JP2001199956A - Method for producing optically active indoline derivative and intermediate for producing the derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an optically active indoline derivative useful as a raw material for manufacturing pharmaceuticals and to provide a method for producing the intermediate therefor. SOLUTION: This indoline derivative is represented by the general formula (I) and useful as a raw material for manufacturing pharmaceuticals and is obtained by treating a compound of the general formula (II) (R1 is H or a protective group; and R2 is cyano group or carbamoyl group) with hydrogen peroxide in the presence of potassium carbonate to obtain a compound of the general formula (III), reacting the resultant with a compound of the general formula (IV) (R3 is H or hydroxyl group) and catalytically reducing the reaction product thereafter.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound represented by the general formula:

[0002]

Embedded image

(Wherein R ¹ is a protecting group for a hydrogen atom or a hydroxyl group, and R ² is a cyano group or a carbamoyl group) and a process for producing the optically active indoline derivative or a salt thereof. General formula useful as a body

[0004]

Embedded image

(Wherein R ¹ and R ² have the same meanings as described above);

[0006]

Embedded image

(Wherein R ¹ and R ² have the same meanings as described above).

More specifically, the present invention provides, for example,
(R) -1- (3-hydroxypropyl) -5- [2- [2- [2- (2,2,2) useful as a therapeutic agent for dysuria)
2-trifluoroethoxy) phenoxy] ethylamino] propyl] indoline-7-carboxamide;
(R) -1- (3-hydroxypropyl) -5- [2-
[2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethylamino] propyl] indole-7-
Carboxamides and their 7-nitrile derivatives (JP-A-6-220015, JP-A-7-330726)
Formula (I) useful as a raw material for the production of
The present invention relates to a method for producing an optically active indoline derivative represented by the formula: and an indoline derivative represented by the formula (II) or (III), which is useful as an intermediate for the production.

[0009]

2. Description of the Related Art Various methods for producing the above-mentioned optically active compound useful as a therapeutic agent for dysuria have been studied, but as in the present invention, a production method using a production raw material obtained by utilizing asymmetric synthesis. Has not yet been reported.

[0010]

DISCLOSURE OF THE INVENTION The present invention relates to a compound represented by the above general formula (I) having a configuration useful as a raw material for the production of pharmaceuticals.
And a method for efficiently producing an optically active indoline derivative or a salt thereof represented by the formula:

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The present inventors have found that the above-mentioned general formula (I)
As a result of intensive studies on a method for producing an optically active indoline derivative or a salt thereof represented by the general formula

[0012]

Embedded image

(In the formula, R ¹ and R ² have the same meanings as described above), the indoline derivative is treated with hydrogen peroxide in the presence of potassium carbonate,

[0014]

Embedded image

(In the formula, R ¹ and R ² have the same meanings as described above.)

[0016]

Embedded image

After reacting with an optically active amine compound represented by the formula (wherein R ³ is a hydrogen atom or a hydroxyl group), catalytic reduction is carried out and, if desired, conversion to a salt thereof to give a compound of the general formula

[0018]

Embedded image

It has been found that the optically active indoline derivative represented by the formula (R ¹ and R ² have the same meaning as described above) or a salt thereof can be stereoselectively and easily produced, and the present invention has been achieved. I've reached the point.

The present invention will be described in detail below. That is, the method for producing an optically active indoline derivative represented by the general formula (I) of the present invention comprises the step of converting the indoline derivative represented by the general formula (II) into N, N-dimethylformamide or dimethylsulfoxide. Using an equimolar to 10-fold molar amount of potassium carbonate and the same equimolar to 10-fold molar amount of hydrogen peroxide with respect to the compound of the above general formula (II),
The mixture is treated at 80 ° C. for about 1 to 24 hours to derive the indoline derivative represented by the general formula (III).
The compound of the formula (I) is equimolar to 2 times the molar amount of the compound of the formula (I).
V) After reacting with an optically active amine compound represented by the formula, catalytic reduction is carried out using a metal catalyst such as platinum oxide according to a conventional method, and if desired, it is acceptable as a raw material for the production of pharmaceuticals according to a conventional method. It can be carried out by converting to a salt.

