JPH0789933A - Production of optically active indoline derivative and intermediate thereof - Google Patents

Abstract

PURPOSE:To provide the process of high-efficiency production of an optically active 5-nitroindoline derivative from racemic 5-nitroindoline derivative. CONSTITUTION:The condensation reaction between 5-nitroindoline derivative of the formula 1 (R<1> is amino-protecting group; R<2> is OH-protecting group) and (S)-(N-substituted cinnamoyl)proline derivative of formula 2 (R<3> is H, halogen, methyl, methoxy, NO2) or its enantiomer provides a diastereomer mixture of the formulas 3a and 3b. The mixture is separated by recrystallization and the products are separately solvolyzed to provide optically active 5-nitroindoline derivatives of the formulas 1a and 1b, respectively. Then, for example, the OH group in the 3-position of the compound of the formula 1b is converted into a leaving group X, a base is allowed to act to eliminate HX to form an exomethylene derivative of formula 5, which is hydroxylated by hydroboration to provide a racemic isomer of the formula 1. In the meantime, a protecting group R<4> is introduced into the OH group in the 3-position of the optically active compound of the formula 1a and the nitro group in the 5-position of the compound of the formula 6 is reduced to provide the optically active 5- aminoindoline derivative of the formula 7.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a 5-nitroindoline derivative which is an optically active intermediate of a cyclopropa [c] pyrrolo [3,2-e] indole derivative which is expected to be used as a carcinostatic agent due to its strong cytotoxicity. And an intermediate for producing the 5-nitroindoline derivative.

[0002]

BACKGROUND OF THE INVENTION Cyclopropa [c] pyrrolo [3,2-e] indole derivatives and pyrrolo [3,2-e], which are expected to be used as carcinostatic agents due to their strong cytotoxicity. It is known that indole derivatives (Japanese Patent Laid-Open No. 60-193989, etc.) have asymmetric carbons and have different activities depending on the enantiomers (Journal of American Chemical Society, 112, 4623). , 1990 and Bioorganic Medicinal Chemistry Letters, Vol. 2, 755, 1992).

Therefore, in order to develop these derivatives as pharmaceuticals, it is necessary to efficiently produce optically pure compounds. Conventionally, it was synthesized using a method with extremely low production efficiency, in which a diastereomer was formed by binding an optical resolution agent to a synthetic intermediate and separating it by high performance liquid chromatography (Journal of American Chemical・ Society, Volume 112, 52
30 pages, 1990, Journal of Organic Chemistry, 53, 695 pages, 1988.
Year and Bio-Organic Medicinal Chemistry Letters, Volume 2, 755, 1992),
Manufacturing on an industrial scale has become difficult.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have found that general formulas (3a) and (3b)

[0005]

[Chemical 12]

(In the formula, R ¹ is a protecting group for an amino group and R ^{2 is}
Is a hydroxyl-protecting group, R ³ is a hydrogen atom, a halogen atom,
It was found that a diastereomer represented by a methyl group, a methoxy group or a nitro group) or a mixture of enantiomers thereof can be easily separated by recrystallization, and the compound represented by the general formula (1
a) and (1b)

[0007]

[Chemical 13]

A method for producing an optically active 5-nitroindoline derivative represented by the formula (wherein R ¹ and R ² are the same as above) with high optical purity has been completed.

Further, the optically active compounds represented by the general formulas (1a) and (1b) are converted into an exomethylene compound (5), which is converted into a racemic compound represented by the general formula (1) to produce an optically active compound. We succeeded in recycling it as a raw material, and completed a production method with high production efficiency of a 5-nitroindoline derivative having high optical purity.

