JPH0429662B2 - - Google Patents

Description

[Detailed Description of the Invention] (a) Field of Industrial Application This invention relates to a derivatization reagent used for separating and analyzing hydroxyl group-containing enantiomers, a method for producing this reagent, and a method for producing a compound using this reagent to separate each enantiomer. Concerning how to separate and analyze each. (B) Prior art Several methods have been considered for separating and analyzing optically isomeric hydroxyl group-containing compounds, especially alcohols, one of which involves converting the compounds into derivatives by reacting them with reagents. There is a method to analyze the derivatives. The compound derivatization reagent is 1-
Phenylethyl isocyanate, trifluoroacetylprolyl chloride, etc. are considered, but
These reagents have low reaction sensitivity to these compounds. Furthermore, the obtained optically isomer compound derivatives had insufficient analytical sensitivity and solubility, making them unsuitable for pretreatment in chromatography for separation analysis. Additionally, these reagents are expensive;
It was never satisfying. (c) Purpose This invention provides a reagent for chiral derivatization of enantiomers of compounds containing hydroxyl groups, including alcohols, and a method for producing this reagent. (d) Configuration Thus, this invention is (+) or (-)-2-
Methyl-1,1'-binaphthalene-2'-carbonylnitrile is provided. The structural feature of this reagent is that it has two planar bulky naphthalene nuclei with a cyanocarbonyl group (-COCN) that easily reacts with hydroxyl groups, making it a novel compound that has not yet been described in the literature. . The compound of this invention can be produced as follows. formula(): (In the formula, R and R' are C _1-4 alkyl groups) by reducing the compound of the formula (): (in the formula, R' is the same as defined above), and then the compound of formula () is halogenated to form formula (): (In the formula, X is a halogen and R' is the same as defined above), which is dehalogenated and decomposed into esters to form the formula (): and nitrile the expression () to form the expression (): (+) or (-)-2-methyl-1,1'-binaphthalene-2'-carbonyl nitrile can be obtained by optical resolution at the step of formula () or the step of (). That is, the reagent of formula () () reduces the ester group of R, () subsequently halogenates the hydroxyl group,
() Dehalogenation of alkyl halides and
It is produced through four steps: ester decomposition of R' and ()cyanocarbonylation. The reaction reagents used in these manufacturing processes may be those conventionally employed, and the reaction conditions may be set according to the reaction reagents used. For example, the reducing agent used in step () includes metal hydride compounds such as lithium aluminum hydride and sodium borohydride, and organometallic compounds such as lithium aluminum tri-tert-oxymonohydride. The halogenation in step () can be carried out in the presence of an acid using hydrogen halide, phosphorus halide, or the like. In step (), R is dehalogenated using the reagent used in step (). Next, R' is subjected to ester decomposition. For example, the above hydrogenation metals may be used for dehalogenation, and strong acids and strong alkalis may be used for ester decomposition of R'. In step (), metal cyanide salts, ammonium cyanide salts, etc. can be used. There are also reaction intermediate products with (+) coordination and (-) coordination, but it is not necessary to separate them during synthesis, and it is better to separate them at a later reaction stage.
That is, it is desirable to separate the (+) and (-) coordinations at the time of synthesizing the compound of formula (), if desired, or it may be done at the stage of synthesizing the compound of formula (). As a separation method, it may be subjected to fractional recrystallization using a suitable solvent such as a lower alcohol. In yet another embodiment, (+) or (-)-2
-Methyl-1,1'-binaphthalene-2'-carbonylnitrile. By using this reagent, an enantiomer of a compound containing a hydroxyl group and an asymmetric carbon at the bonding position is reacted with this reagent in the presence of an organic base to form a corresponding diastereomer. Provided is a separation and analysis method characterized in that chromatography is applied to separate each (+) or (-) enantiomer, followed by fluorescence analysis. The reaction between the reagent of this invention and the enantiomer of the hydroxyl group-containing compound is as follows. The reagent according to the present invention does not emit fluorescence in an unreacted state, and only emits fluorescence when it reacts with a hydroxyl group. This shows that there is no need to remove excess reagent from the reaction product, and the reaction product can be subjected to fluorescence analysis as it is. Furthermore, this reaction is characterized in that it is completed under mild conditions and in a short time, and that the reaction products and reagents do not racemize even if the reaction time is extended. 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 explained below. In addition, lower alcohols such as methanol and ethanol, 1
The reaction with primary and secondary amines is completed at room temperature. Although this active ingredient can be used as a single substance, it is preferably dissolved in an aprotic organic solvent to form a reagent. In particular, when the compound of formula () is used as a fluorescent reagent, the presence of an organic base brings about good results in the reaction with the test sample.
