JP2000302779A - 2-oxoindolin derivative salt and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound useful for obtaining as a high purity crystal not affected by color development due to reaction a compound having excellent cholecystokinin antagonistic action and useful as a prophylactic and therapeutic agent for a pancreatic lesion or the like. SOLUTION: This new compound is expressed by formula I (wherein R is cyano or the like) and is e.g. (S)-3- 1-(2-fluorophenyl)-2,3-dihydro-3-[(3- isoquinolinyl)carbonyl]amino-6-methoxy-2-oxo-1H-indol-3-yl}propionitri le.(-)-10- camphor-sulfonate. The compound of formula I is obtained by making a compound of formula II act on (-)-10-camphor-sulfonic acid in an equimolar state. The reaction is carried out by stirring the reactant in an adequate solvent at 0-50 deg.C for 1-5 h. and the reaction product is easily precipitated by adding the seed crystal. By using the compound of formula I as a production intermediate, the compound of formula II having a purity of >=99.9% is obtained.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel 2-oxoindoline derivative (-)-10-camphorsulfonate, a process for producing the same and (S) -3-using the salt.
[1- (2-fluorophenyl) -2,3-dihydro-
3-[(3-isoquinolinyl) carbonyl] amino-6
-Methoxy-2-oxo-1H-indol-3-yl] propionic acid sodium salt.

[0002]

2. Description of the Related Art (S) -3- [1- (2-Fluorophenyl) -2,3-dihydro-3-[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-
1H-Indol-3-yl] propionic acid sodium salt (hereinafter, referred to as “compound A”) has excellent cholecystokinin antagonism, and is an agent for preventing and treating pancreatic disorders, gastrointestinal diseases or appetite regulating diseases. It is known to be useful as such (JP-A-7-196611 and JP-A-9-40557). Such a compound A is produced by the following synthetic route based on the description in the publication (Reaction Scheme 1).

[0003]

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[Compound 1: (S) -3- [1- (2-fluorophenyl) -2,3-dihydro-3-[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2
-Oxo-1H-indol-3-yl] propionitrile Compound 2: (S) -3- [1- (2-fluorophenyl) -2,3-dihydro-3-[(3-isoquinolinyl) carbonyl] amino -6-methoxy-2-oxo-
1H-Indol-3-yl] propionic acid methyl ester Compound 3: (S) -3- [1- (2-fluorophenyl) -2,3-dihydro-3-[(3-isoquinolinyl) carbonyl] amino-6 -Methoxy-2-oxo-
1H-Indol-3-yl] propionic acid Compound A: (S) -3- [1- (2-fluorophenyl) -2,3-dihydro-3-[(3-isoquinolinyl) carbonyl] amino-6-methoxy -2-oxo-
1H-indol-3-yl] propionic acid sodium salt]

[0005]

However, compound A obtained by such a method has a purity of 99.3-99.
Although it is 5%, and it is a crystal, there is a problem that the recrystallization does not remove coloring. Furthermore, cyano bodies (compound 1), ester bodies (compound 2),
Each of the carboxylic acid compounds (Compound 3) was of an amorphous type, and there was a difficulty in handling in production.

Therefore, in order to develop Compound A as a drug, it is necessary to improve the purity and the production method.

[0007]

Means for Solving the Problems The present inventors have conducted intensive studies to obtain a compound A having a purity of 99.9% or higher and which is not affected by coloring due to the reaction. When (−)-10-camphorsulfonic acid, which is widely used as an optical resolving agent, is allowed to act on a certain cyano body, ester body, or carboxylic acid body, other substances (for example, (+)-10-camphorsulfonic acid, Tartaric acid, diparatoluoyl tartaric acid, etc.)
Compound (A) is obtained as (-)-10-camphorsulfonic acid salt of the compound, and subjected to a reaction to give Compound A.
Was obtained as a stable crystal having high purity and unaffected by coloring derived from the reaction, and completed the present invention.

