JPH0149149B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an improved method for producing ω-indol-3-yl-alkanol compounds. ω-Indol-3-yl-alkanol compounds are widely found in nature and are useful compounds as raw materials for the synthesis of many indole derivatives, indole alkaloids, and pharmaceuticals. Several methods have long been proposed for the synthesis of ω-indol-3-yl-alkanol compounds, among which the following method is known as one that utilizes the Fischer synthesis method using phenylhydrazine as a starting material. ing. A method of heating substituted phenylhydrazine hydrochloride and dihydrofuran in aqueous dioxane for a long time [Khim. Geterotsikl. Soedin., 1972, No.
10, 1366-1367] A method in which substituted phenylhydrazine and 2-hydroxytetrahydrofuran are refluxed in benzene, water is distilled off by azeotropy, and the resulting condensate is further heated at high temperature and under reduced pressure to decompose [ Same magazine;
1974, No. 1, 90-91] Substituted phenylhydrazine and α-formyl-γ
- A method of subjecting butyrolactone to a long-term heating reaction in a hydrous alcohol in the presence of hydrogen chloride [same magazine; 1974, No. 8, 1083-1084]. All of the above-mentioned known methods are unsatisfactory as industrial production methods because the reaction takes a long time, the operations are complicated, and raw materials are difficult to obtain. From this standpoint, the present inventors have conducted extensive research on an economical method for synthesizing ω-indol-3-yl-alkanol compounds, and have completed the present invention. That is, the present invention provides an ω-indol-3-yl-alkanol compound of the following general formula (): [However, in the above formula, R ₁ is a hydrogen atom, a lower alkyl group,
represents an aryl group or an aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group, a lower alkoxyl group, an aryloxyl group, an aralkoxyl group, or a halogen atom; R ₃ represents a hydrogen atom, or It represents a lower alkyl group, and n represents 0 or 1. ] In order to produce a phenylhydrazine compound of the following general formula (): [However, R ₁ and R ₂ in the above formula are respectively as defined above] and the following general formulas () and (): [However, in the above formula, R ₃ and n are each as defined above, and -R ₄ - is

[Formula] or

[Formula] R ₅ represents a lower alkyl group, R ₆ represents a hydrogen atom or a methyl group, k represents 0, 1 or 2, and l represents 1 or 2. ] with at least one selected from the oxacycloalkan-2-ol compounds in a solvent containing at least one alcoholic compound, the reaction being carried out in the presence of a strong acid, The amount of strong acid is the amount necessary to convert at least 1 mole of the phenylhydrazine compound to the strong acid salt thereof per mole of the oxacycloalkan-2-ol compound in the reaction mixture. It is characterized by this. In the method of the present invention, when a phenylhydrazine compound of general formula () is reacted with an oxacycloalkan-2-ol compound of general formula () and/or (), a strong acid is present in the reaction mixture; It is characterized in that the strong acid converts at least 1 mol of the phenylhydrazine compound into its strong acid salt per 1 mol of the oxacycloalkan-2-ol compound. In the above formula (), the lower alkyl group represented by R ₁ preferably has 1 to 4 carbon atoms and can be selected from methyl, ethyl, propyl and butyl groups. The aryl group represented by R ₁ is preferably a phenyl group or tolyl group, and the aralkyl group represented by R ₁ is preferably a benzyl or phenylethyl group. In the above formula (), the lower alkyl group represented by R ₂ preferably has 1 to 4 carbon atoms, and includes methyl, ethyl, propyl,
and butyl groups. Also R ₂
The aryl group represented by is preferably a phenyl or tolyl group, the aralkyl group represented by R ₂ is preferably a benzyl or phenylethyl group, and the alkoxyl group represented by R ₂ is methoxyl, ethoxyl, etc. , or a propoxyl group, and the aryloxyl group represented by R ₂ is preferably phenoxy,
