JPH07128319A - Binaphthalene derivative - Google Patents

Abstract

PURPOSE:To provide a reagent and method for separating and analyzing enantiomer with high sensitivity. CONSTITUTION:The inventive reagent is a chiral derivative reagent composed of (+) or (-)-2-methyl-1,1'-binaphthalene-2'-carbonyl nitrile. The separating/ analyzing method comprises a step for effecting fluorometric analysis by causing (+) or (-)-2-methyl-1,1'-binaphthalene-2'-carbonyl nitrile to react a compound, i.e., enantiomer, containing a hydroxyl group having an asymmetric carbon at the bonding position.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a derivatization reagent used for separating and analyzing a hydroxyl group-containing enantiomer, and a method for separating and analyzing a compound for each enantiomer using this reagent.

[0002]

2. Description of the Related Art Several methods have been considered for separating and analyzing optical isomer hydroxyl-containing compounds, particularly alcohols, and one of them is There is a method of reacting with a reagent to convert into a derivative and analyzing the derivative. Although 1-phenylethylisocyanate, trifluoroacetylprolyl chloride, etc. are considered as the compound derivatizing reagent,
These reagents have low reaction sensitivity to the compounds. Further, the analytical sensitivity and the solubility of the obtained compound derivative according to the optical isomerism are insufficient, and it was unsuitable for the pretreatment of chromatography for the separation analysis. Moreover, these reagents are expensive and never satisfactory.

[0003]

The present invention is directed to a chiral derivatization reagent for an enantiomer of a compound containing a hydroxyl group containing an alcohol and such a reagent to react with an enantiomer of a compound containing a hydroxyl group to highly sensitively detect the enantiomer. It provides a method for separation and analysis.

Thus, the invention is (+) or (-)-
The present invention provides a chiral derivatization reagent composed of 2-methyl-1,1'-binaphthalene-2'-carbonyl nitrile.

The structural feature of this reagent is that it has a cyanocarbonyl group (--COCN) in two planar bulky naphthalene nuclei, which easily reacts with a hydroxyl group, and is novel in the literature. It is a compound.

In the present invention, the reagent can be manufactured as follows. (I): formula

[Chemical 1]

A compound of the formula (II): (wherein R and R ′ are C _1-4 alkyl groups) is reduced:

[Chemical 2]

(Wherein R'is the same as defined above), and then the compound of formula (II) is halogenated to give a compound of formula
(III):

[Chemical 3]

(Wherein X is a halogen and R'is the same as the above definition), and this is dehalogenated and ester-decomposed to give a compound of the formula (IV):

[Chemical 4]

Then, the formula (IV) is nitrileed to obtain the formula (V):

[Chemical 5] To a compound of formula (IV) or (V) and optically resolved (+) or (−)-2-methyl-1,
1'-Binaphthalene-2'-carbonyl nitrile can be obtained.

That is, the reagent of the formula (V) is (i) reduction of the elter group of R, (ii) halogenation of the hydroxyl group,
It is prepared through four steps: (iii) dehalogenation of alkyl halide and ester decomposition of R ′, and (iV) cyanocarbonylation.

The reaction reagents used in these production processes may be those conventionally used, and the reaction conditions may be set according to the reaction reagents used.

Examples of the reducing agent used in the step (i) include lithium hydride compounds such as lithium aluminum hydride and sodium borohydride, and organometallic compounds such as tri-tert-butoxy-lithium aluminum hydride.

The halogenation in the step (ii) can be carried out in the presence of an acid using hydrogen halide, phosphorus halide or the like.

In step (iii), step (i)
The dehalogenation of R can be carried out by using the reagent used in 1. Next, ester decomposition of R'is performed. For example, the above-mentioned metal hydride may be used for dehalogenation, and strong acid and strong alkali may be used for ester decomposition of R '.

In the step (iv), a metal cyanide salt, an ammonium cyanide salt or the like can be used. Some intermediate products of the reaction have (+) and (-) coordinations, but it is not necessary to separate them by force during the synthesis, and it is better to separate them in the later reaction step. That is, when the compound of the formula (V) is synthesized, it is desirable to separate it by each (+) (−) coordination, if desired, and it may be at the stage of synthesizing the compound of the formula (IV).

The separation method may be a fractional recrystallization method using an appropriate solvent such as a lower alcohol.

