JP2001261613A - New optically-active magnetic-anisotropic reagent and method for determining optical purity and absolute configuration using the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an optically-active magnetic-anisotropic reagent having high anisotropic effects without causing racemization when derivatized in determination of an absolute configuration and a derivatizing reagent having large separation factor and capable of providing a diastereomer under a mild derivatizing condition in measurement of an optical purity using a high- performance liquid chromatography(HPLC). SOLUTION: An optically active compound having an aromatic ring and an alcohol capable of imparting high anisotropic effect and a carboxyl group capable of quantitatively reacting with an amine on quaternary carbon atom is produced.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an optically active 2-alkoxypropionic acid substituted at the 2-position with an aromatic ring, a method for producing the same, and a method for determining the optical purity and absolute configuration of optically active alcohols and amines. Things, medicines,
It is used for determining optical purity and absolute configuration required in the field to which pesticides belong and other fields.

[0002]

2. Description of the Related Art Many physiologically active substances such as drugs have compounds having an asymmetric center, and these compounds having an asymmetric center have optical isomers. And as the thalidomide example shows, the absolute configuration of a drug is extremely important. One of the enantiomers is medicinal, the other is often not, and the presence of the other enantiomer may be detrimental. In addition, hydroxyl groups are a major component of physiologically active substances, and many optically active substances having hydroxyl groups are found. Therefore, a method of obtaining only one enantiomer of the optical isomer has been actively studied. For example, as a method for synthesizing an optically active alcohol, a BINAP-Rh complex, oxazaborolidine, M
Numerous methods have been reported, such as an asymmetric reduction method of prochiral ketone using PAC or the like as a catalyst, an optical resolution method using an optically active amine after forming a half ester from an alcohol and phthalic acid. The determination of the absolute configuration and optical purity of the optically active alcohol obtained in the same way as the study of asymmetric reduction and optical resolution has been actively studied, and has become an important analytical task.

[0003] X-ray analysis, C
The D spectrum method and a method of measuring an NMR spectrum after derivatization with an optically active magnetic anisotropic reagent are mentioned. X-ray analysis requires the preparation of a large single crystal sample, which is not a simple method. Also, the measuring equipment is expensive,
It is hard to say that it is a general method. There is a demand for a simple and highly accurate absolute configuration method for optically active alcohols. N
MR is an analytical instrument that can be easily used by researchers and engineers engaged in organic synthesis to identify compounds synthesized, and is widely used. The absolute configuration method using NMR is used as a simple method. That is, in this method, the absolute configuration of the alcohol can be determined by reacting the optically active magnetic anisotropic reagent with the alcohol and then measuring the NMR to observe the chemical shift of the alcohol component. For example, an ester of (S) -α-methoxy-α-trifluoromethyl-α-phenylacetic acid (hereinafter, MTPA) and an optically active secondary alcohol has the following conformation.

[0004]

Embedded image

[0005] The benzene ring is conformed to give the secondary alcohol moiety an anisotropic effect of a high magnetic field shift.
R ¹ of the (S) -MTPA ester is (R) -MTPA
Appears at higher fields than R ^{1 of the} ester. The difference between the chemical shifts of (S) -ester and (R) -ester is represented by Δδ = δ _S −
when the [delta] _R, the positive Δδ as the following models right, negative Δδ becomes left.

[0006]

Embedded image

Here, if the alcohol whose absolute configuration is to be determined is drawn so as to match the model, it will be a correct absolute configuration. As described above, this method is used as a simple and highly general method. In this method, optically active MTPA, optically active α-methoxy-α-phenylacetic acid, optically active α-methoxy-α- (2-naphthyl) acetic acid and the like are used as optically active magnetic anisotropic reagents.

However, in the method using optically active MTPA, in the diastereomer of the ester obtained, the difference Δδ between the two chemical shifts is small, and the absolute configuration cannot be determined with high accuracy. Optically active α-methoxy-α-phenylacetic acid and optically active α-methoxy-α- (2
-Naphthyl) acetic acid has active methine and has a possibility of causing racemization upon esterification, and it is hard to say that it is a satisfactory method for determining the absolute configuration.

