JP2000038378A - Production of 7-hydroxyindole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially obtain in large quantities in high yield the subject derivative useful as a raw material for medicaments by reducing a specific compound followed by eliminating a specific substituent in the above compound and then reaction of another specific compound. SOLUTION: This new compound, a 7-hydroxyinodole derivative of formula IV, is obtained by the following procedure: a compound of formula I (R is methoxymethyl, methoxyethoxymethyl, allyl, α-methylbenzyl or the like) is reduced at about 20-200 deg.C in a solvent (e.g. ethanol) using a reducing agent (e.g. reduced iron) at about 2-6 molar times the compound of formula I to form a compound of formula II, from which a substituent R is eliminated by catalytic reduction or hydrolysis to form 7-hydroxyindole of formula III, which, in turn, is reacted with a compound of the formula YCH2COX (X is a mono- or di-lower alkylamino or cyclic amino; Y is an alcohol-reactive residue) in the presence of a base (e.g. potassium carbonate) in a solvent (e.g. acetone).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing 7-hydroxyindole and a 7-hydroxyindole derivative which are useful as a raw material for producing pharmaceuticals and the like with a high yield.

[0002]

BACKGROUND OF THE INVENTION The present applicant relates to a novel indole derivative having excellent selectivity, having a strong β ₃ adrenergic receptor stimulating action, and being useful as an antidiabetic and antiobesity drug. Has already filed a patent application (WO96 / 16938). 7-hydroxyindole or a 7-hydroxyindole derivative is used as a starting material for the production of this indole derivative, but the industrial production of the compound has a problem in terms of synthesis yield.

As a method for synthesizing 7-hydroxyindole, a method represented by the following formula 15 described in J. Am. Chem. Soc., 76, 5579 (1954) is conventionally known.

[0004]

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[0005] Synth. Commun., 21, 611 (1991).
There is also known a method represented by the following chemical formula 16 described in (1). However, both methods have poor yields.

[0006]

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A useful method for constructing an indole ring is Leimgruber-Batch.
o) The reaction is known. J. Med. Chem., 28, 892 (1985)
Describes the synthesis of 7-methoxyindole using this reaction (Chem. 17). However, this method also has a poor yield, and conversion of a methoxy group at the 7-position to a hydroxy group generally requires severe conditions, resulting in a poor yield.

[0008]

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As described above, it is difficult to industrially produce 7-hydroxyindole and 7-hydroxyindole derivatives in large amounts by any of the conventional production methods.
There is a problem to be solved. Therefore, it is desired to establish a production method capable of producing these compounds in large quantities with high yield.

[0010]

The present invention relates to a method for producing 7-hydroxyindole using semicarbazone (I) as a raw material, and further relates to a method for producing a 7-hydroxyindole derivative via 7-hydroxyindole. . That is, the present invention is:

(1) Formula I

[0012]

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(Wherein R is methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, allyl, tert-butyl, substituted or unsubstituted benzyl, diphenylmethyl, triphenylmethyl or α
-Means a methylbenzyl group. ) To reduce the compound of formula II

[0014]

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(Wherein R is the same as described above), and then the substituent R is eliminated to obtain a compound represented by the following formula:
III

[0016]

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7-hydroxyindole represented by the following formula IV

[0018]

Embedded image YCH ₂ COX IV

(Wherein X represents a mono- or di-lower alkylamino group or a cyclic amino group, and Y represents an alcohol-reactive residue). Equation V

[0020]

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(Where X is the same as above)
A method for producing a hydroxyindole derivative. In addition, the present invention

(2) The following formula VI

[0023]

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(Wherein R ′ represents a substituted or unsubstituted benzyl group, diphenylmethyl group, triphenylmethyl group or α-methylbenzyl group) by catalytic reduction. III

[0025]

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7-hydroxyindole represented by the following formula IV

[0027]

Embedded image YCH ₂ COX IV

(Wherein X and Y are the same as described above), characterized by reacting a compound represented by the following formula V:

[0029]

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(Wherein X is the same as described above)
A method for producing a hydroxyindole derivative.

Here, the terms used in the present specification will be described below.

"Lower alkyl group" and "lower alkyl"
The portion means a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and an isobutyl group. And ethyl groups.

The substituent in the "substituted benzyl group" means a halogen atom, a lower alkyl group, a lower alkoxy group and a nitro group, and specific examples include a 4-methylbenzyl group,
3-methylbenzyl group, 2-methoxybenzyl group, 4-
Examples thereof include a chlorobenzyl group, a 3-bromobenzyl group, and 4-nitrobenzyl.

