GB2127808A

GB2127808A - A process for preparing a hydroxyindole

Info

Publication number: GB2127808A
Application number: GB08325123A
Authority: GB
Inventors: Manabu Matsuoka; Michihiro Tsuchiya; Yoshikazu Tokuda; Takuo Nishida
Original assignee: Tanabe Seiyaku Co Ltd
Current assignee: Tanabe Seiyaku Co Ltd
Priority date: 1982-10-01
Filing date: 1983-09-20
Publication date: 1984-04-18
Also published as: GB8325123D0; JPS5962566A; DE3334951A1; FR2533921B1; FR2533921A1

Abstract

A process for preparing a hydroxyindole of the formula: <IMAGE> which comprises reacting an alkoxyindole of the formula: <IMAGE> wherein R<1> is lower alkyl, with aluminium halide in a solvent which is a halogenobenzene or 1,2- dichloroethane.

Description

SPECIFICATION A process for preparing a hydroxyindole This invention relates to an improved process for preparing a hydroxyindole.

Hydroxyindoles are useful as starting materials in the synthesis of various medicines, alkaloids, amino acids and agricultural chemicals such as serotonine (antidepressant), pindolol (adrenergic B- blocker) and 5-hydroxy-L-tryptophan.

J. Org, Chem., 13, 547, (1948) discloses that hydroxyindoles can be prepared by treating methoxyindoles with aluminium chloride in benzene or with N-methylaniline hydrobromide. However, these known methods are unsatisfactory for the industrial scale preparation of hydroxyindoles because of the poor yields thereof. For example, the treatment of 5-methoxyindole with aluminium chloride in benzene gives 5-hydroxyindole in a yield of 6.1% only, and 5-hydroxyindole and 7-hydroxyindole are obtained only in yields of 1 6 and 3% respectively by treatment of the corresponding methoxyindoles with N-methylaniline hydrobromide.

We have now found unexpectedly that the desired hydroxyindole can be produced in a high yield, such as 49.5 to 86.3%, when a halogenobenzene or 1 ,2-dichloroethane is used as a solvent in the treatment of alkoxyindole with aluminium halide.

Thus, according to the present invention, a hydroxyindole of the formula:

can be prepared by reacting a compound of the formula:

wherein R' is a lower alkyl group with an aluminium halide in a halogenobenzene or 1,2dichloroethane.

Examples of the alkoxyindole which can be used as the starting material of the invention include those of the formula (II) in which R1 is a lower alkyl having from 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl and n-butyl. Among them, preferred examples are those of formula (II) in which R1 is methyl or ethyl. Examples of the solvent to be used in the present invention are chlorobenzene, bromobenzene, fluorobenzene and 1 2-dichloroethane. Either aluminium chloride or aluminium bromide may be used as the aluminium halide, but it is particularly preferred to use anhydrous aluminium halide in the present invention.The preferred amount of the solvent to be used is 10 to 50 ml per gram of compound (II), and the preferred amount of the aluminium halide is 1.0 to 5.0 moles, particularly 2.0 to 3.0 moles, per mole of the compound (II).

The reaction of the present invention is preferably carried out by the steps of dissolving compound (II) in the solvent, adding the aluminium halide thereto and the refluxing the mixture. The reaction may be completed within 0.5 to 1 5 hours. It is preferred to carry out the reaction in an inert gas (e.g. nitrogen or argon gas). It is also preferred to carry it out at a temperature of from 80 to 2000 C. The hydroxyindole (I) thus obtained can be recovered by conventional methods, for example, by adding water to the reaction mixture, neutralizing the aqueous mixture with sodium bicarbonate, filtering off the aluminium hydroxide (i.e. by-product) and then extracting the filtrate with ether.

According to another embodiment of the present invention, the starting compound(ll) which is used in the above-mentioned method can be prepared by reacting a compound of the fomula:

wherein R1 is as defined above and R2 is hydrogen or benzyl, in the vapour phase with ethylene glycol or ethylene oxide in the presence of a silica catalyst, alumina catalyst or silica-alumina catalyst to give a compound of the formula:

wherein R1 and R2 are as defined above, and when R2 is benzyl, further reducing the compound (IV) with an alkali metal in liquid ammonia.

