A METHOD FOR PREPARING OP CHIRAL 2,2- DIMETHYLCYCLOPROPANECARBOXYL DERIVATIVES
Technical field The present invention is related to the method for the preparation of chiral 2 , 2-dimethylcyclopropanecarboxyl derivatives represented by formula 1. More particularly, the present invention is related to the method for the preparation of optically pure (R)-2,2- dimethylcyclopropanecarboxyl derivatives (la) and (s)-2,2- dimethylcyclopropanecarboxyl derivatives (lb) , comprising the following steps of: reacting (RS)-2,2- dimethylcyclopropanecarboxylic acid (2) with optical resolving agent to synthesize diastereomers ,-and resolving the said diastereomers by crystallization or chromatography to obtain optically pure (R)-2,2- dimethylcyclopropanecarboxyl derivatives (la) and (s)-2,2- dimethylcyclopropanecarboxyl derivatives (lb) ;
Wherein, said optical resolving agent is chiral heterocycle compound represented by the formula 3. formula 1
Y is 0, S or N-R5 (wherein, R5 is Cι-C6 alkyl group, aryl group unsubstituted or substituted by Cι-C6 alkoxy group or halogen atom) ; R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen atom, Cι-C3 alkyl group, aryl group unsubstituted or substituted by Cι-C6 alkoxy group or halogen atom, R6-0-CH2 group (wherein R6 is L-CS alkyl group, aryl group unsubstituted or substituted by Cι-C6 alkoxy group or halogen atom) ;and R1 and R3 are combined to form C4-C8 carbocycle, or heterocycle compound containing 0, N or S . Wherein, it is excepted that all of R1, R2, R3 and R4 are H.)
Background of the Invention 2, 2-dimethyleyelopropanecarboxylic acid with optical activity is used in the preparation of pyrethroid insecticide having low toxicity in mammals (UK Patent No. 1,260,847). Further, it is also applied to agricultural chemicals and medicines as an essential material which is being used as the core intermediate of Cilastatin in preventing the solution of carbapenem antibiotic at kidneys (European Patent No. 48,301, European Patent No. 48,025).
Recently, many researches are being performed in order to prepare 2, 2-dimethylcyclopropanecarboxylic acid having various uses into a material with high yield and
pure optical activity. In order to prepare such 2, 2- dimethylcyclopropanecarboxylic acid, first, 2, 2- dimethylcyclopropanecarboxyl derivative, the intermediate of 2, 2-dimethylcyclopropanecarboxylic acid synthesis must be easily synthesized, and must have an optical activity of high purity.
Chiral amine, the most commonly used as optical resolving agent, forms salt when undergoing acid base reaction with (RS)-2, 2-dimethylcyclopropanecarboxylic acid, and the thus obtained salt is crystallized to be resolved into a diastereomer, chiral 2, 2- dimethylcyclopropanecarboxyl derivative. Then, it is hydrolyzed to obtain 2, 2-dimethylcyclopropanecarboxylic acid with optical activity. Such chiral amine can be exemplified by (S) -1-phenylethyl amine (UK Patent No. 1,260,847), quinine (US Patent No. 4,539,208), and 2- diphenylethyl amine (US Patent No. 4,542,235). However, chiral amine has a disadvantage that it should be crystallized several times in order to reach a high optical purity level and it has a low yield. In addition, there is another disadvantage that even though it is possible to prepare 2-diphenylethyl amine of high optical purity and high yield, it is impossible to prepare optical resolving agent, chiral 2-diphenylethyl amine from the natural product and it is expensive.
In another preparation method, chiral alcohol is used as optical resolving agent. This chiral alcohol reacts with (RS) -2, 2-dimethylcyclopropanecarboxylic acid to obtain chiral ester. The thus obtained chiral ester is crystallized to be separated into a diastereomer, chiral 2, 2-dimethylcyclopropanecarboxyl derivative. Then, it is hydrolyzed to obtain 2, 2-dimethylcyclopropanecarboxylic acid with optical activity. Such chiral alcohol can be exemplified by L-menthol (US Patent No. 4,487,956), methyl (S) -mandelate (US Patent No. 5,243,070), and L-N-methyl ephedrine (JP Patent No. 60-56,942). However, chiral alcohol has a disadvantage that it should be crystallized several times in order to reach a high optical purity level and it has a low yield. Further, chical alcohol is expensive.
