JPH0680632A - 2,3-di-substituted-5-hydroxyindole derivative and its production - Google Patents

Abstract

PURPOSE:To obtain a 2,3-di-substituted-5-hydroxyindole derivative useful for dyes, agricultural chemicals, medicines, perfumes and various kinds of recording material uses or as a raw material therefor and a method for producing the derivative. CONSTITUTION:The objective 1-arylamino-2,3-di-substituted-5-hydroxyindole derivative. The objective method for producing the 1-arylamino-2,3-di- substituted-5-hydroxyindole derivative is characterized by reacting a (E) or (Z)-3-(alpha,beta-di-substituted ethenyl)phenol derivative with an aromatic diazonium salt or its precursor. In this derivative, a substituent group is selected from 1-18C alkyl group which may be substituted, aryl group or halogen atom. 4,6,7- Position thereof may be substituted with alkyl group which may be substituted, alkoxy group, aryl group, substituted amino group, halogen atom, acyl group, etc.

Description

Detailed Description of the Invention

[0001]

The present invention relates to 2,3-disubstitution-5-
The present invention relates to derivatives of hydroxyindoles and a method for producing the same.

[0002]

2. Description of the Related Art Indole derivatives having a hydroxy group at the 5-position as proposed in the present invention are described as reducing agents,
It is useful as an intermediate for various applications such as radical quenchers, pharmaceuticals, pesticides, dyes, leuco pigments, raw materials for couplers, raw materials for alkaloids, but it has not been studied much because of its difficulty in synthesis.

[0003]

DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted intensive studies focusing on the fact that this compound is useful for agricultural chemicals, pharmaceuticals, degradable polymers and various recording materials. Then, the present invention was made. The inventor has already
Phenol having an α, β-unsaturated double bond at the position
It has been found that a coupling reaction with a diazonium salt gives a 5-hydroxyindole derivative. See Japanese Patent Application No. 58-248910. However, the steric positional relationship of the substituent with respect to the double bond was not sufficiently clarified there. That is, in the present specification, the reaction in which the hydrogen atom at the β-position is on the same side with respect to the aromatic ring having a hydroxyl group at the 3-position [for convenience, is referred to as (E) type] is shown as a formula. Was there.

However, in a double bond forming reaction utilizing a dehydration reaction from a secondary alcohol, a hydrogen atom at the β-position is located on the same side of an aromatic ring having a hydroxyl group at the 3-position (E type). ) And the opposite case (for convenience,
An equilibrium mixture of about 1: 1 is obtained. Therefore, (Z) and / or (E) -3- (α, β
-The difficulty of separating the di-substituted ethenyl) phenol derivative was assumed. Furthermore, when a diazonium salt is allowed to act on this mixture, a 1: 1 mixture of an indole derivative cycloadded in the molecule and a phenol derivative having an arylazo group at the 4-position and substituted at the 3-position is expected to be formed. Was done. Both of them were considered to have almost the same molecular weight and characteristics, and it was expected that the separation would be even more remarkable. Therefore, the synthesis of 2,3-disubstituted 5-hydroxyindole was expected, but not thoroughly investigated.

However, according to the inventor's subsequent detailed examination, these expectations were unexpectedly completely reversed, and a single 1H-indol-5-ol derivative was obtained in a substantially quantitative yield. It was found. It was found that there was no need to purify the phenol derivative at the stage, and the present invention was completed.
The present invention is a derivative of 2,3-disubstituted-5-hydroxyindoles in high yield without separating (Z) and (E) -3- (α, β-disubstituted vinyl) phenol derivatives. And a method of manufacturing the same. It provides a remarkably simple and advantageous method for industrial production.

[0006]

The above-mentioned problems are characterized in that a diazonium salt is allowed to act on a (Z) and / or (E) -3- (α, β-disubstituted vinyl) phenol derivative in a basic atmosphere. It was solved by developing a 1-arylamino-2,3-disubstituted-5-hydroxyindole derivative and a method for producing the same. After the diazo coupling reaction, it is preferable to use an organic or inorganic acid catalyst in order to accelerate the intramolecular cycloaddition reaction. In the reaction, various solvents, bases, acids or nitrogen gas may be used.

