KR100233960B1 - Analysis for optical purity of alcohol, thiol and amine, and method for preparing high-purity chiral alcohol, thiol and amine - Google Patents

Abstract

The present invention relates to a method for analyzing the optical purity of an enantiomeric mixture using chiral cyclopropane carboxylic acid derivatives and to prepare a high purity chiral compound therefrom. Reacting with and converting into esters, amides or thioesters in the respective diastereomeric mixture.

Description

ANALYSIS FOR OPTICAL PURITY OF ALCOHOL, THIOL AND AMINE, AND METHOD FOR PREPARING HIGH-PURITY CHIRAL ALCOHOL, THIOL AND AMINE}

The present invention relates to a method for analyzing the optical purity of alcohols, thiols, amines and to a process for preparing high purity chiral alcohols, chiral thiols and chiral amines.

Chiral alcohols, amines and thiols are very important intermediates in the development of new drugs and new materials. Therefore, the development of an efficient synthesis method for obtaining them is a very important research issue not only academically but also industrially.

It is widely used to convert an anionic mixture of alcohols, amines or thiols obtained by asymmetric reactions into an analyteable diastereomeric mixture for analyzing the optical purity of the α-methoxy-α- (known as Mosher's acid). Trifluoromethyl) phenyl acetic acid (MTPA) [JA Dale, DL Dull, and HS Mosher, J. Org. Chem. 1969, 34 , 2543; H. Ohta, Y. Miyamae, and Y. Kimura, Chem. Lett . 1989, 379]. However, the price of this compound is very high and uneconomical: (R) -isomer: $ 208.85 / g; (S) -isomer: $ 96.45 / g (quoted from 1996 Aldrich catalog) [ Aldrich: Catalog Handbook of Fine Chemicals 1996-1997].

Accordingly, an object of the present invention is to find a more economical and effective chiral carboxylic acid that can replace MTPA and to prepare a method for analyzing the optical purity of alcohols, amines and thiols, as well as a method for preparing high optical purity chiral alcohols, chiral amines and chiral thiols. It aims to provide.

In order to achieve the above object, the present invention includes the step of converting a chiral cyclopropane carboxylic acid derivative with an alcohol, an amine or a thiol in the enantiomeric mixture to convert it to a diastereomeric mixture of an ester, amide or thioester, Provided are methods for analyzing optical purity of alcohols, amines or thiols.

Hereinafter, the present invention will be described in detail.

The chiral cyclopropane carboxylic acid derivatives used in the optical purity analysis of the alcohols, amines or thiols of the present invention can be easily obtained from catalytic alkenes by catalytic asymmetric synthesis.

That is, when a 1,1-disubstituted ethylene is reacted with a diazo compound using a copper (I) complex bound with a chiral bis (oxazoline) ligand as a catalyst, a cyclopropane carboxylic acid ester having almost pure optical purity is obtained in high yield. DA Evans, KA Woerpel, MM Hinman, and MM Faul, J. Am. Chem. Soc . 1991, 113 , 726, which can be readily converted to carboxylic acids by hydrolysis.

Examples of chiral cyclopropane carboxylic acids used in the present invention include 2,2-dimethylcyclopropane carboxylic acid in the form of R or S, 2,2-diphenylcyclopropane carboxylic acid or 2,2-difluorocyclopropane carboxylic acid. .

Cyclopropane carboxylic acid prepared in this way and the alcohol, amine or thiol present in the enantiomeric mixture is converted to the corresponding esters, amides or thioesters, respectively, and various methods are known as basic organic reactions. Specifically referring to Scheme 1 (see RC Larock, Comprehensive Organic Transformations: A Guide to Functional Group Preparations , VCH, New York, 1989).

(In the above scheme, R ¹ and R ² are different from each other, and each is an alkyl or aryl group.)

In Scheme 1, step 1) is a step of converting a cyclopropane carboxylic acid derivative to a more reactive intermediate using 1,3-dicyclohexacarbodiimide (DCC) (RC Larock, Comprehensive Organic Transformations: A Guide to Functional Group Preparations , VCH, New York, 1989) or by JA Dale, DL Dull, and HS Mosher, J. Org. Chem. 1969, 34 , 2543, using halogenating agents such as SOCl ₂ to introduce good leaving groups such as Cl, Br, I, DCC into cyclopropane carboxylic acid derivatives. Methods of substituting hydroxy groups of carboxylic acids with good leaving groups are known in the art and are listed in several references, such as Larock, supra.

Step 2) is a step of reacting the alcohol, amine or thiol in the form of a mixture of the intermediate compound and the enantiomer to convert it into the corresponding ester, amide or thioester in the form of a diastereomeric mixture. In this case, steps 1) and 2) may be continuously performed without separating the intermediate synthesized in step 1).

Corresponding esters, amides or thioesters formed as such are diastereomers which are different from each other in physical properties such as solubility and can be easily analyzed or separated by conventional separation methods known in the art. Examples of analytical or separation methods include preparative chromatography, gas chromatography (GC), high performance liquid chromatography (HPLC), and Nuclear Magnetic Resonance (NMR), which are obtained from chromatography or NMR. The purity of the original alcohol, amine or thiol can be analyzed by measuring the optical purity of the diastereomers by comparing the area of the peaks on the graph, and the optical rotation of the diastereomer mixture with a polarimeter. The purity can also be determined by measuring. The methods are all introduced in general literature in the art, such as in Laroque.

