Processes for synthesis of cyclic and linear polyamine...

Details Processes for synthesis of cyclic and linear polyamine... Processes for synthesis of cyclic and linear polyamine...

2001-01-11

2003-06-10

Coleman, Brenda (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C540S460000, C540S471000, C540S472000, C540S473000, C540S474000, C540S487000, C544S214000, C544S243000, C544S244000, C544S337000, C546S022000, C546S023000, C546S024000, C548S112000, C548S113000

Reexamination Certificate

active

06576760

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention resides in the field of alkylation reactions, cyclization reactions, and reactions involving substitutions at a nitrogen atom.
2. Description of the Prior Art
Cyclic polyamine chelators, which are cyclic amines whose nitrogen atoms have pendant arms attached thereto that are capable of coordinating metal cations, have a wide range of utility. Chelators of this type are disclosed by Lindoy, L. F.,
The Chemistry of Macrocyclic Ligand Complexes,
University Press, Cambridge, 1989; and Bradshaw, J. S., et al.,
The Chemistry of Heterocyclic Compounds,
John Wiley & Sons, New York, 1993, vol. 51. One use of these chelators is in the treatment of conditions caused by an excess of first transition series elements in the body. Iron overload anemias are examples of such conditions. See Rivkin, G., et al.,
Blood,
vol. 90, no. 10, pp. 4180-4187 (Nov. 15, 1997). Another use is in altering the expression of enzymes containing first transition series metal cations as co-enzymes and by inhibiting replication of mammalian, parasitic, fungal, and bacterial cells and viruses. A disclosure of this use appears in Winchell, H. S., et al., U.S. Pat. No. 5,874,573, issued Feb. 23, 1999. A further use is in the formation of complexes with radioisotopic or paramagnetic metal cations. These complexes are useful in diagnostic radioisotopic and magnetic resonance imaging, and disclosures of how these complexes are used in this manner uses are found in Winchell, H. S., et al., U.S. Pat. Nos. 5,236,695, issued Aug. 17, 1993, 5,380,515, issued Jan. 10, 1995, 5,593,659, issued Jan. 14, 1997, and 5,409,689, issued Apr. 25, 1995.
Known methods for the synthesis of N-substituted cyclic polyamine begin with a laborious and costly multi-step synthesis of the unsubstituted cyclic polyamine. Additional steps are then performed to attach the chelating pendant arms to nitrogen atoms. These methods are disclosed by Parker, D.,
Aza Crowns in Macrocyclic Synthesis,
Oxford Universtiy Press, Oxford, U. K., 1996, and by Wainwright, K. P., “Synthetic and Structural Aspects of the Chemistry of Saturated Polyaza Macrocyclic Ligands Bearing Pendant Coordinating Groups Attached to Nitrogen,”
Coord. Chem. Rev.
1997, p. 166. As noted by Parker, the cyclization reactions when forming medium- and large-ring cyclic polyamines have an unfavorable entropy term to the overall free energy change. This makes it difficult to form cyclic polyaza compounds of medium and large ring sizes. To minimize this adverse thermodynamic effect and to inhibit the formation of undesired products, protective groups are typically added to the nitrogen groups of the linear starting materials. Another means of promoting the reaction is by template syntheses whereby the nitrogen groups that must be joined through a linkage to achieve the desired ring closure are placed in proximity to encourage them to react. A still further alternative is the use of reactive groups on the appropriate nitrogen atoms that are selective toward reaction with each other. In all of these reactions, polymerization competes with cyclization, and cyclization is typically the favored reaction only when the reactants are highly dilute.
The most common methods of forming the cyclic polyaza backbone are those that begin with a linear polyaza compound containing two primary amine groups and varying numbers of secondary amine groups, and proceed by adding one protective group to each of the nitrogen atoms of the linear compound, a typical protective group being p-toluene sulfonyl (“tosyl”). The two amine groups that still contain a H atom (i.e., the amine groups that were originally primary amine groups) are then reacted with a bridging reagent containing two reactive groups capable of undergoing nucleophilic reactions. Examples of bridging groups that are used for this purpose are ditosylated diols, such as for example ditosylated ethylene glycol. The bridging