The amount of the diazonium salt is about 0.60 to 2.0 mol, preferably about 0.93 to 1.0 mol, based on the phenol used in the present invention. Above this range, 2 mol of diazo coupling reaction is likely to occur, and below this range, unreacted phenol as a raw material is likely to remain, and a separation step is essential in both cases. (By further performing a coupling reaction using 2 mol of diazonium salt, the further reacted 6-arylazo-substituted product is quantitatively obtained.) These rings are further alkyl group, alkoxy group, hydroxy group, halogen atom, Aryl group, acyl group, optionally substituted amino group, such as amino group, dialkylamino group, acylamino group, ureido group, alkylamino group, arylamino group, carboxy group, oxo group, alkoxycarbonyl group, and the like Substituent of 1
It may include about 1 to 6 pieces. These may be substituted on the aliphatic unsaturated bond portion or the aromatic ring portion.

Some specific examples of the compound of the present invention are shown below. Examples of the (Z) and / or (E) -3- (α, β-disubstituted ethenyl) phenol derivative include an alkyl group which may be substituted as a side chain substituent, an aryl group,
It is selected from an alkoxy group, an acyl group or an aryloxy group, preferably an alkyl group or an aryl group. These are further acyl group, cyano group, nitro group, halogen atom, hydroxy group, alkoxy group, thioalkoxy group, carboxyl group, substituted amino group, carbamoyl group,
It may have one or more selected from a sulfamoyl group, a pyridyl group, a furyl group, a furoyl group, an azo group, a sulfo group, a chlorobenzoyl group, a ureido group and the like.

These may have two or more kinds as long as they do not interfere with the diazo coupling reaction.
On the other hand, the aromatic ring portion of 3-substituted phenol preferably has a hydrogen atom at the 4-position with respect to the hydroxy group of phenol. The 2-position, 5-position and 6-position may have various substituents which do not interfere with the diazo coupling reaction. That is, an alkyl group, an aryl group, an acyl group,
Cyano group, nitro group, halogen atom, hydroxy group, mercapto group, alkoxy group, carbonyl group, oxa group,
It is selected from a thioalkoxy group, a carboxyl group, a substituted amino group, a carbamoyl group, a sulfamoyl group, an azoxy group, an arylazo group, a sulfo group and a ureido group. These are 5 to 8 members in positions adjacent to each other.
It may have a cyclic structure composed of non-metal atoms.

A ring structure which may contain a 5-membered to 6-membered oxygen atom and / or a sulfur atom is a preferable example. For ease of synthesis, alkyl group, aryl group, acyl group, halogen atom, hydroxy group, alkoxy group,
Substituted amino groups, sulfo groups, carboxyl groups and the like are highly preferred as substituents. Hereinafter, some specific examples will be described in detail. In the present invention, contrary to expectations,
It has been clarified that the (Z) and / or (E) -3- (α, β-disubstituted ethenyl) phenol derivative can be subjected to the diazo coupling reaction as an isomer mixture without separation and purification. . Needless to say, the fact that the indoles can be efficiently obtained is novel and particularly important.

(Z) and / or (E) -3- (α, β-
Dimethyl vinyl) phenol, (Z) and / or (E)
─3- (α, β-diethyl vinyl) phenol, (Z)
And / or (E) -3- (α, β-dibutylvinyl) phenol, (Z) and / or (E) -3- (α, β-diamylvinyl) phenol, (Z) and / or (E)-
3- (α-methyl-β-ethylvinyl) phenol,
(Z) and / or (E) -3- (α-ethyl-β-methylvinyl) phenol, (Z) and / or (E) -3-
(Α-methyl-β-butylvinyl) phenol, (Z)
And / or (E) -3- (α-ethyl-β-amylvinyl) phenol,

Z) and / or (E) -3- (α-hexyl-β-amylvinyl) phenol, (Z) and / or (E) -3- (α-butyl-β-amylvinyl) phenol, (Z ) And / or (E) -3- (α-phenethyl-β-benzylvinyl) phenol, (Z) and / or (E) -3- (α-ethyl-β-amylvinyl) phenol, (Z) and / or Or (E) -3- (α-phenethyl-β-benzylvinyl) phenol, (Z) and / or (E) -3- (α-ethyl-β-amylvinyl) phenol, (Z) and / or (E) ) -3- (α-phenyl-
β-benzyl vinyl) phenol,

(Z) and / or (E) -3- (α-phenyl-β-amylvinyl) phenol, (Z) and / or (E) -3- (α-phenyl-β-benzylvinyl)
Phenol, (Z) and / or (E) -3- (α-tolyl-β-amylvinyl) phenol, (Z) and / or (E) -3- (α-phenyl-β-methylvinyl) phenol, ( Z) and / or (E) -3- (α-phenyl-β-ethylvinyl) phenol, (Z) and / or (E) -3-((α-phenyl-β-butenylvinyl) phenol, (Z) and / or Or (E) -3- (α-tolyl-β-tolyl vinyl) phenol,

(Z) and / or (E) -3- (α, β-
Dimethyl vinyl) -5-methyl-phenol, (Z) and / or (E) -3- (α, β-diethyl vinyl) -5
-Methyl-phenol, (Z) and / or (E) -3-
(Α, β-Dibutylvinyl) -5-methoxy-phenol, (Z) and / or (E) -3- (α, β-Diamylvinyl) -5-chloro-phenol, (Z) and / or (E) ─ 3 ─ (α-methyl ─ β ‐ ethyl vinyl) ─ 5 ─
Fluoro-phenol, (Z) and / or (E) -3-
(Α-ethyl-β-methylvinyl) -6-chloro-phenol, (Z) and / or (E) -3- (α-methyl-
β-butyl vinyl) -6-methoxy-phenol,

(Z) and / or (E) -3- (α-ethyl-β-amylvinyl) -5,6-dimethoxy-phenol, (Z) and / or (E) -3- (α-hexyl-
β-amyl vinyl) -6-fluoro-phenol,
(Z) and / or (E) -3- (α-butyl-β-amylvinyl) -6-benzyloxy-phenol, (Z)
And / or (E) -3- (α-phenethyl-β-benzylvinyl) -5-chloro-phenol, (Z) and / or (E) -3- (α-ethyl-β-amylvinyl) -6
-Fluoro-phenol,

(Z) and / or (E) -3- (α-phenethyl-β-benzylvinyl) -5,6-methylenedioxy-phenol, (Z) and / or (E) -3- (α)
-Ethyl-β-amylvinyl) -6-, ethoxy-phenol, (Z) and / or (E) -3- (α-phenyl-β-benzylvinyl) -6-chloro-phenol,
(Z) and / or (E) -3- (α-phenyl-β-amylvinyl) -6-benzoyl-phenol, (Z) and / or (E) -3- (δ-phenenoxybutyl-ε-
Phenoxypenten-1-yl) -5,6-methylenedioxy-phenol, (Z) and / or (E) -3-
(Δ-methoxybutyl-ε-methoxypenten-1-yl) phenol, (Z) and / or (E) -3- (δ-
Butoxybutyl-ε-butoxypenten-1-yl) phenol,

(Z) and / or (E) -3- (δ-phenenoxybutyl-ε-phenoxypenten-1-yl)
Phenol, (Z) and / or (E) -3- (α-phenyl-β-benzylvinyl) -6-acetyl-phenol, (Z) and / or (E) -3- (α-tolyl-β-
Amyl vinyl) -5-methyl-phenol, (Z) and / or (E) -3- (α-phenyl-β-methyl vinyl) -2-methyl-phenol, (Z) and / or (E) -6- (1-ethyl-1-propenyl) -1,3
-Benzodioxo-4-ol, (Z) and / or (E) -6- (1-butyl-1-pentenyl) -1,3
--Benzodioxo-4-ol, (Z) and / or (E) -6- (1-amyl-1-hexenyl) -1,3
--Benzodioxo-4-ol, (Z) and / or (E) -6- (1-benzyl-1-styryl) -1,3
-Benzodioxo-4-ol, (Z) and / or (E) -3- (α-phenyl-β-ethyl vinyl)-
2,5-Dimethyl-phenol, (Z) and / or (E) -3- (α-phenyl-β-butenylvinyl)-
2-methyl-6-methoxy-phenol, (Z) and /
Or (E) -3- (α-4-tolyl-β-4-tolylvinyl) -6-phenyl-phenol and the like.

