Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-04-06
2001-02-13
Powers, Fiona T. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06187931
ABSTRACT:
TECHNICAL FIELD
The subject of this invention is a high-yield halogen-exchange fluorination reaction which can convert tri- and tetrahalophthalimides in which at least one phthalimide aromatic ring substituent is a non-fluorine halogen into fully-exchanged tri- and tetrafluorophthalimides.
BACKGROUND
The substitution of fluorine for chlorine or another halogen atom at an aromatic carbon of a tri- or tetrahalophthalimide is an integral reaction in the production of many widely used organic compounds. As such, it is a reaction of considerable commercial importance. For example, the conversion of N-methyltetrachlorophthalimide to N-methyltetrafluorophthalimide is an important step in the production of compounds in the Floxacin family of antibiotics, a commonly prescribed, commercially successful group of synthetic drugs.
A problem typically encountered with halogen-exchange fluorination is the propensity for the formation of products in which at least one aromatic carbon remains substituted by a non-fluorine halogen atom. For example, the halogen-exchange fluorination of a tetrachlorinated phthalimide substrate can lead to mono-, di- and trifluorinated products in addition to the tetrafluorinated product, often the desired end product of the reaction. This tendency towards incomplete halogen-exchange fluorination of halophthalimides generally has the effect of reducing the purity and yield of the fully-exchanged product. In particular, the fluorination of tetrachlorophthalimides, typically carried out with a metal fluoride salt in solvents such as sulfolane, often produces substantially only partially-exchanged products, especially when conducted at moderate temperatures such as those in the range of 150° C.
In order to increase the proportion of the fully-exchanged phthalimide, the reaction is often run at temperatures in excess of 200° C., and for durations of ten hours or more. Unfortunately, such high temperatures and long reaction times are often of limited effectiveness, as such conditions can ultimately result in degradation of the phthalimide moiety. In order to allow the use of conditions which are less harsh, it is typical to perform the reaction in the presence of a phase-transfer catalyst.
However, many phase-transfer catalysts can be extremely costly. It is not unusual for the small amount of phase-transfer catalyst utilized to cost more than any other chemical component of the reaction. A further disadvantage associated with these catalysts is that further processing of even residual amounts of phase-transfer catalyst can result in the formation of tarry impurities due to polymerization of the catalyst. Thus, once halogen-exchange fluorination has been conducted, it is often necessary to resort to purification techniques in order to separate the catalyst from the desired product.
A multiple extraction procedure is typically performed to accomplish this end. Unfortunately, extraction and other methods which can be used to remove the catalyst from the reaction mixture following halogen-exchange fluorination can reduce the yield of the desired product and complicate the reaction work-up. Another problem created by the addition of extraction steps to the synthesis is the increased difficulty in recycling solvents due to contamination with extractant reagents. Recycling can be particularly important if the solvent is costly, as in the case of one commonly used solvent, sulfolane. For example, in the event that sulfolane and water were used as solvent and extractant, respectively, the sulfolane would typically need to be dried before reuse.
It would represent a significant advance in the state of the art if a method of halogen-exchange fluorination of tri- and tetrahalophthalimides which contain non-fluorine halogens could be found which can achieve a high yield and rate of production of fully-exchanged product while eliminating the expense, multiple extractions, and solvent recycling problems associated with phase-transfer catalysts.
SUMMARY OF THE INVENTION
A process has been discovered which can provide for high yield and production rate of fully-exchanged, tri- and tetrafluorophthalimides while eliminating the detriments associated with the use of phase-transfer catalysts. It has been found that when the halogen-exchange fluorination of tri- and tetrahalophthalimides, such phthalimides having at least one aromatically substituted non-fluorine halogen atom, is carried out in a sulfoxide solvent at a range of moderate temperatures, omission of the phase-transfer catalyst can actually increase product yield and rate of accumulation with respect to the reaction performed under identical reaction conditions, but in the presence of the phasetransfer catalyst.
Accordingly, this invention provides, inter alia, a process for producing tri- or tetrafluoroaromatics, which process comprises:
a) forming a phase-transfer catalyst-free reaction mixture comprised of (1) a tri- or tetrahalophthalimide in which at least one aromatic carbon atom in the molecule, and preferably in which each of at least three aromatic carbon atoms in the molecule, is substituted by a non-fluorine halogen atom, (2) a metal fluoride salt, and (3) an inert hydrocarbyl sulfoxide solvent; and
b) maintaining said mixture at one or more temperatures in the range of about 135° C. to about 185° C. such that a compound is formed in which each non-fluorine halogen atom of the halophthalimide which is attached to an aromatic carbon atom is replaced by a fluorine atom.
The process of this invention is particularly efficacious when carried out at temperatures in the range of about 135° C. to about 155° C. In a particularly preferred embodiment, 3,4,5,6-tetrachlorophthalimides, especially N-methyl tetrachlorophthalimide is heated with an alkali metal fluoride salt, most preferably potassium fluoride, in dimethyl sulfoxide.
The above and other embodiments will be apparent from the ensuing description and appended claims.
FURTHER DESCRIPTION OF THE INVENTION
The phthalimides used in conducting the process of this invention are tri- or tetrahalophthalimides, e.g. phthalimides which are halogenated in three or four of the following aromatic ring positions: 3, 4, 5 or 6, at least one of said positions being substituted by a halogen other than fluorine. If a trihalophthalimide is utilized, the aromatic ring position which is not substituted by a halogen atom or the imide moiety can be occupied by a substituent which does not impair the ability of the compound to undergo fluorination at the aromatic ring sites occupied by non-fluorine halogens. Carbonyl, cyano, nitro, and other such substituents are permissible. The phthalimide nitrogen can be unsubstituted, or it can bear substituent groups such as alkyl, alkylaryl, alkoxy, hydroxyl, cyano, carboxyl, ester, keto, amino, nitro, sulfonyl, or others which do not impair the ability of the phthalimide to undergo fluorination of the aromatic ring at sites occupied by non-fluorine halogens. Examples of such halophthalimides are 3,4,5,6-tetrabromo-N-hexadecylphthalimide and 3,4,5,6-tetraiodo-N-tetradecylphthalimide. Preferred are tri- and tetrachlorophthalimides. Examples of such are 3,4,5-trichlorophthalimide, 3,4,6-trichlorophthalimide, 3,4,5,6-tetrachloro-N-phenylphthalimide, 3,4,5,6-tetrachloro-N-isobutyl-phthalimide and 3,4,5,6-tetrachloro-N-[2-(diethylamino)ethyl]phthalimide. More preferred are the tetrachlorophthalimides, examples of such being 3,4,5,6-tetrachloro-N-phenyl phthalimide, 3,4,5,6-tetrachloro-N-methylphthalimide, with the latter being the most preferred reactant.
The above phthalimides can be synthesized by methods such as conversion of the corresponding phthalic anhydride to an imide by heating with an amine. The desired aromatic ring substituency can often be imparted to phthalic anhydride prior to imide formation reaction.
Preferably, an alkali metal fluoride salt, an alkaline earth metal fluoride salt or other metal fluoride salt is used as a fluorination agent. Suitable examples include lithium fluoride, sodium fluoride, potassium fluoride, rubidi
Belmont Stephen E.
Everly Charles R.
Liu Yunqi
Albemarle Corporation
Pippenger Philip M.
Powers Fiona T.
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