JPH11322668A - Optical resolution of 1,1'-binaphthyl-2, 2'-dicarboxylic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for optically resolving the subject compound useful as an intermediate for synthesizing a chiral ketone compound, by allowing a specified chiral compound to act on a specified racemic compound and then separating and collecting one of the diastereomeric salts by making use of the difference between the solubilities of the salts. SOLUTION: This method for optically resolving the 1,1'-binaphthyl-2,2'- dicaboxylic acid comprises allowing a chiral 1-cyclohexyl ethylamine of formula II (* exhibits to have chirality) or its salt to act on racemic 1,1'- binaphthyl-2,2'-dicarboxylic acid of formula I or its salt in a solvent such as methanol and then separating and collecting one from two kinds of the produced diastereomic salts by making use of the difference between the solubilities of both the diastereomeric salts. The compound of formula II is preferably used in an amount of 1.0-2.0 mol per mol of the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a formula

[0002]

Embedded image

The present invention relates to a method for optical resolution of racemic 1,1′-binaphthyl-2,2′-dicarboxylic acid represented by

[0004] Equations obtained by optical resolution

[0005]

Embedded image

(** represents that there is axial chirality.) Chiral 1,1'-binaphthyl-2,
2′-dicarboxylic acid is a compound used in an asymmetric epoxidation reaction of a compound having a carbon-carbon double bond.

[0007]

Embedded image

(Alk represents a lower alkylene group; **
Has the same meaning as described above. ) Is a key intermediate for producing the chiral ketone compound represented by the formula (1).

[0009]

2. Description of the Related Art The Journal of American Chemical Society (The Journal of American Chemical Society)
the American Chemical Soc
iey), Vol. 118, pp. 491-492 (1996)
Year) has the formula

[0010]

Embedded image

(** has the same meaning as above) and a chiral ketone compound and oxone <Chemical composition:
_{2KHSO 5 · KHSO 4 · K 2} SO 4, using a DuPont>, if asymmetric epoxidation of the double bond of the transformer stilbene, at room temperature, in a short time, high optical purity oxirane compound KoOsamu rate Is obtained.

Also, Journal of American Chemical Society, Vol. 118, 1311-1.
On page 1312 (1996), the chiral ketone compound [4 ** '] has the formula

[0013]

Embedded image

(** has the same meaning as described above.) It has been suggested that the compound becomes a dioxirane compound and asymmetric epoxidation occurs.
No. pp. 460 (1996) describes that this method is expected to be applied to various asymmetric oxidation reactions.

Journal of American Chemical Society, Vol. 118, pp. 491-492 (1
Supplementary Materials (Supp. 996)
elementary Material) includes a chiral 1,1′-binaphthyl-2,2′-dicarboxylic acid [1 *
*] And 1,3-dihydroxyacetone in anhydrous acetonitrile in the presence of 2-chloro-1-methylpyridinium iodide to give a chiral ketone compound [4
** '].

In this document, the expression

[0017]

Embedded image

As a method for resolving racemic 1,1'-binaphthyl-2,2'-dicarboxylic acid represented by the following formula, Journal of the Chemical Society (Jou
rnalof the Chemical Society
ty) 1242-1251 (1955) and Bulletin of the Chemical Society of
Japan (Bulletin of the Chem)
Ial Society of Japan) No. 61
Volume, pages 1032 to 1034 (1988).

The former has four chiral centers and is a high molecular weight alkaloid of the formula

[0020]

Embedded image

Anhydrous quinine represented by the formula:
There is described a method in which 1′-binaphthyl-2,2′-dicarboxylic acid [1] is reacted in an equimolar manner in ethanol, ether is added to the reaction solution, and the solution is separated based on the difference in solubility of diastereomeric salts. This step was long and complicated.

The latter has six asymmetric centers,
Formulas that are high molecular weight alkaloids

[0023]

Embedded image

Anhydrous brucine represented by the following formula:
1′-binaphthyl-2,2′-dicarboxylic acid [1] is reacted in equimolar with acetone, the reaction solution is cooled to obtain a salt having low solubility, and this salt is dissolved in methanol. A method for obtaining a diastereomer salt by adding and cooling is described, but anhydrous brucine is highly toxic and cannot be used for industrial production.