1-Arylamino-2,3-disubstituted-5
-Hydroxyindole (wherein the substituent is selected from an alkyl group, an alkoxy group, an aryloxy group or an aryl group) can be obtained by reacting a stereoisomeric mixture of the above phenol derivative with a diazonium salt. In the present invention, the type and usage of the diazonium salt will be described later. For convenience, the nomenclature using benzenediazonium salt is representative. It is not necessary for a person skilled in the art to explain that various diazonium salts are easily used in the diazo coupling reaction, and that many commercially available products can be conveniently used.

Specific examples of the indole of the present invention include:
1-anilino-2-methyl-3-ethyl-5-hydroxyindole, 1-anilino-2-ethyl-3-propyl-5-hydroxyindole, 1-anilino-2-butyl-3-amyl-5-hydroxyindole 1-anilino-2-amyl-3-hexyl-5-hydroxyindole, 1-anilino-2-benzyl-3-phenethyl-5-hydroxyindole, 1-anilino-2-phenethyl-3-phenylpropyl-5- Hydroxyindole, 1-anilino-2-octyl-3-nonyl-5
-Hydroxyindole, 1-anilino-2-decyl-
3-dodecyl-5-hydroxyindole,

1-anilino-2-butyl-3-phenyl-5-hydroxyindole, 1-anilino-2-amyl-3-phenyl-5-hydroxyindole, 1-anilino-2-benzyl-3-phenyl-5 -Hydroxyindole, 1-anilino-2-phenethyl-3-phenyl-5-hydroxyindole, 1-phenylamino-2-phenyl-3-benzyl-5-hydroxy-indole, 1-anilino-2-butyl-3-t -Butyl-
5-hydroxyindole, 1-anilino-2-methyl-3-phenyl-5-hydroxyindole, 1-anilino-2-benzyl-3-t-octyl-5-hydroxyindole, 1-anilino-2-phenethyl-3 -Chlorophenyl-5-hydroxyindole,

1-anilino-2-methyl-3-ethyl-
5-hydroxy-6-methyl-indole, 1-anilino-2-ethyl-3-propyl-5-hydroxy-6-
Ethoxy-indole, 1-phenylamino-2-phenyl-3-benzyl-5-hydroxyindole, 1-
Trilylamino-2-phenyl-3-benzyl-5-hydroxyindole, 1-xylylamino-2-tolyl
3-benzyl-5-hydroxy-indole, 1-p-
Sulfophenylamino-2-tolyl-3-benzyl-5
-Hydroxy-indole, 1-p-carboxyphenylamino-2-tolyl-3-benzyl-hydroxy-indole,

1-p-chloro-o-carboxyphenylamino-2-tolyl-3-phenylethyl-5-hydroxy-indole, 1-phenylamino-2- (3-phenoxypropyl) -3- (4-phenoxy) Butyl) ─
5-hydroxy-indole-5, 1-xylylamino-2- (3-phenoxypropyl) -3- (4-phenoxybutyl) -5-hydroxy-indole, 6-ethyl-7-methyl-8- (phenylamino) -8H-1,
3-dioxolo [4,5-g] indo-le-4-o-
, 6-butyl-7-propyl-8- (phenylamino) -8H-1,3-dioxolo [4,5-g] indo-4-ol, 6-phenyl-7-propyl-8 ─
(Phenylamino) -8H-1,3-dioxolo [4,4
5-g] indol-4-ol, 1-phenylamino-2- (3-chlorophenoxypropyl) -3- (4-
α-naphthoxybutyl) -5-hydroxy-indole, 1-xylylamino-2- (4-phenoxybutyl) -3- (4-phenoxybutyl) -5-hydroxy-indole, 1-phenylamino-2- (3-chloro) Phenoxypropyl) -3- (4-α-naphthoxybutyl) -5-hydroxy-indole, 1-xylylamino-2- (4-phenoxybutyl) -3- (4-phenoxyisopentyl) -5-hydroxy-indole,