[0010]

[Chemical 14]

Here, as the protecting group for the amino group of R ¹ , methoxycarbonyl group, isopropoxycarbonyl group, t
-C1-6 linear or branched lower alkoxycarbonyl group such as butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, 2,2,2-trichloro-1,1-dimethylethoxycarbonyl Groups such as haloalkoxycarbonyl group, benzyloxycarbonyl group,
Substituted or unsubstituted aralkyloxycarbonyl group such as 4-methoxybenzyloxycarbonyl group, methanesulfonyl group, benzylsulfonyl group, trifluoromethylsulfonyl group, (methyl group, halogen atom, nitro group,
Substituted sulfonyl groups such as phenylsulfonyl group which may be substituted with methoxy group) are exemplified, and preferably t-
A butoxycarbonyl group is used.

As a protective group for the hydroxyl group of R ^2, a methyl group,
C1-C4 lower alkyl group such as ethyl group, benzyl group, 4-methoxybenzyl group, 2,4-dimethoxybenzyl group, benzhydryl group, arylmethyl group such as trityl group, t-butyldimethylsilyl group, t Examples include alkyl- and aryl-substituted silyl groups such as -butyldiphenylsilyl group, and benzyl group is preferably used.

The compounds represented by the general formulas (3a), (3b) and (5) are all novel substances and important intermediates of the production method of the present invention.

Next, a method for producing an optically active 5-nitroindoline derivative using a racemic 5-nitroindoline derivative (1) using (S)-(N-cinnamoyl) proline as a resolving agent will be described.

[0015]

[Chemical 15]

(First Step) In this step, the (S)-(N-cinnamoyl) proline derivative represented by the general formula (2) is condensed with the 3-position hydroxyl group of the 5-nitroindoline derivative represented by the general formula (1). To give a mixture of diastereomers (3a) and (3b), and by separating them, the optically active 5- or 5-carboxylic acid represented by the general formulas (3a) and (3b).
A nitroindoline derivative is produced.

The production of (3) by condensation of (1) and (2) is carried out by activating the carboxyl group of (2) or by using a condensing agent in a suitable organic solvent triethylamine, diisopropylethylamine, 1,8. -Diazabicyclo [5.4.0] -7-undecene, pyridine, 4-N,
It is carried out in the presence or absence of a base such as N-dimethylaminopyridine or 4-pyrrolidinopyridine.

Known carboxyl group activating and condensing agents (eg Experimental Chemistry Course, 4th Edition, 22)
Vol. 258-271, 1992, Maruzen), preferably dicyclohexylcarbodiimide in the presence of 4-N, N-dimethylaminopyridine. As the solvent used in the reaction, any solvent which does not participate in the reaction can be used, but dichloromethane, chloroform, acetonitrile, tetrahydrofuran or the like is preferably used, and the reaction usually proceeds smoothly at -30 to 50 ° C.

The mixture (3) of diastereomers obtained by the condensation of (1) and (2) can be separated by a usual organic chemical method such as a column chromatography method or a high performance liquid chromatography method. The recrystallization method can be more simply divided into (3a) and (3b). (1) and (2) can be easily produced according to known methods (Tetrahedron Letters, Volume 31, 6699 pages, 1990 and Journal of Chemical Society Perkin Trans I, pages 759, 1986). it can.

(Second Step) In this step, (S)-(N-cinnamoyl) bonded to the 3-position hydroxyl group of the optically active 5-nitroindoline derivative represented by the general formulas (3a) and (3b). The proline portion is removed by solvolysis to produce an optically active 5-nitroindoline derivative represented by the general formulas (1a) and (1b).

Solvolysis conditions include water, methanol, ethanol, isopropyl alcohol, and other straight-chain or branched lower alcohols having 1 to 4 carbon atoms, ethylene glycol, polyhydric alcohols such as glycerin, and N, N.
Aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, 1,4-
An ether solvent such as dioxane is used alone or in a mixture at an appropriate ratio, and inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as acetic acid, citric acid and p-toluenesulfonic acid, sodium hydroxide, potassium hydroxide, Alkali metal salts such as barium hydroxide, sodium hydrogen carbonate, potassium carbonate, barium carbonate, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7
-Undecene, pyridine, 4-N, N-dimethylaminopyridine, organic bases such as 4-pyrrolidinopyridine, and alkali metals such as sodium and potassium at -30 ° C.
A method of reacting at ˜150 ° C. is exemplified, and it is preferably carried out by reacting an aqueous solution of potassium hydroxide in a mixed solvent of methanol-tetrahydrofuran.

