JPH05255245A - 2,3-dihydroindole-3,3-dicarboxylic acid and 2,3-dihydroindole-3-carboxylic acid derivative - Google Patents

Abstract

PURPOSE:To provide two kinds of the new subject carboxylic acid derivatives useful as raw materials for producing optically active compounds which are expected in the application field as an anticancer agent. CONSTITUTION:A 2,3-dihydroindole-3-carboxylic acid derivative of formula I (R<1> is H, 1-4C alkyl; R<2> is H, COOR<1>; X is two H atoms, O, S; R<3> is H, amino group-protecting group; R<4> is H, nitro, amino; R<5> is H, OH-protecting group) and a 2,3-dihydroindole-3-carboxylic acid derivative of formula II (R<6>, R<7> are H, 1-6C alkyl, benzyl, phenyl; Y, Z are O, S, substituted amino), e.g. 6- benzyloxy-3,3-di(methylcarbonyl)-2,3-dihydroindol-2-one and 6-benzyloxy-1-t- butoxycarbonyl-(3S)-hydroxymethyl-2,3-dihydro(1H)-indole. The compound of formula I is obtained from a compound of formula III through a compound of formula IV. The compound of formula II is obtained by reacting a compound of formula V with a compound of formula VI.

Description

Detailed Description of the Invention

[0001]

The present invention relates to the general formula (1)

[0002]

[Chemical formula 26]

(In the formula, R ¹ is a hydrogen atom or a carbon number of 1 to 4
R ² is a hydrogen atom or COOR ¹ (R
¹ is as described above), X represents two hydrogen atoms or a single oxygen atom or sulfur atom, R ³ is a hydrogen atom or an amino-group protecting group, and R ⁴ is a hydrogen atom, a nitro group or 2,3-dihydroindole-3,3-dicarboxylic acid and 2,3-dihydroindole-3-carboxylic acid derivatives each represented by an amino group and R ⁵ represents a hydrogen atom or a hydroxyl-protecting group, and general Formula (2)

[0004]

[Chemical 27]

(Wherein R ³ is a hydrogen atom or a protecting group for an amino group, R ⁴ is a hydrogen atom, a nitro group or an amino group, and R ^{5 is}
Is a hydrogen atom or a hydroxyl-protecting group, R ⁶ and R ⁷ are the same or different and are a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, a benzyl group or a phenyl group, and Y and Z. Are the same or different and each represents an oxygen atom, a sulfur atom, or a substituted imino group), and a 2,3-dihydroindole-3-carboxylic acid derivative.

The general formula (3) produced through the compounds of the above general formulas (1) and (2)

[0007]

[Chemical 28]

The 3-hydroxymethyl-2,3-dihydroindole derivative represented by the formula (R ³ , R ⁴ and R ⁵ are as described above) is useful as a raw material for the production of pharmaceuticals, and particularly has strong cytotoxicity. The optically active cyclopropa [c] pyrrolo [3,2-
e] It can be used as a raw material for producing an indole derivative.

[0009]

Cyclopropa [c] pyrrolo [3,2], which is expected to be used as an anticancer agent due to its strong cytotoxicity
It is known that the -e] indole derivative and the pyrrolo [3,2-e] indole derivative (Japanese Unexamined Patent Publication (Kokai) No. 60-193989, etc.) have one asymmetric carbon atom, and each enantiomer has different activity. (Journal of American Chemical Society, Volume 112, 4623)
P., 1990). Therefore, in order to develop it as a drug, the activity, toxicity, metabolism, etc. must be studied using optically pure compounds.

Conventionally, a method having a very low production efficiency has been known in which an optical resolving agent is bound to a compound of the general formula (3) or a synthetic intermediate thereafter to form a diastereomer, which is separated by high performance liquid chromatography. Was synthesized using (eg, Journal of American Chemical Society, 112, 5230, 199).
0, Journal of Organic Chemistry, 53, 695, 1988). An optically active cyclopropa [c] pyrrolo [3,2-e] indole derivative and an optically active pyrrolo [3,2-e] indole derivative represented by the general formula (3), which are important intermediates for production. There is a constant demand for efficient synthetic methods of such 3-hydroxymethyl-2,3-dihydroindole derivatives.

[0011]

The object of the present invention is to provide cyclopropa [c] pyrrolo [3,2-e] indole derivatives and pyrrolo [3,3, which are expected to be used as anticancer agents.
The purpose of the present invention is to provide an optically active raw material for producing a 2-e] indole derivative.