[0025]

DISCLOSURE OF THE INVENTION The present invention relates to a chiral 1,1 which is a synthetic intermediate of a chiral ketone compound [4 **].
It is intended to provide an industrially advantageous production method of 1'-binaphthyl-2,2'-dicarboxylic acid [1 **].

[0026]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that chiral 1-cyclohexylethylamine [2 *] having a small molecular weight and having only one asymmetric center or a salt thereof is used. , Racemic 1,1'-binaphthyl-
It has been found that 2,2'-dicarboxylic acid [1] or a salt thereof can be resolved, and the present invention has been completed.

That is, the present invention provides the following formula:

[0028]

Embedded image

The racemic 1,1'-binaphthyl-2,2'-dicarboxylic acid or a salt thereof represented by the formula

[0030]

Embedded image

(* Indicates that there is chirality.)
Wherein a chiral 1-cyclohexylethylamine or a salt thereof is acted on, and one diastereomer salt is separated and collected by utilizing the difference in solubility between the two generated diastereomeric salts. The present invention relates to a method for optical resolution of type 1,1′-binaphthyl-2,2′-dicarboxylic acid [1].

Racemic 1,1'-binaphthyl-2,2'-
Dicarboxylic acid [1] has the formula

[0033]

Embedded image

(R) -form represented by the formula:

[0035]

Embedded image

It is sufficient that the (R) -form is contained in any ratio, as well as the (R) -form and the (S) -form in equal amounts. A (S) -isomer may be included, but it is preferable to use an (R) -isomer and an (S) -isomer which are easily available by chemical synthesis.

Racemic 1,1'-binaphthyl-2,2'-
As the salt of the dicarboxylic acid [1], any conventional salt of a carboxylic acid can be used, and an alkali metal salt (for example, sodium salt, potassium salt), an alkaline earth metal salt (for example, magnesium salt, Calcium salts), organic amine salts (eg, benzylamine salts, methylamine salts, ethylamine salts), ammonium salts and the like, and generally, racemic 1,1′-binaphthyl-2,2′- It is preferred to use the dicarboxylic acid [1] in the form of the free acid.

The chiral 1-cyclohexylethylamine [2 *] is represented by the formula

[0039]

Embedded image

(R) -form represented by the formula or a formula

[0041]

Embedded image

There is a (S) -form represented by the following formula, and all isomers are commercially available. By using any one of these isomers, racemic 1,1'-binaphthyl-
Optical resolution of 2,2′-dicarboxylic acid [1] can be performed.

More specifically, when (R) -1-cyclohexylethylamine [2-R] or a salt thereof is used, (R) -1,1′-binaphthyl-2,2′-dicarboxylic acid [1-R] R] forms a sparingly soluble diastereomer salt, and (S) -1-cyclohexylethylamine [2-
When [S] or a salt thereof is used, (S) -1,1′-binaphthyl-2,2′-dicarboxylic acid [1-S] forms a sparingly soluble diastereomer salt.

Therefore, the chiral 1,1′-binaphthyl-2,2′-dicarboxylic acid [1 **] having the desired chirality can appropriately adjust the chirality of the chiral 1-cyclohexylethylamine [2 *]. By choosing
It can be obtained efficiently.

As the salt of chiral 1-cyclohexylethylamine [2 *], any of the conventional salts of amine compounds can be used. For example, mineral salts (eg, hydrochloride, nitrate, sulfate, Phosphate, hydrobromide), organic acid [e.g., organic sulfonate (methanesulfonate, p-toluenesulfonate, etc.), organic carboxylate (acetate, fumarate, phthalic acid) Salt)], but it is preferable to use chiral 1-cyclohexylethylamine [2 *] in a free form.

The chiral 1-cyclohexylethylamine [2 *] or a salt thereof is desirably optically pure, but has an optical purity of 90% or more, particularly, an optical purity of 95% or more. Any one can be suitably used for the purpose of the present invention.