(Third step) In this step, a protecting group R ⁴ is introduced into the 3-position hydroxyl group of the optically active 5-nitroindoline derivative represented by the general formula (1a) to protect it represented by the general formula (6). It is intended to produce a 5-nitroindoline derivative. Here, the hydroxyl-protecting group R ⁴ is a linear or branched lower alkanoyl group having 1 to 6 carbon atoms such as acetyl group, butyryl group, pivaloyl group, benzoyl group, 4-methoxybenzoyl group, 4-nitrobenzoyl group. Examples thereof include aryloyl groups such as groups, t-butyldimethylsilyl groups, alkyl- and aryl-substituted silyl groups such as t-butyldiphenylsilyl groups, and acetyl groups are preferably used. R
The introduction of ⁴ is a known method (eg, “Protective Groups in Organic Synthesis”, 2nd Edition, 6
Pages 8-103, Joan Willie and Sons 19
1991).

(Step 4) In this step, the 5-position nitro group of the optically active 5-nitroindoline derivative represented by the general formula (6) is reduced to give the optically active 5 represented by the general formula (7).
To produce an aminoindoline derivative.

The reduction of the nitro group to the amino group is carried out according to a known method ("Organic Functional Group Preparations", 2nd Edition, Vol. 1, 3).
77-433, Academic Press, 1983
Years), preferably by hydrogenation using platinum, palladium carbon or the like as a catalyst. The reaction is carried out at a reaction temperature of 0 ° to 50 ° C under a hydrogen pressure of 1 to 10 atm. Any solvent can be used as long as it does not participate in the reaction, but ether solvents such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane are preferably used.

(Fifth Step) In this step, the 3-position hydroxyl group of the optically active 5-nitroindoline derivative represented by the general formula (1b) is converted into the leaving group X, and the fifth group represented by the general formula (4) is obtained.
-To produce a nitroindoline derivative. Here, the leaving group X is a halogen atom, OSO ₂ R ⁵ (R ⁵ is substituted with a methyl group, an ethyl group, a benzyl group, a trifluoromethyl group, a halogen atom, a methyl group, a methoxy group, a nitro group, or the like. Represents a phenyl group which may be present). Conversion to the leaving group X is carried out by a known method (for example, tetrahedron letters, vol. 31, p. 6699, 1990).
Year and “Organic Functional Group ·
Preparations, 2nd Edition, Volume 1, pages 619 to 639, Academic Press, 1983).

(Sixth step) In this step, HX is eliminated by allowing a base to act on the optically active 5-nitroindoline derivative represented by the general formula (4) to give the exomethylene derivative represented by the general formula (5). It is manufactured.

As the base used in the reaction, alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate and sodium hydrogen carbonate, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7. -Undecene, pyridine, 4-N,
An organic base such as N-dimethylaminopyridine is used,
Any solvent can be used as long as it does not participate in the reaction, but preferably methanol, ethanol,
Lower alcohols such as butanol, polyhydric alcohols such as ethylene glycol and glycerin, and ether solvents such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane may be used alone or in combination. The reaction proceeds smoothly at -10 ° to 150 ° C.

(Seventh Step) In this step, the 5-nitroindoline derivative represented by the general formula (1), which is a racemate, is obtained by hydrolyzing the exomethylene derivative represented by the general formula (5) by hydroboration. Is manufactured.

Hydroboration can be carried out by a known method (Jikken Kagaku Koza, 4th edition, Volume 20, pages 72 to 81, Maruzen, 1992).
Can be easily done according to (year).

Unnecessary enantiomers are racemized by going through the sixth to seventh steps, and desired enantiomers can be obtained by going through the first to fourth steps again. Further, by performing asymmetric hydroboration in the seventh step, the compound represented by the general formula (5) can be directly converted into an optically active 5-nitroindoline derivative.

