JP2001039979A - PRODUCTION OF OCTAHYDROPYRROLO[3,4-b]PYRIDINE - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain, in high yield, the subject compound useful as an intermediate for medicines, by reducing a specific dioxoctahydropyrrolopyridine using a hydroborate salt in the presence of a specific halide. SOLUTION: This compound of formula II (e.g. 6-benzyloctahydropyrrolo[3,4- b]pyridine) is obtained by reducing a 5,7-dioxoctahydropyrrolo[3,4-b]pyridine of formula I (R1 to R3 are each H or a lower alkyl; and R4 is an aralkyl) (e.g. 6-benzyl-5,7-dioxoctahydropyrrolo[3,4-b]pyridine), normally in a solvent such as tetrahydrofuran, in the presence of a halide of at least one kind of a metal element selected from 3-14 group elements (except platinum group elements) (e.g. aluminum chloride), using a hydroborate such as sodium borohydride at preferably 0 to 40 deg.C, for, in general, about 1 to 5 h.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing octahydropyrrolo [3,4-b] pyridine.

[0002]

2. Description of the Related Art General formula (2):

[0003]

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[Wherein, R ₁ , R ₂ and R ₃ are the same or different and each represent a hydrogen atom or a lower alkyl group. R
₄ represents an aralkyl group. The octahydropyrrolo [3,4-b] pyridine represented by the formula [1] is a compound useful as a pharmaceutical intermediate.

Conventionally, as a method for producing octahydropyrrolo [3,4-b] pyridine represented by the general formula (2), for example, a method described in JP-A-2-69474 is known. . The method described in this publication discloses 6-benzyl-5,7-dioxooctahydropyrrolo [3,4-
b] Pyridine is reduced with lithium aluminum hydride or sodium borohydride to produce 6-benzyl-octahydropyrrolo [3,4-b] pyridine. For example, in the examples of the above-mentioned publication, lithium aluminum hydride in anhydrous tetrahydrofuran is used to form 6
-Benzyl-5,7-dioxooctahydropyrrolo [3,4-b] pyridine is reduced to produce 6-benzyl-octahydropyrrolo [3,4-b] pyridine. Is only 62.8%. Although there is no specific example in the above publication using sodium borohydride as a reducing agent, according to the study of the present inventors, when sodium borohydride is used as a reducing agent, an undesired side reaction proceeds. It was found that the desired 6-benzyl-octahydropyrrolo [3,4-b] pyridine was not formed at all (see Comparative Example 1 described later).

[0006]

SUMMARY OF THE INVENTION The present invention provides a compound represented by the general formula (1):

[0007]

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Wherein R ₁ , R ₂ , R ₃ and R ₄ are as defined above. Octahydropyrrolo [3,4-b] pyridine of the general formula (2) can be produced in higher yield from the 5,7-dioxooctahydropyrrolo [3,4-b] pyridine represented by the formula: It is an object to provide a method.

[0009]

Means for Solving the Problems The present inventors have made intensive studies to develop a method capable of producing octahydropyrrolo [3,4-b] pyridine of the general formula (2) in higher yield. I have piled up. As a result, 5,7-dioxooctahydropyrrolo [3,4-b] pyridine of the general formula (1)
In producing octahydropyrrolo [3,4-b] pyridine of the general formula (2) by reduction with sodium borohydride, an element belonging to Groups 3 to 14 of the periodic table together with sodium borohydride in the reaction system ( However, when a halide of at least one metal element selected from the group consisting of platinum group elements) is present, the reduction reaction proceeds favorably without side reactions, and the desired general formula It has been found that octahydropyrrolo [3,4-b] pyridine (2) can be produced in high yield. The present invention has been completed based on such findings.

That is, the present invention relates to a compound represented by the general formula (1):
Dioxooctahydropyrrolo [3,4-b] pyridine in the presence of a halide of at least one metal element selected from the group consisting of elements from Groups 3 to 14 of the periodic table (excluding platinum group elements) Is reduced using a hydroborate to give the octahydropyrrolo [3,4-
The present invention relates to a method for producing octahydropyrrolo [3,4-b] pyridine, which comprises obtaining b] pyridine.

According to the present invention, 5,7-
Octahydropyrrolo [3,4-b] pyridine of the general formula (2) can be produced from dioxooctahydropyrrolo [3,4-b] pyridine in even higher yield.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formulas (1) and (2), the lower alkyl groups represented by R ₁ , R ₂ and R ₃ include, for example, methyl, ethyl, n-propyl, Examples thereof include linear or branched alkyl groups having 1 to 4 carbon atoms such as an isopropyl group, an n-butyl group, an isobutyl group, and a tert-butyl group, and preferably a methyl group and an ethyl group. .

The aralkyl group represented by R ₄ includes, for example, a benzyl group and a phenethyl group, and a lower alkyl group (a methyl group, an ethyl group, an n-propyl group, an isopropyl group) , An alkyl group having 1 to 4 carbon atoms such as an n-butyl group, preferably a methyl group and an ethyl group), a lower alkoxy group (a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, etc.). At least one substituent selected from the group consisting of an alkoxy group having 1 to 4 carbon atoms, preferably a methoxy group and an ethoxy group) and a halogen atom (a fluorine atom, a chlorine atom and a bromine atom) may be substituted. As the aralkyl group represented by R ₄ , a benzyl group which may have one or more lower alkyl groups on the benzene ring, particularly one or two lower alkyl groups is preferable.

