Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Reexamination Certificate
2000-10-24
2001-11-13
Bernhardt, Emily (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
C544S363000
Reexamination Certificate
active
06316618
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for preparing an optically active (−)9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[2,3-de]([1,4]-benzoxazine-6-carboxylic acid derivative (“pyridobenzoxazine carboxylic acid derivative”) represented by the formula (I) or pharmaceutically acceptable salt thereof having an excellent antimicrobial activity.
wherein,
R
1
represents hydrogen atom or lower alkyl group having 1 to 5 carbon atoms.
2. Description of the Prior Art
A variety of optically active pyridobenzoxazine carboxylic acid derivatives have been prepared and used as active ingredients for antibiotic agents, since the compounds are known to possess higher antimicrobial activity and weaker toxicity than optically inactive racemic mixture(see: Drugs of the Future, 17 (2), 559-563 (1992)).
In general, optically active (−)pyridobenzoxazine carboxylic acid derivatives have been prepared in the art by the following two processes: the first one comprises a step of selective hydrolysis of (±)7,8-fluoro-2,3-dihydro-3-acetoxymethyl-4H-[(1,4]-benzoxazine by hydrolase; and, the second one comprises a step of optical resolution of (±)7,8-fluoro-2,3-dihydro-3-acetoxymethyl-4H-[1,4]-benzoxazine by chemical reagent (see: EP 206,283; Korean Pat. No. 60,571). However, those processes have several drawbacks as followings: 1) theoretically 50% of isomers are lost; 2) high-priced reagent for separation is used; and, 3) complicate process of 8 steps are accompanied, which is not suitable for industrial-scale mass production. To solve the said problems, a process has been developed to. prepare (−)isomer by racemizing (+)isomer obtained as a by-product during the said process (see: Japanese Patent Publication (Hei) 10-357910).
Further, processes for preparing optically active pyridobenzoxazine carboxylic acid derivatives are disclosed in U.S. Pat. Nos. 4,777,253 and 5,237,060 and Korean Pat. No. 125,115 as well. These prior arts suggest that optically active (−)pyridobenzoxazine carboxylic acid derivatives using optically active (L)-alaninol can be prepared without optical resolution, which is represented as the following reaction scheme:
As shown in the scheme above, a starting material of 4,5-difluorobenzoic acid derivative should be employed in the reaction, since fluorine atom among various halogen atoms is essentially required for the last step of substituting proper piperazine for 10-halogen atom. Though this process is improved in a sense that optical resolution step is not necessary, it has revealed a critical demerit that very expensive 4,5-difluorobenzoic acid derivative is required. On the other hand, it has been reported that relatively inexpensive 4-chloro-5-fluorobenzoic acid derivative, whose reactivity is lowered than 4,5-difluorobenzoic acid derivative, leads to substitution reaction at 9-fluorine atom rather than 10-fluorine atom in the last step (see: Chem. Pharm. Bull., 32, 4907-4913 (1984)).
Therefore, there are strong reasons for exploring and developing a process for preparing optically active (−)pyridobenzoxazine carboxylic acid derivative by employing a low-priced material in a simple and economical manner.
SUMMARY OF THE INVENTION
The present inventors successfuly prepared optically active (−)pyridobenzoxazine carboxylic acid derivative, by employing a starting material of (+)ethyl 2-(4-chloro-5-fluoro-2-halo-3-nitobenzoyl)-3-[(1-hydroxypropy-2 (S)-yl)amino]acrylate which is obtainable from low-priced 4-chloro-5-fluorobenzoic acid derivative instead of high-priced 4,5-difluorobenzoic acid derivative, and substituting piperazine for chlorine atom.
A primary object of the present invention is, therefore, to provide a process for preparing optically active (−)pyridobenzoxazine carboxylic acid derivatives.
The other object of the invention is to provide novel compounds which are available as intermediates in the course of preparing the (−)pyridobenzoxazine carboxylic acid derivatives.
