JPS6289660A - Production of 4-oxo-4,5,6,7-tetrahydroindole - Google Patents

Abstract

PURPOSE:To obtain the titled substance useful as an intermediate for medicines from a readily available raw material in good yield in one step and in a short time, by reacting 1,3-cyclohexanedione with such as a haloacetaldehyde, etc., in the presence of ammonia. CONSTITUTION:1,3-Cyclohexanedione is reacted with a haloacetaldehyde or a derivative thereof expressed by formula II or III (X is halogen atom; Y represents halogen atom, lower alkoxy or lower acyloxy; Ac represents acetyl) at 120-200 deg.C (preferably 135-150 deg.C) in the presence of 5-10 equivalents, based on the 1,3-cyclohexanedione, ammonia to obtain the titled substance. The reaction is preferably carried out in water or a homogeneous or two-layer system solvent such as water and alcohol, ether, hydrocarbon, etc., under pressure for 1-7hr in a hermetically sealed vessel.

Description

Detailed Description of the Invention (Technical Field of the Invention) The present invention is directed to a 4-hydroxyindole precursor useful as a synthetic intermediate for a wide range of 4-substituted indole drugs, such as pindolol, psilocin, and bushilocybin, which have antiarrhythmic effects. The present invention relates to a method for producing 4-oxo-4,5,6,7-titrahydroindole.

(Prior Art) Typical conventionally known methods for synthesizing 4-oxo-4,5,6°7-titrahydroindole include the following.

(1) 4-,oxo-4,5 obtained by condensing 1.3-cyclohexanedione and bromopyruvic acid ester
, 6,7-titrahydropenzofuran-3-carboxylic acid with ammonia and urea.

Method of heating with ammonium acetate etc. [Ann.

Chem, 655.20 (1962), Japanese Patent Application Publication No. 1983-
5159 Publication 1 (2) Method of condensing 1,3-cyclohexanedione and aminoacetaldehyde dimethyl acetal [J, O
rq, Chem, 43°3541 (1978)] (3) A method of electrooxidizing 1,3-cyclohexanedione and ethyl vinyl ether and then treating the product with ammonium carbonate [Chem.

Letters 1603 (1980) Ko (4) 1
．． 3-Cyclohexanedione and chloroacetaldehyde are condensed in the presence of a base such as sodium hydroxide or sodium carbonate, and then treated with acid to form 4-oxo-4,5,
A method of forming 6,7-titrahydropenzofuran and then reacting it with ammonia [JP-A-59-27869] A method of ring-closing (5>4-(2-pyrrolyl)butyric acid) [
French Patent No. 1540484, Ch in,
Ther, 5.279 (1970)] (6) N-3-
A method for dehydrogenating and ring-closing oxo-cyclohexylideneethanolamine [JP-A No. 59-144757, JP-A No. 59-144758, among the methods disclosed in No. 1, (
Methods 1), (2), and (3) require expensive reagents as the C2 unit to be reacted with 1,3-cyclohexanedione, or require the use of a large excess of reagents. Method (4) is advantageous in that it does not use expensive reagents, but
, 3-cyclohexanedione and chloroacetaldehyde takes a long time and requires a relatively large amount of solvent.

Method (5) involves starting with expensive pyrrole through several steps, and then using 4-(
The procedure is complicated because 2-pyrrolyl)butyric acid must be synthesized and then cyclized. Method (6) has its own drawbacks, such as the need to use an expensive negative metal compound that cannot be recovered for dehydrogenation, and the conditions for the gas phase dehydrogenation reaction being difficult. Also 4-
In methods (1), (3), and (4), which involve using oxo-4,5,6,7-titrahydropenzofuran, 4-oxo-4,5,6,7 -The disadvantage is that the reaction to obtain titrahydroindole takes 0.5 to 2 days.

(Objective of the Invention) The present invention aims to achieve the desired 4-oxo-4,
A method for producing 5,6,7-titrahydroindole is provided.

(Structure of the Invention) The present invention relates to 1,3-cyclohexanedione and a haloacetaldehyde represented by the following general formula (II> or general formula (In>) or its derivative XCH2CHO(II> (however, the above general formula (II), (In),
X is a halogen atom, Y is a halogen atom or has 1 to 3 carbon atoms
lower alkoxy group or lower acyloxy group, AC
represents an acetyl group) at 120°C in the presence of ammonia.
This is a method for producing 4-oxo-4,5,6°7-titrahydroindole, characterized by carrying out the reaction at ~200°C.

As shown in the reaction formula below, the present invention is characterized in that haloacetaldehyde (ff) is added to 1゜3-cyclohexanedione (I>).
Alternatively, 4-oxo-4°5.6.7-titrahydroindole (IV) is obtained by reacting the derivative (m) in the presence of ammonia.