The aralkoxyl group represented by R ₂ is preferably a benzyloxy or phenylethyloxy group. In the general formula (), the lower alkyl group represented by R ₃ preferably has from 1 to 3 carbon atoms and can be selected from methyl, ethyl and propyl groups. Further, in the general formula (), the lower alkyl group represented by R ₅ preferably has 1 to 3 carbon atoms and can be selected from methyl, ethyl and propyl groups. General formula () used in the method of the present invention
The phenylhydrazine compounds include phenylhydrazine, tolylhydrazine, p-benzylphenylhydrazine, methoxyphenylhydrazine, benzyloxyphenylhydrazine, chlorphenylhydrazine, 1,1-diphenylhydrazine, 1-benzylhydrazine 1-phenylhydrazine,
and 1-methyl-1-phenylhydrazine. The oxacycloalkan-2-ol compound of general formula () used in the method of the present invention includes 2
-(alkoxyalkoxy)-tetrahydrofuran, 2-(alkoxyalkoxy)-tetrahydropyran, and 2-(alkoxyalkoxy)-4
-Methyltetrahydropyran, etc., and
The oxacycloalkan-2-ol compounds of general formula () include 2,2'-(alkylenedioxy)-ditetrahydrofuran, 2,2'-(alkylenedioxy)-ditetrahydropyran and 2,
Examples include 2'-(alkylenedioxy)-di(4-methyltetrahydropyran). That is, the oxacycloalkane ring in the oxacycloalkan-2-ol compounds of general formulas () and () is preferably selected from a tetrahydrofuran ring and a tetrahydropyran ring. In the general formula (), the alkoxyalkoxy group represented by _R5O ( _-CH2 ) _n -O- includes methoxyethoxy, ethoxyethoxy, propoxyethoxy, methoxypropoxy, ethoxypropoxy, propoxypropoxy, methoxybutoxy,
Preferably, it is selected from ethoxybutoxy and propoxybutoxy groups. In addition, in the general formulas () and (), the alkylenedioxy group represented by (-O- _CH2 -CH( _R6 )(- _CH2 ) _k ) _l O- is, in the above formula,
When l=1, the alkylene group is selected from an ethylenedioxy group, a propylenedioxy group having a linear or side chain, and a butylenedioxy group, and l=
In the case of 2, it is preferably selected from an oxy-diethylenedioxy group, an oxy-dipropylenedioxy group in which the alkylene group has a linear or side chain, and an oxy-dibutylenedioxy group. In the method of the present invention, the reaction between the phenylhydrazine compound and the oxacycloalkan-2-ol compound is carried out in a solvent containing at least one alcoholic compound. The alcoholic compounds include monohydric aliphatic alcohols such as methyl alcohol, ethyl alcohol, propyl alcohol and butyl alcohol, dihydric aliphatic alcohols such as ethylene glycol and propylene glycol, aliphatic ether alcohols, etc. for example, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, etc., as well as mixtures of at least one of the above-mentioned alcohol compounds and water. The type of solvent to be manufactured is ω-
It is selected taking into consideration the properties of the indol-3-yl-alkanol compound. This solvent may consist of one type of alcohol compound,
It may be a mixture of two or more types of alcohol compounds, or it may be a mixture of at least one type of alcohol compound and water. In the latter case, it is preferable to contain the alcohol compound in an amount of 10% or more based on water. In the method of the present invention, the phenylhydrazine compound is preferably used in an amount of 1 mol or more per 1 mol of the oxacycloalkan-2-ol compound, and more preferably in an amount of 1.1 mol to 3.0 mol. In this case, the reaction between the phenylhydrazine compound and the oxacycloalkan-2-ol compound is carried out in the presence of a strong acid, and the amount of this strong acid covers at least a portion of the phenylhydrazine compound used, i.e. It is important that the amount is necessary to convert at least 1 mole of phenylhydrazine compound per mole of oxacycloalkan-2-ol compound into its strong acid salt. The strong acid is preferably at least one selected from the group consisting of hydrochloric acid, sulfuric acid, and p-toluenesulfonic acid, which can form a salt with the phenylhydrazine compound of general formula (). . If the phenylhydrazine compound is used in an amount of 1 mole or more per mole of the oxacycloalkan-2-ol compound, the amount of the phenylhydrazine compound in the strong acid salt state is It is preferable that the molar ratio of the phenylhydrazine compound to the remaining amount of the phenylhydrazine compound is 2 or more. Phenylhydrazine compounds that are not in a strong acid salt state are
