Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2000-06-08
2002-12-03
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S493000
Reexamination Certificate
active
06489507
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to processes for the preparation of 3,5-bis(trifluoromethyl)benzoic acid (CAS 725-89-3) which is useful as an intermediate in the preparation of certain therapeutic agents. In particular, the present invention provides a process for the preparation of 3,5-bis(trifluoromethyl)benzoic acid which is an intermediate in the synthesis of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
The preparation of 3,5-bis(trifluoromethyl)benzoic acid from 3,5-bis(tiifluoromethyl)bromobenzene has been reported by Lichtenberger, J.; Weiss, F.
Bull. Chem. Soc. Fr.,
587, (1962). However, this reference quotes only a 49.5% yield of 3,5-bis(trifluoromethyl)benzoic acid from 3,5-bis(tifluoromethyl)bromobenzene.
The general processes disclosed in the art for the preparation of 3,5-bis(trifluoromethyl)benzoic acid result in relatively low and inconsistent yields of the desired product. In contrast to the previously known processes, the present invention provides effective methodology for the preparation of 3,5-bis(trifluoromethyl)benzoic acid in relatively high yield.
It will be appreciated that 3,5-bis(tiifluoromethyl)benzoic acid is an important intermediate for a particularly useful class of therapeutic agents. As such, there is a need for the development of a process for the preparation of 3,5-bis(trifluoromethyl)benzoic acid which is readily amenable to scale-up, uses cost-effective and readily available reagents and which is therefore capable of practical application to large scale manufacture.
Accordingly, the subject invention provides a process for the preparation of 3,5-bis(trifluoromethyl)benzoic acid via a very simple, short and highly efficient synthesis.
SUMMARY OF THE INVENTION
The novel process of this invention involves the synthesis of 3,5-bis(trifluoromethyl)benzoic acid. In particular, the present invention is concerned with novel processes for the preparation of a compound of the formula:
This compound is an intermediate in the synthesis of compounds which possess pharmacological activity. In particular, such compounds are substance P (neurokinin-1) receptor antagonists which are useful e.g., in the treatment of inflammatory diseases, psychiatric disorders, and emesis.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to processes for the preparation of 3,5-bis(trifluoromethyl)benzoic acid of the formula:
A preferred embodiment of the general process for the preparation of 3,5-bis(trifluoromethyl)-benzoic acid is as follows:
In accordance with the present invention, the treatment of the Grignard reagent from 3,5-bis(trifluoromethyl)bromobenzene with carbon dioxide gas at a temperature of less than about 0° C. and preferably less than about −20° C. provides 3,5-bis(trifluoromethyl)benzoic acid in higher yields than the processes disclosed in the art.
In a preferred embodiment, Grignard carboxylation of 3,5-bis-(trifluoromethyl)bromobenzene with Mg/CO
2
in tetrahydrofuran, followed by crystallization of the product gives 3,5-bis(trifluoromethyl)benzoic acid.
In a preferred embodiment, the present invention is directed to a process for the preparation of 3,5-bis(trifluoromethyl)benzoic acid which comprises the reaction of 3,5-bis(trifluoromethyl)bromobenzene with magnesium in tetrahydrofuran to form a Grignard reagent followed by addition of the addition of carbon dioxide gas to the solution of the Grignard reagent in tetrahydrofuran and treatment with a strong acid to give 3,5-bis(trifluoromethyl)benzoic acid.
A specific embodiment of the present invention concerns a process for the preparation of 3,5-bis(trifluoromethyl)benzoic acid of the formula:
which comprises:
treating 3,5-bis(trifluoromethyl)benzene of the formula:
with magnesium in an organic solvent to form the Grignard reagent of the formula:
b) followed by treating the Grignard reagent with carbon dioxide gas in an organic solvent at an initial temperature of less than about 0° C.,
c) followed by treatment of the product therefrom with a strong acid to give 3,5-bis(trifluoromethyl)benzoic acid of the formula:
Preferred organic solvents for conducting the instant process include toluene, tetrahydrofuran (THF), diethyl ether, diglyme, methyl t-butyl ether. The more preferred organic solvent is tetrahydrofuran. In the formation of the Grignard reagent, tetrahydrofuran or diethyl ether are the more preferred organic solvents and tetrahydrofuran is the most preferred organic solvent.
The magnesium employed to prepare the Grignard reagent may be in the form of magnesium granules, magnesium turnings, magnesium dust, magnesium powder, suspension of magnesium in oil, and the like. To minimize safety risks, the use of magnesium granules is preferred.
In the present invention, it is preferred that the carbon dioxide be employed as carbon dioxide gas. It is more preferred that the carbon dioxide gas be at a pressure of 1 to 40 psi, it is still more preferred that the carbon dioxide gas be at a pressure of about 2 to 10 psi and it is even more preferred that the carbon dioxide gas be at a pressure of about 3 psi.
In the reaction of the Grignard reagent with carbon dioxide, it is preferred that the temperature upon addition of the carbon dioxide be less than about 0° C. It is further preferred that the temperature of the reaction mixture upon addition of the carbon dioxide is less than about −10° C. In the reaction of the Grignard reagent with carbon dioxide, it is more preferred that the temperature upon addition of the carbon dioxide be less than about −20° C., it is even more preferred that the temperature upon addition of the carbon dioxide be less than about −40° C., and it is still more preferred that the temperature upon addition of the carbon dioxide be less than about −45° C.
In the present invention, it is preferred that the carbon dioxide be present in solution in the solvent at a concentration which provides optimal reaction with the Grignard reagent. The concentration of the carbon dioxide in the solvent may be enhanced by increasing the pressure of the carbon dioxide gas and/or decreasing the temperature of the solution.
Preferred strong acids for use in the instant process include hydrochloric acid, sulfuric acid, methanesulfonic acid, and the like. A more preferred strong acid for use in the present invention is hydrochloric acid.
Grignard formation from 3,5-bis(trifluoromethyl)bromobenzene under typical conditions using magnesium turnings (4 equiv.) labeled as “suitable for Grignard reactions”, diethyl ether solvent, and slow addition of the starting bromide resulted in facile formation of Grignard adduct (1-2 hours).
The use of less than 2.1 eq of magnesium turnings resulted in incomplete consumption of bromide (residual bromide>2-3 A%), while the use of more than 2.1 eq of magnesium turnings offered no advantage. A comparison of magnesium dust (freshly prepared), powder (50 mesh) and granules (20 mesh) showed that the Grignard reaction was complete for all within 1-2 hours at reflux in THF. The use of one type of magnesium over another (except for turnings) offered no advantage in terms of reaction profile, purity, or yield of the desired product. The use of magnesium granules is preferred, however, because magnesium granules present less of a safety hazard.
The Grignard formation is typically performed in tetrahydrofuran at reflux. The reaction is exothermic and the reaction may be controlled by the rate of addition of the bromide to the magnesium slurry. The reaction mixture is generally aged at reflux until <1 mol % of bromide remains. Grignard formation is usually complete within 2 hours, however reaction times of up to 5 hours give comparable yields of 3,5-bis(trifluoromethyl)benzoic acid.
A solution of the Grignard reagent is then transferred to a pressure bottle where it is treated with a constant pressure of CO
2
. The carboxylation step was initially run at 20-25 psi for 3 hours at ambient temperature. In these preliminary investigations 3,5-b
Cvetovich Raymond
Leazer John
Merck & Co. , Inc.
Reyes Hector M
Rotman Alan L.
Thies J. Eric
Winokur Melvin
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