JPS5973568A - Preparation of tryptamine compound - Google Patents

Abstract

PURPOSE:To obtain advantageously the titled compound which is a synthetic raw material for indole derivatives and medicines, etc., by reacting an easily available cyclopropylcarbonyl compound as a starting raw material with a phenylhydrazine compound in a solvent under acidic conditions. CONSTITUTION:A cyclopropylcarbonyl compound of formula I (R1 is H, alkyl, aryl or aralkyl) is reacted with a phenylhydrazine compound of formula II(R2 is H, alkyl, aryl or aralkyl; R3 is H, alkyl, aryl, aralkyl, alkoxyl or aralkyloxy, etc.) in the presence of a solvent, e.g. ethanol or ethylene glycol monomethyl ether, under acidic conditions with sulfuric acid, p-toluenesulfonic acid, etc. at 70-200 deg.C to give the aimed compound of formula III. The compound of formula I can be easily synthesized from cyclopropanecarbonitrile, etc.

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 and cyclizing the compound.

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

Conventionally, a typical method known as a method for producing tryptamine compounds, particularly tryptamine compounds containing a substituent at the 2-position of the indole nucleus, is as follows: (1) 2-substituted indole is used as a starting material and 17 is substituted at the 3-position of the indole nucleus. A method of introducing an aminoethyl group into 2-substituted tryptamine by various methods.

(Wayland E, No. 1 and
Ronald, F. Lange.

J, Am, Chem, 5oc-811203~1
209 (1959) ) (2) r-haloketone and 7
Synthesis method using Fischer indole synthesis from enylhydrazine. (1(himXGeterots
iklXSoedin 1974 (8) 1085-10
88) is known. However, in method (1), the raw material 2-W-substituted isodore is not easily available;
Method (2) has drawbacks such as difficulty in synthesizing r-haloketones, and has not yet been put into industrial production.

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

That is, the present invention is directed to the general formula (I) [wherein R1 represents a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group]. ] A cyclopropylcarbonyl compound represented by the general formula (It) 3- [wherein R2 represents a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R3 represents a hydrogen atom, an alkyl group, an aryl group, an aralkyl group group, an alkoxy group, an aralkyloquine group, an aryloxy group, or a halogen atom. ] A phenylhydrazine compound represented by the general formula (1) is reacted with a phenylhydrazine compound represented by
) [In the formula, R1, R2, and R3 are the same as defined above. The present invention relates to a method for producing a tryptamine compound represented by the following.

In the method of the present invention, the cyclopropylcarbonyl compound represented by the general formula 0) used as a raw material can be easily produced from, for example, cyclopropanecarbonitrile.

(Keith W, Blake and 1ainG
illies, J, Chem, Soc, Perkin
I 1981700-702) Examples of the cyclopropylcarbonyl compound represented by the general formula (I) include cyclopropanecarboxaldehyde, cyclopropyl methyl ketone, cyclopropylethyl ketone, cyclopropylphenyl ketone, cyclopropyl tolyl ketone, benzyl cyclopropylene Examples include birketone.

Further, as the phenylhydrazine compound represented by the general formula (II), for example, phenylhydrazine, 1-methyl-1-phenylhydrazine, 1,1-diphenylhydrazine, 1-benzyl-1-7enylhydrazine, p-
Examples include methylphenylhydrazine, p-benzyloxyphenylhydrazine, p-7'' romphenylhydrazine, etc. 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, the general formula (II) is present in a solvent.
By dissolving the compound represented by the compound represented by %f in a bath giving acidic conditions, adding a solution of the compound represented by the general formula (1) dropwise thereto, and stirring at a temperature of 7() to 200°C. The reaction proceeds smoothly to give a tryptamine compound represented by the general formula (■).

As the solvent used in the present invention, alcohols such as ethanol and propatool, and ether alcohols such as ethylene 11 alcohol monomethyl ether can be used singly or in mixtures. Furthermore, mixtures of these solvents and other solvents not directly involved 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.

Furthermore, when an acid salt thereof is used instead of compound (lf), acidic conditions can be maintained even 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, and the amino group is transferred. 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 n-propatool 50- to phenylhydrazine hydrochloride 4
．． 349 (30 mmol) was dissolved, and the solution was heated and stirred to reach a temperature of 96°C, when 1.40 f (20 mmol) of cyclopropanecarboxaldehyde was
- A solution dissolved in Propatool 20IId was added dropwise over a period of 40 minutes. Thereafter, the reaction solution was stirred for 2 hours while being boiled and refluxed. After cooling, 200 yards of water! Add 2ff of caustic soda and 100 ml of 30"
After taking out the fdl and washing the entire chloroform layer with water, the chloroform was distilled off under reduced pressure of 7-cm, and the obtained brown oil was distilled under reduced pressure.
1.67 t (yield: 52 t) of 0-b min were obtained.

Example 2 22.41 t (155 mmol) of ferhydrazine hydrochloride was dissolved in 250-2-methyltryptamine n-propanol, and the solution was heated and stirred until the liquid temperature reached 96°C. , cyclopropyl methyl ketone 12.62F (150 mmol)
2. Dissolved in t-n-propatool 30sd.
It was added dropwise over 5 hours. After this, the reaction solution was boiled and refluxed 3.
Stirred for 5 hours. After the reaction was completed, the solvent was distilled off to reduce the liquid volume to about 100ml, and 150ml of water and 7f of caustic soda were added, followed by extraction three times with 100ml of chloroform. After combining the chloroform layers and washing with water, chloroform was distilled off under reduced pressure, and further vacuum distillation was performed to obtain 2-methyltryptamine 19.69 (yield 75) as a fraction of 178-b/2 snow Hf.
%) was obtained.

