JPS5811878B2 - Furo (3 2-B) India-Ruruino Seihou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing furo(3,2-b)indoles, and more particularly to a method for producing a novel furan-fused ring compound having a tranquilizing effect.

Conventionally, it was extremely difficult to directly close a compound substituted at the 2- or 5-position of the furan ring, but the present inventors succeeded in synthesizing a furan-fused ring system compound via the azide compound, and have developed the present invention. Completed the invention.

general formula [In the formula, R1 represents a hydrogen atom or a halogen atom.

R2 is represented by the general formula (wherein R3 represents a lower alkyl group, a hydroxy lower alkyl group, or a lower alkenyl group, or the two R3s represent one nitrogen atom together with the adjacent nitrogen atom, or one nitrogen atom and one oxygen atom) It forms a six-membered hetero ring having .

) or a hetero five-membered phenyl group which may be substituted with a cyan group, or one oxygen atom or one sulfur atom which may be substituted with a nitro group. Indicates an ethynyl group substituted with a ring group.

] 5-(2-aminophenyl)furan compound (hereinafter referred to as compound ①).

) is diazotized and then reacted with alkali azide, general formula (In the formula, R1 and R2 have the same meanings as above.

) is a 5-(2-azidophenyl)furan compound (hereinafter referred to as compound ①).

), and then this compound (1) is ring-closed by heating (wherein R1 and R2 have the same meanings as above).

) (hereinafter referred to as compound ①).

) is the manufacturing method. Here, the lower alkyl group represented by R3 and the lower alkyl moiety of the hydroxy lower alkyl group are lower alkyl groups such as methyl, ethyl, and propyl.

The lower alkenyl group is a lower alkenyl group such as vinyl or allyl.

The six-membered heterocyclic group formed by two R3s together with the adjacent nitrogen atoms is a six-membered heterocyclic group represented by piperidino, morpholino, and the like.

The hetero five-membered ring group represented by R2 is a hetero five-membered ring group represented by 5-nitrofuryl, chenyl, and the like.

In the present invention, diazotization is carried out under acidic conditions at low temperatures by adding nitrite, and azidation is carried out by adding an alkali azide such as sodium azide.

The ring closure of compound (1) is carried out by heat treatment at 150 to 300 DEG C. in an organic solvent that does not participate in the reaction, such as ortho-dichlorobenzene.

Compound (2) obtained by denitrifying and ring-closing compound (1) is purified by conventional purification means such as recrystallization, if necessary.

Note that Compound I, which is a raw material of the present invention, can be easily obtained by the following method.

That is, 5-(2-nitrophenyl) asexual mucilage acid or 5-(2-nitro- 4-monosubstituted phenyl) amorphous mucilage acid, and after decarboxylation, the general formula (wherein R2 has the same meaning as above).

X represents a halogen atom.

) by reacting the halogen atom represented by 5
-(2-nitrophenyl)furan compound or 5-(2
Compound I can be obtained by reducing the -nitro-4 monosubstituted-phenyl)furan compound.

Compound (1) obtained by the present invention is a new compound that has not been described in any literature, and is not only useful as a tranquilizer;
It can also be used as an intermediate for more potent tranquilizers.

Next, the present invention will be explained with reference to Examples.

Example 1 100 g of o-nitroaniline, 320 ml of concentrated hydrochloric acid, 4 ml of water
Add 00 nl and heat to dissolve.

After dissolving, add 50.9% of sodium nitrite to 1% while cooling to 0-5℃.
A solution dissolved in 50 ml of water was added dropwise to obtain a diazonium salt, and a solution prepared by dissolving 150 g of sodium acetate in 500 ml of water and 110 g of amorphous mucilage acid was added thereto.
Next, a solution of 300 g of cupric chloride dissolved in 300 ml of water was added dropwise to obtain 5-(2-nitrophenyl)-2-amorphous mucilage acid, which was decarboxylated in quinoline using activated copper as a catalyst. The reaction was carried out to give 2-(2-nitrophenyl)furan 1
Obtained 50g.

2.2 g of benzoyl chloride was mixed with 30 ml of carbon disulfide, 4.2 g of anhydrous aluminum chloride was added, and after stirring at room temperature for 10 minutes, 3.0 g of the above 2-(2-nitrophenyl)furan was mixed with 6 rfLl of carbon disulfide. After the mixture was added dropwise, the reaction mixture was stirred at room temperature for 1.5 hours, and the reaction mixture was poured into ice water.

This was hydrolyzed to give 4.3 g of 2-benzoyl-5-(
2-nitrophenyl)furan was obtained.