Although the production method of (7) is illustrated in the text by the resolution using (S)-(N-cinnamoyl) proline, (R)-(N-cinnamoyl) proline is used in the production method of the present invention. It goes without saying that the enantiomer of (7) can be obtained.

[0032]

EXAMPLES The following shows the usefulness of the present invention by showing examples, but the present invention is not limited to the examples.

Example 1

[0034]

[Chemical 16]

6-benzyloxy-1- (t-butoxycarbonyl) -3-hydroxymethyl-5-nitro-
2,3-Dihydroindole (30.1 g, 75.1 m
mol), (S)-(N-cinnamoyl) proline (2
7.6 g, 113 mmol) and 4-N, N-dimethylaminopyridine (0.920 g, 7.53 mmol).
Was dissolved in dichloromethane (150 ml) and dicyclohexylcarbodiimide (21.7 g, 105 mm) was added to it.
ol) in dichloromethane (50 ml) under ice cooling.
It was dripped over a period of minutes. After stirring the reaction solution at room temperature for 1 hour,
Acetic acid (2.15 ml, 37.6 mmol) was added and the mixture was further stirred for 1 hour. The reaction solution was filtered, the solvent was evaporated, ethyl acetate (300 ml) was added, and the mixture was left standing under ice cooling for 30 minutes. The residue obtained by filtering off the insoluble matter and concentrating the filtrate is subjected to silica gel column chromatography [dichloromethane-
The impurities were removed with ethyl acetate = 6: 1], methanol (800 ml) was added to the obtained diastereomeric mixture, and the precipitated crystals were collected by filtration. Ethanol (500 ml) was added to this, the mixture was digested, cooled, and the precipitated crystals were collected by filtration (3
17.3 g (36%) of S, 2 ′S) -6-benzyloxy-1- (t-butoxycarbonyl) -3- (N-cinnamoylprolyl) oxymethyl-5-nitro-2,3-dihydroindole. %)Obtained.

Melting point 152-153.5 ° C. [α] _D ²⁵ = −15 ° (C0.44, solvent: dichloromethane) Analytical value (%) Calculated value as C ₃₅ H ₃₇ N ₃ O ₈ ¼H ₂ O : C, 66.50; H, 5.98; N, 6.65 Experimental value: C, 66.46; H, 6.03; N, 6.68 Further, the methanol and ethanol filtrates were concentrated ( Crude product of 3R, 2'S) -6-benzyloxy-1- (t-butoxycarbonyl) -3- (N-cinnamoylprolyl) oxymethyl-5-nitro-2,3-dihydroindole 28. 6 g was obtained as a gum.

Example 2

[0038]

[Chemical 17]

(3S, 2'S) -6-benzyloxy-
To a suspension of 1- (t-butoxycarbonyl) -3- (N-cinnamoylprolyl) oxymethyl-5-nitro-2,3-dihydroindole (4.96 g, 7.90 mmol) in methanol (80 ml). 20% aqueous potassium hydroxide solution (4.43 ml, 15.8 mmol) was added dropwise,
Stir at room temperature for 2.5 hours. Water was added to the reaction solution, extracted with dichloromethane, dried over anhydrous sodium sulfate,
The residue obtained by distilling off the solvent was purified by silica gel column chromatography [hexane-ethyl acetate = 1: 1] and recrystallized from isopropyl ether to give (3S) -6-benzyloxy as yellow needle crystals. -1-
(T-Butoxycarbonyl) -3-hydroxymethyl-
2.63 g of 5-nitro-2,3-dihydroindole
(83%) was obtained.

