Preparation of nitrone derivatives

Details Preparation of nitrone derivatives Preparation of nitrone derivatives

2002-12-20

2004-07-13

Davis, Brian (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

Reexamination Certificate

active

06762322

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed toward a method of preparing nitrone derivatives, and in particular, for preparing nitrone derivatives from a imine intermediate.
2. Description of the Related Art
Nitrones are useful intermediates in a wide variety of applications. For example, nitrones are important as intermediates in organic synthesis, particularly in [3+2] cyclo addition reactions. Nitrones are excellent 1,3-dipoles and capable of reacting with double and triple bonds to form 5-membered heterocyclic ring structures. For example, isoxazolines and isoxazoles are formed by reacting nitrones with carbon-carbon double and triple bonds respectively. Accordingly, nitrones have been utilized for synthesizing various nitrogen containing biologically active compounds, for example, antibiotics, alkyloids, amino sugars, and beta-lactams.
In addition, nitrones are also known for their ability to act as efficient free radical “spin traps”. Nitrones behave as spin trapping agents when a diamagnetic nitrone (the spin trap) reacts with a transient free radical (having a spin) to provide a more stable free radical (referred to as the spin adduct). More specifically, a very reactive oxygen-centered or carbon-centered free radical reacts with the nitrone to generate a new and very stable nitroxide radical adduct. The radical adduct generated may be detectable by electron para-magnetic resonance (EPR) spectroscopy if the stabilized free radical has a reasonable lifetime. Further, information about a spin of a radical can be gleaned from a study of the structure and spectroscopic characteristics of the new radical adduct due to the increased radical stability and lifetime. Thus, techniques utilizing nitrone spin trapping agents are an important method for garnering information on free radicals otherwise difficult or impossible to detect by direct spectroscopic observation due to their exceedingly short lifetimes and low concentrations.
Techniques utilizing nitrone spin trapping agents are also useful for studying free radical responses in biological systems. For example, the toxicity of a synthetic beta amyloid peptide preparation towards glutamine synthesis could be correlated with the characteristics of an EPR signal generated by the spin adduct formed from each batch of synthetic beta amyloid peptide and spin trap. U.S. Pat. No. 6,107,315, issued to Carney, discloses the use of a spin trapping reagent, such as &agr;-phenyl-N-tert-butyl nitrone (PBN), in a suitable pharmaceutical carrier for administration to a patient for the treatment of symptoms associated with aging or other conditions associated with oxidative tissue damage. U.S. Pat. No. 5,723,502, issued to Proctor, discloses a method for ameliorating a cellular dysfunction of a tissue, such as the cosmetic treatment of hair loss and stimulation of hair growth, by administering a nitrone spin trap, such as PBN, to the affected tissue.
More recently, the usefulness of free radical
itrone reactions has been exploited outside the biological field in the areas of rubber antioxidant protection, controlled radical polymerizations, and polymer/filler interactions. Nitrone derivatives as spin trapping agents are useful in controlling or regulating the rate of polymerization in a polymerization reaction. More specifically, the presence of a stable nitrone free radical during the polymerization or copolymerization of monomers provides for control of polymerization and results in polymers having a relatively narrow polydispersity, relative to polymers formed in the absence of a stable nitrone free radical. For example, U.S. Pat. No. 6,333,381 issued to Asada discloses the use of PBN to control the polymerization of various types of rubbers.
There are many proposed methods for the synthesis of nitrone derivatives. One proposed method prepares nitrones directly by condensing an aldehyde and a hydroxylamine.
Comprehensive Organic Chemistry
, vol. 2, pp 196-201, Pergamon Press, (1979). This reference specifically teaches the condensation of benzaldehyde and N-t-butyl hydroxylamine to produce PBN and water. However, many hydroxylamines are either unstable, unavailable and/or expensive. N-t-butyl hydroxylamine, in particular, can be prepared by the reduction of 2-methyl 2-nitropropane, a relatively expensive starting material, with zinc-amalgam or aluminum-amalgam, both of which are heavy metal salt catalysts which present environmental hazards and other problems related to disposal. Another proposed method involves a one-pot generation of PBN from benzaldehyde and 2-methyl 2-nitropropane.
Journal of Organic Chemistry
, vol. 50, pg. 1531 (1985). This method, while simple to conduct on a small scale is costly to scale-up due to the use of expensive 2-methyl 2-nitropropane and zinc as a catalyst. The zinc presents the disposal drawbacks discussed above.
Exotic catalysts have been developed and utilized in an effort to efficiently prepare nitrone derivatives directly from starting materials. In one method, nitrones have been prepared by oxidizing alkyl-alpha-amino acids with a tungstate catalyst in dichloromethane.
Journal of Organic Chemistry
, vol. 59, pg. 6170 (1994). Similarly, methyl trioxorhenium (MTO) has been used as a catalyst to oxidize secondary amines directly to nitrones.
Journal of Organic Chemistry
, vol. 61, pg. 8099 (1996). Still further, permanganate oxidizing agents have been proposed for producing nitrones by directly oxidizing an amine to a nitrone.
Journal of Organic Chemistry
, vol. 54, pg. 126 (1989). However, these methods suffer from the use of expensive heavy-metal catalysts, chlorinated and toxic solvents, strongly acidic and dangerous oxidizing agents, and/or commercially unavailable starting materials, all of which adds to the time and effort involved in preparing the nitrone derivatives. Further, the use of heavy-metal catalysts limits the utility of these methods on a large scale because of the large amounts of catalyst required and costs involved.
In addition to the proposals for the direct preparation of nitrone derivatives from aldehyde starting-materials, multi-step procedures have been proposed. See, for example, European Patent No. WO 0002848. However, these processes suffer from drawbacks. Each reaction intermediate must generally be purified. Additionally, azeotropic solvents, such as toluene, are used to remove water in a lengthy and time-consuming reaction. Further, expensive oxidizing agents are used. For example, one method uses meta-chloroperbenzoic acid (m-CPBA) as an oxidizing agent, which is converted to its sodium salt during the oxidation reaction. This by-product must be separated and discarded prior to performing the next step.
Thus, there is a need to provide a method for the preparation of nitrone derivatives, such as PBN, which omits the use of heavy-metal catalysts and oxidizing agents that are hazardous and expensive. Further, it is desirable to provide a method which utilizes inexpensive starting materials. Still further, it is desirable to provide a method which is efficient and cost-effective on a commercial scale.
SUMMARY OF THE INVENTION
The present invention overcomes the above-mentioned drawbacks by providing an efficient method for the preparation of nitrone derivatives. To this end, and in accordance with the principles of the present invention, one aspect of the invention is directed to a method of preparing nitrone derivatives having a general formula (I)
wherein R
1
and R
2
, are independently selected from the group consisting of substituted or unsubstituted straight, branched, or cyclic alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkaryl, alkoxyl, halo-alkyl, and combinations thereof. Alternatively, R
1
and R
2
taken together with the carbon and nitrogen to which they are attached form a 5-8 membered ring. The method includes the steps of:
reacting an imine compound having a general formula (II)
wherein R
1
and R
2
are as defined above, with an oxidizing agent having a general formula (III)
(R
3
O—S(O)
2

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