[0012]

The present invention has the general formula (3):
Formula (1) used as an intermediate for the production of

[0013]

[Chemical 29]

(In the formula, R ¹ is a hydrogen atom or a carbon number of 1 to 4
R ² is a hydrogen atom or COOR ¹ (R
¹ is as described above), X represents two hydrogen atoms or a single oxygen atom or sulfur atom, R ³ is a hydrogen atom or an amino-group protecting group, and R ⁴ is a hydrogen atom, a nitro group or 2,3-dihydroindole-3,3-dicarboxylic acid and 2,3-dihydroindole-3-carboxylic acid derivative represented by an amino group and R ⁵ represents a hydrogen atom or a hydroxyl group-protecting group, and a general formula (2)

[0015]

[Chemical 30]

(Wherein R ³ is a hydrogen atom or a protecting group for an amino group, R ⁴ is a hydrogen atom, a nitro group or an amino group, and R ^{5 is}
Is a hydrogen atom or a hydroxyl-protecting group, R ⁶ and R ⁷ are the same or different and are a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, a benzyl group or a phenyl group, and Y and Z. Are the same or different and each represents an oxygen atom, a sulfur atom, or a substituted imino group), and a 2,3-dihydroindole-3-carboxylic acid derivative.

The 3-hydroxymethyl-2,3-dihydroindole derivative represented by the general formula (3) is represented by the general formula (1) by the following synthetic steps.
Dihydroindole-3,3-dicarboxylic acid and 2,3
-The dihydroindole-3-carboxylic acid derivative and the 2,3-dihydroindole-3-carboxylic acid derivative represented by the general formula (2) can be used for the production.

[0018]

[Chemical 31]

(First step) In this step, the nitro group of the (2-nitrophenyl) malonic acid derivative having a protected hydroxyl group at the 4-position on the benzene ring represented by the general formula (4) is reduced. An amino group is introduced, and a carbonyl group is introduced between the amino group and methine to give a compound represented by the general formula (1a): 2,3-
It is intended to produce a dihydroindole-3,3-dicarboxylic acid derivative. As the protective group R ⁵ which can be introduced at the 4-position of the benzene ring, those which can exist stably from the first step to the fifth step are selected.

Examples of the hydroxyl-protecting group satisfying the above requirements are methyl group, benzyl group, 4-methoxybenzyl group, 2,4-dimethoxybenzyl group, benzhydryl group, di- (4-methoxyphenyl) methyl group and trityl. Examples include substituted or unsubstituted allylmethyl groups such as groups,
A benzyl group is preferably used. Examples of the ester portion R ′ of malonic acid include a lower alkyl group having 1 to 4 carbon atoms such as a methyl group and an ethyl group, and a methyl group is preferably used.

The 2- (2-nitrophenyl) malonic acid derivative having a hydroxyl group protected at the 4-position on the benzene ring can be prepared by a known method (for example, Journal of Medicinal Chemistry, Vol. 31, p. 590, 1988). Year)
Can be manufactured according to. Reduction of a nitro group to an amino group
Known methods (Organic Functional Group Preparations, Vol. 1, pp. 377-433, 1
983, Academic Press)
It is preferably carried out by hydrogenation using platinum or palladium supported on carbon powder as a catalyst. The reaction is carried out in a solvent under hydrogen pressure of 1 to 10 atm. As the solvent, any solvent can be used as long as it does not participate in the reaction, but preferably an ether solvent such as diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane and an alcohol such as methanol are used. Hydrogenation proceeds smoothly at 0 ° C to 50 ° C.

The amino group produced by hydrogenation immediately undergoes a carbonyl group or thiocarbonyl group introduction reaction in the presence of a tertiary amine such as triethylamine, diisopropylethylamine or pyridine.

That is, as a reagent used for introducing a carbonyl group in which X is an oxygen atom, phosgene, phosgene dimer, triphosgene, carbonyldiimidazole, carbonyldi (2-methylimidazole), dimethyl carbonate,
4-nitrophenyl chloroformate and the like are exemplified, and phosgene dimer and triphosgene are preferably used. As the reaction solvent, any solvent can be used as long as it does not participate in the reaction, but halogen-based hydrocarbons such as dichloromethane, chloroform and trichloroethane are preferably used. The reaction can be performed at -78 ° C to 50 ° C, but at -50
Smoothly progresses from 0 ° C to 0 ° C.