Melting point 110.5-111.5 ° C. [α] _D ²⁵ = + 13 ° (C0.37, solvent: chloroform) Analytical value (%) Calculated value as C ₂₁ H ₂₄ N ₂ O ₆ : C, 62. 99; H, 6.04; N, 7.00 Experimental value: C, 62.80; H, 6.26; N, 7.29 Example 3

[0041]

[Chemical 18]

(3S, 2'S) -6-benzyloxy-
1- (t-butoxycarbonyl) -3- (N-cinnamoylprolyl) oxymethyl-5-nitro-2,3-dihydroindole (17.3 g, 27.6 mmol) was dissolved in tetrahydrofuran (50 ml), Methanol (300 ml) was added. 20% aqueous potassium hydroxide solution (15.5 ml, 55.2 mmol) was added dropwise to this,
The mixture was stirred at room temperature for 2 hours. Dichloromethane was added to the reaction solution, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off to give (3S) -6-
Benzyloxy-1- (t-butoxycarbonyl) -3
-Hydroxymethyl-5-nitro-2,3-dihydroindole was obtained. Dichloromethane (150 ml)
Dissolved in acetic anhydride (5.20 ml, 55.1 mmo
1) and triethylamine (7.70 ml, 55.2).
mmol) was added sequentially and left overnight. The residue obtained by distilling off the solvent was purified by silica gel column chromatography [hexane-ethyl acetate = 2: 1] and recrystallized from ethanol to give yellow needle crystals (3S).
-3-acetoxymethyl-6-benzyloxy-1-
11.9 g (97%) of (t-butoxycarbonyl) -5-nitro-2,3-dihydroindole was obtained.

Melting point 122-123.5 ° C. [α] _D ²⁵ = + 18 ° (C0.45, solvent: chloroform) Analytical value (%) Calculated as C ₂₃ H ₂₆ N ₂ O ₇ : C, 62.43; H, 5.92; N, 6.33 Experimental value: C, 62.33; H, 5.95; N, 6.54 Example 4

[0044]

[Chemical 19]

Crude (3R, 2'S) -6 as described in Example 1
-Benzyloxy-1- (t-butoxycarbonyl)-
3- (N-cinnamoylprolyl) oxymethyl-5-
Nitro-2,3-dihydroindole (28.6 g, 4
6 mmol) in methanol (550 ml) suspension 20
% Aqueous potassium hydroxide solution (28 ml, 100 mmol)
Was added dropwise, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with dichloromethane, washed with saturated saline,
It was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography [hexane-ether = 1: 2], and recrystallized from methanol to give (3R) -6-benzyloxy-yellow needle crystals. 15.4 g (84%) of 1- (t-butoxycarbonyl) -3-hydroxymethyl-5-nitro-2,3-dihydroindole were obtained.

Melting point 112 to 113 ° C. [α] _D ²⁷ = −7.0 ° (C0.37, chloroform) Example 5

[0047]

[Chemical 20]

(R) -6-benzyloxy-1- (t-
Butoxycarbonyl) -3-hydroxymethyl-5-nitro-2,3-dihydroindole (500 mg, 1.
25 mmol) in anhydrous dichloromethane (10 ml) in methanesulfonyl chloride (0.110 ml, 1.
42 mmol) and then triethylamine (0.190 m
1, 1.36 ml) was added dropwise and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography [hexane-ethyl acetate = 2: 1], and ether was added. The precipitated crystals were collected by filtration to obtain yellow powdery crystals of (R) -6-
Benzyloxy-1- (t-butoxycarbonyl) -3
-Methanesulfonyloxymethyl-5-nitro-2,3
-520 mg (87%) of dihydroindole were obtained.

Melting point 161-163 ° C. (decomposition) Analytical value (%) Calculated as C ₂₂ H ₂₆ N ₂ O ₈ S: C, 55.22; H, 5.48; N, 5.85 Experimental value: C , 55.05; H, 5.40; N, 5.83 Example 6

[0050]

[Chemical 21]

(R) -6-benzyloxy-1- (t-
Butoxycarbonyl) -3-methanesulfonyloxymethyl-5-nitro-2,3-dihydroindole (30
0 mg, 627 μmol) of ethanol (12.5 m
l) A 1N aqueous sodium hydroxide solution (0.630) was added to the suspension.
ml, 630 μmol) was added dropwise, and the mixture was stirred at 80 ° C. for 2 hours. The reaction mixture was concentrated, water was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the residue obtained by distilling off the solvent was recrystallized from ethanol to give 6-benzyloxy-1-yellow needle crystals.
211 mg of (t-butoxycarbonyl) -3-methylidene-5-nitro-2,3-dihydroindole (88
%)Obtained.