Therefore, in order to minimize the above disadvantages, a novel optical resolving agent which can be easily synthesized by itself is required to obtain a chiral 2, 2-dimethylcyclopropanecarboxyl derivative with high yield and high purity. Accordingly, the present invention introduced the chiral heterocycle compound of formula 3, which can be easily prepared in various methods and is used in various asymmetric conversion reactions (Ager, D. J. , Prakash, I., Schaad D. Chem . Rev. 1996, 96, 846-859/ Ager, D. J., Prakash, I., Aldrichimic Acta, 1997, 30, 3; Nicolas,
E., Russel, K. C, Hruby, V. J. J. Org . Chem. 1993, 58, 766; Pridgen, L. N. , Prol, J. J". Org. Chem . 1989, 54, 3231; Hsiao, C. L. , 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., Tetraheάron Lett . , 1992, 33 , 3797; Coppola, G. M. , Schuster, H. F., Asymmetric Synthesis : Construction of Chiral Molecules Using Aminoaciάs, Wiley, New York, 1987; Seyden-Penne, J. , Chiral Auxiliaries and Ligands in Asymmetric Synthesis, Wiley Interscience, 1995) . However, no example has been reported wherein the chiral heterocycle compound of formula 3 has been used in the preparation of chiral 2, 2-dimethylcyclopropanecarboxyl derivative of high purity.
Summary of the Invention
Hereupon, the present inventors made an effort in preparing an optical active 2, 2- dimethylcyclopropanecarboxyl derivative with optical activity and high purity, and thus, obtained a diastereomer by reacting (RS)-2, 2-dimethylcyclopropanecarboxylic acid
(2) with a chiral heterocycle compound of formula 3 as an optical resolving agent. The thus obtained diastereomers are crystallized or chromatographed to resolve the diastereomer and prepare an optically pure (R)-2, 2-
dimethylcyclopropanecarboxyl derivative (la) and (S)-2, 2- dimethylcyclopropanecarboxyl derivative (lb) . Further, the present invention has been completed by finding out that this derivative has a high yield and an optical activity of high purity.
It is an object of the present invention to provide a method for preparing (R) or (S)-2, 2- dimethylcyclopropanecarboxyl derivatives represented by formula 1. It is another object of the present invention to provide (R) or (S)-2, 2-dimethylcyclopropanecarboxyl derivatives represented by formula 1.
Best Mode of Carrying Out The Invention The present invention provides the method for the preparation of (R) or (S) -2, 2-dimethylcyclopropanecarboxyl derivatives represented by formula 1. More particularly, the present invention is related to the method for the preparation of optically pure (R)-2,2- dimethylcyclopropanecarboxyl derivatives (la) and (s)-2,2- dimethylcyclopropanecarboxyl derivatives (lb) , comprising the following steps of: reacting (RS)-2,2- dimethylcyclopropanecarboxylic acid (2) with optical resolving agent to synthesize diastereomers ,-and resolving the said diastereomers by crystallization or chromatography
to obtain optically pure (R)-2,2- dimethylcyclopropanecarboxyl derivatives (la) and (s)-2,2- dimethylcyclopropanecarboxyl derivatives (lb) ;
Wherein, said optical resolving agent is chiral heterocycle compound represented by the formula 3. formula 1
Y is 0, S or N-R5 (wherein, Rs is Cι-C6 alkyl group, aryl group unsubstituted or substituted by Cι-C6 alkoxy group or halogen) ; R1, R2, R3 and R4 are independently selected from the group consisting of H, C - 5 alkyl group, aryl group unsubstituted or substituted by Cι-C6 alkoxy group or halogen atom, R6-0-CH2 group (wherein, R6 is C!-C6 alkyl group, aryl group unsubstituted or substituted by Ci- C6 alkoxy group or halogen atom) ; and R1 and R3 are combined to form C-C8 carbocycle, or heterocycle compound containing O, N or S. Wherein, it is excepted that all of R1, R2, R3 and R4 are H.)
More particularly, the said method is comprised of : 1) reacting (RS) -2, 2-dimethylcyclopropanecarboxylic
acid (2) with optical resolving agent represented by formula 3 to synthesize diastereomers (step l.);and
2) resolving the said diastereomers by crystallization or chromatography to obtain optically pure (R) -2 , 2-dimethylcyclopropanecarboxyl derivatives (la) and
(s) -2 , 2-dimethylcyclopropanecarboxyl derivatives (lb) (step
2) .
The said step 1, reaction (RS)-2,2- dimethylcyclopropanecarboxylic acid (2) with optical resolving agent represented by formula 3 to synthesize diastereomers is accomplished by the known method in the art to implement. In the said reaction, various activating agents are used to increase the reactivity of (RS)-2,2- dimethylcyclopropanecarboxylic acid (2) . For example, activating agent selected from the group consisting of phosgene, phosphorus tribromide, phosphorus trichloride, oxalyl chloride and thionyl chloride is reacted with (RS) - 2 , 2-dimethylcyclopropanecarboxylic acid (2) to synthesize acyl halide. Another activating agent selected from the group consisting of ethyl chloroformate, methyl chloroformate, isobutyl chloriformate and methanesulfonyl chloride is reacted with (RS)-2,2- dimethylcyclopropanecarboxylic acid (2) to synthesize anhydride. Also, (RS) -2 , 2-dimethylcyclopropanecarboxylic
acid (2) is reacted with N,N' -dicyclohexylcarbodiimide (DCC) or known coupling reagent to synthesize carbodiimide. Also, (RS) -2, 2-dimethylcyclopropanecarboxylic acid (2) is activated by N,N' -carbonyldiimidazole, 2-ethoxy-N- ethoxycarbonyl-1, 2-dihydroquinoline (EDDQ) or triphenyl phosphine/carbon tetrachloride, thereafter easily reacted in the presence of base.