Processes for the preparation of high purity chiral alcohols, amines or thiols include the separation of diastereoisomers having the desired stereochemistry from the diastereomeric mixtures of esters, amides or thioesters by the conventional methods mentioned above, followed by separation of the separated diastereomers. This can be accomplished by hydrolysis to remove cyclopropane carboxylic acid derivatives and converting them to alcohols, amines or thiols with the desired stereochemistry. Hydrolysis reactions of esters, amides or theoesters are usually carried out under acidic or basic conditions, all of which are also described in the general literature in the art.

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 only to the following examples.

Preparation Example 1 Preparation of (2S) -2,2-dimethylcyclopropane carboxylic acid

Copper anhydrous chloroform (40 ml) was added copper trilate (copper triplate (CuOTf): 56.1 mg, 0.223 mmol) and chiral bisoxazoline (67.0 mg, 0.228 mmol) acting as a ligand to generate a copper catalyst. The reaction mixture was filtrated with glass fibers to obtain a copper catalyst solution, which was then added to a solution of chloroform (20 ml) in which isobutylene (110 g, 2.0 mol) was dissolved at 0 ° C., followed by ethyl diazoacetate ( 28.8 ml, 27 mmol) in chloroform (100 ml) solution was added dropwise. The mixture was stirred while gradually raising the temperature to room temperature over 14 hours. Fractionation was carried out under reduced pressure (30 torr) to obtain (2S) -2,2-dimethylcyclopropane carboxylic acid ethyl ester (35.3 g, 91%;> 99% ee) in a clear liquid state. This ethyl ester was hydrolyzed under an acid catalyst to give (2S) -2,2-dimethylcyclopropane carboxylic acid in almost quantitative yield.

Preparation Example 2 Preparation of (2S) -2,2-diphenylcyclopropane carboxylic acid

(2S) -2,2-diphenylcyclopropane carboxylic acid was obtained in the same manner as in Preparation Example 1, except that 1,1-diphenylethylene was used instead of isobutylene.

Example 1

(2S) -2,2-dimethylcyclopropanecarboxylic acid (200 mg, 1.75 mmol) obtained in Preparation Example 1 was dissolved in dichloromethane solvent (5 ml). N, N-dimethylaminopyridine (214 mg, 1.75 mmol) was added to the solution and stirred. Subsequently, 1-phenylethanol (0.10 ml, 0.87 mmol) and dicyclohexylcarbodiimide (362 mg, 1.75 mmol) were added thereto, followed by stirring at room temperature for 3 hours to confirm that the reaction was completed by thin layer chromatography. The urea produced in the reaction mixture was filtered and the filtrate was analyzed by HPLC and GC, and the analysis conditions and analysis results were as follows:

Gas chromatography (30 m methylsilicone capillary; injector pressure: 7 psi; column temperature: 100-200 ° C., 15 ° C./min): (S, S) -isomer (9.72 min), (S, R) -isomer ( 9.98 minutes)

High performance liquid chromatography (hypersil silica column 3 mm, 4.6 mm x 100 mm; solvent: ethyl acetate in 1% hexane): (S, S) -isomer (3.83 min), (S, R) -isomer (4.10 minutes)

Example 2

Except for using (2S) -2,2-diphenylcyclopropanecarboxylic acid obtained in Preparation Example 2 was carried out in the same manner as in Example 1 to obtain a diastereomeric mixture was analyzed by NMR optical purity.

¹ H NMR (500 MHz, CDCl ₃ ; δ, ppm): (S, S) -isomer: 5.71 (q, J = 6.53 Hz, 1H; CH ₃ -CH-Ph), 2.59 (dd, J = 5.97 Hz , J = 8.10 Hz, 1H; -CH ₂ -CH-), 1.43 (d, J = 6.55 Hz, 3H; -CH ₃ ); (S, R) -isomer: 5.65 (q, J = 6.59 Hz, 1H; CH ₃ -CH-Ph), 2.54 (dd, J = 5.97 Hz, J = 8.10 Hz, 1H; -CH ₂ -CH-) , 1.17 (d, J = 6.65 Hz, 3H; -CH ₃ )

By using the chiral cyclopropane carboxylic acid derivatives as described above, it is possible to economically analyze the optical purity of the mixture of the enantiomers of alcohols, thiols and amines, and can also optically prepare high-purity chiral alcohols, chiral amines and chiral thiols. .

Claims (3)

The chiral cyclopropane carboxylic acid derivatives are reacted with alcohols, amines or thiols present in the enantiomeric mixture to be converted into esters, amides or thioesters in the diastereomeric mixture, respectively, and then the optical purity of the diastereomeric mixture is analyzed. Method for optical purity analysis of alcohol, amine or thiol, comprising the step of. The method of claim 1, A chiral cyclopropane carboxylic acid derivative is a 2,2-dimethylcyclopropane carboxylic acid, 2,2-diphenylcyclopropanecarboxylic acid or 2,2-difluorocyclopropanecarboxylic acid in R or S form. The chiral cyclopropane carboxylic acid derivatives are reacted with alcohols, amines or thiols present in the enantiomeric mixture to be converted into esters, amides or thioesters in the diastereomeric mixture, respectively, and from the diastereomeric mixture having the desired stereochemistry Separating the diastereomers and then hydrolyzing the separated diastereomers to produce an optically high purity chiral alcohol, chiral amine or chiral thiol.