[ (I) (II) (III
) (IV) To explain the above reaction formula in more detail, under the reaction conditions of the present invention, the reaction route is mainly based on the following formula (A>), and in the above formula (B), the acidity of compound (I) and the alkoxide Because of their basicity, steps (C) and (d) are both considered to be reversible reactions, and the rate-determining step in formula (B) is considered to be step (e).On the other hand, the rate-determining step in formula (A>) is clearly considered to be step (a).
> is. Since step (e) of formula (B) is an intramolecular reaction, the activation energy is much smaller than step (a> of formula (A)), so the reaction of formula (B) has priority in reactions at low temperatures. Therefore, it is expected that sufficient reaction heat is required to carry out the reaction of formula (A>, and as in the present invention, compound (I>, ( By reacting II), the target compound (IV) could be obtained in a higher yield than expected. In the present invention, in the early stage of about 1 hour after the start of the reaction, the reaction of the formula (B) Compound (V)t
The present inventors confirmed that 3 and (VI) were not produced at all. As mentioned above, this compound (VI
) and ammonia to obtain the target compound (IV), it takes a considerable time to obtain the target compound (IV), so the compound (IV), which is the target compound of the present invention, is produced through the above compounds (V) and It is clear that there is no such thing.

In the present invention, the ammonia added in step (b)
as well as the base necessary for step (a). At this time, the compound (I) reacts with ammonia instead of compound (II) to give compound (II).
It has also been found that even better yields can be obtained using II).

The raw material compound (II) used in the present invention may be industrially available loroacetaldehyde or bromoacetal, or one of the raw material compounds (III) listed below.
- There is bromoacetaldehyde that can be easily obtained from dibromoethyl acetate, and bromoacetaldehyde is particularly excellent in terms of reactivity and yield. Compound (II>) is difficult to handle in a pure state and is preferably used as an aqueous solution.

The raw material compound (m) used in the present invention includes 1,2-dihalogenoethyl acetate, 1-alkoxy-2-halogenethyl acetate, 1-acyloxy-2- Examples include octogenoethyl acetate, and the halogen thereof is preferably a chlorine atom or a bromine atom, and in the case of 1,2-dihalogenoethyl acetate, it is preferable that the halogens are the same. Alkoxy or acyloxy has 1 or more carbon atoms
3 lower alkoxy or lower acyloxy having 1 to 3 carbon atoms is preferred.

In the present invention, the starting compound (m) is preferably 1,2-dihalogenoethyl acetate from the viewpoint of ease of synthesis, yield, and stimulation, and in particular, 1,2-dihalogenoethyl acetate and 1-acyloxy Particularly preferred is a mixture with -2-HaI''genoethyl acetate. Preferred as the 1,2-dihalogenoethyl acetate is 1,2-dibromoethyl acetate in which the halogen is bromine. A preferred example of the above mixture is a mixture of 1,2-dibromoethyl acetate and 2-bromo-1,1-ethanediol diacetate, and those with a molar ratio of 1:2 to 2:1 are particularly preferred. preferable.

As the raw material compound (1), similar compounds obtained from vinyl esters other than vinyl acetate can also be used.

In the present invention, the amount of starting compound (II> or (I[I)) to be used is 1 to 1 to 1 to 1,3-cyclohexanedione.
A suitable range is 5 equivalents, preferably 1.1 to 1.5 equivalents.

The ammonia used in the present invention can be either ammonia gas or S ammonia water, but it is more advantageous to use ammonia gas because the initial reaction temperature and the amount of solvent can be arbitrarily determined.

The appropriate amount of ammonia to be used is 5 to 30 equivalents, preferably 5 to 10 equivalents, relative to 1,3-cyclohexanedione.

When carrying out the present invention, raw material compounds (I> and (
II> or (III) to water or a homogeneous or two-layer solvent such as water and alcohols, ethers, hydrocarbons, etc., and heating the mixture in the presence of ammonia.

The alcohol used as the solvent is methanol.

Examples of ethers include butanol, such as tetrahydrofuran and dioxane, and examples of hydrocarbons include toluene and hexane. In particular, water or water-alcohol solvents are excellent in terms of reaction smoothness and yield. In the present invention, if the reaction system does not use water, for example, if the reaction is carried out using an alcohol-only solvent, the yield tends to decrease significantly. When ketones (acetone, etc.), esters (ethyl acetate, etc.), and halogenated hydrocarbons (dichloromethane, etc.) are used as solvents, side reactions increase, and carboxylic acids (acetic acid, etc.) tend to make the reaction system acidic. Undesirable.