In the example of the present invention,' (RS)-2,2- dimethylcyclopropanecarboxylic acid (2) is converted to (RS) -2, 2-dimethylcyclopropanecarbonyl chloride by using thionyl chloride or oxalyl chloride as halogen compound. Amine used in the amidation reaction is tertiary C!-C4 alkyl amine. Particularly, the amine is selected from the group consisting of triethyl amine, tripropyl amine, triisopropyl amine and tributyl amine. Preferably, triethyl amine is used.
(RS) -2 , 2-dimethylcyclopropanecarbonyl chloride activated in the step 1 is reacted with chiral heterocycle compound represented by formula 3, optical resolving agent to synthesize Diastereomers of (RS)-2,2- dimethylcyclopropanecarboxyl derivatives . The said optical resolving agent, the compound represented by formula 3 is selected from the group consisting of the compounds represented by the formula 3a or 3b.
formula 3a
formula 3b
(wherein, R1, R2, R3 and R4 are as defined in the above . )
Particularly, 1, 3-oxazolidine-2-one derivatives, 1,3- oxazolidine-2-thione derivatives, 1, 3-thiazolidine-2-thione derivatives and 1, 3-imidazolidine-2-one derivatives, the compound of the formula 3a or 3b in which the X is 0 and the Y is O, the X is 0 and the Y is S, the X is S and the Y is S and the X is 0 and the Y is N-R5, respectively are used as the said optical resolving agent. Preferably, 1,3- oxazolidine-2-one derivatives are used.
More particularly, the said chiral heterocycle compound is the compound represented by the formula 3a;
One of the R1 and R2 is selected from the group consisting of Cι-C3 alkyl group, aryl group unsubstituted or substituted by Cι-C6 alkyl group, Cι-Cβ alkoxy group or halogen atom, or R6-0-CH2 group (wherein R6 is Cι-C3 alkyl group, aryl group unsubstituted or substituted by Cι-C6 alkoxy group or halogen atom) . The other is hydrogen.
Preferably, the X is 0 and the Y is O; One of the R1 and R2 is selected from the group consisting of alkyl group containing methyl group, isopropyl group and t-butyl group, benzyl group containing benzyl group, 4-methoxybenzyl group and 4-chlorobenzyl group, aryl group containing phenyl group and 4-methoxyphenyl group; the other is hydrogen; and both R3 and R4 are hydrogen.
More preferably, the X is O and the Y is 0; one of the R1 and R2 is methyl group, benzyl group or phenyl group; the other is hydrogen atom; and both R3 and R4 are hydrogen .
The said chiral heterocycle compound is the compound represented by the formula 3b;
R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen atom, Cx-C6 alkyl group, aryl group unsubstituted or substituted by Cι-C6 alkoxy group or halogen atom or R6-0-CH2 group (wherein R6 is Cι-C6 alkyl group, aryl group unsubstituted or substituted by Cι-C3
alkoxy group or halogen atom; and R1 and R3 are combined to form C4-C8 carbocycle, or heterocycle compound containing 0, N or S.
Preferably, the X is 0 and the Y is O; R1 and R3 is independently methyl group or phenyl group; and both R2 and R4 are hydrogen.
The prepared diastereomers are resolved to optically pure (R) -2 , 2 -dimethylcyclopropanecarboxyl derivatives (la) and (s) -2 , 2 -dimethylcyclopropanecarboxyl derivatives (lb) by crystallization or chromatography.
Chromatography is operated due to the difference of affinity to the stationary phase attached to the column in the two diastereomers. The condition of chromatography resolution (developing solvent, stationary phase, flowing rate) is selected for those skilled in the art to implement. According to the example of the present invention, the prepared diastereomers are resolved more easily than the ones prepared by using other optical resolving agent. Crystallization is the method using the difference of the solubility of two diastereomers in solvent. According to the example, preferably, the crystallization is accomplished in one or more solvents selected from the group consisting of alcohol containing methanol , ethanol and isopropanol, or hydrocarbon containing hexane, heptane
and cyclopropane, but the solvent is not limited to them.
More preferably, the said crystallization is accomplished in methanol, isopropanol, mixed solvent of hexane and dichloromethane, or mixed solvent of hexane and ethyl acetate. In the crystallization using the said solvent, one of the (R) -2 , 2-dimethylcyclopropanecarboxyl derivatives
(la) and (s) -2 , 2-dimethylcyclopropanecarboxyl derivatives
(lb) is selectively resolved from (RS)-2,2- dimethylcyclopropanecarboxyl derivatives. Crystallization was accomplished one time repeatedly in order that (R) or (S) -2 , 2-dimethylcyclopropanecarboxyl derivatives may be resolved with more selective and improved optical purity.