That is, the present invention provides a compound represented by the following general formula (I):

[0009]

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Wherein R represents a cyano group, a carboxyl group or an alkoxycarbonyl group.
An oxoindoline derivative (-)-10-camphorsulfonic acid salt and a method for producing the same are provided.

Further, the present invention relates to (S) -3- [1- (2
-Fluorophenyl) -2,3-dihydro-3-[(3
-Isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-1H-indol-3-yl] propionic acid (-)-10-camphorsulfonate, and then reacting the sodium compound. (S) -3- [1- (2-fluorophenyl)
-2,3-dihydro-3-[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-1H-
Indole-3-yl] propionic acid sodium salt crystals are provided.

Furthermore, the present invention relates to (S) -3- [1-
(2-fluorophenyl) -2,3-dihydro-3-
[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-1H-indol-3-yl] propionic acid alkyl ester (-)-10-camphorsulfonate is desalted, hydrolyzed, (S) -3- [1
-(2-fluorophenyl) -2,3-dihydro-3-
[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-1H-indol-3-yl] propionic acid sodium salt

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The 2-oxoindoline derivative (II) in the 2-oxoindoline derivative (-)-10-camphorsulfonate (I) of the present invention is based on the type of R 1, compound 2 and compound 3.

The “alkoxy” in the alkoxycarbonyl group represented by R includes, for example, methoxy,
Lower alkoxy such as ethoxy, propoxy, isopropoxy and butoxy is exemplified, and methoxy is particularly preferred.

The 2-oxoindoline derivative of the present invention
(-)-10-Camphorsulfonic acid salt (I) is produced, for example, by reacting (-)-10-camphorsulfonic acid with a 2-oxoindoline derivative (II) according to the following reaction formula 2.

[0016]

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[Where R is the same as above]

A 2-oxoindoline derivative and (-)-1
The reaction with 0-camphorsulfonic acid is usually performed by mixing equimolar amounts of a 2-oxoindoline derivative and (-)-10-camphorsulfonic acid in a suitable solvent at 0 to 50 ° C for 1 to 5 hours. . At this time, a crystal can be easily precipitated by adding a seed crystal.

Any solvent can be used as long as it does not chemically alter these compounds. Examples thereof include acetates such as ethyl acetate and butyl acetate, acetone, acetonitrile, diethyl ether and diisopropyl. Examples thereof include ethers such as ether, dioxane, and tetrahydrofuran; and halogen-based solvents such as methylene chloride and chloroform. These can be used alone or in combination. Further, if necessary, these solvents and water can be appropriately mixed and used. Preferred solvents include ethyl acetate, a mixed solvent of acetone and water, and especially acetone-water (5: 1 to 10: 1). In order to separate and obtain the 2-oxoindoline derivative (−)-10-camphorsulfonate (I) precipitated as crystals, a usual solid-liquid separation method, for example, a method such as filtration or centrifugation is used. The product can be purified by a commonly used purification method such as washing with a suitable solvent (for example, ethyl acetate or the like), dehydration or the like, and recrystallization if necessary.

In the production process of compound A, compound 1 (cyano form), compound 2 (ester form) and compound 3 (carboxylic acid form), which have been conventionally isolated as non-crystalline forms,
By forming (−)-10-camphorsulfonate as described above, they can be obtained as crystals.
Further, by subjecting these (-)-10-camphorsulfonic acid salts to the reaction, it becomes possible to obtain the compound A as a crystal having high purity and being unaffected by the coloring derived from the reaction. Hereinafter, a method for producing compound A using (−)-10-camphorsulfonic acid salt of the present invention will be specifically shown (reaction formula 3).

[0021]

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Wherein Z represents an alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, etc.)