On the other hand, the optical purity is measured by NMR, GC, HP
Several methods using LC and the like are known. G
C, There are a chromatographic method represented by HPLC, a method using an optically active stationary phase, a method using an optically active mobile phase, and a diastereomer method. Among them, the diastereomer method is capable of separating optical isomers and detecting them. A chiral derivatization reagent having excellent separation ability and high resolution and high detection sensitivity has been reported. For example, (−) −
1- (1-naphthyl) ethyl isocyanate [K. Sa
Saki, et al. , J. et al. Chromatog
r. , 585 , 117 (1991)], (+)-or (-)-2-methyl-1,1'-binaphthalene-2 '.
-Carbonyl cyanide [J. Goto, et al. ,
Anal. Sci. , 6 , 261 (1990)].

However, the diastereomer method using the above-mentioned optically active derivatizing reagent has high sensitivity, but the reaction conditions for diastereomer formation are relatively severe. In addition, dissatisfaction also remains regarding the separation between diastereomers, and it is difficult to say that this is a very satisfactory method for measuring optical purity.

[0011]

In determining the absolute configuration, there is a demand for an optically active magnetic anisotropic reagent which has a high anisotropy effect and does not cause racemization during derivatization.
In the measurement of optical purity using HPLC, a derivatization reagent capable of forming a diastereomer under a large degree of separation and mild derivatization conditions is desired.

[0012]

Means for Solving the Problems Accordingly, the inventor has conducted intensive studies and, as a result, completed the present invention. That is, a representative compound of the present invention has the following structural formula

[0013]

Embedded image

(Where R is an alkyl group, which may be substituted): an optically active 2-alkoxy-2- (1-naphthyl) propionic acid represented by the following formula: The method includes a method for determining the absolute configuration and optical purity of an optically active alcohol or amine using 2-alkoxy-2- (1-naphthyl) propionic acid. Among the compounds represented by the above structural formula according to the present invention, 2-methoxy-2- (1-naphthyl) propionic acid (hereinafter referred to as MαN
P) is a known compound, and its production method is to react Pyruvic acid with 1-naphthylmagnesium bromide, and then perform methylation and hydrolysis to obtain MαNP.
Is synthesized and (-)-MαNP is obtained by crystallizing this MαNP with (+)-α-methylbenzylamine [J. Goto, et al. Chem. Phar
m. Bull. , 25 , 849 (1977)]. However, this method avoids enantiomer contamination. The value is far from that of, it is hard to say that it is a pure product.
Further, in this document, the absolute arrangement is not determined.
The inventors of the present invention clarified the relationship between the absolute configuration and the optical rotation for the first time, and found a method for obtaining optically active MαNP at an optical purity of 100%. Pure (S)-(+)-MαNP and (R)-(−)-which the inventors can use for the first time to determine the absolute configuration of an optically active alcohol and the like and to measure the optical purity.
This means that MαNP was provided. Therefore, the compounds of the present invention (S)-(+)-MαNP and (R)-(−)-
MαNP is a novel substance.

The following is a preferred specific example of (S) -Mα
The method for producing NP and (R) -MαNP, the absolute configuration of optically active 2-butanol, and the method for determining optical purity will be described, but the present invention is not limited thereto.

MαNP is reacted with natural (-)-menthol in the presence of a condensing agent to form an ester. The diastereomer of this ester is separated by HPLC and then hydrolyzed to give an optical purity of 100%.
(S) -MαNP and (R) -MαNP can be obtained. In this step, DCC is used as a condensing agent.
-DMAP, triphenylphosphine-diethylazodicarboxylate, triphenylphosphine-2,2 '
-Dipyridyl disulfide, diphenylphosphoryl azide and the like. The solvent that can be used is appropriately selected from methylene chloride, toluene, THF, ethyl ether, or a mixed solvent thereof. Reaction temperature is -80 ° C
To 110 ° C, preferably from 0 ° C to 3 ° C.
Selected between 0 ° C.

(+)-2-butanol and (S) -MαN
P and (R) -MαNP were reacted to form (S) -ester and (R) -ester. The ¹ H NMR spectrum of each diastereomer was measured, the chemical shift of the alcohol component was measured, and Δδ ( = Δ _R −δ _S , p
pm) is obtained as follows.

[0018]

Embedded image

When the protons exhibiting a positive Δδ are drawn on the right side, the result is as described above. Therefore, (+)-2-butanol can be determined to be the (S) -form. As described above, a large Δδ is obtained by the method for determining the absolute configuration using the compounds (S) -MαNP and (R) -MαNP of the present invention. In addition, racemization does not occur during esterification,
Highly accurate measurement is possible.