[0047]

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the optical splitting method of the present invention,
In order for chiral 1-cyclohexylethylamine [2 *] or a salt thereof to act on racemic 1,1'-binaphthyl-2,2'-dicarboxylic acid [1] or a salt thereof, both compounds are dissolved in an appropriate solvent. Can be performed.

Examples of the solvent include racemic 1,1'-binaphthyl-2,2'-dicarboxylic acid [1] or a salt thereof, and chiral 1-cyclohexylethylamine [2 *].
Alternatively, any solvent may be used as long as it dissolves one or both of its salts.

When only one of them is dissolved, the action is a solid-liquid (including a suspension), and when both are dissolved, the action is in a solution. From the viewpoint of the action efficiency, it is preferable to use a solvent that dissolves both and produces an action in a solution.

The reaction in the solution is carried out in one solvent phase by using racemic 1,1'-binaphthyl-2,2'-dicarboxylic acid [1] or a salt thereof and chiral 1-cyclohexylethylamine [2 *] or It is not limited to the case where the salt is dissolved and allowed to act in a single phase, and the racemic 1,1′-
Binaphthyl-2,2'-dicarboxylic acid [1] or a salt thereof and chiral 1-cyclohexylethylamine [2 *] or a salt thereof may be dissolved and act on the interface.

When acting at the interface, a surfactant (for example, sodium alkylbenzenesulfonate) and a phase transfer catalyst (for example,
Quaternary ammonium salts such as tetraethylammonium chloride and tetrabutylammonium bromide, and crown ethers such as 18-crown-6).

Specific examples of such solvents include water, alcohol solvents (eg, methanol, ethanol, propanol, isopropanol), ketone solvents (eg,
Acetone, 2-butanone, methyl isobutyl ketone),
Ester solvents (eg, ethyl acetate), aromatic hydrocarbon solvents (eg, benzene, toluene, xylene),
Halogenated hydrocarbon solvents (eg, methylene chloride, chloroform), saturated aliphatic hydrocarbon solvents (eg, hexane, cyclohexane), amide solvents (eg, dimethylformamide, diethylformamide, dimethylacetamide), ether solvents ( For example, diethyl ether, tetrahydrofuran, 1,4-dioxane),
Sulfoxide solvents (eg, dimethyl sulfoxide)
And the like.

These solvents may be used alone or, if necessary, in a mixture of two or more kinds of solvents at an appropriate ratio. Particularly, water and an alcohol solvent (methanol,
It is preferable to use a mixture of ethanol and the like.

The amount of the chiral 1-cyclohexylethylamine [2 *] or a salt thereof used in the present invention is not particularly limited, but the diastereomer salt to be formed is chiral 1-cyclohexylethylamine [2 *]. Or the salt thereof, and specifically, chiral 1,
1'-binaphthyl-2,2'-dicarboxylic acid [1 **] 1
The salt is formed in a proportion of 1 to 2 mol of chiral 1-cyclohexylethylamine [2 *] per mol.

Any of the salts can be used for optical resolution, but in particular, chiral 1,1′-binaphthyl-
Since a salt formed in a ratio of 2 mol of chiral 1-cyclohexylethylamine [2 *] to 1 mol of 2,2'-dicarboxylic acid [1 **] is preferable, racemic 1,1 '
-Binaphthyl-2,2'-dicarboxylic acid [1] or a salt thereof is mixed with 0.8 to 2.5 moles of chiral 1-cyclohexylethylamine [2 *] or a salt thereof, particularly 1.0 to 2. It is preferable to make 0 mol act.

Racemic 1,1'-binaphthyl-
If 2 mol or less of chiral 1-cyclohexylethylamine [2 *] or a salt thereof is allowed to act on 1 mol of 2,2′-dicarboxylic acid [1] or a salt thereof,
An achiral base may be added.

As the achiral base, a conventional base can be used. For example, an inorganic base [eg,
Alkali metal hydroxide (lithium hydroxide, sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxide (magnesium hydroxide, calcium hydroxide, barium hydroxide)], organic base [for example, organic amine (dimethylamine, Methylamine, ethylamine, etc.]], but it is preferable to use an organic amine, and particularly preferable to use dimethylamine.

