Process for preparing amic acid esters

Details Process for preparing amic acid esters Process for preparing amic acid esters

2002-03-18

2003-06-10

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

06576765

ABSTRACT:

TECHNICAL FIELD
The present invention relates to an improved process for producing an amic acid ester from an amino acid. More particularly, the present invention relates to a process for producing an amic acid ester useful as an intermediate for agrochemicals, from an amino acid (a raw material) easily industrially at a low cost.
BACKGROUND ART
A mixed acid carboxyanhydride process has been known for reaction of the acid moiety of an amic acid obtained from an amino acid (a raw material), with other amine (Nobuo Izumiya et al., “Synthesis Chemistry Series—Peptide Synthesis”, pp. 126 to 129, Oct. 30, 1970, Maruzen K. K.).
In this process, first, the amino group of an amino acid is reacted with a chlorocarbonic acid ester to synthesize an amide; then, the carboxylic acid moiety of the amide is reacted with a chlorocarbonic acid ester to form a mixed acid carboxyanhydride; and the mixed acid carboxyanhydride is reacted with a corresponding amine to synthesize an intended product.
In the process, however, since the formation of the acid carboxyanhydride is slow in the presence of water, the second reaction must be conducted in a non-aqueous system using a water-free solvent. Therefore, the amide synthesized in an aqueous solvent in the first reaction needs to be dehydrated. Moreover, the second reaction needs to be conducted in a non-aqueous system as mentioned above. Accordingly, the process has a problem in that it is complicated for industrial operation.
Moreover, the dehydration step required for the synthesized amide reduces the productivity per unit time, etc. and needs a longer time for heating of the reaction system, resulting in decomposition of intended product, etc. and consequent reduction in yield. Therefore, the above conventional process has a problem in cost as well.
The present invention aims at providing a process for producing an amic acid ester useful as an intermediate for agrochemicals, from an amino acid (a raw material) easily industrially at a low cost.
DISCLOSURE OF THE INVENTION
The above aim has been achieved by the following inventions [1] to [9].
[1] A process for producing an amic acid ester represented by the following general formula (7):
(wherein A is a substituted or unsubstituted lower alkylene group, a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted arylene group, a substituted or unsubstituted cycloalkylalkylene group or a substituted or unsubstituted aralkylene group; R
1
is a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted heterocyclic alkyl group; and R
3
is a hydrogen atom or a lower alkyl group), which process comprises reacting, in the presence of water, an amino acid represented by the following general formula (1):
(wherein A has the same definition as given above) with a halogenated carbonic acid ester represented by the following general formula (2):
(wherein R
1
has the same definition as given above and X is a halogen atom) to form an amide compound represented by the following general formula (3):
(wherein A and R
1
have the same definitions as given above), then reacting the amide compound with a halogenated carbonic acid ester represented by the following general formula (4):
(wherein R
2
is a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted heterocyclic alkyl group; and X is a halogen atom) to form, in the system, a mixed acid carboxyanhydride represented by the following general formula (5):
(wherein A, R
1
and R
2
have the same definitions as given above), and reacting the mixed acid carboxyanhydride with an amine compound represented by the following general formula (6) or salt thereof:
(wherein R
3
has the same definition as given above and Het is a substituted or unsubstituted heterocyclic group).
[2] A process for producing an amic acid ester, set forth in [1], wherein the amino acid represented by the general formula (1) is dissolved in water and reacted with the halogenated carbonic acid ester represented by the general formula (2).
[3] A process for producing an amic acid ester, set forth in [1], wherein the reaction of the amide compound represented by the general formula (3) with the halogenated carbonic acid ester represented by the general formula (4) is conducted in a reaction system comprising water or a water-organic solvent mixture.
[4] A process for producing an amic acid ester, set forth in [1], wherein the reaction of the mixed acid carboxyanhydride represented by the general formula (5) with the amine compound represented by the general formula (6) or its salt is conducted in a reaction system comprising water or a water-organic solvent mixture.
[5] A process for producing an amic acid ester, set forth in [1], wherein all the steps are conducted in one pot (one reactor).
[6] A process for producing an amic acid ester, set forth in [1], wherein the amino acid represented by the general formula (1) is valine and the chlorocarbonic acid ester represented by the general formula (2) is isopropyl chlorocarbonate.
[7] A process for producing an amic acid ester, set forth in [6], wherein all the steps are conducted in one pot (one reactor).
[8] A process for producing an amic acid ester, set forth in [1], wherein the amino acid represented by the general formula (1) is an optically active valine and the amine represented by the general formula (6) is an optically active 1-(6-fluorobenzothiazol-2-yl)ethylamine.
[9] A process for producing an amic acid ester, set forth in [8], wherein all the steps are conducted in one pot (one reactor).
The present inventors made a study in order to achieve the above aim. As a result, the present inventors surprisingly found out that an amic acid ester can be produced in one pot (one reactor) in the presence of water by adding, to an amino acid (prepared in the form of an aqueous solution of its alkali salt), a chlorocarbonic acid ester to form an amide compound, as necessary neutralizing the alkali present in excess with an acid, adding thereto an organic solvent (e.g. toluene) and a catalytic amount of a tertiary amine to convert the reaction system into a two-phase system, reacting further the amide compound with a chlorocarbonic acid ester in the presence of water to form a mixed acid anhydride in the reaction system in the presence of water, and reacting the mixed acid anhydride with an amine compound corresponding to the intended product (when the amine compound is in the form of a salt such as hydrochloride, sulfonate or the like, an alkali is also added); and moreover that when the raw materials used [for example, the amino acid represented by the above general formula (1) and the amine compound represented by the above general formula (6)] are optically active compounds, there can be synthesized an optically active amic acid ester in which the optical purities of the raw materials used are substantially retained. The above findings have led to the completion of the present invention.
BEST MODE FOR CARRYING OUT THE INVENTION
The process of the present invention is described in detail below.
First, description is made on the terms used in this specification.
The term “substituted or unsubstituted” referred to herein means that the group following the term may be unsubstituted or substituted with, for example, halogen atoms including fluorine atom, chlorine atom, bromine atom and iodine atom

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