Here, Step-1, Step-4 and Step-7
Is a step of producing a 2-oxoindoline derivative represented by the formula (I) of the present invention, (-)-10-camphorsulfonic acid salt, wherein Step-2, Step-5 and Step-8 are:
This is a step of desalting (−)-10-camphorsulfonic acid from a 2-oxoindoline derivative (−)-10-camphorsulfonic acid salt (I). Desalting of 2-oxoindoline derivative camphorsulfonate (I) (step-
2, Step-5 and Step-8) are performed, for example, by treating in a mixed solution of an organic solvent and water. That is, the desired 2-oxoindoline derivative is thereby transferred into the organic solvent, and the target substance can be easily separated and purified from the organic layer. Examples of the organic solvent used here include ethyl acetate, chloroform, methylene chloride, toluene, diethyl ether, isopropyl ether and the like, with ethyl acetate being particularly preferred.

Step-3 is a step of converting the cyano form into an ester form by subjecting the cyano form to an acid treatment in an alcohol, followed by hydrolysis. In this reaction, the cyano compound is dissolved in an alcohol such as methanol, ethanol, propanol, isopropanol, or butanol, and reacted with an acid such as hydrochloric acid, hydrobromic acid, or sulfuric acid. It is performed by heating and refluxing for 5 hours.

Step-6 is a step of converting the ester to a carboxylic acid by hydrolysis. The reaction can be carried out in an appropriate solvent using an acid or base reagent at a temperature ranging from cooling to the boiling point of the solvent to be used for 30 minutes to 2 hours. Examples of the acid used include mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and inorganic or organic acids such as trifluoroacetic acid, benzenesulfonic acid, and p-toluenesulfonic acid. And inorganic bases such as sodium oxide and potassium hydroxide. Examples of the solvent include water, methanol, ethanol, isopropanol, acetone, acetonitrile, dioxane, tetrahydrofuran, N, N-dimethylformamide,
N, N-dimethylacetamide, dimethylsulfoxide, a mixed solvent thereof and the like can be mentioned.

Step-9 is a step of reacting a carboxylic acid compound with a sodium compound to form a sodium salt to obtain compound A. In this reaction, the carboxylic acid compound is dissolved in a suitable organic solvent (for example, acetone, acetonitrile, methanol, ethanol, propanol, etc.), and an aqueous solution of a sodium compound such as sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, and the like are added. The reaction can be performed at 60 ° C. for 30 minutes to 2 hours.

In the step -10, the ester (-)-10
-For camphorsulfonate, desalting, hydrolysis,
Next, the reaction with the sodium compound is performed continuously to synthesize the compound A. Each operation of this reaction may be performed in the same manner as described above.

Thus, (S) -3- [1- (2-fluorophenyl) -2,3-dihydro-3-[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2-
Oxo-1H-indol-3-yl] propionic acid
In the production of the sodium salt, the 2-oxoindoline derivative of the present invention, (-)-10-camphorsulfonate (I) is used as a production intermediate to give a purity of 9%.
A high purity of 9.9% or more and a colorless target product can be obtained as crystals. Moreover, the 2-oxoindoline derivative (-)-10-camphorsulfonate (I) can be isolated as a crystal, which is advantageous in industrial production process control.

[0029]

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 (S) -3- [1- (2-full)
Orophenyl) -2,3-dihydro-3-[(3-iso
Quinolinyl) carbonyl] amino-6-methoxy-2-
Oxo-1H-indol-3-yl] propionitrile
Synthesis of Le-(-)-10-Camphorsulfonate Crude (S) -3- [1- (2-fluorophenyl) -2,
20.0 g of 3-dihydro-3-[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-1H-indol-3-yl] propionitrile (41.
6 mmol) in 20 mL of acetone-water (9: 1),
9.66 g of (-)-10-camphorsulfonic acid (4
(1.6 mmol) was added. After dissolution, seed crystals were added and stirred for 3 hours. 100 mL of ethyl acetate was added to the precipitated crystals, and the mixture was stirred for 1 hour, filtered, and washed with 20 mL of ethyl acetate. 60
Drying under reduced pressure at 30 ° C. for 30 minutes gave 26.1 g (87.0%) of colorless crystals. After heating and dissolving 25.0 g of the obtained crystals in 25 mL of acetone-water (9: 1), the mixture was immediately cooled on ice and cooled to 5 ° C.
Then, seed crystals were added and stirred for 1 hour. While cooling with ice, 125 mL of ethyl acetate was added and the mixture was stirred for 30 minutes. The solution was collected by filtration under cooling, washed with 25 mL of ethyl acetate, and dried under reduced pressure at 60 ° C. for 2 hours.
2.5 g (90.0%) of the title compound were obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) 0.92 (3H, s), 1.12 (3H, s), 1.43-1.52 (1H, m), 1.92-2.15
(4H, m), 2.36-2.82 (6H, m), 3.09 (1H, d, J = 15Hz), 3.56 (1
(H, d, J = 15Hz), 3.74 (3H, s), 5.42 (1H, br), 6.22 (1H, s),
6.63 (1H, dd, J = 2.5Hz, 8Hz), 7.26-7.34 (2H, m), 7.42-7.50
(2H, m), 7.62-7.69 (1H, m), 7.93-7.99 (1H, m), 8.04-8.10
(1H, m), 8.17 (1H, d, J = 8Hz), 8.37 (1H, d, J = 8Hz), 8.90 (1
H, s), 9.81 (2H, s) Melting point: 134.5-139 ℃

