Intermediates for the synthesis of benzimidazole derivatives...

Details Intermediates for the synthesis of benzimidazole derivatives... Intermediates for the synthesis of benzimidazole derivatives...

2002-10-16

2004-06-22

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C560S020000, C560S022000

Reexamination Certificate

active

06753347

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a process for the preparation of benzimidazole derivatives and pharmaceutically acceptable salts thereof exhibiting excellent hypoglycemic action and intermediates for their synthesis.
BACKGROUND OF THE INVENTION
Some benzimidazole derivatives having hypoglycemic activity and pharmaceutically acceptable salts thereof and a process for the preparation of these derivatives are disclosed in Japanese Patent Application Publication Hei-9-295970 (European Patent Application Publication number 00745600 and U.S. Pat. No. 5,886,014).
The known method for the preparation of the benzimidazole derivatives comprises:
1) protection of the amino group of a nitroaniline derivative,
(wherein A is an amino protecting group, R is methoxy and the like);
2) a few reactions via the amino-protected nitroaniline derivative to afford an N-methyl-1,2-phenylenediamine derivative, and
3) reaction of the N-methyl-1,2-phenylenediamine derivative by heating with a methoxycarbonylmethyloxybenzylthiazolidinone derivative in the presence of an acid to produce a benzimidazole derivative shown below.
(wherein R is methoxy and the like)
In the method disclosed in Japanese Patent Application Publication Hei-9-295970 (U.S. Pat. No. 5,886,014), the overall yields of the benzimidazole derivatives, especially the two reactions shown above, are low and this method can not practically be used. A practical large scale method for the synthesis of the benzimidazole derivatives is needed, in which method the product is of good purity and is obtained by easy procedures using cheap starting materials, and in good yield.
SUMMARY OF THE INVENTION
We made many efforts in order to find a good synthetic method for a large scale preparation of the benzimidazole derivatives for a long time. We found a good method for the preparation which comprises the reaction of a group of carboxylic acid derivatives with a group of optionally protected amine derivatives.
This invention provides a process for the preparation of the benzimidazole derivatives exhibiting excellent hypoglycemic action or a pharmaceutically acceptable salt thereof and their important synthetic intermediates.
DETAILED DESCRIPTION OF THE INVENTION
This invention is directed to synthetic intermediates of formulae [1], [2] and [3] and processes for preparation illustrated in [4] and [5].
[1] A compound of formula (1) (which is referred to as compound (1) hereinafter) or a pharmaceutically acceptable salt thereof,
(wherein R
1a
, R
2a
, R
3a
and R
4a
are each independently hydrogen, hydroxyl, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, benzyloxy, acetoxy, trifluoromethyl or halogen, and R
5a
and R
6a
are each independently an amino protecting group).
Preferable compounds of formula (1) are:
[1-1] compounds and pharmaceutically acceptable salts thereof according to [1] wherein R
5a
and R
6a
are each independently t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl;
[1-2] compounds and pharmaceutically acceptable salts thereof according to [1] wherein R
5a
and R
6a
are each t-butoxycarbonyl;
[1-3] compounds and pharmaceutically acceptable salts thereof according to any one of [1], [1-1] or [1-2] wherein R
1a
, R
2a
, R
3a
and R
4a
are each independently hydrogen or C
1
-C
4
alkoxy;
[1-4] compounds and pharmaceutically acceptable salts thereof according to any one of [1], [1-1] or [1-2] wherein R
1a
, R
2a
, R
3a
and R
4a
are each independently hydrogen or methoxy; and
[1-5] compounds and pharmaceutically acceptable salts thereof according to [1] wherein R
1a
, R
2a
and R
4a
are each hydrogen, R
3a
is methoxy, and R
5a
and R
6a
are each t-butoxycarbonyl.
The C
1
-C
6
alkyl group of compound (1) is a C
1
-C
6
straight or branched chain alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl, preferably C
1
-C
4
alkyl, more preferably methyl or ethyl and most preferably methyl.
The C
1
-C
6
alkoxyl group of compound (1) is a C
1
-C
6
alkyl described above group attached to an oxygen atom, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, 1-ethylpropoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy or 2-ethylbutoxy, preferably C
1
-C
4
alkoxy, more preferably methoxy or ethoxy and most preferably methoxy.
The halogen atom of compound (1) is, for example, fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
The amino protecting group in the definition of compound (1) is, for example, t-butoxycarbonyl; trityl; (C
6
-C
10
)aryl-methyl, which is optionally substituted with C
1
-C
6
alkyl, C
1
-C
6
alkoxy or halogen, such as benzyl, methylbenzyl, methoxybenzyl, chlorobenzyl, bromobenzyl and naphthylmethyl; or (C
6
-C
10
)aryl-methyloxycarbonyl, which is optionally substituted with C
1
-C
6
alkyl, C
1
-C
6
alkoxy or halogen, such as benzyloxycarbonyl, methylbenzyloxycarbonyl, methoxybenzyloxycarbonyl, chlorobenzyloxycarbonyl, bromobenzyloxycarbonyl and naphthylmethyloxycarbonyl. t-Butoxycarbonyl, benzyl, p-methoxybenzyl, p-bromobenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl and p-bromobenzyloxycarbonyl are preferred; t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl and p-bromobenzyloxycarbonyl are more preferred and t-butoxycarbonyl is particularly preferred.
In compound (1), preferably R
1a
, R
2a
, R
3a
and R
4a
are each independently hydrogen or C
1
-C
4
alkoxy; more preferably R
1a
, R
2a
, R
3a
and R
4a
are each independently hydrogen or methoxy; and most preferably R
1a
, R
2a
and R
4a
are each hydrogen and most preferably R
3a
is methoxy; and preferably R
5a
and R
6a
are each independently t-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-bromobenzyloxycarbonyl and more preferably R
5a
and R
6a
are each t-butoxycarbonyl.
Pharmaceutically acceptable salts in the definition of salts of compound (1) are, for example, hydrohalogenides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide; perchlorates; sulfates; phosphates; carbonates; C
1
-C
6
alkylsulfonates, which are optionally substituted with fluorines, such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, pentafluoroethanesulfonate, propanesulfonate, butanesulfonate, pentanesulfonate and hexanesulfonate; C
6
-C
10
arylsulfonates such as benzenesulfonate and p-toluenesulfonate; carboxylic acid salts such as acetate, propionate, butyrate, benzoate, fumarate, maleate, succinate, citrate, tartarate, oxalate and malonate; and amino acid addition salts such as glutamate and aspartate. Hydrochlorides, sulfates, and carboxylic acid salts are more preferred, and hydrochlorides are particularly preferred. The pharmaceutically acceptable salts of this invention include hydrates and solvates of organic solvents.
Typical compounds of formula (1) are exemplified in the Tables 1 to 4. Throughout the tables the following abbreviations are used with the following meaning:
Exp. Comp. No: Exemplification compound number
Me: methyl, Et: ethyl, Pr: propyl, iPr: isopropyl, Bu: butyl, iBu: isobutyl, sBu: secondary butyl, tBu: tertiary butyl, Bz: benzyl, Ac: acetyl, Boc: tertiary butoxycarbonyl, Z: benzyloxycarbonyl, Moz: p-methoxybenzyloxycarbonyl, 4BrZ: p-bromobenzyloxycarbonyl
TABLE 1
(1)


Exp.
Comp. No.
R
1a
R
2a
R
3a
R
4a
R
5a
═R
6a
1-1
H
H
H
H
Boc
1-2
H
H
MeO
H
Boc
1-3
H
H
EtO
H
Boc
1-4
H
H
PrO
H
Boc
1-5
H

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