Preferably, an organic base is added to the reagent. Specific examples of aprotic organic solvents include chloroform, acetonitrile, benzene, ethyl acetate, tetrahydrofuran, and acetone. Among these, acetonitrile is the best. Examples of the organic base include tertiary alkyl amines such as triethylamine and trimethylamine. The quantitative ratio of aprotic organic solvent and organic base is
Approximately 1:1 is preferred. Further, the concentration of the compound of formula () in these mixtures is not particularly limited, but is, for example, 0.1 to 1%. Since this fluorescent reagent does not emit light in an unreacted state, it may be used in an excess amount relative to the test sample to cause a sufficient reaction. Therefore, a test sample is reacted with the reagent of the present invention in a precolumn, and then subjected to high performance liquid chromatography to separate each optical antipode and detected using a fluorophotometer. The excitation wavelength of the generated fluorescence is 342n
m, the irradiation wavelength is 420 nm, and the detection limit is 200 pg using high performance liquid chromatography. Next, this invention will be explained in more detail using synthesis examples and analysis examples. (e) Example 2 - Synthesis of methyl-1,1'-binaphthalene-2'-carbonylnitrile This synthesis example uses the compound of formula () as a starting material to produce intermediate products (formulas (), (), ()) This shows a method for synthesizing the reagent of the present invention through the steps shown in the following chemical formula. (a means a mixture of compounds with (+) and (-) coordination, b means a compound with (+) coordination, and c means a compound with (-) coordination.) () Methyl 2-hydroxymethyl-1 , 1'-binaphthalene-2'-carboxylate dimethyl 1,1'-binaphthalene-2,2'-dicarboxylate (2.8 g) (J.Chem.Soc.,
Lithium tri-tert-butoxy-aluminum hydride (LiAl(tert-BuO) ₃ H) (8 g) was added to a solution of anhydrous benzene (75 ml) and anhydrous ether (75 ml) mixture of
was added little by little over 2 hours. After acidifying the mixture with 5% hydrochloric acid while cooling on ice, the organic layer was separated and dried over anhydrous sodium sulfate. The organic layer was concentrated and the residue was purified by column chromatography using silica gel (50 g). The fraction eluted with hexane/ethyl acetate (4:1) was recrystallized from hexane/acetone to obtain 1 g of the compound of formula () as colorless plate crystals. The physical properties of the obtained compound were as follows. Melting point 117.5-118.5℃ NMR (CDCl ₃ ) δ: 3.52 (3H, s, -OCH ₃ ),
4.32 (2H, s, -CH ₂ -O-), 6.84-8.02 (12H,
m, Ar-H). Elemental analysis: (as C ₂₃ H ₁₈ O ₃ ) Calculated values: carbon 80.7%, hydrogen 5.26%, measured values: carbon 80.2%, hydrogen 5.28% () Methyl 2-bromomethyl-1,1'-binaphthalene-2'- Carboxylate Add 30% hydrogen bromide/acetic acid solution (5 ml) to a solution of methyl 2-hydroxymethyl-1,1'-binaphthalene-2'-carboxylate (2 g) obtained in () above in acetic acid (10 ml), Stirred at 50°C for 10 minutes. Pour the reaction solution into ice to precipitate crystals,
I took it. The crystals were purified by column chromatography using silica gel, and the fraction eluted with hexane/ethyl acetate (30:1) was recrystallized from hexane/ethyl acetate. 2.2 g of the compound of formula () was obtained as needle-like crystals. The physical properties of the obtained compound were as follows. Melting point 137-138℃ NMR (CDCl ₃ ) δ: 3.46 (3H, s, -OCH ₃ ),
4.10 (1H, d, J=14Hz, -CHBr), 4.24 (1H,
d, J = 14Hz, -CHBr), 6.90-8.20 (12H,
m, Ar-H). Elemental analysis: (as C ₂₃ H ₁₇ OBr) Calculated values: Carbon 68.1%, Hydrogen 4.20%, Measured values: Carbon 68.2%, Hydrogen 4.27% () 2-Methyl-1,1'-binaphthalene-2'-
Carboxylic acid Methyl 2-bromomethyl- obtained in () above
Dissolve 1,1'-binaphthalene-2'-carboxylate (1.9 g) in dimethyl sulfoxide (10 ml), and add sodium borohydride (0.4 g) to this.