As shown in the Scheme 1, particularly illustrating the present invention, carboxylic group of (RS)-2,2- dimethylcyclopropanecarboxylic acid (2) is activated by the activating agent, thereafter activated carboxylic group is reacted with chiral heterocycle compound (3), optical resolving agent in the presence of base to synthesize the diastereomers . The prepared diastereomers are resolved by crystallization or chromatography to prepare optically pure (R) -2 , 2-dimethylcyclopropanecarboxyl derivatives (la) and (s) -2 , 2-dimethylcyclopropanecarboxyl derivatives (lb). Scheme 1
la lb
(wherein, X, Y, R1, R2, R3 and R4 are as defined in the above . )
Also, (R) -2 , 2-dimethylcyclopropanecarboxylic acid and (s) -2 , 2-dimethylcyclopropanecarboxylic acid are prepared by hydrolyzing (R) -2 , 2-dimethylcyclopropanecarboxyl derivatives (la) and (s) -2 , 2-dimethylcyclopropanecarboxyl derivatives (lb) , respectively. Also, if necessary, (R) - 2, 2-dimethylcyclopropanecarboxyl derivatives (la) and (s) - 2 , 2-dimethylcyclopropanecarboxyl derivatives (lb), as an intermediate are directly reacted with other compound to synthesize useful compound.
The present invention provides (R) or (S)-2,2- dimethylcyclopropanecarboxyl derivatives represented by formula 1. formula 1
(wherein, X, Y, R1, R2, R3 and R4 are as defined in the above . )
Preferably, the present invention provides (R) or (S) -2 , 2-dimethylcyclopropanecarboxyl derivatives, the compound of formula 1 in which the X is 0 and the Y is 0; one of the R1 and R2 is selected from the group consisting of alkyl group containing methyl group, isopropyl group, t- butyl group and cyclohexyl group, benzyl group containing benzyl group, 4-methoxybenzyl group and 4-chlorobenzyl group, aryl group containing phenyl group and 4- methoxyphenyl group; the other is hydrogen atoms; and both R3 and R4 are hydrogen. More preferably, the compound represented by formula 4a, formula 4b and formula 4c is provided, formula 4a
formula 4b
formula 4c
The present invention will be explained in more detail with reference to the following examples. However, the following examples are provided only to illustrate the present invention, and the present invention is not limited to them.
Step 1: activation of carboxyl group of (RS)-2,2- dimethylcyclopropanecarboxylic acid <EXAMPLE 1> Preparation of (RS) -2.2-dimethylcyclopropanecarbonyl chloride
In a 100ml flask, (RS)-2,2- dimethylcyclopropanecarboxylic acid (12g, 105mmol) was dissolved in hexane (12g), two drops of dimethylacetamide . The said solution was heated to 70°C, therein thionyl chloride (23.8g, 200mmol) and hexane (50g) were added slowly dropwise with stirring. The said mixed solution was
additionally stirred for 4 hours at 70 °C, thereafter hexane and excess thionyl chloride was removed under reduced pressure. The crude product was evaporated to obtain pure
(RS) -2, 2-dimethylcyclopropanecarbonyl chloride (12.6g, yield : 91%)
XH NMR(CDC13) : δ 1.18 (m, 1H) , 1.28 (s, 6H) , 1.37 (m, 1H) ,
2.15 (dd, 1H)
step 2 preparation of (RS) -2,2- dimethylcyclopropanecarboxyl derivatives
<EXAMPLE 2>
Preparation of 3- ( (RS) -2 ' , 2 ' -dimethylcyclopropanecarboxyl) - (S) -4-benzyl-l, 3-oxazolidine-2-one
(S) -4-benzyl-l, 3-oxazolidine-2-one (1.06g, 5.99mmol) , (RS) -2 , 2-dimethylcyclopropanecarbonyl chloride (1.03g, 7.77mmol) prepared in the said example 1, lithium chloride (0.28g, 6.60mmol) and triethyl amine(0.90g,
8.91mmol) were added to 5ml of tetrahydrofuran at 0°C, thereafter the solution was heated to the room temperature and stirred for 6 hours at the same temperature. The solvent (tetrahydrofuran) was removed under reduced pressure. The resultant solution was dissolved in the 10ml of ethyl acetate, thereafter the solution was washed with IN of NaOH solution, dried with magnesium sulfate and filtered. The filterate was concentrated under reduced pressure. The crude product was purified by chromatography (developing solvent: mixed solution of hexane and ethyl acetate) to obtain 3- ( (RS) -2 ', 2 ' - dimethylcyclopropanecarboxyl) - (S) -4-benzyl-l , 3-oxazolidine- 2-one(1.54g, yield : 94%).