Example 2 (S) -3- [1- (2-full)
Orophenyl) -2,3-dihydro-3-[(3-iso
Quinolinyl) carbonyl] amino-6-methoxy-2-
Oxo-1H-indol-3-yl] propionic acid
Cyl ester / (-)-10-camphorsulfonic acid salt
Synthesis of

(1) (S) -3- obtained in Example 1
[1- (2-fluorophenyl) -2,3-dihydro-
3-[(3-isoquinolinyl) carbonyl] amino-6
-Methoxy-2-oxo-1H-indol-3-yl] propionitrile. (-)-10-camphorsulfonate (20.0 g, 27.7 mmol) in ethyl acetate 20
0 mL, and extracted three times with 200 mL of water.
After washing with 00 mL, the ethyl acetate layer was dried over sodium sulfate, filtered and concentrated, and 12.8 g (96.2%) of (S) -3- [1-
(2-fluorophenyl) -2,3-dihydro-3-
[(3-Isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-1H-indol-3-yl] propionitrile was obtained as a colorless amorphous.

(2) (S) -3- obtained by (1)
[1- (2-fluorophenyl) -2,3-dihydro-
3-[(3-isoquinolinyl) carbonyl] amino-6
-Methoxy-2-oxo-1H-indol-3-yl] propionitrile (50.0 g, 104 mmol) was mixed with methanol (700 mL), and hydrogen chloride was blown into the mixture at an internal temperature of 30 ° C. or lower until saturation. After stirring for 1 hour at room temperature,
Water (3.7 mL) was added, and the mixture was heated under reflux for 1 hour. The mixture was concentrated under reduced pressure, and 400 mL of ethyl acetate and 400 mL of water were added to carry out a liquid separation operation to separate an ethyl acetate layer. Twice with 400 mL of water.
The mixture was extracted with 400 mL of a 5N aqueous sodium hydroxide solution, and the ethyl acetate layer was washed with 400 mL of water and 400 mL of saturated saline, dried over sodium sulfate, filtered, and concentrated to obtain 49.9 g (93.4%) of (S) -3- [ 1- (2-fluorophenyl) -2,3
-Dihydro-3-[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-1H-indol-3-yl] propionic acid methyl ester was obtained as a pale yellow amorphous.