was added and stirred at 60°C for 15 minutes. The reaction solution was poured into ice water and acidified with concentrated hydrochloric acid to precipitate crystals, which were collected. The obtained crystals were purified by column chromatography using silica gel, and the fraction eluted with hexane/ethyl acetate (10:1) was recrystallized from methanol. The methyl ester of the compound of formula (a) (1.4 g) was obtained as colorless needle-like crystals,
The physical properties of the obtained ester were as follows. Melting point 97-98℃ NMR (CDCl ₃ ) δ: 2.04 (3H, s, -OCH ₃ ),
3.44 (3H, s, −OCH ₃ ), 6.88−8.12 (12H, m,
Ar-H). Elemental analysis: (as C ₂₃ H ₁₈ O ₂ ) Calculated values: Carbon 84.6%, Hydrogen 5.56%, Measured values: Carbon 84.6%, Hydrogen 5.52% Next, add 10% water to a methanol (50 ml) solution of the obtained methyl ester. Potassium oxide aqueous solution (30
ml) was added thereto, and the mixture was heated under reflux for 3 hours. The reaction solution was poured into ice water and precipitated crystals were collected. The crystals were recrystallized from hexane/ethyl acetate to obtain a compound of formula (a) in the form of colorless needles, the physical properties of which were as follows. Melting point 232-233℃ NMR (CDCl ₃ ) δ: 1.96 (3H, s, -OCH ₃ ), 6.80-8.12 (12H, m, Ar-H) Elemental analysis: (as C ₂₂ H ₁₆ O ₂ ) Calculated value: Carbon 84.6%, Hydrogen 5.13%, Measured value: Carbon 84.3, Hydrogen 4.93% () 2-Methyl-1,1'-binaphthalene-2'-
Optical resolution of carboxylic acid A solution of anhydrous l-brucine (4.1 g) in ethanol (20 ml) was added to a solution of 2-methyl-1,1'-binaphthalene-2'-carboxylic acid (3.3 g) in ethanol (60 ml), and the mixture was heated at room temperature. I left it there overnight. The precipitated crystals were collected and 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 the (-) coordination formula (c).
The compound was obtained as colorless needle crystals, and its physical properties were as follows. Melting point 229-229.5℃ Optical rotation: [α] ²⁰ _D −41.3° (c = 0.58, chloroform) Elemental analysis: (as C ₂₂ H ₁₆ O ₂ ) Calculated values: carbon 84.6%, hydrogen 5.13%, measured values: carbon 84.3, hydrogen 5.00% The same treatment was performed on the mother liquor of recrystallization with l-brucine, and the compound of formula (b) with (+) coordination was obtained as colorless needle-like crystals, whose physical properties were as follows. . Melting point 232-233℃ Optical rotation: [α] ²⁰ _D +39.8° (c = 0.93, chloroform) Elemental analysis: Measured values: carbon 84.4%, hydrogen 5.10% () 2-Methyl-1,1'-binaphthalene- 2′−
Carbonyl nitrile 2-methyl-1,1'-binaphthalene-2'-carboxylic acid (0.5 g) in anhydrous methylene chloride (30 ml)
Oxalyl chloride (3 ml) was added to the solution and stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain a yellow oil. Dissolve this in anhydrous ethylene chloride (10ml),
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 obtain a red oil. The obtained oil was purified by column chromatography using silica gel (5 g), and the hexane eluted fraction was recrystallized from hexane/petroleum ether. Yellow needle-like compound of formula (a) (240 mg) was obtained,
Its physical properties were as follows. Melting point 109-110℃ IRν _nax (CHCl ₃ ): 2240 (C≡N), 1660 (C=
O) cm ^-1 NMR (CDCl ₃ ) δ: 2.04 (3H, s, −OCH ₃ ), 6.72−8.24 (12H, m, Ar−H) Mass spectrometry m/z: 321 (M ⁺ ) Elemental analysis: ( (As C ₂₃ H ₁₅ ON) Calculated values: Carbon 86.0%, Hydrogen 4.71%, Nitrogen 4.36
%, Measured values: Carbon 86.0%, Hydrogen 4.93%, Nitrogen 3.87
The compound (0.5 g) of formula (b) with (+) coordination obtained in % () was treated in the same manner as above,
A yellow oily compound of formula (b) was obtained, and its physical properties were as follows. Optical rotation: [α] ²⁰ _D +35.8° (c = 1.90, chloroform) Elemental analysis: Measured values: carbon 85.9%, hydrogen 4.73%, nitrogen 4.47
% In addition, the (-)-coordinated compound (0.5 g) of formula (c) obtained in () was treated in the same manner as above to obtain a yellow oily compound of formula (c), whose physical properties are as follows. It was hot. Optical rotation: [α] ²⁰ _D -42.8° (c = 1.05, chloroform) Elemental analysis: Measured values: carbon 85.9%, hydrogen 4.73%, nitrogen 4.47
% Analysis example Each of the methyl esters of 3-hydroxyoctanoic acid, 3-hydroxydecanoic acid, 3-hydroxylauric acid, 3-hydroxystearic acid, and mandelic acid was dissolved in (+)-2-methyl-1,1 in the presence of triethylamine. ′-binaphthalene-2′-
It was quantitatively reacted with carbonyl nitrile at 60°C for 20 minutes to form an ester. The reaction mixture was separated into optical antipodes using high performance liquid chromatography. For high-performance liquid chromatography, Hitachi's 650−
Waters with 10LC fluorescence detector
A 6000A solvent pump was used, and a Cosmosil 5SL column was used. As a mobile phase, a mixed solution of n-pentane/ethyl acetate (30:1) was fed at a rate of 1.0 ml/min. The separated esters were detected by fluorescence and quantitatively analyzed. The results are shown in the table below. [Table] Methyl acid ester
[Table] In the table, K' is the volume ratio, α is the separation factor, and R is the solubility factor. (f) Effects As shown in the table, it was shown that the reagent of this invention separated each enantiomer. By using the reagent of this invention, it is possible to react with enantiomers of compounds containing hydroxyl groups in the precolumn of high performance liquid chromatography, and this reagent does not emit fluorescence by itself; It is understood that since fluorescence is emitted only when it reacts with a hydroxyl group, fluorescence can be detected without removing the reagent present in excess in the reaction solution. This reagent is suitable for quantitative analysis of pharmaceuticals, e.g. β-
It can also be applied to the analysis of fine substances such as sympatholytic agents.

Claims (1)

[Claims] 1 (+) or (-)-2-methyl-1,1'-
Binaphthalene-2'-carbonylnitrile. 2 Formula (): (In the formula, R and R' are C _1-4 alkyl groups) by reducing the compound of the formula (): (in the formula, R' is the same as defined above), and then the compound of formula () is halogenated to form formula (): (In the formula, X is a halogen and R' is the same as defined above), which is dehalogenated and decomposed into esters to form the formula (): and nitrile the expression () to form the expression (): A compound of the formula A method for producing binaphthalene derivatives.