In the present invention, the diastereomer salt formed can be separated by utilizing the difference in solubility between the two diastereomeric salts. That is, one diastereomer salt is precipitated from the solvent and separated from the other diastereomer salt.

Such separation is carried out when a racemic 1,1′-binaphthyl-2,2′-dicarboxylic acid [1] or a salt thereof is allowed to react with a chiral 1-cyclohexylethylamine [2 *] or a salt thereof. The reaction may be performed in the same solvent as the solvent used, or may be performed after the solvent system is once changed.

The method of changing the solvent system may be any conventional method. For example, (a) racemic 1,1′-binaphthyl-2,2′-dicarboxylic acid [1] or a salt thereof which is chiral to its salt -A method in which a solvent is further added to the solvent used when cyclohexylethylamine [2 *] or a salt thereof is allowed to act, (b) a method in which the solvent is completely distilled off, and then the solvent is newly added, (c) ) A method of extracting a diastereomer salt with a solvent which is easily dissolved, and further adding a solvent as necessary.

As a solvent for separating the two diastereomeric salts, a diastereomeric salt of 1,1′-binaphthyl-2,2′-dicarboxylic acid having one chirality and a chirality of the other have a chirality of 1,1′-binaphthyl-2,2′-dicarboxylic acid. Any solvent may be used as long as it has a large difference in the solubility of the diastereomeric salt of 1,1′-binaphthyl-2,2′-dicarboxylic acid.

In particular, the difference between the solubility of one diastereomer salt having chirality at high temperature and the temperature at low temperature is more than that of the other diastereomer salt having chirality at high temperature and at low temperature. It is preferable to use a remarkably large solvent because the separation can be efficiently performed only by a change in the temperature of the solution.

Examples of such a solvent include alcohol solvents (eg, methanol, ethanol, propanol,
A mixed solvent of a solvent that easily dissolves diastereomeric salts such as isopropanol) and a solvent that hardly dissolves diastereomeric salts such as water can be used. Particularly, an alcohol-based solvent (eg, methanol) and water can be used. 4: 1
It is preferred to use solvents mixed at 〜1: 4.

The amount of the solvent is not particularly limited as long as the diastereomer salt having one of the chirality can be separated.
Preferably 20 liters, especially 4-12
It is preferably liter.

The racemic 1,1'-binaphthyl-
In the case where a salt of 2,2′-dicarboxylic acid [1] or a salt of chiral 1-cyclohexylethylamine [2 *] is used, if necessary, separation using a difference in partition coefficient with respect to a solvent may be performed. After removing by-product salts, acids, bases, and the like, diastereomeric salts may be separated and collected.

In the present invention, as a method of precipitating a sparingly soluble diastereomer salt from a diastereomer salt solution, there is a method of changing the temperature of the diastereomer salt solution to carry out the method.

Specifically, after preparing a diastereomer salt solution at an appropriate temperature, the temperature is lowered, whereby a sparingly soluble diastereomer salt can be precipitated.

The temperature conditions in the optical resolution method of the present invention are not particularly limited, and include a temperature range from the freezing point to the boiling point of the solvent to be used. A preferred example is racemic 1,1′-binaphthyl. After reacting -2,2'-dicarboxylic acid [1] or a salt thereof with chiral 1-cyclohexylethylamine [2 *] or a salt thereof at normal temperature to heating, lower the temperature, and then cool to heat. To precipitate a sparingly soluble diastereomer salt.

When precipitating a sparingly soluble diastereomer salt, the solution may be left standing or stirred, but if the precipitation is carried out under stirring, the temperature at each part in the solution may be reduced. Since the difference can be minimized, even if the temperature of the solution is lowered relatively quickly, it is industrially preferable in that a highly pure diastereomer salt can be precipitated.

The other diastereomer salt having high solubility is also separated by removing the solvent in a solution state and then distilling off the solvent or adding a solvent having low solubility for the diastereomer salt to cause precipitation. Other salts (eg, ammonium chloride) can be added to improve the amount of diastereomeric salt precipitated.