(R) -MαNP or (S) -Mα
When an ester is formed from one of the NPs and 2-butanol, and the obtained ester is separated by HPLC, diastereomers can be separated with a separation coefficient α = 1.15 and a resolution Rs = 1.18. For example, this optically active Mα
When the optical purity of (S)-(+)-2-butanol as a commercial product was measured by a method using NP, it was 90 to 93%.
Was between.

[0021]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Preferred embodiments of the present invention will be described below, but these are for the purpose of illustration and do not limit the present invention. It will be apparent to those skilled in the art that variations are possible within the scope of the invention.

Example 1 Optical Resolution of MαNP 0.974 g of MαNP and (1R, 3R, 4S) −
0.793 g of (-)-menthol was added to 4.3 methylene chloride.
and 1.48 g of DCC and 0.2 DMAP.
Add 58 g and stir at room temperature for 21 hours to produce the ester. The methylene chloride solution containing this ester was injected into HPLC under the following conditions, and after 17.3 minutes, (S) -MαNP
The ester eluted and the (R) -MαNP ester eluted after 21.8 minutes. Each of these was separated. HPLC conditions Apparatus: HPLC Tosoh CCPP-D Column: silica gel Inner diameter: 22 mm Length: 300 mm Eluent: hexane: ethyl acetate (10: 1) Flow rate: 8 ml / min

At this time, the separation coefficient was α = 1.83, and the degree of separation was Rs = 4.55. These were separated, hydrolyzed in the presence of sodium methoxide, and precipitated by adding dilute hydrochloric acid to obtain 0.421 g of (S) -MαNP or 0.417 g of (R) -MαNP. The properties of each are as follows.

Properties of (S) -MαNP 2991, 942, 1717, 1601, 1510,
1459, 1242, 1141, 1100, 1050,
911, 780, 730 cm ^-1 ; ¹ H NMR (40
0 MHz, deuterated chloroform) δ 2.04 (3H, s),
3.09 (3H, s), 7.45-7.51 (3H,
m), 7.63 (1H, dd, J = 7.3, 1.0H
z), 7.86-7.88 (1H, m), 7.87 (1
H, d, J = 9.0 Hz), 8.22-8.24 (1
H, m); Elemental analysis value (%) C72.96, H6.24
[Theoretical value of C ₁₄ H ₁₄ O ₃ C 73.03, H 6.1
3]

Physical properties of (R) -MαNP 2991, 942, 1717, 1601, 1510,
1459, 1242, 1141, 1100, 1050,
911, 780, 730 cm ^-1 ; ¹ H NMR (40
0 MHz, deuterated chloroform) δ 2.04 (3H, s),
3.09 (3H, s), 7.45-7.51 (3H,
m), 7.63 (1H, dd, J = 7.3, 1.0H
z), 7.86-7.88 (1H, m), 7.87 (1
H, d, J = 9.0 Hz), 8.22-8.24 (1
H, m); Elemental analysis value (%) C72.96, H6.24
[Theoretical value of C ₁₄ H ₁₄ O ₃ C 73.03, H 6.1
3]

Example 2 Determination of absolute configuration of (+)-2-butanol 62.2 mg of (S) -MαNP and 10 mg of (+)-2-butanol were dissolved in 0.27 ml of methylene chloride.
Add 61.2 mg of DCC and 8.1 mg of DMAP,
Stir at room temperature for 24 hours. After treatment with a small amount of water, add magnesium sulfate to the organic phase, dehydrate, and filter. The methylene chloride was removed from the solution under reduced pressure to obtain (S) -MαNP ester 32.3 mg. Similarly, using (R) -MαNP, 30.0 mg of (R) -MαNP ester was obtained.
¹ H NMR was measured, and Δδ was determined from the chemical shift of the alcohol component. The results are shown in the table.

[0027]

[Table 1] (Δ _R is the chemical shift of (R) -MαNP ester, δ _S
Indicates the chemical shift of (S) -MαNP ester, and Δδ
It is expressed in δ _R -δ _S)

As described below, the absolute configuration of the alcohol component can be considered to be A or B.

[0029]

Embedded image

If the plus of Δδ is drawn on the right, the correct absolute configuration is obtained. Therefore, (+)-2-butanol could be determined to be the (S) -form in the absolute configuration of A.