XH NMR(CDC13) : 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-l, 3-oxazolidine-2-one (R) -4-benzyl-l, 3-oxazolidine-2-one (1. OOg, 5.65mmol),
(RS) -2 , 2-dimethylcyclopropanecarbonyl chloride (0.97g, 7.32mmol) prepared in the said example 1, lithium chloride (0.26g, 6.10mmol) and triethyl amine(0.85g,
8.41mmol) were added to 5ml of tetrahydrofuran at 0°C, thereafter the solution was heated to the room temperature and stirred for 5 hours at the same temperature. The solvent (tetrahydrofuran) was removed under reduced pressure. The resultant solution was dissolved in the 10ml of ethyl acetate, thereafter the solution was washed with IN of NaOH solution, dried with magnesium sulfate and filtered. The filterate was concentrated under reduced pressure. The crude product was purified by chromatography (developing solvent: mixed solution of hexane and ethyl acetate) to obtain 3- ( (RS) -2 ', 2 ' - dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3 -oxazolidine- 2-one(1.43g, yield : 93%).
XH NMR(CDC13) : 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- l, 3 -oxazolidine-2 -one
(S) -4 -phenyl - l , 3 -oxazolidine-2 -one (1 . O Og, 6 . 13mmol) , (RS) -2 , 2 -dimethylcyclopropanecarbonyl chloride ( 1 . 05g,
7.92mmol) prepared in the said example 1, lithium chloride (0.28g, 6.60mmol) and triethyl amine (0.93g, 9.21mmol) were added to 5ml of tetrahydrofuran at 0°C, thereafter the solution was heated to the room temperature and stirred for 7 hours at the same temperature. The solvent (tetrahydrofuran) was removed under reduced pressure. The resultant solution was dissolved in the 10ml of ethyl acetate, thereafter the solution was washed with IN of NaOH solution, dried with magnesium sulfate and filtered. The filterate was concentrated under reduced pressure. The crude product was purified by chromatography
(developing solvent: mixed solution of hexane and ethyl acetate) to obtain 3- ( (RS) -2 ', 2 ' - dimethylcyclopropanecarboxyl) - (S) -4-phenyl-l, 3-oxazolidine- 2-one(1.45g, yield : 91%).
XH NMR(CDC13) : δ 0.90(m, 1H) , 0.96(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>
Preparation of 3- ( (RS) -2 ' , 2 ' -dimethylcyclopropanecarboxyl) - (4S, 5R) -4-methyl-5-phenyl-1, 3-oxazolidine-2-one
(4S, 5R) -4-methyl-5-phenyl-l, -oxazolidine-2-one (1.06g,
5.99mmol) , (RS) -2 , 2-dimethylcyclopropanecarbonyl chloride (1.03g, 7.77mmol) prepared in the said example 1,
lithium chloride (0.28g, 6.60mmol) and triethyl amine(0.90g,
8.91mmol) were added to 5ml of tetrahydrofuran at 0°C, thereafter the solution was heated to the room temperature and stirred for 5 hours at the same temperature. The solvent (tetrahydrofuran) was removed under reduced pressure. The resultant solution was dissolved in the 10ml of ethyl acetate, thereafter the solution was washed with IN of NaOH solution, dried with magnesium sulfate and filtered. The filterate was concentrated under reduced pressure. The crude product was purified by chromatography (developing solvent: mixed solution of hexane and ethyl acetate) to obtain 3- ( (RS) -2 ', 2' - dimethylcyclopropanecarboxyl) - (4S, 5R) -4 -methyl-5-phenyl - 1, 3-oxazolidine-2-one (1.56g, yield : 95%). XH NMR(CDC13) : δ 0.89 (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 3j optical resolution of (RS) -2,2- dimethylcyclopropanecarboxyl derivatives
<EXAMPLE 6>
Optical resolution of 3- ( (RS) -2 ' , ' - dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3-oxazolidine- 2 -one by crystallization 1