DETAILED DESCRIPTION OF THE INVENTION
In carrying out the present invention, a low-priced compound(V) is employed as a starting material which is obtainable from 4-chloro-5-fluoro-2-halo-3-nitrobenzoic acid derivatives by the known process in the art (see: U.S. Pat. No. 5,237,060). As shown in the reaction scheme below, optically active (−) pyridobenzoxazine carboxylic acid derivatives of the invention are prepared by the following steps: i) reacting a compound(V) with a reactive material(VI) or (VII) in the presence of a base to obtain a compound(IV); ii) converting the compound(IV) to a compound(III) in an organic polar solvent and in the presence of a base; iii) reacting the compound(III) with piperazine or N-mono-substituted-piperazine in an organic polar solvent in the presence of a base to obtain a novel compound(II) by so-called one-pot reaction; and, iv) hydrolyzing and cyclizing the compound(II) in an organic solvent in the presence of metal hydroxide to give the optically active compound(I).
R
b
—N═C═Y (VII)
wherein,
X represents a halogen atom;
Z represents a leaving group;
Y represents an oxygen or a sulfur atom;
R
a
represents —C(═O)—R
2
[wherein R
2
represents an alkyl group having 1 to 5 carbon atoms, phenyl group, substituted phenyl group, alkoxy group having 1 to 5 carbon atoms, cycloalkoxy group having 3 to 5 carbon atoms, phenoxy group, substituted phenoxy group, primary or secondary amine group or alkylthio group having 1 to 5 carbon atoms];
R
b
represents alkyl group having 1 to 5 carbon atoms, phenyl group or substituted phenyl group;
R represents the same as Ra above or R
b
—NH—C(═Y)[wherein R
b
and Y represent the same above]; and,
R
1
represents hydrogen atom or alkyl group having 1 to 5 carbon atoms.
Specifically, X includes halogen atom such as chlorine atom and fluorine atom.
Z includes halogen atom such as chloride atom and fluorine atom; carboxylate group; and, alkoxy group.
R
2
includes lower alkyl group having 1 to 5 carbon atoms, such as methyl group, ethyl group, n-propyl group, isopropyl group, t-butyl group, sec-butyl group, n-butyl group, isobutyl group, t-pentyl group, n-pentyl group, isopentyl group and neopentyl group, preferably methyl group and ethyl group; phenyl group; substituted phenyl group such as p-methoxyl phenyl group, 3,5-dimethoxyphenyl group, 3,5-dimethylphenyl group, 2,4,6-trimethylphenyl group, p-chlorophenyl group and p-fluorophenyl group; alkoxy group having 1 to 5 carbon atoms such as methoxy group, ethoxy group, n-propoxy group, t-butoxy group, sec-butoxy group, n-butoxy group, isobutoxy group, t-pentoxy group, isopentoxy group, neopentoxy group and cyclopentoxy group; cycloalkoxy group having 3 to 5 carbon atoms such as cyclopropoxy group, cyclobutoxy group and cyclopentoxy group; phenoxy group; substituted phenoxy group such as p-methoxyphenoxy group, p-chlorophenoxy group and p-fluorophenoxy group; primary or secondary amine group such as methylamine group, dimethylamine group, ethylamine group and diethylamine group; and, alkylthio group having 1 to 5 carbon atoms such as methylthio group, ethylthio group, n-propylthiogroup, isopropylthio group, t-butylthio group, sec-butylthio group, n-butylthio group, isobutylthio group, t-pentylthio group, isopentylthio group and neopentylthio group.
R
b
inqludes lower alkyl group having 1 to 5 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, t-butyl group, sec-butyl group, n-butyl group, isobutyl group, t-pentyl group, n-pentyl group, isopentyl group and neopentyl group; phenyl group; and, substituted phenyl group such as p-methoxyphenyl group, 3,5-dimethoxyphenyl group, 3,5-dimethylphenyl group, 2,4,6-trimethylphenyl group, p-chlorophenyl group and p-fluorophenyl group.
R
1
includes hydrogen atom and lower alkyl group having having 1 to 5 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group
Kim Kyung-Chul
Kim Min-Hwan
Lee Ho-Seong
Park Young-Jun
Bernhardt Emily
Knobbe Martens & Olson Bear LLP.
Samsung Electronics Co,. Ltd.
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