Melting point 147-149 ° C. Analysis value (%) Calculated value as C ₂₁ H ₂₂ N ₂ O ₅ : C, 65.96; H, 5.80; N, 7.33 Experimental value: C, 65.80 H, 5.83; N, 7.30 Example 7

[0053]

[Chemical formula 22]

(R) -6-benzyloxy-1- (t-
Butoxycarbonyl) -3-hydroxymethyl-5-nitro-2,3-dihydroindole (46.3 g, 11
6 mmol) in anhydrous dichloromethane (1 L) solution in methanesulfonyl chloride (9.90 ml, 128 mmo
l), then triethylamine (17.7 ml, 127
(mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to give yellow crystals of (R) -6-.
Benzyloxy-1- (t-butoxycarbonyl) -3
-Methanesulfonyloxymethyl-5-nitro-2,3
-Dihydroindole was obtained. This was dissolved in ethanol-tetrahydrofuran (2: 1, 1.5 L), potassium carbonate (32.0 g, 232 mmol) was added, and the mixture was heated to 70 ° C.
The mixture was stirred for 5 hours. The reaction solution was poured into ice water (2 L), extracted with dichloromethane, dried over anhydrous sodium sulfate, the solvent was distilled off, ether was added to the resulting residue, and the precipitated crystals were collected by filtration to give 6-benzyl. Oxy-1-
34.9 g of (t-butoxycarbonyl) -3-methylidene-5-nitro-2,3-dihydroindole (79
%)Obtained.

Example 8

[0056]

[Chemical formula 23]

6-benzyloxy-1- (t-butoxycarbonyl) -3-methylidene-5-nitro-2,3-
Dihydroindole (34.9 g, 91.3 mmol)
In anhydrous tetrahydrofuran (350 ml) of dimethyl sulfide borane complex (9.10 ml, 95.
(7 mmol) was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 3 hours. After cooling the reaction solution with ice, water (300 ml), 2N aqueous sodium hydroxide solution (59.3 ml, 119 mmo)
l) and 37% aqueous hydrogen peroxide (10.5 ml, 1
(14 mmol) was sequentially added dropwise, and the mixture was stirred at room temperature for 1.5 hours. Saturated saline was added to the reaction solution, which was extracted with dichloromethane, dried over anhydrous sodium sulfate, the solvent was distilled off, and ether was added to the resulting residue, and the precipitated crystals were collected by filtration to give pale yellow powdery crystals. 6-benzyloxy-1-
(T-Butoxycarbonyl) -3-hydroxymethyl-
18.6 g of 5-nitro-2,3-dihydroindole
Obtained. After the filtrate was concentrated, it was purified by silica gel column chromatography [hexane-ethyl acetate = 2: 1 → 1: 1], ether was added, and the precipitated crystals were collected by filtration.
An additional 11.5 g was obtained. Total yield 30.1 g (82
%).

Reference Example 1

[0059]

[Chemical formula 24]

Platinum oxide (22.7 mg, 100 μmo
Tetrahydrofuran (2.5 ml) was added to 1), and (3S) -3-acetoxymethyl-6-benzyloxy-1- (t-butoxycarbonyl) -5-nitro- was added thereto.
2,3-Dihydroindole (443mg, 1.00m
(mol) was added using tetrahydrofuran (2.5 ml), and the mixture was stirred under a hydrogen stream (3 atm) for 1 hour. The reaction mixture was diluted with ethyl acetate, platinum oxide was filtered off, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography [hexane-ethyl acetate = 1: 1] and solidified with hexane-ether. To give a colorless powder (3
S) -3-Acetoxymethyl-5-amino-6-benzyloxy-1- (t-butoxycarbonyl) -2,3-
392 mg (93%) of dihydroindole was obtained.