29.3 g of this 2-benzoyl-5-(2-nitrophenyl)furan was mixed with 18 g of tin, and added with 30 g of concentrated hydrochloric acid.
After dropping 0rnl, the reaction mixture was heated on a water bath for 1 hour while stirring.

After the reaction is completed, it is purified by a conventional method and recrystallized from methanol to obtain 1
2 g of 2-(2-aminophenyl)-5-benzoylfuran was obtained.

m, p, 124-125°C o-nitroaniline and (N,N-dimethyl)carbamoyl chloride, o-nitroaniline and (N,N-jetanol)carbamoyl chloride instead of o-nitroaniline and benzoyl chloride , o-nitroaniline and (N,N-diallyl)carbamoyl chloride, o-nitroaniline and piperidinocarbonyl chloride, o-nitroaniline and morpholinocarbonyl chloride, p-chloro-o-nitroaniline and (N,N- dimethyl)carbamoyl chloride, o-nitroaniline and styryl chloride, o-nitroaniline and 4-cyanostyryl chloride, o-nitroaniline and 2-(5-nitrofuryl)ethynyl chloride, o-nitroaniline and 2-thenyl-ethynyl 2-(2-aminophenyl)-5-(N,N-dimethyl)carbamoyl-furan, m, p, respectively, using chloride, 124-125 °C
; 2-(2-aminephenyl)-5-(N,N-jetanol)carbamoyl-furan, m, p.

127-128°C; 2-(2-aminophenyl)-5-(N,N-diallyl)carbamoyl-furan, m, p, 129-130°C
; 2-(2-aminophenyl)-5-piperidinocarbonyl-furan, m, p, 140°C; 2-(2-aminophenyl)-5-morpholinocarbonyl-furan m, p
, 138-139°C; 2-(2-amino-4-chlorophenyl)-5-(N,N-dimethyl)carbamoyl-
Furan, m, p, 119-120°C; 2-(2-aminophenyl)-5-styryl-furan,
m, p, 128-129°C; 2-(2-aminophenyl)-5-(4-cyanostyryl)-furan, m, p, 130-131°C; 2-(2-aminophenyl)-5-( 2-(2-(5-
nitrofuryl)) ethynyltwofuran, m, p, 1
33-135°C; 2-(2-aminophenyl)-5-(2-(2-chenyl)ethynyltofuran, m, p, 134°C was obtained.

Example 2 10 g of 2-(2-aminophenyl)-5-(N,N-dimethyl)carbamoyl-furan was mixed with concentrated hydrochloric acid and 20 liters of water.
The solution was dissolved in IL1 and cooled to 0 to 5° C. with stirring, and a solution prepared by dissolving 3.0 g of sodium nitrite in 20 d of water was added dropwise thereto, and the mixture was stirred for 1 hour to obtain a diazonium salt.

Subsequently, a solution of 8.5 g of sodium azide dissolved in 30 ml of water was added dropwise, and the mixture was stirred at 0 to 5° C. for 30 minutes, and further stirred at room temperature for 1 hour.

9 and 7 obtained by counting the precipitate in the reaction solution, washing with water, and drying.
g of 2-(2-azidophenyl)-5-(N.

N-dimethyl)carbamoyl-furan was refluxed in 40 ml of ortho-dichlorobenzene for 30 minutes.

The precipitated crystals are then offshored and recrystallized with benzene to produce furo(3,2-b)indole-2-(N,N-dimethyl).
6 g of carboxamidro was obtained.

m, p. 177-178°C Example 3 2-(2-aminophenyl)-5-(N,N-jetanol)carbamoyl-furan log in concentrated hydrochloric acid 30 TIL
1 and 20 rrtl of water, cooled to 0~5°C with stirring, and added 2.4 g of sodium nitrite to 201 nl of water.
A solution dissolved in was added dropwise and stirred for 1 hour to obtain a diazonium salt.

Subsequently, a solution of 7.0 g of sodium azide dissolved in 30 ml of water was added dropwise, and the mixture was stirred at 0 to 5° C. for 30 minutes, and further stirred at room temperature for 50 minutes.

9 and 8 obtained by counting the precipitate in the reaction solution, washing with water, and drying.
g of 2-(2-azidophenyl)-5-(N,N-jetanol)carbamoyl-furan was refluxed in 401 nl of ortho-dichlorobenzene for 30 minutes.