1-anilino-2-butyl-3-amyl
5-hydroxy 6-chloro-indole, 1-anilino-2-amyl-3-hexyl-5-hydroxy-5-methyl-indole, 1-anilino-2-benzyl-3-
Phenethyl-5-hydroxy-5,6-methylenedioxy-indole, 1-anilino-2-phenethyl-3-
Phenylpropyl-5-hydroxy-6-fluoro-indole, 1-anilino-2-octyl-3-nonyl-
5-hydroxy-6-methylindole, 1-anilino-2-decyl-3-dodecyl-5-hydroxy-5-methyl-6-methoxy-indole

1-β-naphthylamino-2-phenyl-
3-benzyl-5-hydroxyindole, 1-tolylamino-2- (3-chlorophenyl) -3- (4-methoxybenzyl) -5-hydroxyindole, 1-xylylamino-2- (2-carboxyphenyl) -3-
(3-hydroxybenzyl) -5-hydroxyindole, 1-p-sulfophenylamino-2-tolyl-3
-Butyl-5-hydroxy-indole, 1-phenylamino-2-tolyl-3- (δ-hydroxybutyl)-
Examples thereof include hydroxy-indole, 1-p-chloro-o-carboxymethylphenylamino-2-tolyl-3-phenylethyl-5-hydroxy-indole and the like. As described in detail in Examples, these compounds are efficiently synthesized by a reaction route which is completely unexpected from the conventional method.

In the present invention, contrary to the conventional prediction of unusual indole ring formation reaction, (Z) and / or (E) -3-
It is particularly important to find that the (α, β-disubstituted vinyl) phenol derivative can be subjected to the diazo coupling reaction without separation and purification, and the indoles can be obtained efficiently. Is. As the diazonium salt, it is particularly preferable to use a diazonium salt derived from an aromatic amine. For the post-treatment, it is preferable to use an acid, an organic or inorganic acid. The reactions using these diazonium salts have already been detailed in the textbooks. For example, S.Patai.The Chemistry
of Diazonium and Diazo Groups.John Wiley & Sons (1
978) .KH Saunders.Aromatic Diazo Compounds3rd ed.E
dward Arnold.A.Katritzky, CWRees.Comprehensive He
terocyclic Chemistry vol.4 (1984) Pergamon Press.
In addition, you can refer to various reaction conditions such as preparation method, addition method, processing conditions or processing temperature in detail in Maruzen's experimental chemistry course (including positive, continuous, and new).

For example, the diazonium salt is preferably prepared in an acidic atmosphere and stored at low temperature. hydrochloric acid,
Inorganic acids such as sulfuric acid, zinc chloride, nitric acid, phosphoric acid, derivatives of boron trifluoride, phosphorus hexafluoride, etc., and organic acids such as acetic acid, benzenesulfonic acid, methanesulfonic acid, halogenoacetic acid are conveniently used. The coupling reaction with the phenols of the present invention is preferably carried out in a basic atmosphere. As the base, various inorganic or organic alkalis are used.
Examples are caustic soda, caustic potash, sodium carbonate, triethylamine, triphenylguanidine, guanidine, and dimethylpiperidine. The most convenient technique is to carry out the coupling reaction under a basic atmosphere and acidify it in the post-treatment. In particular, the reaction at −5 ° C. or lower is preferable in the present invention from the viewpoint of reduction of by-products, but if appropriately controlled, the system is heated to about 120 to 150 ° C. to make the system basic and isolated. It is also possible to facilitate purification.