Melting point 78-80 ° C. [α] _D ²⁵ = + 28 ° (C0.29, solvent: dichloromethane) Analytical value (%) Calculated as C ₂₃ H ₂₈ N ₂ O ₅ 1 / 2H ₂ O: C, 65.54; H, 6.93; N, 6.65 Experimental value: C, 65.81; H, 6.86; N, 6.66 Example 9

[0062]

[Chemical 25]

6-benzyloxy-1- (t-butoxycarbonyl) -3-hydroxymethyl-5-nitro-
2,3-dihydroindole (13.0g, 32.5m
mol), (R)-(N-cinnamoyl) proline (1
2.0 g, 48.8 mmol) and 4-N, N-dimethylaminopyridine (0.40 g, 3.25 mmol) were dissolved in dichloromethane (100 ml), to which dicyclohexylcarbodiimide (9.45 g, 45.5 mm).
ol) in dichloromethane (10 ml) under ice cooling.
It dripped over 5 hours. After dropping, the mixture was stirred at the same temperature for 1.5 hours. Acetic acid (0.93 ml, 16.3 mmo) in the reaction solution
1) was added and the mixture was further stirred for 1 hour. The solvent of the reaction solution was evaporated, ethyl acetate was added, the insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was removed by silica gel column chromatography [hexane-ethyl acetate = 1: 1] to remove impurities, and methanol was added to the obtained diastereomeric mixture.
After digestion and cooling, the precipitated crystals were collected by filtration. Further, ethanol was added to the crude crystals, and the precipitated crystals were collected by filtration again in the same manner to give (3R, 2′R) -6-benzyloxy-1- (t-butoxycarbonyl) -containing yellow flocculent crystals. 3- (N-
Cinnamoylprolyl) oxymethyl-5-nitro-
14.5 g (71%) of 2,3-dihydroindole was obtained.

Melting point 158-159 ° C. [α] _D ²⁵ = + 26 ° (C0.44, dichloromethane) Analytical value (%) Calculated as C ₃₅ H ₃₇ N ₃ O ₈ : C, 66.97; H, 5. 94; N, 6.69 Found: C, 66.93; H, 6.08; N, 6.66 Example 10

[0065]

[Chemical formula 26]

(3R, 2'R) -6-benzyloxy-
A mixed solution of 1- (t-butoxycarbonyl) -3- (N-cinnamoylprolyl) oxymethyl-5-nitro-2,3-dihydroindole (628 mg, 1 mmol) in methanol (12 ml) and tetrahydrofuran (1 ml). 20% aqueous potassium hydroxide solution (0.60 ml)
Was added dropwise, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography [hexane-ethyl acetate = 2: 1] to obtain (R) -6-benzyloxy-1- (t-butoxycarbonyl) -3-hydroxymethyl as yellow powder crystals. -5-nitro-2,3
-300 mg (75%) of dihydroindole was obtained.

Melting point 113 to 115 ° C. [α] _D ²⁵ = -20 ° (C0.37, chloroform) Analytical value (%) Calculated value as C ₂₁ H ₂₄ N ₂ O ₆ : C, 62.99; H, 6 .04; N, 7.00 Found: C, 62.83; H, 6.19; N, 6.91 Example 11

[0068]

[Chemical 27]

(R) -6-benzyloxy-1- (t-
Butoxycarbonyl) -3-hydroxymethyl-5-nitro-2,3-dihydroindole (260 mg, 0.
65 mmol) in dichloromethane (5 ml),
Acetic anhydride (0.14 ml, 1.30 mmol), triethylamine (0.18 ml, 1.30 mmol) and 4
-N, N-dimethylaminopyridine (1.00 mg,
0.01 mmol) was added sequentially, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the obtained residue was purified by silica gel column chromatography [hexane-ethyl acetate = 4: 1], and recrystallized from methanol to give yellow needle crystals of (R) -3-acetoxy. Methyl-6-benzyloxy-1- (t-butoxycarbonyl) -5-nitro-
276 mg (96%) of 2,3-dihydroindole was obtained.