The obtained optically active indoline derivative represented by the above general formula (I) can be prepared, for example, using L-tartaric acid using acetone, isopropanol or methanol, or a mixed solvent (volume: (4: 1 to 1: 4 in a ratio).

The above general formulas (II) and (III) of the present invention
In the compound of formula (I), the hydroxyl-protecting group is not particularly limited as long as it does not adversely affect the conversion reaction to a ketone derivative or asymmetric induction, and examples thereof include an aralkyl group and an aroyl group. The aralkyl group represents a methyl group substituted with an aryl group which may have a substituent such as a phenyl group or a naphthyl group, and the aroyl group has a substituent such as a phenyl group or a naphthyl group. Represents a carbonyl group substituted by an optionally substituted aryl group.

Examples of the substituent of the aryl group which may have a substituent include a straight-chain or branched group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group and a butyl group. Alkyl group, halogen atom such as fluorine atom, chlorine atom, bromine atom, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, etc. linear or branched C1-C6 alkoxy group , Methoxycarbonyl group, ethoxycarbonyl group,
C2 to C7 linear or branched alkoxycarbonyl group such as propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, carbon number such as methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, etc. Examples include 1-6 linear or branched alkylthio, nitro and cyano groups.

The compound represented by the above general formula (II) of the present invention can be prepared, for example, by reacting indoline in an organic solvent such as N, N-dimethylformamide in the presence of triethylamine.

[0025]

Embedded image

(Wherein R is a protecting group for a hydroxyl group) by N-alkylation using an alkylating agent represented by the general formula:

[0027]

Embedded image

After obtaining a compound represented by the formula (wherein R has the same meaning as described above), a Vilsmeier reaction is carried out in the presence of N, N-dimethylformamide and phosphorus oxychloride to give a compound of the general formula

[0029]

Embedded image

(Wherein R has the same meaning as described above), is reacted with nitroethane in the presence of ammonium acetate to give a compound of the general formula

[0031]

Embedded image

After obtaining a nitroolefin compound represented by the formula (R has the same meaning as described above), a reduction reaction is carried out using sodium borohydride in tetrahydrofuran-ethanol, and

[0033]

Embedded image

(Wherein R has the same meaning as described above), and a Vilsmeier reaction is carried out in the presence of N, N-dimethylformamide and phosphorus oxychloride to give a compound of the general formula

[0035]

Embedded image

(Wherein R has the same meaning as described above), is reacted with hydroxylamine in an organic solvent such as ethanol, and then reacted with acetic anhydride in an organic solvent such as tetrahydrofuran. And in the presence of pyridine and, if desired, treatment with a base such as potassium hydroxide or sodium hydroxide in an inert solvent such as ethanol or N, N-dimethylformamide to remove the hydroxyl-protecting group, if desired. Alternatively, it can be produced by introducing a protecting group into a hydroxyl group.

The compound represented by the general formula (I) can be prepared, for example, according to the method described in JP-A-6-220015 or JP-A-7-330726.

[0038]

Embedded image

(Wherein X in the formula is a leaving group), N-alkylation is carried out using an alkylating agent represented by the general formula

[0040]

Embedded image

The compound represented by the formula (wherein R ¹ and R ² have the same meanings as described above) is obtained by oxidizing the indoline ring in the presence of a metal catalyst such as palladium carbon and ammonium formate, if desired. Thereafter, if desired, by removing the hydroxyl-protecting group, the compound can be derived to be useful as a therapeutic agent for dysuria.

As described above, according to the production method of the present invention, the indoline derivative represented by the general formula (II) of the present invention is easily converted via the indoline derivative represented by the general formula (III) of the present invention. By a simple operation, the optically active indoline derivative represented by the general formula (I), which is useful as a raw material for producing a pharmaceutical product, can be produced stereoselectively.