(3) Crude (S) -3- [1-
(2-fluorophenyl) -2,3-dihydro-3-
[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-1H-indol-3-yl] propionic acid methyl ester 49.2 g (95.9 mmol)
Was dissolved in 98 mL of acetone-water (9: 1) and cooled with ice (internal temperature 5 ° C.) to 22.3 of (−)-10-camphorsulfonic acid.
g (95.9 mmol) was added. The seed crystal was put therein and stirred at an internal temperature of 5 ° C. or lower for 1 hour (solidified in the middle and cannot be stirred).
While cooling with ice, 492 mL of ethyl acetate was added to break up the lump, and the mixture was stirred at an internal temperature of 5 ° C. or lower for 1 hour. The solution was collected by filtration when cold, and ethyl acetate 9
Washed with 8 mL, dried under reduced pressure at 80 ° C. for 2 hours, 63.7 g
(88.0%) pale yellow crystals were obtained. Crystal 6 obtained
After dissolving 3.2 g in acetone-water (9: 1) 126 mL with heating (dissolved in a 70 ° C. bath and melt at an internal temperature of 47 ° C.), seed with ice cooling (internal temperature of 5 ° C.), stir for 1 hour (Solidified in the middle and cannot be stirred). While cooling with ice, 631 mL of ethyl acetate was added to break up the lump, and the mixture was stirred at an internal temperature of 5 ° C. or lower for 1 hour. The solution was collected by filtration under cold conditions, washed with 126 mL of ethyl acetate, and dried under reduced pressure at 80 ° C. for 2 hours to obtain 58.7 g (92.9%) of colorless crystals. Recrystallized by the same operation, 54.9 g (93.5%)
Was obtained and recrystallized to give 51.7 g (9
4.2%) of the title compound as colorless crystals.

¹ H-NMR (CDCl ₃ ) 0.92 (3H, s), 1.12 (3H, s), 1.44-1.52 (1H, m), 1.95-2.14
(4H, m), 2.32-2.70 (6H, m), 3.10 (1H, d, J = 15Hz), 3.55 (1
(H, d, J = 15Hz), 3.62 (3H, s), 3.73 (3H, s), 5.46 (1H, br),
6.22 (1H, s), 6.60 (1H, dd, J = 2.5Hz, 8Hz), 7.25-7.50 (4H,
m), 7.66-7.75 (1H, m), 7.91-8.13 (3H, m), 8.34 (1H, d, J =
8Hz), 8.82 (1H, s), 9.55 (1H, s), 9.80 (1H, s) Melting point: 138.5-141 ℃

Example 3 (S) -3- [1- (2-full)
Orophenyl) -2,3-dihydro-3-[(3-iso
Quinolinyl) carbonyl] amino-6-methoxy-2-
Oxo-1H-indol-3-yl] propionic acid
Synthesis of (−)-10-camphorsulfonate

(1) (S) -3- obtained in Example 2
[1- (2-fluorophenyl) -2,3-dihydro-
3-[(3-isoquinolinyl) carbonyl] amino-6
-Methoxy-2-oxo-1H-indol-3-yl] propionic acid methyl ester. (-)-10-Camphorsulfonic acid salt (35.0 g, 46.4 mmol) was suspended in ethyl acetate (400 mL), and suspended in water (400 mL). Extracted twice, washed the ethyl acetate layer with 200 mL of saturated saline, dried over sodium sulfate,
After filtration and concentration, 23.8 g of (S)-[1- (2-fluorophenyl) -2,3-dihydro-3-[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2-
[Oxo-1H-indol-3-yl] propionic acid methyl ester was obtained as a colorless amorphous.

(2) (S) -3- [1 obtained in (1)
-(2-fluorophenyl) -2,3-dihydro-3-
[(3-Isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-1H-indol-3-yl] propionic acid methyl ester 23.0 g (44.8 mmol)
Was dissolved in 230 mL of methanol, and 30 mL (90.0 mmol) of a 3N aqueous sodium hydroxide solution was added dropwise under ice cooling, followed by stirring at room temperature for 3 hours. Concentrate under reduced pressure and add 200 mL of ethyl acetate
And 200 mL of water were added to carry out liquid separation. The aqueous layer was separated, and the ethyl acetate layer was extracted with 100 mL of water. Combine the aqueous layers, 1
The mixture was acidified with a 5% aqueous citric acid solution and extracted with 200 mL of ethyl acetate. 22. The ethyl acetate layer was washed twice with 100 mL of water and 100 mL of saturated saline, dried over sodium sulfate, filtered and concentrated.
0 g (98.4%) of (S) -3- [1- (2-fluorophenyl) -2,3-dihydro-3-[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo- [1H-Indol-3-yl] propionic acid was obtained as a colorless amorphous.