3- ( (RS) -2' ,2' -dimethylcyclopropanecarboxyl) - (R) -4- benzyl-1, 3-oxazolidine-2-one (2. OOg, 7.32mmol) prepared in the example 3 was refluxed and dissolved in 35.0ml of hexane and 4.00ml of ethyl acetate, thereafter the solution was slowly cooled and crystallized. The resultant crude product was filtered to obtain crystal (0.62g, 31.0%). The crystal was analyzed by HPLC . The result showed that 3- ( (S) -2' , 2' -dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3- oxazolidine-2-one and 3-((R)-2',2'- dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3-oxazolidine-
2-one were mixed in a molar ratio of 98.5 : 1.5. (column :
Kromasil, developing solvent : ethyl acetate/hexane = 1/10)
^■H NMR(CDC13) : 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>
Optical resolution of 3- ( (RS) -2 ' , 2' - dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3 -oxazolidine- 2 -one by crystallization 2
3- ( (RS) -2', 2' -dimethylcyclopropanecarboxyl) - (R) -4- benzyl-1, 3-oxazolidine-2-one (4. OOg, 14.7mmol) prepared in the example 3 was refluxed and dissolved in 12.0ml of isopropanol, thereafter the solution was slowly cooled and crystallized. The crude product was filtered to obtain
crystal (1.60g, 40.0%). The crystal was analyzed by HPLC . The result showed that 3-((S)-2', 2'- dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3-oxazolidine- 2-one and 3- ( (R) -2 ', 2 ' -dimethylcyclopropanecarboxyl) - (R) -4- benzyl-1, 3 -oxazolidine-2 -one were mixed in a molar ratio of 97.5 : 2.5. (column : Kromasil, developing solvent : ethyl acetate/hexane = 1/10)
XH NMR(CDC13) : 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>
Optical resolution of 3- ( (RS) -2 ' , 2 ' - dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3-oxazolidine- 2 -one by crystallization 3
2. OOg of crude product, in which 3-((S)-2' ,2'- dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l , 3 -oxazolidine- 2-one and 3- ( (R) -2',2' -dimethylcyclopropanecarboxyl) - (R) -4- benzyl-1, 3-oxazolidine-2-one were mixed in a molar ratio of 91.0:9.0 was refluxed and dissolved in 12.0ml of isopropanol, thereafter the solution was slowly cooled to the room temperature and crystallized. The crude product was filtered to obtain crystal (1.40g, 70.0%). The crystal was analyzed by HPLC. The result showed that 3-((S)-2', 2'- dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3-oxazolidine-
2-one and 3- ( (R) -2 ' , 2 ' -dimrthylcyclopropanecarboxyl) - (R) -4- benzyl-1, 3-oxazolidine-2-one were mixed in a molar ratio of 99.9 : 0.1. Crystallization was accomplished one time repeatedly in order to reach more selective and improved optical resolution. (column : Kromasil, developing solvent : ethyl acetate/hexane = 1/10)
^Η NMR(CDC13) : 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>
Optical resolution of 3-((RS)-2',2'- dimethylcyclopropanecarboxyl) - (S) -4-benzyl-l, 3-oxazolidine- 2 -one by crystallization 2. OOg of 3- ( (RS) -2', 2' -dimethylcyclopropanecarboxyl) - (S) -4-benzyl-l, 3-oxazolidine-2 -one prepared in the example 2 was refluxed and dissolved in 10.0ml of methanol, thereafter the solution was slowly cooled to the room temperature and crystallized. The resultant crude product was filtered to obtain crystal (0.74g, 37.0%). The crystal was analyzed by HPLC. The result showed that 3-((S)-2', 2'- dimethylcyclopropanecarboxyl) - (S) -4-benzyl-l, 3-oxazolidine- 2-one and 3- ( (R) -2 ', 2' -dimethylcyclopropanecarboxyl) - (S) -4- benzyl-1, 3 -oxazolidine-2 -one were mixed in a molar ratio of 5.0 : 95.0. (column : Kromasil, developing solvent : ethyl
acetate/hexane = 1/10)
XH NMR(CDC13) : δ 0.92 (m, IH) , 1.20 (s, 3H) , 1.29(s, 3H) , 1.35 (m, IH) , 2.71 (dd, IH) , 2.79 (dd, IH) , 3.28 (dd, IH) , 4.15 (m, 2H) , 4.65(m, IH) , 7.31 (m, 5H)
<EXAMPLE 10 >
Optical resolution of 3- ( (RS) -2' , 2' - dimethylcyclopropanecarboxyl) - (R) -4-phenyl-l, 3-oxazolidine- 2 -one by crystallization 1 2. OOg of 3- ( (RS) -2', 2' -dimethylcyclopropanecarboxyl) -
