Efficient ligand-mediated Ullmann coupling of anilines and...

Details Efficient ligand-mediated Ullmann coupling of anilines and... Efficient ligand-mediated Ullmann coupling of anilines and...

2001-07-25

2003-04-01

McKane, Joseph K. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S250000, C546S274100, C548S255000, C548S265800, C548S343500, C548S563000

Reexamination Certificate

active

06541639

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to an efficient ligand-accelerated Ullmann coupling reaction of anilines with azoles. The coupling products are useful for preparing factor Xa inhibitors.
BACKGROUND OF THE INVENTION
Factor Xa inhibitors like those of Formulas Ia and Ib shown below:
are currently being investigated as potential drug candidates. As a result, large quantities of these compounds are needed to satisfy clinical demands.
WO98/57951 describes of the synthesis of compounds of formula Ia and Ib as shown below.
In procedure Ia, the resulting imidazolyl-aniline is coupled with 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-pyrazole carboxylic acid and the resulting intermediate is then converted to the final product. Procedure Ia is problematic in that it provides isomers of the imidazolyl-nitrobenzene. In procedure Ib, the resulting imidazolyl-aniline is coupled with 1-(3′-aminobenzisoxozol-5-yl)-3-trifluoromethyl-5-pyrazolecarboxylic acid to provide the final product. Procedure Ib is problematic in that it only provides a 48.5% yield of the imidazolyl-aniline intermediate starting from the bromo-fluoroaniline.
Many different kinds of aryl halides have been used as substrates for the Ullmann-type amination reaction. This most straightforward route to N-(amino)arylimodazoles involves the direct formation of the aromatic carbon-nitrogen bond under the catalysis of a copper(I) salt without protection of the aromatic amino functionality. However, there is almost no precedent to directly employ unprotected aniline derivatives as coupling partners. The free NH
2
functionality on the aryl halides is reported to have a deleterious effect (35-50% yields of unprotected aniline substrates vs 75-100% yields of non-aniline substrates or protected aniline substrates) on the Ullmann coupling reaction (
J. Chem. Soc.
(C) 1969, 312). One report revealed that direct coupling of 4-iodoaniline with imidazole under the Cu(I)-catalyzed condition afforded the desired N-(4-amino)arylimidazole only in 37% yield (
J. Med. Chem.
1988, 31, 2136). Another report observed that no coupling products was obtained when unprotected 2-fluoro-4-iodoaniline was exposed to the Ullmann ether synthesis (
Synthesis,
1998, 1599). In that report, the authors also found that protection of the aromatic amino group to amide or carbamate before being subjected to the Ullmann coupling reaction resulted only in the cleavage of the protection group without formation of any desired coupling product. Therefore, a hydrolytically stable 2,5-dimethylpyrrole derivative of that aniline substrate was prepared. Obviously, two more steps (protection and deprotection) is added to the synthetic sequence in order to form the aromatic carbon-nitrogen or carbon-oxygen bond when the halogenated aniline is used as the coupling substrate.
It can be seen that preparation of factor Xa inhibitors, specifically preparation of azolyl-aniline intermediates useful therein, is difficult. Thus, it is desirable to find efficient syntheses azolyl-anilines that are useful in making factor Xa inhibitors of compounds like those of formulas Ia and Ib.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide novel processes for preparing azolyl-anilines using a ligand-mediated Ullmann coupling reaction.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that imidazolyl-anilines like those shown below (formulas IIa and IIb):
