JPS6150946B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a tryptamine compound, and more specifically, a phenylhydrazine compound and a 4-aminobutanal dialkyl acetal compound are reacted under weak acidity, and the tryptamine compound is produced by condensation and cyclization. It is about the method. Tryptamine compounds themselves have pharmacological effects and are extremely useful compounds as raw materials for the synthesis of indole derivatives and alkaloids. Many methods have been studied for a long time to synthesize tryptamine compounds. For example, there is a method of producing tryptamines using an indole derivative as a starting material by a decarbonylation method or a reduction method. However, this method is not suitable as an industrial production method because it involves a large number of steps, is complicated to operate, and often has a low yield of tryptamines. Another conventional method for producing tryptamine, which utilizes the Fischer synthesis method involving cyclization of phenylhydrazine, is the following method. (1) A method for obtaining tryptamine by condensing and cyclizing phenylhydrazine and 4-aminobutanal dialkyl acetal in the presence of a large excess of anhydrous zinc chloride [JCS 99 270 (1911)]. (2) A method for obtaining a substituted tryptamine compound by condensing and cyclizing substituted phenylhydrazine and 4-chlorobutanal [II Glandberg et al., Khim,
Getentsikle Soecl., 1973 , 213; CA 78 ,
[D.
Desaty et al. croat, chem.Octa 33 , 83
(1961); 37 , 25 (1965): {CA 56 , 4710g
(1962); 63 , 8294d (1965)}. However, method (1) above requires a large excess of anhydrous zinc chloride and has the disadvantage that the yield of the tryptamine compound obtained is low. Said (2)
Both methods are difficult to synthesize the raw material 4-chlorobutanal and are not satisfactory as industrial methods for producing tryptamines. Furthermore, (3)
In this method, when there is a strong electron-donating substituent such as a methoxy group or benzyloxy group on the benzene nucleus of phenylhydrazine, when there is no substituent that can cause a condensation cyclization reaction, or when there is a methyl group If a weak electron-donating substituent such as a halogen is present, the cyclocondensation reaction does not occur, making it impossible to synthesize a tryptamine compound. An object of the present invention is to provide a method for producing tryptamine compounds in a simple process and in high yield. Another object of the present invention is to provide a method for producing tryptamine compounds having various substituents without decomposing the substituents. The method for producing a tryptamine compound of the present invention has the general formula () [However, in the formula, R represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, an aralkyl group, a nitro group, or a halogen atom, and R ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. represents a group, an aryl group, an aralkyl group or a hydroxyalkyl group having 1 to 6 carbon atoms,
R ¹ and R ³ are each the same atom or group as R ₂ , and the formula is R ⁴ CO- group [However, R ⁴ in the formula has 1 carbon atom]
to 6 alkyl group, aryl group, or aralkyl group], and R ¹ , R ² , and R ³ may be the same or different in formula, and

[Formula] The group is

[Formula] (where n represents an integer from 1 to 3, m represents an integer 2 or 3, and X represents a -CH ₂ - group, an oxygen atom, a nitrogen atom, or a sulfur atom) Alternatively, R ₂ represents the alkyl group, R ³ represents the R ⁴ CO- group, R ⁴ represents the alkyl group, and the sum of the number of carbon atoms of both the alkyl groups is 4 to 8, R ² and R ⁴
is a ring-closed bond

[Formula] (where l in the formula represents an integer of 4 to 8) may be formed. ], In producing the tryptamine compound represented by the general formula (): (wherein R and R ¹ are the same as defined above); and a phenylhydrazine compound represented by the general formulas () and (): (In the formula, R ² and R ³ are the same as defined above, and when R ⁵ and R ⁶ are independent from each other, each represents an alkyl group having 1 to 4 carbon atoms, and when they are consecutive, both represent carbon atoms. 4-aminobutanal dialkyl acetal compound represented by the number 2 to 6 alkyl group) in water or a hydrophilic solvent, or a mixed solvent of two or more of these, at a concentration of 0.8 to 4.0.
It is characterized by being reacted at PH. In carrying out the method of the present invention, phenylhydrazine compounds may be used in the form of their strong acid salts, and 4-aminobutanal dialkyl acetal compounds may be used when their amino groups are primary, secondary and tertiary. It may be used in the form of its strong acid salt or, if the amino group is acylated, as it is. Either dissolve each of these in a solvent and react by dropping one of the resulting solutions into the other, or
Or dissolve both compounds in the same solvent and heat the resulting mixed solution at a temperature of 60 to 140°C, preferably 90 to 140°C.