reaction is performed under conditions that do not allow for quaternization of the protected secondary amine groups. The bridging reaction produces a cyclic polyamine backbone of the desired size in which one protective group (such as a tosyl group) is attached to each nitrogen atom in the cycle. Various side products are produced as well. The protected cyclic polyamine is purified and subjected to reactions to remove the protective groups. (When the protective groups are tosyl groups, for example, deprotection is achieved by heating the tosylated cyclic polyamines in strong acid at elevated temperatures.) The deprotected cyclic polyamine product is then purified from the reaction mixture, and additional reactions are performed to attach the desired pendant arms to the nitrogen groups, the pendant arms being groups that are capable of coordinating metal cations.
Template methods have been used in the preparation of a limited number of cyclic polyamines. One such polyamine is cyclam, and a description of its synthesis using a template method is offered by Barefield, E. K., et al.,
Inorg. Synth.,
vol. 16, p. 220 (1976). When metal cation (for example, nickel) is used as the template, the cation must be removed from the reaction mixture to obtain the free cyclic polyamine. The procedure for removing the metal cation often introduces contaminants that must themselves be removed before the cyclic polyamine can be reacted further in syntheses to generate the N-substituted cyclic polyamine chelator.
Cyclization can also be achieved by amide formation, since primary amines are typically favored over secondary amines in reactions between esters and amine groups to form amides. Thus, moderate yields of cyclic compounds containing two amide groups can be obtained in some cases by reacting a linear polyamine containing two primary amine groups with a bridging compound containing two ester groups. An example is the reaction between dipropylamine triamine with the diethyl ester of malonic acid, described by Helps, I. M., et al.,
J. Chem. Soc. Perkin Trans. I
(1989), 2079. This reaction can be followed by reduction of the amide bonds to form the desired amines. As in methods described above, cyclization competes with polymerization, and to achieve selectivity toward cyclization the reactants in these amide formation reactions are typically used in dilute concentrations. Even with dilute reaction mixtures, the yields of the cyclic diamides are often modest, and reduction of the amide bonds and subsequent purification of the desired cyclic polyamine may prove difficult.
A further synthesis route is based on the tendency of &agr;-chloroacetamides to favor reaction with secondary amines. In high dilution, therefore, one can produce certain cyclic diamides by reacting bis-&agr;-chloroacetamides with certain secondary amines. A disclosure of this reaction is offered by Krakowiak, K. E., et al.,
Synlett.
(1993), 611. The resulting diamide is then reduced to obtain the desired cyclic polyamine. This synthesis can only produce cyclic polyamines containing four or more nitrogen groups, and as in the above-described methods, requires highly dilute reactants to favor cyclization over polymerization.
Difficulties also exist in syntheses of N-monoalkylated amines that still contain H atoms attached to one or more of the N atoms, and in which the alkyl substitution on each N atom is a pendant arm capable of coordinating metal cations. Iveson, P. B., et al., “Monitoring the Moedritzer-Irani Synthesis of Aminoalkyl Phosphonates,”
Polyhedron,
vol. 12, no. 19, pp. 2313-23 (1993) demonstrate that primary amines once substituted are disubstituted at a much greater rate than the initial substitution, thereby favoring disubstitution of the primary amine rather than monosubstitution. This difficulty is evidenced by the fact that there are no published reports of direct synthesis of either N,N′,N″-tris(methylenephosphonic acid)-1,4,7-triazaheptane (in which each nitrogen is monosubstituted with a methylenephosphonate moiety) or its esterified products.
SUMMARY OF THE INVENTIO

Affiliated with

Also associated with

Rating

Processes for synthesis of cyclic and linear polyamine... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Processes for synthesis of cyclic and linear polyamine..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Processes for synthesis of cyclic and linear polyamine... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3161209