Process for making benzoic acids

Details Process for making benzoic acids Process for making benzoic acids

1999-04-06

2001-02-20

Killos, Paul J. (Department: 1623)

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

Organic compounds

Carboxylic acids and salts thereof

C562S493000

Reexamination Certificate

active

06191307

ABSTRACT:

TECHNICAL FIELD
The subject of this invention is a process for making benzoic acids from phthalimides.
BACKGROUND
The production of benzoic acids from phthalimides by hydrolysis/decarboxylation is a reaction of considerable commercial importance. The conversion of tetrafluorophthalimide to 2,3,4,5-tetrafluorobenzoic acid, a precursor in the synthesis of Floxacin antibiotics, is an example of the reaction's commercial application. The hydrolysis/decarboxylation reaction can be particularly applicable in cases in which a phthalic acid or phthalic anhydride is converted to a phthalimide in order to protect the diacid or anhydride functionality from being compromised by a process which alters the substituency of the adjacent aromatic ring. Such hydrolysis/decarboxylation can subsequently be implemented to obtain a benzoic acid with the altered ring substituency.
The currently practiced method for hydrolysis/decarboxylation has a serious deficiency in that the reaction requires extremely long reaction times in order to come to substantial completion. Reaction times on the order of days are commonly encountered. Such long reaction times can cause the production of benzoic acids from phthalimides to be the rate limiting step in the synthesis of some organic compounds.
A method of conducting the hydrolysis/decarboxylation which reduces the reaction time presently required for the completion of the reaction would be a welcome contribution to the chemical and pharmaceutical industries.
SUMMARY OF THE INVENTION
It has been found that the addition of certain types of catalytic agents to the reaction has the effect of decreasing the reaction time of the hydrolysis/decarboxylation reaction as much as ten fold.
A catalytic agent, as the term is used herein, is an aprotic, dipolar compound which can solvate the phthalimide at reaction temperatures, and which is, additionally, soluble in water at reaction temperatures. Without desiring to be bound by theory, it is thought that the ability to enhance reaction rate lies in the improved solvation of the phthalimide in the aqueous media due to the presence of the catalytic agent. It has been noted that appropriate organic compounds which have relatively large permanent dipole moments give large decreases in reaction times.
Thus an embodiment of this invention is a process for making a benzoic acid which comprises heating a reaction mixture comprised of (1) a phthalimide, (2) an acid (3) water, and (4) an aprotic, dipolar, water-soluble catalytic agent, to thereby produce a benzoic acid at a rate greater than the rate at which the same benzoic acid would be produced under the same conditions, but in the absence of said catalytic agent. During the process, at least a portion of (1) is in solution in the reaction mixture.
In preferred embodiments, (1) is N-methyltetrafluorophthalimide, (2) is phosphoric acid, and (4) is sulfolane, diethyl ketone, or dimethyl sulfoxide.
Other acids can be used as well. In an additional preferred embodiment, (2) is sulfuric acid, and (4) is dimethyl sulfoxide.
The above and other embodiments will be apparent from the ensuing description and appended claims.
FURTHER DESCRIPTION OF THE INVENTION
Phthalimides which can be utilized in the process of this invention can be substituted or unsubstituted. The phthalimide aromatic ring as well as the imide nitrogen can bear substituents. Suitable substituents on the aromatic ring include, but are not limited to, alkyl, alkoxy, aryl, halogen atom, and others provided that they do not cause the phthalimide to be unable to undergo the hydrolysis/decarboxylation reaction. Suitable substituents on the imide nitrogen include alkyl, alkylhalo, alkoxy, amino, and others which, as in the case of phthalimide aromatic ring substituents, do not prevent the phthalimide from to undergoing hydrolysis/decarboxylation.
