Processes for the preparation of fluorinated benzoic acids

Details Processes for the preparation of fluorinated benzoic acids Processes for the preparation of fluorinated benzoic acids

2001-03-06

2001-12-25

Geist, Gary (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

Reexamination Certificate

active

06333431

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a process for preparing a fluoro benzoic acid.
BACKGROUND ART
Benzo heterocyclic derivatives represented by the formula (1) shown below have excellent antibacterial activity and are useful as antibacterial agents (Japanese Examined Patent Publication No. 96557/1994).
In the formula, R
2
is C
1-6
alkyl. R
3
is a 5- to 9-membered saturated or unsaturated heterocyclic ring residue, the heterocyclic ring residue optionally having one or more substituents. R
4
is cyclopropyl which may be substituted by 1 to 3 substituents selected from the group consisting of C
1-6
alkyl and halogen; phenyl which may be substituted by 1 to 3 substituents selected from the group consisting of C
1-6
alkoxy, halogen and hydroxy on the phenyl ring; C
1-6
alkyl which may be substituted by halogen, C
2-6
alkanoyloxy or hydroxy; C
2-6
alkenyl or thienyl. R is hydrogen or C
1-6
alkyl.
More specifically, the benzo heterocyclic derivatives of the formula (1) and salts thereof have excellent antibacterial activities against various gram-positive bacteria and gram-negative bacteria and are useful for the treatment of various infectious diseases induced by various bacteria in human, other animals and fish and also useful as an external antimicrobial or disinfectant agent for medical instruments and the like. The benzo heterocyclic derivatives of the formula (1) and salts thereof show an excellent antibacterial activity against mycoplasma,
Pseudomonas aeruginosa,
anaerobic bacteria, resistant cells against various antibacterials, clinically isolated strains, and gram negative and gram positive bacteria such as
Enterococcus faecalis
and
Staphyloccocus pyognes
and hence are useful as an antibacterial agent for the treatment of diseases induced by these microorganisms. The benzo heterocyclic derivatives of the formula (1) and salts thereof show low toxicity and less side effect and have characteristic features such as good absorbability and sustained activity. Furthermore, the benzo heterocyclic derivatives of the formula (1) and salts thereof are useful for the treatment of urinary infectious diseases because they are highly excreted via urine, and further because of easy excretion via bile, they are useful for the treatment of intestinal infectious diseases.
According to Japanese Examined Patent Publication No. 96557/1994, the benzo heterocyclic derivatives of the formula (1) and salts thereof are prepared by using a fluoro benzoic acid of the formula (2)
wherein R
2
is as defined above and R
1
is halogen.
According to Japanese Examined Patent Publication No. 96557/1994, as shown below in Reaction Scheme A or B, a fluoro benzoic acid of the formula (2) is prepared by using known starting compounds by a multiple-step process comprising five steps. Thus according to the process described in Japanese Examined Patent Publication No. 96557/1994, a complicated reaction procedure must be carried out to prepare the fluoro benzoic acid of the formula (2). Furthermore, the desired fluoro benzoic acid of the formula (2) is obtained only in a low yield of about 8.3%.
wherein R
1
is as defined above, R
a
is hydrogen or C
1-6
alkyl, R
b
is C
1-6
alkyl, and X
1
is halogen.
wherein R
2
is as defined above and R
c
is C
1-6
alkyl.
Japanese Unexamined Patent Publications Nos. 243692/1990 and 74167/1992 and EP319906 disclose a process for preparing a fluoro benzoic acid of the formula (2) by using a compound of the formula (A), as shown in the following Reaction Scheme C:
The process, however, necessitates undertaking three steps to prepare the desired fluoro benzoic acid by using the compound of the formula (A). Furthermore, the desired fluoro benzoic acid is obtained only in a low yield of about 7.5%, based on the compound of the formula (A).
Japanese Unexamined Patent Publications Nos. 502452/1991 and 291959/1998 and J. Heterocyclic Chem., 27, p1610 (1990) disclose a process for preparing a fluoro benzoic acid of the formula (2) by using a compound of the formula (B), as shown in the following Reaction Scheme D:
wherein R
d
is alkyl.
The process, however, necessitates undertaking seven steps to prepare the desired fluoro benzoic acid by using the compound of the formula (B). Furthermore, the desired fluoro benzoic acid is obtained only in a low yield of about 45.8%, based on the compound of the formula (B).
J. Heterocyclic Chem., 27, p.1611 (1990) and Journal of Medicinal Chemistry, 1991, vol.34, No.3, p.1156 disclose a process for preparing a fluoro benzoic acid of the formula (2) by using the compound of the formula (C), as shown in the following Reaction Scheme E:
wherein R
e
is methyl or ethyl.
The process, however, necessitates undertaking four steps to prepare the desired fluoro benzoic acid by using the compound of the formula (C). Furthermore, the desired fluoro benzoic acid is obtained only in a low yield of about 25 to 30%, based on the compound of the formula (C).
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a single step process for preparing a fluoro benzoic acid of the formula (2) without the necessity of undertaking multiple steps, the fluoro benzoic acid being used as an intermediate for preparing a benzo heterocyclic derivative of the formula (1) which is useful as an antibacterial agent.
Another object of the present invention is to provide a process for preparing the fluoro benzoic acid of the formula (2) by a simple and convenient procedure at low costs, using an easily available compound without using any special reagents.
A further object of the present invention is to provide a process for preparing the fluoro benzoic acid of the formula (2) in high purity and high yield.
A still further object of the present invention is to provide a commercially advantageous process for preparing the fluoro benzoic acid of the formula (2).
In view of such state, the inventors of the present invention carried out extensive research to achieve the above objects. During the research, the present inventors conceived of using as a starting material a fluoro benzoic acid of the formula (3)
wherein R
1
is as defined above. The fluoro benzoic acid of the formula (3) is a compound which is unsubstituted at the 5-position with respect to the carboxyl group.
Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk, Vol.5, p100 (1975) discloses a process for preparing a compound of the formula (F) comprising reacting a compound of the formula (D) with a Grignard reagent (E), as shown in the following Reaction Scheme F:
The process produces the compound of the formula (F) in a high yield, but it is presumably owing to the chemical structure of the compound of the formula (D) used as a starting material. Stated more specifically, the compound of the formula (D) is a compound wherein all the hydrogen atoms on the benzene ring have been replaced by substituents (fluorine atoms and a carboxyl group). Upon substitution reaction with the Grignard reagent (E), a fluorine atom at one of the ortho-positions with respect to the carboxyl group (i.e., at 2- or 6-position) is substituted by R
f
. Whether R
f
replaces either one of the fluorine atoms at the 2- and 6-positions with respect to the carboxyl group, the resulting compound will be a compound represented by the formula (F).
Japanese Examined Patent Publications Nos. 502452/1991 and 291959/1998 disclose a process for preparing a compound of the formula (H), which comprises reacting a compound of the formula (G) with alkyllithium, as shown in the following Reaction Scheme G:
The process produces the compound of the formula (H) in a high yield, but it is presumably owing to the chemical structure of the compound of the formula (G) used as a starting material. Stated more specifically, the compound of the formula (G) is a compound wherein all the hydrogen atoms on the benzene ring have been replaced by substituents (fluorine atoms and a 2-oxazolyl group). Upon substitution reaction with alkyllithium, a fluorine atom at one of the ortho-positions with respect to the 2-oxazolyl grou

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