Melting point 125-126 ° C. [α] _D ²⁵ = -20 ° (C0.45, chloroform) Analytical value (%) Calculated as C ₂₃ H ₂₆ N ₂ O ₇ : C, 62.43; H, 5 .92; N, 6.33 Found: C, 62.14; H, 6.00; N, 6.23 Reference Example 2

[0071]

[Chemical 28]

Tetrahydrofuran (1 ml) was added to platinum oxide (10.2 mg), and (R) -3-acetoxymethyl-6-benzyloxy-1- (t-butoxycarbonyl) -5-nitro-2,3 was added thereto. Dihydroindole (200 mg, 0.45 mmol) was added using tetrahydrofuran (1.2 ml) and hydrogen flow (3 atm).
The mixture was stirred below for 2 hours. The reaction solution was filtered off on Celite, thoroughly washed with ethyl acetate, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography [hexane-ethyl acetate = 2: 1] and solidified from n-hexane to give colorless powder crystals of (R) -3-acetoxymethyl-5-amino-. 6-benzyloxy-1- (t-
129 mg (69%) of butoxycarbonyl) -2,3-dihydroindole was obtained.

Melting point 70 to 71 ° C. [α] _D ²⁶ = −32 ° (C0.29, dichloromethane) Analytical value (%) Calculated as C ₂₃ H ₂₈ N ₂ O ₅ 1 / 4H ₂ O: C, 66. 25; H, 6.89; N, 6.72 Found: C, 66.18; H, 6.98; N, 6.72.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hiroshi Furuta ▲ Yu ▼ 6096 Tomonuma Nogi-cho, Shimotsuga-gun, Tochigi Prefecture

Claims (5)

[Claims] 1. A compound represented by the general formula (1): (Wherein R ¹ represents an amino-protecting group and R ² represents a hydroxyl-protecting group) and a 5-nitroindoline derivative represented by the general formula (2): (In the formula, R ³ represents a hydrogen atom, a halogen atom, a methyl group, a methoxy group or a nitro group) (S)-(N
-Substituted cinnamoyl) proline derivative or general formulas (3a) and (3b) obtained by condensing with an enantiomer thereof. (Wherein R ¹ , R ² and R ³ are the same as defined above) or after separating the mixture of diastereomers or their enantiomers, each is subjected to solvolysis. 1a) and (1b) (Wherein R ¹ and R ² are the same as above), and a method for producing an optically active 5-nitroindoline derivative. 2. General formulas (1a) and (1b): (In the formula, R ¹ represents an amino-protecting group and R ² represents a hydroxyl-protecting group), an enantiomer of an optically active 5-nitroindoline derivative or a mixture thereof (where the mixing ratio is 1: (Excluding one) to a leaving group,
General formula (4) (In the formula, X represents a halogen atom, —OSO ₂ R ⁵ (R ⁵ represents a lower alkyl group having 1 to 4 carbon atoms, an optionally substituted phenyl group, a benzyl group, a trifluoromethyl group), and R ¹ , R ² is the same as the above), and a base is allowed to act on the compound to give a compound of the general formula (5) (Wherein R ¹ and R ² are the same as described above), and an exomethylene derivative represented by the general formula (1) (Wherein R ¹ and R ² are the same as described above), and a method for producing a racemic 5-nitroindoline derivative. 3. A compound represented by the general formula (3a): (Wherein R ¹ is a protecting group for an amino group, R ² is a protecting group for a hydroxyl group, and R ³ is a hydrogen atom, a halogen atom, a methyl group, a methoxy group, or a nitro group). And its antipode. 4. A compound represented by the general formula (3b): (Wherein R ¹ is a protecting group for an amino group, R ² is a protecting group for a hydroxyl group, and R ³ is a hydrogen atom, a halogen atom, a methyl group, a methoxy group, or a nitro group). And its antipode. 5. A compound represented by the general formula (5): (In the formula, R ¹ represents an amino-protecting group, and R ² represents a hydroxyl-protecting group).