JP2001064275A - Optical resolution of isocoumarin derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a low-toxic optically active isocoumarin derivative having immunomodulatory activity and neovascularization inhibitory activity by reaction of the racemic modification of an isocoumarin derivative with an optically active phenylethylamine. SOLUTION: The optical resolution of an isocoumarin derivative comprises the following steps: the racemic modification of an isocoumarin derivative of the formula is reacted with an optically active 1-phenylethylamine in an organic solvent (e.g. dioxane) to form and crystallize the diastereomer salt of one of the optically active modifications of the isocoumarin derivative of the formula and the optically active 1-phenylethylamine; and the diastereomer is then fractionally collected and subsequently decomposed with an acid (e.g. hydrochloric acid) or a base to obtain the objective optically active isocoumarin derivative, wherein, in the isocoumarin derivative of the formula where R is methyl group, to obtain the S-modification (+), 1-phenylethylamine of R- modification (+) is pref. used at 0.3-0.6 molar time the isocoumarin derivative, and the operation is conducted pref. at room temperature (15-25 deg.C) for about 1-3 h under agitation.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound represented by the following formula (I):

Embedded image (Wherein, R represents a C _1-6 linear alkyl group). Here, the C _1-6 linear alkyl group refers to a linear alkyl group having 1 to 6 carbon atoms, and specifically, methyl, ethyl, n-propyl, n-butyl , N-pentyl and n-hexyl groups.

[0002]

BACKGROUND OF THE INVENTION The isocoumarin derivative represented by the above formula (I) has excellent immunoregulatory activity and angiogenesis inhibitory activity and is characterized by low toxicity, so that it is associated with diseases associated with abnormal immunomodulatory activity. It is expected to be applied to the prevention and treatment of diseases associated with angiogenesis (see WO 97/48693). These isocoumarin derivatives have one asymmetric carbon in their structure and have two types of optically active substances, respectively, but no optically resolved example is known. The various actions disclosed in the above publications are due to the racemate. In general, various physiological activities of compounds may differ between optically active substances or racemic forms, and it is necessary to obtain optically active substances in order to obtain more detailed knowledge on biological activities.

[0003]

SUMMARY OF THE INVENTION The present invention provides a method for optically resolving an isocoumarin derivative represented by the above formula (I) to obtain an optically active form thereof.

[0004]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and found that a racemic isocoumarin derivative represented by the above formula (I) and an optically active 1-phenyl An isocoumarin derivative represented by the formula (I) (hereinafter simply referred to as an isocoumarin derivative) is obtained by subjecting ethylamine to a salt-forming reaction in an organic solvent.
Was found to preferentially crystallize a diastereomer salt composed of one of the optically active isomers and optically active 1-phenylethylamine. Then, after separating these diastereomeric salts, it was found that an optically active form of an isocoumarin derivative can be efficiently obtained by decomposing the diastereomer salt with an acid or a base, and completed the present invention.

In the present invention, the isocoumarin derivative to be subjected to optical resolution has one asymmetric carbon as described above, and there are two types of optically active isomers. The racemic forms of these isocoumarin derivatives to be subjected to the optical resolution of the present invention include not only racemic forms, which are equivalent mixtures of the above two kinds of optically active substances, but also mixtures having a high content of one of the optically active substances. .

As the organic solvent used for the salt-forming reaction of diastereomeric salts, ethers such as dioxane, tetrahydrofuran, dimethoxyethane and the like, or a mixed solvent containing two or more of these solvents are used. Can be mentioned. The amount used may be appropriately selected in consideration of the solubility of the isocoumarin derivative and 1-phenylethylamine, and furthermore, their diastereomeric salts. It is by weight, preferably 8 to 12 times by weight. There are two types of optically active 1-phenylethylamine, R-form and S-form, and both optically active forms can be used, and depending on the optically active form of the objective isocoumarin derivative. What is necessary is just to select suitably.

That is, in the case of an isocoumarin derivative in which R is a methyl group in the formula (I), its S-form (+) can be obtained by using R-form (+) 1-phenylethylamine, and conversely In order to obtain the R-form (-) of the isocoumarin derivative, the S-form (-) 1-phenylethylamine may be used. The amount of the optically active 1-phenylethylamine to be used is usually 0.1 to the isocoumarin derivative.
It is 3-0.6 mole times.