In the future, we will collect the precipitate, recrystallize it with ethanol, and
3,2-b) Indole-2-(N,N-jetanol)carboxamidro, 9 g was obtained.

m, p, 240-241 °CExample 4 2-(2-aminophenyl)-5-(N,N-diallyl)carbamoyl-furan 11 was dissolved in 30 TILl of concentrated hydrochloric acid and 20 ml of water, and under stirring 0-5 The mixture was cooled to .degree. C., and a solution of 2.5 g of sodium nitrite dissolved in 20 ml of water was added dropwise thereto, followed by stirring for 1 hour to obtain a diazonium salt.

Subsequently, a solution of 7 g of l-IJium azide dissolved in 30 ml of water was added dropwise, and the mixture was stirred at 0 to 5° C. for 30 minutes, and further stirred at room temperature for 1 hour.

9,1 obtained by counting the precipitate in the reaction solution, washing with water, and drying.
g of 2-(2-azidophenyl)-5-(N.

N-diallyl)carbamoyl-furan was refluxed in 35 ml of ortho-dichlorobenzene for 30 minutes.

The precipitated crystals were collected and recrystallized with ethanol to obtain 8 g of furo(3,2-b)indole-2-(N,N-diallyl)carboxamide.

m, p. 239°C Example 5 10 g of 2-(2-aminophenyl)-,5-piperidi7carbonylfuran was mixed with 25 ml of concentrated hydrochloric acid and 25 ml of water.
1 and cooled to 0 to 5°C with stirring, to which a solution of 2.7 g of sodium nitrite dissolved in 20 ml of water was added dropwise.
After stirring for 1 hour, a diazonium salt was obtained.

Subsequently, a solution of 7.5 g of sodium azide dissolved in 40 ml of water was added dropwise, and the mixture was stirred at 0 to 5° C. for 30 minutes, and further stirred at room temperature for 1 hour.

9 and 8 obtained by counting the precipitate in the reaction solution, washing with water, and drying.
g of 2-(2-azidophenyl)-5-piperidinocarbonyl-furan was refluxed in 35 ml of ortho-dichlorobenzene for 30 minutes.

In the future, the precipitated crystals will be separated and recrystallized with methanol to yield 6.1 g of 2-piperidinocarbonyl-furo (3,2-
b) Indole was obtained.

m, p, 168-1696C Example 6 2-(2-aminophenyl)-5-morpholinocarbonyl-furan In was dissolved in concentrated hydrochloric acid and 20 g of water, cooled to 0-5°C with stirring, and added Sodium nitrate 2.6g
A solution prepared by dissolving .

Subsequently, a solution of 7.2 g of sodium azide dissolved in 30 ml of water was added dropwise, and the mixture was stirred at 0 to 5° C. for 30 minutes, and further stirred at room temperature for 1 hour.

9 and 7 obtained by counting the precipitate in the reaction solution, washing with water, and drying.
．． 9 of 2-(2-azidophenyl)-5-morpholinocarbonyl-furan was dissolved in 35 ml of orthodichlorobenzene.
The mixture was refluxed for 30 minutes.

In the future, the precipitated crystals will be collected and recrystallized with methanol.
6.6 g of -morpholinocarbonyl-furo(3,2-b)indole were obtained.

m, p, 154-155°C Example 7 2-(2-amino-4-chlorophenyl)-5=(N,
N-dimethyl)carbamoyl-furan 10y and concentrated hydrochloric acid 3
0 mA' and cooled to 0 to 5° C. with stirring. A solution prepared by dissolving 2.6 g of sodium nitrite in 20 ml of water was added dropwise thereto, and the mixture was stirred for 1 hour to obtain a diazonium salt.

Next, apply 7.5 g of sodium azide at 30 mA! A solution dissolved in water was added dropwise and stirred at 0 to 5°C for 30 minutes, and further stirred at room temperature for 1 hour.

The precipitate in the reaction solution was separated, washed with water, and dried to obtain 1 (B
i'2-(2-azido-4-chlorophenyl)-5-
(N,N-dimethyl)carbamoyl-furan was refluxed in 35 ml of orthodichlorobenzene for 30 minutes.

Thereafter, the precipitated crystals were separated, and the residue was recrystallized from a mixture of pyridine and water to obtain 5 g of 6-chloro-furo(3,2-b)indole=(N,N-dimethyl)carboxamide.

m, p. 144-145°C Example 8 2-(2-aminophenyl)-5-styryl-furan 1
0 g was dissolved in 30 ml of concentrated hydrochloric acid and 20 ml of water, cooled to 0 to 5°C with stirring, and added with 1 to 2.7 lium of nitrite.
A solution of g dissolved in 20ml of water was added dropwise and stirred for 1 hour.
A diazonium salt was obtained.

Subsequently, a solution of 7.5 g of sodium azide dissolved in 40 ml of water was added dropwise, and the mixture was stirred at 0 to 5° C. for 30 minutes, and further stirred at room temperature for 2 hours.

8 and 7 obtained by counting the precipitate in the reaction solution, washing with water, and drying.
g of 2-(2-azidophenyl)-5-styryl-furan was refluxed in 30 rnl of ortho-dichlorobenzene for 30 minutes.

Afterwards, the precipitated crystals were furnace plated and recrystallized with ethanol.
．． 3 g of 2-styryl-furo(3,2-b)indole was obtained.

m, p, 193-194.5 °C
The mixture was cooled to -5-3° C. with stirring, and a solution prepared by dissolving 2.5 g of sodium nitrite in 20 TIL of water was added dropwise thereto, and the mixture was stirred for 1 hour to obtain a diazonium salt.

Subsequently, a solution of 6.8 g of sodium azide dissolved in 40 ml of water was added dropwise, and the mixture was stirred at 0 to 5° C. for 30 minutes and further stirred at room temperature for 1 hour.

9,0 obtained by counting the precipitate in the reaction solution, washing with water, and drying.
g of 2-(2-azidophenyl)-s-(4-cyanostyryl)furan was refluxed in 35 ml of ortho-dichlorobenzene for 30 minutes.

In the future, the precipitated crystals will be offshored and recrystallized with methanol.
．． 8 g of 2-(4-cyanostyryl)-furo(3,2-
b) Indole was obtained.

m, p, 179-180.5°C Example 10 2-(2-aminephenyl)-5-(2-(2-(5-
Nitrofuryl)) Add 10 g of ethynylcufuran to 3 parts of concentrated hydrochloric acid.
The mixture was dissolved in 0 ml and 20 ml of water, cooled to 0 to 5° C. with stirring, and a solution of 2.4 g of sodium nitrite dissolved in 20 ml of water was added dropwise thereto, and the mixture was stirred for 1 hour to obtain a diazonium salt.

Subsequently, a solution of 6.6 g of sodium azide dissolved in 30 ml of water was added dropwise, and the mixture was stirred at 0 to 5° C. for 30 minutes and further stirred at room temperature for 1 hour.

9 and 8 obtained by filtering the precipitate in the reaction solution, washing with water, and drying.
g of 2-(2-azidophenyl)-5-(2-(2-(
5-Nitrofuryl)]]ethynylfura was refluxed in 40 ml of ortho-dichlorobenzene for 30 minutes.

The precipitated crystals were then heated in a furnace and recrystallized from a methanol/dioxane mixture. Obtained om, p, 201-202 °C Example 11 10 g of 2-(2-aminophenyl)-5-(2-(2-f enyl)ethynylkufuran was dissolved in 30 ml of concentrated salt e and 20 ml of water, The mixture was cooled to 0 to 5°C with stirring, and a solution of 2.7 g of sodium nitrite dissolved in 20 ml of water was added dropwise thereto, and the mixture was stirred for 1 hour to obtain a diazonium salt.

Subsequently, a solution of 7.5 g of sodium azide dissolved in 40 ml of water was added dropwise, and the mixture was stirred at 0 to 5° C. for 30 minutes, and further stirred at room temperature for 1 hour.

9,4 obtained by counting the precipitate in the reaction solution, washing with water, and drying.
g of 2-(2-azidophenyl)-5-(2-(2-f
(enyl)ethynylcufuran was refluxed in 35 ml of ortho-dichlorobenzene for 30 minutes.

The precipitated crystals were collected and recrystallized from a methanol/chloroform mixture to obtain 6.7 g of 2-(2-(2-chenyl)ethynylcufuro(3,2-b)indole).

Claims (1)

[Claims] 1. General formula [wherein R1 represents a hydrogen atom or a halogen atom]. R2 is represented by the general formula (wherein R3 represents a lower alkyl group, a hydroxy lower alkyl group, or a lower alkenyl group, or the two R3s represent one nitrogen atom together with the adjacent nitrogen atom, or one nitrogen atom and one oxygen atom) ), or a phenyl group that may be substituted with a cyan group, or an oxygen atom that may be substituted with a nitro group. 5-membered heterocyclic group having 1 sulfur atom or 1 sulfur atom. ] A 5-(2-aminophenyl)furan compound represented by is diazotized and then reacted with an alkali azide to form a compound represented by the general formula (wherein R1 and R2 have the same meanings as above). A 5-(2-azidophenyl)furan compound represented by the formula (wherein R1 and R2 have the same meanings as above) is obtained, and then this compound is ring-closed by heating. A method for producing the indicated furo(3,2-b) indoles.