Organic compounds -- part of the class 532-570 series – Organic compounds – Percarboxylic acids or salts thereof
Reexamination Certificate
1998-12-17
2002-02-19
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Percarboxylic acids or salts thereof
C562S423000, C562S493000
Reexamination Certificate
active
06348624
ABSTRACT:
FIELD OF THE INVENTION
The subject invention relates to processes for making benzoic acid compounds having certain substituents.
BACKGROUND
Benzoic acid compounds having certain substituents are useful as intermediates in processes for making other compounds, including antimicrobial quinolone compounds, and the like.
SUMMARY OF THE INVENTION
The subject invention involves processes for making 2,4-difluoro-3-Q1-benzoic acid:
wherein Q1 is derived from an electrophilic reagent, comprising the steps of:
(a) treating 1-bromo-2,4-difluorobenzene:
with a strong, non-nucleophilic base; then treating with an electrophilic reagent which provides Q1, or a functional moiety which is then transformed to Q1, producing 1 -bromo-2,4-difluoro-3-Q1 -benzene:
(b) treating the 1-bromo-2,4-difluoro-3-Q1-benzene with an alkali or alkaline earth metal or organometallic reagent; then treating with carbon dioxide, or with a formylating agent followed by oxidation, to produce 2,4-difluoro-3-Q1-benzoic acid.
The subject invention also involves optional additional steps to substitute a non-hydrogen moiety for one or both of the hydrogens attached to the phenyl ring of the 2,4-difluoro-3-Q1-benzoic acid, thus producing:
DESCRIPTION OF THE INVENTION
Glossary of Terms
Unless otherwise specified, the following terms have the indicated meanings when used in this application.
“Alkanyl” is an unsubstituted or substituted, linear or branched, saturated hydrocarbon chain radical having from 1 to about 8 carbon atoms, preferably from 1 to about 4 carbon atoms. Preferred alkanyl groups include methyl, ethyl, propyl, isopropyl, and butyl.
“Alkenyl” is an unsubstituted or substituted, linear or branched, hydrocarbon chain radical having from 2 to about 8 carbon atoms, preferably from 2 to about 4 carbon atoms, and having at least one carbon-carbon double bond.
“Alkynyl” is an unsubstituted or substituted, linear or branched, hydrocarbon chain radical having from 2 to about 8 carbon atoms, preferably from 2 to about 4 carbon atoms, and having at least one carbon-carbon triple bond.
“Alkyl” includes alkanyl, alkenyl, alkynyl, and cycloalkyl as defined herein, unless specifically or necessarily structurally limited otherwise or by other restrictions. Alkyl retains this meaning when it is used as part of another word; examples are provided below (e.g., alkylene, haloalkyl). In such words, alkyl can be replaced by any of alkanyl, alkenyl, or alkynyl to narrow the meaning of such words accordingly. Also, as referred to herein, a “lower” alkyl is a hydrocarbon chain comprised of 1 to about 4, preferably from 1 to about 2, carbon atoms. Preferred alkyl are alkanyl or alkenyl; more preferred is alkanyl.
“Alkylene” is a hydrocarbon diradical. Preferred alkylene includes ethylene and methylene.
“Heteroatom” is a nitrogen, sulfur or oxygen atom. Groups containing one or more heteroatoms may contain different heteroatoms.
“Heteroalkyl” is an unsubstituted or substituted chain radical having from 2 to about 8 members comprising carbon atoms and at least one heteroatom.
“Carbocyclic ring” is an unsubstituted or substituted, saturated, unsaturated or aromatic, hydrocarbon ring radical. Carbocyclic rings are monocyclic or are fused, bridged or spiro polycyclic ring systems. Monocyclic rings contain from 3 to about 9 carbon atoms, preferably 3 to about 6 carbon atoms. Polycyclic rings contain from 7 to about 17 carbon atoms, preferably from 7 to about 13 carbon atoms.
“Cycloalkyl” is a saturated or unsaturated, but not aromatic, carbocyclic ring radical. Preferred cycloalkyl groups are saturated, and include cyclopropyl, cyclobutyl and cyclopentyl, especially cyclopropyl.
“Heterocyclic ring” is an unsubstituted or substituted, saturated, unsaturated or aromatic ring radical comprised of carbon atoms and one or more heteroatoms in the ring. Heterocyclic rings are monocyclic or are fused, bridged or spiro polycyclic ring systems. Monocyclic rings contain from 3 to about 9 carbon and heteroatoms, preferably 3 to about 6 carbon and heteroatoms. Polycyclic rings contain from 7 to about 17 carbon and heteroatoms, preferably from 7 to about 13 carbon and heteroatoms.
“Aryl” is an unsubstituted or substituted aromatic carbocyclic ring radical. Preferred aryl groups include phenyl, 2,4-difluorophenyl, 4-hydroxyphenyl, tolyl, xylyl, cumenyl and naphthyl. Preferred substituents for aryl include fluoro and hydroxy.
“Heteroaryl” is an unsubstituted or substituted aromatic heterocyclic ring radical. Preferred heteroaryl groups include thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, quinolinyl, pyrimidinyl and tetrazolyl.
“Alkoxy” is an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl (i.e., —O-alkyl or —O-alkanyl). Preferred alkoxy groups are saturated, and include methoxy, ethoxy, propoxy and allyloxy.
“Acyl” is a radical formed by removal of the hydroxy from a carboxylic acid (i.e., R-carbonyl or R—C(O)—). Preferred acyl groups include, for example, acetyl, formyl, and propionyl.
“Halo”, “halogen”, or “halide” is a chloro, bromo, fluoro or iodo atom radical.
“Optical isomer”, “stereoisomer”, “diastereomer” as referred to herein have the standard art recognized meanings (Cf.,
Hawley's Condensed Chemical Dictionary
11th Ed.).
Processes for Making Compounds
It is recognized that the skilled artisan in the art of organic chemistry can readily carry out standard manipulations of organic compounds without further direction; that is, it is well within the scope and practice of the skilled artisan to carry out such manipulations. These include, but are not limited to, reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. Examples of these manipulations are discussed in standard texts such as March,
Advanced Organic Chemistry
(Wiley), Carey and Sundberg,
Advanced Organic Chemistry
(Vol. 2), Fieser & Fieser,
Reagents for Organic Synthesis
(16 volumes), L. Paquette,
Encyclopedia of Reagents for Organic Synthesis
(8 volumes), Frost & Fleming,
Comprehensive Organic Synthesis
(9 volumes) and the like.
The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene,
Protecting Groups in Organic Synthesis
. Of course, amino acids used as starting materials with reactive side chains are preferably blocked to prevent undesired side reactions.
The starting material for the subject invention processes is 1-bromo-2,4-difluorobenzene:
A first step of the subject processes is to provide a non-hydrogen moiety (Q1) in the 3-position of the starting material to produce 1-bromo-2,4-difluoro-3-Q1-benzene:
The 1-bromo-2,4-difluorobenzene is treated with a strong, non-nucleophilic base, typically in an aprotic solvent. This base may be any base useful in permutational hydrogen-metal exchange. Preferred bases include lithium diisopropylamide (LDA), lithium 2,2,6,6-tetramethylpiperidide (LiTMP), lithium bis(trimethylsilyl)amide (LTSA), t-butoxide, or other known bases for this purpose. Suitable bases are known in the literature, and can be found in common reference texts as non-nucleophilic bases. Most preferred is LDA, which produces intermediates that are reasonably stable over a range of times and temperatures. It is preferred that this reaction be carried out at a temperature of above about −80° C. and no more than about 40° C., more preferably no more than about room temperature, most preferably no more than about −40° C. Temperature
Almstead Ji-In Kim
Gray Jeffrey Lyle
Ledoussal Benoit
Zheng Xiaomin Sharon
Killos Paul J.
Oh Taylor V.
Roof Carl J.
The Procter & Gamble Co.
Upite David V.
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