(3) Crude (S) -3- obtained in (2)
[1- (2-fluorophenyl) -2,3-dihydro-
3-[(3-isoquinolinyl) carbonyl] amino-6
-Methoxy-2-oxo-1H-indol-3-yl] propionic acid (19.4 g, 38.9 mmol) was dissolved in acetone-water (9: 1) 38 mL, and (-)-10-camphorsulfonic acid 9. 04 g (38.9 mmol) were added. After dissolution, 48 mL of ethyl acetate was added dropwise, seed crystals were added, and the mixture was stirred for 30 minutes (crystal precipitation). 145 mL of ethyl acetate was added, and the mixture was stirred at room temperature for 30 minutes, and then stirred on ice for 30 minutes. The solution was collected by filtration under cooling, washed with 38 mL of ethyl acetate, and dried under reduced pressure at 60 ° C. for 30 minutes to obtain 25.5 g (88.8%) of colorless crystals. 23.4 g of the obtained crystals were dissolved in acetone-water (9: 1).
It was dissolved by heating to 46 mL. Cool to room temperature and add ethyl acetate 5
8 mL was added dropwise, a seed crystal was added, and the mixture was stirred for 30 minutes (crystal precipitation). Ethyl acetate (175 mL) was added, and the mixture was stirred at room temperature for 30 minutes and then ice-cooled for 30 minutes. The solution was collected by filtration when cold, and ethyl acetate 4
Washed with 6 mL, dried under reduced pressure at 60 ° C. for 30 minutes, 21.2 g
(90.6%) colorless crystals were obtained. Recrystallization was performed in the same manner to obtain 19.5 g (92.0%) of colorless crystals, and the recrystallization was repeated to obtain 18.0 g (92.5%) of the title compound as colorless crystals.

¹ H-NMR (CDCl ₃ ) 0.89 (3H, s), 1.08 (3H, s), 1.38-1.47 (1H, m), 1.90-2.12
(4H, m), 2.30-2.45 (6H, m), 3.07 (1H, d, J = 15Hz), 3.54 (1
(H, d, J = 15Hz), 3.73 (3H, s), 4.45 (1H, br), 6.17 (1H, s),
6.58 (1H, dd, J = 2.5Hz, 8.5Hz), 7.23-7.46 (4H, m), 7.63-7.
68 (1H, m), 7.90-7.97 (1H, m), 8.03-8.10 (1H, m), 8.18 (1
(H, d, J = 8.5Hz), 8.35 (1H, d, J = 8.5Hz), 8.76 (1H, s), 9.68
(1H, s), 9.83 (1H, s) Melting point: 168-172 ℃

Example 4 (S) -3- [1- (2-full)
Orophenyl) -2,3-dihydro-3-[(3-iso
Quinolinyl) carbonyl] amino-6-methoxy-2-
Oxo-1H-indol-3-yl] propionic acid
Synthesis of sodium salt (compound A) (1)

(1) (S) -3- obtained in Example 3
[1- (2-fluorophenyl) -2,3-dihydro-
3-[(3-isoquinolinyl) carbonyl] amino-6
-Methoxy-2-oxo-1H-indol-3-yl] propionic acid (-)-10-camphorsulfonate was recrystallized three times, and 20.0 g (27.0 mmol) thereof was obtained.
Was suspended in 200 mL of ethyl acetate and extracted three times with 200 mL of water. The ethyl acetate layer was washed with 200 mL, dried over sodium sulfate, filtered, and concentrated to obtain 12.9 g (95.7%) of (S) -3-.
[1- (2-fluorophenyl) -2,3-dihydro-
3-[(3-isoquinolinyl) carbonyl] amino-6
-Methoxy-2-oxo-1H-indol-3-yl] propionic acid was obtained as a colorless amorphous.

