Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-02
2002-04-16
Stockton, Laura L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06372915
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel production method of an oxazole compound of the formula [7] having a selective inhibitory action on cyclooxygenase-2 (COX-2)
wherein R
1
is an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, R
2
is a lower alkyl or a halogenated lower alkyl, and R
3
is a halogen atom or a hydrogen atom. The present invention also relates to a method for producing intermediates for the production of a compound of the above-mentioned formula [7].
BACKGROUND ART
The above-mentioned compound [7], which selectively inhibits cyclooxygenase-2 (COX-2), is useful as, for example, an antiinfammatory agent. The production method of compound [7] has been already disclosed in the specification of W096/ 19463.
However, the conventional production methods require many treatment steps and the yields of the final product and intermediates therefor are not entirely satisfactory. In addition, the reagent, solvent and the like to be used in each step suffice for use only at laboratory levels and many of them are problematically impractical and cannot be used in industrial production.
DISCLOSURE OF THE INVENTION
The present inventors have studied respective steps in detail and improved them. To be specific, they considered the production method (hereinafter to be referred to as method A) disclosed in W096/ 19463, which is most similar to the present invention.
According to the method A, compound [7′], which is one of the objective compounds of the present invention, is produced by the following Steps 1-4.
Step 1
According to method A, compound [1′] is reacted with ethyl chlorocarbonate in ethyl acetate in the presence of triethylamine to give compound [2′]. When ethyl chlorocarbonate is used as a reagent in this step, ethanol is generated as a by-product and decomposes compound [2′]. To prevent this, a complicated post-treatment such as desalting filtration and concentration is needed after the main reaction, cyclization. Thus, method A is associated with a complicated post-treatment and lower yield of compound [2′] due to the generation of the by-product. The present inventors considered using economical thionyl chloride instead of ethyl chlorocarbonate to solve this problem. As a result, they have found that the use of thionyl chloride obliterates the above-mentioned complicated post-treatment and generation of the by-product, which has led to an improvement in the yield. It has been also found that the unstable compound [2′] can be used in the next step without isolation or purification. These improvements have achieved an increase in the yield.
Step 2
In method A, compound [2′] is reacted with compound [3′] in a tetrahydrofuran suspension of magnesium chloride in the presence of triethylamine to give compound [4′]. Tetrahydrofuran used as a reagent and solvent in this step is not a most suitable solvent in terms of cost, when industrially used in a large amount. Thus, the present inventors have studied solvents to find out a solvent economical and suitable for industrial production, as well as from the aspect of an improved yield. Consequently, they have found that ethyl acetate, which is recited in the specification of WO96/ 19463 as a general example but is not specifically disclosed as an example, can be used to conduct this reaction similarly. This change of solvent offers merits of not only low cost but omission of concentration of the reaction solvent before extraction in the next step (Step 3). This has offered a simultaneous resolution to the problems of reduction of cost and increase in yield. In addition, they have found that the unstable compound [4′] can be used in the next step without isolation or purification. These improvements resulted in an increased yield.
Step 3
In method A, hydrochloric acid is added to compound [4′] in trahydrofuran to allow hydrolysis and decarboxylation. Subsequently, compound [5′] is obtained through post-treatment of concentration of the reaction solvent (tetrahydrofuran), extraction, concentration of the extraction solvent and the like. The present inventors changed tetrahydrofuran, the solvent used in the previous step (Step 2), to ethyl acetate and conducted Step 3 in ethyl acetate, whereby they have succeeded in omitting a step for concentration of tetrahydrofuran before extraction. This has led to the improved yield of compound [5′].
When compared in the yields of Compound [5′] from compound [1′], it was 67.7% by method A but 84.7% by the present invention, thus achieving a 17% increase in the yield.
Step 4
In method A, compound [5′] is reacted with chlorosulfonic acid in chloroform to give compound [6′]. Further, by reacting this compound with aqueous ammonia in tetrahydrofuran without isolation, objective compound [7′] is obtained. The solvent used here is chloroform, which has strong toxicity and is problematic for industrial use. The present inventors have overcome this problem by the use of a method generally exemplified in the specification of WO96/19463 but not specifically shown as an example. Surprisingly, the reaction was found to proceed as smoothly as when chloroform was used, even without a solvent.
The method A is not satisfactory in terms of the yield of the objective compound [7′]. According to method A, compound [7′] is obtained through a post-treatment of concentration of the reaction solvent (tetrahydrofuran), extraction, concentration of the extraction solvent and the like. Like Step 2, the present inventors changed the solvent for amidation from tetrahydrofuran to ethyl acetate to omit concentration of tetrahydrofuran before extraction.
This has led to the elimination of problems associated with the prior art technique, and the yield of compound [7′] from compound [5′] was increased by about 5% from 77.2% to 82.0%.
As mentioned above, the present inventors studied the problems in each step in detail with the aim of improving the yield of the objective compound and establishing the method capable of affording industrial production, and they have found that the use of the above-mentioned solvent, reagent and the like in each step results in the production of the objective compound at a high yield and also an industrially practical production method, which resulted in the completion of the present invention.
Accordingly, the present invention provides the following (1) to (9).
(1) A production method of an oxazole compound of the formula [7]
wherein R
1
is an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, R
2
is a lower alkyl or a halogenated lower alkyl and R
3
is a halogen atom or a hydrogen atom, comprising reacting a compound of the formula [1]
wherein R
1
and R
2
are as defined above, with thionyl chloride in an inert solvent in the presence of a base, to give an oxazolone compound of the formula [2]
wherein R
1
and R
2
are as defined above, subsequently reacting this compound with a compound of the formula [3]
wherein R
3
is as defined above and X is a halogen atom, in ethyl acetate in the presence of a magnesium salt and a base to give a compound of the formula [4]
wherein R
1
, R
2
and R
3
are as defined above, subjecting this compound to hydrolysis and decarboxylation with an acid to give a compound of the formula [5]
wherein R
1
, R
2
and R
3
are as defined above, subjecting this compound to cyclization and sulfonation with a sulfonating agent and chlorination with thionyl chloride to give a compound of the formula [6]
wherein R
1
, R
2
and R
3
are as
Akamatsu Minoru
Hara Katsuyoshi
Matsuda Koji
Japan Tobacco Inc.
Stockton Laura L.
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