Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1998-08-18
2001-03-13
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
active
06201121
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for efficiently preparing a 3-dihalobenzyl-2,4-quinazolinedione derivative represented by FK366 {chemical name: 1-carboxymethyl-3-[(2-fluoro-4-bromo)benzyl]-7-chloro-2,4(1H, 3H)-quinazolinedione}, which is useful as inhibitors against aldose reductases.
More particularly, the present invention relates to a process for preparing a 3-dihalobenzyl-2,4-quinazolinedione derivative, which can be conducted in one pot using a 2,4-quinazolinedione derivative having a carboxyalkyl group at the 1-position of 2,4-quinazolinedione skeleton as the starting material. The process is superior in handling, makes it possible to give the desired compound in a high yield and purity, being useful from the viewpoint of efficiency and the safety and hygiene of workers.
BACKGROUND ART
To prevent and/or treat disorders accompanied with a disorder of polyol metabolism (e.g. neuropathy, retinopathy, nephropathy, etc.) among disorders accompanied with diabetes, the development of representative inhibitors against aldose reductases FK366 represented by the following formula:
has been progressed.
To prepare the above FK366, 2,4-quinazolinedione derivative having a carboxyalkyl group represented by the formula (I):
is an important intermediate. As the process of preparing this intermediate, for example, the following processes have been reported [Chemistry Express, vol.8, no.9, p.761-764 (1993)]:
{circle around (1)}: a process of heating N-alkylanthranilic acid with urea and closing the ring,
{circle around (2)}: a process of subjecting anthranylamide to introduction reaction of carbonyl group by means of phosgene, and the like, to give a quinazolinedione derivative having carboxyalkyl groups not only at the 1-position but also the 3-position,
{circle around (3)}: a process of subjecting a phenylurea derivative obtained by reaction between anthranilic acid and isocyanate to ring-closing reaction to give a quinazolinedione derivative having a carboxyalkyl group at the 3-position, not at the 1-position,
{circle around (4)}: a process of comprising: subjecting a quinazolinedione derivative obtained from 4-chloroanthranyl acid to silylation reaction to give a silylquinazoline derivative; selectively reacting the resulting silylquinazoline derivative at the 1-position with ethyl bromoacetate; and subjecting the reaction product to desilylation reaction to give a quinazolinedione derivative having an ethoxycarbonylmethyl at the 1-position.
However, the above process {circle around (1)} to {circle around (3)} are usually conducted at high temperature (150° C. or more) and by means of toxic reagents (e.g. phosgene, isocyanate, etc.), and they have many problems about yield and handling from an industrial point of view. Furthermore, the above process {circle around (4)}, which is represented by the following reaction scheme:
includes a lot of problems about the operation as follows:
(i) an irritant alkylating agent must be used to selectively subject the quinazolinedione derivative to alkylation reaction at the 1-position of the derivative in the first step;
(ii) because of alkylating of the 1-position of the derivative in the first step, it is required to subject the alkylated derivatives to the silylation reaction; and
(iii) comparatively expensive anthranilic acid is used as a starting material.
Furthermore, an alkylating agent to be used in the above alkylation must be used in combination with a solvent to increase the yield of the desired intermediate.
Accordingly, it has been required to provide a process, which is superior in handling and safety, facilitates waste disposal, and makes it possible to obtain the desired intermediate at low cost. It has also been required to provide a process capable of efficiently obtaining 3-dihalobenzyl-2,4-quinazolinedione derivative as a final desired product by using this intermediate.
DISCLOSURE OF THE INVENTION
Accordingly, an object of the present invention is to provide a process capable of efficiently preparing a 3-dihalobenzyl-2,4-quinazolinedione derivative represented by the following formula (V) including a representative inhibitors against aldose reductases FK366.
Another object of the present invention is to provide a novel process capable of preparing the compound (I), which is a useful intermediate for preparing the above compound (V), in a high yield and purity by using a simple operation under a moderate reaction condition.
BEST MODE FOR CARRYING OUT THE INVENTION
The present inventors have studied about a process of using 2,4-dihalobenzoic acid (VI) which is available easily to the industry, at low cost instead of comparatively expensive anthranilic acid conventionally used as the starting material to achieve the above object. However, a process of preparing the desired intermediate compound (I) in a high yield and purity through a compound (VIII) has never been known comprising selectively reacting the group at the 2-position of the above 2,4-dihalobenzoic acid (VI) with an amino acid derivative to give the compound (VIII).
The present inventors have intensively studied about the above process. As a result, by reacting 2,4-dihalobenzoic acid (VI) with an amino acid derivative in the presence of a copper containing catalyst, a derivative wherein a halogen at the 2-position of the above compound (VI) is selectively substituted could be obtained in a high yield and purity. Furthermore, the present inventors have found that the intermediate compound (I) useful for preparing FK366 (inhibitors against aldose reductases) can be obtained efficiently in a high yield under moderate condition by reacting the derivative obtained above with cyanic acid or its salts or urea and subjecting the reaction product to ring formation reaction. Thus, the present invention has been accomplished.
Furthermore, the present inventors have found a simple process capable of preparing 3-dihalobenzyl-2,4-quinazolinedione derivative (V) as the final desired product in a high yield and purity by means of the intermediate compound (I) thus obtained in one pot. That is, the present invention relates to a process characterized by conducting the following whole step in one pot comprising: introducing a carboxy protective group into the intermediate compound (I) as a starting material to give a compound having the carboxy protective group; reacting the compound obtained with a dihalobenzyl derivative in the presence of a suitable alcohol solvent to give a compound whose group at the 3-position is benzylated; and subjecting the compound obtained to elimination reaction of the carboxy protective group. Furthermore, the present inventors have intensively studied about the processes and found that a hydrogen atom of an imino group at the 3-position of the intermediate compound (I) can be selectively benzylated in the above process of the present invention. The whole preparation step of the final desired compound (V) of the present invention is illustrated as follows.
In obtaining the final desired compound (V), the process of preparing the compound of the formula (I) as an important intermediate can be roughly divided into two manners as follows.
(wherein
X
1
, X
2
and X
3
are independently a halogen atom;
A is an alkylene group;
R
1
is a protected carboxy group;
R
2
is a group to be carboxy group by hydrolysis or oxidation;
L is an acid residue)
The above whole process is summarized as follows.
First, a process for preparing the final desired compound (V) can be divided into the following two manners:
Process A
{circle around (1)} A step of introducing a carboxy protective group into the intermediate compound (I);
{circle around (2)} without isolating the resulting reaction product, a step of reacting it with a dihalobenzyl derivative of the compound (III) to benzylate its 3-position group;
{circle around (3)} without isolating the resulting reaction product, a step of subjecting it to elimination reaction of the carboxy protective group to give the final desired compound (V).
Process B
{circle aroun
Inamoto Yoshitaka
Kamiya Takashi
Masumoto Masayuki
Takehara Hiroyuki
Taniguchi Akihito
Balasubramanian Venkataraman
Fuji Chemical Industry Co., Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Raymond Richard L.
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