Further, in the present invention, the insoluble diastereomer salt is easily precipitated from the reaction solution, so that it is not necessary to inoculate the salt. However, in order to facilitate the precipitation, if necessary, under an appropriate temperature condition, Crystals of the same type as the desired diastereomer salt may be inoculated.

The crystals of the hardly soluble diastereomer salt precipitated from the reaction solution can be collected by a conventional method, for example, by a solid-liquid separation method such as decantation, filtration and centrifugation. be able to.

Although the obtained crystals of the sparingly soluble diastereomer salt have sufficiently high purity as they are, the purity can be further increased by recrystallization as needed.

The diastereomer salt thus separated and collected can be converted into a free acid by salt decomposition or a salt other than the diastereomer salt by salt exchange.
That is, it can be converted to a free acid by a known method (for example, acid treatment), or can be obtained by a known method (for example, base treatment).
Can convert to salts other than diastereomeric salts. Such salts include, for example, sodium salts,
Alkali metal salts such as potassium salts; ammonium salts; organic base salts such as methyl ammonium salts and benzyl ammonium salts.

The chiral 1-cyclohexylethylamine [2 *] or a salt thereof, which is an optical resolving agent, can be recovered from the mother liquor after salt decomposition by an ordinary method and reused.

The raw material used in the present invention, racemic 1,1′-binaphthyl-2,2′-dicarboxylic acid [1]
Can be easily obtained, for example, according to the method described in Journal of the Chemical Society, pp. 1242-1251 (1955).

The thus obtained chiral 1,1′-binaphthyl-2,2′-dicarboxylic acid [1 **] or a salt thereof is converted, if necessary, into a reactive derivative.

[0078]

Embedded image

(Alk has the same meaning as described above) by reacting with a dihydroxyketone compound represented by the formula

[0080]

Embedded image

(** and Alk have the same meanings as described above) can be produced.

The dimer of the dihydroxyketone compound [3] is represented by the formula

[0083]

Embedded image

(Alk has the same meaning as described above).

As Alk, a linear or branched alkylene group having 1 to 6 carbon atoms which may be substituted can be mentioned. As a linear or branched alkylene group,
Examples of the substituent include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a methylmethylene group, a methylethylene group, and an ethylethylene group, and the substituent is a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. , A sulfinyl group, a sulfonyl group, a hydroxy group, a nitro group, a nitrile group and the like. Of these, an unsubstituted alkylene group, particularly a methylene group, is preferred.

Chiral 1,1'-binaphthyl-2,2'-
The reaction of dicarboxylic acid [1 **] or a salt thereof with dihydroxyketone compound [3] or a dimer thereof can be carried out in a suitable solvent in the presence of a dehydrating agent according to a conventional method for ester synthesis. it can.

Solvents used in such a reaction include nitrile solvents such as acetonitrile, amide solvents such as dimethylformamide, ether solvents such as tetrahydrofuran, and optionally halogenated aliphatic hydrocarbon solvents such as dichloromethane. Aromatic hydrocarbon solvents such as toluene and xylene can be used.

Examples of the dehydrating agent include conventional dehydrating agents such as N, N'-dicyclohexylcarbodiimide (DCC), DCC and 1-hydroxybenzotriazole, and azodicarboxylic acid diester.

The reaction can be carried out at -10 to 100 ° C, particularly preferably at 0 to 70 ° C.

Further, chiral 1,1′-binaphthyl-
The 2,2′-dicarboxylic acid [1 **] is reacted with a conventional activator to form a reactive derivative in advance, and then is reacted with a dihydroxyketone compound [3] or a dimer thereof in an appropriate solvent. The reaction may be performed in the presence of a deoxidizing agent.

Examples of the activator include halogenating agents such as thionyl chloride, thionyl bromide, oxalyl chloride, N-chlorosuccinic chloride, and N-bromosuccinimide; p-toluenesulfonic acid chloride, benzenesulfonic acid chloride, and methanesulfonic acid. Sulfonating agents such as acid chloride; mixed acid anhydride forming agents such as isobutyl chlorocarbonate, 2,6-dichlorobenzoic chloride, and 2,4,6-trichlorobenzoic chloride; N-methyl-2-chloropyridinium iodide And the like.

Chiral 1,1'-binaphthyl-2,2'-
Dicarboxylic acid [1 **] forms a reactive derivative by reacting with an activating agent in a suitable solvent in the presence or absence of a base such as pyridine, triethylamine, N-methylmorpholine or the like. be able to.

Solvents used in such a reaction include nitrile solvents such as acetonitrile, amide solvents such as dimethylformamide, ether solvents such as tetrahydrofuran, and optionally halogenated aliphatic hydrocarbon solvents such as dichloromethane and chloroform. Solvents and aromatic hydrocarbon solvents such as toluene and xylene can be used.

The reaction can be carried out at -10 to 100 ° C, particularly preferably at 0 to 70 ° C.

The reaction between the thus obtained reactive derivative of chiral 1,1′-binaphthyl-2,2′-dicarboxylic acid [1 **] and dihydroxyketone compound [3] or a dimer thereof is carried out by deoxidation. In the presence of the agent, it can be performed using the same solvent as the solvent used when forming the reactive derivative,
The reaction is preferably performed at -10 to 150C, particularly preferably at 0 to 100C.

As the deoxidizing agent, triethylamine, N-
Conventional deoxidizing agents such as methylmorpholine can be used.

Furthermore, chiral 1,1'-binaphthyl-
Conversion of 2,2′-dicarboxylic acid [1 **] or a salt thereof to a reactive derivative, and reaction of the reactive derivative with a dihydroxyketone compound [3] or a dimer thereof are performed in the same reaction system. And a chiral 1,1′-binaphthyl-2,2′-dicarboxylic acid [1 **] or a salt thereof,
The reaction can be advanced by simply adding the dihydroxyketone compound [3] or a dimer thereof, a conventional activator, and a base to a solvent and heating.

The chiral ketone compound [4 **] thus obtained can be widely used for various asymmetric epoxidation reactions of carbon-carbon double bonds. For example, in the presence of an oxidizing agent such as oxone, If applied to cinnamic acid derivatives,
An optically active phenylglycidic acid derivative useful as a synthetic intermediate of an optically active 1,5-benzothiazepine derivative can be produced (WO 98/56762).

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.

[0100]

EXAMPLES Example 1 (1) Racemic 1,1'-binaphthyl-2,2'-dicarboxylic acid (685 mg, 2 mmol) and (R) -1-cyclohexylethylamine (509 mg, 4 mmol)
Was dissolved in methanol (5 ml) by heating, and water (5
ml) and allowed to cool under stirring. After cooling to 25 ° C., the mixture is further stirred at the same temperature for 1 hour to precipitate crystals. The precipitated crystals were collected by filtration, washed with a small amount of 50% methanol, and dried by blowing at 60 ° C. to give (R) -1,1′-binaphthyl-
This gives 2,2′-dicarboxylic acid di (R) -1-cyclohexylethylamine (449 mg, 37.6%).

M. p. 169-172 ° C. [α] _D ²⁵ : + 13.0 ° (c = 1.0, methanol) Diastereomeric excess (HPLC): 99.1% de IR (cm ⁻¹ ): 2925, 1580, 1550 , 13
90 1H-NMR δ (DMSO-d ₆ , ppm): 0.8
-1.3 (m, 12H), 0.99 (d, 6H), 1.
5-1.8 (m, 10H), 2.75 (m, 2H),
6.71 (d, 2H), 7.23 (t, 2H), 7.4
6 (t, 2H), 7.65 (d, 2H), 8.02
(T, 4H).

The diastereomer excess (% de)
Is a high performance liquid chromatography (HPL) under the following conditions.
C) (hereinafter, the same applies to the optical purity).

Column: DAICEL CHIRALCE
L OD 4.6 × 250 mm Mobile phase: n-hexane / ethanol / trifluoroacetic acid = 90/10 // 0.1 Flow rate: 1.0 ml / min Detection wavelength: UV-254 nm Temperature: 35 ° C.