In the present invention, the yield of the target product is largely influenced by the reaction temperature, as expected from the reaction mechanism described above. It is preferable that the initial temperature of the reaction is high, and a faster heating rate gives a better yield. However, if the temperature is too high, the decomposition of compound (II) will be promoted, resulting in a decrease in yield.

The preferred reaction temperature in the present invention is 120 to 200'C1
In particular, it is in the range of 135-150'C.

The reaction is preferably carried out in a sealed container under pressure to prevent volatilization of ammonia, and a reaction time of 1 to 7 hours is usually sufficient.

During the reaction, an organic or inorganic acid salt of ammonia such as ammonium carbonate or ammonium acetate may be used in combination with ammonia, or other bases such as sodium hydroxide or sodium bicarbonate may be used.

It can be used as an acid remover for hydrohalic acids, acetic acids, etc. that produce triethylamine and the like as by-products.

After the reaction, the target product, 4-okine-4.5,6°7-titrahydroindole, can be isolated in high purity by solvent extraction of the reactant. Furthermore, pure 4-oxo-4,5,6 can be obtained by conventional purification methods such as recrystallization and chromatography.
, 7-titrahydroindole.

(Effects of the Invention) The present invention is very advantageous as an industrial production method because it is possible to obtain the desired product in a good yield in a short period of time through a one-step reaction using readily available compounds as raw materials.

(Example) Example 1 1.120 ml of 1,3-cyclohexanedione was placed in a pressure-resistant glass tube having a capacity of 200 dl, and 7 ml of 25% ammonia water and 5 d of methanol were added and dissolved. 1 for this
．． 2.95 Cl of 2-dibromoethyl acetate was added, the mixture was sealed, and the mixture was reacted at 145° C. for 7 hours while heating and stirring in an oil bath with a stirrer. After the reaction, methanol was distilled off from the reaction solution under reduced pressure, the residue was extracted with warm ethyl acetate, and the solvent was distilled off under reduced pressure to obtain the target product 4-oxo-4,5,6,7-
Titrahydroindole 0.98C] was obtained (yield 72
．． 4%). This product was analyzed by gas chromatography (column: 0V-225 (5%)/Chromosolve W AW
- Purity 92.4 as determined by DMC3 (hereinafter referred to as GC analysis)
It was found that %. Moreover, the melting point of the product recrystallized from water was 189.8-191.0°C, which was consistent with the known standard.

Example 2 1,3-cyclohexanedione was added to an autoclave with a volume of 56. OC], water 5007, methanol 25
Add M and then add 1,2-dibromoethyl acetate 14
After adding 7.5 q of the mixture, the mixture was sealed, immersed in a 135°C oil bath, and heated and stirred. When the internal temperature reached 80°C, ammonia gas was introduced to maintain the internal pressure of the autoclave at 5.0 to 5.5 atm. After 5 minutes, the internal temperature reached 135°C, and ammonia gas was continued to be introduced at this temperature for 30 minutes, during which time the internal pressure of the autoclave was maintained at 6.0 atm. Thereafter, the introduction of ammonia gas was cut off, and the reaction was continued for 2 hours and 30 minutes at the same temperature. The total amount of ammonia introduced was 51.2Q. After the reaction, the reaction solution was cooled, concentrated under reduced pressure, and extracted with warm ethyl acetate at 60°C. Wash the extract with saturated saline,
The product eluted in the saline solution was extracted and recovered with ethyl acetate, and these extracts were dehydrated and filtered with the addition of 10% active solution. The filtrate was concentrated under reduced pressure to obtain the target product 4-oxo-4゜5.
48.3q of 6.7-titrahydroindole was obtained (yield 71.6%). According to GC analysis, the purity of this product is 97.
．． It was 4%.

Example 3 148mf of vinyl acetate in a 1g No. 4 flask! and glacial acetic acid 35 (7!), and 78 ml of bromine was added dropwise at 5 to 10°C. After further stirring at room temperature for 1 hour, the reaction solution was poured into 400 W of water and 40 M of carbon tetrachloride, and the layers were separated. Extraction was carried out three times with 50 d of carbon tetrachloride.The carbon tetrachloride layers were combined, and water (100 d x 2 times), saturated sodium bicarbonate solution (100 ml x 1 time), and saturated saline (50 d x 1 time) were extracted.
After washing in the following order, it was dehydrated and filtered. Carbon tetrachloride after filtration is distilled off under reduced pressure, and the residue is distilled under reduced pressure to obtain 1
．． 2-dibromoethyl acetate and 2-bromo-1,1
- mixture of ethanediol diacetates (molar ratio 1.5
: 1) 274.74CI to 19I (bp80-125°C/35Torr>.