It may be in the form of a free base or as a salt with a strong acid, such as acetic acid. The presence of the strong acid maintains the reaction mixture in an acidic state, which is an essential condition for the reaction between the phenylhydrazine compound and the oxacycloalkan-2-ol compound to occur. However, it is preferred that the amount of strong acid to be added to the reaction mixture is not in excess of the amount necessary to convert the total amount of phenylhydrazine compound in the reaction mixture to its strong acid salt. It is still not completely clear why the reaction between phenylhydrazine compounds and oxacycloalkan-2-ol compounds is promoted by the presence of certain amounts of strong acids. However, when the amount of strong acid in the reaction mixture is in excess of the amount required to convert the total amount of phenylhydrazine compound in the reaction mixture to its strong acid salt, one intramolecular acetal compound A certain oxacycloalkan-2-ol compound is decomposed, and the decomposition products are polymerized or condensed to produce the desired product, namely,
It has been found that the yield of ω-indol-3-yl-alkanol compounds (tryptophol compounds) is reduced. If the reaction mixture is in basic conditions, no reaction between the phenylhydrazine compound and the oxacycloalkan-2-ol compound will occur. In the specified amount necessary for the strong acid to convert at least 1 mole of phenylhydrazine compound per mole of oxacycloalkan-2-ol compound in the reaction mixture to its strong acid salt, A phenylhydrazine compound is an oxacycloalkane-2-
It can be directly condensed with an ol compound to form an indole ring while preventing undesirable side reactions. The reaction between the phenylhydrazine compound and the oxacycloalkan-2-ol compound is preferably carried out at a temperature of from 70°C to 170°C for as long as necessary to complete the reaction, generally for at least 30 minutes, e.g. It lasts from minutes to hours. If the reaction is carried out at a temperature lower than 70°C, the reaction rate will be low, which is not preferable. The reaction rate peaks at a temperature of 170°C. Therefore, reaction temperatures higher than 170°C are ineffective for increasing the reaction rate. When a phenylhydrazine compound has a highly reactive ether-type substituent attached to its benzene ring, such as a methoxy or benzyloxy group, the reaction temperature when this phenylhydrazine compound is used is It is preferably lower than when other phenylhydrazine compounds are used, for example from 70°C to 90°C. In the method of the present invention, in order to carry out the above reaction, the phenylhydrazine compound and the oxacycloalkan-2-ol compound are separately dissolved in a predetermined amount of an alcoholic solvent, and one of the resulting solutions is dissolved. Alternatively, the temperature of the reaction mixture may be maintained at the desired level. Alternatively, a method may be used in which the phenylhydrazine compound and the oxacycloalkan-2-ol compound are dissolved together in a solvent and the resulting solution is heated to a desired temperature. The resulting product, i.e. ω-indole-
The 3-yl-alkanol compound is separated from the reaction mixture by conventional separation methods. For example, the reaction mixture is mixed with water, then a water-insoluble organic solvent,
For example, the reaction product may be extracted into an organic solvent by mixing with chloroform. The obtained extract is subjected to distillation to remove the organic solvent. This distillation residue is subjected to vacuum distillation or recrystallization to obtain a purified reaction product. The type of ω-indol-3-yl-alkanol compound of the present invention is determined depending on the type of phenylhydrazine compound and the type of oxacycloalkan-2-ol compound used. The ω-indol-3-yl-alkanol compounds of the present invention include β-(indol-3-yl)ethanol (this compound is commonly referred to as tryptophol),
4-methyltryptophol, 5-methyltryptophol, 6-methyltryptophol, 7-methyltryptophol, 6-chlorotryptophol, 7
-chlorotryptophol, 5-bromotryptophol, N-methyltryptophol, N-phenyltryptophol, N-benzyltryptophol,
5-methoxytrypthol, 5-benzyloxytrypthol, γ-(indol-3-yl)
Contains propanol, γ-(indol-3-yl)butanol, etc. The method of the present invention will be further explained by examples. In the examples below, the yield of the product obtained is the ratio of the actually obtained yield of the product to the theoretical yield of the product calculated from the amount of the oxacycloalkan-2-ol compound used. It is expressed as a ratio (%). Example 1 6.51 g (45 mmol) of phenylhydrazine hydrochloride was dissolved in 150 ml of ethylene glycol monomethyl ether and the solution was heated with stirring. When the temperature of the phenylhydrazine salt solution reached 123°C, a solution of 3.45 g (15 mmol) of 1,4-bis(tetrahydrofuran-2-yloxy)butane dissolved in 30 ml of ethylene glycol monomethyl ether was added to the solution. , added dropwise over 30 minutes. The reaction mixture was heated at 122°C to 124°C while maintaining its temperature at a level of
Stir for hours. After the reaction was completed, the reaction mixture was cooled to room temperature. 200ml of cooled reaction mixture
of water and then extracted twice with 200 ml of chloroform each time. The two resulting chloroform extracts were mixed together and the combined extracts were washed with water until the aqueous phase was neutral. This washed extract was distilled under reduced pressure to remove chloroform. The resulting brown oily distillation residue was subjected to distillation under reduced pressure. 168 under a vacuum of 2 mmHg
A yield of 4.4 g of tryptophol was obtained as a distillate at a distillation temperature of between 173°C and 173°C. This yield corresponds to a yield of 91%. The tryptophole obtained had a melting point of 55°C. Example 2 6.51 g (45 mmol) of phenylhydrazine hydrochloride was dissolved in 150 ml of ethylene glycol monomethyl ether and the solution was heated with stirring. The temperature of this phenylhydrazine salt solution is 123
℃, add 3.45 g (15 mmol) of 1,2-bis(tetrahydrofuran-2-
A solution of oxy)ethane in 30 ml of ethylene glycol monomethyl ether was added dropwise and mixed over a period of 1 hour. The reaction mixture was stirred for 2 hours while maintaining the temperature at a level of 122°C to 124°C. After the reaction was completed, the reaction mixture was cooled to room temperature. The cooled reaction mixture was mixed with 200 ml of water and then subjected to two extraction operations, each time with 200 ml of chloroform. The two chloroform extracts were mixed together and the combined extracts were washed with water until the aqueous phase was neutral. The washed extract was distilled under reduced pressure to remove chloroform. The resulting brown oily distillation residue was distilled under reduced pressure. A yield of 4.9 g of γ-(indol-3-yl)-propanol was obtained as distillate at a distillation temperature of 181 DEG to 185 DEG C. under a reduced pressure of 1 mm Hg. This yield corresponds to a yield of 93%. Example 3 2.17 g (15 mmol) of phenylhydrazine hydrochloride was dissolved in 50 ml of ethylene glycol monomethyl ether and the solution was heated with stirring. When the temperature of this solution reached 123°C, a solution of 1.46 g (10 mmol) of 2-methoxyethoxytetrahydrofuran dissolved in 20 ml of ethylene glycol monomethylene ether was added to the solution.
Mixed dropwise over 30 minutes. The reaction mixture was stirred for 1 hour while maintaining the temperature at a level of 122°C to 124°C. After the reaction was completed, the reaction mixture was cooled to room temperature, 100 ml of water was added to it, and then it was subjected to two extraction operations, each time with 100 ml of water.