Heat at 120°C for 30 minutes to 6 hours to allow the two to react. During this reaction, the pH of the reaction solution is always
It is maintained between 0.8 and 4.0, preferably between 2.0 and 3.5. If the PH of the reaction system exceeds 4.0, the reaction between the two will not proceed at all, and only unreacted compounds will be recovered from the reaction system, while if the PH of the reaction system is lower than 0.8, there will be many side reactions. , the yield of tryptamine derivatives decreases. In the method of the present invention, the pH of the reaction system
There are no particular limitations on how to keep the 4-aminobutanal dialkyl acetal compound dropwise into a solution of a strong acid salt of a phenylhydrazine compound. A method of reacting while adjusting the pH of the reaction system to a desired value by dropping a dilute aqueous solution of a strong acid A solution of a phenylhydrazine compound, and 4
- A method in which solutions of aminobutanal dialkyl acetal compounds are adjusted to the above-mentioned desired PH range, and one of these solutions is reacted with the other by dropping a phenylhydrazine compound or its strong acid salt and 4-aminobutanal A method in which both the dialkyl acetal compound and the compound are dissolved in the same solvent, the pH of this solution is adjusted to the desired value with a strong acid, and both compounds are allowed to react with each other.A strong acid is further added to the strong acid salt of the phenylhydrazine compound. A method of reacting the two by dropping a solution of the 4-aminobutanal dialkyl acetal compound (preferably PH4 or higher) into the resulting acidic solution so that the PH of the mixed reaction system is 0.8 to 4.0. Phenylhydrazine compound with a strong acid salt of 4-
When reacting an aminobutanal dialkyl acetal compound, a method may be used in which the former is used in excess of the theoretical amount and the two are reacted while adjusting the pH of the reaction system to 0.8 to 4.0. The method for separating the reaction product thus reacted varies depending on the starting materials and the type of solvent used in the reaction, but for example, the reaction mixture is cooled on ice to remove the tryptamine produced. The compound is taken out as its strong acid salt, or the reaction mixture is concentrated and then left as is, or an alkali is added to liberate the strong acid salt of the tryptamine compound produced,
There are methods such as extracting this with an organic solvent, distilling off the solvent and performing vacuum distillation, or recrystallization. The phenylhydrazine compound used in the method of the present invention has the following general formula (). [In the formula, R represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, an aralkyl group, a nitro group, or a halogen atom, and R ¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, Aryl group, aralkyl group, or R ⁴ CO- group (R ⁴ in the formula is an alkyl group having 1 to 6 carbon atoms,
represents an aryl group or an aralkyl group. Such phenylhydrazine compounds include phenylhydrazine, tolylhydrazine, nitrophenylhydrazine, chlorphenylhydrazine, bromphenylhydrazine, 1,1-diphenylhydrazine,
Examples include 1-benzyl-1-phenylhydrazine, 1-methyl-1-phenylhydrazine, 1-benzoyl, -1-phenylhydrazine, benzyloxyphenylhydrazine, and 1-acetylphenylhydrazine. The 4-aminobutanal dialkyl acetal compound used in the method of the present invention has the following general formula (). [In the formula, R ₂ is a hydrogen atom, the number of carbon atoms is 1 to 6]
represents an alkyl group, an aryl group, an aralkyl group, or an adroxyalkyl group having 1 to 6 carbon atoms, R ³ is the same atom or group as R ² , and the formula is a general formula R ⁴ CO- group (in the formula R ⁴ has 1 carbon atom
to 6 alkyl group, aryl group, or aralkyl group), R ² and R ³ and R ¹ in the above formula may be the same or different, and further,

【ceremony,

[Formula] (However, n in the formula represents an integer from 1 to 3,
m may represent an integer 2 or 3, and X may represent a _-CH2- group, an oxygen atom, a nitrogen atom, or a sulfur atom), and ^R2 may represent the above alkyl group, and ^R3 may represent the above-mentioned alkyl group; R ⁴ represents a CO- group, this R ⁴ represents the alkyl group, and when the sum of the number of carbon atoms of both the alkyl groups is 4 to 8, R ² and R ⁴
is a ring-closed bond,

[Formula] Group (However, l in the formula represents an integer from 4 to 8)
It is a compound containing at least one group of the structure shown below. Examples of such 4-aminobutanal dialkyl acetal compounds include 4-aminobutanal dimethyl acetal, 4-aminobutanal diethylacetal, 4-morpholinobutanal dimethyl acetal, 4-piperidinobutanal dimethyl acetal, 3. 9-bis(3-aminopropyl)-2,4,8,10-tetraoxaspiro[5,5]undecane (hereinafter abbreviated as ATU. Its molecular formula is as follows: ), and these N-methyl, N-ethyl,
N・N-dimethyl, N・N-diethyl, N-cyclohexyl, N-tolyl, N-benzyl, N-
Acetyl, N-propionyl, N-benzoyl,
Examples include N-hydroxyethyl, N-hydroxypropyl, and N-hydroxybutyl substituted products. An example of a method for obtaining these 4-aminobutanal dialkyl acetal compounds is the following method. That is, β-cyanopropionaldehyde obtained by oxo reaction of acrylonitrile is acetalized with alcohol, and then the cyano group is reduced to obtain 4-aminobutanal dialkyl acetal. Further, by alkylating, allylating or acylating the amino group of this compound by a conventional method, an N-substituted 4-aminobutanal dialkyl acetal can be obtained. In the compound of the general formula (), the _-CH2O- group is a residue of an acetalized alcohol, and this alcohol includes monohydric alcohols such as methanol, ethanol, propanol, etc., ethylene glycol, monohydric alcohol, etc.・There are polyhydric alcohols such as 3-butanediol and pentaerythritol. The number of moles of the phenylhydrazine compound and the 4-aminobutanal dialkyl acetal compound used in the method of the present invention may be any theoretical amount of both, and this is sufficient to achieve the purpose.