can be prepared by ligand-accelerated Ullmann coupling of non-protected, halo-substituted anilines and azoles. This is the first time an Ullmann coupling of an aniline has been shown to work efficiently without protection of the aniline nitrogen.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The present invention demonstrates that Cu(I)-catalyzed coupling of iodoanilines to imidazoles is accelerated by a group of hydrolytically stable ligands known to coordinate Cu(I) catalyst. The ligands, preferably the alkyl and aryl bidentate nitrogen and oxygen containing compounds, used in an equimolar amount with respect to Cu(I) catalyst, are found to produce the significant rate acceleration for the coupling reaction. The reaction temperature (100-130° C. vs >150° C.) is significantly lower and the reaction time (4-6 h vs 16-24 h) is significantly shorter with this ligand-accelerated protocol. And also, the coupling yield is improved with the addition of the ligand.
The present method is the first reported actual ligand-accelerated Cu(I)-catalyzed Ullmann coupling of the aryl halides to azoles, including imidazoles. Both Cu(I) salt and ligand used in this method are used in catalytical amounts (5-15%). In the previous reports, both Cu(I) catalyst and ligand were employed excessively (0.2 to 2.0 equivalents). In contrast to Buchwald's report (
Tetrahedron Lett.
1999, 40, 2657), which is the only reported ligands-accelerated Ullmann coupling of aryl halides to imidazoles so far, this method uses only one additive to be as the ligand to promote the reaction. Instead of the use of 10-fold excess of the ligand with respect to the Cu(I) catalyst (
Tetrahedron Lett.
1999, 40, 2657), the method detailed of the present invention employs the equimolar amount of ligand with respect to the copper catalyst.
In an embodiment, the present invention provides a novel process for making a compound of Formula III:
comprising: contacting an aniline of Formula IV with an azole of Formula V in the presence of Cu(I)X
1
and a bidentate ligand:
wherein:
in Formula IV, from 0-1 of the carbon atoms are replaced with N;
in Formula V, from 0-3 of the carbon atoms are replaced with N;
alternatively, the compound of Formula V is benzo-fused and 0-2 of the carbon atoms of the five-membered ring are replaced with N;
X
1
is selected from Cl, Br, I, and SCN;
X
2
is selected from Br or I;
R
1
is selected from H, Cl, F, Br, I, C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkylene-O—C
1-4
alkyl, NH
2
, NH(C
1-4
alkyl), N(C
1-4
alkyl)
2
, C
1-4
alkylene-NH
2
, C
1-4
alkylene-NH(C
1-4
alkyl), C
1-4
alkylene-N(C
1-4
alkyl)
2
, C
3-10
carbocycle substituted with 0-2 R
3
, 5-6 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S and substituted with 0-2 R
3
;
R
2
is selected from H, Cl, F, Br, I, C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkylene-O—C
1-4
alkyl, NH
2
, NH(C
1-4
alkyl), N(C
1-4
alkyl)
2
, C
1-4
alkylene-NH
2
, C
1-4
alkylene-NH(C
1-4
alkyl), C
1-4
alkylene-N(C
1-4
alkyl)
2
, C
3-10
carbocycle substituted with 0-2 R
3
, 5-6 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S and substituted with 0-2 R
3
;
R
3
is selected from Cl, F, Br, I, C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkylene-O—C
1-4
alkyl, NH
2
, NH(C
1-4
alkyl), N(C
1-4
alkyl)
2
, C
1-4
alkylene-NH
2
, C
1-4
alkylene-NH(C
1-4
alkyl), C
1-4
alkylene-N(C
1-4
alkyl)
2
, and NO
2
;
r is 1 or 2; and,
the bidentate ligand is a hydrolytically stabile ligand that is known to ligate with Cu(I) and comprises two heteroatoms selected from N and O.
In a preferred embodiment, the bidentate ligand is selected from tetramethylethylenediamine (TMED), 2,2′-dipyridyl (DPD), 8-hydroxyquinoline (HQL), and 1,10-phenanthroline (PNT) and from 0.01-0.20 equivalents are present, based on the molar amount of aniline present.
In another preferred embodiment, the bidentate ligand is 8-hydroxyquinoline (HQL) or 1,10-phenanthroline (PNT) and from 0.05-0.15 equivalents are present.
In another preferred embodiment, the bidentate ligand is 8-hydroxyquinoline (HQL) and from 0.05-0.15 equivalents are present.
In another preferred embodiment, the bidentate ligand is 1,10-phenanthroline (PNT) and from 0.05-0.15 equivalents are present.
In another preferred embodiment, from 0.01-0.20 equivalents of Cu(I)X
1
are present, based on the molar amount of aniline present.
In another preferred embodiment, from 0.05-0.15 equivalents of Cu(I)X
1
are present.
In another preferred embodi

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