(2) (R) -1,1'-binaphthyl-
2,2′-Dicarboxylic acid di (R) -1-cyclohexylethylamine (298 mg, 0.5 mmol) was suspended in ethyl acetate (5 ml), and 0.5N hydrochloric acid (5 ml) was added to separate the ethyl acetate layer. I do. The obtained ethyl acetate layer was washed with water, concentrated, and the concentrated residue was dried at 80 ° C. to give (R) -1,1′-binaphthyl-2,2′-
Obtain the dicarboxylic acid (171 mg, quantitative).

[Α] _D ²⁵ : + 39.5 ° (c = 1.0, methanol) Optical purity (HPLC): 99.1% ee IR (cm ⁻¹ ): 3065, 1695, 1250 1H-NMR δ ( _{DMSO-d 6, ppm):} 6.8
8 (d, 2H), 7.28 (t, 2H), 7.55
(T, 2H), 8.05 (d, 2H), 8.09 (s,
4H).

Examples 2-3 According to the methods of Examples 1 (1) and (2), racemic 1,1'-binaphthyl-2,2'-dicarboxylic acid was converted to a chiral compound under the conditions shown in Table 1. Optical resolution is performed using 1-cyclohexylethylamine.

Table 1 also shows the results of the analysis of the obtained diastereomeric salts under the above-mentioned HPLC conditions.

[0108]

[Table 1]

A) 1 mol of 1,1'-binaphthyl-2,2'-dicarboxylic acid is used in an amount of 2 mol. B) 1,1'-binaphthyl-2,2'-dicarboxylic acid 1
Solvent amount per g c) Yield based on racemate d) Analysis result by HPLC

Example 4 Racemic 1,1'-binaphthyl-2,2'-dicarboxylic acid (10.3 g, 30 mmol), 50% aqueous dimethylamine solution (2.44 g, 27 mmol) and (R) -1-
Cyclohexylethylamine (4.58 g, 36 mmol
l) was dissolved in methanol (22 ml) by heating, water (50 ml) was added to the reaction solution, and the mixture was allowed to cool under stirring. After cooling to 25 ° C., the mixture is further stirred at the same temperature for 1 hour to precipitate crystals. The precipitated crystals were collected by filtration, washed with 40% methanol (20 ml), and dried by blowing at 60 ° C. to obtain (R) -1,
1'-binaphthyl-2,2'-dicarboxylic acid di (R)-
1-cyclohexylethylamine (6.85 g, 38.
3%).

M. p. 169-172 ° C [α] _D ²⁵ : + 134.6 ° (c = 1.0, methanol) Diastereomeric excess (HPLC): 99.3% de
.

Reference Example 1 trans-4-methoxycinnamic acid methyl ester (192)
mg, 1.0 mmol) in 1,2-dimethoxyethane (15 ml) at room temperature, and then a 4 × 10 ⁻⁴ M ethylenediaminetetraacetic acid disodium salt aqueous solution (10 ml).
Is added, and the product of Example 1- (2) is then added to the Journal of American Chemical Society (The Journal of American Chemical Society).
Chemical Society) Vol. 118, No. 49
Supplementary Materials, pp. 1-492 (1996)
l) Formula obtained by the described method:

[0113]

Embedded image

An optically active ketone compound represented by the formula (40)
mg, 0.1 mmol) and cooled to 0 ° C. by an external bath. Then, Oxone <chemical composition: 2KHSO ₅
・ KHSO ₄・ K ₂ SO ₄ > (6.14 g, 10 mmo
l) and sodium hydrogen carbonate (2.6 g, 31 mmol)
Are added in six portions every hour. After completion of the addition, the mixture is further stirred for 2 hours, and the obtained reaction mixture is poured into half-saturated saline and extracted with ether. The organic layer is washed with a saturated saline solution and then dried over anhydrous magnesium sulfate.

After drying, anhydrous magnesium sulfate was separated by filtration.
The solvent is distilled off from the filtrate. A mixture of ethyl acetate and n-hexane at a ratio of 1: 8 (volume ratio) (9 ml) was added to the obtained residue.
And stirred for 1 hour at room temperature.