This does not preclude the use of either of the two compounds in excess of the stoichiometric amount. Generally, it is preferable to use the phenylhydrazine compound in excess of the theoretical amount in the reaction. The reason is that the phenylhydrazine compound is a weak base, and the salt formed from this and a strong acid has a concentration of about 2 to 4 in its aqueous solution.
Since it exhibits a slightly acidic pH, it is easy to maintain the desired pH range in the method of the present invention. In the method of the present invention, the pH of the reaction system is 0.8 to 4.0.
Acids used to maintain the
Examples include strong organic acids such as toluenesulfonic acid and strong acidic ion exchange resins. The solvent used in the method of the present invention is water, alcohols such as methanol, ethanol, propanol, ethylene glycol, glycerin, glycol ethers, dioxane, etc., or a mixture of two or more thereof. However, it is preferable to select an appropriate solvent depending on the properties of the tryptamine compound to be produced. For example, when the amino group of the tryptamine compound obtained is basic, an aqueous solvent mainly composed of water is preferable, and when the amino group is acylated, a hydrophilic organic solvent or one kind thereof is preferable. A mixture of the above and water is preferred. During the reaction in the method of the present invention, the temperature is preferably 60 to 140°C, more preferably 90 to 120°C. If the reaction temperature is less than 60°C, the reaction will be slow and it may take a long time to complete the reaction, and even if the reaction is carried out at a temperature higher than 140°C, there is no particular merit. The tryptamine compound obtained by the method of the present invention has the following general formula: [In the formula, the symbols R, R ¹ , R ² , and R ³ are the same as in the previous definition]
This is a compound represented by These compounds are obtained corresponding to the two starting materials described above. Examples of tryptamine compounds include tryptamine, N(β)-acetyltryptamine, N(β)-propionyltryptamine, N
(β)-benzoyltryptamine, N(β)-tolyltryptamine, N(β)-acetyl-N
(β)-Benzyltryptamine, N(β)-butyryltryptamine, N(β)-benzyltryptamine, N(β)-cyclohexyltryptamine, N
(β)・N(β)-dimethyltryptamine, N
(α)-phenyltryptamine, N(α)-benzyltryptamine, N(α)-methyltryptamine, 7-methyltryptamine, 5-chlortryptamine, 7-chlortryptamine, 5-bromotryptamine, 4-methyl-tryptamine, 6-methyl-tryptamine, 5-nitrotryptamine,
5-bromo-N-benzoyltryptamine, 5-
Examples include chlor-NN-dimethyltryptamine, 5-methyl-N-benzyltryptamine, and N(β)-hydroxyamyltryptamine. The reason why the method for producing tryptamine compounds of the present invention proceeds so effectively has not been fully clarified. However, the phenylhydrazine compound and the 4-aminobutanal dialkyl acetal compound start to react at a pH of 4 or lower to produce a tryptamine compound, and the reaction occurs at a pH of 0.8 or lower.
When the tryptamine compound produced becomes
It has become clear that a condensation reaction occurs with a 4-aminobutanal dialkyl acetal compound to produce a heterotricyclic compound. Therefore, in order to obtain a tryptamine compound in good yield, the first
It is necessary to promote the production reaction of the tryptamine compound and to suppress the second side reaction, that is, the production reaction of the tricyclic compound. For this purpose, it is necessary to maintain the pH of the reaction system between 0.8 and 4.0. The method for producing tryptamine compounds of the present invention is completely new and has extremely high industrial utility. The present invention will be explained in detail below with reference to Examples. In the examples, the yield is the theoretical yield of the tryptamine compound obtained with respect to the 4-aminobutanal dialkyl acetal compound used, and the PH
The raw material system and the reaction product were measured using glass electrodes, and the reaction solution during the reaction was measured using test paper thymol brew and/or bromophenol brew. Example 1 N(β)-acetyltryptamine Dissolve 2.89 g (20 mmole) of phenylhydrazine hydrochloride in a mixed solvent of 40 ml of water and 40 ml of ethylene glycol, heat and stir this solution until the liquid temperature reaches 97°C.