[0043]

EXAMPLES The contents of the present invention will be described in more detail with reference to the following Reference Examples and Examples, but the present invention is not limited thereto.

Reference Example 1 1- (3-Benzoyloxypropyl) indoline hydrochloride 26.8 g of benzoic acid was dissolved in 90 mL of dry N, N-dimethylformamide, and 30.6 mL of triethylamine and 22.0 mL of 1-bromo-3-chloropropane were dissolved. And stirred at room temperature overnight and at 50 ° C. for 3 hours. 23.6 mL of indoline and triethylamine 3 were added to the reaction mixture.
0.6 mL was added, and the mixture was stirred at 100 ° C. for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with an aqueous sodium hydrogen carbonate solution and brine. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in 350 mL of acetone, 20 mL of concentrated hydrochloric acid was added dropwise with stirring, and the mixture was stirred overnight. The precipitated crystals are collected by filtration, washed with acetone, and dried,
40.2 g of 1- (3-benzoyloxypropyl) indoline hydrochloride as light brown crystals was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 2.35-2.5 (2H, m),
3.3-3.4 (2H, m), 3.5-3.6 (2H, m), 3.8-4.0 (2H, m),
4.4-4.5 (2H, m), 7.3-7.5 (6H, m), 7.55-7.65 (1H,
m), 7.95-8.05 (2H, m)

Reference Example 2 1- (3-Benzoyloxypropyl) -5-formylindoline 18.8 mL of phosphorus oxychloride was added dropwise to 62.5 mL of dry N, N-dimethylformamide under ice-cooling with stirring for about 10 minutes. And stirred for 30 minutes. To the mixture was added 31.8 g of 1- (3-benzoyloxypropyl) indoline hydrochloride little by little, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, stirred for 30 minutes, neutralized with sodium carbonate,
Stir for 30 minutes. The reaction mixture was extracted with ethyl acetate,
The organic layer was washed sequentially with an aqueous sodium hydrogen carbonate solution and brine. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and brown crystal 1- (3-benzoyloxypropyl) -5-formylindoline 32.7 was obtained.
g was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 2.0-2.2 (2H, m), 3.
05 (2H, t, J = 8.5Hz), 3.35-3.45 (2H, m), 3.55-3.65
(2H, m), 4.43 (2H, t, J = 6.2Hz), 6.40 (1H, d, J = 8.0
Hz), 7.4-7.6 (5H, m), 8.0-8.1 (2H, m), 9.66 (1H,
s)

Reference Example 3 1- (3-Benzoyloxypropyl) -5- (2-nitropropenyl) indoline 32.7 g of 1- (3-benzoyloxypropyl) -5-formylindoline was dissolved in 26.5 mL of nitroethane. 10.7 g of ammonium acetate was added, and the mixture was heated under reflux for 1 hour. After cooling, an aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with an aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
The residue was suspended in 250 mL of isopropanol, inoculated and stirred overnight. The precipitated crystals were collected by filtration, washed with cold isopropanol, and dried to obtain 25.6 g of 1- (3-benzoyloxypropyl) -5- (2-nitropropenyl) indoline as red crystals.

¹ H-NMR (CDCl ₃ ) δ ppm: 2.05-2.15 (2H, m),
2.48 (3H, s), 3.0-3.1 (2H, m), 3.3-3.4 (2H, m), 3.
5-3.6 (2H, m), 4.4-4.5 (2H, m), 6.44 (1H, d, J = 8.5
Hz), 7.2-7.3 (2H, m), 7.4-7.5 (2H, m), 7.55-7.65
(1H, m), 8.0-8.1 (3H, m)

Reference Example 4 1- (3-Benzoyloxypropyl) -5- (2-nitropropyl) indoline 14.4 g of sodium borohydride was dried under ice-cooling with 150 mL of dry tetrahydrofuran and 50 m of dry ethanol.
L and suspended in 1- (3-benzoyloxypropyl)
A solution of 50 g of -5- (2-nitropropenyl) indoline in 150 mL of dry tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into 350 mL of ice water, a 50% (V / V) acetic acid aqueous solution was added thereto, and the mixture was stirred at pH = 4 for 1 hour, and then neutralized with sodium hydrogen carbonate.
After the reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1- (3-benzoyloxypropyl) -5 as a red-brown oil. 50.1 g of-(2-nitropropyl) indoline was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.51 (3H, d, J = 6.6H
z), 2.0-2.1 (2H, m), 2.8-3.0 (3H, m), 3.15-3.25 (3
H, m), 3.3-3.4 (2H, m), 4.4-4.5 (2H, m), 4.65-4.75
(1H, m), 6.39 (1H, d, J = 8.0Hz), 6.82 (1H, d, J = 8.0
Hz), 6.85 (1H, s), 7.4-7.5 (2H, m), 7.55-7.65 (1H,
m), 8.0-8.1 (2H, m)

Reference Example 5 1- (3-Benzoyloxypropyl) -7-formyl-5- (2-nitropropyl) indoline 36.2 mL of phosphorus oxychloride was added to 86 mL of dry N, N-dimethylformamide under ice-cooling. The mixture was added dropwise over 20 minutes, and stirred under ice cooling for about 30 minutes. 1- (3-
A solution of 67.8 g of benzoyloxypropyl) -5- (2-nitropropyl) indoline in 57 mL of dry N, N-dimethylformamide was added dropwise over about 35 minutes.
Stirred at C for 2 hours. After cooling, the reaction mixture was cooled to 870 m2 with water.
The mixture was dropped into L while stirring, and the mixture was inoculated and stirred overnight. The precipitated crystals were collected by filtration, washed successively with water and methanol, and dried, and 58.8 g of 1- (3-benzoyloxypropyl) -7-formyl-5- (2-nitropropyl) indoline as yellow crystals was obtained. I got

¹ H-NMR (CDCl ₃ ) δ ppm: 1.54 (3H, d, J = 6.6H
z), 2.1-2.2 (2H, m), 2.92 (1H, dd, J = 6.4, 14.2Hz),
3.0-3.1 (2H, m), 3.19 (1H, dd, J = 7.7, 14.2Hz), 3.
6-3.7 (4H, m), 4.4-4.5 (2H, m), 4.65-4.75 (1H, m),
6.93 (1H, brs), 7.22 (1H, s), 7.4-7.5 (2H, m), 7.5
-7.6 (1H, m), 8.0-8.1 (2H, m), 9.94 (1H, s)

Example 1 1- (3-benzoyloxypropyl) -7-cyano-
5- (2-nitropropyl) indoline 110 g of 1- (3-benzoyloxypropyl) -7-formyl-5- (2-nitropropyl) indoline
The residue was dissolved in 50 mL of dry tetrahydrofuran, 23.2 g of hydroxylamine hydrochloride and 84.2 mL of pyridine were added, and the mixture was stirred at 50 ° C. for 1 hour. Acetic anhydride 52.5mL
And slowly stirred at 50 ° C. for 0.5 hour.
The mixture was heated under reflux for 3 hours. 500 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is acetone 100
The mixture was dissolved in mL, 500 mL of isopropanol was added, and the mixture was inoculated and stirred overnight. The precipitated crystals were collected by filtration, washed with acetone / isopropanol (2/9), and dried to give pale yellow crystals of 1- (3-benzoyloxypropyl) -7-cyano-5- (2-nitropropyl). ) 68.3 g of indoline were obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.53 (3H, d, J = 6.7H
z), 2.1-2.2 (2H, m), 2.85 (1H, dd, J = 6.2, 14.3Hz),
2.9-3.0 (2H, m), 3.12 (1H, dd, J = 7.8, 14.3Hz), 3.
55-3.65 (2H, m), 3.7-3.8 (2H, m), 4.4-4.5 (2H, m),
4.6-4.7 (1H, m), 6.89 (1H, brs), 6.93 (1H, s), 7.4-
7.5 (2H, m), 7.5-7.6 (1H, m), 8.0-8.1 (2H, m)