The precipitated white powder is collected by filtration and dried under reduced pressure to recover the optically active ketone compound (32 mg) (recovery: 80% by weight). On the other hand, the obtained filtrate (HPL
(Yield in C: 91%) was purified by flash column chromatography on silica gel (mobile phase: ethyl acetate: n-hexane = 1: 8 (volume ratio)) to give (2
R, 3S) -3- (4-Methoxyphenyl) glycidic acid methyl ester (135 mg, optical purity: 81% e)
e, isolation yield: 65%).

[0117]

According to the method of the present invention, the racemic type 1,
The optical resolution of 1'-binaphthyl-2,2'-dicarboxylic acid [1] is determined by using a commercially available chiral 1-cyclohexylethylamine [2 *] having a low molecular weight and having only one chiral center. To produce 1,1′-binaphthyl-2,2′-dicarboxylic acid [1 **] having a desired chirality in a high yield and a high optical yield. be able to. Further, since no highly toxic optical resolving agent is used, the method of the present invention is also excellent in terms of safety.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI // C07M 7:00

Claims (10)

[Claims] (1) Formula (1) A racemic 1,1′-binaphthyl-2,2′-dicarboxylic acid or a salt thereof represented by the formula (* Indicates that there is chirality.) 1-cyclohexylethylamine or a salt thereof is reacted with the chiral 1-cyclohexylethylamine shown in FIG. Racemic 1,1'-binaphthyl characterized by separating and collecting salt
Optical resolution method of 2,2′-dicarboxylic acid [1]. 2. The formula: A racemic 1,1′-binaphthyl-2,2′-dicarboxylic acid or a salt thereof represented by the formula (* Indicates that there is chirality.) 1-cyclohexylethylamine or a salt thereof is reacted with the chiral 1-cyclohexylethylamine shown in FIG. A salt characterized in that the salt is separated and collected, and if necessary, the salt is decomposed or converted into a salt other than a diastereomer salt. (** indicates that there is axial chirality.) A method for producing a chiral 1,1'-binaphthyl-2,2'-dicarboxylic acid or a salt thereof represented by the formula: 3. A diastereomer salt to be separated and collected, wherein 1 mol of chiral 1,1′-binaphthyl-2,2′-dicarboxylic acid [1 **] is used per mole of chiral 1-cyclohexylethylamine [2 *] 3. The process according to claim 2, wherein the salt is formed in a proportion of 2 mol. 4. The chiral 1-cyclohexylethylamine has the formula The chiral 1,1′-binaphthyl-2,2′-dicarboxylic acid is an (R) -isomer represented by the following formula: The method according to claim 2 or 3, which is a (R) -isomer represented by the formula: 5. A compound of the formula The racemic 1,1′-binaphthyl-2,2′-dicarboxylic acid or a salt thereof represented by the formula (* Indicates that there is chirality.) A diastereomer salt formed by reacting a chiral 1-cyclohexylethylamine or a salt thereof represented by the formula: 6. The formula (* Indicates that there is chirality, and ** indicates that there is axial chirality.) Chiral 1,1′-binaphthyl-2,2′-dicarboxylic acid [1 *
*] And chiral 1-cyclohexylethylamine [2
*] And salt. 7. A chiral 1,1′-binaphthyl-2,2 ′
The dicarboxylic acid has the formula And a chiral 1-cyclohexylethylamine represented by the formula: The salt according to claim 5, which is a (R) -isomer represented by the formula: 8. A formula obtained by the optical resolution method according to claim 1 or the production method according to claim 2, 3, or 4. (** indicates that there is axial chirality.) After converting a chiral 1,1'-binaphthyl-2,2'-dicarboxylic acid or a salt thereof represented by the formula (1) into a reactive derivative, if necessary, General formula (Alk represents a lower alkylene group), or a dihydroxy ketone compound or a dimer thereof. (** and Alk have the same meanings as described above). 9. A chiral 1,1′-binaphthyl-2,2′-
The dicarboxylic acid [1 **] has the formula Wherein the chiral ketone compound [4 **] is a compound represented by the formula: (Alk represents a lower alkylene group.) The method according to claim 8, which is a (R) -form. 10. The method according to claim 8, wherein Alk is a methylene group.