When it reaches 4-(N-acetylamino)
(PH2.26) Butanal dimethyl acetal 3.50g
A solution of (20 mmole) dissolved in 50 ml of water and adjusted to pH 2.73 with 10% aqueous hydrochloric acid solution was added dropwise over 1 hour. The temperature of the reaction mixture was maintained at 98 to 101°C and heated and stirred for an additional 2 hours, and the pH of the reaction mixture was maintained at 1.5 to 2.3. After the reaction was completed, the reaction solution was allowed to cool to room temperature, extracted twice with 150 ml of chloroform, and the chloroform layers were combined and washed with water until the washing solution became neutral. Chloroform was distilled off under reduced pressure, and 30 ml of hot benzene was added to the resulting yellowish brown oil for extraction. After repeating this operation three times, the benzene solutions were combined, a small amount of petroleum ether was added, and the mixture was left at room temperature overnight. The precipitated crystals were filtered and N
(β)-Acetyltriptan 2.82g (yield 69.6%)
I got it. The melting point of this product was 73-74.5°C. Example 2 N(β)-propionyltryptamine Instead of 4-(N-acetylaminobutanal dimethyl acetal in Example 1, 4-(N-propionylamino)butanal diethyl acetal
The reaction and treatment were carried out in the same manner as in Example 1, except that 4.35 g (20 mmole) was used, and a brown oil was obtained from the chloroform extract. The PH of the reaction mixture was maintained between 1.7 and 2.5. Add 60ml of hot toluene to this, extract and separate, cool the toluene layer on ice,
2.83 g (yield 65.5%) of N(β)-propionyltryptamine was obtained as white prismatic crystals. Melting point: 82-83°C Example 3 N(β)-benzoyltryptamine Dissolve 2.16 g (20 mmole) of phenylhydrazine in a mixed solvent of 100 ml of water and 50 ml of n-propanol, add 50% aqueous sulfuric acid solution, and adjust the pH to 3.15. It was adjusted. In addition, 4.80 g of 3,9-bis(3-N-benzoylaminopropyl)-2,4,8,10-tetraoxaspiro[5,5]undecane
(10 mmole) was added and heated under reflux for 3 hours. The PH of the reaction mixture was maintained between 2.1 and 3.0. After the reaction was completed, the mixture was extracted twice with 70 ml of chloroform, and the chloroform layers were combined and washed with water until the washings became neutral. Chloroform was distilled off under reduced pressure, hot toluene was added to the resulting brown oily residue for extraction, and the toluene layer was cooled to give N(β) as pale yellow plate crystals.
- 3.24 g (61.4%) of benzoyltryptamine was obtained. Melting point 141-142.5°C Example 4 N(β)-toluyltryptamine Phenylhydrazine hydrochloride 3.18g (22mmole)
and 5.11 g (10 mmole) of 3,9-bis(3-N-tolylaminopropyl)-2,4,8,10-tetraoxaspiro[5,5]undecane in n-
Suspend in 80ml of propanol and heat and stir.
The reaction was carried out under reflux for an hour. The PH of the reaction mixture is 1.0
or kept at 2.2. After the reaction, insoluble matter was filtered and n-propanol was distilled off from the filtrate under reduced pressure. To the obtained solid residue, 100 ml of hot toluene was added for extraction. When the toluene layer was cooled on ice, pale yellow prismatic crystals were obtained. 2.56 g (yield 46.0%) of N(β)-tolyltryptamine was obtained. Melting point 124-126°C Example 5 N(β)-acetyl-N(β)-benzyltryptamine 3,9-bis(3-N-acetyl-N-benzylaminopropyl)-2,4,8,10-tetra Oxaspiro [5.5] Undecane 4.91g (10m
The reaction was carried out in the same manner as in Example 4, except that mol) was used. The PH of the reaction mixture was maintained between 1.2 and 2.0. After the reaction was completed, the solvent was distilled off under reduced pressure, and 50 ml of water and 100 ml of chloroform were added to the obtained solid residue, and the chloroform layer was separated and washed with water until the washing liquid became neutral. Add 100 ml of methanol to the reddish-brown oily residue obtained by distilling off chloroform under reduced pressure, dissolve it by heating, and cool it on ice to obtain N(β)-acetyl-N(β)-benzyl as pale yellow needle crystals. 4.37 g (yield 74.7%) of tryptamine was obtained. Melting point 120
~121°C Example 6 N(β)-Butyryltryptamine 2.38 g (22 mmole) of phenylhydrazine was dissolved in 100 ml of isopropanol, and further 4.38 g (23 mmole) of p-toluenesulfonic acid hydrate and 3.9- 4.15 g (10 mmole) of bis(3-N-butyrylaminopropyl)-2,4,8,10-tetraoxaspiro[5,5]undecane was added, and the mixture was heated under reflux for 6 hours with stirring. The PH of the reaction mixture was maintained between 1.5 and 3.0. After cooling the reaction solution and removing the insoluble solids, the isopropanol was distilled off under reduced pressure. The brown oil obtained was extracted with 100 ml of hot benzene. When the benzene extract was left at room temperature, white flaky crystals were obtained. As a result, 2.40 g (yield 52.1%) of N(β)-butyryltryptamine was obtained. Melting point: 87-88.5°C Example 7 N(β)-benzyltryptamine 4.33g (40mmole) of phenylhydrazine was dissolved in 50% of water.
ml, heat and stir the solution with 10% hydrochloric acid aqueous solution to pH 2.48, and when it reaches 98℃,
Add 4.54 g (10 mmole) of 3,9-bis(3-N-benzylaminopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane to 50 g of water.
ml, and a solution adjusted to pH 1.00 with 10% aqueous hydrochloric acid solution was added dropwise over 1 hour. After maintaining the pH of the reaction mixture between 0.8 and 2.0 and the temperature at 98°C for 3 hours, the reaction mixture was cooled on ice, and the precipitated solid was filtered to obtain N( 3.10 g (yield: 54.0 g) of β)-benzyltryptamine hydrochloride was obtained. This was recrystallized from ethanol to obtain white plate-like crystals. Melting point 232-233°C Example 8 N(β)-cyclohexyltryptamine 3,9-bis(3-N-cyclohexylaminopropyl)-2,4,8,10-tetraoxaspiro[5,5]undecane 4.39 g ( The reaction was carried out in the same manner as in Example 7 except that 10 mmole) was used. The PH of the reaction mixture was maintained between 0.8 and 1.8. The reaction solution was allowed to cool to room temperature, and the precipitated solid was filtered to obtain 3.52 g (yield: 63.1%) of N(β)-cyclohexyltryptamine as an orange-red powder solid. This was recrystallized from ethanol to obtain white plate-like crystals. melting point
241-244℃ Example 9 N(β)・N(β)-Dimethyltryptamine A solution of phenylhydrazine in 50ml of water and adjusted to pH 3.67 with 85% phosphoric acid was heated and stirred,
When the reflux temperature of
85% aqueous solution of 3.30 g (10 mmole) of 4,8,10-tetraoxaspiro[5,5]undecane in 50 ml of water.
A solution adjusted to pH 0.8 with phosphoric acid was added dropwise over 1 hour, and the reaction mixture was reacted for 2.5 hours while maintaining the pH of the reaction mixture between 1.0 and 2.5 and the temperature at 100°C. After the reaction was completed, the reaction solution was made strongly alkaline by adding a 48% aqueous sodium hydroxide solution, extracted twice with 50 ml of chloroform, the chloroform layers were combined and washed with water, and then the chloroform was distilled off under reduced pressure. Add 50 ml of n-hexane to the obtained brown oily residue and heat it for 2 hours.
After extraction, the n-hexane was left at room temperature to obtain 2.67 g (yield: 84.1%) of N(β)/N(β)-dimethyltryptamine as pale yellow needle crystals. Melting point 44.5
~46℃ Example 10 N(α)-phenyltryptamine 1,1-diphenylhydrazine salt residual salt 2.21g
(10 mmole) was heated and dissolved in 40 ml of water, and when the temperature reached 90℃, 1.33 g (10 mmole) of 4-aminobutanal dimethyl acetal was dissolved in 40 ml of water.
A solution adjusted to pH 1.90 with % aqueous hydrochloric acid solution was added dropwise over 1 hour, and the reaction mixture was stirred for 3 hours while keeping the pH of the reaction mixture at 1.5 to 2.6 and the temperature at 100°C. After the reaction was completed, the reaction solution was cooled with ice, and the precipitated black flaky crystals were filtered. These crystals were recrystallized with isopropanol to form white plate-like crystals.
(α)-Phenyltryptamine hydrochloride 200g (yield
73.3%). Melting point 268° (decomposition) Example 11 N(α)-benzyltryptamine 1-benzyl-1-phenylhydrazine hydrochloride
The reaction was carried out in the same manner as in Example 10, except that 2.35 g (10 mmole) and 2.17 g (10 mmole) of 4-aminobutanal diethylacetal were used. The PH of the reaction mixture is
It was kept between 2.0 and 3.0. After the reaction was completed, the reaction solution was extracted twice with 50 ml of warm chloroform, the chloroform layers were combined, and the chloroform was distilled off under reduced pressure. The pale yellow residue that solidifies at room temperature is dissolved in ethanol, and ethyl acetate is added and cooled on ice to obtain 1.64 g (yield 57.1%) of N(α)-benzyltryptamine salt residual salt as white small needle crystals. Obtained. Melting point 176.5-178°C Example 12 N(α)-methyltryptamine 1-methyl-1-phenylhydrazine hydrochloride
Using 1.90g (12mmole), ATU1.37g (5m
mole) was dissolved in 40 ml of water, and the reaction was carried out in the same manner as in Example 10, except that the pH of the solution was adjusted to 2.48. The PH of the reaction mixture was maintained between 2.3 and 3.2. After the reaction is complete,
The reaction solution was cooled on ice under reduced pressure to about 1/3 volume, and the precipitated crystals were filtered. 1.80 g (yield: 85.3%) of N(α)-methyltryptamine hydrochloride in the form of white plate-like crystals was obtained. This product was recrystallized from isopropyl alcohol to give white needle-like crystals. Melting point 200.5~
201℃ Example 13 2.69g of p-tolylphenylhydrazine (22m
mole) in 40ml of water, and add 10% hydrochloric acid solution to pH2.65.