Extracted with ml of chloroform. The two chloroform extracts were mixed together and the combined extracts were washed with water until the aqueous phase was neutral. The washed extract was distilled under reduced pressure to remove chloroform, and the resulting brown oily distillation residue was further subjected to vacuum distillation. Then, at a reduced pressure of 5 mmHg, the temperature is 192℃ or
A yield of 6.04 g of tryptophol was obtained as a distillate at a distillation temperature of 197°C. This yield is 77
% yield. The melting point of the tryptopole obtained was 56°C. Examples 4 to 11 A reaction was carried out according to Example 1 using a strong acid salt of phenylhydrazine or phenylhydrazine and its strong acid salt shown in Table 1, a 2-(substituted oxy)tetrahydrofuran compound, and a solvent. Tryptophol could be obtained in the yield shown in Table 1.

[Table] Examples 12 to 16 Nuclear-substituted phenylhydrazine hydrochloride shown in Table 2
75 mmol in 150 ml of ethylene glycol and 150 ml of water
This solution was heated and stirred, brought to a boil, and 50 mmol of 2-methoxyethyloxytetrahydrofuran was added to ethylene glycol while boiling.
A solution dissolved in 20 ml was added dropwise over 30 minutes. Stirring was further continued for 2 hours under the same conditions. After the reaction was completed, the reaction solution was allowed to cool to room temperature, 300 ml of water was added, and extraction was performed twice with 200 ml of chloroform each time. The two obtained chloroform extracts were mixed, and the mixed extract was washed with water until the aqueous phase became neutral. Chloroform was removed from this washed extract by vacuum distillation to obtain a brown oil. This product was distilled under reduced pressure of 0.5 mmHg to obtain nuclear substituted tryptophol. The results were as shown in Table 2.

[Table] Example 17 Dissolve 5.27 g (21 mmol) of p-benzyloxyphenylhydrazine hydrochloride in 100 ml of ethanol, heat and stir this solution, and when the temperature reaches 76°C,
1.42 g (7 mmol) of 1,2-bis(tetrahydrofuran-2-yloxy)ethane was dissolved in ethanol.
A solution of 50 ml was added dropwise over 30 minutes. The reaction solution was kept at 76 to 78°C and reacted for 1 hour with stirring. After the reaction is complete, let the reaction solution cool and add water.
200 ml was added, this solution was extracted twice with 150 ml each of chloroform, and the two solutions were combined. The mixed extract was washed with water until the aqueous phase became neutral. Chloroform was distilled off from this washed extract by vacuum distillation, and the residual oil was fractionated by column chromatography to obtain 1.98 g of 5-benzyloxytryptophol (yield 53%). The melting point of this product was 92-93.5°C. Examples 18-22 The reaction was carried out according to Example 2, except that the compounds shown in Table 3 were used in place of 1,2-bis(tetrahydropyran-2-yloxy)ethane in Example 2, and the ω values were as shown in Table 3. -Indol-3-yl-alkanol compound was obtained with the results shown in the table.

[Table] Examples 23-25 Ethylene glycol monomethyl ether 400ml
1-substituted-1-phenylhydrazine hydrochloride shown in Table 4 was dissolved in the solution, heated with stirring, and heated to 123°C.
When 6.06 g (30 mmol) of 1,2-bis(tetrahydrofuran-2-yloxy)ethane was
ml was added dropwise over 30 minutes. after that,
The reaction was carried out while boiling for 1 hour. After the reaction, the solvent was distilled off to reduce the volume to about 1/3, then 150 ml of water was added and extracted twice with 150 ml of chloroform each, and the two chloroform solutions were combined until the washings became neutral. Washed with water. Chloroform was distilled off under reduced pressure, and the residual liquid was distilled under reduced pressure to obtain the results shown in Table 4.