81 Example 3 24.59 t (155 mmol) of N-methylphenylhydrazine hydrochloride was completely dissolved in 1,2-dimethyltryptamine hydrochloride n-glopanol 400-;
When the temperature of the solution reached 96° C., 12.629° C. of cyclopropyl methyl ketone was boiled and stirred under reflux for 3 hours. After the reaction was completed, about half of the solvent was distilled off and the mixture was cooled, and 1,2-dimethyltryptamine hydrochloride precipitated as crystals, yielding 30.39f of crude crystals. (Yield 9o
h) This product was recrystallized with ethanol to obtain a pure product, and its melting point was measured and found to be 233°C (decomposition).

Example 4 5-Bromo-2-methyltryptamine hydrochloride Example 3 except that p-bromphenylhydrazine hydrochloride 33.53f (150 mmol) was used instead of N-methylphenylhydrazine hydrochloride in Example 3. When reacted and treated in the same manner as in 3, brown crude crystals were obtained. This product was recrystallized from water to obtain 5-bromo-2-methyltryptamine hydrochloride 24.08F (yield 56%). The melting point of this product was 255°C (decomposed).

Example 5 2.5-dimethyltryptamine hydrochloride ethylene glycol monomethyl ether 200- to p-
Methylphenylhydrazine emate 635f (40 mmol) was dissolved, and the solution was heated and stirred until the temperature reached 12
When the temperature reaches 1°C, cyclopropyl methyl ketone 3.
A solution of 37F (40 mmol) dissolved in 40 ml of ethylene glycol monomethyl ether was added dropwise over 30 minutes, and the mixture was reacted under boiling and reflux for 3 hours. After the reaction, the solvent was distilled off under reduced pressure, and the remaining brown solid was recrystallized from water to give 2
．． 5-dimethyltryptamine hydrochloride 6.2Of (yield 6
9%). The melting point of Part B was 229°C (decomposed).

Example 6 200d17Cp-benzyloxyphenylhydrazine hydrochloride 10.03r (40 mmol) of ethanol was dissolved (7, this solution was heated and stirred and when the liquid temperature reached 78°C, 3.37f (40 mmol) of cyclopropyl methyl ketone was dissolved. 7!L of 50tf of ethanol dissolved in 50tf of ethanol:
It was dropped in i hours. Thereafter, the reaction solution was boiled and reacted under reflux for 3 hours. After cooling, add 300ml of water and 2ff of caustic soda.
fi was added and extracted three times with 100-chloroform. After the entire chloroform layer was combined and washed with water, the chloroform was distilled off under reduced pressure to obtain a brown oily gold. This was completely purified by column chromatography, and 5-benzyloxy-2-
3.149 methyltryptamine (yield 28%) was obtained.

The measurement results of NMR were as follows.

1HNMR(CDCts)δ(ppm)+1.8
3(s, 2H1-NH2), 2.26(s, 3
H,, -CHa), 2.82(dt, 4H, -C
H2CH2-), 5.02 (s, 2H.

-CfIzO-), 6.42-7.53 (m, 8
Hlindol H.

phenyi), 8. OO(s, L H,
1ndole NH) 11 Example 7 Dissolve 1,2-diphenyltryptamine n-propanol 200dK1,1-dienylhydrazine hydrochloride 6.62f (30 mmol),
When this solution was heated and stirred and the liquid temperature reached 96°C,
Cyclopropylphenyl ketone 4.39f (30mg) k was dissolved in 50w1t of n-gropanol and was added dropwise over 40 minutes fc. After reacting for 4 hours under boiling and refluxing, the mixture was cooled, 300 ml of water and 2 ml of caustic soda were added, and extracted with chloroform 100 t/-r three times. The chloroform layers were combined, washed with water, and then chloroform was distilled off under reduced pressure to precipitate crystals. Add this crystal to toluene!
11 recrystallized, 1,2-diphenyltryptamine 4.0
3f (yield: 43cm) was obtained. The result of melting point measurement is 148-
The temperature was 151°C. (Literature value: 151-153°C) Example 8 1.2-Dibenzyltryptamine ethylene glycol monomethyl ether 10012-1-benzyl-1-phenylhydrazine hydrochloride 4.
699 (20 mmol) was heated and stirred and when the liquid temperature reached 121°C, benzyl cyclopropyl ketone 3.52F (20 mmol) was dissolved in ethylene glycol monomethyl ether 20rnt. dripped. After reacting for 5 hours under boiling reflux, the mixture was cooled, 300 xi of water and 1 f of caustic soda were added, and the mixture was 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 total column chromatography, and 1,2-dibenzyltryptamine 2
．． 59t (yield: 38t) was obtained.゛The results of elemental analysis were as follows.

(Measurement value') C: 84.58. H near, 07°N:
8.22 (calculated value) C: 84.67, H near, 10°N: 8
．． 23

Claims (1)

[Claims] 1. General formula (I) [In the formula, R1 represents a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group. ] A cyclopropylcarbonyl compound represented by the general formula (n) [wherein R2 represents a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group, and R3 represents a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, or an alkoxy group, aralkyloxy group, aryloxy group, or halogen atom. ] The phenylhydrazine compound represented by the general formula (1) is reacted with gold and in the presence of a solvent under acidic conditions.
) [In the formula, R1, R2, and R3 are the same as defined above. ] A method for producing a tryptamine compound.