Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-26
2002-07-23
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06423849
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a process of preparing a 5-(2-substituted-4-nitrophenyl)-oxazole useful as a starting material of pharmaceuticals, such as an intermediate of a treating agent for hepatitis C and an anticancer agent; a novel oxazole compound, and a process of preparing the novel oxazole compound, particularly a manipulation for isolating the novel oxazole compound from a reaction mixture.
2. Description of the Related Art
A process of preparing a 5-(2-substituted-4-nitrophenyl)-oxazole is described in WO97/40028, in which 2-methoxy(or chloro)-4-nitrobenzaldehyde and tosylmethyl isocyanide are allowed to react.
Known oxazole compounds having a substituent include, for example, a 5-substituted-oxazole-4-carboxylic acid as disclosed in JP-A-Hei.4-134078. The substituents disclosed are substituted phenyl groups, and specific examples of the substituted phenyl groups disclosed are a p-toluyl group and a p-chlorophenyl group. The contemplated use of the oxazole compound in JP-A-Hei.4-134078 is an intermediate of antibiotics only.
The above-described process is disadvantageous in that the starting material is expensive and that the process involves by-products, such as toluenesulfinic acid, treatment of which incur high cost. Therefore it has been demanded to develop an industrially practical process which uses inexpensive starting materials and involves less production of by-products.
The inventors of the present invention had continued researches on novel oxazole compounds useful as a starting material of pharmaceuticals, such as an intermediate of a treating agent for hepatitis C and an anticancer agent, and a process for producing the same, particularly a process of isolating a desired compound from a reaction mixture efficiently.
The present inventors have found that decarboxylation of a 5-(2-substituted-4-nitrophenyl)-oxazolecarboxylic acid, which is a novel compound, provides a 5-(2-substituted-4-nitrophenyl)-oxazole without the above-described problems of the related art and thus completed the present invention.
They have also found that a 5-(2-substituted-4-nitrophenyl)-4-carboalkoxyoxazole, which is a novel compound, can be obtained in high purity through an industrially convenient operation by allowing a 2-substituted-4-nitrobenzoic acid and an isocyanoacetic acid or a derivative thereof to react in an organic solvent and adding water to the reaction mixture to precipitate crystals of the 5-(2-substituted-4-nitrophenyl)-4-carboalkoxyoxazole, which is collected by filtration.
SUMMARY OF THE INVENTION
An object of the invention is to provide a process of producing a 5-(2-substituted-4-nitrophenyl)-oxazole which is useful as a starting material of pharmaceuticals such as a treating agent of hepatitis C and an intermediate of an anticancer agent.
Another object of the invention is to provide a novel oxazole compound useful as a starting material of pharmaceuticals, such as an intermediate of an anticancer agent.
Still another object of the invention is to provide a process of producing the novel oxazole compound.
The present invention is especially achieved by the following means.
(1) A process of preparing a 5-(2-substituted-4-nitrophenyl)-oxazole comprising decarboxylating a 5-(2-substituted-4-nitrophenyl)-4-oxazolecarboxylic acid.
(2) The process according to (1), wherein the decarboxylation is carried out in an aprotic amide solvent containing a protic compound.
(3) The process according to (2), wherein the protic compound is water.
(4) The process according to any one of (1) to (3), wherein the decarboxylation is carried out at 70 to 140° C.
(5) The process according to any one of (1) to (4), wherein water is added to the reaction mixture after completion of the decarboxylation to precipitate the 5-(2-substituted-4-nitrophenyl)-oxazole at a high purity.
(6) The process according to any one of (1) to (5), wherein the 5-(2-substituted-4-nitrophenyl)-4-oxazolecarboxylic acid is a wet cake which is obtained by hydrolyzing a 5-(2-substituted-4-nitrophenyl)-4-carboalkoxyoxazole in an aqueous medium and filtering the reaction mixture.
(7) The process according to any one of (1) to (6), wherein the 5-(2-substituted-4-nitrophenyl)-oxazole is 5-(2-methoxy-4-nitrophenyl)-oxazole.
(8) The process according to any one of (1) to (6), wherein the 5-(2-substituted-4-nitrophenyl)-oxazole is 5-(2-chloro-4-nitrophenyl)-oxazole.
