Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2000-01-05
2002-06-25
Shippen, Michael L. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S774000, C568S778000
Reexamination Certificate
active
06410803
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the preparation of p-fluorophenol by alkaline hydrolysis of p-bromofluorobenzene.
BACKGROUND OF THE INVENTION
One of the major synthetic routes for the preparation of p-fluorophenol, a substance of great commercial importance as an intermediate for various agrochemicals and pharmaceuticals, involves the alkaline hydrolysis of p-bromofluorobenzene in the presence of a copper catalyst. However, the hydrolysis reactions taught in the art are accompanied by the formation of considerable amounts of phenol and other by-products such as difluorodiphenylether and fluorohydroxydiphenylether, the latter two being formed by coupling. The formation of the phenol is particularly problematic, since it cannot be separated from p-fluorophenol by distillation.
The art has attempted to obtain p-fluorophenol in high yields, and simultaneously, to reduce the amounts of the phenol by-product formed during the alkaline hydrolysis of p-bromofluorobenzene, by appropriate selection of the alkaline agents. Boudakian et al., JOC 26, p. 4641 (1961), reported that the use of strong bases such as NaOH had yielded poor results, this reference indicating that calcium hydroxide is a superior base for the hydrolysis. This approach is further supported by U.S. Pat. No. 2,950,325, which suggests using alkaline earth metal oxides or hydroxides, explaining that the phenol by-product tends to form when a strong base, e.g., NaOH or KOH, is employed in the reaction, and also by GB 850,888, which presents unsatisfactory results when NaOH is used as the alkaline agent in the hydrolysis, compared with Ca(OH)
2
.
The applications of other bases, such as NaHF
2
or Ba(OH)
2
, were disclosed in Russian Patent No. 143404 and DE 3430554, respectively.
In conclusion, the art has taught avoidance of the use of strong bases as the alkaline agents in the preparation of p-fluorophenol via the hydrolysis of p-bromofluorobenzene, as they lead to a high degree of phenol contamination. The use of a weak base like Ca(OH)
2
, effectively permits reduction of the formation of phenol but the p-fluorophenol is obtained in a yield of 50 to 70% and large amounts of by-products are formed.
In a copending patent application, International Patent Application No. PCT/IL97100019, it is suggested using a mixture of NaOH and Na
2
CO
3
, which has been found to improve the efficiency of the hydrolysis reaction, providing high yields of the p-fluorophenol while reducing the level of the phenol, to even below 0.1%.
It is an object of the present invention to provide a process for preparing p-fluorophenol via the alkaline hydrolysis of p-bromofluorobenzene, where a strong base is used alone, which gives the product in high yields, contaminated by only low amounts of the phenol, the content of this undesired by-product being in the order of 0.1% or less.
It is another object of the present invention to provide such a process which is industrially advantageous, as it allows high reactor productivity and easy recovery of the product with a minimal amount of waste.
SUMMARY OF THE INVENTION
It has now been found that it is possible to carry out the alkaline hydrolysis of p-bromofluorobenzene in the presence of copper-containing catalysts, to give p-fluorophenol, while employing as the alkaline agent a strong base such as NaOH or KOH solely, and—contrary to what is taught in the art—to obtain p-fluorophenol in high yields while reducing the phenol by-product contamination to a very low level.
The present invention provides a method for the preparation of p-fluorophenol by the alkaline hydrolysis of p-bromofluorobenzene in the presence of a copper-containing catalyst at an elevated temperature under pressure, the alkaline agent being a strong base, characterized in that said p-bromofluorobenzene, copper-containing catalyst and strong base are contacted with water and where at least the base is gradually added to the reaction zone at an essentially uniform flow rate such that the addition of the base lasts at least the time required to complete the reaction in a batch operation, and less than 12 hours, and the molar ratio of the base is between 1.8 to 3 with respect to said p-bromofluorobenzene.
In such an operating mode, the strong base is assumed to be fed into the reaction zone at a rate similar to the reaction rate, thereby avoiding the build up of a high concentration of said strong base in the reaction zone, to which the phenol formation is believed to be attributed. However, regardless of the exact explanation, the fact is that operating in the above described mode yields the desired results which the prior art failed to achieve. By the term “the time required to complete the reaction in a batch operation” is meant the time required to complete a reaction where all the reactants, i.e., the p-bromofluorobenzene, the water, the catalyst and the strong base, are stationary reaction phases. By the term “stationary reaction phase” is meant a. reaction component which is stationary from a point of view outside the reaction zone, said component being fixed within said reaction zone, ie., no flow of this component in or out of the reaction zone occurs, even though of course there may be relative motion of these components within said reaction zone.
According to the present invention, the gradual addition of the strong base to the reaction zone lasts at least the time that would have been required to complete the reaction in a batch operation, which is a well known reaction in the art, and is typically between 2 to 5 hours, and accordingly, the gradual addition of the strong base according to the present invention preferably lasts between 2 to 12 hours. Anyway, the time required to complete the reaction in a batch operation can be evaluated by monitoring the amount of the product, p-fluorophenol, and determining when this amount becomes constant after having increased during the course of the batch reaction.
Surprisingly, the above described mode of operation, wherein at least one of the reactants—the strong base—is not a stationary reaction phase as herein defined, has succeeded, even though a strong base is used, in producing high yields of a very pure p-fluorophenol, accompanied by only minor amounts of phenol by-product, the content of which is about 0.1% and even less. The prior art has only taught employment of a strong base in a batch operation, as explained hereinbefore, and has failed to give satisfactory results for the hydrolysis.
The addition rate specified above is the rate of gradual addition of the strong base to the reaction apparatus previously charged with water, copper catalyst and p-bromofluorobenzene, wherein the water, the copper catalyst and the p-bromofluorophenol are stationary reaction phases as defined herein before. However, it should be understood that according to the present invention, the p-bromofluorobenzene and/or the copper-containing catalyst may not be stationary reaction phases, and they can be introduced in a progressive manner to the reaction zone by feeding them thereto over a certain period of time. One skilled in the art will be able to calculate the flow conditions and to adjust the flow of the strong base into the reaction apparatus in order to maintain the optimal level of the strong base.
The reaction is carried out at temperatures from 180° to 220° C., and preferably at a temperature in the range between 190° to 210° C., under pressure. The strong base according to the present invention is preferably NaOH or KOH, NaOH being usually preferred due to economic considerations. The base is preferably provided as an aqueous solution, the concentration by weight of which varies from 20% to 50%. As indicated above, the molar ratio between the strong base and the p-bromofluorobenzene varies between 1.8 to 3.0.
The copper-containing catalyst according to the present invention is either in the cuprous or cupric oxidation state, and is preferably selected from among Cu
2
O, CuO and CuSO
4
.5H
2
O, the most preferred being Cu
2
O. The molar ratio of p-bromofluorobenzene/
Anderson Kill & Olick
Bromine Compounds Limited
Lieberstein Eugene
Meller Michael N.
Shippen Michael L.
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