Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
1999-04-16
2001-02-20
Tsang, Cecilia (Department: 1613)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
Reexamination Certificate
active
06191300
ABSTRACT:
This invention pertains to the preparation of cyclopropylacetonitrile by reacting a cyclopropylmethyl halide with a cyanide reactant. More specifically, this invention pertains to a novel combination of process steps for the preparation and recovery of cyclopropylacetonitrile beginning with a mixture of cyclopropylmethyl halide, a cyclobutyl halide and a 4-halo-1-butene. The process permits the recovery of substantially pure cyclopropylacetonitrile and cyclobutyl halide, e.g., cyclopropylacetonitrile and cyclobutyl halide each having a purity greater than about 95%.
BACKGROUND
Previous attempts to prepare cyclopropylacetonitrile have proceeded via cyanide displacement of the intermediate cyclopropylmethyl bromide or cyclopropylmethyl chloride. For example, Cartier and Bunce,
J. Am. Chem. Soc.,
85, 935 (1963) reacted cyclopropylmethyl bromide with sodium cyanide in ethanol and isolated pure cyclopropylacetonitrile in 20% yield using preparative gas chromatography. Hanak and Ensslin,
Annalen,
697, 100 (1966) carried out the same reaction and reported a yield of 24%; cyclopropylmethyl chloride gave a yield of only 15%. A substantial improvement is described by Mezzoni et al.,
J. Med. Chem.,
13, 878 (1970) wherein the reaction of cyclopropylmethyl bromide with sodium cyanide in dimethylsulfoxide at 70° C. gave, after a cumbersome workup, a 76% yield of cyclopropylacetonitrile. Finally, Pardo and Morize,
JCS Chem. Comm.,
1982, 1037, mention, in a communication devoid of experimental data or reaction conditions, that cyclopropylacetonitrile was obtained from cyclopropylmethyl bromide in 75% yield using “phase-transfer”.
Cyclopropylmethyl halide, from which the desired cyclopropylacetonitrile may be obtained, can be prepared from cyclopropanemethanol. The simplest process for preparing cyclopropylmethyl halide comprises contacting cyclopropane methanol with an aqueous hydrogen halide solution. However, this process gives a product which comprises a cyclobutyl halide (e.g., cyclobutyl bromide b.p.=108° C.) and a 4-halo-1-butene (e.g., bromobutene b.p.=100° C.) in addition to the desired cyclopropylmethyl halide (e.g., cyclopropylmethyl bromide b.p.=1 06° C.). See, for example, Roberts and Mazur,
J. Am. Chem. Soc.,
72, 2509 (1951). These by-products are very difficult to separate by distillation, a problem exacerbated by the formation of azeotropes of cyclopropylmethyl halide, cyclobutyl halide, and 4-halo-1-butene with common organic solvents. Thus, Cartier and Bunce (vide supra) reacted cyclopropane methanol with PBr
3
at −20° C. to give cyclopropylmethyl bromide contaminated with cyclobutyl bromide and bromobutene. Other workers have avoided the contamination and separation problems by using more selective reagents for converting cyclopropane methanol to cyclopropylmethyl halide. For example, Mitani et al., European Patent Application EP 0 858 988 A1 convert cyclopropane methanol to an intermediate sulfonate ester which is then displaced with bromide ion to give cyclopropylmethyl bromide in good yield and purity. Hrubiec and Smith,
J. Org. Chem.,
49, 431 (1984) used bromine in the presence of triphenylphosphine and dimethylformamide to transform cyclopropane methanol into cyclopropylmethyl bromide. It is apparent that all of these methods for the synthesis of cyclopropylmethyl halide suffer from the need for difficult separations, use intermediate compounds such as sulfonates, or generate wastes which are difficult to handle, e.g., triphenylphosphine oxide. However, the preferred method for preparing cyclopropylmethyl halide for use in producing the subject nitrile would be the reaction of cyclopropane methanol with aqueous hydrogen halide, if the problem of isomer separation could be overcome. As in the case of halide compounds cyclopropylmethyl halide, cyclobutyl halide, and 4-halo-1-butene, the nitrile (or cyano) compounds corresponding to cyclopropylmethyl halide, cyclobutyl halide, and 4-halo-1-butene also are virtually impossible to separate on a commercial scale.
Cyclobutyl halide of acceptable purity also is difficult to obtain. As mentioned above, reaction of the alcohol (i.e., cyclopropane methanol) with aqueous hydrogen halide leads, through rearrangement chemistry, to an appreciable amount of cyclobutyl halide. However, cyclobutyl halide cannot be separated on commercial scale from the co-produced cyclopropylmethyl halide and 4-halo-1-butene. Pure cyclobutyl halide apparently is best prepared by a multistep procedure proceeding via a Hunsdiecker reaction of cyclobutanecarboxylic acid (DuPont et al.,
Syn. Comm.,
20, 1011 (1990)). This process affords cyclobutyl halide contaminated by a 5-8% of cyclopropylmethyl halide and uses stoichiometric amounts of expensive silver nitrate reagent and toxic carbon tetrachloride solvent.
BRIEF SUMMARY OF THE INVENTION
I have developed a process for the preparation of cyclopropyl-acetonitrile in a purity of at least 90 weight percent, preferably at least 95 weight percent, from a halide mixture comprising cyclopropylmethyl halide, cyclobutyl halide and 4-halo-1-butene, which, as mentioned hereinabove, may be readily obtained by the reaction of cyclopropanemethanol with aqueous hydrogen halide. The process also can be utilized to recover cyclobutyl halide in a purity of at least 90 weight percent, preferably at least 95 weight percent. The first embodiment of the present invention provides a process for the preparation of cyclopropylacetonitrile by the steps comprising:
(1) contacting a reactant mixture comprising a cyclopropylmethyl halide, a cyclobutyl halide and a 4-halo-1-butene with an aqueous solution of an alkali metal cyanide in the presence of a phase transfer catalyst to obtain a reaction mixture comprising (i) an organic phase comprising cyclopropylacetonitrile, cyclobutyl halide, 1-cyano-3-butene and phase transfer catalyst and (ii) an aqueous phase comprising a solution of the alkali metal halide and cyanide and phase transfer catalyst;
(2) separating organic phase (i) from aqueous phase (ii) from step (1);
(3) contacting organic phase (i) from step (2) with elemental halogen to obtain a reaction mixture comprising cyclopropylacetonitrile, cyclobutyl halide, 4-cyano-1,2-butane dihalide and phase transfer catalyst; and
(4) subjecting the reaction mixture of step (3) to fractional distillation to obtain overhead vapor products comprising cyclopropylacetonitrile and cyclobutyl halide and a distillation base residues comprising 4-cyano-1,2-butane dihalide and phase transfer catalyst.
As those skilled in the art will recognize, best results are obtained when the halides and elemental halogen used in the process are bromides and bromine.
Cyclopropylacetonitrile and cyclobutyl halides are useful chemical intermediates in the preparation of valuable fine chemicals and pharmaceuticals. The utility of cyclopropylacetonitrile is illustrated by the work of Carney and Wojtkunski,
Org. Prep. Proceed. Int,
5, 25 (1973), Ueno et al.,
J. Med. Chem.,
34, 2468 (1991), Li et al.,
J. Med. Chem.,
39, 3070 (1996), and Janusz et al.,
J. Med. Chem.,
41, 3515 (1998). Cyclobutyl halide likewise is shown to be useful by reference to the work of Fox et al., Published European Patent Application EP 887344 A1 981230, Robinson, PCT Application WO 98/34915 A1 980813), Marfat, PCT Appication WO 98/09961 A1 980312, Myake and Nakao Japanese Kokai JP 07/173169 A2 950711, and Dakkouri and Kehrer Chem. Ber., 114, 3460 (1981).
REFERENCES:
patent: 3454575 (1969-07-01), Mizzoni et al.
patent: 4144269 (1979-03-01), Klenk et al.
patent: 5475151 (1995-12-01), Liang et al.
patent: 5502257 (1996-03-01), Liang et al.
patent: 0 858 988 A1 (1998-08-01), None
patent: 0 887 344 A1 (1998-12-01), None
patent: 1336883 (1973-11-01), None
patent: 07/173169 (1994-07-01), None
patent: WO 98/09961 (1998-03-01), None
patent: WO 98/34915 (1998-08-01), None
Cartier and Bunce, J. Am. Chem. Soc., 85, 933-37 (1963).
Hanak and Ensslin, Annalen, 697, 100-10 (1966).
Mizzoni et al., J. Med. Chem., 13, 878-82 (1970).
Pardo and Morize, JCS Che
Blake Michael J.
Eastman Chemical Company
Gwinnell Harry J.
Murray Joseph
Tsang Cecilia
LandOfFree
Process for the preparation of cyclopropylacetonitrile does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the preparation of cyclopropylacetonitrile, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of cyclopropylacetonitrile will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2614538