As the reagent used for introducing the thiocarbonyl group in which X is a sulfur atom, carbon disulfide, thiocarbonyldiimidazole, thiocarbonyldi (2-methylimidazole), thiophosgene and the like are used. The reaction is carried out without a solvent or in a solvent not involved in the reaction in the presence or absence of a tertiary amine such as triethylamine, diisopropylethylamine, pyridine, etc., and at -50 ° C to 80 ° C.
Proceed with.

When X is a sulfur atom, X can also be converted from an oxygen atom. Examples of reagents used for such conversion include diphosphorus pentasulfide, and Lawson's reagent,
The reaction proceeds smoothly without solvent or in dichloromethane, chloroform, toluene, tetrahydrofuran, dimethoxyethanepyridine at 0 ° C to 80 ° C.

R ⁴ is a hydrogen atom or a nitro group. When it is a nitro group, its introduction is carried out after the introduction of a carbonyl group or a thiocarbonyl group. The introduction of a nitro group is a known method of nitrating a benzene ring (Organic Functional Group Preparations, 1
Vol., Pp. 498-548, 1983, Academic Press).

[Second Step] In this step, X existing at the 2-position of the 2,3-dihydroindole-3,3-dicarboxylic acid derivative represented by the general formula (1a) (X is a sulfur atom or an oxygen atom) (Represented) is converted to a methylene group, and 2,3-dihydroindole-3 represented by the general formula (1b),
It is intended to produce a 3-dicarboxylic acid derivative. X (X
Is a sulfur atom or an oxygen atom), and a known method for reducing an amide or a thioamide to an amine (for example, "Borane Regent", pages 44 to 45, 138 to 1)
40 pages, 1988, Academic Press and "Reductions in Organic Chemistry",
167-169, 199-200, 1984, Joan Willie & Sons). Although R ³ is hydrogen atom or a protecting group of an amino group, R ³
As the protective group for the amino group which can be introduced into, those which can exist stably from the second step to the fifth step are selected. R
³ can be introduced at any stage of X being a sulfur atom, an oxygen atom, or a hydrogen atom obtained by reducing these. As a protecting group for an amino group which satisfies these requirements, a linear or branched lower alkoxycarbonyl group having 1 to 6 carbon atoms such as methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, t-butoxycarbonyl group, etc. Examples include substituted or unsubstituted aralkyloxycarbonyl groups such as benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, benzhydryloxycarbonyl group, di- (4-methoxyphenyl) methoxycarbonyl group and trityloxycarbonyl group. However, a t-butoxycarbonyl group is preferably used.
These protecting groups can be prepared by a known method (Protective Groups in Organic Synthesis, 226-24).
8 page, 1981, Joan Willie & Sons).

[Third Step] In this step, two alkyloxycarbonyl groups present at the 3-position of the 2,3-dihydroindole-3,3-dicarboxylic acid derivative represented by the general formula (1b) are hydrolyzed. A dicarboxylic acid is used, and one of them is removed by decarboxylation to produce a 2,3-dihydroindole-3-carboxylic acid derivative represented by the general formula (1c).

The hydrolysis of the alkyloxycarbonyl group is carried out under basic conditions. Examples of the base used include alkali metal carbonates such as lithium carbonate and potassium carbonate, alkali metals such as sodium hydroxide, potassium hydroxide and lithium hydroxide. Metal hydroxides are exemplified, and as an aqueous solution or in a lower alcohol such as methanol or ethanol, or water-
It is carried out in a mixture of lower alcohols. Reaction is -20 ° C
To proceed smoothly from 100 ° C.

The alkali metal salt of dicarboxylic acid produced by hydrolysis is used as it is in the next reaction without isolation. Decarboxylation is carried out under acidic conditions, and examples of the acid used include organic acids such as formic acid, acetic acid, propionic acid, citric acid and tartaric acid, and inorganic acids such as hydrochloric acid and sulfuric acid.
The reaction is carried out in an aqueous solution or a polar organic solvent such as dimethyl sulfoxide, dimethylformamide, dimethylacetamide or N-methylpyrrolidone, an ether solvent such as ether, tetrahydrofuran, dioxane or dimethoxyethane, various organic solvents such as lower alcohols such as methanol and ethanol. Alternatively, it is performed in a mixed solution of water and these organic solvents. The reaction proceeds smoothly at 0 ° C to 80 ° C.

[Step 4] In this step, the carboxylic acid existing at the 3-position of the 2,3-dihydroindole-3-carboxylic acid derivative represented by the general formula (1c) is activated, and then optically active substitution is carried out. A group is introduced to produce an optically active 2,3-dihydroindole-3-carboxylic acid derivative represented by the general formula (5). A known method for activating the carboxylic acid (for example, chemistry of the di
Amino Acid, Vol. 2, pp. 943-1048, 196
1 year, according to Joan Willie & Sons).

As the optically active substituents, Y and Z are the same or different and are exemplified by an oxygen atom, a sulfur atom and a substituted imino group, preferably an oxygen atom. R ⁶ and R ⁷ are the same or different and each is exemplified by a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, a benzyl group or a phenyl group, preferably R ⁶ is a methyl group. ⁷ is a phenyl group, R
^{When 6} is a benzyl group, a hydrogen atom is selected for R ⁷ . The coupling between the activated carboxylic acid and the optically active substituent is known in the art (for example, Journal of American Chemical Society, 113, 2071, 1991).
Year).

The introduction of the optically active substituent in this step gives rise to two diastereomers, which can be separated or as a mixture to proceed to the next step.

[Fifth Step] In this step, the carbonyl group at the 3-position of the 2,3-dihydroindole-3-carboxylic acid derivative represented by the general formula (2) is reduced to give the general formula (3 ), Which is an optically active 3-hydroxymethyl-2,3-dihydroindole derivative. When the two diastereomers present in the 2,3-dihydroindole-3-carboxylic acid derivative represented by the general formula (2) are separated, the diastereomer having the required configuration is immediately reduced. General formula (3)
Is an optically active 3-hydroxymethyl-2,3-
It can lead to dihydroindole derivatives. Examples of the reagent used for the reduction include sodium borohydride-lithium chloride and lithium borohydride.The reaction is carried out in an ether solvent such as ether, tetrahydrofuran, dioxane or dimethoxyethane, in the presence of a lower alcohol such as methanol or ethanol, or Done in the absence.

The reaction proceeds smoothly at -78 ° C to room temperature.
In addition, known methods (for example, tetrahedron letters,
31: 2849-2852, 1990, or Tetrahedron Letters, 28: 6625-6628.
Page, 1987), the compound is converted into another carboxylic acid derivative and then reduced to give an optically active 3-hydroxymethyl-
It can also be led to a 2,3-dihydroindole derivative.

On the other hand, the separated unnecessary diastereomers can be reused by epimerizing. The epimerization is carried out under basic conditions. As the base, organic lithium amides such as diisopropyllithium amide and 2,2,6,6-tetramethylpiperidinolithium amide, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, 1,8-bisdimethylaminonaphthalene, 1,4
-Diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene and the like 3
Alkali metal carbonates such as primary amines, lithium carbonate and potassium carbonate are used.

Any solvent can be used as long as it does not participate in the reaction, and ether solvents such as ether, tetrahydrofuran, dioxane and dimethoxyethane, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone and the like can be used. A polar solvent is used. The reaction proceeds smoothly between -78 ° C and 100 ° C. In addition, known methods (for example, Tetrahedron Letters, Vol. 31, pages 2849-2852, 1
990, or Tetrahedron Letters, 28, 6
It is also possible to induce the compound into another carboxylic acid derivative by pp. 625 to 6628, 1987) and then to racemize by the above method.

When the two diastereomers are not resolved, the diastereomeric mixture is converted to only one diastereomer before reduction. As the method, after deprotonating the diastereomeric mixture with a base,
By reprotonating, asymmetric protonation at the 3-position is carried out, and only one diastereomer is converted. Examples of the base used include organic lithium amides such as diisopropyl lithium amide and 2,2,6,6-tetramethylpiperidino lithium amide, dibutyl borane acetate, dibutyl borane triflate, tin triflate, zinc triflate, magnesium triflate. Metal salts such as diisopropylethylamine, triethylamine, 1,4-diazabicyclo [2.2.
2] Octane, 1,8-diazabicyclo [5.4.0]
Examples include tertiary amines such as undec-7-ene.

As the reagent for protonation, water or an organic acid such as formic acid, acetic acid, propionic acid, trifluoroacetic acid or trifluoromethanesulfonic acid is used. Any reaction solvent can be used as long as it does not participate in the reaction, but ether solvents such as ether, tetrahydrofuran, dioxane and dimethoxyethane are preferably selected, and the reaction proceeds smoothly at -78 ° C to room temperature. To do. After carrying out the asymmetric protonation in this way, reduction can be carried out by the above-mentioned method to obtain an optically active 3-hydroxymethyl-2,3-dihydroindole derivative.

When R ⁴ is a nitro group, the nitro group can be reduced to an amino group as needed in any step. Reduction of a nitro group to an amino group is a known method (Organic Functional Group Preparations, Vol. 1, pp. 377-433,
1983, Academic Press).

[0041]

EXAMPLES The usefulness of the compounds of the present invention is shown below, but the present invention is not limited to the examples.

Example 1

[0043]

[Chemical 32]

Dimethyl 2- [4- (benzyloxy) -2-nitrophenyl] malonate 325.9 mg (0.1
(mmol) was hydrogenated in 0.5 ml of tetrahydrofuran in the presence of platinum oxide at 3 atm for 30 minutes. The catalyst was filtered off, the solvent was distilled off, and the obtained residue was dissolved in 1 ml of anhydrous methylene chloride, and triethylamine 27.
9 μl (0.2 mmol), phosgene dimer 7.3 μ
1 (0.06 mmol) was added dropwise, and 20 minutes later, the temperature was gradually raised to room temperature. After 40 minutes, the reaction solution was washed with 10% sodium hydrogen carbonate and a saturated saline solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain a residue, which was subjected to preparative thin layer silica gel chromatography (methylene chloride). : Ethyl acetate = 5: 1) and recrystallized from ethyl acetate to give colorless needle crystals of 6-benzyloxy-3,3-di (methoxycarbonyl) -2,3-dihydroindol-2-one. 27.4 mg (77% yield) was obtained.

Melting point: 163.5-164.5 ° C. MS: 355 (M ⁺ ), 296, 220, 91 NMR (CDCl ₃ ) δ: 3.82 (6H, s, COO
CH3), 5.05 (2H, s , PhCH 2 O-),
_{6.65 (1H, s, C 7} -H), 6.70 (1H, d
_{d, J = 2.5,8.3Hz, C 5} -H) 7.30~
7.52 (6H, m, Ar-H), 8.96 (1H,
s, NH).

Example 2

[0047]

[Chemical 33]

35-5.4 mg (1 mM) of 6-benzyloxy-3,3-di (methoxycarbonyl) -2,3-dihydro- (1H) -indole-2-one was dissolved in 10 ml of anhydrous tetrahydrofuran and cooled under ice-cooling. , 1.0 mol of diborane-tetrahydrofuran complex 1.8 ml (1.8
(mM) was added dropwise, the mixture was stirred at room temperature for 40 minutes, and then heated to reflux at 80 ° C. for 3 hours. After cooling, 2 ml of 10% hydrogen chloride-methanol solution was added, and the mixture was heated under reflux at 80 ° C for 15 minutes, poured into saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1).
Was purified by to obtain 175.4 mg (51%) of 6-benzyloxy-3,3-di (methoxycarbonyl) -2,3-dihydro- (1H) -indole.

Melting point 115.5-116.5 ° C. (recrystallized from hexane-ethyl acetate) MS: 341 (M ⁺ ), 282, 132, 91 NMR (CDCl ₃ ) δ: 3.78 (6H, s, COO
CH ₃ ), 4.12 (2H, s, indole ring 2-position),
_{5.01 (2H, s, PhCH 2} O -), 6.31 (1
H, d, J = 2.4Hz, C 7 -H), 6.44 (1
H, dd, J = 2.4,8.3Hz, C 5 -H), 7.
29 to 7.32 (6H, m, Ar-H).

Example 3

[0051]

[Chemical 34]

6-Benzyloxy-3,3-di (methoxycarbonyl) -2,3-dihydro- (1H) -indole 66.2 mg (0.194 mM) and t-butyl carbonate 50.8 mg (0.233 mM) Was reacted overnight in methylene chloride under an argon stream at room temperature. The solvent was distilled off and the residue was purified by preparative thin layer silica gel chromatography (benzene: ethyl acetate = 20: 1) to give 6-benzyloxy-1-t-butoxycarbonyl-3,3-.
Di (methoxycarbonyl) -2,3-dihydro- (1
79.5 mg (93%) of H) -indole was obtained.

Melting point 121 to 122 ° C. (hexane-
Recrystallized from ethyl acetate) MS: 441 (M ⁺ ), 385, 341, 326, 28
2,91 NMR (CDCl ₃ ) δ: 1.56 (9H, s, t-B
uOCO), 3.79 (6H, s, COOCH ₃ ),
4.50 (2H, s, indole ring 2nd position), 5.06
_{(2H, s, PhCH 2 O} -), 6.64 (1H, d
_{d, J = 2.0,8.3Hz, C 5} -H), 7.28~
7.54 (6H, m, Ar-H), 7.66 (1H,
s, C ₇ -H).

Example 4

[0055]

[Chemical 35]

6-benzyloxy-1-t-butoxycarbonyl-3,3-di (methoxycarbonyl) -2,3
-Dihydro- (1H) -indole 441.5 mg (1
(mM) was suspended in 10 ml of methanol, 0.6 ml of 20% aqueous potassium hydroxide solution was added, and the mixture was heated at 50 ° C. for 1 hour, and then the solvent was distilled off. The residue is tetrahydrofuran 5m
Dissolve in 1 l, add 10 ml of 20% acetic acid aqueous solution, 50 ° C
It was heated for 30 minutes. The reaction solution was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated to give crystals. When this is washed with ether-hexane, the desired 6-benzyloxy-1-t-
331.2 mg of butoxycarbonyl-2,3-dihydro- (1H) -indole-3-carboxylic acid was obtained.
The filtrate was concentrated and purified by preparative thin layer silica gel chromatography to obtain 27.7 mg of the desired product (total 3
58.9 mg, 97%) was obtained.

Melting point 176-177 ° C. (recrystallized from hexane-ethyl acetate) MS: 369 (M ⁺ ), 313, 269, 224, 91 NMR (CDCl ₃ ) δ: 1.56 (9H, s, t-B
uOCO), 4.06 to 4.21 (2H, s, indole ring 2 position), 4.37 (1H, m, indole ring 3
Position), 5.06 (2H, s, PhCH ₂ O-), 6.5
9 (1H, dd, J = 2.4, 8.3 Hz, C ₅ −
H), 7.27 (1H, d, J = 8.3 Hz, C ₄ −
H), 7.24 to 7.54 (6H, m, Ar-H),
_{7.66 (1H, s, C 7} -H).

Example 5

[0059]

[Chemical 36]

6-benzyloxy-1-t-butoxycarbonyl-2,3-dihydro- (1H) -indole-
3-Carboxylic acid 184.7 mg (0.5 mM) was dissolved in tetrahydrofuran 1 ml, and thionyl chloride 1 was added under ice cooling.
After adding 82.4 ml (2.5 mM) dropwise and stirring for 2 hours,
The solvent was distilled off. (S)-(-)-4-benzyl-2-
Oxazolidinone (132.9 mg, 0.75 mM) was dissolved in tetrahydrofuran (3 ml), and n-butyllithium (469 μl, 0.75 mM) was added dropwise at -78 ° C to give 1
After stirring for 5 minutes, a solution of the above residue in 1 ml of tetrahydrofuran was added dropwise at the same temperature. After 1 hour, saturated sodium hydrogen carbonate and saturated saline were added to the reaction solution, and the mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 58.3 mg of amide A and 7 of amide B.
0.5 mg, each obtained as a colorless foam.

Amide Form A: NMR (CDCl ₃ ) δ: 1.58 (9H, s), 2.
81 (1H, dd, J = 9.8, 13.2Hz), 3.
34 (1H, dd, J = 10.3, 13.2Hz),
4.24-4.30 (4H, m), 4.64-4.68
(1H, m), 5.06 (2H, s), 5.33 (1
H, br), 6.58 (1H, dd, J = 2.4, 8.
3Hz), 7.04 (1H, d, J = 8.3Hz),
7.19 to 7.44 (11H, m), 7.71 (1H,
br).

Amide Form B: NMR (CDCl ₃ ) δ: 1.57 (9H, s), 2.
77 (1H, dd, J = 9.5, 13.7 Hz), 3.
23 (1H, dd, J = 2.9, 13.7 Hz), 4.
06-4.19 (1H, m), 4.24-4.43 (2
H, m), 4.42 (1H, dd, J = 3.7, 11.
7 Hz), 4.69 to 4.74 (1 H, m), 5.07
(2H, s), 5.39 (1H, br), 6.91 (1
H, dd, J = 2.4, 8.3 Hz), 7.12-7.
44 (11H, m), 7.72 (1H, br).

