Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Chemical aftertreatment – e.g. – acylation – methylation – etc.
Reexamination Certificate
2000-03-22
2003-05-13
Celsa, Bennett (Department: 1639)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Chemical aftertreatment, e.g., acylation, methylation, etc.
C530S333000, C530S334000, C530S335000, C530S336000, C530S337000, C530S338000, C530S344000, C544S180000, C544S183000, C564S123000, C564S161000, C564S170000, C546S347000
Reexamination Certificate
active
06562944
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to adding a polymer-bound base as an improvement for the method of preparing an amide library by the by-product free generation of PFP esters.
2. Description of the Related Art
Pentafluorophenyl (PFP) esters are commonly used as activated intermediates for the generation of amides, which play a key role in biological and chemical systems (i.e. amides are the predominant functional groups of peptides and many organic molecules). Treatment of carboxylic acids, including N-protected amino acids with certain activated PFP esters under mild conditions results in the formation of these activated building blocks that can, in turn, be used to form internal or external amides.
PFP esters derived from carboxylic acids characterized by a low pKa can be used to prepare activated carboxylic acids via a mixed anhydride intermediate. Pentafluorophenyl trifluoroacetate (PFP-TFA) is known to be an excellent PFP ester for the simultaneous protection and activation of carboxylic acids, including amino and thiol carboxylic acids. Gayo, L. M., Suto, M. J.,
Tetrahedron Letters
37, 4915-18 (1996). The treatment of carboxylic acids, with PFP-TFA in tetrahydrofuran or N,N-dimethylformamide at room temperature provides the corresponding trifluroracetyl-protected, pentafluorophenol-activated derivative. Other reagents such as 9-fluorenylmethylpentafluorophenyl carbonate or pentafluorophenyl acetate can also be used to form an activated PFP ester.
The major problem with the current methods of producing the PFP esters is that all require the presence of an organic base such as pyridine, present in as much as five equivalents. This results in the generation of by-products such as ureas and ammonium salts which can be difficult to remove. Further, such by-products hamper the synthesis, isolation and biological screening of biologically active compounds. For this reason, crude PFP esters must be chromatographed over silica gel or recrystalized to afford relatively pure product.
It is also desirable to find a simpler reaction system for preparing carboxamides than using 1-hydroxybenzotriazole hydrate (HOBT)/o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU). Further, the HOBT/HBTU system does not work well on hindered moieties, such as, for example, hindered indanols or furan contain amines.
It is therefore necessary to develop an improvement of the current methodologies that allows for the automated synthesis of amide libraries in solution phase without requiring laborious separation of by-products.
SUMMARY OF THE INVENTION
This invention provides for the improved method of preparing an activated carboxylic acid as the pentafluorophenyl (PFP) ester using pentafluorophenyl trifluoroacetate (PFP-TFA) in the presence of polyvinylpyridine and poly-DMAP (poly-4-dimethlyaminopyridine) (catalyst). This invention also provides for the improved method of coupling the activated ester with a nucleophile, e.g. amines and thiols, in the presence of polymeric reagents and catalysts. The invention further provides for the preparation of carboxamides and carboxamide libraries using the improved method of preparing an activated carboxylic acid as the pentafluorophenyl (PFP) ester using PFP-TFA in the presence of polyvinylpyridine and poly-DMAP (catalyst). The invention further provides for the preparation of carboxamides and carboxamide libraries using the improved method of coupling the activated ester with a nucleophile, e.g. amines and thiols, in the presence of polymeric reagents and catalysts. For example, known compounds such as the anticholinergic agent N-(1,2-diphenylethyl)nicotinamide (I) can be prepared using the method of the present invention.
In yet another embodiment, this invention provides for the improved method of preparing a carboxamide by generating a PFP ester using pentafluorophenyl diphenylphosphinate (PFP-DPP)/dimethyl formamide (DMF) in the presence of a resin and subsequently treating such ester with an amine in the presence of a suitable base.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved method of activating carboxylic acids as the pentafluorophenyl (PFP) ester using PFP-TFA in the presence of polyvinylpyridine and poly-DMAP (catalyst). Removal of the excess reagent by filtration and evaporation is easily achieved. No chromatography or recrystalization is required with this improved method.
The present invention also relates to an improved method for making a carboxamide by treating a PFP ester with an amine in the presence of polymeric reagents and catalysts, used to remove excess reagent. For example, excess reagent can be removed using scavenger resins, e.g. polymeric amine resins, if the intermediate PFP ester is used in excess, or poly-isocyanate or acidic ion exchange resin, if the amine is used in excess. Thus, the use of polymeric reagents and catalysts ensures easy work-up and provides extremely pure products.
An illustration of an embodiment of the invention is given in Scheme I.
The invention further provides for the preparation of carboxamides and carboxamide libraries using the improved method of preparing an activated carboxylic acid as the pentafluorophenyl (PFP) ester using PFP-TFA in the presence of polyvinylpyridine and poly-DMAP (catalyst). The invention further provides for the preparation of carboxamides and carboxamide libraries using the improved method of coupling the activated ester with a nucleophile, e.g. amines, in the presence of polymeric reagents and catalysts.
The present invention further relates to an improved method of preparing a carboxamide by generating a PFP ester using pentafluorophenyl diphenylphosphinate (PFP-DPP)/dimethyl formamide (DMF) in the presence of a resin such polyvinylpyridine and subsequently treating such ester with an amine in the presence of a base, such as, for example, a tertiary amine. A preferred embodiment of this method is the preparation of a carboxamide on a heterocyclic ring such as an oxazole,or a furan. Another preferred embodiment of this method is the use of disopropyethylamine as the tertiary base. An illustration of this method is depicted in Scheme II.
The disclosures in this application of all articles and references, including patents, are incorporated herein by reference.
REFERENCES:
patent: 4562253 (1985-12-01), Prager et al.
patent: 5244892 (1993-09-01), Suzue et al.
Jiang et al., Tet. Lett. vol. 34, No. 42 (1993) pp. 6705-6708.*
Kim et al., J. Chem. Soc., Chem. (1985) p. 473.*
Gayo, L.M., et al., Tetrahedron Lett. 37:4915-18, 1996.
Kolb Hartmuth C.
Sun Qun
Celsa Bennett
Lexicon Pharmaceuticals
McDonnell & Boehnen Hulbert & Berghoff
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