The silica catalyst or silica-alumina catalyst which is used in the above-mentioned vapour phase reaction may optionally contain a metal oxide such as an alkali metal oxide, an alkaline earth metal oxide, zinc oxide, chromium oxide, nickel oxide, cobalt oxide or silver oxide. A suitable amount of the metal oxide contained in the catalyst is from 0.1 to 50 w/w %, preferably 0.1 to 20 w/w %. In carrying out the vapour phase reaction, it is preferable to vaporize the compound (III) and ethylene glycol or ethylene oxide in a vaporizer and the introduce the vapour of the compounds into a reactor. The preferred molar ratio of ethylene glycol or ethylene oxide to the compound (III) is in the range of 0.2 to 1 5, preferably 0.5 to 10. Alternatively, the vapour of these compounds may be introduced into the reactor together with an inert diluent.Examples of the inert diluent are steam, nitrogen gas, carbon dioxide, benzene vapour, toluene vapour or a mixture of these gases. When such a diluent is used, the initial partial pressure of compound (III) should preferably be in the range of from 0.01 to 0.1 atm. It is preferred to carry out the reaction at a temperature of from 250 to 4000C, preferably 275 to 3500C.

The reaction may be carried out either under reduced pressure, atmospheric pressure or increased pressure, but can usually be carried out under atmospheric pressure. Moreover, a contact time (W/F) which is defined by the following formula should preferably be within the range of 5 to 500 g-cat.hr/mol, preferably 10 to 200 g-cat.hr/mole.

Amount time (W/F) = (W g) of the catalyst packed Contact time (W/F) = Total amount per hour (F mole/hr) of the gases which are fed to the reactor After contacting the compound (III) with ethylene glycol or ethylene oxide in the vapour phase with the catalyst as above, the reaction mixture is cooled and collected as a condensed solution.The condensed solution mainly alkoxyindole (II) and unreacted starting compounds, which can be separated from each other by conventional methods such as extraction or distillation or by converting them to acid addition salts thereof (e.g. hydrochloride or sulfate). According to the above-mentioned method of the invention, 1 -benzyl-4 and/or 6-alkoxyindole is obtained in a high selectivity such as 85% from N-benzylm-anisidine, 6-alkoxyindole is obtained selectively in an amount of 37.0 to 43.9% from m-anisidine and 1 -benzyl-5-alkoxyindole is obtained selectively in an amount of 35.2% from N-benzyl-p-anisidine.

Furthermore, the 1 -benzyl-alkoxyindole obtained in the vapour phase reaction can be converted into the desired alkoxyindole (II) be reducing it with an alkali metal in liquid ammonia. The reduction is preferably carried out by dissolving the 1 -benzyl-alkoxyindole compound in liquid ammonia, and then adding an alkali metal thereto. Dissolution of-the 1-benzyl-alkoxyindole compound in liquid ammonia may be carried out by dissolving the alkoxyindole compound in an organic solvent (e.g. ether, benzene or toluene), and then adding the organic solution to liquid ammonia. It is preferred to use the organic solvent in a minimum amount sufficient to dissolve the 1 -benzyl-alkoxyindole compound.Liquid ammonia should preferably be used in an amount of not less than 3 parts by volume, preferably 3 to 10 parts by volume, per part by volume of the organic solvent. Suitable examples of the alkali metal are sodium, potassium or lithium. The alkali metal is generally used in an amount of not less than 2.5 moles, preferably 2.8 to 50 moles more preferably 2.8 to 10 moles, per mole of the 1 -benzyl-alkoxyindole compound. The desired alkoxyindole (II) thus obtained is recovered by convention methods, for example, by the steps of adding ethanol to the reaction mixture, evaporating ammonia from the ethanol solution, adding water to the residue thus obtained, evaporating ethanol from the aqueous solution and then extracting the resulting solution with toluene.

As can be seen from the foregoing, the above-mentioned method of the present invention is quite advantageous for an industrial scale production of hydroxyindoles in that the hydroxyindole (I) can be obtained in a high yield such as 49.5 to 86.3% from the alkoxyindole which is readily produced by the vapor phase reaction.

Practical and presently-preferred embodiments of the present invention are illustratively shown in the following Examples. In the following Examples, the analytical values were estimated by gas chromatography, and each product was identified by mass spectrum, nuclear magnetic resonance spectrum and infrared spectrum. Further, the yield of the alkoxyindole (II) and selectively to the alkoxy indole (II) are defined as follows:

Mole of Molt or the alkoxyindole Yield of compound produced the alkoxyindole = - x100 compound(%) Mole of the compound (III) fed

- to Mole of the alkoxyindole Selectivity to compound produced the alkoxyindole = x 100 compound (%) Mole of the compound (III) reacted Example 1 (1) A tubular quartz-reactor of 10 mm in inside diameter and 200 mm in length is packed with 2 g of a catalyst shown in Table 1, and heated with a tubular electric furnace. A mixture of m-anisidine vapor, ethylene glycol vapor, steam, toluene vapor and nitrogen gas is charged into the reactor under the following conditions.

