Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2000-01-27
2001-07-24
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
Reexamination Certificate
active
06265616
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to partially fluorinated amines, or more particularly to a process for preparing trifluoroisopropylamine.
Partially fluorinated amines are known in the art to be useful chemical intermediates. In particular, 1,1,1-trifluoro-2-propylamine, or trifluoroisopropylamine, is known to be a useful intermediate in the preparation of fluorinated pharmaceutical compounds such as antihypertensives. Such use is described in U.S. Pat. No. 4,378,366, which is incorporated herein by reference. Trifluoroisopropylamine has also been used in the manufacture of dyes. (See, J. B. Dickey et al., Ind. Eng. Chem., 48 (1956) 209).
Trifluoroisopropylamine (CF
3
CH(CH
3
)NH
2
) has been made by several routes, however none are of these methods are favorable for large scale manufacture. One process involves a reaction of alanine with sulfur tetrafluoride. However, the desired amine is only produced in 29% yield, and the process uses an expensive and toxic raw material, SF
4
, under pressure in a batch process. (See M. S. Raash, J. Org. Chem., 27 (1962) 1406). In another process, a hydrochloride salt is produced rather than producing the amine directly. This salt is prepared from the hydrolysis of the N-benzylidene derivative of trifluoroisopropylamine, which in turn was prepared in two steps from 1,1,1,5,5,5-hexafluoro-2,4-pentanedione. The initial reaction from this expensive starting material gives the desired intermediate, N-benzylimine of trifluoroacetone, but in only 29% yield. (See T. Ono, et al, J. Org. Chem., 61 (1966) 6563). In an improved variation of this procedure, trifluoroacetone is treated with phenylethylamine in ether in the presence of molecular sieves to give the corresponding imine. (See V. A. Soloshonok, et al, J. Org. Chem., 62 (1997) 3030). This is followed by isomerization with a base and, finally, hydrolysis to give trifluoroisopropylamine hydrochloride. While the overall yield of the salt is good, the process involves the use of an expensive base and its separation from the isomerization product.
One attractive method for commercial-scale manufacture of trifluoroisopropylamine is a 3-step process starting with the preparation of trifluoroacetone in 83% yield from the commercially available ethyl trifluoroacetoacetate. (See A. L. Henne and R. L. Pelley, J. Am. Chem. Soc., 74 (1952) 1426). The trifluoroacetone is then converted into its corresponding oxime in 85% yield. (See R. A. Shepard and P. L. Sciaraffa, J. Org, Chem., 31 (1966) 964). Finally, the oxime is reduced with lithium aluminum hydride in ether, followed by treatment of the ethereal solution with hydrochloric acid to give the amine hydrochloride in 57% yield. (See U.S. Pat. No. 4,378,366).
Attempts to reduce trifluoroacetone oxime catalytically have met with only limited success. The reduction of this oxime over Raney-nickel at 60° C. and at 2000 psi hydrogen pressure in ether is known. (See Ind. Eng. Chem., 48 (1956) 209). Following treatment of the ethereal solution with gaseous HCl, the hydrochloride salt was obtained in 30% yield. Using a similar procedure, except that PtO
2
was used as the reduction catalyst, the amine hydrochloride was likewise obtained in 27% yield. (See R. A. Shepard, et al, J, Org, Chem., 31 (1966) 964). Each of these known procedures suffer from drawbacks such as requiring the use of expensive reagents, low yield in one of the reactions, and preparation of the hydrochloride during the isolation procedure, necessitating yet another process step to generate the free amine.
It would therefore be desirable to provide a means to prepare trifluoroisopropylamine by a method more suitable to large-scale manufacture, and which has fewer drawbacks compared to previously known methods. It would be especially desirable to provide a means of reducing trifluoroacetone oxime directly to the amine using a process for which the yield is high and in which the free amine can be isolated without the intermediacy of the hydrochloride salt.
It has now been unexpectedly found that trifluoroisopropylamine can be prepared in good yield and conversion by the catalytic reduction of trifluoroacetone oxime in the vapor phase, with hydrogen in the presence of a reduction catalyst. The results obtained from reducing trifluoroacetone oxime to trifluoroisopropylamine represent a substantial improvement over known methods, catalytic or otherwise. Studies on liquid phase reductions reveal the disadvantageous effect of by-product water on the reaction rate, although the prior art provides no clue of this effect. These studies also show a surprising dependence for trifluoroisopropanol formation on the catalyst. The results of the vapor phase reduction studies were much better. For example, we discovered that the use of platinum, rhodium and/or palladium catalysts, which were not very effective in the liquid phase produce good results in the vapor phase. See examples 9 through 16. It has been discovered that the use of platinum, rhodium and/or palladium catalysts at high temperatures counterbalanced the effect of the byproduct water on the reaction rate. It has been discovered that by conducting the reaction in the vapor phase, the catalyst was able to counteract the effect of the byproduct water on the reaction rate. Compare example 7 with example 12. It was further an unexpected result that the difficulties associated with conversion to the alcohol, due to by-product water, could be overcome with the use of these catalysts at the significantly higher reaction temperatures used in the vapor phase process of this invention.
DESCRIPTION OF THE INVENTION
The invention provides a process for producing trifluoroisopropylamine which comprises reducing trifluoroacetone oxime in the vapor phase with hydrogen in the presence of a reduction catalyst.
The invention also provides a continuous process for producing trifluoroisopropylamine which comprises continuously reducing trifluoroacetone oxime in the vapor phase with gaseous hydrogen in the presence of a reduction catalyst.
In the practice of the present invention, trifluoroacetone oxime is reduced with hydrogen, preferably gaseous hydrogen, in the presence of a reduction catalyst and preferably in the absence of solvents. Trifluoroacetone oxime may be produced by the oximation of trifluoroacetone (R. A. Shepard and P. L. Sciaraffa J. Org. Chem., 31 (1966) 964). The trifluoroacetone oxime is reduced by reacting it with hydrogen. In the preferred embodiment, trifluoroacetone oxime is reacted with at least a stoichiometric amount of hydrogen gas and preferably an excess of hydrogen gas. Preferably the mole ratio of hydrogen to oxime ranges from about 2 to about 50, more preferably from about 2 to about 20, and most preferably from about 2 to about 10.
The reduction of trifluoroacetone oxime takes place in the presence of a reduction catalyst. Suitable reduction catalysts nonexclusively include platinum, rhodium, palladium and combinations thereof These reduction catalysts are commercially available from Engelhard. The reduction catalyst is preferably present on a support, most preferably an inert support. Suitable supports nonexclusively include carbon and alumina. One preferred carbon support is activated carbon of 4-8 mesh. Another preferred alumina support is ⅛″ alumina pellets. These supports as well as the catalysts on the supports may be acquired commercially from Engelhard.
In one preferred embodiment, the process of the present invention is conducted where the reduction catalyst comprises platinum, and the support comprises carbon. In another preferred embodiment, the process of the present invention is conducted where the reduction catalyst comprises rhodium, and the support comprises alumina (Al
2
O
3
).
The reduction catalyst is preferably on a support material and present in an amount of from about 0.5% by weight to about 20% by weight, more preferably from about 0.5% by weight to about 15% by weight, and most preferably from about 0.5% by weight to about 10% by weight relative to the support material. O
Davis Brian J.
Honeywell International , Inc.
Richter Johann
Szuch Colleen D.
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