In yet another embodiment, (+) or (-)-2-methyl-1,1'-binaphthalene-2'-
The present invention provides a chiral derivatization reagent comprising carbonyl nitrile. By using this reagent, the enantiomer of a compound containing a hydroxyl group and having an asymmetric carbon at its bonding position is reacted with this reagent in the presence of an organic base to form the corresponding diastereomer, which is chromatographed. A separation and analysis method is provided, which comprises separating each of the (+) or (-) enantiomers, followed by fluorescence analysis.

The reaction between the reagent of the present invention and the enantiomer of the hydroxyl group-containing compound is as follows.

[0020]

[Chemical 6]

The reagent according to the present invention does not fluoresce in an unreacted state, but only fluoresces when it reacts with a hydroxyl group.
This indicates that the reaction product can be directly subjected to fluorescence analysis without the need to remove excess reagents from the reaction product.
Furthermore, this reaction is completed under mild conditions and in a short time, and even if the reaction time is extended, the reaction products and reagents are not racemized.

The reagent according to the present invention reacts specifically and extremely well with primary alcoholic hydroxyl groups and secondary alcoholic hydroxyl groups. It does not react with sterically hindered secondary alcoholic hydroxyl groups or tertiary alcoholic hydroxyl groups. Specific examples thereof are described below. The reaction with lower alcohols such as methanol and ethanol, primary and secondary amines is completed at room temperature.

This active ingredient can be used as a simple substance, but is preferably dissolved in an aprotic organic solvent to give a reagent. In particular, when the compound of formula (V) is used as a fluorescent reagent, the presence of an organic base brings about a favorable result in the reaction with the test sample, and therefore it is preferable to add the organic base to the reagent.

Specific examples of the aprotic organic solvent include:
Examples include chloroform, acetonitrile, benzene, ethyl acetate, tetrahydrofuran, acetone and the like.
Of these, acetonitrile is the most suitable. Examples of the organic base include tertiary alkylamines such as triethylamine and trimethylamine.

The amount ratio of the aprotic organic solvent to the organic base is preferably about 1: 1. The concentration of the compound of formula (V) in these mixtures is not particularly limited, but is, for example, 0.1 to 1%.

Since this fluorescent reagent does not fluoresce in an unreacted state, it may be used in an excess amount with respect to the test sample to allow sufficient reaction.

Therefore, the sample to be tested is reacted with the reagent of the present invention in a pre-column in advance, and the sample is subjected to high performance liquid chromatography to separate the optical antipodes and to detect with a fluorometer. The generated fluorescence has an excitation wavelength of 342 nm and an irradiation wavelength of 420 nm, and the detection limit is 200 pg when using high performance liquid chromatography.

[0028]

The present invention will be described in more detail with reference to synthesis examples and analysis examples.

Synthesis Example 2-Thimel-1,1'-binaphthalene-2'-carboni
Synthesis of Lunitrile This synthetic example shows a method for synthesizing the reagent of the present invention using a compound of formula (I) as a starting material and intermediate products (formula (II), (III), (IV)). It goes through the process represented by the chemical formula.

[0030]

[Chemical 7]

(I) methyl 2-hydroxymethyl-1,
1'-Binaphthalene-2-2'-carboxylate dimethyl 1,1'-binaphthalene-2,2'-dicarboxylate (2.8 g) (J. Chem. Soc., 195).
2,1242 to a mixed solution of anhydrous benzene (75 ml) -anhydrous ether (75 ml) of tri-tert-butoxy-lithium aluminum hydride (LiAl (tert-BuO) ₃ H) (8 g).
Added little by little over time. The mixture was acidified with 5% hydrochloric acid under ice cooling, the organic layer was separated, and dried over anhydrous sodium sulfate. The organic layer was concentrated and the residue was washed with silica gel (50
Purified by column chromatography using g). The fraction eluted with hexane / ethyl acetate (4: 1) was recrystallized from hexane / acetone to obtain 1 g of the compound of the formula (II) as colorless plate crystals. The physical properties of the obtained compound were as follows. Mp 117.5 to 118.5 ° _{C NMR (CDCl 3) δ:} 3.52 (3H, s, -OC
_{H 3), 4.32 (2H,} s, -CH 2 -O -), 6.
84-8.02 (12H, m, Ar-H). Elemental analysis: _{(C 23 H} 18 as _{O 3)} Calculated: Carbon 80.7%, hydrogen 5.26%, Found: Carbon 80.2
%, Hydrogen 5.28%

(Ii) methyl 2-bromomethyl-1,
1'-Binaphthalene-2'-carboxylate Methyl 2-hydroxymethyl-1, obtained in (i) above
1'-Binaphthalene-2'-carboxylate (2 g)
30% hydrogen bromide / acetic acid solution in acetic acid (10 ml) solution
(5 ml) was added, and the mixture was stirred at 50 ° C for 10 minutes. The reaction solution was poured into ice to precipitate crystals, which was collected by filtration. The crystals were purified by column chromatography on silica gel, and the fraction eluted with hexane / ethyl acetate (30: 1) was recrystallized from hexane / ethyl acetate. Compound of formula (III) 2.2
g was obtained as needle crystals. The physical properties of the obtained compound were as follows. Melting point 137-138 ° C NMR (CDCl ₃ ) δ: 3.46 (3H, s, -OC
_{H 3), 4.10 (1H,} d, J = 14Hz, -CHB
r), 4.24 (1H, d, J = 14Hz, -CHB
r), 6.90-8.20 (12H, m, Ar-H). Elemental _{analysis: (C 23} H 17 as OBr) Calculated: carbon 68.1%, hydrogen 4.20%, Found: Carbon 68.2
%, Hydrogen 4.27%

(Iii) 2-Methyl-1,1′-binaphth
Thallene-2′-carboxylic acid Methyl 2-bromomethyl-1,1 ′ obtained in the above (ii)
-Binaphthalene-2'-carboxylate (1.9 g)
Was dissolved in dimethyl sulfoxide (10 ml), sodium borohydride (0.4 g) was added thereto, and the mixture was added at 60 ° C.
And stirred for 15 minutes. The reaction solution was poured into ice water, acidified with concentrated hydrochloric acid to precipitate crystals, which was collected by filtration. The obtained crystals were purified by column chromatography on silica gel, and the hexane / ethyl acetate (10: 1) elution fraction was recrystallized from methanol. The methyl ester (1.4 g) of the compound of formula (IVa) was obtained as colorless needle crystals, and the physical properties of the obtained ester were as follows. Melting point 97-98 ° C NMR (CDCl ₃ ) δ: 2.04 (3H, s, —CH
_{3), 3.44 (3H, s} , -OCH 3), 6.88-
8.12 (12H, m, Ar-H). Elemental analysis: _{(C 23 H} 18 _{O 2)} Calculated values: carbon 84.6%, hydrogen 5.56%, found: 84.6%, hydrogen 5.52% and then the resulting methyl ester in methanol ( 50 ml)
A 10% aqueous potassium hydroxide solution (30 ml) was added to the solution, and the mixture was heated under reflux for 3 hours. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration. The crystals were recrystallized from hexane / ethyl acetate to give the compound of formula (IVa) in the form of colorless needles, which had the following physical properties. Mp _{232~233 ° C NMR (CDCl 3)} δ: 1.96 (3H, s, -CH
_{3), 6.80-8.12 (12H, m} , Ar-H) Elemental analysis: _{(C 22 H} 16 _{O 2)} Calculated values: carbon 84.6%, hydrogen 5.13%, Found: Carbon 84.3
%, Hydrogen 4.93%

(Iv) 2-Methyl-1,1′-binaphtha
Optical resolution of len-2'-carboxylic acid 2-methyl-1,1'-binaphthalene-2'-carboxylic acid (3.3 g) in ethanol (60 ml) was added to anhydrous l
-A solution of brucine (4.1 g) in ethanol (20 ml) was added and left at room temperature overnight. The precipitated crystals are collected by filtration,
It was purified by fractional crystallization from ethanol several times. The obtained salt was acidified with 5% hydrochloric acid and then extracted with ethyl acetate.
The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was recrystallized from hexane / acetone to obtain a compound of formula (IVc) with (-) coordination as colorless needle crystals, the physical properties of which are as follows. It was as it was. Melting point 229 to 229.5 ° C

[0035]

[Outer 1] Elemental analysis: _{(C 22 H} 16 _{O 2)} Calculated values: carbon 84.6%, hydrogen 5.13%, Found: Carbon 84.3
%, Hydrogen 5.00% The same treatment was carried out on the mother liquor of recrystallization with 1-brucine to obtain a compound of formula (IVb) with (+) coordination as colorless needle crystals, the physical properties of which are as follows. there were. Melting point 232-233 ° C

[0036]