As the hydroborate, conventionally known ones can be widely used, and examples thereof include lithium borohydride, sodium borohydride, potassium borohydride, zinc borohydride, and sodium cyanoborohydride. Among them, alkali borohydrides such as lithium borohydride, sodium borohydride and potassium borohydride are preferable, and sodium borohydride is particularly preferable.

The amount of the hydroborate used is not particularly limited, but may be 2 to 1 mol of 5,7-dioxooctahydropyrrolo [3,4-b] pyridine of the general formula (1). It is good to be more than mol (theoretical amount), preferably 2.5 mol to 7 mol, particularly preferably 3 mol to 5 mol.

In the present invention, a halide of at least one metal element selected from the group consisting of elements of Groups 3 to 14 of the periodic table (excluding platinum group elements) is present in the reaction system. The halides of such metal elements are preferably Group 3 such as yttrium and lanthanoid elements (lanthanum, cerium, etc.), Group 4 such as titanium and zirconium, Group 8 such as iron, Group 9 such as cobalt, Examples thereof include chlorides of metal elements belonging to Group 12 such as zinc, Group 13 such as aluminum and gallium, and Group 14 such as tin, and more preferably aluminum (III) chloride, iron (III) chloride, and the like. Tin (IV) chloride, gallium (III) chloride and the like can be mentioned.

The amount of the metal element halide used depends on the type of the hydroborate used and cannot be said unconditionally. However, the amount of the metal element halide is usually 1 mol per mol of the hydroborate. / 4mol ~
1 mol, preferably 1/3 mol to 1/2 mol, is used.

The reduction reaction of the present invention is usually performed in a solvent. As the solvent, conventionally known solvents can be widely used as long as they do not adversely affect the reaction.
Ethers such as diethylene glycol dimethyl ether are particularly preferred.

The reduction reaction of the present invention proceeds at room temperature, under cooling and under heating, but the reaction is usually carried out at 0 ° C. to the boiling point of the solvent used, preferably at 0 to 40 ° C. . The reaction time is generally about 1 to 5 hours.

After completion of the above reaction, the desired compound of the general formula (2)
Of octahydropyrrolo [3,4-b] pyridine is easily isolated and purified from the reaction mixture according to a conventionally known isolation and purification means.

[0021]

The present invention will be further clarified with reference to the following examples.

Example 1 A 500-ml four-necked flask was charged with 56 g of tetrahydrofuran, and 5.6 g (42 mmol) of anhydrous aluminum chloride was dissolved while cooling to 0 ° C. To the resulting solution, a solution of 6.1 g (25 mmol) of 6-benzyl-5,7-dioxooctahydropyrrolo [3,4-b] pyridine dissolved in 61 g of tetrahydrofuran was added dropwise with stirring, and then hydrogen was added. 4.7 g of sodium borohydride (12
(5 mmol) and reacted at room temperature for 5 hours. After completion of the reaction, a 10% by weight aqueous solution of sodium hydroxide was added dropwise to the obtained reaction solution while paying attention to foaming, mixed to decompose excess sodium borohydride and aluminum chloride, and extracted with toluene. . Separate the aqueous layer and the organic layer, charge the organic layer in a 500 ml four-necked flask,
50 ml of 5% by weight hydrochloric acid was added, and the mixture was stirred under reflux for 5 hours. After cooling, an aqueous layer and an organic layer were separated. A 48% by weight aqueous sodium hydroxide solution was added to the obtained aqueous layer to adjust the pH to 14%.
Then, extraction with 50 ml of toluene was performed three times. The resulting toluene layers were combined, toluene was removed, concentrated, and distilled to obtain 4.6 g of 6-benzyl-octahydropyrrolo [3,4-b] pyridine (yield: 85%).

Comparative Example 1 A reaction was carried out in the same manner as in Example 1 except that anhydrous aluminum chloride was not used. As a result of analyzing the obtained reaction solution by gas chromatography, formation of 6-benzyl-octahydropyrrolo [3,4-b] pyridine was not observed. Approximately half of 6-benzyl-5,7-dioxooctahydropyrrolo [3,4-b] pyridine as the starting compound remains in the reaction solution, and the remainder is a mixture of various partially reduced products of the starting compound. there were.

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Claims (1)

[Claims] 1. General formula (1): [Wherein, R ₁ , R ₂ and R ₃ are the same or different and each represent a hydrogen atom or a lower alkyl group. R ₄ represents an aralkyl group. ] Is represented by the following formula: 3-1.
Reduction with a hydroborate in the presence of a halide of at least one metal element selected from the group consisting of Group 4 elements (excluding the platinum group elements) is carried out using a hydroborate to give a compound of the general formula (2): Wherein R ₁ , R ₂ , R ₃ and R ₄ are the same as above. Octahydropyrrolo [3,4-b] pyridine represented by the following formula: