Chemistry of carbon compounds – Miscellaneous organic carbon compounds – C-metal
Reexamination Certificate
2004-01-28
2004-11-09
Vollano, Jean F. (Department: 1621)
Chemistry of carbon compounds
Miscellaneous organic carbon compounds
C-metal
C568S319000
Reexamination Certificate
active
06814895
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to processes for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one (CAS 30071-93-3) which is useful as an intermediate in the preparation of therapeutic agents. In particular, the present invention provides a process for the preparation of 1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-one which is an intermediate in the synthesis of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
The general processes disclosed in the art for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one 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 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one in relatively high yield and with a lower degree of exothermicity and, hence, a greater degree of safety.
It will be appreciated that 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one 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 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one 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 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one via a very simple, short and highly efficient synthesis.
SUMMARY OF THE INVENTION
The novel process of this invention involves the synthesis of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one. 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 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one of the formula:
An embodiment of the general process for the preparation of 3,5-bis(trifluoromethyl)-benzoic acid is as follows:
wherein:
X is selected from chloro, bromo and iodo; and
R is C
1-8
alkyl.
In accordance with the present invention, the treatment of acetic anhydride with the Grignard reagent prepared by an exchange reaction between 3,5-bis(trifluoromethyl)bromobenzene and a C
1-8
alkyl magnesium halide provides 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one in higher yields and in a safer, more efficient route than the processes disclosed in the art.
In the present invention, C
1-8
as in C
1-8
alkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbons in a linear or branched arrangement, such that C
1-8
alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl. In the present invention halo or halide is intended to include chloro, bromo and iodo.
In a preferred embodiment, the present invention is directed to a process for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one which comprises the exchange reaction of 3,5-bis(trifluoromethyl)bromobenzene with a C
1-8
alkyl magnesium halide in THF to form a Grignard reagent followed by addition of the Grignard reagent to acetic anhydride to give 1-(3,5-bis(trifluoromethyl)phenyl)-ethan-1-one.
Another embodiment of the present invention is directed to a process for the preparation of 1-(3,5-bis(trifluoromethyl)-phenyl)ethan-1-one which comprises the reaction of 3,5-bis(trifluoromethyl)bromobenzene with ethyl magnesium bromide in tetrahydrofuran to form 1-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide followed by addition of the Grignard reagent to an excess of acetic anhydride to give 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one.
A specific embodiment of the present invention concerns a process for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide of the formula:
which comprises:
treating 3,5-bis(trifluoromethyl)bromobenzene of the formula:
with a Grignard reagent selected from:
ethyl magnesium bromide, isopropyl magnesium chloride, ethyl magnesium chloride and isopropyl magnesium bromide, in an organic solvent to form 1-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide.
Another specific embodiment of the present invention concerns a process for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide of the formula:
which comprises:
treating 3,5-bis(trifluoromethyl)bromobenzene of the formula:
with ethyl magnesium bromide or isopropyl magnesium chloride in an organic solvent to form 1-(3,5-bis(trifluoromethyl)phenyl)magnesium bromide.
Another specific embodiment of the present invention concerns a process for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one of the formula:
which comprises:
a) treating 3,5-bis(trifluoromethyl)benzene of the formula:
with a Grignard reagent selected from:
ethyl magnesium bromide, isopropyl magnesium chloride, ethyl magnesium chloride and isopropyl magnesium bromide, in an organic solvent to form a Grignard reagent of the formula:
b) followed by contacting the Grignard reagent with acetic anhydride in an organic solvent to give 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one of the formula:
Another specific embodiment of the present invention concerns a process for the preparation of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one of the formula:
which comprises:
a) treating 3,5-bis(trifluoromethyl)benzene of the formula:
with a Grignard reagent selected from: ethyl magnesium bromide and isopropyl magnesium chloride, in an organic solvent to form a Grignard reagent of the formula:
b) followed by contacting the Grignard reagent with acetic anhydride in an organic solvent to give 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one of the formula:
In the present invention it is preferred that the Grignard reagent is added to the acetic anhydride.
In a more preferred embodiment, following step (b) excess acetic anhydride is removed by the addition of an aqeueous solution of a base, such as sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, and the like.
Preferred solvents for conducting the instant process comprise an organic solvent which is selected from toluene, tetrahydrofuran (G), diethyl ether, diglyme, and methyl t-butyl ether. The most 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 C
1-8
alkyl magnesium halide is preferably selected from ethyl magnesium bromide, isopropyl magnesium chloride, ethyl magnesium chloride and isopropyl magnesium bromide, more preferably selected from ethyl magnesium bromide and isopropyl magnesium chloride, and even more preferably ethyl magnesium bromide. The magnesium employed to prepare the alkyl Grignard reagent may be in the form of magnesium granules, magnseium turnings, magnesium dust, magnesium powder, suspension of magnesium in oil, and the like. To mimimize safety risks, the use of magnesium granules is preferred.
Formation of the Grignard of 1-(3,5-bis(trifluoromethyl)phenyl)-bromide may be performed in tetrahydrofuran at between about 30 and 35° C. 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 may be 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 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one.
Alternatively, to minimize solvent loss, the Grignard formation may be performed in tetrahydrofuran at a temperature range betwe
Asai Tomoyuki
Cvetovich Raymond
Yodogawa Yoshiko
Merck & Co. , Inc.
Thies J. Eric
Vollano Jean F.
Winokur Melvin
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