A solution of 3.49 g of p-tolylphenylhydrazine hydrochloride in 50 ml of water was heated and stirred, and when the temperature reached 97°C, 2.58 g of 4-aminobutanal dimethyl acetal (20 ml of
mole) in 30 ml of water and PH with 10% hydrochloric acid aqueous solution.
2.60 was added dropwise over 1 hour. Further, the reaction mixture was heated under reflux for 3 hours while maintaining the pH between 1.7 and 2.6, and then the reaction mixture was cooled on ice and the precipitated orange-red plate-like crystals were collected by filtration to obtain 3.72 g of 5-methyltryptamine hydrochloride (yield: 88.3%) was obtained. When this was reconstituted from alcohol, pale green plate-like crystals were obtained. Melting point: 293°C (decomposition) Examples 14-17 The following substituted tryptamines were synthesized in the same manner as in Example 13.

[Table] Example 18 5-Bromo-N-benzoyltryptamine 1.87 g (10 m
mole) and 2.40 g (5 mmole) of 3,9-bis(3-N-benzoylaminopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane
A mixed solvent of water and ethylene glycol (1:1)
After adjusting the pH to 2.25 with 85% phosphoric acid, the reaction mixture was kept at a pH of 2.0 to 2.7 with stirring, and reacted at reflux temperature (110°C) for 2.5 hours.
After the reaction, extract twice with 50 ml of chloroform,
After combining the chloroform layers and washing them with water, 50 ml of toluene was added to the brown oil obtained by distilling off the chloroform under reduced pressure and dissolved by heating.The solid that precipitated after being left at room temperature was collected by filtration and a pale 5-bromo-N-benzoyltryptamine as yellow prismatic crystals
2.84 g (yield 82.8%) was obtained. Melting point: 173-174°C Example 19 5-chloro-N·N-dimethyltryptamine p-chlorophenylhydrazine hydrochloride 1.79g
(10 mmole) was heated and dissolved in 40 ml of water, and when it reached reflux temperature, 1.65 g of 3,9-bis(3-dimethylaminopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane (5mmole)
A solution of 50 ml of aqueous solution adjusted to pH 2.04 with 10% aqueous hydrochloric acid was added dropwise over 1 hour, and the pH of the reaction mixture was adjusted to
1.3 to 2.0, and 3 while keeping the temperature at 98℃.
Allowed time to react. After the reaction was completed, the reaction solution was concentrated to 1/3 volume, cooled on ice, and the precipitated solid was collected by filtration. This solid was recrystallized from i-propyl alcohol to give 2.35 g of 5-chloro-N·N-dimethyltryptamine hydrochloride as white granular crystals (yield 90.7%).
was gotten. Melting point 192-194°C Example 20 5-Methyl-N-benzyltryptamine p-tolylhydrazine hydrochloride 1.91g (12m
mole) and 2.27 g (5 mmole) of 3,9-bis(3-N-benzylaminopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane
(PH of this aqueous solution: 1.51) The reaction was carried out in the same manner as in Example 7, except that the solution was used. The pH of the reaction mixture is between 0.8 and
Retained at 1.2. After the reaction is completed, the reaction solution is cooled on ice, the precipitated solid is filtered, and this solid is recrystallized from ethanol and ethyl acetate.
2.49 g (yield: 83.0%) of 5-methyl-N-benzyltryptamine hydrochloride was obtained as white flaky crystals. Melting point: 196-198°C Example 21 1-Methyl-N・N-dimethyltryptamine 1-Methyl-1-phenylhydrazine 1.47g
(12 mmole) in 40 ml of water and diluted with 10% hydrochloric acid aqueous solution.
The same acetal as in Example 7 was reacted in the same manner using a solution adjusted to pH 2.51. PH of reaction mixture
is kept between 1.8 and 2.5. After the reaction was completed, the reaction solution was made strongly alkaline by adding a 48% aqueous sodium hydroxide solution, extracted twice with 50 ml of chloroform, the chloroform layers were combined, and the chloroform was distilled off under reduced pressure. The obtained dark red oily residue was dissolved in alcohol, an ethanol solution of picric acid was added, and the precipitated powdery solid was collected by filtration. This solid was recrystallized from alcohol to give orange plate-shaped crystals.
2.91 g (yield 72.1%) of picrate of -methyl-N.N-dimethyltryptamine was obtained. melting point
180-182℃ Example 22 Tryptamine In a 200 ml four-necked flask equipped with a Dimroth condenser, dropping funnel, thermometer and airtight stirrer, add 50 ml (HCl; 50 mmole) of a 1.0N aqueous hydrochloric acid solution and 4.33 g (40 mmole) of phenylhydrazine. ) and heated and stirred. While maintaining the liquid temperature at 90℃, add 5.35g of 4-aminobutanal dimethyl acetal (40m
mole) and 40ml of 1.0N hydrochloric acid aqueous solution (HCl; 40ml)
A solution dissolved in mole) was added dropwise over a period of 2 hours. After the dropwise addition, the pH of the reaction mixture was further adjusted to 0.8.