[Outside 2] Elemental analysis: measured value: carbon 84.4%, hydrogen 5.10%

(V) 2-Methyl-1,1′-binaphthale
Oxalyl chloride (3 ml) was added to a solution of methylene- 2'-carbonylnitrile 2-methyl-1,1'-binaphthalene-2'-carboxylic acid (0.5 g) in anhydrous methylene chloride (30 ml), and the mixture was stirred at room temperature for 2 hours. It was stirred. The reaction solution was concentrated to give a yellow oily substance. This was dissolved in anhydrous methylene chloride (10 ml), trimethylsilyl cyanide (3 ml) and zinc iodide (1 mg) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to give a red oily substance. The obtained oil was purified by column chromatography on silica gel (5 g), and the hexane elution fraction was recrystallized from hexane / petroleum ether. A yellow needle-like compound of the formula (Va) (240 mg) was obtained, and the physical properties thereof were as follows. Mp _{109~110 ° C IRν max (CHCl 3} ): 2240 (C = N), 1
^{660 (C = O) cm -} 1 NMR (CDCl 3) δ: 2.04 (3H, s, -C
_{H 3), 6.72-8.24 (12H,} m, Ar-H) Mass spectrometry ^{m / z: 321 (M +} ) Elemental _{analysis: (C 23 H} 15 as ON) Calculated: Carbon 8
6.0%, hydrogen 4.71%, nitrogen 4.36%, measured value:
Carbon (6.0%), hydrogen (4.93%), and nitrogen (3.87%) (iv), and the compound (0.5 g) of the formula (IVb) with (+) coordination obtained was treated in the same manner as above to give a yellow color. An oily compound of formula (Vb) was obtained, which had the following physical properties.

[0038]

[Outside 3] Elemental analysis: measured value: carbon 85.9%, hydrogen 4.73%,
Nitrogen 4.47% The compound (0.5 g) of the formula (IVc) with the (-) coordination obtained in (iv) was treated in the same manner as above to obtain the compound of formula (IVc) as a yellow oil, Its physical properties were as follows:

[0039]

[Outside 4] Elemental analysis: measured value: carbon 85.9%, hydrogen 4.73%,
Nitrogen 4.47%

Analytical Example 3-hydroxyoctanoic acid, 3-hydroxydecanoic acid,
Methyl esters of 3-hydroxylauric acid, 3-hydroxystearic acid and mandelic acid were each added in the presence of triethylamine to (+)-2-methyl-1,1′-
Binaphthalene-2'-carbonyl nitrile 2 at 60 ° C
The reaction was quantitatively performed for 0 minutes to give an ester.

The reaction mixture was separated for each optical antipode by high performance liquid chromatography. In the high performance liquid chromatography, a Waters 6000A solvent feeder equipped with a Hitachi 650-10LC fluorescence detector was used, and a Cosmo-sil 5SL column was used as the column. A mixed solution of n-pentane / ethyl acetate (30: 1) was sent as a mobile phase at a rate of 1.0 ml / min. The separated ester was fluorescently detected and quantitatively analyzed. The results are shown in the table below.

[0042]

[Table 1]

In the table, k'denotes a volume ratio, α is a separation factor, and R is a lysis factor.

As shown in the table, it was shown that the enantiomers were separated by the reagent of the present invention.

By using the reagent of the present invention, the enantiomer of the compound containing a hydroxyl group can be reacted in the precolumn of high performance liquid chromatography, and the reagent does not fluoresce by itself, and the hydroxyl group It is understood that since fluorescence is emitted only after the reaction with, it is possible to detect fluorescence without removing the reagent excessively present in the reaction solution.

This reagent can also be applied to quantitative analysis of medicines, for example, analysis of fine substances such as β-sympatholytic agents in biological fluids.

[Procedure amendment]

[Submission date] December 5, 1991

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Title of invention

[Correction method] Change

[Correction content]

Title of the invention Binaphthalene derivative

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Claims (2)

[Claims] 1. (+) or (−)-2-methyl-1,
A chiral derivatization reagent comprising 1'-binaphthalene-2'-carbonyl nitrite. 2. An enantiomer of a compound containing a hydroxyl group and having an asymmetric carbon atom at its bonding position is (+) or (−)-2-methyl-1,1′-binaphthalene-2′-.
Carbonyl nitrile is reacted in the presence of an organic base to form the corresponding diastereomer, which is chromatographed to separate (+) or (-) enantiomers and the enantiomers are analyzed fluorometrically. Separation analysis method characterized by.