Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
1998-02-27
2003-07-22
Keys, Rosalynd (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C564S190000, C568S020000
Reexamination Certificate
active
06596898
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for preparing optically active halogenated cyclopropane derivatives which are useful as synthetic intermediates for the preparation of synthetic new quinolone antibacterial agents having excellent activity and safety.
BACKGROUND ART
Among the new quinolone antibacterial agents having excellent antibacterial activity, synthetic antibacterial agents having a fluorocyclopropyl group at the 1-position of the quinolone nucleus have both excellent antibacterial activity and safety, and accordingly, they are expected as clinically useful drugs (Japanese Patent Unexamined Publication (KOKAI) No. (Hei) 2-231475/1990). Optically active 2-fluorocyclopropanecarboxylic acid and derivatives thereof having a specific stereochemical configuration, i.e., (1S, 2S), are important as synthetic intermediates for these compounds.
(1S,2S)-2-fluorocyclopropanecarboxylic acid is heretofore prepared by the steps of addition of bromofluorocarbene to butadiene to produce 1-bromo-1-fluoro-2-vinylcyclopropane; oxidation of the vinyl group to obtain a carboxylic acid and then esterification and successive debromination of the resulting product; separation of a cis-isomer from the resulting reaction mixture by distillation; hydrolysis of the ester group of the cis-isomer to afford a carboxylic acid; and optical resolution of the resulting carboxylic acid (see, the reaction scheme set out below).
Another method for preparing (1S,2S)-2-fluorocyclopropanecarboxylic acid is known which comprises the steps of reacting a vinyl halogenide with a diazoacetic acid derivative in the presence of a variety of metal catalysts, optionally followed by additional dehalogenation reaction, separation of stereoisomers, and optical resolution (Japanese Patent Unexamined Publication (KOKAI) No. (Hei) 6-949911994 and Japanese Patent Unexamined Publication (KOKAI) No. (Hei) 5-194323/1993). However, no metal catalyst having one or more chiral ligands was used in the aforementioned processes.
These preparing processes involve the step of optical resolution of the desired optically active compound having (1S,2S)-configuration after the preparation of the racemic 1,2-cis-2-fluorocyclopropanecarboxylic acid derivative, and the (1R,2R)-isomer, which comprises the half of the racemate, have to be removed as waste matter. Therefore, these processes are not efficient from economical and industrial viewpoints.
The object of the present invention is to provide an efficient and convenient process for preparing optically active halogenated cyclopropane derivatives which are useful for the manufacture of the optically active (1S,2S)-2-fluorocyclopropane-carboxylic acid or derivatives thereof. More specifically, the object of the present invention is to provide a process for preparing the aforementioned optically active halogenated cyclopropane derivatives by a stereoselective reaction using readily available starting materials.
DISCLOSURE OF THE INVENTION
The inventors of the present invention conducted various studies to achieve the foregoing object, and as a result, they found that a 2-fluoro-2-chlorocyclopropanecarboxylic acid derivative can be obtained stereoselectively and in high yield by reacting a diazoacetic acid derivative with 1-fluoro-1-chloroethylene, for example, in the presence of a metal catalyst having one or more chiral ligands. The inventors of the present invention also found that the optically active 2-fluoro-cyclopropanecarboxylic acid derivatives having the desired stereochemical configuration, i.e., (1S,2S), can be prepared in high yield by subjecting the aforementioned 2-fluoro-2-chlorocyclopropanecarboxylic acid derivative to dehalogenation reaction. The present invention was achieved on the basis of these findings.
The present invention thus provides a process for preparing compounds represented by the following general formula (I):
wherein:
X represents chlorine atom, bromine atom, or iodine atom;
R represents a C
1-10
(containing 1-10 carbon atoms) alkyloxy group which may have one or more halogen atoms or one or more C
1-10
alkyloxy groups;
an aralkyloxy group constituted by one or more aryl groups which may have a substituent(s) and a C
1-10
alkyloxy group;
an aryloxy group having an aryl groups which may be substituted;
a C
1-10
alkylthio group which may have one or more halogen atoms;
an aralkylthio group constituted by an aryl group which may have a substituent(s) and a C
1-10
alkylthio group;
amino group; or
a substituted amino group which has one or more substituents selected from the group consisting of a C
1-10
alkyl group, an aryl group which may be substituted, an aralkyl group constituted by an aryl group which may have a substituent(s) and a C
1-10
alkyl group, and an acyl group;
provided that substituents of the substituted aryl groups are selected from the group consisting of a halogen atom, a C
1-10
alkyl group, a C
1-10
halogenoalkyl group, a C
1-10
alkyloxy group, a carbamoyl group which may be substituted, hydroxyl group, nitro group, cyano group, and an amino group which may be substituted,
characterized in that the process comprises the step of allowing a compound represented by the formula: N
2
CHCOR wherein R is the same as that defined above react with a compound represented by the formula: CH
2
═CXF wherein X is the same as that defined above in the presence of a catalyst comprising a metal atom selected from the group consisting of a transition metal of group 8, molybdenum, and copper, together with at least one chiral ligand selected from the group consisting of a carboxylic acid-type ligand, an amide-type ligand, a phosphine-type ligand, an oxime-type ligand, a sulfonic acid-type ligand, 1,3-diketone-type ligand, a Schiff base-type ligand, an oxazoline-type ligand, and a diamine-type ligand to preferentially produce a stereoisomer of the compound of the general formula (I) wherein the stereochemical configuration at the I-position is S-configuration.
According to preferred embodiments of the above invention, there are provided the aforementioned process which preferentially produces a stereoisomer of a compound of the general formula (I) wherein the stereochemical configuration at the 1-position is S-configuration and the substituent represented by —COR and the fluorine atom is in cis-configuration; the aforementioned process which preferentially produces a stereoisomer of the compound of the general formula (I) wherein the stereochemical configuration at the 1-position is S-configuration and the substituent represented by —COR and the fluorine atom is in trans-configuration; the aforementioned process wherein X is chlorine atom or bromine atom; the aforementioned process wherein R is a C
1-10
alkyloxy group; the aforementioned process wherein R is a C
1-6
alkyloxy group; and the aforementioned process wherein R is ethoxy group.
As preferred embodiments of the aforementioned invention, there are also provided the aforementioned process which is carried out in the presence of said catalyst containing at least one chiral ligand selected from the group consisting of a carboxylic acid-type ligand and an amide-type ligand; the aforementioned process which is carried out in the presence of a catalyst containing at least one chiral ligand selected from the group consisting of a carboxylic acid-type ligand and an amide-type ligand together with at least one ligand selected from the group consisting of a halogen-type ligand, a phosphine-type ligand, an oxime-type ligand, a sulfonic acid-type ligand, a 1,3-diketone-type ligand, a Schiff base-type ligand, and a carbon monoxide type ligand; the aforementioned process which is carried out in the presence of a catalyst containing at least one chiral ligand selected from the group consisting of a carboxylic acid-type ligand and an amide-type ligand together with at least one ligand selected from the group consisting of a halogen-type ligand, a phosphine-type ligand, and a carbon monoxide type ligand; and the aforementioned process which is carried out in the presence of said
Akiba Toshifumi
Ebata Tsutomu
Ikeya Takanobu
Sasaki Mikio
Wakita Ryuhei
Daiichi Pharmaceutical Co. Ltd.
Greenblum & Bernstein P.L.C.
Keys Rosalynd
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