The reaction was carried out at 90° C. for 2 hours while maintaining the temperature between 1.5 and 1.5. After the reaction was completed, the reaction solution was concentrated under reduced pressure to about half its volume and crystallized under ice cooling to obtain 5.59 g of tryptamine hydrochloride as granular crystals. The purity of this product was 97% and the yield was 69%. Melting point 248-249°C Example 23 Tryptamine 4-aminobutanal diethyl acetal in place of 4-aminobutanal dimethyl acetal
When the reaction was carried out in the same manner as in Example 22 except that 6.45 g (40 mmole) was used, 5.02 g of tryptamine hydrochloride was obtained.
I got it. The purity of this stuff is 96% and the yield is 61
It was %. Example 24 Tryptamine Using the same apparatus as in Example 22, dissolve 5.80 g (40 mmole) of phenylhydrazine hydrochloride in 50 ml (HCl; 5 mmole) of 0.1N aqueous hydrochloric acid solution and heat at 98-100°C.
50 ml of an aqueous solution of pH 7.5 obtained by neutralizing 5.48 g (20 mmole) of ATU with hydrochloric acid was added dropwise over 1.5 hours, and the mixture was further stirred at the same temperature for 3 hours. The PH of the reaction mixture was maintained between 0.8 and 2.0. After the reaction is complete, add 48% aqueous sodium hydroxide solution to the reaction solution to adjust the pH of the solution to 10, and add chloroform.
Extracted twice with 100 ml. Chloroform was removed from the chloroform layer under reduced pressure, and the residue was distilled to obtain 4.54 g of tryptamine (71% yield) as a fraction at 163-165°C/0.5 mmHg. When this product was dissolved in hot benzene and cooled, it became plate-shaped crystals. Example 25 Tryptamine Dissolve 2.90 g (20 mmole) of phenylhydrazine hydrochloride in 50 ml (HCl; 10 mmole) of 0.2N aqueous hydrochloric acid solution, heat and stir at 98-100°C, and dissolve 2.74 g (10 mmole) of ATU.
mole) in 50 ml of n-propyl alcohol and neutralized with 15% aqueous hydrochloric acid solution was added dropwise over 1 hour. After the dropwise addition was completed, the reaction solution was refluxed at 88° C., and the reaction was continued for an additional 3 hours while maintaining this temperature and pH between 0.8 and 2.0. After the reaction was completed, the reaction solution was concentrated to about half its volume and treated in the same manner as in Example 3 to obtain 2.02 g of tryptamine (yield: 63%). Example 26 Tryptamine Using the same equipment as in Example 22, 7.23 g (50 mmole) of phenylhydrazine hydrochloride and 6.86 g of ATU
(25 mmole) in 100 ml of water, and in this aqueous solution, 18.32 g of 10% hydrochloric acid aqueous solution (HCl; 50.1 mmole)
When added, the pH of the aqueous solution became 3.05. Keep this at a pH of 1.8 to 2.8 and stir
The reaction was carried out at 98-100°C for 4 hours. After the reaction was completed, the same treatment as in Example 24 was carried out to obtain 5.12 g of tryptamine (yield: 64%). Comparative Example 1 In Example 25, 50 ml (HCl; 50 mmole) of 1N hydrochloric acid aqueous solution was used instead of 0.2N hydrochloric acid aqueous solution.
It was reacted and treated in the same manner. The PH of the reaction mixture was 0.08 to 0.1. tryptamine
A large amount of resinous distillation residue, 0.72 g (yield 23%), was obtained. Examples 27 to 30 and Comparative Examples 2 and 3 Reactions were carried out according to Example 22 while changing the pH of the aqueous hydrochloride solutions of phenylhydrazine and ATU. The results are shown in Table 1.

[Table] Comparative example 4 Phenylhydrazine hydrochloride 7.23g (50mmole)
was heated and dissolved in 80ml of 25% acetic acid aqueous solution until the temperature of the solution was 80℃.
When it reaches, add ATU6.86g (25mmole).
A solution dissolved in 20 ml of 25% acetic acid aqueous solution was added dropwise over 1 hour. While maintaining the pH of the reaction mixture at 6.0 to 6.5 and the temperature at 80℃, the reaction mixture was heated and stirred for 20 hours. After the reaction was completed, thin layer chromatography (developing agent: ethyl acetate-isopropanol-28%
Detection using aqueous ammonia (45:35:20; coloring agent: 0.2% alcohol solution of ninhydrin) revealed that only trace amounts of tryptamine were produced. Example 31 Tryptamine Into a four-necked flask equipped with a Dimroth condenser, dropping funnel, thermometer, and airtight stirrer, 50 ml of a phenylhydrazine hydrochloride solution with a pH of 3.0 prepared from 4.33 g (40 mmole) of phenylhydrazine and hydrochloric acid was added. and heated and stirred. Keeping the liquid temperature at 98-100℃, neutralize ATU5.48g (20mmole) with hydrochloric acid,
50 ml of an aqueous solution with a pH of 3.0 was added dropwise over 1.5 hours, and the mixture was stirred at the same temperature for an additional 3 hours to carry out the reaction. The pH of the reaction mixture during the reaction was 2.0 to 3.0, and was 2.61 at the end of the reaction. 25% to this reaction mixture.