(2) Crude (S) -3- obtained in (1)
[1- (2-fluorophenyl) -2,3-dihydro-
3-[(3-isoquinolinyl) carbonyl] amino-6
-Methoxy-2-oxo-1H-indol-3-yl] propionic acid (12.9 g, 25.8 mmol) was dissolved in acetonitrile (150 mL), and an aqueous sodium carbonate solution (2.1 g / 30 mL) was added. Stirred. After concentration under reduced pressure, the residue was dissolved by heating in 150 mL of acetonitrile, and the insolubles were removed by filtration while hot. The filtrate was concentrated, dissolved by heating in 150 mL of acetonitrile-water (100: 1), and stirred for 2 hours while cooling. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain 13.2 g of colorless crystals. Recrystallization from acetonitrile-water (100: 1) 130 mL, 1
2.8 g (95.1%) of the title compound were obtained as colorless crystals.

The chemical purity of the obtained crystal was measured by HPLC analysis under the following measurement conditions, and it was 99.9% or more.

[Operating conditions] Detector: UV absorption spectrophotometer (measuring wavelength: 230 nm) Column: L-Column ODS 4.6 mm inner diameter × 1
50 mm, 5 μm (Chemical Inspection Association) Column temperature: constant temperature around 40 ° C. Mobile phase: Dissolve 15.6 g of sodium dihydrogen phosphate dihydrate in 1000 mL of water and adjust the pH to 3.0 with phosphoric acid. ,
Further, 2 g of sodium lauryl sulfate is added and dissolved. 400 mL of acetonitrile is added to 600 mL of this solution. Flow rate: 1 mL / min

Example 5 (S) -3- [1- (2-full)
Orophenyl) -2,3-dihydro-3-[(3-iso
Quinolinyl) carbonyl] amino-6-methoxy-2-
Oxo-1H-indol-3-yl] propionic acid
Synthesis of sodium salt (compound A) (2) (S) -3- [1- (2-fluorophenyl) -2,3-dihydro-3-[(3-isoquinolinyl) carbonyl] obtained in Example 2 Amino-6-methoxy-2-oxo-1H-indol-3-yl] propionic acid methyl ester (-)-10-camphorsulfonic acid salt 2
3.0 g (30.5 mmol) of methanol was suspended in 340 mL of methanol, and 50 mL of a 3N aqueous sodium hydroxide solution was added dropwise under ice cooling, followed by stirring at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and 200 mL of ethyl acetate and 200 mL of water were added to carry out liquid separation. Separate the aqueous layer,
Further, the ethyl acetate layer was extracted with 100 mL of water. The aqueous layers were combined, acidified with a 15% aqueous citric acid solution, and ethyl acetate 20%.
Extracted with 0 mL. The ethyl acetate layer was washed twice with 100 mL of water and 100 mL of saturated saline, dried over sodium sulfate, filtered, and concentrated.
15.2 g of a colorless amorphous was obtained. This amorphous was dissolved in 200 mL of acetonitrile, an aqueous sodium carbonate solution (2.4 g / 30 mL) was added, and the mixture was stirred at 50 ° C. for 1 hour. After concentration under reduced pressure, the residue was dissolved by heating in 200 mL of acetonitrile, and the insolubles were removed by filtration while hot. The filtrate was concentrated, dissolved by heating in 200 mL of acetonitrile-water (100: 1), and stirred for 2 hours while cooling. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain 15.5 g of colorless crystals. The crystals were recrystallized from 150 mL of acetonitrile-water (100: 1) to give 15.0 g (94.3%) of the title compound as colorless crystals.

The obtained crystals were analyzed for chemical purity by HPLC analysis in the same manner as in Example 4. The results are shown in Table 1 and FIG.

