Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-11
2001-07-31
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
06268512
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing 3-methyl-2-oxoindoline, which is a chemical intermediate for producing various fine chemicals including ketoprofen (chemical name: 2-(3-benzoylphenyl) propionic acid) which is known as an anti-inflammatory agent.
BACKGROUND ART
Various conventional processes for producing 3-methyl-2-oxoindoline (chemical formula (2)) have hitherto been proposed, typical examples of which are as follows:
(A) reduction of &agr;-(2-nitrophenyl) propionic acid (Ann., 227, 274 (1885)).
(B) heating of propionylphenylhydrazide (chemical formula (1)) using; calcium oxide (Monatsh., 18, 533 (1897)).
(C) heating of propionylphenylhydrazide using calcium hydride (Org. Syn., Coll. Vol., IV, 657).
(D) oxidation of skatole using persulfuric acid (J. Chem. Soc., 1958, 3726).
(E) heating of 2-chloropropionylanilide, which is produced by condensating aniline and 2-chloropropionyl chloride, in the presence of aluminum chloride (Tetrahededoron, 24, 6093 (1968), J. Med., Chem., 25, 446 (1970)).
(F) reaction of o-nitrotoluene to produce 2-(2-nitrophenyl) 1,3-propanediol by using formaldehyde in the presence of base, followed by oxidation thereof to produce 2-(2-nitrophenyl) propenal by dehydration using dimethylsulfoxide-dicyclohexylcarbodiimide, reaction thereof to produce epoxide using hydrogen peroxide, and reduction by hydrogenation (Bull. Chem. Soc., 62, 4061 (1989).
However, the process (A), in which the starting material has not been produced by an industrial process, needs numbers of steps and is not practical.
Although the process (B) is simple and excellent, a large amount of calcium oxide (secondary raw material) that is about four times as much as the main raw material in weight and that about ten times in molar ratio is consumed to advance the reaction. Therefore, as for after treatment of the reaction, since water addition accompanying heat generation and neutralization using a large amount of hydrochloric acid are necessary in order to treat the residual calcium oxide, it is very hard to implement iron an industrial scale.
In the process (C), calcium hydride is used instead of calcium oxide used in the process (B). However, calcium hydride is an expensive reagent, and the control of reaction is difficult since a rapid reaction takes place upon heating, and the after treatment of neutralizing excess calcium hydride is very difficult to implement, therefore the practice according to the process (C) in an industrial scale is very hard to implement.
In the process (D), the starting material, i.e. skatole is expensive, and the process does not result in an inexpensive process.
A supplementary test of the process (E) has revealed a generation of structural isomer, i.e. 2-oxazolinone (chemical formula (3)), separation of which is difficult even in its recrystallization refining. 2-oxazolinone has the same molecular formula and a similar structure with 3-methyl-2-oxoindoline, i.e. an objective chemical, and its separation by normal refining method such as recrystallization method is difficult to implement, therefore the process (E) is not practical.
The process (F) includes many steps and uses expensive reagents, therefore it is very hard to implement in an industrial scale.
Although 3-methyl-2-oxoindoline is a chemical intermediate (Japanese Patent Application No. H9-111236) for producing ketoprofen that has been proposed by the present inventors and is expected as a chemical intermediate for producing various fine chemicals from the viewpoint of its stricture, its producing process in an industrial scale has not yet been established.
The present inventors have already proposed an efficient process for producing ketoprofen (Japanese Patent Application No. H9-111236), in which 3-methyl-2-oxoindoline (chemical formula (2)) is benzoylated to be 5-benzoyl-3-methyl-2-oxoindoline, then an amide bond in a five-membered ring of which is cleavaged using a basic compound and then, a generated aromatic amino group is replaced by a hydrogen atom. An example of the reaction is shown in a chemical formula (4) as follows:
The above mentioned process (B) for producing 3-methyl-2-oxoindoline is an excellent process because inexpensive starting, materials are used, however according to the reference, a large amount of calcium oxide that is about four times as much as the main raw material of propionylphenylhydrazine in weight is used and therefore, its after treatment of the reaction is very difficult (see the following comparative example No. 1). A study has revealed that reducing the necessary amount of calcium oxide results in marked decrease in the yield (see the following comparative examples No. 2 and 3).
In addition, a further study has revealed that a certain amount of calcium oxide makes the reaction advance rapidly, therefore, the temperature control becomes difficult to implement (see the following comparative examples No. 4).
The present inventors have studied to solve the two problems mentioned above and reached the present invention in which an organic solvent such as tetrahn, which can stand at reaction temperature 190 to 230° C., can be employed so as to solve the problems.
It is therefore an objective of the present invention to provide an efficient process for producing 3-methyl-2-oxoindoline that is a key chemical intermediate for producing ketoprofen efficiently.
DISCLOSURE OF INVENTION
In order to attain the above objective, the present invention is to provide a process for producing 3-methyl-2-oxoindoline as defined by the following chemical formula (2), comprising heating of propionylphenylhydrazide as defined by the following chemical formula (1) in the presence of at least one kind of basic calcium compound, characterized in that an organic solvent withstanding at least at a temperature of 180° C. in the presence of the basic calcium compound is employed by at least an amount of equal weight to that of the propionylphenylhydrazide.
With the construction of the present invention mentioned above and as apparent from the following Examples, even when the amount of calcium oxide is reduced down to as little as 15% of a conventionally used amount, at least 75% of a corresponding yield attained conventionally has been achieved. That is, not only control of the reaction and easy after treatment but also a high yield has been achieved.
The starting material of the present invention, i.e. propionylphenylhydrazide (chemical formula (1)) can be easily synthesized with a high yield by a reaction between commercially available phenylhydrazine and anhydrous propionic acid.
As the secondary raw material of the present invention, basic calcium compounds such as calcium oxide, calcium carbide, calcium hydride and calcium alkoxide are suitably used. When calcium hydroxide or calcium carbonate is used, no reaction takes place or no desirable result is attained
From the viewpoints of the economy and easiness of the after treatment after the reaction, calcium oxide is most preferably used. In addition, a reactant system that can generate a basic calcium compound, for example, a reactant system consisting of calcium chloride, sodium hydride and sodium methoxide, is also included in the secondary raw material of the present invention.
The organic solvent withstanding at least at a temperature of 180° C. in the presence of the basic calcium compound is preferably a hydrocarbon having aromaticity such as tetralin and diisopropyl benzene, unsaturated hydrocarbon such as 1,5,9-cyclododecatriene, various amines such as xylidine, ethylaniline, diethylaniline, tributylamine, quinoline and 1,8-diazabicyclo[5,4,0]-7-undecene, ethers such as diphenyl ether, butylphenyl ether, hexyl ether and diethylene glycol dibutyl ether, and hydrocarbon containing halogen such as 1,2,4-trichlorobenzene, but the organic solvent is not limited to the above examples. Above all, tetralin is most preferably used since tetralin is inexpensive and easy to handle.
The organic solvent withstanding at least at a temperature of 180° C. in the presence of basic calcium
Higashikawa Tetsuro
Kondo Hisao
McDermott & Will & Emery
McKane Joseph K.
Medical Information Services, Inc.
Sackey Ebenezer
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