Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-05
2003-10-14
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06632950
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates the preparation of compounds useful as monomers in the preparation of polyamides, and more particularly to novel methods and novel intermediates for the preparation of 3-hydroxypyrrole monomers for polyamides that are useful in nucleotide sequence recognition.
Certain polyamides derived from heteroaryl amino acid monomers are capable of binding to dsDNA and have been found useful in the recognition of nucleotide sequences as well as other applications. See, for example, Dervan U.S. Pat. No. 5,998,140 and Urbach et al., “Sequence Selectivity of 3-Hyroxypyrrole/Pyrrole Ring Pairings in the DNA Minor Groove,”
J. Am. Chem. Soc.,
1999, 121, 11621-11629. Polyamides containing various combinations of amino acid units respectively comprising pyrrole, hydroxypyrrole and imidazole moieties have been found particularly suitable for this purpose. G/C base pairs have been found to be complemented by the juxtaposed combination of N-methylimidazole/N-methylpyrrole, C/G pairs by N-methylpyrrole/N-methylimdazole, and T/A pairs by N-methylpyrrole/N-methylpyrrole or N-methyl-3-hydroxypyrrole/N-methylpyrrole. Polyamides containing these combinations can form intracellular complexes by complementation with sequences in dsDNA, the complementation being advantageously facilitated by providing a hairpin turn in the polyamide, or may be accomplished by using two amide oligomers.
Methods for the preparation of hairpin polyamide polymers and monomers useful in their synthesis are described in the above-cited Dervan patent and Urbach et al. article. An earlier article of Momose et al., “3-Hydroxypyrrole. I. A General Synthetic Route to 4,5-Unsubstituted Alkyl 3-Hydroxypyrrole-2-carboxylates,”
Chem. Pharm. Bull.,
26(7), 2224-2238 (1979) also describes methods for the preparation of amino acids derivatives of 3-hydroxypyrrole.
A particularly preferred monomer for the preparation of heteroaryl polyamides is the 3-hydroxypyrrole derivative corresponding to the formula
wherein R
1
is typically methyl, and R
b
a protective group to block side reactions during the course of the polyamide synthesis. Urbach describes a method for producing such monomer in which ethyl 4-carboxyl-3-hydroxy-1-methylpyrrole-2-carboxylate is reacted with diphenylphosphoryl azide in the presence of triethylamine in acetonitrile to form the isocyanate which is thereafter reacted with benzyl alcohol to produce ethyl 4-[(benzyloxycarbonyl)amino]-3-hydroxy-1-methyl-2-carboxylate. The latter compound is reacted with methyl iodide in the presence of 4-dimethylaminopyridine and potassium carbonate in acetone to produce the 3-methoxy derivative, after which di(t-butyl) carbonate and 10% Pd/C are added to the mixture, and the mixture stirred under a hydrogen atmosphere to produce ethyl 4-[(t-butoxycarbonyl)amino]-3-methoxy-2-carboxylate. The latter compound is saponified to the 2-carboxylic acid, which is useful as a monomer in the synthesis of polyamides of the type effective in the sequence identification procedures described in Dervan U.S. Pat. No. 5,998,140 and the Urbach article.
In the synthesis of Urbach, the steps required to introduce a blocked 4-amino group have an adverse tendency to decarboxylate at the 4-position, especially in the presence of water. Thus, for satisfactory monomer synthesis per the Urbach route, it is necessary that measures be taken to substantially exclude moisture from the reaction mixture. Moreover, the synthesis described by Urbach involves release of nitrogen gas from the reaction mixture. Unless the reaction conditions are carefully controlled, the rate of gas release may potentially pose an operational hazard, particularly in large scale synthesis.
In synthesis of the polyamides, it is also important that the 3-hydroxy group be protected so that it does not participate in side reactions which produce branched or cross-linked polyamides that are less suitable for nucleotide recognition than are the unbranched polyamides described by Dervan and Urbach. After polymerization, the O-methyl group is removed since the free hyroxyl is the desired structure for use in nucleic acid binding. Although O-methylation provides very satisfactory protection of the 3-hydroxy group during the polymerization reaction, and is a preferred protective procedure for many applications, the O-methyl group can be difficult to remove after the polymerization is complete. It would, therefore, be useful to provide other protective groups which are effective to prevent branching or cross-linking during the polymerization but more susceptible to removal from the polyamide product.
SUMMARY OF THE INVENTION
Among the objects of the present invention may be noted the provision of a method for the preparation of heteroaryl amino acid monomers useful in the preparation of polyamides; the provision of such a method which avoids the loss of desired substituents from the heteraryl ring during the course of synthesis reactions; the provision of such a process which can be constantly operated without rapid gas release from any reaction step; the provision of alternative protective groups at the 3-position of a 3-hydroxypyrrole derivative; and the provision of novel intermediates useful in the synthesis of monomers for bioactive polyamides.
Briefly, therefore, the invention is directed to a process for the preparation of a compound of Formula II
wherein R
1
and R
3
substituted or unsubstituted alkyl (preferably C
1
to C
6
), alkenyl (preferably C
2
to C
6
), alkynyl (preferably C
2
to C
6
), aralkyl, or aryl; R
2
is substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, alkylcarbonyl, haloalkylcarbonyl, aralkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, arylkoxycarbonyl, aryloxycarbonyl or substituted silyl; R
4
is hydrogen or methyl; and R
5
is a carbamate-forming blocking group. The process comprises reducing the nitro group of a compound of Formula IV
wherein R
1
, R
2
, R
3
and R
4
are as defined above, thereby producing a compound of Formula III
wherein R
1
, R
2
, R
3
and R
4
are as defined above. The compound of Formula III is contacted with a blocking group reagent thereby substituting a blocking group on the 4-amino group.
The invention is further directed to a process for the preparation of the compound of Formula III. The process comprises reducing the nitro compound of a group of Formula IV.
The invention is further directed to a process for the preparation of the compound of Formula IV. In this process a 3-hydroxypyrrole derivative corresponding to Formula V
or the keto tautomer of the 3-hydroxypyrrole derivative, the keto tautomer corresponding to the structure
wherein R
1
, R
3
and R
4
are as set forth above, with a blocking reagent effective to form an —OR
2
group at the 3-position of the compound of Formula V.
The invention is further directed to a process for the preparation of a 3-hydroxypyrrole derivative corresponding to Formula V or the keto tautomer thereof (as corresponding to Formula Va). The process comprises contacting a compound of Formula VII with a reagent effective for promoting ring closure. The compound of Formula VII corresponds to the structure
wherein R
1
, R
3
and R
4
are as defined above and —OR
6
is a leaving group.
The invention is further directed to a process for the preparation of a compound corresponding to Formula VII. In this process a compound of Formula VIII is reacted with an N-substituted glycine ester corresponding to Formula IX. The compound of Formula VIII has the structure
wherein R
1
and R
6
are as defined above and R
7
is a leaving group. The compound of Formula IX has the structure
R
1
NHCH
2
C(O)OR
3
wherein R
1
is as defined above.
The invention is further directed to a process for the preparation of the compound corresponding to Formula XI
or the keto tautomer thereof
wherein R
1
, R
3
, R
4
and R
5
are as defined above. The process comprises contacting a compound of Formula XII and/or the keto tautomer thereof with a blocking group re
Phillion Dennis P.
Singh Megh
McKane Joseph K.
Pharmacia Corporation
Senniger Powers Leavitt & Roedel
Small Andrea D.
LandOfFree
Process for the preparation of derivatives of... 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 derivatives of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of derivatives of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3130324