Example 2 1- (3-benzoyloxypropyl) -7-cyano-
5- (2-oxopropyl) indoline 1- (3-benzoyloxypropyl) -7-cyano-
Dissolve 50.0 g of 5- (2-nitropropyl) indoline in 250 mL of dry N, N-dimethylformamide,
After adding 35.1 g of potassium carbonate, 25.9 mL of a 30% aqueous hydrogen peroxide solution was added little by little at room temperature, followed by stirring at 50 ° C. overnight. Water was added to the reaction mixture, and ethyl acetate was added.
Extracted times. The organic layers were combined, washed sequentially with an aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel: 350 mesh, 750 g, developing solvent: hexane / ethyl acetate = 7/3 to 2/1) to obtain 33.4 g of crude crystals. The obtained crude crystals were dissolved in 10 mL of ethyl acetate, 250 mL of hexane was added little by little, and the mixture was inoculated and stirred overnight. The precipitated crystals were collected by filtration, washed with hexane, and dried overnight at 40 ° C. under reduced pressure to give pale yellow crystals of 1- (3-benzoyloxypropyl) -7-cyano-5- (2-oxopropyl).
27.5 g of indoline were obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 2.16 (3H, s) 2.1-2.
2 (2H, m), 2.9-3.0 (2H, m), 3.53 (2H, s), 3.6-3.7
(2H, m), 3.7-3.8 (2H, m), 4.4-4.5 (2H, m), 6.94 (1
H, brs), 6.96 (1H, s), 7.4-7.5 (2H, m), 7.5-7.6 (1
H, m), 8.0-8.1 (2H, m)

Example 3 7-carbamoyl-1- (3-hydroxypropyl)-
5- (2-oxopropyl) indoline 7-carbamoyl-1- (3-hydroxypropyl)-
The same treatment as in Example 2 was performed using 5- (2-nitropropyl) indoline to obtain 7-carbamoyl-1- (3-hydroxypropyl) -5- (2-oxopropyl) indoline.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.75-1.9 (2H, m),
2.16 (3H, s), 2.9-3.1 (3H, m), 3.2-3.3 (2H, m), 3.
4-3.5 (2H, m), 3.60 (2H, s), 3.7-3.8 (2H, m), 5.83
(1H, brs), 6.56 (1H, brs), 7.01 (1H, brs), 7.15
(1H, brs)

Example 4 (R) -5- (2-Aminopropyl) -1- (3-benzoyloxypropyl) -7-cyanoindoline L-tartrate 1- (3-benzoyloxypropyl) -7-cyano −
3.34 g of 5- (2-oxopropyl) indoline was dissolved in 30 mL of tetrahydrofuran, and 1.265 g of L-2-phenylglycinol was added.
g was added, and the mixture was stirred overnight at 50 ° C. and normal pressure under a hydrogen atmosphere.
The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained mixture having a diastereomer ratio of 3.8: 1 was mixed with 50 parts of ethanol.
Dissolve in 3 mL, 3.1 mL of 3 mol / L hydrochloric acid and 10%
Add 500 mg of palladium carbon, and add
The mixture was stirred overnight at 0 ° C and normal pressure. The insoluble material was removed by filtration, an aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with an aqueous solution of sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in 38 mL of acetone, and a solution of 1.315 g of L-tartaric acid in 38 mL of water was added little by little, and the mixture was allowed to stand. The precipitated crystals were collected by filtration and mixed with acetone / water (1/1).
Washed in 1). The obtained crystals were mixed with acetone / water (1 /
1) The mixture was heated and dissolved in 70 mL, activated carbon was added in an amount of 0.2 g, the activated carbon was removed by filtration while hot, and the filtrate was allowed to stand at room temperature. The precipitated crystals were collected by filtration and washed with acetone / water (1/1). The obtained crystals were dissolved by heating in 70 mL of acetone / water (1/1) and left as it was at room temperature. The precipitated crystals are collected by filtration,
After washing with acetone / water (1/1) and drying under reduced pressure, (R) -5- (2-aminopropyl) -1- (3-benzoyloxypropyl) -7 having an optical purity of 97.6% ee. −
1.54 g of cyanoindoline L-tartrate were obtained.

¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.08 (3H, d, J = 6.
5 Hz), 2.0-2.1 (2H, m), 2.5-2.6 (1H, m), 2.7-2.8
(1H, m), 2.9-3.0 (2H, m), 3.3-3.4 (1H, m), 3.55-3.
65 (2H, m), 3.65-3.75 (2H, m), 3.8-3.9 (2H, m), 4.
35-4.45 (2H, m), 7.04 (1H, s), 7.10 (1H, s), 7.45-
7.55 (2H, m), 7.6-7.7 (1H, m), 7.9-8.0 (2H, m)

Example 5 (R) -5- (2-Aminopropyl) -7-carbamoyl-1- (3-hydroxypropyl) indoline 7-carbamoyl-1- (3-hydroxypropyl)-
1.38 g of 5- (2-oxopropyl) indoline was dissolved in 20 mL of tetrahydrofuran, and 0.64 mL of (R) -2-phenylethylamine and pyridinium p-
After adding 25 mg of toluenesulfonate and stirring at room temperature for 1 hour, 13 mg of platinum oxide was added, and the mixture was stirred at 60 ° C. and normal pressure under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (developing solvent: methylene chloride / methanol = 50/1), and crystallized from ethyl acetate / hexane to obtain 574 mg of a diastereomer mixture of 92% de. The obtained diastereomer mixture (472 mg) was dissolved in ethanol (5 mL), 2 mol / L hydrochloric acid (1.24 mL) and 10% palladium carbon (50 mg) were added, and the mixture was stirred at 70 ° C. under normal pressure under a hydrogen atmosphere overnight. The insoluble matter was removed by filtration, and a 2 mol / L aqueous sodium hydroxide solution was used.
After adding 24 mL, the solvent was distilled off under reduced pressure. The residue was subjected to aminopropyl silica gel column chromatography (developing solvent: methylene chloride / methanol = 50/1 to 3).
0/1) and then crystallized from ethyl acetate to give 1
(R) -5- (2-aminopropyl) -7 with 00% ee
-190 mg of carbamoyl-1- (3-hydroxypropyl) indoline were obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.11 (3H, d, J = 6.3
Hz), 1.75-1.9 (2H, m), 2.41 (1H, dd, J = 8.1, 13.5 H
z), 2.62 (1H, dd, J = 5.1, 13.5 Hz), 2.95-3.05 (2H,
m), 3.05-3.15 (1H, m), 3.15-3.25 (2H, m), 3.4-3.5
(2H, m), 3.7-3.8 (2H, m), 5.74 (1H, brs), 6.68 (1H,
brs), 7.03 (1H, brs), 7.18 (1H, brs)

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C204 AB01 BB04 CB03 DB01 EB01 FB17 GB10 GB15

Claims (3)

[Claims] 1. A compound of the general formula (Wherein R ¹ is a hydrogen atom or a protecting group for a hydroxyl group,
R ² is a cyano group or a carbamoyl group), is treated with hydrogen peroxide in the presence of potassium carbonate to obtain a compound represented by the general formula: (Wherein R ¹ and R ² have the same meanings as above) to give an indoline derivative represented by the general formula: (Wherein R ³ is a hydrogen atom or a hydroxyl group), followed by catalytic reduction and, if desired, conversion to a salt thereof. ] (Wherein R ¹ and R ² have the same meanings as described above), or a method for producing an optically active indoline derivative or a salt thereof. 2. A compound of the general formula (Wherein R ¹ is a hydrogen atom or a protecting group for a hydroxyl group,
R ² is a cyano group or a carbamoyl group). 3. A compound of the general formula (Wherein R ¹ is a hydrogen atom or a protecting group for a hydroxyl group,
R ² is a cyano group or a carbamoyl group).