Examples of suitable phthalimides include, but are not limited to, 4-methoxymethylphthalimide, 3-chloro-5-cyanophthalimide, 3,6-difluorophthalimide, 4-octylphthalimide, 4-(2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)phthalimide, 3,4,5-t-butyl-6-cyanophthalimide, 4-iodo-phthalimide, 3,6-diacetylphthalimide, 2,3-dihydro-1,3-dioxo-6[(2-propenylamino)carbonyl]-1H-isoindole-5-carboxylic acid, 3,5,6-trichlorophthalimide, 5,6-diiodophthalimide, 3-methylaminophthalimide, 4,5-dicyanophthalimide, 2,3-dihydro-1,3-dioxo-1H-Isoindoline-4-carboxylic acid, 4,5-bis(trifluoromethyl)-phthalimide, 3,4,5,6-tetrafluorophthalimide, N-methyl-3-chloro-5-cyanophthalimide, N-phenyl-3,4,5,6-tetrachlorophthalimide, N-methyl-3,6-dimethoxyphthalimide, N-[2-(diethylamino)ethyl]-3,4,5,6-tetrachlorophthalimide, N-methyl-4-bromophthalimide, N-methyl-3,4,5,6-tetra-chlorophthalimide, N-methyl-3,4,5,6-tetrafluorophthalimide, N-(p-bromophenyl)-4,6-dibromo-3-hydroxyphthalimide, N-4-pentynyl-3-chlorophthalimide, N-methyl-3,4,5-triaminophthalimide, N-hexadecyl-3,4,5,6-tetrabromophthalimide, and N-tetradecyl-3,4,5,6-tetraiodophthalimide. Preferable are halo-phthalimides such as 3,6-difluorophthalimide, 4-iodophthalimide, 5,6-diiodophthalimide, 3,4,5,6-tetrachlorophthalimide, N-phenyl-3,4,5,6-tetrachlorophthalimide, N-[2-(diethylamino)ethyl]-3,4,5,6-tetrachlorophthalimide, N-methyl-4-bromophthalimide, N-methyl-3,4,5,6-tetrachlorophthalimide, N-methyl-3,4,5,6-tetrafluorophthalimide, N-(p-bromophenyl)-4,6-dibromo-3-hy-droxyphthalimide, N-4-pentynyl-3-chlorophthalimide, N-hexadecyl-3,4,5,6-tetrabromophthalimide, and N-tetradecyl-3,4,5,6-tetraiodophthalimide. More preferable are N-aliphatic and N-aryl halophthalimides such as N-phenyl-3,4,5,6-tetrachlorophthalimide, N-methyl-4-bromophthalimide, N-methyl-3,4,5,6-tetrachlorophthalimide, N-methyl-3,4,5,6-tetrafluorophthalimide, N-4-pentynyl-3-chlorophthalimide, N-hexadecyl-3,4,5,6-tetrabromophthali-mide, N-tetradecyl-3,4,5,6-tetraiodophthalimide. Most preferable is N-methyl-3,4,5,6-tetrafluorophthalimide.
In conducting the process, an acid is utilized as a catalyst. Very strong organic acids such as trifluoroacetic acid may be used. However, mineral acids are preferable. Some examples of such are nitric acid, hydrochloric acid, sulfuric acid, phosphorous acid and phosphoric acid. Most preferable is phosphoric acid.
In the practice of this invention, it has been found that the catalytic agents which most efficaciously reduce the reaction time are those which are water-soluble yet retain the ability to solvate the phthalimide. To enable the practice of this invention, it is preferable to utilize a catalytic agent-phthalimide combination in which the catalytic agent has a water-solubility of at least about 5 grams of catalytic agent per 100 mL of water at 130° C., and the phthalimide has a solubility in the catalytic agent of at least about 0.1 gram of phthalimide per gram of catalytic agent at 130° C. Examples of such catalytic agent/phthalimide combinations are acetone/N-phenyl-3,4,5,6-tetrachlorophthalimide, diethyl sulfone/N-methyl-3,4,5,6-tetrafluorophthalimide, diethyl sulfone/N-phenyl-3,4,5,6-tetrafluorophthalimide, dimethyl sulfone/N-methyl-3,4,6-trifluorophthal-imide, sulfolane/N-methyl-3,4,6-trifluorophthalimide, sulfolane/N-phenyl-3,4,5,6-tetrafluorophthalimide, diethyl ketone/N-methyl-3,4,5,6-tetrachlorophthalimide, diethylketone/N-methyltetrafluorophthalimide, sulfolane/N-methyltetrafluorophthalimide, dimethyl sulfoxide/N-methyltetrafluorophthalimide. It is more preferable to utilize a catalytic agent-phthalimide combination in which the catalytic agent has a water-solubility of at least about 10 grams of catalytic agent per 100 mL of water at 130° C., and the phthalimide has a solubility in the catalytic agent of at least about 0.1 grams of phthalimide per gram of catalytic agent at 130° C. Examples of such are dimethyl sulfoxide/N-methyltetrachlorophthalimide, dimethyl sulfoxide/N-phenyltetrachlorophthalimide, sulfolane/N-phenyltetrachlorophthalimide, sulfolane/N-methyltetrachlorophthalimide. It is most preferable to utilize a catalytic agent-phthalimide combination, such as sulfolane/N-methyltetra-chlorophthalimide, in which the

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