【table】

Claims (1)

[Scope of Claims] 1 ω-indol-3-yl-alkanol compound of the following general formula (): [However, in the above formula, R ₁ is a hydrogen atom, a lower alkyl group,
represents an aryl group or an aralkyl group, R ₂ represents a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group, a lower alkoxyl group, an aryloxyl group, an aralkoxyl group, or a halogen atom; R ₃ represents a hydrogen atom, or It represents a lower alkyl group, and n represents 0 or 1. ] In order to produce a phenylhydrazine compound of the following general formula (): [However, R ₁ and R ₂ in the above formula are respectively as defined above] and the following general formulas () and (): [However, in the above formula, R ₃ and n are each as defined above, and R ₄ is
[Formula] or [Formula], R ₅ represents a lower alkyl group, R ₆ represents a hydrogen atom or a methyl group, and R ₇ represents a hydrogen atom or a lower alkyl group. k represents 0, 1 or 2, and l represents 1 or 2. ] in a solvent containing at least one alcoholic compound, the reaction being carried out in the presence of a strong acid. ,
The amount of strong acid is per mole of the oxacycloalkan-2-ol compound in the reaction mixture,
A method for producing an ω-indol-3-yl-alkanol compound, characterized in that the amount is necessary to convert at least 1 mol of the phenylhydrazine compound into the strong acid salt thereof. 2. The method of claim 1, wherein the lower alkyl group represented by R ₁ in the general formula () has from 1 to 4 carbon atoms. 3. The method according to claim 1, wherein the aryl group represented by R ₁ in the general formula () is a phenyl or tolyl group. 4. The method according to claim 1, wherein the aralkyl group represented by R ₁ in the general formula () is benzyl or phenylethyl group. 5. The method of claim 1, wherein the lower alkyl group represented by _R2 in the general formula () has from 1 to 4 carbon atoms. 6. The method according to claim 1, wherein in the general formula (), the aryl group represented by R ₂ is a phenyl or tolyl group. 7. The method according to claim 1, wherein in the general formula (), the aralkyl group represented by R ₂ is a benzyl or phenylethyl group. 8. The method according to claim 1, wherein in the general formula (), the alkoxyl group represented by R ₂ is a methoxyl, ethoxyl, or propoxyl group. 9. The method according to claim 1, wherein in the general formula (), the aryloxyl group represented by R ₂ is a phenoxy or tolyloxy group. 10. The method according to claim 1, wherein in the general formula (), the aralkoxyl group represented by R ₂ is benzyloxy or phenylethyloxy group. 11. The method according to claim 1, wherein in the general formula (), the lower alkyl group represented by R ₃ has from 1 to 3 carbon atoms. 12. The method of claim 1, wherein in the general formula (), the lower alkyl group represented by R ₅ has from 1 to 3 carbon atoms. 13. The method according to claim 1, wherein the strong acid is at least one selected from the group consisting of hydrochloric acid, sulfuric acid, and p-toluenesulfonic acid. 14 Claim 1, wherein the oxacycloalkane ring in the oxacycloalkan-2-ol compounds of the general formulas () and () is a tetrahydrofuran ring or a tetrahydropyran ring.
The method described in section. 15. The method of claim 1, wherein the phenylhydrazine compound of general formula () is used in an amount of from 1.1 to 3 moles per mole of the oxacycloalkan-2-ol compound. 16. Claim 1, wherein the molar ratio of the amount of the phenylhydrazine compound in the strong acid salt state to the remaining amount of the phenylhydrazine compound not in the strong salt state is 2 or more. the method of. 17 The solvent is a monohydric aliphatic alcohol, 2
2. The method according to claim 1, which comprises at least one selected from the group consisting of polyhydric aliphatic alcohols, aliphatic ether alcohols, and mixtures of one or more of the aforementioned compounds and water. 18. The method of claim 1, wherein the reaction is carried out at a temperature of 70°C to 170°C.