Reaction conditions: Contact time (W/F): 19.6 g-cat.hr/mole Initial partial pressure (atm): m-Anisidine vapor 0.0205 Ethylene glycol vapor 0.0410 Steam 0.642 Toluene vapor 0.135 Nitrogen gas 0.161 The effluent gas is cooled by a condenser and collected as a condensed solution. The condensed solution is analyzed by gas chromatography about 5 hours after the reaction is started. The results are shown in Table 1.

TABLE 1

Reaction Yield of Selectivity to Nos. Catalysts temperature (OC) 6-methoxyindole (%) 6-methoxyindole (%) 1 Neobead P} 325 30.9 37.0 2 Neobead D**} 300 25.5 43.9 Note: *l Chemical composition (% by weight) of Neobead P (manufactured by Mizusawa Chemical Industry Co., Ltd): Al=03: SiO2:Na20 = 88 :9 :3 **) Chemical composition (% by weight) of Neobead D (manufactured by Mizusawa Chemical Industry Co., Ltd): Al203:SiO2=90: 10 (2) 4.41 g of 6-methoxyindole are dissolved in 100 ml of chlorobenzene. After the air in the reaction vessel is replaced by nitrogen, 9.98 g of anhydrous aluminium chloride are added thereto and the mixture is refluxed for one hour. After the reaction, water is added to the reaction mixture under stirring and the aqueous solution is neutralized with sodium bicarbonate. Aluminium hydroxide formed is filtered off and the filtrate is extracted with ether. The extract is evaporated under reduced pressure to remove the solvent.The residue is dissolved in acetone and the acetone solution is analyzed by gas chromatography. 6-Hydroxyindole is obtained in a yield of 74.2% Example 2 (1) N-Benzyl-m-anisidine is treated in the same manner as described in Example 1-(1) under the following reaction conditions, whereby 1-benzyl-4-methoxyindole and 1-benzyl-6-methoxyindole are obtained as shown in Table 2.

Reaction conditions: Contact time (W/F): 1 9.6 g-cat.hr/mole Initial partial pressure (atm): N-Benzyl-m-anisidine vapor 0.0205 Ethylene glycol vapor 0.205 Steam 0.495 Toluene vapor 0.119 Nitrogen gas 0.161 TABLE 2

Yield I (%) Selectivity (%) Reaction temperature 1 -Benzyl-4- 1 -Benzyl-6- 1 -Benzyl-4- 1 -Benzyl-6 Catalyst - (%) methoxyindole methoxyindole methoxyindole methoxyindole Neobead P* 300 6.1 43.9 10.5 75.8 Note: * :: same as shown in the footnote of Table 1 1 -Benzyl-4-methoxyindole and 1 -benzyl-6-methoxyindole obtained above are separated from each other by silica gel chromatography (solvent: carbon tetrachloride:cyclohexane:toluene = 10:5:1).

(2) 0.47 g of 1 -benzyl-6-methoxyindole is dissolved in 20 ml of toluene, and the mixture is added to 200 ml of liquid ammonia under stirring at -35 to -450C. 2 g of sodium are added gradually to the mixture, and the mixture is stirred for one hour. After the reaction, ethanol is added to the mixture until the blue solution is decolorized. The solution is evaporated to remove ammonia, water is added to the residue and the mixture is evaporated to remove ethanol. The aqueous solution thus obtained is extracted with toluene. The extract is evaporated under reduced pressure. The residue thus obtained is dissolved in acetone and analyzed by gas chromatography. 6-Methoxyindole is obtained in a yield of 92.6%.

(3) 6-Hydroxyindole is prepared by treating 6-methoxyindole in the same manner as described in Example 1-(2).

Example 3 (1 ) N-Benzyl-p-anisidine is treated in the same manner as described in Example 1-(1) under the following reaction conditions. The results are shown in Table 3.

Reaction conditions: Contact time (W/F): 1 9.6 g-cathr/mole Initial partial pressure (atm.): N-Benzyl-p-anisidine vapor 0.0205 Ethylene glycol vapor 0.205 Steam 0.495 Toluene vapor 0.119 Nitrogen gas 0.161 TABLE 3

Reaction | Yield of 1 -benzyl-5- Selectivity to 1-benzyl-5- Catalyst temperature ( C) methoxyindole (%) methoxyindole (%) Neobead P* 300 25.7 35.2 Note: * :: same as shown in the footnote of Table 1 The above-mentioned reaction is carried out in the same manner as described above except that ethylene oxide is used instead of ethylene glycol and the contact time (W/F) is adjusted to 49.6 g-cat.hr/mole, whereby 1 -benzyl-5-methoxyindole is obtained in a yield of 20.9% and a selectivity of 25.8%.

(2) 1 -Benzyl-5-methoxyindole is treated in the same manner as described in Example 2-(2) under the reaction conditions shown in Table 4. 5-Methoxyindole is thereby obtained in a yield shown in Table 4.

TABLE 4

Reaction conditions Amounts of Liquid Yield of 1 -benzyl-5- Solvent ammonia Metals 5-methoxyindole methoxyindole (g) (ml) (ml) (9) (%) 10 Toluene (40) 200 Sodium (3.5) 98 43.1 I Benzene (200) 600 Sodium (12) 1 83.1 24.3 Ether (150) 450 Sodium (11.5) 78.9 5.0 Ether (70) 300 Potassium (4.3) 52.3 (3) 4.41 g of 5-methoxyindole are dissolved in 100 ml of a solvent. After the air in the reaction vessel is replaced by nitrogen, 9.98 g of anhydrous aluminium chloride are added to the mixture. The mixture is refluxed for a period of time and then treated in the same manner as described in Example 1 -(2). 5-Hydroxyindole is thereby obtained in a yield shown in Table 5.

TABLE 5

Yield of Solvents Reaction time (hr) 5-hydroxyindole (%) Chlorobenzene 1 82.6 Fluorobenzene 7 86.3 Fluorobenzene 7 86.3 Bromobenzene 1 1 49.5 12-dichloroethane 14 74.2 When the above-mentioned reaction is carried out in benzene (reaction time: 6 hours hydroxyindole is obtained in a yield of 25.2% only.

Claims

1. A process for preparing a hydroxyindole of the formula:

which comprises reacting alkoxyindole of the formula:

wherein R1 is a lower alkyl group, with an aluminium halide in a solvent which is a halogenobenzene or 1,2-dichloroethane.

2. A process as claimed in claim 1 wherein the solvent is chlorobenzene, bromobenzene, fluorobenzene or 1,2-dichloroethane.

3. A process as claimed in claim 1 or claim 2 wherein the aluminium halide is aluminium chloride or aluminium bromide.

4. A process as claimed in any one of the preceding claims wherein the amount of solvent used is from 10 to 50 ml per gram of the alkoxyindole, and the amount of aluminium halide used is from 1.0 to 5.0 moles per mole of the alkoxyindole.

5. A process as claimed in any one of the preceding claims wherein the reaction is carried out at a temperature in the range of from 80 to 2000C.

6. A process as claimed in any one of the preceding claims wherein the starting compound of formula (II) is prepared by reacting a compound of the formula:

wherein R' is a lower alkyl group and R2 is a hydrogen atom or a benzyl group, with ethylene glycol or ethylene oxide in the vapour phase in the presence of a silica catalyst, alumina catalyst or silica-alumina catalyst to produce an alkoxyindole of the formula:

wherein R1 and R2 are as defined above, and when R2 is a benzyl group, further treating the alkoxyindole with an alkali metal in liquid ammonia.

7. A process as claimed in claim 6 wherein the silica catalyst, alumina catalyst or silica-alumina catalyst contains at least one alkali metal oxide, alkaline earth metal oxide, zinc oxide, chromium oxide, nickel oxide, cobalt oxide or silver oxide in an amount of from 0.1 to 50 w/w%.

8. A process as claimed in claim 7 wherein the vapor phase reaction is carried out by contacting a gaseous mixture of the compound (111)0.2 to 15 moles, per mole of the compound (lil), of ethylene glycol or ethylene oxide and an inert diluent with a silica catalyst, alumina catalyst or silica-alumina catalyst at a temperature in the range of from 250 to 4000C for a contact time of 5 to 500 g-cat.hr/mole under atmospheric pressure.

9. A process as claimed in claim 8 wherein the reduction is carried out by treating compound (IV) with not less han 2.5 moles per mole of compound (IV), of sodium, potassium or lithium in liquid ammonia.

10. A process for the preparation of a hydroxyindole substantially as hereinbefore described in any one of the Examples.

11. A hydroxyindole whenever prepared by a process as claimed in any one of the preceding claims.