Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-11
2002-10-01
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C544S219000, C546S133000, C548S190000, C560S001000, C560S008000, C560S009000, C560S012000, C564S123000, C564S138000, C564S139000
Reexamination Certificate
active
06458948
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method of preparing carboxylic acid derivatives and, particularly, amide compounds or ester compounds.
The invention further relates to a condensing agent comprising a quaternary ammonium salt and, particularly, to a condensing agent that is preferably used for the preparation of amide compounds or ester compounds.
BACKGROUND ART
Carboxylic acid derivatives and, particularly, amide compounds and ester compounds are very important compounds for forming basic skeleton of various organic compounds such as medicine, agricultural chemicals, dyestuffs, high-molecular compounds, etc. Therefore, study has long been forward concerning how to prepare carboxylic acid derivatives.
As methods of preparing amide compounds, for example, there have generally been proposed a method of preparing amide compounds by the exchange reaction of ester compounds with amine compounds, as well as a method of preparing amide compounds directly from carboxylic acid compounds and amine compounds. As methods of preparing ester compounds, there have been generally proposed a method of preparing ester compounds directly from carboxylic acid compounds and alcohol compounds in the presence of an acid, and a method of preparing ester compounds by forming a carboxylic acid halide by reacting carboxylic acid compounds with an acid halide agent such as thionyl chloride, and acting it upon an alcohol compound.
However, the method of preparing amide compounds is conducted under a heated condition, and cannot be applied to the compounds that are thermally unstable or to the compounds having an amino group and an alkoxycarbonyl group in the same molecule. Further, the method of preparing ester compounds is conducted under an acidic condition, and cannot be applied to compounds that are not stable against acids.
In order to solve this problem, a variety of methods have been proposed by using a condensing agent for preparing amide compounds under mild conditions. A method that is most widely used industrially is the one that uses carbodiimide condensing agents as represented by a dicylohexylcarbodiimide and a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.
However, many of the carbodiimide condensing agents are those compounds that cause such problems as a rash, and require careful attention from the standpoint of working environment. Besides, when they are used for the condensation reaction in protonic organic solvent, a high reaction yield is not expected.
While the carbodiimide condensing agents cause rash to the skin and require attention for the handling thereof, a 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride proposed as a condensing agent for the synthesis of amide compounds by Z. J. Kaminski et al. [Journal of Organic Chemistry, Vol. 63, pp. 4248-4255, 1998] is free from the above-mentioned problem and is drawing attention.
As a method of preparing ester compounds under mild conditions, further, a method has been proposed by Mukaiyama et al. that uses a condensing agent comprising a pyridinium oxide compound (Bulletin of Chemical Society of Japan, Vol. 50, pp. 1863-1866, 1977).
According to the method of preparing amide compounds by using a condensing agent proposed by Kaminski et al disclosed in the above literature, however, the carboxylic acid compound and the condensing agent are reacted together in an equal molar amount to once form a reactive derivative which is an intermediate product and, then, the reactive derivative is reacted with the amine compounds to obtain an amide compound. Therefore, the yield greatly fluctuates ranging from 17 to 73%, which is not satisfactory.
Further, the pyridinium oxide compound used for the preparation of the ester compounds must use methyl iodide that has been pointed out to be carcinogenic at the time of preparing the pyridinium oxide compound, and, hence, requires careful attention concerning the working environment.
Thus, preparations of the carboxylic acid derivatives using the conventional condensing agents are never satisfactory with regard to reaction yield, handling of the condensing agent, or safety during the preparation thereof.
DISCLOSURE OF THE INVENTION
It is an object of the present invention to provide a method of preparing carboxylic acid derivatives, which is capable of conducting the condensation reaction under mild conditions and of obtaining carboxylic acid derivatives and, particularly, amide compounds or ester compounds in high yields.
It is another object of the present invention to provide a condensing agent that makes it possible to obtain carboxylic acid derivatives in high yields.
According to the present invention, there is provided a method of preparing carboxylic acid derivatives comprising mixing a quaternary ammonium salt represented by the following general formula (I), a carboxylic acid compound and a compound having a nucleophilic functional group, to condense the carboxylic acid with the compound having the nucleophilic functional group,
wherein
E is a monovalent or divalent organic group having one or two tertiary amino groups;
n is 1 when E has one tertiary amino group, and is 2 when E has two tertiary amino groups,
R1 and R2 are, independently from each other, alkyl groups having 1 to 4 carbon atoms or aryl groups having 6 to 8 carbon atoms;
a is 1 or 2, and is 1 when n is 1; and
Z-
(n/a)
is a counter anion having a valency of (n/a),
In the above general formula (I), E can be concretely expressed as
wherein R4 may be the same or different, and are monovalent organic groups in which at least an atom bonded to a quaternary nitrogen atom is a carbon atom, and plural R4 may be bonded together to form a divalent or trivalent organic group,
when it has one tertiary amino group, and can be expressed as
wherein R4 may be the same or different, and are monovalent organic groups in which at least an atom bonded to a quaternary nitrogen atom is a carbon atom, R5 is a divalent organic group in which at least an atom bonded to the quaternary nitrogen atom is a carbon atom, and all of, or some of, R4 and R5 may be bonded together to form one or more organic groups having valencies of 2 to 6,
when it has two tertiary amino groups.
According to the preparation method of the present invention, the condensation is carried out in water, in a protonic organic solvent or in an organic solvent containing water and, particularly, by reusing the organic solvent containing water.
The compound having a nucleophilic functional group is an amine compound, and the carboxylic acid derivative is an amide compound. For example, (1) a cephem compound is prepared as an amide compound by using a 2-aminothiazolylacetic acid derivative as a carboxylic acid compound and by using a 7-aminocephalosporanic acid derivative as an amine compound. Further, (2) a peptide compound is prepared as an amide compound by using an aminoacid derivative of which the amino group is protected as a carboxylic acid compound and by using an aminoacid derivative of which the carboxylic acid is protected as an amine compound.
The compound having a nucleophilic functional group is an alcohol compound, and the carboxylic acid derivative is an ester compound. In this case, there is used an aminoacid compound derivative of which the amino group is protected as a carboxylic acid compound.
The quaternary ammonium salt represented by the above-mentioned general formula (I) is at least a quaternary ammonium salt selected from quaternary ammonium salts represented by the following general formulas (I′) and (II),
wherein
R1 and R2 are, independently from each other, alkyl groups having 1 to 4 carbon atoms or aryl groups having 6 to 8 carbon atoms;
E′ is a monovalent organic group having one tertiary amino group; and
X− is a chloro anion, a perchlorate anion, or a boron tetrafluoride anion,
and
wherein R1 and R2 are, independently from each other, alkyl groups having 1 to 4 carbon atoms or aryl groups having 6 to 8 carbon atoms; and
X− is a chloro anion, a perchlorate anion, o
Hirano Naoki
Iwasaki Fumiaki
Kunishima Munetaka
Miharu Michiko
Saijyo Masako
Sherman & Shalloway
Tokuyama Corporation
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