[0049]

[Table 1]

Comparative Example (S) -3- [1- (2-fluorophenyl) -2,3
-Dihydro-3-[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-1H-indol-3-yl] propionic acid methyl ester 500 m
g (0.974 mmol) in 5 mL of ethyl acetate,
226 mg of (+)-10-camphorsulfonic acid (0.
974 mmol) was added, but no crystals precipitated. Further, even when the inner wall of the eggplant flask was rubbed under ice cooling, no crystallization occurred. In addition, it was left for 5 days, but no change was observed. In a similar manner, hydrochloric acid, (±) -tartaric acid,
Crystallization was attempted with (+)-tartaric acid, (−)-tartaric acid, (+)-ditoluoyltartaric acid, (−)-ditoluoyltartaric acid, malonic acid, oxalic acid, maleic acid, and fumaric acid, but none of them crystallized. Was.

[0051]

EFFECT OF THE INVENTION The 2-oxoindoline derivative of the present invention
By using (-)-10-camphorsulfonic acid salt (I), (S) -3- [1- (2-fluorophenyl) -2,3 having an excellent cholecystokinin antagonistic action.
-Dihydro-3-[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-1H-indol-3-yl] propionic acid sodium salt can be advantageously produced in terms of production process control, and 99.9% It can be obtained as high purity and colorless crystals.

[Brief description of the drawings]

1 shows a HPLC measurement chart of compound A obtained in Example 5. FIG.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Ryu Nakao 2512-1 Numagami, Oshikiri, Konan-cho, Osato-gun, Saitama Prefecture F term in Zeria Shinyaku Kogyo Co., Ltd. F-term (reference) 4C063 AA01 BB09 CC15 DD06 EE01 4C086 AA03 AA04 BC30 GA07 GA16 NA06 ZA66

Claims (6)

[Claims] 1. A compound represented by the following general formula (I) [Wherein R represents a cyano group, a carboxyl group or an alkoxycarbonyl group]. 2-oxoindoline derivative (-)-10-camphorsulfonate. 2. The following general formula (II): (Wherein, R represents a cyano group, a carboxyl group or an alkoxycarbonyl group), and (-)-10-camphorsulfonic acid is allowed to act on the 2-oxoindoline derivative represented by the formula: A method for producing a 2-oxoindoline derivative / (−)-10-camphorsulfonic acid salt. 3. (S) -3- [1- (2-Fluorophenyl) -2,3-dihydro-3-[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-
[1H-indol-3-yl] propionic acid. (-)-
(S) -3- characterized by desalting 10-camphorsulfonic acid salt and then reacting with a sodium compound.
[1- (2-fluorophenyl) -2,3-dihydro-
3-[(3-isoquinolinyl) carbonyl] amino-6
-Methoxy-2-oxo-1H-indol-3-yl] propionic acid sodium salt crystal production method. 4. (S) -3- [1- (2-Fluorophenyl) -2,3-dihydro-3-[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-
[1H-indol-3-yl] propionic acid. (-)-
When 10-camphorsulfonic acid salt is (S) -3- [1-
(2-fluorophenyl) -2,3-dihydro-3-
[(3-Isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-1H-indol-3-yl] propionic acid alkyl ester. (-)-10-camphorsulfonic acid salt is desalted and hydrolyzed, Then (-)-
The method according to claim 3, which is obtained by reacting 10-camphorsulfonic acid. 5. (S) -3- [1- (2-Fluorophenyl) -2,3-dihydro-3-[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-
(S) -3- [1] wherein 1H-indol-3-yl] propionic acid alkyl ester (-)-10-camphorsulfonate is desalted, hydrolyzed, and then reacted with a sodium compound. -(2-Fluorophenyl) -2,3-dihydro-3-[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-
1H-Indol-3-yl] propionic acid sodium salt production method. 6. An (S) -3- [1- (2-fluorophenyl) -2,3-dihydro-3-[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-
[1H-indol-3-yl] propionic acid alkyl ester. (-)-10-camphorsulfonic acid salt,
(S) -3- [1- (2-fluorophenyl) -2,3
-Dihydro-3-[(3-isoquinolinyl) carbonyl] amino-6-methoxy-2-oxo-1H-indol-3-yl] propionitrile. (-)-10-camphorsulfonic acid salt, The product obtained by hydrolyzing after acid treatment in an alcohol, and then reacting with (−)-10-camphorsulfonic acid.
Production method as described.