(R) -4-phenyl-l, 3 -oxazolidine-2 -one prepared in the example
4 was refluxed and dissolved in mixed solution of 20.0ml of hexane and 6.00ml of ethyl acetate, thereafter the solution was slowly cooled to the room temperature and crystallized. The resultant crude product was filtered to obtain crystal (0.50g, 25%) . The crystal was analyzed by HPLC. The result showed that 3-((S)-2', 2 ' -dimethylcyclopropanecarboxyl) - (R) -4-phenyl-l, 3-oxazolidine-2 -one and 3-((R)-2',2'- dimethylcyclopropanecarboxyl) - (R) -4-phenyl-l , 3 -oxazolidine- 2-one were mixed in a molar ratio of 6.0 : 94.0. (column : Kromasil, developing solvent : ethyl acetate/hexane = 1/4)
XH NMR(CDC13) : δ 0.90 (m, IH) , 1.15 (s, 3H) , 1.25(m, IH) , 1.29(s, 3H) , 2.82(dd, IH) , 4.27(m, IH) , 4.70(m, IH) , 5.48(m, IH) , 7.35 (m, 5H)
< EXAMPLE 11>
Optical resolution of 3- ( (RS) -2 ' ,2' - dimethylcyclopropanecarboxyl) - (R) -4-phenyl-l, 3-oxazolidine- 2-one by crystallization 2 2. OOg of crude product, in which 3-((S)-2',2'- dimethylcyclopropanecarboxyl) - (R) -4-phenyl-l , 3 -oxazolidine- 2-one and 3- ( (R) -2 ', 2 ' -dimethylcyclopropanecarboxyl) - (R) -4- phenyl-1 , 3 -oxazolidine-2 -one were mixed in a molar ratio of 82.0:18.0 was refluxed and dissolved in 30.0ml of isopropanol, thereafter the solution was slowly cooled to the room temperature and crystallized. The crude product was filtered to obtain crystal (0.64g, 32%). The crystal was analyzed by HPLC. The result showed that 3-((S)-2', 2'- dimethylcyclopropanecarboxyl) - (R) -4-phenyl-l , 3 -oxazolidine- 2-one and 3- ( (R) -2' ,2' -dimethylcyclopropanecarboxyl) - (R) -4- phenyl-1, 3 -oxazolidine-2 -one were mixed in a molar ratio of 99.0 : 1.0. (column : Kromasil, developing solvent : ethyl acetate/hexane = 1/4)
XH NMR(CDC13) : δ 0.89 (m, IH) , 0.90 (s, 3H) , 1.23 (m, IH) , 1.29(s, 3H) , 2.87(dd, IH) , 4.26 (m, IH) , 4.70(m, IH) , 5.44(m, IH) , 7.35 (m, 5H)
<EXAMPLE 12>
Optical resolution of 3- ( (RS) -2 ' , 2 ' - dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3 -oxazolidine-
2-one by chromatography l.OOg of 3- ( (RS) -2 ', 2' -dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3-oxazolidine-2-one prepared in the example 3 was resolved by chromatography to obtain 3-((S)-2',2'- dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l , 3 -oxazolidine- 2-one(0.45g, 1.65mmol) and 3- ( (R) -2' , 2 ' - dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3-oxazolidine- 2-one(0.46g, 1.68mmol) . (the condition of chromatography resolution: Si02 230~400 mesh, developing solvent: ethyl acetate/hexane=l/7) .
3- ( (S) -2' ,2' -dimethylcyclopropanecarboxyl) - (R) -4- benzyl-1, 3 -oxazolidine-2 -one; 1H NMR(CDC13): δ 0.93 (m, IH) , 1.20(s, 3H) , 1.30(s, 3H) , 1.35(m, IH) , 2.75 (m, 2H) , 3.30(m, IH) , 4.14 (m, 2H) , 4.64 (m, IH) , 7.29 (m, 5H) 3- ( (R) -2',2' -dimethylcyclopropanecarboxyl) - (R) -4- benzyl-1, 3 -oxazolidine-2 -one; 1H NMR(CDC13): δ 0.97 (m, IH) , 1.16(s, 3H) , 1.27(s, 3H) , 1.35(m, IH) , 2.85(m, 2H) , 3.30(m, IH) , 4.14 (m, 2H) , 4.66 (m, IH) , 7.29 (m, 5H)
<EXAMPLE 13>
Optical resolution of 3- ( (RS) -2' ,2" - dimethylcyclopropanecarboxyl) - (S) -4-phenyl-l, 3-oxazolidine- 2-one by chromatography
0.50g of 3- ( (RS) -2 ', 2' -dimethylcyclopropanecarboxyl) - (S) -4-phenyl-l, 3-oxazolidine-2-one was resolved by
chromatography to obtain 3-((S)-2',2'- dimethylcyclopropanecarboxyl) - (S) -4-phenyl-l, 3 -oxazolidine- 2-one(0.21g, 0.81mmol) and 3-((R)-2',2'- dimethylcyclopropanecarboxyl) - (S) -4-phenyl-l, 3-oxazolidine- 2-one(0.22g, 0.85mmol) . (the condition of chromatography resolution: Si02 230~400 mesh, developing solvent: ethyl acetate/hexane=l/4) .
