JPH0967374A - Method for producing 8-methylpyrroloindole derivative - Google Patents

Abstract

(57) Abstract: A method for efficiently producing a pyrroloindole derivative, which is expected to be used as an antibacterial or antitumor agent, is provided. A method for producing a pyrroloindole derivative represented by the following general formula (2) using a pyrroloindole derivative represented by the following general formula (1). Embedded image (In the formula, R ¹ is a protecting group for an amino group, R ² is a protecting group for a hydroxyl group, R ³ is a linear or branched lower alkyl group having 1 to 6 carbon atoms, X ¹ is a halogen atom, OH, OSO. ₂ R ⁴ (R ⁴
Represents a lower alkyl group, an aralkyl group, or an optionally substituted aryl group. ) Or OR ⁵ (R ⁵ is a hydroxyl-protecting group), X ² is a halogen atom, OH or OSO ₂ R ⁴ . )

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a pyrroloindole derivative which is expected to be used as an antibacterial or antitumor agent.

[0002]

2. Description of the Related Art Heretofore, there have been disclosed methods for producing several 7-methylcyclopropapyrroloindole derivatives and 8-methylpyrroloindole derivatives and their intermediates, which are expected to be used as antibacterial and antitumor agents. (For example, Japanese Patent Publication No. 2-502005, EP-0359454, JP-A No. 3-14581).

[0003]

[Problems to be Solved by the Invention] 7-Methylcyclopropapyrroloindole derivatives and 8 known so far
-Manufacturing intermediate of methylpyrroloindole derivative Gasman reaction is used in the manufacturing method of intermediate, and since this reaction must be carried out at extremely low temperature and complicated operation, it is not always an efficient method as an industrial manufacturing method. It was

An object of the present invention is to provide an efficient method for producing the intermediate.

[0005]

Means for Solving the Problems As a result of intensive studies, the present inventors reduced the specific pyrroloindole derivative, and thus the key of the pyrroloindole derivative expected to be used as an antibacterial and antitumor agent. The inventors have found that an 8-methylpyrroloindole derivative, which is a synthetic intermediate, can be efficiently obtained, and completed the present invention.

That is, the present invention is based on the general formula (1)

[0007]

Embedded image

(Wherein R ¹ is an amino-protecting group, R ² is a hydroxyl-protecting group, R ³ is a linear or branched lower alkyl group having 1 to 6 carbon atoms, X ¹ is a halogen atom, OH, OS
O ₂ R ⁴ (R ⁴ represents a lower alkyl group, an aralkyl group or an optionally substituted aryl group) or OR ⁵ (R ⁵
Represents a hydroxyl-protecting group). ) A general formula (2) characterized by reducing a pyrroloindole derivative represented by

[0009]

Embedded image

(In the formula, X ² is a halogen atom, OH or O
SO ₂ R ⁴ (R ⁴ represents a lower alkyl group, an aralkyl group, or an aryl group which may be substituted), and R ¹
And R ² are the same as above. The present invention relates to a method for producing an 8-methylpyrroloindole derivative represented by (4).

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The amino group-protecting group for R ¹ is a straight-chain or branched chain having 1 to 6 carbon atoms such as methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group and t-butoxycarbonyl group. Branched lower alkoxycarbonyl group; 2,2,2-trichloroethoxycarbonyl group and 2,2,2-trichloro-1,1-
Haloalkoxycarbonyl groups such as dimethylethoxycarbonyl group; benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, benzhydrylcarbonyl group, bis (4-methoxyphenyl) methoxycarbonyl group, trityloxycarbonyl group and fluorenylmethoxy. A substituted or unsubstituted aralkyloxycarbonyl group such as a carbonyl group; a substituted sulfonyl group such as a methylsulfonyl group, a phenylsulfonyl group, a 4-methylphenylsulfonyl group, a 4-methoxyphenylsulfonyl group and a 4-nitrophenylsulfonyl group is used.

As the protective group for the hydroxyl group of R ² , a straight-chain or branched lower alkyl group having 1 to 6 carbon atoms such as methyl group and ethyl group, benzyl group, 4-methoxybenzyl group, 2,4- Substituted or unsubstituted aralkyl groups such as dimethoxybenzyl group, benzhydryl group, bis (4-methoxyphenyl) methyl group and trityl group are used.

As the linear or branched lower alkyl group having 1 to 6 carbon atoms for R ³ , for example, a methyl group, an ethyl group, an isopropyl group and the like are used.

The lower alkyl group, aralkyl group and optionally substituted aryl group for R ⁴ are, for example, methyl group, benzyl group, phenyl group, 4-methylphenyl group, 4-methoxyphenyl group and 4-nitro group. A phenyl group etc. can be mentioned.