The present invention will be described below with reference to examples. Synthesis Example-1 Synthesis of (Z) and / or (E) -3- (α-ethyl-1-propenyl) phenol (Examples in which both α-position and β-position are alkyl groups are shown. 3- (1- Ethyl-propen-1-yl) Synthesis of phenol) 4 mol equivalent of ethylmagnesium bromide was reacted with m-hydroxybenzoic acid ethyl ester to give 3-
(3-Hydroxyphenyl) -3-pentanol was obtained. This was heat-treated at 175 ° C. with acidic potassium sulfate and dehydrated to obtain the desired 3- (α-ethyl-1-propenyl) phenol. Boiling point is 143.5-145
C / 14 mmHg was shown.

The product showed a single spot on TLC. Liquid chromatography (Shimadzu CHROMATO
When PAC-C-R4A) was used for the separation at detection wavelengths of 240 nm and 280 nm, the existence of two components showing a peak intensity of approximately 1: 1 at any wavelength was confirmed. this is,
It shows that (Z) -3- (α-ethyl-1-propenyl) phenol and (E) -3- (α-ethyl-1-propenyl) phenol are present at a ratio of approximately 1: 1. As described above, two types of stereoisomers are produced in the dehydration reaction of the tertiary alcohol.

Synthesis Example 2 Synthesis of (Z) and / or (E) -3- (α-phenyl-1-propenyl) phenol (Examples in which the α-position is an aryl group and the β-position is an alkyl group are shown. 3-Synthesis of (1-phenyl-propen-1-yl) phenol) Prepared from 3-methoxyphenylmagnesium bromide and propiophenone in a flask equipped with a stirrer and equipped with a nitrogen gas inlet tube 3- ( α-phenyl-
1-propenyl) anisole 9.2 g (boiling point 178-
180 ° C / 13mmHg), and pyridine hydrochloride 10g
Was added. Continue to stir vigorously at 200 ° C. for about 3 hours while gradually passing nitrogen gas. Then, post-treatment was performed using benzene as an extraction solvent. Yield about 8g. this,
Purification by column chromatography using a mixed solvent of hexane-acetic acid ethyl ester. Thus, (Z) and / or (E) -3- (α-phenyl-β-methylvinyl) phenol was obtained.

Synthesis Example 3 Synthesis of (Z) and / or (E) -6- (1-ethyl-1-propenyl) -1,3-benzodioxo-l-4-ol (unsaturated group at 3-position) Here, an example of a phenol in which the substituents at the 5,6-positions are bonded to each other to form a ring is shown.
(Synthesis of 1-ethyl-1-propenyl) -5,6-methylenedioxyphenol) In a flask, weigh 4-hydroxy-1,3-benzodioxole-6-carboxylic acid propyl ester. This was reacted with excess ethylmagnesium bromide in THF according to a conventional method. The resulting tertiary alcohol was dehydrated using an acid catalyst and purified in the same manner as above to obtain the desired product. Melting point 82-6 ° C. Yield 55%. CH analysis, calculated value. C: 58.92. H: 5.39. Measured value. C: 5
8.71. H: 5.47.

Synthesis Example 4 Synthesis of (Z) and / or (E) -3- (1-ethyl-1-propenyl) -6-methylphenol (unsaturated group at 3-position and alkyl group at 6-position) An example of phenol substituted with is shown below.) Same as Synthesis Example-3. Weigh out 4-hydroxy-5-methylbenzoic acid ethyl ester. An excess of ethylmagnesium bromide was reacted with this. The produced tertiary alcohol was dehydrated using an acid catalyst to obtain the desired product.
liquid. Yield 70%. From NMR and HRMS, it was confirmed to be the desired product.

Synthesis Example 5 Synthesis of (Z) and / or (E) -3- (1-ethyl-1-propenyl) -6-methoxyphenol (unsaturated group at 3-position and alkoxy group at 6-position) An example of phenol substituted with is shown below.) Same as Synthesis Example-3. Weigh 4-hydroxy-5-methoxybenzoic acid methyl ester. An excess of ethylmagnesium bromide was reacted with this. The produced tertiary alcohol was dehydrated using an acid catalyst to obtain the desired product. liquid. Yield 72%. From NMR and HRMS, it was confirmed to be the desired product.

The method of the present invention will be described in detail below with reference to examples.