(9) The process according to any one of (1) to (8), wherein the 5-(2-substituted-4-nitrophenyl)-4-oxazolecarboxylic acid is a wet cake which is obtained by allowing a 2-substituted-4-nitrobenzoic acid or a derivative thereof and an isocyanoacetic acid or a derivative thereof in an organic solvent, adding water to the reaction mixture to precipitate crystals, collecting the crystals by filtration to obtain a 5-(2-substituted-4-nitrophenyl)-4-carboalkoxyoxazole, hydrolyzing the 5-(2-substituted-4-nitrophenyl)-4-carboalkoxyoxazole in an aqueous medium and filtering the reaction mixture.
(10) The process according to (9), wherein water, which is added to the reaction mixture after the reaction with a 2-substituted-4-nitrobenzoic acid or a derivative thereof and an isocyanoacetic acid or a derivative thereof in an organic solvent, is added in an amount of 0.5 to 4 parts by weight per part by weight of the organic solvent.
(11) An oxazole compound which is 5-(2-substituted-4-nitrophenyl)-4-oxazolecarboxylic acid.
(12) An oxazole compound which is 5-(2-substituted-4-nitrophenyl)-4-carboalkoxyoxazole
(13) A process of preparing a 5-(2-substituted-4-nitrophenyl)-oxazolecarboxylic acid comprising hydrolyzing a 5-(2-substituted-4-nitrophenyl)-carboalkoxyoxazole in an aqueous medium.
(14) A process of preparing a 5-(2-substituted-4-nitrophenyl)-4-carboalkoxyoxazole comprising allowing a 2-substituted-4-nitrobenzoic acid or a derivative thereof and an isocyanoacetic acid or a derivative thereof.
(15) The oxazole compound according to (11) or (12), wherein the substituent at the 2-position of the nitrophenyl moiety is an alkoxy group or a halogen atom.
DETAILED DESCRIPTION OF THE INVENTION
Examples of the above substituent (i.e., the substituent at the 2-position of the nitrophenyl moiety) include an alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy) and a halogen atom (e.g., chloro, bromo). Preferred examples thereof includes methoxy, ethoxy and chloro.
The 5-(2-substituted-4-nitrophenyl)-oxazole prepared by the process of the invention is represented by formula (I):
wherein R
1
represents a substituent.
Useful substituents as R
1
include an alkoxy group (e.g., methoxy, ethoxy, propoxy or butoxy) and a halogen atom (e.g., chlorine or bromine), with a methoxy group, an ethoxy group and a chlorine atom being preferred.
Specific examples of the oxazole compound represented by formula (I) are 5-(2-methoxy-4-nitrophenyl)-oxazole, 5-(2-ethoxy-4-nitrophenyl)-oxazole, and 5-(2-chloro-4-nitrophenyl)-oxazole.
The oxazole compound (I) can be produced by decarboxylating a 5-(2-substituted-4-nitrophenyl)-4-oxazolecarboxylic acid (hereinafter referred to as an oxazolecarboxylic acid). The reaction is preferably carried out in an aprotic amide solvent containing at least one protic compound.
Examples of the aprotic amide include N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N,N,N′,N′-tetramethylurea, N-methylpyrrolidone, and N-formylpiperidine. From the standpoint of boiling point, yield, and cost, N,N-dimethylformamide is particularly preferred among them. Other solvents can be used in combination as long as is consistent with the scope of the invention.
Useful protic compounds include alcohols, carboxylic acids, phenols, and water. Water and alcohols are preferred from the viewpoint of yield, handling properties, ease of isolating a desired compound, and cost.
Examples of the alcohols include aliphatic ones, such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, sec-butanol, t-butanol, n-amyl alcohol, isoamyl alcohol, hexanol, and octanol; alicyclic ones, such as c
Hirata Kazumasa
Katsuura Akio
Tsuzuki Keisuke
Yonezawa Azusa
McKane Joseph K.
Rader & Fishman & Grauer, PLLC
The Nippon Synthetic Chemical Industry Co., Ltd.
Wright Sonya
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