JPH0212468B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is a novel method for producing a tryptamine compound, particularly a compound having a substituent at the 2-position of the indole nucleus. More specifically, the present invention relates to a method for producing a tryptamine compound by reacting a cyclopropylcarbonyl compound and a phenylhydrazine compound under acidic conditions in the presence of a solvent to form a condensed ring.

Tryptamine compounds themselves have pharmacological effects and are extremely useful compounds as raw materials for the synthesis of indole derivatives, alkaloids, and pharmaceuticals.

Conventionally, typical methods known for producing tryptamine compounds, especially tryptamine compounds containing a substituent at the 2-position of the indole nucleus, include (1) Using 2-substituted indole as a starting material, various types are added to the 3-position of the indole nucleus. A method of introducing an aminoethyl group to produce a 2-substituted tryptamine. (Wayland E.Noland and Ronald.F.
Lange, J.Am.Chem.Soc. 81 1203-1209
(1959)) (2) Synthesis from γ-haloketone and phenylhydrazine using Fitscher's indole synthesis. (Khim, Geterotsikl, Soedin 1974 (8)
1085-1088) are known. However, method (1) has drawbacks such as the fact that 2-substituted indole as a raw material is not easily available, and method (2) has drawbacks such as difficulty in synthesizing γ-haloketones, making it difficult to carry out industrial production. It has not yet been reached.

As a result of intensive research into methods for producing tryptamine compounds, particularly 2-substituted tryptamine compounds, the present inventors discovered that a cyclopropylcarbonyl compound, a new raw material completely unknown in this type of reaction, was combined with a phenylhydrazine compound. We have discovered a method for easily producing tryptamine compounds, particularly 2-substituted tryptamine compounds, by reaction.

That is, the present invention is based on the general formula () [In the formula, R ₁ represents a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group. ] A cyclopropylcarbonyl compound represented by
General formula () [In the formula, R ₂ represents a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ₃ represents a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, an alkoxy group, an aralkyloxy group, an aryloxy group, or a halogen atom represents. ] A general formula () characterized by reacting a phenylhydrazine compound represented by in the presence of a solvent under acidic conditions. [In the formula, R ₁ , R ₂ and R ₃ are the same as defined above. ] The present invention relates to a method for producing a tryptamine compound shown in the following.

In the method of the present invention, the cyclopropylcarbonyl compound represented by the general formula () used as a raw material can be easily produced from, for example, cyclopropanecarbonitrile. (Keith W.Blake and
Iain Gillies.J.Chem.Soc.Perkin I 1981 700
~702) Examples of the cyclopropylcarbonyl compound represented by the general formula () include cyclopropanecarboxaldehyde, cyclopropylmethylketone, cyclopropylethylketone, cyclopropylphenylketone, cyclopropyltolyl ketone, benzylcyclopropylketone, etc. can be given.

Further, as the phenylhydrazine compound represented by the general formula (), for example, phenylhydrazine, 1-methyl-1-phenylhydrazine, 1,
1-diphenylhydrazine, 1-benzyl-1-
Phenylhydrazine, p-methylphenylhydrazine, p-benzyloxyphenylhydrazine,
Examples include p-bromphenylhydrazine.
In carrying out the present invention, mineral acid salts and organic acid salts of these phenylhydrazine compounds can also be used directly.

In one embodiment of the present invention, a compound represented by the general formula () and a substance that provides acidic conditions are dissolved in a solvent, and a solution of the compound represented by the general formula () is added dropwise to the solution. The reaction proceeds smoothly by stirring at a temperature of ~200°C to give a tryptamine compound represented by the general formula ().

As the solvent used in the present invention, alcohols such as ethanol and propanol, and ether alcohols such as ethylene glycol monomethyl ether can be used singly or in mixtures. Furthermore, mixtures of these solvents and other solvents that do not directly participate in the reaction can also be used.

As the substance providing acidic conditions used in the present invention, mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as p-toluenesulfonic acid can be used.
Further, when using an acid salt thereof instead of the compound (), acidic conditions can be maintained without adding a substance that maintains acidic conditions.

The reason why the synthesis reaction of the present invention proceeds effectively is not clear, but after the cyclopropylcarbonyl compound is directly condensed with the phenylhydrazine compound under acidic conditions, the cyclopropane ring opens, resulting in the transfer of the amino group. It is thought that an indole nucleus is formed in parallel.

Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 Tryptamine 4.34 g (30 mmol) of phenylhydrazine hydrochloride was dissolved in 50 ml of n-propanol, this solution was heated and stirred, and when the liquid temperature reached 96°C, 1.40 g (20 mmol) of cyclopropanecarboxaldehyde was dissolved in 50 ml of n-propanol. mmol) dissolved in 20 ml of n-propanol,
It was added dropwise over 40 minutes. Thereafter, the reaction solution was stirred for 2 hours while being boiled and refluxed. After cooling, 200 ml of water and 2 g of caustic soda were added, and the mixture was extracted three times with 100 ml of chloroform. The chloroform layers were combined and washed with water, then the chloroform was distilled off under reduced pressure, and the resulting brown oil was distilled under reduced pressure. , 180~185℃/4mm
Tryptamine 1.67g (yield 52%) as Hg fraction
I got it.

Example 2 2-Methyltryptamine Dissolve 22.41 g (155 mmol) of phenylhydrazine hydrochloride in 250 ml of n-propanol, heat and stir this solution, and when the liquid temperature reaches 96°C, cyclopropyl methyl A solution of 12.62 g (150 mmol) of ketone dissolved in 30 ml of n-propanol was added dropwise over 2.5 hours. After this, the reaction solution was stirred for 3.5 hours under boiling reflux. After the reaction was completed, the solvent was distilled off to reduce the liquid volume to about 1/3, then 150 ml of water and 7 g of caustic soda were added, and the mixture was diluted with 100 ml of chloroform.
Extracted twice. After combining the chloroform layers and washing with water, chloroform was distilled off under reduced pressure, and further vacuum distillation was performed to obtain 19.6 g (yield: 75%) of 2-methyltryptamine as a fraction at 178-180°C/2 mmHg. .

Example 3 1,2-dimethyltryptamine hydrochloride 24.59 g (155 mmol) of N-methylphenylhydrazine hydrochloride was dissolved in 400 ml of n-propanol, heated and stirred, and when the liquid temperature reached 96°C, cyclo 12.62 g (150 mmol) of propyl methyl ketone dissolved in 30 ml of n-propanol
It dripped in time. Thereafter, the reaction solution was stirred for 3 hours under boiling reflux. After the reaction was completed, about half of the solvent was distilled off and cooled, and 1,2-dimethyltryptamine hydrochloride precipitated as crystals, yielding 30.3 g of crude crystals.
I got g. (Yield: 90%) This product was recrystallized with ethanol to obtain a pure product. When the melting point was measured, it was 233°C (decomposition).

Example 4 5-Bromo-2-methyltryptamine hydrochloride Example 3, except that 33.53 g (150 mmol) of p-bromo phenylhydrazine hydrochloride was used instead of N-methylphenylhydrazine hydrochloride in Example 3. When the reaction and treatment were carried out in the same manner as in 3, brown crude crystals were obtained. This product was recrystallized with water and 24.08g of 5-bromo-2-methyltryptamine hydrochloride
(yield 56%). The melting point of this product was 255°C (decomposition).

Example 5 2,5-dimethyltryptamine hydrochloride ethylene glycol monomethyl ether 200ml
6.35g of p-methylphenylhydrazine hydrochloride
(40 mmol) was heated and stirred, and when the temperature reached 121°C, 3.37 g (40 mmol) of cyclopropyl methyl ketone was added dropwise to 40 ml of ethylene glycol monomethyl ether over 30 minutes. , and reacted for 3 hours under boiling and reflux. After the reaction, the solvent was distilled off under reduced pressure, and the remaining brown solid was recrystallized from water to obtain 6.20 g (yield: 69%) of 2,5-dimethyltryptamine hydrochloride. The melting point of this product was 229°C (decomposition).

Example 6 5-Benzyloxy-2-methyltryptamine Dissolve 10.03 g (40 mmol) of p-benzyloxyphenylhydrazine hydrochloride in 200 ml of ethanol, heat and stir this solution, and when the liquid temperature reaches 78°C , 3.37 g of cyclopropyl methyl ketone
(40 mmol) dissolved in 50 ml of ethanol was added dropwise over 1 hour. Thereafter, the reaction solution was boiled and reacted under reflux for 3 hours. After cooling, 300 ml of water and 2 g of caustic soda were added, and the mixture was extracted three times with 100 ml of chloroform. After combining the chloroform layers and washing with water,
Chloroform was distilled off under reduced pressure to obtain a brown oil.
This was purified by column chromatography to obtain 3.14 g (yield 28%) of 5-benzyloxy-2-methyltryptamine. The NMR measurement results were as follows.

¹ HNMR (CDCl ₃ ) δ (ppm): 1.83 (s, 2H, -
NH ₂ ), 2.26 (s, 3H, -CH ₃ ), 2.82 (dt, 4H, -
CH ₂ CH ₂ −), 5.02 (s, 2H, −CH ₂ O−), 6.42−
7.53 (m, 8H, indol H, phenyl), 8.00 (s,
1H, indole N H) Example 7 1,2-diphenyltryptamine 6.62 g (30 mmol) of 1,1-diphenylhydrazine hydrochloride was dissolved in 200 ml of n-propanol, and the solution was heated and stirred until the liquid temperature reached When the temperature reached 96℃, 4.39g of cyclopropylphenyl ketone
(30 mmol) dissolved in 50 ml of n-propanol was added dropwise over 40 minutes. After reacting for 4 hours under boiling reflux, the mixture was cooled, 300 ml of water and 2 g of caustic soda were added, and extracted three times with 100 ml of chloroform. The chloroform layers were combined, washed with water, and then chloroform was distilled off under reduced pressure to precipitate crystals. The crystals were recrystallized from toluene to obtain 4.03 g (43% yield) of 1,2-diphenyltryptamine.
The result of melting point measurement was 148-151°C. (Literature value: 151-153℃) Example 8 1,2-dibenzyltryptamine Ethylene glycol motomethyl ether 100ml
1-benzyl-1-phenylhydrazine hydrochloride
4.69 g (20 mmol) was dissolved in 20 ml of ethylene glycol monomethyl ether and 3.52 g (20 mmol) of benzyl cyclopropyl ketone was dissolved in 20 ml of ethylene glycol monomethyl ether for 15 minutes. It was dripped. After reacting for 5 hours under boiling reflux, the mixture was cooled, 300 ml of water and 1 g of caustic soda were added, and extracted three times with 100 ml of chloroform. After the chloroform layers were combined and washed with water, the chloroform was distilled off under reduced pressure to obtain a brown oil. This was purified by column chromatography to obtain 2.59 g (yield 38%) of 1,2-dibenzyltryptamine. The results of elemental analysis were as follows.

(Measurement value) C: 84.58, H: 7.07, N: 8.22 (Calculated value) C: 84.67, H: 7.10, N: 8.23

Claims (1)

[Claims] 1 General formula () [In the formula, R ₁ represents a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group. ] A cyclopropylcarbonyl compound represented by
General formula () [In the formula, R ₂ represents a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R ₃ represents a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, an alkoxy group, an aralkyloxy group, an aryloxy group, or a halogen atom represents. ] A general formula () characterized by reacting a phenylhydrazine compound represented by in the presence of a solvent under acidic conditions. [However, in the formula, R ¹ , R ² and R ³ are the same as defined above. ] A method for producing a tryptamine compound.