As the protective group for the hydroxyl group of R ⁵ , a straight-chain or branched lower alkanoyl group having 1 to 6 carbon atoms such as formyl group, acetyl group, methoxyacetyl group, phenoxyacetyl group and pivaloyl group; chloroacetyl Group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group and the like, which has a straight or branched lower haloalkanoyl group having 1 to 6 carbon atoms; and may be substituted such as benzoyl group and 4-phenylbenzoyl group. Aroyl group; linear or branched lower alkoxycarbonyl group having 1 to 6 carbon atoms such as methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group and t-butoxycarbonyl group; 2,2,2-trichloroethoxycarbonyl group And 2,2,2-trichloro-1,1-dimethylethoxycarbo Haloalkoxycarbonyl groups such as Le group; a benzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, benzhydryl carbonyl group,
A bis (4-methoxyphenyl) methoxycarbonyl group,
A substituted or unsubstituted aralkyloxycarbonyl group such as a trityloxycarbonyl group and a fluorenylmethoxycarbonyl group is used.

As a substituent on the aryl group in R ¹ , R ² , R ⁴ and R ⁵ , a lower alkyl group having 1 to 6 carbon atoms, a lower alkoxy group having 1 to 6 carbon atoms, a halogen atom,
Examples thereof include a nitro group and a phenyl group.

The reducing agent used in this reaction is R ¹
Any one can be used as long as it does not impair the amino-protecting group and the R ² hydroxyl-protecting group, and preferably, a diborane tetrahydrofuran complex, a dimethyl sulfide complex, a pyridine complex, a trimethylamine complex and the like. Examples thereof include diborane reagent, lithium aluminum hydride, N-methylpyrrolidine complex of lithium aluminum hydride, lithium aluminum hydride-aluminum chloride, diisobutylaluminum hydride, bis (2-methoxyethoxy) aluminum sodium hydride, and the like. Tetrahydrofuran complex of diborane is more preferable. And diborane reagents such as dimethyl sulfide complex, pyridine complex and trimethylamine complex.

The amount of the reducing agent used is preferably 5 to 20 equivalents relative to the compound of the general formula (1).

Any solvent can be used as long as it does not participate in the reaction, and the reaction proceeds smoothly at -78 ° C to 100 ° C.

[0020]

The usefulness of the present invention will be shown below with reference to Examples, but the present invention is not limited thereto.

Embodiment 1

[0022]

Embedded image

(S) -1-acetoxymethyl-5-benzyloxy-3-t-butoxycarbonyl-1,2,
Methyl 3,6-tetrahydropyrrolo [3,2-e] indole-8-carboxylate 100 mg (0.20 mmo
1) was dissolved in anhydrous tetrahydrofuran, and 2 ml of a solution of a tetrahydrofuran complex of diborane (1.0M, 2.0
mmol) was added, and the mixture was heated under reflux for 19 hours under an argon stream. A 10% aqueous citric acid solution was added to the reaction solution, and the mixture was heated with stirring for 15 minutes. After extraction with ethyl acetate, the extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The residue obtained by concentration is purified by silica gel column chromatography (dichloromethane: ethyl acetate = 6: 1) to give (S) -5-benzyloxy-3-t-butoxycarbonyl-1-hydroxymethyl-8-. Methyl-1,
39.2 mg (48%) of 2,3,6-tetrahydropyrrolo [3,2-e] indole was obtained.

[0024] NMR (CDCl ₃ ) δ: 1.58 (9H, s), 2.40 (3H, s), 3.6
0-3.80 (2H, m), 3.82-3.94 (1H, m), 4.01 (1H, dd, J
= 9Hz, J = 11Hz), 4.20 (1H, brd, J = 10Hz), 5.21
(2H, s), 6.92 (1H, s), 7.35 (1H, t, J = 7Hz), 7.40
(2H, t, J = 7Hz), 7.47 (1H, d, J = 7Hz), 7.71 (1
H, brs), 8.09 (1H, brs).

[0025]

EFFECTS OF THE INVENTION By reducing the indole derivative represented by the general formula (1) produced by the present invention, several 7-methylcyclopropapyrroloindole derivatives and 8 which are expected to be used as anticancer agents The 8-methylpyrroloindole derivative represented by the general formula (2), which is a synthetic intermediate of the methylpyrroloindole derivative, can be easily produced.

Claims (1)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R ¹ is a protecting group for an amino group, R ² is a protecting group for a hydroxyl group, R ³ is a linear or branched lower alkyl group having 1 to 6 carbon atoms, X ¹ is a halogen atom, OH, OSO. ₂ R ⁴ (R ⁴
Represents a lower alkyl group, an aralkyl group, or an optionally substituted aryl group. ) Or OR ⁵ (R ⁵ is a hydroxyl-protecting group). ) A general formula (2) characterized by reducing a pyrroloindole derivative represented by: (In the formula, X ² is a halogen atom, OH and OSO ₂ R ⁴ (R ⁴
Represents a lower alkyl group, an aralkyl group, or an optionally substituted aryl group. ) And R ¹ and R ² are the same as above. The manufacturing method of the 8-methyl pyrrolo indole derivative represented by these.