Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-08-07
1997-12-09
McKane, Joseph
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548248, C07D26104
Patent
active
056962711
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP95/00211 filed Feb. 15, 1995.
FIELD OF THE INVENTION
This invention relates to a process for the preparation of 3-isoxazolecarboxylic acid which is useful as an intermediate for producing condensed imidazopyridine derivatives which are described, for example, in Japanese Patent Publication (Kokai) No. 286973/1993 and its corresponding European Patent Publication No. 556008A.
DESCRIPTION OF PRIOR ART AND PROBLEMS TO BE SOLVED
3-Isoxazolecarboxylic acid has been synthesized by various methods. For instance, as shown in the reaction scheme below, ethoxycarbonylnitrile oxide was reacted with vinylethyl ether to obtain ethyl 5-ethoxyisoxazoline-3-carboxylate, and then the ethoxy group was removed Tchelitcheff, Bull. Soc. Chim. France 1962, 2215!. ##STR2##
This method, however, has a disadvantage that the ethyl chloroximinoactate, a starting material of the nitrile oxide, upon touching skin, could cause a rash on the skin.
Further, in J. Chem. Soc., Chem. Commun., 17 (1991), a method for the preparation of ethyl 3-isoxazolecarboxylate is described. This method uses ethyl chloroximinoacetate as a starting material, which also causes a rash on the skin, and it is hard to handle.
J. Org. Chem. 26, 2976 (1961) discloses, a method for the preparation of 3-isoxazolecarboxylic acid as shown in the reaction scheme below. This method is not suitable for industrial production of the acid because of its poor reaction efficiency. ##STR3##
In view of the above problems, the inventors of the present invention have explored an industrially-applicable synthetic method for 3-isoxazolecarboxylic acid, and they have developed a novel process for the preparation of the acid.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of 3-isoxazolecarboxylic acid of the formula (III): ##STR4## characterized in that a compound of the formula (I): ##STR5## wherein R.sup.1 is a lower alkyl, R.sup.2 is a carboxy protecting group, X is a halogen atom, and Y is a hydrogen atom, or X and Y together may form a single bond, is reacted with hydroxylamine to obtain a compound of the formula (II): ##STR6## wherein R.sup.1 and R.sup.2 are as defined above, and then the resultant product is treated with alkali.
Each step of the above overall process also constitues another invention. That is, the process for the production of 5-alkoxyisoxazoline-3-carboxylic acid derivatives of the above formula (II), which process is characterized in that a compound of the formula (I): ##STR7## wherein R.sup.1, R.sup.2, X and Y are as defined above, is reacted with hydroxylamine, is also part of the present invention.
Further, a process for the production of 3-isoxazolecarboxylic acid of the formula (III): ##STR8## which process is characterized in that a compound of the formula (II): ##STR9## wherein R.sup.1 is a lower alkyl and R.sup.2 is a carboxy protecting group, is treated with alkali, is also part of the present invention.
The process of the present invention may be shown in the following reaction scheme. ##STR10## hydroxylamine. The reaction temperature is usually from about -20.degree. to about 80.degree. C., preferably from 0.degree. to 40.degree. C. The reaction is carried out in the presence or absence of a solvent. As the solvent, ethers (ethyl ether, tetrahydrofuran, etc.), aromatic hydrocarbons (benzene, toluene, etc.), and halogenated hydrocarbons (chloroform, dichloromethane, etc.) may be exemplified. Hydroxylamine may be used preferably in an amount of about 1 to 4 molar equivalents to the starting material.
The starting materials (a) and (b) may be prepared according to the following reaction scheme as described in L. F Tietze, Synthesis, 274 (1988): ##STR11##
Although this reaction produces a mixture of the compounds (a) and (b), the compound (a) is readily converted into the compound (b) during isolation and purification for example, by distillation, thereby the single compound (b) is obtained. The compound (a) is known to be unstable as intermediate, and i
REFERENCES:
patent: 5514505 (1996-05-01), Limburg et al.
Otto Mumm et al., "Uber die freie Aceton-oxalsaure und ihre Abkommlinge", Chemische Berichte, vol. 45, 1912, pp. 3042,3045,3046.
"Dehydrochlorination of Hydroximic Acid Chlorides by the Use of Organotin Compounds: An Application for Synthesis of Isoxazolines and Isoxazoles", Moriya et al., J. Chem. Soc. pp. 17-18 vol 1., 1991.
Chomei Nobuo
Takada Susumu
Uenaka Masaaki
McKane Joseph
Shionogi & Co. Ltd.
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