Example 6 Amide derivative A (18.7 mg, 35.4 mM) was dissolved in tetrahydrofuran (0.5 ml), and acetic acid (7 μl) and n-triethylborane (1.0 mol tetrahydrofuran solution) 4
2.5 μl was added and the mixture was stirred for 1 hour and then at 0 ° C. lithium borohydride (2.0 mol tetrahydrofuran solution) 3
5.4 μl was added dropwise and 1 hour later, the temperature was raised to room temperature and the mixture was stirred for 30 minutes. 10% Citric acid was added to the reaction solution, stirred for 1.5 hours, and extracted with ethyl acetate. The organic layer was washed successively with water, 10% aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate = 1: 1) to give 6-benzyloxy-1-t-butoxycarbonyl-colorless gum.
(3S) -Hydroxymethyl-2,3-dihydro- (1
H) -indole was obtained in 9.6 mg (76%).

[Α] ²³ _D + 26.4 ° (c 0.6
4, dichloromethane) (reference value [α] ²⁵ _D + 25.0 ° (c 0.4, dichloromethane), Journal of American Chemical Society, Volume 112, 5238, 1990.
3) Similarly, from amide B33.6 mg (63.6 mM)
21.7 mg (96%) of R form was obtained. [Α] ²³ _D- 26.3 ° (c 0.434, dichloromethane).

Example 7 1 mg (1.9 mmol) of amide B was dissolved in 0.2 ml of a solvent, a solvent containing 0.38 μmol (0.2 equivalent) of DBU was added thereto, and the mixture was heated at 50-60 ° C. for 7 hours. did.

The ratio of epimerization was measured by high performance liquid chromatography (Hibar LiChrosorb Si60).
7 μm, hexane: ethyl acetate = 2: 1), the epimerization ratio in each solvent was as follows.

[0067]

[Table 1]

[0068]

INDUSTRIAL APPLICABILITY As described above, by using the compound of the present invention, cyclopropa [c] pyrrolo [3,2-e] indole derivatives and pyrrolo [3,2-e], which are expected to be used as carcinostatic agents. Optically active 3-hydroxymethyl-2,3, an important intermediate for the production of indole derivatives
-It is possible to efficiently produce a dihydroindole derivative.

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Claims (13)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ² represents a hydrogen atom or COOR ¹ (R ¹ is as described above), and X represents two hydrogen atoms or a single hydrogen atom. One oxygen atom or sulfur atom, R ³ is a hydrogen atom or an amino group protecting group, R ⁴ is a hydrogen atom, a nitro group or an amino group, and R ⁵ is a hydrogen atom or a hydroxyl group protecting group). 2,3-
Dihydroindole-3,3-dicarboxylic acid and 2,3
-Dihydroindole-3-carboxylic acid derivatives. 2. A general formula (2): (In the formula, R ³ is a hydrogen atom or an amino group protecting group, R ⁴ is a hydrogen atom, a nitro group or an amino group, R ⁵ is a hydrogen atom or a hydroxyl group, and R ⁶ and R ⁷ are the same or (Differently represent a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, a benzyl group or a phenyl group, and Y and Z are the same or different and represent an oxygen atom, a sulfur atom or a substituted imino group) A 2,3-dihydroindole-3-carboxylic acid derivative represented by: 3. A compound represented by the general formula (4): (In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ⁵ represents a hydrogen atom or a protective group for a hydroxyl group). Four
a) [Chemical formula 4] (Wherein R ¹ and R ⁵ have the same meaning as described above). 4. A compound represented by the general formula (4a): (Wherein R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ⁵ represents a hydrogen atom or a protective group for a hydroxyl group) is reacted with a carbonyl or thiocarbonyl introducing reagent. A general formula (1a) characterized by: (In the formula, Xa represents an oxygen atom or a sulfur atom, and R ¹ and R ⁵ have the same meanings as described above). 5. A compound represented by the general formula (1b): (Wherein R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ⁵ represents a hydrogen atom or a protective group for a hydroxyl group), and a sulfurizing agent is allowed to act on the compound. General formula (1c): (Wherein R ¹ and R ⁵ have the same meaning as described above). 6. A compound represented by the general formula (1d): (In the formula, R ¹ is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ³ is a hydrogen atom or an amino group protecting group, R ⁵ is a hydrogen atom or a hydroxyl group protecting group, and X is 2 A compound represented by a hydrogen atom or a single oxygen atom or a sulfur atom) is reacted with a nitrating agent, and a general formula (1e): (Wherein R ¹ , R ³ , R ⁵ and X have the same meanings as described above). 7. A compound represented by the general formula (1f): (In the formula, R ¹ is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ³ is a hydrogen atom or a protecting group for an amino group, R ⁴ is a hydrogen atom, a nitro group or an amino group, and R ⁵ is A reducing agent acts on a compound represented by a hydrogen atom or a hydroxyl-protecting group, and Xa represents an oxygen atom or a sulfur atom). (Wherein R ¹ , R ³ , R ⁴ and R ⁵ have the same meanings as described above). 8. A compound represented by the general formula (1h): (In the formula, R ¹ represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ⁴ represents a hydrogen atom, a nitro group or an amino group, and R ⁵
Is a hydrogen atom or a hydroxyl-protecting group, and X is two hydrogen atoms or a single oxygen atom or a sulfur atom). Formula (1i): (In the formula, R ^3a represents a protecting group for an amino group, and R ¹ , R ⁴ , R
⁵ and X have the same meanings as described above). 9. A compound represented by the general formula (1g): (In the formula, R ¹ is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ³ is a hydrogen atom or a protecting group for an amino group, R ⁴ is a hydrogen atom, a nitro group or an amino group, and R ⁵ is A compound represented by a hydrogen atom or a hydroxyl group-protecting group) is hydrolyzed, and then decarboxylated. (Wherein R ³ , R ⁴ and R ⁵ have the same meanings as described above). 10. A compound represented by the general formula (1j): (Wherein R ³ represents a hydrogen atom or an amino group protecting group, R ⁴ represents a hydrogen atom, a nitro group or an amino group, and R ⁵ represents a hydrogen atom or a hydroxyl group protecting group) or a compound thereof. Reactive derivative and general formula (5) (R ⁶ and R ⁷ are the same or different and are a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, a benzyl group or a phenyl group, and Y and Z are the same or different and are oxygen atoms. , A sulfur atom, or a substituted imino group) is reacted with the compound represented by the general formula (2) (Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Y and Z have the same meanings as described above). 11. A compound represented by the general formula (2a): (In the formula, R ³ is a hydrogen atom or an amino group protecting group, R ⁴ is a hydrogen atom, a nitro group or an amino group, R ⁵ is a hydrogen atom or a hydroxyl group protecting group, R ⁶ and R ⁷ are the same or Differently, a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, a benzyl group or a phenyl group, and Y and Z are the same or differently an oxygen atom, a sulfur atom or a substituted imino group. ), An optically active compound represented by the formula (1) or a mixture of two diastereomers is treated with a base.
A method for epimerizing the compound represented by a). 12. A compound represented by the general formula (2): (In the formula, R ³ is a hydrogen atom or an amino group protecting group, R ⁴ is a hydrogen atom, a nitro group or an amino group, R ⁵ is a hydrogen atom or a hydroxyl group protecting group, and R ⁶ and R ⁷ are the same or Different from each other, a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, a benzyl group or a phenyl group, and Y and Z are the same or different from each other, an oxygen atom, a sulfur atom or a substituted imino group. ) A compound represented by the general formula (3): (Wherein R ³ , R ⁴ and R ⁵ have the same meanings as described above). 13. A compound represented by the general formula (6): (In the formula, R ^1a is COOR ¹ ; Or CH ₂ OH, R ^1b is a hydrogen atom or COOR ¹ (wherein R ¹ is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ⁶ and R ⁷ are the same or different and are a hydrogen atom or a carbon number. 1 to 6 linear or branched lower alkyl group, benzyl group, phenyl group, Y and Z are the same or different and each represents an oxygen atom, a sulfur atom or a substituted imino group), and R ³ is a hydrogen atom. Or a protecting group for an amino group, R ⁵ is a protecting group for a hydrogen atom or a hydroxyl group, and X is two hydrogen atoms or a single oxygen atom or a sulfur atom). A general formula (7) characterized by: (Wherein R ^1a , R ^1b , R ³ , R ⁵ and X have the same meanings as described above).