83. from the above mixture. OC] was collected and placed in an autoclave at 1 on each side, and to this was added 38.65 Q of 1,3-cyclohexanedione, 3907 Q of water, and 130 m of methanol.
1 was added thereto, sealed, immersed in a 135°C oil bath, and heated and stirred. When the internal temperature reached 80°C, ammonia gas was introduced to maintain the internal pressure of the autoclave at 5.0 to 5.5 atm. 3
After 135 minutes, the internal temperature of the autoclave reached 135°C, and then ammonia gas was introduced at that temperature for 45 minutes, and the internal pressure of the autoclave was increased to 5.
The pressure was maintained at 5 atm. After that, the introduction of ammonia gas was cut off,
The reaction was continued for 4 hours and 15 minutes at the same temperature. The total amount of ammonia introduced was 36.2 g.

After the reaction, the reaction solution was cooled and the same post-treatment as in Example 2 was carried out.
-oxo-4,5,6,7-titrahydroindole 3
5.36 g was obtained (yield 75.9%).

Purity by GO analysis was 97.7%.

Example 4 1.12q of 1,3-cyclohexanedione was placed in a pressure-resistant glass tube with a capacity of 200all, and 2.4d of a 40% by weight aqueous chloroacetaldehyde solution, 4.2ml of 25% by weight aqueous ammonia, and 5d of methanol were sequentially added, sealed, and stirred. The reaction was continued at 145° C. for 7 hours.

The treatment after the reaction was the same as in Example 1, and the target product was 0.68C.
1 was obtained (yield 50.4%). Purity by GC analysis is 8
It was 1.3%.

Example 5 21 ml of 25x4% ammonia water was placed in a pressure-resistant glass tube with a capacity of 200 d, and 8.85 CI of 1,2-dibromoethyl acetate was added and dissolved at 60° C. or lower to obtain an ammonia aqueous solution of bromoacetaldehyde. 1.3 for this
- 3.36 liters of cyclohexanedione and 15 liters of methanol
d was added, sealed, and reacted at 135°C for 5 hours. The treatment after the reaction was the same as in Example 1 to obtain the target product 2.41G (yield 59.5%). Purity by GC analysis is 92.7
%Met.

Example 6 A mixture of 94.6 CJ of bromoacetal and 10 he of water and 10 g of an acidic ion exchange resin (Diaion PK-2284 manufactured by Mitsubishi Chemical Corporation) were added to a flask equipped with a reflux device and refluxed for 4 hours. After cooling, the resin was filtered off. The filtrate was washed with 300ml of water.The filtrate was diluted with 44% of 1,3-cyclohexanedione.
The mixture was added to a 1 g autoclave containing 8 q and 20 M methanol, sealed, and heated in an oil bath at 135° C. with stirring.

When the internal temperature reached 90°C, ammonia gas was introduced to maintain the internal pressure of the autoclave at 5.0 to 5.5 atm. After 7 minutes, when the internal temperature reached 135°C, ammonia gas was introduced at that temperature for 30 minutes, and the internal pressure of the autoclave was increased to 6.
The pressure was maintained at 0 atmospheres. After that, the introduction of ammonia gas was cut off,
The reaction was continued for 2 hours and 30 minutes at the same temperature. The total amount of ammonia introduced was 40.30. After the reaction, the reaction solution was cooled and subjected to the same post-treatment as in Example 2 to obtain 4-oxo-4゜5.
．． 30.99 CI of 6.7-titrahydroindole was obtained (yield 57.4%). Purity by GC analysis is 92.
It was 2%.

Example 7 1.2-dibromoethyl acetate 0.730 of the target product was obtained in the same manner as in Example 1 except that 1.88 g of 1,2-dichloroethyl acetate was used instead of 2.95 CJ of 1.2-dibromoethyl acetate (yield: 54.1%). Purity by GO analysis is 73.8%
Met.

Examples 8 to 10 The procedures in Table 1 were carried out in the same manner as in Example 1, except that the compound of general formula (DI) in Table 1 was used instead of 1,2-dibromoethyl acetate, and the reaction was carried out at 135°C for 5 hours. Got the results.

Note: Me: methyl group, Pr: propyl group Comparative Example 1 The same procedure as in Example 4 was carried out except that the reaction temperature was 100°C, and 0.27q of the target product (yield 20%) was obtained.
The purity of this product was 79.3%.

Claims (1)

[Claims] 1,3-cyclohexanedione and a haloacetaldehyde represented by the following general formula (II) or general formula (III) or a derivative thereof are reacted at 120°C to 200°C in the presence of ammonia. 4-oxo-4,5,6,
Method for producing 7-tetrahydroindole. General formula (II) XCH_2CHO General formula (III) ▲ Numerical formulas, chemical formulas, tables, etc. 3 lower alkoxy group or lower acyloxy group, AC represents an acetyl group)