"Cyclic amino group" means a 5- to 7-membered cyclic amino group, and specific examples thereof include a pyrrolidinyl group, a morpholinyl group, a piperidinyl group, and a hexahydroazepinyl group, preferably a pyrrolidinyl group. And a piperidinyl group.

The "alcohol-reactive residue" is, specifically, a halogen atom, a lower alkylsulfonyloxy group such as methanesulfonyloxy, ethanesulfonyloxy, etc.
And arylsulfonyloxy groups such as benzenesulfonyloxy and p-toluenesulfonyloxy.

The "halogen atom" includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

"Secondary amine" refers to an amine disubstituted with a lower alkyl group or an aralkyl group, and specific examples include dimethylamine, diethylamine, methylbenzylamine, dibenzylamine and the like.

The term "aralkyl group" means a lower alkyl group in which one or more hydrogens are substituted with an aryl group, and specific examples include a benzyl group.

"Cycloalkyl group" means a cyclic alkyl group having 3 to 6 carbon atoms.

"Lower alkoxy group" means a linear or branched alkoxy group having 1 to 6 carbon atoms, and specific examples include methoxy, ethoxy, propoxy, isopropoxy and butoxy groups. And preferably methoxy and ethoxy.

Next, the manufacturing method of the present invention will be described below. The 7-hydroxyindole represented by the formula III and the 7-hydroxyindole derivative represented by the general formula V according to the present invention can be produced by the method shown in the following formula.

[0042]

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(In the formula, R, R 'and X are the same as described above.)

According to the production method of the present invention, 7-hydroxyindole represented by the formula III is produced from the compound represented by the general formula I or the compound represented by the general formula VI in one or two steps. be able to.

Step A and Step B : Preparation of 7-hydroxyindole (III) from a compound represented by the general formula I via a compound represented by the general formula II

7-Hydroxyindole (III) can be obtained by reducing a compound represented by the general formula I with a suitable reducing agent in a suitable solvent to give a compound represented by the general formula II, followed by catalytic reduction or hydrolysis. Can be manufactured. Examples of the reduction method in step A include a method using a reducing agent such as zinc dust, reduced iron, tin powder, stannous chloride, and titanium chloride, a method using hydrazine in the presence of Raney nickel, a catalytic hydrogen reduction in the presence of Raney nickel, and the like. Is mentioned. The amount of the reducing agent to be used is about 2 to about 6 times, preferably about 3 to about 5 times, the molar amount of the compound of the formula I. The reaction temperature varies depending on the type of the reducing agent, but is usually about 20 ° C. to about 200 ° C., preferably about 50 ° C. to about 150 ° C.
° C. The solvent is appropriately selected depending on the type of the reducing agent to be used, and includes methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, dimethylformamide, water and the like, and each is used alone or in combination of two or more.

Whether the catalytic reduction or hydrolysis is performed in step B is appropriately selected depending on the type of the substituent R of the compound represented by the general formula II.

As the catalytic reduction, catalytic hydrogen reduction or catalytic hydrogen transfer reduction is used. The catalytic hydrogen reduction is performed in the presence of a catalyst such as palladium carbon, palladium hydroxide, platinum oxide, and Raney nickel, in a suitable solvent, under a hydrogen atmosphere, at normal pressure or under pressure. The reaction temperature is usually about 20 ° C ~
About 80 ° C. Further, as the catalytic hydrogen transfer reduction, ammonium formate, formic acid, cyclohexene,
The reaction is performed in a suitable solvent using hydrazine or the like. Examples of the solvent include alcohols such as methanol and ethanol,
Ethyl acetate, acetic acid, water and the like can be mentioned, and each is used alone or in combination of two or more.

The hydrolysis is carried out in an appropriate solvent under acidic conditions. The reaction temperature depends on the type of the substituent R,
Usually it is about 0 ° C to about 150 ° C. Preferably about 20 ° C
About 100 ° C. Examples of the acid include hydrochloric acid, bromic acid, trifluoroacetic acid, sulfuric acid, formic acid, acetic acid, methanesulfonic acid and the like. Examples of the solvent include alcohols such as methanol and ethanol, acetonitrile, water, dimethylformamide and the like, and these are used alone or in combination of two or more.

Step C : From the compound represented by the general formula VI to 7
-Production of hydroxyindole (III)

7-Hydroxyindole (III) can also be produced in one step by catalytic reduction of the compound represented by the general formula VI. Catalytic reduction is the usual method,
It can be carried out by a catalytic hydrogen reduction method or a catalytic hydrogen transfer reduction method. The catalytic hydrogen reduction is performed in the presence of a catalyst such as palladium carbon, palladium hydroxide, platinum oxide, and Raney nickel, in a suitable solvent, under a hydrogen atmosphere, at normal pressure or under pressure. The reaction temperature is usually about 20 ° C to about 80 ° C. The catalytic hydrogen transfer reduction is carried out in an appropriate solvent using ammonium formate, formic acid, cyclohexene, hydrazine or the like as a hydrogen source. As the solvent, methanol, alcohols such as ethanol, ethyl acetate, acetic acid,
Water and the like are used, and each is used alone or in combination of two or more.

Step D : 7-hydroxyindole (III)
Of compound represented by general formula V from

The compound represented by the general formula V can be produced by reacting 7-hydroxyindole (III) with the compound represented by the general formula IV in a suitable solvent in the presence of a base. The reaction temperature varies depending on the type of the starting compound used, but is usually from room temperature to about 200 ° C. Examples of the solvent include aromatic hydrocarbons such as benzene and toluene, ketones such as acetone and methyl ethyl ketone, ethers such as tetrahydrofuran and dioxane, alcohols such as ethanol and isopropanol, acetonitrile, dimethylformamide and 1,3-dimethyl. -2-
And imidazolidinone. These solvents are used alone or in combination of two or more.

Examples of the base include alkali carbonates such as sodium carbonate and potassium carbonate, alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali hydroxides such as sodium hydroxide and potassium hydroxide and triethylamine, tributylamine, N- Organic bases such as methylmorpholine are exemplified.

When a compound in which Y is chlorine or bromine in the general formula IV is used, an alkali metal iodide such as sodium iodide and potassium iodide and a tetraalkylammonium halide such as tetra-n-butylammonium chloride are added. Then, the reaction proceeds smoothly, which is preferable.

Next, the production of the compound represented by the general formula I, which is the starting compound of the present invention, will be described below. The compound represented by the general formula I can be produced by the method shown in the following formula.

[0057]

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(Wherein R ₁ and R ₂ each independently represent a lower alkyl group, or R ₁ and R ₂ together represent a cyclic amino group, and R ₃ and R ₄ are each independently Represents a lower alkyl group, an aralkyl group or a cycloalkyl group, or R ₃ and R ₄ together represent a cyclic acetal group, and R is the same as described above.)

Step 1 : Preparation of a compound represented by the general formula IX from a compound represented by the general formula VII

The compound represented by the general formula IX is represented by the general formula VII
And a formamide acetal represented by the general formula VIII in the presence of a secondary amine or a cyclic amine in a suitable solvent or without a solvent.

The reaction temperature is usually about 25 ° C. to about 200 ° C., preferably about 100 ° C. to about 160 ° C. As the solvent, dimethylformamide, diethylene glycol dimethyl ether, hexamethylphosphoryltriamide and the like are used, and dimethylformamide is preferable. Suitable amines include dimethylamine, diethylamine, pyrrolidine, piperidine and the like. The formamide acetal represented by the general formula VIII is a known compound or can be produced by a known method. Suitable compounds include N, N-dimethylformamide diethyl acetal, N, N-dimethylformamide dimethyl acetal, N-formylpyrrolidine dimethyl acetal, 2-dimethylamino 1,3-dioxolan, N-
Formylpiperidine dimethyl acetal, N, N-dimethylformamide dibenzyl acetal, N, N-dimethylformamide dicyclohexyl acetal, N, N-dimethylformamide dineopentyl acetal, N, N-dimethylformamide diisopropyl acetal, N, N-
Dimethylformamide di-n-heptyl acetal and the like.

Step 2 : Preparation of a compound represented by the general formula I from a compound represented by the general formula IX

The compound represented by the general formula I can be produced by reacting the compound represented by the general formula IX with semicarbazide or an acid addition salt thereof under acidic conditions.

The reaction temperature is usually from room temperature to about 50 ° C. Examples of the solvent include water, ethanol and the like. Examples of the acid include acetic acid, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid and the like.

[0065]

Industrial Applicability According to the production method of the present invention, 7-hydroxyindole and 7-hydroxyindole derivative useful as raw materials for medicines and the like can be produced in large quantities in good yield.