The salt formation reaction between the isocoumarin derivative and the optically active 1-phenylethylamine can be carried out, for example, by the following operation. That is, an isocoumarin derivative is dissolved in an organic solvent, and an optically active 1-
Add phenylethylamine and react. The optically active 1-phenylethylamine may be added as it is, or may be added after being dissolved in an organic solvent in advance.

The reaction between the isocoumarin derivative and the optically active 1-phenylethylamine is completed by stirring at room temperature (15 to 25 ° C.) for about 1 to 3 hours. After completion of the reaction, one of the optically active forms of the isocoumarin derivative forms a diastereomer salt with optically active 1-phenylethylamine, and the diastereomer salt is crystallized by cooling or concentrating the reaction solution. Can be put out.

Depending on the conditions, some of the diastereomeric salts may have already been crystallized, and the diastereomeric salts may be fractionated as they are. However, more operations may be performed by performing operations such as cooling and concentration. It is preferable that the diastereomer salt be crystallized before fractionation. The crystallized diastereomer salt can be easily removed by a solid-liquid separation means such as ordinary filtration and centrifugation.

The diastereomeric salt of the optically active isocoumarin derivative thus obtained and the optically active 1-phenylethylamine can be easily converted into an optically active form by decomposition with an acid or a combination of decomposition with a base and acid treatment. An isocoumarin derivative can be obtained.

First, the case where an optically active isocoumarin derivative is obtained by decomposing a diastereomer salt with an acid will be described. As the acid, an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or the like is usually used, and its use amount is usually 1 to 5 times the molar amount of the diastereomer salt. These acids are usually used as an aqueous solution, and the concentration thereof is usually 1 to 30.
%, Preferably 5 to 20% by weight.

The decomposition treatment with an acid may be carried out simply by mixing the diastereomer salt and an aqueous solution of the acid, and the mixture is treated at room temperature (15 to 2).
(5 ° C.). When the diastereomer salt is decomposed with an acid, usually, an optically active form of the isocoumarin derivative precipitates, which may be removed by filtration, solid-liquid separation means such as centrifugation, or the reaction mixture is added to water. A substantially insoluble organic solvent may be added to extract an optically active form of the isocoumarin derivative, and the organic solvent may be removed from the obtained organic layer by distillation.

When this organic solvent is used, there is no problem if it is added in advance when the organic solvent is acid-decomposed.
Organic solvents substantially insoluble in water include diethyl ether, ethers such as methyl t-butyl ether, toluene, aromatic hydrocarbons such as xylene, chloroform,
Halogenated hydrocarbons such as dichloromethane, ethyl acetate, esters such as isoamyl acetate, and the like,
The amount used is usually 1 to 10 times the weight of the diastereomer salt subjected to the acid decomposition treatment.

Next, the case where the diastereomer salt is decomposed with a base to remove the optically active 1-phenylethylamine, and then an acid is added to make the solution acidic to obtain an optically active isocoumarin derivative will be described. . As the base, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide is usually used, and the amount of the base is usually 1 to 5 times the molar amount of the diastereomer salt. These bases are usually used as an aqueous solution, and the concentration is usually 1 to 30% by weight, preferably 5 to 20% by weight.

The decomposition treatment with a base may be carried out by simply mixing the diastereomer salt and an aqueous solution of the base,
(25 ° C.). When the diastereomer salt is decomposed with a base, usually, optically active 1-phenylethylamine is separated as an oil layer. This is separated as it is or extracted by adding an organic solvent substantially insoluble in water,
When liquid separation is performed to remove the optically active 1-phenylethylamine and then adding an inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid to the remaining aqueous layer to make the liquid acidic, the optically active form of the isocoumarin derivative is usually obtained. Settles. The subsequent separation operation can be performed in the same manner as in the above-described method of separating from the precipitate obtained by acid decomposition.

The organic solvent substantially insoluble in water used in the decomposition of the diastereomer salt with a base includes ethers such as diethyl ether and methyl t-butyl ether; aromatic hydrocarbons such as toluene and xylene; Halogenated hydrocarbons such as chloroform and dichloromethane,
Esters such as ethyl acetate and isoamyl acetate are exemplified, and the amount of the ester used is usually 1 to 10 times the weight of the diastereomer salt subjected to the decomposition treatment with the base.

The optically active form of the isocoumarin derivative is obtained by acid-decomposing the diastereomer salt in this way or by preliminarily decomposing with a base to separate the optically active 1-phenylethylamine and then making the liquid acidic. Can be obtained.

