Process for production of indole derivatives and...

Details Process for production of indole derivatives and... Process for production of indole derivatives and...

2001-11-13

2003-06-03

Chang, Ceila (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S223000

Reexamination Certificate

active

06573384

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel, industrially superior process for the production of 1,4-substituted cyclic amine compound such as those disclosed in WO 98/43956 which are useful as pharmaceuticals and to intermediates thereof.
PRIOR ART
Among the 1,4-substituted cyclic amine compounds disclosed in WO 98/43956, indole compounds which are target compounds of the present invention have been prepared primarily by synthesizing corresponding indoline compounds and then oxidizing the indoline compounds.
This is because the NH group in the indoles has low reactivity and, therefore, it is difficult to directly add a side chain thereto.
In the oxidation of the indoles, various oxidizing agents can be used, and manganese dioxide is frequently used. However, the oxidation using manganese dioxide is rate-limited by stirring because it is a heterogeneous reaction, and therefore a large-volume treatment on an industrial scale is hardly achieved. In addition, since the reactivity of the oxidation depends on the degree of activation of the catalyst, the reaction usually takes several hours to complete, and in some cases, takes one day or longer. Moreover, when manganese dioxide is re-used repeatedly, its activity decreases, and this may have a large effect on production costs.
On the other hand, other oxidizing agents, such as permanganates, hydrogen peroxide, nitric acid, lead tetraacetate, mercuric acetate, potassium nitrosodisulfate (Fremy's salt), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and tetrachldrobenzoquinone (chloranil) have good reactivity. However, with such oxidizing agents, there have been problems such as the occurrence of adverse side reactions due to their high activities, poor storage properties, toxicity and poor safety, and generally being expensive, and therefore are not always suitable for industrial applications.
In these situations, the present inventors have conducted extensive studies for the purpose of developing a novel production process which is useful from the viewpoints of stability of raw materials, production costs, ease of operation (e.g., workability, safety, non-toxicity), purity of the final product and so on.
As a result, the inventors have found that the process described in detail hereinbelow can solve the above-mentioned problems at a stroke and have accomplished the present invention.
DISCLOSURE OF THE INVENTION
Accordingly, the object of the present invention is to provide a novel process for the production of indole compounds which are useful as fine chemicals such as pharmaceuticals, and to provide intermediates for the process.
Herein, the indole compound (I) according to the present invention is represented by the following formula:
wherein R
1
represents hydroxymethyl group, carboxyl group, a lower alkoxycarbonyl group or a carbamoyl group in which the nitrogen atom may be substituted; R
2
represents an aryl. group which may be substituted, a heteroaryl group which may be substituted or a benzoheteroaryl group which may be substituted; and n is 0 or an integer from 1 to 6.
In the above definition, the hydroxymethyl group refers to a group represented by the formula —CH
2
OH, and the carboxyl group refers to a group represented by the formula —COOH.
The lower alkoxycarbonyl group refers to a group represented by the formula —COOR, wherein R represents a linear or branched lower alkyl group having 1 to 6 carbon atoms.
The carbamoyl group which may be substituted refers to a carbamoyl group in which the nitrogen atom may be substituted by a lower alkyl group or the like, wherein the nitrogen atom may be included in a cyclic amine. Specifically, for example, carbamoyl (—CONH
2
), N-methylcarbamoyl (—CONHCH
3
), N,N-dimethylcarbamoyl (—CON(CH
3
)
2
), N-ethylcarbamoyl (—CONHC
2
H
5
), N,N-diethylcarbamoyl (—CON(C
2
H
5
)
2