[0066]

EXAMPLES The present invention will be described more specifically with reference to examples below, but the present invention is not limited to these examples. Confirmation of the compound was carried out by elemental analysis, hydrogen nuclear magnetic resonance ⁽¹ H-NMR) spectrum analysis and the like.

In the following embodiments, the following abbreviations may be used to simplify the description.

J: coupling constant, s: singlet, d: doublet, t: triplet, q: quadruple, m: multiplet.

Reference Example 1: Production of 3-benzyloxy-2-nitrotoluene

2-nitro-m-cresol (30.6 g, 200 mm
ol) in methyl ethyl ketone (30 ml), anhydrous potassium carbonate (27.6 g, 200 mmol) and benzyl bromide (34.2 g, 2
00 mmol) and heated to reflux for 4 hours. After cooling the reaction solution to room temperature, it was washed with water, an aqueous sodium hydroxide solution, water, and saturated saline in this order. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the title compound (50.8
g) was obtained quantitatively.

Reference Example 2 : Production of 3-benzyloxy-2-nitrophenylacetaldehyde semicarbazone

The 3-benzyloxy-2- obtained in Reference Example 1
Nitrotoluene (9.72 g, 40 mmol), pyrrolidine (6.6
1 ml, 80 mmol) and a solution of dimethylformamide (10.63 ml, 80 mmol) in dimethylformamide (30 ml) were heated to reflux at 130 ° C. for 5 hours under an argon atmosphere. The reaction solution was ice-cooled, diluted with diisopropyl ether (40 ml), added with a 2N hydrochloric acid (60 ml) solution of semicarbazide hydrochloride (5.36 g, 48 mmol) and water (10 ml), and stirred for 10 minutes. . The insoluble solid was collected by filtration, washed with water and diisopropyl ether, and dried to give the title compound (9.77 g, 74%) as pale yellow crystals. 184-185 ° C

¹ H-NMR spectrum (DMSO-d ₆ ): 3.46 (2H, d,
J = 6Hz), 5.27 (2H, s), 6.15 (2H, s), 7.01 (1H, d, J = 8H
z), 7.16 (1H, t, J = 6Hz), 7.27-7.43 (6H, m), 7.51 (1H,
t, J = 8Hz), 9.98 (1H, s).

Example 1 Preparation of 7-benzyloxyindole

A solution of ammonium chloride (1.07 g, 20 mmol) in ethanol (40 ml) -water (20 ml) was reduced iron (2.23 g).
g, 40 mmol) and stirred. 3- obtained in Reference Example 2
After adding benzyloxy-2-nitrophenylacetaldehyde semicarbazone (3.28 g, 10 mmol),
The mixture was refluxed for 1 hour. After the reaction solution was cooled to room temperature, insolubles were removed by filtration through celite and washed with toluene. After the filtrate was distilled off under reduced pressure to the extent that ethanol disappeared, water was added and the mixture was extracted with toluene. The toluene layer was washed with diluted hydrochloric acid, water, and saturated saline in this order. After adding anhydrous sodium sulfate and activated carbon, the mixture was allowed to stand and filtered, and the filtrate was concentrated under reduced pressure until the amount of toluene became about 3 ml. The residue was recrystallized from n-hexane,
7-Benzyloxindole (1.70 g, 76%) was obtained as pale brown crystals. 73 ° C

¹ H-NMR spectrum (CDCl ₃ ): 5.20 (2H, s),
6.54 (1H, t, J = 3Hz), 6.71 (1H, d, J = 7Hz), 7.02 (1H,
t, J = 7Hz), 7.16 (1H, t, J = 3Hz), 7.27 (1H, d, J = 7Hz),
7.32-7.52 (5H, m), 8.40 (1H, s).

Example 2 : Preparation of 7-hydroxyindole

The 3-benzyloxy-2- obtained in Reference Example 2
Nitrophenylacetaldehyde semicarbazone (4.
92 g, 15 mmol) in ethanol (50 ml)
Palladium carbon (0.4 g) was added, and medium pressure reduction (about 3 kgf / cm ² ) was performed at room temperature for 2 hours. After absorbing the theoretical amount of hydrogen, the catalyst was removed by filtration and the solvent was distilled off under reduced pressure at 40 ° C or lower. Chloroform (50 ml) and 10% citric acid aqueous solution (20 ml) were added to the residue, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure at 40 ° C. or lower to give the title compound (1.6 g, 80%) as pale purple crystals. Melting point 95-96 ° C

¹ H-NMR spectrum (CDCl ₃ ): 5.15 (1H, s),
6.53 (1H, t, J = 3Hz), 6.55 (1H, d, J = 8Hz), 6.94 (1H,
t, J = 8Hz), 7.17 (1H, t, J = 3Hz), 7.25 (1H, d, J = 8Hz),
8.38 (1H, s).

Example 3 Preparation of 7-hydroxyindole

To a solution of 7-benzyloxyindole (5.0 g, 22 mmol) obtained in Example 1 in ethanol (50 ml) was added:
10% palladium on carbon (0.5 g) was added, and the mixture was subjected to medium pressure reduction (about 3 kgf / cm ² ) at room temperature for 2 hours. After uptake of the theoretical amount of hydrogen, the catalyst was filtered off. Under reduced pressure at 40 ° C. or lower, the title compound (2.93 g) was obtained quantitatively as pale purple crystals. Melting point 95-96 ° C

Example 4 Preparation of 7-indoleoxyacetic acid diethylamide

To a solution of 7-hydroxyindole (13.3 g, 100 mmol) obtained in Example 2 or 3 in acetone (100 ml) was added potassium carbonate (16.6 g), chloroacetic acid diethylamide (16.5 g, 110 mmol) and iodide. Potassium (1.66 g)
Was added and the mixture was heated under reflux for 3 hours. After cooling with ice, insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. Chloroform (200 ml) and water (100 ml) were added to the residue and stirred. The chloroform layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and diisopropyl ether (100 ml) was added to the residue.
The precipitated crystals were collected by filtration and dried to give the title compound (22 g, 90%) as colorless crystals. Melting point 123-124 ° C

¹ H-NMR spectrum (CDCl ₃ ): 1.16 (3H, t, J =
7Hz), 1.21 (3H, t, J = 7Hz), 3.35 (2H, q, J = 7Hz), 3.43
(2H, q, J = 7Hz), 4.80 (1H, s), 6.53 (1H, t, J = 3Hz),
6.69 (1H, d, J = 7Hz), 6.99 (1H, t, J = 7Hz), 7.21 (1H,
t, J = 3Hz), 7.32 (1H, d, J = 7Hz), 9.44 (1H, s).

Claims (3)

[Claims] [Claim 1] The following formula I (In the formula, R is a methoxymethyl group, a methoxyethoxymethyl group, a tetrahydropyranyl group, an allyl group, a tert-butyl group, a substituted or unsubstituted benzyl group, a diphenylmethyl group, a triphenylmethyl group, or an α-methylbenzyl group. By reducing the compound represented by the following formula II: (Wherein R is the same as described above), and then the substituent R is eliminated to obtain a compound represented by the following formula III: 7-hydroxyindole represented by the following formula:
IV A compound represented by the formula: YCH ₂ COX IV (wherein X represents a mono- or di-lower alkylamino group or a cyclic amino group, and Y represents an alcohol-reactive residue) The following formula V is characterized in that: (Wherein X is the same as described above.) A method for producing a 7-hydroxyindole derivative represented by the formula: 2. A compound represented by the following formula VI: (Wherein R ′ represents a substituted or unsubstituted benzyl group, diphenylmethyl group, triphenylmethyl group or α-methylbenzyl group) by catalytic reduction of a compound represented by the following formula III: ] YCH ₂ COX IV wherein X represents a mono- or di-lower alkylamino group or a cyclic amino group, and Y represents an alcohol-reactive residue. Wherein the compound is represented by the following formula V: (Wherein X is the same as described above.) A method for producing a 7-hydroxyindole derivative represented by the formula: 3. A compound of the following formula I (In the formula, R is a methoxymethyl group, a methoxyethoxymethyl group, a tetrahydropyranyl group, an allyl group, a tert-butyl group, a substituted or unsubstituted benzyl group, a diphenylmethyl group, a triphenylmethyl group, or an α-methylbenzyl group. By reducing a compound represented by the following formula II: (Wherein R is the same as described above), and then the substituent R is eliminated. A method for producing 7-hydroxyindole represented by the formula: 4. The following formula VI: Wherein R ′ represents a substituted or unsubstituted benzyl group, a diphenylmethyl group, a triphenylmethyl group or an α-methylbenzyl group. III A method for producing 7-hydroxyindole represented by the formula: