Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-05-24
2003-02-04
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
06515141
ABSTRACT:
TECHNICAL FIELD
This invention relates to a novel process for the preparation of a 3-acylindole or the salt thereof useful for various synthetic intermediates or bioactive compounds.
BACKGROUND ART
Acylation into the 3 position of an indole is conducted by conventional and general processes, such as Friedel-Crafts and Vilsmeier reactions. However, the indole is unstable in an acidic condition, for example in the presence of a Lewis acid, and decomposition occurs at the same time. Hence, the yield of the product is very low. Furthermore, in the case of a reaction conducted via an indolemagnesium intermediate using a Grignard reagent, the product generally cannot be obtained in a high yield. In an example of benzoyl chloride, the yield is low, 32%, according to C. Alberti, Gazz. Chim. Ital. 89, 1033 (1959). According to a recent report for solving this problem by C. Yang et al., Synthetic Communications, 27, 2125 (1997), an indolemagnesium intermediate is further converted into an indolezinc intermediate, and the intermediate undergoes a reaction in the presence of a Lewis acid, whereby the product is obtained in a high yield of 77%. However, the operations for this process are complicated. In addition, methylene chloride, Lewis acid and zinc, which may cause problems in environmental protection, are required to be processed. Hence, this process has many problems as an industrial synthesis process. In order to develop an industrial synthesis process that can be carried out at low cost without causing environmental problems, the inventors of this invention have made studies mainly on improvement in yield in an acylation reaction via an indolemagnesium intermediate.
SUMMARY OF THE INVENTION
This invention is intended to provide a novel process for the preparation of a 3-acylindole or the salt thereof at a high yield.
The inventors of this invention have made various studies on the reaction conditions of a Grignard reaction via an indolemagnesium intermediate.
Regarding an addition process, an acylation agent is added to an indolemagnesium intermediate according to literature. However, it was found that a high yield was obtained by reversing the order of the addition, that is, by adding the indolemagnesium intermediate to the acylation agent. Furthermore, the inventors of this invention have also made studies on reaction solvents, the preparation of a Grignard reagent, reaction temperatures, etc.
DISCLOSURE OF THE INVENTION
This invention relates to a process for the preparation of a 3-acylindole or the salt thereof by obtaining an intermediate activated by adding a Grignard reagent prepared by the action of an alkyl halide and magnesium in the presence of a base in a hydrocarbon-based solvent to an indole or the salt thereof under cooling, and by reacting the intermediate with an acylation agent under cooling.
As a result of studies on the industrial synthesis process for the 3-acylindole, the inventors of this invention have found that the 3-acylindole or the salt thereof can be obtained economically, excellently in environmental protection and easily in operation by obtaining an intermediate activated by adding the Grignard reagent prepared by the action of an alkyl halide and magnesium in the presence of a base in a hydrocarbon-based solvent to an indole or the salt thereof under cooling, and by reacting the intermediate with an acylation agent under cooling, and have completed this invention suited for synthesis in large volume.
Suitable salts for the compounds used for this invention are conventional non-toxic salts and include an acid addition salt such as an organic acid salt (e.g. acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.) and an inorganic acid salt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), or a salt with an amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.), or a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.), and the like.
Th e process for the preparation in accordance with this invention will be described below in detail.
The 3-acylindole or the salt thereof can be produced by obtaining an intermediate activated by adding the Grignard reagent prepared by the action of an alkyl halide and magnesium in the presence of a base in a hydrocarbon-based solvent to an indole or the salt thereof under cooling, and by reacting the intermediate with an acylation agent under cooling.
The acylation agent used for this invention is an acid halide that is used in the form of an acid cloride in particular. Suitable “acyl group” of the acylation agent may include a conventional acyl group used in the chemical field, for example, aromatic acyl such as benzil that may be substituted.
The hydrocarbon-based solvent may include, for example, benzene, toluene, hexane, heptane, etc.
Alkyl halide may include, for example, ethyl iodide, n-butyl iodide, n-propyl bromide, i-propyl bromide, etc.
The reaction is carried out in the presence of an inorganic base or an organic base, for example, alkali metal hydrogencarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzilamine, etc., in which triethylamine is preferable.
The reaction temperature is not critical and the reaction is usually carried out under cooling, preferably below 20° C., more preferably below 10° C.
The compound obtained according to the above-mentioned process can be isolated and purified in a conventional manner, for example, pulverization, recrystalization, column chromatography, reprecipitation, and the like.
REFERENCES:
patent: 5013837 (1991-05-01), Ward et al.
patent: 149419 (1985-07-01), None
patent: 171037 (1986-02-01), None
patent: 0592438 (1997-08-01), None
patent: 96/07660 (1996-03-01), None
E. Wenkert et al.: “Yuehchukene analogues” J. Org. Chem., vol. 53, pp. 3170-3177 1988.
Goto Shunsuke
Ike Kazuo
Takasuka Kiyoaki
Fujisawa Pharmaceutical Co. Ltd.
McKane Joseph K.
Small Andrea D.
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