JPH06122686A - Method for optical resolution of racemic modification - Google Patents

Abstract

PURPOSE:To optically resolve a racemic modification simply in high yield by reacting a racemic modification of a benzodiazepine derivative useful as a CCK antagonist with an optically active acid and separating formed diastereomer salts. CONSTITUTION:A racemic modification of a compound of having I [R<1> is aryl; X is O or group of formula II (R<4> is H or lower alkyl); A is direct bond or lower alkylene] or its salt is reacted with an optically active acid (preferably L-tartaric acid) to give two diastereomer salts comprising a compound of formula III and the optically active acid and a compound of formula IV and the optically active acid and the salts are separated. The separation of the diastereomer salts is carried out by taking advantage of difference in solubility in a solvent such as an alcohol. For example, (3RS)-3-amino-1-(2- fluorophenyl)-3,4,6,7-tetrahydro-4-oxopyrrolo[3,2,1-jk][1,4]benzodiaze pine may be cited as the racemic modification.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing a compound having a CCK antagonistic action, useful as a medicine, and useful as a synthetic intermediate for a compound having a CCK antagonistic action, and used in the medical field. To be done.

[0002]

2. Description of the Related Art A racemate of a compound represented by the following general formula (I) and its optical resolution method are known from JP-A-2-111774.

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
The optical resolution method of No. 774 requires a number of steps and is not satisfactory in terms of yield. Therefore, it is not suitable as an industrial production method. The present invention provides an industrial production method which is excellent in terms of simplicity and yield.

[0003]

The present invention has the general formula:

[Chemical 6] [Wherein R ¹ is an aryl group which may have a suitable substituent, X is —O— or

[Chemical 7] (In the formula, R ⁴ represents hydrogen or a lower alkyl group), and A represents a bond or a lower alkylene group which may have a lower alkyl group] The present invention relates to a resolution method and a method for isomerizing an optically active substance of the compound. Compound (I) according to the present invention
Alternatively, the optical resolution of the racemate of the salt is performed according to the following method.

Optical division

[Chemical 8] [Wherein R ¹ , A and X have the same meanings as described above] That is, the present invention is directed to reacting a racemate of compound (I) or a salt thereof with an optically active acid (II) to form two diastereomers. Salt [Compound (Ia) and optically active acid (II)
And a salt of the compound (Ib) with an optically active acid (II)], and separation is performed based on the difference in solubility in a solvent. This reaction is usually carried out, for example, with an alcohol (eg methanol,
The reaction can be carried out in a solvent such as ethanol), tetrahydrofuran, acetone, dioxane, etc., but the reaction can be carried out in any other solvent as long as it does not adversely influence the reaction. The reaction temperature is not particularly limited,
Usually, the reaction is performed under cooling or heating. Suitable acids in the optically active acid (II) include carboxylic acids such as tartaric acid, mandelic acid and malic acid.

The molar ratio of the racemate and the optically active acid (II) used in the reaction is not particularly limited, but usually 1:
It is carried out in the range of 0.5 to 1: 2, preferably about 1: 1. The resulting diastereomeric salt can be separated by a difference in solubility in a solvent such as alcohol (eg, methanol, ethanol, etc.). For example, depending on the type of solvent used in the reaction, the resulting diastereomeric salt is directly separated in the reaction solution, or the reaction solution containing the diastereomeric salt is concentrated and a solvent is added, and the solubility in the solvent is adjusted. Can be separated from the difference. The compound (Ia) or (Ib) thus obtained and the optically active acid (I
The free compound (Ia) or (Ib) can be obtained by treating the salt with I) by a conventional method, for example, treating with a base. The present invention further relates to the isomerization method shown below.

Isomerization method

[Chemical 9] [Wherein R ¹ , A and X are as defined above, R ² is an amino group and R ³ is hydrogen, or R ² is hydrogen and R ^{3 is}
Means an amino group. ] That is, compound (Id) or a salt thereof can be produced by reacting compound (Ic) or a salt thereof with a catalytic amount of an aldehyde. This reaction is usually an alcohol (eg methanol,
The reaction can be carried out in a solvent such as ethanol), tetrahydrofuran, acetone, dioxane, etc., but the reaction can be carried out in any other solvent as long as it does not adversely influence the reaction. The reaction temperature is not particularly limited,
Usually, the reaction is performed under cooling or heating. Examples of the aldehyde used in this reaction include an aldehyde represented by the general formula: R-CHO (wherein R represents an aryl group which may have a suitable substituent). It is assumed that this isomerization is caused by the following reaction mechanism.

[0007]

[Chemical 10] [Wherein R, R ¹ , A and X have the same meanings as described above] Therefore, by combining the optical resolution method and the isomerization method of the present application, the S-form (Ia) or the R-form can be obtained in high yield from the racemate. -The body (Ib) can be obtained. For example, the optical resolution method and the isomerization method can be combined as follows.

Combined Method The racemate of compound (I) or a salt thereof is reacted with an optically active acid (II) to form a diastereomeric salt,
One of the diastereomeric salts can be obtained by obtaining one salt from the difference in solubility in a solvent, further adding an aldehyde to the residue, and optionally adding an optically active acid (II). By repeating this operation as needed, one optically active substance can be obtained in high yield from the racemate. To give one specific reaction example,
It is as follows. formula:

[Chemical 11] Alcohol (eg methanol)
By reacting with L-tartaric acid in the formula:

[Chemical 12] The S-form L-tartrate represented by is selectively crystallized. The crystals were collected by filtration, and 3,5-dichlorosalicylaldehyde was added to the mother liquor, whereby the R-form in the mother liquor remained at the same time as the isomerization (or added as necessary).
-Reacting with tartaric acid, the S-form L-tartrate is crystallized.

In the above and subsequent descriptions of this specification, preferred examples and explanations of various definitions included in the scope of the present invention will be described in detail. The term “lower” means 1 to 6 carbon atoms unless otherwise specified. Preferable “aryl group” for R ¹ and R include phenyl, naphthyl and the like, and the aryl group is halogen, amino group, lower alkoxy group, mono (or di or tri) halo (lower) alkyl group, hydroxy group. It may have one or more suitable substituents such as groups, preferably one to three. Suitable "halogen" and suitable "halogen moiety" of "mono (or di or tri) halo (lower) alkyl group" include chlorine, bromine, fluorine and iodine.

Suitable "lower alkoxy groups" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy,
Examples include tertiary pentyloxy and hexyloxy. Suitable "lower alkylene group" is methylene,
Examples thereof include linear alkylene groups having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, such as ethylene, trimethylene, tetramethylene, pentamethylene or hexamethylene, and the lower alkylene group is a lower alkyl group. It may have one or more, preferably 1 to 3. Suitable "lower alkyl group" and "mono (or di or tri) halo (lower) alkyl group" are preferably "lower alkyl moiety", such as methyl, ethyl,
A straight chain having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, tertiary pentyl, hexyl or the like. Branched chain alkyl groups are mentioned. Hereinafter, the present invention will be described with reference to examples.

Example 1 L-tartaric acid (1.32 g) was dissolved in methanol (10 ml) at an internal temperature of 25 to 27 ° C. to prepare (3RS) -3-amino-
1- (2-fluorophenyl) -3,4,6,7-tetrahydro-4-oxopyrrolo [3,2,1-jk]
A solution of [1,4] benzodiazepine (2.59 g) in methanol (16 ml) is added dropwise over 5 minutes. Internal temperature of the solution 2
After slowly stirring at 5 to 27 ° C for about 5 minutes, the mixture is left at about 25 ° C for 2 hours and 30 minutes. The reaction mixture was triturated with methanol (5 ml), the precipitate was collected by filtration with a Nutsche, and washed with cold methanol (5 ml × 3 times) (the obtained filtrate and washing liquid were obtained in Example 2).
After that, dry under reduced pressure (50 ° C, 2 hours 30 minutes),
(3S) -3-Amino-1- (2-fluorophenyl)
L of -3,4,6,7-tetrahydro-4-oxopyrrolo [3,2,1-jk] [1,4] benzodiazepine
-Obtaining the tartrate salt (1.3 g) (purity: 98.4%).
The L-tartrate salt obtained above (1.2 g) was added to water (113 m).
After dissolving in 1), chloroform (38 ml) was added, and then sodium hydrogen carbonate (0.45 g) was added with stirring to adjust the pH to 7
Adjust to. The mixture is stirred for about 10 minutes and the chloroform layer is separated. In addition, chloroform (19m
Extract with l). Combine the chloroform layers and wash with water (19
ml × 1), dried over magnesium sulfate, and filtered.
The filtrate and washing solution were concentrated under reduced pressure, and the residue was dried under reduced pressure (room temperature,
2 hours) and then (3S) -3-amino-1- (2-fluorophenyl) -3,4,6,7-tetrahydro-4-
Oxopyrrolo [3,2,1-jk] [1,4] benzodiazepine (0.87 g) is obtained. The physical properties of this compound were in agreement with those of the standard product (known compound).

Example 2 The filtrate and washing solution obtained in Example 1 are combined and concentrated under reduced pressure. Dissolve the residue in methanol (21 ml), and set the internal temperature to 25
The mixture is stirred at ˜26 ° C., 3,5-dichlorosalicylaldehyde (50 mg) is added, and the mixture is slowly stirred at the same temperature for 30 minutes and then left at about 23 ° -25 ° C. for 3 hours. Further at room temperature overnight (1
Leave for 4 hours and 40 minutes. The reaction mixture was added to methanol (1
(0 ml) and the precipitate is filtered with a Nutsche filter, washed with cold methanol (5 ml x 4 times), and dried under reduced pressure (40 ° C, 2
(3S) -3-amino-1- (2-fluorophenyl) -3,4,6,7-tetrahydro-4-oxopyrrolo [3,2,1-jk] [1,4] benzodiazepine L-tartrate (1.6 g) (purity: 97.1
%). The L-tartrate salt (1.47 g) obtained above is added to a mixed liquid of water (76 ml) and ethyl acetate (38 ml), and dissolved with stirring. The insoluble matter is removed with powder filter paper and washed with water (38 ml). Separate the aqueous layer in the filtrate. The separated aqueous layer was washed with ethyl acetate (29 ml x 2
Then, chloroform (38 ml) is added, and then sodium hydrogen carbonate (0.56 g) is added. Mix about 10
After stirring for 1 minute, the chloroform layer is separated. Chloroform (19 ml) is added to the aqueous layer for extraction. The chloroform layers are combined, washed with water (15 ml × 1), dried over magnesium sulfate and filtered. The filtrate and washings were combined, concentrated under reduced pressure, and dried under reduced pressure (room temperature, 2 hours) to give (3S) -3-amino-1
-(2-Fluorophenyl) -3,4,6,7-tetrahydro-4-oxopyrrolo [3,2,1-jk] [1,
4] Benzodiazepine (0.85 g) is obtained. The physical properties of this compound were in agreement with those of the standard product (known compound).

Example 3 (3S) -3-amino-1-obtained in Examples 1 and 2
(2-Fluorophenyl) -3,4,6,7-tetrahydro-4-oxopyrrolo [3,2,1-jk] [1,
4] Combine the benzodiazepines (1.72 g) and methanol (8.6 ml) and ethanol (25.8 ml).
It is dissolved in the mixed solution of and stirred at an internal temperature of 30 ° C. To this, a solution of L-tartaric acid (0.83 g) in ethanol (8.6 ml) was added dropwise at an internal temperature of 30 ° C for 5 minutes. After the dropping, a mixture of ethanol and methanol (4:
1) (8.6 ml) is added, and the mixture is slowly stirred at an internal temperature of 25 to 30 ° C. for 3 hours. The precipitate was collected by filtration with a Nutsche and mixed with cold ethanol and methanol (1: 1) (23 m
l) and then dried under reduced pressure (40 ° C, 2 hours).
S) -3-Amino-1- (2-fluorophenyl)-
L of 3,4,6,7-tetrahydro-4-oxopyrrolo [3,2,1-jk] [1,4] benzodiazepine
-The tartrate salt (2.22 g) (purity: 99.6%) is obtained.

Claims (2)

[Claims] 1. A general formula: [Wherein, R ¹ is an aryl group which may have a suitable substituent, X is —O— or (In the formula, R ⁴ represents hydrogen or a lower alkyl group), and A represents a bond or a lower alkylene group which may have a lower alkyl group] The optical resolution method for the racemate, which comprises reacting the body with an optically active acid and separating the resulting diastereomeric salt. 2. A general formula: [Wherein, R ¹ is an aryl group which may have a suitable substituent, X is —O— or (In the formula, R ⁴ represents hydrogen or a lower alkyl group), A is a bond, or a lower alkylene group which may have a lower alkyl group, and R ² is an amino group, R ³
Represents hydrogen, or R ² represents hydrogen and R ³ represents an amino group], and an optically active compound represented by the formula: or a salt thereof is reacted with an aldehyde to give a compound represented by the general formula: An isomerization method of an optically active compound, which comprises obtaining another optically active compound represented by the formula: wherein R ¹ , R ² , R ³ , A and X have the same meanings as defined above, or a salt thereof.