Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2000-06-08
2002-02-26
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
Reexamination Certificate
active
06350915
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 preparation of 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one from 3,5-bis(trifluoromethyl)benzoyl chloride has been reported by Posner, G. H.; Whitten, C. E.
Tetrahedron. Lett
., 4647 (1970). The disclosed process involves the addition of dimethyl copper lithium to 3,5-bis(trifluoromethyl)benzoyl chloride in an ethereal solvent. However, this reference requires multiple steps to obtain 1-(3,5-bis(trifluoro-methyl)phenyl)ethan-1-one from 3,5-bis(trifluoromethyl)bromobenzene, and a much more efficient and cost-effective process to 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one would be highly desirable.
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(trifluoro-methyl)phenyl)ethan-l-one in relatively high yield.
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:
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 acetic anhydride with the Grignard reagent from 3,5-bis(trifluoromethyl)bromobenzene provides 1-(3,5-bis(tri fluoromethyl)phenyl)ethan-1-one in higher yields and in a more efficient route than the processes disclosed in the art.
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 reaction of 3,5-bis(trifluoromethyl)bromobenzene with magnesium 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.
A 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 magnesium 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 (THF), 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 magnesium employed to prepare the 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.
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 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 may be 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 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.
To minimize solvent loss, however, the Grignard formation may be performed in tetrahydrofuran at a temperature range between about 0 and 20° C., and preferably a reaction temperature range between about 0 and 10° C.
In the present invention, it is preferred that the Grignard reagent be added to the acetic anhydride. In the present invention, it is also preferred that an excess of acetic anhydride be present when reacting the Grignard reagent. In the present invention, it is more preferred that the Grignard reagent be added to an excess of acetic anhydride.
Surprisingly, the presence of an excess of acetic anhydride (i.e. greater than a 1:1 molar ratio) is important to providing high yields of the desired product. When the acetic anhydride was added to the Grignard reagent at 20° C. an exothermic reaction resulted which produced a bis-adduct of the formula:
Surprisingly, however, when the Grignard reagent was added to acetic anhydride, little byproduct was formed and 1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-one was obtained in 85-90% yield.
In the present invention, it is preferred that the Grignard reagent is added to cooled acetic anhydride In the present invention, it is more preferred that the Grignard reagent is added slowly (over a period of 1-2 hr, for example) to a cooled mixture of acetic anhydride in either tetrahydrofuran or tert-butyl methylether, maintaining the temperature at −10 to −15° C.
In the addition of the Grignard reagent with acetic anhydride, it is preferred that the temperature of the acetic anhydride upon addition of the Grignard reagent be less than about 0° C.,
McKane Joseph K.
Merck & Co. , Inc.
Murray Joseph
Rose David L.
Thies J. Eric
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