3- ( (S) -2',2' -dimethylcyclopropanecarboxyl) - (s) -4- phenyl-1, 3 -oxazolidine-2 -one; XH NMR(CDC13): δ 0.90 (m, IH) , 1.15(s, 3H) , 1.25(m, IH) , 1.29(s, 3H) , 2.82(dd, IH) , 4.27(m, IH) , 4.70(m, IH) , 5.48(m, IH) , 7.35(m, 5H)
3- ( (R) -2' , 2 ' -dimethylcyclopropanecarboxyl) - ( S) -4- phenyl-1,3 -oxazolidine-2 -one; ^Η NMR(CDC13): δ 0.89 (m, IH) , 0.90(s, 3H) , 1.23(m, IH) , 1.29(s, 3H) , 2.87(dd, IH) , 4.26(m, IH) , 4.70 (m, IH) , 5.44 (m, IH) , 7.35 (m, 5H)
<EXAMPLE 14>
Optical resolution of 3- ( (RS) -2 ' , 2 ' - dimethylcyclopropanecarboxyl) - (4S,5R) -4-methyl-5-phenyl- 1, 3 -oxazolidine-2 -one by chromatography
1. Og of 3- ( (RS) -2 ' , 2 ' -dimethylcyclopropanecarboxyl) -
(4S, 5R) -4-methyl-5-phenyl-l, 3 -oxazolidine-2 -one was resolved by chromatography to obtain 3-((S)-2',2'- dimethylcyclopropanecarboxyl) - (4S,5R) -4-methyl-5-phenyl- 1, 3 -oxazolidine-2 -one (0.43g, 1.58mmol) and 3-((R)-2',2'-
dimethylcyclopropanecarboxyl) - (4S,5R) -4 -methyl-5 -phenyl - 1, 3 -oxazolidine-2 -one (0.44g, 1.61mmol) . (the condition of chromatography resolution: Si02 230~400 mesh, developing solvent: ethyl acetate/hexane=l/6) . 3-((S)-2',2' -dimethylcyclopropanecarboxyl) - (4S, 5R) -4- methyl-5-phenyl-l,3-oxazolidine-2-one; 1H NMR(CDC13) : δ 0.89(d, 3H) , 0.93(m, IH) , 1.16(s, 3H) , 1.27(s, 3H) , 1.28 (m, IH) , 2.94 (dd, IH) , 4.80 (m, IH) , 5.65 (d, IH) , 7.37 (m, 5H)
3- ( (R) -2' ,2' -dimethylcyclopropanecarboxyl) - ( 4S,5R) -4- methyl-5-phenyl-l,3-oxazolidine-2-one; XH NMR(CDC13) : δ 0.88(d, 3H) , 0.92(m, IH) , 1.12(s, 3H) , 1.32(s, 3H) , 1.33(m, IH) , 2.75 (dd, IH) , 4.74 (m, IH) , 5.67 (d, IH) , 7.37 (m, 5H)
step 4 : hydrolysis of (R) or (S) -2,2- dimethylcyclopropanecarboxyl derivatives <EXAMPLE 15>
Preparation of (S) -2, 2 -dimethylcyclopropanecarboxylic acid via hydrolysis
Crude product (2. OOg, 32mmol) , in which 3-((S)-2' ,2'- dimethylcyclopropanecarboxyl) - (R) -4-benzyl-l, 3-oxazolidine- 2-one and 3- ( (R) -2' ,2' -dimethylcyclopropanecarboxyl) - (R) -4- benzyl-1, 3 -oxazolidine-2 -one were mixed in a molar ratio of 99.9:0.1 was dissolved in mixed solution of 20ml of tetrahydrofuran and 6ml of H20, thereafter the solution was
cooled to 0°C. 30% H202 solution (2.8g, 29mmol) and 10% LiOH
solution (0.9g, 16.9mmol) were subsequently added dropwise therein. The solution was stirred for 4 hours, thereafter 30.0% sodium sulfite solution was added to remove excess H20, and concentrated under reduced pressure to remove tetrahydrofuran. Dichloromethane was added to the resultant acqueous solution, and extracted to recycle (4R) -4-benzyl- 1, 3-oxazolidine-2-one . The solution was acidified with 2N hydrochloric acid solution, and extracted with ethyl acetate. The extract was dried with magnesium sulfate, and filtered to obtain a filterate. The filterate was concentrated and evaporated under reduced pressure to obtain pure (S) -2 , 2 -dimethylcyclopropanecarboxylic acid(749mg, 90%, [a] D 20=147 (c=l, CHC13) . XH NMR(CDC13) : δ 0.92 (m, IH) , 1.12 (m, IH) , 1.17 (s, 3H) , 1.24(s, 3H) , 1.50 (m, IH)
Industrial applicability
As described above, in accordance with the present invention, a pure (R) or (S)-2, 2- dimethylcyclopropancarboxyl derivative (la, lb) with high purity, which is easily synthesized by itself is prepared by using a chiral heterocycle compound of formula 3 as a novel optical resolving agent. This compound is reacted with activated (RS)-2, 2 -dimethylcyclopropancarbonyl chloride, and the thus obtained diastereomer is
crystallized or chromatographed to prepare a pure (R) or (S)-2, 2-dimethylcyclopropancarboxyl derivative (la, lb). Chiral heterocycle compound of formula 3 is used as a novel optical resolving agent in the preparation method of the present invention to synthesize 2, 2- dimethylcyclopropancarboxyl derivatives of high purity, which can be industrially mass produced, and this is hydrolyzed to obtain (R) or (S)-2, 2- dimethylcyclopropancarboxylic acid.