t -butyl, and cyclohexyl; Benzyl groups including benzyl, 4-methoxybenzyl, and 4-chlorobenzyl; An aryl group comprising phenyl and 4-methoxyphenyl, the other is hydrogen and R ³ and R ⁴ are hydrogen. The derivative according to claim 11, wherein the derivative is a compound represented by the following formula (4a). Formula 4a The derivative of claim 11, wherein the derivative is a compound represented by the following Chemical Formula 4b. Formula 4b The derivative of claim 11, wherein the derivative is a compound represented by the following Chemical Formula 4c. Formula 4c