), N-methyl-N-ethylcarbamoyl (—CON(CH
3
)C
2
H
5
), N-propylcarbamoyl (—CONHC
3
H
7
), 1-pyrrolidinylcarbonyl, 1-pyrazolynylcarbonyl, 1-piperidylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl and 4-thiomorpholinylcarbonyl groups. Among these, N-methylcarbamoyl, N-ethylcarbamoyl or N-propylcarbamoyl group is preferred from the viewpoints of pharmacological activity and safety.
The aryl group which may be substituted refers to a group derived from an aromatic ring such as a phenyl or naphthyl group, which may not be substituted or have a substituent. Examples of the substituent include the following members.
(1) halogen atom;
(2) hydroxyl group;
(3) a lower alkyl group;
(4) a lower alkoxy group;
(5) a lower alkoxyalkoxy group;
(6) an amino group in which the nitrogen atom may be substituted;
(7) nitro group;
(8) cyano group;
(9) formyl group;
(10) a lower acyl group;
(11) an aromatic acyl group;
(12) a heteroarylcarbonyl group;
(13) a halogenated lower alkyl group;
(14) a lower alkoxyalkoxy group;
(15) a hydroxy(lower)alkyl group;
(16) a hydroxy(lower)alkoxy group;
(17) a lower alkoxycarbonyl group;
(18) a carbamoyl group in which the nitrogen atom may be substituted;
(19) a lower alkylsulfonyl group;
(20) a lower alkylsulfinyl group;
(21) a sulfamoyl group in which the nitrogen atom may be substituted;
(22) a lower acylamino group;
(23) a lower alkoxycarbonylamino group;
(24) a lower alkylsulfonylamino group;
(25) an arylsulfonylamino group in which the nitrogen atom may be substituted;
(26) a lower alkylsulfonyloxy group;
(27) an alkylenedioxy group;
(28) an aralkyl group;
(29) an aralkyloxy group; and
(30) a tri(lower)alkylsilyl group.
Among these, a halogen atom is more preferred. Specific examples of the halogen atom include fluorine, chlorine, bromine and iodine atoms. Chlorine or fluorine atom is more preferable with regards to pharmacological activity and safety.
The heteroaryl group which may be substituted refers to a group which is derived from a hateroaromatic ring and it may not be substituted or have a substituent. Specific examples thereof include furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl and pyrimidinyl groups. The substituent includes those described for the aryl group which may be substituted.
The benzoheteroaryl group which may be substituted refers to a group which is derived from a benzoheteroaromatic ring and may not be substituted or have a substitutent. Specific examples thereof include indolyl, benzothiazolyl, benzoimidazolyl, quinolyl, isoquinolyl, phthaladinyl, quinoxanyl and quinazolynyl groups. The substituent includes those described for the aryl group which may be substituted.
Herein, more specifically as the indole compound (I) according to the present invention, the following compounds may be proposed, but is not limited thereto.
(1) 1-[1-(2-Fluorophenethyl)piperidin-4-yl]-6-methylcarbamoylmethyl indole;
(2) 1-[1-(2-fluorophenethyl)piperidin-4-yl]-6-(N,N-dimethylcarbamoyl)methyl indole;
(3) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-methylcarbamoylmethyl indole;
(4) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-ethylcarbamoylmethyl indole; and
(5) 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-(1-piperidinylcarbonyl)methyl indole.
Sequentially, the 2-halogenated indole compound (II) according to the present invention is represented by the following formula:
wherein X represents a halogen atom; and R
1
, R
2
and n have the same meanings as defined above.
The 2-halogenated indole compound (II) is a novel compound and is useful as an intermediate in the novel process for the production of the indole compound (I) of the present invention.
More specifically as the 2-halogenated indole compound (II), the following compounds may be proposed, but is not limited thereto:
(1) ethyl [1-[1-(2-fluorophenethyl)piperidin-4-yl]-2-chloroindol-6-yl]acetate;
(2) ethyl [1-[1-(2-fluorophenethyl)piperidin-4-yl]-2-bromoindol-6-yl]acetate;
(3) ethyl [1-[1-(3-fluorophenethyl)piperidin-4-yl]-2-chloroindol-6-yl]acetate;
(4) ethyl [1-[1-(3-fluorophenethyl)piperidin-4-yl]-2-bromoindol-6-yl]aceta

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