Example 3 Measurement of Optical Purity by HPLC (S) -MαNP 62.2 mg and 2-butanol 10
mg was dissolved in 0.27 ml of methylene chloride, and DCC
Add 61.2 mg and 8.1 mg of DMAP, and add 2 mg at room temperature.
Stir for 4 hours to produce the ester. Then, the reaction solution is treated with a small amount of water, magnesium sulfate is added to the organic phase, and the organic phase is dehydrated and filtered. The solution was concentrated to obtain an HPLC sample. HPLC conditions are as follows. HPLC conditions Column: Silica gel Inner diameter 22 mm Length 300 mm Eluent: Hexane: ethyl acetate (10: 1) Flow rate: 8 ml / min Detector: UV 254 nm

When the obtained ester was separated by HPLC under the above conditions, two diastereomers could be sufficiently separated. At this time, the separation coefficient α = 1.15 and the degree of separation Rs = 1.18 were obtained.

[0033]

As described above, the compound of the present invention has a naphthalene ring, a methyl group, a methoxy group, and a hydroxyl group on a quaternary carbon atom.
An optically active compound having a carboxyl group that reacts quantitatively with an amino group and has no active hydrogen. Therefore, racemization does not occur during derivatization. The process for producing optically active MαNP according to the present invention comprises reacting natural l-menthol with racemic MαNP to form an ester, separating the diastereomer of this ester by HPLC, and then hydrolyzing it. is there. Therefore, (S)-and (R) -MαNP can be simultaneously produced with an optical purity of 100%. In the determination of the optical purity or the absolute configuration of an optically active compound using a derivatization reagent, the optical purity of the derivatization reagent and the progress of racemization in the derivatization reaction greatly affect the measurement accuracy. The present invention is a derivatization reagent having an optical purity of 100% and does not cause racemization in the derivatization reaction. Therefore, the absolute configuration and optical purity of the optically active compound can be measured with extremely high accuracy.
Moreover, it is a simple method.

As described above, the present invention can precisely and easily determine the optical purity and absolute configuration of an optically active compound, which are important issues in the development and research of pharmaceuticals, agricultural chemicals, functional materials, and the like. This is a useful invention.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Yusuke Kasai 3-3-1, Yawata 3-chome, Aoba-ku, Sendai, Miyagi F-term (reference) 4H006 AA01 AA02 AC83 AD15 AD17 BB11 BC10 BC19 BJ50 BP10 BS30

Claims (7)

[Claims] (1) The following structural formula: (However, R is an alkyl group and may be substituted. Ar is an aromatic ring and may be substituted.) 2. Ar is a 1-naphthyl group, a 2-naphthyl group,
The compound according to claim 1, wherein one kind is selected from an anthracen-9-yl group and a phenyl group. 3. A 2-alkoxy-2- (1-naphthyl) propionic acid is reacted with (1R, 3R, 4S)-(-)-menthol to produce an ester derivative, and a diastereomer is separated by HPLC. (S) -2-alkoxy-2- (1-naphthyl) propionic acid or (R) -2-alkoxy-2-
A method for producing (1-naphthyl) propionic acid. 4. An (S) -2-alkoxy-2- (1-naphthyl) propionic acid and (R) -2-alkoxy-
A method for determining the absolute configuration of an optically active alcohol, comprising reacting 2- (1-naphthyl) propionic acid with an optically active alcohol to lead to an ester derivative, and measuring NMR of each ester derivative. 5. An (S) -2-alkoxy-2- (1-naphthyl) propionic acid and (R) -2-alkoxy-
A method for determining the absolute configuration of an optically active amine, comprising reacting 2- (1-naphthyl) propionic acid with an optically active amine to lead to an amide derivative, and measuring NMR of each amide derivative. 6. An optically active alcohol comprising one of (S) -2-alkoxy-2- (1-naphthyl) propionic acid and (R) -2-alkoxy-2- (1-naphthyl) propionic acid. A method for determining the optical purity of an optically active alcohol, comprising reacting it to an ester derivative, and separating and detecting the derivative by HPLC. 7. An optically active amine comprising either (S) -2-alkoxy-2- (1-naphthyl) propionic acid or (R) -2-alkoxy-2- (1-naphthyl) propionic acid. The reaction is led to an amide derivative,
A method for determining the optical purity of an optically active amine, comprising separation and detection by PLC.