On the other hand, the optically active isocoumarin derivative which is in an enantiomeric relationship with the optically active isocoumarin derivative which has formed a diastereomer salt remains after the diastereomer salt is separated by solid-liquid separation. It is abundant in solutions such as filtrate and centrifugal supernatant. In some cases, an organic solvent can be obtained from these solutions by distilling off the organic solvent, but can be obtained with high optical purity, but usually has an enantiomeric relationship with the optically active 1-phenylethylamine used earlier in these solutions. By adding the other optically active 1-phenylethylamine and performing the same operation, it can be obtained efficiently.

[0020]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.

Example 1 2- (8-hydroxy-6-methoxy-1-oxo-1
4.41 g (16.7 mmol) of racemic H-2-benzopyran-3-yl) propionic acid was added to dioxane 45.
Then, 2.13 ml (16.7 mmol) of (S) -1-phenylethylamine was added thereto, and the mixture was added at room temperature (20 ml).
C.) for 3 hours. The precipitated crystals are filtered,
2.05 g of the (S) -1-phenylethylamine salt of (R) -2- (8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl) propionic acid
Was obtained (63.8% yield). The obtained diastereomer salt was dissolved in 1M hydrochloric acid (50 ml), and ethyl acetate (100 ml) was added.
ml was added and extracted. The organic layer was separated, washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off under reduced pressure to give (R) -2- (8-hydroxy-6-methoxy-1). 1.17 g of -oxo-1H-2-benzopyran-3-yl) propionic acid was obtained (yield: 83.1%).

Optical rotation -27.6 ° (c 0.5, methanol) Optical purity (% ee)> 99.0

Example 2 The filtrate obtained by filtering the diastereomer salt in Example 1 was adjusted to be acidic (pH 2) with 1M hydrochloric acid, and extracted with 200 ml of ethyl acetate. Separate the organic layer,
After washing with water and saturated saline in this order and drying over anhydrous sodium sulfate, ethyl acetate was distilled off under reduced pressure. The residue was dissolved in 23 ml of dioxane, and 2.13 ml (16.7 mmol) of (R) -1-phenylethylamine was added.
The mixture was stirred at room temperature (20 ° C.) for 3 hours. The precipitated crystals were filtered to give (S) -2- (8-hydroxy-6-methoxy-
(R) -1-phenylethylamine salt of 1-oxo-1H-2-benzopyran-3-yl) propionic acid
96 g was obtained (61.0% yield).

The resulting diastereomer salt was treated with 1M hydrochloric acid 5
0 ml, further added ethyl acetate 100 ml,
Extracted. The organic layer was separated, washed successively with water and saturated saline and dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off under reduced pressure to give (S) -2- (8-hydroxy-6-methoxy-1). -Oxo-1H-2-benzopyran-3-yl) propionic acid was obtained in an amount of 1.11 g (yield: 82.5).
%).

Optical rotation + 29.0 ° (c 0.5, methanol) Optical purity (% ee)> 99.0

The optical purity of the above optically active substance was determined by HPLC analysis under the following conditions. (HPLC analysis conditions) Column: ULTRON ES-OVM (φ4.6 × 15
Mobile phase: 0.02 M phosphate buffer (pH 3.0) -methanol (85:15) Detection: UV 244 nm Flow rate: 1 ml / min The retention time under these conditions is 20 minutes for the (R) form. , (S) was 26 minutes.

The method for optical resolution of an isocoumarin derivative of the present invention comprises steps that are easy to scale up, such as crystallization, extraction, and filtration. Therefore, the isocoumarin derivative can be optically resolved industrially advantageously, and an optically active substance having high efficiency and high purity can be obtained.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Tomio Takeuchi 5-111 Higashi Gotanda Shinagawa-ku, Tokyo 5-111 New Fuji Mansion 701 F term (reference) 4C062 GG08 4C086 AA04 BA08 GA16 4H006 AA02 AC83 AD15 AD30 BB15 BB25

Claims (3)

[Claims] 1. A compound represented by the following formula (I): (Wherein, R represents a C _1-6 linear alkyl group) and a racemic isocoumarin derivative represented by the formula:
Reacting with phenylethylamine in an organic solvent,
An isocoumarin derivative represented by the formula (I), which forms and crystallizes a diastereomer salt of one optically active form of the isocoumarin derivative represented by the formula (I) and 1-phenylethylamine which is optically active. Optical splitting method. 2. The method according to claim 1, wherein R is a methyl group. 3. The optical resolution method according to claim 1, wherein the organic solvent is dioxane, tetrahydrofuran, dimethoxyethane, or a mixed solvent containing two or more of these solvents.