Neutralize by adding sodium hydroxide aqueous solution and adjust the pH of the liquid.
was set to 10, and extraction was performed twice with 100 ml of chloroform. From the extracted chloroform layer, chloroform was distilled off under reduced pressure, and the residue was subjected to vacuum distillation.
Tryptamine 4.36g as fraction at °C/0.5mmHg
(Theoretical yield: 68.0%). Example 32 Tryptamine Phenylhydrazine hydrochloride in the apparatus of Example 31
An aqueous solution of 5.42 (37.5 mmole) dissolved in 50 ml of water
The temperature was 90℃. A solution of 3.23 g (25 mmole) of 4-amino-butanal dimethyl acetal dissolved in 50 ml of water and adjusted to pH 4.23 with a 15% aqueous hydrochloric acid solution was added dropwise over 1.5 hours. After the dropwise addition was completed, the mixture was allowed to react under reflux for 2.5 hours. The pH of the reaction solution during dropping and reaction is 2.0 to 2.8, and 2.27 at the end of the reaction.
It was hot. The reaction solution was concentrated to about half its volume under reduced pressure and crystallized under ice cooling to obtain crude tryptamine hydrochloride, which was then recrystallized from aqueous ethanol (85:155) to obtain 3.61 g of tryptamine hydrochloride. . This substance is a white prismatic crystal with a melting point of 247-249℃.
The yield was 62.0%. Example 33 Tryptamine Example 31 except that instead of hydrochloric acid to neutralize ATU in Example 31, an aqueous solution adjusted to pH 2.95 with 85% phosphoric acid was used and the reaction after dropping was carried out at a pH of 1.8 to 2.5 for 5.5 hours. 2.83 g (yield 44.1%) of tryptamine was obtained. Example 34 Tryptamine Instead of the hydrochloric acid that neutralizes ATU in Example 31, an aqueous solution whose pH was adjusted to 2.37 with 50% sulfuric acid was used.
The procedure of Example 31 was followed except that the reaction after the addition was carried out at a pH of 1.2 to 2.1 for 3 hours, yielding 3.61 g of tryptamine.
(yield 56.3%). Example 35 Tryptamine 2.70 g (25 mmole) of phenylhydrazine
3.43 g (12.5 mmole) of ATU was dissolved in 50 ml of n-propanol, and p-toluenesulfonic acid was added to adjust the pH to 3.5. When this mixture was reacted under reflux for 4 hours, the pH during the reaction was 2.1 to 3.0, and when it was cooled to room temperature, a white solid precipitated and the pH of the solution was 3.3. Take out the precipitated crystals,
Tryptamine p-toluenesulfonate 4.00g
(yield 48.1%). Dissolve this in water,
The solid was made alkaline by adding sodium hydroxide, and the precipitated solid was recrystallized from benzene and identified as tryptamine.

Claims (1)

[Claims] 1 General formula () [However, in the formula, R is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, an aralkyl group,
R 2 represents a nitro group or a halogen atom, R ² represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, an aralkyl group, or a hydroxyalkyl group having 1 to 6 carbon atoms, and R ¹ and
R ³ is the same atom or group as R ² , or R ⁴ CO−
Group [However, R ⁴ in the formula has 1 to 6 carbon atoms]
represents an alkyl group, aryl group, or aralkyl group], and R ¹ , R ² , and R ³ may be the same,
The formulas may be different, and the [formula] group is [formula] (where n represents an integer from 1 to 3, m represents an integer 2 or 3,
X represents a _-CH2- group, an oxygen atom, a nitrogen atom, or a sulfur atom. ) may also represent R ₂
represents the alkyl group, and R ³ is the R ⁴ CO
- group, and this R ⁴ represents the alkyl group, and when the sum of the number of carbon atoms of both the alkyl groups is 4 to 8, R ² and R ⁴ form a ring-closing bond, and the [Formula] group (where the formula (l represents an integer from 4 to 8). ], In producing the tryptamine compound represented by the general formula (): (In the formula, R and R ¹ are the same as defined above.) A phenylhydrazine compound represented by the general formulas () and (): (In the formula, R ² and R ³ are the same as defined above, and when R ⁵ and R ⁶ are independent from each other, each represents an alkyl group having 1 to 4 carbon atoms, and when they are consecutive, both represent carbon atoms. 4-aminobutanal dialkyl acetal compound represented by (representing an alkyl group of numbers 2 to 6) in water or a hydrophilic solvent or
0.8 to 4.0 in a mixed solvent of two or more of these
1. A method for producing a tryptamine compound, characterized in that the reaction is carried out at a pH of . 2. The method of claim 1, wherein the reaction is carried out at a temperature of 60 to 140°C.