【Example】

Example 1 1-anilino-2-methyl-3-ethyl-5-hydroxy-indole (Z) and / or (E) -3- (α obtained in Synthesis Example-1
-Ethyl-β-methylvinyl) phenol 1.64
g, triethylamine 10 ml, methanol 50 m
1 and 100 ml of acetone are added to the eggplant-shaped flask. Cool it to below -10 ° C and stir vigorously. According to a conventional method, benzenediazonium salt prepared from 0.93 g of aniline was gradually added thereto. After the addition was completed, the cooling bath was removed and the mixture was stirred for 30 minutes. This is 60
It was added to a solution obtained by adding 10 ml of 35% hydrochloric acid water to 0 ml of water. The organic phase was extracted with ethyl acetate and post-treated in the usual way, and the solvent was distilled off.

The product showed a substantially single spot on TLC, and the presence of the product derived from the fact that the raw material had two components was not detected. Column chromatography was performed to obtain crystals. White crystals with a melting point of 134.2 to 135.4 ° C.
Obtained in% yield. From this fact, it is found that not only the (Z) form but also the (E) form, which is easily assumed to be extremely disadvantageous for the cycloaddition reaction, performs the indole ring forming reaction in the present invention. did.

Example 2 1- (2-methoxy-5-chlorophenylamino) -2
-Methyl-3-ethyl-5-hydroxy-indole (Z) and / or (E) -3- (α obtained in Synthesis Example-1
-Ethyl-β-methylvinyl) phenol 0.81
g, 5 ml of triethylamine and 50 ml of acetone are added to an eggplant-shaped flask. Cool it to below -10 ° C and stir vigorously. An equivalent amount of commercially available Diazo Red
RC (diazonium salt prepared from 2-methoxy-5-chloroaniline) is added slowly. After the addition was completed, the cooling bath was removed and the mixture was stirred for 30 minutes. This was added to a liquid prepared by adding 5 ml of 35% hydrochloric acid water to 300 ml of water.

The organic phase was extracted with ethyl acetate and post-treated in a conventional manner, and the solvent was distilled off. The product is T
An almost single spot was shown on the LC, and the presence of a product derived from the fact that the raw material was binary was not detected. The crude yield was 1.1 g. Thus, it was revealed that not only the (Z) form but also the (E) form undergoes an indole ring forming reaction even if the diazonium salt used is changed.

Example 3 1-anilino-2-methyl-3-phenyl-5-hydroxy-indole (Z) and / or (E) -3- (α obtained in Synthesis Example-2
-Phenyl-β-methylvinyl) phenol 1.50
g, 5 ml of triethylamine and 100 ml of acetone
Is added to the eggplant-shaped flask. Cool it to below -10 ° C and stir vigorously. According to the standard method, 0.93
Benzene diazonium salt prepared from g aniline is added slowly. After the addition was completed, the cooling bath was removed and the mixture was stirred for about 2 hours. This was added to a 2000 ml beaker in which 10 ml of 35% hydrochloric acid water was added to 600 ml of water. The organic phase was extracted with ethyl acetate and post-treated according to a conventional method to distill off the solvent. The product showed almost a single spot on TLC, and the presence of the product corresponding to the isomer was not detected. Column chromatography was performed to obtain white crystals having a melting point of 139.8 to 140.7 ° C. Yield 8
6%. The CH analysis value showed H, 5.87: C, 80.40: N, 8.88, which was in good agreement with the calculated value.

Example 4 1-Phenylamino-2-phenyl-3-benzyl-5
-Hydroxy-indole Other than substituting 3- (1-benzyl-β-phenylethenylphenol) for (Z) and / or (E) -3- (α-phenyl-β-methylvinyl) phenol of Example 3 Is 1-phenylamino-2-phenyl-3-benzyl-5-hydroxy-indole.Also known as (1-phenylamino-2-phenyl-3-benzyl-1H-indole-5-ol). Yield 88%, melting point 13
6.2-138.2 ° C.

Example 5 1-Phenylamino-2-β-phenylethyl-3-γ
-Phenylpropyl-1H-indole-5-ol The (Z) and / or (E) -3- (α-phenyl-β-methylvinyl) phenol of Example 3 was replaced with 3- (1-phenylpropyl- δ-Phenyl-1-butenyl) phenol, but 1-phenylamino-2-
β-Phenylethyl-3-γ-phenylpropyl-1H
-I got an indole-5-hole. Yield 84%. Melting point
123.2-124 ° C.

Example 6 1-Phenylamino-2- (3-phenoxypropyl)
─ 3- (4-phenoxybutyl) -1H ─ indole ─
5-ol The (Z) and / or (E) -3- (α-phenyl-β-methylvinyl) phenol of Example 3 was replaced with 3- (1-phenoxybutyl-ε-phenoxy-1-pentenyl). 1-Phenylamino-
2- (3-phenoxypropyl) -3- (4-phenoxybutyl) -1H-indole-5-ol was obtained. Yield 85%. Liq.

Example 7 6-Ethyl-7-methyl-8- (phenylamino) -8
H-1,3-dioxolo [4,5-g] -indole-
4-ol The (Z) and / or (E) -3- (α-phenyl-β-methylvinyl) phenol of Example 3 was 6- (1-ethyl-1-propenyl) shown in Synthesis Example 3. -1,3-Benzodioxole-4-ol
-Ethyl-7-methyl-8- (phenylamino) -8H
-1,3-Dioxolo [4,5-g] -indole-4
─ Got it. Yield 46%. Melting point 85.2-88.
2 ° C.

Example 8 2,6-Dimethyl-3-ethyl-1- (phenylamino) -1H-indole-5-ol The 3- (α-phenyl-β-methylvinyl) phenol of Example 3 was used. 2,6-Dimethyl-3-ethyl-1- (phenylamino) -1H- was obtained in the same manner except that 3- (1-ethyl-1-propenyl) -6-methylphenol shown in Synthesis Example 4 was replaced. I got an indole-5 ol. Yield 82%. Melting point 130.2-131.8 [deg.] C. CH analysis,
Calculated values. C: 77.11. H: 7.19. N: 10.0
0. Measured value. C: 77.04. H: 7.32. N: 9.
92.

Example 9 3-Ethyl-6-methoxy-2-methyl-1- (phenylamino) -1H-indole-5-ol Example 3 (Z) and / or (E) -3- The same except that (α-phenyl-β-methylvinyl) phenol is replaced with (Z) and / or (E) -3- (1-ethyl-1-propenyl) -6-methoxyphenol shown in Synthesis Example 5. Then, 3-ethyl-6-methoxy-2-methyl-1-
(Phenylamino) -1H-indole-5-ol was obtained. Yield 82%. Melting point 135.2-136.8 ° C.
CH analysis, calculated value. C: 72.95. H: 6.80.
N: 9.45. Measured value. C: 73.03. H: 6.9
5. N: 9.39.

As shown in these examples, it has been clarified that the reaction of this E / Z mixture is a general method which does not depend on the size and type of various substituents. From this fact, it was revealed that the (E) form, which is easily assumed to be extremely disadvantageous for the cycloaddition reaction, can also be used for the indole ring formation reaction by the method of the present invention. Conventionally, a convenient method for synthesizing a 5-hydroxyindole derivative is substantially Nenitzescu.
Only the law was found. In addition, in the method already proposed by the present inventor, when the stereoisomer is used as a starting material, it is expected to be difficult to separate the product as a starting material and the product which is supposed to have similar properties. It was However, from the fact that the findings that completely disappoint were obtained, this "indole ring formation reaction utilizing an intramolecular cycloaddition reaction" proposed in the present invention will be used in the future, including serotonin, hydroxytryptophan, etc. Will bring a powerful weapon to the development of heterocyclic compounds.

Claims (2)

[Claims] 1. 1-Arylamino-2,3-disubstituted-5
-Hydroxyindole (wherein the substituent is selected from an optionally substituted alkyl group, alkoxy group, aryloxy group or aryl group). 2. A 1-arylamino compound characterized in that a diazonium salt is allowed to act on a mixture of (Z) and (E) -3- (α, β-disubstituted ethenyl) phenol derivatives.
Process for producing 2,3-disubstituted-5-hydroxyindole derivative.