JPS5984864A - Preparation of 4-substituted indole - Google Patents

Abstract

PURPOSE:To prepare the titled substance useful as a preparation raw material of physiologically active substances, by the dehydrogenative oxidation of a 4-methylidene-4,5,6,7-tetrahydroindole derivative in the presence of an 8-group metal catalyst such as Pd. CONSTITUTION:The objective compound of formula II can be prepared by the dehydrogenative oxidation of the compound of formula I (R<1> is CN, COOH, or alkoxycarbonyl; R<2> is H, alkyl, aralkyl or amino-protecting group) in the presence of an 8-group metal catalyst (preferably Pd catalyst). The reaction is preferably carried out in a solvent such as aromatic hydrocarbon, ether, etc. The side reactions such as disproportionation reaction, etc. can be suppressed by blowing an inert gas such as nitrogen, argon, etc. in the reaction system during the reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (wherein R1 is a cyano group, a carboxyl group, or a cyano group, and 'R2 is a protecting group for hydrogen, an alkyl group, an aralkyl group, or an amino group). ) The present invention relates to a method for producing a 4-substituted indole represented by

The protecting group for the amino group used in the present invention is a tosyl group,
alkoxycarbonyl group, aryloxycarbonyl group,
This refers to a group such as an acyl group that can be easily eliminated.

4 represented by the general formula (I) obtained according to the present invention
-Substituted indoles are useful as raw materials for producing compounds with various physiological activities such as ergot alkaloids ('H, P
Iieninger and K-8uhr, 13
Er, .

9 (L 1980 (1957L H, Plienin
ger and W.

M'A11ler, Ber, + 93+ 2024
(1960).

Conventionally, among the compounds obtained by the present invention, for example, methods for producing 4-cyanmethylindole, 4-indoleacetic acid and derivatives thereof include (1) 1-acetamino-5,8
- Dihydronaphthalene tube A method in which ozonolysis is performed at low temperature and then synthesized through several steps (H, Pieninger a
nd K, 5uhr, Ber, +89+270 (
1956)) and 2-methyl-3-nitrobenzoic acid 9
Method of synthesis through 10 or more steps [Q8, Font
icello and J, J, Baldwin,
J, Org.

Chem., 44.4003 (1979)) and conventional methods, both require a long number of steps and are complicated to operate, making them difficult to adopt industrially.

The inventors of the present invention have discovered and completed the present invention as a result of intensive studies on an industrial method for producing 4f-converted indole.

The present invention relates to the general formula 4 (wherein 1 is a cyano group, a carboxyl group, or an alkoxycarbonyl group, and R2 is hydrogen, an alkyl group, an aralkyl group, or a protecting group for an amine group).
-Methylidene-4,5,6,7-titrahydroindole derivative by dehydrogenation oxidation, the above general formula α)
A 4-substituted indole represented by the following formula is produced.

4- represented by the general formula (6), which is the raw material of the present invention
Methylidene-4,5,6,7-titrahydroindole is a compound that can be easily obtained by condensing 4-oxo-4,5,6,7-titrahydroindole with a phosphonic acid ester. Yes (see reference side below) 0 The present invention relates to 4-oxo-4,5 represented by the general formula
, 6,7-titrahydroindole is dehydrogenated and oxidized. Dehydrogenation can be achieved by a method using an oxidizing agent such as Floranil, DDQ, manganese dioxide, mercury acetate, palladium (2) salt, etc., or a method using a catalyst, but from the viewpoint of reaction efficiency, economical efficiency, etc., the method using a catalyst is preferred. It is preferable to do so.

As the catalyst, a Group 8 metal catalyst is used, for example, palladium catalyst such as palladium-carbon, palladium-silica gel, palladium oxide, platinum-carbon, platinum-silica gel, platinum oxide, ruthenium-carbon, etc. be able to.

However, it is preferable to use a palladium catalyst because of its high activity.

When carrying out the reaction, it is desirable to carry out the reaction in a solvent.
For example, aromatic hydrocarbons such as xylene/., mesitylene, and p-cymene, and ethers such as diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, and diphenyl ether can be used.

The reaction proceeds at 100-250C, but in order to obtain the target product with good yield, it is preferable to carry out the reaction at 140-220C.0 When carrying out the present invention, an inert gas such as nitrogen or argon is blown into the reaction system. It is preferable to carry out the reaction while the reaction is being carried out, since any side reactions can be suppressed before the disproportionation reaction.

The present invention will be explained in more detail below using Examples and Reference Examples.

Reference example 1 40% chloroacetaldehyde in about 10ml of ethyl acetate
Add 2ml of aqueous solution and about 3rrLl of water, and add 1.0g (12ml) of sodium bicarbonate to this solution under water cooling.
J mol)° was added and stirred. Add to this 1.12g (7
) A solution of 1,3-cyclohexanedione dissolved in 5 rnl of water was added dropwise at a rate of about 0.05 ml/11 minutes, and after the dropwise addition was completed, the mixture was stirred overnight at room temperature. Thereafter, the mixture was made acidic with sulfuric acid, stirred for 1 hour, and the ethyl acetate layer was separated. After washing with 7 aqueous potassium carbonate solutions to remove unreacted 1°3-cyclohexanedione, it was dried over magnesium sulfate. The solvent was distilled off, and the residue was applied to a silica gel column and flushed with dichloromethane to obtain 1.09 g (yield: 80%) of 4-oxo-4,5,6,7-titrahydrobenfuran. .

Reference Example 2 1.0 g of 4-oxo-4,5,6,7-titrahydrobenzofuran was mixed with 3 #L of ethanol and aqueous ammonia (29
%) 7- and reacted in a sealed tube at 150C for 12 hours. After the reaction was completed, the reaction mixture was concentrated, and the residue was applied to a silica gel column and flushed with acetone-ethyl acetate to give 4-oxo-4,5,6,7-titrahydroindole 950#lf (yield: 96%). %) was obtained.

Reference Example 3-1 0.528 g (11 mmol) of 509b sodium hydride was suspended in tetrahydrofuran, stirred at room temperature in an argon stream, and 2.6 g (14.7 mmol) of dimethyl cyanogen methylphosphonate was added little by little. , the sodium salt of dimethyl cyanomethylphosphonate was prepared.

To this was added 1.35 g (10 mmol) of 4-oxo-4,5,6,7-titrahydroindole, and the mixture was heated under reflux for 24 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate. This extracted layer was washed twice with water, dried over magnesium sulfate, and concentrated by distilling off ethyl acetate. The residue was applied to a silica gel column and flushed with hexane followed by dichloromethane, resulting in a mixture of stereoisomers of 4-cyanomethylidene-4,5.
, 6,7-titrahydroindole is 1.15g173
．． Obtained as a white solid with 0% yield. By performing fractional crystallization from ethyl acetate, only one isomer could be isolated. The physical data of the product are shown in the table.

Reference example 4 1 = CN i (, 2 = C) 13 Reference example 5 1 = CN Rs = CH2Ph Reference example 6 ) t, " = C
N R''=80□C6H4゜CH3-P (hereinafter referred to as TS) Instead of 4-oxo-4,5,6,7-titrahydroindole, 1-methyl-4-oxo-4,5,6, 7-
Reference except that titrahydroindole, 1-benzyl-4-okine-4.5.6.7-titrahydroindole and 4-oxo-1-toluenesulfonyl-4,5,6,7-titrahydroindole were used. By reacting and treating in the same manner as in Example 3, the respective corresponding
4-cyanomethylidene-1-methyl-4,5,6,7-
Titrahydroindole, 1-benzyl-4-cyanomethylidene-4,5,6,7-titrahydroindole and 4-cyanomethylidene-1-toluenesulfonyl-4
, 5,6,7-titrahydroindole was obtained.

The results were shown in the paper.Example 7 0.27 g (5.5 mmol) of 50L% sodium hydride was suspended in tetrahydrofurine, stirred at room temperature under an argon stream, and ethoxycarbonylmethylphosphonate was added to the solution. Diethyl acid 1.6g (7.1 mmol)? The sodium salt of diethyl ethoxycarbonylmethylphosphonate was prepared. In addition, 4-okino 1-
Add 1.45 g (5.0 mmol) of toluenesulfonyl-415°6.7-tetrahydroindole,
The mixture was heated to reflux for an hour. After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate. Wash this extracted layer twice with water,
After drying with magnesium sulfate, ethyl acetate was distilled off and concentrated. The residue was applied to a silica gel column and flushed with hexane followed by dichloromethane, yielding 4-ethoxycarbonylmethylethene-4-)luenesulfonyl-4°5,6 as a mixture of stereoisomers of Q. 1.54 g of 7-tetrahydroindole was obtained as a white solid in a yield of 85.6-. Only one isomer was isolated by fractional crystallization from a mixed solvent of ethyl acetate and hexane.

The physical data of the product are shown in Table ■.

Reference example 8 i(”=CO□C2H5R2-H reference side 9⇠1=CO□C'z'H5⇠2=CH3 Reference example 10 R
'=CO□C2H5几2=C) i2Ph instead of 4
-oxo-4,5,6,7-tetrahydroindole,
1-Methyl-4-oxo-4,5,6゜7-tetrahydroindole and 1-benzyl-4-oxo-4,5,
By reacting and treating in the same manner as in Reference Example 7 except for using 6,7-tet2hydroindole, the respective corresponding 4-ethoxycarbonylmethylidene-4
, 5,6,7-tetrahydroindole, 4-ethoxycarbonylmethylidene-1-methyl-4,5,6,7-
Tetrahydroindole and 1-benzyl-4-ethoxycarbonylmethylidene-4,5,6,7-tetrahydroindole were obtained. The results are shown in Table ■.

JP-A-59-84864 (6) Example 1 H 0.50 g (3.2 mmol) of 4-cyanomethylidene-4,5,6,7-teto-2hydroindole, 0.50 g (3.2 mmol) of
25 g of 5-thipalladium-carbon catalyst was added to about 3.5 ml of diethylene glycol diethyl ether and 200 t was added while bubbling argon gas directly into the reaction mixture.
The mixture was heated and stirred at :' for 3 hours. After the reaction was completed, a large amount of dichloromethane was added to the reaction mixture, and the 5% palladium-carbon catalyst was removed by filtration. Dichloromethane was distilled off from the oral liquid, about 30 d of hexane was added to the residue, and the reaction mixture was cooled to precipitate 4-cyanomethylindole as a white solid. Yield 0.34g, Yield 68
．． The physical data for the 7% product is shown below.

Melting point = 114-115C NMR (incDc4): δ3.92 (s, 2H)
, 6.46~6.58 (my IH), 702~
7.42 (m.

4H) l 8.36 (m+ 1'H) ppmI (KBr): 3380,2240,1580,149
0crn'MS (mlz): 156 (M+,
1d) Right 0 (1B) Elemental analysis value: Calculated value as C1oH8N2 C, 76, 90; l-1, 5, 16; N, 1
7.94°Actual measurement CI 76.90; H, 4,98
;N, 17.93゜Example 2 几1=CN
几2=CH3 Example 3) L1=CN R2
=CHPh Example 4 R”=CN R12=
In place of Ts4~cyanomethylidene-4,5,6,7-teto-2hydroindole, 4-cyanomethylidene-1-
Methyl-4,5,6,7-tetrahydroindole, 1
-benzyl-4-cyanomethylidene-4,5,6,7-
Tetrahydroindole and 4-cyanomethylidene-1
The corresponding 4-cyanomethyl-1-methylindole, 1-benzyl-4
-cy, anomethylindole and 4-cyanomethyl-1
-Toluenesulfonylindole is obtained.

The results are shown in Table ■.

Example 5 1-benzyl-4-ethoxycarbonylmethylidene-4
, 5,6,7-tetrahydroindole 78 kg (0,2
6 mmol) and 39 Misaki's 5% palladium-carbon catalyst were added to about IIrLl of diethylene glycol diethyl ether and heated and stirred at 200C for 3 hours while bubbling argon gas directly into the reaction mixture. After the reaction was completed, a large amount of dichloromethane was added to the reaction mixture, and the 5% palladium-carbon catalyst was removed by filtration. Dichloromethane was distilled off from the oral fluid, and diethylene glycol diethyl ether was removed by immersing it in a water bath of about 80 υ and reducing the pressure with a vacuum pump, and 1-benzyl-4-ethoxycarbonylmethyl intole was obtained. , collection 4i
76f was obtained in a yield of 97.4%.

The physical data of the product are shown below.

NM几(inCDCJ3): δ1.21 (t, 3
H, J = 7Hzρ.

3.86 Css 2H) , 4.11 (q, 2H2
J-7)iz), 5.22 (s, 2H)', 6
．． 57 (d.

IH, J=3Hz) t 6.90-7.34 (m.

9H), ppm ■几(ltqusd film): 1730+
1605+ 1580+1495cm ・MS (m/z): 293 (M+, 56) +
220-(67,) +91 (100).

Example 6 几! =C02C2H5几2=HExample 7
几'=C02C2H,R2=CH3Example 8 几1:CO□C2H5R2=:'l'B1-benzyru4
-4-ethoxycarbonylmethylidene-4,5,6,7-tetrahydroindole, 4-ethoxycarbonylmethylidene-1-methyl-4 instead of ethoxycarbonylmethylidene-4,5,6,7-tetrahydroindole
, 5,6,7-tetrahydroindole and 4-ethoxycarbonylmethylidene-1-toluenesulfonyl-4
, 5,6,7-Tetrahydroindole was used, and the same reaction and treatment as in Example 5 were carried out. -methylindole and 4-ethoxycarbonylmethyl-1-)
Luenesulfonylindole was obtained. The results are shown in Table ■.

Table - ■ Patent Applicant Procedures Amendment Written by Kazuo Wakasugi, Commissioner of the Japan Patent Office, January 3, 1980 1゜ Indication of the case 1982 Patent Application No. 193433 No. 26, Ming name Process for producing 4-substituted indoles 3. Person making the amendment Contents of the amendment in column 5 of "Detailed Description of the Invention" of the specification (1) "Dimethyl" on page 9, line 11 of the specification of the present application is corrected to "diethyl."

(2) Table on page 26 of the same page - Replace "几" in the item name with "R1"
and corrected "lt2" to "gi".

that's all

Claims (1)

[Scope of Claims] 4-it-substituted indole represented by the general formula, which is obtained by dehydrogenating and oxidizing a 4-methylidene-4,5,6,7-titrahydroindole preventer represented by the general formula The equal usage method (in the formula
1 (, 1 is a cyan group, a carboxyl group, or an alkoxycarbonyl group, and 2 is a protecting group for hydrogen, an alkyl group, an aralkyl group, or an amino group.) (2) Dehydrogenation is performed in the 8th step. The method according to claim (1), which is carried out in the presence of a Group 8 metal catalyst. (3) The method according to claim (2), wherein the Group 8 metal catalyst is a palladium catalyst. the method of